Discovery of piperidinyl aminopyrimidine derivatives as IKK-2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.03.044

A serine-threonine kinase IKK-2 plays an important role in activation of NF-κB through phosphorylation of the inhibitor of NF-κB (IκB). As NF-κB is a major transcription factor that regulates genes responsible for cell proliferation and inflammation, development of selective IKK-2 inhibitors has been an important area of anti-inflammatory and anti-cancer research. In this study, to obtain active and selective IKK-2 inhibitors, various substituents were introduced to a piperidinyl aminopyrimidine core structure. The structure-activity relationship study indicated that hydrogen, methanesulfonyl, and aminosulfonyl groups substituted at the piperidinylamino functionality provide high inhibitory activity against IKK-2. Also, morpholinosulfonyl and piperazinosulfonyl group substituted at the aromatic ring attached to the aminopyrimidine core significantly increased the inhibitory activity of the resulting derivatives. In particular, compound 17 with the aromatic piperazinosulfonyl substituent showed the most potent (IC₅₀ = 1.30 μM) and selective (over other kinases such as p38α, p38β, JNK1, JNK2, JNK3, and IKK-1) inhibitory activity against IKK-2.

Full text of DOI:10.1016/j.bmcl.2011.03.044

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3002–3006
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of piperidinyl aminopyrimidine derivatives as IKK-2 inhibitors
Sora Kim a,b, Jin Kyo Jung a,c, Hyo Seon Lee a, Youngjae Kim a,d, Jiyoon Kim a,e, Kihang Choi b, Du-Jong Baek c,
Bongjin Moon e, Kwang-Seok Oh f, Byung Ho Lee f, Kye Jung Shin a,g, Ae Nim Pae a, Ghilsoo Nam a,
Eun Joo Roh a, Yong Seo Cho a, Hyunah Choo a,d,
⇑
a Life/Health Division, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea
b Department of Chemistry, Korea University, Seongbuk-gu, Seoul 136-713, Republic of Korea
c Department of Chemistry, College of Natural Sciences, Sangmyung University, Seoul 110-743, Republic of Korea
d Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, Republic of Korea
e Department of Chemistry, Sogang University, Seoul, Republic of Korea
f Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
g College of Pharmacy, The Catholic University of Korea, Seongsim Campus, Bucheon, Gyeonggi-do, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A serine–threonine kinase IKK-2 plays an important role in activation of NF-jB through phosphorylation
of the inhibitor of NF-jB (IjB). As NF-jB is a major transcription factor that regulates genes responsible
Received 19 January 2011
Revised 9 March 2011
Accepted 11 March 2011
Available online 17 March 2011
for cell proliferation and inflammation, development of selective IKK-2 inhibitors has been an important
area of anti-inflammatory and anti-cancer research. In this study, to obtain active and selective IKK-2
inhibitors, various substituents were introduced to a piperidinyl aminopyrimidine core structure. The
structure–activity relationship study indicated that hydrogen, methanesulfonyl, and aminosulfonyl
groups substituted at the piperidinylamino functionality provide high inhibitory activity against IKK-2.
Also, morpholinosulfonyl and piperazinosulfonyl group substituted at the aromatic ring attached to
the aminopyrimidine core significantly increased the inhibitory activity of the resulting derivatives. In
particular, compound 17 with the aromatic piperazinosulfonyl substituent showed the most potent
Keywords:
Rheumatoid arthritis
Inflammation
Aminopyrimidine
IKK-2
(IC50 = 1.30
lM) and selective (over other kinases such as p38
a
, p38b, JNK1, JNK2, JNK3, and IKK-1) inhib-
Kinase inhibitor
itory activity against IKK-2.
Ó 2011 Elsevier Ltd. All rights reserved.
NF-
responsible for anti-apoptosis, proliferation, and inflammation.1–3
NF- B suppression is beneficial in a host of animal models of
j
B is a major transcription factor that regulates genes
pathway is important for inflammation and the innate immune
system.9,10 Also, activation of IKK-2 stimulates anti-apoptotic and
proliferative pathways. Taken together, inhibitors of IKK-2 have
been being developed for treatment of inflammatory diseases such
as rheumatoid arthritis (RA) and chronic obstructive pulmonary
disease (COPD) as well as cancer.11,12 IMD-1041,13 GMX-1778
(CHS 828),14 and teglarinad chloride (GMX-1777)15 ( Fig. 1) are
three major IKK-2 inhibitors under clinical investigation for the
management of COPD (IMD-1041) and solid tumors and lym-
phoma (CHS828 and GMX-1777).
j
inflammatory disease and many therapeutic agents including cor-
ticosteroids, leflunomide, sulfasalazine, and aspirin are known to
mediate at least some of their effects through NF-
NF- B is sequestered as a dimer in the cytosol of unstimulated
cells via non-covalent interactions with the inhibitor proteins
(I B), and signals that induce NF- B activity cause phosphoryla-
tion of I Bs, their dissociation and subsequent degradation, allow-
ing NF- proteins to enter the nucleus and induce gene
expression.9 Phosphorylation of I
Bs and thereby activation of
NF- B is catalyzed by a serine–threonine kinase complex, I B ki-
nase (IKK), which is composed of three subunits, IKK-1 (IKK ),
IKK-2 (IKKb), and NEMO (IKK ). Among the subunits, IKK-2 plays
an important role in activation of NF- B, resulting in enhanced
production of TNF- IL-1, intercellular adhesion molecule
j
B blockade.4–8
j
j
j
j
jB
In contrast to the elucidated role of IKK-2 in the NF-jB pathway,
j
IKK-1 deficient mice presented an unexpected phenotype includ-
ing skeletal and skin abnormalities.16 Therefore, development of
selective IKK-2 inhibitors has been an important area of anti-
inflammatory and anti-cancer research. Among IKK-2 inhibitors,
aminopyrimidine derivatives have been reported to possess selec-
tivity over IKK-1.17 Herein, we describe our initial lead optimiza-
tion study of piperidinyl aminopyrimidines which led to
identification of novel selective IKK-2 inhibitors.
j
j
a
c
j
a,
(ICAM)-1, and cyclooxygenase (COX)-2, which indicates that this
Compounds with an aminopyrimidine core structure are com-
petitive inhibitors of IKK-2 with respect to the cofactor, ATP.17 As
most kinases uses ATP as a cofactor, it seems to be very difficult
⇑
Corresponding author. Tel.: +82 2 958 5157; fax: +82 2 958 5189.
E-mail address: hchoo@kist.re.kr (H. Choo).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.044

S. Kim et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3002–3006
CF3
3003
NC
N
N
O
O
X
N
H
N
H
N
H
CF3
Cl
OH
GMX-1778
IMD-1041
(assuming structure)
O
NC
O
O
O
N
N
O
O
O
Cl
O
N
H
N
H
Cl
teglarinad chloride
Figure 1. IKK inhibitors in clinical trials.
H
N
H
H
N
N
N
N
N
S
N
O
O
N
O
N
S
N
O
S
O
S
NH2
NH2
O
O
S
N
O
S
N
B IKK-2 IC50 19 nM
N
H
N
H
A IKK-2 IC50 64 nM
C IKK-2 IC50 11 nM
Figure 2. IKK-2 inhibitors with an aminopyrimidine core structure.
to obtain selectivity to IKK-2 over other kinases. According to the
literatures, however, introduction of proper substituents to the
core structure makes compounds selective to IKK-2 (Fig. 2).17 In
this study, we introduced an aryl group and a piperidin-4-yl group
at C4 and 2-NH2 position of the aminopyrimidine core structure,
respectively, to obtain inhibitory activity and selectivity to IKK-2.
The synthesis of title compounds, piperidinyl aminopyrimi-
dines, was started with 1-acetyl-4-substituted benzenes 1–4
(Scheme 1). The compounds 1–4 were treated with DMF-DMA
(N,N-dimethylformamide dimethyl acetal) at 150 °C to afford the
corresponding N,N-dimethylamino derivatives 5–8 in 82–98%
yields, which were converted to the compounds 9–12 with the
aminopyrimidine core structure. Treatment of one vinylogous
amide 5 with guanidine provided the aminopyrimidine core via
addition–elimination to the vinylogous amide 5 followed by cycli-
zation. Reductive amination of N-Boc-4-piperidone with the free
aminopyrimidine intermediate thus obtained, in the presence of
TiCl(OiPr)3 and NaBH(OAc)3 provided 9 in 20% yield for two steps.
On the other hand, direct condensation of the other vinylogous
amides 6–8 with N-(N-Boc-4-piperidinyl)-guanidinium chloride
in EtOH gave the corresponding aminopyrimidine derivatives
10–12 in 34–46% yields. The Boc protecting groups of the com-
pounds 9–12 were removed under acidic conditions with 30%
TFA in CH2Cl2 to give 13–16 in 66–99% yields. The carbobenzyloxy
(Cbz) protecting group in 16 was also removed by hydrogenolysis
to afford a piperazine-substituted compound 17.
18a–18m in 27–75% yields. Also, treatment of 13 with chlorosulfo-
nyl isocyanate and t-BuOH in CH2Cl2 followed by Boc-deprotection
under acidic conditions (30% TFA) provided the aminosulfonyl-
substituted derivative 18n in 80% yield. The compound 13 was
converted to the corresponding benzoylated compounds such as
3-F-, 4-F-, 3-OMe-, 4-OMe-, 2,4-di-OMe-, and 4-CF3-benzoylated
compounds (18o–18t) in 28–75% yields by using the appropriately
substituted benzoyl chlorides in the presence of pyridine and
DMAP in CH2Cl2 at À78 °C. N-Butylaminocarbonyl-piperidinyl ami-
nopyrimidine derivative 18u was obtained in 35% yield by reacting
13 with n-butyl isocyanate in pyridine at 120 °C. Reductive amina-
tion of formaldehyde with 13 afforded the methylated derivative
18v in 47% yield.
A selected group of the substituted aminopyrimidine deriva-
tives were prepared from compounds 14–16. Thus, the compound
14 was converted to 19l, 19n, and 19v with methanesulfonyl,
aminosulfonyl, and methyl groups substituted at the piperidinyla-
mino functionality. The compound 15 also underwent methane-
sulfonylation and aminosulfonylation to afford the derivatives
20l and 20n, respectively, and the same reactions with 16 followed
by Cbz deprotection furnished 22l and 22n.
A total of 33 compounds with the aminopyrimidine core struc-
ture were synthesized and biologically evaluated against IKK-2.
Assay for IKK-2 inhibitors was done by using TR-FRET (Time-Re-
solved Fluorescence Resonance Energy Transfer) method on IMAPÒ
platform.18 For the assay, 5-carboxyfluoresceinylated (5-FAM)
Various substituents such as sulfonyl, benzoyl, urea, and methyl
group were introduced to the free piperidinylamino functionality
of the compound 13. Thus, the compound 13 was treated with var-
ious benzenesulfonyl chlorides with aromatic substituents or
alkylsulfonyl chlorides such as CH3SO2Cl and CF3SO2Cl under basic
conditions to give the corresponding sulfonylated derivatives
I
j
B
a
-derived peptide, 5-FAM-GRHDSGLDSMK-NH2, was used as
substrate of IKK-2 and IMAP binding reagent and terbium donor
were added for detection reaction. In the primary assay,
inhibition of each compound at fixed concentration (10
against IKK-2 was measured and, only for those compounds which
showed more than 50% inhibition, the half maximal inhibitory
%
lM)

3004
S. Kim et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3002–3006
H
N
N
X
N
O
N
NBoc
O
b or c
a
X
X
1 X = Cl
9 X = Cl
5 X = Cl
O
O
O
S
O
N
N
N
O
N
S
O
N
N
N
O
2 X =
S
O
N
N
N
O
10 X =
6 X =
O
S
O
O
S
O
O
S
O
3
11
N
X =
7
N
X =
X =
O
S
O
O
S
O
O
S
O
4 X =
NCBz
12 X =
NCBz
8 X =
NCBz
d
a Y = PhSO2
b Y = 2-F-PhSO2
H
N
H
c Y = 3-F-PhSO2
N
X
N
N
d
Y = 4-F-PhSO2
e Y = 2,4-diF-PhSO2
N
N
N
NH
f, g, h, i or j
Y
f Y = 3-OCH3-PhSO2
g Y = 4-OCH3-PhSO2
h
Y = 2,5-diOCH3-PhSO2
i Y = 2-CF3-PhSO2
j Y = 3-CF3-PhSO2
k Y = 4-CF3-PhSO2
X
13 X = Cl
18 X = Cl
l
Y = CH3SO2
O
S
O
O
S
O
O
S
O
O
O
S
O
O
S
O
O
S
O
O
m Y = CF3SO2
N
N
O
N
N
N
O
14 X =
19 X =
n Y = NH2SO2
o
Y = 3-F-PhCO
p Y = 4-F-PhCO
15
20
N
X =
X =
q Y = 3-OCH3-PhCO
r Y = 4-OCH3-PhCO
s
Y = 2,4-diOCH3-PhCO
16 X =
17 X =
N
N
NCBz
21 X =
22 X =
N
N
NCBz
NH
t Y = 4-CF3-PhCO
u Y = n-butyl-NHCO
v Y = CH3
e
e
S
O
NH
S
O
Scheme 1. Synthesis of piperidinyl aminopyrimidine derivatives. Reagents and conditions: (a) DMF-DMA, 150 °C; (b) guanidine, EtOH, 80 °C; N-Boc-4-piperidone, TiCl(OiPr)3,
NaBH(OAc)3, AcOH, CH2Cl2, rt; (c) N-(N-Boc-4-piperidinyl)-guanidinium chloride, EtOH, 80 °C; (d) 30% TFA in CH2Cl2, rt; (e) Pd(OH)2/C, H2, MeOH, EtOAc, H2O, AcOH, rt; (f)
various sulfonyl chlorides, DIPEA, CH2Cl2, rt; (g) chlorosulfonyl isocyanate, t-BuOH, CH2Cl2; 30% TFA in CH2Cl2, rt; (h) substituted benzoyl chlorides, DMAP, pyr, CH2Cl2,
À78 °C; (i) N-butyl isocyanate, pyr, 120 °C; (j) 37% HCHO, MeOH, NaBH(OAc)3, rt.
concentration (IC50) was evaluated. The inhibitory activity of the
piperidinyl aminopyrimidine derivatives with 4-chlorophenyl
group and various substituents at nitrogen of the piperidine ring
(13 and 18a–v) are summarized in Table 1. Among the piperidinyl
aminopyrimidine derivatives, only three compounds (13, 18l, and
18n) showed more than 50% inhibition with 75.03%, 73.58%, and
70.86% inhibitions, respectively. Compounds 18a–18k with ben-
zenesulfonyl groups did not inhibit IKK-2 activity significantly.
On the other hand, compounds 18l and 18n with methanesulfonyl
and aminosulfonyl groups were potent inhibitors of the IKK-2 with
19.70 lM. From these results, it was clear that the piperidinyl
aminopyrimidine derivatives with substituents such as H, CH3SO2,
NH2SO2, and CH3 at the piperidine moiety showed potent inhibi-
tory activity against the target enzyme.
With the optimized piperidinyl substituents (Y = H, CH3SO2,
NH2SO2, CH3) in hand, the structure–activity relationship of the
aromatic substituent at the chlorine position was then investi-
gated. Thus, instead of the chlorine atom, morpholinosulfonyl, N-
methylpiperazinosulfonyl, and piperazinosulfonyl groups were
introduced at the X position of the aromatic substituent of the ami-
nopyrimidine core structure, and the inhibitory activity against
IKK-2 of the resulting piperidinyl aminopyrimidine derivatives
was evaluated (Table 2). The inhibitory activity of the morphol-
inosulfonyl-substituted derivatives 14 (Y = H) and 19l (Y = CH3SO2)
was as potent as the corresponding compounds 13 and 18l (X = Cl).
IC50 values of 3.67 and 3.80
pound 18m with a trifluoromethanesulfonyl group showed low
inhibitory activity (% inhibition at 10 M is only 13.90%). Com-
lM, respectively. In contrast, the com-
l
pounds 18o–18t with benzoyl groups showed as low activities as
the benzenesulfonyl-substituted derivatives (18a–18k). The com-
pound 18u with n-butylaminocarbonyl group showed low activity
with 32.16% inhibition. The compound 18v with methyl group also
showed low activity with 38.68% inhibition and an IC50 value of
The compounds 19n (Y = NH2SO2, IC50 = 0.92
(Y = CH3, IC50 = 5.60 M) showed improved activities compared
with the corresponding chlorine-substituted derivatives 18n
lM) and 19v
l

S. Kim et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3002–3006
3005
(X = Cl, Y = NH2SO2, IC50 = 3.80
l
M) and 18v (X = Cl, Y = CH3,
tory activities than the corresponding compounds 13, 18l, and 18n
with aromatic chlorine substituent. The IC50 values of 15 and 20n
IC50 = 19.70 M). On the other hand, the compounds 15, 20l, and
l
20n with N-methylpiperazinosulfonyl group showed lower inhibi-
were 7.02 and 4.25 lM, respectively. In case of the piper-
azinosulfonyl-substituted derivatives (17, 22l, and 22n), the com-
Table 1
pound 17 (Y = H) was a potent inhibitor with an IC50 value of
1.30 lM. However, the compounds 22l and 22n with methanesul-
fonyl and aminosulfonyl group as X showed similar activities as
the corresponding compounds 18l (X = Cl, Y = CH3SO2) and 18n
IKK-2 inhibitory activities of piperidinyl aminopyrimidine derivatives with 4-
chlorophenyl group
H
N
N
(X = Cl, Y = NH2SO2) with IC50 values of 3.14 and 3.85
respectively.
lM,
N
N
Y
The most active compounds 19n and 1720 were biologically
evaluated against other kinases such as IKK-1, p38a, p38b, JNK1,
JNK2, and JNK3 to obtain selectivity information. The results are
shown in Table 3. Selectivity to IKK-2 is necessary to reduce side
effects possibly occurring with inhibition of other kinases. The
compound 19n (X = morpholinosulfonyl, Y = NH2SO2) did not show
significant inhibitory activity against IKK-1 but no selectivity was
Cl
13 and 18a~v
Entry Compounds
Y
% Inhibition at
10 M (%)
IC50
M)
l
(
l
1
2
3
4
5
6
7
8
9
13
H
PhSO2
2-F-PhSO2
3-F-PhSO2
4-F-PhSO2
75.03
17.59
20.31
15.12
13.47
3.20
observed over the other kinases such as p38
and JNK3. On the other hand, the compound 17 (X = piper-
azinosulfonyl, Y = H) showed good selectivity over p38 , p38b,
a, p38b, JNK1, JNK2,
a
18a
18b
18c
18d
18e
18f
18g
18h
—
—
—
—
—
—
—
—
a
a
a
a
JNK1, JNK2, and JNK3 as well as IKK-1. Therefore, the selectivity
to IKK-2 seems to be more dependent on the X substituent but
the role of the piperazinosulfonyl group of 17 in the inhibitory
activity as well as selectivity to IKK-2 necessitates further
investigation.
a
2,4-Di-F-PhSO2 19.68
a
3-OCH3-PhSO2
4-OCH3-PhSO2
2,5-Di-OCH3-
PhSO2
2-CF3-PhSO2
3-CF3-PhSO2
4-CF3-PhSO2
CH3SO2
CF3SO2
NH2SO2
3-F-PhCO
4-F-PhCO
3-OCH3-PhCO
4-OCH3-PhCO
2,4-Di-OCH3-
PhCO
4-CF3-PhCO
n-C4H9NHCO
CH3
12.74
26.15
19.58
a
a
a
In summary, in order to obtain active and selective IKK-2
inhibitors, various substituents were introduced to the piperidinyl
aminopyrimidine core structure. First, the structure–activity rela-
tionship of the piperidinyl amino substituent (Y) was investigated
(13 and 18a–18v, Table 1), which indicated that the relatively
small substituents such as hydrogen, methanesulfonyl and
aminosulfonyl group show better inhibitory activity against
IKK-2. Then, substituents such as morpholinosulfonyl, N-meth-
ylpiperazinosulfonyl, and piperazinosulfonyl group were intro-
duced at the 4-position of the aromatic ring attached to the
aminopyrimidine core (X) (14, 15, 17, and 19–21, Table 2). Among
the derivatives thus prepared, compounds 19n and 17 showed the
most potent inhibitory activity against IKK-2. In addition, the com-
pound 17 showed good selectivity over other kinases such as IKK-
10
11
12
13
14
15
16
17
18
19
20
18i
18j
18k
18l
18m
18n
18o
18p
18q
18r
18s
26.57
14.10
15.60
73.58
13.90
70.86
38.79
39.04
40.15
32.25
42.79
—
—
—
a
a
3.67
a
—
3.80
a
—
—
—
—
a
a
a
a
—
a
21
22
23
18t
18u
18v
24.29
32.16
38.68
—
—
a
19.70
a
24
Reference
—
0.15
compound19
1, p38a, p38b, JNK1, JNK2, and JNK3. Based on this information,
further optimization study of the inhibitory activity as well as
a
Not determined.
Table 2
IKK-2 inhibitory activities of piperidinyl aminopyrimidine derivatives
H
N
N
N
O
S
O
O
S
O
O
S
N
N
N
O
X =
N
Y
N
NH
X
O
Entry
Compounds
X
Y
% Inhibition at 10
l
M (%)
IC50 (lM)
1
2
3
4
14
19l
19n
19v
H
82.51
61.51
89.55
67.06
2.09
2.20
0.92
5.60
O
S
O
CH3SO2
NH2SO2
CH3
N
O
5
6
7
15
20l
20n
O
S
O
O
S
O
H
59.35
43.15
67.11
7.02
—
4.25
a
CH3SO2
NH2SO2
N
N
N
8
9
10
17
22l
22n
H
84.08
76.09
70.90
1.30
3.14
3.85
CH3SO2
NH2SO2
NH
a
11
Reference compound19
—
0.15
a
Not determined.

3006
S. Kim et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3002–3006
15. Fuchs, D.; Rodriguez, A.; Eriksson, S.; Christofferson, R.; Sundberg, C.;
Table 3
Azarbayjani, F. Int. J. Cancer 2010, 126, 2773.
Selectivity of compounds 19n and 17 over other kinases (IC50 values in lM)
16. Takeda, K.; Takeuchi, O.; Tsujimura, T.; Itami, S.; Adachi, O.; Kawai, T.; Sanjo,
H.; Yoshikawa, K.; Terada, N.; Akira, S. Science 1999, 284, 313.
Entry Compounds IKK-2 IKK-1 p38
a
p38b JNK1
JNK2 JNK3
17. (a) Sors, A.; Jean-Luis, F.; Begue, E.; Parmentier, L.; Dubertret, L.; Dreano, M.;
Courtois, G.; Bachelez, H.; Michel, L. Clin. Cancer Res. 2008, 14, 901; (b)
Bingham, A. H.; Davenport, R. J.; Fosbeary, R.; Gowers, L.; Knight, R. L.; Lowe, C.;
Owen, D. A.; Parry, D. M.; Pitt, W. R. Bioorg. Med. Chem. Lett. 2008, 18, 3622; (c)
Crombie, A. L.; Sum, F.-W.; Powell, D. W.; Hopper, D. W.; Torres, N.; Berger, D.
M.; Zhang, Y.; Gavriil, M.; Sadler, T. M.; Arndt, K. Bioorg. Med. Chem. Lett. 2010,
20, 3821; (d) Bingham, A. H.; Davenport, R. J.; Gowers, L.; Knight, R. L.; Lowe, C.;
Owen, D. A.; Parry, D. M.; Pitt, W. R. Bioorg. Med. Chem. Lett. 2004, 14, 409; (e)
Palanki, M. S. S.; Erdman, P. E.; Ren, M.; Suto, M.; Bennett, B. L.; Manning, A.;
Ransone, L.; Spooner, C.; Desai, S.; Ow, A.; Totsuka, R.; Tsao, P.; Toriumi, W.
Bioorg. Med. Chem. Lett. 2003, 13, 4077; (f) Palanki, M. S. S.; Gayo-Fung, L. M.;
Shevlin, G. I.; Erdman, P.; Sato, M.; Goldman, M.; Ransone, L. J.; Spooner, C.
Bioorg. Med. Chem. Lett. 2002, 12, 2573.
18. (a) Oh, K.-S.; Lee, S.; Choi, J. K.; Lee, B. H. Comb. Chem. High Throughput Screening
2010, 13, 790; (b) Nagarajan, S.; Doddareddy, M. R.; Choo, H.; Cho, Y. S.; Oh, K.-
S.; Lee, B. H.; Pae, A. N. Bioorg. Med. Chem. 2009, 17, 2759.
19. Murata, T.; Shimada, M.; Kadono, H.; Sakakibara, S.; Yoshino, T.; Masuda, T.;
Shimazaki, M.; Shintani, T.; Fuchikami, K.; Bacon, K. B.; Ziegelbauer, K. B.;
Lowinger, T. B. Bioorg. Med. Chem. Lett. 2004, 14, 4013and the structure of the
reference compound is as follows:
1
2
19n
17
0.92
1.30
20.37 4.7
>30 >30
0.21
>30
0.48 1.9 0.88
19.73 >30
>30
selectivity for IKK-2 of the piperidinyl aminopyrimidine deriva-
tives will be performed in due course.
Acknowledgment
This work was supported by Development of Bio-oriented Tech-
nology Program (2010-0029603) through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education,
Science and Technology and Korea Institute of Science and Tech-
nology (KIST).
References and notes
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20. Spectral data of compound 19n: 1H NMR (300 MHz, DMSO-d6) d 8.45 (d,
J = 5.00 Hz, 1H), 8.34 (d, J = 8.26 Hz, 2H), 7.86 (d, J = 8.41 Hz, 2H), 7.36 (d,
J = 7.43 Hz, 1H), 7.24 (d, J = 5.15 Hz, 1H), 6.74 (s, 2H), 3.82–3.97 (m, 1H), 3.65 (t,
J = 4.26 Hz, 4H), 3.44–3.53 (m, 2H), 2.92 (t, J = 4.51 Hz, 4H), 2.60–2.77 (m, 2H),
1.92–2.06 (m, 2H), 1.51–1.70 (m, 2H); 13C NMR (75 MHz, DMSO-d6) d 162.36,
160.04 (2C), 141.96, 136.49, 128.57, 128.12, 106.77, 65.76, 47.61, 46.35, 45.64,
30.93; MS (TOF, ES+, M+Na) 505.2, and spectral data of compound 17: 1H NMR
(300 MHz, MeOD-d4) d 8.40 (d, J = 5.27 Hz, 1H), 8.34 (d, J = 8.43 Hz, 2H), 7.89 (d,
J = 8.30 Hz, 2H), 7.22 (d, J = 5.18 Hz, 1H), 4.08–4.25 (m, 1H), 3.32–3.46 (m, 2H),
2.96–3.13 (m, 6H), 2.84–2.95 (m, 4H), 2.16–2.31 (m, 2H), 1.67–1.77 (m, 2H);
13C NMR (75 MHz, MeOD-d4)
d 163.35, 161.91, 158.92, 141.67, 137.17,
127.92, 127.47, 106.36, 46.58, 46.26, 44.46, 43.55, 29.97; MS (TOF, ES+, M+H)
403.0.
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Pharmacol. 2010, 65, 1165.