Thienopyridine ureas as dual inhibitors of the VEGF and Aurora kinase families

Article abstract of DOI:10.1016/j.bmcl.2012.03.035

In an effort to identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations.

Full text of DOI:10.1016/j.bmcl.2012.03.035

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3208–3212
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Thienopyridine ureas as dual inhibitors of the VEGF and Aurora kinase families
⇑
Michael L. Curtin , Robin R. Frey, H. Robin Heyman, Niru B. Soni, Patrick A. Marcotte, Lori J. Pease,
Keith B. Glaser, Terrance J. Magoc, Paul Tapang, Daniel H. Albert, Donald J. Osterling, Amanda M. Olson,
Jennifer J. Bouska, Zhiwen Guan, Lee C. Preusser, James S. Polakowski, Kent D. Stewart, Chris Tse,
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 identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen
of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series
of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl
urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles
that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is
currently undergoing Phase I clinical trials in solid and hematological cancer populations.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 17 February 2012
Revised 5 March 2012
Accepted 7 March 2012
Available online 14 March 2012
Keywords:
Aurora kinase inhibitors
KDR kinase inhibitors
Thienopyridine ureas
Pyrazoles
Antitumor activity
ABT-348
The Aurora kinases are a family of serine/threonine kinases that
mediate multiple events in cell division.1 Humans have three Aur-
ora kinases, A, B and C, that are differentially localized and mediate
distinct functions during mitosis. Because the Aurora kinases play a
key role in mitosis and are overexpressed in multiple human tumor
lines, there has been considerable interest in developing Aurora ki-
nase inhibitors as antitumor agents. A number of small-molecule
pan-Aurora kinase inhibitors have been reported and there are sev-
eral compounds currently in Phase I/II clinical trials for cancer.2
Preclinically, it has been shown that pan-Aurora inhibitors repro-
duce the phenotype of Aurora B selective agents and it has been
suggested that the clinical behavior of pan-Aurora inhibitors will
resemble compounds selectively targeting Aurora B rather than
Aurora A.3
The VEGF receptor family of RTKs, most notably VEGFR2 or KDR,
mediates the biological function of vascular endothelial growth
factor (VEGF) which is a regulator of vascular permeability and
an inducer of endothelial cell proliferation, migration and survival.
Accordingly, interruption of the KDR mediated signaling cascade
can provide therapeutic benefit in human cancers as demonstrated
by the FDA approval of the anti-VEGF antibody Avastin™ and four
small molecule KDR kinase inhibitors.4
The established notion of inhibiting multiple kinases involved
in tumor progression with a single small molecule5 and the com-
pelling antitumor effects elicited by multi-targeted KDR kinase
inhibitors such as sunitinib6 and linifanib7 led us to screen Abbott
proprietary KDR kinase inhibitors for activity against a broad panel
of kinases. This screen revealed that the previously disclosed8 thi-
enopyridine urea series of KDR inhibitors possessed modest but
promising Aurora B activity and it was believed that dual inhibitors
of these two enzymes could have unique clinical applications.9
Compound 1 from this series was a potent inhibitor of KDR, both
enzymatically (IC50 = 9 nM)10,11 and cellularly (IC50 = 32 nM),12
and a weak inhibitor of Aurora B, enzymatically (IC50 = 487 nM)10
and cellularly (IC50 = 4200 nM).13,14 Herein is described the effort
to increase the Aurora B inhibitory activity of this series as well
as improve other properties including oral bioavailability and
in vivo antitumor activity. Because established SAR indicated that
substitution of the thienopyridine C7 position and urea terminal
phenyl was allowed and could be varied while maintaining KDR
inhibition, we focused on those two areas of the molecule. This
work led to the discovery of inhibitor 2 (ABT-348), a potent inhib-
itor of Aurora B as well as the VEGF and PDGF families of receptor
tyrosine kinases, which is currently in Phase I clinical trials in solid
and hematological cancer populations (see Fig. 1).
The preparation of 2 is shown in Scheme 1 and exemplifies the
general preparation of the 7-substituted thienopyridine ureas. Su-
zuki coupling of thienopyridine 38 with N-Boc-protected 4-aniline
⇑
Corresponding author.
E-mail address: mike.curtin@abbott.com (M.L. Curtin).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.035

M. L. Curtin et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3208–3212
3209
analogs with potent KDR inhibition while potent Aurora B inhibi-
tion was more difficult to establish. For example, while alkenyl
(7), alkynyl (8) and carboxamide (9) substitution provided potent
inhibition of both KDR and Aurora B, phenyl (10) and phenyl bio-
isosteres including furyl (11) and thiophene (12) failed to give po-
F
H
N
H
N
H
N
H
N
O
NH2
S
O
NH2
S
N
N
7
tent Aurora
B inhibition. Examination of other heteroaryl
3
1
2
substituents at this position revealed that while 3-pyrrole (13)
and 3-pyrazole (14) gave somewhat better Aurora B enzymatic po-
tency than other small heterocycles, the 4-pyrazole (15 and 16)
was uniquely able to provide robust KDR and Aurora B activity.
The SAR of urea phenyl substitution using the (N-meth-
ylpyrazol-4-yl) moiety at C7 is shown in Table 2 which includes
in vivo efficacy. It can be seen that a number of phenyl substituents
provided inhibitors with excellent KDR and Aurora B enzymatic/
cellular potency as well as potent oral activity. More specifically,
2-, 3- and 4-substitution (17, 16, 18) was allowed as was unsubsti-
tuted phenyl (19). The electronic nature of the substituents were
not crucial for enzymatic activity as halides (20–23), methoxyl
(24, 25), and trifluoromethoxyl (26) substituents gave potent com-
pounds; some electron-poor substituents (27) diminished cellular
and in vivo potency. It can be seen that most inhibitors in Table
2 possessed potent activity (ED50 <10 mg/kg) in the UE model;
for comparison, inhibitor 1 was inactive up to 30 mg/kg in this as-
say. Disubstitution of the urea terminal phenyl was also allowed
(data not shown).
(ABT-348)
N
N
HO
Figure 1. Thienopyridine urea kinase inhibitors.
O
B
O
HN
d
N
O
B
NH2
O
NH2
Br
N
5
NH2
N
e
HO
N
N
a,b,c
S
S
4
3
I
The effect of pyrazole substitution on KDR, Aurora B and UE
activity is shown in Table 3. Consistent with the SAR shown in Ta-
ble 1, many pyrazole substituents gave potent KDR inhibitors while
Aurora B activity was less general. For example, while N-methyl
was well tolerated, increasing the bulk of the pyrazole N-alkyl sub-
stituents adversely affected Aurora activity (compare 21, 28, 29
and 30). However, if one or more heteroatoms were present in this
substituent, Aurora activity, both enzymatic and cellular, was re-
stored. This included sulfones (31), tertiary amines (32), amides
(33), alcohols (2, 34) or combinations of these moieties (35). It
should be mentioned that attempts to improve the generally low
aqueous solubility of these compounds with pyrazole substituents
bearing tertiary amines (e.g., 32 and 35) ultimately failed due to
high clearance and low oral bioavailability in vivo as reflected in
a lack of UE assay activity (e.g., 32).
F
NH2
H
N
H
NH2
S
N
N
O
NH2
S
f
N
6
2
N
N
HO
N
N
HO
Scheme 1. Reagents: (a) tert-Butyl 4-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-
yl)phenylcarbamate, cat. Pd(PPh3)4, Na2CO3, DME/H2O, 90 °C; (b) N-iodosuccini-
mide, DMF; (c) TFA, 70% (three steps); (d) ethylene carbonate, Cs2CO3, neat, 100 °C,
55%; (e) PdCl2(dppf), Na2CO3, THF/MeOH/H2O, 80 °C, 80%; (f) 3-fluorophenyl
isocyanate, NMM, DMF, À20 °C, 80%.
Modeling of thienopyridine 2 in an inactive conformation of
Aurora B kinase was carried out to rationalize this SAR and the re-
sults are shown in Fig. 2a. In addition to the canonical hinge and
back pocket interactions, the C7 substituent projects into a sol-
vent-accessible extended-hinge region, that is flanked by hydro-
phobic residues Leu93 and Gly160 that narrow the available
volume for substituents. This model agrees with the observation
that large or branched substituents are less well accommodated,
and that heteroatoms are adequately solvated. While the origin
of the C7 substitution-based boost in Aurora B potency is not en-
tirely clear, the pyrazole appears to optimally fit the ‘extended-
hinge’ region of this enzyme as depicted in Fig. 2b.
Safety testing indicated that some analogs were potent inhibi-
tors of Cyp3A4,16 including time-dependent inhibition,17 while
others were devoid of this activity. In general, para-substitution
of the diphenyl urea or increasing the bulk of the pyrazole substi-
tuent would decrease or eliminate Cyp3A4 inhibition altogether.
For example, inhibitor 21 was a moderate inhibitor of Cyp3A4
boronate followed by selective C7 iodination and N-deprotection
provided iodide 4.15 Suzuki coupling of 4 with N-(2-hydroxy-
ethyl)pyrazole boronate 5, prepared in one step from the N-unsub-
stituted pyrazole boronate, gave aniline 6. Treatment of 6 with a
small excess (1.05 equiv) of isocyanate at low temperature
(À20 °C), to avoid bis-urea formation, provided compound 2 in
45% yield over the five linear steps. Iodide 4 was a versatile inter-
mediate that could be coupled to a variety of alkenyl, alkynyl, aryl
and heteroaryl boronate esters/boronic acids as well as carbon
monoxide to give the corresponding methyl ester.
The prepared analogs were assessed for enzymatic activity
against a panel of kinases including KDR, Aurora A and B, Flt-1,
Flt-3, cKit, CSF1R and FGFR; compounds with sufficient KDR and
Aurora B enzymatic activity (<50 nM) were examined for cellular
activity in a KDR autophosphorylation assay and polyploidy induc-
tion assay (Aurora B activity). Inhibitors with potent cellular activ-
ity in both assays (<50 nM) were tested in an estradiol-induced
mouse uterine edema model11 which evaluated acute in vivo
KDR activity after oral dosing. Selected inhibitors were then as-
sessed in xenograft mouse tumor models with cancer cell lines
such as HT1080 (human fibrosarcoma) and RS4;11 (human
leukemia).
(IC50 7.9
(IC50 2.7
l
M) that was more potent after a 15 min preincubation
l
M) whereas analogs such as 25, 28, 34 and 2 had only
weak activity (<20%) up to 10
dependency.
lM (2, IC50 >30 lM) with no time
A summary of the mouse pharmacokinetic data for several
inhibitors is shown in Table 4. In contrast to earlier compounds
such as 1, the C7 pyrazole-substituted analogs were generally char-
acterized by improved half-lives, relatively low clearance and good
The effect of C7 substitution on enzymatic and cellular KDR and
Aurora B inhibitory activity using the 3-methylphenyl urea is
shown in Table 1. In general, a variety of C7 substituents provided

3210
M. L. Curtin et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3208–3212
Table 1
SAR of C7 substitution
H
H
N
N
O
NH2
S
N
R
13
Compd
R
IC50 (nM)
EC15 polyploidy (nM)
12
KDR10
9
KDRcell
Aur B10
487
1
7
H
32
4140
87
6
7
22
80
11
MeHN
O
O
8
8
141
Me2N
MeHN
9
2
1
13
46
10
Phenyl
13
33
3280
Not tested
11
12
8
9
14
31
100
179
>300
>300
O
S
13
14
15
16
4
6
2
3
1
3
68
66
8
389
161
31
N
H
N
N
H
14
14
N
N
H
16
55
N
N
Table 2
SAR of urea terminal phenyl substitution
H
N
R
H
N
O
NH2
N
S
N
N
Compd
R
IC50 (nM)
EC15 (nM) Polyploidy13
ED50 (mg/kg, po) uterine edema11
KDR10
Aur B10
16
17
18
19
20
21
22
23
24
25
26
27
3-Me
2-Me
4-Me
H
2-F
3-F
3-Cl
4-Cl
2-OMe
4-OMe
4-OCF3
3-CONH2
3
2
6
3
3
3
7
8
6
6
3
2
16
8
50
6
18
9
70
48
52
114
17
23
55
2
64
9
<30
6
18
27
>100
57
12
1.0
3.5
1.0
0.3
1.1
0.3
2.0
0.3
8.0
1.3
2.6
>10
413

M. L. Curtin et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3208–3212
3211
Table 3
SAR of pyrazole substitution
F
H
N
H
N
O
NH2
S
N
N
R
N
Compd
R
IC50 (nM)
EC15 (nM) polyploidy13
ED50 (mg/kg, po) uterine edema11
KDR10
Aur B10
21
28
29
30
Me
3
15
25
25
9
31
177
529
6
4
0.3
1.5
1.1
n-Pr
i-Bu
i-Pent
355
Not tested
Not tested
31
32
33
1
4
6
11
4
<3
1
10
>10
0.4
SO2
N
8
O
N
5
2
2
3
7
1
12
2
3.2
1.2
HO
HO
34
35
2
2
<1
Not tested
N
HO
Figure 2. (a) Model of thienopyridine 2 bound to active site of Aurora B (inactive conformation) with hinge hydrogen bonds to Glu155 C@O and Ala157 N–H and urea
hydrogen bond to Asp218 N–H. (b) N-(2-ethoxy)pyrazole moiety of 2 (wire-mesh surface) occupying the ‘extended-hinge’ region of Aurora B. Residues Leu93 (top) and
Gly160 (bottom) form the surface (green) that flanks the pyrazole unit.
oral bioavailability. Consistent with the uterine edema screening
data, these inhibitors provided significant exposure with oral dos-
ing and were potent inhibitors of tumor growth in murine models.
For example, compounds 16, 21 and 28 demonstrated significant
tumor growth inhibition (>70%) in the HT1080 model when dosed
orally at 10 mg/kg, daily.
In general this series of compounds exhibited some degree of
hERG blockade18 as measured in a patch clamp assay and efforts
to completely eliminate this activity while retaining the other re-
quired properties were unsuccessful. For example, compound 2
had an IC50 of 1
dog, this analog prolonged QT by 11 ms at a plasma concentration
l
M19 in this assay. However, in the anesthetized

3212
M. L. Curtin et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3208–3212
Table 4
References and notes
Mouse pharmacokinetic data of selected compoundsa
1. Marumoto, T.; Zhang, D.; Saya, H. Nat. Rev. Cancer 2005, 5, 42.
2. Matthews, N.; Visintin, C.; Hartzoulakis, B.; Jarvis, A.; Selwood, D. L. Expert Rev.
Anticancer Ther. 2006, 6, 109.
3. (a) Yang, H.; Burke, T.; Dempsey, J.; Diaz, B.; Collins, E.; Toth, J.; Beckmann, R.;
Ye, X. FEBS Lett. 2005, 579, 3385; (b) Girdler, F.; Gascoigne, K. E.; Eyers, P. A.;
Hartmuth, S.; Crafter, C.; Foote, K. M.; Keen, N. J.; Taylor, S. S. J. Cell Sci. 2006,
119, 3664.
4. For a review of VEGF biology, see: Ferrara, N.; Gerber, H. P.; LeCouter, J. Nat.
Med. 2003, 9, 669; For an overview of the most recently approved KDR
inhibitor, see: Commander, H.; Whiteside, G.; Perry, C. Drugs 2011, 71, 1355.
5. Fojo, T. Oncologist 2008, 13, 277.
Compd
iv (3 mg/kg)
po (10 mg/kg)
F (%)
AUC (
lgÁh/mL)
t1/2 (h)
VD (L/kg)
Cl (L/hÁkg)
1
16
21
25
28
34
2
0.3
1.5
3.6
1.3
0.8
2.9
4.7
1.7
2.3
0.9
1.5
1.2
1.2
1.7
4.0
1.1
0.2
0.9
1.0
0.3
0.3
0.45
5.64
44.0
5.22
5.26
14.6
18.6
18
59
78
44
52
42
47
6. Mendel, D. B.; Laird, A. D.; Xin, X.; Louie, S. G.; Christensen, J. G.; Li, G.; Schreck,
R. E.; Abrams, T. J.; Ngai, T. J.; Lee, L. B.; Murray, L. J.; Carver, J.; Chan, E.; Moss, K.
G.; Haznedar, J. O.; Sukbuntherng, J.; Blake, R. A.; Sun, L.; Tang, C.; Miller, T.;
Shirazian, S.; McMahon, G.; Cherrington, J. M. Clin. Cancer Res. 2003, 9, 327.
7. Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bauch, J. L.; Bouska, J. J.;
Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.; Harris, C. M.; Hickman, D.; Guo, J.; Li,
J.; Marcotte, P. A.; Marsh, K. C.; Moskey, M. D.; Martin, R. L.; Olson, A. M.;
Osterling, D. J.; Pease, L. P.; Soni, N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.;
Reuter, D. R.; Davidsen, S. K.; Michaelides, M. R. J. Med. Chem. 2007, 50, 1584.
8. Heyman, H. R.; Frey, R. R.; Bousquet, P. F.; Cunha, G. A.; Moskey, M. D.; Ahmed,
A. A.; Soni, N. B.; Marcotte, P. A.; Pease, L. J.; Glaser, K. B.; Yates, M.; Bouska, J. J.;
Albert, D. H.; Black-Schaefer, C. L.; Dandliker, P. J.; Stewart, K. D.; Rafferty, P.;
Davidsen, S. K.; Micahelides, M. R.; Curtin, M. L. Bioorg. Med. Chem. Lett. 2007,
17, 1246.
a
PK studies in CD1(ICR) males.
Table 5
Kinase inhibition profile of 2
a
a
Kinase
IC50 (nM)
Kinase
IC50 (nM)
KDR
4
2
12
32
3
FYN
FGFR1
ALK
ROCK1
IGF1R
JAK2
JAK3
CDK9
GSK3a
110
188
363
456
539
Aur B
Aur A
Flt1
PDGFRb
CSF1R
LCK
9. Several Aurora inhibitors with measureable activity against KDR were
disclosed after this work was completed. For one example, ENMD-2076, see:
Fletcher, G. C.; Brokx, R. D.; Denny, T. A.; Hembrough, T. A.; Plum, S. M.; Fogler,
W. E.; Sidor, C. F.; Bray, M. R. Mol. Cancer Ther. 2011, 10, 126.
16
3
>10,000
>10,000
>10,000
>10,000
10. KDR and Aurora
B enzymatic IC50 values were determined using a
ABL
RET
12
7
homogeneous time-resolved fluorescence (HTRF) kinase assay with an ATP
concentration of 1 mM as described in Ref. 11.
a
11. Dai, Y.; Guo, Y.; Frey, R. R.; Ji, Z.; Curtin, M. L.; Ahmed, A. A.; Albert, D. H.;
Arnold, L.; Barlozzari, T.; Bauch, J. L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.;
Glaser, K. B.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh, K. C.; Moskey, M. D.; Pease, L.
J.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Wishart, N.; Davidsen, S. K.;
Michaelides, M. R. J. Med. Chem. 2005, 48, 6066.
12. The KDR cellular IC50 values represent inhibition of KDR phosphorylation in
NIH3T3 cells stably transfected with full length human KDR. The procedure
was followed as described in Ref. 11.
13. Aurora B cellular activity was assessed by measuring induction of polyploidy in
the NCI-H1229 (NSCLC) cell line as described in Ref. 14. Initial dose-response
data obtained with this assay indicated that maximal polyploid response to
inhibitors typically did not exceed 50% and was associated with apoptosis and
loss in cell number. To avoid this complexity, a threshold potency, defined as
the concentration necessary to produce DNA content >4 N in 15% of the cell
TR-FRET assay.
of 32.1
l
M and by 25 ms at 117
l
M which represent 10- and 36-
M.
fold the predicted oral human Cmax of approximately 3.7
l
After considering the efficacy, pharmacokinetic and safety pro-
files of all analogs, it was decided that inhibitor 2 would be taken
through advanced preclinical evaluation. Evaluation of 2 for inhib-
itory activity across a panel of kinases revealed a unique kinome
profile (Table 5), characterized by potent inhibition of the VEGFR,
PDGFR and SRC families in addition to the Aurora inhibition.20
Compound 2 is lipophilic in nature (logD 4.5 at pH 7) with low
population (EC15), was chosen rather than the more common EC50
.
14. McClellan, W. J.; Dai, Y.; Abad-Zapatero, C.; Albert, D. H.; Bouska, J. J.; Glaser, K.
B.; Magoc, T. J.; Marcotte, P. A.; Osterling, D. J.; Stewart, K. D.; Davidsen, S. K.;
Michaelides, M. R. Bioorg. Med. Chem. Lett. 2011, 21, 5620.
15. For an improved synthesis of this intermediate, see: Engstrom, K. M.; Baize, A.
L.; Franczyk, T. S.; Kallemeyn, J. M.; Mulhern, M. M.; Rickert, R. C.; Wagaw, S. J.
Org. Chem. 2009, 74, 3849.
16. (a) Pelkonen, O.; Turpeinen, M.; Hakkola, J.; Honkakoski, P.; Hukkanen, J.;
Raunio, H. Arch. Toxicol. 2008, 82, 667; (b) Nettleton, D. O.; Einolf, H. J. Curr.
Topics Med. Chem. 2011, 11, 382.
17. Riley, R. J.; Grime, K.; Weaver, R. Expert Opin. Drug Metab. Toxicol. 2007, 3, 51.
18. (a) Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. J. Med. Chem. 2006, 49,
5029; (b) Vandenberg, J. I.; Walker, B. D.; Campbell, T. J. Trends Pharm. Sci. 2001,
22, 240.
19. Assay run in the absence of plasma protein.
20. For a more extensive account of the preclinical in vitro characterization of
inhibitor 2, see: Albert, D. H. et al. to be submitted.
21. For a detailed summary of the preclinical in vivo characterization of inhibitor 2
in a broad range of tumor types, see: Donawho, C. K. et al. Clin. Cancer Res., to
be submitted.
aqueous solubility (<78 lM, physiological pH range), high
permeability and extensive protein binding (>99%, all species
tested). The pharmacokinetic profile is characterized by low
plasma clearance (Clp <0.3 L/hÁkg), moderate volumes of distribu-
tion (Vss 0.4–1.2 L/kg) and half-lives of 4–5 h in mouse, rat and
dog. Inhibitor 2 demonstrates significant antitumor efficacy in both
solid and hematological xenograft models after intravenous, mini-
pump or parenteral once-weekly dosing.21
In summary, a series of thienopyridine ureas with potent activ-
ity against both KDR and Aurora B has been identified. SAR work
has provided analogs with significant cellular activity, favorable
oral PK profiles in multiple species and robust antitumor activity
in multiple preclinical models. Compound 2 from this series was
advanced into clinical trials.