Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PROTEASE INHIBITORS
FIELD OF THE INVENTION
This invention relates in general to diacyl hydrazine protease inhibitors,
particularly such inhibitors of cysteine and serine proteases, more
particularly compounds
which inhibit cysteine proteases, even more particularly compounds which
inhibit cysteine
proteases of the papain superfamily, yet more particularly compounds which
inhibit
cysteine proteases of the cathepsin family, most particularly compounds which
inhibit
cathepsin K. Such compounds are particularly useful for treating diseases in
which
cysteine proteases are implicated, especially diseases of excessive bone or
cartilage loss,
e.g., osteoporosis, periodontitis, and arthritis.
BACKGROUND OF THE INVENTION
Cathepsins are a family of enzymes which are part of the papain superfamily of
cysteine proteases. Cathepsins B, H, L, N and S have been described in the
literature.
Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were
disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin
K has been
recently expressed, purified, and characterized. Bossard, M. J., et al., (
1996) J. Biol. Chem.
271, 12517-12524; Drake, F.H., et aL, (1996) J. Biol. Chem. 271, 12511-12516;
Bromme,
D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the
literature. The designation cathepsin K is considered to be the more
appropriate one.
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 A1, and
references cited therein. Two bacterial cysteine proteases from P. b
ngivallis, called
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gingipains, have been implicated in the pathogenesis of gingivitis. Potempa,
J., et al.
( 1994) Perspectives in Drug Discovery and Design, 2, 445-458.
Cathepsin K is believed to play a causative role in diseases of excessive bone
or
cartilage loss. Bone is composed of a protein matrix in which spindle- or
plate-shaped
crystals of hydroxyapatite are incorporated. Type I collagen represents the
major structural
protein of bone comprising approximately 90% of the protein matrix. The
remaining 10%
of matrix is composed of a number of non-collagenous proteins, including
osteocalcin,
proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone
sialoprotein. Skeletal bone undergoes remodelling at discrete foci throughout
life. These
foci, or remodelling units, undergo a cycle consisting of a bone resorption
phase followed
by a phase of bone replacement.
Bone resorption is carried out by osteoclasts. which are multinuclear cells of
hematopoietic lineage. The osteoclasts adhere to the bone surface and form a
tight sealing
zone, followed by extensive membrane ruffling on their apical (i.e.,
resorbing) surface.
I S This creates an enclosed extracellular compartment on the bone surface
that is acidified by
proton pumps in the ruffled membrane, and into which the osteoclast secretes
proteolytic
enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at
the bone
surface, while the proteolytic enzymes digest the protein matrix. In this way,
a resorption
lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts
lay down a new
protein matrix that is subsequently mineralized. In several disease states,
such as
osteoporosis and Paget's disease, the normal balance between bone resorption
and
formation is disrupted, and there is a net loss of bone at each cycle.
Ultimately, this leads
to weakening of the bone and may result in increased fracture risk with
minimal trauma.
Several published studies have demonstrated that inhibitors of cysteine
proteases
are effective at inhibiting osteoclast-mediated bone resorption, and indicate
an essential
role for a cysteine proteases in bone resorption. For example, Delaisse, et
al., Biochem. J.,
1980, 192, 365, disclose a series of protease inhibitors in a mouse bone organ
culture
system and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-
Phe-Ala-CHN2)
prevent bone resorption, while serine protease inhibitors were ineffective.
Delaisse, et al.,
Biochern. Biophys. Res. Commun., 1984, 125, 441, disclose that E-64 and
leupeptin are also
effective at preventing bone resorption in vivo, as measured by acute changes
in serum
calcium in rats on calcium deficient diets. Lerner, et al., J. Bone Min. Res.,
1992, 7, 433,
disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits
PTH stimulated
bone resorption in mouse calvariae. Other studies, such as by Delaisse, et
al., Bone, 1987,
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8, 305, Hill, et al., J. Cell. Biochem., 1994, 56, 118, and Evens, et al., J.
Cell. Physiol.,
1992, ISO, 221, also report a correlation between inhibition of cysteine
protease activity
and bone resorption. Tezuka, ei al., J. Biol. Chem., 1994, 269, I 106, Inaoka,
et al.,
Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al., FEBS Lett.,
1995, 357, 129
disclose that under normal conditions cathepsin K, a cysteine protease, is
abundantly
expressed in osteoclasts and may be the major cysteine protease present in
these cells.
The abundant selective expression of cathepsin K in osteoclasts strongly
suggests
that this enzyme is essential for bone resorption. Thus, selective inhibition
of cathepsin K
may provide an effective treatment for diseases of excessive bone loss,
including, but not
limited to, osteoporosis, gingival diseases such as gingivitis and
periodontitis, Paget's
disease, hypercalcemia of malignancy, and metabolic bone disease. Cathepsin K
levels
have also been demonstrated to be elevated in chondroclasts of osteoarthritic
synovium.
Thus, selective inhibition of cathepsin K may also be useful for treating
diseases of
excessive cartilage or matrix degradation, including, but not limited to,
osteoarthritis and
rheumatoid arthritis. Metastatic neoplastic cells also typically express high
levels of
proteolytic enzymes that degrade the surrounding matrix. Thus, selective
inhibition of
cathepsin K may also be useful for treating certain neoplastic diseases.
Several cysteine protease inhibitors are known. Palmer, ( 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,
nitriles, 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
ineversible
inhibitors of cysteine protease. Published International Patent Application
No. WO
94/04172, and European Patent Application Nos. EP 0 525 420 AI, EP 0 603 873
A1, and
EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit
the
cysteine proteases cathepsins B, H and L. International Patent Application No.
PCT/US94/08868 and European Patent Application No. EP 0 623 592 A1 describe
alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL-
lb
convertase. Alkoxymethyl and mercaptomethyl ketones have also been described
as
inhibitors of the serine protease kininogenase (International Patent
Application No.
PCT/GB91/01479).
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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.,
Biochem. J., 1968,107, 103, Garker et al., Biochem. J., 1974, 139, 555, Gray
et al.,
Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. Chem., 1984, 259, 4279,
Powers et al., J.
Biol. Chem., 1984, 259, 4288, and are known to inhibit serine proteases. In
addition,
Magrath et al., J. Med. Chem., 1992, 35, 4279, Baggio et al., Biochemistry,
1996, 35, 3551
and Xing et al., J. Med. Chem. 1998, 41, 1344 discloses certain azapeptide
esters as
cysteine protease inhibitors.
Diacyl carbohydrazides have recently been disclosed as inhibitors of cathepsin
K
by Thompson et al., Proc. Natl. Acad. Sci., U.S.A., 1997, 94, 14249 and in
International
Patent Application No. WO 97/16433.
Antipain and leupeptin are described as reversible inhibitors of cysteine
protease in
McConnell et al., J. Med. Chem., 33, 86; and also have been disclosed as
inhibitors of
serine protease in Umezawa et al., 45 Meth. Enrymol. 678. E64 and its
synthetic analogs
are also well-known cysteine protease inhibitors (Barren, Biochem. J., 201,
189, and
Grinde, Biochem. Biophys. Acta, , 701, 328).
Thus, a structurally diverse variety of cysteine protease inhibitors have been
identified. However, these known inhibitors are not considered suitable for
use as
therapeutic agents in animals, especially humans, because they suffer from
various
shortcomings. These shortcomings include lack of selectivity, cytotoxicity,
poor solubility,
and overly rapid plasma clearance. A need therefore exists for methods of
treating diseases
caused by pathological levels of cysteine proteases, including cathepsins,
especially
cathepsin K, and for novel inhibitor compounds useful in such methods.
We have now discovered a novel class of diacyl carbohydrazide compounds which
are protease inhibitors, most particularly of cathepsin K.
SUMMARY OF THE INVENTION
An object of the present invention is to provide diacyl hydrazine protease
inhibitors, particularly such inhibitors of cysteine and serine proteases,
more particularly
such compounds which inhibit cysteine proteases, even more particularly such
compounds
which inhibit cysteine proteases of the papain superfamily, yet more
particularly such
compounds which inhibit cysteine proteases of the cathepsin family, most
particularly such
compounds which inhibit cathepsin K, and which are useful for treating
diseases which
may be therapeutically modified by aitering the activity of such proteases.
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Accordingly, in the first aspect, this invention provides a compound according
to
Formula I.
In another aspect, this invention provides a pharmaceutical composition
comprising
a compound according to Formula I and a pharmaceutically acceptable carrier,
diluent or
excipient.
In yet another aspect, this invention provides intermediates useful in the
preparation of the compounds of Formula I.
In still another aspect, this invention provides a method of treating diseases
in
which the disease pathology may be therapeutically modified by inhibiting
proteases,
particulariy cysteine and serine proteases, more particularly cysteine
proteases, even more
particularly cysteine proteases of the papain superfamily, yet more
particularly cysteine
proteases of the cathepsin family, most particularly cathepsin K.
In a particular aspect, the compounds of this invention are especially useful
for
treating diseases characterized by bone loss, such as osteoporosis and
gingival diseases,
such as gingivitis and periodontitis, or by excessive cartilage or matrix
degradation, such as
osteoarthritis and rheumatoid arthritis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of Formula I:
R2 O
Z
R3 N ,
N ~--.~ L
1'=X
wherein:
L is selected from the group consisting of:C2_6alkyl, Ar-CO_6alkyl, Het-
CO_6alkyl,
CH(R4)NRSR6, CH(R4)Ar, CH(R4)OAr', and NR4R~;
X, Y, Z are independently selected from the group consisting of: N, O, S and
CR 10,
provided that at least two of X, Y and Z are heteroatoms and at least one of
X, Y and Z is
N, or one of X, Y and Z is C=N, C=C or N=N and the other two are CR10 or N,
provided
that X, Y and Z together comprise at least two N;
-- indicates a single or double bond in the five-membered heterocycle;
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R', R I , R2, R5, R I 0, R I 2, R I 6 and R 17 are independently selected from
the group
consisting of: H, CI_6alkyl, C2_6alkenyl, Ar-CO_6aikyl, and Het-C~6alkyl;
R3 is selected from the group consisting of: C3_6alkyI, Ar, Het, CH(R I I )Ar,
CH(RI I)OAr, NRI IR12~ CH(RI I)NR12R13~ and
~~~ L
Y=X
R4, R I I , and R I5 are independently selected from the group consisting of:
H, C I _
6alkyl, C2_balkenyl, C2_6alkynyl, C3_ I I cycloalkyl-CO_6-alkyl, Ar-CO_6alkyl,
Ar-C~_
6alkenyl, Ar-C2_6alkynyl, Het-CO_6aIkyl, Het-C2_6aikenyl, Het-C2_6alkynyl,
CI_6alkyl,
optionally substituted by ORg, SR8, NR8R9, N(R~C02R', C02R', CONRIORI 1, ~d
N(C=NH)NH2;
R6 and R13 are independently selected from the group consisting of: R14,
R 14C(O), R 14C(S), R 14OC(O), and R 140C(O)NR9CH(R I 5)(CO);
R7 is selected from the group consisting of: CI_6alkyl, CI_6alkenyl, C3_
6cycloalkyl-CO_6-alkyl, Ar-CO_6alkyl, and Het-CO_6alkyl;
IS R4 and R7 may be combined to form a 3-7 membered monocyclic or 7-10-
membered bicyclic carbocyclic or heterocyclic ring, optionally substituted
with I-4 of CI_
6alkyl, Ar-C0.6alkyl, Het-CO_6alkyl, CI_6alkoxy, Ar-C~6alkoxy, Het-CO_6alkoxy,
OH,
(CH2)I-6NR8R9, O(CH2)I_6NR8R9;
Rgand R9 are independently selected from the group consisting of: H, C I
_6alkyl,
C2_6alkenyl, Ar-CO_6alkyl, Het-CO_6aIkyl, and R16R17NC2_6alkyl;
R 14 is selected from the group consisting of: C I _6alkyI, C2_6alkenyl, Ar-
CO_
6alkyl, and Het-CO_6alkyl;
and pharmaceutically acceptable salts, hydrates and solvates thereof.
Compounds of Formula I wherein R I and R2 are H are preferred.
Also preferred are compounds of Formula I wherein X is S, Y is CH, and Z is N.
Also preferred are compounds of Formula I wherein:
R3 is preferably:
O R's
Ris~N
H
wherein R I S is:
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N \
W Oi l / Oi
C I/ ~ I\
N iN
I / N~ F \
I / I I
N ~
/ . F / . \~ -NH
;
~O
Me0 \
\ \
Me I ~ I ~ I
I \ I \ N \
N N~ ~ N N NON
..-
. CN
I \ O/ F3C / I I \
~N \ O N~
;
I \ w0 I \ O O ~ \ ~ \
N iN C / /
O \/ ; Me v ,
\ ~ ~ ~ /
/ /
N
' ~ ;
F3 ~ \ S
\~ ~\ ~\
N HO /
o
' ~ ;
H
N
I/ I\
F3C0 ~O /
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I
N I \ ~\ N I / \ N
/ O \
> >
Me0
N I
/ \ NH - N ~ Me0 /
F
H OMe
> ,
HN \
H / \ NH I \ N ( /
/ H
I
N
I / ~ ~ ~ I / /
N N
H , ; OMe ,
y
Me0 / \ NH w ~ \
CI / \ NH I /
Me0 N
y
/ \ O
Me0 / \ O CI / ~ O
OMe
/\~ /\
Me0 NH / \ O
CI
Me0 \
I \ \ \ N IN
Me0 / . I / ~ N
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CI
\ / \ S Me0
I -- \ ~ ~ \ NH
Me0 ~ N
S ~ / ~ N ~ I \
F C ~ \~ -- ~ O
3
-N . CF3 , OMe
CI
OMe
N ~ ~ N \
. \ S . Me0 f
N S \ N O
'_ \ ~ S \
s \ s
S \ CI \
N N CN~\ I ~
; N . CI
O
\ I ~ ~N N
Me02S O O J
S
F3C0 ~ \ NH N N j
G
S
S
~\ i ~ N\
S~ ~N\/~N~N
I
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O
\ Me0 / ~ !
NN I
S O ~ Me0
N
O
I ~ F3C / N S
!
CF3 , N
F3C
/ \ S \N-~O \
N ! ~ I ,
Me0
\ s
N\~ / \ o ~~ !
S N
1
,N~\ / \ p NCO / \
HN~ \
N N ~N N
~N N
N / HNJ
NCO O ~N~O O
/ \ l t / \ I
, ;
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I
w.I ~N~N n ~ \ O
N , H02C
~N~O O O
O ~ ~ ~ I
O
N
n ~ \ CF3 HO C ~ ~ \O
O C02H .,-
R 16 is selected from the group consisting of:
and
L is preferably:
N ,' N ~ \
I _N\
to ° ~
. . ;
.~ N
:and
Compounds of Formula I selected from the following group are particularly
preferred embodiments of the present invention:
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N-(2-(N-cyclopropyl-N-cyclopropyimethylamino)thiazol-4-ylcarbonyl)-N =[N-(6-
methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methyipropyl)amino]thiazol-4-ylcarbonyl)-N'-[N-(6-
phenylnicotinoyl)-L-ieucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylarnino)thiazol-4-ylcarbonyl]-N'-[N-(2 -
pyridinylmethoxycarbonyl)-L-(3 -tent-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyl]-N =[N-[4-(2-
pyridinyl)benzoyl]-L-leucinyl)hydrazide;
N-[2-[N-cyclopropyi-N-(2-methyipropyl)amino)thiazol-4-ylcarbonyl)-N'-[N-(6-
methylpicolinoyl)-L-leucinyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-{3,4-
difluorobenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyi-N-(2-methyipropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
methylimidazol-5-ylcarbonyi)-L-ieucinyl]hydrazide:
N-(N-(3,4-dimethoxybenzoyl)-L-leucinyl]-N =[2-( I -naphthyl)thiazol-4-
ylcarbonyl]hydrazide;
N-[N-(3,4-difluorobenzoyl)-L-leucinyl)-N =[2-( I-naphthyl)thiazol-4-
ylcarbonyl]hydrazide;
N-[N-(5-butylpicolinoyl)-L-leucinyl]-N=[2-( I-naphthyl)thiazol-4-
ylcarbonyi)hydrazide;
N-[2-(I-naphthyl)thiazol-4-ylcarbonyl]-N=[N-(3-propyloxypicolinoyl)-L-
leucinyl]hydrazide;
N-[2-(1-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-[6-( 1-pyrrolyl}nicotinoyl]-L-
leucinyl)hydrazide;
N-[2-( 1-naphthyl)thiazol-4-ylcarbonyl]-N =[N-[6-( I -pyrazolyi)nicotinoyl)-L-
leucinyl]hydrazide;
N-[N-[6-( 1-imidazolyl)nicotinoylJ-L-leucinyl]-N'-[2-( I -naphthyl)thiazol-4-
ylcarbonyl]hydrazide;
(IS)-N-[4-[1-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2-yicarbonyl]-N'
[2-(2-
benzyloxyphenyl)thiazol-4-ylcarbonyl]hydrazide;
(1S)-N-[4-[I-(N-benzyloxycarbonylamino)-3-methylbutyl)thiazol-2-ylcarbonyl]-
N=[2-(1-
naphthyl)thiazol-4-ylcarbonyl]hydrazide;
( 1 S)-N-[4-[ 1-(N-benzyloxycarbonylamino)-3-methylbutyl)thiazol-2-ylcarbonyl]-
N =[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
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( 1 S)-N-[4-[ 1-(N-benzyloxycarbonylamino)-3-methy!butyl]thiazol-2-ylcarbonyl]-
N =[2-[N-
methyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[N'-(5-butyl-2-pyridinylrnethoxycarbonyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[N-(5-butyl-2-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-[N-cyclopropyl-N-
(2-
methylpropyl)amino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-( 1-naphthyl)thiazol-4-ylcarbonyl]-N =[N-[6-(4-
trofluoromethylphenyl)nicotinoyl]-L-
leucinyl]hydrazide;
N-[N-(6-methylpicolinoyl)-L-leucinyl)-N'-[2-( 1-naphthyl)thiazol-4-
ylcarbonyl]hydrazide;
N-[2-(1-naphthyl)thiazol-4-yicarbonyl]-N'-[N-[4-(2-pyridinyl)benzoyl]-L-
leucinyl]hydrazide;
N-[N-(5-butyl-2-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-( 1-
naphthyl)thiazol-4-
ylcarbonyl]hydrazide;
N-[2-( 1-naphthyl)thiazol-4-ylcarbonyl]-N'-[N-(6-phenyldicotinoyl)-L-
leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonylJ-N=[N-(6-
phenylnicotinoyl)-L-~i -ten-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-[4-(2-
pyridinyl)benzoyl]-L-/3-ten-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropy!)amino]thiazol-4-ylcarbonyl]-N =[N-(2-
methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanyl]hydrazide;
( 1 S)-N-[4-[ 1-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-
N'-[2-(2-
chlorophenoxymethyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopenly!-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-(2-
pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-yicarbonyl]-N =[N-(6-
methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-(N-(6-
phenylnicotinoyl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-[4-(2-
pyridinyl)benzoyl]-L-leucinyl]hydrazide;
N-[N-(S-butylpicolinoyl)-L-leucinyl]-N'-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
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N-[N-(S-butylpicolinoyl}-L-(3-cyclopropylalanyl]-N'-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonylJ-N'-[N-[4-(2-
pyridinyl)benzoyl]-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
methylimidazol-5-ylcarbonyl)-L-leucinyl]hydrazide;
N-[N-(S-butylpicolinoyl)-L-leucinyl]-N =[2-[N-cyclopentyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-[6-(
1-
pyrrolyl)nicotinoyl]-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-( 1-
pyrrolyl)nicotinoyl]-L-leucinyl]hydrazide;
N-(2-[N-cyclopentyl-N-(2-methylpropyI)amino]thiazol-4-ylcarbonyl]-N'-(N-(3,4-
dimethoxybenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-(3,4-
dimethoxybenzoyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[6-( 1-
pyctolyl)nicotinoyl]-L-(3-cyclopropylatanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[6-( 1-
imidazolyl)nicotinoylJ-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[6-{ 1-
pyrazolyl)nicotinoyl]-L-(i-cyclopropylalanyl]hydrazide:
N-[2-[N-cyclopropyl-N-(2-methylpropyl)aminoJthiazol-4-yicarbonyl]-N'-[N-[6-( 1-
pyrrolyl)nicotinoyl]-L-(3-ten-butylalanyl]hydrazide;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyl]-N'-[N-(3,4-
difluorobenzoyl)-L-~i-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonylJ-N =[N-(3,4-
dimethoxybenzoyl)-L-(3-cyclopropylalanylJhydrazide;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-(4-
methylimidazol-5-ylcarbonyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-(2-
pyridinylmethoxycarbonyl)-L-leucinyl]hydra2ide;
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N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-
pyridinylmethoxycarbonyl)-L-~3-cyclopropylalanyl]hydrazide;
N-[2-IN-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4-
methylenedioxybenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-{4-
methoxybenzoyl)-L-~i-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-(3,4-
difluorobenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-(3,4-
dimethoxybenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
methylimidazol-5-ylcarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4-
difluorobenzoyl)-L-~i-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4-
dimethoxybenzoyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-(4-
methylimidazol-5-ylcarbonyl)-L-[3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
methyl-2-
phenyloxazol-4-ylacetyl)-L-~i-cyclopropylalanyl]hydrazide;
N-[N-(benzothiazol-6-ylcarbonyl)-L-leucinyl]-N =[2-[N-cyclobutyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyi-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
trifluoromethylbenzoyl)-L-~i-cyclopropylalanyl]hydrazide;
N-(N-benzothiophen-2-ylcarbonyl-L-(3-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-
(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[4-
methyl-2-(4-
trifluoromethylphenyl)thiazol-5-ylcarbonyl}-L-leucinyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-(4-
hydroxymethylbenzoyl)-L-~3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =(N-(4-
hydroxymethylbenzoyl)-L-(3-cyclopropylalanyl]hydrazide;
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N-(N-benzothiophen-2-ylcarbonyl-L-(3-cyclopropylalanyl}-N'-[2-[N-cyclopentyl-N-
(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N'-[N-(2,3-
dihydrobenzofuran-5-ylcarbonyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-indole-
2-
ylcarbonyl-L-(3-tent-butylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-( 1-
methylindole-2-ylcarbonyl)-L-~i-ten-butylalanyl]hydrazide;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
trifluoromethoxybenzoyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
propyloxybenzoyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[3-(2-
pyridinyl)benzoyl]-L-leucinyI]hydrazide;
N-(2-(N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[4-
methyl-2-
(4-trifluoromethylphenyl)thiazol-5-ylcarbonyl]-L-leucinyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[3-(2-
pyridinyl)benzoyl]-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
methyl-2-
phenyloxazol-4-ylcarbonyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
trifluoromethylbenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-{2-methylpropyl)amino]thiazol-4-ylcarbonyl)-N'-[N-{2,3-
dihydrobenzofuran-5-ylcarbonyl)-L-leucinyl]hydrazide;
N-(N-benzothiazol-6-ylcarbonyl-L-leucinyl)-N=[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-(N-benzothiophen-2-ylcarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
methyl-2-
phenyloxazol-4-ylcarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-( 1-
methylindole-2-ylcarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclobutyll-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2,3-
dihydrobenzofuran-5-ylcarbonyl)-L-Ieucinyl]hydrazide;
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N-[2-[N-cyclobutyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyl]-N =[N-(5-
fluoroindole-2-ylcarbonyl)-L-leucinyl]hydrazide;
N-(N-benzothiophen-2-ylcarbonyl-L-leucinyl)-N =[2-[N-cyclobutyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonylJ-N =[N-(5-
methyl-2-
phenylimidazol-4-ylcarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonylJ-N =[N-(3,4,5-
trimethoxybenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
fluoroindole-2-ylcarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol- 4-ylcarbonyl]-N'-[N-(5-
hydroxyindole-2-ylcarbonyl)-L-leucinylJhydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonylJ-N'-(N-indole-
4-
ylcarbonyl-L-~3-cyclopropylalanyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-indole-
5-
ylcarbonyl-L-~3-cyciopropylalanyl)hydrazide;
N-(N-benzimidazol-5-ylcarbonyl-L-(3-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N-
(2-
methylpropyl}amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-(5-
fluoroindole-2-ylcarbonyl)-L-~i-cyclopropylalanylJhydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyl]-N =[N-(4-
methyl-2-
phenylthiazol-5-ylcarbonyl}-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
methyl-2-
phenyloxazol-4-ylcarbonyl)-L-~i-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-(4-
methoxyquinolin-2-ylcarbonyl)-L-(3-cyclopropylalanyl]hydrazide;
N-(2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-(5,6-
dimethoxyindole-2-ylcarbonyl)-L-(3-cyclopropylalanylJhydrazide;
N-[N-(5-chloroindole-2-ylcarbonyl)-L-~i-cyclopropylalanyl]-N'-[2-[N-
cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonylJhydrazide;
N-(N-benzothiazol-6-ylcarbonyl-L-(3-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-
(2-
methylpropyl)amino]thiazol-4-ylcarbonylJhydrazide;
N-[2-[N-cyclopropyl-N-{2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
flurorbenzimidazol-2-ylcarbonyl)-L-~i-cyclopropylalanyl]hydrazide;
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N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonylJ-N'-(N-
quinolin-3-
ylcarbonyl-L-(3-cyclopropylalanyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4.-ylcarbonyl]-N'-[N-(5-
methoxybenzofuran-2-ylcarbonyl)-L-~i-cyclopropylalanyl]hydrazide;
N-(2-[N-cyclopropyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyi]-N=[N-(7-
methoxybenzofuran-2-ylcarbonyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[N-(5-chlorobenzofuran-2-ylcarbonyl)-L-(3-cyclopropylalanyi]-N'-[2-[N-
cyclopropyl-N-
(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methyIpropyl)aminoJthiazol-4-ylcarbonylJ-N'-[N-(4-
trifluoromethoxybenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-( 1-
methylindole-2-ylcarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
methylindole-2-ylcarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl}amino]thiazol-4-ylcarbonyl]-N=[N-(~-
methoxyindole-2-ylcarbonyl)-L-leucinylJhydrazide;
N-(N-benzofuran-2-ylcarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[N-(2-chloro-3,4-dimethoxybenzoyl)-L-leucinyl]-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
methoxyindole-2-ylcarbonyl)-L-[3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-
isoquinolin-3-
ylcarbonyl-L-~i-cyclopropylalanyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-indole-
2-
ylcarbonyl-L-~3-cyclopropylalanyl}hydrazide;
N-(N-benzofuran-2-ylcarbonyl-L-~i-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)aminoJthiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[6-( 1-
pyrrolidinyl)nicotinoylJ-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-(4-
methyl-2-
phenylthiazol-5-ylcarbonyl)-L-leucinyl]hydrazide;
N-[N-(5-chlorobenzofuran-2-ylcarbonyl)-L-leucinyl]-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
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N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-(5-
methoxybenzofuran-2-ylcarbonyl)-L-leucinyl]hydrazide;
N-(N=benzimidazol-5-ylcarbonyl-L-IeucinyI)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyI]hydrazide:
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-(5,6-
dimethoxyindole-2-ylcarbonyl)-L-Ieucinyl]hydrazide;
N-[N-(5-chloroindole-2-ylcarbonyl)-L-leucinyl]-N =[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
methoxy-3-
methylbenzoyl)-L-leucinyl]hydrazide;
N-[N-[2-(2-chlorophenyl)-4-methylthiazol-5-ylcarbonyl]-L-leucinyl]-N'-[2-[1V-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
methoxyindole-2-ylcarbonyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[4-
methyl-2-
(4-trifluoromethylphenyl)thiazol-5-ylcarbonyl]-L-~i-
cyclopropylalanyl]hydrazide;
N-[2-[N-cyciopropyl-N-(2-rnethylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-
trifluoromethyl-4-azabenzothiophen-2-ylcarbonyl}-L-~3-
cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-(2-
phenyl-5-
trifluoromethyloxazol-4-ylcarbonyl)-L-leucinyl]hydrazide:
N-(2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-(4-
methoxyquinolin-2-ylcarbonyl)-L-leucinyl]hydrazide:
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3-
methoxy-
4,5-methylenedioxybenzoyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(N-indole-
2-
ylcarbonyl-L-leucinyl)hydrazide;
N-[2-(N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(7-
methoxybenzofuran-2-ylcarbonyl)-L-leucinyl]hydrazide;
N-[N-(3-chlorobenzothiophen-2-ylcarbonyl)-L-leucinyl]-N'-[2-[N-cyclopropyl-N-
(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =(N-indole-
6-
ylcarbonyl-L-Ieucinyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3-
methylthiophene-2-ylcarbonyl}-L-leucinyl]hydrazide;
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N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2,6-
dimethoxynicotinoyi)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[2-(2-
pyridinyI)thiophen-5-ylcarbonyl]-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[2-(2-
mercaptopyridinylmethyl)furan-5-ylcarbonyl]-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =(N-indole-
6-
ylcarbonyl-L-leucinyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[4-
methyl-2-
(2-methylthiazol-4-yl)thiazol-5-ylcarbonyl]-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[2-( 1-
pyrrolyl)benzothiazol-6-ylcarbonyl]-L-Ieucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4-
dichlorobenzoyl)-L-~i-cyclopropylalanyl]hydrazide;
N-[2-(N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-
methanesolfonylbenzoyl)-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazoI-4-ylcarbonyl]-N'-[N-(2-
phenyl-5-
trifluoromethyloxazol-4-ylcarbonyl)-L-~-cyclopropylalanyl]hydrazide;
N-[N-[2-(2-chlorophenyl)-4-methylthiazol-5-ylcarbonyl]-L-~3-cyclopropylalanyl]-
N'-[2-[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3,4-
dimethoxybenzoyl)-L-(3-cyclohexylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-
trifluoromethyl-4-azabenzothiophen-2-ylcarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-(2,6-
dimethoxynicotinoyl)-L-leucinyl]hydrazide;
(2S)-N-(N-benzodioxan-2-ylcarbonyl-L-(3-cyclopropylalanyl)-N =[2-[N-
cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[2-(2-
pyridinyl)thiophen-5-ylcarbonyl]-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =(N-
propionyl-L-
leucinyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[2-(4-
motpholino)pyrimidin-5-ylcarbonyl]-L-~i-cyclopropylalanyl]hydrazide;
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N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[4-
methyl-2-
(2-methylthiazol-4-yl)thiazol-5-ylcarbonyl]-L-~3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[2-( 1-
pyrrolyl)benzothiazol-6-ylcarbonyl]-L-~i-cyclopropylalanylJhydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyI)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
trifluoromethoxyindol-2-ylcarbonyl)-L-~i-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methyipropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[2-( 1-
pyrrolidino)pyrimidin-5-ylcarbonyl]-L-(3-cyclopropylalanyl]hydrazide;
N-(N-butyryl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-
4-
ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(3-
methylbutyryl)-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyi-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]-N =[N-(3,4-
dimethoxybenzoyl)-L-cyclohexylglycinyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonylJ-N'-(N-
thieno[2,3-
b]thiophen-2-ylcarbonyi-L-leucinyl)hydrazide;
N-[N-(5-ten-butyl-3-methylthieno[2,3-b]thiophen-2-ylcarbonyl)-L-leucinylJ-N
=[2-[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyiJhydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyl]-N =[N-[2-[N-
[2-
(N,N-dimethylamino)ethylJ-N-methylamino]pynimidin-5-ylcarbonyl]-L-~i-
cyclopropylalanyl]hydrazide;
N-[2-jN-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[4-(
1.2,3-
thiadiazol-~-yloxy)benzoyl]-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5,6-
dimethoxybenzofuran-2-ylcarbonyl)-L-~3-cyclopropylalanylJhydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[5-(4-
triflouormethylphenyl)oxazol-4-ylcarbonylJ-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[4-
methyl-2-
(5-trifluoromethylpyridin-2-yI)thiazol-5-ylcarbonyl]-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[4-
methyl-2-
(3-trifluoromethylphenyl)thiazol-5-ylcarbonyl]-L-leucinyI]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonylJ-N =[N-[3-[2-
(N,N-
dimethylamino)ethoxy]-4-methoxybenzoylJ-L-~i-cyclopropylalanyl]hydrazide;
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N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl}-N =[N-[5-[2-
(4-
morpholino)ethoxy]benzofuran-2-ylcarbonyl]-L-(3-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyi-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl)-N =[N-[4-
methyl-2-
(2-thienyl)thiazol-5-ylcarbonyl]-L-leucinyi]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methyipropyl)amino)thiazol-4-ylcarbonyl]-N'-[N-(3-[2-
(N,N-
dimethylamino)ethoxy]-4-methoxybenzoyl]-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl)-N =[N-[5-[2-
(N,N-
dimethyiamino)ethoxy)benzofuran-2-ylcarbonylj-L-~i-
cyclopropylalanyi]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[5-(2-
( 1-
piperidinyl)ethoxy]benzofuran-2-ylcarbonyl]-L-(3-cyciopropyialanyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-rnethylpropyl)amino)thiazol-4-yicarbonyl]-N'-(N-
thieno[2,3-
b]thiophen-2-ylcarbonyl-L-(3-cyclopropylalanyl)hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl)-N'-[N-[4-
methyl-2-
(5-trifluoromethylpyridin-2-yl)thiazol-5-ylcarbonyl]-L-~3-
cyclopropylalanyl)hydrazide:
N-(2-[N-cyclopropyl-N-(2-methylpropyl)amino)thiazol-4-ylcarbonyl]-N'-[N-(5,6-
dimethoxybenzofuran-2-ylcarbonyl)-L-ieucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[2-(4-
morpholino)pyrimidin-4-ylcarbonyl]-L-(3-cyciopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[2-( 1-
piperazinyl)pyrimidin-4-ylcarbonyl]-L-~i-cyclopropylalanyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[2-( 1-
piperazinyl)pyrimidin-5-ylcarbonyl]-L-(3-cyclopropylalanyi]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methyipropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[5-[2-
(N,N-
dimethylamino)ethoxy]benzofuran-2-ylcarbonyl]-L-leucinyi]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[7-[2-
(1-
piperidinyl)ethoxy]benzofuran-2-ylcarbonyl]-L-leucinyl]hydrazide;
N-[2-[N-cyciopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[7-[2-
(N,N-
dimethylamino)ethoxy]benzofuran-2-ylcarbonyl]-L-leucinyl]hydrazide;
N-[2-(N-cyclopropyl-N-(2-methylpropyl)amino)thiazol-4-ylcarbonyl]-N =[N-[2-[N-
[2-
(N,N-dimethylamino)ethyl]-N-methylamino)pyrimidin-4-ylcarbonyi]-L-~i-
cyclopropylalanyl)hydrazide;
N-[2-(2-benzyloxyphenyI)thiazol-4-ylcarbonyl]- N=[2-(1-naphthyl)thiazol-4-
ylcarbonyl]hydrazide;
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N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[7-[2-
(N,N-
dimethylamino)ethoxy]benzofuran-2-ylcarbonyl]-L-(3-
cyclopropylalanyl]hydrazide;
N-[N-(5-carboxymethoxybenzofuran-2-ylcarbonyl}-L-~i-cyclopropylalanyl]-N'-[2-
[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(7-(2-
(4-
moipholino)ethoxy]benzofuran-2-ylcarbonyl]-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[3,4-(
1,3-
propylenedioxy)benzoyl]-L-leucinyl]hydrazide;
N-[N-(7-carboxymethoxybenzofuran-2-ylcarbonyl)-L-(3-cyclopropylalanyl]-N'-[2-
[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[5-(3-
triflouormethylphenyl}oxazol-4-ylcarbonyl}-L-leucinyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[5-[2-
(4-
morpholino}ethoxy]benzofuran-2-ylcarbonyl]-L-leucinyl]hydrazide;
N-[N-(5-carboxybenzofuran-2-yicarbonyl)-L-(3-cyclopropylalanyl]-N=[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide; and
N-[N-(7-carboxymethoxybenzofuran-2-ylcarbonyl)-L-leucinyl]-N'-[2-[N-
cyclopropyl-N-
(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide.
Definitions
The present invention includes all hydrates, solvates, complexes and prodrugs
of
the compounds of this invention. Prodrugs are any covalently bonded compounds
which
release the active parent drug according to Formula I in vivo. If a chiral
center or another
form of an isomeric center is present in a compound of the present invention,
all forms of
such isomer or isomers, including enantiomers and diastereomers, are intended
to be
covered herein. Inventive compounds 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 traps
(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.
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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. Biochem., 158, 9 ( 1984).
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.
"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,
neopentyl and hexyl and the simple aliphatic isomers thereof. Any C1_6alkyl
group may be
optionally substituted independently by one to five halogens, S R16, O R16,
N(R16)2,
C(O)N(R16)2, carbamyl or C1_4alkyl, where R16 is C1_6alkyl. Cpalkyl means that
no
alkyl group is present in the moiety. Thus, Ar-Cpalkyl is equivalent to Ar.
"C3_1 lcycloalkyl" as applied herein is meant to include substituted and
unsubstituted cyclopropane, cyclobutane, cyclopentane, cyclohexane,
cycloheptane,
cyclooctane, cyclononane, cyclodecane, cycloundecane.
"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 are 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.
As used herein "Ar" represents phenyl or naphthyl, optionally substituted by
one or
more of Ph-CO_6alkyl, Het-CO-6 alkyl, C 1 _6alkyl, C 1 _6alkoxy, Ph-CO-
6alkoxy, Het-CO-
6alkoxy, OH, NR8R9, Het-S-C~6alkyl, (CH2)1-60H, (CH2)1-6NR8R9, O(CH2)1-
6IVR8R9, (CH2)0-6C02R', O(CH2)1_6CO~R', (CH2)1-6502, CF3, OCF3 or halogen; Ph
and Het may be optionally substituted with one or more of C1_6alkyl,
C1_6alkoxy, OH,
(CH2)1-6NR8R9, O(CH2)1-6~8R9, CO2R', CF3, or halogen; two C1_6alkyl or C1-
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6alkoxy groups may be combined to form a 5-7 membered ring, saturated or
unsaturated,
fused onto the Ar ring;
As used herein "Ar' "represents phenyl or naphthyl, optionally substituted by
one or
more of Ph-CO_6alkyl, Het-C~6alkyl, Cl_6alkyl, C1-6alkoxy, Ph-C~6alkoxy, Het-
C0.
balkoxy, OH, (CH2)1-6NR8R9, O(CH2)1-6NR$R9, or halogen; Ph may be optionally
substituted with one or more of C1_6alkyl, C1-6alkoxy, OH, (CH2)1-6NR8R9,
O(CH2)1-
6NR8R9, C02R', or halogen; two C 1-6alkyl groups may be combined to form a 5-7
membered ring, saturated or unsaturated, fused onto the Ar' ring;
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 be optionally substituted as with Ar
(including on the
nitrogens) Examples of such heterocycles include piperidinyl, piperazinyl, 2-
oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl,
pyrrolyl, 4-
piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl,
pyrazinyl,
oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl,
thiazolinyl,
thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl,
benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzoxazolyl,
thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Het can
be optionally
substituted as with Ar (including on the nitrogens).
"5-7 membered ring, saturated or unsaturated, fused onto the Ar ring" means a
fused bicyclic ring system such as indane, 1,2,3,4-tetrahydrodecalin,
methylenedioxyphenyl, 1,2-ethylenedioxyphenyl and 1,3-propylenedioxyphenyl.
Here and throughout this application the term CO denotes the absence of the
substituent group immediately following; for instance, in the moiety
ArC~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 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
CA 02335876 2000-12-21
WO 99/66925 PCT/US99/14561
fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers
to the
benzyloxycarbonyl radical.
Certain reagents are abbreviated herein. DCC refers to
dicyclohexylcarbodiimide,
DMAP is 2,6-dimethylaminopyridine, EDC refers to N-ethyl-
N'(dimethylaminopropyl)-
carbodiimide. HOBT refers to 1-hydroxybenzotriazole, DMF refers to dimethyl
formamide, BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate, DMAP is dimethylaminopyridine, NMM is N-methylmorpholine,
TFA refers to trifluoroacetic acid, THF refers to tetrahydrofuran. Jones
reagent is a
solution of chromium trioxide, water, and sulfuric acid well-known in the art.
Methods of Preparation
The compounds of the present invention may be conveniently prepared by the
methods set forth in Schemes 1 - 3 below.
Compounds of the formula I wherin X = S, Y = CH, Z = N and L = NR4R~, are
prepared by methods analogous to those described in Scheme 1.
Scheme 1
d
RCHO -~- R U N ~ Ra --~- R~NHRa ~ R°N~NCSNHCOPh -
1 2 3 (RCHZ = R~) 4
S~ S
R4N~NCSNH
RaR' '~~ N CO2Et RaR~ ~\ N ~ CONHNHZ
5 6
O O
S ~\ N i ~ h S ; ~1 H
RaR~ ~. '~ _ N h R3 -.~.. RaR~ ~~ j~ N ~ N ~ ~ NHZ
N ~ H N w,. i H
O O R"
g 9
S \ O
H H ,a
RaR~~~N~N_H~N~R
~O ,TR" ~'''O
a) R4NH2, CH2C12; b) Na(OAc)3BH, CH2C12; c) PhCONCS, CHC13; d) K2C03, MeOH,
H20; e) Et02CCOCH2Br, EtOH; f) H2NNH2-H20, EtOH; g) R3C02H, EDC~HCI, 1-
HOBT, DMF; h) TFA, CH2C12; i) R14C02H, EDC~HCI, 1-HOBT, DMF.
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WO 99/66925 PCT/US99/14561
An aldehyde (such as cyclopropanecarboxaldehyde or isobutyraldehyde) ( I -
Scheme 1) was treated with a primary amine (such as cyclopropylamine,
cyclobutylamine
or cyclopentylamine) in methylene chloride to provide 2-Scheme I, which was
treated with
sodium triacetoxyborohydride in methylene chloride to afford 3-Scheme I.
Treatment of 3-
Scheme 1 with benzoyl isothiocyanate in chloroform provided 4-Scheme 1, which
was
treated with potassium carbonate in methanol/water to give 5-Scheme 1.
Treatment of 5-
Scheme I with ethyl bromopyrivate in ethanol provided 6-Scheme I, which was
treated
with hydrazine hydrate in ethanol to give 7-Scheme I . Treatment of 7-Scheme 1
with a
carboxylic acid (such as N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-
butylalanine,
N-tert-butoxycarbonyl-L-leucine, N-(2-pyridinylmethoxycarbonyl)-L-(3-ten-
butylalanine,
N-(5-butyl-2-pyridinylmethoxycarbonyl)-L-leucine, N-(2-methyl-3-
pyridinylmethoxycarbonyl}-L-~i-ten-butylalanine, N-(2-
pyridinylmethoxycarbonyl)-L-
leucine, (IS)-1-(benzyloxycarbonyl)amino-I-(4-carboxythiazol-2-yl)-3-
methylbutane, N-
ten-butoxycarbonyl-L-~3-ten-butylalanine, N-ten-butoxycarbonyl-L-~i-
cyclopropylalanine,
N-tent-butoxycarbonyl-L-~i-cyclohexylalanine or N-ten-butoxycarbonyl-L-
cyclohexylglycine) and a peptide coupling reagent (such as EDC~HCI/I-HOBT) in
an
aprotic solvent (such as DMF~ provided 8-Scheme 1. When R3C02H was a N-ten-
butoxycarbonyl protected amino acid, treatment of 8-Scheme 1 with
trifluoroacetic acid in
dichloromethane provided 9-Scheme 1, which was treated with a carboxylic acid
(such as
6-phenylnicotinic acid, 4-(2-pyridinyl)benzoic acid, 6-methylpicolinic acid,
3,4-
difluorobenzoic acid, 4-methylimidazole-5-carboxylic acid, 5-butylpicolinic
acid, 6-(I-
pyrrolyl)nicotinic acid, 3,4-dimethoxybenzoic acid, 6-( I-imidazolyl)nicotinic
acid, 6-( 1-
pyrazolyl)nicotinic acid, 3,4-methylenedioxybenzoic acid, 4-methoxybenzoic
acid, 5-
methyl-2-phenyl-4-oxazoleacetic acid, benzothiazole-6-carboxylic acid, 4-
trifluoromethylbenzoic acid, benzothiophene-2-carboxylic acid, 4-methyl-2-(4-
trifluoromethylphenyl)thiazole-5-carboxylic acid, 4-hydroxymethylbenzoic acid,
2,3-
dihydrobenzofuran-5-carboxylic acid, indole-2-carboxylic acid, I-methylindole-
2-
carboxylic acid, 4-trifluoromethoxybenzoic acid, 4-propyloxybenzoic acid, 3-(2-
pyridinyl)benzoic acid, 5-methyl-2-phenyloxazole-4-carboxylic acid, 5-
fluoroindole-2-
carboxylic acid, 4(5)-methyl-2-phenylimidazole-5(4)-carboxylic acid, 3,4,5-
trimethoxybenzoic acid, 5-hydroxyindole-2-carboxylic acid, indole-4-carboxylic
acid,
indole-5-carboxylic acid, benzimidazole-5-carboxylic acid, 4-methyl-2-
phenylthiazole-5-
carboxylic acid, 4-methoxyquinoline-2-carboxylic acid, 5,6-dimethoxyindole-2-
carboxylic
acid, 5-chloroindole-2-carboxylic acid, 4-fluorobenzimidazole-2-carobxylic
acid,
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WO 99/66925 PCT/US99/14561
quinoline-3-carboxylic acid, 5-methoxybenzofuran-2-carobxylic acid, 5-
methoxybenzofuran-2-carobxylic acid, 5-chlorobenzofuran-2-carobxylic acid, 5-
metliylindole-2-carboxylic acid, 5-methoxyindole-2-carboxylic acid, benzofuran-
2-
catboxylic acid, 2-chloro-3,4, dimethoxybenzoic acid, isoquinoline-2-
carboxylic acid, 6-(1-
pyrrolidino)nicotinic acid, 4-methoxy-3-methylbenzoic acid, 2-(2-chlorophenyl)-
4-
methylthiazole-5-carboxylic acid, 4-methoxyindole-2-carboxylic acid, 6-
trifluoromethyl-4-
azabenzothiophene-2-carboxylic acid, 2-phenyl-5-trifluoromethyloxazole-4-
carboxylic
acid, 3-methoxy-4,5-methylenedioxybenzoic acid, 3-chlorobenzothiophene-2-
carboxylic
acid, indole-6-carobxylic acid, 3-methylthiophene-2-carboxylic acid, 2,6-
dimethxoynicotinic acid, 2-(2-pyridinyl)thiophene-5-carboxylic acid,
isovaleric acid, 2-(2-
mercaptopyridinylmethyl)furan-5-carboxylic acid, 4-methyl-2-(2-methylthiazol-4-
yl)thiazole-5-carboxylic acid, 2-(I-pyrrolyl)benzothiazole-6-carboxylic acid,
3,4-
dichlorobenzoic acid, 4-methanesulfonylbenzoic acid, benzodioxane-2-carboxylic
acid.
propionic acid, 2-(4-morpholino)pyrimidine-5-cargboxylic acid, 5-
trifluoromethxoyindole-
2-carboxylic acid, 2-( 1-pyrrolidino)pyrimidine-5-carboxylic acid, butyric
acid, thieno[2,3-
b]thiophene-2-carboxylic acid, 5-ten-butyl-3-methylthieno[2,3-b]thiophene-2-
carboxylic
acid, 2-(N,N-dimethylamino)ethyl]-N-methylamino]pyrimidine-5-carboxylic acid,
4-(1,2,3-
thiadiazol-5-yloxy)benzoic acid, 5,6-dimethoxybenzofuran-2-carboxylic acid, 5-
(4-
triflouormethylphenyl)oxazole-4-carboxylic acid, 4-methyl-2-(5-
trifluoromethylpyridin-2-
yl)thiazole-5-carboxylic acid, 4-methyl-2-(3-trifluoromethylphenyl)thiazole-5-
carboxylic
acid, 3-[2-(N,N-dimethylamino)ethoxy]-4-methoxybenzoic acid, 5-[2-(4-
morpholino)ethoxy]benzofuran-2-carboxylic acid, 4-methyl-2-(2-thienyl)thiazole-
5-
carboxylic acid, 5-[2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid,
5-[2-(1-
piperidinyl}ethoxy]benzofuran-2-carboxylic acid, 2-(4-morpholino)pyrimidine-4-
carboxylic acid, 2-(4-ten-butoxycarbonyl-1-piperazinyl)pyrimidine-4-carboxylic
acid, 2-
(4-ten-butoxycarbonyl-1-piperazinyl)pyrimidine-5-carboxylic acid, 7-[2-(1-
piperidinyl)ethoxy]benzofuran-2-carboxylic acid, 7-[2-(N,N-
dimethylamino)ethoxy]benzofuran-2-carboxylic acid, 2-[N-[2-(N,N-
dimethylamino)ethyl]-
N-methylamino]pyrimidine-4-carboxdylic acid, 5-ten-
butoxycarbonylmethoxybenzofuran-
2-carboxylic acid, 7-[2-(4-motpholino)ethoxy]benzofuran-2-carboxylic acid, 3,4-
(I,3-
propylenedioxy)benzoic acid, 7-ten-butoxycarbonylmethoxybenzofuran-2-
carboxylic acid,
5-(3-triflouormethylphenyI)oxazole-4-carboxylic acid or 5-ten-
butoxycarbonylbenzofuran-
2-carboxylic acid) and a peptide coupling reagent (such as EDC-HCl/1-HOBT} in
an
aprotic solvent (such as DM)~ to give 10-Sheme 1. When R14C02H is 2-(4-tert-
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WO 99/66925 PCT/US99/14561
butoxycarbonyl-1-piperazinyl)pyrimidine-4-carboxylic acid, 2-(4-ten-
butoxycarbonyl-1-
piperazinyl)pyrimidine-5-carboxylic acid, 5-ten-
butoxycarbonylmethoxybenzofuran-2-
carboxylic acid, 7-ten-butoxycarbonylmethoxybenzofuran-2-carboxylic acid or S-
ten-
butoxycarbonylbenzofuran-2-carboxylic acid, the tert-butyl protecting groups
were
removed from 10-Scheme 1 by treatment with trifluoroacetic acid in
dichloromethane.
Scheme 2
S
b c
EtOZCCOCH2Br ~ HZN y ~ COzEt ~ Br ~\ N ~ COZEt
N
3
' S~ H O
Ar ~~ N ~~ C02Et Ar N CONHNH2 Ar N i ~ H R
O
_4 _5
6
S -, O O
H i~ g S W H I,i H
t : ', N NH ~, ~ ~ , ~a
Ar~~N~ ,N~ 2 Ar~~ ~N,N~N~R
H '1R(» N / ~~ ~ H
O R" O
7 8
a) Thiourea, EtOH; b) i. NaN02, 16% aqueous HBr; ii. CuBr, 16% aqueous HBr;
iii. HBr
(cat.), EtOH; c) ArB(OH)2, Pd(PPh3)4, NaHC03, toluene, EtOH, H20; d) H2NNH~-
H~O,
EtOH; e) R3CO~H, EDC~HCI, 1-HOBT, DMF; f) TFA, CH~Cl2; g) R14C02H, EDC~HCI,
1-HOBT, DMF.
Compounds of the formula I wherin X = S, Y = CH, Z = N and L = Ar, are
prepared by methods analogous to those described in Scheme 2. Ethyl
bromopyruvate (1-
Schem 2) was treated with thiourea in refluxing ethanol to provide 2-Scheme 2,
which wass
treated successively with sodium nitrite and copper (I) bromide in 16% aqueous
HBr, and
the product was heated in ethanol with a catalytic amount of HBr to give 3-
Scheme 2.
Treatment of 3-Scheme 2 with an arylboronic acid (such as 1-naphthylboronic
acid or 2-
benzyloxyphenylboronic acid), tetrakis(triphenylphosphine)paIlladium(0) and
sodium
bicarbonate in refluxing toluene/ethaonUwater provided 4-Scheme 2, which was
treated
with with hydrazine hydrate in ethanol to provide 5-Scheme 2. Treatment of 5-
Scheme 2
with a carboxylic acid (such as N-ten-butoxycarbonyl-L-leucine, (1S)-1-
(benzyloxycarbonyl)amino-1-(4-carboxythiazol-2-yl)-3-methylbutane, N-(5-butyl-
2-
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WO 99/66925 PCT/US99/14561
pyridinylmethoxycarbonyl)-L-leucine or 2-(1-naphthyl)thiazole-4-carboxylic
acid) and a
peptide coupling reagent (such as EDC~HCI/1-HOBT) in an aprotic solvent (such
as DMF)
provided 6-Scheme 2. When R3CO~H was N-ten-butoxycarbonyl-L-leucine, treatment
of
6-Scheme 2 with trifluoroacetic acid in dichloromethane provided 7-Scheme 2,
which was
treated with a carboxylic acid (such as 3,4-dimethoxybenzoic acid, 3,4-
difluorobenzoic
acid, 5-butylpicolinic acid, 3-propyloxypicoiinic acid, 6-(1-
pyrrolyl)nicotinic acid, 6-(1-
pyrazolyl)nicotinic acid, 6-( 1-imidazolyl)nicotinic acid, 6-(4-
trofluoromethylphenoxy)nicotinic acid, 6-methylpicoIinic acid, 4-(2-
pyridinyl)benzoic acid
or 6-phenylnicotinic acid) and a peptide coupling reagent (such as EDC~HCU1-
HOBT) in
an aprotic solvent (such as DMF) to give 8-Sheme 2.
Compounds of the formula I wherin X = S, Y = CH and Z = N, are prepared by
methods analogous to those described in Scheme 1.
Scheme 3
S
LC02H -ate- LCONH2 -~- LCSNH2 -'~" L~~~ C02Et
N
1 2 3
O
L~~~CONHNH ~ L~~ ~ N~N~R3
N 2 N I H
_5 O
6
a) i-BuOCOCI, NMM, NH3, THF; b) Lawesson's reagent, THF; c) i. EtO~CCOCH~Br,
CH2Cl2; ii. TFAA, Py, CH~C12; d) H2NNH2~H20, EtOH; e) R3C02H, EDC~HCI, 1-
HOBT, DMF.
Treatment of 1-Scheme 3 with isobutyl chloroformate, N-methylmorpholine and
ammonia in THF provided 2-Scheme 3, which was treated with Lawesson's reagent
in THF
to give 3-Scheme 3. Treatment of 3-Scheme 3 with ethyl bromopyruvate in
dichloromethane followed by treatment with trifluoroacetic anhydride and
pyridine in
methylene chloride provided 4-Scheme 3, which was treated with hydrazine
hydrate in
ethanol to give 5-Scheme 3. Treatment of 5-Scheme 3 with a carboxylic acid
(such as (1S)-
1-benzyloxycarbonylamino-1-(4-carboxythiazol-2-yl)-3-methylbutane) and a
peptide
CA 02335876 2000-12-21
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coupling reagent (such as EDC~HCI/I-HOB'I~ in an aprotic solvent (such as DMF)
gave 6-
Scheme 3.
Referring to the methods of preparing the compounds of Formula I set forth in
Schemes 1-3 above, the skilled artisan will appreciate that the present
invention includes all
novel intermediates required to make the compounds of Formula I. More
specifically, the
present invention includes the following compounds:
3-(6-methyl)pyridylcarbinol;
L-~i-ten-butylalanine methyl ester;
~i-isocyanato-L-(3-ten-butyialanine methyl ester;
N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine methyl ester;
N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine;
N-cyclopropylmethylcyclopropylamine;
N-benzoyl-N'-cyclopropyl-N'-cyclopropylmethylthiourea;
N-cyclopropyl-N-cyclopropyImethylthiourea;
ethyl 2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazole-4-carboxylate;
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonylJhydrazide;
ethyl 6-phenylnicotinate;
6-phenylnicotinic acid;
N-cyclopropyl-N-(2-methylpropyl)amine;
N-benzoyl-N'-cyclopropyl-N'-(2-methylpropyl)thiourea;
N-cyclopropyl-N-(2-methylpropyl)thiourea;
ethyl 2-[N-cyclopropyl-N-(2-methylpropyl)amino)thiazole-4-carboxylate;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyl]hydrazide;
N-(N-tent-butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)aminoJthiazol-4-ylcarbonylj-N'-(L-
leucinyl)hydrazide;
N-(2-pyridinylmethoxycarbonyl)-L-~i-tert-butylalanine methyl ester;
N-(2-pyridinylmethoxycarbonyl)-L-~i-tert-butylalanine;
4-carbomethoxyphenylboronic acid;
methyl 4-(2-pyridinyl)benzoate;
4-(2-pyridinyl)benzoic acid;
ethyl 2-( 1-naphthyl)thiazole-4-carboxylate;
31
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2-( 1-naphthyl)thiazole-4-ylcarbonylhydrazide;
N-(N-ten-butoxycarbonyl-L-leucinyl)-N=[2-( 1-naphthyl)thiazol-4-
ylcarbonyl]hydrazide;
N-(L-leucinyl)-N'-[2-( 1-naphthyl)thiazol-4-ylcarbonyl]hydrazide;
N-ten-butoxycarbonyl-L-~i-ten-butylalanine;
S N-(N-ten-butoxycarbonyl-L-(3-ten-butylalanyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-(L-(3-ten-butylalanyl)-N =[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-
4-
ylcarbonyl]hydrazide;
N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-j3-ten-butylalanine methyl ester;
N-(2-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine;
2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonylhydrazide;
N-cyclopentyl-N-(2-methylpropyl)amine;
N-benzoyl-N'-cyclopentyl-N =(2-methylpropyl)thiourea;
N-cyclopentyl-N-(2-methylpropyl)thiourea;
ethyl2-(N-cyclopentyl-N-(2-methylpropyl)amino]thiazole-4-carboxylate;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-(N-ten-butoxycarbonyl-L-leucinyl)-N =[2-)N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide;
N-[2-(N-cyclopropyl-N-cyclopropylmenthylamino)thiazol-4-ylcarbonyl]-N =(L-
leucinyl)hydrazide;
(S)-2-ten-butoxycarbonylaminopent-4-enoic acid;
N-tent-butoxycarbonyl-L-~3-cyclopropylalanine methyl ester;
N-ten-butoxycarbonyl-L-(3-cycloprQpylalanine;
N-(N-ten-butoxycarbonyl-L-~i-cyclopropylalanyl)-N =[2-)N-cyclopropyl-N-
cyciopropylmethylamino)thiazol-4-yicarbonyl]hydrazide;
N-(L-(3-cyclopropylalanyl)-N'-[2-(N-cyclopropyl-N-
cyclopropylmenthylamino)thiazol-4-
ylcarbonyi]hydrazide;
N-(N-ten-butoxycarbonyl-L-leucinyl)-N =[2-[N-cyclopentyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(L-
leucinyl)hydrazide;
N-(N-ten-butoxycarbonyl-L-~i-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
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N-(L-~i-cyclopropylalanyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-
ylcarbonyl]hydrazide;
N-(N-tert-butoxycarbonyl-L-~i-cyclopropylalanyl)-N =[2-[N-cyclopentyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclopentyl-N-(2-methylpropyl)amino)thiazol-4-ylcarbonyl)-N'-(L-~i-
cyclopropylalanyl)hydrazide;
N-cyclobutyl-N-(2-methylpropyl)amine;
N-benzoyl-N'-cyclobutyl-N =(2-methylpropyl)thiourea;
N-cyclobutyl-N-(2-methylpropyl)thiourea;
ethyl2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazole-4-carboxylate;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyljhydrazide;
L-~i-cyclopropylalanine methyl ester;
(3-isocyanato-L-(3-cyclopropylalanine methyl ester;
N-(2-pyridinylmethoxycarbonyl)-L-~i-cyclopropylalanine methyl ester;
N-(2-pyridinylmethoxycarbonyl)-L-(3-cyclopropylalanine;
N-(N-ten-butoxycarbonyl-L-leucinyl)-N =[2-[N-cyclobutyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-(L-
leucinyl)hydrazide;
N-(N-ten-butoxycarbonyl-L-(3-cyclopropylalanyl)-N'-[2-[N-cyclobutyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-( L-~i-
cyclopropylalanyl)hydrazide;
N-(N-ten-butoxycarbonyl-L-~i-cyclohexylalanyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino)thiazol-4-ylcarbonyl]hydrazide;
N-(L-~i-cyclohexylalanyl)-N=[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-
4-
ylcarbonyl]hydrazide;
ethyl 2-(4-morpholino)pyrimidine-5-carboxylate;
2-(4-morpholino)pyrimidine-5-carboxylic acid;
ethyl 2-( 1-pyrrolidino)pyrimidine-5-carboxylate;
2-(1-pyrrolidino)pyrimidine-5-carboxylic acid;
N-(N-ten-butoxycarbonyl-L-~i-cyclohexylglycinyl)-N'-[2-)N-cyclopropyl-N-
cyclopropylmethyl2imino)thiazol-4-ylcarbonyl]hydrazide;
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N-(L-(3- cyclohexylglycinyl)-N'-[2-(N-cyclopropyl-N-
cyclopropylmenthylamino)thiazol-
4-ylcarbonyl]hydrazide;
ethyl 2-[N-[2-(N,N-dimethylam'ino)ethyl]-N-methylaminoJpyrimidine-S-
carboxylate;
2-[N-[2-(N,N-dimethylamino~thyl)-N-methylamino]pyrimidine-5-carboxylic acid;
ethyl5-hydroxybenzofuran-2-carboxylate;
ethyl 5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylate;
5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylic acid;
ethyl 5-[2-(N,N-dimethylamino)ethoxyJbenzofuran-2-carboxylate;
5-[2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid;
ethyl 5-[2-(1-piperidinyl)ethoxy)benzofuran-2-carboxylate;
5-[2-( 1-piperidinyl)ethoxy]benzofuran-2-carboxylic acid;
ethyl 2-(4-ten-butoxycarbonyl-1-piperazinyl)pyrimidine-4-carboxylate;
2-(4-tent-butoxycarbonyl-I-piperazinyl)pyrimidine-4-carboxylic acid;
N-[N-[2-(4-ten-butoxycarbonyl-I-piperazinyl)pyrimidin-4-ylcarbonyl]-L-~i-
cyclopropylalanyl]-N=[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-
ylcarbonyl]hydrazide;
ethyl 2-(4-ten-butoxycarbonyl-1-piperazinyl)pyrimidine-5-carboxy late;
2-(4-ten-butoxycarbonyl-I-piperazinyl}pyrimidine-5-carboxylic acid;
N-[N-[2-(4-rert-butoxycarbonyl-I-piperazinyl)pyrimidin-S-ylcarbonyl]-L-~i-
cyclopropylalanyl]-N'-[2-[N-cyciopropyl-N-(2-methylpropyl)amino]thiazol-4-
ylcarbonyl]hydrazide;
ethyl 7-hydroxybenzofuran-2-carboxylate;
ethyl 7-[2-(1-piperidinyl)ethoxy]benzofuran-2-carboxylate;
7-[2-(1-piperidinyl)ethoxy]benzofuran-2-carboxylic acid;
ethyl 7-[2-(I-piperidinyl)ethoxy]benzofuran-2-carboxylate;
7-[2-(1-piperidinyl)ethoxy]benzofuran-2-carboxylic acid;
ethyl 7-[2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylate;
7-[2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid;
ethyl 2-[N-[2-(N,N-dimethylamino)ethyl]-N-methylamino]pyrimidine-4-
carboxylate;
2-[N-[2-(N,N-dimethylamino)ethyl]-N-methylamino]pyrimidine-4-carboxylic acid;
2-( 1-naphthyl)thiazole-4-carboxylic acid;
benzyl 5-hydroxybenzofuran-2-carboxylate;
benzyl 5-tent-butoxycarbonylmethoxybenzofuran-2-carboxylate;
5-ten-butoxycarbonylmethoxybenzofuran-2-carboxylic acid;
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WO 99/66925 PCT/iJS99/14561
N-[N-(5-ten-butoxycarbonylmethoxybenzofuran-2-ylcarbonyl)-L-(3-
cyclopropylalanyl]-
N'-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
ethyl 7-[2-( 1-morpholino)ethoxy]benzofuran-2-carboxylate;
7-[2-(1-morpholino)ethoxy]benzofuran-2-carboxylic acid;
benzyl7-hydroxybenzofuran-2-carboxylate;
benzyl 7-ten-butoxycarbonylmethoxybenzofuran-2-carboxylate;
7-ten-butoxycarbonylmethoxybenzofuran-2-carboxylic acid;
N-[N-(7-ten-butoxycarbonylmethoxybenzofuran-2-ylcarbonyl)-L-(3-
cyclopropylalanyl]-N'-
[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
benzyl5-methoxycarbonylbenzofuran-2-carboxylate;
5-methoxycarbonylbenzofuran-2-carboxylic acid;
N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =(N-(5-
methoxycarbonylbenzofuran-2-ylcarbonyl)-L-(3-cyclopropylalanyl]hydrazide; and
N-[N-(7-ten-butoxycarbonylmethoxybenzofuran-2-ylcarbonyl)-L-leucinyl]-N =[2-[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide;
and all salts, hydrates and solvates thereof.
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 ORGANIC
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 SYN'IT~SIS, 2d Ed., Pierce Chemical Co., Rockford, III., 1984. are
generally
illustrative of the technique and are incorporated herein by reference.
Synthetic methods to prepare the compounds of this invention frequently employ
protective groups to mask a reactive functionality or minimize unwanted side
reactions.
Such protective groups are described generally in Green, T.W, PROTECTIVE
GROUPS IN
ORGANIC SYN'I~SIS, 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.
CA 02335876 2000-12-21
WO 99/66925 PCTlUS99/14561
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,
trifluoroacenc,
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 canon; or with an appropriate organic
amine. Cations
such as Li+, Na+, K+, Ca'~'~', Mg'~'f' 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.
This invention also provides a pharmaceutical composition which comprises a
compound according to Formula I and a phanmaceutically acceptable carrier,
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.
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
dihydrate, terra albs,
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
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WO 99/66925 PCT/US99114561
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 protease inhibitors, particularly as
inhibitors of cysteine and serine proteases, more particularly as inhibitors
of cysteine
proteases, even more particularly as inhibitors of cysteine proteases of the
papain
superfamily, yet more particularly as inhibitors of cysteine proteases of the
cathepsin
family, most particularly as inhibitors of cathepsin K. The present invention
also provides
useful compositions and formulations of said compounds, including
pharmaceutical
compositions and formulations of said compounds.
The present compounds are useful for treating diseases in which cysteine
proteases
are implicated, including infections by pneumocystis carinii, trypsanoma
cruzi, trypsanoma
brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria,
tumor metastasis,
metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially
diseases in
which cathepsin K is implicated, most particularly diseases of excessive bone
or cartilage
loss, including osteoporosis, gingival disease including gingivitis and
periodontitis,
arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's
disease;
hypercalcemia of malignancy, and metabolic bone disease.
Metastatic neoplastic cells also typically express high levels of proteolytic
enzymes
that degrade the surrounding matrix, and certain tumors and metastatic
neoplasias may be
effectively treated with the compounds of this invention.
The present invention also provides methods of treatment of diseases caused by
pathological levels of proteases, particularly cysteine and serine proteases,
more
particularly cysteine proteases, even more particularly as inhibitors of
cysteine proteases of
the papain superfamily, yet more particularly cysteine proteases of the
cathepsin family,
which methods comprise administering to an animal, particularly a mammal, most
particularly a human in need thereof a compound of the present invention. The
present
invention especially provides methods of treatment of diseases caused by
pathological
levels of cathepsin K, which methods comprise administering to an animal,
particularly a
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WO 99/66925 PCT/US99/14561
mammal, most particularly a human in need thereof an inhibitor of cathepsin K,
including
a compound of the present invention. The present invention particularly
provides methods
for treating diseases in which cysteine proteases are implicated, including
infections by
pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia
fusiculata; as
well as in schistosomiasis, malaria, tumor metastasis, metachromatic
leukodystrophy,
muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is
implicated,
most particularly diseases of excessive bone or cartilage loss, including
osteoporosis,
gingival disease including gingivitis and periodontitis, arthritis, more
specifically,
osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of
malignancy, and
metabolic bone disease.
This invention further provides a method for treating osteoporosis or
inhibiting
bone loss which comprises internal administration to a patient of an effective
amount of a
compound of Formula I, alone or in combination with other inhibitors of bone
resorption,
such as bisphosphonates (i.e., allendronate), hormone replacement therapy,
anti-estrogens,
or calcitonin. In addition, treatment with a compound of this invention and an
anabolic
agent, such as bone motphogenic protein, iproflavone, may be used to prevent
bone loss or
to increase bone mass.
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 K. 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 mglkg/day. 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 this invention may also be administered orally to the
patient, in
a manner such that the concentration of drug is sufficient to inhibit bone
resorption or io
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.
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No unacceptable toxicological effects are expected when compounds of the
present invention are administered in accordance with the present invention.
Biological Assays
The compounds of this invention 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 K proteolytic catalytic activity
All assays for cathepsin K were carried out with human recombinant enzyme.
Standard assay conditions for the determination of kinetic constants used a
fluorogenic
peptide substrate, typically Cbz-Phe-Ara AMC, and were determined in 100 mM Na
acetate at pH 5.5 containing 20 mM cysteine and ~ 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. Independent
experiments
found that this level of DMSO had no effect on enzyme activity or kinetic
constants. 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 (Kl.app) were calculated
according to
equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140):
v = V,nA l (Ka(I + IlKI. app) +AJ ( 1 )
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WO 99/66925 PCT/US99/14561
where v is the velocity of the reaction with maximal velocity Vm , A is the
concentration
of substrate with Michaelis constant of Ka, and I is the concentration of
inhibitor.
For those compounds whose progress curves showed downward curvature
characteristic of time-dependent inhibition, the data from individual sets was
analyzed to
give lobs according to equation 2:
[AMC] - vss t + (vp - vss~ h - exP f-kobstJ~ ~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 lobs were then
analyzed as a
linear function of inhibitor concentration to generate an apparent second
order rate
constant (lobs / inhibitor concentration or lobs / [I]) describing the time-
dependent
inhibition. A complete discussion of this kinetic treatment has been fully
described
(Morrison et al., Adv. Enrymol. Relat. Areas Mol. Biol., 1988, 61, 201).
Human Osteoclast Resorption Assay
Aliquots of osteoclastoma-derived cell suspensions were removed from liquid
nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640
medium by
centrifugation (1000 rpm, 5 min at 4°C). The medium was aspirated and
replaced with
marine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated
for 30
min on ice The cell suspension was mixed frequently.
The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, S
min at 4°C) and then transferred to a sterile 15 mL centrifuge tube.
The number of
mononuclear cells were enumerated in an improved Neubauer counting chamber.
Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse
IgG,
were removed from their stock bottle and placed into 5 mL of fresh medium
(this washes
away the toxic azide preservative). The medium was removed by immobilizing the
beads
on a magnet and is replaced with fresh medium.
The beads were mixed with the cells and the suspension was incubated for 30
min
on ice. The suspension was mixed frequently. The bead-coated cells were
immobilized on
a magnet and the remaining cells (osteoclast-rich fraction) were decanted into
a sterile 50
mL centrifuge tube. Fresh medium was added to the bead-coated cells to
dislodge any
trapped osteoclasts. This wash process was repeated x 10. The bead-coated
cells were
discarded.
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WO 99/66925 PCT/US99/14561
The osteoclasts were enumerated in a counting chamber, using a large-bore
disposable plastic pasteur pipette to charge the chamber with the sample. The
cells were
pelleted by centrifugation and the density of osteoclasts adjusted to I .Sx
1041mL in EMEM
medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium
bicarbonate. 3
mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL
centrifuge
tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the
appropriate
treatment was added (diluted to SO uM in the EMEM medium). Also included were
appropriate vehicle controls, a positive control (87MEM 1 diluted to 100
ug/mL) and an
isotype control (IgG2a diluted to 100 ug/mL). The tubes were incubate at
37°C for 30 min.
0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-
well
plate and incubated at 37°C for 2 h. Each treatment was screened in
quadruplicate. The
slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate)
and then
placed into fresh treatment or control and incubated at 37°C for 48 h.
The slices were then
washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M
sodium
cacodylate) for 5 min., following which they were washed in water and
incubated in buffer
for 5 min at 37°C. The slices were then washed in cold water and
incubated in cold acetate
buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated,
and the slices were
air dried following a wash in water.
The TRAP positive osteoclasts were enumerated by bright-field microscopy and
were then removed from the surface of the dentine by sonication. Pit volumes
were
determined using the Nikon/Lasertec ILM21 W confocal microscope.
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
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(cm-I). 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 KieseIgel 60 (230-400 mesh) silica gel.
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.
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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 the 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 I
Preparation of N-f2-(N-cyclonropyl-N-cyclopropylmethylamino)thiazol-4
ylcarbonvll N'
IN-(6-methyl-3-nvridinvlmethoxvcarbonyl) L Q tent butylalanyllhvdrazide
a) 3-(6-methyl)pyridylcarbinol
To a sorting solution of ethyl 6-methylnicotinate ( 1.3 g, 8.6 mmol) in
diethyl ether
(50 mL) at 0 (3C was added dropwise lithium aluminum hydride (9.5 mL, 9.5
mmol, I.OM
in THF~. After stirring at room temperature for 2h, the reaction was quenched
by
successive addition of water (0.360 mL), 15% NaOH (0.360 mL), and water (1.1
mL). The
mixture was filtered and the fiitrate concentrated to yield the title compound
as a yellow oil
(0.852 g, 81 %). MS (ESI]: 124.0 (M+H)+.
b) L-(3-ten-butylalanine methyl ester hydrochloride
To a suspension of L-(3-ten-butylalanine (2.0 g, 13.8 mmol) in 2.2-
dimethoxypropane (75 mL) was added concentrated HCI ( 12 mL). After standing
at room
temperature for 16h, the mixture was concentrated and the residue dissolved in
ethyl
acetate. The organic layer was washed with 7.5% aqueous sodium carbonate (2x)
then
dried (MgS04), filtered and concentrated to yield the free base which was
treated with 1.0
eq HCl in diethyi ether. The precipitate was filtered off to yield the
hydrochloride salt as a
white solid (1.32 g, 49%). MS (ESI}: 159.7 (M+H)+.
c) ~i-isocyanato-L-(3-tert-butyIalanine methyl ester
To a suspension of the compound of Example 1 (b) ( 1.32 g, 6.75 mmol) in
dichloromethane (50 mL) was added pyridine (2.1 g, 27 mmol). The solution was
taken to
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0 ~C and a solution of triphosgene (0.862 g, 2.90 mmol) in dichloromethane (
10 mL) was
added dropwise over 40 min. After stirring at 0 ~iC for 2h, the solution was
partitioned
between O.SN HCl and dichloromethane. The organic layer was washed
successively with
cold O.SN HCI, cold water, and cold brine, dried (MaS04), filtered and
concentrated to
S yield the title compound as a pale yellow oil (1.24 g, 99%). 1HNMR (400 MHz,
CDCl3) j3
3.99 (dd, 1H), 3.81 (s, 3H), 1.89 (dd, 1H), 1.58 (dd, 1H), 0.97 (s, 9H).
d) N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine methyl ester
A solution of the compound of Example 1(c} (0.404 g, 2.18 mmol) and the
compound of Example 1 (a) (0.269 g, 2.18 mmol) in toluene (3 mL) was heated at
reflux for
16h. The solution was then concentrated and purified by column chromatography
(silica
gel; ethyl acetate/hexane) to yield the title compound as a yellow solid
(0.447 g, 71 %). MS
(ESn: 309.3 (M+H)+.
1S e) N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine
To a stirring solution of the compound of Example 1 (d) (0.447 g, 1.4S mmol)
in
THF (7.0 mL) and water (7.0 mL) was added lithium hydroxide monohydrate (0.069
g, 1.60
mmol). After stirring at reflux for 16h, the solution was concentrated and the
residue was
dissolved in water and acidified with leq IN HCI. The mixture was frozen and
placed on a
lyophilizer for 16h to yield the title compound as an off white solid (0.426
g, 100%). MS
(ESn: 295.2 (M+H)+.
f) N-cyclopropylmethylcyclopropylamine
Cyclopropylamine (6.6 g, 115.4 mmol, 8.0 mL) and cyclopropylcarboxaldehyde
2S (8.09 g, 11 S.4 mmol, 8.6 mL) were dissolved in methylene chloride (40 mL)
and allowed to
stir at room temperature. After two hours, the mixture was dried (MgS04),
filtered and
concentrated to afford the pure inane, which was dissolved in ether (SO mL),
the solution
was cooled to 0 oC and lithium aluminum hydride (l70 mmol, 170 mL, 1 M in
ether) was
added slowly. The solution mixture was stirred for two hours and then quenched
at 0 oC
with water, sodium hydroxyde (15%), water. The solid was removed by filtration
and
washed with ether. The filtrate was dried (MgS04), filtered and concentrated
to afford the
title compound as a colorless liquid (6.10 g, 47%). MS (ESn: 111.9 (M+H)+.
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g) N-benzoyl-N=cyclopropyl-N=cyclopropylmethylthiourea
The compound of Example I (f) (6.10 g, 54.86 mmol) was dissolved in chlorofonm
( 100 mL) and benzoyl isothiocyanate (8.95 g, 54.86 mmol, 8.00 mL) was added.
After
stirring 45 minutes at room temperature, the solution was concentrated to give
the title
compound as an orange solid (15.05 g, 100%). MS (ESn: 275.1 (M+H)+.
h) N-cyclopropyl-N-cyclopropylmethylthiourea
The compound of Example 1 (g) ( 15.05 g, 54.86 mmol) was dissolved in methanol
(100 mL} and water (100 mL), potassium carbonate (22.7 g, 164.6 mmol) was
added and
the solution was heated at reflux overnight. The reaction mixture was
concentrated,
redissolved in ethyl acetate, washed with sodium bicarbonate, water and dried
(MgS04),
filtered and concentrated to afford the title compound as a yellow solid (9.34
g, 100%). MS
(ESn: 170.9 (M).
i) ethyl 2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazole-4.-carboxylate
The compound of Example I(h) (9.34 g, 54.86 mmol) was dissolved in 50 mL of
ethanol upon heating. The solution was cooled to room temperature and
ethyIbromopyruvate (10.7 g, 54.86 mmol, 6.8 mL) was added. The reaction
mixture was
heated at reflux for 30 minutes, then concentrated. The residue was
partitioned between
ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was
extracted
with ethyl acetate and the combined organic phases were washed with saturated
brine, dried
{MgS04), filtered and concentrated to give an orange oil. The crude product
was passed
trough silica gel eluting with ethyl acetate/ hexane ( 1:3) to give the title
compound as a
yellow oil (13.53 g, 93%). MS (ESn: 267.2 (M+H)+.
j) N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-yicarbonyl]hydrazide
The compound of Example I (i) ( 13.53 g, 50.80 mmol) was dissolved in 100 mL
ethanol and hydrazine monohydrate (25.4 g, 508 mmol, 24.6 mL) was added. The
solution
was heated at reflux for 2 hours, then concentrated. The crude product was
passed trough
silica gel eluting with 10% methanol in methylene chloride to give the title
compound as a
yellow solid (11.04 g, 86%). MS (ESn: 253.1 (M+H)+.
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k) N-[2-(N-cyclopropyl-N-cyclopropyimethylamino)thiazol-4-ylcarbonyl]-N=[N-(6-
methyl-
3-pyridinylmethoxycarbonyl)-L-(3-tent-butylalanyl]hydrazide
To a stirring solution of the compound of Example 1(e) (160 mg, 0.48 mmol) in
2.5
mL of DMF was added the compound of Example 1(j) (120 mg, 0.48 mmol), 1-
hydroxybenzotriazole (6.0 mg, 0.05 mmol), and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol). After stirring at room
temperature
for 16 h, the solution was partitioned between ethyl acetate and water. The
aqueous layer
was extracted with ethyl acetate. The combined organic layers were washed with
saturated
brine, dried (MgS04), filtered and concentrated. The crude product was
purified by
column chromatography on silica gel (6% methanol in methylene chloride) to
afford the
title compound as a white solid (200 mg, 80%). MS (ES17: 529.3 (M+H)+.
Example 2
Preparation of N-f2-fN-cvcloyroovl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyll N' fN
(6-nhenvlnicotinoyi -L-leucinyl)_hydrazide
a) tetrakis[tris(o-tolyl)phosphine]palladium(0)
Palladium acetate (450 mg, 2.0 mmol) was dissolved in toluene (50 mL) and
treated
with tris{o-tolyl)phosphine (800 mg, 2.63 mmol). The solution was heated to
50°C for
three minutes and cooled to room temperature. The solution was reduced to a
quarter of its
volume and, after addition of hexane (50 mL), the precipitate was filtered off
and dried
under vacuum to give the title compound as a yellow solid (670 mg, 71 %),
which was
dissolved in dimethylacetamide (8.4 mL) and the catalyst solution was degassed
and purged
with argon several times before use.
b) ethyl 6-phenylnicotinate
Ethyl-6-chloronicotinate ( I .7 g, 9.16 mmol), phenylboronic acid acid ( 1.675
g,
13.74 mmol) and potassium carbonate (2.5 g, 18.32 mmol) were dissolved in
ortho-xylene
(20 mL) and the solution was heated to 100°C. When the temperature was
reached a freshly
prepared solution of the compound of Example 2(a) (60 (3L, 0.009 mmol} was
injected and
the reaction mixture was heated at 130°C overnight. Subsequently the
cooled reaction
mixture was extracted twice with methylene chloride. The combined organic
layers were
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washed with water. The solvent was then removed under vacuum to give a brown
oil. The
crude residue was purified by column chromatography on silica gel (ethyl
acetate/hexane,
1:10) to give the title compound as a white solid (2.035 g, 98%). MS (ESn:
228.2
(M+H)+.
c) 6-phenylnicotinic acid
Following the procedure of Example 1 (e), except substituting ethyl 6-
phenylnicotinate for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-rert-
butylalanine
methyl ester, the title compound was prepared as a white solid ( I65 mg, 10%).
MS (ESn:
200.1 (M+H)+.
d) N-cyclopropyl-N-(2-methylpropyl)amine
Cyclopropylamine (3.3 g, 57.7 mmol, 4.0 mL) and isobutyraldehyde (4.04 g, 57.7
mmol, 5.25 mL) were dissolved in methylene chloride (40 mL) and allowed to
stir at room
temperature. After two hours, the mixture was dried (MgS04), filtered and
concentrated to
afford the pure imine, which was dissolved in methylene chloride (200 mL), the
solution
was cooled to 0 oC and sodium triacetoxyborohydride (30.5 g, 144.25 mmol) was
added.
The mixture was allowed to stir for two hours and then washed with sodium
bicarbonate
{5% aqueous), dried (MgS04), filtered and concentrated to afford the title
compound as a
colorless liquid (2.25 g, 35%). MS (ESn: 114.1 (M+H)+.
e) N-(N-tent-butoxycarbonyl-L-leucinyl)-N=[2-[N-cyciopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1(g)-1(k}, except substituting N-
cyclopropyl-
N-(2-methylpropyl)amine for N-cyclopropylmethylcyclopropylamine in step (g),
and N-
tert-butoxycarbonyl-L-leucine for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-
ten-
butylalanine in step (k), the title compound was prepared as a white solid (
1.66 g, 96%).
MS (ESn: 468.2 (M+H)+.
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f) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino)thiazol-4-ylcarbonyi)-N=(L-
leucinyl)hydrazide
To a stirring solution of the compound of Example 2(e) ( 1.66 g, 3.54 mmoi) in
10
ml of methylene chloride was added 5 mL of trifluoroacetic acid. After
stirring one hour at
room remperature the solution was concentrated and the residue was redissolved
in
methylene chloride, washed with saturated aqueous sodium bicarbonate, dried
(MgS04),
filtered and concentrated to afford the title compound as a yellow solid (1.30
g, 100%). MS
(ESn: 368.3 (M+H)+.
g) N-[2-[N-cyclopropyl-N-(2-methylpropyl)aminojthiazol-4-ylcarbonyl]-N'-[N-(6-
phenylnicotinoyl)-L-leucinylJhydrazide
Following the procedure of Example i (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyl)-N=[L-Ieucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cycIopropylmethylamino)thiazol-4-ylcarbonyl)hydrazide and 6-
phenyInicotinic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-
butylalanine,
the title compound was prepared as a white solid (200 mg, 69%). MS (ESn: 549.4
(M+H)+.
Example 3
Preparation of N-(2-(N-cvclonropyl-N-cyclonronvlmethylamino)thiazol-4
vlcarbonyll N'
(N-(2 -pyridinylmethoxvcarbonyl)-L_J3-ten-butvlalanvllhvdrazide
Following the procedure of Example 1(c)-I(k), except substituting 2-
pyridylcarbinol for 6-methyl-3-pyridylcarbinol in step (d), the title compound
was prepared
as a white solid (123 mg, 70%). MS (ESI): 515.2 (M+H)+.
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Example 4
Preparation of N-f2-fN-cvclopropyl-N-(2-methv~ropy~aminolthiazol-4-vlcarbonytl
N' 1N
f4-(2-nyridinyl)benzoyll-L-leucinyllh drazide
a) 4-carbomethoxyphenylboronic acid
4-Formylbenzene boronic acid (2.05 g, 13.67 mmol) and potassium cyanide (6.2
g,
95.7 mmol) were dissolved in methanol (250 mL). Activated manganese dioxide
(2.4 g,
273.4 mmol} was added and the mixture was stirred at room temperature for two
days. The
solution was then filtered through ceIite, concentrated and partitioned
between ethyl acetate
and hydrochloric acid (3N), then washed with water and saturated brine. The
organic phase
was dried (MgS04), filtered and concentrated to afford the title compound as a
white solid
(2.2 g, 89%). MS (ESn: 179.0 (M-H)+.
b) methyl 4-(2-pyridinyl)benzoate
2-Bromopyridine ( 1.44 g, 9.12 mmol, 0.87 mL), the compound of Example 4(a)
(2.135 g, 11.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg,
0.18 mmol)
were suspended in toluene (30 mL} and ethanol (30 mL) and sodium carbonate
(2.5 g, 23.71
mmol) was then added. The mixture was stirred at 90°C overnight. The
solution was
partitioned between ethyl acetate and water, then washed successively with
water and brine.
The organic phase was dried (MgS04), filtered and concentrated to give an
orange solid.
The crude residue was purified by column chromatography on silica gel (ethyl
acetate/hexane, I :3 then 2: I and 3:1 ) to give the title compound as a white
solid (970 mg,
50%). MS (ESn: 214.1 (M+H)+.
c) 4-(2-pyridinyl}benzoic acid
Following the procedure of Example 1 (e), except substituting methyl 4-{2-
pyridinyl)benzoate for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-
butylalanine
methyl ester, the title compound was prepared as a white solid (1.1 g, 100%).
MS (ESn:
200.1 (M+H)+.
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d) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[4-
(2-
pyridinyl)benzoyl]-L-leucinyl]hydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)aminojthiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-(2-
pyridinyl)benzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-
butylalanine,
the title compound was prepared as a white solid (90 mg, 44%). MS (ESn: 549.2
(M+H)+.
Example 5
Preparation of N-f2-fN-cycloprouyl-N-(2-methylnropvl)aminolthiazol-
4.~Icarbonyll N' fN
(6-methvluicolinoyl)-L-leucinvllhydrazide
Following the procedure of Example I(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethyiamino)thiazol-4-ylcarbonyl]hydrazide and 6-
methylpicolinic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-
butylalanine,
the title compound was prepared as a white solid (I30 mg, 86%). MS (ESn: 487.2
(M+H)+.
Example 6
Preparation of N-12-fN-cvclonronvl-N-(2-methylpropvl)aminolthiazol-4
vlcarbonyll N' fN
(3,4-difluorobenzoyll-L-leucinvl hydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)aminojthiazol-4-ylcarbonylj-N=(L-leucinyl]hydrazide for N-(2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyljhydrazide and 3,4-
difluorobenzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-tert-
butylalanine,
the title compound was prepared as a white solid (130 mg, 93%). MS (ESl):
508.2
(M+H)+.
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Example 7
Preparation of N-f2-fN-cvclonropyl-N- 2-methylpropyl)aminolthiazol-4
lcarbonyll N' fN
C4-methylimidazol-5-yIcarbonyl)-L-leucinyllhvdrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
methylirnidazole-5-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-
L-(3-ten-
butylalanine, the title compound was prepared as a white solid (80 mg, 69%).
MS (ESn:
476.3 (M+H)+.
Example 8
Preparation of N-fN-(3 4-dimethoxybenzoyl -L-leucinyll-N=f2-(1
naphthvl)thiazol-4
ylcarbonvllhydrazide
a) ethyl 2-aminothiazole-4-carboxylate hydrobromide
Following the procedure of Example 1 (i), except substituting thiourea for N-
cyclopropyl-N-cyclopropylmethylthiourea, the title compound was prepared as as
pale
yellow crystals (132.74 g, 85%). MS (ESn: 172.9 (M+H)+.
b) 2-bromothiazole-4-carboxylic acid
To a stirring suspension of the compound of Example 8(a) (32.11 g, 0.127 mol)
in
16% HBr (aq) (40 OmL) at 0°C a solution of NaN02 (9.11 g, 0.132 mol) in
water ( 16 mL)
was added. After stirring for 35 nun, CuBr (20.6 g, 0.144 mol) was added
followed by an
additional 150 mL of 16% HBr(aq). The mixture was heated at 70°C for Ih
and
immediately filtered. The filtrate was saturated with NaCl and extracted with
ethyl acetate
(2 x 500 mL). The organic phases were combined, dried (MgS04), filtered and
concentrated to a brown solid. This was combined with solid collected by
filtration and
used without further purification or characterization in the next step.
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c) ethyl 2-bromothiazole-4-carboxylate
The compound of Example 8(b) was heated at reflux in EtOH (1 L) for lh then
filtered. To the filtrate was added 48% (aq) HBr (3.2 mL). The solution was
returned to
reflux for 24h. After concentrating the solution, it was redissolved in EtOAc
( 1 L) and
washed successively with saturated aqueous NaHC03 ( 1 L) and brine ( 1 L). The
organic
layer was dried (MgS04), filtered, decolorized with charcoal, filtered through
Celite, and
concentrated to give the title compound as a pale yellow solid (16.95 g, 56%
from
aminothiazole). 1HNMR (400MHz, CDC13) (3 8.13 (s, 1H), 4.41 (q, 2H), 1.40 (t,
3H).
d) ethyl 2-(1-naphthyl)thiazole-4-carboxylate
To a stirring mixture of the compound of Example 8(c) (13.7 g, 0.0581 mol), I-
naphthalene boronic acid ( 13.0 g, 0.0754 mol), and
tetrakis(triphenylphosphine)palladium(0) (2.7 g, 4 mol%) in EtOH (125 mL) and
toluene
( 125 mL) was added NaHC03 ( 1 S 1 mL, 1.0 M in water). After stirring at
reflux for 4h the
mixture was cooled and partitioned between 1N HCl (750 mL) and ethyl acetate
(750 mL).
The organic layer was washed with brine, dried (MgS04), filtered and
concentrated. The
residue was purified by column chromatography (silica gel, ethyl acetate/
hexane} to yield
the title compound as a foamy solid. ( 10.4 g, 63%). MS {ESI): 284.2 (M+H)+.
e) 2-(I-naphthyl)thiazole-4-ylcarbonylhydrazide
Following the procedure of Example 1(j), except substituting ethyl 2-(I-
naphthyl)thiazole-4-carboxylate for ethyl 2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazole-4-carboxylate, the title compound was prepared
as a pale
yellow solid (9.7 g, 98%). MS (ESn: 270.1 (M+H)+.
f) N-{N-rent-butoxycarbonyl-L-leucinyl)-N=[2-(1-naphthyl)thiazol-4-
ylcarbonyl]hydrazide
Following the procedure of Example 1 (k), except substituting 2-( 1-
naphthyl)thiazole-4.-carbohydrazide for N-[2-{N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and N-ten-butoxycarbonyl-
L-
leucine for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the
title
compound was prepared as a white solid (10.38 g, 97%). MS (ESI): 483.3 (M+H)+.
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g) N-(L-leucinyl)-N=[2-(1-naphthyl)thiazol-4-ylcarbonylJhydrazide
Following the procedure of Example 2(f), except substituting N-(N-ten-
butoXycarbonyl-L-leucinyl)-N=[2-( 1-naphthyl)thiazol-4-ylcarbonylJhydrazide
for N-(N-tert-
butoxycarbonyl-L-leucinyl)-N =[2-[N-cyclopropyl-N-(2-
methylpropyl)aminoJthiazol-4-
ylcarbonylJhydrazide, the title compound was prepared as an off white solid
(8.02 g, 98%).
MS (ESn: 383.2 (M+H)+.
h) N-[N-(3,4-dimethoxybenzoyl)-L-leucinylJ-N=[2-(1-naphthyl)thiazol-4-
ylcarbonylJhydrazide
Following the procedure of Example 1(k), except substituting N-(L-leucinyl)-N'-
[2-
( 1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3,4-dimethoxybenzoic
acid
for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(i-ten-butylalanine, the title
compound
was prepared as a white solid (0.089 g, 50%). MS (ES)]: 547.2 (M+H)+.
Example 9
Preparation of N-fN-(3 4-difluorobenzoyl)-L-leucinyll N' f2 (1
naphthlrl)thiazol-4
ylcarbonvllhydrazide
Following the procedure of Example 1(k), except substituting N-(L-leucinyl)-
N=[2-
( 1-naphthyl)thiazol~-ylcarbonylJhydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonylJhydrazide and 3,4-difluorobenzoic
acid for
N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-J3-ten-butylalanine, the title
compound was
prepared as a white solid (0.131 g, 77%). MS (ESn: 523.1 (M+H)+.
Example 10
Preparation of N-fN-(5-butylpicolinoYl)-L-leucinyll N' f2 (1 naphthyl)thiazol-
4-
ylcarbonvllh~drazide
Following the procedure of Example 1(k), except substituting N-(L-leucinyl)-N'-
[2-
( 1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
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cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-butylpicolinic
acid for N-(6-
methyl-3-pyridinylmethoxycarbonyl)-L-~-ten-butylalanine, the title compound
was
prepared as a white solid (0.114 g, 64%). MS (ESn: 544.2 (M+H)+.
Example 11
Preparation of N-f2-(1-nanhthvl)thiazol-4-vlcarbonvll N' fN (3
nropvloxypicolinoyl) L
leucinyllhydrazide
Following the procedure of Example 1 (k), except substituting N-(L-leucinyl}-N
=[2-
( 1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3-propyloxypicolinic
acid for
N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title
compound was
prepared as a white solid (0.060 g, 34%). MS (ESI): X46.2 (M+H)+.
Example 12
Prevaration of N-f2-( 1-naphthvl)thiazol-4-vlcarbonyll N' fN f6 ( 1
nyrrolyl)nicotino ly 1 L-
leucinyll)~drazide
Following the procedure of Example 1(k), except substituting N-(L-leucinyl)-
N=(2-
( 1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarhonyl]hydrazide and 6-( 1-
pyrrolyl)nicotinic acid
for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title
compound
was prepared as a white solid (0.093 g, 52%). MS (ESI): 553.2 (M+H)+.
Example 13
Preparation of N-f2-(1-naphthvl)thiazol-4-ylcarbonvll N' fN f6-(1
pvrazolvl)nicotinovll L
leucinvllhydrazide
Following the procedure of Example 1 (k), except substituting N-(L-leucinyl)-
N'-[2-
(1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
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cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 6-(1-
pyrazolyl)nicotinic acid
for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine, the title
compound
was prepared as a white solid (0.130g, 72%). MS (ESn: 554.2 (M+H)+.
Example 14
Preparation of N-fN-f6-(1-imidazol 1 nicotinoyll L leucinyll N' f2 (1
naphthyl)thiazol-4-
vlcarbonyllhydrazide
Following the procedure of Example 1(k), except substituting N-(L-leucinyl)-N'-
[2-
(1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 6-( 1-
imidazoIyl)nicotinic acid
for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-tent-butylalanine, the title
compound
was prepared as a white solid (0.121 g, 67%). MS (ES)7: 554.2 (M+H)+.
Example 15
Preparation of (IS)-N-f4-f 1-(N-benzylo~carbonylamino) 3 methvlbutyllthiazol 2
ylcarbonyll-N=f2-l2-benzyloxyphenyl)thiazol-4-ylcarbonyllhydrazide
a) N-benzyloxycarbonyl-(L)-leucinamide
To a solution of N-benzyloxycarbonyl-L-leucine (3.5 g, 13.2 mmol ) in dry THF
(40 mL) at -40 °C was added isobutylchlorofonnate ( 1.8 g, 13.2 mmol)
and N-
methylmorphiline (2.8 g, 27.7mmo1). After 15 minutes of stirring, ammonia was
bubbled
through the mixture for an additional 15 minutes, then warmed to room
temperature and
allowed to stir for 2 hours. The mixture was filtered and the filtrate
concentrated in vacuo
to yield title compound as a white solid (3.2 g, 92%). MS (ESn: 265.2 (M+H)+.
b) N-benzyloxycarbonyl-L-leucinethioamide
To a stirring solution of the compound of Example 15(a) (3.2 g, 12.4 mmoi) in
dry
THF (50 mL) was added Lawesson's reagent (3.0 g, 7.46 mmol) and the mixture
was stirred
at room temperature under argon overnight. The solvent was evaporated and the
residue
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purified by column chromatography (silica gel, ethyl acetate/hexane) to give
the title
compound as a white solid (3.21 g, 92%). MS (ESn: 281.1 (M+H)+.
c) (1S)-I-(benzyloxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)-3-
methylbutane
The compound of Example 15(b) (3.21 g, I I.5 mmol) was stirred in dry acetone
(100 mL) under argon at -10 °C. Ethylbromopyruvate (2.5 g, 12.6 mmol)
was added and
stirred for lh at -10 °C. The solution was poured into a well stirred
mixture of chloroform
and water and then into saturated sodium bicarbonate solution. The organic
phase was
separated and the aqueous layer extracted with chloroform. The combined
organic extracts
were dried (MgS04), filtered and concentrated to an oil. The oily residue was
treated with
TFAA (2.6 g, 12.6 mmol) and pyridine (2.0 g, 25.3 mmol) in dichloromethane for
lh at -20
°C. Excess solvent was removed in vacuo and the residue was dissolved
in
dichloromethane. The solution was washed with saturated aqueous sodium
bicarbonate and
I.ON KHS04 until pH 7 was reached. The solution was dried (MgS04), filtered
and
concentrated to an oil which was purified by column chromatography (silica
gel, ethyl
acetate/hexane) to give the title compound as a white solid (3.59 g, 83%). MS
(ESn: 377.2
(M+H)+.
d) (1S)-1-(benzyloxycarbonyl)amino-I-(4-carboxythiazol-2-yl)-3-methylbutane
Following the procedure of Example I(e), except substituting (1S)-1-
(benzyloxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane for N-(6-
methyl-
3-pyridinylmethoxycarbonyl)-L-(3-ten-butylaianine methyl ester, the title
compound was
prepared as an off white solid (3.2 g, 100%). MS (ESn: 349.3 (M+H)+.
e) 2-benzyloxybromobenzene
To a stirring solution of 2-bromophenol (10.0 g, 57.8 mmol), and benzyl
bromide
(9.9 g, 57.8 mmol) in acetone (150 mL) was added K2C03 (12.0 g, 86.7 mmol).
After
stirring at reflux for 4h, the mixture was partitioned between ethyl acetate
and water. The
organic layer was washed with brine, dried (MgS04), filtered and concentrated.
The
residue was purified by column chromatography (silica gel, ethyl
acetate/hexane) to yield
the title compound as a colorless oil (15.2 g, 57.8 mmol). 1HNMR (400 MHz,
CDC13) (3
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7.62 (m, 1H), 7.54 (m, 2H), 7.45 (m, 2H), 7.37 (m, 1H), 7.28 (m, 1H), 6.98 (m,
1H), 6.91
(m, 1 H), 5.17 (s, 2H).
f) 2-benzyloxyphenylboronic acid
To a stirring solution of the compound of Example 15(e) (15.2 g, 57.8 mmol} in
THF (100 mL) at -78 °C was added dropwise n-BuLi (23.1 mL, 2.SM in
hexane, 57.8
mmol). The mixture stirred at -78 °C for 25 min when added via
cannulation to a stirring
solution of triisopropylborate (54.4 g, 289 mmol) in THF ( 100 mL) at -78
°C. After
warming to room temperature and stirring for 3h, the mixture was poured into
3N HCl ( 100
mL) and extracted with ethyl acetate (3 x 200 riiL,). The organic layers were
combined,
washed successively with water and brine, dried (MgS04), filtered and
concentrated. The
residue was purified by column chromatography (silica gel, ethyl
acetate/hexane) to yield
the title compound as a pale yellow solid (6.9 g, 52%). 1HNMR (400 MHz, CDCl3)
(3 7.90
(d, 1H), 7.42 (m, 6H), 7.07 (t, 1H), 7.02 (d, 1H), 6.05 (s, 2H), 5.16 (s, 2H).
g) ethyl 2-(2-benzyloxyphenyl)thiazole-4-carboxylate
To a stirring solution of the compound of Example 8(c) (4.0 g, 16.9 mmol), the
compound of Example 15(f) (4:19 g, 18.8 mmol),
tetrakis(triphenylphosphine)palladium(0)
(0.65 g, 0.57 mmol) in dimethoxyethane (60 mL) was added cesium fluoride (8.58
g, 56.5
mmol) and the mixture was heated at 85 °C for 16 h.
Tetrakis(triphenylphosphine)palladium(0) (0.65 g, 057 mmol) was added and
heating at 85
°C was continued for 5 h. The mixture was diluted with water (60 mL)
and extracted with
ethyl acetate (2 x 120 mL). The combined extracts were washed with saturated
aqueous
NaHC03 and saturated brine, dried (MgS04), filtered and concentrated. The
residue was
purified by flash chromatography on 180 g of 230-400 mesh silica gel, eluting
with 15%
ethyl acetate in hexanes, to provide the title compound as a white solid (3.22
g, 56%). MS
(ESn: 340.3 (M+H)+.
h) 2-(2-benzyloxyphenyl)thiazol-4-ylcarbonylhydrazide
Following the procedure of Example 1(j), except substituting ethyl 2-(1-
naphthyl)thiazole-4-carboxylate for ethyl 2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazole-4-carboxylate, the title compound was prepared
as a
white solid (2.02 g, 87%): MS (ESn: 326.2 (M+H)+.
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i) (IS)-N-[4-[1-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-
N=[2-(2-
benzyloxyphenyl)thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1 (k), except substituting 2-(2-
benzyloxyphenyl)thiazol-4-ylcarbonylhydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and (1S)-I-
(benzyloxycarbonyl)amino-I-(4-carboxythiazol-2-yl)-3-methylbutane for N-(6-
methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title compound was
prepared as a
white solid (0.171 g, 73%). MS (ESn: 656.1 (M+H)+.
Example 16
Preparation of (IS)-N-f4-f 1-(N-benzyloxvcarbonylamino) 3 methylbutyllthiazol
2
~carbonvll-N=f2-( 1-naphthyl)thiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 1 (k), except substituting 2-( I-
naphthyl)thiazole-4-carbohydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and (IS)-I-
(benzyloxycarbonyl)amino-1-(4-carboxythiazol-2-yl)-3-methylbutane for N-(6-
methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title compound was
prepared as a
white solid (O.I30 g, 60%). MS (ESn: 600.4 (M+H)+.
Example 17
Preparation of (1S)-N-f4-f 1-(N-benzyloxycarbonylamino) 3 methvlbutyl]thiazol
2
ylcarbonyll-N=f2-(N-cycloaropyi-N-cycionrop lmethylamino)thiazol-4
ylcarbonyllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-(N-
cyclopropyl-
N-cyclopropylmethylamino)thiazol-4-ylcarbonylJhydrazide for N-[2-(N-
cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and (1S)-1-
(benzyloxycarbonyl)amino-I-(4-carboxythiazol-2-yl)-3-methylbutane for N-(6-
methyl-3-
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pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title compound was
prepared as a
white solid (0.176 g, 84%). MS (ESn: 583.3 (M+H)+.
Example 18
Preparation of (1S)-N-f4-f I-(N-benzvlox carbonylamino)-3-meth~lbutyllthiazol-
2-
ylcarbonyll-N=f2-fN-methyl-N-l2-methvlpropyl)aminolthiazol-4
ylcarbon~rllh~drazide
Following the procedure of Example 1 (g)-1 (k), except substituting N-
cyclopropyl-
N-(2-methylpropyl)amine for N-cyclopropylmethylcyclopropylamine in step (g),
and (1S)-
1-(benzyloxycarbonyl)amino-1-(4-carboxythiazol-2-yl)-3-methylbutane for N-(6-
methyl-3-
pyridinylmethoxycarbonyl)-L-~3-ten-butylalanine in step (k), the title
compound was
prepared as a white solid (0.177 g, 88%). MS (ESl): 559.2 (M+H)+.
Example 19
Preparation of N-fN-(5-butyl-2-p~dinylmethoxycarbonvl)-L-leucinyll-N=f2-yN-
cyclopropyl-N-cyclopropylmeth ly amino,thiazoi-4-ylcarbonyIlhydrazide
Following the procedure of Example 1(a)-1{k), except substituting 5-
butylpicolinic
acid for methyl 6-methylnicotinate in step (a), and L-leucine methyl ester for
L-~i-tert-
butylaIanine methyl ester in step (c), the title compound was prepared as a
white solid (110
mg, 73%). MS (ESn: SS7.4 (M+H)+.
Example 20
Preparation of N-fN-(5-but~pyridinylmethoxycarbonyl)-L-leucinyIl-N=f2-fN-
cyclopropvl-N-(2-methvlpropyl)aminolthiazoi-4-vlcarbonyllhvdrazide
Following the procedure of Example 1(a)-I(k), except substituting 5-
butylpicolinic
acid for methyl 6-methylnicotinate in step (a), L-leucine methyl ester for L-
~3-tert-
butylalanine methyl ester in step (c), and N-cyclopropyl-N-(2-
methylpropyl)amine for N-
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cyclopropylmethylcyclopropylamine in step (g), the title compound was prepared
as a white
solid (128 mg, 45%). MS (ESI): 559.3 (M+H)+.
Example 21
Preparation of N-f2-(1-naphthyl)thiazol-4-ylcarbonyll-N=fN-f6-(4-
trofluoromethylphenyl)nicotinoyll-L-leucinyllhydrazide
Following the procedure of Example 1(k), except substituting N-(L-leucinyl)-
N=[2-
(1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 6-(4
trofluoromethylphenyl)nicotinic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-
rent-butylalanine, the title compound was prepared as a white solid (0.164 g,
78%). MS
(ESn: 648.1 (M+H)+.
Example 22
Preparation of N-fN-(6-methvlpicolinoyl)-L-leucinyll-N=f2-(1-naphthyl)thiazol-
4-
vlcarbonyllh~drazide
Following the procedure of Example 1(k), except substituting N-(L-leucinyl)-
N=[2-
(1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 6-methylpicolinic
acid for N-
(6-methyl-3-pyridinylmethoxycarbonyl)-L-~3-ten-butylalanine, the title
compound was
prepared as a white solid (0.108 g, 66%). MS (ESn: 502.2 (M+H)+.
Example 23
Preparation of N-f2-(1-naphthyl)thiazol-4-ylcarbonyl]-N'-fN-f4-(2
pyridinvl)benz~l]-L-
leucinvllhydrazide
Following the procedure of Example 1(k), except substituting N-(L-leucinyl)-N'-
(2-
(1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
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cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-(2-
pytidinyl)benzoic acid
for N-{6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-tent-butylalanine, the title
compound
was prepared as a white solid (0.084 g, 46%). MS (ESn: 564.2 (M+H)+.
Example 24
Preparation of N-fN-(5-butyl-2-pyridinylmethoxycarbon~l)-L-leucinyll-N=j2-(I-
naphthyllthiazol-4-yicarbonyllhydrazide
Following the procedure of Example I(a)-I(e) and 1(k), except substituting 5-
butylpicolinic acid for methyl 6-methylnicotinate in step (a), L-leucine
methyl ester for L-(3-
tert-butylalanine methyl ester in step (c), and 2-(I-naphthyl)thiazole-4-
carbohydrazide for
N-[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide in
step
(k), the title compound was prepared as a white solid (0.141 g, 75%). MS (ESn:
574.2
(M+H)+.
Examvle 25
Preparation of N-f2-ll-naphthyl)thiazol-4-vlcarbonyll-N=fN-
(6=phenxldicotinoyl)-L-
leucinvllh,~rdrazide
Following the procedure of Example I (k), except substituting N-(L-leucinyl)-
N'-[2-
( 1-naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 6-phenylnicotinic
acid for N-
(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-tert-butylalanine, the title
compound was
prepared as a white solid (0.095 g, 52%). MS (ESn: 564.2 (M+H)+.
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Example 26
Preparation of N-f2-1N-cyclopropyl-N-(2-methylprop,~minolthiazol-4-~lcarbonyl]-
N=1N-
(6-phenvlnicotinoyll-L-~i-ten-butylalanvllhydrazide
S
a) N-ten-butoxycarbonyl-L-(3-ten-butylalanine
L-(3-tert-butyl alanine (300 mg, 2.06 mmol) was dissolved in dioxane (4 mL),
water
(2 mL) and a solution of 1 N sodium hydroxyde (2 mL) and taken to 0°C.
Di-tert-butyl
dicarbonate (495 mg, 2.27 mmol) was added and the mixture was allowed to stir
at room
ZO temperature for two hours. The solution was then concentrated and
redissolved in water (5
mL) and ethyl acetate was added. The aqueous phase was acidified to reach pH 3
with 0.3
N KHS04, then extracted twice with ethyl acetate. The combined organic layers
were
washed with water, dried (MgS04), filtered and concentrated to give the title
compound as
a colorless oil.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-tert-
butoxycarbonyl-L-~-tert-butylalanyl]hydrazide
Following the procedure of Example 1(g)-1(k), except substituting N-
cyclopropyl-
N-(2-methylpropyl)amine for N-cyclopropylmethylcyclopropylamine in step (g),
and N-
tent-butoxycarbonyl-L-~i-ten-butylalanine for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-
(3-ten-butylalanine in step (k), the title compound was prepared as a white
solid ( 1.2 g,
76%). MS (ES~: 482.3 (M+H)+.
c) N-[2-[N-cyclopropyl-N-(2-rnethylpropyl)amino]thiazol-4-ylcarbonyl]-N=(L-~i-
tert-
butylalanyl)hydrazide
Following the procedure of Example 2(f), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-ten-butoxycarbonyl-L-(3-
tert-
butylalanyl]hydrazide for N-(N-tent-butoxycarbonyl-L-leucinyl)-N =[2-[N-
cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide, the title compound was
prepared as a
white solid (0.95 g, 100%). MS (ESn: 382.3 (M+H)+.
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d) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(6-
phenylnicotinoyl)-L-~i-ten-butylalanyl]hydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol~-ylcarbonyl]-N =(L-(3-ten-
butylalanyl)hydrazide for N-
[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
6-
phenylnicotinic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-
butylalanine,
the title compound was prepared as a white solid (90 mg, 77%). MS (ESn: 563.2
(M+H)+.
Example 27
Prevaration of N-f2-fN-cyclopropyl-N-(2-methylpropyl)amino'[thiazol-4-
ylcarbonyll-N=fN-
f4-(2-pyridin~)benzoyll-L-Q-ten-but~alanvllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=(L-(3-ten-
butylalanyl)hydrazide for N-
[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
4-(2-
pyridinyl)benzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-
butylalanine,
the title compound was prepared as a white solid (53 mg, 38%). MS (ESn: 563.2
(M+H)+.
Example 28
Preparation of N-f2-fN-cvclopropyl-N-(2-methylnrop~l)aminolthiazol-4-
ylcarbonyll-N=fN-
(2-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-butyialanvllhvdrazide
Following the procedure of Example 1(a)-1(k), except substituting methyl 2-
methylnicotinate acid for methyl 6-methylnicotinate in step (a) and N-
cyclopropyl-N-(2-
methylpropyl)amine for N-cyclopropylmethylcyclopropylamine in step (g), the
title
compound was prepared as a white solid (125 mg, 89%). MS (ESn: 531.2 (M+H)+.
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Example 29
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4-
lcarbon,~rll-N'-fN-
(2 p~ylmethoxycarbonyl)-L-~i-ten-butylalanyllhydrazide
Following the procedure of Example I(b)-1(k), except substituting 2-
pyridylcarbinol for methyl 6-methyl-3-pyridinylcarbinol in step (d) and N-
cyclopropyl-N-
(2-methylpropyl)amine for N-cyclopropylmethylcyclopropylamine in step (g), the
title
compound was prepared as a white solid (100 mg, 54%). MS (ESn: 517.2 (M+H)+.
Example 30
Preparation of (1S)-N-f4-f 1-(N-benzyloxycarbonylamino)-3-meth Iy
butyllthiazol-2-
ylcarbonyll-N =f 2-(2-chlorophenox~yl)thiazol-4-vlcarbonyllhvdrazide
Following the procedure of Example I(j)-1(k), except substituting ethyl 2-(2-
chlorophenoxymethyl)thiazole-4-carboxylate for ethyl 2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazole-4-carboxylate in step (j) and (1S)-I-
(benzyloxycarbonyl)amino-1-(4-carboxythiazol-2-yl)-3-methylbutane for N-(6-
methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine in step (k), the title
compound was
prepared as a white solid (O.OI6 g, 56%). MS (ESA: 614.2 (M+H)+.
Example 31
Preparation of N-f2-fN-cvciopentyl-N-(2-methylpronyl)amino~thiazol-4-
~lcarbonyll-N=fN-
(2-pyridinylmethoxycarbonvl)-L-Ieucinyllhydrazide
Following the procedure of Example 1 (c)-1 (k), except substituting L-leucine
methyl
ester hydrochloride for L-(i-ten-butylalanine methyl ester hydrochloride in
step (c), 2-
pyridylcarbinol for methyl 6-methyl-3-pyridinylcarbinol in step (d), and
cyclohexylamine
for cyclopropyolamine and isobutyraldehyde for cyclopropanecarboxaidehyde in
step (f),
the title compound was prepared as a white solid (95 mg, 62%). MS (ESn: 531.2
(M+H)+.
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Example 32
Preparation of N-f2-fN-cvclo~ropyl-N-(2-methvlprowlZamin~thiazol-4-ylcarbonvll-
N=fN-
i6-methyl-3-yyridinylmethoxvcarbonvl)-L-~i-ten-butylalanyllhydrazide
Following the procedure of Example I(a)-1(k), except substituting N-
cyclopropyl-
N-(2-methylpropyl)amine for N-cyclopropylmethylcyclopropylamine in step (g),
the title
compound was prepared as a white solid (110 mg, 75%). MS (ESn: 531.3 (M+H)+.
Exaraple 33
Preparation of N-f2-(N-cycloprop ~~1-N-cvclopropylmethylamino)thiazol-4-
vlcarbonvll-N=
f N-l6 phenvlnicotinoyl)-L-leucinvllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-
cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine in
step
(e), the title compound was prepared as a white solid (75 mg, 49%). MS (ESI):
547.3
(M+H)+.
Example 34
Preparation of N-f2-(N-cyclo~ropyl-N-cvcl~rop3rlmethylamino)thiazol-4-
vlcarbonvll-N=
IN-f4-(2-p,~dinyl)benzovll-L-leucinvllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-
cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine in
step
(e) and 4-(2-pyridinyl)benzoic acid for 6-phenylnicotinic acid in step (g),
the title
compound was prepared as a white solid (135 mg, 70%). MS (ESn: 547.3 (M+H)+.
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Example 35
Preparation of N-f N-(5-butyl~icolinoyl)-L-leuci ~ 11-N =f 2-(N-c cly onr_opyl-
N-
cycloprop l~ylamino)thiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-
cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine in
step
(e) and 5-butylpicolinic acid for 6-phenylnicotinic acid in step (g), the
title compound was
prepared as a white solid (100 mg, 61%). MS (ESI): 527.4 (M+H)+.
Example 36
Preparation of N-1N-(5-butylpicolinoy_I)-L=j3-cycloproyylalanvll-N=12-(N-
cvclopronyl-N-
cycloPropylmethvlamino)thiazol-4-ylcarbon~ydrazide
a) (S)-2-ten-butoxycarbonylaminopent-4-enoic acid
Following the procedure of Example 26(a), except substituting (S)-2-amino-4-
pentenoic acid for L-~i-ten-butyl alanine, the title compound was prepared as
a white solid
(10.11 g, 86%). MS(ESn: 453.2 (2M+Na)+.
b) N-ten-butoxycarbonyl-L-(3-cyclopropylalanine methyl ester
To a stirring solution of the compound of Example 36(a) (7.81 g, 36.3 mmol) in
ether (100 mL) at 0 °C was added a solution of diazomethane (made from
10 eq. of I-
methyl-3-nitro-1-nitrosoguanidine in ether (500 mL) and 40% NaOH (500 mL) at 0
°C).
After stirring for 10 min., Pd(OAc)2 (0.300 g) was added to the solution.
After 20min., the
solution was concentrated and the residue was filtered through a short plug of
silica gel to
remove unused catalyst. Concentration of the solution yielded the title
compound as a
golden yellow oil (8.29 g, 99%). IH NMR (400 MHz, CDC13) ~i 5.17 (d, IH), 4.39
(m,
IH), 3.73 (s, 3H), 1.66 (t, 2H), 1.44 (s, 9H), 0.68 (m, IH), 0.49 (m, 2H),
0.08 (m, 2H).
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c) N-ten-butoxycarbonyl-L-~i-cyclopropylalanine
Following the procedure of Example 1 (e), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine methyl ester for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine methyl ester, the title
compound was
prepared as a tan oil (1.2 g, 17%). MS (ESn: 481.4 (2M+Na)+.
d) N-[N-(5-butylpicolinoyl)-L-[3-cyclopropylalanyl]-N'-[2-(N-cyclopropyl-N-
cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-
cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine
and N-
ten-butoxycarbonyl-L-~-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine
in step (e)
and 5-butylpicolinic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid ( 130 mg, 76%). MS (ESn: 525.3 (M+H)+.
Example 37
Preparation of N-f2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-
ylcarbon~l N=
LN-f4-(2~~ridinvl)benzoyll-L-(3-cvcloprop ly alan~ydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-
cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine
and N-
ten-butoxycarbonyl-L-(3-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine
in step (e)
and 4-(2-pyridinyl)benzoic acid for 6-phenyinicotinic acid in step (g), the
title compound
was prepared as a white solid (96 mg, 70%). MS (ES>7: 545.3 (M+H)+.
Example 38
Preparation of N-f2-fN-cyclopentyl-N-(2-meth~propyl)amino]thiazol-4-ylcarbon~l-
N=fN-
(4-methylimidazol-5-ylcarbonvl)-L-leucinyllhvdrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclopentylamine for cyclopropylamine in step (d) and 4-methylimidazole-5-
carboxylic
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acid for 6-phenylnicotinic acid in step (g), the title compound was prepared
as a white solid
(80 mg, 79%). MS (ESn: 504.3 (M+H)+.
Example 39
Preparation of N-fN-(5-butylyicolinoyl)-L-leucinyll-N=f2-fN-cyclopentyl-N-(2-
methylpropyl)aminolthiazol-4-vlcarbonvllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclopentylamine for cyclopropylamine in step (d) and 5-butylpicolinic acid
for 6-
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (70 mg,
63%). MS (ES)7: 557.3 (M+H)+.
Example 40
Preparation of N-f2-(N-cyclopropyl-N-cvclopropylmethylamino)thiazol-4-
vlcarbonyll-N=
[N-f6-(1-pyrrolyl)nicotinoyll-L-(i-~cloprop Iy alanyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-
cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine
and N-
tent-butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine
in step (e)
and 6-(1-pyrrolyl)nicotinic acid for 6-phenylnicotinic acid in step (g), the
title compound
was prepared as a white solid ( 115 mg, 89%). MS (ESI): 534.3 (M+H)+.
ExamQe 41
Preparation of N-f2-fN-cycloprop 1-y N-(2-methylnropyl)aminolthiazol-4-
~carbonyll-N'-fN-
f 6-( 1-pyrrolyl)nicotinoyll-L-leucin~lhvdrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 6-(1-
pyrrolyl)nicotinic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-
butylalanine,
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the title compound was prepared as a white solid (100 mg, 83%). MS (ESn: 538.2
(M+H)+.
Example 42
Preparation of N-f2-fN-cvclopentyl-N-(2-methylpro~,yl)aminolthiazol-4-
ylcarbonyll-N=fN-
(3.4-dimethoxybenzoyl)-L-leucinyllhydrazide
Following the procedure of Example 2(d)-2{g), except substituting
cyclopentylamine for cyclopropylamine in step (d) and 3,4-dimethoxybenzoic
acid for 6-
phenylnicotinic acid in step {g), the title compound was prepared as a white
solid (80 mg,
81%). MS (ESn: 560.3 (M+H)+.
Example 43
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-
4:ylcarbonyll-N=fN-
(3.4-dimethoxvbenzovl)-L- 3,L-c~clopropylalanvlihydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
3,4-dimethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (110 mg, 95%). MS (ESI): 530.3 (M+H)+.
Example 44
Preparation of N j2-fN-c~loprogyl_N-(2-methylpro~,yl)aminolthiazol-4-
ylcarbonvl)-N=fN-
f 6-( 1=pyrrolyl)nicotinoyll-L-~3-cyclopropylalanyIlhydrazide
Following the procedure of Example 2(e)-2(g}, except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
6-(1-pyrrolyl)nicotinic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (160 mg, 97%). MS (ESn: 536.3 (M+H)+.
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Example 45
Pr~aration of N-f2-fN-cvclopropyl-N-(2-methvlpropYl)aminolthiazol-4-
vlcarbon3r11-N=fN-
f6-(I-imidazolyl)nicotinoyll-L f3-cyclopron IY alan~rIlhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyI-L-~i-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine in
step (e) and
6-(1-imidazolyl)nicotinic acid for 6-phenylnicotinic acid in step (g), the
title compound was
prepared as a white solid (42 mg, 36%). MS (ESn: 537.4 (M+H)+.
Example 46
Preparation of N-f2-fN-cyclopropyl-N-(2-meth~uropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
f6-(1-pyrazolyl)nicotino l~~i~vclopropylalanyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
6-(1-pyrazolyl)nicotinic acid for 6-phenylnicotinic acid in step (g), the
title compound was
prepared as a white solid (110 mg, 96%). MS (ESn: 537.3 (M+H)+.
Example 47
Preparation of N-f2-fN-cyclopropyl-N-(2-methvlpropyl)aminolthiazol-4-
ylcarbon~l-N=fN-
f 6-( 1-pyrrolyl)nicotinovll-L-j3-ten-butvlalanLlhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=(L-~i-ten-
butylalanyl)hydrazide for N-
[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
6-(1-
pyrrolyl)nicotinic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~3-ten-
butylalanine,
the title compound was prepared as a white solid (90 mg, 76%). MS (ESn: 552.3
(M+H)+.
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Example 48
Preyaration of N-f2-fN-cyclopentyl-N-(2-methyl~ropyl)aminolthiazol-4-
ylcarbonyll-N'-fN-
L3 4-difluorobenzo ly )-L-j3-cycloprogylalanyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclopentylamine for cyclopropylamine in step (d), N-tent-butoxycarbonyl-L-~i-
cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in step (e) and 3,4-
difluorobenzoic
acid for 6-phenylnicotinic acid in step (g), the title compound was prepared
as a white solid
( 118 mg, 89%). MS (ESn: 534.3 (M+H)+.
Example 49
Preparation of N-f2-fN-cyclopentyl-N-(2-methylpropyl)aminolthiazol-4-
yicarbonyll-N=fN-
(3,4-dimethoxybenzovl)-L-[3-cyclopropylalanyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclopentylamine for cyclopropylamine in step (d), N-ten-butoxycarbonyl-L-(3-
cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in step (e) and 3,4-
dimethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (86 mg, 64%). MS (ESn: 558.3 (M+H)+.
Example 50
Preyaration of N-f2-fN-cyclopentyl-N-(2-methylpropvl)aminolthiazol-4-
ylcarbonyll-N'-fN-
(4-methylimidazol-5-vlcarbonyl)-L-(3-c cloyropylalanyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclopentylamine for cyclopropylamine in step (d), N-ten-butoxycarbonyl-L-~i-
cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in step (e) and 4-
methylimidazole-
5-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound
was prepared as
a white solid ( 100 mg, 71 %). MS (ESn: 502.3 (M+H)+.
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Example 51
Preparation of N-f2-fN-c~clobutyl-N-(2-methvlnropyl)aminolthiazol-4-
vlcarbonvll-N=fN-
(2-p,Yridinylmethoxycarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 1(c)-1(k), except substituting L-leucine
methyl
ester hydrochloride for L-(3-ten-butylalanine methyl ester hydrochloride in
step (c), 2-
pyridylcarbinol for 6-methyl-3-pyridylcarbinol in step (d), and
cyclobutylamine for
cyclopropylamine and isobutyraldehyde for cyclopropanecarboxaldehyde in step
(f), the
title compound was prepared as a white solid (0.192 g, 83%). MS (ESn: 517.3
(M+H)+.
Example 52
Preparation of N-f2-fN-cyclobutvl-N-l2-methylprogyl)aminolthiazol-4-
vlcarbonyll-N=fN-
(2-,pyridinvlmethox~carbonyl)-L-~i-cyciovronylalanyIlhydrazide
a) L-~3-cyclopropylalanine methyl ester hydrochloride
Following the procedure of Example 2(f), except substituting N-ten
butoxycarbonyl-L-~i~yclopropylalanine methyl ester for N-(N-ten-butoxycarbonyl-
L
leucinyl)-N =[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-
ylcarbonyi]hydrazide,
the title compound was prepared as a white solid (2.2 g, 30%). MS (ESn: 144..0
(M+H)+.
b) N-[2-[N-cyclobutyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(2-
pyridinylmethoxycarbonyl)-L-(i-cyclopropylalanyl]hydrazide
Following the procedure of Example 1(c)-1(k), except substituting L-(3-
cyclopropylalanine methyl ester hydrochloride for L-(3-ten-butylalanine methyl
ester
hydrochloride in step (c), 2-pyridylcarbinol for 6-methyl-3-pyridylcarbinol in
step (d), and
cyclobutylamine for cyclopropylamine and isobutyraldehyde for
cyclopropanecatboxaldehyde in step (f), the title compound was prepared as a
white solid
(0.192 g, 83%). MS (ESn: 515.3 (M+H)+.
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Example 53
Preparation of N-f2-fN-cvclo~ropvl-N-(2-meth l~nropyl)aminolthiazol-4-
ylcarbonyll-N'-fN-
(3.4-methvlenediox~benzovl)-L-leucinvllhvdrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol~-ylcarbonylJ-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3,4-
methylenedioxybenzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-
ten-
butylalanine, the title compound was prepared as a white solid (91 mg, 100%).
MS (ESn:
516.3 (M+H)+.
Example 54
Preparation of N-f2-fN-cyclopronyl-N-(2-methylpropvl)aminolthiazol-4-
ylcarbonyll-N=fN-
(4-methoxybenzo I~-L-[i-c~pro_p l~yllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-methoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (110 mg, 87%). MS (ESI): 500.3 (M+H)+.
Example 5~
Preparation of N-f2-fN-cyclobutyl-N-(2-methylnroyyl)aminolthiazol-4-~carbonyll-
N=fN-
13.4-difluorobenzoyl)-L-leucinyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d) and 3,4-difluorobenzoic acid for 6-
phenylnicotinic acid in
step (g), the title compound was prepared as a white solid (0.125 g, 76%). MS
(ESn: 522.3
(M+H)+.
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Example 56
Preparation of N-f2-fN-cyclobutyl-N-(2-methylpropyl)aminolthiazol-4~lcarbonvll-
N=fN-
(3.4-dimethoxybenzovl)-L-leucinvllhydrazide
S
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d) and 3,4-dimethoxybenzoic acid for 6-
phenylnicotinic acid
in step (g), the title compound was prepared as a white solid (0.148 g, 86%).
MS (ESn:
546.4 (M+H)+.
Example 57
Preparation of N-f2-fN-cvclobutyl-N-(2-methyleropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
(4-methylimidazol-5=ylcarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d) and 4-methylimidazole-5-carboxylic acid for 6-
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.092 g,
60%). MS (ESn: 490.3 (M+H)+.
Example 58
Preparation of N-f2-fN-cvclobutyl-N-(2-methylpropvl)aminolthiazol-4.-
ylcarbonYll-N'-fN-
(3,4-difluorobenzoyl)-L j3-cvclopropylalanyllh, drazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d), N-ten-butoxycarbonyl-L-~i-cyclopropylalanine
for N-tert-
butoxycarbonyl-L-leucine in step (e) and 3,4-difluorobenzoic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (0.095g,
63%). MS (ESn:
520.3 (M+H)+.
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Example 59
Preparation of N-f2-fN-cvclobu~l-N-(2-methvlpropvl)amino]thiazol-4-elcarbonyll-
N'-fN-
3.4-dimethoxybenzoyl)-L-(3-cyclopropylalanyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d), N-tent-butoxycarbonyl-L-(3-
cyclopropylalanine for N-tert-
butoxycarbonyl-L-leucine in step (e) and 3,4-dimethoxybenzoic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (0.100 g,
64%). MS
(ESI): 544.3 (M+H)+.
Example 60
Preparation of N-f2-fN-cyclobutyl-N-(2-meth~nropyl)aminolthiazol-4-ylcarbonyll-
N=(N-
(4-methvlimidazol-5-ylcarbonvl)-L-~i-cvcloprogylalanyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d), N-ten-butoxycarbonyl-L-(3-cyclopropylalanine
for N-tert-
butoxycarbonyl-L-leucine in step (e) and 4-methylinudazole-5-carboxylic acid
for 6-
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.076 g,
54%). MS (ESn: 488.4 (M+H)+.
Example 61
Preparation of N-f2-fN-c clobut~-N-(2-methylprogyl)aminolthiazol-4-~carbonyll-
N=fN-
(5-methyl-2-nhenyloxazol-4-ylacetyl)-L-~i-cvclopropylalanyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d), N-ten-butoxycarbonyl-L-(3-cyclopropyialanine
for N-tert-
butoxycarbonyl-L-leucine in step (e) and 5-methyl-2-phenyloxazole-4-acetic
acid for 6-
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.115 g,
69%). MS (ESn: 579.4 (M+H)+.
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Example 62
Preparation of N-fN-(benzothiazol-6-vlcarbon~rl)-L-leucinyll-N'-f2-[N-c~clobut
1-y N-l2-
methvlpropvl)aminolthiazol-4-vlcarbonyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutyiamine
for cyclopropylamine in step (d) and benzothiazole-6-carboxylic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (0.119 g,
70%). MS
(ESn: 543.3 (M+H)+.
Example 63
Preparation of N-f2-fN-cyclopropyl-N-(2-methylvropvl)aminolthiazol-4-
ylcarbonyll-N=fN-
(4-trifluoromethvlbenzoyl)-L-(3-cYclonrovvlalanyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyi-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-trifluoromethylbenzoic acid for 6-phenylnicotinic acid in step (g), the
title compound was
prepared as a white solid (83 mg, 81 %). MS (ESn: 538.3 (M+H)+.
Example 64
Preparation of N-(N-benzothiophen-2 ylcarbonyl-L-~i-cvcloprop"ylalanyl)-N=f2-
fN-
c~propyl-N-(2-methylpropyl)aminolthiazol-4-~carbonvllh drazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~3-cyclopropylaianine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
benzothiophene-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the
title compound
was prepared as a white solid (50 mg, 32%). MS (ESn: 526.3 (M+H)+.
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Example 65
Preparation of N-f2-fN-cvclobutvl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyll-N'-fN-
f4-methyl-2-(4-trifluoromethvlphenvl)thiazol-5-vlcarbonyl)-L-leucinvllh
drazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step {d) and 4-methyl-2-{4-
trifluoromethylphenyl)thiazole-5-
carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was
prepared as a
white solid (0.168 g, 82%). MS (ES>): 651.4 (M+H)+.
Example 66
Preparation of N-f2-fN-cyclobutvl-N-(2-methy~ropyl)aminolthiazol-4-ylcarbonvll-
N=fN-
(4-hydroxymethylbenzo ly )-L-L-(3-cycl~ropylalanyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d), N-tent-butoxycarbonyl-L-~i-
cyclopropylalanine for N-tert-
butoxycarbonyI-L-leucine in step (e) and 4-hydroxymethylbenzoic acid for 6-
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.098 g,
66%). MS (ESl]: 514.4 (M+H)+.
Example 67
Preparation of N-f2-fN-cyclopropvl-N-(2-methylpropyl)aminolthiazol-
4=ylcarbonyll-N=fN-
(4-hydroxymethylbenzoyl)-L-~3-c~cloprwlalanyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-hydroxymethylbenzoic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (90 mg, 86%). MS (ES>]: 500.3 (M+H)+.
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Example 68
Preparation of N-(N-benzothiovhen-2~Icarbonvl-Lei-cycloproEylalanyl)-N=f2-fN-
c_~lopentyl-N-(2-methylprowl)aminolthiazol-4-ylcarbo ~rllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclopentylamine for cyclopropylamine in step (d), N-ten-butoxycarbonyl-L-(3-
cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in step (e) and
benzothiazole-6-
carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was
prepared as a
white solid (90 mg, 82%). MS (ESn: 552.2 (M+H)+.
Example 69
Preparation of N-f~-(N-cyclopropyl-N-cycloproQylmethylamino)thiazol-4
ylcarbonyll N'
IN-(2,3-dihvdrobenzofuran-5 ylcarbonvl)-L-~i-~clo~, ropylalan~~razide
Following the procedure of Example 2(e)-2(g), except substituting N-
cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine
and N-
ten-butoxycarbonyl-L-~i-cyclopropytalanine for N-ten-butoxycarbonyl-L-leucine
in step (e)
and 2,3-dihydrobenzofuran-5-carboxylic acid for 6-phenylnicotinic acid in step
(g), the title
compound was prepared as a white solid (98 mg, 85%). MS (ESI): 510.3 (M+H)+.
Example 70
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyll-N'-fN-
indole-2-vlcarbonyliL-(3-ten-but ly alanyllh drazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =(L-[i-ten-
butylalanyl)hydrazide for N-
[2-(N-cyciopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
indole-
2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-
butylalanine, the
title compound was prepared as a white solid (102 mg, 75%). MS (ESn: 525.4
(M+H)+.
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Example 71
Preparation of N-f2-fN-cvclopropyl-N-(2-methylproQyl)aminolthiazol-4-
Ylcarbon~rll N' fN
S ( I-methylindole-2-ylcarbonyl)-L-(3-ten-butylalanvllhydrazide
Following the procedure of Example I (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=(L-(3-ten-
butylalanyl)hydrazide for N-
[2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
1-
methylindole-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~i-tert-
butylalanine, the title compound was prepared as a white solid (65 mg, 70%).
MS (ES>):
539.4 (M+H)+.
Example 72
Preparation of N-f2-fN-cyclopentyl-N-(2-methylprogyl~aminolthiazol-4-
ylcarbonyll-N=fN-
(4-trifluoromethoxybenzoyl)-L-~i-cvclopro-pylalanyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclopentylamine for cyclopropylamine in step (d), N-tert-butoxycarbonyl-L-~i
cyclopropylalanine for N-ten-butoxycarbonyl-L-ieucine in step (e) and 4
trifluoromethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (70 mg, 56%). MS (ESI): 582.4(M+H)+.
Example 73
Preparation of N-f2-fN-cvclopentyl-N-(2-methylnropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
(4-propylox benzoyl)-L-~3~-c~lopropylalanylll~drazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclopentylamine for cyclopropylamine in step (d), N-ten-butoxycarbonyl-L-(3-
cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in step (e) and 4-
propyioxybenzoic
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acid for 6-phenylnicotinic acid in step (g), the title compound was prepared
as a white solid
(95 mg, 67%). MS (ESl7: 556.4(M+H)+.
Example 74
Preparation of N-f2-fN-cvclopropyl-N-(2-methylpro~yl)aminolthiazol-4-
ylcarbonyll-N=fN-
f 3-(2-pyridinvl)benzo~l]-L-leucinyllhydrazide
a) 3-(2-pyridinyl)benzoic acid
Following the procedure of Example 4(a)-4(c), except substituting 3-
formylbenzene
boronic acid (3.2 g, 21.34 mmol) for 4-formylbenzene boronic acid in step (a),
the title
compound was obtained as a white solid ( 1.05 g). MS (ESI): 200. I (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-[3-
(2-
pyridinyl)benzoyl]-L-leucinyl]hydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyi]hydrazide for N-[2-
(N-
cycIopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3-(2-
pyridinyl)benzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-tent-
butylalanine,
the title compound was prepared as a white solid (65 mg, 43%). MS (ESI): 549.4
(M+H)+.
Example 75
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
f 4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylcarbonyll-L-
leucinyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
methyl-2-(4-
trifluoromethylphenyl)thiazole-5-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxy-
carbonyl)-L-~i-ten-butylalanine, the title compound was prepared as a white
solid ( 165 mg,
95%). MS (ESn: 637.4 (M+H)+.
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Example 76
Preparation of N-f2-fN-cyclobutyl-N-(2-methylpronvl)aminolthiazol-4-
Ylcarbonyll-N=fN-
f3-(2-pyridinyl)benzoyll-L-d-cyclopropylalanvllh~razide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d), N-tent-butoxycarbonyl-L-[3-
cyclopropylalanine for N-terr-
butoxycarbonyl-L-leucine in step (e) and 3-(2-pyridinyl)benzoic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (O.OI9 g,
12%). MS
(ESn: 561.4 (M+H)+.
Examgle 77
Preparation of N-f2-fN-c cl~yl-N-(2-methylpropyl)aminolthiazol-4-~carbonyll-N'-
fN-
IS (5-methyl-2-phenyloxazol-4-~lcarbonvl)-Lei-cyclopropylalanylh~drazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyciopropylamine in step (d), N-ten-butoxycarbonyl-L-~i-cyclopropylalanine
for N-tert-
butoxycarbonyl-L-leucine in step (e) and 5-methyl-2-phenyloxazole-4-carboxylic
acid for 6-
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.150 g,
92%). MS (ESn: 565.4 (M+H)+.
Example 78
Preparation of N-f2-1N-cycloprogyl-N-(2-meth~nro~yl)aminolthiazol-4.-
yicarbonyll-N=fN-
(4-trifluoromethylbenzovl)-L-leucinvllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
trifluoromethylbenzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-
tert-
butylalanine, the title compound was prepared as a white solid (103 mg, 88%).
MS (ESl7:
540.3 (M+H)+.
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Example 79
Preparation of N-f2-fN-cvcloprowl-N-(2-methyloronvl)aminolthiazol-4-
ylcarbonvll-N'-fN-
(2.3-dihy-drobenzofuran-5-ylcarbonvl)-L-leucinvllhydrazide
Following the procedure of Example I(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyi)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 2,3-
dihydrobenzofuran-5-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-
ten-butylalanine, the title compound was prepared as a white solid (120 mg,
68%). MS
(ESn: 514.3 (M+H)+.
Example 80
Preparation of N-(N-benzothiazol-6-ylcarbonvl-L-leucinyl)-N=f2-fN-c~propyl-N-
(2-
meth~rlpropyl)aminolthiazol-4-vlcarbonyllh~ide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4.-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
benzothiazole-
6-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-
butylalanine, the
title compound was prepared as a white solid ( 114 mg, 97%). MS (ESI): 529.4
(M+H)+.
Example 81
Preparation of N-(N-benzothiophen-2=ylcarbon~eucinyl)-N=f2-fN-cyclopronyl-N-(2-
methylproyyl)aminolthiazol-4.-vlcarbon~ydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
benzothiophene-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~i-ten-
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butylalanine, the title compound was prepared as a white solid (130 mg, 88%).
MS (ESn:
528.3 (M+H)+.
ExamQle 82
Preparation of N-f2-fN-cvclonropyl-N-(2-methylpropvl)aminolthiazol-4-
ylcarbonvll-N'-fN-
(5-methyl-2-,~henyioxazol-4-ylcarbonyl)-L-IeucinyIlhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-
methyl-2-
phenyloxazole-4-carboxylic acid for N-(6-methyl-3-pyridinyimethoxycarbonyl)-L-
(3-ten-
butylalanine, the title compound was prepared as a white solid ( 140 mg, 90%).
MS (ESn:
553.4 (M+H)+.
Example 83
Preparation of N-f2-fN-cyclobutyl-N-(2-methy_lnropyl)aminolthiazol-4-
ylcarbonvll-N'-fN-
( 1-methylindole-2-vlcarbonyl)-L-leucin rLllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d) and 1-methylindole-2-carboxylic acid for 6-
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.122 g,
78%). MS (ESn: 539.4 (M+H)+.
Example 84
Preparation of N-f2-fN-cyclobutyll-N-(2-methYlyropyl)aminolthiazol-4-
~carbonyll-N=fN-
(2,3-dihydrobenzofuran-5-vlcarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d) and 2,3-dihydrobenzofuran-5-carboxylic acid
for 6-
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phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.064 g,
42%). MS (ESI}: 528.3 (M+H)+.
Example 85
Preparation of N-f2-fN-cyciobutyl-N-(2-methylnropvl)aminolthiazol-4-
ylcarbonyll-N=fN-
(5-fluoroindole-2-ylcarbonyl)-L-leucinyllhvdrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyclopropylamine in step (d) and 5-fluoroindole-2-carboxylic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (0.107 g,
68%). MS
(ESn: 543.4 (M+H)+.
Example 8b
Preparation of N-(N-benzothiophen-2~lcarbonyl-L-leucinyl)-N=f2-fN-cyclobutyl-N-
(2-
methylpropvl)aminolthiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 2(d)-2(g), except substituting
cyclobutylamine
for cyciopropylamine in step (d) and benzothiophene2-carboxylic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (0.130 g,
83%). MS
(ESn: 542.4 (M+H)+.
Exa ale 87
Preparation of N-f2-fN-cyclopropyl-N-(2-meth~lpropyl)aminolthiazol-4-
vlcarbonyll-N=fN-
(5-methyi-2-phenylimidazol-4-ylcarbonyl)-L-leucinyllh~razide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-
methyl-2-
phenylimidazole-4-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-
L-(3-tert-
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butylalanine, the title compound was prepared as a white solid (75 mg, 62%).
MS (ESn:
552.5 (M+H)+.
Example 88
Preparation of N-f2-fN-cyclo~ropvl-N-(2-methvlpropvl)aminolthiazol-4-
ylcarbonyll-N=fN-
(3.4.5-trimethoxybenzoyl)-L-leucinvllhvdrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazoi-4-ylcarhonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3,4,5-
trimethoxybenzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-tert-
butylalanine, the title compound was prepared as a white solid ( 105 mg, 81
%). MS (ESn:
562.4 (M+H)+.
Example 89
Preparation of N-f2-fN-cyclopr_wl-N-(2-meth~yrog~aminolthiazol-4-ylcarbon~l-
N=fN-
(5-fluoroindole-2-vlcarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-(2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-
fluoroindole-
2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-
butylalanine, the
title compound was prepared as a white solid (90 mg, 90%). MS (ES17: 529.4
(M+H)+.
Example 90
Preparation of N-f2-fN-c~propyl-N-(2-methylpropvl)aminolthiazol-4-vlcarbonyll-
N=fN-
S5-h dy roxyindole-2-ylcarbon~rl)-L-leucinyllh~drazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
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cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl)hydrazide and 5-
hydroxyindole-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~i-ten-
butylalanine, the title compound was prepared as a white solid (90 mg, 45%).
MS (ESn:
527.2 (M+H)+.
Example 91
Preparation of N-f2-(N-cyclopro~yl-N-(2-meth~propyl)aminolthiazol-4-
ylcarbonyll-N=(N-
indole-4-vlcarbonyl-L-~3-c clonr ,pvlalanyhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
indole-4-carboxylic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (0.091 g, 60%). MS (ESn: 509.3 (M+H)+.
Example 92
Preparation of N-f2-fN-cvclopropyl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbomrl]-N=(N-
indole-5 ~rlcarbonyl-L-(3-cycloproyylalanyl)hydrazide
Following the procedure of Example 2(e)-2(g}, except substituting N-ten-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
indole-5-carboxylic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (0.105 g, 69%). MS (ESn: 509.3 (M+H)+.
Example 93
Preparation of N-(N-benzinudazol-5-ylcarbonyl-L-[i-cvclopropylalan~rl)-N'-f2-
fN-
cyclopropyl-N-(2-methylprop l~nolthiazol-4- lcarbonyllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~3-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine in
step (e) and
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benzimidazole-5-carboxylic acid for 6-phenylnicotinic acid in step (g), the
title compound
was prepared as a white solid (0.147 g, 95%). MS (ESn: 510.3 (M+H)+.
Example 94
Preparation of N-f2-fN-cyclonropyl-N-(2-methyloroQyl)aminolthiazol-4-
ylcarbonvll-N=fN-
(5-fluoroindole-2-ylcarbonyl)-L- i~-cvcloprowlalanvllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5-fluoroindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the
title compound
was prepared as a white solid (0.117 g, 74%). MS (ESn: 527.3 (M+H)+.
Example 95
Preparation of N-f2-fN-cvclopropvl-N-(2-meth~lprop~aminolthiazol-4-ylcarbon~ll-
N=fN-
(4-methyl-2-phenylthiazol-5-ylcarbon 1~-~i-cyclopropylalanvllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-methyl-2-phenylthiazole-5-carboxylic acid for 6-phenylnicotinic acid in step
(g), the title
compound was prepared as a white solid (0.088 g, 52%). MS (ESn: 567.3 (M+H)+.
Example 96
Preparation of N-f2-fN-c~lopropyl-N-(2-methylyro-pyl)aminolthiazol-4-
ylcarbon~ll-N=fN-
(5-meth~phenyloxazol-4-Ylcarbonyl)-L-~i-cycloprog lyalanyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5-methyl-2-phenylthiazole-4-carboxylic acid for 6-phenylnicotinic acid in step
(g), the title
compound was prepared as a white solid (0.113 g, 68%). MS (ES17: 551.3 (M+H)+.
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Example 97
Preparation of N-f2-fN-cyclopropyl-N-(2-meth ly prop,y~aminolthiazol-4-
ylcarbonyll-N=fN-
(4-methoxyquinolin-2-ylcarbonvl)-L-(3-cyclopropvlalan~rllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-methoxyquinoline-2-carboxylic acid for 6-phenylnicotinic acid in step (g),
the title
compound was prepared as a white solid (0.088 g, 53%). MS (ESI): 551.3 (M+H)+.
Example 98
Preparation of N-f2-fN-cycloyropyl-N-l2-methvl~ropyl)aminolthiazol-4-
~carbonyll-N=fN-
(5,6-dimethoxyindole-2-ylcarbon ly )-L-L-(3-cvclopropvlalanyllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-(3-cyclopropylaianine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5,6-dimethoxyindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g),
the title
compound was prepared as a white solid (0.097 g, 57%). MS (ESn: 569.4 (M+H)+.
Example 99
Preparation of N-fN-(5-chloroindole-2 ylcarbon 1)-y L-(3-c~rclopropylalanyl]-
N=f2-fN-
cyclopropyl-N-(2-methylpropyl)aminolthiazol-4-~lcarbonyllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert
butoxycarbonyl-L-~i-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine in
step (e) and
5-chloroindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the
title compound
was prepared as a white solid (0.073 g, 45%). MS (ESI): 543.2 (M+H)+.
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Examgle 100
Preparation of N-lN-benzothiazoi-6-ylcarbon~~3~vcloprog l~alanyl)-N=(2 jN-
cyclopropvl-N-(2-methvlpropvl)aminolthiazol-4-vlcarbonyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
benzothiazole-6-carboxylic acid for 6-phenylnicotinic acid in step (g), the
title compound
was prepared as a white solid (0.104 g, 66%). MS (ESn: 527.2 (M+H)+.
Example 101
Preparation of N-12-fN-cvclopropvl-N-l2-methyl-propyl)aminolthiazol~-
vlcarbonvll-N=fN-
(4-flurorbenzimidazol-2-vlcarbonvl)-L-~i-cvclopropylalanvllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert
butoxycarbonyl-L-~3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-fluorobenzimidazole-2-carboxylic acid for 6-phenylnicotinic acid in step
(g), the title
compound was prepared as a white solid (0.101 g, 64%). MS (ESn: 528.2 (M+H)+.
Example 102
Preparation of N-12-1N-cyclopropyi-N-(2-methypropyl)aminolthiazol-4-
ylcarbonyll-N =(N-
quinolin-3-vlcarbonyl-L-~i-cyclopropylalanyl)hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
quinoline-3-carboxylic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (0.111 g, 71%). MS (ESn: 521.3 (M+H)+.
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Example 103
Preparation of N-f2-fN-cvclogroovl-N-(2-meth,~nropgirl)aminolthiazol-4-
ylcarbonyll-N=fN-
(5-methoxybenzofuran-2-ylcarbonyll-L-(3- cyclo~ropylalanvllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine in
step (e) and
5-methoxybenzofuran-2-carboxylic acid for 6-phenylnicotinic acid in step (g),
the title
compound was prepared as a white solid (0.110 g, 68%). MS (ESn: 540.3 (M+H)+.
Exam~ie 104
Preparation of N-f2-fN-cvclopropvl-N-(2-methvlpropyl)aminolthiazol-4-
ylcarbonyll-N'-fN-
(?-methoxybenzofuran-2-vlcarbonyl)-L- j3-cvclo~ro_pylalany-llhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
7-methoxybenzofuran-2-carboxylic acid for 6-phenylnicotinic acid in step (g),
the title
compound was prepared as a white solid (0.120 g, 74%). MS (ESn: 540.3 (M+H)+.
Example 105
Preparation of N-fN-(5-chlorobenzofuran-2-ylcarbonvl)-L-(3-cyclopro~ylalanyll-
N=f2-fN-
cyclopropyl-N-(2-methylpropyl aminolthiazol-4.~rlcarbonyllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5-chlorobenzofuran-2-carboxylic acid for 6-phenylnicotinic acid in step (g),
the title
compound was prepared as a white solid (0.105 g, 64%). MS (ESn: 544.2 (M+H)+.
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Example 106
Preciaration of N-f2-fN-cvclopropyl-N-l2-methvlprop~,)aminolthiazol-4-
vlcarbonvll-N=fN-
(4-trifluoromethoxY,benzoyl)-L-leucinyllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
trifluoromethoxybenzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~3-
tert-
butylalanine, the title compound was prepared as a white solid ( I 13 mg,
90%). MS (ESn:
556.3 (M+H)+.
Example 107
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4
ylcarbonylZN=1N-
( I-methylindole-2 ylcarbonyl)-L-leucinyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-yicarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 1-
methylindole-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~i-tert-
butylalanine, the title compound was prepared as a white solid ( 125 mg, 91
%). MS (ESn:
525.3 (M+H)+.
Example 108
Preparation of N-f2-fN-cvclopropvl-N-l2-methylpropYl)aminolthiazol-4-
vlcarbonvll-N=fN-
(5-methylindole-2 ylcarbonvl)-L-leucinyllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-(2-
(N-
cyclopropyl-N-cyclopropylmethylanuno)thiazol-4-ylcarbonyl]hydrazide and 5-
methylindole-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
(3-tert-
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butylalanine, the title compound was prepared as a white solid (63 mg, 49%).
MS (ESn:
525.4 (M+H)+.
Example 109
Preparation of N-f2-fN-cyclo~rogvl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
(S-methoxyindole-2-ylcarbon~L-leucinyl_l>~drazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-
methoxyindole-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
(3-tert-
butylalanine, the title compound was prepared as a white solid (136 mg, 89%).
MS (ESn:
541.3 (M+H)+.
Example 110
Preparation of N-(N-benzofuran-2-vlcarbonyl-L-leucinyl)-N=f2-fN-cYclopropyl-N-
(2-
methylpropyl)aminolthiazol-4-ylcarbon~lhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
benzofuran-2-
carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-
butylalanine, the
title compound was prepared as a white solid (94 mg, 75%). MS (ESn: 512.3
(M+H)+.
Examele 111
Preparation of N-fN-(2-chloro-3,4-dimethoxybenzoyl)-L-leucinyll-N=f2-fN-
c~clopropyl-N-
(2-methvlpropyl)aminolthiazol-4-ylcarbon~lhvdrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
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cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl)hydrazide and 2-
chloro-3,4-
dimethoxybenzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~3-ten-
butylalanine, the title compound was prepared as a white solid (80 mg, 61 %).
MS (ESn:
566.2 (M+H)+.
Example 112
Pre~uation of N-f2-IN-cy-clopropyl-N-(2-methylprop)rl)aminolthiazol-4-
vlcarbonyll-N'-1N-
(5 methoxyindole-2-ylcarbonvl)-L-(3-cycloQropylalanvllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5-methoxyindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the
title
compound was prepared as a white solid (0.079 g, 49%). MS (ESn: 539.3 (M+H)+.
Example 113
Preparation of N-12-1N-cyclonrowl-N-(2-methylnropyl)aminolthiazol-4-
vlcarbonvll-N=(N-
iso4uinolin-3-ylcarbon~-L-i~-cycloprop l~vl)hydrazide
Following the procedure of Example 2(e)-2(g}, except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
isoquinoline-3-carboxylic acid for 6-phenylnicotinic acid in step (g}, the
title compound
was prepared as a white solid (0.096 g, 61 %). MS (ESn: 521.2 (M+H)+.
Example 114
Preparation of N-f2-fN-c~clopropvl-N-(2-methylpropvl)aminolthiazol-4-
vlcarbonvll-N'-(N-
indole-2-ylcarbonvl-L-Ii-cvclopropylalanvl)hvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyciopropylalanine for N-tert-butoxycarbonyl-L-leucine in
step (e) and
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indole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (0.110 g, 72%). MS (ESI): 509.3 (M+H)+.
Example 115
Preparation of N-(N-benzofuran-2ylcarbonvl-L-~i-cycloprop l~anyl)-N=f2-fN-
cyclo~ronyl-N-(2-methylnropyl)aminolthiazol-4-ylcarbonyllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
i0 butoxycarbonyl-L-~i-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine
in step (e) and
benzofuran-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (0.099 g, 65%). MS (ESn: 510.3 (M+H)+.
Example 116
Preparation of N-f2-fN-cvclopropyl-N-(2-meth~lyropyl)aminolthiazol-4-
vlcarbonyll-N'-tN-
f 6-( 1-pyrrolidinyl)nicotinoyll-L-leucinvllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 6-(1-
pyrrolidinyl)nicotinic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-
tert-
butylalanine, the title compound was prepared as a white solid (180 mg, 55%).
MS (ESI):
542.3 (M+H)+.
Exa~le l I7
Preparation of N-f2-fN-cyclopropyl-N-(2-methylprooyl)aminolthiazol-4-
vlcarbonvll-N=fN-
~4-methyl-2-phenylthiazol-5-vlcarbonyl)-L-leucin~llhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-(N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
methyl-2-
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phenylthiazole-5-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~3-ten-
butylalanine, the title compound was prepared as a white solid (130 mg, 93%).
MS (ESn:
569.3 (M+H)+.
$ Example 118
Preparation of N-fN-(S-chlorobenzofuran-2-vlcarbonyl)-L-leucinvll-N'-f2-fN-
cyclopropyl-
N-(2-meth~lprowl)aminolthiazol-4-~carbonvllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-
chlorobenzofuran-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-
L-(3-tert-
butylalanine, the title compound was prepared as a white solid (125 mg, 88%).
MS (ESn:
546.1 (M+H)+.
Example 119
Preparation of N-f2-fN-cycloQropyl-N-(2-methvlpropgirl)aminolthiazol-
4ylcarbonyll-N=fN-
(5-methoxybenzofuran-2 ylcarbonyl)-L-leucinYllhydrazide
Following the procedure of Example I (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-
methoxybenzofuran-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-
ten-butylalanine, the title compound was prepared as a white solid (95 mg,
72%). MS
(ESn: 542.3 (M+H)+.
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Example 120
Preparation of N-(N-benzimidazol-5-ylcarbonyl-L-leucinyl)-N =f 2-fN-
cvclonronyl-N-(2-
meth~uropyl)aminolthiazol-4.-~carbonyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
benzimidazole-
S-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~-tert-
butylalanine, the
title compound was prepared as a white solid (65 mg, 50%). MS (ESI): 512.3
(M+H)+.
Example 121
Preparation of N-j2-fN-cvclo~ropyl-N-(2-methy_lprop,Yl~aminolthiazol-4-
vicarbonvll-N=fN-
(5 6-dimethoxvindole-2-ylcarbonvl)-L-leucinyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5,6-
dimethoxyindole-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-
L-(3-tert-
butylalanine, the title compound was prepared as a white solid (77 mg, 48%).
MS (ESI):
571.3 (M+H)+.
Example 122
Preparation of N-fN-(5-chloroindole-2-ylcarbonyl)-L-leucinvll-N=f2-fN-
cyclopronyl-N-(2-
meth"~,l~ropyl)aminolthiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-
chloroindole-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~3-tert-
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butylalanine, the title compound was prepared as a white solid (105 mg, 89%).
MS (ESn:
545.2 (M+H)+.
Example 123
Preparation of N-f2-fN-cyclopropyl-N-!2-met~lnrovyl)aminolthiazol-4-
ylcarbonvll-N'-fN-
(4-methoxy-3-meth~benzoyl)-L-leucinyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
methoxy-3-
methylbenzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-ten-
butylalanine,
the title compound was prepared as a white solid ( 110 mg, 98%}. MS (ESn: 516.
(M+H)+.
Example 124
Preparation of N-fN-f2-(2-chloronhenyl)-4-methylthiazol-5-yl_carbonyll-L-
leucinvll-N'-f2-
jN-cycloQropyl-N-(2-methvlprop~)aminolthiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 2-(2-
chlorophenyl)-4-methylthiazole-5-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-tent-butylalanine, the title compound was
prepared as a
white solid (108 mg, 84%). MS (ESn: 603.2 (M+H)+.
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Example 125
Preparation of N-f2-fN-cvcl~ropvl-N-(2-methylvropvl)aminolthiazol-4-ylcarbo~ll-
N=fN-
~4-methoxyindole-2-ylcarbo~l)-L-(3-cyclopropylalanvllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-methoxyindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the
title
compound was prepared as a white solid (0.035 g, 22%). MS (ESI7: 539.2 (M+H)+.
Example 126
Preparation of N-f2-fN-cvclopropyl-N-l2-methylpropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
L4-methyl-2-(4-trifluorometh~nhenyl)thiazol-5-ylcarbonvll-L-(i-
cvclopropvlalanvIlhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-rert-butoxycarbonyl-L-leucine in
step (e) and
4-methyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxylic acid for 6-
phenylnicotinic acid
in step (g), the title compound was prepared as a white solid (0.125 g, 66%).
MS (ESn:
635.3 (M+H)+.
Example 127
Preparation of N-(2-fN-cycloprowl-N-(2-meth~propyl)aminolthiazol-4-ylcarbonvll-
N'-fN-
(6-trifluoromethyl-4-azabenzothiophen-2~ylcarbonyl)-L~3-
c~clopropvlalan~ydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
6-trifluoromethyl-4-azabenzothiophene-2-carboxylic acid for 6-phenylnicotinic
acid in step
(g), the title compound was prepared as a white solid (0.094 g, 53%). MS
(ES)): 595.2
(M+H)+.
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Example 128
Preparation of N f2 fN cyclo."propyl N (2 met)~Ipronyl)aminolthiazol-4-
vlcarbonvll-N=fN-
~2 uhenyl 5 trifluorometh~oxazol~-ylcarbonvl)-L-leucinvllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl}amino]thiazol-4-ylcarbonyl]-N =[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 2-
phenyl-5-
trifluoromethyloxazole-4-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-
(3-tent-butylalanine, the title compound was prepared as a white solid (130
mg, 96%). MS
(ESn: 607.2 (M+H)+.
Example 129
Preparation of N f2 -fN-cycl~ronyl N (2 meth~vrop~)aminolthiazol-4-vlcarbonvll-
N' fN-
~4-methoxvauinolin-2-vlcarbonvl)-L-leucinvlThydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
methoxyquinoline-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-
L-~i-
tert-butylalanine, the title compound was prepared as a white solid ( 100 mg,
74%). MS
(ES)]: 553.3 (M+H)+.
Exam~e 130
Preparation of N f2 fN c~clopro~vl N (2 meth~lpronyl)aminolthiazol-4-
vlcarbonvll-N=fN-
~3 methoxv-4 5-methylenedioxybenzoyl)-L-leucinvIlhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3-
methoxy-
4,5-methylenedioxybenzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~i-tert-
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butylalanine, the title compound was prepared as a white solid (46 mg, 40%).
MS (ESn:
546.3 (M+H)+.
Example 131
Preparation of N-f2-fN-c~i~ropyl-N-(2-methylQropyl)amino]thiazol-4-ylcarbonvll-
N=(N-
indole-2-ylcarbonyl-L-leucin~l)hydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and indole-
2-
carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-
butylalanine, the
title compound was prepared as a white solid (95 mg, 79%). MS (ESn: 511.3
(M+H)+.
Example 132
Preparation of N-f2-fN-cyclopro~yl-N-(2-meth~vropyl)aminolthiazol-4-
Ylcarbonyll-N=!N-
(7-methoxybenzofuran-2-ylcarbonvl)-L-leucinyllhydrazide
Following the procedure of Example 1 (k}, except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 7-
methoxybenzofuran-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-
ten-butylalanine, the title compound was prepared as a white solid (90 mg,
76%). MS
(ESn: 542.2 (M+H)+.
Example 133
Pr~aration of N-fN-(3-chlorobenzothiophen-2-ylcarbonvl)-L-leucinvll-N'-f2-fN-
cyclopropyl-N-(2-methyl-uropyl)aminolthiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
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cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3-
chlorobenzothiophene-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-
(i-teri-butylalanine, the title compound was prepared as a white solid ( 120
mg, 92%). MS
(ES)): 562.1 (M+H)+.
Example 134
Preparation of N-f2-fN-cvclonropyl-N-!2-methvlpropyl)aminolthiazol-4
ylcarbo~ll N' (N
indole-6-ylcarbonyl-L-leuci ~1)hydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
{N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and indole-
(r
carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~3-ten-
butylalanine, the
title compound was prepared as a white solid (50 mg, 48%). MS (ESn: 511.3
(M+H)+.
Example 135
Preparation of N-f2-fN-cvclonronvl-N-!2-methylpropyl)aminolthiazol-4
~carbonyll N' fN
(3-methvlthionhene-~-vlcarbonyl)-L-feucinyllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3-
methylthiophene-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-
L-~i-ten-
butylalanine, the title compound was prepared as a white solid (110 mg, 89%).
MS (ESn:
492.3 (M+H)+.
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Example 136
Preparation of N-f2-fN-cvclovropyl-N-(2-methvlpropyl)aminolthiazol-4-
lcarbonyll N' fN
(2.6-dimethoxynicotinoyl)-L-(3-cvcloyronvlalanyllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
2,6-dimethoxynicotinic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (0.099 g, 62%). MS (ESI): 531.3 (M+H)+.
Example 137
Preparation of N-f2-fN-cyclonropyl-N-(~-meth~~propyl)aminolthiazol-4
ylcarbonyll N' fN
I2-(2-nvridinyl)thioyhen-5-ylcarbon Iy 1-L-(3-cyclopropylalanyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e} and
2-(2-pyridinyl)thiophene-5-carboxylic acid for 6-phenylnicotinic acid in step
(g}, the title
compound was prepared as a white solid (0.103 g, 62%). MS (ESn: 553.2 (M+H)+.
Example 138
Preparation of N-!2-fN-cyclopropvl-N-(2-methylpropyl)aminolthiazol-4-
vicarbonyll N' !N
f 2-(2-mercaptouyridinylmethyl)furan-5-ylcarbonyl l-L-Q-c~lopropylalanyl
lhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
2-(2-mercaptopyridinylmethyi)furan-5-carboxylic acid for 6-phenylnicotinic
acid in step
(g), the title compound was prepared as a white solid (0.129 g, 74%). MS (ESn:
583.3
(M+H)+.
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Example I39
Preparation of N-f2-fN-cvclonropvl-N-(2-methvlpropyl)aminolthiazol-4- lcarbon
1 N' (N
indole-6-vIcarbonyl-L-leuciny])h drazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol~i-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethyiamino)thiazol-4-ylcarbonyl]hydrazide and indole-
6-
carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyt)-L-~3-ren-
butylalanine, the
title compound was prepared as a white solid (51 mg, 44%). MS (ESn: 51 I.3
(M+H)+.
Example 140
Preparation of N-f2-fN-cyclonroovl-N-(2-methylpropyl)aminohhiazol-4-
ylcarbonvll N fN
f4-methyl-2-(2-methvlthiazol-4-vl)thiazol 5 ylcarbonyll L leuciny~h dy razide
Following the procedure of Example 1 (k), except substituting N-[2-
[N~yclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[L-leucinylJhydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonylJhydrazide and 4-
methyi-2-(2-
methylthiazol-4-yl)thiazole-5-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title compound was
prepared as a
white solid (120 mg, 86%). MS (ESn: 590.2 (M+H)+.
Example 14I
Preparation of N-f2-fN-cyclonrouyl-N-(2-methvlnronvl aminoithiazol-4-
ylcarbon~J N' fN
I2-(I-ovn:olvl)benzothiazol-6-ylcarbonyll Lvllhvdrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinylJhydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 2-(I-
pyrrolyl)benzothiazole-6-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-
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~i-tert-butylalanine, the title compound was prepared as a white solid (90 mg,
64%). MS
(ESI): 594.4 (M+H)+.
Example 142
Preparation of N-f2-fN-cvclopropyl-N-(2-methylpropyl)aminolthiazol-4
ylcarbonyll N' fN
(3,4-dichlorobenzo 1~~3-cyclopropylalanlrllh drazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
3,4-dichlorobenzoic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (0.086 g, 53%). MS (ESn: 538.2 (M+H)+.
Example 143
Preparation of N-f2-fN-cvclonropyl-N-(2-methylpropylZaminolthiazol-4
ylcarbonyll N' fN
(4-methanesulfonvlbenzoyl)-L,~3-cyclopropylalanyllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-methanesulfonylbenzoic acid for 6-phenylnicotinic acid in step (g), the
title compound
was grepared as a white solid (0.1 I6 g, 70%). MS (ES)]: 548.1 (M+H)+.
Example 144
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4
ylcarbonyll N' fN-
(2-nhenyl-5-trifluoromethyloxazol-4- l~carbonvl)-L-(3-
cyclopropylalanvllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyI-L-leucine in
step (e) and
2-phenyl-5-trifluoromethyloxazole-4.-carboxylic acid for 6-phenylnicotinic
acid in step (g),
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the title compound was prepared as a white solid (0.1 I 1 g, 61 %). MS (ES)]:
605.3
(M+H)+.
Example 145
Preparation of N-fN-f2-(~-chlorophenvl)-4 methylthiazol 5 ylcarbonvll L Q
cvcloaronvlalanvll-N=f2-fN-cvclopropyl N l2 methylpropyDaminolthiazol-4
ylcarbonvllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~i~yclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
2-(2-chlorophenyl)-4-methylthiazole-5-carboxlyic acid for 6-phenylnicotinic
acid in step
(g), the title compound was prepared as a white solid (0.076 g, 41 %). MS
(ESn: 601.3
(M+H)+.
Example 146
Preparation of N-f2-fN-cyclonronvl-N-(2 methvlpropyl)aminolthiazol-4
ylcarbonyll N' fN
(3.4-dimethoxvbenzovl)-L-Q-cyclohe~lalanyllhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-cyclohexylaianine for N-ten-butoxycarbonyl-L-leucine in step
(e) and
3,4-dimethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title
compound was
prepared as a white solid (85 mg, 59%). MS (ESn: 572.4 (M+H)+.
Example 147
Preparation of N-I2-fN-cvclonropvl-N-(2-methvlpro~,yl)aminolthiazol-4
ylcarbonyll N' [N
(6-trifluoromethvl-4-azabenzothiophen 2 ylcarbonyl) L leucinyllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)aminoJthiazol-4-ylcarbonyl]-N=[L-leucinyl)hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 6-
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trifluoromethyl-4-azabenzothiophene-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title compound was
prepared as a
white solid (130 mg, 94%). MS (ESn: 597.2 (M+H)+.
Example 148
Prevaration of N-f2-fN-cvclonropvl-N-(2-meth 1 ropyl)aminolthiazol-4-
vlcarbonyll N' fN
(2.6-dimethoxynicotinovl)-L-leucinylLhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)aminojthiazol-4-ylcarbonylj-N=[L-IeucinyIjhydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 2,6-
dimethoxynicotinic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-j3-ren-
butylalanine, the title compound was prepared as a white solid (90 mg, 76%).
MS (ESn:
533.3 (M+H)+.
Example 149
P_renaration of (2S)-N-(N-benzodioxan-2-ylcarbon ILL B-cyclopropylalanyl) N'L
fN-
cyclonronyl-N-(2-methylnropyl)aminolthiazol-4 Icarbonyllh drazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
S-benzodioxane-2-carboxlyic acid for 6-phenylnicotinic acid in step (g), the
title compound
was prepared as a white solid (0.080 g, 50%). MS (ESn: 528.2 (M+H)+.
Example 150
Preparation of N-f2-fN-cycIouronvl-N-(2-methylprop~aminolthiazol-4~lcarbonyll
N' LN
f2-(2-nyridinvl)thionhen-S-ylcarbonvll-L-leucinvllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)aminojthiazol-4-ylcarbonylj-N=[L-leucinyljhydrazide for N-[2-
(N-
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cyclopropyl-N-cyclopropylmethylamino)thiazol-4.-ylcarbonyl]hydrazide and 2-(2-
pyridinyl)thiophene-5-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl~L-(3-
ten-butylalanine, the title compound was prepared as a white solid (115 mg,
74%). MS
(ESn: 555.2 (M+H)+.
Example 151
Preparation of N-f2-fN-cvclonronvl-N-(2-methvlpropy~aminolthiazol-4
vlcarbonyll N' IN
~ropionyl-L-leucinyl)I~drazide
Following the procedure of Example I(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl)hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl)hydrazide and
propionic acid
for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-tent-butylalanine, the title
compound
was prepared as a white solid (85 mg, 74%). MS (ESI): 424.3 (M+H)+.
Example 15~
Preparation of N-f2-fN-cvclooronvl-N-(2 methyI ropYl)aminolthiazol-4
vlcarbonyl N' fN
j2-(4-moroholino)nvrimidin-5-ylcarbonyll L ~i cvcloprop lalanv,_llh drazide
a) 2-ethoxycarbonylmalondialdehyde
To a stirring mixture of sodium hydride ( 1.26 g, 31.6 mmol, 60% dispersion in
mineral oil) and ethyl formate ( 19.5 g, 263 mmol) in diethyl ether ( 100 mL,)
at 0 ~iC was
added ethyl 3,3-diethoxypropionate (5.0 g, 26.3 mmol) dropwise over 2h. The
solution
then stirred at 5 (3C for lOh and room temperature for 16h. The mixture was
poured into
cold water and washed with ether. The aqueous layer was acidified to pH of 3
with 10%
HCI and extracted with dichloromethane (3x). The organic layers were combined,
washed
with saturated brine, dried (MgS04), filtered and concentrated to yield the
title compound
as a colorless oil (2.4 g, 63%). 1HNMR (400MHz, CDC13) (3 9.08 (s, 2H), 4.3I
(s, 1H),
4.18 (q, 2H), I.23 (t, 3H).
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b) ethyl 2-methyithiopyrimidine-5-carboxylate
To a solution of anhydrous sodium acetate ( 1.5 g, 19.1 mmol) in DMF (90 mL)
was
added -S-methylisothiourea sulfate (2.5 g, 9.1 mmol) followed by the compound
of Example
152(a) (2.4 g, 15.4 mmol). After stirring at 85(3C for 16h, the mixture was
cooled, diluted
with water and extracted with diethyl ether (2x). The organic layers were
combined, dried
(MgS04), filtered and concentrated. The residue was purified by column
chromatography
(silica gel, ethyl acetate/hexane) to yield the title compound as a white
solid (1.52 g, 85%).
MS (ESn: 199.1 (M+H)+.
c) ethyl 2-methanesulfonylpyrimidine-5-carboxylate
To a stirring solution of the compound of Example 152(b) (0.300 g, I .52 mmol)
in
dichloromethane (25 mL) was added m-chloroperoxybenzoic acid (0.706 g, 4.1
mmol).
After stirring at room temperature for 3h, the solution was diluted with
dichloromethane
and washed with saturated aqueous sodium bicarbonate. The organic layer was
dried
(MgS04), filtered and concentrated. The residue was purified by column
chromatography
(silica gel, ethyl acetate/hexane) to yield the title compound as a white
solid (0.222 g, 63%).
1HNMR (400MHz, CDCI3) ~i 9.41 (s, 2H), 4.50 (q, 2H), 3.38 (s, 3H), 1.42 (t,
3H).
d) ethyl 2-(4-morpholino)pyrimidine-5-carboxylate
After stirring for 16h at 100(3C, a solution of the compound of Example 152(c)
(0.100 g, 0.435 mmol) in morpholine (2 mL) was diluted with ethyl acetate and
washed
with water. The organic layer was dried (MgS04), filtered and concentrated to
yield the
title compound as a white solid (0.068 g, 6690). IHNMR (400MHz, CDC13) (3 8.81
(s, 2H),
4.31 (q, 2H), 3.89 (t, 4H), 3.72 (t, 4H), 1.32 (t, 3H).
e) 2-(4-morpholino)pyrimidine-5-carboxylic acid
Following the procedure of Example 1 (e), except substituting ethyl 2-(4-
morphoiino)pyrimidine-5-carboxylate for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-
ten-butylalanine methyl ester, the title compound was prepared as a white
solid (0.060 g,
100%). MS(ESI7: 210.0 (M+H)+.
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f) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl)-N'-[N-[2-
(4-
morpholino)pyrimidin-5-ylcarbonyl)-L-(3-cyclopropyIalanyl)hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cycIopropylalanine for N-tent-butoxycarbonyl-L-leucine in
step (e) and
2-(4-morpholino)pyrimidine-5-carboxylic acid for 6-phenylnicotinic acid in
step (g), the
title compound was prepared as a white solid (0.107 g, 70%). MS (ESn: 557.3
(M+H)+.
Example 153
Prevaration of N-f2-fN-cyclopropyl-N-(2-metl~Inropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
f4-methyl-2-(2-methylthiazol-4-yl)thiazol-5-ylcarbon 1~1_L~i-
cyclopr~ylalan~lhvdrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
4-methyl-2-(2-methylthiazol-4-yl)thiazole-5-carboxylic acid for 6-
phenylnicotinic acid in
step (g), the title compound was prepared as a white solid (0.118 g, 67%). MS
(ES)): 588.3
(M+H)+.
Example 154
Preparation of N-f2-fN-c~clo-pronvl-N-(2-meth~vropvl)aminolthiazol-4.-
ylcarbonyll-N=fN-
I2-(1-nvrrolvl)benzothiazol-6-ylcarbon ly 1;L_(3-cvclopro~ ly alanyl]h~ide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
2-(1-pyrrolyl)benzothiazole-6-carbonyl acid for 6-phenylnicotinic acid in step
(g), the title
compound was prepared as a white solid (0.107 g, 60%). MS (ESn: 592.3 (M+H)+.
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Example 155
Pre station of N- 2- N-c clo ro 1-N 2-meth 1 ro 1 amino thiazol-4- lcarbon i -
N= N-
(5-trifluoromethoxvindol-2- l~bonvll-L~3-cvclopronvlalanvllh drazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-teucine in
step (e) and
5-trifluoromethoxyindole-2-carboxyiic acid for 6-phenylnicotinic acid in step
(g), the title
compound was prepared as a white solid (0.096 g, 54%). MS (ESA: 593.2 (M+H)+.
Example 156
Preparation of N-f2-jN-cvclonronvl-N-(2-methvlpropYl)aminolthiazol-4
vlcarbonyll N' (N
j2-(1-nyrrolidino)nvrimidin-5-ylcarbonvll-L-Q-cvclopr~ylalan 1 h drazide
a) 2-( 1-pyrrolidino)pyrimidine-5-carboxylic acid
Following the procedure of Example 152(x)-152(e), except substituting
pyrrolidine
for morpholine in step (d), the title compound was prepared as a white solid
(0.057 g,
100%). MS (ESn: 193.9 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol.-4-ylcarbonyl)-N=[N-[2-
(1-
pyn:olidino)pyrimidin-5-ylcarbonyl]-L-~i-cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
2-(1-pyrrolidino)pyrimidine-5-carboxylic acid for 6-phenylnicotinic acid in
step (g), the
title compound was prepared as a white solid (0.074 g, 51 %). MS (ESn: 541.3
(M+H)+.
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Example 157
Preparation of N-(N-but~ryl-L-leucinvl)-N=f2-fN-cycloprop ly N (2-
methylnronvllaminolthiazol-4-vlcarbonvllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyi]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
butyric acid
for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title
compound
was prepared as a white solid (130 mg, 87%). MS (ESn: 438.3 (M+H)+.
Example 158
Preparation of N-f2-fN-cyclo~rooyl-N-(2-methvlpropyl)aminolthiazol-4-
ylcarbonyll-N=fN
(3-methylbutyryl)-L-Ieucinyllh drazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyI-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-Ieucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
isovaleric acid
for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-[3-ten-butylalanine, the title
compound
was prepared as a white solid (110 mg, 85%). MS (ESn: 4523 (M+H)+.
Example 159
Preparation of N-f2-(N-cycloprop ~~1-N-c clonrop lmetl~lamino)thiazol-4-
ylcarbonyll N'
jN-(3,4-dimethoxybenzovl)-L-cyclohexvl~l, cinyllhydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-
cyclopropylmethylcyclopropylamine for N-cyclopropyi-N-(2-methylpropyl)amine
and N-
tent-butoxycarbonyl-L-cyclohexylglycine for N-ten-butoxycarbonyl-L-leucine in
step (e),
and 3,4-dimethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the
title compound
was prepared as a white solid (90 mg, 53%). MS (ESn: 556.3 (M+H)+.
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Example 160
Preparation of N-f2-fN-cyclonropyl-N-(2-methylpropyl)aminolthiazol-4- lcy
arbonyll N' (N
thienof2,3-b)thiophen-2-vlcarbo~l-L-leucinvl)hvdrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl)hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and
thieno[2,3-
b]thiophene-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-(3-
tert-
butylalanine, the title compound was prepared as a white solid (115 mg, 83%).
MS (ESn:
534.3 (M+H)+.
Example I61
Preparation of N-fN-(5-ten-butyl-3-methylthienof2 3-blthi~hen 2 ylcarbonyl) L
leuci~ll
N=f2-fN-cvcloorooyl-N-(2-meth~propyl)aminolthiazol-4 ylcarbonyllhvdrazide
Following the procedure of Example I(k), except substituting N-[2-[N-
cyclopropyl-
N-{2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-ten-
butyl-3-
methylthieno[2,3-b]thiophene-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine, the title compound was
prepared as a
white solid (140 mg, 85%). MS (ESl7: 604.2 (M+H)+.
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Example 162
Preparation of N-(2-fN-cvclopropyl-N-(2-methvlpro~yl)aminolthiazol-4-
ylcarbonyll-N'-(N-
(2-fN-f 2-(N.N-dimethylamino)ethyll-N-methylamino),p,Yrimidin-5-ylcarbonyll-L-
i~-
cvclopropylalanyllhydrazide
a) 2-[N-[2-(N,N-dimethylamino}ethyl]-N-methylamino]pyrimidine-5-carboxylic
acid
Following the procedure of Example 152(a)-152(e), except substituting N,N,N=
trimethylethylenediamine for morpholine in step (d), the title compound was
prepared as a
white solid (0.125 g, 100%). MS (ESn: 225.1 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[2-
[N-[2-
(N,N-dimethylamino)ethyl]-N-methyl~mino]pyrimidin-5-ylcarbonyl}-L-~-
cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~3-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine in
step (e) and
2-[N-[2-(N,N-dimethylamino)ethyl]-N-methylamino]pyrimidine-5-carboxylic acid
for 6
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.073 g,
48%). MS (ES)7: 572.3 (M+H)+.
Example 163
Preparation of N-f2-fN-c~propyl-N-(2-meth~propyl)aminolthiazol-4~lcarbonyll-
N=(N-
j4-(1.2,3-thiadiazol-5-yloxy benzoyll-L-leucinyllhvdrazide
Following the procedure of Example 1(k), except substituting N-[2-(N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4.-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
(1,2,3-
thiadiazol-5-yloxy)benzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~i-ten-
butylalanine, the title compound was prepared as a white solid (125 mg, 85%).
MS (ESn:
572.2 (M+H)+.
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Example 164
Preparation of N-f2-fN-cvclopropyl-N-(2-methvlpropyl)aminolthiazol-4-
ylcarbonyll-N'-fN-
(5.6-dimethoxvbenzofuran-2-ylcarbonyl)-L-(3-cvcloprowlalanvllh drazide
a) 2-hydroxy-4,5-dimethoxybenzaldehyde
To a stirring solution of 2-benzyloxy-4,5-dimethoxybenzaldehyde ( 1.0 g, 3.67
mmol) in ethyl acetate (25 mL) was added 10% palladium on carbon (0.50 g). The
mixture
was stirred under a hydrogen atmosphere for 4h, then filtered through Celite.
The filtrate
was concentrated to yield the title compound as a pale yellow solid (0.632 g,
95%). 1H
NMR (400 MHz, CDC13) ~i 11.41 (s, 1H), 9.72 (s, 1H), 6.89 (s, 1H), 6.48 (s,
1H), 3.91 (s,
3H), 3.88 (s, 3H).
b} 4,5-dimethoxy-2-ethoxycarbonylmethoxybenzaldehyde
Following the procedure of Example 15(e), except substituting 2-hydroxy-4,5-
dimethoxybenzaldehyde for 2-bromophenol and ethyl bromoacetate for benzyl
bromide, the
title compound was prepared (0.758 g, 82%). 1H NMR (400 MHz, CDCl3) j3 10.39
(s, 1H),
7.30 (s, 1H), 6.41 (s, 1H), 4.72 (s, 2H), 4.22 (q, 2H), 3.90 (s, 3H), 3.83 (s,
3H), 1.26 (t, 3H).
c) ethyl 5,6-dimethoxybenzofuran-2-carboxyiate
A mixture of the compound of Example 164(b) (0.758 g, 2.8 mmol) and potassium
carbonate (0.975 g, 7.1 mmol) was stirred at 80 (3C in DMF (20 mL) for Sh. The
mixture
was cooled and partitioned between ethyl acetate and water. The organic layer
was washed
with water and satruated brine then dried (MgS04), filtered and concentrated.
The residue
was purified by column chromatography (silica gel, ethyl acetate/hexane) to
yield the title
compound as a white solid (0.405 g, 58%). 1H NMR (400 MHz, CDC13) (3 7.45 (s,
1H),
7.10 (s, 1H), 7.04 (s, 1H), 4.41 (q, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 1.41 (t,
3H).
d) 5,6-dimethoxybenzofuran-2-carboxylic acid
Following the procedure of Example 1 (e), except substituting ethyl 5,6-
dimethoxybenzofuran-2-carboxylate for N-(6-methyl-3-pyridinylmethoxycarbonyl}-
L-~i-
tert-butylalanine methyl ester, the title compound was prepared as a white
solid (0.263 g,
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73%). 1H NMR (400 MHz, CDCl3) (3 7.40 (s, 1H), 7.03 (s, 1H), 7.01 (s, IH),
3.90 (s, 3H),
3.88 (s, 3H).
e) N-[2-(N-cyclopropyl-N-(2-methylpropyl)amino]thiazol..4-ylcarbonyl]-N ={N-
(5,6-
dimethoxybenzofuran-2-ylcarbonyl)-L-~i-cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5,6-dimethoxybenzofuran-2-carboxylic acid for 6-phenylnicotinic acid in step
(g), the title
compound was prepared as a white solid (0.126 g, 74%). MS (ES>): 570.3 (M+H)T.
Example 165
Preparation of N-f2-fN-cvclopropyl-N-(2-methylpropyl)aminolthiazol-
4=ylcarbonyll N' fN
f5-(4-triflouormethylnhenyl)oxazol-4-ylcarbonyl -L-leucinvllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-(4-
triflouormethylphenyl)oxazole-4-carboxylic acid for N-(6-methyl-3-
pyridinyimethoxycarbonyl)-L-{i-ten-butylalanine, the title compound was
prepared as a
white solid (90 mg, 55%). MS (ESn: 607.3 (M+H)+.
Example 166
Preparation of N-f2-(N-cyclopropyl-N-(2-meth-ylpropyl)aminolthiazol-4-
ylcarbon~rll N' fN
(4-methyl-2-(5-trifluoromethylpyridin-2- 1)thiazol-5 ylcarbo~ll L-
leucinyllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
methyl-2-(5-
trifluoromethylpyridin-2-yi)thiazole-5-carboxylic acid for N-(6-methyl-3-
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pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title compound was
prepared as a
white solid (113 mg, 63%). MS (ES)7: 638.2 (M+H)+.
Example 167
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyIl-N'-fN-
f4-methyl-2-(3-trifluoromethvlphenvl)thiazol-5-vlcarbonyll-L-
leucinyllhvdrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyi]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4.-ylcarbonyl]hydrazide and 4-
methyl-2-(3-
trifluoromethylphenyl)thiazole-5-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine. the title compound was
prepared as a
white solid (142 mg, 95%). MS (ESn: 637.3 (M+H)+.
Example 168
Prevaration of N-f2-fN-cyclopropyl-N-(2-methvlpropyl)aminolthiazol-4-
vlcarbonvll N' fN
f 3-f 2-(N,N-dimethylamino)ethoxyl-4-methoxybenzovll-L-(3-
cvclopropylalanyllhvdrazide
a) methyl 3-[2-(N,N-dimethylamino)ethoxy]-4-methoxybenzoate
To a stirring mixture of sodium hydride (5.8 g, 145 mmol, 60% dispersion in
mineral oil) in DMF (80 mL) was added slowly a solution of methyl-3-hydroxy-4-
methoxybenzoate ( 11.0 g, 60 mmol) in DMF (80 mL). After stirring for 30 min,
N,N-
dimethylaminoethylchloride hydrochloride (9.5 g, 66 mmol) was added slowly.
After
stirring for 16h at 80 (3C, the solution was diluted with saturated brine and
extracted with
ethyl acetate (2x). The organic layers were combined and washed with water and
brine the
dried (MgS04), filtered and concentrated. The residue was purified by column
chromatography (silica gel, methanol/dichloromethane) to yield the title
compound as an
off white solid (9.45 g, 62%). MS (ESn: 254.2 (M+H)+.
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b) 3-[2-(N,N-dimethylamino)ethoxy]-4-methoxybenzoic acid
Following the procedure of Example 1 (e), except substituting methyl 3-[2-(N,N-
dimethylamino)ethoxy]~-methoxybenzoate for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-
L-~-ten-butylalanine methyl ester, the title compound was prepared as a pale
yellow solid
(2.39 g, 100%). MS (ESI): 240.2 (M+H)+.
c) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-(3-
[2-(N,N-
dimethylamino)ethoxy]-4-methoxybenzoyl]-L-~i-cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
3-(2-(N,N-dimethylamino)ethoxy]-4-methoxybenzoic acid for 6-phenylnicotinic
acid in step
(g), the title compound was prepared as a white solid (0.133 g, 75%). MS
(ESI): 586.3
(M+H)+.
Example 169
Preparation of N-f2-fN-c~loprowl-N-(2-methylyropyl)aminolthiazol-4-ylcarbonyll-
N=fN-
f 5-f2-(4-morpholino)ethoxylbenzofurart-2-ylcarbonvll-L-(3-
cvclo~ro~ylalanvllhvdrazide
a) ethyl 5-hydroxybenzofuran-2-carboxylate
To a mixture of aluminum chloride (6.3 g, 47.7 mmol) and ethanethiol (4.5 g,
72.9
mmol) in dichloromethane (81 mL) at 0 ~iC was added ethyl 5-methoxybenzofuran-
2-
carboxylate (3.0 g, 13.6 mmol). After stirring for 16h at room temperature,
the mixture was
poured into water, acidified with 3N HCI and extracted with dichloromethane
(2x). The
organic layers were combined, washed with saturated brine, dried (MgS04),
filtered and
concentrated. The residue was purified by column chromatography (silica gel,
ethyl
acetate/hexane) to yield the title compound as a white solid (2.16 g, 77%). 1H
NMR (400
MHz, CDCI3) ~ 7.45 (m, 2H), 7.08 (m, 1H), 7.02 (m, 1H), 5.35 (s b, 1H), 4.44
(q, 2H), 1.42
(t, 3H).
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b) ethyl 5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylate
To a solution of the compound of Example 169(a) (0.200 g 0.971 mmol), 4-(2-
hydroxyethyl)morpholine (0.165 g, 1.26 mmol), and triphenylphosphine (0.331 g,
1.26
mmol) in THF (4 mL) at 0 ~iC was added dropwise diisopropylazodicarboxylate
(0.254 g,
I .26 mmol). After stirring at room temperature for 16h, the solution was
concentrated and
purified by column chromatography (silica gel, ethyl acetate/hexane) to yield
the title
compound as a white solid (0.235 g, 76%). 1H NMR (400 MHz, CDC13) ~i 7.48 (m,
2H),
7.07 (m, 2H), 4.43 (q, 2H), 4.14 (m, 2H), 3.76 (m, 4H), 2.86 (m, 2H), 2.61 (m,
4H), 1.40 (t,
3H).
c) 5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylic acid
Following the procedure of Example 1 (e), except substituting ethyl 5-[2-(4-
morpholino)ethoxy]benzofuran-2-carboxylate for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-tent-butylalanine methyl ester, the title
compound was
IS prepared as a white solid (0.150 g, 70%). MS (ESI): 292.1 (M+H)+.
d) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[5-
[2-(4-
morpholino~thoxy]benzofuran-2-ylcarbonyl]-L-(3-cyclopropyialanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylic acid for 6-phenylnicotinic
acid in step
(g), the title compound was prepared as a white solid (0.141 g, 73%). MS (ESn:
639.3
(M+H)+.
Example 170
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4
ylcarbon~il N' fN
I4-methyl-2-(2-thienvl)thiazol-5-vlcarbonyli-L-leucinyllhydrazide
Following the procedure of Example I(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-
methyl-2-(2-
thienyl)thiazole-5-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-
L-~i-tert-
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butylalanine, the title compound was prepared as a white solid ( 126 mg, 77%).
MS (ESn:
575.2 (M+H)+.
Example 171
Preparation of N-f2-fN-cvcloprop~l-N-(2-methvlprwl)aminolthiazol-4-vlcarbon~ll-
N=fN-
f 3-f 2-(N,N-dimethvlamino)ethoxyl-4-methoxvbenzoyll-L-leucinyl l hvdrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3-[2-
(N,N-
dimethylamino)ethoxy}-4-methoxybenzoic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine, the title compound was
prepared as a
white solid (60 mg, 20%). MS (ESn: 589.4 (M+H)+.
Example 172
Preparation of N-f2-fN-cvclopropvl-N-(2-methpropel)aminojthiazol-4ylcarbonyll
N=fN-
IS-f 2-(N.N-dimethylamino)ethoxylbenzofuran-2-vlcarbonyll-L~3-
cyclopropylalanyllhydrazide
a) 5-[2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid
Following the procedure of Example 169(a)-169(c), except substituting 2-
dimethylaminoethanol for 4-(2-hydroxyethyl)morpholine in step (b), the title
compound
was prepared as a white solid (0.139 g, 100%). 1H NMR (400 MHz, CDC13) ~i 7.36
(d,
1H), 7.12 (m, 2H), 7.00 (d, 1H), 4.32 (t, 2H), 3.56 (t, 2H), 2.95 (s, 6H).
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
[2-(N,N-
dimethylamino)ethoxy]benzofuran-2-ylcarbonyl]-L-~3-cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5-[2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid for 6-
phenylnicotinic acid
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in step (g), the title compound was prepared as a white solid (0.131 g, 73%).
MS (ESn:
597.3 (M+H)+.
Example 173
Preparation of N-f2-fN-cvclopropyl-N-(2-methylprowl)aminolthiazol-4-
vlcarbonyll-N'-fN-
f 5-f 2-( 1-niperidinvl)ethoxylbenzofuran-2-vlcarbonyll-L-Q-
cyclopro~vlalanyllh dy razide
a) 5-[2-(1-piperidinyl)ethoxy]benzofuran-2-carboxylic acid
Following the procedure of Example 169(x)-169(c), except substituting 2-(1-
piperidinyl)ethanol for 4-(2-hydroxyethyl)morpholine in step (b), the title
compound was
prepared as a white solid (0.185 g, 100°Io). MS (ESn: 290.1 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[5-
[2-(1-
piperidinyl)ethoxy]benzofuran-2-ylcarbonyl]-L-~i-cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5-[2-(1-piperidinyl)ethoxy]benzofuran-2-carboxylic acid for 6-phenylnicotinic
acid in step
(g), the title compound was prepared as a white solid (0.131 g, 68%). MS (ESn:
637.4
(M+H)+.
Example 174
Preparation of N-f2-fN-cyclo~ropyl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyll N=(N
thienof2,3-blthiophen-2-ylcarbonyl-L=j3-cyclo-propylalanyl)hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine in
step (e) and
thieno[2,3-b]thiophene-2-carboxylic acid for 6-phenylnicotinic acid in step
(g), the title
compound was prepared as a white solid (0.089 g, 56%). MS (ESn: 532.3 (M+H)+.
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Example 175
Preparation of N-f2-fN-cyclonropvl-N-(2-methprowl)anunolthiazol-4-ylcarbonyll-
N=fN-
f4-methvl-2-(5-trifluoromethvlpyridin-2-vI)thiazol-5-vlcarbonyll-L=j3-
cvcloprop, lY alan~ydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~i-cyclopropylalanine for N-tent-butoxycarbonyl-L-leucine in
step (e) and
4-methyl-2-(5-trifluoromethylpyridin-2-yl}thiazole-5-carboxylic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (0.142 g,
74%). MS
(ESn: 636.2 (M+H)+.
Example 176
Preparation of N-f2-fN-cyclonronyl-N-(2-methylpropyl)aminolthiazol-4-
vlcarbon~]-N=fN-
(5.6-dimethoxybenzofuran-2-ylcarbonvl)-L-leucinyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5,6-
dimethoxybenzofuran-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-
ten-butylalanine, the title compound was prepared as a white solid (90 mg,
64%). MS
(ES)]: 572.3 (M+H)+.
Example 177
Preparation of N-f2-fN-cyclonropyl-N-(2-methvlQrop 1 amino]thiazol-
4=ylcarbonyil-N'-fN-
f 2-(4-mornholino)oyrimidin-4-ylcarbonyll-L-Q-cyclopro~ylalan~llhydrazide
a) 2-methylthiopyrimidine-4-carboxylic acid potassium salt
To a suspension of 5-bromo-2-methylthiopytzmidine-4-carboxylic acid ( 1.25 g,
5.0
mmol) in methanol (60 mL) in a Purr bottle was added potassium hydroxide
(0.630 g, 11.2
mmol) following by 10% palladium on BaS04 (0.630 g, 50% w/w). After shaking
under
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hydrogen on a Parr shaker at 35 psi for 3h, the mixture was filtered through
Celite. The
filtrate was concentrated to yield the title compound without any further
isolation. IH
NMR (400 MHz, MeOH-c~ (3 8.59 (d, IH), 7.48 (d, IH), 2.60 (s, 3H).
b) ethyl 2-methylthiopyrimidine-4-carboxylate
Following the procedure of Example 8(c), except substituting 2-
methylthiopyrimidine-4-carboxylic acid potassium salt for 2-bromothiazole-4-
carboxylic
acid, the title xompound was prepared as an oily yellow solid (0.851 g, 86%).
IH NMR
(400 MHz, CDCl3) ~i 8.72 (d, IH), 7.58 (d, IH), 4.44 (q, 2H), 2.62 (s, 3H),
1.45 (t, 3H).
c) 2-(4-morpholino)pyrimidine-4-carboxylic acid
Following the procedure of Example 152(c)-152(e), except substituting ethyl 2-
methylthiopyrimidine-4-carboxylate for ethyl 2-methylthiopyrimidine-5-
carboxylate in step
(c), the title compound was prepared as a white solid (0.125 g, 100%). IH NMR
(400
MHz, CDCl3) (3 8.48 (d, 1H), 7.17 (d, 1H), 3.82 (t, 4H), 3.72 (t, 4H).
d) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[2-
(4-
morpholino)pyrimidin-4-ylcarbonyl]-L-~3-cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
2-(4-motpholino)pyrimidine-4-carboxylic acid for 6-phenylnicotinic acid in
step (g), the
title compound was prepared as a white solid (0.132 g, 79%). MS (ESn: 557.4
(M+H)+.
Example 178
Preparation of N-f2-fN-cvclopronvl-N-(2-methy~ropyl)aminolthiazol-4-
vlcarbonvll-N=fN-
f 2-( 1-oiyerazinyl)pvrimidin-4-ylcarbon~l-L~J~,yclopropylalanyllhvdrazide
a) 2-(4-ten-butoxycarbonyl-1-piperazinyl)pyrimidine-4-carboxylic acid
Following the procedure of Example 152(c)-152(e), except substituting ethyl 2-
methylthiopyrimidine-4-carboxylate for ethyl 2-methylthiopyrimidine-5-
carboxylate in step
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(c) and 4-ten-butoxycarbonylpiperazine in dichloromethane for morpholine in
step (d), the
title compound was prepared as a white solid (0.258 g, 99%). MS (ESn: 309.3
(M+H)+.
b) N-[N-[2-(4-tent-butoxycarbonyl-1-piperazinyl)pyrimidin-4-ylcarbonyl]-L-~i-
cyclopropylalanyl]-N=[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-
ylcarbonyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
2-(4-ten-butoxycarbonyl-1-piperazinyl)pyrimidine-4-carboxylic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (0.137 g,
69%). MS
(ESn: 656.4 (M+H)+.
c) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[2-
(1-
piperazinyl)pyrimidin-4-ylcarbonyl]-L-(3-cyclopropyialanyl]hydrazide
Following the procedure of Example 2(f), except substituting N-[N-[2-(4-tert-
butoxycarbonyl-1-piperazinyl)pyrimidin-4.-ylcarbonyl]-L-~i-cyclopropylalanyl]-
N =[2-[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-(N-
tert-
butoxycarbonyl-L-leucinyl)-N =[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-
ylcarbonyl]hydrazide, the title compound was prepared as a white solid (0.079
g, 68%).
MS (ESn: 556.2 (M+H)+.
Example 179
Preparation of N-f2-fN-cyclopropyl-N-(2-methyl, ropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
I2-( 1-pinerazinvl)pyrimidin-5-vlcarbonyll-L-~i-cycloprwlalanyllhydrazide
a) 2-(4-ten-butoxycarbonyl-1-piperazinyl)pyrimidine-5-carboxylic acid
Following the procedure of Example 152(a)-152(e), except substituting N-tert-
butoxycarbonylpiperazine in dichloromethane for motpholine in step(d), the
title compound
was prepared as a white solid (0.330 g, 96%). MS (ESn: 309.4 (M+H)+.
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b) N-[N-[2-(4-ten-butoxycarbonyl-I-piperazinyl)pyrimidin-4-ylcarbonyl]-L-~3-
cyclopropylalanyl]-N'-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-5-
ylcarbonyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-Ieucine in
step (e) and
2-(4-ten-butoxycarbonyl-1-piperazinyl)pyrimidine-5-carboxylic acid for 6-
phenylnicotinic
acid in step (g), the title compound was prepared as a white solid (0.138 g,
70%). MS
(ESI}: 656.4 (M+H)+.
c) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N =[N-[2-
( 1-
piperazinyl)pyrimidin-5-ylcarbonyl]-L-(3-cyclopropylalanyl]hydrazide
Following the procedure of Example 2(~, except substituting N-[N-[2-(4-ten-
butoxycarbonyl-I-piperazinyl)pyrimidin-4-ylcarbonyl]-L-~i-cyclopropylalanyl]-
N=[2-[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-5-ylcarbonyI]hydrazide for N-(N-
ten-
IS butoxycarbonyl-L-leucinyl)-N=[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4-
ylcarbonyl]hydrazide, the title compound was prepared as a white solid (0.056
g, 48%). MS
(ESn: 556.3 (M+H)+.
Example 180
Preparation of N-12-fN-cvclopropvl-N-(2-methylpropyl)amino thiazol-4-
ylcarbon~rll-N=(N-
IS-f 2-(N,N-dimethylamino)ethoxylbenzofuran-2-ylcarbonvll-L-leucin~lhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl)hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-[2-
(N,N-
dimethylamino)ethoxy]benzofuran-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-tert-butylalanine, the title compound was
prepared as a
white solid (20 mg, 15%). MS (ESn: 599.2 (M+H)+.
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Example 181
Preparation of N-f2-fN-cycloprop~-N-(2-methvlpropvl)aminolthiazol-4-ylcarbon
1~[N-
f 7-f 2-t I-piperidin 1)e~ thoxylbenzofuran-2~lcarbo~tl L-leucinyllh~rdrazide
a) 7-[2-(1-piperidinyl)ethoxy]benzofuran-2-carboxylic acid
Following the procedure of Example 169(x)-169(c), except substituting ethyl 7-
methoxybenzofuran-2-carboxylate for ethyl 5-methoxybenzofuran-2-carboxylate in
step (a)
and 2-( I-piperidinyl)ethanol for 4-(2-hydroxyethyl)morpholine in step (b),
the title
compound was prepared as a white solid. MS (ESn: 290.2 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[7-
(2-(1-
piperidinyl)ethoxy]benzofuran-2-ylcarbonyl]-L-leucinyl]hydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 7-[2-
(1-
piperidinyl)ethoxy]benzofuran-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title compound was
prepared as a
white solid (60 mg> 35%). MS (ES17: 639.4 (M+H)+.
Example 182
Preparation of N-f2-fN-cyclopropyl-N-(2-methylorowl)amino]thiazol-4-
vlcarbonvll-N'-1N-
f7-f2-(N.N-dimethvlaminolethoxylbenzofuran-2 ylcarbonvll-L-leucinyllhydrazide
a) 7-[2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid
Following the procedure of Example 169(a)-169(c), except substituting ethyl 7-
methoxybenzofuran-2-carboxylate for ethyl 5-methoxybenzofuran-2-carboxylate in
step (a)
and 2-(N,N-dimethylamino)ethanol for 4-(2-hydroxyethyl)morpholine in step (b),
the title
compound was prepared (350 mg, 100%). MS (ES)7: 250.1 (M+H)+.
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b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[N-[7-
[2-(N,N-
dimethylamino)ethoxy]benzofuran-2-ylcarbonyl]-L-leucinyl]hydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyciopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyi-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 7-[2-
(N,N-
dimethylamino)ethoxy)benzofuran-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine, the title compound was
prepared as a
white solid (25 mg, 16%). MS (ESI): 599.4 (M+H)+.
Example 183
Preparation of N-f2-1N-cyclopropyl-N-(2-methylnropyl)aminolthiazol-4
ylcarbonyll-N=fN-
f 2-fN-f2-(N.N-dimethylamino)ethvll-N-methvlaminolnyrimidin-4-vlcarbonyll-L-
i~,-
cyclopropyiaianyllhydrazide
a) 2-[N-[2-(N,N-dimethylamino)ethyl]-N-methyiamino]pyrimidine-4-carboxylic
acid
Following the procedure of Example 177(a)-177(c), except substituting N,N,N=
trimethylethylenediamine for morpholine in step (c), the title compound was
prepared as a
white solid (0.182 g, 99%). MS (ESn: 225.1 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl)-N=[N-[2-
[N-[2-
(N,N-dimethylamino)ethyl]-N-methylamino]pyrimidin-4-ylcarbonyl]-L-~i-
cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
2-[N-[2-(N,N-dimethylamino)ethyl]-N-methylamino]pyrimidine-4-carboxylic acid
for 6-
phenylnicotinic acid in step (g), the title compound was prepared as a white
solid (0.127 g,
74%). MS (ESn: 572.5 (M+H)+.
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Exartlple 184
Preparation of N-f2-f2-benzyloxyphenyl)thiazol-4-ylcarbonyll- N'-f2-(1-
naphthyl)thiazol-4-
vlcarbonyllhvdrazide
a) 2-( 1-naphthyl)thiazole-4-carboxylic acid
Following the procedure of Example 1(e), except substituting ethyl 2-(1-
naphthyl)thiazole-4-carboxylate for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-
~i-tert-
butylalanine methyl ester, the title compound was prepared as an off white
solid (0.359 g,
100%). MS (ESn: 256.0 (M+H)+.
b) N N-[2-(2-benzyloxyphenyl)thiazol-4-yicarbonyl]- N=[2-(1-naphthyl)thiazol-4-
ylcarbonyl]hydrazide
Following the procedure of Example 15(e)-15(i), except substituting the
compound
of Example 2-(1-naphthyl)thiazole-4-carboxylic acid for (1S)-1-
(benzyloxycarbonyl)amino-
1-{4-carboxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a
white solid
(0.078 g, 82%). MS (ESn: 563.2 (M+H)+.
Example 185
Preparation of N-f2-fN-cvclopropvl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyll-N=fN-
f 7-f 2-(N,N-dimethylamino)ethoxylbenzofuran-2-ylcarbonyll-L-
cyclopropylalanvll ~drazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
7-[2-(N,N-dimethylamino)ethoxy]benzofuran-2-carboxylic acid for 6-
phenylnicotinic acid
in step (g), the title compound was prepared as a white solid (0.071 g, 40%).
MS (ESn:
597.5 (M+H)+.
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Example 186
Preparation o~N~S-carboxymethox~benzofuran-2~ricarbonyl)-L-(3-
cyclopropvlalanvll-
N =f 2-f N-cyclopropyl-N-(2-methvlnronvl)aminolthiazol-4-YlcarbonLlbydrazide
a) benzyl5-hydroxybenzofuran-2-carboxylate
A solution of the compound of Example 169(a) (0.200 g, 0.907 mmol) and lithium
hydroxide monohydrate (0.045 g, 1.07 mmol) in THF (3 mL) and water (3 mL) was
stirred
at reflux for 2h. The solution was concentrated to a pale yellow solid and
dissolved in
benzyl alcohol (5 mL,) and concentrated HCl ( 1 mL). After stirring at 100 (3C
for 24h, the
solution was diluted with ethyl acetate and washed successively with saturated
aqueous
NaHC03, water and saturated brine. The organic layer was dried (MgS04),
filtered and
concentrated. The residue was purified by column chromatography (silica gel,
ethyl
acetate/hexane) to yield the title compound as a white solid (0.094 g, 39%).
IH NMR (400
MHz, CDC13) (3 7.43 (m, 7H), 7.06 (d, IH), 7.00 (dd, IH), 5.40 (s, 2H).
b) benzyl 5-ten-butoxycarbonylmethoxybenzofuran-2-carboxylate
Following the procedure of Example 15(e), except substituting benzyl 5-
hydroxybenzofuran-2-carboxylate for 2-bromophenol and ten-butyl bromoacetate
for
benzyl bromide, the title compound was prepared (0.134 g, 100%). IHNMR (400
MHz,
CDC13) (3 7.44 (m, 4H), 7.36 (m, 3H), 7.12 (dd, IH), 7.02 (d, IH), 5.38 (s,
2H), 4.52 (s,
2H), 1.48 (s, 9H).
c) 5-ten-butoxycarbonylmethoxybenzofuran-2-carboxylic acid
Following the procedure of Example 164(a), except substituting benzyl 5-tert-
butoxycarbonylmethoxybenzofuran-2-carboxylate for 2-benzyloxy-4,5-
dimethoxyben2aldehyde, the title compound was prepared as a pale yellow solid
(0.102 g,
100%). IHNMR (400 MHz, CDC13) ~i 7.40 (m, 2H), 7.04 (dd, 1H), 6.98 (d, IH),
4.50 (s,
2H), 1.41 (s, 9H).
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d} N-[N-(5-ten-butoxycarbonylmethoxybenzofuran-2-ylcarbonyl)-L-(3-
cyclopropylalanyl]-
N =[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-tert-
butoxycarbonyl-L-(3-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
5-tent-butoxycarbonylmethoxybenzofuran-2-carboxylic acid for 6-phenylnicotinic
acid in
step (g), the title compound was prepared as a white solid {0.170 g, 81%). MS
(ESn: 640.4
(M+H)+.
e) N-[N-(5-carboxymethoxybenzofuran-2-ylcarbonyl)-L-(3-cyclopropylalanyl]-N'-
[2-[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 2(f), except substituting N-[N-(5-tert-
butoxycarbonylmethoxybenzofuran-2-ylcarbonyl)-L-(3-cyclopropylalanyl]-N'-[2-[N-
cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide for N-(N-
tert
butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-
methylpropyl)amino]thiazol-4
ylcarbonyl]hydrazide, the title compound was prepared as a white solid (0.128
g, 83%).
MS (ESn: 584.3 (M+H)+.
Example 187
Preparation of N-f2-fN-cyclopropyl-N-(2-methyloropyl)aminolthiazol-4-
]rlcarbonvll-N=fN-
j7-f 2-(4-morpholino)ethoxylbenzofuran-2-ylcarbonyll-L-leucinvllhydrazide
a) 7-[2-(4-morpholino)ethoxy]benzofuran-2-carboxylic acid
Following the procedure of Example 169(a)-169(c), except substituting ethyl 7-
methoxybenzofuran-2-carboxylate for ethyl 5-methoxybenzofuran-2-carboxylate in
step (a),
the title compound was prepared as a white solid. MS (ESn: 292.3 (M+H)+.
b) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino)thiazol-4-ylcarbonyl]-N'-[N-[7-
[2-{4-
morpholino)ethoxy]benzafuran-2-ylcarbonyl]-L-leucinyl]hydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-
[2-(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 7-[2-
(4-
morpholino)ethoxy]benzofuran-2-carboxylic acid for N-(6-methyl-3-
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pyridinylmethoxycarbonyl)-L-(3-ten-butylalanine, the title compound was
prepared as a
white solid (65 trig, 34%). MS (ESn: 641.4 (M+H)+.
Example 188
Preparation of N-f2-fN-cyclopropyI-N-(2-methylpropyl)aminolthiazol-4-
ylcarbonyll-N'1N-
j3,4-(1,3-Qropylenediox )~yll-L-leucinyllhydrazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino)thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl)hydrazide and 3,4-
(1,3-
propylenedioxy)benzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L-~i-
tert-
butylalanine, the title compound was prepared as a white solid ( 100 mg, 61
%). MS (ESn:
543.9 (M+H)+.
Example 189
Preparation of N-fN-(7-carboxvmethoxybenzofuran-2-vlcarbon
1~(3~yclonrwlalanvll-
N'-f2-fN-cyclopropyl-N-(2-methvlpropyl)aminolthiazol-4-ylcarbonyllhydrazide
Following the procedure of Example 186(a)-186(e), except substituting ethyl 7-
hydroxybenzofuran-2-carboxylate for ethyl 5-hydroxybenzofuran-2-carboxylate in
step (a),
the title compound was prepared as a white solid (0.076 g, 55%). MS (ES)):
584.3
(M+H)+.
Example 190
Preparation of N-f2-fN-cyclopropyl-N-(2-methylpropyl)aminolthiazol-4-
ylcarbon)r11-N=fN-
f 5-(3-triflouormethvlphenyl)oxazol-4-ylcarbonyl]-L-leucinyllh~drazide
Following the procedure of Example 1(k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyi)-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 5-(3-
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triflouormethylphenyl)oxazole-4-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine, the title compound was
prepared as a
white solid (105 mg, 37%). MS (ESn: 607.1 (M+H)+.
Example I91
Preparation of N-f2-fN-cyclo~ropyl-N-l2-methvipropvl)aminolthiazol-4-
vlcarbonyll-N=fN-
[5-f 2-(4-moipholino)ethox~nzofuran-2-vlcarbonyl l-L-leucinyllhydrazide
Following the procedure of Example 1 (k), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N=[L-leucinyl]hydrazide for N-[2-
(N-
cyclopropyl-N-cyclopropylmethylamino)thiazol-4.-ylcarbonyl]hydrazide and 5-[2-
(4-
morpholino)ethoxy]benzofuran-2-carboxylic acid for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-(3-tent-butyiaianine, the title compound was
prepared as a
white solid (150 mg, 48%). MS (ESn: 641.2 (M+H)+.
ExamQle 192
Preparation of N-fN-(5-carbox~zofuran-2-vlcarbon 1~~3~yclopropylalanyll-N=f2-
fN-
cycloprop~rl-N-(2-methylpropyl)aminolthiazol-4-ylcarbonyllhydrazidea) 4-
benzyloxycarbonylmethoxy-3-formylbenzyaldehyde
To a mixture of S-formylsalicylaldehyde (2.2 g, 14.7 mmoI) and potassium
bromide
(5.0 g, 36.8 mmol) in acetone (50 mL) was added benzyl bromoacetate (4.8 g,
16.1 mmol).
After stirring at reflux for 6h, the mixture was diluted with ethyl acetate
and washed with
water and brine. The organic layer was dried (MgS04), filtered and
concentrated to yield
the title compound (4.13 g, 94%). 1H NMR (400 MHz, CDCl3) (3 10.56 (s, 1H),
9.95 (s,
1H), 8.38 (s, 1H), 8.0? (d, 1H), 7.38 (m, SH), 6.95 (d, 1H), 5.26 (s, 2H),
4.91 (s, 2H).
b) benzyl 5-formylbenzofuran-2-carboxylate
Following the procedure of Example 164(c), except substituting 4-
benzyloxycarbonylmethoxy-3-formylbenzyaldehyde for 4,5-dimethoxy-2-
ethoxycarbonylmethoxybenzaldehyde, the title compound was prepared as a white
solid
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{1.78 g, 46%). 1H NMR (400 MHz, CDC13) (3 10.09 (s, 1H), 8.24 (s, 1H), 8.05
(d, 1H),
7.71 (d, 1H), 7.68 (s, 1H), 7.42 (m, 5H), 5.43 (s, 2H).
c) benzyl 5-carboxybenzofuran-2-carboxylate
To a solution of the compound of Example 192(b) (0.380 g, 0.1.36 mmol) in THF
(5 mL) and t-butanol ( 1 mL) was added slowly a solution of sodium chlorite
(0.245 g 2.71
mmol) and sulfamic acid (0.277 g, 2.86 mmol) in water (2 mL). After stirring
at room
temperature for 3h, the solution was partitioned between ethyl acetate and
water. The
organic layer was washed successively with water, saturated aqueous sodium
bicarbonate,
and saturated brine then dried {MgS04), filtered and concentrated to yield the
title
compound as an off white solid (0.272 g, 68%). 1H NMR (400 MHz, CDCI3) ~i 8.52
(s,
1H), 8.23 (d, 1H), 7.67 (m, 2H), 7.49 (m, 2H), 7.41 (m, 3H), 5.46 (s, 2H).
d) benzyl 5-methoxycarbonylbenzofuran-2-carboxylate
To a solution of the compound of Example 192(c) (0.214 g, 0.723 mmol) in
diethyl
ether (20 mL) at 0 (3C was added dropwise diazomethane until a yellow color
persists after
5 min. of stirring. The solution was then concentrated and the residue
purified by column
chromatography (silica gel, ethyl acetate/hexane) to yield the title compound
as a white
solid (0.219 g, 98%). 1H NMR (400 MHz, CDCI3) ~i 8.45 (s, 1H), 8.17 (d, 1H),
7.65 (m,
2H), 7.50 (m, 2H), ?.40 (m, 2H), 7.27 (s, 1H), 5.46 (s, 2H), 3.97 (s, 3H).
e) 5-methoxycarbonylbenzofuran-2-carboxylic acid
Following the procedure of Example 164(a), except substituting benzyl 5-
methoxycarbonylbenzofuran-2-carboxylate for 2-benzyloxy-4,5-
dimethoxybenzaldehyde,
the title compound was prepared as a white solid (0.152 g, 100%). 1H NMR (400
MHz,
CDCl3) (3 8.4I (s, 1H), 8.12 (dd, 1H), 7.60 (m, 2H), 3.94 (s, 3H).
f) N-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonylJ-N'-[N-(5-
methoxycarbonylbenzofuran-2-ylcarbonyl)-L-~i-cyclopropylalanyl]hydrazide
Following the procedure of Example 2(e)-2(g), except substituting N-ten-
butoxycarbonyl-L-~i-cyclopropylalanine for N-ten-butoxycarbonyl-L-leucine in
step (e) and
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5-methoxycarbonylbenzofuran-2-carboxylic acid for 6-phenylnicotinic acid in
step (g), the
title compound was prepared as a white solid (0.102 g, 55%). MS (ESn: 568.1
(M+H)+.
g) N-[N-(5-carboxybenzofuran-2-ylcarbonyl)-L-~3-cyclopropylalanyl]-N'-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]hydrazide
Following the procedure of Example 1 (e), except substituting N-[2-[N-
cyclopropyl-
N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(5-
methoxycarbonylbenzofuran-2-
ylcarbonyl)-L-(3-cyclopropylalanyl]hydrazide for N-(6-methyl-3-
pyridinylmethoxycarbonyl)-L-~i-ten-butylalanine methyl ester, the title
compound was
IO prepared as an off white solid (0.023 g, 23%). MS (ES>]: 554.2 (M+H)+.
Example 193
Prevaration of N-fN-(7-carboxymethoxybenzofuran-2-ylcarbonvl)-L-leucinvll-N'-
f2-1N-
cyclo_prowl-N-(2-meth~nropyl)aminolthiazol-4-ylcarbonyllh~razide
Following the procedure of Example 186(a)-I86(e), except substituting ethyl 7-
hydroxybenzofuran-2-carboxylate for ethyl 5-hydroxybenzofuran-2-carboxylate in
step (a)
and N-ten-butoxycarbonyl-L-leucine for N-ten-butoxycarbonyl-L-(i-
cyclopropylalanine in
step (d), the title compound was prepared as a white solid (55 mg, 86%). MS
(ESI}: 586.1
(M+H)+.
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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