7-Oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides: Synthesis and biological activity of a new class of highly potent inhibitors of human cytomegalovirus DNA polymerase

Article abstract of DOI:10.1016/j.bmcl.2007.05.010

We report a new class of non-nucleoside antivirals, the 7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides, some of which possess remarkable potency versus a broad spectrum of herpesvirus DNA polymerases and excellent selectivity compared to human DNA

Full text of DOI:10.1016/j.bmcl.2007.05.010

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3840–3844
7-Oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides:
Synthesis and biological activity of a new class of highly
potent inhibitors of human cytomegalovirus DNA polymerase
Scott D. Larsen,* Zhijun Zhang, Brian A. DiPaolo, Peter R. Manninen,
Douglas C. Rohrer, Michael J. Hageman, Todd A. Hopkins, Mary L. Knechtel,
Nancee L. Oien, Bob D. Rush, Francis J. Schwende, Kevin J. Stefanski, Janet L. Wieber,
Karen F. Wilkinson, Kathyrn M. Zamora, Michael W. Wathen and Roger J. Brideau
Pfizer Global Research and Development, 2800 Plymouth Rd., Ann Arbor, MI 48105, USA
Received 4 April 2007; revised 3 May 2007; accepted 4 May 2007
Available online 10 May 2007
Abstract—We report a new class of non-nucleoside antivirals, the 7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides, some of
which possess remarkable potency versus a broad spectrum of herpesvirus DNA polymerases and excellent selectivity compared to
human DNA polymerases. A critical factor in the level of activity is hypothesized to be conformational restriction of the key 2-aryl-
2-hydroxyethylamine sidechain by an adjacent methyl group.
Ó 2007 Elsevier Ltd. All rights reserved.
Human herpesviruses, including herpes simplex type 1
and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), Ep-
stein-Barr virus (EBV), and human cytomegalovirus
(HCMV), are common and usually self-limiting in
otherwise healthy individuals. However in the im-
mune-impaired, each of these viruses and the emerging
human herpesviruses (HHV-6, -7, and -8) can cause
severe disease, and together they remain a significant
health threat. The nucleoside antivirals ganciclovir
(GCV) and acyclovir (ACV), the nucleotide antiviral
cidofovir (CDV), the pyrophosphate analog foscarnet
(PFA), and the newly described antisense agent, Formi-
virsen, have been approved for treatment of certain her-
petic infections in patients but are less than ideal due to
either their associated toxicity, limited efficacy against
only one or two human herpesviruses, or the require-
ment for non-oral route of delivery.1–3 Additionally,
for certain classes of anti-herpetic drugs, resistance
issues may develop during treatment periods. Thus,
drug-resistant HSV, VZV, and CMV strains have been
identified,4–6 and cross-resistance of herpesviruses to
antiviral drugs has been described.7
Nucleoside based antivirals, including GCV, ACV, and
famciclovir (FCV), require phosphorylation by
a
viral-specific thymidine kinase and subsequent cellular
enzymes to generate an active form, the nucleoside tri-
phosphate. The triphosphate acts as a substrate for the
viral DNA polymerase, competes with the binding of
the natural 20-deoxynucleoside triphosphate, and
thereby leads to partial or complete chain termination.8
We have targeted the herpesvirus DNA polymerase, a
proven molecular target, to identify broad-spectrum
anti-herpetic agents due to its high degree of homology
between nearly all of the eight human herpesviruses.9
We have previously reported on the anti-herpetic activ-
ity in cells and in animals of a novel series of 4-oxo-1,4-
dihydroquinoline carboxamides (DHQs) (e.g., 1, Fig. 1)
that demonstrated broad-spectrum inhibition of
HCMV, HSV-1, HSV-2, and VZV, as well as activity
against EBV and HHV-8 polymerases.10,11 The DHQs
are mixed competitive inhibitors of nucleoside binding
and are not cross-resistant to GCV-resistant HCMV
or to acyclovir-resistant HSV-1 mutants.10d Schnute
et al. subsequently demonstrated broad inhibition of
human herpesvirus polymerases with a related series of
Keywords: Herpesvirus; Cytomegalovirus; HCMV; Herpes; VZV;
HSV; Conformational restriction; Antiviral; Non-nucleoside.
*
Corresponding author. Tel. +1 734 622 2535; fax: +1 734 622 1407;
e-mail: scott.d.larsen@pfizer.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.010

S. D. Larsen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3840–3844
3841
O
O
4-oxo-4,7-dihydrothienopyridines (DHTPs), exemplified
by 2a.12 In contrast to the kinetics determined for the
DHQs, this exemplar proved to be a competitive inhib-
itor of dTTP incorporation into the primer template by
HCMV polymerase.
O
O
S
S
i, ii
OEt
OEt
OHC
N
H
N
H
R1
R1
4
3
Previous structure–activity relationship (SAR) work had
established the critical importance of the 4-chlorobenzyl
amide, the pyridone N-methyl group, and the
aminomethyl sidechain for potent antiviral activity.10a,12
Recently, Schnute et al. demonstrated that the 2-aryl-2-
hydroxyethylamine sidechain (e.g., 2b) endows the
DHTP template with significantly improved activity.
This work culminated in the identification of 2c, which
was selected for advanced preclinical development.13
O
O
O
O
iv
S
iii
HO
S
OEt
OEt
OHC
N
N
R1
R1
5
6
O
O
Cl
S
v, vi
N
H
N
Cl
R1
Earlier SAR work also indicated that substitution of the
DHQ template 1 in the 8-position afforded analogs with
improved potency (unpublished results). Since the
DHTP template did not offer the same opportunity for
SAR exploration, we considered investigating the iso-
meric 7-oxo-1,4-dihydrothieno[3,2-b] pyridine (isoD-
HTP) series, represented by 8. Synthesis of initial
analogs from this class is summarized in Scheme 1.14
The known bicyclic esters 315 were regioselectively
formylated via the corresponding dianions, affording
aldehydes 4 in excellent yield. It is worth noting that at-
tempted Vilsmeir formylation of 3 or monoanionic
formylation of N-methylated 3 was completely unsuc-
cessful at installing the key C-2 aldehyde group. N-
Methylation of 4 followed by borohydride reduction
of the carboxaldehyde of 5 provided alcohols 6. The req-
uisite 4-chlorobenzylamide was installed via simple heat-
ing of 6 with the corresponding amine under basic
conditions. After reaction with methanesulfonyl chlo-
ride, chlorides 7 were obtained, which were used to pre-
pare final analogs 8 by simple alkylation of the requisite
sidechain amines. Non-commercial hydroxyethylamines
were prepared as previously described.13
7
O
O
7
G
vii
S
2
N
H
6
5
3
R1
N4
Cl
8
Scheme 1. Reagents and conditions: (i) 3 equiv LDA, THF, ꢀ78 °C,
1 h; (ii) DMF, ꢀ78 °C (20 min) ! 0 °C, 93% overall; (iii) K2CO3, MeI,
DMF, 50 °C, 24 h, 81%; (iv) NaBH(OAc)3, 1,2-DCE, HOAc,
0 °C ! rt, 4 h, 93%; (v) 7 equiv 4-Cl–PhCH2NH2, 25% NaOMe/
MeOH, 50 °C, 20 h, 88%; (vi) MsCl, DMAP, collidine, DMF, rt, 2 h,
99%; (vii) GH, i-Pr2NEt, DMF, 60 °C, 3 h, 55–80%. Yields are given
for R1 = Me. Detailed experimental procedures can be found in Ref.
14.
ity against HCMV pol, was less potent than the
corresponding DHTP 2b. To our surprise, however, sim-
ple addition of a methyl group at the 3-position (8b)
improved the polymerase IC50 by a full order of magni-
tude, rendering the isoDHTP template more potent than
the DHTP template. This remarkable phenomenon
proved to be general across a range of other 2-aryl-2-
hydroxyethylamine sidechains (8d–8q, Table 1).
Corresponding improvements in plaque reduction IC50
of similar or even greater magnitude were also realized.
New compounds were assayed for their ability to inhibit
HCMV polymerase and to inhibit plaque formation in
human foreskin fibroblast cells infected with HCMV
(Table 1).10b,12 The prototype 2-phenyl-2-hydroxyethyl-
amine isoDHTP analog 8a, while possessing good activ-
Interestingly, the C-3 methyl provided no benefit when
the sidechain was morpholine (8v vs 8w), suggesting that
the methyl group itself does not augment binding, but
perhaps instead effects a beneficial conformational
change in the adjacent aryl ethanolamine sidechain. This
hypothesis was supported by the observation that the
C-3 methyl group was in fact detrimental when
the sidechain was N-methyl phenylalaninol (8t vs 8u).
The unique conformational demands presented by the
isoDHTP 3-methyl are also apparent in the complete
inactivity of 8x, an analog which bears a benzylmorph-
oline sidechain that confers reasonably good activity to
the DHTP template (HCMV pol IC50 = 0.5 lM, unpub-
lished results). Nevertheless, similarities with DHTP
SAR are still apparent in the requirement for an
N-methyl group on the 2-aryl-2-hydroxyethylamine
sidechain (8c) and the superiority of the (R)-enantiomer
of 8m compared to the (S)-enantiomer (8s vs 8r).
O
O
5
8
4
N
N
H
O
N1
Cl
1
O
N
O
G
N
H
S
Cl
2a: G = morpholinyl (HCMV pol IC50 = 1.1 μM)
2b: G = PhCH(OH)CH2NMe (HCMV pol IC50 = 0.10 μM)
2c: G = (R)-2-pyr-CH(OH)CH2NMe (HCMV pol IC50= 0.06 μM)
Figure 1. Lead carboxamide CMV pol inhibitors.

3842
S. D. Larsen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3840–3844
Table 1. Biological activity of dihydrothieno[3,2-b]pyridines 8
O
N
O
G
S
N
H
Cl
R1
b
c
Compound
Ga
R1
H
CMV pol IC50 (lM)
Plaque IC50 (lM)
8a
8b
8c
8d
8e
8f
Ph–CH(OH)CH2NMe
Ph–CH(OH)CH2NMe
Ph–CH(OH)CH2NH
0.58
0.041
10.6
0.22
0.017
0.16
0.02
0.21
0.019
0.18
0.02
0.25
0.032
0.59
0.072
0.14
0.017
0.31
0.026
0.42
12.4
2.3
nd
0.04
15
Me
Me
H
4-HO–Ph–CH(OH)CH2NMe
4-HO–Ph–CH(OH)CH2NMe
3-MeO–Ph–CH(OH)CH2NMe
3-MeO–Ph–CH(OH)CH2NMe
3-Indolyl–CH(OH)CH2NMe
3-Indolyl–CH(OH)CH2NMe
2-Furyl–CH(OH)CH2NMe
2-Furyl–CH(OH)CH2NMe
2-Pyr–CH(OH)CH2NMe
2-Pyr–CH(OH)CH2NMe
2-Thiazolyl–CH(OH)CH2NMe
2-Thiazolyl–CH(OH)CH2NMe
2-Pyrazinyl–CH(OH)CH2NMe
2-Pyrazinyl–CH(OH)CH2NMe
(S)-2-Pyr–CH(OH)CH2NMe
(R)-2-Pyr–CH(OH)CH2NMe
PhCH2CH(CH2OH)NMe
PhCH2CH(CH2OH)NMe
Morpholin-4-yl
0.15
0.0004
0.1
Me
H
8g
8h
8i
Me
H
0.002
0.5
Me
H
0.03
0.1
8j
8k
8l
Me
H
0.004
nd
8m
8n
8o
8p
8q
8r
8s
8t
Me
H
0.01
nd
Me
H
0.04
0.15
0.06
0.06
0.002
nd
Me
Me
Me
H
8u
8v
8w
8x
Me
H
>1
nd
Morpholin-4-yl
(R)-3-Benzylmorpholin-4-yl
Me
Me
3.0
>5
>5
>20
a Unless otherwise noted, sidechains are racemic.
b Inhibition of human cytomegalovirus DNA polymerase.
c Inhibition of plaque formation in human foreskin fibroblasts infected with HCMV. nd, not determined.
Table 2. Activity versus calculated sidechain conformational mobility
We were intrigued by the possibility that the 3-methyl
group might actually be restricting the rotational free-
dom of the 2-aryl-2-hydroxyethyl sidechain into a favor-
able conformation for binding, which would constitute
an interesting example of non-covalent conformational
restriction.16 To support this hypothesis, the 3D struc-
tures of a pair of analogs differing only in the presence
or absence of the C-3 methyl group (8d and 8e) were
modeled. The graphical modeling program MOSAIC17
was used to build a preliminary structural model for
each compound using structural templates in MOSAIC
derived from analysis of crystal structure data contained
in the Cambridge Crystal Structure Database18 (CCSD).
Each of these structures was then minimized using the
structural potential energy minimization and conforma-
tional search program BATCHMIN.17 An MM2*
potential function19 filtered by a generalized Born solva-
tion model20 was employed for the energy evaluations
and minimization. The conformational flexibility of
the C-2 side chain of each compound was explored using
the systematic pseudo-Monte-Carlo search feature of
BATCHMIN to find minimum energy rotational iso-
mers. The five rotatable bonds of the side chain (colored
red in Table 2) were searched considering 10,000 rota-
tional poses and retaining those conformations calcu-
lated to be within 5 kcal/mol of the lowest energy
conformation. The flexible amide sidechain was omitted
from these calculations to reduce the complexity of the
calculation and computation time required. The number
O
O
N
S
N
HO
H
OH
N
Cl
R1
a
Compound
R1
CMV pol IC50 (lM)
No. conf.b
8d
8e
H
Me
0.22
0.02
30
6
a Inhibition of human cytomegalovirus polymerase.
b Number of rotational isomers (red bonds) within 5 kcal/mol of the
lowest energy conformation.
of conformations obtained for each search is given in
Table 2.
The computational data in Table 2 support our hypoth-
esis that the superior activity is associated with attenu-
ated conformational freedom of the amine sidechain.
8e, possessing the C-3 methyl group, has only six low en-
ergy conformations available to it. Removal of the C-3
methyl group (8d) allows the C-2 sidechain to adopt a
full 30 conformations within the same energy range,
and at the same time reduces the polymerase inhibitory
activity by an order of magnitude. Distribution of 8d
into a greater number of low energy conformations
would be expected to increase the entropy of binding,
explaining the overall decrease in activity.

S. D. Larsen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3840–3844
3843
Unfortunately the superior activity of the isoDHTP ser-
ies was associated with very poor aqueous solubility.
Among the analogs in Table 1, one of the most soluble
was 8m (0.7 lg/mL). Efforts to improve the solubility are
summarized in Table 3. Other heterocycles were exam-
ined with limited success, the best being imidazole (9d)
at 2.6 lg/mL. Changing the benzyl amide phenyl to pyr-
idine (9a) dramatically improved solubility, but at an
unacceptable cost to activity. Polar substituents on the
sidechain phenyl also improved solubility, but increases
beyond 2.7 lg/mL (9h) were not possible without losing
too much activity (9i and 9k). Replacing the chlorine on
the benzyl amide with fluorine effected approximately a
10-fold improvement in solubility (9e vs 9f) but again
this costs a penalty with regard to activity. Ultimately
the best balance of activity and solubility was realized
with pyrimidine analog 9n, although it is also worth not-
ing the excellent activity and improved solubility of the
3-hydroxy-6-pyridyl analog 9j.
Selected isoDHTP analogs were evaluated in a rat phar-
macokinetic model, and complete antiviral and selected
PK data for the two possessing the best bioavailabilities
(8s and 9n) are presented in Table 4. Data for bench-
mark antivirals and the DHTP preclinical candidate 2c
are included for comparison. An examination of the
two pyridyl analogs 8s and 2c reveals the superior anti-
viral activity of the isoDHTP template; however, the
isoDHTP analog suffers from inferior solubility and a
greater propensity to inhibit the hERG channel. hERG
blockage is considered to be a significant cardiovascular
risk factor when selecting compounds for advanced
development.21 The fluoro isoDHTP analog 9n,
although possessing somewhat less impressive antiviral
activity than 8s, has much better solubility and a mark-
edly improved hERG profile. It is also noteworthy that
the HSV-1 plaque reduction IC50 of 9n is nearly 10-fold
lower than that of the DHTP development candidate,
perhaps due at least in part to its superior solubility.
Table 3. Biological activity and solubility of dihydrothieno[3,2-b]pyridinesa
O
O
N
S
N
Ar2
Ar1
H
OH
N
9
Ar1
Ar2
CMV pol IC50 (lM)
Plaque IC50 (lM)
Aq soln (lg/mL)
b
c
Compound
8m
9a
9b
9c
9d
9e
9f
2-Pyridyl
2-Pyridyl
2-Pyrazinyl
4-Cl–Ph
4-Cl-3-pyr
4-Cl–Ph
4-Cl–Ph
4-Cl–Ph
4-Cl–Ph
4-F–Ph
0.032
1.2
0.01
nd
0.7
30
0.017
0.20
0.25
0.06
0.015
0.45
0.035
0.8
0.25
1.9
2.6
0.4
6.8
0.11
2.7
19
3-Pyridazinyl
2-Imidazolyl
3-Pyrazolyl
0.08
0.51
3-Pyrazolyl
4-NH2SO2Ph
3-AcNHPh
9g
9h
9i
4-Cl–Ph
4-Cl–Ph
4-Cl–Ph
4-Cl–Ph
4-Cl–Ph
4-Cl–Ph
4-Cl–Ph
4-F–Ph
0.10
0.093
1.8
0.5
0.02
nd
4-Me2NCH2Ph
3-OH–Pyridin-6-yl
4-HOOC–Ph–
2-Pyrimidinyl
(R)-2-Pyrimidinyl
(R)-2-Pyrimidinyl
9j
0.0097
0.030
0.037
0.015
0.067
0.0004
4.2
5.0
>117
1.3
1.4
19
9k
9l
0.015
0.004
0.05
9m
9n
a
Unless otherwise noted, sidechains are racemic.
b Inhibition of human cytomegalovirus DNA polymerase.
c Inhibition of plaque formation in human foreskin fibroblasts infected with HCMV. nd, not determined.
Table 4. Broad-spectrum antiviral, PK, and safety data of isoDHTP analogs versus DHTP 2c and established therapies
F%d hERG IC20 (lM)
a
b
Compound
Polymerase IC50 (lM)
HCMV HSV-1 VZV Human DNA-pol HCMV HSV-1 VZV
Antiviral IC50 (lM)
Aq soln CL
(lg/mL) (L/h/kg)c
2c
0.061
0.027
0.067
0.076
0.023
0.13
0.021
>20 (a)
0.10
0.002
0.05
3.0
1.2
0.41
2.1
0.002 10
2.8
1.4
2.1
45
30
29
0.5
0.1
2.0
8s
9n
0.0058 >20 (a)
0.054
0.001
0.02
8.1
0.3
19
>20 (a)
Acyclovir
Ganciclovir
Foscarnet
>20
1.3
nd
nd
2.5
nd
nd
<0.28 (c)
2.6 (a)
2.3 (d)
Aphidicolin 0.4
AZT-TP 22.1
0.5
3.3
0.6
5.8
a Inhibition of human cytomegalovirus DNA polymerase.
b Inhibition of plaque formation in human foreskin fibroblasts infected with HCMV.
c Dosed iv (5 mg/kg) in rats.
d Dosed po (15 mg/kg) in rats. nd, not determined.

3844
S. D. Larsen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3840–3844
M. L.; Huang, A.; Vaillancourt, V. A.; Vera, E. E.; Oien,
N. L.; Hopkins, T. A.; Wieber, J. L.; Wilkinson, K. F.;
Rush, B. D.; Schwende, F. J.; Wathen, M. W. Antiviral
Res. 2002, 54, 19; (c) Knechtel, M. L.; Huang, A.;
Vaillancourt, V. A.; Brideau, R. J. J. Med. Virol. 2002,
68, 234; (d) Oien, N. L.; Brideau, R. J.; Hopkins, T. A.;
Wieber, J. L.; Knechtel, M. L.; Shelly, J. A.; Anstadt, R.
A.; Wells, P. A.; Poorman, R. A.; Huang, A.; Vaillan-
court, V. A.; Clayton, T. L.; Tucker, J. A.; Wathen, M. W.
Antimicrob. Agents Chemother. 2001, 46, 724.
We have established that the DHTP template can be
modified to accommodate substitution in the same re-
gion as C-8 of the DHQ template with only minimal
diminution in activity. Furthermore we observed that
simple methyl substitution at C-3 of the new isoDHTP
template effects a dramatic boost in potency, which
may be due to conformational restriction of the key 2-
aryl-2-hydroxyethylamine sidechain, an hypothesis that
is supported by both SAR and modeling. A compound
was identified from this class (9n) with antiviral activity
nearly equivalent to the DHTP development candidate
2c, but which also possesses improved solubility and re-
duced hERG liability. Additional SAR studies on C-3
and N-4 substitution will be reported in due course.
11. Hartline, C. L.; Harden, E. A.; Williams-Aziz, S. L.;
Kushner, N. L.; Brideau, R. J.; Kern, E. R. Antiviral Res.
2005, 65, 97.
12. Schnute, M. E.; Cudahy, M. M.; Brideau, R. J.; Homa, F.
L.; Hopkins, T. A.; Knechtel, M. L.; Oien, N. L.; Pitts, T.
W.; Poorman, R. A.; Wathen, M. W.; Wieber, J. L.
J. Med. Chem. 2005, 48, 5794.
13. Schnute, M. E.; Anderson, D. J.; Brideau, R. J.; Ciske, F.
L.; Collier, S. A.; Cudahy, M. M.; Eggen, M.; Genin, M.
J.; Hopkins, T. A.; Judge, T. M.; Kim, E. J.; Knechtel, M.
L.; Nair, S. J.; Nieman, J. A.; Oien, N. L.; Scott, A.; Tanis,
S. P.; Vaillancourt, V. A.; Wathen, M. W.; Wieber, J. L.
Bioorg. Med. Chem. Lett. 2007, 17. doi:10.1016/
j.bmcl.2007.03.102.
Acknowledgments
The authors thank the laboratories of Michael J. Genin,
James A. Nieman, Mark E. Schnute, and Steven P. Tan-
is for generously providing some of the amine sidechains
utilized in this work.
14. Detailed experimental procedures can be found in: WO 03/
059878 and WO 03/059912.
15. (a) Elliott, R. L.; O’Hanlon, P. J.; Rogers, N. H.
Tetrahedron 1987, 43, 3295; (b) Ife, R. J.; Brown, T. H.;
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17. MOSAIC is a graphical molecular modeling program
developed at Pharmacia using an early version of Macro-
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Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
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440) as starting point.
18. Information about the Cambridge Crystal Structure
Database is available on the internet at the following
address; www.ccdc.cam.ac.uk/.
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