H. Shimizu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 904–908
907
a-c
Boc
N
HO
O
HO
BOMO
N
N
Boc
H
Boc
N
N
O
N
a,b
N
9
N
8
N
N
Br
17
d
F
e
F
OH
N
Boc
N
O
18
BOMO
HO
Boc
11c
10
H
N
c,d
or
e,f
f,g
or
h-j
R3
N
R3
N
N
R2
H2N
N
R2
HO
R2 R3
R4
N
Boc
Boc
N
12a R2:OMe, R3:H
12b R2:H, R3:OMe
12c R2:F, R3:H
11a R2:OMe, R3:H
11b R2:H, R3:OMe
11c R2:F, R3:H
N
H
O
5a-5d, 6
12d R2:H, R3:F
11d R2:H, R3 :F
Boc
N
H
N
g,i
k-m
H3C
N
or
h,i
N
N
N
N
Boc
N
H2N
Boc
N
N
N
H
14
13
R4
F
F
H
N
CH3
NH
N
CH3
O
O
N
N
O
O
NH
H
Boc
n
19
7a-7k
+
12d
F
N
H
CHO
H
N
Boc
H
N
N
15
16
N
j,k
N
N
N
H
N
N
N
CH3
Scheme 1. Syntheses of pyrrolidine derivatives. Reagents and conditions: (a) LiBH4,
THF 0 °C to rt, 94%; (b) BOMCl, DIPEA, 0 °C to rt, CH2Cl2 79%; (c) HCO2H, DIAD, Ph3P,
THF, reflux then 1 N NaOH aq, THF-MeOH, rt, 75%; (d) Deoxo-FluorÒ, CH2Cl2, À78 °C
to rt, 35%; (e) H2, Pd/C, MeOH; (f) DPPA, DIAD, Ph3P, THF; (g) Ph3P, THF, H2O (quant.
2 steps for 12a, 46% 2 steps from 12b); (h) MsCl, Et3N, CH2Cl2; (i) NaN3, DMF,
50–60 °C; (j) H2, 5% Pd/C, EtOH (43% 4 steps for 12c, 62% 3 steps for 12d); (k) TFAA,
Et3N, CH2Cl2, 81%; (l) MeI, NaH, DMF, 79%; (m) K2CO3, MeOH, 88%; (n) NaBH3CN,
AcOH, MeOH, 36%. Boc: tert-Butyloxycarbonyl, BOM: Benzyloxymethyl.
O
F
OH
N
O
O
N
H
20
7l
Scheme 2. The combination of imidazo[1,2-b]pyridazine scaffold and pyrrolidine
units. Reagents and conditions: (a) (Boc)2O, DMAP, CH2Cl2, 93%; (b)
4-(dihydroxyboryl)benzoic acid, Pd(PPh3)2Cl2, K2CO3, 1,4-dioxane-water (3:2),
77%; (c) 12a, 12b, 12c, 12d or 14 DMT-MM, DMF; (d) TFA, CH2Cl2 (74% 2 steps
for 5a, 23% 2 steps for 5b, 20% 2 steps for 5c, 94% 2 steps for 5d via 19); (e) 14,
EDCÁHCl, HOBt, Et3N, 92%; (f) 4 N HCl in dioxane, 96%.; (g) R4X (MeI, EtI, n-PrI, BnBr,
1-chloro-3-(chloromethyl)benzene, 1-chloro-4-(chloromethyl)benzene, cinnamyl
bromide, t-butyl chloroacetate, 4-chloromethylbenzoic acid or 1-[(2-iodoeth-
oxy)methyl]-4-methoxybenzene), NaH, DMF; (h) PhI, CuI, K2CO3, DMF, 150 °C; (i)
TFA, CH2Cl2, 71% 2 steps for 7a, 39% 2 steps for 7b, 35% 2 steps for 7c, 69% 2 steps for
7d, 43% 2 steps for 7e, 44% 2 steps for 7f, 18% 2 steps for 7g, 14% 2 steps for 7h, 32%
2 steps for 7i (to cleave Boc groups and t-Bu ester), 40% 2 steps for 7j (to cleave Boc
groups and the PMB group), 18% 2 steps for 7k; (j) 16, DMT-MM, DMAP, Et3N, DMF
71%; (k) TFA, CH2Cl2, 76%. PMB: p-methoxybenzyl.
to primary amines 12a–12d via the azide moiety. Pyrrolidine
derivative 14 was synthesized by methylation of 13 by way of
trifluoroacetamide. Benzylamine derivative 16 was prepared by
reductive amination of aldehyde 15 with 12d (Scheme 1).
Compounds 5a–5d, 6 and 7l were synthesized by the condensa-
tion reaction of carboxylic acid 18 or 2013 and amines 12a, 12b,
12c, 12d or 16 followed by the cleavage of the Boc group.23
Compounds 7a–7k were prepared by alkylation of amide
nitrogen of compound 19 by various alkyl halides followed by
the cleavage of protective groups. 1-[(2-Iodoethoxy)methyl]-4-
methoxybenzene was prepared as indicated in a previous report.24
N-Phenyl derivative 7h was formed by coupling with iodobenzene
(Scheme 2).
In conclusion, we have discovered potent compounds by the
modification of the substituents in the 3-position of imidazo[1,2-
b]pyridazine derivatives based on two strategies.
One strategy is the introduction of an electron-withdrawing
group on the pyrrolidine ring to adjust polarity for better perme-
ability. Another is the introduction of hydrophobic substituents
to the amide nitrogen to improve affinity for IKKb. We believe that
these substituents interact with the pocket which is newly made
after the activation loop moving out.
Acknowledgements
We are grateful to the member of Drug Metabolism & Pharma-
cokinetics Research Laboratories for the measurement and valida-
tion of physicochemical data.
References and notes
1. Sen, R.; Baltimore, D. Cell 1986, 47, 921.
2. (a) Li, Q.; Verma, I. M. Nat. Rev. Immunol. 2002, 2, 725; (b) Hayden, M. S.; Ghosh,
S. Cell 2008, 132, 344.
3. Brown, K. D.; Claudio, E.; Siebenlist, U. Arthritis Res. Ther. 2008, 10, 1.
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43.
5. Senftleben, U.; Karin, M. Crit. Care Med. 2002, 30, S18.
6. (a) Karin, M.; Lin, A. Nat. Immunol. 2002, 3, 221; (b) Coussens, L. M.; Werb,
Z. Nature 2002, 420, 860; (c) Kim, H. J.; Hawke, N.; Baldwin, A. S. Cell Death
Differ. 2006, 13, 738; (d) Perkins, N. D.; Gilmore, T. D. Cell Death Differ.
2006, 13, 759.
We have acquired orally active compounds such as 7c and 7f
that showed increased IKKb inhibitory activities and TNFa produc-
tion inhibitory activities in mice. Further investigation of IKKb
inhibitors will be reported in the near future.