Synthesis and SAR studies of imidazo-[1,2-a]-pyrazine Aurora kinase inhibitors with improved off-target kinase selectivity

Article abstract of DOI:10.1016/j.bmcl.2012.03.051

The structure-activity relationships of new Aurora A/B kinase inhibitors derived from the previously identified kinase inhibitor 12 are described. Introduction of acetic acid amides onto the pyrazole of compound 12 was postulated to influence Aurora A/B selectivity and improve the profile against off-target kinases. The SAR of the acetic acid amides was explored and the effect of substitution on enzyme inhibition as well as mechanism-based cell activity was studied. Additionally, several of the more potent inhibitors were screened for their off-target kinase selectivity.

Full text of DOI:10.1016/j.bmcl.2012.03.051

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3544–3549
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR studies of imidazo-[1,2-a]-pyrazine Aurora kinase
inhibitors with improved off-target kinase selectivity
Matthew E. Voss a, , Matthew P. Rainka a, Mike Fleming a, Lisa H. Peterson a, David B. Belanger b,
⇑
M. Arshad Siddiqui b, Alan Hruza c, Johannes Voigt c, Kimberly Gray d, Andrea D. Basso d
a AMRI Global, 26 Corporate Circle, PO Box 15098, Albany, NY 12212, USA
b Department of Medicinal Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA
c Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
d Department of Oncology Discovery Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The structure–activity relationships of new Aurora A/B kinase inhibitors derived from the previously
identified kinase inhibitor 12 are described. Introduction of acetic acid amides onto the pyrazole of com-
pound 12 was postulated to influence Aurora A/B selectivity and improve the profile against off-target
kinases. The SAR of the acetic acid amides was explored and the effect of substitution on enzyme inhibi-
tion as well as mechanism-based cell activity was studied. Additionally, several of the more potent inhib-
itors were screened for their off-target kinase selectivity.
Received 4 November 2011
Revised 8 March 2012
Accepted 13 March 2012
Available online 21 March 2012
Keywords:
Ó 2012 Published by Elsevier Ltd.
Aurora kinase inhibitors
Imidazo[1,2-a]pyrazine
Selective kinase inhibitor
The Aurora kinases are a member of the Ser/Thr family of ki-
nases and play a vital role in the cell cycle during mitosis.1 Cur-
rently three isoforms have been identified, Auroras A, B, and C.
Aurora A and B both have been demonstrated to have essential
roles in the cell cycle and Aurora C is believed to have a function
related to Aurora B but with limited expression. While both Aurora
A and B operate during mitosis, they affect different components of
the cell cycle progression. Aurora A has been associated with cell
cycle events including mitotic entry and exit, bipolar spindle
assembly, and centromere maturation. Aurora B has been shown
to phosphorylate histone H3, regulate chromosomal remodeling,
kinetochore-spindle attachment, and cytokinesis. Inhibition of
Aurora A results in G2/M delay, followed by apoptotic cell death,
while inhibition of Aurora B gives rise to aberrant cell division fol-
lowed by apoptosis. Dual inhibitors of Aurora A and B display the
Aurora B phenotype.2 These kinases have been found to be over ex-
pressed in a number of tumors which has instigated exploration of
anism based cell assay. While 12 satisfied or met desired criteria
for activity the molecule had low solubility and <60 nM inhibition
against off-target kinases VEGFR2, LCK, Chk1 IRAK4 and moderate
potency (360 nM) against RSK2 (Table 4).6 Based upon X-ray stud-
ies of the initial lead series,5a modeling studies of the expected key
interactions of 12 with Aurora A are presented in Figure 1. The
molecule binds in the adenosine triphosphate (ATP) binding pocket
with the catalytically active ‘DFG-in’ conformation. The core N1
and 8-NH side chain form a hydrogen bonding network with Ala
213 in the hinge binding region and the 3-pyrazole NH forms a
hydrogen bond with Asp 274. The piperidine isothiazole is located
on a hydrophobic region at the front of the ATP binding pocket and
extends toward the solvent accessible front. The bioactive confor-
mation of this portion of the molecule is stabilized by a polar
interaction between the isothiazole sulfur and N7 of the imi-
dazo[1,2-a]pyrazine core. Previous published examples of dual
Aurora A/B inhibitors suggested that by extending the molecule
deeper into a hydrophilic binding pocket at the back of the ATP
binding site improved selectivity for Aurora A/B over other off-
target kinases.4e During the development of SAR around compound
12, we became interested in exploring compounds that were
substituted on the pyrazole nitrogen. We postulated that a side
chain at this position could reach into the hydrophobic pocket
improving selectivity. This binding mode also could potentially
influence Aurora A verse Aurora B selectivity leading to selective
inhibitors.7 In particular, we were interested in examining substi-
tuted acetic acid amides at this position.8
this family of kinases as a possible target for cancer therapy.3
A
number of Aurora kinase inhibitors are currently being examined
in clinical trials in addition to several preclinical programs.2b,4
We have previously described our efforts towards the develop-
ment of dual Aurora A/B inhibitors.5 This work led to the discovery
of several potent inhibitors, including compound 12 which had
excellent inhibition of Aurora A and B and was potent in our mech-
⇑
Corresponding author.
E-mail address: matthew.voss@amriglobal.com (M.E. Voss).
0960-894X/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2012.03.051

M. E. Voss et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3544–3549
3545
Ala213
amide was replaced by isosteres and preparing amide analogs 7
on larger scale. In this example pyrazole borate ester 9 was alkyl-
ated with 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole 8 to pro-
duce aryl amide mimetic 10. With this approach the entire side
chain could be appended onto iodide 4 in one step and acid depro-
tection of the SEM group affords analogs 11.
CH3
HN
N
N
H
O
S
1
OH
N
O
3
H
8
NH
N
N
N
Initially a number of aliphatic or aromatic amides were pre-
pared utilizing the chemistry described in Schemes 1 and 2. All
compounds were studied for there inhibition of Aurora A and B. Po-
tent molecules were then tested in a mechanistic cell-based assay
where the ability to inhibit the Aurora B mediated phosphorylation
of histone H3 was measured.10 The ability of these analogs to inhi-
bit Aurora A/B is summarized in Table 1. The parent carboxylic
acids (13 and 14) were also tested for enzyme inhibition; however,
these compounds displayed only weak inhibition of both Aurora A
and B. Primary amide 15 displayed good inhibition of Aurora B
(IC50 = 28 nM) with 50-fold selectivity over Aurora A, however 15
did not inhibit phosphorylation of histone-H3 in our mechanism-
based cell assay. Secondary amides 16 and 17 maintain moderate
selectivity for Aurora B (IC50 = 193 nM and 44 nM) but were less
potent and 17 displayed no cell activity. When tertiary amides
were prepared such as dimethyl amide analog 18 no inhibition of
either Aurora A or B was found. Introduction of polar functionality
in the amide side chain (compounds 19 and 20) produced only
weak or no enzyme activity against Aurora A or B consistent with
the proposed hydrophobic nature of the binding site. Encouraging
results were obtained when a benzyl amide analog 21 was tested.
This compound displayed excellent enzyme potency for both
Aurora A (IC50 = 21 nM) and Aurora B (IC50 = 613 nM), and had
good cell-based activity with an IC50 = 129 nM. Also encouraging
were the results of anilide 22 showing good enzyme inhibition of
N
N
Asp274
6
CH3
Figure 1. Summary of key interactions between 12 and Aurora A.
The synthesis of the desired compounds was carried out in a
straightforward manner depicted in Scheme 1. The starting mate-
rial for our sequence was 6-bromo-8-thiomethylimidazopyrazine
1 which was readily available on a multigram scale.5d Palladium-
mediated methylation was followed by selective iodination with
NIS to give compound 2. The thiomethyl was activated for dis-
placement by oxidation to the sulfone with m-CPBA and displaced
with methyl 5-aminoisothiazole-3-carboxylate in DMF to afford 3.
Selective DIBAL-H reduction of the methyl ester produced the
intermediate aldehyde in excellent yield. Subsequent reductive
amination under standard conditions and protection of the free
biaryl NH with SEMCl provided our key iodide intermediate 4.9
A
Suzuki–Miyaura coupling of the pyrazole boronate 5 with iodide
4 afforded compound 6 in good to moderate yield. Removal of
the t-butyl group and concomitant SEM-deprotection with TFA
afforded an intermediate carboxylic acid, which was readily con-
verted to compound 7 in good to excellent yields. A similar, but
more convergent end game is presented in Scheme 2. This se-
quence was particularly useful in preparing a series were the
I
I
H3C
H3C
I
N
N
Br
H3C
N
a, b
c, d
e, f, g
N
N
N
HN
N
N
N
N
N
N
S
S
SEM
4
N
N
R
SCH3
SCH3
2
1
3
N
CO2CH3
Ot-Bu
NR1R2
N
N
N
N
O
O
H3C
H3C
h
i, j
N
N
N
N
HN
N
S
N
O
O
N
S
B
SEM
N
N
R
R
O
N N
5
7
N
N
6
Ot-Bu
Scheme 1. Reagents and conditions: (a) Trimethylboroxine, Pd(PPh3)4, K2CO3, DMF, 100 °C, 63%; (b) NIS, DMF, 60 °C, 64%; (c) m-CPBA, DCM; (d) NaH, DMF, methyl 5-
aminoisothiazole-3-carboxylate, 90% for two steps; (e) SEMCl, DMF, NaH, 40%; (f) DIBAL-H, À78 °C, THF, 95%; (g) amine, NaB(OAc)3H, DCE, rt, 99%; (h) PdCl2dppf, K3PO4,
dioxane, H2O, 90 °C, 79%; (i) TFA, CH2Cl2, 79%: (j) HNR1R2, HATU, DIPEA, DMF.
N
N
N
O
N
H3C
N
N
O
a
O
O
Cl
N
N
O
b, c
N
N
N
S
B
N
4
O
O
HN
11
N
NH
N
B
N
R
10
8
9
N
Scheme 2. Reagents and conditions: (a) K2CO3, DMA, 35%. (b) PdCl2dppf, K3PO4, dioxane, H2O, 90 °C, 51%. (c) HCl, 1,4-dioxane, sonication 42%.

3546
M. E. Voss et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3544–3549
Table 1
SAR of N-substituted pyrazoles 12–27
R1
N
N
H3C
N
N
N
S
HN
N
R
N
Compd
R
R1
H
Aur Aa IC50 (nM)
Aur Ba IC50 (nM)
phos-HH3a EC50 (nM)
50
12
H
64
613
OH
13
14
15
16
H
1,828
836
363
146
28
NTb
O
O
O
O
OH
CH3
H
NT
NH2
NHCH3
1567
>3000
>1000
NT
H
193
H
N
17
18
19
H
1803
44
>1000
NT
O
O
N(CH3)2
H
>3000
>3000
>3000
761
H
N
CH3
N(CH3)2
NT
O
O
O
N
20
H
>3000
>3000
NT
H
N
21
22
23
CH3
CH3
CH3
21
613
51
129
327
NT
O
O
H
N
34
CH3
N
1627
261
O
N
24
25
26
27
CH3
H
18
613
613
613
21
534
HN
N
64
64
583
>1000
>1000
887
O
N
N
H
N
O
N
H
HN
a
For assay conditions see footnote 10.
Not tested.
b
both Aurora A (IC50 = 34 nM) and Aurora B (IC50 = 51 nM), as well
as moderate cell-based potency (IC50 = 327 nM). Consistent with
earlier observations, any attempt at modifying these compounds
to tertiary amides (analog 23) resulted in decreased inhibition. Fi-
nally a series of amide bond isosteres was synthesized with the
assumption that replacement of the amide bond would produce
compounds with improved ADMET properties. Phenyl oxadiazoles
25 and 26 proved to be excellent dual inhibitors of Aurora A and B
and phenyl imidizole 27 was active in Aurora B however these ana-
logs demonstrated only weak activity in the cell assay. Based on
the results from Table 1, compounds 21 and 22 were selected as
starting points for additional SAR development.
The SAR results from the benzyl acetamide analogs are provided
in Table 2. We first prepared a series of mono- and di-fluorinated

M. E. Voss et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3544–3549
3547
Table 2
SAR of aryl- and heteroaryl- aminomethylamides 27–42
H
N
N
N
Ar
O
H3C
N
N
N
S
HN
N
R
N
Compd
R
Ar
Aur Aa IC50 (nM)
Aur Ba IC50 (nM)
phos-HH3a IC50 (nM)
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
H
H
H
H
2-F-phenyl
3-F-phenyl
4-F-phenyl
44
30
40
45
613
613
613
613
613
35
175
155
41
161
439
1,107
178
70
469
234
416
870
389
>1,000
NTb
NT
442
NT
NT
NT
NT
2,3-di-F-phenyl
3,5-di-F-phenyl
3-Trifluoromethylphenyl
4-Trifluoromethylphenyl
3-Dimethylaminophenyl
3-Methoxyphenyl
4-Methoxyphenyl
3-Pyridyl
4-Pyridyl
2-Oxazolyl
2-Furanyl
2-Thienyl
H
22
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
413
>3,000
859
57
1,931
434
2,447
168
213
27
NT
193
613
a
For assay conditions see footnote 10.
Not tested.
b
Table 3
SAR of aryl- and heteroaryl-amides 43–58
H
N
N
Ar
N
O
H3C
N
N
N
S
HN
N
R
N
Compd
R
Ar
Aur Aa IC50 (nM)
Aur Ba IC50 (nM)
phos-HH3a IC50 (nM)
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
H
H
H
H
2-F-phenyl
3-F-phenyl
4-F-phenyl
2,3-di-F-phenyl
3,5-di-F-phenyl
2-Thiazolyl
2-Thiadiazolyl
2-Pyridazinyl
2-Pyridyl
198
340
53
122
1,223
100
30
638
185
186
12
68
239
<4
102
753
35
613
30
613
94
613
18
388
892
412
58
2,378
>1,000
>1,000
951
285
NT
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
45
32
3-Pyridyl
4-Pyridyl
118
613
91
282
613
28
83
4-Pyridyl-N-oxide
4-(3-Hydroxy)-pyridyl
4-(3-F)-pyridyl
2-(6-F)-pyridyl
3-(2-F)-pyridyl
402
NTb
62
164
110
81
a
For assay conditions see foot note 10.
Not tested.
b
benzyl amine analogs (28–32), and all showed excellent enzyme
inhibition of both Aurora A (IC50 = 22–45 nM) and Aurora B
(IC50 = 613 nM). Unfortunately, these compounds exhibited only
modest cell-based potency (IC50 = 234–870 nM). Substituting other
halogens in the place of fluorine only produced less active analogs
(data not shown). Other phenyl ring substitution such as trifluoro-
methyl, dimethylamino, or methoxy (33–37) also led to com-
pounds with decreased potency compared to the fluoro analogs.

3548
M. E. Voss et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3544–3549
Table 4
Selectivity (IC50, nM) of selected compounds against various kinases
Compd
Aur A
Aur B
VEGFR2
LCK
Chk1
IRAK4
RSK2
12
42
46
53
56
64
27
122
12
613
613
613
613
613
4
12
20
300
20
100
300
56
873
1,423
1,142
1,219
360
234
481
108
253
579
>3,000
731
271
7700
4,300
1,100
6,800
64
In an effort to improve the solubility and absorption a series of pyr-
idyl and five-membered ring heterocycles were also explored. The
3- and 4-pyridyl derivatives 38 and 39 lost significant potency in
the enzyme assay while the 2-oxazolyl and 2-furanyl compounds
40 and 41 had modest potency in Aurora A and B. We found that
the 2-thienyl analog 42 had excellent enzyme potency (Aurora A
IC50 = 27 nM, Aurora B IC50 6 13 nM) and reasonable cell-based
activity (IC50 = 193 nM), however taken as a series these analogs
did not have desirable cell-based potency.
We next focused our attention on refining the SAR of aryl amide
22, the results of which are presented in Table 3. As with the ben-
zyl amine SAR, a series of mono- and di-fluoroaryl amides were
prepared (43–48) and their ability to inhibit Aurora A/B was ex-
plored. As we had seen in the benzyl series these analogs generally
showed good potency in Aurora A /B with moderate activity in the
cell assay (phos-HH3). However there were two outliers, the 3,5-
di-fluorophenyl analog 47 which was less active and of particular
interest was 2,3-di-fluorophenyl analogs 46, which displayed good
inhibition of both Aurora A (IC50 = 122 nM) and B (IC50 6 13 nM),
and had cell-based potency similar to 12 (phos-HH3,
EC50 = 58 nM). Encouraged by these results phenyl ring isosteres
were explored. Compounds derived from thiazoles, thiadiazoles,
and pyridazinyl rings (48, 49, 50) displayed good enzyme inhibi-
tion, however lacked mechanism-based cell potency. Several ami-
nopyridine analogs were also prepared and their activity was
found to correlate to the regiochemistry of the aminopyridine.
While the 2- and 3-aminopyridines 51 and 52 had moderate en-
zyme and cell potency the 4-aminopyridine containing analog 53
had excellent potency in both enzyme and cell assays (Aurora A
IC50 = 12 nM, Aurora B IC50 6 13 nM, phos-HH3 EC50 = 83 nM).
Addition of polar functional groups such as the pyridine N-oxide
55 and 3-hydroxyl pyridine 56 led to compounds with reduced
activity. However, the potency of this series could be further opti-
mized by combining fluorine with the aminopyridine. Once again,
the regiochemistry of the aminopyridine proved critical, and it was
found the 4-amino-3-fluoropyridine 56 provided optimal potency
(Aurora A 64 nM, Aurora B IC50 6 13 nM, phos-HH3 EC50 = 62 nM)
over regioisomers 57 and 58.
At this point with several potent cell active Aurora inhibitors in
hand the off-target kinase selectivity was examined relative to our
lead analog 12. While compound 12 was a potent Aurora A/B inhib-
itor, it also displayed good potency (<60 nM) against several other
kinases and Table 4 compares Aurora A/B potency with off-target
kinases VEGFR2, LCK, Chk1, IRAK4, and RSK2. From the benzyl ser-
ies the 2-aminomethyl thiophene amide 42 had 15- to 50-fold
improvement in selectivity over the tested off-target kinases. The
2,3-difluorphenyl inhibitor 46 improved the selectivity by achiev-
ing P400 nM potencies against the tested kinases except for
Chk 1 where it was equipotent to 12. The 4-pyridyl derivative 53
improved the Chk 1 selectivity fivefold, but suffered a minor loss
in overall selectivity when compared to 46. Finally the 3-fluoro
pyridyl compound 56 demonstrated >10-fold selectivity against
Chk 1 and 20- to 100-fold selectivity against the other tested
kinases clearly showing that these analogs improve off-target
selectivity compared to the unsubstituted pyrazole derivative 12.
In reviewing the Aurora A/B inhibition data it was obvious while
the selectivity over off-target kinases improved, the majority of the
Figure 2. X-ray structure of compound 56 (green) overlaid with X-ray of SCH
1473759 (magenta).11,5e
compounds demonstrated little or no preference for Aurora B over
Aurora A and only a few simple amides such as 15 and 17 had rea-
sonable Aurora B selectivity. This SAR seemed to be inconsistent
with our postulated binding confirmation and we turned to X-ray
crystallography to help us understand the binding mode of these
inhibitors. Figure 2 has an overlay of X-ray structure of 3-fluoro-
4-pyridyl acetamide 56 in Aurora A with an earlier published
structure of SCH 1473759.5c,11 The imidazo[1,2-a]pyrazine core,
6-aminoisothiazole, and 3-pyrazole overlap with the previous
structure however, instead of binding to the protein in an extended
conformation the acetamide side chain is almost orthogonal to
pyrazole. The pyridine is oriented towards the glycine rich loop were
the pyridyl nitrogen has a hydrogen bond to the NH of Phe 144. This
interaction moves the glycine rich loop about 1.5 Å closer to the
inhibitor when compared to the X-ray structure of SCH 1473759
and while the acetamide NH of 56 maintains a hydrogen bond with
Asp 274, the DFG loop is pushed out by approximately 1 Å to accom-
modate the increased bulk of the acetamide.
In summary, a new series of dual Aurora A/B kinase inhibitors
has been developed based on compounds containing acetic acid
amides. These inhibitors demonstrated excellent enzyme inhibi-
tion mechanism-based cell activity, and an improved profile
against off-target kinases. X-ray crystallographic analysis gave an
unexpected mode of binding allowing us to rationalize the desired
improvement in off-target selectivity. The most potent compounds
contained an aminopyridine amide motif and the activity of these
amides was related to the regiochemistry of the aminopyridine.
The 4-aminopyridine with fluorine substitution at the 3-position
was found to be optimal substituent.
Acknowledgments
We thank Drs. John Piwinski, Neng-Yang Shih, Paul Kirschmeier,
W. Robert Bishop, Paul Zavodny and Mark Sawicki for supporting
this project and the collaboration. We would also like to thank
Drs. Jayaram Tagat and Tao Yu for helpful discussion on the synthe-
sis of these compounds.
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9. For this study piperidine and ( ) 3-methylpiperdine were used
interchangeably. Synthesis of the individual enantiomers in previous series
demonstrated biochemical equivalence.
10. For a detailed description of the biochemical assays see footnote 15 in Ref. 5d.
11. The coordinates for compound 56 have been deposited in the RcSB Protein
Data Bank under the Accession Code 3VAP.