Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.7b00386

Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.

Full text of DOI:10.1021/acsmedchemlett.7b00386

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Letter
Design and Synthesis of Piperazine Sulfonamide Cores
Leading to Highly Potent HIV-1 Protease Inhibitors
Christopher James Bungard, Peter D. Williams, Jurgen Schulz, Catherine M. Wiscount, M. Katharine
Holloway, Marie Loughran, Jesse J. Manikowski, Hua-Poo Su, David Jonathan Bennett, Lehua Chang,
Xin-jie Chu, Alejandro Crespo, Michael P. Dwyer, Kartik Keertikar, Gregori Joseph Morriello, Andrew W
Stamford, Sherman T. Waddell, Bin Zhong, Bin Hu, Tao Ji, Tracy L Diamond, Carolyn Bahnck-Teets, Steven
S. Carroll, John F. Fay, Xu Min, William J Morris, Jeanine E. Ballard, Michael D. Miller, and John A McCauley
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00386 • Publication Date (Web): 13 Nov 2017
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Design and Synthesis of Piperazine Sulfonamide Cores Leading to
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Christopher J. Bungard,*a Peter D. Williams,a Jurgen Schulz,a Catherine M. Wiscount,a M. Katharine
Holloway,a H. Marie Loughran,a Jesse J. Manikowski,a HuaꢀPoo Su,a David J. Bennett,a Lehua Chang,b
XinꢀJie Chu,b Alejandro Crespo,b Michael P. Dwyer,b Kartik Keertikar,b Gregori J. Morriello,b Andrew
W. Stamford,b Sherman T. Waddell,b Bin Zhong,c Bin Hu,c Tao Ji,c Tracy L. Diamond,a Carolyn
BahnckꢀTeets,a Steven S. Carroll,a John F. Fay,a Xu Min,a William Morris,b Jeanine E. Ballard,a Miꢀ
chael D. Miller,a and John A. McCauley.a
aMerck & Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA.
bMerck & Co., Inc., 126 E. Lincoln Ave., Rahway, NJ 07065, USA.
cWuXi AppTec, 288 Fute Zhong Road, Shanghai 200131, China.
KEYWORDS: HIVꢀ1 protease inhibitors, MKꢀ8718, PLꢀ100, piperazine sulfonamide.
ABSTRACT: Using the HIVꢀ1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic
piperazine sulfonamide core was designed and synthesized. The resulting HIVꢀ1 protease inhibitor containing this core showed an
60ꢀfold increase in enzyme binding affinity and
a
10ꢀfold increase in antiviral activity relative to MK-8718.
HIVꢀ1 protease is a critical enzyme in the lifecycle of the
virus, serving to catalyze the proteolytic cleavage of polypepꢀ
tide precursors into mature enzymes and structural proteins
that are essential components of HIVꢀ1.1 Inhibitors of this
enzyme prevent conversion of HIVꢀ1 particles into their maꢀ
ture infectious form, and so it follows that HIVꢀ1 protease
inhibitors represent an important therapeutic approach for the
treatment of HIVꢀ1 infection.2ꢀ4 Recently, we reported the
discovery of MK-8718, an HIVꢀ1 protease inhibitor containꢀ
ing a novel morpholine aspartate binding group.5 A key feaꢀ
ture of this inhibitor is that the morpholine amine forms the
key interaction with the Aspꢀ25A and Aspꢀ25B acidic residues
of the enzyme, in contrast to the majority of inhibitors where a
hydroxyl group plays this role.6 Herein we report further optiꢀ
mization of the enzyme bound conformation of these amine
based class of inhibitors.
order to simplify the synthesis of the initial proof of principal
target, a simplified right hand side derived from 3,3ꢀbis(4ꢀ
fluorophenyl)propanoic acid was utilized.8 Synthesis of our
initial design is outlined in Scheme 1. Commercially available
racemic 1 was sulfonylated to afford piperazine sulfonamide
2. Dess–Martin oxidation9 gave aldehyde 3 which underwent
Wittig olefination using (2ꢀnitrobenzyl)triphenylphosphonium
bromide10 to afford olefin 4. Concomitant reduction of the
nitro and olefin functionalities under hydrogenation conditions
yielded
aniline
5.
Coupling
of
3,3ꢀbis(4ꢀ
fluorophenyl)propanoic acid with aniline 5 afforded amide 6.
Elaboration to the desired target was achieved by Bocꢀ
deprotection and resolution of the ensuing enantiomers to afꢀ
ford 7 and 8. Antiviral activity of both enantiomers 7 and 8
was measured and pleasingly enantiomer 7 showed significant
activity in a cell based antiviral assay (EC50 = 27 nM).11 With
this active compound in hand, we decided to pursue an xꢀray
crystal structure of 7 bound to HIVꢀ1 protease to confirm our
hypothesis that the sulfonamide moiety had displaced the waꢀ
ter molecule present in the enzyme bound structure of MK-
8718. Gratifyingly, the crystal structure of 7 bound to HIVꢀ1
protease, shown in Figure 2, indeed showed that no bridging
water was present, and the sulfone of 7 was directly hydrogen
bonded to the Ile50A and Ile50B residues of the enzyme. Also
evident from the crystal structure of 7 was that the preferred
stereochemistry at the 2ꢀposition of the piperazine moiety was
Inspiration for the design of our next generation inhibitors
came from examining the enzyme bound conformations of
MK-87185 and PL-1007 (Figure 1). It can be seen that the
morpholine oxygen of MK-8718 binds to the flap of the enꢀ
zyme (Ile50A and Ile50B) via a bridging water. In contrast, the
sulfonamide moiety present in PL-100 binds directly to the
Ile50A and Ile50B residues. This observation led us to design
the hybrid core shown below in Figure 1. The so designed
piperazine sulfonamide would retain the amine to form the key
interaction with the Aspꢀ25A and Aspꢀ25B acidic residues,
while the sulfonyl group would displace the bridging water
and bind directly to the flap Ile50A and Ile50B residues. In
the
(S)ꢀ
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Figure 1. Hybrid design concept based on the binding modes of MK-8718 and PL-100 (pdb codes 5IVT and 2QMP).
O
O
O
O
F
F
S
S
S
S
O
O
O
O
H
N
N
N
CHO
N
N
a
b
c
d
OH
OH
NO2
NH2
N
N
N
N
N
Boc
Boc
Boc
Boc
Boc
1
2 (71%)
3 (88%)
4 (21%)
5 (69%)
e
O
S
O
O
F
F
F
F
F
F
S
S
O
O
O
N
N
N
f
+
H
H
H
N
F
N
F
N
F
N
H
N
H
N
Boc
O
O
O
7 (45%)
8 (45%)
6 (83%)
Scheme 1a
aReagents and conditions: (a) PhSO2Cl, Hunig’s base, CH2Cl2, ꢀ78 °C to RT; (b) Dess–Martin periodinane, CH2Cl2, 0 °C; (c) K2CO3, 18ꢀ
crownꢀ6, (2ꢀnitrobenzyl)triphenylphosphonium bromide, DME, RT; (d) Pearlman's catalyst, H2 balloon, CF3CH2OH, RT; (e) 3,3ꢀBis(4ꢀ
fluorophenyl)propanoic acid, T3P®, Hunig’s base, EtOAc, RT; (f) TFA, CH2Cl2, RT, then Chiralpak® AD.
configuration, opposite to that which is preferred for the morꢀ
pholine core of MK-8718. This was in concurrence with reꢀ
sults from earlier modelling studies of the piperazine sulfonaꢀ
mide core, which showed the HIVꢀ1 protease binding conforꢀ
mation of the (S)ꢀenantiomer to be lower in energy than that of
the corresponding (R)ꢀenantiomer. Although piperazine sulꢀ
fonamide 7 displayed good antiviral activity, in vitro metabolꢀ
ic studies revealed that the unsubstituted left hand side of the
piperazine ring was susceptible to significant metabolic oxidaꢀ
tion. This prompted us to investigate whether functionalization
of the unsubstituted side of the piperazine ring would be tolerꢀ
ated with respect to antiviral activity. In order to introduce a
methyl group on the left hand side of the piperazine in a regioꢀ
and stereoꢀcontrolled manner, the route shown in Scheme 2
was
utilized.12
The
route
starts
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Figure 2. X-ray crystal structure of 7 bound to HIV-1 protease showing hydrogen bonding to Ile50A and Ile50B residues.
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Scheme 2a
aReagents and conditions: (a) LiAlH4, 2ꢀMeꢀTHF, 0 °C; (b) K2CO3, 18ꢀcrownꢀ6, (2ꢀnitrobenzyl)triphenylphosphonium bromide, DME,
RT; (c) Pearlman's catalyst, 50 psi H2, EtOAc/MeOH, RT; (d) 3,3ꢀBis(4ꢀfluorophenyl)propanoic acid, T3P®, Hunig’s base, EtOAc, RT;
(e) TFA, H2O, CH2Cl2; RT; (f) (i) PhSO2Cl, NEt3, DMF, 0 °C; (ii) Diazeneꢀ1,2ꢀdiylbismorpholinomethanone, PBu3, THF, RT; (g) (R)ꢀ2ꢀ
Aminopropanꢀ1ꢀol, 1,2ꢀDCE, 40 °C; (h) (i) Boc2O, NEt3, CH2Cl2, RT; (ii) Diazeneꢀ1,2ꢀdiylbismorpholinomethanone, PBu3, THF, RT; (i)
TFA, CH2Cl2, RT.
with readily available and configurationally stable Weinreb
amide 9. Reduction of 9 afforded aldehyde 10,13 which underꢀ
went Wittig olefination to give 11. Reduction of both the oleꢀ
fin and nitro groups afforded aniline 12, which was coupled
with 3,3ꢀbis(4ꢀfluorophenyl)propanoic acid to afford amide
13. Deprotection of 13 afforded amino alcohol 14 which was
converted to aziridine 15 via a sulfonylation and subsequent
intramolecular Mitsunobu14 reaction. Opening of aziridine 15
with (R)ꢀ2ꢀaminopropanꢀ1ꢀol, followed by Bocꢀprotection
afforded 16, which was converted to piperazine 17 via an inꢀ
tramolecular Mitsunobu reaction. Bocꢀdeprotection afforded
the desired target 18. Aziridine 15 was used to synthesize all
four methylꢀsubstituted isomers as shown in Figure 3. Altꢀ
hough 20 and 21 with methyl substituents at the 6ꢀposition of
the piperazine showed similar potency to unsubstituted piperaꢀ
zine 7, we were intrigued by the xꢀray crystal structure of the
less potent analogue 18 bound to HIVꢀ1 protease, as shown in
Figure 4. It can be seen that the phenyl group on the sulfonaꢀ
mide
moiety
and
the
meꢀ
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Figure 3.
viral ac-
(EC50)11 of
logues 18
formed
amino
hol open-
aziridine
Anti-
tivity
ana-
21
via
alco-
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–
ing of
15.
Figure 4. X-ray crystal structure of 18 bound to HIV-1 protease showing steric clash leading to design of a bicyclic piperazine.
thyl group on the piperazine ring lie in close proximity to each
other, likely creating an unfavorable steric interaction in the
binding conformation of the molecule. This observation led us
to consider forming a bicyclic ring, with a bond joining the
sulfone to the piperazine ring. Molecular modelling suggested
a three carbon chain length would be optimal for locking the
molecule in the bioactive conformation. Synthesis of this tarꢀ
get is shown in Scheme 3 and began with commercially availꢀ
able amino alcohol 22. Aziridine formation via sulfonylation
and Mitsunobu ring closure afforded intermediate 23. Aziriꢀ
dine 23 was opened with (R)ꢀ2ꢀaminopentꢀ4ꢀenꢀ1ꢀol and subꢀ
sequent Bocꢀprotection yielded 24. An intramolecular
Mitsunobu reaction gave piperazine 25 and subsequent magꢀ
nesium/MeOH mediated deprotection15 cleanly removed the
phenylsulfonyl moiety in the presence of both the NBoc and
OBn moieties to give 26. Sulfonylation of 26 gave metathesis
precursor 27 which underwent ring closure mediated by Zhan
Catalystꢀ1B16 to give bicyclic compound 28. Hydrogenation of
28 reduced the olefin and removed the benzyl group yielding
29. Dess–Martin oxidation, followed by Corey Fuchs alkyne
formation17 via dibromide 31 afforded alkyne 32. Sonogashira
coupling,18 followed by reduction of so formed 33 afforded
aniline 34. Coupling 3,3ꢀbis(4ꢀfluorophenyl)propanoic acid
with aniline 34 and subsequent Bocꢀdeprotection gave the
bicyclic target 35. We were pleased to observe that bicyclic
compound 35 retained good antiviral activity (EC50 = 21
nM).11 The xꢀray crystal structure of 35 bound to HIVꢀ1 proteꢀ
ase, as shown in Figure 5, revealed the expected binding
mode, whereby the sulfonyl group forms hydrogen bonds diꢀ
rectly to flap Ile50A and Ile50B residues, taking the place of
the bridging water present in the crystal structure of MK-8718
bound to HIVꢀ1 protease. With this new core in hand, we deꢀ
cided to incorporate the highly optimized pieces of MK-8718
into a molecule containing this core. The synthesis was carried
out starting with alkyne 32 as shown in Scheme 4. Soꢀ
nogashira coupling, followed by
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Scheme 3a
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a
(a) (i) PhSO2Cl, NEt3, DMF, 0 °C; (ii) DIAD, PBu3, THF, 0 °C; (b) (i) (R)ꢀ2ꢀAminopentꢀ4ꢀenꢀ1ꢀol, THF, 45 °C; (ii) Boc2O, NEt3,
CH3CN, 45 °C; (c) DIAD, PBu3, THF, RT; (d) Mg, MeOH, sonication, RT; (e) 2ꢀChloroethanesulfonyl chloride, NEt3, CH2Cl2, RT; (f)
Zhan Catalystꢀ1B, 1,2ꢀDCE, 50 °C; (g) Pearlman's catalyst, H2 balloon, EtOAc, RT; (h) Dess–Martin periodinane, CH2Cl2, RT; (i) PPh3,
CBr4, CH2Cl2, RT; (j) EtMgBr, THF, 0 °C; (k) 3ꢀFluoroꢀ2ꢀiodoaniline, (PPh3)2PdCl2, CuI, NEt3, CH3CN, 70 °C; (l) Pearlman's catalyst, H2
balloon, EtOH, RT; (m) (i) 3,3ꢀBis(4ꢀfluorophenyl)propanoic acid, T3P®, Hunig’s base, EtOAc, RT; (ii) HCl, dioxane, RT.
Ile50B
Ile50A
2.8 Å
2.9 Å
O
S
N
F
F
O
H
N
H
F
N
O
35
Antiviral EC50 = 21 ± 2 nM
aReagents and conditions: (a) (i) 5ꢀFluoroꢀ4ꢀiodopyridinꢀ3ꢀamine,
(PPh3)2PdCl2, CuI, NEt3, CH3CN, 70 °C; (ii) Pearlman's catalyst,
H2 balloon, EtOH, RT; (b) (2S,3S)ꢀ2ꢀazidoꢀ3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ
(3,5ꢀdifluorophenyl)propanoic acid, POCl3, pyridine, 0 °C; (c) (i)
PMe3, THF/H2O, 0 °C; (ii) HCl, dioxane/CH2Cl2, RT.
Asp25A
Asp25B
Figure 5. Antiviral activity (EC50)11 and X-ray crystal struc-
ture of 35 bound to HIV-1 protease.
which translated into potent antiviral activity (EC50 = 2.8 nM)
in a cell based assay. As shown in Table 1, this represents a
significant potency improvement relative to MKꢀ8718 (bindꢀ
ing IC50 = 700 pM, antiviral EC50 = 27 nM). In addition, the
potency of 38 compares favorably to market leading HIVꢀ1
protease inhibitors Atazanavir and Darunavir.
In summary, through a series of structure based design iteraꢀ
tions, a novel bicyclic piperazine sulfonamide aspartyl proteꢀ
ase binding core was identified. This core produced an 60ꢀfold
increase in HIVꢀ1 protease binding affinity and a 10ꢀfold inꢀ
crease in antiviral activity relative to MK-8718.
reduction afforded amine 36. Coupling of amine 36 with
(2S,3S)ꢀ2ꢀazidoꢀ3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ(3,5ꢀ
difluorophenyl)propanoic acid5 gave amide 37, which, after
azide reduction and Bocꢀdeprotection produced thefinal comꢀ
pound 38. This compound showed exquisite enzyme binding
affinity (IC50 = 12 pM) for HIVꢀ1 protease,
Scheme 4a
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(4) Midde, N. M.; Patters, B. J.; Rao, P.; Cory, T. J.; Kumar, S. Invesꢀ
tigational protease inhibitors as antiretroviral therapies. Expert Opin.
Investig. Drugs, 2016, 25 (10), 1189–1200.
1
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5
6
7
8
Table 1. Enzyme affinity and antiviral activity of key mol-
ecules
(5) Bungard, C. J.; Williams, P. D.; Ballard, J. E.; Bennett, D. J.;
Beaulieu, C.; BahnckꢀTeets, C.; Carroll, S. S.; Chang, R. K.; Dubost,
D. C.; Fay, J. F.; Diamond, T. L.; Greshock, T. J.;Hao, L.; Holloway,
K. M.; Felock, P. J.; Gesell, J. J.; Su, H.; Manikowski, J. J.; McKay,
D. J.; Miller, M.; Min, X.; Molinaro, C.; Moradei, O. M.; Nantermet,
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Sanjay, S. K.; Truong, V. L.; Vijayasaradhi, S.; Wiscount, C. M.;
Vacca, J. P.; Crane, S. N.; McCauley, J. A. Discovery of MKꢀ8718,
an HIVꢀ1 protease inhibitor containing a novel morpholine aspartate
binding group. ACS Med. Chem. Lett., 2016, 7 (7), 702–707.
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Heinrikson, R. L.; Schneider, J.; Kent, S. B.; Wlodawer, A., Structure
at 2.5ꢀA resolution of chemically synthesized human immunodefiꢀ
ciency virus type 1 protease complexed with a hydroxyethyleneꢀbased
inhibitor, Biochemistry 1991, 30, (6), 1600ꢀ9.
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loway, M. K.; Wu, J. J.; Stranix, B. R.; Panchal, C.; Wainberg, M. A.;
Vacca, J. P. J. PLꢀ100, a novel HIVꢀ1 protease inhibitor displaying a
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(8) Tiwari, P. K.; Aidhen, I. S. A Weinreb amide based building block
for convenient access to β,βꢀdiarylacroleins: Synthesis of 3ꢀ
arylindanones. Eur. J. Org. Chem. 2016, 15, 2637ꢀ2646.
Enzyme19
IC50 (pM)
Antiviral11
EC50 (nM)
Compound
700 ± 600
12 ± 1
27 ± 7
2.8 ± 0.4
12 ± 4
7 ± 2
MK-8718
38
9
40 ± 30
13 ± 3
Atazanavir
Darunavir
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ASSOCIATED CONTENT
Supporting Information
Synthetic experimental details for the synthesis of 7, 8, 18 – 21,
and 35, descriptions of primary biological assays, procedures for
coꢀcrystallization studies, and a table of crystallographic statisꢀ
tics, along with in vivo rat pharmacokinetic data for 7, 18, 20, and
21 are available free of charge (PDF) on the ACS Publications
website at DOI: xxxxxx. Xꢀray crystallographic data for 7, 18, 19,
20, 21, and 35 bound to HIVꢀ1 protease have been deposited in
the RCSB protein data bank (pdb codes 6B36, 6B3C, 6B3F,
6B38, 6B3G, 6B3H).
(9) Dess, D. B.; Martin, J. C. Readily accessible 12ꢀIꢀ5 oxidant for the
conversion of primary and secondary alcohols to aldehydes and
ketones. J. Org. Chem. 1983, 48, 4155ꢀ4156.
(10) Carmosin, R. J.; Carson, J. R.; Pitis, P. M. Preparation of octahyꢀ
dropyrroloꢀ[3,4ꢀc]carbazoles
WO9965911A1.
useful
as
analgesic
agents.
AUTHOR INFORMATION
Corresponding Author
(11) Assay for inhibition of viral infection as described in the supportꢀ
ing information, run in the presence of 50% NHS, potency reported as
a EC50 (average of at least n=2 runs).
(12) Crestey, F.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Expedited
protocol for construction of chiral regioselectively Nꢀprotected monoꢀ
substituted piperazine, 1,4ꢀdiazepane building blocks. J. Org. Chem.,
2009, 74, (15), 5652–5655.
(13) Sawamura, M.; Nakayama, Y.; Kato, T.; Ito, Y. Gold(I)ꢀ
catalyzed asymmetric aldol reaction of NꢀmethoxyꢀNꢀmethylꢀαꢀ
isocyanoacetamide (αꢀisocyano Weinreb amide). An efficient syntheꢀ
sis of optically active βꢀhydroxy αꢀamino aldehydes and ketones. J.
Org. Chem. 2016, 15, 2637ꢀ2646.
(14) Samanta, K.; Panda, G. Regioselective ringꢀopening of amino
acidꢀderived chiral aziridines: an easy access to cisꢀ2,5ꢀdisubstituted
chiral piperazines. Chem. Asian J. 2011, 6, 189 – 197.
(15) Nyasse, B.; Grehn, L.; Ragnarsson, U. Mild, efficient cleavage of
arenesulfonamides by magnesium reduction. Chem. Commun. 1997,
11, 1017ꢀ1018
(16) Zhan, Z. Preparation of ruthenium complex ligand, ruthenium
complexes, supported ruthenium complex catalysts for olefin metathꢀ
esis, WO 2007003135A1.
(17) Corey, E. J.; Fuchs, P. L. Synthetic method for conversion of
formyl groups into ethynyl groups. Tetrahedron Lett. 1972, 36, 3769ꢀ
72
(18) Sonogashira, K., Development of PdꢀCu catalyzed crossꢀ
coupling of terminal acetylenes with sp2ꢀcarbon halides. J. Organ-
omet. Chem. 2002, 653, (1ꢀ2), 46ꢀ49.
(19) Assay for inhibition HIVꢀ1 protease as described in the supportꢀ
ing information, potency reported as an IC50 (average of at least n=2
runs).
* Eꢀmail: christopher_bungard@merck.com
Phone: 215ꢀ652ꢀ5002
ABBREVIATIONS
HIV = human immunodeficiency virus; Ile = isoleucine; Asp =
aspartic acid; Boc = tertꢀbutyloxycarbonyl; 1,2ꢀDCE = 1,2ꢀ
dichloroethane; DIAD = diisopropyl azodicarboxylate; DME =
1,2ꢀdimethoxyethane; DMF = dimethylformamide; EtOAc = ethyl
acetate; MeOH = methanol; NEt3 = triethylamine; PBu3 = tribuꢀ
tylphosphine; RT
=
room temperature; T3P®
=
1ꢀ
propanephosphonic anhydride; THF = tetrahydrofuran; TFA =
trifluoroacetic acid.
REFERENCES
(1) EricksonꢀViitanen, S.; Manfredi, J.; Viitanen, P.; Tribe, D. E.;
Tritch, R.; Hutchison, C. A., 3rd; Loeb, D. D.; Swanstrom, R., Cleavꢀ
age of HIVꢀ1 gag polyprotein synthesized in vitro: sequential cleavꢀ
age by the viral protease. AIDS Res Hum Retroviruses 1989, 5, (6),
577ꢀ91.
(2) Kohl, N. E.; Emini, E. A.; Schleif, W. A.; Davis, L. J.; Heimbach,
J. C.; Dixon, R. A. F.; Scolnick, E. M.; Sigal, I. S., Active human
immunodeficiency virus protease is required for viral infectivity.
Proc. Natl. Acad. Sci. U. S. A. 1988, 85, (13), 4686ꢀ90.
(3) Ghosh, A. K.; Osswald, H. L.; Prato, G. Recent progress in the
development of HIVꢀ1 protease inhibitors for the treatment of
HIV/AIDS. J. Med. Chem., 2016, 59 (11), 5172–5208.
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