Indian Patents
Title of Invention

MODULATORS OF CELLULAR ADHESION
Abstract The present invention provides compounds having formula (1): and pharmaceutically acceptable derivatives thereof, wherein R1-R4, n, p, A, B, D, E, L and AR1 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).
Full Text This application is a divisional application of 1233/kolnp/2006, filed on may 11,
2006.
Field Of The Invention
The present invention relates to compounds of general formula (I), capable of modulating
interactions between CAMs and leukointegrins. It also relates to pharmaceutical compositions of
the compounds which are useful as modulators of the CD11/CD18 family of cellular adhesion
molecules. Thus these compounds are useful, for example, for the treatment of various LFA-1 -
related disorders including immune and/or inflammatory disorders.
Background Of The Invention
Research conducted over the last decade has helped elucidate the molecular events
attending cell-cell interactions in the body, especially those events involved in the movement and
activation of cells in the immune system. See generally, Springer, T. Nature, 1990, 346, 425-
434. Cell surface proteins, and especially the Cellular Adhesion Molecules ("CAMs") and
"leukointegrins", including LFA-1, MAC-1 and gpl50.95 (referred to as CD18/CDlla,
CD18/CDllb, and CD18/CDllc, respectively) have correspondingly been the subject of
pharmaceutical research and development having as its goal the intervention in the processes of
leukocyte extravasation to sites of injury and leukocyte movement to distinct targets. For
example, it is presently believed that prior to the leukocyte extravasation, which is a mandatory
component of the inflammatory response, activation of integrins constitutively expressed on
leukocytes occurs and is followed by a tight ligand/receptor interaction between integrins (e.g.,
LFA-1) and one or several distinct intercellular adhesion molecules (ICAMs) designated ICAM-
1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on blood vessel endothelial cell surfaces
and on other leukocytes. The interaction of the CAMs with the leukointegrins is a vital step in
the normal functioning of the immune system. It is believed that immune processes such as
antigen presentation, T-cell mediated cytotoxicity and leukocyte extravasation all require cellular
adhesion mediated by ICAMs interacting with the leukointegrins. See generally Kishimoto, T.
K.; Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.; Springer, T. Current
Biology, 1994, 4, 506-532.
Clearly, because of the role that the interaction of the CAMs and the leukointegrins plays
in the immune response, it would be desirable to modulate these specific interactions to achieve a
desired therapeutic result (e.g., inhibition of the interaction in the event of an overactive immune
response). Significantly, it has been demonstrated that the antagonism of the interaction between
the CAMs and the leukointegrins can be realized by agents directed against either component.
Specifically, blocking of the CAMs, such as for example ICAM-1, or the leukointegrins, such as
for example LFA-1, by antibodies directed against either or both of these molecules effectively
inhibits inflammatory responses. In vitro models of inflammation and immune response
inhibited by antibodies to CAMs or leukointegrins include antigen or mitogen-induced
lymphocyte proliferation, homotypic aggregation of lymphocytes, T-cell mediated cytolysis and
antigen-specific induced tolerance. The relevance of the in vitro studies are supported by in vivo
studies with antibodies directed against ICAM-1 or LFA-1. For example, antibodies directed
against LFA-1 can prevent thyroid graft rejection and prolong heart allograft survival in mice
Gorski, A.; Immunology Today, 1994, 15, 251-255). Of greater significance, antibodies directed
against ICAM-1 have shown efficacy in vivo as anti-inflammatory agents in human diseases such
as renal allograft rejection and rheumatoid arthritis (Rothlein, R. R.; Scharschmidt, L., in:
Adhesion Molecules; Wegner, C. D., Ed.; 1994, 1-38, Cosimi, C. B.; et al., J. Immunol. 1990,
744, 4604-4612 and Kavanaugh, A.; et al. Arthritis Rheum. 1994, 37, 992-1004) and antibodies
directed against LFA-1 have demonstrated immunosuppressive effects in bone marrow
transplantation and in the prevention of early rejection of renal allografts (Fischer, A.; et al.
Lancet, 1989, 2, 1058-1060 and Le Mauff, B.; et al, Transplantation, 1991, 52, 291-295).
As described above, the use of anti-LFA-1 or anti-ICAM-1 antibodies to antagonize this
interaction has been investigated. Additionally, the use of LFA-1 or ICAM-1 peptides,
fragments or peptide antagonists {see, for example, US Patents 5,149,780, 5,288,854, 5,340,800,
5,424,399, 5,470,953, Published PCT applications WO 90/03400, WO90/13316, WO90/10652,
W091/19511, WO92/03473, WO94/11400, WO95/28170, JP4193895, EP314863, EP362526,
EP362531), and small molecule antagonists have been investigated. For example, several small
molecules have been described in the literature which affect the interaction of CAMs and
leukointegrins. A natural product isolated from the root of Trichilia rubra was found to be
inhibitory in an in vitro cell binding assay (Musza, L. L.; et al, Tetrahedron, 1994, 50, 11369-
11378). One series of molecules (Boschelli, D. H.; et al., J. Med. Chem. 1994, 37, 111 and
Boschelli, D. H.; et al., J. Med. Chem. 1995, 38, 4597-4614) was found to be orally active in a
reverse passive Arthus reaction, an induced model of inflammation that is characterized by
neutrophil accumulation (Chang, Y. H.; et al, Eur. J. Pharmacol. 1992, 69, 155-164). Another
series of molecules was also found to be orally active in a delayed type hypersensitivity reaction
in rats (Sanfilippo, P. J.; et al., J. Med. Chem. 1995, 38, 1057-1059). All of these molecules
appear to act nonspecifically, either by inhibiting the transcription of ICAM-1 along with other
proteins or act intracellularly to inhibit the activation of the leukointegrins b; an unknown
mechanism, and none appear to directly antagonize the interaction of the CAMs with the
leukointegrins.
Clearly, although several classes of compounds have been investigated for therapeutic use, there
remains a need for the development of novel therapeutics that are capable of modulating
interactions between CAMs and leukointegrins. In particular, it would be desirable to develop
therapeutics capable of selectively targeting (preferably inhibiting) the interaction between LFA-
and ICAM-1 that would be useful as a therapeutic agent for immune and/or inflammatory
disorders.
Summary of the Invention
As discussed above, there remains a need for the development of novel therapeutics that are
capable of modulating interactions between CAMs and leukointegrins. The present invention
provides novel compounds of general formula (I),

and pharmaceutical compositions thereof, as described generally and in subclasses herein,
which compounds are useful as modulators of the CD11/CD18 family of cellular adhesion
molecules. Thus these compounds are useful, for example, for the treatment of various LFA-1-
related disorders including immune and/or inflammatory disorders.
In yet another aspect, the present invention provides methods for treating any disorder mediated
through the CD11/CD18 family of cellular adhesion molecules comprising administering to a
subject in need thereof a therapeutically effective amount of a compound of the invention.
Definitions
The term "aliphatic", as used herein, includes both saturated and unsaturated, straight chain (i.e.,
unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or
more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is
intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used
herein, the term "alkyl" includes straight and branched alkyl groups. An analogous convention
applies to other generic terms such as "alkenyl", "alkynyl" and the like. Furthermore, as used
herein, the terms "alkyl", "alkenyl", "alkynyl" and the like encompass both substituted and
unsubstituted groups. In certain embodiments, as used herein, "lower alkyl" is used to indicate
those alkyl groups (substituted, unsubstituted, branched or unbranched) having about 1 -6 carbon
atoms.
In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain
.bout 1 -20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the invention contain about 1-10 aliphatic carbon atoms. In yet other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8
aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups
employed in the invention contain about 1 -6 aliphatic carbon atoms. In yet other embodiments,
the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-4 carbon atoms.
Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-
propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl,
tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more
substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl,
butenyl, 1 -methyl-2-buten-l-yl, and the like. Representative alkynyl groups include, but are not
limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
The term "alicyclic", as used herein, refers to compounds which combine the properties of
aliphatic and cyclic compounds and include but are not limited to monocyclic, or polycyclic
aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with
one or more functional groups. As will be appreciated by one of ordinary skill in the art,
"alicyclic" is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and
cycloalkynyl moieties, which are optionally substituted with one or more functional groups.
Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH2-
cyclopropyl, cyclobutyl, -CH2-cyclobutyl, cyclopentyl, -CH2-cyclopentyl, cyclohexyl, -CH2-
cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again,
may bear one or more substituents.
The term "alkoxy" or "alkyloxy", as used herein refers to a saturated (i.e., O-alkyl) or
unsaturated (i.e., O-alkenyl and O-alkynyl) group attached to the parent molecular moiety
through an oxygen atom. In certain embodiments, the alkyl group contains about 1 -20 aliphatic
carbon atoms. In certain other embodiments, the alkyl group contains about 1-10 aliphatic
carbon atoms. In yet other embodiments, the alkyl group employed in the invention contains
about 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-6
aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-4 aliphatic
carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy,
isopropoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, neopentoxy, n-hexoxy and the like.
The term "thioalkyl" as used herein refers to a saturated (i.e., S-alkyl) or unsaturated (i.e., S-
alkenyl and S-alkynyl) group attached to the parent molecular moiety through a sulfur atom. In
certain embodiments, the alkyl group contains about 1-20 aliphatic carbon atoms. In certain
other embodiments, the alkyl group contains about 1-10 aliphatic carbon atoms. In yet other
embodiments, the alkyl group employed in the invention contains about 1-8 aliphatic carbon
atoms. In still other embodiments, the alkyl group contains about 1-6 aliphatic carbon atoms. In
yet other embodiments, the alkyl group contains about 1-4 aliphatic carbon atoms. Examples of
thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-
butylthio, and the like.
The term "alkylamino" refers to a group having the structure -NHR'wherein R' is alkyl, as
defined herein. The term "aminoalkyl" refers to a group having the structure NH2R'-, wherein
R' is alkyl, as defined herein. In certain embodiments, the alkyl group contains about 1-20
aliphatic carbon atoms. In certain other embodiments, the alkyl group contains about 1-10
aliphatic carbon atoms. In yet other embodiments, the alkyl group employed in the invention
contains about 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains
about 1 -6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1 -4
aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino,
ethylamino, iso-propylamino and the like.
Some examples of substituents of the above-described aliphatic (and other) moieties of
compounds of the invention include, but are not limited to aliphatic; alicyclic; heteroaliphatic;
heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;
alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio;
arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2;
-CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -
OCO2Rx; -OCON(Rx)2; -N(RX)2; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of Rx
independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,
aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any
of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents
described above and herein may be substituted or unsubstituted, branched or unbranched,
saturated or unsaturated, and wherein any of the aryl or heteroaryl substituents described above
and herein may be substituted or unsubstituted. Additional examples of generally applicable
ubstituents are illustrated by the specific embodiments shown in the Examples that are
described herein.
In general, the term "aromatic moiety", as used herein, refers to a stable mono- or polycyclic,
unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or
unsubstituted. In certain embodiments, the term "aromatic moiety" refers to a planar ring having
p-orbitals perpendicular to the plane of the ring at each ring atom and satisfying the Huckel rule
where the number of pi electrons in the ring is (4n+2) wherein n is an integer. A mono- or
polycyclic, unsaturated moiety that does not satisfy one or all of these criteria for aromaticity is
defined herein as "non-aromatic", and is encompassed by the term "alicyclic".
In general, the term "heteroaromatic moiety", as used herein, refers to a stable mono- or
polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may be
substituted or unsubstituted; and comprising at least one heteroatom selected from O, S and N
within the ring (i.e., in place of a ring carbon atom). In certain embodiments, the term
"heteroaromatic moiety" refers to a planar ring comprising at least on eheteroatom, having p-
orbitals perpendicular to the plane of the ring at each ring atom, and satisfying the Huckel rule
where the number of pi electrons in the ring is (4n+2) wherein n is an integer.
It will also be appreciated that aromatic and heteroaromatic moieties, as defined herein may be
attached via an alkyl or heteroalkyl moiety and thus also include -(alkyl)aromatic, -
(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties.
Thus, as used herein, the phrases "aromatic or heteroaromatic moieties" and "aromatic,
heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -
(heteroalkyl)heteroaromatic" are interchangeable. Substituents include, but are not limited to,
any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties,
or for other moieties as disclosed herein, resulting in the formation of a stable compound.
The term "aryl", as used herein, does not differ significantly from the common meaning of the
term in the art, and refers to an unsaturated cyclic moiety comprising at least one aromatic ring.
In certain embodiments, "aryl" refers to a mono- or bicyclic carbocyclic ring system having one
or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,
indanyl, indenyl and the like.
The term "heteroaryl", as used herein, does not differ significantly from the common meaning of
the term in the art, and refers to a cyclic aromatic radical having from five to ten ring atoms of
/hich one ring atom is selected from S, O and N; zero, one or two ring atoms are additional
heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon,
the radical being joined to the rest of the molecule via any of the ring atoms, such as, for
example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,
isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the
like.
It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl groups) can be
unsubstituted or substituted, wherein substitution includes replacement of one or more of the
hydrogen atoms thereon independently with any one or more of the following moieties including,
but not limited to: aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic;
aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy;
aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl;
Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH; -CH2CH2OH; -CH2NH2; -
CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -OCON(Rx)2; -N(RX)2; -
S(O)Rx; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of RX independently includes, but is not
limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl,
heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of
the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents
described above and herein may be substituted or unsubstituted, branched or unbranched,
saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl, heteroaryl, -
(alkyl)aryl or -(alkyl)heteroaryl substituents described above and herein may be substituted or
unsubstituted. Additionally, it will be appreciated, that any two adjacent groups taken together
may represent a 4, 5, 6, or 7-membered substituted or unsubstituted alicyclic or heterocyclic
moiety. Additional examples of generally applicable substituents are illustrated by the specific
embodiments shown in the Examples that are described herein.
The term "cycloalkyl", as used herein, refers specifically to groups having three to seven,
preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case
of aliphatic, alicyclic, heteroaliphatic or heterocyclic moieties, may optionally be substituted
with substituents including, but not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic;
aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl;
,eteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -
CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -
OCO2Rx; -OCON(Rx)2; -N(RX)2; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of Rx
independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,
aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or
heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic,
alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or
unsubstituted, branched or unbranched, saturated or usaturated, and wherein any of the aromatic,
heteroaromatic, aryl or heteroaryl substituents described above and herein may be substituted or
unsubstituted. Additional examples of generally applicable substituents are illustrated by the
specific embodiments shown in the Examples that are described herein.
The term "heteroaliphatic", as used herein, refers to aliphatic moieties in which one or more
carbon atoms in the main chain have been substituted with a heteroatom. Thus, a heteroaliphatic
group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen,
phosphorus or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be
linear or branched, and saturated o runsaturated. In certain embodiments, heteroaliphatic
moieties are substituted by independent replacement of one or more of the hydrogen atoms
thereon with one or more moieties including, but not limited to aliphatic; alicyclic;
heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl;
alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -
CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -
OCO2Rx; -OCON(Rx)2; -N(RX)2; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of Rx
independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,
aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or
heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic,
alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or
unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the
aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be
substituted or unsubstituted. Additional examples of generally applicable substituents are
.lustrated by the specific embodiments shown in the Examples that are described herein.
The term "heterocycloalkyl", "heterocycle" or "heterocyclic", as used herein, refers to
compounds which combine the properties of heteroaliphatic and cyclic compounds and include,
but are not limited to, saturated and unsaturated mono- or polycyclic cyclic ring systems having
5-16 atoms wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the
nitrogen and sulfur heteroatoms may be optionally be oxidized), wherein the rirg systems are
optionally substituted with one or more functional groups, as defined herein. In certain
embodiments, the term "heterocycloalkyl", "heterocycle" or "heterocyclic" refers to a non-
aromatic 5-, 6- or 7- membered ring or a polycyclic group wherein at least one ring atom is a
heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be
optionally be oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused
six-membered rings having between one and three heteroatoms independently selected from
oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-
membered ring has 0 to 2 double bonds and each 7-membered ring has 0 to 3 double bonds, (ii)
the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom
may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an
aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, heterocycles
such as furanyl, thiofuranyl, pyranyl, pyrrolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidiny] isooxazolyl,
isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl,
oxatriazolyl, thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, dithiazolyl, dithiazolidinyl, tetrahydrofuryl, and benzofused derivatives thereof.
In certain embodiments, a "substituted heterocycle, or heterocycloalkyl or heterocyclic" group is
utilized and as used herein, refers to a heterocycle, or heterocycloalkyl or heterocyclic group, as
defined above, substituted by the independent replacement of one, two or three of the hydrogen
atoms thereon with but are not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic;
aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl;
heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; F; Cl; Br; I; - OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH;
-CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)Rx; -CO2(Rx); -CON(Rx)2; -OC(O)Rx; -OCO2Rx; -
OCON(Rx)2; -N(RX)2; -S(O)2Rx; -NRx(CO)Rx wherein each occurrence of RX independently
.icludes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic,
heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or
heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic,
alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or
unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the
aromatic, heteroaromatic, aryl or heteroaryl substitutents described above and herein may be
substituted or unsubstituted. Additional examples or generally applicable substituents are
illustrated by the specific embodiments shown in the Examples, which are described herein.
Additionally, it will be appreciated that any of the alicyclic or heterocyclic moieties described
above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples
of generally applicable substituents are illustrated by the specific embodiments shown in the
Examples that are described herein.
The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine,
bromine and iodine.
The term "haloalkyl" denotes an alkyl group, as defined above, having one, two, or three halogen
atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl,
trifluoromethyl, and the like.
The term "amino", as used herein, refers to a primary (-NH2), secondary (-NHRX), tertiary (-
NRxRy) or quaternary (-N+RxRyRz) amine, where Rx, Ry and R2 are independently an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as defined herein.
Examples of amino groups include, but are not limited to, methylamino, dimethylamino,
ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino,
piperidino, trimethylamino, and propylamine
The term "acyl", as used herein, refers to a group having the general formula -C(=O)R, where R
is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as
defined herein.
The term "sulfonamido", as used herein, refers to a group of the general formula -SO2NRxRy,
where Rx and Ry are independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic, heteroaromatic or acyl moiety, as defined herein.
The term "benzamido", as used herein, refers to a group of the general formula PhNRx-, where
Rx is hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic
r acyl moiety, as defined herein.
The term "C1-6alkylidene", as used herein, refers to a substituted or unsubstituted, linear or
branched saturated divalent radical consisting solely of carbon and hydrogen atoms, having from
one to six carbon atoms, having a free valence "-" at both ends of the radical.
The term "C2-6alkenylidene", as used herein, refers to a substituted or unsubstituted, linear or
branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having
from two to six carbon atoms, having a free valence "-" at both ends of the radical, and wherein
the unsaturation is present only as double bonds and wherein a double bond can exist between
the first carbon of the chain and the rest of the molecule.
As used herein, the terms "aliphatic", "heteroaliphatic", "alkyl", "alkenyl", "alkynyl",
"heteroalkyl", "heteroalkenyl", "heteroalkynyl", and the like encompass substituted and
unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms
"alicyclic", "heterocyclic", "heterocycloalkyl", "heterocycle" and the like encompass substituted
and unsubstituted, and saturated and unsaturated groups. Additionally, the terms "cycloalkyl",
"cycloalkenyl", "cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl",
"heterocycloalkynyl", "aromatic", "heteroaromatic", "aryl", "heteroaryl" and the like encompass
both substituted and unsubstituted groups.
By the term "protecting group", has used herein, it is meant that a particular functional moiety,
e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another
reactive site in a multifunctional compound. In preferred embodiments, a protecting group reacts
selectively in good yield to give a protected substrate that is stable to the projected reactions; the
protecting group must be selectively removed in good yield by readily available, preferably
nontoxic reagents that do not attack the other functional groups; the protecting group forms an
easily separable derivative (more preferably without the generation of new stereogenic centers);
and the protecting group has a minimum of additional functionality to avoid further sites of
reaction. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be
utilized. For example, in certain embodiments, as detailed herein, certain exemplary oxygen
protecting groups are utilized. These oxygen protecting groups include, but are not limited to
methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM
(methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM or MPM (p-
methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl
thers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS
(triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-
butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz),
trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and ketals. In certain
other exemplary embodiments, nitrogen protecting groups are utilized. These nitrogen
protecting groups include, but are not limited to, carbamates (including methyl, ethyl and
substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N-
Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain
other exemplary protecting groups are detailed herein, however, it will be appreciated that the
present invention is not intended to be limited to these protecting groups; rather, a variety of
additional equivalent protecting groups can be readily identified using the above criteria and
utilized in the present invention. Additionally, a variety of protecting groups are described in
'Protective Groups in Organic Synthesis" Third Ed. Greene, T.W. and Wuts, P.G., Eds., John
Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by
reference.
The term "natural amino acid" as used herein refers to any one of the common, naturally
occurring L-amino acids found in naturally occurring proteins: glycine (Gly), alanine (Ala),
valine (Val), leucine (Leu), isoleucine (Ile), lysine (Lys), arginine (Arg), histidine (His), proline
(Pro), serine (Ser), threonine (Thr), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp),
aspartic acid (Asp), glutamic acid (Glu), asparagine (Asn), glutamine (Gln), cysteine (Cys) and
methionine (Met).
The term "unnatural amino acid" as used herein refers to all amino acids which are not natural
amino acids. This includes, for example, a-, ß-, D-, L- amino acid residues, and compounds of
the general formula wherein the side chain R is other than the amino acid side
chains occurring in nature.
More generally, the term "amino acid", as used herein, encompasses natural amino acids and
unnatural amino acids.
The term "bioisosteres", as used herein, generally refers to two or more compounds or moieties
at possess similar molecular shapes and/or volumes. In certain embodiments, bioisosteres have
approximately the same distribution of electrons. In certain other embodiments, bioisosteres
exhibit similar biological properties. In preferred embodiments, bioisosteres possess similar
molecular shapes and volumes; have approximately the same distribution of electrons; and
exhibit similar biological properties.
As used herein, the term "isolated", when applied to the compounds of the present invention,
refers to such compounds that are (i) separated from at least some components with which they
are associated in nature or when they are made and/or (ii) produced, prepared or manufactured
by the hand of man.
The term, "pharmaceutically acceptable derivative", as used herein, denotes any
pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other
adduct or derivative which, upon administration to a patient, is capable of providing (directly or
indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a
derivative of a compound, usually with significantly reduced pharmacological activity, which
contains an additional moiety, which is susceptible to removal in vivo yielding the parent
molecule as the pharmacologically active species. An example of a pro-drug is an ester, which is
cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and
materials and methods for derivatizing the parent compounds to create the pro-drugs, are known
and may be adapted to the present invention. Certain exemplary pharmaceutical compositions
and pharmaceutically acceptable derivatives will be discussed in more detail herein, below.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are,
within the scope of sound medical judgment, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation, allergic response and the like, and
are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of
amines, carboxylic acids, and other types of compounds, are well known in the art. For example,
S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ
during the final isolation and purification of the compounds of the invention, or separately by
reacting a free base or free acid function with a suitable reagent, as described generally below,
'or example, a free base function can be reacted with a suitable acid. Furthermore, where the
compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and
alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically
acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,
succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate,
benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide,
2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate,
palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate,
valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts
include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations
formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate,
loweralkyl sulfonate and aryl sulfonate.
As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in
vivo and include those that break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example, those derived from
pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,
cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has
not more than 6 carbon atoms. Examples of particular esters include formates, acetates,
propionates, butyrates, acrylates and ethylsuccinates.
As used herein, the term "pharmaceutically acceptable prodrugs" refers to those prodrugs of the
compounds of the present invention which are, within the scope of sound medical judgment,
uitable for use in contact with the issues of humans and lower animals with undue toxicity,
irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic forms, where possible, of the
compounds of the invention. The term "prodrug" refers to compounds that are rapidly
transformed in vivo to yield the parent compound of the above formula, for example by
hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as
Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987, both of which are incorporated herein by reference.
The term "LFA-1 mediated disorders", as used herein refers generally to pathological states
caused by cell adherence interactions involving the LFA-1 receptor on lymphocytes. Examples
of such disorders include, but are not limited to T-cell inflammatory responses such as
inflammatory skin diseases including psoriasis; responses associated with inflammatory bowel
disease (such as Crohn's disease and ulcerative colitis); adult respiratory distress syndrome,
dermatitis, meningitis, encephalitis, uveitic, allergic conditions such as eczema and asthma and
other conditions involving infiltration of T-cells and chronic inflammatory responses, skin
hypersensitivity reactions (including poison ivy and poison oak), atherosclerosis, leukocyte
adhesion deficiency, autoimmune diseases such as rheumatoid arthritis, systemic lupus
erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune
thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, type 1 diabetes,
juvenile onset diabetes, and immune responses associated with delayed hypersensitivity
mediated by cytokines and T-lymphocytes typically found in tuberculosis, sarcoidosis,
polymyositis, granulomatosis, and vasculitis, pernicious anemia, diseases involving leukocyte
diapedesis, CNS inflammatory disorder, multiple organ injury syndrome secondary to
septicaemia or trauma, autoimmune haemolytic anemia, myethamia gravis, antigen-antibody
complex mediated diseases, and all types of transplantations, including graft vs. host or host vs.
graft disease.
The term "LFA-1 antagonist", as used herein, generally refers to inventive compounds, as
described herein, that act as a competitive inhibitors of the CD1 la and/or CD 18 interaction with
ICAM-1, ICAM-2 or ICAM-3.
The term "treating", as used herein generally means that the compounds of the invention can be
sed in humans or animals with at least a tentative diagnosis of disease. The compounds of the
invention will delay or slow the progression of the disease thereby extending the individual's life
span.
The term "preventing" as used herein generally means that the compounds of the present
invention are useful when administered to a patient who has not been diagnosed as possibly
having the disease at the time of administration, but who would normally be expected to develop
the disease or be at increased risk for the disease. In certain embodiments, compounds of the
invention slow the development of disease symptoms, delay the onset of disease, or prevent the
individual from developing the disease at all.
As used herein the term "biological sample " includes, without limitation, cell cultures or extracts
thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood,
saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. For example, the term
"biological sample" refers to any solid or fluid sample obtained from, excreted by or secreted by
any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and
multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and
in particular a healthy or apparently healthy human subject or a human patient affected by a
condition or disease to be diagnosed or investigated). The biological sample can be in any form,
including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or
cell fractions; or a biopsy, or a biological fluid. The biological fluid may be obtained from any
site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine,
bile, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom,
aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained
from an abscess or any other site of infection or inflammation), or fluid obtained from a joint
(e.g. a normal joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout
or septic arthritis). The biological sample can be obtained from any organ or tissue (including a
biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or
medium conditioned by any cell, tissue or organ. Biological samples may also include sections of
tissues such as frozen sections taken for histological purposes. Biological samples also include
mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids
generated by partial or complete fractionation of cell or tissue homogenates. Although the
sample is preferably taken from a human subject, biological samples may be from any animal,
plant, bacteria, virus, yeast, etc. The term animal, as used herein, refers to humans as well as
non-human animals, at any stage of development, including, for example, mammals, birds,
reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are
considered to be pluralities of animals. In certain exemplary embodiments, the non-human
animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep,
cattle, a primate, or a pig). An animal may be a transgenic animal or a human clone. If desired,
the biological sample may be subjected to preliminary processing, including preliminary
separation techniques.
Detailed Descritpion of Certain preferred Embodiments of the Invention
The present invention provides compounds that modulate interactions between intracellular
adhesion molecules (e.g., ICAM-1, -2 and -3) and the leukocyte integrin family of receptors. In
certain embodiments, the inventive compounds are antagonists and are useful for the treatment of
CD11/CD18 mediated disorders. In certain embodiments of special interest, the inventive
compounds are useful for the treatment of Mac-1 and LFA-1 mediated disorders. In still other
embodiments, the compounds are useful for the treatment of LFA-1 mediated disorders, for
example, inflammatory disorders and autoimmune disorders to name a few.
1) General Description of Compounds of the Invention
The compounds of the invention include compounds of the general formula (I) as further defined
below:

and pharmaceutically acceptable derivatives thereof;
wherein R1 and R2 are each independently hydrogen, an amino acid side chain, an
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, or
wherein R1 and R2 taken together are an alicyclic or heterocyclic moiety, or together are
wherein RIA is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic,
aromatic or heteroaromatic moiety;
R3 is -C(=O)OR3A, -C(=O)H, -CH2OR3A, -CH2O-C(=O)-alkyl, -C(=O)NH(R3A) or -
CH2X0; wherein each occurrence of R3A is independently hydrogen, a protecting group,
an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety,
or R3A, taken together with R1 or R2, forms a heterocyclic moiety; wherein X is a
halogen selected from F, Cl, Br or I;
R4, for each occurrence, is independently hydrogen, halogen, -CN, -NO2, an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, or is -GRGI
wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
n is an integer from 0-3;
AR1 is an aromatic, heteroaromatic, alicyclic or heterocyclic moiety;
A, B, D and E are connected by either a single or double bond, as valency permits;
wherein each occurrence of A, B, D and E is independently C=O, CRiRii, NRi, CRi, N, O,
S, S(=O) or SO2; wherein each occurrence of R' is independently hydrogen, halogen, -
CN, -NO2, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety, or is -GRG1 wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -
C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are
independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety, or any two adjacent occurrences of R', taken together, represent
an alicyclic, heterocyclic, aromatic or heteroaromatic moiety;
p is an integer from 0-4; and
L is absent or is V-W-X-Y-Z, wherein each occurrence of V, W, X, Y and Z is
independently absent, C=O, NRL1, -O-, -C(RL1)=, =C(RL1)-, -C(RL1)(RL2), C(=N-O-RL1),
C(=N-RL1), -N=, S(O)0-2; a substituted or unsubstituted C1-6alkylidene or C2_
6alkenylidene chain wherein up to two non-adjacent methylene units are independently
optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NRL3-, -OC(=O)-, -
OC(=O)NRL3-, -NRL3NR14-, -NRL3NRL4C(=O)-, -NRuC(=O)-, -NRL3CO2-, -
NRL3C(=O)NRL4-, -S(=O)-, -SO2-, -NRL3SO2-, -SO2NRL3-, -NRL3SO2NRL4-, -O-, -S-, or
-NRL3-; wherein each occurrence of RL3 and RL4 is independently hydrogen, alkyl,
heteroalkyl, aromatic, heteroaromatic or acyl; or an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety; and each occurrence of RLI and RL2 is
independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio,
protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy,
azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido,
benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or
heteroaromatic moiety, or wherein one or more occurrences of RL1 and RL2, taken
together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic
moiety or form an aromatic or heteroaromatic moiety.
In another aspect, the invention provides compounds of formula (II):

wherein AR has one of the following structures:

and pharmaceutically acceptable derivatives thereof;
wherein R1, R2, R3, R4, A, B, D, E, n, p are as defined generally above and in classes and
subclasses herein; and
Y1, Y2 and Y3 are each independently CR4 or N;
with the proviso that, when AR has the structure:
wherein Y1 is CH or N and p is 0-2,
then R4 is not carbocycle, aryl, heteroaryl or heterocyle, and A, B, D and E do not
comprise a carbocyclic, aryl, heteroaryl or heterocyclic moiety.
In certain embodiments, for compounds of formula (II), AR represents a moiety having one of
the following structures:


wherein each occurrence of n is an integer from 0-6; each occurrence of R4 is
independently hydrogen, halogen, CN, isocyanate, NO2, -P(=O)(YRP5)2, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic moiety, or is -GRG1 wherein G is -O-, -S-, -NRG2-, -
CO-, -SO-, -SO2-, -C(=O)0-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and
RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic
moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is
independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be
hydrogen; and each occurrence of R4A is independently hydrogen, an alkyl, cycloalkyl,
heteroalkyl, heterocyclic moiety or a nitrogen protecting group; wherein any two adjacent
occurrences of R4 and R4A, taken together, may form a cycloalkyl, heterocyclic, aryl or
heteroaryl moiety. In certain exemplary embodiments, AR has the structure:
In yet other exemplary embodiments, AR has the structure: wherein
each occurrence of X0 is independently a halogen selected from F, Cl, Br and I. In certain
embodiments, each occurrence of X° is Cl.
A number of important subclasses of each of the foregoing classes deserve separate mention;
these subclasses include subclasses of the foregoing classes in which:
i) R1 and R2 are each independently hydrogen, an amino acid side chain. -(CH2)mOH, -
(CH2)maryl, -(CH2)mheteroaryl, wherein m is 0-6, -CH(R1A)(OR1B), -CH(R1A)(NHR1B), U-T-Q,
or an alkyl, cycloalkyl, heteroalkyl or heterocyclic moiety optionally substituted with U-T-Q,
wherein U is absent, -O-, -S(O)0-2-, -SO2N(R1A), -N(R1A)-, -N(R1A)C(=O)-, -N(R1A)C(=O)-O-, -
N(R1A)C(=O)-N(R1B)-, -N(RIA)-SO2-, -C(=O)-, -C(=O)-O-, -O-C(=O)-, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, -C(=O)-N(R1A)-, -O-C(=O)-N(R1A)-, -C(=N-R1E)-, -C(=N-R1K)-O-, -
C(=N-R1E)-N(R1A)-, -O-C(=N-R1E)-N(R1A)-, -N(R1A)C(=N-R1E), -N(R1A)C(=N-R1B)-O-,
N(R1A)C(=N-R1F)-N(R1B)-, -P(=O)(OR1A)-O-, or-P(=O)(R1A)-O-; wherein T is absent, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, beteroalkylaryl
or heteroalkylheteroaryl moiety, and wherein Q is hydrogen, halogen, cyano, isocyanate, -OR1B,
-SR1B; -N(R1B)2) -NHC(=O)OR1B, -NHC(=O)N(R1B)2, -NHC(=O)R1B, -NHSO2R1B, -
NHSO2N(R1B)2, -NHSO2NHC(=O)OR1B, -NHC(=O)NHSO2R1B, -C(=O)NHC(=O)OR1B, -
C(=O)NHC(=O)R1B, -C(=O)NHC(=O)N(R1B)2, -C(=O)NHSO2R1B, -C(=O)NHSO2N(R1B)2, -
(=S)N(R1B)2, -SO2R1B, -SO2-O-R1B, -SO2-N(R1B)2, -SO2-NHC(=O)OR1B, -SO2-NHC(=O)-
N(R1B)2, -SO2-NHC(=O)R1B, -O-C(=O)N(RIB)2, -O-C(=O) R1B, -O-C(=O)NHC(=O)R1B, -O-
C(=O)NH-SO2R1B, -O-SO2R1B, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or wherein R1 and R2 taken together are a cycloalkyl or heterocyclic moiety,
or together are r1a; wherein each occurrence of RIA and R is independently hydrogen, an
alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, -COR10, or-CONR1CR1D;
wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety; and R1E is hydrogen, an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, -CN,
-OR1C, -NR1CR1D or -SO2RIC;
ii) R3 is carboxyl, protected carboxyl or a prodrug thereof, wherein R3 is C(=O)R3A, wherein R3A
is hydroxy, alkoxy, cycloalkoxy, aralkoxy, arcycloalkoxy, aryloxy, alkylcarbonyloxyalkyloxy,
alkoxycarbonyloxyalkyloxy, alkoxycarbonylalkyloxy, cycloalkylcarbonyloxyalkyloxy,
cycloalkoxycarbonyloxyalkyloxy, cycloalkoxycarbonylalkyloxy, arylcarbonyloxyalkyloxy,
aryloxycarbonyloxyalkyloxy, arylcarbonyloxyalkyloxy, alkoxyalkylcarbonyloxyalkyloxy, or one
or the structures:

iii) R3 is -C(=O)OR3A, -C(=O)H, -CH2OR3A, -CH2O-C(=O)-alkyl, -C(=O)NH(R3A), or -CH2X();
wherein each occurrence of R3A is independently hydrogen, a protecting group, an alkyl,
ycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R3A,
taken together with R or R , forms a heterocyclic moiety; wherein X° is a halogen selected from
F, Cl, Br or I;
iv) R3 is -C(=O)OR3A; wherein R3A is hydrogen, a protecting group, an alkyl, cycloalkyl,
heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R3A, taken
together with R1 or R2, forms a heterocyclic moiety;
v) R3 is -C(=O)OR3A; wherein R3A is C1-5alkyl;
vi) R3 is -C(=O)OR3A; wherein R3A is C1-3alkyl;
vii) R3 is -C(=O)OR3A; wherein R3A is ethyl;
viii) R3 is -C(=O)OR3A; wherein R3A is benzyl;
ix) R3 is CO2H;
x) R3 is -C(=O)OR3A, wherein R3A is as defined in any one of subsets ii)-ix) above, and -
C(=O)NHC(R1)(R2)R3 is a moiety having the following structure:

wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and Rs is hydrogen,
alkyl, heteroalkyl, aryl, heteroaryl, or is -G0RG1 wherein G0 is -O-, -S- or -NRG2-, and
RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety;
xi) Compounds of subset x) above wherein -C(=O)NHCH(CO2R3A)CH(RS)Ar2 has the following
stereochemistry:

xii) R3 is -C(=O)OR3A, wherein R3A is as defined in any one of subsets ii)-ix) above, and -
C(=O)NHC(R1)(R2)R3 is a moiety having the following structure:

wherein R1A is Ar2, -OR1B, -SR1B or -NR1BR1C; or an alkyl or heteroalkyl moiety; and
Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; wherein R1B and R1C are
independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or
R1B and R1C, taken together with the nitrogen atom to which they are attached, form a
heterocylic or heteroaryl moiety;
xiii) Compounds of subset xii) above wherein -C(=O)NHCH(CO2R3A)CH2NHC(=O)R1A has the
following stereochemistry:
xiv) R3 is -C(=O)OR3A, wherein R3A is as defined in any one of subsets ii)-ix) above, and -
C(=O)NHC(R')(R2)R3 is a moiety having the following structure:

wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R2A is hydrogen,
C1-6alkyl, C2-6alkenyl, -C(=O)R2B or -SO2R2B, wherein R2B is alkyl, cycloalkyl,
heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with a substituent on
Ar2, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety;
xv) Compounds of subset xiv) above wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)Ar2 has the
following stereochemistry:

xvi) R3 is -C(=O)OR3A, wherein R3A is as defined in any one of subsets ii)-ix) above, and -
C(=O)NHC(R1)(R2)R3 is a moiety having the following structure:

wherein R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, -C(=O)R2B or -SO2R2B,
wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A,
taken together with R2C or R2D, forms a substituted or unsubstituted heterocyclic or
heteroaryl moiety; R2C is hydrogen, CN, -C=NMe, =NO2, =NC(=O)NH2, =NS(O)2R,
=NS(O)2NRR, -SO2R2G, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,
heteroaryl, alkylaryl or alkylheteroaryl moiety; wherein R and R' are each independently
hydrogen or methyl, and R2G is lower alkyl; and R2D is Ar2, hydrogen, halogen, CN, NO2,
an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G
is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl
moiety;
xvii) Compounds of subset xvi) above wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D
has the following stereochemistry:

xviii) Compounds of subset xvii) above wherein -
C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D has the following structure:

wherein R2E and R2F are each independently hydrogen, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or
R2E and R2F , taken together, form a substituted or unsusbtituted heterocyclic or
heteroaryl moiety;
xix) Compounds of subset xvii) above wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D
has the following structure:

wherein R2C is hydrogen, CN, -C=NMe, =NO2, =NC(=O)NH2, =NS(O)2R, or
=NS(O)2NRR'; wherein R and R' are each independently hydrogen or methyl;
xx) Compounds of subset xvii) above wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D
has the following structure:

wherein R2C is hydrogen, CN, -C=NMe, =NO2, =NC(=O)NH2, =NS(O)2R, or
=NS(O)2NRR'; wherein R and R' are each independently hydrogen or methyl;
xxi) Compounds of subset xvii) above wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D
has the following structure:

xxii) Compounds of subset xvii) above wherein -
C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D has the following structure:

xxiii) Compounds of subsets xvii) and xviii) above wherein -
C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D has the following structure:

or bioisosteres thereof;
wherein R2A, R2D, R2E and R2F are as defined in xvi) and xviii) above;
xxiv) Compounds of subset xxiii) above wherein the bioiosteres have one of the following
structures:

wherein R2C is lower alkyl;
xxv) Compounds of subset xxiii) above wherein R2D is, or R2E and R2F together with the nitrogen
atom to which they are attached form, a moiety having one of the structures:

wherein s is an integer between 0 and 6; each occurrence of RP1 is independently
hydrogen, halogen, CN, isocyanate, NO2, -P(=O)(YRP5)2, an alkyl, cycloalkyl,
heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -
GRGI wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -
OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an
alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl
moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is
independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP3 may also be
hydrogen; and each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl,
or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent
occurrences of Rp and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or
heteroaryl moiety;
xxvi) Compounds of subset xxv) above wherein R2D is, or R2E and R2F together with the nitrogen
atom to which they are attached form, a moiety having one of the structures:

wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, -OCH3, -
OH, -NH2, -NHCH3, or-N(CH3)2;
xxvii) Compounds of subset xxvi) above wherein R2D is, or R2E and R2F together with the
nitrogen atom to which they are attached form, a moiety having one of the structures:

xxviii) R3 is -C(=O)OR3A, wherein R3A is as defined in any one of subsets ii)-ix) above, and -
C(=O)NHC(R1)(R2)R3 is a moiety having the following structure:

wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety;
xxix) Compounds of subsets x)-xii), xiv)-xv) and xxviii); and compounds of subset xvi) wherein
R2D is Ar2; wherein Ar2 is one of the following structures:

wherein each occurrence of s is an integer from 0-6; w is an integer from 1-6; X1 is
CHRP1 or NRP2; X2 and X3 are independently CHRP1, NRP2, CHSO2RP3 or NSO2RP3;
each occurrence of RPI is independently hydrogen, halogen, CN, isocyanate, NO2, -
P(=O)(YRP5)2, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -
(aliphatic)aryl or -(aliphatic)heteroaryl moiety, or is -GRG1 wherein G is -O-, -S-, -
NR02-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -
SO2NR -, and R and R are independently hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, -(aliphatic)aryl or -(aliphatic)heteroaryl
moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is
independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be
hydrogen; and each occurrence of R is independently hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkyl aryl,
or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent
occurrences of RP1 and RP2 , taken together, may form a cycloalkyl, heterocyclic, aryl or
heteroaryl moiety; and each occurrence of RP3 is independently alkyl, aryl, heteroaryl or
N(RP2)2.
.xx) Compounds of subset xxix) above wherein Ar2 is one of the following structures:

wherein s, X1, X2 and X are as defined in xx) above; X5 is O, S or NRP2; each
occurrence of RPI is independently hydrogen, halogen, CN, isocyanate, NO2, -
P(=O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl
or alkylheteroaryl moiety, or is -GRG1 wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-,
-C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are
independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,
alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O;
each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y
is O RP5 may also be hydrogen; each occurrence of RP2 is independently hydrogen, an
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl,
alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting
group; wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a
cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and each occurrence of R is
independently alkyl, aryl, heteroaryl or-N(RP2)2;
xxxi) Compounds of subset xxx) above wherein each occurrence of RP1 is independently
hydrogen, halogen, -P(=O)(YRP5)2, lower alkyl or heteroalkyl moiety, or is -GRGI wherein G is
-O-, -S-, -NRG2- or -SO2-, and RGI and RG2 are independently hydrogen, lower alkyl or aryl; each
occurrence of Y is independently a bond or O; each occurrence of RP5 is independently lower
alkyl, or when Y is O RP5 may also be hydrogen; and each occurrence of RP2 is independently
hydrogen, lower alkyl or a nitrogen protecting group; wherein any two adjacent occurrences of
RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety;
xxxii) Compounds of subset xxx) above wherein Ar2 has one of the following structures:

wherein X1 is N or CRPI; s is an integer from 0-6; each occurrence of RP1 is
independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl,
heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRGI wherein G
is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;
and RP3 is independently lower alkyl or aryl;
xxxiii) Compounds of subsets xxix), xxx) and xxxii) wherein s is 0;
xxxiv) Compounds of subsets xxix), xxx) and xxxii) wherein s is 1;
xxxv) Compounds of subsets xxix), xxx) and xxxii) wherein s is 2;
xxxvi) Compounds of subsets x) and xi) above wherein Ar2 is one of the following structures:


wherein s is an integer from 0-2; each occurrence of RPI is independently hydrogen,
halogen, CN, isocyanate, NO2, -ORG1, -S RGI, -NRGIR02-, an alkyl, cycloalkyl,
heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each
occurrence of Y is independently a bond or O; each occurrence of RP5 is independently
lower alkyl, or when Y is O RP5 may also be hydrogen; each occurrence of RP2 is
independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen
protecting group; R is lower alkyl or -N(RP2)2; and RG1 and RG2 are independently
hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or
alkylheteroaryl moiety;
xxxvii) Compounds of subsets x) and xi) above wherein Ar2 is one of the following structures:

xxxviii) Compounds of subsets x) and xi) above wherein Ar2 is one of the following structures:

wherein Rp3 is lower alkyl; and RP2 and RG1 are independently hydrogen or lower alkyl;
xxxix) Compounds of subsets x) and xi) above wherein Ar2 is one of the following structures:

wherein RP3 is lower alkyl and RG1 is hydrogen or lower alkyl;
xl) Compounds of subsets x) and xi) above wherein Rs is hydrogen, hydroxyl or lower alkoxy
and Ar2 is one of the following structures:

wherein RP3 is lower alkyl; and RG1 is hydrogen or lower alkyl;
xli) Compounds of subsets xii) and xiii) wherein R1A is alkyl or -NR1BR1C; wherein R1B and R1C
are independently hydrogen or lower alkyl;
xlii) Compounds of subsets xii) and xiii) wherein R1A is -NH2 or a moiety having the structure:

wherein RP1 is independently hydrogen, hydroxyl, lower alkyl or lower heteroalkyl; and
each occurrence of RP2 is independently hydrogen or lower alkyl;
xliii) Compounds of subsets xii) and xiii) wherein RIA is -NH2 or a moiety having the structure:

wherein RP1 is hydrogen or lower alkyl;
xliv) Compounds of subsets xii) and xiii) wherein R1A is cycloalkyl, aryl, or a moiety having one
of the structures:

wherein s is an integer between 0 and 6; each occurrence of R is independently
hydrogen, halogen, CN, isocyanate, NO2, -P(=O)(YRP5)2, an alkyl, cycloalkyl,
heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -
GRG1 wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -
OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RGI and RG2are independently hydrogen, an
alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl
moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is
independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be
hydrogen; and each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl,
or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent
occurrences of RP1 and Rp2, taken together, may form a cycloalkyl, heterocyclic, aryl or
heteroaryl moiety;
xlv) Compounds of subset xliv) wherein s is an integer between 0 and 2; each occurrence of RPI
is independently lower alkyl or is -GR wherein G is -O- or -NR -, and R and R are
independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,
alkylaryl or alkylheteroaryl moiety; and each occurrence of RP2 is independently hydrogen, lower
ilkyl, aryl or heteroaryl;
xlvi) Compounds of subsets xxi) and xxii) wherein RIA is a moiety having one of the structures:

wherein s is an integer between 0 and 2; X is halogen; each occurrence of R is
independently hydrogen, hydroxyl, lower alkyl or lower heteroalkyl; G is -O- or -NR -,
and RGI and RG2 are independently hydrogen or lower alkyl; and RP2 is independently
hydrogen or lower alkyl;
xlvii) Compounds of subset xlvi) wherein RIA is a moiety having one of the structures:

wherein G is -O- or -NR -, and R and R are independently hydrogen or lower alkyl;
xlviii) R3 is -C(=O)OR3A, wherein R3A is as defined in any one of subsets ii)-ix) above, and -
C(=O)NHC(R1)(R2)R3 is a moiety having the following structure:

wherein RP3 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety;
xlix) compounds of subsets xiv)-xv) above wherein -NH(R2A)Ar2 has one of the following
structures:

wherein X1 is N or CRP1; s is an integer from 0-5; and each occurrence of RP1 is
independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl,
heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR ' wherein G
is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NR02C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;
and Rp3 is alkyl, heteroalkyl, aryl or heteroaryl;
1) compounds of subset xlix) above wherein s is 0;
li) compounds of subset xlix) above wherein RP1 is hydrogen, halogen or lower alkyl;
lii) compounds of subset li) above wherein RPI is hydrogen, chloro or methyl;
liii) compounds of subset xlix)above wherein RP3 is lower alkyl;
liv) compounds of subset liii) above wherein RP3 is methyl;
lv) compounds of subset xlix) above wherein -NH(R2A)Ar2 has the following structure:

wherein RPI is hydrogen, halogen or lower alkyl;
lvi) compounds of subset xlix) above wherein -NH(R2A)Ar2 has the following structure:

lvii) Compounds of subsets xvii) having the following structure:

or bioisosteres thereof;
wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, -OCH3, -
OH, -NH2, -NHCH3 or -N(CH3)2; R2A is hydrogen, C2-6alkyl, C2-6alkenyl, aryl,
heteroaryl, -C(=O)R2B or -SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl,
heterocyclyl, aryl or heteroaryl; and q is 1 or 2;
lviii) Compounds of subset lvii) above wherein the bioisosteres have one of the following
structures:

wherein q is 1 or 2; and R2C is lower alkyl;
lix) Compounds of subset xxviii) wherein -C(=O)NHC(=CHAr2)CO2R3A has one of the
following structures:

wherein RP3 is lower alkyl or aryl; X1 and X2 are independently M or CRP1; X3 is O, S or
NRP2; wherein RP1 is hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl,
heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G
is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NRG2C(=O)- or -SO2NRG2-, and RGI and RG2 are independently hydrogen, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;
and Rp2 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety;
lx) Compounds of subset xxviii) wherein -C(=O)NHC(=CHAr2)CO2R3A has the following
structure:

wherein X1 is N or CH;
lxi) R is -C(=O)OR3A, wherein R3A is as defined in any one of subsets ii)-ix) above, and -
C(=O)NHC(R1)(R2)R3 has the structure -C(=O)NHC(=C(Rs)Ar2)CO2R3A wherein R3Aand Rs,
taken together, form a substituted or unsubstituted heterocyclic moiety;
lxii) Compounds of subset lxi) wherein -C(=O)NHC(=C(Rs)Ar2)CO2R3A has one of the
following structures:

wherein Ar2 is as defined in classes and subclasses herein; and X1 is O, S or NH;
lxiii) Compounds of subset lxi) wherein -C(=O)NHC(=C(Rs)Ar2)CO2R3A has one of the
following structures:

wherein X1 is O, S or NH; and X2 is N or CH;
lxiv) L is absent, -C(=O), -CH2C(=O)NH-, -CH2NH-C(=O)-, -O-CH2-C(=O)-, -CH2-CH2-
C(=O)-, -CH=CH-C(=O)NH-CH2-, -CH(OH)-CH2-O-, -CH(OH)-CH2-N(CH3)-, CH(OH)-CH2-
CH2-, -CH2-CH2-CH(OH)-, -O-CH2-CH(OH)-, -O-CH2-CH(OH)-CH2-, -O-CH2-CH2-CH(OH)-,
O-CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH(OH)-CH2-O, -CH2-CH2-O-, -CH-(CH3)-NH-
C(=O)-, -CH2-NH-SO2-, -NH-SO2-CH2-, -CH2-SO2-NH-, -SO2NH-CH2-, -C(=O)-NH-C(=O)-, -
NH-C(=O)-NH-, -NH-C(=O)-NH-CH2-, -CH2-NH-C(=O)-NH-, -C(=O)-NH-CH2-C(=O)-NH, -
NH-C(=O)-O-, -O-C(=O)-NH-; or a substituted or unsubstituted Ci.6alkylidene or C2.
6alkenylidene chain wherein up to two non-adjacent methylene units are independently
optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR'3-, -0C(=O)-, -OC(=O)NRL3-
, -NRL3NRL4-, -NRL3NRL4C(=O)-, -NRL3C(=O)-, -NRL3CO2-, -NRL3C(=O)NRU-, -S(=O)-, -SO2-
, -NRL3SO2-, -SO2NRL3-, -NRL3SO2NRL4-> -O-, -S-, or -NRL3-; wherein each occurrence of RL3
and RL4 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl;
lxv) L is absent, -C(=O), or a substituted or unsubstituted C1-6alkylidene or C2-6alkenylidene
chain wherein up to two non-adjacent methylene units are independently optionally replaced by -
C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NRL3-, -OC(=O)-, -OC(=O)NRL3-, -NRL3NRL4-, -
NR13NRL4C(=O)-, -NRL3C(=O)-, -NR13CO2-, -NRL3C(=O)NRL4-, -S(=O)-, -SO2-, -NRL3SO2-, -
SO2NRL3-, -NRL3SO2NRL4-, -O-, -S-, or -NRL3-; wherein each occurrence of RL3 and RL4 is
independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl;
lxvi) L is absent;
Ixvii) L is-C(=O);
lxviii) L is absent, -C(=O), -CH2C(=O)NH-, -CH2NH-C(=O)-, -O-CH2-C(=O)-, -CH2-CH2-
C(=O)-, -CH=CH-C(=O)NH-CH2-, -CH(OH)-CH2-O-, -CH(OH)-CH2-N(CH3)-, CH(OH)-CH2-
CH2-, -CH2-CH2-CH(OH)-, -O-CH2-CH(OH)-, -O-CH2-CH(OH)-CH2-, -O-CH2-CH2-CH(OH)-,
- 3-CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH(OH)-CH2-O, -CH2-CH2-O-, -CH-(CH3)-NH-
C(=O)-, -CH2-NH-SO2-, -NH-SO2-CH2-, -CH2-SO2-NH-, -SO2NH-CH2-, -C(=O)-NH-C(=O)-, -
NH-C(=O)-NH-, -NH-C(=O)-NH-CH2-, -CH2-NH-C(=O)-NH-, -C(=O)-NH-CH2-C(=O)-NH, -
NH-C(=O)-O-, or -O-C(=O)-NH-;
lxix) L is -(CH2)q- wherein q is 1-5;
lxx)L is -CH2-;
lxxi) L is -(CH2)3-;
wherein each occurrence of r is an integer from 0-6; X1, X2, X3 and X4 are each
independently N or CRQl; AR3 is a heterocyclic, aryl or heteroaryl moiety; each
occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN,
isocyanate, NO2, CF3, NRQ3QRQ4, -SO2RQ3 alkyl-NRQ3RQ4, alkyl-C(=O)-NRQ3RQ4, alkyl-
C(=O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each
occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic,
heteroaliphatic, aryl or heteroaryl moiety; and RQ2 is hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl,
or heteroalkylheteroaryl moiety or a nitrogen protecting group;
lxxiv) AR1 is one of the following structures:


wherein each occurrence of r is an integer from 0-6; X1, X2, X3 and X4 is independently
N or CRQ1; X5 is O, S or NRQ2; AR3 is a heterocyclic, aryl or heteroaryl moiety; each
occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN,
isocyanate, NO2, CF3, NRQ3QRQ4, -SO2RQ3, alkyl-NRQ3RQ4, alkyl-C(=O)-NRQ3RQ4, alkyl-
C(=O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each
occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic,
heteroaliphatic, aryl or heteroaryl moiety; and RQ2 is hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl,
or heteroalkylheteroaryl moiety or a nitrogen protecting group;
lxxv) AR1 is one of the following structures:

wherein r is as defined above; X1, X2, X3 and X4 is independently N or CH; X5 is CHRQ1
or NH; each occurrence of RQ1 is independently hydrogen, ORQ3 , OCF3, SRQ3, halogen,
CN, isocyanate, NO2, CF3, NRQ3QRQ4, -SO2RQ3 alkyl-NRQ3RQ4, alkyl-C(=O)-NRQ3RQ4
alkyl-C(=O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each
occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic,
heteroaliphatic, aryl or heteroaryl moiety; and RQ2 is hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl,
or heteroalkylheteroaryl moiety or a nitrogen protecting group;
lxxvi) AR is one of the following structures:


lxxxi) R4, for each occurrence, is independently hydrogen, halogen, -CN, -NO2, an alkyl,
alkylenyl; alkynyl; cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or
alkylheteroaryl moiety, or is -GRGI wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-
, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently
hydrogen, an alkyl, alkylenyl; alkynyl; cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,
alkylaryl or alkylheteroaryl moiety;
lxxxii) R4, for each occurrence, is independently hydrogen, halogen, or lower alkyl;
lxxxiii) R4, for each occurrence, is independently hydrogen or chloro;
lxxxiv) n is 0;
lxxxv) n is 2;
lxxxvi) n is 2 and each occurrence of R4 is a halogen;
lxxxvii) n is 2 and each occurrence of R4 is Cl;
lxxxviii) p is 1;
lxxxix) p is 2; and/or
xc) Compounds of formula (II) wherein when -C(=O)NHC(R')(R2)R3 has the structure:

wherein Y1 is N or CRQ1; X1, X2, X3 and X4 are independently CRQ1; X5 is NRQ1, O or S;
r is 0-3; and each occurrence of RQ1 is independently CN, NO2, halogen, CF3, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety
or is GRG1 wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -C0-6alkylSO2-, -C0_
6alkylSO2NRG2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)- or -NRG2C(=O)-, and RG1 and RG2
are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,
heteroaryl, alkylaryl or alkylheteroaryl moiety.
It will be appreciated that for each of the classes and subclasses described above and herein, any
one or more occurrences of aliphatic or heteroaliphatic may independently be substituted or
unsubstituted, cyclic or acyclic, linear or branched and any one or more occurrences of aryl,
heteroaryl, cycloaliphatic, cycloheteroaliphatic may be substituted or unsubstituted.
The reader will also appreciate that all possible combinations of the variables described in i)-
through xc) above (e.g., R1, R2 , R3, R4, L, and AR1, among others) are considered part of the
invention. Thus, the invention encompasses any and all compounds of formula I or II generated
by taking any possible permutation of variables R1, R2, R3, R4, L, AR1, etc. and other
variables/substituents (e.g., X1, X2, X3, X4, R1A, R2A, R2C, R2D, etc.) as further defined for R1, R2,
R3, R4, L, AR1, etc. described in i)- through xc) above.
For example, an exemplary combination of variables described in i)- through xc) above includes
those compounds of Formula I wherein:
R1 and R2 are each independently hydrogen, an amino acid side chain, -(CH2)mOH, -
(CH2)maryl, -(CH2)mheteroaryl, wherein m is 0-6, -CH(RIA)(OR1B), -CH(R1A)(NHR1B),
U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally
substituted with U-T-Q, wherein U is absent, -O-, -S(O)0-2-, -SO2N(R1A), -N(R1A)-, -
N(R1A)C(=O)-, -N(R1A)C(=O)-O-, -N(R1A)C(=O)-N(R1B)-, -N(R1A)-SO2-, -C(=O)-, -
C(=O)-O-, -O-C(=O)-, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -C(=O)-N(R1A)-, -O-
C(=O)-N(R1A)-, -C(=N-R1E), -C(=N-R1E)-O-, -C(=N-R1E)-N(R1A)-, -O-C(=N-R1E)-
N(R1A)-, -N(R1A)C(=N-R1E), -N(R1A)C(=N-R1E)-O-, N(RIA)C(=N-R1E)-N(R1B)-, -
P(=O)(ORIA)-O-, or -P(=O)(R1A)-O-; T is absent, an aliphatic, heteroaliphatic, aryl,
heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is hydrogen, halogen, cyano,
isocyanate, -ORIB, -SR1B; -N(R1B)2, -NHC(=O)OR1B, -NHC(=O)N(R1B)2, -NHC(=O)R1B,
-NHSO2R1B, -NHSO2N(R1B)2, -NHSO2NHC(=O)OR1B, -NHC(=O)NHSO2R1B, -
C(=O)NHC(=O)OR1B, -C(=O)NHC(=O)R1B, -C(=O)NHC(=O)N(R1B)2,
C(=O)NHSO2R1B, -C(=O)NHSO2N(R1B)2, -C(=S)N(R1B)2, -SO2R1B, -SO2-O-R1B, -SO2-
N(R1B)2, -SO2-NHC(=O)OR1B, -SO2-NHC(=O)-N(R1B)2, -SO2-NHC(=O)R1B, -O-
C(=O)N(R1B)2, -O-C(=O) R1B, -O-C(=O)NHC(=O)R1B, -O-C(=O)NH-SO2R1B, -O-
SO2R , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R1 and R2
taken together are an alicyclic or heterocyclic moiety, or together are wherein
each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, -
COR1C, or -CONR1CR1D; wherein each occurrence of RIC and R1D is independently
hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or
alkylheteroaryl moiety; and RIE is hydrogen, an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, -CN, -OR1C, -NR1CRID
or -SO2RIC;
R3 is -C(=O)OR3A, -C(=O)H, -CH2OR3A, -CH20-C(=O)-alkyl, -C(= G)NH(R3A), -
CH2X°; wherein each occurrence of R3A is independently hydrogen, a protecting group,
an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl,
alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, or R3A, taken together
with R or R2, forms a heterocyclic moiety; wherein X° is a halogen selected from F, CI,
Br or I;
R4, for each occurrence, is independently hydrogen, halogen, -CN, -NO2, an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl
moiety, or is -GRGI wherein G is -O-, -S-, -NR02-, -CO-, -SO-, -SO2-, -C(=O)O-, -
C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1 and R02 are
independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,
heteroaryl, alkylaryl or alkylheteroaryl moiety;
AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or
heterocyclic moiety;
A, B, D and E are connected by either a single or double bond, as valency permits;
wherein each occurrence of A, B, D and E is independently C=O, CRR", NR1, CR1, N, O,
S, S(=O) or SO2; wherein each occurrence of R1 is independently hydrogen, halogen, -
CN, -NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl,
alkylaryl or alkylheteroaryl moiety, or is -GRGI wherein G is -O-, -S-, -NRG2-, -CO-, -
SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1
and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent
occurrences of R1, taken together, represent an alicyclic, heteroalicyclic, aryl, or
heteroaryl moiety; and
L is absent or is V-W-X-Y-Z, wherein each occurrence of V, W, X, Y and Z is
independently absent, C=O, NRL1, -O-, -C(RL1)=, =C(RLI)-, -C(RLI)(RL2), C(=N-O-RL1),
C(=N-RLI), -N=, S(O)0-2; a substituted or unsubstituted Ci^alkylidene or C2.
6alkenylidene chain wherein up to two non-adjacent methylene units are independently
optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NRL3-, -OC(=O)-, -
OC(=O)NRL3-, -NRL3NRL4-, -NRL3NRL4C(=O)-, -NRL3C(=O)-, -NRL3CO2-, -
NRL3C(=O)NRL4-, -S(=O)-, -SO2-, -NRL3SO2-, -SO2NRL3-, -NR13SO2NRL4-, -O-, -S-, or
-NR1'3-; wherein each occurrence of RL3 and RL4 is independently hydrogen, alkyl,
heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence
of RL1 and RL2 is independently hydrogen, hydroxyl, protected hydroxyl, amino,
protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl,
formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy,
mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or
more occurrences of RL1 and RL2, taken together, or taken together with one of V, W, X,
Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety.
Other exemplary combinations are illustrated by compounds of the following subgroups I
through XIV:
I) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):
wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RB1,
RB2 and RE are independently hydrogen or substituted or unsubstituted lower alkyl. In certain
embodiments, R4A and R4B are each Cl. In yet other embodiments, one of RB1 and RB2 is
hydrogen, the other is substituted or unsubstituted lower alkyl. In certain exemplary
embodiments, RB1 and RB2 are each hydrogen. In certain other exemplary embodiments, RB1 and
RB2 are each lower alkyl. In certain exemplary embodiments, RB1 and RB2 are each methyl. In
other embodiments, R is hydrogen. In yet other embodiments, R is substituted or unsubstituted
lower alkyl. In yet other embodiments, RE is substituted or unsubstituted methyl, ethyl, propyl,
i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl or n-hexyl. In certain
embodiments, R4A and R4B are each Cl; and RBl and RB2 are each hydrogen.
II) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):
wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and Rn is
hydrogen or substituted or unsubstituted lower alkyl. In certain embodiments, R A and R are
each Cl. In other embodiments, RE is hydrogen. In yet other embodiments, RE is substituted or
unsubstituted lower alkyl. In yet other embodiments, RE is substituted or unsubstituted methyl,
ethyl, propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl or n-hexyl.
III) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):

wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RE is
hydrogen or substituted or unsubstituted lower alkyl. In certain embodiments, R4A and R4B are
each Cl. In other embodiments, RE is hydrogen. In yet other embodiments, RE is substituted or
unsubstituted lower alkyl. In yet other embodiments, RE is substituted or unsubstituted methyl,
ethyl, propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl or n-hexyl.
IV) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):

wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RE is
hydrogen or substituted or unsubstituted lower alkyl. In certain embodiments, R A and R are
each Cl. In other embodiments, RE is hydrogen. In yet other embodiments, RE is substituted or
unsubstituted lower alkyl. In yet other embodiments, RE is substituted or unsubstituted methyl,
ethyl, propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl or n-hexyl.
V) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):

wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; RA is
hydrogen, lower alkyl or acyl; and RE is hydrogen or substituted or unsubstituted lower alkyl. In
certain embodiments, R4A and R4B are each Cl. In other embodiments, RE is hydrogen. In yet
other embodiments, RE is substituted or unsubstituted lower alkyl. In yet other embodiments, R1:
is substituted or unsubstituted methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-
pentyl, sec-pentyl, tert-pentyl or n-hexyl.
VI) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):
wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; RA1, R^,
RB1,and RB2 are independently hydrogen or substituted or unsubstituted lower alkyl. In certain
embodiments, R4A and R4B are each Cl. In certain embodiments, RA1, RA2, RB1 And RB2are each
hydrogen.
VII) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):
wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RA and
R are independently hydrogen or substituted or unsubstituted lower alkyl. In certain
embodiments, R4A and R4B are each Cl. In certain embodiments, RA and RB are each hydrogen.
VIII) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):

wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RA is
hydrogen or substituted or unsubstituted lower alkyl. In certain embodiments, R4A and R4B are
each Cl. In certain embodiments, RA is hydrogen.
IX) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):
wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RB is
hydrogen or substituted or unsubstituted lower alkyl. In certain embodiments, R4A and R4B are
each CI. In certain embodiments, RB is hydrogen.
X) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):

wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RA is
hydrogen or substituted or unsubstituted lower alkyl. In certain embodiments, R4A and R4B are
each CI. In certain embodiments, RA is hydrogen.
XI) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):

wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; RA, RB and
RE are independently hydrogen or substituted or unsubstituted lower alkyl. In certain
embodiments, R A and R4B are each Cl. In certain embodiments, RA and RB are each hydrogen.
In certain other embodiments, RE is hydrogen. In yet other embodiments, RA, RB and RE are
each hydrogen.
XII) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):
wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; RA, RB and
RE are independently hydrogen or substituted or unsubstituted lower alkyl. In certain
embodiments, R4A and R4B are each CI. In certain embodiments, RA and RB are each hydrogen.
In certain other embodiments, R is hydrogen. In yet other embodiments, RA, RB and RE are
each hydrogen.
XIII) Compounds having the structure (and pharmaceutically acceptable derivatives
thereof):

wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and A and
B are independently N or CH. In certain embodiments, R4A and R4B are each Cl. In certain
embodiments, A is N. In certain embodiments, A is CH. In certain embodiments, B is N. In
certain embodiments, A is CH. In certain embodiments, A and B are each N. . In certain
embodiments, A is CH. In certain embodiments, A and B are each CH.
XIV) Compounds having the structure (and pharmaceuticalLY acceptable derivatives
thereof):

wherein R4A and R4 are independently a halogen selected from F, Cl, Br or I; and A and
B are independently N or CH. In certain embodiments, R4A and R4B are each CI. In certain
embodiments, A is N. In certain embodiments, A is CH. In certain embodiments, B is N. In
certain embodiments, A is CH. In certain embodiments, A and B are each N. In certain
embodiments, A is CH. In certain embodiments, A and B are each CH.
In certain embodiments, for compounds of classes I-XIV above, AR1-L- is a moiety
having one of the following structures:

and -C(=O)NHC(R1)(R2)R3 is a moiety having one of the following structures:

or bioisosteres thereof;
wherein R2A and R3A are as defined in classes and subclasses herein; and R2D is a moiety
having one of the following structures:

wherein s is an integer between 0 and 6; each occurrence of RP1 is independently hydrogen,
halogen, CN, isocyanate, NO2, -P(=O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic,
aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR ' wherein G is -O-, -S-, -NRG2-, -
CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1
and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,
heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or
O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl. or when Y is O
RP5 may also be hydrogen; and each occurrence of Rp2 is independently hydrogen, an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,
heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two
adjacent occurrences of RP1 and Rp2, taken together, may form a cycloalkyl, heterocyclic, aryl or
heteroaryl moiety.
In certain embodiments, R2A and R3A are each hydrogen.
In certain embodiments, R2D is a moiety having one of the structures:

wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, -OCH3, -
OH, -NH2, -NHCH3, or -N(CH3)2.
In certain embodiments, R2D is a moiety having one of the structures:


It will also be appreciated that for each of the subgroups I-XIV described above, a variety of
other subclasses are of special interest, including, but not limited to those classes described
above i)-xc) and classes, subclasses and species of compounds described above and in the
examples herein.
Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can
exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive
compounds and pharmaceutical compositions thereof may be in the form of an individual
enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of
stereoisomers. In certain embodiments, the compounds of the invention are enantiopure
compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are
provided.
Furthermore, certain compounds, as described herein may have one or more double bonds that
can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally
encompasses the compounds as individual isomers substantially free of other isomers and
alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. In
addition to the above-mentioned compounds per se, this invention also encompasses
pharmaceutically acceptable derivatives of these compounds and compositions comprising one
or more compounds of the invention and one or more pharmaceutically acceptable excipients or
additives.
Compounds of the invention may be prepared by crystallization of compound of formula (I) or
(II) under different conditions and may exist as one or a combination of polymorphs of
compound of general formula (I) or (II) forming part of this invention. For example, different
polymorphs may be identified and/or prepared using different solvents, or different mixtures of
solvents for recrystallization; by performing crystallizations at different temperatures; or by
using various modes of cooling, ranging from very fast to very slow cooling during
crystallizations. Polymorphs may also be obtained by heating or melting the compound followed
by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR
spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram
and/or other techniques. Thus, the present invention encompasses inventive compounds, their
derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically
acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable
compositions containing them.
2) Pharmaceutical Compositions
As discussed above this invention provides novel compounds that have biological properties
useful for the treatment of Mac-1 and LFA-1 mediated disorders.
Accordingly, in another aspect of the present invention, pharmaceutical compositions are
provided, which comprise any one of the compounds described herein (or a prodrug,
pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and
optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, these
compositions optionally further comprise one or more additional therapeutic agents.
Alternatively, a compound of this invention may be administered to a patient in need thereof in
combination with the administration of one or more other therapeutic agents. For example,
additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical
composition with a compound of this invention may be an approved anti-inflammatory agent, or
it may be any one of a number of agents undergoing approval in the Food and Drug
Administration that ultimately obtain approval for the treatment of any disorder mediated by
Mac-1 or LFA-1. It will also be appreciated that certain of the compounds of present invention
can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable
derivative thereof.
As described above, the pharmaceutical compositions of the present invention additionally
comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all
solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents,
isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the
like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences,
Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various
carriers used in formulating pharmaceutical compositions and known techniques for the
preparation thereof. Except insofar as any conventional carrier medium is incompatible with the
compounds of the invention, such as by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of the pharmaceutical
composition, its use is contemplated to be within the scope of this invention. Some examples of
materials which can serve as pharmaceutically acceptable carriers include, but are not limited to,
sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch;
cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and
cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and
suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil;
corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl
laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer
solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can also be present in the
composition, according to the judgment of the formulator.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically
acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to
the active compounds, the liquid dosage forms may contain inert diluents commonly used in the
art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed,
groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert
diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying
and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be
formulated according to the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a sterile injectable solution,
suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed
are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile,
fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any
bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-
retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions
which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to
use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug
from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid
suspension or crystalline or amorphous material with poor water solubility. The rate of
absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed absorption of a parenterally
administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in
biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include (poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be
prepared by mixing the compounds of this invention with suitable non-irritating excipients or
carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at
ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
In such solid dosage forms, the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate
and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic
acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating
agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption
accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example,
cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i)
lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form
may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings and other coatings
well known in the pharmaceutical formulating art. They may optionally contain opacifying
lgents and can also be of a composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples
of embedding compositions that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin
capsules using such excipients as lactose or milk sugar as well as high molecular weight
polethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as
noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be
prepared with coatings and shells such as enteric coatings, release controlling coatings and other
coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active
compound may be admixed with at least one inert diluent such as sucrose, lactose and starch.
Such dosage forms may also comprise, as in normal practice, additional substances other than
inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and
microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also
comprise buffering agents. They may optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or preferentially, in a certain part of
the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions
which can be used include polymeric substances and waxes.
The present invention encompasses pharmaceuticalLY acceptable topical formulations of
inventive compounds. The term "pharmaceutically acceptable topical formulation", as used
herein, means any formulation which is pharmaceutically acceptable for intradermal
administration of a compound of the invention by application of the formulation to the
epidermis. In certain embodiments of the invention, the topical formulation comprises a carrier
system. Pharmaceutically effective carriers include, but are not limited to, solvents (e.g.,
alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders,
emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any
other carrier known in the art for topically administering pharmaceuticals. A more complete
listing of art-known carriers is provided by reference texts that are standard in the art, for
example, Remington's Pharmaceutical Sciences, 16th Edition, 1980 and 17th Edition, 1985, both
published by Mack Publishing Company, Easton, Pa., the disclosures of which are incorporated
herein by reference in their entireties. In certain other embodiments, the topical formulations of
the invention may comprise excipients. Any pharmaceutically acceptable excipient known in the
art may be used to prepare the inventive pharmaceutically acceptable topical formulations.
Examples of excipients that can be included in the topical formulations of the invention include,
but are not limited to, preservatives, antioxidants, moisturizers, emollients, buffering agents,
solubilizing agents, other penetration agents, skin protectants, surfactants, and propellants, and/or
additional therapeutic agents used in combination to the inventive compound. Suitable
preservatives include, but are not limited to, alcohols, quaternary amines, organic acids,
parabens, and phenols. Suitable antioxidants include, but are not limited to, ascorbic acid and its
esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and
chelating agents like EDTA and citric acid. Suitable moisturizers include, but are not limited to,
glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents
for use with the invention include, but are not limited to, citric, hydrochloric, and lactic acid
buffers. Suitable solubilizing agents include, but are not limited to, quaternary ammonium
chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants
that can be used in the topical formulations of the invention include, but are not limited to,
vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.
In certain embodiments, the pharmaceutically acceptable topical formulations of the invention
comprise at least a compound of the invention and a penetration enhancing agent. The choice of
topical formulation will depend or several factors, including the condition to be treated, the
physicochemical characteristics of the inventive compound and other excipients present, their
stability in the formulation, available manufacturing equipment, and costs constraints. As used
herein the term " penetration enhancing agent " means an agent capable of transporting a
pharmacologically active compound through the stratum corneum and into the epidermis or
dermis, preferably, with little or no systemic absorption. A wide variety of compounds have been
evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin.
See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.),
CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin
penetration enhancers, and Buyuktimkin et al, Chemical Means of Transdermal Drug
Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K.,
Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, 111. (1997). In certain
exemplary embodiments, penetration agents for use with the invention include, but are not
limited to, triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe-vera gel), ethyl alcohol,
isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400,
propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl
laurate, glycerol monooleate, and propylene glycol monooleate) and N-methyl pyrrolidone.
In certain embodiments, the compositions may be in the form of ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches. In certain exemplary embodiments,
formulations of the compositions according to the invention are creams, which may further
contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid,
palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred. Creams of the
invention may also contain a non-ionic surfactant, for example, polyoxy-40-stearate. In certain
embodiments, the active component is admixed under sterile conditions with a pharmaceutically
acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic
formulation, eardrops, and eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use of transdermal patches,
which have the added advantage of providing controlled delivery of a compound to the body.
Such dosage forms are made by dissolving or dispensing the compound in the proper medium.
As discussed above, penetration enhancing agents can also be used to increase the flux of the
compound across the skin. The rate can be controlled by either providing a rate controlling
membrane or by dispersing the compound in a polymer matrix or gel.
It will also be appreciated that the compounds and pharmaceutical compositions of the present
invention can be formulated and employed in combination therapies, that is, the compounds and
pharmaceutical compositions can be formulated with or administered concurrently with, prior to,
or subsequent to, one or more other desired therapeutics or medical procedures. The particular
combination of therapies (therapeutics or procedures) to employ in a combination regimen will
take into account compatibility of the desired therapeutics and/or procedures and the desired
therapeutic effect to be achieved. It will also be appreciated that the therapies employed may
achieve a desired effect for the same disorder (for example, an inventive compound may be
administered concurrently with another anti-inflammatory agent), or they may achieve different
effects (e.g., control of any adverse effects).
In certain embodiments, the pharmaceutical compositions of the present invention further
comprise one or more additional therapeutically active ingredients (e.g., anti-inflammatory
and/or palliative). For purposes of the invention, the term "Palliative " refers to treatment that is
focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is
not curative. For example, palliative treatment encompasses painkillers, antinausea medications
and anti-sickness drugs.
3) Research Uses, Pharmaceutical Uses and Methods of Treatment
Research Uses
According to the present invention, the inventive compounds may be assayed in any of the
available assays known in the art for identifying compounds having the ability to modulate
adhesion between intracellular adhesion molecules and the leukocyte integrin family of
receptors; to antagonize CD11/CD18 receptors associated with leukocytes and/or to antagonize
Mac-1 and/or LFA-1. For example, the assay may be cellular or non-cellular, in vivo or in vitro,
high- or low-throughput format, etc.
Thus, in one aspect, compounds of this invention which are of particular interest include those
which:
modulate adhesion between intracellular adhesion molecules (e.g., ICAM-1, -2 and -3) and the
leukocyte integrin family of receptors;
exhibit the ability to antagonize CD11/CD18 receptors associated with leukocytes;
exhibit the ability to antagonize Mac-1 and/or LFA-1; and
are useful for the treatment of LFA-1 mediated disorders.
As detailed in the exemplification herein, in assays to determine the ability of compounds to
modulate T-cell adhesion to 5dICAM-Ig (e.g., cell attachment assay), certain inventive
compounds exhibited IC50 values exhibit IC50 values values uM. In certain other embodiments, inventive compounds exhibit IC50 values other embodiments, inventive compounds exhibit IC50 values inventive compounds exhibit IC50 values compounds exhibit IC50 values IC50 values 750 nM. In certain other embodiments, inventive compounds exhibit IC50 values certain other embodiments, inventive compounds exhibit IC50 values embodiments, inventive compounds exhibit IC50 values exemplary compounds exhibited IC50 values compounds exhibited IC50 values exhibited IC50 values values In other embodiments, exemplary compounds exhibited IC50 values embodiments, exemplary compounds exhibited IC50 values Pharmaceutical Uses and Methods of Treatment
As discussed above, certain of the compounds as described herein exhibit activity generally as
modulators of adhesion between intracellular adhesion molecules. More specifically,
compounds of the invention demonstrate the ability to antagonize CD11/CD18 receptors
associated with leukocytes and in certain embodiments exhibit the ability to antagonize LFA-1
interactions. Thus, in certain embodiments, compounds of the invention are useful for the
treatment of LFA-1 mediated disorders.
Accordingly, in another aspect of the invention, methods for treating (or preventing) of LFA-1
mediated disorders are provided comprising administering a therapeutically effective amount of
a compound of formula (I) or (II) as described herein, to a subject in need thereof. In certain
embodiments, a method for the treatment of LFA-1 mediated disorders is provided comprising
administering a therapeutically effective amount of an inventive compound, or a pharmaceutical
composition comprising an inventive compound to a subject in need thereof, in such amounts
and for such time as is necessary to achieve the desired result.
In certain embodiments, the method involves the administration of a therapeutically effective
amount of the compound or a pharmaceutically acceptable derivative thereof to a subject
(including, but not limited to a human or animal) in need of it.
As discussed above this invention provides novel compounds that have biological properties
useful for the treatment of Mac-1 and/or LFA-1 mediated disorders. In certain embodiments, the
inventive compounds as useful for the treatment of psoriasis, responses a-sociated with
inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), dermatitis,
meningitis, encephalitis, uveitis, allergic conditions such as eczema and asthma, conditions
involving infiltration of T-cells and chronic inflammatory responses, skin hypersensitivity
reactions (including poison ivy and poison oak), artherosclerosis, autoimmune diseases such as
rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis,
Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis,
Sjorgen's syndrome, juvenile onset diabetes and immune responses associated with delayed
hypersensitivity mediated by cytokines and T-lymphocytes typically found in tuberculosis,
sarcoidosis, polymyositis, granulomatosis and vasculitis, pernicious anemia, diseases involving
leukocyte diapedeses, CNS inflammatory disorder, multiple organ injury syndrome secondary to
septicaemia or trauma, autoimune hemolytic anemia, myasthemia gravis, antigen-antibody
complex mediated diseases, all types of transplantations, including graft versus host or host
/ersus graft disease, HIV and rhinovirus infection, and pulmonary fibrosis to nairn- a few.
As described in more detail herein, in general, compounds of the invention are useful as
antagonists of the interaction between intracellular adhesion molecules (e.g., ICAM-1, 2 or 3)
and the leukocyte integrin family of receptors. Thus, in certain embodiments, the present
invention provides compounds useful for the treatment of disorders mediated by the CD11/CD18
family of cellular adhesion molecules. In certain embodiments of special interest, the present
invention provides compounds useful for the treatment of disorders mediated by Mac-1 and/or
LFA-1. For example, compounds of the invention are particularly useful for the treatment
inflammatory disorders, organ graft rejection and autoimmune disorders, to name a few.
Thus, as described above, in another aspect of the invention, a method for the treatment of
disorders mediated by the CD11/CD18 family of cellular adhesion molecules is provided
comprising administering a therapeutically effective amount of a compound of formula (I) or (II)
as described herein, to a subject in need thereof. In certain embodiments of special interest the
inventive method is used for the treatment of disorders mediated by Mac-1 or LFA-1. It will be
appreciated that the compounds and compositions, according to the method of the present
invention, may be administered using any amount and any route of administration effective for
the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules.
For example, in certain exemplary embodiments, compounds of the invention are useful as
antagonists of the interaction between Mac-1 or LFA-1 and intracellular adhesion molecules
(e.g., ICAM-1) and thus the compounds are useful for the treatment of LFA-1 mediated disorders
including, but not limited to, psoriasis, responses associated with inflammatory bowel disease
(such as Crohn's disease and ulcerative colitis), dermatitis, meningitis, encephalitis, uveitis,
allergic conditions such as eczema and asthma, conditions involving infiltration of T-cells and
chronic inflammatory responses, skin hypersensitivity reactions (including poison ivy and poison
oak), atherosclerosis, autoimmune diseases such as rheumatoid arthritis, systemic lupus
erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune
thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, juvenile onset
diabetes, and immune responses associated with delayed hypersensitivity mediated by cytokines
and T-lymphocytes typically found in tuberculosis, sarcoidosis, polymyositis, granulomatosis
and vasculitis, pernicious anemia, diseases involving leukocyte diapedesis, CNS inflammatory
disorder, multiple organ injury syndrome secondary to septicaemia or trauma, autoimmune
hemolytic anemia, myasthemia gravis, antigen-antibody complex mediated diseases, all types of
transplantations, including graft versus host or host versus graft disease, HIV and rhinovirus
infection, pulmonary fibrosis and the like, to name a few. Thus, the expression "effective
amount" as used herein, refers to a sufficient amount of agent to antagonize the interaction
between intracellular adhesion molecules (e.g., ICAM) and the leukocyte integrin family of
receptors, and to exhibit a therapeutic effect. The exact amount required will vary from subject
to subject, depending on the species, age, and general condition of the subject, the severity of the
infection, the particular therapeutic agent, its mode of administration, and the like. The
compounds of the invention are preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage unit form" as used herein
refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It
will be understood, however, that the total daily usage of the compounds and compositions of the
present invention will be decided by the attending physician within the scope of sound medical
judgment. The specific therapeutically effective dose level for any particular patient or organism
will depend upon a variety of factors including the disorder being treated and the severity of the
disorder; the activity of the specific compound employed; the specific composition employed;
the age, body weight, general health, sex and diet of the patient; the time of administration, route
of administration, and rate of excretion of the specific compound employed; the duration of the
treatment; drugs used in combination or coincidental with the specific compound employed; and
like factors well known in the medical arts (see, for example, Goodman and Gilman's, "The
Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J.Hardman and L. Limbird,
eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein by reference in its
entirety).
Another aspect of the invention relates to a method for inhibiting the interaction between LFA-1
and ICAM-1 in a biological sample or a patient, which method comprises administering to the
patient, or contacting said biological sample with a compound of formula I or II or a
composition comprising said compound.
Another aspect of the invention relates to a method for inhibiting the CD11a and/or CD18
interaction with ICAM-1, ICAM-2 or ICAM-3 in a biological sample or a patient, which method
comprises administering to the patient, or contacting said biological sample with a compound of
formula I or II or a composition comprising said compound.
furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a
desired dosage, the pharmaceutical compositions of this invention can be administered to
humans and other animals orally, rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal
spray, or the like, depending on the severity of the infection being treated. In certain
embodiments, the compounds of the invention may be administered at dosage levels of about
0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1
mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the
desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or
greater than 50 mg/kg (for example 50-100 mg/kg) can be administered to a subject. In certain
embodiments, compounds are administered orally or parenterally.
Treatment Kit
In other embodiments, the present invention relates to a kit for conveniently and effectively
carrying out the methods in accordance with the present invention. In general, the
pharmaceutical pack or kit comprises one or more containers filled with one or more of the
ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited
for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a
number of unit dosages, and may also include a card having the dosages oriented in the order of
their intended use. If desired, a memory aid can be provided, for example in the form of
numbers, letters, or other markings or with a calendar insert, designating the days in the
treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or
calcium dietary supplements, either in a form similar to or distinct from the dosages of the
pharmaceutical compositions, can be included to provide a kit in which a dosage is taken every
day. Optionally associated with such container(s) can be a notice in the form prescribed by a
governmental agency regulating the manufacture, use or sale of pharmaceutical products, which
notice reflects approval by the agency of manufacture, use or sale for human administration.
Equivalents
The representative examples that follow are intended to help illustrate the invention, and are not
intended to, nor should they be construed to, limit the scope of the invention. Indeed, various
nodifications of the invention and many further embodiments thereof, in addition to those shown
and described herein, will become apparent to those skilled in the art from the full contents of
this document, including the examples which follow and the references to the scientific and
patent literature cited herein. It should further be appreciated that the contents of those cited
references are incorporated herein by reference to help illustrate the state of the art.
The following examples contain important additional information, exemplification and guidance
that can be adapted to the practice of this invention in its various embodiments and the
equivalents thereof.
Exemplification
The compounds of this invention and their preparation can be understood further by the
examples that illustrate some of the processes by which these compounds are prepared or used.
It will be appreciated, however, that these examples do not limit the invention. Variations of the
invention, now known or further developed, are considered to fall within the scope of the present
invention as described herein and as hereinafter claimed.
1) General Description of Synthetic Methods:
The practitioner has a a well-established literature of macrolide chemistry to draw upon, in
combination with the information contained herein, for guidance on synthetic strategies,
protecting groups, and other materials and methods useful for the synthesis of the compounds of
this invention.
The various references cited herein provide helpful background information on preparing
compounds similar to the inventive compounds described herein or relevant intermediates, as
well as information on formulation, uses, and administration of such compounds which may be
of interest.
Moreover, the practitioner is directed to the specific guidance and examples provided in this
document relating to various exemplary compounds and intermediates thereof.
The compounds of this invention and their preparation can be understood further by the
examples that illustrate some of the processes by which these compounds are prepared or used.
It will be appreciated, however, that these examples do not limit the invention. Variations of the
invention, now known or further developed, are considered to fall within the scope of the present
invention as described herein and as hereinafter claimed.
According to the present invention, any available techniques can be used to make or prepare the
inventive compounds or compositions including them. For example, a variety of solution phase
synthetic methods such as those discussed in detail below may be used. Alternatively or
additionally, the inventive compounds may be prepared using any of a variety combinatorial
techniques, parallel synthesis and/or solid phase synthetic methods known in the art.
It will be appreciated as described below, that a variety of inventive compounds can be
synthesized according to the methods described herein. The starting materials and reagents used
in preparing these compounds are either available from commercial suppliers such as Aldrich
Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are
prepared by methods well known to a person of ordinary skill in the art following procedures
described in such references as Fieser and Fieser 1991, "Reagents for Organic Synthesis", vols 1-
17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 "Chemistry of Carbon Compounds",
vols. 1-5 and supps, Elsevier Science Publishers, 1989; "Organic Reactions", vols 1-40, John
Wiley and Sons, New York, NY, 1991; March 2001, "Advanced Organic Chemistry", 5th ed.
John Wiley and Sons, New York, NY; and Larock 1990, "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations", 2nd ed. VCH Publishers. These
schemes are merely illustrative of some methods by which the compounds of this invention can
be synthesized, and various modifications to these schemes can be made and will be suggested to
a person of ordinary skill in the art having regard to this disclosure.
The starting materials, intermediates, and compounds of this invention may be isolated and
^purified using conventional techniques, including filtration, distillation, crystallization,
chromatography, and the like. They may be characterized using conventional methods, including
physical constants and spectral data.
General Reaction Procedures:
Unless mentioned specifically, reaction mixtures were stirred using a magnetically driven stirrer
bar. An inert atmosphere refers to either dry argon or dry nitrogen. Reactions were monitored
either by thin layer chromatography, by proton nuclear magnetic resonance (NMR) or by high-
pressure liquid chromatography (HPLC), of a suitably worked up sample of the reaction mixture.
General Work Up Procedures:
Unless mentioned specifically, reaction mixtures were cooled to room temperature or below then
juenched, when necessary, with either water or a saturated aqueous solution of ammonium
chloride. Desired products were extracted by partitioning between water and a suitable water-
immiscible solvent (e.g. ethyl acetate, dichloromethane, diethyl ether). The desired product
containing extracts were washed appropriately with water followed by a saturated solution of
brine. On occasions where the product containing extract was deemed to contain residual
oxidants, the extract was washed with a 10% solution of sodium sulphite in saturated aqueous
sodium bicarbonate solution, prior to the aforementioned washing procedure. On occasions
where the product containing extract was deemed to contain residual acids, the extract was
washed with saturated aqueous sodium bicarbonate solution, prior to the aforementioned
washing procedure (except in those cases where the desired product itself had acidic character).
On occasions where the product containing extract was deemed to contain residual bases, the
extract was washed with 10% aqueous citric acid solution, prior to the aforementioned washing
procedure (except in those cases where the desired product itself had basic character). Post
washing, the desired product containing extracts were dried over anhydrous magnesium sulphate,
and then filtered. The crude products were then isolated by removal of solvent(s) by rotary
evaporation under reduced pressure, at an appropriate temperature (generally less than 45°C).
General Purification Procedures:
Unless mentioned specifically, chromatographic purification refers to flash column
chromatography on silica, using a single solvent or mixed solvent as eluent. Suitably purified
desired product containing elutes were combined and concentrated under reduced pressure at an
" appropriate temperature (generally less than 45°C) to constant mass. Final compounds were
dissolved in 50% aqueous acetonitrile, filtered and transferred to vials, then freeze-dried under
high vacuum before submission for biological testing.
1) Synthesis of Exemplary Compounds:
Unless otherwise indicated, starting materials are either commercially available or readily
accessibly through laboratory synthesis by anyone reasonably familiar with the art. Described
generally below, are procedures and general guidance for the synthesis of compounds as
described generally and in subclasses and species herein. In addition, synthetic guidance can be
found in published PCT applications WO 99/49856 and WO 02/059114, the entire contents of
which are hereby incorporated by reference.
EXAMPLE 1
This example describes the synthesis of

which was prepared according to Scheme 1A and the procedure below.
a) A solution of 3-methoxyphenylethylamine (0.2 mol) and formaldehyde (0.22 mol) in aqueous
HCl (20%, 500 mL) was heated at 80 °C for 4 hours. The reaction was then concentrated to
dryness, and the residue was dissolved in hydrobromic acid (40% aqueous, 500 mL), and
rcfluxed for 24 hours. The reaction was concentrated to give a brownish solid, which was used
without purification. To the residue was added water (200 mL) and tetrahydrofuran ("THF")
(300 mL), and to the resulting mixture was very carefully added with sodium carbonate (solid,
0.5 mol), followed by di-tert-butyl dicarbonate (0.3 mol). After 15 hours at room temperature,
the reaction was extracted with ethyl acetate (1 L), and the organic extract was washed with
saturated potassium dihydrophosphate and brine, dried over anhydrous magnesium sulfate and
filtered.
The residue after concentration of the filtrate was dissolved in dichloromethane ("DCM"; 100
mL), and to it was slowly added acetic acid (500 mL) and surfuryl chloride (0.6 mol). After the
reaction mixture was stirred at room temperature for 24 hours, the reaction was concentrated to
dryness, and further dried under high vacuum for 2 hours. The crude product was used without
further purification for next step. The crude product was dissolved in water/THF (200 mL/400
mL), and to it was added carefully and slowly sodium carbonate (0.5 mol) with good stirring,
followed by di-tert-butyl dicarbonate (0.3 mol). After the reaction mixture was stirred for 12
hours, the reaction was carefully neutralized with phosphoric acid (2 M) to pH about 7. The
resulting mixture was extracted with ethyl acetate (500 mL x2), and the combined extracts were
washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
The crude solid was recrystalized from ethyl acetate and hexane (about 1:2 ratio) to yield a white
solid. The mother liquid was concentrated and purified by column, eluting with 0-10% ethyl
acetate in 4:1 hexane:methylene chloride. The combined yield is 14.5 g (23% from commercial
3-methoxyphenethylamine). MS (API-ES+) m/z: 262, 264, 266 (M+H-tert-butyl+).
The product obtained above was dissolved in DCM (100 mL) and pyridine (50 mL). The
resulting solution was cooled to —40 °C, and to it was added triflic anhydride (51 mmol) slowly.
After the reaction mixture was gradually warmed to room temperature over 4 hours, the reaction
.mixture was partitioned between ethyl acetate (500 mL) and water (100 mL), and the organic
layer was washed with water (100 mL, twice) and brine (50 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated. The residue was purified by columm, eluting with
0-5% ethyl acetate in 5:1 hexane:DCM to give the corresponding triflate (9.73 g, 48% yield).
A mixture of 10mmol of the triflate, l.Ommol of 1,3-diphenylphosinepropane ("dppp") and
40mmol of di-isopropylethylamine ("DIEA") in 100mL of dry dimethylformamide ("DMF") and
50mL of anhydrous CH3OH was flushed with CO for 15 min, and then 1.0mmol of Pd(OAc)2
was added under the atmosphere of CO. Subsequently, the resulting mixture was stirred at 70 °C
overnight under an atmosphere of CO. The solvent was removed and the residue was purified by
column chromatography using EtOAc/hexane = 1/4 (v/v) as the eluent to give compound 1.1 with
a 56% yield. ESI-MS (m/z): (M+)+Na 382.1; 1H NMR (CD3OD, 400MHz): d 7.32 (s, 1H), 4.60
s, 2H), 3.95 (s, 3H), 3.69 (m, 2H), 2.84 (m, 2H), 1.50 (s, 9H) ppm.
b) A mixture of 1.1 (5 mmol) and 30mmol of LiI in 20mL of pyridine was reflux overnight.
The solvent was removed and the residue was dissolved in EtOAc. The resulting solution was
then washed with saturated aqueous NH4Cl and dried with anhydrous Na2SO4. The solvent was
removed and the residue was dried in vacuo to give a quantitative yield of compound 1.3. The
crude product was carried on the next step without further purification. ESI-MS (m/z): (M - tBu
+1), 290.
c) A solution of Boc-Dap-OH (10 mmol) in methanol (30 mL) was treated with
trimethylsilyldiazomethane until the color remained light yellow for 10 seconds. The mixture
was concentrated, and the residue was dissolved in DCM (30 mL). To the solution was added
triethylamine (20 mmol) and followed by 3-thienylcarboxyl chloride (11 mmol). After 0.5 hour
at room temperature, the reaction was filtered through silica gel, and concentrated. The residue
was purified by column with 10-50% ethyl acetate in hexane. The product obtained this way
was dissolved in DCM (10 mL) and treated with HC1 (4 M in dioxane, 10 mL). After 5 hours,
the reaction was concentrated to give the title compound (60-80% overall yield).
d) A mixture of 1.2 (4 mmol), 1.3 (4.4 mmol), 5.0 mmol of o-(7-azabenzotriazol-1-yl)-
N,N,N',N'-tetramethyluronium fluorophosphate ("HATU") and 20mmol of Et3N in 20mL of
DMF was stirred at room temperature overnight. The solvent was removed and the residue was
purified by column chromatography using CH2Cl2/EtOAc = 6/4 (v/v) as eluent to give compound
1.4 with a 60% yield. ESI-MS (m/z): (M+l) 556.1.
e) A solution of 2mmol of 1.4 in 9mL of TFA and 3mL of CH2Cl2 was stirred at room
temperature for 6 hours. The solvent was then removed and the residue was diluted with
saturated aqueous NaHCO3. The mixture was extracted with EtOAc for 3 times. The extracts
were then dried with anhydrous Na2SO4. The solvent was removed and the residue was dried in
vacuo to give compound 1.5 which was used without further purification. ESI-MS (m/z): (M+1)
456.1.
f) Intermediate compound 1.11 was prepared according to Scheme 1B and the procedure
below.
SCHEME 1B

To a solution of 100 mmol of commercially available 6-hydroxy-[2H]-benzofuran-3-one
(compound 1.8) and 150 mmol of imidazole in 300 mL of dry DMF was added 110 mmol of tert-
butyldimethylsilylchloride ("TBDMSC1") at room temperature, the resulting mixture was stirred
at room temperature overnight. The solvent was removed, and the residue was diluted with 100
mL of EtOAc, washed with saturated aqueous NH4Cl, and dried with anhydrous Na2SO4. The
solvent was removed, and the residue was purified to give corresponding intermediate in 70%
yield. ESI-MS (m/z): (M+H+) 265.1.
The intermediate is dissolved in 100 mL of CH3OH was added 20 mmol of NaBH4 at room
temperature. After stirring at room temperature for 12 hours, the reaction mixture was treated
with 10 mL of acetone. Subsequently, 60 mL of 4.0 N HC1 were added to the mixture, and the
mixture was stirred at room temperature overnight. The organic solvent was removed, and the
residue was extracted with EtOAc for several times. The extract was then washed with brine and
dried with anhydrous Na2SO4. The solvent was removed and the residue was dissolved in 100
mmol of Et3N and 180 mL of dry CH2Cl2 was added 66 mmol of PhNTf2 at 0°C, the resulting
mixture was stirred at room temperature overnight. The solvent was removed, and the residue
was purified to give compound 1.9 in 90% yield. 1H NMR (400 MHz, CD3Cl): d 7.75 (d, J=1.9
Hz, 1H), 7.66 (d, J =8.5 Hz, 1H), 7.50 (s, 1H), 7.21 (d, J =8.5 Hz, 1H), 6.85 (d, J =1.9 Hz, 1H)
ppm.
A mixture of 50 mmol of compound 1.9, 2.5 mmol of dppp (diphenylphosphine-1,3-propane)
and 2.5 mmol of Pd(OAc)2 in 100 mmol of DIEA, 125 mL of dry DMF, and 125 mL of
anhydrous MeOH was stirred at 65°C under an atmosphere of CO overnight. The solvent was
removed and the residue was purified by column chromatography to give compound 1.10 in 65%
yield. 1H NMR (400 MHz, CDCl3): d 8.23 (s, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.78 (s, 1H), 7.65 (d,
J= 8.3 Hz, 1H), 6.85 (s, 1H), 3.97 (s, 3H) ppm; ESI-MS (m/z): (M+1) 177.10.
A mixture of 20 mmol of compound 1.10 and 80 mmol of LiOH.H2O in 60 mL of THF and 15
mL of H2O was stirred at room temperature for 1 hour, followed by adding 80 n.L of 1.0N aq.
HC1. The organic solvent was removed and the residue was diluted with 50 mL of brine. The
mixture was then extracted with EtOAc, and the extract was dried with anyhydrous Na2SO4. The
solvent was removed and the residue was dried in vacuo to give a quantitative yield of compound
11. 1H NMR (400 MHz, CD3OD): d 8.14 (s, 1H), 7.92 (m, 2H), 7.67 (d, J=8.5 Hz, 1H), 6.92
(s, 1H) ppm; ESI-MS (m/z): (M+H+) 163.1.
g) A mixture of 0.25 mmol of compound 1.11 and 0.26 mmol of HATU in 1 mmol of DIEA
and 2 mL of DMF was stirred at room temperature for 30 min, followed by adding a solution of
0.22 mmol of compound 1.5 in 1 mL of DMF. The resulting mixture was stirred 45°C for 12
hours. The solvent was removed, and the residue was purified to give compound 1.6 in 50-65%
yield. Subsequently, compound 1.6 was hydrolyzed with LiOH (1.0 M aqueous, 0.5 mL) in THF
(3 mL) for 2 hours. The rexaction mixture was then acidified with HC1 (aqueous), extracted with
ethyl acetate (50 mL), dried over anhydrous magnesium sulfate and concentrated to give
compound 1 in quantitative yield. 1H NMR (400 MHz, CD3OD): d 7.91 (s, 1H), 7.75 (d, J= 8.0
Hz, 1H), 7.67 (s, 3H), 7.36 (d, J= 8.0 HZ, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 5.01 (t, J= 6.8 Hz, 1H),
4.68 and 4.89 (m, 2H), 3.85 (d, J= 6.8 Hz, 2H), 3.70 and 4.02 (m, 2H), 2.93 (m, 2H) ppm; ESI-
MS(/n/z):(M+1)586.10.
EXAMPLE 2
This example describes the synthesis of

which was prepared according to the procedure of Example lg except that 4-chlorobenzoic acid
was used instead of compound 1.11. 1H NMR (400 MHz, CD3OD): d 7.64 (m, 2H), 7.35-7.49
(m, 5H), 7.11 (s, 1H), 4.98 (t, J= 8.0 Hz, 1H), 4.63 and 4.88 (m, 2H), 3.83 (d, J= 8.0 Hz, 2H),
3.68 and 3.98 (m, 2H), 2.89 (m, 2H) ppm; ESI-MS (m/z): (M+1) 579.90.
EXAMPLE 3
This example describes the synthesis of

which was prepared according to Scheme 2 and the procedure below.
a) To a solution of 10 mmol of commercially available 3.1 in 20 mL of MeOH and 20 mL
of CH2Cl2 was slowly added 20 mmol of 2.0M TMSCHN2 in hexanes at 0 °C, and the resulting
mixture was stirred at room temperature for 30 minutes. The solvent was removed and the
residue was dried in vacuo to give crude 3.2.
b) Compound 3.2 was then stirred with 15 mmol of isopropylazide in the presence of 0.2
mmol of Cul, 0.2 mmolf of Et3N in 50 mL of CH3CN at room temperature overnight. The
solvent was removed and the residue was purified by column chromatography to give compound
3.3 in 55% yield. ESI-MS (m/z): (M+1) 313.20.
c) A mixture of 2 mmol of compound 3.3 in 10 mL of 4.0 N HCl in dioxane was stirred at
room for 12 hours. The solvent was removed and the residue was dried in vacuo to give
compound 3.4 in quantitative yield. ESI-MS (m/z): (M+l) 213.10.
d) A solution of 1.1 (3.60 g, 10 mmol) in DCM (20 mL) was treated with HCl in 1,4-
dioxane (4.0 M, 10 mL) at room temperature. After 2 hours, the reaction was concentrated to
give compound 3.5 in quantitative yield.
e) Example 3.5 (10 mmol) was mixed with EDC (2.11 g, 11 mmol), N,N-
dimethylaminopyridine ("DMAP", 0.1 g), triethylamine (2.02 g) and Example 1.11 (1.62g, 10
mmol) in anhydrous DMF (50 mL). After 15 hours at room temperature, the reaction mixture
was diluted with ethyl acetate (200 mL), washed with water (30 mL, 3 times), dried with
anhydrous magnesium sulfate and filtered. The residue after concentration of the filtrate was
purified by column eluting with 10-30% ethyl acetate in hexane to give the title compound (3.7
g, 92%): ESI-MS (m/z): (M+1) 213.1.
0 Compound 3.7 was made according to Example lb except that compound 3.6 was used
instead of compound 1.1.
g) A mixture of 0.25 mmol of compound 3.7 and 0.26 mmol of HATU in 1 mmol of DIEA
and 2 mL of DMF was stirred at room temperature for 30 minutes, followed by adding a solution
of 0.22 mmol of compound 3.4 in 1 mL of DMF. The resulting mixture was stirred 45°C for 4
hours. The solvent was removed, and the residue was purified to give intermediate ester, which
was subsequently treated with LiOH in THF and water to give the desired compound 3 in
quantitative yield. 1H NMR (400 MHz, CD3OD) d 7.90 (s, 2H), 7.74 (m, 1H), 7.64 (s, 1H), 7.34
(m, 1H), 6.93 (s, 1 H), 5.03 (m, 1H), 4.82 (m, 1 H), 4.65 and 4.88 (m, 2H), 3.72 and 3.97 (m,
2H), 3.40 (m, 1H), 3.18 (m, 1H), 2.90 (m, 2H), 1.55 (m, 6H) ppm; ESI-MS (m/z): (M+l) 570.1.
EXAMPLE 4
This example describes the synthesis of

vvhich was prepared according to Scheme 3 and the procedure below.
a) Boc-DAP-OH (0.2 g, 1.0 mmol), 2,4-dichloropyrimidine (0.29g, 2.0 mmol), and
diisopropylethylamine (0.51 mL, 2.9 mmol) in ethanol (5 mL) were heated to 75 °C for 14 hours.
The reaction mixture was cooled to room temperature and the solvent removed under reduced
pressure. The resulting crude product 4.1 was pure enough to carry forward to the next chemical
transformation.
b) Crude residue 4.1 (0.31 g, 1.0 mmol) was dissolved in 9:1 benzene: methanol (5 mL).
Trimethylsilyldiazomethane (1.0 mL, 2.0M in hexanes) was added slowly to the stirring reaction
mixture and stirred for an additional 1 hour. The solvents were removed under reduced pressure
to obtain oily crude residue. Purification by silica gel column chromatography using 50% ethyl
acetate in hexanes was performed to afford pure 4.2 (0.21 g, 65%).
c) Compound 4.2 (0.2 lg, 0.6 mmol) was dissolved in dichloromethane (5 mL).
Trifluoroacetic acid (2.5 mL) was added and the reaction was stirred for 1 hour. The resulting
reaction mixture was concentrated to remove any excess trifluoroacetic acid to afford amine 4.3
in quantitative yield.
d) Compound 4.4 was made according to Example 3d-f except that 4-chlorobenzoic acid
was used instead of compound 1.11.
e) Compound 4 was made according to Example 3g except that compound 4.4 was used
instead of compound 3.7 and compound 4.3 was used instead of compound 3.4.
EXAMPLE 5

a) To a solution of methane sulfonamide (1.01 g, 10.7 mmol) in 15 mL DMF was added 20
M aqueous NaOH (0.68 mL, 13.6 mmol), resulting in a white precipitate. The solution was
cooled to 0°C, carbon disulfide (0.4 mL, 6.63 mmol) slowly added, and stirred at 0°C for 15
minutes. Additional 20M aqueous NaOH (0.32mL, 6.4 mmol) and carbon disulfide (0.2mL, 3.31
mmol) were added and the reaction stirred at 0°C for 20 minutes, then raised to room
emperature. At 30 minutes all precipitate had returned to solution, and the reaction mixture was
cooled to 0°C. Methyl iodide (1.33 mL, 21.364 mmol) was added and the reaction stirred at 0°C
for 20 minutes and at room temperature for 1.5 hours. 20 mL water was added to the reaction
and extracted five times with ethyl acetate. The combined organic extracts were dried over
MgSO4 and concentrated to dryness. Recrystallization from hot ethyl acetate and hexanes
afforded 1.44 g compound 5.1. ESI-MS (m/z): (M+H+) 200.0.
b) To a solution of Boc-Dap-OH (109 mg, 0.53 mmol) and compound 5.1 (125.7 mg, 0.632
mmol) in 5mL ethanol was added 1.0M aqueous NaOH (0.8 mL, 0.8 mmol). The reaction was
stirred until conversion was complete, and then concentrated to dryness. The residue was
dissolved in water and washed three times with ether. The aqueous layer was acidified to pH 1
with 2.0M phosphoric acid, and extracted four times with ethyl acetate. The combined ethyl
acetate extracts were dried over MgSO4 and concentrated to dryness to afford 160.4 mg of
compound 5.2. ESI-MS (m/z): (M+Na+) 378.0.
c) To a solution of compound 5.2 (160.4 mg, 0.452 mmol) in 1:1 dichloromethaneimethanol
was added trimethylsilyldiazomethane as a 2.0 M solution in ether (0.4 mL, 0.8 mmol). The
reaction was stirred at room temperature until conversion to the methyl ester was complete, and
then concentrated to dryness. The product was purified via flash chromatography to afford
146.6mg of compound 5.3. ESI-MS (m/z): (M+Na+) 270.0; 1H NMR (400 MHz, chloroform-d)
5 1.46 (s, 9H), 2.42 (s, 3H), 3.02 (s, 3H), 3.63 (m, 1H), 3.75 (m, 1H), 3.82 (s, 311), 4.51 (m, 1H).
d) To a solution of compound 5.3 (146.6mg, 0.40mmol) in 2mL methanol was added
ammonia, 7N in methanol (0.6 mL, 4.2 mmol). This mixture was cooled to 0 °C, and a solution
of silver nitrate (75.5 mg, 0.444 mmol) in 0.4 mL acetonitrile was dropwise added. The reaction
was stirred and allowed to reach room temperature. At three hours solvent was removed, the
residue suspended in ethyl acetate, and filtered through celite. The filtrate was concentrated to
dryness and redissolved in dichloromethane, to which was added HC1, 4.0 M in dioxane (0.5mL,
2.0 mmol). This solution was stirred at room temperature for 8 hours and concentrated to
dryness to afford compound 5.4 as an HCl salt. ESI-MS (m/z): (M+H+) 239.
e) Compound 5 was made according to Example 3g except that compound 4.1 was used
instead of 3.7 and compound 5.4 was used instead of compound 3.4. ESI-MS (m/z): (M+H')
590.0.
EXAMPLE 6
This example describes the synthesis of

which was prepared according to Scheme 5 and the procedure below.

a) A solution of (L)-Boc-Dap-OH (10 mmol), dimethyl N-cyanodithioimniocarbonate (10
mmol) and DIEA (30 mmol) in ethanol was stirred at room temperature for 1 hour. Then,
pyrrolidine (20 mmol) was added, and the reaction was heated at 65 °C for 10 hours. The
reaction mixture was then diluted with ethyl acetate (150 mL), and was extracted with saturated
NaH2PO4 (50 mL, the queous layer pH is between 4-6), water (50 ml) and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The crude product
was dissolved in 4:1 DCM:MeOH, cooled at 0°C and to it was added trimthylsilyldiazomethane
until it stays yellow for 30 seconds. The solution is concentrated and the residue was purified by
column with 30-100% ethyl acetate in hexane to give the title compound in 20-30% yield. MS
(m/z): 240(M-99).
b) Compound 6.1 (72 mg, 0.20 mmol) in DCM (1 mL) was treated with HCl (4 M in
dioxane) for 2 hours. The reaction mixture was concentrated to give compound 6.2.
c) Compound 6 was made according to Example 3g except that compound 6.2 was used
instead of compound 3.4. 1H NMR (400 MHz, CDCl3) d 7.77 (s, 1 H), 7.63 (m, 3 H), 7.37 (d, 1
H), 6.85 (s, 1 H), 6.32 (d, 1 H), 4.68 (s, 2 H), 4.31 (m, 1 H), 3.85 (m, 2 H), 3.60 (m, 4 H), 2.88
(m, 2 H), 1.89 (m, 4 H) ppm; ESI-MS (m/z): (M+1) 597.1.
EXAMPLE 7
This example describes the synthesis of

which was prepared according to Scheme 6 and the procedure below.

a) To a solution of H-2-Mercapto-His-OH (598.8 mg, 3.2 mmol) in 5mL methanol was
added 0.26mL sulfuric acid. This mixture was stirred at room temperature for 18 hours.
Additional sulfuric acid (0.1 ml., 0.6 mmol) was added and the reaction stirred at 50 °C for 4.5
hours. Sodium carbonate (850.3 mg, 8.02 mmol) was slowly added, and the reaction
concentrated via rotary evaporation to remove most of the methanol. 6 mL THF and 3 mL water
were added with sodium carbonate (0.851 g, 8.03 mmol) and Boc2O (696.5 mg, 3.19 mmol).
The reaction was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed
with water and brine. The organic layer was dried over MgSO4 and concentrated to dryness.
Purification via flash chromatography afforded 283.5mg of compound 7.1. ESI-MS (m/z):
(M+H+) 316.1.
b) Compound 7.1 (283.5 mg, 0.90 mmol) and 3-chloroperoxybenzoic acid (568.4 mg, 2.53
mmol) were dissolved in 6 mL dichloromethane and stirred at room temperature for 1.5 hours.
The reaction was diluted with dichloromethane and poured into 1.0 M potassium carbonate. The
aqueous layer was adjusted to neutral pH with 2.0 M phosphoric acid and extracted three times
with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated
to dryness. Purification via flash chromatography afforded 240.8 mg of compound 7.2. ESI-MS
(m/z): 370.1(M+Na+), 248.1 (M-Boc+H+); 1H NMR (400 MHz, CDCl3) d 1.43(s, 9H), 3.l4(m,
2H), 3.26(s, 3H), 3.74(s, 3H),4.61(m, 1H), 7.02(s, 1H).
c) To a solution of compound 7.2 (240.8 mg, 0.6931 mmol) in dichloromethane was added
HCI, 4.0 M in dioxane (1.0 mL, 4.0 mmol). The reaction was stirred at room temperature for 1.5
hours and then concentrated to dryness to afford compound 7.3 as an HCl salt. ES1-MS (m/z):
(M+H+) 248.
d) Compound 7 was made according to Example 3g except that compound 4.1 was used
instead of compound 3.7 and compound 7.3 was used instead of compound 3.4. ESI-MS (m/z):
(M+H+) 599.0; 1H NMR (400 MHz, CDCl3) d 2.88(s, 2H), 3.10(m, 1H), 3.21(s, 3H), 3.34(m,
1H), 3.67(1H), 3.97(1H), 4.63(1H), 4.85(1H), 5.04(dd, 1H), 7.19 (s, 1H), 7.49(m, 5H).
EXAMPLE 8
This example describes the synthesis of

which was prepared according to Scheme 7A and the procedure below.

a) A three-neck flask containing 32 mmol of LiC1 was flamed with a gas lamp in vacuo,
followed by flushing with N2. This sequence was repeated for 3 times in order to get dry LiC1.
To the flask was added 10 mmol of (R, R)-(-)-pseudoephedrine glycinamide hydrate (A. G.
Myers el al J. Org. Chem. 64: 3322-3327 (1999)) and 30 mL of dry THF at room temperature
under an atmosphere of N2. The suspension was then treated with 31 mmol of LiHMDS (1.0 M
in THF) at 0°C with stirring for 1hour, followed by adding a solution of 10 mmol of 3-
methylthiobenzyl chloride (S. Laufer et al J. Med. Chem. 45: 2733-2740 (2002)) in 5 mL of dry
THF. The resulting mixture was stirred at 0°C overnight and quenched by adding 10 mL of
water. The solvent was removed, and the residue was diluted with 50 mL of water. The mixture
was extracted with CH2Cl2 for 3 times. The organic extract was combined and dried with
anhydrous Na2SO4. Subsequently, the solvent was removed, and the residue was purified to give
the desired alkylated intermediate in 70% yield. ESI-MS (m/z): (M+H+) 359.2.
A mixture of 5 mmol of the alkylated intermediate in 12 mL of 1.0 N NaOH was refluxed until
the starting material was consumed. The mixture was diluted with 20 mL, of water and extracted
with CH2C12 for 3 times. The aqueous phase was then stirred with 6 mmol of (Boc)2O and 12
mmol of NaHCO3 in 30 mL of 1,4-dioxane for 15 hours. The organic solvent was removed, and
the residue was diluted with 30 mL of water and extracted with CH2Cl2. The aqueous phase was
subsequently treated with solid citric acid to adjust the pH value to 4.0, flowed by extracting with
EtOAc for 3 times. The organic extract was dried with anyhydrous Na2SO4. The solvent was
removed, and the residue was dried in vacuo to give compound 8.2 in quantitative yield. ESI-
MS (m/z): (M+H+) 334.10.
b) A mixture of 5 mmol of compound 8.2 in 10 mL of CH3OH and 10 mL of CH2Cl2 was
added 10 mmol of (trimethylsilyl)diazomethane (2.0 M in hexanes) at 0 °C, the resulting mixture
was stirred at room temperature for 30 minutes. The solvent was removed, and the residue was
dried in vacuo to give the desired ester in quantitative yield. ESI-MS (m/z): (M+H+) 348.10.
To a solution of the ester in 20 mL of CH3OH and 2 mL of water was added 12 mmol of Oxone
at room temperature, and the resulting suspension was stirred at room temperature for 15 hours.
The reaction mixture was concentrated and diluted with 50 mL of EtOAc, washed with water,
and dried with anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo
to give compound 8.3 in quantitative yield. 1H NMR (400 MHz, CD3Cl): d 7.82 (m, 1H), 7.69
(s, 1H), 7.50 (m, 1H), 7.43 (m, 1H), 5.03 (m, 1H), 4.62 (m, 1 H), 3.74 (s, 3H), 3.26 (m, 1H), 3.09
(m, 1H), 3.03 (s, 3H), 1.39 (s, 9H) ppm; ESI-MS (m/z): (M-/Boc+H') 258.1.
c) A mixture of 2 mmol of compound 8.3 in 10 mL of 4.0 N HCl in dioxane was stirred at
room temperature for 15 hours. The solvent was removed, and the residue was dried in vacuo to
give compound 8.4 in quantitative yield as an HCl salt. 1H NMR (400 MHz, CD3OD): d 7.95
(m, 1H), 7.87 (s, 1H), 7.64 (m, 2H), 4.44 (t, J= 6.85 Hz, 1H), 3.82 (s, 3H), 3.41 (m, 1H), 3.29
(m, 1H), 3.13 (s, 3H) ppm; ESI-MS (m/z): (M+H+) 258.10.
d) Compound 8 was made according to Example 3g except that compound 4.1 was used
instead of compound 3.7 and compound 8.4 was used instead of compound 3.4. 1H NMR (400
MHz, CD3OD): d 7.92 (s, 1H), 7.81 (d, .7=7.92 Hz, 1H), 7.68 (d, J= 7.83 Hz), 7.56 (t, J= 7.83
Hz, 1H), 7.30-7.49 (m, 5H), 5.06 (m, 1H), 4.60 and 4.83 (m, 2H), 3.95 and 3.66 (m, 2H), 3.44 (d,
J=13.44 Hz, 1H), 3.14 (m, 1H), 3.08 (s, 3H), 2.85 (m, 2H) ppm; ES1-MS (m/z): (M+H+) 609.05.
e) Compound 8.4 can also be prepared according to Scheme 7B and the procedure below.

A mixture of 8.5 (1.0 mmoL), methyl iodide (1.2 mmoL) and potassium carbonate (2 mmoL) in
20 mL of acetone was heated at 50°C for 3 hours. The solvent of the reaction mixture was
removed under reduced pressure. The residue was partitioned between EtOAc and water. The
aqueous solution was extracted with EtOAc, and combined organic solution was washed with
brine, dried over Na2SO4, filtered, concentrated. The crude product as a white solid (yield 98%)
was used for next step without purification.
To a solution of the compound (1 mmoL) made above in 4 mL of THF at 0 oC was added LiAlH4
(1.1 mmoL) slowly. The reaction mixture was allowed to warm to room temperature and stirred
for 1 hour. The reaction was added consecutively with water, 15% aqueous NaOH and water
with strong stirring. The filtration and evaporation of filtrate provided the crude product 8.6
(yield 92%). No purification was needed. 1H NMR (400 MHz, CDCl3) d 3.05 (s, 3 H), 4.75 (s, 2
H), 7.53 (t, 7=7.58 Hz, 1 H), 7.62 (d, .7=7.34 Hz, 1 H), 7.81 (d, .7=7.83 Hz, 1 H), 7.93 (s, 1 H).
Solid tetrapropylammonium perruthenate ("TPAP", 0.05 mmol) was added in one portion to a
stirred mixture of compound 8.6 (1 mmoL), 4-methylmorpholine N-oxide ("NMO"; 1.5 mmol.)
and powdered 4A molecular sieve (equal weight to that of NMO) in 5 mL of DCM at room
temperature under N2. The reaction mixture was stirred at room temperature, for 1 hour, and
then filtered through a short pad of silica gel, eluting with mixture of DCM and AcOEt (1:1).
The filtrate was concentrated and the residue was purified with chromatography (SiO2,
AcOEt/hexane 2:1) to afford compound 8.7 (yield 72%). 1H NMR (400 MHz, CDCl3) d 3.14 (s,
3 H), 7.81 (t, J=7.58 Hz, 1 H), 8.21 (t, 7=9.05 Hz, 2 H), 8.46 (s, 1 H), 10.12 (s, 1 H) ppm.
The N, N', N' A'Vtetramethylguanidine ("TMG"; 1.05 mmole) was added slowly to a solution of
(d,l)-Cbz-a-phosphonoglycine trimethylester (1.1 mmole) in 4 ml of DCM at room temperature.
After 15 minutes, the mixture was cooled to -30°C and compound 8.7 (1 mmole) added
dropwise. The mixture was kept at -30°C for 20 minutes and slowly allowed to warm to 0°C.
The solution was diluted with AcOEt and washed consecutively with 1 N NaHSO4 and brine.
The solution was dried (Na2SO4), and solvent evaporated to provide crude product. Purification
of thecrude product on chromatography (Si02, AcOEt/hexanes/DCM 3:3:1) to give product 8.8
(yield 72%). 1H NMR (400 MHz, CDCl3) d 2.97 (s, 3 H), 3.86 (s, 3 H), 5.08 (s, 2 H), 6.78 (s, 1
H), 7.34 (d, J=6.36 Hz, 5 H), 7.50 (t, J=7.83 Hz, 1 H), 7.72 (d, J=7.34 Hz, 1 H), 7.85 (d, J=7.34
Hz, 1 H), 8.04 (s, 1 H). Olefmic proton in the minor trans isomer at 7.19 ppm (s, 1H). ES1-MS
(m/z): (M+H+) 346.
To the solution of 8.8 (1 mmole) in MeOH (20 mL, presparged with nitrogen gas) in a glass
pressure vessel was added chiral catalyst (+)-bis((2S,5S)-2,5-
dimethylphospholano)benzene(cyclooctadiene)rhodium(I)tetrafluoroborate (0.01 mmole). The
reactor was then pressurized with H2 to 40 psi and shaking was continued at room temperature
for 17 hours. The solvent was evaporated. The residue was dissolved in AcOEt and filtered
through a plug of SiO2 with AcOEt. The filtrate was evaporated to provide the crude product 8.9.
(yield, 72%). 1H NMR (400 MHz, CDCl3) d 2.98 (s, 3 H), 3.13 (dd, J=13.69, 6.36 Hz, 1 H), 3.29
(m, 1 H), 3.76 (s, 3 H), 4.69 (m, 1 H), 5.06 (m, 2 H), 5.44 (d, J=6.85 Hz, 1 H), 7.31 (m, 5 H),
7.41 (d, 7=7.34 Hz, 1 H, 7.47 (t, 7=7.83 Hz, 1 H), 7.72 (s, 1 H), 7.82 (d, 7=7.34 Hz, 1 H). ES1-
MS (m/z): (M+H+) 348.
The compound 8.9 was hydrogenated (Pd/C, MeOH,) with a hydrogen balloon to afford
compound 8.4 (yield 98%). ES1-MS (m/z): (M+H+) 258.
EXAMPLE 9
This example describes the synthesis of
a) Compound 9.1 was made according to Example ld-e except that compound 8.4 was used
instead of compound 1.3.
b) Compound 9 was made according to Example 3g except that compound 9.1 was used
instead of compound 3.7 and 2-hydroxycinnamic acid was used instead of compound 3.4. 1H NMR (400 MHz, CD3OD) d 7.92 (m, 2H), 7.81 (m, 1 H), 7.68 (s, 1 H), 7.58 (m, 2 H), 7.28 (m, 2
H), 7.18 (m, 1 H), 6.84 (m, 2 H), 5.07 (m, 1 H), 4.80 and 4.88 (m, 2H), 3.96 (m, 2H), 3.42 (m,
1H), 3.15 (m, 1H), 3.08 (s, 3H), 2.71-2.91 (m, 2H) ppm; ESI-MS (m/z): (M+H+) 617.10.
EXAMPLE 10
This example describes the synthesis of

which was prepared according to Example 3g except that compound 9.1 was used instead of
compound 3.7 and 2-fiuorocinnamic acid was used instead of compound 3.4. 1H NMR (400
MHz, CD3OD) d 7.92 (s, 1 H), 7.81 (m, 3H), 7.68 (m, lH),7.57(m, lH),7.42(m, lH),7.29(m,
2H), 7.23 (m, 1H), 7.16 (m, 1H), 5.06 (m, 1H), 4.81 and 4.88 (m, 2H), 3.82 and 3.97 (m, 2H),
3.44 (m, 1 H), 3.16 (m, 1 H), 3.08 (s, 3 H), 2.86 and 2.93 (m, 2H) ppm; ESI-MS (m/z): (M+HT)
619.10.
EXAMPLE 1 1
This example describes the synthesis of

which was prepared according to Example 3g except that compound 9.1 was used instead of
compound 3.7 and 6-indazolecarboxyIic acid was used instead of compound 3.4. 1H NMR (400
MHz, CD3OD) d 8.13 (s, 1H), 7.93 (m, 3H), 7.83 (m, 1H), 7.70 (m, 1H), 7.60 (m, 1H), 7.20 and
7.34 (m, 1H), 5.06 (m, 1H), 4.64 and 4.88 (m, 2H), 3.69 and 3.98 (m, 2H), 3.40 (m, 1H), 3.15
(m, 1H), 3.08 (s, 3H), 2.88 (m, 2H) ppm; ESI-MS (m/z): (M+H+) 615.15.
EXAMPLE 12
This example describes the synthesis of

which was prepared according to Example 3g except that compound 9.1 was used instead of
compound 3.7 and 2-indolecarboxylic acid was used instead of compound 3.4. 1H NMR (400
MHz, CD3OD) d 7.93 (s, 1H), 7.83 (m, 2H), 7.72 (m, 1H), 7.83 (m, 1H), 7.57 (m, 1H), 7.45 (m,
1H), 7.27 (s, 1H), 7.20 (m, 1H), 7.07 (m, 1H), 6.93 (s, 1H), 5.08 (m, 1H), 4.88 (m, 2H), 4.07 (m.
2H), 3.46 (m, 1H), 3.15 (m, 1H), 3.08 (s, 3H), 2.96 (m, 2H) ppm; ESI-MS (m/z): (M+H+) 614.10.
EXAMPLE 13
This example describes the synthesis of

which was prepared according to Example 3g except that compound 9.1 was used instead of
compound 3.7 and 2-quinolinecarboxylic acid was used instead of compound 3.4. 1H NMR (400
MHz, CD3OD) d 8.51 (m, 1H), 8.08 (m, 1H), 8.01 (m, 1H), 7.94 (m, 1H), 7.84 (m, 2H), 7.70 (m,
3H), 7.58 (m, 1H), 7.36 and 7.04 (m, 1H), 5.07 (m, 1H), 4.78 and 4.95 (m, 2H), 3.79 and 4.08
(m, 2H), 3.45 (m, 1H), 3.17 (m, 1H), 3.09 (s, 3H), 2.97 (m, 2H) ppm; ES1-MS (m/z): (M+H+)
626.10.

a) To a solution of 3-carboxylbenzenesulfonyl chloride (3.54 g, 16 mmol) in ethyl acetate
(50 mL) at 0 °C was added concentrated ammonia (2.5 mL). The reaction was neutralized with
HCl in dioance (20 mL), diluted with ethyl acetate (100 mL), dried with anhydrous sodium
sulfate and filtered. Concentration of the filtrate yielded the title compound, which was used
without purification.
b) Crude compound 14.1 was dissolved in THF (50 mL), to it was added borane (1.0 M in
THF, 50 mL) over 20 minute period. After the reaction was stirred at room temperature for 15
hours, the reaction was diluted with brine (20 mL) and water (10 mL), extracted with ethyl
acetate (100 mL). The organic extract was dried over anhydrous sodium sulfate and filtered.
Concentration of the filtrate yielded the title compound, which was used without further
purification.
c) To crude compound 14.2 solution in DCM (100 mL) was added activated 4A molecular
sieve powder (8 g), pyridinium dichromate (7.55 g, 20 mmol). After the reaction was stirred at
room temperature for 2 hours, the reaction mixture was filtered through silica gel (50 g), rinsed
with ethyl acetate. The residue after concentration of the filtrate was purified by silca gel
column with 30-50% ethyl acetate in hexane to give compound 14.3 (477mg, 16%, 3 steps).
ESI-MS (m/z): (M+H+) 186.
d) Compound 14.4 was made according to Example 8c except that compound 14.3 was used
instead of compound 8.7. MS (ESI+) m/z: 260 (M+H+).
e) Compound 14 was made according to Example 3g except that compound 14.4 was used
instead of compound 3.4. 1H NMR (400 MHz, CD3OD) d 7.89 (s, I H), 7.80 (s, 1 H), 7.75 (m, 2
H), 7.64 (s, 1 H), 7.57(d, 1 H), 7.34 (d, 2 H), 6.93 9s, 1 H), 5.00 (m, 1 H), 3.99 (m, 1 H), 3.73 (m,
1 H),3.40(dd, 1 H),3.12(dd, 1 H), 2.89 (m, 2 H) ppm; ESI-MS (m/z): 616 (M+H+).
EXAMPLE 15
This example describes the synthesis of

which was prepared according to Scheme 10 and the procedure below.
a) To a solution of 0.2 mol of furan in 200 ml of dry THF was added 0.2 mol of n-BuLi
(1.6 M in hexanes) at -78 °C, the resulting solution was stirred at room temperature for 4 hours.
Subsequently, the mixture was cooled to -78 °C and treated with 0.21 mol of dimethyl disulfide,
and the mixture was stirred at room temperature overnight, followed by adding 10 ml. of
saturated aqueous NH4Cl. The mixture was concentrated at room temperature, and the residue
was diluted with 200 mL of saturated aqueous NH4Cl and extracted with ether. The extract was
then washed with brine and dried with anhydrous Na2SO4. The solvent was removed, and the
residue was distilled to collect the fraction at 135-140 °C/760 mmHg to give compound 15.1 in
55% yield. 1H NMR (400 MHz, CD3Cl): d 7.50 (s, 1H), 6.45 (m, 1H), 6.39 (s, 1H), 2.42 (s, 3H)
ppm.
b) To a solution of 0.1 mol of compound 15.1 in 100 mL of dry THF was added 0.1 mol of
rt-BuLi (1.6 M in hexanes) at -78 °C, the resulting solution was stirred at room temperature for 4
hours. Subsequently, the mixture was cooled to -78 °C and treated with 0.12 mol of dry DMF,
and the mixture was stirred at room temperature overnight. The reaction was quenched by
adding 10 mL of saturated aqueous NH4Cl, and the mixture was concentrated. The residue was
diluted with 100 mL of brine and extracted with EtOAC. The extract was washed with brine and
dried with anhydrous Na2SO4. The solvent was removed and the residue was purified to give the
title compound in 65% yield. 1H NMR (400 MHz, CD3Cl): d 9.52 (s, 1H), 7.24 (d, J= 3.4 Hz,
1H), 6.42 (d, J= 3.4Hz, 1H), 2.60 (s, 3H) ppm; ESI-MS (m/z): (M+H+) 143.1.
c) A mixture of 50 mmol of compound 15.2 and 120 mmol of w-CPBA in 100 mL of
CH2Cl2 was stirred at room temperature overnight. The mixture was diluted with 150 mL of
CH2Cl2, and the mixture was washed with saturated aqueous NaHCO3 for several times. The
solution was then dried with anhydrous Na2SO4 and concentrated. The residue was purified to
give compound 15.3 in 70% yield. 1H NMR (400 MHz, CD3Cl): d 9.83 (s, 1H), 7.33 (m, 2H),
3.27 (s, 3H) ppm; ESI-MS (m/z): (M+H+) 175.0.
d) Compound 15.4 was made according to Example 8e except that compound 15.3 was used
instead of 8.7. ESI-MS (m/z): (M+H+) 248.1.
e) Compound 15 was made according to Example except that compound 15.4 was used
instead of 3.4. 1H NMR (400 MHz, CD3OD): d 7.92 (s, 1H), 7.76 (m, 1H), 7.67 (s, 1H), 7.34 (m,
1H), 7.13 (s, 1H), 6.69 (s, 1H), 6.49 (s, 1H), 5.11 (m, 1H), 4.73 and 4.88 (m, 2H), 3.76 and 4.02
(m, 2H), 3.46 (m, 1H), 3.30 (m, 1H), 3.17 (s, 3H), 2.94 (m, 2H) ppm; ESI-MS (m/z): (M+H+)
605.05.
EXAMPLE 16
This example describes the synthesis of

which was prepared according to the procedure below.
To a solution of 0.2 mmol of compound 8.4 (Example 8c or 8e) in 1 mmol of Et3N and 5 mL of
dry CH2Cl2 was added 0.22 mmol of 2,6-dichlorobenzoyl chloride at 0°C, the resulting mixture
was stirred at room temperature for 12 hours. The solvent was removed and the residue was
dried in vacuo. Subsequently, the residue was treated with 0.8 mmol of LiOH-H2O in 2 mL of
THF and 0.5 mL of H2O. After stirring at room temperature for 30 minutes, the reaction mixture
was added 1.0 mL of 1.0N aq. HCl. The organic solvent was removed, and the residue was
diluted with 10 mL of brine. The mixture was extracted with EtOAc and the extract was dried
with anhydrous Na2SO4 The solvent was removed and the residue was dried in vacuo to give the
desired compound in 65% yield. 1H NMR (400 MHz, CD3OD) d 7.92 (s, 1 H), 7.82 (d, J=6.85
Hz, 1 H), 7.71 (d, 7=6.85 Hz, 1 H), 7.56 (t, J=7.83 Hz, 1 H), 7.34 (m, 3 H), 5.08 (dd, J=9.78,
4.89 Hz, 1 H), 3.45 (dd, J =14.67, 4.89 Hz, 1 H), 3.14 (dd, J =14.67, 9.78 Hz, 1 H), 3.08 (s, 3 H)
ppm: ESI-MS (m/z): (M+H+) 416.00.
EXAMPLE 17
This example describes the synthesis of

which was prepared according to the procedure below.
Compound 6.1 (Example 6a, 0.2 mmol) in DCM (1 mL) was treated with HCl in dioxane (4.0 M,
1 mL). After lhour, the solvent was evaporated. The residue and 1 mmol of Et3N and 5 mL of
dry CH2Cl2 was added 0.22 mmol of 2,6-dichlorobenzoyl chloride at 0 °C, the resulting mixture
was stirred at room temperature for 15 hours. The solvent was removed and the residue was
dried in vacuo. Subsequently, the residue was treated with 0.8 mmol of LiOHH2O in 2 mL of
THF and 0.5 mL of H2O. After stirring at room temperature for 30 minutes, the reaction mixture
was added 1.0 mL of 1.0 N aqueous HCl. The organic solvent was removed, and the residue was
diluted with 10 mL of brine. The mixture was extracted with EtOAc and the extract was dried
with anhydrous Na2SO4 The solvent was removed and the residue was dried in vacuo to give the
desired compound.
EXAMPLE 18
This example describes the synthesis of

which is prepared according to Scheme 11 and the procedure below.
a) 1 equivalent of LiAlH4 (1.0M in THF) was added to a 0 oC solution of 1 equivalent of
compound ethyl 6-indazolecarboxylate (Batt,D.G., J Med.Chem. 43: 41-58 (2000)) at -78 °C.
The reaction was stirred at -78 °C for another 30 minutes, and then warmed to 0°C. An aqueous
solution of 1 equivalent of 1M NaOH was added slowly. The resulting slurry was filtered thru a
plug of Celite and washed with a copious amount of ethyl acetate. The combined organics were
dried with MgSO4 and concentrated in vacuo to provide the alcohol 18.1 in high enough purity to
be used without further purification.
b) 1.1 equivalent of Dess-Martin periodinane was added to 1 equivalent of 18.1 in
dichloromethane. After stirring the reaction for 3 hours at room temperature, the resulting
precipitate was removed by filtering thru a plug of celite. The celite plug was washed with
dichloromethane. The combined organics were concentrated to provide the aldehyde 18.2 in
high enough purity to be used without further purification.
c) 2.1 equivalents of ethyl magnesium bromide (0.5M in THF) were added to a pre-cooled
solution containing 18.2 in THF at 0°C. After 30 minutes, the reaction was warmed to room
temperature and stirred for an additional 2 hours. The resulting reaction mixture was diluted
with ethyl acetate and washed with water. The organic layer was then dried with MgSO4,
filtered, and concentrated in vacuo. The residue was then purified on silica gel column
chromatography (gradient elution using ethyl acetate and hexanes) to provide pure compound
18.3.
d) To a mixture of 4-amino-2,6-dichlorophenol (1 equivalent) in 3:2 THF/H2O was added
NaHCO3 (1.1 equivalent) and Boc2O (1.1 equivalent), after stirring overnight, the reaction was
extracted with ether, and dried with MgSO4, filtered, and concentrated in vacuo. The residue
18.4 was used without purification.
e) To a solution of phenol 18.4 (1 equivalent) and 2,6-lutidine (2.2 equivalent) in DCM at -
78°C was added triflic anhydride (1.2 equivalent). After the reaction mixture was gradually
warmed to room temperature overnight, the reaction mixture was diluted with ether, washed with
water, dried with MgSO4, filtered, and concentrated in vacuo. The residue was then purified on
silica gel column (gradient elution using ethyl acetate and hexanes) to provide pure compound
18.5.
f) A mixture of 10mmol of the triflate 18.5 , l.Ommol of dppp and 40mmol of DIEA (in
100mL of dry DMF and 50mL of anhydrous CH3OH was flushed with CO for 15 minutes, and
then 1.0mmol of Pd(OAc)2 was added under the atmosphere of CO. Subsequently, the resulting
mixture was stirred at 70 °C overnight under an atmosphere of CO. The solvent was removed
and the residue was purified by column chromatography with 10-30% EtOAc in hexane to give
compound 18.6.
g) 1 equivalent of Boc-aniline 18.6 was dissolved carefully in 6 M aqueous H2SO4, and the
mixture was then cooled to 0 °C. To it was added slowly with vigorous stirring sodium nitrite
(1.1 equivalent in water), followed by sodium iodide (5 equivalent) in 1.5 hours. After the
reaction was stirred at room temperature for overnight, the reaction was diluted with ether,
washed with water, dried with MgSO4, filtered, and concentrated in vacuo. The residue was then
purified on silica gel column (gradient elution using ethyl acetate and hexanes) to provide pure
compound 18.7.
h) 1 equivalent of iodide 18.7, 1 equivalent of alkyne 18.3, 0.05 equivalent of Cul, and 5
equivalents of triethylamine were dissolved in benzene and the solution degassed by bubbling N2
thru a syringe needle and into the solution for 15 minutes. 0.05 equivalent of PdCl2(dppf). DCM
was added. After 4 hours, the reaction was diluted with ethyl acetate and washed with water,
brine. The organic layer was then dried with MgSO4, filtered, and concentrated in vacuo. The
residue was then purified on silica gel column chromatography (gradient elution using ethyl
acetate and hexanes) to provide pure compound 18.8.
i) 1 equivalent of 18.8 was dissolved in MeOH and 5 % Rh/Al2O3 (20 weight%) was added.
Under reduced pressure, oxygen was removed from the flask. The internal pressure was restored
by the addition of hydrogen gas delivered using a hydrogen filled balloon. The reaction was
stirred under an atmosphere of hydrogen gas for 14 hours. The reaction was filtered thru a pad
of celite and concentrated in vacuo. The residue was then purified on silica gel column
chromatography (gradient elution using ethyl acetate and hexanes) to provide pure compound
18.9.
j) 4 equivalents of Lil was added to 1 equivalent of compound 18.9 in pyridine. The
reaction was refluxed for 14 hours, then allowed to cool to room temperature. The reaction was
concentrated and the resulting residue was partitioned between ethyl acetate and water. The
aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over
MgSO4, filtered, and concentrated. The residue was then purified on silica gel column
chromatography (gradient elution using ethyl acetate and methanol) to provide pure compound
18.10.
k) 1 equivalent of compound 18.10, 1 equivalent ofcompound 8.4 (Example 8c or 8e), and 3
equivalents of D1EA were dissolved in DMF. 1.1 equivalent of HATU was added. The reaction
was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl
acetate and washed with water, brine. The combined organics were dried with MgSO4, filtered.
and concentrated. The residue was then purified on silica gel column chromatography (gradient
elution using ethyl acetate and hexanes) to provide pure intermediate ester. The ester was
dissolved in methanol followed by addition of 2 equivalents of 1M LiOH(aq). Upon completion,
the excess solvents were removed under reduced pressure and the resulting acid was then
purified by reverse phase HPLC to give pure compound 18.
EXAMPLE 19
This example describes the synthesis of

which was prepared by treating a solution of compound 18 (Example 18) in DCM/TFA (1:1
ratio) with triethylsilane (10 equivalent). After LC-MS showed that the starting material was
completely consumed, the reaction was concentrated, and the residue was purified by reverse
phase HPLC to give the title compound.
EXAMPLE 19
This example describes the synthesis of

which was prepared according to Scheme 12 and the procedure below.

a) A solution of 1 equivalent of compound 18.7 (Example 18g) in THF at -40 °C was
treated with 1.0 equivalent of isopropylmagnesium bromide. After 0.5 hour, DMF (5
equivalents) was added, and the reaction was warmed to room temperature over night. The
reaction mixture was diluted with ethyl acetate and washed with water, brine. The organic layer
was then dried with MgSO4, filtered, and concentrated in vacuo. The residue was then purified
on silica gel column chromatography (gradient elution using ethyl acetate and hexanes) to
provide pure compound 20.1.
b) To a solution of aldehyde 20.1 (1 equivalent) in THF at -78 °C was added 2.1 equivalents
of ethnyl magnesium bromide (0.5 M in THF). After the reaction was warmed to room
temperature and stirred for an additional 2 hours. The resulting reaction mixture was diluted
with ethyl acetate and washed with water. The organic layer was then dried with MgSO4,
filtered, and concentrated in vacuo. The residue was then purified on silica gel column
chromatography (gradient elution using ethyl acetate and hexanes) to provide pure compound
20.2.
c) 1 equivalent of compound 20.2, 1 equivalent of l-chloro-4-iodobenzene. 0.05 equivalent
of Cul, and 5 equivalents of triethylamine were dissolved in benzene and the solution degassed
by bubbling N2 thru a syringe needle and into the solution for 15 minutes. 0.05 equivalent of
PdCl2(dppf)-DCM was added. After 4 hours, the reaction was diluted with ethyl acetate and
washed with water, brine. The organic layer was then dried with MgSO4, filtered, and
concentrated in vacuo. The residue was then purified on silica gel column chromatography
(gradient elution using ethyl acetate and hexanes) to provide pure compound 20.3.
d) 1 equivalent of compound 20.3 was dissolved in MeOH. 5% Rh/Al2O3 was added.
Under reduced pressure, oxygen was removed from the flask. The internal pressure was restored
by the addition of hydrogen gas delivered using a hydrogen filled balloon. The reaction was
stirred under an atmosphere of hydrogen gas for 14 hours. The reaction was filtered thru a pad
of celite and concentrated in vacuo. The residue was then purified on silica gel column
chromatography (gradient elution using ethyl acetate and hexanes) to provide pure compound
20.4.
e) 4 equivalents of Lil was added to 1 equivalent of compound 20.4 in pyridine. The
reaction was refluxed for 14 hours, then allowed to cool to room temperature. The reaction was
concentrated and the resulting residue was partitioned between ethyl acetate and water. The
aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over
MgSO4, filtered, and concentrated. The residue was then purified on silica gel column
chromatography (gradient elution using ethyl acetate and methanol) to provide pure compound
20.5.
f) 1 equivalent of compound 20.5, 1 equivalent of compound 8.4 (Example 8c or 8e), and 3
equivalents of DIEA were dissolved in DMF. 1.1 equivalent of HATU was added. The reaction
was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl
acetate and washed with water, brine. The combined organics were dried with MgSO4, filtered,
and concentrated. The residue was then purified on silica gel column chromatography (gradient
elution using ethyl acetate and hexanes) to provide pure compound 20.6.
g) 1 equivalent of compound 20.6 was dissolved in methanol followed by 2 equivalents of
1M LiOH(aq). Upon completion, the excess solvents were removed under reduced pressure and
the resulting acid was then purified by reverse phase HPLC and lyophilized to a pure powder
compound 20.
EXAMPLE 21
This example describes the synthesis of
which was prepared according to Scheme 13 and the procedure below.

a) A solution of bromine (461 µL, 9.00 mmol) in methanol (6.0 mL) was prepared at -
78oC. The cold solution was added dropwise to a mixture of KCN (1.85 g, 19.0 mmol) in
methanol (6.0 mL) under nitrogen at -78°C. After 20 minutes, a solution of pyrrole (0.624 mL,
9.00 mmol) in methanol (20 mL) was added. The mixture was allowed to reach -40°C and
stirred for 0.5 hour. It was then poured into ice-water and extracted with ether (3x). The organic
layers were combined and washed with saturated sodium thiosulfate and brine. The organic
phase was then dried (Na2SO4) and concentrated. The crude residue was purified by flash
chromatography (0-50% ethyl acetate in hexane) to yield 734 mg (66%) of compound 21.1 as a
clear oil, Rf0.24 (10% ethyl acetate in hexane). 1H NMR (CDCl3) d 8.68 (br s, I H), 7.03 (s, 1
H), 6.69 (s, 1 H), 6.32 (s, 1 H). ES (+) MS m/e = 125 (M + H)+.
b) To a solution of 21.1 (614 mg, 4.95 mmol) and iodomethane (0.340 mL, 5.45 mmol) in
methanol (40 mL) under nitrogen at -10°C was added dropwise aqueous sodium hydroxide (9.90
mL, 1 M, 9.90 mmol). The mixture is warmed to ambient temperature and stirred for 0.5 h.
Excess sodium hydroxide is then quenched by the addition of dry ice. The mixture is tiluted with
brine and extracted with dichloromethane (3x), The combined organic layers are dried (Na2SO4)
and concentrated to yield 504 mg (90%) of compound 21.2 as a dark oil, Rf 0.35 (10% ethyl
acetate in hexane). 1H NMR (CDCl3) d 8.31 (br s, 1 H), 6.84 (s, 1 H), 6.38 (s, 1 H), 6.24 (s, 1 H),
2.36 (s, 3 H).
c) To a 0°C solution of compound 21.2 (100 mg, 0.884 mmol) in methanol (4.0 mL) was
added dropwise sodium periodate (208 mg, 0.972 mmol) in water (4.0 mL). The mixture is
allowed to reach room temperature and after 15 minutes LC/MS and TLC indicated complete
disappearance of compound 21.2. The mixture was then filtered, concentrated, and the residue
was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with
ethyl acetate and the combined organic phases were washed with brine, dried (Na2SO4) and
concentrated to yield 63 mg (55%) of compound 21.3 as a dark oil, Rf 0.25 (ethyl acetate). 1H
NMR (CDCl3) d 11.74 (br s, 1 H), 7.00 (s, 1 H), 6.65 (s, 1 H), 6.20 (s, 1 H), 3.03 (s, 3 H). ES (+)
MS m/e= 130 (M + H)+.
d) To a solution of compound 21.3 (60 mg, 0.464 mmol) in dichloromethane (2.0 mL) was
added trifluoroacetic acid (1.0 mL). After 15 minutes, LC/MS and TLC indicated complete
consumption of compound 21.3. The solvent was removed in vacuo and the residue was dried
under high vacuum to yield 60 mg (100%) of compound 21.4 as an oil, Rf0.11 (ethyl acetate), 1H
NMR (CDCl3) d 9.16 (br s, 1 H), 7.28 (s, 1 H), 6.94 (s, 1 H), 6.66 (s, 1 H), 3.02 (s, 3 11). ES (+)
MS m/e= 130(M + H)+
e) To a mixture of compound 21.4 (60 mg, 0.464 mmol) and Cs2CO3 (378 mg, 1.16 mmol)
was added a solution of compound 21.5 (Ferreira et al, Tetrahedron Letters, 39: 9575 (1998); 140
mg, 0.464 mmol) in acetonitrile. The resulting mixture was stirred at 60°C until LC/MS and
TLC indicated complete consumption of the starting material (~1 hour). The mixture was cooled
to room temperature, diluted with ethyl acetate and washed with water and brine. The organic
layer was dried (Na2SO4) and concentrated. The crude residue was purified by flash
chromatography (0-100% ethyl acetate in hexane) to yield 1 14 mg (57%) of compound 21.6 as a
viscous oil, Rf 0.31 (ethyl acetate). 1H NMR (CDCl3) d 7.05 (s, 1 H), 6.75 (s, 1 H), 6.50 (s, 1 H),
5.25 (m, 1 H), 4.65 (m, 1 H), 4.40 (m, 1 H), 3.79 (s, 3 H), 2.79 (s, 3 H), 1.47 (s, 18 H). ES (+)
MS m/e = 275 (M - Boc - t-Bu+ 2 H)+.
f) To a solution of compound 21.6 (114 mg, 0.265 mmol) in dichloromethane (1.00 mL) is
added mCPBA (89.0 mg, 0.397 mmol) portionwise. After 5 minutes at room temperature,
LC/MS and TLC indicated complete disappearance of compound 21.6. The mixture was filtered
and concentrated. The crude residue was purified by flash chromatography (0-50% ethyl acetate
in hexane) to yield 89.0 mg (75%) of compound 21.7 as a clear oil, Rf0.45 (50% ethyl acetate in
hexane). 1H NMR (CDCl3) d 7.22 (s, 1 H), 6.69 (s, 1 H), 6.50 (s, 1 H), 5.27 (m, 1 H), 4.65 (m, 1
H), 4.45 (m, 1 H), 3.79 (s, 3 H), 305 (s, 3 H), 1.48 (s, 18 H). ES (+) MS m/e = 247 (M - 2 Boc +
3 H)+.
g) To a solution of compound 21.7 (89.0 mg, 0.0.199 mmol) in dichloromethane (0.50 mL)
was added HCl (4.00 mL, 4.0 M in dioxane). The resulting mixture was stirred at ambient
temperature until LC/MS indicated complete deprotection (-1 hour). The mixture was
concentrated and the residue was dried under high-vacuum to yield 53 mg (100%) of compound
21.8 as white powder. ES (+) MS m/e = 247 (M + H)+.
h) A mixture of compound 21.8 (53.0 mg, 0.199 mmol), compound 4.1 (Example 4a, 77.0
mg, 0.199 mmol), HATU (79.0 mg, 0.209 mmol), and triethyl amine (0.1 11 mL, 0.796 mmol) in
DML (1.00 mL) was stirred at room temperature over night. The mixture was then diluted with
ethyl acetate and washed with 1.0 M aqueous HC1, saturated NaHCO3, and brine. The organic
layer was dried (Na2SO4) and concentrated. The crude residue was purified by flash
chromatography (0-100% ethyl acetate in hexane) to yield 70.3 mg (58%) of compound 21.9 as a
white solid, Rf 0.16 (75 %ethyl acetate in hexane). 1H NMR (CDCl3) d 7.46-7.39 (m, 5 H), 7.28
(s, 1 H), 6.73 (s, 1 H), 6.69 (br s, 1 H), 6.48 (s, 1 H), 5.13 (m, 1 H), 4.83 (br s, 1 H), 4.56 (m, 1
H), 3.85 (s, 3 H), 3.70 (m, 1 H), 3.04 (s, 3 H), 2.91 (br s, 2 H), 2.81 (s, 2H). ES (+) MS m/e =
614 (M + H)+.
i) To a solution of 21.9 (70.3 mg, 0.115 mmol) in THF (1.00 mL) was added LiOH
(aqueous 1.0 M, 0.360 mL, 0.360 mmol). The resulting mixture was stirred at room temperature
until TLC and LC/MS indicated complete hydrolysis (~0.5 hour). The reaction was then
quenched by the addition of 1.0 M aqueous HCl (0.400 mL) and concentrated to dryness. The
residue was taken up in dimethylsulfoxide ("DMSO"; 4.0 mL) and purified by preparative RP-
HPLC. The fractions containing pure compound were consolidated and concentrated. The
residue was lyophilized under high-vacuum for 48 hours to yield 33.8 mg (49%) of compound 21
as a white powder. 1H NMR (CDCl3) d 7.46-7.39 (m, 4 H), 7.28 (m, 2 H), 7.15 (br s, 1 H), 6.77
(s, 1 H), 6.38 (s, 1 H), 5.74 (br s, 2 H), 5.04 (m, 1 H), 4.83 (br s, 1 H), 4.53 (m, 3 H), 3.69 (m, 1
H), 3.00 (s, 3 H), 2.85 (br s, 2 H). ES (+) MS m/e = 600 (M + H)+.
EXAMPLE 22

a) A solution of 5.0g (28.2 mmol) of compound 22.1 (Plobeck et al, J.Med.Chem. 43:3878-
3894 (2000)) and sulfuryl chloride (100 mmol each, added at the beginning of the reaction and
after 15 hours) in acetic acid (50 mL) was refluxed for 36 hours. The off white solid after
concentration of the reaction mixture was rinsed with ether, and to the resulting crude product
was added DCM (50 mL), followed by BBr3 (1.0 M in DCM, 100 mL). After 6 hours, the
reaction mixture is concentrated, and water (50 mL) was carefully added. The resulting
precipitate is collected by suction filtration and dried to give crude compound 22.2 in
quantitative yield.
b) The crude compound 22.2 was dissolved in DCM/pyridine (50 mL/50 mL) and cooled to
0 °C. To it was slowly added triflic anhydride (42.3 mmol), and the reaction was then stirred at
room temperature for 6 hours. The reaction mixture was partitioned between ethyl acetate (200
mL) and water (50 mL), and the organic layer was washed with water (30 mL, twice) and brine,
dried over anhydrous sodium sulfate and filtered. The residue after concentration of the filtrate
was purified by silica gel column chromatography to give compound compound 22.3 (3.16 g,
32%). ES1-MS (m/z): (M+H+) 364/366.
c) Carbon monoxide gas was bubbled through a mixture of compound 22.3 (581 mg, 1.6
mmol), BiNAP (0. 2 mmol), palladium acetate (0.2 mmol), triethylamine (1 mL), anhydrous
methanol (3 mL) and anhydrous DMF (3 mL) for 10 min, then the reaction was heated at 65 °C
under a carbon monoxide balloon for 15 hours. The reaction mixture was partitioned between
ethyl acetate (100 mL) and water (25 mL), and the organic layer was washed with water (25 mL,
twice) and brine, dried over anhydrous magnesium sulfate and filtered. The residue after
concentration of the filtrate was purified by silica gel column to give compound 22.4 (213 mg,
49%). ESI-MS (m/z): (M+H+) 274/276.
d) To a suspension of sodium hydride (24 mg, 1.0 mmol) in THF (2 mL) was added
compound 22.4 (63 mg, 0.23 mmol), 4-chlorobenzyl chloride (55 mg, 0.34 mmol) and
tetrabutylammonium iodide (10 mg). After 6 hours, the reaction was diluted with ether and
filtered through silica gel, rinsed with ether. The residue after concentration of the filtrate was
purified by silica gel column to give compound 22.5 (50 mg, 55 %). ESI-MS (m/z): (M+H+)
398/400.
e) A mixture of compound 22.5 (50 mg) and 1 mmol of Lil in 2 mL of pyridine was reflux
overnight. The reaction was concentrated in vacuo and the residue was further dried by high
vacuum for 2 hour. The resulting crude compound 22.6 was used without further purificaiton.
ESI-MS (m/z):(M+l), 384.
f) Compound 22 was prepared according to Example 3g except that compound 22.6 was
used instead of compound 3.7 (yield: 82%). 1H NMR (400 MHz, dmso-d6): 9.12 (d, 1 H), 8.54
(t, 1 H), 7.90 (s, 1 H), 7.77 (dd, 1 H), 7.72 (dd, 1 H), 7.42 (d, 2 H), 7.35 (d, 2 H), 7.16 (dd, 1 H),
4.77 (m, 1 H), 4.70 (s, 2 H), 3.64 (m, 2 H), 3.53 (t, 2 H), 3.01 (t, 2 H) ppm. ESI-MS (m/z):
(M+H+) 580.
EXAMPLE 23
This example describes the synthesis of
a) To a solution of Trit-Ser-Ome (compound 23.1, 10 mmol) and triethylamine in DCM (40
mL) was added slowly methanesulfhonyl chloride (11 mml), after 12 hours, the reaction was
extracted with ether (100 mL), washed with water, dried over anhydrous magnesium sulfate and
filtered. Concentration of the filtrate gave compound 23.2, which was used without further
purification.
b) Solution of the crude compound 23.2, sodium azide (20 mmol) in DMF was stirred for 15
hours. The reaction was extracted with ether (100 mL), washed with water, dried over
anhydrous magnesium sulfate and filtered. The residue after concentration of the filtrate was
purified by column, eluting with 0-20% ethyl acetate in hexane to give compound 23.3.
c) A mixture of 1 mmol of compound 23.3, 1.5 mmol of cyclopropylacetylene, 0.02 mmol
of Cul, and 0.02 mmol of Et3N in 6 mL of CH3CN was stirred at room temperature overnight.
The solvent was removed and the residue was purified to give compound 23.4 in 65% yield. H
NMR (400 MHz, CD3OD): d 7.80 (s, 1H), 7.29-7.31 (m, 6H), 7.15-7.23 (m, 9H), 4.49 (m, 2H),
3.73 (m, 1H), 3.16 (s, 3H), 1.99 (m, 1H), 0.99 (m, 2H), 0.80 (m, 2H) ppm; ES1-MS (m/z):
(M+H+)453.15.
d) A mixture of 0.5 mmol of compound 23.4 in 2 mL of 4.0 N HCl in dioxane was stirred at
room temperature for I hours. The solvent was removed and the residue was diluted with 10 mL
of water. The mixture was extracted with ether for 3 times, and the aqueous phase was dried
with lyophilizer to give compound 23.5 in quantitative yield. ES1-MS (m/z): (M+H+) 212.15.
e) Compound 23 was prepared according to Example 3g except that compound 4.4 was used
instead of compound 3.7 and compound 23.5 was used instead of compound 3.4. 1H NMR (400
MHz, CD3OD): d 7.74 (s, 1H), 7.33 and 7.49 (m, 5H), 5.25 (m, 1H), 4.63-4.92 (m, 4H), 3.99 and
3.68 (m, 2H), 2.89 (m, 2H), 1.91 (m, 1H), 0.95 (m, 2H), 0.75 (m, 2H) ppm; ESI-MS (m/z):
(M+H+) 562.10.
EXAMPLE 24

a) To a solution of 50 mmol of l-bromo-3,5-difluorobenzene in 100 mL of dry DMF was
added 50 mmol of NaSCH3 at 0 °C, the resulting mixture was stirred at room temperature
overnight and treated with 10 mL of saturated aqueous NH4Cl. The mixture was diluted with 1 L
of water, extracted with hexane for several times. The extract was washed with waster and dried
with anhydrous Na2SO4. The solvent was removed and the residue was purified to give
compound 24.2 in 90% yield. 1H NMR (400 MHz, CD3Cl): d 7.15 (s, 1H), 7.02 (d, J= 8.3 Hz,
1H), 6.89 (d, J= 9.2 Hz, 1H), 2.50 (s, 3H) ppm.
b) A mixture of 40 mmol of compound 24.2 and 42 mmol of CuCN in 100 mL of dry DMF
was stirred at 150 °C overnight. The mixture was diluted with 500 mL of water, extracted with
ether for several times. The mixture was then washed with diluted aqueous NH4OH and water
and dried with anhydrous Na2SO4. The solvent was removed; the residue was purified to give
compound 24.3 in 50% yield. 1H NMR (400 MHz, CD3Cl): d 7.28 (s, 1H), 7.17 (d, J= 9.2 Hz,
1H), 7.11 (d, J= 6.8 Hz, 1H), 2.53 (s, 3H) ppm; ESI-MS (m/z): (M+H+) 168.0.
c) A mixture of 20 mmol of compound 24.3 and 22 mmol of KOH in 25 mL of EtOH and
35 mL of H2O was stirred at 60 °C for 30 minutes. The mixture was concentrated, the residue
was diluted with 100 mL of water, extracted with EtOAc for several time. The extract was dried
with anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give a
crude product of compound 24.4. The crude was carried on the next step without further
purification. ESI-MS (m/z): (M+H+) 187.0.
d) To a solution of 20 mmol of compound 24.4 in 60 mL of dry THF was added 24 mmol of
LiAlH4 (1.0 M in THF) at 0 °C. After stirring at room temperature overnight, the reaction
mixture was carefully added saturated aqueous NH4Cl. The resulting suspension was then
concentrated. The residue was dissolved in 200 mL of 1.0 N HCl and extracted with EtOAc for
several times. The extract was dried with anhydrous Na2SO4 and concentrated. Subsequently.
the residue was purified to give 5-fluoro-3-methylmercapto-l-benzeyl alcohol in 81% yield.
1H NMR (400 MHz, CD3Cl): 5 7.03 (s, 1H), 6.86 (m, 2H), 4.69 (s, 2H), 2.51 (s, 3H) ppm; ESI-MS
(m/z): (M+H+) 173.1.
A mixture of 15 mmol of 5-fluoro-3-methylmercapto-l-benzeyl alcohol and 20 mmol of SOCl2
in 30 mL of dry CH2Cl2 was refluxed for several hours. The mixture was then diluted with 100
mL of CH2Cl2, washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, and brine
and dried with anhydrous Na2SO4. The solvent was removed and the residue was purified to
give compound 24.5 in 85% yield.
e) Compound 24.6 was prepared according to Example 3a-c except that compound 24.5 was
used instead of 3-methylthiobenzyl chloride.
f) Compound 24 was prepared according to Example 3g except that compound 24.6 was
used instead of compound 3.7. 1H NMR (400 MHz, CD3OD): d 7.92 (s, 1 H), 7.80 (s, 1H), 7.75
(d, J= 7.83 Hz, 1H), 7.74 (s, 1H), 7.59 (d, J= 7.34 Hz, 1H), 7.49 (d, J= 9.29 Hz, 1H), 7.07 and
7.35 (m, 2H), 6.96 (s, 1H), 5.10 (dd, J= 9.78, 4.40 Hz, 1H), 4.72 and 4.91 (m, 2H), 3.77 and 4.00
(m, 2H), 3.50 (dd, J= 14.18, 4.40 Hz, 1H), 3.20 (m, 1H), 2.91 (m, 2H) ppm; ESI-MS (m/z):
(M+H+) 633.10.
EXAMPLE 25
This example describes the synthesis of

a) To a solution of 5.0 mmol of compound 3.2 (Example 3a), 0.25 mmol of Pd(PPh2)2Cl2,
and 0.25 mmol of Cul in 15 mmol of degassed Et3N and 40 mL of degassed toluene was added
5.5 mmol of isobutyryl chloride at 0 °C. The resulting mixture was stirred at room temperature
overnight and treated with 20 mL of saturated aqueous NaHCO3. The organic layer was
separated and dried with anhydrous Na2SO4. The solvent was removed and the residue was
purified by column chromatography to give compound 25.1 in 80% yield. 1H NMR (400 MHz,
CD3OD): d 4.38 (m, 1H), 3.74 (s, 3H), 2.91 (m, 2H), 2.61 (m, 1H), 1.44 (s,9H), 1.14 (d, J= 6.85
Hz, 6H) ppm; ESI-MS (m/z): (M+H+) 320.01.
b) To a solution of 1.0 mmol of compound 25.1 in 3 mL of CH3OH was added 1.0 mmol of
NH2NH2 at 0 °C, the resulting mixture was stirred for another 30 minutes. The solvent was
removed, and the residue was purified give compound 25.2 in 65% yield.
1H NMR (400 MHz, CD3OD): 6.28 and 5.95 (s, s, 1 H), 4.39 and 4.19 (m, 1H), 3.72 (s, 3H), 2.91
(m, 2H), 2.70 and 2.98 (m, 1H), 1.43 and 1.45 (s,s, 9H), 1.12 and 1.27 (m, 6H) ppm; ESI-MS
(m/z): (M+H+) 312.20.
c) A mixture of 0.5 mmol of compound 25.2 in 4 mL of 4.0 N HCl in dioxane was stirred at
room temperature for 12 hours. The solvent was removed and the residue was dried in vacuo to
give compound 25.3. ESI-MS (m/z): (M+H+) 212.10.
d) Compound 25 was prepared according to Example 3g except that compound 4.4 was used
instead of compound 3.7 and compound 25.3 was used instead of compound 3.4.
1H NMR (400 MHz, CD3OD): 7.15-7.54 (m, 5H), 6.38 (s, 1H), 5.06 (dd, J= 9.78, 4.89 Hz, 1H),
4.66 and 4.88 (m, 2H), 4.01 and 3.71 (m, 2H), 3.41 (dd, J= 15.41, 4.65 Hz, 1H), 3.18 (dd, J=
15.16, 4.65 Hz, 1H), 3.07 (m, 1H), 2.92 (m, 2H), 1.32 (d, J= 7.34 Hz, 6H) ppm; ESI-MS (m/z):
(M+H+) 563.10.
EXAMPLE 26

a) A solution of compound 26.1 (12.4 g, 75 mmol) and NH4BF4 (10.5 g, 100 mmol) in
water (85 mL) was treated with concentrated HCl (15 mL), cooled to 3 °C, and treated dropwise
over 25 minutes with a solution of NaNO2 (5.18 g, 75 mmol) in water (12 mL). The resulting
thick slurry was stirred for 35 minutes, and the solid was collected by filtration, rinsed with
water, methanol, and ether, and dried under N2. The solid was added in one portion to a stirred
mixture of KOAc (8.1 g, 82.5 mmol) and 18-crown-6 (0.5 g, 1.9 mmol) in chloroform (170 mL).
After 70 minutes, water (170 mL) was added, and the layers were separated. The aqueous phase
was extracted with chloroform, and the combined organic layers were rinsed with water, dried,
and concentrated. The residue was triturated with hexane and the resulting solid isolated by
filtration to provide 8.85 g (67% yield) of compound 26.2 as a dull yellow powder. 1H NMR
(CDCl3) d 3.96 (s, 3H), 7.80 - 7.85 (m, 2H), 8.14 (s, 1H), 8.27 (s, 1H); BS (+) MS m/e =
177(M+1).
b) A solution of compound 26.2 (5.0 g, 28.4 mmol) in THF (56 mL) was treated with LiOH
(21 mL of a 2M aqueous solution, 42 mmol), and the reaction mixture is stirred at 50 °C. After 4
hours, the reaction mixture was cooled to room temperature and diluted with water. The basic
aqueous layer was rinsed with diethyl ether, acidified to pH 3-4 by the addition of 1 M HC1, and
extracted with ethyl acetate. The aqueous layer was extracted further with ethyl acetate, and the
combined organic layers were rinsed with brine, dried over MgSO4, and concentrated to afford
4.0 g (87% yield) of compound 26.3. 1H MMR (CD3OD) d 7.79 - 7.87 (m, 2H), 8.14 (s, 1H),
8.29 (s,lH); ES (+) MS m/e = 163(M+1).
c) A solution of compound 1.1 (7.5 g, 20.8 mmol) in DCM (30 mL) was treated with TFA
(10 mL). After 1 hour, the reaction mixture was concentrated to afford 7.8 g (100% yield) of
compound 26.4. ES (+) MS m/e = 261(M+1).
d) A solution of compound 26.3 (7.8 g, 20.8 mmol), compound 26.4 (3.4 g, 20.8 mmol),
1-hydroxybenzotriazole hydrate ("HOBt", 3.5 g, 22.3 mmol), and diisopropylethylamine
("D1EA",14 mL, 83.3 mmol) in DMF (100 mL) was treated with EDC1 (4.4 g, 22.3 mmol).
After 2 h, the reaction mixture was treated with 1 M HCl and extracted with ethyl acetate. The
combined organic extracts were rinsed with NaHCCh (sat'd), rinsed with brine, rinsed with
water, dried over MgSO4, and concentrated to afford 8.4 g (99% yield) of the title compound.
ES(+)MS m/e = 404(M+l).
e) A solution of compound 26.5 (8.4 g, 20.8 mmol) in pyridine (70 mL) was treated with
lithium iodide (11.1 g, 83.1 mmol), and the reaction mixture was heated to 100 °C. After 16
hours, the reaction mixture was cooled to room temperature and diluted with 1 M NaOH (aq).
The basic aqueous layer was rinsed with diethyl ether to remove most of the pyridine. The
aqueous portion was then carefully acidified with concentrated HCl to pH 3-4. The resulting
slurry was filtered. The precipitate was collected and dissolved in THF, while the filtrate was
extracted with ethyl acetate. The THF and ethyl acetate solutions were combined, rinsed with
brine, dried over MgSO4, and concentrated to afford 7.1 g (88% yield) of compound 26.6. ES
(+)MS m/e = 390(M+l).
f) A solution of compound 26.6 (3.06 g, 7.83 mmol) and DIEA (4.6 mL, 25,4 mmol) in
dimethylformamide ("DMF") was treated with HATU (3.06 g, 8.06 mmol), and the resulting
mixture was stirred at room temperature. After 20 minutes, the reaction mixture was treated
sequentially with HCIH-DAP(Boc)-OMe (2.18 g, 8.59 mmol) and N,N-dimethylaminopyridine
("DMAP", 0.568 g, 4.65 mmol). After 2.5 hours, the reaction was diluted with ethyl acetate,
washed with three portions of water, washed with one portion of brine, dried over MgSO4, and
concentrated. Flash column chromatography afforded 3.91 g (84% yield) of compound 26.7. 1H
NMR (400 MHz, chloroform-d) d: 1.42 (s, 9H), 2.81 (s, 2H), 3.70 (m, 2H), 3.75 (2H), 3.81 (s.
3H), 4.82 (m, 21H), 4.99 (m, 1H), 7.21 (d, 2H), 7.59 (s, 1H), 7.81 (d, 1H), 8.l0(s, 1H). MS
(AP1-ES+) m/z: 590.2 (M+H+). 534.1(M-tButyl+H+), 490.1(M-Boc+H+).
g) A solution of compound 26.7 (3.91 g, 6.62 mmol) in DCM was treated with HCl (8.3 mL
of a 4 M dioxane soln, 33.2 mmol), and the resulting mixture was stirred at room temperature.
After 2 hours, the reaction mixture was concentrated to afford the HCl salt, which was used
without further purification. The HCl salt (3.94 g, 6.99 mmol) and triethylamine ("TEA", 3.0
mL, 21.5 mmol) in methanol was treated with N-cyanoimido-S,S-dimethyl-dithiocarbonate (1.37
g, 8.43 mmol), and the reaction mixture was stirred at 50 °C. After 3.5 hours, the reaction
mixture was concentrated to remove most of the methanol, diluted with ethyl acetate, washed
with two portions of water, washed with one portion of brine, dried over MgSO4, and
concentrated. Flash column chromatography afforded 3.27 g (80% yield) of compound 26.8
(MS (API-ES+) m/z: 588.2(M+H+). A solution of compound 26.8 (0.10 mmol) was made in 4:1
methanol/dichloroethane ("DCE", 2.5 mL) and treated sequentially with 2 M methanolic
ammonia (0.25 mmol) and silver nitrate (0.10 mmol). The reaction mixture was stirred at 50 oC
until complete conversion is observed through monitoring by LCMS. The reaction mixture was
then filtered through celite, and KOH (0.1 mL of a 2 M methanolic soln, 0.2 mmol) was added.
The reaction mixture was stirred once again at 50 °C. After 2-4 hours the reaction mixture was
directly subjected to preparatory HPLC purification to afford compound 26.
EXAMPLE 27
This example describes the synthesis of

where RA and RB are each independently hydrogen, aliphatic, aromatic, heteroaromatic, or
together form a cyclic moiety. These compounds are made according to the procedure of
Example 26 except that a substituted amine of the formula HNRARB is used instead of ammonia
in step g. Illustrative examples of substituted amines and the resulting compounds are shown in
Table 1.

EXAMPLE 28
This example describes the synthesis of

which is made according to Scheme 19 and the procedure below.

a) Compound 28.4 is prepared from 28.1 in three chemical steps, following the procedure
published in Okada, T. et al Chem. Phar. Bull. 1993,47(1), 126-131; Frigola, J. et all Med.
Chem. 1993, 36(7), 801-810 as shown above. A solution of commercially available 28.1 in
DCM is treated with trifluoromethanesulfonyl chloride in the presence of base to provide 36.2.
Next, this product is dissolved in dimethoxyethane ("DME"), and the mesylate moiety is
displaced by dimethylamine. Finally, Pd/C-catalyzed hydrogenolysis in MeOH at 45 PS1 H2 (g)
affords compound 28.4.
b) Compound 28 is synthesized according to the procedure of Example 26 except 3-
(dimethylamino)cyclobutanol (35.1) is used instead of ammonia in step g.
EXAMPLE 29
This example describes the synthesis of

which is made according to Scheme 20 and the procedure below.

a) To a solution of benzyl-3-pyrroline-l-carboxylate (compound 29.1, 10 mmol) in THF (15
mL) was added N-methyl morphline (22 mmol) and OSO4 (2 mL of a 2.5 wt% in t-BuOH), and
the resulting mixture was stirred at room temperature overnight. The solvent was removed; the
residue was dissolved in EtOAc (100 mL), washed with dilute aq. Na2SO3, sat. aq. NH4Cl, and
brine, and dried with anhydrousNa2SO4. The solvent was removed and the residue was purified
by column chromatography to give compound 29.2 in 55% yield. EIMS (m/z): calcd. for
C12H15NO4 (M+)+Na 260.1, found 260.1; 1H NMR (CD3OD, 400MHz): d 7.31-7.38 (m, 5H),
5.13 (j, 2H), 4.17 (m, 2H), 3.58 (m, 2H), 3.34 (m, 2H) ppm.
b) A mixture of compound 29.2 (1.0 mmol) and 10% Pd/C (0.1 mmol) in methanol (5 mL)
is stirred at room temperature for several hours under an atmosphere of H2. The reaction mixture
is filtered, the filtrate is concentrated, and the residue is dried in vacuo to give compound 29.3.
c) Compound 29 is synthesized according to the procedure of Example 26 except that (3R,
4S)-(dihydroxy)pyrrolidine (29.3) is used instead of ammonia in step g.
EXAMPLE 30
This example describes the synthesis of

which was prepared according to Scheme 21 and the procedure below.

a) A mixture of (3R, 4R)-benzyl-3, 4-pyrrolidindiol (compound 30.1, 1 mmol) and 20%
Pd(OH)2/C (0.1 mmol) in methanol (10 mL) is shaken at room temperature for several hours
under 45 psi of H2. (g). The reaction mixture is filtered, the filtrate is concentrated, and the
residue is dried in vacuo to give compound 30.2.
b) Compound 30 is synthesized according to the procedure of Example 26 except that
compound 30.2 is used instead of ammonia in step g.
EXAMPLE 31
This example describes the synthesis of

which is prepared according to Scheme 22 and the procedure below.

a) A mixture of commercially available benzyl 3-pyrroline-l-carboxylate (compound 28.1,
10 mmol) and m-CPBA (12 mmol) in DCM (50 mL) was stirred at room temperature overnight.
The reaction mixture was diluted with DCM (100 mL) and washed sequentially with sat. aq.
Na2SO3, and brine. The organic layer was dried with anhydrous Na2SO4 and then concentrated.
The residue was purified by chromatography to give compound 31.1 in 80% yield. E1MS (m/z):
calcd. for C2H13NO3 (M+)+Na 242.1, found 242.1; 1H NMR (CDCl3, 400MHz): d 7.36-7.37 (m,
5H), 5.13 (.v, 2H), 3.89 (m, 2H). 3.70 (m, 2H), 3.41 (m, 2H) ppm.
b) A mixture of compound 31.1 (5 mmol) in cone. aq. NH3 (20 mL) is stirred at 65°C
overnight. The reaction mixture was concentrated and dried in vacuo to give compound 31.2.
This material is used without further purification.
c) A solution of compound 31.2 (10 mmol) and Et3N (20 mmol) in dry THF (100 mL) at -
20° C is treated dropwise with TFAA (10 mmol) over 1 hour. After 1 h, the reaction mixture is
quenched with sat. aq. NH4Cl (1 mL). The solvent is removed and the residue is dissolved in
DCM (100 mL). The mixture is subsequently washed sequentially with sat. aq. NH4C1, sat. aq.
NaHCO3, and brine. The organic layer is dried with anhydrous Na2SO4, the solvent was
removed, and the residue is purified by chromatography to afford compound 31.3.
d) A solution of compound 31.3 (5 mmol) and Et3N (10 mmol) dry DCM (20 mL) at 0°C is
treated dropwise with MsCl (5.5 mmol), and the mixture is allowed to come gradually to room
temperature. After 1 hour at room temperature, the reaction mixture containing in situ generated
31.4 is treated with DBU (30 mmol), and the resulting mixture is stirred at for several hours. The
solvent is removed, and the residue is purified by chromatography to afford compound 31.5.
e) A mixture of compound 31.5 (3 mmol) and K2CO3 (6 mmol) in 2/1 (v/v) MeOH/H2O (15
mL) is stirred at room temperature. After 24 h, the solvent is removed; the residue is treated with
sat aq. NaHCO3 (20 mL), and the mixture is extracted with DCM several times. The extract is
dried with Na2CO3., the solvent is removed, and the residue is purified by chromatography to
afford compound 31.6.
0 A mixture of compound 31.6 (2 mmol), NaHCO3 (3 mmol), and Boc2O (2.2 mmol) in 1:1
1,4-dioxane/water (20 mL) is stirred at room temperature for several hours. The mixture is
diluted with brine (50 mL) and extracted with EtOAc several times. The combined extracts are
washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue is purified by
chromatography to give the N-Boc protected intermediate. A mixture of this intermediate (1
mmol) and 10% Pd/C (0.1 mmol) in MeOH (5 mL) is stirred at room temperature for several
hours under an atmosphere of H2 (g). The reaction mixture is filtered, the filtrate is concentrated,
and the residue is dried in vacuo to afford compound 31.7.
g) Compound 31 is prepared according to Example 26g except that compound 31.7 is used
instead of ammonia.
EXAMPLE 32
This example describes the synthesis of

which is prepared according to Scheme 23 and the procedure below.

a) A mixture of compound 31.2 (2 mmol), NaHCO3 (3 mmol), and BoC2O (2.2 mmol) in 1:1
1,4-dioxane/water (20 mL) is stirred at room temperature for several hours. The mixture is
diluted with brine (50 mL) and extracted with EtOAc several times. The combined extracts are
washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue is purified by
chromatography to afford compound 32.3.
b) A mixture of compound 32.3 (1 mmol) and 10% Pd/C (0.1 mmol) in MeOH (5 mL) is
stirred at room temperature for several hours under an atmosphere of H2 (g). The reaction
mixture is filtered, the filtrate is concentrated, and the residue is dried in vacuo to afford
compound 32.4.
c) Compound 32 is prepared according to Example 26g except that compound 32.4 is used
instead of ammonia.
EXAMPLE 33
This example describes the synthesis of

which is prepared according to Scheme 24 and the procedure below.

a) A solution of compound 33.1 (10 mmol) and DIEA (25 mmol) in DCM (20 mL) at 0 °C
is treated dropwise with benzyl chloroformate (10 mmol), and the reaction mixture is allowed to
come to room temperature. After 2 h at RT, the reaction mixture is diluted with ethyl acetate
(100 mL), rinsed with 1 M HCl (50 mL), rinsed with brine, dried over MgSO4, and concentrated
to afford compound 33.2.
b) A solution of compound 33.2 (10 mmol) and N-melhyl morpholine (22 mmol) in THF
(15 mL) is treated with OSO4 (2 mL of a 2.5 wt% in t-BuOH), and the resulting mixture is
stirred at room temperature overnight. The solvent is removed. The residue is dissolved in
EtOAc (100 mL), washed with dilute aq. Na2SO3, sat. aq. NH4Cl, and brine, and then dried over
anhydrous Na2SO4. The solvent is removed, and the residue is purified by column
chromatography to give the title compound.
c) A mixture of compound 33.3 (1.0 mmol) and 10% Pd/C (0.1 mmol) in methanol (5 mL)
is stirred at room temperature for several hours under an atmosphere of H2. The reaction mixture
is filtered, the filtrate is concentrated, and the residue is dried in vacuo to give compound 33.4.
d) Compound 33 is prepared according to Example 26g except that compound 33.4 is used
instead of ammonia.
EXAMPLE 34
This example describes the synthesis of

which is prepared according to Scheme 25 and the procedure below.

a) A mixture of Tl(OAc) (17.6 g, 54.5 mmol) in dried acetic acid (40 mL) is refluxed with
stirring for 1 hour and then cooled to room temperature. Compound 32.2 (34.6 mmol) and
iodine (8.46 g, 33.3 mmol) are added, and the resulting suspension is heated to reflux. After 9
hours, the reaction mixture is cooled to room temperature, and the yellow Tll precipitate is
removed by filtration with ether rinses. The filtrate is concentrated, and the residue is dissolved
in ethyl acetate, dried over MgSO4, and reconcentrated to afford compound 34.1.
b) A mixture of 34.1 (1.0 mmol) and 10% Pd/C (0.1 mmol) in methanol (5 mL) is stirred at
room temperature for several hours under an atmosphere of H2. The reaction mixture is filtered,
the filtrate is concentrated, and the residue is dried in vacuo to give compound 34.2.
c) Compound 34 is prepared according to Example 26g except that compound 34.2 is used
instead of ammonia.
EXAMPLE 35
This example describes the synthesis of

which is prepared according to Scheme 26 and the procedure below.

a) A mixture of compound 35.1 (10 mmol) in ethanol (20 mL) is saturated with HCl (g) and
stirred at room temperature overnight. The solvent is removed, the residue is dissolved in DCM
(100 mL), the resulting solution is treated sequentially with TEA (30 mmol) and BnBr (1 1
mmol), and the reaction mixture is heated to reflux. After 12 h, the reaction mixture is cooled to
room temperature and concentrated. The residue is dissolved in EtOAc (150 mL), washed with
brine, and dried over anhydrous Na2SO4. The solvent is removed and the residue is purified by
chromatography to afford compound 35.2.
b) A solution of LiBH4 (20 mmol) in dry THF (20 mL) at room temperature is treated in a
dropwise fashion with a solution of compound 35.2 (5 mmol) in THF (5 mL). After stirring
overnight, the reaction mixture is quenched by adding several drops of water. The mixture is
concentrated, diluted with brine (50 mL), and extracted several times with 9/1 (v/v) EtOAcli-
PrOH, The combined extracts are dried over anhydrous Na2SO4, the solvent is removed, and the
residue is purified by chromatography to afford compound 35.3.
c) A solution of compound 35.3 (2 mmol) and TEA (2.2 mmol) in dry THF (10 mL) at -
78°C is treated dropwise with trifluoroacetic anhydride ("TFAA", 2.2 mmol). After several
hours, the mixture is treated with TEA (6 mmol), and the reaction mixture is heated to reflux.
The mixture then is concentrated, and the residue is dissolved in THF (10 mL) and treated with
water (2.5 mL). This mixture is treated with NaOH (10 mmol) with vigorous stirring at room
temperature for several hours. The solvent is removed, and the residue is treated with sat. aq.
NaHCO3 (20 mL) and extracted several times with 9/1 (v/v) EtOAc/i-PrOH. The combined
extracts are dried over anhydrous Na2SO4, the solvent is removed, and the residue is purified by
chromatography to afford compound 35.4.
d) A mixture of compound 35.4 (1 mmol) and 20% Pd(OH)2/C (0.1 mmol) in methanol (10
mL) is shaken at room temperature for several hours under 45 psi of H2. (g). The reaction
mixture is filtered, the filtrate is concentrated, and the residue is dried in vacuo to give compound
35.5.
e) Compound 35 is prepared according to Example 26g except that compound 35.5 is used
instead of ammonia.
EXAMPLE 36
This example describes the synthesis of
which was prepared according to Example 35 except that (2R, 4S)-4-hydroxyproline (trans-D-
Hyp-OH) was used instead of compound 35.1.
EXAMPLE 37
This example describes the synthesis of

which was prepared according to Example 35 except that (2S, 4R)-4-hydroxyproline (trans-1-
Hyp-OH) was used instead of compound 35.1.
EXAMPLE 38
This example describes the synthesis of

a) A solution of HCl.H-DAP(Boc)-OMe (10 mmol) and DIEA (11 mmol) in DCM (50 mL)
at 0 °C is treated dropwise with benzoyl chloride (11 mmol). Over 3 h the reaction mixture is
allowed to warm to room temperature. The reaction mixture is concentrated, and the residue is
purified by chromatography. This intermediate is treated with a solution of 4 M HCl in dioxane,
and the resulting mixture is stirred at room temperature. After 1 h, the solvent is removed to
afford compound 38.1, which is used without further purification.
b) A solution of compound 38.1 (10 mmol) and DIEA (12 mmol) in DCM (50 mL) at 0 °C
is treated dropwise with p-nitrophenyl chloroformate (11 mmol), and the reaction mixture is
allowed to warm to room temperature. After 2 hours, the reaction mixture is concentrated, and
the residue is purified by chromatography to afford compound 38.2.
c) A solution of compound 38.2 (10 mmol) and TEA (25 mmol) in 1:1 DCE/DMF (10 mL)
is treated with 2 M methanolic ammonia (18 mmol), and the mixture is heated to 40 °C. After 15
hours, the reaction mixture is concentrated, and the residue is purified by chromatography to
afford compound 38.3.
d) A mixture of compound 38.3 (1.0 mmol) and 10% Pd/C (0.1 mmol) in methanol (10 mL)
is shaken at room temperature for several hours under 45 psi of H2. (g). The reaction mixture is
filtered, the filtrate is concentrated, and the residue is dried in vacuo to give compound 38.4.
e) A solution of compound 26.6 (8.0 mmol) and DIEA (25. mmol) in DMF is treated with
HATU (8.0 mmol), and the resulting mixture was stirred at room temperature. After 20 minutes,
the reaction mixture is treated sequentially with compound 38.4 (8.6 mmol) and DMAP (0.5
mmol), and the mixture is then heated to 60 °C. After 2.5 hours, the reaction is diluted with ethyl
acetate, washed with three portions of water, washed with one portion of brine, dried over
MgSO4, and concentrated. Flash column chromatography affords compound 38.5.
f) A solution of compound 38.5 (0.15 mmol) in methanol (1 mL) was treated with 2 M
methanolic KOH (0.45 mmol), and the reaction mixture is heated to 50 °C. After 3 hours, the
reaction mixture is concentrated to dryness and the residue is subjected to preparatory HPLC
purification to afford compound 38.
EXAMPLE 39
This example describes the synthesis of

where RA and RB are each independently hydrogen, aliphatic, aromatic, heteroaromatic, or
together form a cyclic moiety. These compounds are made according to the procedure in
Example 38 except that a substituted amine of the formula HNRARB is used instead of ammonia
in step c. Illustrative examples of substituted amines and the resulting compounds are shown in
Table 2.

EXAMPLE 40
This example describes the synthesis of

which is prepared according to Scheme 28 and the procedure below.
SCHEME 28
a) Commercially available compound 40.1 (10 mmol) in THF (50 mL) is treated with
sodium hydrosulfite (50 mmol) in water (20 mL). After 8 hours at room temperature, the
reaction is extracted with ethyl acetate (100 mL), and the organic extract is washed with water
and brine, dried over anhydrous magnesium sulfate and filtered to give the crude compound
40.2.
b) To a slurry of compound 40.2 (10 mmol), ammonium tetrafluoroborate (12.5 mmol) in
water (12 mL) is added concentrated HCl (2 mL). The reaction is cooled to 0 °C, and to it is
added sodium nitrite (10 mmol). After the reaction is stirred for 1 hour at 0 °C, the solid is
collected by filtration, rinsed with methol, ether and dried under vacuum. The resulting solid is
added to a stirring solution of HOAc (3 mL), 18-crown-6 (0.3 mmol) in chloroform (20 mL).
After 1 hour, water (10 mL) and DCM (20 mL) are added. The organic layer is separated, dried
by magnesium sulfate and filtered. The residue after concentration of the filtrate is triturated
with hexane to give product 40.3.
c) Compound 40.4 was made according to the procedure for the preparation of compound
6.1 except that R-3-(+)-pyrrolidinol was used instead of pyrrolidine.
d) Compound 40.4 is desolved in DCM, and is treated with triethylamine (1.5 eq) and acetic
anhydride (1.2 eq). The resulting solution is filtered through silica gel, concentrated. The
residue is then purified by silica gel column chromagraphy to yield compound 40.5.
e) Compound 40.5 in DCM is treated with anhydrous 4 N HCl in dioxane (2.0 eq). After
starting material disappears, the reaction is concentrated to give compound 40.6.
0 Compound 40.7 is made according to the procedure for the preparation of compound 1.5
except that compound 40.6 is used instead of 1.3.
g) Compound 40.8 is made according to the procedure for the preparation of compound 1.6
except that compounds 40.7 and 40.3 are used instead of compounds 1.5 and 1.11.
h) Compound 40 is made according to the procedure for the preparation of compound 1
except that compound 40.8 is used instead of 1.6.
EXAMPLE 41
This example describes the synthesis of

which is prepared according to Scheme 29 and the procedure below.

Compound 41 is made according to the procedure for the preparation of compound 3 except that
compounds 18.10 and 40.6 are used instead of 3.4 and 3.7. The enantiomerically pure
compounds are isolated using chiral column chromatography.
EXAMPLE 42
This example describes the synthesis of
which is prepared according to Scheme 30 and the procedure below.
a) A solution of compound 18.7 (10 mmol), 1 -ethoxy-1 -ethenyltributyltin (10.5 mmol),
Pd(PPh)4 (0.5 mmol) in dimethoxyethane (DME, 50 mL) is heated at 80 °C until compound 18.7
disappears. The reaction is cooled to room temperature, and to it is added 4N aqueous HCl (5
mL). The reaction is stirred for 3 hours and extracted with ether (80 mL). The organic extract is
washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The
residue is purified by column chromatography to give compound 42.1.
b) A solution of compound 42.1 in THF at -78 °C is treated with LDA (2.0 eq). After 1
hour, a solution of compound 18.2 (1.0 eq) in THF is added to the dry ice cooled reaction. After
another 3 hours, saturated aqueous NH4Cl is added to the reaction and the mixture is allowed to
warm to room temperature. The reaction mixture is partitioned between ethyl acetate and water,
and the organic layer is washed with water and brine, dried with anhydrous magnesium sulfate
and filtered. The residue after concentration of the filtrate is purified by silica gel column to give
compound 42.2.
c) A solution of compound 42.2 in ethanol is treated with sodium borohydride (2.0 eq).
After 1 hour, the reaction mixture is partitioned between ethyl acetate and water, and the organic
layer is washed brine, dried with anhydrous magnesium sulfate and filtered. The residue after
concentration of the filtrate is purified by silica gel column to give compound 42.3.
d) A mixture of 42.3 Lil (3 eq) in pyridine is reflux overnight. The solvent is removed and
the residue is dissolved in EtOAc. The resulting solution is then washed with saturated aqueous
NH4Cl and dried with anhydrous Na2SO4. The solvent is removed and the residue is dried in
vacuo to give a quantitative yield of compound 42.4. The crude product was carried on the next
step without further purification.
e) Compound 42 is made according to the procedure for the preparation of compound 3
except that compounds 42.4 and 40.6 are used instead of 3.4 and 3.7. The enantiomerically pure
compounds are isolated using chiral column chromatography.
EXAMPLE 43
This example describes the synthesis of

which is prepared according to Scheme 31 and the procedure below.

a) A solution of compound 18.2 in ethanol is treated with hydroxylamine (1.05 eq). After
10 hours, the reaction is concentrated and the residue is dried under vacuum to give compound
43.1.
b) A solution of 43.1 is hydrogenated with 20% Pd(OH)2/C as a catalyst at 45 psi of
hydrogen to give compound 43.2.
c) A solution of commercially available 43.3 in carbon tetrachloride is treated with N-
chlorosuccinimide (NCS, 3 eq). The reaction mixture is then diluted with ethyl acetate, washed
with 1N NaOH, water and brine, dried over anhydrous MgSO4 and filtered. The crude product is
recrystalized from hot ethanol to give compound 43.4.
d) A solution of 43.4 in THF is treated with LiOH (2 eq, 2.0 N aqueous). After most
starting material is consumed, the mixture is then diluted with ethyl acetate, washed with
saturated ammonium chloride, water and brine, dried over anhydrous MgSO4 and filtered. The
crude product is recrystalized from hot ethanol to give compound 43.5.
e) A solution of 43.5, 43.2 (1.1 eq) and EDC (1.0 eq) in DMF is stirred for 10 hours at room
temperature. The mixture is then diluted with ethyl acetate, washed with saturated ammonium
chloride, water and brine, dried over anhydrous MgSO4 and filtered. The crude product is then
refluxed with formic acid until LC-MS indicates the reaction is completed. Solvent is
evaporated, and the crude product is purified by silica gel column to give compound 43.6.
f) A mixture of 43.6 Lil (3 eq) in pyridine is reflux overnight. The solvent is removed and
the residue is dissolved in EtOAc. The resulting solution is then washed with saturated aqueous
NH4Cl and dried with anhydrous Na2SO4. The solvent is removed and the residue is dried in
vacuo to give a quantitative yield of compound 43.7. The crude product was carried on the next
step without further purification.
g) Compound 43 is made according to the procedure for the preparation of compound 3
except that compounds 43.7 and 40.6 are used instead of 3.4 and 3.7.
Diversification:
It will also be appreciated that each of the components used in the synthesis of inventive
compounds can be diversified either before synthesis or alternatively after the construction of the
core structure of formula (I). As used herein, the term "diversifying" or "diversify" means
reacting an inventive compound (I) or any of the precursor fragments (or any classes or
subclasses thereof) at one or more reactive sites to modify a functional moiety or to add a
functional moiety (e.g., nucleophilic addition of a substrate). Described generally herein are a
variety of schemes to assist the reader in the synthesis of a variety of compounds, either by
diversification of the intermediate components or by diversification of the core structures as
described herein, and classes and subclasses thereof. It will be appreciated that a variety of
diversification reactions can be employed to generate compounds other than those described in
the Exemplification herein. As but a few examples, where a double bond is present in the
compound structure, epoxidation and aziridation can be conducted to generate epoxide and
aziridine derivatives of compounds described herein. For additional guidance available in the
art, the practitioner is directed to "Advanced Organic Chemistry", March, J. John Wiley & Sons,
2001, 5th ed., the entire contents of which are hereby incorporated by reference.
2) Biological Data:
As discussed above, LFA-ICAM interactions have been directly implicated in numerous
inflammatory disease states including, but not limited to graft rejection, dermatitis, psoriasis,
asthma and rheumatoid arthritis. Thus, compounds capable of modulating adhesion between
intracellular adhesion molecules (e.g., ICAM-1, -2 and -3) and the leukocyte integrin family of
receptors would be useful in the development of novel therapeutics. Described below are certain
assays used for the determination of ICAM-1 :LFA Receptor binding, Human T-Cell Adhesion,
and T-Cell proliferation which are described in published PCT applications WO 99/49856 and
WO 02/05114, the entire contents of which are hereby incorporated by reference. WO 99/49856
also describes the preparation and purification of full-length LFA-1 from 293 cells, the
preparation of a plasmid for expression of a human ICAM-1 immunoadhesion, and the
generation of ICAM-1 immunoadhesion expressing 293 cell line.
ICAM-1 :LFA Receptor Binding Assay (protein/protein assay):
Competitive inhibition of the CD11a/CD 18-ICAM-l interaction is quantitated by adding known
amounts of inhibitors according to the two protein/protein assay systems described below:
Forward Format LFA-1:ICAM-1 Assay (PPFF):
Purified full length recombinant human LFA-1 protein is diluted to 2.5 µg/ml in 0.02 M Hepes,
0.15M NaCl, and 1 mM MnCl2 and 96-well plates (50 µl/well) are coated overnight at 4°C. The
plates are washed with wash buffer (0.05% Tween in PBS) and blocked for lh at room
temperature with 1% BSA in 0.02M Hepes, 0.15 M NaCl, and 1 mM MnCl2. Plates are washed.
50 (0,1/well inhibitors, appropriately diluted in assay buffer (0.5% BSA in 0.02M Hepes, 0.15M
NaCl, and 1 mM MnCl2), are added to a 2X final concentration and incubated for lh at room
temperature. 50 µl/well of purified recombinant human 5 domain ICAM-Ig, diluted to 50ng/ml
in assay buffer, is added and incubated 2h at room temperature. Plates are washed and bound
ICAM-Ig is detected with Goat anti-HuIgG(Fc)-HRP for lh at room temperature. Plates are
washed and developed with 100 µl/well TMB substrate for 10-30' at room temperature.
Colorimetric development is stopped with 100 µl/well 1M H2PO4 and read at 450 nM on a
platereader.
An alternative protein/protein assay system below also quantitates competitive inhibition of the
CD11a/CD18-ICAM-l interaction.
PLM2 Antibody Capture LFA-1:ICAM-1 Assay (PLM2)
A non-function blocking monoclonal antibody against human CD 18, PLM-2 (as described by
Hildreth, et al., Molecular Immunology, Vol. 26, No. 9, pp. 883-895, 1989), is diluted to 5 µg/ml
in PBS and 96-well flat-bottomed plates are coated with 100 µl/well overnight at 4°C. The
plates are blocked with 0.5% BSA in assay buffer (0.02 M Hepes, 0.15 M NaCl, and 1 mM
MnCl2) 1 h at room temperature. Plates are washed with 50 mM Tris pH 7.5, 0.;1M NaCI,
0.05% Tween 20 and 1 mM MnCb. Purified full-length recombinant human LFA-1 protein is
diluted to 2 µg/ml in assay buffer and 100 ml/well is added to plates and incubated at 1 h at
37°C. Plates are washed 3X. 50 µl/well inhibitors, appropriately diluted in assay buffer, are
added to a 2X final concentration and incubated for 30' at 37°C. 50 µl/well of purified
recombinant human 5 domain ICAM-1g, diluted to 161 ng/ml (for a final concentration of 80
ng/ml) in assay buffer, is added and incubated 2 h at 37°C. Plates are washed and bound ICAM-
lg is detected with Goat anti-HuIgG(Fc)-HRP for 1h at room temperature. Plates are washed and
developed with 100 µl/well TMB substrate for 5-10' at room temperature. Colorimetric
development is stopped with 100 µl/well 1M H3PO4 and read at 450 nM on a platereader.
Human T-Cell Adhesion Assay (cell attachment assay)
The T-cell adhesion assay is performed using a human T-lymphoid cell line HuT 78. Goat anti-
HulgG(Fc) is diluted to 2 µg/ml in PBS and 96-well plates are coated with 50 µl/well at 37°C for
1 h. Plates are washed with PBS and blocked for 1 h at room temperature with 1% BSA in PBS.
5 domain ICAM-lg is diluted to 100 ng/ml in PBS and 50 µl/well was added to the plates O/N at
4QC. HuT 78 cells are centrifuged at 100 g and the cell pellet is treated with 5 mM EDTA for ~
5' at 37°C in a 5% CO2 incubator. Cells are washed in 0.14 M NaCl, 0.02 M Hepes, 0.2%
glucose and 0.1 mM MnCl2 (assay buffer) and centrifuged. The cells are resuspended in assay
buffer to 3.0 x 106c/ml. Inhibitors are diluted in assay buffer to a 2X final concentration and pre-
incubated with HuT78 cells for 30' at room temperature. 100 µl/well of cells and inhibitors are
added to the plates and incubated at room temperature for 1 h. 100 µl/well PBS is added and the
plates are sealed and centrifuged inverted at 100 g for 5'. Unattached cells are flicked out of the
plate and excess PBS is blotted on a paper towel. 60 µl/well p-nitrophenyl n-acetyl-p-D-
glucosaminide (0.257 g to 100 ml citrate buffer) is added to the plate and incubated for 1.5 h at
37°C. The enzyme reaction is stopped with 90u,l/well 50 mM glycine/5mM EDTA and read on a
platereader at 405 nM. HUT 78 cell adhesion to 5dICAM-Ig is measured using the p-nitrophenyl
n-acetyl-ß-D-glucosaminide method of Landegren, U. (1984). J. Immunol. Methods 57, 379-
388.
T-Cell Proliferation Assay:
This assay is an in vitro model of lymphocyte proliferation resulting from activation, induced by
engagement of the T-cell receptor and LFA-1, upon interaction with antigen presenting cells
(Springer, Nature 346: 425 (1990)).
Microtiter plates (Nunc 96 well ELISA certified) are pre-coated overnight at 4°C with 50 µl of 2
µg/ml of goat anti-human Fc(Caltag H10700) and 50 µl of 0.07 µg/ml monoclonal antibody to
CD3 (Immunotech 0178) in sterile PBS. The next day coat solutions are aspirated. Plates are
then washed twice with PBS and 100 u.1 of 17 ng/ml 5d-ICAM-1-IgG is added for 4 hours at
37°C. Plates are washed twice with PBS prior to addition of CD4+ T cells. Lymphocytes from
peripheral blood are separated from heparinized whole blood drawn from healthy donors. An
alternative method is to obtain whole blood from healthy donors through leukophoresis. Blood
is diluted 1:1 with saline, layered and centrifuged at 2500 x g for 30 minutes on LSM (6.2 g
Ficoll and 9.4 g sodium diztrizoate per 100 ml) (Organon Technica, NJ). Monocytes are
depleted using a myeloid cell depletion reagent method (Myeloclear, Cedarlane Labs, Hornby,
Ontario, Canada). PBLs are resuspended in 90% heat-inactivated Fetal Bovine serum and 10%
DMSO, aliquoted, and stored in liquid nitrogen. After thawing, cells are resuspended in RPMI
1640 medium (Gibco, Grand Island, NY) supplemented with 10% heat-inactivated Fetal Bovine
serum (Intergen, Purchase, NY), ImM sodium pyruvate, 3 mM L-glutamine, ImM nonessential
amino acids, 500 µg/ml penicillin, 50 µg/ml streptomycin, 50 µg/ml gentamycin (Gibco).
Purification of CD4+ T cells are obtained by negative selection method (Human CD4 Cell
Recovery Column Kit # CL110-5 Accurate). 100,000 purified CD4+ T cells (90% purity) per
microtiter plate well are cultured for 72 hours at 37°C in 5% CO2 in 100 ml of culture medium
(RPMI 1640 (Gibco) supplemented with 10% heat inactivated FBS (Intergen), 0.1mM non-
essential amino acids, 1 nM Sodium Pyruvate, 100 units/ml Penicillin, 100 µg/ml Streptomycin.
50 µg /ml Gentamicin, 10 mM Hepes and 2 mM Glutamine). Inhibitors are added to the plate at
the initiation of culture. Proliferative responses in these cultures are measured by addition of 1
µCi/well titrated thymidine during the last 6 hours before harvesting of cells. Incorporation of
radioactive label is measured by liquid scintillation counting (Packard 96 well harvester and
counter). Results are expressed in counts per minute (cpm).
In vitro Mixed Lymphocyte Culture Model:
The mixed lymphocyte culture model, which is an in vitro model of transplantation (A.J.
Cunningham, "Understanding Immunology, Transplantation Immunology" pages 157-159
(1978) examines the effects of various LFA-1 antagonists in both the proliferative and effector
arms of the human mixed lymphocyte response.
Isolation of Cells: Mononuclear cells from peripheral blood (PBMC) are separated from
heparanized whole blood drawn from healthy donors. Blood is diluted 1:1 with saline, layered,
and centrifuged at 2500 x g for 30 minutes on LSM (6.2 g Ficoll and 9.4 g sodium diztrizoate per
100 ml) (Organon Technica, NJ). An alternative method is to obtain whole blood from healthy
donors through leukophoresis. PBMCs are separated as above, resuspended in 90% heat
inactivated Fetal Bovine serum and 10% DMSO, aliquoted and stored in liquid nitrogen. After
thawing, cells are resuspended in RPMI 1640 medium (Gibco, Grand Island, NY) supplemented
with 10% heat-inactivated Fetal Bovine serum (Intergen, Purchase, NY), 1 mM sodium pyruvate,
3 mM L-glutamine, 1 mM nonessential amino acids, 500 µg/ml penicillin, 50 µg /ml
streptomycin, 50 µg/ml gentamycin (Gibco).
Mixed Lymphocyte Response (MLR): One way human mixed lymphocyte cultures are
established are in 96-well flat-bottomed microtiter plates. 1.5 x 105 responder PBMCs are co-
cultured with an equal number of allogeneic irradiated (3000 rads for 3 minutes, 52 seconds
stimulator PBMSc in 200 µl of complete medium. LFA-1 antagonists are added at the initiation
of cultures. Cultures are incubated at 37°C in 5% CO2 for 6 days, then pulsed with 1 u.Ci/well of
3H-thymidine (6.7 Ci/mmol, NEN, Boston, MA) for 6 hours. Cultures are harvested on a
Packard cell harvester (Packard, Canberra, Canada). [3H] TdR incorporation is measured by
liquid scintillation counting. Results are expressed as counts per minute (cpm).
WE Claim
1. An isolated compound having the structure (I):

and pharmaceutically acceptable derivatives thereof;
wherein R1 and R2 are each independently hydrogen, an amino acid side chain, -
(CH2)mOH, -(CH2)maryl, -(CH2)mheteroaryl, wherein m is 0-6, -CH(R1A)(OR1B), -
CH(R1A)(NHR1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic
moiety optionally substituted with U-T-Q, wherein U is absent, -O-, -S(O)0-2-, -
SO2N(R1A), -N(R1A)-, -N(R1A)C(=O)-, -N(R1A)C(=O)-O-, -N(R1A)C(=O)-N(R1B)-, -
N(R1A)-SO2-, -C(=O)-, -C(=O)-O-, -O-C(=O)-, aryl, heteroaryl, alkylaryl,
alkylheteroaryl, -C(=O)-N(R1A)-, -O-C(=O)-N(R1A)-, -C(=N-R1B)-, -C(=N-R1B)-O-, -
C(=N-R1B)-N(R1A)-, -O-C(=N-R1B)-N(R1A)-, -N(R1A)C(=N-R1B)-, -N(R1A)C(=N-R1B)-O-,
N(R1A)C(=N-R1B)-N(R1B)-, -P(=O)(OR1A)-O-, or -P(=O)(R1A)-O-; T is absent, an
aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is
hydrogen, halogen, cyano, isocyanate, -OR1B, -SR1B; -N(RIB)2, -NHC(=O)OR1B, -
NHC(=O)N(R1B)2, -NHC(=O)R1B, -NHSO2R1B, -NHSO2N(R1B)2,
NHSO2NHC(=O)OR1B, -NHC(=O)NHSO2R1B, -C(=O)NHC(=O)OR1B,
C(=O)NHC(=O)R1B, -C(=O)NHC(=O)N(RIB)2, -C(=O)NHSO2R1B,
C(=O)NHSO2N(R1B)2, -C(=S)N(R1B)2, -SO2R1B, -SO2-O-R1B, -SO2-N(R1B)2, -SO2-
NHC(=O)OR1B, -SO2-NHC(=O)-N(R1B)2, -SO2-NHC(=O)R1B, -O-C(=O)N(R1B)2, -O-
C(=O) R1B, -O-C(=O)NHC(=O)R1B, -O-C(=O)NH-SO2R1B, -O-SO2R1B, or an aliphatic
heteroaliphatic, aryl or heteroaryl moiety, or wherein R1 and R2 taken together are an
alicyclic or heterocyclic moiety, or together are R1A; wherein each occurrence of R
and RlB is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic,
aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, -COR1C, or -CONR1CR1D; wherein
each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic,
heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1B is hydrogen,
an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or
alkylheteroaryl moiety, -CN, -OR1C, -NR1CR1D or -SO2R1C;
R3 is -C(=O)OR3A, -C(=O)H, -CH2OR3A, -CH2O-C(=O)-alkyl, -C(=O)NH(R3A), -
CH2X0; wherein each occurrence of R3A is independently hydrogen, a protecting group,
an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl,
alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, or R3A, taken together
with R1 or R , forms a heterocyclic moiety; wherein X° is a halogen selected from F, Cl,
Br or I;
R4, for each occurrence, is independently hydrogen, halogen, -CN, -NO2, an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl
moiety, or is -GRGI wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -
C(=O)NRG2-, -OC(=O)-. -NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are
independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,
heteroaryl, alkylaryl or alkylheteroaryl moiety;
n is an integer from 0-4;
AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or
heterocyclic moiety;
A, B, D and E are connected by either a single or double bond, as valency permits;
wherein each occurrence of A, B, D and E is independently C=O, CR'R", NR', CR', N, O.
S, S(=O) or SO2; wherein each occurrence of R' is independently hydrogen, halogen, -
CN, -NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl.
alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is -O-, -S-, -NRG2-, -CO-, -
SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1
and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent
occurrences of R', taken together, represent an alicyclic, heteroalicyclic, aryl, or
heteroaryl moiety;
p is an integer from 0-4; and
L is absent or is V-W-X-Y-Z, wherein each occurrence of V, W, X, Y and Z is
independently absent, C=O, NRL1, -O-, -C(R1.1)=, =C(R1.1)-, -C(RL1)(RL2), C(=N-O-RL1),
C(=N-RL1), -N=, S(O)0-2; a substituted or unsubstituted C1-6alkylidene or C2-
6alkenylidene chain wherein up to two non-adjacent methylene units are independently
optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-. -C(=O)NRL3-, -OC(=O)-. -
OC(=O)NRL3-. -NRL3NRL4-. -NRL3NRL4C(=O)-. -NRL3C(=O)-. -NRL3CO2-, -
NRL3C(=O)NRL4-, -S(=O)-. -SO2-, -NRL3SO2-, -SO2NRL3-, -NRL3SO2NRL4-, -O-, -S-, or
-NRL3-; wherein each occurrence of RL3 and RL4 is independently hydrogen, alkyl,
heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence
of RL1 and RL2 is independently hydrogen, hydroxyl, protected hydroxyl, amino,
protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl,
formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy,
mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or
more occurrences of RL1 and RL2, taken together, or taken together with one of V, W, X,
Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety.
2. The compound of claim 1, wherein R3 is carboxyl, protected carboxyl or a prodrug thereof,
wherein R3 is C(=O)R3A, wherein R3A is hydroxy, alkoxy, cycloalkoxy, aralkoxy, arcycloalkoxy,
aryloxy, alkylcarbonyloxyalkyloxy, alkoxycarbonyloxyalkyloxy, alkoxycarbonylalkyloxy,
cycloalkylcarbonyloxyalkyloxy, cycloalkoxycarbonyloxyalkyloxy,
cycloalkoxycarbonylalkyloxy, arylcarbonyloxyalkyloxy, aryloxycarbonyloxyalkyloxy,
arylcarbonyloxyalkyloxy, alkoxyalkylcarbonyloxyalkyloxy, or one of the structures:

3. The compound of claim 1, wherein - C(=O)NHC(R1)(R2)R3 is a moiety having the following
structure:
wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R8 is hydrogen,
alkyl, heteroalkyl, aryl, heteroaryl, or is -G°RG1 wherein G° is -O-, -S- or -NRG2-, and
RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety.
4. The compound of claim 1, wherein - C(=O)NHC(R1)(R2)R3 is a moiety having the following
structure:
wherein R1A is Ar2, -OR1B, -SR1B or -NR1BR1C; or an alkyl or heteroalkyl moiety; and
Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; wherein R1B and R1C are
independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or
R1B and R1C, taken together with the nitrogen atom to which they are attached, form a
heterocylic or heteroaryl moiety.
5. The compound of claim 1, wherein - C(=O)NHC(R1)(R2)R3 is a moiety having the following
structure:

wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R2A is hydrogen.
C1-6alkyl, C2-6alkenyl, -C(=O)R2B or -SQ2R2B, wherein R2B is alkyl, cycloalkyl.
heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with a substituent on
Ar2, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety.
6. The compound of claim 1, wherein -C(=O)NHC(R1)(R2)R3 is a moiety having the following
structure:
wherein t is 1-3; and Rp3 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety.
7. The compound of claim 6, wherein t is 2 and RP3 is alkyl, cycloalkyl, heterocyclic, aryl or
heteroaryl moiety.
8. The compound of claim 1, wherein - C(=O)NHC(R')(R )R is a moiety having the following
structure:
wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety.
9. The compound of claim 1, wherein - C(=O)NHC(R1)(R2)R3 is a moiety having the following
structure:
wherein R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, -C(=O)R2B or -SO2R2B,
wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A,
taken together with R2C or R2D, forms a substituted or unsubstituted heterocyclic or
heteroaryl moiety; R2C is hydrogen, CN, -C=NMe, =NO2, =NC(=O)NH2, =NS(O)2R,
=NS(O)2NRR', -SO2R2G, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,
heteroaryl, alkylaryl or alkylheteroaryl moiety; wherein R and R' are each independently
hydrogen or methyl, and R" is lower alkyl; and R is Ar2, hydrogen, halogen, CN, NO2,
an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G
is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NRG2C(=O)- or -SO2NRG2-, and RGI and RG2 are independently hydrogen, an aliphatic,
alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl
moiety.
10. The compound of claim 6, wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D is a
moiety having the following structure:

wherein R2E and R2F are each independently hydrogen, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or
R2E and R2F , taken together, form a substituted or unsusbtituted heterocyclic or
heteroaryl moiety.
11. The compound of claim 6, wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D is a
moiety having one of the following structures:

wherein R2C is hydrogen, CN, -C=NMe, =NO2, =NC(=O)NH2, =NS(O)2R, or
=NS(O)2NRR'; wherein R and R' are each independently hydrogen or methyl.
12. The compound of claim6, wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D is a
moiety having one of the following structures:

or bioisostere thereof;
wherein R ' and R are each independently hydrogen, or an aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or
R2E and R2F , taken together, form a substituted or unsusbtituted heterocyclic or
heteroaryl moiety.
13. The compound of claim 9, wherein the bioiostere has one of the following structures:

14.The compound of claim 9, wherein R2D is, or R2E and R2F together with the nitrogen atom to
which they are attached form, a moiety having one of the structures:

wherein s is an integer between 0 and 6; each occurrence of RPI is independently
hydrogen, halogen, CN, isocyanate, NO2, -P(=O)(YRP5)2, an alkyl, cycloalkyl,
heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -
GRG1 wherein G is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -
OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an
alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl
moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is
independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be
hydrogen; and each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl,
or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent
occurrences of RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or
heteroaryl moiety.
15 The compound of claim 11, wherein R2D is, or R2E and R2F together with the nitrogen atom to
which they are attached form, a moiety having one of the structures:

wherein each occurrence of RPE is independently hydrogen, halogen, methyl, -
OCH3, -OH, -NH2, -NHCH3, or-N(CH3)2.
16. The compound of claim 12, wherein R2D is, or R2E: and R2F together with the nitrogen atom to
which they are attached form, a moiety having one of the structures:


17. The compound of claim 12, wherein -C(=O)NHCH(CO2R3A)CH2N(R2A)C(=NR2C)R2D has
the structure:
or bioisostere thereof;
wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, -OCH3, -
OH, -NH2, -NHCH3 or -N(CH3)2; R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl.
heteroaryl, -C(=O)R2B or -SO2R2B wherein R2B is alkyl, cycloalkyl, heteroalkyl,
heterocyclyl, aryl or heteroaryl; and q is 1 or 2.
18. The compound of claim 17, wherein the bioisostere has one of the following structures:
wherein q is 1 or 2; and R2C is lower alkyl.
19. The compound of claim 3, wherein R3A is independently hydrogen, lower alkyl, phenyl or
benzyl.
20. The compound of claim 3 wherein Ar2 is one of the following structures:

wherein s is an integer from 0-2; each occurrence of RP1 is independently hydrogen,
halogen, CN, isocyanate, NO2, -ORG1, -S RG1, -NRG1RG2-, an alkyl, cycloalkyl,
heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each
occurrence of Y is independently a bond or O; each occurrence of RP3 is independently
lower alkyl, or when Y is O RP5 may also be hydrogen; each occurrence of RP2 is
independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen
protecting group; RP3 is lower alkyl or -N(RP2)2; and RG1 and RG2 are independently
hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or
alkylheteroaryl moiety.
21. The compound of claim 16 wherein Ar2 is one of the following structures:

22. The compound of claim 3 wherein Ar2 is one of the following structures:

wherein RP3 is lower alkyl and RG1 is hydrogen or lower alkyl.
23. The compound of claim 4 wherein R1A is -NH2 or a moiety having the structure:

wherein RP1 is independently hydrogen, hydroxyl, lower alkyl or lower heteroalkyl; and
each occurrence of RP2 is independently hydrogen or lower alkyl.
24. The compound of claim 23 wherein R1A is -NH2 or a moiety having the structure:

wherein R is hydrogen or lower alkyl.
25. The compound of claim 4 wherein R1A is a moiety having one of the structures:

wherein s is an integer between 0 and 2; each occurrence of RP1 is independently lower
alkyl or is -GRG1 wherein G is -O- or -NRG2-, and RG1 and RG2 are independently
hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or
alkylheteroaryl moiety; and each occurrence of RP2 is independently hydrogen, lower
alkyl, aryl or heteroaryl.
26. The compound of claim 25 wherein R1A is a moiety having one of the structures:

wherein G is -O- or -NRG2-, and RG1 and RG2 are independently hydrogen or lower alkyl.
27. The compound of claim 5, wherein -NH(R2A)Ar2 is one of the following structures:

wherein X1 is N or CRP1; s is an integer from 0-5; and each occurrence of RP1 is
independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl,
heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G
is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;
and RP3 is alkyl, heteroalkyl, aryl or heteroaryl.
28. The compound of claims 27, wherein -NH(R2A)Ar2 has the following structure:

wherein R is hydrogen, halogen or lower alkyl.
29. The compound of claim 8, wherein -C(=O)NHC(R1)(R2)R3 is one of the following structures:

wherein RP3 is lower alkyl or aryl; X1 and X2 are independently N or CRP1; X3 is O, S or
NRP2; wherein RP1 is hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl,
heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G
is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;
and RP2 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety.
30. The compound of claim 29, wherein RP3 is lower alkyl; and Rp2 is hydrogen or lower alkyl.
31. The compound of any one of claims 3, 4, 5 and 8, or claim 9 where R2D is Ar2, wherein Ar2 is
one of the following structures:

wherein s, X1, X2 and X3 are as defined in xx) above; X5 is O, S or NRP2; each
occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, -
P(=O)(YRP5)2, an alkyl. cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl
or alkylheteroaryl moiety, or is -GR ' wherein G is -O-, -S-, -NR -, -CO-, -SO-, -SO2-,
-C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are
independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,
alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O;
each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y
is O R may also be hydrogen; each occurrence of RP2 is independently hydrogen, an
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl,
alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting
group; wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a
cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and each occurrence of RP3 is
independently alkyl, aryl, heteroaryl or-N(RP2)2
32. The compound of claim 31 wherein Ar2 is one of the following structures:

wherein X1 is N or CRP1; s is an integer from 0-6; each occurrence of RPI is
independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl,
heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR ' wherein G
is -O-, -S-, -NRG2-, -CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -
NRG2C(=O)- or -SO2NRG2-, and RG1 and RG2 are independently hydrogen, an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;
and RP3 is independently lower alkyl or aryl
33. The compound of claim 1, wherein -C(=O)NHC(R1)(R2)R3 has the structure -
C(=O)NHC(=C(RS)Ar2)CO2R3A wherein R3Aand RS, taken together, form a substituted or
unsubstituted heterocyclic moiety.
34. The compound of claim 33, wherein -C(=O)NHC(=C(R5)Ar2)CO2R3A is one of the following
structures:

35. The compound of claim 33, wherein -C(=O)NHC(=C(R8)Ar2)CO2R3A is one of the following
structures:

wherein X1 is O, S or NH; and X2 is N or CH.
36. The compound of claim 1, wherein L is absent, -C(=O), -CH2C(=O)NH-, -CH2NH-C(=O)-, -
O-CH2-C(=O)-, -CH2-CH2-C(=O)-, -CH=CH-C(=O)NH-CH2-, -CH(OH)-CH2-O-, -CH(OH)-
CH2-N(CH3)-, -CH(OH)-CH2-CH2-, -CH2-CH2-CH(OH)-, -O-CH2-CH(OH)-, -O-CH2-CH(OH)-
CH2-, -O-CH2-CH2-CH(OH)-, O-CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH(OH)-CH2-O, -
CH2-CH2-O-, -CH-(CH3)-NH-C(=O)-, -CH2-NH-SO2-, -NH-SO2-CH2-, -CH2-SO2-NH-, -
SO2NH-CH2-, -C(=O)-NH-C(=O)-, -NH-C(=O)-NH-, -NH-C(=O)-NH-CH2-, -CH2-NH-C(=O)-
NH-, -C(=O)-NH-CH2-C(=O)-NH, -NH-C(=O)-O-, or -O-C(=O)-NH-; or a substituted or
unsubstituted C1-6alkylidene or C2-6alkenylidene chain wherein up to two non-adjacent
methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -
C(=O)NRL3-, -OC(=O)-, -OC(=O)NRL3-, -NRL3NRL4-. -NRL3NRL4C(=O)-, -NRl3C(=O)-. -
NRL3CO2-, -NRL3C(=O)NRL4-. -S(-O)-, -SO2-, -NRL3SO2-, -SO2NRL3-. -NRL3SO2NRL4-, -O-, -
S-, or -NR -; wherein each occurrence of R and R is independently hydrogen, alkyl,
heteroalkyl, aryl, heteroaryl or acyl.
37. The compound of claim I, wherein L is absent, -C(=O), -CH2C(=O)NH-, -CH2NH-C(=O)-, -
O-CH2-C(=O)-, -CH2-CH2-C(=O)-, -CH=CH-C(=O)NH-CH2-, -CH(OH)-CH2-O-, -CH(OH)-
CH2-N(CH3)-, -CH(OH)-CH2-CH2-, -CH2-CH2-CH(OH)-, -O-CH2-CH(OH)-, -O-CH2-CH(OH)-
CH2-, -O-CH2-CH2-CH(OH)-, O-CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH(OH)-CH2-O, -
CH2-CH2-O-, -CH-(CH3)-NH-C(=O)-, -CH2-NH-SO2-, -NH-SO2-CH2-, -CH2-SO2-NH-, -
SO2NH-CH2-, -C(=O)-NH-C(=O)-, -NH-C(=O)-NH-, -NH-C(=O)-NH-CH2-, -CH2-NH-C(=O)-
NH-, -C(=O)-NH-CH2-C(=O)-NH, -NH-C(=O)-O- or -O-C(=O)-NH.
38. The compound of claim 1, wherein L is absent, -C(=O), or a substituted or unsubstituted C1-
6alkylidene or C2-6alkenylidene chain wherein up to two non-adjacent methylene units are
independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NRL3-, -OC(=O)-, -
OC(=O)NRL3-, -NRL3NRL4-, -NRL3NRL4C(=O)-, -NRL3C(=O)-, -NRL3CO2-, -NRL3C(=O)NRL4-.
-S(=O)-, -SO2-, -NRL3SO2-, -SO2NRL3-, -NRL3SO2NRL4-, -O-, -S-, or -NRL3-; wherein each
occurrence of RL3 and R1'4 is independently hydrogen or methyl.
39. The compound of claim 1, wherein L is absent.
40. The compound of claim 1, wherein L is -C(=O).
41. The compound of claim 1, wherein L is a substituted or unsubstituted C1-6alkylidene or C2.
ealkenylidene chain wherein up to two non-adjacent methylene units are independently
optionally replaced by -C(=O)-, -C(=O)NRL3-, -OC(=O)-, -NRL3C(=O)-, -S(=O)-, -SO2-, -
NRL3SO2-, -SO2NRL3-, -O- or -NRL3-; wherein each occurrence of RL3 and RL4 is independently
hydrogen or methyl.
42. The compound of claim 1, wherein L is -(CH2)q- wherein q is 1-5.
43. The compound of claim 1, wherein L is a moiety having the structure:

44. The compound of claim 1, wherein AR1 is one of the following structures:
wherein each occurrence of r is an integer from 0-6; X1, X2, X3 and X4 is independently
N or CRQ1; X5 is O, S or NRQ2; AR3 is a heterocyclic, aryl or heteroaryl moiety; each
occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN,
isocyanate, NO2, CF3, NRQ3QRQ, -SO2RQ3, alkyl-NRQ3RQ4, alkyl-C(=O)-NRQ3RQ4 alkyl-
C(=O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each
occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic,
heteroaliphatic, aryl or heteroaryl moiety; and RQ2 is hydrogen, an aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl,
or heteroalkylheteroaryl moiety or a nitrogen protecting group.
45. The compound of claim 44, wherein AR1 is one of the following structures:


wherein X0 is F or Cl; X2 is N or CRQ1; X5 is CH, O, S or NH; RQ1 is hydrogen, methyl, -
CF3, -OCH3,- OCF3 or halogen.
46. The compound of claim 45, wherein AR1 is one of the following structures:

47. The compound of claim 46, wherein AR1 is one of the following structures:

48. The compound of claim 1, wherein AR1-L- is one of the following structures:

49. The compound of claim 48, wherein AR'-L- is one of the following structures:

50 The compound as claimed in claim 1 wherein AR1-L- is a moiety having one of the following
structures:

and -C(=O)NHC(R1)(R2)R3 is a moiety having one of the following structures:

or bioisosteres thereof;
wherein R2A and R3A are as defined in classes and subclasses herein; and R2D is a moiety
having one of the following structures:

wherein s is an integer between 0 and 6; each occurrence of RP1 is independently hydrogen,
halogen, CN, isocyanate, NO2, -P(=O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic,
aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is -O-, -S-, -NRG2-, -
CO-, -SO-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)- or -SO2NRG2-, and RG1
and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,
heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or
O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O
R may also be hydrogen; and each occurrence of R is independently hydrogen, an aliphatic,
alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,
heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two
adjacent occurrences of RPI and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or
heteroaryl moiety.
51. The compound of claim 50 wherein R2A and R3A are each hydrogen.
52. The compound of claim 50 wherein R2D is a moiety having one of the structures:

wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, -OCH3, -
OH, -NH2, -NHCH3, or-N(CH3)2.
53. The compound of claim 52 wherein R2D is a moiety having one of the structures:

54. A pharmaceutical composition comprising a compound of claim 1
and pharmaceuticalLY acceptable derivatives thereof; and
a pharmaceutically acceptable carrier or diluent, and optionally further comprising an
additional therapeutic agent.
55. The pharmaceutical composition of claim 54, wherein the compound is present in an amount
effective to modulate adhesion between intracellular adhesion molecules (e.g., ICAM-1, -2 and --
3) and the leukocyte integrin family of receptors.
56. The pharmaceutical composition of claim 54, wherein the compound is present in an amount
effective to antagonize CD11/CD18 receptors associated with leukocytes.
57. The pharmaceutical composition of claim 54, wherein the compound is present in an amount
effective to antagonize Mac-1 and/or LFA-1.
58. A compound of the following structure:

or pharmaceutically acceptable salts thereof; wherein
-C(=O)NHC(R1)(R2)R3 is a moiety having the following structure:
R3A is hydrogen;
RS is hydrogen;
Ar2 is:
s is an integer of 1;
each occurrence of RP1 is independently hydrogen, halogen, or -GRG1, wherein G is -SO2-, or -
SO2NRG2-; and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety;
RB1, RB2 and RE are hydrogen;
R4A and R4B are each Cl;
L is C=O; and
AR1 is

59. The compound of claim 58, wherein RP1 is selected from the group consisting of halogen and
-GRG1, wherein G is -SO2- and RG1 is methyl.
60. The compound of claim 59, wherein AR1 is

and RP1 is selected from the group consisting of F and SO2CH3.
61. A pharmaceutical composition comprising a compound of claim 58 and a pharmaceutically
acceptable carrier or diluent, and optionally further comprising an additional therapeutic agent.

The present invention provides compounds having formula (1):

and pharmaceutically acceptable derivatives thereof, wherein R1-R4, n, p, A, B, D, E, L
and AR1 are as described generally and in classes and subclasses herein, and additionally
provides pharmaceutical compositions thereof, and methods for the use thereof for the
treatment of disorders mediated by the CD11/CD18 family of cellular adhesion
molecules (e.g., LFA-1).

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Patent Number 279168
Indian Patent Application Number 3759/KOLNP/2010
PG Journal Number 02/2017
Publication Date 13-Jan-2017
Grant Date 13-Jan-2017
Date of Filing 08-Oct-2010
Name of Patentee SARCODE BIOSCIENCE, INC.
Applicant Address 1000 MARINA BOULEVARD, SUITE 250, BRISBANE, CA 94005, UNITED STATES OF AMERICA
Inventors:
# Inventor's Name Inventor's Address
1 SHEN, WANG 1719 MONTICELLO ROAD, SAN MATEO CA 94402 UNITED STATES OF AMERICA
2 BARR, KENNETH 4016 18TH STREET SAN FRANCISCO, CA 94114 UNITED STATES OF AMERICA
3 OSLOB, JOHAN D. 1191 LOCHINVAR AVENUE SUNNYVALE, CA 94087 UNITED STATES OF AMERICA
4 ZHONG, MIN 912 BEACH PARK BOULEVARD UNIT 93 FOSTER CITY, CA 94404 UNITED STATES OF AMERICA
PCT International Classification Number C07D 409/12
PCT International Application Number PCT/US2004/036942
PCT International Filing date 2004-11-05
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/517,535 2003-11-05 U.S.A.
2 60/560,517 2004-04-08 U.S.A.