Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase

Article abstract of DOI:10.1016/j.bmcl.2012.12.028

Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5- carboxamide inhibitors of Sky kinase resulted in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky inhibition.

Full text of DOI:10.1016/j.bmcl.2012.12.028

Accepted Manuscript
Optimization of Highly Selective 2,4-Diaminopyrimidine-5-carboxamide In‐
hibitors of Sky Kinase
Noel A. Powell, Jennifer K. Hoffman, Fred L. Ciske, Jeffrey T. Kohrt, Sangita
M. Baxi, Yun-Wen Peng, Min Zhong, Cornel Catana, Jeff Ohren, Lisa A. Perrin,
Jeremy J. Edmunds
PII:
S0960-894X(12)01612-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2012.12.028
BMCL 19913
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Please cite this article as: Powell, N.A., Hoffman, J.K., Ciske, F.L., Kohrt, J.T., Baxi, S.M., Peng, Y-W., Zhong,
M., Catana, C., Ohren, J., Perrin, L.A., Edmunds, J.J., Optimization of Highly Selective 2,4-Diaminopyrimidine-5-
carboxamide Inhibitors of Sky Kinase, Bioorganic & Medicinal Chemistry Letters (2012), doi: http://dx.doi.org/
10.1016/j.bmcl.2012.12.028
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Optimization of Highly Selective 2,4-Diaminopyrimidine-5-
carboxamide Inhibitors of Sky Kinase
Noel A. Powell,* Jennifer K. Hoffman,† Fred L. Ciske,‡ Jeffrey T. Kohrt,§ Sangita M.
Baxi,** Yun-Wen Peng, Min Zhong,§ Cornel Catana, Jeff Ohren, Lisa A. Perrin, and
Jeremy J. Edmunds,††
Pfizer Global Research & Development, Michigan Laboratories, Ann Arbor, MI 48105
This is where the receipt/accepted dates will go; Received Month XX, 2000; Accepted Month XX, 2000 [BMCL RECEIPT]
Abstract—Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase resulted
in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky
inhibition. ©2000 Elsevier Science Ltd. All rights reserved.
In the preceding paper, we reported the discovery and
initial SAR of a series of 2,4-diaminopyrimidine-5-
carboxamide inhibitors of Sky kinase.1 Sky is a
tyrosine kinase receptor for the Gas6 (growth arrest
specific gene 6) ligand, which plays a critical role as a
platelet response amplifier, enhancing platelet
aggregration and granule secretion to known
endogenous agonists.2,3 Previous studies from our
laboratories have demonstrated that Sky specific
antibodies inhibit human platelet degranulation and
aggregation to the same extent as Gas6 inhibition, and
result in comparable efficacy to clopidogrel treatment in
a mouse model of thrombosis with no significant
increase in bleeding time.4 Therefore, Sky inhibitors
are of interest as an arterial anti-thrombosis treatment
with a reduced risk of bleeding side affects.
Our initial structure-activity relationship (SAR) studies
in the 2,4-diaminopyrimidine-5-carboxamide series
demonstrated that high kinase selectivity could be
achieved by filling the Ala571 subpocket with a
benzylamino substituent at the 2-position of the
pyrimidine core. However, early compounds suffered
from high clearance and poor oral bioavailability due to
rapid first pass metabolism. We undertook further SAR
studies to improve the metabolic stability of the 2,4-
diaminopyrimidine-5-carboxamide template.
Amide sidechain analogs were prepared as described in
Scheme 1. Condensation of 1 with cyclopentyl amine
* Corresponding author at present address: Eisai Inc, 4 Corporate Drive, Andover, MA 01810, USA. Tel: +1 978 837 4683;
email: noel_powell@eisai.com
† Current address: Hamilton Company, 4970 Energy Way, Reno, NV 89502
‡ Current address: Cayman Chemical, 1180 East Ellsworth Road, Ann Arbor, MI 48108
§ Current address: Pfizer Worldwide Research & Development, Eastern Point Road, Groton, CT 06442, USA
** Current address: Pfizer Worldwide Research & Development, 10646 Science Center Drive, San Diego, CA 92121, USA
†† Current address: Abbott Labs, 381 Plantation Street, Worcester, MA 01605, USA

Scheme 1. a) cyclopentylamine, Et3N, CH3CN, 80 °C; b) m-CPBA,
CH2Cl2, 0 °C; c) 2,5-dichlorobenzylamine, Et3N, 1,4-dioxane, reflux; d)
NaOH, MeOH, reflux; e) RNH2, HATU, Et3N, DMF.
OEt
afforded the 4-(cyclopenthylamino)-pyrimidine 2.
Oxidation of the thiomethyl and displacement of the
resulting sulfone with 2,5-dichlorobenzylamine
provided the 2,4-diaminopyrimidine 3. Hydrolysis of
the ester and amide bond formation yielded the desired
analogs 4-14. Analogs with a 3,5-dichloroanilino
substituent at the pyrimidine 2-position were prepared
as described in Scheme 2. Condensation of 25 with neat
2,5-dichloroaniline provided the 2-aminopyrimidinone
26,5 which was converted to the chloride by refluxing
in thionyl chloride. The chloride was then displaced
with a primary amine to give the 2,4-diaminopyrimidine
OEt
N
O
a
b,c
N
O
HN
N
OH
26
MeS
N
OH
25
Cl
Cl
N
OEt
HN
N
O
N
O
OEt
OEt
d,e
HN
N
NH
R
HN
N
NH
b,c
a
N
O
N
O
R
27
MeS
N
Cl
MeS
N
NH
15-19
Cl
Cl
Cl
Cl
1
2
Scheme 2. a) 3,5-dichloroaniline, neat, 150 °C; b) SOCl2, reflux; c) R-
NH2, Et3N, CH3CN, reflux; d) NaOH, MeOH, reflux; e) N-Methyl-4-
aminopiperidine, HATU, Et3N, DMF.
R
O
OEt
HN
N
O
N
d,e
Cl HN
N
NH
Cl HN
N
NH
3
4-12
Cl
Cl
Table 1. Amide sidechain SAR and ADME properties

a
IC50 data is an average of duplicate runs using an ELISA kinase assay with 60 μM ATP. b Aqueous solubility measured at pH 6.5. c PAMPA artificial
membrane assay.
ester 27. Hydrolysis of the ester and subsequent
amide bond formation with the N-methyl-4-
aminopiperidine yielded analogs 15-19.
stability was observed.
We hypothesized that
although the primary site of metabolism was blocked,
alternative sites of metabolism on the highly lipophilic
compound (cLogP = 6.06) now became dominant.
Since the butyrolactam ring is exposed to the solvent
face,1 the affect of other polar solubilizing groups in
the amide sidechain on the microsomal stability was
examined. To keep the cLogP low, we opted to
conduct the amide sidechain SAR with the 2-
methoxybenzyl group at the 2-position of the
pyrimidine ring. Replacing the butyrolactam ring with
a hydroxyl group (7) resulted in improved Sky
inhibition activity, but had no affect on HLM stability
and reduced aqueous solubility and cellular
permeability. Likewise, a pendant acetamide (8) gave
no improvement in HLM stability. A dramatic
improvement in HLM stability was observed in the
introduction of an acidic tetrazole (9, HLM t1/2 = 60
min), along with a modest increase in the RLM half-
life and improved aqueous solubility and permeability.
However, the presence of the acidic tetrazole in the
amide sidechain led to a 3-fold decrease in Sky
As previously reported, both the 2-methoxybenzyl
analog 4 and the 2,5-dichlorobenzyl analog 5
exhibited rapid HLM and RLM metabolism (Table
1).1 The electron-rich benzyl ring of analog 4
appeared to be a likely site of metabolism upon visual
inspection. However, replacing the methoxy ether
with electron-withdrawing halogen atoms had no
affect on the metabolic stability, indicating that the
primary site of metabolism was elsewhere in the
molecule. Metabolite identification by LC-MS-MS
methods after incubation in human microsomes
indicated the primary metabolite was actually the
product of oxidative hydroxylation at the α-carbonyl
carbon in the butyrolactam ring. Our attempts to
directly block that site of metabolism by replacement
of the methylene with an oxygen atom resulted in 6
with significant improvement in Sky inhibition
potency, however, no improvement in HLM or RLM

inhibition
activity
and,
counter-intuitively,
resulted in good aqueous solubility, cellular
permeability was drastically reduced. Indeed, analog
13 exhibited no oral bioavailability in the rat (Table
2), presumably due to the poor absorption across the
gut wall. Therefore, we sought to further improve the
metabolic stability and increase cellular permeability
of the series. We recognized that the benzylic
methylene in the 2-amino group represented a
potential site of metabolism. We found that the 2-
aminobenzyl group could be replaced by a 2-anilino
group, specifically a 3,5-dichloroanilino group, which
exhibited single-digit nanomolar Sky inhibition
activity and excellent HLM and RLM stability (15,
significantly increased dofetilide binding activity. We
found that improved HLM stability could also be
obtained by the introduction of basic amines in the
amide sidechain. A N,N-dimethyl-4-aminobutyl chain
exhibited similar Sky inhibition activity (10, IC50
0.50 μM), a 2.9-fold increase in HLM stability (HLM
1/2 = 40 min), and excellent aqueous solubility. A (1-
=
t
methylpiperidin-4-yl)amino sidechain also exhibited
similar Sky inhibition activity (11, IC50 = 0.52 μM),
good aqueous solubility a 2-fold increase in HLM
stability (t1/2 = 40 min), and improved metabolic
stability in rat liver microsomes (RLM t1/2 = 56 min).
As observed previously, replacement of the 2-
methoxybenzyl group with the 2,5-dichlorobenzyl
group resulted in decreased HLM stability (12, HLM
Sky IC50 = 0.002 μM, HLM t1/2 = 120 min, RLM t1/2
=
60 min). However, the trans-2,4-diaminocyclohexane
ring again resulted in poor permeability. Accordingly,
we sought to replace the basic amine in the ribose
binding region with neutral polar groups. Replacing
the trans-2,4-diaminocyclohexane ring with a 4-
aminotetrahydropyran gave similar Sky inhibition
potency (16, Sky IC50 = 0.002 μM) and moderate
HLM stability, but poor permeability. A cyclic amide
sidechain also exhibited potent Sky inhibition and
good HLM stability, but poor cellular permeability
(17, Sky IC50 = 0.002 μM, PAMPA permeability = 0.2
t1/2
= 14 min) and decreased solubility and
permeability, presumably due to the increased
lipophilicity of the 2,5-dichlorobenzyl group (cLogP =
5.77). However, analog 12 exhibited excellent RLM
stability. The increased RLM stability of 11 and 12
translated into 41% and 32% oral bioavailability in the
rat, respectively (Table 3). While the in vivo clearance
for analogs 11 and 12 remained at or above the hepatic
blood flow for the rat, we believe that the increased
volume of distribution reflects an increase in protein
binding that reduces the plasma free fraction. In any
event, the resulting improved oral bioavailability of
×
10-6 cm/sec) In contrast, alcohol-containing
sidechains resulted in potent Sky inhibition and good
HLM stability with a relative increase in permeability
(18 and 19, PAMPA permeability = 2.0 and 1.4 × 10-6
cm/sec, respectively). Analog 19 also exhibited good
aqueous solubility and was chosen for PK dosing.
Unfortunately, analog 19 exhibited increased in vivo
clearance and no detectable plasma levels after oral
dosing in the rat (Table 2). Although we were
successful in improving the Sky inhibition activity,
metabolic stability in HLM and RLM, and aqueous
solubility via incorporation of polar functionality in
the 3-amino sidechain that binds in the ribose binding
region, these polar functionalities result in poor
cellular permeability that severely limits the oral
bioavailability.
analogs 11 and 12 represents
a
significant
improvement over earlier analogs.1
In addition to the improved oral bioavailability in the
rat, analogs 11 and 12, which contain the N-methyl-4-
aminopiperidine amide sidechain, also exhibit superior
functional activity in both the functional P-selectin
and platelet aggregation assays versus the
corresponding analogs 4 and 5 with the N-(3-
aminopropyl)-butyrolactam amide sidechain. The P-
selectin assay measures the expression of P-selectin on
the surface of platelets as a biomarker for platelet
activation.6
While the improved RLM stability directly translated
into improved oral bioavailability in the rat, we
focused upon improving the HLM stability to ensure
future druggability. Our attempts to improve the
HLM stability by blocking metabolism of the amide
sidechain appeared to be stymied by the overall
The >100-fold improvement in Sky inhibition that was
achieved by the incorporation of polar functionalities
into the 4-amino sidechain did not translate into
significantly improved activity in the platelet
activation functional assays (Table 3). Analog 15
exhibited submicromolar activity in the P-selectin
inhibition assay (IC50 = 0.40 μM) and single digit
micromolar activity in the platelet aggregation assay
(IC50 = 1.4 μM). While analogs 16 and 19 showed P-
lipophilicity of the compounds.
We turned to
decreasing the lipophilicity by introducing polar
substituents into the 4-amino group which binds in the
ribose region of the ATP binding site (Table 3), a
strategy also recently demonstrated for other members
Table 2. In vivo rat PK profile of selected compounds.a
of the HGFR kinase family.7
We found that
Analog t1/2
Cl
Vdss
AUC
Cmax
F
(%)
41
32
0
(hr) (mL/min/kg) (L/kg) (ng·hr/mL) (ng/mL)
introduction of a basic amine into the 4-amino cyclic
ring led to improved Sky inhibition activity (13 and
14, Sky IC50 = 0.19 and 0.04 μM, respectively), as
well as improved HLM stability (t1/2 = 38 and 23 min,
respectively). Although the additional basic amine
11
12
13
19
3.5
8
0.2
13
73
40
40
55
18
25
0.4
2.7
302
680
0
74
35
25
0
0
0
aValues are means of duplicate experiments. Sprague-Dawley rats were

dosed as a suspension in 5% PEG-200/95% (0.5% w:w) methyl-
cellulose.
IV dose
=
1
mg/kg, PO dose
=
5
mg/kg
Table 3. 2-Benzylamino and 2-Anilino SAR and ADME properties
a
IC50 data is an average of duplicate runs using an ELISA kinase assay with 60 μM ATP. b Aqueous solubility measured at pH 6.5. c PAMPA artificial
membrane assay.
Table 4. Amide replacement SAR and ADME properties

N
N
HN
Het
Cl
NH
R
Cl
c
Dofetilide CYP2D6
Binding %I @ 3
Ki ( M)
HLM RLM Aqueous
Permeability
Sky
P-Selectin
2
R NH
PSA
clogP
ID
a
Het
-6
( 10 cm/sec)
IC ( M)
50
M
IC ( M)
50
t
1/2
t
1/2
Solubility
b
(min) (min)
( M)
*
0.092
0.0007
0.044
1.6
1.0
3.0
4.92 87.9 21
6.04 79.1 28
4.52 92.2 120
3
1.3
0.35
1.5
20
21
22
5.2
2.3
200
0.2
0.03
1.0
81
69
88
HN
NH
N
O
*
6
HN
N
N
O
O
O
O
31
HN
*
N
HO
HO
HO
0.15
>80
6.03 79.3 48
60
2.7
23
200
<0.01
24
*
F
HN
Br
0.015
3.9
4.88 79.3 30
31
24
5.2
0.3
>100
1
HN
c
IC50 data is an average of duplicate runs using an ELISA kinase assay with 60 μM ATP. b Aqueous solubility measured at pH 6.5. PAMPA artificial
membrane assay.
selectin inhibition activity comparable to analogs 11
and 12, analogs 17 and 18 exhibited the most potent
activity in the P-selectin assay in this series (P-selectin
IC50 = 0.43 and 0.58 μM, respectively). Analog 15
may show superior functional activity because of
better cellular permeability than is predicted by the
PAMPA artificial membrane permeability assay.
amino-4-hydroxy-tetrahydrofuran moiety of 19. We
found that a 3-pyridyl ring was a good replacement for
the amide sidechain, as analog 22 showed good Sky
inhibition potency (Sky IC50 = 0.044 μM) with
improved HLM and RLM stability, aqueous solubility,
and PAMPA permeability. However, 22 was still a
potent inhibitor of CYP2D6 and showed no
improvement in dofetilide binding inhibition.
Conversion of the 3-pyridyl ring to a 4-fluorophenyl
ring resulted in decreased CYP2D6 and dofetilide
binding inhibition, but also resulted in a significant
We hypothesized that reducing the polar surface area
and the number of basic amines and potential
hydrogen bond donors by replacing the amide
sidechain with a small heterocyclic ring or neutral
atom would lead to improved cellular permeability
and subsequently improved functional activity and
oral bioavailability, (Table 4). On the basis of SAR
data from another series identified in our HTS (data
not shown), we chose to replace the amide sidechain
with a 3-methylisoxazole while maintaining the basic
amine in the ribose binding region. Analogs 20 and
21 exhibited potent Sky inhibition (Sky IC50 = 0.092
and 0.0007 μM, respectively) and good functional
activity in the P-selectin assay (IC50 = 1.6 and 1.0 μM,
respectively). Although the PAMPA permeability
data predicts that the more potent 21 would possess
poor cellular permeability, the decreased polar surface
area of 21 did result in improved functional activity.
However, both analogs 20 and 21 exhibited reduced
HLM and RLM stability, as well as significant
dofetilide binding and CYP2D6 inhibition. To remove
the dofetilide binding and CYP2D6 inhibition and
improve the cellular permeability, we replaced the
basic amine in the ribose binding region with the 3-
decrease in the Sky inhibition activity (23, Sky IC50
=
0.15 μM). We found that the most successful
replacement of the amide sidechain was a simple
bromine atom, which resulted in potent Sky inhibition
(24, Sky IC50 = 0.015 μM), moderate functional P-
selectin inhibition, good HLM and RLM stability, and
no significant inhibition of CYP2D6 and dofetilide
binding. However, the low aqueous solubility and
PAMPA permeability was still not predictive of good
oral bioavailability.
The broad kinase selectivity that we had previously
observed for this series1 was improved as the level of
Sky inhibition activity increased throughout our SAR
investigations (Table 5). Analogs 11 and 12, with the
N-(4-aminopiperidine) amide sidechain and 2-
aminobenzyl group, exhibited improved selectivity
against 32 kinases with significant activity in HGFR,
Axl, and Mer, which are other members of the HGFR
subfamily of kinases. The 2,5-dichlorobenzyl group
in 12 resulted in additional activity in Abl, CKI-δ, and

Lck. Conversion of the 2,5-dichlorobenzyl group to
the 3,5-dichloroanilino group and addition of a basic
amine in the ribose binding region resulted in greatly
improved kinase selectivity, as analog 15 exhibited
>100 fold selectivity against 47/48 kinases screened,
with activity only against the fellow HGFR kinase
family member, Mer. Replacement of the basic amine
in the ribose binding region with the non-basic 3-
amino-4-hydroxy-tetrahydrofuran ring in analog 19
resulted in >100 fold selectivity against all 48 kinases
screened. In addition, replacement of the entire amide
sidechain with a 3-methylisoxazole exhibited excellent
selectivity in 46/48 kinases with some activity in
MAP4K4 and Mer (analog 21).
heterocyclic rings or a non-basic bromine atom while
maintaining potent Sky inhibition and functional P-
selectin activity. Analog 24 exhibited the best profile
of Sky inhibition, functional activity, metabolic
stability, and inhibition of CYP2D6 and dofetilide
binding, although the aqueous solubility and cellular
permeability are not predictive of good oral
bioavailability. We believe that these results will aid
in the future design of Sky inhibitors with improved
drug-like properties, and that analogs 11 and 12
represent suitable tool compounds for use in in vitro
and in vivo studies to probe the effects of Sky
inhibition.
References
Table 5. Heatmap of kinase selectivity for selected compounds.a
1. Powell, N. A.; Hoffman, J.; Ciske, F. L.; Kohrt, J.
T.; Kaufman, M.; Quin, J.; Sheehan, D.; Edmunds, J. J.;
Delaney, A.; Baxi, S.; Peng, Y.-W.; Bourbonaise, F,;
Lee, D.-Y.; Schwende, F.; Chen, H.; Catana, C.; Ohren,
J.; Perrin, L. A. Bioorg. Med. Chem. Lett. Submitted.
2. Saller, F.; Burnier, L.; Schapira, M.; Angelillo-
Scherrer, A. Blood Cells, Molecules, and Diseases 2006,
36, 373-378.
3. Angelillo-Scherrer, A.; de Frutos, P. G.; Aparicio,
C.; Melis, E.; Savi, P.; Lupu, F.; Arnout, J.; Dewerchin,
M.; Hoylaerts, M. F.; Herbert, J.-M.; Collen, D.;
Dahlbäck, B.; Carmeliet, P. Nature Med. 2001, 7, 215-
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ABL
AKT1
Aurora-A
BTK
CAMK1
CDK2/cyclni A
CDK6/ cyclinD3
CHK1
CHK2
CK2
CKI-delta
CLK1
ECK
EGFR
FGFR1
GSK3-beta
IKK-beta
IKK
INSR
JAK3
LCK
MAP3K9
MAP4K4
MAPK1/ERK2
MAPKAPK- 2
MARK1
MASK
MST2
MYLK2
NEK2
4. Gould, W. R.; Baxi, S. M.; Schroeder, R.; Peng, Y.
W.; Leadley, R. J.; Peterson, J. T.; Perrin, L. A. J.
Thromb. Haemost. 2005, 3, 733-741.
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PDK1
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PKA
5. Ozeki, K.; Ichikawa, T.; Takehara, H.; Tanimura, K.;
Sato, M.; Yaginuma, H. Chem. Pharm. Bull. 1989, 37,
1780-1787.
PKC-betaI
PKCzeta
ROCK1
S6K_T389E_D3E
SAPK2A/p38
SGK
6. a) Shattil, S. J.; Cunningham, M.; Hoxie, J. A. Blood
1987, 70, 307-315. b) Sbrana, S.; Della Pina, F.; Rizza,
A.; Buffa, M.; De Filippis, R.; Gianetti, J.; Clerico, A.
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SRC
TAOK3
TGFR-1
TRK-A
VEGFR2/FLK1
HGFR
Ax
Me
PF-03860333_Fold
PF-03971839_Fold
PF0- 4336135_Fold
PF0- 4350377_Fold
PF-04396796_Fold
11
12
15
19
21
a
Fold selectivity (kinase IC50/Sky IC50) colored by green = >100 fold,
yellow = 10-100 fold, red = <10 fold. IC50 data for individual kinases
can be found in the Supplementary Information available on-line.
In summary, we found that improved rat liver
microsome (RLM) stability in a series of 2,4-
diaminopyrimidine-5-carboxamide inhibitors of Sky
kinase could be achieved by modification of the amide
sidechain. This effort resulted in analogs 11 and 12,
which exhibited good RLM stability and good oral
bioavailability in the rat. To aid in future druggability,
we were able to improve HLM stability by replacing
the 2-benzylamino substituent with a 2-anilino group.
Sky inhibition could also be improved by the addition
of polar basic and non-basic functionalities in the 4-
amino group that binds in the ribose binding region,
although this resulted in reduced cellular permeability.
The amide sidechain could be replaced with small

Highly Selective 2,4-Diaminopyrimidine-5-
carboxamide Inhibitors of Sky Kinase
Noel A. Powell, Jennifer K. Hoffman, Fred L. Ciske,
Jeffrey T. Kohrt, Sangita M. Baxi, Yun-Wen Peng, Min
Zhong, Cornel Catana, Jeff Ohren, Lisa A. Perrin, and
Jeremy J. Edmunds
Pfizer Global Research & Development, Michigan
Laboratories, Ann Arbor, MI 48105 USA
Optimization of the ADME properties of a series of 2,4-
diaminopyrimidine-5-carboxamide inhibitors of Sky kinase
resulted in the identification of highly selective compounds
with properties suitable for use as in vitro and in vivo tools to
probe the effects of Sky inhibition.