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NH
2
Q
1
8
1
N
N
N
6
3
5
R
1
1
Figure 4.2
1,3-Disubstituted imidazopyrazine.
4.3 Rationale for Imidazopyrazine-derived IGF-1R
Inhibitors
Our interest in identifying small-molecule IGF-IR kinase inhibitors for
oncology-directed applications centered on the underexploited imidazo[ 1,5-
a]pyrazine core (Figure 4.2). This novel 6/5 heteroaryl template offers several
advantages as a priviledged kinase scaffold, as it retains key pharmacophoric
donor/acceptor interactions with the kinase hinge region through the N7 and 8-
NH
2
moieties, mimicking the adenine core of the natural ATP substrate.
Additionally, the imidazo[1,5-a]pyrazine template facilitates efforts to build
upon structure-activity relationships (SARs) derived from programs targeting
various kinase inhibitors. For example, the 6/5 bicyclic heteroaryl class, such as
the thieno-, pyrrolo-, and pyrazolopyrimidines, have served as adenine hinge-
binding mimetics in a number of kinase inhibitor programs.
18,32
The imida-
zopyrazine scaffold benefits from (1) synthetic flexibility at C3, where sub-
stituents (R
1
) are derived from common carboxylic acids, (2) stable attachment
of both hetero and carbon atoms to C3 directly or through a methylene linker,
and (3) the inclusion of C1 substituents (Q
1
) either in the first step through a
linear route or at the last step through a convergent route. As such, we report
herein the progression of a novel series of 1,3-disubstituted 8-aminoimidazo
[1,5-a]pyrazines (1) IGF-IR TKIs from hit to lead to investigational new drug
(IND), with the ultimate discovery of OSI-906 as a potent, selective, orally
bioavailable dual IGF-1R/IR inhibitor that is currently progressing through
clinical trials.
4.4 Synthetic Routes to Imidazopyrazine-derived
IGF-1R Inhibitors
Two routes, linear and convergent, were employed to allow for modifications at
C1 and C3 of the imidazopyrazine core.
33,34
Scheme 4.1 illustrates the generic
linear route involving the direct ortho-metallation of 2-chloropyrazine (2) in the
presence of a preformed solution of lithium tetramethylpiperidide, followed by
quenching with various aldehydes to afford alcohol 3. Conversion of alcohol 3
to amine 4 via the Gabriel synthesis proceeded through a Mitsunobu reaction
with phthalimide, followed by unmasking of the amine through reaction with
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