First generation 5-vinyl-3-pyridinecarbonitrile PKCθ inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.08.086

A series of 5-vinyl-3-pyridinecarbonitriles were synthesized and evaluated as PKCθ inhibitors. The systematic optimization of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-3-pyridinecarbon itrile 3 resulted in the identification of compound 23e

Full text of DOI:10.1016/j.bmcl.2009.08.086

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5829–5832
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
First generation 5-vinyl-3-pyridinecarbonitrile PKCh inhibitors
a
a
a
a
a
Chuansheng Niu a, , Diane H. Boschelli , L. Nathan Tumey , Niala Bhagirath , Joan Subrath , Jaechul Shim ,
*
Yan Wang a, Biqi Wu a, Clark Eid a, Julie Lee b, Xiaoke Yang b, Agnes Brennan b, Divya Chaudhary b
a Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, United States
b Wyeth Research, Inflammation, 200 Cambridge Park Drive, Cambridge, MA 02140, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 5-vinyl-3-pyridinecarbonitriles were synthesized and evaluated as PKCh inhibitors. The sys-
tematic optimization of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-3-pyridinecarboni-
trile 3 resulted in the identification of compound 23e as a potent PKCh inhibitor with good selectivity
over PKCd.
Received 15 July 2009
Revised 24 August 2009
Accepted 26 August 2009
Available online 29 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
PKCh inhibitor
Selectivity
PKCd
3-pyridinecarbonitrile
The protein kinase Cs (PKCs) are a family of serine-threonine ki-
nases that vary in their expression and mode of activation.1 The
search for more potent and selective PKCh inhibitors with better
physicochemical properties, we expanded SAR studies for the 3-
pyridinecarbonitriles by replacement of the phenyl group at C-5
with other groups. Herein we report on the synthesis and biologi-
cal activities of the first generation of 5-vinyl-3-pyridinecarboni-
trile PKCh inhibitors.
conventional or classical isoforms (
a
, b, and
c) require both cal-
cium and diacylglycerol (DAG), the novel isoforms (d,
e, g
, and h)
require only DAG and the atypical isoforms (n and k) require nei-
ther calcium or DAG.
PKCh, a novel isoform, is predominantly expressed on lympho-
cytes and mast cells and plays a key role in T cell signaling.2,3 Stud-
ies with PKCh knock out (KO) mice showed that these animals were
resistant to the development of T cell mediated diseases including
asthma,4,5 arthritis6 and multiple sclerosis.7,8 These findings sug-
gest that small molecule inhibitors of PKCh may be useful in the
treatment of various autoimmune diseases. Among the PKC iso-
forms, PKCd has the closest homology to PKCh.3 The ATP binding
sites of these two kinases differ by only one amino acid. Selectivity
for PKCh is desirable considering reports that PKCd deficiency in
mice led to a hyperproliferation of B cells and overproduction of
inflammatory cytokines.9,10 Therefore PKCd was used as the pri-
mary counter assay in our PKCh inhibitor program.
NH
O
N
HN
N
N
CN
1
Starting from intermediate 213 the (E)-isomer 3 and the (Z)-isomer
4 were prepared utilizing Suzuki coupling as shown in Scheme 1.
Analog 3 having IC50 values of 8.3 nM and 72 nM for the inhibition
of PKCh and PKCd, respectively, was more potent and selective than
4, which had IC50 values of 79 nM and 350 nM for the inhibition of
PKCh and PKCd.
A
number of small molecules have been reported to be
ATP-competitive inhibitors of PKCh including 3-pyridinecarbonitr-
iles,11–15 thieno[2,3-b]pyridine-5-carbonitriles,16–18 and 2,4-diami-
no-5-nitropyrimidines.19 Earlier research in our lab identified the
5-phenyl-3-pyridinecarbonitrile 113 which had an IC50 value of
7.4 nM for the inhibition of PKCh and an IC50 value of 51 nM for
the inhibition of PKCd. However, compound 1 had metabolic stabil-
ity issues and its selectivity against PKCd was only 6.9-fold. To
NH
NH
a
NH
b
HN
HN
HN
CN
CN
I
CN
N
N
N
3
2
4
* Corresponding author. Tel.: +1 845 602 5996; fax: +1 845 602 5561.
E-mail address: niuc@wyeth.com (C. Niu).
Scheme 1. Reagents: (a) trans-2-phenylvinylboronic acid, Pd(PPh3)4, aq NaHCO3,
DME; (b) cis-2-phenylvinylboronic acid, Pd(PPh3)4, aq NaHCO3, DME.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.086

5830
C. Niu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5829–5832
Keeping the C-5 group on the pyridine ring of 3 constant, ana-
O2N
O2N
H2N
b
d
a
logs were prepared varying the indolyl group at C-4 (Scheme 2).
Reaction of key intermediate 513 with 5-aminoindole gave 6. Suzu-
ki coupling of 6 with trans-2-phenylvinylboronic acid provided 7a.
Coupling of 5 to trans-2-phenylvinylboronic acid gave compound
8, which was then reacted with 4-aminoindole, 6-aminoindole,
5-amino-1-methylindole, and 5-amino-2-methylindole to provide
7b–e, respectively. As shown in Table 1, using 3 as the reference
compound, the 5-indolyl analog 7a had threefold reduced potency.
The 4-indolyl isomer 7b was slightly less potent in inhibiting PKCh
than 3. However, the 6-indolyl analog 7c with an IC50 value of
1400 nM had greatly reduced PKCh inhibitory activity. Reduced po-
tency was also observed with the 2-Me-5-indolyl analog 7e which
had an IC50 value of only 360 nM. The 1-Me-5-indolyl analog 7d
had greatly decreased activity illustrating the importance of the
proton at N-1 of the indole. These SAR studies showed the same
trend as in our earlier report.13
N
N
N
H
H
H
9
10
11
NO2
NH
NH
c
AcHN
H2N
AcHN
R1
12
13
14
R2
R2
N
N
R1
HN
Cl
HN
f
e
I
CN
I
CN
CN
N
N
N
16a-e
5
15a-e
Further variation of the substituents on the indole ring resulted
in two new indolyl headpieces as depicted in Scheme 3. 5-Amino-
2,4-dimethylindole 11 was obtained by following the reported pro-
cedure for the preparation of 5-amino-4-methylindole20 starting
from 2-methyl-5-nitroindole 9. Conversion of 12 to substituted in-
dole 13 was achieved by using vinyl Grignard reagent.21 Removal
of the acetyl protecting group produced the desired 5-amino-4,7-
dimethylindole 14. Reaction of these indolyl headpieces 11, 14,
5-amino-1,4-dimethylindole, 5-amino-6-chloroindole, and 5-ami-
no-7-chloro-4-methylindole with 5 provided 15a–e, respectively.
Heck reaction of 15a with styrene gave 16a. Suzuki coupling of
Scheme 3. Reagents: (a) MeMgBr, THF; (b) H2, Pd/C, MeOH; (c) CH2CHMgBr, THF;
(d) KOH, EtOH; (e) for 15a: 11, EtOH; for 15b: 14, EtOH; for 15c: 5-amino-1,4-
dimethylindole, EtOH; for 15d: 5-amino-6-chloroindole, EtOH; for 15e: 5-amino-7-
chloro-4-methylindole, EtOH; (f) for 16a: styrene, Pd(OAc)2, P(o-tolyl)3, TEA, DMF;
for 16b and 16c: trans-2-phenylvinylboronic acid, Pd(PPh3)4, aq NaHCO3, DME; for
16d: trans-2-phenylvinylboronic acid pinacol ester, Pd(PPh3)4, aq NaHCO3, DME; for
16e: trans-2-phenylvinylboronic acid, Pd(PPh3)2Cl2, aq NaHCO3, DME.
15b–e with trans-2-phenylvinylboronic acid or its pinacol ester
provided analogs 16b–e, respectively. Although analogs 16a–e
had 4 to 25-fold reduced PKCh inhibitory activity compared to 3,
increased selectivity over PKCd was observed with 16b–e (Table
1). Among them, the 4,7-dimethyl-5-indolyl analog 16b was the
most potent and selective compound with an IC50 value of 34 nM
for the inhibition of PKCh and 41-fold selectivity over PKCd.
Next, replacement of the NH group at C-4 of 3 with O and NMe
was achieved as outlined in Scheme 4. Reaction of 5-hydroxyindole
or 5-hydroxy-4-methylindole with 5 gave intermediates 17a and
17b, respectively. Suzuki coupling of 17a and 17b with trans-2-
phenylvinylboronic acid afforded analogs 18a and 18b with an
ether linker at C-4. Both 18a and 18b had reduced inhibition of
PKCh activity compared to 3. Interestingly, addition of a methyl
group at C-4 of the indole ring of 18a to give the 4-methylindole
analog 18b resulted in an almost eightfold increase in activity with
good selectivity, compared to 18a. Treatment of 19 with 8 provided
20 bearing the NMe group at C-4. This analog also had significantly
reduced activity for the inhibition of PKCh with an IC50 value of
only 440 nM (Table 2). This SAR revealed that the C-4 NH group
is critical for PKCh inhibitory activity and is consistent with what
NH
b
NH
Cl
HN
N
HN
N
I
CN
b
a
I
CN
CN
R
N
5
6
7a
Cl
HN
CN
CN
c
N
N
8
7b-e
Scheme 2. Reagents: (a) 5-aminoindole, EtOH; (b) trans-2-phenylvinylboronic acid,
Pd(PPh3)4, aq NaHCO3, DME; (c) aminoindoles, EtOH.
Table 1
PKCh and PKCd inhibitory activity of C-5-vinylphenyl 3-pyridinecarbonitriles with
varying indolyl groups at C-4
NH
NH
R
O
R
O
Cl
I
CN
b
a
R
HN
I
CN
CN
CN
N
5
N
N
N
17a: R = H
17b: R = Me
18a: R = H
18b: R = Me
Ex
R
PKCh IC50 nM23
PKCd IC50 nM23
d/h
3
7a
7b
7c
7d
7e
16a
16b
16c
16d
16e
4-Me-5-indolyl
5-Indolyl
4-Indolyl
8.3
24
13
1400
4700
360
70
34
190
65
72
240
96
8.7
10
7.4
NA23
14
2.2
8.9
41
NH
H
N
c
NT23
64,000
800
N
N
6-Indolyl
N
CN
1-Me-5-indolyl
2-Me-5-indolyl
2,4-Di-Me-5-indolyl
4,7-Di-Me-5-indolyl
1,4-Di-Me-5-indolyl
6-Cl-5-indolyl
7-Cl-4-Me-5-indolyl
H
19
620
20
1400
3500
1100
880
18
17
11
Scheme 4. Reagents: (a) for 17a: 5-hydroxyindole, K2CO3, MeCN; for 17b: 5-hydr-
oxy-4-methylindole, K2CO3, MeCN; (b) trans-2-phenylvinylboronic acid, Pd(PPh3)4,
aq NaHCO3, DME; (c) 8, EtOH.
77

C. Niu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5829–5832
5831
Table 2
Table 3
PKCh and PKCd inhibitory activity of 3-pyridinecarbonitriles with various groups at C-
PKCh and PKCd inhibitory activities of C-5-vinylphenyl 3-pyridinecarbonitriles with
4 and C-5
alkoxy groups on the phenyl ring
NH
NH
R
X
HN
RO
CN
L
CN
Ring
N
N
Ex
R
Ring
L
X
PKCh
PKCd
h/d
Ex
OR
PKCh
PKCd
d/h
T1/2 (min)
IC50 nM23
IC50 nM23
IC50 nM23
IC50 nM23
RLM23
3
Me
H
Me
H
Me
Me
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Cyclohexyl
Vinyl
Vinyl
Vinyl
Vinyl
Ethyl
Vinyl
NH
O
O
NMe
NH
NH
8.3
690
90
440
34
72
8.7
NA23
18
23
20
23a
23b
23c
23d
2-OMe
3-OMe
4-OMe
2-OCH2CH2-N-Me-
piperazine
3-OCH2CH2-N-Me-
piperazine
4-OCH2CH2-N-Me-
piperazine
8.2
7.0
13
110
62
150
34
13
8.9
12
18a
18b
20
21
22
NT23
1600
10,000
670
7.6
4.5
5
21
5
26
420
16
23e
23f
4.7
3.6
53
41
11
11
was seen in the 4-(indol-5-ylamino)thieno[2,3-b]pyridine-5-car-
bonitriles and other series of 3-pyridinecarbonitriles.13,16
23g
23h
23i
2-OCH2CH2-pyrrolidine
3-OCH2CH2-pyrrolidine
4-OCH2CH2-pyrrolidine
13
4.7
9.1
140
25
81
11
5.3
8.9
10
11
21
Saturation of the C-5 vinyl bridge of 3 by hydrogenation gave
the C-5 ethyl analog 21 (Scheme 5). Replacement of the phenyl ring
of 3 with cyclohexane produced analog 22. As shown in Table 2,
while 21 and 22 were weaker PKCh inhibitors than 3, modestly en-
hanced selectivity over PKCd was observed.
NH
NH
The above SAR studies demonstrated the critical role of the 5-
amino-4-methylindole group at C-4 and of the C-5 vinylphenyl
group to achieve good potency for the inhibition of PKCh. The
earlier report on the series of 5-phenyl-3-pyridinecarbonitriles
revealed that incorporating a water solubilizing group on the phe-
nyl ring to provide analogs such as 1, improved the PKCh inhibitory
activity and physicochemical properties.13 Therefore further SAR
studies focused on the modification of the C-5 vinylphenyl group.
The analogs in Table 3 were prepared as shown in Scheme 6. Heck
reaction of 2 with 2-methoxystyrene afforded 23a. Suzuki coupling
of 2 to 3- or 4-methoxyphenylvinyl boronic acids gave 23b and
23c. Treatment of 2 with tributyl(vinyl)tin gave 24, which was
reacted with 2-, 3- or 4-bromophenyl 2-chloroethyl ether followed
by reaction with amines, providing compounds 23d–h bearing
water solubilizing groups on the phenyl ring. Heck coupling of 24
with 1-[2-(4-bromophenoxy)ethyl]pyrrolidine provided 23i.
The 2-OMe analog 23a had an IC50 value of 8.2 nM for the inhi-
bition of PKCh and was 13-fold selective over PKCd. The 3-OMe
analog 23b retained the potency and selectivity of 3. The 4-OMe
analog 23c had an IC50 value of 13 nM for the inhibition of PKCh
with slightly enhanced selectivity over PKCd. Analogs 23d–i bear-
ing water solubilizing groups had IC50 values ranging from 3.6 to
13 nM for the inhibition of PKCh. Minimal variation in selectivity
a
HN
HN
RO
NH
CN
I
CN
N
N
23a-i
2
b
c
HN
N
CN
24
Scheme 6. Reagents: (a) for 23a: 2-methoxystyrene, Pd(OAc)2, P(o-tolyl)3, TEA,
DMF; for 23b: 3-methoxyphenylvinyl boronic acid pinacol ester, Pd(PPh3)4, satd
NaHCO3, DME; for 23c: 4-methoxyphenylvinyl boronic acid, Pd(PPh3)4, satd
NaHCO3, DME; (b) tributyl(vinyl)tin, Pd(PPh3)4, toluene, DMF; (c) for 23d–h: (1)
2-, 3-, or 4-bromophenyl 2-chloroethyl ether, Pd(OAc)2, P(o-tolyl)3, TEA, DMF; (2)
amines, NaI, DME; for 23i: 1-[2-(4-bromophenoxy)ethyl]pyrrolidine, Pd(OAc)2, P(o-
tolyl)3, TEA, DMF.
for PKCh over PKCd was seen, with 23d–i being 4.5–11-fold selec-
tive. Of these, 23d had an IC50 value of 7.6 nM for the inhibition of
PKCh, but was only 4.5-fold selective over PKCd. Switching the sol-
ubilizing group from the ortho- to para-position on the phenyl ring
increased the potency and selectivity with 23f having IC50 values of
3.6 nM and 41 nM for the inhibition of PKCh and PKCd, respec-
tively. Analog 23f was also more potent and selective than the pre-
viously reported inhibitor 1. Good potency and selectivity was seen
with the meta-substituted analog 23e, which had an IC50 value of
4.7 nM for the inhibition of PKCh with 11-fold selectivity over
PKCd. Great improvement in rat liver microsome metabolic stabil-
ity was also observed with 23e which had a half-life of 21 min
compared to 23d (5 min) and 23f (5 min). Analog 23g had an IC50
value of 13 nM for the inhibition of PKCh and was 11-fold selective
over PKCd. The isomer 23h increased the PKCh inhibitory potency
(4.7 nM), but was only 5.3-fold selective over PKCd. Analog 23i
had IC50 values of 9.1 nM and 81 nM for the inhibition of PKCh
and PKCd, respectively. It also had improved metabolic stability
in rat liver microsomes with a half-life of 21 min compared to
23g (10 min) and 23h (11 min).
NH
NH
a
HN
N
HN
N
CN
CN
3
21
NH
NH
b
+
HN
N
HN
N
I
CN
CN
2
22
Scheme 5. Reagents: (a) H2, Pd/C, MeOH; (b) Pd(OAc)2, P(o-tolyl)3, TEA, DMF.

5832
C. Niu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5829–5832
Analog 23e was profiled against additional PKC family mem-
bers. While 23e had IC50 values of 330 nM and 7 nM for the inhibi-
tion of the novel isoforms PKC and PKC , respectively, it was a
weak inhibitor of PKCb (IC50 = 1.3 M), a classical isoform. No inhi-
bition of PKCf, an atypical isoform, was observed (IC50 >100 M).
Additional kinase profiling of 23e provided IC50 values of 520 nM
isopropyl analog 32 had further reduced activity with an IC50 value
of greater than 19 M for the inhibition of PKCh.
l
g
e
In summary, we have described the synthesis and biological
evaluation of the first generation of 5-vinyl-3-pyridinecarbonitriles
as PKCh inhibitors. This report identified compound 23e as a potent
PKCh inhibitor with good selectivity over PKCd. With this founda-
tion, we are continuing to develop the SAR of this series. Ongoing
efforts to further enhance the potency of this series against PKCh,
selectivity over PKCd, and optimize the physicochemical properties
of the series will be reported in due course.
l
l
for both Lyn and Lck and greater than 8
and ROCK1.
lM for MK2, p38, PDGFR,
The cellular activity of 23e was evaluated in an assay using T
cells stimulated with anti-CD3 and anti-CD28 to induce IL-2
expression.11 Analog 23e blocked the production of IL-2 with an
IC50 value of 110 nM in the T cells isolated from wild-type (WT)
mice. As was expected based on the rather selective inhibition of
PKCh, the compound had a greatly reduced activity with T cells
from PKCh KO mice (IC50 >3300 nM). It should be noted that some
of the activity in these cell assays may be due to off target activities
by 23e. In pharmaceutical profiling assays, 23e had good perme-
ability of 3.28 ꢀ 10ꢁ6 cm/s in a PAMPA format, but poor solubility
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
selectivity results, the Wyeth Discovery Synthetic Chemistry and
Chemical Development departments for the preparation of multi
gram batches of both 5 and 5-amino-4-methylindole, Zhen Lin
and Angela Bretz for the rat liver microsome half-lives, and Dr. Tar-
ek Mansour for his support.
at pH 7.4 (5 lg/mL). It also exhibited acceptable metabolic stability
in mouse and human liver microsomes with half-lives of 16 min
and 20 min, respectively.
Lastly, modification of the C-6 position of 3 by addition of an al-
kyl group is shown in Scheme 7. Bromination of 6-methylpyridone
2522 followed by treatment with 1,10-carbonyldiimidazole and
ammonium hydroxide gave pyridone 26. Subsequently, dehydra-
tion and concomitant chlorination of 26 with phosphorus oxychlo-
ride afforded the key intermediate 27. Reaction of 27 with
5-amino-4-methylindole followed by Suzuki coupling with trans-
2-phenylvinylboronic acid produced C-6 methyl substituted ana-
log 28. Treatment of 27 with lithium bis(trimethylsilyl)amide fol-
lowed by the addition of iodomethane gave intermediates 29 and
30. The desired analog 31 with an ethyl group at C-6 and 32 with
an isopropyl group at the C-6 position were prepared by the same
procedure used for the preparation of 28. The methyl substituted
analog 28 retained potency as compared to 3, with an IC50 value
of 9 nM for the inhibition of PKCh. This was accompanied by en-
hanced selectivity for PKCd (IC50 = 250 nM). However, extending
the methyl group at the C-6 position to an ethyl group, as in 31 sig-
References and notes
1. Spitaler, M.; Cantrell, D. A. Nat. Immunol. 2004, 5, 785.
2. Hayashi, K.; Altman, A. Pharmacol. Res. 2007, 55, 537.
3. Baier, G.; Telford, D.; Giampa, L.; Coggeshall, K. M.; Baier-Bitterlich, G.; Isakov,
N.; Altman, A. J. Biol. Chem. 1993, 268, 4997.
4. Salek-Ardakani, S.; So, T.; Halteman, B. S.; Altman, A.; Croft, M. J. Immunol.
2004, 173, 6440.
5. Marsland, B. J.; Soos, T. J.; Spaeth, G.; Littman, D. R.; Kopf, M. J. Exp. Med. 2004,
200, 181.
6. Healy, A. M.; Izmailova, E.; Fitzgerald, M.; Walker, R.; Hattersley, M.; Silva, M.;
Siebert, E.; Terkelsen, J.; Picarella, D.; Pickard, M. D.; LeClair, B.; Chandra, S.;
Jaffee, B. J. Immunol. 2006, 177, 1886.
7. Salek-Ardakani, S.; So, T.; Halteman, B. S.; Altman, A.; Croft, M. J. Immunol.
2005, 175, 7635.
8. Tan, S.-L.; Zhao, J.; Bi, C.; Chen, X. Y. C.; Hepburn, D. L.; Wang, J.; Sedgwick, J. D.;
Chintalacharuvu, S. R.; Na, S. J. Immunol. 2006, 176, 2872.
9. Mecklenbraeuker, I.; Saijo, K.; Zheng, N. Y.; Leitges, M.; Tarakhovsky, A. Nature
2002, 416, 860.
10. Miyamoto, A.; Nakayama, K.; Imaki, H.; Hirose, S.; Jiang, Y.; Abe, M.;
Tsukiyama, T.; Nagahama, H.; Ohno, S.; Hatakeyama, S.; Nakayama, K. I.
Nature 2002, 416, 865.
nificantly reduced the PKCh inhibitory activity (IC50 = 1.4 lM). The
11. Cole, D. C.; Asselin, M.; Brennan, A.; Czerwinski, R.; Ellingboe, J. W.; Fitz, L.;
Greco, R.; Huang, X.; Joseph-McCarthy, D.; Kelly, M. F.; Kirisits, M.; Lee, J.; Li, Y.;
Morgan, P.; Stock, J. R.; Tsao, D. H. H.; Wissner, A.; Yang, X.; Chaudhary, D. J.
Med. Chem. 2008, 51, 5958.
12. Dushin, R. G.; Nittoli, T.; Ingalls, C.; Boschelli, D. H.; Cole, D. C.; Wissner, A.; Lee,
J.; Yang, X.; Morgan, P.; Brennan, A.; Chaudhary, D. Bioorg. Med. Chem. Lett.
2009, 19, 2461.
13. Boschelli, D. H.; Wang, D.; Prashad, A. S.; Subrath, J.; Wu, B.; Niu, C.; Lee, J.;
Yang, X.; Brennan, A.; Chaudhary, D. Bioorg. Med. Chem. Lett. 2009, 19, 3623.
14. Subrath, J.; Wang, D.; Wu, B.; Niu, C.; Boschelli, D. H.; Lee, J.; Yang, X.; Brennan,
A.; Chaudhary, D. Bioorg. Med. Chem. Lett. 2009, 19, 5423.
15. Prashad, A. S.; Wang, D.; Subrath, J.; Wu, B.; Lin, M.; Zhang, M.-Y.; Kagan, N.;
Lee, J.; Yang, X.; Brennan, A.; Chaudhary, D.; Xu, X.; Leung, L.; Wang, J.;
Boschelli, D. H. Bioorg. Med. Chem. Lett. 2009, 19, 5423.
16. Boschelli, D. H.; Wu, B.; Barrios Sosa, A. C.; Chen, J.; Asselin, M.; Cole, D. C.; Lee,
J.; Yang, X.; Chaudhary, D. Bioorg. Med. Chem. Lett. 2008, 18, 2850.
17. Tumey, L. N.; Boschelli, D. H.; Lee, J.; Chaudhary, D. Bioorg. Med. Chem. Lett.
2008, 18, 4420.
O
O
Cl
COOH
CONH2
Br
Br
CN
a
b
N
H
N
H
N
25
26
27
c
d
Cl
N
Br
CN
NH
R
HN
29 R = Et
30 R = i-Pr
CN
18. Wu, B.; Boschelli, D. H.; Lee, J.; Yang, X.; Chaudhary, D. Bioorg. Med. Chem. Lett.
2009, 19, 766.
c
N
28
NH
19. 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.;
Homon, C. A.; Farrell, T. M.; Grbic, H.; Hu, H.; Kaplita, P. V.; Liu, L. H.; Spero, D.
M.; Jeanfavre, D. D.; O’Shea, K. M.; White, D. M.; Woska, J. R.; Brown, M. L.
Bioorg. Med. Chem. Lett. 2007, 17, 225.
HN
CN
20. Jeon, Y. T.; Gluchowski, C. WO9731636, 1997.
21. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30,
2129.
22. Kilbourn, E. E.; Seidel, M. C. J. Org. Chem. 1972, 37, 1145.
23. For assay protocols see Ref. 11. The IC50 values are the mean of at least two
separate determinations with typical variation of less than 30% between
replicate values. NT: compound was not tested. NA: selectivity ratio is not
available. RLM: rat liver microsome.
R
N
31 R = Et
32 R = i-Pr
Scheme 7. Reagents: (a) (1) Br2, HOAc, pyridine; (2) 1.CDI, DMF; 2. aq NH4OH; (b)
POCl3; (c) (1) 4-Me-5-NH2-indole, EtOH; (2) trans-2-phenylvinylboronic acid,
Pd(PPh3)4, aq NaHCO3, DME; (d) LiHMDS, MeI, THF.