Discovery of novel P3 sulfonamide-capped inhibitors of HCV NS3 protease. Inhibitors with improved cellular potencies

Article abstract of DOI:10.1016/j.bmc.2009.05.012

Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-α or PEG-interferon alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only ～50% of the patients showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034 (1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we have further explored various novel structures with the aim of improving enzyme and cellular binding activities of 1. Herein, we disclose our efforts toward the identification of a novel P₃ sulfonamide-capped inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one of these inhibitors bound to the enzyme revealed a hydrogen bond of the P₃ sulfonamide group to Cys-159 which resulted in improved binding and cellular potency.

Full text of DOI:10.1016/j.bmc.2009.05.012

Bioorganic & Medicinal Chemistry 17 (2009) 4486–4495
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery of novel P3 sulfonamide-capped inhibitors of HCV NS3 protease.
Inhibitors with improved cellular potencies
*
Srikanth Venkatraman , Mellissa Blackman, Wanli Wu, Latha Nair, Ashok Arasappan, Angela Padilla,
Stéphane Bogen, Frank Bennett, Kevin Chen, John Pichardo, Xiao Tong, Andrew Prongay, Kuo-Chi Cheng,
Viyyoor Girijavallabhan, F. George Njoroge
Schering Plough Research Institute, K-15, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 February 2009
Revised 1 May 2009
Accepted 5 May 2009
Available online 9 May 2009
Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepa-
tocellular carcinoma, which affects more than 200 million people worldwide. Currently the only thera-
peutic regimens are subcutaneous interferon-
a or PEG-interferon alone or in combination with oral
ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its effi-
cacy against the predominant genotype (genotype 1) is moderate at best, with only ꢀ50% of the patients
showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034
(1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to
be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we
have further explored various novel structures with the aim of improving enzyme and cellular binding
activities of 1. Herein, we disclose our efforts toward the identification of a novel P3 sulfonamide-capped
inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one
of these inhibitors bound to the enzyme revealed a hydrogen bond of the P3 sulfonamide group to Cys-
159 which resulted in improved binding and cellular potency.
Keywords:
HCV
Boceprevir
Replicon
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
protease.5 This central role played by NS3 protease in the develop-
ment of mature hepatitis C virus makes it an excellent target for
Hepatitis C virus is the primary etiological agent responsible for
non-A, non-B hepatitis, transmitted by unscreened blood transfu-
sions. Majority of these infections turn chronic with slow progres-
sion to liver cirrhosis and hepatocellular carcinoma.1 Pegylated
drug discovery. Development of small molecule inhibitors of this
enzyme would potentially arrest the processing of the aforemen-
tioned polyprotein required for viral replication. This has been a
field of intense investigation by various groups worldwide.6 We re-
cently disclosed the synthesis and development of Boceprevir, SCH
503034 (1),7 which is a selective, potent, orally bioavailable HCV
NS3 protease inhibitor that is efficacious in humans and currently
undergoing Phase III clinical trials. Several other molecules includ-
ing VX950, ITMN-191, MK-7009, TMC435350, and BILN 2061 have
also been advanced to clinical trials and found to be effective.6
As shown in Figure 1, 1 demonstrated a Kꢁi = 14 nM in the con-
a-interferon alone or in combination with ribavirin is the preferred
treatment for HCV infections.2 Interferon therapy is effective only
in ꢀ50% of patients infected with genotype-1. Lack of effective
methods to treat genotype-1 HCV infections, and interferon non-
responders necessitates discovery of new drugs. Investigational
new therapies are primarily focused toward the inhibition of key
viral enzymes in virus life cycle vital for HCV replication and
maturation.3
tinuous enzyme binding assay8 and an EC90 = 0.35
lM in the repli-
Hepatitis C virus is a positive strand RNA virus of ꢀ9600 kB. It
encodes a polyprotein of ꢀ3000 amino acids that are post-transla-
tionally modified to produce mature virions.4 The encoded poly-
protein contains all the structural and nonstructural proteins
C-E1-E2-P7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. It undergoes an
autocatalytic cleavage of NS2-NS3 junction followed by cleavage
of the NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B catalyzed by NS3
con-based cellular assay.9 It also demonstrated excellent
selectivity against human neutrophil elastase (HNE). Compound
1 was readily absorbed in rats and dogs demonstrating acceptable
PK. In an effort to develop a potential back-up to 1, we decided to
identify an inhibitor that was fivefold more potent than 1 in the
replicon cellular assay while maintaining similar enzyme binding
and HNE selectivity. Herein, we describe our efforts in the identifi-
cation of P3-capped sulfonamide series of inhibitors that were sig-
nificantly more potent than 1 in the enzyme and cellular assays
and demonstrated good PK in rats.
* Corresponding author. Tel.: +1 908 740 3758; fax: +1 908 740 7252.
E-mail address: Srikanth.Venkatraman@spcorp.com (S. Venkatraman).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.05.012

S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
4487
O
H
N
NH2
Ki* =14 nM
HNE/HCV = 2200
Replicon EC90 = 0.35 µM
BocHN
COOH
OCH3
a
N
+
OCH3
N
H
N
R3
O
O
O
HN
N
H
BocHN
O
O
O
O
R3
10
11
9
Boceprevir, 1 (Sch 503034)
Figure 1.
OCH3
OCH3
O2N
c
b
N
N
H
N
O
O
O
O
HCl.
H2N
While investigating the SAR in the P3 capping of 1, it was ob-
served that replacement of tert-butyl urea group with valine-de-
rived P3 capping group yielded 2, a compound that showed some
improvement in cellular activity. Further SAR in this region dem-
onstrated that replacement of the P3 valine cap with appropriately
modified sulfonamide moiety resulted in compound 3 (see Figure
O
O
R3
R3
12
13
f
OR
d
N
O
S
O
2) which exhibited an EC90 = 0.13 lM. In the current work, we de-
H
N
H
N
O
R6
N
O
scribe our efforts in modifying 3 and report identification of a sul-
fonamide and sulfonyl urea series of inhibitors that have improved
cellular potency compared to 1.
R5 R4
O
R3
; 14
R = CH3
e
R = OH; 15
2. Chemistry
OH
H
g
N
NHR1
Reduction of amino acids of type 4 with LiAlH4, followed by pro-
tection of the resultant amino alcohol with Boc2O yielded com-
pounds of type 5 (Scheme 1). Protected amino alcohol of type 5
was converted to diamine of type 6 by reaction with PPh3, phthal-
N
O
O
R2
O
O
H
N
H
O
O
S
N
R6
N
O
O
R5 R4
O
O
R3
16
O
H
N
NHR1
N
O
O
R2
H
N
H
N
O
H
S
R6
N
NH2
N
R5 R4
R3
O
N
H
N
H
N
O
O
O
O
17
O
Scheme 2. Reagents and conditions: (a) HATU, NMM, DMF/CH2Cl2, rt; (b) 4 M HCl
in dioxane; (c) 4-nitrophenylchloroformate, NMM, CH2Cl2; (d) (i) 7, NMM, CH3CN;
(ii) Cs2CO3, R5I, DMF; (e) aq LiOH, THF, rt; (f) HClꢂH2NCH(R2)CH(OH)CONHR1, HATU,
NMM, CH2Cl2/DMF, 0 °C; (g) Dess–Martin reagent (R1 not H) or EDCIꢂHCl, DMSO,
CHCl2COOH (R1 = H).
Ki* = 0.006 µM
EC90 = 0.20 µM
2
O
H
N
NH2
O
S
O
N
O
H
H
O
imide and DEAD followed by deprotection of phthalimido group
with hydrazine. Amines of type 6 were converted to sulfonamides
7 by treatment with suitable sulfonyl chloride followed by depro-
tection of the Boc group with 4 M HCl. Amine salts of type 7, were
directly used to synthesize inhibitors or converted to isocyanates
of type 8 by treatment with phosgene.
N
N
N
O
O
Ki* = 0.008 µM
EC90 = 0.13 µM
3
Figure 2.
Syntheses of inhibitors derived from amines of type 7 and iso-
cyanates of type 8 were accomplished using procedures shown in
Scheme 2. Thus, coupling of P3 amino acid 9 with proline derivative
1010 using HATU protocol resulted in dipeptides of type 11 which
were converted to amine salts of type 12 by treatment with 4 M
HCl in dioxane. Reaction of amine salts of type 12 with isocyanates
of type 8 resulted in compounds of type 14 (R5 = H). Alternatively,
amine salts 12 were treated with 4-nitrophenyl chloroformate to
yield 4-nitrophenyl carbamate 13 which on treatment with 7
yielded ureas of type 14 (R5 = H). Further alkylation of sulfonamide
nitrogen with methyl iodide in the presence of Cs2CO3 introduced
the N-alkyl that resulted in compound of type 14 (R5 = methyl).
Hydrolysis of methyl ester yielded acid 15 which was coupled with
P1 hydroxy amide segment to yield hydroxy amides of type 16.
These hydroxy amide derivatives were oxidized to targets of type
17 using methods previously described.7
NHBoc
HOOC
NH2
NHBoc
H2N
a
HO
b
R4
R4
5
R4
6
4
O
S
O
O
NCO
S
O
NH2
.HCl
R6
R6
N
c
d
N
H
H
R4
R4
8
7
Scheme 1. Reagents and conditions: (a) (i) LiAlH4, THF, reflux; (ii) Boc2O; (b) (i)
PPh3, phtalimide, DEAD, THF; (ii) NH2NH2, ethanol; (c), (i) R6SO2Cl, Et3N, CH2Cl2; (ii)
4 M HCl in dioxane; (d) COCl2, satd aq NaHCO3, CH2Cl2.

4488
S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
Table 1
Table 2
O
O
H
N
H
N
NH2
NH2
N
N
O
S
O
R6
O
O
H
N
H
N
R2
O
O
H
N
H
N
O
O
S
N
O
N
O
R7 R4
R5
O
O
R6
R5
R2
Kiꢁ
(l
M)a
EC90
0.55
(lM)
Compd
R4
R7
H
Kiꢁ
(
l
M)a
EC90
0.14
(lM)
Compd
24
0.008
0.013
0.005
0.080
0.012
18
H
0.010
0.006
0.031
0.004
0.023
0.012
25
26
27
H
0.25
19
20
21
22
Me
H
0.13
2.00
0.35
0.60
0.10
H
0.075
—
Me
Me
Me
Me
H
28
0.40
S
S
Kꢁi value represents for a mixture of diastereomers at P1 and within twofold for
a
95% confidence.
23
Me
Table 3
Kꢁi value represents for a mixture of diastereomers at P1 and within twofold for
a
95% confidence.
O
H
N
NH2
N
O
R4
O
H
N
H
N
O
O
3. Discussion
S
N
O
O
Effect of P4-sulfonamide methyl group on cellular activity: Initially,
we explored the effect of N substitution on the cellular activity of
inhibitors of type 3 (Table 1). The phenylsulfonamide analog com-
Compd
R4
Kiꢁ
(
l
M)b
EC90
0.15
(l
M)
Rat AUC (l
M h)11
pound 18 that lacked the N-methyl substitution had a Kꢁi = 0.01
lM
and a replicon cellular activity EC90 = 0.55
sponding N-methylated derivative 19 had a Kꢁi = 0.006
EC90 = 0.13 M, a fourfold improvement in cellular potency com-
pared to 18. Similarly, the methyl sulfonamide-derived compound
20 lacking the N-methyl substituent had a Kꢁi = 0.031
M and
EC90 = 2.0 M, whereas the N-methylated analog 21 demonstrated
a Kꢁi = 0.004
M and EC90 = 0.35 M; a sixfold improvement in cel-
l
M, whereas the corre-
29
0.005
0.004
0.005
0.06
0.00
0.09
Me
Me
lM and
l
30
31
0.15
0.09
l
l
l
l
lular activity. A similar improvement was also observed in the thi-
ophene-capped compound where the N-methylated compound 23
32
0.004
0.004
0.06
0.08
0.11
NA
(Kꢁi = 0.012
l
M and EC90 = 0.1
the corresponding non-methylated compound 22 (Kꢁi = 0.023
and EC90 = 0.6 M). It was worth noting that the thiophene sulfon-
lM) was sixfold more potent than
S
lM
l
33a
amide derivative 23 also had improved cellular potency compared
to the first generation compound 1.
N
a
Having demonstrated that the N-methylation had profound ef-
fect on the cellular activity we next decided to evaluate the effect
of P4 substitutions on cellular activity (see Table 2). The cyclobu-
tyl alanine P1 analog of 19, inhibitor 24 demonstrated similar
b-methylcyclohexylglycine P3 was used.
Kꢁi value represents for a mixture of diastereomers at P1 and within twofold for
b
95% confidence.
binding and cellular activities (Kꢁi = 0.008
lM, EC90 = 0.14
lM) to
in inhibitor 26 (Kꢁi = 0.005
lM and EC90 = 0.075 lM) with a two-
19. However, 24 demonstrated improved HNE/HCV selectivity
compared to 19 (3100 vs 680). Substituting valine with isoleucine
fold improved activity over 24 and fourfold improvement in com-
parison to first generation compound 1. We further probed the P4
region by introducing quaternary amino acids. Thus, incorpora-
resulted in compound 25 (Kꢁi = 0.013
l
M and EC90 = 0.25
with a slight loss in both enzyme potency and cellular activity.
Incorporation of -branched amino acid tert-butylglycine resulted
lM)
tion of
a
-methyl leucine resulted in compound 27
a
(Kꢁi = 0.080
lM) with a 20-fold loss in activity compared to 25.

S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
4489
Constriction of R4 and R7 into a ring, resulted in spirocyclohexyl
derivative 28 (Kꢁi = 0.012
M and EC90 = 0.4 M). In summary,
Table 5
l
l
SAR studies of P4 capping groups identified tert-butyl glycine as
an optimal substituent that facilitated the achievement of im-
proved enzyme binding as well as cellular activity. It was there-
fore decided to further investigate SAR of subsequent inhibitors
using this substituent as the P4 residue.
O
H
N
NH
N
O
R4
O
R2
O
H
N
H
N
O
S
N
O
We next explored the effect of various substituents of the sul-
fonamide moiety. As outlined in Table 3 introduction of methyl
O
R3
R4
sulfonamide group resulted in compound 29 with Kꢁi = 0.005
lM
Cpd.
R2
R3
Kiꢁ
(
l
M)a
EC90
0.10
(lM)
and EC90 = 0.15 lM, a twofold improvement in cellular activity
compared to 1. The replacement of methyl sulfonamide with ethyl
sulfonamide resulted in an equipotent compound 30
37
0.006
0.006
0.006
0.011
Me
Me
(Kꢁi = 0.004
l
M and EC90 = 0.15
evaluated by incorporating cyclopropyl sulfonamide resulting in
compound 31 (Kꢁi = 0.005
M and EC90 = 0.09 M) with improved
cellular activity compared to 1. Incorporating thiophene and pyri-
dyl sulfonamides resulted in inhibitors 32 (Kꢁi = 0.004
M and
EC90 = 0.06 M and EC90 = 0.08 M) with
M) and 33 (Kꢁi = 0.004
lM). The effect of branching was
l
l
38
39
0.06
0.08
0.10
l
O
O
l
l
l
S
S
further improved cellular activity. We were very encouraged by
this result and decided to evaluate some of the very active com-
pounds in rapid rat assay to evaluate their pharmacokinetic prop-
erties.11 As shown in Table 3, the oral PK of these inhibitors in rats
N
O
O
40
N
was poor. Compound 32 had an AUC = 0.11 lM h and 30 demon-
strated no oral PK at all.
Kꢁi value represents for a mixture of diastereomers at P1 and within twofold for
a
Having established that introduction of sulfonamide yielded
compounds with improved cellular potencies we next decided to
explore ways to improve their pharmacokinetics. Previously, in
the discovery of 1 we had demonstrated that the replacement of
a primary ketoamide with an allyl amide group at P01 in combina-
tion with P1 norleucine, or norvaline resulted in compounds with
improved PK.7 We therefore decided to investigate allyl amide ana-
logs of these more potent sulfonamide derivatives.
95% confidence.
1.02 lM h) as 35. From these studies it was clear that one could
improve oral exposure of these classes of compounds by synthesiz-
ing the corresponding allyl amide derivatives. However, these allyl
amide compounds needed further improvement in replicon cellu-
lar potency.
As shown in Table 4 the ethyl sulfonamide derivative 34 had a
To improve the cellular potency of these allyl amide inhibitors
we decided to explore the effect of varying of P1 and P3 residues.
Once again our previous experience with the discovery of 1 had
demonstrated that the P1 and P3 had a synergistic effect on enzyme
binding and replicon cellular potency. We therefore explored the
effect of substitution of P3 from tert-butyl glycine with cyclohexyl-
glycine, and indanylglycine. Table 5 summarizes the effect of these
modifications on potency.
Kꢁi = 0.010
lM and EC90 = 0.15 lM. Introduction of allyl moiety at
P01 resulted in a compound with similar cellular activity compared
to primary amide derivative 30, however it exhibited some rat PK
(AUC0–6 h = 0.34
pound derived from thiophene sulfonamide 32 resulted in com-
pound 35 which had an EC90 = 0.26 and had much
improved PK (AUC0–6 h = 1.38 M h). Similarly allylamide deriva-
tive of 2-pyridine sulfonamide resulted in compound 36 with good
lM h). The introduction of an allyl amide in com-
lM
a
l
It was clear that introduction of indanylglycine had a profound
effect on the cellular potency of these compounds. In the series of
compounds containing ethyl sulfonamide-derived P3 cap, intro-
duction of P3 indanylglycine with P1 norvaline resulted in com-
cellular activity (EC90 = 0.18
lM) and similar PK (AUC0–6 h
=
Table 4
pound 37 with Kꢁi = 0.006
l
M
and EC90 = 0.1
incorporation of norleucine at P1 resulted in compound 38 with
Kꢁi = 0.006
M and EC90 = 0.06 M, a fivefold improvement in cellu-
lM. The
l
l
O
H
lar activity relative to 1. The analog containing dimethylsulfonyl
N
NH
N
urea cap along with P3 indanyl glycine and P1 norvaline (40) dem-
O
R4
O
H
N
H
O
onstrated enzyme binding Kꢁi = 0.011
lM and EC90 = 0.10 lM,
O
S
N
N
O
whereas the corresponding analog containing P1 norleucine and
O
P3 cyclohexylglycine, compound 39, had an enzyme activity of
Kꢁi = 0.006
lM and EC90 = 0.08 lM (see Table 5).
Cpd.
R4
Kiꢁ
(
l
M)a
EC90
0.15
(
lM)
Rat AUC (
lM h)
Compounds 38 and 39 were further evaluated for their rat PK in
the rapid rat assay. Compound 38 demonstrated an AUC0–
34
0.010
0.010
0.34
Me
S
6h = 1.2
dosed at 10 mpk. Evaluation of 38 in monkeys achieved an
AUC = 0.69 M h when dosed at 3 mpk in monkeys.
lM h and compound 39 had an AUC0-6h = 1.74 lM h when
l
35
0.26
0.18
1.38
1.02
The X-ray structure of a phenyl sulfonamide-capped inhibitor
41 bound to HCV NS3 protease was solved and is shown in Figure
3. From the structure, it was clear that P1 cyclobutyl moiety occu-
pied S1 pocket. As previously described P2 dimethylcyclopropylpr-
oline residue adopted a bent conformation that allowed maximum
overlap of the methylenes of proline and cyclopropyl ring to
Ala-156. The conformation adopted by cyclopropanated proline
36
0.014
N
Kꢁi value represents for a mixture of diastereomers at P1 and within twofold for
95% confidence.
a

4490
S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
To improve the oral availability of these compounds, a P01 allyl
amide series were chosen for further investigation. Although these
series of compounds displayed poor enzyme binding and replicon
cellular potency, by systematic optimization of P3, P1, and the P4
sulfonamide groups, two series of compounds derived from ethyl-
sulfonamide capping with P3 indanyl glycine and P4 dimethylsulfo-
nyl urea derived cap with P3 cyclohexyl glycine were identified.
These groups provided compounds with excellent binding and
improved cellular potencies. Evaluation of these potent com-
pounds in rapid rat and rapid monkey assays also identified com-
O
H
N
NH2
N
O O
S
H
N
H
N
O
O
N
O
H
O
*
41
Ki = 0.013
µ
M
His57
pound 38 (Kꢁi = 0.006
(AUC = 1.2 M h) and monkey (AUC = 0.69
lM and EC90 = 0.060
lM) with a good rat
Arg155
l
lM h). The X-ray struc-
ture of a phenyl sulfonamide-capped derivative bound to the NS3
protease was solved. It revealed novel interaction of the oxygens
of P4 sulfonamide moiety to Cys-159, in addition to interactions
observed in 1 that contributed to enhancement in enzyme binding
and replicon cellular potency.
Gln41
Asp168
5. Experimental
5.1. General
Lys136
N
DrysolventswerepurchasedfromAldrichorAcrosandwereused
withoutfurther purification. Other solvents or reagents were used as
obtained except when otherwise noted. Analytical thin layer chro-
matography (TLC) was performed on pre-coated silica gel plates
available from Analtech. Column chromatography was performed
using Merck Silica Gel 60 (particle size 0.040–0.055 mm, 230–400
mesh), or using Biotage or Isco chromatographic systems. Many
compounds were further purified using Varian normal phase HPLC
with YMC-diol column with a solvent system solvent A (hexanes)
and solvent B (a mixture of isopropanol, CH2Cl2, and acetonitrile).
Visualization wasaccomplishedwithUVlightorbystainingwithba-
sic KMnO4 solution, methanolic H2SO4, or Vaughn’s reagent. NMR
spectra were recorded in CDCl3 or DMSO-d6 unless otherwise noted
Cys159
Ile132
Figure 3. X-ray structure of inhibitor 41 bound to NS3 protease.
allowed the methyl group proximal to the carbonyl to interact with
His-57 and the methyl group distal to carbonyl to interact with
Ala-156 and Arg-155. P3 tert-butyl glycine occupied the S3 pocket
while P4 valine group at S4 pocket interacted with the protease
effectively. The electrophilic ketoamide reversibly trapped Ser-
139 to form a covalent bond with the enzyme and the hydrogen
of the P1 amide donated a hydrogen bond to the peptidic back bone
of the protein, locking the inhibitor to the surface.
In addition to van der Walls contacts, inhibitor 41 formed a ser-
ies of specific hydrogen bonds with the protein surface. Mapping
out these various hydrogen bonding interactions that existed be-
tween inhibitor and NS3 protease, it was evident that the urea
nitrogens donated two hydrogen bonds to Ala-157. Additionally,
the nitrogen of the P1 norvaline donated a hydrogen bond to Arg-
155 and oxygen of P3 carbonyl group accepted a hydrogen bond
from the Ala-157. In addition to these hydrogen bonds that existed
in interaction of 1, the P4 sulfonamide group made important inter-
action to the peptidic backbone; Oxygens of the sulfonamide group
accepted a hydrogen bond to Cys-159 enhancing binding and spec-
ificity. The combination of hydrophobic interactions and the array
of hydrogen bonds contributed for improved binding (Kꢁi ) and cel-
lular potency of these inhibitors.
in either 300, 400 or 500 MHz (1H NMR), or 75, 100 or 125 MHz (13
C
NMR). Mass spectra were obtained using electron spray or FAB ion-
ization methods. 1H NMR and 13C NMR described for the final prod-
ucts comprise two sets of signals (representing two molecules)
accounting for two diastereomers at P1.
5.1.1. (S)-tert-Butyl-1-hydroxy-3,3-dimethylbutan-2-
ylcarbamate (5)
(L)-tert-Leucine (10.0 g, 96 mmol) was slowly added under reflux
to a solution of LiAlH4 (152 mL, 1 M soln in THF). The reaction mix-
ture was refluxed for 6 h and cooled to 0 °C and carefully quenched
by addition of aq NaOH (10%, 10 mL) and water (10 mL). It was stir-
red at rt for 10 min and treated with di-tert-butyldicarbonate
(18.22 g, 84 mmol) and stirred overnight at 60 °C. The reaction mix-
ture was filtered, the filtrate was concentrated in vacuo, and the res-
idue was purified by chromatography (SiO2, EtOAc/hexnaes) to yield
Boc-protected tert-leucinol 5 (10.2 g, 62%).
5.1.2. (R)-tert-Butyl-1-amino-3,3-dimethylbutan-2-
ylcarbamate (6, R4 = tert-butyl)
4. Conclusions
A flame dried flask was charged with phthalimide (5.5 g,
37.5 mmol), dry THF (30 mL), PPh3 (19.6 g, 75.0 mmol), and 5
(5.5 g, 25 mmol).The reaction mixture was cooled to 0 °C and trea-
ted with DEAD (10.8 g, 62.5 mmol) dropwise. The reaction mixture
was stirred at rt. for 2 h and concentrated in vacuo. The residue
was purified by chromatography (SiO2 EtOAc/hexanes 2:3) to yield
pthalimide displaced product (3.94 g, 67%). MS (ESI, m/z relative
intensity) 715 [(2 M+Na)+, 15], 369 [(M+Na)+, 30], 347 (M+, 10),
264 (100), 247 (80).
In search of a second generation compound to Sch 503034 (1)
we have identified a novel series of P4 sulfonamide-derived inhib-
itors that have improved enzyme binding (Kꢁi ) and cellular potency
(EC90) by 8–10-fold with respect to 1. Initially, novel valine-derived
diamine residues capped with sulfonamide groups were identified
as excellent P3 capping group that enhanced enzyme binding of
inhibitors of type 1. The replicon cellular potencies of these inhib-
itors were optimized by introduction of a methyl group at the sul-
fonamide nitrogen, and by identification of tert-butyl glycine as an
optimal P4 group. Primary ketoamide inhibitors of type 32 were
The isolated phthalimide derivative (4.00 g, 11.5 mmol) was
treated with hydrazine (2 M soln in ethanol, 25 mL) and stirred
achieved and shown to have EC90 < 0.1 lM.

S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
4491
at rt. overnight. The reaction mixture was filtered and the filtrate
was concentrated in vacuo to yield 7 (2.5 g ꢀ100%) which was used
in the next reaction without purification. 1H NMR (400 MHz,
DMSO-d6), d, 6.47 (d, 1H, J = 9.5 Hz), 3.11 (dt, 1H, J = 2.9 &
10.3 Hz), 2.66 (dd, 1H, J = 2.9 & 12.4 Hz), 2.33 (dd, 1H, J = 2.2 &
12.4 Hz), 1.37 (s, 3H), 0.79 (s, 3H). 13C NMR (100 MHz, DMSO-d6),
d, 157.2, 77.8, 62.6, 41.6, 39.6, 29.0, 27.3 MS (ESI, m/z relative inten-
sity) 239 [(M+Na)+, 10], 217[(M+1)+, 20], 161 (100), 117 (40).
was separated and washed with water. The organic layer was dried
(MgSO4), filtered, concentrated in vacuo and the residue was puri-
fied by chromatography (SiO2, EtOAc/Hexanes) to yield 14
(R5 = CH3, 93 mg, 50%) as a colorless solid; 1H NMR (400 MHz,
DMSO-d6), d, 6.15 (d, 1H, J = 10.3 Hz), 6.01 (d, 1H, J = 10.3 Hz),
4.23 (d, 1H, J = 10.3 Hz), 4.16 (s, 1H), 3.94 (d, 1H, J = 11.0 Hz),
3.77 (dd, 1H, J = 5.1 & 10.3 Hz), 3.62 (s, 3H), 3.62–3.57 (m, 1H),
3.20 (dd, 1H, J = 3.7 &, 10.3 Hz), 2.95 (dd, 1H, J = 11.0 & 3.0 Hz),
2.82 (s, 3H), 2.73 (s, 3H), 1.48 (dd, 1H, J = 5.9 & 7.3 Hz), 1.38 (d,
1H, J = 7.3 Hz), 0.97 (s, 3H), 0.91 (s, 9H), 0.78 (s, 9H), 0.75 (s, 3H).
13C NMR (125 MHz, DMSO-d6), d 172.4, 171.9, 158.8, 59.4, 57.7,
55.8, 52.7, 51.1, 47.8, 36.9, 35.2, 35.1, 34.9, 30.4, 27.7, 27.0, 26.9,
26.6, 19.6, 13.0; MS (ESI, m/z relative intensity) 539 [(M+Na)+,
50], 517 [(M+1)+, 100], 348 (100).
A solution of ester 14 (90.2 mg, 0.17 mmol) was dissolved in THF
and H2O (approximately 3:1 ratio) and treated with LiOHꢂH2O
(18 mg, 0.44 mmol). The reaction mixture was treated with MeOH
untilhomogeneous.The reactionmixturewasstirredatrtfor approx-
imately 3 h. The reaction mixture was treated with 1 M aq HCl and
concentrated in vacuo. The organic layer was extracted with CH2Cl2,
dried (MgSO4), filtered, and concentrated in vacuo to yield carboxylic
acid 15 that was used in the next step without purification.
5.1.3. (S)-N-(2-Amino-3,3-dimethylbutyl)methanesulfonamide
(7, R6 = Me, R5 = H, R4 = tert-butyl)
A solution of 6 (2.12 g, 9.8 mmol) in CH2Cl2 was cooled to 0 °C
and treated with Et3N (3.3 mL, 24.5 mmol) and methanesulfonyl
chloride (1.68 g, 17.7 mmol) and stirred at rt for 3 h. The reaction
mixture was diluted with CH2Cl2 and the residue was washed with
aq HCl (1 M), brine, dried (MgSO4), filtered, concentrated in vacuo,
and purified by chromatography (SiO2, acetone/hexanes) to yield
mesylated product which was deprotected in the next step.
1.62 g (5.5 mmol) of this mesylated product was dissolved in 4 M
HCl in dioxane and was stirred at rt for 1 h. The reaction mixture
was concentrated in vacuo to yield 7 which was used in the next
step without further purification.
5.1.4. (1R,2S,5S)-Methyl-3-((S)-3,3-dimethyl-2-((4-
5.1.7. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
nitrophenoxy)carbonylamino)butanoyl)-6,6-dimethyl-3-
dioxopropyl]-3-[2(S)-[[[[2,2-dimethyl-1(S)-[[methyl-
azabicyclo[3.1.0]hexane-2-carboxylate (13, R3 = tBu)
(methylsulfonyl)amino]methyl]propyl]amino]carbonyl]amino]-
3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]
hexane-2(S)-carboxamide (29)
A solution of amine 127 (R3 = tBu, 19.5 g, 61.16 mmol) in CH2Cl2
(200 mL) at ꢃ78 °C was treated with NMM (18.56 g, 183.47 mmol),
4-nitrophenyl chloroformate (14.80 g, 73.39 mmol) and stirred at
rt for 24 h. The reaction mixture was concentrated in vacuo, di-
luted with EtOAc (1 L) and washed with excess aq NaHCO3 (1 L),
brine (1 L), dried (MgSO4), filtered, concentrated in vacuo and puri-
fied by chromatography (SiO2, EtOAc/Hexanes) to yield 13 (19.4 g,
71%) as a colorless foam. 1H NMR (300 MHz, CDCl3), d, 8.24 (d, 2H,
J = 9.4 Hz), 7.28 (d, 2H, J = 9.4 Hz), 5.79 (d, 1H, J = 9.9 Hz), 4.51 (s,
1H), 4.30 (d, 1H, J = 9.4 Hz), 3.96–3.85 (m, 2H), 3.78 (s, 3H), 1.49
(d, 2H, J = 2.2 Hz), 1.11 (s, 9H), 1.05 (s, 3H), 0.92 (s, 3H).
A solution of 15 (220 mg, 0.438 mmol) was dissolved in 1:1 DCM/
DMF. It was cooled to ꢃ20 °C and was treated with amine
salt7(110 mg, 0.525 mmol), HATU (250 mg, 0.657 mmol), and
NMM (111 mg, 1.1 mmol). The mixture was stirred at ꢃ20 °C over-
nightand concentratedin vacuo. The residue was diluted with EtOAc
(200 ml) and washed with aqueous HCl (1 M soln.), satd aq NaHCO3
and brine. The reaction mixture was dried (MgSO4), filtered, concen-
trated in vacuo to yield 16 that was used as it is in the next step.
The crude hydroxy amide 16 (288 mg, 0.44 mmol) was dissolved
in 1:1 DMSO/DCM (5 ml). It was cooled to 0 °C and treated with EDCI
(843 mg, 4.4 mmol) and dichloroacetic acid (284 mg, 2.2 mmol). The
mixture was stirred at room temperature for 3 h. It was diluted with
EtOAcandwaswashedwith1 M NaHSO3, satdaq NaHCO3, andbrine.
The organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was purified by column chromatography
(SiO2, acetone/hexanes 3:7) to yield 29 as a colorless solid 1H NMR
(500 MHz, DMSO-d6), d, 8.29 (d, 1H, J = 7.3 Hz), 8.19 (d, 1H,
J = 7.3 Hz), 8.02 (s, 1H), 7.98 (s, 1H), 7.76 (s, 1H), 7.75 (s, 1H), 6.15
(d, 1H, J = 11.0 Hz), 6.14 (d, 1H, J = 11.0 Hz), 6.06–6.04 (m, 2H),
4.99–4.95 (m, 1H), 4.87–4.84 (m, 1H), 4.28 (s, 1H), 4.27 (s, 1H),
4.22 (dd, 2H, J = 6.0 & 3.7 Hz), 3.91 (t, 2H, J = 10.7 Hz), 3.80–3.74
(m, 2H), 3.64 (dt, 2H, J = 2.8 & 10.4 Hz), 3.22 (dd, 2H, J = 3.2 &
11.0 Hz), 3.01–2.95 (m, 2H), 2.85 (s, 6H), 2.76 (s, 6H), 2.00–0.77
(m, 22H), 1.00 (s, 3H), 0.99 (s, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.81 (s,
9H), 0.81 (s, 9H), 0.80 (s, 3H), 0.77 (s, 3H); 13C NMR (125 MHz,
DMSO-d6), d, 198.6, 197.9, 171.7, 171.7, 171.5, 171.4, 163.9, 163.7,
158.9, 158.8, 60.2, 59.9, 57.9, 57.8, 55.8, 52.9, 52.7, 51.1, 48.3, 48.2,
37.6, 37.5, 37.0, 36.9, 35.2, 35.1, 35.0, 34.9, 33.0, 31.5, 31.4, 28.8,
28.6, 28.2, 27.8, 27.6, 27.1, 26.9, 19.3, 18.7, 18.5, 13.4; MS (ESI, m/z
relative intensity) 655 [(M+1)+, 30], 348 (100).
5.1.5. (1R,5S)-Methyl-3-((S)-2-(3-((S)-3,3-dimethyl-1-
(methylsulfonamido)butan-2-yl)ureido)-3,3-
dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
carboxylate (14; R3 = R4 = tBu; R6 = Me; R5 = H)
A solution of 7 (1.48 g, 6.44) in dry dichloromethane was cooled
to 0 °C and was treated with Et3N (2.14 mL, 16.1 mmol) and 13
(2.88 g, 6.44 mmol) in CH2Cl2. The mixture was stirred at ꢃ20 °C
overnight. It was diluted with CH2Cl2 and washed with brine, then
it was dried and concentrated in vacuo. The crude product was
purified by column chromatography (EtOAc/Hexanes 0?50%) to
yield 14 as a colorless solid. 1H NMR (400 MHz, CDCl3), d, 5.79 (d,
1H, J = 9.5 Hz), 5.64 (bt, 1H, J = 5.13 Hz), 5.11 (br s, 1H), 4.41 (d,
1H, J = 9.5 Hz), 4.39 (s, 1H), 3.96 (d, 1H, J = 10.3 Hz), 3.86 (dd, 1H,
J = 5.1 & 5.3 Hz), 3.71 (s, 3H), 3.60 (bt, 1H, J = 8.8 Hz), 3.42–3.37
(m, 1H), 1.48–1.39 (m, 2H), 1.00 (s, 3H), 0.98 (s, 9H), 0.84 (s, 9H),
0.83 (s, 3H); 13C NMR (125 MHz, CDCl3), d, 172.6, 172.3, 159.4,
60.1, 58.5, 52.6, 48.1, 44.6, 41.4, 35.5, 34.5, 30.6, 26.8, 26.8, 26.5,
19.8, 12.8, 28.0; MS (ESI, m/z relative intensity) 1028 [(2 M+Na),
20], 525 [(M+Na), 50], 503 [(M+1)+, 90], 344 (100).
5.1.6. (1R,5S)-3-((S)-2-(3-((S)-3,3-Dimethyl-1-(N-methyl-
methylsulfonamido)butan-2-yl)ureido)-3,3-dimethylbutanoyl)-
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (14;
R3 = R4 = tBu; R6 = R5 = Me)
5.1.8. (1R,5S)-N-[3-Amino-1-(cyclopropylmethyl)-2,3-
dioxopropyl]-3-[3,3-dimethyl-2(S)-[[[[2-methyl-1(R)-
[[methyl(phenylsulfonyl)amino]methyl]propyl]amino]-
carbonyl]amino]-1-oxobutyl]-6,6-dimethyl-3-
A solution of 14 (R5 = H, 200 mg, 0.39 mmol) in dry DMF
(5.00 mL) was treated with Cs2CO3 (194.5 mg, 0.59 mmol) and
azabicyclo[3.1.0]hexan-2(S)-carboxamide (19)
methyl iodide (123.8
lL, 1.98 mmol) and was stirred at rt for 4 h.
1H NMR (500 MHz, DMSO-d6), d, 8.38 (d, 1H, J = 6.5 Hz), 8.32 (d,
1H, J = 7.5 Hz), 8.01 (s, 1H), 7.99 (s, 1H), 7.77–7.69 (m, 12H), 6.16
The reaction mixture was diluted with EtOAc and the organic layer

4492
S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
(d, 1H, J = 10.0 Hz), 6.13 (d, 1H, J = 10.0 Hz), 5.98 (d, 2H, J = 9.5 Hz),
5.12–5.08 (m, 1H), 5.07–5.03 (m,1H), 4.33–4.26 (m, 2H), 4.22–4.15
(m, 4 H), 3.92–3.88 (m, 2H), 3.79–3.73 (m, 2H), 2.98–2.94 (m, 2H),
2.75–2.71 (m, 2H), 2.64 (s, 6H), 1.78–1.31 (m, 10 H), 1.01 (s, 3H),
0.99 (s, 3H), 0.91–0.86 (m, 20 H), 0.81–0.77 (m, 18H), 0.43–0.37
(m, 4 H), 0.31–0.04 (m, 4 H); 13C NMR (125 MHz, DMSO-d6), d,
198.4, 197.9, 171.8, 171.6, 171.5, 171.4, 163.8, 163.5, 158.8,
158.7, 137.6, 133.7, 130.2, 127.9, 60.3, 60.2, 59.9, 58.0, 57.9, 55.0,
52.8, 52.4, 48.3, 35.9, 35.9, 35.2, 31.5, 31.4, 29.8, 27.7, 27.6, 27.2,
27.0, 26.9, 20.5, 19.3, 16.9, 13.4, 13.3, 8.7, 8.5, 5.9, 5.2, 4.9; MS
(ESI, m/z relative intensity) MS (ESI, m/z relative intensity) 743
[(M+CH3OH+Na)+, 20], 711 [(M+Na)+, 10], 689 [(M+1)+, 50], 396
(100), 129 (70).
3.66 (m, 4 H), 3.00 (s, 1H), 2.97–2.94 (m, 1H), 2.75–2.70 (m, 1H),
2.69 (s, 1H), 2.64 (s, 3H), 2.61 (s, 3H), 1.86–1.28 (m, 24 H), 1.00
(s, 3H), 0.99 (s, 3H), 0.91 (m, 18H), 0.81–0.78 (m, 18H). 13C NMR
(125 MHz, DMSO-d6), d, 198.6, 197.9, 171.7, 171.6, 171.5, 171.3,
163.9, 163.7, 158.8, 158.7, 137.6, 133.7, 130.2, 127.9, 60.2, 60.0,
58.0, 57.9, 52.9, 52.8, 52.7, 52.3, 48.2, 37.6, 36.5, 35.9, 35.2, 33.0,
31.5, 29.8, 28.7, 28.6, 28.2, 27.1, 26.9, 27.8, 27.6, 20.4, 18.7, 19.3,
18.5, 16.9, 13.3; MS (ESI, m/z relative intensity) 757 [(M+CH3OH+-
Na)+, 20], 725 [(M+Na)+, 10], 703 [(M+1)+, 50], 396 (100), 129 (40).
5.1.12. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-6,6-dimethyl-3-[2(S)-[[[[2(S)-methyl-1(S)-
[[methyl(phenylsulfonyl)amino]methyl]butyl]amino]-
carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-3-
5.1.9. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-3-[3,3-dimethyl-2(S)-[[[[2-methyl-1(S)-
[[(methylsulfonyl)amino]methyl]propyl]amino]-
carbonyl]amino]butyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-
2(S)-carboxamide (20)
azabicyclo[3.1.0]hexane-2(S)-carboxamide (25)
1H NMR (500 MHz, DMSO-d6), d, 8.29 (d, 1H, J = 7.3 Hz), 8.18 (d,
1H, J = 7.6 Hz), 8.02 (s, 1H), 7.98 (s, 1H), 7.77–7.62 (m, 12H), 6.16
(d, 1H, J = 9.7 Hz), 6.14 (d, 1H, J = 9.4 Hz), 6.01 (d, 2H, 9.5 Hz),
4.99–4.95 (m, 1H), 4.88–4.84 (m, 1H), 4.29 (s, 1H), 4.28 (s, 1H),
4.19 (dd, 2H, J = 7.3 & 10.1 Hz), 3.89 (t, 2H, J = 11.1 Hz), 3.79–3.70
(m, 4 H), 3.00 (d, 1H, J = 6.3 Hz), 2.97 (d, 1H, J = 5.7 Hz), 2.80–2.75
(m, 2H), 2.64 (s, 6H), 2.01–1.93 (m, 4 H), 1.84–1.64 (m, 4 H), 1.65–
1.56 (m, 4 H), 1.49–1.40 (m, 6H), 1.30–0.79 (m, 28 H), 1.01 (s, 3H),
1.00 (s, 3H), 0.91 (s, 9H), 0.90 (s, 9H); 13C NMR (125 MHz, DMSO-
d6), d, 198.6, 197.9, 171.7, 171.5, 171.3, 163.9, 163.7, 158.7,
158.6, 137.8, 133.7, 130.2, 127.9, 60.2, 60.0, 58.0, 57.9, 52.9, 52.7,
52.3, 48.2, 37.6, 37.5, 37.1, 36.0, 35.2, 33.0, 32.1, 31.5, 31.4, 29.2,
28.7, 28.6, 28.2, 27.8, 27.6, 27.1, 26.9, 24.3, 22.9, 19.3, 18.7, 18.5,
16.4, 16.4, 16.3, 14.7, 13.3, 12.4; MS (ESI, m/z relative intensity)
717 [(M+1)+, 100], 410(88).
1H NMR (500 MHz, DMSO-d6), d, 8.29 (d, 1H, J = 7.5 Hz), 8.19 (d,
1H, J = 7.5 Hz), 8.01 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.75 (s, 1H),
6.95 (d, 1H, J = 6.0 Hz), 6.93 (d, 1H, J = 5.5 Hz), 6.17–6.13 (m, 2H),
5.97 (d, 1H, J = 9.5 Hz), 5.96 (d, 1H, J = 9.0 Hz), 4.96–4.95 (m, 1H),
4.92 (d, 1H, J = 11.0 Hz), 4.88–4.84 (m, 1H), 4.74 (d, 1H,
J = 11.0 Hz), 4.29 (s, 1H), 4.28 (s, 1H), 4.24–4.18 (m, 2H), 3.94–
3.74 (m, 4 H), 3.58–3.51 (m, 2H), 2.95–2.83 (m, 2H), 2.88 (s, 3H),
2.70 (s, 3H), 1.99–1.27 (m, 24 H), 1.01 (s, 3H), 1.00 (s, 3H), 0.92
(s, 9H), 0.91 (s, 9H), 0.79–0.76 (m, 18H); 13C NMR (125 MHz,
DMSO-d6), d, 198.6, 197.9, 171.7, 171.6, 171.5, 171.4, 163.9,
163.7, 159.0, 158.9, 60.3, 60.2, 60.0, 58.1, 58.0, 58.0, 54.4, 53.0,
52.7, 48.3, 48.2, 45.9, 39.1, 37.6, 37.5, 36.6, 35.2, 33.1, 33.0, 31.5,
31.4, 29.6, 29.6, 28.8, 28.7, 28.6, 28.5, 28.3, 27.7, 27.0, 20.3, 19.3,
18.7, 18.6, 17.4, 13.4, 13.3; MS (ESI, m/z relative intensity) 649
[(M+Na)+, 10], 627 [(M+1)+, 40], 117 (100).
5.1.13. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-3-[2(S)-[[[[2,2-dimethyl-1(S)-
[[methyl(phenylsulfonyl)amino]methyl]propyl]amino]-
carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hexane-2(S)-carboxamide [26]
5.1.10. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-3-[3,3-dimethyl-2(S)-[[[[2-methyl-1(S)-
[[methyl(2-thienylsulfonyl)amino]methyl]propyl]amino]-
carbonyl]amino]-1-oxobutyl]-6,6-dimethyl-3-
1H NMR (500 MHz, DMSO-d6), d 8.28 (d, 1H, J = 7.5 Hz), 8.17 (d,
1H, J = 7.5 Hz), 8.02 (s, 1H), 7.98 (s, 1H), 7.77 (bd, 6H), 7.69 (bt, 2H),
7.62 (bt, 4 H), 6.15 (d, 1H, J =7.5 Hz), 6.13 (d, 1H, J = 7.5 Hz), 6.04 (d,
2H, J = 10 Hz), 4.99- 4.95 (m, 1H), 4.89–4.85 (m, 1H), 4.28 (s, 1H),
4.27 (s, 1H), 4.24 (dd, 2H, J = 7.0 & 4.8 Hz), 3.92 (t, 2H, J = 8.8 Hz),
3.81–3.74 (m, 2H), 3.64 (dt, 2H, J =10 & 2.5 Hz), 3.03 (bt, 1H,
J = 3.0 Hz), 3.00 (bt, 1H, J =3.0 Hz), 2.91–2.86 (m, 2H), 2.63 (s,
6H), 2.52–2.45 (m, 1H), 2.41–2.33 (m, 1H), 2.01–1.89 (m, 4 H),
1.82–1.55 (m, 12H), 1.45–1.42 (m, 2H), 1.28 (dd, 2H, J = 6.0 &
4.0 Hz), 1.00 (s, 3H), 0.99 (s, 3H), 0.93 (s, 9H), 0.92 (s, 9H), 0.82
(s, 9H), 0.81 (s, 9H), 0.78 (s, 3H), 0.77 (s, 3H). 13C NMR (125 MHz,
DMSO-d6), d, 198.6; 197.9; 171.7; 171.7; 171.6; 171.4; 163.9;
163.7; 158.8; 158.8; 138.1; 133.6; 130.2; 127.9; 60.2; 60.0; 57.9;
57.8; 56.1; 52.9; 52.7; 51.3; 51.3; 48.3; 48.2; 37.6; 37.5; 35.8;
35.2; 35.2; 35.1; 35.0; 33.0; 33.0; 31.5; 31.4; 28.8; 28.6; 28.2;
27.8; 27.6; 27.1; 27.0; 26.9; 19.3; 18.7; 18.6; 13.4; 13.3; MS (ESI,
m/z relative intensity) 717 [(M+1)+, 100], 410 (60), 126 (30).
azabicyclo[3.1.0]hexane-2(S)-carboxamide (23)
1H NMR (500 MHz, DMSO-d6), d, 8.29 (d, 1H, J = 7.3 Hz), 8.18 (d,
1H, J = 7.6 Hz), 8.01 (d, 2H, J = 4.7 Hz), 8.02–8.00 (br s, 1H), 7.98 (s,
1H), 7.77 (s, 1H), 7.76 (s, 1H), 7.66 (d, 2H, J = 4.2 Hz), 7.26 (t, 2H,
J = 4.7 Hz), 6.17 (d, 1H, J = 6.6 Hz), 6.15 (d, 1H, J = 6.9 Hz), 6.00 (d,
2H, J = 9.1 Hz), 4.29 (s, 1H), 4.28 (s, 1H), 4.22–4.19 (m, 2H), 3.91–
3.70 (m, 8 H), 2.96 (dd, 2H, J = 6.6 & 13.2Hz), 2.73 (dd, 2H, J = 7.8
& 12.6 Hz), 2.68 (s, 6H), 1.98–1.95 (m, 4 H), 1.81–1.58 (m, 16H),
1.44–1.41 (m, 2H), 1.28 (t, 2H, J = 7.3 Hz), 1.01 (s, 3H), 1.00 (s,
3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.81 (s, 3H), 0.80 (d, 6H, J = 6.9 Hz),
0.79 (s, 3H), 0.79 (d, 6H, J = 6.9 Hz). 13C NMR (125 MHz, DMSO-
d6), d, 198.6, 197.9, 171.7, 171.6, 158.8, 158.7, 134.0, 133.2,
129.0, 137.4, 60.2, 60.0, 58.0, 53.0, 52.7, 52.4, 52.9, 48.3, 36.1,
37.6, 37.5, 35.2, 33.0, 31.5, 31.4, 29.8, 28.7, 28.6, 28.2, 27.8, 27.6,
27.1, 26.9, 20.4, 19.3, 18.7, 18.5, 16.9, 13.3. MS (ESI, m/z relative
intensity) 709 [(M+1)+, 15], 402 (100), 374 (30), 308 (45).
5.1.14. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-3-[2(S)-[[[[1,3-dimethyl-1-
5.1.11. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-3-[3,3-dimethyl-2(S)-[[[[2-methyl-1(R)-
[[methyl(phenylsulfonyl)amino]methyl]propyl]amino]-
carbonyl]amino]-1-oxobutyl]-6,6-dimethyl-3-
[[methyl(phenylsulfonyl)amino]methyl]butyl]amino]-
carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hexan-2(S)-carboxamide (27)
1H NMR (500 MHz, DMSO-d6), d, 8.29, 8.27 (2d, 1H, J = 7.6 Hz),
8.23, 8.20 (2 d, 1H, J = 7.3 Hz), 8.01 (s, 1H), 7.97 (s, 1H), 7.76–
7.62 (m, 12H), 6.12–6.09 (m, 2H), 5.97 (d, 2H), 4.97–4.91 (m,
1H), 4.86–4.83 (m, 1H), 4.24 (s, 1H), 4.19 (s, 1H), 4.13–4.07 (m,
2H), 3.81–3.70 (m, 4 H), 2.64, 2.61 (s, 3H), 2.61 (s, 3H), 1.99–1.13
(m, 28 H), 1.16 (s, 3H), 1.13 (s, 3H), 0.98–0.54 (m, 46H); 13C NMR
(125 MHz, DMSO-d6), d, 198.6, 197.9, 171.7, 171.5, 171.3, 163.9,
azabicyclo[3.1.0]hexan-2(S)-carboxamide (24)
1H NMR (500 MHz, DMSO-d6), d, 8.29 (d, 1H, J = 7.3 Hz), 8.18 (d,
1H, J = 6.9 Hz), 8.02 (s, 1H), 7.98 (s, 1H), 7.78–7.62 (m, 12H), 6.17
(d, 1H, J = 8.0 Hz), 6.15 (d, 1H, J = 10.5 Hz), 5.98 (d, 2H, J = 7.9 Hz),
5.00–4.95 (m, 1H), 4.92 (d, 1H, J = 10.7 Hz), 4.89–4.83 (m, 1H),
4.74 (d, 1H, J = 11.3 Hz), 4.28 (s, 2H), 4.22–4.18 (m, 2H), 3.95–

S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
4493
163.7, 157.7, 137.9, 137.8, 133.7, 130.2, 127.9, 60.2, 59.9, 57.5,
5.1.18. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-3-[2(s)-[[[[2,2-dimethyl-1(S)-
[[methyl(2-pyridinylsulfonyl)amino]methyl]propyl]amino]
carbonyl]amino]-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-
3-azabicyclo[3.1.0]hexane-2(S)-carboxamide (33)
57.3, 56.9, 56.8, 56.1, 52.9, 52.7, 48.3, 45.0, 43.0, 37.8, 37.6, 37.5,
36.5, 35.2, 35.1, 33.0, 32.9, 31.4, 28.7, 28.6, 28.2, 27.8, 27.7, 27.1,
26.8, 26.0, 25.9, 24.7, 24.6, 26.8, 24.2, 24.1, 24.1, 19.3, 18.7, 18.5,
19.2, 13.5, 13.2; MS (ESI, m/z relative intensity) 731 [(M+1)+, 40],
424 (100).
1H NMR (500 MHz, DMSO-d6), d 8.75 (d, 2H, J = 4.0 Hz), 8.26 (s,
1H), 8.25 (s, 1H), 8.09 (dt, 2H, J =2.0 & 7.5 Hz), 8.05–7.98 (m, 3H),
7.91 (d, 1H, J = 8.0 Hz), 7.77 (s, 2H), 7.70–7.67 (m, 2H), 6.17 (d,
1H, J = 9.5 Hz), 6.15 (d, 1H, J = 10.0 Hz), 6.00–5.99 (dd, 2H, J = 8.0
& 10.0 Hz), 5.02–4.93 (m, 1H), 4.88–4.81 (m, 1H), 4.32–4.22 (m, 4
H), 3.98 (d, 1H, J =10.5 Hz), 3.94 (d, 1H, J =10.0 Hz), 3.84–3.81 (m,
1H), 3.79–3.76 (m, 1H), 3.67 (t, 2H, J = 10.5 Hz), 3.30–3.27 (b,
2H), 3.02 (t, 2H, J =10.5 Hz), 2.78 (s, 6H), 2.03–1.93 (m, 4 H),
1.87–0.75 (m, 44 H), 1.00 (s, 3H), 0.99 (s, 3H), 0.96 (s, 9H), 0.81
(s, 9H), 0.79 (s, 3H), 0.78 (s, 3H). 13C NMR (125 MHz, DMSO-d6),
d, 198.6, 198.2, 198.0, 171.7, 171.6, 171.6, 171.3, 163.9, 163.7,
158.8, 158.7, 157.2, 151.0, 139.5, 127.9, 123.3, 60.4, 60.0, 58.3,
58.3, 56.2, 53.0, 52.7, 52.3, 48.3, 48.2, 37.9, 37.7, 37.6, 36.4, 35.0,
34.9, 34.5, 34.3, 34.1, 34.1, 33.0, 33.0, 31.4, 28.8, 28.6, 28.3, 28.2,
27.8, 27.6, 27.0, 26.9, 26.9, 26.7, 22.2, 22.0, 20.1, 20.0, 19.3, 19.3,
18.7, 18.5, 13.4, 13.3. MS (ESI, m/z relative intensity) 780
[(M+Na)+, 10], 758 [(M+1)+, 60], 451 (100).
5.1.15. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-3-[3,3-dimethyl-2(S)-[[[[1-[[methyl(phenylsulfonyl)
amino]methyl]cyclohexyl]amino]carbonyl]amino]-1-
oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-
carboxamide (28)
1H NMR (500 MHz, DMSO-d6), d, 8.27 (d, 1H, J = 7.3 Hz), 8.18 (d,
1H, J = 7.3 Hz), 8.01 (s, 1H), 7.97 (s, 1H), 7.77–7.64 (m, 12H), 6.27–
6.21 (m, 2H), 5.93 (s, 2H), 4.99–4.94 (m, 1H), 4.87–4.83 (m, 1H),
4.22 (s, 2H), 4.16–4.05 (m, 2H), 3.86–3.81 (m, 2H), 3.74–3.69 (m,
2H), 3.22–3.14 (m, 4 H), 2.60 (2s, 6H), 1.98–0.87 (m, 42H), 0.96
(s, 3H), 0.95 (s, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.63 (s, 3H), 0.61 (s,
3H); 13C NMR (125 MHz, DMSO-d6), d, 198.6, 197.9, 171.7, 171.4,
163.9, 163.7, 157.8, 157.7, 137.9, 133.7, 130.2, 127.9, 60.2, 59.9,
57.5, 57.4, 56.9, 55.1, 52.9, 52.7, 48.2, 43.0, 38.0, 37.6, 37.5, 35.0,
33.7, 33.5, 33.0, 32.9, 31.4, 31.3, 28.7, 28.6, 28.2, 27.8, 27.6, 26.9,
26.2, 21.4, 21.3, 19.2, 18.7, 18.5, 13.2, 13.1; MS (ESI, m/z relative
intensity) 751 [(M+Na)+, 25], 729 [(M+1)+, 85], 422 (20), 117 (100).
5.1.19. (1R,5S)-N-[1-(Propyl)-2,3-dioxo-2-(2-propenylamino)
propyl]-3-[2(S)-[[[[1(S)-[[(ethylsulfonyl)methylamino]methyl]-
2,2-dimethylpropyl]amino]carbonyl]amino]-3,3-dimethyl-1-
oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-
carboxamide (34)
5.1.16. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]-3-[2(S)-[[[[1(S)-[[(ethylsulfonyl)methylamino]
methyl]-2,2-dimethylpropyl]amino]carbonyl]amino]-3,3-
dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-
2(S)-carboxamide [30]
1H NMR (500 MHz, DMSO-d6), d 8.87 (t, 1H, J = 6.0 Hz), 8.81 (t,
1H, J = 6.0 Hz), 8.38 (d, 1H, J = 6.5 Hz), 8.33 (d, 1H, J = 7.0 Hz),
6.12 (d, 1H, J = 10.5 Hz), 6.10 (d, 1H, J = 11.0 Hz), 6.06 (d, 1H,
J = 4.0 Hz), 6.04 (d, 1H, J = 4.5 Hz), 5.84–5.76 (m, 2H), 5.13–5.05
(m, 4 H), 5.00–4.96 (m, 1H), 4.95–4.85 (m, 1H), 4.29 (s, 1H), 4.28
(s, 1H), 4.22 (d, 1H, J = 4.5 Hz), 4.20 (d, 1H, J = 4.5 Hz), 3.93–3.89
(m, 2H), 3.80–3.71 (m, 6H), 3.63 (dt, 2H, J = 10 & 2.5 Hz), 3.26 (b,
1H), 3.23 (b, 1H), 3.06–3.00 (m, 6H), 2.78 (s, 6H), 1.74–1.65 (m,
2H), 1.55–1.23 (m, 10 H), 1.18 (t, 6H), 1.07 (s, 3H), 0.99 (s, 3H),
0.90 (s, 18H), 0.90–0.85 (m, 6H), 0.80 (s, 21H), 0.77 (s, 3H). 13C
NMR (125 MHz, DMSO-d6), d, 224.4, 198.2, 197.6, 171.9, 171.7,
171.6, 171.5, 162.0, 161.6, 158.9, 158.9, 135.0, 135.0, 116.4,
116.4, 60.2, 59.9, 58.0, 57.9, 55.9, 54.4, 54.3, 50.9, 48.3, 45.3,
45.2, 41.7, 35.4, 35.1, 35.1, 35.0, 35.0, 32.5, 31.5, 31.5, 27.8, 27.7,
27.1, 27.0, 19.5, 19.4, 19.3, 19.3, 14.4, 14.3, 13.4, 13.4, 8.7. MS
(ESI, m/z relative intensity) 683 [(M+1)+, 100], 362 (30).
1H NMR (500 MHz, DMSO-d6), d, 8.29 (d, 1H, J = 7.3 Hz), 8.19 (d,
1H, J = 7.6 Hz), 8.02 (s, 1H), 7.98 (s, 1H), 7.76 (s, 1H), 7.75 (s, 1H),
6.14–6.11 (m, 2H), 6.06–6.03 (m, 2H), 4.99–4.95 (m, 1H), 4.88–
4.84 (m, 1H), 4.28 (s, 1H), 4.27 (s, 1H), 4.24–4.20 (m, 2H), 3.90 (s,
1H), 3.89 (s, 1H), 3.82–3.74 (m, 2H), 3.63 (dt, 2H, J = 2.8 &
10.7 Hz), 3.26 (b, 1H), 3.23 (b, 1H), 3.06–3.00 (m, 6H), 2.79 (s,
3H), 2.78 (s, 3H), 2.00–1.93 (m, 4 H), 1.81–1.54 (m, 12H), 1.44–
1.41 (m, 2H), 1.28 (dd, 2H, J = 5.3
& 7.5 Hz), 1.18 (t, 6H,
J = 7.2 Hz), 1.19–1.15 (m, 2H), 1.01 (s, 3H), 0.99 (s, 3H), 0.92 (s,
9H), 0.91 (s, 9H), 0.81 (s, 18H), 0.79 (s, 3H), 0.77 (s, 3H);13C NMR
(125 MHz, DMSO-d6), d, 198.6, 197.9, 171.7, 171.5, 171.4, 163.9,
163.7, 158.9, 158.8, 60.2, 59.9, 58.0, 57.9, 55.9, 55.8, 52.9, 52.7,
50.9, 48.3, 45.3, 45.2, 37.6, 37.5, 35.3, 35.1, 35.0, 33.0, 31.5, 31.4,
30.4, 28.8, 28.6, 28.2, 27.8, 27.6, 27.1, 26.9, 19.3, 18.7, 18.5, 13.4,
13.4, 8.6. MS (ESI, m/z relative intensity) 669 [(M+1)+, 50], 362
(100).
5.1.20. (1R,5S)-N-[1-(Propyl)-2,3-dioxo-3-(2-propenylamino)
propyl]-3-[2(S)-[[[[2,2-dimethyl-1(S)-[[methyl(2-
5.1.17. (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-
thienylsulfonyl)amino]methyl]propyl]amino]carbonyl]amino]-
3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]
hexane-2(S)-carboxamide (35)
dioxopropyl]-3-[2(S)-[[[[1(S)-[[(cyclopropylsulfonyl)methyl-
amino]methyl]-2,2-dimethylpropyl]amino]carbonyl]amino]-
3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-
1H NMR (500 MHz, DMSO-d6), d, 8.85 (t, 1H, J = 6.0 Hz), 8.82 (t,
1H, J = 6.0 Hz), 8.38 (d, 1H, J = 6.5 Hz), 8.31 (d, 1H, J = 7.5 Hz), 7.99
(dd, 2H, J = 5.0 & 1.0 Hz), 7.65 (dd, 2H, J = 1.0 & 4.0 Hz), 7.25 (dd,
2H, J = 3.5 & 1.0 Hz), 6.14–5.30 (m, 4 H), 5.84–5.76 (m, 2H), 5.13–
5.05 (m, 4 H), 5.00–4.96 (m, 1H), 4.91–4.86 (m, 1H), 4.30 (s, 1H),
4.28 (s, 1H), 4.24 (d, 1H, J = 9.5 Hz), 4.23 (d, 1H, J = 10.0 Hz), 3.93
(d, 1H, J = 9.5 Hz), 3.92 (d, 1H, J = 9.5 Hz), 3.81 – 3.64 (m, 8 H),
3.02 (bd, 2H, J = 12.5 Hz), 2.86 (bt, 2H, J = 12.5 Hz), 2.68 (s, 6H),
1.79–1.62 (m, 2H), 1.55 – 1.24 (m, 10 H), 1.07 (s, 3H), 0.99 (s,
3H), 0.72 (s, 18H), 0.82 (s, 18H), 0.80 (s, 3H), 0.77 (s, 3H), 0.93–
0.86 (m, 6H).13C NMR (125 MHz, DMSO-d6), d, 198.2, 197.6,
171.9, 171.8, 171.6, 171.4, 162.0, 161.6, 158.9, 158.8, 137.9,
135.1, 135.0, 133.8, 132.9, 128.9, 116.5, 116.4, 60.2, 59.9, 57.9,
57.8, 56.1, 54.4, 54.3, 51.6, 48.2, 48.2, 41.7, 36.0, 35.2, 35.0, 35.0,
32.5, 31.5, 27.8, 27.7, 27.1, 27.0, 19.5, 19.4, 19.3, 14.4, 14.3, 13.4,
13.3. MS (ESI, m/z relative intensity) 737 [(M+1)+, 100], 416 (30).
azabicyclo[3.1.0]hexane-2(S)-carboxamide (31)
1H NMR (500 MHz, DMSO-d6), d, 8.29 (d, 1H, J = 7.3 Hz), 8.18 (d,
1H, J = 7.6 Hz), 8.01(s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.75 (s, 1H),
6.15–6.13 (m, 2H), 6.06–6.04 (m, 2H), 4.99–4.95 (m, 1H), 4.88–
4.84 (m, 1H), 4.27 (2 s, 2H), 4.22 (d, 1H, J = 6.6 Hz), 4.20 (d, 1H,
J = 6.6 Hz), 3.90 (t, 2H, J = 10.1 Hz), 3.79–3.73 (m, 2H), 3.69–3.65
(m, 2H), 3.03–2.97 (m, 2H), 2.79 (s, 6H), 2.58–2.54 (m, 4 H),
2.03–1.94 (m, 4 H), 1.81–1.73 (m, 6H), 1.66–155 (m, 6H), 1.49–
1.26 (m, 4 H), 1.00 (s, 3H), 0.99 (s, 3H), 0.90 (s, 9H), 0.89 (s, 9H),
0.81 (s, 18H), 0.79 (s, 3H), 0.77 (s, 3H), 2.02–0.76 (m, 10 H); 13C
NMR (125 MHz, DMSO-d6), d, 198.6, 197.9, 171.7, 171.5, 171.4,
163.7, 158.9, 158.8, 60.2, 59.9, 58.0, 57.9, 56.0, 52.9, 52.7, 51.3,
48.3, 37.6, 35.7, 35.1, 35.0, 33.0, 33.0, 31.5, 31.4, 31.3, 28.7, 28.6,
28.3, 28.2, 27.6, 27.5, 27.1, 26.9, 19.3, 18.7, 18.5, 13.4, 13.4, 4.9,
4.8. MS (ESI, m/z relative intensity) 681 [(M+1)+, 20], 374 (100).

4494
S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
5.1.21. (1R,5S)-N-[1-(Propyl)-2,3-dioxo-3-(2-propenylamino)
propyl]-3-[2(S)-[[[[2,2-dimethyl-1(S)-[[methyl(2-
5.1.24. (1R,5S)-3-[2(S)-(2,3-Dihydro-1H-inden-2-yl)-2-[[[[1(S)-
[[[(dimethylamino)sulfonyl]methylamino]methyl]-2,2-
thienylsulfonyl)amino]methyl]propyl]amino]carbonyl]amino]-
3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]-
hexane-2(S)-carboxamide (36)
dimethylpropyl]amino]carbonyl]amino]acetyl]-N-[1-[1,2-
dioxo-2-(2-propenylamino)ethyl]butyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hexane-2(S)-carboxamide (40)
1H NMR (500 MHz, DMSO-d6), d, 8.88 (t, 1H, J = 6.0 Hz), 8.82 (t,
1H, J = 6.0 Hz), 8.75 (d, 2H, J = 4.5 Hz), 8.38 (d, 1H, J = 6.5 Hz), 8.30
(d, 1H, J = 7.5 Hz), 8.10 (dt, 2H, J = 1.5 & 7.5 Hz), 7.91 (d, 2H,
J = 8.0 Hz), 7.68 (dd, 2H, J = 5.0 & 3.0 Hz), 6.14 (d, 1H, J = 10.5 Hz),
6.11 (d, 1H, J = 9.5 Hz), 6.04 (d, 2H, J = 10.0 Hz), 5.84–5.76 (m,
2H), 5.13–5.05 (m, 4 H), 5.00–4.96 (m, 1H), 4.92–4.85 (m, 1H),
4.30 (s, 1H), 4.28 (s, 1H), 4.24 (d, 1H, J = 10 Hz), 4.23 (d, 1H,
J = 10 Hz), 4.00–3.91 (m, 2H), 3.80–3.64 (m, 8 H), 3.31–2.92 (m,
2H), 3.03 (bt, 2H, J = 13.0 Hz) 2.78 (s, 6H), 1.75–1.66 (m, 2H),
1.57–1.24 (m, 10 H), 1.09 (s, 3H), 0.99 (s, 3H), 0.92 (s, 18H),
0.92–0.85 (m, 6H), 0.81 (s, 21H), 0.78 (s, 3H). 13C NMR (125 MHz,
DMSO-d6), d 198.2, 197.6, 171.9, 171.8, 171.6, 171.4, 162.0, 161.6,
158.8, 158.7, 157.2, 151.0, 139.5, 135.0, 135.0, 127.9, 123.3,
116.4, 116.4, 60.2, 59.9, 57.9, 57.8, 56.3, 54.4, 54.3, 52.3, 48.2,
41.7, 36.4, 35.2, 35.2, 35.0, 35.0, 32.5, 31.5, 31.5, 27.8, 27.7, 27.2,
27.0, 27.0, 26.9, 19.5, 19.4, 19.3, 19.3, 14.4, 14.3, 13.4, 13.3. MS
(ESI, m/z relative intensity) 754 [(M+Na)+, 20], 732 [(M+1)+, 100],
411 (30).
1H NMR (500 MHz, DMSO-d6), d, 8.90 (t, 1H, J = 6.0 Hz), 8.87 (t,
1H, J = 6.0 Hz), 8.43 (d, 1H, J = 6.6 Hz), 8.29 (d, 1H, J = 7.5 Hz), 7.20–
7.10 (m, 8 H), 6.28 (d, 1H, J = 9.1 Hz), 6.26 (d, 1H, J = 9.1 Hz), 5.89
(d, 2H, J = 10.0 Hz), 5.85–5.78 (m, 2H), 5.15–5.06 (m, 4 H), 5.03–
4.96 (m, 2H), 4.33–4.27 (m, 4 H), 3.85–3.71 (m, 8 H), 3.65–3.60
(m, 4 H), 3.22–3.18 (m, 2H), 3.00–2.63 (m, 8 H), 3.73 (s, 3H), 2.72
(s, 3H), 2.70 (s, 12H), 1.77–1.26 (m, 10 H), 1.00 (s, 3H), 0.99 (s,
3H), 0.82 (s, 9H), 0.81 (s, 9H), 0.93–0.80 (m, 16H); 13C NMR
(125 MHz, DMSO-d6), d, 198.2, 197.8, 171.9, 171.8, 171.6, 171.5,
161.8, 161.7, 158.7, 143.3, 143.3, 143.2, 143.2, 135.0, 135.0,
127.0, 126.9, 125.2, 125.2, 125.0, 116.4, 116.4, 60.6, 60.1, 58.7,
55.9, 54.5, 54.3, 51.6, 49.0, 42.5, 42.4, 41.7, 38.5, 36.0, 35.9, 35.6,
34.8, 33.7, 32.6, 32.4, 31.7, 31.6, 31.0, 27.6, 27.4, 27.0, 26.9, 26.8,
25.8, 19.6, 19.6, 19.4, 19.4, 14.4, 14.4, 13.5, 13.4; MS (ES) m/z rela-
tive intensity 758 [(M+1)+, 100], 495 (34), 437 (43).
References and notes
1. (a) World health organization Fact sheet number 164, October 2000.; (b)
Wasley, A.; Alter, M. J. Semin. Liver Dis. 2000, 20, 1; (c) Brown, R. S., Jr.; Gaglio, P.
J. Liver Transpl. 2003, 9, S10.
5.1.22. (1R,5S)-3-[2(S)-(2,3-Dihydro-1h-inden-2-yl)-2-[[[[1(S)-
[[(ethylsulfonyl)methylamino]methyl]-2,2-dimethylpropyl]
amino]carbonyl]amino]acetyl]-N-[1-[1,2-dioxo-2-(2-
propenylamino)ethyl]butyl]-6,6-dimethyl-3-azabicyclo[3.1.0]-
hexane-2(S)-carboxamide (37)
2. (a) McHutchison, J. G.; Gordon, S. C.; Schiff, E. R.; Shiffman, M. L.; Lee, W. M.;
Rustgi, V. K.; Goodman, Z. D.; Ling, M.-H.; Cort, S.; Albrecht, J. K. N. Eng. J. Med.
1998, 339, 1485; (b) Davis, G. L.; Esteban-Mur, R.; Rustgi, V.; Hoefs, J.; Gordon,
S. C.; Trepo, C.; Shiffman, M. L.; Zeuzem, S.; Craxi, A.; Ling, M.-H.; Albrecht, J. N.
Eng. J. Med. 1998, 339, 1493; (c) Zeuzem, S.; Feinman, S. V.; Rasenack, J.;
Heathcote, E. J.; Lai, M.-Y.; Gane, E.; O’Grady, J.; Reichen, J.; Diago, M.; Lin, A.;
Hoffman, J.; Brunda, M. J. N. Eng. J. Med. 2000, 343, 1666; (d) Heathcote, E. J.;
Shiffman, M. L.; Cooksley, W. G. E.; Dusheiko, G. M.; Lee, S. S.; Balart, L.;
Reindollar, R.; Reddy, R. K.; Wright, T. L.; Lin, A.; Hoffman, J.; De Pamphilis, J. N.
Eng. J. Med. 2000, 343, 1673; (e) Manns, M. P.; McHutchison, J. G.; Gordon, S. C.;
Rustgi, V. K.; Shiffman, M.; Reindollar, R.; Goodman, Z. D.; Koury, K.; Ling, M.-
H.; Albrecht, J. K.; International Hepatitis Interventional Therapy Group Lancet
2001, 358, 958.
3. (a) Llinas-Brunet, M.; Bailey, M. D.; Bolger, G.; Brochu, C.; Faucher, A.-M.;
Ferland, J. M.; Garneau, M.; Ghiro, E.; Gorys, V.; Grand-Maitre, C.; Halmos, T.;
Lapeyre-Paquette, N.; Liard, F.; Poirier, M.; Rheaume, M.; Tsantrizos, Y. S.;
Lamarre, D. J. Med. Chem. 2004, 47, 1605; (b) Perni, R. B.; Farmer, L. J.; Cottrell,
K. M.; Court, J. J.; Courtney, L. F.; Deininger, D. D.; Gates, C. A.; Harbeson, S. L.;
Kim, J. L.; Lin, C.; Lin, K.; Luong, Y.-P.; Maxwell, J. P.; Murcko, M. A.; Pitlik, J.;
Rao, B. G.; Schairer, W. C.; Tung, R. D.; Van Drie, J. H.; Wilson, K.; Thomson, J. A.
Bioorg. Med. Chem. Lett. 2004, 14, 1939; (c) Lamar, J.; Victor, F.; Snyder, N.;
Johnson, R. B.; Wang, Q. M.; Glass, J. I.; Chen, S.-H. Bioorg. Med. Chem. Lett. 2004,
14, 263; (d) Nizi, E.; Koch, U.; Ontoria, J. M.; Marchetti, A.; Narjes, F.;
Malancona, S.; Matassa, V. G.; Gardelli, C. Bioorg. Med. Chem. Lett. 2004, 14,
2151; (e) Priestley, E. S.; De Lucca, I.; Ghavimi, B.; Erickson-Viitanen, S.;
Decicco, C. P. Bioorg. Med. Chem. Lett. 2002, 12, 3199; (f) Han, W.; Hu, Z.; Jiang,
X.; Decicco, C. P. Bioorg. Med. Chem. Lett. 2000, 10, 711; (g) Zhang, R.; Durkin, J.
P.; Windsor, W. T. Bioorg. Med. Chem. Lett. 2002, 12, 1005; (h) Bogen, S.;
Saksena, A. K.; Arasappan, A.; Gu, H.; Njoroge, F. G.; Girijavallabhan, V.;
Pichardo, J.; Butkiewicz, N.; Prongay, A.; Madison, V. Bioorg. Med. Chem. Lett.
2005, 15, 4515; (i) Victor, F.; Lamar, J.; Snyder, N.; Yip, Y.; Guo, D.; Yumibe, N.;
Johnson, R. B.; Wang, Q. M.; Glass, J. I.; Chen, S.-H. Bioorg. Med. Chem. Lett. 2004,
14, 257.
4. Kaito, M.; Watnabe, S.; Tsukiyama-Kohara, K.; Yamaguchi, K.; Kobayashi, Y.;
Konishi, M.; Yokoi, M.; Ishida, S.; Suzuki, S.; Kohara, M. J. Gen. Virol. 1994, 75,
1755.
5. (a) Bartenschlager, R. J. Viral Hepatitis 1999, 6, 165; (b) Bartenschlager, R.;
Ahlborn-Laake, L.; Mous, J.; Jacobsen, H. J. Virol. 1993, 67, 3835; (c) Reed, K. E.;
Rice, C. M. Molecular characterization of hepatitis C virus. In Hepatitis C Virus;
Reesink, H. W., Ed.; Karger: Basel, Switzerland, 1998; pp 1–37; (d) Lindenbach,
B. D.; Rice, C. M. Nature 2005, 436, 933.
6. (a) Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.;
Bös, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A.-M.;
Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagacé, L.; LaPlante, S. R.; Narjes, H.;
Poupart, M.-A.; Rancourt, J.; Sentjens, R. E.; George, T. S.; Simoneau, B.;
Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C.-L.; Llinàs-
Brunet, M. Nature 2003, 186; (b) Yip, Y.; Victor, F.; Lamar, J.; Johnson, R.; Wang,
Q. M.; Barket, D.; Glass, J.; Jin, L.; Liu, L.; Venable, D.; Wakulchik, M.; Xie, C.;
Heinz, B.; Villarreal, E.; Colacino, J.; Yumibe, N.; Tebbe, M.; Munroe, J.; Chen, S.-
H. Bioorg. Med. Chem. Lett. 2004, 14, 251; (c) Dymock, B. W. Emerg. Drugs 2001,
6, 13; (d) De Francesco, R.; Migliaccio, G. Nature 2005, 436, 953; (e) Perni, R. B.;
Almquist, S. J.; Byrn, R. A.; Chandorkar, G.; Chaturvedi, P. R.; Courtney, L. F.;
Decker, C. J.; Dinehart, K.; Gates, C. A.; Harbeson, S. L.; Heiser, A.; Kalkeri, G.;
1H NMR (DMSO-d6, 500 MHz), d, 8.90 (t, 1H, J = 6.0 Hz), 8.87 (t,
1H, J = 6.3 Hz), 8.43 (d, 1H, J = 6.6 Hz), 8.29 (d, 1H, J = 7.6 Hz), 7.18–
7.10 (m, 8 H), 6.31–3.24 (m, 2H), 5.92 (d, 2H, J = 10.4 Hz), 5.85–5.78
(m, 2H), 5.15–4.96 (m, 4 H), 5.03–4.97 (m, 2H), 4.30–4.27 (m, 4 H),
3.86–3.61 (m, 10 H), 3.23 (m, 1H), 3.20 (m, 1H), 3.09–2.99 (m, 6H),
2.90–2.64 (m, 8 H), 2.80 (s, 3H), 2.79 (s, 3H), 1.75–1.69 (m, 2H),
1.58–1.48 (m, 3H), 1.43–1.24 (m, 9H), 1.18 (t, 6H, J = 7.6 Hz), 1.00
(s, 3H), 0.99 (s, 3H), 0.90 (t, 3H, J = 7.3 Hz), 0.89 (t, 3H, J = 7.3 Hz),
0.84–0.82 (m, 24 H). 13C NMR (DMSO-d6, 125 MHz), d, 198.2,
197.7, 172.0, 171.8, 171.5, 161.8, 161.7, 158.7, 143.3, 143.2,
135.0, 127.0, 126.9, 125.2, 125.1, 125.0, 116.4, 60.6, 60.1, 55.6,
54.6, 54.4, 54.1, 50.9, 50.9, 47.6, 47.5, 44.9, 42.6, 42.5, 41.7, 36.0,
35.9, 35.7, 35.4, 34.9, 31.7, 31.6, 30.1, 28.4, 28.3, 27.6, 27.5, 27.0,
26.9, 22.6, 22.5, 19.4, 14.5, 13.5, 13.4, 8.6.
5.1.23. (1R,5S)-3-[2(S)-Cyclohexyl-2-[[[[1(S)-[[[(dimethylamino)
sulfonyl]methylamino]methyl]-2,2-dimethylpropyl]amino]-
carbonyl]amino]acetyl]-n-[1-[1,2-dioxo-2-(2-propenylamino)-
ethyl]pentyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-
carboxamide (39)
1H NMR (DMSO-d6, 500 MHz), d, 8.88 (t, 1H, J = 5.7 Hz), 8.84
(t, 1H, J = 5.7 Hz), 8.38 (d, 1H,
J =6.3 Hz), 8.24 (d, 1H,
J = 7.3 Hz), 6.04 (d, 2H, J = 8.2 Hz), 6.02 (d, 2H, J = 8.8 Hz), 5.86–
5.77 (m, 4 H), 5.13–5.06 (m, 3H), 4.95–4.91 (m, 1H), 4.27 (s,
1H), 4.24 (s, 1H), 4.15–4.09 (m, 2H), 3.92–3.90 (m, 2H), 3.80–
3.71 (m, 6H), 3.61 (t, 2H, J = 9.5 Hz), 3.19 (bd, 2H), 2.92 (t, 2H,
J = 11.4 Hz), 2.71 (s, 6H), 2.69 (s, 12H), 1.75–1.65 (m, 2H),
1.65–1.59 (m, 8 H), 1.49–1.25 (m, 14 H), 1.12 (br s, 6H), 1.07
(s, 3H), 0.99 (s, 3H), 0.87–0.80 (m, 20 H), 0.80 (s, 18H); 13C
NMR (DMSO-d6, 125 MHz), d, 198.1, 197.7, 171.9, 171.9, 171.7,
161.9, 161.6, 158.6, 135.0, 135.0, 116.4, 116.3, 60.5, 60.0, 58.7,
56.1, 55.9, 55.9, 54.6, 54.4, 51.6, 49.0, 47.7, 47.6, 41.7, 38.5,
36.0, 34.9, 34.9, 31.0, 30.1, 29.8, 29.6, 29.1, 29.1, 28.4, 28.2,
27.6, 27.6, 27.0, 26.9, 26.3, 26.3, 26.3, 25.8, 22.5, 22.5, 19.4,
19.4, 14.5, 13.5, 13.4; MS (ES) m/z relative intensity
739[(M+1)+, 100], 475(40), 403(80).

S. Venkatraman et al. / Bioorg. Med. Chem. 17 (2009) 4486–4495
4495
KolaczkowsKi, E.; Lin, K.; Luong, Y.-P.; Rao, B. G.; Taylor, W. P.; Thomson, J. A.;
Tung, R. D.; Wei, Y.; Kwong, A. D.; Lin, C. Antimicrob. Agents Chemother. 2006, 50,
899; (f) Liverton, N. J.; Holloway, M. K.; McCauley, J. A.; Rudd, M. T.; B., John W.;
Carroll, S. S.; DiMuzio, J.; Fandozzi, C.; Gilbert, K. F.; Mao, S.-S.; McIntyre, C. J.;
Nguyen, K. T.; Romano, J. J.; Stahlhut, M.; Wan; Bang-Lin; Olsen, D. B.; Vacca, J.
P. J. Am. Chem. Soc. 2008, 130, 4607; (g) Brazil, M. Nat. Rev. Drug Disc. 2003, 212,
945.
J.-M.; Prelusky, D.; Kormacher, W.; White, R.; Bogonowich-Knipp, S.; Pavlovsky,
A.; Prudence, B.; Saksena, A. K.; Ganguly, A.; Piwinski, J.; Girijavallabhan, V.;
Njoroge, F. G. J. Med. Chem. 2006, 49, 6074.
8. (a) Zhang, R.; Beyer, B. M.; Durkin, J.; Ingram, R.; Njoroge, F. G.; Windsor, W. T.;
Malcolm, B. A. Anal. Biochem. 1999, 270, 268; (b) Morrison, J. F.; Walsh, C. T. Adv.
Enzymol., Meister, A. Eds.; 1988, 61, 201.
9. Lohmann, V.; Körner, F.; Koch, J.-O.; Herian, U.; Theilmann, L.; Bartenschlager,
R. Science 1999, 285, 110.
10. (a) Mamai, A.; Zhang, R.; Natarajan, A.; Madalengoitia, J. S. J. Org. Chem.
2001, 66, 455; (b) Zhang, R.; Madalengoitia, J. S. J. Org. Chem. 1999, 64,
330.
11. Cox, K. A.; Dunn-Meynell, K.; Korfmacher, W. A.; Broske, L.; Nomeir, A. A.; Lin,
C. C.; Cayen, M. N.; Barr, W. H. Drug Discovery Today 1999, 4, 232.
7. Venkatraman, S.; Bogen, S. L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, E.; Liu,
Y.-T.; Lovey, R.; Hendrata, S.; Huang, Y.; Pan, W.; Parekh, T.; Pinto, P.; Popov, V.;
Pike, R.; Ruan, S.; Santhanam, B.; Vibulbhan, B.; Wu, W.; Yang, W.; Yang, W.;
Kong, J.; Liang, X.; Wong, J.; Liu, R.; Butkiewicz, N.; Chase, R.; Hart, A.; Agarwal,
S.; Ingravallo, P.; Pichardo, J.; Kong, R.; Baroudy, B.; Malcolm, B.; Guo, Z.;
Prongay, A.; Madision, V.; Broske, L.; Cui, X.; Cheng, K.-C.; Hsieh, T. Y.; Brisson,