Ketoamide-based inhibitors of cysteine protease, cathepsin K: P3 modifications

Article abstract of DOI:10.1021/jm040107n

Osteoporosis is a disease characterized by skeletal fragility. Cathepsin K, a lysosomal cysteine protease, has been implicated in the osteoclast mediated bone resorption. Inhibitors of this protease could potentially treat this skeletal disease. The prese

Full text of DOI:10.1021/jm040107n

J . Med. Chem. 2004, 47, 5057-5068
5057
Ketoa m id e-Ba sed In h ibitor s of Cystein e P r otea se, Ca th ep sin K: P 3
Mod ifica tion s
Francis X. Tavares,*† David N. Deaton,† Larry R. Miller,‡ and Lois L. Wright§
Department of Medicinal Chemistry, Discovery Research Biology, and Department of Molecular Pharmacology,
GlaxoSmithKline, Research Triangle Park, North Carolina 27709
Received May 26, 2004
Osteoporosis is a disease characterized by skeletal fragility. Cathepsin K, a lysosomal cysteine
protease, has been implicated in the osteoclast mediated bone resorption. Inhibitors of this
protease could potentially treat this skeletal disease. The present work describes exploration
of the spatial requirements of the S3 subsite by the use of various sterically demanding P3
substituents. Sulfur and oxygen linked heterocycles as well as those without heteroatom linkers
were found to provide potent inhibitors of cathepsin K. Representative examples from these
series also afforded quite good selectivity ratios against most cathepsins tested. The tolerability
of the S3 subsite for sterically demanding groups that provide potency and selectivity enhances
the attractiveness of P3 changes to improve the physiochemical properties of inhibitors in the
developments of compounds for the treatment of osteoporosis.
In tr od u ction
Osteoporosis, a systemic skeletal disease, is charac-
terized by low bone mass and microarchitectural dete-
rioration of bone tissue. Osteoporosis results in an
increase in bone fragility and susceptibility to fracture.
Bone is a mechanically optimized connective tissue that
is maintained in dynamic equilibrium via bone resorp-
tion by osteoclasts and bone formation by osteoblasts.
F igu r e 1.
A shift or uncoupling of this dynamic process favoring
resorption results in osteoporosis. Cysteine proteases
have been implicated in this osteoclast-mediated resorp-
tion of the bone matrix.1 The expression of cathepsin
K, a cysteine protease of the papain superfamily, is
abundant and selective in osteoclasts suggesting that
this enzyme is crucial for bone resorption.2a,b In addition,
there are several reports implicating cathepsin K in
bone resorption.3-7 Recent work has shown that cathe-
psin K, and not cathepsin L, is the major protease
responsible for human osteoclastic bone resorption.6
Further, complex formation with glycosaminoglycans
specifically enhances collagenase activity of cathepsin
K in osteoclasts, while potently inhibiting collagenase
activity of other cysteine proteases such as cathepsins
L and S.6c These studies suggest that selective inhibition
of cathepsin K could provide an effective therapy for the
treatment of osteoporosis.
Cysteine proteases make up the vast majority of
lysosomal proteases. There are currently 11 members
of the human cathepsin cysteine protease family that
are involved in protein degradation. Compared to cathe-
psin K, the physiological role and pathological implica-
tions of many cathepsins are less well understood.
Various irreversible inhibitors such as epoxides, pepti-
dyl vinyl sulfones, and acyloxymethyl ketones have been
reported in the literature.10 To avoid potential antige-
nicity due to covalent modification of proteins via
irreversible inhibition, a selective reversible inhibitor
was desired. Numerous warheads have been utilized in
reversible cysteine protease inhibitors12-16 There has
also been a recent report on the use of noncovalent
amides as cathepsin K inhibitors.17,25b This group was
particularly interested in exploring R-ketoamides as
reversible inhibitors of cathepsin K. The ketoamide class
of inhibitors has been widely employed for inhibiting
serine proteases.16,18 Herein is described its application
in the inhibition of the cysteine protease, cathepsin K.19
Reports on the development of potent, selective, and
orally bioavailable inhibitors were recently described
from this laboratory.19a,d Those papers were primarily
focused on modifications at the P′ and P2 regions of
ketoamide-based inhibitors. The present report deals
with exploring the spatial requirements of the S3
subsite keeping preferred hydrophobic P2 (cyclobutyl)
and P′ (R-methylbenzyl) moieties constant (Figure 1).
Exploration of the S3 region would allow for opportuni-
ties in improving upon the potency and physiochemical
properties of these ketoamide-based inhibitors of cathe-
psin K.
Ch em istr y
The syntheses of the compounds 10a , 13a -21a , and
23a -31a involved the formation of the key intermediate
diol 2 that was formed by the reduction of diethylcy-
clobutane dicarboxylate with LAH. The sulfur-linked
cyclobutyl analogues 10a , 13a -18a were formed using
* To whom correspondence should be addressed. Phone: (919) 483-
7456. Fax: (919) 483-6053. E-mail: francis.x.tavares@gsk.com.
† Department of Medicinal Chemistry.
‡ Department of Molecular Pharmacology.
§ Discovery Research Biology.
10.1021/jm040107n CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/08/2004

5058 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Sch em e 1. Synthetic Route to Alcoholsa
Tavares et al.
methylene spacers, were synthesized by alkylation of
ethyl cyclobutanecarboxylate with either benzyl 2-bro-
moethyl ether or benzyl 3-bromopropyl ether, followed
by reduction of the ester with LAH to afford the alcohols
5a and 5b. The hydroxyl group was protected using tert-
butyldimethylsilyl chloride followed by the subsequent
deprotection of the benzyl ether with Pd/C under
hydrogen to afford 6a and 6b. Compounds 11a , 12a , and
22a were then synthesized from 6a and 6b using either
Mitsunobu conditions or direct displacement of the
halide as described in Scheme 1. The synthesis of the
target compounds 10-31 is shown in Scheme 4. The
acid 6 was converted to the mixed anhydride by treat-
ment with isopropyl chloroformate followed by the
reduction of the anhydride with sodium borohydride to
afford the alcohol. Oxidation of the alcohol with sulfur
trioxide pyridine complex followed by the treatment
with (R)-R-methylbenzylisonitrile in the presence of
benzoic acid using the Passerini conditions afforded the
R-acyloxyamides 7.20 The ester and the carbamate
groups were removed in a single step by treatment with
sodium hydroxide to afford the â-amino-R-hydroxyamide
8. Compound 8 was reacted with the appropriate
chloroformates of the P2-P3 alcohols to afford 10b-
31b. Oxidation of the hydroxyl with Dess-Martin
reagent gave the final products 10-31.
a
t
(a) LAH, THF, reflux; (b) aryl thiol, PPh3, tBuO2CNNCO2 Bu,
DCM (X ) S); NaH, THF/DMF (1:1), aryl halide (X ) O); (c) BnCl,
NaH, THF/DMF; (d) MeSO2Cl, DCM, Et3N; (e) KCN, DMF, H2O,
130 °C; (f) diethyldithiophosphate, THF, H2O, reflux; (g) R-bromo
ketone, CH3CN; BBr3, DCM.
Sch em e 2. Synthetic Route to Alcoholsa
Resu lts a n d Discu ssion
Modifications in the P′ and P2 regions were described
in earlier reports,19a,d wherein it was found that the P′
substituent afforded potent and selective ketoamide-
based inhibitors irrespective of the P2 substituent. In
the current work, extension of the side chain on the P2
cyclobutyl moiety was explored with the hope of iden-
tifying a preferred P3 substituent that could potentially
π-π stack with 67Tyr in the S3 subsite to enhance the
potency, selectivity, and physiochemical properties of
this class of inhibitors. A recent report describing the
effects of P3 substitution on the potency and selectivity
of nonpeptidic cathepsin K inhibitors was recently
disclosed by others, indicating that P3 modifications
could potentially provide selective cathepsin K inhibi-
tors.21 In the present work various heteroatom (sulfur,
oxygen) as well as carbon-linked P3 substituents were
studied (Table 1). The N-methylimidazole compound 10,
with one methylene spacer, was found to be a potent
inhibitor of cathepsin K (IC50 ) 61 nM). Increasing the
conformational flexibility via extension of the carbon
linker to reach deeper into the S3 subsite as in com-
pounds 11 and 12 resulted in a loss in activity. The
three-methylene spacer 12, was reasonably more potent
than the two-methylene spacer 11 (IC50 ) 1900 nM).
Addition of a p-chlorophenyl group as in compound 13
(IC50 ) 230 nM) resulted in a 4-fold decrease in activity
(10 vs 13). Movement of the phenyl substituent closer
a
N-Methylpiperazine (23a ), N-phenylpiperazine (24b), mor-
pholine (25a ), DMF, 90 °C.
Mitsunobu conditions involving the treatment of the diol
2 with triphenylphosphine and di-tert-butyl azodicar-
boxylate followed by the subsequent addition of the thiol
component (Scheme 1). The oxygen-linked cyclobutyl
analogues 19a -21a , 26a -29a , containing one methyl-
ene spacer, were synthesized by monodeprotonation of
the diol 2 with sodium hydride followed by displacement
of the halide group (Scheme 1). Compound 21a , obtained
in Scheme 1, was used as an intermediate for the
synthesis of analogues 23a -25a involving the treat-
ment with various secondary amines in DMF to displace
the chloride moiety (Scheme 2). The thiazole analogues
30a , 31a were synthesized as shown in Scheme 1. The
diol 2 was monobenzyl-protected followed by subsequent
formation of the mesylate with methanesulfonyl chlo-
ride. The mesylate was treated with potassium cyanide
to afford compound 3. The cyanide functionality was
then reacted with diethyldithiophosphate to afford the
intermediate thioamide that was converted to the thia-
zoles by treatment with R-halo ketones. The compounds
11a , 12a , and 22a (Scheme 3), possessing two or three
Sch em e 3. Synthetic Route to Alcoholsa
a
(a) LDA, THF, benzyl 2-bromoethyl ether (5a ); LDA, THF, benzyl 3-bromopropyl ether (5b); (b) LAH, THF, reflux; (c) TBSCl; (d)
t
t
Pd/C, H2; (e) PPh3, BuO2CNNCO2 Bu, DCM (X ) S); NaH, THF/DMF (1:1), aryl halide (X ) O).

Inhibitors of Cystein Protease
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5059
Sch em e 4. Synthetic Route to Targets 10-31a
a
i
(a) PrOCOCl, Et3N; (b) NaBH4; (c) SO3-Py; (d) (R)-R-methylbenzylisonitrile, PhCOOH; (e) NaOH, EtOH, reflux; (f) chloroformates,
Hunig’s base, DCM; (g) Dess-Martin, DCM or (COCl)2, DMSO, DCM, -60 °C; NEt3.
Ta ble 1. Inhibitory Potencies (IC50) vs Human Cathepsin Ka
a
The IC50 values are the mean of two or three inhibition assays. Individual data points in each experiment were within 3-fold range
of each other.
in space to the cyclobutyl P2 group in the hope of
improving any putative 67Tyr interaction in the S3
subsite gave compound 14 (IC50 ) 87 nM) that had
equivalent potency. Replacement of the N-methyl group
with a sulfur as in compound 15 (IC50 ) 17 nM) afforded
a more potent inhibitor (10 vs 15). This increase in
activity for 15 may result from a lower desolvation cost
to remove associated water from the sulfur versus
nitrogen analogue 10. Alternatively, the loss of the
methyl substituent may allow a more favorable binding

5060 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Tavares et al.
Ta ble 2. Inhibitory Potencies (IC50) vs Human Cathepsins K,
L, S, V, H, and B
interaction. The ring-constrained analogue 16 was less
active than the thiazole 15 but was an equipotent
inhibitor of cathepsin K compared to the starting
imidazole 10. Incorporation of a six-membered hetero-
cycle resulted in an increase in potency relative to the
imidazole 10. The pyrimidine analogue 17 (IC50 ) 11
nM) was a very potent inhibitor of cathepsin K, sup-
porting the earlier suggestion that the methyl substitu-
ent of the imidazole 10 impairs a more favorable binding
interaction. Addition of a p-chlorophenyl substituent to
the six-membered heterocycle also afforded a potent
inhibitor 18 (IC50 ) 9 nM). Interestingly, such a
substitution in the five-membered heterocycle resulted
in a loss in activity (10 vs 13 and 17 vs 18). Replacement
of the sulfur linker with an oxygen atom projecting the
substituents at an angle closer to a tetrahedral carbon
was then studied (19-29). Although, there was no
appreciable loss in activity in the oxygen-linked thiazole
analogue 19 (IC50 ) 37 nM) compared to the sulfur-
coupled analogue 15 (IC50 ) 17 nM), there was a
significant drop of 23-fold in the activity for the six-
membered pyrimidine analogue (17 vs 20). Movement
of the oxygen from the 2- to the 4-position of the
pyrimidine ring afforded compound 21 (IC50 ) 85 nM).
As before, the increase in conformational flexibility by
addition of a three-methylene spacer as in analogue 22
(IC50 > 12 000) was found to have a detrimental effect
on potency. A similar observation was encountered in
the five-membered ring substitution (10 vs 12). In an
effort to hopefully improve drug properties, the chlorine
on the pyrimidine ring was substituted with water-
solubilizing groups as in compounds 23-25; these were
found to be generally more or less equipotent. Interest-
ingly, a larger group that could go deeper into the S3
subsite as in compound 24 (IC50 ) 30 nM) was quite
well accommodated. Constrained analogue 26 was also
found to be quite potent. Movement of the phenyl
substituent closer to the cyclobutyl P2 moiety as in
compound 29 (IC50 ) 57 nM) did not affect the potency
of the inhibitor. A similar observation was also made
for the five-membered heterocycle (14 and 29). Addition
of a p-tolyl group to thiazole 19 gave compound 27 (IC50
) 150 nM) with a 4-fold drop in potency (19 vs 27).
However, the thiadiazole analogue 28 (IC50 ) 50 nM)
resulted in a gain in potency versus 27. Having gone
through the heteroatom-linked P3 substituents, hetero-
cyclic analogues having one methylene spacer were next
studied (30, 31). The trifluoromethyl thiazole analogue
30 (IC50 ) 7.9 nM) was found to be a potent inhibitor of
cathepsin K. Replacement of the trifluoromethyl with
a phenyl group that would reach deeper in the S3
subsite afforded compound 31 (IC50 ) 5.5 nM) that was
apparently the most potent inhibitor in this P3 inhibitor
series. These last two heteroaryl analogues have the P3
moiety one atom closer to the P2 substituent. Their
excellent inhibitory potency may arise from reduced
entropic cost resulting from decreased conformational
flexibility.
a
IC50
S/K*
4.0
22
,
nM
compd
K
L/K*
V/K*
H/K*
B/Kb
15
31
17
5.5
250
220
41
20
>720
>230
390
660
a
The IC50 values are the mean of two or three inhibition assays.
Individual data points in each experiment were within 3-fold range
b
of each other. Represents selectivity ratios over the other cathe-
psins (e.g., L/K ) IC50(cathepsin L)/IC50(cathepsin K).
groups were also found not to confer selectivity for the
ketoamide-based inhibitors. Since P3 substitution was
not explored in those studies,19a,d it was gratifying to
find that compounds 15 and 31 were fairly selective.
Addition of a P3 heterocyclic group as in 15 provided
good selectivity over cathepsins B, H, L, and V. Incor-
poration of a larger P3 group as in 31, in addition to B,
H, and L, also provided some degree of selectivity over
cathepsins S and V.
Con clu sion
The present work was undertaken to study the spatial
requirements of the P3 group desiring to enhance the
potency and selectivity of the ketoamide-based inhibi-
tors. Previous work from these laboratories described
work on the P′ and P2 substituents that afforded potent
and selective cathepsin K inhibitors. This work involved
attaching substituents via heteroatoms such as sulfur
and oxygen to the cyclobutyl P2 group previously
studied. Both five- and six-membered heterocyclic re-
placements were explored. It was found that the S3
subsite could accommodate a variety of groups without
significant loss in potency against cathepsin K. Further,
direct attachment of a heterocyclic moiety without
heteroatom linkers such as thiazoles also afforded quite
potent inhibitors of cathepsin K. These P3 modifications
provided inhibitors that were generally selective. The
fact that various sterically demanding groups provide
some degree of selectivity enhances the utility of these
inhibitors for further development in the treatment of
osteoporosis.
Exp er im en ta l Section
Ch em istr y. Gen er a l Meth od s. Melting points were de-
termined using a Thomas-Hoover melting point apparatus and
are uncorrected. Unless stated otherwise, reagents were
obtained from commercial sources and were used directly.
Reactions involving air- or moisture-sensitive reagents were
carried out under a nitrogen atmosphere. If not specified,
reactions were carried out at ambient temperature. Silica gel
(EM Science, 230-400 mesh) was used for chromatographic
purification unless otherwise indicated. Anhydrous solvents
were obtained from Aldrich (Sure Seal). 1H NMR spectra were
recorded on a Varian spectrometer; chemical shifts are re-
ported in parts per million (ppm) relative to TMS. The
following abbreviations are used to describe peak patterns
when appropriate: b ) broad, s ) singlet, d ) doublet, t )
triplet, q ) quartet, m ) multiplet. High-performance liquid
chromatography (HPLC) was performed on a Beckman 126
with a Beckman 166 UV detector (monitoring at 215 nm) with
a Rainin Dynamax-60A column using a gradient consisting of
20/80 A/B to 10/90 A/B over 20 min, where A) 1% aqueous
trifluoroacetic acid (TFA), B ) 1% TFA in CH3CN. Elemental
analyses, performed by Atlantic Microlab, Inc., Norcross, GA,
were within 0.4% of the theoretical values calculated for C,
H, and N.
Selectivity. Compounds 15 and 31 were chosen from
Table 2 as representative examples for selectivity stud-
ies. From previous work in these laboratories,19a it was
known that the P′ and P1 groups used in the present
work did not confer complete selectivity over the other
cathepsins. Further, various sterically demanding P2
1-{[(1-Me t h y l-1H -im id a zo l-2-y l)s u lfa n y l]m e t h y l}-
cyclob u t yl)m et h yl
(1S)-1-(Oxo{[(1R)-1-p h en ylet h yl]-

Inhibitors of Cystein Protease
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5061
(1-{2-[(1-Me t h yl-1H -im id a zol-2-y l)su lfa n y l]e t h y l}-
am in o}acetyl)pen tylcar bam ate (10). [1-(Hydr oxym eth yl)-
cyclobu tyl]m eth a n ol (2). To a solution of diethyl 1,1-
cyclobutanedicarboxylate, (10.0 g, 50.0 mmol) in diethyl ether
(200 mL) cooled to 0 °C was added a 1.0 M solution of lithium
aluminum hydride in THF (200 mL) over 15 min. The reaction
mixture was then warmed to room temperature and left to
stir for 3 h. A 20% sodium hydroxide solution (200 mL) was
then added followed by addition of diethyl ether. The organic
layer was isolated, dried with magnesium sulfate, and con-
centrated under vacuum to give a yellow oil, which was
purified by silica gel chromatography using ethyl acetate as
the eluent to afford 5.5 g (95%) of [1-(hydroxymethyl)cyclobu-
cyclob u t yl)m et h yl
(1S)-1-(Oxo{[(1R)-1-p h en ylet h yl]-
a m in o}a cetyl)p en tylca r ba m a te (11). {1-[2-(Ben zyloxy)-
eth yl]cyclobu tyl}m eth a n ol (5a ). A solution of ethyl cy-
clobutanecarboxylate (3.0 g, 23 mmol) in THF (10 mL) was
added to a -78 °C solution of LDA (25.74 mmol) in 45 mL of
THF. The reaction mixture was warmed to 0 °C (15 min) and
then cooled to -78 °C, followed by the addition of benzyl
2-bromoethyl ether (3.64 mL, 25.74 mmol) in THF (10 mL).
The reaction mixture was gradually warmed to room temper-
ature over 16 h, and then the reaction was quenched with
saturated ammonium chloride (20 mL). The reaction mixture
was concentrated, and ethyl acetate was added. The organic
layer was isolated, dried with magnesium sulfate, and con-
centrated under vacuum to afford an oil, which was purified
by silica gel chromatography using ethyl acetate/hexane (1:4)
as the eluent to afford 4.3 g (70%) of ethyl 1-[2-(benzyloxy)-
1
tyl]methanol as a colorless oil. H NMR (300 MHz, CDCl3) δ
3.73 (s, 4H), 2.81 (br s, 2H), 2.02-1.89 (m, 4H), 1.78 (t, J ) 8
Hz, 2H).
(1-{[(1-Me t h yl-1H -im id a zol-2-yl)su lfa n yl]m e t h yl}-
cyclob u t yl)m et h a n ol (10a ). To a solution of [1-(hydroxy-
methyl)cyclobutyl]methanol (1.0 g, 8.6 mmol) in dichlo-
romethane (20 mL) was added triphenylphosphine (2.48 g, 9.48
mmol) and di-tert-butylazodicarboxylate (2.18 g, 9.48 mmol).
After the mixture was stirred for 5 min, 1-methyl-2-mercap-
toimidazole (1.03 g, 9.05 mmol) was added as a solid. After
being stirred for 2 h, the reaction mixture was concentrated
under vacuum and the residual was purified using silica gel
chromatography, eluting with ethyl acetate/hexane (3:7) to
afford 1.3 g (71%) of (1-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]-
methyl}cyclobutyl)methanol as a yellow oil. 1H NMR (300
MHz, CDCl3) δ 6.95 (s, 1H), 6.87 (s, 1H), 6.54 (s br 1H), 3.62
(s, 2H), 3.56 (s, 3H), 3.43 (s, 2H), 1.98-1.75 (m, 6H).
1
ethyl]cyclobutanecarboxylate as a colorless oil. H NMR (300
MHz, CDCl3) δ 7.31-7.22 (m, 5H), 4.01 (q, J ) 7.1 Hz, 2H),
4.40 (s, 2H), 2.4 (t, J ) 6.7 Hz, 2H), 1.92-1.84 (m, 8H), 1.14
(t, J ) 7.1 Hz, 3H). GC-MS m/z 263 (M + H).
To a solution of ethyl 1-[2-(benzyloxy)ethyl]cyclobutanecar-
boxylate (2.0 g, 7.63 mmol) obtained from the above procedure
in diethyl ether (20 mL) at 0 °C was added a 1.0 M solution of
lithium aluminum hydride in THF, 15.9 mL (15.9 mmol), and
the contents were stirred for 2 h. The reaction was quenched
with 20 mL of 20% sodium hydroxide solution. After filtration,
the organic phase was isolated, dried with magnesium sulfate,
and concentrated under vacuum to afford 1.6 g (95%) of {1-
1
[2-(benzyloxy)ethyl]cyclobutyl}methanol as a colorless oil. H
(1-{[(1-Me t h yl-1H -im id a zol-2-yl)su lfa n yl]m e t h yl}-
cyclob u t yl)m et h yl (1S)-1-(1-H yd r oxy-2-oxo-2-{[(1R)-1-
p h en yleth yl]a m in o}eth yl)p en tylca r ba m a te (10b). To a
solution of (1-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl}-
cyclobutyl)methanol (0.132 g, 0.625 mmol) in dichloromethane
(2 mL) cooled to 0 °C was added a 1.0 M solution of phosgene
in toluene (0.94 mL, 1.41 mmol), and the contents were stirred
for 16 h. The reaction mixture was concentrated, and the
residual was dissolved in THF (3 mL) and added to a 0 °C
solution of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]hep-
tanamide (0.165 g, 0.63 mmol) and N,N-diisopropylethylamine
(0.325 mL, 1.89 mmol) in THF (2 mL). After the mixture was
stirred for 6 h, ethyl acetate (30 mL) and saturated sodium
chloride (20 mL) were added. The organic phase was isolated,
dried using magnesium sulfate, and concentrated under
vacuum to afford the crude product, which was purified by
silica gel chromatography using ethyl acetate (100%) as the
eluent to afford 0.220 g (70%) of (1-{[(1-methyl-1H-imidazol-
2-yl)sulfanyl]methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-
oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a
NMR (300 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 4.54 (s, 2H), 3.55
(t, J ) 5.9 Hz, 2H), 2.03-1.83 (m, 10H).
2-[1-({[ter t-Bu tyl(dim eth yl)silyl]oxy}m eth yl)cyclobu tyl]-
eth an ol (6a). To a solution of {1-[2-(benzyloxy)ethyl]cyclobutyl}-
methanol (1.6 g, 7.27 mmol) in dichloromethane (16 mL) was
added tert-butyldimethylsilyl chloride (1.20 g, 7.99 mmol) and
imidazole (0.98 g, 14.54 mmol), and the contents were stirred
for 16 h. Saturated ammonium chloride was added, and the
layers were separated. The organic layer was dried with
magnesium sulfate and concentrated under vacuum. To the
crude silyl alcohol was added methanol (20 mL) and 10%
palladium on carbon (0.24 g). The reaction mixture was stirred
in an atmosphere of hydrogen for 16 h. The contents were
filtered over Celite, and the filtrate was concentrated under
vacuum to afford 2-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-
cyclobutyl]ethanol as a colorless oil, 1.71 g (97%). 1H NMR (300
MHz, CDCl3) δ 3.57 (s, 2H), 3.55 (t, J ) 5.7 Hz, 2H), 1.87-
1.59 (m, 8H), 0.87 (s, 9H), 0.05 (s, 6H).
(1-{2-[(1-Me t h yl-1H -im id a zol-2-y l)su lfa n y l]e t h y l}-
cyclobu tyl)m eth a n ol (11a ). 1-Methyl-1H-imidazole-2-thiol
were prepared using the same experimental procedure as in
example 10a to afford 2-({2-[1-({[tert-butyl(dimethyl)silyl]oxy}-
1
colorless oil. H NMR (300 MHz, CDCl3) δ 7.63-7.52 (m, 1H),
7.41 (m, 1H), 7.39-7.15 (m, 5H), 6.91, 6.98 (2s, 1H), 6.03 (s
br, 1H), 5.69 (m, 1H), 5.19-5.11 (m, 1H), 4.18-3.95 (m, 4H),
3.61, 3.63 (2s, 2H), 3.28 (m, 2H), 2.21-1.61 (m, 10H), 1.60-
1.16 (m, 5H), 0.90 (m, 3H). LC-MS m/z 503 (M + H).
1
methyl)cyclobutyl]ethyl}sulfanyl)-1-methyl-1H-imidazole. H
NMR (300 MHz, CDCl3) δ 7.22 (s, 1H), 7.01 (s, 1H), 3.58 (s,
3H), 3.43 (s, 2H), 1.85-1.73 (m, 6H), 2.91 (t, J ) 5.7 Hz, 2H),
1.48 (s, 9H), 1.21 (t, J ) 4.4 Hz, 2H), 0.04 (s, 6H). GC-MS
m/z 341 (M + H).
(1-{[(1-Me t h yl-1H -im id a zol-2-yl)su lfa n yl]m e t h yl}-
cyclob u t yl)m et h yl
(1S)-1-(Oxo{[(1R)-1-p h en ylet h yl]-
a m in o}a cet yl)p en t ylca r b a m a t e (10). To a solution of
(1-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl}cyclobutyl)-
methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}-
ethyl)pentylcarbamate (0.182 g, 0.364 mmol) in dichlo-
romethane (3 mL) cooled to -60 °C was added oxalyl chloride
(0.079 mL, 0.91 mmol) and DMSO (0.129 mL, 1.82 mmol),
followed by triethylamine (0.204 mL, 1.45 mmol). After being
stirred for 15 min, the reaction mixture was warmed to room
temperature and applied directly to a silica gel column using
ethyl acetate (100%) as the eluent to afford 0.052 g (29%) of
(1-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl}cyclobutyl)-
methyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl-
carbamate as a colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.41-7.30 (m, 6H), 7.17 (d, J ) 8.1 Hz, 1H), 6.98 (s, 1H), 5.41
(m, 1H), 5.23-5.11 (m, 2H), 4.16 (s, 2H), 3.58 (s, 3H), 3.36 (s,
2H), 2.07-1.89 (m, 6H), 1.48-1.16 (m, 6H), 1.56 (d, J ) 6.9
Hz, 3H), 0.89 (t, J ) 6.9 Hz, 3H). Anal. C, H, N
To 2-({2-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]-
ethyl}sulfanyl)-1-methyl-1H-imidazole (1.39 g, 4.1 mmol) in
THF (10 mL) obtained in the above procedure was added a
1.0 M solution of TBAF in THF (4.92 mL, 5.33 mmol), and the
contents were stirred for 16 h. The reaction mixture was
concentrated, and the residual was poured directly onto a
column of silica gel using ethyl acetate/hexane as the eluent
to afford 0.57 g (62%) of (1-{2-[(1-methyl-1H-imidazol-2-yl)-
sulfanyl]ethyl}cyclobutyl)methanol as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ 6.94 (s, 1H), 6.82 (s, 1H), 5.30 (s br, 1H),
3.66 (s, 2H), 3.47 (s, 3H), 2.94 (m, 2H),1.99-1.64 (m, 8H).
(1-{2-[(1-Me t h yl-1H -im id a zol-2-y l)su lfa n y l]e t h y l}-
cyclob u t yl)m et h yl (1S)-1-(1-H yd r oxy-2-oxo-2-{[(1R)-1-
p h en yleth yl]a m in o}eth yl)p en tylca r ba m a te (11b). The
title compound was prepared using the same experimental
procedure as in example 10b from (1-{2-[(1-methyl-1H-imida-
zol-2-yl)sulfanyl]ethyl}cyclobutyl)methanol as the alcohol com-

5062 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
ponent and (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]-
Tavares et al.
({[5-(4-Ch lor oph en yl)-1-m eth yl-1H-im idazol-2-yl]su lfan yl}-
m eth yl)cyclobu tyl]m eth a n ol (13a ). The title compound was
prepared using the same experimental procedure as in ex-
ample 10a from [1-(hydroxymethyl)cyclobutyl]methanol and
5-(4-chlorophenyl)-1-methyl-1H-imidazole-2-thiol. 1H NMR (300
MHz, CDCl3) δ 7.41-7.25 (m, 5H), 3.62 (s, 2H), 3.49 (s, 3H),
3.46 (s, 2H), 2.04-1.63 (m, 6H),
1
heptanamide as the amino alcohol component. H NMR (300
MHz, CDCl3) δ 8.24 (m, 1H), 7.35-7.23 (m, 5H), 7.02 (s, 1H),
6.93, 6.90 (2s, 1H), 5.67 (m, 1H), 5.16 (m, 2H), 4.22-3.74 (m,
4H), 3.65 (s, 3H), 2.95 (m, 2H), 2.03-1.79 (m, 8H), 1.49 (d, J
) 7.0 Hz, 3H), 1.36-1.27 (m, 6H), 0.91 (m, 3H). LC-MS m/z
517 (M + H).
(1-{2-[(1-Me t h y l-1H -im id a zo l-2-y l)su lfa n y l]e t h yl}-
[1-({[5-(4-Ch lor op h en yl)-1-m et h yl-1H -im id a zol-2-yl]-
su lfa n yl}m eth yl)cyclobu tyl]m eth yl (1S)-1-(1-Hyd r oxy-2-
oxo-2-{[(1R)-1-p h en ylet h yl]a m in o}et h yl)p en t ylca r b a -
m a te (13b). The title compound was prepared using the same
experimental procedure as in example 10b from [1-({[5-
(4-chlorophenyl)-1-methyl-1H-imidazol-2-yl]sulfanyl}methyl)-
cyclobutyl]methanol as the alcohol component and (3S)-3-
amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide as the
amino alcohol component. 1H NMR (300 MHz, CDCl3) δ 7.41-
7.20 (m, 10 H), 7.02 (s, 1H), 5.33 (d, J ) 8.2 Hz, 1H), 5.12-
5.05 (m, 2H), 4.30 (s, 1H), 4.17-4.04 (m, 3H), 3.89 (m, 2H),
3.55 (s, 2H), 3.32, 3.38 (2s, 2H), 2.03-1.88 (m, 6H), 1.55-1.22
(m, 9H), 0.82 (m, 3H). LC-MS m/z 613 (M + H).
[1-({[5-(4-Ch lor op h en yl)-1-m et h yl-1H -im id a zol-2-yl]-
su lfa n yl}m eth yl)cyclobu tyl]m eth yl (1S)-1-(Oxo{[(1R)-1-
ph en yleth yl]am in o}acetyl)pen tylcar bam ate (13). The title
compound was prepared using the same experimental proce-
dure as in example 11 from [1-({[5-(4-chlorophenyl)-1-methyl-
1H-imidazol-2-yl]sulfanyl}methyl)cyclobutyl]methyl (1S)-1-(1-
hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentyl-
carbamate as the alcohol component. 1H NMR (300 MHz,
CDCl3) δ 7.41-7.11 (m, 11H), 7.08 (s, 1H), 5.40 (m, 1H), 5.09
(m, 2H), 4.12 (s, 2H), 3.54 (s, 3H), 3.45 (s, 2H), 2.08-1.90 (m,
6H), 1.55-1.29 (m, 8H), 0.87 (t, J ) 6.7 Hz, 3H). Anal. C, H,
N
cyclob u t yl)m et h yl
(1S)-1-(Oxo{[(1R)-1-p h en ylet h yl]-
a m in o}a cet yl)p en t ylca r b a m a t e (11). To a solution of
(1-{2-[(1-methyl-1H-imidazol-2-yl)sulfanyl]ethyl}cyclobutyl)-
methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}-
ethyl)pentylcarbamate (11b) (0.143 g, 0.27 mmol) in dichlo-
romethane (2.0 mL) was added sodium bicarbonate (0.031 g,
0.375 mmol) followed by the addition of Dess-Martin perio-
dinane (0.137 g, 0.32 mmol). The reaction mixture was stirred
for 15 min and poured directly onto a silica gel column using
ethyl acetate/hexane (3:7) as the eluent to afford 0.086 g (63%)
of the title compound as a colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.44-7.33 (m, 6H), 7.30 (s, 1H), 7.14 (s, 1H), 5.11 (d,
J ) 7.3 Hz, 1H), 5.09 (m, 2H), 4.07 (s, 2H), 3.76 (s, 3H), 3.02
(s, 2H), 2.03-1.85 (m, 10H), 1.56 (d, J ) 6.8 Hz, 3H), 1.52-
1.27 (m, 4H), 0.87 (t, J ) 6.8 Hz, 3H). Anal. C, H, N
(1-{3-[(1-Me t h yl-1H -im id a zol-2-yl)su lfa n yl]p r op yl}-
cyclob u t yl)m et h yl
(1S)-1-(Oxo{[(1R)-1-p h en ylet h yl]-
a m in o}a cetyl)p en tylca r ba m a te (12). Eth yl 1-[3-(Ben zyl-
oxy)p r op yl]cyclobu ta n eca r boxyla te (5b). The title com-
pound was prepared using the same experimental procedure
as in example 5a using benzyl 3- bromopropyl ether as the
electrophile. 1H NMR (300 MHz, CDCl3) δ 7.38-7.30 (m, 5H),
4.53 (s, 2H), 4.14 (t, J ) 7.1 Hz, 2H), 3.48 (t, J ) 6.4 Hz, 2H),
2.49-2.43 (m, 2H), 2.08-1.72 (m, 6H), 1.53 (m, 2H),1.27 (t, J
) 7.1 Hz, 3H).
(1-{[(1-P h e n yl-1H -im id a zol-2-yl)su lfa n yl]m e t h yl}-
P r ep a r a tion of 3-[1-({[ter t-Bu tyl(d im eth yl)silyl]oxy}-
m eth yl)cyclobu tyl]-1-p r op a n ol (6b). The title compound
was prepared from ethyl 1-[3-(benzyloxy)propyl]cyclobutan-
ecarboxylate using the same experimental procedure as in
example 6a . 1H NMR (300 MHz, CDCl3) δ 3.62 (s, 2H), 3.46
(s, 2H), 1.84-1.41 (m, 11H), 0.88 (s, 9H), 0.03 (s, 6H).
P r ep a r a tion of (1-{3-[(1-Meth yl-1H-im id a zol-2-yl)su l-
fa n yl]p r op yl}cyclobu tyl)m eth a n ol (12a ). The title com-
pound was prepared from 3-[1-({[tert-butyl(dimethyl)silyl]oxy}-
methyl)cyclobutyl]-1-propanol using the same experimental
procedure as in example 11a . 1H NMR (300 MHz, CDCl3) δ
7.30 (s, 1H), 7.07 (s, 1H), 3.91 (s br, 1H), 3.69 (s, 3H), 3.55 (s,
2H), 2.91 (t, J ) 6.6 Hz, 2H), 1.91-1.70 (m, 8H),1.58-1.46
(m, 2H).
cyclob u t yl)m et h yl
(1S)-1-(Oxo{[(1R)-1-p h en ylet h yl]-
a m in o}a cetyl)p en tylca r ba m a te (14). (1-{[(1-P h en yl-1H-
im idazol-2-yl)su lfan yl]m eth yl}cyclobu tyl)m eth an ol (14a).
The title compound was prepared using the same experimental
procedure as in example 10a using [1-(hydroxymethyl)cyclobu-
tyl]methanol and 1-phenyl-1H-imidazole-2-thiol. 1H NMR (300
MHz, CDCl3) δ 7.50-7.07 (m, 7H), 3.63 (s, 2H), 3.40 (s, 2H),
1.93-1.69 (m, 6H). GC-MS m/z 275 (M + H).
(1-{[(1-P h e n yl-1H -im id a zol-2-yl)su lfa n yl]m e t h yl}-
cyclobu tyl)m eth yl (1S)-1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-
p h en yleth yl]a m in o}eth yl)p en tylca r ba m a te (14b). The
title compound was prepared using the same experimental
procedure as in example 20b using (1-{[(1-phenyl-1H-imidazol-
2-yl)sulfanyl]methyl}cyclobutyl)methanol as the alcohol com-
ponent and (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]-
P r ep a r a tion of (1-{3-[(1-Meth yl-1H-im id a zol-2-yl)su l-
fa n yl]p r op yl}cyclobu tyl)m eth yl
(1S)-1-(1-Hyd r oxy-2-
1
heptanamide as the amino alcohol component. H NMR (300
o x o -2-{[(1R )-1-p h e n y le t h y l]a m in o }e t h y l)p e n t y lc a r -
ba m a te (12b). The title compound was prepared using the
same experimental procedure as in example 11b from
(1-{3-[(1-methyl-1H-imidazol-2-yl)sulfanyl]propyl}cyclobutyl)-
methanol as the alcohol component and (3S)-3-amino-2-hy-
droxy-N-[(1R)-1-phenylethyl]heptanamide as the amino alcohol
MHz, CDCl3) δ 7.50-7.06 (m, 13 H), 5.55 (s br, 1H), 5.20-
5.09 (m, 2H), 4.10 (s br, 1H), 4.02-3.87 (m, 3H), 3.30 (s, 2H),
2.04-1.79 (m, 6H), 1.50-1.25 (m, 9H), 0.79 (m, 3H). LC-MS
m/z 565 (M + H).
(1-{[(1-P h e n yl-1H -im id a zol-2-yl)su lfa n yl]m e t h yl}-
cyclobu tyl)m eth yl
1
(1S)-1-(Oxo{[(1R)-1-p h en yleth yl]-
component. H NMR (300 MHz, CDCl3) δ 7.49-7.05 (m, 6H),
a m in o}a cetyl)p en tylca r ba m a te (14). The title compound
was prepared using the same experimental procedure as in
example 11 using (1-{[(1-phenyl-1H-imidazol-2-yl)sulfanyl]-
methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-
phenylethyl]amino}ethyl)pentylcarbamate as the starting al-
cohol component. 1H NMR (300 MHz, CDCl3) δ 7.50-7.06 (m,
13 H), 5.46 (m, 1H), 5.15-5.05 (m, 2H), 4.0 (s, 2H), 3.47 (s,
2H), 2.08-1.65 (m, 6H), 1.52 (d, J ) 6.7 Hz, 3H), 1.39-0.92
(m, 6H), 0.85 (t, J ) 7.0 Hz, 3H). Anal. C, H, N
{1-[(1,3-Th iazol-2-ylth io)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(Oxo{[(1R )-1-p h e n yle t h yl]a m in o}a ce t yl)p e n t ylca r -
bam ate (15). {1-[(1,3-Th iazol-2-ylth io)m eth yl]cyclobu tyl}-
m eth a n ol (15a ). The title compound was prepared using the
same experimental procedure as in example 10a using [1-(hy-
droxymethyl)cyclobutyl]methanol and 1,3-thiazole-2-thiol. 1H
NMR (300 MHz, CDCl3) δ 7.64 (d, J ) 3.3 Hz, 1H), 7.56 (d, J
) 3.2 Hz, 1H), 3.39 (s, 2H), 3.34 (s, 2H), 1.60-1.41 (m, 6H).
GC-MS m/z 216 (M + H).
6.99 (s, 1H), 6.91 (s, 1H), 5.64 (m, 1H), 5.12 (m, 1H), 4.14, (m,
4H), 3.95 (m, 1H), 3.62, 3.64 (2s, 3H), 3.25 (m, 2H), 2.08-1.71
(m, 12H), 1.49 (d, J ) 6.8 Hz, 3H), 1.41-1.32 (m, 4H), 1.29
(m, 3H). LC-MS m/z 531 (M + H).
P r ep a r a tion of (1-{3-[(1-Meth yl-1H-im id a zol-2-yl)su l-
fa n yl]p r op yl}cyclobu tyl)m eth yl
(1S)-1-(Oxo{[(1R)-1-
ph en yleth yl]am in o}acetyl)pen tylcar bam ate (12). The title
compound was prepared using the same experimental proce-
dure as in example 11 using (1-{3-[(1-methyl-1H-imidazol-2-
yl)sulfanyl]propyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-
2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as the
alcohol component. 1H NMR (300 MHz, CDCl3) δ 7.12-7.45
(m, 7H), 6.99 (s, 1H), 5.56-5.33 (m, 2H), 5.16 (m, 1H), 4.01 (s,
2H), 3.67 (s, 3H), 3.01 (s, 2H), 2.08-1.89 (m, 7H), 1.85-1.61
(m, 12H), 0.87 (m, 3H). Anal. C, H, N
[1-({[5-(4-Ch lor op h en yl)-1-m et h yl-1H -im id a zol-2-yl]-
su lfa n yl}m eth yl)cyclobu tyl]m eth yl (1S)-1-(Oxo{[(1R)-1-
p h en ylet h yl]a m in o}a cet yl)p en t ylca r b a m a t e (13). [1-

Inhibitors of Cystein Protease
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5063
1
{1-[(1,3-Th iazol-2-ylth io)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]a m in o}eth yl)-
p en tylca r ba m a te (15b). The title compound was prepared
using the same experimental procedure as in example 10b
using {1-[(1,3-thiazol-2-ylthio)methyl]cyclobutyl}methanol as
the alcohol component and (3S)-3-amino-2-hydroxy-N-[(1R)-
1-phenylethyl]heptanamide as the amino alcohol component.
1H NMR (300 MHz, CDCl3) δ 7.66 (d, J ) 3.3 Hz, 1H), 7.35-
7.20 (m, 5H), 5.64 (m, 1H), 5.14-5.00 (m, 3H), 4.21-4.17 (m,
6H), 3.87 (m, 1H), 1.88 (m, 1H), 1.51 (d, J ) 6.7 Hz, 3H), 1.41-
1.1 (m, 11 H), 0.90 (m, 3H). LC-MS m/z 506 (M + H).
component. H NMR (300 MHz, CDCl3) δ 8.50 (d, J ) 4.8 Hz,
2H), 7.37-7.25 (m 5H), 7.15 (d, J ) 7.8 Hz, 1H), 6.95 (t, J )
4.8 Hz, 1H), 5.56 (d, J ) 8.5 Hz, 1H), 5.09 (m, 1H), 4.96 (d, J
) 5.5 Hz, 1H), 4.20-4.06 (m, 3H), 3.86 (m, 1H), 3.49 (s, 2H),
2.07-1.73 (m, 6H), 1.83-1.61 (m, 2H), 1.48 (d, J ) 7 Hz, 3H),
1.37-1.26 (m, 4H), 0.92 (m, 3H). LC-MS m/z 501 (M + H).
{1-[(2-P y r i m i d i n y ls u lfa n y l)m e t h y l]c y c lo b u t y l}-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
p en tylca r ba m a te (17). The title compound was prepared
using the same experimental procedure as in example 11 with
{1-[(2-pyrimidinylsulfanyl)methyl]cyclobutyl}methyl (1S)-1-(1-
hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcar-
{1-[(1,3-Th iazol-2-ylth io)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(Oxo{[(1R )-1-p h e n yle t h yl]a m in o}a ce t yl)p e n t ylca r -
ba m a te (15). The title compound was prepared using the
same experimental procedure as in example 11 using 1-[(1,3-
thiazol-2-ylthio)methyl]cyclobutyl}methyl (1S)-1-(1-hydroxy-
2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as
1
bamate as the starting alcohol. H NMR (300 MHz, CDCl3) δ
8.43 (d, J ) 4.6 Hz, 2H), 7.31-7.08 (m, 6H), 6.88 (t, J ) 4.7
Hz, 1H), 5.25 (d, J ) 7.2 Hz, 1H), 4.89-5.20 (m, 2H), 4.08 (s,
2H), 3.43 (s, 2H), 2.03-1.80 (m, 6H), 1.79-1.42 (m, 5H), 1.41-
1.25 (m, 4H), 0.81 (s br, 3H). Anal. C, H, N
1
the starting alcohol. H NMR (300 MHz, CDCl3) δ 7.60-7.26
[1-({[4-(4-C h lo r o p h e n y l)-2-p y r im id in y l]s u lfa n y l}-
m eth yl)cyclobu tyl]m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yl-
eth yl]am in o}acetyl)pen tylcar bam ate (18). [1-({[4-(4-Ch lo-
r op h en yl)-2-p yr im id in yl]su lfa n yl}m et h yl)cyclob u t yl]-
m eth a n ol (18a ). The title compound was prepared using the
same experimental procedure as in example 10a from [1-(hy-
droxymethyl)cyclobutyl]methanol and 4-(4-chlorophenyl)-2-
(m, 7H), 5.32-5.09 (m, 4H), 4.18 (s, 2H), 3.56 (s, 2H), 1.99-
1.63 (m, 8H), 1.56 (d, J ) 6.3 Hz, 3H), 1.34-1.22 (m, 4 H),
0.89 (s br, 3H). Anal. C, H, N.
{1-[(1,3-Ben zoxa zol-2-ylsu lfa n yl)m et h yl]cyclob u t yl}-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
p en tylca r ba m a te (16). {1-[(1,3-Ben zoxa zol-2-ylsu lfa n yl)-
m eth yl]cyclobu tyl}m eth a n ol (16a ). The title compound was
prepared using the same experimental procedure as in ex-
ample 10a using {1-[(1,3-benzoxazol-2-ylsulfanyl)methyl]-
cyclobutyl}methanol as the thiol component. 1H NMR (300
MHz, CDCl3) δ 7.67-7.25 (m, 4H), 3.61 (s, 2H), 3.46 (s br, 1H),
3.35 (s, 2H), 1.54-1.31 (m, 6H). GC-MS m/z 250 (M + H).
1
pyrimidinethiol. H NMR (300 MHz, CDCl3) 8.49 (d, J ) 5.4
Hz, 1H), 7.95 (d, J ) 8.5 Hz, 2H), 7.44 (d, J ) 8.7 Hz, 2H),
7.32 (d, J ) 5.5 Hz, 1H), 4.18 (t, J ) 7.1 Hz, 1H), 3.54 (d, J )
7.0 Hz, 2H), 3.47 (s, 2H), 2.03-1.69 (m, 6H), GC-MS m/z 320
(M + H).
[1-({[4-(4-C h lo r o p h e n y l)-2-p y r im id in y l]s u lfa n y l}-
m et h yl)cyclob u t yl]m et h yl (1S)-1-(1-H yd r oxy-2-oxo-2-
{[(1R)-1-ph en yleth yl]am in o}eth yl)pen tylcar bam ate (18b).
The title compound was prepared using the same experimental
procedure as in example 10b from [1-({[4-(4-chlorophenyl)-2-
pyrimidinyl]sulfanyl}methyl) cyclobutyl] methanol as the
alcohol component and (3S)-3-amino-2-hydroxy-N-[(1R)-1-
phenylethyl] heptanamide as the amino alcohol component.
1H NMR (300 MHz, CDCl3) 8.50 (d, J ) 5.0 Hz, 1H), 7.99 (d,
J ) 7.5 Hz, 2H), 7.44 (d, J ) 8.4 Hz, 2H), 7.30-7.15 (m, 7H),
5.10-4.93 (m, 3H), 4.15 (m, 3H), 3.80 (m, 1H), 3.52 (s, 2H),
2.04-1.91 (m, 6H), 1.82-1.23 (m, 9H), 0.82 (m, 3H). LC-MS
m/z 611 (M + H).
[1-({[4-(4-C h lo r o p h e n y l)-2-p y r im id in y l]s u lfa n y l}-
methyl)cyclobutyl]methyl(1S)-1-(Oxo{[(1R)-1-phenylethyl]-
a m in o}a cetyl)p en tylca r ba m a te (18). The title compound
was prepared using the same experimental procedure as in
example 23c from [1-({[4-(4-chlorophenyl)-2-pyrimidinyl]-
sulfanyl}methyl) cyclobutyl]methyl (1S)-1-(1-hydroxy-2-oxo-2-
{[(1R)-1-phenylethyl]amino}ethyl) pentylcarbamate as the
alcohol component. 1H NMR (300 MHz, CDCl3) 8.52 (d, J )
5.3 Hz, 1H), 8.02 (d, J ) 8.4 Hz, 2H), 7.45 (d, J ) 8.4 Hz, 2H),
7.34-7.25 (m, 6H), 7.09 (d, J ) 7.3 Hz, 1H), 5.24-5.04 (m,
3H), 4.17 (s, 2H), 3.55 (s, 2H), 2.03-1.95 (m, 6H), 1.56 (m, 2H),
1.52 (d, J ) 6.6 Hz, 3H), 1.38-1.28 (m, 4H), 0.84 (t, J ) 6.3
Hz, 3H). Anal. C, H, N
{1-[(1,3-Ben zoxa zol-2-ylsu lfa n yl)m et h yl]cyclob u t yl}-
m eth yl (1S)-1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]-
a m in o}eth yl)p en tylca r ba m a te (16b). The title compound
was prepared using the same experimental procedure as in
example 10b with {1-[(1,3-benzoxazol-2-ylsulfanyl)methyl]-
cyclobutyl}methanol as the alcohol component and (3S)-3-
amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide as the
1
amino alcohol component. H NMR (300 MHz, CDCl3) δ 7.60
(d, J ) 7.3 Hz, 1H), 7.45 (d, J ) 7.4 Hz, 1H), 7.44-7.24 (m,
7H), 7.16 (d, J ) 7.8 Hz, 1H), 5.62 (m, 1H), 5.14 (m, 1H), 4.80
(s br, 1H), 4.36-4.09 (m, 3H), 3.87 (m, 1H), 3.63 (s, 2H), 2.02-
1.68 (m, 8H), 1.63-1.26 (m, 7H), 0.92 (m, 3H). LC-MS m/z
540 (M + H).
P r epar ation of {1-[(1,3-Ben zoxazol-2-ylsu lfan yl)m eth yl]-
cyclobu tyl}m eth yl
(1S)-1-(Oxo{[(1R)-1-p h en yleth yl]-
a m in o}a cetyl)p en tylca r ba m a te (16). The title compound
was prepared using the same experimental procedure as in
example 11 with {1-[(1,3-benzoxazol-2-ylsulfanyl)methyl]-
cyclobutyl}methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenyleth-
yl]amino}ethyl)pentylcarbamate as the starting alcohol. 1H
NMR (300 MHz, CDCl3) δ 7.53 (d, J ) 7.3 Hz, 1H), 7.37 (d, J
) 7.6 Hz, 1H), 7.31-7.07 (m, 7H), 5.26 (d, J ) 7.5 Hz, 1H),
5.07-4.98 (m, 3H), 4.12 (s, 2H), 3.58 (s, 2H), 2.03-1.81 (m,
6H), 1.48 (d, J ) 6.4 Hz, 3H), 1.42-1.23 (m, 6H), 0.80 (t, J )
6.3 Hz, 3H). Anal. C, H, N.
{1-[(2-P y r i m i d i n y ls u lfa n y l)m e t h y l]c y c lo b u t y l}-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
pen tylcar bam ate (17). {1-[(2-P yr im idin ylsu lfan yl)m eth yl]-
cyclob u t yl}m et h a n ol (17a ). {1-[(2-Pyrimidinylsulfanyl)-
methyl]cyclobutyl}methanol was prepared using the same
experimental procedure as in example 10a using 2-mercap-
topyrimidine instead of 1-methyl-2-mercaptoimidazole as the
{1-[(1,3-Th iazol-2-yloxy)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(Oxo{[(1R )-1-p h e n yle t h yl]a m in o}a ce t yl)p e n t ylca r -
ba m a te (19). {1-[(1,3-Th ia zol-2-yloxy)m eth yl]cyclobu tyl}-
m eth a n ol (19a ). To a solution of [1-(hydroxymethyl)cyclobu-
tyl]methanol (0.5 g, 4.31 mmol) in DMF/THF (1:1) (15 mL)
was added a 60% dispersion of sodium hydride in oil (0.165 g,
4.31 mmol). After the mixture was stirred for 15 min, 2-bro-
mothiazole (0.71 g, 4.31 mmol) was added and the contents
heated at reflux for 3 h. A saturated solution of sodium
bicarbonate was added followed by ethyl acetate. The organic
phase was isolated, dried with magnesium sulfate, and
concentrated under vacuum. The crude product was purified
by silica gel chromatography using ethyl acetate/hexane (2:3)
as the eluent to afford 0.340 g (40%) of {1-[(1,3-thiazol-2-yloxy)-
methyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300
MHz, CDCl3) δ 7.05 (d, J ) 3.8 Hz, 1H), 6.64 (d, J ) 3.9 Hz,
1H), 4.51 (s, 2H), 3.59 (s, 2H), 2.03-1.72 (m, 6H). GC-MS m/z
200 (M + H).
1
thiol component. H NMR (300 MHz, CDCl3) δ 8.51 (d, J ) 5
Hz, 2H), 7.01 (t, J ) 4.9 Hz, 1H), 4.39 (t, J ) 7.3 Hz, 1H), 3.55
(d, J ) 7.1 Hz, 2H), 3.43 (s, 2H), 2.06-1.82 (m, 6H). GC-MS
m/z 211 (M + H).
{1-[(2-P y r i m i d i n y ls u lfa n y l)m e t h y l]c y c lo b u t y l}-
m eth yl (1S)-1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]-
a m in o}eth yl)p en tylca r ba m a te (17b). The title compound
was prepared using the same experimental procedure as in
example 20b with {1-[(2-pyrimidinylsulfanyl)methyl]cyclobutyl}-
methanol as the alcohol component and (3S)-3-amino-2-hy-
droxy-N-[(1R)-1-phenylethyl]heptanamide as the amino alcohol

5064 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Tavares et al.
{1-[(1,3-Th iazol-2-yloxy)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]a m in o}eth yl)-
p en tylca r ba m a te (19b). The title compound was prepared
using the same experimental procedure as in example 10b
using {1-[(1,3-thiazol-2-yloxy)methyl]cyclobutyl}methanol as
the alcohol component and (3S)-3-amino-2-hydroxy-N-[(1R)-
1-phenylethyl]heptanamide as the amino alcohol component.
1H NMR (300 MHz, CDCl3) δ 8.25 (d, J ) 5.8 Hz, 1H), 7.34-
7.26 (m, 5H), 6.63 (d, J ) 5.7 Hz, 1H), 5.44 (m, 1H), 5.07 (m,
1H), 4.94 (d, J ) 7.6 Hz, 1H), 4.54 (d, J ) 4.5 Hz, 1H), 4.37-
4.18 (m, 5H), 3.74 (m, 1H), 1.47 (d, J ) 6.9 Hz, 3H), 1.42-
0.91 (m, 12 H), 0.81 (m, 3H). LC-MS m/z 490 (M + H).
was prepared using the same experimental procedure as in
example 10b from (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}-
cyclobutyl)methanol as the alcohol component and (3S)-3-
amino-2-hydroxy-N-[(1R)-1-phenylethyl] heptanamide as the
1
amino alcohol component. H NMR (300 MHz, CDCl3) δ 8.29
(d, J ) 5.6 Hz, 1H), 7.32-7.10 (m, 6H), 6.67 (d, J ) 5.7 Hz,
1H), 5.61-5.53 (m, 1H), 5.13-5.08 (m, 1H), 4.79, 4.89 (2d, J
) 5, 5.6 Hz, 1H), 4.36, 4.39 (2s, 2H), 4.38-4.18 (m, 3H), 3.84
(m, 1H), 2.07-1.50 (m, 10 H), 1.47-1.26 (m, 5H), 0.88 (m, 3H).
LC-MS m/z 519 (M + H).
(1-{[(2-Ch lor o-4-p yr im id in yl)oxy]m eth yl}cyclobu tyl)-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
p en tylca r ba m a te (21). The title compound was prepared
using the same experimental procedure as in example 11 from
(1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-
1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pen-
tylcarbamate as the alcohol component. 1H NMR (300 MHz,
CDCl3) δ 8.31 (m, 5.7 Hz, 1H), 7.41-7.29 (m, 5H), 7.13 (d, J )
7.1 Hz, 1H), 6.69 (d, J ) 5.6 Hz, 1H), 5.29 (d, J ) 7.5 Hz, 1H),
5.18-5.08 (m, 2H), 4.41 (s, 2H), 4.20 (s, 2H), 2.07-1.71 (m,
7H), 1.56 (d, J ) 6.8 Hz, 3H), 1.26-1.32 (m, 5H), 0.88 (t, J )
6.5 Hz, 3H). Anal. C, H, N
(1-{3-[(2-Ch lor o-4-p yr im id in yl)oxy]p r op yl}cyclobu tyl)-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
p en tylca r ba m a te (22). (1-{3-[(2-Ch lor o-4-p yr im id in yl)-
oxy]p r op yl}cyclobu tyl)m eth a n ol (22a ). 3-[1-({[tert-Butyl-
(dimethyl)silyl]oxy}methyl)cyclobutyl]-1-propanol (6b) and 2,4-
dichloropyrimidine were reacted using the same experimental
procedure as in example 19a to afford the intermediate 4-{3-
[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]propyloxy}-
2-chloropyrimidine. 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J )
5.7 Hz, 1H), 6.59 (d, J ) 5.7 Hz, 1H), 4.33 (t, J ) 6.4 Hz, 2H),
3.44 (s, 2H), 1.81-1.51 (m, 8H), 1.21 (m, 2H), 0.84 (s, 9H),
-0.002 (s, 6H). GC-MS m/z 371 (M + H).
{1-[(1,3-Th iazol-2-yloxy)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(Oxo{[(1R )-1-p h e n yle t h yl]a m in o}a ce t yl)p e n t ylca r -
ba m a te (19). The title compound was prepared using the
same experimental procedure as in example 11 using {1-[(1,3-
thiazol-2-yloxy)methyl]cyclobutyl}methyl (1S)-1-(1-hydroxy-2-
oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as
1
the starting alcohol. H NMR (300 MHz, CDCl3) δ 7.35-7.26
(m, 6H), 7.11 (s, 1H), 6.67 (s, 1H), 5.27-5.08 (m, 3H), 4.40 (s,
2H), 4.18 (s, 2H), 1.98-1.81 (m, 6H), 1.65 (m, 2H), 1.53 (d, J
) 6 Hz, 3H), 1.42-1.21 (m, 4 H), 0.85 (s br, 3H). Anal. C, H,
N
{1-[(2-P yr im id in yloxy)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(Oxo{[(1R )-1-p h e n yle t h yl]a m in o}a ce t yl)p e n t ylca r -
ba m a te (20). {1-[(2-P yr im id in yloxy)m eth yl]cyclobu tyl}-
m eth a n ol (20a ). The title compound was prepared using the
same experimental procedure as in example 19a from [1-(hy-
droxymethyl)cyclobutyl]methanol and 2-chloropyrimidine. 1H
NMR (300 MHz, CDCl3) δ 8.50-8.47 (m, 2H), 6.95-6.89 (m,
1H), 4.48 (s, 2H), 3.63 (d, J ) 5.9 Hz, 2H), 3.02 (t, J ) 6.2 Hz,
1H), 2.01-1.78 (m, 6H). GC-MS m/z 195 (M + H).
{1-[(2-P yr im id in yloxy)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(1-h yd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]a m in o}eth yl)-
p en tylca r ba m a te (20b). The title compound was prepared
using the same experimental procedure as in example 10b
from {1-[(2-pyrimidinyloxy)methyl]cyclobutyl}methanol as the
alcohol component and (3S)-3-amino-2-hydroxy-N-[(1R)-1-
phenylethyl]heptanamide as the amino alcohol component. 1H
NMR (300 MHz, CDCl3) δ 8.46 (m, 2H), 7.26 (m, 6H), 6.92-
6.72 (m, 1H), 5.29 (m, 1H), 5.05 (m, 2H), 4.51 (s, 2H), 4.46-
3.94 (m, 3H), 3.83 (m, 1H), 2.03-1.80 (m, 8H), 1.48-1.23 (m,
7H), 0.82 (m, 3H). LC-MS m/z 485 (M + H).
The above compound was desilylated using the same
experimental procedure as in example 11a to afford (1-{3-[(2-
chloro-4-pyrimidinyl)oxy]propyl}cyclobutyl)methanol. 1H NMR
(300 MHz, CDCl3) δ 8.31 (d, J ) 5.6 Hz, 1H), 6.69 (d, J ) 5.7
Hz, 1H), 4.43 (t, J ) 6.3 Hz, 2H), 3.61 (s, 2H), 1.98-1.46 (m,
10H).
(1-{3-[(2-Ch lor o-4-p yr im id in yl)oxy]p r op yl}cyclobu tyl)-
m eth yl (1S)-1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]-
a m in o}eth yl)p en tylca r ba m a te (22b). The title compound
was prepared using the same experimental procedure as in
example 10b from (1-{3-[(2-chloro-4-pyrimidinyl)oxy]propyl}-
cyclobutyl)methanol as the alcohol component and (3S)-3-
amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide as the
{1-[(2-P yr im id in yloxy)m eth yl]cyclobu tyl}m eth yl (1S)-
1-(Oxo{[(1R )-1-p h e n yle t h yl]a m in o}a ce t yl)p e n t ylca r -
ba m a te (20). The title compound was prepared using the
same experimental procedure as in example 11 from {1-[(2-
pyrimidinyloxy)methyl]cyclobutyl}methyl (1S)-1-(1-hydroxy-
2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as
1
amino alcohol component. H NMR (300 MHz, CDCl3) δ 8.30
(d, J ) 5.6 Hz, 1H), 7.38-7.17 (m, 6H), 6.69 (d, J ) 5.7 Hz,
1H), 5.62 (d, J ) 8.8 Hz, 1H), 5.33 (m, 1H), 4.98 (d, J ) 5.6
Hz, 1H), 4.40 (m, 2H), 4.15-3.86 (m, 3H), 1.89-1.58 (m, 14H),
1.52 (d, J ) 7.0 Hz, 3H), 1.39 (m, 2H), 0.92 (m, 3H). LC-MS
m/z 547 (M + H).
1
the alcohol component. H NMR (300 MHz, CDCl3) δ 8.50 (d,
J ) 4.8 Hz, 2H), 7.37 - 7.26 (m, 5H), 7.08 (d, J ) 7.4 Hz, 1H),
6.91 (t, J ) 4.8 Hz, 1H), 5.25 (d, J ) 7.7 Hz, 1H), 5.11-5.04
(m, 2H), 4.35 (s, 2H), 4.24 (s, 2H), 2.0-1.94 (m, 6H), 1.52 (d,
J ) 6.9 Hz, 3H), 1.36-1.27 (m, 6H), 0.82 (t, J ) 6.5 Hz, 3H).
Anal. C, H, N
(1-{3-[(2-Ch lor o-4-p yr im id in yl)oxy]p r op yl}cyclobu tyl)-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
p en tylca r ba m a te (22). The title compound was prepared
using the same experimental procedure as in example 11 using
(1-{3-[(2-chloro-4-pyrimidinyl)oxy]propyl}cyclobutyl)methyl (1S)-
1-(1-h ydr oxy-2-oxo-2-{[(1R)-1-ph en ylet h yl]a m in o}et h yl)-
pentylcarbamate as the alcohol component. 1H NMR (300
MHz, CDCl3) δ 8.32 (d, J ) 5.7 Hz, 1H), 7.41-7.29 (m, 5H),
7.17 (d, J ) 7.9 Hz, 1H), 6.70 (d, J ) 5.7 Hz, 1H), 5.32 (d, J )
8.2 Hz, 1H), 5.19 (m, 2H), 4.42 (t, J ) 6.2 Hz, 1H), 4.08 (s,
2H), 1.94-1.61 (m, 15H), 1.59 (d, J ) 7.1 Hz, 3H), 1.37 (m,
2H), 0.92 (t, J ) 6.7 Hz, 3H). Anal. C, H, N
[1-({[2-(4-Met h yl-1-p ip er a zin yl)-4-p yr im id in yl]oxy}-
m et h yl)cyclob u t yl]m et h yl (1S)-1-(Oxo{[(1R)-1-p h en yl-
eth yl]am in o}acetyl)pen tylcar bam ate (23). [1-({[2-(4-Meth -
yl-1-p ip er a zin yl)-4-p yr im id in yl]oxy}m eth yl)cyclobu tyl]-
m eth a n ol (23a ). To a solution of (1-{[(2-chloro-4-pyrimidinyl)-
oxy]methyl}cyclobutyl)methanol (21a ) (0.5 g, 2.19 mmol) in
DMF (5.0 mL) was added N-methylpiperidine (0.36 mL, 3.28
mmol), and the contents heated at 90 °C for 3 h. The reaction
mixture was concentrated under vacuum and taken directly
(1-{[(2-Ch lor o-4-p yr im id in yl)oxy]m eth yl}cyclobu tyl)-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
p en tylca r ba m a te (21). (1-{[(2-Ch lor o-4-p yr im id in yl)oxy]-
m et h yl}cyclob u t yl)m et h a n ol (21a ). To a solution of [1-
(hydroxymethyl)cyclobutyl]methanol (1.00 g, 8.62 mmol) in 20
mL THF/DMF (1:1) was added a 60% dispersion of sodium
hydride in oil (0.413 g, 8.62 mmol). The reaction mixture was
stirred for 15 min, and 2,4-dichloropyrimidine (1.28 g, 8.62
mmol) was added. After being stirred for 2 h, the reaction
mixture was concentrated under vacuum and the residue was
purified using silica gel chromatography and ethyl acetate/
hexane (2:3) as eluent to afford 0.9 g (51%) of (1-{[(2-chloro-
4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol as a colorless
oil. 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J ) 5.7 Hz, 1H),
6.69 (d, J ) 7 Hz, 1H), 4.51 (s, 2H), 3.67 (s, 2H), 2.35 (s br,
1H), 2.05-1.87 (m, 6H).
(1-{[(2-Ch lor o-4-p yr im id in yl)oxy]m eth yl}cyclobu tyl)-
m eth yl (1S)-1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]-
a m in o}eth yl)p en tylca r ba m a te (21b). The title compound

Inhibitors of Cystein Protease
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5065
1
to the next step. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J ) 5.6
Hz, 1H), 5.97 (d, J ) 5.5 Hz, 1H), 4.41 (s, 2H), 3.81 (t, J ) 5.1
Hz, 4H), 3.63 (s, 2H), 2.45 (t, J ) 5.1 Hz, 4H), 2.35 (s, 3H),
1.97-1.91 (m, 6H).
N-methylpiperidine. H NMR (300 MHz, CDCl3) δ 8.04 (d, J
) 5.7 Hz, 1H), 5.99 (d, J ) 5.7 Hz, 1H), 4.38 (s, 2H), 3.75 (m,
4H), 3.62 (s, 2H), 2.15 (m, 4H), 1.95-1.89 (m, 6H).
[1-({[2-(4-Mor p h olin yl)-4-p yr im id in yl]oxy}m e t h yl)-
cyclob u t yl]m et h yl (1S)-1-(1-H yd r oxy-2-oxo-2-{[(1R)-1-
p h en yleth yl]a m in o}eth yl)p en tylca r ba m a te (25b). The
title compound was prepared using the same experimental
procedure as in example 10b using [1-({[2-(4-morpholinyl)-4-
pyrimidinyl]oxy}methyl)cyclobutyl]methanol as the alcohol
component and (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]-
[1-({[2-(4-Met h yl-1-p ip er a zin yl)-4-p yr im id in yl]oxy}-
m et h yl)cyclob u t yl]m et h yl (1S)-1-(1-H yd r oxy-2-oxo-2-
{[(1R)-1-ph en yleth yl]am in o}eth yl)pen tylcar bam ate (23b).
The title compound was prepared using the same experimental
procedure as in example 10b starting with [1-({[2-(4-methyl-
1-piperazinyl)-4-pyrimidinyl]oxy}methyl)cyclobutyl]meth-
anol as the alcohol component and (3S)-3-amino-2-hydroxy-
N-[(1R)-1-phenylethyl]heptanamide as the amino alcohol com-
ponent. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J ) 5.6 Hz, 1H),
7.34-7.20 (m, 5H), 5.97 (d, J ) 5.6 Hz, 1H), 5.63 (d, J ) 8.0
Hz, 1H), 5.06 (m, 1H), 4.26 (s, 2H), 4.21-4.07 (m, 3H), 3.83
(m, 4H), 2.49 (m, 4H), 2.35 (s, 3H), 2.06-1.94 (m, 6H), 1.70-
1.22 (m, 12 H), 0.89 (m, 3H). LC-MS m/z 599 (M + H).
1
heptanamide as the amino alcohol component. H NMR (300
MHz, CDCl3) δ 8.06 (d, J ) 5.6 Hz, 1H), 7.37-7.25 (m, 5H),
7.13 (d, J ) 7.8 Hz, 1H), 6.01 (d, J ) 5.7 Hz, 1H), 5.56 (d, J )
8.8 Hz, 1H), 5.12-5.07 (m, 1H), 4.91 (d, J ) 4.4 Hz, 1H), 4.32-
4.09 (m, 5H), 3.79 (m, 5H), 2.07-1.49 (m, 12H), 1.46 (d, J )
6.9 Hz, 3H), 1.36-1.27 (m, 4H), 0.91 (m, 3H). LC-MS m/z 570
(M + H).
[1-({[2-(4-Met h yl-1-p ip er a zin yl)-4-p yr im id in yl]oxy}-
m et h yl)cyclob u t yl]m et h yl (1S)-1-(Oxo{[(1R)-1-p h en yl-
eth yl]a m in o}a cetyl)p en tylca r ba m a te (23). The title com-
pound was prepared using the same experimental procedure
as in example 11 using [1-({2-(4-methyl-1-piperazinyl)-4-
pyrimidinyl]oxy}methyl)cyclobutyl]methyl (1S)-1-(1-hydroxy-
2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as
[1-({[2-(4-Mor p h olin yl)-4-p yr im id in yl]oxy}m e t h yl)-
cyclobu tyl]m eth yl
(1S)-1-(Oxo{[(1R)-1-p h en yleth yl]-
a m in o}a cetyl)p en tylca r ba m a te (25). The title compound
was prepared using the same experimental procedure as in
example 11 using [1-({[2-(4-morpholinyl)-4-pyrimidinyl]oxy}-
methyl)cyclobutyl]methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-
phenylethyl]amino}ethyl)pentylcarbamate as the starting ma-
1
1
the starting material. H NMR (300 MHz, CDCl3) δ 8.61 (m,
terial. H NMR (300 MHz, CDCl3) δ 8.07 (d, J ) 5.7 Hz, 1H),
1H), 8.10 (m, 1H), 7.36-7.33 (m, 5H), 7.26 (d, J ) 7.2 Hz, 1H),
6.07 (d, J ) 4.6 Hz, 1H), 5.01 (m, 1H), 4.20 (m, 1H), 4.07 (m,
1H), 3.76 (m, 4H), 2.43 (m, 4H), 2.28 (s, 3H), 2.15-1.90 (m,
6H), 1.49 (d, J ) 8.1 Hz, 3H), 1.38-1.11 (m, 9H), 0.84 (t, J )
6.8 Hz, 3H). Anal. C, H, N.
[1-({[2-(4-P h en yl-1-p ip er a zin yl)-4-p yr im id in yl]oxy}-
m eth yl)cyclobu tyl]m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yl-
eth yl]am in o}acetyl)pen tylcar bam ate (24). [1-({[2-(4-P h en -
yl-1-p ip er a zin yl)-4-p yr im id in yl]oxy}m eth yl)cyclobu tyl]-
m eth a n ol (24a ). The title compound was prepared from (1-
{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol us-
ing the same experimental procedure as in example 23a using
1-phenylpiperazine. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J )
5.6 Hz, 1H), 7.21 (m, 2H), 6.92-6.82 (m, 3H), 5.93 (d, J ) 5.6
Hz, 1H), 4.37 (s, 2H), 3.90 (m, 4H), 3.58 (s, 2H), 3.18 (m, 4H),
2.54 (s br, 1H), 1.91-1.61 (m, 6H).
[1-({[2-(4-P h en yl-1-p ip er a zin yl)-4-p yr im id in yl]oxy}-
m et h yl)cyclob u t yl]m et h yl (1S)-1-(1-H yd r oxy-2-oxo-2-
{[(1R)-1-ph en yleth yl]am in o}eth yl)pen tylcar bam ate (24b).
The title compound was prepared using the same experimental
procedure as in example 10b using [1-({[2-(4-phenyl-1-piper-
azinyl)-4-pyrimidinyl]oxy}methyl)cyclobutyl]methanol as the
alcohol component and (3S)-3-amino-2-hydroxy-N-[(1R)-1-
phenylethyl]heptanamide as the amino alcohol component. 1H
NMR (300 MHz, CDCl3) δ 8.09 (d, J ) 5.7 Hz, 1H), 7.35-6.90
(m, 11H), 6.03 (d, J ) 5.5 Hz, 1H), 5.15-5.06 (m, 2H), 4.98 (s
br, 1H), 4.46-4.12 (m, 5H), 4.01 (m, 4H), 3.98 (m, 1H), 3.28
(m, 4H), 2.08-1.61 (m, 8H), 1.51 (d, J ) 7.0 Hz, 3H), 1.32-
1.27 (m, 4H), 0.88 (m, 3H), LC-MS m/z 645 (M + H).
7.38-7.29 (m, 5H), 7.12 (d, J ) 8.1 Hz, 1H), 6.03 (d, J ) 5.5
Hz, 1H), 5.08-5.33 (m, 3H), 4.29 (s, 2H), 4.20 (s, 2H), 3.81
(m, 8H), 2.11-1.96 (m, 8H), 1.56 (d, J ) 6.6 Hz, 3H), 1.31-
1.26 (m, 4H), 0.88 (s br, 3H). Anal. C, H, N.
{1-[(Th ien o[3,2-d]pyr im idin -4-yloxy)m eth yl]cyclobu tyl}-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
p en t ylca r b a m a t e (26). {1-[(Th ien o[3,2-d ]p yr im id in -4-
yloxy)m eth yl]cyclobu tyl}m eth a n ol (26a ). The title com-
pound was prepared using the same experimental procedure
as in example 19a using [1-(hydroxymethyl)cyclobutyl]metha-
1
nol and 4-chlorothieno[3,2-d]pyrimidine. H NMR (300 MHz,
CDCl3) δ 8.70 (s, 1H), 7.87 (d, J ) 5.3 Hz, 1H), 7.49 (d, J ) 5.4
Hz, 1H), 4.69 (s, 2H), 3.61 (d, J ) 5.8 Hz, 2H), 3.36 (t, J ) 6.4
Hz, 1H), 2.01-1.82 (m, 6H). GC-MS m/z 251 (M + H).
{1-[(Th ien o[3,2-d]pyr im idin -4-yloxy)m eth yl]cyclobu tyl}-
m eth yl (1S)-1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]-
a m in o}eth yl)p en tylca r ba m a te (26b). The title compound
was prepared using the same experimental procedure as in
example 10b using {1-[(thieno[3,2-d]pyrimidin-4-yloxy)methyl]-
cyclobutyl}methanol as the alcohol component and (3S)-3-
amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide as the
1
amino alcohol component. H NMR (300 MHz, CDCl3) δ 8.71
(s, 1H), 7.82 (m, 1H), 7.52-7.09 (m, 7H), 5.11-5.04 (m, 2H),
4.83 (m, 1H), 4.54 (s, 2H), 4.36-4.10 (m, 3H), 3.79 (m, 1H),
2.03-1.88 (m, 6H), 1.83-1.23 (m, 9H), 0.82 (m, 3H). LC-MS
m/z 541 (M + H).
{1-[(Th ien o[3,2-d]pyr im idin -4-yloxy)m eth yl]cyclobu tyl}-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
p en tylca r ba m a te (26). The title compound was prepared
using the same experimental procedure as in example 11 using
{1-[(thieno[3,2-d]pyrimidin-4-yloxy)methyl]cyclobutyl}meth-
yl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-
[1-({[2-(4-P h en yl-1-p ip er a zin yl)-4-p yr im id in yl]oxy}-
m eth yl)cyclobu tyl]m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yl-
eth yl]a m in o}a cetyl)p en tylca r ba m a te (24). The title com-
pound was prepared using the same experimental procedure
as in example 11 using [1-({[2-(4-phenyl-1-piperazinyl)-4-
pyrimidinyl]oxy}methyl)cyclobutyl]methyl (1S)-1-(1-hydroxy-
2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as
1
pentylcarbamate as the starting alcohol component. H NMR
(300 MHz, CDCl3) δ 8.75 (s, 1H), 7.83 (d, J ) 5.6 Hz, 1H),
7.51 (d, J ) 5.3 Hz, 1H), 7.41-7.12 (m, 6H), 5.29 (d, J ) 8.1
Hz, 1H), 5.14-5.03 (m, 2H), 4.59 (s, 2H), 4.23 (s, 2H), 2.08-
1.68 (m, 6H), 1.65-1.51 (m, 5H), 1.39-1.27 (m, 4H), 0.83 (t, J
) 6.4 Hz, 3H). Anal. C, H, N.
1
the alcohol component. H NMR (300 MHz, CDCl3) δ 8.10 (d,
J ) 5.7 Hz, 1H), 7.41-7.30 (m, 8H), 7.14-6.90 (m, 3H), 6.04
(d, J ) 5.7 Hz, 1H), 5.32-5.08 (m, 3H), 4.33 (s, 2H), 4.22 (s,
2H), 4.0 (t, J ) 5.1 Hz, 4H), 3.28 (t, J ) 4.9 Hz, 4H), 2.12-
1.98 (m, 7H), 1.96 (m, 4H), 1.33-1.27 (m, 4H), 0.89 (t, J ) 6.2
Hz, 3H). Anal. C, H, N.
[1-({[4-(4-Meth ylp h en yl)-1,3-th ia zol-2-yl]oxy}m eth yl)-
cyclobu tyl]m eth yl
(1S)-1-(Oxo{[(1R)-1-p h en yleth yl]-
a m in o}a cetyl)p en tylca r ba m a te (27). [1-({[4-(4-Meth yl-
ph en yl)-1,3-th iazol-2-yl]oxy}m eth yl)cyclobu tyl]m eth an ol
(27a ). The title compound was prepared using the same
experimental procedure as in example 19a from [1-(hydroxy-
methyl)cyclobutyl]methanol and 2-chloro-4-(4-methylphenyl)-
1,3-thiazole. 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J ) 8.0 Hz,
2H), 7.16 (d, J ) 8.0 Hz, 2H), 6.78 (s, 1H), 4.62 (s, 2H), 3.77 (t,
J ) 6.8 Hz, 1H), 3.60 (d, J ) 6.7 Hz, 2H), 2.35 (s, 3H), 2.04-
1.90 (m, 6H). GC-MS m/z 290 (M + H).
[1-({[2-(4-Mor p h olin yl)-4-p yr im id in yl]oxy}m e t h yl)-
cyclobu tyl]m eth yl
(1S)-1-(Oxo{[(1R)-1-p h en yleth yl]-
a m in o}a cetyl)p en tylca r ba m a te (25). [1-({[2-(4-Mor p h oli-
n yl)-4-pyr im idin yl]oxy}m eth yl)cyclobu tyl]m eth an ol (25a).
[1-({[2-(4-Morpholinyl)-4-pyrimidinyl]oxy}methyl)cyclobutyl]-
methanol was prepared using the same experimental proce-
dure as in example 23a using N-methylmorpholine instead of

5066 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Tavares et al.
[1-({[4-(4-Meth ylp h en yl)-1,3-th ia zol-2-yl]oxy}m eth yl)-
cyclob u t yl]m et h yl (1S)-1-(1-H yd r oxy-2-oxo-2-{[(1R)-1-
p h en yleth yl]a m in o}eth yl)p en tylca r ba m a te (27b). The
title compound was prepared using the same experimental
procedure as in example 10b from [1-({[4-(4-methylphenyl)-
1,3-thiazol-2-yl]oxy}methyl)cyclobutyl]methanol as the alcohol
component and (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]-
component and (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]-
heptanamide as the amino alcohol component. H NMR (300
MHz, CDCl3) δ 7.54-7.22 (m, 12H), 6.12 (m, 1H), 5.22-4.99
(m, 2H), 4.54 (m, 1H), 4.23-3.89 (m, 4H), 2.84 (s br, 1H), 2.59
(m, 3H), 2.04-1.90 (m, 6H), 1.50-1.23 (m, 9H), 0.79 (m, 3H).
LC-MS m/z 575 (M + H).
1
(1-{[(6-Met h yl-4-p h en ylp yr id a zin -3-yl)oxy]m et h yl}-
1
heptanamide as the amino alcohol component. H NMR (300
cyclobu tyl)m eth yl
(1R)-1-(Oxo{[(1R)-1-p h en yleth yl]-
MHz, CDCl3) δ 7.69 (m, 2H), 7.33-7.01 (m, 7H), 6.79 (m, 2H),
5.06-4.99 (m, 3H), 4.44 (m, 2H), 4.21-4.12 (m, 3H), 3.81 (m,
1H), 2.37 (s, 3H), 2.05-1.73 (m, 6H), 1.68-1.24 (m, 9H), 0.83
(m, 3H). LC-MS m/z 580 (M + H).
a m in o}a cetyl)p en tylca r ba m a te (29). The title compound
was prepared using the same experimental procedure as in
example 11 from (1-{[(6-methyl-4-phenyl-3-pyridazinyl)oxy]-
methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-
phenylethyl]amino}ethyl)pentylcarbamate as the alcohol com-
ponent. 1H NMR (300 MHz, CDCl3) δ 7.58-7.14 (m, 12H),
5.19-5.06 (m, 3H), 4.53 (s, 2H), 4.12 (s, 2H), 2.65 (s, 3H), 2.03-
1.92 (m, 6H), 1.53 (m, 2H), 1.52 (d, J ) 6.9 Hz, 3H), 1.41-
1.28 (m, 4H), 0.83 (s br, 3H). Anal. C, H, N.
[1-({[4-(4-Meth ylp h en yl)-1,3-th ia zol-2-yl]oxy}m eth yl)-
cyclobu tyl]m eth yl
(1S)-1-(Oxo{[(1R)-1-p h en yleth yl]-
a m in o}a cetyl)p en tylca r ba m a te (27). The title compound
was prepared using the same experimental procedure as in
example 11 from [1-({[4-(4-methylphenyl)-1,3-thiazol-2-yl]oxy}-
methyl)cyclobutyl]methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-
phenylethyl]amino}ethyl)pentylcarbamate as the alcohol com-
ponent. 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J ) 7.9 Hz, 2H),
7.34-7.18 (m, 7H), 7.08 (d, J ) 7.0 Hz, 1H), 6.79 (s, 1H), 5.26
(d, J ) 7.5 Hz, 1H), 5.16 - 5.40 (m, 2H), 4.49 (s, 2H), 4.21 (s,
2H), 2.36 (s, 3H), 2.03-1.93 (m, 6H), 1.37-1.29 (m, 4H), 1.52
(m, 5H), 0.84 (t, J ) 6.2 Hz, 3H). Anal. C, H, N.
{1-[(4-Me t h yl-1,3-t h ia zol-2-yl)m e t h y l]c yc lo b u t y l}-
m eth yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)-
pen tylcar bam ate (30). {1-[(Ben zyloxy)m eth yl]cyclobu tyl}-
a ceton itr ile (3). To a solution of [1-(hydroxymethyl)cyclobu-
tyl]methanol (2) (8.0 g, 69 mmol) in 120 mL of THF/DMF (1:
1) was added a 60% dispersion of sodium hydride in oil (3.30
g, 69 mmol), and the contents were stirred for 30 min. Benzyl
bromide (8.6 mL, 72.4 mmol) was then added, and the contents
were stirred for 2 h. The reaction was quenched with aqueous
ammonium chloride followed by the addition of diethyl ether.
The organic phase was isolated, dried using magnesium
sulfate, and concentrated under vacuum to afford the crude
product, which was purified by silica gel chromatography using
ethyl acetate/hexane (3:7) as the eluent to afford 12.0 g (86%)
of the intermediate {1-[(benzyloxy)methyl]cyclobutyl}methanol
(1-{[(3-P h e n y l-1,2,4-t h ia d ia zo l-5-y l)o x y ]m e t h y l}-
cyclobu tyl)m eth yl
(1S)-1-(Oxo{[(1R)-1-p h en yleth yl]-
a m in o}a cetyl)p en tylca r ba m a te (28). (1-{[(3-P h en yl-1,2,4-
th ia d ia zol-5-yl)oxy]m eth yl}cyclobu tyl)m eth a n ol (28a ).
The title compound was prepared using the same experimental
procedure as in example 19a from [1-(hydroxymethyl)cyclobu-
tyl]methanol and 5-chloro-3-phenyl-1,2,4-thiadiazole. 1H NMR
(300 MHz, CDCl3) δ 8.10 (m, 2H), 7.39 (m, 3H), 4.63 (s, 2H),
3.62 (d, J ) 6.4 Hz, 2H), 2.71 (t, J ) 6.4 Hz, 1H), 1.88-1.97
(m, 6H). GC-MS m/z 277 (M + H).
1
as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.33-7.25 (m,
5H), 4.49 (s, 2H), 3.66 (d, J ) 6 Hz, 2H), 3.52 (s, 2H), 2.53 (t,
J ) 6 Hz, 1H), 1.91-1.73 (m, 6H). GC-MS m/z 207 (M + H).
(1-{[(3-P h e n y l-1,2,4-t h ia d ia zo l-5-y l)o x y ]m e t h y l}-
cyclob u t yl)m et h yl (1S)-1-(1-H yd r oxy-2-oxo-2-{[(1R)-1-
p h en yleth yl]a m in o}eth yl)p en tylca r ba m a te (28b). The
title compound was prepared using the same experimental
procedure as in example 10b using (1-{[(3-phenyl-1,2,4-thia-
diazol-5-yl)oxy]methyl}cyclobutyl)methanol as the alcohol com-
ponent and (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]-
To a solution of {1-[(benzyloxy)methyl]cyclobutyl}methanol
(12.0 g, 59.0 mmol) in dichloromethane (180 mL) was added
TEA (9.93 mL, 70.8 mmol) at 0 °C followed by the addition of
methanesulfonyl chloride (5.02 mL, 64.9 mmol). After the
mixture was stirred for 2 h, saturated sodium chloride solution
was added. The organic phase was isolated, dried using
magnesium sulfate, and concentrated under vacuum to afford
the crude product, which was used directly in the next step.
1H NMR (300 MHz, CDCl3) δ 7.39-7.32 (m, 5H), 4.57 (s, 2H),
4.30 (s, 2H), 3.52 (s, 2H), 2.98 (s, 3H), 1.95 (m, 6H).
To a solution of the crude {1-[(benzyloxy)methyl]cyclobutyl}-
methyl methanesulfonate (16.75 g, 59.0 mmol), obtained from
the above procedure, in DMF (150 mL) and water (15 mL) was
added KCN (4.97 g, 88.5 mmol), and the contents were heated
at 130 °C for 5 h. The reaction mixture was cooled and diluted
with ether and water, and the layers were separated. The
organic phase was dried using magnesium sulfate and con-
centrated under vacuum to afford the crude product, which
was purified by silica gel chromatography using ethyl acetate/
hexane (1:3) as the eluent to afford 8.0 g (88%) of {1-
[(benzyloxy)methyl]cyclobutyl}acetonitrile as a colorless oil. 1H
NMR (300 MHz, CDCl3) δ 7.43 - 7.29 (m, 5H), 4.59 (s, 2H),
3.5 (s, 2H), 2.6 (s, 2H), 2.08-1.92 (m, 6H).
1
heptanamide as the amino alcohol component. H NMR (300
MHz, CDCl3) δ 8.23 (m, 2H), 7.48-7.26 (m, 8H), 7.13 (d, J )
7.9 Hz, 1H), 5.63 (m, 1H), 5.07 (m, 1H), 4.78 (d, J ) 5.5 Hz,
1H), 4.57 (s, 2H), 4.27-4.10 (m, 3H), 3.85 (m, 1H), 2.09-1.80
(m, 6H), 1.47 (d, J ) 6.8 Hz, 3H), 1.32-1.25 (m, 6H), 0.94 (m,
3H). LC-MS m/z 567 (M + H).
(1-{[(3-P h e n y l-1,2,4-t h ia d ia zo l-5-y l)o x y ]m e t h y l}-
cyclobu tyl)m eth yl
(1S)-1-(Oxo{[(1R)-1-p h en yleth yl]-
a m in o}a cetyl)p en tylca r ba m a te (28). The title compound
was prepared using the same experimental procedure as in
example 11 using (1-{[(3-phenyl-1,2,4-thiadiazol-5-yl)oxy]-
methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-
phenylethyl]amino}ethyl)pentylcarbamate as the starting al-
1
cohol. H NMR (300 MHz, CDCl3) δ 8.23 (m, 2H), 7.49-7.29
(m, 8H), 7.12 (d, J ) 7.8 Hz, 1H), 5.34-5.10 (m, 3H), 4.60 (s,
2H), 4.26 (s, 2H), 2.08-1.99 (m, 6H), 1.55 (d, J ) 6.5 Hz, 3H),
1.34-1.24 (m, 6H), 0.88 (s br, 3H). Anal. C, H, N.
(1-{[(6-Met h yl-4-p h en ylp yr id a zin -3-yl)oxy]m et h yl}-
{1-[(4-Tr iflu or om e t h yl-1,3-t h ia zol-2-yl)m e t h yl]c y-
clobu tyl}m eth a n ol (30a ). To a solution of {1-[(benzyloxy)-
methyl]cyclobutyl}acetonitrile (3) (9.7 g, 45 mmol) in THF (100
mL) and water (10 mL) was added diethyldithiophosphate
(15.13 mL, 90.2 mmol), and the contents were heated at reflux
for 16 h. Ethyl acetate and water were added, and the layers
were separated. The organic phase was dried using magnesium
sulfate and concentrated under vacuum to afford the crude
product, which was purified by silica gel chromatography using
ethyl acetate/hexane (1:4) as the eluent to afford 8.0 g (71%)
of 2-{1-[(benzyloxy)methyl]cyclobutyl}ethanethioamide as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.0 (s br 2H), 7.39-
7.30 (m, 5H), 4.59 (s, 2H), 3.58 (s, 2H), 3.09 (s, 2H), 2.14-1.87
(m, 6H).
cyclobu tyl)m eth yl
(1R)-1-(Oxo{[(1R)-1-p h en yleth yl]-
a m in o}a cet yl)p en t ylca r b a m a t e (29). (1-{[(6-Met h yl-4-
p h en yl-3-p yr id a zin yl)oxy]m eth yl}cyclobu tyl)m eth a n ol
(29a ). The title compound was prepared using the same
experimental procedure as in example 19a from [1-(hydroxy-
methyl)cyclobutyl]methanol and 3-chloro-6-methyl-4-phenylpy-
ridazine. 1H NMR (300 MHz, CDCl3) δ 7.58-7.25 (m, 6H), 4.64
(s, 2H), 3.59 (d, J ) 6.2 Hz, 2H), 3.05 (t, J ) 6.6 Hz, 1H), 2.63
(s, 3H), 2.0-1.73 (m, 6H). GC-MS m/z 285 (M + H).
(1-{[(6-Met h yl-4-p h en ylp yr id a zin -3-yl)oxy]m et h yl}-
cyclob u t yl)m et h yl (1R)-1-(1-H yd r oxy-2-oxo-2-{[(1R)-1-
p h en yleth yl]a m in o}eth yl)p en tylca r ba m a te (29b). The
title compound was prepared using the same experimental
procedure as in example 10b from (1-{[(6-methyl-4-phenyl-3-
pyridazinyl)oxy]methyl}cyclobutyl)methanol as the alcohol
To a solution of 2-{1-[(benzyloxy)methyl]cyclobutyl}ethane-
thioamide (0.5 g, 2.01 mmol), obtained in the above procedure,

Inhibitors of Cystein Protease
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21 5067
in acetonitrile (10 mL) was added 1-bromo-4,4,4-trifluoro-2-
butanone (0.383 g, 2.01 mmol), and the contents were stirred
at room temperature for 3 h. The mixture was concentrated
under vacuum and the residual was purified by silica gel
chromatography using ethyl acetate/hexane (1:4) as the eluent
to afford 0.417 g (83%) of the intermediate benzyloxy com-
pound as a colorless oil. To a solution of this intermediate
(0.750 g, 2.2 mmol) in dichloromethane (15 mL) was added a
1.0 M solution of boron tribromide (2.2 mL, 2.2 mmol), and
the contents were stirred at room temperature for 16 h. After
the reaction was quenched with methanol (10 mL), the
contents were concentrated under vacuum and the residual
was purified by silica gel chromatography using ethyl acetate/
hexane (1:9) as the eluent to afford 0.16 g (29%) of the title
was warmed to room temperature and applied directly to a
silica gel column using ethyl acetate/hexane (3:7) as the eluent
to afford 0.19 g (96%) of {1-[(4-phenyl-1,3-thiazol-2-yl)methyl]-
cyclobutyl}methyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}-
1
acetyl)pentylcarbamate as a colorless oil. H NMR (300 MHz,
DMSO-d6) δ 9.21 (d, J ) 8.4 Hz, 1H), 7.98 (m, 3H), 7.64 (d, J
) 7.6 Hz, 1H), 7.25-7.23 (m, 8 H), 4.96-5.01 (m, 1H), 4.80
(m, 1H), 4.01 (s, 2H), 3.30 (s, 2H), 2.12-1.64 (m, 10 H), 1.42
(d, J ) 7 Hz, 3H), 1.29-1.21 (m, 2H), 0.822 (t, J ) 7 Hz, 3H).
Anal. C, H, N.
Biologica l Da ta . Protocols used for the enzyme assays were
described in a previous paper (ref 19a).
Ack n ow led gm en t. The authors thank Randy Rut-
kowski, Robert J ohnson, and Peter Kitrinos for analyti-
cal support.
1
compound as a pale-yellow oil. H NMR (300 MHz, CDCl3) δ
7.25 (s, 1H), 3.35 (s, 2H), 2.82 (s, br 2H), 2.02-1.91 (m, 6H).
{1-[(4-Tr iflu or om et h yl-1,3-t h ia zol-2-yl)m et h yl]cyclo-
bu tyl}m eth yl (1S)-1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yl-
eth yl]a m in o}eth yl)p en tylca r ba m a te (30b). The title com-
pound was prepared using the same experimental procedure
as in example 10b from (1-{[4-(trifluoromethyl)-1,3-thiazol-2-
Su p p or tin g In for m a tion Ava ila ble: Results from el-
emental analysis. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
yl]methyl}cyclobutyl)methanol. H NMR (300 MHz, CDCl3) δ
7.34-7.13 (m, 6H), 5.16-5.09 (m, 1H), 4.84 (m, 1H), 4.24-
4.12 (m, 2H), 3.82 (m, 1H), 3.60 (m, 1H), 3.34 (s, 2H), 2.82 (s,
2H), 2.02-1.92 (m, 6H), 1.65 (m, 2H), 1.49 (d, J ) 6.7 Hz, 3H),
1.47-1.27 (m, 4H), 0.85 (m, 3H). LC-MS m/z 542 (M + H).
Refer en ces
(1) (a) Marcus, R.; Feldman, D.; Kelsey, J . In Osteoporosis, 1st ed.;
Academic Press: New York, 1996. (b) Baron, R. Anatomy and
Ultrastructure of Bone. In Primer on the Metabolic Bone Diseases
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{1-[(4-Tr iflu or om et h yl-1,3-t h ia zol-2-yl)m et h yl]cyclo-
bu t yl}m et h yl (1S)-1-(Oxo{[(1R)-1-p h en ylet h yl]a m in o}-
a cetyl)p en tylca r ba m a te (30). The title compound was pre-
pared using the same experimental procedure as in example
11 from (1-{[4-(trifluoromethyl)-1,3-thiazol-2yl]methyl}cyclo-
butyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]-
amino}ethyl)pentylcarbamate as the alcohol component. 1H
NMR (300 MHz, CDCl3) δ 7.35-7.11 (m, 7H), 5.33 (m, 1H),
5.12-5.05 (m, 2H), 4.15 (s, 2H), 2.82 (s, 2H), 2.04-1.92 (m,
6H), 1.61 (m, 2H), 1.53 (d, J ) 6.6 Hz, 3H), 1.42-1.31 (m, 4H),
0.86 (s br, 3H). Anal. C, H, N.
{1-[(4-P h en yl-1,3-th ia zol-2-yl)m eth yl]cyclobu tyl}m eth -
yl (1S)-1-(Oxo{[(1R)-1-p h en yleth yl]a m in o}a cetyl)p en tyl-
ca r ba m a te (31). {1-[(4-P h en yl-1,3-th ia zol-2-yl)m eth yl]-
cyclobu tyl}m eth a n ol (31a ). 2-{1-[(Benzyloxy)methyl]cyclo-
butyl}ethanethioamide and phenacyl bromide were reacted
using the same experimental procedure as in example 30a to
provide the intermediate 2-({1-[(benzyloxy)methyl]cyclobutyl}-
methyl)-4-phenyl-1,3-thiazole. 1H NMR (300 MHz, CDCl3) δ
8.02 (s, 1H), 7.96-7.25 (m, 10H), 4.60 (s, 2H), 3.50 (s, 2H),
3.35 (s, 2H), 2.13-1.95 (m, 6H).
2-({1-[(Benzyloxy)methyl]cyclobutyl}methyl)-4-phenyl-1,3-
thiazole (0.7 g, 2.0 mmol) obtained in the above procedure was
deprotected using boron tribromide following the same proce-
dure as in example 30a to afford the title compound. 1H NMR
(300 MHz, CDCl3) δ 8.01 (s, 1H), 7.92-7.29 (m, 5H), 4.13 (t, J
) 6.7 Hz, 1H), 3.66 (d, J ) 6 Hz, 2H), 3.3 (s, 2H), 2.08-1.94
(m, 6H). GC-MS m/z 260 (M + H).
{1-[(4-P h e n yl-1,3-t h ia zol-2-yl)m e t h yl]c yc lob u t yl}-
m eth yl (1S)-1-(1-Hyd r oxy-2-oxo-2-{[(1R)-1-p h en yleth yl]-
a m in o}eth yl)p en tylca r ba m a te (31b). The title compound
was prepared using the same experimental procedure as in
example 10b from {1-[(4-phenyl-1,3-thiazol-2-yl)methyl]cyclo-
butyl}methanol (31a ) to afford a colorless oil. 1H NMR (300
MHz, CDCl3) δ 7.90, 7.92 (2s, 1H), 7.46-7.18 (m, 10 H), 5.61
(d, J ) 8.8 Hz, 1H), 5.14-5.01 (m, 2H), 4.19-4.06 (m, 4H),
3.88 (m, 1H), 3.23 (s, 2H), 2.21-1.50 (m, 10 H), 1.46 (d, J ) 7
Hz, 3H), 1.37-1.27 (m, 2H), 0.94 (m, 3H). LC-MS m/z 550
(M + H).
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{1-[(4-P h en yl-1,3-th ia zol-2-yl)m eth yl]cyclobu tyl}m eth -
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1-phenylethyl]amino}ethyl)pentylcarbamate (0.2 g, 0.364 mmol)
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chloride (0.079 mL, 0.91 mmol) and DMSO (0.129 mL, 1.82
mmol), followed by the addition of triethylamine (0.204 mL,
1.45 mmol). After being stirred for 15 min, the reaction mixture

5068 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
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