Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor

Article abstract of DOI:10.1016/j.bmcl.2008.03.057

We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.

Full text of DOI:10.1016/j.bmcl.2008.03.057

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2985–2989
Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-
1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-
5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737),
an in vivo active potent VEGFR-2 inhibitor
a,
a
a
a
b
*
´
Rejean Ruel, Carl Thibeault, Alexandre L’Heureux, Alain Martel, Zhen-Wei Cai,
Donna Wei,b Ligang Qian,b Joel C. Barrish,b Arvind Mathur,b Celia D’Arienzo,b
John T. Hunt,b Amrita Kamath,b Punit Marathe,b Yueping Zhang,b
George Derbin,c Barri Wautlet,b Steven Mortillo,b Robert Jeyaseelan, Sr.,b
Benjamin Henley,b Ravindra Tejwani,c Rajeev S. Bhide,b George L. Trainor,b
Joseph Fargnolib and Louis J. Lombardob
aBristol-Myers Squibb, Research and Development, Candiac, Que., Canada J5R 1J1
bBristol-Myers Squibb, Research and Development, Princeton, NJ 08543, USA
cBristol-Myers Squibb, Research and Development, New Brunswick, NJ 08903, USA
Received 16 January 2008; revised 18 March 2008; accepted 18 March 2008
Available online 22 March 2008
Abstract—We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibi-
tors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure–activity relationship studies, biochemical
potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical
in vivo activity against human tumor xenograft models.
Ó 2008 Elsevier Ltd. All rights reserved.
Angiogenesis, the formation of new blood vessels from
preexisting microvasculature, is a complex process that
normally occurs during wound healing, organ regenera-
tion, and the female reproductive cycle.1 It can also oc-
cur in cancer whereby the newly created capillaries
supply growing tumors with nutrients and allow waste
removal.2 Vascular endothelial growth factor (VEGF)
is a key pro-angiogenic cytokine released by many tu-
mors and the angiogenic activity of the VEGF family
of proteins is mediated by three VEGFR receptors
(VEGFR-1, VEGFR-2, and VEGFR-3). The VEGFR-
2 receptor, the principal kinase involved in multiple
processes of angiogenesis, has therefore become an
attractive cancer target for which many small molecule
inhibitors have shown promising results in preclinical
and clinical studies.3
We recently disclosed a series of potent indole-based
VEGFR-2 kinase inhibitors from which emerged
BMS-540215, a compound with excellent enzymatic po-
tency against VEGFR-2, a good kinase selectivity pro-
file, an acceptable safety profile, and robust preclinical
in vivo activity against a variety of human tumor xeno-
graft models.4 Our clinical prodrug candidate BMS-
582664 was subsequently developed to improve the
pharmaceutic and pharmacokinetic properties of the
parent indole BMS-540215 (1).4 This report now de-
scribes the synthesis, structure–activity relationship
(SAR), and antitumor activity of the corresponding 7-
azaindoles.
Keywords: Angiogenesis; Inhibitors; Kinase; VEGFR-2; Pyrrol-
otriazine.
We first investigated a series of 7-azaindoles bearing
C-6 ether side-chains. The 7-azaindole analog 2 and
BMS-540215 (1) were essentially equipotent against
*
Corresponding author. Tel.: +1 514 732 3213; fax: +1 514 751
2502; e-mail: rruel@ambrilia.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.057

2986
Table 1. SAR at the R2 , R4 , R5,
R. Ruel et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2985–2989
0
0
X
and L positions of (R)-1-(4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-alkyllpyrrolo[2,1-f][1,2,4]triazin-6-
yloxy)propan-2-ol and (R)-1-(4-(1H-pyrrolo[2,3-b]pyridin-5-ylamino)-5-alkyllpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ola
H
X
N
R2'
R5
L
4
3'
R4'
N
HO
O
6
N
N
0
0
Compound
X
L
R2
R4
R5
VEGFR-2,
a
IC50 (lM)
Mouse 4-h oral exposure AUCc (lM h)
1
2
3
4
5
6
CH
N
O
Me
Me
H
F
Me
Me
Me
Me
Me
i-Pr
0.025
0.019
0.027b
0.122
0.223
0.165
136.0
29.6
11.1
NDd
ND
O
F
N
O
F
N
O
Me
Me
H
H
H
H
N
NH
NH
N
ND
a IC50 values are reported as the mean of at least three individual determinations. Variability around the mean was <20%. For assay conditions see
Ref. 5a.
b Value reported from two experiments (var. <10%).
c Compounds were evaluated in 4-h exposure study in mice at 50 mg/kg and formulated as solutions of 1:1 PEG(poly(ethylene glycol))400:water.
d ND, data not determined.
0
0
Table 2. SAR at the R6, R5, R2 and R4 positions of N-(1H-
pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine
VEGFR-2 but the azaindole analog showed decreased
plasma exposure upon oral administration in mice
0
(Table 1). Removing the R2 methyl substituent retained
high biochemical potency but 3 also showed poor plas-
H
N
N
R2'
ma exposure. A number of other structural modifica-
R5
0
HN
4
tions including: (i) removal of the R4 fluorine, (ii) the
oxygen to amine linker replacement, and (iii) the R5 iso-
propyl substitution, provided compounds 4–6 respec-
tively, which showed 6- to 12-fold decreases in potency
against VEGFR-2 kinase.
3'
R4'
R6
N
N
N
0
0
Compound R6
R5
R2
R4
VEGFR-2,
a
IC50 (lM)
Related 4-phenylaminopyrrolo[2,1-f][1,2,4]triazine-
based VEGFR-2 kinase inhibitors bearing C-6 esters, es-
ter isosteres and amides have been studied previously.5
This study showed that, with respect to biochemical po-
tency, an isopropyl group was the optimum C-5 alkyl
substitution with pyrrolotriazines bearing C-4 amino
substitution. Consistent with these findings, introduc-
tion of a R5 isopropyl group in ester 8 indeed gave a
10-fold increase in potency against VEGFR-2 compared
to the R5methyl analog 7 (Table 2). Compounds 9–17
described in Table 2 represent a selection of various ester
isosteres studied in this series. Oxadiazole 9 was a more
potent (ꢀ4-fold) inhibitor of VEGFR-2 (IC50 = 30 nM)
than the corresponding des-fluoro analogs 10 and 11.
However, the chemical stability of fluoro analogs related
to 9 was a concern since we had observed ring forming
reactions leading to pentacyclic intermediates under
acidic conditions. For example, ester 18 gave rise to
the pentacyclic compound 19 when treated with acid
(Scheme 1). Likewise, the potential for the formation
of a pentacyclic intermediate derived from 14 precluded
any further investigation on this and related fluoro ana-
logs. The des-fluoro analogs 12 and 13 bearing regioiso-
meric oxadiazole rings, in turn, were found to be more
potent than 10 and 11. Finally, oxadiazole analogs
15–17 were prepared and tested against VEGFR-2. In
essence, these analogs bearing various C-2 substituents
off the oxadiazole ring were equipotent to 13 except
7
Me
i-Pr
H
H
H
H
0.121
0.017
COOMe
8
9
10
11
i-Pr
i-Pr
H
H
F
0.030
0.096
0.113
N
H
H
i-Pr Me
O
N
N
N
12
13
14
i-Pr
H
H
H
F
0.031
0.025
0.013b
O
i-Pr Me
i-Pr Me
N
O
Et
15
i-Pr Me
H
0.036
N
O
SMe
16
17
i-Pr Me
i-Pr Me
H
H
0.150
0.025
N
N
N
O
NHMe
N
a IC50 values are reported as the mean of at least three individual
determinations. Variability around the mean was <35%. For assay
conditions see Ref. 5a.
b Value reported from one experiment.
for the thiomethyl analog 16 which showed about 5-fold
decrease in potency. An activated sulfoxide intermediate
was prepared from 16 and used to introduce various

R. Ruel et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2985–2989
2987
H
N
F
N
N
N
HN
NH
pH < 7
N
N
MeOOC
MeOOC
N
N
N
N
19
VEGFR-2 IC50 > 400 nM
18
VEGFR-2 IC50 = 16 nM
Scheme 1. Formation of pentacyclic intermediate 19 from 4-fluoro-5-amino-7-azaindole precursor 18 under acidic conditions.
Table 5. Kinase selectivity profile of compounds 12 and 13
nucleophiles into this region of the inhibitor which
a
12 IC50 (nM)
should be solvent exposed according to molecular mod-
eling.5 Attempts to modulate the properties of the com-
pound using this strategy afforded various analogs from
which the aminomethyl derivative 17 stood out,
although 13 was still a superior compound overall based
on additional profiling provided below.
Enzyme
13 IC50 (nM)
VEGFR-2 (human)
Flk-1 (mouse)
VEGFR-1
FGFR-1
31
25
53
NDb
ND
268
78
61
389
PDGFR-b
EGFR
HER-2
>2000
>1000
>5000
>2000
>50,000
>50,000
150
500
Additional profiling data of compounds 12, 13, and 17
are provided in Tables 3–5. These potent VEGFR-2
inhibitors were further profiled with respect to CYP3A4
and hERG patch-clamp inhibit,ion (Table 3).6 Increased
LCK
PKCac
185
>50,000
>50,000
JAK-3c
a IC50 values are reported as the mean of at least three individual
determinations. Variability around the mean was <20%.
b ND, data not determined.
inhibition of CYP3A4 activity was observed with the
0
R2 -Me analogs 13 and 17. However, although substitu-
tion on azaindole ring indeed resulted in higher
CYP3A4 inhibition (13 vs 12), it also afforded com-
pounds with improved kinase selectivity profile (vide in-
fra). Likewise, the des-methyl azaindole analog 12 was
further differentiated by its lower activity in hERG
patch-clamp assay.
c Value reported from one experiment.
ance and lower bioavailability in comparison with the
0
R2 -Me analogs 13 and 17. When 13 was administered
at 30 mg/kg orally as a suspension in 0.5% methocel
and at 5 mg/kg intravenously in PEG400:0.01 N HCl
(1:1), the compound was rapidly absorbed with a Tmax
of 0.5 h, a favorable half-life of 2.9 h, and mean resi-
dence time (MRT) of 2.7 h. The measured oral bioavail-
ability (Fpo) in this experiment was high (>100%) and 13
had low clearance (Cl) and a moderate volume of distri-
bution (Vss). In vivo exposure from solid dosage formu-
lation was assessed in the rat as well. At a similar dose
(30 mg/kg) the measured oral bioavailability in the rat
was 68% and AUC was 287 lM h for a crystalline sus-
pension of 13 in 0.5% methocel. Aqueous solubility for
compound 13 was found to be low at pH 6.5 (2.8 lg/
mL) and increased with a decrease in pH to 400 lg/
mL at pH 2; however despite low solubility and poten-
Compounds 12, 13, and 17 were also evaluated in mouse
pharmacokinetic studies6 (Table 4). The unsubstituted
azaindole 12 showed decreased exposure, higher clear-
Table 3. CYP3A4 and hERG Inhibition of compounds 12, 13, and 17a
b
Compound
CYP 3A4 IC50 (lM)
hERG inhibitionb
12
13
>40
11.5
29% at 10 lM
64% at 10 lM
(IC50 = 6.6 lM)
64% at 10 lM
17
6.4
a IC50 values are reported as the mean of at least three individual
determinations. Variability around the mean was <50%.
b For assay details, see Ref. 5a.
Table 4. Parameters for 12, 13, and 17 in a 24-h PK study in micea,b
Compound
Dose (mg/kg)
AUCtot (lM h)
t1/2 (h)
MRT (h)
1.7
Cl (ml/min/kg)
18
Vss (L/kg)
Fpo (%)
12
iv, 5
po, 30
12.4
21.7
1.2
4.5
1.9
29
13
17
iv, 5
po, 30
25
182
2.9
2.5
2.7
4.3
8.5
4.5
1.4
1.2
>100
99
iv, 5
po, 30
46
272
2.8
2.8
a Data taken from a composite serum-concentration profile of nine mice (male, Balb-c). For assay details see Ref. 5a.
b Vehicle: iv: 12: PEG400:sodium phosphate buffer, 0.1 M, pH 2 (70:30). Compounds 13 and 17: PEG400:0.01N HCl (1:1). po: 12: 100% Capmul
MCM. 13 and 17: 0.5% methocel.

2988
R. Ruel et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2985–2989
Table 6. Cell proliferation data of compound 13
plant) inhibited tumor growth in a dose-dependent man-
ner. Tumor growth inhibition was indeed observed at
both doses over the dosing period, with a slightly greater
delay in tumor growth observed at the higher dose. No
overt toxicity (weight loss, morbidity) was observed at
either dose. Pharmacokinetic analysis using multiple
time points during a 24-h-period after the last dose
(i.e., at day 15) revealed a Cmax of 1.03 lM and
AUC = 11 lM h at the minimum efficacious dose level
of 7.5 mg/kg. The higher dose level resulted in a slightly
higher than proportional increase in these blood levels
(Cmax of 2.64 lM and AUC = 30 lM h). Antitumor
activity was evident at both doses as demonstrated by
P50% tumor growth inhibition over one tumor volume
doubling time which was 4 days in this study. Rather
than directly affecting the tumor, the robust in vivo
activity of 13 is likely driven by its antiangiogenic prop-
erties based on the high cellular potencies of VEGF- and
FGF- stimulated HUVECs combined with weak cellular
potency in multiple tumor cell lines, most notably L2987
(IC50 > 2.5 lM). The activity of 13 in this tumor
xenograft model (MED = 7.5 mg/kg) was therefore
significantly higher than the first generation inhibitor
BMS-540215 (1) for which the minimum efficacious dose
was 60 mg/kg using the same model and dosing regimen.
Other tumor xenografts of different histological origins
were also used to assess the broad spectrum in vivo effi-
cacy of 13. The latter was found active in all models used
(e.g., H3396, HCT-116VM, and colo-205) and systemat-
ically showed good in vivo activity at modest dose.
Plasma protein binding, which was found to be 97.2%
for 13 in human sera, did not represent a problem with
these inhibitors.
a
13 IC50 (nM)
Cell
VEGF-HUVECb
bFGF-HUVEC
L-2987 tumor
N87 tumor
13
138
>2500
>10,000
>10,000
>10,000
H1993 tumor
GTL-16 tumor
a IC50 values are reported as the mean of at least three individual
determinations. Variability around the mean was <20%.
b Human umbilical vein endothelial cells stimulated by VEGF.
tial for pH-dependent absorption, rodents consistently
showed satisfactory exposure.
0
By comparison with the des-methyl analog 12, the R2
methyl analog 13 showed a better kinase selectivity pro-
file. The substituted analog 13 indeed showed decreased
activity versus EGF, HER-2, LCK, and PDGFR-b ki-
nases (Table 5). Furthermore, 13 had moderate potency
against VEGFR-1 and FGFR-1, two other kinases
implicated in angiogenesis. It also showed good potency
against Flk-1, the mouse homolog of VEGFR-2.
The inhibition of proliferation of HUVEC cells (human
umbilical vein endothelial cells) by 13 was measured
(Table 6). The cellular potencies of 13 against VEGF-
and bFGF-stimulated HUVECs were high (IC50 = 13
and 138 nM respectively) but 13 showed low anti-prolif-
erative potency against a panel of tumor cell lines. In
particular, activity of 13 against L2987 human lung car-
cinoma cell line used in the in vivo tumor xenograft
mouse efficacy model was low (IC50 > 2.5 lM).
The synthesis of 13 outlined in Scheme 2 starts with the
palladium-catalyzed reaction between commercially
available aminopyridine 20 and isopropenyl acetate
which, after catalytic hydrogenation, provided azaindole
21. Intermediate 21 was then coupled with chloroimi-
date 225 in DMF in the presence of diisopropylethyl-
amine to provide 13 in 93% yield.7
Compound 13 was therefore tested for anti-tumor activ-
ity in vivo against the human L2987 xenograft solid tu-
mor in athymic mice at two dose levels (7.5 and 15 mg/
kg) (Fig. 1). The treatment and control group size con-
sisted of 9–10 mice. Once daily oral administration of
13 in Capmul for 14 days (day 21 to day 34 post-im-
In summary, a novel series of N-(1H-pyrrolo[2,3-b]pyri-
din-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine VEGFR-2
inhibitors was identified. Biochemical potency and ki-
nase selectivity optimization afforded 5-isopropyl-6-(5-
1400
Control Vehicle (Capmul)
13 7.5 mg/kg
13 15 mg/kg
1200
1000
800
600
400
200
0
H
O2N
Br
N
N
a,b
N
NH2
H2N
H
20
N
21
N
Cl
HN
c
O
O
N
N
N
21
+
N
N
N
N
N
N
N
20
30
40
22
13
Days Post-implant
Scheme 2. Synthesis of 13. Reagents and conditions: (a) isopropenyl
acetate, Pd2dba3, Bu3SnOMe, 2-dicyclohexylphosphino-20-40-60-triiso-
propyl biphenyl, toluene, sealed tube, 135 °C; (b) H2, Pd/C, ethanol,
89%, two steps; (c) (i-Pr)2NEt, DMF, 93%.
Figure 1. In vivo antitumor activity of 13 versus L-2987 human
xenograft in athymic mice with dosing for 14 days from day 21 to day
35 post-implant (shown by black dots).

R. Ruel et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2985–2989
2989
C.; Ruggeri, B. A.; Dionne, C. A.; Vaught, J. L.; Mallamo,
J. P.; Hudkins, R. L. J. Med. Chem. 2003, 46, 5375; (f)
Beebe, J. S.; Jani, J. P.; Knauth, E.; Goodwin, P.; Higdon,
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Harriman, S.; Atherton, J.; Hillerman, S.; Soderstrom, C.;
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Marx, M. A.; Schaeffer, T.; Whalen, P. M.; Roberts, W. G.
Cancer Res. 2003, 63, 7301; (g) Hennequin, L. F.; Stokes, E.
methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,
3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (13)
as an orally active compound in the L2987 xenograft
model of human lung carcinoma. This compound
demonstrated tumor growth inhibition during the
dosing period and was considered for further develop-
ment based on its favorable pharmacokinetic, potency
and kinase selectivity profile.
´
S. E.; Thomas, A. P.; Johnstone, C.; Ple, P. A.; Ogilvie, D.
J.; Dukes, M.; Wedge, S. R.; Kendrew, J.; Curwen, J. O.
J. Med. Chem. 2002, 45, 1300; (h) Abrams, T. J.; Murray,
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Acknowledgments
We thank Dr. Robert Kramer for scientific advice and
the Discovery Analytical Sciences (Bristol-Myers
Squibb) for compound characterization.
4. (a) Bhide, R. S.; Cai, Z.-W.; Zhang, Y.-Z.; Qian, L.; Wei,
D.; Barbosa, S.; Lombardo, L. J.; Borzilleri, R. M.; Zheng,
X.; Wu, L. I.; Barrish, J. C.; Kim, S.-H.; Leavitt, K.;
Mathur, A.; Leith, L.; Chao, S.; Wautlet, B.; Morillo, S.;
Jeyaseelan, R.; Kukral, D.; Hunt, J. T.; Kamath, A.; Furra,
A.; Vyas, V.; Marathe, P.; D’Arienzo, C.; Derbin, G.;
Fargnoli, J. J. Med. Chem. 2006, 49, 2143; (b) Cai, Z.-W.;
Zhang, Y.; Borzilleri, R. M.; Qian, L.; Barbosa, S.; Wei, D.;
Zheng, X.; Wu, L.; Fan, J.; Shi, Z.; Wautlet, B.; Mortillo,
S.; Jeyaseelan, R.; Kukral, D. W.; Kamath, A.; Marathe,
P.; D’Arienzo, C.; Derbin, G.; Barrish, J. C.; Robl, J. A.;
Hunt, J. T.; Lombardo, L. J.; Fargnoli, J.; Bhide, R. S. J.
Med. Chem. 2008, 51, 1976.
Supplementary data
Full experimental details and characterization data for
compounds 2–19 are available. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.bmcl.2008.03.057.
5. (a) Borzilleri, R. M.; Zheng, X.; Qian, L.; Ellis, C.; Cai, Z.-
W.; Wautlet, B.; Mortillo, S.; Jeyaseelan, R.; Kukral, D.
W.; Fura, A.; Kamath, A.; Vyas, V.; Tokarski, J. S.;
Barrish, J. C.; Hunt, J. T.; Lombardo, L. J.; Fargnoli, J.;
Bhide, R. S. J. Med. Chem. 2005, 48, 3991; (b) Borzilleri, R.
M.; Fargnoli, J.; Fura, A.; Gerhardt, T.; Goyal, B.; Hunt, J.
T.; Mortillo, S.; Qian, L.; Tokarski, J.; Vyas, V.; Wautlet,
B.; Zheng, X.; Bhide, R. S. Bioorg. Med. Chem. 2005, 15,
1429.
6. For the assay conditions of in vitro kinase, cellular
proliferation, metabolic stability, cytochrome P450 and
pharmacokinetics, see Ref. 5a. See Supporting information
for hERG assay conditions.
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Tables
1 and 2 proceeded similarly using alternate
syntheses of chloroimidates (see Refs.5a and 5b) and
azaindoles (see Refs.7a and 7b): (a) Thibault, C.; L’Heu-
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