Indian Patents
Title of Invention

CASPASE INHIBITORS AND USES THEREOF
Abstract The present invention provides a compound of formula (I): wherein the variables are as defined herein. The present invention also provides processes for preparing the compounds of formula (1), and intermediates thereof, pharmaceutical compositions comprising those compounds, and methods of using the compounds and compositions.
Full Text Field of the Invention
[0001] This invention relates to compounds, and
compositions thereof, that are useful as caspase inhibitors.
[00021 This invention also relates to processes for
preparing these compounds.
[0003] This invention further relates to pharmaceutical
compositions comprising said compounds and to the use of the
compounds and compositions thereof for the treatment of
diseases and disorders related to caspase-mediated conditions.
Background of the Invention
[0004] Caspases are a family of cysteine protease enzymes
that are key mediators in inflammation. Caspase-1 (ICE)
processes pre-IIi-lp to produce the active form of IL-ip [WO
99/47545]. ICE has also been linked to the conversion of pro-
IGIF to IGIF and/or to the production of IFN-y [Id.]. Both IL-
1P and IFN-y contribute to the pathology associated with
inflammatory, infectious, and autoimmune diseases (see, e.g.,
WO 99/47545; J. Invest. Dermatology, 120(1), pp. 164-167
(2003); Br. J. Dermatology, 141, pp. 739-746 (1999); Science,

282, pp. 490-493 (1998); Schweiz. Med. Wochenschr., 130, pp.
1656-1661 (2000)].
[0005] Caspases are also key mediators in the signaling
pathways for apoptosis and cell disassembly [N.A. Thorriberry,
Chem. Biol., 5, pp. R97-R103 (1998)]. 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.
[0006] 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 improve survival after endotoxic
shock [H. Yaoita et al., Circulation, 97, pp. 276-281 (1998);
M. Endres et al., J. Cerebral Blood Flow and Metabolism, 18,
pp. 238-247, (1998); Y. Cheng et al., J. Clin. Invest., 101,
pp. 1992-1999 (1998); A.G. Yakovlev et al., J. Neurosci., 17,
pp. 7415-7424 (1997); I. Rodriguez et al., J. Exp. Med., 184,
pp. 2067-2072 (1996); Grobmyer et al., Mol. Med., 5, p. 585
(1999)] .
[0007] However, due to their peptidic nature, such
inhibitors are typically characterized by undesirable

pharmacological properties, such as poor cellular penetration
and cellular activity, poor oral absorption, poor stability
and rapid metabolism [J.J. Plattner and D.W. Norbeck, in Drug
Discovery Technologies, C.R. Clark and W.H. Moos, Eds. (Ellis
Horwood, Chichester, England, 1990), pp. 92-126]. This has
hampered their development into effective drugs. These and
other studies with peptidic caspase inhibitors have
demonstrated that an aspartic acid residue is involved in a
key interaction with the caspase enzyme [K.P. Wilson et al.,
Nature, 370, pp. 270-275 (1994); Lazebnik et al., Nature, 371,
p. 346 (1994)].
[0008] Accordingly, peptidyl and non-peptidyl aspartic acid
compounds are useful as caspase inhibitors.
[0009] A need nevertheless exists for compounds that have
the ability to act as caspase inhibitors, particularly with
selective activity against certain caspases.
Summary of the Invention
[0010] The present invention provides a compound of formula
I:
wherein the variables are as defined herein.
[0011] The present invention also provides processes for
preparing these compounds, compositions, pharmaceutical
compositions, and methods of using such compounds and
compositions for inhibiting caspases. These compounds are
particularly useful as selective caspase-l/capase-8
inhibitors.

Detailed Description of the Invention
[0012] The present invention provides a compound of formula
I:

R is R3C(0)-, HC(0), R3S02-, R30C(0), (R3;2NC(0),
(R1) (H)NC(O) . R3C(0)C(0)-, R3-, (R5) 2NC (0) C (0) ,
R1 is H, aliphatic, cycloaliphatic, aryl, heterocyclyi,
heteroaryl, cycloalkyl-aliphatic-, cycloalkenyl-aliphatic-,
aryl-aliphatic-, heterocyclyl-aliphatic-, or heteroaryl-
aliphatic-, wherein any hydrogen atom is optionally and
independently replaced by Re and any set of two hydrogen atoms
bound to the same atom is optionally and independently
replaced by carbonyl;
Ring A i 3:

wherein, in each ring, any hydrogen atom is optionally and
independently replaced by R4 and any set of two hydrogen atoms
bound to the same atom is optionally and independently
replaced by carbonyl;

R3 is aliphatic, cycloaliphatic, aryl, heterocyclyl,
heteroaryl, cycloaliphatic-aliphatic-, aryl-aliphatic-,
heterocyclyl-aliphatic-, or heteroaryl-aliphatic-; or two R3
groups bound to the same atom form together with that atom a
3-10 membered aromatic or nonaromatic ring; wherein any ring
is optionally fused to an aryl, heteroaryl, cycloalkyl, or
heterocyclyl; wherein up to 3 aliphatic carbon atoms may be
replaced by a group selected from 0, N, NR9, S, SO, and S02,
wherein R3 is substituted with up to 6 substituents
independently selected from R8;
R4 is halogen, -OR9, -NO2, -CN, -CF3, -0CF3, -R9, 1,2-
methylenedioxy, 1,2-ethylenedioxy, -N(R9)2, -SR9, -SOR9, -SO2R9,
-S02N(R9)2, -SO3R9, -C(0)R9, -C(0)C(0)R9, -C (0)C (0)0R9,
-C(0)C(0)N(R9)2, -C(0)CH2C(0)R9, -C(S)R9, -C(S)OR9, -C(0)0R9,
-OC(0)R9, -C(0)N(R9)2, -OC(0)N(R9)2, -C (S)N(R9) 2, -(CH2)0-
2NHC(0)R9, -N(R9)N(R9)COR9, -N(R9)N(R9) C (O) OR9,
-N(R9)N(R9)CON(R9)2, -N(R9)S02R9, -N(R9) S02N(R9)2, -N(R3)C (0)OR9,
-N(R9)C(0)R9, -N(R9)C(S)R9, -N(R9) C (O)N(R9) 2/ -N(R9) C (S)N(R9) 2,
-N(COR9)COR9, -N(OR9)R9, -C (=NH)N(R9)2, -C (0)N(OR9)R9,
-C(=NOR9)R9, -OP (O) (OR9) 2, -P(0)(R9)2, -F(0)(OR9)2, or
-P(O) (H)(0R9);
R2 is -C(R5) (Rs) (R7) , aryl, heteroaryl, or C3_7 cycloalkyl;
R5 is H or a Ci_6 straight-chained or branched alkyl;
R6 is H or a Ci-s straight-chained or branched alkyl;
R7 is -CF3, -C3-7cycloalkyl, aryl, heteroaryl, heterocycle,
or a C1-6 straight-chained or branched alkyl, wherein each
carbon atom of the alkyl is optionally and independently
substituted with R10,-
Or R5 and R7 taken together with the carbon atom to which
they are attached form a 3-10 membered cycloaliphatic;
R8 and R8' are each independently halogen, -OR9, -N02, -CN,
-CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-ethylenedioxy,

-N(R9)2, -SR9, -SOR9, -S02R9, -S02N(R9)2, -SO3R9, -C(0)R9,
-C(0)C(0)R9, -C(0)C(0)OR9, -C{0)C(0)N(R9)2, -C (0)CH2C (O)R9,
-C{S)R9, -C(S)OR9, -C(0)OR9, -OC(0)R9, -C(0)N(R9)2, -OC (O)N(R9) 2,
-C(S)N(R9)2, -(CH2)0-2NHC(O)R9, -N(R9)N(R9)COR9,
-N(R9)N(R9)C(0)OR9, -N(R9)N(R9)CON(R9)2, -N(R9)S02R9,
-N(R9)S02N(R9)2, -N(R9)C(0)OR9, -N(R9)C(0)R9, -N(R9)C(S)R9,
-N(R9)C(0)N(R9)2, -N(R9)C(S)N(R9)2, -N(COR9)COR9, -N(OR9)R9,
-C(=NH)N(R9)2, -C(0)N(OR9)R9, -C{=NOR9)R9, -OP (O) (OR9) 2,
-P(O) (R9)2, -P(O) R9 is hydrogen, aliphatic, cycloaliphatic, aryl,
heterocyclyl, heteroaryl, cycloaliphatic-aliphatic-, aryl-
aliphatic-, heterocyclyl-aliphatic-, or heteroaryl-aliphatic-;
wherein any hydrogen atom is optionally and independently
replaced by R8 and any set of two hydrogen atoms bound to the
same atom is optionally and independently replaced by
carbonyl;
R10 is halogen, -OR11, -N02, -CN, -CF3, -OCF3; -R11, or
-SR11,- wherein R11 is Ci-4-aliphatic-.
[0013] The present invention also provides a compound of
formula II:


R1 is H, aliphatic, cycloalkyl (e.g., cyclopentyl),
cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-
aliphatic- cycloalkenyl-aliphatic-, aryl-aliphatic-,
heterocyclyl-aliphatic-, or heteroaryl-aliphatic-, wherein any
hydrogen atom is optionally and independently replaced by R8
and any set of two hydrogen atoms bound to the same atom is
optionally and independently replaced by carbonyl;
Ring A is:

wherein, in each ring, any hydrogen atom is optionally and
independently replaced by R4 and any set of two hydrogen atoms
bound to the same atom is optionally and independently
replaced by carbonyl (or in-an alternative embodiment,
carbonyl or (C3-C6) spirocycle;)
R4 is halogen, -OR9, -N02, -CN, -CF3, -OCF3, -R9, 1,2-
methylenedioxy, 1,2-ethylenedioxy, -N(R9)2, -SR9, -SOR9, -S02R9,
-S02N(R9)2, -SO3R9, -C(0)R9, -C(0)C(0)R9, -C(0) C (O)OR9,
-C(0)C(0)N(R9)2, -C(0)CH2C(0)R9, -C(S)R9, -C(S)OR9, -C(0)0R9,
-OC(0)R9, -C(0)N(R9)2, -OC(0)N(R9)2, -C(S)N(R9)2, ~(CH2)0-
2NHC(0)R9, -N(Rs)N(R9)COR9,. -N(R9)N(R9) C (0)0R9,
-N(R9)N(R9)CON(R9)2, -N(R9)S02R9, -N(R9) S02N(R9) 2, -N(R9)C (0) OR9,
-N(R9)C(0)R9, -N(R9)C(S)R9, -N(R9) C (0)N(R9)2/ -N(R9)C (S)N(R9) 2,
-N(COR9)COR9, -N(OR9)R9, -C (=NH)N(R9)2, -C(0)N(OR9)R9,
-C(=NOR9)R9, -0P(0) (OR9)2, -P(0)(R9)2, -P(O)(0R9)2, or
-P(0) (H) (OR9);
R2 is -C(R5) (R6) (R7) , aryl, heteroaryl, or -C3-7 cycloalkyl;
R5 is H or a C1-6 straight-chained or branched alkyl;
R6 is H or a C1-6 straight-chained or branched alkyl;

R7 is -CF3, -C3-7 cycloalkyl, aryl, heteroaryl,
heterocycle, or a Ci_6 straight-chained or branched alkyl,
wherein each carbon atom of the alkyl is optionally and
independently substituted with R10;
(or in an alternative embodiment, R5 and R7 taken together
with the carbon atom to which they are attached form a 3-10
membered cycloaliphatic) ;
R3 is phenyl, thiophene, or pyridine, wherein each ring is
optionally substituted with up to 5 groups independently
selected from R8 , and wherein at least one position on the
phenyl, thiophene, or pyridine adjacent to bond x is
substituted by R12, wherein R12 has no more than 5 straight-
chained atoms;
R8 and R8 are each independently halogen, -OR9, -NO2, -CN,
-CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-ethylenedioxy,
-N(R9)2, -SR9, -SOR9, -SO2R9, -S02N(R9)2, -SO3R9, -C(0)R9,
-C(0)C(0)R9, -C(0)C(0)OR9, -C(0)C(0)N(R9)2, -C (0)CH2C (0) R9,
-C(S)R9, -C(S)OR9, -C(0)0R9, -OC(0)R9, -C(0)N(R9)2, -OC (O)N(R9) 2,
-C(S)N(R9)2, -(CH2)0.2NHC(O)R9, -N (R9)N(R9) COR9,
-N(R9)N(R9)C(0)0R9, -N(R9)N(R9)CON(R9)2, -N(R9)S02R9,
-N(R9)S02N(R9)2, -N(R9)C(0)OR9, -N(R9) C (0) R9, -N(R9) C (S)R9,
~N(R9)C(0)N(R9)2, -N(R9)C(S)N(R9)2, -N(C0R9) COR9, -N(OR9)R9,
-C(=NH)N(R9)2, -C(0)N(0R9)R9, -C(=NOR9)R9, -OP (0) (OR9) 2,
-P(0) (R9)2r -P(0)(OR9)2, and -P(0)(H)(OR9);
R9 is hydrogen, aliphatic, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heteroaryl, cycloaliphatic-aliphatic-, aryl-
alipriatic-, heterocyclyl-aliphatic-, or heteroaryl-aliphatic-;
(in certain embodiments, any hydrogen atom of R9 is optionally
and independently replaced by R8 and any set of two hydrogen
atoms bound to the same atom is optionally and independently
replaced by carbonyl; provided that if R9 is substituted with a

R8, wherein the R8 comprises a R9 substituent, then that R9
substituent is not substituted with RB) ;
R10 is halogen, -OR11, -N02, -CN, -CF3, -OCP3, -R11, or
-SR11;
R11 is Ci-4-aliphatic-; and
R12 is halogen, -OR11, -N02, -CN, -CF3, -OCF3, -R11, -SR9.
[0014] As used in the definition of R12, "straight-chained
atoms" refers to atoms that are linearly bound, regardless of
whether those atoms also have atoms bound in a branched
fashion. According to this definition, an ethyl group and a
trifluoromethoxy group each have three straight-chained atoms,
and a methyl group has two straight-chained atoms. In the
above embodiment, R12 has no more than 5 straight-chained
atoms. In two other embodiments, R12 has no more than 4
straight-chained atoms and no more than 3 straight-chained
atoms. In yet other embodiments, R12 has 2 straight-chained
atoms or 1 atom.
[0015] As used herein, a position adjacent to the bond x
refers to a position which is located next to the position at
which x is bound. In an aryl ring, this position is often
called "the ortho position* or, in the case of a phenyl ring,
it may be called "the 2-positiori". By way of example, in the
structures immediately below, R12 is bound to the phenyl,
thiophcne, and pyridine rings at *the position adjacent to
bond x".


[0016] In one embodiment of this invention, R is R3C(0)-.
[0017] In come embodiments, R3 is optionally substituted
Cj-icaryl or heteroaryl. In other embodiments R3 is optionally
substituted phenyl. In yet other embodiments, R3 is a 8-10
membered optionally substituted heteroaryl (i.e. quinoline,
isoquinoline, or quinazoline) In yet other embodiments, R3 is
an optionally substituted 5-6 merabered heteroaryl (i.e.,
pyridyl, pyrimidyl, pyrozinyl, thiophenyl, furanyl,
thiazolyl) .
[0018] In some embodiments, R3 is optionally and
independently substituted by 0-5 R8' groups.
[0019] In one embodiment, the compound of this invention is
represented by formula II:

wherein:
a) R3 is phenyl, thiophene, or pyridine;
b) each ring is optionally substituted with up to 5
groups independently selected from R8 ; and
c) at least one position on the phenyl, thiophene, or
pyridine adjacent to bond x is substituted by R12,
wherein R12 has no more than 5 straight-chained atoms.
[0020] Another embodiment of this invention provides a
compound, wherein Y is:


[0021] In one embodiment of this invention, R1 is
substituted with up to 3 groups selected independently from
carbonyl and R8.
[0022] In another embodiment, R1 is Ci-i2aliphatic or
C3-iocycloalkyl, wherein each R1 is optionally substituted with
1-3 groups selected independently from R8. In yet another
embodiment, R1 is a straight-chain or branched Ci-4 alkyl that
is optionally substituted with 1-3 groups selected
independently from R8.
[0023] In cne embodiment, R1 is an unsubstituted, straight-
chain or branched Ci-« alkyl (e.g., ethyl, isopropyl, n-propyl,
or n-butyl) . In another embodiment, R1 is ethyl.
[0024] In any of these embodiments, R8 is halogen, -CR*,
-CN, -CF3, -OCF3, or -R9. In another embodiment wherein R8 is
-R9, that R9 is benzyl.
[0025] In another embodiment, Y is

[0026] In another embodiment. Ring A is substituted with up
to 3 groups (preferably, 1 group) selected independently from
carbonyl and R*.
[0027] In one embodiment, Ring A is:


optionally substituted with R*.
[0028] In yet another embodiment, Ring A is:

optionally substituted with R4.
[0029] In another form of this embodiment, Ring A is
unsubstituted proline (i.e., R* is hydrogen).
[0030] In yet another embodiment, Ring A is:

[0032] In any of these embodiments, R* is halogen, -OR9,
-CF3, -OCF3, -R9, or -SR9. In certain embodiments R* is H.
[0033] In one embodiment, R2 is a C3.4 branched alkyl group.
[0034] In another embodiment, R5 is H or -CH3, R6 is -CH3,
and R7 is -CH3.
[0035] In another embodiment, R12 is -OCF3, -OCH3, -CF3,
-CH3, -CH2CH3, -Cl, or -F.
[0036] In yet another embodiment, R'2 is -CF3, -CH3, -Cl, or
-F.
[0037] In yet another embodiment, R:2 is -CH3, -Cl, or -F.
[0038] In another embodiment, each R8 , if present, is
independently halogen, -OR9, -N02, -CN, -CK3, -0CF3, -R9, 1,2-
methylencdioxy, 1,2-ethylenedioxy, -N(R9)2, -SR9, -SOR9, -S02R9,
-S03N(R9)2, -C(0)R9, -C(0)C(0)N(R9)2, -C(0)N(R9)2, -OC (0)N (R9) 2,

-(CH2)o-2NHC(0)R9, -N(R9)S02R9, -N(R9) S02N(R9) 2, -N(R9) C(0)0R9,
-N(R9)C(0)R9, or -N(R9)C(0)N(R9)2.
[0039] In another embodiment, R8' is -NH2, ~N(R9)2,
-N(R9)C(0)R5, -OCF3, -OR9, -CF3, -R9, -SR9, or halo. In this
embodiment, halo is, preferably, CI or F and R9 is, preferably,
straight or branched Ci-« alkyl.
[0040] According to one embodiment, this invention provides
coinpounds of formula III:

wherein the variables are as defined in any of the embodiments
herein.
[0041] In one forn of this embodiment, the compound has the
stereochemistry indicated below:

wherein the variables are as defined in any of the embodiments
herein.
[0042] In other forms of this embodiment, the compound has
the stereochemistry indicated below:


wherein the variables are as defined in any of the embodiments
herein.
[0043] According to another embodiment, this invention
provides compound of formula IV:

wherein the variables are as defined in any of the embodiments
herein.
[0044] In one form of this embodiment, the conpour.d has the
stereochemistry indicated below:

wherein the variables are as defined in any of the embodiments
herein.
[0045] The embodiments herein may be combined to provide a
compound according to this invention.
[0046] According to one embodiment, the present invention
provides a compound selected frora Table 1 below:
Table 1





















11-66
[0048] In certain embodiments of this invention, the
variable definitions are selected from those depicted in the
compounds of Table 1 and/or Table 2.
[0049] As used herein, a specified number atoms includes
any integer therein. For example, a group having from 1-4
atoms, could have 1, 2, 3, or 4 atoms.
[0050] As used herein, an aliphatic group includes
straight-chained and branched groups having thn 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
alky! groups (preferably having from 1 to 6 atoms).
[0051] Cycloaikyl and cycloalkenyl groups have between 3
and 10 carbon atoms and are monocyclic or bicyclic, including
linearly fused, bridged, or spirocyclic.
[0052] As used herein, "aromatic group" or "aryi" refers; to
a 6-10-raenbered ring system that contains at least one
aromatic ring. Examples of aromatic rings include phenyl and
naphthyl.
[0053] As used herein a "beteroaryl" refers to ring system
having 5-10 members and 1, 2, or 1 heteroatoms independently

selected from N, N(R9), 0, S, SO, and SOz-, wherein at least
one ring is heteroaromatic (e.g., pyrLdyl, thiophene, or
thiazole).
[00541 As used herein a "heterocycLe" refers to ring system
having 3-10 members and 1, 2, or 3 hefceroatoms independently
selected from N, N(R9) , 0, S, SO, and JSO2, wherein no ring is
aromatic (e.g., piperidine and morphoLine) .
[0055] Further examples of heteroar-yl rings include
2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,
4-imidazolyl, 5-imidazolyl, benzimidaztolyl, 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-tetra.zolyl) , triazolyl (e.g. ,
2-triazolyl and 5-triazolyl) , 2-thienyl, 3-thienyl,
benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl) ,
pyrazolyl (e.g., 2-pyrazolyl} , isothia.zolyl, 1,2,3-
oxadiazolyl, 1,2,5-oxadiazolyl, 1,2, 4-oxadiazolyl,
1,2,3-triazolyl, 1,2,3-thiadiazolyl, L , 3 , 4-thiadiazolyl,
1,2,5-thiadiazolyl, purinyl, pyrazinyL , 1,3,5-triazinyl,
quinolinyl (e.g., 2-quinolinyl, 3-guin.olinyl, 4-quinolinyl) ,
and isoquinolinyl (e.g., 1-isoquinoliruyl, 3-isoquinolinyl, or
4-isoquinolinyl).
[0056] Further examples of heterocyclic rings include 3-1H-
benzimidazol-2-one, 3-(l-alkyl)-benziiaidazol-2-one; 2-
tetrahydrofuranyl, 3-tetrahydrofuranyl ,
2-tetrahydrothiophenyl, 3-tetrahydrotb_iophenyl, 2-morpholino,
3-morpholino, 4-morpholino, 2-thiomorp>holino, 3-
thiomorpholino, 4-thiomorpholino, l-pyrrolidinyl, 2-
pyrrolidinyl, 3-pyrrolidinyl, 1-tetrah.ydropiperazinyl, 2-
tetrahydropiperazinyl, 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, tetrahydroisoquinolinyl, benzothiolane,
benzodithiane, and 1, 3-dihydro-imidazol-2-one.
[0057] Each of the above aliphatic, aryl, cycloaliphatic,
heteroaryl, and heterocyclyl may contain appropriate
substituents (preferably up to 5) independently selected from,
for example, carbonyl and Rs. Preferred substituents are
halogen, -OR9, -N02, -CF3, -OCF3, -R9, oxo, -OR9, -0-benzyl, -O-
phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, -N(R9)2,
-C(0)R9, -CO0R9 or -CON(R9)2, wherein R9 is defined herein (and
is preferably H, (C1-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.
[0058] It will be apparent to one skilled in the art that
certain compounds of this invention may exist in tautomeric
forms or hydrated 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.
[0059] 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 t»y a deuterium or tritium, or
the replacement of a carbon by a 13C- or "c-enriched carbon are
within the scope of this invention.
[0060] The compounds of this invention may be obtained by
any method, including general, synthetic methods known to
those skilled in the art for analogous compounds (see e.g., WO
99/47545). For the purposes off illustration, the following
Schemes for the synthesis of the compounds of the present
invention are provided.
[0061] The following abbrevi-ations are used:
BDC is l-(3-dimethylaminopropyL )-3-ethylcarbodiimide
HOBt is 1-hydroxybenzotriazole
THF is tetrahydrofuran
TFA is trifluoroacetic acid
DCM is dichloromethane
DMAP is 4-dimethylaminopyridinei
DIPEA is diisopropylethylamine
DMF is dimethylformamide
TFA is trifluoroacetic acid
Z is benzyloxycarbonyl
1H NMR is nuclear magnetic resonance
TLC is thin layer chromatograph-y


[0062] Scheme I depicts a general route to prepare the
compounds E and F disclosed in this invention. The amino
group of species A, readily obtained from reduction of the cc-
carboxylic group of aspartic acid (protected with PGi as an
ester), is coupled to the carboxylic acid moiety of species B
(N-protected with PG2) to give species C. PGi and PG2 are
orthogonal protecting groups (i.e., protecting groups where a
protecting group may be selectively removed in the presence of
another protecting group. Ideally, PGi should be able to be
removed without removing PG2 and-vice versa). Here, the
aspartate part of the molecule is then manipulated in an
oxidation/ketalisation/ deprotection/cyclisation sequence to
give species D. The Ring A portion of D is then
functionalized further to give species E which is part of the
disclosed invention. Deprotection of the ketal gives species
F which represent the other part of the disclosed invention.
[0063] In various embodiments of this invention, PG2 is a
suitable amine protecting group, including but not limited to,
the amine protecting groups described in T.W. Greene & P.G.M
Wutz, "Protective Groups in Organic Synthesis", 3rd Edition,

John Wiley & Sons, Inc. (1999 and other editions) ("Greene").
A "Z" protecting group (benzyloxycarbonyl) is a particularly
useful N-protecting group for use in connection with this
invention. In compounds wherein PG2 is protecting the nitrogen
of a proline, PG2 is preferably z. it should be understood
that modified Z groups (*Z-type protecting groups") employed
in connection with the compounds and processes of this
invention would also fall within the scope of this invention.
For example, Z could be substituted at the CH2 group or the
phenyl group with R8 (preferably halo or Ci-g straight-chained
or branched alkyl) to provide a Z-type protecting group.
[0064] In various embodiments of this invention, PGi is a
suitable carboxylic acid protecting group, including but not
limited to the acid protecting groups described in Greene. In
certain embodiments, PGi is C1-6 straight-chained or branched
alkyl group. A t-butyl group is a particularly useful acid
protecting group for use in connection with this invention.
[0065] In Scheme I, compound A is a modified aspartic acid
residue. In addition to compound A, other modified aspartic
acid residues, including the following, have been reported:

wherein, PG3 and PG4 are appropriate protecting groups. These
modified aspartic acids may be prepared by methods known to
skilled practitioners. See, for example, United States Patent
Application Publication US 2002/0042376 (especially page 9,
paragraph [0121] and pages 21-22, paragraph [0250] and the
documents cited at paragraph [0123]) and United States Patent
6,235,899. See also, C. Gros et al. "Stereochemical control
in the preparation of a-amino N-methylthiazolidine Masked

Aldehydes used for Peptide Aldehyde Synthesis" Tetrahedron,
58, pp. 2673-2680 (2002); K.T. Chapman, "Synthesis of a Potent
Reversible Inhibitor of Interleukin-S Converting Enzyme"
Bjoorg. Med. Chem. Letts., 2, pp. 613-618 (1382); M.D.
Mullican et al. "The Synthesis and Evaluation, of Peptidyl
Aspartyl Aldehydes as Inhibitors of ICE"' 4, pp. 2359-2364
(1994); M.H. Chen, et al. "An Efficient Stereoselective
Synthesis of [3S(1S,9S) ]-3-[ [[9- (Benzoylamino)octahydro-6,10-
Dioxo-6H-pyridazino- (1,2-a) (1,2) -Diazepin-l-vl]-carbonyl]
amino] -4-oxobutanoic acid, an interleukin converting enzyme
(ICE) Inhibitor" 9, pp. 1587-1592 (1999). Accordingly, Scheme
I (and also Scheme III below) could be modified to use these
other aspartic acid residues.

Reagent and conditions: (a) R3COOH, HOBt, DMftJ?, EDC, THF; (b)
R3CONHCH(R2)COOH, HOBt, DMAP, EDC, THF; (C) 2M HC1, MeCN.

[0065] Scheme II depicts formation of compounds of formula
I and II, wherein. Ring A is unsubstituted proline. Here the
cyclic acetal form of a compound of this invention is depicted
as formula I and the aldehyde form, is depicted as formula II.
Compounds having a Ring A other than unsubstituted proline
could .be substituted in the methods depicted in Scheme I.
[0067] Scheme II depicts the routes utilized to prepare
compounds of formulae I and II. Compounds I can be prepared
from compounds 1 by condensation of the amino group in 1 with
the suitably functionalized carboxylic acid (or derivative).
In this step, standard coupling reagents to form amide bonds
have been depicted; other conditions known in the art to form
amide bonds can also be used.
[0068] As known zo skilled practitioners, a carboxylic acid
(-C(O)OH) can be coupled to the amine under appropriate
conditions for coupling amines and carboxylic acids.
Alternatively, in such couplings, a carboxylic acid derivative
(-C(O)X) may be employed instead of the carboxylic acid. It
should be understood that in the context of coupling an amine
and a carboxylic acid derivative, the derivative would
activate the acid to facilitate coupling to an amine.
Appropriate X groups are essentially leaving groups and are
known to skilled practitioners. 'March's Advanced organic
Chemistry*, 5th Ed., lid.: Smith, M.B. and March, J., John
Wiley & Sons, Now York: 2001.
[0069] Typical conditions for coupling an amine and an acid
include combining a suitable solvent, a carboxylic acid, a
base, and a peptide-coupliny reayenl. Examples of suitable
conditions are described in US2002/C042376 and WO 31/81330,
the entireties of which are hereby incorporated by reference.
In certain embodiments, the conditions are as described in the
Schemes and Examples herein.

10070] Examples of appropriate derivatives include, lout are
not limited to, compounds of the formula RX wherein X is CI,
F, 0C(=0)R" (R" is aliphatic or aryl), SH, SR, SAr, or SeAr.
In some embodiments R is C(=0). Suitable conditions foar using
these appropriate derivatives are known in the art.

[0071] Scheme III depicts a possible route to prepare
compounds 7 and compounds 1 described in scheme I. Compound
2, readily obtained from reduction of the a-carboxylic c^roup
of aspartic acid, is coupled to N-protected proline (or other
ring, wherein Ring A is other than unsubstituted proline) to
form 3. Here, the proline is N-protected with a Z
(benzyloxycarbonyl) group. Compounds 3 are then oxidized into
the aldehydes 4 which are acetalized in situ to give the

acetals 5. Acetals can be formed in the presence of I^-OH (or
a suitable acetal forming reagent), a protic acid (for
example, TsOH), or a Lewis acid, and a suitable solvent.
Examples of suitable acetal forming reagents that form
compounds wherein R1 is to become ethyl can be considered
ethanol equivalents and include, but are not limited to,
triethylorthoformate or a diethylacetal, such as a
(CH3)2C(0CH2CH3)2. Preferably, the solvent is CH2C12, toluene,
or chlorobenzene. Appropriate protic acids include, but are
not limited to, TEA, p-TsOH. Appropriate Lewis acids
include, but are not limited to TiCl4 [0072] In Scheme III, the oxidation of compounds 3 to
compounds 4 is depicted as being done under Swern conditions.
Other oxidation conditions may also be employed to prepare
compounds of this invention. Preferred oxidation conditions
are those that a mild and relatively quick to minimize
epimerization at the acid side chain of the modified aspartic
acid residue. In one embodiment, the oxidation step is a
TEMPO oxidation (see Example 1-1, Method C, below) . Other
oxidation conditions include a Dess-Martin oxidation and a
tetrapropylammonium perruthenate (TPAP) oxidation.
[0073] Aldehydes 4 may be isolated but are preferably
carried through directly to 5 without isolation. Deprotection
of the terfc-butyl ester (in 5) is accompanied by spontaneous
ring cyclization to give a mixture of diastereoisomers which
were separated by column chromatography to give the
enantiomerically pure syn ketals 6 and anti ketals (not
represented in this scheme). The deprotection may be done
under protic acid or Lewis acid conditions in an appropriate
solvent. Appropriate solvents include, but are not limited
to, toluene, chlorobenzene, and DCM. Appropriate protic acids
include, but are not limited to, TPA, p-TsOH. Appropriate

Lewis acids include, but are not limited to TiCli, MgBr2, and
ZnCl2. For clarity of the scheme, only syn ketals are
represented in the next steps to form compounds 7 and 1 but
the same sequence may be used to form anti ketals. Compounds
6 are submitted to hydrogenolysis and the resulting compounds
7 are reacted with Z-protected aminoacids, using conditions
known in the art to prepare amide bonds, to yield compounds 9.
Compounds 7 may be generated and used in situ. If isolated,
it is preferable to use compounds 7 relatively soon after
generation. Compounds 9 are finally submitted to
hydrogenolysis to give compounds 1, which can be used directly
to prepare compounds I, as depicted in Scheme II.
[0074] Alternatively, compounds 7 can be used to prepare
compounds I, as depicted in Scheme II. In this preparation,
an amino acid residue and the desired N-terminal group is
prepared in one step (see, Scheme II, reaction (b)).
[0075] As described in connection with Scheme I, aspartic
acid derivatives other than compounds 2 can be employed to
obtain compounds of this invention.

Reagent and conditions: (a) ROH / HOBt / DMAP / EDC/ THF or
RC1 / Et3N / DCM; (b) RNHCH(R2) COOH, HOBt, DMAP, EDC, THF; (c)
2M HC1, MeCN.

[00761 Scheme IV depicts formation of compounds of formula
III and IV, wherein Ring A is 2-Aza-bicyclo[2.2.l]-heptane-3-
carboxylic acid. Here the cyclic acetal form of a compound of
this invention is depicted as formula III and the aldehyde
form is depicted as formula IV. Scheme IV depicts the routes
utilized to prepare compounds of formulae III and IV.
Compounds III can be prepared from compounds 11 by
condensation of the amino group in 11 under conditions to
provide the desired R group, such as suitably functionalized
carboxylic acid (or derivative), sulfonic acid (or
derivative), chloroformate or carbamoyl chloride (or
isocyanate), for example, under appropriate reaction
condition. In this step, standard coupling reagents to form
CO-NH bonds have been depicted; other conditions known in the
art to form CO-NH (or alkyl-N, or £02-N) bonds can also be used
to provide the desired compound comprising R-N.
Alternatively, compounds I can be prepared from compounds 17
by condensation of the amino group in 17 with the suitably
functionalized carboxylic acid (or derivative), sulfonic acid
(or derivative), chloroformate or carbamoyl chloride (or
isocyanate). In this step, standard coupling reagents to form
CO-NH bonds have been depicted; other conditions known in the
art to form CO-NH bonds can also be used.

either commercially available, reported in the literature, or
may be prepared according to methods known in the literature.
[0078] For clarity of the scheme, only syn ketals are
represented in the next steps to form compounds 17 and 11 but
the same sequence may be used to form anti ketals. Compounds
16 are submitted to hydrogenolysis and the resulting compounds
17 are reacted with Z-protected aminoacids, using conditions
known in the art to prepare amide bonds, to yield compounds
19.
[0079] Alternatively, compounds 17 can be used to prepare
compounds III, as depicted in Scheme IV. Compounds 19 are
finally submitted to hydrogenolysis to give compounds 11,
which can be used directly to prepare compounds III, as
depicted in Scheme IV.
[0080] The R3COOH used in Scheme II are either commercially
available, reported in the literature, or prepared according
to methods known in the literature. For compound 11-30, 2-
chloro-3-methoxybenzoic acid was prepared as in J.Org.Chem,
59, 1994, 2939-2944.
[0081] For compound 11-32, 2-chloro-3-
trifluoromethoxybenzoic acid was prepared from 2-amino-3-
trifluoromethoxybenzoic acid (prepared as in J.Org.Chem, 68,
2003, 4693-4699) using a Sandmeyer replacement of the amino
group by a chloro, according to a method substantially similar
to the one reported in J.Org.Chem, 59, 1994, 2939-2944.
[0082] Accordingly, this invention also provides a process
for preparing a compound of this invention.

[0083] In one embodiment is provided a process for
preparing a compound of formula I:

and the other variables are as defined in any of the
embodiments herein;
comprising reacting a compound of formula 1:

wherein the variables are as defined in any of the embodiments
herein; and a compound of formula RX, wherein X is OH or an
appropriate derivative (i.e., leaving group)/ in the presence
of conditions for coupling an amine and an acid (when X is OH)
or an amine and an appropriate acid derivative (when X is not
OH (i.e., a leaving group; for example, Cl) to provide the
compound of formula I.
[0084] Another embodiment provides a process for preparing
a compound of formula I:

wherein Y is:
and the other variables are as defined in any of the
embodiments herein;
comprising reacting a compound of formula 7:

wherein the variables are as defined in any of the embodiments
herein, and a compound of formula KNHCH(R2)C(0)X, wherein X is
OH or an appropriate derivative, in the presence of conditions
for coupling an amine and an acid (when X is OH) or an
appropriate acid derivative (when x is not OH; for example, X
is CI) to provide the compound of formula I.
[0085] Yet another embodiment of this invention provides a
process for preparing a compound of formula IV:


wherein the variables are as defined in any of the embodiments
herein, comprising reacting a compound of formula I:
wherein Y is:
wherein R and R1 are each independently as defined in any of
the embodiments herein, under hydrolysis conditions, to
provide the compound of formula II. In certain embodiments, R
is R3C(=0) . In yet other embodiments, when A is proline, R is
R3C(=0). Hydrolysis conditions for converting I to II are well
known to skilled practitioners (see e.g., Greene). Such
conditions include an appropriate solvent (e.g., acetonitrile)
and aqueous acid (e.g., 2M HCl).
[0086] Another embodiment provides a process for preparing
a compound of formula 6-A:


wherein PG2 is a suitable nitrogen protecting group and R1 is
as defined in any of the embodiments herein, comprising
reacting a compound of formula 5-A:

under suitable ring cyclization conditions, to provide the
compound of formula 6-A. Suitable ring cyclization conditions
include an acid and a suitable solvent; for example, TFA in
DCM.
[0087] Another embodiment provides a process for preparing
a compound of formula 5-A:

comprising reacting a compound of formula 4-A:

in tlie presence of R^-OH (or a suitable acetal forming
reagent), protic or Lewis acid (for example, TsOH) , and a
suitable solvent to provide the compound of formula 5-A.
[00 88] Another embodiment provides a process for preparing
a compound of formula 4-A:


under suitable oxidation conditions (for example, a Swern
oxidation: Mancuso, A.J.,- Swern, D. Synthesis, 1981, 165-185)
to provide the compound of formula 4-A. Preferred oxidation
conditions include a TEMPO oxidation (see.Example 1-1,
Method C, below) .
[0089] Another embodiment provides a process for preparing
a compound of formula 3-A:

comprising:
reacting a compound of formula 2:

with a compound of formula 20-A:


under conditions for coupling an amine and a carboxylic acid
(when X is OH), or an amine and an appropriate carboxylic acid
(when X is not OH), to provide the compound of formula 3-A.
[0090] Another embodiment provides a process for preparing
a compound of formula 6:

wherein PG2 is a suitable nitrogen protecting group and R1 is
as defined in any of the embodiments herein, comprising
reacting a compound of formula 5:

under suitable cyclization conditions, to provide the compound
of formula 6.
[0091] Another embodiment provides a process for preparing
a compound of formula 5:


comprising reacting a compound of formula 4:

in the presence of R^-OH (or a suitable acetal forming
reagent) , protic or Lewis acid (for example, TsOH), and a
suitable solvent to provide the compound of formula 5.
Preferably, tlie solvent is CH2CI2, toluene, or chlorobenzene.
[0092] Another embodiment provides a process for preparing
a compound of formula 4:

comprising reacting a compound of formula 3 :

under suitable oxidation conditions (for example a Swern
oxidation) to provide the compound of formula 4. Preferred
oxidation conditions include a TEMPO oxidation (see Example
1-1, Method C, below) .
[0093] Another embodiment provides a process for preparing
a compound of formula 3:


under conditions for coupling an amine and a carboxylic acid
(when X is OH) , or an amine and an appropriate carboxylic acid
(when x is not OH), to provide the compound of formula 3.
[0094] Another embodiment provides a process for preparing
a compound of formula 16:

wherein PG2 is a suitable nitrogen protecting group and R1 is
as defined in any of the embodiments herein, comprising
reacting a compound of formula 15:


under suitable cyclization conditions, to provide the compound
of formula 16.
[0095] Another embodiment provides a process for preparing
a compound of formula 15:

comprising reacting a. compound of formula 14:

in the presor.ce of Rx-OK (or a suitable acetal forming
reagent), protic or Lewis acid (for example, TsOH), and a
suitable solvent to provide the compound of formula 15.
[0096] Another embodiment provides a process for preparing
a compound of formula 14:

comprising reacting a compound of f onr.ula 13:


under suitable oxidation conditions (example, a Swern
oxidation) to provide the compound of formula 14.
[0097] Another embodiment provides a process for preparing
a compound of formula 13:

comprising reacting- a compound of formula 2 with a compound
of formula 21:
under conditions for coupling an amine and a carboxylic acid
(when X is OH) , or an amine and an appropriate carboxylic acid
(when X is not OH), to provide the compound of formula 13.
[0098] Another embodiment provides a process for preparing
a compound of formula 22 :

comprising reacting a compound of formula 23:


in the presence of K^-OH (or a suitable acetal forming
reagent), protic or Lewis acid (for example, TsOH), and a
suitable solvent to provide the compound of formula 22.
Acetal forming equivalents Include, but are not limited to,
triethylorthoformate, a diethylacetal, such as a
(CH3)2C(OCH2CH3)2. Preferably, the solvent is CH2C12, toluene,
or chlorobenzene.
[0099] Another embodiment provides a process for preparing
a compound of formula 23 comprising reacting a compound of
formula 2:
under suitable oxidation conditions (example Swern) to provide
the compound of formula 23.
[0100] Another embodiment provides a process for preparing
a compound of formula 5-A

wherein PGi is a suitable carboxylic acid protecting group, PG2
is a suitable nitrogen-protecting group, and R1 is as defined
in any one of claims 1 or 5-9, comprising:

reacting a compound of formula 20-A:

under conditions for coupling an amine and a carboxylic acid
(when x is OH), or an amine and an appropriate carboxylic acid
(when X is an appropriate leaving- group), to provide the
compound of formula 5-A.
' [0101] Another embodiment provides a process for preparing
a compound of formula 5:

comprising reacting a compound of formula 20:

with a compound of formula 22


under conditions for coupling an amine and a carboxylic acid
(when X is OH) , or an amine and an appropriate carboxylic acid
(when X is not OH), to provide the compound of formula 5.
[0102] Another embodiment provides a process for preparing
a compound of formula 5-A:

comprising reacting a compound of formula 21:

with a compound of formula 22

under conditions for coupling an amine and a carboxylic acid
(when X is OH) , or an amine and an appropriate carboxylic acid
(when X is not OH) , to provide the compound of formula 5-A.

[0*103] In accordance with, this invention, the processes may-
be used alone or in combination to provide a compound of this
invention.
[0104] Certain specific embodiments of this invention
provide processes for preparing compounds 4 from 3 (in
embodiments where compounds 4 are isolated); 5 from 3 (in
embodiments where compounds 4 is not isolated but carried on
directly, e.g., generated in situ); 5 from 4; and 6 from 5
according to the methods disclosed herein. In a preferred
embodiment, compounds 6 are prepared from, compounds 5;
compounds 5 are prepared from compounds 4 (whether isolated or
not); and compounds 4 are prepared from 3 . Preferably,
compounds 6 are used in the preparation of proline containing
caspase inhibitors. Such proline containing caspase
inhibitors include, but are not limited to, those disclosed in
WO 95/35308, WO 99/47545, WO.01/81330, and WO 01/90063 (which
are all incorporated herein by reference) . For example,
compound IA (and stereoisomers thereof) of WO 01/90063 (which
are specifically incorporated herein by reference) could be
prepared as disclosed herein (see, e.g., page 13). For the
avoidance of doubt, it should be understood that such proline
containing compounds could be depicted by formula I except
that Ring A is pyrrolidine (i.e. is derived from
proline) ..
[0105] The processes for converting compounds 6 to proline
containing caspase inhibitors are preferably as disclosed
herein. The processes for preparing compounds 3 are also
preferably as disclosed herein. However other processes known
to skilled practitioners could be used to convert compounds 6
to proline containing caspase inhibitors and/or to prepare
compounds 3.

[0106] other embodiments of this invention provide the
compounds of formula 3 to 6, 3-A to 6-A, and 13-16.
[0107] One embodiment of this invention provides the
compounds of formula 4A:

[0108] Another embodiment of this invention provides the
compounds of formula 4:

[0109] Another embodiment of this invention provides the
compounds of formula 14:

[0110] One embodiment of this invention provides the
compounds of formula 5-A:

[0111] Another embodiment of this invention provides the
compounds of formula 5:


[0112] Another embodiment of this invention provides the
compounds of formula 15:

[0113] One embodiment of this invention provic3.es the
compounds of formula 3-A:

[0114] Another embodiment of this invention provides the
compounds of formula 3:

[0115] Another embodiment of this invention provides the
compounds of formula 13:


[0116] In all the above embodiments, the variables are as
defined in any of the embodiments herein. In a preferred form
of 3, PG2 is Z and PGi is Ci-s straight-chained or branched
alkyl group (preferably a t-butyl group), either alone or in
combination.
[0117] As would be realized by skilled practitioners
certain process steps may be accomplished in discrete steps or
in situ. For example, deprotection and subsequent reaction of
an amine may be accomplished by step-wise (by isolating the
amine) or in a one step procedure (without isolating trie
amine).
[0118] In certain embodiments, the above processes are
conducted as described herein (e.g., in the schemes, examples,
and accompanying description) .
[0119] Compounds such as 3 could be used in processes for
preparing proline containing compounds, such as caspase
inhibitors. Proline containing caspase inhibitors include,
but are not limited to, those disclosed in WO 95/35308, WO
99/47545, WO 01/81330, and WO 01/90063 (which are all
incorporated herein by reference) . For example, compound IA
(and stereoisomers thereof) of WO 01/90063 (which are
specifically incorporated herein by reference) could be
prepared as disclosed herein (see, e.g., page 13).
[0120] The compounds utilized in the compositions and
methods 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


Reagent and conditions: (a) EDC, HOBt, DMAP, DIPEA, THF; (b)
Swern; (c) I^OH, 3A sieves, DCM, TsOH; (d) TFA, DCM; (e) H2,
Pd(OH)2, StOAC, DMF, Et3KT; (f) EDC, HOBt, Et3N, EtOAc, DMF; (g)
H2, Pd/C, Citrate Acid.
[0077] Scheme V depicts a possible route to prepare
compounds 17 and compounds 11 described in scheme III.
Compound 2, readily obtained from reduction of the (X-
carboxylic group of aspartic acid, is coupled to N-protected
2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid 10 (prepared as
in Tetrahedron: Asymmetry, 13, 2002, 25-28) to form 13.
Compound 13 is then oxidized into the aldehyde 14 which is
acetalized in situ to give the acetals 15. Deprotection of
the fcerfc-butyl ester is accompanied by spontaneous ring
cyclization to give a mixture of diastereoisomers which were
separated by column chromatography to give the
enantiomerically pure syix ketals 16 and anti ketals (not
represented in this scheme) . Alternative Ring A groups are

solubility to allow administration by injection, alter
metabolism and alter rate of excretion.
[0121] 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 C6-ioaryl, CF3, CI, F, OMe, OEt,
OCF3, CN, or NMe2;
a Ci_6 cycloalkyl, wherein 1-2 carbon atoms in trie
cycloalkyl is optionally replaced with -0- or -NR9-.
[0122] Compounds of this invention having a carbonyl group
may be similarly derivatized as, e.g., an acetal, ketal, oxime
(=N0R9), hydrazine (=NN(R9)2), thioacetal, or thioketal.
[0123] Appropriate derivatives of amines are known in the
art and are also included within the scope of this invention.
[0124] Certain of the above derivatives would include the
protective groups known to skilled practitioners (see, e.g.,
Greene). As would be recognized by a skilled practitioner,
these protective groups may also be employed in the processes
of this invention.
[0125] The compounds of this invention may be assayed for
their ability to inhibit apoptosis, the release of IL-1|3 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.
[0126] Assays for caspase activity are described in W0
99/47545.
[0127] According to another embodiment, the present
invention provides a pharmaceutical composition comprising:

a) a compound of the invention, as defined herein,
or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable carrier, adjuvant
or vehicle.
[0128] It should be understood that compounds and
pharmaceutically acceptable salts thereof are included within
this invention are. If pharmaceutically acceptable salts of
the compounds of this invention arre utilized in these
compositions, those salts are prefferably 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, persu.lfate, 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.
[0129] Also, the basic nitrogen-containing groups can be
guaternized 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, brromides and iodides, aralkyl

halides, such as benzyl and phenethyl bromides and others.
Water or oil-soluble or dispersible products are thereby
obtained.
[0130] 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-block polymers, polyethylene
glycol and wool fat.
[0131] According to a preferred embodiment, the
compositions of this invention are formulated for
pharmaceutical administration to a mammal, preferably a human
being.
[0132] 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.
[0133] 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 wettin.g agents and
suspending agents. The sterile injectable preparation may
also be a sterile injectable solution or su.spension in a
non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Ajnong 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, an.y 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 injectable^, 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 carboxymethy-1 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 othar emulsifying
agents or bioavailability enhancers which a.re commonly used in
the manufacture of pharmaceutically acceptable solid, liquid,
or other dosage forms may also be used for the purposes of
formulation.
[0134] The pharmaceutical compositions of this invention
may be orally administered in any orally acceptable dosage
form including, but not limited to, capsule.s, tablets, aqueous
suspensions or solutions. In the case of tablets for oral
use, carriers which are commonly used inclu.de 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 ffor oral use, the active
ingredient is combined with emulsifying- and suspending agents.
If desired, certain sweetening, flavoring or coloring agents
may also be added.
[0135] 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 inclu.de cocoa butter,
beeswax and polyethylene glycols.
[0136] The pharmaceutical compositions of this invention
may also be administered topically, especially when the target
of treatment includes areas or organs rreadily accessible by
topical application, including diseases of the eye, the skin,
or the lower intestinal tract. SuitaKLe topical formulations
are readily prepared for each of these areas or organs.
[0137] Topical application for the Lower intestinal tract
can be effected in a rectal suppositoiy formulation (see
above) or in a suitable enema formulati_on.
Topically-transdermal patches may also be used.
[0138] For topical applications, the pharmaceutical
compositions may be formulated in a sui-table ointment
containing the active component suspended or dissolved in one
or more carriers. Carriers for topical, administration of the
compounds of this invention include, bu.t 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.
[0139] 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. In one embodiment, the compositions are as
formulated in, e.g., U.S. Patent 6,645,994 aiid/or U.S. Patent
6,630,473.
[0140] 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.
[0141] The above-described compounds and compositions are
particularly useful in therapeutic applications relating to an
IIJ-1 mediated disease, an apoptosis mediated disease, an
inflammatory disease, an autoimmune disease, a destructive
bone disorder, a proliferative disorder, an infectious disease
(e.g., bacterial infections, preferably, eye infections), a
degenerative disease, a disease associated with cell death, an
excess dietary alcohol intake disease, a viral mediated
disease, retinal disorders, uveitis, inflammatory peritonitis.

osteoarthritis, pancreatitis, asthma, adult respiratory-
distress syndrome, glomerulonephritis, rheumatoid arthritis,
systemic lupus erythematosus, scleroderma, chronic
thyroiditis, Grave's disease, autoimmune gastritis, diabetes,
autoimmune hemolytic anemia, autoimmune neutropenia,
thrombocytopenia, chronic active hepatitis, myasthenia
gravis, inflammatory bowel disease, Crohn's disease,
psoriasis, atopic dermatitis, scarring, graft vs. host
disease, organ transplant rejection, organ apoptosis after
burn injury, osteoporosis, leukemias and related disorders,
myelodysplastic syndrome, multiple myeloma-related bone
disorder, acute myelogenous leukemia, chronic myelogenous
leukemia, metastatic melanoma, Kaposi's sarcoma, multiple
myeloma, hemorrhagic shock, sepsis, septic shock, burns,
Shigellosis, Alzheimer's disease, Parkinson's disease,
Huntington's disease, Kennedy's disease, prion disease,
cerebral ischemia, epilepsy, myocardial ischemia, acute and
chronic heart disease, myocardial infarction, congestive heairt
failure, atherosclerosis, coronary artery bypass graft, spina.1
muscular atrophy, amyotrophic lateral sclerosis, multiple
sclerosis, HIV-related encephalitis, aging, alopecia,
neurological damage due to stroke, ulcerative colitis,
traumatic brain injury, spinal cord injury, hepatitis-B,
hepatitis-C, hepatitis-G, yellow fever, dengue fever, Japanese
encephalitis, various forms of liver disease, renal disease,
polycystic kidney disease, H. pylori-associated gastric and
duodenal ulcer disease, HIV infection, tuberculosis,
meningitis, toxic epidermal necrolysis, pemphigus, and
autoinflammatory diseases (sometimes referred to as
autoinflammatory fever syndromes) and related syndromes such
as Muckle-faells Syndrome (MWS), Familial cold urticaria (FCU> ,
Familial Mediterranean Fever (FMF), Chronic Infantile

Neurological Cutaneous and Articular Syndrome (CINCAS), a.k.a.
Neonatal Onset Multisystem Inflammatory Disease (NOMID),
TNPRl-Associated Periodic Syndrome (TRAPS), and Hyper-IgD
periodic fever Syndrome (HIDS). The compounds and
compositions are also useful in treating complications
associated with coronary artery bypass grafts. The compounds
and compositions are also useful for decreasing IGIF (also
known as IL-18) or IFN-y production. The compounds and
compositions are also useful in immunotherapy as a cancer
treatment.
[0142] The compounds and compositions may also be used in
methods for preserving cells. These methods would be useful
for preserving organs, particularly those intended for
transplant, or blood products.
[0143] The compounds of this invention are useful as dual
caspase-1 and capase-8 inhibitors. Without being bound by
theory, the R2 and R3 groups of the compounds of this invention
appear to be related to this surprising activity. Bridged A
groups of the compounds of this invention, such as
also appear to be related to this surprising
activity. As such, the compounds and compositions of this
invention are particularly useful in treating or preventing
inflammatory conditions.
[0144] According to another embodiment, the compositions of
this invention may further comprise another therapeutic agent
(i.e., one or more additional agents). Such agents include,
but are not limited to, thrombolytic agents such as tissue
plasminogen activator and streptokinase. When an additional
agent is used, the additional 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.
[0145] The amount of compound present in the compositions
of this invention should be sufficient to cause a detectable
decrease in the severity of the disease or in caspase activity
and/or cell apoptosis, as measured by any of the assays known
in the art.
[0146] Dosage levels of between about 0.01 and about 50 or
about 100 mg/kg body weight per day, preferably between 0.5
and about 75 mg/kg body weight per day and most preferably
between about 1 and about 25 or about 50 mg/kg body weight per
day of the active ingredient compound are useful in a
monotherapy.
[0147] Typically, a compound or composition 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.
[0148] When the compositions of this invention comprise a
combination of a compound of this invention 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 about 100%, and more preferably
between about 10% to about 80% of the dosage normally
administered in a monotherapy regime.

[0149] Upon improvement of a patient's condition, a
maintenance dose of a compound, composition or combination of
this invention may be administered, if necessary.
Subsequently, the dosage or frequency of administration, or
both, may be reduced, as a function of the symptoms, to a
level at which the improved condition is retained when the
symptoms have been alleviated to the desired level, treatment
should cease. Patients may, however, require intermittent
treatment on a long-term basis upon any recurrence of disease
symptoms.
[0150] As the skilled practitioner will appreciate, lower
or higher doses than those recited above may be required. It
should be understood that a specific dosage and treatment
regimens 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,
the severity and course of the particular disease, the
patient's disposition to the disease being treated, and the
judgment of the treating physician. The amount of active
ingredients will also depend upon the particular compound and
other therapeutic agent, if present, in the composition.
[0151] In a preferred embodiment, the invention provides a
method of treating a patient, preferably a mammal, having one
of the aforementioned diseases, comprising the step of
administering to said patient a compound or 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.
[0152] The compounds of this invention may also be
incorporated into compositions for coating implantable medical
devices, such as prostheses, artificial valves, vascular
grafts, stents and catheters. Accordingly, the present
invention, in another aspect, includes a composition for
coating an implantable device comprising a compound of the
present invention and a carrier suitable for coating said,
implantable device. In still another aspect, the present
invention includes an implantable device coated with a
composition comprising a compound of the present invention and
a carrier suitable for coating said implantable device.
[0153] Another aspect of the invention relates to
inhibiting caspase activity in a biological sample, which >
method comprises contacting said biological sample with a
compound of this invention or a composition comprising said
compound. The term "biological sample", as used herein,
includes, without limitation, cell cultures or extracts
thereof; biopsied material obtained from a mammal or extracts
thereof; and blood, saliva, urine, feces, semen, tears, or
other body fluids or extracts thereof.
[0154] Inhibition of caspase activity in a biological
sample is useful for a variety of purposes that are known to
one of skill in the art. Examples of such purposes include,
but are not limited to, blood transfusion, organ-
transplantation, biological specimen storage, and biological
assays.
[0155] The compounds of this invention are useful in
methods for preserving cells, such as may be needed for an
organ transplant or for preserving blood products. Similar

uses for caspase inhibitors have been reported [Schierle et
al., Nature Medicine, 5, 97 (1999)]. The method involves
treating the cells or tissue to be preserved with a solution
comprising the caspase inhibitor. The amount of caspase
inhibitor needed will depend on the effectiveness of the
inhibitor for the given cell type and the length of time
required to preserve the cells from apoptotic cell death.
[01563 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.
[0157] 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.
Example i-l
(S,S, S,R)-1-[(25)-(3-Methoxy-2-methyl-benzoylamino)-3-methyl-
butyryl] -pyrrolidine- (25) -carboxylic acid [ (2J?) -ethoxy-5-oxo-
tetrahydro-furan-(35) -yl]-amide


Method A
(S)-3-Andno-4-hydroxy-butyric acid tart-butyl ester

[0158] A solution of (S)-benzyloxycarbonylamino-4-hydroxy-
butyric acid fcert-butyl ester (prepared as described in Michel
etal, Helvetica Chimica Acta 1999, 1960)(0.94g) in ethyl
acetate (15 ml) was hydrogenated over palladium
hydroxide/carbon (20% w/w, 160mg). The catalyst was removed
via filtration through celite. Concentration of the filtrate
in vacuo afforded the subtitle compound as a colorless oil
(486mg, 91%); aH NMR (400MHz,CDCl3) 8 1.48 (9H, s) , 1.95 (3H,
brs), 2.28 (1H, dd), 2.46 (1H, dd), 3.29 (1H, brm), 3.42 (1H,
m), 3.60 (1H, m).
Method B
(IS)-2-((S)-2-fcejrt-Butoxycarbonyl-l-hydroxymethyl-
ethylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester

[0159] To a stirred solution of (S)-3-Amino-4-hydroxy-
butyric acid tert-butyl ester (800mg, 4.57mmol) and Z-Pro-OH
(1.14g, 4.57mmol) in THF (30ml) was added 2-
hydroxybenzotriazole hydrate (741mg, 1.2eq,), DMAP (698mg,
1.25eq.), diisopropylethylamine (1.03ml, 1.3eq.) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC,
1.05g, 1.2eq.). The resulting mixture was stirred at ambient
temperature for 18 hours then diluted with ethyl acetate. The
mixture was then washed with water, saturated aqueous sodium
bicarbonate solution and brine, dried over magnesium sulfate,

filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography (60% ethyl
acetate/petrol) to afford the sub-title compound as a
colorless solid (1.483g, 90%); MS ES (+) 407.3.
Method C
(IS) -2- ( (S) -2-tert-Butoxycarbonyl-l-formyl-ethylcarbamoyl) -
pyrrolidine-1-carboxylic acid benzyl ester

[0160] A solution of (IS)-2-((S)-2-terfc-Butoxycarbonyl-l-
hydroxymethyl-ethylcarbamoyl) -pyrrolidine-1-carboxylic acid
benzyl ester (10 g) in DCM (100 ml) was cooled to 0°C under
nitrogen. 2,2,6,6-tetramethylpiperidinyloxy (TEMPO, 38 mg)
was then added followed by trichloroisocyanuric acid (6 g),
portionwise over 30 minutes. The mixture was stirred at
ambient temperature for 2 hours, then filtered through celite.
The filtrate was washed with water, 1M sodium thiosulfate
solution and water. Drying over magnesium sulfate and
concentration under reduced pressure gave the sub-title
compound as a pale yellow oil (9.92 g, 99%); XH NMR (400MHz,d-6
DMSO) 8 1.38 (9H, d), 1.79-1,86 (3H, m), 2.08-2.23 (1H, m),
2.36-2.51 (1H, 2 x dd), 2.61-2.86 (1H, 2 x dd), 3.88-3.46 (2H,
m), 4.24-4.30 (2H, m), 5.05 (2H, quin), 7.28-7.37 (5H. m) ,
8.59-8.64 (1H, 2 x d) , 9.21 (0.57H, s), 9.37 (0.43H, s).

Method D
(IS)-2-((S) -1- terfc-Butoxycarbonylmethyl-2,2-diethoxy-
ethylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester

[0161] To a solution of (lS)-2-((S)-2-fcert-Butoxycarbonyl-
l-formyl-ethylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl
ester (4.98 g) in dichloromethane (70 ml) was added triethyl
orthoformate (6.2 mL) and p-toluenesulfonic acid monohydrate
(47 mg). The resulting mixture was stirred at ambient
temperature until no aldehyde remained by TLC. The mixture was
concentrated in vacuo, the re-dissolved in dichloromethane (35
mL) . Saturated aqueous sodium bicarbonate solution (35 mL)
was then added and the organic phase removed. This was washed
with water and brine, dried (magnesium sulfate), filtered and
concentrated under reduced pressure. This gave the sub-title
compound as a pale yellow oil (4.85 g, 82%); XH NMR (400MHz,d-6
DMSO) 5 1.04-1.11 (6H, m), 1.35-1.37 m), 2.01-2.49 (3H, m) , 3.43-3.52 (6H, m), 4.05-4.29 (3H, m) ,
4.96-5.06 (2H, m) , 7.27-7.38 (5H, m), 7.80 (0.5H, d), 7.88
(0.5H, d).
Method E
(lS)-2-( (2R, 3S)-2-Ethoxy-5-oxo-tetrahydro-furan-3-
ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester 6.1
(IS)-2-((2S, 3S)~2-Ethoxy-5-oxo-tetrahydro-furan-3-
ylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester 6.2


[0162] A solution of (IS)-2-((S)-1-fcert-
Butoxycarbonylmethyl-2,2 -diethoxy-ethyl carbamoyl) -pyrrolidine-
1-carboxylic acid benzyl ester (4.85 g) in dichloromethane (25
ml) was cooled to 0°C under nitrogen. Trifluoroacetic acid (6
ml) was then added and the mixture stirred at 0°C for 15
minutes, then warmed to ambient temperature and stirred until
the reaction was complete by TLC. The mixture was then diluted
with dichloromethane (90 ml) and saturated aqueous sodium
bicarbonate solution (13 0 ml) and stirred for 15 minutes. The
organic phase was then removed and washed with 1:1 saturated
aqueous sodium bicarbonate/brine (100 ml), the combined
aqueous washings was re-extracted with DCM (100 ml) and the
combined organic layers dried (magnesium sulfate), filtered
and concentrated under reduced pressure. This afforded the
sub-title compound as a mixture of epimers at the ketal centre
(C2) . The epimers were separated on silica gel, eluting with
30% acetone/petrol. ,Syn-isomer 6.1 (white solid); 1H NMR
(400MHz,d-6 DMSO) 5 1.08-1.17 (3H, m), 1.78-2.01 2.08-2.12 (1H, m) , 2.37-2.57 (1H, 2 x dd), 2.61-2.79 (1H, 2 x
dd) , 3.35-3.51 (2H, m) , 3.55-3.68 (1H, m), 3.71-3.82 (1H, d) ,
4.20-4.32 (1H, iu) , 4.52-4.61 (1H, m) , 4.98-5.11 (2H, m) , 5.53-
5.58 (1H, m), 7.24-7.42 377.3 (100%), ES - 375.3 (10%); Anti-isomer 6.2 (colorless
oil); XH NMR (400MHz,d-6 DMSO) 5 1.08-1.19 (3H, m) , 1.78-1.89
(3H, m) , 2.10-2.34 (1H, m) , 2.92-3.07 (1H, 2 x dd), 3.36-3.51
(3H, m), 3.62-3.78 (2H, m) , 4.12-4.21 m), 7.28-7.40 (5H, m) , 8.51-8.58 (lH, m); MS ES + 377.4
(100%), ES - 375.3 (10%).
(IS) -2- ((2R, 3S) -2-Methoxy-5-oxo-tetrahydro-furan-3-
ylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester 6.3

(lS)-2-((2Sf3S)-2-Methoxy-5-oxo-tetrahydro-furan-3-
ylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester 6.4

[0163] Prepared in a similar manner to that described in
methods A-E, using trimethylorthoformate in step D, to afford
the sub-title compounds as a mixture of epimers 6.3 and 6.4.
The epimers were separated on silica gel eluting with 30% to
40% 2-Butanone/Petrol to 70% Acetone/Petrol. Syn-isomer 6.3
(viscous colorless oil); hi NMR (400MHz,d-6 DMSO) 5 1.77-1.89
(3H, m), 2.07-2.12 (1H, m) , 2.32-2.43 (1H, 2 x d) , 2.55-2.61
(1H, 2 x d), 2.71-2.81 (1H, 2 x d) , 3.39-3.62 (4H, m), 4.21-
4.30 (lH, m), 4.57-4.64 (1H, m) , 5.01-5.09- (2H, m) , 5.42-5.47
(1H, m) , 7.27-7.42 (5H, m) , 8.24-8.31 (1H, m); Anfci-isomer 6.4
(white solid); XH NMR (400MHz;d-6 DMSO) 8 1.79-1.90 2.09-2.21 (1H, m) , 2.23-41 (1H, 2 x d) , 2.91-3.05 (1H, 2 x
dd), 3.35-3.71 (5H, m) , 4.09-4.21 (2H, m), 4.98-5.19 (3H, m) ,
7.28-7.41 (5H, m), 8.51-8.58 (1H, m).
(IS) -2- ((2R,3S)-2-Isopropoxy-5-oxo-tetrahydro-£uran-3-
ylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester 6.5
(IS) -2- ((2S, 3S)-2-Isopropoxy-5-oxo-tetrahydro-furan-3-
ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester 6.6


[0164] • prepared in a similar manner to that described in
Methods A-E, using triisopropylorthoformate in step D, to
afford the sub-title compound as a mixture of epimers 6.5 and
6.6. The epimers were separated on silica gel eluting with 3 0%
to 40% 2-Butanone/Petrol. Syn-isomer 6.5 (colorless gum); 1H
NMR (400MHz,d-6 DMSO) 8 1.07-1.16 (6H, m) , 1.81-1.86 (2H, m) ,
2.37-2.71 (2H, m) , 3.35-3.53 (2H, m), 3.86-3.90 (1H, m), 4.18-
4.24 (1H, m) , 4.46-4.55 (1H, m) , 4.95-5.10 (2H, m), 5.63 {1H,
d), 7.27-7.38 (5H, m) , 8.22-8.30 (lH, m); MS ES + 391.3
(100%); Anti-isomer 6.6 (white solid); ^ NMR (400MHz,d-6 DMSO)
5 1.07-1.15 (6H, m), 1.78-1.82 (3H, m), 2.07-2.41 (2H, m) ,
2.87-3.01 (1H, m) , 3.35-3.50 (2H, m) , 3.74-3.96 (lH, m), 4.07-
4.18 (2H, m), 4.95-5.11 (2H, m) , 5.22 (1H, 2 xs), 7.24-7.39
(5H, m), 8.48-8.53 (1H, m) ; MS ES + 391.4 (100%).
(IS)-2-((2R, 3S)-2-Propoxy-5-oxo-tetrahydro~furan-3-
ylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester 6.7
(IS)-2-((2S,3S)-2-Propoxy-5-oxo-tetrahydro-furan-3-
ylcarbamoyl)-pyrrolidine-l-carboxylic acid benzyl ester 6.8

[0165] Prepared in a similar manner to that described in
methods A-E, using tripropylorthoformate in step D, to afford
the sub-title compounds as a mixture of epimers 6.7 and 6.8.
The epimers were separated on silica gel eluting with 3 0% to
40% 2-Butanone/Petrol. Syn-isomer 6.7 (colorless gum); ^"H NMR
(400MHz,d-6 DMSO) 8 0.84-0.93 (3H, m) , 1.55 (2H, m), 1.81-1.89
(3H, m) , 2.08-2.22 (1H, m) , 2.37-2.61 (1H, 2 x dd) , 2.71-2.80
(1H, 2 x dd), 3.31-3.53 (2H, m), 3.60-3.69 (1H, m), 4.52-4.61 (1H, m) , 4.95-5.11 (2H, m), 5.50 (lH, m),

7.27-7.36 (5H, m), 8.27 (lH, m); Anti-isomer 6.8 (colorless
oil); ^NMR (400MHz,d-6 DMSO) 5 0.82-0.90 (3H, m), 1.46-1.57
(2H, m), 1.77-1.89 (3H, m), 2.06-2.41 (1H, m) , 2.90-3.05 (1H,
2 x dd), 3.33-3.66 m) , 7.28-7.37 (5H, m) , 8.5K1H, m) .
(lS)-2-( (2R,3S)-2-Butoxy-5-oxo-tetrahydro-fiiran-3~
ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester 6.9
(lS)-2-( (2S,3S)-2-Butoxy-5-oxo-tetrahydro-furan-3-
ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester 6.10

[0166] Prepared in a similar manner to that described in
methods A-E, using tributylorthoformate in step D, to afford
the sub-title compounds as a mixture of epimers 6.9 and 6.10.
The epimers were separated on silica gel eluting with 30% to
40% 2-Butanone/Petrol. Syn-isomer 6.9 (colorless gum); 1H NMR
(400MHz,d-6 DMSO) § 0.86-0.92 (3H, m) , 1.28-1.37 (2H, m) ,
1.45-1.54 (2H, m) , 1.79-1.88 (3Hr m), 2.07-2.21 (1H, m), 2.35-
2.78 (2H, m), 3.31-3.54 (2H, m), 3.63-3.70 (1H, m), 4.21-4.29
(1H, m), 4.51-4.61 (1H, m), 4.95-5.09 (2H, m) , 5.50 (lH,.m),
7.27-7.37 (5H, m), 8.25 (1H, m); Anti-isomer 6.10 (colorless
oil); XH NMR (400MHz,d-6 DMSO) 5 0.85-0.93 (3H, m), 1.26-1.36
(2H, m) , 1.44-1.56 (2H, m), 1.77-1.90 (3H, m) , 2.08-2.40 (1H,
m), 2.89-3.05 (1H, 2 x dd) , 3.34-3.70 (5H, m), 4.08-4.19 (2H,
m), 4.95-5.10 (3H, m) , 7.28-7.39 (5H, m) , 8.53(lH, m).

Method F
{(S)-1-[(1R, 3S,4S)-3-((2R, 3S)-2-Ethoxy-5-oxo-tetrahydro-furan-
3ylcarbamoyl)-2-pyrrolidine-2-carbonyl]-2,2-dimethyl-propyl}-
carbamic acid benzyl ester

[0167] To a solution of (lS)-2-((2R, 3S)-2-Ethoxy-5-oxo-
tetrahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid
benzyl ester 6.1 (4.68g) in ethyl acetate (160ml) and DMF
(25ml) was added triethylamine (2.5g) followed by palladium
hydroxide/carbon (20% w/w, lg) . The mixture was stirred under
an atmosphere of hydrogen until no starting material was
present by TLC. The catalyst was removed by filtration through
celite. To the filtrate was added (S)-2-
benzyloxycarbonylamino-3,3-dimethyl-butyric acid (4.93g),
hydroxybenzotriazole hydrate (2.01g) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC,
2.85g). The resulting mixture was stirred at ambient
temperature overnight. Saturated aqueous sodium bicarbonate
solution (180ml) was then added and the organic phase removed.
This was washed with saturated aqueous ammonium chloride (180
ml), then brine (180ml), dried (magnesium sulfate), filtered
and concentrated under reduced pressure. The crude product was
purified on silica gel, eluting with 40-75% ethyl
acetate/petrol. The sub-title compound was obtained as a white
foam (4.02g, 66%); ^ MR (400MHz, CDCl3) 8 0.97 (9H, s) , 1.14
(3H, t), 1.79-1.94 (3H, m) , 2.02-2.10 (1H, m), 2.44 (1H, dd) ,
2.75 (1H, dd), 3.52-3.66 (2H, m), 3.70-3.79 (2H, m), 4.22 (1H,
d), 4.38-4.41 (1H, m) , 4.48-4.58 (lH, m), 5.03 (2H, q), 5.56

(1H, d.) , 7.26 (1H, d), 7.29-7.40 (5H, m] , 8.24 (1H, d) ; MS ES
+- 490.6 (100%), ES - 488.8 (10%).
Method G
[S, S, S,R) -1- [ (2S) - (3-Methoxy-2-methyl-benzoylairri.no) -3-ntethyl-
bufcyryl] -pyrrolidine- (23) -carboxylic acid [ (2R) -ethoxy-5-oxo-
tetrahydro-furan- (3S) -yl] -amide

[0168] To a solution of {(S)-1-[(1R,3S,4S)-3-((2R,3S)-2-
Eth.oxy-5-oxo-tetrahydro-furan-3ylcarbamoyl)-2-pyrrolidine-2-
carbonyl] -2,2-dimethyl-propyl}-carbamic acid benzyl ester
(344nig) in ethyl acetate (20ml)was added palladium
hydroxide/carbon (20% w/w, 74mg) . The mixture was stirred
under an atmosphere of hydrogen until no starting material was
present by TLC. The catalyst was removed by filtration through
celite and the filtrate concentrated under reduced pressure to
give the amine as a brown foam (260mg) . A portion of this
material (153mg) was dissolved in THF and 3-methoxy-2-methyl
benzoic acid (146mg>, diisopropylamine (191jil) ,
hydroxybenzotriazole hydrate (77mg) and l-(3- ,
dimethylaminopropyl)-3-ethylcarbodiiird.de hydrochloride (EDC,
109mg) were added. The resulting mixture was stirred at
ambient temperature for 24 hours then diluted with saturated
aqueous sodium bicarbonate. The organic phase was removed and
washed with saturated aqueous ammonium chloride, then brine,
dried (magnesium sulfate) , filtered and concentrated under
reduced pressure. The crude product was purified on silica
gel, eluting with ethyl acetate. This gave the sub-title
compound as a white solid (138mg, 62%) ; analytical data
summarized in Table 3.

[0169] Compounds of .formula 1-2 to 1-58 have been prepared
by methods substantially similar to those described in Example
i-l.
Example 1-2
(S,S, S,R) -1- [ (25) - pyrrolidine-(25)-carboxylic acid [ (2R) -ethoxy-5-oxo-
tetrahydro-furan- (35) -yl] -amide

(S,S, S,R) -1- [3-Methyl- (25) - (2-trif luoromethoxy-benzoylamino) -
butyryl] -pyrrolidine- (25) -carboxylic acid [ (2i?) -ethoxy-5-oxo-
tetrahydro-furan- (35) -yl] -amide

{S,S, S,R) -1- [ (25)- (3-Hydroxy-2-methyl-benzoylamino)-3-methyl-
butyryl]-pyrrolidine-(25)-carboxylic acid [ (2R) -ethoxy-5-oxo-
tetrahydro-furan- (3S) -yl] -amide


Example 1-5
[S, S, S,R) -1-1 (2S) - (3-Amino-2-methyl-benzoylamino) -3-methyl-
butyryl] -pyrrolidine- (2S)-carboxylic acid [ (2R) -ethoxy-5-oxo-
tetrahydro-£uran- (35) -yl] -amide

(S,S,S,R)-1— [ (23)-(2, 6-Dichloro-benzoylamino)-3-methyl-
butyryl] -pyrrolidine- (23) -carboxylic acid [ (2i?)-ethoxy-5-oxo-
tetrahydro-f uran- (3S) -yl] -amide

(8, S, S,R) -N- { (15) - [ (23) - ((2R) -Ethoxy-5-oxo-tetrahydro-furan-
(3S0-ylcarbamoyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl}-2-
methyl-nicotinamide
(S, S,SrR)~N- { (IS) - [ (2S)-( (2R) -Ethoxy-5-oxo-tetrahydro-furan-
[33) -ylcarbamoyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl}-4-
methyl -nicotinamide

Example 1-9
(S, S, S,R) -l-{3-Methyl- (25) - [ (3-methyl-thiophene-2-carbonyl) -
amino] -butyryl}-pyrrolidine- (2S) -carboxylic acid [ (2.R)-ethoxy-
5-oxo-tetrahydro-furan- (3£) -yl] -amide

(S,S, S,R) -2 , 3-Dicliloro-W-{ (IS) - [ (2S) -( (2R) -ethoxy-5-oxo-
tetrahydro-furan- (35) -ylcarbamoyl) -pyrrolidine-1-carbonyl] -2-
methyl -propyl }-isonicotinamide

(S, S, S,R) -3 , 5-Dicb.loro-.AM (IS) - [ (25) - ( (2H) -ethoxy-5-oxo-
tetrahydro-furan- (35) -ylcarbamoyl) -pyrrolidine-1-carbonyl]-2-
methyl-propyl }-isonicotinamide


Example 1-12
(S, S, S,R) -1- [ (2S) - (3 -Methoxy-2 -methyl-benzoylamiiio 1-3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2R)-
ethoxy-5-oxo-tetrab.ydro-furan- (3S) -yl] -amide

(S, S, S,R) -1- [ (25) - (3-Methoxy-2-methyl-benzoylamino) -3-methyl-
butyryl] -pyrrolidine- (25) -carboxylic acid [ (2J?)-methoxy-5-oxo-
fcetrahydro- f uran- (3 S) -yl ] -amide

(S, 3,S,R) -1- [ (2S) - (3-Methoxy-2-methyl-benzoylamino) -3-methyl-
butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2K)-isopropoxy-5-
oxo-tetrahydro-furan- (35) -yl] -amide

(S,S,S,R)-1-i (2S)- (3-Methoxy-2-methyl-benzoylamino)-3-methyl~
butyryl] -pyrrolidine- (2S) -carboxylic acid [5-oxo- (2.R) -propoxy-
5-tetrah.ydro-furan- (3S) -yl] -amide




Example 1-20
(S,S, S,R) -1- [3,3-Dimethyl- (2S) - (2-trifluoromethyl-
benzoylamino) -butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2R) -
isopropoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide

(S, 3, S,R) -1- [ (2S) - (2-Chloro-benzoylamino) -3,3-dimethyl-
butyryl]-pyrrolidine-(2S)-carboxylic acid [(2R)~ethoxy-5-oxo-
tetrahydro-furan- (3S) -yl] -amide

[S,S, S,R) -1- [3,3-Dimethyl- (2S) - (2-trifluoromethyl-
benzoylamino) -butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2R) -
ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide

(S,S, S,R) -l-[ (2S) - (2-Chloro-benzoylamino) -3, 3-dimethyl-
butyryl]-pyrrolidine-(2S)—carboxylic acid [5-oxo- (2R) -propoxy-
tetrahydro-furan- (3S) -yl] -amide


Example 1-24
(S,S, S,R)- 1- [ (2S) - (2-Chloro-benzoylamino) -3,3-dimethyl-
butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2R) -butoxy-5-oxo-
tetrahydro-furan-(3S)-yl]-amide

(S, S, SfR)-l-[ (2S) -(2-Chloro-3-trifluoromethoxy-benzoylamino) -
3, 3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2R) -
ethoxy-5-oxo-tetrahydro-furan- (3S ) -yl] -amide

(5, S, S,R) -1- [ (2S) - (2-Chloro-benzoylamino) -3-methyl-butyryl] -
pyrrolidine- (2S) -carboxylic acid [5-oxo-(2R)-propoxy-
tetrahydro-furan-(3S)-yl]-amide

{S,S,S,S)~l-[ (2S)- (2-Chloro-benzoylamino) -3-methyl-butyryl]-
pyrrolidine-(2S)-carboxylic acid [5-oxo- (2S) -propoxy-
tetrahydro-furan-(3S)-yl]-amide


Example 1-28
(S,S, s,3) -1-[ (2S) - (2-Chloro-benzoylaini.no) -3-methyl-butyryl] -
pyrrolidine- (2S)-carboxylic acid [ (2S)-ethoxy-5-oxo-
tetrahydro-furan-(3S)-yl]-amide

(S,S,S,R)-l-[ (2S)- (2-Chloro-benzoylamino) -3-methyl-butyryl]-
pyrrolidine-(2S)-carboxylic acid [ (2R)-butoxy-5-oxo-
tetrahydro-furan- (3S) -yl] -amide

{S,S, S, 3) -1- [ (2S) - (2-Chloro-benzoylamino) -3-methyl-butyryl] -
pyrrolidine-(2S)-carboxylic acid [ (2S) -butoxy-5-oxo-
tetrahydro-furan- (3S) -yl] -amide

(S,S, S,R) -1- [ (2S) - (2-Chloro-benzoylaiaino) -3-methyl-butyryl] -
pyrrolidine-(2S)-carboxylic acid [ (2R)-isopropoxy-5-oxo-
tetrahydro-furan- (3S) -yl] -amide


Example 1-32
(S, S, S,S) -1- [ (2S) - (2-Chloro-benzoylamino) -3-methyl-butyryl] -
pyrrolidine- (2S)-carboxylic acid [ (2S) -d.sopropoxy-5-oxo-
tetrahydro-furan-(3 S)-yl]-amide

{S, S, S,R) -1- [ (2S) - (2-Chloro-3-cyclopropyloxy-benzoylamino) -
3,3-dimet±iyl-butyryl]-pyrrolidine-(2S)-carboxylic acid [(2R)-
ethoxy-5-oxo-tetrahydro-f-uran- (3S) -yl] -amide

(S,SrS,R)-l-[ (2S) - (2-Chloro-3-methyl -benzoylamino) -3,3-
dimetliyl-butyryl]-pyrrolidine-(2S)-carboxylic acid [(2R)-
ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide

(S, S, S,R)-1- [ (2S) - (2-chloro-3-methoxy-benzoylamino) -3-methyl-
butyryl] -pyrrolidine- {2S) -carboxylic aci-d [ (2R) -ethoxy-5-oxo-
tetrahydro-furan- (3S) -yl] -amide


Example 1-36
(5,5,5,i?)-l-[(2S)-(2-Chloro-3-ethyl -benzoylamino) -3,3-
dimethy1-butyryl] -pyrrolidine- (2S)-carboxylic acid C(2R)-
ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide

(S,S,S,R)-l-\. (25)- (2-chloro-4-methoxy-benzoylamino)-3-metliyl-
butyryl] -pyrrolidine- (23) -carboxylic acid [ (2R) -ethoxy-5-oxo-
tetrahydro-ruran- (35) -yl]-amide

(5,5, S,R) -l-[ (2S) - (2-Chloro-3-cyclopropylmetriyl -
benzoylamino) -3,3 -dimethyl-butyryl] -pyrrolidine- (2S) -
carboxylic acid [ (2R) -ethoxy-5-oxo-tetrahydro-furan- (3S)-yl] -
amide

(5, S, S,R) -1- [ (2S) - (2-Chloro-3-hydroxy -benzoylamino) -3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid [ ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide


(S, S, S,R) -1- [ (2S) - (2-Chloro-4-acetamido-benzoylairiino) -3-
methyl-butyryl]-pyrrolidine-(2S)-carboxylic acid [(2R)-ethoxy-
5-oxo-tetrahydro-furan.-(3S)-yl]-amide

{S,S, S,R) -1- [ (2S) - (2-Chloro-3-acetamido -benzoylamino) -3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2R) -
ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide

(3,S,S,R)~1-[(2S)-(2-methyl -3-acetamido -benzoylamino)-3,3-
dimethyl-butyryl]-pyrrolidine-(2S)-carboxylic acid [(2R)-
ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide


Example 1-43
(StS,S,R) -1-t (2S)-(2-Chloro-4-acetamido -benzoylamino)-3 ,3 -
dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2R) -
ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide

[S,S,S,R)-l-l (2S) - (2-fluoro -4-acetamido -benzoylamino)-3, 3-
dimethyl-butyryl]-pyrrolidine-( 2S)-carboxylic acid [(2R)-
ethoxy-5-oxo-tetrahydro-furan- ( 3S) -yl] -amide

{3,S,S,R) -1- [ (2S) - (2-fluoro -4- eicetamido-benzoylamino) -3-
methyl-butyryl] -pyrrolidine- (2S } -carboxylic acid [ (2R) -etraoxy-
5-oxo-tetrahydro-furan-(3S)-yl] -amide

(S, S, S,R)-1- [ (2S)- (2-chloro -4-isopropyloxy -benzoylamino) -3-
methyl-butyryl ]-pyrrolidine-(2S )-carboxylic acid [ (2R)-etraoxy-
5-oxo-tetrahydro-furan-(3S)-yl] -amide


(S,S,S,i?)-l-[ (2S)-(2-chloro -4-hydroxy -benzoylamino) -3,3-
dimethyl-buty:ryl]-pyrrolidine- ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide

(S,S,S,R)-l-[(2S)-(2-chloro -4-methoxymethyl -benzoylamino)-
3, 3-dimethyl-butyryl] -pyrrolidine-(2S)-carboxylic acid [(2R)-
ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide

{S,S,S,R)-l-[(2S)-(2-Chloro-4-isobutyrylamido -benzoylamino)-
3 ,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2B.) -
ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide


Example 1-50
(3, S, S,R) -1- [ (2S) - (2-Chloro-4-acetamido —benzoylamino) -3-
cyclohexyl] -pyrrolidine- (2S) -carboxylic acid [(2R)-ethoxy-5-
oxo-tetrahydro-furan- (3S) -yl] -amide

(S, S, S,R) -1- [ (2S) - (2-Chloro-4-methoxycarfc>onylamino -
benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -
carboxylic acid [ (2R)-ethoxy-5-oxo-tetrahrydro-furan-(3S)-yl] -
amide

[S,3,S,R)-1- [ (2S)- (2-Chloro-3-phenoxy -benzoylamino) -3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carbojcylic acid [ eth.oxy-5-oxo-tetrahydro-furan- (3S) -yl] -ainide

(S, S, S,R) -1- [ (2S)-(2-Chloro-4-thiazolylarciino -benzoylamino)-
3 ,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid [ (2R) -
ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide


{S,S,S,R)-1-[(2S)-(3-Amino-2-chloro-benzoylamino)-3-methyl-
butyryl]-pyrrolidine- (2S)-carboxylic acid [ (2R) -ethoxy-5-oxo-
tetrahydro-furan-(3 S)-yl]-amide

(5,S, S,R)- 1-[(2S)-(2-Chloro-benzoylamino)-3rthiazol-4-yl-
propionyl]-pyrrolidine-(2S)-carboxylic acid [(2R)-ethoxy-5-
oxo-tetrahydro-furan-(3S)-yl]-amide :

(S,3, S,R)- 1-[(2S)-{3-Methoxy-2-methyl-benzoylamino)-3-
th.iazol-4-yl-propionyl]-pyrrolidine-(2S)-carboxylic acid
[(2R)-ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide


Example 1-57
{S,S,S,R)- l-[(2S)-(2-Chloro-3-methoxy-benzoylamino)-3,3-
dimethyl-butyryl]-pyrrolidine-(2S)-carboxylic acid [(2R)-
ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide

{S,S,S,R)- l-[(2S)-(2-Chloro-benzoylanrino)-3,3-dimethyl-
butyryl]-piperidine-(2S)-carboxylic acid [(2R)-ethoxy-5-oxo-
tetrahydro-furan-(3S)-yl]-amide

2-[(2S)-(3-Metlioxy-2-methyl-benzoylamino)-3,3-dimethyl-
butyryl]-2-(IS,4R)-aza-bicyclo[2.2.l]heptane-(3S)-carboxylic
acid [(2R)-ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide

METHOD H
(1R,3S,43)-3((S)-2-fcerfc-Butoxycarbonyl-l-hydroxymethyl-
ethylcarbamoyl)-2-aza-bicyclo[2.2.l]heptane-2-carboxylic acid
benzyl ester


[0170] To a stirred solution of (S)-3-Amino-4-hydroxy-
butyric acid terfc-butyl ester (486mg) and (1R,3S,4S}-2-Aza-
bicyclo[2.2.l]heptane-2,3-dicarboxylic acid 2 benzyH ester
(prepared as described in Tararov etal, Tett. Asymm . 2002, 13,
25-28) (767mg) in THF (18ml) was added 2-hydroxybenzotriazole
hydrate (452mg), DMAP (426mg), diisopropylethylamine (631D1)
and 1- (3-dimethylaminopropyl) -3 -ethylcarbodiimide
hydrochloride (EDC, 641mg). The resulting mixture was stirred
at ambient temperature for 18 hours then diluted with ethyl
acetate. The mixture was then washed with water, saturated
aqueous sodium bicarbonate solution and brine, driecd over'
magnesium sulfate, filtered and concentrated under ^reduced
pressure. The residue was purified by flash "chromatography
(60% ethyl acetate/petrol) to afford the sub-title compound as
a colorless oil (l.lg, 91%); % NMR (400MHz,d-6 DMSO) 5 1.13-
1.25 (1H, m), 1.30-1.48 (9H, m), 1.49-1.88 ,{6H, m), 2.20-2.52
(2H, m), 3.09-3.34 (2H, m), 3.64 (1H, d), 4.00-4.16 (2H, brm),
4.80 (1H, m), 4.90-5.15 (2H, m) , 7.21-7.41 (5H, m) , 7.50-7.75
(1H, m); MS ES (+) 433.37.
Method I
(lR,3S,4S)-3-((S)-2-fcert-Butoxycarbonyl-l-formyl-
ethylcarbamoyl) -2-aza-bicyclo [2.2. l]heptane-2-carb03cylic acid
benzyl ester


[0171] A solution of (1R,3S,4S)-3((S)-2-fcert-
ButoxYcarbonyl-1-hydroxymethyl-ethylcarbamoyl)-2-aza-
bicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (l.lg) in
DCM (10ml) was cooled to 0°C under nitrogen. 2,2,6,6-
tetramethylpiperidinyloxy (TEMPO, 4mg) was then added followed
by trichloroisocyanuric acid (621mg) portionwise over 30
minutes. The mixture was stirred at ambient temperature for 1
hour, then filtered through celite. The filtrate was washed
with water, 1M sodium thiosulfate solution and brine. Drying
over magnesium sulfate and concentration under reduced
pressure gave the sub-title compound as a colorless oil
(698mg, 64%); ^K NMR (400MHz,d-6 DMSO) 8 1.16-1.89 (16H, m) ,
2.30-2.80 (2H, m) , 3.68-3.81 (1H, m) , 4.19 (1H, brm) , 4.39.
(1H, m), 4.91-5.16 (2H, m), 7.21-7.43 (5H, m), 8.45 (0.4H, d),
8.60 (0.6, d), 9.19 (0.6H, s), 9.37 (0.4H, s).
Method J
(1R,3S,4S)-3-((S)-l-fcerfc-Butoxycarbonylmethyl-2,2-diethoxy-
ethylcarbamoyl)-2-aza-bicyclo[2.2.l]heptane-2-carboxylic acid
benzyl ester
[0172] To a solution of (1R,3S,4S)-3-({S)-2-tert-
Butoxycarbonyl-1-formyl-ethylcarbamoyl)-2-aza-
bicyclo [2.2. l]heptane-2-carboxylic acid benzyl ester (698mg)
in dichloromethane (10ml) was added triethyl orthoformate
(720mg) and p-toluenesulfonic acid monohydrate (6mg). The

resulting mixture was stirred at ambient temperature -until no
aldehyde remained by TLC. Saturated aqueous sodium
bicarbonate solution was then added and the organic pliase
removed. This was washed with water and brine, dried
(magnesium sulfate), filtered and concentrated under zreduced
pressure. This gave the sub-title compound as a pale yellow
oil (635mg, 78%); 1H NMR (400MHz,d-6 DMSO) 8 0.96-1.15 (6H, m) ,
1.26-1.84 (16H, m), 2.20-2.50 (2H, m) , 3.40-3.81 (5H, m) ,
4.10-4.28 (2H, m) , 4.37 (1H, m), 4.88-5.14 {2H, m), 7.20-7.40
(5H, m), 7.65 (0.5H, d), 7.80 (0.5H, d).
Method K
(lR,3S,4S)-3-((2R,3S)-2-Ethoxy-5-oxo-tetrahyaro-furan-3-
ylcarbamoyl)-2-aza-bicyclo[2.2.l]heptane-2-carboxylic acid
benzyl ester
[0173] A solution of (1R,3S,4S)-3-((S)-1-fcert-
Butoxycarbonylmethyl-2,2-diethoxy-ethylcarbamoyl) -2-a za-
bicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (635mg)
in dichloromethane (3ml) was cooled to 0°C under nitrogen.
Trifluoroacetic acid (0.7ml) was then added and the mixture
stirred at 0°C for 15 minutes, then warmed to ambient
temperature and stirred until' the reaction was comple-te by
TLC. The mixture was then diluted with dichloromethane (10ml)
and saturated aqueous sodium bicarbonate solution (14ml). The
organic phase was then removed and washed with 1:1 saturated
aqueous sodium bicarbonate/brine (8ml), dried (magnesium
sulfate), filtered and concentrated under reduced pressure.
This afforded the sub-title compound as a mixture of epimers
at the ketal centre. The epimers were separated on silica gel,

eluting with 30% 2~bu.tan.one/petrol. Syn-isomer (oil) (115mg,
23%); ^ NMR (400MHz,d-6 DMSO) 8 0.80-1.91 (10H, m), 2.35-2.79
(2H, m), 3.56 (1H, m), 3.66-3.80 (2H, m) , 4.18 (1H, m), 4.59
(1H, m) , 4.94-5.11 (2H, m), 5.53 (1H, d) , 7.20-7.40 (5H, m) ,
8.18 (0.5H, d), 8.27 (0.5H, d); MS ES + 403.31 (100%), ES -
401.37 (15%); Anti-isomer (oil)(103mg, 20%); XH NMR (400MHz,d-6
DMSO) 8 0.80-1.85 (10H, m), 2.25-2.60 (lH, m), 2.95 (1H, m) ,
3.42 (1H, m), 3.5-3.75 (2H, m) , 4.88-5.15 (3H, m) , 7.21-7.40
(5H, m), 8.50 (0.4H, d) , 8.59 (0.6H, d).
Method L
{(S)-1-[(1R,3S,4S)-3-((2R,3S)-2-Ethoxy-5-oxo-tetrahydro-furan-
3ylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carbonyl]-2,2-
dimethyl-propyl}-carbamic acid benzyl ester

[0174] To a solution of (1R,3S,4S)-3-((2R,3S)-2-Ethoxy-5-
oxo-tetrahydro-furan-3-ylcarbamoyl)-2-aza-
bicyclo [2.2.l]heptane-2-carboxylic acid benzyl ester (5g) in
ethyl acetate (160ml) and DMF (25ml) was added triethylamine
(2.5g) followed by palladium hydroxide/carbon (20% w/w, lg) .
The mixture was stirred under an atmosphere of hydrogen until
no starting material was present by TLC. The catalyst was
removed by filtration through celite. To the filtrate was
added (S)-2-benzyloxycarbonylamino-3,3-dimethyl-butyric acid
(4.93g), hydroxybenzotriazole hydrate (2.01g) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC,
2.85g). The resulting mixture was stirred at ambient
temperature overnight. Saturated aqueous sodium bicarbonate
solution (180ml) was then added and the organic phase removed.
This was washed with saturated aqueous ammonium chloride (180

ml), then brine (180ml), dried (magnesium sulfate), filtered
and concentrated under reduced pressure. The crude product was
purified on silica gel, eluting with 40-75% ethyl
acetate/petrol. The sub-title compound was obtained as a white
foam (5.25g, 81%); XH NMR (400MHz,d-6 DMSO) S 0.85-1.03 (10H,
m), 1.07-1.20 (3H, t), 1.30 (lH, m) , 1.40 (1H, m), 1.50-1.80
(3H, m), 1.93 (1H, m), 2.40-2.50 (1H, m), 2.78 (1H, m), 3.60
(1H, m), 3.78 (1H, m), 3.89 (1H, s), 4.26 (1H, d) , 4.52 (2H,
m) , 4.96-5.12 (2H, m), 5.56 (1H, d) , 7.10 (1H, d), 7.24-7.40
(5H, m), 8.27 (1H, d); MS ES + 516.93 (100%), ES - 515.05
(100%).
Method M
(1R, 3S,4S)-2-[(S)-2-(3-methoxy-2-methylbenzoylamino)-3,3-
dimethyl-butyryl] -2-aza-bicyclo [2.2.1]heptane-3-carboxylic
acid ((2R, 3S) -2-ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide

[0175] To a solution of {(S)-1-[(1R,3S,4S)-3-((2R,3S)-2-
Ethoxy-5-oxo-tetrahydro-furan-3ylcarbamoyl)-2-aza-
bicyclo[2.2.l]heptane-2-carbonyl]-2,2-dimethyl-propyl}-
carbamic acid benzyl ester (370mg) in ethyl acetate (20ml)was
added palladium hydroxide/carbon (20% w/w, 74mg) . The mixture
was stirred under an atmosphere of hydrogen until no starting
material was present by TLC. The catalyst was removed by
filtration through celite and the filtrate concentrated under
reduced pressure to give the amine as a brown foam (272mg). A
portion of this material (167mg) was dissolved in THF and 3-
methoxy-2-methyl benzoic acid (146mg), diisopropylamine
(191D1), hydroxybenzotriazole hydrate (77mg) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC,

109mg) were added. The resulting mixture was stirred at
ambient temperature for 24 hours then diluted with saturated
aqueous sodium bicarbonate. The organic phase was removed and
washed with saturated aqueous ammonium chloride, then brine,
dried (magnesium sulfate), filtered and concentrated under
reduced pressure. The crude product was purified on silica
gel, eluting with ethyl acetate. This gave the sub-title
compound as a white solid (121mg, 52%); XH NMR (400MHz,CDCl3) 8
1.10 (9H, s), 1.28 (3H, t), 1.43-1.56 (1H, m), 1.79-1.86 (3H,
m) , 1.99 (1H, brd), 2.29 (3H, s), 2.30-2.37 dd), 3.02 (1H, brs), 3.66-3.74 (1H, m), 3.87 (3H, s), 3.88-
3.94 (1H, m), 4.16 (IE, brs), 4.54 (1H, brs), 4.66-4.74 (1H,
m), 4.97 (1H, d), 5.46 (1H, d), 6.44 (1H, brd), 6.93 (1H, d) ,
7.00 (1H, d), 7.22 (1H, t), 7.78 (1H, brd); IR (solid) cm"1
2960, 1791, 1624, 1505, 1438, 1261, 1115, 975;. MS ES + 530; ES
- 528.
[0176] Compounds of formula 1-60 to 1-73 have been prepared
by methods substantially similar to those described in Example
1-59.
Example 1-60
2-[(2S)-(2-Chloro-benzoylamino)-3 , 3-dimethyl-butyryl]-2-
(lS,4R)-aza-bicyclo[2.2.1]heptane-(3S)-carboxylic acid [(2R)-
ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide

2-[(2S)-(4-Acetylamino-2-chloro-benzoylamino)-3,3-dimethyl-
butyryl]-2-(IS,4R) -aza-bicyclo[2.2.1]heptane-(3S)-carboxylic
acid [(2R)-ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide


2-[(2S)-(2-Chloro-4-propionylamino-benzoylamino)-3,3-dimethyl-
butyryl]-2-(IS,4R)-aza-bicyclo[2.2.1]heptane-(3S)-carboxylic
acid [ (2B.) -ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide

2-[(2S)-(2-Chloro-3-isobutyrylamino-benzoylamino)-3,3-
dimethyl-butyryl]-2- (IS, 4R) -aza-bicyclo [2.2 .l]heptane- (3S) -
carboxylic acid [(2R)-ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-
amide

2-[(2S)-(2-Fluoro-3-methoxy-benzoylamino)-3,3-dimethyl-
butyryl]-2-(1S,4R)-aza-bicyclo[2.2.l]heptane-(3S)-carboxylic
acid [(2R)-ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide

2- [ (2S) - (2-Fluoro-3-methoxy-benzoylamiiio) -3-methyl-butyryl] -2-
(1S,4R)-aza-bicyclo[2.2.l]heptane-(3S)-carboxylic acid [(2R)-
ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide


2- [ (2S)-(3-methoxy-2-methyl-benzoylamino) -3 ,3-dimethyl-
butyryl]-2-(IS,4R)-aza-bicyclo[2.2.l]heptane-(3S)-carboxylic
acid [(2S)-ethoxy-5-oxo-tetrahydro-furan-(3S) -yl]-amide

2-[(2S)-(2-Chloro-benzoylamino)-3,3-dimethyl-butyryl]-2-
(IS,4R)-aza-bicyclo[2.2.1]heptane-(3S)-carboxylic acid [(2S)-
e thoxy-5-oxo-1etrahydro-furan-(3 S)-yl]-amide

2-[(2S)-(4-Acetylairtino-3-chloro-benzoylamino) -3,3-dimethyl-
butyryl]-2-(IS,4R)-aza~bicyclo[2.2.1]heptane-(3S)-carboxylic
acid [(2R)-ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide

2-[(2S)-(3-Chloro-4-propionylamino-benzoylamino)-3,3-dimethyl-
butyryl] -2- (IS, 4R) -aza-bicyclo [2 .2 .1]heptane- (3S) -carboxylic
acid [(2R)-ethoxy-5-oxo-tetrahydro-furan-(3S)-yl]-amide


2- [ (2S) - (isoquinolin-1-yicaxbonylamino) -3,3-dimethyl-butyryl] -
2-(IS, 4R)-aza-bicyclo[2.2.l]heptane-(3S)-carboxylic acid
[(2R)-ethoxy-5-oxo-tetrahydro-£uran-(3S)-yl]-amide

2-[ (2S)- (4-Amino-3-chloro-benzoylamino)-3, 3-dimethyl-butyryl] -
2- (IS, 4R)-aza-bicyclo[2.2.i]heptane-(3S)-carboxylic acid
[ (2R)-ethoxy-5-oxo-tctrahydro-furan-(3S)-yl]amidc

2-[(2S)-(4-Amino-3-chloro-benzoylamino)-3-methyl-butyryl]-2-
(lS,4R)-aza-bicyclo[2.2.1]heptar.e-(3S)-carboxylic acid t(2R)-
ethoxy-5-oxo-tetrahydro-furan- (3S) -yl j -amide

2-[(2S)-(isoquinolin-1-ylcarbonylamino)-3,3-dimethyl-butyryl]-
2-(1S,4R)-aza-bicyclo[2.2.1]heptane-(3S)-carboxylic acid
[
































Example II-5
(5,5,5) - (35) - ( {1- [3-Methyl- (25) - (2-trifluoromethoxy-
benzoylamino) -butyryl] -pyrrolidine- (25) -carbonyl}-amino) -4-
oxo-butyric acid
{S,S,S) - (35) - ({1- [ (23) - (3-Hydroxy-2-methyl-benzoylamino) -3-
me thy 1-butyryl] -pyrrolidine- (2 5) -carbonyl}-amino) -4-oxo-
butyric acid
(SrS,S)-{3S)-({l-[ (25)-(3-Amino-2-methyl-benzoylamino)-3-
methyl-butyryl] -pyrrolidine- {2S} -carbonyl}-amino) -4-oxo-
butyric acid
(5,S,5) - (35) - ({1- [ (25) - (2, 3-Dichloro-benzoylamino) -3-methyl-
butyryl] -pyrrolidine- (25) -carbonyl} -amino) -4-oxo-butyric acid


Example 11-9
(3,3, S) - (35) - ({1- [ (25) - (2-Chloro-3-trif luoromethyl-
benzoylamino) -3-methyl-butyryl] -pyrrolidine- [2S) -carbonyl}-
amino)-4-oxo-butyric acid

(S,S, 5) - (35) - ({1- [ (25) - (3-Chloro-2-methyl-benzoylamino) -3-
methy 1-butyryl] -pyrrolidine- (25) -carbonyl} -amino) -4-oxo-
butyric acid
(5,5,5) - (35) - ({1- [ (25) - (2,4-Dichloro-benzoylam±no) -3-methyl-
butyryl] -pyrrolidine- (25) -carbonyl} -amino) -4-'03co-butyric acid

(5,5,5)- (35) - ({1- [ (25) - (2, 5-Dichloro-benzoylamino) -3-methyl-
butyryl] -pyrrolidine- (25) -carbonyl}-amino) -4-o:xo-butyric acid


Example n-13
[S,S,S)~{3S)-[{1-[{2S)-(2,6-Dichloro-benzoylamino) -3-methyl-
butyryl] -pyrrolidine- (25) -carbonyl}-amino) -4-oxo-butyric acid

{S, S, S) - (3S) - ( {1- [ (25) - (2, 6-Methyl-benzoylamino) -3-methyl-
butyryl] -pyrrolidine- {23) -carbonyl}-amino) -4-oxo-butyric acid

(S, S, S) - (3S) - [ (1- {3-Methyl- (2S) - [ (2-methyl-pyri carbonyl) -amino] -butyryl}-pyrrolidine- (23) -carbonyl) -amino] -4-
oxo-butyric acid
(S,S/5)-(35)-[(l-{3-Methyl-(25)-[(4-methyl-pyriaine-3-
carbonyl) -amino] -butyryl}-pyrrolidine- (2S) -carbonyl) -amino] -4-
oxo-butyric acid


Example 11-17
(S,S,S) - (35) - [ (l-{3-Methyl- (2S) - [ (3-methyl-thiophene-2 -
carbonyl) -amino] -butyryl}-pyrrolidine- (25) -carbonyl) -aonino] -4-
oxo-butyric acid
(5, S,S) - (35) - [ (l-{ (2.5) - [ (2, 3-Dichloro-pyridine-4-carbonyl) -
amino] -3-methyl-buty:ryl}-pyrrolidine- (25) -carbonyl) -amino] -4-
oxo-butyric acid
(5, S, 5) - (35) - [ (l-{ (2 S) - [ (3 , 5-Dichloro-pyridine-4-carbonyl) -
amino] -3-methyl-butyryl}-pyrrolidine- (25) -carbonyl) -amino] -4-
oxo-butyric acid
(5,5,5)-(35)-({l-[ (2^)- dimethyl-butyryl] -pyrrolidine- (25) -carbonyl}-amino) -4—oxo-
butyric acid

Example 11-21
{S, S,S)-4-Oxo-(3S)-({1-[4,4,4-trifluoro-(2S)-(2-methyl-3 -
methoxy-benzoylamino) -butyryl] -pyrrolidine- (2S) -carbonyl }-
amino)-butyric acid

{S,3, S) -{38) - { {1- [ (2S) - (5-Methoxy-2-methyl-benzoylamino) -3-
me thy1-butyryl]-pyrrolidine-{2S)-carbonyl}-amino)-4-oxo-
butyric acid
{SfS,S)-(3S)-({1-[(2S)-(3-Methoxy-2-methyl-benzoylamino) -3-
thiazol-4-yl-propionyl]-pyrrolidine-(2S)-carbonyl}-amino) -4-
oxo-butyric acid
{S,S, 3) -(3S)-({1-C(2S)-(2-Chloro-benzoylamino)-4,4,4-
trifluoro-butyryl] -pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-
butyric acid

Example 11-25
(S, S,S) - (3S) - ({1- [ (2S) - (2-Chloro-benzoylamino) -3-thiazol-4-yl-
propionyl] -pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-butyric
acid

(3, S, S) - (3 S) - ({1- [3,3 -Dimethyl- (2S) - (2-methyl-benzoylamino) -
butyryl]-pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-butyric acid

{S,S,S) - (35) - {{1- [3-Methyl- (2S) - (2-trif luoromethyl-
benzoylamino) -butyryl]-pyrrolidine- (2S) -carbonyl}-amino) -4-
oxo-butyric acid
(S, S, S) - (35) - ({1- [ (2S) - (2-Chloro-benzoylamino) -3, 3-dimethyl-
butyryl] -pyrrolidine- (2S) -canrbonyl}-amino) -4-oxo-butyric acid


Example 11-29
{S, S,S) - (35) - ({1- [3,3-Dimethyl- (2S) - (2-trifluoromethyl-
benzoylamino) -butyryl] -pyrrolidine- (2S) -carbonyl}-amino) -4-
oxo-butyric acid
(3, S, S) - (33) - ({1- [ (2S) - (2-Chloro-3-methox^-benzoylamino) -3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carboiryl}-amino) -4-oxo-
butyric acid

(S, S, S) - (3S) - ({1- [ (2S) - (2-Fluoro-3-rnethox=y-benzoylamino) -3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carboixyl}-amino) -4-oxo-
butyric acid
{3fS,3)-{33)-{{l-[ (2S) - (2-Chloro-3-trif liaoromethoxy-
benzoylamino) -3 ,3-dimethyl-butyryl] -pyrrolidine- (2S) -
carbonyl}-amino)-4-oxo-butyric acid


Example 11-33
(S, S, S)- (3S)-({1-[(2S)-(2-Chloro-3-cyclopropyloxy-
benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -
carbonyl}-amino)-4-oxo-butyric acid

{S,S,S)-{3S)-({1-[(2S)-(2-Chloro-3-methyl -benzoylamino)-3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-
butyric acid
(S,S,S) - (35) - ({l-[ (2S) - (2-chloro-3-methoxy -benzoylamino) -3-
methyl-butyryl] -pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-
butyric acid
(S,S,S)-{3S)-({l-[(2S)-(2-Chloro-3-ethyl -benzoylamino)-3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-
butyric acid


Example 11-37
(S,S, S) - [3S) - ({1- [ (2S) - (2-chloro-4-metlioxy -benz oylaraino) -3-
methyl-butyryl]-pyrrolidine- (2S) -carbonyl}-amino ) -4-oxo-
butyric acid
[S,S, S) - (3S) -(£!-[ (2S) - benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -
carbonyl}-amino)-4-oxo-butyric acid

(S, 3, S) - (3S) - ( {1- [ (2S) - {2-Chloro-3-hydroxy -benzroyl amino) -3,3-
dimethyl-butyryl] -pyrrolidine- (2S) -carbonyl}-ami-no) -4-oxo-
butyric acid
{S,S,S)-(3S)-({l-[ (2S)~ (2-chloro-4-acetamido -benzoylamino) -3-
methyl-butyryl] -pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-
butyric acid

Example 11-41
(S,S,S)-(3S)-({l-[(2S)-(2-Chloro-3-acetamido -benzoylamino)- .
3,3-dimethyl-butyryl]-pyrrolidine-(2S)-carbonyl}-amino)-4-oxo-
butyric acid

(S,S,S) -(3S)-({l-[(2S)-(2-methyl -3-acetamido -benzoylamino)-
3,3-dimethyl-butyryl]-pyrrolidine-(2S)-carbonyl}-amino)-4-oxo-
butyric acid
(S,5,S)-(3S)-({l-[(2S)-(2-chloro -4-acetamido -benzoylamino)-
3,3-dimethyl-butyryl]-pyrrolidine-(2S)-carbonyl}-amino)-4-oxo-
butyric acid
(S,S,S)-(2S)-{{±-[(2S)-(2-fluoro -4-acetamido -benzoylamino)-
3,3-dimethyl-butyryl]-pyrrolidine-(2S)-carbonyl}-amino)-4-oxo-
butyric acid


(S,S,S)-(3S)-({!-[ (2S)-(2-fluoro -4-acetamido -benzoylamino)-
3-methyl-butyryl] -pyrrolidine- (2S) -carbonyl} —amino) -4-oxo-
butyric acid

(S',S,S)-(3S)-({l-[(2S)-{2-chloro -4-isopropyILoxy -
benzoylamino)-3-methyl-butyryl]-pyrrolidine- (2S) -carbonyl}-
amino)-4-oxo-butyric acid

{S,S,S)-(3S)-{{1-1 (2S)-(2-chloro -4-hydroxy -benzoylamino)-
3,3-dimethyl-butyryl] -pyrrolidine- (2S) -carbo:nyl}-amino) -4-oxo-
butyric acid

(£?,£,S)- benzoylamino) -3 , 3-dimethyl-butyryl] -pyrrolidine- (2S) -
carbonyl}-amino)-4-oxo-butyric acid


{3,S,S)-{3S)-{{l-[(2S)-(2-chloro -4-isobutyrylamido -
benzoylamino)-3,3-dimethyl-butyryl]-pyrrolidine-(2S)-
carbonyl}-amino)-4-oxo-butyric acid

(S, S, S)- {,33)- ({l-[ (2S)- (2-chloro -4-acetamido -benzoylamino)-
3-cyclob.exyl] -pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-butyric
acid
i
(S,S,S)-{33)-({l-[(2S)-(2-chloro -4-methoxycarbonylamino -
benzoylamino)-3,3-dimethyl-butyryl]-pyrrolidine-(2S)-
carbonyl}-amino)-4-oxo-butyric acid

{S,S,3)-(3S) -({1-[(2S)-(2-chloro -3-phenoxy -benzoylamino)-
3,3-dimethyl-butyryl]-pyrrolidine-(2S)-carbonyl}-amino)-4-oxo-
butyric acid


(S,S,S)-(3S)-({l-l(2S)-(2-chlozo -6-amino -benzoylamino)-3-
methyl-butyryl] -pyrrolidine- (2S) -carbonyl}-amino) -4-oxo-
butyric acid
(S, S, S) -(33) -({1-[(2S)-(2-chloro-benzoylamino)-3,3-dimethyl-
butyryl]-piperidine-(2S)-carbonyl}-amino)-4-oxo-butyric acid

(3S) - ({2- [ (2S) - (3-Methoxy-2-methyl-benzoylamino) -3,3-dimethyl-
butyryl] -2- (IS, 4R)-aza-bicyclo [2.2.1]heptane- amino)-4-oxo-butyric acid

(3S) - ( {2- [ (2S)-(2-Chloro-benzoylamino)-3, 3-dimethyl-butyryl]-
2- (IS,4R)-aza-bicyclo[2.2.1]heptane-(3S)-carbonyl}-amino)-4-
oxo-butyric acid


(3S)-({2-[(2S)-(4-Acetylamino-2-chloro-benzoylamino)-3,3-
dimethyl-butyryl]-2-(1S,4R)-aza-bicyclo[2.2.l]heptane-(3S)-
carbonyl}-amino)-4-oxo-butyric acid

(3S)-({2-[(2S)-(2-Chloro-4-propionylamino-benzoylamino)-3,3-
dimethyl-butyryl]-2-(IS,4R)-aza-bicyclo[2.2.1]heptane-(3S) -
carbonyl}-amino)-4-oxo-butyric acid

(3S)-{{2-[(2S)-(2-Chloro-3-isobutyrylamino-benzoylaraino)-3,3-
dimethyl-butyryl]-2-(1S,4R)-aza-bicyclo[2.2.1]heptane-(3S)-
carbonyl}-amino)-4-oxo-butyric acid

(3S) - ({2-1 (2S) - (2-Fluoro-3-methoxy-benzoylamino) -3,3-dimethyl-
butyryl]-2-(IS,4R) -aza-bicyclo[2.2.1]heptane-(3S)-carbonyl}-
amino)-4-oxo-butyric acid


(3S)-({2-[(2S)-(2-Fluoro-3-methoxy-benzoylamino)-3-methyl-
butyryl]-2-(IS,4R)-aza-bicyclo[2.2.1]heptane-(3S)-carbonyl}-
amino)-4-oxo-butyric acid

(3S)-({2-[(2S)-(4-Acetylamino-3-chloro-benzoylamino)-3,3-
dimethyl-butyryl]-2-(IS,4R)-aza-bicyclo[2.2.1] heptane-(3S)-
carbonyl}-amino)-4-oxo-butyric acid

(3S)-({2-[(2S)-(3-Chloro-4-propionylamino-benzoylamino)-3,3-
dimethyl-butyryl]-2-(IS,4R)-aza-bicyclo[2.2.1]heptane-(3S)-
carbonyl}-amino)-4-oxo-butyric acid


Example 11-64
(3S)-({2-[(2S)-(Isoquinolin-1-ylcarbonylamino)-3,3-dimethyl-
butyryl]-2-(IS,4R)-aza-bicyclo[2.2.1]heptane-(3S)-carbonyl}-
amino)-4-oxo-butyric acid

(3S)-{{2-[(2S)-(4-Amino-3-chloro-benzoylamino)-3,3-dimethyl-
butyryl]-2- (IS,4R)-aza-bicyclo[2.2 .l]heptane- (3S)-carbonyl}-
amino)-4-oxo-butyric acid

(3S)-({2-[(2S)-(4-Amino-3-chloro-benzoylamino)-3-methyl-
butyryl]-2-(IS,4R)-aza-bicyclo[2.2.1]heptane-(3S)-carbonyl}-
amino)-4-oxo-butyric acid

[0179] The characterization data for compounds ll-l to
II-6S is summarized in Table 4 below and includes HPLC, LC/MS
(observed) and XH NMR data, -"n NMR data was obtained at 400
MHz, and was found to be consistent with structure.






















EXAMPLE III
BIOLOGICAL METHODS
[0180] Compounds of this invention may be tested using the
methods described below. Table 5 lists caspase-1 and caspase-
8 enzyme inhibition data for compounds II-1-II-25. In the
Table, compounds with a Ki of compounds with a Ki of 10-20 are assigned category B, and
compounds with a Ki of 21-30 are assigned category C.
Xn Vitro Assays
Enzyme Inhibition
[0181] Ki values for test compounds with caspase-1 and
caspase-8 were obtained by the method of Margolin et al. (J.

Biol. Chem., 272 pp. 7223-7228 (1997)). Other caspases may be
assayed simiLarly (see, e.g., WO 99/47545). Assays were
performed in 10 mM Tris (Sigma Corp, St Louis MO) pH 7.5, 1 mM
Dithiothreitol (DTT, Research Organic INC, Cleveland, OH) and
0.1% CHAPS (Pierce, Rockford IL) at 37 °C. For caspase-3, a
solution of 8% glycerol was added to the assay buffer to
improve enzyme stability. A 65 uL aliquot of the assay buffer
and 5 uL alicjuot of the appropriate dilutions of inhibitor in
DMSO where pipetted into a 96 well plate, treated with 10 uL
of caspase, then diluted in assay buffer (0.5-40 nM active
protein by active site titration) . A control containing DMSO
but no compound was included for each determination. The
plates were then incubated for 15 minutes at 37 °C, before
addition of the appropriate substrate (20 uL, final
concentration 1-4 x KM, final assay volume 100 uli) to initiate
the reaction. Reaction rates were measured at 37°C either by
following the time dependant increase in absorbance at 405 nM
(for the pNA substrates) or in fluorescence (Ex 390, Em 460)
(for the AMC substrates). The rates obtained were plotted
against inhibitor concentration and the data fit to the
Morrison tiglat-binding equation for competitive inhibitors
(Morrison, J. F. , Biochem. Biophys. Acta, 185 pp. 269-286
(1969)). The substrates used for the individual assays were
as follows:
[0182] Caspase-1 Suc-YVAD-pNA (Bachem, King of Prussia, PA)
(final concentration in the assay 80 uM) ;
[0183] Caspase-8 Ac-DEVD-pNA (Bachem, King of Prussia, PA)
(final concentration in assay 80 uM) .







PBMC Cell Assay
IL-lp Assay with a. Mixed Population of Human Peripheral Blood
Mononuclear Cells (PBMC) or Enriched Adherent Mononuclear
Cells
[0184] Processing of pre-IL-1^ 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:
[0185] An initial dilution series of test compound in DMSO
or ethanol is prepared, with a subsequent dilution into RPMI-
10% FBS media (containing 2 niM 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 Ki for a test compound determined in an ICE
inhibition assay is generally used for the primary compound
screen.
[0186] Generally 5-6 compound dilutions are tested and the
cellular component of the assay is performed in duplicate,
with duplicate EL.ISA determinations on each cell culture
supernatant,

PBMC Isolation and IL-1 Assay:
[0187] Buffy coat cells isolated from one pint human blood
(yielding 40-45 ml final volume plasma plus cells) are diluted
with media to 80 ml and LeukoPREP separation tubes (Becton
Dickinson) are each overlaid with 10 ml of cell suspension.
After 15 min centrifugation at 1500-1800 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 10^ cells/ml.
[0188] 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 o£ 5% CO2 ■
[0189] 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 Eppendorf tubes. It may
be noted that the cell pellet may be utilized for a
biochemical evaluation of pre-lL-ip and/or mature IL-1|} content
in cytosol extracts by western blotting or ELISA with pre-IL-
ip specific antisera.

Isolation of Adherent Mononuclear cells:
[0190] 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 10^ cells per well.
The addition of test compounds, LPS, cell incubation
conditions and processing of supernatants proceeds as
described above.
ELISA:
[0191] Quantikiine kits (R&D Systems) may be used for the
measurement of mature IL-1|5. Assays are performed according
to the manufacturer's directions. Mature IL-lp 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 1:2 0 dilutions of supernatants from LPS-positive
controls to select the optimal dilution for supernatants in
the test panel.
[0192] The inb-ibitory potency of the compounds can be
represented by an. IC50 value, which is the concentration of
inhibitor at which 50% of mature IL-ip is detected in the
supernatant as compared to the positive controls.
[0193] The skilled practitioner realizes that values
obtained in cell assays may depend on multiple factors. The
values may not necessarily represent fine quantitative
results.
[0194] Selected compounds of this invention have been
tested for inhibition of IL-lp release from PBMCs with IC50
values between 30 0nM and 4uM.

Whole Blood Assay for IL-lft Production
[0195] Whole blood assay IC50 values for compounds of this
invention may be obtained using the method described below:
Purpose:
[0196] The whole blood assay is a simple method for
measuring the production of iL-ip (or other cytokines) and the
activity of potential inhibitors. The complexity of this
assay system, with its full complement of lymphoid and
inflammatory cell types, spectrum of plasma proteins and red
blood cells is an ideal in vitro representation of human in
vivo physiologic conditions.
Materials;
Pyrogen-free syringes (~ 30 cc)
Pyrogen-free sterile vacuum tubes containing lyophilized
Na2EDTA (4.5 mg/10 ml tube)
Human whole blood sample (- 30-50 cc)
1.5 ml Eppendorf tubes
Test compound stock solutions {- 25mM in DMSO or other
solvent)
Endotoxin -free sodium chloride solution (0.9%) and HBSS
Lipopolysacchsride (Sigma; Cat.# L-3012) stock solution at
lmg/ml in HBSS
IL-lp ELISA Kit (R&D Systems; Cat # DLB50)
TNFa ELISA Kit (R&D Systems; Cat # DTA50)
Water bath or incubator
Whole Blood Assay Experimental Procedure:
[0197] Set incubator or water bath at 30 °C. Aliquot
0.25ml of blood into 1.5 ml eppendorf tubes. Note: be sure
to invert the whole blood sample tubes after every two
aliquots. Differences in replicates may result if the cells
sediment and are not uniformly suspended. Use of a positive

displacement pipette will also minimize differences between
replicate aliguots.
[0198] Prepare drug dilutions in sterile pyrogen-free
saline by serial dilution. A dilution series which brackets
the apparent K^ for a test compound determined in an ICE
inhibition assay is generally used for the primary compound
screen. For extremely hydrophobic compounds, prepare compound
dilutions in fresh plasma obtained from the same blood donor
or in PBS-containing 5% DMSO to enhance solubility.
[0199] Add 25 ul test compound dilution or vehicle control
and gently mix the sample. Then add 5.0 ul LPS solution (250
ng/ml stocked prepared, fresh: 5.0 ng/ml final concentration
LPS), and mix again. Incubate the tubes at 30 °C in a water
bath for 16-18 hr with, occasional mixing. Alternatively, the
tubes can be placed in a rotator set at 4 rpm for the same
incubation period. This assay should be set up in duplicate
or triplicate with the following controls: negative control -
no LPS; positive control - no test inhibitor; vehicle control
- the highest concentration of DMSO or compound solvent used
in the experiment. Additional saline is added to all control
tubes to normalize volumes for both control and experimental
whole blood test samples.
[0200] After the incubation period, whole blood samples are
centrifuged for 10 minutes at ~ 2000 rpm in the microfuge,
plasma is transferred to a fresh microfuge tube and
centrifuged at 1000 x g to pellet residual platelets if
necessary. Plasma samples may be stored frozen at -70 °C
prior to assay for cytokine levels by ELISA.
ELISA:
[0201] R&D Systems (614 McKinley Place N.E. Minneapolis,
MN 55413) Quantikine kits may be used for measurement of IL-ip
and TNF-a. The assays are performed according to the

manufacturer's directions. IL-ip levels of ~ 1-5 ng./ml in
positive controls among a range of individuals may be
observed. A 1:200 dilution of plasma for all samples is
usually sufficient for experiments for ELISA results to fall
on the linear range of the ELISA standard curves. It may be
necessary to optimize standard dilutions if you observe
differences in the whole blood assay. Nerad, J.L. et al., J.
Leukocyte Biol., 52, pp. 687-692 (1992).
[0202] Selected compounds of this invention have been
tested for inhibition of IL-ip release from whole blood with
IC50 values between luM and 40uM.
In Vivo Assays
[0203] Compounds of this invention may be tested in in vivo
assays such as those described in WO 99/47545.
[0204] WO 99/47545 and all the other documents cited herein (
are hereby incorporated by reference.
[0205] 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 the scope of this invention 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 H, Ci.i2aliphatic, C3.iocycloaliphatic, C6-ioaryl, 5-10 membered heterocyclyl, 5-10
membered heteroaryl, (C3-iocycloalkyl)-(Ci.i2aliphatic)-, cycloalkenyl-(Ci-i2aliphatic)-,
(C6-ioaryl)-(Ci.i2aliphatic)-, (5-10 membered heterocyclyl)-(C1.i2aliphatic)-, or (5-10 membered
heteroaryl)-(Ci.i2aliphatic)-, wherein any hydrogen atom is optionally and independently
replaced by R8 and any set of two hydrogen atoms bound to the same atom is optionally and
independently replaced by carbonyl;
Ring A is:

wherein, in each ring, any hydrogen atom is optionally and independently replaced by R4 and
any set of two hydrogen atoms bound to the same atom is optionally and independently
replaced by carbonyl;
R3 is phenyl, thiophene, or pyridine, wherein each ring is optionally substituted with up
to 5 groups independently selected from R8, and wherein at least one position on the phenyl,

thiophene, or pyridine adjacent to bond x is substituted by R12, wherein R12 has no more than 5
straight-chained atoms;
R4 is halogen, -OR9, -N02, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-
ethylenedioxy, -N(R9)2, -SR9, -SOR9, -S02R9, -S02N(R9)2, -SO3R9, -C(0)R9, -C(0)C(0)R9,
-C(0)C(0)OR9, -C(0)C(0)N(R9)2, -C(0)CH2C(0)R9, -C(S)R9, -C(S)OR9, -C(0)0R9,
-OC(0)R9, -C(0)N(R9)2, -OC(0)N(R9)2, -C(S)N(R9)2, -(CH2)o.2NHC(0)R9, -N(R9)N(R')COR9,
-N(R9)N(R9)C(0)OR9, -N(R9)N(R9)CON(R9)2, -N(R9)S02R9, -N(R9)S02N(R9)2,
-N(R9)C(0)OR9, -N(R9)C(0)R9, -N(R9)C(S)R9, -N(R9)C(0)N(R9)2, -N(R9)C(S)N(R9)2,
-N(COR9)COR9, -N(OR9)R9, -C(=NH)N(R9)2, -C(0)N(OR9)R9, -C(=NOR9)R9, -OP(0)(OR9)2,
-P(0)(R9)2, -P(0)(OR9)2, or -P(0)(H)(OR9);
R2 is -C(R5)(R6)(R7), C6-ioaryl, 5-10 membered heteroaryl, or C3.7 cycloalkyl;
R5 is H or a Cw straight-chained or branched alkyl;
R6isH or a Ci.6 straight-chained or branched alkyl;
R7 is -CF3, -C3.7cycloalkyl, Cs-ioaryl, 5-10 membered heteroaryl, heterocycle, or a C«
straight-chained or branched alkyl, wherein each carbon atom of the alkyl is optionally and
independently substituted with R10;
Or R5 and R7 taken together with the carbon atom to which they are attached form a 3-
10 membered cycloaliphatic;
Rs and R8' are each independently halogen, -OR9, -N02, -CN, -CF3, -OCF3, -R9, 1,2-
methylenedioxy, 1,2-ethylenedioxy, -N(R9)2, -SR9, -SOR9, -S02R9, -S02N(R9)2, -S03R9,
-C(0)R9, -C(0)C(0)R9, -C(0)C(0)OR9, -C(0)C(0)N(R9)2, -C(0)CH2C(0)R9, -C(S)R9,
-C(S)OR9, -C(0)OR9, -OC(0)R9, -C(0)N(R9)2, -0C(0)N(R9)2, -C(S)N(R9)2, -(CH2y
2NHC(0)R9, -N(R9)N(R9)COR9, -N(R9)N(R9)C(0)OR9, -N(R9)N(R9)CON(R9)2, -N(R9)S02R9,
-N(R9)S02N(R9)2, -N(R9)C(0)OR9, -N(R9)C(0)R9, -N(R9)C(S)R9, -N(R9)C(0)N(R9)2,
-N(R9)C(S)N(R9)2, -N(C0R9)C0R9, -N(OR9)R9, -C(=NH)N(R9)2, -C(0)N(OR9)R9,
-C(=NOR9)R9, -OP(0)(OR9)2, -P(0)(R9)2, -P(0)(OR9)2, and -P(0)(H)(OR9);
R9 is hydrogen, Ci.i2aliphatic, C3-iocycloaliphatic, C6.ioaryl, 5-10 membered
heterocyclyl, 5-10 membered heteroaryl, (C3.i0cycloaliphatic)-(Ci-i2aliphatic)-, (Ce-ioaryl)-
(Ci-i2aliphatic)-, (5-10 membered heterocyclyl)-(Ci.)2aliphatic)-, or heteroaryl-(Ci.i2aliphatic)-;

wherein any hydrogen atom is optionally and independently replaced by R8 and any set of two
hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
R10 is halogen, -OR11, -N02, -CN, -CF3, -OCF3, -R", or -SR11; wherein R11 is Cw-
aliphatic-;
R11 is Ci-4-aliphatic-; and
R12 is halogen, -OR11, -N02, -CN, -CF3, -OCF3, -R", -SR9.
2. The compound as claimed in claim 1 wherein Y is

3. The compound as claimed in claim 2, wherein R1 is Ci.12aliphatic or C3.i0cycloalkyl, wherein
each group is optionally substituted with 1-3 groups selected independently from R8.
4. The compound as claimed in claim 3 wherein R1 is a straight-chain or branched CM alkyl
that is optionally substituted with 1-3 groups selected independently from R8.
5. The compound as claimed in claim 4 wherein R1 is an unsubstituted, straight-chain or
branched CM alkyl.
6. The compound as claimed in claim 5, wherein R1 is ethyl, isopropyl, n-propyl, or n-butyl.
7. The compound as claimed in claim 6, wherein R1 is ethyl.
8. The compound as claimed in any one of claims 2-7 wherein R8 is halogen, -OR9, -CN, -CF3,
-OCF3, or -R9.
9. The compound as claimed in claim 8, wherein R8 is benzyl.

10. The compound as claimed in claim 1 wherein Y is

11. The compound as claimed in any one of claims 1-10, wherein ring A is:

optionally substituted by R4.
12. The compound as claimed in any one of claims 1-11 wherein R4 is halogen, -OR9, -CF3,
-OCF3, -R9, or -SR9.
13. The compound as claimed in claim 12, wherein R4 is H.
14. The compound as claimed in any one of claims 1-13 wherein R2 is a C3.4 branched alkyl
group.
15. The compound as claimed in any one of claims 1-14 wherein Rs is H or -CH3, R6 is -CH3,
and R7 is -CH3.
16. The compound as claimed in any one of claims 1-15 wherein R12 has no more than 4
straight-chained atoms.
17. The compound as claimed in claim 16 wherein R12 has no more than 3 straight-chained
atoms.

18. The compound as claimed in claim 17, wherein R12 is -OCF3, -OCH3, -CF3, -CH3,
-CH2CH3, -CI, or -F.
19. The compound as claimed in claim 18, wherein R12 is -CF3, -CH3, -CI, or -F.
20. The compound as claimed in claim 19, wherein R12 is -CH3, -CI, or -F.
21. The compound as claimed in any one of claims 1-20 wherein each R8 is independently
halogen, -OR9, -N02, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-ethylenedioxy, -N(R9)2,
-SR9, -SOR9, -SO2R9, -S02N(R9)2, -C(0)R9, -C(0)C(0)N(R9)2, -C(0)N(R9)2, -OC(0)N(R9)2,
-(CH2)0.2NHC(O)R9, -N(R9)S02R9, -N(R")S02N(R9)2, -N(R9)C(0)OR9, -N(R9)C(0)R9, or
-N(R9)C(0)N(R")2.
22. The compound as claimed in claim 21 wherein each R8 is independently -NH2, -N(R9)2,
-N(R9)C(0)R9, -OCF3, -OR9, -CF3, -R9, -SR9, or halo.
23. A compound selected from












a compound as claimed in any one of claims 1-23; and
b) a pharmaceutically acceptable carrier, adjuvant or vehicle.
25. A composition for treating a disease in a patient, wherein said disease is an IL-1 mediated
disease, an apoptosis mediated disease, an inflammatory disease, an autoimmune disease, an
autoinflammatory disease, a destructive bone disorder, a proliferative disorder, an infectious
disease, a degenerative disease, a disease associated with cell death, an excess dietary alcohol
intake disease, a viral mediated disease, retinal disorders, uveitis, inflammatory peritonitis,
osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis,
rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's
disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune
neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory
bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, graft vs. host disease,
organ transplant rejection, organ apoptosis after burn injury, osteoporosis, leukemias and
related disorders, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute
myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's
sarcoma, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burns, Shigellosis,
Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy's disease, prion
disease, cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic heart disease,
myocardial infarction, congestive heart failure, atherosclerosis, coronary artery bypass graft,
spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related
encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic
brain injury, spinal cord injury, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue
fever, Japanese encephalitis, various forms of liver disease, renal disease, polycystic kidney
disease, H. pylori-associated gastric and duodenal ulcer disease, HIV infection, tuberculosis,
meningitis, toxic epidermal necrolysis, pemphigus, Muckle-Wells Syndrome, Familial Cold
Urticaria, Familial Mediterranean Fever, Chronic Infantile Neurological Cutaneous and
Articular Syndrome, Neonatal Onset Multisystem Inflammatory Disease, TNFR1 -Associated
Periodic Syndrome, or Hyper-IgD periodic fever Syndrome.

2 6. A process for preparing a compound of formula I:

and the other variables are as defined in any one of claims 1-9 or 11-22;
comprising reacting a compound of formula 1:

wherein the variables are as defined in any one of claims 1-9 or 11-22 and a compound of
formula RX, wherein X is OH or an appropriate derivative or leaving group, in the presence of
conditions for coupling an amine and an acid (when X is OH) or appropriate acid derivative
(when X is an appropriate leaving group) to provide the compound of formula I.
2 7. A process for preparing a compound of formula I:

wherein Y is:


and the other variables are as defined in any one of claims 1-9 or 11-22;
comprising reacting a compound of formula 7-A:

wherein the variables are as defined in any one of claims 1-9; and a compound of formula
RNHCH(R2)C(0)X, wherein X is OH or an appropriate derivative or leaving group, in the
presence of conditions for coupling an amine and an acid (when X is OH) or appropriate acid
derivative (when X is not OH) to provide the compound of formula I.
28. A process for preparing a compound of formula IV:

wherein the variables are as defined in any one of claims 1 or 10-22, comprising reacting a
compound of formula I:


wherein Y is:
wherein R1 is as defined in any one of claims 1 -9 under hydrolysis conditions, to provide the
compound of formula II.
29. A process for preparing a compound of formula 3-A:

wherein PGi is a suitable carboxylic acid protecting group;
PG2 is a suitable nitrogen-protecting group; and ring A is as defined in claim 1; comprising:
reacting a compound of formula 2-A:

wherein PGi is a suitable carboxylic acid protecting group;
and a compound of formula 20-A:

wherein PG2 is a suitable nitrogen-protecting group; ring A is as defined in claim 1; and
X is OH or an appropriate leaving group, under conditions for coupling an amine and a
carboxylic acid (when X is OH) or an amine and an appropriate carboxylic acid (when X is an
appropriate leaving group) to provide the compound of formula 3-A.
30. A process for preparing a compound of formula 3:

wherein PGi is a suitable carboxylic acid protecting group and PG2 is a suitable
nitrogen-protecting group; comprising:
reacting a compound of formula 2-A:

wherein PGi is a suitable carboxylic acid protecting group;
with a compound of formula 20:

wherein PG2 is a suitable nitrogen-protecting group and X is OH or an appropriate leaving
group;

under conditions for coupling an amine and a carboxylic acid (when X is OH), or an amine and
an appropriate carboxylic acid (when X is an appropriate leaving group), to provide the
compound of formula 3.
31. A compound of formula 5-A:

wherein PGi is a suitable carboxylic acid protecting group; PG2 is a suitable nitrogen-
protecting group; and R1 and Ring A are as defined in any one of claims 1-9.
32. A compound of formula 5:
wherein Z is a Z-type protecting group and PGi and R1 are as defined in claim 40.
33. A compound of formula 3-A:

wherein PGi, PG2, and Ring A, are as defined in claim 31.
34. A compound of formula 3:


wherein Z is a Z-type protecting group and PGi is as defined in claim 31.
35. A compound of formula 4A:

wherein Ring A, PGi and PG2 are as defined in claim 31.
36. A compound of formula 4:
wherein Z is a Z-type protecting group and PGi is as defined in claim 31.


The present invention provides a
compound of formula (I): wherein the variables are
as defined herein. The present invention also provides
processes for preparing the compounds of formula (1),
and intermediates thereof, pharmaceutical compositions
comprising those compounds, and methods of using the
compounds and compositions.

Documents:

02474-kolnp-2006-abstract.pdf

02474-kolnp-2006-claims.pdf

02474-kolnp-2006-correspondence others.pdf

02474-kolnp-2006-description(complete).pdf

02474-kolnp-2006-form-1.pdf

02474-kolnp-2006-form-3.pdf

02474-kolnp-2006-form-5.pdf

02474-kolnp-2006-international publication.pdf

02474-kolnp-2006-international search authority report.pdf

02474-kolnp-2006-pct others.pdf

02474-kolnp-2006-priority document.pdf

2474-KOLNP-2006-ABSTRACT 1.1.pdf

2474-KOLNP-2006-AMANDED CLAIMS.pdf

2474-KOLNP-2006-AMANDED PAGES OF SPECIFICATION.pdf

2474-KOLNP-2006-ASSIGNMENT.pdf

2474-KOLNP-2006-CORRESPONDENCE.pdf

2474-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

2474-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2474-KOLNP-2006-EXAMINATION REPORT.pdf

2474-KOLNP-2006-FORM 1-1.1.pdf

2474-KOLNP-2006-FORM 13.1.pdf

2474-KOLNP-2006-FORM 13.pdf

2474-KOLNP-2006-FORM 18.1.pdf

2474-kolnp-2006-form 18.pdf

2474-KOLNP-2006-FORM 2.pdf

2474-KOLNP-2006-FORM 3-1.1.pdf

2474-KOLNP-2006-FORM 3.pdf

2474-KOLNP-2006-FORM 5.pdf

2474-KOLNP-2006-GPA.pdf

2474-KOLNP-2006-GRANTED-ABSTRACT.pdf

2474-KOLNP-2006-GRANTED-CLAIMS.pdf

2474-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

2474-KOLNP-2006-GRANTED-FORM 1.pdf

2474-KOLNP-2006-GRANTED-FORM 2.pdf

2474-KOLNP-2006-GRANTED-SPECIFICATION.pdf

2474-KOLNP-2006-OTHERS.pdf

2474-KOLNP-2006-OTHERS1.1.pdf

2474-KOLNP-2006-PA.pdf

2474-KOLNP-2006-PETITION UNDER RULE 137.pdf

2474-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

abstract-02474-kolnp-2006.jpg


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Patent Number 251854
Indian Patent Application Number 2474/KOLNP/2006
PG Journal Number 15/2012
Publication Date 13-Apr-2012
Grant Date 12-Apr-2012
Date of Filing 30-Aug-2006
Name of Patentee VERTEX PHARMACEUTICALS INCORPORATED
Applicant Address 130 WAVERLY STREET, CAMBRIDGE, MA 02139, UNITED STATES OF AMERICA
Inventors:
# Inventor's Name Inventor's Address
1 CHARRIER JEAN-DAMIEN 2 EASTERFIELD GROVE, WANTAGE OXFORDSHIRE OX12 7LL, GREAT BRITAIN
2 MORTIMORE MICHAEL WALRUS HOUSE, 156 THE HILL, BURFORD, OXFORDSHIRE OX18 4QY, GREAT BRITAIN
3 O'DONNELL MICHAEL 7 FERRY COURT,WILSHAM ROAD,ABINGDON,OXFORDSHIRE OX 14 5 TA,
4 RUTHERFORD ALISTAIR 11 READE AVENUE,ABINGDON, OXFORDSHIRE OX 14 3 YE
5 RAMAYA SHARN 31 PINE RIDGE ROAD,BURGHFIELD COMMON, BERKSHIRE RG7 3NB
6 STUDLEY JOHN R 29 WILLOW BROOK ABINGDON OXFORDSHIRE OX14 1TD, GREAT BRITAIN
7 TRUDEAU MARTIN 24 RANDOLPH DRIVE,TEWKSBURY,MA 01876
8 LOOKER ADAM 46 MEACHAM ROAD,APARTMENT 1, SOMERVILLE,MA 02133
9 DURRANT STEVEN 12 WICK CLOSE,ABINGDON OXFORDSHIRE OX 14 2 NQ,GREAT BRITAIN
PCT International Classification Number C07D 405/12
PCT International Application Number PCT/US2005/006540
PCT International Filing date 2005-02-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/548,610 2004-02-27 U.S.A.
2 60/629,661 2004-11-19 U.S.A.
3 60/629,743 2004-11-19 U.S.A.