S. Bond et al. / Bioorg. Med. Chem. Lett. 25 (2015) 969–975
971
O
O
O
O
O
OH
O
OH
O
N
a
e (10-20% yield)
b
c,d
N
N
70% yield
30% yield
57% yield
or f (20-75% yield)
N
N
H
N
O
F
O
F
O
HO
HO
X
1m
5l
5m
6m
O
OH
1n X = CH2CH3
1o X = CH2CH2CH3
1p X = CH(CH3)2
1q X = CH2(cyclopropyl)
1r X = CH2CN
1s X = CH2CH2OCH3
1t X = CH2COOCH3
1u X = CH2CONH2
1v X = CH2COCH3
Scheme 2. Reagents and conditions: (a) pyridine hydrochloride, 195 °C, 5 h; (b) ethylenediamine, xylenes, Dean–Stark, reflux, 7 h; (c) 4-fluorobenzoyl chloride, pyridine, 0 °C
to rt; (d) 1 M NaOH (aq.), MeOH, rt, 30 min; (e) XOH, PS-PPh3, DEAD, THF, 0 °C to rt; (f) XBr or XCl, K2CO3, acetone, reflux.
the phenol was then carried out using Mitsunobu or alkylation
chemistry.
improvement in activity compared to the original hit. Further
functionalisation of the ether substituent demonstrated that the
introduction of a nitrile (compound 1r) or an additional ether
group (compound 1s) was tolerated without improving activity,
while the introduction of polar, electron-withdrawing groups
(compounds 1t–v) resulted in losses of potency. The change in aryl
substitution position did not result in a significant change in
potency when the chloro substituent was investigated (compare
1a to 1w), but caused considerable losses in activity when the
substituents were ethers (compare 1r to 1x and 1s to 1y).
The introduction of 3-substituted phenyl R1 groups was
achieved by nitration of the commercially available keto-acid 5c
followed by reduction to give amine 7 (Scheme 3). This was used
to access chloro-substituted intermediate 5w and phenol 8 which
were then carried through the remaining steps of the synthesis
to give targets 1w–y.
The importance of the R1 group for activity against RSV was
demonstrated when its replacement with a hydrogen (compound
1b) resulted in an inactive compound (see Table 2). The presence
of a substituent on the aromatic ring was also found to be desir-
able, with the phenyl analogue 1c showing a loss of activity when
compared to its 4-chlorophenyl counterpart (1a). Attempts to
replace the chloro substituent on the phenyl ring with a small
range of different functional groups (compounds 1d–i) generally
resulted in compounds with similar or slightly reduced potency.
Replacement of the phenyl group with 2- or 3-pyridine
(compounds 1j and 1k) gave compounds with poor or no activity.
Varying substituent chain length did not have a significant impact
on activity; little variation was seen among the alkyl-substituted
compounds (compounds 1f–h), and a less than two-fold change
in potency was observed within the alkyl ether series (compounds
1l, 1n and 1o). Chain branching was not well tolerated in either
series (compounds 1i and 1p), however the introduction of a cyclo-
propylmethylether substituent (compound 1q) gave a three-fold
A preliminary investigation into the SAR around the R2 group
was also conducted. Compounds were synthesised according to
the chemistry outlined in Scheme 4. Analogues lacking carbonyl
functionality at R2 were synthesised by direct condensation of keto
acid 5a with the appropriate mono-functionalised ethylenedia-
mine.17 The remaining compounds were synthesised from the core
6a. A range of conditions were investigated for the formation of
amides and ureas 1ac–1av, and performing the reaction in pyridine
was again found to be the most effective method.
The presence of the R2 substituent was found to be critical for
activity against RSV, with the core (6a) proving to be inactive
(see Table 3). Removal of the carbonyl functionality (compounds
1aa and 1ab) also rendered compounds inactive, while replacing
the 4-fluorobenzoyl group with its corresponding homologue
(compound 1ac) resulted in a loss of potency. Investigation of a
small set of 4-substituted benzoyl analogues revealed that
O
O
O
O
O
OH
O
OH
O
OH
O
N
N
a,b
c
d
e
64% yield
77% yield
74% yield
N
N
H
Cl
Cl
O
F
H2
N
Cl
5c
7
5w
6w
1w
30% yield
O
f
O
O
O
OH
N
N
N
e,g
43% yield
d
h
O
53% yield
62-76% yield
N
N
N
H
HO
O
HO
O
O
X
F
F
HO
8
9
10
1x X = CH2CN
1y X = CH2CH2OMe
Scheme 3. Reagents and conditions: (a) HNO3, H2SO4, 0 °C; (b) H2, Pd/C, EtOH, rt, 6 h; (c) H2SO4 (aq.), NaNO2, 0 °C, 1 h, then CuCl, HCl (aq.), rt, o/n; (d) ethylenediamine,
xylenes, Dean–Stark, reflux, 5 h; (e) 4-fluorobenzoyl chloride, pyridine, 0 °C to rt; (f) NaNO2, H2SO4 (aq.), 0 °C, 1 h then rt to 50 °C, 2 h; (g) 1 M NaOH (aq.), MeOH, rt, 1 h; (h)
XBr or XCl, K2CO3, acetone, reflux, 30 h.