Toward second generation hepatitis C virus NS3 serine protease inhibitors: Discovery of novel P4 modified analogues with improved potency and pharmacokinetic profile

Article abstract of DOI:10.1021/jm801616e

Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavaila

Full text of DOI:10.1021/jm801616e

2806
J. Med. Chem. 2009, 52, 2806–2817
Toward Second Generation Hepatitis C Virus NS3 Serine Protease Inhibitors: Discovery of
Novel P4 Modified Analogues with Improved Potency and Pharmacokinetic Profile
Ashok Arasappan,* Angela I. Padilla, Edwin Jao, Frank Bennett, Stephane L. Bogen, Kevin X. Chen, Russell E. Pike,
Mousumi Sannigrahi, Joana Soares, Srikanth Venkatraman, Bancha Vibulbhan, Anil K. Saksena, Viyyoor Girijavallabhan,
Xiao Tong, Kuo-Chi Cheng, and F. George Njoroge
Schering Plough Research Institute, Kenilworth, New Jersey 07033
ReceiVed December 22, 2008
Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma,
and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel,
potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical
trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving
the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new
P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether
and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation
of the P′ secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining
the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed
superior potency and very good oral as well as target organ exposure in rats.
Introduction
Hepatitis C virus (HCVa) infection is a global health crisis
leading to liver cirrhosis, hepatocellular carcinoma, and liver
failure in humans.1 It has been estimated that 3% of the human
population worldwide is chronically infected with HCV.2
R-Interferon monotherapy and R-interferon-ribavirin combina-
tion therapy are the standard treatment for this infection.3 While
therapeutic effectiveness has been improved with the introduc-
tion of pegylated version of R-interferon, it is still far from ideal
for the hard to treat genotype-1 patients.4 Hence, there is an
unmet medical need to discover and develop new and more
effective protocols for the treatment of HCV infection.
Figure 1. Profile of 1 (SCH 503034).
HCV is a positive stranded RNA virus belonging to the
Flaviviridae family. Upon entering a suitable host cell, the HCV
genome encodes a polyprotein of approximately 3000 amino
acid residues. Post-translational modification of the polyprotein
is mediated by host and viral proteases, ultimately resulting in
viral replication. Intense efforts were focused in the past decade
to discover novel small molecule agents that directly inhibit
viral replication. Since the identification of this virus, the NS3
serine protease contained within the N-terminal region of the
NS3 protein has been studied extensively.5 This chymotrypsin-
like serine protease is implicated in viral replication and
therefore is an attractive target for HCV antiviral therapeutics.6
Proof of concept studies in humans have validated this hypoth-
esis.7 We recently disclosed the synthesis and development of
Boceprevir, (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2-3-di-
oxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)-amino]carbonyl]amino]-
3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-
2(S)-carboxamide (SCH 503034), 1,8 a selective, potent, orally
bioavailable HCV NS3 protease inhibitor that is efficacious in
humans and currently undergoing phase III clinical trials. Other
molecules, including (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-
2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-
N-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)octahydro-
cyclopenta[c]pyrrole-1-carboxamide, (VX950) currently in phase
III studies, have also been advanced to clinical trials and found
to be effective.9
As shown in Figure 1, inhibitor 1 exhibited Ki* ) 14 nM in
the enzyme binding assay,10 EC90 ) 350 nM in the cell-based
replicon assay,11 and acceptable pharmacokinetic profile in rats.
In our efforts to identify a second generation HCV NS3 serine
protease inhibitor, we focused on improving the potency and
pharmacokinetic profile of the inhibitor. On the basis of the
X-ray crystal structure of 1 bound to the NS3 protease,
exploration of the P4 area seemed attractive since additional
interaction with the enzyme may improve the potency. Herein,
we will detail our studies in the P4 area, specifically the
introduction of ether and carbamate capped P4 moieties, which
resulted in inhibitors with very good potency. Comprehensive
SAR studies, along with the introduction of a P′ secondary
amide residue to increase metabolic stability, provided inhibitors
with appreciable enhancement in the rat pharmacokinetic profile.
Synthesis of Inhibitors. Synthesis of ether cap derived target
compounds are shown in Scheme 1. Etherification of (S) N-Boc-
tert-leucinol under neutral conditions followed by deprotection
resulted in 2. Treatment with phosgene provided the isocyanate
3. Reaction of previously described8 intermediate 4 with
isocyanate 3 followed by ester hydrolysis afforded the ether
* To whom correspondence should be addressed. Schering Plough
Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033. Phone:
908-740-2607. Fax: 908-740-7152. Email: ashok.arasappan@spcorp.com.
a Abbreviations: HCV, hepatitis C virus; DM periodinane, Dess-Martin’s
periodinane; Cys159, cysteine159; ꢀ-MeChg, ꢀ-methylcyclohexyl glycine;
norval, norvaline; norleu, norleucine; C6 h, liver concentration at 6 h.
10.1021/jm801616e CCC: $40.75
2009 American Chemical Society
Published on Web 04/16/2009

Hepatitis C Virus NS3 Serine Protease Inhibitors
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2807
Scheme 3a
Scheme 1a
a a. MeI, CuO, MeCN; b. 4M HCl/dioxane; c. Phosgene (20% in toluene),
CH2Cl2, aq. NaHCO3; d. 3, DIPEA, CH2Cl2; e. Aq LiOH, THF; f. 6, EDCI,
HOOBt, NMM, CH2Cl2, DMF; g. DM periodinane, CH2Cl2.
a a. RNCO, CuCl, DMF; b. 4M HCl/dioxane; c. phosgene (20% in
toluene), CH2Cl2, aq. NaHCO3; d. DIPEA, CH2Cl2; e. DIPEA, CH2Cl2; f.
aq. LiOH, THF; g. 6, EDCI, HOOBt, NMM, CH2Cl2, DMF; h. DM
periodinane, CH2Cl2.
Scheme 2a
Scheme 4a
a a. 4-Nitrophenylchloroformate, DIPEA, CH2Cl2; b. 2, DIPEA, CH2Cl2;
c. Aq LiOH, THF.
capped intermediate 5. Coupling of the P4-P2 acid 5 with
P1-P′ intermediate 6 followed by oxidation (Dess-Martin or
modified Moffatt protocol) provided the required P4 ether
capped inhibitors 7 in 60-75% yield. A variation of the
isocyanate methodology to obtain intermediate 5 is shown in
Scheme 2. Thus, amine hydrochloride 4 was treated with
4-nitrophenyl chloroformate to provide the activated carbamate
8, which was subsequently converted to the required acid 5 via
treatment with 2 followed by basic hydrolysis.
Synthesis of P4 carbamate capped inhibitors is described in
Scheme 3. Treatment of (S)N-Boc-tert-leucinol with isocyanates
(commercial or prepared via reaction of known amines with
phosgene solution) using copper chloride and subsequent
removal of the t-Boc protecting group delivered compound 9.
Conversion to isocyanate 10 essentially followed the previously
described procedures. P4-P2 acid 11 was obtained using two
routes: treatment of amine hydrochloride 9 with activated
carbamate 8, followed by hydrolysis or reaction of isocyanate
10 with known P3-P2 intermediate 4, followed by LiOH
hydrolysis. Final assembly of P4 capped inhibitors 12 was
carried out as described above in a two step protocol. Scheme
4 depicts the synthesis of N,N-dimethyl carbamate capped
inhibitor 15. Thus, (S)N-Boc-tert-leucinol was converted to the
activated carbonate 13 via treatment with 4-nitrophenyl chlo-
roformate. Reaction of 13 with N,N-dimethylamine hydrochlo-
ride followed by deprotection afforded the required intermediate
14, which was further processed to inhibitor 15 using procedures
described earlier.
a a. 4-Nitrophenylchloroformate, DIPEA, CH2Cl2; b. dimethylamine
hydrochloride, DIPEA, CH2Cl2; c. 4M HCl in dioxane; d. 8, DIPEA, CH2Cl2;
e. aq LiOH, THF; f. 6, EDCI, HOOBt, NMM, CH2Cl2, DMF; h. DM
periodinane, CH2Cl2.
interactions. It also revealed the presence of the cysteine159
(Cys159) residue on the protease surface in close proximity to
the S4 pocket. On the basis of these observations, we decided
to incorporate groups off the urea P3 cap of 1 that could interact
with Cys159. Our investigation resulted in the identification of
(S)-tert-leucinol derived ethers and carbamates as suitable P4
moieties, with the carbamate cap providing superior potency.
During our studies that led to the discovery of 1, we also
observed that inhibitors containing the P′ secondary amide
residue exhibited good rat pharmacokinetic profile, presumably
due to greater metabolic stability of the secondary amide
compared to that of the primary amide moiety present in 1.
Hence, in order to improve the pharmacokinetic profile of P4
capped inhibitors, we set out to incorporate the P′ secondary
amide residue. Introduction of the allyl amide P′ residue
provided significant enhancement in rat pharmacokinetic proper-
ties. Results of our studies are described below.
Our investigation toward the identification of a suitable second
generation HCV NS3 serine protease inhibitor started with the
introduction of tert-leucinol derived ethers and carbamates as
P4 moieties. Incorporation of methyl ether capped tert-leucinol
derived urea cap onto the core of 1 gave compound 16, which
resulted in a loss of enzyme potency (Ki* ) 120 nm).
Interestingly, variation of the P3 moiety resulted in restoring
Results and Discussion
The X-ray crystal structure of 1 bound to the NS3 protease
indicated that exploration of the P4 area may result in additional

2808 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Arasappan et al.
Table 1
Table 2
the potency. Thus, P3 cyclohexylglycine derived inhibitor 17
was essentially equipotent to 1 (Ki* ) 30 nm, EC90 ) 300 nM).
Similar results were obtained with P3 ꢀ-methylcyclopentyl
glycine derived inhibitor 19 (Ki* ) 22 nm, EC90 ) 400 nM).
However, introduction of P3 ꢀ-methylcyclohexyl glycine or
2-indanylglycine (18 or 20, respectively) improved replicon
potency further, with EC90 of 150 nM and 200 nM, respectively.
Both inhibitors showed good enzyme potency as well (see Table
1).
a P3 tLeu.
Table 3
Having improved the replicon potency in the P4 ether capped
series (via modification of P3), we then decided to study the
effect of P4 substitutions. The results are shown in Table 2.
Replacement of the t-butyl group at P4 with i-propyl moiety
was tolerated (21, Ki* ) 12 nM, EC90 ) 200 nM). Disubstitution
at the P4 R-center resulted in a loss of potency (compounds 22
and 23). Further ether modifications (24 and 25) also resulted
in diminished potency. Additionally, inhibitor 20 with good
replicon potency displayed poor exposure (AUC ) 0.1 µM·h)
when dosed orally in rats. Hence, in an effort to further improve
the replicon potency and address pharmacokinetic issues, we
then turned our attention toward incorporating the carbamate
moiety at the P4 position.
Targets derived from the P4 carbamate moiety were synthe-
sized as described in Schemes 3 and 4. Since 2-indanyl glycine
and ꢀ-methylcyclohexyl glycine at P3 exhibited a similar profile
and, moreover, due to ease of availability of the former, our
studies in the carbamate series were initiated with 2-indanyl
glycine residue at P3 (Table 3). Introduction of the methyl
carbamate cap resulted in encouraging results, with 27 showing
good potency (Ki* ) 9 nM, EC90 ) 200 nM). Extending the
cap by an additional carbon atom provided ethyl carbamate
capped inhibitor 28, which improved the potency further (Ki*
) 7 nM, EC90 ) 100 nM). Incorporation of other alkyl groups
were also well tolerated (compounds 29 and 30, with EC90
)
200 nM). N,N-Disubstitution resulted in a loss of potency (31,
Ki* ) 23 nM, EC90 ) 300 nM). Thus, the ethyl carbamate cap
afforded the best potency. We then varied the P3 residue to
find out its effect on potency of the inhibitor. Both tert-leucine
and cyclohexylglcine at P3, while retaining the binding potency,
exhibited diminished replicon potency (32 and 33). Once again,
P3 ꢀ-methylcyclohexyl glycine containing inhibitor 34 displayed
a profile similar to that of compound 28 with the 2-indanyl
glycine P3 residue. Inhibitor 28, with a very good potency

Hepatitis C Virus NS3 Serine Protease Inhibitors
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2809
Table 4
profile, was evaluated for oral exposure in rats. Unfortunately,
28 displayed low oral exposure (AUC ) 0.3 µM, 10 mpk) when
dosed in rats. Furthermore, rat liver concentration was also not
optimal (244 ng/g after 1 h). We observed a similar PK profile
for a few other inhibitors (unpublished results) containing the
P′ primary amide moiety.
at P′ exhibited Ki* of 28 nM and replicon EC90 of 150 nM.
While 41, with P1 norleu was less potent (EC90 ) 400 nM),
butynyl glycine P1 inhibitor 42 displayed very good potency
profile (Ki* ) 9 nM, EC90 ) 150 nM). Introduction of propyl
amide (43, Ki* ) 16 nM, EC90 ) 200 nM) or ethyl amide (44,
Ki* ) 21 nM, EC90 ) 200 nM) were also well tolerated at P′.
Thus, for the P4 ethylcarbamate capped inhibitors, the optimal
P3/P1/P′ combination turned out to be ꢀ-methylcyclohexyl
glycine/butynyl glycine/allyl amide, respectively.
During our exploratory studies that led to the discovery of 1,
we observed that P′ secondary amides, specifically allyl amides,
provided inhibitors with very good rat PK profile. In an attempt
to improve the PK profile of P4 carbamate derived inhibitors,
we then set out to introduce an allyl residue at the P′ position.
We also knew from our previous studies that the P1 cyclobutyl
alanine moiety was not well tolerated with the incorporation of
an allyl (or similar small alkyl) residue at P′. Because of these
considerations, our P′ SAR studies were carried out with various
P1 surrogates to identify the appropriate P1-P′ combination.
Results obtained with P′ secondary amides are shown in Table
4. Compound 35 demonstrated that the P1 cyclopropylalanine
containing inhibitor displayed a similar potency profile compared
to that of P1 cyclobutylalanine derived inhibitor 28 (Table 3).
Introduction of the allyl residue at the P′ position resulted in
36 with a loss of potency. Further variation of the P1 moiety
(norval 37, norleu 38, and butynylglycine 39) resulted in a loss
in replicon potency. Interestingly, 39 with butynylglycine P1
displayed very good enzyme potency (Ki* ) 10 nM).
Having established the appropriate substitution pattern for
the inhibitor core, we then decided to study the effect of cap
variation once again in an attempt to improve the overall profile
of the inhibitor. Since propyl (40) and butynyl (42) residues at
P1 displayed similar replicon potency, we decided to use both
moieties for further SAR studies. We varied alkyl substitution
on the carbamate cap, and the results are shown in Table 5.
Replacement of ethyl carbamate with i-propyl carbamate
afforded equipotent inhibitors (45, EC90 ) 150 nM; 46, EC90
) 150 nM). Incorporation of the i-butyl carbamate cap improved
the replicon potency of P1 butynylglycine inhibitor (48, EC90
) 70 nM). Cyclizing the terminal carbon atoms of i-butyl
carbamate to cyclopropylmethyl carbamate resulted in inhibitors
(49 and 50) with improved replicon potency (EC90 ) 100 nM
and 70 nM, respectively). Increasing the ring size to cyclohexyl
resulted in a loss of potency (51 and 52), clearly indicating the
appropriate size requirement for the P4 carbamate cap. Modi-
fications were carried out at the P4 position as well. However,
When a similar study was carried out with the P3 ꢀ-meth-
ylcyclohexyl glycine residue, improvement in replicon potency
was observed (Table 4). Thus, 40 with norval P1 and allyl amide

2810 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Arasappan et al.
Table 5
Figure 2. Model of inhibitor 42 docked to the surface of NS3 protease.
Table 6. Rat PK Data (po, 10 mpk) for Selected Compounds
compd
AUC (µM·h)0-6 h
liver conc. C6 (ng/g)
h
37
45
46
48
50
42
0.7
6.6
7.9
4.9
na
808
1111
750
581
1106
5.0
26 (F)43%)a
a AUC (µM·h)0-24 h
.
glycine residue showed excellent oral exposure and good target
organ concentration in rats.
Figure 2 depicts a model of inhibitor 42 docked onto the NS3
protease surface. The core (P3-P′) displayed interactions similar
to those observed previously8 for other inhibitors. Significantly,
the P4 moiety was buried well into the S4 pocket, thus gaining
additional hydrophobic interactions. The carbonyl oxygen of
the carbamate moiety seemed to be in close proximity for the
hydrogen bonding interaction with Cys159. These two additional
interactions resulted in improved potency for this class of
inhibitors.
Conclusions
Our exploration toward a suitable second generation HCV
NS3 serine protease inhibitor resulted in the discovery of P4
ether and carbamate-derived compounds that provided fruitful
results. Key hydrogen bond with Cys-159 and additional
hydrophobic interactions with the enzyme S4 pocket may have
resulted in enhanced potency. The ether-capped inhibitors
improved replicon potency, but exhibited poor oral PK (in rats).
While carbamate-capped inhibitors containing the P′ primary
amide moiety improved the replicon potency, oral exposure in
rats were poor as well. Incorporation of the P′ secondary amide,
especially the allyl moiety, retained the potency and improved
rat oral exposure significantly. Moreover, selected compounds
displayed good distribution in the target organ, with liver
exposure of 7-15 × EC90 at the 6 h time point. From our SAR
studies, ꢀ-methylcyclohexylglycine was the preferred moiety
at the P3 position, with the t-leucinol derived carbamate cap
being the preferred P4 moiety. Compound 42, incorporating the
preferred moieties displayed replicon EC90 ) 150 nM, with very
good oral exposure in rats (AUC ) 26 µM·h, F ) 46%) and
high liver concentration (1106 ng/g at 6 h). Additionally,
inhibitors 48 and 50 exhibited superior binding (Ki* ) 9 and 7
nM, respectively) and replicon potency (EC90 ) 70 nM). Thus,
we achieved potency (EC90) improvement 5× over that of 1,
with significant enhancement in rat PK properties. In summary,
thorough SAR studies with the introduction of ether and
a P4 ) Chg; b P4 ) spiroChg.
both moieties, cyclohexyl (53 and 54) and spirocyclohexyl (55
and 56) at P4, resulted in diminished enzyme and replicon
potency.
Selected compounds with good potency were evaluated in
rat PK study and the results are listed in Table 6. The compounds
were dosed orally (10 mpk) as a suspension in 0.4% HPMC.
Compound 37, with 2-indanylglycine residue at P3, did not show
appreciable AUC (0.7 µM.h) when dosed orally at 10 mpk.
Interestingly, compounds with P3 ꢀ-methylcyclohexyl glycine
residue displayed very good exposure. Thus, inhibitor 45
containing the P1-norval moiety exhibited an oral AUC of 6.6
µM·h with good concentration in the liver (808 ng/g at 6 h).
The corresponding P1-butynyl analogue, 46, showed slightly
better AUC (7.9 µM · h) and even higher liver concentration
(1111 ng/g). The isobutyl and cyclopropylmethyl-capped car-
bamate analogues, 48 and 50, displayed very good PK profile
as well. Finally, the ethyl carbamate-capped inhibitor 42
exhibited the best PK profile with an AUC of 26 µM·h and an
oral bioavailability of 43%. This compound also demonstrated
good liver concentration when measured at the 6 h time point
(1106 ng/g). Clearly, inhibitors with the ꢀ-methylcyclohexyl

Hepatitis C Virus NS3 Serine Protease Inhibitors
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2811
was separated, and the aqueous layer was extracted with dichlo-
romethane (2 × 30 mL). The combined organic layer was washed
with saturated sodium bicarbonate solution (100 mL) and brine (100
mL), dried (Na2SO4), filtered, and concentrated. The crude residue
was purified in a prepacked silica cartridge using 0-20% EtOAc
in CH2Cl2 to give 0.46 g of the methyl ester intermediate. This
material was taken in THF/MeOH (10 mL each) and treated with
aq. 1 M LiOH (2.6 mL) at room temperature for 4 h. The reaction
mixture was concentrated, and the residue was acidified with aq. 1
N HCl (25 mL). The aqueous layer was extracted with CH2Cl2 (2
× 25 mL). The combined organic layer was washed with water
(50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concen-
trated to give 0.44 g of 11, LC-MS (M + H+) ) 523.1.
carbamate-derived P4 caps resulted in novel HCV NS3 serine
protease inhibitors with improved potency and pharmacokinetic
profile.
Experimental Section
General Methods. Reagents and solvents, including anhydrous
THF, dichloromethane, and DMF, were purchased from Aldrich,
Acros, or other commercial sources and were used without further
purification. Reactions that were moisture sensitive or using
anhydrous solvents were performed under either nitrogen or argon
atmosphere. Analytical thin layer chromatography (TLC) was
performed on precoated silica gel plates obtained from Analtech.
Visualization was accomplished with UV light or by staining with
basic KMnO4 solution or ethanolic H2SO4 solution. Compounds
were purified by flash chromatography either on a glass column
using Merck silica gel 60 (230-400 mesh) or on an ISCO RediSep
disposable silica gel prepacked cartridges. NMR spectra were
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)-
ethyl]-4-pentynyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo-
[3.1.0]hex-3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]car-
bonyl]amino]-3,3-dimethylbutyl ethylcarbamate (42). To a cold
(0 °C) solution of the above-described intermediate 11 (0.25 g, 0.478
mmol) and intermediate 6 (P1 ) butynyl, R′ ) allyl, 0.12 M in
CH2Cl2, 5.14 mL, 0.622 mmol) in CH2Cl2/DMF (9 mL/6 mL) were
added HATU (0.24 g, 0.621 mmol) and DIPEA (0.264 mL, 1.434
mmol). The reaction mixture was maintained between 0-10 °C,
over 16 h. The reaction mixture was diluted with CH2Cl2 (40 mL)
and washed with saturated ammonium chloride solution (30 mL),
saturated sodium bicarbonate solution (30 mL), water (30 mL), and
brine (30 mL), dried (Na2SO4), filtered, and concentrated. The crude
residue was then taken in CH2Cl2 (12 mL) and treated with Dess-
Martin’s periodinane (0.405 g, 0.956 mmol) at room temperature
for 4 h. The reaction mixture was diluted with CH2Cl2 (40 mL),
washed with 10% aq sodium thiosulfate solution (50 mL), saturated
sodium bicarbonate solution (2 × 50 mL), and brine (50 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified in a
prepacked silica cartridge using 20-50% acetone in hexanes to
1
recorded at 300, 400, or 500 MHz for H and at 75, 100, or 125
MHz for 13C on a Bruker or Varian spectrometer with CDCl3 or
DMSO-d6 as solvent. The chemical shifts are given in ppm,
referenced to the deuterated solvent signal. Purity of target
compounds were determined using LC-MS analysis. LC/MS
analyses were performed using an Applied Biosystems API-150
mass spectrometer and a Shimadzu SCL-10A LC system. Column:
Phenomenex Gemini C18, 5 µm, 50 mm × 4.6 mm ID. Gradient:
from 90% water, 10% CH3CN, 0.05%TFA, 5 min to 5% water,
95% CH3CN, 0.05% TFA in 5 min. UV detection: 254 nm. Purity
of targets compounds was g95%.
(1R,2S,5S)-Methyl-6,6-dimethyl-3-((S)-2-(1-methylcyclohexyl)-
2-((4-nitrophenoxy)carbonylamino)acetyl)-3-azabicyclo[3.1.0]hexane-
2-carboxylate (8, P3 ) ꢀ-MeChg). To a cold (10 °C) solution of
previously described intermediate 412 (3.1 g, 8.66 mmol) in
dichloromethane (50 mL) was added pyridine (1.76 mL, 21.7 mmol)
followed by 4-nitrophenyl chloroformate (5.24 g, 26 mmol).
Reaction temperature was maintained for 16 h. The reaction mixture
was then quenched with saturated ammonium chloride solution (50
mL). The organic layer was separated, and the aqueous layer was
extracted with dichloromethane (2 × 40 mL). The combined organic
layer was washed with saturated sodium bicarbonate solution (100
mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated.
The crude residue was purified in a prepacked silica cartridge using
0-20% EtOAc in CH2Cl2 to give 3.74 g of 8. 1H NMR (CDCl3) δ
8.24-8.21 (m, 2H), 7.28-2.26 (m, 2H), 5.79 (d, J ) 9.75 Hz,
1H), 4.51 (app. s, 1H), 4.30 (d, J ) 9.41 Hz, 1H), 3.97-3.88 (m,
2H), 3.77 (s, 3H), 1.63-1.42 (m, 11H), 1.12-1.05 (m, 7H), 0.92
(s, 3H).
(S)-2-Amino-3,3-dimethylbutyl ethylcarbamate hydrochloride
(9, R ) Et). To a solution of (S)-N-t-boc-leucinol (4 g, 18.43 mmol)
in DMF (180 mL) was added copper (I) chloride (1.86 g, 18.8
mmol) followed by ethyl isocyanate (1.88 mL, 23.96 mmol). The
reaction mixture was stirred at room temperature for 4 h when TLC
(20/80 EtOAc/CH2Cl2) indicated reaction completion. The reaction
mixture was diluted with diethyl ether (350 mL) and filtered through
a pad of Celite. The filtrate was washed with water (100 mL) and
brine (100 mL), dried (Na2SO4), filtered, and concentrated to give
5.24 g of the N-t-boc protected intermediate (LC-MS ) 289.1, M
+ H+). This material (4.73 g) was treated with 4 M HCl in dioxane
(70 mL) at room temperature for 4.5 h. The reaction mixture was
then concentrated to provide 3.8 g of 9. LC-MS (M + H+) ) 189.1.
(1R,2S,5S)-3-((2S,6S)-6-tert-Butyl-2-(1-methylcyclohexyl)-4,9-di-
oxo-8-oxa-3,5,10-triazadodecane)-6,6-dimethyl-3-azabicyclo[3.1.0]-
hexane-2-carboxylic acid (11, P3 ) ꢀ-MeChg, R ) Et). To a cold
(0 °C) solution of the above-described intermediates, 8 (0.5 g, 1.03
mmol) and 9 (0.3 g, 1.33 mmol) in dichloromethane (40 mL) was
added DIPEA (0.57 mL, 3.075 mmol). The reaction mixture was
maintained at that temperature for 12 h. At this time, another portion
of 9 was added (0.12 g), and the temperature was maintained for
an additional 5 h when TLC (20/80 EtOAc/CH2Cl2) indicated
reaction completion. The reaction mixture was then quenched with
saturated ammonium chloride solution (50 mL). The organic layer
1
give 0.243 g of 42 as a mixture of two diastereomers. H NMR
(500 MHz, DMSO-d6) δ 8.88 and 8.77 (app.t, J ) 5.99 and 6.30
Hz, 1H), 8.52 and 8.44 (d, J ) 6.93 and 7.56 Hz, 1H), 6.78 (br. s,
1H), 6.09 (d, J ) 9.45 Hz, 1H), 6.02 (d J ) 9.77 Hz, 1H),
5.83-5.74 (m, 1H), 5.13-5.04 (m, 2H), 5.03-4.97 (m, 1H), 4.24
(s, 1H), 4.20 (d, J ) 7.88 Hz, 1H), 4.01 (d, J ) 11.03 Hz, 1H),
3.90 (d, J ) 10.40 Hz, 1H), 3.84-3.72 (m, 4H), 3.59-3.55 (m,
1H), 2.99-2.95 (m, 2H), 2.79 (app. t, J ) 2.52 Hz, 1H), 2.36-2.31
(m, 2H), 2.01-1.94 (m, 1H), 1.73-1.65 (m, 1H), 1.56-1.07 (m,
12H), 0.99-0.78 (complex, 21H). 13C NMR (100 MHz, DMSO-
d6) δ 197.53, 197.06, 172.10, 171.42, 161.68, 158.89, 156.98,
135.34, 135.06, 134.98, 116.47, 116.33, 84.33, 84.13, 72.65, 72.54,
64.59, 60.08, 58.70, 56.98, 54.19, 48.27, 41.70, 37.82, 35.89, 34.89,
34.39, 34.10, 31.38, 30.46, 29.93, 29.18, 27.88, 27.33, 26.93, 26.88,
26.78, 22.19, 22.01, 19.93, 19.35, 15.91, 15.56, 15.20, 13.50. LCMS
(M + H)+: 699.2.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-diooxopropyl]-
3-[2(S)-cyclohexyl-2-[[[[1(S)-(methoxymethyl)-2,2-dimethylpro-
pyl]amino]carbonyl]amino]-1-oxoethyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hexane-2(S)-carboxamide (17). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.29 and 8.09 (d, J ) 7.25 and 7.56 Hz, 1H), 8.01
(d, J ) 12.92 Hz, 1H), 7.78 (d, J ) 8.51 Hz, 1H), 6.01 (app. d, J
) 9.45 Hz, 1H), 5.87 (app. t, J ) 7.88 Hz, 1H), 4.95-4.89 (m,
1H), 4.26 and 4.22 (s, 1H), 4.13-4.06 (m, 1H), 3.88 (d, J ) 12.92
Hz, 1H), 3.80-3.70 (m, 1H), 3.51-3.47 (m, 1H), 3.25-3.19 (m,
5H), 2.46-2.30 (m, 1H), 2.00-1.92 (m, 2H), 1.80-1.40 (m, 16H),
1.30-1.25 (m, 1H), 1.14-1.08 (m, 2H), 1.00-0.80 (m, 15H); 13
C
NMR (125 MHz, DMSO-d6) δ 198.58, 198.06, 171.96, 171.84,
171.81, 171.64, 163.80, 163.67, 158.82, 73.43, 60.62, 60.07, 58.89,
56.83, 56.34, 56.14, 52.81, 47.75, 47.64, 37.70, 37.59, 34.78, 34.75,
33.03, 31.58, 29.89, 29.72, 29.36, 29.28, 28.74, 28.67, 28.46, 28.27,
28.20, 27.58, 26.97, 26.90, 26.41, 19.45, 18.68, 18.63, 13.53, 13.44.
LCMS (M + H)+: 604.1.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-
3-[2(S)-[[[[1(S)-(methoxymethyl)-2,2-dimethylpropyl]amino]car-
bonyl]amino]-2-(1-methylcyclohexyl)-1-oxoethyl]-6,6-dimethyl-

2812 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Arasappan et al.
3-azabicyclo[3.1.0]hexane-2(S)-carboxamide (18). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.27 and 8.10 (d, J ) 7.56 and 7.56 Hz, 1H), 8.03
and 7.98 (s, 1H), 7.77 (s, 1H), 6.17-6.09 (m, 1H), 6.01-5.98 (m,
1H), 4.99-4.95 and 4.87-4.83 (m, 1H), 4.26-4.19 (m, 2H),
3.94-3.89 (m, 1H), 3.82-3.75 (m, 1H), 3.53-3.49 (m, 1H),
3.23-3.05 (m, 5H), 2.49-2.35 (m, 1H), 2.00-1.88 (m, 2H),
1.80-1.70 (m, 3H), 1.66-1.08 (m, 15H), 0.99-0.94 (m, 6H),
0.80-0.72 (m, 12H); 13C NMR (125 MHz, DMSO-d6) δ 198.65,
198.02, 171.80, 171.69, 171.63, 171.41, 163.92, 163.71, 158.95,
158.88, 73.52, 60.42, 60.04, 58.89, 56.86, 52.96, 52.69, 48.33,
48.28, 37.86, 37.65, 37.56, 34.86, 34.80, 33.00, 32.96, 31.41, 30.46,
28.77, 28.64, 28.58, 28.28, 28.25, 27.58, 26.94, 26.91, 26.77, 22.19,
22.01, 19.99, 19.91, 19.34, 19.30, 18.72, 18.55, 13.53, 13.46. HRMS
calcd for C33H56N5O6 (M + H)+: 618.4230. Found: 618.4237.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-
3-[2(S)-[[[[1(S)-(methoxymethyl)-2,2-dimethylpropyl]amino]car-
bonyl]amino]-2-(1-methylcyclopentyl)-1-oxoethyl]-6,6-dimethyl-
3-azabicyclo[3.1.0]hexane-2(S)-carboxamide (19). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.28 and 8.15 (d, J ) 7.25 and 7.25 Hz, 1H), 8.02
and 7.97 (bs, 1H), 7.76 (d, J ) 4.09 Hz, 1H), 6.13 (app. t, J )
10.40 Hz, 1H), 6.01-5.98 (m, 1H), 4.97-4.93 and 4.86-4.82 (m,
1H), 4.35-4.31 (m, 1H), 4.28 and 4.24 (s, 1H), 3.92-3.89 (m,
1H), 3.79-3.72 (m, 1H), 3.53-3.49 (m, 1H), 3.23-3.18 (m, 5H),
2.49-2.30 (m, 1H), 2.01-1.93 (m, 2H), 1.79-1.42 (m, 14H),
18.35, 13.45, 13.37. HRMS calcd for C32H54N5O6(M + H)+:
604.4074. Found: 604.4087.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-
3-[2(S)-[[[[1(S)-(methoxymethyl)-1-methylbutyl]amino]carbon-
yl]amino]-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-3-azabi-
cyclo[3.1.0]hexane-2(S)-carboxamide (22). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.26 and 807 (d, J ) 8.19 and 8.51 Hz, 1H), 8.02
and 7.98 (s, 1H), 7.76 (s, 1H), 6.11 (app. t, J ) 9.77 Hz, 1H), 5.82
(s, 1H), 4.98-4.93 and 4.87-4.82 (m, 1H), 4.29 and 4.25 (s, 1H),
4.21-4.14 (m, 1H), 3.98-3.93 (m, 1H), 3.81-3.72 (m, 1H),
3.34-3.31 (m, 2H), 3.22 (s, 3H), 2.49-2.36 (m, 1H), 1.99-1.14
(m, 24H), 1.09 (s, 3H), 1.00-0.92 (m, 6H), 0.90-0.80 (m, 6H);
13C NMR (125 MHz, DMSO-d6) δ 198.64, 198.01, 171.82, 171.64,
171.66, 171.43, 163.85, 163.70, 158.10, 158.00, 78.21, 60.45, 60.03,
59.41, 58.20, 55.29, 52.98, 52.71, 48.30, 39.38, 37.75, 37.66, 37.57,
34.52, 34.36, 34.09, 33.00, 32.96, 31.42, 28.77, 28.64, 28.29, 28.25,
27.89, 27.73, 27.00, 26.96, 26.74, 23.27, 22.18, 21.99, 20.03, 19.95,
19.35, 18.71, 18.55, 17.10, 15.41, 13.46, 13.38. HRMS calcd for
C33H56N5O6 (M + H)+: 650.4493. Found: 650.4512.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-
3-[2(S)-[[[[1(R)-(methoxymethyl)-1,3-dimethylbutyl]amino]car-
bonyl]amino]-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hexane-2(S)-carboxamide (23). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.27 and 8.07 (d, J ) 7.56 and 7.25 Hz, 1H), 8.02
and 7.98 (s, 1H), 7.77 (s, 1H), 6.12 (app. t, J ) 9.45 Hz, 1H), 5.80
(bs, 1H), 4.98-4.94 and 4.88-4.84 (m, 1H), 4.29 and 4.25 (d, J
) 14.81 Hz, 1H), 4.19 (app. t, J ) 10.08 Hz, 1H), 3.95 (dd, J )
10.40, 18.60 Hz, 1H), 3.82-3.75 (m, 1H), 3.27-3.25 (m, 2H), 3.22
(s, 3H), 2.49-2.35 (m, 1H), 2.00-1.92 (m, 2H), 1.81-1.14 (m,
21 H), 1.12-0.81 (m, 18H); 13C NMR (125 MHz, DMSO-d6) δ
198.64, 198.02, 171.81, 171.70, 171.66, 171.38, 163.89, 163.71,
157.93, 157.86, 78.69, 69.37, 60.46, 60.04, 59.34, 58.09, 56.68,
55.65, 52.98, 52.71, 48.32, 44.60, 44.54, 37.89, 37.87, 37.67, 37.58,
34.53, 34.37, 34.14, 33.00, 32.97, 31.44, 30.45, 28.77, 28.64, 28.30,
28.25, 27.88, 27.75, 26.98, 26.94, 26.77, 25.58, 25.21, 24.10, 23.82,
22.20, 22.01, 20.05, 19.96, 19.39, 19.35, 18.71, 18.55, 13.62, 13.53.
HRMS calcd for C34H58N5O6 (M + H)+: 632.4387. Found:
632.4405.
1.28-1.16 (m, 2H), 0.99-0.96 (m, 6H), 0.90-0.70 (m, 12H); 13
C
NMR (125 MHz, DMSO-d6) δ 198.64, 198.01, 171.93, 171.80,
171.72, 171..64, 163.93, 163.69, 158.96, 158.88, 73.49, 60.33,
59.97, 58.88, 56.87, 56.61, 56.47, 52.91, 52.69, 48.20, 48.12, 46.28,
37.63, 37.52, 36.56, 36.46, 36.20, 36.06, 34.84, 34.79, 33.02, 33.96,
31.53, 31.46, 28.77, 28.64, 28.25, 27.58, 26.95, 25.13, 25.10, 24.85,
19.34, 18.72, 18.58, 13.54, 13.48. HRMS calcd for C32H54N5O6
(M + H)+: 604.4074. Found: 604.4101.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]3-
[2(S)-(2,3-dihydro-1H-inden-2-yl)-2-[[[[1(S)-(methoxymethyl)2,2-
dimethylpropyl]amino]carbonyl]amino]-1-oxoethyl]-6,6-dimethyl-
3-azabicyclo[3.1.0]hexane-2(S)-carboxamide (20). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.34 and 8.17 (d, J ) 7.56 and 7.25 Hz, 1H), 8.04
(d, J ) 13.24 Hz, 1H), 7.79 (bs, 1H), 7.20-7.14 (m, 2H), 7.11-7.09
(m, 2H), 6.25 (d, J ) 9.14 Hz, 1H),5.92 (d, J ) 9.77 Hz, 1H),
5.00-4.94 (m, 1H), 4.32-4.24 (m, 2H), 3.82 (d, J ) 13.55 Hz,
1H), 3.77-3.63 (m, 1H), 3.52-3.47 (m, 1H), 3.25-3.22 (m, 2H),
3.20 (s, 3H), 2.90-2.60 (m, 5H), 2.49-2.35 (m, 1H), 2.04-1.95
(m, 2H), 1.83-1.73 (m, 3H), 1.68-1.59 (m, 3H), 1.43-1.26 (m,
2H), 1.00 and 0.98 (s, 3H), 0.83-0.80 (m, 12H); 13C NMR (125
MHz, DMSO-d6) δ 198.60, 198.95, 171.88, 171.71, 171.65, 163.79,
163.70, 158.77, 143.44, 143.43, 143.20, 143.19, 127.03, 126.97,
125.28, 125.06, 73.40, 60.74, 58.91, 56.87, 54.50, 54.18, 52.89,
52.83, 47.68, 47.51, 42.77, 42.52, 37.58, 37.54, 36.03, 35.84, 35.80,
34.78, 33.08, 31.64, 31.61, 28.69, 28.27, 28.19, 27.59, 26.95, 26.88,
19.48, 18.68, 13.57, 13.50. HRMS calcd for C35H52N5O6 (M + H)+:
638.3918. Found: 638.3944.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-
3-[2(S)-[[[[1(S)-[(1,1-dimethylethoxy)methyl]-2,2-dimethylpro-
pyl]amino]carbonyl]amino]-2-(1-methylcyclohexyl)acetyl]-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxamide (24). The
1
product was isolated as a mixture of two diastereomers. H NMR
(500 MHz, DMSO-d6) δ 8.25 and 8.04 (d, J ) 8.19 and 8.51 Hz,
1H), 8.02 and 7.98 (s, 1H), 7.77 (s, 1H), 6.23 (d, J ) 9.77 Hz,
1H), 5.91-5.87 (m, 1H), 4.98-4.94 and 4.88-4.84 (m, 1H),
4.29-4.23 (m, 2H), 3.95-3.90 (m, 1H), 3.82-3.75 (m, 2H),
3.33-3.20 (m, 2H), 2.49-2.35 (m, 1H), 1.99-1.91 (m, 2H),
1.85-1.71 (m, 3H), 1.65-1.14 (m, 15H), 1.09 (s, 9H), 0.99-0.94
(m, 6H), 0.82 (s, 9H), 0.80 and 0.76 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 198.63, 198.01, 171.81, 171.68, 171.65, 171.41,
163.90, 163.71, 158.91, 158.85, 110.47, 72.95, 62.68, 60.42, 59.96,
58.38, 58.27, 57.62, 52.98, 52.71, 48.28, 48.23, 37.67, 37.57, 34.91,
34.83, 34.42, 34.31, 34.20, 34.15, 32.99, 32.97, 31.41, 30.44, 28.77,
28.65, 28.30, 28.24, 28.08, 27.89, 27.62, 26.95, 26.91, 26.87, 26.78,
22.22, 22.02, 20.15, 20.08, 19.29, 18.71, 18.55, 13.44, 13.35. LCMS
(M + H)+: 660.2.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-
3-[2-[[[[1(S)-(methoxymethyl)-2-methylpropyl]amino]carbonyl]-
amino]-2(S)-(1-methylcyclohexyl)-1-oxoethyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hexane-2(S)-carboxamide (21). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.26 and 8.07 (d, J ) 7.25 and 7.25 Hz, 1H), 8.01
and 7.97 (s, 1H), 7.76 (s, 1H), 6.13 (app. t, J ) 9.45 Hz, 1H), 5.97
(d, J ) 9.45 Hz, 1H), 4.99-4.94 and 4.88-4.84 (m, 1H), 4.27-4.21
(m, 2H), 3.94-3.89 (m, 1H), 3.83-3.75 (m, 1H), 3.54-3.50 (m,
1H), 3.28-3.18 (m, 5H), 2.49-2.30 (m, 1H), 1.98-1.92 (m, 2H),
1.81-1.71(m, 3H), 1.65-1.09 (m, 16H), 1.00-0.94 (m, 6H),
0.79-0.74 (m, 9H); 13C NMR (125 MHz, DMSO-d6) δ 198.64,
198.00, 171.79, 171.62, 171.33, 163.90, 163.71, 158.85, 158.76,
73.96, 60.42, 60.03, 59.07, 58.58, 54.14, 52.97, 52.71, 48.31, 48.27,
37.83, 37.66, 37.58, 34.55, 34.41, 34.19, 33.00, 32.97, 31.40, 31.42,
29.83, 29.77, 28.77, 28.64, 28.29, 28.25, 27.83, 27.67, 26.96, 26.92,
26.76, 22.18, 22.00, 20.35, 20.01, 19.94, 19.33, 19.30, 18.71, 18.55,
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-
[2(S)-[[[[1-[(1,1-dimethylethoxy)methyl]cyclohexyl]amino]carbonyl]-
amino]-2-(1-methylcyclohexyl)acetyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hexane-2(S)-carboxamide (25). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.26 and 8.06 (d, J ) 7.25 and 8.19 Hz, 1H), 8.02
and 7.98 (s, 1H), 7.76 (s, 1H), 6.12 (app. t, J ) 8.82 Hz, 1H), 5.66
(s, 1H), 4.99-4.93 and 4.88-4.82 (m, 1H), 4.29 and 4.25 (s, 1H),
4.20 (app. t, J ) 11.66 Hz, 1H), 3.99-3.93 (m, 1H), 3.81-3.72
(m, 1H), 3.24-3.20 (m, 2H), 2.49-2.36 (m, 1H), 2.01-1.90 (m,
2H), 1.85-1.14 (m, 28H), 1.07 (s, 9H), 0.99-0.92 (m, 6H), 0.82
and 0.80 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 198.64, 198.00,

Hepatitis C Virus NS3 Serine Protease Inhibitors
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2813
171.83, 171.80,k 171.67, 171.48, 163.89, 163.71, 157.90, 157.82,
72.60, 69.38, 67.15, 60.45, 60.03, 58.02, 56.66, 54.89, 52.98, 52.70,
48.29, 37.80, 37.66, 37.58, 34.54, 34.44, 34.17, 32.99, 32.96, 32.66,
31.89, 31.39, 30.43, 28.77, 28.64, 28.27, 27.86, 27.71, 26.99, 26.95,
26.77, 26.31, 22.19, 22.01, 21.63, 20.09, 19.35, 19.32, 18.71, 18.55,
13.49, 13.42. HRMS calcd for C37H62N5O6 (M + H)+: 672.4700.
Found: 672.4731.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-
3-[2(S)-[[[[2,2-dimethyl-1(S)-[(phenylmethoxy)methyl]propyl]-
amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-
3-azabicyclo[3.1.0]hexane-2(S)-carboxamide (26). HRMS calcd
for C36H56N5O6 (M + H)+: 654.4230. Found: 654.4246.
7.56 Hz, 1H), 8.04 (d, J ) 12.92 Hz, 1H), 7.79 (bs, 1H), 7.21-7.14
(m, 2H), 7.11-7.09 (m, 2H), 6.75 (bs, 1H), 6.24 (d, J ) 9.14 Hz,
1H), 5.91 (bs, 1H), 4.99-4.94 (m, 1H), 4.31-4.24 (m, 2H),
4.02-3.98 (m, 1H), 3.82-3.79 (m, 2H), 3.66-3.54 (m, 2H), 2.92-
2.58 (m, 5H), 2.49-2.35 (m, 1H), 2.03-1.93 (m, 2H), 1.83-1.73
(m, 3H), 1.68-1.57 (m, 3H), 1.46-1.38 (m, 2H), 1.21 (s, 9H),
1.00-0.97 (m, 3H), 0.82-0.81 (m, 12H); 13C NMR (125 MHz,
DMSO-d6) δ 198.61, 198.15, 171.82, 171.66, 163.79, 163.69,
158.70, 155.62, 143.48, 143.45, 143.24, 143.21, 127.03, 126.95,
125.23, 125.08, 110.22, 60.78, 60.19, 57.01, 52.92, 52.79, 50.20,
47.70, 47.56, 42.78, 42.56, 37.63, 37.56, 36.04, 35.90, 35.86, 34.85,
33.08, 31.65, 29.53, 28.69, 28.28, 28.19, 27.68, 27.56, 27.31, 26.96,
26.88, 19.52, 18.68, 13.59, 13.53. LCMS (M + H)+: 723.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[3-Amino-1-(cyclobutylmethyl)-2,3-di-
oxopropylamino]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]-
hex-3-yl]-1(S)-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]amino]car-
bonyl]amino]-3,3-dimethylbutyl Dimethylcarbamate (31). The
2(S)-[[[[2-[(1R,5S)-2(S)-[[[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]amino]carbo-
nyl]amino]-3,3-dimethylbutyl Methylcarbamate (27). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.34 and 8.16 (d, J ) 6.93, 7.56 Hz, 1H), 8.04 (d, J
) 12.92 Hz, 1H), 7.79 (d, J ) 4.09 Hz, 1H), 7.21-7.10 (m, 4H),
6.91 (d, J ) 4.41 Hz, 1H), 6.26 (d, J ) 8.82 Hz, 1H), 5.92 (d, J )
9.77 Hz, 1H), 4.99-4.94 (m, 1H), 4.33-4.24 (m, 2H), 4.06 (d, J
) 13.82 Hz, 1H), 3.88-3.80 (m, 2H), 3.77-3.64 (m, 1H),
3.61-3.55 (m, 1H), 2.90-2.79 (m, 2H), 2.75-2.61 (m, 3H), 2.56
(d, J ) 4.72 Hz, 3H), 2.49-2.36 (m, 1H), 2.02-1.95 (m, 2H),
1.84-1.73 (m, 3H), 1.68-1.58 (m, 3H), 1.45-1.37 (m, 1H),
1
product was isolated as a mixture of two diastereomers. H NMR
(500 MHz, DMSO-d6) δ 8.33 and 8.15 (d, J ) 6.30 and 7.56 Hz,
1H), 8.03 (d, J ) 11.66 Hz, 1H), 7.78 (bs, 1H), 7.17-7.10 (m,
4H), 6.30 (d, J ) 8.51 Hz, 1H), 5.97 (d, J ) 10.08 Hz, 1H),
4.99-4.92 (m, 1H), 4.31-4.24 (m, 2H), 4.11 (d, J ) 11.03 Hz,
1H), 3.85-3.76 (m, 2H), 3.66-3.60 (m, 2H), 2.90-2.62 (m, 11H),
2.49-2.36 (m, 1H), 2.02-1.95 (m, 2H), 1.84-1.75 (m, 3H),
1.70-1.58 (m, 3H), 1.45-1.39 (m, 1H), 1.33-1.27 (m, 1H),
1.00-0.97 (m, 3H), 0.90-0.80 (m, 12H); 13C NMR (125 MHz,
DMSO-d6) δ 198.61, 198.16, 171.63, 171.58, 171.50, 163.78,
163.68, 158.64, 156.63, 143.41, 143.38, 143.11, 127.00, 125.20,
125.11, 65.58, 60.78, 60.16, 56.84, 54.29, 53.98, 52.93, 52.83,
47.71, 47.53, 42.61, 42.42, 37.58, 37.54, 36.85, 36.29, 36.03, 35.87,
35.61, 34.46, 33.10, 31.61, 28.69, 28.29, 28.19, 27.61, 27.39, 26.94,
26.86, 19.46, 18.68, 13.55, 13.48. HRMS calcd for C37H55N6O7
(M + H)+: 695.4132. Found: 695.4149.
1.34-1.24 (m, 1H), 1.02-0.98 (m, 3H), 0.84-0.81 (m, 12H); 13
C
NMR (125 MHz, DMSO-d6) δ 198.61, 198.16, 171.83, 171.61,
163.79, 163.69, 158.68, 157.68, 143.45, 143.23, 127.02, 126.95,
125.32, 125.07, 64.72, 60.73, 60.16, 57.05, 52.91, 52.82, 47.68,
47.51, 42.78, 42.56, 37.61, 37.55, 36.04, 35.86, 35.81, 35.75, 34.78,
34.75, 33.08, 31.65, 31.63, 28.70, 28.29, 28.19, 27.88, 27.35, 26.97,
26.88, 19.49, 18.69, 18.67, 13.57, 13.51. HRMS calcd for
C36H53N6O7 (M + H)+: 681.3976. Found: 681.3991.
(1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-
3-[2(S)-[[[[1(S)-[[[(ethylamino)carbonyl]oxy]methyl]-2,2-dimeth-
ylpropyl]amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxamide (32). The
2(S)-[[[[2-[(1R,5S)-2(S)-[[[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]amino]carbo-
nyl]amino]-3,3-dimethylbutyl Ethylcarbamate (28). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.34 and 8.16 (d, J ) 7.88 and 7.25 Hz, 1H), 8.04
(d, J ) 12.93 Hz, 1H), 7.80 (d, J ) 4.10 Hz, 1H), 7.18-7.04 (m,
5H), 6.26-6.6.25 (m, 1H), 5.93-5.91 (m, 1H), 4.99-4.94 (m, 1H),
4.30-4.23 (m, 2H), 4.05-4.03 (m, 1H), 3.88-3.54 (m, 4H),
3.02-2.97 (m, 2H), 2.91-2.59 (m, 5H), 2.49-2.35 (m, 1H),
2.03-1.95 (m, 2H), 1.85-1.71 (m, 3H), 1.68-1.58 (m, 3H),
1.43-1.39 (m, 1H), 1.33-1.24 (m, 1H), 1.02-0.98 (m, 6H),
0.89-0.76 (m, 12H). 13C NMR (100 MHz, DMSO-d6) δ 198.62,
198.16, 171.84, 171.67, 164.09, 163.80, 158.89, 157.01, 143.46,
143.27, 127.03, 127.01, 125.30, 125.07, 110.23, 64.54, 60.72, 60.16,
57.01, 54.48, 53.06, 52.91, 52.82, 47.69, 47.52, 42.82, 42.57, 37.60,
37.54, 36.03, 36.85, 35.93, 35.82, 34.78, 33.09, 33.07, 31.66, 30.48,
28.70, 28.28, 28.20, 27.68, 27.55, 27.34, 26.96, 26.88, 19.48, 18.68,
15.96, 13.58, 13.51. LCMS (M + H)+: 695.4.
1
product was isolated as a mixture of two diastereomers. H NMR
(500 MHz, DMSO-d6) δ 8.29 and 8.20 (d, J ) 7.3 and 7.0 Hz,
1H), 8.02 and 7.97 (app. s, 1H), 7.76-7.74 (m, 1H), 7.01-6.96
(m, 1H), 6.08-6.02 (m, 2H), 4.99-4.95 and 4.88-4.83 (m, 1H),
4.27 (app. s, 1H), 4.21-4.16 (m, 1H), 4.04-4.02 (m, 1H),
3.92-3.74 (m, 3H), 3.60-3.56 (m, 1H), 2.99-2.96 (m, 2H),
1.99-1.94 (m, 2H), 1.81-1.72 (m, 2H), 1.66-1.54 (m, 2H),
1.45-1.41 (m, 1H), 1.28-1.25 (m, 2H), 1.00-0.77 (complex, 29H).
2(S)-[[[[2-[(1R,5S)-2(S)-[[[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-cyclohexyl-2-oxoethyl]amino]carbonyl]amino]-3,3-
dimethylbutyl Ethylcarbamate (33). The product was isolated as
a mixture of two diastereomers. 1H NMR (500 MHz, DMSO-d6) δ
8.29 and 8.09 (d, J ) 7.2 and 7.9 Hz, 1H), 7.99 and 8.01 (app. s,
1H), 7.77 and 7.78 (app. s, 1H), 6.98-6.96 (m, 1H), 6.03-6.00
(m, 1H), 5.90-5.86 (m, 1H), 4.95-4.90 (m, 1H), 4.25 and 4.22
(app. s, 1H), 4.12-4.00 (m, 2H), 3.93-3.73 (m, 3H), 3.70-3.58
(m, 1H), 2.99-2.97 (m, 2H), 2.49-2.46 and 2.37-2.31 (m, 1H),
2.01-1.96 (m, 2H), 1.81-1.40 (m, 10H), 1.31-1.24 (m, 2H),
1.12-0.88 (complex, 16H), 0.82 (s, 9H). 13C NMR (100 MHz,
DMSO-d6) δ 198.60, 198.07, 175.20, 171.95, 171.81, 171.59,
163.70, 158.71, 156.98, 64.62, 60.61, 56.98, 52.84, 47.75, 37.76,
37.63, 35.89, 34.85, 33.06, 31.62, 28.75, 28.68, 28.29, 28.23, 27.37,
26.98, 26.93, 26.44, 19.43, 18.69, 15.91, 13.54, 13.44. LCMS (M
+ H)+: 661.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]amino]carbo-
nyl]amino]3,3-dimethylbutyl (1-methylethyl)carbamate (29). The
1
product was isolated as a mixture of two diastereomers. H NMR
(500 MHz, DMSO-d6) δ 8.37 and 8.17 (d, J ) 7.25 and 7.56 Hz,
1H), 8.05 (d, J ) 13.24 Hz, 1H), 7.80 (bs, 1H), 7.22-7.09 (m,
4H), 6.96 (bs, 1H), 6.25 (d, J ) 10.40 Hz, 1H), 5.92 (d, J ) 8.82
Hz, 1H), 5.00-4.94 (m, 1H), 4.28-4.24 (m, 2H), 4.04 (d, J )
11.66 Hz, 1H), 3.85-3.55 (m, 5H), 2.90-2.78 (m, 2H), 2.76-2.59
(m, 3H), 2.49-2.35 (m, 1H), 2.02-1.95 (m, 2H), 1.83-1.73 (m,
3H), 1.68-1.57 (m, 3H), 1.43-1.23 (m, 2H), 1.06-0.98 (m, 9H),
0.84-0.80 (m, 12H). LCMS (M + H)+: 709.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-
3,3-dimethylbutyl Ethylcarbamate (34). The product was isolated
2(S)-[[[[2-[(1R,5S)-2(S)-[[[3-Amino-1-(cyclobutylmethyl)-2,3-
dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]amino]carbo-
nyl]amino]-3,3-dimethylbutyl (1,1-dimethylethyl)carbamate (30).
1
as a mixture of two diastereomers. H NMR (500 MHz, DMSO-
d6) δ 8.26 and 8.09 (d, J ) 6.30 and 9.14 Hz, 1H), 8.02 and 7.98
(s, 1H), 7.77 (s, 1H), 6.98 (t, J ) 7.25 Hz, 1H), 6.11 (app. d, J )
11.35 Hz, 1H), 6.02 (app. d, J ) 9.45 Hz, 1H), 4.99-4.95 and
4.87-4.83 (m, 1H), 4.26-4.21 (m, 2H), 4.01-3.98 (m, 1H), 3.90
1
The product was isolated as a mixture of two diastereomers. H
NMR (500 MHz, DMSO-d6) δ 8.34 and 8.17 (d, J ) 6.93 and

2814 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Arasappan et al.
(app. t, J ) 11.03 Hz, 1H), 3.84-3.75 (m, 2H), 3.60-3.55 (m,
1H), 3.00-2.95 (m, 2H), 1.98-1.93 (m, 2H), 1.80-1.72 (m, 3H),
1.66-1.07 (m, 15H), 0.99-0.94 (m, 9H), 0.84-0.77 (m, 12H).
(Note: 1 proton is apparently hidden under the solvent peak). LCMS
(M + H)+: 675.4.
6.26-6.22 (m, 1H), 5.92 (br. d, J ) 9.16 Hz, 1H), 5.84-5.77 (m,
1H), 5.11-5.05 (m, 2H), 4.99-4.95 (m, 1H), 4.31-4.27 (m, 2H),
4.07-4.03 (m, 1H), 3.85-3.56 (m, 6H), 3.01-2.99 (m, 2H),
2.91-2.60 (m, 5H), 1.80-1.73 (m, 1H), 1.56-1.25 (m, 7H),
1.02-0.82 (complex, 21H). LCMS (M + H)+: 723.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[3-Amino-1-(cyclopropylmethyl)-2,3-
dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]amino]carbo-
nyl]amino]-3,3-dimethylbutyl Ethylcarbamate (35). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.45 and 8.32 (d, J ) 7.56 and 6.94 Hz, 1H), 8.04
(d, J ) 7.25 Hz, 1H), 7.78 (d, J ) 7.88 Hz, 1H), 7.22-7.04 (m,
5H), 6.28-6.6.22 (m, 1H), 5.96-5.90 (m, 1H), 5.17-5.10 (m, 1H),
4.32-4.20 (m, 2H), 4.05-4.02 (m, 1H), 3.83 (app. d, J ) 10.1
Hz, 2H), 3.75-3.58 (m, 2H), 3.02-2.97 (m, 2H), 2.89-2.58 (m,
5H), 1.73-1.63 (m, 1H), 1.56-1.26 (m, 3H), 1.02-0.98 (m, 6H),
2(S)-[[[[1(S)-(2,3-Dihydro-1H-inden-2-yl)-2-[(1R,5S)-2(S)-[[[1-
[1,2-dioxo-2-(2-propenylamino)ethyl]-4-pentynyl]amino]carbo-
nyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]ami-
no]carbonyl]amino]-3,3-dimethylbutyl Ethylcarbamate (39). The
1
product was isolated as a mixture of two diastereomers. H NMR
(500 MHz, DMSO-d6) δ 8.89 (app. t, J ) 5.99 Hz, 1H), 8.51 (d,
J ) 6.93 Hz, 1H), 7.21-7.09 (m, 4H), 7.03 (bs, 1H), 6.25 (bs,
1H), 5.92 (d, J ) 10.71 Hz, 1H), 5.83-5.75 (m, 1H), 5.15-5.05
(m, 2H), 5.03-4.97 (m, 1H), 4.28-4.21 (m, 2H), 4.05 (app. d, J
) 8.51 Hz, 1H), 3.85-3.55 (m, 6H), 3.02-2.96 (m, 2H), 2.90-2.81
(m, 3H), 2.75-2.62 (m, 3H), 2.33-2.22 (m, 2H), 2.05-1.96 (m,
1H), 1.78-1.71 (m, 1H), 1.42-1.25 (m, 2H), 1.02-0.97 (m, 6H),
0.83-0.82 (m, 12H); 13C NMR (125 MHz, DMSO-d6) δ 197.55,
172.10, 171.92, 171.71, 161.91, 158.75, 157.01, 143.45, 143.23,
135.99, 135.01, 126.96, 125.39, 125.16, 116.47, 84.22, 72.79, 64.50,
60.27, 56.99, 54.25, 47.62, 41.70, 35.92, 34.80, 31.53, 30.46, 29.78,
27.75, 27.34, 26.92, 19.52, 15.96, 15.56, 13.60, 13.55. HRMS calcd
for C39H55N6O7 (M + H)+: 719.4132. Found: 719.4119.
0.89-0.75 (m, 13H), 0.47-0.35 (m, 2H), 0.15-0.02 (m, 2H). 13
C
NMR (100 MHz, DMSO-d6) δ 198.49, 198.07, 171.90, 171.78,
171.67, 171.62, 163.71, 163.53, 158.69, 157.01, 143.44, 143.40,
143.12, 126.96, 125.32, 125.09, 109.93, 64.58, 64.53, 60.59, 60.14,
57.02, 55.13, 54.95, 47.71, 47.60, 42.71, 42.61, 36.00, 35.93, 35.88,
35.82, 34.79, 31.70, 30.46, 27.63, 27.57, 27.34, 26.98, 26.89, 26.80,
19.50, 15.96, 13.59, 13.53, 8.83, 8.71, 5.92, 5.23, 5.04, 4.90. LCMS
(M + H)+: 681.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)-
ethyl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-
3,3-dimethylbutyl Ethylcarbamate (40). The product was isolated
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-(Cyclopropylmethyl)-2,3-dioxo-3-
(2-propenylamino)propyl]amino]carbonyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hex-3-yl]-1(S)-(2,3-dihydro-1H-inden-2-yl)-2-
oxoethyl]amino]carbonyl]amino]-3,3-dimethylbutylEthylcarbamate
(36). The product was isolated as a mixture of two diastereomers.
1H NMR (500 MHz, DMSO-d6) δ 8.91-8.85(m, 1H), 8.50 and
8.39 (d, J ) 6.62 and 7.25 Hz, 1H), 7.22-7.09 (m, 4H), 7.03 (bs,
1H), 6.26 (d, J ) 7.56 Hz, 1H), 5.92 (d, J ) 8.51 Hz, 1H),
5.84-5.76 (m, 1H), 5.14-5.05 (m, 3H), 4.32-4.21 (m, 2H), 4.05
(app. d, J ) 11.03 Hz, 1H), 3.84 (app. d, J ) 9.77 Hz, 2H),
3.75-3.55 (m, 4H), 3.01-2.97 (m, 2H), 2.91-2.59 (m, 5H),
1.76-1.67 (m, 1H), 1.55-1.28 (m, 3H), 1.01-0.98 (m, 6H),
1
as a mixture of two diastereomers. H NMR (500 MHz, DMSO-
d6) δ 8.87 and 8.81 (app. t, J ) 5.99 Hz, 1H), 8.35 and 8.23 (d, J
) 6.93 and 7.56 Hz, 1H), 6.97 (d, J ) 5.04 Hz, 1H), 6.09 (app. t,
J ) 10.40 Hz, 1H), 6.01 (d, J ) 8.19 Hz, 1H), 5.84-5.75 (m, 1H),
5.13-5.04 (m, 2H), 5.00-4.95 and 4.93-4.87 (m, 1H), 4.28-4.22
(m, 2H), 4.01 (app. d, J ) 10.08 Hz, 1H), 3.91 (app. t, J ) 10.08
Hz, 1H), 3.86-3.64 (m, 4H), 3.62-3.56 (m, 1H), 2.98-2.94 (m,
2H), 1.74-1.65 (m, 1H), 1.55-1.06 (m, 15H), 1.00-0.78 (complex,
24H). 13C NMR (100 MHz, DMSO-d6) δ 198.21, 197.65, 171.98,
171.80, 171.60, 171.31, 163.71, 163.36, 162.03, 161.69, 158.82,
156.96, 156.92, 135.33, 135.01, 116.46, 116.37, 64.60, 60.34, 59.95,
58.68, 57.01, 54.37, 48.31, 41.70, 37.86, 35.89, 34.84, 34.52, 34.40,
34.13, 32.56, 31.55, 31.47, 27.35, 26.98, 26.92, 26.88, 26.77, 22.20,
22.02, 19.99, 19.58, 19.44, 19.30, 15.91, 14.44, 14.24, 13.51, 13.45.
LCMS (M + H)+: 689.2.
0.92-0.80 (m, 13H), 0.47-0.36 (m, 2H), 0.14-0.03 (m, 2H); 13
C
NMR (125 MHz, DMSO-d6) δ 198.01, 197.59, 171.94, 171.77,
171.67, 161.64, 161.43, 158.69, 157.00, 143.52, 135.11, 127.04,
125.35, 125.10, 116.48, 116.42, 64.54, 60.52, 60.11, 57.01, 55.46,
55.27, 47.70, 47.57, 42.67, 41.73, 35.93, 35.80, 31.70, 31.62, 27.64,
27.59, 27.34, 26.98, 26.90, 19.50, 15.96, 13.57, 13.52, 8.83, 8.72,
5.99, 5.92, 5.26, 5.04. HRMS calcd for C39H57N6O7 (M + H)+:
721.4289. Found: 721.4301.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)-
ethyl]pentyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-
3,3-dimethylbutyl Ethylcarbamate (41). The product was isolated
2(S)-[[[[1(S)-(2,3-Dihydro-1H-inden-2-yl)-2-[(1R,5S)-2(S)-[[[1-
[1,2-dioxo-2-(2-propenylamino)ethyl]butyl]amino]carbonyl]-6,6-
dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]amino]carbo-
nyl]amino]-3,3-dimethylbutyl Ethylcarbamate (37). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.91 and 8.87(t, J ) 5.99 and 5.67 Hz, 1H), 8.44 and
8.31 (d, J ) 6.93 and 7.56 Hz, 1H), 7.20-7.09 (m, 4H), 7.04 (app.
t, J ) 5.04 Hz, 1H), 6.24(app. t, J ) 8.51 Hz, 1H), 5.92 (d, J )
9.45 Hz, 1H), 5.84-5.77 (m, 1H), 5.13-5.05 (m, 2H), 5.02-4.96
(m, 1H), 4.29-4.21 (m, 2H), 4.05 (app. d, J ) 12.92 Hz, 1H),
3.82-3.56 (m, 6H), 3.01-2.96 (m, 2H), 2.89-2.59 (m, 5H),
1.74-1.66 (m, 1H), 1.55-1.46 (m,1H), 1.44-1.24(m, 4H),
1.01-0.98 (m, 6H), 0.90-0.87 (m, 3H), 0.82 (m, 12H); 13C NMR
(125 MHz, DMSO-d6) δ 198.22, 197.80, 172.05, 171.82, 171.66,
161.87, 158.67, 157.06, 143.29, 135.05, 135.02, 127.01, 126.98,
126.91, 125.09, 116.47, 116.38, 110.00, 64.53, 60.64, 57.09, 54.58,
54.28, 41.71, 36.00, 35.92, 35.84, 34.79, 32.58, 32.43, 27.62, 27.56,
27.34, 26.99, 26.88, 19.71, 19.60, 19.50, 15.99, 14.46, 14.41, 13.59,
13.52. HRMS calcd for C38H57N6O7 (M + H)+: 709.4289. Found:
709.4284.
1
as a mixture of two diastereomers. H NMR (500 MHz, DMSO-
d6) δ 8.89 and 8.83 (app.t, J ) 5.99 and 6.30 Hz, 1H), 8.36 and
8.25 (d, J ) 6.62 and 7.56 Hz, 1H), 6.99 (d, J ) 5.04 Hz, 1H),
6.18-6.07 (m, 1H), 6.02-5.99 (m, 1H), 5.84-5.75 (m, 1H),
5.17-5.02 (m, 2H), 4.98-4.94 and 4.87-4.83 (m, 1H), 4.28-4.20
(m, 2H), 4.00 (d, J ) 9.14 Hz, 1H), 3.91 (app. t, J ) 9.14 Hz,
1H), 3.84-3.71 (m, 4H), 3.64-3.56 (m, 1H), 2.99-2.94 (m, 2H),
1.77-1.68 (m, 1H), 1.56-1.06 (m, 17H), 0.99-0.78 (complex,
24H). 13C NMR (100 MHz, DMSO-d6) δ 198.19, 197.62, 173.71,
171.99, 171.80, 171.37, 162.02, 161.66, 158.88, 158.82, 156.98,
141.38, 135.04, 135.00, 133.30, 130.89, 128.99, 125.03, 116.43,
116.33, 95.34, 69.37, 64.59, 60.31, 59.94, 58.95, 56.95, 56.69,
54.50, 48.31, 41.69, 37.52, 35.89, 34.84, 34.33, 34.10, 31.64, 31.53,
31.50, 30.46, 30.19, 30.04, 28.39, 28.18, 27.33, 26.97, 26.92, 26.86,
26.75, 22.63, 22.58, 22.54, 22.19, 22.00, 19.96, 19.31, 15.91, 14.55,
13.52, 13.44. LCMS (M + H)+: 703.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[2-(Ethylamino)-1,2-dioxoethyl]-
4-pentynyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-
3,3-dimethylbutyl ethylcarbamate (44). The product was isolated
2(S)-[[[[1(S)-(2,3-Dihydro-1H-inden-2-yl)-2-[(1R,5S)-2(S)-[[[1-
[1,2-dioxo-2-(2-propenylamino)ethyl]pentyl]amino]carbonyl]-
6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]amino]car-
bonyl]amino]-3,3-dimethylbutyl Ethylcarbamate (38). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.92-8.85 (m, 1H), 8.43 and 8.30 (app. d, J ) 6.4
and 7.3 Hz, 1H), 7.18-7.10 (m, 1H), 7.04-7.00 (m, 1H),
1
as a mixture of two diastereomers. H NMR (500 MHz, DMSO-
d6) δ 8.71 and 8.61 (app. t, J ) 6.0 and 6.1 Hz, 1H), 8.47-8.45
and 8.42 (m and d, J ) 7.0 Hz, 1H), 7.01-6.91 (m, 1H), 6.20-6.08
(m, 2H), 5.03-4.99 and 4.79-4.73 (m, 1H), 4.25-4.22 (m, 2H),
4.02-3.73 (m, 4H), 3.60-3.56 (m, 1H), 3.17-3.06 (m, 2H),

Hepatitis C Virus NS3 Serine Protease Inhibitors
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2815
3.00-2.93 (m, 2H), 2.80 (s, 1H), 2.38-2.20 (m, 2H), 1.90-1.82
(m, 1H), 1.72-1.65 (m, 1H), 1.55-0.76 (complex, 36H). LCMS
(M + H)+: 687.2.
3.86-3.68 (m, 4H), 3.60-3.56 (m, 1H), 2.80 (s, 1H), 2.78-2.75
(m, 2H), 2.37-2.19 (m, 2H), 2.00-1.89 (m, 1H),1.84-1.01 (m,
14H), 0.99-0.69 (m, 24H). 13C NMR (100 MHz, DMSO-d6) δ
197.54, 172.13, 172.10, 161.69, 158.91, 157.32, 135.07, 134.99,
116.48, 84.15, 72.67, 64.61, 60.08, 58.73, 56.97, 54.20, 48.74,
48.27, 41.71, 37.82, 34.89, 34.39, 34.12, 34.09, 31.38, 30.47, 29.93,
29.18, 29.12, 27.87, 27.32, 26.94, 26.88, 26.79, 22.20, 22.01, 20.84,
19.90, 19.36, 15.57, 13.51, 13.46. LCMS (M + H)+: 727.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)-
ethyl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-
3,3-dimethylbutyl (1-methylethyl)carbamate (45). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.88 and 8.82 (app. t, J ) 5.99 and 6.30 Hz, 1H),
8.36 and 8.25 (d, J ) 6.93 and 7.56 Hz, 1H), 6.90 (br. s, 1H), 6.09
(app. t, J ) 10.08 Hz, 1H), 6.02 (d, J ) 8.82 Hz, 1H), 5.83-5.75
(m, 1H), 5.12-5.04 (m, 2H), 4.99-4.95 and 4.90-4.86 (m, 1H),
4.28-4.20 (m, 2H), 4.00 (d, J ) 9.14 Hz, 1H), 3.90 (app. t, J )
9.77 Hz, 1H), 3.84-3.68 (m, 4H), 3.62-3.53 (m, 2H), 1.73-1.64
(m, 1H), 1.54-1.07 (m, 15H), 1.03-0.78 (complex, 27H). 13C
NMR (100 MHz, DMSO-d6) δ 198.22, 197.65, 171.99, 171.81,
171.58, 171.40, 162.02, 161.65, 158.90, 158.84, 156.32, 141.33,
135.34, 135.05, 135.01, 131.96, 131.24, 130.87, 129.00, 127.17,
121.29, 116.45, 116.36, 64.68, 60.32, 59.95, 58.69, 56.93, 54.38,
48.29, 43.12, 41.70, 37.84, 34.11, 32.53, 31.54, 31.47, 30.46, 27.80,
27.73, 27.31, 26.97, 26.91, 26.77, 23.41, 23.33, 22.18, 22.00, 19.93,
19.87, 19.60, 19.44, 19.35, 19.31, 14.46, 14.35, 13.52, 13.46. LCMS
(M + H)+: 703.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)eth-
yl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-
1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-3,3-
dimethylbutyl (cyclopropylmethyl)carbamate (49). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.90 and 8.84 (d, J ) 5.99 Hz, 1H), 8.38 and 8.29
(d, J ) 6.62 and 7.25 Hz, 1H), 7.13-7.09 (m, 1H), 6.11-6.01 (m,
2H), 5.83-5.75 (m, 1H), 5.11-5.04 (m, 2H), 4.99-4.95 and
4.90-4.86 (m, 1H), 4.26 and 4.24 (s, 1H), 4.20 (app. t, J ) 9.45
Hz, 1H), 4.02 (d, J ) 9.77 Hz, 1H), 3.90 (app. t, J ) 9.77 Hz,
1H), 3.84-3.67 (m, 4H), 3.61-3.55 (m, 1H), 2.85-2.82 (m, 2H),
1.74-1.64 (m, 1H), 1.54-1.06 (m, 16H), 0.99-0.78 (complex,
21H), 0.38-0.34 (m, 2H), 0.15-0.10 (m, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 198.21, 197.65, 171.99, 171.80, 171.59, 171.38,
162.02, 161.68, 158.90, 158.84, 157.21, 135.05, 135.01, 116.45,
116.36, 64.79, 60.31, 59.96, 58.73, 56.99, 54.36, 48.28, 45.42,
41.70, 37.83, 34.91, 34.87, 34.49, 34.39, 34.36, 34.11, 32.54, 31.54,
31.47, 30.46, 27.80, 27.75, 27.35, 26.97, 27.92, 26.76, 22.19, 22.01,
19.95, 19.89, 19.59, 19.49, 19.44, 19.32, 14.45, 14.34, 13.52, 13.46,
12.00, 3.90. LCMS (M + H)+: 715.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)ethyl]-
4-pentynyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-
3,3-dimethylbutyl (1-methylethyl)carbamate (46). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.88 and 8.77 (app. t, J ) 5.90 and 6.30 Hz, 1H),
8.54 and 8.44 (d, J ) 6.93 and 8.19 Hz, 1H), 6.90 (br. s, 1H), 6.08
(app. t, J ) 8.51 Hz, 1H), 6.02 (d, J ) 10.08 Hz, 1H), 5.83-5.73
(m, 1H), 5.13-5.05 (m, 2H), 5.03-4.97 (m, 1H), 4.24 (s, 1H),
4.21 (d, J ) 7.88 Hz, 1H), 4.00 (d, J ) 10.4 Hz, 1H), 3.90 (d, J )
10.08 Hz, 1H), 3.85-3.73 (m, 4H), 3.71-3.55 (m, 2H), 2.79 (app.
t, J ) 2.52 Hz, 1H), 2.36-2.18 (m, 2H), 2.01-1.89 (m, 1H),
1.79-1.66 (m, 1H), 1.53-1.20 (m, 12H), 1.04-0.78 (complex,
24H). 13C NMR (100 MHz, DMSO-d6) δ 197.54, 197.07, 172.10,
171.44, 161.68, 158.90, 135.98, 135.06, 134.98, 116.47, 116.33,
84.13, 72.66, 72.54, 64.40, 60.08, 58.75, 56.97, 54.19, 48.29, 43.12,
41.70, 37.81, 34.91, 34.39, 34.09, 31.39, 29.93, 27.88, 27.31, 26.93,
26.88, 26.77, 23.41, 23.33, 22.19, 22.02, 19.91, 19.35, 15.57, 15.20,
13.51, 13.46. LCMS (M + H)+: 713.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)ethyl]-
4-pentynyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-
3,3-dimethylbutyl (cyclopropylmethyl)carbamate (50). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.88 and 8.77 (t, J ) 5.99 Hz, 1H), 8.54 and 8.44 (d,
J ) 6.94 Hz, 1H), 7.09 (bs, 1H), 6.11-6.01 (m, 2H), 5.83-5.74
(m, 1H), 5.15-5.05 (m, 2H), 5.03-4.98 (m, 1H), 4.24 (s, 1H),
4.20 (d, J ) 7.57 Hz, 1H), 4.03-4.00 (m, 1H), 3.90 (d, J ) 10.40
Hz, 1H), 3.85-3.66 (m, 4H), 3.61-3.55 (m, 1H), 2.84 (app. t, J )
6.30 Hz, 2H), 2.80 (app. t, J ) 2.52 Hz, 1H), 2.37-2.19 (m, 2H),
2.01-1.91 (m, 1H), 1.73-1.03 (m, 14H), 1.02-0.74 (complex,
21H), 0.37-0.34 (m, 2H), 0.14-0.07 (m, 2H). 13C NMR (100 MHz,
DMSO-d6) δ 197.54, 172.10, 171.43, 161.69, 135.99, 134.98,
116.48, 116.40, 96.84, 96.74, 84.17, 84.09, 72.76, 72.61, 71.67,
64.83, 64.72, 58.82, 58.12, 56.89, 54.07, 48.25, 45.30, 41.70, 37.88,
35.05, 34.32, 34.01, 31.40, 30.35, 30.04, 29.21, 27.34, 27.01, 26.91,
26.70, 22.24, 22.02, 19.90, 19.40, 15.55, 13.47, 13.00, 12.05, 3.90.
LCMS (M + H)+: 725.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)eth-
yl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-
1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-3,3-
dimethylbutyl (2-methylpropyl)carbamate (47). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.85 and 8.79 (app. t, J ) 5.99 Hz, 1H), 8.33 and
8.21 (d, J ) 6.93 and 7.25 Hz, 1H), 6.99 (d, J ) 4.41 Hz, 1H),
6.10-6.00 (m, 2H), 5.83-5.76 (m, 1H), 5.12-5.05 (m, 2H),
5.00-4.96 and 4.91-4.87 (m, 1H), 4.28-4.20 (m, 2H), 4.02 (d, J
) 11.03 Hz, 1H), 3.91 (app. t, J ) 9.77 Hz, 1H), 3.86-3.68 (m,
4H), 3.64-3.57 (m, 1H), 2.77 (app. t, J ) 5.99 Hz, 2H), 1.74-1.60
(m, 1H), 1.54-1.07 (m, 16H), 1.00-0.76 (m, 27 H). 13C NMR
(100 MHz, DMSO-d6) δ 198.20, 197.64, 171.97, 171.80, 171.61,
171.41, 162.04, 161.71, 158.83, 157.31, 135.05, 135.01, 116.47,
116.38, 64.65, 60.35, 59.97, 58.70, 56.97, 56.70, 54.39, 48.75,
48.28, 41.70, 37.86, 34.86, 34.53, 34.41, 34.14, 32.58, 32.55, 31.54,
31.47, 30.46, 29.11, 27.81, 27.75, 27.34, 26.98, 26.93, 26.77, 22.19,
22.02, 20.82, 19.94, 19.90, 19.58, 19.43, 19.35, 13.51, 13.45. LCMS
(M + H)+: 717.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)ethyl]-
4-pentynyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-
3,3-dimethylbutyl (2-methylpropyl)carbamate (48). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.88 and 8.78 (app. t, J ) 5.99 Hz, 1H), 8.54 and
8.44 (d, J ) 6.62 Hz, 1H), 7.04 (br. s, 1H), 6.08 (d, J ) 11.66 Hz,
1H), 6.02 (d, J ) 9.46 Hz, 1H), 5.87-5.73 (m, 1H), 5.14-5.05
(m, 2H), 5.03-4.98 (m, 1H), 4.24 (s, 1H), 4.20 (d, J ) 7.88 Hz,
1H), 4.01 (d, J ) 11.03 Hz, 1H), 3.90 (d, J ) 10.40 Hz, 1H),
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)eth-
yl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-
1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-3,3-
dimethylbutyl (cyclohexylmethyl)carbamate (51). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.88 and 8.82 (t, J ) 5.99 Hz, 1H), 8.36 and 8.24 (d,
J ) 6.62 and 7.56 Hz, 1H), 7.00-6.96 (m, 1H), 6.07 (app. t, J )
10.71 Hz, 1H), 6.02 (d, J ) 10.71 Hz, 1H), 5.83-5.76 (m, 1H),
5.12-5.04 (m, 2H), 4.99-4.95 and 4.90-4.86 (m, 1H), 4.30 and
4.26 (s, 1H), 4.22 (app. t, J ) 8.82 Hz, 1H), 4.02 (d, J ) 11.35
Hz, 1H), 3.91 (app. t, J ) 10.08 Hz, 1H), 3.82-3.69 (m, 4H),
3.60-3.55 (m, 1H), 2.80-2.75 (m, 2H), 1.74-1.59 (m, 6H),
1.54-1.07 (m, 21H), 0.99-0.78 (complex, 21H). 13C NMR (100
MHz, DMSO-d6) δ 198.22, 197.66, 171.99, 171.81, 171.58, 171.40,
162.02, 161.65, 158.89, 158.83, 157.29, 135.05, 135.01, 116.44,
116.36, 64.68, 60.31, 59.95, 58.68, 56.92, 54.34, 48.27, 47.46,
41.70, 38.50, 37.83, 37.81, 34.83, 34.55, 34.41, 34.10, 32.52, 31.55,
31.47, 31.14, 30.47, 27.33, 26.97, 26.94, 26.77, 26.27, 22.18, 22.02,
19.91, 19.85, 19.60, 19.44, 19.35, 19.32, 14.46, 14.35, 13.52, 13.46.
LCMS (M + H)+: 757.2.
2(S)-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)ethyl]-
4-pentynyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]-

2816 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Arasappan et al.
3,3-dimethylbutyl (cyclohexylmethyl)carbamate (52). The product
was isolated as a mixture of two diastereomers. 1H NMR (500 MHz,
DMSO-d6) δ 8.85 and 8.75 (t, J ) 5.99 Hz, 1H), 8.50 and 8.42 (d,
J ) 6.93 Hz, 1H), 6.95 (br. s, 1H), 6.07 (d, J ) 11.03 Hz, 1H),
6.02 (d, J ) 9.45 Hz, 1H), 5.83-5.74 (m, 1H), 5.13-5.05 (m,
2H), 5.03-4.97 (m, 1H), 4.24 (s, 1H), 4.21 (d, J ) 6.62 Hz, 1H),
4.02 (d, J ) 10.71 Hz, 1H), 3.91 (d, J ) 10.40 Hz, 1H), 3.83-3.68
(m, 4H), 3.60-3.57 (m, 1H), 2.80-2.77 (m, 3H), 2.34-2.20 (m,
2H), 2.00-1.91 (m, 1H), 1.74-1.08 (m, 24H), 0.99-0.76 (m, 18
H). 13C NMR (100 MHz, DMSO-d6) δ 197.52, 197.06, 172.51,
172.44, 172.09, 171.45, 162.35, 161.73, 158.90, 157.29, 135.98,
134.98, 116.49, 116.36, 84.32, 84.15, 72.59, 72.50, 64.70, 60.09,
58.72, 56.95, 56.70, 54.21, 48.26, 47.47, 41.71, 38.50, 37.83, 34.87,
34.46, 34.11, 31.39, 31.13, 30.47, 29.97, 27.90, 27.33, 26.94, 26.80,
26.27, 22.21, 22.04, 19.93, 19.35, 15.56, 13.49, 13.44. LCMS (M
+ H)+: 767.2.
[1-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)ethyl]-
4-pentynyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-
3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]ami-
no]cyclohexyl]methyl Ethylcarbamate (56). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.88 and 8.78 (t, J ) 5.99 Hz, 1H), 8.50 and 8.44 (d,
J ) 6.93 and 7.25 Hz, 1H), 6.99 (app. t, J ) 5.04 Hz, 1H), 6.19
(app. t, J ) 10.08 Hz, 1H), 5.83-5.74 (m, 2H), 5.14-5.05 (m,
2H), 5.03-4.96 and 4.77-4.70 (m, 1H), 4.26 (s, 1H), 4.22-4.15
(m, 1H), 4.04-3.94 (m, 3H), 3.80-3.68 (m, 3H), 3.00-2.95 (m,
2H), 2.79 (app. t, J ) 2.52 Hz, 1H), 2.34-2.20 (m, 2H), 2.01-1.92
(m, 2H), 1.87-1.66 (m, 2H), 1.57-0.81 (complex, 32H). 13C NMR
(100 MHz, DMSO-d6) δ 197.54, 197.08, 172.13, 172.11, 171.88,
171.45, 161.68, 158.85, 157.06, 135.98, 135.06, 134.98, 116.47,
116.34, 116.00, 84.31, 84.14, 72.68, 72.56, 69.01, 60.26, 60.06,
58.18, 54.44, 54.23, 48.27, 41.70, 37.67, 35.85, 34.41, 34.11, 32.41,
31.37, 30.46, 29.93, 27.85, 26.98, 26.91, 26.77, 26.11, 22.17, 21.99,
21.41, 20.01, 19.38, 15.94, 15.57, 15.22, 13.31, 13.24. LCMS (M
+ H)+: 711.2.
2(S)-Cyclohexyl-2-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-dioxo-2-(2-prope-
nylamino)ethyl]butyl]amino]carbonyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hex-3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]-
amino]carbonyl]amino]ethyl Ethylcarbamate (53). The product was
Acknowledgment. We thank the Structural Chemistry
Department at Schering-Plough Research Institute for NMR and
MS analysis for all new compounds. We thank Dr. Z. Guo for
modeling studies. We thank Dr. L. Nair for assistance in the
preparation of the experimental section of this manuscript.
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.85 and 8.79 (t, J ) 5.99 Hz, 1H), 8.33 and 8.19 (d,
J ) 6.93 and 7.25 Hz, 1H), 7.02 (br. s, 1H), 6.11 (app. t, J )
10.08 Hz, 1H), 5.99 (d, J ) 10.08 Hz, 1H), 5.84-5.76 (m, 1H),
5.12-5.05 (m, 2H), 5.00-4.96 and 4.92-4.87 (m, 1H), 4.32-4.22
(m, 2H), 3.92 (app. t, J ) 9.45 Hz, 1H), 3.87-3.71 (m, 5H),
3.62-3.57 (m, 1H), 3.03-2.96 (m, 2H), 1.72-1.06 (m, 27H),
1.01-0.80 (complex, 15H). 13C NMR (100 MHz, DMSO-d6) δ
198.21, 197.65, 171.95, 171.77, 171.53, 171.34, 162.02, 161.71,
158.70, 158.65, 156.86, 135.31, 135.05, 135.01, 131.96, 131.23,
127.15, 116.47, 116.39, 64.80, 60.36, 59.96, 58.52, 54.39, 53.43,
48.26, 41.70, 37.85, 37.83, 35.90, 34.54, 34.41, 34.16, 32.59, 31.54,
31.47, 30.47, 30.20, 28.30, 27.80, 27.72, 27.02, 26.96, 26.90, 26.74,
26.66, 22.19, 21.99, 20.04, 19.99, 19.57, 19.44, 19.33, 19.28, 15.88,
14.44, 14.33, 13.35, 13.27. LCMS (M + H)+: 715.2.
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2(S)-Cyclohexyl-2-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-dioxo-2-(2-prope-
nylamino)ethyl]-4-pentynyl]amino]carbonyl]-6,6-dimethyl-3-
azabicyclo[3.1.0]hex-3-yl]-1(S)-(1-methylcyclohexyl)-2-oxoethyl]-
amino]carbonyl]amino]ethyl Ethylcarbamate (54). The product was
1
isolated as a mixture of two diastereomers. H NMR (500 MHz,
DMSO-d6) δ 8.88 and 8.78 (app. t, J ) 6.0 and 5.9 Hz, 1H), 8.52
and 8.44 (d, J ) 7.2 and 6.9 Hz, 1H), 7.07-7.05 (m, 1H),
6.14-6.09 (m, 1H), 5.99 (br. d, 1H), 5.82-5.73 (m, 1H), 5.13-5.02
(m, 2H), 5.00-4.96 and 4.74-4.70 (m, 1H), 4.25 (s, 1H), 4.21
(app. d, J ) 6.6 Hz, 1H), 3.91-3.72 (m, 6H), 3.69-3.57 (m, 1H),
3.00-2.95 (m, 2H), 2.79 (app. s, 1H), 2.33-2.21 (m, 2H),
2.00-1.88 (m, 1H), 1.69-0.78 (complex, 36H). 13C NMR (100
MHz, DMSO-d6) δ 196.59, 171.13, 170.40, 160.73, 157.76, 155.92,
134.03, 115.53, 115.39, 83.37, 83.18, 71.74, 71.62, 59.11, 55.75,
53.27, 52.45, 40.75, 36.86, 34.94, 33.45, 33.19, 30.43, 29.52, 29.25,
28.99, 27.32, 26.91, 26.02, 25.82, 25.72, 21.24, 21.05, 19.04, 18.40,
14.96, 14.62, 12.40. LCMS (M + H)+: 725.2.
[1-[[[[2-[(1R,5S)-2(S)-[[[1-[1,2-Dioxo-2-(2-propenylamino)ethyl]-
butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-
1(S)-(1-methylcyclohexyl)-2-oxoethyl]amino]carbonyl]amino]cyc-
lohexyl]methyl Ethylcarbamate (55). The product was isolated as
a mixture of two diastereomers. 1H NMR (500 MHz, DMSO-d6) δ
8.89 and 8.84 (app. t, J ) 6.1 and 6.0 Hz, 1H), 8.36 and 8.22 (d,
J ) 7.0 and 7.3 Hz, 1H), 7.01-6.98 (m, 1H), 6.22-6.17 (m, 1H),
5.82-5.75 (m, 2H), 5.12-5.04 (m, 2H), 4.98-4.94 and 4.90-4.86
(m, 1H), 4.28 and 4.25 (s, 1H), 4.18 (br. t, 1H), 4.03-3.94 (m,
3H), 3.80-3.68 (m, 3H), 3.00-2.94 (m, 2H), 1.96-1.93 (br. d,
1H), 1.81-1.79 (br. d, 1H), 1.72-1.64 (m, 1H), 1.53-0.75
(complex, 38H). 13C NMR (100 MHz, DMSO-d6) δ 197.28, 196.72,
171.06, 170.88, 161.05, 160.70, 156.11, 134.41, 134.10, 131.03,
130.31, 126.22, 115.51, 115.41, 68.05, 59.41, 58.98, 55.75, 53.48,
47.37, 40.75, 36.77, 34.91, 33.16, 31.58, 31.46, 30.58, 30.51, 29.52,
26.76, 26.08, 26.01, 25.81, 25.16, 21.21, 21.04, 20.46, 19.07, 19.02,
18.67, 18.52, 18.44, 18.39, 15.01, 13.52, 13.42, 12.38, 12.30. LCMS
(M + H)+: 701.2.
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