Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases

Article abstract of DOI:10.1016/j.bmcl.2011.06.041

In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors.

Full text of DOI:10.1016/j.bmcl.2011.06.041

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5620–5624
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases
⇑
William J. McClellan , Yujia Dai, Cele Abad-Zapatero, Daniel H. Albert, Jennifer J. Bouska, Keith B. Glaser,
Terry J. Magoc, Patrick A. Marcotte, Donald J. Osterling, Kent D. Stewart, Steven K. Davidsen,
Michael R. Michaelides
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrim-
idine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a
series of potent and selective Aurora inhibitors.
Received 2 May 2011
Revised 7 June 2011
Accepted 10 June 2011
Available online 29 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aurora kinase
Anti-cancer
Thienopyrimidine
Orally bioavailable
Aurora kinases are serine–threonine kinases that are key regu-
lators of mitotic progression. The Aurora kinase protein family con-
sists of three members, designated A, B, and C. Aurora A is essential
for the establishment of the bipolar mitotic spindle and localizes at
the centrosomes and poles of the spindle assembly. The TPX2 pro-
tein binds Aurora A and the complex governs centrosome function
and spindle assembly.1 Aurora B is a chromosomal passenger
protein,2 forming complexes with the inner centromere protein
(INCENP), survivin and borealin3 early in mitosis. During cytokine-
sis, the Aurora B passenger complex localizes to the microtubules
at the spindle equator regulating chromosome alignment, bipolar
attachment and segregation. Aurora B also maintains the localiza-
tion of key checkpoint proteins Mad2 and BubR1 to the kineto-
core.4 Aurora C localizes at the spindle poles late in mitosis and
is thought to have a chromosome passenger function similar to
Aurora B.5 Upregulation and over expression of Aurora A and Aur-
ora B can lead to genetic instability (gain or loss of whole chromo-
somes) by the over phosphorylation of normal cell cycle targets
and the aberrant phosphorylation of cytoplasmic targets.6 The
resultant chromosomal instability is a common feature of many
cancer types.7 Aurora B inhibition by small molecules has been
shown to deregulate cell division but not chromosome duplication
leading to polyploidy and subsequent apoptosis.8 Targeting Aurora
kinases by small molecule intervention has become an attractive
anti-cancer strategy.9
As part of our effort to discover Aurora kinase inhibitors, a high
throughput screen of the Abbott compound collection revealed
that 1 was a potent inhibitor of both Aurora A and Aurora B
(IC50 = 20 and 15 nM, respectively, 100 lM ATP). As we tried to
optimize this pyrrolopyrimidine template, we were interested in
replacing the pyrrolopyrimidine core with a thienopyrimidine
moiety (2), which has been shown by us to be a favorable struc-
tural template for kinase inhibitors (Fig. 1).10 This effort has led
to the identification of a series of potent and orally bioavailable thi-
enopyrimidine based Aurora kinase inhibitors. In this Letter we re-
port their synthesis, structure–activity relationships (SAR) and
in vitro characterization.
First, we prepared several thienopyrimidine analogs of 2 using
the chemistry outlined in Scheme 1. 2-Cyanothioacetamide was
condensed at 50 °C with ethyl bromopyruvate in 4:1 pyridine/ace-
tic acid11 to provide thiophene 3. Cyclization with formamide at
170 °C followed by ester saponification gave rise to the thienopyr-
imidine carboxylic acid 4. Substituted 4-phenoxyanilines were
H
N
O
H
N
O
5
NH2
N
NH2
N
N
N
6
N
O
S
O
R
2
1
⇑
Corresponding author.
E-mail address: william.j.mcclellan@abbott.com (W.J. McClellan).
Figure 1.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.041

W. J. McClellan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5620–5624
5621
Table 1
O
NH2
CO2H
S
Enzymatic Aurora and cellular Aurora (polyploidy) data for compounds of general
structure
CO2Et
Br
NC
H2N
CO2Et
b, c
CN
N
H2N
O2N
S
S
a
O
R
N
3
4
NH2 O
N
N
H
d,e
N
R'
S
F
O
R
O
a
a
Compd
R
R0
IC50 (nM)
EC15 (lM)
R
NH
2 O
H2N
N
N
N
H
Aur A
Aur B
Polyploidy
f
5a
5b
H
4-Me
H
H
25
100
31
6.1
4.5
S
5a,b
NTb
N
NH
8a
8b
8c
8d
8e
8f
H
15
11
36
120
7
NT
NT
5.5
NT
4
>3.0
>0.1
>10
>10
3.7
NH2
N
N
NMe
CO2H
CO2Et
Br
H
NC
H2N
h, b, c
g
N
N
N
3
N
NMe
S
3-Me
4-Me
3-Cl
4-Cl
S
R
6
7a, R = H
7b, R = CH3
N
NMe
N
NMe
R
O
N
NMe
O
27
NT
>3.0
R
NH
S
2 O
a
H2N
N
Assayed in the presence of 100
Ref. 14.
lM ATP concentration, for assay conditions, see
N
H
N
b
Not tested.
N
f
N
8a-f
R'
Scheme 1. Reagents and conditions: (a) AcOH/pyridine = 4/1 (v/v), 50 °C, 43%; (b)
formamide, 170 °C, 36%; (c) LiOH, THF, MeOH, H2O, 65 °C, 79%; (d) substituted
phenol, KF–Al2O3, 18-crown-6, CH3CN, reflux, 37%; (e) Fe, NH4Cl, H2O/EtOH/THF,
85 °C, 38%; (f) HATU, DIPEA, DMF, rt, 61–75%; (g) bromine, CH2Cl2, rt, 94%; (h)
N-TIPS or N-methylpyrazoloboronic acid pinacol ester, Pd(Ph3P)4, Na2CO3, DME,
H2O, microwave,120 °C, 60%.
H
H
N
N
R
O
NH2
S
O
N
N
H
N
R'
prepared by KF-Al2O3/18-crown-6 assisted displacement of fluo-
ride with substituted phenols,12 followed by nitro reduction with
iron powder. An HATU assisted coupling reaction with a variety
of 4-phenoxyanilines gave compounds 5a and b. To further explore
the Aurora inhibitory potency of the thienopyrimidine core, com-
pounds were prepared with pyrazole and N-methyl pyrazole at
C6. Bromide 6 was subjected to Suzuki reactions using the appro-
priate boronic ester. For compound 8a, the TIPS protecting group
was lost during the formamide cyclization step.
Figure 2. Urea containing target molecules for increased potency against Aurora
kinase.
ates, 11 were prepared starting with mono-BOC protected
phenylenediamine. Reaction with various isocyanates followed
by BOC removal with TFA gave the required ureas. HATU coupling
reactions with carboxylic acids 4, 7b, 9 or 10 provided the final
urea containing targets 12a–q.
As shown in Table 1, amide containing thienopyrimidine diphe-
nyl ethers were also potent inhibitors of Aurora A and B. Exhibiting
an IC50 value of 25 nM against Aurora A at 100 lM ATP, compound
Enzyme and cellular activities of the urea containing analogs
against Aurora kinases are shown in Table 2. Confirming our spec-
ulation for increased activity with urea substituents, the series
exhibits consistent Aurora A and B enzyme potency. Also, as we
had hoped, celluar activity as measured by induction of nuclear
polyploidy was improved in most cases. Compounds unsubstituted
at C6 of the thienopyrimidine core and either unsubstituted on the
distal phenyl ring or with the introduction of small substituents
gave very good enzyme and cellular activity. Compounds 12p
and q with morpholino and 4-methylpiperazino substituents at
C6 were only weakly active in the cellular assay. Compound 12i,
with a morpholinomethyl on the distal phenyl ring was also inac-
tive in the cell. With the exception of thiophene 12l and the cyclo-
pentyl analog 12n, replacement of the terminal phenyl with a
small heterocycle (12j, k) or cyclic alkyls (12m) gave reduced en-
zyme and cellular potency.
5a was virtually equipotent to 1. Compounds 8a, b, and e with pyr-
azole substitution at C6 had an IC50 of less than 20 nM against Aur-
ora A. Compounds 8c and e were also potent against Aurora B.
Aurora B inhibition is known to induce nuclear polyploidy.13 The
polyploid morphology occurs following a failed cytokinesis, lead-
ing to greater than 2N chromosome number and eventual apopto-
sis. Induction of nuclear polyploidy is a measure of Aurora cellular
activity and is expressed as EC15 values. In Table 1, polyploidy re-
sults for the diphenyl ether analogs are shown and were found to
be very weak or completely inactive.
Given the well established utility of diphenyl ureas for effective
interaction with the kinase hydrophobic back pocket,15 we were
interested in exploring compounds as shown in Figure 2, hoping
to improve both the Aurora enzyme and cellular activities.
Compounds of this type were prepared as shown in Scheme 2.
Morpholino and 4-methylpiperazinyl substituted carboxylic acids
9 and 10 were prepared from the tetrasubstituted thiophene 6
using a thermal displacement of the bromide, followed by cycliza-
tion with formamide and ester saponification. The urea intermedi-
To rationalize the observed inhibitory activity of these com-
pounds against Aurora A and B, a binding model of 12d to Aurora
A kinase was prepared using a back pocket diaryl urea–inhibitor
complex as template.16 This model (Fig. 3) gave excellent fit of
the urea unit and putative hinge binding thienopyrimidine unit

5622
W. J. McClellan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5620–5624
NH2
CO2H
R'
CO2Et
Br
NC
H2N
a, b, c
N
S
N
S
N
N
6
O
9
R'=
NMe
10 R'=
O
HN
R
N
NH2
NH
H
NH2
4, 7b, 9 or 10
d, e
O
NH2
N
NH
R'
f
O
R
HN
N
BOC
Figure 3. Modeled structure of compound 12d, docked into Aurora A enzyme ATP
binding pocket showing proposed hinge interaction, internal hydrogen bond, urea
hydrogen bond, and back pocket hydrophobic interaction.
NH
S
11 a-h
12 a-q
R= aryl, heteroaryl, cycloalkyl
R'= H,
bonding interactions with the backbone carbonyl group of Glu
211 and the backbone NH of Ala 213 of the Aurora A hinge region,
respectively. A proposed internal hydrogen bond between the
amide carbonyl and the amino group on the pyrimidine in 12d
may help position the diphenyl urea portion of the molecule into
the back pocket of Aurora A for optimal interaction. Lys 162 is posi-
tioned to donate a hydrogen bond to the urea carbonyl. A hydro-
phobic back pocket comprised of Leu 164, Leu 169, and Leu 178
sidechains surrounds the terminal tolyl group. The presence of
the urea-Lys 162 hydrogen bond provides a rationale for the in-
creased potency of ureas 12a and d over the diphenyl ethers 5a
and b, respectively.
Inspite of the encouraging Aurora enzymatic and cellular po-
tency of the urea containing secondary amide linked compounds
12a–q, the series exhibited poor pharmacokinetic properties. Most
compounds tested were characterized by poor solubility, short iv
half lives and low or negligible oral bioavailability, as exemplified
by 12a and c (Table 4).
It has been observed by us in a related series of bi-aryl ureas and
by others17 that increasing the flexibility and reducing the molec-
ular planarity and symmetry can have a positive effect on solubility
and oral bioavailability. Compounds of the type shown in Table 2
were modified in this way by changing the linear, para attachment
of the bi-phenyl urea to a meta attachment. Synthesis of these
compounds is shown in Scheme 3. Carboxylic acid 4 was coupled
with either mono BOC-protected 1,3-phenylenediamine or 3-
BOC-aminomethylaniline to give compounds 17 and 18. Deprotec-
,
,
N
N
N
O
N
NMe
Scheme 2. Reagents and conditions: (a) morpholine or 4-methylpiperazine, 130 °C,
65%; (b) formamide, 170 °C, 36%; (c) LiOH, THF, MeOH, H2O, 65 °C, 79%; (d) RNCO,
CH2Cl2, ꢀ25 °C to rt, 85–95%; (e) TFA, CH2Cl2, 0 °C; (f) HATU, DIPEA, DMF, rt,
61–86%.
Table 2
Enzymatic Aurora and cellular Aurora (polyploidy) data for compounds of general
structure
H
H
N
N
R
O
NH2 O
N
N
H
N
R'
S
a
a
Compd
R0
R
IC50 (nM)
EC15 (nM)
Aur A
Aur B
Polyploidy
12a
12b
12c
12d
12e
12f
H
H
H
H
H
H
H
H
Ph
NTb
8.9
2.1
2.1
1.4
2.6
5.8
14
0.50
0.20
NTb
<0.20
<0.20
<0.20
0.20
0.80
<1.0
17
<1.0
<1.0
<1.0
1.0
2-Me-Ph
3-Me-Ph
4-Me-Ph
3-F-Ph
3-Cl-Ph
3-OMe-Ph
12g
12h
20
68
2-F, 5-CF3-Ph
H
O
N
O
N
H2N
N
12i
H
6.6
0.6
>100
(CH2) NH2
n
a, b
4
12j
12k
12l
12m
12n
H
H
H
H
H
3-Isoxazolo
2-Thiazolo
3-Thiophenyl
Cyclopropyl
Cyclopentyl
5.6
4.1
0.40
19
88
NT
<0.20
0.50
0.20
208
112
<1.0
>300
15
S
N
17 n = 0
18 n = 1
2.7
c
N
12o
3-Me-Ph
15.4
<0.20
102
N
N
N
12p
12q
Ph
14.3
10.9
7.8
2.9
160
R
O
O
NH
H
N
O
(CH2) NH
n
H2N
N
3-Me-Ph
>100
N
a
Assayed in the presence of 100
Ref. 14.
l
M ATP concentration, for assay conditions, see
S
N
b
Not tested.
19
n = 0
20 a-i n = 1
of 12d. This model suggests that these compounds bind to the ATP
binding site of Aurora A in a DFG-out conformation. The amino
group on the pyrimidine and its adjacent sp2 N form hydrogen
Scheme 3. Reagents and conditions: (a) N-BOC-meta-phenylenediamine or 3-BOC
aminomethylaniline, HATU, DIPEA, DMF, rt, 82%; (b) TFA, CH2Cl2, rt, 95%; (c)
substituted phenyl isocyanate, CH2Cl2, 0 °C to rt, 45–55%.

W. J. McClellan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5620–5624
5623
Table 4
Mouse pharmacokinetic data
H
N
H
O
O
N
H2N
N
H2N
N
Compd
iv
t1/2 (h)
iv
iv
po
F (%)
S
S
Vd (L/kg)
Cl (L/h kg)
AUC (lM h)
HN
HN
HN
HN
O
O
N
N
12a
12c
20a
20c
20e
20h
0.53
0.63
2.0
1.7
1.5
1.2
4.7
0.97
3.0
0.21
0.68
1.5
5.2
0.52
1.4
1.0
0.5
21
22
0.36
1.2
12.5
1.7
18.7
8.7
Aur A IC50 820 nM
Aur B 79
Aur A IC50 816 nM
Aur B 69
0.09
0.19
36.0
23.3
16.5
20.0
2.4
Figure 4.
Table 5
Kinase selectivity profile of compound 20h
Table 3
Enzymatic Aurora and cellular Aurora (polyploidy) data for compounds of general
structure
a
Compd 20h IC50
(lM)
Aur A
AurB
Alk
Jak2
p38
<0.003
<0.003
>10.0
>10.0
>10.0
2.9
TrkA
Src
Rock1
KDR
Jnk1a
Gsk3
>10.0
>10.0
>10.0
0.66
>10.0
2.1
H
O
N
(CH2) NH
n
H2N
N
NH
O
S
R
N
Lck
a
a
a
Assayed in the presence of 100
concentration.
lM ATP
Compd
n
R
IC50 (nM)
EC15 (nM)
Aur A
Aur B
Polyploidy
19
0
1
1
1
1
1
1
1
1
1
H
H
NTb
2.5
280
2.0
6.0
27
136
172
6.0
0.2
57
35
3.8
29
0.7
19
1.3
1.0
23
354
2.0
28
5.0
<1.0
3.2
23
19
1.0
1.0
20a
20b
20c
20d
20e
20f
20g
20h
20i
2-CH3
3-CH3
4-CH3
4-CF3
3-Et
2-F
3-F
3-Cl
greatly improved by meta substitution and a one carbon homologa-
tion at the urea point of attachment. These compounds also dis-
played high selectivity for Aurora within the tested kinome.
References and notes
4.6
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Not tested.
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20a–i.
One carbon homologated, para linked compounds were also
investigated. Compounds 21 and 22 (Fig. 4) were prepared analo-
gously as described in Scheme 3. These compounds were found
to be significantly less potent than the parent non-homologated
versions.
Compounds with the meta regiochemistry and one carbon
homologation in most cases exhibited excellent in vitro and cellu-
lar potency. Since compounds in this subseries approached the
limit of detection in the low ATP Aurora assay, testing was done
at the more physiologically relevant 1 mM ATP level (Table 3).
Compounds with the meta attachment and one carbon homolo-
gation also had improved pharmacokinetics compared to the lin-
ear, para linked analogs. These compounds consistently exhibit
good plasma blood levels with oral bioavailabilities often greater
than 10%. Representative compounds are shown in Table 4 along
with the para linked analogs 12a and 12c.
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drugs at varying concentrations were added into duplicate wells containing
cells and culture media (RPMI 1640, 10% fetal calf serum) and incubated at
37°C for 48 h. The plates were then washed with PBS and the adherent cells
fixed by incubating with 3% formalin for 1 h. After washing four times with
PBS, the cells were then stained with Hoechst and subjected to fluorescent
(360i/460e) microscopic high content analysis to determine the effect of test
These urea containing thienopyrimidine amides were highly
selective for the Aurora kinases. To demonstrate the kinase selec-
tive profile of these ureas, the inhibitory activity of 20h against a
number of kinases is listed Table 5.
In summary, we identified an amide containing pyrrolopyrimi-
dine high throughput screening lead for Aurora kinase. The original
hit was then transposed to a thienopyrimidine template. Addition
of a diphenyl urea in place of the initial diphenyl ether led to Aur-
ora inhibitors with potent in vitro enzyme activity. The poor phar-
macokinetic properties of the para linked diphenyl ureas were

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W. J. McClellan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5620–5624
drug on nuclear size. Polyploid cells (P4 N) were defined as those having
nuclear area >750
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16. Cee, V. J.; Cheng, A. C.; Romero, K.; Bellon, S.; Mohr, C.; Whittington, D. A.; Bak,
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