Facile preparation of new 4-phenylamino-3-quinolinecarbonitrile Src kinase inhibitors via 7-fluoro intermediates: Identification of potent 7-amino analogs

Article abstract of DOI:10.1016/j.bmc.2007.09.028

A more efficient preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (2), the penultimate intermediate in the synthesis of bosutinib (1a), was developed. New 7-alkoxy-4-phenylamino-3-quinolinecarbonitrile Src

Full text of DOI:10.1016/j.bmc.2007.09.028

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 405–412
Facile preparation of new 4-phenylamino-3-quinolinecarbonitrile
Src kinase inhibitors via 7-fluoro intermediates: Identification
of potent 7-amino analogs
Diane H. Boschelli,a,* Biqi Wu,a Fei Ye,a Haris Durutlic,a Jennifer M. Golas,b
Judy Lucasb and Frank Boschellib
aChemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA
bDepartment of Oncology, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA
Received 9 August 2007; revised 11 September 2007; accepted 13 September 2007
Available online 18 September 2007
Abstract—A more efficient preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (2),
the penultimate intermediate in the synthesis of bosutinib (1a), was developed. New 7-alkoxy-4-phenylamino-3-quinolinecarbonit-
rile Src inhibitors were prepared from 5 and 9, the 6-ethoxy and 6-hydrogen analogs of 2. In addition, the fluoro group of 2 was
readily displaced by primary and secondary amines to give 7-amino analogs. Two of these 7-amino analogs, 15 and 18, were potent
Src inhibitors with in vivo activity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Bosutinib, SKI-606, (1a), a Src kinase inhibitor with a 3-
quinolinecarbonitrile core is currently in Phase II clini-
cal trials for the treatment of solid tumors.16,17 The ori-
ginal preparation of 1a started with methyl vanillate and
was executed in eight steps.18,19 Several analogs of 1a,
with diverse 7-alkoxy groups are also potent Src kinase
inhibitors including the 7-(2-methoxyethoxy) derivative
1b.20 This analog was initially prepared by a nine-step
route. Subsequently it was found that 7-alkoxy-4-phe-
nylamino-3-quinolinecarbonitriles could be obtained
by displacement of the 7-fluoro group of 2 with alco-
hols.21 For example, treatment of 2 with 3-(4-methylpi-
perazin-1-yl)propanol in dimethylformamide in the
presence of sodium hydride provided 1a. This key 7-flu-
oro intermediate not only shortened the route to previ-
ously prepared Src inhibitors, but also facilitated the
preparation of new analogs. We report here an im-
proved synthesis of 2, along with further exploration
of reactions of both 2 and some additional 7-fluoro-3-
quinolinecarbonitrile derivatives that allow for the prep-
aration of novel Src kinase inhibitors.
The non-receptor tyrosine kinase Src plays a fundamental
role in several signal transduction pathways.1–3 Tumors
often contain high levels of this kinase and recent studies
suggest that Src is a major player in tumor progression
and metastatic growth.4–6 Src phosphorylates focal adhe-
sion kinase (FAK),7 resulting in an increase in cell motil-
ity, and b-catenin, resulting in a disruption of E-cadherin
associated cell–cell contacts.8,9 These events contribute to
a breakdown in tissue structure that facilitates the disper-
sion of cancer cells. As a result of these findings, several
small molecule Src inhibitors are being pursued for the
treatment of cancer, including pyrido[2,3-d]pyrimi-
dines,10 pyrrolo[2,3-d]pyrimidines,11 purines,12 quinazo-
lines,13 thiazoles,14 and benzotriazines.15
Cl
Cl
O
Cl
Cl
O
HN
HN
4
6
O
O
CN
O
O
CN
3
2
O
N
N
N
1
7
N
1a
1b
2. Chemistry
The initial route to 2 involved a thermal cyclization that
was not optimal for large scale synthesis.21 As shown in
Scheme 1, a new route was developed, wherein reaction
Keywords: Src; 3-Quinolinecarbonitrile; SKI-606; kinase.
*
Corresponding author. Tel.: +1 845 602 3567; fax: +1 845 602
5561; e-mail: bosched@wyeth.com
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.09.028

406
D. H. Boschelli et al. / Bioorg. Med. Chem. 16 (2008) 405–412
Cl
Cl
O
RO
F
Cl
Cl
O
HN
RO
F
O
a
b
RO
F
CN
N
H
N
NH2
H
N
CN
2: R = Me
5: R = Et
3: R = Me
4: R = Et
Scheme 1. Reagents: (a) 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide, triethylothofomate, iso-propanol; (b) phosphours oxychloride,
acetonitrile.
of 3-fluoro-p-anisidine, 2-cyano-N-(2,4-dichloro-5-
methoxyphenyl)acetamide, and triethylorthoformate
provided the 2-cyano-2-propenamide intermediate 3 as
a mixture of cis and trans isomers.22 Treatment of 3 with
phosphorus oxychloride in acetonitrile resulted in direct
formation of 2. This route avoided the high temperature
step of the original route and was also shorter and con-
vergent. A variation of this chemistry was also used to
prepare the 7-iodo and 7-bromo analogs of 2.23 Scheme
2 shows the versatility of this synthetic sequence. Reac-
tion of 4-ethoxy-3-fluoroaniline under similar conditions
led to the 6-ethoxy derivative 5, via intermediate 4.
Analogous to the earlier reaction with 2, treatment of
5 with 3-(4-methylpiperazin-1-yl)propanol provided 6,
the 6-ethoxy analog of 1a. Additional alcohols could
be used in this reaction, with 2-methoxyethanol provid-
ing 7, the 6-ethoxy analog of 1b.
resulting in 14, the 5-desmethoxy aniline derivative of
11.
While there are several reports of 7-alkoxy-3-quinoline-
carbonitrile Src inhibitors, 7-amino analogs have not
been previously disclosed in the literature. We were
pleased to find that the 7-fluoro group of 2 could be read-
ily displaced with amines.24,25 As shown in Scheme 4,
reaction of 2 with 1-(3-aminopropyl)-4-methylpiperazine
in 1-methyl-2-pyrrolidinone at elevated temperature pro-
vided 15, the 7-amino analog of 1a. The 7-amino analog of
1b, namely 16, was obtained by reaction of 2 with 2-meth-
oxyethylamine, using the amine as the solvent, and heat-
ing in a sealed tube. The solubilizing amine group was
further varied to include morpholine (17) and dimethyl-
amine (18). The 7-fluoro group of 2 was also readily
displaced by secondary amines, as demonstrated by the
reaction of 2 with N,N,N0-trimethyl-1,3-propanediamine
to provide 19.
The further versatility of these 7-fluoro intermediates is
shown in Scheme 3. Formation of the amidine of 2-ami-
no-4-fluorobenzoic acid with dimethylformamide
diethyl acetal followed by reaction with the anion of
acetonitrile resulted in 8. Chlorination of 8 with
phosphorus oxychloride followed by addition of 2,4-di-
chloro-5-methoxyaniline gave 9. Treatment of 9 with
3-(4-methylpiperazin-1-yl)propanol provided 10, while
treatment of 9 with 2-methoxyethanol provided 11, the
6-desmethoxy analogs of 1a and 1b, respectively. Alter-
natively, the reaction sequence could be varied such that
the initial step is displacement of the 7-fluoro group of 8,
with subsequent conversion of the 4-one substituent to
chloro and finally, displacement of the 4-chloro group
with an aniline. This route is exemplified by the reaction
of 8 with 2-methoxyethanol to give 12. In order for this
transformation to go to completion, it was necessary to
use a large excess of sodium hydride and the alcohol as
the solvent. Reaction of 12 with thionyl chloride and a
catalytic amount of N,N-dimethylformamide provided
13, with subsequent treatment with 2,4-dichloroaniline
3. Biology
A cell-based assay was used to evaluate these com-
pounds as Src inhibitors. This assay uses a rat fibroblast
line that expresses a v-Src fusion with the catalytic do-
main of human c-Src.18 Inhibition of the anchorage
independent proliferation of these cells is a direct result
of the inhibition of Src activity. Analogs 1a and 1b had
IC50s in this assay of 100 and 190 nM, respectively.19,20
As shown in Table 1, the 6-ethoxy analogs of 1a and 1b,
6, and 7, had comparable IC50 values of 85 and 180 nM.
A more pronounced effect was observed with the 6-des-
methoxy analogs 10 and 11 with these analogs being
7- to 8-fold less active than 1a and 1b. Removal of the
5-methoxy group from the aniline of 11 resulted in
another large decrease in activity with 14 having an
IC50 value of greater than 10 lM. The 7-amino analog
of 1a, namely 15, had reduced activity, as did 16, the
Cl
Cl
O
Cl
Cl
O
HN
HN
O
F
CN
O
CN
a
N
RO
N
5
6: R =(CH2)3-N-methylpiperazine
7: R =(CH2)2-OMe
Scheme 2. Reagents: (a) ROH, sodium hydride, N,N-dimethylformamide.

D. H. Boschelli et al. / Bioorg. Med. Chem. 16 (2008) 405–412
407
Cl
Cl
O
Cl
O
Cl
O
HN
CO2H
NH2
HN
CN
CN
a
b
c
CN
CN
F
F
N
H
RO
N
F
N
9
8
10: R =(CH2)3-N-methylpiperazine
11: R =(CH2)2-OMe
d
O
Cl
e
CN
MeO
MeO
O
N
H
O
N
13
12
Cl
Cl
f
HN
CN
MeO
O
N
14
Scheme 3. Reagents: (a) 1—Dimethylformamide diethyl acetal; 2—n-butyl lithium, acetonitrile; (b) 1—thionyl chloride, cat. N,N-dimethylform-
amide, 2—2,4-dichloro-5-methoxyaniline, pyridine HCl, 2-ethoxyethanol; (c) ROH, sodium hydride, N,N-dimethylformamide; (d) sodium hydride,
2-methoxyethanol; (e) thionyl chloride, cat N,N-dimethylformamide; (f) 2,4-dichloro-5-methoxyaniline, pyridine HCl, 2-ethoxyethanol.
7-amino analog of 1b. Two additional amino analogs, 17
and 18, had comparable activity to 15. However, meth-
ylation of the 7-amino group of 18 led to decreased
activity, with 19 having an IC50 value of only 2.7 lM.
solubility (>100 lg/mL at pH 7.4) compared to 15, and a
slightly decreased permeability of 7.3 · 10ꢀ6 cm/s. Both
compounds gave less than 34% inhibition of CYPS
3A4, 2D6, and 2C9 when tested at 3 lM, and had good
stability in mouse plasma with more than 70% of the
parent remaining after 300 min. Administration of a sin-
gle 50 mg/kg po dose of 15 (vehicle of 0.5% methylcellu-
lose and 0.4% polysorbate 80) to nude mice provided
plasma levels of 790, 520, and 100 ng/mL after 4, 8,
and 24 h, respectively. A similar study with 18 provided
plasma levels of 610, 410, and 80 ng/mL. In an earlier
study, 1a had plasma levels of 1060 and 47 ng/mL at
time points of 4 and 24 h.17 Since the exposure levels
of 15 and 18 met the criteria for evaluation in vivo, both
compounds were tested in an efficacy study. The HT29
human colon tumor line was chosen due to the repro-
ducible activity of 1a in this xenograft model.17 In the
first study the tumors were staged to approximately
250 mg in size prior to dosing. Both 15 and 1a were
administered as a single oral dose of 150 mg/kg for
14 days. At the end of dosing, 15 provided a T/C of
63%, while 1a provided a T/C of 40%. In the second
Selected analogs were tested in an ELISA format Src ki-
nase assay,18 wherein 1a and 1b were previously re-
ported to have IC50 values of 1.2 and 2.9 nM,
respectively.19,20 There was a good correlation of the
rank order of activity seen in this isolated Src enzyme as-
say with that observed in the Src cell assay.26 The 6-eth-
oxy analog of 1a, 6, had an IC50 value of 1.2 nM, and
15, the 7-amino analog of 1a, was also potent having
an IC50 value of 1.8 nM. While 18 had an IC50 value
of 2.3 nM, 19, its methylated derivative, had reduced
activity (IC50 = 31 nM).
The 7-amino analogs 15 and 18 had acceptable proper-
ties as measured in standard pharmaceutical profiling
assays. Compound 15 had a solubility of 32 lg/mL at
pH 7.4 and a permeability of 10.7 · 10ꢀ6 cm/s, as mea-
sured in a PAMPA assay. Compound 18 had increased
Cl
Cl
O
Cl
Cl
O
HN
HN
a
O
CN
O
F
CN
R'RN
N
N
2
15: R =(CH2)3-N-methylpiperazine, R' = H
16: R =(CH2)2-OMe, R' = H
17: R =(CH2)3-morpholine, R' = H
18: R =(CH2)3-NMe2, R' = H
19: R =(CH2)3-NMe2, R' = Me
Scheme 4. Reagents: (a) RR0NH, 1-methyl-2-pyrrolidinone or sealed tube.

408
D. H. Boschelli et al. / Bioorg. Med. Chem. 16 (2008) 405–412
Table 1. Src inhibitory activity
Cl
Cl
Y
HN
X
CN
RZ
N
X
Y
Z
R
Src
IC50 nM18
1a
1b
6
OMe
OMe
OEt
OEt
H
OMe
OMe
OMe
OMe
OMe
OMe
H
O
O
O
O
O
O
O
(CH2)3N-Me-piperazine
(CH2)2OMe
10019
19020
85
(CH2)3N-Me-piperazine
(CH2)2OMe
7
180
710
10
11
14
15
16
17
18
19
(CH2)3N-Me-piperazine
(CH2)2OMe
(CH2)2OMe
H
1,600
>10,000
360
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
NH
NH
NH
NH
NMe
(CH2)3N-Me-piperazine
(CH2)2OMe
1,500
390
300
(CH2)3N-morpholine
(CH2)3NMe2
(CH2)3NMe2
2,700
xenograft study, the tumors were staged to 235 mg and
administration of 18 and 1a as a single oral dose of
150 mg/kg for 14 days resulted in a T/C of 75% for 18
and a T/C of 51% for 1a. The reduced activity of both
15 and 18 in this model may be a reflection of the re-
duced Src activity of these compounds compared to 1a.
Solvents and reagents obtained from commercial
sources were used without purification, unless noted.
The reported yields are for purified material and are
not optimized. Reactions were carried out under an inert
atmosphere, either nitrogen or argon. Flash chromatog-
raphy was performed with Baker 40 lM silica gel.
We are continuing to prepare new 7-amino-4-anilino-3-
quinolinecarbonitriles via the various 7-fluoro interme-
diates. In addition, we have found that the 7-fluoro
group of 2 is readily displaced by sulfur nucleophiles
including ethanethiol and benzyl mercaptan and more
highly functionalized 7-thiol analogs are in progress.23
5.1.1. 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-
fluoro-4-methoxyphenyl)amino]-2-propenamide (3). To a
suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphe-
nyl)acetamide23 (1.00 g, 3.86 mmol) in 200 mL of iso-
propanol was added 3-fluoro-p-anisidine (0.60 g,
4.25 mmol). This mixture was heated to reflux to give
a clear yellow solution. To this solution, triethylortho-
formate (1.72 mL, 10.34 mmol) was added dropwise
and the reaction mixture was heated at reflux overnight.
An additional 2 mL of triethylorthoformate was added
and the mixture was heated at reflux overnight. An addi-
tional 2 mL of triethylorthoformate was added and the
mixture was heated at reflux overnight. The mixture
was allowed to cool to room temperature and the white
solid was collected by filtration, washed with iso-propa-
nol, and dried overnight at ꢁ40 ꢁC under reduced pres-
sure. Purification by suspension in hot ethyl acetate
followed by addition of cold hexanes gave 1.08 g
(68%) of 3 as a white solid, mp 275–276 ꢁC; MS 408.1
(MꢀH)ꢀ. Analysis for C18H14Cl2FN3O3: calcd C,
52.70; H, 3.44; N, 10.24. Found: C, 52.44; H, 3.26; N,
10.14.
4. Conclusions
A new route to 2, the key 7-fluoro-3-quinolinecarbonit-
rile used in the preparation of the clinical compound 1a,
was reported. The synthesis and use of additional 7-flu-
oro-3-quinolinecarbonitrile intermediates to prepare
new C-6 substituted analogs was disclosed along with
the finding that 7-amino-3-quinolinecarbonitriles could
be obtained by reaction of 2 with primary or secondary
amines. Two of these 7-amino derivatives, 15 and 18,
had in vivo efficacy, albeit lower than that of 1a.
5. Experimental
5.1. General methods
5.1.2. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-
6-methoxy-3-quinolinecarbonitrile (2). To a suspension
of 3 (360 mg, 0.88 mmol) in 40 mL of acetonitrile was
added 100 lL of methanol. The reaction mixture was
heated to reflux and phosphorous oxychloride
(0.65 mL, 7.0 mmol) was added dropwise via syringe.
After 2 h the mixture became a clear orange solution.
This solution was heated at reflux overnight. After
24 h, the reaction mixture was cooled in an ice-bath
and the solid was collected by filtration, washing with
Melting points were determined in open capillary tubes
on a Meltemp melting point apparatus and are uncor-
rected. H NMR spectra were recorded using a DRX-
1
400 spectrometer. Chemical shifts (d) are in parts per
million referenced to Me4Si. Electrospray (ES) mass
spectra were recorded in positive mode on a Micromass
Platform spectrometer. Electron impact (EI) mass spec-
tra were obtained on a Finnigan MAT-90 spectrometer.

D. H. Boschelli et al. / Bioorg. Med. Chem. 16 (2008) 405–412
409
cold acetonitrile and then suspended in tetrahydrofuran.
The acetonitrile filtrate and the tetrahydrofuran suspen-
sion were combined, concentrated ammonium hydrox-
ide was added and the mixture stirred for 1 h. Water
was added and stirring was continued for 2 h. The
resulting solids were combined, washed with hot water,
and dried under reduced pressure at ꢁ40 ꢁC, overnight,
to provide 189 mg (55%) of 2 as orange crystals, mp
heated at 125 ꢁC for 3 h. The reaction mixture was then
poured into saturated aqueous sodium bicarbonate and
stirred for 1 h. The aqueous solution was extracted with
10% methanol in dichloromethane. The organic layer
was washed with brine, dried over magnesium sulfate
and concentrated in vacuo. The residue was purified by
preparative thin layer chromatography, eluting with
15% methanol in dichloromethane. Trituration with hex-
ane provided 116 mg (44%) of 6 as a light brown solid,
mp 137–138 ꢁC. 1H NMR (400 MHz, DMSO-d6) d
1.42 (t, J = 7 Hz, 3H), 1.96 (m, 2H), 2.16 (s, 3H), 2.24–
2.49 (complex m, 10H), 3.85 (s, 3H), 4.20 (m, 4H), 7.32
(s, 2H), 7.74 (s, 1H), 7.82 (s, 1H), 8.40 (s, 1H), 9.57 (s,
1
219–221 ꢁC; H NMR (400 MHz, DMSO-d6) d 3.87 (s,
3H), 4.02 (s, 3H), 7.36 (s, 1H), 7.65–7.80 (m, 2H), 8.08
(d, J = 9 Hz, 1H), 8.48 (s, 1H), 9.85 (s, 1H); MS 392.0
(MꢀH)+. Analysis for C18H12Cl2FN3O2Æ0.5 H2O: calcd
C, 53.88; H, 3.27; N, 10.48. Found: C, 54.09; H, 3.20;
N, 10.24.
1H);
MS
542.0
(MꢀH)ꢀ.
Analysis
for
C27H31Cl2N5O3Æ0.6 H2O: calcd C, 58.40; H, 5.84; N,
12.61. Found: C, 58.31; H, 5.71; N, 12.43.
5.1.3. 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-
ethoxy-3-fluorophenyl)amino]-2-propenamide (4). To a
suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphe-
nyl)acetamide25 (5.9 g, 22.7 mmol) in 400 mL of iso-pro-
panol was added 4-ethoxy-3-fluoroaniline (3.7 g,
23.8 mmol). This mixture was heated to reflux to give
a clear solution. To this solution, triethylorthoformate
(11.6 mL, 69.6 mmol) was added dropwise and the reac-
tion mixture was heated at reflux for 18 h. Additional
triethylorthoformate (11.6 mL, 69.6 mmol) was added
dropwise and the reaction mixture was heated at reflux
for 42 h. The mixture was allowed to cool to room tem-
perature and the solid was collected by filtration,
washed with ethyl acetate, and then dried in vacuo at
40 ꢁC to give 6.4 g (67%) of 4 as a gray solid, mp 245–
5.1.6.
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-eth-
oxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile (7). A
mixture of 5 (138 mg, 0.34 mmol), 2-methoxyethanol
(4 mL) and sodium hydride (54 mg of a 60% dispersion
in mineral oil, 1.36 mmol) was heated at reflux over-
night. Additional sodium hydride (135 mg of a 60% dis-
persion in mineral oil, 3.38 mmol) was added and the
reaction mixture was heated at reflux overnight. Addi-
tional sodium hydride (54 mg of a 60% dispersion in
mineral oil, 1.36 mmol) was added and the reaction mix-
ture was heated at reflux overnight. The reaction mix-
ture was cooled to room temperature and partitioned
between ice water and dichloromethane. The organic
layer was washed with brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was
purified by preparative thin layer chromatography, elut-
ing with 5% methanol in dichloromethane to give a deep
yellow solid, which was washed with diethyl ether con-
taining dichloromethane, to provide 105 mg (67%) of 7
as a light tan solid, mp 215–217 ꢁC. 1H NMR
(400 MHz, DMSO-d6) d 1.43 (t, J = 7 Hz, 3H), 3.35 (s,
3H), 3.76 (m, 2H), 3.86 (s, 3H), 4.22 (q, J = 7 Hz, 2H),
4.30 (m, 2H), 7.33 (s, 1H), 7.36 (s, 1H), 7.74 (s, 1H),
7.82 (s, 1H), 8.41 (s, 1H), 9.59 (s, 1H); MS 462.1
(MꢀH)+. Analysis for C22H31Cl2N3O4Æ0.3 H2O: calcd
C, 56.49; H, 4.66; N, 8.99. Found: C, 56.59; H, 4.64;
N, 8.95.
247 ꢁC;
MS
424.1
(MꢀH)+.
Analysis
for
C19H16Cl2FN3O3: calcd C, 53.79; H, 3.80; N, 9.90.
Found: C, 53.39; H, 3.97; N, 9.69.
5.1.4.
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-eth-
oxy-7-fluoro-3-quinolinecarbonitrile (5). A suspension of
4 (6.28 g, 14.8 mmol) in 54 mL of acetonitrile and
2.0 mL of methanol was heated to reflux and phospho-
rous oxychloride (8.3 mL, 88.8 mmol) was added drop-
wise. The mixture was heated at reflux for 17 h. The
resultant solution was concentrated in vacuo and aceto-
nitrile was added to the residue. The solid was collected
by filtration, washing with acetonitrile. The solid was
suspended in tetrahydrofuran and neutralized with con-
centrated ammonium hydroxide. After stirring for
30 min, water was added and the mixture was stirred
for 1 h. The solid was collected by filtration, washing
with water, followed by 1:1 diethyl ether and hexane.
The light yellow solid was dried in vacuo to provide
5.1.7. 7-Fluoro-4-hydroxy-3-quinolinecarbonitrile (8). A
suspension of 2-amino-4-fluorobenzoic acid (10.2 g,
65.8 mmol) and dimethylformamide diethyl acetal
(58 mL) was heated at reflux for 6 h. The solution was
cooled to room temperature and concentrated in vacuo.
The dark oil was passed through a pad of magnesol
eluting with methylene chloride to provide 17.2 g of
ethyl 2-{[(1E)-(dimethylamino)methylidene]amino}-4-flu-
orobenzoate as a red oil, MS 239.1 (MꢀH)+.
1
2.2 g (37%) of 5, mp 185–187 ꢁC; H NMR (400 MHz,
DMSO-d6) d 1.95 (t, J = 7 Hz, 3H), 3.87 (s, 3H), 4.29
(q, J = 7 Hz, 2H), 7.39 (s, 1H), 7.66–7.81 (m, 2H), 8.09
(d, J = 9 Hz, 1H), 8.49 (s, 1H), 9.80 (s, 1H); MS 406.1
(MꢀH)+. Analysis for C19H14Cl2FN3O2Æ0.4 H2O: calcd
C, 55.20; H, 3.61; N, 10.16. Found: C, 55.25; H, 3.53;
N, 10.15.
To a solution of 2.5 M n-butyl lithium in tetrahydro-
furan (53.6 mL, 134 mmol) in 54 mL of tetrahydrofu-
ran at ꢀ78 ꢁC was added dropwise a solution of
acetonitrile (7.1 mL, 136 mmol) in 100 mL of tetrahy-
drofuran. After stirring at ꢀ78 ꢁC for 10 min, a
solution of ethyl 2-{[(1E)-(dimethylamino)methyli-
dene]amino}-4-fluorobenzoate (14.5 g, 60.9 mmol) in
100 mL of tetrahydrofuran was added over a period
5.1.5.
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-eth-
oxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-car-
bonitrile (6). A mixture of 5 (200 mg, 0.49 mmol), 3-(4-
methylpiperazin-1-yl)propanol (155 mg, 0.98 mmol)
and sodium hydride (196 mg of a 60% dispersion in min-
eral oil, 4.6 mmol) in 5 mL of dimethylformamide was

410
D. H. Boschelli et al. / Bioorg. Med. Chem. 16 (2008) 405–412
of 1.5 h. Stirring was continued at ꢀ78 ꢁC for 2 h,
then the temperature was slowly allowed to warm to
ꢀ10 ꢁC. The mixture was then cooled to ꢀ78 ꢁC and
acetic acid (18.3 g, 305 mmol) was added dropwise.
The reaction mixture was allowed to warm to room
temperature and stirred for 3 days. The precipitate
was collected by filtration washing with tetrahydrofu-
ran, water, diethyl ether, ethyl acetate and then
additional diethyl ether to give 7.95 g (69%) of 8 as
5.1.10.
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-(2-
methoxyethoxy)-3-quinolinecarbonitrile (11). Following
the procedure used to prepare 10, a mixture of 9
(300 mg, 0.83 mmol), 2-methoxyethanol (187 mg
2.46 mmol), and sodium hydride (259 mg of a 60% dis-
persion in mineral oil, 27.5 mmol) in 6 mL of dimethyl-
formamide was heated at 125 ꢁC for 18 h to provide
1
194 mg (56%) of 11 as a tan solid, mp 182–183 ꢁC. H
NMR (400 MHz, TFA/DMSO-d6) d 3.35 (s, 3H), 3.78
(m, 2H), 3.89 (s, 3H), 4.38 (m, 2H), 7.42 (s, 1H), 7.60
(s, 1H), 7.62 (d, J = 10 Hz, 1H), 7.88 (s, 1H), 8.71 (s,
1H), 9.21 (s, 1H); MS 416.1 (MꢀH)ꢀ. Analysis for
C20H17Cl2N3O3: calcd C, 57.43; H, 4.10; N, 10.05.
Found: C, 57.36; H, 4.09; N, 9.89.
1
an off-white solid, mp >250 ꢁC. H NMR (400 MHz,
DMSO-d6) d 7.31–7.39 (complex m, 2H), 8.19 (m,
1H), 8.73 (s, 1H); MS 187.0 (MꢀH)ꢀ. Analysis for
C10H5FN2OÆ0.20 H2O: calcd C, 62.63; H, 2.84; N,
14.61. Found: C, 62.55; H, 2.71; N, 14.29.
5.1.8. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-
3-quinolinecarbonitrile (9). A mixture of 8 (2.02 g,
10.7 mmol) and a few drops of dimethylformamide in
16 mL of thionyl chloride was heated at reflux for
1.5 h. The reaction mixture was concentrated in vacuo.
Toluene (20 mL) was added and the mixture was again
concentrated in vacuo to provide 2.18 g of 4-chloro-7-flu-
oro-3-quinolinecarbonitrile as a yellow solid, MS 207.0
(MꢀH)+. A mixture of 4-chloro-7-fluoro-3-quinolinecar-
bonitrile (2.10 g, 10.2 mmol), 2,4-dichloro-5-methoxyan-
iline (2.15 g, 11.2 mmol), and pyridine hydrochloride
(1.18 g, 10.2 mmol) in 50 mL of 2-ethoxyethanol was
heated at 115 ꢁC for 3 h. After cooling, the mixture was
concentrated in vacuo. The residue was suspended in sat-
urated aqueous sodium bicarbonate and stirred for 4 h.
The precipitate was filtered and washed with water and
diethyl ether to provide 1.78 g (48%) of 9 as a tan solid,
5.1.11. 7-(2-Methoxyethoxy)-4-oxo-1,4-dihydro-3-quino-
linecarbonitrile (12). A mixture of sodium hydride
(500 mg of a 60% dispersion in mineral oil, 12.5 mmol)
and 8 (1.30 g, 6.9 mmol) in 2-methoxyethanol (30 mL)
was heated at reflux overnight. Additional sodium hy-
dride (250 mg of a 60% dispersion in mineral oil,
6.25 mmol) was added and the reaction mixture was
heated at reflux overnight. Additional sodium hydride
(250 mg of a 60% dispersion in mineral oil, 6.25 mmol)
was added and the reaction mixture was heated at reflux
for 8 h. The reaction mixture was cooled to room tem-
perature and partitioned between ethyl acetate and sat-
urated aqueous sodium bicarbonate. The basic layer was
acidified with aqueous hydrochloric acid and the resul-
tant solid was collected by filtration to provide 1.05 g
1
(62%) of 12 as a white solid, mp >250 ꢁC. H NMR
(300 MHz, DMSO-d6) d 3.32 (s, 3H), 3.70 (m, 2H),
4.21 (m, 2H), 7.02 (s, 1H), 7.08 (d, J = 9 Hz, 1H), 8.03
(d, J = 9 Hz, 1H), 8.61 (s, 1H), 12.60 (br s, 1H); MS
243.1 (MꢀH)ꢀ Analysis for C13H12N2O3Æ0.25 H2O:
calcd C, 62.77; H, 5.07; N, 11.26. Found: C, 62.53; H,
4.68; N, 11.22.
1
mp 199–201 ꢁC. H NMR (400 MHz, DMSO-d6) d 3.83
(s, 3H), 7.12 (s, 1H), 7.44 (m, 1H), 7.49 (d, J = 10 Hz,
1H), 7.60 (s, 1H), 8.37 (s, 1H), 8.53 (s, 1H); MS 360.0
(MꢀH)ꢀ. Analysis for C17H10Cl2FN3 OÆ0.4 H2O:
calcd C, 55.28; H, 2.95; N, 11.38. Found: C, 55.45; H,
2.98; N, 11.13.
5.1.12. 4-Chloro-7-(2-methoxyethoxy)-3-quinolinecarbo-
nitrile (13). A thick suspension of 12 (800 mg,
5.1.9. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[3-(4-
methyl)piperazin-1-yl]propoxy]-3-quinolinecarbonitrile (10).
To a solution of 3-(4-methylpiperazin-1-yl)propanol
(174 mg, 1.1 mmol) in 7 mL of dimethylformamide at
room temperature was added sodium hydride (220 mg
of a 60% dispersion in mineral oil, 5.5 mmol) in por-
tions. After the addition was complete, the mixture
was heated at 100 ꢁC for 10 min, then 9 (200 mg,
0.55 mmol) was added, and the resulting mixture was
heated at 125 ꢁC for 23 h. After cooling, the reaction
mixture was concentrated in vacuo and the residue
was treated with saturated aqueous sodium bicarbonate
for 1 h. The precipitate was filtered, washed with water
and air-dried, then purified by preparative thin layer
chromatography, eluting with 15% methanol in dichlo-
romethane. Trituration with a mixture of diethyl ether
and hexane (1:1) provided 71 mg (26%) of 10 as a light
3.28 mmol) in 10 mL of thionyl chloride and a catalytic
amount of dimethylformamide was heated at reflux for
1 h. The reaction mixture was cooled to room tempera-
ture and concentrated in vacuo. Toluene was added and
the solids were collected by filtration to provide 748 mg
1
(87%) of 13 as an off-white solid, mp 143–145 ꢁC. H
NMR (400 MHz, TFA/DMSO-d6) d 3.34 (s, 3H), 3.72
(m, 2H), 4.22 (m, 2H), 7.09 (m, 2H), 8.05 (d,
J = 9.5 Hz, 1H), 8.65 (s, 1H), MS 263.2 (MꢀH)+.
5.1.13. 4-[(2,4-Dichlorophenyl)amino]-7-(2-methoxyeth-
oxy)-3-quinolinecarbonitrile (14).
A mixture of 13
(262 mg, 1.0 mmol), 2,4-dichloroaniline (195 mg,
1.2 mmol), and pyridine hydrochloride (140 mg,
1.2 mmol) in 10 mL of 2-ethoxyethanol was heated at re-
flux for 30 min. The reaction mixture was cooled to
room temperature, partitioned between ethyl acetate
and saturated aqueous sodium bicarbonate. The organic
layer was washed with a 1:1 mixture of saturated aque-
ous sodium bicarbonate and 5 N sodium hydroxide. The
organic layer was dried over magnesium sulfate, filtered,
and concentrated in vacuo. Purification by column chro-
matography, eluting with a gradient of 1:1 ethyl acetate:
1
tan solid, mp 154–156 ꢁC. H NMR (400 MHz, TFA/
DMSO-d6) d 2.25 (m, 2H), 2.92 (s, 3H), 3.25–3.90 (com-
plex m, 10H), 3.88 (s, 3H), 4.32 (m, 4H), 7.43 (s, 1H),
7.52–7.63 (complex m, 2H), 7.87 (s, 1H), 8.69 (s, 1H),
9.14 (s, 1H); MS 497.9 (MꢀH)ꢀ. Analysis for C25H27
Cl2N5O2Æ0.8 H2O: calcd C, 58.32; H, 5.60; N, 13.60.
Found: C, 58.32; H, 5.30; N, 13.28.

D. H. Boschelli et al. / Bioorg. Med. Chem. 16 (2008) 405–412
411
hexane to all ethyl acetate provided 103 mg (26%) of 14,
mp 144–145 ꢁC. 1H NMR (400 MHz, TFA/DMSO-d6) d
3.35 (s, 3H), 3.77 (m, 2H), 4.38 (m, 2H), 7.40 (s, 1H),
7.60–7.65 (m, 2H), 7.73 (d, J = 9 Hz, 1H), 7.92 (s, 1H),
8.67 (d, J = 9Hz, 1H), 9.16 (s, 1H); MS 388.0 (MꢀH)ꢀ.
Analysis for C19H15Cl2N3O2: calcd C, 58.78; H, 3.89; N,
10.82. Found: C, 58.86; H, 3.90; N, 10.76.
amine in 8% yield as a white solid, mp 165–167 ꢁC, fol-
lowing flash column chromatography eluting with 30%
methanol in dichloromethane. 1H NMR (400 MHz,
DMSO-d6) d 1.76 (m, 2H), 2.17 (s, 6H), 2.33 (t,
J = 6 Hz, 2H), 2.90 (s, 3H), 3.26 (m, 2H), 3.84 (s, 3H),
3.97 (s, 3H), 6.37 (s, 1H), 6.77 (s, 1H), 7.21 (s, 1H),
7.63 (s, 1H), 7.70 (s, 1H), 8.30 (s, 1H), 9.27 (s, 1H);
MS 474.1 (MꢀH)+. Analysis for C23H25Cl2N5O2Æ1.0
H2O: calcd C, 56.10; H, 5.53; N, 14.22. Found: C,
55.97; H, 5.68; N, 14.23. Via the procedure used to pre-
pare 15 (use of 1-methyl-2-pyrrolidinone as solvent), 18
was obtained from 2 and 3-dimethylamino-1-propyl-
amine in 44% yield as a white solid, mp 163–165 ꢁC, fol-
lowing flash column chromatography eluting with a
gradient of 5% methanol in dichloromethane to 1%
aqueous ammonium hydroxide in 25% methanol in
dichloromethane. Analysis for C23H25Cl2N5O2Æ1.4
H2O: calcd C, 55.29; H, 5.61; N, 14.02. Found: C,
55.51; H, 5.54; N, 14.01.
5.1.14. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-meth-
oxy-7-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-quino-
linecarbonitrile (15). A mixture of 2 (200 mg, 0.51mmol)
and 1-(3-aminopropyl)-4-methylpiperazine (512 mg,
3.25 mmol) in 1.0 mL of 1-methyl-2-pyrrolidinone was
heated at 105 ꢁC for 29 h. The reaction mixture was
cooled to room temperature and treated with saturated
aqueous sodium bicarbonate for 1 h. The precipitate
was filtered, washed with water, and air-dried, then puri-
fied by flash chromatography, eluting with a gradient of
5% methanol in dichloromethane to 25% methanol in
dichloromethane. Trituration with ethyl ether containing
several drops of dichloromethane provided 158 mg (59%)
5.1.18. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-{[3-
(dimethylamino)propyl]-(methyl)amino]-6-methoxy-3-quin-
olinecarbonitrile (19). Via the procedure used to prepare
16, 19 was obtained from 2 and N,N,N0-trimethyl-1,3-
propanediamine in 27% yield as a light yellow solid, mp
1
of 15 as an off-white solid, mp 215–217 ꢁC. H NMR
(400 MHz, DMSO-d6) d 1.80 (m, 2H), 2.20 (m, 2H),
2.92–2.49 (complex m, 10H), 3.28 (s, 3H), 3.84 (s, 3H),
3.99 (s, 3H), 6.68 (s, 1H), 6.76 (s, 1H), 7.22 (s, 1H), 7.64
(s, 1H), 7.70 (s, 1H), 8.30 (s, 1H), 9.29 (s, 1H); MS 529.2
(MꢀH)+. Analysis for C26H30Cl2N6O2: calcd C, 58.98;
H, 5.71; N, 15.87. Found: C, 59.09; H, 5.77; N, 15.70.
1
116–117 ꢁC. H NMR (400 MHz, DMSO-d6) d 1.68 (m,
2H), 2.10 (s, 6H), 2.21 (t, J = 7 Hz, 2H), 2.90 (s, 3H),
3.85 (s, 3H), 3.99 (s, 3H), 7.10 (s, 1H), 7.27 (s, 1H),
7.72 (s, 1H), 8.33 (s, 1H), 9.51 (s, 1H); MS 486.2
(MꢀH)ꢀ. Analysis for C24H27Cl2N5O2: calcd C, 59.02;
H, 5.57; N, 14.34. Found: C, 58.89; H, 5.67; N, 13.94.
5.1.15. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-meth-
oxy-7-[(2-methoxyethylamino]-3-quinolinecarbonitrile (16).
A mixture of 2 (250 mg, 0.64 mmol) and 2-methoxyethyl-
amine (1 mL) was heated at 105 ꢁC in a sealed tube for
6 h. The reaction mixture was cooled to room tempera-
ture, diluted with ethyl acetate, and washed with brine.
The organic layer was dried over sodium sulfate, filtered,
and concentrated. The residue was stirred with ethyl ace-
tate then filtered to give 170 mg (45%) of 16 as a white so-
Acknowledgments
The authors acknowledge the Wyeth Analytical Chemi-
cal Technology Department for the spectral data and
pharmaceutical profiling results, Dr. Ana Carolina Bar-
rios Sosa for the repreparation of 18, the Wyeth Drug
Safety and Metabolism Department for the nude mouse
microsome stability and plasma level determinations,
members of the Wyeth Oncology Department for the
kinase profiling data and Carlo Etienne for assistance
with the xenograft studies. We also thank Drs. Dennis
Powell, Kim Arndt, Jay Gibbons, Phil Frost and Tarek
Mansour for their support.
1
lid, mp 165–166 ꢁC. H NMR (400 MHz, DMSO-d6) d
3.30 (s, 3H), 3.42 (m, 2H), 3.59 (t, J = 6 Hz, 2H), 3.84
(s, 3H), 3.97 (s, 3H), 5.90 (s, 1H), 6.84 (s, 1H), 7.22 (s,
1H), 7.66 (s, 1H), 7.70 (s, 1H), 8.30 (s, 1H), 9.32 (s,
1H); MS 445.1 (MꢀH)ꢀ. Analysis for C21H20Cl2N4O3:
calcd C, 56.39; H, 4.51; N, 12.53. Found: C, 56.11; H,
4.37; N, 12.17.
5.1.16. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-meth-
oxy-7-[(3-morpholin-4-ylpropyl)amino]-3-quinolinecar-
bonitrile (17). Via the procedure used to prepare 15,
17 was obtained from 2 and 4-(3-aminopropyl)morphol-
ine in 59% yield as an off-white solid, mp 220–221 ꢁC.
1H NMR (400 MHz, DMSO-d6) d 1.80 (m, 2H), 3.35–
2.48 (complex m, 6H), 3.24–3.35 (m, 2H), 3.36 (m, 4H),
3.84 (s, 3H), 3.98 (s, 3H), 7.33 (s, 1H), 6.60 (s, 1H), 6.79
(s, 1H), 7.21 (s, 1H), 7.65 (s, 1H), 7.70 (s, 1H), 8.30 (s,
1H), 9.28 (s, 1H); MS 516.1 (MꢀH)+. Analysis for
C25H27Cl2N5O3: calcd C, 58.14; H, 5.27; N, 13.56. Found:
C, 58.28; H, 5.40; N, 13.67.
References and notes
1. Schwartzberg, P. L. Oncogene 1998, 17, 1463.
2. Frame, M. C. Biochim. Biophys. Acta 2002, 1602, 114.
3. Parsons, S. J.; Parsons, J. T. Oncogene 2004, 23, 7906.
4. Summy, J. M.; Gallick, G. E. Clin. Cancer Res. 2006, 12,
1398.
5. Alvarez, R. H.; Kantarjian, H. M.; Cortes, J. E. Cancer
2006, 107, 1918.
6. Chen, T.; George, J. A.; Taylor, C. C. Anti-Cancer Drugs
2006, 17, 123.
7. Mitra, S. K.; Schlaepfer, D. D. Curr. Opin. Cell Biol. 2006,
18, 516.
8. Avizienyte, E.; Wyke, A. W.; Jones, R. J.; McLean, G. W.;
Westhoff, M. A.; Brunton, V. G.; Frame, M. C. Nat. Cell
Biol. 2002, 4, 632.
5.1.17. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-{[3-
(dimethylamino)propyl]amino}-6-methoxy-3-quinolinecar-
bonitrile (18). Via the procedure used to prepare 16, 18
was obtained from 2 and 3-dimethylamino-1-propyl-

412
D. H. Boschelli et al. / Bioorg. Med. Chem. 16 (2008) 405–412
9. Irby, R. B.; Yeatman, T. J. Cancer Res. 2002, 62, 2699.
17. Golas, J. M.; Lucas, J.; Etienne, C.; Golas, J.; Discafani,
C.; Sridharan, L.; Boghaert, E.; Arndt, K.; Ye, F.;
Boschelli, D. H.; Li, F.; Titsch, C.; Huselton, C.; Chau-
dhary, I.; Boschelli, F. Cancer Res. 2005, 65, 5358.
18. Boschelli, D. H.; Wang, Y. D.; Ye, F.; Wu, B.; Zhang, N.;
Dutia, M.; Powell, D. W.; Wissner, A.; Arndt, K.; Weber,
J. M.; Boschelli, F. J. Med. Chem. 2001, 44, 822.
19. Boschelli, D. H.; Ye, F.; Wang, Y. D.; Dutia, M.;
Johnson, S. L.; Wu, B.; Miller, K.; Powell, D. W.;
Yaczko, D.; Young, M.; Tischler, M.; Arndt, K.; Disca-
fani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.;
Weber, J. M.; Boschelli, F. J. Med. Chem. 2001, 44, 3965.
20. Boschelli, D. H.; Ye, F.; Wu, B.; Wang, Y. D.; Barrios
Sosa, A. C.; Yaczko, D.; Powell, D.; Golas, J. M.; Lucas,
J.; Boschelli, F. Bioorg. Med. Chem. Lett. 2003, 13, 3797.
21. Boschelli, D. H.; Wang, Y. D.; Johnson, S.; Wu, B.; Ye,
F.; Barrios Sosa, A. C.; Golas, J. M.; Boschelli, F. J. Med.
Chem. 2004, 47, 1599.
22. Sutherland, K. W.; Feigelson, G. B.; Boschelli, D. H.;
Blum, D. M.; Strong, H. L. US Patent Application
2005043537, 2005.
23. Boschelli, D. H.; Wu, B.; Ye, F.; Wang, Y.; Golas, J. M.;
Lucas, J.; Boschelli, F. J. Med. Chem. 2006, 49, 7868.
24. Boschelli, D. H.; Wang, Y. D.; Johnson, S. L.; Berger, D.
M. US Patent 6780996, 2004.
25. For the displacement of the 7-fluoro group of a related 3-
quinolinecarbonitrile, see: Dutia, M.; Berger, D. M.;
Wang, Y.; Torres, N.; Abrous, L.; Powell, D. W.; Mallon,
R.; Wojiciechowicz, D.; Kim, S.; Feldberg, L.; Collins, K.
Abstracts of Papers, 230th ACS National Meeting, MEDI-
409, 2005.
26. For the Src enzyme assay, the IC50 values represent means
of two separate determinations with typical variations of
less than 30% between replicate values. For the Src cell
assay, compounds 7, 11, 14–16, and 19 were tested one
time in an IC50 determination via a 11 point titration. The
IC50 values for the other compounds represent means of at
least two separate determinations with typical variations
of less than 40% between replicate values.
10. Klutchko, S. R.; Hamby, J. M.; Boschelli, D. H.; Wu, Z.;
Kraker, A. J.; Amar, A. M.; Hartl, B. G.; Shen, C.; Klohs,
W. D.; Steinkampf, R. W.; Driscoll, D. L.; Nelson, J. M.;
Elliott, W. L.; Roberts, B. J.; Stoner, C. L.; Vincent, P.
W.; Dykes, D. J.; Panek, R. L.; Lu, G. H.; Major, T. C.;
Dahring, T. K.; Hallak, H.; Bradford, L. A.; Showalter,
H. D. H.; Doherty, A. M. J. Med. Chem. 1998, 41, 3276.
11. Rucci, N.; Recchia, I.; Angelucci, A.; Alamanou, M.; Del
Fattore, A.; Fortunati, D.; Susa, M.; Fabbro, D.; Bolo-
gna, M.; Teti, A. J. Pharm. Exp. Ther. 2006, 318, 161.
12. Summy, J. M.; Trevino, J. G.; Lesslie, D. P.; Baker, C. H.;
Shakespeare, W. C.; Wang, Y.; Sundaramoorthi, R.;
Metcalf, C. A., 3rd; Keats, J. A.; Sawyer, T. K.; Gallick,
G. E. Mol. Cancer Ther. 2005, 4, 1900.
13. Hennequin, L. F.; Allen, J.; Breed, J.; Curwen, J.; Fennell,
M.; Green, T. P.; Lambert van der Brempt, C.; Morgentin,
R.; Norman, R. A.; Olivier, A.; Otterbein, L.; Ple, P. A.;
Warin, N.; Costello, G. J. Med. Chem. 2006, 49, 6465.
14. Lombardo, L. J.; Lee, F. Y.; Chen, P.; Norris, D.; Barrish,
J. C.; Behnia, K.; Castaneda, S.; Cornelius, L. A.; Das, J.;
Doweyko, A. M.; Fairchild, C.; Hunt, J. T.; Inigo, I.;
Johnston, K.; Kamath, A.; Kan, D.; Klei, H.; Marathe, P.;
Pang, S.; Peterson, R.; Pitt, S.; Schieven, G. L.; Schmidt,
R. J.; Tokarski, J.; Wen, M. L.; Wityak, J.; Borzilleri, R.
M. J. Med. Chem. 2004, 47, 6658.
15. Noronha, G.; Barrett, K.; Boccia, A.; Brodhag, T.; Cao,
J.; Chow, C. P.; Dneprovskaia, E.; Doukas, J.; Fine, R.;
Gong, X.; Gritzen, C.; Gu, H.; Hanna, E.; Hood, J. D.;
Hu, S.; Kang, X.; Key, J.; Klebansky, B.; Kousba, A.; Li,
G.; Lohse, D.; Mak, C. C.; McPherson, A.; Palanki, M. S.
S.; Pathak, V. P.; Renick, J.; Shi, F.; Soll, R.; Splittgerber,
U.; Stoughton, S.; Tang, S.; Yee, S.; Zeng, B.; Zhao, N.;
Zhu, H. Bioorg. Med. Chem. Lett. 2007, 17, 602.
16. Messersmith, W. A.; Krishnamurthi, S.; Hewes, B. A.;
Zacharchuk, C. M.; Abbas, R.; Martins, P.; Dowling, E.;
Volkert, A.; Martin, E.; Daud, A. I. J. Clin. Oncol., In
ASCO Annual Meeting Proceedings Part I 2007; Vol. 25,
No. 18S, Abstract 3552.