Syntheses and EGFR and HER-2 kinase inhibitory activities of 4-anilinoquinoline-3-carbonitriles: Analogues of three important 4-anilinoquinazolines currently undergoing clinical evaluation as therapeutic antitumor agents

Article abstract of DOI:10.1016/S0960-894X(02)00598-X

The syntheses and biological evaluations of 4-anilinoquinoline-3-carbonitrile analogues of the three clinical lead 4-anilinoquinazolines Iressa, Tarceva, and CI-1033 are described. The EGFR and HER-2 kinase inhibitory activities and the cell growth inhibition of the two series are compared with each other and with the clinical lead EKB-569. Similar activities are observed between these two series.

Full text of DOI:10.1016/S0960-894X(02)00598-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2893–2897
Syntheses and EGFR and HER-2 Kinase Inhibitory Activities of
4-Anilinoquinoline-3-carbonitriles:Analogues of Three Important
4-Anilinoquinazolines Currently Undergoing Clinical Evaluation
as Therapeutic Antitumor Agents
Allan Wissner,* M. Brawner Floyd, Sridhar K. Rabindran, Ramaswamy Nilakantan,
Lee M. Greenberger, RuShen, Yu-Fen Wang and Hwei-RuTsou
Chemical Sciences and Oncology and Immunoinflammatory Research, Wyeth Research, 401 N. Middletown Road, Pearl River,
NY 10965, USA
Received 19 April 2002; accepted 12 July 2002
Abstract—The syntheses and biological evaluations of 4-anilinoquinoline-3-carbonitrile analogues of the three clinical lead 4-anil-
inoquinazolines IressaTM, TarcevaTM, and CI-1033 are described. The EGFR and HER-2 kinase inhibitory activities and the cell
growth inhibition of the two series are compared with each other and with the clinical lead EKB-569. Similar activities are observed
between these two series.
# 2002 Elsevier Science Ltd. All rights reserved.
Receptor protein tyrosine kinases play a key role in
signal transduction pathways that regulate cell division
and differentiation. Overexpression of certain growth
factor receptor kinases such as Epidermal Growth Fac-
tor Receptor (EGFR) as well as the related Human
Epidermal Growth Factor Receptor (HER-2, also
known as erbB-2) are markers for poor prognosis in
many human cancers.1,2 Compounds which inhibit the
kinase activity of EGFR and/or HER-2 after binding of
its cognate ligand, are of potential interest as new ther-
apeutic antitumor agents.3 The middle of the past dec-
ade was marked by the discovery of the
4-anilinoquinazolines, a series of potent and selective
ATP-competitive inhibitors of EGFR and HER-2
kinases.4,5 A number of these inhibitors have, by now,
entered clinical trial.6 One of the first to do so was the
compound IressaTM, 1, developed by the group at
AstraZeneca.7 This compound is currently in Phase III
trial. A second inhibitor, currently under development
by Oncogene Sciences, is TarcevaTM (OSI-774), 2.8 This
compound is also in Phase III trial.
While the above two compounds function as conven-
tional reversible binding inhibitors of the target
enzymes, other groups,9 including ourselves,10 have
been working with irreversible binding inhibitors. These
irreversible inhibitors are believed to function in this
*Corresponding author. Tel.: +1-845-602-3580; fax: +1-845-602-
5561; e-mail: wissnea@wyeth.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00598-X

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A. Wissner et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2893–2897
manner by virtue of the fact that they form a covalent
bond to a Cys residue (Cys 773 in EGFR and Cys 805 in
HER-2) located in the ATP binding pocket of these
enzymes. The Parke Davis group, now part of Pfizer, is
studying CI-1033, 3.11 This compound is now in early
clinical trial.
2-butanone in the presence of the phase transfer catalyst
tri-n-butyl ammonium iodide (TBAI) gave 11. This
could be nitrated in acetic acid selectively to give 12.
Reduction of the nitro group to give 13 followed by
amidine formation using DMF acetal gave intermediate
14. Cyclization to the hydroxyquinoline was accom-
plished by treating 14 with the lithium anion of CH3CN
in THF at À78 ꢀC, quenching with HOAc, and warming
to room temperature. The chloroquinoline 16 was pre-
pared by refluxing 15 in an excess of SOCl2 followed by
an extractive basic workup. Finally, the aniline group
was introduced giving 5 by refluxing 3-chloro-4-fluoro-
aniline and 16 in ethoxyethanol using a catalytic
amount of pyridine hydrochloride.
We recently described the discovery and EGFR kinase
inhibitory activity of a class of 4-anilinoquinoline-3-
carbonitriles.12 These inhibitors were derived, based on
modeling studies, from the 4-anilinoquinazolines. In
subsequent reports, we also described the inhibition of
Src13 and MAP14 kinases by members of this series.
Ultimately, this series was optimized resulting in the
irreversible binding EGFR kinase inhibitor EKB-569,
4.15 We recently initiated a Phase I clinical trial with this
compound.
A similar strategy was used to prepare 6, the cyanoqui-
noline analogue of TarcevaTM. This is shown in Scheme
2. The diol 17 was bis-alkylated with 1-bromo-2-meth-
oxy-ethane using K2CO3 and a catalytic amount of
TBAI in refluxing acetone. Nitration of 18 in acetic acid
was accomplished selectively to give 19. Reduction of
the nitro group using iron powder and HOAc in reflux-
ing EtOH furnished 20. In this case, the amidine 21 was
prepared using DMF and POCl3. This compound was
cyclized to the hydroxyquinoline 22 using the lithium
anion of CH3CN as described above. Chlorinating of 22
was accomplished in refluxing POCl3. The chloro deri-
vative 23 was then reacted with 3-ethynylaniline in
refluxing ethoxyethanol in the presence of a catalytic
amount of pyridine-HCl to give 6 in good yield.
Given the obvious importance of the quinazolines 1–3,
we prepared the corresponding quinoline-3-carbonitrile
analogues of these compounds 5–7. This paper describes
these syntheses and presents the results of a comparison
of the in vitro activities associated with these com-
pounds.
The synthesis of 5, the cyanoquinoline analogue of
IressaTM, is shown in Scheme 1. Fisher esterification of
8 gave 9 in good yield. Alkylation of the hydroxyl group
of 9 with the halide 10 using K2CO3 in refluxing
A different method, that of Bredereck,16 was used to
construct the quinoline-3-carbonitrile ring system of 7,
the analogue of the irreversible binding inhibitor CI-
1033 as shown in Scheme 3. The dimethylformamidine
derivative of 3-methoxyaniline was nitrated under
anhydrous conditions in HOAc to give the intermediate
24. Reaction of 24 with NCCH2CO2Et gave 25 as a
mixture of isomers which on thermal cyclization in
refluxing Dowtherm gave the 4-hydroxyquinoline 26.
The intermediate 26 was then demethylated by heating
in molten pyridine hydrochloride and then realkylated
with tosylate 27 using K2CO3 in DMF at 75 ꢀC to
introduce the 3-carbon side chain and give 28. The
4-chloro substituent was introduced by refluxing in an
excess of POCl3. The 4-anilino group was incorporated
by refluxing 3-chloro-4-fluoroaniline and 29 in iso-
propanol. The aliphatic chloro group of 30 was replaced
with the morpholine group by heating a toluene solu-
tion of the compound with excess morpholine and cat-
alytic quantities of NaI and the phase transfer catalyst
TBAI.
The nitro group was reduced with iron powder and
HOAc in refluxing methanol. Finally, the amino group
of 32 was acylated with acryloyl chloride and Hunig’s
base in THF to introduce the Michael acceptor func-
tional group to give desired inhibitor 7.
Scheme 1. Synthesis of the IressaTM analogue 5: (a) H2SO4, CH3OH,
reflux; (b) TBAI, K2CO3, 2-butanone, reflux; (c) HNO3, HOAc; (d)
H2, Pd/C, EtOAc, EtOH; (e) DMF-DMA; (f) n-BuLi, CH3CN, THF,
À78 ꢀC then HOAc, 25 ꢀC; (g) SOCl2, reflux; (h) EtOCH2CH2OH,
pyridine-HCl (cat), reflux.
The biological results for the quinazoline inhibitors 1–3
and the respective quinoline-3-carbonitrile inhibitors 5–
7 are shown in Table 1. For comparison we also include
data for our own inhibitor 4 (EKB-569). These com-

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2895
Scheme 2. Synthesis of the TarcevaTM analogue 6: (a)
CH3OCH2CH2Br, K2CO3, TBAI, acetone, reflux; (b) HNO3, HOAc,
40 ꢀC; (c) Fe, HOAc, EtOH, reflux; (d) POCl3, DMF, 55 ꢀC (e) n-BuLi,
CH3CN, THF, À78 ꢀC then HOAc, 25 ꢀC; (f) POCl3, reflux; (g) pyri-
dine-HCl (cat), EtOCH2CH2OH, reflux.
Scheme 3. Synthesis of the CI-1033 analogue 7: (a) DMF–DMA; (b)
HNO3, HOAc, Ac2O; (c) NCCH2CO2Et, HOAc, reflux; (d) Dow-
therm, reflux; (e) pyridine-HCl, 210 ꢀC; (f) Cl(CH2)3OTs (27), K2CO3,
DMF, 75 ꢀC; (g) POCl3, reflux; (h) i-PrOH, reflux; (i) morpholine, NaI
(cat), TBAI (cat), toluene, reflux; (j) Fe, HOAc, MeOH, reflux; (k)
acryloyl chloride, i-Pr2NEt, THF, 0 ꢀC.
pounds were evaluated for their ability to inhibit the
autophosphorylation of EGFR and HER-2 kinases
using a solid-phase ELISA assay. We previously poin-
ted out that the IC50 values that we measure in these
kinase assays are routinely higher than determinations
made by other workers and the reasons for this are dis-
cussed in an earlier publication.10a The compounds were
also evaluated for their ability to inhibit the growth of
several cell lines; these data are also shown in Table 1.
Three human carcinoma cell lines were used: A431
(epidermoid) which over-expresses EGFR, SKBR3
(breast) which over-expresses HER-2 and to a lesser
extent EGFR, and SW620 (colon) which is believed not
to express either EGFR or HER-2 to a significant
extent. Full experimental details for these assays have
already been reported.10a
Table 1. EGFR and HER-2 kinase and cell growth inhibition assay results
Compda
Enzyme assays
Cell-based assays
EGFRb (mM)
HER-2b (mM)
A431c (mg/mL)
SKBR3c (mg/mL)
SW620c (mg/mL)
1
5
2
6
3
7
4
0.515
1.04
1.45
0.850
0.074
0.080
0.083
1.604
14.70
18.52
11.75
0.529
1.692
1.229
0.276
0.250
0.608
0.173
0.083
0.120
0.030
0.174
0.332
0.868
0.071
0.102
0.030
0.007
>5
>5
>5
0.680
1.450
0.770
0.317
aAll new compounds were fully characterized by NMR, MS, and elemental analyses; see ref 17.
bConcentration in mM needed to inhibit the autophosphorylation of the cytoplasmic domain of the enzyme by 50% as determined from the dose–
response curve. Values are averages of duplicate determinations.
cDose–response curves were determined at five concentrations. The IC50 values are the concentrations in mg/mL needed to inhibit cell growth by
50% as determined from these curves. Reported IC50 values are averages of at least two determinations.

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A. Wissner et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2893–2897
With respect to the cell assays, it is evident that each
compound is a better inhibitor of the A431 and
SKBR3 cell lines than the SW620 line. This is con-
sistent with the mechanism of cell growth inhibition
being reliant, to some degree, on the target kinases.
The fact that some of these compounds do inhibit the
growth of the SW620 line at higher concentrations
could suggest that this line has some dependence on
EGFR or HER-2 even though these receptors are not
expressed to a significant degree or that these com-
pounds inhibit cell growth by an undefined mechanism
at these concentrations.
On the whole, the activities of the quinazoline inhibitors
compared to those of the respective quinoline-3-carbo-
nitrile inhibitors are similar in both the enzyme and cell
assays. With respect to EGFR kinase inhibition, activ-
ities between related pairs of compounds differ by no
more than 2-fold. A similar situation is evident with
respect to HER-2 inhibition except for the pair 1 and 5
where the quinazoline appears to be a significantly bet-
ter inhibitor of this enzyme than the quinoline-3-carbo-
nitrile. However, this large difference in potency is not
evident in the cell assays. With respect to the cell assays,
again, there is no major difference in activities when
comparing related pairs with IC50’s differing no more
than 3-fold with the exception of the pair 2 and 6 where,
in this case, the quinoline-3-carbonitrile 6 is significantly
more potent than the related quinazoline 2. There is a
trend suggesting that the irreversible binding inhibitors
3, 4, and 7 appear to be somewhat more potent inhibi-
tors of the enzymes and of cell growth compared to the
reversible binding inhibitors 1, 2, 5, and 6.
In our earlier work,12 we proposed binding models for
both the quinazoline and quinoline-3-carbonitrile class
of inhibitors at the ATP binding pocket of EGFR using
a homology model of the enzyme which was constructed
based on two other kinases, FGF Receptor-1 for the N-
terminal lobe and Hematopoietic Cell Kinase (HcK) for
the C-terminal lobe. With these binding models, we sug-
gested that these two types of inhibitors bind in a very
similar manner where the N3 atom of the quinazoline
inhibitor interacts with a bridging water molecule which,
in turn, interacts with a residue on the protein backbone
(Thr 830). This is similar to the situation that has been
observed for a 4-anilinoquinazoline complexed to P38-
MAP kinase.18 For the quinoline-3-carbonitrile based
inhibitors, we proposed that this water molecule is dis-
placed and the nitrogen atom of the cyano group interacts
with this same residue. In essence, we are suggesting that
the carbocyano group of the cyanoquinoline is bioisos-
teric with the azomethine group of the quinazoline
hydrogen bonded to the water molecule. Such a situa-
tion has actually been demonstrated with an unrelated
enzyme.19 In addition, given the electron withdrawing
properties of a cyano group, the charge distribution
within the quinoline-3-carbonitrile ring system was
shown to be similar to that of the quinazoline ring sys-
tem with its H-bonded water molecule. Continuing with
the same theme, we built models for the quinazolines 1–3
and their respective cyanoquinoline counterparts 5–7
complexed to EGFR kinase. We docked each compound
into the ATP-binding site in a manner similar to our pre-
vious work. The complexes were energy minimized using
the CharmM forcefield as implemented in QuantaTM
software.20 As in our previous work, we allowed the entire
Figure 1. Binding models of 1–3 and the quinoline-3-carbonitrile
counterparts 5–7. (a) Overlap of 1 (cyan), and 5 (red). (b) Overlap of 2
(cyan), and 6 (red). (c) Overlap of 3 (cyan) and 7 (red). In each case, note
the H-bond to Met 769 and the water-bridged H-bond to Thr 830. The
hydrogen-bonds between the quinoline-3-carbonitrile N1 and Met 769
are shown in magenta, while the other hydrogen bonds are in yellow.

A. Wissner et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2893–2897
2897
system of protein, ligand, and water molecules to move
during minimization. As one might expect, the binding
models of the quinazoline and quinoline-3-carbonitrile
versions were very similar in each case. Figure 1 shows
the three pairs of models. In each case, the N1 atom of
the quinazoline is hydrogen-bonded to the backbone
nitrogen of Met 769, while the N3 atom is hydrogen-
bonded to the sidechain hydroxyl of Thr 830 via a water
molecule. In the quinoline-3-carbonitrile counterparts,
the N1 atom is similarly hydrogen-bonded to Met 769
while the water molecule is displaced by the cyano group
with the nitrogen atom of that group within a distance
where it can interact with the Thr residue.
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11. (a) Slichenmyer, W. J.; Elliott, W. L.; Fry, D. W. Seminars
Oncol. 2001, 28, 80. (b) McNamara, D. J. Abstracts of Papers,
222nd ACS National Meeting, Chicago, IL, USA, Aug 26–30,
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12. Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B.,
Jr.; Greenberger, L. M.; Gruber, B. C.; Johnson, B. D.;
Mamuya, N.; Nilakantan, R.; Reich, M. F.; Shen, R.; Tsou,
H.-R.; Upeslacis, E.; Wang, Y.-F.; Wu, B.; Ye, F.; Zhang, N.
J. Med. Chem. 2000, 43, 3244.
13. (a) Wang, Y. D.; Miller, K.; Boschelli, D. H.; Ye, F.; Wu,
B.; Floyd, M. B.; Powell, D. W.; Wissner, A.; Weber, J. M.;
Boschelli, F. Bioorg. Med. Chem. Lett. 2000, 10, 2477. (b)
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. (c) Boschelli,
D. H.; Ye, F.; Wang, Y. D.; Dutia, M.; Johnson, S. L.; Wu,
B.; Miller, K.; Powell, D. W.; Yaczko, D.; Young, M.; Tisch-
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Given the similar binding modes predicted by the mod-
els for these two classes of inhibitors, the conclusion of
the present study, namely, that quinazoline-based com-
pounds 1–3 have similar inhibitory activities compared
to the respective quinoline-3-carbonitrile compounds
5–7, is not surprising.
Acknowledgements
The authors wish to thank Drs. Philip Frost, Tarek
Mansour, and Janis Upeslacis for their support and
encouragement. We also would like to thank the mem-
bers of the Wyeth Discovery Analytical Chemistry
group for analytical and spectroscopic determinations.
14. (a) Zhang, N.; Wu, B.; Powell, D.; Wissner, A.; Floyd,
M. B.; Kovacs, E. D.; Toral-Barza, L.; Kohler, C. Bioorg. Med.
Chem. Lett. 2000, 10, 2825. (b) Zhang, N.; Wu, B.; Eudy, N.;
Wang, Y.; Ye, F.; Powell, D.; Wissner, A.; Feldberg, L. R.;
Kim, S. C.; Mallon, R.; Kovacs, E. D.; Toral-Barza, L.;
Kohler, C. A. Bioorg. Med. Chem. Lett. 2001, 11, 1407.
15. Torrance, C. J.; Jackson, P. E.; Montgomery, E.; Wissner,
A.; Kinzler, K. W.; Vogelstein, B.; Frost, P.; Discafani, C. M.
Nat. Med. 2000, 6, 1024.
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7.3–7.2 (m, 2H), 4.41 (m, 2H), 4.23 (m, 2H), 4.22 (s, 1H), 3.75
(m, 4H), 3.36 (s, 3H), 3.34 (s, 3H); MS (ESI) m/z 418.1
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J=6.3 Hz, 2H), 3.96 (s, 3H), 3.57 (m, 4H), 2.45 (t, J=7.0 Hz,
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1
(c) For 7: H NMR (DMSO-d6) d 9.73 (s, 1H), 9.57 (s, 1H),
8.93 (s, 1H), 7.47 (m, 1H), 7.45 (s, 1H), 7.40 (d, J=9.1 Hz,
1H), 7.25 (m, 1H), 6.73 (dd, J=17.0, 10.1 Hz, 1H), 6.29 (dd,
J=17.0, 1.9 Hz, 1H), 5.81 (dd, J=10.1, 1.9 Hz, 1H), 4.31 (t,
J=6 Hz, 2H), 3.58 (m, 4H), 2.5–2.4 (m, 6H), 2.01 (m, 2H); MS
(ESI) m/z 510.3, 512.2 (M+H)+. Anal. calcd for
C26H25ClFN5O3 (0.5H2O): C, 60.17; H, 5.05; N, 13.49.
Found: C, 60.07; H, 5.20; N, 13.20.
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