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In-Depth Information
O
Cl
Cl
R
1
N
X
N
H
a
c
d
2
N
N
9
7 (X = OH)
8 (X = NH
2
)
b
Cl
Cl
NH
2
I
I
N
N
N
e
f
g
1
N
N
N
N
N
N
R
1
R
1
R
1
12
10
11
Scheme 4.2
Reagents and conditions: (a) 2 M nBuLi in hexanes, tetramethyl-
piperidine, -78 1C, then DMF, MeOH, and NaBH
4
; (b) phthalimide,
DIAD, PPh
3
, THF; then NH
2
NH
2
, EtOH/CH
2
Cl
2
(3:1), 16 h; (c)
R
1
CO
2
H, EDC, HOBT, CH
2
Cl
2
or R
1
COCl, DIEA, CH
2
Cl
2
; (d) POCl
3
,
MeCN, 80 1C, (e) NIS, DMF, rt, 16 h; (f) NH
3
,Pr
i
OH, 110 1C, 24 h; (g)
Pd(PPh
3
)
4
, DME/H
2
O (4:1), 100 1C, K
2
CO
3
,Q
1
-B(OH)
2
/Q
1
-B(pin).
ATP concentration of 100 mmol L
1
. Compounds which displayed biochemical
activities below 1 mM were further tested for inhibition of IGF-I-stimulated
receptor autophosphorylation in intact cells, where an NIH-3T3 line stably
overexpressing full-length human IGF-IR (LISN) was employed in a capture
ELISA assay.
With two synthetic methods in place to afford 1,3-disubstituted 8-amino-
imidazopyrazines, analoging efforts focused on the synthesis of a series of
C1- and C3-substituted imidazopyrazines. From those efforts emerged 3-
BnOC
6
H
4
-1-cyclobutylimidazopyrazine (1a) (IGF-1R biochemical IC
50
¼
606
nM) (Table 4.1).
33
Further SAR development around this early hit revealed
that the 3-BnOC
6
H
4
moiety was preferred at the C1 position of the imidazo-
pyrazine core when compared to phenyl (1b), 3-MeOC
6
H
4
(1c), 4-MeOC
6
H
4
(1d), 4-BnOC
6
H
4
(1e), or 4-PhOC
6
H
4
(1f). The preliminary SAR around
the C3 position of the imidazopyrazine core when Q
1
¼
3-BnOC
6
H
4
suggested
that critical mass was required (R
1
¼
H, compound 1k,IC
50
410 mM),
preferably a cycloalkyl group (1a, 1g, 1i,or1j) and specifically cyclobutyl
(1a). Additionally, phenyl (1h) was tolerated, but the larger naphthyl group (1l)
was not.
To further expand the SAR around initial hit 1a, the role of the benzyloxy
moiety was assessed. In short, the unsubstituted benzyloxy moiety was pre-
ferred, as substitution of the terminal phenyl ring with cycloalkyl or heteroaryl
(Table 4.2) or substitution on the terminal phenyl ring (Table 4.3) resulted in
slight or extreme losses in biochemical and/or cellular IGF-1R potency.
33
With the establishment of this initial SAR, the next phase of SAR devel-
opment explored substitution on the cycloalkyl moieties at position C3 of the
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