Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 1: C2-Symmetric inhibitors with diyne and biphenyl linkers

Article abstract of DOI:10.1016/j.bmcl.2014.12.046

The discovery of C₂-symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This study revealed the paramount importance of the aromatic character of the linker to achieve high genotype 1a potency.

Full text of DOI:10.1016/j.bmcl.2014.12.046

Bioorganic & Medicinal Chemistry Letters 25 (2015) 936–939
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 1:
C2-Symmetric inhibitors with diyne and biphenyl linkers
Simon Giroux a, , Darius Bilimoria , Caroline Cadilhac , Kevin M. Cottrell , Francois Denis ,
⇑
b
b
a
b
b
a
a
b
a
Evelyne Dietrich , Nigel Ewing , James A. Henderson , Lucille L’Heureux , Nagraj Mani ,
Mark Morris , Olivier Nicolas , T. Jagadeeswar Reddy , Subajini Selliah , Rebecca S. Shawgo ,
Jinwang Xu , Nathalie Chauret , Francoise Berlioz-Seux , Laval C. Chan , Sanjoy K. Das
Anne-Laure Grillot , Youssef L. Bennani , John P. Maxwell
a
b
b
b
a
a
b
a
b
b,
,
a
a
a
a
Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA 02210, USA
Vertex Pharmaceuticals Canada Inc., 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery of C -symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two
2
Received 24 October 2014
Revised 10 December 2014
Accepted 12 December 2014
Available online 30 December 2014
straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This
study revealed the paramount importance of the aromatic character of the linker to achieve high geno-
type 1a potency.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
NS5a
HCV
Hepatitis C
Thienoimidazole
The hepatitis C virus currently affects an estimated 130–
70 million people worldwide.1 Long-term HCV infection leads to
NS5A is essential for RNA replication5 and virion assembly6
but its exact role is still unclear. Thus, the elucidation of
NS5A’s role remains an active area of investigation.7 Several
NS5A inhibitors are currently under clinical investigations with
1
many different diseases such as liver fibrosis, liver cirrhosis and
1
hepatocellular carcinoma (HCC). Since 2011, the standard of care
8
9
(
SOC) has evolved from a two-drug combination (pegylated
daclatasvir (Bristol-Myers Squibb), ledipasvir (Gilead Sciences),
1
0
11
12
interferon-
interferon-
a
a
+ ribavirin) to a three-drug combination (pegylated
+ ribavirin + NS3Á4A inhibitor). The addition of an
ABT-267
(AbbVie), MK-8742
(Merck) and GSK-2336805
(GlaxoSmithKline) being the frontrunners. Very recently, the
Ò
NS3Á4A protease inhibitor, such as Incivek™ or Victrelis™, greatly
increases the sustained virological response (SVR) and reduces
the treatment duration.2 Despite this significant progress, the
resistance profiles and genotypic coverages of the current SOC reg-
imens could still be dramatically improved. Moreover, a regimen
FDA granted approval for Gilead’s Harvoni , the first once-daily
single tablet regimen for the treatment of patients with
chronic genotype 1 infections. HarvoniÒ consists of a combi-
nation of sofosbuvir (NS5B inhibitor) and ledipasvir (NS5A
inhibitor).
13
that would abolish injections of pegylated interferon-
desirable and is a current focus in ongoing clinical trials.
a
is highly
One requisite feature of several NS5A inhibitors, originating
from the ground-breaking work of Bristol-Myers-Squibb,8 is the
presence of imidazole moieties flanking phenyl or aromatic linkers
that join terminal methylcarbamate-capped pyrrolidine-valine
groups. In several cases, the imidazole rings can be fused to a
phenyl ring such as in ledipasvir (Gilead) in which the resulting
benzimidazole is highlighted in red (Fig. 1). A [5,5]-bicyclic
moiety such as a thienoimidazole appeared to us as a logical
choice in our search of novel chemical entities in the NS5A area.
Herein, we describe our early synthetic efforts leading to potent
thienoimidazole-based HCV NS5A inhibitors.
3
Currently, the most investigated inhibitor classes are the NS3Á4A
1
b
1b
protease inhibitors, the NS5B polymerase inhibitors and the
1
b,4
NS5A inhibitors.
Unlike the NS3Á4A protease and the NS5B polymerase, NS5A
has no known enzymatic function. It has been shown that
⇑
Corresponding author.
Present address: AngioChem, 201 President-Kennedy Ave., Suite PK-2880,
Montreal, QC H2X 3Y7, Canada.
http://dx.doi.org/10.1016/j.bmcl.2014.12.046
0
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

S. Giroux et al. / Bioorg. Med. Chem. Lett. 25 (2015) 936–939
937
Scheme 2. Synthesis of the terminal alkyne 6.
Figure 1. Chemical structures of daclatasvir, ledipasvir and ombitasvir.
Scheme 1. Preparation of the thienoimidazole intermediate 4. Yields with the
sequence with R = Me.
1
In order to investigate if the thienoimidazole moiety could rep-
resent a suitable replacement to the classical imidazole and benz-
imidazole moieties, an efficient and scalable route to access the
strained [5,5]-core was required. Starting with the N-Boc prolinal
derivatives 1 (R = H or Me), a condensation with glyoxal in a meth-
2
Scheme 3. Synthesis of C -symmetric diyne inhibitors 10a and 10b. Yields with the
sequence with R1 = Me.
anolic solution of ammonia led to the
a-prolino imidazole which
was dibrominated with NBS to afford 2 (Scheme 1). The dibromo-
imidazole 2 was protected with a SEM group (SEMCl/NaH/THF) and
the adduct was mono-formylated via a transmetalation with
n-BuLi, immediately followed by a DMF quench to give the bromo-
aldehyde intermediate 3 in 48% yield over two steps. Exposure of 3
to a solution of NaOEt and ethyl mercaptoacetate in refluxing EtOH
1
4
afforded the thienoimidazole 4 in 81% yield (Scheme 1).
At this point, we reasoned that we could either access the final
compounds with diyne or biphenyl linkers using intermediate 4 as
a diverging point in both synthetic routes. The precursor for the
diyne linker could be accessed via a simple 3-step sequence
(
Scheme 2). Reduction of the ester group to the alcohol immediately
15
followed by a Dess–Martin oxidation gave aldehyde 5 which was
subjected to a Bestmann homologation16 leading to the terminal
alkyne 6 in 63% yield. Alternatively, the ester 4 could be hydrolyzed
1
7
to acid 7 in good yield. A Hunsdiecker-type bromodecarboxylation
was effected to smoothly deliver the bromothienoimidazole 8 in
0% yield. However, all attempts to couple 8 with arylboronic acids
met with failure. More specifically, extensive protodehalogenation
8
2
Scheme 4. Synthesis of C -symmetric biphenyl inhibitor 13.

9
38
S. Giroux et al. / Bioorg. Med. Chem. Lett. 25 (2015) 936–939
Table 1
HCV replicon activity and pharmacokinetic data2
0,21
Compd Structures
HCV replicona (nM)
Cytotoxicitya
M)
CC50
Sprague–Dawley pharmacokinetics (IV)
Cl (mL/min/Kg) 1/2 (h) ss (L/Kg)
(
l
Genotype
a EC50
Genotype
1b EC50
T
V
1
1
0a
0b
281
184
0.386
0.170
6.1
8.2
5.2
—
3.3
—
1
>20
>20
>20
—
See
Ref.
0.018
0.024
0.006
—
—
—
1
9
1
3
6
8.0
4.5
2.2
a
EC50’s and CC50’s have been ran in duplicates.
was observed as well as other decomposition products and ulti-
mately, another route to access the biphenyl linkers was
developed.
To access diyne linkers, the terminal alkyne 6 was homodimer-
ized by exposure to the Sonogashira conditions in the presence of
benzoquinone to give the diyne 9 in 98% yield. The SEM groups and
Boc groups were cleaved using a solution of 4 M HCl in dioxane and
the two resulting proline motifs were capped with the requisite
The encouraging potency as well as the favorable IV pharmaco-
kinetic data (Table 1) obtained for the C -symmetric thienoimidaz-
oles prompted us to investigate this subseries in greater detail. We
were particularly interested to investigate the effect of breaking
the C -symmetry on the overall potency. The details of this inves-
2
tigation are reported in the following Letter.
2
1
8
Acknowledgment
2
(S)-methoxycarbonyl valine groups to afford C -symmetric inhibi-
tors 10a and 10b (Scheme 3).
A previously published18 synthetic route was utilized to access
The authors would like to thank Mark N. Namchuk, Ann D.
Kwong and Jean Bédard for insightful discussion.
aryl-flanked thienoimidazoles giving efficient access to bromophe-
nyl derivative 11 and boronate 12. A Suzuki coupling between 11
and 12, followed by N-Boc deprotections and proline cappings with
References and notes
the (S)-methoxycarbonyl valine groups led to the C
inhibitor 13 (Scheme 4).
2
-symmetric
1
2
.
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The HCV replicon activity C
3 are shown in Table 1. The genotype 1a and 1b potency of the
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2
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