Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.06.063

A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.

Full text of DOI:10.1016/j.bmcl.2016.06.063

Accepted Manuscript
Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A
inhibitors
Michael P. Dwyer, Kerry M. Keertikar, Lei Chen, Ling Tong, Oleg Selyutin,
Anilkumar G. Nair, Wensheng Yu, Guowei Zhou, Brian J. Lavey, De-Yi Yang,
Michael Wong, Seong Heon Kim, Craig A. Coburn, Stuart B. Rosenblum,
Qingbei Zeng, Yueheng Jiang, Bandarpalle B. Shankar, Razia Rizvi, Amin A.
Nomeir, Rong Liu, Sony Agrawal, Ellen Xia, Rong Kong, Ying Zhai, Paul
Ingravallo, Ernest Asante-Appiah, Joseph A. Kozlowski
PII:
S0960-894X(16)30674-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.06.063
BMCL 24016
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 May 2016
23 June 2016
24 June 2016
Please cite this article as: Dwyer, M.P., Keertikar, K.M., Chen, L., Tong, L., Selyutin, O., Nair, A.G., Yu, W., Zhou,
G., Lavey, B.J., Yang, D-Y., Wong, M., Kim, S.H., Coburn, C.A., Rosenblum, S.B., Zeng, Q., Jiang, Y., Shankar,
B.B., Rizvi, R., Nomeir, A.A., Liu, R., Agrawal, S., Xia, E., Kong, R., Zhai, Y., Ingravallo, P., Asante-Appiah, E.,
Kozlowski, J.A., Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.06.063
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bioorganic & Medicinal Chemistry Letters
Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A
inhibitors
Michael P. Dwyera,* Kerry M. Keertikara, Lei Chena, Ling Tonga, Oleg Selyutina, Anilkumar G. Naira,
Wensheng Yua, Guowei Zhoua, Brian J. Laveya, De-Yi Yanga, Michael Wonga, Seong Heon Kima, Craig A.
Coburna, Stuart B. Rosenbluma, Qingbei Zenga, Yueheng Jianga, Bandarpalle B. Shankara, Razia Rizvia,
Amin A. Nomeirb, Rong Liuc, Sony Agrawalc, Ellen Xiac, Rong Kongc, Ying Zhaic, Paul Ingravalloc, Ernest
Asante-Appiahc and Joseph A. Kozlowskia
aDiscovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd. Kenilworth, NJ 07033, USA
bDrug Metabolism, Merck Research Laboratories, 2000 Galloping Hill Rd. Kenilworth, NJ 07033, USA
cDiscovery Biology, Merck Research Laboratories, 2000 Galloping Hill Rd. Kenilworth, NJ 07033, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV
NS5A inhibitors to examine the influence of modifications of this region on the overall HCV
virologic resistance profiles.
Accepted
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Hepatitis C
NS5A
Infectious Diseases
indole
capping
structural (NS) viral proteins such as NS2, NS3 (protease),
NS4A, NS4B, NS5B (polymerase), and NS5A. NS5A is a large
1. Introduction
According to the World Health Organization, over 130-150
million individuals have been infected worldwide with hepatitis
C virus (HCV) with about three million new patients contracting
HCV each year.1 While HCV is often asymptomatic, it can
progress to chronic hepatitis leading to liver cirrhosis and in
many cases hepatocellular carcinoma. Previously, the standard
of care for the treatment of HCV was a combination of
interferon-α (PEG-IFN-α) and ribavirin (RBV) which
demonstrated poor tolerability as well as only moderate efficacy
towards the most predominant genotype (GT), GT1, in the
world.2 More recently, two HCV protease inhibitors, boceprevir
and telaprevir, have been added to the above-mentioned standard
of care to provide a sustained virologic response (SVR) of 70–
80% in genotype 1 HCV-infected subjects.3 The current focus
towards improving response rates and curing HCV has centered
around the identification of superior direct-acting antiviral agents
(DAAs) which might confer more effective, tolerable, interferon-
sparing treatment regimens. Towards this end, drug discovery
efforts have centered upon the discovery of new therapeutic
agents interfering with HCV replication which include non-
phosphoprotein (49 kDa) which has no known enzymatic activity
but has been shown to be essential for viral RNA replication.4
Although the exact role of this protein in the HCV replication
cycle remains uncertain, the value of NS5A inhibition as a
therapeutic target5,6 has been demonstrated in the clinic and this
area of study remains active in both academia and the
pharmaceutical industry.7 To date, four NS5A inhibitors have
gained regulatory approval and are shown in Figure 1.8-11

Figure 2. Retrosynthetic analysis of tetracyclic indole capped derivatives.
Initial chemistry efforts focused upon preparation of the
required methyl carbamate (Moc) caps from -amino acids
which are shown in Scheme 1. Treatment of 5 with methyl
chloroformate under Schotten-Baumann conditions afforded the
Moc-protected amino acids 6 which could be used directly
without purification.
Figure 1. Approved HCV NS5A inhibitors.8-11
Scheme 1. a) ClCO2Me, NaOH, NaHCO3, H2O.
In a continued effort to explore the tetracyclic indole class of
NS5A inhibitors, efforts were undertaken to examine the impact
of structural modifications of the two imidazole L-Pro-L-Val
methyl carbamate (Moc) regions (Figure 1). While a brief SAR
exploration had been previously conducted in an earlier series
(MK-4882) to replace the two terminal L-valine methyl
carbamate moieties (Val Moc),11 we sought to explore the impact
on the virologic profile of broader changes to the amino acid end
caps in the current series.
In addition to the Moc amino acid caps from Scheme 1,
several (R)-phenyl glycine-derived caps were prepared directly
from the commercially available substituted (R)-phenyl glycine
starting materials shown in Scheme 2.12 Treatment of 7 with 1,4-
dibromobutane under basic conditions afforded acid 8 while the
corresponding dialkylated acids 9 were prepared by reductive
amination in the presence of excess aldehyde (Scheme 2).
In order to access the “capped” tetracyclic indole
derivatives, a flexible, convergent synthetic route to assemble
these derivatives was developed, which is shown in Figure 2.
The parent molecule, 1, was disconnected into a chiral tetracyclic
indole core (2), a common bromo imidazole Boc-L-proline
fragment 3, and different carboxylic acid fragments 4 which
would provide the diversity for this study. At the outset, the
tetracyclic indole core bearing the (S)-phenyl configuration at the
aminal position was selected as a point for comparison to the
impact that the structural changes might have on the overall
virologic profile. In addition, we wanted to access the tetracyclic
indole cores which allowed for variation of the substitution at X
and Y.
Scheme 2. a) 1,4-dibromobutane, Na2CO3; b) R1CHO, NaCNBH3.
The preparation of the required bromoimidazole Boc-L-
proline fragment 3 is illustrated in Scheme 3.11 Oxidation of the
Boc-L-prolinol 10 with Dess-Martin periodinane followed by
condensation with glyoxal in the presence of 7M ammonia in
MeOH afforded the imidazole 11. Bromination with NBS
afforded the intermediate dibromo adduct which was treated
under reductive conditions employing Na2SO3 to afford bromide
3 which was ready for coupling.

Incorporation of either an S-threonine (25) or methoxy-capped S-
threonine side chain (26) led to dramatic losses in GT1a Y93H
activity. However, introduction of the methoxy homoserine and
the homo 4-tetrahydropyran moieties (27 and 28) led to
compounds that possessed reasonable profiles against both wild-
type (1a and 2b) as well as mutant genotypes (1a Y93H and 1a
L31V). With the emerging SAR in Table 1 suggesting the value
of having an oxygen in the side chain, additional compounds
were prepared to explore this trend which are summarized in
Table 2. The (R)-tetrahydrofuran amide (29) as well as the
spirocyclic tetrahydropyran Moc derivative (30) demonstrated at
least a 1000-fold loss in replicon activity across genotypes. Not
surprisingly, compound 31 confirmed the preferred (S)-
stereochemistry of the side chain in the Moc derivatives as found
in compound 24. Interestingly, several (R)-phenyl glycine
derivatives (32 and 34) possessed improved GT2b activity at the
expense of GT1a Y93H as shown in Table 1.14 Also of note, the
substitution on both the phenyl ring and amine for these analogs
proved to be very influential in the potencies against both wild-
type and mutant genotypes as illustrated by compounds 33 and
35. In light of the emergence of several interesting non-valine
derived caps from Tables 1 and 2, efforts were initiated to
prepare mixed cap tetracyclic indole derivatives bearing a single
L-Val Moc cap along with an optimized cap from the initial SAR
screening. It was unclear what the impact of this mixed capping
on both the overall virologic profile as well as pharmacokinetic
profile in rat.
Scheme 3. a) Dess-Martin periodinane, CH2Cl2, 0 oC; b) glyoxal, 7N NH3 in
MeOH, rt; c) NBS, THF then Na2SO3, EtOH/H2O, reflux.
Having prepared the key caps and bromoimidazole fragments,
attention initially focused on preparation of tetracyclic indole
derivatives bearing identical caps on both flanking pyrrolidines.
The synthetic preparation of symmetric capped derivatives is
shown in Scheme 4.11 Utilizing a Fischer indole synthesis
protocol, 5-bromoacetophenone 12 was condensed with p-
bromophenylhydrazine under acidic conditions to form the
intermediate hydrazone which was treated at high temperature
with PPA to afford the intermediate indole 13. Treatment of 13
with ,-dibromotoluene and K2CO3 afforded the tetracyclic
indole derivative 14. With this key intermediate in hand,
attention turned toward accessing the enantiomerically pure
aminal intermediate with the (S)-stereochemistry.13 Compound
14 was subjected to chiral SFC separation to yield the
enantiomerically pure aminal 15.12 Treatment of dibromide
intermediate 15 with two equivalents of bis(pinacolato)diboron in
the presence of KOAc and PdCl2(dppf) afforded the intermediate
bis-pinacol boronate ester which was then treated with two
equivalents of bromoimidazole intermediate 3 to afford the bis
Boc adduct 16. Global deprotection was achieved with HCl
followed by treatment with various carboxylic acid caps afforded
the final compounds 17-35 (Scheme 4).
Table 1. In vitro virologic profiles of symmetrical Moc capped tetracyclic
indole derivatives 17-28.
Genotype, EC90 (nM)a
1a
Y93H
1a
L31V
Compd
R
1a
2b
11
MK-
8742
17
0.006
28
1
0.042
0.016
>100
65
>100
>100
6.4
1.6
18
Scheme 4. a) 1. p-bromophenylhydrazine, AcOH, EtOH, reflux; then 2.
PPA, 110 oC; b) ,-dibromotoluene, K2CO3, DMF, 100 oC; c)
bis(pinacolato)diboron, KOAc, PdCl2(dppf), dioxane, 110 oC then
bromoimidazole 3, 1M Na2CO3, PdCl2(dppf), THF, 90 oC; d) 4N HCl,
MeOH; e) RCO2H, HATU, DIPEA, DMF.
19
0.011
0.028
0.014
>100
>100
52
>100
>100
>100
1.8
>100
4.1
20
21
The virologic profile of the matched Moc cap tetracyclic
indole analogs, against several HCV wild-type (WT) genotypes
(1a and 2b) and resistant mutants (Y93H and L31V), are
summarized in Table 1. Simple alkyl, branched alkyl, as well as
cycloalkyl side chains (17-22) demonstrated weaker activity
across GT2b, GT1a Y93H, and GT1a L31V replicon assays.
Introduction of a difluoro moiety into the cyclohexyl group (23)
showed improved activity versus both GT1a Y93H and GT1a
L31V when compared to compounds 17-22. Since these
modifications did not improve the overall virologic profiles,
efforts focused upon the introduction of additional functionality
such oxygen into the sidechain region. Introduction of a 4-
tetrahydropyran group led to compound 24 which showed an
improved virologic profile against both GT2b and GT1a L31V
genotypes albeit at the expense of GT1a shown in Table 1.
22
23
0.10
>100
77
>100
39
11
0.030
0.65
24
0.060
1.2
23
<0.2
25
26
0.019
>1
17
>100
>100
ntb
>100
>100

followed by HATU-mediated coupling with
carboxylic acid afforded the final compounds 41-49 shown in
Tables 3 and 4.
a different
27
28
0.061
0.10
91
18
46
40
2.1
0.77
aValues are the mean of two (n =2) runs. See ref 15 for assay details.
bnt = not tested
Table 2. In vitro virologic profiles of additional symmetrical capped
tetracyclic indole derivatives 29-35.
Genotype, EC90 (nM)a
1a
Y93H
1a
L31V
Compd
R
1a
2b
Scheme 5. a) 1. p-bromophenylhydrazine, AcOH, EtOH, reflux; then 2.
PPA, 110 oC; b) ,-dibromotoluene, K2CO3, DMF, 100 oC; (c)
bis(pinacolato)diboron, KOAc, PdCl2(dppf), dioxane, 110 oC then
bromoimidazole 3, 1M Na2CO3, PdCl2(dppf), THF, 90 oC; d) 4N HCl,
MeOH; e) RCO2H, HATU, DIPEA, DMF; f) bis(pinacolato)diboron, KOAc,
Pd2(dba)3, dioxane, 120 oC then 3, 1M Na2CO3, THF, 90 oC; g) 4N HCl,
MeOH; h) R1CO2H, HATU, DIPEA, DMF.
29
1
>100
>100
>100
>100
>100
30
31
1.4
8.6
>100
>100
The in vitro virologic profiles of the mixed cap derivatives
are summarized in Table 3. While these analogs generally
showed a slight loss in GT1a activity, both of the differentially
substituted isopropyl/4-tetrahydropyran derivatives (41 and 46)
demonstrated comparable activity versus GT2b, GT1a Y93H,
and GT1a L31V to the base compound (Table 3). In addition, the
>100
>100
>100
2.1
32
33
0.30
0.98
0.87
methylene
extended
4-tetrahydropyran
derivative
44
demonstrated a similar virologic profile to these analogs (Table
3). It should be pointed out the combination of a “non-optimal”
spirocyclic 4-tetrahydropyran Moc cap with a valine Moc in
compound 45 did improve the both the GT1a and GT1a L31V
activities compared to the bis adduct (30) but GT2b or GT1a
Y93H remained unchanged. The other combinations (42-43, 47-
48) in Table 3 demonstrated reasonable activity across both wild-
type and mutant genotypes. In addition to the methyl carbamate
caps, combination of a (R)-phenyl glycine derived cap with the
L-Val Moc cap in compound 49 (Table 4) was intriguing as it
demonstrated the ability to improve the GT1a and GT1a Y93H
activity compared to the bis phenyl glycine derivative 34 found
in Table 2.
>100
>100
>100
34
35
0.27
3.9
3.1
13
>100
>100
0.6
3.9
aValues are the mean of two (n =2) runs. See ref 15 for assay details.
In order to access the mixed capped tetracyclic indole
derivatives, a modified synthetic route, based upon Scheme 4,
was adopted which relied upon the preparation of a differentially
substituted tetracyclic indole fragment 39 shown in Scheme 5.
The preparation begins with a two-step Fisher indole synthesis
using 5-chloroacetophenone 36 followed by a SFC separation
provided
the
enantiomerically
pure
indole
39.16
Functionalization of the bromide of 39 was achieved by
treatment under the previously described borylation/Suzuki
coupling employing PdCl2(dppf) and bromoimidazole 3 to afford
the intermediate Boc adduct which was deprotected and
subjected to HATU coupling with the requisite carboxylic acid
fragment to afford 40 (Scheme 5). With compound 40 in hand,
treatment
with
Pd2(dba)3
in
the
presence
of
bis(pinacolato)diboron and KOAc afforded the intermediate
boronate which was treated directly with bromoimidazole 3 to
afford the Boc-protected intermediate. Treatment with HCl

Table 5. Rat pharmacokinetic profiles of 24 and 46.
Dose
(mpk)
AUC
(M.h)
Cmax
(M)
T ½
(h)
Cl
F%
Compd
(ml/min/kg)
5
2.4
--
82
--
0
24
0.004
ndb
0.02
46a
10
--
0.031
aTmax = 0.75 h, 1h conc = 0.030 M; bnd = not determined
Table 3. In vitro virologic profiles of mixed Moc capped tetracyclic indole
derivatives 41-48.
In conclusion, a systematic capping effort was carried out on
the tetracyclic indole scaffold, which identified several non-Val
Moc caps which appear to show modest improvements in the
Genotype, EC90 (nM)a
1a
Y93H
1a
L31V
R
R1
Compd
1a
2b
11
overall in vitro virologic profile.
More specifically, the
MK-
8742
0.006
28
11
1
incorporation of either (S)-4-tetrahydropyran methyl carbamate
(24) or (R)-phenyl glycine diethylamino (34) caps into this series
in a matched sense produced analogs with improved activity
versus both GT1b and GT1a L31V. In addition, these caps
could also be partnered with a L-Val Moc cap to produce mixed
capped compounds with intriguing mutant profiles against both
GT1a Y93H and GT1a L31V. While the capped derivatives
described in this work demonstrated poor rat pharmacokinetic
profiles, the combination of these caps with additional structural
modifications to the scaffold may hold promise in producing
analogs with even better resistance profiles.17 These analogs
provide a platform onto which new derivatives with improved
pharmacokinetic profiles and stability may emerge. These efforts
will be the topic of future disclosures.
41
42
0.060
9
0.6
0.039 35
54
34
ntb
43
0.018
0.014
23
0.89
44
45
46
8.9
24
>100
11
0.33
14.7
0.4
0.035 >100
Acknowledgments
0.061
4
The authors would like to thank Dr. Rebecca Ruck for the
generous supply of synthetic intermediates and Dr. Peter Meinke
for helpful discussions during manuscript preparation.
47
48
0.062
0.060
5
50
77
1.1
4.3
50
aValues are the mean of two (n =2) runs. See ref 15 for assay details.
bnt = not tested.
References and notes
1.
Hepatitis C-global prevalence (update). WHO wkly. Epidemio. rec
1999, 74, 425.
2.
3.
4.
Keam, S. J.; Cvetkovic, R. S. Drugs 2008, 68, 1273.
Sheridan, C. Nat. Biotechnol. 2011, 29, 553.
Tellinghuisen, T. L; Marcotrigiano, J.; Rice, C. M. Nature 2005,
435, 374.
5.
a) Schmitz, U.; Tan, S.-L. Recent Pat. Anti-Infect. Drug Discovery
2008, 3, 77. b) Conte, I.; Giuliano, C.; Ercolani, C.; Narjes, F.;
Koch, U.; Rowley, M.; Altamura, S.; De Francesco, R.;
Neddermann, P.; Migliaccio, G.; Stansfield, I. Bioorg. Med.
Chem. Lett. 2009, 19, 1779. c) Lemm, J. A.; O’Boyle, D.; Liu,
M.; Nower, P. T.; Colonno, R.; Deshpande, M. S.;Snyder, L. B.;
Martin, S. W.; St Laurent, D. R.; Serrano-Wu, M. H.; Romine, J.
L.; Meanwell, N. A.; Gao, M. J. Virol. 2010, 84, 482.
Gao, M.;Nettles, R. E.; Belema, M.; Snyder, L. B.; Nguyen, V. N.;
Fridell, R. A.; Serrano-Wu, M. H.; Langley, D. R.; Sun, J.-H.;
O’Boyle, D. R., II; Lemm, J. A.; Wang, C.;Knipe, J. O.; Chien, C.;
Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.; Hamman, L. G.
Nature 2010, 465, 96.
Table 4. In vitro virologic profile of R-phenylglycineEt2/L-Val Moc capped
tetracyclic indole derivative 49.
Genotype, EC90 (nM)a
6.
7.
Compd
49
1a
0.045
2b
4
1a Y93H
44
1a L31V
ntb
aValues are the mean of two (n =2) runs. See ref 15 for assay details.
bnt = not tested
a) Pawlotsky, J.-M. J. Hepatol. 2013, 59, 375. b) Rai, D.; Wang,
L.; Jiang, X.; Zhan, P.; Jia, H.; DeClercq, E.; Liu, X. Curr. Med.
Chem. 2015, 22, 1860.
Having identified a number of different cap modifications that
possessed intriguing virologic profiles, it remained to look at the
pharmacokinetic profiles of representative examples of both
matched and mixed capping series. Towards this end, the
pharmacokinetic profiles of compounds 24 and 46 in rat are
summarized in Table 5. The bis-THP Moc derivative 24
demonstrated very poor oral exposure and very high clearance.
Likewise, the differentially capped analog, 46, also demonstrated
inferior pharmacokinetic properties.
8.
9.
Belema M.; Meanwell, N.A. J. Med. Chem. 2014, 57(12), 5057.
DeGoey, D. A.; Randolph, J. T.; Liu, D.; Pratt, J.; Hutchins, C.;
Donner, P.; Krueger, A. C.; Matulenko, M.; Patel, S.; Motter, C.
E.; Nelson, L.; Keddy, R.; Tufano, M.; Caspi, D. D.; Krishnan, P.;
Mistry, N.; Koev, G.; Reisch, T. J.; Mondal, R.; Pilot-Matias, T.;
Gao, Y.; Beno, D. A.; Maring, C. J.; Molla, A.; Dumas, E.;
Campbell, A.; Williams, L.; Collins, C.; Wagner, R.; Kati, W. M.
J. Med. Chem. 2014, 57(5), 2047.
10. Link, J. O.; Taylor, J. G.; Xu, L.; Mitchell, M.; Guo H.; Liu, H.;
Kato, D.; Kirschberg, T.; Sun, J.; Squires, N.; Parrish, J.; Keller,
T.; Yang, Z.; Yang, C.; Matles, M.; Wang, Y.; Wang, K.; Cheng,

G.; Tian, Y.; Mogalian, E.; Mondou, E.; Cornpropst, M.; Perry, J.;
Desai, M. C. J. Med. Chem. 2014, 57(5), 2033.
11. Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. A.;
Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.;
Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.;
Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W.
ChemMedChem 2013, 8, 1930.
12. Lavoie, R.; Bender, J. A.; Romine, J. L.; Ruediger, E. H.;
Bachand, C.; Lopez, O. D.; Chen, Q.; Belema, M.; Kadow, J. F.;
Hamann, L. G. WO 2011/060000 A1.
13. SFC conditions: Chiralpak AD column, 30% MeOH/AcCN (2:1)
in CO2. Each enantiomer from the SFC separation (15 and the
epimer) was progressed thru the synthetic sequence in Scheme 4
to prepare both Moc L-Val diastereomers to compare against
MK-8742 to confirm the stereochemistry at the aminal position.
14. For a recent report containing phenylglycine-derived caps, see:
Belema, M.; Nguyen, V. N.; Bachand, C.; Deon, D. H.; Goodrich,
J. T.; James, C. A.; Lavoie, R.; Lopez, O. D.; Martel, A.; Romine,
J. L.; Ruediger, E. H.; Snyder, L. B.; St. Laurent, D. R.; Yang, F.;
Zhu, J.; Wong, H. S.; Langley, D. R.; Adams, S. P.; Cantor, G. H.;
Chimalakonda, A.; Fura, A.; Johnson, B. M.; Knipe, J. O.; Parker,
D. D.; Santone, K. S.; Fridell, R. A.; Lemm, J. A.; O’Boyle II, D.
R.; Colonno, R. J.; Gao, M.; Meanwell, N. A.; Hamann, L. G. J.
Med. Chem. 2014, 57(5), 2013.
15. Kozlowski, J. A.; Rosenblum, S. B.; Coburn, C. A.; Shankar, B.
B.; Anilkumar, G. N.; Chen, L.; Dwyer, M. P.; Jiang, Y.;
Keertikar, K. M.; Lavey, B. J.; Seluytin, O. B.; Tong, L.; Wong,
M.; Yang, D.-Y.; Yu, W.; Zhao, G.; Wu, H.; Hu, B.; Zhong, B.;
Sun, F.; Ji, T.; Shen, C.; Rizvi, R.; Zeng, Q. WO 2012/041014
A1.
16. SFC conditions: Chiralpak AD column, 30% MeOH/AcCN (2:1)
in CO2. Each enantiomer from the SFC separation (39 and the
epimer) was progressed thru the synthetic sequence in Scheme 5
to prepare both Moc L-Val diastereomers to compare against
MK-8742 to confirm the stereochemistry at the aminal position.
17. For recent reports on structural modifications around the aminal
position of the tetracyclic indole core series, see: Yu, W.; Coburn,
C. A.; Anilkumar, G. N.; Wong, M.; Tong, L.; Dwyer, M. P.; Hu,
B.; Zhong, B.; Hao, J.; Yang, D.-Y.; Seluytin, O.; Jiang, Y.;
Rosenblum, S. B.; Kim, S. H.; Lavey, B. J.;Zhou, G.; Rizvi, R.;
Shankar, B. B.; Zeng, Q.; Chen, L.; Agrawal, S.; Carr, D,; Rokosz,
L.; Liu, R.; Curry, S.; McMonagle, P.; Ingravallo, P.; Lahser, F.;
Asante-Appiah, E.; Nomeir, A.; Kozlowski, J. A. Bioorg. Med.
Chem Lett., 2016,doi:10.1016/j.bmcl.2016.06.056, in press.
*Corresponding Author (MPD) tel: (732) 594-1733;
michael.dwyer@merck.com.