Discovery of novel P2 substituted 4-biaryl proline inhibitors of hepatitis C virus NS3 serine protease

Article abstract of DOI:10.1016/j.bmcl.2013.05.046

Inhibitors of hepatitis C virus NS3 serine protease often incorporate a large P2 moiety to interact with the surface of the enzyme while shielding part of the catalytic triad. This feature is important in many inhibitors in order to have the necessary potency needed for efficacy. In this Letter we explore some new P2 motifs to further exploit this region of the enzyme. In a continuing effort to replace the often found 4-hydroxyproline P2 core found in the majority of inhibitors for this target, various directly attached aryl derivatives were evaluated. Of these, the 2,4-disubstituted thiazole core proved to be the most interesting. SAR around this motif has lead to compounds with K_i's in the high picomolar range and provided cellular potencies in the single digit nM range.

Full text of DOI:10.1016/j.bmcl.2013.05.046

Accepted Manuscript
Discovery of novel P2 substituted 4-biaryl proline inhibitors of hepatitis C virus
NS3 serine protease
Murray D. Bailey, Teddy Halmos, Christopher T. Lemke
PII:
S0960-894X(13)00641-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.05.046
BMCL 20507
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
25 March 2013
9 May 2013
13 May 2013
Please cite this article as: Bailey, M.D., Halmos, T., Lemke, C.T., Discovery of novel P2 substituted 4-biaryl proline
inhibitors of hepatitis C virus NS3 serine protease, Bioorganic & Medicinal Chemistry Letters (2013), doi: http://
dx.doi.org/10.1016/j.bmcl.2013.05.046
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Discovery of novel P2 substituted 4-biaryl proline
inhibitors of hepatitis C virus NS3 serine protease
Murray D. Bailey*, Teddy Halmos, Christopher T. Lemke
Leave this area blank for abstract info.
O
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IC50 = 1.1 nM
EC50 = 9 nM

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery of novel P2 substituted 4-biaryl proline inhibitors of hepatitis C virus
NS3 serine protease
Murray D. Bailey*, Teddy Halmos, Christopher T. Lemke
Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec,H7S 2G5, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Inhibitors of hepatitis C virus NS3 serine protease often incorporate a large P2 moiety to interact
with the surface of the enzyme while shielding part of the catalytic triad. This feature is
important in many inhibitors in order to have the necessary potency needed for efficacy. In this
paper we explore some new P2 motifs to further exploit this region of the enzyme. In a
continuing effort to replace the often found 4-hydroxyproline P2 core found in the majority of
inhibitors for this target, various directly attached aryl derivatives were evaluated. Of these, the
2,4-disubstituted thiazole core proved to be the most interesting. SAR around this motif has lead
to compounds with Ki’s in the high picomolar range and provided cellular potencies in the single
digit nM range.
Keywords:
Hepatitis C virus
HCV NS3 protease
P2 4-biaryl proline
HCV Protease inhibition
2009 Elsevier Ltd. All rights reserved.

Hepatitis C virus (HCV) infection has been estimated to infect approximately
2% of the world’s population1 and is the leading cause of chronic inflammation of
the liver leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in
humans. Until recently, treatment consisted of a combination of pegylated
interferon agents with ribavirin, a broad range nucleoside antiviral. This therapy is
known to be suboptimal for a large number of patients and new treatments were
needed in order to reach more patients who presently respond poorly to the current
regiment.2 The first direct acting antivirals agents (DAA) boceprevir (Victrelis) and
telaprevir (Incivek/Incivo) were recently introduced as an add on to the current
therapy, considerably improving the response rate.3 A number of other agents are
now in late-stage clinical development.4
The first proof-of-concept study for a NS3/4A protease inhibitor originated from
our laboratories with BILN 2061 (ciluprevir), a macrocyclic inhibitor containing a
C-terminal carboxylic acid.5 While development of ciluprevir was discontinued,
linear analogs also based on peptide substrates were pursued leading ultimately to
faldaprevir (BI 201335),6 which is completing phase III clinical trials. A number of
other macrocyclic and linear analogs of NS3 protease inhibitors have appeared in
the literature, many of which contain acid bioisosteres or active site covalent
reversible binding groups.7,8,9,10 In particular, introduction of an acyl-sulfonamide
bioisostere11 at the C-terminal end of these substrate-based inhibitors was found to
improve potency dramatically allowing for truncations at other sites of the
inhibitor.
We have successfully shown that a substituted P2 hydroxyproline moiety as
found in both ciluprevir and faldaprevir 1 is a valuable fragment in the
development of protease inhibitors. The nature of this group is thought to shield

part of the catalytic triad from water, namely Asp81 and His57.12 While a number
of protease inhibitors have incorporated smaller non-aromatic P2 derived proline
derivatives such as boceprevir, telaprevir and narlaprevir13, the majority of the
current clinical candidates still contain variations of the hydroxyproline fragment
originally found in ciluprevir5. Interestingly, the smaller non-aromatic P2
containing inhibitors rely on the incorporation of covalent reversible P1/P1’
binding groups for potency while the larger hydroxyproline derivatives rely on
ionic interactions in the P1/P1’region, often incorporating an acyl-sulfonamide
group. In our continuing efforts to diversify and exploit the P2 region of the
protease, several novel P2 arrangements have been reported by us including
directly attached 4-triazole substituted proline analogs 214 and more recently 4-
phenyl substituted prolines derivatives 3 (Scheme 1)15. It was shown in these later
two examples that a biaryl group attached to the 4-position of the P2 proline
moiety was necessary to obtain the desired level of potencies for these series. In
this paper, we continue to explore these motifs by examining alternatives to the
triazole core found in compound 2 in order to generate novel P2 proline fragments
and to discover new ways of interacting with the S2 region of the enzyme.
As a starting point, we first replaced the central triazole ring found in compound
2 with other heterocyclic ring systems in Scheme 2 where the IC50 values are from
a genotype 1 assay and the EC50 values from a replicon assay16. Replacement of the
triazole ring by either an N-linked phenyl imidazole 4 or phenyl pyrazole ring 5
did not lead to any improvement in the overall profile of this series. The imidazole
ring in particular was least tolerated due probably to the more polar nature of this
group. Substituting the central ring for either the 2- or the 4-attached thiazolyl
phenyl rings (compounds 6 and 7) produced compounds with good potency and
generally improved HLM stability and Caco-2 values over the other analogs. Of

the two isomeric thiazolyl derivatives, compound 7 exhibited the best overall
profile and therefore was selected for further studies.
Beginning with the phenyl derivative 7, several heterocyclic replacements of the
terminal phenyl group were prepared and exemplified by the pyridine analog 8 in
Table 1. None of these type of ring replacements were beneficial to cellular
potency, likely a result of the lipophilic nature of the pocket. Retaining the phenyl
group as in compound 7, mono-substitution on the ring was explored by first
walking a methoxy group around the ring as shown with compounds 9, 10, and 11.
Interestingly, while the para and meta substitutions were tolerated (compounds 9
and 10), the ortho substituted analog 11 resulted in an important ortho substituent
effect. This substitution resulted in nearly a 4-fold improvement in intrinsic
potency and a 5-fold improvement in cellular potency over compound 7, delivering
our first sub-nM potency compound in the series. With the discovery of this ortho
methoxy group effect, a number of other small ortho ether substituents were
screened including the ethoxy group (compound 12), however these analogs were
all equipotent to 11. Other ortho groups evaluated included among others the Me
and F analogs (compounds 13, 14) which were detrimental to potency. With the
finding of this ortho methoxy group effect on potency, we revisited the
regioisomeric 4-phenylthiazol-2-yl analog (not shown) of compound 11 and found
this to be more than 3-fold less potent, consistent with our original finding.
Having established this novel P2 moiety, a molecular model based on in-house
X-ray structures was created with compound 11 in the presence of the NS3
protease as shown in Figure 1, Panel A. The thiazole moiety was shown to adopt a
pseudo axial conformation on the P2 proline ring which allows for the phenyl
group to nestle against the P2 binding pocket, similar to that described previously

with Arg155 being desolvated and forming a salt-bridge with Asp16817. The biaryl
groups are modelled nearly coplanar (~120) allowing the two rings to conform to a
slight ridge formed between residues Asp81 and Arg155. The important ortho
methoxy group is oriented with its oxygen atom largely solvated and its methyl
group filling a small pocket adjacent to the backbone carbonyl oxygen of Asp79. It
is interesting to note that this same position was central to a key halogen bond in
the binding of faldaprevir17. It is possible that the favourable interactions of the
methyl group within this pocket explain the superiority of compound 11 over
compounds 13 and 14. This model also suggested that substitution at the 3-position
is largely blocked by Val78, but further favorable surface interactions with the P2
pocket may be achieved with substitutions at the 5-position on the phenyl ring.
Armed with this information, we next explored the possibility of incorporating a
second substituent around the phenyl ring as shown in Table 2. Systematic
substitution at each of the available positions on the phenyl ring with a second
methoxy group was first explored. While substitution at the 3- and 4-positions as in
compounds 15 and 16 were somewhat tolerated, substitution at the 6-position was
the least tolerated likely due to a reinforcement of a non-planar orientation and the
seemingly tight fit in the pocket resulting in the significant loss in potency
observed for compound 17. As suggested by the modeling study, the best
placement of the second methoxy group at the 5-position provided the 2,5-
disubstituted analog 18 which gave an improvement in cellular potency by 2-fold
over compound 11. Next, the 5-methoxy group was replaced by other substituents
as found in the Me and F analogs (compounds 19 and 20) but none of these
analogs reached the potency of compound 18. Since compound 18 was expected to
be near the wall of the IC50 assay, the Ki value was determined for this particular
compound and found to be in the range of 230 M. In order to improve potency

further, introduction of a methyl -substituted cyclopropane on the terminal acyl
sulfonamide generated compound 21 with an IC50 = 1.1 nM and EC50 = 9 nM
which represented our most potent compound in this series. Some ADME
properties were determined for these two analogs (Scheme 3). Both compounds
had modest stability against human liver microsomes (18: HLM = 69 min, 21:
HLM = 57 min) but good cell permeability as measured by the Caco-2 model (18:
7 x 10-6 cm/sec, 21: 12 x 10-6 cm/sec).
As a further exercise, analogs from three distinct series were superimposed in
the model to visualize the subtle differences in the P2 group orientations (Figure 1,
Panel B). As can be seen from this figure, the 2-phenyl-4-thiazolyl proline
derivative 11 samples different space relative to the biphenyl type analogs
highlighted by fragment 3 or the more extensive P2 hydroxyproline analog found
in faldaprevir. This comparison visualizes compound 11 being shifted more
towards the P1 residue relative to the biphenyl analog 3 and occupied a much
smaller region than the hydroxyproline derivative 1. Subtle differences in the
orientations and size of these P2 derivatives could have important implications for
the resistance profiles of these different series. From preliminary data, we found
compound 18 shifted 8 and 10-fold for mutations A156T and D168V respectively,
somewhat less than analogous hydroxyproline derivatives (data not shown).
The synthesis of the 2-aryl substituted 4-thiazole analogs have been exemplified
by the preparation of compound 7 as outlined in Scheme 4. Starting from brosylate
22 which has previously been described5, potassium cyanide displacement of the
brosylate group under thermal conditions gave nitrile 23. The nitrile group was
hydrolyzed under acidic conditions using MeOH-HCl followed by the selective
hydrolysis of the methyl ester intermediate with 1N NaOH to afford the mono acid
24. Using a 3-step protocol, acid 24 was first activated with isobutyl chloroformate

at 0oC followed by treatment with a solution of diazomethane. Following a simple
work-up in EtOAc and saturated aqueous NaHCO3, the crude material was purified
by SiO2 chromatography to give the pure diazoketone intermediate. This
intermediate was next treated dropwise at 0oC with 48% aq. HBr over several
minutes before being poured into EtOAc and quenched with saturated aqueous
NaHCO3 to supply the -bromoketone intermediate 25 in nearly quantitative yield.
The -bromoketone was then condensed with thiobenzamide at 65oC followed by
the hydrolysis of the terminal ester with 1N NaOH at rt (16h) to give the
corresponding acid 26. Other analogs were prepared from this key -bromoketone
intermediate by substituting the appropriate aryl thioamide derivatives. Activation
of 26 with isobutyl chloroformate generated the azalactone intermediate 27 which
was subsequently opened with cyclopropane sulfonamide under LiHMDS
conditions. The regioisomeric 4-phenyl-2-thiazolyl analog 6 was prepared by
conversion of the cyano intermediate 23 to the corresponding thioamide in a sealed
tube with H2S and NEt3/dioxane. The corresponding thioamide was then treated
with the appropriate -bromoketone to generate the desired thiazole ring system,
followed by the same sequence as outlined in Scheme 4. The N-linked analogs
(compounds 4 and 5) were prepared by a simple SN2 displacement of the brosylate
intermediate with the desired functionalized heterocycle.
In summary, we have reported on our continuing effort to diversify and provide
novel P2 fragments to inhibit the HCV NS3 serine protease. This study provided a
new series of potent 2-phenyl-4-thiazolyl proline analogs which incorporates an
acyl-sulphonamide P1’ residue required for the level of potency needed for
successful clinical compounds of this target. From modeling studies this new P2
moiety occupies the S2 pocket in a slightly different manner than the
hydroxyproline or the 4-biarylproline analogs previously described by our group.

The two beneficial methoxy groups affixed to the phenyl ring both sample
different areas of the S2 region of the enzyme. The ortho methoxy group on the
terminal phenyl ring conforms to a slight ridge between Asp81 and Arg155
whereas the 5-methoxy group occupies open space in the opposite direction. These
two interactions improved potency significantly for this series and provided
compounds 18 with an IC50 value of 0.9 nM and a Ki value in the high picomolar
range. Our most potent compound in the replicon assay was compound 21 with an
IC50 = 1.1 nM and EC50 = 9 nM. Both compounds exhibited good initial profiles
for both the stability and permeability data which would hopefully translate into
favourable parameters for PK studies. The syntheses of these new 4-thiazolyl
proline analogs were readily accomplished by way of a common -bromoketone
intermediate developed in our laboratory.
Acknowledgements
The authors wish to thank Dr. Lisette Lagacé, Lyne Lamarre, Nathalie Dansereau,
Ewald Welchner and Erika Scouten for IC50 and EC50 determinations. We would
also like to thank Dr. Jianmin Duan, Josie De Marte and Christine Zouki for the
determination of valuable DDS parameters. Finally we thank Drs. Michael Bös and
Michael Cordingley for their guidance and support during this work.
References
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E.; Girijavallabhan, V.; and Njoroge, F. G. Antimicrob. Agents Chemother.
2006, 50, 1013
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P.; Bös, M.; Cameron, D.; Cartier, M.; Cordingley, M. G.; Faucher, A-M.;
Goudreau, N.; Kawai, S.; Kukolj, G.; Legace., L.; LaPlante, S.; Naejes, H.;
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M., Ghiro, E., Gorys, V., Goulet, S., Halmos, T., Kawai, S.,Naud, J.,
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Table 1. Modification of Terminal Aryl Group
R
S
N
O
O
O
H
N
N
S
O
N
H
N
O
O
H
O
EC50 (nM)
175
Compound
IC50 (nM)
2.7
R group
7
8
N
12
915
530
O
9
5.2
O
10
11
3.4
140
35
O
O
0.74
12
13
14
0.78
6.0
37
800
235
F
1.8

Table 2. Disubstitution Study of Aryl Group
R
S
N
O
O
O
H
N
N
S
O
N
H
N
O
O
H
O
EC50 (nM)
Compound
IC50 (nM)
0.74
R group
O
11
15
16
35
O
O
4.1
2.2
240
89
O
O
O
17
18
17
2200
16
O
O
0.9
O
O
O
19
20
1.7
1.1
27
28
F

S
N
Br
N
O
N
O
O
N
N
N
O
H
N
N
N
O
OH
2
N
O
O
X
H
O
P3
P1
P2
O
1: Faldaprevir
MW = 869
N
IC50 : 3 nM
EC50: 3 nM
3
Scheme 1. Modification of the central P2 proline fragment

Compound 2
IC50 = 2.7 nM
Compound 7
IC50 = 2.7 nM
EC50 = 175 nM
HLM(T1/2) = 135 min
EC50 = 430 nM
HLM(T1/2) = 94 min
Caco-2 = 1.1x10-6 cm/sec
Caco-2 = 4.6x10-6 cm/sec
Compound 4
IC50 = 1.8 nM
Compound 5
IC50 = 2.5 nM
Compound 6
IC50 = 3.2 nM
EC50 = 1340 nM
EC50 = 320 nM
EC50 = 580 nM
HLM(T1/2) = 221 min
Caco-2 = 0.2x10-6 cm/sec
HLM(T1/2) = 6 min
Caco-2 = 0.7x10-6 cm/sec
HLM(T1/2) = 143 min
Caco-2 = 4.4x10-6 cm/sec
Scheme 2. Effect on Modification of the Central Heterocyclic Core (IC50's are gt1)

O
O
O
O
S
S
N
N
O
O
O
O
O
O
H
H
N
N
S
N
N
S
O
N
O
N
H
H
N
O
N
O
O
O
H
H
O
O
18
21
IC50 = 0.9 nM (Ki = 230 pM)
EC50 = 16 nM
IC50 = 1.1 nM
EC50 = 9 nM
Stability: HLM = 69 min
Stability: HLM = 57 min
Caco-2 permeability = 12 x 10-6 cm/sec
Caco-2 permeability = 7 x 10-6 cm/sec
Scheme 3. Profile of compounds 18 and 21

Br
S
N
O
OH
O
O
O
O
i
O
O
O
ii-iii
O
O
H
N
H
H
N
N
N
N
N
O
O
O
N
O
N
N
O
O
H
H
H
O
O
O
O
O
O
22
24
23
Br
S
O
N
iv-vi
O
vii-viii
O
O
H
ix
O
N
N
H
O
N
N
N
O
OH
H
N
H
O
O
O
O
O
25
26
S
S
N
N
O
O
O
x
O
O
H
S
N
N
N
N
N
N
O
H
N
O
H
H
O
O
O
O
O
7
27
Scheme 4. i) KCN in DMSO, 55oC, 24h, 97% (ii) MeOH-HCl, 16 h, 100% (iii) THF, MeOH, H2O, 1N
NaOH, 1.5h, 96% (iv) THF, NEt3, IBCF, 0oC, 1.5h (v) Diazomethane in ether, 0oC, 1h, 49% over 2-steps
(vi) THF 48% aq. HBr, 0oC, 30 min, 99% (vii) THF, thiobenzamide, 65oC, 1h (viii) MeOH, H2O, 1N NaOH,
rt, 16h, 100% over 2-steps (ix) DCM, IBCF, NEt3, 1h, 100% (x) cyclopropane sulfonamide, THF, at - 15oC,
1M LHMDS, warm to rt, 16h, 51%.