SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding

Article abstract of DOI:10.1016/j.bmcl.2017.02.030

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.

Full text of DOI:10.1016/j.bmcl.2017.02.030

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
SAR of amino pyrrolidines as potent and novel protein-protein
interaction inhibitors of the PRC2 complex through EED binding
⇑
Michael L. Curtin , Marina A. Pliushchev, Huan-Qiu Li, Maricel Torrent, Justin D. Dietrich, Clarissa G. Jakob,
Haizhong Zhu, Hongyu Zhao, Ying Wang, Zhiqin Ji, Richard F. Clark, Kathy A. Sarris, Sujatha Selvaraju,
Bailin Shaw, Mikkel A. Algire, Yupeng He, Paul L. Richardson, Ramzi F. Sweis, Chaohong Sun,
Gary G. Chiang 1, Michael R. Michaelides
AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as
novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the
indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and
cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-
concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model.
X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 17 January 2017
Revised 10 February 2017
Accepted 14 February 2017
Available online xxxx
Keywords:
PRC2
EED
Protein-protein interaction inhibitor (PPI)
Cancer
Polycomb-group proteins mediate gene silencing by modifying
histone tails and altering high-order chromatin structure. Poly-
comb repressive complex 2 (PRC2) catalyzes the mono-, di- and
tri-methylation of histone H3 at lysine 27 and is essential for ver-
tebrate development and cellular differentiation.1 Trimethylation
of lysine 27 of histone 3 (H3K27me3) is an epigenetic hallmark
of repressed chromatin and results in transcriptional repression.
The PRC2 complex consists of three core components: SUZ12 (sup-
pressor of zeste 12); EZH2 (enhancer of zeste homolog 2) or its
close homolog EZH1; and EED (embryonic ectoderm develop-
ment).2 EZH2 is the catalytic subunit responsible for histone
methylation and EED has both a scaffolding function as well as
an H3K27me3-binding function.3 The interaction between EED
and chromatin is achieved through the binding of trimethyl lysine
into the central pocket or ‘aromatic cage’ formed by the seven WD-
40 repeats of EED.4 The direct association of the PRC2 complex to
H3K27me3 through EED catalyzes the successive methyltrans-
ferase activity of PRC2 and results in the propagation of the
H3K27me3 histone mark with subsequent silencing of target genes
through generation of heterochromatin.5
Multiple cancer genome sequencing studies have revealed that
the function of the PRC2 complex and H3K27 methylations are fre-
quently disrupted on the genetic level and, in many human can-
cers, hyper-methylation of H3K27 results in the abnormal
silencing of genes that would otherwise control proliferation and
induce cellular differentiation.6 The importance of the PRC2 com-
plex in tumorigenesis has been validated by the robust in vivo
activity of multiple EZH2 inhibitors which disrupt PRC2 function
by blocking H3K27 methylation via competition with methyl-
donating co-factor S-adenosyl methionine (SAM);7 several of these
agents have advanced to cancer clinical trials (e.g., GSK126,8
EPZ64389). We hypothesized that inhibition of H3K27me3-binding
to EED would be an alternative approach to disrupt the function of
the PRC2 complex. Studies in the literature, including those of sta-
bilized
a-helix EZH2 peptides that selectively inhibit H3K27
trimethylation,10 provided precedent for this approach and it was
anticipated that such ‘EED inhibitors’ would be, at the very least,
complementary to the more mature EZH2 inhibitors.
The effort to validate this hypothesis began with a high-
throughput, small molecule screen utilizing a thermal shift assay
(TSA) with EED protein11 and led to the identification of pyrrolidine
1 (Fig. 1), an efficient but modestly potent ligand of EED. Orthogo-
nal methods confirmed that 1 is stoichiometrically bound by EED
protein and allosterically inhibits activity of PRC2 complex
in vitro;12 X-ray crystallography revealed that this binding occurs
⇑
Corresponding author at: AbbVie, 1 North Waukegan Road, AP10/Rm 207, North
Chicago, IL 60064-3500, United States.
E-mail address: mike.curtin@abbvie.com (M.L. Curtin).
Current address: eFFECTOR Therapeutics, 11180 Roselle St., Suite A, San Diego, CA
1
92121, United States.
http://dx.doi.org/10.1016/j.bmcl.2017.02.030
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Curtin M.L., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.02.030

2
M.L. Curtin et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
1 occupies the H3K27me3 peptide binding pocket, including that
of the trimethyllysine itself, thus confirming competitive binding
against the peptide. While the H3K27me3- and pyrrolidine-bound
structures are globally very similar, our structure reveals a remark-
able remodeling of the H3K27me3 binding pocket to accommodate
the pyrrolidine ligand. Substantial rotamer changes in Trp364,
Tyr365 and Arg367 (Fig. 2a) disrupt the aromatic cage which ordi-
narily accommodates the trimethyllysine ammonium to expose a
larger, more druggable binding pocket. This alternate rotamer ori-
entation of Tyr365 creates a new aromatic cage consisting of three
residues (Phe97, Tyr148, Tyr365) which now accommodates the
pyrrolidine core of 1 (Fig. 2b). The p-methoxybenzyl ring occupies
the space previously held by Tyr365 while Arg367 adjusts to make
a cation-p interaction; other key interactions include a hydrogen
bond from the dimethylamine to a highly-coordinated water as
well as highly optimized hydrophobic and van der Waals interac-
tions between the rings of the indole and protein (i.e., Phe97,
Tyr148, Tyr365, Arg414). This initial structure suggested to us that
the N-benzyl and indole moieties would be amenable to
modification.
Fig. 1. Structures of screening hit 1 and tool compound 212 with molecular weight,
EED binding potency and ligand efficiency (LE = 1.4 Â pKi/# of heavy atoms).
Compound 1 is racemic and compound 2 is a mixture of two diastereomers with
pyrrolidine stereochemistry as shown.
The SAR work began with a thorough survey of N-benzyl sub-
stituents and revealed a strong preference for 2,6-disubstitution
(Table 1). While the high throughput screening hit 1 and the
at the H3K27 binding site of EED (see below). We now disclose the
SAR and physicochemical characterization of this pyrrolidine series
which led to the identification of our tool compound 2,12 a novel
inhibitor of the PRC2 complex through disruption of EED/
H3K27me3 binding.13
N-benzyl analog
9 were only modest ligands for EED, the
2-bromo-6-fluorobenzyl compound 10 had double-digit nanomo-
lar binding potency as did the 2-chloro-6-fluorobenzyl (11) and
2-fluoro-6-methylbenzyl (12) analogs. The importance of 2,6-dis-
ubstitution was further demonstrated by the somewhat attenuated
binding potency of the 2-fluorobenzyl (13) and 2-fluoro-5-methyl-
benzyl (14) analogs although 2-fluoro substitution alone was
generally beneficial to potency (data not shown). Regarding the
pyrrolidine stereochemistry, The (3R,4S) single enantiomer 10
was 5-fold more potent than the (3S,4R) enantiomer (not shown)
and exemplified the modest but consistent preference of EED for
the (R)-dimethylamino pyrrolidine enantiomers.
In an attempt to restrict the conformational freedom of
the benzyl moiety and increase the ligand-receptor contact while
enforcing the favorable binding conformation observed with the
o-methoxybenzyl in the crystal structure of analog 1, we annulated
the o-methyl and benzyl methylene of 12 into an indane bicycle
(15). While this provided a compound that was an equipotent bin-
der with 12, this analog was substantially more potent cellularly;
whereas benzyl analogs 10, 11 and 12 are micromolar inhibitors
of H3K27 trimethylation and proliferation of the Pfeiffer cell line,
indane 15 is a submicromolar inhibitor of histone trimethylation
with modestly improved antiproliferative activity. The enhance-
ment of cellular activity was a robust benefit of replacing benzyl
with indane (see Table 5 below); the origin of this potency boost
is unclear and cannot be explained by cellular permeability as
compounds 10, 11, 12 and 15 are all highly permeable (1–
3 Â 10À6 cm/s) as measured in the parallel artificial membrane
permeability assay (PAMPA).
The synthesis of pyrrolidine 1 is shown in Scheme 1 and exem-
plifies the preparation of many of the compounds in this work. The
a,b-unsaturated nitro 3 was treated with azomethine ylide precur-
sor 4 in the presence of TFA to give pyrrolidine 5 via [3+2] dipolar
cycloaddition; the (E)-alkene exclusively provided racemic pyrro-
lidine with trans stereochemistry.14 Nitro reduction of 5 with
Raney-Ni/hydrogen and reductive amination of the resulting
amine 6 with formaldehyde/sodium triacetoxyborohydride pro-
vided dimethylamino pyrrolidine 7. Hydrogenolysis in the pres-
ence of palladium hydroxide gave pyrrolidine
8 which was
converted to compound 1 by reductive amination with o-methoxy-
benzaldehyde in the presence of sodium triacetoxyborohydride.
Modification of ylide precursor 4 allowed for the convenient prepa-
ration of substituted-benzyl intermediates while chiral supercriti-
cal fluid chromatography (SFC) of intermediates such as nitro 5 or
N-benzyl 7 provided analogs as single enantiomers. Intermediates
6 and 8 allowed for the rapid examination of amino substituents
while indole and pyrrolidine modification/replacement were the
most difficult as they required distinct syntheses.
New analogs were assessed for EED binding potency using a TR-
FRET assay with a pyrrolidine-based Oregon green (488) probe.15
Potent EED ligands were then simultaneously examined in cellular
assays that measured selective inhibition of H3K27 trimethylation
over six days in several human tumor cell lines (e.g., G-401,
OCILY19)15 and proliferation over ten days in multiple tumor cell
lines including Pfeiffer (human diffuse large B-cell lymphoma).15
These cell lines were chosen, in part, for their known phenotypic
sensitivity to EZH2 inhibitors and the selectivity of the antiprolifer-
ative activity was routinely counter-screened against cell lines
known to be insensitive to EZH2 inhibition (e.g., human RD). Com-
pounds were also evaluated in a primary ADME screen that
included mouse in vitro intrinsic clearance and microsomal protein
binding.
Regarding indane stereochemistry, comparison of binding
potencies of the single enantiomer 15, bearing an (S)-indane stere-
ocenter, and indane 16, bearing an (R)-indane stereocenter,
demonstrates the recurring preference for the (S)-indane stereo-
center. An overlay of the X-ray crystal structures of protein bound
benzyl 10 (PDB ID: 5U8A) and indane 15 (PDB ID: 5U8F) in Fig. 3
demonstrates the desired conformational restriction resulting from
the indane and while it’s not clear why a large enhancement in
binding potency was not observed, the preference for the (S)-
indane stereochemistry is readily understood.
As mentioned above, the structure of EED (residues
D
77-441-
hereafter referred to as
D
EED)4 complexed with pyrrolidine 1
(PDB ID: 5U69) was determined by co-crystallization;16 compar-
ison of this structure with a previously published structure of
EED binding an H3K27me3 peptide (PDB ID: 3JZG)4 revealed that
Physicochemically, this initial set of compounds was very lipo-
philic with cLogP’s of 4–5 and tPSA’s of 10–20 (3/75 rule fail); not
surprisingly, the intrinsic clearance in mouse microsomes of the
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M.L. Curtin et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
Scheme 1. Reagents: (a) cat. trifluoroacetic acid, DCM, 0 °C then rt, 78%; (b) Zn, sat. NH4Cl, THF/EtOH, 0 °C then rt, 36%; (c) HCHO, NaCNBH4, cat. acetic acid, MeOH, 84%; (d)
30 psi H2, wet 20% Pd(OH)2/C, trifluoroethanol, 74%; (e) 2-methoxybenzaldehyde, NaBH(OAc)3, 1,2-dichloroethane, 70%.
Fig. 2. (a) Superposition of 1-
protein in white) shows how 1 induces two key residues for binding trimethyllysine, Tyr365 and Trp364, to adopt alternate conformations and form a druggable binding
pocket. (b) Binding site interactions of 1. Hydrogen bonds are indicated by dashed lines and the 2Fo-Fc electron density map calculated at 1.28 Å for 1 is contoured at 1
DEED complex (PDB ID: 5U69; 1 as orange sticks, protein in blue) and D
EED-H3K27me3 complex (PDB ID: 3JZG;4 peptide as yellow sticks,
r
.
compounds in Table 1 was very high (>1000 L/h/kg) when microso-
mal binding was factored in. Using the pIC50 values of the G-401
trimethylation assay, the lipophilic efficiency (LipE)17 was mod-
estly increased between compounds 12 (0.6) and 15 (1.7) but it
was clear that an important goal of subsequent SAR would be to
reduce the lipophilicity of these compounds and increase the LipE
values which would presumably provide lower intrinsic clearance
and reasonable PK profiles.
In an effort to better define the SAR of indane binding and intro-
duce more polarity to these compounds, analogs such as those in
Table 2 were prepared. Indanes 17 and 18 demonstrated the mod-
est but persistent benefit of the ‘ortho’ fluorine while tetrahydron-
aphthalene 19 showed that small changes to the indane system
would usually result in some loss of binding potency. Addition of
heteroatoms to the indane, as in 20 and 21, reduced cLogP values
(3.2 and 3.8, respectively) and intrinsic clearance (data not shown)
but gave unacceptable losses in potency. Replacement of benzyl or
indane with heterocycles such as imidazopyridine (22), imidazopy-
rimidine (23), imidazole (24) or pyrazole (25) completely abro-
gated EED binding. Overall, modification or replacement of the
benzyl or indane functionality indicated that the binding at the
‘indane pocket’ and the electronics of Arg367 stacking were very
sensitive to structural changes.
While no data is provided here, we found that any modification
to the dimethylamino moiety or to the pyrrolidine ring was detri-
mental to binding potency, consistent with the crystal structure
data that indicated a highly optimized hydrogen bond and van
der Waals interactions between the dimethylamino pyrrolidine
and EED protein with bound waters.
The initial crystal structure data indicated that the indole of this
series should be modifiable and, more importantly, that the ‘top
edge’ of the indole or any indole replacement projects out towards
water-exposed protein and could represent an opportunity to add
polar functionalities that would reduce the lipophilicity of these
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M.L. Curtin et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Table 1
SAR of N-benzyl substituents.
Cmpd*
R1
TR-FRET binding15 Ki (nM)
6-day H3K27me3
Pfeiffer 10-day CTG15 IC50 (nM)
AlphaLISA15 IC50 (nM)
G-401
OCILY19
1
9
600
1500
10*
11
13
53
12
4100
6900
2400
8300
9500
3300
3300
>10,000
2400
12*
13
14
330
160
15*
16*
11
290
660
1100
129
*
All compounds are racemic unless noted with an asterisk.
EED binders. In fact, addition of a carboxamide to the 4-position of
the indole (e.g., 26 in Table 3) was well tolerated and lowered the
cLogP (3.9 versus 5.3 for 10). Replacement of indole with phenyl
(27) gave an encouragingly modest loss in binding potency and
would provide a valuable scaffold for further functionalization
(see below) while pyridyl (28) was also reasonably tolerated. In
an effort to increase sp3 character, the indole was also replaced
with various alkyls, cycloalkyls and non-aromatic heterocycles
and we found that while some (e.g. 29 and 32) were not suitable,
others (e.g., 30 and 31) were surprisingly well-tolerated despite
their small size and simplicity.
Building on the SAR above, Table 4 shows examples of our effort
to project polar functionalities out of the EED binding site towards
solvated protein using para-substituted phenyl or other linear scaf-
folding units; compounds bearing meta-substituted phenyls were
substantially less potent (data not shown). Whereas the 4-benza-
mide analog 34 was roughly equipotent with the unsubstituted
phenyl (33), projecting the polar functionality further out of the
Fig. 3. Superposition of 10-
DEED complex (PDB ID: 5U8A; 10 as green sticks) and
15- EED complex (PDB ID: 5U8F; 15 as cyan sticks).
D
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M.L. Curtin et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
5
Table 2
SAR of indane substitution and replacement.
Cmpd*
R1
TR-FRET binding15 Ki (nM)
11
Cmpd*
R1
TR-FRET binding15 Ki (nM)
610
15
21*
F
F
O
17
18
19
20
45
22
23
24
25
>50,000
>50,000
>50,000
>50,000
N
N
66
F
N
N
N
78
N
N
260
N
N
N
*
All compounds are racemic unless noted with an asterisk.
Table 3
SAR of indole substitution and replacement.
R1
N
F
N
Br
Cmpd*
R1
TR-FRET binding15 Ki (nM)
13
Cmpd*
R1
TR-FRET binding15 Ki (nM)
230
10*
29
N
26*
23
30
O
59
O
N
N
27
28
Ph
78
49
31
32
71
Me
380
N
*
All compounds are racemic unless noted with an asterisk.
protein using a pyrazole (35) or piperazinyl (36, 37) ‘extension’
provided single-digit nanomolar binders. The use of other combi-
nations of linkers as in examples 38, 39 and 40 provided potent
analogs as well. The X-ray crystal structure of phenyl pyrazole 35
(Fig. 4) confirmed the notion that the polar terminus rests in a
water-exposed area of the protein near several polar residues,
although no obvious hydrogen bond between the carboxamide
and protein or protein-bound water was observed. Not surpris-
ingly, these polar modifications reduced the cLogP of these com-
pounds by several log units and resulted in compounds with
improved unbound in vitro intrinsic clearance versus those of the
compounds in Table 1.
Combining the 2-fluoroindane substituent with water-exposed,
polar functionalities reliably provided potent EED binders with
substantial cellular activity as demonstrated by compounds 41–
44 in Table 5. A few of these sub-nanomolar EED binders, including
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M.L. Curtin et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Table 4
SAR of indole replacements bearing polar functionalities.
Cmpd*
R1
TR-FRET binding15 Ki (nM)
cLogP
mouse CLint,u,scaled (L/hr/kg)
33
34
Ph
56
18
4.5
3.0
1300
97
35
36
2.6
2.6
2.2
3.5
225
170
37
2.1
5.0
9900
38
0.65
2.9
39
40
5.3
4.6
1.6
276
268
-0.6
*
All compounds are racemic.
the PoC compound
2
(PDB ID: 5K0 M),12 gave double-digit
(cLogP’s >3, tPSA <50). Accordingly, the intrinsic clearance of these
potent analogs was still high and translated into suboptimal in vivo
PK profiles.19 While this profile necessitated high, subcutaneous
doses of 2 in the PoC tumor inhibition studies, this inhibitor proved
to be a valuable tool compound.
nanomolar inhibition of H3K27 trimethylation and selective
antiproliferative activity in the Pfeiffer cell line.18 The combination
of lowered cLogP values and improved cellular activities resulted in
considerably improved LipE values (e.g., 3.4 for 2 versus 0.6 for
12);17 despite improvements to polarity, the EED binders with
acceptable biological activity remained stubbornly lipophilic
While the detailed in vitro and in vivo biological characteriza-
tion of analog 2 has recently been published elsewhere and is
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M.L. Curtin et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
7
Table 5
Data for selected examples of optimized analogs including PoC compound 2.
Cmpd*
R1
TR-FRET
6-day H3K27me3
Pfeiffer 10-day CTG15
IC50 (nM)
cLogP
3.4
LipE#
4.1
mouse CLint,u,scaled
(L/h/kg)
binding15 Ki (nM)
AlphaLISA15 IC50 (nM)
G-401
33
OCILY 19
41*
0.29
50
33
220
42
0.45
230
280
130
3.2
3.4
120
43
0.74
190
100
98
3.0
3.7
44
1.0
31
57
180
65
69
3.7
3.8
3.8
3.4
1100
660
2*
0.31
44
*
All compounds are racemic unless noted with an asterisk; all compounds are epimeric mixtures at the indane stereocenter.
LipE = pIC50 -cLogP where IC50 is that for the G-401 6-day H3K27me3 AlphaLISA.
#
beyond the scope of this paper,12 it is important to mention that
when mice inoculated with the human Pfeiffer cell line were dosed
with 2 (300 mg/kg, s.c., two times per week for 5 weeks), substan-
tial on-target tumor growth inhibition was observed for >10 weeks
beyond dosing. This efficacy compared favorably to that of the clin-
ical EZH2 inhibitor GSK126 dosed at 50 mg/kg, i.p., QDx36. This
result, in part, validated the hypothesis that inhibition of
H3K27me3-binding to EED could be an alternative approach to dis-
rupting the function of the PRC2 complex.
In summary, we have used structure-based drug design to opti-
mize the modestly potent EED ligand 1 into sub-nanomolar, indane
pyrrolidine ligand 2 which displays potent, target-based cellular
activity and significant in vivo efficacy in a mouse tumor model.
This crystallography-driven work used ring constraint and the
strategic placement of polar functionalities to increase potency
while decreasing cLogP. Compound 2 represents a valuable tool
to further interrogate the role of the PRC2 complex in tumor initi-
ation and maintenance.
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M.L. Curtin et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
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nan for the tumor growth inhibition data. All authors are employ-
ees or former employees of AbbVie. This study was sponsored by
AbbVie. AbbVie contributed to the study design, research, and
interpretation of data, writing, reviewing, and approving the
manuscript.
Use of the IMCA-CAT beamline 17-ID at the Advanced Photon
Source was supported by the companies of the Industrial Macro-
molecular Crystallography Association through a contract with
Hauptman-Woodward Medical Research Institute. Use of the
Advanced Photon Source was supported by the U.S. Department
of Energy, Office of Science, Office of Basic Energy Sciences, under
Contract No. DE-AC02-06CH11357.
Research described in this paper was performed using beamline
08ID-1 at the Canadian Light Source, which is supported by the
Canada Foundation for Innovation, Natural Sciences and Engineer-
ing Research Council of Canada, the University of Saskatchewan,
the Government of Saskatchewan, Western Economic Diversifica-
tion Canada, the National Research Council Canada, and the
Canadian Institutes of Health Research.
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15. For assay details, see the Supplementary Information and Ref.
12
.
16. For crystallization, data collection and structure refinement procedures, see the
Supplementary Information.
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18. It should be mentioned that two-diastereomer mixtures, (3R,4S) at the
pyrrolidine but epimeric at the indane stereocenter as in 41 and 2, were used
for biological characterization and in vivo studies due to synthetic availability.
However, this could be justified by the fact that the two-diastereomer mixture
of compounds such as 41 were virtually indistinguishable in our assays from
the single diastereomer bearing an (S)-indane stereocenter (data not shown).
19. For example, a 3 mg/kg intravenous dose of compound 2 in mouse had a total
clearance of 1.7 L/h/kg and a half-life of 1 h with no oral bioavailability.
A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2017.02.
030.
Please cite this article in press as: Curtin M.L., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.02.030