C-5 substituted heteroaryl-3-pyridinecarbonitriles as PKCθ inhibitors: Part II

Article abstract of DOI:10.1016/j.bmcl.2009.07.113

We previously reported that a 3-pyridinecarbonitrile analog with a furan substituent at C-5 and a 4-methylindol-5-ylamino substituent at C-4, 1, was a potent inhibitor of PKCθ (IC₅₀ = 4.5 nM). Replacement of the C-5 furan ring of 1 with bicycli

Full text of DOI:10.1016/j.bmcl.2009.07.113

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5799–5802
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
C-5 substituted heteroaryl-3-pyridinecarbonitriles as PKCh inhibitors: Part II
a,*
a
a
a
a
b
b
Amar S. Prashad , Daniel Wang , Joan Subrath , Biqi Wu , Melissa Lin , Mei-Yi Zhang , Natasha Kagan ,
c
c
c
c
d
e
e
Julie Lee , Xiaoke Yang , Agnes Brennan , Divya Chaudhary , Xin Xu , Louis Leung , Jack Wang ,
Diane H. Boschelli
a
a
Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, United States
Wyeth Research, Chemical Sciences, CN 8000, Princeton, NJ 08543, United States
Wyeth Research, Inflammation, 200 Cambridge Park Drive, Cambridge, MA 02140, United States
Wyeth Research, Drug Safety and Metabolism, 1 Burtt Road, Andover, MA 01810, United States
b
c
d
e
Wyeth Research, Drug Safety and Metabolism, 500 Arcola Road, Collegeville, PA 19426, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We previously reported that a 3-pyridinecarbonitrile analog with a furan substituent at C-5 and a 4-
methylindol-5-ylamino substituent at C-4, 1, was a potent inhibitor of PKCh (IC50 = 4.5 nM). Replacement
of the C-5 furan ring of 1 with bicyclic heteroaryl rings, led to compounds with significantly improved
potency against PKCh. Analog 6b with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpipera-
zin-1-yl)methyl]-1-benzofuran-2-yl group at C-5 had an IC50 value of 0.28 nM for the inhibition of PKCh.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 June 2009
Revised 22 July 2009
Accepted 24 July 2009
Available online 28 July 2009
Keyword:
PKCh
Protein kinases are critical regulators of cellular processes in
normal and disease states. The protein kinase C family is a group
Compound 1 displayed reasonable potency against PKCh kinase
activity with an IC50 value of 4.5 nM and had 10-fold selectivity
of serine threonine kinases that share sequence and structural
against PKCd, however it suffered from poor metabolic stabil-
1
15,16
homology. The classical PKC isoforms,
a
, bIbII, and
c, require the
ity.
In an effort to improve on the stability of 1, the C-5 furan
second messengers calcium and diacylglycerol (DAG). The novel
ring was replaced with various bicyclic heteroaryls while retaining
the optimal 4-methylindol-5-ylamino substituent at the 4-posi-
tion. A key intermediate 2 (Scheme 1) that facilitated the synthesis
of these compounds has been previously reported.12 Using this
intermediate many analogs of the desired bicyclic heteroaryl series
were prepared in an expedient manner.
isoforms, d, , and h, require DAG but not calcium. The atypical
e, g
isoforms, f and k, do not require either calcium or diacylglycerol.
PKCh is found predominantly in T cells and skeletal muscle. It
has been demonstrated that PKCh plays an integral role in the acti-
vation and survival of T cells.2 Validation studies using PKCh
knock-out (KO) mice have established therapeutic utility in dis-
eases such as multiple sclerosis, arthritis, asthma, inflammatory
–4
5
NH
bowel disease, and transplant rejection. However, despite this di-
verse therapeutic potential there is only scant published work on
selective small molecules targeting PKCh. Boehringer Ingelheim
has disclosed a series of 2,4-diaminopyrimidines,6 and we previ-
HN
CN
,7
O
N
8
,9
ously reported that thieno[2,3-b]pyridine-5-carbonitriles and 3-
N
1
0–12
pyridinecarbonitriles
can be used as templates for inhibitors
N
1
of this kinase. Regarding the 3-pyridinecarbonitriles, we earlier
demonstrated that a 4-methyl-5-indolyl amino group at the 4-po-
sition was optimum for potency against PKCh and selectivity
Thus advanced intermediate 2 was subjected to typical Suzuki
protocol using benzofuran-2-boronic acid and benzothiophene-2-
boronic acid to prepare compounds 3a and 4a, respectively
1
2
against PKCd. We used PKCd as our primary counter screen since
PKCd KO mice were found to be susceptible to the development of
(
Scheme 1). In order to add water solubilizing groups to the bicy-
1
3,14
autoimmune diseases.
clic heteroaryls, the 5-formyl analogs of benzofuran and benzo-
thiophene were prepared. The 5-formyl analog of benzofuran, 3b,
was prepared via a Stille coupling of 2 and 5, 2-(tributylstannyl)-
5
-benzofurancarboxaldehyde (Scheme 1). The stannane was
*
Corresponding author. Tel.: +1 845 602 5310; fax: +1 845 602 5561.
E-mail address: prashaa@wyeth.com (A.S. Prashad).
prepared by a two-step sequence involving DIBAL-H reduction of
0
960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.113

5
800
A. S. Prashad et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5799–5802
logs, exemplified by 3a, 6a, and 6b (IC50 = 1.7, 1.3, 0.28 nM, respec-
tively) showed greater potency against PKCh kinase activity than
their benzothiophene counterparts exemplified by 4a, 7a, and 7b
NH
NH
HN
R
X
HN
N
(
IC50 = 23, 2.5, 0.67 nM, respectively). This increase in potency
I
CN
a
CN
was accompanied by enhanced selectivity over PKCd in all three
of the examples mentioned above. For example, 6b (benzofuran
series) had an IC50 value of 17 nM for PKCd inhibition which corre-
sponds to a 61-fold selectivity for PKCh over PKCd, whereas for 7b
N
3a: X=O; R=H
3
4
4
b: X=O; R=CHO
2
a: X=S; R=H
b: X=S; R=CHO
(
benzothiophene series) the IC50 value was 9.9 nM which
b,c
corresponds to a 15-fold selectivity for PKCh over PKCd. Since the
benzofuran series exhibited superior potency for PKCh inhibitory
activity and enhanced selectivity over PKCd compared to the
benzothiophene series, further modifications were confined to
the benzofuran series.
Table 2 shows various benzofuran analogs, 6a–m where the
amine in the reductive amination protocol was varied (see
Scheme 2). Compounds 6a–m with various types of amine substit-
uents displayed generally good potency against PKC theta, ranging
from an IC50 value of 0.28 nM for 6b to 15 nM for 6l. Many of the
compounds with secondary amine substituents, such as 6a, b, d
were significantly more selective for PKCh over PKCd than those
compounds with primary amine substituents, whereas others such
as 6c,e exhibited similar selectivity. In fact, the most selective
compound with a secondary amine was 6b having a selectivity of
NC
OHC
O
O
SnBu3
5
Scheme 1. (a) Reagents and conditions: for 3a: 2.0 equiv benzofuran-2-boronic
acid, 0.05 equiv Pd(PPh aq Na CO DME, 80 °C, 2 h; for 3b: 1.5 equiv 5,
.05 equiv Pd(PPh , DMF, 80 °C, 2 h; for 4a: 1.1 equiv benzothiophene-2-boronic
acid, 0.05 equiv Pd(PPh , aq Na CO , DME, 100 °C, 12 h; for 4b: 1.1 equiv 2-(4,4,
,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophene-5-carboxaldehyde, 0.05
equiv Pd(PPh , aq Na CO , DME, 100 °C, 12 h; (b) 1.2 equiv DIBAL-H, CH Cl
SnCl,
3
)
4
,
2
3
,
0
3 4
)
3
)
4
2
3
5
3
)
4
2
3
2
2
,
À15 °C, 10 min; (c) 3.3 equiv nBuLi, 1.1 equiv N-Me-piperazine, 2.2 equiv Bu
3
THF, 0 °C, 6h.
R2
N
NH
NH
R1
O
H
X
HN
X
HN
N
6
1-fold for PKCh over PKCd. The most selective compound with a
a
CN
CN
primary amine substituent was 6i having a selectivity of 10-fold
for PKCh over PKCd.
N
At this juncture, the N-Me-piperazine analog, 6b, exhibited the
best overall potency and selectivity profile and hence an expanded
SAR (structure–activity relationships) analysis was conducted on
this piperazine moiety. Table 2 shows SAR on analog 6b where
the substituent on the distal N of the piperazine ring was varied.
These compounds were prepared (Scheme 2) using the corre-
sponding amine in the reductive amination protocol with 3b. In
going from a methyl to an ethyl substituent; that is, from 6b to
3
b: X=O
6a-m: X=O
7a,b: X=S
4b: X=S
1
2
Scheme 2. (a) Reagents and conditions: for 6a–i, k, m: 3.0 equiv R R NH, 5.5 equiv
1
2
AcOH, 3.0 equiv Na(OAc)
3
BH, THF/EtOH, rt, 12 h; for 6j, l: 4.0 equiv R R NH,
BH, CH Cl /NMP, rt, 12 h; for 7a: 2.0 equiv
R R NH, 1.2 equiv AcOH, 1.3 equiv NaCNBH , EtOH, rt, 12 h; for 7b: 5.0 equiv
BH, THF, rt, 12 h.
4
.0 equiv AcOH, 5.0 equiv Na(OAc)
3
2
2
1
2
3
1
2
R R NH, 5.0 equiv AcOH, 5.0 equiv Na(OAc)
3
6
6
j, the PKCh IC50 value decreased only slightly, from 0.28 nM in
b to 0.48 nM in 6j, while the PKCd inhibitory activity was virtually
1
-benzofuran-5-carbonitrile to give the corresponding aldehyde
unchanged (IC50 = 17 and 16 nM for 6b and 6j, respectively). Ana-
log 6k, with a 2-dimethylamino(ethyl) substituent on the N of
the piperazine ring, had about 10-fold reduced potency for PKCh
inhibition relative to 6b, and its selectivity for PKCh over PKCd
was significantly lower. The methyl sulfone, 6l (PKCh IC50 = 15 nM),
and 2-pyridyl, 6m (PKCh IC50 = 13 nM), analogs however, exhibited
both diminished activity and selectivity relative to 6b. The methyl
substituted analog, 6b, stood out as the most potent and selective
compound of all the analogs not only in the piperazine subseries
but also in the entire C-5 benzofuran series.
which upon treatment with nBuLi/N-Me-piperazine and tributyltin
chloride resulted in intermediate 5. The 5-formyl analog of benzo-
thiophene, 4b, was prepared in a similar manner to 3a and 4a using
the corresponding boronic acid, pinacol ester as shown in Scheme
1. The aldehydes 3b and 4b were then subjected to a reductive
amination protocol, as shown in Scheme 2, using various amines
to provide analogs shown in Tables 1 and 2.
Table 1 shows three exact comparisons between benzofuran
and benzothiophene analogs. In all three cases the benzofuran ana-
Table 1
PKCh and PKCd inhibitory activity of benzofurans and benzothiophenes
NH
R
X
HN
CN
N
Ex
X
R
PKCh21 IC50 nM
PKCd21 IC50 nM
PKCd/PKCh
3a
4a
6a
7a
6b
7b
O
S
O
S
O
S
H
H
CH
CH
CH
CH
1.7
23
1.3
2.5
0.28
0.67
57
154
25
5.2
17
9.9
33
7
19
2
61
15
2
2
2
2
–piperidine
–piperidine
–N–Me–piperazine
–N–Me–piperazine

A. S. Prashad et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5799–5802
5801
Table 2
PKCh and PKCd inhibitory activity of benzofuran analogs with various substitutions at C-5
R2
N
NH
R1
O
HN
N
CN
Ex
NR1R2
PKCh21 (IC50 nM)
PKCd21 (IC50 nM)
PKCd/PKCh
6
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
g
h
i
Piperidine
N-Me-piperazine
1.3
0.28
6.4
2.9
13
1.4
1.6
2.3
1.5
0.48
2.4
15
25
17
44
43
121
10
13
21
16
16
19
61
7
15
9
7
8
9
10
33
8
9
12
2
Me N
Pyrrolidine
Morpholine
NH-cyclohexyl
NH(CH
NH(CH
2
)
)
2
OH
OH
2
3
NHCH
N-Et-piperazine
N-(CH NMe -piperazine
N-SO Me-piperazine
2
CH(OH)CH
2
OH
j
k
l
)
2 2
2
20
138
149
2
m
N-2-Pyridyl-piperazine
13
HN
NH
gle oxidation product (M+16). The major metabolite in monkey
and human microsomes was loss of the methyl group from the
N-Me-piperazine to give 8. This desmethyl analog was seen as a
minor metabolite in the rat and dog microsome studies. To iden-
tify the site of the oxidative metabolism, a large scale incubation
of 6b with rat microsomes was carried out to provide enough
material for an NMR study. Comparison of the proton spectra of
the parent and metabolite revealed the most significant difference
to be the chemical shifts of the N-Me of the piperazine and of the
adjacent methylene protons. The N-Me signal of 6b was observed
at 2.20 ppm while the corresponding signal for the metabolite
was at 3.16 ppm, suggesting that the major M+16 metabolite
was oxidation of the nitrogen substituted with the Me group to
provide 9. Accordingly these analogs were prepared in order to
assess their PKCh and PKCd inhibitory activities (Scheme 3). In
the preparation of 8, a similar reductive amination protocol as
in Scheme 2 was used where the amine was N-Boc piperazine.
After the reductive amination, the N-Boc group was cleaved with
trifluoroacetic acid to give 8. In the preparation of 9, 1-methylpi-
NH
O
H
N
O
HN
O
HN
a,b
CN
CN
N
N
c
8
3
b
O
N
NH
N
O
HN
CN
N
9
Scheme 3. Reagents and conditions: (a) 4.0 equiv N-Boc-piperazine, 4.0 equiv
AcOH, 5.0 equiv Na(OAc) BH, CH Cl /NMP, rt, 12 h; (b) 10% trifluoroacetic acid/
CH Cl , rt, 2h; (c) 5.0 equiv 1-methylpiperazine-1-oxide, 4.0 equiv AcOH, 5.0 equiv
Na(OAc) BH, CH Cl /NMP, rt, 12 h.
3
2
2
2
2
3
2
2
17
perazine-1-oxide was subjected to a reductive amination proto-
col with 3b to provide 9. Both of these metabolites displayed
about 20-fold decreased potency against PKCh activity compared
to 6b (Table 3). However, their selectivities over PKCd were quite
different with 8 having a selectivity of less than onefold while
that of 9 was 18-fold, both being significantly lower, relative to
that of 6b (61-fold).
Incubation of 6b with rat, mouse, and human liver microsomes
fortified with cytosol provided half-lives of 27, 17, and 26 min,
respectively. Reduced half-lives of 12 and 10 min were observed
with dog and monkey microsomes. Metabolite ID by LC/MS/MS
identified the major metabolite of 6b in rats and dogs to be a sin-
Table 3
Enzyme and cell activity of 6b and its metabolites
R
N
NH
N
O
HN
CN
N
Ex
R
PKCh21 (IC50 nM)
PKCd21 (IC50 nM)
WT T-cell IL221 (IC50 nM)
KO T-cell IL221 (IC50 nM)
6
8
9
b
Me
H
Me(O)
0.28
5.3
6.1
17
4.3
110
21
16
360
880
1500
>10,000

5
802
A. S. Prashad et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5799–5802
The cellular activities of 6b and its metabolites were evaluated
selectivity results, the Wyeth Discovery Synthetic Chemistry and
Chemical Development departments for the preparation of multi-
gram batches of both 2 and 5-amino-4-methylindole, Judy Tran
for the rat, mouse and human liver microsome half-lives, Adiba
Watanyar for the dog and monkey liver microsome half-lives and
the CYP IC50s, Uma Raut and Jennifer Spencer-Pierce for the rat
PK study, James Atherton for the rat plasma metabolite ID study
and Dr. Tarek Mansour for his support.
in assays using murine T cells stimulated with anti-CD3 and anti-
CD28 to induce IL-2 expression.10 With T cells from WT mice, 6b,
blocked the production of IL-2 with an IC50 value of 21 nM, a four-
1
5,16
fold increase in activity compared to that of 1 (IC50 = 86 nM
).
Reduced activity was seen in a corresponding assay with T cells
isolated from PKCh KO mice where 6b had an IC50 value of
.88 lM. This sub-micromolar IC50 seen in 6b for PKCh deficient
0
cells may be due, in part, to the inhibition of other kinases that
are involved in IL-2 production. The desmethyl metabolite of 6b;
that is, 8 had similar WT T cell IL-2 activity (IC50 = 16 nM) as 6b
whereas the N-oxide metabolite, 9, had greatly reduced activity
References and notes
1
2
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IC50 = 360 nM). It is unclear why there is a lack of correlation be-
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Marsland, B. J.; Kopf, M. Trends Immunol. 2008, 29, 179–185.
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While 6b only weakly inhibited PKCb (IC50 = 0.8
l
M), a classical
Cywin, C. L.; Dahmann, G.; Prokopowicz, A. S.; Young, E. R. R.; Magolda, R. L.;
Cardozo, M. G.; Cogan, D. A.; DiSalvo, D.; Ginn, J. D.; Kashem, M. A.; Wolak, J. P.;
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isoform, more potent inhibition of PKC and PKC
e
g, two novel PKCs
was observed, with 6b having IC50 values of 2.5 and 33 nM, respec-
tively. No inhibition of PKCn, an atypical isoform, was observed
(
IC50 >100
l
M). Some additional kinase profiling was done for 6b.
7. Prokopowicz, A. S.; Cywin, C. L.; Dahmann, G.; Young, E. R. R.; Magolda, R. L.;
Cardozo, M. G.; Cogan, D. A.; DiSalvo, D.; Ginn, J. D.; Kashem, M. A.; Wolak, J. P.;
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Compound 6b displayed exquisite selectivity for PKCh over other
kinases including MK2, p38, IKK, PDGFR, and ROCK1 having IC50
values of greater than 9
served for Lyn and Lck with 6b having IC50 values of 0.73 and
.26 M, respectively. However, this still represents an impressive
lM. Relatively lesser selectivity was ob-
8.
Boschelli, D. H.; Wu, B.; Barrios Sosa, A. C.; Chen, J.; Asselin, M.; Cole, D. C.; Lee,
0
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1
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Morgan, P.; Stock, J. R.; Tsao, D. H. H.; Wissner, A.; Yang, X.; Chaudhary, D. J.
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In pharmaceutical profiling assays, 6b had a good permeability
À6
of 3.96 Â 10 cm/s in a PAMPA format, with excellent solubility at
pH 4.5 (>100 lg/mL). In assays looking at the reversible inhibition
11. Dushin, R. G.; Nittoli, T.; Ingalls, C.; Boschelli, D. H.; Cole, D. C.; Wissner, A.; Lee,
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IC50s of greater than 10 M (CYPs 1A2, 2A6, 2C9, 2C19, 2D6, and
A4). Furthermore this compound was also a weak hERG inhibitor
having an IC50 value of greater than 30 M.
l
2009, 19, 2461.
3
12. Boschelli, D. H.; Wang, D.; Prashad, A. S.; Subrath, J.; Wu, B.; Niu, C.; Lee,
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Following a single iv dose of 2 mg/kg to male Sprague Dawley
rats, 6b had a clearance of 55 mL/min/kg and a volume of distribu-
tion of 7.3 L/kg. Following a single oral dose of 10 mg/kg, 6b had a
1
1
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present at about 20% with the N-oxide 9 being present at about 8%.
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Acknowledgments
We thank the Wyeth Chemical Technology department for
compound characterization and the pharmaceutical profiling re-
sults, the Wyeth Screening Sciences department for the kinase
1. For assay protocols see Ref. 10. IC50 values represent the mean of at least two
determinations.