Bioorganic & Medicinal Chemistry Letters 16 (2006) 1924–1928
Novel non-benzimidazole chk2 kinase inhibitors
Kelly J. McClure,* Liming Huang, Kristen L. Arienti, Frank U. Axe,
Anders Brunmark, Jon Blevitt and J. Guy Breitenbucher
Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA
Received 28 October 2005; revised 19 December 2005; accepted 22 December 2005
Available online 25 January 2006
Abstract—In a recent paper, [Arienti, K. L.; Brunmark, A.; Axe, F. U.; McClure, K. M.; Lee, A.; Blevitt, J.; Neff, D. K.; Huang, L.;
Crawford, S.; Chennagiri, R. P.; Karlsson, L.; Brietenbucher, J. G. J. Med. Chem. 2005, 48, 1873], we described the discovery of a
class of benzimidazole chk2 kinase inhibitors, exemplified by compound 1, which had radio-protective effects in human T-cells sub-
jected to ionizing radiation. Here, a series of non-benzimidazole analogs intended to define the scope of the SAR about this new
series of inhibitor, and allow for refinement of the binding model of these compounds to the chk2 kinase is described.
Ó 2006 Elsevier Ltd. All rights reserved.
Radiotherapy is still the most commonly used treatment
for cancer patients, with >50% of all cancer patients
receiving some sort of radiotherapy. Side effects from
radiation therapy represent a major clinical problem,
which seriously affects both quality-of-life and clinical
outcome. Despite major improvements in the use of fo-
cused and fractionated dosing of radiation side effects
are still generally dose limiting. Thus, compounds that
act to increase the therapeutic window of radiotherapy
would have great clinical utility in the treatment of can-
cer. Additionally, such an agent might find utility in pro-
tecting humans from occupational exposure to ionizing
radiation.
model, is described. To probe the SAR of the benzimid-
azole-containing analogues, we replaced the benzimid-
azole core with closely related 5,6-fused heterocycles.
Maintaining a constant geometric arrangement of pen-
dant groups allowed for the precise determination of
the critical binding elements of the benzimidazole group.
The routes utilized to arrive at these analogues as well as
their corresponding biological data are reported below
(Table 1).
O
N
H2N
O
N
H
Chk2 is a serine/threonine kinase that was first described
in 1998.2 Chk2 is involved in the cellular response to
DNA strand breaks that occur upon exposure to c-radi-
ation.3 Chk2 knockout mice demonstrate increased sur-
vival to radiation. These animals also show suppressed
apoptosis in thymus, hippocampus, and skin tissues
after exposure to c-radiation.4,5 As a result, inhibition
of chk2 would be expected to be radio protective and
potentially useful as an adjunct to radiotherapy.
1
Simple methyl substitution at either nitrogen of the imid-
azole, as represented in compounds 4 and 7 of Table 1,
was accessed utilizing the route shown in Scheme 1.
In the first step, the fluoro group of 4-fluoro-3-nitroben-
zoic acid (2) was displaced with methylamine followed
by conversion of the acid to a primary amide, and nitro
reduction giving the diamine intermediate 3. The dia-
mine was then oxidatively condensed under standard
conditions with 4-aryloxybenzaldehyde giving com-
pound 4 in good yield. Compound 7 was prepared in a
similar fashion starting from 3-fluoro-4-nitrobenzoic
acid.
(4-Aryloxy-phenyl)benzimidazoles such as compound 1
(also compounds 1a, 1b and 1c in Table 1) were discov-
ered to be potent inhibitors of the chk2 kinase.1 In this
paper, a series of benzimidazole replacement analogues,
which were designed to further define the SAR of this
series of inhibitors as well as refine the existing binding
The benzoxazoles 9 and 11 were prepared via the route
shown in Scheme 2.
*
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.12.096