2-Aminobenzimidazoles as potent Aurora kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.07.016

This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a

Full text of DOI:10.1016/j.bmcl.2009.07.016

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5158–5161
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Aminobenzimidazoles as potent Aurora kinase inhibitors
*
Min Zhong , Minna Bui, Wang Shen, Subramanian Baskaran, Darin A. Allen, Robert A. Elling,
W. Michael Flanagan, Amy D. Fung, Emily J. Hanan, Shannon O. Harris, Stacey A. Heumann, Ute Hoch,
Sheryl N. Ivy, Jeffrey W. Jacobs, Stuart Lam, Heman Lee, Robert S. McDowell, Johan D. Oslob, Hans E. Purkey,
Michael J. Romanowski, Jeffrey A. Silverman, Bradley T. Tangonan, Pietro Taverna, Wenjin Yang,
Josh C. Yoburn, Chul H. Yu, Kristin M. Zimmerman, Tom O’Brien, Willard Lew
Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the discovery and key structure–activity relationship (SAR) of a series of 2-amino-
benzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the
biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing
in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous sol-
ubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular,
6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
Received 23 April 2009
Revised 28 June 2009
Accepted 2 July 2009
Available online 9 July 2009
Keywords:
Aurora kinase inhibitor
Urea bioisostere
Ó 2009 Elsevier Ltd. All rights reserved.
2-Aminobenzimidazole
Aurora kinases1–6 belong to the family of serine/threonine ki-
nases and are composed of three isoforms in mammals: Aurora
A, Aurora B, and Aurora C. They are expressed during G2/M phase
of the cell cycle and are critical for the proper regulation of mito-
sis.7–9 For example, Aurora A controls centrosome maturation
and mitotic spindle formation; Aurora B ensures chromosome seg-
regation and alignment as part of the chromosomal passenger pro-
tein complex; and Aurora C, though not well understood, is
thought to function similarly to Aurora B. Over-expression of Aur-
ora kinases is observed in various tumor cells.10–14 It is believed
that inhibition of Aurora kinases could lead to the G2 arrest of can-
cer cells and subsequently promote the death of cancer cells.
Therefore, Aurora kinases have emerged as attractive oncology tar-
gets for small-molecule drug discovery.6,15–17 As a result, many
Aurora kinase inhibitors, including Aurora A selective, Aurora B
selective, and pan-Aurora kinase inhibitors, have been discovered
and advanced to human clinical trials.18–26
of a biaryl urea moiety. In order to address this issue, a number of
strategies, such as introduction of polar functionalities,25 applica-
tion of urea bioisoteres, and preparation of prodrugs,27 were con-
sidered in our search of backup compounds to 1c. Herein, we
report the preparation of 2-aminobenzimidazole (Fig. 2) as a
Figure 1. Potent Aurora kinase inhibitors bearing a biaryl urea residue.
Recently, we reported the discovery of potent Aurora kinase
inhibitor SNS-314 (1c) (Fig. 1), which exhibits a compelling pre-
clinical profile and entered clinical trials in patients with solid tu-
mors.25,26 Structurally, 1c is comprised of a thieno[3,2-d]pyrimi-
dine as a purine mimetic and a biaryl urea residue as an
essential binding element in the DFG pocket. 1c displays low aque-
ous solubility which could be potentially attributed to the presence
* Corresponding author. Present address: Presidio Pharmaceuticals, Inc., 1700
Owens Street, Suite 585, San Francisco, CA 94158, USA. Tel.: +1 415 655 7567.
E-mail address: mzhong@presidiopharma.com (M. Zhong).
Figure 2. 2-Aminobenzimidazole as a bioisostere of biaryl urea.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.016

M. Zhong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5158–5161
5159
bioisostere of the biaryl urea residue of 1c. This effort led to the
discovery of a series of potent 2-aminobenzimidazole-based Aur-
ora kinase inhibitors with improved intrinsic solubility.
As demonstrated by the crystal structure of 1b (Fig. 1), which is
a structurally close analog of 1c, complexed with humanized
mouse Aurora A, the urea residue, containing one hydrogen-bond
acceptor and two hydrogen-bond donors, forms a strong hydro-
gen-bonding network with the protein through several water mol-
ecules in the DFG binding pocket.25 It has been well documented
that imidazole can serve as a bioisostere of urea.28 Also, the pres-
ence of an imidazole residue in a molecule could potentially im-
prove the intrinsic solubility. Preliminary computational
modeling also suggested that 2a–b overlapped well with the crys-
tal structure of 1b. Accordingly, several analogs were prepared to
explore the viability of benzimidazole and other 1,3-azoles as urea
bioisosteres for inhibition of Aurora kinases.
Scheme 2. Reagents and conditions: (a) 1,10-carbonyldiimidazole (for 8a, X = O) or
1,10-thiocarbonyldiimidazole (for 8b, X = S), THF, rt, 30 min; 2-iodoaniline (for 8a)
or 2-bromoaniline (for 8b), rt, overnight; (b) CuI, 1,10-phenanthroline, acetonitrile,
80 °C; 55% (8a, X = O, two steps) or 70% (8b, X = S, two steps).
As shown in Scheme 1, treatment of readily available aminothi-
azole 325,29 with 1,10-thiocarbonyl-diimidazole, followed by addi-
tion of
a
substituted 1,2-diaminoarene gives
a
thiourea
intermediate, which is cyclized in the presence of DCC to afford
4a–b.30 After removal of the Boc- groups from 4a–b, the corre-
sponding free amines react with 4-chlorothieno[3,2-d]pyrimidine
to yield 2a–b, respectively. The same approach was applied to
the syntheses of 5a–b and 6a–h with commercially available 3-
Scheme 3. Reagents and conditions: (a) 4-chlorothieno[3,2-d]pyrimidine, DIEA,
DMF, 90 °C, 75%; (b) Zn, NH4Cl, MeOH, 60 °C, 4 h, 90%; (c) N,N0-bis-Boc-S-
methylisothiourea, THF, 60 °C, 4 h, 80%; (d) 4 M HCl/dioxane, quantitative; (e)
butan-2,3-dione (for 12a) or 2-bromo-1-phenylethanone (for 12b), K2CO3, MgCO3,
THF, 60 °C, 4 h, 55% (for 12a) or 60% (for 12b).
or
4-N-Boc-aminomethyl-aniline
and
3-
or
4-N-Boc-
aminoethylaniline.
As described in Scheme 2, a copper-catalyzed cyclization of
either a urea or a thiourea intermediate derived from 7 yields
the corresponding benzoxazole 8a or benzothiazole 8b31 for the
preparation of 6f–g.
Compound 9 can be readily converted into guanidine-contain-
ing intermediate 11, which is subsequently treated with either
butan-2,3-dione or 2-bromo-1-phenylethanone to yield function-
alized 2-aminoimidazole 12a or 12b (Scheme 3).
to the proteins. Subsequently, 5a–b and 6a–b were designed to ex-
plore the optimal distance and angle of the terminal phenyl ring of
the benzimidazole series relative to the thieno[3,2-d]pyrimidine
residue.
While 5a–b exhibit comparable potency to 2a–b and 6a shows
drastically reduced activity in Aurora B assay, 6b34 demonstrates
good potency in Aurora A and B and BrdU assays, and improved
aqueous solubility. Introduction of an additional nitrogen atom
into the benzimidazole residue (6c–d) does not further improve
the solubility relative to 6b while the potency is significantly
weaker. The ‘NH’ moiety in the benzimidazole residue is important
to the activity, as N-methyl benzimidazole analog 6e, benzoxazole
analog 6f, and benzothiazole analog 6g display reduced potency in
both Aurora B and BrdU assays. Replacement of the benzimidazole
residue of 6b with a substituted imidazole moiety (12a–b) signifi-
cantly decreases the potency against Aurora B. As expected, the
corresponding benzimidazole analogs of 1b–c (6h–i) maintain
comparable potency while having improved solubility. Further-
more, a differently constrained benzimidazole analog (15) showed
much worse activity in the Aurora B enzymatic assay compared to
6h.
Benzimidazole analog 15 was synthesized as depicted in
Scheme 4 to compare with 6h. Boc-protection of readily available
13,32 followed by reduction of the NO2 group, condensation with
3-trifluoromethylphenyl thioisocyanate, and cyclization in the
presence of DCC gives key precursor 14 for the synthesis of 15.
Since the biaryl urea series (SNS-314 series) has comparable
activity against both Aurora A and B,25 an Aurora B enzymatic as-
say and a BrdU cell proliferation assay were used to preliminarily
test the initial set of benzimidazole analogs. Subsequently, selected
compounds were further evaluated in an Aurora A enzymatic as-
say. As outlined in Table 1, benzimidazoles 2a–b were found to
be much less potent than the corresponding urea analogs 1a–b,
but the kinetic solubility33 was improved as expected. Although
earlier SAR of the biaryl urea series indicates that the introduction
of a CF3 group onto the phenyl residue of 1a enhances the activity
against both Aurora A and B (1a vs 1b),25 this effect was not ob-
served on these benzimidazole derivatives (2a vs 2b). One plausi-
ble explanation of this difference in potency lies in the different
trajectory of the terminal phenyl ring in 2a compared to 1a due
to the presence of a structurally constrained benzimidazole ring.
This in turn leads to different binding affinities of the molecules
The relatively more potent 6h–i were evaluated with FACS anal-
ysis, a cell-based mechanistic assay used to measure Aurora kinase
inhibition.25 Compounds 6h–i show weaker potency in FACS anal-
ysis relative to its urea analogs 1b–c. It is worth mentioning that,
as do other pan-Aurora or Aurora B-selective kinase inhibi-
tors,21,23,35 6h–i arrest HCT116 cells at G2 phase and cause poly-
Scheme 1. Reagents and conditions: (a) 1,10-thiocarbonyldiimidazole, THF, rt, 30 min; substituted 2-aminoaniline, rt, overnight; DCC, 60 °C, 1 h; 35–75% (three steps); (b)
4 M HCl/dioxane, quantitative; (c) 4-chlorothieno[3,2-d]pyrimidine, DIEA, DMF, 90 °C, 65–90%.

5160
M. Zhong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5158–5161
Scheme 4. Reagents and conditions: (a) Boc2O, NaHCO3, THF/H2O, rt, 2 h, 90%; (b) 10% Pd/C, MeOH, H2, 1 atm, rt, 2 h, quantitative; (c) 3-trifluoromethylphenyl
thioisocyanate, THF, rt, 2 h; DCC, THF, 60 °C, 1 h; 55% (two steps); (d) 4 M HCl/dioxane, quantitative; (e) 4-chlorothieno[3,2-d]pyrimidine, DIEA, DMF, 90 °C, 65%.
Table 1
SAR of the 2-aminobenzimidazole analogs
R1 R2
Aurora A IC50
(nM)
Aurora B IC50
(nM)
BrdU EC50
(nM)
FACS EC50
(nM)
Solubilityd
M)
Mouse iv PKe
CL (mL/min/
a
b
c
Compound
n
X
Y
Z
U
V
(
l
t1/2
(h)
Kg)
1a
1b
1c
2a
2b
5a
5b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
52
22
9
120
14
31
420
620
580
1400
>10,000
10
45
13
6
16–63
<16
<16
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
16–63
16–63
63–250
63–250
NT
<16
16–63
NT
100–200
50–100
50–100
400–500
100–200
NT
NT
NT
>1000
>1000
1.4
48
1400
490
NT
NT
NT
28
NT
NT
NT
NT
NT
NTf
1900
8500
NT
NT
41
1
2
1
2
2
2
2
2
2
2
2
2
2
2
2
2
CH CH NH
CH CH NH
CH CH NH
CH CH NH
CH CH
CH CH
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
N
CH
CH
N
83
270
NT
NT
400
NT
5
9
80
161
NT
<1
140
280
120
2500
6
8
21
63
600
5
>1000
>1000
CH CH NMe CH CH
CH CH
CH CH
O
S
CH CH
CH CH
CH CH
CH CH
CH CH
CH CH
CH CH
200–300
100–200
750–1000
>1000
750–1000
400–500
>1000
100–200
100–200
>1000
CH CH NH
CH CH NH
CH CH NH
CF3 40
Cl 28
CF3 64
CF3 NT
CF3 NT
CF3 17
0.61
0.45
85
39
N
CH
CH NH
NH
H
H
H
H
N
6m
6n
12a
12b
15
CH CH NH
CH CH NH
N
N
CH
CH
1.5
32
Cl
20
NT
NT
NT
10
17
5600
>10,000
1400
NT
NT
NT
NT
NT
>1000
NT
a
Typically average of at least two experiments. Variation generally is <100%. See Ref. 25 for assay protocols.
Cellular proliferation as determined by BrdU incorporation using HCT116 cell line.
Cell-cycle profile as determined by FACS analysis performed with 16 nM, 63 nM, 250 nM, and 1000 nM of a compound in HCT116 cell line, See Ref. 25 for assay protocol.
b
c
EC50s reported as a range when P50% of the DNA content is 4 N or higher.
d
Kinetic solubility reported as a range of low and high solubility at pH 4.0. For compounds having a low solubility of 1000 lM or higher, the value is reported as >1000 lM.
PK experiments were carried out using a group of three mice administrated iv with a single dose of 5 mg/kg of a testing compound. Blood samples were taken at nine
e
different time points (0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h post dose) and the plasma concentrations were determined by LC/MS/MS.
f
Not tested.
ploidy (formation of 8 N or higher cells). Compounds 6h–i were
also progressed into mouse iv PK studies; however, they have
shorter t1/2 compared to biaryl-urea analog 1c (Table 1).
results are contradictory to the ones of the un-substituted benz-
imidazole analogs (6c–d vs 6b). Balanced activities against both
Aurora A and Aurora B kinases are observed for 6h–i and 6m–n,
which suggest that these benzimidazole derivatives are similar to
those biaryl ureas (1a–c), having low selectivity against these
two proteins. Importantly, 6m exhibits an improved mouse iv PK
profile over its non-nitrogen substituted analog 6h. This PK result
is comparable to that of 1c. It should be noted that 6m has a much
lower solubility than its non-nitrogen substituted derivative 6h.
In summary, we have successfully discovered a series of potent
2-aminobenzimidazole-based Aurora kinase inhibitors derived
from SNS-314 (1c). This series of compounds offers better aqueous
solubility compared to their corresponding biaryl-urea analogs
while maintaining good activity profile in various enzymatic and
cell-based assays. In particular, 6m demonstrates a comparable
mouse iv PK profile to 1c. The discovery of this series of potent
benzimidazole-based Aurora kinase inhibitors represents another
The much improved solubility encouraged us to structurally
modify 6h–i to search for compounds with strong in vitro potency,
pharmaceutically acceptable physicochemical properties, and a
good PK profile. As summarized in Table 1, although the introduc-
tion of a fluorine atom at the ortho-position of the central phenyl
ring could potentially stabilize the molecule in vivo by reducing
its electron density, significantly decreased activity in both BrdU
and FACS analysis was observed (6j vs 6h). Replacement of the cen-
tral phenyl ring with a pyridyl moiety also causes a drop in the po-
tency against Aurora B (6k–l vs 6h). Interestingly, the installation
of a nitrogen atom onto the benzimidazole residue either retains
(6n vs 6i) or improves (6m vs 6h) the potency in all the in vitro as-
says, including Aurora A and B kinase assays, BrdU, and FACS anal-
ysis, that were used in the process of compound evaluation. These

M. Zhong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5158–5161
5161
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Jacobs, J. W.; Lam, J.; Lawrence, C. E.; McDowell, R. S.; Nannini, M. A.; Shen, W.;
Silverman, J. A.; Sopko, M. M.; Tangonan, B. T.; Teague, J.; Yoburn, J. C.; Yu, C. H.;
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Acknowledgment
We gratefully thank Dr. Daniel A. Erlanson for critical reading
and discussions.
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to provide insight of the binding of the compound to the protein. 6b has a
similar binding mode as that of 1b:25 thieno[3,2-d]pyrimidine binds in the
hinge region while benzimidazole residue binds tightly in the DFG pocket. The
pyrimidine residue forms hydrogen-bonding with the –NH of Ala213 (3.3 Å).
Also, the aminoimidazole residue forms a bidentate H-bond interaction (3.5 Å
and 2.8 Å) with the carboxylic acid residue of Glu194; however, there is no
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