Synthesis and SAR of novel 1,1-dialkyl-2(1H)-naphthalenones as potent HCV polymerase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.11.088

A series of gem-dialkyl naphthalenone derivatives with varied alkyl substitutions were synthesized and evaluated according to their structure-activity relationship. This investigation led to the discovery of potent inhibitors of the hepatitis C virus at l

Full text of DOI:10.1016/j.bmcl.2007.11.088

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 568–570
Synthesis and SAR of novel 1,1-dialkyl-2(1H)-naphthalenones
as potent HCV polymerase inhibitors
Todd D. Bosse,* Daniel P. Larson, Rolf Wagner, Doug K. Hutchinson,
Todd W. Rockway, Warren M. Kati, Yaya Liu, Sherie Masse, Tim Middleton,
Hongmei Mo, Debra Montgomery, Wen Jiang, Gennadiy Koev,
Dale J. Kempf and Akhter Molla
Infectious Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
Received 27 August 2007; revised 20 November 2007; accepted 20 November 2007
Available online 28 November 2007
Abstract—A series of gem-dialkyl naphthalenone derivatives with varied alkyl substitutions were synthesized and evaluated accord-
ing to their structure–activity relationship. This investigation led to the discovery of potent inhibitors of the hepatitis C virus at low
nanomolar concentrations in both enzymatic and cell-based HCV genotype 1a assays.
Ó 2007 Elsevier Ltd. All rights reserved.
Hepatitis C virus (HCV) is a small RNA virus that be-
longs to the family flaviviridae and is the sole member
of the genus hepacivirus. Six major genotypes and more
than 100 subtypes of HCV have been identified, having
marked geographic variation in relative frequencies. The
most common genotypes in the United States are geno-
types 1a and 1b (approximately 75%), 2a and 2b
(approximately 15%), and 3 (approximately 7%).1
ment and also six months post-treatment. Besides being
only somewhat effective, the current therapies are costly
and cause a variety of side effects, including depression,
irritability, headaches, anemia, and nausea. HCV infec-
tion represents a major unmet medical need, therefore,
the discovery of novel, small molecules that successfully
treat HCV infection remains an area of intense focus for
the pharmaceutical industry.
An estimated 180 million people are chronically infected
with HCV worldwide; with 3–4 million newly infected
patients each year. In the United States, an estimated
4.1 million people (1.6%) have been infected with
HCV, of whom 3.2 million are chronically infected.
Chronic HCV infection is a major cause of liver fibrosis
and hepatocellular carcinoma.2 Currently, the standard
of care for the treatment of HCV is pegylated inter-
feron-a (IFN-a) in combination with ribavirin.3 This
combination therapy yields a sustained viral response
(SVR) for about 50% of patients with genotype 1, 4, 5,
and 6 HCV and a response for about 85% of patients in-
fected with genotype 2 and 3 HCV.2 A sustained viral re-
sponse occurs when there is no trace of HCV RNA
present in the patient’s blood immediately after treat-
The virus is made up of a core protein, two enveloped
proteins E1 and E2, and non-structural proteins NS2–
NS5 that are essential for viral replication, translation,
and polyprotein processing.3 Efforts to develop anti-
HCV agents have focused on the inhibition of key viral
enzymes. Most pharmaceutical research can be catego-
rized into the following types: E2 binding inhibitors,
NS2 protease inhibitors, NS3 protease inhibitors,
NS5A inhibitors, helicase inhibitors, IRES inhibitors,
and polymerase inhibitors. Our research has focused
on the virally encoded RNA-directed RNA polymerase
as the primary initial antiviral target. The NS5B portion
of the HCV genome encodes for the polymerase, an en-
zyme that is pivotal in viral replication and is thus a pri-
mary target for drug development.3
Previous work described the discovery of N-1-hetero-
alkyl-4-hydroxyquinolon-3-yl-benzothiadiazines, analog
1 (Fig. 1), which eventually led to a new series where the
B ring was transformed to include a quaternary carbon
center, analog 2 (Fig. 1). This new scaffold was the basis
Keywords: Polymerase; Inhibitors; Benzothiadiazines; Hepatitis; HCV;
Naphthalenones.
*
Corresponding author. Tel.: +1 847 938 4442; fax: +1 847 938
2756; e-mail: todd.bosse@abbott.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.088

T. D. Bosse et al. / Bioorg. Med. Chem. Lett. 18 (2008) 568–570
569
deprotonation of commercially available benzyl 2-phe-
nylpropanoate 3 (or benzyl 2-butanoate in the synthesis
of ethyl/isoamyl derivative 4h) with lithium hexamethyl-
disilazane in THF. This step was followed by alkylation
using the appropriate vinyl or alkyl halide8 to yield the
racemic benzyl ester.
Hydrogenation of the double bond and hydrogenolysis
of the benzyl ester occurred in a one-pot reaction to give
the corresponding carboxylic acids (4a–g). The diethyl
esters (5a–g) were synthesized by first converting the car-
boxylic acids (4a–g) to the corresponding acid chlorides,
followed by addition of the acid chlorides to the magne-
sium enolate of diethyl malonate. The esters (5a–g) were
treated with neat methanesulfonic acid to afford the
dihydronaphthalene esters, which were then decarboxyl-
ated to afford the hydroxynaphthalenone analogs 6a–g.
The next step of the synthesis involved treatment of ana-
logs 6a–g with tris-methylsulfanyl-methane sulfuric acid
monomethyl ester salt9 to give the dithioketene acetal
compounds (7a–g). Treatment with (4-amino-3-sulfa-
moyl-phenyl)-carbamic acid tert-butyl ester10 followed
by deprotection with HCl yielded the hydrochloride
Figure 1. Examples of N-1-heteroalkyl-4-hydroxyquinolon-3-yl-ben-
zothiadiazine (1) and symmetrical gem-dialkyl naphthalenone (2) HCV
polymerase inhibitors.
for a series of symmetrically substituted gem-dialkyl
naphthalenones.4,5 The scaffold consisted of four six-
membered rings; the A-ring consisted of a phenyl ring
that lacks any substitution, the B-ring containing the
gem-dialkyl substitution site, the C-ring containing the
thiadiazine ring, and the D-ring consisting of a phenyl
ring with a methane sulfonamide substitution (Fig. 2).
In the N-1-heteroalkyl-4-hydroxyquinolon-3-yl-ben-
zothiadiazine series, the most potent inhibitors con-
tained small alkyl or carbocyclic substituents and
exhibited IC50’s between 50–100 and 200–400 nM
against genotype 1b and 1a HCV polymerase, respec-
tively.4 Our lead compound became the dipropyl substi-
tuted compound 2 (Fig. 1), which is a selective inhibitor
of HCV genotype 1a replication, with an IC50 of 99 nM
in the HCV polymerase enzyme assay and an EC50 of
603 nM in a cell-based assay.5 In a logical extension of
the investigation of dialkyl analogs, our attention turned
toward unsymmetrical dialkyl compounds. Specifically,
we investigated the SAR of methyl/alkyl substitution
at the 1-position of the tetracyclic core.6 Most of our
SAR investigations were limited to analogs with substi-
tutions on the 1-position of the B-ring and 7-position of
the D-ring. Since earlier investigations of the SAR at the
7-position of the tetracyclic thiadiazines revealed the
optimal substitution to be the methyl sulfonamide, ana-
logs with this substituent were chosen as the basis for
our unsymmetrical dialkyl series.7
Figure 2. Unsymmetrical gem-dialkyl naphthalenone HCV polymer-
ase inhibitors.
The synthesis of the gem-dialkyl naphthalenones is out-
lined in Scheme 1. The synthesis was initiated by the
Scheme 1. Reagents and conditions: (a) LiHMDS, THF, ꢀ78 °C, 30 min, then DMI, RCH2Br, LiI, 72–99%; (b) Pd/C, H2, EtOAc, 93–98%; (c) oxalyl
chloride, DMF, hexane, 2 h, then MgCl2, diethyl malonate, Et3N, acetonitrile, 50 °C, 18 h, crude; (d) methanesulfonic acid, 18 h, 51–89%; (e) 1 N
aqueous HCl, dioxane, 100 °C, 2 h, 57–75%; (f) ðMeSÞ CþMeSO4ꢀ, pyridine, dioxane, 100 °C, 1 h, 30–99%; (g) (4-amino-3-sulfamoyl-phenyl)-
3
carbamic acid tert-butyl ester, toluene, reflux, 6 h, 77–98%; (h) 4 M HCl/dioxane, CH2Cl2, 1 h, 84–90%; (i) methane sulfonyl chloride, pyridine,
acetone, 18 h, 75–96%; (j) aqueous NaOH, 2 h, 95–99%.

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T. D. Bosse et al. / Bioorg. Med. Chem. Lett. 18 (2008) 568–570
salts of the aniline tetracycles (8a–g). The methane sul-
fonamides were prepared from 8a–g and then converted
to their corresponding sodium salts to afford the target
compounds (9a–g).
result in an overall decrease in potency, our next step in
the SAR investigation was to identify an alkyl chain size
that was large enough to result in diminished activity.
Our theory was confirmed with large alkyl substituted
compounds 9e and 9g, a 14- and 79-fold decrease,
respectively, in IC50’s relative to compound 9d.
The in vitro biological activity of this series of gem-dial-
kyl naphthalenones is shown in Table 1. Our SAR plan
involved systematically increasing the steric bulk of sub-
stituent R to find the optimal size and shape. The initial
set of compounds in our SAR library demonstrated an
improvement in potency compared to the lead com-
pound 2. Even the weakest analog of the initial set, com-
pound 9a, showed a 5-fold increase in IC50 and a 3-fold
increase in EC50. Compound 9h, where R2 is ethyl, was
synthesized to establish if methyl substitution was best
for the series. This compound showed the methyl substi-
tution to be 2-fold more potent in IC50 and equipotent in
EC50 when compared to the corresponding ethyl analog.
As the synthesis of our library expanded, we continued to
see improvements in activity that corresponded to the in-
creased size of the substituent in the 1-position. Analogs
with substitutions of iso-amyl (compound 9c) and neo-
hexyl (compound 9d) emerged as the most potent inhib-
itors. Although the enzymatic assay showed compounds
9c and 9d to have nearly equal potency, the cell-based as-
say showed analog 9d to have nearly a 5-fold improve-
ment in replicon potency. Compound 9d showed a 10-
fold improvement in IC50 and a 75-fold improvement
in EC50 compared to the lead compound 2. Substituents
slightly larger in size than that in compound 9d, as shown
by the methylcyclohexyl analog 9f, resulted in roughly
equal potency in the enzyme assay but showed a 15-fold
decrease in the cell-based assay as compared to com-
pound 9d.
In summary, the structure–activity relationships of no-
vel gem-dialkyl naphthalenones as HCV polymerase
inhibitors were explored. Attempts to increase potency
by modifications on the 1-position carbon of the B-ring
have been successful. This series of inhibitors proved to
have nanomolar inhibition of both genotype 1a HCV
polymerase and the genotype 1a HCV replicon, with
the optimized methyl-neo-hexyl compound showing a
10- and 75-fold increase in potency, respectively, over
the initial lead compound.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.11.088.
References and notes
1. Hoofnagle, J. H. Hepatology 2002, 36, S21.
2. Ikeda, M.; Abe, K.; Yamada, M.; Dansako, H.; Naka, K.;
Kato, N. Hepatology 2006, 44, 117.
3. Gordon, C. P.; Keller, P. A. J. Med. Chem. 2005, 48, 1.
4. Pratt, J. K.; Donner, P.; McDaniel, K. F.; Maring, C. J.;
Kati, W. M.; Mo, H.; Middleton, T.; Lui, Y.; Ng, T.; Xie,
Q.; Zhang, R.; Montgomery, D.; Molla, A.; Kempf, D. J.;
Kohlbrenner, W. Bioorg. Med. Chem. Lett. 2005, 15, 1577.
5. Hutchinson, D.K., et al. Patent Application WO 2005/
019191, 2005.
Since it was our hypothesis, based on modeling data,
that larger substituents than the neo-hexyl group would
6. All compounds discussed in this publication were pre-
pared as the racemic mixture. Enantiomerically pure
compounds were prepared at a later date and will be
discussed in future publications.
7. Rockway, T. W.; Zhang, R.; Liu, D.; Betebenner, D. A.;
McDaniel, K. F.; Pratt, J. K.; Maring, C. J.; Kati, W. M.;
Middleton, T.; Montgomery, D.; Molla, A.; Kempf, D. J.;
Beno, D.; Jiang, W.; Masse, S. Bioorg. Med. Chem. Lett.
2006, 16, 3833.
Table 1. In vitro enzymatic and cell-based inhibitory activities
Compounds R1
R2 Genotype 1a Replicon
1a EC50
(nM)
IC50
(nM)
9a
9b
Me
Me
20
15
184
52
8. All vinyl halides were commercially available except 1-iodo-
3,3-dimethyl-butane, 1-bromo-5,5-dimethyl-hex-2-ene, and
(3-bromo-propenyl)-cyclohexane.
1-Iodo-3,3-dimethyl-
9c
9d
9e
Me
Me
7
38
8
butane was made by conversion of the hydroxyl group of
3,3-dimethyl-butan-1-ol with iodine, triphenylphosphine,
and imidazole in dichloroethane. 1-Bromo-5,5-dimethyl-
hex-2-ene was made by reacting 3,3-dimethyl-butyralde-
hyde with vinylmagnesium bromide to give 5,5-dimethyl-
hex-1-en-3-ol, which was then reacted with 1,5-hexadiene
and thionyl bromide to yield the desired vinyl bromide. (3-
bromo-propenyl)-cyclohexane was synthesized using the
same procedure described for 1-bromo-5,5-dimethyl-hex-2-
ene.
10
Me 138
NT
9f
Me
13
121
NT
49
9. The tris-methylsulfanyl-methane sulfuric acid mono-
methyl ester salt was synthesized by reacting dimethylsul-
fate with dimethyl trithiocarbonate at 90 °C for 1 h and
washing with diethyl ether.
10. Goldfarb, A. R.; Berk, B. J. Am. Chem. Soc. 1943, 65,
738.
9g
9h
Me 791
Et
17