Inhibitors of HCV NS5B polymerase: Synthesis and structure-activity relationships of N-1-benzyl and N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine analogs containing substituents on the aromatic ring

Article abstract of DOI:10.1016/j.bmcl.2006.04.022

A series of non-nucleoside HCV NS5B polymerase inhibitors based on the N-1-benzyl or N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine core substituted in the D-ring aromatic moiety have been prepared and evaluated. Aromatic substituents extending from position 7 of the D-ring exhibited excellent potency against both genotypes 1a and 1b.

Full text of DOI:10.1016/j.bmcl.2006.04.022

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3833–3838
Inhibitors of HCV NS5B polymerase: Synthesis and structure–
activity relationships of N-1-benzyl and N-1-[3-methylbutyl]-4-
hydroxy-1,8-naphthyridon-3-yl benzothiadiazine analogs
containing substituents on the aromatic ring
Todd W. Rockway,* Rong Zhang, Dachun Liu, David A. Betebenner,
Keith F. McDaniel, John K. Pratt, David Beno, Debra Montgomery, Wen W. Jiang,
Sherie Masse, Warren M. Kati, Tim Middleton, Akhteruzzaman Molla,
Clarence J. Maring and Dale J. Kempf
Infectious Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories,
200 Abbott Park Road, Abbott Park, IL 60064-6217, USA
Received 25 February 2006; revised 8 April 2006; accepted 10 April 2006
Available online 2 May 2006
Abstract—A series of non-nucleoside HCV NS5B polymerase inhibitors based on the N-1-benzyl or N-1-[3-methylbutyl]-4-hydroxy-
1,8-naphthyridon-3-yl benzothiadiazine core substituted in the D-ring aromatic moiety have been prepared and evaluated. Aromatic
substituents extending from position 7 of the D-ring exhibited excellent potency against both genotypes 1a and 1b.
Ó 2006 Elsevier Ltd. All rights reserved.
Hepatitis C virus (HCV) is a human pathogen affecting
approximately 3% of the world’s population.1 Left
untreated, HCV infection can lead to chronic hepatitis,
liver cirrhosis, and hepatocellular carcinoma. Viral iso-
lates of hepatitis C are classified into six genotypes with
genotypes 1 and 2 being the most prevalent in the Unit-
ed States, Europe, and Japan.2 The current standard for
drug therapy consists of a combination of pegylated
a-interferon (IFN-a) and ribavirin the use of which is
often limited by safety and tolerability issues. The
response rate for patients infected with viral genotypes
1, 4, 5, and 6 virus is approximately 48%, while patients
infected with genotypes 2 and 3 exhibit an 88% response
rate.3 Therefore, the need for more effective and tolera-
ble agents for the treatment of HCV, especially for
patients with genotype 1 virus, has stimulated an intense
research effort. Significant efforts have been directed
toward several targets within the HCV genome, includ-
ing NS3 protease/helicase complex and NS5B RNA-
dependent RNA polymerase (RdRp).4 Recent publica-
tions5–12 have described efforts toward the development
of small molecule inhibitors of NS5B RdRp. Nucleo-
side5 and non-nucleoside inhibitors binding within the
palm region7–10 of the NS5B RdRp as well as alloste-
ric6,11,12 inhibitors binding in the palm domain at the
junction with the thumb region of the enzyme have been
described. We recently described preliminary structure–
activity inhibition data of the non-nucleoside N-1-alkyl-
4-hydroxy-quinolon-3-yl benzothiadiazine class of
NS5B RdRp inhibitors.8 The benzothiadiazine class of
molecule is illustrated in Figure 1.
O
O
S
R7
R6
OH
N
D
C
N
H
B
A
R5
N
N
R1
O
R1 = Benzyl (1)
R
1 = 3-Methylbutyl (2)
Figure 1. General naphthyridone-based benzothiadiazine structure
depicting the A-, B-, C-, D-rings, where the B-ring substituent is
designated by R1 and the D-ring substituent positions 5, 6, and 7 are
designated by R5, R6, and R7.
Keywords: HCV NS5B polymerase; N-1-Benzyl or N-1-3-methylbutyl-
4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine.
*
Corresponding author. Tel.: +847 937 5938; e-mail: todd.w.
rockway@abbott.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.022

3834
T. W. Rockway et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3833–3838
The benzothiadiazine class of HCV inhibitors can be de-
scribed as a tetracyclic system containing four distinct
regions defined by each of the rings labeled A, B, C,
and D. The A- and B-rings are represented by the N-
1-substituted-1,8-naphthyridonyl ring system, initially
described by Darcy et al. in 2003.13 The C- and D-ring
structure describes the benzothiadiazine moiety, where
the C-ring contains the cyclic amino sulfonamide moiety
and the D-ring is depicted by the aromatic ring moiety.
tion 6 of the D-ring is indeed close to the protein. There-
fore, position 6 on the D-ring did not appear to be
amenable for further modification. However, the possi-
bility of improving potency with larger substituents in
positions 5 and 7 was still open to investigation.
Table 2 illustrates the effect of either hydrophobic or
larger polarizable substituents at position 5 or 7 on the
genotype 1 inhibition potency.
This report describes the synthesis and biological evalu-
ation of analogs based on both the N-1-benzyl-4-hy-
droxy-1,8-naphthyridon-3-yl benzothiadiazine class, 1,
and the N-1-[3-methylbutanyl]-4-hydroxy-1,8-naph-
thyridon-3-yl benzothiadiazine class, 2, possessing sub-
stituents on the D-ring in positions 5, 6, and 7. Initial
studies were directed toward an investigation of the ef-
fect of D-ring substituents on polymerase inhibition of
compound 1. The analogs in this series were designed
to test the effect of small D-ring substituents on enzyme
inhibition. Compound 1 was substituted with either
methoxy or hydroxy groups in positions 5, 6, and 7 on
the D-ring and most of the compounds exhibited potent
genotype 1b enzyme inhibition but weak genotype 1a
inhibition.
Small hydrophobic groups, for example, methyl groups,
are tolerated in both positions 5 and 7, compounds 8
and 9, respectively, with no loss in genotype 1b potency.
However, increasing the size of the substituent to bromo
produced a 3-fold loss in potency for the position 7 ana-
log (compound 10), and a 12-fold loss in potency for the
position 5 analog 11. We compared the effect of replac-
ing the benzyl group in the N-1 position on the B-ring,
compound 1 with a B-ring, N-1-3-methylbutyl substitu-
ent, compound 2. The potency for each compound in
genotype 1b was similar, however, the genotype 1a
potency of compound 2 was superior to compound 1,
exhibiting a 7-fold improvement in enzyme inhibitory
potency. We next tested the effect of either hydroxyl or
methoxy substituents in positions 5 and 7 on the more
potent compound 2. Table 3 illustrates the effect of these
substituents on genotype 1a and 1b inhibitory potency.
The data presented in Table 1 suggest that analogs
substituted in position 7 proved to be the least affected
by substituents, maintaining essentially the same poten-
cy as parent compound 1. Position 5, compound 3, and
position 6, compound 4, however, exhibited at least a
20- to 30-fold loss in potency compared to compound
1. Removal of the methyl group in compounds 3 and
4 produced compounds 6 and 7. In this case, compound
6 was equipotent to compound 1 against genotype 1b,
however, compound 7 showed no improvement in
potency from 4. We concluded from this study that po-
sition 6 in the D-ring was possibly very close to the en-
zyme and could not tolerate groups other than hydrogen
at this position. Inspection of the recently published X-
ray structure of compound 210 suggested to us that posi-
Table 2. Effect of large or hydrophobic substituents on genotype 1
potency in the N-1-benzyl series of analogs
O
O
S
R7
R6
OH
N
N
H
R5
N
N
R1
O
Compound
R1
R5
R6
R7
IC50 (lM)
1b
1a
8
9
Benzyl
Benzyl
Benzyl
Benzyl
H
H
H
H
H
Me
H
0.23
25.7
6.7
Me
H
0.096
0.756
1.17
10
11
Br
H
16.75
6.2
Table 1. Effect of D-ring hydroxy and methoxy substituents on
genotype 1 inhibition in the N-1-benzyl series of analogs18
Br
O
O
S
R7
R6
OH
N
Table 3. Effect of methoxy and hydroxyl D-ring substituents on
genotype 1 inhibition in the N-1-[3-methylbutyl] series of analogs
N
H
R5
N
N
O
O
O
R1
S
R7
R6
OH
N
Compound
R1
R5
R6
R7
IC50 (lM)a
N
H
R5
1b
1a
N
N
O
1
3
4
5
6
7
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
H
H
H
H
0.083
2.12
3.9
5.8
18
R1
OMe
H
H
Compound R1
R5
R6 R7
IC50 (lM)
1b 1a
0.81
OMe
H
H
ND
8.31
8.37
ND
H
OMe
H
0.076
0.054
2.51
OH
H
H
OH
H
2
12
13
14
3-Methylbutyl H
3-Methylbutyl OMe
H
H
H
H
H
H
0.041
1.17
17.58
1.13
0.39
a IC50 values in all tables are means of at least two independent
determinations, standard deviation 10%. Detailed protocols can be
found in the supplementary material.
3-Methylbutyl
3-Methylbutyl
H
H
OMe 0.065
OH 0.042

T. W. Rockway et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3833–3838
3835
In this series of compounds, there is a more pronounced
NO2
NO2
effect of D-ring substituents on the genotype 1a enzyme
inhibitory potency. Although compound 13 is equipo-
tent to compound 5 in genotype 1b, compound 13 is
8-fold more potent in genotype 1a and 15- to 18-fold
more potent than the position 5 analog, 12, in both
genotypes 1a and 1b. Removal of the methyl group from
compound 13 produced compound 14, which exhibited
submicromolar potency in both genotypes 1a and 1b.
Although, the genotype 1b potency for both N-1-benzyl
and N-1-isoamyl series was similar, compound 14 was
chosen as the lead compound for further modification
because this analog possessed improved genotype 1a
potency.
Cl
S
a
MeO
MeO
b, c
NO2
NO
2 O
O
NH2
S
S
MeO
MeO
NO
NH2
2 O
S
O
O
O
d
S
NH2
NH2
Scheme 1 represents our synthetic approach for the
preparation of suitably substituted position 5 and 7 sul-
fonamide precursors. Provided the necessary aniline was
commercially available, the procedure described by Gir-
ard et al.14 successfully produced many position 5 and 7
substituted analogs.
MeO
MeO
MeO
O
O
S
NH2
O
S
N
e, f
O
NH2
N
H
OMe
O
O
The synthetic route described in Scheme 1 when applied
to meta-substituted anilines could provide two possible
compounds. An alternative procedure outlined in
Scheme 2 was used to prepare the corresponding posi-
tion 6 D-ring sulfonamide precursors. The method de-
scribed by Topliss et al.15 provided position 6 analogs
with unequivocal regiochemistry.
Scheme 2. Reagents and conditions: (a) BnSH, Na2CO3, EtOH, H2O,
5 h, reflux, 96%; (b) Cl2 (g) HOAc, H2O, 15 min, 5 °C; (c) NH4OH
(concd), CH2Cl2, 30 min, 5 °C, 88%; (d) Fe, NH4Cl, MeOH/H2O,
1.5 h, reflux, 71%; (e) EtCO2CH2COCl, Et3N, CH2Cl2, 20 °C, 3.5 h; (f)
Na2CO3, EtOH, 3.5 h, reflux, 82%.
O
O
S
OMe
O
In order to rapidly prepare a diverse set of O-alkylated
position 7 D-ring derivatives, the synthetic route out-
lined in Scheme 3 was chosen.
N
O
N
H
O
S
OMe
OH
N
EtO
a
O
O
N
H
The assembly of the 7-methoxy analog, 12, was achieved
according to literature procedures.8,14,15
N
N
R1
O
N
N
R1
O
R1 = Benzyl or 3-Methylbutyl
Deprotection of the methyl group with boron tribro-
mide provided compound 14. Alternatively, removal of
the benzyl group from the 7-benzyloxy analog, 16, was
effected by refluxing 16 in THF for 1 h with ammonium
formate, palladium hydroxide, and 10% palladium on
O
O
O
O
S
OH
S
b
OH
OMe
OH
N
N
N
H
N
H
N
N
R1
O
N
N
N
R1
O
O
O
O
O
O
O
S
O
R4
OH
S
OH
N
OH
N
S
Br
Br
a,b
Br
c
HN
N
H
N
H
H2N
O
N
H
N
N
R1
O
N
R1
O
R1 = 3-Methylbutyl, 15- 23
O
O
O
S
R1 = 3-Methylbutyl, 14
O
O
S
Br
O
c
H2N
H2N
HN
Scheme 3. Reagents and conditions: (a) NaH, THF, reflux, 3 h then
HOAc, reflux, 1 h; (b) BBr3/solvent, À78 to 0 °C, 20 h; (c) RX/DMF,
Cs2CO3, TBAI, rt, 8–15 h.
O
N
H
O
O
S
Br
O
N
S
Br
carbon. All analogs listed in Table 4 were prepared from
compound 14 as outlined in Scheme 3.
d, e
H2N
H2N
O
N
H
Analogs possessing hydrophobic groups, compounds
15–17, exhibit modest to weak genotype 1b and 1a
potency. The incorporation of more polar substituents
in position 7, compounds 18–23, exhibited only a slight
(approximately 2- to 3-fold) improvement in genotype
Scheme 1. Reagents and conditions: (a) chlorosulfonyl isocyanate,
nitroethane, À40 °C, then warm to 0 °C, 15 min; (b) AlCl3, 110 °C,
30 min; (c) 50% aqueous H2SO4, reflux, 4 h (42%); (d) EtCO2CH2-
COCl, Et3N, CH2Cl2, 20 °C, 3.5 h; (e) Na2CO3, EtOH, 3.5 h, reflux,
82%.

3836
T. W. Rockway et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3833–3838
Table 4. Comparison of non-polar and polar alkoxy D-ring position 7
substituents of compound 14 on Genotype 1 inhibition potencies
O
O
O
O
S
NH2
S
OH
N
OH
N
N
N
a,b
O
O
N
H
N
H
S
O
OH
N
R4
N
O
N
O
N
H
N
N
R1
O
O
O
O
N
S
NHR4
O
OH
Compound R1
R4
IC50 (lM)
N
S
NH2
OH
N
c
N
1b
1a
H
N
N
N
O
H
15
16
17
18
19
20
21
22
23
3-Methylbutyl CH2CH2CH3
3-Methylbutyl CH2Ph
0.93
1.49
0.85
1.62
ND
5
N
O
25-31
3-Methylbutyl CH2CO2tBu
3-Methylbutyl CH2COOH
3-Methylbutyl CH2CONMe2
24
0.057 0.367
0.07
0.934
0.18
Scheme 4. Reagents and conditions: (a) NH4NO3, concd H2SO4, 0 °C,
30 min, 81%; (b) Fe, NH4Cl, MeOH/THF/H2O (3:3:1), 65 °C, 1 h,
65%; (c) RX, Cs2CO3, DMF, microwave, 100 °C, 1 h or RSO2Cl,
CH2Cl2, Et3N, 20 h, rt.
3-Methylbutyl CH2CONHMe 0.08
3-Methylbutyl CH2CONH2
3-Methylbutyl CH2CH2NH2
3-Methylbutyl CH2CN
0.016 0.046
0.051 0.637
0.025 0.141
Table 5. Effect of D-ring position 7 amino substituents on genotype 1
inhibition
1b inhibitory potency compared to compound 13, but a
marked improvement in the inhibitory potency for geno-
type 1a. Compound 21 was approximately 10-fold more
potent in genotype 1a inhibitory potency over the pre-
cursor analog 14. The substantial improvement in
potency for compound 21 suggested to us that extension
from position 7 of the D-ring especially with a polar
group effected a more favorable interaction of the inhib-
itor with the enzyme. The recently published structure10
illustrated that position 7 of the benzothiadiazine D-ring
was amenable to substitution with polar groups which
extend into an open mainly hydrophilic region.
O
O
S
NHR4
OH
N
N
N
H
N
O
Compound
R4
H
IC50 (lM)
HCV NS5B
genotype 1b
HCV NS5B
genotype 1a
We investigated the effect on enzyme inhibition potency
when the oxygen atom at position 7 was replaced with a
nitrogen atom. The goal was to determine whether the
hydrogen bond-accepting capability of the oxygen atom
at position 7 was contributing to improved inhibitory
potency or the replacement with a potential hydrogen
bond-donating NH would improve the potency further.
We prepared a series of analogs according to the
sequence outlined in Scheme 4.
24
25
26
27
28
29
30
31
0.023
0.024
0.034
0.070
0.007
0.003
0.005
0.006
0.31
0.12
CH2CN
CH2CONH2
COCF3
SO2Ph
0.47
0.906
0.041
0.008
0.022
0.002
SO2iPr
SO2(CH2)3CH3
SO2Me
Nitration of compound 2 with ammonium nitrate in
cold concentrated sulfuric acid provided nitration exclu-
sively in position 7 of the D-ring in approximately
30 min. Reduction of the nitro group with iron and
ammonium chloride in refluxing methanol, tetrahydro-
furan, and water cleanly produced D-7 amino com-
pound, 24, in good yield. Alkylation of the amino
group using standard conditions, Cs2CO3, RX, DMF,
and room temperature, was sluggish requiring long reac-
tion times and low yields, even when heating to 100 °C.
Alternatively, alkylation of compound 24 was achieved
cleanly by heating the reagents mentioned previously
at 100 °C for 1 h in a microwave reactor.
genotype 1a and 1b inhibitory potency. In fact, com-
pound 26 was approximately 10-fold less potent in geno-
type 1a than the corresponding oxygen-alkylated analog
21. The amide analog, 27, showed no improvement in
potency, however, the incorporation of alkyl or phenyl
sulfonyl groups, compounds 28–31, improved potency
significantly. Compound 31 exhibited potent genotype
1 inhibition, approximately 3-fold more potent in geno-
type 1b than compound 21 and 20-fold more potent
than compound 21 in genotype 1a. Presently, we can
only speculate as to the importance of the NH versus
the oxygen with respect to improved enzyme inhibition.
Comparing the enzyme inhibition potencies between
analogs, 21 and 26, for example, compound 26 shows
a loss of approximately 10-fold in genotype 1a inhibition
suggesting that the position 7 amino group has either no
interaction with the protein or produces a different posi-
tion of the acetamide side chain such that the interaction
Table 5 presents the genotype 1 inhibition for a series of
D-ring position 7 amino compounds. The two most po-
tent oxygen-alkylated analogs, 21 and 23, were prepared
in the amino series and exhibited no improvement in

T. W. Rockway et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3833–3838
3837
Table 6. Comparison of position 7 D-ring substituents on genotype 1b
inhibition in cell culture
The analog was administered as a solution in vehicle
at a dose of 5 mg/kg and exhibited 35% bioavailability.
The Cmax was low (0.18 lM), the plasma AUC was
2.54 (mg h)/ml with modest clearance (0.74 L/h/kg),
and the half-life was 2 h. We analyzed the liver tissue
drug concentrations for compound 21 and determined
the liver to plasma ratio at 8 h to be 54. Suggesting that
a significant amount of the compound accumulated in
the liver over the course of the experiment.
O
O
S
R4
OH
N
N
N
H
N
O
Compound R4
HCV NS5B HCV NS5B
genotype 1b genotype 1b
EC50 (lM)a EC50 (lM)a, 40%
human serum
A series of N-1-benzyl and N-1-[3-methylbutyl]-4-
hydroxy-1,8-naphthyridon-3-yl benzothiadiazine ana-
logs were prepared and evaluated as inhibitors against
NS5B RdRp genotype 1 enzyme. The oxyacetamide,
compound 21, exhibited excellent inhibition of both
genotype 1 strains and showed excellent genotype 1b
inhibition of viral replication in a cell-based assay. Com-
pound 21 exhibited modest pharmacokinetic properties,
however, the liver to plasma ratio suggested that the
compound was accumulating in the liver, the site of
HCV replication. Compounds 21 and 31, when evaluat-
ed in the HCV replicon assay containing 40% human
serum, showed an approximate 30- to 400-fold loss in
potency when compared to the values obtained in 5%
fetal calf serum. Subsequent measurements of com-
pounds 21 and 31 in the presence of serum plasma pro-
teins demonstrated that these compounds were highly
protein bound. The corresponding N-alkylated acetam-
ide, 26, exhibited comparable enzyme inhibition potency,
however, the cell-based replicon activity was reduced
approximately 6-fold. The sulfonamide series of D-ring
position 7 analogs, 28–31, exhibited excellent genotype
1b and 1a enzyme inhibition. However, only compounds
29 and 31 exhibited potent cell-based enzyme inhibition.
The improved inhibitory potency of compound 31 in the
cell-based system may be explained by the smaller size of
the methylsulfonamide group when compared to the oxy-
acetamide group in compound 21.
21
24
26
28
29
30
31
OCH2CONH2
NH2
0.078
0.48
0.45
1.69
0.11
2.74
ND
ND
ND
ND
ND
1.31
NHCH2CONH2
NHSO2Ph
NHSO2iPr
NHSO2(CH2)3CH3 1.00
NHSO2Me 0.003
a EC50 values in all tables are means of at least two independent
determinations, standard deviation 10%. Detailed protocols can be
found in the supplementary material.
of the side chain with the protein is weaker. The signif-
icant improvement in enzyme inhibition potency,
especially genotype 1a, for the sulfonamide analogs sug-
gests that this substituent apparently improves the
inhibitor–protein interaction, again, by extending a
polar substituent into a hydrophilic region. However,
without the aid of an X-ray structure of a compound
31–protein complex, we cannot determine whether any
significant protein–inhibitor interactions contribute to
the observed enzyme inhibitory potency enhancement.
Several analogs containing either D-7 alkoxy,
compound 14 or D-7 amino, compound 24, substituents
were evaluated in the cell-based HCV replicon
system16,17 against genotype 1b, and the data are listed
in Table 6.
In summary, we have discovered a series of position 7
D-ring substituted N-1-3-methylbutyl-4-hydroxy-1,8-
naphthyridone benzothiadiazines exhibiting improved
enzyme inhibition potency and significantly improved
cell culture activity. Further evaluation and structural
improvements of this particular substituted class of ben-
zothiadiazines are continuing.
Compound 21 exhibited an approximately 5-fold loss in
the cell-based system inhibition potency when compared
with the corresponding genotype 1b isolated enzyme
inhibitory potency. Analogs 24, 26, and 29 show a
10- to 40-fold loss in cellular inhibition potency while
analogs 28 and 30 exhibited a further loss (200-fold) in
cellular inhibitory potency when compared with the iso-
lated enzyme inhibitory potency. Analog 31, however,
showed no loss in cellular inhibitory potency when com-
pared with the corresponding enzyme inhibition poten-
cy. Compounds 21 and 31 were tested in the cell-based
HCV replicon system containing 40% human serum, in
order to determine the effect of plasma protein binding
on biological activity. Each compound showed an
approximate loss of 30- to 400-fold when compared to
the replicon assay performed in 5% fetal calf serum,
indicating the compounds to be highly plasma protein
bound. Compounds 21 and 31 were subsequently deter-
mined to be greater than 99% plasma protein bound.
Detailed biological protocols for biochemical IC50
determinations and cell culture replicon assay EC50
determinations are available in the Supplementary data.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.2006.
04.022.
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2. Zein, N. N. Clin. Microbiol. Rev. 2000, 13, 223.
Finally, we evaluated the pharmacokinetic properties of
compound 21 as an orally administered agent in rats.

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18. All compound structures were consistent by 1H
NMR, ESI MS with purity >95% by HPLC and
LC-MS.