Imidazo[1,2-a]pyridines with potent activity against herpesviruses

Article abstract of DOI:10.1016/j.bmcl.2007.02.079

Synthesis of a series of 2-aryl-3-pyrimidyl-imidazo[1,2-a]pyridines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the 2-aryl, 3-heteroaryl as well as other imidazopyridine substituents are

Full text of DOI:10.1016/j.bmcl.2007.02.079

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2735–2739
Imidazo[1,2-a]pyridines with potent activity against herpesviruses
Kristjan S. Gudmundsson* and Brian A. Johns
Department of Medicinal Chemistry, Infectious Diseases Center of Excellence for Drug Discovery,
GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA
Received 24 January 2007; revised 28 February 2007; accepted 28 February 2007
Available online 3 March 2007
Abstract—Synthesis of a series of 2-aryl-3-pyrimidyl-imidazo[1,2-a]pyridines with potent activity against herpes simplex viruses is
described. Synthetic approaches allowing for variation of the 2-aryl, 3-heteroaryl as well as other imidazopyridine substituents
are outlined and resulting effects on antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar
or better than acyclovir are described.
Ó 2007 Elsevier Ltd. All rights reserved.
The herpesvirus family (Herpesviridae) is highly dissem-
inated in nature and most animal species host at least
one member. This family contains eight known human
viruses, amongst them herpes simplex virus 1 (HSV-1)
and herpes simplex virus 2 (HSV-2).1 HSV-1 and
HSV-2 cause mucocutaneous infections, resulting in
cold sores (HSV-1) and genital lesions (HSV-2), respec-
tively. A key feature of these viruses is their ability to
cause latent and chronic infection of neurons, which
upon reactivation leads to recurrent lesions at the muco-
cutaneous area of initial infection.2 Much research has
been focused on HSV-1 and HSV-2 as these viruses have
a high incidence rate (ꢀ1.6 million new cases of HSV-2
predicted per year in the US) and a high prevalence of
50–95% (HSV-1) and 6–50% (HSV-2).3
(4-hydroxyquinoline-3-carboxamides)10 and viral heli-
case inhibitors (thiazolylphenyl and thiazolylamide)11
have recently received considerable attention.
We have recently disclosed a series of pyrazolo[1,5-
a]pyridines, such as 1, which show potent and selective
inhibition of HSV-1 and -2 (Fig. 1).12 We became inter-
ested in the corresponding imidazo[1,2-a]pyridines as
they can be substituted in the same fashion as the pyr-
azolopyridines, furthermore imidazopyridines have been
widely used in medicinal chemistry. We have disclosed
the synthesis of the imidazopyridine 2.13 Herein we ex-
pand on the synthetic approaches and describe several
novel imidazopyridines and their anti-HSV activity.
Initially we chose to prepare several methoxyphenyl
analogs as we have previously shown those to be very
potent for the related pyrazolopyridine series.12b Con-
densation of 2-amino-3-chloropyridine 3 with commer-
cially available a-bromo ketone 4 was used to prepare
Previous drug discovery efforts targeting herpes simplex
viruses has primarily focused on the development of
nucleoside analogs that target the viral polymerase.4
The discovery of acyclovir (Zovirax),5 was a milestone
in the development of antiviral drugs and was followed
by a number of other nucleoside analogs (valacyclovir,6
famciclovir7 and penciclovir).
HN
HN
1
N
8
Though numerous strategies and considerable effort
have been spent in the search for the next generation
antiherpetic therapy, it has proved difficult to outper-
form acyclovir.8 Immunomodulators (imiquimod and
resiquimod),9 nonnucleoside viral polymerase inhibitors
N
N
2
N
F
F
N
6
3
N
N
N
N
H
N
H
Keywords: Imidazo[1,2-a]pyridine; Antiherpetic; HSV.
*
1
2
Corresponding author. Tel.: +1 919 483 5862; fax: +1 919 483
6053; e-mail: Kristjan.S.Gudmundsson@gsk.com
Figure 1. Pyrazolopyridine and imidazopyridine scaffolds.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.079

2736
K. S. Gudmundsson, B. A. Johns / Bioorg. Med. Chem. Lett. 17 (2007) 2735–2739
imidazopyridine core 5 as outlined in Scheme 1. We
have previously shown13 that an efficient route to con-
struct the C-3 pyrimidine is to build the pyrimidine from
alkynyl ketones via a cyclization with guanidines.
8-position could be coupled with cyclopentylamine
using Buchwald amination conditions (Pd(OAc)2, rac-
BINAP, Cs2CO3).14 Demethylation with BBr3 in
CH2Cl2 gave phenol 11, that could be alkylated with
allylbromide or cyclopropylmethylbromide to give,
respectively, 12 and 13.
Thus, formylation of 5 under Vilsmeier–Haack condi-
tions gave an excellent yield of the remarkably stable
aldehyde 6. This aldehyde was treated with the commer-
cially available ethynyl Grignard reagent at low temper-
ature to give the propargyl alcohol in excellent yield.
This alcohol was easily oxidized to ketone 7 using
MnO2. Other oxidation methods (e.g., Swern and
Dess–Martin oxidations) gave lower yields. Treatment
of the alkynyl ketone 7 with cyclopentylguanidine 8, re-
sulted in formation of the 8-chloro intermediate 9. Ini-
tial attempts at thermally displacing the 8-chloro
substituent of 9 with cyclopentylamine failed, but the
By chosing differently substituted commercially avail-
able a-bromoacetophenones, the substitution pattern
of the 2-phenyl moiety was further altered. Substituents
were chosen based on our previous experience from the
analogous pyrazolopyridine series, where small substitu-
ents generally appeared to be preferred over large
groups (halogen, alkyl, alkoxy and cyano substituents
gave best antiviral activity).12b Thus m-substituted alk-
oxy derivatives (14–17) as well as nitriles (18 and 19)
and a methyl derivative (20) were prepared in a similar
fashion as outlined in Scheme 1 starting from commer-
cially available a-bromoacetophenones. The nature of
the substituent or location (meta vs para) on the 2-phe-
nyl moiety did not significantly alter anti-HSV activity
as shown by the fact that strongly electron withdrawing
groups (fluoro) showed similar potency as the strongly
electron donating groups (methoxy) and both of these
showed comparable activity to nitrile substituents. For
further studies we chose to focus on p-fluorophenyl
derivatives (such as 2) as these showed excellent anti-
HSV activity while containing a non-reactive substituent
with low molecular weight.
Cl
a
O
MeO
Cl
NH2
N
Br
N
3
4
Cl
N
b
MeO
N
H
MeO
c
N
6
5
O
Cl
d
N
MeO
N
e
NH
HCl
H2N
The synthetic method outlined in Scheme 1 was thus
used to make a small set of 8-amino-2-(p-fluoro-
phenyl)-derivatives 21–24 via a Buchwald coupling
methodology. These indicate that secondary alkyl-
amines are favored at the C8 position.
7
N
O
H
8
NH
Cl
N
N
N
MeO
MeO
N
N
Cl
Cl
9
10
N
N
a
N
I
N
F
N
N
F
N
N
N
H
H
27
28
B(OH)2
29
NH
Cl
NH
NH2
N
N
N
N
N
HO
g
f
F
RO
N
F
N
N
N
b
11
N
N
c
30
N
N
H
N
H
F
R
12 R=p-O-allyl
13 R=p-O-CH2cPr
N
N
31 R=Cl
F
N
d
Scheme 1. Reagents and conditions: (a) NaHCO3 (1 equiv), EtOH,
reflux, 6 h, (73%); (b) POCl3 (2 equiv), DMF, rt, 12 h (86%); (c)
Ethynyl magnesium bromide (2 equiv), THF, À78–0 °C, 2 h. Then
MnO2 (10-fold excess), CH2Cl2, 1 h (51%, two steps); (d) cyclopentyl
guanidine HCl (1.5 equiv), K2CO3 (1.5 equiv), EtOH, 80 °C, 12 h
(50%); (e) Pd(OAc)2 (0.2 equiv), BINAP (0.3 equiv), Cs2CO3 (2 equiv),
cyclopentylamine (neat), 100 °C, 18 h (53%); (f) BBr3 (1.1 equiv),
CH2Cl2 À78 °C to rt, 15 h (70%); (g) allyl bromide or cyclo-
propylmethylbromide (1.5 equiv), Cs2CO3 (2 equiv), DMF, 80 °C,
3 h (34% for 12; 47% for 13).
32 R=c-PentylNH
N
H
Scheme 2. Reagents and conditions: (a) NIS (1.5 equiv), CH2Cl2, rt
12 h, (80%); (b) PdCl2(PPh3)2 (0.2 equiv), aq Na2CO3 (2 equiv), DMF,
100 °C, 12 h, (81%); (c) cyclopentylamine (neat), 150 °C, 3 days, (76%);
(d) Pd(OAc)2 (0.2 equiv), BINAP (0.3 equiv), Cs2CO3 (2 equiv),
cyclopentylamine (neat), 100 °C, 18 h (27%).

K. S. Gudmundsson, B. A. Johns / Bioorg. Med. Chem. Lett. 17 (2007) 2735–2739
Table 1. HSV-1 antiviral activity and cytotoxicity of C8-substituted imidazopyridine analogs
2737
R3
N
N
N
R1
R2
N
N
H
a
b
Compound
Subst. R1
Subst. R2
Subst. R3
IC50 (lM)
CC50 (lM)
2
9
p-F
p-OCH3
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
c-Pent
Me
c-PentNH
Cl
0.59
1.43
0.48
3.40
0.57
0.27
1.73
0.71
3.13
0.30
0.32
0.36
1.61
0.51
0.80
1.88
0.26
9.3
>40
30.1
>10
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
32c
p-OCH3
p-OH
c-PentNH
c-PentNH
c-PentNH
c-PentNH
Cl
p-OCH2CH@CH2
p-OCH2c-Propyl
m-OCH3
m-OCH3
c-PentNH
c-PentNH
c-PentNH
c-PentNH
c-PentNH
c-PentNH
c-PropylNH
n-ButylNH
1-pyrrolidinyl
2-methoxyethylNH
Cl
m-OH
m-OCH2CH@CH2
p-CN
m-CN
p-CH3
p-F
p-F
p-F
32
>40
>40
>40
>40
>40
p-F
p-F
p-F
p-F
Me
c-Pent
c-PentNH
c-PentNH
>5
0.6
1
ACV
—
Acyclovir
—
—
—
—
0.26
0.39
>160
>200
a Vero cells, HSV-1, SC-16 strain. IC50 is the concentration at which 50% efficacy in the antiviral assay is observed using a capture hybrid method.12b
b
CC50 is the concentration at which 50% cytotoxicity is observed.
c Analog contains a C3-pyridine rather than C3-pyrimidine.
For the pyrazolopyridine series we had observed that
lipophilic alkylamines (cyclopentylamine being optimal)
were the preferred 2-pyrimidinyl substituents.12d This
also appears to be the case for the imidazopyridines.
Derivatives prepared with methylguanidine, 25 and 26,
showed reduced anti-HSV activity.
We were also interested in seeing how a C3 2-aminopyri-
dine substituent compared with the 2-aminopyrimi-
dine substituent. Thus 3-iodoimidazopyridine 28 was
synthesized (Scheme 2) from 27 by treatment with
N-iodosuccinimide.
Subsequent Suzuki coupling of 28 and boronic acid 29
gave the 2-fluoropyridine 30. Displacement of the
2-fluorine with cyclopentylamine under thermal
conditions gave the 2-aminopyridine 31 in good yield.
Br
a
O
F
Cl
Cl
a
O
Br
NH2
N
F
34
33
Br
NH2
N
N
N
N
42
34
F
F
Cl
HN
N
N
N
b
Br
R
N
N
N
F
F
N
N
N
N
b
Cl
Cl
N
N
H
N
H
43
44
N
35
36 R=NHc-pent
37 R=H
N
N
H
N
H
Scheme 3. Reagents and condition: (a) for conditions see Scheme 1; (b)
Pd(OAc)2 (0.2 equiv), BINAP (0.3 equiv), Cs2CO3 (2 equiv), cyclo-
pentylamine (neat), 100 °C, 18 h (43% of 36 and 12% of 37).
Scheme 4. Reagents and condition: (a) for conditions see Scheme 1; (b)
Pd(OAc)2 (0.2 equiv), BINAP (0.3 equiv), Cs2CO3 (2 equiv), cyclo-
pentylamine (neat), 100 °C, 18 h (50%).

2738
K. S. Gudmundsson, B. A. Johns / Bioorg. Med. Chem. Lett. 17 (2007) 2735–2739
Table 2. HSV-1 antiviral activity and cytotoxicity of C6-, C8-substituted imidazopyridine analogs
Y
N
F
N
X
N
N
N
a
b
Compound
Subst. X
Subst. Y
IC50 (lM)
CC50 (lM)
35
36
37
38
39
40
41
43
44
45
46
47
1
Br
c-PentNH
H
4.08
0.33
3.3
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>160
>200
H
H
Br
H
Me
1.16
0.15
1.53
0.12
1.11
0.37
0.80
0.22
0.30
0.26
0.39
c-PentNH
H
c-PropylNH
Me
Me
Me
Cl
Cl
Cl
c-PentNH
Br
c-PentNH
Br
Br
Br
—
n-ButylNH
—
—
ACV
Acyclovir
a Vero cells, HSV-1, SC-16 strain. IC50 is the concentration at which 50% efficacy in the antiviral assay is observed using a capture hybrid method.12b
bCC50 is the concentration at which 50% cytotoxicity is observed.
Buchwald coupling of 31 and cyclcopentylamine gave
the desired analog 32. While the C3-pyridine analog 32
was equipotent to the C3-pyrimidine analog (2) it did
not offer any advantage over 2. Furthermore, concerns
about potential cytochrome inhibition of the 2-amino-
pyridine moiety prompted us to stick with the C3 pyrim-
idine moiety for further investigations.
in a similar fashion as outlined in Scheme 3 from 2-ami-
no-3-methyl-5-bromopyridine. Interestingly the C6
cyclopentylamino analogs 36 and 39 are at least equally
potent to their C8 counterpart 2, thus giving more op-
tions for location of the alkylamine substituent during
further optimization.
As both C6 as well as C8 alkylamine substituted com-
pounds had shown good potency we became interested
in looking at additional 6,8-disubstituted compounds.
The 6,8-disubstituted derivatives 43–47 were prepared
as outlined in Scheme 4. Here Buchwald coupling condi-
tions could be used to cleanly replace the C8 halogen
without any noticeable reaction of the C6 halogen.
Given the potent anti-HSV activity of several of the C8-
substituted imidazopyridines, we were interested in
studying how different substitution patterns would affect
antiviral activity. We were especially interested in seeing
how moving the C8 cyclopentylamino substitutent to
the C6 position would affect activity. As can be seen in
Table 1, alkylamines at C8 showed better activity than
halogens (e.g., 9 vs 10; 14 vs 15) and we were curious
if the improved potency of the C-8 alkylamines could
partially be explained by electron donating effects onto
the imidazopyridine N-1. Moving the electron donating
alkylamine substituent to C6 would continue to allow
resonance electron donation to the N-1 imidazopyridine
nitrogen.
Several of these 6,8-disubstituted derivatives (44, 46 and
47) showed very promising potency (Table 2).
The above SAR study has begun to delineate the SAR of
the imidazopyridine scaffold. Several molecules with
potency similar or better than the current gold standard
acyclovir were identified, thus establishing the imidazo-
pyridine scaffold as an interesting template for anti-HSV
drug discovery.
The 6-chloro substituent was found to be much less
reactive than the corresponding 8-chloro position. Thus
C6 alkylamine substituted compounds could not be effi-
ciently prepared by replacement of a 6-chloro group un-
der Buchwald conditions, but required preparation of
the more reactive 6-bromo derivatives. The 6-cyclopen-
tylamino derivative 36 was thus prepared from the
6-bromo-imidazopyridine 35 via a Buchwald coupling
methodology. A by-product of this coupling was the
reduced 6-protio derivative 37. Low reactivity of the
6-chloro substituent toward Pd catalyzed coupling
conditions is in contrast to the relative ease of coupling
of 8-position with alkylamines under Buchwald
conditions. The 8-methyl analogs 38–41 were prepared
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