Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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NOVEL SUCCINATE COMPOUNDS, COMPOSITIONS AND METHODS OF
USE AND PREPARATION
S
CROSS-REFERENCE TO RELATED APPLICATIONS
The application claims priority to L'.S, Patent Application No. 09/466,402,
filed on December 17, 1999, the disclosure of which is incorporated herein in
its
entirety.
BACKGROUND OF THE INVENTION
Field of the invention
This invention is directed to novel succinate compounds. This invention is
also directed to uses of these compounds in various medicinal applications,
including
treating disorders amenable to treatment by peptidyl deformylase inhibitors.
This
invention is still further directed to pharmaceutical compounds comprising
these
compounds and methods of synthesis thereof.
State of the Art
Treatment of microbial infection in host organisms requires an effective means
to kill the microbe while doing as little harm to the host as possible.
Accordingly,
agents which target characteristics unique to a pathology-causing
microorganism are
desirable for treatment. Penicillin is an extremely well known example of such
an
agent. Penicillin acts by inhibiting biosynthesis of bacterial cell walls.
Since
mammalian cells do not require cell walls for survival, administration of
penicillin to
a human infected with bacteria can kill the bacteria without killing human
cells.
However, the use of antibiotics and antimicrobials has also resulted in
increased resistance to these agents. As bacteria become resistant to older,
more
widely used antimicrobial agents, new antimicrobials must be developed in
order to
provide effective treatments for human and non-human animals suffering from
microbial infection.
Peptide deformylase is a metallopeptidase found in prokaryotic organisms
such as bacteria. Protein synthesis in prokaryotic organisms begins with N-
formyl
methionine (fMet). After initiation of protein synthesis, the formyl group is
removed
by the enzyme peptide deformylase (PDF); this activity is essential for
maturation of
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proteins. It has been shown that PDF is required for bacterial growth (Chang
et al. J.
Bacteriol. 171:4071-4072 (1989); Meinnel T, Blanquet S, J. Bacteriol.
176(23):7387-
90 (1994); Mazel D et al., EMBOJ. 13(4):914-23 (1994 )). Since protein
synthesis in
eukaryotic organisms does not depend on fMet for initiation, agents that will
inhibit
PDF are attractive candidates for development of new antimicrobial and
antibacterial
drugs. Prokaryotic organisms, including disease-causing prokaryotes, are
described in
Balows, A., H.G. Truper, M. Dworkin, W. Harder, and K.-H. Schleifer (eds.),
The
Prokaryotes, 2nd ed., New York: Springer-Verlag, 1992; and Holt, J.G. (editor-
in-
chief). Bergey's Manual of Systematic Bacteriology, Vols. 1-4, Baltimore:
Williams
& Wilkins, 1982, 1986, 1989.
PDF is part of the metalloproteinase superfamily. While PDF clearly shares
many of the features which characterize metalloproteinases, it differs from
other
members of the superfamily in several important respects. First, the metal ion
in the
active enzyme appears to be Fe (II), or possibly another divalent cationic
metal,
instead of the zinc ion more commonly encountered. Rajagopalan et al., J. Am.
Chem. Soc., 119:12418-19 (1997). Second, the divalent ion appears to play an
important role, not only in catalysis, but also in the structural integrity of
the protein.
Third, the third ligand of the divalent ion is a cysteine, rather than a
histidine or a
glutamate, as in other metalloproteinases and is not located at the C-terminal
side of
the HEXXH motif but far away along the amino acid sequence and N-terminal to
the
motif. Finally, the solution structure shows significant differences in the
secondary
and tertiary structure of PDF compared to other prototypical
metalloproteinases see
Meinnel et al. J. Mol. Biol. 262:375-386 (1996). PDF from E. coli, Bacillus
stearothermophilus, and Thermus thermophilus have been characterized see
Meinnel
et al., JMoI Biol 267:749-761 (1997). The enzyme studied by Meinnel et al.
contained a zinc ion as the divalent ion and the structural features
summarized above
were obtained from zinc-containing proteins. The structure of the protein has
also
been determined by NMR (see O'Connell et al., J. Biomol. NMR 13(4):311-24
( 1999)).
Metalloproteinases are critical to many aspects of normal metabolism. The
class known as matrix metalloproteinases (MMPs) are involved in tissue
remodeling,
such as degradation of the extracellular matrix. These enzymes are believed to
play a
role in normal or beneficial biological events such as the formation of the
corpus
luteum during pregnancy (see Liu et al., Endocrinology 140(11):5330-8 (1999)),
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wound healing (Yamagiwa et al., Bone 25(2):197-203 (1999)), and bone growth in
healthy children (Bord et al., Bone 23(1):7-12 (1998)). Disorders involving
metalloproteinases have been implicated in several diseases such as cancer,
arthritis,
and autoimmune diseases.
Because of the importance of MMPs in normal physiological processes, it
would be preferable to develop agents that inhibit PDF, a metalloproteinase
present
only in prokaryotes, while avoiding significant inhibition of MMPs.
Alternatively,
PDF inhibitors which also inhibit MMPs can be of use where the therapeutic
benefits
of inhibiting PDF outweigh the risk of side effects from MMP inhibition.
A wide variety of compounds have been developed as candidate inhibitors of
MMPs and other metalloproteinases, and much effort has also been directed at
synthetic methods for these compounds and related compounds. See Izquierdo-
Martin et al. (1992) J. Am. Chem. Soc. 114:325-331; Cushman et al. (1981)
Chapter 5
"Specific Inhibitors of Zinc Metallopeptidases" in Topics in Molecular
Pharmacology
(Burgen & Roberts, eds.); Mohler et al. Nature 370:218-220 (1994); Gearing et
al.,
Nature 370:555-557 (1994); McGeehan et al., Nature 370:558-561 (1994); U.S.
Patent Nos. 4,052,511, 4,303,662, 4,311,705, 4,321,383, 4,599,361, 4,804,676,
5,128,346, 5,256,657, 5,268,384, 5,447,929, 5,453,423, 5,552,419, 5,614,625,
5,643,908, 5,712,300, and 5,869,518; European patent publications EP 236872,
EP 274453, EP 334244, EP 423943, EP 489577, EP 489579, EP 497192, EP 574758;
and International PCT Patent Applications Publication Nos. WO 90/05716,
WO 90/05719, WO 91/02716, WO 92/13831, WO 92/22523, WO 93/09090,
WO 93/09097, WO 93/20047, WO 93/24449, WO 93/24475, WO 94/02446,
WO 94/02447, WO 94/21612, WO 94/25434, WO 94/25435, WO 95/33731,
WO 96/25156, WO 96/26918 WO 97/30707, WO 97/49674, WO 98/55449, and
WO 99/02510.
Research on inhibitors of PDF is much less extensive than that for inhibitors
of MMPs. N-formyl hydroxylamine derivatives are described in International
Patent
Application WO 99/39704. Peptide aldehyde inhibitors of PDFs are described in
Durand et al., Arch. Biochem. Biophys., 367(2):297-302 (1999). The PDF
inhibitor
(S)-2-O-(H-phosphonoxy)-L-caproyl-L-leucyl-p-nitroanilide is described in Hao
et
al., Biochemistry 38:4712-4719 (1999), and peptidyl H-phosphonate inhibitors
of
PDF are discussed in Hu et al., Bioorg. Med. Chem. Lett. 8:2479-2482 (1998).
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Formylated peptides and pseudopeptides are described in Meinnel et al.,
Biochemistry
38(14):4288-4295 (1999) as inhibitors of PDF.
In view of the importance of identifying new antibiotics to treat bacteria
resistant to existing antibiotics, and the relatively small amount of work
that has been
carned out on PDF inhibitors, it is desirable to develop novel inhibitors of
PDF for
evaluation and use as antibacterial and antimicrobial agents. The present
invention
fulfills this need.
SUMMARY OF THE INVENTION
In one aspect, this invention is directed to a compound of Formula (I):
R6 .Rr
O Rs R4
H0. N' (Y)n
/~(\N
R~ R2 O R6 R~
wherein:
Rl is hydrogen, halo, -OH, -RgOR9, -R9, -OR9, -SH, -SR9, -NH2, -NHR9
-NR9R,o, -NHC(=O)H, -NR9C(=O)H, -NHC(=O)R9, -NR9C(=O)Rlo, -NHC(=O)NHZ,
-NR9C(=O)NH2, -NHC(=O)NHR~, -NHC(=O)NR9Rlo, -NR9C(=O)NR9aR10~
-NHC(°O)OR9, -NR~C(=O)OR,o, -NHS(=O)ZR9, -NR9S(=O)ZR~o, -NHS(=O)ZOR9,
or
-NR9S(=O)ZOR~o where Rg is selected from the group consisting of -C,-C,2
alkylene,
substituted alkylene, or heteroalkylene, -C~-C12 alkenylene, substituted
alkenylene, or
heteroalkenylene, -C~-C~Z alkynylene, substituted alkynylene, or
heteroalkynylene,
and -(C~-C8 alkylene or substituted alkylene)"~-(C3-CIZ arylene or
heteroarylene)-(CI-
C8 alkyl or substituted alkyl)"Z where n1 and n2 are independently 0 or 1; and
R9, R9a
and Rio are independently selected from the group consisting of -C,-C~2 alkyl,
substituted alkyl, or heteroalkyl, -C~-C12 alkenyl, substituted alkenyl, or
heteroalkenyl, -C,-C~Z alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C1-C8
alkyl or substituted alkyl)"3-(C3-C12 arylene or heteroarylene)-(C~-Cg alkyl
or
substituted alkyl)"4 where n3 and n4 are independently 0 or l;
RZ is independently hydrogen or -R9 wherein R9 is as defined above;
R3 is hydrogen, halo, -R11, -OH, -ORl 1, -RAZORS 1, -SH, -SRS,, -NH2, -NHR> >,
-NR> >R13, -NHC(=O)H, -NR,1C(=O)H, -NHC(=O)Ri,, -NR"C(=O)R13,
-NHC(=O)NHZ, -NRI,C(=O)NH2, -NHC(=O)NHRII, -NHC(=O)NRuRl3,
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-NR11C(=O)~11aR13~ -NHC(=O)ORl l~ -NR11C(=O)OR13~ -NHS(=O)zRl3~
-NR11S(=O)zRl3, -NHS(=O)zORll, or-NR11S(=O)zORl3, where Rlz is selected from
the group consisting of -C1-Clz alkylene, substituted alkylene, or
heteroalkylene, -C1-
Clz alkenylene, substituted alkenylene, or heteroalkenylene, -C1-Clz
alkynylene,
S substituted alkynylene, or heteroalkynylene, and -(C1-C8 alkylene or
substituted
alkylene)ns-(C3-Clz arylene or heteroarylene)-(C1-C$ alkyl or substituted
alkyl)~6
where n5 and n6 are independently 0 or 1; and Rll, Rlla and R13 are
independently
selected from the group consisting of -C1-Clz alkyl, substituted alkyl, or
heteroalkyl,
-C1-Clz alkenyl, substituted alkenyl, or heteroalkenyl, -C1-Clz alkynyl,
substituted
alkynyl, or heteroalkynyl, and -(C1-C8 alkyl or substituted alkyl)"-(C3-Clz
arylene or
heteroarylene)-(C1-Cg alkyl or substituted alkyl)"$ where n7 and n8 are
independently
0 or 1;
R4 is hydrogen or -Rl1 where -Rl1 is as defined above;
n is an integer from 1 to 5;
zero or one Y is selected from the group consisting of -O-, -NRl1- where Rl 1
is
as defined above, and -S-, and all remaining Y are -CR6R~- where Rb and R~ are
each independently selected from the group consisting of hydrogen, -R14, -OH, -
ORIa,
-SH~ -SRIa~ -~z~ -NHR14~ '~14R15~ -C(=O)H~ -C(=O)Rla~ -C(=O)~z
-C(=O)NHR14, -C(=O)NR14R15, -C(=O)OH, -C(=O)OR14, -C(=O)SH, -C(=O)SRIa,
-C(=O)CH3, -C(=O)CH2R14, -C(=O)CHR14R15, -C(=O)CR14R15R16~ -C(=O)OCH3,
-C(=O)OCHZRIa~ -C(-~)OCHR14R15~ -C(-~)~CR14RISR16~ -S(-~)2~2~
-S(-~)2~R14~ -S(-O)2~14R15~ -NHC(=O)H, -N(R14)C(-O)H, -NHC(-O)R15
-N(Rla)C(=O)Rls~ -NHC(=O)ORIa~ -NHS(=O)zH~ -N(R14)S(°O)zH~ -
NHS(=O)zORls~
-N(R14)S(=O)zORls, -N(H)S(=O)zRls, -N(R14)S(=O)zRls and where two vicinal R~
or
R~ groups combine to form a substituted or unsubstituted -C4-Clo cyclic alkyl,
cyclic
heteroalkyl, aryl or heteroaryl group where R14, R15 and R16 are each
independently
selected from the group consisting of -C1-Clz alkyl, substituted alkyl, or
heteroalkyl,
-C1-Clz alkenyl, substituted alkenyl, or heteroalkenyl, -C1-Clz alkynyl,
substituted
alkynyl, or heteroalkynyl, alkoxy, and -(C1-Cg alkyl or substituted alkyl)~9-
(C3-Clz
arylene or heteroarylene)-(C1-C8 alkyl or substituted alkyl)"lowheren9 and n10
are
independently 0 or 1; or when R14 and R15 are attached to a nitrogen atom they
can
combine to form a substituted or unsubstituted -C4-Clo cyclic alkyl, cyclic
heteroalkyl, aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
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Preferably the compound of Formula (I) inhibits peptidyl deformylase at an
ICSO of less than or equal to about 100 nm, preferably of less than or equal
to 10 nm,
more preferably of less than or equal to 1 nm.
Preferably the compound of Formula (I) displays a selectivity for peptidyl
deformylase over at least one metalloproteinase selected from the group
consisting of
ACE and Matrilysin of greater than or equal to about 10 times, more preferably
of
greater than or equal to about 100 times, still more preferably of greater
than or equal
to about 1000 times.
In a second aspect, this invention is directed to pharmaceutical compositions
comprising a therapeutically effective amount of a compound of Formula (I) or
a
pharmaceutically acceptable salt thereof and a pharmaceutically acceptable
excipient.
In a third aspect, this invention is directed to a method of treatment of a
disease in a mammal treatable by administration of a peptidyl deformylase
inhibitor
which method comprises administration of a therapeutically effective amount of
a
pharmaceutical composition comprising a therapeutically effective amount of a
compound of Formula (I) or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable excipient either alone or in combination with
other
pharmacologically active agents. In particular, the compounds of this
invention are
useful in treating microbial diseases. The microbial infection can be due to
bacteria,
other prokaryotes, or other organisms, including parasites, dependent on
peptide
deformylase for growth or survival.
In a fourth aspect, this invention is directed to the use of a compound of
Formula (I) or a pharmaceutically acceptable salts thereof in the preparation
of a
medicament for use in the treatment of diseases mediated by peptidyl
deformylase
enzyme.
In a fifth aspect, this invention is directed to a method for identifying
compounds useful in treating microbial infections, comprising performing an
assay to
identify compounds which meet the criterion of either i) an ICSO for peptide
deformylase of less than or equal to about 1 ~M, or ii) an MIC for a disease-
causing
pathogen of less than or equal to about 32 pg/ml; performing an assay to
identify
compounds which meet the criterion of iii) displaying a selectivity for
peptide
deformylase over at least one metalloproteinase selected from the group
consisting of
Angiotensin Converting Enzyme (ACE) and Matrilysin of greater than or equal to
about 10 times; and selecting compounds which meet either both criteria i) and
iii), or
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both criteria ii) and iii). More preferably, the compounds so identified meet
the
criterion of either i) an ICso for peptide deformylase of less than or equal
to about 100
nM, or ii) an MIC for a disease-causing pathogen of less than or equal to
about 10
~ g/ml.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms as used in the specification have
the following meaning.
The term "alkyl" refers to saturated aliphatic groups including straight-
chain,
branched-chain, cyclic groups, and combinations thereof, having the number of
carbon atoms specified, or if no number is specified, having 1 to 12 carbon
atoms.
Examples of alkyl groups include, but are not limited to, groups such as
methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,
neopentyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl,
cyclobutylethyl,
1 S cyclopentylmethyl, cyclopentylethyl, and adamantyl. Cyclic alkyl groups
can consist
of one ring, including, but not limited to, groups such as cycloheptyl, or
multiple
fused rings, including, but not limited to, groups such as adamantyl or
norbornyl.
The term "alkylene" means a saturated divalent aliphatic groups including
straight-chain, branched-chain, cyclic groups, and combinations thereof,
having the
number of carbon atoms specified, or if no number is specified, having 1 to 12
carbon
atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methyl-
propylene, butylene, pentylene, cyclopentylmethylene, and the like.
The term "substituted alkyl" means an alkyl group as defined above that is
substituted with one or more substituents, preferably one to three
substituents selected
from the group consisting of halogen (fluoro, chloro, bromo, and iodo,
preferably
fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino,
hydroxyl,
mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy,
carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be
suitably
blocked, if necessary for purposes of the invention, with a protecting group.
The
phenyl group may optionally be substituted with one to three substituents
selected
from the group consisting of halogen (fluoro, chloro, bromo, and iodo,
preferably
fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino,
hydroxyl,
mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy,
carboxaldehyde,
carboalkoxy and carboxamide. Examples of substituted alkyl groups include, but
are
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not limited to, -CF3, -CFZ-CF3, hydroxymethyl, 1- or 2-hydroxyethyl,
methoxymethyl,
1- or 2-ethoxyethyl, carboxymethyl, 1- or 2- carboxyethyl,
methoxycarbonylmethyl,
1- or 2-methoxycarbonyl ethyl, benzyl, and the like.
The term "substituted alkylene" means an alkylene group as defined above that
S is substituted with one or more substituents, preferably one to three
substituents,
selected from the group consisting of halogen (fluoro, chloro, bromo, and
iodo,
preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or
dialkylamino,
hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro,
thioalkoxy,
carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be
suitably
blocked, if necessary for purposes of the invention, with a protecting group.
The
phenyl group may optionally be substituted with one to three substituents
selected
from the group consisting of halogen (fluoro, chloro, bromo, and iodo,
preferably
fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino,
hydroxyl,
mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy,
carboxaldehyde,
carboalkoxy and carboxamide. Examples of substituted alkyl groups include, but
are
not limited to, -CFZ-, -CFZ-CFZ-, hydroxymethylene, 1- or 2-hydroxyethylene,
methoxymethylene, 1- or 2-ethoxyethylene, carboxymethylene, 1- or 2-carboxy-
ethylene, and the like.
The term "alkenyl" refers to unsaturated aliphatic groups including straight-
chain, branched-chain, cyclic groups, and combinations thereof, having the
number of
carbon atoms specified, or if no number is specified, having 1 to 12 carbon
atoms,
which contain at least one double bond (-C=C-). Examples of alkenyl groups
include,
but are not limited to, allyl vinyl, -CHZ-CH=CH-CH3, -CHZ-CHz-cyclopentenyl
and
-CHZ-CHZ-cyclohexenyl where the ethyl group can be attached to the
cyclopentenyl,
cyclohexenyl moiety at any available carbon valence.
The term "alkenylene" refers to unsaturated divalent aliphatic groups
including
straight-chain, branched-chain, cyclic groups, and combinations thereof,
having the
number of carbon atoms specified, or if no number is specified, having 1 to 12
carbon
atoms, which contain at least one double bond (-C=C-). Examples of alkenylene
groups include, but are not limited to, -CH=CH-, -CHZ-CH=CH-CHZ-,
-CHz-CH(cyclopentenyl)- and the like.
The term "alkynyl" refers to unsaturated aliphatic groups including straight-
chain, branched-chain, cyclic groups, and combinations thereof, having the
number of
carbon atoms specified, or if no number is specified, having 1 to 12 carbon
atoms,
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which contain at least one triple bond ( -C---C-). Examples of alkynyl groups
include,
but are not limited to, acetylene, 2-butynyl, and the like.
The term "alkynylene" refers to unsaturated divalent aliphatic groups
including straight-chain, branched-chain, cyclic groups, and combinations
thereof,
having the number of carbon atoms specified, or if no number is specified,
having 1 to
12 carbon atoms, which contain at least one triple bond ( -C---C-). Examples
of
alkynylene groups include, but are not limited to, -C---C-, -C=C-CHZ-, and the
like.
The term "substituted alkenyl" or "substituted alkynyl," refers to the alkenyl
and alkynyl groups as defined above that are substituted with one or more
substituents, selected from the group consisting of halogen, alkoxy, acyloxy,
amino,
hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro,
thioalkoxy,
carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be
suitably
blocked, if necessary for purposes of the invention, with a protecting group.
Examples of substituted alkenyl and alkynyl groups include, but are not
limited to,
-CH=CF2, hydroxyethenyl, methoxypropenyl, hydroxypropynyl, and the like.
The term "substituted alkenylene" or "substituted alkynylene," refers to the
alkenylene and alkynylene groups as defined above that are substituted with
one or
more substituents, selected from the group consisting of halogen, alkoxy,
acyloxy,
amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro,
thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality
that can
be suitably blocked, if necessary for purposes of the invention, with a
protecting
group.
The term "aryl" or "Ar" refers to an aromatic carbocyclic group of 6 to 14
carbon atoms having a single ring (including, but not limited to, groups such
as
phenyl) or multiple condensed rings (including, but not limited to, groups
such as
naphthyl or anthryl), and includes both unsubstituted and substituted aryl
groups.
Substituted aryl is an aryl group that is substituted with one or more
substituents,
preferably one to three substituents, selected from the group consisting of
alkyl,
alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino,
hydroxyl,
mercapto, carboxy, benzyloxy, phenyl, aryloxy, benzyl, cyano, nitro,
thioalkoxy,
carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be
suitably
blocked, if necessary for purposes of the invention, with a protecting group.
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Representative examples include, but are not limited to, naphthyl, phenyl,
chlorophenyl, iodophenyl, methoxyphenyl, carboxyphenyl, and the like.
The term "arylene" refers to the diradical derived from aryl (including
substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-
phenylene, 1,4-phenylene, 1,2-naphthylene and the like.
The term "amino" refers to the group -NHz.
The term "thioalkoxy " means a radical -SR where R is an alkyl as defined
above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.
The term "mono and "dialkylamino" means a radical -NHR and -NRR'
respectively where R and R' independently represent an alkyl group as defined
herein.
Representative examples include, but are not limited to dimethylamino,
methylethylamino, di(1-methylethyl)amino, (cyclohexyl)(methyl)amino,
(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino,
(cyclohexylmethyl)(methyl)-
amino, (cyclohexylmethyl)(ethyl)amino, and the like.
1 S The term "acyloxy" means a radical -OC(O)R, where R is hydrogen, alkyl,
aryl, heteroaryl or substituted alkyl wherein alkyl, aryl, heteroaryl, and
substituted
alkyl are as defined herein. Representative examples include, but are not
limited to
formyl, acetyloxy, cylcohexylcarbonyloxy, cyclohexylmethylcarbonyloxy,
benzoyloxy, benzylcarbonyloxy, and the like.
The term "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refers to alkyl,
alkenyl, and alkynyl groups respectively as defined above, that contain the
number of
carbon atoms specified (or if no number is specified, having 1 to 12 carbon
atoms)
which contain one or more heteroatoms, preferably one to three heteroatoms, as
part
of the main, branched, or cyclic chains in the group. Heteroatoms are
independently
selected from the group consisting of -NR-, -NRR, (where each R is hydrogen or
alkyl), -S-, -O-, -SR (R is hydrogen or alkyl), -OR (R is hydrogen or alkyl),
and P;
preferably -NR where R is hydrogen or alkyl and/or O. Heteroalkyl,
heteroalkenyl,
and heteroalkynyl groups may be attached to the remainder of the molecule
either at a
heteroatom (if a valence is available) or at a carbon atom. Examples of
heteroalkyl
groups include, but are not limited to, groups such as -O-CH3, -CHZ-O-CH3,
-CHZ-CHZ-O-CH3, -S-CHZ-CHZ-CH3, -CHZ-CH(CH3)-S-CH3,
-CHZ-CHZ-NH-CHZ-CH3, 1-ethyl-6-propylpiperidino, 2-ethylthiophenyl,
piperazino,
pyrrolidino, piperidino, morpholino, and the like. Examples of heteroalkenyl
groups
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include, but are not limited to, groups such as -CH=CH-NH-CH(CH3)-CH3, and the
like.
The term "carboxaldehyde" means -CHO.
The term " carboalkoxy" means -C(O)OR where R is alkyl as defined above
and include groups such as methoxycarbonyl, ethoxycarbonyl, and the like.
The term "carboxamide" means -C(O)NHR or -C(O)NRR'where R and R'
are independently hydrogen or alkyl as defined above. Representative examples
include groups such as aminocarbonyl, methylaminocarbonyl,
dimethylaminocarbonyl, and the like.
The term "heteroaryl" or "HetAr" refers to an aromatic carbocyclic group of 3
to 9 ring atoms forming a single ring and having at least one hetero atom,
preferably
one to three heteroatoms including, but not limited to, heteroatoms such as N,
O, P, or
S, within the ring. Representative examples include, but are not limited to
single ring
such as imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinly, pyrrolyl,
pyridyl,
thiophene, and the like, or multiple condensed rings such as indolyl,
quinoline,
quinazoline, benzimidazolyl, indolizinyl, benzothienyl, and the like.
The heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl groups can be
unsubstituted or substituted with one or more substituents, preferably one to
three
substituents, selected from the group consisting of alkyl, alkenyl, alkynyl,
benzyl,
halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto,
carboxy, benzyloxy, phenyl, aryloxy, cyano, nitro, thioalkoxy, carboxaldehyde,
carboalkoxy and carboxamide, or a functionality that can be suitably blocked,
if
necessary for purposes of the invention, with a protecting group. Examples of
such
substituted heteroalkyl groups include, but are not limited to, piperazine,
pyrrolidine,
morpholine, or piperidine, substituted at a nitrogen or carbon by a phenyl or
benzyl
group, and attached to the remainder of the molecule by any available valence
on a
carbon or nitrogen, -NH-SOZ-phenyl, -NH-(C=O)O-alkyl, -NH-(C=O)O-alkyl-aryl,
and the like. The heteroatom(s) as well as the carbon atoms of the group can
be
substituted. The heteroatom(s) can also be in oxidized form.
The term "heteroarylene" refers to the diradical group derived from heteroaryl
(including substituted heteroaryl), as defined above, and is exemplified by
the groups
2,6-pyridylene, 2,4-pyridinylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-
benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl, and the like.
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The term "heteroalkylene", "heteroalkenylene", and "heteroalkynylene"
refers to the diradical group derived from heteroalkyl, heteroalkenyl, and
heteroalkynyl (including substituted heteroalkyl, heteroalkenyl, and
heteroalkynyl), as
defined above.
The term "alkylaryl" refers to an alkyl group having the number of carbon
atoms designated, appended to one, tvvo, or three aryl groups.
The term "alkoxy" as used herein refers to an alkyl, alkenyl, or alkynyl
linked
to an oxygen atom and having the number of carbon atoms specified, or if no
number
is specified, having 1 to 12 carbon atoms. Examples of alkoxy groups include,
but are
not limited to, groups such as methoxy, ethoxy, tent-butoxy, and allyloxy.
The term "aryloxy" as used herein refers to an aryl group linked to an oxygen
atom at one of the ring carbons. Examples of alkoxy groups include, but are
not
limited to, groups such as phenoxy, 2-, 3-, or 4-methylphenoxy, and the like.
The term "halogen" as used herein refer to Cl, Br, F or I substituents,
preferably fluoro or chloro.
The term "-(C~-C~Z) alkyl, substituted alkyl, or heteroalkyl" means an alkyl,
substituted alkyl or heteroalkyl group respectively as defined above and
having 1 to
12 carbon atoms. For example, when R~ is -(C~-C12) alkyl, substituted alkyl,
or
heteroalkyl it means that R, can be -(C~-C12) alkyl or -(C~-C1z)substituted
alkyl, or -
(C~-C~z)heteroalkyl.
The term "-(C~-C~2) alkenyl, substituted alkenyl, or heteroalkenyl" means an
alkenyl, substituted alkenyl, or heteroalkenyl group as defined above and
having 1 to
12 carbon atoms.
The "-(C,-C1z) alkynyl, substituted alkynyl, or heteroalkynyl" means an
alkynyl, substituted alkynyl, or heteroalkynyl group as defined above and
having 1 to
12 carbon atoms.
The term "-(Cl-C~2) alkylene, substituted alkylene, or heteroalkylene" means
an alkylene, substituted alkylene, or heteroalkylene group as defined above
and
havingl to 12 carbon atoms.
The term "-(C1-C~Z) alkenylene, substituted alkenylene, or heteroalkenylene"
means that the alkenylene, substituted alkenylene, or heteroalkenylene group
as
defined above and having 1 to 12 carbon atoms.
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The term " -(C1-C~Z) alkynylene, substituted alkynylene, or heteroalkynylene"
means an alkynylene, substituted alkynylene, or heteroalkynylene group as
defined
above and having 1 to 12 carbon atoms.
The term "and -(C~-Cg alkylene or substituted alkylene)"5-(C3-CIZ arylene or
heteroarylene)-(C~-Cg alkyl or substituted alkyl)" where n5 and n6 are
independently
0 or 1" means that "when n5 and/or n6 are 0 then -(C1-C8 alkylene or
substituted
alkylene)"5 and/or -(C~-Cg alkylene or substituted alkylene)"6" are a covalent
bond or
when n5 and/or n6 are 1, then the alkylene or substituted alkylene group is
present
and can have 1 to 8 carbon atoms. The term -(C3-C1z arylene or heteroarylene)-
means that the arylene has 6 to 12 carbon atoms (e.g., phenylene, naphtylene,
and the
like) and heteroarylene groups have 3 to 12 carbons atoms and additionally
contain
one to three heteroatoms including, but not limited to, heteroatoms such as N,
O, P, or
S, within the ring (e.g., 2,6-pyridylene, 2,4-pyridinylene, 1,2-quinolinylene,
1,8-
quinolinylene, 1,4-benzofuranylene, 2,5-pyridylene, 2,5-indolenyl, and the
like) in
accordance with the definition of the heteroarylene above. Additionally, it
will be
recognized by a person skilled in the art that when "-(C~-Cg alkylene or
substituted
alkylene)- " and "-(CI-Cg alkyl or substituted alkyl)- " are a covalent bond
then -
(C3-C~Z arylene or heteroarylene)- is an aryl or heteroaryl group as defined
above.
"Protecting group" refers to a chemical group that exhibits the following
characteristics: 1 ) reacts selectively with the desired functionality in good
yield to
give a protected substrate that is stable to the projected reactions for which
protection
is desired; 2) is selectively removable from the protected substrate to yield
the desired
functionality; and 3) is removable in good yield by reagents compatible with
the other
functional groups) present or generated in such projected reactions. Examples
of
suitable protecting groups can be found in Greene et al. (1991) Protective
Groups in
Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York). Preferred
amino
protecting groups include, but are not limited to, benzyloxycarbonyl (CBz), t-
butyl-
oxycarbonyl (Boc), t-butyldimethylsilyl (TBDIMS), 9-fluorenylmethyl-
oxycarbonyl
(Fmoc), or suitable photolabile protecting groups such as 6-nitroveratryloxy
carbonyl
(Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl
dimethoxybenzil, 5-bromo-7-nitroindolinyl, and the like. Preferred hydroxyl
protecting groups include Fmoc, TBDIMS, photolabile protecting groups (such as
nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem
(methoxy ethoxy methyl ether). Particularly preferred protecting groups
include
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NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxy-
methyloxycarbonyl).
"Inhibitor" refers to a compound that interferes with the interaction between
a
target and its respective substrates) or endogenous ligand(s). Target
molecules
include, but are not limited to, enzymes and receptors. Enzyme inhibitors have
been
extensively studied from kinetic and mechanistic standpoints; see, e.g.,
Fersht, A.,
Enzyme Structure and Mechanism, 2nd Ed., New York, W.H. Freeman, 1985. A
useful measure of the effectiveness of a compound at inhibiting enzyme
catalysis is
the ICso of that compound. The ICso of a compound can determined by the
equation
y = yo/(1 + [In]/ICso)
where y is the measured reaction velocity, yo is the reaction velocity in the
absence of
inhibitor, and [In] is the inhibitor concentration. Solving this equation at
the inhibitor
concentration [In] when y = y~/2 yields ICso of the inhibitor for the enzyme
under
study. Useful inhibitors have an ICSO equal to or less than about 10 TM,
preferably
equal to or less than about 1 TM. More preferably, the inhibitor has an ICso
equal to
or less than about 100 nM, still more preferably equal to or less than about
10 nM,
even more preferably equal to or less than about lnM. Most preferably,
inhibitors
have an ICso equal to or less than about 100 pM, or equal to or less than
about 10 pM.
A selective inhibitor refers to an inhibitor that will inhibit the activity of
one
macromolecule, typically an enzyme, while exhibiting little or no inhibitory
effect on
another macromolecule, typically another enzyme. The compounds of the
invention
are particularly useful in that they display selective inhibition of peptidyl
deformylase
while exhibiting much lower inhibitory activity towards metalloproteinases
such as
matrilysin. The selectivity of an enzyme inhibitor can be indicated by
dividing the
ICSO of the compound for the enzyme which is not intended to be inhibited, by
the
ICSO of the compound for the enzyme which is intended to be inhibited. Thus,
if a
compound has an ICso for matrilysin of 1 pM, and an ICso for peptidyl
deformylase of
0.01 ~M, the compound displays a 100-fold (or 100 times) selectivity for
peptidyl
deformylase over matrilysin, or alternatively is said to be 100 times more
selective for
peptidyl deformylase compared to matrilysin. Useful compounds display a
selectivity
of greater than or equal to about 10 times, preferably greater than or equal
to about
100 times, more preferably greater than or equal to about 1000 times, still
more
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preferably greater than or equal to about 10,000, for peptidyl deformylase
over one or
more other metalloproteinases, for example for peptidyl deformylase over
matrilysin.
The compounds of the invention are intended for use in eukaryotic animals.
Preferably, the animal is a vertebrate; more preferably, the animal is a
mammal; most
preferably, the animal is a human.
By "hydroxamic acid derivative," "hydroxamic acid derivative compound,"
"hydroxamic acid compound," "hydroxamate derivative," "hydroxamate derivative
compound," or "hydroxamate compound" is meant any compound containing the
functional group HN(OH)-C(=O)-.
Compounds that have the same molecular formula but differ in the nature or
sequence of bonding of their atoms or the arrangement of their atoms in space
are
termed "isomers". Isomers that differ in the arrangement of their atoms in
space are
termed "stereoisomers". Stereoisomers that are not mirror images of one
another are
termed "diastereomers" and those that are non-superimposable mirror images of
each
other are termed "enantiomers". When a compound has an asymmetric center, for
example, it is bonded to four different groups, a pair of enantiomers is
possible. An
enantiomer can be characterized by the absolute configuration of its
asymmetric
center and is described by the R- and S-sequencing rules of Cahn and Prelog,
or by the
manner in which the molecule rotates the plane of polarized light and
designated as
dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A
chiral
compound can exist as either individual enantiomer or as a mixture thereof. A
mixture containing equal proportions of the enantiomers is called a "racemic
mixture".
The compounds of this invention may possess one or more asymmetric
centers; such compounds can therefore be produced as individual (R)- or (S)-
stereoisomers or as mixtures thereof. For example, if the R6 substituent in a
compound of Formula (I) is 2-hydroxyethyl, then the carbon to which the
hydroxy
group is attached is an asymmetric center and therefore the compound of
Formula (I)
can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the
description
or naming of a particular compound in the specification and claims is intended
to
include both individual enantiomers and mixtures, racemic or otherwise,
thereof. The
methods for the determination of stereochemistry and the separation of
stereoisomers
are well-known in the art (see discussion in Chapter 4 of "Advanced Organic
Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).
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A "pharmaceutically acceptable excipient" means an excipient that is useful
iri
preparing a pharmaceutical composition that is generally safe, non-toxic and
neither
biologically nor otherwise undesirable, and includes an excipient that is
acceptable for
veterinary use as well as human pharmaceutical use. A "pharmaceutically
acceptable
excipient" as used in the specification and claims includes both one and more
than one
such excipient.
A "pharmaceutically acceptable salt" of a compound means a salt that is
pharmaceutically acceptable and that possesses the desired pharmacological
activity
of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric
acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like;
or formed
with organic acids such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic
acid,
succinic acid, malic acid, malefic acid, fumaric acid, tartaric acid, citric
acid, benzoic
acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic
acid,
2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,
lauryl sulfuric
acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid,
stearic acid,
muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either
is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion,
or an
aluminum ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the
like.
A compound of Formula (I) may act as a pro-drug. Prodrug means any
compound which releases an active parent drug according to Formula (I) in vivo
when
such prodrug is administered to a mammalian subject. Prodrugs of a compound of
Formula (I) are prepared by modifying functional groups present in the
compound of
Formula (I) in such a way that the modifications may be cleaved in vivo to
release the
parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy,
amino, or sulfhydryl group in compound (I) is bonded to any group that may be
cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group,
respectively. Examples of prodrugs include, but are not limited to esters
(e.g., acetate,
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formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylamino-
carbonyl)
of hydroxy functional groups in compounds of Formula (I), and the like.
"Treating" or "treatment" of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the
disease not to develop in a mammal that may be exposed to or predisposed to
the
disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the
disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its
clinical symptoms.
A "therapeutically effective amount" means the amount of a compound that,
when administered to a mammal for treating a disease, is sufficient to effect
such
treatment for the disease. The "therapeutically effective amount" will vary
depending
on the compound, the disease and its severity and the age, weight, etc., of
the mammal
1 S to be treated.
PREFERRED EMBODIMENTS
While the broadest definition of this invention is set forth in the Summary of
the Invention, certain compounds of Formula (I) are preferred. For example,
(A) (i) A preferred group of compounds is that wherein R~ is hydrogen or
hydroxy,
preferably hydroxy. The stereochemistry at the carbon carrying the Rl group is
(R) or
(
(ii) Another preferred group of compounds is that wherein Rl is halo;
preferably
chloro or fluoro; more preferably fluoro. The stereochemistry at the carbon
carrying
the R, group is (R) or (,5~, preferably (.S~ when Rl is fluoro.
Within the above preferred groups, a more preferred group of compounds is
that wherein RZ and R~ are hydrogen.
(iii) Yet another preferred group of compounds is that wherein R3 is hydrogen
or
R,l where Rl~ is -Cl-C1z alkyl or-(C1-Cg alkylene)"~-(C3-C~2 aryl or
heteroaryl),
preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-
butyl, n-pentyl,
iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4-
dimethylbutyl,
benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-
butyl.
The stereochemistry at the carbon carrying the R3 group is (R) or (,5~,
preferably (R).
(iv) Yet another preferred group of compounds is that wherein the
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R6 R~
~N~c~')n
R6 R~
group is a group of formula:
/R~
~N~ )n
wherein:
n is 1 or 2, preferably 1; and
R~ is:
(a) -C(=O)NRI4R,s where R14 and Rls are independently selected from the group
consisting of hydrogen, -(CI-C~2) alkyl, substituted alkyl, or heteroalkyl, -
(C~-C~z)
alkenyl, substituted alkenyl, or heteroalkenyl, -(CI-C~Z) alkynyl, substituted
alkynyl,
or heteroalkynyl, alkoxy, and -(CI-Cg alkyl or substituted alkyl)n9-(C3-C12
arylene or
heteroarylene)-(C1-Cg alkyl or substituted alkyl)"lo where n9 and n10 are
independently 0 or 1; or R14 and R~5 combine to form a substituted or
unsubstituted -
(C4-C~o)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group.
Preferably, R~ is -C(=O)NR~4R15 where RI4 and R~5 are each independently
hydrogen or-(Cl-C~Z) alkyl, alkoxy, aryl, heteroaryl or R14 and RCS, when
attached to
the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl
group.
More preferably, R~ is -C(=O)NHR15 where RIS is H or-(CI-Ci2) alkyl, aryl,
or heteroaryl or -C(=O)NRI4R,5 where R14 and R,Sform a substituted or
unsubstituted
-(C4-Clo)cyclic heteroalkyl.
Even more preferably R~ is n-butylaminocarbonyl, tert-butylaminocarbonyl,
benzylaminocarbonyl, l,1-dimethylpropylaminocarbonyl, 2-(cyclohexen-1-yl)-
ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylamino-
carbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl-aminocarbonyl,
pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylamino-
carbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-phenylaminocarbonyl,
quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3-
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phenoxyphenylaminocarbonyl, 3,4-dichlorophenyl-aminocarbonyl, 4-tert-
butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl,
2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl, 5-phenyl-
thiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol-
2-
ylaminocarbonyl, 3-trifluoromethoxyphenyl-aminocarbonyl, 2,5-dimethylphenyl-
aminocarbonyl, 2,5-dimethoxyphenylamino-carbonyl, 3,4-dichlorophenyl-
aminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-phenoxyphenylaminocarbonyl,
2-hydroxybutylaminocarbonyl, 4-hydroxybutyl-aminocarbonyl, 1,4-benzodioxan-6-
ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-
yl-
aminocarbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 3-methylbutyl-
aminocarbonyl,
n-pentylaminocarbonyl, cyclohexylaminocarbonyl, S-methylthiazol-2-ylamino-
carbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 2,4-dimethoxyphenyl-
aminocarbonyl,
3,4-methylenedioxyphen-5-yl-methylaminocarbonyl, allylaminocarbonyl, 2-methyl-
allylaminocarbonyl, pyrrolidin-1-ylcarbonyl, ethylaminocarbonyl, phenylamino-
carbonyl, indan-1-ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-yl-
aminocarbonyl, 3,4-difluorophenyl-aminocarbonyl, 5-methylisoxazol-S-yl-
aminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N
methyl-N phenylaminocarbonyl, 2-propylamino-carbonyl, 2-phenylpropyl-
aminocarbonyl, n-propylaminocarbonyl, N ethyl-N (n-butyl)aminocarbonyl,
benzylaminocarbonyl, thiazolidin-1-ylcarbonyl, piperazin-1-yl-carbonyl,
piperidin-1-
ylcarbonyl, azetidin-1-ylcarbonyl, homopiperdin-1-ylcarbonyl, pyrimidin-2-
ylamino-
carbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl,
pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylamino-
carbonyl.
~ In particular, R~ is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl,
ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or
thiazol-
2-ylaminocarbonyl.
More particularly, R~ is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl,
ethylaminocarbonyl or thiazol-2-ylaminocarbonyl. The stereochemistry at the C2
carbon atom of the pyrrolidine ring, i.e., carbon carrying the R~ group is
either (R) or
(,5~, preferably (,5~; or
(b) R~ is -NHC(=O)OR,4 where R,4 is hydrogen, -(C~-C1z) alkyl,
substituted alkyl, or heteroalkyl, -(C~-C~Z) alkenyl, substituted alkenyl, or
heteroalkenyl, -(C~-C~2) alkynyl, substituted alkynyl, or heteroalkynyl,
alkoxy, or
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-(C~-Cg alkyl or substituted alkyl)~9-(C3-C~z arylene or heteroarylene)-(C~-C$
alkyl or
substituted alkyl)nlo where n9 and n10 are independently 0 or 1.
Preferably, R~ is -NHC(=O)OR,4 where R~4 is hydrogen or-(C~-Clz) alkyl,
alkoxy, aryl, heteroaryl; or
(c) R~ is -C(=O)ORl4 where R14 is hydrogen, -(C1-Clz) alkyl, substituted
alkyl, or heteroalkyl, -(C~-C,z) alkenyl, substituted alkenyl, or
heteroalkenyl, -(C1-
C,z) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C~-C$ alkyl
or
substituted alkyl)"9-(C3-C~z arylene or heteroarylene)-(C1-C8 alkyl or
substituted
alkyl)nio where n9 and n10 are independently 0 or 1.
Preferably, R~ is -C(=O)ORI~ where R~4 is hydrogen or-(Cl-Clz) alkyl,
alkoxy, aryl, or heteroaryl.
More preferably, -C(=O)OR14 where R,4 is alkyl, even more preferably R~ is
tert-butoxycarbonyl. The stereochemistry at the Cz carbon atom of the
pyrrolidine
ring, i.e., carbon carrying the R~ group is either (R) or (S~, preferably (S~.
The above defined embodiments of (i) - (iv) are employed either singularly or
in any combination.
(B) Another preferred group of compounds is represented as Formula (IIa):
O RW
R3 Ra
HON NyY)n
H Ri R2 O R'6X'R~
(IIa)
wherein:
R~ is -OH, -OR9, -RgOR~, -SH, -SR9, -NHz, -NHR9 -NR9Rlo, -NHC(=O)H,
-NR9C(=O)H, -NHC(=O)R9, -NR~C(=O)Rlo, -NHC(=O)NHz, -NR9C(=O)NHz,
-NHC(=O)NHR9, -NHC(=O)NR9Rlo, -NR9C(=O)IVR9aR10~ -NHC(=O)OR9,
-NR9C(=O)OR~O, -NHS(=O)zR9, -NR9S(=O)zRlo, -NHS(=O)zOR9, or
-NR9S(=O)zORlo where R$ is selected from the group consisting of -C~-Clz
alkylene,
-C,-C~z alkenylene, and -C~-Clz alkynylene and R9, Rya and Rlo are
independently
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selected from the group consisting of -C1-Clz alkyl, -C1-Clz alkenyl, and -C1-
Clz
alkynyl;
Rz is hydrogen or -R9 where R9 is as defined above;
R3 is -Rl l, -OH, -OR11, -RIZORII~ -SH, -SRII, -NHz, -NHRI l -NR11R13~
-NHC(=O)H, -NR11C(=O)H, -NHC(=O)R11, -NR11C(=O)R13, -NHC(=O)NHz,
-NR11C(=O)NHz, -NHC(=O)NHRI l, -NHC(=O)NR11R13~ -NR11C(=O)NR11aR13~
-NHC(=O)ORII~ -~llC(-~)OR13~ -NHS(=O)2R13~ -~lls(-~)2R13~
-NHS(=O)zORll, or-NR11S(=O)zORl3, where R,z is selected from the group
consisting of -C1-Clz alkylene, substituted alkylene, or heteroalkylene, -C1-
Clz
alkenylene, substituted alkenylene, or heteroalkenylene, -C1-Clz alkynylene,
substituted alkynylene, or heteroalkynylene, and -(C1-Cg alkylene or
substituted
alkylene)ns-(C3-Clz arylene or heteroarylene)-(C1-C$ alkyl or substituted
alkyl)"6
where n5 and n6 are independently 0 or 1; and R11, Rl la, and R13 are
independently
selected from the group consisting of -C1-Clz alkyl, substituted alkyl, or
heteroalkyl,
-C1-Clz alkenyl, substituted alkenyl, or heteroalkenyl, -C1-Clz alkynyl,
substituted
alkynyl, or heteroalkynyl, and -(C1-C$ alkyl or substituted alkyl)n7-(C3-Clz
arylene or
heteroarylene)-(C1-Cg alkyl or substituted alkyl)"g where n7 and n8 are
independently
Oorl;
R4 is hydrogen or Rl1 where Rl1 is as defined above;
n is an integer from 1 to 5;
zero or one Y is selected from the group consisting of -O-, -NRl l- where Rl l
is
as defined above, and -S-, and all remaining Y are -CR6R~- where R~ and R~ are
each
independently selected from the group consisting of hydrogen, -R14, -OH, -
OR14, -SH,
-SRl4~ -~2~ -NHR14~ -~14R15~ -C(-~)H~ -C(-~)R14~ -C(-~)~Z~ -C(-0)~RI4~
-C(=O)NRl4Rls, -C(=O)OH, -C(=O)OR14, -C(=O)SH, -C(=O)SR14, -C(=O)CH3,
-C(=O)CHZR14, -C(=O)CHRI4Rls, -C(=O)CR14R1sR16, -C(=O)OCH3,
-C(=O)OCHZR14~ -C(=O)OCHRI4Rls~ -C(=O)OCR14R1sR16~ -S(=O)z~z
-S(=O)zNHRl4, -S(=O)2~14RI5~ -NHC(=O)H, -N(R14)C(=O)H, -NHC(=O)Rls~
-N(R14)C(°O)Rls~ -NHS(=O)zH, -N(R14)S(=O)zH~ -NHS(=O)zORls~
-N(R14)S(=O)zORls, -N(H)S(=O)zRls, -N(R14)S(=O)zRls and where two vicinal R6
or
R~ groups combine to form a substituted or unsubstituted C4-C1o cyclic alkyl,
cyclic
heteroalkyl, aryl or heteroaryl group; where R14, Rls and R16 are each
independently
selected from the group consisting of-C1-Clz alkyl, substituted alkyl, or
heteroalkyl,
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-C,-C1z alkenyl, substituted alkenyl, or heteroalkenyl, -C~-C~2 alkynyl,
substituted
alkynyl, or heteroalkynyl, and -(C~-C$ alkyl or substituted alkyl)n9-(C3-C~2
arylene or
heteroarylene)-(C1-Cg alkyl or substituted alkyl)n~owhere n9 and n10 are
independently 0 or 1; or a pharmaceutically acceptable salt thereof.
Within this group of compounds (IIa), a preferred group of compounds is that
wherein the embodiments of (i) - (iv) defined below are employed either
singularly or
in any combination:
(i) A preferred group of compounds is that wherein R~ is hydrogen or
hydroxy and the stereochemistry at the carbon carrying the R~ group is (R) or
(,5~,
preferably (,5~.
(ii) Another preferred group of compounds is that wherein RZ and R4 are
hydrogen.
(iii) Another preferred group of compounds is that wherein R3 is hydrogen
or R9 where R~ is -C1-C~2 alkyl or-(C1-Cg alkylene)"~-(C3-C12 aryl or
heteroaryl)
where n7, preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tent-butyl,
n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4-
dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more
preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is
(R) or
(S~, preferably (R).
(iv) Another preferred group of compounds is that wherein the
R6 R~
~N~(~')n
R6 R~
group is a group of formula:
R~
~N~
n
wherein:
n is 1 or 2, preferably l; and
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R~ is:
(a) -C(=O)NR~4R15 where R~4 and R~5 are independently selected from the
group consisting of hydrogen, -(C~-C~2) alkyl, substituted alkyl, or
heteroalkyl, -(C~-
C,2) alkenyl, substituted alkenyl, or heteroalkenyl, -(C~-C~2) alkynyl,
substituted
alkynyl, or heteroalkynyl, alkoxy, and -(C1-C$ alkyl or substituted alkyl)"-
(C3-Clz
arylene or heteroarylene)-(C1-C8 alkyl or substituted alkyl)n~owhere n9 and
n10 are
independently 0 or 1.
Preferably, R~ is -C(=O)NR~4R~5 where R14 and Rls are each independently
hydrogen or-(C~-C~2) alkyl, alkoxy, aryl, heteroaryl. More preferably, R~ is
-C(=O)NHR~S where R~5 is H or-(CI-C12) alkyl, aryl, or heteroaryl.
Even more preferably R~ is n-butylaminocarbonyl, tert-butylaminocarbonyl,
benzylaminocarbonyl, 1,1-dimethylpropylaminocarbonyl, 2-(cyclohexen-1-yl)-
ethylaminocarbonyl, indan-S-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylamino-
carbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethylaminocarbonyl,
pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethyl-
aminocarbonyl, 3,4-methylenedioxyphenylaminocarbonyl, quinolin-3-
ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl,
3-phenoxyphenylaminocarbonyl, 3,4-dichlorophenylaminocarbonyl, 4-tert-
butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl,
2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl,
5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl,
thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenylaminocarbonyl,
2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylamino-arbonyl,
3,4-dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl,
3-phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl-
aminocarbonyl, 1,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-
ylaminocarbonyl,
methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl-
aminocarbonyl, 3-methylbutylaminocarbonyl, n-pentylaminocarbonyl,
cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-
yl-
aminocarbonyl, 2,4-dimethoxyphenylaminocarbonyl, 3,4-methylenedioxyphen-5-yl-
methylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl,
ethylaminocarbonyl, phenylaminocarbonyl, indan-1-ylaminocarbonyl,
2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenyl-
aminocarbonyl, 5-methylisoxazol-S-ylaminocarbonyl, 3-
fluorophenylaminocarbonyl,
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4-fluorophenylaminocarbonyl, N methyl-N phenylaminocarbonyl, 2-propylamino-
carbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N ethyl-N (n-
butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1-ylcarbonyl, pyrimidin-
2-
ylaminocarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-yl-
aminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
In particular, R~ is ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-
ylaminocarbonyl, or thiazol-2-ylaminocarbonyl. More particularly, R~ is
phenylaminocarbonyl or pyrimidin-2-ylaminocarbonyl. The stereochemistry at the
C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R~ group is
either (R)
or (S~, preferably (,5~; or
(b) -NHC(=O)OR~4 where R14 is hydrogen, -(C~-C,z) alkyl, substituted
alkyl, or heteroalkyl, -(Cl-Clz) alkenyl, substituted alkenyl, or
heteroalkenyl, -(C1-
Clz) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C~-C$ alkyl
or
substituted alkyl)"9-(C3-C,z arylene or heteroarylene)-(C1-C8 alkyl or
substituted
alkyl)"lowhere n9 and n10 are independently 0 or 1. Preferably, R~ is -
NHC(=O)ORIa
where R14 is hydrogen or-(C~-C,z) alkyl, alkoxy, aryl, heteroaryl; or
(c) -C(=O)OR~4 where Rl4 is hydrogen, -(C1-Clz) alkyl, substituted alkyl,
or heteroalkyl, -(C1-C~z) alkenyl, substituted alkenyl, or heteroalkenyl, -(C~-
Clz)
alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C~-C$ alkyl or
substituted
alkyl)"9-(C3-C~z arylene or heteroarylene)-(C1-C8 alkyl or substituted
alkyl)nlo where
n9 and n10 are independently 0 or 1. Preferably, R~ is -C(=O)ORl4 where R14 is
hydrogen or-(C1-C~z) alkyl, alkoxy, aryl, or heteroaryl. More preferably,
-C(=O)ORl4 where R~4 is alkyl, even more preferably R~ is tert-butoxycarbonyl.
The
stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon
carrying the
R~ group is either (R) or (.5~, preferably (S~.
(C) Another preferred group of compounds is represented by Formula (IIb):
R~
O Rs Ra
HON N
R~ R2 O
(IIb)
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WO 01/44179 PCT/US00/34128
wherein:
Rl is -R9, -OH, -ORS, -RgOR9, -SH, -SR9, -NHZ, -NHR~ -NR9Rlo,
-NHC(=O)H, -NR9C(=O)H, -NHC(=O)R9, -NR~C(=O)Rlo, -NHC(=O)NH2,
-NR9C(=O)NH2, -NHC(=O)NHR9, -NHC(=O)NR9R10~ -NR9C(-O)NR9aRlo~
-NHC(=O)OR9, -NR9C(=O)ORIO, -NHS(=O)ZR9, -NR9S(=O)2Rlo, -NHS(=O)ZOR9, or
-NR9S(=O)ZORIO where R8 is selected from the group consisting of -C1-C12
alkyl,
substituted alkyl, or heteroalkyl, -C1-C1z alkenyl, substituted alkenyl, or
heteroalkenyl, -C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C1-Cg
alkyl or substituted alkyl)"1-(C3-C12 arylene or heteroarylene)-(C1-Cg alkyl
or
substituted alkyl)~Z where n1 and n2 are independently 0 or 1; and R9, Rya,
and Rlo are
each independently selected from the group consisting of -C1-C12 alkyl,
substituted
alkyl, or heteroalkyl, -C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl,
-C1-C12
alkynyl, substituted alkynyl, or heteroalkynyl, and -(C1-C$ alkyl or
substituted
alkyl)"3-(C3-C12 arylene or heteroarylene)-(C1-C$ alkyl or substituted
alkyl)n4 where
n3 and n4 are independently 0 or 1;
RZ is -H or -R9 where R9 is as defined above;
R3 is -R11, -OH, -ORl 1, -R120R11, -SH, -SRl l, -NH2, -NHRI l, -NRaRb~
-~C(=O)H~ -~11C(=~)H~ -~C(=~)Rll~ -~llC(=~)R13~ -NHC(=O)NH2
-NR11C(-O)NH2, -NHC(=O)NHRlI, -NHC(=O)NR11R13, -NRtIC(=O)NRl laRl3~
-NHC(=O)ORII, -NR11C(-O)OR13, -NHS(=O)ZRII, -NR11S(-O)2R13~
-NHS(=O)ZOR11, or-NR11S(=O)ZOR13 where R12 is selected from the group
consisting of -C1-C12 alkylene, substituted alkylene, or heteroalkylene,
-C1-C12 alkenylene, substituted alkenylene, or heteroalkenylene, -C1-C12
alkynylene,
substituted alkynylene, or heteroalkynylene, and -(C1-Cg alkylene or
substituted
alkylene)"5-(C3-C12 arylene or heteroarylene)-(C1-C8 alkyl or substituted
alkyl)nb
where n5 and n6 are independently 0 or 1; and R11, Rl la, and R13 are
independently
selected from the group consisting of -C1-C12 alkyl, substituted alkyl, or
heteroalkyl,
-C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -C1-C12 alkynyl,
substituted
alkynyl, or heteroalkynyl, and -(C1-C8 alkyl or substituted alkyl)~~-(C3-C1z
arylene or
heteroarylene)-(C1-C8 alkyl or substituted alkyl)ng where n7 and n8 are
independently
0 or 1;
R4 is hydrogen or -Rl 1 where Rl 1 is as defined above;
R~ is -C(=O)H, -C(=O)R14, -C(°O)NH2, -C(=O)NHR14, -C(=O)NRlaRls~
-C(=O)SH, or -C(=O)SR14 where where R14 and R15 are independently selected
from
CA 02393825 2002-06-06
WO 01/44179 PCT/US00/34128
the group consisting of -C~-C~z alkyl, substituted alkyl, or heteroalkyl, -C,-
C,2
alkenyl, substituted alkenyl, or heteroalkenyl, -CI-C,Z alkynyl, substituted
alkynyl, or
heteroalkynyl, and -(C~-C8 alkyl or substituted alkyl)n9-(C3-C~2 arylene or
heteroarylene)-(C~-Cg alkyl or substituted alkyl)"~o where n9 and n10 are
independently 0 or 1; and where R~ is -C(=O)NR~4R15, then the R14 and R~5
groups
additionally can combine to form a substituted or unsubstituted C4-Clo cyclic
alkyl,
cyclic heteroalkyl, aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
Within this group of compounds, a preferred group of compounds is that
wherein the embodiments of (i) - (iv) defined below are employed either
singularly or
in any combination:
(i) A preferred group of compounds is that wherein Rl is hydroxy and the
stereochemistry at the carbon carrying the RI group is (R) or (5~, preferably
(,5~.
(ii) Another preferred group of compounds is that wherein RZ is hydrogen.
(iii) Another preferred group of compounds is that wherein R3 is hydrogen
or R9 where R9 is -C~-C12 alkyl or -(C1-C8 alkylene)"5-(C3-C~2 aryl or
heteroaryl)
where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl,
tent-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-
methylpentyl, 4-
dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more
preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is
(R) or
(S~, preferably (R).
(iv) Yet another preferred group of compounds is that wherein R~ is:
(a) -C(=O)NHR,4 where R,4 is selected from the group consisting of -(C~-
C~2) alkyl, substituted alkyl, or heteroalkyl, -(C~-C~2) alkenyl, substituted
alkenyl, or
heteroalkenyl, -(CI-C12) alkynyl, substituted alkynyl, or heteroalkynyl,
alkoxy, and -
(C~-C$ alkyl or substituted alkyl)n~-(C3-C,2 arylene or heteroarylene)-(C~-C$
alkyl or
substituted alkyl)~,owhere n9 and n10 are independently 0 or 1. Preferably, R~
is
-C(=O)NHR~4 where Rl4 is -(C~-C~Z) alkyl, alkoxy, aryl, or heteroaryl. More
preferably, R~ is -C(=O)NHR~4 where R14 is -(C~-C~z) alkyl, aryl, or
heteroaryl. Even
more preferably R~ is n-butylaminocarbonyl, tert-butylaminocarbonyl,
benzylaminocarbonyl, 1,l-dimethylpropylaminocarbonyl, 2-(cyclohexen-1-yl)-
ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-
ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl-
aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-
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ylmethylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-
phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-
biphenylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 3,4-dichlorophenyl-
aminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl,
indan-
2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylamino-
carbonyl, 5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylamino-
carbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenyl-
aminocarbonyl,
2,5-dimethylphenylaminocarbonyl, 2,S-dimethoxyphenylamino-carbonyl, 3,4-
dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-phenoxy-
phenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl-
aminocarbonyl, 1,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-
ylaminocarbonyl,
methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl-
aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl,
cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-
yl-
aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-yl-
methylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl,
pyrrolidin-1-
ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1-ylaminocarbonyl,
2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenyl-
aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-
fluorophenylaminocarbonyl,
4-fluorophenylaminocarbonyl, N methyl-N phenylaminocarbonyl, 2-propylamino-
carbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N ethyl-N (n-
butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1-ylcarbonyl, piperazin-
1-yl-
carbonyl, piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, homopiperdin-1-
ylcarbonyl,
pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-methylpyrimidin-
2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl,
imidazol-2-ylaminocarbonyl. In particular, R~ is piperidin-1-ylcarbonyl,
azetidin-1-ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-yl-
aminocarbonyl, or thiazol-2-ylaminocarbonyl.
More particularly, R~ is phenylaminocarbonyl or pyrimidin-2-ylamino-
carbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring,
i.e.,
carbon carrying the R~ group is either (R) or (S~, preferably (,5~; or
(b) R~ is -C(=O)OR~4 where R,4 is selected from the group consisting of
hydrogen, -(C,-C,2) alkyl, substituted alkyl, or heteroalkyl, -(C,-C~Z)
alkenyl,
substituted alkenyl, or heteroalkenyl, -(C,-C,z) alkynyl, substituted alkynyl,
or
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heteroalkynyl, alkoxy, and -(CI-C8 alkyl or substituted alkyl)"9-(C3-C~Z
arylene or
heteroarylene)-(C~-Cg alkyl or substituted alkyl)",o where n9 and n10 are
independently 0 or 1. Preferably, R~ is -C(=O)OR~4 where R1~ is hydrogen, -(C~-
C~z)
alkyl, alkoxy, aryl, or heteroaryl. More preferably, -C(=O)OR,4 where R~4 is
alkyl,
even more preferably R~ is tert-butoxycarbonyl. The stereochemistry at the C2
carbon atom of the pyrrolidine ring, i.e., carbon carrying the R~ group is
either (R) or
(S~, preferably (S~.
(D) Another preferred group of compounds if represented by Formula (IIc):
R~
O R3 Ra
HON N
R~ R2 O
(IIc)
wherein:
Rl is -OH, -OR9, -SH or -SR9 wherein R9 is selected from the group
consisting of -C~-C12 alkyl, substituted alkyl, or heteroalkyl, -C~-Ciz
alkenyl,
substituted alkenyl, or heteroalkenyl, -C,-C~Z alkynyl, substituted alkynyl,
or
heteroalkynyl, and -(C1-C8 alkyl or substituted alkyl)"1-(C3-C~2 arylene or
heteroarylene)-(Ci-Cg alkyl or substituted alkyl)"Z where n1 and n2 are
independently
0 or 1;
RZ is hydrogen;
R3 is -Rl l, -OH, -ORS l, -Ri2OR11, -SH, -SR1,, -NH2, -NHR, I,
-~11R13~ -NHC(=O)H, -NR,1C(=O)H, -NHC(=O)R,1, -NR1,C(=O)R13,
-NHC(=O)NH2, -NRI,C(-O)NH2, -NHC(=O)NHR11, -NHC(=O)NR11R~3,
-~liC(=~)~11aR13~ -NHC(=O)ORIa -NRaC(-O)OR,3~ -NHS(=O)ZRIa
-NR"S(=O)ZR,3, -NHS(=O)ZOR», or-NR1~S(=O)zORl3 where R~z is selected from
the group consisting of -C1-C~Z alkylene, substituted alkylene, or
heteroalkylene, -C~-
C~2 alkenylene, substituted alkenylene, or heteroalkenylene, -C1-C12
alkynylene,
substituted alkynylene, or heteroalkynylene, and -(C,-Cg alkylene or
substituted
alkylene)"5-(C3-C~z arylene or heteroarylene)-(C~-C$ alkyl or substituted
alkyl) n6
where n5 and n6 are independently 0 or 1; and R> > and R~3 are independently
selected
from the group consisting of -C1-C~2 alkyl, substituted alkyl, or heteroalkyl,
-C1-Clz
28
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WO 01/44179 PCT/US00/34128
alkenyl, substituted alkenyl, or heteroalkenyl, -C~-C~z alkynyl, substituted
alkynyl, or
heteroalkynyl, and -(C~-Cg alkyl or substituted alkyl)"-(C3-C~z arylene or
heteroarylene)-(CI-C8 alkyl or substituted alkyl)n8 where n7 and n8 are
independently
Oorl;
R4 is hydrogen or -R> > wherein Rl, is as defined above; and
R~ is -C(=O)OR~4, where RI4 is selected from the group consisting of -C1-C~z
alkyl, substituted alkyl, or heteroalkyl, -C~-C~z alkenyl, substituted
alkenyl, or
heteroalkenyl, -C~-Clz alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C1-Cg
alkyl or substituted alkyl)~9-(C3-Clz arylene or heteroarylene)-(C1-Cg alkyl
or
substituted alkyl)"lo where n9 and n10 are independently 0 or 1; or
a pharmaceutically acceptable salt thereof.
In another embodiment of this series of compounds, Rl is -OH or -OR9. In
another embodiment of this series of compounds, R3 is -C~-Clz alkyl, such as
C4 alkyl
and R4 is H. In another embodiment of this series of compounds, R,4 is -C(=O)O-
C,-
Clz alkyl, such as -C(=O)O-C~-C4 alkyl, for example -C(=O)O-t-butyl.
(E) Another preferred group of compounds if represented by Formula (IId):
R~
O Rs
HON N
O
(IId)
wherein:
R3 is -R> > where R" is selected from the group consisting of -C~-Clz alkyl,
substituted alkyl, or heteroalkyl, -C~-C~z alkenyl, substituted alkenyl, or
heteroalkenyl, -C1-Clz alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C,-C8
alkyl or substituted alkyl)n~-(C3-Clz arylene or heteroarylene)-(C~-Cg alkyl
or
substituted alkyl)"g where n7 and n8 are independently 0 or 1; and
R~ is -C(=O)OR~4 where RI4 is selected from the group consisting of-C1-Ciz
alkyl, substituted alkyl, or heteroalkyl, -C~-C~z alkenyl, substituted
alkenyl, or
heteroalkenyl, -C,-C~z alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C~-C8
alkyl or substituted alkyl)"9-(C3-Clz arylene or heteroarylene)-(C1-Cg alkyl
or
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WO 01/44179 PCT/US00/34128
substituted alkyl)mowhere n9 and n10 are independently 0 or 1; or a
pharmaceutically
acceptable salt thereof.
In one embodiment , R3 is -(C~-C,Z)alkyl, preferably n-butyl. In another
embodiment of this series of compounds, R~ is -C(O)O-C~-C~Z alkyl, such as
-C(O)O-C1-C4 alkyl, for example -C(O)O-tert-butyl.
(F) Another preferred group of compounds if represented by Formula (IIe):
R~
O R3
HO,N~N
H '~ ~O
(IIe)
wherein:
R3 is -R> > where -R~ 1 is selected from the group consisting of -C1-C,2
alkyl,
substituted alkyl, or heteroalkyl, -CI-C~2 alkenyl, substituted alkenyl, or
heteroalkenyl, -C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C~-Cg
alkyl or substituted alkyl)"-(C3-C,2 arylene or heteroarylene)-(C1-Cg alkyl or
substituted alkyl)"8 where n7 and n8 are independently 0 or 1;
R~ is -NH2, -NHR~3, or -NHRI4Rls where R~3, R~4 and Rls are independently
selected from the group consisting of -Cl-C~2 alkyl, substituted alkyl, or
heteroalkyl, -
C1-C,2 alkenyl, substituted alkenyl, or heteroalkenyl, -C1-C~2 alkynyl,
substituted
alkynyl, or heteroalkynyl, and -(C~-Cg alkyl or substituted alkyl)n9-(C3-C~z
arylene or
heteroarylene)-(C1-C8 alkyl or substituted alkyl)"~o where n9 and n10 are
independently 0 or 1; or where RI4 and Rls combine to form a substituted or
unsubstituted C4-Coo cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl
group; or a
pharmaceutically acceptable salt thereof.
In one embodiment of this series of compounds, R3 is C1-C,2 alkyl, preferably
n-butyl. In another embodiment of this series of compounds, R~ is -NHR,3 where
Ri3
is as defined above.
(G) Another preferred group of compounds if represented by Formula (IIf):
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R7a
O R3 Rib
HO~N~N
H - ~O ~R~c
Rid
(IIf)
wherein:
R3 is -R11 wherein Rl1 is selected from the group consisting of hydrogen,
-C~-C~2 alkyl, substituted alkyl, or heteroalkyl, -C1-C~Z alkenyl, substituted
alkenyl, or
heteroalkenyl, -C~-C,Z alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C1-Cg
alkyl or substituted alkyl)"-(C3-C~Z arylene or heteroarylene)-(C~-C$ alkyl or
substituted alkyl)"g where n7 and n8 are independently 0 or 1;
Rya, Rib, R~~ and Rid are independently selected from the group consisting of
hydrogen, -C~-Clz alkyl, substituted alkyl, or heteroalkyl, -C~-C~2 alkenyl,
substituted
alkenyl, or heteroalkenyl, -C,-C~Z alkynyl, substituted alkynyl, or
heteroalkynyl, and
-(C~-Cg alkyl or substituted alkyl)n~-(C3-C1z arylene or heteroarylene)-(C~-C8
alkyl or
substituted alkyl)"lo where n9 and n10 are independently 0 or l; or two
vicinal R~
groups can combine to form a substituted or unsubstituted C4-Coo cyclic alkyl,
cyclic
heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt
thereof.
In one embodiment of this series of compounds, R3 is n-butyl. In another
embodiment of this series of compounds, at least one R~ is selected from the
group
consisting of-C(=O)OR,4, -OH, -ORI4, -R,4, -NH(C=O)OR~4, or -NH(C=O)Rls,
where R~4 and R~5 are independently selected from the group consisting of -Cl-
C~2
alkyl, substituted alkyl, or heteroalkyl, -CI-C12 alkenyl, substituted
alkenyl, or
heteroalkenyl, C1-C~2 alkynyl, substituted alkynyl, or heteroalkynyl, and (C~-
Cg alkyl
or substituted alkyl)"9-(C3-C~2 arylene or heteroarylene)-(C1-Cg alkyl or
substituted
alkyl)"~owhere n9 and n10 are independently 0 or 1.
(H) Another preferred group of compounds if represented by Formula (IIg):
31
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R7a
O R3
HO~N~N
H '~ ~O
(IIg)
wherein:
R3 is -R> > where Rl l is selected from the group consisting of hydrogen, -C1-
C12 alkyl, substituted alkyl, or heteroalkyl, -C1-C~2 alkenyl, substituted
alkenyl, or
heteroalkenyl, -C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C~-Cg
alkyl or substituted alkyl)"-(C3-C~2 arylene or heteroarylene)-(C~-C$ alkyl or
substituted alkyl)"8 where n7 and n8 are independently O or 1; and
Rya is selected from the group consisting of hydrogen, -Cl-C12 alkyl,
substituted alkyl, or heteroalkyl, -C~-C~z alkenyl, substituted alkenyl, or
heteroalkenyl, -C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C1-Cg
alkyl or substituted alkyl)n9-(C3-C~Z arylene or heteroarylene)-(C~-C$ alkyl
or
substituted alkyl)n~owhere n9 and n10 are independently 0 or 1; or a
pharmaceutically
acceptable salt thereof.
In another embodiment of this series of compounds, Rya is -CHZ-Rd where Rd
is selected from the group consisting of H, -C,-C,Z alkyl, substituted alkyl,
or
heteroalkyl, -C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, -C1-C12
alkynyl,
substituted alkynyl, or heteroalkynyl, and -(C1-C$ alkyl or substituted
alkyl)"9-(C3-C,z
arylene or heteroarylene)-(C1-C8 alkyl or substituted alkyl)mo where n9 and
n10 are
independently 0 or 1. In another embodiment of this series of compounds, Rd is
selected from the group consisting of -O-CH3, -OH, -NH-(C=O)-CH3, and
-N'
(I) Another preferred group of compounds if represented by Formula (IIh):
32
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R~
O
O R3
HO~N~N
H TCH3 ~O
(IIh)
wherein:
R3 is -Rl l where R> > is selected from the group consisting of hydrogen, -C~-
C1z alkyl, substituted alkyl, or heteroalkyl, -C~-C~2 alkenyl, substituted
alkenyl, or
heteroalkenyl, -C,-C,Z alkynyl, substituted alkynyl, or heteroalkynyl, and -
(C~-Cg
alkyl or substituted alkyl)n~-(C3-C~Z arylene or heteroarylene)-(C1-Cg alkyl
or
substituted alkyl)"$ where n7 and n8 are independently 0 or 1; and
R~ is selected from the group consisting of -R14 or -ORl4 where R~4 is
selected from the group consisting of -C~-C~Z alkyl, substituted alkyl, or
heteroalkyl, -
C1-C,Z alkenyl, substituted alkenyl, or heteroalkenyl, -C~-C~Z alkynyl,
substituted
alkynyl, or heteroalkynyl, and -(C1-C$ alkyl or substituted alkyl) n9-(C3-C~z
arylene or
heteroarylene)-(C~-Cg alkyl or substituted alkyl) ~lo where n9 and n10 are
independently 0 or 1; or
a pharmaceutically acceptable salt thereof.
In one embodiment of this series of compounds, R3 is n-butyl. In another
embodiment of this series of compounds, R~ is -OCH3 or -O-tert-butyl.
(J) Another preferred group of compounds if represented by Formula (IIi):
R30a R30b
O R3
HO~N~N R3oc
H - ~O R3oe R3od
(IIi)
wherein:
R3 is -Rl~ where Rl, is hydrogen, -C,-C,Z alkyl, substituted alkyl, or
heteroalkyl, -Cl-C~2 alkenyl, substituted alkenyl, or heteroalkenyl, -CI-C,2
alkynyl,
substituted alkynyl, or heteroalkynyl, or -(C~-Cg alkyl or substituted alkyl)"-
(C3-C,2
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arylene or heteroarylene)-(C~-C8 alkyl or substituted alkyl)"$ where n7 and n8
are
independently 0 or 1; and
R3oa, R3on~ R3o~~ R3oa~ and R3oe are independently selected from the group
consisting of hydrogen, -C,-C~2 alkyl, substituted alkyl, or heteroalkyl, -C1-
Clz
alkenyl, substituted alkenyl, or heteroalkenyl, -C~-C,z alkynyl, substituted
alkynyl, or
heteroalkynyl, and -(C~-C8 alkyl or substituted alkyl)n~-(C3-C~z arylene or
heteroarylene)-(C~-C$ alkyl or substituted alkyl)"~o where n9 and n10 are
independently 0 or l; or where two vicinal R3o groups can combine to form a
substituted or unsubstituted C4-Coo cyclic alkyl, cyclic heteroalkyl, aryl or
heteroaryl
group; and all salts and stereoisomers thereof.
In one embodiment of this series of compounds, at least one R3o is selected
from the group consisting of -C(=O)OR,S and -C(=O)Rls, where R,5 is
independently
selected from the group consisting of Cl-Clz alkyl, substituted alkyl, or
heteroalkyl,
C~-C~z alkenyl, substituted alkenyl, or heteroalkenyl, C~-Clz alkynyl,
substituted
alkynyl, or heteroalkynyl, and (C1-Cg alkyl or substituted alkyl)n9-(C3-C~z
arylene or
heteroarylene)-(C~-C$ alkyl or substituted alkyl)",o where n9 and n10 are
independently 0 or 1.
(K) Another preferred group of compounds if represented by Formula (IIj):
R~
O Rs
HO,N~~N
H ~R~ ~ ~O
(IIj )
where:
R~ is halo;
R3 is hydrogen, Rll, -OH, -OR", -RIZORI, -SH, -SRS,, -NHz, -NHR",
-NR~1R~3, -NHC(=O)H, -NR"C(=O)H, -NHC(=O)R~,, -NRiIC(=O)R13,
-NHC(-O)NHz, -NRl IC(=~)~2~ -NHC(=O)NHR11, -NHC(=O)NR11R13~
-NRnC(=O)NW taRt3~ -NHC(=O)OR, a -NRI,C(=O)OR,3~ -NHS(=O)zRl3~
-NR> > S(=O)zR~3, -NHS(=O)zOR~ l, or -NR> > S(=O)zORl3, where Rlz is selected
from
the group consisting of -Cl-C~z alkylene, substituted alkylene, or
heteroalkylene, -C,
C~z alkenylene, substituted alkenylene, or heteroalkenylene, -C~-C~z
alkynylene,
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substituted alkynylene, or heteroalkynylene, and -(C~-C8 alkylene or
substituted
alkylene)"s-(C3-Clz arylene or heteroarylene)-(C1-Cg alkyl or substituted
alkyl)"6
where n5 and n6 are independently 0 or 1; and R11, Rl la and R13 are
independently
selected from the group consisting of -C1-Clz alkyl, substituted alkyl, or
heteroalkyl, -
C1-Clz alkenyl, substituted alkenyl, or heteroalkenyl, -C1-Clz alkynyl,
substituted
alkynyl, or heteroalkynyl, and -(C1-C8 alkyl or substituted alkyl)"-(C3-Clz
arylene or
heteroarylene)-(C1-Cg alkyl or substituted alkyl)"g where n7 and n8 are
independently
0 or 1;
R~ is hydrogen, R14, -OH, -OR14, -SH, -SR14, -NHz, -NHR14, -NRl4Rls~
-C(=O)H, -C(=O)R14~ -C(-O)~2~ -C(-O)~R14~ -C(-O)~l4Rls~ -C(=O)OH
-C(=O)OR14, -C(=O)SH, -C(=O)SR14, -C(=O)CH3, -C(=O)CH2R14, -C(=O)CHRI4Rls,
-C(=O)CR14R1sR16, -C(=O)OCH3, -C(=O)OCHZR14, -C(=O)OCHRI4Rls,
-C(=O)OCR14R1sR16~ -S(=O)zNHz~ -S(=O)zNHRl4, -S(=O)zNRl4Rls~ -NHC(=O)H,
-N(R14)C(=O)H~ -NHC(=O)Rls~ -N(R14)C(=O)Rls~ -NHC(=O)OR14~ -NHS(=O)zH
-N(R14)S(=O)zH~ -NHS(=O)zORls~ -N(R14)S(=O)zORls~ -N(H)S(=O)zRls~ or
-N(R14)S(=O)zRls, or where two vicinal R6 or R~ groups combine to form a
substituted or unsubstituted -C4-Clo cyclic alkyl, cyclic heteroalkyl, aryl or
heteroaryl
group where R14, Rls and Rlb are each independently selected from the group
consisting of -C1-Clz alkyl, substituted alkyl, or heteroalkyl, -C1-Clz
alkenyl,
substituted alkenyl, or heteroalkenyl, -C1-Clz alkynyl, substituted alkynyl,
or
heteroalkynyl, and -(C1-C$ alkyl or substituted alkyl)"9-(C3-Clz arylene or
heteroarylene)-(C1-Cg alkyl or substituted alkyl)"lo where n9 and n10 are
independently 0 or 1; or when R14 and Rls are attached to a nitrogen atom they
can
combine to form a substituted or unsubstituted C4-Clo cyclic alkyl, cyclic
heteroalkyl,
aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
Within this group of compounds, a preferred group of compounds is that
wherein the embodiments of (i) - (iii) defined below are employed either
singularly or
in any combination:
(i) A preferred group of compounds is that wherein Rl is fluoro. The
stereochemistry at the carbon carrying the R1 group is (R) or (~, preferably
(,5~.
(ii) Another preferred group of compounds is that wherein R3 is hydrogen
or R9 where R~ is -C~-Clz alkyl or -(C1-C$ alkylene)"s-(C3-Clz aryl or
heteroaryl)
where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl,
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WO 01/44179 PCT/US00/34128
tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-
methylpentyl, 4,4-
dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more
preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is
(R) or
(,5~, preferably (R); and
(iii) R~ is:
(a) -C(=O)NRIqR~s, where R~4 and R~5 are independently hydrogen, -(C~-
C12) alkyl, substituted alkyl, or heteroalkyl, -(Cl-C~2) alkenyl, substituted
alkenyl, or
heteroalkenyl, -(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl,
alkoxy, or
-(C1-Cg alkyl or substituted alkyl)"9-(C3-C~2 arylene or heteroarylene)-(C1-Cg
alkyl or
substituted alkyl)n~owhere n9 and n10 are independently 0 or 1; or R14 and Rls
combine to form a substituted or unsubstituted -(C4-Clo)cyclic alkyl, cyclic
heteroalkyl, aryl or heteroaryl group.
Preferably, R~ is -C(=O)NR~4R~5 where R~4 and Rls are each independently
hydrogen or -(C1-C12) alkyl, alkoxy, aryl, heteroaryl or R14 and Rls, when
attached to
the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl
group.
More preferably, R~ is -C(=O)NHR,S where R15 is H or -(C~-C1z) alkyl, aryl, or
heteroaryl or -C(=O)NR~4R15 where R,4 and RlSform a substituted or
unsubstituted
-(C4-C,o)cyclic heteroalkyl.
Even more preferably R~ is n-butylaminocarbonyl, tert-butylaminocarbonyl,
benzylaminocarbonyl, 1,1-dimethylpropylaminocarbonyl, 2-(cyclohexen-1-yl)-
ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-
ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl-
aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-
ylmethylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-
phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-
biphenylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 3,4-dichlorophenyl
aminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl,
indan-
2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-
ylaminocarbonyl, 5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-
ylaminocarbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenyl-
aminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylamino-
carbonyl, 3,4-dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-
phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl-
aminocarbonyl, 1,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-yl-
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aminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol-
2-yl-aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl,
cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-
yl-aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-
yl-methylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl,
pyrrolidin-1-ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1-
ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-
difluorophenyl-aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluoro-
phenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N methyl-N phenylamino-
carbonyl, 2-propylamino-carbonyl, 2-phenylpropylaminocarbonyl, n-propylamino-
carbonyl, N ethyl-N (n-butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1-
ylcarbonyl, piperazin-1-yl-carbonyl, piperidin-1-ylcarbonyl, azetidin-1-
ylcarbonyl,
homopiperdin-1-ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin-1-
ylcarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl,
pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
In particular, R~ is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl,
ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or
thiazol-
2-ylaminocarbonyl.
More particularly, R~ is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl,
ethylaminocarbonyl or thiazol-2-ylaminocarbonyl. The stereochemistry at the C2
carbon atom of the pyrrolidine ring, i.e., carbon carrying the R~ group is
either (R) or
(,5~, preferably (,5~; or
(b) R~ is -NHC(=O)OR~4 where R~4 is hydrogen, -(C~-C12) alkyl,
substituted alkyl, or heteroalkyl, -(C~-C~2) alkenyl, substituted alkenyl, or
heteroalkenyl, -(C~-C12) alkynyl, substituted alkynyl, or heteroalkynyl,
alkoxy, or -
(C~-Cg alkyl or substituted alkyl)n9-(C3-C,Z arylene or heteroarylene)-(C,-Cg
alkyl or
substituted alkyl)",o where n9 and n10 are independently 0 or 1. Preferably,
R~ is
-NHC(=O)OR~4 where R,4 is hydrogen or-(C~-C~2) alkyl, alkoxy, aryl,
heteroaryl; or
(c) R~ is -C(=O)OR~4 where R14 is hydrogen, -(C~-C,2) alkyl, substituted
alkyl, or heteroalkyl, -(C~-C12) alkenyl, substituted alkenyl, or
heteroalkenyl, -(C~-
C~z) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C~-Cg alkyl
or
substituted alkyl)"9-(C3-CIZ arylene or heteroarylene)-(C~-Cg alkyl or
substituted
alkyl)n~owhere n9 and n10 are independently 0 or 1. Preferably, R~ is -
C(=O)OR»
where R~4 is hydrogen or-(Cl-C12) alkyl, alkoxy, aryl, or heteroaryl. More
preferably,
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WO 01/44179 PCT/US00/34128
-C(=O)OR~4 where Rl4 is alkyl, even more preferably R~ is tent-butoxycarbonyl.
The
stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon
carrying the
R7 group is either (R) or (,5~, preferably (,5~.
Preferred compounds of the Invention are:
N hydroxy-3-[(,S~-(n-butyl)-3-(2-(S~-1,1-dimethylethyloxycarbonyl)-
pyrrolidin-1-carbonyl)]-2-(,S~fluoropropionamide;
N hydroxy-3-[(S~-(n-butyl)-3-(2-(S~-pyridin-1-ylcarbonyl)pyrrolidin-1-
carbonyl)]-2-(S~-fluoropropionamide;
N hydroxy-3-[(S~-(n-butyl)-3-(2-(S~-azetidin-1-ylcarbonyl)-pyrrolidin-1-
carbonyl)]-2-(,S~-fluoropropionamide;
N hydroxy-3-[(S~-(n-butyl)-3-(2-(,S~-ethylaminocarbonyl)pyrrolidin-1-
carbonyl)]-2-(,S~-fluoropropionamide;
N hydroxy-3-[(S~-(n-butyl)-3-(2-(,S~-phenylaminocarbonyl)-pyrrolidin-1-
carbonyl)]-2-(,S~-hydroxypropionamide;
N hydroxy-3-[(,S~-(n-butyl)-3-(2-(,S~-pyrimidin-2-ylaminocarbonyl)pyrrolidin-
1-carbonyl)]-2-(,S~-hydroxypropionamide; and
N hydroxy-3-[(S~-(n-butyl)-3-(2-(,S~-thiazol-2-ylaminocarbonyl)-pyrrolidin-1-
carbonyl)]-2-(S~-fluoropropionamide.
GENERAL SYNTHETIC SCHEME
Compounds of this invention can be made by the methods depicted in the
reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are
either available from commercial suppliers such as Aldrich Chemical Co.,
(Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie,
or Sigma (St. Louis, Missouri, USA) or are prepared by methods known to those
skilled in the art following procedures set forth in references such as Fieser
and
Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons,
1991);
Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier
Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and
Sons,
1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),
and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,
1989).
These schemes are merely illustrative of some methods by which the compounds
of
38
CA 02393825 2002-06-06
WO 01/44179 PCT/US00/34128
this invention can be synthesized, and various modifications to these schemes
can be
made and will be suggested to one skilled in the art having referred to this
disclosure.
The starting materials and the intermediates of the reaction may be isolated
and purified if desired using conventional techniques, including but not
limited to
filtration, distillation, crystallization, chromatography, and the like. Such
materials
may be characterized using conventional means, including physical constants
and
spectral data.
Preparation of compounds of Formula (I)
Compounds of Formula (I) can be prepared by methods well known in the art
of organic chemistry. Representative synthetic procedures for preparing
compounds
of the present invention are illusted and described in detail below. For
example,
compounds of Formula (I) can be prepared as described in Schemes A -D below.
A compound of Formula (I) where R~, Rz, and R4 are hydrogen, and R3, R6,
R~, Y, and n are as defined in the Summary of the Invention can be prepared as
1 S described in Scheme A below.
Scheme A
Rs R~
HN' '(Y)n ~ R7
O Rs X O Rs
Rs R~ N~(Y)n
OH RO
RO
2 O Rs R~
O
3
1 optional
O R3 Rs~ ~
R6 R~
N (Y)n O Rs
RO ~ N (Y)n
o ~ NH20H HORN
R6 7
O Rs R~
4
(R3/R6/R~ modified) (1)
Treatment of a solution of a mono-protected succinate of formula 1 where R is
an alkyl group such as methyl, ethyl, and the like, and R3 is as defined in
the
Summary of the Invention, with an N,N-dialkylamine of formula 2, where R6 and
R~
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WO 01/44179 PCT/US00/34128
are as defined in the Summary of the Invention, provides a 3-aminocarbonyl-
propionate derivative of formula 3. The reaction is typically carried out in
the
presence of an inert, polar aprotic solvent (e.g. DMF, dioxane, etc.) in the
presence of
a non-nucleophilic base (e.g. triethylamine, diisopropylethylamine, etc.) and
a
coupling reagent (e.g. EDCI, PyBOP, DIC, etc.). The reaction is initially
started at
low temperature, such as 0 °C, and then allowed to warm to room
temperature, and
then stirred for several hours. Some compounds of formula 1 are commercially
available. Others can be prepared by methods well known in the art. For
example
mono-methyl succinate, mono-4-methyl-2-(R)-methylsuccinate is available
commercially, while mono-4-methyl-2-(R)-butylsuccinate as described in detail
in
Example 16 below.
Amines of formula 2 are commercially available or they can be prepared by
methods well known in the art. For example, N, N dialkylamines such as
pyrrolidine,
piperidine, piperazine, morpholine, thiomorpholine, homopiperidine,
homopiperazine,
proline tert-butyl ester, L-proline-2-methylamide, (S)-(+)-2-(methoxymethyl)-
pyrrolidine, L-proline-N methoxy-N methylamide, (S)-2-(pyrrolidinylmethyl)-
pyrrolidine, L-proline-N morpholineamide, L-proline-N,N dimethylamide,
homoproline methyl ester, L-homoproline tent-butylester, 3-(R)- tert-butoxy-L-
proline-O- t-butyl ester, pipecolinic acid, 1,2,3,4-tetrahydroquinoline, 1-
hydroxyethylpiperazine, 2-hydroxyethylpiperidine, 3-hydroxypiperidine, 4-
hydroxypiperidine, 4-hydroxyproline, L-tetrahydroisoquinoline tert-butyl
ester, 3-(N
Boc-amino)pyrrolidine, and N Boc-L-prolinol are commerically available. Other
N,N-dialkylamines 2 such as 2-acetylaminomethylpyrrolidine can be prepared
from
N Boc-L-prolinol as described in Example 16 below. traps-3-Acetoxy-L-proline O-
tert-butyl ester can be prepared from Cbz protected traps-3-hydroxy-L-proline
as
described in Example 17 below which can then be converted to traps 3-hydroxy-L-
proline O-tert-butyl ester, if desired, by hydrolysis of the acetoxy group in
traps-3-
acetoxy-L-proline O-tert-butyl ester as described in Example 17 below.
Also, it will be recognized by a person skilled in the art that if compound 1
and /or 2 have additional reactive groups, then they must be suitably
protected prior to
carrying out the coupling reaction. Examples of suitable protecting groups and
their
introduction and removal are described in T.W. Greene and G. M. Wuts,
"Protecting
Groups in Organic Synthesis" Third Ed., Wiley, New York, 1999 and references
cited
therein. For example, if R6 or R~ is a carboxyl group or a hydroxy group then
it can
CA 02393825 2002-06-06
WO 01/44179 PCT/US00/34128
be protected as a t-butyl ester or benzyl ester or other suitable protecting
group prior
to the coupling reaction.
Compound 3 can optionally be converted to a compound of formula 4 where
prior to converting it to a compound of Formula (I). This would be desirable
if
certain groups) in compound 3, e.g., R3, R6, and/or R~ had to transformed to
other
groups) within the scope of the invention prior to introducing the hydroxamate
group
in the molecule. For example, a compound of formula 3 where R6 or R~ is a tert-
butoxyamino group, can be converted to a corresponding compound of formula 4
where R6 or R~ is an acetylamino group by first treating 3 with an acid such
as diluted
hydrochloric acid at ambient temperature to provide a corresponding compound
of
formula 3 where R6 or R~ is an amino group, followed by treatment with an
acetylating agent such as acetic anhydride in the present of an organic base
such as
pyridine.
A compound of formula 3 where R6 and\or R~ is a hydroxy can be converted
to a compound of formula 4 where R~ and\or R~ is a sulfonamido group (i.e., -
NHSOZRIS where Rls is as defined in the Summary of the Invention) by first
converting the hydroxy group into amino group, followed by treatment with a
sulfonylating agent. A detailed description of this transformation is provided
in
Example 34 below.
A compound of formula 3 where R6 and\or R~ is a suitably protected carboxyl
group can be converted to a compound of formula 4 where R6 and\or R~ is an
aminocarbonyl group (i.e., -CONHR~4 or-CONR~4Rl5 where R14 and R~5 is as
defined in the Summary of the Invention) by first deprotecting the carboxy
group and
then treating with an amine of formula -NHR~4 or -NR14R,5 (where R,4 and R15
is as
defined in the Summary of the Invention). Briefly, the reaction conditions for
deprotecting of the carboxy group will depend on the nature of the protecting
group.
For example, if it is a benzyl ester, then treatment with hydrogen gas and an
appropriate catalyst (e.g., 10 % palladium on carbon) will liberate the free
carboxylic
acid. The amination reaction is typically carried out in the presence of an
inert, polar
aprotic solvent (e.g. DMF, dioxane, etc.) with a non-nucleophilic base (e.g.
triethylamine, diisopropylethylamine, etc.) and a coupling reagent (e.g. EDCI,
PyBOP, DIC, etc.). The reaction is initially started at low temperature, such
as 0 °C,
and then allowed to warm to room temperature, and then stirred for several
hours.
Many amines of formulae NHR14 and NHR~4R15 are available commercially, or can
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be readily prepared by methods well known in the art. For example,
methylamine,
aniline, 2-aminothiazole, etc., are commercially available. Others can be
prepared,
for example, via reductive amination of an aldehyde, or Fukuyama alkylation of
a
suitable nitroaryl sulfonamide followed by cleavage of the sulfonamide to
liberate the
S desired amine.
Compound 3 or 4 is then converted to a hydroxamate compound of Formula
(I) by treating it at 0 °C with aqueous 50 % hydroxylamine in a polar
organic solvent
such as dioxane and the like. After the reaction is complete the mixture is
then
purified by preparative reverse-phase (C I8) HPLC to afford compound of
Formula
(I). If desirable, suitable O-protected hydroxylamine such as O-benzylhydroxyl-
amine can also be used to give an O-protectedhydroxamate compound. Removal of
the protecting group will provide a compound of Formula (I).
A compound of Formula (I) can be converted to other compounds of Formula
(I) by methods well known in the art. Some such methods are described below.
Compounds of Formula (I) containing a hydroxy group may be prepared by de-
alkylation/benzylation of an alkyloxylbenzyloxy substituent; and those
containing an
acid group, by hydrolysis of an ester group. Similarly, a compound of Formula
(I)
having an alkenyl or alkynyl group can be prepared by reacting a corresponding
compound of Formula (I) containing a bromine or iodine atom with
trimethylsilylacetylene under the Castro-Stephens reaction conditions.
Furthermore, a
compound of Formula (I) containing an alkoxy group may be prepared by
alkylation
of hydroxy substituent. A compound of Formula (I) containing a carboxy group
can
be prepared by hydrolyzing an ester group in a corresponding compound of
Formula
(I) under acid hydrolysis reaction conditions. The resulting carboxy group can
optionally be converted to an amido group, if desired, by first converting the
carboxy
group to an activated ester derivative e.g., treating the carboxy compound
with
dicyclohexyl carbodiimide, DEAD and the like, followed by treatment with an
amine.
It will be recognized by a person skilled in the art that some of these
transformations
can be carried out prior to converting the compound of formula 5 to a compound
of
Formula (I).
A compound of Formula (I) where R, is hydroxy, RZ, and R4 are hydrogen,
and R3, R6, R~, Y, and n are as defined in the Summary of the Invention can be
prepared as described in Scheme B below.
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Scheme B
OH O R3X OH O
Rs R~
HN, '(Y)n
R3 R X3
HO OH Me2C(OMe2)z or OH Rs R~
OH O PhC(OMe)3, H+ Ra~O O 2
Rb
8
R3
H3C0 OCH3 base H3C0 OCH3 base
Ra and Rb =Me or
Ra= Ph and Rb =Me
Rs R~ Rs R7
Rs Rs ~
~(Y)n base ' '(Y)n
H3C0
Ra~O O ~ R~ OH O ~ R~
Rb
g 10
optional
R3 R~R~ R
3
H3C0 X (Y)n ~ HOHN X (Y)n
OH O Rs R~ NH2OH OH O Rs R~
11
(R3/R6/R~ different than in 10)
Treatment of dimethyl malate 5 under strongly basic conditions with an
appropriate alkylhalide R3X (where R3 is alkyl, alkenyl, alkynyl, substituted,
heteroalkyl and X is halo such as chloro, bromo, or iodo) provides 2-
substituted
dimethyl malate 6. The reaction is typically earned out in a polar aprotic
solvent such
as THF, and the base is typically lithium diisopropylamide (LDA). The reaction
is
initially earned out at a low temperature, preferably at about - 78 °C,
and then
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allowed to slowly warm to room temperature. The reaction is then stirred for
several
hours. The reaction is typically higher yielding when R3X is an allylic
halide. After
the alkylation is complete the resulting olefin can be reduced, if desired, to
provide a
compound of formula 6 where R3 is alkyl. The typically reduction procedure
involves
a suspension of 6 and a catalyst (e.g., 10 % palladium on carbon) in a solvent
such as
ethylacetate and would be stirred under a hydrogen atmosphere for several
hours to
afford the corresponding compound of formula 6 where R3 is alkyl. Many
compounds of formula R3X are commercially available or they can be prepared by
methods well known in the art. For example, iodomethane, benzylbromide,
crotylbromide, allylbromide, vinylbromide are commercially available. Others
can be
prepared from the corresponding alcohol by first activating the hydroxy group
as ap-
toluenesulfonate ester (tosyl ester), followed by tosylate displaced with a
halide ion in
a modified Finkelstein procedure to afford an alkylhalide as described in
working
examples below.
Treatment of 6 with a base affords a malic acid derivative of formula 7. The
base can be an inorganic base such as lithium hydroxide or potassium
hydroxide, and
is most preferably sodium hydroxide. This reaction is usually performed in a
polar,
protic solvent such as methanol. Treatment of 7 with an orthoacetate, such as
trimethylorthobenzoate, in the presence of an acidic catalyst affords an
orthoester 8
(Ra is -Ph and Rb is -OMe). This reaction is ideally performed with a co-
solvent,
preferably in a mixture of toluene. The reaction is ideally performed at a
higher
temperature, most preferably at 110 °C. The catalyst is typically a
sulfonic acid, such
asp-toluenesulfonic acid, or most preferably camphorsulfonic acid.
Alternatively, treatment of 7 with 2,2-dimethoxypropane in the presence ofp
toluenesulfonic acie provides an acetonide of formula 8 where Ra and Rb are
methyl.
Treatment of the orthoester or acetonide 8 with a dialkylamine of formula 2
under the reaction conditions described in Scheme A provides a compound of
formula
9 which upon treatment with a base, preferably the salt of an alcohol, and
more
preferably sodium methoxide in an alcoholic solvent then provides a 2-hydroxy-
3-
aminocarbonyl-propionate derivative of formula 10.
Compound 10 is then optionally converted to a compound of formula 11 for
reasons discussed in Scheme A such as derivatizing the R3, R6 and/or R~ groups
prior
to converting it to a compound of Formula (I). Alternatively, compound 10 it
can be
directly converted to a compound of Formula (I) as described in Scheme A
above.
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It will be recognized by a person skilled in the art that the hydroxy group in
compound 10 can be replaced by various other R, groups as defined in the
Summary
of the Invention prior to converting it to a compound of Formula (I). Some
representative examples are discussed below:
(i) the hydroxy group in compound 10 can be replaced by a fluoro group prior
to
converting it to a compound of Formula (I) as shown below.
O R3 ~~ ~ O R3 R6 R~
H3C0 N~(Y)n ~ H3C0 N~(Y)n
OH O ~/\R~ F O R6xRr
12
optional NH20H
O R3 Rs~ ~ O Rs Rs~ r
N/~(\(Y)n N/Y\(Y)n
H3C0 ~ HOHN
F O ~ R~ NH2OH F O R6 Rr
13 (I)
(R3/R~/R7 different than in 12)
The hydroxyl group at the C2 carbon in compound 10 can be replaced by a
10 fluoro group by first converting the hydroxyl group into an active ester
followed by
displaced with fluorine to afford compound 12. The reaction is performed in a
halogenated solvent, such as dichloromethane (DCM), in the presence of an
organic
base, such as pyridine. The alcohol is typically activated as a sulfonate
ester,
preferably the trifluoromethane-sulfonate. This esterification reaction is
typically
carried out at a low temperature, preferably about -20 °C. The active
ester is then
reacted with a fluoride ion, typically derived from tris(dimethylamino)sulfur-
(trimethylsilyl)difluoride (TAS-F). This reaction is also carned out at a low
temperature, preferably at about -50 °C, and then slowly allowed to
warm to ambient
temperature. Compound 12 is then converted to a compound of Formula (I) either
directly or through compound 13 as described above. A detailed description of
this
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procedure is provided in Example 6 below. It will be noted that the
stereochemistry at
the C2 carbon atom is inverted during this transformation.
(ii) the hydroxy group in compound 10 can be converted to an alkoxy under
alkylation reaction conditions such as treatment of 10 with an alkyl halide
such as
methyl iodide, ethyl iodide, benzyl bromide, and the like, in the presence of
a strong
base such as sodium hydride and in a polar solvent such as dimethylformamide.
Detailed description of this procedure is provided in Example 45 below.
(iii) the hydroxy group in compound 10 can be converted to benzoyloxy group by
first converting it into an activated ester such as a sulfonate ester,
preferably the
trifluoromethanesulfonate, followed by treatment with tetrabutyl ammomium
benzoate. Detailed description of this procedure is provided in Example 47
below.
(iii) the hydroxy group in compound 10 can be converted to thiol group by
first
converting it into an activated ester such as a sulfonate ester, preferably
the
trifluoromethanesulfonate, followed by treatment potassium thioacetate.
Detailed
description of this procedure is provided in Example 48 below.
(iv) the hydroxy group in compound 10 can be converted to an azido or amino
group or it's derivatives by first converting it into an activated ester such
as a
sulfonate ester, preferably the trifluoromethanesulfonate, followed by
treatment with
sodium azide. The azide group can optionally reducted under catalytic
hydrogenation
reaction conditions to give an amino group which can be further derivatized by
methods well known in the art. Detailed description of this procedure is
provided in
Example 49 and 34 below.
(vi) the maintainence of the stereochemistry at the carbon atom carrying the
hydroxy group in compound 10, the C2 carbon, can be achieved by carrying out
double inversion as illustrated and described below.
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Rs R~ Rs R~
O R3 ~ O R3 ~
N (Y)n i. Tf20,pyridine N' '(Y)n CH30-Na+
H3co ~! ~ ~ ii. Bu4NOBz H3co ~ ---'
OH O Rs R~ OBz O
Rs R~
14
Rs R~ O R R~ ~
o Rs i. Tf20,pyridine
N~(Y)n N (Y)n
H CO
H3C0 ~ ii. TAS-F 3
OH O F O
Rs R~ s ~
16
optional NH20H
O R3 R, , ~ O R3 Rs~ ~
N~(Y)n NX(Y)n
H3C0 , ~ HOHN
F O ~ R~ NH20H F O Rs R~
17
(R3/R~/R~ different than in 16)
The hydroxyl at the C-2 carbon of intermediate 10 is converted to an active
ester as described above in (i) above. Nucleophilic substitution with a
variety of
nucleophiles such as acetate anion, or more preferably, tetrabutylammonium
5 benzoate, provides intermediate 14. This reaction proceeds in a hydrocarbon
solvent,
preferably in toluene. One skilled in the art will understand that the above
nucleophilic displacement reaction results in an inversion of stereochemistry
at the C-
2 position.
Compound 14 is treated with a base to afford hydroxy derivative 15. This base
10 is preferably the salt of an alcohol such as sodium methoxide, sodium
ethoxide and
the like, and more preferably sodium methoxide. The reaction proceeds in an
alcoholic solvent such as methanol, ethanol and the like, most preferably in
methanol.
Compound 15 is re-activated as a sulfonate ester, preferably a
trifluoromethane sulfonate as described above and then treated with a
fluorination
15 reagent, preferably TAS-F, to afford the corresponding fluoro intermediate
16 which
has the same stereochemistry at the C-2 carbon as in intermediate 10.
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Compound 16 or 17 is then converted to a compound of Formula (I) as
discussed above.
A compound of Formula (I) can also be prepared as illustrated in Scheme C
S below.
Scheme C
off R3
°~ w
0
HOzC~C02Fm OI' R3
ArgoGel-Wang i) 19 J~ ~
or O' v 'C02H
ii) piperidine 20
ArgoGel-OH
R~ ~
i) PFP-OTFA/pyridine O R3
N (Y)n NH20H
R6 R~ O
ii HN~(Y)n
) 21
R6 R~
2
R~ 7
O Rs
N' '(Y)n
HOH XN
O Rs R~
(I)
Treatment of a suspension of ArgoGel-Wang or ArgoGel-OH resin with an
Fm-protected succinic acid of formula 19 (wherein R3 is as defined in the
Summary of
the Invention) in the presence of a coupling agent such as di-isopropylazo-
dicarboxylate and triphenylphosphine, followed by treatment with piperidine
provides
a resin bound Fm-protected succinic acid 20. The coupling reaction is carried
out in a
polar solvent such as dichloromethane in the presence of a base such as
dimethylaminopyridine. The reaction is typically carned out at ambient
temperature.
Treatment of 20 with PFP-OTFA and pyridine, followed by treatment with an
amine 2
then provides resin bound 3-aminocarbonylpropionate 21. The reaction is
carried out
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in the presence of a non-nucleophilic base such as pyridine,
diethylisopropylamine,
2,4,6-collidine, and the like. The reaction is typically carried out at
ambient
temperature. Treatment of 21 with hydroxylamine then provides a compound of
Formula (I).
A compound of Formula (I) where R, & RZ are fluoro and Rz, R3, R6, R~, Y
and n are as defined in summary of the invention can be prepared as
illustrated in
Scheme D below.
Scheme D
O R3 O R3
o pH t-butanol o o base
o p DIC/DMAP ~o 0
8 22
O R3 O Rs base
Tf20/ o
O ~ Me0
Meo . pyridine
OH O OTf O
23 24
O R3 O R3
1. XeF2/BF3.Et02) ..,,,
O Me0
Me0
0 2. TFA/CH2C12 F o
25 26
R6 R~ O R3 R6 R~
O R ~3
---~ .,,,,F ~ NH20H ..,,vF N
N (Y)n ~ HOHN \ /(Y)n
Me0 . -.
Rs R~ . _
F O ~ F O R6 R~
H N~(Y) n (I)
27
R6 R~
2
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Treatment of a compound of formula 8 with an alcohol such as tert-butanol in
the presence of a suitable coupling agent such as DIC and a base such as DMAP
provides the corresponding tert-butyl ester of formula 22. Treatment of 22
with a
base such as sodium methoxide in methanol provides 2-hydroxysuccinate
derivative
of formula 23. Compound 23 is then converted to a trifluoromethanesulfonate
ester
derivative 24 using triflic anhydride in the presence of a base such as
triethyamine,
pyridine and the like. Treatment of 24 with a base such as triethylamine
provides a
malefic acid derivative of formula 25 which upon reaction with xenon
difluoride in the
presence of boron trifluoride etherate provides a 2,3-difluorosuccinate
derivative.
Removal of the tent-butyl group with trifluoroacetic acid provides the
corresponding
succinic acid derivative 26 which is then converted to a compound of Formula
(I) as
described above.
Administration, Utility and Testing
Administration and Pharmaceutical Composition
The present invention also provides pharmaceutical compositions which
comprise a bioactive hydroxamic acid compound or derivative, or a
pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable Garner. The
compositions
of the invention include those in a form adapted for oral, topical or
parenteral use and
can be used for the treatment of bacterial infection in animals, preferably
mammals,
more preferably humans.
The antibiotic compounds, also referred to herein as antimicrobial compounds,
according to the invention can be formulated for administration in any
convenient
way for use in human or veterinary medicine, by analogy with other
antibiotics. Such
methods are known in the art (see, e.g., Remin. ton's Pharmaceutical Sciences,
Easton, PA: Mack Publishing Co.) and are not described in detail herein.
The composition can be formulated for administration by any route known in
the art, such as subdermal, inhalation, oral, topical or parenteral. The
compositions
can be in any form known in the art, including but not limited to tablets,
capsules,
powders, granules, lozenges, creams or liquid preparations, such as oral or
sterile
parenteral solutions or suspensions. The compounds can also be administered in
liposome formulations. The compounds can also be administered as prodrugs,
where
the prodrug administered undergoes biotransformation in the treated mammal to
a
form which is biologically active.
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The topical formulations of the present invention can be presented as, for
instance, ointments, creams or lotions, solutions, salves, emulsions,
plasters, eye
ointments and eye or ear drops, impregnated dressings and aerosols, and can
contain
appropriate conventional additives such as preservatives, solvents to assist
drug
penetration and emollients in ointments and creams.
The formulations can also contain compatible conventional Garners, such as
cream or ointment bases and ethanol or oleyl alcohol for lotions. Such Garners
can be
present, for example, from about 1 % up to about 99% of the formulation. For
example, they can form up to about 80% of the formulation.
Tablets and capsules for oral administration can be in unit dose presentation
form, and can contain conventional excipients such as binding agents, for
example
syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone;
fillers, for
example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine;
tabletting lubricants, for example magnesium stearate, talc, polyethylene
glycol or
1 S silica; disintegrants, for example potato starch; or acceptable wetting
agents such as
sodium lauryl sulphate. The tablets can be coated according to methods well
known
in standard pharmaceutical practice.
Oral liquid preparations can be in the form of, for example, aqueous or oily
suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a
dry
product for reconstitution with water or another suitable vehicle before use.
Such
liquid preparations can contain conventional additives, such as suspending
agents, for
example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl
cellulose,
carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats;
emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-
aqueous
vehicles (which can include edible oils), for example almond oil, oily esters
such as
glycerine, propylene glycol, or ethyl alcohol; preservatives, for example
methyl or
propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional
flavoring or
coloring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing
the compound and a sterile vehicle, water being preferred. The compound,
depending
on the vehicle and concentration used, can be either suspended or dissolved in
the
vehicle or other suitable solvent. In preparing solutions, the compound can be
dissolved in water for injection and filter sterilized before filling into a
suitable vial or
ampoule and sealing. Advantageously, agents such as a local anesthetic
preservative
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and buffering agents can be dissolved in the vehicle. To enhance the
stability, the
composition can be frozen after filling into the vial and the water removed
under
vacuum. The dry lyophilized powder is then sealed in the vial and an
accompanying
vial of water for injection can be supplied to reconstitute the liquid prior
to use.
Parenteral suspensions are prepared in substantially the same manner except
that the
compound is suspended in the vehicle instead of being dissolved and
sterilization
cannot be accomplished by filtration. The compound can be sterilized by
exposure to
ethylene oxide before suspending in the sterile vehicle. Advantageously, a
surfactant
or wetting agent is included in the composition to facilitate uniform
distribution of the
compound.
The compositions can contain, for example, from about 0.1 % by weight to
about 99% by weight, e.g., from about 10-60% by weight, of the active
material,
depending on the method of administration. Where the compositions comprise
dosage units, each unit will contain, for example, from about 1-500 mg of the
active
ingredient. The dosage as employed for adult human treatment will range, for
example, from about 1 to 3000 mg per day, for instance 1500 mg per day
depending
on the route and frequency of administration. Such a dosage corresponds to
about
0.015 to 50 mg/kg per day. Suitably the dosage is, for example, from about 5
to 20
mg/kg per day.
Utility
The hydroxamate compounds of the present invention can be used for the
treatment or prevention of infectious disorders caused by a variety of
bacterial or
prokaryotic organisms. Examples include Gram positive and Gram negative
aerobic
and anaerobic bacteria, including Staphylococci, for example S. aureus and S.
epidermidis; Enterococci, for example E. faecalis and E. faecium;
Streptococci, for
example S. pneumoniae; Haemophilus, for example H. influenza; Moraxella, for
example M. catarrhalis; and Escherichia, for example E. coli. Other examples
include Mycobacteria, for example M. tuberculosis; intercellular microbes, for
example Chlamydia and Rickettsiae; and' Mycoplasma, for example M. pneumoniae.
In one embodiment, compositions, for treating or preventing infectious
disorders are provided, comprising a hydroxamic acid compound or derivative as
disclosed herein in combination with a pharmaceutically acceptable carrier.
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In another embodiment, there is provided a dosage amount of a hydroxamic
acid compound or derivative as disclosed herein in an effective amount for the
treatment, prevention or alleviation of a disorder, such as an infectious
disorder.
Hydroxamic acid compounds or derivatives can be screened for activity against
different microbial agents and appropriate dosages can be determined using
methods
available in the art.
The compounds can be used to treat a subject to treat, prevent, or reduce the
severity of an infection. Subjects include animals, plants, blood products,
cultures
and surfaces such as those of medical or research equipment, such as glass,
needles,
surgical equipment and tubing, and objects intended for temporary or permanent
implantation into an organism. Treating a subject includes, but is not limited
to,
preventing, reducing, or eliminating the clinical symptoms caused by an
infection of a
subject by a microorganism; preventing, reducing, or eliminating an infection
of a
subject by a microorganism; or preventing, reducing, or eliminating
contamination of
a subject by a microorganism. The microorganism involved is preferably a
prokaryote, more preferably a bacterium.
In one embodiment, methods of treating or preventing an infectious disorder in
a subject, such as a human or other animal subject, are provided, by
administering an
effective amount of a hydroxamic acid compound or derivative as disclosed
herein to
the subject. In one embodiment, the compound is administered in a
pharmaceutically
acceptable form optionally in a pharmaceutically acceptable carrier. As used
herein,
an "infectious disorder" is any disorder characterized by the presence of a
microbial
infection, such as the presence of bacteria. Such infectious disorders
include, for
example central nervous system infections, external ear infections, infections
of the
middle ear, such as acute otitis media, infections of the cranial sinuses, eye
infections,
infections of the oral cavity, such as infections of the teeth, gums and
mucosa, upper
respiratory tract infections, lower respiratory tract infections,
genitourinary infections,
gastrointestinal infections, gynecological infections, septicemia, bone and
joint
infections, skin and skin structure infections, bacterial endocarditis, burns,
antibacterial prophylaxis of surgery, and antibacterial prophylaxis in
immunosuppressed patients, such as patients receiving cancer chemotherapy, or
organ
transplant patients. The compounds and compositions comprising the compounds
can
be administered by routes such as topically, locally or systemically. Systemic
application includes any method of introducing the compound into the tissues
of the
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body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous,
intraperitoneal, subcutaneous, sublingual, nasal, vaginal, rectal, and oral
administration. The specific dosage of antimicrobial to be administered, as
well as
the duration of treatment, can be adjusted as needed.
Additionally, the compounds of this invention can also be used to prepare a
composition in an inert diluent which is useful in inhibiting bacterial
growth.
An "inert diluent" means an excipient that is useful in preparing a
composition that is
generally safe, non-toxic and neither biologically nor otherwise undesirable.
Representative pharmaceutical formulations containing a compound of
Formula (I) are described below.
Testing
The ability of the compounds of this invention to inhibit peptide deformylase
was measured by in vitro assay described in detail in Biological Example
below. The
antimicrobial activity of the compounds of this invention was tested as
described in
detail in Biological Example 2 below. The selective inhibition of PDF compared
to
MMP-7 (Matrilysin) by the compounds of this invention was tested as described
in
detail in Biological Example 3 below.
EXAMPLES
The following preparations and examples are given to enable those skilled in
the art to more clearly understand and to practice the present invention. They
should
not be considered as limiting the scope of the invention, but merely as being
illustrative and representative thereof.
Abbreviations
The following abbreviations are used:
AcOH, HOAc = acetic acid
Ac20 = acetic anhydride
BOC, Boc = t-butyloxycarbonyl
DCC = dicyclohexylcarbodiimide
DCM = dichloromethane
DIC = diisopropylcarbodiimide
DIAD = diisopropylazodicarboxylate
DIEA = diisopropylethylamine
DMF = dimethylformamide
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EDC = N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
Et = ethyl
EtOAc = ethyl acetate
Fmoc, FMOC = 9-fluorenylmethyloxycarbonyl
HATU = O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
HBTU = O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HHMPA = (4-hydroxymethyl-3-methoxyphenoxy)-alkanoic acid
HMP resin = hydroxymethylphenoxy resin
HOAt = 1-hydroxy-7-azabenzotriazole
HOBt = 1-hydroxybenzotriazole
Me = methyl
Mem = methoxy ethoxy methyl ether
MeOH = methanol
MMP = matrix metalloproteinase
Mom = methoxy methyl ether
NMM = N-methyl morpholine
NPEOC = 4-nitrophenethyloxycarbonyl
NPEOM = 4-nitrophenethylmethyloxycarbonyl
NVOC = 6-nitroveratryloxycarbonyl
NVOM = nitroveratryloxymethyl ether
PEG-PS resins or PS-PEG resin = polyethylene glycol-polystyrene graft
copolymer
resins
PFP-OTFA = pentafluorophenyl trifluoroacetate
PyBOP = benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate
PyBROP = bromotripyrrolidinophosphonium hexafluorophosphate
RT = room temperature
TBP = tributylphosphate
TBS, TBDIMS = t-butyldimethylsilyl
tBu = t-butyl
TES = triethylsilane
TFA = trifluoroacetic acid
TGS resin = TENTAGEL S resin
TGS NHZ resin = TENTAGEL S NHZ resin
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THF = tetrahydrofuran
THP = 2-tetrahydropyranyl
TMAD = N,N,N',N'-tetramethylazodicarboxamide (1,1'-Azobis(N,N-
dimethylformamide))
TMOF = trimethylorthoformate
TPP = triphenyl phosphine
TsCI = tosyl chloride
TsOH = toluenesulfonic acid
Trt = trityl
SYNTHETIC EXAMPLES
GENERAL PROCEDURE A
Synthesis of N-hydrox'~-3-aminocarbonylpropionamide
(following Scheme A)
R6 R~
O R3
N' '(Y)n
HOH XN
O Rs R~
Step 1
To a solution of mono-protected succinate e.g., mono-4-methyl 2-(R)-
butylsuccinic acid 1 (1 mmol) in DMF was added dialkylamine 2 (1 mmol), DIEA
(0.4 mL, 2.3 mmol), and an activating reagent (e.g. EDC, PyBOP, DIC, DCC,
etc.; 1
mmol). The mixture was stirred overnight, then diluted with ethyl acetate and
washed
with aqueous HCl (1 N), water, saturated sodium bicarbonate, brine, and then
dried
(NazS04). The filtrate was concentrated and then purified on silica gel (Merck
60;
ethyl acetate/hexane) to afford 3-aminocarbonylpropionate 3.
Step 2
3-Aminocarbonylpropionate 3 (0.1 mmol) was treated with dioxane (1 mL)
and hydroxylamine (50% in water, 2 mL) for 1 to 3 days, and then can be
purified by
preparative reverse-phase (C 18) HPLC to afford the desired N-hydroxy-3-
aminocarbonylpropionamide.
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GENERAL PROCEDURE B
Synthesis of N-hydroxy-3-(R)-n-butyl-3-aminocarbon~propionamide
Alternate method
R6 R~
~O
N' '(Y)n
HOH XN
O Rs R~
To mono-4-methyl 2-(R)-butylsuccinic acid (0.2 mmol) in dioxane (1 mL) was
added amine 2 (0.2 mmol), DIEA (0.4 mmol) and an activating reagent (e.g. EDC,
PyBOP, DIC, DCC, etc.; 0.2 mmol); and the mixture was stirred for 2 h. Aqueous
50% hydroxylamine was added (1.5 mL) and the mixture was stirred an additional
1-2
days. The reaction mixture can then be purified by preparative reverse-phase
(C 18)
HPLC to afford N-hydroxy-3-(R)-n-butyl-3-aminocarbonylpropionamide.
GENERAL PROCEDURE C
Synthesis of N-hydroxy-3-(R)-n-butyl-3-[2-(,S~-aminocarbonylpyrrolidin-1-
ylcarbonyl)-2-(S~-hydroxypropionamide
HN
H 1 ) C02Me J~ R~4NH2
PyBOP CO2Me PygpP
2) LiOH
C-1 C-2
O O
N
o : NH20H HO~H N
O O O N~R~a OH O O N~R~a
H H
C-3 C-4
Step 1
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To 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid C-1 (prepared in
four steps from dimethyl malate; see Example 21 for details) in DMF was added
proline O-methyl ester, DIEA and HATU and the solution stirred 4 hours.
Standard
aqueous workup afforded the desired amide, which was dissolved in methanol and
treated with lithium hydroxide to yield 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-
yl)-1-
(2-(S)-carboxypyrrolidin-1-ylcarbonyl)pentane C-2.
Step 2
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-carboxypyrrolidin-1-
ylcarbonyl)pentane C-2 in DMF was added an amine R~4NHz, DIEA and HATU and
the solution stirred for 2 h. Aqueous workup followed by silica gel
chromatography
afforded 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-
aminocarbonylpyrrolidin-
1-ylcarbonyl)pentane C-3.
Step 3
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-aminocarbonyl-
pyrrolidin-1-ylcarbonyl)pentane C-3 in dioxane was treated with 50 % aqueous
hydroxylamine for 4 h. The reaction mixture was then purified by preparative
reverse-phase (C18) HPLC to afford N-hydroxy-3-(R)-n-butyl-3-[2-(S)-
aminocarbonylpyrrolidin-1-ylcarbonyl)-2-(S)-hydroxypropionamide C-4.
GENERAL PROCEDURE D
Synthesis of N-hydroxy-3-(R)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-1-yl-
carbonyl)propionamide
(following Scheme C~
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i I off
~o~ w
0
ArgoGel-Wang 1 ) "~2~ 1 ) PFP-OTFA/Py
COZFm
or .DIAD/PPh3 2) Rs~,
2) pipendine _ . HN' '(Y)n
ArgoGel-OH R/~(\R
s
Rs R~ Rs R~
NH20H o
NX(Y)n ~ HON N' '(Y)n
XH
Rs R~ D_3 O Rs R~
Step 1
To ArgoGel resin (20 g) solvated in DCM was added 2-(R)-n-butylsuccinate
1-(9-fluorenyl) ester (10.0 g, 23.2 mmol), diisopropylazodicarboxylate (DIAD;
4.8
mL, 24.3 mmol) and triphenylphosphine (PPh3, 6.38 g, 24.3 mmol); the reaction
mixture was shaken for 6 h. The resin is filtered and was washed with DCM
(3x),
MeOH (3 x) and DMF (3 x). A solution of piperidine (40 mL, 10% in DMF) was
added and the resin mixture is shaken for 3 h. The resin was filtered and then
washed
sequentially with DMF (3x), DCM (2x), MeOH (2x) and DMF (3x) to afford
intermediate D-1.
Step 2
To resin D-1 in DMF was added PFP-OTFA and pyridine and the mixture was
shaken for 4 h. The resin was filtered and washed with DMF (3x), MeOH (2x),
DCM
(2x), and ether (2x) and dried under vacuum. To a portion of the resin was
added a
solution of an amine (1 mmol) and DIEA (1.5 mmol) in DMF (1 mL). The resin was
shaken overnight, filtered and washed with DMF, MeOH, and DCM to afford D-2.
Step 3
To D-2 was added dioxane (0.5 mL) and aqueous 50% hydroxylamine (1 mL).
After 18 h, the cleavage products were drained and then purified by
preparative
reverse-phase (C18) HPLC to afford the desired hydroxamate D-3.
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GENERAL PROCEDURE E
Synthesis of N-hydroxy-3-(R)-n-butyl-3-[2-(S~-aminocarbonylpyrrolidin-1-yl-
carbonyl)propionamide
HN
H 1 ) C02Bn ~~ 1 ) R~4R~5NH
PyBOP co2H 2) NH20H
2) HZ/Pd
E-1 E-2
o
HON N
H
O O N~R~a
E-3 \R15
Step 1
To a solution of mono-4-methyl 2-(R)-butylsuccinic acid, (prepared in three
steps from hexanoylchloride and t-butyl bromoacetate as described below; 1
mmol) in
DMF was added proline O-benzyl ester (1 mmol), DIEA (0.4 mL, 2.3 mmol), and a
coupling reagent (e.g. EDCI, PyBOP, DIC, etc.; 1 mmol). The mixture was
stirred
overnight, then diluted with ethyl acetate and washed with aqueous HCl (1 N),
water,
saturated sodium bicarbonate, brine, and then dried (Na2S04). The filtrate was
concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane)
to afford
methyl-3-(R)-butyl-3-(2-(,S~-benzyloxycarbonylpyrrolidin-1-
ylcarbonyl)propionate.
To this amide (0.1 mmol) in ethylacetate (10 mL) was added 10 % Pd/C (100 mg)
and
the solution stirred under a hydrogen atmosphere for 8 h. The suspension was
filtered
through a Celite plug and then concentrated to afford methyl-3-(R)-butyl-3-(2-
(,S~-
carboxypyrrolidin-1-ylcarbonyl)propionate E-2.
Step 2
To methyl-3-(R)-butyl-3-(2-(,S~-carboxycarbonylpyrrolidin-1-ylcarbonyl)-
propionate E-2 (100 mg) in DMF (1 mL) was added an amine (1 equivalent), DIEA
(2.5 equivalents) and HATU ( 1 equivalent) and the reaction stirred for 4 h.
The
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solution was then cooled to 0 °C, 50 % aqueous hydroxylamine was added
(400 ~L),
and the reaction stirred at 4 °C for 4 hours to 3 days, depending upon
the succinate.
The crude reaction mixture was then purified by preparative reverse-phase
(C18)
HPLC to afford the desired compound methyl-3-(R)-butyl-3-(2-(S~-amino-
carbonylpyrrolidin-1-ylcarbonyl)propionate E-3.
GENERAL PROCEDURE F
Synthesis of N-hydroxy-3-(R)-n-butyl-3-[2-(,S~-aminocarbonylpyrrolidin-1-yl-
carbonyl)-2-(,S~-hydroxypropionamide
Me LDA ~ H2
MeO~ I I
OH O B~ Me0 Me Pd/C M~ Me
OH O OH
F-1 F-2 F-3
H
1)
NaOH ' Me2C(OMe)2' Cozen
H
MeOH Hp . H H+ PyBOP
pH 2) H2, Pd/C
F-4 F-5
1 ) PyBOP, RNHZ
N
0 2) NHZOH HORN
CO2H ~R
OH O
~H
F-6 F-7
Step 1
To a solution of diisopropylamine (14 mL, 100 mmol) in THF at 0°C
was
added n-butyllithium (2.5 M in hexane, 40 mL, 100 mmol) over 10 min. The
mixture
was stirred at RT for 30 min., and then added via cannula to a -78 °C
solution of
dimethyl malate F-1 (7.71 g, 47.6 mmol) in THF (130 mL). The mixture was
warmed
to -20 °C over 2 h, and then cooled to -78 °C. Crotyl bromide
(8.1 g, 60 mmol) was
added, then the mixture was allowed to warm to room temperature and then
stirred
overnight. The solution was then cooled to -10 °C and quenched with
NH4C1 (10%,
100 mL). The THF was removed and the residue extracted with ethyl acetate
(2x200
mL). The combined organic layers were washed with HCl (1N, 3x50 mL), saturated
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aqueous sodium bicarbonate (3x50 mL), and brine, then dried over NaZS04. The
solution was filtered and concentrated to give a residue, which was purified
on silica
gel (ethyl acetate/hexane 1:4) to afford (2S, 3R)-3-(2-butenyl)-2-
hydroxysuccinic
dimethyl ester F-2 (2.5 g, 24%).
Step 2
To (2S,3R)-3-(2-butenyl)-2-hydroxysuccinic dimethyl ester F-2 (2.5 g) in
ethyl acetate (50 mL) was added 10 % Pd/C (0.25g) and the reaction stirred
under a
hydrogen atmosphere for 20 h. The suspension was filtered through a pad of
Celite,
washed with EtOAc (3x) and then concentrated in vacuo to afford (2S,3R)-3-(n-
butyl)-2-hydroxysuccinic dimethyl ester F-3.
Step 3
To (2S,3R)-3-(n-butyl)-2-hydroxysuccinic dimethyl ester F-3 in methanol (28
mL) was added a solution of NaOH (2.2 g, 55 mmol) in water (28 mL). After 24 h
the MeOH was removed, the crude reaction was acidified with HCl (6N, 12 mL) to
pH = 1, and then extracted with ethyl acetate (3 x 50mL). The combined organic
layers were dried (NaZS04) and concentrated to give (2S,3R)-3-(n-butyl)-2-
hydroxysuccinic acid F-4 (1.96 g, 90%).
Step 4
To a solution of (2S, 3R)-3-(n-butyl)-2-hydroxysuccinic acid F-4 (300 mg,
1.58 mmol) in 2,2-dimethoxypropane (10 mL) was added p-toluenesulfonic acid
(20
mg) and the reaction was stirred at room temperature for 16 h. The solution
was
diluted with dichloromethaneand washed with brine, dried (Na2S04) and then
purified
by silica gel chromatography to afford 1.2 mmol 2-(2,2-dimethyl-4-oxo-1,3-
dioxolan-
5-yl)hexanoic acid F-5 (78 %).
Step 5
To a solution of 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid F-5
(1.2 mmol) in DCM (10 mL) was added L-Pro-OBn (1.2 mmol), PyBOP (1.2 mmol),
and DIEA (2.5 mmol). The mixture was stirred overnight, then concentrated, and
purified on silica gel (ethylacetate/hexane 1:4) to afford 275 mg of the
desired amide
(45%). To the product in ethylacetate (25 mL) was added 10 % Pd/C (50 mg) and
the
reaction stirred under a hydrogen atmosphere for 8 h. The suspension was
filtered
through a pad of Celite, washed with EtOAc (3x) and then concentrated in vacuo
to
afford 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-carboxy-pyrrolidin-1-
ylcarbonyl)pentane F-6 (quant.).
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Step 6
To 1-(2,2-dimethyl- 4-oxo-1,3-dioxolan-5-yl)-1-(2-(,S~-carboxy-pyrrolidin-1-
ylcarbonyl)pentane F-6 (50 mg) in dioxane (1 mL) was added an amine RNHZ (1
equivalent), DIEA (2.5 equivalents) and HATU or PyBOP (1 equivalent) and the
solution stirred for 4 h. The reaction was then cooled to 0 °C, 50 %
aqueous
hydroxylamine was added (400 ~L), and the solution stirred at 4 °C for
8 hours. The
crude reaction mixture was then purified by preparative reverse-phase (C 18)
HPLC to
afford N-hydroxy-3-(R)-n-butyl-3-[2-(S~-aminocarbonylpyrrolidin-1-yl-carbonyl)-
2-
(,S~-hydroxypropionamide F-7.
GENERAL PROCEDURE G
Synthesis of N-hydroxy-3-(,S~-n-butyl-3-[2-(,S~-aminocarbonylpyrrolidin-1-yl-
carbonyl)-2-(R)-fluoropropionamide
HN
CoZt6u ' CH301~1a''
PyBOP
O ~ O O OH O O
G-1
G_2 G_3
1) Tf20, pyridine HCI, Dioxane
2) TASF ' Me0 F N ' Me0 F N
O O O OH
G-4 G-5
1) R~R2NH, HATU
1 ~N
2) NH20H, 0°C HORN
F O
Rp
1 S G-6
Step 1
To 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid G-1 (10 mmol;
prepared as described in Method F, above) in DMF (50 mL) was added proline O-t-
butyl ester (10 mmol), DIEA (25 mmol) and PyBOP (10 mmol) and the solution
stirred for 8 h. The reaction was diluted with ethyl acetate and washed with
water,
sodium bicarbonate, brine, and then dried (Na2S04). The filtrate was
concentrated
and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford 1-
(2 ,2-
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dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(,S)-tert-butoxycarbonylpyrrolidin-1-yl-
carbonyl)pentane G-2 (5 mmol, 50 %).
Step 2
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S~-tert-butoxy-
carbonylpyrrolidin-1-ylcarbonyl)pentane G-2 (5 mmol, 50 %) (5 mmol) in
methanol
(20 mL) was added sodium methoxide (catalytic; pH adjusted to 10) and the
solution
stirred for 1 hour. Amberlite IR-120 resin (H+ form) was added, then the
solution was
filtered and concentrated to afford methyl 3-(R)-n-butyl-3-[2-(S~-tert-butoxy-
carbonylpyrrolidin-1-yl-carbonyl)-2-(,S~-hydroxypropionate G-3 (quant.).
Step 3
To methyl 3-(R)-n-butyl-3-[2-(S~-tert-butoxycarbonylpyrrolidin-1-yl-
carbonyl)-2-(,S~-hydroxypropionate G-3 (5 mmol) in DCM (5 mL) was added
pyridine
(15 mmol), the reaction was cooled to -20 °C, then triflic anhydride
was added (7.5
mmol). The solution was stirred for 1 hour, then washed with aqueous citric
acid,
sodium bicarbonate and brine, then dried (Na2S04) and concentrated. The
intermediate triflate was then resuspended in DCM and cooled to - 50
°C.
Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (5
mmol)
and the solution allowed to warm to rt. The reaction mixture was washed with
aqueous sodium bicarbonate and brine, dried (Na2S04) and concentrated then
purified
on silica gel (ethylacetate/hexanes) to afford 2.3 mmol (45 %) of methyl 3-
(,S~-n-
butyl-3-[2-(S~-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(R)-
fluoropropionate
G-4.
Step 4
To methyl 3-(,S~-n-butyl-3-[2-(,S~-tert-butoxycarbonylpyrrolidin-1-yl-
carbonyl)-2-(R)-fluoropropionate G-4 (2.3 mmol) was added 4 N HCl in dioxane
(10
mL), the solution stirred for 2 h, then evaporated to dryness to afford 2.3
mmol of
methyl 3-(S~-n-butyl-3-[2-(.S~-carboxypyrrolidin-1-yl-carbonyl)-2-(R)-
fluoropropionate G-5 (quant.). To intermediate G-5 (0.15 mmol) in dioxane (1
mL)
was added an amine (0.15 mmol), DIEA (0.38 mmol), and HATU or other coupling
reagent (0.15 mmol) and the solution stirred for 8 h. The reaction was cooled
to 0 °C,
aqueous 50 % hydroxylamine was added (0.5 mL) and the reaction stirred for 4
h.
The crude reaction mixture was then purified by preparative reverse-phase
(C18)
HPLC to afford N-hydroxy- 3-(,S~-n-butyl-3-[2-(,5~-aminocarbonylpyrrolidin-1-
yl-
carbonyl)-2-(R)-fluoropropionamide G-6.
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GENERAL PROCEDURE H
Synthesis of N-hydroxy-3-(S~-n-butyl-3-[2-(,S~-aminocarbonylpyrrolidin-1-yl-
carbonyl)-2-(,S~-fluoropropionamide
. N 1 ) TfzO, pyridine ~ ~~o N CH30Na' H CO N
a . ~ I ' H ~ s
2) BUQNOBZ BZ O-"O' ' H O'
H-~ ~ \ H-2 H_ 3
1) Tf20, pyridine HG 1) R~R2NH, HATU
2) TASF H'CO : N ~ H'CO _ NY 2) HZNOH, 0 °C HO~H _ N'
O O x O J~~ppH ~ 0~~~
H-a H-s H_s
St. ep 1
To methyl 3-(R)-n-butyl-3-[2-(.S~-tert-butoxycarbonylpyrrolidin-1-yl-
carbonyl)-2-(S~-hydroxypropionate H-1 (10 mmol; prepared as described in
Method
G, above) in DCM (10 mL) was added pyridine (30 mmol), the reaction was cooled
to
-20 °C then triflic anhydride (15 mmol) was added. The solution was
stirred for 1
hour, then washed with aqueous citric acid, sodium bicarbonate and brine, then
dried
(NaZS04) and concentrated. The resulting oil was dissolved in toluene (30 mL),
cooled to 0 °C, then treated with tetrabutylammonium benzoate. After
1.5 h, the
reaction was concentrated and then purified on silica gel
(ethylacetate/hexanes) to
afford 8.7 mmol of methyl 3-(R)-n-butyl-3-[2-(S~-tert-butoxycarbonylpyrrolidin-
1-yl-
carbonyl)-2-(R)-benzoyloxypropionate H-2 (87 %).
St_ ep 2
To methyl 3-(R)-n-butyl-3-[2-(S~-tert-butoxycarbonylpyrrolidin-1-yl-
carbonyl)-2-(R)-benzoyloxypropionate H-2 (8.7 mmol) in methanol (25 mL) at 0
°C
was added sodium methoxide (catalytic; pH adjusted to 10) and the solution
stirred
for 2 h. Amberlite IR-120 resin (H+ form) was added, then the solution was
filtered
and concentrated to afford methyl 3-(R)-n-butyl-3-[2-(,S~-tert-butoxycarbonyl-
pyrrolidin-1-yl-carbonyl)-2-(R)-hydroxypropionate H-3 (quant.).
Step 3
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To methyl 3-(R)-n-butyl-3-[2-(,S~-tert-butoxycarbonylpyrrolidin-1-yl-
carbonyl)-2-(R)-hydroxypropionate H-3 (8.7 mmol) in DCM (10 mL) was added
pyridine (25 mmol), the reaction was cooled to -20 °C, then triflic
anhydride (12.5
mmol) was added. The solution was stirred for 1 hour, then worked up as
described
above. The intermediate triflate was resuspended in DCM and cooled to -50
°C.
Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (8.7
mmol)
and the solution allowed to warm to rt. The reaction mixture was washed with
aqueous sodium bicarbonate and brine, dried (Na2S04) and concentrated, then
purified on silica gel (ethylacetate/hexanes) to afford 4.3 mmol (SO %) of
methyl 3-
(,S~-n-butyl-3-[2-(S~-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(,S~-
fluoropropionate H-4.
Step 4
To methyl 3-(S~-n-butyl-3-[2-(S~-tert-butoxycarbonylpyrrolidin-1-yl-
carbonyl)-2-(,S~-fluoropropionate H-4 (4.3 mmol) was added 4 N HCl in dioxane
(15
mL), the solution stirred for 2 h, then evaporated to dryness to afford 4.3
mmol of
methyl 3-(~-n-butyl-3-[2-(,S~-carboxypyrrolidin-1-yl-carbonyl)-2-(S~-fluoro-
propionate H-5 (quant.). To H-5 (0.15 mmol) in dioxane (1 mL) was added an
amine
(0.15 mmol), DIEA (0.38 mmol), and HATU or similar coupling reagent (0.15
mmol)
and the solution stirred for 8 h. The reaction was cooled to 0 °C,
aqueous SO
hydroxylamine was added (0.5 mL) and the reaction stirred for 4 h. The crude
reaction mixture was then purified by preparative reverse-phase (C18) HPLC to
afford N hydroxy-3-(S~-n-butyl-3-[2-(.S~-aminocarbonylpyrrolidin-1-yl-
carbonyl)-2-
(,S~-fluoropropionamide H-6.
GENERAL PROCEDURE I
Synthesis of N-hydroxy-3-(R)-n-butyl-3-[2-(,S~-(tert-butoxycarbonyl)-
pyrrolidin-1-yl
carbonyl)-2-(,S~-hydroxypropionamide
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PhC( OMe )3
- ,- ~ ~ p a
~ 0
Ho OH O CSA, Toluene pf,~-O O HA~ p~' oMe I-2
I-1
MeOH/MeONa
NH20H H~ NHZOH
N
H OH O OH O
I-3 G-3
Step 1
To a solution of (2S,3R)-3-(n-butyl)-2-hydroxysuccinic acid F-4 (300 mg, 1.58
S mmol) and powdered molecular sieves ( 1 g ) in trimethyl orthobenzoate (5
mL) and
toluene ( Sml ) was added 10-Camphorsulfonic acid (20 mg) and the reaction was
heated at 110°C under vacuum ( 20 torr ) for 5 h. The solution was
diluted with ethyl
acetate , filtered through Celite and washed with brine, dried (Na2S04) and
then
purified by silica gel chromatography to afford 1.2 mmol 2-(2-methoxy-2-phenyl
-4-
oxo-1,3-dioxolan-5-yl)hexanoic acid I-1 (40 %).
Step 2
To 2-(2-methoxy-2-phenyl -4-oxo-1,3-dioxolan-5-yl)hexanoic acid I-1 (10
mmol; prepared as described in Method I, above) in DMF (50 mL) was added
proline
O-t-butyl ester (10 mmol), DIEA (25 mmol) and PyBOP (10 mmol) and the solution
1 S stirred for 8 h. The reaction was diluted with ethyl acetate and washed
with water,
sodium bicarbonate, brine, and then dried (Na2S04). The filtrate was
concentrated
and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford 1-
(2 -
methoxy-2-phenyl -4-oxo-1,3-dioxolan-S-yl)-1-(2-(S)-tert-
butoxycarbonylpyrrolidin-
1-yl-carbonyl)pentane I-2 (5 mmol, 50 %).
Step 3
To 1-(2-methoxy-2-phenyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-tert-butoxy-
carbonylpyrrolidin-1-ylcarbonyl)pentane I-2 (5 mmol, 50 %) (S mmol) in
methanol
(20 mL) was added sodium methoxide (catalytic; pH adjusted to 10) and the
solution
stirred for 1 hour. Amberlite IR-120 resin (H+ form) was added, then the
solution was
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filtered and concentrated to afford methyl 3-(R)-n-butyl-3-[2-(S~-tert-butoxy-
carbonylpyrrolidin-1-yl-carbonyl)-2-(,S~-hydroxypropionate G-3 (quant.).
Step 4
To G-3 and I-2 ($Omg) in dioxane (1 mL) was added aqueous $0
$ hydroxylamine (0.$ mL) and the reaction stirred for 16 h. The crude reaction
mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-
hydroxy-3-(R)-n-butyl-3-[2-(,S~-(tert-butoxycarbonyl)-pyrrolidin-1-yl-
carbonyl)-2-(S~-
hydroxypropionamide.
GENERAL PROCEDURE J
Synthesis of N-hydroxy-3-(S~-n-butyl-3-[2-(S~-aminocarbonylpyrrolidin-1-yl-
carbonyl)-2-(R,S~-fluoropropionamide
H O H
LDA ~ F
CI + ,:
o ~ LDA
1 / R = Ethyl
Hexanoyl 4-(s)-benzyl J_~ R = tert.Butyl
chloride oxazolidin-2-one
O H~ )n
1 )BnOLI - BnOH
0
H ~ HO~ )n
F ~ 2)Pd-C l HZ N
F O NHZOH H F O Rs
J_2 / J_3 J_4
1$
Ste~l
To a solution of 4-(S~-benzyloxazolidin-2-one ($6 mmol) (Aldrich,
Milwaukee, Wisconsin) in THF at -78 °C was added 2.$ M n-BuLi in
hexane (22.4
mL, $6 mmol) and the reaction stirred at -78 °C for 2 hr. To this was
added via
cannula a -78 °C solution of hexanoyl chloride (6$ mmol) in THF and the
mixture
stirred at -78 °C for 2 hr, then allowed to warm to room temperature
and stirred
overnight. The reaction was then quenched with aqueous saturated NH4Cl,
extracted
with ethyl acetate, dried, and purified by silica gel chromatography
(hexanes/ethyl
acetate) to afford N hexanoyl-4-(,S~-benzyloxazolidin-2-one J-1.
2$ Step 2
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To a solution of N hexanoyl-4-(S~-benzyloxazolidin-2-one (7.3 mmol) in THF
at -78 °C was added 1.0 M sodium hexamethyldisilazide (NaHMDS, 8.8
mmol) and
the reaction stirred at -78 °C for 1 hr. A solution of alkyl
iodofluorooacetate (8.8
mmol) in THF was then added dropwise, and the resulting mixture was stirred at
-78
°C for 1 hr and then at room temperature overnight. The reaction was
quenched with
NH4C1, concentrated, then suspended in ethyl acetate and washed with 0.5 N HCl
and
brine, dried, and purified by silica gel chromatography (ethyl
acetate/hexanes) to
afford the alkyl 3-(S~-(n-butyl)-3-[4-(,S~-benzyloxazolidin-2-one-3-
ylcarbonyl)-2-
(RS~-(fluoro)propionate J-2.
Step 3
To alkyl 3-(S~-(n-butyl)-3-[4-(S~-benzyloxazolidin-2-one-3-ylcarbonyl)-2-
(RS~-(fluoro)propionate (1.44 mmol) in THF at 0°C was added LiOBn (5.76
mmol )
in benzyl aicohol and the reaction stirred at 0°C for 3 hr. The
reaction was then
quenched with 5% KHS04, concentrated, suspended in ethyl acetate and subjected
to
standard aqueous workup. The crude product was purified by silica gel
chromatography (methanol/dichloromethane) to afford alkyl 3-(R)-(n-butyl)-2-
(R,S~-
(fluoro)propionate J-3.
Step 4
To J-3 (0.15 mmol) in dioxane (1 mL) was added an amine (0.15 mmol),
DIEA (0.38 mmol), and HATU or similar coupling reagent (0.15 mmol) and the
solution stirred for 8 h. The reaction was cooled to 0 °C, aqueous 50
hydroxylamine was added (0.5 mL) and the reaction stirred for 4 h. The crude
reaction mixture was then purified by preparative reverse-phase (C18) HPLC to
afford N hydroxy-3-(S~-n-butyl-3-[2-(S~-aminocarbonylpyrrlidin-1-yl-carbonyl)-
2-
(RSV-fluoropropionamide J-4.
Example 1
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)
pyrrolidin-1-ylcarbonyl]propionamide
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0
0
N
HOHN
O
The title compound was prepared according to General Procedure A from
mono-methyl 2-(R)-butylsuccinic acid and L-proline tert-butyl ester. This
compound
has also been prepared according to General Procedure D using L-proline tent-
butyl
ester as the amine. 'H NMR (300 MHz, CDC13) 8 0.89 (t, J=7.2 Hz, 3 H), 1.43
(s,
9H), 1.24-1.71 (m, 6H), 1.86-2.43 (m, SH), 2.53 (dd, J=10.5 and 13.2 Hz, 1 H),
3.06
(m, 1H), 3.45-3.80 (m, ZH), 4.28-4.40 (m, 1H).
Example 2
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butylaminocarbonyl)-
pyrrolidin-1-ylcarbonyl]propionamide
O N
O N J.,
HOHN
O
The title compound was prepared according to General Procedure A from
mono-methyl 2-(R)-butylsuccinic acid and L-proline t-butylamide hydrochloride.
1H
NMR (300 MHz, CDC13) : 8 0.77 (t, J=7.2 Hz, 3H), 1.19 (s, 9H), 1.28-2.00 (m,
10H),
2.08 (dd, J= 4.1 and 9.6 Hz, 1 H), 2.26 (dd, J =9.6 and 15 Hz, 1 H), 2.99 (m,
1 H), 3.47
(m, 1H), 3.63 (dd, J=9.0 and 16.8 Hz, 1H), 4.28 (dd, J=1.9 and 7.8 Hz, IH).
Example 3
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(methylaminocarbonyl)-
pyrrolidin-1-ylcarbonyl]propionamide
O N
O N~ \
HOHN
O
Small-scale synthesis
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The title compound was prepared according to General Procedure A from
mono-methyl 2-(R)-butylsuccinic acid and L-proline methylamide hydrochloride.
'H
NMR (300 MHz, CDC13): 8 0.80 (t, J=7.2 Hz, 3H), 1.28-2.50 (m, 12H), 2.98 (m,
1H), 3.47 s, 3H), 3.58 (m, 2H), 4.27 (m, 1H).
Large-scale synthesis
St_ ep 1
To a solution of Boc-Pro-OH (5 g, 23.2 mmol), methylamine (2M in THF, 15
mL, 30 mmol), EDC (4.79 g, 25 mmol), and HOBt (3.38 g, 25 mmol) in THF (150
mL) was added DIEA (4.35 mL, 25 mmol) and the mixture stirred overnight. THF
was removed, the residue was dissolved in ethyl acetate and then washed with
aqueous HCl (1 N, 2x), 5% KHS04 (2x), saturated sodium bicarbonate, brine,
dried
(Na2S04), concentrated, and purified on silica gel (Merck 60, ethyl
acetate/hexanes)
to give N-Boc-(2-methylaminocarbonyl)pyrrolidine (3.3 g, 63%).
St_ep2
N-Boc-(2-methylaminocarbonyl)pyrrolidine (3.3 g, 14.5 mmol) was treated
with HCl (4 N in dioxane, 10 mL) for 1 h. The solvent was removed and the
white
solid treated with mono-methyl 2-(R)-butylsuccinic acid (2.82 g, 15 mmol),
HOBt
(2.02 g, 15 mmol), EDC (2.88 g, 15 mmol) and DIEA (6.96 mL, 40 mmol) in THF
for
16 h. Similar work-up and purification gave the methyl ester (2.2 g). A
solution of
methyl ester and lithium hydroxide (400 mg, 10 mmol) in methanol ( 1 S mL) and
water ( 10 mL) was stirred for 16 h. Methanol was removed and the aqueous
layer
was acidified to pH =1 and extracted with ethyl acetate (4x). The organic
layers were
dried (NaZS04) and concentrated to afford 3-(R)-(n-butyl)-3-[(2-(S~-
(methylamino-
carbonyl)pyrrolidin-1-ylcarbonyl]propionic acid as a white solid (1.5 g).
Step 3
To a solution of 3-(R)-(n-butyl)-3-[(2-(S~-(methylaminocarbonyl)-
pyrrolidin-1-ylcarbonyl]propionic acid (1.5 g, 5.28 mmol), O-
benzylhydroxylamine
(932 mg, 5.84 mmol), HOBt (784 mg, 5.84 mmol), and DIEA (2.3 mL, 13.2 mmol) in
THF (100 mL) was added EDC (1.12 g, 5.84 mmol) and the reaction stirred for 16
h.
Conventional work-up and purification gave N benzyloxy-3-(R)-(n-butyl)-3-[(2-
(S~-
(methylaminocarbonyl)pyrrolidin-1-ylcarbonyl]propionamide (1.56 g).
A solution of N benzyloxy-3-(R)-(n-butyl)-3-[(2-(S~-(methylaminocarbonyl)-
pyrrolidin-1-ylcarbonyl]propionamide (1.5 g) in ethyl acetate (50 mL) was
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hydrogenated over Pd/C for 14 h. The mixture was filtered through a pad of
Celite,
washed with ethyl acetate, and concentrated to give N hydroxy-3-(R)-(n-butyl)-
3-[(2-
(S~-(methylamino-carbonyl)pyrrolidin-1-ylcarbonyl]propionamide (1.1 g).
Example 4
S Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(methoxymethyl)-
pyrrolidin-1-ylcarbonyl]propionamide
0 0
~Me
HOHN
O
The title compound was prepared according to General Procedure A from (S~-
(+)-2-(methoxymethyl)pyrrolidine and mono-methyl 2-(R)-butylsuccinic acid. 1H
NMR (300 MHz, CDC13): b 0.90 (t, J=7.5 Hz, 3H), 1.22-1.64 (m, 6H), 1.84-2.05
(m,
2H), 1.84-2.05 (m, 2H), 2.25-2.42 (m, 1H), 2.51-2.66 (m, 1H), 2.99-3.16 (m,
1H),
3.33 (s, 3H), 3.38 (dd, J=1.9 and 6.9 Hz, 1H), 3.44 (bd, J = 6.9 Hz, 1H), 3.47-
3.54
(m, 1 H), 3.61-3.69 (m, 1 H), 4.24 (m, 1 H).
Example 5
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(N methoxy-N methylamino
carbonyl)pyrrolidin-1-ylcarbonyl]propionamide
Me
O N
O N~ home
HOHN
O
The title compound was prepared according to General Procedure A from L-
proline N-methoxyl N-methylamide hydrochloride and mono-methyl 2-(R)-
butylsuccinic acid. 1H NMR (300 MHz, CDCl3): 8 0.80 (t, J=7.2 Hz, 3H), 1.27-
2.60
(m, 12H), 3.05 (m, 1H), 3.19 (s, 3H), 3.72 (m, 2H), 3.78 (s, 3H), 4.85 (m,
1H).
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Example 6
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(S~-(methoxycarbonyl)
pyrrolidin-1-ylcarbonyl]propionamide
0 0
O N
HOHN
O
The title compound was prepared according to General Procedure A from L-
proline methyl ester hydrochloride and mono-methyl 2-(R)-butylsuccinic acid.
'H
NMR (300 MHz, CDC13): 8 0.90 (m, 3H), 1.23-1.70 (m, 6H), 1.86-2.09 (m, 3H),
2.15-2.62 (m, 3H), 3.01-3.17 (m, 1 H), 3.59 -3.86 (m, 2H), 3.71 (s, 3H), 4.42-
4.53(m,
1H).
Example 7
Synthesis of N hydroxy-3-(R)-(3-methylpropyl)-3-[(2-(,S~-(tert-butoxycarbonyl)
pyrrolidin-1-ylcarbonyl]propionamide
0
0 ots~
HO~ N",
N v
H
O
The title compound was prepared according to General Procedure A from L-
proline t-butyl ester hydrochloride and mono-methyl 2-(R)-isobutylsuccinic
acid. 'H
NMR (300 MHz, CDC13): 8 0.90-0.99 (m, 6H), 1.27-2.58 (m, 18H), 2.78-2.91 (m,
1H), 3.08-3.18 (m, 1H), 3.43-3.81 (m, 3H), 4.26-4.40 (m, 2H).
Example 8
SynthesisofNhydroxy-3-(R)-(n-butyl)-3-(pyrrolidin-1-ylcarbonyl)propionamide
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Me
O /~
HON N. 1
VH
O
The title compound was prepared according to General Procedure A using
pyrrolidine as the amine and mono methyl-2-(R)-butylsuccinic acid. MS (APCI)
m/z
= 243 [M+H].
Example 9
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(pyrrolidin-1-ylmethyl)
pyrrolidin-1-ylcarbonyl]propionamide
Me
O i N
HON N
H
O
The title compound was prepared according to General Procedure A from 2-
(S)-(pyrrolidin-1-ylmethyl)pyrrolidine and mono-methyl 2-(R)-butylsuccinic
acid.
MS (APCI) m/z = 326 [M+H].
Example 10
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(S~-(morpholin-4-ylcarbonyl)-
pyrrolidin-1-ylcarbonyl]propionamide
Me
O L ~O
HON N
H
O
The title compound was prepared according to General Procedure D using L-
proline N-morpholinylamide as the amine. MS (APCI) m/z = 356 [M+H].
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Example 11
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(dimethylaminocarbonyl)
pyrrolidin-1-ylcarbonyl]propionamide
M e2
HOH
O
The title compound was prepared according to General Procedure A from L-
proline N,N-dimethylamide hydrochloride and mono-methyl 2-(R)-butylsuccinic
acid.
MS (APC>] m/z = 314 [M+H].
Example 12
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[4-(R)-(tert-butoxy-2-(,S~-tert-
butoxycarbonyl)pyrrolidin-1-ylcarbonyl]propionamide
HOHN
O
OIBu
The title compound was prepared according to General Procedure A from 3-
(R)-O-tert-butyloxy-L-proline t-butyl ester and mono-methyl 2-(R)-
butylsuccinic acid.
MS (APC>7 m/z = 415 [M+H].
Example 13
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-(methoxycarbonyl)piperidin-1
ylcarbonyl]propionamide
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Me
OMe
H0.
H O
The title compound was prepared according to General Procedure A from (t)-
homoproline methyl ester and mono-methyl 2-(R)-butylsuccinic acid. MS (APCI)
m/z = 315 [M+H].
Example 14
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(tert-
butoxycarbonyl)piperidin-1
ylcarbonyl]propionamide
HO~ N
H O
The title compound was prepared according to General Procedure D using L-
homoproline t-butyl ester as the amine. MS (APCI) m/z = 357 [M+H].
Example 15
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-(tert-butoxycarbonyl)-
tetrahydroisoquinolin-1-ylcarbonyl]propionamide
,nne
H
The title compound was prepared according to General Procedure A from L-
tetrahydroisoquinoline t-butyl ester and mono-methyl 2-(R)-butylsuccinic acid.
MS
(APCI) m/z = 405 [M+H].
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Example 16
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(acetamidomethyl)pyrrolidin-1
ylcarbonyl]propionamide
/NHAc
HOH
Step 1
To a solution of 4-(.S~-benzyloxazolidin-2-one (56 mmol) (Aldrich,
Milwaukee, Wisconsin) in THF at -78 °C was added 2.5 M n-BuLi in
hexane (22.4
mL, 56 mmol) and the reaction stirred at -78°C for 2 hr. To this was
added via
cannula a -78 °C solution of hexanoyl chloride (65 mmol) in THF and the
mixture
stirred at -78 °C for 2 hr, then allowed to warm to room temperature
and stirred
overnight. The reaction was then quenched with aqueous saturated NH4C1,
extracted
with ethyl acetate, dried, and purified by silica gel chromatography
(hexanes/ethyl
acetate) to afford N hexanoyl-4-(,S~-benzyloxazolidin-2-one.
Step 2
To a solution of N hexanoyl-4-(S~-benzyloxazolidin-2-one (7.3 mmol) in THF
at -78°C was added 1.0 M sodium hexamethyldisilazide (NaHMDS, 8.8 mmol)
and
the reaction stirred at -78°C for 1 hr. A solution of methyl
bromoacetate (8.8 mmol)
in THF was then added dropwise, and the resulting mixture was stirred at -
78°C for 1
hr and then at room temperature overnight. The reaction was quenched with
NH4C1,
concentrated, then suspended in ethyl acetate and washed with 0.5 N HCl and
brine,
dried, and purified by silica gel chromatography (ethyl acetate/hexanes) to
afford the
methyl 3-(R)-(n-butyl)-3-[4-(,S~-benzyloxazolidin-2-one-3-
ylcarbonyl)propionate.
Step 3
To methyl 3-(R)-(n-butyl)-3-[4-(S~-benzyloxazolidin-2-one-3-ylcarbonyl)-
propionate (1.44 mmol) in THF/water at 0°C was added 30% HZOZ (5.76
mmol) and
solid lithium hydroxide (1.44 mmol) and the reaction stirred at 0°C for
3 hr. The
reaction was then quenched with 2.0 M NaZS03, concentrated, suspended in ethyl
acetate and subjected to standard aqueous workup. The crude product was
purified by
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silica gel chromatography (methanol/dichloromethane) to afford methyl 3-(R)-(n-
butyl)-propionate.
Step 4
To Boc-L-prolinol (1 mmol) (Advanced Chemtech, Louisville, KY) in THF at
0°C was added mesitylenesulfonylchloride (MsCI, 1.2 mmol) and DIEA (1.5
mmol)
and the solution allowed to warm to rt, then stirred an additional hour. Solid
sodium
azide was added (1.5 mmol) and the reaction was allowed to stir overnight.
Conventional aqueous workup followed by silica gel chromatography afforded the
N-
Boc-(,S~-(2-azidomethyl)pyrrolidine.
Step 5
A solution of the N-Boc-(S~-(2-azidomethyl)pyrrolidine in ethylacetate was
added to 10% Pd/C and the reaction evacuated and flushed with hydrogen gas
three
times. The reaction was then stirred under a hydrogen atmosphere overnight,
then
filtered through a pad of celite and concentrated to dryness. The resulting
amine was
dissolved in DMF and then acylated with acetic anhydride to afford the N-Boc-
(,S~-(2-
acetamidomethyl)pyrrolidine. The Boc group was deprotected with 1N HC1 in
dioxane to afford the desired (S~-(2-acetamidomethyl)pyrrolidine.
Step 6
The title compound was prepared from (,S~-(2-acetamidomethyl)pyrrolidine
and methyl 3-(R)-(n-butyl)propionate according to General Procedure A.
MS (APCI) m/z = 314 [M+H].
Example 17
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(4-(R)-hydroxy-2-(,S~-tert
butoxycarbonyl)pyrrolidin-1-ylcarbonyl]propionamide
o Lo
HON N
H
O
OH
Small-scale synthesis
Step 1
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Cbz-protected traps-3-hydroxy-L-proline (20 g, 75 mmol) in DCM was
treated with 60 ml of acetic anhydride and 10 mL of pyridine. The solution was
stirred at rt for 18 hours, then the reaction was quenched with icewater,
extracted with
EtOAc (3 x 200 mL), and the organic layer washed with water, brine, and dried
over
MgSOa. Concentration in vacuo gave Cbz-protected traps-3-acetoxy-L-proline as
a
colorless oil.
Step 2
To a solution of Cbz-protected traps-3-acetoxy-L-proline (75 mmol) in dry
dioxane was added tent-butyl alcohol (14.2 mL, 150 mmol),
diisopropylcarbodiimide
(23 mL, 147 mmol), and DMAP (2.3 g) and the mixture was stirred at rt for two
days.
The reaction was concentrated to an oil and purified via silica gel
chromatography
(hexanes/ethyl acetate) to afford the desired Cbz-protected traps-3-acetoxy-L-
proline
t-butyl ester. ESMS (negative): 362 (M-1).
Step 3
To Cbz-protected traps-3-acetoxy-L-proline t butyl ester (1 mmol) in ethyl
acetate (10 mL) was added 10% Pd/C and the reaction evacuated and flushed with
hydrogen gas three times. The reaction was then stirred under a hydrogen
atmosphere
overnight, then filtered through a pad of celite and concentrated to dryness
to afford
the desired traps-3-acetoxy-L-proline t-butyl ester. MS (APCI negative) m/z
357 [M-
H]. 1H NMR (300 MHz, CD30D) A 4.0 (m, 2H), 3.75 (m, 2H), 3.10 (m, 1H), 2.85
(m, 1H), 2.40 (m, 2H), 2.2 (m, 2H), 2.0 (m, 2H), 1.65 to 1.0 (m, 15H), 0.90
(m, 3H).
Step 4
The title compound was prepared according to General Procedure A using
traps-3-acetoxy-L-proline O-t-butyl ester and methyl 3-(R)-(n-
butyl)propionate. The
final treatment with hydroxylamine removed the acetyl group from the 3-hydroxy
group of the proline.
Large-scale synthesis
Step 1
To traps-3-acetyloxy-L-proline t-butyl ester (11.8 mmol) in DCM (60 mL)
was added mono-methyl 2-(R)-butylsuccinic acid (11.2 mmol), DIEA (23.6 mmol)
and PyBOP (11.8 mmol) and the solution stirred for 16 h. The reaction was
concentrated to an oil and purified on silica gel (Merck 60;
hexanes/ethylacetate) to
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afford 2.2 g of methyl 3-(R)-(n-butyl)-3-[(4-(R)-acetoxy-2-(,S~-tert-
butoxycarbonyl)pyrrolidin-1-ylcarbonyl]propionate as a clear oil 5 (SO%).
St_ ep 2
To methyl 3-(R)-(n-butyl)-3-[(4-(R)-acetoxy-2-(,S~-tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]propionate (5.5 mmol) in methanol (25 mL) was added
water
(1 mL) and LiOH-HZO (12.1 mmol) and the solution stirred 20 h. Standard
aqueous
work-up afforded 3-(R)-(n-butyl)-3-[(4-(R)-hydroxy-2-(,S~-tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]propionic acid 2 g of a colorless oil which solidified
upon
standing (quant.).
Step 3
To a solution of 3-(R)-(n-butyl)-3-[(4-(R)-hydroxy-2-(S~-tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]propionic (5.51 mmol) in DCM (30 mL) was added O-
benzylhydroxylamine-HCL (6.06 mmol), DIEA (13.3 mmol) and PyBOP and the
solution stirred for 18 h. Standard aqueous work-up followed by silica gel
chromatography (Merck 60; ethylacetate) afforded 1.14 g of the protected N-
benzyloxy- 3-(R)-(n-butyl)-3-[(4-(R)-hydroxy-2-(,S~-tert-
butoxycarbonyl)pyrrolidin-1-
ylcarbonyl]propionamide as a white gum (45%). This was dissolved in
ethylacetate
(50 mL), 5% Pd/C was added (110 mg), and a hydrogen atmosphere introduced.
After 16 h the reaction was filtered through celite and concentrated to afford
810 mg
of the title compound as a white foam (89%).
Example 18
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(4-(,S~-hydroxy-2-(,S~-tert
butoxycarbonyl)pyrrolidin-1-ylcarbonyl]propionamide
0
0
HON
H
O
OH
To methyl 3-(R)-(n-butyl)-3-[(4-(R)-hydroxy-2-(,S~-tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]propionate (prepared by General Procedure A, omitting
the
final treatment with NHZOH) in THF was added chloroacetic acid, TPP and DIAD
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and the reaction stirred 18 h. The chloroacetate ester was purified on silica
gel
(Merck 60; hexanes/ethylacetate), dissolved in dioxane and then treated with
aqueous
50% hydroxylamine. The reaction mixture was purified by preparative reverse-
phase
(C18) HPLC to afford the title compound. MS (APCI negative) m/z 357 [M-H].
Example 19
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(4-(R)-methoxy-2-(S~-tert
butoxycarbonyl)pyrrolidin-1-ylcarbonyl]propionamide
o~~
'/~\0
HON N
H
O
OCH3
To methyl 3-(R)-(n-butyl)-3-[(4-(R)-hydroxy-2-(,S~-tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]propionate in THF at 0 °C was added sodium
hydride (60%
dispersion in mineral oil) and the mixture stirred for 1 h. Iodomethane was
added,
and the reaction allowed to wam to rt and then stirred an additional 2 h.
Standard
aqueous work-up followed by purification on silica gel afforded the
penultimate
methyl ester. This was dissolved in dioxane and then treated with aqueous 50%
hydroxylamine for 48 h. The reaction mixture was purified by preparative
reverse-
phase (C18) HPLC to afford the title compound. MS (APCI negative) m/z 371 [M-
H].
Example 20
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[3-(R,S~-(tert-butoxycarbonyl-
amino)pyrrolidin-1-ylcarbonyl]propionamide
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H ~~ H
O
The title compound was prepared according to General Procedure B from (~)-
3-(N-Boc-amino)pyrrolidine (obtained from TCI America, Portland, Oregon) and
mono-4-methyl 2-(R)-butylsuccinic acid. MS (APCI) m/z 358[M+H].
Example 21
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-(tert-
butoxycarbonyl)pyrrolidin-1
ylcarbonyl]-2-(,S~-hydroxypropionamide
0
o ~o~
HON
H
OH
The title compound was prepared according to General Procedure F or I . 1H
NMR (300 MHz, CDC13): 8 0.93 (t, J= 7.5 Hz, 3 H), 1.31-1.49 (m, 4H), 1.44 (s,
9H),
1.76-2.23 (m, 6H), 3.23 (dt, J=2.5 and 7.5 Hz, 1 H), 3.67-3.77 (m, 1 H), 3.55-
3.64 (m,
1H), 4.26 (d, J=2.5 Hz, 1H), 4.32 (dd, J=4.2 and 8.7 Hz, 1 H). ES-MS: calcd.
For
C,~H3oNz06(358.43); found: 359 [M+1].
1 S Example 22
Synthesis ofN hydroxy-3-(R)-(n-butyl)-3-[2-(S~-(methylaminocarbonyl)pyrrolidin-
1
ylcarbonyl]-2-(S~-hydroxypropionamide
~H3
O
H OH O
The title compound was prepared according to General Procedure C from
methylamine. MS (APCI negative) m/z 314 [M-H].
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Example 23
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-
(dimethylaminocarbonyl)pyrrolidin
1-ylcarbonylJ-2-(,S~-hydroxypropionamide
~~CH3
H II
OH O
The title compound was prepared according to General Procedure C from
N,N-dimethylamine. MS (APCI negative) m/z 328 [M-H].
Example 24
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(tert-
butylaminocarbonyl)pyrrolidin-
1-ylcarbonyl]-2-(S~-hydroxypropionamide
H
O
H
OH
The title compound was prepared according to General Procedure C from t-
butylamine. MS (APCI negative) m/z 356 [M-H].
Example 25
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(morpholin-4-
ylcarbonyl)pyrrolidin-
1-ylcarbonyl]-2-(S~-hydroxypropionamide
i
H0.
H
OH O
The title compound was prepared according to General Procedure C from
morpholine. MS (APCI negative) m/z 370 [M-H].
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Example 26
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[3-(R,S~-(acetylamino)pyrrolidin-1-yl
carbonyl]propionamide
H0.H ~~NHCOCH3
0
To methyl 3-(R)-(n-butyl)-3-[3-(R,S~-(tert-butoxycarbonylamino)pyrrolidin-1-
ylcarbonyl]propionate, prepared from (t)-3-(N-Boc-amino)pyrrolidine (TCI
America,
Portland, Oregon) and mono-4-methyl 2-(R)-butylsuccinic acid, was added 4 N
HCl
in dioxane and the solution stirred for 4 h. The solution was evaporated to
dryness,
dissolved in dioxane, and then treated with acetic anhydride and pyridine and
stirred
for 2 h. Aqueous 50% hydroxylamine was added and the solution stirred for 2 d.
The
crude reaction mixture was purified by preparative reverse-phase (C18) HPLC to
afford the title compound. MS (APCI negative) m/z 298 [M-H].
Example 27
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[3-(R,S~-(2-phenylethylcarbonylamino)
pyrrolidin-1-ylcarbonyl]propionamide
H0.H ~NH
o ~ ~
O
To methyl 3-(R)-(n-butyl)-3-[3-(RSV-(tert-butoxycarbonylamino)pyrrolidin-1-
ylcarbonyl]propionate, prepared from (t)-3-(N-Boc-amino)pyrrolidine and mono-4-
methyl 2-(R)-butylsuccinic acid, was added 4 N HCl in dioxane and the solution
stirred for 4 h. The solution was evaporated to dryness, dissolved in dioxane,
and
then treated with 3-phenylpropionic acid, DIEA, and HATU and stirred for 2 h.
Aqueous 50% hydroxylamine was added and the solution stirred for 2 d. The
crude
reaction mixture was purified by preparative reverse-phase (C 18) HPLC to
afford the
title compound.
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Example 28
Synthesis ofN hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(methoxycarbonyl)pyrrolidin-1
ylcarbonyl]-2-(,S~-methylpropionamide
o C02CH3
HON
H
CH3
Step 1
To mono t-butyl 2-(R)-(n-butyl)succinic acid (2.0 g, 8.70 mmol; prepared in
three steps from hexanoylchloride using the procedure of Example 16, Step A
for the
synthesis of monomethyl-2-R-butylsuccinic acid, with substitution of t-butyl
bromoacetate for methyl bromoacetate) in anhydrous THF (40 mL) at -78
°C was
added LDA (2.2 eq., 19.1 mmol, 9.56 ml of a 2.0 M solution in THF/hexane/ethyl-
benzene) and the reaction stirred for 1 h. Iodomethane (11.3 mmol, 1.6 g) was
then
added and the reaction allowed to warm to room temperature over 2 h. The
solution
was quenched with methanol (ca. 5 mL), evaporated to dryness, and the residue
dissolved in ethylacetate (50 mL). This solution was extracted with saturated
sodium
bicarbonate (3 x 30 mL), the combined aqueous layers acidified to pH 3 with 1
N
HCI, and these were extracted with ethylacetate (3 x 50 mL). The combined
organic
layers were dried (NaZS04), concentrated, and purified by silica gel
chromatography
(Merck 60; 95:5 DCM/methanol) to afford mono t-butyl 2-(R)-(n-butyl)-3-(R,S~-
methylsuccinic acid as a light orange oil (1.25 g). The ratio of R/S
diastereomers was
> 6:1.
Step 2
An aliquot of mono t-butyl 2-(R)-(n-butyl)-3-(R,S~-methylsuccinic acid (1.0 g,
4.10 mmol) was epimerized by first dissolving it in THF (22 mL), cooling to -
78 °C
and then adding LDA (9.02 mmol, 4.52 mL of a 2.0 M solution). The solution was
allowed to warm to rt over 2 hours, then cooled back down to -78 °C and
quenched
with methanol (1.7 mL). This epimerization procedure was repeated once more,
then
an aqueous work-up was performed as described above to afford 700 mg of mono t-
butyl 2-(R)-(n-butyl)-3-(RSV-methylsuccinic acid. 'H NMR analysis of this
product
suggested approximately 2:1 ratio of R/S diastereomers.
Step 3
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To mono t-butyl 2-(R)-(n-butyl)-3-(R,S~-methylsuccinic acid (680 mg, 1.39
mmol, prepared in step 2 above) in DCM (15 mL) was added L-proline methyl
ester
hydrochloride (3.34 mmol, 554 mg), DIEA (1.28 mL, 7.34 mmol) and then PyBOP
(1.74 g, 3.34 mmol). The reaction was stirred for 16 h, concentrated to
dryness, and
then purified via silica gel chromotography (1:1 hexanes/ethylacetate) to
afford mono
t-butyl 3-(R)-(n-butyl)-3-[2-(S~-methoxycarbonyl)pyrrolidin-1-ylcarbonyl]-2-
(,S~-
methylpropionate (260 mg).
Step 4
The t-butyl group was removed from mono t-butyl 3-(R)-(n-butyl)-3-[2-(,S~-
methoxycarbonyl)pyrrolidin-1-ylcarbonyl]-2-(,S~-methylpropionate (260 mg, 732
pmol) using 1:2 TFA/DCM, followed by evaporation of the TFA and solvent. To
the
resulting product in DCM (5 mL) at 0 °C was added O-benzylhydroxylamine
hydrochloride (129 mg, 805 ~mol), HOBt (112 mg, 732 pmol), DIEA (708 ~L, 1.61
mmol) and then solid EDC (154 mg, 805 ~mol) and the reaction allowed to warm
to rt
and then stirred overnight. The reaction was evaporated to dryness, and
purified on a
silica gel column (1:1 hexanes/ethylacetate) to afford N benzyloxy-3-(R)-(n-
butyl)-3-
[2-(,S~-methoxycarbonyl)pyrrolidin-1-ylcarbonyl]-2-(S~-methylpropionamide as a
colorless glass (212 mg).
Step 5
To N benzyloxy- 3-(R)-(n-butyl)-3-[2-(S~-methoxycarbonyl)pyrrolidin-1-
ylcarbonyl]-2-(S~-methylpropionamide (40 mg) in methanol (3 mL) was added 10%
Pd/C (10 mg). The reaction was evacuated briefly under high-vacuum, and the
atmosphere replaced with 1 atm hydrogen gas (balloon). This procedure was
repeated
twice more, then the suspension was stirred under HZ gas for 3 h. The reaction
was
then filtered through a plug of celite to afford the title compound as a
clear, colorless
gum (31 mg). MS (APCI) m/z 315 [M+H].
Example 29
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Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-(3-trifluoromethylbenzylamino
carbonyl)pyrrolidin-1-ylcarbonyl]propionamide
~3
H
G
" d
The title compound was prepared according to General Procedure D from L-
proline-(4-trifluoromethyl)benzylamide. MS (APCI) m/z 444 [M+H].
Example 30
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(.S~-
(cyclohexylmethylaminocarbonyl)
pyrrolidin-1-ylcarbonyl]propionamide
- H/
G
HOw
H
V
The title compound was prepared according to General Procedure A from
mono-methyl 2-(R)-butylsuccinic acid and L-proline-(cyclohexyl)methylamide. MS
(APCI) m/z 382 [M+H].
Exam 1p a 31
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[3-(RSV-((4-trifluoromethylbenzyl)
aminocarbonyl)piperidin-1-ylcarbonyl]propionamide
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The title compound was prepared according to General Procedure A from
mono-methyl 2-(R)-butylsuccinic acid and (t)-3-carboxypiperidine-(4-trifluoro-
methylbenzyl)amide. MS (APCI) m/z 458 [M+H].
Example 32
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(S~-(hydroxymethyl)
pyrrolidin-1-ylcarbonyl]propionamide
H
H
The title compound was prepared according to General Procedure A from
mono-methyl 2-(R)-butylsuccinic acid and L-prolinol. MS (A.PCI) m/z 273[M+H].
Example 33
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(S~-(pyrrolidin-1-ylmethyl)
pyrrolidin-1-ylcarbonyl]propionamide
H0.
H
O
The title compound was prepared according to General Procedure A from
mono-methyl 2-(R)-butylsuccinic acid and (,S~-2-(N pyrrolidinylmethyl)-
pyrrolidine.
MS (APCI) m/z 326 [M+H].
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Example 34
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[4-(S)-(phenylsulfonamido)-2-(,S~
(tent-butyloxycarbonyl)pyrrolidin-1-ylcarbonyl]propionamide
o COZ-t-butyl
HON
H O _
1l
. ~~NHS
O
Step 1
To mono methyl 3-(R)-(n-butyl)-3-[2-(,S~-tert-butoxycarbonyl)-4-(R)-
hydroxypyrrolidin-1-ylcarbonyl]propionate (1.4g, 3.92 mmol; prepared according
to
General Procedure A from methyl 2-(R)-butylsuccinic acid and traps-L-hydroxy-
proline tert-butyl ester) in DCM at -20°C was slowly added
methanesulfonyl chloride
(MeSOZCI) (0.62mL, 7.84 mmol) and the reaction stirred 4 h. DCM was removed in
vacuo, and the residue was dissolved in EtOAc (100 mL), washed with saturated
NaHC03, dilute HCl (5%) and brine and then dried (MgS04). Concentration in
vacuo
afforded methyl 3-(R)-(n-butyl)-3-[2-(,S~-tert-butoxycarbonyl)-4-(R)-mesyloxy-
pyrrolidin-1-ylcarbonyl]propionate which was used directly without further
purification.
Step 2
To methyl 3-(R)-(n-butyl)-3-[2-(,S~-tert-butoxycarbonyl)-4-(R)-mesyloxy-
pyrrolidin-1-ylcarbonyl]propionate in DMF (30 mL) was added NaN3 (2.6g) and
the
resulting solution heated at 65°C for 48. The DMF was removed in vacuo
and the
residue was purified by silica gel column chromatography to afford 1.3 gram of
the
desired methyl 3-(R)-(n-butyl)-3-[2-(S~-tert-butoxycarbonyl)-4-(S~-azido-
pyrrolidin-
1-ylcarbonyl]propionate.
Step 3
Methyl 3-(R)-(n-butyl)-3-[2-(S~-tert-butoxycarbonyl)-4-(S~-azido-pyrrolidin-
1-ylcarbonyl]propionate (1.3 g, 3.4 mmol) was hydrogenated at rt with Pd-C
(10%)
for 18 h. The reaction was filtered through a pad of celite, and washed with
EtOAc.
Concentration of the filtrate yielded 1.2 g of methyl 3-(R)-(n-butyl)-3-[2-(S~-
tert-
butoxycarbonyl)-4-(,S~-aminopyrrolidin-1-ylcarbonyl]propionate.
Step 4
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Phenylsulfonyl chloride (2 eq.) was added slowly to a solution of methyl 3-
(R)-(n-butyl)-3-[2-(S~-tert-butoxycarbonyl)-4-(S~-azido-pyrrolidin-1-
ylcarbonyl]-
propionate (ca. 0.1 g) in DCM (1mL) and pyridine (0.1 mL) at 0 °C. The
solution
was allowed to warm to rt and then stirred an additional 2 h. The solvent was
removed in vacuo, the residue dissolved in EtOAc (5 mL) and washed with HCl
solution (S%), NaHC03 (sat.) and brine. Concentration in vacuo gave the crude
methyl 3-(R)-(n-butyl)-3-[2-(~-tert-butoxycarbonyl)-4-(S~-phenylsulfonamido-
pyrrolidin-1-ylcarbonyl]propionate which was directly converted to the
corresponding
hydroxamate by treatment with aqueous 50% NHZOH (1 mL) and dioxane (2 mL) at
rt for 3 days. The final product N hydroxy-3-(R)-(n-butyl)-3-[4-(S)-
(phenylsulfonamido)-2-(,S~-(tert-butyloxycarbonyl)pyrrolidin-1-ylcarbonyl]-
propionamide was purified by preparative HPLC. 'H NMR (CD30D): 8 7.90 (m,
2H), 7.60 (m, 3H), 4.15(t, J=7.9 Hz, 1H), 4.0 (m, 1H), 3.90 (m, 1H), 3.25(m,
1H),
2.90 (m, 1H), 2.35 (m, 2H), 2.15 (m, 3H), 1.75(m, 1H), 1.60 to 1.20 (m, 13H),
0.90
ppm (s, 3H); MS (APCI negative) m/z 496 [M-1].
Example 35
Synthesis of N hydroxy-3-(R)-(n-pentyl)-3-[(2-(,S~-(tert-butoxycarbonyl)
pyrrolidin-1-ylcarbonyl]propionamide
The title compound was prepared according to General Procedure A from
mono-methyl 2-(R)-pentylsuccinic acid and L-proline t-butyl ester. MS (APCI)
m/z
357 [M+H].
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Example 36
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)
pyrrolidin-1-ylcarbonyl]-2-(,S~-methoxypropionamide
o COz-t-butyl
HON
H
O
H3C~0
Step 1
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S~-tert-
butoxycarbonylpyrrolidin-1-ylcarbonyl)pentane (4 mmol; prepared as described
previously using, tent-butyl ester of compound F-6, General Procedure F) in
methanol
(20 mL) was added 1 m MeONa ( 1 ml) and stirred for 1 h. The reaction was
neutralized with H+ resin , filtered, and the filtrate was concentrated to
dryness.
The residue purified on silica gel to afford methyl 3-(R)-(n-butyl)-3-[(2-(S~-
(tert-
butoxycarbonyl)-pyrrolidin-1-ylcarbonyl]-2-(S~-hydroxypropionate.
Step 2
To a solution of methyl 3-(R)-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]-2-(,S~-hydroxypropionate (1 mmol) in DMF (10 ml) was
added NaH. After 30 minutes, methyl iodide (3 mmol) was added and the solution
stirred an additional hour. The reaction was then diluted with ethyl acetate,
washed
with water, dried with NaZS04, filtered and concentrated. The crude methyl
ether was
dissolved in dioxane, treated with aqueous 50% hydroxylamine, and stirred for
two
days. The crude reaction mixture was purified by preparative reverse-phase
(C18)
HPLC to afford the title compound. MS (APCI negative) m/z 371 [M-H].
Example 37
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)
pyrrolidin-1-ylcarbonyl]-2-(R)-hydroxypropionamide
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o COZ-t-butyl
HON
H
OH o
To a solution of triflic anhydride (1.2 mmol) in CHZC12 (5 ml) at -
15°C was
added pyridine (2.5 mmol) followed by the addition of a solution of methyl 3-
(R)-(n-
butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)pyrrolidin-1-ylcarbonyl]-2-(~-hydroxy-
propionate (1 mmol, see Example 36 for preparation) in dichloromethane. The
reaction was allowed to warm to -5°C over 1 hour, then the solution was
washed with
aqueous 10% citric acid, water and sodium bicarbonate solutions, then dried
(Na2S04)
and concentrated. This residue was dissolved in toluene (10 ml) and treated
with
tetrabutylammonium benzoate (TBAB, 2 mmol) for 1 hour. After removal of
solvent,
the residue was purified on silica gel (hexanes/ethylacetate) to afford methyl
3-(R)-(n-
butyl)-3-[(2-(S~-(tert-butoxycarbonyl)pyrrolidin-1-ylcarbonyl]-2-(R)-
benzoyloxy-
propionate. Treatment of this intermediate with aqueous hydroxylamine/dioxane
solution for 2 days, followed by purification via semi-preparative HPLC
provided title
compound. MS (APCI) m/z 359 [M+H].
Example 38
Synthesis of N hydroxy-3-(.S~-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)
pyrrolidin-1-ylcarbonyl]-2-(R)-thiolpropionamide
o cot-t-butyl
HON
H
SH o
To methyl 3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-
carbonyl]-2-(,S~-hydroxypropionate (see Example 36 for preparation) in THF is
added
triphenylphosphine (TPP), diisopropylazodicarboxylate (DIAD) and thioacetic
acid
and the solution stirred overnight. Aqueous work-up and purification on silica
gel
affords methyl 3-(S~-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)pyrrolidin-1-
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ylcarbonyl]-2-(R)-acetylthiopropionate. This compound was dissolved in
degassed
dioxane and aqueous 50% hydroxylamine, then stirred for 2 d. The crude
reaction
mixture was purified by preparative reverse-phase (C 18) HPLC to afford the
title
compound.
Example 39
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)
pyrrolidin-1-ylcarbonyl]-2-(S~-thiolpropionamide
o COZ-t-butyl
HON
H
~H o
To a solution of triflic anhydride (Tf20, 1.2 mmol) in CHZC12 (5 ml) at -
15°C
was added pyridine (2.5 mmol) followed by the addition of a solution of methyl
3-
(R)-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-carbonyl]-2-(R)-
hydroxypropionate (1 mmol, prepared as described in Example 40, below) in DCM.
The reaction was allowed to warm to -5°C over 1 hr, then the solution
was washed
with aqueous 10% citric acid, water, and sodium bicarbonate solution, then
dried
(NaZS04) and concentrated. This residue was dissolved in THF (5 ml) and
treated
with potassium thioacetate (2 mmol) for 1 h. After removal of solvent, the
residue
was purified on silica gel (hexanes/ethyl acetate) to afford methyl 3-(R)-(n-
butyl)-3-
[(2-(S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-carbonyl]-2-(.S~-
acetylthiopropionate.
Treatment of this compound with aqueous hydroxylamine/dioxane solution for 2
days, followed by purification via semi-preparative HPLC, provided the title
compound. MS(APCI) m/z 375 [M+H].
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Example 40
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]-2-(R)-methoxypropionamide
o C02-t-butyl
HON
H
O
H3C~0
Methyl 3-(R)-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-
carbonyl]-2-(R)-benzoyloxypropionate (prepared as described in Example 37) was
de-
O-benzoylated by treatment with methanolic sodium methoxide at 0°C for
2 hours.
The solution was neutralized with IR-120 (H+) resin, filtered, concentrated
and
purified on silica gel (hexanes/ethyl acetate) to afford methyl 3-(R)-(n-
butyl)-3-[(2-
(S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-carbonyl]-2-(R)-hydroxypropionate. To
a
solution of methyl 3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)pyrrolidin-
1-yl-
carbonyl]-2-(R)-hydroxypropionate in DMF at 0°C was added sodium
hydride and the
reaction stirred for 1 hour. Methyl iodide was added and the reaction stirred
for 1
hour at 0°C, then allowed to warm to rt and stirred an additional 2 h.
Conventional
aqueous workup afforded the intermediate ether, which was treated with
dioxane/aqueous hydroxylamine followed by purification via semi-preparative
HPLC
to afford the title compound. MS (APCI) m/z 373 [M+H].
Example 41
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]-2-(R)-methylthiopropionamide
o COZ-t-butyl
HON
H
O
H3C~S
To a solution of triflic anhydride (1.2 mmol) in CHzCIz (S ml) at -
15°C is
added pyridine (2.5 mmol) followed by the addition of a solution of methyl 3-
(R)-(n-
butyl)-3-[(2-(S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-carbonyl]-2-(S~-hydroxy-
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propionate (prepared as described in Example 36 above; 1 mmol) in
dichloromethane.
The solution is concentrated to dryness, dissolved in DMF and then treated
with
sodium thiomethoxide. Aqueous work-up followed by purification on silica gel
affords methyl 3-(,S~-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-
carbonyl]-2-(R)-methylthiopropionate which is dissolved in dioxane, treated
with
aqueous 50% hydroxylamine, and then stirred for 2 d. The crude reaction
mixture is
purified by preparative reverse-phase (C18) HPLC to afford title compound.
Example 42
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]-2-(,5~-methylthiopropionamide
o COZ-t-butyl
HON
H
O
H3C~S
To a solution of triflic anhydride (1.2 mmol) in CH2CI2 (5 ml) at -
15°C is
added pyridine (2.5 mmol) followed by the addition of a solution of methyl 3-
(R)-(n-
butyl)-3-[(2-(S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-carbonyl]-2-(R)-hydroxy-
propionate (prepared as described in Example 40; 1 mmol) in dichloromethane.
The
solution is concentrated to dryness, dissolved in DMF and then treated with
sodium
thiomethoxide. Aqueous work-up followed by purification on silica gel affords
methyl 3-(S~-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-
carbonyl]-2-(,S~-
methylthiopropionate which is dissolved in dioxane, treated with aqueous 50%
hydroxylamine, and then stirred for 2 d. The crude reaction mixture is
purified by
preparative reverse-phase (C 18) HPLC to afford the title compound.
Example 43
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(2-cyclohex-1-enylethyl
aminocarbonyl)pyrrolidin-1-ylcarbonyl]propionamide
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1~
"N
HON ~ H
H O
Step 1
To methyl 3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)pyrrolidin-1-yl-
carbonyl]propionate (1 mmol; prepared in one step from mono-4-methyl 2-(R)-
butylsuccinic acid and L-proline t-butyl ester) was added 1 M HCl in dioxane
(5 mL)
and the solution stirred 4 h. Conventional aqueous workup afforded methyl 3-
(R)-(n-
butyl)-3-[(2-(S~-(carboxy)pyrrolidin-1-yl-carbonyl]propionate.
Step 2
To methyl 3-(R)-(n-butyl)-3-[(2-(S~-(carboxy)pyrrolidin-1-yl-
carbonyl]propionate (0.2 mmol) in dioxane (1 mL) was added 2-(1-cyclohexenyl)-
ethyl amine (0.22 mmol), DIEA (0.22 mmol) and HATU (0.22 mmol) and the
reaction stirred for 2 h. Aqueous 50 % hydroxylamine was then added (1 mL),
and
the reaction stirred an additional 24 h. The reaction mixture was purified by
preparative reverse-phase (C18) HPLC to afford the title compound. MS (APCI)
m/z
394 [M+H].
Example 44
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[(2-(,S~-(phenylaminocarbonyl)
pyrrolidin-1-ylcarbonyl]propionamide
HO~H O N
H
The title compound was prepared as described in Example 43, above, using
aniline in place of 2-(1-cyclohexenyl)ethylamine. MS (APCI) m/z 362 [M+H].
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Example 45
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(tert-butoxycarbonyl)
pyrrolidin-1-carbonyl]-2-(R)-azidopropionamide
o C02-t-butyl
HON
H
N o
3
To a solution of methyl 3-(R)-(n-butyl)-3-[(2-(S~-(tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]-2-(,S~-hydroxypropionate (intermediate G-3 from
General
Procedure G, 2 mmol) in DCM (10 mL) was added pyridine (6 mmol), the reaction
was cooled to -20 °C, then triflic anhydride (4 mmol) was added. The
solution was
stirred for 1 hour and after the usual work-up was concentrated, resuspended
in DMF
( 10 mL), and treated with sodium azide (2.5 mmol). The reaction was stirred
for 16 h,
then diluted with ethylacetate, washed with water, saturated aqueous sodium
bicarbonate, and brine, then dried (Na2S04) and puriifed on silica gel
(ethylacetate/hexanes) to afford methyl 3-(R)-(n-butyl)-3-[(2-(S~-(tert-
butoxycarbonyl)-pyrrolidin-1-ylcarbonyl]-2-(R)-azidopropionate. To a solution
of the
azido compound (0.5 mmol) in dioxane (2 mL) was added aqueous 50
hydroxylamine (1 mL) and the reaction stirred for 48 h. The crude reaction
mixture
was then purified by preparative reverse-phase (C 18) HPLC to afford the title
compound. 'H NMR(CDC13): 8 4.28-4.24 (dd, J = 5.1 & 4.6Hz, 1H), 3.92 (d, J =
9.8
Hz,IH), 3.80-3.74 (m, 1H), 3.64-3.57 (m, 1H), 3.16-3.09 (m, 1H), 2.22-1.91 (m,
4H),
1.89-1.76 (m, 2H), 1.43 (s, 9H), 1.40-1.35 (m, 4H), 0.92 (t, J = 6.7 Hz). ES-
MS:
calcd. For C»Hz9N505 (383.3); found: 384 [M+1].
Example 46
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(tert-butoxycarbonyl)-
pyrrolidin-1-carbonyl]-2-(S~-sulfonyloxypropionamide
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o C02-t-butyl
HON
H
H03S0 0
To a solution of methyl 3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]-2-(S~-hydroxypropionate (intermediate G-3 from
General
Procedure G, 2 mmol) in DMF (10 mL) was added pyridinium sulfurtrioxide (2.2
mmol) and the solution stirred for 1 h. The reaction was diluted with
ethylacetate and
washed with saline, dried (NaZS04) and concentrated to afford methyl 3-(S~-(n-
butyl)-
3-[(2-(S~-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl]-2-(S~-
sulfonyloxypropionate.
This sulfonyloxy compound was dissolved in dioxane, treated with aqueous 50
hydroxylamine (1 mL) and the reaction stirred for 48 h. The crude reaction
mixture
was then purified by preparative reverse-phase (C 18) HPLC to afford the title
compound. 'H NMR (CDC13): 8 4.63 (m, 2H), 4.19-3.82 (m, 2H), 3.79-3.67 (m,
1H),
2.36-1.83 (m, 4H), 1.81-1.59 (2H), 1.45 (s, 9H), 1.34-1.26 (m, 2H), 0.89 (t, J
= 6.3
Hz). ES-MS: calcd. For Cl~H3pN2O9S (438.49); found: 439.2 [M+1].
Example 47
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(tert-butoxycarbonyl)
pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
HO~
O ~0~
N
H
O
The title compound was prepared by treatment of methyl 3-(S~-(n-butyl)-3-[(2-
(,S~-(tert-butoxycarbonyl)pyrrolidin-1-ylcarbonyl]-2-(S~-fluoropropionate
(intermediate H-4, General Procedure H), with aqueous 50 % hydroxylamine
followed by purification on preparative reverse-phase (C18) HPLC. 'H NMR
(CDCl3) 8 5.16-4.98 (dd, JH2,3 = 6.8 Hz & ~H,F= 47 Hz, 1H), 4.39-4.35 (dd, J =
4.4 &
3.8 Hz, 1H), 3.78 (m, 1H), 3.66-3.61 (m, 1H), 3.31-3.22 (m, 1H), 2.24-1.91 (m,
4H),
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1.77-1.70 (m, 2H), 1.44 (s, 9H), 1.40-1.23 (m, 4H), 0.89 (t, J = 6.9 & 7.2
Hz). ES-
MS: calcd. For C,7H29FN205 (360.42); found: 361 [M+1].
Example 48
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-(tert-butoxycarbonyl)-
pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
O
HO~
N
H F O
The title compound was prepared by treatment of methyl 3-(,S~-(n-butyl)-3-[(2-
(,S~-(tert-butoxycarbonyl)pyrrolidin-1-ylcarbonyl]-2-(R)-fluoropropionate
(intermediate G-4, General Procedure G), with aqueous 50 % hydroxylamine
followed by purification on preparative reverse-phase (C18) HPLC. 1H NMR
(CDC13): 8 5.32-5.13 (dd, JH2,3 = 8.3 Hz & JH,F = 48 Hz, 1H), 4.54-4.51 (t, J
= 4.1 Hz,
1 H), 3.93-3.87 (m, 1 H), 3.84-3.77 (m, 1 H), 3.45-3.40 (m, 1 H), 2.43-2.11
(m, 4H),
2.10-1.95 (m, 2H), 1.63 (s, 9H), 1.58-1.52 (m, 4H), 1.10 (t, J = 6.6 & 7.1 Hz,
3H).
ES-MS: calcd. For C,~HZ9FNz05 (360.42); found: 361 [M+1].
Example 49
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(tert-butoxycarbonyl)-
pyrrolidin-1-carbonyl]-2-oxopropionamide
o C02-t-butyl
HON
O O
To a solution of methyl 3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)-
pyrrolidin-1-ylcarbonyl]-2-(,S~-hydroxypropionate (intermediate G-3 from
General
Procedure G, 2 mmol) in DCM (10 mL) at 0 °C was added pyridinium
dichromate
(2.2 mmol) and the solution stirred for 2h. The reaction was quenched with
methanol,
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then diluted with ethylacetate and washed with water, aqueous bicarbonate, and
brine,
then dried (NazS04) and puriifed on silica gel (ethylacetate/hexanes) to
afford methyl
3-(R)-(n-butyl)-3-[(2-(,S~-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl]-2-
oxo-
propionate. To a solution of the 2-oxo intermediate (0.5 mmol) in dioxane (2
mL)
was added aqueous 50 % hydroxylamine (1 mL) and the reaction stirred for 48 h.
The
crude reaction mixture was then purified by preparative reverse-phase (C18)
HPLC to
afford the title compound. 1H NMR (CDC13): b 4.41-4.39 (dd, J = 4.4 Hz), 4.29-
4.24
(m, 1 H), 3.99-3.96 (m, 1 H), 3.70-3.67 (m, 1 H), 2.29-1.97 (m, 4H), 1.79-1.77
(m, 2H),
1.43 (s, 9H), 1.37-1.35 (m, 4H), 0.91 (t, J = 6.7 & 7.1 Hz, 3H). ES-MS: calcd.
For
C»HZ8N206(356.41); found: 357.4 [M+1].
Example 50
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(n-butylaminocarbonyl)
pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
i
J~~
HO~
The title compound was prepared according to General Procedure G from n-
butylamine. 1H NMR (CDC13): 8 7.07 (t, J = 5.2 & 5.5Hz, 1H), 5.13 (dd, Ji-
,2,3= 8.5
Hz &. JH,F = 47 Hz, 1H), 4.48-4.46 (dd, J = 4.9 Hz, 1H), 3.68-3.55 (m, 2H),
3.25-3.16
(m, 3H), 2.23-2.18 (m, 2H), 2.15-2.09 (m,4H), 2.06-1.80(m,4H), 1.52-
1.43(m,4H),
1.32(t,J=7.5Hz,3H), 0.90(t,J=6.6&7.2Hz). ES-MS: cfalcd. For Cl~H3oFN304
(359.44); found: 360.3 [M+1], 382.4 [M+Na].
Example 51
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(S~-(benzylaminocarbonyl)
pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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. ovN w
H0.N
H F
The title compound was prepared according to General Procedure G from
benzylamine. 'H NMR (CDC13): b 7.47-7.40 (m, 5H), 4.66-4.60 (dd, J = 5.1 Hz &
47
Hz, 1H), 4.58-4.45 (m, 1H), 3.97-3.76 (m, 4H), 3.35-3.28 (m, 1H), 2.31-1.94
(m, 6H),
1.61-1.45 (m, 4H), 1.07 (t, J = 6.6 Hz, 3H). ES-MS: calcd. For C,~HZgFN304
(393.45); found: 394.3 [M+1], 416.2 [M+Na].
Example 52
Synthesis ofN hydroxy-3-(S~-(n-butyl)-3-[2-(S~-(1,1-dimethylpropylamino
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
HO~
Q H
wN~~
N
H
F O
The title compound was prepared according to General Procedure G from 1,1-
dimethylpropylamine. 'H NMR (CDC13): 8 5.34-5.16 (dd, J = 7.9 & 8.3 Hz, JH,F =
47
Hz), 4.61 (d, J = 4.6 Hz), 3.80-3.78 (m, 2H), 3.40-3.35 (m, 1H), 2.39-1.84 (m,
8H),
1.53-1.44 (m, 10H), 1.09 (t, J = 6.8 Hz, 3H), 1.01 (t, J = 7.7 Hz, 3H). ES-MS:
calcd.
For C~gH32FN304 (373.46); found: 374.4 [M+1], 396.2 [M+Na].
Example 53
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(2-cyclohex-1-enylethylamino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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~H
H
The title compound was prepared according to General Procedure G from 2-
(1-cyclohexenyl)ethylamine. 1H NMR (CDC13): 8 7.11 (t, J = 4.6 & 5.2 Hz, 1H),
5.62 (bs, 1 H), 5.32-5.13 (dd, J = 9.3 & 9.6 Hz, JH,F = 47 Hz, 1 H), 4.64-4.63
(m, 1 H),
3.81-3.73 (m, 2H), 3.59-3.52 (m, 1H), 3.50-3.37 (m, 3H), 2.31-2.16 (m, 9H),
2.10-
1.99 (m, 2H), 1.79-1.52 (m, 9H), 1.09 (t, J = 6.5 & S.SHz). ES-MS: calcd. For
CZ~H3qFN3O4(411.51); found: 412.4[M+1], 434.5 [M+Na].
Example 54
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(indan-5-ylamino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
H
O\ /
HO~
N
H F
The title compound was prepared according to General Procedure G from 5-
aminoindan. 'H NMR (CDCl3): 8 7.52 (s,lH), 7.35 (d, J = 8 Hz, 1H), 7.21 (d, J
= 8
Hz, 1H), 5.34-5.15 (dd, J =8.2 & 8.5 Hz, JH,F = 47 Hz, 1H), 4.86-4.84 (m, 1H),
3.80-
3.78 (m, 2H), 3.36-3.31 (m, 1H), 3.06-2.96 (m, 4H), 2.41-1.97 (m, 8H), 1.58-
1.48 (m,
4H), 1.04 (t, J = 6.6 & 7.2 Hz, 3H). ES-MS: calcd. For CZZH3oFN3O4 (419.49);
found: 420.3 [M+1].
Example 55
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-(4,5-dimethylthiazol-2-
ylamino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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_I
N
HO~
The title compound was prepared according to General Procedure G from 2-
amino-4,5-dimethylthiazole. 1H NMR (CDCl3): 8 5.32-5.13 (dd, J = 8.3 & 7.9 Hz,
JH,F = 47 Hz, 1H), 4.83-4.80 (m, 1H), 3.97-3.85 (m, 2H), 3.40-3.38 (m, 1H),
2.51 (s,
3H), 2.50 (s, 3H), 2.33-2.21 (m, 4H), 2.18-1.95 (m, 2H), 1.59-1.49 (m, 4H),
1.07 (t, J
= 6.6 & 7.2 Hz, 3H). ES-MS: calcd. For C,gH27FN4O4S (414.50); found: 415.4
[M+1], 437.3 [M+Na].
Example 56
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(S~-(4-phenoxyphenyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
H
OPh
HO~
The title compound was prepared according to General Procedure G from 4-
phenoxyaniline. 1H NMR (CDCl3): b 7.69-7.16 (m, 2H), 7.53-7.46 (m, 2H), 7.29-
7.24 (m, 1 H), 7.18-7.06 (m, 4H), 5.37-5.20 (dd, J = 7.8 Hz, J~.~,F = 47 Hz, 1
H), 4.90-
4.85 (m, 1H), 3.92-3.82 (m, 2H), 3.33-3.37 (m, 1H), 2.47-2.36 (m, 2H), 2.30-
2.00 (m,
4H), 1.50-1.13 (m, 4H), 1.02 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For
CzsH3oFN3~s (471.52); found: 472.4 (M+1].
Example 57
Synthesis of N hydroxy-3-(.S~-(n-butyl)-3-[2-(S~-(cyclopropylmethylamino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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H0~
H
The title compound was prepared according to General Procedure G from
(aminomethyl)cyclopropane. 'H NMR (CDC13): 8 6.90 (t, J = 5.2 Hz, 1H), 4.99-
4.82
(dd, J = 6.4 & 8 Hz, JH,F = 49.8 & 48.6 Hz,lH), 4.34-4.32 (m, 1H), 3.56-3.47
(m, 2H),
3.09-2.85 (m, 3H), 2.09-1.83 (m, 4H), 1.67-1.64 (m, 2H), 1.30-1.11 (m, 5H),
0.72 (t, J
= 6.9 & 7.1 Hz, 3H), 0.33-0.29 (dd, J = 5.3 Hz, 2H), 0.05-0.00 (dd, J = 4.6
Hz, 2H).
ES-MS: calcd. For CI~HZgFN304 (357.42); found: 358.4 [M+1].
Example 58
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-(pyridin-3-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
J /
~J
HON N
H
The title compound was prepared according to General Procedure G from 3-
aminopyridine. 'H NMR (DMSO-D6): 8 9.15 (s, 1H), 8.62 (d, J = 4.2 Hz, 1H),
8.42
(d, J = 8.2 Hz, 1H), 7.88-7.83 (dd, J = 5.3 & 4.9 Hz, 1H), 5.09-4.91 (dd, J =
8 Hz, JH,H
= 48.6 Hz, 1H), 4.60-4.56 (dd, J = 4.8 Hz, 1H), 3.92-3.89 (m, 1H), 3.87-3.79
(m, 1H),
3.42-3.35 (m, 1H), 2.37-2.04 (m, 4H), 1.81-1.51 (m, 2H), 1.50-1.39 (m, 4H),
1.04 (t, J
= 6.9 & 7.2 Hz, 3H). ES-MS: calcd. For C~gH25FN404 (380.41); found: 381.3
[M+1].
Example 59
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((pyridin-4-ylmethyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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HO~
N
H
F
The title compound was prepared according to General Procedure G from 4-
(aminomethyl)pyridine. 1H NMR (DMSO-D6): 8 8.94-8.86 (m, 3H), 7.94-7.93 (m,
1 H), 5.14-4.95 (dd, J = 7.7 Hz, JH,F = 48.4 Hz, 1 H), 4.68-4.67 (m, 1 H),
4.51-4.47 (m,
1H), 3.95-3.75 (m, 3H), 3.38-3.35 (m, 1H), 2.33-2.01 (m, 4H), 1.99-1.79 (m,
2H),
1.41-1.38 (m, 4H), 0.92 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For
C19H27FN4Oq
(394.44); found: 395.4 [M+1].
Example 60
Synthesis of N hydroxy-3-(.S~-(n-butyl)-3-[2-(,S~-(morpholin-4-
ylcarbonyl)pyrrolidin-
1-carbonyl]-2-(R)-fluoropropionamide
.a
The title compound was prepared according to General Procedure G from
morpholine. ~H NMR (CDCl3): 8 5.30-5.11 (dd, J = 8.2 Hz, JH,F = 47.6 Hz, 1H),
5.06-5.04 (t, J = 3.6 & 4.4 Hz, 1H), 3.92-3.67 (m, l OH), 3.44-3.42 (m, 1H),
2.40-1.98
(m, 6H), 1.74-1.52 (m, 4H), 1.10 (t, J = 6.8 & 7.4 Hz, 3H). ES-MS: calcd. For
C»Hz8FN305 (373.42); found: 374.3[M+1].
Exam 1p a 61
Synthesis of N-hydroxy-3-(S~-(n-butyl)-3-[2-(S~-(3,4-methylenedioxyphenyl-
aminocarbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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Q H
-\vN /
O
H0.N
H F
The title compound was prepared according to General Procedure G from 3,4-
(methylenedioxy)aniline. 'H NMR (CDC13): 8 7.47 (s, 1H), 7.34 (d, J = 2Hz,
1H),
6.99-6.95 (dd, J = 2Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 6.08 (s, 2H), 5.36-
5.17 (dd, J =
8.5 & 8.8 Hz, JH,F = 47 Hz, 1 H), 4. 82-4.81 (dd, J = 4.4 Hz, 1 H), 3.84-3.80
(m, 2H),
3.38-3.33 (m, 1H), 2.40-1.97 (m, 6H), 1.57-1.52 (m, 4H), 1.059 (t, J = 6.9 &
7.1 Hz,
3H). ES-MS: calcd. For CZOH26FN306(423.44); found: 424.3 [M+1].
Example 62
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(quinolin-3-ylamino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
H
~vN ~ \ \
HO~ ~ N
The title compound was prepared according to General Procedure G from 3-
aminoquinoline. 'H NMR (CDC13): 8 9.32 (s,lH), 8.31 (d, J = 8.8 Hz, 1H), 8.03-
7.81
(m, 3H), 7.48-7.46 (m, 2H), 5.35-5.17 (dd, J = 7.7 & 8 Hz, JrI,F = 47 Hz, 1H),
4.89-
4.85 (m, 1H), 3.90-3.85 (m, 2H), 3.45-3.37 (m, 1H), 2.41-2.02( m, SH), 1.67-
1.52 (m,
SH), 1.10 (t, J = 6.9 & 5.7 Hz, 3H). ES-MS: calcd. For CZZH27FNqO4 (430.47);
found: 431.3 [M+1].
Example 63
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-(methylaminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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i
The title compound was prepared according to General Procedure G from
methylamine. 'H NMR (CDC13): b 7.30 (d, J = 5.6 Hz, 1H), 5.30-5.12 (dd, J =
7.9 &
8.8 Hz, JH,F = 47 Hz, 1H), 3.84-3.82 (m, 2H), 3.41-3.39 (m, 1H), 2.95 (s, 3H),
2.32-
1.99 (m, 6H), 1.63-1.51 (m, 4H), 1.09 (t, J = 6.4 & 4.9 Hz, 3H). ES-MS: calcd.
For
C~aHzaFN3~a (317.36); found 318.3 [M+1].
Example 64
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(S~-((4-biphenyl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
H
o~ / I
H°~ I
The title compound was prepared according to General Procedure G from 4-
phenylaniline. 'H NMR (CDCl3): 8 7.75-7.46 (m, 10H), 5.39-5.21 (dd, J = 8.8
Hz,
JH,F = 47 Hz, 1H), 4.91-4.89 (m, 1H), 3.85-3.83 (m, 2H), 3.41-3.36 (m, 1H),
2.45-2.02
(m, 6H), 1.63-1.50 (m, 4H), 1.06 (t, J = 6.6 & 7.4 Hz, 3H). ES-MS: calcd. For
CZSH3oFN30a(455.52); found456.3 [M+1].
Example 65
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[(2-(,S~-((3-
phenoxyphenyl)aminocarbonyl)
pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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i
HO~
OPh
The title compound was prepared according to General Procedure G from 3-
phenoxyaniline. 1H NMR (CDC13): 8 7.53-7.46 (m, 4H), 7.35-7.25 (m, 3H), 7.18-
7.14 (m, 2H), 6.85-6.18 (m, 1H), 5.35-5.16 (dd, J = 8.8 Hz, JH,F = 47 Hz, 1H),
4.84-
4.82 (m, 1H), 3.81-3.78 (m, 2H), 3.36-3.31 (m, 1H), 2.41-1.97 (m, 6H), 1.53-
1.46 (m,
4H), 1.02 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C25H3oFN305 (471.52);
found
472.4 [M+1].
Example 66
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((3,4-dichlorophenyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
i
ci
i
Ho~ ~ ci
is
The title compound was prepared according to General Procedure G from 3,4-
dichloroaniline. 1H NMR (CDC13): 8 7.78 (s, 1H), 7.47-7.32 (m, 2H), 5.35-5.16
(dd,
J = 8.8 Hz, JH,F = 47 Hz, 1H) 4.82-4.80 (m, 1H), 3.85-3.79 (m, 2H), 3.36-3.31
(m,
1H), 2.35-2.03 (m, 6H), 1.67-1.54 (m,4H), 1.10 (t, J = 6.6 & 6.8 Hz, 3H). ES-
MS:
calcd. For Cl9HZaC12FN304(444.11); found: 448.2 [M+1].
Example 67
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((4-tert-butylphenyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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J /
HO~
The title compound was prepared according to General Procedure G from 4-
tert-butylaniline. 1H NMR (CDC13): 8 7.67(m,2H), 7.57-7.45 (m, 3H), 5.35-5.16
(dd,
S J = 8.2 & 8.5 Hz, JH,F = 47 Hz, 1H), 4.85 (d, J = 4.4 Hz, 1H), 3.83-3.80 (m,
2H), 3.39-
3.34 (m, 1H), 2.43-2.00 (m,6H), 1.57-1.45 (m, 13H), 1.023 (t, J = 6.6 & 7.1
Hz, 3H).
ES-MS: calcd. For C23H3qFN3O4 (435.53); found: 436.4 [M+1].
Example 68
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(tert-butylaminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
H
OvN\
HO
The title compound was prepared according to General Procedure G from tert-
butylamine. 'H NMR (CDCl3): 8 5.33-5.14 (dd, J = 8 Hz, JH,F = 48 Hz, 1H), 4.58
(d,
J = 4.7 Hz, 1H), 3.81-3.79 (m, 2H), 3.42-3.39 (m, 1H), 2.40-1.98 (m, 10H),
1.55-1.49
(m, 13H), 1.11 (t, J = 5.8 & 6.6 Hz, 3H). ES-MS: calcd. For C»H3oFN3O4
(359.44);
found: 360.3 [M+1].
Example 69
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(S~-((indan-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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H
wN
H
The title compound was prepared according to General Procedure G from 2-
aminoindan. 'H NMR (CDC13): 8 7.48-7.33 (m, 4H), 5.25-5.07 (dd, J = 8.5 Hz,
JH,F
S = 47.5 Hz, 1 H), 4.86-4.80 (m, l H), 4.57-4.5 5 (m, l H), 3.78-3.76 (m,2H),
3.51-3.42
(m,2H), 3.35-3.30 (m,lH), 3.01-2.92 (m,2H), 2.37-2.27 (m,2H), 2.17-1.92
(m,2H),
1.52-1.42 (m,4H), 1.08 (t, J = 6.8 Hz, 3H). ES-MS: calcd. For CZZH30FN3~4
(419.49); found: 420.6 [M+1].
Example 70
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(S~-((2,2-dimethylpropyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
O ~N~
HO~ N
The title compound was prepared according to General Procedure G from 2,2-
dimethylpropylamine. 1H NMR (CDC13): 8 7.28 (t, J = 6 Hz, 1H), 5.36-5.18 (dd,
J =
8.4 Hz, Jr,,F = 47.5 Hz, 1H), 4.75 (d, J = 5.2 Hz, 1H), 3.85-3.77 (m, 2H),
3.40-3.35 (m,
1H), 3.29-3.19 (m, 2H), 2.50-2.27 (m, 2H), 2.17-2.13 (m, 2H), 2.09-1.98
(m,2H),
1.53-1.51 (m,4H ), 1.08 (bs,3H ). C~gH32FN3Oq (373.24); found: 374.4 [M+1].
Example 71
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,f)-((4-phenylthiazol-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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The title compound was prepared according to General Procedure G from 2-
amino-4-phenylthiazole. 1H NMR ( CDC13): 8 7.92-7.90 (m, 2H), 7.71 (m, 3H),
7.46
(s,lH), 7.28 (s,lH), 5.37 - 5.18 (dd, J = 8.5 & 8.2 Hz, JH,F = 47 Hz, 1H),
4.95-4.93
(m,lH), 3.99-3.95 (m,2H), 3.43-3.38 (m,lH), 2.54-2.26 (m,4H), 2.21-1.96
(m,2H),
1.62-1.50 (m,4H), 1.08 (t, J = 6.9 & 7.1 Hz, 3H). ES-MS: calcd. For
CZZHZ~FN404S
(462.54); found: 463.4 [M+1 ].
Example 72
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((5-phenylthiadiazol-2-
yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
H
H _
O~
N-N
O~
N
H
F
The title compound was prepared according to General Procedure G from 2-
amino-5-phenylthiadiazole. 1H NMR (CDC13): 8 8.08-8.05 (m,2H), 7.68-7.48 (m,
3H), 5.45-5.26 (dd, J = 9.2 Hz, JH,F = 47 Hz, 1H), 4.99-4.97 (m,lH), 3.96-3.94
(m,2H), 3.38-3.36 (m,lH), 2.50-1.98 (m, 6H), 1.61-1.51 (m,4H), 1.09 (t, J =
6.9 Hz,
3H). ES-MS: calcd. For CZ~HZ~FN504S (463.53); found: 464.2 [M+1].
Example 73
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(S~-((5-ethylthiadiazol-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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H
OvN
~N-N
HON N
H
F
The title compound was prepared according to General Procedure G from 2-
amino-5-ethylthiadiazole. 'H NMR (CDC13): 8 5.43-5.24 (dd, J = 9.6 Hz, JH,F =
47.5
Hz, 1H), 5.00-4.98 (m, 1H), 3.97-3.88 (m, 1H), 3.38-3.36 (m,2H), 3.27-3.20 (m,
2H), 2.47-2.21 (m, 4H), 2.19-1.97 (m,2H), 1.58 (t, J = 7.7 Hz, 3H), 1.58-1.49
(m,
4H), 1.09 (t, J = 6.8 & 7.2 Hz, 3H). ES-MS: calcd. For C»Hz6FN504S (415.48);
found: 416.2 [M+1].
Example 74
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(S~-((3-
trifluoromethoxyphenyl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
H
O~N ~ OCF3
H0~
N
H
F O
The title compound was prepared according to General Procedure G from 3-
(trifluoromethoxy)aniline. 'H NMR (CDC13): ~ 7.71 (s,lH), 7.48-7.41 (m, 2H),
7.29
(t, J = 8.2 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 5.39-5.21 (dd, J = 9.3 & 8.8
Hz, 1H),
4.88-4.86 (m, 1H), 3.85-3.82 (m, ZH), 3.39-3.37 (m,lH), 2.41-2.04 (m, 6H),
1.61-
1.53 (m, 4H), 1.06 (t, J = 6.9 Hz, 3H). ES-MS: calcd. For CzoHzsFaN3~s
(463.42);
found: 454.2 [M + 1].
Exam 1p a 75
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((benzthiazol-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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H
O N
~' '~ / \
HO~
N
H F
The title compound was prepared according to General Procedure G from 2-
aminobenzothiazole. 1H NMR (CDCl3): S 7.99-7.92 (dd, J = 7.5 & 8.2 Hz, 2H),
7.70-7.64 (dd, J = 8 & 7.6 Hz, 1H), 7.56 (t, J = 7.9 & 8.5 Hz, 1H), 5.43-5.24
(dd, J =
8.2 & 8.5 Hz, JH,F = 47 Hz, 1H), 5.04 - 5.01 (m, 1H), 4.00-3.97 (m, 2H), 3.47-
3.42
(m, 1H), 2.57-2.21 (m, 4H), 2.00 - 1.97 (m, 2H), 1.64-1.52 (m, 4H), 1.09 (t, J
= 6.8
& 7.2 Hz, 3H). ES-MS: calcd. For CZOH25FN404S (436.50); found: 437.3 [M+1].
Example 76
Synthesis of N hydroxy-3-(,5~-(n-butyl)-3-[2-(,S~-((2,5-dimethylphenyl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
H
O\ ~ \
HO~
The title compound was prepared according to General Procedure G from 2,5-
dimethylaniline. 1H NMR (CDC13): 8 7.81 (s,lH), 7.22 (d, J = 7.7 Hz, 1H), 7.05
(d, J
= 7.9 Hz, 1H), 5.42-5.23 (dd, J = 8.5 Hz, JH,F = 47 Hz, 1H), 4.99-4.97 (m,
1H), 3.83-
3.79 (m, 2H), 3.40-3.35 (m, 1H), 2.66-2.63 (m, 2H), 2.47 (s, 3H), 2.38 (s,
3H), 2.24-
2.19 (m,2H), 2.18-1.99 (m, 2H), 1.64-1.46 (m, 4H), 0.99 (t, J = 6.6 & 6.9 Hz,
3H).
ES-MS: calcd. For CzlH3oFN34a (407.48); found: 408.3 [M+1].
Example 77
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((2,5-dimethoxyphenyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(R)-fluoropropionamide
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The title compound was prepared according to General Procedure G from 2,5-
dimethoxyaniline. 'H NMR (CDC13): 8 8.22 (d, J = 3 Hz, 1H), 6.96 (d, J = 8.8
Hz.
1H), 6.79 - 6.75 (dd, J = 3 Hz, 1H), 5.41-5.22 (dd, J = 8 Hz; JH,F = 47 Hz,
1H), 4.92-
4.90 (m, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.95-3.85 (m, 2H), 3.45-3.39 (m,
1H), 2.56-
2.23 (m, 4H), 2.02-1.99 (m, 2H), 1.64-1.49 (m, 4H), 1.00 (t, J = 6.3 & 7.1 Hz,
3H).
ES-MS: calcd. For CZ~H3pFN3O6 (439.48); found: 440.4 [M + 1].
Example 78
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((4,5-dimethylthiazol-2-
yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
H
O~
1~
N
HON
H
F
The title compound was prepared according to General Procedure H from 2-
amino-4,5-dimethylthiazole. 1H NMR (CDC13): 8 5.32-5.14 (dd, J = 5.7 Hz, J,-
I,F =
47 Hz, 1 H), 4.85 - 4.81 (dd, J = 6 & 5.3 Hz, 1 H), 4.03-3.99 (m, 2H), 3.53-
3.43 (m,
1H), 2.52 (s, 3H), 2.50 (s, 3H), 2.36-2.22 (m, 4H), 2.19-1.79 (m, 2H), 1.60-
1.50 (m,
4H), 1.08 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For ClgH2~F N404S (414.50);
found: 415.4 [M + 1 ].
Example 79
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((3,4-dichlorophenyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
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Q, _H CI
~~Y N
H ~ CI
The title compound was prepared according to General Procedure H from 3,4-
dichloroaniline. 'H NMR (CDC13): 8 7.94 (s, 1H), 7.48-7.46 (m, 2H), 5.38-5.21
(dd,
J = 4.4 Hz, JH,F = 47 Hz, 1H), 4.73-4..71 (m, 1H), 3.92-3.91 (m, 2H), 3.53-
3.52 (m,
1H), 2.53-1.97 (m, 6H), 1.59-1.58 (m, 4H), 1.09 (t, J = 6.9 Hz, 3H). ES-MS:
calcd.
For C,9HZ4C12FN3O4S (447.11); found: 448.2 [M+1].
Example 80
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((benzthiazol-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
HO~
N
H
F
The title compound was prepared according to General Procedure H from 2-
aminobenzothiazole. 'H NMR (CDCl3): 8 7.66 (t, J = 7.7 Hz, 2H), 7.34 (t, J =
6.9 &
7.9 Hz, 1 H), 7.26 (t, J=7.7 & 7.4 Hz, 1 H), 5.10-5.92 (dd, J = 5.8 Hz; JH,F =
47 Hz,
1 H), 4.75-4.73 (m, 1 H), 3.75-3.70 (m, 2H), 3.30-3.21 (m, 1 H), 2.24-1.97 (m,
4H),
1.70-1.56 (m, 2H), 1.33-1.25 (m, 4H), 0.78 (t , J = 6.8 Hz, 3H). ES-MS: calcd.
For
CZOHZSF N404S (436.50 ); found: 437.3 [M + 1 ].
Example 81
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((3-phenoxyphenyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
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H
O~ ~ Ph
HON
H
F
The title compound was prepared according to General Procedure H from 3-
phenoxyaniline. 'H NMR (CDC13): 8 7.62-7.51 (m, 5H), 7.50-7.43 (m, 1H), 7.42-
7.30 (m, 1H), 7.28-7.16 (m, 2H), 6.90-6.86 (m, 1H), 5.32-5.14 (dd, J = 5.3 Hz,
JH,F =
47 Hz, 1H), 4.76-4.74 (m, 1H), 3.89-3.87 (m, 2H), 3.51-3.41 (m, 1H), 2.47-1.92
(m,
6H), 1.53-1.51 (m, 4H), 1.05 (t, J = 6.9 & 7.1 Hz, 3H). ES-MS: calcd. For
CzsH3oFN30s (471.52 ); found: 472.4 [M+1].
Example 82
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(S~-((2-(R,S~-hydroxybutyl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(.S~-fluoropropionamide
H
O yN~\~
HOwN~,
H
F
The title compound was prepared according to General Procedure H from (~)-
2-hydroxy-n-butylamine. 1H NMR (CD30D): 8 5.09-4.92 (dd, J = 8.8 Hz, JH,F = 47
Hz, 1H), 4.63-4..59 (m, 1H), 4.03-3.90 (m, 1H), 3.88-3.79 (m, 1H), 3.76-3.73
(m,
1H), 3.51 (s, 2H), 3.46-3.23 (m, 1H), 2.41-2.14 (m, 4H), 1.79-1.52 (m, 8H),
1.17 (t, J
= 7.3 Hz, 3H), 1.11 (t, J = 6 & 7.4 Hz, 3H). ES-MS: calcd. For C~7H3oFN305
(375.44); found: 376.4 [M+1].
Example 83
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,5~-((4-hydroxybutyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
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i
a
OH
The title compound was prepared according to General Procedure H from 4-
aminobutanol. 1H NMR (CD30D): 8 5.07-4.90 (dd, J = 8.8 Hz, JF,,F = 47 Hz, 1H),
4.60-4.55 (dd, J = 4.5 & 4.9 Hz, 1H), 4.05-3.92 (m, 1H), 3.90-3.81 (m, 1H),
3.76 (s,
2H), 3.51 (s, 2H), 3.44-3.38 (m, 1H), 2.44-2.10 (m, 6H), 1.86-1.63 (m, 4H),
1.60-
1.52 (m, 2H), 1.14 (t , J = 6.8 Hz, 3H). ES-MS: calcd. For Cl~H3oF N305
(375.44);
found: 376.4 [M+1].
Example 84
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((3,4-
methylenedioxyphenyl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
H
o~ I w
HO~
The title compound was prepared according to General Procedure H from 3,4-
(methylenedioxy)aniline. 'H NMR (CDC13): 7.19 (s, 1H), 6.86 (d, J = 8 Hz, 1H),
6.67 (d, J = 8 Hz, 1 H), 5.89 (s, 2H), 5.13-4.96 (dd, J = 4.4 Hz, JH,F = 47
Hz, 1 H),
4.55-4.53 (m, 1H), 3.76-3.72 (m,2H), 3.30-3.21 (dd, J = 4.1 Hz, 1H), 2.26-2.24
(m,
2H), 2.01-1.95 (m, 2H), 1.73 (bs, 2H), 1.32 (bs, 4H), 0.86 (t, J = 6.3 Hz,
3H). ES-
MS: calcd. For CZOHz6FN3O6 (423.44); found: 424.3 [M+1].
Example 85
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(S~-((1,4-benzodioxan-6-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
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H
HON / O~
H
F
The title compound was prepared according to General Procedure H from 1,4-
benzodioxan-6-amine. 'H NMR (CDC13): S 7.14 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H),
6.74, (d, J = 8.5 Hz, 1H), 5.14-4.97 (dd, J = 4.5 Hz, JH,F = 47 Hz, 1H), 4.58-
4.56 (m,
1H), 4.20 (s, 4H), 3.73-3.64 (m2H), 3.49-3.21 (m, 1H), 2.30-2.27 (m, 2H), 2.01-
1.94 (m, 2H), 1.74 (bs, 2H), 1.32 (bs, 4H), 0.85 (t, J = 6.6 & 7.1 Hz, 3H). ES-
MS:
calcd. For CZIHZgFN3O6 (437.46); found: 438.3 [M+1].
Example 86
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(~-((isoquinolin-3-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
O~N
H J
The title compound was prepared according to General Procedure H from 6-
aminoisoquinoline. 1H NMR (CDC13): S 9.89 (s, 1H), 9.63 (s, 1H), 7.85 (d, J =
8.5
Hz, 1H), 7.71 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 5.16-4.99 (dd, J = 5.8 Hz,
J,.,,F = 47
Hz, 1H), 4.76-4.73 (m, 1H), 3.85 (m, 2H), 3.41-3.25 (m, 1H), 2.35-1.99 (m,
4H),
1.33-1.25 (m, 6H), 0.85 (t, J = 6.8 & 7.1 Hz, 3H). ES-MS: calcd. For
CZZHz~FN404
(430.47); found: 431.3 [M+1].
Example 87
Synthesis ofN hydroxy-3-(S~-(n-butyl)-3-[2-(S~-(methylaminocarbonyl)pyrrolidin-
1-
carbonyl]-2-(,S~-fluoropropionamide
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H
O~N~
HO~
The title compound was prepared according to General Procedure H from
methylamine. 'H NMR (CD30D): 8 5.064.90 (dd, J = 8.7 Hz, JH,F = 47 Hz, 1H),
4.58-4.54 (dd, J = 5 Hz, 1H), 4.05-4.00 (m, 1H), 3.99-3.82 (m, 1H), 3.50-3.49
(m,
1H), 2.93 (s, 3H), 2.40-2.08 (m, 4H), 1.79-1.51 (m, 6H), 1.21 (t, J = 6.8 Hz,
3H).
ES-MS: calcd. For C14H24FN3~4 (317.36); found: 318.3 [M+1].
Example 88
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(S~-((5-phenylthiadiazol-2-
yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
HO~
o yN
N-N
N
H
F
The title compound was prepared according to General Procedure H from 2-
amino-5-phenylthiadiazole. 'H NMR (CDC13 + DMSO-D6): 8 7.47-7.34 (m, 5H),
5.06-5.03 (dd, J = 7.7 Hz, JH,F = 47 Hz, 1 H), 5.02-4.87 (m, 1 H), 3.80-3.71
(m, 2H),
3.31-3.28 (m, 1H), 2.18-2.12 (m, 4H), 1.73-1.33 (m, 6H), 0.87 (t, J = 6.7 Hz,
3H).
ES-MS: calcd. For CZ~HZ6FNSO4S (463.53); found: 464.2 [M+1].
Example 89
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(n-
butylaminocarbonyl)pyrrolidin-1
carbonyl]-2-(,5~-fluoropropionamide
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H
O~NIw
HO~
F
The title compound was prepared according to General Procedure H from n-
butylamine. 1H NMR (CDC13): 8 7.21 (t, J = 6.5 & 5.5 Hz, 1H), 5.14-4.97 (dd, J
=
5.8 Hz, JH,F = 47 Hz, 1H), 3.65-3.57 (m, 2H), 3.30-3.16 (m, 3H), 2.23-2.17 (m,
2H),
1.97-1.72 (m, 2H), 1.69-1.50 (m, 2H), 1.48-1.25 (m, 8H), 0.92-0.87 (m, 6H). ES-
MS: calcd. For C»H3oFN304 (359.44); found: 360.3 [M+1].
Example 90
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(S~-((thiazol-2-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
HO~
F
The title compound was prepared according to General Procedure H from 2-
aminothiazole. 1H NMR (CDC13 + DMSO-D6): 8 7.40 (d, J = 3.6 Hz, 1H), 6.95 (d,
J
= 3.6 Hz, 1H), 5.05-4.88 (dd, J = 7.4 Hz, JH,F = 47 Hz, 1H), 4.86-4..84 (m,
1H), 3.84-
3.71 (m, 2H), 3.33-3.23 (m, 1H), 2.16-1.99 (m, 4H), 1.72-1.30 (m, 6H), 0.84 9
(t, J =
6.8 & 7.1 Hz, 3H). ES-MS: calcd. For C16H23FN4O4S (386.44); found: 387.4
[M+1].
Example 91
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(S~-((4-methylthiazol-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
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H
o~N~ /
Ho~
The title compound was prepared according to General Procedure H from 2-
amino-4-methylthiazole. 1H NMR (CDC13 + DMSO-D6): 8 6.49 (s, 1H), 5.10-4.92
(dd, J = 6.6 Hz, Jt~,F = 47 Hz, 1H), 4.85-.4.83 (m, 1H), 3.79-3.68 (m, 2H),
3.37-3.23
(m, 1 H), 2.31 (s, 3H), 2.22-1.99 (m, 4H), 1.74-1.52 (m, 2H), 1.29-1.27 (m,
4H), 0.83
(t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For C»HZSFN404S (400.47); found:
401.6
[M+1].
Example 92
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(S~-((4-phenylthiazol-2-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
The title compound was prepared according to General Procedure H from 2-
amino-4-phenylthiazole. 1H NMR (CDC13): b 7.38-7.26 (m, 5H), 6.95 (s, 1H),
5.15-
5.01 (dd, J = 4.2 Hz, JI-~,F = 47Hz, 1 H), 4.99-4.83 (m, 1 H), 3.76-3.70 (m,
2H), 3.31-
3.27 (m, 1H), 2.15-1.99 (m, 4H), 1.72-1.50 (m, 2H), 1.44-1.25 (m, 4H), 0.81
(t, J =
6.6 & 7.1 Hz, 3H). ES-MS: calcd. For CzZH2~FN404S (462.54); found: 463.5
[M+1].
Example 93
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((2,2-dimethylpropyl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
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O~N
HOwN
H
F
The title compound was prepared according to General Procedure H from 2,2-
dimethylpropylamine. 'H NMR (CDC13): 8 7.16 (t, J = 6 Hz, 1H), 5.14-4.96 (dd,
J =
6.1 Hz, JH,F = 47 Hz, 1 H), 4.55-4.48 (m, 1 H), 3.69-3.61 (m, 2H), 3.31-3.22
(m, 1 H),
3.14-3.07 (m, 1H), 2.98-2.91 (m, 1H), 2.24-1.96 (m, 4H), 1.72-1.63 (m, 2H),
1.33-
1.30 (m, 4H), 0.88 (m, 12H). ES-MS: calcd. For C~8H32FN304 (373.46); found:
374.7 [M+1].
Example 94
Synthesis of N-hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((3-methylbutyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
H
O~N
HO~
N
H F
1 S The title compound was prepared according to General Procedure H from 3-
methylbutylamine. 'H NMR (CDC13): 8 7.17 (t, J = 5.2 Hz, 1H), 5.13-4.95 (dd, J
=
6.1 Hz, JH,F = 47 Hz, 1H), 4.47-4.44 (m, 1H), 3.66-3.57 (m, 2H), 3.31-3.17 (m,
3H),
2.23-2.17 (m, 2H), 1.96-1.91 (m, 2H), 1.74-1.54 (m, 3H), 1.42-1.32 (m, 6H),
0.91-
0.87 (m, 9H). ES-MS: calcd. For C18H32FN3O4 (373.46); found: 374.7 [M+1].
Example 95
Synthesis of N-hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((n-pentyl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
H
O~N
HO~
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The title compound was prepared according to General Procedure H from
amylamine. 'H NMR (CDC13): 8 7.18 (t, J = 5.2 Hz, 1H), 5.13-4.95 (dd, J = 6
Hz,
JH,F = 47 Hz, 1H), 4.47-4.45 (m, 1H), 3.66-3.64 (m, 2H), 3.31-3.14 (m, 3H),
2.23-
2.17 (m, 2H), 1.96-1.93 (m, 2H), 1.76-1.63 (m, 2H), 1.52-1.42 (m, 3H),1.34-
1.26
(m, 8H), 0.91-0.85 (m, 6H). ES-MS: calcd. For C~gH32FN3O4 (373.46); found:
374.7 [M+1 ].
Exam In a 96
Synthesis of N hydroxy-3-(.S~-(n-butyl)-3-[2-(,S~-((cyclohexyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
H
O~N
HON
H
F
The title compound was prepared according to General Procedure H from
cyclohexylamine. 1H NMR (CDC13): 8 7.00 (d, J = 8.2 Hz, 1H), 5.14-4.96 (dd, J
=
6.2 Hz, JH,F = 47 Hz, 1H), 4.461.44 (m, 1H), 3.73-3.59 (m, 3H), 3.31-3.22 (m,
1H),
2.19-2.10 (m, 4H), 1.96-1.64 (m, 6H ), 1.33-1.27 (m, 6H), 1.20-1.12 (m, 4H),
0.89
(t, J = 6.6 Hz, 3H). ES-MS: calcd. For C~9H32FN3O4 (385.47); found: 386.7
[M+1].
Example 97
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(S~-((n-propyl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
H
O~N~
HO~
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The title compound was prepared according to General Procedure H from
propylamine. 'H NMR (CDC13 + DMSO-D6): 8 7.24 (t, J = 5.2 Hz, 1H), 4.99-4.80
(dd, J = 8.8 Hz, J,.,,F = 47 Hz, 1H), 4.59-4.57 (m, 1H), 3.72-3.56 (m, 2H),
3.37-3.12
(m, 3H), 2.31-2.26 (m, 2H), 2.09-1.84 (m, 4H), 1.66-1.43 (m, 2H), 1.28-1.03
(m,
4H), 0.91-0.87 (m, 6H). ES-MS: calcd. For C~6HZgFN3O4 (345.41); found: 346.6
[M+1].
Example 98
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((5-methylthiazol-2-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-fluoropropionamide
H
O N
HO~ N
N
H F
The title compound was prepared according to General Procedure H from 2-
amino-5-methylthiazole. 'H NMR (CDC13): 8 7.31 (s, 1H), 5.32-5.14 (dd, J = 6.1
Hz, JH,F = 47 Hz, 1H), 4.8-4.83 (m, 1H), 4.03-3.94 (m, 2H), 3.53-3.44 (m, 1H),
2.62
(s, 3H), 2.58-2.21 (m, 4H), 1.99-1.78 (m, 2H), 1.54-1.45 (m, 4H), 1.08 (t, J =
6.6 &
7.4 Hz, 3H). ES-MS: calcd. For C]~H25FN4O4S (400.47); found: 401.6 [M+1].
Example 99
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((3,4-dimethoxybenzyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
HO~
-'N
H
F
The title compound was prepared according to General Procedure H from 2,4-
dimethoxybenzylamine. 'H NMR (CDC13): 6 7.31 (d, J = 8 Hz, 1H), 6.67-6.58 (m,
2H), 5.30-5.14 (dd, J = 2 Hz, JH,F = 47 Hz, 1H), 4.67-4.45 (m, 3H), 4.00 (s,
3H), 3.98
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(s, 3H), 3.86-3.78 (m, 2H), 3.45-3.39 (m, 1H), 2.37-2.13 (m, 4H), 1.89-1.84
(m,
2H), 1.47-1.45 (m, 4H), 1.04 (t, J = 6.3 & 7.1 Hz, 3H). ES-MS: calcd. For
Cz2H3zFN306 (453.51); found: 454.8 [M+1].
Example 100
Synthesis ofN hydroxy-3-(S~-(n-butyl)-3-[2-(S~-(piperidin-1-
ylcarbonyl)pyrrolidin-1
carbonyl]-2-(,S~-fluoropropionamide
H
The title compound was prepared according to General Procedure H from
piperidine. 1H NMR (CDC13): 8 5.14-4.97 (dd, J = 6.SHz, JH,F = 47 Hz, 1H),
4.91-
4.87 (m, 1H), 3.80-3.47 (m, 6H), 3.39-3.21 (m, 1H), 2.22-1.83 (m, 3H), 1.65-
1.27 (m,
13H), 0.90 (t, J = 7 Hz, 3H). ES-MS: calcd. For C~gH3oFN304(371.45); found:
372.4
[M+1].
Example 101
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-(azetidin-1-
ylcarbonyl)pyrrolidin-1
carbonyl]-2-(,S~-fluoropropionamide
HO~
N
H
F O O
The title compound was prepared according to General Procedure H from
azetidine. 'H NMR (CD30D): b 5.10-4.92 (dd, J = 8.7 Hz, JI,,F = 47 Hz, 1H),
4.73-
4.65 (m, IH), 4.60-4.57 (m, 1H), 4.49-4.41 (m, 1H), 4.32-4.21 (m, 1H), 4.18-
4.12 (m,
1H), 4.06-3.99 (m, 1H), 3.89-3.81 (m, 1H), 2.59-2.41 (m, 2H), 2.41-2.30 (m,
ZH),
2.28-2.05 (m, 2H), 1.84-1.49 (m, 6H), 1.11 (t, J = 7 Hz, 3H). ES-MS: calcd.
For
C16H26FN30a (343.39); found: 344.4 [M+1 ].
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Example 102
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((N-pyridin-2-yl)methylamino
carbonyl)-pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
w
CH3
H0.
H
OH O
The title compound was prepared according to General Procedure F from N-
methyl-2-amino pyridine. 1H NMR (CDC13): 8 8.75-8.04 (m, 2H),7.71-7.46 (m,2H),
4.76 bs, 1H), 4.46 (bs, 1H), 3.93-3.63 (m, 2H), 3.56 (s,3H), 3.42-3.39 ( m,
1H), 2.28-
2.00 (m, 6H), 1.66-1.62 (m, 4H), 1.13 (t, J = 7 Hz, 3H). ES-MS: calcd. For
C»HzgN405 (392.45); found: 393.6 [M+1].
Example 103
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-((3,4-methylenedioxybenzyl)-
aminocarbonyl)pyrrolidin-1-carbonyl]-2-(.S~-fluoropropionamide
O
ovN
HO~
F
The title compound was prepared according to General Procedure H from
piperonylamine. 'H NMR (CDC13): 7.63(s, 1H), 6.93 (d, J = 9.9 Hz, 2H), 6.11
(s,
2H), 5.30-5.13 (dd, J = 5.5 Hz, JH,F= 47 Hz, 1H), 4.62-4.39 (m ,3H), 3.97-3.71
(m,
2H), 3.48-3.39 (m, 1H), 2.38-2.13 (m, 4H), 1.87-1.85 (m, 2H), 1.49-1.48 (m,
4H),
1.05 (t, J = 6.3 Hz, 3H). ES-MS: calcd. For CZ~HZ$FN306 (437.46); found: 438.7
[M+1 ].
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Example 104
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-
((allyl)aminocarbonyl)pyrrolidin-1
carbonyl]-2-(~-fluoropropionamide
H
O~N
The title compound was prepared according to General Procedure H from
allylamine. 'H NMR (CDC13): 8 6.06-5.95 (m, 1H), 5.39-5.17 (m, 3H), 4.69.67
(m, 1H), 4.05-3.85 (m, 4H), 3.51-3.44 (m, 1H), 2.40-2.17 (m, 4H), 1.91-1.89
(m,
2H), 1.62-1.53 (m, 4H), 1.09 (t, J = 6.3 Hz, 3H). ES-MS: calcd. For
C1~H26FN304
(343.39); found: 344.7 [M+1].
Example 105
Synthesis of N hydroxy-3-(,S~-(n-butyl)-3-[2-(,S~-((2-
methylallyl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(,S~-fluoropropionamide
N
HO N
The title compound was prepared according to General Procedure H from 2-
methylallylamine. 'H NMR (CDC13): 8 5.34-5.16 (dd, J = 5.8 Hz, J,-,,F = 47 Hz,
1H),
5.00 (s, 2H) 4.73-4.66 (m, 1H), 4.05-3.87 (m, 4H), 3.51-3.43 (m, 1H), 2.43-
2.17 (m,
4H), 1.90 (s, 3H), 1.86-1.84 (m, 2H), 1.66-1.53 (m, 4H), 1.08 (t, J = 6.6 Hz,
3H).
ES-MS: calcd. For C»Hz$FN304 (357.42); found: 358.6 [M+1].
Example 106
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-(morpholin-4-
ylcarbonyl)pyrrolidin
1-carbonyl]-2-(,S~-fluoropropionamide
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O N
HO~
H
F
The title compound was prepared according to General Procedure H from
morpholine. 'H NMR (CDC13): 8 5.34-5.16 (dd, J = 6.2 Hz, JH,F = 47 Hz, 1H),
5.08-5.05 (m, 1H), 4.00-3.71 (m, 10H), 3.68-3.43 (m, 1H), 2.42-1.83 (m, 6H),
1.78-
1.50 (m, 4H), 1.10 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For CI~HZgFN305
(373.42); found: 374.5 [M+1].
Example 107
Synthesis of N hydroxy-3-(S~-(n-butyl)-3-[2-(S~-(pyrrolidin-1-
carbonyl)pyrrolidin-1-
carbonyl]-2-(S~-fluoropropionamide
O yN,
HON
H
F O
The title compound was prepared according to General Procedure H from
pyrrolidine. 'H NMR (CDC13): 8 5.34-5.17 (dd, J = 6.5 Hz, J,-~,F = 47 Hz, 1H),
4.86-
4.82 (m, 1 H), 3.94-3.89 (m, 4H), 3.77-3.71 (m, 1 H), 3.64-3.42 (m, 2H), 2.38-
2.20
25
(m, 2H), 2.18-1.74 (m, 8H), 1.65-1.48 (m, 4H), 1.10 (t, J = 6.9 & 7.2 Hz, 3H).
ES-
MS: calcd. For CI~HZgFN304 (357.42); found: 358.5 [M+1].
Example 108
Synthesis ofN hydroxy-3-(S~-(n-butyl)-3-[2-(,S~-
((ethyl)aminocarbonyl)pyrrolidin-1
carbonyl]-2-(.S~-fluoropropionamide
H
O~N~
HO~
N
H F
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The title compound was prepared according to General Procedure H from
ethylamine. 1H NMR (CDC13): S 5.35-5.19 (d, J,-,,F = 47 Hz, 1H), 4.64-4.60 (m,
1H),
3.85-3.78 (m, 2H), 3.45-3.19 (m, 3H), 2.44-2.13 (m, 4H), 1.93-1.84 (m, 2H),
1.55-
1.38 (m, 4H), 1.30 (t, J = 7.2 Hz & 6.9 Hz, 3H), 1.10 (bs, 3H ). ES-MS: calcd.
For
CisHz6FN30a (331.38); found: 332.5 [M+1].
Example 109
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4-phenoxyphenyl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
OvNH
N
The title compound was prepared according to General Procedure F from 4-
phenoxyaniline. 'H NMR (CDC13): 8 7.48-6.92 (m, 9H), 4.55-4.53 (d, J = 6.0 Hz,
1H), 4.29-4.29 (d, J = 2.2 Hz, 1H), 3.73 (bs, 2H), 3.27 (bs, 1H), 2.29-1.78
(m, 6H),
1.41-1.36 (m, 4H), 0.89 (t, J = 6.6 & 7.14 Hz, 3H). ES-MS: calcd. For
C25H31N3~6
(469.54); found: 470.4 [M+1 ].
Example 110
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((phenyl)aminocarbonyl)-
pyrrolidin
1-carbonyl]-2-(,S~-hydroxypropionamide
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OvNH
HO~
N
H
OH
The title compound was prepared according to General Procedure F from
aniline. 1H NMR (CDCl3): 8 7.52-7.03 (m, 6H), 4.58-4.55 (d, J = 8.0 Hz, 1H),
4.28-
4.27 (d, J = 2.4 Hz, 1H), 3.71 (bs, 2H), 3.262 (bs, 1H), 2.31-1.77 (m, 6H),
1.41-1.33
(m, 4H), 0.89 (t, J = 6.6 & 7.4 Hz, 3H). ES-MS: calcd. For C19Hz7N3O5
(377.44);
found: 378.3 [M+1 ].
Example 111
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((indan-1-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
O~NH
HO~ -
N
H
OH
The title compound was prepared according to General Procedure F from 1-
aminoindan. 1H NMR (CDC13): 8 7.27-7.15 (m, 4H), 5.38 (t, J = 8.2 & 7.7 Hz,
1H),
4.45 (bs, 1H), 4.18 (bs, 1H), 3.64 (m, 2H), 3.20-3.18 (m, 1H), 2.98-2.49 (m,
4H),
2.24-1.73 (m, 6H), 1.95-1.326 (m, 4H), 0.88 (t, J = 6.0 & 5.5 Hz, 3H).
ES-MS: calcd. For CZZH3iNs4s (417.51); found: 418.4 [M+1]
Example 112
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((2-methoxyethyl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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O~NH
HON
OH
" - d
The title compound was prepared according to General Procedure F from 2-
methoxyethylamine. 'H NMR (CDC13): 8 4.45-4.27 (d, J = 6.87 Hz, 1H), 4.255
(bs,
1H), 3.69-3.29 (m, 9H), 2.15-1.77 (m, 6H), 1.43-1.3 (m, 4H), 0.92 (t, J =
6.593 &
6.867 Hz, 3H). ES-MS: calcd. For C~6H29N3O6 (359.42); found: 360.3 [M+1J.
Example 113
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((indan-5-yl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
~NH
HO~
N
H
OH O
The title compound was prepared according to General Procedure F from 5-
aminoindan. 'H NMR (CDC13): 8 7.46-7.08 (m, 3H), 4.57-4.55 (d, J = 67.14 Hz,
1H), 4.28 (bs, 1H), 3.71 (bs, 2H), 3.26 (bs, 1H), 2.87-2.79 (dd, J = 6.87 &
7.14 Hz,
4H), 2.3-1.77 (m, 8H), 1.35 (bs, 4H), 0.89 (t, J = 6.32 & 6.87 Hz, 3H). ES-MS:
calcd. For CZZH31N3~5 (417.51); found: 418.4 [M+1].
Example 114
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4,5-dimethylthiazol-2-
yl)amino
carbonyl)-pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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~~NH
N
H0. _
H
OH O
The title compound was prepared according to General Procedure F from 2-
amino-4,5-dimethylthiazole. 'H NMR (CDCl3): 8 4.60 (bs, 1H), 4.25 (bs, 1H),
3.79
(t, J = 5.77 & 4.67 Hz, 2H), 3.26 (bs, 1H), 2.30-2.24 (m, 8H), 1.74-2.12 (m,
4H), 1.36
(m, 4 H), 0.901 (t, J = 6.77 & 6.87 Hz, 3H). ES-MS: calcd. For C,8Hz8N405S
(412.51); found: 413.3 [M+1].
Example 115
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((quinolin-3-yl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
O~NH
H0.N
H I
OH O
The title compound was prepared according to General Procedure F from 3-
aminoquinoline. 'H NMR (CDCl3): 8 8.17-7.26 (m, 6H), 4.68 (m, 1H), 4.32 (m,
1H), 3.77-3.67 (d, J = 30.217 Hz, 2H), 3.22 (bs, 1H), 2.17-1.69 (m, 6H), 1.30
(bs,
4H), 0.89-0.82 (m, 3H). ES-MS: calcd. For CZZHZgN405 (428.49); found: 429.3
[M+1].
Example 116
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,f)-((benzthiazol-2-yl)amino-
carbonyl)
pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
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HO~
/ .
wNH
N
H
OH O
The title compound was prepared according to General Procedure F from 2-
aminobenzothiazole. 'H NMR (DMSO-d6): 8 8.18-7.49 (m, 4H), 4.802 (bs, 1H),
3.98-3.94 (d, J = 9.066 Hz, 1H), 3.59 (bs, 2H), 3.11 (bs, 1H), 2.11-1.38 (m,
10H),
1.06-1.04 (m, 3H). ES-MS: calcd. For CZOH26N4O5S (434.52); found: 435.3 [M+1].
Example 117
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((3,4-difluorophenyl)amino-
carbonyl)-pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
H
F
O~NH
~N
H
OH O
The title compound was prepared according to General Procedure F from 3,4-
difluoroaniline. 'H NMR (CDC13): 8 7.60-6.97 (m, 3H), 4.49-4.61 (d, J = 7.97
Hz,
1H), 4.29-4.28 (d, J = 2.2 Hz, 1H), 3.79-3.69 (m, 2H), 3.26 (bs, 1H), 2.36-
1.76 (m,
6H), 1.49-1.35 (m, 4H), 0.918 (t, J = 6.867 & 7.143 Hz, 3H). ES-MS: calcd. For
C»Hz5FZN305 (413.42); found: 414.3 [M+1].
Example 118
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((3,4-dichlorophenyl)amino
carbonyl)-pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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I
C
ovrvH
HO~
H OH
The title compound was prepared according to General Procedure F from 3,4-
dichloroaniline. 'H NMR (CDC13): 8 7.94-7.44 (m, 3H), 4.73-4.71 (d, J = 8.24
Hz,
1H), 4.52-4.51 (d, J = 2.8 Hz, 1H), 3.95-3.94 (m, 2H), 3.49 (t, J =5.8 & 6.0
Hz, 1H),
2.52-1.99 (m, 6H), 1.70-1.57 (m, 4H), 1.122 (t, J = 6.9 & 7.1 Hz, 3H).
ES-MS: calcd. For C1~HZSC1zN305 (445.1); found: 446.3 [M+1].
Example 119
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((5-methylisoxazol-3-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
O
OwNH
HO~
H OH
The title compound was prepared according to General Procedure F from 3-
amino-5-methylisoxazole. 'H NMR (DMSO-d6): 8 6.64-5.95 (m, 1H), 4.66-4.62
(dd, J = 4.9 & 4.7 Hz, 1H), 4.01-3.93 (m, 1H), 3.76-3.70 (m, 1H), 3.56 (bs,
3H), 3.11-
3.05 (t, J = 8.8, 1H), 2.70-2.00 (m, 6H), 1.59-1.37 (m, 4H), 1.02 (t, J = 5.8
& 7.1 Hz,
3H). ES-MS: calcd. For C17H26NqO6 (382.42); found: 383.3 [M+1].
Exam 1p a 120
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((3-
phenoxyphenyl)aminocarbonyl)
pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
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~NH
H 1A
H
OH O
The title compound was prepared according to General Procedure F from 3-
phenyoxyaniline. 1H NMR (CDC13): 8 7.55-6.88 (m, 9H), 4.75-4.72 (d, J = 7.7
Hz,
1H), 4.47 (bs, 1H), 3.90-3.88 (m, 2H), 3.46-3.44 (m, 1H), 2.51-1.96 (m, 6H),
1.65-
1.53 (m, 4H), 1.09 (t, J = 6.7 & 7.1 Hz, 3H). ES-MS: calcd. For CZSH3,N3O6
(469.54); found: 470.4 [M+1].
Example 121
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4-phenylthiazol-2-yl)amino-
carbonyl)-pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
HO~
i
O~NH
N
H
OH O
The title compound was prepared according to General Procedure F from 2-
amino-5-phenylthiazole. 1H NMR (CDCl3): 8 7.94-7.28 (m, 6H), 4.89-4.88 (d, J =
4.4 Hz, 1 H), 4.47-4.47 (d, J = 2.5 Hz, 1 H), 3 .92-4.05 (m, 2H), 3 .48-3.44
(m, 1 H),
2.54-1.95 (m, 6H), 1.57-1.48 (m, 4H), 1.10 (t, J = 6.6 & 7.7 Hz, 3H). ES-MS:
calcd.
For CZZH2gN405S (460.55); found: 461.2 [M+1].
Example 122
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,5~-((2-
fluorophenyl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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~ F
O~NH
OH
The title compound was prepared according to General Procedure F from 2-
fluoroaniline. 'H NMR (CDC13): b 8.42-7.23 (m, 4H), 4.97-4.95 (d, J = 6.9 Hz,
1H),
4.49 (bs, 1H), 3.96-3.83 (m, 2H), 3.49 (t, J = 5.5 & 7.4 Hz, 1H), 2.61-2.01
(m, 6H),
1.64-1.46 (m, 4H), 1.06 (t, J = 6.6 & 7.1 Hz, 3H). ES-MS: calcd. For
C19Hz6FN30s
(395.43); found: 396.4 [M+1].
Example 123
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((3-
fluorophenyl)aminocarbonyl)
pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
F
O~NH
HO~
N
H
OH O
The title compound was prepared according to General Procedure F from 3-
fluoroaniline. 'H NMR (CDC13): 8 7.66-6.92 (m, 4H), 4.75-4.73 (d, J = 8.0 Hz,
1H),
4.52 (bs, 1H), 3.94 (t, J = 8.5 & 8.81 Hz, 2H), 3.49 (bs, 1H), 2.57-1.99 (m,
6H), 1.70-
1.56 (m, 4H), 1.12 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For C19H26FN305
(395.43); found: 396.3 [M+1].
Example 124
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4-
fluorophenyl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
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H
HO~
H OH
The title compound was prepared according to General Procedure F from 4-
fluoroaniline. 'H NMR (CDCl3): 8 7.71-7.13 (m, 4H), 4.74-4.71 (d, J = 8.2 Hz,
1H),
4.51-4.49 (d, J = 2.8 Hz, 1 H), 3.96-3.90 (m, 2H), 3.52-3.46 (m, 1 H), 2.5 8-
1.96 (m,
6H), 1.69-1.54 (m, 4H), 1.11 (t, J = 6.9 Hz, 3H). ES-MS: calcd. For
C19HZ6FN3O5
(395.43); found: 396.3 [M+1].
Example 125
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((N phenyl-N methylamino)
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
I\
oyN~
OH
The title compound was prepared according to General Procedure F from N-
methylaniline. 'H NMR (CDC13): 8 7.26-7.5 (m, SH), 4.38 (d, J = 7.1 Hz, 1H),
4.24
(bs, 1H), 3.69-3.65 (m, 5H), 3.33-3.20 (m, 1H), 2.08-1.82 (m, 6H), 1.49-1.36
(m, 4H),
0.94 (t, J = 7.1 Hz, 3H). ES-MS: calcd. For CZOH29N305 (391.47); found: 392.4
[M+1].
Example 126
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((ethyl)aminocarbonyl)-
pyrrolidin-1
carbonyl]-2-(,S~-hydroxypropionamide
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-1
O~NH
OH
The title compound was prepared according to General Procedure F from
ethylamine. 'H NMR (CDC13): 8 4.39-4.37 (d, J = 6.0 Hz, 1H), 4.25-4.24 (d, J =
2.5
Hz, 1H), 3.69-3.52 (m, 4H), 3.20-3.32 (m, 1H), 2.25-1.76 (m, 6H), 1.44-1.25
(m, 4H),
1.183-1.11 (m, 3H), 0.94-0.85 (m, 3H). ES-MS: calcd. For C15H27N3O5 (329.4);
found: 330.4 [M+1].
Exam 1p a 127
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((2-propyl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
~yNH
HO~
N
H OH
The title compound was prepared according to General Procedure F from 2-
aminopropane. 1H NMR (CDC13): 8 4.41-4.38 (d, J = 8.0 Hz, 1H), 4.26-4.25 (d, J
=
2.2 Hz, 1 H), 4.01-3.94 (dd, J = 6.6 Hz, 1 H), 3.66 (t, J = 7.4 Hz, 2H), 3.25-
3.22 (m,
1H), 2.21-1.77 (m, 6H), 1.44-1.22 (m, 4H), 1.19-1.1 l (m, 6H). 0.893 (t, J =
6.6 Hz,
3H). ES-MS: calcd. For C»Hz9N3O5 (343.42); found: 344.4 [M+1].
Example 128
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((2,2-dimethylpropyl)
aminocarbonyl)pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
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H0~
o vNH
N __
H
OH
The title compound was prepared according to General Procedure F from 2,2-
dimethylpropylamine. 1H NMR (CDC13): 8 4.52-4.5 (d, J = 6.0 Hz, 1H), 4.26-4.25
(d,
S J = 2.5 Hz, 1H), 3.7-3.59 (m, 2H), 3.28-3.22 (m, 1H), 3.12-2.94 (m. 2H),
2.29-1.73
(m, 6H), 1.44-1.33 (m, 4H), 0.93-0.88 (m, 12H). ES-MS: calcd. For C~gH33N3O5
(371.48); found: 372.4 [M+1].
Example 129
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((1,1-dimethylpropyl)-
aminocarbonyl)-pyrrolidin-1-carbonyl]-2-(.S~-hydroxypropionamide
O~NH
HO~
N
H
OH O
The title compound was prepared according to General Procedure F from 1,1-
dimethylpropylamine. 1H NMR (CDC13): 8 4.42-4.40 (d, J = 7.7 Hz, 1H), 4.26
(bs,
1 H), 3.67-3.61 (m, 2H), 3.26-3.22 (t, J = 5.0 & 7.1 Hz, 1 H), 2.22-1.65 (m,
6H), 1.44-
1.24 (m, 6H), 0.94-0.79 (m, 6H). ES-MS: calcd. For C~gH33N3O5 (371.48); found:
372.4 [M+1].
Example 130
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((cyclohexyl)aminocarbonyl)
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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)yNH
H
The title compound was prepared according to General Procedure F from
cyclohexylamine. 'H NMR (CDC13): 8 4.43-4.40 (d, J = 8.0 Hz, 1H), 4.26-4.25
(d, J
= 2.5 Hz, 1H), 3.66-3.63 (d, J = 7.4 Hz, 3H), 3.27-3.21 (m, 1H), 2.21-1.10 (m,
20H),
0.94-0.89 (m, 3H). ES-MS: calcd. For C~9H33N3O5 (383.49); found: 384.3 [M+1].
Example 131
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((thiazol-2-yl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
O
HO~
OH
The title compound was prepared according to General Procedure F from 2-
aminothiazole. 'H NMR (CDC13): ~ 7.5-7.04 (m, 2H), 4.66 (t, J = 5.0 Hz, 1H),
4.27-
4.26 (d, J = 2.5 Hz, 1H), 3.86-3.76 (m, 2H), 3.3-3.25 (m, 1H), 2.34-1.74 (m,
6H),
1.36-1.28 (m, 4H), 0.93-0.86 (m, 3H). ES-MS: calcd. For C,6H24N405S (384.46);
found: 385.2 [M+1].
Example 132
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4-methylthiazol-2-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
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HO~
~v
oyNH
N
H
OH O
The title compound was prepared according to General Procedure F from 2-
amino-4-methylthiazole. 'H NMR (CDC13): 8 6.62-6.61(d, J = 1.1 Hz, 1H), 4.65-
4.63
(dd, J = 4.7 & 5.2 Hz, 1H), 4.26-4.25 (d, J = 2.5 Hz, 1H), 3.85-3.78 (dd, J =
6.0 & 7.4
Hz, 2H), 3.29-3.25 (dd, J = 5.2 & 5.0 Hz, 1H), 2.46-1.69 (m, 9H), 1.38-1.27
(m, 4H),
0.893-0.85 (m, 3H). ES-MS: calcd. For C»HZ~N405S (398.48); found: 399.3 [M+1].
Example 133
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((2-
phenylpropyl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
w
O~NH
OH
The title compound was prepared according to General Procedure F from 1-
amino-2-phenylpropane. 'H NMR (CDC13): 8 7.3-6.78 (m, SH), 5.17 (bs, 1H), 4.34
(bs, 1H), 4.21 (bs, 1H), 3.61-3.16 (m, 4H), 3.25-3.22 (m, 1H), 2.92 (bs, 1H),
2.09-
1.09 (m, 13H), 0.94-0.83 (m, 3H). ES-MS: calcd. For CZZH33N3O5 (419.52);
found:
420.3 [M+1].
Example 134
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((n-propyl)aminocarbonyl)
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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O~NH
OH
The title compound was prepared according to General Procedure F from
S propylamine. 1H NMR (CDC13): 8 4.44-4.41 (d, J = 7.4 Hz, 1H), 4.25 (bs, 1H),
3.67-3.65 (d, J = 5.5 Hz, 2H), 3.24-3.14 (m, 3H), 2.23-1.79 (m, 6H), 1.54-1.35
(m,
6H), 0.94-0.85 (m, 6H). ES-MS: calcd. For C,6Hz9N3O5 (343.42); found: 344.4
[M+1].
Example 135
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((N butyl-N
methylamino)carbonyl)
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
wNw
OH
The title compound was prepared according to General Procedure F from N
ethyl-n-butylamine. 1H NMR (CDC13): 8 4.74 (t, J = 3.9 Hz, 1H), 4.25 (bs, 1H),
3.73-3.02 (m, 7H), 2.16-1.74 (m, 6H), 1.53-1.23 (m, 8H), 1.08 (t, J = 6.9 &
7.1 Hz,
2H), 0.98-0.88 (m, 9H). ES-MS: calcd. For C,9H35N3O5 (358.50); found: 386.4
[M+1].
Example 136
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((tert-butyl)aminocarbonyl)
pyrrolidin-1-carbonyl]-2-(.S~-hydroxypropionamide
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~NH
H
OH O
The title compound was prepared according to General Procedure F from t-
butylamine. 1H NMR (CDC13): 8 4.36-4.34 (d, J = 6.7 Hz, 1H), 4.31-4.25 (d, J =
6.5
Hz, 1H), 3.65-3.55 (m, 2H), 3.26-3.22 (m, 1H), 2.2-1.8 (m, 6H), 1.5-1.3 (m,
13H),
0.94-0.85 (m, 3H). ES-MS: calcd. For C17H31N3O5 (357.45); found: 358.4 [M+1].
- Example 137
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((n-pentyl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
~O~NH
H
OH
The title compound was prepared according to General Procedure F from n-
pentylamine. 1H NMR (CDCl3): 8 4.44-4.41 (d, J = 7.4 Hz, 1H), 4.24 (d, J = 2.2
Hz,
1H), 3.71-3.62 (m, 2H), 3.27-3.15 (m, 3H), 2.26-1.74 (m, 6H), 1.52-1.24 (m,
10H),
0.94-0.86 (m, 6H). ES-MS: calcd. For C1gH33N3O5 (371.48); found: 372.4 [M+1].
Example 138
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((3-
methylbutyl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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o vNH
OH
The title compound was prepared according to General Procedure F from 3-
methyl-1-butylamine. ~H NMR (CDC13): 8 4.44-4.41 (d, J = 7.4 Hz, 1H), 4.25-
4.24
(d, J = 2.5 Hz, 1H), 3.71-3.61 (m, 2H), 3.27-3.17 (m, 3H), 2.64-1.77 (m, 6H),
1.63-
1.33 (m, 7H), 0.94-0.88 (m, 9H). ES-MS: calcd. For C~gH3N3O5 (271.48); found:
372.5 [M+1].
Example 139
Synthesis of N-hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-
((benzyl)aminocarbonyl)pyrrolidin-
1-carbonyl]-2-(,S~-hydroxypropionamide
O~NH
HO~
N
H
OH
The title compound was prepared according to General Procedure F from
benzylamine. 1H NMR (CDC13): 8 7.37-7.21 (m, 5H), 4.49-4.29 (m, 3H), 4.20-4.19
(d, J = 2.5 Hz 1H), 3.71-3.62 (m, 2H), 3.19 (t, J = 7.4 & 5.5 Hz, 1H), 2.22-
1.73 (m,
6H), 1.32-1.29 (m, 4H), 0.88 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS: calcd. For
C2oHZ~N305 (391.47); found: 392.4 [M+1].
Example 140
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(.S~-((pyridin-2-yl)aminocarbonyl)
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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~N
O vNH
HO~
The title compound was prepared according to General Procedure F from 2-
aminopyridine. 'H NMR (CDC13): b 8.4-7.47 (m, 4H), 4.87-4.83 (m, 1H), 4.47-
4.46
(d, J = 2.8 Hz, 1H), 4.04-3.87 (m, 2H), 3.5-3.48 (t, J = 2.8 & 4.9 Hz, 1H),
2.52-1.95
(m, 6H), 1.63-1.56 (m, 4H), 1.11 (t, J = 7.1 Hz, 3H). ES-MS: calcd. For
C1gH26N40s
(378.43); found: 377.2 [M-1].
Example 141
Synthesis ofN hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((thiazolidin-1-
yl)aminocarbonyl)-
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
vN~s
°~
HO~
N
H
OH
The title compound was prepared according to General Procedure F from
thiazolidine. 'H NMR (CDC13): 8 4.94-4.66 (m, 3H), 4.46-4.45(d, J = 2.2 Hz,
1H),
4.24-3.84 (m, 4H), 3.46-3.18 (m, 3H), 2.37-2.01 (m, 6H), 1.68-1.53 (m, 4H),
1.12 (t, J
= 7.417 & 6.767 Hz, 3H). ES-MS: calcd. For C16HZ~N305S (373.47); found: 374.6
[M+1].
Example 142
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((thiadiazolidin-5-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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~v
O~NH
OH
The title compound was prepared according to, General Procedure F from 2-
aminothiadiazole. 'H NMR (CDC13): b 7.47-7.46 (d, J = 5.5 Hz, 1H), 5.03-5.02
(d, J
= 5.5 Hz, 1H), 4.49-4.47 (d, J = 3.4 Hz, 1H), 4-3.89 (m, 2H), 3.45-3.44 (d, J
= 3.6 Hz,
1H), 2.4-1.9 (m, 6H), 1.53 (bs, 4H), 1.08 (t, J = 6.6 & 6.9 Hz, 3H). ES-MS:
calcd.
For CISH23NS~SS (385.44); found: 386.5 [M+1].
Example 143
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(.S~-((5-phenylthiadiazolidin-2-
yl)-
aminocarbonyl)-pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
HO~
'N
O~NIH
N
N
H
OH
The title compound was prepared according to General Procedure F from 2-
amino-5-phenylthiadiazole. 1H NMR (CDC13): 8 7.82-7.21 (m, 5H), 4.82-4.79 (d,
J =
7.4 Hz, 1H), 4.24-4.23 (d, J = 3.6 Hz, 1H), 3.76-3.62 (m, 2H), 3.20-3.19 (d, J
= 3.6
Hz, 1H), 2.18-1.95 (m, 6H), 1.68-1.66 (m, 4H), 0.807 (t, J = 6.6 & 7.2 Hz,
3H). ES-
MS: calcd. For CZ,HZ~NSOSS (461.54); found: 462.7 [M+1].
Example 144
Synthesis of N hydroxy-3-(R)-(n-3-methylbutyl)-3-[2-(,S~-(tert-butoxycarbonyl)
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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HON N
H
OH
O
The title compound was prepared according to General Procedure F from 3-
methyl-1-bromo-2-butene and proline -O-t-butyl ester. 'H NMR (CDC13): 8 4.52
(t,
J = 4.4 Hz, 1 H), 4.46 (t, J = 1.3 & 2.2 Hz, 1 H), 3.93-3.76 (m, 1 H), 3.4-
3.34 (m, 2H),
2.41-1.95 (m, 6H), 1.81-1.49 (m, 12H), 1.10 (t, J = 6.6 & 6.9 Hz, 6H). ES-MS:
calcd. For C18H32N206 (372.46); found: 373.5 [M+1].
Example 145
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4-methylthiazol-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]propionamide
1 S The title compound was prepared according to General Procedure E from 2-
amino-4-methylthiazole. 'H NMR (DMSO-d6): 8 6.74 (s, 1H), 4.48 (dd, 8.5 & 4.7
Hz, 1H), 3.75-3.63 (m, 1H), 3.61-3.55 (m, 1H), 2.95 (bs, 1H), 2.25 (s, 3H),
2.23-1.80
(m, 6H), 1.45-1.25 (m, 6H), 0.85 (t, 6.6 Hz, 3H). ES-MS: cald. For C~7HZ6N4O4S
(382.17); found 383.6 [M+1].
Example 146
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((5-phenylthiadiazol-2-
yl)amino
carbonyl)pyrrolidin-1-carbonyl]propionamide
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H0.
The title compound was prepared according to General Procedure E from 2-
amino-5-phenylthiadiazole. 'H NMR (DMSO-d6): 810.3 (s, 1H), 7.94 (m, 2H), 7.53
(m, 3H), 4.56 (dd, 8.5 & 4.8 Hz, 1H), 3.8-3.59 (m, 2H), 2.96 (bs, 1H), 2.29-
1.86 (m,
6H), 1.45-1.27 (m, 6H), 0.87 (t, 6.6 Hz, 3H). ES-MS: cald. For CZ1HZ~N504S
(445.18); found 446.5 [M+1].
Example 147
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4,5-dimethylthiazol-2-
yl)amino-
carbonyl)pyrrolidin-1-carbonyl]propionamide
HO N
0 S
H
The title compound was prepared according to General Procedure E from 2-
amino-4,5-dimethylthiazole. 1H NMR (DMSO-d6): 8 4.45 (dd, 8.2 & 4.8 Hz, 1H),
3.74-3 .62 (m, 1 H), 3.60-3.5 5 (m, 1 H), 2.93 (bs, 1 H), 2.22 (s, 3H), 2.1 S
(s, 3H), 2.11-
1.78 (m, 6H), 1.46-1.25 (m, 6H), 0.85 (t, 6.3 Hz, 3 H). ES-MS: cald. For
C18HZ8N4O4S (396.18); found 397.5 [M+1].
Example 148
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Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((3-phenoxyphenyl)amino
carbonyl)pyrrolidin-1-carbonyl]propionamide
The title compound was prepared according to General Procedure E from 3-
phenoxyaniline. 'H NMR (DMSO-d6): 8 7.42 (m, 2H), 7.37 (m, 3H), 7.15 (m, 1H),
7.02 (m, 2H), 6.69 (m, 1H), 4.35 (dd, 8.0 & 4.5 Hz, 1H), 3.71-3.45 (m, 2H),
2.93 (bs,
1H), 2.28-1.82 (m, 6H), 1.42-1.22 (m, 6H), 0.82 (t, 6.3 Hz, 3H). ES-MS: cald.
For
C25H31N3~5 (453.23); found 454.5 [M+1].
Example 149
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((3,4-
methylenedioxybenzyl)amino
carbonyl)pyrrolidin-1-carbonyl]propionamide
HON N
H
O O H ~ \
O
The title compound was prepared according to General Procedure E from
piperonylamine. 'H NMR (DMSO-d6): 8 10.4 (bs, 1H), 8.18 (m, 1H), 6.87-6.69 (m,
3H), 6.00-5.96 (m, 2H), 4.29-4.11 (m, 2H), 3.71-3.53 (m, 2H), 2.92 (bs, 1H),
2.29-
1.76 (m, 6H), 1.49-1.21 (m, 6H), 0.84 (m, 3H). ES-MS: cald. For CZ,H29N3O6
(419.21); found 420.5 [M+1].
Example 150
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Synthesis of N hydroxy-3-(~-(n-butyl)-3-[2-(S~-((benzthiazol-2-yl)amino
carbonyl)pyrrolidin-1-carbonyl]propionamide
HO~
The title compound was prepared according to General Procedure E from 2-
aminobenzothiazole. ES-MS: cald. For CZOH26N404S (418.17); found 419.4 [M+1].
Example 151
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4-phenylthiazol-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]propionamide
HON N
H
'N
H
The title compound was prepared according to General Procedure E from 2-
amino-4-phenylthiazole. ES-MS: cald. For CZZHZgN4O4S (444.18); found 445.5
[M+1 ]
Example 152
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(piperazin-1-
ylcarbonyl)pyrrolidin-
1-carbonyl]-2-(,S~-hydroxypropionamide
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HO~
N N
H
OH O
O
~NH
The title compound was prepared according to General Procedure F from
piperazine. 'H NMR (CD30D): 8 4.25-4.15 (m, 2H), 4.14 -3.82 (m, 4H), 3.72-3.45
(m, 6H), 3.36-3.29 (m, 1H), 2.46-2.04 (m, 4H), 1.83-1.49 (m, 6H), 1.12 (t, J =
7 Hz).
ES-MS: calcd. For C~7H3o N4O5 (370.44); found: 371.4 [M+1].
Example 153
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(piperidin-1-
ylcarbonyl)pyrrolidin-1-
carbonyl]-2-(S~-hydroxypropionamide
The title compound was prepared according to General Procedure F from
piperidine. 1H NMR (CDC13): 8 5.07-5.03 (m, 1H), 4.45 (d, J = 2.6 Hz, 1H),
3.97-
3.82 (m, 4H), 3.71-3.56 (m, 2H), 3.47-3.40 (m, 1H), 2.37-2.14 (m, 4H), 2.09-
1.98 (m,
4H), 1.96-1.61 (m, 4H), 1.59-1.52 (m, 4H), 1.12 (t, J = 7 Hz, 3H). ES-MS:
calcd. For
ClgH3~N3O5 (369.46); found: 370.3 [M+1].
Example 154
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(azetidin-1-
ylcarbonyl)pyrrolidin-1-
carbonyl]-2-(,S~-hydroxypropionamide
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HON N
H
OH O
O
The title compound was prepared according to General Procedure F from
azetidine. 'H NMR (CDC13): 8 4.67-4.55 (m, 2H), 4.53-4.31 (m, 3H), 4.28-4.16
(m,
1H), 3.94-3.83 (m, 1H), 3.81-3.77 (m, 1H), 3.43-3.38 (m, 1H), 2.55-2.45 (m,
2H),
2.37-2.22 (m, 2H), 2.20-2.07 (m, 2H), 2.05-1.91 (m, 2H), 1.66-1.47 (m, 4H),
1.01 (t, J
= 7 Hz, 3H). ES-MS: calcd. For C~6HZ~N3O5 (341.40); found: 342.3 [M+1].
Example 155
Synthesis ofN hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-(homopiperazin-1-ylcarbonyl)-
pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
The title compound was prepared according to General Procedure F from
hexamethyleneimine. 'H NMR (CDC13): 8 5.00-4.96 (m, 1H), 4.44 (d, J = 2.7 Hz,
1H), 3.97-3.82 (m, 2H), 3.79-3.59 (m, 4H), 3.44-3.38 (m, 1H), 2.41-2.30 (m,
2H),
2.19-1.83 (m, 8H), 1.82-1.69 (m, 4H), 1.67-1.50 (m, 4H), 1.10 (t, J = 7 Hz,
3H). ES-
MS: calcd. For C19H33N3O5 (383.48); found: 384.4 [M+1].
Example 156
Synthesis of N-hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((pyrimidin-2-yl)amino-
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
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H N
HON
H HO o
Step 1
To Cbz-protected-L-proline (20 mmol) in DCM (100 mL) was added
thionylchloride (200 mmol) and the solution heated to reflux for 20 min. The
reaction
was concentrated to dryness and the residue coevaporated two times with DCM.
An
aliquot (6.7 mmol) in DCM (3 mL) was added to a 0 °C solution of 2-
amino-
pyrimidine in pyridine (3 mL) and the reaction stirred overnight. The reaction
was
concentrated, the residue dissolved in ethylacetate and then washed with
water, 10
citric acid, saturated NaHC03 and brine, then dried (NaZS04) to afford N-Cbz-
(2-(S~-
pyrimidin-2-ylaminocarbonyl)pyrrolidine, which was used without further
purification.
Step 2
To afford N-Cbz-(2-(,S~-pyrimidin-2-ylaminocarbonyl)pyrrolidine (5.0 mmol)
in HOAc (10 mL) was added 30 % HBr in acetic acid and the solution stirred for
40
min. The reaction was quenched by addition of 100 mL ethylether, and the
resulting
precipitate collected and recrystalized from MeOH/Et20 to afford 3.5 mmol
afford of
2-(,S~-(pyrimidin-2-ylaminocarbonyl)pyrrolidine hydrobromide salt (70 %).
Step 3
To 2-(,S~-(pyrimidin-2-ylaminocarbonyl)pyrrolidine hydrobromide (200 pmol)
in DMF (2 mL) was added DIEA (500 pmol), compound G-1, (General Procedure G,
200 pmol) and solid HATU (200 ~mol) and the reaction stirred 4 h. The reaction
was
cooled to 0 °C, diluted with aqueous 50 % hydroxylamine (600 pL),
stirred for 4 h,
and then purified via preparative reverse-phase (C18) HPLC to afford the title
compound. 'H NMR (DMSO-d6): b 10.85 (bs, 1H), 8.84 (d, J = 5.0 Hz, 2H), 7.37
(t,
J = 5.0 Hz, 1H), 4.98-4.83 (bs, 1H), 4.04-3.95 (m, 2H), 3.78-3.65 (m, 1H),
3.18-3.05
(m, 1H), 2.39-2.25 (m, 4H), 1.57-1.38 (m, 6H), 1.00 (t, J = 6.6 Hz, 3H). ES-
MS:
calcd. For C,~H25N505 (379.4162); found: 380.3 [M+1].
Example 157
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Synthesis ofN hydroxy-3-(R)-(n-butyl)-3-[2-(S~-(4-methylpiperazin-1-
ylcarbonyl)
pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
° The title compound was prepared according to General Procedure F from
N-
methylpiperazine. 1H NMR (CD30D): b 4.24-4.12 (m, 2H), 3.89-3.86 (m, 2H),
3.64-3.51 (m, 4H), 3.35-3.19 (m, 1H), 3.14 (s, 3H), 2.46-2.08 (m, 4H), 1.85-
1.53 (m,
6H), 1.11 (t, J = 7 Hz). ES-MS: calcd. For ClgH3zN4O5 (384.47); found: 385.3
[M+1].
Example 158
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((4-methylpyrimidin-2-
yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
HEN
H
The title compound was prepared as described in General Procedure F from 4-
methyl-2-aminopyrimidine. 1H NMR (DMSO-d6): b 8.57 (d, J = 5.2 Hz, 1H), 7.16
(d, J = 5.2 Hz, 1H), 4.9 (bs, 1H), 3.93-3.85 (m, 2H), 3.67-3.60 (m, 1H), 3.02-
2.90 (m,
1H), 2.50 (s, 3H), 2.3-2.15 (m, 1H), 2.10-1.98 (m, 3H), 1.55-1.28 (m, 6H),
0.904 (t, J
= 6.2 Hz, 3H). ES-MS: calcd. For C~gHZ~N505 (393.4431); found: 394.3 [M+1].
Example 159
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Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((pyrimidin-4-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
HO~
N
H
The title compound was prepared as described in General Procedure F from 4-
aminopyrimidine. 'H NMR (DMSO-d6): 8 8.91 (d, J = 0.55 Hz, 1H), 8.66 (d, J =
6.1
Hz, 1 H), 8.04 (dd, J = 6.1 & 1.1 Hz, 1 H), 4.64-4.60 (m, 1 H), 3 . 87-3 .75
(m, 1 H), 3 .61-
3.51 (m, 1H), 2.93-2.88 (m, 1H), 2.17-2.05 (m, 1H), 1.98-1.83 (m, 3H), 1.45-
1.18 (m,
6H), 0.83 (t, J = 6.3 Hz, 3H). ES-MS: calcd. For Cl~Hz5N505 (379.4162); found:
380.1 [M+1].
Example 160
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(,S~-((pyrazin-2-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(S~-hydroxypropionamide
HO~
The title compound was prepared as described in General Procedure F from
aminopyrazine. 'H NMR (DMSO-d6): 8 9.30 (d, J = 1.4 Hz, 1H), 8.41-8.35 (m,
2H),
4.66-4.62 (m, 1 H), 3.88-3.76 (m, 2H), 3.60-3.53 (m, 1 H), 2.94-2.89 (m, 1 H),
2.17-
2.11 (m, 1H), 2.00-1.84 (m, 3H), 1.42-1.18 (m, 6H), 0.82 (t, J = 6.6 Hz, 3H).
ES-MS:
calcd. For C,7HZSN505 (379.4162); found: 380.4 [M+1].
Example 161
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Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-(pyrrolidin-1-
ylcarbonyl)pyrrolidin
1-ylcarbonyl]-2-(,S~-hydroxypropionamide
H
O~N N
H
OH
O N
S The title compound was prepared according to General Procedure F from
pyrrolidine. 'H NMR (CDCI3): 8 4.83-4.79 (m, 1H), 4.44 (d, J = 2.4 Hz, 1H),
3.96-
3.85 (m, 2H), 3.77-3.73 (m, 2H), 3.64-3.56 (m, 2H), 3.42-3.16 (m, 1H), 2.39-
2.22 (m,
2H), 2.19-1.96 (m, 8H), 1.66-1.50 (m, 4H), 1.11 (t, J = 7 Hz, 3H). ES-MS:
calcd. For
C17H29N3O5 (355.43); found: 356.4 [M+1].
Example 162
Synthesis of N hydroxy-3-(R)-(n-butyl)-3-[2-(S~-((imidazol-2-yl)amino
carbonyl)pyrrolidin-1-carbonyl]-2-(,S~-hydroxypropionamide
HO~
The title compound was prepared as described in General Procedure F from 2-
amino-imidazole. 'H NMR (DMSO-d6): 8 7.24 (s, 2H), 4.50-4.46 (m, 1H), 3.83-
3.61
(m, 3H), 2.94-2.88 (m, 1H), 2.21-2.11 (m, 1H), 2.05-1.94 (m, 3H), 1.41-1.18
(m, 6H),
0.81 (t, J = 6.0 Hz, 3H). ES-MS: calcd. For C,6Hz5N505 (367.4052); found:
368.4
[M+1].
Formulation Examples
The following are representative pharmaceutical formulations containing a
compound of Formula (I).
Example 1
Tablet formulation
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The following ingredients are mixed intimately and pressed into single scored
tablets.
Quantity per
Ingredient tablet, mg
compound of this invention 400
cornstarch SO
croscarmellose sodium 25
lactose 120
magnesium stearate 5
Example 2
Capsule formulation
The following ingredients are mixed intimately and loaded into a hard-shell
gelatin capsule.
Quantity per Ingredient capsule,
mg
compound of this invention 200
lactose, spray-dried 148
magnesium stearate 2
Example 3
Suspension formulation
The following ingredients are mixed to form a suspension for oral
administration.
Ingredient Amount
compound of this invention 1.0 g
fumaric acid 0.5 g
sodium chloride 2.0 g
methyl paraben 0.15 g
propyl paraben 0.05 g
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granulated sugar 25.0 g
sorbitol (70% solution) 13.00 g
Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 ml
colorings 0.5 mg
distilled water q.s. to 100 ml
Example 4
Injectable formulation
The following ingredients are mixed to form an injectable formulation.
Ingredient
Amount
compound of this invention 0.2 mg-20 mg
sodium acetate buffer solution, 0.4 M 2.0 ml
HCl (1N) or NaOH (1N) q.s. to suitable pH
water (distilled, sterile) q.s. to 20 ml
Example 5
Suppository formulation
A suppository of total weight 2.5 g is prepared by mixing the compound of the
invention with Witepsol~ H-15 (triglycerides of saturated vegetable fatty
acid;
Riches-Nelson, Inc., New York), and has the following composition:
compound of the invention 500 mg
Witepsol~ H-15
balance
Biological Examples
Example 1
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Inhibition ofpeptide deformylase activity
The PDF/FDH coupled assay (Lazennec, C. & Meinnel, T., Anal. Biochem.
224:180-182 (1997)) was used. In this coupled assay, the formate released by
PDF
from its substrate fMAS is oxidized by the coupling enzyme FDH, reducing one
molecule of NAD+ to NADH, which causes an increase in absorption at 340 nm.
All
assays were carried out at room temperature in a buffer of 50 mM HEPES, pH
7.2, 10
mM NaCI, 0.2 mg/mL BSA, in half area 96-well microtiter plates (Corning). The
reaction was initiated by adding a mixture of 0.5 Unit/mL FDH, 1 mM NAD+, and
flVIAS at the desired concentration. To determine ICSO (the concentration
needed to
inhibit 50% of enzyme activity) values, PDF was pre-incubated for 10 min with
varying concentrations of actinonin, and the deformylation reaction was
initiated by
the addition of reaction mixture containing 4 mM fMAS. The initial reaction
velocity, y, was measured as the initial rate of absorption increase at 340 nm
using a
SpectraMax plate reader (Molecular Devices, Sunnyvale, CA). The inhibitor
concentration [In] at which 50% of the enzyme activity is inhibited, ICSO, was
calculated using the following formula:
Y = Ya/(1 + [~~/ICSO)
where y° is the reaction velocity in the absence of inhibitor. Solving
this equation for
ICso at the [In] when y = y°/2 yields ICSO. The ICSO was calculated
based on a
nonlinear least-square regression fit using a commercial software package
(DeltaGraph 4.0).
Using this assay, the ICSO of various compounds were determined. The ICSo
for the various compounds was determined against deformylase enzyme containing
nickel or zinc as the metal ion. The compound tested had an IC50 of less than
2 ~,M
against deformylase enzyme containing nickel as the metal ion and less than 9
~M
against deformylase enzyme containing zinc as the metal ion
Example 2
Assay for testing antimicrobial activity
Minimum inhibitory concentrations (MICs) were determined using the
microdilution method in 96-well format plates. Compounds were suspended in
DMSO at 5 or 10 mg/ml and stored at 4°C until used. They were diluted
in Mueller-
Hinton Broth (MHB) or Trypticase Soy Broth (TSB) and used for MIC
determination.
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The range of concentrations tested was 64-0.0625 Tg/ml final concentration
using a
two-fold dilution system.
The inoculum was prepared from cells grown on Trypticase Soy Agar (TSA)
and incubated overnight at 35 °C, 5 to 10 colonies were used to
inoculate MHB or
TSB broths, and the culture was incubated overnight at 35°C. The
overnight culture
was diluted 1:10, incubated for one hour at 35°C, diluted to the
appropriate inoculum
size and applied to the wells containing broth and test compound. Inoculum
sizes
were 2x 104 CFU/ml.
Plates were incubated at 35°C for 48 hours and MIC were recorded
after 18
hours of incubation for bacteria. MIC was defined as the lowest concentration
of
compound that does not produce visible growth after incubation.
Minimum inhibitory concentrations for various compounds against H.
influenza and S. aureus was approximately 64 pg/mL or less.
Minimum inhibitory concentrations for certain compounds of the Invention
against S.
aureus, S. epidermidis, E. faecium, S. pneumoniae, H. influenzae, H.
influenzae acr,
M. catarrhalis, E. coli and E. coli acr was approximately 64 pg/mL or less.
Example 3
Demonstration of Selective Inhibition of PDF Compared to MMP-7 (Matrilysin)
As noted previously, inhibitors which are selective for peptidyl deformylase
over matrix metalloproteinases are desirable in order to avoid side effects.
In order to test the compounds of the invention for possible inhibitory
effects
on matrix metalloproteinases, the following assay for MMP-7 (matrilysin) was
used.
MMP-7 (Matrilysin) Assay:
Matrilysin activity is assayed using a thio-peptide (Pro-Leu-Gly-S-Leu-Leu-
Gly) as substrate. Upon enzyme hydrolysis, the thiolate is released as a
product. The
thiolate thus generated reacts with DTNB (dithionitrobenzene), giving rise to
a yellow
color which is monitored at 405 nm. The assay is carned out at room
temperature; the
assay buffer contains 50 mM Tricine, pH 7.5, 0.2 M NaCI, 10 mM CaClz, and
0.05%
Brij, in a half area 96-well microtiter plate. The reaction is initiated by
adding a
mixture of 200 TM DTNB and 100 TM thiopeptide in buffer. To determine ICSO
(the
concentration needed to inhibit 50% of enzyme activity) values, MMP-7 was
preincubated for 10 minutes with varying concentrations of compounds, and the
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hydrolysis initiated by the addition of reaction mixture containing
thiopeptide and
DTNB. The reaction rate was recorded as the absorbance increase in OD4os over
30
minutes using a SpectraMax plate reader (Molecular Devices, Sunnyvale, CA).
The
inhibitor concentration [In] at which 50% of the enzyme activity is inhibited,
ICso
was calculated using the following formula:
y = y°/(1 + [In]/ICso)
where y° is the reaction velocity in the absence of inhibitor. Solving
this
equation for ICso at the [In] when y = y°/2 yields ICso.
Using this assay, the ICso of various compounds were determined. The
compounds of the Invention tested were at least approximately 800 times more
select
for PDF than MMP-7. Similar selectivity of the compounds for peptidyl
deformylase
over MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, MT-MMP-1, and tissue necrosis
factor converting enzyme was observed. Similar selectivity was also observed
over
other metalloproteinases such as angiotensin converting enzyme.
Example 4
Discontinuous PDF Assay
The gene for PDF was cloned from S. aureus and E. coli by PCR
amplification. The PDF proteins were overexpressed in E. coli. The native Fe2+
containing PDF or its more stable surrogate Ni2+-containing PDF were prepared
according to Wagner et al. (1998) Biochemical & Biophysical Research
Communications 246:342-6. Both enzymes have similar activity as reported in
the
literature. Discontinuous assay is carried out in a buffer of 10 mM NaCI and
50 mM
HEPES, pH 7.2. Typically, 2 nM of PDF was incubated with inhibitor for 30
minutes
prior to the addition of 4 mM fMAS substrate. The deformylation proceeded at
room
temperature for 30 minute. The enzyme activity is directly proportional to the
amount
of formate released, which can be quantified by monitoring the absorbance
increase at
340 nm after the addition of 1 mM of NAD+ and 0.5 U/ml of formate
dehydrogenase.
Example 5
Mouse septicemia model for determining in vivo efficacy
CD 1 female out-bred mice (Charles River Laboratories) weighing 18-22
grams each were injected intraperitoneally with 0.5 ml of a suspension
containing
5x 10' cfu of S. aureus (Smith strain) in 7% hog gastric mucosa (mucin). The
mice
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were treated, either subcutaneously (SC), intravenously (IV) or orally (PO),
lhr and
Shr after infection. Six groups of six mice each were given different dosage
levels
representing two-fold dilutions of each compound (range of 100mg/kg - 0.1
mg/kg).
Vancomycin was used as the control antibiotic and was administered SC.
Compounds were formulated in PBS and untreated controls were dosed with
vehicle
alone.
Deaths in each group were monitored daily for 6 days and cumulative
mortality was used to determine the 50% protective doses (PDSO), which were
calculated using the method of Reed and Muench.
The foregoing invention has been described in some detail by way of
illustration and example, for purposes of clarity and understanding. It will
be
obvious to one of skill in the art that changes and modifications may be
practiced
within the scope of the appended claims. Therefore, it is to be understood
that the
above description is intended to be illustrative and not restrictive. The
scope of the
invention should, therefore, be determined not with reference to the above
description, but should instead be determined with reference to the following
appended claims, along with the full scope of equivalents to which such claims
are
entitled.
All patents, patent applications and publications cited in this application
are
hereby incorporated by reference in their entirety for all purposes to the
same extent
as if each individual patent, patent application or publication were so
individually
denoted.
162
