2642
L. S. Harikrishnan et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2640–2644
Table 1. SAR for benzoxazole A-ring substitutions against human
CETP
which takes into consideration off-target interactions
in plasma. The 5-cyano compound 30 and the 5-cya-
no-7-chloro compound 45 exhibited the best potencies
across both SPA and WPA.
O
O
7
Z
O
N
6
NH
A
4
The synthetic approach utilized to examine the B-ring in
the 2-arylbenzoxazole series is detailed in Scheme 2.
Condensation of aminophenol 47 with chlorooxime 48
followed by reduction gave the aminobenzoxazole 49
in 94% yield. From intermediate 49, the B-ring was ex-
plored in an array format using one of the two proce-
5
a
Compound
Z
SPA IC50
(lM)
WPA IC50
(lM)
4
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
5
SC 795 (Fig. 1)
0.003
>32
>32
>32
1.1
0.036
NT
NT
NT
31
dures. Acylation with
a range of commercially
available aryloxyacetyl chlorides provided the product
amides 51 directly in 29–81% isolated yield.12 Alterna-
tively, to facilitate more extensive exploration of the B
aryl ring, aniline 49 was acylated with chloroacetyl chlo-
ride to obtain the a-chloro amide 50 in 89% yield. Dis-
placement of the chlorine of 50 with phenols in an
array format yielded the resulting purified phenyl ethers
51 in 10–40% isolated yield.12 The average purity (by
HPLC-UV) of the final products was 98%.
4-Me
4-NO2
5-Me
5-COOMe
5-COOH
5-F
>32
>32
>32
>32
11
NT
NT
NT
NT
71
5-OMe
5-OCF3
5-SO2Et
5-Ph
9.3
1.9
NT
NT
27
5-CH2OH
5-Ac
5-tBu
1.3
1.2
18
Select results from exploration of the substitution on the
2-arylbenzoxazole B-ring are provided in Table 2.
Mono-substitution at the 2, 3, or 4 positions with a vari-
ety of substituents revealed that small alkyl groups and
halogens are generally well-tolerated, although haloge-
nation at the 2 position appears to lead to less active
analogs (55 and 64). Several disubstituted analogs (80–
85) provided further improvements in inhibitory po-
tency both in the SPA and WPA. However, disubstitu-
tion at the 2,5-, 2,6-, or 3,5-positions led to a
significant loss of activity (86–90) suggesting that substi-
tutions were permitted along only one edge of the phe-
nyl ring. A limited set of 2,3,4-trisubstituted analogs
was also examined (e.g., 91–94, 97, 99, and 100). These
proved to be well tolerated, exhibiting comparable SPA
activity to the best di-substituted compounds. Among
them, compounds 99 and 100, which contain the best
A-ring mono-substitution (5-CN) and the best B-ring
trisubstitutions, had low nM SPA IC50s and were the
most potent in WPA (WPA IC50 ca. 1 lM) in the series.
>32
0.59
0.47
0.44
0.12
0.057
13
NT
51
5-CF3
5-Cl
21
28
5-Br
5-NO2
18
5-CN
6-Me
3.3
NT
NT
NT
NT
NT
NT
NT
100
80
6-Cl
6-OMe
6-NO2
>32
>32
>32
>32
>32
>32
1.7
6-COOMe
6-F
6-(Piperidin-1-yl)
7-Me
7-COOMe
7-COOH
5,7-DiMe
5-Me-7-Ac
5-Cl-7-Br
5,7-DiCl
5,7-BisCF3
5-CN-7-Cl
5-Cl-7-NO2
3.5
>32
0.28
0.24
0.097
0.088
0.092
0.052
0.049
NT
8.9
27
41
42
43
44
45
46
26
11
9.1
2.5
18
In summary, high-throughput screening of the BMS
sample collection identified 2-arylbenzoxazole 5 with
submicromolar SPA and modest WPA in vitro activi-
ties. An array synthesis approach was taken to rapidly
a NT, not tested.
Cl
a or b,
OH
A-ring methyl groups from 5 led to a loss of activity.
Reintroduction of a single methyl substitution at the 4
position also led to an inactive analog. However, the
activity was partially recovered by methyl substitution
at the 5, 6, or 7 positions. Incorporation of amino phe-
nols allowed more extensive surveying of the 5, 6, and 7
positions of the benzoxazole. The data indicate that
mono substitution at the 5 position is preferred, with
smaller nitro and cyano groups (29 and 30) exhibiting
enhanced SPA and WPA activities. Disubstitution at
the 5 and 7 positions was also examined further, and
provided a modest improvement in inhibitory potency
in the SPA assay, although no significant improvement
was seen in the physiologically more relevant WPA
O
N
NO2
c
+
NH2
N
OH
94%
NH2
48
49
47
e
89%
O
Cl
O
O Ar
O
N
f
O
N
NH
NH
10-40%
51
50
Scheme 2. Synthetic route to vary B-ring. Reagents and conditions: (a)
EtOH, rt, 1 day; (b) EtOH, 100 °C, l-wave, 5 min; (c) Zn, HOAc,
MeOH; (d) Aryloxyacetylchloride, pyridine, DCM; (e) Chloroacetyl-
chloride, Na2CO3, DCM; (f) ArXH, Na2CO3, cat. KI, acetone,
MeCN, DMSO, 75 °C, 12 h.