5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases

Article abstract of DOI:10.1016/j.bmcl.2007.06.019

Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel sy

Full text of DOI:10.1016/j.bmcl.2007.06.019

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4947–4954
5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors
of EGFR and HER2 protein tyrosine kinases
Harold Mastalerz,a,* Ming Chang,b Ping Chen,b Brian E. Fink,b Ashvinikumar Gavai,b
Wen-Ching Han,b Walter Johnson,a David Langley,a Francis Y. Lee,b Kenneth Leavitt,b
Punit Marathe,b Derek Norris,b Simone Oppenheimer,b Bogdan Sleczka,b James Tarrant,a
John S. Tokarski,b Gregory D. Vite,b Dolatrai M. Vyas,a Henry Wong,a Tai W. Wong,b
Hongjian Zhangb and Guifen Zhanga
aDepartments of Oncology Chemistry and Computer Aided Drug Design, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, CT 06492-1951, USA
bDepartments of Oncology Chemistry, Discovery Biology, Pharmaceutical Candidate Optimization, and Computer Aided Drug
Design, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA
Received 18 April 2007; revised 1 June 2007; accepted 7 June 2007
Available online 10 June 2007
Abstract—Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were
found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for
the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft mod-
els and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solu-
bilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the
inhibitor.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The epidermal growth factor receptor (EGFR, ErbB1 or
HER1) and the human epidermal growth factor recep-
tor 2 (HER2, ErbB2) are members of the ErbB family
of receptor tyrosine kinases that have been clinically val-
idated as targets for cancer therapy.1 Their frequent co-
expression in a variety of tumor types and their capacity
to form heterodimers with other members of the ErbB
family provide a strong rationale for simultaneously tar-
geting both of these receptors.2 We have reported stud-
ies of pyrrolotriazine reversible dual EGFR and HER2
kinase inhibitors with C-5 solubilizing groups that iden-
tified morpholine ether 1a3 and homopiperazine 1b4 as
lead compounds (Fig. 1). Both showed potent kinase
inhibition, antiproliferative activity, and good oral effi-
cacy in EGFR and HER2 driven human tumor xeno-
graft models. It was hypothesized that their C-5
solubilizing groups extend into the ribose-phosphate
portion of the ATP binding pocket where they can
participate in multiple hydrogen bonding interactions.
A possible limitation of these compounds was that their
kinase inhibition tended to drop off when modifications
were made at other sites, notably C-4. Since this could
limit efforts to optimize their efficacy, we continued to
explore the SAR of C-5 solubilizing groups to find those
that imparted more robust kinase inhibition. This report
highlights the SAR of pyrrolotriazine dual EGFR/
HER2 kinase inhibitors with a C-5 aminopiperidine sol-
ubilizing group, for example, 1c. Their in vitro perfor-
mance was generally found to be superior to that of
analogs with our other leading C-5 solubilizing groups.
New chemistry was developed to prepare C-4 analogs
of 1c using parallel synthesis and the results of the eval-
uation of some of the interesting leads that emerged
from this are disclosed.
Compounds 1c–1g were made by heating sulfoxide 24
with an excess of the mono-N-Boc protected diamine
of interest and then deprotecting the product (Scheme
1).5a Compound 1c could also be made by heating 2 with
an excess of piperidin-4-amine. In this case, regioisomer
1d was also formed (<10% yield) and it was removed by
Keywords: EGFR; HER2; Pyrrolotriazine; Kinase inhibitor.
*
Corresponding author. Tel.: +1 203 677 7773; e-mail:
harold.mastalerz@bms.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.019

4948
H. Mastalerz et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4947–4954
N
N
F
F
N
N
H2N
HN
HN
N
R
AcO
R
N
4
5
3
N
N
6
R
N
N
N
2
N
1
7
O
3 R = OMe
5 R = Me
4 R = OMe
6 R = Me
NH
R =
N
H2N
N
NH
O
1a
1b
Scheme 2. Reagents and conditions: tert-butylpiperidin-4-ylcarbamate
(10 equiv), CH3CN, microwave, 170 ꢁC, 30 min followed by 50% TFA/
CH2Cl2, 0 ꢁC, about 40% overall.
1c
Figure 1. C-5 substituted pyrrolotriazine dual EGFR and HER2
kinase inhibitors.
Ar
Cl
HN
BrEt3N
Cl
R
c
a, b
N
N
N
N
N
F
N
N
N
N
N
N
O
5
7
HN
S
6a R = Br
6b R = NEt3Br
Ph
1c - g
N
N
H2N
Ar
N
d
HN
N
2
N
N
N
Scheme 1. Reagents and conditions: N-Boc protected diamine
(10 equiv), 130 ꢁC, 35 h, sealed tube, followed by 40% TFA/CH2Cl2.
8
Scheme 3. Reagents and conditions: (a) NBS (1.15 equiv), AIBN
(0.1 equiv), CCl4, 80 ꢁC, 2 h; (b) excess TEA, THF, rt, overnight, 75%
overall; (c) H2NAr (1 equiv), N,N-dimethylacetamide, 70 ꢁC, 3–5 h
then tert-butylpiperidin-4-ylcarbamate (1 equiv), DIPEA (1 equiv),
70 ꢁC, overnight, then TFA/CH2Cl2, about 50% overall.
preparative HPLC. N-Methyl derivative 1h was pre-
pared by heating 1c with ethyl formate and then reduc-
ing the resulting formamide with lithium aluminum
hydride. Heating 1c with excess 1,3-dioxolan-2-one gave
hydroxyethyl derivative 1i. Michael addition of 1c to
methyl vinyl sulfone gave 1j. N,N-Dimethyl derivative
1k was prepared by reductive amination of 1c with aque-
ous formaldehyde in the presence of acetic acid. N-acyl-
ation of 1c with acetic anhydride in methanol afforded
1l. Treatment of 1c with acetoxyacetyl chloride followed
by saponification of the resulting acetoxyacetamide gave
1m. Compound 1n was prepared by heating 2 with ex-
cess 4-methylpiperidin-4-amine.6
to give 4-anilino intermediates, 7, which, on further
heating with tert-butylpiperidin-4-ylcarbamate followed
by deprotection, gave the C-4 analogs 8a–j.
Aniline 10 was used to make the pyridine N-oxide 8j. It
was prepared by protection of the amino group of 9 fol-
lowed by N-oxidation and deprotection (Scheme 4).
The 6-methoxy and 6-methyl analogs, 4 and 6, were pre-
pared by heating acetates, 3 and 5,4 with excess tert-
butylpiperidin-4-ylcarbamate and then removing the
protecting group (Scheme 2).
Our studies of pyrrolotriazine dual EGFR and HER2
kinase inhibitors with diamino C-5 solubilizing groups
identified 4-aminopiperidine 1c as a promising lead. It
showed comparable kinase inhibition and slightly better
antiproliferative potency (Table 1) against the N87 cell
line, a human gastric carcinoma that overexpresses both
The synthesis outlined in Scheme 1 was not suited for
the rapid preparation of C-4 analogs of 1c since the
C-4 substituent is introduced early in the synthesis.
Therefore a method for the parallel synthesis of C-4 ana-
logs of 1c was developed. We previously reported4 that
bromide 6a, obtained by reaction of 5 with N-bromosuc-
cinimide in the presence of a radical initiator, reacted
with primary or secondary amines to give mixtures of
products. However, triethylamine was found to react
selectively with 6a to give the triethylammonium bro-
mide, 6b, as a weighable solid (Scheme 3).5b It reacted
with anilines on brief heating in N,N-dimethylacetamide
O
O
a, b
N
N
O
H2N
Cl
H2N
Cl
9
10
Scheme 4. Reagents and conditions: (a) Boc2O (1.1 equiv), THF,
80 ꢁC, 6 h, 92%; (b) MCPBA (1.5 equiv), CH2Cl2, 2 h, then TFA, rt,
2 h, 96%.

H. Mastalerz et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4947–4954
Table 1. Structure–activity relationship for C-5 analogs
4949
N
F
N
HN
N
R
N
N
Compound
R
IC50 (lM)
N87b
HER2a
0.055
EGFRa
0.061
HT29c or A2780d
O
1a
0.083
8.7c
HN
O
1b
1c
1d
0.027
0.023
0.076
0.033
0.035
0.11
0.11
0.035
1.15
3.6c
4.3c
5c
N
HN
H2N
N
H
N
HN
3.9c
6.5c
2.9c
7.3c
5.4c
NDe
7.6c
>10c
9.5c
6.1c
N
1e
1f
0.070
0.052
0.038
0.054
0.031
0.19
0.06
0.83
0.81
0.14
0.078
0.073
0.70
0.45
0.29
0.31
0.070
H2N
N
0.050
0.035
0.063
0.048
0.20
H2N
H2N
1g
1h
1i
N
MeHN
HO
N
HN
N
MeSO2
1j
HN
N
1k
1l
0.11
0.10
Me2N
AcNH
N
N
0.18
0.38
O
1m
1n
0.12
0.11
HO HN
N
H2N
Me
0.043
0.050
N
a Recombinant HER2 cytoplasmic sequence is expressed in Sf9 insect cells as an untagged protein and purified by ion-exchange chromatography.
HER2 kinase activity is measured under the same conditions as for EGFR. See Ref. 7 for assay conditions. IC50 values are reported as means of at
least three determinations. Variability around the mean value was <15%.
b Cell line N87 is a human gastric carcinoma that overexpresses both EGFR and HER2, see Ref. 7.
c Cell lines HT29 (human colon carcinoma) and A2780 (human ovarian carcinoma) do not depend on EGFR or HER2 signaling.
d Cell lines HT29 (human colon carcenoma) and A2780 (human ovarian carcinoma) do not depend on EGFR or HER2 signaling.
e ND, not determined.

4950
H. Mastalerz et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4947–4954
EGFR and HER27,8, but not against the HT29 cell line,
a human colon carcinoma that does not depend on
EGFR or HER2 signaling, and provided a check for
off-target antiproliferative effects. The SAR of 1c was
explored to see if improvements were possible. The
transposed analog, 1d, and the pyrrolidines, 1f and 1g,
showed slightly reduced kinase inhibition and signifi-
cantly lower cellular potency. Substitution on the piper-
idine 4-amino group was allowed in some instances, for
example, the methyl and hydroxyethyl derivatives, 1h
and 1i, showed potency similar to that of 1c. However
disubstitution, for example, N,N-dimethyl analog 1j,
or substituents that reduced the basicity of the piperi-
dine 4-amino group, for example, ethyl sulfone 1k and
N-acyl analogs, 1l and 1m, reduced potency.
C-5 side chain and the C-4 aniline NH group. This
would prearrange the two side chains in a conformation
that is similar to that of the inhibitor when it is in the
ATP binding pocket (see modeling discussion). Similar
intramolecular hydrogen bonding is possible in the case
of the C-5 morpholine ether analogs but it would be
weaker and therefore these analogs would not benefit
from the same entropic stabilization. Homopiperazine
11b exhibited weaker antiproliferative activity than
aminopiperidine 8a and this may reflect poorer cell per-
meability. A striking example of differences between
analogs with these solubilizing groups was seen for their
6-methoxy derivatives. Aminopiperidine 12c was signif-
icantly more potent than morpholine ether 12a and
homopiperazine 12b. This suggests that the aminopiperi-
dine is functioning as more than a solubilizing group; it
is also enhancing the binding affinity of the inhibitor in
the ATP binding pocket to overcome the effect of less
tolerated structural features such as C-6 substitution.
Overall, a broader range of potent analogs were possible
with the C-5 aminopiperidine solubilizing group and
they became the focus of our optimization studies.
Compounds with the leading C-5 solubilizing groups
and the 4-(aminofluorobenzylindazole) side chain, 1a,
1b, and 1c, showed comparable potency in the kinase
and cellular assays. However, when modifications were
made at other sites in the molecule, it was found that
analogs with C-4 diamino solubilizing groups showed
better in vitro potency than their morpholine ether
counterparts. For example, when the 4-(aminofluorob-
enzylindazole) side chain was replaced by the fluoro-
benzyloxyaniline side chain9 of the dual EGFR/HER2
kinase inhibitor, lapatinib, the aminopiperidine and
homopiperazine, 8a and 11b, exhibited more potent ki-
nase inhibition than the morpholine ether analog, 11a
(Table 2). One reason for this may be that analogs with
the diamino solubilizing group can form an intramolec-
ular hydrogen bond between the tertiary amine in the
This began with a preliminary exploration of the C-4
side chain of 1c. Analogs were generated by parallel syn-
thesis and some of the more interesting results are sum-
marized in Table 3. The 2-picolyl analog, 8b, showed
comparable kinase potency but reduced antiproliferative
effects. The 3-picolyl analog, 8c, was more HER2 selec-
tive while the 4-picolyl analog, 8d, was less potent. The
5-methyl derivative of 8c, 8e, regained EGFR inhibition
and showed a profile similar to that of 1c. The 3-picolyl
Table 2. Structure–activity relationship for modified C-5 analogs
R1
R3
R2
HN
N
N
N
Compound
R1
R2
R3
IC50 (lM)
HER2a
0.56
EGFRa
N87b
0.61
O
11a
11b
8a
0.56
HN
O
H
O
F
0.041
0.032
0.25
0.048
0.038
0.43
0.60
0.083
3.4
N
HN
Cl
H2N
N
O
12a
12b
12c
HN
O
OMe
0.17
0.19
3.7
N
N
F
HN
N
0.043
0.040
0.43
H2N
N
a IC50 values are reported as means of at least three determinations. Variability around the mean value was <15%.
b Data for HT29 (human colon carcinoma) or A2780 (human ovarian carcinoma) cell lines that do not depend on EGFR or HER2 signaling were
comparable for these compounds with IC50’s in the 3–4 lM range.

Table 3. Structure–activity relationship for C-4 analogs
NH2
Ar
N
HN
N
N
N
Compound
Ar
IC50 (lM)
Metabolic
stabilityd
Mouse 4 h exposuree
4 h plasma concentrations
Fold over HER2 IC50 Fold over EGFR IC50
HER2a
EGFRa
N87
HT29b or A2780c
AUC0–4 h (lM h)
(lM)
1c
8b
0.023
0.035
0.035
0.047
0.035
0.12
4.3b
0.05
0.01
14
2.7
120
77
N
N
F
N
N
N
>10c
3.6
1.6
4.5
nd
46
34
24
nd
68
N
8c
8d
8e
0.034
0.19
0.19
0.53
0.019
0.086
0.47
>5c
>5c
>5c
0.01
nd
22
130
nd
N
N
N
N
N
nd
9.9
N
N
0.013
0.036
0.06
1.3
100
N
O
N
8f
0.036
0.060
0.15
0.23
0.18
2.7c
3.5c
nd
30
7.5
1.8
210
30
50
21
Cl
N
8g
0.085
0.00
7.8
O
Cl
N
8h
0.022
0.036
0.058
2.0c
0.04
13
3.7
170
100
O
Cl
(continued on next page)

4952
H. Mastalerz et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4947–4954
ether, 8f, was more HER2 selective like its indazole ana-
log, 8c. The 5-methyl derivative, 8g, showed balanced
kinase inhibition but lower antiproliferative potency.
The 2-picolyl ether, 8h, and the pyrazine, 8i, both exhib-
ited profiles similar to that of 1c. Surprisingly, N-oxide
8j retained much of the potency of its parent, 8h. It
was not expected that its polar C-4 side chain would
be tolerated in the hydrophobic selectivity pocket of
the ATP binding site. Overall, the C-4 analogs exhibited
good metabolic stability and 4 h exposure after oral
administration to mice. Several compounds showed 4 h
drug plasma levels that were more than 50-fold higher
than their HER2 and EGFR IC50’s.
Analogs with promising in vitro potency and 4 h oral
exposure were evaluated in vivo in N87 human gastric
carcinoma (HER2 and EGFR driven) and GEO hu-
man colon carcinoma (EGFR driven) athymic mouse
xenograft models and these data, together with those
for homopiperazine 1b, are summarized in Table 4. Ex-
cept for N-oxide 8j, all of the compounds were active
and produced dose-dependent antitumor effects in the
N87 model. Of these, 1c possessed the highest activity
and potency. At its optimal dose (180 mg/kg), it yielded
133% TGI and remained active at dose levels as low as
60 mg/kg. This was comparable to homopiperazine 1b
but the latter had to be dosed twice a day to achieve
this level of activity. Compounds 8f and 8g possessed
robust activity in N87 at high dose levels and had sim-
ilar potency at the minimum efficacious dose, 120 mg/kg.
Compound 8i only showed borderline activity at the
highest tested dose. Against the GEO colon carcinoma
this series suffered a considerable loss of activity. Com-
pound 1c demonstrated antitumor activity, 85% TGI at
its maximum tolerated dose of 240 mg/kg. The homo-
piperazine 1b again had to be dosed twice a day to
achieve a similar level of activity. All of the other
tested compounds were inactive at doses as high as
180 mg/kg. It is difficult to account for these results
since the in vivo tumor models were primarily em-
ployed as screens to sort through a large number of
leads and negative results were generally not followed
up. Compounds like 8e would have been expected to
perform better in these models. Possibly low solubility
may have resulted in a less than dose-proportional in-
crease in exposure at higher doses. In the case of 8h,
high protein binding in mouse serum (>99.9%) may
have been detrimental to in vivo efficacy. Additionally,
although the oral exposure for these analogs was gen-
erally good out to 4 h, in some cases it may have sub-
sequently dropped below efficacious levels with once a
day dosing. The most active compound, 1c, was further
profiled and showed a more than dose-proportional in-
crease in oral exposure in the rat (data not shown). If
this also occurred in mice, it may have helped 1c’s per-
formance in these xenograft models.
Compound 1c was screened in a small panel of kinases
(Table 5) and found to be less selective than morpholine
ether analog 1a.3 Its inhibition of VEGFR-2, the vascu-
lar endothelial growth factor receptor-2, was only
14-fold less than that of EGFR and is suggestive of
AEE-788, the Novartis EGFR, HER2, and VEGF

H. Mastalerz et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4947–4954
4953
Table 4. In vivo antitumor activity of orally administered compounds against established N87 and GEO xenografts implanted subcutaneously in
athymic micea
Compound
N87b
% TGI
GEOc
% TGI
Dosee (mg/kg)
MEDd
Dosee (mg/kg)
MEDd
1b
1c
8e
8h
8i
180f MTD
180 OD
121
133
89
90
60
135f MTD
240 MTD
180 HTD
78
85
90
120
180 HTD
240 HTD
180 HTD
120
120
180
Inactive 60–180 mg/kg
NDg
110
63
NDg
180 HTD
180 HTD
Inactive 60–180 mg/kg
Inactive 60–180 mg/kg
8j
a Tween 80–PEG400–water, 10/40/50 was the vehicle and experimental details can be found in Ref. 7.
b QD · 21 dosing schedule.
c QD · 10 dosing schedule.
d MED, minimum efficacious dose. Activity is defined as % TGI P 50%.
e MTD, maximum tolerated dose; OD, optimal dose; HTD, highest test dose.
f BID · 14 dosing schedule.
g ND, not determined.
Table 5. Kinase selectivity profile for 1a and 1c
a
Kinase
IC50 (lM)
1a
1c
EGFR
HER2
Met
0.061
0.055
6.5
0.035
0.023
3.9
LCK
>5
0.71
0.48
1.9
VEGFR2
CDK2
p38
>10
>50
>50
>50
ND
>50
>50
2.2
PKA
PKC
a IC50 values are reported as means of at least three determinations.
Variability around the mean value was <15%.
receptor tyrosine kinase inhibitor that is currently in
clinical trials.10
Figure 2. Predicted binding mode of compound 1c modeled in the
X-ray structure of the lapatinib/EGFR kinase complex, see Ref. 11.
The C-5 side chain extends into the ribose-phosphate binding region
where the protonated amino group off the piperidine ring may form
hydrogen bonds with Asp831, Asn818, and/or Arg817. Image created
with Pymol from DeLano Scientific LLC, San Carlos, CA, USA,
http://www.pymol.org.
A potential binding mode for compound 1c in the ATP
binding site was modeled after the X-ray structure of the
complex between lapatinib and EGFR kinase and is
shown in Figure 2.11 The docked poses were energy min-
imized in Maestro12 using the OPLS-AA force field13
and the GBSA continuum model,14 an implicit solvation
model. The results were similar to those previously re-
ported for the homopiperazine 1b4 and quinazoline
EGFR and HER2 specific kinase inhibitors with C-5
solubilizing groups.15 The pyrrolotriazine core is ori-
ented in the ATP binding site such that there is a hydro-
gen bond between N-1 and the hinge region Met769
NH. The C-4 benzyl indazole group extends back into
would require
interpretation.
a
HER2 crystal structure for
In summary, pyrrolotriazine dual EGFR/HER2 kinase
inhibitors with a C-5 aminopiperidine solubilizing group
generally exhibited an in vitro profile that was superior
to that of analogs with our previously reported C-5 sol-
ubilizing groups. It is hypothesized that this solubilizing
group extends into the ribose-phosphate portion of the
ATP binding pocket and enhances the binding affinity
of the inhibitor. New synthetic methodology was devel-
oped to permit the parallel synthesis of C-4 analogs with
the new solubilizing group. Our initial efforts generated
a variety of interesting leads and they were evaluated in
tumor xenograft models. The 4-(aminofluorobenzylin-
dazole) analog, 1c, was found to exhibit the best antitu-
mor activity. We have continued our studies
of pyrrolotriazines with C-5 aminopiperidine solubiliz-
ing groups as dual EGFR/HER2 inhibitors and have
a
deep hydrophobic pocket formed partially by
Met742 of helix a-C and Phe382 of the activation loop.
The C-5 substituent extends out into the ribose-phos-
phate pocket where the protonated amino group off
the piperidine ring can hydrogen bond with the side
chains of Asp831 and Asn818 and also with the back-
bone carbonyl oxygen of Arg817. In this model there
was also an intramolecular hydrogen bond between
the C4 aniline NH and the piperidine tertiary N atom.
However, intriguing SAR such as the HER2 selectivity
of picolyl analog 8c and the switch to potent dual
EGFR/HER2 inhibition for its methyl analog, 8e,

4954
H. Mastalerz et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4947–4954
8. Additional cell proliferation data (not shown) using the
HER2 overexpressing BT-474 human breast tumor cell
line and a constitutively activated Sal2 murine salivary
gland tumor that expresses a CD8HER2 fusion protein
were found to track with those observed for the N87 cell
line.
9. Petrov, K. G.; Zhang, Y.-M.; Carter, M.; Cockerill, G. S.;
Dickerson, S.; Gauthier, C. A.; Guo, Y.; Mook, R. A.;
Rusnak, D. W.; Walker, A. L.; Wood, E. R.; Lackey, K.
E. Bioorg. Med. Chem. Lett. 2006, 16, 4686.
10. Traxler, P.; Allegrini, P. R.; Brandt, R.; Brueggen, J.;
Cozens, R.; Fabbro, D.; Grosios, K.; Lane, H. A.;
McSheehy, P.; Mestan, J.; Meyer, T.; Tang, C.; Wart-
mann, M.; Wood, J.; Caravatti, G. Cancer Res. 2004, 64,
4931.
11. Wood, E. R.; Truesdale, A. T.; McDonald, O. B.;
Yuan, D.; Hassell, A.; Dickerson, S. H.; Ellis, B.;
Pennisi, C.; Horne, E.; Lackey, K.; Alligood, K. J.;
Rusnak, D. W.; Gilmer, T. M.; Shewchuk, L. Cancer
Res. 2004, 64, 6652.
12. Schrodinger, L.L.C. 2003. 32nd Floor, Tower 45, 120
West Forty-Fifth Street, New York, 10036.
13. Kaminski, G. A.; Friesner, R. A.; Tirado-Rives, J.;
Jorgensen, W. L. J. Phys. Chem. B 2001, 105, 6474.
14. Yu, Z.; Jacobson, M. P.; Friesner, R. A. J. Comput. Chem.
2006, 27, 72.
15. (a) Ballard, P.; Bradbury, R. H.; Harris, C. S.; Hennequin,
L. F. A.; Hickinson, M.; Johnson, P. D.; Kettle, J. G.;
Kinowska, T.; Leach, A. G.; Morgentin, R.; Pass, M.;
Ogilvie, D. J.; Olivier, A.; Warin, N.; Williams, E. J.
Bioorg. Med. Chem. Lett. 2006, 16, 1633; (b) Ballard, P.;
Bradbury, C. S.; Hennequin, L. F. A.; Hickinson, M.;
Johnson, P. D.; Kettle, J. G.; Kinowska, T.; Morgentin,
R.; Ogilvie, D. J.; Olivier, A. Bioorg. Med. Chem. Lett.
2005, 15, 4226.
broadened the scope of our efforts, particularly with re-
spect to the C-4 substituent. The results will be reported
in future publications.
References and notes
1. (a) Baselga, J.; Arteaga, C. L. J. Clin. Oncol. 2005, 23,
2445; (b) Kamath, S.; Buolamwini, J. K. Med. Res. Rev.
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2. Baselga, J. Ann. Oncol. 2002, 13, 8.
3. Mastalerz, H.; Chang, M.; Chen, P.; Dextraze, P.; Fink, B.
E.; Gavai, A.; Goyal, B.; Han, W.-C.; Johnson, W.;
Langley, D.; Lee, F. Y.; Marathe, P.; Mathur, A.;
Oppenheimer, S.; Ruediger, E.; Tarrant, J.; Tokarski, J.
S.; Vite, G. D.; Vyas, D. M.; Wong, H.; Wong, T. W.;
Zhang, H.; Zhang, G. Bioorg. Med. Chem. Lett. 2007, 17,
2036.
4. Mastalerz, H.; Chang, M.; Gavai, A.; Johnson, W.;
Langley, D.; Lee, F. Y.; Marathe, P.; Mathur, A.;
Oppenheimer, S.; Tarrant, J.; Tokarski, J. S.; Vite, G.
D.; Vyas, D. M.; Wong, H.; Wong, T. W.; Zhang, H.;
Zhang, G. Bioorg. Med. Chem. Lett. 2007, 17, 2828.
5. (a) For experimental procedures, see: Mastalerz, H;
Zhang, G.; Tarrant, J.; Vite, G.D. US 6,908,916.; (b)
Gavai, A.V.; Han, W.-C.; Chen, P.; Ruediger, E.H.;
Mastalerz, H; Fink, D.; Norris, D.J. US 7,064,203.
6. Prepared using a procedure similar to that described by:
Jiang, X.-H.; Song, Y.-L.; Long, Y.-Q. Bioorg. Med.
Chem. Lett. 2004, 14, 3675.
7. Wong, T. W.; Lee, F. Y.; Yu, C.; Luo, F. R.; Oppenhei-
mer, S.; Zhang, H.; Smykla, R. A.; Mastalerz, H.; Fink, B.
E.; Hunt, J. T.; Gavai, A. V.; Vite, G. D. Clin. Cancer Res.
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