S. R. Selness et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5851–5856
5853
Scheme 2. Synthesis of N-benzyl pyridinones from 4-hydroxy-6-methylpyran-2-one. Reagents and conditions: (a) NH4OH (aq); (b) ArylCH2X, K2CO3/DMF; (c) Br2, AcOH, 0 °C
or NBX, AcCN; (d) ArylCH2X or heteroarylmethylene halide, NaH/THF, reflux; (e) ArylCH2NH2 or heteroarylCH2NH2, H2O, reflux.
oxide with the appropriate benzyl alcohol affords the correspond-
ing aryloxypyridine-N-oxide, 4. Acetic anhydride mediated rear-
rangement of 4 produces the pyridinone, 5. Halogenation of 5
can be accomplished with molecular bromine or NBX (X = Br, I or
Cl) to yield the corresponding 3-halopyridinone, 6. Alkylation of
6 with various benzyl halides gives the 3-halo-N-substituted
pyridinone, 7. The iodo precursor, 7b, is converted to the C3 vinyl
pyridinone via a Stille coupling reaction to afford pyridinone 8a.
Catalytic hydrogenation of 8a afforded the C3 ethyl analog, 8b.
The C3 methyl, trifluoromethyl and cyano analogs (8c–e) were pre-
pared via metal mediated coupling reactions (Scheme 1).
Two alternative syntheses were pursued to generate a series of
6-methyl-N-substituted pyridinone derivatives as outlined in
Scheme 2. Condensation of 4-hydroxy-6-methylpyran-1-one with
aqueous NH4OH gives the hydroxy pyridinone, 9. Alkylation of 9
with a benzyl halide affords the benzyloxy pyridinone, 10. Haloge-
nation of 10 under the conditions in Scheme 1 generates the 3-
halopyridinone, 11. Initial attempts at alkylation of 11 with a ben-
zyl or heteroarylmethylene halide under several conditions re-
sulted in mixtures of O- and N-alkylated products. We found that
the use of NaH/THF favored the formation of the desired N-substi-
tuted pyridinone, 12. Alternatively, condensation of 4-hydroxy-6-
methylpyran-1-one with a substituted benzyl or heteroarylmeth-
ylene amine yields the N-substituted pyridinone, 13 in moderate
to good yields. This condensation was reported to proceed in n-bu-
tyl alcohol.11 We observed bis-addition of the amine under these
conditions which was avoided by using water as the solvent. This
minimized the bis-adduct formation and facilitated isolation of
13. Installation of the halide is accomplished via treatment with
bromine or NCX to afford the 3-halo-N-substituted pyridinone,
14. Benzylation of 14 with a substituted benzyl halide provided
the desired pyridinone, 12a–f.
substituted benzyloxy groups were investigated.7,8 We concluded
that the 2,4-difluorobenzyloxy group was optimal for potency
and focused our attention on the N-benzyl substituent.
As shown in Table 2, ortho-substituted N-benzyl groups were
not tolerated compared to the meta- or para-substituted N-benzyl
groups (12a–f). Carboxamide substitution in the para-position
afforded several potent compounds (12f, 12h–k) with activity be-
low 100 nM. Compounds 12h, 12i and 12k were shown to be active
in a rat lipopolysaccharide (rLPS) model of inflammation.12,13
A
series of heterocyclic replacements were investigated in an effort
to reduce the log D of the series and to improve the metabolic sta-
bility of the series. The pyridines 12o and 12p showed modest
activity against p38 but exhibited good activity in rLPS. This was
attributed to improved metabolic stability and better bioavailabil-
ity relative to 1.
In an effort to engage Asp 112 the amines 16, 17, 18 and 19
were prepared (via BH3/dimethylsulfide reductions of 12b, 12c,
12g and 12h, respectively). Although their enzyme activities
against p38a did not improve relative to the neutral carboxamides,
significant in vivo activity in rLPS was achieved for 16 and 19.
Investigation of neutral analogs of 16 and 17 identified 20, 21
and 22 as potent inhibitors of p38a. These were prepared via acyl-
ation of 16, 17 and the chloro analog of 17 with glycolic acid.
Table 1
Potency and selectivity (as measured by inhibition of JNK2) of 4-benzyloxy-3-halo-N-
substituted pyridinones and 4-benzyloxy-3-alkyl-N-substituted pyridinones
Compd
R
Ar
Ph
Ar0
Ph
p38
a
IC50
(
l
M) JNK2 IC50 (lM)
1
2
3
Br
0.68
0.07
0.07
0.90
3.10
43
>200
>200
0.32
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
Cl
I
H
Br
Br
Br
Ph
Ph
Ph
4-Cl–Ph
4-F–Ph
Ph
Ph
Ph
NA
Initially, we investigated the role of the C3 position and its con-
tribution to the activity of the series. Chloro and bromo groups
were identified as preferred as shown by the activity of 1 and 7a
(Table 1). The halogen group at C3 occupies a shallow lipophilic
pocket adjacent to the deep selectivity pocket as defined by
Thr106. Additionally, we used activity against JNK2 to evaluate
the potential for kinase selectivity. As shown in Table 1 this series
was highly selective versus JNK2. Based on historical data from
both the diaryl five-membered heterocycles such as 3 and the
new class of fused ring systems such as 2, a limited number of halo
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
4-F–Ph 1.90
3-F–Ph 0.62
2,4-DiF–Ph 3-F–Ph 0.13
CHCH2 Ph
Et
Me
CF3
CN
Ph
Ph
Ph
72
6.1
5.3
Ph
Ph
Ph
3-F–Ph 50
2,4-DiF–Ph 3-F–Ph 9.9
NA—not assessed.