L. Tong et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
F
Br
Br
OH
O
F
Br
Br
N
a
b
Br
O
N
H
F
HO
3d
3e
3f
O
Boc
N
N
F
c
X
N
N
H
N
HN
NBoc
O
X
3h
O
Moc-Val
F
N
N
X
SFC separation
Moc-Val
d,e
N
active isomer
N
H
N
HN
N
2-10
O
X
3i
O
Scheme 2. Reagents and conditions: (a) (1) p-Bromophenylhydrazine, AcOH, EtOH, reflux; 65% then (2) PPA, 110 °C; (b) 3-methoxybenzaldehyde, p-toluenesulfonic acid,
o-xylene, 170 °C, 15 h.; (c) bis(pinacolato)diboron, KOAc, PdCl2(dppf), dioxane, 110 °C then bromoimidazole 3c, 1 M Na2CO3, Pd(dppf)Cl2, THF, 90 °C; (d) 4 N HCl, MeOH; (e)
Moc-L-valine, HATU, DIPEA, DMF.
with polyphosphoric acid (PPA) to afford indole 3e. Treatment of
3e with 3-methoxybenzaldehyde, p-toluenesulfonic acid in o-
xylene at 170 °C gave 3f. Treatment of dibromide intermediate 3f
with two equivalents of bis(pinacolato)diboron in the presence of
KOAc and Pd(dppf)Cl2 afforded the intermediate bis-pinacol boro-
nic ester, the key coupling partner. Reaction of this core under pal-
ladium catalysis with two equivalents of bromoimidazole
intermediates 3c afforded the bis Boc adducts 3h. Global deprotec-
tion with HCl followed by HATU promoted double amide coupling
(S)-isomer 5, but was weaker versus GT2b and GT3a. While neither
compound 4 or 5 displayed an overall profile that was improved as
compared to 1, it did demonstrate that both genotype and mutant
potencies were sensitive to changes at the 4-position. The prefer-
ence of 4-proline to 3-proline was evident in comparison between
compounds 4 and 6. We also investigated the impact of fusing the
3,4 positions with a cyclopropyl group. This modification proved
to be detrimental to potency as exemplified by compound 7. Bridg-
ing the 3 and 5 positions on the proline, with a second ring, as shown
by compound 8 also failed to demonstrate meaningful improve-
ment. Overall, the data in Table 1 suggested the methoxy proline
at the 4-position was preferred, but in comparison to 1, we did not
see an improvement in the overall profile.
We next expanded the diversity of proline variants at the 4-
position of the proline ring, with a focus on improving the
GT1a_Y93H activity. We were encouraged by the improvement
that compound 4 showed versus this mutant and wanted to see
if we could broaden its activity profile to also cover GT1a_L31V,
GT2b and GT3a. With this objective in mind we maintained the
beta-configuration for the substituents described in Table 2, ana-
logs 9–15, with the variations made simultaneously to both proline
rings (P1 = P2). The 4-fluoro analog 9 improved the GT1a_Y93H
potency into the picomolar range, but it also showed a detrimental
effect in GT2b potency. The difluoromethoxy derivative 10 was less
potent in GT1a_Y93H, when compared with its methoxy counter-
part 4 and was also weaker in GT2b and GT3a (10 vs 4). Spiro-fused
rings were also examined, as exemplified by 11 and 12. Compound
11 exhibited potency roughly comparable to 1, while 12 demon-
strated an improvement in GT1a_Y93H (0.44 nM for 12 and
5.76 nM for 1). The fused-cyclopropyl proline analog 13 demon-
strated improved activity for GT1a_Y93H, but exhibited weaker
potency in GT1a_L31V, when compared to 1. Increasing the size
of the ring fused to the proline had a detrimental effect on the
in vitro profiles as illustrated by 14 and 15.
reactions with Moc-L-valine afforded the final compounds as mix-
tures of two epimeric aminal compounds.22 The mixtures were
subjected to SFC chiral separation to afford compounds as the sin-
gle, more potent diastereomer of the pair. Unless otherwise noted,
the more active diastereomer is reported in the SAR tables.
The synthesis of mixed proline analogs begins as in Scheme 3.
Using a Fisher indole synthesis, the 5-bromoacetophenone 11a
was converted to indole 11b. This material was cyclized under
the standard conditions to afford 11c which was ready for selective
functionalization of the bromide. Intermediate 11c was subjected
to the borylation/Suzuki coupling protocol used previously utiliz-
ing Pd(dppf)Cl2 as catalyst to afford the mono-coupled material
which after HCl deprotection and capping yielded chloride 11d.
With compound 11d in hand, treatment with Pd2(dba)3 in the
presence of bis(pinacolato)diboron and KOAc afforded the interme-
diate boronate which was treated directly with bromoimidazole 3c
to afford the Boc-protected intermediate. Treatment with HCl fol-
lowed by capping afforded compound 11e which underwent SFC
chiral separation to afford final compounds 7–8, 16–21, 22–25
and 27 shown in Tables 1 and 3–6. Compounds in present commu-
nication were synthesized according to previously published
patent proccedures.21,22
Our first intent was to have a general scan for tolerability of
groups and preferred substitution patterns, on the proline rings.
Table 1 summarizes the data for this investigation. For this purpose,
prolines bearing a methyl at the 5 position were examined first.
Compounds 2 and 3, which were diastereomers of methyl group,
both showed lower potency across the board. Interestingly, differ-
ences in the relative activity of the individual diastereomers were
observed, with compound 2 exhibiting a moderately better profile
than compound 3. Activity at the 4 position of the proline ring was
examined with a methoxy substitution. The (R)-methoxy isomer 4
was superior in GT1a_Y93H potency compared to the corresponding
Although the proline analogs 9 and 13 (Table 2) demonstrated
improved GT1a_Y93H potency, their GT2b potency was slightly
lower. Therefore, we sought to investigate the impact of indepen-
dent substitution of either the left or the right proline, on potency.
Table 3 summarizes data for this investigation. The combination of
a 4-fluoro-proline on the left with an unsubstituted proline on the
right, compound 16, showed a profile similar to compound 17,
which possessed the reversed combination of prolines. Both