Note: Descriptions are shown in the official language in which they were submitted.
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PROTEASE INHIBITORS
FIELD OF THE INVENTION
This invention relates in general to the use of 4-amino-azepan-3-one protease
inhibitors, particularly such inhibitors of cathepsin S, in the treatment of
diseases in which
cathepsin S is implicated, especially treatment or prevention of autoimmune
disease;
treatment or prevention of a disease state caused by the formation of
atherosclerotic lesions
and complications arising therefrom; and diseases requiring inhibition, for
therapy, of a
class II MHC-restricted immune response, inhibition of an asthmatic response,
inhibition of
an allergic response, inhibition of immune response against a transplanted
organ or tissue, or
inhibition of elastase activity in atheroma; and novel compounds for use
therewith.
BACKGROUND OF THE INVENTION
Cathepsins are a family of enzymes which are part of the papain superfamily of
cysteine proteases. Cathepsins I~, B, H, L, N and S have been described in the
literature.
Cathepsins function in the normal physiological process of protein degradation
in
animals, including humans, e.g., in the degradation of connective tissue.
However, elevated
levels of these enzymes in the body can result in pathological conditions
leading to disease.
Thus, cathepsins have been implicated as causative agents in various disease
states,
including but not limited to, infections by pneumocystis carinii, trypsanoma
cruzi,
trypsanoma brucei brucei, and Crithidia fusiculata; as well as in
schistosomiasis, malaria,
tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy,
and the
like. See International Publication Number WO 94/04172, published on March 3,
1994, and
references cited therein. See also European Patent Application EP 0 603 873
Al, and
references cited therein. Two bacterial cysteine proteases from P.
gingivallis, called
gingipains, have been implicated in the pathogenesis of gingivitis. Potempa,
J., et al. (1994)
Perspectives in Drug Discovery arid Design, 2, 445-458. Cathepsin K is
believed to play a
causative role in diseases of excessive bone or cartilage loss. See
International Publication
Number WO 97/16433 , published on May 9, 1997, and references cited therein.
Pathological levels of cathepsin S have been implicated in a variety of
disease
states. For instance, mice treated with inhibitor exhibited attenuated
antibody response
indicating that selective inhibition of cathepsin S may provide a therapeutic
strategy for
asthma and autoimmune disease processes. Riese, Richard J., et al., J. Clirz.
Izzvest. 199
101 ( 11), 2351-2363. Thus, selective inhibition of cathepsin S may provide an
effective
treatment for diseases requiring, for therapy or prevention: inhibition of a
class II MHC-
-1-
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restricted immune response; treatment and/or prevention of an autoimmune
disease state
such as rheumatoid arthritis, multiple sclerosis, juvenile-onset diabetes,
sytemic lupus
erythematosus, discoid lupus erythematosus, pemphigus vulgaris, pemphigoid,
Grave's
disease, myasthenia gravis, Hashimoto's thyroiditis, scleroderma,
dermatomysositis,
Addison's disease, pernicious anemia, primary myxoedema, thyrotoxicosis,
autoimmune
atrophic gastritis, stiff-man syndrome, Goodpasture's syndrome, sympathetic
opthalamia,
phacogenic uveitis, autoimmune haemolytic anaemia, idiopathic thrombocytopenic
purpura,
idiopathic leucopenia, primary biliary cirrhosis, active chronic hepatitis,
cryptogenic
cirrhosis, ulcerative colitis, Sjogren's syndrome, and mixed connective tissue
diease;
inhibition of an asthmatic response; inhibition of an allergic response;
inhibition of immune
response against transplanted organ or tissue (see I. Roitt, J. Brostoff, D.
Male, I»zrzzu»ology,
Fifth Edition, 1998, p.368; R. J. Riese, et al Immuzzity,1996, 4, 357-366; GP
Shi, et al
1»zmurzity 1999, 10, 197-206; T. Nakagawa, et al hn»zunity 1999, 10, 207-217;
and International Publication No: WO 97/40066); inhibition of elastase
activity in atheroma;
and treatment or prevention of a disease state caused by the formation of
atherosclerotic
lesions or complications arising therefrom (G. K. Sukhova, et al J. Cli».
Invest. 1998, 102,
576).
Several classes of cysteine protease inhibitors are known. Palmer et. al.
(1995) J.
Med. Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly
inhibit cysteine
proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of
compounds, such
as aldehydes, nitrites, a-ketocarbonyl compounds, halomethyl ketones,
diazomethyl
ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl
compounds have also been reported to inhibit cysteine proteases. See Palmer,
id, and
references cited therein.
U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as
irreversible
inhibitors of cysteine protease. Published International Patent Application
No. WO
94/04172, and European Patent Application Nos. EP 0 525 420 A1, EP 0 603 873
A1, and
EP 0 611 756 A2 describe allcoxymethyl and mercaptomethyl ketones which
inhibit the
cysteine proteases cathepsins B, H and L. International Patent Application No.
PCT/LTS94/08868 and and European Patent Application No. EP 0 623 592 A1
describe
alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL-
1(3convertase. Alkoxymethyl and mercaptomethyl ketones have also been
described as
inhibitors of the serine protease kininogenase (International Patent
Application No.
PCT/GB91/01479).
-2-
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Azapeptides which are designed to deliver the azaamino acid to the active site
of
serine proteases, and which possess a good leaving group, are disclosed by
Elmore et al.,
Biochezzz. J., 1968, 107, 103, Garker et al., Bioclaezn. J.,1974, 139, 555,
Gray et al.,
Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. Clzenz., 1984, 259, 4279,
Powers et al., J.
Biol. Chezn., 1984, 259, 4288, and are known to inhibit serine proteases. In
addition, J.
Med. Clzezn., 1992, 35, 4279, discloses certain azapeptide esters as cysteine
protease
inhibitors.
Antipain and leupeptin are described as reversible inhibitors of cysteine
protease in
McConnell et al., J. Med. Clzezn., 33, 86; and also have been disclosed as
inhibitors of serine
protease in Umezawa et al., 45 Metla. Ezzzynzol. 678. E64 and its synthetic
analogs are also
well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and
Grinde,
Biochezn. Baoplzys. Acta, , 701, 328).
1,3-diamido-propanones have been described as analgesic agents in U.S. Patent
Nos.4,749,792 and 4,638,010.
A variety of cysteine and serine protease inhibitors, especially of cathepsin
K, have
been disclosed in International Publication Number WO 97/16433 , published on
May 9;
1997.
We have now discovered that certain 4-amino-azepan-3-one compounds inhibit
cathepsin S, and are useful in the treatment of diseases in which cathepsin S
is implicated.
SUMMARY OF THE INVENTION
An object of the present invention is to provide methods of treatment which
use 4-
amino-azepan-3-one carbonyl protease inhibitors of cathepsin S of Formula I
and which are
useful for treating diseases which may be therapeutically modified by altering
the activity of
cathepsin S.
In a particular aspect, the methods of this invention are especially useful
for
treatment or prevention of autoimmune disease; treatment or prevention of a
disease state
caused by the formation of atherosclerotic lesions and complications arising
therefrom; and
diseases requiring inhibition, for therapy, of a class II MHC-restricted
immune response,
inhibition of an asthmatic response, inhibition of an allergic response,
inhibition of immune
response against a transplanted organ or tissue, or inhibition of elastase
activity in atheroma.
Another object of the present invention is to provide novel compounds for use
in the
present methods.
-3-
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DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of inhibiting cathepsin S comprising
administering to an animal, particularly a mammal, most particularly a human
being in need
thereof, an effective amount of a compound of Formula I:
N
~O
N
wherein:
Rl is selected from the group consisting of:
O O O
R
Ra/ N RsiX
3 3
R ; R and R
R2 is selected from the group consisting of: H, Cl_6alkyl, C3_6cycloalkyl-Cp_
galkyl, Ar-Cp_6alkyl, Het-Cp_6alkyl, R9C(O)-, R9C(S)-, R9S02-, R90C(O)-,
i
N C(O) N~ CH2
R9R11NC(O)-~ R9R11NC(S)_~ R9(R11)NS02- I ~ ,' and
Rs
R~rN~W
~ IR$ ;
R3 is selected from the group consisting of: H, C1_6alkyl, C3-6cycloalkyl-Cp_
6alkyl, CZ_6alkenyl, C~_6alkynyl, HetCp_6alkyl, ArCp_6alkyl, Ar-ArCp_6alkyl,
Ar-HetCp-
6alkyl, Het-ArCp_6alkyl, and Het-HetCp_6alkyl;
R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine
ring;
R4 is selected from the group consisting of: H, Cl_6alkyl, C3_6cycloalkyl-Cp_
6alkyl, Ar-Cp_6alkyl, Het-Cp_6alkyl, RSC(O)-, RSC(S)-, R5S02-, RSOC(O)-,
RSR13NC(O)-, and RSR13NC(S)-;
-4-
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RS is selected from the group consisting of: H, C1_6alkyl, C2_6alkenyl, C2_
6alkynyl, Cg_6cycloalkyl-CO_6alkyl, Ar-CO-6alkyl and Het-CO_6alkyl;
R6 is selected from the group consisting of: H, C1_6alkyl, Cg_6cycloalkyl-CO-
galkyl, Ar-Cp_6alkyl, and Het-CO-6alkyl;
R~ is selected from the group consisting of: H, C1_6alkyl, Cg-6cycloalkyl-CO_
6alkyl, Ar-CO_6alkyl, Het-CO-6alkyl, R10C(O)-, R10C(S)-, R10S02-, R100C(O)-,
R10R14NC(O)-, and R10R14NC(S)-;
Rg is selected from the group consisting of: H, C 1_6alkyl, C2_6alkenyl,
C2_6alkynyl, HetCp_6alkyl and ArCO-6alkyl;
R9 is selected from the group consisting of: C1_6alkyl, C3-6cycloalkyl-
CO_6alkyl,
Ar-Cp-galkyl and Het-CO_6alkyl; ,
R10 is selected from the group consisting of: C1_6alkyl, Cg-6cycloalkyl-
CO_6alkyl,
Ar-CO-6alkyl and Het-Cp_6allcyl;
R11 is selected from the group consisting of: H, C1-6alkyl, Ar-CO_6alkyl, and
Het-
CO_6alkyl;
R12 is selected from the group consisting of: H, C1_6alkyl, Ar-CO_6alkyl, and
Het-
CO_6alkyl;
R13 is selected from the group consisting of: H, C1_6alkyl, Ar-CO_6alkyl, and
Het-
CO-6alkyl;
R14 is selected from the group consisting of: H, C1_6alkyl, Ar-CO_6alkyl, and
Het-
CO_6alkyl;
R' is selected from the group consisting of: H, C1_6alkyl, Ar-CO_6alkyl, and
Het-
CO-6alkyl;
R" is selected from the group consisting of: H, C1_6alkyl, Ar-Cp_6alkyl, or
Het-Cp-
6alkyl;
R"' is selected from the group consisting of: H, C1_6alkyl, C3-6cycloalkyl-CO-
6alkyl, Ar-Cp_6alkyl, and Het-CO-6alkyl;
X is selected from the group consisting of: CH2, S, and O;
Z is selected from the group consisting of: C(O) and CH2;
and pharmaceutically acceptable salts, hydrates and solvates thereof.
O
R'
R4/ N
3
In compounds of Formula I, R1 is preferably R . In such
compounds:
-5-
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R3 is selected from the group consisting of: H, C1_6alkyl, C3_6cycloalkyl-CO_
6alky1,C2_6allcenyl, C2_6alkynyl, Het-CO_6alkyl and Ar-CO_6alkyl, preferably
C3_
6cycloalkyl-Cp_6alkyl and C1_6alkyl, especially selected from the group
consisting of:
cyclohexylmethyl and 2,2-dimethyl propyl, more preferably C3_6cycloalkyl-
CO_6alkyl,
most preferably cyclohexylmethyl;
R4 is selected from the group consisting of: H, C1_6alkyl, C3_6cycloalkyl-CO_
6alkyl, Ar-CO_6alkyl, Het-CO_6alkyl, RSC(O)-, RSC(S)-, RSS02-, RSOC(O)-,
R5R13NC(O)-, and R5R13NC(S)-, preferably RSC(O)-.
RS is selected from the group consisting of: C1_6alkyl, C2_6alkenyl,
C2_6alkynyl,
Cg_6cycloalkyl-CO_6alkyl, Ar-CO_6alkyl or Het-CO_6alkyl. Preferably RS is
selected from
the group consisting of: C1_6alkyl, C3_6cycloalkyl-CO_6alkyl, Ar-CO_6alkyl and
Het-CO_
6alkyl. More preferably RS is selected from the group consisting of:
furanyl, especially furan-2-yl and furan-3-yl, more especially aryl
substituted
furanyl, even more especially 5-(4-chloro-phenyl)-furan-2-yl and 5-(3-
trifluoromethyl-
phenyl)-furan-2-yl;
benzofuranyl, especially benzofuran-2-yl, more especially C1_6alkoxy
substituted
benzofuranyl, particularly 5,6-dimethoxy-benzofuran-2-yl and 5-(2-morpholin-4-
yl-
ethoxy)benzofuran-2-yl;
thiophenyl, especially thiophene-3-yl and thiophene-2-yl, more especially Het-
CO_
6alkyl-thiophenyl; particularly 5-pyridin-2-yl-thiophene-2-yl, more especially
C1_6alkyl
thiophenyl, particularly 5-methyl-thiophene-2-yl and 3-methyl-thiophene-2-yl;
more
especially C1_6alkoxy -thiophenyl, particularly 3-ethoxy-thiophene-2-yl;
faro[3,2-b]-pyridine-2-yl, especially C1_6alkyl-faro[3,2=b]-pyridine-2-yl,
more
especially 3-methyl-faro[3,2-b]-pyridine-2-yl;
thiazolyl, especially thiazole-5-yl, more especially Het-Cp_6alkyl-thiazolyl,
particularly 4-methyl-2-pyridin-2-yl-thiazole-5-yl;
phenyl, especially halogen substituted phenyl, particularly bromophenyl, more
particularly 4-bromophenyl;
cyclobutyl;
cyclopentyl;
tetrahydrofuranyl, tetrahydrofuran-2-yl;
selenophenyl, especially selenophene-2-yl; and
thieno[3,2-b]thiophenyl, especially thieno[3,2-b]thiophene-2-yl.
R' is selected from the group consisting of: H, C1_6alkyl, Ar-CO_6alkyl, and
Het-
CO_6alkyl, preferably H.
-6-
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- R" selected from the group consisting of: H, C1_6alkyl, Ar-CO_6alkyl, and
Het-CO_
6alkyl, preferably H.
In compounds of Formula I, R2 is selected from the group consisting of: H, C1_
6alkyl, Cg_6cycloalkyl-CO_6alkyl, Ar-CO_6alkyl, Het-CO_6alkyl, R9C(O)-, R9C(S)-
,
c~o~
R9S02-, R90C(O)-, R9R11NC(O)-, R9R11NC(S)-, R9R11NS02-,
R6
cH2 R~iN~Zw
and R
Preferably R2 is selected from the group consisting of: R9S02 and Cl_6alkyl.
When R2 is C1_6alkyl, C1_6alkyl is preferably propyl. R2 is most preferably
R9S02.
R9 is selected from the group consisting of: C1_6alkyl, C3_6cycloalkyl-
CO_6alkyl,
Ar-CO_6alkyl, and Het-CO_6alkyl, preferably Het-CO_6allcyl, more preferably
pyridinyl and
1-oxy-pyridinyl. When R2 is R9S02, R9 is even more preferably 'selected from
the group
consisting of: pyridin-2-yl and 1-oxy-pyridin-2-yl. Most preferably, R9 is
pyridin-2-yl.
\ More preferred are compounds of Formula I wherein:
R1 is
O
R'
R4/N
R3
R2 is R9S02;
R3 is C3_6cycloalkyl-CO_6alkyl;
R4 is R5C(O);
RS is Het-CO_6alkyl;
R9 is Het-CO_6alkyl;
R' is H
R" is H; and
R"' is C1_6alkyl.
Even more preferred are compounds of Formula I wherein:
R1 is
-
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O
R'
R4/N
R3
R2 is R9S02;
R3 is cyclohexylmethyl;
R4 is R5C(O);
RS is selected from the group consisting of: furanyl, especially furan-2-yl,
and
thiophenyl, especially thiophene-3-yl;
R9 is selected from the group consisting of: pyridin-2-yl and 1-oxy-pyridin-2-
yl,
preferably pyridin-2-yl;
R'isH
R" is H; and
R"' is selected from the group consisting of: H and C1_6alkyl. When R"' is C1_
6alkyl, R"' is:
especially selected from the group consisting of: methyl, ethyl, propyl,
butyl, pentyl
and hexyl, more especially methyl;
preferably selected from the group consisting of: 5-, 6- or 7- C1-6alkyl,
especially
selected from the group consisting of: 5-, 6- or 7-methyl, -ethyl, -propyl, -
butyl, -pentyl and
-hexyl, more especially selected from the group consisting of: 5-, 6- or 7-
methyl;
more preferably selected from the group consisting of: 6- or 7- C1_6alkyl,
especially
selected from the group consisting of: 6- or 7-methyl, -ethyl, -propyl, -
butyl, -pentyl and -
hexyl, more especially selected from the group consisting of: 6- or 7-methyl;
yet more preferably cis-7- C1_6alkyl as shown in Formula Ia:
R ~ R"
N
O
s
N
2
R»~' R
Ia
wherein R"' is C1_6alkyl, especially selected from the group consisting of:
methyl, ethyl,
propyl, butyl, pentyl and hexyl;
most preferably cis-7- methyl, as shown in Formula Ia wherein R"' is methyl.
_g_
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Compounds of Formula I selected from the following group are particularly
preferred for use in the present invention:
0
N ..,,
o " _1I
" O N p N
benzofuran-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-
sulfonyl)-azepan-4-
ylcarbamoyl]-ethyl }-amide;
F
F
F I a I / H N ",. _ / \
O O
O
5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-
oxo-1-
IO (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
of
0
a Vi
N ""~~
I _~ i \
I / H O
O
5-(4-chloro-phenyl)-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
of
a ° H ° p q.
I N N ", I I % \
/ H N
O
O
5-(4-chloro-phenyl)-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-
oxy-pyridine-
2-sulfonyl) -azepan-4-ylcarbamoyl]-ethyl }-amide;
F
F °
F I / H N'~.. N
O ~ O
°
5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-
oxo-1-(I-oxy-
pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
-9-
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,o _ 0 0
o I,
-° ~ f
o
0
5,6-dimethoxy-benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
O o s~
/ I o N~ \\
O N~N~~... O
.,..
H
O
b
furan-2-carboxylic acid { (S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2,-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
o vs~
\ / I ~ '~~~~'~o
O~ .(~N
N
O
b
benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
i
O OS N
O "~~i.\\
S~N~ .(I~'j1 .O
N
H
O
b
thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
- 10-
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i
-N O 8
O N~ \\
N , ""~ O
O ~ N
H
O
b
3-methyl-furo[3,2-b]-pyridine-2-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-
methyl-3-
oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-
[3-oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-
1-(pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
5-pyridin-2-yl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
-11-
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0 0 _
° \ _1I
N N N II
'° p N
O
furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl }-amide;
0
o ~ o~
S N
\ I N N-O N
H
O
thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl] -ethyl }-amide;
s o
p o
N N N o N
H
O
thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl] -ethyl}-amide;
0
o ~ o~
\ I N~N N-O N
H /
O
5-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2,-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
- 12-
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0 0 _
~ _1I
O
O
3-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
° °_
° v _n
\ N~ N DI N
N
S
O
3-ethoxy-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
4-bromo-N-{ (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-
ylcarbamoyl]-
ethyl }-benzamide;
0
/~ /JI~I~ °II ~ II
~N~N N-IO N
O
cyclobutanecarboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl }-amide;
-13-
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0
I I
N -OI N
N
O
cyclopentanecarboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl }-amide;
~ _Ii~
...
N N
N
O
(S)-tetrahydro-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-
2-sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
0 0 _
\ _1I
0
N N
N
O
(R)-tetrahydro-furan-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-
2-sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
0
° ~ _1I
I N~N N II
O N
O O
furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl}-amide;
5-pyridin-2-yl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
-14-
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4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-
1-(1-oxy-
pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-
[3-oxo-1-
( 1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
0 0
\ _1I
0
N N IO N+
N
-
furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-
sulfonyl)-azepan-
4-ylcarbamoyl]-ethyl }-amide;
0
o ~ -Is~
O ~ N N IO N
O O_
furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-
sulfonyl)-azepan-
4-ylcarbamoyl]-ethyl }-amide;
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0
~~ ° ~ _1I
s° '1 N N N II N+
O
°
thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
0
° _1I
s
N N N 0I N+
° _
thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
o °
° \ _1I
s
N N N 0I N+
O O-
5-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
0
° ~ _II~
s
N N N I°I N
°
3-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
II~
S N
N -OI N
O O 0_
.
3-ethoxy-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
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0
'~ _p
Se
N N N pI N /
O
b
selenophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[(R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
0
O I N~N,\~~......
~~//O
b
furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-I-propyl-
azepan-4-
ylcarbamoyl)-ethyl]-amide;
0
o ~N
S / N~N ",.
O
thiophene-3-carboxylic acid [(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-
propyl-azepan-
4-ylcarbamoyl)-ethyl]-amide;
\ / °
N~N, ~.....
O
IS
benzofuran-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-
propyl-
azepan-4-ylcarbamoyl)-ethyl]-amide;
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° D DOS N
H ° \N/ \O
°~N~H "".
IOI D
b
2,2,4-trideutero-Furan-2-carboxylic acid { (S)-2-cyclohexyl-1-[(4S,7R)-7-
methyl-3-oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
i
o~ \ I
O O NiS' N
~N
S ,C~b~,~~ O
~N
O
thiophene-3-carboxylic acid {(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide;
i
0 o s ~N
~ ' _ ~° ~~~~ 'o
~N~N'' "~e
IO'
1~
furan-2-carboxylic acid {(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide; and
i
° os ~N I
S~N N
O
thieno[3,2-b] thiophene-2-carboxylic acid {(S)-3,3-dimethyl-1-[(4S,7R)-7-
methyl-3-oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide.
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Compounds of Formula I selected from the following, group are more
particularly
preferred for use in the present invention:
i
O OS N
~I 'N O ,~ I~/,\O
O~ ~N ,
II H
O
b
furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; and
i
O OS N
O
\\
S ~~ ~N ,~~~.I~.""'O
1f NN
H
O
b
thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide.
The following compound of Formula I is the most preferred for use in the
present
invention:
0 Ds
I O N~ \\
N ,~."" O
O ~ N
H
O
b
-
furan-2-carboxylic acid { (S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide.
The present invention provides the following novel compounds:
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5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-
[3-oxo-I-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-
1-(pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide; . .
5-pyridin-2-yl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-I-[3-oxo-I-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
o °
° \ _1I
\ N
\ O
O
furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl }-amide;
0
o ~ o _
I N~N N-O N
H
O
thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl] -ethyl }-amide;
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s o
0 0 _
N O N
H
O
thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl] -ethyl}-amide;
0
o ~ o~
N~N N-O N
H
O
5-methyl-thiophene-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
0 0 _
s I ~ ~ _1I
N N II
N ~ O
O
3-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-0~o-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
° o
° \ _II~
N~ N ~p N
N
S
O
3-ethoxy-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl}-amide;
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4-bromo-N-{ (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-
ylcarbamoyl]-
ethyl}-benzamide;
0
° ~ _1I
N N ~I N
N'
O
cyclobutanecarboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl }-amide;
°
~ /I'I~ °II ~ II
tI N Y 'N N-OI N
0
cyclopentanecarboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl }-amide;
~ _ii
O
....1~
N
N I N
O
(S)-tetrahydro-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-
2-sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl}-amide;
0 0 _
o ~ N-sl
N of N
N
O
(R)-tetrahydro-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-
2-sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
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0 0 _
\ _1I
N N 0I
N'
O O
furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl }-amide;
5-pyridin-2-yl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-
1-(1-oxy-
pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-
[3-oxo-1-
(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
o _
\ _1I
0
N N OI N+
N
O -
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furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-
sulfonyl)-azepan-
4-ylcarbamoyl]-ethyl }-amide;
0
° ~ _1I
O ~ N N N I°I
O O_
furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-
sulfonyl)-azepan-
4-ylcarbamoyl]-ethyl }-amide;
0
° ~ _II~
S \ N N N I I
p N
O p'
thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl}-amide;
0
° ~ _1I
s
N N N IOI N.
O I'
O
20
thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide;
° o _
0
N N II ~. ~
N O N
° _
5-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
0
S N
N
O
3-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
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3-ethoxy-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide;
0
Se O ~ SI
N
N.
O
b
selenophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[(R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide; and
i
O D DOS \N
I H II \N/ ~O
H,..~
O~N~ ' ..
b
2,2,4-trideutero-Furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-
3-oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide.
Specific representative compounds used in the present invention are set forth
in
Examples 1-44.
Compared to the corresponding 5 and 6 membered ring compounds, the 7
membered ring compounds used in the present invention are configurationally
more stable
at the carbon center alpha to the ketone.
The present invention also uses deuterated analogs of the inventive compounds.
Representative examples of such deuterated compounds are set forth in Examples
7 and 41.
A representative synthetic route for the deuterated compounds of the present
invention are
set forth in Scheme 3 and Examples 7 and 41, below. The deuterated compounds
used in
the present invention exhibit superior chiral stability compared to the
protonated isomer.
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Definitions
The compounds used in the present invention include all hydrates, solvates,
complexes and prodrugs. Prodrugs are any covalently bonded compounds which
release the
active parent drug according to Formula I i~a vivo. If a chiral center or
another form of an
isomeric center is present in a compound used in the present invention, all
forms of such
isomer or isomers, including enantiomers and diastereomers, are intended to be
covered
herein. Compounds used in the present methods containing a chiral center may
be used as a
racemic mixture, an enantiomerically enriched mixture, or the racemic mixture
may be
separated using well-known techniques and an individual enantiomer may be used
alone. In
cases in which compounds have unsaturated carbon-carbon double bonds, both the
cis (Z)
and trans (E) isomers are within the scope of this invention. In cases wherein
compounds
may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric
form is
contemplated as being included within this invention whether existing in
equilibrium or
predominantly in one form.
The meaning of any substituent at any one occurrence in Formula I or any
subformula thereof is independent of its meaning, or any other substituent's
meaning, at any
other occurrence, unless specified otherwise.
Abbreviations and symbols commonly used in the peptide and chemical arts are
used herein to describe the compounds of the present invention. In general,
the amino acid
abbreviations follow the IUPAC-IUB Joint Commission on Biochemical
Nomenclature as
described in Eur-. J. Bioeh.er~a., 158, 9 (1984).
"Proteases" are enzymes that catalyze the cleavage of amide bonds of peptides
and
proteins by nucleophilic substitution at the amide bond, ultimately resulting
in hydrolysis.
Such proteases include: cysteine proteases, serine proteases, aspartic
proteases, and
metalloproteases. The compounds of the present invention are capable of
binding more
strongly to the enzyme than the substrate and in general are not subject to
cleavage after
enzyme catalyzed attack by the nucleophile. They therefore competitively
prevent proteases
from recognizing and hydrolyzing natural substrates and thereby act as
inhibitors.
The term "amino acid" as used herein refers to the D- or L- isomers of
alanine,
arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid,
glycine, histidine,
isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,
threonine, tryptophan,
tyrosine and valine.
"Hydrogen" or "H" includes all of its possible isotopes, including "deuterium"
or
"D" or "2H"; and "tritium" or "T" or "3H".
"C1_(alkyl" as applied herein is meant to include substituted and
unsubstituted
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-
pentyl, isopentyl,
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neopentyl and hexyl and the simple aliphatic isomers thereof. C1_6allcyl may
be optionally
substituted by a moiety selected from the group consisting of: OR12, C(O)R12,
SR12,
S(O)R12, NR122, R12NC(O)ORS, C02R12, C02NR122, N(C=NH)NH2, Het, C3_
6cycloalkyl, and Ar; where RS is selected from the group consisting of: H,
C1_6alkyl, C2_
6alkenyl, C2_6alkynyl, Cg_6cycloalkyl-CO_6alkyl, Ar-CO_6alkyl and Het-
CO_6alkyl; and
R12 is selected from the group consisting of: H, C1_6alkyl, Ar-CO_6alkyl, and
Het-CO_
6alkyl;
"C3_6cycloalkyl" as applied herein is meant to include substituted and
unsubstituted
cyclopropane, cyclobutane, cyclopentane and cyclohexane.
"C2_6 alkenyl" as applied herein means an alkyl group of 2 to 6 carbons
wherein a
carbon-carbon single bond is replaced by a carbon-carbon double bond.
C2_6alkenyl
includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the
several
isomeric pentenes and hexenes. Both cis and trans isomers axe included.
"C2_6alkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon
single bond is replaced by a carbon-carbon triple bond. C2_6 alkynyl includes
acetylene, 1-
propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of
pentyne and
hexyne.
"Halogen" means F, Cl, Br, and I.
"Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more
of
Ph-CO-6alkyl; Het-Cp_6alkyl; C1_6alkoxy; Ph-CO-6alkoxy; Het-CO_6allcoxy; OH,
(CH2)1_
6NR15R16; O(CH2)1_6NR15R16; C1_6alkyl, OR17, N(R17)2, SR17, CF3, N02, CN,
CO2R17, CON(R17), F, Cl, Br or I; where R15 and R16 are H, C1_6alkyl, Ph-
CO_6alkyl,
naphthyl-CO_6alkyl or Het-CO_6alkyl; and R17 is phenyl, naphthyl, or
C1_6alkyl.
As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered
monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-
membered tricyclic
heterocyclic ring which is either saturated or unsaturated, and which consists
of carbon
atoms and from one to three heteroatoms selected from the group consisting of
N, O and S,
and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized,
and the
nitrogen heteroatom may optionally be quaternized, and including any bicyclic
group in
which any of the above-defined heterocyclic rings is fused to a benzene ring.
The
heterocyclic ring may be attached at any heteroatom or carbon atom which
results in the
creation of a stable structure, and may optionally be substituted with one or
two moieties
selected from CO_6Ar, C1_(alkyl, OR17, N(R17)2, SR17, CF3, N02, CN, C02R17,
CON(R17), F, Cl, Br and I, where R17 is phenyl, naphthyl, or C1_6alkyl.
Examples of such
heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-
oxopiperidinyl, 2-
oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,
pyrrolidinyl, pyrazolyl,
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pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl,
oxazolidinyl, oxazolinyl,
oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl,
quinuclidinyl,
indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl,
benzoxazolyl, furanyl, benzofuranyl, thiophenyl, benzo[b]thiophenyl,
thieno[3,2-
b]thiophenyl, benzo[1,3]dioxolyl, 1,8 naphthyridinyl, pyranyl,
tetrahydrofuranyl,
tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide,
thiamorpholinyl
sulfone, and oxadiazolyl, as well as triazolyl, thiadiazolyl, oxadiazolyl,
isothiazolyl,
imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl which are
available by routine
chemical synthesis and are stable. The term heteroatom as applied herein
refers to oxygen,
nitrogen and sulfur.
Here and throughout this application the term CO denotes the absence of the
substituent group immediately following; for instance, in the moiety ArCp-
6alkyl, when C is
0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety
ArCO_6alkyl is identified
as a specific aromatic group, e.g., phenyl, it is understood that the value of
C is 0.
Certain radical groups are abbreviated herein. t-Bu refers to the tertiary
butyl
radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the
fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers
to the
benzyloxycarbonyl radical.
Certain reagents are abbreviated herein. m-CPBA refers to 3-
chloroperoxybenzoic
acid, EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide, P-EDC refers
to
polymer supported EDC, DMF refers to dimethyl formamide, DMSO refers to
dimethyl
sulfoxide, NMM is N-methylmorpholine, TEA refers to triethylamine, TFA refers
to
trifluoroacetic acid, and THF refers to tetrahydrofuran.
, Methods of Preparation
Compounds of the general formula I may be prepared in a fashion analogous to
that
outlined in Schemes 1 to 5. Alkylation of benzyl-N-allylcarbamate (1) with a
base such as
sodium hydride and S-bromo-1-pentene provides the dime 2 (Scheme 1). Treatment
of 2
bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride olefin
metathesis
catalysts developed by Grubbs provides the tetrahydroazepine 3. Epoxidation of
3 with
oxidizing agents common to the art such as m-CPBA provides the epoxide 4.
Nucleophilic
epoxide ring opening may be effected with a reagent such as sodium azide to
provide the
azido alcohol 5 which may be reduced to the amino alcohol 6 under conditions
common to
the art such as 1,3-propanedithiol and triethylamine in methanol or
triphenylphosphine in
THF and water. The amine of compound 6 may be protected with with di-tert-
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butyldicarbonate to provide the N-Boc derivative 7 (Scheme 2). Removal of the
benzyloxycarbonyl protecting group may be effected by treatment of 7 with
hydrogen gas in
the presence of a catalyst such as 10°Io Pd/C to provide the amine 8.
Treatment of amine 8
with a sulfonyl chloride such as 2-pyridinesulfonyl chloride in the presence
of a base such
as N-methylmorpholine or triethylamine provides the sulfonamide derivative 9.
Removal of
the tert-butoxycarbonyl protecting group may be effected with an acid such as
hydrochloric
acid to provide intermediate 10. Coupling of 10 with an acid such as N-Boc-
phenylalanine
in the presence of a coupling agent common to the art such as HBTU or polymer
supported
EDC provides the alcohol intermediate 11. Removal of the tert-butoxycarbonyl
protecting
group under acidic conditions provides amine 12. Coupling of 12 with an acid
such as
benzofuran-2-carboxylic acid in the presence of a coupling agent such as HBTU
or polymer
supported EDC provides alcohol 13. Alcohol 13 may be oxidized with an oxidant
common
to the art such as pyridine sulfur trioxide complex in DMSO and triethylamine
or the Dess-
Martin periodinane to provide the ketone 14.
Scheme 1
I
a ~~ b
~N~O ~ ~ ~N~O i ~ N O w
O O O
1 2 3
OH
~N O \ I ~ N3~N~o \ ~ a
O O
4 5
OH
HzN
N~O w
O
6
Reagents and conditions: (a) NaH, 5-bromo-1-pentene, NaH; (b)
bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, CHZCh,
reflux; (c) na-
CPBA, CHZC12; (d) NaN3, NH4Cl, CH30H, HZO; (e) TEA, 1,3-propanedithiol, CH30H.
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Scheme 2
OH H OH H OH
HzN~N i ~ a l o O N~N i ~ b ~O~N
O ~NH
O I IO
6 7 8 ,
OH OH
BocNH - ~ d H2N~ i I a
N \\ N
O O O O
9 10
OH H OH
BocNH \ ~ f ~ H N~N
z
O ~N,S. N O ~N~S N
O ~O O~~O
11 12
O O N O
H OH
O H O N~N'S N I ~ / \ O H O N,Sv N
~~ i
O O O O
13 14
Reagents and conditions: (a) Di-tert-butyldicarbonate, THF; (b) H2, 10% Pd/C,
EtOAc;
(c) 2-pyridylsulfonyl chloride, TEA, DMF; (d) HCI, EtOAc; (e) N-Boc-
cylohexylalanine,
P-EDC, CHzCI,; (f) HCI, CH~C12; (g) benzofuran-2-carboxylic acid, P-EDC,
CHZCl2; (h)
Dess-Martin periodinane, methylene chloride.
The deuterated compound of the Example 7 may be conveniently prepared
according to Scheme 3. The skilled artisan will understand from Example 7 and
Scheme 3
how to make any of the the deuterated compounds of the present invention.
The individual diastereomers of benzofuran-2-carboxylic acid { (S)-3-methyl-1-
IS [(2,2',4-trideuterio)-3-oxo-I-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-
butyl}amide 16
and 17 may be prepared as outlined in Scheme 3
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Scheme 3
0
H
N1~~H / I \
o ~N~ IOI O i
\ S
O
iN
a, b
D D O D N ~ D O p
II N / I \ D I ~ II N / I \
O N~ p H O i + ~ N p H O i
\ ~S ~ S
I ~N O I ~N O
16 17
Reagents and Conditions: a.) CD30D;Dz0 (10:1), TEA; b.) HPLC separation.
5
Treatment of the diastereomeric ketones 15 with triethylamine in CD30D:Dz0 at
reflux provides the deuterated analog as a mixture of diastereomers which are
separated by
HPLC to provide the deuterated compounds 16 and 17.
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Scheme 4
1) PPh3, IZ ~ Grubbs
CbzNH\ -0H 2 ~MgCI NCbz
cat. Cul Me
~Br
NaH NCbz
major Me
mCPBA
NCbz O OH
N3
Me ~ Cbz NaN3
1
NCbz
minor Me
Me
1) PPh3 1) HCI, dioxane
2) Boc-Cha-OH, HBTU OH 2) EDC
3) H2, Pd/C H
BocNH N°~ / \ off
N ~I
4) 2-pyridyl sulfonyl O ~S N o 0
chloride
Me O O 3) Dess-Martin periodinane
O
H
N N ,~ /
p H ~ I
NwS
Me O \O
In
Scheme 4, carbobenyzloxy-D-alaninol (Cbz-D-alaninol)is first converted to an
iodide, then
is reacted with allyl Grignard with a copper (I) catalyst or a similar allyl
organometallic
reagent. The amine is then alkylated with allyl iodide. Grubbs' catalyst is
then used to form
the azapine ring by ring closing metathesis. Epoxidation of the alkene
followed by
separation of the diastereomers followed by opening of the epoxide of the
minor component
with sodium azide provides the intermediate azido alcohol. Reduction of the
azide followed
by acylation of the amine with a protected amino acid such as Boc-
cyclohexylalanine,
followed by deprotection of the Cbz gives the intermediate secondary amine,
which is then
sulfonylated with a sulfonyl chloride such as pyridine sulfonyl sulfonyl
chloride.
Deprotection of the Boc group followed by acylation with an acylating agent
such as 2-furan
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carboxylic acid, HBTU, NMM, and final oxidation of the secondary alcohol to
the ketone
provides the desired products.
Scheme 5
OH ECHO H 1) HCI, dioxane
OH 2) EDC
H N~,
BocNH N%. -~ BocNH off
O N
NH NaBH4 O ~ I o 0
Me Me
3) S03 pyridine
O ~' O
H
N N ~.
O H O N~
Me
Intermediate (S)-3-Cyclohexyl-N-((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-yl)-2-
methyl-
propionamide, as described in Scheme 4, is reductively aminated with an
aldehyde or a
ketone such as propionaldehyde, then treated with a reducing agent such as
sodium
borohydride. Deprotection of the Boc group followed by acylation with an
acylating agent
such as 2-furan carboxylic acid, HBTU, NMM, and final oxidation of the
secondary alcohol
to the ketone provides the desired products.
The starting materials used herein are commercially available amino acids or
are
prepared by routine methods well known to those of ordinary skill in the art
and can be
found in standard reference books, such as the COMPENDIUM OF ORGANTC
SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience).
Coupling methods to form amide bonds herein are generally well known to the
art.
The methods of peptide synthesis generally set forth by Bodansky et al., THE
PRACTICE
OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E. Gross and J.
Meienhofer,
THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID
PHASE
PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984. are
generally
illustrative of the technique and are incorporated herein by reference.
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Synthetic methods to prepare the compounds of this invention frequently employ
protective groups to mask a reactive functionality or minirriize unwanted side
reactions.
Such protective groups are described generally in Green, T.W, PROTECTIVE
GROUPS IN
ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term "amino
protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz
groups and
derivatives thereof as known to the art. Methods for protection and
deprotection, and
replacement of an amino protecting group with another moiety are well known.
Acid addition salts of the compounds of Formula I are prepared in a standard
manner in a suitable solvent from the parent compound and an excess of an
acid, such as
hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic,
trifluoroacetic,
malefic, succinic or methanesulfonic. Certain of the compounds form inner
salts or
zwitterions which may be acceptable. Cationic salts are prepared by treating
the parent
compound with an excess of an alkaline reagent, such as a hydroxide, carbonate
or alkoxide,
containing the appropriate cation; or with an appropriate organic amine.
Canons such as
Li+, Na+, K+, Ca++, Mg++ and NH4+ are specific examples of canons present in
pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates
(such as acetate
and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are
examples of anions
present in pharmaceutically acceptable salts.
The methods of the present invention may be practiced by administering a
pharmaceutical composition which comprises one or more compounds according to
Formula
I and a pharmaceutically acceptable earner, diluent or excipient. Accordingly,
the
compounds of Formula I may be used in the manufacture of a medicament.
Pharmaceutical
compositions of the compounds of Formula I prepared as hereinbefore described
may be
formulated as solutions or lyophilized powders for parenteral administration.
Powders may
be reconstituted by addition of a suitable diluent or other pharmaceutically
acceptable
carrier prior to use. The liquid formulation may be a buffered, isotonic,
aqueous solution.
Examples of suitable diluents are normal isotonic saline solution, standard 5%
dextrose in
water or buffered sodium or ammonium acetate solution. Such formulation is
especially
suitable for parenteral administration, but may also be used for oral
administration or
contained in a metered dose inhaler or nebulizer for insufflation. It may be
desirable to add
excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia,
polyethylene
glycol, mannitol, sodium chloride or sodium citrate.
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Alternately, these compounds may be encapsulated, tableted or prepared in an
emulsion or syrup for oral administration. Pharmaceutically acceptable solid
or liquid
carriers may be added to enhance or stabilize the composition, or to
facilitate preparation of
the composition. Solid carriers include starch, lactose, calcium sulfate
dehydrate, terra alba,
magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
Liquid carriers
include syrup, peanut oil, olive oil, saline and water. The carrier may also
include a
sustained release material such as glyceryl monostearate or glyceryl
distearate, alone or with
a wax. The amount of solid carrier varies but, preferably, will be between
about 20 mg to
about 1 g per dosage unit. The pharmaceutical preparations are made following
the
conventional techniques of pharmacy involving milling, mixing, granulating,
and
compressing, when necessary, for tablet forms; or milling, mixing and filling
for hard
gelatin capsule forms. When a liquid carrier is used, the preparation will be
in the form of a
syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid
formulation
may be administered directly p.o. or filled into a soft gelatin capsule.
For rectal administration, the compounds of this invention may also be
combined
with excipients such as cocoa butter, glycerin, gelatin or polyethylene
glycols and molded
into a suppository.
Utility of the Present Invention
The compounds of Formula I are useful as inhibitors of cathepsin S. The
present
invention provides methods of treatment of diseases caused by pathological
levels of
cathepsin S, which methods comprise administering to an animal, particularly a
mammal,
most particularly a human in need thereof a therapeutically effective amount
of an inhibitor
of cathepsin S, including one or more compounds of the present invention.
The present invention particularly provides methods for treating the following
diseases in which cathepsin S is implicated:
treatment and/or prevention of an autoimmune disease state such as rheumatoid
arthritis, multiple sclerosis, juvenile-onset diabetes, sytemic lupus
erythematosus, discoid
lupus erythematosus, pemphigus vulgaris, pemphigoid, Grave's disease,
myasthenia graves,
Hashimoto's thyroiditis, scleroderma, dermatomysositis, Addison's disease,
pernicious
anemia, primary myxoedema, thyrotoxicosis, autoimmune atrophic gastritis,
stiff man
syndrome, Goodpasture's syndrome, sympathetic opthalamia, phacogenic uveitis,
autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, idiopathic
leucopenia, primary biliary cirrhosis, active chronic hepatitis, cryptogenic
cirrhosis,
ulcerative colitis, Sjogren's syndrome, and mixed connective tissue diease;
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treatment and/or prevention of a disease state caused by the formation andlor
complications of atherosclerotic lesions;
diseases which require for therapy:
inhibition of a class II MHC-restricted immune response;
inhibition of an asthmatic response;
inhibition of an allergic response;
inhibition of immune response against transplanted organ or tissue; and
inhibition of elastase activity in atheroma.
The present methods contemplate the use of one or more compounds of Formula I,
alone or in combination with other therapeutic agents.
For acute therapy, parenteral administration of a compound of Formula I is
preferred. An intravenous infusion of the compound in 5% dextrose in water or
normal
saline, or a similar formulation with suitable excipients, is most effective,
although an
intramuscular bolus injection is also useful. Typically, the parenteral dose
will be about
0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to
maintain the
concentration of drug in the plasma at a concentration effective to inhibit
cathepsin S. The
compounds are administered one to four times daily at a level to achieve a
total daily dose
of about 0.4 to about 400 mg/kglday. The precise amount of an inventive
compound which
is therapeutically effective, and the route by which such compound is best
administered, is
readily determined by one of ordinary skill in the art by comparing the blood
level of the
agent to the concentration required to have a therapeutic effect.
The compounds of Formula I may also be administered orally to the patient, in
a
manner such that the concentration of drug is sufficient to inhibit bone
resorption or to
achieve any other therapeutic indication as disclosed herein. Typically, a
pharmaceutical
composition containing the compound is administered at an oral dose of between
about 0.1
to about 50 mg/kg in a manner consistent with the condition of the patient.
Preferably the
oral dose would be about 0.5 to about 20 mg/kg.
No unacceptable toxicological effects are expected when compounds of Formula I
are administered in accordance with the present methods.
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Biological Assays
The compounds used in the present methods may be tested in one of several
biological assays to determine the concentration of compound which is required
to have a
given pharmacological effect.
Determination of cathepsin S proteolytic catalytic activity
All assays for cathepsin S were carned out with human recombinant enzyme.
Standard assay conditions for the determination of kinetic constants used a
fluorogenic
peptide substrate, typical°ly Cbz-Val-Val-Arg-AMC, and were determined
in 100 mM Na
acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate
solutions
were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final
substrate
concentration in the assays. All assays contained 10% DMSO. All assays were
conducted at
ambient temperature. Product fluorescence (excitation at 360 nM; emission at
460 nM) was
monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader.
Product
progress curves were generated over 20 to 30 minutes following formation of
AMC product.
Inhibition studies
Potential inhibitors were evaluated using the progress curve method. Assays
were
carried out in the presence of variable concentrations of test compound.
Reactions were
initiated by addition of enzyme to buffered solutions of inhibitor and
substrate. Data
analysis was conducted according to one of two procedures depending on the
appearance of
the progress curves in the presence of inhibitors. For those compounds whose
progress
curves were linear, apparent inhibition constants (KZ aPP) were calculated
according to
equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140):
v = V»ZA l(Ka(1 + 1/KZ aPP~ +AJ (1)
where v is the velocity of the reaction with maximal velocity V,n , A is the
concentration of
substrate with Michaelis constant of Ka, and 1 is the concentration of
inhibitor.
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For those compounds whose progress curves showed downward curvature
characteristic of time-dependent inhibition, the data from individual sets was
analyzed to
give kobs according to equation 2:
[AMC] = vss t + (v p - vss) ~l - ~xP f -kobst)7 ~ kobs (2)
where [AMC] is the concentration of product formed over time t, vp is the
initial reaction
velocity and vss is the final steady state rate. Values for kobs were then
analyzed as a linear
function of inhibitor concentration to generate an apparent second order rate
constant (kobs
/ inhibitor concentration or kobs / [I]) describing the time-dependent
inhibition. A complete
discussion of this kinetic treatment has been fully described (Morrison et
al., Adv. Enzymol.
Relat. Areas Mol. Biol., 1988, 61, 201).
General
Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz
using,
respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDC13 is
deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD30D is
tetradeuteriomethanol. Chemical shifts are reported in parts per million (d)
downfield from
the internal standard tetramethylsilane. Abbreviations for NMR data are as
follows: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublets, dt =
doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling
constant
measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a
Perkin-Elmer
683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were
recorded on a
Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded
in
transmission mode, and band positions are reported in inverse wavenumbers (cm
1). Mass
spectra were taken on either VG 70 FE, PE Syx API III, or VG ZAB HF
instruments, using
fast atom bombardment (FAB) or electrospray (ES) ionization techniques.
Elemental
analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting
points were
taken on a Thomas-Hoover melting point apparatus and are uncorrected. All
temperatures
are reported in degrees Celsius.
Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were
used for thin layer chromatography. Both flash and gravity chromatography were
carried
out on E. Merck Kieselgel 60 (230-400 mesh) silica gel.
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Where indicated, certain of the materials were purchased from the Aldrich
Chemical
Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New
Jersey, and
Advanced Chemtech, Louisville, Kentucky.
S Examples
In the following synthetic examples, temperature is in degrees Centigrade
(°C).
Unless otherwise indicated, all of the starting materials were obtained from
commercial
sources. Without further elaboration, it is believed that one skilled in the
art can, using the
preceding description, utilize hhe present invention to its fullest extent.
These Examples are
given to illustrate the invention, not to limit its scope. Reference is made
to the claims for
what is reserved to the inventors hereunder.
Example 1
Preparation of Benzofuran-2-carboxylic acid ((S)-2-cyclohexyl-1-f3-oxo-1-
(pyridine-2-
sulfon 1)-azepan-4 ylcarbamoyll-ethyl)-amide.
0
O H O
N.".
I ~~~H N-S
O O N
a.) Allyl-pent-4-enyl-carbamic acid benzyl ester
To a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF was added
benzyl ally)-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a dropwise
fashion. The
mixture was stirred at room temperature for approximately 10 minutes whereupon
5-bromo-
1-pentane (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction
was
heated to 40°C for approximately 4 hours whereupon the reaction was
partitioned between
dichloromethane and water. The organic layer was washed with water (2x's),
brine, dried
(MgS04), filtered and concentrated. Column chromatography of the residue (10%
ethyl
acetate:hexanes) provided 10.3 grams of the title compound as an oil: MS(EI)
260 (M+H+)'
b.) 2,3,4,7-Tetrahydro-azepine-1-carboxylic acid benzyl ester
To a solution of compound of Example la (50 g) in dichloromethane was added
bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (5.0 g). The
reaction was
heated to reflux until complete as determined by TLC analysis. The reaction
was
concentrated ira vacuo. Column chromatography of the residue (50%
dichloromethane:hexanes) gave 35 g of the title compound: MS(EI) 232 (M+H+)
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c.) 8-Oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester
To a solution of the compound of Example 1b (35 g, 1.5 mol) in CHZC12 was
added
rn-CPBA (78 g, 0.45 mol). The mixture was stirred overnight at room
temperature
whereupon it was filtered to remove the solids. The filtrate was washed with
water and
saturated NaHC03 (several times). The organic layer was dried (MgSO,~,
filtered and
concentrated to give 35 g of the title compound which was of sufficient purity
to use in the
next step: MS(EI) 248 (M+H+), 270 (M+Na+)
d.) 4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester
To a solution of the epoxide from Example lc (2.0 g, 8.1 mmol) in
methanol:water
(8:1 solution) was added NH4C1 (1.29 g, 24.3 mmol) and sodium azide (1.58 g,
24.30
mmol). The reaction was heated to 40°C until complete consumption of
the starting epoxide
was observed by TLC analysis. The majority of the solvent was removed in
vaccco and the
remaining solution was partitioned between ethyl acetate and pH 4 buffer. The
organic
. layer was washed with sat. NaHC03, water, brine dried (MgSO,~), filtered and
concentrated.
Column chromatography (20% ethyl acetate:hexanes) of the residue provided 1.3
g of the
title compound: MS(EI) 291 (M+H+) plus 0.14 g of trans-4-hydroxy-3-
azido=hexahydro-
1H-azepine
e.) 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester
To a solution of the azido alcohol of Example 1d (1.l g, 3.79 mmol) in
methanol
was added triethylamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.l mL,
11.37 mL).
The reaction was stirred until complete consumption of the starting material
was observed
by TLC analysis whereupon the reaction was concentrated in vacico. Column
chromatography of the residue (20% methanol:dichloromethane) provided 0.72 g
of the title
compound: MS(EI) 265 (M+H+).
f.) 4-tart-Butoxycarbonylamino-3-hydroxy-azepane-1-carboxylic acid benzyl
ester
To a stirring solution of 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl
ester
(Example 1e, 1.04 g, 3.92mmo1) in THF was added di-teat-butyldicarbonate
(0.864 g). After
stirring at room temperature for 30 minutes, the reaction mixture was diluted
with
diethylether and extracted with saturated NaHC03. The organic layer was dried
over
anhydrous Na2S0ø, filtered, concentrated, and purified by silica gel column to
give the title
compound as a yellow oil (0.963 g, 2.64 mmol, 67%). MS (ESI): 365.03 (M+H+).
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g.) 3-Hydroxy-azepan-4-yl-carbamic acid-tart-butyl ester
To a solution of 4-tart-butoxycarbonylamino-3-hydroxy-azepane-1-carboxylic
acid
benzyl ester (Example 1f, 0.9638, 2.64mmo1) in ethyl acetate (16 mL) was added
10%
palladium on carbon (500 mg). After stirring the solution at room temperature
for 48 hours,
the mixture was filtered through celite. The filterate was concentrated to
yield the title
compound ( 0.529 g, 2.29mmo1, 87%). MS(ESI): 231.92 (M+H+).
h.) 3-Hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl-carbamic acid-tart-butyl
ester
To a solution of 3-hydroxy-azepan-4-yl-carbamic acid-tart-butyl ester (Example
1g,
0.529, 2.29 mmol) in DCM (20 mL) was added triethylamine (232 mg) and pyridine-
2-
sulfonyl chloride (410 mg, 2.32 mmol). After stirring at room temperature for
30 minutes,
the mixture was washed with saturated NaHC03.The organic layer was dried,
filtered,
concentrated and purified on a silica gel column to give the title compound as
a solid
0.5838, 1.57mmol, 68%).
MS(ESI): 372.95 (M+H+).
i.) 4-Amino-1-(pyridine-2-sulfonyl)-azepan-3-of
To a stirring solution of 3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl-
carbamic
acid-tart-butyl ester (Example 1h, 0.583 g, 1.57mmo1) in ethyl acetate (0.5
mL) was added
HCl (4M in dioxane) (3.9 mL). After stirring the reaction mixture for 30
minutes at room
temperature, the mixture was concentrated to yield a white solid. The solid
was treated with
NaOH and then extracted with ethylacetate. The organic layer was dried,
filtered, and
concentrated to yield a yellow solid (0.347 g, 1.28 mmol, 81 %).
MS (ESI) 272.93 (M+H+).
j.) {(S)-2-Cyclohexyl-1-[3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-
ylcarbamoyl]-
ethyl }-carbamic acid-test-butyl ester
To a solution of 4-amino-1-(pyridine-2-sulfonyl)-azepan-3-of (Example 1i, 19
mg,
0.070 mmol) in CHzCl, was added N-Boc-cyclohexylalanine (28.5 mg, 0.106mmo1),
1-
hydroxybenzotriazole (16.1 mg, 0.12 mmol), and P-EDC (140 mg, 0.14 mmol ) in
CHZCh
. After shaking at room temperature overnight, the mixture was treated with PS-
Trisamine.
After shaking for another 2 hours, the mixture was filtered and concentrated
to yield the title
compound as a solid. MS (ESI) 525 (M+H~).
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k.) (S)-2-Amino-3-cyclohexyl-N-[3-hydroxy-I-(pyridine-2-sulfonyl)-azepan-4-yl]-
propionamide
To a stirring solution of {(S)-2-cyclohexyl-I-[3-hydroxy-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl}-carbamic acid-tert-butyl ester (Example 1j, 34
mg, 0.07
mmol) in CHzCl2 (0.50 mL) was added HCl (4M in dioxane) (0.165 mL). After
stirring at
room temperature for 30 minutes, the mixture was concentrated, giving a white
solid. The
white solid was azeotroped with toluene then treated with MP-carbonate (0.35
mmol) in
methanol. After four hours of shaking, the mixture was filtered and
concentrated to give the
title compound as a solid. MS(ESI) 425.03 (M+H+).
l.) Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-hydroxy-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide
To a solution of (S)-2-amino-3-cyclohexyl-N-[3-hydroxy-1-(pyridine-2-sulfonyl)-
azepan-4-yl]-propionamide (Example 1k, 27 mg, 0.070 mmol) in CHZCl2 was added
benzofuran-2-carboxylic acid (17.0 mg, 0.106 mmol), 1-hydroxybenzotriazole
(16.1: mg,
0.12 mmol), and P-EDC (140 mg, 0.14 mmol ) in CHZCIZ . After shaking at room
temperature overnight, the mixture was treated with PS-Trisamine. After
shaking for
another 2 hours, the mixture was filtered and concentrated to yield the title
compound as a
solid. MS (ESI) 568.79 (M+H)+.
m.) Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide
To a stirring solution of benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-I-[3-
hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide (Example
11, 37 mg,
.070. mmol) in CHzCl2 (0.5 mL) was added IDess-Martin reagent (45 mg, 0.105
mmol). After
stirring for 30 minutes, solutions of sodium thiosulfate (10% in water, 0.50
mL) and
saturated aqueous sodium bicarbonate (0.50 mL) were added simultaneously to
the reaction.
The mixture was then extracted with dichloromethane (2 times). The organic
layer was
dried, filtered, and concentrated . The residue was purified on a preparative
R,R-Whelk-O
column by HPLC to yield the two diastereomers of the title compound as solids
(first
eluting: 4.5mg, second eluting: 4.5 mg). MS (ESI) 566.87 (M+H+); 1H NMR
(400Hz,
CDC13): 8 8.67(m), 7.95(m), 7.63(m), 7.50(m), 7.02(m), 6.83(m), 5.25(m),
4.76(m), 4.14(t),
3.88(d), 2.74(m), 2.16(m), 1.88(m), 1.66-0.94(m).
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Examule 2
Preparation of 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid ~S)-2-
c~clohexyl-1-
f (R)-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4=ylcarbamoyll-ethyl ~-amide
0
I
F
F F / I / H II N.", N-IoSI
O ~ O
O
Following the procedure of Example 1 (1) -1 (m) except substituting 5-(3-
trifluoromethylphenyl)-furan-2-carboxylic acid for benzofuran-2-carboxylic
acid in step
1(1), the title compound was purified to yield two diastereomers as solids:
1H-NMR (400Hz, CDC13): 8 8.67(m), 7.93(m), 7.58(m), 7.24(m), 6.83(m), 5.18(m),
4.76(m), 4.27(t), 3.85(d), 2.78(m), 2.16(m), 1.85(m), 1.52-1.02(m).
Example 3
. . Preparation of 5~4-Chloro-phen~)-furan-2-carboxylic acid ~(S)-2-cyclohexyl-
1-f3-oxo-1-
~pyridine-2-sulfon 1~)-azepan-4-ylcarbamoyll-ethyl ~-amide
ci
/ I O N N °'' O
" H O N 0
O
Following the procedure of Example 1(1) - 1(m), except substituting 5-(4-
chloro-
phenyl)-furan-2-carboxylic acid for 2-benzofurancarboxylic acid in step 1(1),
the title
compound was purified to yield two diastereomers as solids: 1H-NMR (400Hz,
CDC13): 8
8.62(m), 7.93(m), 7.65(d), 7.47(m), 7.38(t), 7.20(m), 6.92(m), 6.72(d),
5.18(m), 4.77(m),
4.09(t), 3.84(d), 2.73(m), 2.33-1.02(m).
Example 4
Preparation of 5-(4-Chloro-phenyl)-furan-2-carbox lic acid (S)-2-cyclohex~l-1-
f3-oxo-1-
( 1-oxy-pyridine-2-sulfonyl) -azepan-4-ylcarbamoyll-ethyl ~-amide
ci
/ H O O+
I O N N.,,. N-IOSI
/ H
O O
Following the procedure of Example 1(h) - 1(m), except substituting 5-(4-
chloro-
phenyl)-furan-2-carboxylic acid for benzofuran-2-carboxylic acid in step 1(1)
and 2-
pyridine-N-oxide sulfonyl chloride for pyridine-2-sulfonyl chloride in step
1(h), the title
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compound was purified to yield two diastereomers as solids: IH-NMR (400Hz,
CDC13): 8
8.26(m), 8.12(t), 7.73-7.21(m), 6.76(t), 5.09(m), 4.82(m), 4.10(d), 3.88(dd),
3.54(s),
2.79(m), 2.19-1.02(m).
Example S
Preparation of 5-(3-Trifluoromethyl-~phen~)-furan-2-carboxylic acid (S)-2-
cyclohexyl-1-
f 3-oxo-1-( 1-ox~pyridine-2-sulfonyl)-azepan-4-ylcarbamoyll-ethyl )-amide
F
F O
F ~ / H N'II N-O
O
O
Following the procedure of Example 1(h) - 1(m), except 5-(3-trifluoromethyl- .
phenyl)-furan-2-carboxylic acid for 2-benzofurancarboxylic acid in step 1 (1)
and 2-pyridine-
N-oxide sulfonyl chloride for pyridine-2-sulfonyl chloride in step 1(h), the
title compound
.. was purified to yield two diastereomers as solids: 1H-NMR (400Hz, CDC13): 8
8.26(m),
8.11(t), 8.02-7.23(m), 6.86(t), 5.11(m), 4.82(m), 4.14(t), 3.90-3.85(d),
3.16(s), 3.88(m),
2.25-1.02(m).
Example 6
Preparation of 5,6-Dimethoxy-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-
f3-oxo-1-
( 1-oxy-pyridine-2-sulfo~l)-azepan-4-ylcarbamoyll-ethyl 1-amide
'° H ° ~.
O N N ~~,,
O ~ / H
O N
O
Following the procedure of Example 1(h) - 1(m), except 5,6-dimethoxy-
benzofuran-2-carboxylic acid in step 1(I) and 2-pyridine-N-oxide sulfonyl
chloride for
pyridine-2-sulfonyl chloride in step 1(h), the title compound was purified to
yield two
diastereomers as solids: IH-NMR (400Hz, CDCl3): ~ 8.25-7.37(m), 7.07(d),
5.02(m),
4.88(m), 4.12(d), 3.96(s), 3.94(s), 3.84(d), 3.73(s), 2.86(t), 2.20(m), 1.94-
I.OZ(m).
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Example 7
Preparation of Benzofuran-2-carboxylic acid ~(S)-3-methyl-1-f(2,2',4-
trideuterio)-3-oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoXll-butyl ? amide
O D
N .",
O H _II
~~H O D N S N
\ p
a.) 4-((S)-2-tart-Butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-
azepan-
1-carboxylic acid benzyl ester
To a solution of 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester of
Example 1e (720 mg, 2.72 mmol) in CH2Cl2 was added EDC (S21 mg), HOBt (368 mg)
and N-Boc-leucine (630 mg). The reaction was maintained at room temperature
until
complete consumption of the starting material was observed by TLC analysis.
The reaction
was diluted with ethyl acetate and washed with 1N HCl, sat. I~2C03, water,
brine, dried
(MgS04), filtered and concentrated. Column chromatography of the residue (3%
methanol:dichloromethane) gave 1.0 g of the title compound: MS(EI) 478 (M+H+).
b.) [(S)-1-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tart
butyl
ester
To a solution of the compound of Example 7a (1.0 g) and 10% PdIC (catalytic)
in
ethyl acetate:methanol (2:1 solution) was affixed a balloon of hydrogen. The
reaction was
stirred until complete consumption of the starting material was observed by
TLC analysis.
The reaction was filtered to remove the catalyst and the filtrate was
concentrated in vaccia to
provide 0.82 g of the title compound: MS(EI) 344 (M+H+).
c.) { (S)-1-[3-Hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-
butyl }-carbamic acid tart-butyl ester
Generation of 2-pyridinesulfonylchloride: A solution of 2-mercaptopyridine
(2.23 g
in 33 ml 9N HCl) was cooled to 0°C. Chlorine gas was bubbled into the
solution for 90 min,
taking care to maintain the temperature at 0°C. Ice cooled ethyl
acetate was added followed
by slow addition of ice cooled sat'd NaHC03 until the pH of the water layer
was
approximately 9. The organic layer were then washed with brine and dried over
MgSO4.
Evaporation of the ethyl acetate gave 3.5g of the crude 2-
pyridinesulfonylchloride as a light
yellow liquid.
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To a solution of [(S)-1-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-
carbamic acid tert butyl ester of Example 7b ( 12 g, 34.93 mmol) in
dichloromethane was
added triethylamine (5.8 mL, 41.92 mmol) followed by the dropwise addition of
2-
pyridinesulfonylchloride (7.45 g, 41.92 mmol). The reaction was stirred until
complete as
determined by TLC analysis. The mixture was then washed with sat. NaHC03,
water, brine,
dried (Na2SOA), filtered and concentrated. Column chromatography (75% ethyl
acetate:hexanes to 100% ethyl acetate) of the residue provided 15 g of the
title compound:
MS 484 (M+)
d.) (S)-2-Amino-4-methyl-pentanoic acid-[3-hydroxy-1-(pyridine-2-sulfonyl)-
azepan-
4-yl]-amide
To a solution of {(S)-1-[3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-
ylcarbamoyl]-
3-methyl-butyl}-carbamic acid tert-butyl ester of Example 7c (14.3 g) in
methanol was
added 4 M HCl in dioxane. The reaction was stirred at room temperature until
complete as
determined by TLC analysis whereupon it was concentrated to provide 14 g of
the title
compound: MS (EI) 385 (M+H+).
e.) Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-hydroxy-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-butyl } amide
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-1-(pyridine-2-
sulfonyl)-azepan-4-yl]-amide of Example 7d (0.15 g) in dichloromethane was
added TEA
(0.11 mL), HOBt (49 mg), EDC (69 mg) and benzofuran-2-carboxylic acid (58 mg).
The
reaction was stirred until complete. Workup and column chromatography (5%
methanol:ethyl acetate) provided the title compound: MS(EI) 529 (M+H+).
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f.) Benzofuran-2-carboxylic acid { (S)-3-methyl-1-[3-oxo-1-(pyridine-2-
sulfonyl)-
azepan-4-ylcarbamoyl]-butyl } amide
To a solution of the alcohol of Example 7e (0.11 g) in DMSO was added TEA
(0.17
mL) and pyridine sulfur trioxide complex (99 mg). The reaction was stirred at
room
temperature for approximately 2 hours whereupon it was partitioned between
ethyl acetate
and water. The organic layer was washed with brine, dried, filtered and
concentrated.
Column chromatography of the residue (10% CH30H:EtOAc) provided 75 mg of the
title
compound as a mixture of diastereomers: 'H NMR (CDC13): 8 1.0 ( m, 6H), 1.5-
2.1 ( m,
5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (dd, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m,
1H), 7.2-7.3
(m, 3H), 7.4 (m, 4H), 7.6 (m, 1H), 8.0 ( m, 2H), 8.7 (m, 1H); MS(EI): 527
(M+H+, 40%).
g.) of Benzofuran-2-carboxylic acid {(S)-3-methyl-1-[(2,2~,4-trideuterio)-3-
oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide
To a solution of benzofuran-2-carboxylic acid {(S)-3-methyl-1-[3-oxo-1-
(pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl } amide of Example 7f (0.03 g) in
DzO:CD30D
(0.4:4 mL) was added triethylamine (0.04 mL). The reaction was heated to
reflux for 2
hours whereupon it was concentrated and dried under vacuum. The residue was
the
redissolved in the same mixture and heated to reflux overnight. The reaction
was
concentrated and the residue purified by column chromatography (5%
methanol:dichloromethane) to provide the title compound (0.02 g): 'HNMR: 8 1.0
(m, 6H),
1.5-2.2 (m, 6H), 2.7 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H), 7.4-8.0 (m, 8H), 8.7
(m, 1H);
MS(EI): 529 (M+, 45%).
The diastereomeric mixture was separated by HPLC to provide the faster eluting
diastereoemer: MS(EI): 530 (M+H+,100%) and the slower eluting diastereomer:
MS(EI):
530 (M+H+,100%).
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Example 8
Furan-2-carboxylic acid { (S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0 o s~
-o
_ ~ 0
O~~~N'
II H
O
b
a. ((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester
Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5
g,
184 mmol) in CHZC12 (231 ml), then was cooled to 0 degrees C. Iodine (23.3 g,
91.8 mmol)
was added to the suspension. The reaction mixture turned yellow, then faintly
brown. After
5 minutes ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid benzyl ester (9.59 g,
45.9 mmol)
was added and the reaction mixture was warmed to RT then stirred for 3 h.
Then, H20 (7
ml) was added and the reaction mixture was partitioned between CHZC12 (300 ml)
and HZO
(600 ml). The aqueous layer was extracted again with CHZCl2 (200 ml). The
combined
organic layer was then washed with a solution of 1:9 aq. saturated Na~S203 :
H20 ( 140 ml),
then brine (400 ml). The combined organics were dried with MgS04, filtered,
concentrated
in vacuo, then filtered through a plug of silica gel washing with 15% EtOAc/
hexanes (1.5
liter). The solution was concentrated irz vacuo, then the solid was washed
with hexane and
the resultant white solid was used in the next reaction without further
purification (1 1g,
75%).
b. ((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester
Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in
distilled
THF (24 ml), then was cooled to -78 degrees C. A solution of allyl magnesium
chloride
(9.4 ml, 2M in THF, Aldrich) was added dropwise, then the solution was stirred
for 30
minutes. ((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7
mmol) in
distilled THF (3 ml) was added dropwise, then the reaction was warmed to -40
degrees C
and was stirred for 2.5 h. The reaction mixture was quenched with aq. sat.
NH,~Cl (4 ml) at
--40 degrees C, warmed to RT and the gray reaction mixture turned sky blue.
THF was
removed izz vaczao. Then, Et.,O was added and the reaction mixture was
filtered to remove
precipitated solids. The solids were washed with additional EtzO. The combined
organics
were extracted with 10% NH40H (3x), then brine. The combined organics were
dried with
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MgS04, filtered, concentrated in vacuo, then filtered through a plug of silica
gel washing
with 20% EtOAc/ hexanes (100 ml). The solution was concentrated ira vacLao,
then the
resultant colorless oil was used in the next reaction without further
purification (0.8 g, 73%).
c. Allyl-((R)-1-methyl-pent-4-enyl)-carbamic acid benzyl ester
((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester (790 mg, 3.39 mmol) was
dissolved in DMF (8 ml) and was cooled to 0 degrees C. Sodium hydride (60%
dispersion,
271 mg, 6.78 mmol) was added and the reaction was stirred for 15 minutes.
Allyl bromide
(1.23 g, 0.88 ml, 10.17 mmol) was added and the reaction mixture was stirred
for 3 h at 0
degrees C. HZO (10 ml) was added, then 2N HCl was added dropwise adjusting the
pH to 1.
The reaction mixture was extracted with Et20 (2 x 50 ml). The combined
organics were
washed with aq. 2N HCl, then aq. NaHC03, then brine. The combined organics
were dried
with MgS04, filtered, concentrated irz vacuo, then chromatographed on silica
gel (5%
EtOAc/ hexanes) to yield the title compound as a colorless oil (883 mg, 95%).
d. 2-Methyl-2,3,4,7-tetrahydro-azepine-f-carboxylic acid benzyl ester
Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester (0.872 g, 3.19 mmol)
was
dissolved in CHZC12 (10 ml) and a stream of argon gas was bubbled into the
reaction
mixture for 10 minutes. Then bis(tricyclohexylphosphine)benzylidine
ruthenium(IV)
dichloride (Strem Chemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was added
and the
reaction mixture was refluxed for 2 h. Additional
bis(tricyclohexylphosphine)benzylidine
ruthenium(IV) dichloride ( mg, 0.0108 mmol) was added and the reaction mixture
was
refluxed for an additional 1.5 hours. The reaction was cooled to RT under
argon overnight,
then was concentrated in vacuo by rotary evaporation, then was chromatographed
(silica gel,
5% EtOAc/ hexanes) to give the title compound (0.72 g, 92%): 1H NMR: 7.35-7.20
(m,
5H), 5.65 (1H, m), 5.13 (2H, AB), 4.45-4.05 (m, 2H), 3.56 (1H, d), 2.25-2.10
(m, 2H), 1.90-
1.60 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+
= 246.2.
e. (1S,4R,7R)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid
benzyl ester
m-Chloro-perbenzoic acid (1.10 g, 57-86% pure) was added to a solutiomof 2-
methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (0.72 g, 2.94
mmol) in
CH~CI2 at 0 degrees C. The reaction mixture was stirred for half an hour, then
was warmed
to RT. Additional m-chloro-perbenzoic acid (0.660 g, 57-86% pure) was added
and the
reaction was stirred 2 h. The reaction mixture was concentrated ira vacLro by
rotary
evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and the reaction
mixture was
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filtered. The filtrate was concentrated irz vacuo by rotary evaporation, then
was
chromatographed (silica gel, 20% EtOAc:hexanes) to give (1S,4R,7S)-4-methyl-8-
oxa-3-
aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.450 g, 75%) and the
title
compound (0.15 g, 25% yield): 1H NMR: 7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-
4.15 (m,
2H), 3.27 (1H, d), 3.12-2.95 (1H, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12
(3H, d); Liquid
Chromatgraphy/Electrospray mass spec: M+H+ = 262Ø
f. (2R,5S,6S)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl
ester
Sodium azide (0.139 g, 2.14 mmol) was added to a solution of (1S,4R,7R)-4-
methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.186
g, 0.71
mmol) and ammonium chloride (0.114 g, 2.14 mmol) in MeOH ( 1.5 ml) and H20
(0.15 ml),
then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by
rotary
evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10
ml). The
organic layer was then extracted with water, brine, dried with MgS04,
filtered, concentrated
in vaczco by rotary evaporation, and chromatographed (silica gel, 20%
EtOAc/hexanes) to
yield the title compound (0.192 g, 89%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-
3.67 (m,
2H), 3.10 (1H, d), 1.85-1.53 (m, 4H), 1.09 (3H, d); Liquid
Chromatgraphy/Electrospray
mass spec: M+H+ = 305.2.
g. (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl
ester
Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of (2R,5S,6S)-
5-
azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.193 g,
0.635 mmol) in
THF (10 ml) and H20 (0.04 ml), then was heated to 45 degrees C overnight. The
reaction
mixture was then diluted with toluene (100 ml x 2) and was azeotroped in vacuo
by rotary
evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et20 and
the
resulting salt was collected following filtration and was used in the next
reaction without
further purification (0.27 g, 90%).
h. (2R,5S, 6S)-5-((S)-2-tert-Butoxycarbonylamino-3-cyclohexyl-propanoylamino)-
2-
methyl-3-hydroxy-azepane-1-carboxylic acid benzyl ester
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.0 g, 5.36 mmol) was added to
a
solution of Boc-cyclohexylalanine (1.2 g, 4.45 mmol), 4-methylmorpoline (1.35
g, 1.50 ml,
13.4 mmol), hydroxybenztriazole (0.72 g, 5.36 mmol), and (2R,5S,6S)-5-Amino-6-
hydroxy-
2-methyl-azepane-1-carboxylic acid benzyl ester (1.4 g, 4.45 mmol) in DMF (20
ml). The
reaction was stirred overnight at RT, then was diluted with EtOAc (100 ml),
washed with
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HZO (50 ml), brine (50 ml), dried with magnesium sulfate, filtered,
concentrated in vacuo by
rotary evaporation, and chromatographed (silica gel, 50% EtOAc/hexanes) to
yield the title
compound (1.70 g, 72 %): Electrospray mass spec: M+H+ = 532.4
i. [(S)-2-Cyclohexyl-1-((3S, 4S,7R)-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-
ethyl]-
carbamic acid tert-butyl ester
(2R,5S, 6S)-5-((S)-2-tert-Butoxycarbonylamino-3-cyclohexyl-propanoylamino)-2-
methyl-6-hydroxy-aaepane-1-carboxylic acid benzyl ester (1.70 g, 3.20 mmol)
was
dissovled in ethanol(30 ml). Then 10% Pd/C (0.34 g, 0.32 mmol) was added and
the
reaction was stirred overnight under a balloon filled with hydrogen gas. The
reaction
mixture was filtered through Celite, concentrated in vacuo by rotary
evaporation and was
used in the next reaction without further purification (1.2 g): Electrospray
mass spec:
M+H+ = 398.4.
j. {(S)-2-Cyclohexyl-1-[(3S, 4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl }-carbamic acid tert-butyl ester
2-Pyridine sulfonyl chloride (0.53 g, 3.30 mmol) was added to a solution [(S)-
2-
Cyclohexyl-1-((3S, 4S,7R)-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-ethyl]-
carbamic
acid tert-butyl ester (1. 2 g, 3.00 mmol), triethylamine (1.02 g, 10.0 mmol) in
CHZCIz (20
ml) and was stirred at RT for 30 minutes. The reaction mixture was diluted
with EtOAc
( 100 ml), washed with H20, brine, dried with magnesium sulfate, filtered,
concentrated irz
vacuo by rotary evaporation, and chromatographed (silica gel, 1:1 hexane/EtOAc
) to yield
the title compound (1.3 g, 80%): Electrospray mass spec: M+H+= 539.2.
k. (S)-2-Amino-3-cyclohexyl-N-[(3S, 4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-
sulfonyl)-
azepan-4-yl]-propionamide
HCl in dioxane (4.0 M, 15.0 ml) was added to a stirred solution of {(S)-2-
Cyclohexyl-1-[(3S, 4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-
ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (1.30 g, 2.40 mmol) in MeOH
(5.0 ml).
The reaction mixture was stirred for 2h at RT, then was concentrated irz
vaczzo by rotary
evaporation and was used in the next reaction without further purification (
1.2 g).
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1. Furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-
1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.069 g, 0.36 mmol) was added
to a solution of furan-2-carboxylic acid (0.040 g, 0.36 mmol), (S)-2-Amino-3-
cyclohexyl-N-
[(3S, 4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-
propionamide (0.15
g, 0.30 mmol), diisopropylethylamine (0.15 g, 0.20 ml, 1.2 mmol),
hydroxybenztriazole
(0.049 g, 0.36 mmol) in DMF (2.0 ml) and was stirred at RT overnight. The
reaction
mixture was then warmed to RT and was stirred overnight. The reaction mixture
was
diluted with EtOAc (30 ml), washed with HBO, brine, dried with magnesium
sulfate,
filtered, concentrated in vacuo by rotary evaporation, and chromatographed
(silica gel, 2.5%
MeOH/ CHZC12 ) to yield the title compound (0.15 g, 95%): Electrospray mass
spec: M+H+
= 533.2.
m. Furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
Dess-Martin periodinane (0.15 g, 0.35 mmol) was added to a solution of Furan-2-
carboxylic
acid {(S)-2-cyclohexyl-1-[(3S,4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-
sulfonyl)-azepan-
4-ylcarbamoyl]-ethyl }-amide (0.15 g, 0.28 mmol) in CHZCIz (2.0 ml) and was
stirred at RT
for 1 h. The solution was washed with 10% aq. NaZS203, then aq. sat. NaHC03,
then brine.
Purification by column chromatography (3%MeOH/CHZCl2) gave the title compound
(0.12
g, 80%): 1H NMR: 8.73(d, 1 H), 7.62(m, 2 H), 7.53(m, 2 H), 7.13(s, 1 H),
6.94(d, 1 H),
6.77(d, 1 H), 6.51(m, 1 H), 5.18(m, 1 H), 4.77(d, 1 H), 4.63(m, 1 H), 4.25(m,
1 H), 3.86(d, 1
H), 2.10(m, 2 H), 1.87-0.93(m, 18 H); Electrospray mass spec: M+H+ = 531.2.
Examine 9
Preparation of Benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-
methyl-3-oxo-
1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
o ~s~
~ ~ ~.N
O- 'T( N
~~O
b
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Following the procedure of Example 8 (a-m), except substituting "benzofuran-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.74(d, 1
H),
7.96(m, 3 H), 7.55(m, 1 H), 7.42(m, 2 H), 7.28(m, 2 H), 6.77(d, 1 H), 6.51(m,
1 H), 5.I4(m,
1 H), 4.77(d, 1 H), 4.69(m, 1 H), 4.43(m, 1 H), 3.85(d, 1 H), 2.18(m, 2 H),
1.85-0.98(m, 18
H); Electrospray mass spec: M+H+ = 581.3.
Example 10
Preparation of Thiophene-3-carboxylic acid { (S)-2-cyclohexyl-1-[(4S,7R)-7-
methyl-3-oxo-
1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0 o s~
o N~ ~~
S / N~ ,~ ~~..,.n0
N
H
O
b
Following the procedure of Example 8 (a-m), except substituting "thiophene-3-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.74(d, 1
H),
8.00(m, 2 H), 7.66(d, 1 H), 7.46(m, 3 H), 7.28(d, 1 H), 6.90(d, 1 H), 5.14(m,
1 H), 4.43(m, 1
H), 3.82(d, 1 H), 2.16(m, 2 H), 1.90-0.96(m, 18 H); Electrospray mass spec:
M+H+ = 547.2.
Example 11
Preparation of 3-Methyl-furo[3,2-b]- pyridine-2-carboxylic acid { (S)-2-
cyclohexyl-1-
[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-
amide
i
-N
O
H O N ~O
O N N , ,..,..
I H
O
b
Following the procedure of Example 8 (a-m), except substituting "3-methyl-
furo[3,2-b]-
pyridine-2-carboxylic acid" for "furan-2-carboxylic acid" gave the title
compound: 1H
NMR: 8.75(d, 1 H), 7.98(m, 2 H), 7.55(m, 1 H), 7.40(m, 2 H), 7.33(m, 1 H),
6.75(d, 1 H),
6.50(m, 1 H), 5.09(m, 1 H), 4.79(d, 1 H), 4.68(m, 1 H), 4.47(m, 1 H), 3.87(d,
1 H), 2.55(s,3
H), 2.17(m, 1 H), 1.93-0.93(m, 19 H); Electrospray mass spec: M+H+ = 596.4.
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Example 12
Preparation of 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-
2-
cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-
amide
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester (as described in Marquis,
Robert W., et al
J. Med. Cl2ern. 44 2001) for "(2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-
carboxylic acid benzyl ester" and "5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.54(s,
1H), 8.00(m,
2 H), 7.55-7.05(m, 7 H), 5.16(m, 1 H), 4.81-3.52(m, 15 H), 3.14(br, 2 H),
2.71(t, 1 H), 2.21- '
0.95(m, 16 H); Electrospray mass spec: M+H+ = 712.4.
Example 13
Preparation of 4-Methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid {(S)-2-
cyclohexyl-1-[3-
oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0
O N = O
N O N ~H~N
S /
N
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "4-Methyl-2-pyridin-2-yl-
thiazole-5-
carboxylic acid" for "furan-2-carboxylic acid" gave the title compound: 1H
NMR: 8.66(d, 1
H), 8.55(d, 1 H), 7.98(m, 2 H), 7.65(m, 2 H), 7.50(m, 2 H), 7.44(m, 1 H),
7.31(t, 1 H),
7.06(d, 1 H), 5.17(m, 1 H), 4.79(m, 1 H), 4.65(d, 2 H), 4.00(d, 1 H), 3.83(d,
1 H), 2.75(t, 1
H), 2.59(s, 3H), 2.40(m, 2 H), 1.84-0.90(m, 15 H);; Electrospray mass spec:
M+H+ = 625.4.
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Example 14
Preparation of 5-Pyridin-2-yl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-
[3-oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,SS,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "5-Pyridin-2-yl-thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.68(d, 1
H),
8.54(d, 1 H), 7.93(m, 2 H), ~7.71(m, 2 H), 7.53(m, 2 H), 7.48(m, 1 H), 7.31(t,
1 H), 7.03(d, 1
H), 5.16(m, 1 H), 4.78(m, 1' H), 4.65(d, 2 H), 4.10(d, 1 H), 3.82(d, 1 H),
2.76(t, 1 H),
2.40(m, 2 H), 1.88-0.89(m, 15 H); Electrospray mass spec: M+H+ = 610.2.
Example 15
Preparation of Furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-
2-sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide
0 0 _
° \ II
\ . N~ N-OI N
\ 4 N
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,SS,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" gave the title compound: 1H
NMR: 8.70-
8.68(d, 1H), 7.98(m, 2H), 7.53(m, 2H), 7.16-7.12(m, 2H), 6.81-6.75(m, 1H),
6.53(s, 1H),
5.31-5.10(m~ 1H), 4.81-4.68(m, 2H), 4.13-4.09(d, 1H), 3.93-3.80(d, 1H), 2.77-
2.69(m, 1H),
2.26-0.90(m, 17H); Electrospray mass spec: M+H+ = 517.4.
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Example 16
Preparation of Thiophene-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl] -ethyl}-amide
0
o -~ o _
101
H
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "Thiophene-2-carboxylic
acid " for
"furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.70-8.69(d, 1H),
7:99-
7.82(m, 2H), 7.60-7.51(m, 3H), 7.12-7.10(m, 2H), 6.55-6.53(d, 1H), 5.14-
5.11(m, 1H),
4.78-4.67(m, 2H), 4.10-4.07(d, 1H), 3.89-3.84(d, 1H), 2.81-2.74(m, 1H), 2.26-
2.16(m, 2H),
1.86-0.90(m, 15H);; Electrospray mass spec: M+H+ = 533.2.
Example 1'7
Preparation of Thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl] -ethyl}-amide
s o
0 0 _
N N N ~ N
H
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" fox "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "Thiophene-3-carboxylic
acid " for
"furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.72-8.71(d, 1H),
8.15-
8.00(m, 3H); 7.56-7.30(m, 3H), 7.15-7.12(br, 1H), 6.70(br, 1H), 5.20(m, 1H),
4.90-4.70(m,
2H), 4.15(m, 1H), 3.90(d, 1H), 2.90-2.70(m, 1H), 2.28-0.97(m, 17H);
Electrospray mass
spec: M+H+ = 533.4.
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Example 18
Preparation of 5-Methyl-thiophene-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-
oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0 0 _
s H °
N~N N-O N
H
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,SS,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "5-Methyl-thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.69-
8.67(d, 1H),
7.97-7.90(m, 2H), 7.52-7.28(m, 3H), 6.74-6.49(m, 2H), 5.18-5.08(m, 1H); 4.77-
4.63(m,
2H), 4.28-4.26(d, 1H), 3.87-3.80(d, 1H), 2.78-2.66(m, 1H), 2.51(s, 3H), 2.25-
0.88(m, 17H);;
Electrospray mass spec: M+H+ = 547.2.
Example 19
Preparation of 3-Methyl-thiophene-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-
oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0 0 _
~ _1I
N _ N II
O
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "3-Methyl-thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.69-
8.68(d, 1H),
7.97-7.89(m, 2H), 7.53-7.50(m, 1H), 7.32-7.17(m, 2H), 6.91-6.84(d, 1H), 6.34-
6.32(d, 1H),
5.16-5.11(m, 1H), 4.79-4.70(m, 2H), 4.31-4.10(d, 1H), 3.85-3.81(d, 1H), 2.76-
2.69(m, 1H),
2.55(s, 3H), 2.26-0.89(m, 17H) ; Electrospray mass spec: M+H+ = 547.2.
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Example 20
Preparation of 3-Ethoxy-thiophene-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-
oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "3-Ethoxy-thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.69-
8.67(d; 1H),
7.96-7.90(m, 2H), 7.60-7.28(m, 4H), 6.92-6.83(d, 1H), 5.15-5.10(m, 1H), 4.74-
4.56(m, 2H),
4.30-4.08(m, 3H), 3.84-3.77(d, 1H), 2.72-2.66(m, 1H), 2.25-0.89(m, 20H);
Electrospray
mass spec: M+H+ = 577.2.
Example 21
Preparation of 4-Bromo-N-{ (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-
azepan-4-
ylcarbamoyl]-ethyl}-benzamide
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" fox "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "4-bromo-benzoic acid" for
"furan-2-
carboxylic acid" gave the title compound: 1H NMR: 8.71(d, 1 H), 8.00(m, 2 H),
7.69(d, 2
H), 7.52(m, 3 H), 7.26(d, 1 H), 6.91 (d, 1 H), 5.22(m, 1 H), 4.77(m, 2 H),
4.14(d, 1 H),
3.85(d, 1 H), 2.71(t, 1 H), 2.31(m, 2 H), 1.86-0.91(m, 15 H); Electrospray
mass spec: M+H+
= 605.2.
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Example 22
Preparation of Cyclobutanecarboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0
_II~
N N ~I N
N
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and " Cyclobutanecarboxylic
acid" for
"furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.68 (d, 1H), 7.97-
7.90(m,
2H), 7.71-7.48(m, 1H), 7.19-7.12(d, 1H), 6.81-6.79(d, 1H), 5.08(m, 1H), 4.72-
4.48(m, 2H),
4.05-4.01(d, 1H), 3.86-3.79(d, 1H), 3.11-3.05(m,lH), 2.80-2.70(m, 1H), 2.32-
0.80(m, 23H);
Electrospray mass spec: M+H+ = 505.4.
Example 23
Preparation of Cyclopentanecarboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide
0
_I I
N N II
N ~ O N
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and " Cyclopentanecarboxylic
acid" for
"furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.70-8.69(d, 1H),
7.99-
7.92(m, 2H), 7.55-7.51(m, 1H), 7.09-7.08(d, 1H), 5.89-5.87(d, 1H), 5.10(m,
1H), 4.71-
4.70(d, 1H), 4.65(m, 1H), 4.07-4.03(d, 1H), 3.89-3.84(d, 1H), 2.82-2.58(m,
2H), 2.15(m,
2H), 1.90-0.89(m, 23H); Electrospray mass spec: M+H+ = 519.4.
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Example 24
Preparation of (S)-Tetrahydro-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-
oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0 0 _
,,,,1 _
N ~ II \ /
N p N
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "(S)-Tetrahydro-furan-2-
carboxylic
acid " for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.67(d,
1H),
7.96(m, 2H), 7.53(m, 1H), 6.96(m, 2H), 5.13(m, 1H), 4.75(m, 1H), 4.41(m, 2H),
4.07-
3.91(m, 4H), 2.68(m, 1H), 2.35-0.92 (m, 21H); Electrospray mass spec: M+H+=
521.4.
Example 25
Preparation of (R)-Tetrahydro-furan-2-carboxylic acid { (S)-2-cyclohexyl-1-[3-
oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
o _
\ _1I
0
N N Io
N
O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "(R)-Tetrahydro-furan-2-
carboxylic
acid " for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.71(d,
1H),
7.96(m, 2H), 7.53(m, 1H), 7.12(m, 2H), 5.10(m, 1H), 4.72(m, 1H), 4.46(m, 2H),
4.11-
3.95(m, 4H), 2.74(m, 1H), 2.35-0.92 (m, 21H); Electrospray mass spec: M+H+ =
521.4.
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Examule 26
Preparation of Furan-3-carboxylic acid { (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-
2-sulfonyl)-
azepan-4-ylcarbamoyl]-ethyl }-amide
0 0
\ _II~
N N ~I N
N
O O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "furan-3-carboxylic acid"
for "furan-2-
carboxylic acid" gave the title compound: 1H NMR: 8.70-8.68(d, 1H), 7.99-
7.92(m, 3H),
7.54-7.44(m, 2H), 7.19-7.18(d, 1H), 6.59-6.57(m, 2H), 5.14-5.09(m, 1H), 4.79-
4.63(m, 2H),
4.07-4.04(d, 1H), 3.89-3.84(d, 1H), 2.83-2.76(m, 1H), 2.23-0.91(m, 17H);
Electrospray
mass spec: M+H+ = 517.4.
Example 27
Preparation of 5-Pyridin-2-yl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-
[3-oxo-1-(1-
oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "5-Pyridin-2-yl-thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" and "oxy-pyridine-2-sulfonyl chloride" for
"2-pyridine
sulfonyl chloride" gave the title compound: 1H NMR: 8.55(d, 1 H), 8.05(d, 1
H), 8.03(d, 1
H), 7.73-7.09(m, 9 H), 5.06(m, 1 H), 4.80(m, 2 H), 4.11(d, 1 H), 3.84(d, 1 H),
2.90(t, I H),
2.22(m, 1 H), 2.10-0.88(m, 15 H); Electrospray mass spec: M+H+ = 626.4.
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Example 28
Preparation of 4-Methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid { (S)-2-
cyclohexyl-1-[3-
oxo-1-( 1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "4-Methyl-2-pyridin-2-yl-
thiazole-5-
carboxylic acid" for "furan-2-carboxylic acid" and "oxy-pyridine-2-sulfonyl
chloride" for
"2-pyridine sulfonyl chloride" gave the title compound: 1H NMR: 8.53(d, 1 H),
8.08(d, I
H), 8.03(d, 1 H), 7.77-7.05(m, 9 H), 5.03(m, 1 H), 4.75(m, 2 H), 4.13(d, 1 H),
3.80(d, 1 H),
2.88(t, 1 H), 2.67(s, 3 H), 2.22 (m, 1 H), 2.10-0.88(m, 15 H); Electrospray
mass spec: M+H+
= 641.4.
Example 29
Preparation of 5-(2-Morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid { (S)-
2-
cyclohexyl-I-[3-oxo-1-( 1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl
}-amide
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-I-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-I-carboxylic acid benzyl ester" and "5-(2-Morpholin-4-yl-
ethoxy)-
benzofuran-2-carboxylic acid" for "furan-2-carboxylic acid" and "oxy-pyridine-
2-sulfonyl
chloride" for "2-pyridine sulfonyl chloride" gave the title compound: 1H NMR:
8.23(br, 1
H), 8.06(d, 2 H), 7.48-7.00(m, 8 H), 5.03(m, 1 H), 4.80(m, 2 H), 4.59(m, 2 H),
4.27(m, 2 H),
4.09-3.33(m, 9 H), 3.29(m, 2 H), 2.80(m, 2 H), 2.27-0.88(m, 14 H);
Electrospray mass spec:
M+H+ = 712.4.
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Example 30
Preparation of Furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl } -amide
0 0 _
\ _1I
0
N to N.
N
O p-
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and " Furan-2-carboxylic acid"
for "furan-2-
carboxylic acid" and "oxy-pyridine-2-sulfonyl chloride" for "2-pyridine
sulfonyl chloride"
gave the title compound: 1H NMR: 8.24-8.23(d, 1H), 8.14-8.11(m, 1H), 7.50-
7.39(m, 3H),
7.14(d, 1H), 7.01-6.99(d, 1H), 6.78-6.76(d, 1H), 6.52-6.51(d, 1H), 5.04-
4.91(m, 2H), 4.72-
4.66(d, IH), 4.14-4.10(d, 1H),~.3.93-3.88(d, 1H), 2.85-2.79(m, 1H), 2.25-
0.94(m, 17H);
Electrospray mass spec: M+H+ = 533.4.
Example 31
Preparation of Furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0
° ~ _1I
O ~ N N N IOI N.
O O_
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "Furan-3-carboxylic acid"
for "furan-2-
carboxylic acid" and "oxy-pyridine-2-sulfonyl chloride" for "2-pyridine
sulfonyl chloride"
gave the title compound: 1H NMR: 8.25-8.23(d, 1H), 8.14-8.11(m, 1H), 7.97(s,
1H), 7.51-
7.39(m, 3H), 7.04-7.03(d, 1H), 6.67(s, 1H), 6.50-6.48(d, 1H), 5.06-4.88 (m,
2H), 4.74-
4.68(m, 1H), 4.13-4.09(d, 1H), 3.93-3.88(d, 1H), 2.86-2.79(m, 1H), 2.23-
0.93(m, 17H);
Electrospray mass spec: M+H+ = 533.4.
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Example 32
Preparation of Thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0
° ~ _1I
S ~ N N N 0I N.
O O_
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "Thiophene-3-carboxylic
acid " for
"furan-2-carboxylic acid" and "oxy-pyridine-2-sulfonyl chloride" for "2-
pyridine sulfonyl
chloride" gave the title compound:.1H NMR: 8.24-8.22(d, 1H), 8.12-8.09(m, 1H),
7.95(s,
1H), 7.49-7.19(m, 5H), 6.59-6.57(d, 1H), 5.05-5.01 (m, 1H), 4.83-4.74(m, 2H),
4.10-4.06(d,
1H), 3.92-3.87(d, 1H), 2.91-2.85(m, 1H), 2.26-0.92(m, 17H); Electrospray mass
spec:
M+H+ = 549.4.
Example 33
Preparation of Thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-
pyridine-
2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0
° ~ _1I
s
-
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,5S,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "Thiophene-2-carboxylic
acid " for
"furan-2-carboxylic acid" and "oxy-pyridine-2-sulfonyl chloride" for "2-
pyridine sulfonyl
chloride" gave the title compound: 1H NMR: 8.24-8.23(d, 1H), 8.13-8.10(m, 1H),
7.58-
7.38(m, 4H), 7.11-7.07(m, 2H), 6.79-6.77(d, 1H), 5.04-4.69(m, 3H), 4.12-
4.08(d, 1H), 3.92-
3.87(d, 1H), 2.85-2.79(m, 1H), 2.21-0.90(m, 17H); Electrospray mass spec: M+H+
= 549.4.
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Example 34
Preparation of 5-Methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-
1-(1-oxy-
pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide
0 0 _
0
N N II ~. ~
. N O N
O -
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,SS,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "5-Methyl-thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" and "oxy-pyridine-2-sulfonyl chloride" fox
"2-pyridine
sulfonyl chloride" gave the title compound: 1H NMR: 8.23-8.22(d, 1H), 8.11-
8.08(d, 1H),
7.49-7.24(m, 4H), 6.75-6.74(s, 1H), 6.62-6.60(d, 1H), 5.03-4.71 (m, 3H), 4.09-
4.05(d, 1H),
3.90-3.85(d, IH), 2.88-2.83(m, 1H), 2.67(s, 3H), 2.35-0.88(m, 17H);
Electrospray mass
spec: M+H+ = 563.2.
Example 35
Preparation of 3-Methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-
1-(1-oxy-
pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0 0 _
N~ N II ~. /
N O N
O O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,SS,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "3-Methyl-thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" and "oxy-pyridine-2-sulfonyl chloride" for
"2-pyridine
sulfonyl chloride" gave the title compound: IH NMR: 8.23-8.22(d, 1H), 8.11-
8.09(d, 1H),
7.49-7.17(m, 4H), 6.93-6.91(s, 1H), 6.27(m, 1H), 5.06-4.70(m, 3H), 4.14-
4.11(d, 1H), 3.91-
3.86(d, 1H), 2.87-2.81(m, 1H), 2.56(x, 3H), 2.28-0.93 (m, 17H) ; Electrospray
mass spec:
M+H+ = 563.2.
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Examule 36
Preparation of 3-Ethoxy-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-
1-(1-oxy-
pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0 0 _
0
N~ N II ~. /
N O N
p p O
Following the procedure of Example 8 (i-m), except substituting "(3S,4S)-4-
Amino-3-
hydroxy-azepane-1-carboxylic acid benzyl ester" for "(2R,SS,6S)-5-Amino-6-
hydroxy-2-
methyl-azepane-1-carboxylic acid benzyl ester" and "3-Ethoxy-thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" and "oxy-pyridine-2-sulfonyl chloride" for
"2-pyridine
sulfonyl chloride" gave the title compound: 1H NMR: 8.24-8.22(d, 1H), 8.11-
8.09(d, 1H),
7.60-7.31(m, SH), 6.88-6.87 (d, 1H), 5.06-4.65(m, 3H), 4.37-4.27(m, 1H), 4.12-
4.08(d, 1H),
3.88-3.83(d, 1H), 2.84-2.77(rii, 1H), 2.28-0.92(m, 21H); Electrospray mass
spec: M+H+'=
593.2.
Example 37
Preparation of Selenophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[(R)-7-methyl-
3-oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
0
_II~
Se N
N N of
0
Following the procedure of Example 8 (i-m), except substituting "selenophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.64(d, 1
H),
8.14(d, 1 H), 7.84(m, 2 H), 7.64(d, 1 H), 7.42(m, 1 H), 7.22(m, 1 H), 6.88(d,
1 H), 6.60(d, 1
H), 5.01(m, 1 H), 4.71(d, 1 H), 4.50(m, 1 H), 4.34(m, 1 H), 3.77(d, 1 H),
2.05(m, 2 H), 1.78-
0.82(m, 18 H); Electrospray mass spec: M+H+ = 593.2.
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Example 38
Preparation of Furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-
oxo-1-
propyl-azepan-4-ylcarbamoyl)-ethyl]-amide
0
~N
..,"
N
O
b
a. [(S)-2-Cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-
ylcarbamoyl)-
ethyl]-carbamic acid tert-butyl ester
[(S)-2-Cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-ylcarbamoyl)-
ethyl]-carbamic acid-tent-butyl ester (Example la-I, 1.5 g, 3.78 mmol) was
dissolved in
CHZCIz(30.mL), then propionaldehyde (0.41 mL, 5.67 mmol) was added. Then,
sodium
borohydride (1.6 g, 7.56 mmol) was added and the reaction mixture was stirred
at RT for 1
h. The reaction mixture was concentrated in vaczzo by rotary evaporation, then
the filtrate
(silica gel, 1-4% MeOH/ CH2C12) to yield the title compound as a white solid
(84%, 1.4 g):
Electrospray mass spec: M+H+ = 440.4.
b. (S)-2-Amino-3-cyclohexyl-N-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-
yl)-
propionamide
HCl in dioxane (4.0 M, 15 ml) was added to a stirred solution of [(S)-2-
Cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-
ethyl]-
carbamic acid tert-butyl ester (1.4 g, 3.0 mmol) in MeOH (5 ml). The reaction
mixture was
stirred for 2h at RT, then was concentrated izz vaczzo by rotary evaporation
and was used in
the next reaction without further purification (1.4 g).
c. Furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-
1-propyl-
azepan-4-ylcarbamoyl)-ethyl]-amide
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.10 g, 0.53 mmol) was added to
a solution of furan-2-carboxylic acid (0.059 g, 0.53 mmol), (S)-2-Amino-3-
cyclohexyl-N-
((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-yl)-propionamide (0.15 g,
0.36 mmol),
4-methylmorpholine (0.14 g, 0.16 ml, 1.44 mmol), hydroxybenztriazole (0.071 g,
0.53
mmol) in DMF (2.0 ml) and was stirred at RT overnight. The reaction mixture
was then
warmed to RT and was stirred overnight. The reaction mixture was diluted with
EtOAc (30
ml), washed with H20, brine, dried with magnesium sulfate, filtered,
concentrated in vacL~o
by rotary evaporation, and chromatographed (silica gel, 2.5% MeOH/ CH~Ch ) to
yield the
title compound (0.12 g, 76%): Electrospray mass spec: M+H+ = 434.2.
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d. Furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S,7R)-7-methyl-3-oxo-1-
propyl-azepan-
4-ylcarbamoyl)-ethyl]-amide
Sulfur trioxide-pyridine complex (0Ø35 g, 2.2 mmol) was added to a solution
of
Furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-
propyl-
azepan-4-ylcarbamoyl)-ethyl]-amide (0.19 g, 0.44 mmol) in DMSO (4.0 ml) and
triethylamine (0.61 ml, 4.4 mmol) was stirred at RT for 1 h. The reaction
mixture was
diluted with water, then was extracted with EtOAc. Then, the organic layer was
was
extracted with brine. The combined organics were dried with magnesium sulfate,
filtered,
concentrated in vacuo, and purified by column chromatography (3% methanol/
methylene
chloride) gave the title compound (0.15 mg, 79%): 1H NMR: 7.44(s, 1 H),
7.11(d, 1 H),
7.04(d, 1 H), 6.92(d, 1 H), 6.49(d, 1 H), 5.29(m, 1 H), 4.69(m, 1 H), 3.40(d,
1 H), 3.08(m, 2
H), 2.51 (m, 2 H), 1.88-0.81 (m, 29 H); Electrospray mass spec: M+H+ = 432.2.
Examule 39
Preparation of Thiophene-3-carboxylic acid [(S)-2-cyclohexyl-1-((4S,7R)-7-
methyl-3-oxo-
1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide
0
0
O
Following the procedure of Example 38 (a-c), except substituting "thiophene-3-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 7.62(d, 1
H), 7.40(d,
1 H), 7.04(d, 1 H), 6.80(d, 1 H), 6.45(d, 1 H), 5.27(m, 1 H), 4.66(m, 1 H),
3.44(d, 1 H),
3.09(m, 2 H), 2.54(m, 2 H), 1.87-0.87(m, 29 H); Electrospray mass spec: M+H+ =
448.4.
Examule 40.
Preparation of Benzofuran-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S,7R)-7-
methyl-3-oxo-
1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide
0
\ / ~ ' ~~II , ...".
O NY '
N
O
b
Following the procedure of Example 38 (a-c), except substituting "benzofuran-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 7.98(d, 1
H),
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7.45(m, 2 H), 7.27(s, 2 H), 6.90(d, 1 H), 6.50(d, 1 H), 5.28(m, 1 H), 4.67(m,
1 H), 3.40(d, 1
H), 3.06(m, 2 H), 2.56(m, 2 H), 1.88-0.80(m, 29 H); Electrospray mass spec:
M+H+ = 482.4.
Examule 41
Preparation of 2,2,4-Trideutero-Furan-2-carboxylic acid { (S)-2-cyclohexyl-1-
[(4S,7R)-7-
methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl }-amide
i
D O
O D \S
I H II \N/ \O
O~N~H",1D
b
a. Furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-
(pyridine-2-
sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide is dissolved in d4-methanol
(CD30D) and
DSO (10:1), then triethyl amine is added and the reaction mixture is stirred
for 3 days.
Azeotroping with toluene by concentrating in vacuo provides the title
compound.
Example 42
Preparation of Thiophene-3-carboxylic acid { (S)-3,3-dimethyl-1-[(4S,7R)-7-
methyl-3-oxo-
1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide
i
o~ ~ I
O O NiS~ N
N O
N
O
Following the procedure of Example 8 (a-m), except substituting "N-Boc-tert-
butylalanine" for "Boc-L-cyclohexylalanine" and "thiophene-3-carboxylic acid"
for "furan-
2-carboxylic acid" gave the title compound: 1H NMR: 8.72(m, 1 H), 7.96(m, 2
H), 7.48(m,
2 H), 7.00(m, 3 H), 6.60(m, 2 H), 5.18(m, 1 H), 4.67(m, 2 H ), 4.42(m, 1 H),
3.88(m, 1H),
2.87(m, 2 H), 2.22(m, 2 H), 1.95(m, 1 H), 1.70(m, 2 H), 1.01 (m, 12 H);
Electrospray mass
spec: M+H+ = 521.4.
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Examule 43
Preparation of Furan-2-carboxylic acid {(S)-3,3-dimethyl-1-[(4S,7R)-7-methyl-3-
oxo-1-
(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide
i
0 o s wN
O~N
N
O
Following the procedure of Example 8 (a-m), except substituting "N-Boc-tert-
butylalanine" for "Boc-L-cyclohexylalanine" gave the title compound: 1H NMR:
8.73(d, 1
H), 7.95(m, 3 H), 7.54(m, 1 H), 7.41(m, 1H), 7.32(m, 1H), 7.26(s, 1 H),
7.01(d, 1 H),
6.56(d, 1 H), 5.08(m, 1 H), 4.73(m, 2 H), 4.43(m, 1 H), 3.88(d, 1 H), 2.18(m,
2 H), 1.70(m,
3 H), I.04(s, 9 H), 0.98(d, 3 H); Electrospray mass spec: M+H+ = 505.4.
Example 44
Preparation of Thieno[3,2-b] thiophene-2-carboxylic acid {(S)-3,3-dimethyl-1-
[(4S,7R)-7-
methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl }-amide
i
s o o.
N~S\O N
S N N ..~~.
O
I5 Following the procedure of Example 8 (a-m), except substituting "N-Boc-tert-
butylalanine" for "Boc-L-cyclohexylalanine" and " thieno[3,2-b] thiophene-2-
carboxylic
acid" for "furan-2-carboxylic acid" gave the title compound: 1H NMR: 8.73(d, 1
H),
7.92(m, 3 H), 7.52(m, 2 H), 7.27(m, 1H), 7.09(br, 1 H), 6.80(br, 1 H), 5.10(m,
1 H), 4.77(m,
2 H), 4.40(m, 1 H), 3.87(d, 1 H), 1.90(m, 5 H), 1.05(s, 9 H), 0.95(d, 3 H);
Electrospray mass
spec: M+H+ = 577.2.
The above specification and Examples fully disclose how to make and use the
compounds of the present invention. However, the present invention is not
limited to the
particular embodiments described hereinabove, but includes all modifications
thereof within
the scope of the following claims. The various references to journals, patents
and other
publications which are cited herein comprise the state of the art and are
incorporated herein
by reference as though fully set forth.
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