Discovery of fused tricyclic core containing HCV NS5A inhibitors with pan-genotype activity

Article abstract of DOI:10.1016/j.bmcl.2016.04.084

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.

Full text of DOI:10.1016/j.bmcl.2016.04.084

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of fused tricyclic core containing HCV NS5A inhibitors with
pan-genotype activity
b
a
a
a
a
Wensheng Yu a, , Craig A. Coburn , De-Yi Yang , Peter T. Meinke , Michael Wong , Stuart B. Rosenblum ,
Kevin X. Chen a, George F. Njoroge a, Lei Chen a, Michael P. Dwyer a, Yueheng Jiang a, Anilkumar G. Nair a,
Oleg Selyutin a, Ling Tong a, Qingbei Zeng a, Bin Zhong c, Tao Ji c, Bin Hu c, Sony Agrawal d, Ellen Xia d,
Ying Zhai d, Rong Liu e, Rong Kong e, Paul Ingravallo e, Ernest Asante-Appiah e, Amin Nomeir f,
James Fells g, Joseph A. Kozlowski a
⇑
a Department of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA
b Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
c WuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China
d Department of In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
e Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
f Department of PPDM, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
g Department of Structural Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and
robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all
oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research
efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such
as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 22 March 2016
Revised 27 April 2016
Accepted 28 April 2016
Available online xxxx
Keywords:
HCV NS5A inhibitor
Hepatitis C
Direct-acting antiviral agents (DAA)
Pan-genotype activity
Tricyclic
Elbasvir
Hepatitis C virus (HCV) is the leading cause of chronic liver dis-
ease and liver transplants in the developed world. The World
Health Organization (WHO) estimates that approximately 3% of
the world’s population are infected with HCV.1 The diversity in
the virus is impressive with seven major genotypes (GT1-7) pre-
sent and multiple subtypes identified for each. However, currently
approximately 90% of all HCV infections are associated with geno-
types 1, 2, and 3. Until 2013, treatment of the disease was focused
on interferon-based therapy and was limited by both efficacy and
tolerability.2 Addition of HCV protease inhibitors, such as telapre-
vir or boceprevir, to the therapy improved response rates for geno-
type 1 patients,3 but unfortunately left many patients without a
cure, leaving open a need for improved treatment regimens. Cur-
rent HCV therapy targets interferon-free, direct-acting antiviral
agents (DAA) with reduced overall treatment durations, broader
coverage of HCV patient sub-populations, and increased rates of
sustained virologic response (SVR). Typically, these treatment reg-
imens utilize two or more DAAs, each targeting a different mecha-
nism of action in the life cycle of HCV. SVR rates have been
dramatically improved with this approach and it continues to be
an important strategy for improving clinical outcomes for HCV
patients.4,5
The HCV NS5A protein is a multifunctional RNA binding protein
essential for HCV replication.6 NS5A encodes no known enzymatic
function but has been shown to serve multiple functions at various
stages of the HCV life cycle including involvement in both viral
replication and virion assembly.6 Over the past decade, NS5A has
become an attractive pharmacological target and inhibitors of
NS5A have become an integral part of fixed-dose combination
(FDC) regimens.7 To date, four NS5A inhibitors are available for
use in clinical practice for HCV treatment: daclatasvir,8 ledipasvir,9
ombitasvir,10 and elbasvir.11
⇑
Corresponding author.
E-mail address: wensheng.yu@merck.com (W. Yu).
http://dx.doi.org/10.1016/j.bmcl.2016.04.084
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Yu, W.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.084

2
W. Yu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
O
O
N
O
N
N
H
O
N
O
N
N
H
O
H
N
N
H
N
O
MK-8742
Figure 1. MK-8742 in vitro potency profile.11
Figure 2. Overlay of anthracene-imidazole core (yellow) and MK-8742 core
(purple).
During our work in the development of NS5A inhibitors we
noted that changes in the core structure, while holding the remain-
der of the molecule constant, could modulate both the wild-type
HCV and mutant potency profiles.11,12 To further interrogate this
observation, we undertook an effort to study a variety of fused tri-
cyclic cores, each possessing a different shape and length.
Using MK-8742 (Fig. 1) as a reference point for comparison, we
elected to maintain the bisimidazole–proline–valine methyl carba-
mate unchanged and vary only the core. At the outset of this work,
we were curious if a tricyclic core could impart a potency profile
similar to that of the tetracyclic indole based core. Molecular mod-
eling indicated that analogs with a fused tricyclic core have com-
paratively shorter spacing between the two imidazole–proline
moieties compared to our tetracyclic core.13 In addition, one could
alter the attachment points of the imidazole proline moieties to the
tricycle in order to perturb the spatial projection of these moieties.
The ability to modulate both the length of the core and the projec-
tion of the imidazole–proline moiety into space was attractive as it
allowed for considerable variation in the overall size and shape of
the molecules.
The investigation was started by preparing a simple anthracene
core, retaining the imidazoles in a ‘para’ or ‘linear’ arrangement. It
was reasoned that this core should provide an overall shape and
projection of the imidazoles that would mimic the tetracyclic core,
but being only slightly shorter in length (based on molecular mod-
eling,13 anthracene is ꢀ13% shorter than the tetracyclic core of MK-
8742, Fig. 2). Preparation of 4 is illustrated in Scheme 1. 2,6-Dibro-
moanthracene 1 was converted to the pinacol boron diester 2
while compound 3 was prepared according to published proce-
dures.14,15 Suzuki coupling between 2 and 3 followed by removal
of the Boc groups and installation of the (S)-valine methyl carba-
mate afforded target 4. The chloro- or methyl-substituted anthra-
cene analogs 10 and 11 (Table 1) were prepared according to
Scheme 1 except starting with the commercially available substi-
tuted anthracene.
O
Br
B
a
O
N
Boc
N
N
+
Br
O
N
H
Br
B
O
1
2
3
O
O
N
O
N
O
b, c, d
N
H
NH
O
NH
N
N
H
O
4
Scheme 1. Preparation of 4. Reagents and conditions: (a) Bis-pinacol diborate, Pd
(dppf)Cl2, KOAc, dioxane, 110 °C, 15 h, 73%. (b) Pd(dppf)Cl2, Na2CO3, THF/H2O
(10:1), reflux, 15 h, 61%. (c) HCl, MeOH, 0.5 h, 100%. (d) (Methoxycarbonyl)-
L-valine,
BOP, DIPEA, DMF, 10 h, 65%.
Table 1
EC50 (nM) values for compounds 4, 10–1616
O
O
O
N
N
N
O
O
N
H
A
O
NH
N
NH
N
H
ID
A
GT-1a GT-1b GT-2a GT-3a GT-1a Y93H
1
1
4
0.006
0.05
0.001
0.003
0.005
0.01
0.06
0.6
87
66
2
Cl
10
2
1
11
12
0.02
0.05
0.005
0.01
0.005
0.04
0.5
nt
42
2
1
1050
2
N
CN
1
1
13a
0.3
0.01
1
nt
nt
2
N
N
Efforts were then focused upon introduction of heterocycles
into the anthracene core. Acridine analogs (12, 13) and phenazine
analog (14) were prepared from commercially available dibromi-
nated starting materials using the chemistry route outlined in
Scheme 1. Benzo[1,2-b:4,5-b0]difuran analog 15 was prepared
according to the chemistry route shown in Scheme 2. The prepara-
tion began with benzofuran formation between phenol 5 and
known pyrrolidine 611 to afford benzofuran intermediate 7. In a
separate step, 7 was treated again with 6 to install a second benzo-
furan which was then treated with HCl to afford diamine 8. Treat-
ment of 8 with Moc Val 9 under HATU coupling conditions afforded
15. Naphtho[2,1-b]furan analog 16 was prepared in a same manner
as 15.
14
15
16
0.06
0.03
>10
0.06
0.001
0.01
0.1
0.05
0.3
0.2
nt
61
nt
2
N
O
2
1
O
O
2
nt
1400
1
nt = not tested.
a
With 10% FBS added in the assay.
upper double digit nM range. Incorporation of a methyl group or
chloride into the C9 position of the anthracene core (10 and 11)
showed a comparable profile to 4 except for a 10-fold loss in activ-
ity against GT3a. Addition of a basic nitrogen, into the middle ring
of anthracene (12), was tolerated except for a significant loss of
potency toward GT1a Y93H (Table 1). A nitrile group was installed
Table 1 summarizes the HCV wild-type (GT1a, 1b, 2a, 3a) and
mutant (GT1a Y93H) virologic profile for various tricyclic deriva-
tives.16 The anthracene derivative 4 was potent against the wild
type virus, but its GT1a Y93H EC50 value was weaker and in the
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W. Yu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
OH
F
O
O
NO2
Boc
N
N
OH
I
b
Boc
N
I
NO2
OH
O
a
a
N
+
N
H
O
+
I
Br
HN
OH
5
Br
Br
Br
6
7
17
18
19
O
N
N
O
b,c
H
N
H
N
OH
NO2
+
N
H
O
N
H
HO2C
R1
R2
N
H
O
O
O
b
8
9
Br
Br
O
Br
21a: R1 = Br, R2 = H
21b:
20
O
N
1 = H, R2 = Br
O
O
O
N
R
N
O
d
N
H
NH
O
N
H
O
N
H
N
O
Scheme 3. Preparation of compounds 21a and 21b. Reagents and conditions: (a)
K2CO3, DMF, 110 °C, 3 h, 91%. (b) BBr3, ꢁ78 °C to rt, 3 h, 97%. (c) t-BuOK, DMF,
120 °C, 3 h, 87% for 21a and 21b.
15
Scheme 2. Preparation of 15. Reagents and conditions: (a) Pd(PPh3)2Cl2, CuI, Et3N,
80 °C, 15 h, 22%. (b) 6, Pd(PPh3)2Cl2, CuI, Et3N, 80 °C, 15 h, 38%. (c) HCl, MeOH, rt,
0.5 h, 100%. (d) HATU, DIPEA, DMF, rt, 15 h, 33%.
intermediates 21a and 21b used for the preparation of 4a,10a-
dihydrodibenzo[b,e][1,4]dioxine analogs 23 and 24 were prepared
according to Scheme 3.17 SNAr reaction between 17 and 18 afforded
ether 19 which was de-methylated with BBr3 to give 20. Base-
mediated ring closure of 20 afforded a mixture of 21a and 21b
which were progressed to 23 and 24 using the chemistry outline
in Scheme 1. Dibenzo[b,f][1,4]oxazepin-11(10H)-one analogs 25
and 26 as well as dibenzo[b,f][1,4]oxazepine analogs 27 and 28
were prepared from their known dibromide starting materials13
according to chemistry outlined in Scheme 1.
Activity values for compounds 22–28 are summarized in
Table 2. Anthracene-9,10-dione analog 22 was comparable to
anthracene analog 4 with the exception of a 10-fold loss in activity
in GT2a. Derivatives 23 and 24 possess the same core structure but
utilize a different substitution pattern where 23 has the two imida-
zole–proline moieties in a non-linear arrangement and 24 displays
them in a linear arrangement. Molecular overlay of 23 and 24 with
MK-8742 using ROCS13 revealed that 24 can adopt a similar confor-
mation as MK-8742, while 23 has a slight offset due to the differ-
ence in substitution pattern (Fig. 3). This difference in overlap
implicates the importance of the linear substitution pattern, where
changing the connection to a nonlinear one leads to a less favorable
overlay with 23. As predicted by the molecular modeling, analog
24 showed better potency than 23, especially against both GT1a
Y93H and GT2a. This result was consistent with the data generated
at the C9 position of 12 to modulate the basicity, to afford com-
pound 13, which showed diminished potency. However, phenazine
core derivative, 14, showed a potency profile similar to the anthra-
cene analog 4. Benzo[1,2-b:4,5-b0]difuran analog 15 and naphtho
[2,1-b]furan analog 16 contain either one or two fused furan rings.
The connectivity of 16 results in a slightly different projection of
the imidazole–proline moieties relative to the linear anthracene,
but the projection of 15 was more linear and similar to 4. The activ-
ity of 16 was reduced significantly versus 15 (GT1a and GT1a
Y93H) and we speculated the projection of 16 was the cause and
not the introduction of the furan moiety as 15 did not show the
potency loss.
With the SAR data from Table 1 in hand, attention was turned
toward preparation of analogs bearing fused tricyclic cores, with
a non-aromatic ring in the middle (Table 2). To further explore
the effect of a different projection of the imidazole–proline moiety
on HCV genotype activity, three cores were prepared with two
unique substitution patterns (six compounds) for comparison.
The 4a,9a-dihydroanthracene-9,10-dione analog 22 was prepared
from commercially available 2,6-dibromoanthracene-9,10-dione
based on the chemistry outlined in Scheme 1. The dibrominated
Table 2
EC50 (nM) values for compounds 22–2816
O
O
O
N
N
N
O
O
N
H
A
O
NH
N
NH
N
H
ID
R
GT-1a
GT-1b
0.007
GT-2a
0.7
GT-1a Y93H
35
O
1
22
0.09
2
O
O
2
1
1
23
24
0.1
0.09
0.6
350
16
O
O
0.01
0.009
0.01
2
O
O
N
25a
26a
145
950
0.2
40
310
nt
nt
1
1
2
O
O
N
>1000
2
2
O
N
27a
28a
220
40
0.06
0.5
55
55
nt
nt
O
1
1
N
2
O
nt = not tested.
With 10% FBS added in the assay.
Figure 3. Overlay of compounds 23 (teal-blue), 24 (lime-green) and MK-8742 core
(orange).
a
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4
W. Yu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
for compounds 15 and 16 (Table 1) where a linear molecule is
preferred. Compounds 25 and 26, which possessed the fused 6-7-
6 tricyclic system, demonstrated a loss in activity across all geno-
types (Table 2). Elimination of the carbonyl group found in the core
of compounds 25 and 26, yielded derivatives 27 and 28 which
showed slightly improved potency but they are still significantly
weaker than other NS5A inhibitors.
upon Scheme 4. When 31 was treated with ethyl magnesium bro-
mide or pentyl magnesium bromide, the corresponding olefins
resulted from the elimination of the tertiary alcohol were also
obtained as one of the products. These olefin intermediates were
converted to the final products (44, 46) by using the chemistry out-
lined in Scheme 1. Finally, the geminal dimethyl derivative, 47, was
prepared from 31 by known methods.18
Having identified compounds 22 and 24 as possessing interest-
ing virologic profiles (Table 2), efforts were focused upon the
preparation of structurally related cores to these two analogs.
Scheme 4 shows a general chemistry approach to a variety of
derivatives which are listed in Table 3. The preparation of xan-
then-9-one analog 37 began with compound 29 which was pre-
pared according to Scheme 3. Hydrolysis of the nitrile group of
29 afforded acid 30 which upon treatment with TFAA induced a
ring closure to afford 2,7-dibromodibenzo[b,e][1,4]dioxine 31.
Compound 31 was processed forward to yield final adduct 37 via
the chemistry outlined in Scheme 1. The corresponding sulfone
and sulfide analogs (38 and 39) were prepared by the chemistry
in Scheme 4 using commercially available dibromo starting mate-
rials. Treatment of 31 with methyl magnesium bromide afforded
tertiary alcohol 32 which was reduced to 2,6-dibromo-9-methyl-
9H-xanthene 33. Compound 33 was used to prepare 42 by stan-
dard methods (Scheme 1). Besides methyl, analogs with different
alkyl groups (43, 45) were also prepared by similar methods based
The preparation of 2,7-dibromo-phenoxazine core 36 is shown
in Scheme 5. Compound 34 was prepared according to the chem-
istry described in Scheme 3. The nitro group was reduced followed
by ring closure to afford dibromide 35. Treatment of 35 under alky-
lation conditions afforded 36, which was subjected to standard
conditions to prepare 40. The chemistry outlined in Scheme 5
was also used to prepare 41. Introduction of the phenyl group to
the nitrogen atom of phenoxazine of intermediate 35 was done
according to literature precedent.19
The wild-type and mutant genotype EC50 values for analogs 37–
47 are summarized in Table 3. Compound 37, which contained a
hybrid core of 22 and 24, possessed comparable wild-type activity
(GT1a, 1b, 2a) to either 22 or 24 alone but demonstrated a signifi-
cant loss in activity versus GT1a Y93H. This was a surprising result
as 22 had shown good potency against GT1a Y93H possessing two
carbonyl groups in the same region. Sulfone 38 showed potency
loss against all the genotypes tested. In contrast to sulfone 38, sul-
fide analog 39 showed good activity against all genotypes, includ-
ing GT1a Y93H. Interestingly, 10-methyl-10H-phenoxazine analog
40 did not experience the same potency loss against GT1a Y93H
that was observed for the acridine analog 12 (Table 1), however
the 10-phenyl-10H-phenoxazine analog 41 showed reduced activ-
ity against both GT1a and GT2a.
With the emerging SAR trend that non-basic and lipophilic
groups are preferred in the core, additional analogs bearing alkyl
substitution are shown in Table 3. The 9-methyl-9H-xanthene ana-
log 42 and corresponding ethyl derivative 43 showed a virologic
profile similar to one another. The olefin analog 44 demonstrated
a similar profile to 43 with GT1a Y93H EC50 in the single digit
nanomolar range. The cyclopropyl analog 45 showed a potency
profile comparable to the methyl analog 42. However, bigger sub-
stituents or disubstitution hurt the GT1a Y93H potency as demon-
strated by compounds 46 and 47.
CN
CO2H
O
O
O
b
a
Br
Br
Br
Br
O
31
Br
c
Br
29
30
OH
Br
d
Br
Br
O
Br
O
32
33
Scheme 4. Preparation of compounds 31 and 33. Reagents and conditions: (a)
NaOH, EtOH, reflux, 20 h, 100%. (b) TFAA, DCM, 0 °C, 98%. (c) MeMgBr, THF, rt, 16 h,
83%. (d) Me3SiH, TFA, DCM, reflux, 16 h, 53%.
Table 3
EC50 (nM) values for compounds 37–4716
A small set of tricyclic core derivatives were evaluated in phar-
macokinetic studies in rat and the results are summarized in
Table 4. All derivatives showed moderate to good bioavailability
O
O
X
O
N
N
N
O
O
N
H
O
NH
N
NH
O
N
H
ID
X
GT-1a
0.01
GT-1b
0.002
GT-2a
0.1
GT-3a
nt
GT-1a Y93H
1730
I
NO2
H
N
O
Br
a, b
N
Br
O
c
37
1
2
O
2
Br
Br
O
Br
O
Br
O
1
34
35
36
S
S
38
39
40
>1
0.06
0.002
0.007
0.8
16
0.3
0.3
2380
21
0.04
0.09
0.06
0.07
1
2
Scheme 5. Preparation of compound 36. Reagents and conditions: (a) SnCl2, EtOH,
100 °C, 4 h, 51%. (b) Pd(OAc)2, Xanphos, Cs2CO3, THF, 79%. (c) NaH, MeI, DMF, rt, 2 h,
N
70
1
2
94%.
Ph
N
41a
42
43
44
5
0.008
0.009
0.004
0.007
3
nt
nt
47
24
9
1
1
2
2
0.05
0.02
0.06
0.004
0.005
0.03
0.08
0.07
0.4
Table 4
Rat PK profiles of selective compoundsa,b
1
1
2
2
ID
Dose (po, mpk)
t1/2 (h)
CL (ml/min/kg)
AUC (po,
l
Mꢂh)
F (%)
4
10
10
5
5
10
10
3.0
0.9
1.4
1.3
1.2
1.6
7.7
14.0
6.4
15
32
19
13.0
46
37
26
25
69
39
23
24
39
40
47
1.6
4.5
1.1
2.8
2.3
45a
0.03
0.004
0.004
0.2
46
1
1
2
2
46
47
>0.1
0.02
0.006
0.005
0.05
0.4
0.3
260
130
1
2
<0.02
a
Male Sprague–Dawley rats were used. Compound was dosed at 2 mg/kg, IV in
nt = not tested.
With 10% FBS added in the assay.
60% PEG200 as well as PO at indicated doses in 10% Tween 80.
a
b
For the rat PK profile of MK-8742, please see Ref. 11.
Please cite this article in press as: Yu, W.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.084

W. Yu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
5
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coupled with moderate clearance based upon total compound.
Anthracene 4 stood out among this group as also possessing rea-
sonable exposure as well as a half-life of 3 h. Unfortunately, the
other derivatives demonstrated relatively short T1/2 which limited
their progression.
In conclusion, a number of fused tricyclic core inhibitors of
NS5A with potent wild-type and mutant genotype activity have
been identified. We confirmed that a linear structure arrangement
on the core is necessary to retain good potency. A basic nitrogen, or
a single carbonyl, or sulfonyl group in the core are not tolerated.
Compounds selected for rat PK study showed reasonable rat oral
bioavailability with intermediate half-life. Additional efforts
focused upon core modifications are the subject of future
publications.
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Keertikar, K.; Zhou, G.; Dwyer, M.; Kim, S. H.; Shankar, B.; Yu, W.; Tong, L.;
Chen, L.; Mazzola, R.; Caldwell, J.; Tang, H.; Allard, M.; Buckle, R. N.; Gauuan, P.
J. F.; Holst, C. L.; Martin, G. S.; Naicker, K. P.; Vellekoop, S.; Agrawal, S.; Liu, R.;
Kong, R.; Ingravallo, P.; Xia, E.; Zhai, Y.; Nomeir, A.; Kozlowski, J. A. Bioorg. Med.
Chem. Lett. 2016, 26, 1475.
Supplementary data
13. Alignment was performed using Rapid Overlay of Chemical Structures (ROCS v.
3.2.0.4) software. A single low-energy conformation of MK-8742 was used as
the query molecule to align the compounds. Omega software v. 2.5.1.4
(OpenEye Scientific Software, Inc., Santa Fe, NM, USA) was used to generate up
to 500 conformations of each compound using default parameters. ROCS was
then employed to superimpose MK-8742 and other compounds. Results were
visualized using PYMOL (v. 1.7).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.04.
084. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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336; (b) Gijsen, H. J. M.; Berthelot, D.; Zaja, M.; One, B. B.; Geuens, I.; Mercken,
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Please cite this article in press as: Yu, W.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.084