Title of Invention

3-[2-(3-ACYLAMINO-2-OXO-2H-PYRIDIN-1-YL)-ACETYLAMINO]-4-OXO-PENTANOIC ACID DERIVATIVES AS CASPASE INHIBITORS

Abstract The present invention provides a compound of formula (I): wherein R1 , R2 ,R3 ,R4 ,and R5 are as defined herein. The present invention also provides pharmaceutical compositions and methods using such compositions for treating a caspase-mediated diseases and processes for preparing the compounds of the invention.
Full Text

Field of the Invention
[0001] This invention is in the field of medicinal
chemistry and relates to compounds, and pharmaceutical
compositions thereof, that inhibit caspases that mediate cell
apoptosis and inflammation. The invention also relates to
processes for preparing these compounds. The invention
further relates to methods of using the compounds and
pharmaceutical compositions of this invention to treat
diseases where caspase activity is implicated.
Background of the Invention
[0002] Apoptosis, or programmed cell death, is a principal
mechanism by which organisms eliminate unwanted cells. The
deregulation of apoptosis, either excessive apoptosis or the
failure to undergo it, has been implicated in a number of
diseases such as cancer, acute inflammatory and autoimmune
disorders, ischemic diseases and certain neurodegenerative
disorders (see generally Science, 1998, 281, 1283-1312; Ellis
et al., Ann. Rev. Cell. Biol., 1991, 7, 663).
[0003] Caspases are a family of cysteine protease enzymes
that are key mediators in the signaling pathways for
apoptosis and cell disassembly (Thornberry, Chem. Biol.,
1998, 5, R97-R103) . These signaling pathways vary depending

on cell type and stimulus, but all apoptosis pathways appear
to converge at a common effector pathway leading to
proteolysis of key proteins. Caspases are involved in both
the effector phase of the signaling pathway and further
upstream at its initiation. The upstream caspases involved
in initiation events become activated and in turn activate
other caspases that are involved in the later phases of
apoptosis.
[0004] Caspase-1, the first identified caspase, is also
known as interleukin converting enzyme or "ICE. Caspase-1
converts precursor interleukin-10 ("plL-iP") to the
pro-inflammatory active form by specific cleavage of pIL-1β
between Asp-116 and Ala-117. Besides caspase-1 there are
also eleven other known human caspases, all of which cleave
specifically at aspartyl residues. They are also observed to
nave stringent requirements for at least four amino acid
residues on the N-terminal side of the cleavage site.
[0005] The caspases have been classified into three groups
depending on the amino acid sequence that is preferred or
primarily recognized. The group of caspases, which includes
caspases 1, 4, 5 and 13, have been shown to prefer
hydrophobic aromatic amino acids at position 4 on the N-
terminal side of the cleavage site. Another group which
includes caspases 2, 3 and 7, recognize aspartyl residues at
both positions 1 and 4 on the N-terminal side of the cleavage
site, and preferably a sequence of Asp-Glu-X-Asp. A third
group, which includes caspases 6, 8, 9 and 10, tolerate many
amino acids in the primary recognition sequence, but seem to
prefer residues with branched, aliphatic side chains such as
valine and leucine at position 4.
[0006] The caspases have also been grouped according to
their perceived function. The first subfamily consists of

caspases-1 (ICE), 4, 5 and 13. These caspases have been
shown to be involved in pro-inflammatory cytokine processing
and therefore play an important role in inflammation.
Caspase-1, the most studied enzyme of this class, activates
the IL-1β precursor by proteolytic cleavage. This enzyme
therefore plays a key role in the inflammatory response.
Caspase-1 is also involved in the processing of interferon-y
inducing factor (IGIF, also known as IL-18) which stimulates
the production of interferon gamma, a key immunoregulator
that modulates antigen presentation, T-cell activation and
cell adhesion.
[0007] The remaining caspases make up the second and third
subfamilies. These enzymes are of central importance in the
intracellular signaling pathways leading to apoptosis. One
subfamily consists of the enzymes involved in initiating
events in the apoptotic pathway, including transduction of
signals from the plasma membrane. Members of this subfamily
include caspases-2, 8, 9 and 10. The other subfamily,
consisting of the effector capsases 3, 6 and 7, are involved
in the final downstream cleavage events that result in the
systematic breakdown and death of the cell by apoptosis.
Caspases involved in the upstream signal transduction
activate the downstream caspases, which then disable UNA
repair mechanisms, fragment BNA, dismantle the cell
cytoskeleton and finally fragment the cell.
£0008] Knowledge of the four amino acid sequence primarily
recognized by the caspases has been used to design caspase
inhibitors. Reversible tetrapeptide inhibitors have been
prepared having the structure
CH3CO-[P4]-[P3]-[P2]-CH{R)CH2CO2H where P2 to P4 represent an
optimal amino acid recognition sequence and R is an aldehyde,
nitrile or ketone capable of binding to the caspase cysteine

sulfhydryl. Rano and Thornberry, Chem. Biol. 4, 149-155
(1997); Mjalli, et al., Bioorg. Med. Chem. Lett. 3, 2689-2692
(1993); Nicholson et al., Nature 376, 37-43 (1995).
Irreversible inhibitors based on the analogous tetrapeptide
recognition sequence have been prepared.
[0009] The utility of caspase inhibitors to treat a
variety of mammalian disease states associated with an
increase in cellular apoptosis has been demonstrated using
peptidic caspase inhibitors. For example, in rodent models
caspase inhibitors have been shown to reduce infarct size and
inhibit cardiomyocyte apoptosis after myocardial infarction,
to reduce lesion volume and neurological deficit resulting
from stroke, to reduce post-traumatic apoptosis and
neurological deficit in traumatic brain injury, to be
effective in treating fulminant liver destruction, and to
improved survival after endotoxic shock. Yaoita et al.,
Circulation, 97, 276 (1998); Endres et al., J Cerebral Blood
Flow and Metabolism, 18, 238, (1998); Cheng et al., J". Clin.
Invest., 101, 1992 (1998); Yakovlev et al., J" Neuroscience,
17, 7415 (1997); Rodriguez et al., J. Exp. Med., 184, 2067
(1996); Grobmyer et al., Mol. Med., 5, 585 (1999).
[0010] In general, the peptidic inhibitors described above
are very potent against some of the caspase enzymes.
However, this potency has not always been reflected in
cellular models of apoptosis. In addition peptide inhibitors
are typically characterized by undesirable pharmacological
properties such as poor oral absorption, poor stability and
rapid metabolism. Plattner and Norbeck, in Drug Discovery-
Technologies, Clark and Moos, Eds. (Ellis Horwood,
Chichester, England, 1990).
[0011] Recognizing the need to improve the pharmacological
properties of the peptidic caspase inhibitors, peptidomimetic
inhibitors have been reported. Amongst these, inhibitors

where the P3 amino acid has been replaced by derivatives of
3-aminopyridin-2-ones and 5-aminopyrimidin-4-ones have been
reported (U.S. Patent 5,756,466 (Bemis et al.); PCT
Publication No. WO 95/35308 (Bemis et al.); Dolle et al. J.
Med. Chem. 39, 2438, (1996); Golec et al. Bioorg. Med. Chem.
Lett. 7, 2181, (1997); Semple et al, Biorg. Med. Chem. Lett.
7, 1337, (1997)).
[0012] Due to the inherent problems of the peptidic
inhibitors, there continues to be a need for small molecule,
nonpeptide caspase inhibitors that are potent, stable, and
penetrate membranes to provide effective inhibition of
apoptosis in vivo. Such compounds would be extremely useful
in treating the aforementioned diseases where caspase enzymes
play a role.
Summary of the Invention
[0013] The present invention provides a compound of
formula I:

wherein: R1, R2, R3, R4, and R5 are as defined herein.
[0014] The present invention also provides pharmaceutical
compositions comprising a compound of formula 1 and methods
of using such compounds and compositions for treating
caspase-mediated diseases. The present invention also
provides processes for preparing the compounds of formula I.
Detailed Description of the Invention
[0015] The present invention provides a compound of
formula I:


wherein:
R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-,
(R6) (H)NC(O)-, R6C(O)C(O)-, (R6)2NC(O)C(O)-,
(R6) (H)NC(O)C(O)-, or R6OC(O)C(O)-;
R2 is hydrogen, -CF3, halo, -OR7, -NO2, -OCF3, -CN, or R8;
R3 is -T-R9;
R4 is -COOH or -COOR8;
R5 is -CH2F or -CH2O-2,3,5,6-tetrafluorophenyl;
R6 is R6a or R6b; two R6 groups, together with the
same atom to which they are bound, optionally form a 3-
to 10-membered aromatic or nonaromatic ring; wherein the
ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a
(C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon
atoms may be replaced by a group selected from O, N,
N(R7) , S, SO, and SO2; and wherein each R6 is
independently substituted with up to 6 substituents
independently selected from R;
R6a and R6b are each independently
(C1-C3)-aliphatic-,
(C4-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C6-C10)-aryl-,
(C3-C10)-heterocyclyl-,
(C5-C10)-heteroaryl-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)-aliphatic-,

(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl(C1-C12)-aliphatic-;
R is halogen, -OR7, -OC(O)N(R7)2, -NO2, -CN, -CF3, -OCF3, -R7,
oxo, thioxo, =NR7, =N(OR7), 1,2-methylenedioxy, 1,2-
ethylenedioxy, -N(R7)2, -SR7, -SOR7, -SO2R7, -SO2N(R7)2, -SO3R7,
-C(O)R7, -C(O)C(O)R7, -C(O)C{0)OR7, -C(O)C(O)N(R7)2,
-C(O)CH2C(O)R7, -C(S)R7, -C(S)OR7, -C(O)OR7, -OC(O)R7,
-C(O)N(R7)2, -OC(O)N(R7)2, -C(S)N(R7)2, - (CH2)O-2NHC(O)R7,
-W(R7)N(R7)COR7, -N(R7)N(R7)C(O)OR7, -N(R7)N(R7)CON(R7)2,
-N(R7)SO2R7, -N(R7)SO2N(R7)2, -N(R7)C(O)OR7, -N{R7)C(O)R7,
-N(R7)C(S)R7, -N(R7)C(O)N(R7)2, -N(R7)C(S)N(R7)2, -N(COR7)COR7,
-N(OR7)R7, -C(=NR7)N(R7)2, -C(O)N(OR7)R7, -C(=NOR7)R7,
-OP(O) (OR7)2, -P(O)(R7)2, -P(O)(OR7)2, or -P(O) (H) (OR7);
two R7 groups together with the atoms to which they are
bound optionally form a 3- to 10-membered aromatic or non-
aromatic ring having up to 3 heteroatoms independently
selected from N, N(R7) , O, S, SO, or SO2, wherein the ring is
optionally fused to a (C6-Cl0)aryl, (C5-C10)heteroaryl, (C3-
C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any
ring has up to 3 substituents selected independently from J2;
or
each R7 is independently selected from:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-{C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein R7
has up to 3 substituents selected independently from J2; and

J2 is halogen, -OR7, -OC(O)N(R7)2, -NO2, -CN, -CF3, -OCF3 -R7,
oxo, thioxo, =NR7, =NOR7, 1,2-methylenedioxy, 1,2-
ethylenedioxy, -N(R7)2, -SR7, -SOR7, -SO2R7, -SOaH(R7)a,
-SO3R7, -C(O)R7, -C(O)C(O)R7, -C(O)C(O)0R7, -C(O)C(O)N(R7)2,
-C(O)CH2C(O)R7, -C(S)R7, -C(S)OR7, -C(O)OR7, -OC(O)R7,
-C(O)N(R7)2, -OC(O)N(R7)2, -C(S)N(R7)2, - (CH2)o-2NHC(O)R7,
-N(R7)N(R7)COR7, -N(R7)N{R7)C{0)OR7, -N(R7)N(R7)CON(R7)2,
-N(R7)SO2R7, -N(R7)SO2N(R7)2f -N(R7)C(O)OR7, -N(R7)C(O)R7,
-N(R7)C(S)R7, -N(R7)C(O)N(R7}2, -N(R7)C(S)N(R7)2,
-N(COR7)COR7, -N(OR7)R7, -CN, -C(=NR7)N(R7)2, -C(O)N(OR7)R7,
-C(=NOR7)R7, -OP(O) (OR7)2, -P{0) (R7)2, -P(O) (0R7)2, or
-P(O) (H) (OR7) ; and
R8 is
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10) -heterocyclyl-,
(C5-C10)-heteroaryl-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12}-aliphatic-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-, wherein up to 3
aliphatic carbon atoms may be replaced with a group
selected from O, N, N(R7) , S, SO, and SO2; and wherein R8 is
optionally substituted with up to 6 substituents
independently selected from R.
T is a direct bond or (C1-C6) aliphatic wherein up to 2
aliphatic carbon atoms in T may be optionally replaced
with S, -SO-, SO2, O, N(R7) , or N in a chemically stable
arrangement; wherein each T may be optionally substituted
with up to 3 R substituents;
R9 is optionally substituted (C6-C10)-aryl or
(C5-C10)-heteroaryl;

[0016] According to one embodiment of this invention, R1 is
R6C(O)-, (R6)2NC(O)-, R6C(O)C(O)-, (R6)2NC(O)C(O)-,
(R6) (H)NC(O)C(O)-, or R6OC(O)C(O)-. In some embodiments, R6
is R6a. In other embodiments, R6 is Ra.
[0017] According to another embodiment R1 is HC(O)-,
R6SO2-, R6OC(O)-, or (R6) (H)NC{0)-. In some embodiments R6 is
R6a. In other embodiments, R6 is R653.
[0018] According to another embodiment R1 is R6C(O)- or
R6SO2-. In another embodiment, R1 is R6C(O)-. In another
embodiment, R1 is R6SO2~-
[0019] According to another embodiment of this invention R1
is (R6)2NC(O)-, (R6) (H)NC(O)-, or (R6)OC(O)-. In a preferred
embodiment, R1 is (R6)2NC(O)-. In another preferred
embodiment, R1 is (R6) (H)NC(O)-. In yet another preferred
embodiment, R1 is (R6)OC(O)-.
[0020] According to one embodiment of this invention, R6 is
R6a. According to another embodiment, R6 is R653. According to
a third embodiment, R6 is R6a or R613.
[0021] In one embodiment of this invention,
R6a is
(C4-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
{C6-C10)-aryl-,
(C3-C10)-heterocyclyl-,
(C5-C10)-heteroaryl-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl(C1-C12)-aliphatic-, or two R6a
groups, together with the atom to which they are attached,
optionally form a 3- to 10-membered aromatic or nonaromatic
ring; wherein the ring is optionally fused to a (C6-
ClO)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a

(C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon
atoms may be replaced by a group selected from O, N, N(R7),
S, SO, and SO2; and wherein R6a is substituted with up to 6
substituents independently selected from R;
R6* is R6a or (C1-C3)-aliphatic-.
[0022] in another embodiment of this invention, R6a is
(C1-C4)-aliphatic,
(C3-C10)-cycloaliphatic,
(C3-C10)-heterocyclyl,
(C5-C10)-heteroaryl,
(C6-C10)-aryl-(Cl-C12)-aliphatic (it being understood
that optionally up to 3 aliphatic carbon atoms may be
replaced by a group selected from O, N, N(R7) , S, SO, and SO2;
and wherein R6a is optionally substituted with up to 6
substituents independently selected from R; or R6a is
substituted as disclosed in any of the embodiments herein) .
[0023] In another embodiment, each R6a is independently
(C4)-aliphatic,
(C3-CIO)-cycloaliphatic,
(C3-C10)-heterocyclyl,
(C5-C10)-heteroaryl,
(C6-C10)-aryl-, or
(C6-C10)-aryl-(Cl-C12)-aliphatic (it being understood
that optionally up to 3 aliphatic carbon atoms may be
replaced by a group selected from O, N, N(R7), S, SO, and SO2;
and wherein R6a is optionally substituted with up to 6
substituents independently selected from R; or Rto is
substituted as disclosed in any of the embodiments herein) .
[0024] In one embodiment, each R6a is independently (C4)-
aliphatic-, (C3-C7)-cycloaliphatic, (C6-C10)-aryl-, or (C5-
C10) -heteroaryl; wherein the heteroaryl and aryl are
independently and optionally substituted, or each R6 together

with, the N-atom to which it is attached is a (C3-C7)-
cycloaliphatic;
[0025] According to another embodiment, each R6a is
independently (C3-C7)-cycloaliphatic, (C6-C10) -aryl-, or (C5-
C10)-heteroaryl, wherein the heteroaryl and aryl are
independently and optionally substituted, or each R6 together
with the N-atom to which it is attached is a (C3-C7)-
cycloaliphatic.
[0026] In another embodiment, each R6a is independently
(C4)-aliphatic-, (C5-C10)-heteroaryl-, or (C6-C10)-aryl-;
wherein the heteroaryl or aryl is optionally substituted or
wherein two R6a groups together with the N-atom to which they
are attached form a (C3-C7) -cycloaliphatic group; in a
preferred embodiment each R6a is independently (C5-C10)-
heteroaryl- or (C6-C10)-aryl-.
[0027] In another embodiment, each R6a is independently H,
(C4)-aliphatic-, or (C6-C10)-aryl-; In a preferred embodiment
each R6a is (C6-C10) -aryl-; or each R6a, together with the N-
atom to which it is attached, is a (C3-C7)-cycloaliphatic;
[0028] In another embodiment, each R6a is independently
(C4)-aliphatic- or (C6-C10)-aryl-; wherein the aryl is
optionally substituted or wherein two R6 groups, together with
the N-atom to which they are attached, form a {C3-C7)-
cycloaliphatic; In another embodiment, each R6a is
independently (C6-C10) -aryl-.
[0029] According to certain embodiments, each R6b is
independently R6a or (C1-C3)-aliphatic-.
[0030] According to one embodiment of this invention, R2 is
hydrogen, C1-, C2-, C3-, or C4-alkyl-, -CF3, -CI, -OR7, -NO2,
-OCF3, or -CN. More preferably, R2 is hydrogen, Cl-alkyl-,
C2-alkyl-, or CF3. More preferably, R2 is hydrogen or CF3.

[0031] According to one embodiment, T is (C1-C4) aliphatic
wherein up to one aliphatic carbon atom may be replaced with
a group selected from O, N, N(R7), and S.
[0032] According to another embodiment, T is (C1-C4)
aliphatic wherein zero aliphatic carbons atom are replaced
with a group selected from O, N, N(R7), and S.
[0033] In yet another embodiment, T is a direct bond,
-CH2-, -CH(Me)-, -CH2-CH2-, -CH2-O-CH2-, -CH(Me)-O-CH2-, or
-CH2-CH2-O-CH2-.
[0034] In one embodiment T is -CH2- or -CH2-CH2-; In
another embodiment T is -CH2-.
[0035] According to another embodiment, R9 is optionally
substituted C6 aryl or C5-heteroaryl.
[0036] According to one embodiment, R9 is substituted
phenyl. Examples of preferred phenyl substituents for R9 .
include halogen, -OR7, -NO2, -CF3, -OCF3, -R7, -O-benzyl,
-O-phenyl, 1,2-methyl enedioxy, 1,2-ethylenedioxy, -N(R7)2,
-C(O)R7, -CO0R7 and -CON (R7)2 wherein R7 is defined as above.
[0037] According to another embodiment, R9 is unsubstituted
phenyl.
[0038] According to one embodiment, R5 is -CH2O-2,3,5,6-
tetrafluorophenyl.
[0039] According to another embodiment, R5 is -CH2F.
[0040] According to another embodiment, R8 is
(C1-C12)-alkyl. More preferably, R8 is (C1-C4)-alkyl.
[0041] According to a preferred embodiment, each R and J2
are independently halogen, -OR7, -OC(O)N(R7)2, -NO2, -CN, -CF3,
-OCF3, -R7, oxo, 1,2-methylenedioxy, 1,2-ethylenedioxy,
-N(R7)2, -C(O)R7, -C(O)C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)N(R7)2,
or -OC(O)N(R7>2.
[0042] As used herein, the carbon atom designations may
have the indicated integer and any intervening integer. For
example, the number of carbon atoms in a (C1-C4) -alkyl group

is 1, 2, 3, or 4. It should be understood that these
designation refer to the total number of atoms in the
appropriate group. For example, in a (C3-C10) -heterocyclyl
the total number of carbon atoms and heteroatoms is 3 (as in
aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.
[0043] As used herein, an aliphatic group includes
straight-chained and branched groups having the specified
number of atoms. If the number of atoms is unspecified, the
aliphatic group has from 1 to 12 carbon atoms. As would be
understood, alkenyl and/or alkynyl' aliphatic groups have a
minimum of 2 carbon atoms. Preferred aliphatic groups are
alkyl groups (preferably having from 1 to 6 atoms) .
[0044] Accordingly, unless otherwise specified, preferred
aliphatic groups of this invention are alkyl groups and have
1, 2, 3, 4, 5, or 6 carbon atoms. More preferred alkyl
groups have 1, 2, 3, or 4 carbon atoms. Preferred alkenyl
and alkynyl groups of this invention have 2, 3, 4, 5, or, 6
carbon atoms and more preferably, from 2, 3, or 4 carbon
atoms.
[0045] Cycloalkyl and cycloalkenyl groups have between 3
and 10 carbon atoms and are monocyclic or bicyclic, including
linearly fused, bridged, or spirocyclic. A cycloaliphatic
group is, preferably, a cycloalkyl or a cylc°alkenyl. More
preferred cycloaliphatic groups are 3-, 4-, 5-, 6-, or 7-
membered rings that are, more preferably, cycloalkyl rings.
[0046] As used herein, "aromatic group" or "aryl" refers
to a 6-1O-membered ring system that contains at least one
aromatic ring. Example of aromatic rings include phenyl and
naphthyl.
[0047] As used herein a "heteroaryl" refers to ring system
having 5-10 members and 1, 2, or 3 heteroatoms independently
selected from N, N(R7) , O, S, SO, and SO2-, wherein at least
one ring is heteroaromatic (e.g., pyridyl, thiophene, or

thiazole). Preferred heteroaryl groups axe 5- or 6-membered
rings having 1 or 2 heteroatoxns. In certain embodiments of
this invention, more preferred heteroaryl groups are those
that have contain a "=N" group.
[0048] Examples of heteroaryl rings include 2-furanyl, 3-
furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-
imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-
isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl {e.g.,
3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,
tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl
and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl,
benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,
2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-
oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-
thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,
purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-
quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl
(e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
[0049] As used herein a "heterocycle" refers to ring
system having 3-10 members and 1, 2, or 3 heteroatoms
independently selected from N, N(R7), O, S, SO, and SOa,
wherein no ring is aromatic (e.g., piperidine and
morpholine). Preferred heterocyclyl groups are 5- or
6-membered rings having 1 or 2 heteroatoms.
[0050] Examples of heterocyclic rings include
3-lH-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-
tetrahydrofuranyl, 3-tetrahydrofuranyl,
2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino,
3-morpholino, 4-morpholino, 2-thiomorpholino, 3-
thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-
pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-

tetraliydropiperazinyl, 3-tetrahydropiperazinyl, 1-
piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-
pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl,
2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl,
3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-
imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl,
indolinyl, tetrahydroquinolinyl, tetrahydroisoguinolinyl,
benzothiolane, benzodithiane, and l,3-dihydro-imidazol-2-one.
[0051] Any of these cycloalipbatic, heterocyclyl, and
heteroaryl groups are optionally fused with a 5- or
6-membered aryl or heteroaryl ring. Furthermore, each of any
aliphatic, aryl, cycloaliphatic, heteroaryl, and heterocyclyl
may contain appropriate substituents (preferably up to 5,
more preferable up to 3, and even more preferably, 0 or 1)
independently selected from, for example, carbonyl and R.
Preferred substituents (including R and «T2) are halogen, -OR7,
-NO2, -CF3, -OCF3, -R7, oxo, -OR7, -O-benzyl, -O-phenyl, 1,2-
methylenedioxy, 1,2-ethylenedioxy, -N(R7)2, -C(O)R7, -CO0R7 or
-CON(R7>2, wherein R7 is defined herein (and is preferably H,
(Cl-C6)-alkyl, or (C2-C6)~alkenyl and alkynyl), with (C1-C6)-
alkyl being most preferred) . It should be understood that
this definition would include a perfluorinated alkyl group.
[0052] In embodiments of this invention where R is a
substituent on a nitrogen atom, preferred R groups are
selected from the group consisting of -R7, -SOR7, -SO2R7,
-SO2N(R7)2, -SO3R7, -C(O)R7, -C(O)C(O)R7, -C(O)C(O)OR7,
-C(O)C(O)N(R7)2, -C(O)CH2C(O)R7, -C(S)R7, -C(S)OR7, -C(O)0R7,
-C(O)N(R7)2, -C(S)N(R7)2, -(CH2)O-2NHC(O)R7, -N(R7)N(R7)COR7,
-N(R7)N(R7)C(O)0R7, -N(R7)N(R7)CON(R7)2, -N(R7)SO2R7,
-N(R7)SO2N(R7)2, -N(R7)C(O)0R7, -N(R7)C(O)R7, -N(R7)C(S)R7,
-N(R7)C(O)N(R7)2, -N(R7)C(S)N(R7)2, -N(COR7)COR7, -N(0R7)R7,
-C(=NR7)N(R7)2, -C(O)N(OR7)R7, -C(=NOR7)R7, -0P(O) (OR7)2,
-P(O) (R7)2, -P(O) (0R7)2, and -P(O) (H) (OR7), wherein R7 is

defined herein (and is preferably H, (Cl-C6)-alkyl, or (C2-
C6)-alkenyl and alkynyl), with (Cl-C6)-alkyl being most
preferred). More preferably, such R groups are selected from
the group consisting of -R7 and -C(O)R7.
[0053] It should be understood that as small molecule,
nonpeptide caspase inhibitors, the compounds of this
invention would have a reasonable number of substituents,
particularly in the variables that are themselves
substituents. Accordingly, if a first R7 group comprises a J2
substituent that comprises a second R7 group, the second R7
group would preferably not be substituted with another J2
group.
[0054] In preferred compounds of this invention, the
stereochemistry is as depicted below:

[0055] Any of the embodiments disclosed herein may be
combined to provide alternative embodiments of this
invention. Specific embodiments of this invention may be
selected from the substituents depicted in the compounds of
Table 1.
[0056] The compounds of the present invention are broad
caspase inhibitors and have an improved ability over reported
compounds to inhibit apoptosis.
[0057] According to one embodiment, this invention
provides a compound of formula la or lb:


[0058] According to another embodiment, this invention
provides a compound of formula Ic or Id:

wherein R1, R2, R3, and R4 are as defined in any of the
embodiments herein.
[0059] According to a more preferred embodiment, this
invention provides a compound of formula II, selected from
Table 1 below:

Table 1. Compounds of the invention.
In the table below, the following definitions are used:
*Ph" is phenyl, "En" is benzyl [-CH2-Ph], ~Et" is ethyl
[-CH2-CH3] , and "I-Pr" is isopropyl [-CH(CH3)2] -



[0060] According to another embodiment, the present
invention provides a pharmaceutical composition
comprising:

a) a compound of formula I, as defined herein, or a
pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable carrier, adjuvant
or vehicle.
[0061] it will be apparent to one skilled in the art
that certain compounds of this invention may exist in
tautomeric forms or hydra ted forms, all such forms of the
compounds being within the scope of the invention.
Unless otherwise stated, structures depicted herein are
also meant to include all stereochemical forms of the
structure; i.e., the R and S configurations for each
asymmetric center. Therefore, single stereochemical
isomers as well as enantiomeric and diastereomeric
mixtures of the present compounds are within the scope of
the invention. Unless otherwise stated, structures
depicted herein are also meant to include compounds that
differ only in the presence of one or more isotopically
enriched atoms. For example, compounds having the
present structures except for the replacement of a
hydrogen by a deuterium or tritium, or the replacement of
a carbon by a 13C- or 14C-enriched carbon are within the
scope of this invention.
[0062] The compounds of this invention may be prepared
in general by methods known to those skilled in the art
for analogous compounds and by the preparative examples
that follow, /see, for example, WO 2004/106304, which is
incorporated herein by reference. yFor the purposes of
illustration, the following Schemes I-III for the
synthesis of the compounds of the present invention are
provided. It should be understood that any protective
group depicted in the schemes may be varied as

appropriate in view of compatibility with other
substituents.
[0063] Various protecting groups may be used in the
methods of this invention (see, e.g., T.W. Greene & P.G.M
Wutz, "Protective Groups in Organic Synthesis", 3rd
Edition, John Wiley & Sons, Inc. (1999) and the earlier
editions of this book). Typical functional groups that
must be protected are amines. Any amines and other
functional groups may be protected according to methods
known in the art. Compounds, including amines, may be
used with or without isolation from the reaction
mixtures.

Scheme I (a) EDC/DMAP/HOBt/THF; (b) Dess-Martin
periodinane; (c) TFA/DCM
[0064] In Scheme I above, the following abbreviations
are used: EDC is 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide; HOBt is 1-hydroxybenzotriazole; THF is
tetrahydrofuran; TFA is trifluoroacetic acid; DCM is

dichloromethane; DMAP is 4-dimethylaminopyridine. Acid 1
is coupled to amino alcohol 2. Here the coupling is
depicted using EDC/DMAP/HOBt/THF, however, other suitable
conditions may also be tised. Depending on the nature of
R4 and R5 an amino ketone may be used, in place of the
amino alcohol, thus avoiding the subsequent oxidation
step. In the case of fluoromethyl ketones where R5 is
CH2F, the amino alcohol 2 may be obtained according to the
method of Revesz efc al., Tetrahedron Lett. 1994, 35,
9693. In the case of tetrafluorophenoxy ketones where R5
is -CH2O-2,3,5, 6-tetraf luorophenyl, amino alcohol 2 may be
obtained by methods analogous to those of Semple et al.,
Bioorganic and Medicinal Chemistry Letters, 1997, 7, 1337
(Scheme II).
[0065] Finally the hydroxy group in compound 3 is
oxidized (e.g., with Dess-Martin periodinane) and the
resulting compound treated appropriately according to the
nature of R4. For example, in product I if R4 is a
carboxylic acid, then R4 in 3 is preferably an ester that
is hydrolyzed in the final step of the scheme. If that
ester is a t-butyl ester (i.e., if R4 is CC^tBu),
treatment with trifluoroacetic acid will give the acid.
The ester is preferably a t-butyl ester when the other
substituents in I are compatible with acidic conditions.
[0066] If R4 in product I is an ester, the desired
ester may be prepared by esterifying the corresponding
acid or by having the desired ester group already present
in compound 2.


Scheme II (a)KF/DMF/ArOH; (b) NaBRj/THF; (c) H2/Pd/C/MeOH
[0067] In scheme II above, the following abreviations
are used: KF is potassium fluoride; DMF is N,N-
dimethylformamide; ArOH is 2,3,5,6-tetrafluorophenol; THF
is tetahydrofuran; MeOH is methanol. Commercially
available bromoketone 4 (R4=CO2tBu) is reacted with
2,3,5,6-tetrafluorophenol and potassium fluoride to give
phenoxy ketone 5. The ketone is then reduced with a
suitable reducing agent, for example, sodium borohydride,
to give the alcohol 6, which is hydrogenated by using
hydrogen gas and a suitable catalyst, for example,
palladium on carbon, to give the amino alcohol 2 (R4=
CO2tBu, RS= CH2O-2,3,5,6-tetrafluorophenyl).


Scheme III (a)H2 Pd/C MeOH; (b) R^-Cl, Na2CO3, H20/THF;
(c) (CF3SO2)20/ 2,6-Lutidine, DCM; (d) NaH, THF; (e)
TFA/DCM; (f) R^Cl, Et3Nr DMAP, DCM;
[0068] In Scheme III the folowing abreviatons are
used: Cbz is a benzyloxycarbonyl protecting group; MeOH
is methanol; DCM is dichloromethane; TPA is
trifluoroacetic acid; DMAP is 4-dimethylaminopyridine;
THF is tetrahydrofuran. Pyridone acid derivatives 1 can
be prepared in chiral form using the synthetic sequence
shown in Scheme III. Commercially available
nitropyridone is reduced to the amine with hydrogen and
palladium/carbon. The amino group is then functionalised
with the appropriate electrophile: in the case of Rl=Cbz
the benzyloxycarbonyl protected amine is prepared using a
procedure similar to that described by Warner et al J".
Med. Chem. 1994, 37(19), 309O-3099. For the other cases
the amine is derivatised using standard methods.
(R)-tert-butyl-2-hydroxy ester is treated with
trif luoromethanesulphonic anhydride and 2, 6-lutidine in
DCM to give the corresponding trif late. Reaction of the

triflate with the anion of the ftuictionalized 2-
hydroxypyridine (prepared by deprotonation with sodium
hydride in THF) gives the N-alkylated pyridone. When R1
is a benzyloxycarbonyl protecting group it can be removed
at this stage using hydrogen and palladium on carbon to
give the amine; this is then reacted with an appropriate
electrophile, triethylamine and DMAP in DCM. For example
if R1 is required to be R6C=0 (an amide) then an
appropriately substituted acid chloride may be used. If
R1 is required to be R6S{=0)2 (sulphonamide) then an
appropriately substituted sulfonyl chloride may be used.
If R1 is (R6)2N(C=0) (urea) then an appropriately
substituted carbamoyl chloride or isocyanate may be used.
The other R1 groups may be prepared accordingly. Acid 1
is then prepared by deprotection of the ester by, for
example, using trifluoroacetic acid. The acid is then
coupled to amino alcohol 2 (Scheme 1).

Scheme IV (a) NaOMe, MeOH; (b) LiOH/H20/dioxane; (c)DPPA,
TEA, BnOH, dioxane; (d)H2 Pd/C MeOH; (e) R^Cl, EtaN,
DMAP, DCM; (f) TFA/DCM;
In Scheme IV the folowing abreviations are used: MeOH is
methanol; DPPA is diphenylphosporyl azide; BnOH is benzyl

alcohol; TEA is triethylamine; DCM is dichloromethane;
TFA is trifluoroacetic acid; THF is tetrahydrofuran;
Pyridone acids derivatives 1 can be prepared in chiral
form using an alternative route, depicted in Scheme TV.
Reaction of 2-(3-Methoxy-allylidene)-malonic acid
dimethyl ester and aminoacid fcerfc-butyl esters in the
presence of methoxide gives the cyclised pyridone
product. Hydrolysis of the methyl ester into the acid,
followed by treatment of the acid under Curtius
rearrangement conditions in the presence of benzyl
alcohol give the benzyloxycarbonyl protected
aminopyridone. The benzyloxycarbonyl protecting group is
removed under hydrogenolysis conditions and the resulting
amine is then reacted with an appropriate electrophile,
triethylamine and DMAP in DCM. For example if R1 is
required to be R6C=0 (an amide) then an appropriately
substituted acid chloride may be used. If R1 is required
to be R6S(=0)2 (sulphonamide) then an appropriately
substituted sulfonyl chloride may be used. If R1 is
(R6)2N(C=0) (urea) then an appropriately substituted
carbamoyl chloride or isocyanate may be used. The other
R1 groups may be prepared accordingly. Acid 1 is then
prepared by deprotection of the ester by, for example,
using trifluoroacetic acid. The acid is then coupled to
amino alcohol 2 (Scheme 1) .
[0069] Therefore, another embodiment of this invention
provides a process for preparing a compound of formula I:


wherein R1, R2, R3, R4, and R5, are as defined in any of
the embodiments herein, comprising:
(a) reacting a compound of formula (III) :

wherein:
R10 is -NO2, -C(O)OR11, R6C(O)N(H)-, R6SO2N(H)-,
R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6C(O)C(O)N(H)-,
(R6)2NC(O)C(O)N(H)-, or R6OC(O)C(O)N(H)-;
R11 is independently hydrogen, (C1-C12) -aliphatic-, (C3-
C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-
heterocyclyl-, (C5-C10}-heteroaryl-, (C3-C10)-
cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(Cl-
C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-
aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-,
wherein up to 3 aliphatic carbon atoms may be replaced
with a group selected from O, N(H), N(R7) , S, SO, and
SO2; and wherein R11 is optionally substituted with up
to 6 substituents independently selected from R; and
R, R2, R3, and R6 are as defined in any of the embodiments
of formula (I) herein;
with a compound of formula (IV) :

wherein Y is either a carbonyl group or an OH group; and
R4 and R5 are as defined in any of the embodiments of
formula (I) herein;

in the presence of peptide coupling conditions and a
solvent;
provided that if Y is an. OH group, then the process
further comprises (b) oxidizing the OH group to provide
the compound of formula (I); and
provided that if R10 is -NO2, -CfOJOR11, or -CN, the
process comprises the further step of converting the -NO2,
-C(O)0R1:L, or -CN into R6C(O)N(H)-, R6SO2N(H)-,
R6OC{0)N(H)-, (R6)2NC(O)N(H)-, R6C(O)C(O)N(H) -,
(R6)2NC(O)C(O)N(H)-, or R6OC(O)C(O)N(H) -.
[0070] The coupling conditions may be any known to
skilled practitioners for forming peptidyl bonds.
Preferred coupling conditions are EDC/DM&P/HOBt. A
preferred solvent in the above embodiment is THF.
[0071] In a preferred embodiment, the compound of
formula (III):

wherein R2, R3, and R9 are as defined herein;
is prepared by a process comprising:
(c) reacting a compound of formula (V):

wherein R, R2, R3, and RxD are as defined herein;
in a solvent in the presence of deprotecting conditions.
[0072] The deprotecting conditions will depend on the
specific protecting group (i.e., R11) . For example, if R11

is t-butyl, then preferred deprotecting conditions would
include acid hydrolysis. A preferred acid is TFA. A
preferred solvent is DCM. More preferably the solvent
and the hydrolyzing conditions comprise TFA and DCM. If
R11 is methyl or ethyl, then preferred deprotecting
conditions would be basic (e.g., aqueous NaOH) . If R11 is
benzyl, then the benzyl group could be removed by
hydrogenolysis.
[0073] In a preferred embodiment, the compound of
formula (V) :

wherein R2, R3, R10, and R11 are as defined herein;
is prepared by a process comprising:
(d) reacting a compound of formula (VI):

wherein R2 and R10 are as defined herein;
with a compound of formula (VII):

wherein X is a suitable leaving group; and
R3 and R11 are as defined herein;
in the presence of a solvent and a base.

[0074] Preferably, X is -I, -Br, -CI, -OH, an
alkylsulfonate, or an aryl sulfonate. When X is -OH, an
appropriate leaving group may be generated in situ (e.g.,
as in the Mitsunobu reaction) . Preferred sulfonates
include -O-trifluoromethanesulfonate, -O-
methanesulfonate, -O-benzenesulfonate, -O-p-
toluenesulfonate, -O-m-nitrobenzenesulfonate, and -O-p-
nitrobenzenesulfonate. Suitable leaving groups useful in
the methods of this invention are well known in the art.
See, e.g., "March's Advanced Organic Chemistry", 5th Ed.,
Ed.: Smith, M.B. and March, J., John Wiley & Sons, New
York (2001).
[0075] Any solvent that is compatible with the
generation of anions may be used. Preferred solvents
include DMF, toluene, and THF.
[0076] Suitable bases include any that may remove a
proton from the hydroxy group in (V) . Such bases include
BuLi, LDA, LHMDS, and NaH. Preferably, the base is NaH.
[0077] Another embodiment of this invention provides a
process for preparing a compound of formula (VTII) :

wherein:
R2 is -CF3, -CI, -OR7, -NO2, -OCF3/ -CN, or R8; and
R3, R8, R10, and R11 are as defined herein;
comprising the step of (e) reacting a compound of formula
(IX):


wherein R2 and R10 are as defined herein;
with a compound of formula (VII) :

wherein R3 and R11 are as defined herein; and
X is a suitable leaving group;
in the presence of a solvent and a base.
[0078] Preferably, X is -I, -Br, -CI, -OH, an
alkylsulfonate, or an aryl sulfonate. When X is -OH, an
appropriate leaving group may be generated in situ (e.g.,
as in the Mitsunobu reaction). Preferred sulfonates
include -O-tri fluoromethanesulfonate,
-O-methanesulfonate, -O-benzenesulfonate,
-O-p-toluenesulfonate, -O-m-nitrobenzenesulfonate, and
-O-p-nitrobenzenesulfonate.
[00793 Any solvent is compatible with the generation
of anions may be used. Such solvents include DMF,
toluene, and THF. Preferably, the solvent is THF.
[0080] Suitable bases include any that may remove a
proton from the hydroxy group in (V) . Such bases include
BuLi, LDA, LHMDS, and NaH. Preferably, the base is NaH.
[0081] Another embodiment of this invention provides a
process for preparing a compound of formula (I):


wherein R1, R2, R3, R4, and R5, are as defined in any of
the embodiments herein, comprising:
(a) reacting a compound of formula (VI or IX):

wherein:
R10 is -NO2, -CfOJOR11, -CN, R6C(O)N{H)-, R6SO2N(H)-,
R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6C(O)C(O)N(H)-,
(R6)2NC(O)C(O)N(H)-, or R6OC(O)C(O)N(H)-; and
R2, R3, and R6 are as defined herein;
with a compound of formula (X) :

wherein Y is either a carbonyl group or an OH group; and
R4 and R5 are as defined herein;
in the presence of any of the coupling conditions defined
herein and a solvent;
provided that if Y is an OH group, then the process
further comprises (b) oxidizing the OH group to provide
the compound of formula (I); and
provided that if R10 is -NO2, -CfOjOR11, or -CN, the
process comprises the further step of converting the -NO2,
-C(O)OR1:L, or -CN into R6bC(O)N(H)-, R6aSO2N(H)-,

R^OCfOWH)-, (R^aNCtONdJ)-, R^CIOJCIONIH)-,
(R^hNCCOJCfOWH)-, or R^OC(O) C (O)N(H) -.
[0082] If pharmaceutically acceptable salts of the
compounds of this invention are utilized in these
compositions, those salts are preferably derived from
inorganic or organic acids and bases. Included among
such acid salts are the following: acetate, adipate,
alginate, aspartate, benzoate, benzene sulfonate,
bisulfate, butyrate, citrate, camphorate, camphor
sulfonate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate,
glucoheptanoate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate,
oxalate, pamoate, pectinate, persulfate, 3-phenyl-
propionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, tosylate and undecanoate. Base
salts include ammonium salts, alkali metal salts, such as
sodium and potassium salts, alkaline earth metal salts,
such as calcium and magnesium salts, salts with organic
bases, such as dicyclohexylamine salts,
N-methyl-D-glucamine, and salts with amino acids such as
arginine, lysine, and so forth.
[0083] Also, the basic nitrogen-containing groups can
be quaternized with such agents as lower alkyl halides,
such as methyl, ethyl, propyl, and butyl chloride,
bromides and iodides; dialkyl sulfates, such as dimethyl,
diethyl, dibutyl and diamyl sulfates, long chain halides
such as decyl, lauryl, myristyl and stearyl chlorides,
bromides and iodides, aralkyl halides, such as benzyl and
phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.

[0084] The compounds of this invention may also be
modified by appending appropriate functionalities to
enhance selective biological properties. Such
modifications are known in the art and include those
which increase biological penetration into a given
biological system (e.g., blood, lymphatic system, central
nervous system), increase oral availability, increase
solubility to allow administration by injection, alter
metabolism and alter rate of excretion.
[0085] For example, a. carboxylic acid group in a
compound of this invention may be derivatized as, for
example, an ester. Preferred esters would be those
derived from:
a Ci_6 straight-chained or branched alkyl,
alkenyl, or alkynyl, wherein the alkyl, alkenyl, or
alkynyl is optionally substituted with aryl, CP3/ Cl, F,
OMe, OEt, OCF3, CN, or NMe2;
a Ci_6 cycloalkyl, wherein 1-2 carbon atoms in
the cycloalkyl is optionally replaced with -O- or -NR9-.
[0086] Compounds of this invention having a carbonyl
group may be similarly derivatized as, e.g., an acetal,
ketal, oxime (=NOR9), hydrazine (=NN(R9)2>, thioacetal, or
thioketal.
[0087] Appropriate derivatives of amines are known in
the art and are also included within the scope of this
invention.
[0088] Certain of the above derivatives would include
the protective groups known to skilled practitioners
(see, e.g., T.W. Greene & P.G.M Wutz, "Protective Groups
in Organic Synthesis", 3rd Edition, John Wiley & Sons,
Inc. (1999)). Typical functional groups that must be
protected are amines. Any amines and other functional
groups may be protected according to methods known in the

art. Compounds, including amines, may be used with or
without isolation from the reaction mixtures. As would
be recognized by a skilled practitioner, these protective
groups may also be employed in the processes of this
invention.
[0089] Without being bound by theory, applicants'
cyclic acetal compounds are believed to be prodrugs.
That is, the acetal portion is cleaved in vivo to provide
a corresponding acid-aldehyde compound. As would be
recognized by a skilled practitioner," chemical compounds
may be metabolized in vivo, e.g., at a site other than
the prodrug cleavage site. Any such metabolites are
included within the scope of this invention.
[0090] The compounds of this invention may be assayed
for their ability to inhibit apoptosis, the release of
IL-lp or caspase activity directly. Assays for each of
the activities are known in the art. However, as would
be recognized by a skilled practitioner, a prodrug
compound of this invention should be active only in
assays where the prodrug moiety would be cleaved,
typically in in vivo assays. Selected assays are
described below.
[0091] Pharmaceutically acceptable carriers that may
be used in these compositions include, but are not
limited to, ion exchangers, alumina, aluminum stearate,
lecithin, serum proteins, such as human serum albumin,
buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium

trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-blocJc polymers,
polyethylene glycol and wool fat.
[0092] According to a preferred embodiment, the
compositions of this invention are formulated for
pharmaceutical administration to a mammal, preferably a
human being.
[0093] Such pharmaceutical compositions of the present
invention may be administered orally, parenterally, by
inhalation spray, topically, rectally, nasally, buccally,
vaginally or via an implanted reservoir. The term
"parenteral* as used herein includes subcutaneous,
intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic,
intralesional and intracranial injection or infusion
techniques. Preferably., the compositions are
administered orally or intravenously.
[0094] Sterile injectable forms of the compositions of
this invention may be aqueous or oleaginous suspension.
These suspensions may be formulated according to
techniques known in the art using suitable dispersing or
wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example
as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water.
Ringer's solution and isotonic sodium chloride solution.
In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this
purpose, any bland fixed oil may be employed including

synthetic mono- or di-glycerides. Fatty acids, such as
oleic acid and its glyceride derivatives are useful in
the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or
castor oil, especially in their polyoxyethylated
versions. These oil solutions or suspensions may also
contain a long-chain alcohol diluent or dispersant, such
as carboxymethyl cellulose or similar dispersing agents
which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including
emulsions and suspensions. Other commonly used
surfactants, such as Tweens, Spans and other emulsifying
agents or bioavailability enhancers which are commonly
used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for
the purposes of formulation.
[0095] The pharmaceutical compositions of this
invention may be orally administered in any orally
acceptable dosage form including, but not limited to,
capsules, tablets, aqueous suspensions or solutions. In
the case of tablets for oral use, carriers which are
commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule
form, useful diluents include lactose and dried corn
starch. When aqueous suspensions are required for oral
use, the active ingredient is combined with emulsifying
and suspending agents. If desired, certain sweetening,
flavoring or coloring agents may also be added.
[0096] Alternatively, the pharmaceutical compositions
of this invention may be administered in the form of
suppositories for rectal administration. These can be
prepared by mixing the agent with a suitable

non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and
therefore will melt in the rectum to release the drug.
Such materials include cocoa butter, beeswax and
polyethylene glycols.
[0097] The pharmaceutical compositions of this
invention may also be administered topically, especially
when the target of treatment includes areas or organs
readily accessible by topical application, including
diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily
prepared for each of these areas or organs.
[0098] Topical application for the lower intestinal
tract can be effected in a rectal suppository formulation
(see above) or in a suitable enema formulation.
Topically-transdermal patches may also be used.
[0099] For topical applications, the pharmaceutical
compositions may be formulated in a suitable ointment
containing the active component suspended or dissolved in
one or more carriers. Carriers for topical
administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying
wax and water. Alternatively, the pharmaceutical
compositions can be formulated in a suitable lotion or
cream containing the active components suspended or
dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60,
cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,
benzyl alcohol and water.

[0100] For ophthalmic use, the pharmaceutical
compositions may be formulated as micronized suspensions
in isotonic, pH adjusted sterile saline, or, preferably,
as solutions in isotonic, pH adjusted sterile saline,
either with our without a preservative such as
benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated
in an ointment such as petrolatum.
[0101] The pharmaceutical compositions of this
invention may also be administered by nasal aerosol or
inhalation. Such compositions are prepared according to
techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or
dispersing agents.
[0102] The above-described compositions are
particularly useful in therapeutic applications relating
to an IL-1 mediated disease, an apoptosis mediated
disease, an inflammatory disease, an autoimmune disease,
a destructive bone disorder, a proliferative disorder, an
infectious disease, a degenerative disease, a disease
associated with cell death, or various forms of liver
disease. Such diseases include those related to
rheumatology and autoimmunity, such as rheumatoid
arthritis, osteoarthritis, osteoporosis, systemic lupus
erythematosus, scleroderma, chronic thyroiditis, Grave's
disease, myasthenia gravis, autoimmune neutropenia,
autoimmune hemolytic anemia, thrombocytopenia, juvenile
rheumatoid arthritis, gout, Behcet's syndrome, Still's
syndrome, macrophage activation syndrome, and
sarcoidosis; autoinflammatory syndromes, such as

cryopyrin-associated Periodic Syndromes (sometimes
referred to as autoinflammatory fever syndromes),
(including Muckle-Wells syndrome, familial cold urticaria
(also known as familial cold autoinf lammatory syndrome),
chronic infantile neurological cutaneous and articular
syndrome (a.k.a. neonatal onset multisystem inflammatory
disease)), familial mediterranean fever, TNFRl-Associated
Periodic Syndrome (TRAPS), Hyper-IgD periodic fever
Syndrome (HIDS), and Blau's syndrome, as well as systemic
onset juvenile idiopathic arthritis (also known as
Still's disease), and macrophage activation syndrome;
dermatology/ such as psoriasis, atopic dermatitis,
scarring, alopecia, acne vulgaris, and pemphigus, as well
as toxic epidermal necrolysis; respiratory, such as
asthma, adult respiratory distress syndrome, cystic
fibrosis, emphysema, chronic bronchitis, chronic
obstructive pulmonary disease, and idiopathic pulmonary
fibrosis; internal medicine, such as inflammatory
peritonitis, inflammatory bowel disease, Crohn's disease,
ulcerative colitis, autoimmune gastritis, H.pylori-
associated gastric and duodenal ulcer disease, diabetes,
pancreatitis, glomerulonephritis, chronic active
hepatitis, excess dietary alcohol intake disease, renal
disease, polycystic kidney disease, burns, organ
apoptosis after burn injury, haemorrhagic shock, organ
failure (e.g., hepatic failure, acute renal failure, and
acute respiratory failure), and endometriosis;
transplants, such as graft vs. host disease (GVHD) and
organ transplant rejection; oncology, such as leukemias
and related disorders, myelodysplastic syndrome, multiple
myeloma-related bone disorder, acute myelogenous
leukemia, chronic myelogenous leukemia, "metastatic
melanoma, Kaposi's sarcoma, and multiple myeloma;

cardiovascular, such as chronic heart disease, acute
heart disease, myocardial infarction, myocardial
ischemia, congestive heart failure, atherosclerosis,
coronary artery bypass graft (CABG), and acute coronary
syndrome; the central and peripheral nervous systems,
such as Alzheimer's disease, Parkinson's disease,
Huntington's disease, Kennedy's disease, prion disease,
cerebral ischemia, epilepsy, spinal muscular atrophy,
amyotrophic lateral sclerosis, multiple sclerosis, HIV-
related encephalitis, traumatic brain injury, spinal cord
injury, neurological damage due to stroke, diabetic
neuropathy, and acute and chronic pain, as well as
seizures, seizure disorders, and convulsions;
ophthalomology, such as uveitis, retinal disorders,
diabetic retinopathy, glaucoma, and keratitis, as well as
eye infections, injuries, allergies, chemical
irritations, burns, dry eye, Sjogren's syndrome, and
aging of the eye (see, e.g., WO 2005/053665, which is
incorporated by reference); infectious diseases, such as
viral mediated disease, sepsis, septic shock,
Shigellosis, hepatitis-B, hepatitis-C, hepatitis-G,
yellow fever, dengue fever, Japanese encephalitis, HIV
infection, tuberculosis, meningitis, Pseudomonas
infection, and Acinetobacter infection, as well as other
bacterial, viral, parasitic, or fungal infections,
particularly eye infections; and other diseases, such as
aging. The compounds and compositions are also useful in
treating complications associated with coronary artery
bypass grafts. The amount of compound present in the
above-described compositions should be sufficient to
cause a detectable decrease din the severity of the
disease or in caspase activity and/or cell apoptosis, as
measured by any of the assays known in the art.

[0103] According to another embodiment, the
compositions of this invention may further comprise
another therapeutic agent. Such agents include, but are
not limited to, thrombolytic agents such as tissue
plasminogen activator and streptokinase. When a second
agent is used, the second agent may be administered
either as a separate dosage form or as part of a single
dosage form with the compounds or compositions of this
invention. Accordingly, a combined preparation for
simultaneous, separate, or sequential use is provided by
this invention.
[0104] Dosage levels of between about 0.01 and about
100 mg/kg body weight per day, preferably between about
0.5 and about 75 mg/kg body weight per day of the
protease inhibitor compounds described herein are useful
in a monotherapy for the prevention and treatment of a
disease involving caspase activity and/or apoptosis.
[0105] Typically, the pharmaceutical compositions of
this invention will be administered from about 1 to about
5 times per day or alternatively, as a continuous
infusion. Such administration can be used as a chronic
or acute therapy. The amount of active ingredient that
may be combined with the carrier materials to produce a
single dosage form will vary depending upon the host
treated and the particular mode of administration. A
typical preparation will contain from about 5% to about
95% active compound (w/w) . Preferably, such preparations
contain from about 20% to about 80% active compound.
[0106] When the compositions of this invention
comprise a combination of a compound of formula I and one
or more additional therapeutic or prophylactic agents,
both the compound and the additional agent should be
present at dosage levels of between about 10 to 100%, and

more preferably between about 10 to 80% of the dosage
normally administered in a monotherapy regimen.
[0107] It should also be understood that a specific
dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and
the judgment of the treating physician and the severity
of the particular disease being treated. The amount of
active ingredients will also depend upon the particular
compound and other therapeutic agent, if present, in the
composition.
[0108] In a preferred embodiment, the invention
provides a method of treating a mammal, having one of the
aforementioned diseases, comprising the step of
administering to said mammal a pharmaceutically
acceptable composition described above. In this
embodiment, if the patient is also administered another
therapeutic agent or caspase inhibitor, it may be
delivered together with the compound of this invention in
a single dosage form, or, as a separate dosage form.
When administered as a separate dosage form, the other
caspase inhibitor or agent may be administered prior to,
at the same time as, or following administration of a
pharmaceutically acceptable composition comprising a
compound of this invention.
[0109] In order that this invention be more fully
understood, the following preparative and testing
examples are set forth. These examples are for the
purpose of illustration only and are not to be construed
as limiting the scope of the invention in any way. ^-NMR

spectra were recorded at 400 MHz using a Bruker DPX 400
instrument. Mass spec, samples were analyzed on a
MicroMass Quattro Micro mass spectrometer operated in
single MS mode with electrospray ionization.
Example II.1
3 (R, S) - [2 (S) - (3-Benzoylandno-2-oxo-22-T-pyridin-l-yl) -3-
phenyl-propionylamino] -5-fluoro-4-oxo-pentanoic acid

Method A:
(S) -2- (3-Benzyloxycarboiiylamino-2-oxo-2J3r-pyridin-l-yl) -3-
phenyl-propionic acid tart-butyl ester

[0110] To a cooled (0°C) solution of (R)-2-Hydroxy-3-
phenyl-propionic acid tert-butyl ester (2.50 g, 15.6
mmol) in dichloromethane (50 mL), was slowly added 2,6-
lutidine (3.3 g, 30.8 mmol) and then
trifluoromethanesulfonic anhydride (8.25 g, 29.2 mmol).
The resulting mixture was stirred at 0°C for 1 hour, then
partitioned between tert-butylmethyl ether (200 mL) and
an aqueous solution of 1M HC1 (60 mL). The organic layer
was washed with brine (60 mL), dried (sodium sulfate),
filtered and concentrated to afford the triflate as a
light brown oil.
[0111] To a solution of (2-oxo-l,2-dihydro-pyridin-3-
yl)-carbamic acid benzyl ester (P. Warner et al., J. Med.

Chem., 37, 19, 1994, 309O-3099) (4.34 g, 17.8 mtnol) in dry
THF (100 mL) was added sodium hydride (60% dispersion,
711 mg, 17.8 nraiol) and the solution was stirred at room
temperature for 45 minutes. The reaction mixture was
then slowly transferred with a canula onto a solution of
the trif late prepared above in THF (30 mL). The reaction
mixture was stirred at room temperature for 90 minutes
and quenched with aqueous ammonium chloride (20 mL) .
Most of the solvent was evaporated and the residue was
partitioned between EtOAc and saturated aqueous NH4CI.
The organic layer was washed with brine (30 mL), dried
(MgSO4), filtered and evaporated. The residue was
purified by flash chromatography (10% ethyl
acetate/hexane) to afford the title compound as a
colourless oil (5.1 g, 76%); XH NMR (400 MHz, CDCI3) 5
1.48 (9H, s), 3.35 (1H, dd), 3.65 (1H, dd), 5.23 (2H, s),
5.53 (1H, m), 6.18 (1H, t), 6.85 (1H, d), 7.12 (2H, m),
7.2O-7.48 (8H, m), 7.82 (1H, s), 7.98 (1H, m).
Method B:
(S) -2- (3-Amino-2-oxo-2ir-'pyridin-l-yl) -3-phenyl-propionic
acid terfc-butyl ester

[0112] To a solution of (S)-2-(3-
benzyloxycarbonylamino-2-oxo-2ff-pyridin- 1-yl) -3 -phenyl-
propionic acid fcert-butyl ester (4 g, 8.92 mmol) in a
mixture of MeOH (40 mL) and EtOAc (10 mL) was added 10%
Pd/C (500 mg) . The mixture was degassed and stirred at
room temperature for 4 hours under an atmosphere of
hydrogen (balloon pressure) . The reaction mixture was

filtered through a short pad of celite which was then
flushed with MeOH. The combined filtrates were
evaporated under reduced pressure to afford the title
compound as a white solid (2.6 g, 92%); XH NMR (400 MHz,
CDC13) 5 1.48 (9H, s), 3.32 (1H, dd), 3.52 (1H, dd), 3.95
(2H, br s), 5.55 (1H, dd), 6.00 (1H, t) , 6.55 (1H, d),
6.72 (1H, d), 7.18-7.35 (5H, m).
Method C:
(S)-2- (3-Benzoylamino-2-oxo-2fl"-pyridin-l-yl) -3-phenyl-
propionic acid ttert-butyl ester

[0113] To a cooled (0°C) solution of (S)-2-(3-amino-2-
oxo-2iJ-pyridin-l-yl)-3-phenyl-propionic acid fcert-butyl
ester (2.6 g, 8.26 mmol) in dichloromethane (50 mL) was
added triethylamine (918 rag, 9.09 mmol) and DMAP (20 mg)
followed by dropwise addition of benzoyl chloride (1.27
g, 9.1 mmol) . The reaction mixture was stirred at room
temperature for 12 hours and then partitioned between
EtOAc and sat. aqueous NH4CI. The organic layer was
washed with water (30 ml), brine (30 mL), dried (MgSCU),
filtered and evaporated. The residue was purified by
flash chromatography (1O-25% ethyl acetate/petrol ether)
to afford the title compound as a colourless oil (2.07 g,
60%); XH NMR (400 MHz, CDCI3) 5 1.48 (9H, s) , 3.35 (1H,
dd), 3.55 (1H, dd), 5.5 (1H, m), 6.26 (1H, t), 6.90 (1H,
d), 7.15 (2H, m), 7.28 (3H, m), 7.52 (3H, m), 7.95 (2H,
m) , 8.52 (1H, d), 9.22 (1H, br s).

Method Dt
(S) -2- (3-Benzoylamino-2-oxo-2ff-pyridin-l-yl) -3-phenyl-
propionic acid

[0114] A solution of (S)-2-(3-benzoylamino-2-oxo-2ff-
pyridin-l-yl)-3-phenyl-propionic acid tert-butyl ester
(2.07 g, 4.95 mmol) in dichloromethane (25 mL) was cooled
to 0°C. Trifluoroacetic acid (25 ml) was added and the
resulting mixture allowed to warm to room temperature and
stir for 5 hours. The mixture was then concentrated
under reduced pressure and the residue re-dissolved in
dichloromethane. This process was repeated several times
in order to remove excess trifluoroacetic acid. The
resulting solid was slurried in diethyl ether, filtered
and washed with more diethyl ether. The solid was then
dried to constant weight under vacuum. This gave the
title product as a white solid (1.61 g, 90%); XR NMR (400
MHz, CDC13) 8 3.48 (1H, dd) , 3.65 (1H, dd) , 5.32 (1H, m) ,
6.35 (1H, t), 6.80 (1H, m)7 7.08 (2H, d) , 7.27-7.35 (3H,
m), 7.56-7.65 (3H, m), 7.92 (2H, d), 8.65 (1H, d), 9.18
(1H, br s).

Method E:
3 phenyl-propionylamino] -5-f luoro-4 (R, S) -hydroxy-pentanoic
acid fcert-butyl ester

[0115] A stirred mixture of (S)-2-(3-benzoylamino-2-
oxo-2H-pyridin-l-yl) -3 -phenyl-propionic acid (2.20 g,
6.07 mmol), 3 (R, S) -Amino-5-fluoro-4 (R, S) -hydroxy-
pentanoic acid tert-butyl ester (1.39 g, 6.68 mmol), HOBt
(902 mg, 6.68 mmol), DMAP (853 mg, 6.98 mmol) and THF (20
mL) was cooled to 0°C then EDC (1.28 mg, 6.68 mmol) was
added. The mixture was allowed to warm to room
temperature during 16h then concentrated under reduced
pressure. The residue was purified by flash
chromatography (3O-70 to 55-45% ethyl acetate/hexane) to
afford the title compound as a white foam (1.23 g, 32%);
XH NMR (400 MHz, CDC13) 8 0.88-0.93 (3H, m) , 1.35-1.42
(9H, 2s), 2.5O-2.65 (2H, m) , 3.2O-3.35 (2H, m) , 3.60 (1H,
m), 3.98 (1H, m ), 4.1O-4.32 (3H, m), 5.62-5.70 (1H, m),
6.44 (1H, m), 6.8O-6.98 (1H, m), 7.21-7.41 (5H, m), 7.55-
7.62 (3H, m), 7.95 (2H, m), 8.58 (1H, t), 9.18 (1H, br
s).

Method F:
3 (R, S) - [2 (S) - (3-Benzoylandno-2-oxo-2ff-pyridin-l-yl) -3-
phenyl-propionylamino] -5-fluoro-4-oxo-pentanoic acid
terfc-butyl ester

[0116] A stirred solution of 3{R,S)-[2(S)- benzoylamino-2-oxo-2H-pyridin-l-yl)-3-phenyl-
propionylainino]-5-fluoro-4(R, S)-hydroxy-pentanoic acid
tert-butyl ester (1.23 g, 2-23 mmol) in anhydrous DCM (25
mL) was treated with 1, l,l-triacetoxy-l,l-dihydro-l,2- •
benziodoxol-3 (lH)-one (Dess-Martin periodinane) (1.13 g,
2.67 mmol) at 0°C. The resulting mixture was kept at 0°C
for 2 hours, diluted with ethyl acetate, then poured into
a 1:1 mixture of saturated aqueous sodium hydrogen
carbonate and saturated aqueous sodium thiosulfate. The
organic layer was removed and the aqueous layer re-
extracted with ethyl acetate. The combined organic
extracts were dried (Magnesium sulfate) and concentrated.
The residue was purified by flash chromatography (4O-60%
ethyl acetate /petrol ether) to afford the title compound
as a red gum (776 mg, 64%); XH NMR (400 MHz, CDC13) 8
1.32-1.40 (3H, s), 2.60 (1H, m), 2.92 (1H, m), 3.27 (1H,
m), 3.61 (1H, m), 4.78-4.88 (1H, m), 4.97-5.05 (2H, m) ,
5.77 (1H, m), 6.43 {1H, m), 7.22-7.38 (7H, m) , 7.54-7.65
(3H, m), 7.95 (2H, m), 8.62 (1H, m) , 9.22 (1H, m).
Method G:
3 (R, S) - [2 (S) - (3-Benzoylamino-2-oxo-2H-pyridin-l-yl) -3-
phenyl-propionylamino] -5-fluoro-4-oxo-pentanoic acid


[0117] A solution of 3(R,S)-[2(S)-(3-benzoylamino-2-
oxo-2ff-pyridin-l-yl) -3-phenyl-propionylamino] -5-f luoro-4-
oxo-pentanoic acid terfc-butyl ester (776 mg, 1.41 mmol)
in dichloromethane (6 mL) was cooled to 0°C.
Trifluoroacetic acid (2 ml) was added and the resulting
mixture allowed to warm to room temperature and stir for
3 hours. The mixture was then concentrated under reduced
pressure and the residue redisolved in dichloromethane.
This process was repeated several times in order to
remove excess trifluoroacetic acid. The solid was then
dried to constant weight under vacuum. This gave the
title product as a pink solid (627 mg, 90%); *H NMR (400
MHz, d6-DMSO) 5 2.59-2.95 (2H, m) , 3.34-3.47 (2H, m) ,
4.3O-4.81 (2H, m), 5.15-5.33 (2H, m) , 5.87-6.09 (1H, m) ,
6.38 (1H, t), 7.15-7.32 (5H, m) , 7.6O-7.78 (4H, m) , 7.92
(2H, d), 8.17-8.21 (1H, m), 9.01-9.11 (1H, m), 9.28 (1H,
m), 12.51 (1H, br s) ; 19P NMR (376 MHz, d6-DMSO, proton-
decoupled) S -226.8, 232.6; M+H 494.4, M-H 492.4.
Example II.2
3 (R, S) - [2 (S) - (3-Benzoylamino-2-oxo-2H-pyridin-l-yl)-4-
phenyl-butyrylamino]-5-fluoro-4-oxo-pentanoic acid


[0118] Prepared according to methods A and D-6 using
N- (2 -Oxo-1,2-dihydro-pyridin-3-yl) -benzamide and (R) -2 -
hydroxy-4-phenyl-butyric acid fcerfc-butyl ester (prepared
using a method similar to that reported in Lei et al., J.
Carbohydrate Chemistry, 15, 4, 1996, 485-500) in method
A; white solid; IR (solid) 1643, 1578, 1521, 1490, 1213,
753 cm-1; *H NMR (400Mhz, d6-DMSO) 82.3-2.9 (6H, m), 3.5-
3.7 (2H, m), 4.3-4.7 (3H, m), 5.1-5.35 (1.5H, m), 5.6-5.8
(1H, m), 6.4-6.45 (1H, m) , 7.2-7.35 (5H, m) , 7.6-7.8 (4H,
m), 7.9-8.0 (2H, m) , 8.3-8.35 (1H, m), 8.9-9.0 (1H, m),
9.35-9.4 (1H, m) ; M+H 508.4, M-H 506.4.
Example II.3
3 (R, S) - [2 (S) - (3-Benzoylamino-5-methyl-2-oxo-2H-pyridin-l-
yl) -3-phenyl-propionylamino] -5-fluoro-4-oxo-pentanoic
acid

[0119] Prepared according to methods A and D-G using
N- {5 -methyl-2 -oxo-1,2-dihydro-pyridin-3 -yl) -benzamide and
(R) -2-Hydroxy-3-phenyl-propionic acid fcert-butyl ester in
step A; white solid; IR (solid) 1650, 1516, 1224, 692
cm"1; XH NMR (400 MHz, d6-DMSO) 8 0.83-0.86 (3H, m) , 2.3O-
2.67 (4H, m), 4.32-4.95 (2H, m), 5.12-5.24 (1H, m), 5.83-
6.04 (1H, m), 7.15-7.61 (9H, m), 7.86-7.88 (2H, m), 8.11-
8.12 (1H, m, 8.7O-9.02 (1H, m), 9.21 br s); M+H 508.4, M-H 506.4.
Example II.4
3 (R, S) -{2 (S) - [3- (2, 6-Dimethyl-benzoylamino) -2-oxo-2ff-
pyridin-1-yl]-3-phenyl-propionylamino}-5-fluoro-4-oxo

-pentanoic acid

[0120] Prepared according to methods A-G using 2,6
dimethyl- benzoyl chloride in method C; off-white solid;
XH NMR (400MHz, d6-DMSO> 52.50 (6H, s), 2.51-2.98 (2H,
m), 3.15-3.45 (2H, m) , 4.15-3.30 (3H, m), 5.61-6.00 (1H,
m), 6.25 (1H, m), 7.0O-7.25 (8H, m), 7.45-7.70 (1H, m),
8.12 (1H, m), 8.65-9.10 (2H, m) ; 19F (376 MHz, d6-DMSO,
proton-decoupled) 5 -226.8, -226.8, -227.5, -230.8,
-231.8, -232.7, -232.8, -232.8, -232.9, -233.4; M+H
522.5, M-H 520.5.
Example II.5
3 (R, S) -{2 (S) - [3- (2, 6-Dichloro-benzoylamino) -2-oxo-2ff-
pyridin-1-yl'] -3-phenyl-propionylamino} -5-f luoro-4-oxo-
pentanoic acid

[0121] Prepared according to methods A-G using 2,6
dichloro- benzoyl chloride in method C; XH NMR (400 MHz,
d6-DMSO) 8 2.35-2.99 (2H, m) , 3.05-3.50 (2H, m) , 4.15-
5.35 (3H, m), 5.66-6.05 (1H, m) , 6.29 (1H, ra), 7.1O-7.30
(5H, m), 7.37-7.52 (3H, m) , 7.51-7.70 (1H, m), 8.25 (1H,
m), 8.7O-9.11 (1H, m) , 10.0O-10.15 (1H, m) ; 19F (376 MHz,
d6-DMSO, proton-decoupled) 5 -226.7, -226.8, -230.7,
-231.4, -232.6, -232.7, -232.9; M+H 562.28, M-H 560.28.

Example II.6
3 (R, S) -{2 (S) - [3- (3,3-Diethyl-ureido) -2-oxo-2H-pyridin-l-
yl] -3 ~phenyl-propionylami.no }-5-f luoro-4-oxo-pentanoic
acid

Method H:
(S)-2-[3-(3,3-Diethyl-ureido)-2-oxo-2H-pyridin-l-yl]-3-
phenyl-propionic acid tert-butyl ester

[0122] To a cooled (0°C) solution of (S)-2-(3-Amino-2-
oxo-2ff-pyridin-l-yl)-3-phenyl-propionic acid tert-butyl
ester (500 mg, 1.59 mmol) in dichloroethane (3 mL) was
added triethylamine (0.254 mL, 1.82 mmol). This solution
was added dropwise to a solution of diphosgene (0.11 mL,
0.91 mmol) in dichloroethane (7 mL) at 0°C over 10
minutes. The reaction mixture was stirred at room
temperature for 90 minutes and then partitioned between
EtOAc and aqueous 1M HCl. The organic layer was washed
with brine, dried (MgSO*) , filtered and evaporated to
afford the isocyanate as a brown oil.
[0123] To a cooled (0°C) solution of the isocyanate
prepared above (541 mg, 1.59 mmol) in dichloroethane (8
mL) was added triethylamine (0.24 mL, 1.75 mmol) followed
by diethylamine (0.16 mL, 1.59 mmol) . The reaction
mixture was stirred at room temperature for 3 hours and

then partitioned between EtOAc and aqueous 1M HC1. The
organic layer was washed with brine, dried (MgSO4),
filtered and evaporated to afford a brown oily residue
which was purified by flash column chromatography (25-75%
ethyl acetate/hexane) to afford the diethylurea as a
light pink oil- aH NMR (400 MHz, CDCl3) 8 1.48 (9H, s) ,
3.35 (1H, dd), 3.55 (1H, dd), 5.5 (1H, m), 6.26 (1H, t),
6.90 (1H, d), 7.15 (2H, m), 7.28 (3H, m) , 7.52 (3H, m) ,
7.95 (2H, m), 8.52 (1H, d), 9.22 (1H, br s) .
[0124] This intermediate was involved in the sequence
described in methods D-G to afford example II.6 as a pale
pink solid; IR (solid) 1794, 1737, 1664, 1640, 1588,
1515, 1458, 1414, 1382, 1353, 1220, 1066 cm-1; XH NMR (400
MHz, d6-DMSO) 8 1.08-1.12 (6H, m) , 2.5O-2.90 (2H, m) ,
3.2O-3.55 (6H, m) , 4.3O-5.30 (3H, m),5.85 (1H, m), 6.19
(1H, m), 7.15-7.37 (6H, m), 7.64 (1H, m) , 7.86 (1H, m) ,
9.00 (1H, m) ; 19F (376 MHz, d6-DMSO, proton-decoupled) 8
-226.8, -226.8, -230.8, -231.6, -232.9, -233.0; M+H 489.4
M-H 487.4.
Example II.7
5-Fluoro-4-oxo-3 (R, S) - [2 (S) - (2-oxo-3-phenylacetylamino-
2H-pyridin-l-yl)-3-phenyl-propionylamino-pentanoic acid

[0125] Prepared according to methods A-G using phenyl
acetyl chloride in method C; Pale pink solid; IR (solid)
1789, 1742, 1685, 1643, 1587, 1516, 1451 cm-1; XH NMR (400
MHz, d6-DMSO) 8 2.5O-2.90 (2H, m) , 3.27-3.41 (2H, m) ,
3.76 (2H, s), 4.3O-5.30 (3H, m), 5.90 (1H, m) , 6.17 (1H,

m), 7.15-7.31 (10H, m) , 7.50 (1H, m), 8.00 (1H, m) , 8.85
(1H, m), 9.25 (1H, m); 19F (376 MHz, d6-DMSO, proton-
decoupled) 8 -222.0, -222.1, -226.0, -226.5, -227.9,
-228.0; M+H 508.5, M-H 506.5.
Example II.8
3 (S) -{2 (S)-[3- (2,6-Dichloro-benzoylamino) -2-oxo-2JT-
pyridin-1-yl]-3-phenyl-propionylamino}-4-oxo-5-(2,3,5
,6-tetrafluoro-phenoxy)-pentanoic acid

[0126] Prepared according to methods A-G using 2,6
dichloro- benzoyl chloride in method C and 3(S)-Amino-
4(R,S)-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic
acid tert-butyl ester in step E; Pink Solid; IR
(solid) 1675, 1634, 1511, 1429 cm-1; *H NMR (400 MHz, d6-
DMSO) 8 2.61-2.80 (2H, m), 3.29-3.52 (2H, m), 4.67-4.73
(1H, m), 5.22 (2H, dd), 5.87-5.93 (1H, m), 6.26-6.31 (1H,
m), 7.12-7.28 (5H, m), 7.41-7.72 (5H, m), 8.26 (1H, d),
9.12 (1H, d), 10.05 (1H, s); 19F (376 MHz, d6-DMSO,
proton-decoupled) 8 -140.5, -140.6, -140.6, -140.6,
-141.0, -141.0, -141.0, -141.1, -156.9, -156.9, -156.9,
-156.9, -157.0; M+H 708.1 M-H 706.0.
Example II.9
5-Fluoro-4-oxo-3(R,S)-{2(S)-[2-oxo-3-(3-phenyl-ureido)-
2If-pyridin-l-yl] -3-phenyl-propionylamino}-pentanoic acid


[0127] Prepared according to methods A-G using phenyl
isocyanate in method C; Off white solid; IR (solid) 1780,
1737, 1671, 1638, 1601, 1544, 1498 cm"1; XH NMR (400 MHz,
d6-DMSO) 82.5O-2-90 (2H, m) , 3.2O-3.55 (2H, m), 4.3O-5.30
(3H, m) , 5.90 (1H, m) , 6.20 (1H, m) , 6.85 (1H, m), 7.1O-
7.45 (11H, m), 8.00 (1H, m), 8.50 (1H, m), 9.00(1H, m),
9.50 (1H, m) , 12.50 (1H, br s) ; 19F (376 MHz, d6-DMSO,
proton-decoupled) 5-226.8, -226.8, -227.5, -230.9,
-231.3, -232.7, -232.8, -233.4; M+H 509.5 M-H 507.45.
Example 11.10
3 (R, S) - [2 (S) - (3-Benzoylamino-2-oxo-5-trif luorometh.yl~2.H-
pyridin-1-yl) -3-phenyl-propionylamino] -5-fluoro-4-oxo-
pentanoic acid

[0128] Prepared from N- (2-oxo-5-trifluoromethyl-l,2-
dihydro-pyridin-3-yl)-carbamic acid benzyl ester
according to methods A-G; IR solid 1655, 1521, 1450,
1322, 1173, 1127 cm"1; ; XH NMR (400 MHz, d6-DMSO) 8 2.6O-
2.91 (2H, m) , 3.45-3.64 (2H, m) , 4.65 (1H, m>, 5.18-5.37
(2H, m), 5.81-5.97 (1H, m), 7.16-7.25 (5H, m) , 7.52-7.63
(3H, m), 7.89-7.91 (2H, m), 8.02-8.14 (1H, m), 8.35 (1H,
s), 9.1O-9.19 (1H, m), 9.41 (1H, br s), 12.69 (1H, br s);

19F (376 MHz, d6-DMSO, proton-decoupled) 8-61.3. -61.3,
-226.7, -226.9, -232.6, -232.7; M+H 562.4, M-H 560.4.
Example II.11
5-Fluoro-3(R,S)-[2(S)-(3-isobutyrylanri.no-2-oxo-2ff-
pyridin-1-yl) -3 -phenyl -propionylanri.no] -4-oxo-pentanoic
acid

[0129] Prepared according to methods A-G using
isobutyryl chloride in method C; off-white solid; *H NMR
(400 MHz, d6-DMSO) 5 1.05 (6H, m) , 2.5O-2.99 (3H, m) ,
3.11-3.50 (2H, m), 4.2O-5.35 (3H, m) , 5.7O-6.10 (1H, m) ,
6.21 (1H, m), 7.07-7.28 (5H, m) , 7.4O-7.60 (1H, m) , 7.85-
8.15 (1H, m), 8.65-9.10 (2H, m) ; 19F (376 MHz, d6-DMSO,
proton-decoupled) 8-226.7, -226.8, -230.7, -231.3,
-232.7, -232.7; M+H 460.2, M-H 458.2.
Example 11.12
3(R,S)-[2(S)-(3-Benzoylamino-2-oxo-2#-pyridin-l-yl)-3-
thi ophen-3-yl-propionylairri.no]-5-fluoro-4-oxo-pentanoic
acid

[0130] Prepared according to methods A and D-6 using
#-(2-0xo-l,2-dihydro-pyridin-3-yl)-benzamide and 2-
Hydroxy-3-thiophen-3-yl-propionic acid tert-butyl ester
(prepared using a method similar to that reported in Lei

et al., J. Carbohydrate Chemistry, 15, 4, 1996, 485-500)
in method A; IR (solid) 1675, 1644, 1578, 1521, 705 cm-1;
*H NMR (400Mhz, d6-DMSO) 82.6-2.9 (2H, m) , 3.5-3.7 (2H,
m) , 4.3-4.7 6.3-6.4 (1H, m), 6.8-6.9 (2H, m) , 7.15-7.2 (1H, ra), 7.3-
7.35 (1H, m), 7.4-7.6 (4H, m), 7.9-7.9 (2H, m) , 8.2-8.25
(1H, m), 9.O-9.1 (1H, m), 9.25-9.3 (1H, m) ; M+H 500.4,
M-H 498.4.
Example 11.13
5-Fluoro-4-oxo-3 (R, S) - [2 (S) - (2-oxo-3-propionylamino-2ff-
pyridin-1-yl)-3-phenyl-propionylamino]-pentanoic acid

[0131] Prepared according to methods A-G using
propionyl chloride in method C; beige solid; aH NMR
(400Mhz, d6-DMSO) 5 0.99-1.02 (3H, m) , 2.36-2.42 (2H, m) ,
2.53-2.94 (2H, m), 3.21-3.45 (3H, m), 4.33-5.29 (3H, m) ,
5.8O-6.02 (1H, m), 6.16-6.21 (1H, m), 7.11-7.23 (5H, m) ,
7.43-7.53 (1H, m), 8.08-8.13 (1H, m) , 8.68-9.05 (2H, m) ,
12.50 (1H, br s); M+H 446.4, M-H 444.4.
Example 11.14
3(R,S)-[2(S)-(3-Benzoylamino-2-oxo-2H-pyridin-l-yl)-3-
thiophen-2-yl-propionylamino]-5-fluoro-4-oxo-pentanoic
acid


[0132] Prepared according to methods A and D-G using
JNr-(2-Oxo-l,2-dihydro-pyridin-3-yl)-benzamide and 2-
hydroxy-3-thiophen-2-yl-propionic acid tert-butyl ester
(prepared using a method similar to that reported in Lei
et al., J. Carbohydrate Chemistry, 15, 4, 1996, 485-500)
in method A; IR (solid) 1644, 1521, 705 cm"1; XH NMR (400
MHz, d6-DMSO) 52.6-2.9 (2H,m) , 3.5-3.7 (2H,m), 4.3-4.7
(3H,m), 5.1-5.35 (1.5H,m), 5.7-5.9 (lH,m), 6.3-6.4 (1H,
m), 6.8-6.9 (2H, m), 7.3-7.35 (1H, m), 7.4-7.7 (4H, m) ,
7.9-8.0 (3H, m), 8.2-8.25 (1H, m), 9.O-9.1 (1H, m), 9.25-
9.3 (1H, m) ; M+H 500.4, M-H 498.4
Example 11.15
3 (R, S) - [2 (S) - (3-Benzoylamino-2-oxo-2fl'-pyridin-l-yl) -3-
(lH-indol-3-yl) -propionylamino] -5-f luoro-4-oxo-pentanoic
acid

Method X
(S) -3- [2- fcerfc-Butoxycarbonyl-2- (3-methoxycarbonyl-2-oxo-
2H-pyridin-l-yl)-ethyl]-indole-1-carboxylic acid tert-
butyl ester


[0133] To a solution of (S)-3- (2-Amino-2-fcerfc-
butoxycarbonyl-et&yl)-indole-l-carboxylic acid terfc-butyl
ester (2.5 g, 7 mmol) in methanol (15 ml) was added 2-(3-
methoxy-allylidene)-malonic acid dimethyl ester (1.5 g, 7
mmol) and stirred overnight at room temperature. Sodium
methoxide (78 mg, 1.4 mmol) was added and stirred for
three hours at room temperature. The reaction mixture
was diluted with water (50 ml) and extracted with
ethylacetate (60 ml) . The organic layer was washed with
brine, dried (MgSO4) , filtered and evaporated to afford
the crude product, which was perified by flash
chromatography (3O-70% ethylacetate/petroleum ether) to
afford the title compound as a white solid (2.3 g, 57%);
XH NMR (400 MHz, CDCl3) 5 1.43 (9H, s), 1.72 (2H, m) , 3.91 (3H, m) , 5.68 (1H, br s), 6.08 (1H, t),
7.2-7.5 (5H, m), 8.15 (2H, m); M+H 497.5, M-H 495.5.
Method tf
(S) -3- [2-fcerfc-Butoxycarbonyl-2- (3-carboxy-2-oxo-2H'-
pyridin-1-yl)-ethyl]-indole-1-carboxylic acid terfc-butyl
ester

[0134] To a solution of (S)-3-[2-fcerfc-Butoxycarbonyl-
2- (3-methoxycarbonyl-2-oxo-2£T-pyridin-l-yl) -ethyl] -
indole-1-carboxylic acid terfc-butyl ester (2.3 g, 4.7
mmol) in dioxane (60 ml) was added a lithium hydroxide
(115mg, 4.7 mmol) in water (30 ml). The mixture was

stirred overnight at room temperature. The mixture was
diluted with water, acidified to pH-3 with 1M HCl and
extracted with ethylacetate. The organic layer was
washed with brine, dried (MgSO4), filtered and evaporated
to afford the crude product as a white solid was used in
the next stage without further purification (1.9 g, 85%);
XH NMR (400 MHz, CDC13) 51.45 (9H, s) , 1.74 (9H, s) , 3.50
(2H, m), 5.65 (1H, br s), 6.08 (1H, t), 7.2-7.5 (5H, m) ,
8.15 (2H, m) ;
Method K
3- [2- (3-Benzyloxycarbonylamino-2-oxo-2H-pyridin-l-yl) -2-
tert-butoxycarbonyl-ethyl]-indole-l-carboxylic acid terfc-
butyl ester

[0135] To a stirred solution of (S}-3-[2-fcert-
Butoxycarbonyl-2- (3-carboxy-2-oxo-2ff-pyridin-l-yl) -
ethyl] -indole-1-carboxylic acid tert-butyl ester (1.8 g,
3.7 mmol) in dioxane was added triethylamine (580 mg, 5.9
mmol), diphenylphosphoryl azide 91.5 g, 5.6 inniol) and
benzyl alcohol (680 mg, 6.3 mmol) and the mixture
refluxed at 100 C for 18 hours. The mixture was
concentrated and partitioned between ethylacetate and
saturated bicarbonate. The organic layer was washed with
brine, dried (MgSO4), filtered and evaporated to afford
the crude product, which was purified by flash
chromatography (3O-70% ethylacetate/petroleum ether) to

afford the title compound as a white solid (1.3 g, 59%);
*H NMR (400 MHz, CDCl3) 61.48 (9H,s), 1.73 (9H, s) , 3.45
(1H, m) , 3.65 (1H, m), 5.2-5.25 (2H, m), 5.60 (1H, m),
6.15 (1H, t), 6.85 (1H, m), 7.25-7.55 (9H, m) , 7.95 (1H,
m), 8.02-8.18 (2H, m);
[0136] The product from method K was involved in the
sequence of reactions B-G to afford the title compound as
an off white solid; IR (solid) 1669, 1643, 1578, 1522,
1490, 1212 cm"1; XH NMR (400 MHz, d6-DMSO) 8 2.5-2.8 (2H,
m), 3.4-3.6 (2H, m) , 4.35-4.6 (1H, m) , 4.65-4.8 (1H, m) ,
5.15-5.3 (1H, m) , 5.85-6.0 (1H, m), 6.3-6.35 (1H, m),
6.9-7.1 (3H, m), 7.25-7.3 (1H, m), 7.5-7.9 (8H, m), 8.2-
8.25 (1H, m), 9.1-9.3 (2H, m) , 10.8-10.9 (1H, br s); .4O-
7.60 (1H, m), 7.85-8.15 (lH, m), 8.65-9.10 (2H, m) ; 19F
(376 MHz, d6-DMSO, proton-decoupled) 8-226.3, 226.7,
-232.5, -232.6; M+H 533.0, M-H 530.9.
.Example 11.16
3 (R, S) - [2 (S) - (3-Ethanesulfonylamino-2-oxo-2Jir-pyridin-l-
yl) -3-phenyl-propionylamino] -5-f luoro-4-oxo-pentanoic
acid

[0137] Prepared according to methods A-G using
ethanesulfonyl chloride in method C; Pale blue solid; IR
(solid) 1787, 1742, 1685, 1643, 1590, 1551, 1456 cm"1; XH
NMR (400 MHz, d6-DMSO) 5 1.03-1.14 (3H, m) , 2.51-2.94 (4H,
m), 3.3O-3.41 (2H, m) , 4.3O-5.30 (3H, m), 5.90 (1H, m),
6.20 (1H, m) , 7.14-7.26 (7H, m), 7.58 (1H, m) , 8.80 (1H,

m); "F (376MHZ, d6-DMSO, proton-decoupled) 6-226.8,
-230.8, -232.8, -232.9; M+H 482.4 M-H 480.4.
Example 11.17
3 {R, S) - [4-Benzyloxy-2 (S) - (2-oxo-3-propionylamino-2H-
pyridin-1-yl) -butyrylamino] -5-f luoro-4-oxo-pentanoic acid

[0138] Prepared according to the methods A and D-6
using (R) -4-benzyloxy-2-hydroxy-butyric acid terfc-butyl
ester (prepared using a method similar to- that reported
in Lei et al., J. Carbohydrate Chemistry, 15, 4, 1996,
485-500) in method A; Pale pink solid; IR (solid) 1784,
1740, 1675, 1589, 1515, 1451, 1368 cm-1; XH NMR (400 MHz,
d6-DMSO) 8 1.23-1.27 (3H, t), 2.20 (1H, m) , 2.46-2.48
(2H, m) , 2.50 (1H, m), 2.75-3.09 (2H, m), 3.39 (1H, m),
3.55 (1H, m), 4.42-4.50 (3H, m), 4.7O-5.01 (2H, m), 5-47-
5.87 (1H, m), 6.40 (1H, m) , 6.98 (1H-, m) , 7.02-7.06 (5H,
m) , 7.68 (1H, m) , 8.26 (1H, m) , 8.48 (1H, m); 19F (376
MHz, CDC13, proton-decoupled) 5-230.2, -230.46, -231.9,
-232,4; M+H 490.4, M-H 488.4.
Example 11.18
3 (R, S) - [3 (S) -Benzyloxy-2 (S) - (2-oxo-3-propionylamino-2H-
pyridin-1-yl) -butyrylamino] -5-fluoro-4-oxo-pentanoic acid


[0139] Prepared according to the methods A and D-G
using 3 (S)-Benzylo:^-2-(R)-hydroxy-butyric acid fcerfc-
butyl ester (prepared using a method similar to that
reported in Lei et al., 1996, 485-500) in method A; IR (solid) 1738, 1644, 1518,
1371, 1205 cm"1; XH NMR (400 MHz, d6-DMSO) 5 1.13-1.25 (3H,
m), 1.25-1.35 (3H, m), 2.4O-2.5 (2H, m), 2.7-3.2 (2H, m) ,
4.3-5.2 (6H, m), 6.4O-6.5 (1H, m), 7.3-7.55 (5H, m), 7.68
(1H, m) , 8.3-8.4 (1H, m) , 8.5-8.6 (1H, m) ; M+H 490.4, M-H
488.4.
Example 11.19
5-Fluoro-4-oxo-3 (R, S) - [2 (R, S) - (2-oxo-3-propionylamino-2iI-
pyridin-1-yl) -2-phenyl-acetylamino] -pentanoic acid

[0140] Prepared according to methods A and D-G using
Bromo-phenyl-acetic acid methyl ester in step A; IR
(Solid) 1671, 1643, 1581, 1520 cm-1; XH NMR (400Mhz, d6-
DMSO) 51.O-1.08 (3H, m) , 2.4-2.5 (2H, m) , 2.6-2.9 (2H,
m) , 4.3-4.8(2H, m), 5.2-5.4 (2H, m) , 6.15-6.25 (1H, m) ,
6.7-6.8 (1H, m), 7.3-7.4 (2H, m), 7.4-7.5 (3H, m), 8.2-
8.25 (1H, m) , 9.1-9.3 (1H, m); M+H 432.4, M-H 430.4.

Example 11.20
3 (R, g) - [3-Benzyloxy-2 (S) - (2-oxo-3-propionylamino-2J?-
pyridin-1-yl) -prcpionylamino] -5-f luoro-4-oxo-pentanoic
acid

[0141] Prepared according to the methods A and D-G
using (R)-3-Benzyloxy-2-hydroxy-propionic acid tart-butyl
ester (prepared using a method similar to that reported
in Lei et al., J. Carbohydrate Chemistry, 15, 4, 1996,
485-500) in method A; Off-white solid; XH NMR {400 MHz,
d6-DMSO) 8 1.05 (3H, t) , 2.3O-2.90 (4H, m) , 3.95-4.15 (2H,
m), 4.2O-4.80(4H, m ), 5.05-5.40 (2H, m), 5.70 (1H, m),
6.35 (1H, m), 7.30 (5H, m), 7.4O-7.55 (1H, m) , 8.25 (1H,
m), 8.95 (1H, m) , 9.15 (1H, m); 19F (376 MHz, CDC13,
proton-decoupled) 8 -226.9, -232.9; M+H 476.3.
Example 11.21
Enzyme Assays
[0142] The assays for caspase inhibition are based on
the cleavage of a fluorogenic substrate by recombinant,
purified human Caspases -1, -3, or -8. The assays are
run in essentially the same way as those reported by
Garcia-Calvo et al. («T. Biol. Chem. 273 (1998), 32608-
32613) , using a substrate specific for each enzyme. The
substrate for Caspase-1 is Acetyl-Tyr-Val-Ala-Asp-amino-
4-methylcoumarin. The substrate for Caspases -3 and -8
is Acetyl-Asp-Glu-Val-Asp-amino-4-methylcoumarin. Both
substrates are known in the art.

[0143] The observed rate of enzyme inactivation at a
particular inhibitor concentration, kobs/ is computed by
direct fits of the data to the equation derived by
Thornberry et al. (Biochemistry 33 (1994),. 3943-3939)
using a nonlinear least-squares analysis computer program
(PRISM 2.0; GraphPad software). To obtain the second
order rate constant, kinact/ kobs values are plotted against
their respective inhibitor concentrations and kinact values
are subsequently calculated by computerized linear
regression.
[0144] Inhibition of caspases-1, -3, and -8 activity
for selected compounds of this invention was determined
by the above method. Compounds II.1-II.20 inhibited
caspase-1 with a kinact of >60,000 M^s"1, caspase-3 with a
kinact between 0 and 300,000 M^s"1, and caspase-8 with a
kinact of at >35,000 MTV1.
Example 11.22
PBMC Cell Assay
IL-1/3 Assay with a Mixed Population of Human Peripheral
Blood Mononuclear Cells (PBMC) or Enriched Adherent
Mononuclear Cells
[0145] Processing of pre-IL-ip by ICE may be measured
in cell culture using a variety of cell sources. Human
PBMC obtained from healthy donors provides a mixed
population of lymphocyte subtypes and mononuclear cells
that produce a spectrum of interleukins and cytokines in
response to many classes of physiological stimulators.
Adherent mononuclear cells from PBMC provides an enriched
source of normal monocytes for selective studies of
cytokine production by activated cells.
Experimental Procedure:

[0146] An initial dilution series of test compound in
DMSO or ethanol is prepared, with a subsequent dilution
into RPMI-10% FBS media (containing 2 mM L-glutamine, 10
mM HEPES, 50 U and 50 ug/ml pen/strep) respectively to
yield drugs at 4x the final test concentration containing
0.4% DMSO or 0.4% ethanol. The final concentration of
DMSO is 0.1% for all drug dilutions. A concentration
titration which brackets the apparent K^ for a test
compound determined in an ICE inhibition assay is
generally used for the primary compound screen.
[0147] Generally 5-6 compound dilutions are tested and
the cellular component of the assay is performed in
duplicate, with duplicate ELISA determinations on each
cell culture supernatant.
PBMC Isolation and IL-1 Assay:
[0148] Buffy coat cells isolated from one pint human
blood (yielding 4O-45 ml final volume plasma plus cells)
are diluted with media to 80 ml and LeukoPKEP separation
tubes (Becton Dickinson) are each overlaid with 10 ml of
cell suspension. After 15 min centrifugation at 150O-
1800 xg, the plasma/media layer is aspirated and then the
mononuclear cell layer is collected with a Pasteur
pipette and transferred to a 15 ml conical centrifuge
tube (Corning) . Media is added to bring the volume to 15
ml, gently mix the cells by inversion and centrifuge at
300 xg for 15 min. The PBMC pellet is resuspended in a
small volume of media, the cells are counted and adjusted
to 6 x 106 cells/ml.
[0149] For the cellular assay, 1.0 ml of the cell
suspension is added to each well of a 24-well flat bottom
tissue culture plate (Corning), 0.5 ml test compound
dilution and 0.5 ml LPS solution (Sigma #L-3012; 20 ng/ml

solution prepared in complete RPMI media; final LPS
concentration 5 ng/ml) . The 0.5 ml additions of test
compound and LPS are usually sufficient to mix the
contents of the wells. Three control mixtures are run
per experiment, with either LPS alone, solvent vehicle
control, and/or additional media to adjust the final
culture volume to 2.0 ml. The cell cultures are
incubated for 16-18 hr at 37 °C in the presence of 5%
co2.
[0150] At the end of the incubation period, cells are
harvested and transferred to 15 ml conical centrifuge
tubes. After centrifugation for 10 min at 200 xg,
supernatants are harvested and transferred to 1.5 ml
Bppendorf tubes. It may be noted that the cell pellet
may be utilized for a biochemical evaluation of pre-IL-lfi
and/or mature IL-ip content in cytosol extracts by
Western blotting or ELISA with pre-IL-ip specific
antisera.
Isolation of Adherent Mononuclear cells:
[0151] PBMC are isolated and prepared as described
above. Media (1.0 ml) is first added to wells followed
by 0.5 ml of the PBMC suspension. After a one hour
incubation, plates are gently shaken and nonadherent
cells aspirated from each well. Wells are then gently
washed three times with 1.0 ml of media and final
resuspended in 1.0 ml media. The enrichment for adherent
cells generally yields 2.5-3.0 x 105 cells per well. The
addition of test compounds, LPS, cell incubation
conditions and processing of supernatants proceeds as
described above.

ELISA:
[0152] Quantikine kits (R&D Systems) may be used for
the measurement of mature IL-ip. Assays are performed
according to the manufacturer's directions. Mature IL-ip
levels of about 1-3 ng/ml in both PBMC and adherent
mononuclear cell positive controls are observed. ELISA
assays are performed on 1:5, 1:10 and 1:20 dilutions of
supernatants from LPS-positive controls to select the
optimal dilution for supernatants in the test panel.
10153} The inhibitory potency of the compounds can be
represented by an IC50 value, which is the concentration
of inhibitor at which 50% of mature IL-1J3 is detected in
the supernatant as compared to the positive controls.
[0154] The skilled practitioner realizes that values
obtained in cell assays may depend on multiple factors.
The values may not necessarily represent fine
quantitative results.
[0155] Selected compounds of this invention have been
tested for inhibition of IL-10 release from PBMCs with
IC50 values between 300nM and 10JXM.
Anti-Fas Induced Apoptosis Assay
[0156] Cellular apoptosis may be induced by the
binding of Fas ligand (FasL) to its receptor, CD95 (Fas).
CD95 is one of a family of related receptors, known as
death receptors, which can trigger apoptosis in cells via
activation of the caspase enzyme cascade. The process is
initiated by the binding of the adapter molecule
FADD/MORT-1 to the cytoplasmic domain of the CD-95
receptor-ligamd complex. Caspase-8 then binds FADD and
becomes activated, initiating a cascade of events that
involve the activation of downstream caspases and
subsequent cellular apoptosis. Apoptosis can also be

induced in cells expressing CD95 e.g., the Jurkat E6.1 T
cell lymphoma cell line, using an antibody, rather than
FasL, to crosslink the cell surface CD95. Anti-Fas-
induced apoptosis is also triggered via the activation of
caspase-8. This provides the basis of a cell based assay-
to screen compounds for inhibition of the caspase-8-
mediated apoptotic pathway.
Experimental Procedure
[0157] Jurkat E6.1 cells are cultured in complete
medium consisting of RPMI-1640 (Sigma No) + 10% foetal
calf serum (Gibco BRL No. 10099-141) + 2mM L-glutamine
(Sigma No. G-7513) . The cells are harvested in log phase
of growth. 100 ml of cells at 5-8x105 cells/ml are
transferred to sterile 50ml Falcon centrifuge tubes and
centrifuged for 5 minutes at lOOxg at room temperature.
The supernatant is removed and the combined cell pellets
resuspended in 25ml of complete medium. The cells are
counted and the density adjusted to 2xl06cells/ml with
complete medium.
[0158] The test compound is dissolved in dimethyl
sulfoxide (DMSO) (Sigma No. D-2650) to give a lOOmM stock
solution. This is diluted to 400/M in complete medium,
then serially diluted in a 96-well plate prior to
addition to the cell assay plate.
[0159] 100^1 of the cell suspension (2x106 cells) is
added to each well of a sterile 96-well round-bottomed
cluster plate (Costar No. 3790). 50#1 of compound
solution at the appropriate dilution and 50jtl of anti-Fas
antibody, clone CH-11 (Upstate, Cat No.l 544 675) at a
final concentration of lOng/ml, are added to the wells.
Control wells are set up minus antibody and minus
compound but with a serial dilution of DMSO as vehicle
control. The plates are incubated for 16-18hrs at 37°C

in 5% CO2 and 95% humidity.
[0160] Apoptosis of the cells is measured by the
quantitation of DNA fragmentation using a ^Cell Death
Detection Assay' from Roche diagnostics. No. 1544 675.
After incubation for 16-18hrs the assay plates are
centrifuged at lOOxg at room temperature for 5 minutes.
150fil of the supernatant are removed and replaced by
150/xl of fresh complete medium. The cells are then
harvested and 200^1 of the lysis buffer supplied in the
assay kit are added to each well. The cells are
triturated to ensure complete lysis and incubated for 30
minutes at 4°C. The plates are then centrifuged at
1900xg for 10 minutes and the supernatants diluted 1:20
in the incubation buffer provided. 100#1 of this
solution is then assayed according to the manufacturer's
instructions supplied with the kit. OD405nm is measured
20 minutes after addition of the final substrate in a
SPECTRAmax Plus plate reader (Molecular Devices).
OD405nm is plotted versus compound concentration and the
IC50 values for the compounds are calculated using the
curve-fitting program SOFTmax Pro (Molecular Devices)
using the four parameter fit option.
Selected compounds have been tested in this assay and
shown to inhibit Fas-induced apoptosis of Jurkat cells
with IC50 values between 0.013fiM and 8\M.
[0161] While we have described a number of embodiments
of this invention, it is apparent that our basic examples
may be altered to provide other embodiments which utilize
the compounds and methods of this invention. Therefore,
it will be appreciated that Ithe/ scope of this invention^v.
is to be defined by the appended claims rather than by

the specific embodiments that have been represented by-
way of example above.

We claim:
1. A compound of formula I:

wherein:
R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, (R6)
(H)NC(O)-, R6C(O)C(O)-, (R6)2NC(O)C(O)-, (R6) (H) NC (O) C (O) -,
or R6OC(O)C(O)-;
R2 is hydrogen, -CF3, -halo, -OR7, -NO2, -OCF3, -CN, or R8;
R3 is -T-R9;
R4 is -COOH or -COOR8;
R5 is -CH2F or -CH2O-2,3,5,6-tetrafluorophenyl;
R6 is R6a or R6b; two R6 groups, together with
the atom to which they are bound, optionally form a 3- to
10-membered aromatic or nonaromatic ring; wherein any
ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a
(C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon
atoms may be replaced by a group selected from O, N,
N(R7), S, SO, and SO2; and wherein each R6 is
independently substituted with up to 6 substituents
independently selected from R;
R6a and R6b are each independently
(C1-C3)-aliphatic-,
(C4-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,

(C6-C10)-aryl-,
(C3-C10)-heterocyclyl-,
(C5-C10)-heteroaryl-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl(C1-C12)-aliphatic-;
R is halogen, -OR7, -OC (O) N (R7) 2, -NO2, -CN, -CF3, -OCF3,
-R7, oxo, thioxo, =NR7, =N(OR7), 1,2-methylenedioxy, 1,2-
ethylenedioxy, -N(R7)2, -SR7, -SOR7, -SO2R7, -SO2N(R7)2, -SO3R7,
-C(O)R7, -C(O)C(O)R7, -C(O)C(O)OR7, -C (O) C (O) N (R7) 2,
-C(O)CH2C(O)R7, -C(S)R7, -C(S)OR7, -C(O)OR7, -OC(O)R7,
-C(O)N(R7)2, -OC(O)N(R7)2, -C(S)N(R7)2, - (CH2) O-2NHC (O) R7,
-N(R7)N(R7)COR7, -N(R7)N(R7)C(O)OR7, -N (R7) N (R7) CON (R7) 2,
-N(R7)SO2R7, -N(R7)SO2N(R7)2, -N (R7) C (O) OR7, -N (R7) C (O) R7,
-N(R7)C(S)R7, -N(R7)C(O)N(R7)2, -N (R7) C (S) N (R7) 2, -N (COR7) COR7,
-N(OR7)R7, -C(=NR7)N(R7)2, -C (O)N (OR7) R7, -C(=NOR7)R7, -OP (O)
(OR7)2, -P(O)(R7)2, -P(O) (OR7)2, or -P(O) (H) (OR7);
two R7 groups together with the atoms to which they
are bound optionally form a 3- to 10-membered aromatic or
non-aromatic ring having up to 3 heteroatoms independently
selected from N, N(R7), O, S, SO, or SO2, wherein the ring
is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,
(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein
any ring has up to 3 substituents selected independently
from J2; or
each R7 is independently selected from:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,

(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein
R7 has up to 3 substituents selected independently from J2;
and
J2 is halogen, -OR7, -OC (O) N (R7)2, -NO2, -CN, -CF3, -OCF3, -R7,
oxo, thioxo, =N(R7), =NO(R7), 1,2-methylenedioxy, 1,2-
ethylenedioxy, -N(R7)2, -SR7, -SOR7, -SO2R7, -SO2N(R7)2,
-SO3R7, -C(O)R7, -C(O)C(O)R7, -C(O)C(O)0R7, -C (O) C (O) N (R7) 2,
-C(O)CH2C(O)R7, -C(S)R7, -C(S)OR7, -C(O)OR7, -OC(O)R7,
-C(O)N(R7)2, -OC(O)N(R7)2, -C(S)N(R7)2, - (CH2) O-2NHC (O) R7,
-N(R7)N(R7)COR7, -N(R7)N(R7)C(O)OR7, -N (R7) N (R7) CON (R7) 2,
-N(R7)SO2R7, -N(R7)SO2N(R7)2, -N (R7) C (O) OR7, -N (R7) C (O) R7,
-N(R7)C(S)R7, -N(R7)C(O)N(R7)2, -N (R7) C (S) N (R7) 2,
-N (COR7) COR7, -N(OR7)R7, -CN, -C (=NR7) N (R7) 2, -C (O) N{OR7) R7,
-C(=NOR7)R7, -OP (O) (OR7) 2, -P(O) (R7)2, -P(O)(OR7)2, or -P (O)
(H) (OR7) ; and
R8 is (C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C6-C10)-aryl-,
(C3-C10)-heterocyclyl-,
(C5-C10)-heteroaryl-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, or
(C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to
3 aliphatic carbon atoms may be replaced with a group
selected from O, N, N(R7), S, SO, and SO2; and wherein R8
is optionally substituted with up to 6 substituents
independently selected from R;

T is a direct bond or (C1-C6) aliphatic wherein up to 2
aliphatic carbon atoms in T may be optionally replaced
with S, SO, SO2, O, N(R7), or N in a chemically stable
arrangement; wherein each T may be optionally substituted
with up to 3 R substituents;
R9 is optionally substituted (C6-C10)-aryl or
(C5-C10)-heteroaryl.
2. The compound as claimed in claim 1 wherein R5
is -CH2O-2,3,5,6-tetrafluorophenyl.
3. The compound as claimed in claim 1 wherein R5
is -CH2F.
4. The compound as claimed in any one of claims 1-
3, wherein R1 is R6C(O)-, (R6)2NC(O)-, R6C (O) C (O)-,
(R6)2NC(O)C(O)-, (R6) (H)NC(O)C(O)-, or R6OC(O)C(O)- wherein
R6 is R6b.
5. The compound as claimed in any one of claims 1-
3, wherein R1 is HC(O)-, R6SO2-, R6OC(O)-, or (R6) (H) NC (O) -
wherein R6 is R6a.
6. The compound as claimed in claim 4 or claim 5.

7. The compound as claimed in any one of claims 1
-3, wherein R1 is R6C(O)-.
8. The compound as claimed in any one of claims 1
-3, wherein R1 is R6SO2-.

9. The compound as claimed in any one of claims 1
-3, wherein R1 is (R6)2NC(O)-.
10. The compound as claimed in any one of claims
1-3, wherein R1 is (R6) (H)NC(O)-.
11. The compound as claimed in any one of claims
1-3, wherein R1 is (R6)OC(O)-.
12. The compound as claimed in any one of claims
1-3, 5-11 wherein R6a is
(C4-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C6-C10)-aryl-,
(C3-C10)-heterocyclyl-,
(C5-C10)-heteroaryl-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(Cl-C12)-aliphatic-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl(C1-C12)-aliphatic-, or two R6a
groups, together with the same atom to which they are
bound, independently form together with that atom a 3-
to 10-membered aromatic or nonaromatic ring; wherein
any ring is optionally fused to a (C6-C10)aryl, (C5-
C10)heteroaryl, (C3-C10)cycloalkyl, or a
(C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon
atoms may be replaced by a group selected from O, N,
N(R7), S, SO, and SO2; and wherein R6a is independently
substituted with up to 6 substituents independently
selected from R;
R6b is R6a or (C1-C3)-aliphatic-.

13. The compound as claimed in any one of claims
1-11, wherein R6a is
(C4)-aliphatic
(C3-C10)-cycloaliphatic-,
(C3-C10)-heterocyclyl-,
(C5-C10)-heteroaryl-,
(C6-C10)-aryl-, or
(C6-C10)-aryl-(Cl-C12)-alkyl-; wherein up to 3
aliphatic carbon atoms may be replaced by a group selected
from O, N, N(R7), S, SO, and SO2; and wherein R6a is
optionally substituted.
14. The compound as claimed in any one of claims
1-13 wherein R6a is (C5-C10)-heteroaryl- or (C6-C10)-aryl-;
wherein the heteroaryl or aryl is optionally substituted or
wherein each R6a, together with the N-atom to which it is
bound, is a (C3-C7)-cycloaliphatic group.
15. The compound as claimed in claims 14,
wherein each R6a is independently (C5-C10)-heteroaryl- or
(C6-C10)-aryl-, wherein the aryl is optionally substituted.
16. The compound as claimed in any one of claims
13-15, wherein each R6b is R6a or (C1-C3)-aliphatic.
17. The compound as claimed in any one of claims
1-16, wherein R2 is hydrogen, CF3, or CH3.
18. The compound as claimed in claim 17, wherein
R2 is hydrogen or CF3.

19. The compound as claimed in any one of claims
1-18 wherein T is a bond or (C1-C4) aliphatic wherein up to
one aliphatic carbon atom may be replaced with a group
selected from O, N, N(R7), and S.
20. The compound as claimed in claims 19 wherein
T is a direct bond, -CH2-, -CH(Me)-, -CH2-CH2-, -CH2-O-CH2-,
-CH(Me)-O-CH2-, or -CH2-CH2-O-CH2-.
21. The compound as claimed in claims 19 wherein
T is (C1-C4) aliphatic wherein zero carbon atom are
replaced with a group selected from O, N, N(R7), and S.

22. The compound as claimed in claim 21, wherein
T is -CH2- or -CH2-CH2-.
23. The compound as claimed in claim 22,
wherein T is -CH2-.

24. The compound as claimed in any one of claims
1-23, wherein R9 is an optionally substituted C6-aryl or C5-
heteroaryl.
25. The compound as claimed in claim 24, wherein
R9 is optionally substituted phenyl.
26. The compound as claimed in claim 25, wherein
R9 is an unsubstituted phenyl.
27. A compound selected from Table 1
wherein
"Ph" is phenyl;

"Bn" is benzyl [-CH2-Ph] ;
"Et" is ethyl; [-CH2-CH3] ; and
"I-Pr" is isopropyl [-CH(CH3)2];


and

28. A pharmaceutical composition comprising:
a) a compound as claimed in any one of claims 1-27;
and
b) a pharmaceutically acceptable carrier, adjuvant or
vehicle.
29. A compound as claimed in claim 1 for
inhibiting caspases that mediate 1L-1 mediated diseases and
cell apoptosis mediated disease.
30. A process for preparing a compound as
claimed in claim 1
comprising:
(a) reacting a compound of formula (III):


wherein:
R10 is -NO2, -C(O)OR11, -CN, R6C(O)N(H)-, R6SO2N(H)-,
R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6C (O) C (O) N (H)-,
(R6)2NC(O)C(O)N(H)-, or R6OC (O) C (O) N (H)-;
R11 is independently hydrogen, (C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-
heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-
cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-
(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-
aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-,
wherein up to 3 aliphatic carbon atoms may be replaced
with a group selected from O, N, N(R7), S, SO, and SO2;
and wherein R11 is optionally substituted with up to 6
substituents independently selected from R; and
R, R2, R3, and R6 are as definedin claim 1;
with a compound of formula (IV):

wherein Y is either a carbonyl group or an OH group; and
R4 and R5 are as defined in claim 1;
in the presence of EDC, DMAP, and HOBt andTHF;

provided that if Y is an OH group, then the process further
comprises (b) oxidizing the OH group to provide the
compound of formula (I); and
provided that if R10 is -NO2, -C(O)OR11, or -CN, the process
comprises the further step of converting the -NO2, -C(O)OR11,
or -CN into R6C(O)N(H)-, R6SO2N(H)-, R6OC (O) N (H)-,
(R6)2NC(O)N(H)-, R6C(O)C(O)N(H)-, (R6) 2NC (O) C (O) N (H)-, or
R6OC(O)C(O)N(H)-.
31. The process as claimed in claim 30, wherein
the compound of formula (III):

wherein R2, R3, and R10 are as defined in claim 1;
is prepared by a process comprising:
(c) reacting a compound of formula (V):
wherein:
R11 is independently hydrogen,
(C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-,
(C6-C10)-aryl-,
(C3-C10)-heterocyclyl-,

(C5-C10)-heteroaryl-,
(C3-C10)-cycloaliphatic-(Cl-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-, wherein up to
3 aliphatic carbon atoms may be replaced with a group
selected from O, N, N(R7), S, SO, and SO2; and
R, R2, R3, R7, and R10 are as definedin claim 1;
in the presence of deprotecting conditions selected from
acid hydrolysis, aqueous basic conditions, or
hydrogenolysis.
32. The process as claimed in claim 31, wherein the
compound of formula (V):

wherein R2, R3, R10, and R11 are as defined in claim 31;
is prepared by a process comprising:
(d) reacting a compound of formula (VI):

wherein R2 and R10 are as defined in claim 31;

with a compound of formula (VII):

wherein X is a suitable leaving group; and
R3 and R11 are as defined above;
in the presence of a solvent selected from DMF, toluene, or
THF and a base selected from BuLi, LDA, LHMDS, or NaH.
33. A process for preparing a compound of formula
(VIII):

Wherein R2, R3, and R10 are as defined in claim 1;
R11 is independently hydrogen,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C6-C10)-aryl-,
(C3-C10)-heterocyclyl-,
(C5-C10)-heteroaryl-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3
aliphatic carbon atoms may be replaced with a group
selected from O, N(H), N(R), S, SO, and SO2; and wherein

R11 is optionally substituted with up to 6 substituents
independently selected from R;
comprising the step of (e) reacting a compound of formula
(IX) :

wherein R2 and R10 are as defined above;
with a compound of formula (VII):

wherein R3 and R11 are as defined above; and
X is a suitable leaving group;
in the presence of a solvent selected from DMF, toluene, or
THF and a base selected from BuLi, LDA, LHMDS, or NaH.
34. A process for preparing a compound as
claimed in claim 1
comprising:
(a) reacting a compound of formula (III):

wherein:

R10 is -NO2, -C(O)OR11/ -CN, R6C(O)N(H)-, R6SO2N(H)-,
R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6C (O) C (O) N (H) -,
(R6)2NC(O)C(O)N(H)-, or R6OC (O) C (O) N (H)-;
R11 is independently hydrogen, (C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-
heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-
cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-
(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-
aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-,
wherein up to 3 aliphatic carbon atoms may be replaced
with a group selected from O, N, N(R7), S, SO, and SO2;
and wherein R11 is optionally substituted with up to 6
substituents independently selected from R; and
R2and R6 are as defined above;
with a compound of formula (X):

wherein Y is either a carbonyl group or an OH group; and
R3, R4 and R5 are as defined above;
in the presence of EDC, DMAP, and HOBt andTHF;
provided that if Y is an OH group, then the process further
comprises (b) oxidizing the OH group to provide the
compound of formula (I); and
provided that if R10 is -NO2, -C(O)0R11, or -CN, the process
comprises the further step of converting the -NO2, -C(O)0R11,
or -CN into R6C(O)N(H)-, R6SO2N(H)-, R6OC (O) N (H)-,

(R6)2NC(O)N(H)-, R6C(O)C(O)N(H)-, (R6) 2NC (O) C (O) N (H)-, or
R6OC(O)C(O)N(H)-.




[54) Title: 3-[2-(3-ACYLAMINO-2-OXO-2H-PYRIDIN-1-YL)-ACRTYLAMINO]-4-OXO-PINTANOIC ACID DERIVATIVES
AS CASPASE INHIBITORS

(57) Abstract: The present invention provides a compound of formula (I): wherein R1 , R2 ,R3 ,R4 ,and R5 are as defined herein. The
present invention also provides pharmaceutical compositions and methods using such compositions for treating a caspase-mediated
diseases and processes for preparing the compounds of the invention.

Documents:

01912-kolnp-2007-abstract.pdf

01912-kolnp-2007-assignment.pdf

01912-kolnp-2007-claims.pdf

01912-kolnp-2007-correspondence others 1.1.pdf

01912-kolnp-2007-correspondence others.pdf

01912-kolnp-2007-description complete.pdf

01912-kolnp-2007-form 1.pdf

01912-kolnp-2007-form 3.pdf

01912-kolnp-2007-form 5.pdf

01912-kolnp-2007-gpa.pdf

01912-kolnp-2007-international publication.pdf

01912-kolnp-2007-international search report.pdf

01912-kolnp-2007-other pct form.pdf

01912-kolnp-2007-priority document.pdf

1912-KOLNP-2007-(23-04-2012)-CORRESPONDENCE.pdf

1912-KOLNP-2007-(23-04-2012)-DESCRIPTION (COMPLETE).pdf

1912-KOLNP-2007-(23-04-2012)-FORM-1.pdf

1912-KOLNP-2007-(23-04-2012)-FORM-13.pdf

1912-KOLNP-2007-(23-04-2012)-FORM-2.pdf

1912-KOLNP-2007-(23-04-2012)-FORM-3.pdf

1912-KOLNP-2007-(23-04-2012)-FORM-5.pdf

1912-KOLNP-2007-(23-04-2012)-OTHERS.pdf

1912-KOLNP-2007-(23-04-2012)-PETITION UNDER RULE 137.pdf

1912-KOLNP-2007-ASSIGNMENT.pdf

1912-KOLNP-2007-CANCELLED PAGES.pdf

1912-KOLNP-2007-CORRESPONDENCE.pdf

1912-KOLNP-2007-EXAMINATION REPORT.pdf

1912-KOLNP-2007-FORM 13.pdf

1912-KOLNP-2007-FORM 18.pdf

1912-KOLNP-2007-GPA.pdf

1912-KOLNP-2007-GRANTED-ABSTRACT.pdf

1912-KOLNP-2007-GRANTED-CLAIMS.pdf

1912-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

1912-KOLNP-2007-GRANTED-FORM 1.pdf

1912-KOLNP-2007-GRANTED-FORM 2.pdf

1912-KOLNP-2007-GRANTED-FORM 3.pdf

1912-KOLNP-2007-GRANTED-FORM 5.pdf

1912-KOLNP-2007-GRANTED-SPECIFICATION-COMPLETE.pdf

1912-KOLNP-2007-INTERNATIONAL PUBLICATION.pdf

1912-KOLNP-2007-INTERNATIONAL SEARCH REPORT & OTHERS.pdf

1912-KOLNP-2007-PETITION UNDER RULE 137.pdf

1912-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

1912-KOLNP-2007-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

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Patent Number 256282
Indian Patent Application Number 1912/KOLNP/2007
PG Journal Number 22/2013
Publication Date 31-May-2013
Grant Date 29-May-2013
Date of Filing 28-May-2007
Name of Patentee VERTEX PHARMACEUTICALS INCORPORATED
Applicant Address 130, WAVERLY STREET, CAMBRIDGE, MA
Inventors:
# Inventor's Name Inventor's Address
1 CHARRIER, JEAN-DAMIEN UNIT 88, MILTON PARK, ABINGDON OXFORDSHIRE, OX14 4RY
2 MORTIMORE, MICHAEL UNIT 88, MILTON PARK, ABINGDON OXFORDSHIRE, OX14 4RY
3 STUDLEY, JOHN, R. UNIT 88, MILTON PARK, ABINGDON OXFORDSHIRE, OX14 4RY
4 KNEGTEL, RONALD UNIT 88, MILTON PARK, ABINGDON OXFORDSHIRE, OX14 4RY
PCT International Classification Number C07D 213/75
PCT International Application Number PCT/US2005/042139
PCT International Filing date 2005-11-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/630926 2004-11-24 U.S.A.