Table 3 Synthesis and c-Met enzymatic activity of quinolines 21a–k
Science & Technology Major Project on “Key New Drug Creation
and Manufacturing Program” (2009ZX09301-001, 2009ZX09103-
062), the Natural Science Foundation of China for Distinguished
Young Scholars (No 30725046), and Program of Shanghai Subject
Chief Scientist (No 10XD1405100).
Notes and references
Entry
R
R¢
Yield
IC50 (mM)a
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87.
1 (21a)
2 (21b)
3 (21c)
4 (21d)
5 (21e)
6 (21f)
7 (21g)
8 (21h)
9 (21i)
10 (21j)
11 (21k)
1b
H
Cl
Me
MeO
EtO
Me2N
Ph
2-thienyl
H
H
H
H
H
H
H
H
80%
63%
78%
75%
79%
74%
83%
81%
79%
78%
71%
—
0.33
0.03
0.22
0.12
0.40
0.28
0.16
0.08
0.07
0.28
4.4
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2-furyl
H
H
1-Me-pyrazol-4-yl
1-Me-pyrazol-4-yl
—
cyclopropyl
—
0.00093
a In vitro kinase assays were performed with the indicated purified
recombinant c-Met kinase domains, IC50s were calculated by Logit method
from the results of at least three independent tests with six concentrations
each. b Our previously reported8 c-Met inhibitor
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inhibitory activity at the c-Met enzyme, while quinoline 21k bear-
ing a C2-substituent did not show appreciable activity. It was found
that compounds containing a small electron-donating substituent
at the C6 of the triazolopyridazine fragment showed similar IC50
values in 0.1~0.4 mM range (entries 1,3–6). Higher potency was
observed on compounds 21b, 21h and 21i possessing IC50 values
less than 100 nM. Overall, all these compounds were much less
potent, in comparison to the parent compound 1. However, in
view of the higher cellular activity15 of the triazolopyridazine-
containing compound 20, compound 1 only showed moderate
activity in the cell indicating that triazolopyridazine analogues
may have better cell permeability. Therefore, these compounds
will be subjected to further cellular biological assay.
In summary, we have developed a highly effective one-pot syn-
thetic strategy to access 3-amino-quinolines by using a modified
Friedla¨nder’s protocol. A series of novel multi-substituted quino-
lines bearing diverse C3-piperazinyl functions were synthesized in
good yields. Such method not only enables the synthesis of our
early reported c-Met inhibitor on a large scale, but also provides
a way to generate novel quinolines with multi-substituents for
further structure–activity relationship (SAR) study.
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Acknowledgements
The authors are grateful to Shanghai Commission of Science and
Technology (10410702600, 10JC1417100, 10dz1910104), National
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5930–5933 | 5933
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