SUBSTITUTED PHENYLALANINE TYPE COMPOUNDS WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY VLA-4

COMPOSES DE TYPE PHENYLALANINE SUBSTITUEE INHIBANT UNE ADHESION DE LEUCOCYTES REGULEE PAR VLA-4

English Abstract

Disclosed are compounds which bind VLA-4. Certain of these compounds also
inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by
VLA-4. Such compounds are useful in the treatment of inflammatory diseases in
a mammalian patient, e.g., human, such as asthma, Alzheimer's disease,
atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease,
rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial
ischemia. The compounds are also be administered for the treatment of
inflammatory brain diseases such as multiple sclerosis.

French Abstract

L'invention concerne des composés se liant à VLA-4. Certains de ces composés inhibent également une adhésion de leucocytes et, notamment, une adhésion de leucocytes régulée par VLA-4. Ces composés s'utilisent dans le traitement d'affections inflammatoires chez un patient mammalien, par exemple un humain, l'affection consistant par exemple en asthme, maladie d'Alzheimer, athérosclérose, syndrome démentiel du SIDA, diabète, affection intestinale inflammatoire, polyarthrite rhumatoïde, transplantation de tissus, métastase tumorale et ischémie myocardique. Les composés peuvent également être administrés pour le traitement d'affections cérébrales inflammatoires telles que la sclérose en plaques.

Claims

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WHAT IS CLAIMED IS:
1. A compound of formula I:
<IMG>
where
R1 is selected from the group consisting of alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic,
substituted
heterocylic, heteroaryl and substituted heteroaryl;
R2 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and where R1 and R2 together with the
nitrogen atom bound to R2 and the SO2 group bound to R1 form a heterocyclic
or a substituted heterocyclic group;
R3 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic and, when R2 does not form
a
heterocyclic group with R1, R2 and R3 together with the nitrogen atom bound
to R2 and the carbon atom bound to R3 can form a heterocyclic or a substituted
heterocyclic group;
R5 is -(CH2)x -Ar-R5' where R5' is selected from the group consisting
(a) substituted alkylcarbonylamino with the proviso that at least one of the
substituents on the substituted alkyl moiety is selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino,
acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy,
substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl,
carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted

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cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,
carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted
heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone,
thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,
thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted
thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic,
substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy,
heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl,
-OS(O)2-heteroaryl, -OS(O)2-substituted heteroaryi, -OS(O)2-heterocyclic,
-OS(O)2-substituted heterocyclic, -OSO2-NRR where R is hydrogen or alkyl,
-NRS(O)2-alkyl, -NRS(O)2-substituted alkyl, -NRS(O)2-aryl,
-NRS(O)2-substituted aryl, -NRS(O)2-heteroaryl, -NRS(O)2-substituted
heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)Z-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted
heteroaryl, -NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic
where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and
di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted
arylamino, mono- and di-heteroarylamino, mono- and di-substituted
heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted
heterocyclic amino, and unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;

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(b) alkoxyaryl substituted on the alkoxy moiety with a substituent selected
from the group consisting of carboxyl and -COOR where R is alkyl,
substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(c) aryl and heteroaryl;
(d) -NR'R' wherein each R' is independently selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and
substituted heterocyclic with the proviso that at least one of R' is
substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted
heterocyclic and with the further proviso that when R' is substituted alkyl at
least one of the substituents on the substituted alkyl moiety is selected from
the group consisting of alkoxy, substituted alkoxy, acyl, acylamino,
thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino,
thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen,
hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
cycloalkyl,
carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted
aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-substituted
alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O),-heteroaryl, -NRS(O)2-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,

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-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(e) -alkoxy-NR"R" wherein each R" is independently selected from the
group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl,
substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic with the proviso that when each R" is substituted
alkyl then at least one of the substituents on the substituted alkyl moiety is
selected from the group consisting of alkoxy, substituted alkoxy, acyl,
acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl
amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidine, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted

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thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-substituted
alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2 substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(f) substituted alkenyl or substituted alkynyl with the proviso that at least
one of the substituents on the substituted alkenyl/alkynyl moiety is selected
from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,

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heterocyclic, and substituted heterocyclic with the proviso that when
substituted with substituted alkyl then at least one of the substituents on
the
substituted alkyl moiety is selected from the group consisting of alkoxy,
substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-
substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,

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substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -S02-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(g) substituted aryloxy and substituted heteroaryloxy with the proviso that
at least one substituent on the substituted aryloxy/heteroaryloxy is other
than
halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl,
alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy,
alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea;
(h) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted
heterocyclic, -substituted alkoxy-heterocyclic and -substituted
alkoxy-substituted saturated heterocyclic;
(i) -O-heterocyclic and -O-substituted heterocyclic;
(j) tetrazolyl;
(k) -NR-SO2-substituted alkyl where R is hydrogen, alkyl or aryl, with the
proviso that at least one substituent on the alkyl moiety of the substituted
alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl,
1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(l) alkenylsulfonylamino, alkynylsulfonylamino, substituted
alkenylsulfonylamino and substituted alkynylsulfonylamino;
(m) substituted alkoxy with the proviso that the substitution on the alkyl
moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated
heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and

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aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl,
1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(n) amidine and amidine substituted with from 1 to 3 substituents
independently selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
(o) -C(O)NR"'R"' where each R"' is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic with the proviso that when one R"' is unsaturated
heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with
halogen,
hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl,
alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy,
alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea, then the other R"' is alkyl, substituted alkyl (other than
unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted
cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic
and
substituted heterocyclic;
(p) -NR12C(O)-R8 where R8 is selected from the group consisting of
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic, and R12 is alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
(q) -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl or -SO2-alkyl;
(r) -NR'C(O)NR9R9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted

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cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and each R9 is independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic:
(s) -NR'C(O)OR9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and, R9 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
(t) -aminocarbonyl-(N-formylheterocycyl); and
(u) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted
heterocyclyl,
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
x is an integer of from 1 to 4;
Q is -C(X)NR7- wherein R7 is selected from the group consisting of
hydrogen and alkyl; and X is selected from the group consisting of oxygen and
sulfur;
and pharmaceutically acceptable salts thereof.
2. A compound of formula IA:
<IMG>
where
R1 is selected from the group consisting of alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic,
substituted
heterocylic, heteroaryl and substituted heteroaryl;

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R2 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and R1 and R2 together with the nitrogen
atom bound to R2 and the SO2 group bound to R1 can form a heterocyclic or a
substituted heterocyclic group;
R3 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic and, when R2 does not form
a
heterocyclic group with R1, R2 and R3 together with the nitrogen atom bound
to R2 and the carbon atom bound to R3 can form a heterocyclic or a substituted
heterocyclic group;
R5 is -(CH2)x-Ar-R5' where R5' is selected from the group consisting
(a) substituted alkylcarbonylamino with the proviso that at least one of the
substituents on the substituted alkyl moiety is selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino,
acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy,
substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl,
carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted
cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,
carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted
heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone,
thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,
thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted
thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic,
substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy,
heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl,
-OS(O)2-heteroaryl, -OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic,
-OS(O)2-substituted heterocyclic, -OSO2-NRR where R is hydrogen or alkyl,

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-NRS(O)2-alkyl, -NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-
substituted
aryl, -NRS(O)2-heteroaryl, -NRS(O}2-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted
heteroaryl, -NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic
where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and
di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted
arylamino, mono- and di-heteroarylamino, mono- and di-substituted
heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted
heterocyclic amino, and unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic,
and substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2 substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,

-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(b) alkoxyaryl substituted on the alkoxy moiety with a substituent selected
from the group consisting of carboxyl and -COOR where R is alkyl,
substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(c) aryl and heteroaryl;
(d) -NR'R' wherein each R' is independently selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and
substituted heterocyclic with the proviso that at least one of R' is
substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted
heterocyclic and with the further proviso that when R' is substituted alkyl at
least one of the substituents on the substituted alkyl moiety is selected from
the group consisting of alkoxy, substituted alkoxy, acyl, acylamino,

--186--
thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino,
thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen,
hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
cycloalkyl,
carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted
aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-substituted
alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O)2-heterocyclic,
-NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2 NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted

--187--
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2 substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(e) -alkoxy-NR"R" wherein each R" is independently selected from the
group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl,
substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic with the proviso that when each R" is substituted
alkyl then at least one of the substituents on the substituted alkyl moiety is
selected from the group consisting of alkoxy, substituted alkoxy, acyl,
acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl
amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidine, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-
heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O)2-
heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,

--188--
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyciic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cb2, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(f) substituted alkenyl or substituted alkynyl with the proviso that at least
one of the substituents on the substituted alkenyl/alkynyl moiety is selected
from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic, and substituted heterocyclic with the proviso that when
substituted with substituted alkyl then at least one of the substituents on
the
substituted alkyl moiety is selected from the group consisting of alkoxy,
substituted alkoxy, aryl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidine, guanidinosulfone, thiol, thioalkyl,

--189--
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-substituted
alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O)2-heterocyclic,
-NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cb2, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(g) substituted aryloxy and substituted heteroaryloxy with the proviso that
at least one substituent on the substituted aryloxy/heteroaryloxy is other
than
halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl,

--190--
alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy,
alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea;
(h) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted
heterocyclic, -substituted alkoxy-heterocyclic and -substituted
alkoxy-substituted saturated heterocyclic;
(i) -O-heterocyclic and -O-substituted heterocyclic;
(j) tetrazolyl;
(k) -NR-SO2-substituted alkyl where R is hydrogen, alkyl or aryl, with the
proviso that at least one substituent on the alkyl moiety of the substituted
alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl,
1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(l) alkenylsulfonylamino, alkynylsulfonylamino, substituted
alkenylsulfonylamino and substituted alkynylsulfonylamino;
(m) substituted alkoxy with the proviso that the substitution on the alkyl
moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated
heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and
aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl,
1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(n) amidine and amidine substituted with from 1 to 3 substituents
independently selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
(o) -C(O)NR"'R"' where each R"' is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,

--191--
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic with the proviso that when one R"' is unsaturated
heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with
halogen,
hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl,
alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy,
alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea, then the other R"' is alkyl, substituted alkyl (other than
unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted
cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic
and
substituted heterocyclic;
(p) -NR12C(O)-R8 where R8 is selected from the group consisting of
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic, and R12 is alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
(q) -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl or -SO2-alkyl;
(r) -NR'C(O)NR9R9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and each R9 is independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic:
(s) -NR'C(O)OR9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and, R9 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;

--192--
(t) -aminocarbonyl-(N-formylheterocycyl); and
(u) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted
heterocyclyl,
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
x is an integer of from 1 to 4;
R6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl
(3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted
cycloalkoxy, -O-(N-succinimidyl), -NH-adamantyl, -O-cholest-5-en-3-.beta.-yl,
-NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted
aryl, -NH(CH2)p COOY where p is an integer of from 1 to 8 and Y is as defined
above, -OCH2NR9R10 where R9 is selected from the group consisting of
-C(O)-aryl and -C(O)-substituted aryl and R10 is selected from the group
consisting of
hydrogen and -CH2COOR11 where R11 is alkyl, and -NHSO2Z where Z is
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic;
Q is -C(X)NR7- wherein R7 is selected from the group consisting of
hydrogen and alkyl; and X is selected from the group consisting of oxygen and
sulfur;
and pharmaceutically acceptable salts thereof
with the proviso that when R1 is p-CH3-~-, R6 is methoxy, Q is
-C(O)NH-, and R2 and R3 are joined to form a pyrrolidinyl group, then R5 is
not p-[-OCH2CH2N(C2H5)2]-benzyl-, p-[-OCH2CH2N(isopropyl)2]-benzyl-,
p-[-OCH2CH2-1-pyrrolidinyl)-benzyl-, p-[-OCH2CH2-1-(4-pyrimidinyl)piper-
azinyl]-benzyl-, p-[-OCH2CH2-N-morpholinyl)]-benzyl-, or p-[-OCH2CH2-N-
piperidinyl)]-benzyl-.
3. A compound according to Claims 1 or 2 wherein R1 is selected
from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl.

--193-
4. A compound according to Claim 3 wherein R1 is selected from the
group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl,
1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl,
2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl,
4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl,
4-(CH3C(O)NH-)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl,
3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl,
4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl,
1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl,
4-methylamidinophenyl, 4-[CH3SC(=NH))phenyl, 5-chloro-2-thienyl,
2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,3,4-
thiadiazol-2-yl, 4-[H2NC(S))phenyl, 4-aminophenyl, 4-fluorophenyl,
2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-
yl,
4-(3'-dimethylamino-n-propoxy)-phenyl, and 1-methylpyrazol-4-yl.
5. A compound according to Claims 1 or 2 wherein R2 is selected
from the group consisting of hydrogen, methyl, phenyl, benzyl, -(CH2)2-2-
thienyl,
and -(CH2)2-~.
6. A compound according to Claims 1 or 2 wherein R1 and R2
together with the nitrogen atom bound to R2 and the SO2 group bound to R1
are joined to form a heterocyclic group or substituted heterocyclic group.
7. A compound according to Claims 1 or 2 wherein R2 and R3
together with the nitrogen atom bound to R2 substituent and the carbon bound
to the R3 substituent form a heterocyclic group or a substituted heterocyclic
group.
8. A compound according to Claims 1 or 2 wherein R3 is selected
from the group consisting of methyl, phenyl, benzyl, diphenylmethyl,
-CH2CH2-COOH, -CH2-COOH, 2-amidoethyl, iso-butyl, t-butyl,
-CH2O-benzyl and hydroxymethyl.

--194--
9. A compound according to Claims 1 or 2 wherein Q is
-C(O)NH- or -C(S)NH-.
10. A compound according to Claims 1 or 2 wherein R5 is selected
from the group consisting of:
4-[NH2CH2C(O)NH-]benzyl, 4-[HOOCCH2CH2C(O)NH-]benzyl,
4-[-NHC(O)CH2NHBoc]benzyl, 4-[-NHC(O)CH(CH3)NHBoc]benzyl,
4-[-NHC(O)CH(CH2~)NHBoc]benzyl, 4-[-NHC(O)CH2NHC(O)NH-3'-
methylphenyl]benzyl, 4-(-NHC(O)CH(NHBoc)(CH2)4NHCb2]benzyl,
4-[-NHC(O)CH2CH(C(O)OCH2~)-NHCb2]benzyl, 4-~-benzyl,
4-[-NHC(O)CH(CH2CH2CH2CH2NH2)NHBoc]benzyl,
4-[H2NCH2CH2CH2C(O)NH-]benzyl, 4-(BocHNCH2CH2CH2-
C(O)NH-)benzyl, 4-[~CH2OCH2(BocHN)CHC(O)NH-]benzyl,
4-[CH3NHCH2CH2CH2C(O)NH-]benzyl, 4-(N-methylpiperidin-4-oxy)-benzyl,
4-[CH3N(Boc)CH2CH2CH2C(O)NH-]benzyl,
4-[~CH2OCH2(H2N)CHC(O)NH-]benzyl, 4-[HO(O)C(Cb2-NH)CHCH2CH2-
C(O)NH-]benzyl, 4-[~CH2O(O)C(Cb2-NH)CHCH2CH2-C(O)NH-]benzyl,
4-[HO(O)C(NH2)CHCH2CH2-C(O)NH-]benzyl,
4-[CH3(N-Boc)NCH2C(O)NH-]benzyl, 4-[CH3NHCH2C(O)NH-]benzyl,
4-[(CH3)2NCH2C(O)NH-]benzyl, 4-[-O-CH(COOH)~]benzyl,
4-[2-carboxylphenyl-]-benzyl, 4-[2-carboxylmethylphenyl-]-benzyl
4-[~CH2OC(O)NHCH2CH2NH-]benzyl, 4-N[-(SO2)CH3]-
CH2CH2CH2N(CH3)2]benzyl, 4-t-butyl-O(O)CCH2-O-benzylNH]benzyl,
4-[N,N-di(4-N,N dimethylamino)benzyl)amino]benzyl,
4-(2-formyl-1,2,3,4-tetrahydroisoquinolin-3-yl-CH2NH)benzyl,
4-[-OCH2CH2-1'-(4'-pyrimidinyl)-piperazinyl]-benzyl,
4-[-OCH2CH2-(1'-piperidinyl)-benzyl, 4-[-OCH2CH2-(1'-pyrrolidinyl)]-
benzyl, 4-[-OCH2CH2CH2-(1'-piperidinyl)]-benzyl,
4-[(CH3)2NCH2CH2CH2-O-]benzyl, 4-[(CH3)2NCH2CH2O-]-benzyl,
4-[-OCH2CH2CH2-(1'-(4'-methylpiperazinyl))]-benzyl,
4-[-OCH2CH2CH2-4-(3'-chlorophenyl)-piperazin-1-yl]-benzyl,

--195--
4-[-OCH2CH2N(~)CH2CH3]-benzyl, 4-[-OCH2-3'-(N-Boc)-piperidinyl]-
benzyl, 4-[-O-(3-(N-Boc)-piperidinyl]benzyl,
3-[-O-(N-methylpiperidin-4-yl]benzyl, 4-[-O-(N-methylpiperidin-4-yl]benzyl,
4-[di-iso-propylamino-CH2CH2O-]-benzyl, 4-[N 3-methylbutyl-N-trifluoro-
methanesulfonyl)amino]benzyl, 4-[-OCH2CH2-(N-morpholinyl)]-benzyl,
4-[-OCH2CH(NHBoc)CH2cyclohexyl]-benzyl, 4-[OCH2CH2-(N-piperidinyl]-
benzyl, 4-[-OCH2CH2CH2-(4-m-chlorophenyl)-piperazin-1-yl]-benzyl,
4-[-OCH2CH2-(N-homopiperidinyl)-benzyl, 4-[-OCH2CH2N(benzyl)2]-benzyl,
3-[-OCH2CH2CH2N(CH3)2]-benzyl, 4-[-OCH2CH2N(C2H5)2]-benzyl,
4-[-OCH2CH2CH2N(C2H5)2]-benzyl, 4-[-OCH2CH2N(C2H5)2]-benzyl,
4-[-OCH2CH2CH2N(CH3)benzyl]-benzyl, 4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethyl-O-]benzyl, [cyclopentylacetylenyl]-benzyl, 4-[-C~C-~-4'~]-benzyl,
4-[-C~C-CH2-O-S(O)2-4'-CH3-~]-benzyl, 4-[-C~C-CH2NHC(O)NH2]-benzyl,
4-[-C~C-CH2-O-(4'-COOCH2CH3)~]-benzyl, 4-[-C~C-CH(NH2)-cyclohexyl]-
benzyl, 4-[-C~C-CH2-O-phenyl]-benzyl, 4-[-C~C-CH2OCH3]-benzyl,
4-[-C~C-CH2-O-(4'-C(O)OC2H5)phenyl]-benzyl, 4-[-C=C-
CH2CH(C(O)OCH3)2]-benzyl, 4-[-C~C-CH2CH( NHC(O)CH3)C(O)OH]-
benzyl, 4-[-C~C-CH2-NH-(4,5-dihydro-4-oxo-5-phenyl-oxazol-2yl)]-benzyl,
4-[-OCH2CH2CH2-(N-morpholino)]-benzyl, 4-[-OCH2COOH]-benzyl,
4-[-OCH2COO-t-butyl]-benzyl, 4-(-N(SO2CH3)(CH2)3-N(CH3)2]-benzyl,
4-[-NHS(O)2CF3]-benzyl, 4-[-C(=NH)NH2]-benzyl, 4-[-NHSO2-CH2Cl]-
benzyl, 4-[-OCH2C(O)NH-benzyl]-benzyl, 4-[-OCH2C(O)O-benzyl]-benzyl,
4-[-OCH2C(O)OH]-benzyl, 4-[-OCH2CH2-1-(4-hydroxy-4-(3-methoxypyrrol-
2-yl)-piperazinyl]-benzyl, 4-[-OCH2C(O)NH2]-benzyl, 4-[-OCH2C(O)NH-t-
butyl]-benzyl, 4-[-OCH2CH2-1-(4-hydroxy-4-phenyl)-piperidinyl]-benzyl,
4-[-NHSO2-CH=CH2]-benzyl, 4-[-NHSO,-CH2CH2Cl]-benzyl, 4-benzyl-
benzyl, 4-[-OCH2C(O)piperidin-1-yl]benzyl,
4-[-OCH2C(O)N(CH(CH3)2)2]benzyl, 4-amidinobenzyl, 4-acetamidobenzyl,
4-(N-methyl)acetamidobenzyl, 4(-NHC(O)CH2NHC(O)NH-fluorescin)benzyl,
4-(NHC(O)CH2CH(NH2)COOH, (1-toluenesulfonylimidizol-4-yl)-methyl-,
[(1-N,N-dimethylaminosulfonyl)-imidizol-4-yl]methyl-, 4-(N-toluenesulfonyl-
amino)benzyl, and 4-[N-methyltrifluoroacetamido)phenyl.

--196--
11. A compound according to Claim 2 wherein R6 is selected from the
group consisting of 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy,
ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy,
2-.alpha.-iso-propyl-4-(i-methylcyclohexoxy, 2-.beta.-isopropyl-4-.beta.-
methylcyclohexoxy,
-NH2, benzyloxy, -NHCH2COOH, -NHCH2CH2COOH, -NH-adamantyl,
-NHCH2CH2COOCH2CH3, -NHSO2-p-CH3-~, -NHOR8 where R8 is hydrogen,
methyl, iso-propyl or benzyl, O-(N-succinimidyl),
-O-cholest-5-en-3-.beta.-yl, -OCH2-OC(O)C(CH3)3, -O(CH2)2NHC(O)W where z
is 1 or 2 and W is selected from the group consisting of pyrid-3-yl,
N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, -NR"C(O)-R' where R'
is aryl, heteroaryl or heterocyclic and R" is hydrogen or
-CH2C(O)OCH2CH3.
12. A compound selected from the group consisting of:
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonylglycyl)amino]-
L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(glycyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(carboxy)propionamido]-L-pheny-
lalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-L-
alanyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-D-
alanyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-D-
phenylalanyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[3-
(fluorescein)thiouriedo]acetamido}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonylglycyl)amino]-
L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[3-(3-
methylphenyl)uriedo]acetamido}-L-phenylalanine

--197--
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N.alpha.-tert-butoxylcarbonyl-
N.epsilon.-
carbobenzyloxy-L-lysyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[.gamma.-(.alpha.-benzyl-N.alpha.-
carbobenzyloxy-L-
aspartyl)amino]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N.alpha.-tert-butoxylcarbonyl-L-
lysyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[.gamma.-(L-aspartyl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(4-aminobutyramido)-L-phenylalanine
N-toluene-4-sulfonyl)-L-prolyl-4-[4-(N-tert-butoxyl-
carbonylamino)butyramido]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-methylamino)butyramido]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-tert-butoxylcarbonyl-N-
methylamino)butyramido]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(O-benzyl)-L-seryl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[.delta.-(D,L-glutamyl)amino]-L-
phenylala-
nine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxyl-
carbonylsarcosyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(N-tert-butoxyl-
carbonylsarcosyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino]-L-phenylalanine
ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(sarcosyl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N,N-dimethylglycyl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(N,N-
dimethylglycyl)amino]-L-phenylalanine

--198--
N-(toluene-4-sulfonyl)-L-prolyl-4-(.alpha.-carboxybenzyloxy)-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenyl]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(methoxycarbonyl)phenyl]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{N-[2-(N-
carbobenzyloxyamino)ethyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{N-[2-(N-
carbobenzyloxyamino)ethyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[3-(N,N-dimethylamino)propyl]-
N-[trifluoromethanesulfonyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[4-[(tert-
butoxycarbonyl)methoxy]benzyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N,N-di[4-(N,N-
dimethylamino)benzyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[(2-formyl-1,2,3,4-
tetrahydroisoquinolin-3-yl)methyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-N-methyl-L-serinyl-4-[3-(N,N-dimethylamino-
propoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[2-{N,N-
dimethylamino)ethoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N-dimethylamino)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N-ethyl-N-phenylamino)ethoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N-diisopropylamino)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-cyclohexyl-2-(N-tert-
butoxycarbonylamino)propoxy]-L-phenylalanine methyl ester
N-(thiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine

--199--
N-(5-chlorothiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N-diethylamino)ethoxy]-L-
phenylalanine
N-(2,5-dichlorothiophene-3-sulfonyl)-L-prolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(1-methylpyrazole-4-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N-diethylamino)propoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine
N-(thiazole-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N-methyl-N-
benzylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N-diethylamino)propoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N-methyl-N-
benzylamino)propoxy]-L-phenylalanine methyl ester
N-(1-methylimidazole-4-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)-
propoxy]-L-phenylalanine
N-(2-methylthiadiazole-5-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-thiaprolyl-4-[3-(N,N-dimethylamino)propoxy]-
L-phenylalanine
N-(4-cyanobenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(3,3-dimethyl)prolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine ethyl ester

--200--
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-(cyclopentyl)ethynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-{2-[4-
(phenyl)phenyl]ethynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(toluene-4-
sulfonyloxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(ureido)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(4-
ethoxycarbonylphenoxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-(1-aminocyclohex-1-
yl)ethynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(phenoxy)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(phenoxy)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(methoxy)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(methoxy)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-ethoxycarbonylphenoxy)prop-1-
ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(4-ethoxycarbonylphenoxy)prop-1-
ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4,4-di(methoxycarbonyl)but-1-ynyl]-
D,L-phenylalanine

--201--
N-(toluene-4-sulfonyl)sarcosyl-4-[4,4-di(methoxycarbonyl)but-1-ynyl]-
D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(4-acetamido-4-carboxybut-1-ynyl)-
D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-(4-acetamido-4-carboxybut-1-ynyl)-
D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[(4,5-dihydro-4-oxo-5-
phenyloxazol-2-yl)amino]prop-1-ynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-{3-[(4,5-dihydro-4-oxo-5-phenyloxazol-
2-yl)amino]prop-1-ynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenoxy]-L-phenylalanine
methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[4-(pyrimidin-2-yl)piperazin-1-
yl]ethoxy}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin-1-yl)propoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(pyrrolidin-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin-1-yl)propoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[4-(3-chlorophenyl)piperazin-1-
yl]propoxy}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(1-tert-butoxycarbonylpiperidin-3-
yl)methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(morpholin-4-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(1-tert-butoxycarbonyipiperidin-3-
yl)methoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(piperidin-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[4-(3-chlorophenyl)piperazin-1-
yl]propoxy}-L-phenylalanine methyl ester

--202--
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1-yl)ethoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin-1-yl)propoxy]-
L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(pyrrolidin-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin-1-yl)propoxy]-
L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(morpholin-4-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[4-(3-methoxythien-2-yl)-4-
hydroxypiperidin-1-yl]ethoxy}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-(1-methylpiperidin-4-oxy)-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(1-methylpiperidin-4-oxy)-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-(1-methylpiperidin-
4-oxy)-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-(1,1-dioxothiomorpholin-3-carbonyl)-4-(1-
methylpiperidin-4-oxy)-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-(1,1-dioxothiomorpholin-3-carbonyl)-4-(1-
methylpiperidin-4-oxy)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-(1-methylpiperidin-
4-oxy)-L-phenylalanine
N-(.alpha.-toluenesulfonyl)-L-prolyl-4-(1-methylpiperidin-4-oxy)-L-
phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(trifiuoromethanesulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(trifluoromethanesulfonyl)amino-L-
phenylalanine

--203--
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(chloromethanesulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(vinylsulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-(N-trifluoromethanesulfonyl-N-
isobutyl)amino-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(vinylsulfonyl)amino-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-benzylaminocarbony)methoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-L-phenylalanine
methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(aminocarbonyl)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butylaminocarbonyl)methoxy]-
L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(4-phenyl-4-hydroxypiperidin-1-
yl)ethoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(piperidin-1-ylcarbonyl)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N, N-
diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N,N-
diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(amidino)phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(aminocarbonyl)phenylalanine

--204--
N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methylacetamido)-L-phenylalanine
isopropyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methylacetamido)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methyltrifluoroacetamido)-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-(N-methylpiperidinoxy)-
phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiapropyl-L-(4-
methylpiperidinoxy) phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
and pharmaceutically acceptable salts thereof as well as any of the ester
compounds recited above wherein one ester is replaced with another ester
selected from the group consisting of methyl ester, ethyl ester, n-propyl
ester,
isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl
ester.
13. A method for binding VLA-4 in a biological sample which
method comprises contacting the biological sample with a compound
<IMG>
where
R1 is selected from the group consisting of alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic,
substituted
heterocylic, heteroaryl and substituted heteroaryl;

--205--
R2 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and R1 and R2 together with the nitrogen
atom bound to R2 and the SO2 group bound to R1 can form a heterocyclic or a
substituted heterocyclic group;
R3 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic and, when R2 does not form
a
heterocyclic group with R1, R2 and R3 together with the nitrogen atom bound
to R2 and the carbon atom bound to R3 can form a heterocyclic or a substituted
heterocyclic group;
R5 is -(CH2)x-Ar-R5' where R5' is selected from the group consisting
(a) substituted alkylcarbonylamino with the proviso that at least one of the
substituents on the substituted alkyl moiety is selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino,
acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy,
substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl,
carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted
cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,
carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted
heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone,
thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,
thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted
thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic,
substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy,
heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl,
-OS(O)2-heteroaryl, -OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic,
-OS(O)2-substituted heterocyclic, -OSO2-NRR where R is hydrogen or alkyl,

--206--
-NRS(O)2-alkyl, -NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-
substituted aryl, -NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-
alkyl, -NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-
substituted aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted
heteroaryl, -NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic
where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-
(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted
arylamino, mono- and di-heteroarylamino, mono- and di-substituted
heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted
heterocyclic amino, and unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic,
and substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cb2, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-
aryl, -SO2 substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -
SO2-
heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is hydrogen
or alkyl;
(b) alkoxyaryl substituted on the alkoxy moiety with a substituent selected
from the group consisting of carboxyl and -COOR where R is alkyl,
substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(c) aryl and heteroaryl;
(d) -NR'R' wherein each R' is independently selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and
substituted heterocyclic with the proviso that at least one of R' is
substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted
heterocyclic and with the further proviso that when R' is substituted alkyl at
least one of the substituents on the substituted alkyl moiety is selected from
the group consisting of alkoxy, substituted alkoxy, acyl, acylamino,

--207--
thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino,
thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen,
hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-
substituted
aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-
substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O)2-
heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted

--208--
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(e) -alkoxy-NR"R" wherein each R" is independently selected from the
group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl,
substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic with the proviso that when each R" is substituted
alkyl then at least one of the substituents on the substituted alkyl moiety is
selected from the group consisting of alkoxy, substituted alkoxy, acyl,
acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl
amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-substituted
alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2 substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O)2-heterocyclic,
-NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,

--209--
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR.-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR.-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2ZNRR where R is
hydrogen
or alkyl;
(f) substituted alkenyl or substituted alkynyl with the proviso that at least
one of the substituents on the substituted alkenyl/alkynyl moiety is selected
from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic, and substituted heterocyclic with the proviso that when
substituted with substituted alkyl then at least one of the substituents on
the
substituted alkyl moiety is selected from the group consisting of alkoxy,
substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, vitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,

--210--
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-substituted
alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O)2-heterocyclic,
-NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(g) substituted aryloxy and substituted heteroaryloxy with the proviso that
at least one substituent on the substituted aryloxy/heteroaryloxy is other
than
halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl,

--211--
alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy,
alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea;
(h) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted
heterocyclic, -substituted alkoxy-heterocyclic and -substituted
alkoxy-substituted saturated heterocyclic;
(i) -O-heterocyclic and -O-substituted heterocyclic;
(j) tetrazolyl;
(k) -NR-SO2-substituted alkyl where R is hydrogen, alkyl or aryl, with the
proviso that at least one substituent on the alkyl moiety of the substituted
alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl,
1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(l) alkenylsulfonylamino, alkynylsulfonylamino, substituted
alkenylsulfonylamino and substituted alkynylsulfonylamino;
(m) substituted alkoxy with the proviso that the substitution on the alkyl
moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated
heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and
aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl,
1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(n) amidine and amidine substituted with from 1 to 3 substituents
independently selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
(o) -C(O)NR'''R''' where each R''' is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,

--212--
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic with the proviso that when one R''' is unsaturated
heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with
halogen,
hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl,
alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy,
alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea, then the other R''' is alkyl, substituted alkyl (other than
unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted
cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic
and
substituted heterocyclic;
(p) -NR12C(O)-R8 where R8 is selected from the group consisting of
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic, and R12 is alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
(q) -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl or -SO2-alkyl;
(r) -NR'C(O)NR9R9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and each R9 is independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic:
(s) -NR'C(O)OR9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and, R9 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryi, heterocyclic and substituted heterocyclic;

--213--
(t) -aminocarbonyl-(N-formylheterocycyl); and
(u) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted
heterocyclyl,
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
x is an integer of from 1 to 4;
R6' is selected from the group consisting of, hydroxy,
2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy,
cycloalkoxy, substituted cycloalkoxy, -O-(N-succinimidyl), -NH-adamantyl,
-O-cholest-5-en-3-.beta.-yl, -NHOY where Y is hydrogen, alkyl, substituted
alkyl,
aryl, and substituted aryl, -NH(CH2)PCOOY where p is an integer of from 1 to
8 and Y is as defined above, -OCH2NR9R10 where R9 is selected from the
group consisting of-C(O)-aryl and -C(O)-substituted aryl and R10 is selected
from the group consisting of hydrogen and -CH2COOR11 where R11 is alkyl,
and -NHSO2Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
Q is -C(X)NR7- wherein R7 is selected from the group consisting of
hydrogen and alkyl; and X is selected from the group consisting of oxygen and
sulfur;
and pharmaceutically acceptable salts thereof
with the proviso that when R1 is p-CH3-.PHI.-, R6 is methoxy, Q is
-C(O)NH-, and R2 and R3 are joined to form a pyrrolidinyl group, then R5 is
not p-[-OCH2CH2N(C2H5)2]-benzyl-, p-[-OCH2CH2N(isopropyl)2]-benzyl-,
p-[-OCH2CH2-1-pyrrolidinyl)-benzyl-, p-[-OCH2CH2-1-(4-pyrimidinyl)piper-
azinyl]-benzyl-, p-[-OCH2CH2-N-morpholinyl)]-benzyl-, or p-[-OCHCH2-N-
piperidinyl)]-benzyl-
under conditions wherein said compound binds to VLA-4.
14. The method according to Claim 13 wherein R1 is selected from the
group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
heterocyclic,
substituted heterocylic, heteroaryl and substituted heteroaryl.

-214-
15. The method according to Claim 14 wherein R1 is selected from the
group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl,
1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl,
2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl,
4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl,
4-(CH3C(O)NH-)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl,
3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl,
4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl,
1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl,
4-methylamidinophenyl, 4-[CH3SC(=NH)]phenyl, 5-chloro-2-thienyl,
2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,3,4-
thiadiazol-2-yl, 4-[H2NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl,
2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2
yl, 4-(3'-dimethylamino-n-propoxy)-phenyl, and 1-methylpyrazol-4-yl.
16. The method according to Claim 13 wherein R2 is selected from the
group consisting of hydrogen, methyl, phenyl, benzyl, -(CH2)2-2-thienyl, and
-(CH2)2-.PHI..
17. The method according to Claim 13 wherein R1 and R2 together
with the nitrogen atom bound to R2 and the SO2 group bound to R1 are joined
to form a heterocyclic group or substituted heterocyclic group.
18. The method according to Claim 13 wherein R2 and R3 together
with the nitrogen atom bound to R2 substituent and the carbon bound to the R3
substituent form a heterocyclic group or a substituted heterocyclic group.
19. The method according to Claim 13 wherein R3 is selected from the
group consisting of methyl, phenyl, benzyl, diphenylmethyl,
-CH2CH2-COOH, -CH2-COOH, 2-amidoethyl, iso-butyl, t-butyl,
-CH2O-benzyl and hydroxymethyl.

-215-
20. The method according to Claim 13 wherein Q is -C(O)NH- or
-C(S)NH-.
21. The method according to Claim 13 wherein R5 is selected from the
group consisting of:
4-[NH2CH2C(O)NH-]benzyl, 4-[HOOCCH2CH2C(O)NH-]benzyl,
4-[-NHC(O)CH2NHBoc]benzyl, 4-[-NHC(O)CH(CH3)NHBoc]benzyl,
4-[-NHC(O)CH(CH2.PHI.)NHBoc]benzyl, 4-[-NHC(O)CH2NHC(O)NH-3'-
methylphenyl]benzyl, 4-[-NHC(O)CH(NHBoc)(CH2)4NHCbz]benzyl,
4-[-NHC(O)CH2CH(C(O)OCH2.PHI.)-NHCbz]benzyl, 4-.PHI.-benzyl,
4-[-NHC(O)CH(CH2CH2CH2CH2NH2)NHBoc]benzyl,
4-[H2NCH2CH2CH2C(O)NH-]benzyl, 4-(BocHNCH2CH2CH2-
C(O)NH-)benzyl, 4-[.PHI.CH2OCH2(BocHN)CHC(O)NH-]benzyl,
4-[CH3NHCH2CH2CH2C(O)NH-]benzyl, 4-(N-methylpiperidin-4-oxy)-benzyl,
4-[CH3N(Boc)CH2CH2CH2C(O)NH-]benzyl,
4-[.PHI.CH2OCH2(H2N)CHC(O)NH-]benzyl, 4-[HO(O)C(Cbz-NH)CHCH2CH2-
C(O)NH-]benzyl, 4-[.PHI.CH2O(O)C(Cbz-NH)CHCH2CH2-C(O)NH-]benzyl,
4-[HO(O)C(NH2)CHCH2CH2-C(O)NH-]benzyl,
4-[CH3(N Boc)NCH2C(O)NH-]benzyl, 4-[CH3NHCH2C(O)NH-]benzyl,
4-[(CH3)ZNCH2C(O)NH-]benzyl, 4-[-O-CH(COOH).PHI.]benzyl,
4-[2-carboxylphenyl-]-benzyl, 4-[2-carboxylmethylphenyl-]-benzyl
4-[.PHI.CH2OC(O)NHCH2CH2NH-]benzyl, 4-N[-(SO2)CH3]-
CH2CH2CH2N(CH3)2]benzyl, 4-t-butyl-O(O)CCH2-O-benzylNH]benzyl,
4-[N,N di(4-N,N dimethylamino)benzyl)amino]benzyl,
4-(2-formyl-1,2,3,4-tetrahydroisoquinolin-3-yl-CH2NH)benzyl,
4-[-OCH2CH2-1'-(4'-pyrimidinyl)-piperazinyl]-benzyl,
4-[-OCH2CH2-(1'-piperidinyl)-benzyl, 4-[-OCH2CH2-(1'-pyrrolidinyl)]-
benzyl, 4-[-OCH2CH2CH2-(1'-piperidinyl)]-benzyl,
4-[(CH3)2NCH2CH2CH2-O-]benzyl, 4-[(CH3)2NCH2CH2O-]-benzyl,
4-[-OCH2CH2CH2(1'-(4'-methylpiperazinyl))]-benzyl,
4-[-OCH2CH2CH2-4-(3'-chlorophenyl)-piperazin-1-yl]-benzyl,

-216-
4-[-OCH2CH2N(.PHI.)CH2CH3]-benzyl, 4-[-OCH2-3'-(N-Boc)-piperidinyl]-
benzyl, 4-[-O-(3-(N-Boc)-piperidinyl]benzyl,
3-[-O-(N-methylpiperidin-4-yl]benzyl, 4-[-O-(N-methylpiperidin-4-yl]benzyl,
4-[di-iso-propylamino-CH2CH2O-]-benzyl, 4-[N 3-methylbutyl-N trifluoro-
methanesulfonyl)amino]benzyl, 4-[-OCH2CH2-(N-morpholinyl)]-benzyl,
4-[-OCH2CH(NHBoc)CH2cyclohexyl]-benzyl, 4-[OCH2CH2-(N-piperidinyl]-
benzyl, 4-[-OCH2CH2CH2-(4-m-chlorophenyl)-piperazin-1-yl]-benzyl,
4-[-OCH2CH2-(N-homopiperidinyl)-benzyl, 4-[-OCH2CH2N(benzyl)2]-benzyl,
3-[-OCH2CH2CH2N(CH3)2]-benzyl, 4-[-OCH2CH2N(C2H5)2]-benzyl,
4-[-OCH2CH2CH2N(C2H5)2]-benzyl, 4-[-OCH2CH2N(C2H5)2]-benzyl,
4-[-OCH2CH2CH2N(CH3)benzyl)-benzyl, 4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethyl-O-]benzyl, [cyclopentylacetylenyl]-benzyl, 4-[-C~C-.PHI.-4'.PHI.]-
benzyl,
4-[-C~C-CH2-O-S(O)2-4'-CH3-.PHI.]-benzyl, 4-[-C~C-CH2NHC(O)NH2]-benzyl,
4-[-C~C-CH2-O-(4'-COOCH2CH3).PHI.]-benzyl, 4-[-C~C-CH(NH2)-cyclohexyl]-
benzyl, 4-[-C~C-CH2-O-phenyl]-benzyl, 4-[-C~C-CH2OCH3]-benzyl,
4-[-C~C-CH2-O-(4'-C(O)OC2H5)phenyl]-benzyl,
4-[-C~C-CH2CH(C(O)OCH3)2]-benzyl, 4-[-C~C-CH2CH(NHC(O)CH3)C(O)OH]-benzyl,
4-[-C~C-CH2-NH-(4,5-dihydro-4-oxo-5-phenyl-oxazol-2yl)]-benzyl,
4-[-OCH2CH2CH2-(N-morpholino)]-benzyl, 4-[-OCH2COOH]-benzyl,
4-[-OCH2COO-t-butyl]-benzyl, 4-[-N(SO2CH3)(CH2)3-N(CH3)2]-benzyl,
4-[-NHS(O)2CF3]-benzyl, 4-[-C(=NH)NH2]-benzyl, 4-[-NHSO2-CH2CI]-benzyl,
4-[-OCH2C(O)NH-benzyl]-benzyl, 4-[-OCH2C(O)O-benzyl]-benzyl,
4-[-OCH2C(O)OH]-benzyl, 4-[-OCH2CH2-1-(4-hydroxy-4-(3-methoxypyrrol-
2-yl)-piperazinyl]-benzyl, 4-[-OCH2C(O)NH2]-benzyl, 4-[-OCH2C(O)NH-t-
butyl]-benzyl, 4-[-OCH2CH2-1-(4-hydroxy-4-phenyl)-piperidinyl]-benzyl,
4-[-NHSO2-CH=CH2]-benzyl, 4-[-NHSO2-CH2CH2Cl]-benzyl,
4-benzyl-benzyl, 4-[-OCH2C(O)piperidin-1-yl]benzyl,
4-[-OCH2C(O)N(CH(CH3)2)2]benzyl, 4-amidinobenzyl, 4-acetamidobenzyl,
4-(N-methyl)acetamidobenzyl, 4(-NHC(O)CH2NHC(O)NH-fluorescin)benzyl,
4-(NHC(O)CH2CH(NH2)COOH, (1-toluenesulfonylimidizol-4-yl)-methyl-,
[(1-N,N dimethylaminosulfonyl)-imidizol-4-yl]methyl-, 4-(N toluenesulfonyl-
amino)benzyl, and 4-[N methyltrifluoroacetamido)phenyl.

-217-
22. The method according to Claim 13 wherein R6' is selected from
the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy,
ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy,
2-.alpha.-isopropyl-4-.beta.-methylcyclohexoxy, 2-.beta.-isopropyl-4-.beta.-
methylcyclohexoxy,
-NH2, benzyloxy, -NHCH2COOH, -NHCH2CH2COOH, -NH-adamantyl,
-NHCH2CH2COOCH2CH3, -NHSO2-p-CH3-.PHI., -NHOR8 where R8 is hydrogen,
methyl, iso-propyl or benzyl, O-(N-succinimidyl),
-O-cholest-5-en-3-.beta.-yl, -OCH2-OC(O)C(CH3)3, -O(CH2)z NHC(O)W where z
is 1 or 2 and W is selected from the group consisting of pyrid-3-yl,
N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, -NR"C(O)-R' where R'
is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH2C(O)OCH2CH3.
23. The method according to Claim 13 wherein said compound is
selected from the group consisting of:
N (toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxylcarbonylglycyl)amino]-
L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(glycyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(carboxy)propionamido]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxylcarbonyl-L-
alanyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxylcarbonyl-D-
alanyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxylcarbonyl-D-
phenylalanyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-(2-[3-
(fluorescein)thiouriedo]acetamido}-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonylglycyl)amino]-
L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-{2-[3-(3-
methylphenyl)uriedo]acetamido}-L-phenylalanine

-218-
N (toluene-4-sulfonyl)-L-prolyl-4-[(Na-tert-butoxylcarbonyl-N~-
carbobenzyloxy-L-lysyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[.gamma.-(.alpha.-benzyl-N.alpha.-
carbobenzyloxy-L-
aspartyl)amino]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[(N.alpha.-tert-butoxylcarbonyl-L-
lysyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[.gamma.-(L-aspartyl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(4-aminobutyramido)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N tert-butoxyl-
carbonylamino)butyramido]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-methylamino)butyramido]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4-{N-tert-butoxylcarbonyl-N-
methylamino)butyramido]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(O-benzyl)-L-seryl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[.delta.-(D,L-glutamyl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxyl-
carbonylsarcosyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(N-tert-butoxyl-
carbonylsarcosyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[{sarcosyl)amino]-L-phenylalanine
ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(sarcosyl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[{N,N-dimethylglycyl)amino]-L-
phenylalanine
N-{toluene-4-sulfonyl)-L-{5,5-dimethyl)thiaprolyl-4-[(N,N-
dimethylglycyl)amino]-L-phenylalanine

-219-
N-(toluene-4-sulfonyl)-L-prolyl-4-(.alpha.-carboxybenzyloxy)-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenyl]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(methoxycarbonyl)phenyl]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{N-[2-(N
carbobenzyloxyamino)ethyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{N-[2-(N
carbobenzyloxyamino)ethyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[3-(N,N-dimethylamino)propyl]-
N-[trifluoromethanesulfonyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[4-[(tert-
butoxycarbonyl)methoxy]benzyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N,N-di[4-(N,N
dimethylamino)benzyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[(2-formyl-1,2,3,4-
tetrahydroisoquinolin-3-yl)methyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy)-L-
phenylalanine
N-(toluene-4-sulfonyl)-N-methyl-L-serinyl-4-[3-(N,N-dimethylamino-
propoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[2-(N,N-
dimethylamino)ethoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N-dimethylamino)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl}-L-prolyl-4-[2-(N-ethyl-N-phenylamino)ethoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N-diisopropylamino)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-cyclohexyl-2-(N-tert-
butoxycarbonylamino)propoxy]-L-phenylalanine methyl ester
N-(thiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine

-220-
N-(5-chlorothiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino}-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N- diethylamino)ethoxy]-L-
phenylalanine
N-(2,5-dichlorothiophene-3-sulfonyl)-L-prolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(1-methylpyrazole-4-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N-diethylamino)propoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine
N-(thiazole-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N methyl-N-
benzylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N-diethylamino)propoxy]-L-
phenylalanine
N- (toluene-4-sulfonyl)-L-prolyl-4-[3-(N- methyl-N-
benzylamino)propoxy]-L-phenylalanine methyl ester
N-(1-methylimidazole-4-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)-
propoxy]-L-phenylalanine
N-(2-methylthiadiazole-5-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-thiaprolyl-4-[3-(N,N-dimethylamino)propoxy]-
L-phenylalanine
N-(4-cyanobenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(3,3-dimethyl)prolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine ethyl ester

-221-
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-(cyclopentyl)ethynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-{2-[4-
(phenyl)phenyl]ethynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(toluene-4-
sulfonyloxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(ureido)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(4-
ethoxycarbonylphenoxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-{1-aminocyclohex-1-
yl)ethynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(phenoxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(phenoxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(methoxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(methoxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-ethoxycarbonylphenoxy)prop-1-
ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(4-ethoxycarbonylphenoxy)prop-1-
ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4,4-di(methoxycarbonyl)but-1-ynyl]-
D,L-phenylalanine

-222-
N-(toluene-4-sulfonyl)sarcosyl-4-[4,4-di(methoxycarbonyl)but-1-ynyl]-
D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(4-acetamido-4-carboxybut-1-ynyl)-
D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-(4-acetamido-4-carboxybut-1-ynyl)-
D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[(4,5-dihydro-4-oxo-5
phenyloxazol-2-yl)amino]prop-1-ynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-{3-[(4,5-dihydro-4-oxo-5-phenyloxazol-
2-yl)amino]prop-1-ynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenoxy]-L-phenylalanine
methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[4-(pyrimidin-2-yl)piperazin-1-
yl)ethoxy}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin-1-yl)propoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(pyrrolidin-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin-1-yl)propoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[4-(3-chlorophenyl)piperazin-1-
yl]propoxy}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(1-tert-butoxycarbonylpiperidin-3-
yl)methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(morpholin-4-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(1-tert-butoxycarbonylpiperidin-3-
yl)methoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(piperidin-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[4-(3-chlorophenyl)piperazin-1-
yl]propoxy}-L-phenylalanine methyl ester

-223-
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1-yl)ethoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin-1-yl)propoxy]-
L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(pyrrolidin-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin-1-yl)propoxy]-
L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(morpholin-4-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-t2-[4-(3-methoxythien-2-yl)-4-
hydroxypiperidin-1-yl]ethoxy)-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-(1-methylpiperidin-4-oxy)-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(1-methylpiperidin-4-oxy)-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-(1-methylpiperidin-
4-oxy)-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-(1,1-dioxothiomorpholin-3-carbonyl)-4-(1-
methylpiperidin-4-oxy)-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-(1,1-dioxothiomorpholin-3-carbonyl)-4-(1-
methylpiperidin-4-oxy)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-(1-methylpiperidin-
4-oxy)-L-phenylalanine
N-(a-toluenesulfonyl)-L-prolyl-4-(1-methylpiperidin-4-oxy)-L-
phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(trifluoromethanesulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N (trifluoromethanesulfonyl)amino-L-
phenylalanine

-224-
N-(toluene-4-sulfonyl)-L-prolyl-4-N (chloromethanesulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N (vinylsulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-(N trifluoromethanesulfonyl-N
isobutyl)amino-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N (vinylsulfonyl)amino-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N benzylaminocarbony)methoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-L-phenylalanine
methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(aminocarbonyl)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butylaminocarbonyl)methoxy]-
L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(4-phenyl-4-hydroxypiperidin-1-
yl)ethoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(piperidin-1-ylcarbonyl)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N,N-
diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N,N
diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(amidino}phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(aminocarbonyl)phenylalanine

-225-
N-(toluene-4-sulfonyl)-L-prolyl-4-(N methylacetamido)-L-phenylalanine
isopropyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-(N methylacetamido)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(N methyltrifluoroacetamido)-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,IV
dimethylamino)propoxy]-L-phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-(N methylpiperidinoxy)-
phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiapropyl-L-(4-
methylpiperidinoxy) phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
and pharmaceutically acceptable salts thereof as well as any of the ester
compounds recited above wherein one ester is replaced with another ester
selected from the group consisting of methyl ester, ethyl ester, n-propyl
ester,
isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl
ester.
24. The method according to Claim 23 wherein said compound is:
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxylcarbonylglycyl)amino]-
L-phenylalanine.
25. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of one or more the
compounds of the formula:

-226-
<IMG>
where
R1 is selected from the group consisting of alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic,
substituted
heterocylic, heteroaryl and substituted heteroaryl;
R2 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and R1 and R2 together with the nitrogen
atom bound to R2 and the SO2 group bound to R1 can form a heterocyclic or a
substituted heterocyclic group;
R3 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic and, when R2 does not form
a
heterocyclic group with R1, R2 and R3 together with the nitrogen atom bound
to R2 and the carbon atom bound to R3 can form a heterocyclic or a substituted
heterocyclic group;
R5 is -(CH2)X Ar-R5' where R5' is selected from the group consisting
(a) substituted alkylcarbonylamino with the proviso that at least one of the
substituents on the substituted alkyl moiety is selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino,
acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy,
substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl,
carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted
cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,
carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted
heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone,

--227--
thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,
thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted
thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic,
substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy,
heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl,
-OS(O)2-heteroaryl, -OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic,
-OS(O)2-substituted heterocyclic, -OSO2-NRR where R is hydrogen or alkyl,
-NRS(O)2-alkyl, -NRS(O)2-substituted alkyl, -NRS(O)2-aryl,
-NRS(O)2-substituted aryl, -NRS(O)2-heteroaryl, -NRS(O)2-substituted
heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted
heteroaryl, -NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic
where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and
di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted
arylamino, mono- and di-heteroarylamino, mono- and di-substituted
heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted
heterocyclic amino, and unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic,
and substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(b) alkoxyaryl substituted on the alkoxy moiety with a substituent selected
from the group consisting of carboxyl and -COOR where R is alkyl,
substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,

--228--
(c) aryl and heteroaryl;
(d) -NR'R' wherein each R' is independently selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and
substituted heterocyclic with the proviso that at least one of R' is
substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted
heterocyclic and with the further proviso that when R' is substituted alkyl at
least one of the substituents on the substituted alkyl moiety is selected from
the group consisting of alkoxy, substituted alkoxy, acyl, acylamino,
thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino,
thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen,
hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-
substituted
aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-
heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,

--229--
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(e) -alkoxy-NR"R" wherein each R" is independently selected from the
group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl,
substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic with the proviso that when each R" is substituted
alkyl then at least one of the substituents on the substituted alkyl moiety is
selected from the group consisting of alkoxy, substituted alkoxy, acyl,
acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl
amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,

--230--
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-
heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(f) substituted alkenyl or substituted alkynyl with the proviso that at least
one of the substituents on the substituted alkenyl/alkynyl moiety is selected
from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic, and substituted heterocyclic with the proviso that when
substituted with substituted alkyl then at least one of the substituents on
the

--231--
substituted alkyl moiety is selected from the group consisting of alkoxy,
substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2
heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional

--232--
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SO2-alkyl, -SO2-substituted alkyl, -SO2-
alkenyl,
-SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl,
-SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl,
-SO2-heterocyclic, -SO2-substituted heterocyclic and -SO2NRR where R is
hydrogen
or alkyl;
(g) substituted aryloxy and substituted heteroaryloxy with the proviso that
at least one substituent on the substituted aryloxy/heteroaryloxy is other
than
halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl,
alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy,
alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea;
(h) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted
heterocyclic, -substituted alkoxy-heterocyclic and -substituted
alkoxy-substituted saturated heterocyclic;
(i) -O-heterocyclic and -O-substituted heterocyclic;
(j) tetrazolyl;
(k) -NR-SO2-substituted alkyl where R is hydrogen, alkyl or aryl, with the
proviso that at least one substituent on the alkyl moiety of the substituted
alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl,
1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(l) alkenylsulfonylamino, alkynylsulfonylamino, substituted
alkenylsulfonylamino and substituted alkynylsulfonylamino;
(m) substituted alkoxy with the proviso that the substitution on the alkyl
moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated
heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and
aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl,

--233--
1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(n) amidine and amidine substituted with from 1 to 3 substituents
independently selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
(o) -C(O)NR'''R''' where each R''' is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic with the proviso that when one R''' is unsaturated
heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with
halogen,
hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl,
alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy,
alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea, then the other R''' is alkyl, substituted alkyl (other than
unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted
cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic
and
substituted heterocyclic;
(p) -NR12C(O)-R8 where R8 is selected from the group consisting of
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic, and R12 is alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
(q) -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted
heteroaryl or -SO2-alkyl;
(r) -NR'C(O)NR9R9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and each R9 is independently selected from the group consisting

--234--
of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic:
(s) -NR'C(O)OR9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and, R9 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
(t) -aminocarbonyl-(N-formylheterocycyl); and
(u) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted
heterocyclyl,
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
x is an integer of from 1 to 4;
R6' is selected from the group consisting of, hydroxy,
2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy,
cycloalkoxy, substituted cycloalkoxy, -O-(N-succinimidyl), -NH-adamantyl,
-O-cholest-5-en-3-(3-yl, -NHOY where Y is hydrogen, alkyl, substituted alkyl,
aryl, and substituted aryl, -NH(CH2)p COOY where p is an integer of from 1 to
8 and Y is as defined above, -OCH2NR9R10 where R9 is selected from the
group consisting of -C(O)-aryl and -C(O)-substituted aryl and R10 is selected
from the group consisting of hydrogen and -CH2COOR11 where R11 is alkyl,
and -NHSO2Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
Q is -C(X)NR7- wherein R7 is selected from the group consisting of
hydrogen and alkyl; and X is selected from the group consisting of oxygen and
sulfur;
and pharmaceutically acceptable salts thereof
with the proviso that when R1 is p-CH3-.PHI.-, R5 is methoxy, Q is
-C(O)NH-, and R2 and R3 are joined to form a pyrrolidinyl group, then R5 is
not p-[-OCH2CH2N(C2H5)Z]-benzyl-, p-[-OCH2CH2N(isopropyl)2]-benzyl-,

--235--
[-OCH2CH2-1-pyrrolidinyl)-benzyl-, p-[-OCH2CH2-1-(4-pyrimidinyl)piperazinyl]
-benzyl-, p-[-OCH2CH2-N-morpholinyl)]-benzyl-, or p-[-OCH2CH2-N-piperidinyl)]-
benzyl-
under conditions wherein said compound binds to VLA-4.
26. The pharmaceutical composition according to Claim 13 wherein
R1 is selected from the group consisting of alkyl, substituted alkyl, aryl,
substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and
substituted heteroaryl.
27. The pharmaceutical composition according to Claim 26 wherein
R1 is selected from the group consisting of 4-methylphenyl, methyl, benzyl,
n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl,
2,4,6-trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl,
3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl,
3,4-dimethoxyphenyl, 4-(CH3C(O)NH-)phenyl, 4-trifluoromethoxyphenyl,
4-cyanophenyl, isopropyl, 3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl,
4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-
chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl,
4-amidinophenyl, 4-methylamidinophenyl, 4-[CH3SC(=NH)]phenyl, 5-chloro-2-
thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-
1,3,4-thiadiazol-2-yl, 4-[HZNC(S)]phenyl, 4-aminophenyI, 4-fluorophenyl, 2-
fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-
yl,
4-(3'-dimethylamino-n-propoxy)-phenyl, and 1-methylpyrazol-4-yl.
28. The pharmaceutical composition according to Claim 25 wherein
R2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl,
-(CH2)2-2-thienyl, and -(CH2)2-.PHI..
29. The pharmaceutical composition according to Claim 25 wherein
R1 and R2 together with the nitrogen atom bound to R2 and the SO2 group

-236-
bound to R1 are joined to form a heterocyclic group or substituted
heterocyclic
group.
30. The pharmaceutical composition according to Claim 25 wherein
R2 and R3 together with the nitrogen atom bound to R2 substituent and the
carbon bound to the R3 substituent form a heterocyclic group or a substituted
heterocyclic group.
31. The pharmaceutical composition according to Claim 25 wherein
R3 is selected from the group consisting of methyl, phenyl, benzyl,
diphenylmethyl, -CH2CH2-COOH, -CH2-COOH, 2-amidoethyl, iso-butyl,
t-butyl, -CH2O-benzyl and hydroxymethyl.
32. The pharmaceutical composition according to Claim 25 wherein Q
is -C(O)NH- or -C(S)NH-.
33. The pharmaceutical composition according to Claim 25 wherein
R5 is selected from the group consisting of:
4-[NH2CH2C(O)NH-]benzyl, 4-[HOOCCH2CH2C(O)NH-]benzyl,
4-[-NHC(O)CH2NHBoc]benzyl, 4-[-NHC(O)CH(CH3)NHBoc]benzyl,
4-[-NHC(O)CH(CH2.PHI.)NHBoc]benzyl, 4-[-NHC(O)CH2NHC(O)NH-3'-
methylphenyl]benzyl, 4-[-NHC(O)CH(NHBoc)(CH2)4NHCbz]benzyl,
4-[-NHC(O)CH2CH(C(O)OCH2.PHI.)-NHCbz]benzyl, 4-.PHI.-benzyl,
4-[-NHC(O)CH(CH2CH2CH2CH2NH2)NHBoc]benzyl,
4-[H2NCH2CH2CH2C(O)NH-]benzyl, 4-(BocHNCH2CH2CH2-
C(O)NH-)benzyl, 4-[.PHI.CH2OCH2(BocHN)CHC(O)NH-]benzyl,
4-[CH3NHCH2CH2CH2C(O)NH-]benzyl, 4-(N-methylpiperidin-4-oxy)-benzyl,
4-[CH3N(Boc)CH2CH2CH2C(O)NH-]benzyl,
4-[.PHI.CH2OCH2(H2N)CHC(O)NH-]benzyl, 4-[HO(O)C(Cbz-NH)CHCH2CH2-
C(O)NH-]benzyl, 4-[.PHI.CH2O(O)C(Cbz-NH)CHCH2CH2-C(O)NH-]benzyl,
4-[HO(O)C(NH2)CHCH2CH2-C(O)NH-]benzyl,
4-[CH3(N-Boc)NCH2C(O)NH-]benzyl, 4-[CH3NHCH2C(O)NH-]benzyl,

--237--
4-[(CH3)2NCH2C(O)NH-]benzyl, 4-[-O-CH(COOH).PHI.]benzyl,
4-[2-carboxylphenyl-]-benzyl, 4-[2-carboxylmethylphenyl-]-benzyl
4-[.PHI.CH2OC(O)NHCH2CH2NH-]benzyl, 4-N[-(SO2)CH3]-
CH2CH2CH2N(CH3)2]benzyl, 4-t-butyl-O(O)CCH2-O-benzylNH]benzyl,
4-[N,N di(4-N,N dimethylamino)benzyl)amino]benzyl,
4-(2-formyl-1,2,3,4-tetrahydroisoquinolin-3-yl-CH2NH)benzyl,
4-[-OCH2CH2-1'-(4'-pyrimidinyl)-piperazinyl]-benzyl,
4-[-OCH2CH2-(1'-piperidinyl)-benzyl, 4-[-OCH2CH2-(1'-pyrrolidinyl)]-
benzyl, 4-[-OCH2CH2CH2-(1'-piperidinyl)]-benzyl,
4-[(CH3)2NCH2CH2CH2-O-]benzyl, 4-[(CH3)2NCH2CH2O-]-benzyl,
4-[-OCH2CH2CH2-(1'-(4'-methylpiperazinyl))]-benzyl,
4-[-OCH2CH2CH2-4-(3'-chlorophenyl)-piperazin-1-yl]-benzyl,
4-[-OCH2CH2N(.PHI.)CH2CH3]-benzyl, 4-[-OCH2-3'-(N-Boc)-piperidinyl]-
benzyl, 4-[-O-(3-(N-Boc)-piperidinyl]benzyl,
3-[-O-(N-methylpiperidin-4-yl]benzyl, 4-[-O-(N-methylpiperidin-4-yl]benzyl,
4-[di-iso-propylamino-CH2CH2O-]-benzyl, 4-[N 3-methylbutyl-N-trifluoro-
methanesulfonyl)amino]benzyl, 4-[-OCH2CH2-(N-morpholinyl)]-benzyl,
4-[-OCH2CH(NHBoc)CH2cyclohexyl]-benzyl, 4-[OCH2CH2-(N-piperidinyl]-
benzyl, 4-[-OCH2CH2CH2-(4-m-chlorophenyl)-piperazin-1-yl]-benzyl,
4-[-OCH2CH2-(N-homopiperidinyl)-benzyl, 4-[-OCH2CH2N(benzyl)2]-benzyl,
3-[-OCH2CH2CH2N(CH3)2]-benzyl, 4-[-OCH2CH2N(C2H5)2]-benzyl,
4-[-OCH2CH2CH2N(C2H5)2]-benzyl, 4-[-OCH2CH2N(C2H5)2]-benzyl,
4-[-OCH2CH2CH2N(CH3)benzyl]-benzyl, 4-[2-(2-azabicyclo[3.2.2]octan-2-yl)
ethyl-O-]benzyl,[cyclopentylacetylenyl]-benzyl, 4-[-C~C-.PHI.-4'.PHI.]-benzyl,
4-[-C~C-CH2-O-S(O)2 4'-CH3-.PHI.]-benzyl, 4-[-C~C-CH2NHC(O)NH2]-benzyl,
4-[-C~C-CH2-O-(4'-COOCH2CH3).PHI.]-benzyl, 4-[-C~C-CH(NH2)-cyclohexyl]-
benzyl, 4-[-C~C-CH2-O-phenyl]-benzyl, 4-[-C~C-CH2OCH3]-benzyl,
4-[-C~C-CH2-O-(4'-C(O)OC2H5)phenyl]-benzyl, 4-[-C~C-
CH2CH(C(O)OCH3)2]-benzyl, 4-[-C~C-CH2CH(NHC(O)CH3)C(O)OH]-
benzyl, 4-[-C~C-CH2 NH-(4,5-dihydro-4-oxo-5-phenyl-oxazol-2yl)]-benzyl,
4-[-OCH2CH2CH2-(N-morpholino)]-benzyl, 4-[-OCH2COOH]-benzyl,
4-[-OCH2COO-t-butyl]-benzyl, 4-[-N(SO2CH3)(CH2)3-N(CH3)2]-benzyl,

--238--
4-[-NHS(O)2CF3]-benzyl, 4-[-C(=NH)NH2]-benzyl, 4-[-NHSO2-CH2Cl]-
benzyl, 4-[-OCH2C(O)NH-benzyl]-benzyl, 4-[-OCH2C(O)O-benzyl]-benzyl,
4-[-OCH2C(O)OH]-benzyl, 4-[-OCH2CH2-1-(4-hydroxy-4-(3-methoxypyrrol-2-yl)
-piperazinyl]-benzyl, 4-[-OCH2C(O)NH2]-benzyl, 4-[-OCH2C(O)NH-t-butyl]
-benzyl, 4-[-OCH2CH2-1-(4-hydroxy-4-phenyl)-piperidinyl]-benzyl,
4-[-NHSO2-CH=CH2]-benzyl, 4-[-NHSO2-CH2CH2Cl]-benzyl, 4-benzyl-benzyl,
4-[-OCH2C(O)piperidin-1-yl]benzyl,
4-[-OCH2C(O)N(CH(CH3)2)2]benzyl, 4-amidinobenzyl, 4-acetamidobenzyl,
4-(N-methyl)acetamidobenzyl, 4(-NHC(O)CH2NHC(O)NH-fluorescin)benzyl,
4-(NHC(O)CH2CH(NH2)COOH, (1-toluenesulfonylimidizol-4-yl)-methyl-,
[(1-N,N dimethylaminosulfonyl)-imidizol-4-yl]methyl-, 4-(N-
toluenesulfonylamino)
benzyl, and 4-[N methyltrifluoroacetamido)phenyl.
34. The pharmaceutical composition according to Claim 25 wherein
R6' is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl
(3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy,
neo-pentoxy, 2-.alpha.-iso-propyl-4-.beta.-methylcyclohexoxy, 2-(3-isopropyl-4-
.beta.-
methylcyclohexoxy, -NH2, benzyloxy, -NHCH2COOH, -NHCH2CH2COOH,
-NH-adamantyl, -NHCH2CH2COOCH2CH3, -NHSO2 p-CH3-.PHI., -NHOR8
where R8 is hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl),
-O-cholest-5-en-3-.beta.-yl, -OCH2-OC(O)C(CH3)3, -O(CH2)2NHC(O)W where z
is 1 or 2 and W is selected from the group consisting of pyrid-3-yl,
N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, -NR"C(O)-R' where R'
is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH2C(O)OCH2CH3.
35. The pharmaceutical composition according to Claim 25 wherein
said compound is selected from the group consisting of:
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonylglycyl)amino]-
L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(glycyl)amino]-L-phenylalanine

--239--
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(carboxy)propionamido]-L-phenyl-
alanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-L-
alanyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-D-
alanyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-D-
phenylalanyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[3-
(fluorescein)thiouriedo]acetamido}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonylglycyl)amino]-
L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[3-(3-
methylphenyl)uriedo]acetamido}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N.alpha.-tert-butoxylcarbonyl-
N.epsilon.-
carbobenzyloxy-L-lysyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[y-(.alpha.-benzyl-N.alpha.-
carbobenzyloxy-L-
aspartyl)amino]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N.alpha.-tert-butoxylcarbonyl-L-
lysyl)
amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[y-(L-aspartyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(4-aminobutyramido)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-tert-butoxyl-
carbonylamino)butyramido]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-methylamino)butyramido]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-tert-butoxylcarbonyl-N-
methylamino)butyramido]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(O-benzyl)-L-seryl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[.delta.-(D,L-glutamyl)amino]-L-
phenylalanine

--240--
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxyl-
carbonylsarcosyl)amino]-L-phenylalanine
N-{toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(N-tert-butoxyl-
carbonylsarcosyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino]-L-phenylalanine
ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(sarcosyl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N,N-dimethylglycyl)amino]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(N,N-
dimethylglycyl)amino]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(.alpha.-carboxybenzyloxy)-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenyl]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(methoxycarbonyl)phenyl]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{N-[2-(N-
carbobenzyloxyamino)ethyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{N-[2-{N-
carbobenzyloxyamino)ethyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[3-(N,N-dimethylamino)propyl]-
N-[trifluoromethanesulfonyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[4-[(tert-
butoxycarbonyl)methoxy]benzyl]amino}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N,N-di[4-(N,N-
dimethylamino)benzyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-4-{N-[{2-formyl-1,2,3,4-
tetrahydroisoquinolin-3-yl)methyl]amino}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine

--241--
N-(toluene-4-sulfonyl)-N methyl-L-serinyl-4-[3-(N,N dimethylamino-
propoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[2-(N,N-
dimethylamino)ethoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N dimethylamino)ethoxy)-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N-ethyl-N-phenylamino)ethoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N diisopropylamino)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-cyclohexyl-2-(N-tert-
butoxycarbonylamino)propoxy]-L-phenylalanine methyl ester
N-(thiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)propoxy]-L-
phenylalanine
N-(5-chlorothiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N diethylamino)ethoxy]-L-
phenylalanine
N-(2,5-dichlorothiophene-3-sulfonyl)-L-prolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(1-methylpyrazole-4-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N diethylamino)propoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-[3-(N,N dimethylamino)propoxy]-L-
phenylalanine
N-(thiazole-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N methyl-N-
benzylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N diethylamino)propoxy]-L-
phenylalanine

--242--
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N-methyl-N-
benzylamino)propoxy]-L-phenylalanine methyl ester
N-(1-methylimidazole-4-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)-
propoxy]-L-phenylalanine
N-(2-methylthiadiazole-5-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)-
propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-thiaprolyl-4-[3-(N,N-dimethylamino)propoxy]-
L-phenylalanine
N-(4-cyanobenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(3,3-dimethyl)prolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N-
dimethylamino)propoxy)-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-(2-(2-azabicyclo[3.2.2]octan-2-yl)
ethoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(2-(2-azabicyclo[3.2.2]octan-2-yl)
ethoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylaianyl-4-[2-(cyclopentyl)ethynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-[4-
(phenyl)phenyl] ethynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(toluene-4-
sulfonyloxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(ureido)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-(3-(4-
ethoxycarbonylphenoxy)prop-1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-(1-aminocyclohex-1-yl)
ethynyl]-D,L-phenylalanine

--243--
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(phenoxy)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(phenoxy)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(methoxy)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(methoxy)prop-1-ynyl]-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-ethoxycarbonylphenoxy)prop-1-
ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[3-(4-ethoxycarbonylphenoxy)prop-1-
ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4,4-di(methoxycarbonyl)but-1-ynyl]-
D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-[4,4-di(methoxycarbonyl)but-1-ynyl]-
D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(4-acetamido-4-carboxybut-1-ynyl)-
D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-(4-acetamido-4-carboxybut-1-ynyl)-
D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[(4,5-dihydro-4-oxo-5-
phenyloxazol-2-yl)amino]prop-1-ynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-4-{3-[(4,5-dihydro-4-oxo-5-phenyloxazol-
2-yl)amino]prop-1-ynyl}-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenoxy]-L-phenylalanine
methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[4-(pyrimidin-2-yl)piperazin-1-yl]
ethoxy}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin-1-yl)propoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(pyrrolidin-1-yl)ethoxy]-L-
phenylalanine

--244--
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin-1-yl)propoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[4-(3-chlorophenyl)piperazin-1-yl]
propoxy}-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(1-tert-butoxycarbonylpiperidin-3-yl)
methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(morpholin-4-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(1-tert-butoxycarbonylpiperidin-3-yl)
methoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(piperidin-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{3-[4-(3-chlorophenyl)piperazin-1-yl]
propoxy}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1-yl)ethoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin-1-yl)propoxy]-
L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(pyrrolidin-1-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin-1-yl)propoxy]-
L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(morpholin-4-yl)ethoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-{2-[4-(3-methoxythien-2-yl)-4-
hydroxypiperidin-1-yl]ethoxy}-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-3-(1-methylpiperidin-4-oxy)-D,L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(1-methylpiperidin-4-oxy)-D,L-
phenylalanine

--245--
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-(1-methylpiperidin-
4-oxy)-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-(1,1-dioxothiomorpholin-3-carbonyl)-4-(1-
methylpiperidin-4-oxy)-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-(1,1-dioxothiomorpholin-3-carbonyl)-4-(1-
methylpiperidin-4-oxy)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-(1-methylpiperidin-
4-oxy)-L-phenylalanine
N-(.alpha.-toluenesulfonyl)-L-prolyl-4-(1-methylpiperidin-4-oxy)-L-
phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(trifluoromethanesulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(trifluoromethanesulfonyl)amino-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(chloromethanesulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(vinylsulfonyl)amino-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-(N-trifluoromethanesulfonyl-N-
isobutyl)amino-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-N-(vinylsulfonyl)amino-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-benzylaminocarbony)methoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-L-phenylalanine
methyl ester

--246--
N-(toluene-4-sulfonyl)-L-prolyl-4-[(aminocarbonyl)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butylaminocarbonyl)methoxy]-
L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(4-phenyl-4-hydroxypiperidin-1-yl)
ethoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(piperidin-1-ylcarbonyl)methoxy]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N,N-
diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N,N-
diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(amidino)phenylalanine
N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(aminocarbonyl)phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methylacetamido)-L-phenylalanine
isopropyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methylacetamido)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methyltrifluoroacetamido)-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N-
dimethylamino)propoxy]-L-phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-4-(N-methylpiperidinoxy)-
phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiapropyl-L-(4-
methylpiperidinoxy) phenylalanine t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
t-butyl ester
N-(toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
and pharmaceutically acceptable salts thereof as well as any of the ester
compounds recited above wherein one ester is replaced with another ester

--247--
selected from the group consisting of methyl ester, ethyl ester, n-propyl
ester,
isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl
ester
36. A method for the treatment of an inflammatory disease in a patient
mediated by VLA-4 which methods comprise administering to the patient the
pharmaceutical composition of Claim 25.
37. The method according to Claim 36 wherein said inflammatory
disease is selected from the group consisting of asthma, Alzheimer's disease,
atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset
diabetis), inflammatory bowel disease (including ulcerative colitis and
Crohn's
disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation,
tumor
metastasis, meningitis, encephalitis, stroke, and other cerebral traumas,
nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and
acute
leukocyte-mediated lung injury such as that which occurs in adult respiratory
distress syndrome.

Description

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
SUBSTITUTED PHENYLALANINE TYPE COMPOUNDS WHICH
INHIBIT LEUKOCYTE ADHESION MEDIATED BY VLA-4
Cross-Reference to Related An~lication
This application claims the benefit of U.S. Provisional Application No.
601 , which was converted pursuant to 37 C.F.R. ~ 1.53(c)(2)(i) from
U.S. Patent Application No. 08/920,394, filed July 31, 1997.
This invention relates to compounds which inhibit leukocyte adhesion
and, in particular, leukocyte adhesion mediated by VLA-4.
B;e
The following publications, patents and patent applications are cited in
this application as superscript numbers:
' Hemler and Takada, European Patent Application Publication
No. 330,506, published August 30, 1989
Elices, et al., Cell, ~Q:577-584 (1990)
; Springer, Nature, 3.4f~:425-434 ( 1990)
Osborn, Cell, b,2:3-6 (1990)
Vedder, et al., Surgery,19~:509 (1989)
Pretolani, et al., J. Exp. Med., 1$0:795 (1994)
Abraham, et al., J. Clin. Invest., 9:776 (1994)
8 Mulligan, et al., J. Immunology,15Q:2407 (1993)

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__ 2 __
Cybulsky, et al., Science, 251:788 (1991)
to Li, et al., Arterioslcer. Thromb.,1~:197
( 1993)
" Sasseville, et al., Am. J. Path., L44:27
(1994)
'z Yang, et al., Proc. Nat. Acad. Science (USA),
QQ:10494 ( 1993)
'3 Burkly, et al., Diabetes, 43:529 (1994)
Baron, et al., J. Clin. Invest., 9.x:1700
(1994)
'S Hamann, et al., J. Immunology,152:3238 (1994)
1 S '6 Yednock, et al., Nature, 3:63 ( 1992)
" Baron, et al., J. Exp. Med.,1ZZ:57 (1993)
'8 van Dinther-Janssen, et al., J. Immunology,14Z:4207
(1991)
van Dinther-Janssen, et al., Annals. Rheumatic
Dis., 5:672
(1993)
zo Elices, et al., J. Clin. Invest., 2'x:405
(1994)
z' Postigo, et al., J. Clin. Invest., $x:1445
{1991)
zz Paul, et al., Transpl. Proceed., 25.:813
(1993)
z3 Okarhara, et al., Can. Res., 54:3233 (1994)
za paavonen, et al., Int. J. Can., 5$:298 (
1994)
zs Schadendorf, et al., ,l. Path.,1ZQ:429 (1993)
z6 Bao, et al., Diff , 52.:239 ( 1993)
z' Lauri, et al., British J. Cancer, 4$:862
(1993)
z8 Kawaguchi, et al., Japanese J. Cancer Res.,
.$x:1304 (1992)
29 Kogan, et al., U.S. Patent No. 5,510,332,
issued April 23, 1996
3 International Patent Appl. Publication No.
WO 96/01644

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__ 3 __
All of the above publications, patents and patent applications are
herein incorporated by reference in their entirety to the same extent as if
each
individual publication, patent or patent application was specifically and
individually indicated to be incorporated by reference in its entirety.
VLA-4 (also referred to as a4~31 integrin and CD49d/CD29), first
identified by Hemler and Takada', is a member of the (31 integrin family of
cell surface receptors, each of which comprises two subunits, an a chain and a
~3 chain. VLA-4 contains an a4 chain and a ~i 1 chain. There are at least nine
X31 integrins, all sharing the same (31 chain and each having a distinct a
chain.
These nine receptors all bind a different complement of the various cell
matrix
molecules, such as fibronectin, laminin, and collagen. VLA-4, for example,
binds to fibronectin. VLA-4 also binds non-matrix molecules that are
expressed by endothelial and other cells. These non-matrix molecules include
VCAM-1, which is expressed on cytokine-activated human umbilical vein
endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for
the
fibronectin and VCAM-1 binding activities and each activity has been shown
to be inhibited independently.2
Intercellular adhesion mediated by VLA-4 and other cell surface
receptors is associated with a number of inflammatory responses. At the site
of an injury or other inflammatory stimulus, activated vascular endothelial
cells express molecules that are adhesive for leukocytes. The mechanics of
leukocyte adhesion to endothelial cells involves, in part, the recognition and
binding of cell surface receptors on leukocytes to the corresponding cell
surface molecules on endothelial cells. Once bound, the leukocytes migrate
across the blood vessel wall to enter the injured site and release chemical
mediators to combat infection. For reviews of adhesion receptors of the
immune system, see, for example, Springer' and Osborn4.

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__ 4 __
Inflammatory brain disorders, such as experimental autoimmune
encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are
examples of central nervous system disorders in which the
endothelium/leukocyte adhesion mechanism results in destruction to otherwise
healthy brain tissue. Large numbers of leukocytes migrate across the blood
brain barner (BBB) in subjects with those inflammatory diseases. The
leukocytes release toxic mediators that cause extensive tissue damage
resulting
in impaired nerve conduction and paralysis.
In other organ systems, tissue damage also occurs via an adhesion
mechanism resulting in migration or activation of leukocytes. For example, it
has been shown that the initial insult following myocardial ischemia to heart
tissue can be further complicated by leukocyte entry to the injured tissue
causing still further insult (Vedder et a1.5). Other inflammatory conditions
1 S mediated by an adhesion mechanism include, by way of example, asthmab-g,
Alzheimer's disease, atherosclerosis9-'°, AIDS dementia",
diabetes'2-'a
(including acute juvenile onset diabetis), inflammatory bowel disease's
(including ulcerative colitis and Crohn's disease), multiple sclerosis'6-",
rheumatoid azthritis'8'~', tissue transplantation22, tumor metastasis23-za~
meningitis, encephalitis, stroke, and other cerebral traumas, nephritis,
retinitis,
atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-
mediated lung injury such as that which occurs in adult respiratory distress
syndrome.
In view of the above, assays for determining the level VLA-4 in a
biological sample containing VLA-4 would be useful, for example, to
diagnosis VLA-4 mediated conditions. Additionally, despite these advances
in the understanding of leukocyte adhesion, the art has only recently
addressed
the use of inhibitors of adhesion in the treatment of inflammatory brain
diseases and other inflammatory conditions29~3o. The present invention
addresses these and other needs.

CA 02290747 1999-11-19
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__ S __
SUMMARY OF THE INVENTION
This invention provides compounds which bind to VLA-4. Such
compounds can be used, for example, to assay for the presence of VLA-4 in a
sample and, in pharmaceutical compositions to inhibit cellular adhesion
S mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The
compounds of this invention have a binding affinity to VLA-4 as expressed by
an ICso of about 1 S ,uM or less (as measured by Example 136 below) which
compounds are defined by formula I below:
R' O
II
R'-S02-N(R2)-C-Q-CH-C-OH I
H RS
1S
where
R' is selected from the group consisting of alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic,
substituted heterocylic, heteroaryl and substituted heteroaryl;
R2 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and where R' and R~ together with the
nitrogen atom bound to RZ and the SOz group bound to R' form a heterocyclic
2S or a substituted heterocyclic group;
R3 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic and, when RZ does not form
a
heterocyclic group with R', Rz and R3 together with the nitrogen atom bound
to RZ and the carbon atom bound to R3 can form a heterocyclic or a substituted
heterocyclic group;
RS is -(CHZ)X Ar-R5~ where R5~ is selected from the group consisting
(a) substituted alkylcarbonylamino with the proviso that at least one of
the substituents on the substituted alkyl moiety is selected from the group

CA 02290747 1999-11-19
WO 99106431 PCT/US98/15313
__6__
consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino,
acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy,
substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl,
S carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted
cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,
carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted
heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone,
thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,
thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted
thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic,
substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy,
heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O)Z-alkyl,
-OS(O)2-substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)2-
heteroaryl, -OS(O)Z-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-
substituted heterocyclic, -OSOZ-NRR where R is hydrogen or alkyl,
-NRS(O)2-alkyl, -NRS(O)Z-substituted alkyl, -NRS(O)z-aryl, -NRS(O)2-
substituted aryl, -NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl,
-NRS(O)z-heterocyclic, -NRS(O)z-substituted heterocyclic, -NRS(O)2-NR-
alkyl, -NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)z-NR-
substituted aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)Z NR-substituted
heteroaryl, -NRS(O)2-NR.-heterocyclic, -NRS(O)2-NR-substituted heterocyclic
where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-
(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted
arylamino, mono- and di-heteroarylamino, mono- and di-substituted
heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted
heterocyclic amino, and unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic,
and substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
_- '7 __
alkyl groups substituted with -S02-alkyl, -SOZ-substituted alkyl, -SOZ-
alkenyl,
-SOZ-substituted alkenyl, -SOZ-cycloalkyl, -SOZ-substituted cycloalkyl, -SOZ-
aryl, -SOZ-substituted aryl, -SOZ-heteroaryl, -SOz-substituted heteroaryl, -
S02-
heterocyclic, -SOz-substituted heterocyclic and -SOzNRR where R is hydrogen
or alkyl;
(b) alkoxyaryl substituted on the alkoxy moiety with a substituent
selected from the group consisting of carboxyl and -COOR where R is alkyl,
substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(c) aryl and heteroaryl;
(d) -NR'R' wherein each R' is independently selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and
substituted heterocyclic with the proviso that at least one of R' is
substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted
heterocyclic and with the further proviso that when R' is substituted alkyl at
least one of the substituents on the substituted alkyl moiety is selected from
the group consisting of alkoxy, substituted alkoxy, acyl, acylamino,
thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino,
thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen,
hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-
substituted
aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)z-alkyl, -OS(O)Z-
substituted alkyl, -OS(O)z-aryl, -OS(O)Z-substituted aryl, -OS(O)z-heteroaryl,

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__ g __
-OS(O)2 substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSOZ-NRR where R is hydrogen or alkyl, -NRS(O)Z-alkyl,
-NRS(O)z-substituted alkyl, -NRS(O)2-aryl, -NRS(O)z-substituted aryl,
-NRS(O)Z-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O}z-
heterocyclic, -NRS(O)z-substituted heterocyclic, -NRS(O)z-hTR-alkyl,
-NRS(O)z-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)z-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SOz-alkyl, -S02 substituted alkyl, -SOZ-
alkenyl,
-SOZ-substituted alkenyl, -SOz-cycloalkyl, -SOz-substituted cycloalkyl,
-SOZ-aryl, -SOZ-substituted aryl, -SOZ-heteroaryl, -SOz-substituted
heteroaryl,
-SOz-heterocyclic, -S02-substituted heterocyclic and -SOZNRR where R is
hydrogen or alkyl;
(e) -alkoxy-NR"R" wherein each R" is independently selected from
the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic, and substituted heterocyclic with the proviso that when each R"
is substituted alkyl then at least one of the substituents on the substituted
alkyl
moiety is selected from the group consisting of alkoxy, substituted alkoxy,
acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl
amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted

CA 02290747 1999-11-19
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__9_-
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
S substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)Z-
substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)z-heteroaryl,
-OS(O)z-substituted heteroaryl, -OS(O)z-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSOz-NRR where R is hydrogen or alkyl, -NRS(O)2-alkyl,
-NRS(O)z-substituted alkyl, -NRS(O)z-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O)z-
heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)Z-NR-substituted alkyl, -NRS(O)z-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR.-substituted heteroaryl,
-NRS(O)z-NR-heterocyclic, -NR.S(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-{substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SOZ-alkyl, -SOz-substituted alkyl, -SOZ-
alkenyl,
-SOZ-substituted alkenyl, -S02-cycloalkyl, -SOZ substituted cycloalkyl, -SOZ-
aryl, -SOZ substituted aryl, -SOz-heteroaryl, -SOZ-substituted heteroaryl, -
SOZ-

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__ 10 __
heterocyclic, -SOZ-substituted heterocyclic and -S02NRR where R is hydrogen
or alkyl;
(f) substituted alkenyl or substituted alkynyl with the proviso that at
least one of the substituents on the substituted alkenyl/alkynyl moiety is
S selected from the group consisting of alkyl, substituted alkyl, aryl,
substituted
aryl, cycloalkyl, substituted cycloalkyI, heteroaryl, substituted heteroaryl,
heterocyclic, and substituted heterocyclic with the proviso that when
substituted with substituted alkyl then at least one of the substituents on
the
substituted alkyl moiety is selected from the group consisting of alkoxy,
substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitre, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidine, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)z-
substituted alkyl, -OS(O)z-aryl, -OS(O)2-substituted aryl, -OS(O)z-heteroaryl,
-OS(O)z-substituted heteroaryl, -OS(O)z-heterocyclic, -OS(O)z-substituted
heterocyclic, -OS02-NRR where R is hydrogen or alkyl, -NRS(O)z-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)z-aryl, -NR.S(O)2-substituted aryl,
-NRS(O)Z-heteroaryl, -NRS(O)z-substituted heteroaryl, -NR.S(O)z-
heterocyclic, -NRS(O)Z-substituted heterocyclic, -NRS(O)z NR-alkyl,
-NRS(O)Z-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)Z-NR-substituted
aryl, -NRS(O)Z-NR-heteroaryl, -NRS(O)z-NR-substituted heteroaryl,

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-- 11 --
-NRS(O)z-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SOz-alkyl, -SOz-substituted alkyl, -SOZ-
alkenyl,
-SOZ-substituted alkenyl, -SOZ-cycloalkyl, -SOZ-substituted cycloalkyl, -SOz-
aryl, -SOz-substituted aryl, -SOZ-heteroaryl, -SOZ-substituted heteroaryl, -
SOz-
heterocyclic, -S02-substituted heterocyclic and -SO~NRR where R is hydrogen
or alkyl;
(g) substituted aryloxy and substituted heteroaryloxy with the proviso
that at least one substituent on the substituted aryloxy/heteroaryloxy is
other
than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy,
alkyl,
alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy,
alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyioxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea;
(h) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted
heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy-
substituted saturated heterocyclic;
(i) -O-heterocyclic and -O-substituted heterocyclic;
(j) tetrazolyl;
(k) -NR-SOZ substituted alkyl where R is hydrogen, alkyl or aryl, with
the proviso that at least one substituent on the alkyl moiety of the
substituted
alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-
dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,

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-- 12 --
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(1) alkenylsulfonylamino, alkynylsulfonylamino, substituted
alkenylsulfonylamino and substituted alkynylsulfonylamino;
(m) substituted alkoxy with the proviso that the substitution on the
alkyl moiety of said substituted alko.;y does not include alkoxy-NR"R",
unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl
and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-
dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(n) amidine and amidine substituted with from 1 to 3 substituents
independently selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
(o) -C(O)NR"'R"' where each R"' is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic with the proviso that when one R"' is unsaturated
heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with
halogen,
hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl,
alkynyl, 1,2-dioxyrnethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy,
alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea, then the other R"' is alkyl, substituted alkyl (other than
unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted
cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic
and
substituted heterocyclic;
(p) -NR'ZC(O)-R8 where Ra is selected from the group consisting of
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted

CA 02290747 1999-11-19
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-- 13 --
heterocyclic, and R'2 is alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
(q) -SOz-aryl, -SOz-substituted aryl, -SOz-heteroaryl, -SOZ-substituted
S heteroaryl or -SOZ-alkyl;
(r) -NR'C(O)NR9R9 wherein R' is selected from the group consisting
of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and each R~ is independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic:
(s) -NR'C(O)OR9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and, R9 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
(t) -aminocarbonyl-(N-formylheterocycyl); and
(u) -alkyl-C{O)NH-heterocyclyl and -alkyl-C(O)NH-substituted
heterocyclyl,
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
x is an integer of from 1 to 4;
Q is -C(X)NR'- wherein R' is selected from the group consisting of
hydrogen and alkyl; and X is selected from the group consisting of oxygen and
sulfur;
and pharmaceutically acceptable salts thereof
In another embodiment, the compounds of this invention can also be
provided as prodrugs which convert (e.g., hydrolyze, metabolize, etc.) in vivo
to a compound of for:.lula I above. In a preferred example of such an
embodiment, the carboxylic acid of the compound of formula I is modified

CA 02290747 1999-11-19
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-- 14 --
into a group which, in vivo, will convert to a carboxylic acid (including
salts
thereof). In a particularly preferred embodiment, such prodrugs are
represented by compounds of formula IA:
R3 O
II
R '-SOz-N(R~)-CH-Q-CH-C-R6 IA
Rs
where
R' is selected from the group consisting of alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic,
substituted heterocylic, heteroaryl and substituted heteroaryl;
1 S RZ is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, cycloalkyi, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and R' and RZ together with the nitrogen
atom bound to R2 and the SOZ group bound to R' can form a heterocyclic or a
substituted heterocyclic group;
R3 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic and, when Rz does not form
a
heterocyclic group with R', Rz and R3 together with the nitrogen atom bound
to Rz and the carbon atom bound to R3 can form a heterocyclic or a substituted
heterocyclic group;
RS is -(CHZ)X Ar-R5~ where R5~ is selected from the group consisting
(a) substituted alkylcarbonylamino with the proviso that at least one of
the substituents on the substituted alkyl moiety is selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino,
acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyi,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonylaxy, aryloxy,
substituted aryloxy, cyano, vitro, halogen, hydroxyl, carboxyl, carboxylalkyl,
carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted

CA 02290747 1999-11-19
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-- 1 S --
cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,
carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted
heterocyclic, cycloalkyl, substituted cycloalkyl, guanidine, guanidinosulfone,
thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,
thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted
thioheteroaryl, thioheterocyclic, substi~uted thioheterocyclic, heterocyclic,
substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy,
heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O)z-alkyl,
-OS(O)2-substituted alkyl, -OS(O)z-aryl, -OS(O)2-substituted aryl, -OS(O),-
heteroaryl, -OS(O)z-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O),-
substituted heterocyclic, -OSOZ-NRR where R is hydrogen or alkyl,
-NRS(O)z-alkyl, -NRS(O)2-substituted alkyl, -NRS(O)2-aryl, -NRS(O)z-
substituted aryl, -NRS(O)Z-heteroaryl, -NRS(O)z-substituted heteroaryl,
-NRS(O)z-heterocyclic, -NRS(O)z-substituted heterocyclic, -NRS(O)2-NR-
alkyl, -NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)z-NR-
substituted aryl, -NRS(O)Z-NR-heteroaryl, -NRS(O)2-NR-substituted
heteroaryl, -NRS(O)z NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic
where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-
(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted
arylamino, mono- and di-heteroarylamino, mono- and di-substituted
heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted
heterocyclic amino, and unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic,
and substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SOZ-alkyl, -SOZ-substituted alkyl, -SOZ-
alkenyl,
-S02-substituted alkenyl, -SOZ-cycloalkyl, -SOZ-substituted cycloalkyl, -SOz-
aryl, -SOZ substituted aryl, -SOZ-heteroaryl, -SOz-substituted heteroaryl, -
SOz-
heterocyclic, -SOz-substituted heterocyclic and -SOzNRR where R is hydrogen
or alkyl;

CA 02290747 1999-11-19
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-- 16 --
(b) alkoxyaryl substituted on the alkoxy moiety with a substituent
selected from the group consisting of carboxyl and -COOR where R is alkyl,
substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(c) aryl and heteroaryl;
(d) -NR'R' wherein each R' is independently selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and
substituted heterocyclic with the proviso that at least one of R' is
substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted
heterocyclic and with the further proviso that when R' is substituted alkyl at
least one of the substituents on the substituted alkyl moiety is selected from
the group consisting of alkoxy, substituted alkoxy, acyl, acylamino,
thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino,
thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
i 5 aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen,
hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-
substituted
aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)z-alkyl, -OS(O)2
substituted alkyl, -OS(O)2-aryl, -OS(O)2-substituted aryl, -OS(O)z-heteroaryl,
-OS(O)2 substituted heteroaryl, -OS(O)Z-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSOZ NRR where R is hydrogen or alkyl, -NRS(O)Z-alkyl,
-NRS(O)Z-substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)Z-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O)z-
heterocyclic, -NRS(O)Z-substituted heterocyclic, -NRS(O)z NR-alkyl,

CA 02290747 1999-11-19
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__ 1 ~ -_
-NRS(O)z-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryi,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SOz-alkyl, -SOz-substituted alkyl, -SOZ-
alkenyl,
-SOZ-substituted alkenyl, -SOZ-cycloalkyl, -SOz-substituted cycloalkyl, -SOZ-
aryl, -SOz-substituted aryl, -SOz-heteroaryl, -SOZ-substituted heteroaryl, -
SOZ-
heterocyclic, -SOz-substituted heterocyclic and -S02NRR. where R is hydrogen
or alkyl;
(e) -alkoxy-NR"R" wherein each R" is independently selected from
the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic, and substituted heterocyclic with the proviso that when each R"
is substituted alkyl then at least one of the substituents on the substituted
alkyl
moiety is selected from the group consisting of alkoxy, substituted alkoxy,
acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl
amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalky, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__ 1 g _-
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)z-
substituted alkyl, -OS{O)2-aryl, -OS(O)z-substituted aryl, -OS(O)z-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)Z-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSOZ-NRR where R is hydrogen or alkyl, -NRS(O)Z-alkyl,
-NRS(O)z-substituted alkyl, -NRS(O)2-aryl, -NRS(O)z-substituted aryl,
-NRS(O)~-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O)2-
heterocyclic, -NRS(O)z-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)Z-NR-substituted alkyl, -NRS(O)z-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)z-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)Z-NR-heterocyclic; -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -S02-alkyl, -SOz-substituted alkyl, -SOz-
alkenyl,
-S02-substituted alkenyl, -SOZ-cycloalkyl, -SOz-substituted cycloalkyl, -SOZ-
aryl, -SOZ-substituted aryl, -SOZ-heteroaryl, -SOZ-substituted heteroaryl, -
SOz-
heterocyclic, -SOz-substituted heterocyclic and -SOZNRR where R is hydrogen
or alkyl;
(f) substituted alkenyl or substituted alkynyl with the proviso that at
least one of the substituents on the substituted alkenyl/alkynyl moiety is
selected from the group consisting of alkyl, substituted alkyl, aryl,
substituted
aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,

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heterocyclic, and substituted heterocyclic with the proviso that when
substituted with substituted alkyl then at least one of the substituents on
the
substituted alkyl moiety is selected from the group consisting of alkoxy,
substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbouyloxy, aryloxy, substituted aryloxy,
cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,
substituted
thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
substituted thioheterocyclic, heterocyclic, substituted heterocyclic,
i 5 cycloalkoxy, substituted cycloalkyoxy, heteroayrioxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)z-alkyl, -OS(O)2-
substituted alkyl, -OS(O)2-aryl, -OS(O)Z-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)z-heterocyclic, -OS(O)z-substituted
heterocyclic, -OSOZ-NRR where R is hydrogen or alkyl, -NRS(O)z-alkyl,
-NRS(O)z-substituted alkyl, -NRS(O)Z-aryl, -NRS(O)2 substituted aryl,
-NR.S(O)Z-heteroaryl, -NRS(0)z-substituted heteroaryl, -NRS(O)2-
heterocyclic; -NRS(O)2-substituted heterocyclic, -NRS(O)z-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-substituted
aryl, -NRS(O)2 NR-heteroaryl, -NRS(O)Z-NR-substituted heteroaryl,
-NR.S(O)Z-NR-heterocyclic, -NRS(O)Z-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,

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substituted heteroaryl, heterocyclic and substituted heterocyclic, and
substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted
alkyl groups substituted with -SOZ-alkyl, -SOZ-substituted alkyl, -SOZ-
alkenyl,
-SOZ-substituted alkenyl, -SOZ-cycloalkyl, -SO,-substituted cycloalkyl, -SOZ-
aryl, -SOZ-substituted aryl, -SOZ-heteroaryl, -SOZ-substituted heteroaryl, -
SOZ-
heterocyclic, -SOZ-substituted heterocyclic and -SOZNRR where R is hydrogen
or alkyl;
(g) substituted aryloxy and substituted heteroaryloxy with the proviso
that at least one substituent on the substituted aryloxy/heteroaryloxy is
other
than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy,
alkyl,
alkenyi, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy,
alkynoxy, alkylamino, alkenylamino, aIkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea;
(h) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted
heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy-
substituted saturated heterocyclic;
(i) -O-heterocyclic and -O-substituted heterocyclic;
(j) tetrazolyl;
(k) -NR-SOz-substituted alkyl where R is hydrogen, alkyl or aryl, with
the proviso that at least one substituent on the alkyl moiety of the
substituted
alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-
dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
aikoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(1) alkenylsulfonylamino, alkynylsulfonylamino, substituted
alkenylsulfonylamino and substituted alkynylsulfonylamino;
(m) substituted alkoxy with the proviso that the substitution on the
alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R",
unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl

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and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro,
trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-
dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino,
alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
(n) amidine and amidine substituted with from 1 to 3 substituents
independently selected from alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
(o) -C(O)NR"'R"' where each R"' is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic with the proviso that when one R"' is unsaturated
heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with
halogen,
hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl,
alkynyl, 1,2-dioxymethyIene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy,
alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
N,N-dialkylurea, then the other R"' is alkyl, substituted alkyl (other than
unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted
cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic
and
substituted heterocyciic;
(p) -NR'zC(O)-R$ where R8 is selected from the group consisting of
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic, and R'Z is alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
(q) -S02-aryl, -SOZ-substituted aryl, -SOz-heteroaryl, -SOz-substituted
heteroaryl or -SOZ alkyl;
(r) -NR'C(O)i~TR9R9 wherein R' is selected from the group consisting
of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted

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cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and each R9 is independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic:
(s) -NR'C(O)OR9 wherein R' is selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and, R9 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
(t) -aminocarbonyl-(N-formylheterocycyl); and
{u) -alkyl-C(O)NH-heterocyclyl and -alkyl-C{O)NH-substituted
heterocyclyl,
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
x is an integer of from 1 to 4;
R6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-
3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted
cycloalkoxy, -O-{N-succinimidyl), -NH-adamantyl, -O-cholest-5-en-3-p-yl,
-NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted
aryl, -NH(CHz)PCOOY where p is an integer of from 1 to 8 and Y is as defined
above, -OCHZNR9R'° where R9 is selected from the group consisting of -
C(O)-
aryl and -C(O)-substituted aryl and R'° is selected from the group
consisting of
hydrogen and -CHZCOOR" where R" is alkyl, and -NHSOzZ where Z is
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic;
Q is -C{X)NR'- wherein R' is selected from the group consisting of
hydrogen and alkyl; and X is selected from the group consisting of oxygen and
sulfur;
and pharmaceutically acceptable salts thereof
with the proviso that when R' is p-CH3-c~-, R6 is methoxy, Q is

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-C(O)NH-, and Rz and R3 are joined to form a pyrrolidinyl group, then RS is
not p-[-OCHzCHZN(CZHS)z]-benzyl-, p-[-OCHZCHZN(isopropyl)z]-benzyl-,
p-[-OCHZCHz-1-pyrrolidinyl)-benzyl-, p-[-OCHZCHz-1-(4-pyrimidinyl)piper-
azinyl]-benzyl-,p-[-OCHZCHz-N-morpholinyl)]-benzyl-, orp-(-OCHZCHz-N-
S piperidinyl)]-benzyl-.
Preferably, in the compounds of formula I and IA above, R~ is selected
from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl.
Even more preferably R~ is selected from the group consisting of 4-
methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-
naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2-
(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-
trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4-
(CH3C(O)NH-)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl,
3,5-di-(trifluoromethyl)phenyi, 4-t-butylphenyl, 4-t-butoxyphenyl, 4
nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-S-chloropyrazol-4-yl, phenethyl,
1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-
methylamidinophenyl, 4-[CH3SC(=NH)]phenyl, S-chloro-2-thienyl, 2,5-
dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,3,4-
thiadiazol-2-yl, 4-[HZNC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2-
fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-
yl, 4-(3'-dimethylamino-n-propoxy)-phenyl, and 1-methylpyrazol-4-yl.
Preferably, in the compounds of formula I and IA above, Rz is
hydrogen, methyl, phenyl, benzyl, -(CHz)z-2-thienyl, and -(CHz)z-~.
In one embodiment, R' and Rz together with the nitrogen atom bound
to Rz and the SOz group hound to R~ are joined to form a heterocyclic group or
substituted heterocyclic group. Preferred heterocyclic and substituted
heterocyclic groups include those having from S to 7 ring atoms having 2 to 3
heteroatoms in the ring selected from nitrogen, oxygen and sulfur which ring

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is optionally fused to another ring such as a phenyl or cyclohexyl ring to
provide for a fused ring heterocycle of from 10 to 14 ring atoms having 2 to 4
heteroatoms in the ring selected from nitrogen, oxygen and sulfur.
Specifically preferred R'/Rz joined groups include, by way of example,
benzisothiazolonyl (saccharin-2-yl).
In one preferred embodiment, R2 and R' together with the nitrogen
atom bound to RZ substituent and the carbon bound to the R' substituent form
a heterocyclic group or a substituted heterocyclic group of 4 to 6 ring atoms
having 1 to 2 heteroatoms in the ring selected from nitrogen, oxygen and
sulfur which ring is optionally substituted with 1 to 2 substituents selected
from fluoro, methyl, hydroxy, amino, phenyl, thiophenyl, thiobenzyl or can be
fused to another ring such as a phenyl or cycloalkyl ring to provide for a
fused
ring heterocycle of from 10 to 14 ring atoms having 1 to 2 heteroatoms in the
ring selected from nitrogen, oxygen and sulfur. Such heterocyclic rings
include azetidinyl (e.g., L-azetidinyl), thiazolidinyl (e.g., L-
thiazolidinyl),
piperidinyl (e.g., L-piperidinyl), piperizinyl (e.g., L-piperizinyl),
dihydroindolyl (e.g., L-2,3-dihydroindol-2-yl), tetrahydroquinolinyl (e.g.,
L-1,2,3,4-tetrahydroquinolin-2-yl), thiomorpholinyl (e.g., L-thiomorpholin-3-
yl), pyrrolidinyl (e.g., L-pyrrolidinyl), substituted pyrrolidinyl such as 4
hydroxypyrrolidinyl (e.g., 4-a-(or ~3-)hydroxy-L-pyrrolidinyl), 4
fluoropyrrolidinyl (e.g., 4-a-(or (3-)fluoro-L-pyrrolidinyl), 3-phenyl-
pyrrolidinyl (e.g., 3-a-(or (3-)phenyl-L-pyrrolidinyl), 3-
thiophenylpyrrolidinyl
(e.g., 3-a-(or ~-)thiophenyl-L-pyrrolidinyl), 4-aminopyrrolidinyl (e.g., 4-a-
(or
(3-)amino-L-pyrrolidinyl), 3-methoxypyrrolidinyl (e.g., 3-a-{or ~i-)methoxy-L-
pyrrolidinyl), 4,4-di-methylpyrrolidinyl, substituted piperizinyl such as 4-N-
Cbz-piperizinyl, substituted thiazolidinyl such as S,5-dimethylthiazolindin-4-
yl, 1,1-dioxo-thiazolidinyl (e.g., L-1,1-dioxo-thiazolidin-2-yl), substituted
1,1-
dioxo-thiazoiidinyl such as L-1,1-dioxo-S,5-dimethylthiazolidin-2-yl, 1,1-
dioxothiomorpholinyl (e.g., L-1,1-dioxo-thiomorpholin-3-yl) and the like.

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Preferably, in the compounds of formula I and IA above, R' includes
all of the isomers arising by substitution with methyl, phenyl, benzyl,
diphenylmethyl, -CH2CH2-COOH, -CHZ-COOH, 2-arnidoethyl, iso-butyl, t-
butyl, -CH20-benzyl and hydroxymethyl. Additionally, in another preferred
embodiment, R3 and RZ together with the nitrogen atom bound to RZ can form
a heterocyclic group or substituted heterocyclic ,,croup.
Q is preferably -C(O)NH- or -C(S)NH-.
RS is preferably selected from all possible isomers arising by
substitution with the following groups:
4-[NHZCHZC(O)NH-]benzyl, 4-[HOOCCHZCHZC(O)NH-]benzyl,
4-[-NHC(O)CHzNHBoc]benzyl, 4-[-NHC(O)CH(CH3)NHBoc]benzyl,
4-[-NHC(O)CH(CH2~)NHBoc]benzyl, 4-[-NHC(O)CHZNHC(O)NH-3'-
methylphenyl]benzyl, 4-[-NHC(O)CH(NHBoc)(CHZ)4NHCbz]benzyl,
4-[-NHC(O)CHZCH(C(O)OCHZ~)-NHCbz]benzyl, 4-~-benzyl,
4-[-NHC(O)CH(CHZCHZCHZCHZNHZ)NHBoc]benzyl,
4-[HZNCHZCHZCHZC(O)NH-]benzyl, 4-(BocHNCH2CH2CH2-
C(O)NH-)benzyl, 4-[~CHzOCH2(BocHN)CHC(O)NH-]benzyl,
4-[CH3NHCHZCH2CHzC(O)NH-]benzyl, 4-(N-methylpiperidin-4-oxy)-benzyl,
4-[CH3N(Boc)CHZCHzCHzC(O)NH-]benzyl,
4-[~CHZOCHZ(HZN)CHC(O)NH-]benzyl, 4-[HO(O)C(Cbz-NH)CHCHZCHz-
C(O)NH-]benzyl, 4-[tpCHzO(O)C(Cbz-NH)CHCHzCH2-C(O)NH-]benzyl,
4-[HO(O)C(NHZ)CHCHZCHZ-C{O)NH-]benzyl,
4-[CH3(N Boc)NCH2C(O)NH-]benzyl, 4-(CH3NHCHzC(O)NH-]benzyl,
4-[(CH3)zNCH2C(O)NH-]benzyl, 4-[-O-CH(COOH)~]benzyl,
4-(2-carboxylphenyl-]-benzyl, 4-[2-carboxylmethylphenyl-]-benzyl
4-[~CHzOC(O)NHCHZCHZNH-]benzyl, 4-N[-(SOZ)CH3]-
CH2CHzCH2N(CH3)z]benzyl, 4-t-butyl-O(O)CCHz-O-benzylNH]henzyl,
4-[N,N di(4-N,N dimethylamino)benzyl)amino]benzyl,
4-(2-formyl-1,2,3,4-tetrahydroisoquinolin-3-yl-CHzNH)benzyl,

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4-[-OCHZCH~-1'-(4'-pyrimidinyl)-piperazinyl]-benzyl,
4-[-OCHZCHZ-(1'-piperidinyl)-benzyl, 4-[-OCHZCHZ-(1'-pyrrolidinyl)]-
benzyl, 4-[-OCHzCH2CHz-(1'-piperidinyl)J-benzyl,
4-[(CH3)ZNCHzCHzCH2-O-]benzyl, 4-[(CH3)ZNCHZCHZO-]-benzyl,
4-[-OCHZCHZCHz-( 1 '-(4'-methylpiperazinyl))]-benzyl,
4-[-OCHZCHzCHz-4-(3'-chlorophenyl)-piperazin-1-yl]-benzyl,
4-[-OCHZCHzN(~)CHZCH3)-benzyl, 4-(-OCHz-3'-(N-Boc)-piperidinylJ-
benzyl, 4-[-O-(3-(N-Boc)-piperidinyl)benzyl,
3-[-O-(N-methylpiperidin-4-yl]benzyl, 4-[-O-(N-methylpiperidin-4-yl]benzyl,
4-[di-iso-propylamino-CHZCH20-]-benzyl, 4-[N 3-methylbutyl-N trifluoro-
methanesulfonyl)amino)benzyl, 4-[-OCHZCHZ-(N-morpholinyI)]-benzyl,
4-[-OCHZCH(NHBoc)CHzcyclohexyl]-benzyl, 4-[OCH2CH2-(N-piperidinyl]-
benzyl, 4-[-OCHZCHZCHz-{4-m-chlorophenyl)-piperazin-1-yl]-benzyl,
4-[-OCHzCHz-(N-homopiperidinyl)-benzyl, 4-[-OCHzCHZN(benzyl),]-benzyl,
1 S 3-[-OCHZCHZCHzN(CH3)Z]-benzyl, 4-[-OCHZCHZN(CzHs)Z]-benzyl,
4-[-OCHZCHzCHzN(C2H5)Z]-benzyl, 4-[-OCH2CHZN(CZHS)z)-benzyl,
4-[-OCHZCHZCHZN(CH3)benzyl)-benzyl, 4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethyl-O-]benzyl, [cyclopentylacetylenyl)-benzyl, 4-[-C---C-c~-4'c~)-benzyl,
4-[-C---C-CHz-O-S(O)2-4'-CH3-~]-benzyl, 4-[-C---C-CHzNHC(O)NH2]-benzyl,
4-[-C=C-CHZ-O-(4'-COOCHzCH3)~]-benzyl, 4-[-C---C-CH(NH2)-cyclohexyl]
benzyl, 4-[-C=C-CHz-O-phenyl]-benzyl, 4-[-C---C-CHZOCH3]-benzyl,
4-[-C--_C-CHz-O-(4'-C(O)OCzHS)phenyl]-benzyl, 4-[-C---C-
CHZCH(C(O)OCH3)Z]-benzyl, 4-[-C=C-CHZCH( NHC(O)CH3)C(O)OH]-
benzyl, 4-[-C---C-CHZ NH-(4,5-dihydro-4-oxo-5-phenyl-oxazol-2y1)]-benzyl,
~-[-OCHZCHZCH2-(N-morpholino)]-benzyl, 4-[-OCHZCOOH]-benzyl,
4-[-OCH2C00-t-butyl]-benzyl, 4-[-N(SOZCH3)(CH2)3-N(CH3)2)-benzyl,
4-[-NHS(O)zCF3]-benzyl, 4-[-C(=NH)NH2]-benzyl, 4-[-NHSOZ-CHZCI]-
benzyl, 4-[-OCHZC(O)NH-benzyl]-benzyl, 4-[-OCH2C(O)O-benzyl)-benzyl,
4-[-OCHZC(O)OHJ-benzyl, 4-[-OCH2CHz-1-(4-hydroxy-4-(3-methoxypyrrol-
2-yl)-piperazinyl]-benzyl, 4-[-OCHZC(O)NHZ]-benzyl, 4-[-OCH2C(O)NH-t-
butyl)-benzyl, 4-[-OCH2CHZ-1-(4-hydroxy-4"phenyl)-piperidinyl]-benzyl,

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__
4-[-NHSOZ-CH=CHZ]-benzyl, 4-[-NHSOZ-CHzCH2C1]-benzyl, 4-benzyl-
benzyl, 4-[-OCHZC(O)piperidin-1-yl]benzyl,
4-[-OCHZC(O)N(CH(CH3)z)Z]benzyl, 4-amidinobenzyl, 4-acetamidobenzyl,
4-(N-methyl)acetamidobenzyl, 4(-NHC(O)CHzNHC(O)NH-fluorescin)benzyl,
S 4-(NHC(O)CHZCH(NHZ)COOH, (1-toluenesulfonylimidizol-4-yl)-methyl-,
[(1-N,N dimethylaminosulfonyl)-imic.izol-4-yl]methyl-, 4-(N toluenesulfonyl-
amino)benzyl, and 4-[N methyltrifluoroacetamido)phenyl.
In the compounds of formula IA, R6 is preferably 2,4-dioxo-
tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy,
t-butoxy, cyclopentoxy, neo-pentoxy, 2-a-iso-propyl-4-[i-methylcyclohexoxy,
2-[i-isopropyl-4-[3-methylcyclohexoxy, -NHZ, benzyloxy, -NHCH,COOH,
-NHCHZCHZCOOH, -NH-adamantyl, -NHCHZCHZCOOCHzCH3, -NHSOz p-
CH3-~, -NHORB where Rg is hydrogen, methyl, iso-propyl or benzyl, O-(N-
succinimidyl), -O-cholest-5-en-3-[3-yl, -OCH2-OC(O)C(CH3)3,
-O(CHz)ZNHC(O)W where z is 1 or 2 and W is selected from the group
consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-
yl, -NR"C(O)-R' where R' is aryl, heteroaryl or heterocyclic and R" is
hydrogen or -CHZC(O)OCHzCH3.
Preferred compounds within the scope of formula I and IA above
include by way of example:
30
N (toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxyl-
carbonylglycyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(glycyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(carboxy)propionamido]-L-
phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-L-
alanyl)amino]-L-phenylalanine
N (toluene-4-sulfonyi)-L-prolyl-4-[(N tent-butoxylcarbonyl-D-
3 5 alanyl)amino]-L-phenylalanine

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__ 2g __
N (toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxylcarbonyl-D-
phenylalanyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-{2-[3-
(fluorescein)thiouriedo]acetamido}-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(N tert-butoxyl-
carbonylglycyl)amino]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-{2-[3-(3-
methylphenyl)uriedo]acetamido}-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(Na-tert-butoxylcarbonyl-NE-
carbobenzyloxy-L-lysyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-['y-(a-benzyl-Na-carbobenzyloxy-L-
aspartyl)amino]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[(Na-tert-butoxylcarbonyl-L-
lysyl)amino]-L-phenylalanine
N (toluene-4-suifonyl)-L-prolyl-4-[y-(L-aspartyl)amino]-L-phenyIala-
nine
N (toluene-4-sulfonyl)-L-prolyl-4-(4-aminobutyramido)-L-phenylala-
nine
N (toluene-4-sulfonyl)-L-prolyl-4-[4-(N tert-butoxyl-
carbonylamino)butyramido]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[4-(N methylamino)butyramido]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[4-(N tert-butoxylcarbonyl-N
methylamino)butyramido]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(O-benzyl)-L-seryl)amino]-L-
phenylalanine
N (toluene-4-sulfonyl}-L-prolyl-4-[8-(D,L-glutamyl)amino]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxyl-
carbonylsarcosyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-{5,5-dimethyl)thiaprolyl-4-[(N tent-butoxyl-
carbonylsarcosyl)amino]-L-phenylalanine

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-_ 2g _-
N (toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino]-L-phenylalanine
ethyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(sarcosyl)aminoJ-
L-phenylalanine
N {toluene-4-sulfonyl)-L-prolyl-4-[(N,14'-dimethylglycyl)amino]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[(N,N
dimethylglycyl)amino]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-(a-carboxybenzyloxy)-L-
phenylalanine
N {toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenylJ-L-phenylala-
nine
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(methoxycarbonyi)phenyl]-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-{N [2-(N
carbobenzyloxyamino)ethylJamino}-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-{N [2-(N
carbobenzyloxyamino)ethyl]amino}-L-phenylalanine methyl ester
N {toluene-4-sulfonyl)-L-prolyl-L-4-{N [3-(N,N
dimethylamino)propylJ-N [trifluoromethanesulfonylJamino}-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-L-4-{N [4-[(tert-
butoxycarbonyl)methoxy]benzyl]amino}-L-phenylalanine methyl ester
N {toluene-4-sulfonyl)-L-prolyl-L-4-{N,N di[4-(N,N
dimethylamino)benzyl]amino}-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-L-4-{N [(2-formyl-1,2,3,4-
tetrahydroisoquinolin-3-yl)methyl]amino } -L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)propoxyJ-
L-phenylalanine
N (toluene-4-sulfonyl)-N methyl-L-serinyl-4-[3-(N,N-dimethylamino-
propoxy]-L-phenylalanine methyl ester

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WO 99/06431 PCT/US98/15313
-- 30 --
N {toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[2-(N,N
dimethylamino)ethoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-proIyl-4-[2-(N,N dimethylamino)ethoxy]-L-
phenylalanine
N (toiuene-4-sulfonyl)-L-prolyl-4-[2-(N ethyl-N
phenylamino)ethoxyJ-L-phenylalanine methyl ester
N (toluene-4-sulfonyi)-L-prolyl-4-[2-(N,N diisopropylamino)ethoxyJ-
L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-cyclohexyl-2-(N tert-
butoxycarbonylamino)propoxyJ-L-phenylalanine methyl ester
N (thiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)-
propoxy]-L-phenylalanine
N (5-chIorothiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)-
propoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N diethylamino)ethoxy]-L-
phenylalanine
N {2,S-dichlorothiophene-3-sulfonyl)-L-prolyl-4-[3-(N,N
dimethylamino)propoxy]-L-phenylalanine
N (1-methylpyrazole-4-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)-
propoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N diethylamino)propoxy]-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-3-[3-(N,N dimethylamino)propoxy]-
L-phenylalanine
N (thiazole-2-sulfonyl)-L-prolyl-4-[3-(N,N dimethylamino)propoxy]-
L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(N methyl-N
benzylamino)propoxy]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N diethylamino)propoxy]-L-
phenylaianine
N-(toluene-4-sulfonyl)-L-prolyl-4-[3-{N methyl-N
benzylamino)propoxy]-L-phenylalanine methyl ester

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WO 99/06431 PCT/US98/15313
-- 31 --
N (1-methylimidazole-4-sulfon,~l)-L-prolyl-4-[3-(N,lV
dimethylamino)propoxy]-L-phenylalanine
N (2-methyIthiadiazole-5-sulfonyl)-L-prolyl-4-[3-(N,N
dimethylamino)propoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-thiaprolyl-4-[3-(N,IV
dimethylamino)propoxy]-L-phenylalanine
N (4-cyanobenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N
dimethylamino)propoxy]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-(3,3-dimethyl)prolyl-4-[3-{N,N
dimethylamino)propoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N
dimethylamino)propoxy]-L-phenylalanine ethyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethoxy]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-4-[3-(N,N
dimethylamino)propoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(2-azabicyclo[3.2.2]octan-2-
yl)ethoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-(cyclopentyl)ethynyl]-
D,L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4- f 2-[4-
(phenyl)phenyl] ethynyl } -D,L-phenylalanine
N (toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(toluene-4-
3 5 sul fonyloxy)prop-1-ynyl]-D,L-phenylalanine
N (toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(ureido)prop-1-ynyl]-
D,L-phenylalanine
N (toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(4-
ethoxycarbonylphenoxy)prop-1-ynyl]-D,L-phenylalanine
N (toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-(1-aminocyclohex-1-
yl)ethynyl]-D,L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(phenoxy)prop-1-ynyl]-D,L-
phenylalanine

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 32 --
N (toluene-4-sulfonyl)sarcosyl-4-[3-(phenoxy)prop-1-ynylJ-D,L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(methoxy)prop-1-ynyl]-D,L-
phenylalanine
N (toluene-4-sulfonyl)sarcosyl-4-[3-(methoxy)prop-1-ynyl]-D,L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(4-ethoxycarbonylphenoxy)prop-
1-ynyl]-D,L-phenylalanine
N (toluene-4-sulfonyl)sarcosyl-4-[3-(4-ethoxycarbonylphenoxy)prop-
1-ynyl]-D,L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-4-[4,4-di(methoxycarbonyl)but-1-
ynylJ-D,L-phenylalanine
N (toluene-4-sulfonyl)sarcosyl-4-[4,4-di(methoxycarbonyl)but-1-
ynyl]-D,L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-(4-acetamido-4-carboxybut-1-ynyl)-
D,L-phenylalanine
N (toluene-4-sulfonyl)sarcosyl-4-(4-acetamido-4-carboxybut-1-ynyl)-
D,L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-{3-[(4,5-dihydro-4-oxo-5-
phenyloxazol-2-yl)amino]prop-1-ynyl}-D,L-phenylalanine
N (toluene-4-sulfonyl)sarcosyl-4-{3-[(4,5-dihydro-4-oxo-S-
phenyloxazol-2-yl)amino]prop-1-ynyl }-D,L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenoxy]-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-{2-[4-(pyrimidin-2-yl)piperazin-1-
yl]ethoxy}-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin-1-yl)propoxy]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(pyrrolidin-1-yl)ethoxy]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin-1-yl)propoxy]-L-
phenylalanine methyl ester

CA 02290747 1999-11-19
WO 99/06431 PCTNS98/15313
--33--
N (toluene-4-sulfonyl)-L-prolyl-4-{3-[4-(3-chlorophenyl)piperazin-1-
yl]propoxy}-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(1-tert-butoxycarbonylpiperidin-3-
yl)methoxy]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(morpholin-4-yl)ethoxy]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(1-tert-butoxycarbonylpiperidin-3-
yl)methoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(piperidin-1-yl)ethoxy]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-{3-[4-(3-chlorophenyl)piperazin-1-
yi]propoxy}-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1-yl)ethoxy)-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1-yl)ethoxy]-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin-1
yl)propoxy]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-3-[2-(pyrrolidin-1-yl)ethoxy]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin-1-
yl)propoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-3-[2-(morpholin-4-yl)ethoxy]-L-
3 S phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-{2-[4-(3-methoxythien-2-yl)-4-
hydroxypiperidin-1-yl]ethoxy}-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-3-(1-methylpiperidin-4-oxy)-D,L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-(1-methylpiperidin-4-oxy)-D,L-
phenylalanine
N {toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-(I-
methylpiperidin-4-oxy)-L-phenylalanine ethyl ester

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 34 --
N (toluene-4-sulfonyl)-L-(1,1-dioxothiomorpholin-3-carbonyl)-4-(1-
methylpiperidin-4-oxy)-L-phenylalanine ethyl ester
N (toluene-4-sulfonyl)-L-(1,1-dioxothiomorpholin-3-carbonyl)-4-(1-
methylpiperidin-4-oxy)-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-( 1-
methylpiperidin-4-oxy)-L-phenylalanine
N (a-toluenesulfonyl)-L-prolyl-4-(1-methylpiperidin-4-oxy)-L-
phenylalanine ethyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-N-(trifluoromethanesulfonyl)amino-
L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-N (trifluoromethanesulfonyl)amino-
L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-N (chloromethanesulfonyl)amino-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-N (vinylsulfonyl)amino-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-(N trifluoromethanesulfonyl-N
isobutyl)amino-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-N (vinylsulfonyl)amino-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(N benzylaminocarbony)methoxy]-
L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L-
phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-L-
phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[(aminocarbonyl)methoxy]-L-
phenylalanine

CA 02290747 1999-11-19
WO 99!06431 PCT/US98/15313
-- 35 --
N (toluene-4-sulfonyl)-L-prolyl-4-[(N tert-
butylaminocarbonyl)methoxy]-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[2-{4-phenyl-4-hydroxypiperidin-1-
yl)ethoxy]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[(piperidin-1-yicarbonyl)methoxy]-
L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-[(N,N
diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-[(N,N
diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester
N (toluene-4-sulfonyl)sarcosyl-D,L-4-(amidino)phenylalanine
N (toluene-4-sulfonyl)sarcosyl-D,L-4-(aminocarbonyl)phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-4-(N methylacetamido)-L-
phenylalanine isopropyl ester
N (toluene-4-sulfonyl)-L-prolyl-4-(N methylacetamido)-L-
phenylalanine
N {toluene-4-sulfonyl)-L-prolyl-4-(N methyltrifluoroacetamido)-L-
phenylalanine methyl ester
N (toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-[3-(N,N
dimethylamino)propoxy]-L-phenylalanine t-butyl ester
N (toluene-4-sulfonyl)-L-prolyl-L-4-(N methylpiperidinoxy)-
phenylalanine t-butyl ester
N (toluene-4-sulfonyl)-L-(5,5-dimethyl)thiapropyl-L-(4-
methylpiperidinoxy) phenylalanine t-butyl ester
N (toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
t-butyl ester
N (toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
and pharmaceutically acceptable salts thereof as well as any of the
ester compounds recited above wherein one ester is replaced with another

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 36 --
ester selected from the group consisting of methyl ester, ethyl ester, n-
propyl
ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and
tert-
butyl ester.
This invention also provides methods for binding VLA-4 in a
biological sample which method comprises contacting the biological sample
with a compound of formula I or IA above under conditions wherein said
compound binds to VLA-4.
Certain of the compounds of formula I and IA above are also useful in
reducing VLA-4 mediated inflammation in vivo.
This invention also provides pharmaceutical compositions comprising
a pharmaceutically acceptable carrier and a therapeutically effective amount
of
1 S one or more the compounds of formula I or IA above with the exception that
R3 and RS are derived from L-amino acids or other similarly configured
starting materials. Alternatively, racemic mixtures can be used.
The pharmaceutical compositions may be used to treat VLA-4
mediated disease conditions. Such disease conditions include, by way of
example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia,
diabetes (including acute juvenile onset diabetis), inflammatory bowel disease
(including ulcerative colitis and Crohn's disease), multiple sclerosis,
rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis,
encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic
dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung
injury such as that which occurs in adult respiratory distress syndrome.
Accordingly, this invention also provides methods for the treatment of an
inflammatory disease in a patient mediated by VLA-4 which methods
comprise administering to the patient the pharmaceutical compositions
described above.

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__ 3~ __
Preferred compounds of formula I and IA above include those set forth
in Table I below:

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__3g__
~
2 x x ~ %h
w w W
w w .E~'
-, .b ., cn
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CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
--39--
x x x x z x x x
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CA 02290747 1999-11-19
WO 99!06431 PCT/US98/15313
-- 40 --
a a a a a a a a
I I I I
n , n ~ n n
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CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 41 --
a a a a a a a
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CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 42 --
yo b a a b b 'o
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CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 43 --
'o a a a a b
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G1 P~ P1 a1 W ~_
~ ~G 1 ~ ~
'~ ~G k' H
'~ ~ G
1 i1 1 ~ 'y 1 ~1 . ' 1
~ ~ ~ ~ ' ~
O 'J-
~, ~ ~,~ O 'a' W
,~. a
p; c; p; c; p; a; ; p;
w w ~ w ' w '< '
~ ~ ~ ~ ~ ~ w
o ~ ' ' o 5' ~' 5' v
o c o c
~ ~ ~
y ~ ~. N C!i
~ 5 ~ r~ ~ ~ n~ ~
n~ n~
v v ~ ~ ~
W
n_
"""' 7C
fD
~.
.y
...
b G.
a 'o ;
Q ~ b ~ n
0 o
x ~ n ~ ~ ~ x
x Z 'n o x ~ x x ,.
'
n ~ x ~ ~ ~ '. .- z
x z
x z ~~ ~' z z z
x x?
z z ,~ ~ ;~ n ~ ~ ~n
R x
n n ~ ~ x ~o 0
x ~ ~ ~
x x ~, 0
N ~ Q, ~ a, O
f~C ~ _ N
. . ~ n
. ~t
~
~G ~ k JC N x
f
i i N i '"n
i
0
x x x x x x x x x
w w w

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__
'_'. N
a a N a a o r~'~ a
z
n ~ n z ~ ~~:
~
x ,. ~ ~.
o
~, .~. .~ ~, a
o
q
~ ~ ~W W ~
b w
~ ~ ~ :~ ~ ~ ~e
~ ~ :~ -,
7 x?
; 70 ~ 7d 0 ., ~ g ~ -~
o' ~ g c
~ o a
op II ogll oa o~ o~ o~ o
II II II II
o o ~ ~ o
o n
n
c n o o ~ n n
n o ~ ~
. n . .
~
.t ~ ~ ~ n
~ ~ ~ ~
i7. i~.
7~7
a
.e a a
a
.,
o = O O ~ o O p
x x
N N
n x z
z z x t
N N
x z x = x z z
x
z z z n
n z n n ~ ~ n
x z z x ~
_ N N .-T
N N '. ,r ~. ; ~ N
C ~ ~ ~
N
'G
~G ~G 'G
i ~ i
i
C
x z
z ~ c ~ x
z
a

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 45 --
~. N 1
b
x x z x
W ~ W ~ ~ ~ W
~
_ 1
1
~x~ ~x~ ~. ~xr r~'7c r.~'x~~
x -
x~ ; ~ x, - I
N N N ~; TJ G~ 'C TJ a~
~ 1 ~ ~ W~ I ~ ~ ~1 ~ N t
~ ~
W ~ ~ ~ ,C
.~ .- r x ~ _ r cn ~ -, ~ -, , a'
cn ., v-
~_ _a; c~ n 1 ~_ _~; o o ~ o ~ 0 ~
n a vl x'J n 1 II
n n
a
_ n ~ _ '~ a:
~ n ~e II
~ ~'
x~ x~ -
W W Lr W
a . n: N ~' ;
N ~' . n
_ . .
I N ~ 1 .
1 I
W
b
1
b b b b b b '
1 I n n
n ~ 1 I
0 0 0
x x ~
~ ~ ~
N N N x
x ~ T n
x ~ x
W
x x x
x x x z z z
z
x ~ x ~ x x
,r .. ..
W N N N
r a a
~e
T
1 I i
I
1
U
W W
W

CA 02290747 1999-11-19
WO 99/06431 PCT/~JS98/15313
-- 46 --
a a a b c a b ~ 'o
n ~ n n n
x x x x x x x x x
w -
w
r n ;V ~-.
x
I n I t~ ~ s ,v
~ W ~ ? '
w ~ .'. ~ O
70 SC ~ ~
K 70
. ,J C7 .G
, , o ~ o 0
$ g ~ ~
x x x x a n 1 x 1 n
o o .
a; ~; o; v .~ g;
a~ o~ m cn ~ a:
~ ~ ~ ~ C~ ~
~' ~ o ~' ~ o'
o ~ o o
_ ~
..
- r ;= r
.n .~ .n .n
~' ~ ~ o
x z =
, N
"1
-e- ~ ..
.. ~e-
.r
1
b ~ '~ 'C WO
b
~' ~'
III ~ n
n "a ~ N x x
'
I I ~ ..-.. N
('7 C7 i e~ N N N '~'-''-' ~
N
x ~ o ~ I z z z '
x "o to ~ ~ ~ = x x
" I n
x ~ ~ ~~ z x x
o b ~ o " "
o a '$- I ~ , ~ ~ T ~
W
z ~ I ~ ~ N = z "I
~ ~'
x ~. ~ N O C O .'
~
N
wI .~ ~ 1 O ~,
.
I
CAD I ~ tC ~G
'G 1 1 I
I
x x x x x x x x x

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
'o a a v a b a a a a a
~ n ~ ~ ~ ~ n
x x x x x x x x x x x
w w w W -
'$ ~ '~ w ~-~- -$.
~
C, r, ~. c- ~.,
w w w W W I
~ ~ ;~ ~p ~
1 i !7 ~ n \ n ~
n \ n
\ \
H ~ 1 ~ ''~~C' ~ _1
~ 1 "1
~
" ~ o f7 ~ n ~ o n ~ o
o x n o a a x x x
g o o
n a
o ~ x a x o_~ x ~
y
o; ~; '" G: ~; n.
w sv d ~ a~
~ ~ ~ ~ ~
. ...
y yr v/ v Vi yr
V1 f/1 N f7 fn
n r7 n n
n ~
. .
~ ~_
~'
x x _4 r n
i
~Y ~1
a
~ a
a .e ' a
n
a ~ ~ n n a a n
y y ~ a ; ~. I y
n
n ~
uln
x x m iii n
x x
~ o o " ~ ~ ~ ~ o
z n ~ ~? ~b ~ x x x x c
~ s
- _ N N ~r
/1 ~ o ~'
n o o .~ ~ o o ,~ o
~ ~
0 0 0 ' ~'o x x
0 o
n n n o o =..~ .r.~ ~
p
x x x ~ n
x n
N x ~ ~r~. ~ y
x ~ ~
n i v.r _ N ~ ~ i
'~ ~ 't~ fSL
t
_ N ~
(
D
N
i n
i
o U 0 o O 0 0 0 o O 0
x x x x x x x x x x
*rB

CA 02290747 1999-11-19
WO 99/06431 _'48__ PCTNS98/15313
b b b b b b b b b
~
x s ~ x s z z z ~?
r~
~ .. -.
~ ~ ~ ~ x~ ~ ' a~ ~
~ a~ ~ ~
~ ~
,
~1 ~1 ~1 rt "1 1 n ~ o
~ ~ ., ~ g ~ ~ $' C'7
. . g ~
O
, o . o ~ o ~ o o ~ x o ~ = N
o a o II II ~ II II
II o II
~
II
o; c: o; a: ii ci
d p; ~; w ~ ~
~ ~ ~ ~ ~ ~
0 5'0 a o 5'0 a '
~ ~ ~ ~ o
.
3
~
w w
'O a b a
'
O ~ ~, .o b ~ ~ o
C) O ~ ~e n C7
~ i
b n ~ x ~ ~ ~ ~n ii
~
x (7 ' o ~ ~ n n
? n
o ~ ~= x Vo ~ ''' ''-
z
~z ~z
x C'~ g x x
, -n
C7 ~ 'b ~ b' x N N '.''z '_"";n
~ ~ =
y x .d ~ . :; ~ ~ =. = C7
-y C7 a ~.
,CD,~ C ~ N ~ N N Cn ~ c
x In
,'-, O K ~< O
0. C
~
"~. ~ ~ ~ ~ ~~ ~0. ..r
~
N ~ '~ O O 't
~ ~
e x x ,
i O O
i ' '
x z ~ z x z
s s x

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__ 49 __
ye 'o a a b 'o a
x x x
x ~ T x S
r, r w r, t= r w r, r ;C1~ ;i~
w ;t7 w w 70 w w n w
x1 N x1 x7 ~ ~ ;~ , ,
N N ~ , n
' t~
o w v ~ w ~ n v w w w b
w '' ~ ~ v ~ ~ v ~ d ~ d
~ m
v~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ cr a
o ~ o ~ -~ ~ o ~ ~ ~
o~ II oall o II~ ll o~II o IIo II o II
o~ oa o_a c~ o~
iiwe o::~ iiw~ Q::~ n:~~ a~ e c:~~ a
~ r. , ,
o 5' 5 5' ~' 5' o' o'
o 0 o o o o
9 ~ ~ '~ ~ '~ ~ ~ ~e ~ '~ ~ '~
e ~ ~ ' 3 ~e 3 ' 9 3 -
' 3
'
yr n a 41 ~ C:V fi ~ :A ~ r ~ f) v ~
Vl n 'A fn n Vf 4! 'l J
a
O ~ O ~- O o 0
x _
n r~
x ~ 'o x x r.,
~ x x
N:. N' ~ 0 x x z
0
'
.
x ~ ~ .~~ ,n~ o
x
~N
' ~ C7 ~
O O' T_3 ~ "
~ ~ x , o
n:
5. ~ . . c:
N
'
-, -, _. ~ 5
n: a .
'<
~
a . .P . .. e
-r
c ~c ~. .: a'
N c~9 ~ N
C ~ n W
.
i
0 ~ O ~ O 0
s x x x x x

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 50 --
a a a a a a a a
, , , , ,
x x x x x x x
w w w a
A. n
, _ _ _ _ r" r W
X, x ~ ~ (" ~~ ~" t"' W
W W W W TJ
~ ~ ~ ~
o x y s ~ n
a ~. n "S . ~ ~ ~ ~ -w ~ -' b
~ :h ~ :n ~ ~ 7d %h
~ ~
o r- x cn . ~ o ~ , , ~ s
~ o ~ o ~ o
~ o
~~ II n o a o ~ o l o ~ o ~
II II II 5 o ~ II II
l II
... o n a ~ a ~ G G; G. G;
~. O ~ ~ ~ y m w a~
~ n ~ ~ ~
. .
N~ ~ x~ 5.0 S.o 5.0 'o.o 0 ~ =
~ ~ ~ ~ 5 5
~
o n ~e ~ ~ ~ ~ ~ e ~
~ ~
n
N
.a a ? ~ a a
... O O ~ g a O
n
' x o
W ~ ~ ~ n
~
z ~ x x ~'x
b b
N ~'"
~o R ~-~ z
x
_
G fl. ~y ~ b ~o O x
o 'G
~ N ..:
.icea a .~o, ~ =
'!'
~e v ~ ~. c: "v o
. Q.
O O
, a. N 'G W'
co a
~ ~ C
' ;
, ,
x = ~ Z = ~ O :n
~ ~ x
w
x w
w

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 51 --
'o ~ a ~ c b
x ~ z x ~ x ~ x
~a
c
' $ ~ $
a
W ~ ~ ~ r~.~ ~:. ~ ~ C7 X x ~ X x
W W W ~ O
x
n \ ~ \ ~ \ \ O \
" n ~ n
rb ~ ~~ ~ 70~G 7C~ n S n "
H ~ -~ ~ r, ~ W
( w p C~ ~,
!/~
._ r N O
O ~~ O I G ~~O (~~G tn 1 'C
~ ~ ~ ~ I ~; (~ 'G ~ N
~I ~~
am p n:me a:m~ aa: ~ v imC:~~.
~
o ~ ~' ~ a' ~ o~ ~ :. x
~ ~ o ~ r
,
n, v n.~ n.G. C,, C n.
~ ~
N
a n ~ n
b
n
_
n
Zt f~ f9
n n ~ ~ ~ 'G
G
b _ _
f.
O O -, .,
f7 n n c: ii a c_: 70
~n 'n a ~ 5 a
'"; ~ .p ~ i~
C' 0' 'G ~G
. W.
i i
i ~ (~D (~C
N
'.C
i i
O O
0 ~
0 0 O O x
"
x x ~ x x n
x x

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 52 --
a a a a a a a a
, , ,
, ~ ,
z ~ x x x z x z
w$- e- ~- ~- ~.~. we.
rWxl rWx~ rW~o rWx~ ~W~ ; wx rW~ c-Wx~
~ ; '~ '~ ~ ~: b
~o ~ ~ d
x ~
" ~
g
n o ~ o_ o c ~ o ~ o_ o ~
n a ~ n a a a
a
a: ii a : c: a : c : n: ~ :
: c: ~ ~ ~ ~ : .e
~ ~e ~ ~e ' ~ '
a' ~' '
G ~
~ t~ ~ n n o n ~ :m ~ ~
' ' ' ~ 3 r
' ' '
... ... .r v - V .r ,r .~
w H H v~ f: ~ H :n
n n n n n r'
'C ,~ b a
O ~ O
n n n < 3b z
0
x o _
ac ~'
x W o
0 0
0 =~ ~a
~ z ~
z z
x ~ ~ ~ o~ x
' ~
'- x
' c
o ~ =
~
,
.
Z
o N
N
i n K
~
i i '
I
, i n n n
z x x z z x x z '
w w W w

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
--53--
a 'n a a a a a a a
~ n n ~ ~ n ~ n
'
z x w z x x x x x x?
,
.e.
~,w~ ~,',.'~c='''~~,'''~p; '.'gypy,~~ ~w~
x ~ ~ ~ ~ ~
~! x
~
-, , ~ , ~ , ~ ., ., -,
~ ~ a s
a z ~ o ~ ~ J 3 3 ~ ~ ~ c ~ x
n a ~ a n a ,.
a
z x z
.~ b
'
a
a
'bx x
;. :. ~ -'
x b
n x z ~ ~ y ~ x
z z "Z ~ ~ ~ '
a.'., c;
x ~bN z
z ~ ~ ~ , o
d ~
~
,z z o 0 0 ~ x
"
'-
n n ~ 0. ~, x
a s
~o ~ ~ ~ _c
N =
i i ~ ~ C~'~
0 N ~
O ; O i O
f~D f~D C'
n i
i
0 0 ~ o 0 0 o x
z x x z x ac z z x
N

CA 02290747 1999-11-19
WO 99/06431 PCT/US98115313
-- 54 --
a a a a a a a a
n ~ n
x x x x x x x x
_
w wa we. ;e- a
.e-
a
~
pW ~ rW~ rwz ~.Wx~ ~W~ ~Wz r
~x~
xw ~ ~ ~
'o ~ ~~ w ~ ~ w ~ w ~ a~
w '~ 'o w ~ ~
w 'v
~ w
~
.rte '~ ~ ~ ~ ~ s -, ., .,
t" cn ~ o-
o a ~_; v~ o ~ o c ' o ~ o ~ o
II (-~ il II ~ II II II 5
~ II II
y
_ a : c a ~ a ~ G w G
w ~ _ ~ w ~ ~ c
... w' ~
U n ~
: '
l7' G f~' n' n' ~' n' n'
f~'
fn ; N ~, ~;.. yn ~ W ~ ;n ,..
W v~ c N
a
Z? 'b b
Z a
Z
.
0 0 ~ ~ ~ 2
'= c '<
a ~ -- -
3
' ;~ c c ~
-~ ~ _e c w
0 0
~ ~
~ C a
o
_
re ~ B ~ o o w c:
~e o. o. ~e .~ ~ c
a
cps ~ s a _~ '_~ o a
~ ~ .
f y B ~ ~ ~e
'.
~e
'
i i N
O
i
o ~
0
~ 0 0 o x x~
x x z z
:, W
w

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 5 5 --
a a a
z z z
~e- a ~e-
a
~x
_N
L
N
[""
US
o II1 II .y....n II
~ o ~ v~
a ~_;
_ ~ o; " '~ _
' ~ ''"
n
a
o'o ~ 5'c~ - .T=
~3 ~.~~ ~. c:
w
2
3
a a
c
O O
O
x~
x z x

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 56 --
DETAILED DESCRIPTION OF THE INVENTION
As above, this invention relates to compounds which inhibit leukocyte
adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
However, prior to describing this invention in further detail, the following
terms will first be defined.
D fi~tlans
As used herein, "alkyl" refers to alkyl groups preferably having from 1
to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is
exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
"Substituted alkyl" refers to an alkyl group, preferably of from 1 to 10
carbon atoms, having from 1 to 5 substituents selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino,
acyloxy, amino, amidino, alkylamidino, thioamidino, alkylthioamidinio,
aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,
aryloxylaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitre,
carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,
carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl,
carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,
guanidine, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,
thioaryl,
substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl,
thioheteroaryl,
substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic,
heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic,
substituted
heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)z-alkyl, -OS(O)2-
substituted alkyl, -OS(O)z aryl, -OS(O)2-substituted aryl, -OS(O)2-heteroaryl,
-OS(O)Z substituted heteroaryl, -OS(O)Z-heterocyclic, -OS(O)Z-substituted
heterocyclic, -OSOz-NRR where R is hydrogen or alkyl,

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
_-
-NRS(O)Z alkyl, -NRS(O)Z-substituted alkyl, -NRS(O)2 aryl, -NRS(O)2
substituted aryl, -NRS(O)2-heteroaryl, -NRS(O)Z-substituted heteroaryl,
-NRS(O)2-heterocyclic, -NRS(O)Z-substituted heterocyclic, -NRS(O)2-NR-
alkyl, -NR.S(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)2-NR-
substituted aryl, -NRS(O)z-NR-heteroaryl, -NRS(O)2-NR-substituted
heteroaryl, -NRS(O)2-NR-heterocyclic, -NRS(O)Z-NR-substituted heterocyclic
where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-
(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted
arylamino, mono- and di-heteroarylamino, mono- and di-substituted
heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted
heterocyclic amino, unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic
and substituted alkyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkyi/substituted
alkyl groups substituted with -SOZ-alkyl, -SOZ-substituted alkyl, -SOZ-
alkenyl,
-SOZ substituted alkenyl, -S02-cycloalkyl, -SOz substituted cycloalkyl,
-SOZ aryl, -SOZ substituted aryl, -SOz-heteroaryl, -SOz substituted
heteroaryl,
-SOZ-heterocyclic, -SOZ substituted heterocyclic and -SOZNRR where R is
hydrogen or alkyl.
"Alkoxy" refers to the group "alkyl-O-" which includes, by way of
example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,
sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
"Substituted alkoxy" refers to the group "substituted alkyl-O-".
"Acyl" refers to the groups H-C{O)-, alkyl-C(O)-, substituted alkyl-
C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted
alkynyl-C(O)- cycloalkyl-C{O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-,
substituted aryl-C(O)-, heteroaryl-C{O)-, substituted heteroaryl-C(O),
heterocyclic-C(O)-, and substituted heterocyclic-C(O)- wherein alkyl,

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
_- sg __
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, substituted cycioalkyl, aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Acylamino" refers to the group -C(O)NRR where each R is
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined
to
form together with the nitrogen atom a heterocyclic or substituted
heterocyclic
ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic
are
as defined herein.
"Thiocarbonylamino" refers to the group -C(S)NRR where each R is
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
substituted
heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined
to
form, together with the nitrogen atom a heterocyclic or substituted
heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic are as defined herein.
"Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-
C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-,
substituted alkynyl-C(O)O-, aryl-C(0)O-, substituted aryl-C(O)O-, cycloalkyl-
C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted
heteroaryl-C(O)O-, heterocyclic-C(O)0-, and substituted heterocyclic-C(O)O-
wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 59 --
substituted alkynyl, cycioalkyl, substituted cycloalkyl, aryl, substituted
aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic
are
as defined herein.
"Alkenyl" refers to alkenyl group preferably having from 2 to 10
carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1
and preferably from 1-2 sites of alkenyl unsaturation.
"Substituted alkenyl" refers to alkenyl groups having from 1 to 5
substituents selected from the group consisting of alkoxy, substituted alkoxy,
acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,
thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,
aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,
carboxyl,
1 S carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-
substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl,
carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,
guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,
thioaryl,
substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl,
thioheteroaryl,
substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic,
heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)Z
substituted alkyl, -OS(O)2-aryl, -OS(O)Z substituted aryl, -OS(O)z-heteroaryl,
-OS(O)Z-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSOz-NR.R where R is hydrogen or alkyl, -NRS(O)z-alkyl,
-NRS(O)Z substituted alkyl, -NRS(O)2-aryl, -NRS(O)2-substituted aryl,
-NRS(O)z-heteroaryl, -NRS(O)z-substituted heteroaryl, -NRS(O)2-
heterocyclic, -NRS(O)Z-substituted heterocyclic, -NRS(O)z NR-alkyl,

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-NRS(O)2 NR-substituted alkyl, -NRS(O)Z-NR-aryl, -NRS(O)z-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2 NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)z-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic and
substituted alkenyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted
alkenyl groups substituted with -SOZ-alkyl, -SO,-substituted alkyl, -SOZ-
alkenyl, -SOz-substituted alkenyl, -SOZ-cycloalkyl, -SOZ-substituted
cycloalkyl, -SOz aryl, -SOZ-substituted aryl, -SOz-heteroaryl, -SOZ-
substituted
heteroaryl, -S02-heterocyclic, -SOZ-substituted heterocyclic and -SOZNRR
where R is hydrogen or alkyl.
"Alkynyl" refers to alkynyl group preferably having from 2 to 10
carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1
and preferably from 1-2 sites of alkynyl unsaturation.
"Substituted alkynyl" refers to alkynyl groups having from I to 5
substituents selected from the group consisting of alkoxy, substituted alkoxy,
acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,
thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,
aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,
carboxyl,
carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-
substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl,
carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
carboxyl-substituted heterocyclic, cycioalkyl, substituted cycloalkyl,

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guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,
thioaryl,
substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl,
thioheteroaryl,
substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic,
heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,
S cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)z-
substituted alkyl, -OS(O)z-aryl, -OS(O)2-substituted aryl, -OS(O)z-heteroaryl,
-OS(O)Z-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)z-substituted
heterocyclic, -OSOZ-NRR where R is hydrogen or alkyl, -NRS(O)Z-alkyl,
-NRS(O)Z-substituted alkyl, -NRS(O)2-aryl, -NRS(O)Z-substituted aryl,
-NRS(O)z-heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O)2-
heterocyclic, -NRS(O)Z-substituted heterocyclic, -NRS(O)z-NR-alkyl,
-NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O)z-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)z-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic and
substituted alkynyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted
alkynyl groups substituted with -SOz-alkyl, -SOz substituted alkyl, -SOZ-
alkenyl, -SOZ substituted alkenyl, -SOZ-cycloalkyl, -S02-substituted
cycloalkyl, -SOZ-aryl, -SOZ-substituted aryl, -SOZ-heteroaryl, -SOZ-
substituted
heteroaryl, -SOZ-heterocyclic, -SOZ substituted heterocyclic and -SOZNRR
where R is hydrogen or alkyl.

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"Amidino" refers to the group HZNC- and the term "alkylamidino"
NH
refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC-).
NH
15
"Thioamidino" refers to the group RSC- where R is hydrogen or
NH
alkyl.
"Aminoacyl" refers to the groups -NRC(O)alkyl,
-NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substituted
cycloalkyl, -NRC(O)alkenyI, -NRC(O)substituted alkenyl, -NRC(O)alkynyl,
-NRC(O)substituted alkynyl, -NRC(O)aryl, -NRC(O)substituted aryl,
-NRC(O)heteroaryl, -NRC{O)substituted heteroaryl, -NRC(O)heterocyclic,
and -NRC(O)substituted heterocyclic where R is hydrogen or alkyl and
wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl,
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic
are
as defined herein.
"Aminocarbonyloxy" refers to the groups -NRC(O)O-alkyl,
-NRC(O)O-substituted alkyl, -NRC(0)O-alkenyl, -NRC(O)O-substituted
alkenyl, -NRC(O)O-alkynyl, -NRC(O)O-substituted alkynyl, -NRC(O)O-
cycloalkyl, -NRC(O)O-substituted cycloalkyl, -NRC(O)O-aryl, -NRC{O)O-
substituted aryl, -NRC(O)O-heteroaryl, -NRC(O)O-substituted heteroaryl,
-NRC(O)O-heterocyclic, and -NRC(O)O-substituted heterocyclic where R is
hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic are as defined herein.

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"Oxycarbonylamino" refers to the groups -OC(O)NH2, -OC(O)NRR,
-OC(O)NR-alkyl, -OC(O)NR-substituted alkyl, -OC(O)NR-alkenyl,
-OC(O)NR-substituted alkenyl, -OC(O)NR-alkynyl, -OC(O)NR-substituted
alkynyl, -OC(O)NR-cycloalkyl, -OC(O)NR-substituted cycloalkyl,
-OC(O)NR-aryl, -OC(O)NR-substituted aryl, -OC(O)NR-heteroaryl,
-OC{O)NR-substituted heteroaryl,- OC(O)NR-heterocyclic, and
-OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or where each
R is joined to form, together with the nitrogen atom a heterocyclic or
substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic are as defined herein.
"Oxythiocarbonylamino" refers to the groups -OC(S)NHZ,
-OC{S)NRR, -OC(S)NR-alkyl, -OC(S)NR-substituted alkyl, -OC(S)NR-
alkenyl, -OC(S)NR-substituted alkenyl, -OC(S)NR-alkynyl, -OC(S)NR-
substituted alkynyl, -OC(S)NR-cycloalkyl, -OC(S)NR-substituted cycloalkyl,
-OC(S)NR-aryl, -OC(S)NR-substituted aryl, -OC(S)NR-heteroaryl,
-OC(S)NR-substituted heteroaryl, -OC(S)NR-heterocyclic, and
-OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or where each
R is joined to form together with the nitrogen atom a heterocyclic or
substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic are as defined herein.
"Aminocarbonylamino" refers to the groups -NRC(O)NRR,
-NRC(O)NR-alkyl, -NRC(O)NR-substituted alkyl, -NRC(O)NR-alkenyl,
-NRC(O)NR-substituted alkenyl, -NRC(O)NR-alkynyl, -NRC(O)NR-
substituted alkynyl, -NRC(O)NR-aryl, -NRC(O)NR-substituted aryl,
-NRC(O)NR-cycloalkyl, -NRC(O)NR-substituted cycloalkyl, -NRC(O)NR-
heteroaryl, and -NRC(O)NR-substituted heteroaryl, -NRC(O)NR-heterocyclic,

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and -NRC(O)NR-substituted heterocyclic where each R is independently
hydrogen, alkyl or where each R is joined to form together with the nitrogen
atom a heterocyclic or substituted heterocyclic ring as well as where one of
the
amino groups is blocked by conventional blocking groups such as Boc, Cbz,
formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,
substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic are as defined herein.
"Aminothiocarbonylamino" refers to the groups -NRC(S)NRR,
-NRC(S)NR-alkyl, -NRC(S)NR-substituted alkyl, -NRC(S)NR-alkenyl,
-NRC(S)NR-substituted alkenyl, -NRC(S)NR-alkynyl, -NRC(S)NR-
substituted alkynyl, -NRC(S)NR-aryl, -NRC(S)NR-substituted aryl,
-NRC(S)NR-cycloalkyl, -NRC(S)NR-substituted cycloalkyl, -NRC(S)NR-
I S heteroaryl, and -NRC(S)NR-substituted heteroaryl, -NRC(S)NR-heterocyclic,
and -NRC(S)NR-substituted heterocyclic where each R is independently
hydrogen, alkyl or where each R is joined to form together with the nitrogen
atom a heterocyclic or substituted heterocyclic ring as well as where one of
the
amino groups is blocked by conventional blocking groups such as Boc, Cbz,
formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,
substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic are as defined herein.
"Aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group of
from 6 to I4 carbon atoms having a single ring (e.g., phenyl) or multiple
condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may
not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7y1,
and the like). Preferred aryls include phenyl and naphthyl.
Substituted aryl refers to aryl groups which are substituted with from 1
to 3 substituents selected from the group consisting of hydroxy, acyl,

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acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl,
amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,
aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy,
substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,
substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,
carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl,
carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl,
substituted
thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,
substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino,
guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl,
heterocyciic,
substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,
substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -S(O)Z-alkyl, -S(O)2-substituted
alkyl, -S(O)2-cycloalkyl, -S(O)2-substituted cycloalkyl, -S(O)Z-alkenyl, -
S(O)z-
substituted alkenyl, -S(O)Z aryl, -S(O)2-substituted aryl, -S(O)Z-heteroaryl,
-S(O)z-substituted heteroaryl, -S(O)2-heterocyciic, -S(O)2-substituted
heterocyclic, -OS(O)z-alkyl, -OS(O)z-substituted alkyl, -OS(O)2 aryl, -OS(O)z-
substituted aryl, -OS(O)2-heteroaryl, -OS(O)Z-substituted heteroaryl, -OS(O)2-
heterocyclic, -OS(O)Z-substituted heterocyclic, -OSOZ-NRR where R is
hydrogen or alkyl, -NRS(O)z alkyl, -NRS(O)Z-substituted alkyl, -NRS(O)z-
aryl, -NRS(O)2-substituted aryl, -NRS(O)Z-heteroaryl, -NRS(O)2-substituted
heteroaryl, -NRS(O)2-heterocyclic, -NRS(O)z-substituted heterocyclic,
-NRS(O)Z-NR,-alkyl, -NRS(O)2-NR-substituted alkyl, -NRS(O)z-NR-aryl,
-NRS(O)2-NR-substituted aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-
substituted heteroaryl, -NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted
heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono-
and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-
substituted arylamino, mono- and di-heteroarylamino, mono- and di-

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substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-
substituted heterocyclic amino, unsymmetric di-substituted amines having
different substituents selected from alkyl, substituted alkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and amino groups on the substituted aryl blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or substituted with
-SOzNRR where R is hydrogen or alkyl.
"Aryloxy" refers to the group aryl-O- which includes, by way of
example, phenoxy, naphthoxy, and the like.
"Substituted aryloxy" refers to substituted aryl-O- groups.
"Aryloxyaryl" refers to the group -aryl-O-aryl.
"Substituted aryloxyaryl" refers to aryloxyaryl groups substituted with
from 1 to 3 substituents on either or both aryl rings selected from the group
consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino,
aminoacyl, aminocarbonyloxy, aminocarbonylamino,
aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy,
cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl,
carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl,
carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl,
substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl,
substituted
thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,
substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino,
guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl,
heterocyclic,

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substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,
substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -S(O)2 alkyl, -S(O)z-substituted
alkyl, -S(O)2-cycloalkyl, -S(O)Z-substituted cycloalkyl, -S(O)Z-alkenyl, -
S{O)2-
substituted alkenyl, -S(O)Z aryl, -S(O)Z-substituted aryl, -S(O)Z-heteroaryl,
-S(O)2- _substituted heteroaryl, -S(O),-heterocyclic, -S(O)z-substituted
heterocyclic, -OS(O)2-alkyl, -OS(O)z-substituted alkyl, -OS(O)2-aryl, -OS(O)z-
substituted aryl, -OS(O)Z-heteroaryl, -OS(O)Z-substituted heteroaryl, -OS(O)Z-
heterocyclic, -OS(O)2-substituted heterocyclic, -OSOZ-NRR where R is
hydrogen or alkyl, -NRS{O)z-alkyl, -NRS(O)Z-substituted alkyl, -NRS(O)Z-
aryl, -NRS(O _}~-substituted aryl, -NRS(O)z-heteroaryl, -NRS(O),-substituted
heteroaryl, -NRS(O)2-heterocyclic, -NRS(O)z-substituted heterocyclic,
-NRS(O)z NR-alkyl, -NRS(O)2 NR-substituted alkyl, -NRS(O)z-NR-aryl,
-NRS(O)Z-NR-substituted aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)z-NR-
substituted heteroaryl, -NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted
heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono-
and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-
substituted arylamino, mono- and di-heteroarylamino, mono- and di-
substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-
substituted heterocyclic amino, unsymmetric di-substituted amines having
different substituents selected from alkyl, substituted alkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and amino groups on the substituted aryl blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or substituted with
-SOZNRR where R is hydrogen or alkyl.
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 8 carbon atoms
having a single cyclic ring including, by way of example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclooctyl and the like. Excluded from this
definition
are mufti-ring alkyl groups such as adamantanyl, etc.

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"Cycloalkenyl" refers to cyclic alkenyl groups of from 3 to 8 carbon
atoms having single or multiple unsaturation but which are not aromatic.
"Substituted cycloalkyl" and "substituted cycloalkenyl" refer to a
cycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbon atoms,
having from 1 to 5 substituents selecied from the group consisting of oxo
(=O), thioxo (=S), alkoxy, substituted alkoxy, acyl, acylamino,
thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino,
aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,
aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitre,
carboxyl,
carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-
substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl,
carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloaikyl,
guanidine, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,
thioaryl,
substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl,
thioheteroaryl,
substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic,
heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted
heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)Z-
substituted alkyl, -OS(O)z-aryl, -OS(O)2-substituted aryl, -OS(O)Z heteroaryl,
-OS(O)2 substituted heteroaryl, -OS(O)Z-heterocyclic, -OS(O)2-substituted
heterocyclic, -OSOZ NRR where R is hydrogen or alkyl, -NRS(O)z-alkyl,
-NRS(O)z-substituted alkyl, -NRS(O)Z-aryl, -NRS(O)2 substituted aryl,
-NRS(O)2 heteroaryl, -NRS(O)Z-substituted heteroaryl, -NRS(O)z
heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O)2-NR-alkyl,
-NRS(O)2 NR-substituted alkyl, -NRS(O)Z-NR-aryl, -NRS(O)z NR-substituted
aryl, -NRS(O)Z NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2 NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted

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alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic and
substituted alkynyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted
alkynyl groups substituted with -SOz-alkyl, -SOZ-substituted alkyl, -SOZ-
alkenyl, -S02-substituted alkenyl, -SO~-cycloalkyl, -S02-substituted
cycloalkyl, -SOZ-aryl, -SOZ-substituted aryl, -SOz-heteroaryl, -SO~-
substituted
heteroaryl, -SOZ-heterocyclic, -SOz-substituted heterocyclic and -SOzNR.R
where R is hydrogen or alkyl.
"Cycloalkoxy" refers to -O-cycloalkyl groups.
"Substituted cycloalkoxy" refers to -O-substituted cycloalkyl groups.
"Guanidino" refers to the groups -NRC(=NR)NRR,
-NRC(=NR)NR-alkyl, -NRC(=NR)NR-substituted alkyl, -NRC(=NR)NR-
alkenyl, -NRC(=NR)NR-substituted alkenyl, -NRC(=NR)NR.-alkynyl,
-NRC(=NR)NR-substituted alkynyl, -NRC(=NR)NR-aryl,
-NRC(=NR)NR-substituted aryl, -NRC(=NR)NR-cycloalkyl,
-NRC(=NR)NR-heteroaryl, -NRC(=NR)NR-substituted heteroaryl,
-NRC(=NR)NR.-heterocyclic, and -NRC(=NR)NR-substituted heterocyclic
where each R is independently hydrogen and alkyl as well as where one of the
amino groups is blocked by conventional blocking groups such as Boc, Cbz,
formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,
substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted
heterocyclic are as defined herein.
"Guanidinosulfone" refers to the groups -NRC(=NR)NRSO,-alkyl,

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-NRC(=NR)NRSOZ substituted alkyl, -NRC(=NR)NRSOZ-alkenyl,
-NRC(=NR)NRSOZ-substituted alkenyl, -NRC(=NR)NRSOz-alkynyl,
-NRC(=NR)NRSOZ-substituted alkynyl, -NRC(=NR)NRSOZ-aryl,
-NRC(=NR)NRSOZ-substituted aryl, -NRC(=NR)NRSOz-cycloalkyl,
-NRC(=NR)NRSOZ-substituted cycloalkyl, -NRC(=NR)NRSOZ-heteroaryl,
and -NRC(=NR)NRSOZ-substituted heteroaryl, -NRC(=NR)NRS02-
heterocyclic, and -NRC(=NR)NRSOZ-substituted heterocyclic where each R is
independently hydrogen and alkyl and wherein alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl,
heterocyclic and substituted heterocyclic are as defined herein.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and
preferably is either chloro or bromo.
"Heteroaryl" refers to an aromatic carbocyclic group of from 2 to 10
carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and
sulfur within the ring. Such heteroaryl groups can have a single ring (e.g.,
pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or
benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and
furyl.
"Substituted heteroaryl" refers to heteroaryl groups which are
substituted with from 1 to 3 substituents selected from the group consisting
of
hydroxy, acyl, acylamino, thiocarbonylarnino, acyloxy, alkyl, substituted
alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl,
aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,
substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted
cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,
substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted
alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,

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-_ ~ 1 __
carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
heteroaryl,
carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido,
cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted
thioaryl,
thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted
S thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl,
substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl,
substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,
substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,
heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
oxythiocarbonylamino, -S(O)z-alkyl, -S(O)z-substituted alkyl, -S(O)Z-
cycloalkyl, -S(O)2-substituted cycloalkyl, -S(O)2-alkenyl, -S(O)z-substituted
alkenyl, -S(O)Z-aryl, -S(O)2-substituted aryl, -S(O),-heteroaryl, -S(O)2-
substituted heteroaryl, -S(O)2-heterocyclic, -S(O)Z-substituted heterocyclic,
-OS(O)2-alkyl, -OS(O)2-substituted alkyl, -OS(O)z-aryl, -OS(O)2-substituted
aryl, -OS(O)2-heteroaryl, -OS(O)2-substituted heteroaryi, -OS(O)2-
heterocyclic, -OS(O)Z-substituted heterocyclic, -OSOz-NRR where R is
hydrogen or alkyl, -NRS(O)2-alkyl, -NRS(O)2-substituted alkyl, -NRS(O)Z-
aryl, -NRS(O)2-substituted aryl, -NRS(O)2-heteroaryl, -NRS(O)z-substituted
heteroaryl, -NRS(O)2-heterocyclic, -NRS(O)2-substituted heterocyclic,
-NRS(O)2-NR-alkyl, -NRS(O)2-NR-substituted alkyl, -NRS(O)2-NR-aryl,
-NRS(O)z-NR-substituted aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)2-NR-
substituted heteroaryl, -NRS(O)Z-NR-heterocyclic, -NRS(O)z-NR-substituted
heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono-
and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-
substituted arylamino, mono- and di-heteroarylamino, mono- and di-
substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-
substituted heterocyclic amino, unsymmetric di-substituted amines having
different substituents selected from alkyl, substituted alkyl, aryl,
substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic and amino groups on the substituted aryl blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or substituted with
-SOzNRR where R is hydrogen or alkyl.

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__ ~2 __
"Heteroaryloxy" refers to the group -O-heteroaryl and "substituted
heteroaryloxy" refers to the group -O-substituted heteroaryl.
"Heterocycle" or "heterocyclic" refers to a saturated or unsaturated
group having a single ring or multiple condensed rings, from 1 to 10 carbon
atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen
within the ring wherein, in fused ring systems, one or more the rings can be
aryl or heteroaryl.
"Saturated heterocyclic" refers to heterocycles of single or multiple
condensed rings lacking unsaturation in any ring (e.g., carbon to carbon
unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen
unsaturation, and the like).
"Unsaturated heterocyclic" refers to non-aromatic heterocycles of
single or multiple condensed rings having unsaturation in any ring (e.g.,
carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to
nitrogen unsaturation, and the like).
"Substituted heterocyclic" refers to heterocycle groups which are
substituted with from 1 to 3 substituents selected from the group consisting
of oxo (=O), thioxo (=S), alkoxy, substituted alkoxy, acyl, acylamino,
thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino,
aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,
aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,
carboxyl,
carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-
substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl,
carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,
guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,
thioaryl,
substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl,
thioheteroaryl,
*rB

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substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic,
heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,
cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted
heteroaryloxy, heterocyciyloxy, substituted heterocyclyloxy,
oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(O)2-
substituted alkyl, -OS(O)Z-aryl, -OS(O)2 substituted aryl, -OS(O)z-heteroaryl,
-OS(O)2-substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O)Z-substituted
heterocyclic, -OSOz-NRR where R is hydrogen or alkyl, -NRS(O)Z-alkyl,
-NRS(O)2-substituted alkyl, -NRS(O)z-aryl, -NRS(O)2-substituted aryl,
-NRS(O)2-heteroaryl, -NRS(O)Z-substituted heteroaryl, -NRS(O)z-
heterocyclic, -NRS(O)Z-substituted heterocyclic, -NRS(O)z-NR-alkyl,
-NRS(012-NR-substituted alkyl, -NRS(O)Z-NR-aryl, -NRS{O)z-NR-substituted
aryl, -NRS(O)2-NR-heteroaryl, -NRS(O)z-NR-substituted heteroaryl,
-NRS(O)2-NR-heterocyclic, -NRS(O)2-NR-substituted heterocyclic where R is
hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,
mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,
mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic
amino, unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic and
substituted alkynyl groups having amino groups blocked by conventional
blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted
alkynyl groups substituted with -SOZ-alkyl, -SOZ-substituted alkyl, -SOz-
alkenyl, -SOZ-substituted alkenyl, -SOZ-cycloalkyl, -SOz-substituted
cycloalkyl, -S02-aryl, -SO~-substituted aryl, -SOZ-heteroaryl, -SOZ-
substituted
heteroaryl, -SOz-heterocyclic, -S02-substituted heterocyclic and -SOzNRR
where R is hydrogen or alkyl.
Examples of heterocycles and heteroaryls include, but are not limited
to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,
pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine,
*rB

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quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,
quinoxaline, quinazoline, cinnoiine, pteridine, carbazole, carboline,
phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole,
phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine,
piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-
tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,
benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine,
tetrahydrofuranyl, and the like.
"Saturated substituted heterocyclic" refers to substituted heterocycles
of single or multiple condensed rings lacking unsaturation in any ring (e.g.,
carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to
nitrogen unsaturation, and the like).
"Unsaturated substituted heterocyclic" refers to non-aromatic
substituted heterocycles of single or multiple condensed rings having
unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to
nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).
"Heterocyclyloxy" refers to the group -O-heterocyclic and "substituted
heterocyclyloxy" refers to the group -4-substituted heterocyclic.
"Substituted alkylcarbonylamino" refers to the group -NHC(O)-
substituted alkyl.
"Thiol" refers to the group -SH.
"Thioalkyl" refers to the group -S-alkyl.
"Substituted thioalkyl" refers to the group -S-substituted alkyl.
"Thiocycloalkyl" refers to the groups -S-cycloalkyl.

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"Substituted thiocycloalkyl" refers to the group -S-substituted
cycloalkyl.
"Thioaryl" refers to the group -S-aryl and "substituted thioaryl" refers t
the group -S-substituted aryl.
"Thioheteroaryl" refers to the group -S-heteroaryl and "substituted
thioheteroaryl" refers to the group -S-substituted heteroaryl.
"Thioheterocyclic" refers to the group -S-heterocyclic and "substituted
thioheterocyclic" refers to the group -S-substituted heterocyclic.
"Pharmaceutically acceptable salt" refers to pharmaceutically
acceptable salts of a compound of Formula I which salts are derived from a
variety of organic and inorganic counter ions well known in the art and
include, by way of example only, sodium, potassium, calcium, magnesium,
ammonium, tetraalkylammonium, and the like; and when the molecule
contains a basic functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and
the like.
The compounds of this invention can be prepared from readily
available starting materials using the following general methods and
procedures. It will be appreciated that where typical or preferred process
conditions (i.e., reaction temperatures, times, mole ratios of reactants,
solvents, pressures, etc.) are given, other process conditions can also be
used
unless otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvent used, but such conditions can be determined by
one skilled in the art by routine optimization procedures.

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Additionally, as will be apparent to those skilled in the art,
conventional protecting groups may be necessary to prevent certain functional
groups from undergoing undesired reactions. Suitable protecting groups for
various functional groups as well as suitable conditions for protecting and
deprotecting particular functional groups .are well known in the art. For
example, numerous protecting groups are described in T. W. Greene and G.
M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley,
New York, 1991, and references cited therein.
Furthermore, the compounds of this invention will typically contain
one or more chiral centers. Accordingly, if desired, such compounds can be
prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or
diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers
(and enriched mixtures) are included within the scope of this invention,
unless
otherwise indicated. Pure stereoisomers (or enriched mixtures) may be
prepared using, for example, optically active starting materials or
stereoselective reagents well-known in the art. Alternatively, racemic
mixtures of such compounds can be separated using, for example, chiral
column chromatography, chiral resolving agents and the like.
In a preferred method of synthesis, the compounds of formula I and IA
wherein Q is -C{O)NR'- are prepared by first coupling an amino acid of
formula II:
R3
Rz-NH-CH-COOH II
wherein R2, R3 and R4 are as defined above, with a sulfonyl chloride of
formula III:
*rB

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__
R'-SOz-C1 III
wherein R' is as defined above, to provide an N sulfonyl amino acid of
formula IV:
S
R'
R'-SOz-N(Rz)-CH-COOH IV
wherein R'-R3 are as defined above.
This reaction is typically conducted by contacting the amino acid of
formula II with at least one equivalent, preferably about 1.1 to about 2
equivalents, of sulfonyl chloride III in an inert diluent such as
dichloromethane and the like. Generally, the reaction is conducted at a
temperature ranging from about -70°C to about 40°C for about 1
to about 24
hours. Preferably, this reaction is conducted in the presence of a suitable
base
to scavenge the acid generated during the reaction. Suitable bases include, by
way of example, tertiary amines, such as triethylamine, diisopropylethyiamine,
N methylmorpholine and the like. Alternatively, the reaction can be
conducted under Schotten-Baumann-type conditions using aqueous alkali,
such as sodium hydroxide and the like, as the base. Upon completion of the
reaction, the resulting N sulfonyl amino acid IV is recovered by conventional
methods including neutralization, extraction, precipitation, chromatography,
filtration, and the like.
The amino acids of formula II employed in the above reaction are
either known compounds or compounds that can be prepared from known
compounds by conventional synthetic procedures. Examples of suitable
amino acids for use in this reaction include, but are not limited to, L-
proline,
traps-4-hydroxyl-L-proline, cis-4-hydroxyl-L-proline, traps-3-phenyl-L-
proline, cis-3-phenyl-L-proline, L-(2-methyl)proline, L-pipecolinic acid, L-

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__ ~g _-
azetidine-2-carboxylic acid, L-indoline-2-carboxylic acid, L-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-
(5,5-dimethyl)thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic
acid, glycine, 2-tert-butylglycine, D,L-phenylglycine, L-alanine, a-
methylalanine, N methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D,L-
phenylsarcosine, L-aspartic acid ~3-tert-butyl ester, L-glutamic acid ~y-tert-
butyl ester, L-(O-benzyl)serine, 1-aminocyclopropanecarboxylic acid, 1-
aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid
(cycloleucine) 1-aminocyclohexanecarboxylic acid, L-serine and the like. If
desired, the corresponding carboxylic acid esters of the amino acids of
formula
II, such as the methyl esters, ethyl esters and the like, can be employed in
the
above reaction with~the sulfonyl chloride III. Subsequent hydrolysis of the
ester group to the carboxylic acid using conventional reagents and conditions,
i.e., treatment with an alkali metal hydroxide in an inert diluent such as
methanol/water, then provides the N sulfonyl amino acid IV.
Similarly, the sulfonyl chlorides of formula III employed in the above
reaction are either known compounds or compounds that can be prepared from
known compounds by conventional synthetic procedures. Such compounds
are typically prepared from the corresponding sulfonic acid, i.e., from
compounds of the formula R'-S03H where R' is as defined above, using
phosphorous trichloride and phosphorous pentachloride. This reaction is
generally conducted by contacting the sulfonic acid with about 2 to 5 molar
equivalents of phosphorous trichloride and phosphorous pentachloride, either
neat or in an inert solvent, such as dichloromethane, at temperature in the
range of about 0°C to about 80°C for about 1 to about 48 hours
to afford the
sulfonyl chloride. Alternatively, the sulfonyl chlorides of formula III can be
prepared from the corresponding thiol compound, i.e., from compounds of the
formula R'-SH where R' is as defined above, by treating the thiol with
chlorine (C12) and water under conventional reaction conditions.

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__
Examples of sulfonyl chlorides suitable for use in this invention
include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl
chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, 1-
naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-
toluenesulfonyl chloride, a-toluenesulfonyl chloride, 4-
acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4-
tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2-
carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4-
dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 3,4-
dimethoxybenzenesulfonyl chloride, 3,5-ditrifluoromethylbenzenesulfonyl
chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl
chloride, 2-methoxycarbonylbenzenesulfonyl chloride, 4-
methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-
thioamidobenzenesulfonyl chloride, 4-trifluoromethylbenzenesulfonyl
1 S chloride, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,6-
trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-
thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonyl chloride, 2,5-
dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonyl chloride, 2-methyl-
4-thiazolesulfonyl chloride, 1-methyl-4-imidazolesulfonyl chloride, 1-methyl-
4-pyrazolesulfonyl chloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl
chloride, 3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride, and the
like. If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acid
anhydride may be used in place of the sulfonyl chloride in the above reaction
to. form the N sulfonyl amino acids of formula IV.
The intermediate N sulfonyl amino acids of formula IV can also be
prepared by reacting a sulfonamide of formula V:
R'-SOZ-NH-Rz V

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__ g0 -_
wherein R~ and RZ are as defined above, with a carboxylic acid derivative of
the formula L(R3)CHCOOR where L is a leaving group, such as chloro,
bromo, iodo, mesylate, tosylate and the like, R3 is as defined above and R is
hydrogen or an alkyl group. This reaction is typically conducted by contacting
S the sulfonamide V with at least one equivalent, preferably 1.1 to 2
equivalents,
of the carboxylic acid derivative in the presence of a suitable base, such as
triethylamine, in an inert diluent, such as DMF, at a temperature ranging from
about 24°C to about 37°C for about 0.5 to about 4 hours. This
reaction is
further described in Zuckermann et al., J. Am. Chem. Soc., 1992, 114, 10646-
10647. Preferred carboxylic acid derivatives for use in this reaction are a-
chloro and a-bromocarboxylic acid esters such as tert-butyl bromaacetate, and
the like. When an carboxylic acid ester is employed in this reaction, the
ester
group is subsequently hydrolyzed using conventional procedures to afford an
N sulfonyl amino acid of formula IV.
The compounds of formula I are then prepared by coupling the
intermediate N sulfonyl amino acid of formula IV with an amino acid
derivative of formula VI:
O
II
R'-NH-CH-C-R6 V I
Rs
wherein Rs-R' are as defined above. This coupling reaction is typically
conducted using well-known coupling reagents such as carbodiimides, BOP
reagent (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphonate) and the like. Suitable carbodiimides include, by way
of example, dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide (EDC) and the like. If desired, polymer supported forms of
carbodiimide coupling reagents may also be used including, for example,
those described in Tetrahedron Letters, 34(48), 7685 (1993). Additionally,

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__ g 1 __
well-known coupling promoters, such as N-hydroxysuccinimide, 1-
hydroxybenzotriazole and the like, may be used to facilitate the coupling
reaction.
This coupling reaction is typically conducted by contacting the N
sulfonylamino acid IV with about 1 to about 2 equivalents of the coupling
reagent and at least one equivalent, preferably about 1 to about 1.2
equivalents, of amino acid derivative VI in an inert diluent, such as
dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N
dimethylformamide and the like. Generally, this reaction is conducted at a
temperature ranging from about 0°C to about 37°C for about 12 to
about 24
hours. Upon completion of the reaction, the compound of formula I is
recovered by conventional methods including neutralization, extraction,
precipitation, chromatography, filtration, and the like.
Alternatively, the N sulfonyl amino acid IV can be converted into an
acid halide and the acid halide coupled with amino acid derivative VI to
provide compounds of formula I. The acid halide of VI can be prepared by
contacting VI with an inorganic acid halide, such as thionyl chloride,
phosphorous trichloride, phosphorous tribromide or phosphorous
pentachloride, or preferably, with oxalyl chloride under conventional
conditions. Generally, this reaction is conducted using about 1 to 5 molar
equivalents of the inorganic acid halide or oxalyi chloride, either neat or in
an
inert solvent, such as dichloromethane or carbon tetrachloride, at temperature
in the range of about 0°C to about 80°C for about 1 to about 48
hours. A
catalyst, such as N,N dimethylformamide, may also be used in this reaction.
The acid halide of N-sulfonyl amino acid IV is then contacted with at
least one equivalent, preferably about 1.1 to about 1.5 equivalents, of amino
acid derivative VI in an inert diluent, such as dichloromethane, at a
temperature ranging from about -70°C to about 40°C for about 1
to about 24
hours. Preferably, this reaction is conducted in the presence of a suitable
base

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__ g2 __
to scavenge the acid generated during the reaction. Suitable bases include, by
way of example, tertiary amines, such as triethylamine, diisopropylethylamine,
N methylmorpholine and the like. Alternatively, the reaction can be
conducted under Schotten-Baumann-type conditions using aqueous alkali,
such as sodium hydroxide and the like. Upon completion of the reaction, the
compound of formula I is recovered by conventional methods including
neutralization, extraction, precipitation, chromatography, f ltration, and the
like.
Alternatively, the compounds of formula I can be prepared by first
forming a diamino acid derivative of formula VII:
R' R' O
( I II
Rz-NH-CH-C(O)N-CH-C-R6 VII
Rs
wherein RZ, R3 and Rs - R' are as defined above. The diamino acid derivatives
of formula VII can be readily prepared by coupling an amino acid of formula
II with an amino acid derivative of formula VI using conventional amino acid
coupling techniques and reagents, such carbodiimides, BOP reagent and the
like, as described above. Diamino acid VII can then be sulfonated using a
sulfonyl chloride of formula III and using the synthetic procedures described
above to provide a compound of formula I.
The amino acid derivatives of formula VI employed in the above
reactions are either known compounds or compounds that can be prepared
from known compounds by conventional synthetic procedures. For example,
amino acid derivatives of formula VI can be prepared by C-alkylating
commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee,
Wisconsin, USA) with an alkyl or substituted alkyl halide. This reaction is
typically conducted by treating the diethyl 2-acetamidomalonate with at least

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__ g3 __
one equivalent of sodium ethoxide and at least one equivalent of an alkyl or
substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours.
The
resulting C-alkylated malonate is then deacetylated, hydrolyzed and
decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6
to about 12 hours to provide the amino acid, typically as the hydrochloride
salt.
Examples of amino acid derivatives of formula VI suitable for use in
the above reactions include, but are not limited to, L-4-nitrophenylalanine
methyl ester, L-tyrosine methyl ester, D,L-homo-4-nitrophenylalanine methyl
ester, L-(O-benzyl)tyrosine methyl ester, L-3,5-diiodotyrosine methyl ester, L-
3-iodotyrosine methyl ester and the like. If desired, of course, other esters
or
amides of the above-described compounds may also be employed.
For ease of synthesis, the compounds of formula I are typically
prepared as an ester, i.e., where R6 is an alkoxy or substituted alkoxy group
and the like. If desired, the ester group can be hydrolysed using conventional
conditions and reagents to provide the corresponding carboxylic acid.
Typically, this reaction is conducted by treating the ester with at least one
equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium
hydroxide, in an inert diluent, such as methanol or mixtures of methanol and
water, at a temperature ranging about 0°C to about 24°C for
about 1 to about
12 hours, Alternatively, benzyl esters may be removed by hydrogenolysis
using a palladium catalyst, such as palladium on carbon. The resulting
carboxylic acids may be coupled, if desired, to amines such as ~i-alanine
ethyl
ester, hydroxyamines such as hydroxylamine and N hydroxysuccinimide,
alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamine
and O-benzylhydroxylamine, and the like, using conventional coupling
reagents and conditions as described above.
As will be apparent to those skilled in the art, other functional groups
present on any of the substituents of the compounds of formula I can be

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__ g4 __
readily modified or derivatized either before or after the above-described
coupling reactions using well-known synthetic procedures. For example, a
nitro group present on a substituent of a compound of formula I or an
intermediate thereof may be readily reduced by hydrogenation in the presence
of a palladium catalyst, such as palladium on carbon, to provide the
corresponding amino group. This rea;,tion is typically conducted at a
temperature of from about 20°C to about 50°C for about 6 to
about 24 hours
in an inert diluent, such as methanol. Compounds having a nitro group on the
RS substituent can be prepared, for example, by using a 4-nitrophenylalanine
derivative and the like in the above-described coupling reactions.
Similarly, a pyridyl group can be hydrogenated in the presence of a
platinum catalyst, such as platinum oxide, in an acidic diluent to provide the
corresponding piperidinyl analogue. Generally, this reaction is conducted by
treating the pyridine compound with hydrogen at a pressure ranging from
about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the
catalyst at a temperature of about 20°C to about 50°C for about
2 to about 24
hours in an acidic diluent, such as a mixture of methanol and aqueous
hydrochloric acid. Compounds having a pyridyl group can be readily prepared
by using, for example, (i-(2-pyridyl)-, ~3-(3-pyridyl)- or (3-(4-pyridyl)-L
alanine derivatives in the above-described coupling reactions.
Additionally, when the RS substituent of a compound of formula I or an
intermediate thereof contains a primary or secondary amino group, such amino
groups can be further derivatized either before or after the above coupling
reactions to provide, by way of example, amides, sulfonamides, ureas,
thioureas, carbamates, secondary or tertiary amines and the like. Compounds
having a primary amino group on the RS substituent may be prepared, for
example, by reduction of the corresponding nitro compound as described
above. Alternatively, such compounds can be prepared by using an amino
acid derivative of formula VI derived from lysine, 4-aminophenylalanine and
the like in the above-described coupling reactions.

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__ gs __
By way of illustration, a compound of formula I or an intermediate
thereof having a substituent containing a primary or secondary amino group,
such as where RS is a (4-aminophenyl)methyl group, can be readily N acylated
using conventional acylating reagents and conditions to provide the
corresponding amide. This acylation reaction is typically conducted by
treating the amino compound with at least one equivalent, preferably about 1.1
to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling
reagent such as a carbodiimide, BOP reagent (benzotriazol-1-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphonate) and the like, in an
inert diluent, such as dichloromethane, chloroform, acetonitrile,
tetrahydrofuran, N,N dimethylformamide and the like, at a temperature
ranging from about 0°C to about 37°C for about 4 to about 24
hours.
Preferably, a promoter, such as N hydroxysuccinimide, 1-hydroxy-
benzotriazole and the like, is used to facilitate the acylation reaction.
Examples of carboxylic acids suitable for use in this reaction include, but
are
not limited to, N tert-butyloxycarbonylglycine, N tert-butyloxycarbonyl-L-
phenylalanine, N tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic
acid, N tert-butyloxycarbonylisonipecotic acid, N methylisonipecotic acid, N-
tert-butyloxycarbonylnipecotic acid, N tert-butyloxycarbonyl-L-
tetrahydroisoquinoline-3-carboxylic acid, N (toluene-4-sulfonyl)-L-proline
and the like.
Alternatively, a compound of formula I or an intermediate thereof
containing a primary or secondary amino group can be N acylated using an
acyl halide or a carboxylic acid anhydride to form the corresponding amide.
This reaction is typically conducted by contacting the amino compound with
at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the
acyl halide or carboxylic acid anhydride in an inert diluent, such as
dichloromethane, at a temperature ranging from about of about -70°C to
about
40°C for about 1 to about 24 hours. If desired, an acylation catalyst
such as 4-
(N,N dimethylamino)pyridine may be used to promote the acylation reaction.
The acylation reaction is preferably conducted in the presence of a suitable

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base to scavenge the acid generated during the reaction. Suitable bases
include, by way of example, tertiary amines, such as triethylamine,
diisopropylethylamine, N methylmorpholine and the like. Alternatively, the
reaction can be conducted under Schotten-Baumann-type conditions using
aqueous alkali, such as sodium hydroxide and the like.
Examples of acyl halides and carboxylic acid anhydrides suitable for
use in this reaction include, but are not limited to, 2-methyipropionyl
chloride,
trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-
bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoro-methylbenzoyl
chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride,
acetic
anhydride, succinic anhydride, and the like. Carbamyl chlorides, such as N,N
dimethylcarbamyl chloride, N,N diethylcarbamyl chloride and the like, can
also be used in this reaction to provide ureas. Similarly, dicarbonates, such
as
di-tert-butyl dicarbonate, may be employed to provide carbamates.
In a similar manner, a compound of formula I or an intermediate
thereof containing a primary or secondary amino group may be N sulfonated
to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride.
Sulfonyl halides and sulfonic acid anhydrides suitable for use in this
reaction
include, but are not limited to, methanesulfonyl chloride,
chloromethanesulfonyl chloride, p-toluenesulfonyl chloride,
trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl
chlorides, such as dimethylsulfamoyl chloride, can be used to provide
sulfamides (e.g., >N-SOz N<).
Additionally, a primary and secondary amino group present on a
substituent of a compound of formula I or an intermediate thereof can be
reacted with an isocyanate or a thioisocyanate to give a urea or thiourea,
respectively. This reaction is typically conducted by contacting the amino
compound with at least one equivalent, preferably about 1.1 to about 1.2
equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as

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toluene and the like, at a temperature ranging from about 24°C to about
37°C
for about 12 to about 24 hours. The isocyanates and thioisocyanates used in
this reaction are commercially available or can be prepared from commercially
available compounds using well-known synthetic procedures. For example,
S isocyanates and thioisocyanates are readily prepared by reacting the
appropriate amine with phosgene or thiop:~osgene. Examples of isocyanates
and thioisocyanates suitable for use in this reaction include, but are not
limited
to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-
methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate,
ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl
thioisocyanate, 3-(N,N diethylamino)propyl thioisocyanate, phenyl
thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein
isothiocyanate (isomer I) and the like.
Furthermore, when a compound of formula I or an intermediate thereof
contains a primary or secondary amino group, the amino group can be
reductively alkylated using aldehydes or ketones to form a secondary or
tertiary amino group. This reaction is typically conducted by contacting the
amino compound with at least one equivalent, preferably about 1.1 to about
1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on
the amino compound of a metal hydride reducing agent, such as sodium
cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran,
mixtures thereof and the like, at a temperature ranging from about 0°C
to
about 50°C for about 1 to about 72 hours. Aldehydes and ketones
suitable for
use in this reaction include, by way of example, benzaldehyde, 4-
chlorobenzaldehyde, valeraldehyde and the like.
In a similar manner, when a compound of formula I or an intermediate
thereof has a substituent containing a hydroxyl group, the hydroxyl group can
be further modified or derivatized either before or after the above coupling
reactions to provide, by way of example, ethers, carbamates and the like.
Compounds having a hydroxyl group on the RS substituent, for example, can

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be prepared using an amino acid derivative of formula VI derived from
tyrosine and the like in the above-described reactions.
By way of example, a compound of formula I or an intermediate
thereof having a substituent containing a hydroxyl group, such as where R5 is
a (4-hydroxyphenyl)methyl group, can be readily O-alkylated to form ethers.
This O-alkylation reaction is typically conducted by contacting the hydroxy
compound with a suitable alkali or alkaline earth metal base, such as
potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the
like, to form the alkali or alkaline earth metal salt of the hydroxyl group.
This
salt is generally not isolated, but is reacted in situ with at least one
equivalent
of an alkyl or substituted alkyl halide or sulfonate, such as an alkyl
chloride,
bromide, iodide, mesylate or tosylate, to afford the ether. Generally, this
reaction is conducted at a temperature ranging from about 60°C to about
150°C for about 24 to about 72 hours. Preferably, a catalytic amount of
sodium or potassium iodide is added to the reaction mixture when an alkyl
chloride or bromide is employed in the reaction.
Examples of alkyl or substituted alkyl halides and sulfonates suitable
for use in this reaction include, but are not limited to, tert-butyl
bromoacetate,
N tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl a-
bromophenylacetate, 2-(N ethyl-N-phenylamino)ethyl chloride, 2-(N,N
ethylamino)ethyl chloride, 2-(N,N diisopropylamino)ethyl chloride, 2-(N,N-
dibenzylamino)ethyl chloride, 3-(N,N ethylamino)propyl chloride, 3-(N-
benzyl-N-methylamino)propyl chloride, N (2-chloroethyl)morpholine, 2-
(hexamethyleneimino)ethyl chloride, 3-(N methylpiperazine)propyl chloride,
1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine, 2-(4-hydroxy-4-
phenylpiperidine)ethyl chloride, N tert-butyloxycarbonyl-3-piperidinemethyl
tosylate, and the like.
Alternatively, a hydroxyl group present on a substituent of a compound
of formula I or an intermediate thereof can be O-alkylating using the

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__ g9 _-
Mitsunobu reaction. In this reaction, an alcohol, such as 3-(N,N
dimethylamino)-I-propanol and the like, is reacted with about 1.0 to about 1.3
equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of
diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a
temperature ranging from about -10°C to about 5°C for about 0.25
to about 1
hour. About I.0 to about I .3 equivalents of a hydroxy compound, such as N
tert-butyltyrosine methyl ester, is then added and the reaction mixture is
stirred at a temperature of about 0°C to about 30°C for about 2
to about 48
hours to provide the O-alkylated product.
In a similar manner, a compound of formula I or an intermediate
thereof containing a aryl hydroxy group can be reacted with an aryl iodide to
provide a diaryl ether. Generally, this reaction is conducted by forming the
alkali metal salt of the hydroxyl group using a suitable base, such as sodium
hydride, in an inert diluent such as xylenes at a temperature of about -25
°C to
about 10°C. The salt is then treated with about I.1 to about 1.5
equivalents of
cuprous bromide dimethyl sulfide complex at a temperature ranging from
about 10°C to about 30°C for about 0.5 to about 2.0 hours,
followed by about
I .I to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate
and the like. The reaction is then heated to about 70°C to about
150°C for
about 2 to about 24 hours to provide the diaryl ether.
Additionally, a hydroxy-containing compound can also be readily
derivatized to form a carbamate. In one method for preparing such
carbamates, a hydroxy compound of formula I or an intermediate thereof is
contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl
chloroformate in an inert diluent, such as dichloromethane, at a temperature
ranging from about -25°C to about 0°C for about 0.5 to about 2.0
hours.
Treatment of the resulting carbonate with an excess, preferably about 2 to
about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5
to
2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or
secondary amine provides the carbamate. Examples of amines suitable for

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__ 90 -_
using in this reaction include, but are not limited to, piperazine, 1-
methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine,
pyrrolidine, piperidine and the like.
Alternatively, in another method for preparing carbamates, a hydroxy-
containing compound is contacted with about 1.0 to about 1.5 equivalents of a
carbamyl chloride in an inert diluent, such as dichloromethane, at a
temperature ranging from about 25°C to about 70°C for about 2 to
about 72
hours. Typically, this reaction is conducted in the presence of a suitable
base
to scavenge the acid generated during the reaction. Suitable bases include, by
way of example, tertiary amines, such as triethylamine, diisopropylethylamine,
N methylmorpholine and the like. Additionally, at least one equivalent (based
on the hydroxy compound) of 4-(N,N dimethylamino)pyridine is preferably
added to the reaction mixture to facilitate the reaction. Examples of carbamyl
1 S chlorides suitable for use in this reaction include, by way of example,
dimethylcarbamyl chloride, diethyicarbamyl chloride and the Like.
Likewise, when a compound of formula I or an intermediate thereof
contains a primary or secondary hydroxyl group, such hydroxyl groups can be
readily converted into a leaving group and displaced to form, for example,
amines, sulfides and fluorides. For example, derivatives of 4-hydroxy-L-
proline can be converted into the corresponding 4-amino, 4-thio or 4-fluoro-L-
proline derivatives via nucleophilic displacement of the derivatized hydroxyl
group. Generally, when a chiral compound is employed in these reactions, the
stereochemistry at the carbon atom attached to the derivatized hydroxyl group
is typically inverted.
These reactions are typically conducted by first converting the
hydroxyl group into a leaving group, such as a tosylate, by treatment of the
hydroxy compound with at least one equivalent of a sulfonyl halide, such as p-
toluenesulfonyl chloride and the like, in pyridine. This reaction is generally
conducted at a temperature of from about 0°C to about 70°C for
about 1 to

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about 48 hours. The resulting tosylate can then be readily displaced with
sodium azide, for example, by contacting the tosylate with at least one
equivalent of sodium azide in an inert diluent, such as a mixture of N,N
dimethylformamide and water, at a temperature ranging from about 0°C to
about 37°C for about 1 to about 12 hours to provide the corresponding
azido
compound. The azido group can then b~ reduced by, for example,
hydrogenation using a palladium on carbon catalyst to provide the amino (-
NHz) compound.
Similarly, a tosylate group can be readily displaced by a thiol to form a
sulfide. This reaction is typically conducted by contacting the tosylate with
at
least one equivalent of a thiol, such as thiophenal, in the presence of a
suitable
base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent,
such as N,N dimethylformamide, at a temperature of from about 0°C to
about
37°C for about 1 to about 12 hours to provide the sulfide.
Additionally,
treatment of a tosylate with molpholinosulfur trifluoride in an inert diluent,
such as dichloromethane, at a temperature ranging from about 0°C to
about
37°C for about i2 to about 24 hours affords the corresponding fluoro
compound.
Furthermore, a compound of formula I or an intermediate thereof
having a substituent containing an iodoaryl group, for example, when RS is a
(4-iodophenyl)methyl group, can be readily converted either before or after
the
above coupling reactions into a biaryl compound. Typically, this reaction is
conducted by treating the iodoaryl compound with about 1.1 to about 2
equivalents of an arylzinc iodide, such as 2-(methoxycarbonyl)phenylzinc
iodide, in the presence of a palladium catalyst, such as palladium
tetra(triphenylphosphine), in an inert diluent, such as tetrahydrofuran, at a
temperature ranging from about 24°C to about 30°C until reaction
completion. This reaction is further described, for example, in Rieke, J. Org.
Chem. 1991, 56, 1445.

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In some cases, the compounds of formula I or intermediates thereof
may contain substituents having one or more sulfur atoms. Such sulfur atoms
will be present, for example, when the amino acid of formula II employed in
the above reactions is derived from L-thiazolidine-4-carboxylic acid, L-(5,5-
dimethyl)thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic acid
and the like. When present, such sulfur atoms can be oxidized either before or
after the above coupling reactions to provide a sulfoxide or sulfone compound
using conventional reagents and reaction conditions. Suitable reagents for
oxidizing a sulfide compound to a sulfoxide include, by way of example,
hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate
and the like. The oxidation reaction is typically conducted by contacting the
sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing
reagent in an inert diluent, such as dichloromethane, at a temperature ranging
from about -50°C to about 75°C for about 1 to about 24 hours.
The resulting
suifoxide can then be further oxidized to the corresponding sulfone by
contacting the sulfoxide with at least one additional equivalent of an
oxidizing
reagent, such as hydrogen peroxide, MCPBA, potassium permanganate and
the like. Alternatively, the sulfone can be prepared directly by contacting
the
sulfide with at least two equivalents, and preferably an excess, of the
oxidizing
reagent. Such reactions are described further in March, "Advanced Organic
Chemistry", 4th Ed., pp. 1201-1202, Wiley Publisher, 1992.
As described above, the compounds of formula I having an RZ
substituent other an hydrogen can be prepared using an N-substituted amino
acid of formula II, such as sarcosine, N methyl-L-phenylalanine and the like,
in the above-described coupling reactions. Alternatively, such compounds can
be prepared by N alkylation of a sulfonamide of formula I or IV {where R~ is
hydrogen) using conventional synthetic procedures. Typically, this N-
alkylation reaction is conducted by contacting the sulfonamide with at least
one equivalent, preferably 1.1 to 2 equivalents, of an alkyl or substituted
alkyl
halide in the presence of a suitable base, such as potassium carbonate, in an
inert diluent, such as acetone, 2-butanone and the like, at a temperature

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ranging from about 25 °C to about 70°C for about 2 to about 48
hours.
Examples of alkyl or substituted alkyl halides suitable for use in this
reaction
include, but are not limited to, methyl iodide, and the like.
Additionally, the sulfonamides of formula I or IV wherein RZ is
hydrogen and R' is a 2-alkoxycarbonylaryl group can be intramolecularly
cyclized to form 1,2-benzisothiazol-3-one derivatives or analogues thereof.
This reaction is typically conducted by treating a sulfonamide, such as N-(2-
methoxycarbonylphenylsulfonyl)glycine-L-phenylalanine benzyl ester, with
about 1.0 to I .5 equivalents of a suitable base, such as an alkali metal
hydride,
in a inert diluent, such as tetrahydrofuran, at a temperature ranging from
about
0°C to about 30°C for about 2 to about 48 hours to afford the
cyclized I,2-
benzisothiazol-3-one derivative.
Lastly, the compounds of formula I where Q is -C(S)NR'- are can
prepared by using an amino thionoacid derivative in place of amino acid II in
the above described synthetic procedures. Such amino thionoacid derivatives
can be prepared by the procedures described in Shalaky, et al., J. Org. Chem.,
0.1:9045-9048 (199b) and Brain, et al., J. Org. Chem., (2:3808-3809 (1997)
and references cited therein.
When employed as pharmaceuticals, the compounds of formula I and
IA are usually administered in the form of pharmaceutical compositions.
These compounds can be administered by a variety of routes including oral,
rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
These compounds are effective as both injectable and oral compositions. Such
compositions are prepared in a manner well known in the pharmaceutical art
and comprise at least one active compound.
This invention also includes pharmaceutical compositions which
contain, as the active ingredient, one or more of the compounds of formula I

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and IA above associated with pharmaceutically acceptable carriers. In making
the compositions of this invention, the active ingredient is usually mixed
with
an excipient, diluted by an excipient or enclosed within such a carrier which
can be in the fonm of a capsule, sachet, paper or other container. When the
excipient serves as a diluent, it can be a solid, semi-solid, or liquid
material,
which acts as a vehicle, carrier or medium for the active ingredient. Thus,
the
compositions can be in the form of tablets, pills, powders, lozenges, sachets,
cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid
or in a liquid medium), ointments containing, for example, up to 10% by
weight of the active compound, soft and hard gelatin capsules, suppositories,
sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active
compound to provide the appropriate particle size prior to combining with the
other ingredients. If the active compound is substantially insoluble, it
ordinarily is milled to a particle size of less than 200 mesh. If the active
compound is substantially water soluble, the particle size is normally
adjusted
by milling to provide a substantially uniform distribution in the formulation,
e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose,
sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose,
polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as talc,
magnesium stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and propylhydroxy-
benzoates; sweetening agents; and flavoring agents. The compositions of the
invention can be formulated so as to provide quick, sustained or delayed
release of the active ingredient after administration to the patient by
employing procedures known in the art.

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The compositions are preferably formulated in a unit dosage form,
each dosage containing from about 5 to about 100 mg, more usually about 10
to about 30 mg, of the active ingredient. The term "unit dosage forms" refers
to physically discrete units suitable as unitary dosages for human subjects
and
other mammals, each unit containing a predetermined quantity of active
material calculated to prodace the desir°d therapeutic effect, in
association
with a suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range and is
generally administered in a pharmaceutically effective amount. It, will be
understood, however, that the amount of the compound actually administered
will be determined by a physician, in the light of the relevant circumstances,
including the condition to be treated, the chosen route of administration, the
actual compound administered, the age, weight, and response of the individual
patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical excipient to form a solid
preformulation composition containing a homogeneous mixture of a
compound of the present invention. When referring to these preformulation
compositions as homogeneous, it is meant that the active ingredient is
dispersed evenly throughout the composition so that the composition may be
readily subdivided into equally effective unit dosage forms such as tablets,
pills and capsules. This solid prefonnulation is then subdivided into unit
dosage forms of the type described above containing from, for example, 0.1 to
about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise
compounded to provide a dosage form affording the advantage of prolonged
action. For example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope over the
former. The two components can separated by enteric layer which serves to
*rB

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resist disintegration in the stomach and permit the inner component to pass
intact into the duodenum or to be delayed in release. A variety of materials
can be used for such enteric layers or coatings, such materials including a
number of polymeric acids and mixtures of polymeric acids with such
materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present
invention may be incorporated for administration orally or by injection
include
aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and
flavored emulsions with edible oils such as cottonseed oil, sesame oil,
coconut
oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and
suspensions in pharmaceutically acceptable, aqueous or organic solvents, or
mixtures thereof, and powders. The liquid or solid compositions may contain
suitable pharmaceutically acceptable excipients as described supra. Preferably
the compositions are administered by the oral or nasal respiratory route for
local or systemic effect. Compositions in preferably pharmaceutically
acceptable solvents may be nebulized by use of inert gases. Nebulized
solutions may be breathed directly from the nebulizing device or the
nebulizing device may be attached to a face masks tent, or intermittent
positive pressure breathing machine. Solution, suspension, or powder
compositions may be administered, preferably orally or nasally, from devices
which deliver the formulation in an appropriate manner.
The following formulation examples illustrate the pharmaceutical
compositions of the present invention.
Hard gelatin capsules containing the following ingredients are
prepared:

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Quantity
Active Ingredient 30.0
Starch 305.0
Magnesium stearate 5.0
The above ingredients are mixed and filled into hard gelatin capsules
in 340 mg quantities.
A tablet formula is prepared using the ingredients below:
Quantity
,~bletl
Active Ingredient 25.0
Cellulose, microcrystalline 200.0
Colloidal silicon dioxide 10.0
Stearic acid 5.0
The components are blended and compressed to form tablets, each
weighing 240 mg.
Formulation Exam lm a 3
A dry powder inhaler formulation is prepared containing the following
components:
Wei t
Active Ingredient
Lactose 95
The active mixture is mixed with the lactose and the mixture is added
to a dry powder inhaling appliance.
Fnrmulati~n .xam~t_e 4
Tablets, each containing 30 mg of active ingredient, are prepared as
follows:

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Quantity
IrigL~1~11t ~111g(ta
Active Ingredient 30.0 mg
Starch 45.0 mg
Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone
(as 10% solution in water) 4.0 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1.0 mo
Total 120 mg
The active ingredient, starch and cellulose are passed through a No. 20
mesh U.S. sieve and mixed thoroughly. The solution of polyvinyl-pyrrolidone
is mixed with the resultant powders, which are then passed through a 16 mesh
U.S. sieve. The granules so produced are dried at 50° to
60°C and passed
through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium
stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are
then added to the granules which, after mixing, are compressed on a tablet
machine to yield tablets each weighing 150 mg.
Form_~ lation ,xa~ ln~_e 5
Capsules, each containing 40 mg of medicament are made as follows:
Quantity
Ing>~snt (gig/-ERs ~- l~e~
Active Ingredient 40.0 mg
Starch 109.0 mg
Magnesium stearate 1.0 mo
Total 150.0 mg
The active ingredient, cellulose, starch, an magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin
capsules in 150 mg quantities.

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Suppositories, each containing 25 mg of active ingredient are made as
follows:
Active Ingredient 25 mg
Saturated fatty acid glycerides to 2,000 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve and
suspended in the saturated fatty acid glycerides previously melted using the
minimum heat necessary. The mixture is then poured into a suppository mold
of nominal 2.0 g capacity and allowed to cool.
Formulation Example 77
Suspensions, each containing 50 mg of medicament per 5.0 ml dose are
made as follows:
Active Ingredient 50.0 mg
Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose ( 11
%)
Microcrystalline cellulose (89%) 50.0 mg
Sucrose 1.75 g
Sodium benzoate 10.0 mg
Flavor and Color q.v.
Purified water to 5.0 ml
The medicament, sucrose and xanthan gum are blended, passed through a
No. 10 mesh U.S. sieve, and then mixed with a previously made solution of
the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
The sodium benzoate, flavor, and color are diluted with some of the water and
added with stirring. Sufficient water is then added to produce the required
volume.

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Quantity
'(mg/s=a~='~
Active Ingredient 15.0 mg
Starch 407.0 mg
Magnesium stearate 3_
Total 425.0 mg
The active ingredient, cellulose, starch, and magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin
capsules in 560 mg quantities.
Formulation Examu_l~-9_
An intravenous formulation may be prepared as follows:
Active Ingredient 250.0 mg
Isotonic saline 1000 ml
l~e~
A topical formulation may be prepared as follows:
L~di~nt Q.~anti>~
Active Ingredient 1-10 g
Emulsifying Wax 30 g
Liquid Paraffin 20 g
White Soft Paraffin to 100 g
The white soft paraffin is heated until molten. The liquid paraffin and
emulsifying wax are incorporated and stirred until dissolved. The active
ingredient is added and stirring is continued until dispersed. The mixture is
then cooled until solid.
Another preferred formulation employed in the methods of the present
invention employs transdermal delivery devices ("patches"). Such transdermal

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patches may be used to provide continuous or discontinuous infusion of the
compounds of the present invention in controlled amounts. The construction
and use of transdermal patches for the delivery of pharmaceutical agents is
well known in the art. ~, U.S. Patent s,023,2s2, issued June 11, 1991,
s herein incorporated by reference. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical agents.
When it is desirable or necessary to introduce the pharmaceutical
composition to the brain, either directly or indirectly. Direct techniques
usually involve placement of a drug delivery catheter into the host's
ventricular system to bypass the blood-brain barrier. One such implantable
delivery system used for the transport of biological factors to specific
anatomical regions of the body is described in U.S. Patent 5,011,472 which is
herein incorporated by reference.
is
Indirect techniques, which are generally preferred, usually involve
formulating the compositions to provide for drug latentiation by the
conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is
generally achieved through blocking of the hydroxy, carbonyl, sulfate, and
primary amine groups present on the drug to render the drug more lipid
soluble and amenable to transportation across the blood-brain barner.
Alternatively, the delivery of hydrophilic drugs may be enhanced by
intra-arterial infusion of hypertonic solutions which can transiently open the
blood-brain barrier.
zs
Lrtitit~
The compounds of this invention can be employed to bind VLA-4 (a4(3,
integrin) in biological samples and, accordingly have utility in, for example,
assaying such samples for VLA-4. In such assays, the compounds can be
bound to a solid support and the VLA-4 sample added thereto. The amount of
VLA-4 in the sample can be determined by conventional methods such as use
of a sandwich ELISA assay. Alternatively, labeled VLA-4 can be used in a

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competitive assay to measure for the presence of VLA-4 in the sample. Other
suitable assays are well known in the art.
In addition, certain of the compounds of this invention inhibit, in vivo,
adhesion of leukocytes to endothelial cells mediated by VLA-4 and,
accordingly, can be used in the treatment of diseases mediated by VLA-4.
Such diseases include inflammatory diseases in mammalian patients
such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes
(including acute juvenile onset diabetes), inflammatory bowel disease
(including ulcerative colitis and Crohn's disease), multiple sclerosis,
rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis,
encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic
dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung
injury such as that which occurs in adult respiratory distress syndrome.
The biological activity of the compounds identified above may be assayed
in a variety of systems. For example, a compound can be immobilized on a
solid surface and adhesion of cells expressing VLA-4 can be measured. Using
such formats, large numbers of compounds can be screened. Cells suitable for
this assay include any leukocytes known to express VLA-4 such as T cells, B
cells, monocytes, eosinophils, and basophils. A number of leukocyte cell lines
can also be used, examples include Jurkat and 0937.
The test compounds can also be tested for the ability to competitively
inhibit binding between VLA-4 and VCAM-1, or between VLA-4 and a
labeled compound known to bind VLA-4 such as a compound of this
invention or antibodies to VLA-4. In these assays, the VCAM-1 can be
immobilized on a solid surface. VCAM-1 may also be expressed as a
recombinant fusion protein having an Ig tail (e.g., IgG) so that binding to
VLA-4 may be detected in an immunoassay. Alternatively, VCAM-1
expressing cells, such as activated endothelial cells or VCAM-1 transfected
fibroblasts can be used. For assays to measure the ability to block adhesion
to

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brain endothelial cells, the assays described in International Patent
Application
Publication No. WO 91/05038 are particularly preferred. This application is
incorporated herein by reference in its entirety.
Many assay formats employ labelled assay components. The labelling
systems can be in a variety of forms. T'~e label may be coupled directly or
indirectly to the desired component of the assay according to methods well
known in the art. A wide variety of labels may be used. The component may
be labelled by any one of several methods. The most common method of
detection is the use of autoradiography with'H, ~'SI,'SS, ~~C, or'zP labelled
compounds or the like. Non-radioactive labels include ligands which bind to
labelled antibodies, fluorophores, chemiluminescent agents, enzymes and
antibodies which can serve as specific binding pair members for a labelled
ligand. The choice of label depends on sensitivity required, ease of
conjugation with the compound, stability requirements, and available
instrumentation.
Appropriate in vivo models for demonstrating efficacy in treating
inflammatory responses include EAE (experimental autoimmune
encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other
inflammatory models dependent upon a4 integrins.
Compounds having the desired biological activity may be modified as
necessary to provide desired properties such as improved pharmacological
properties (e.g., in vivo stability, bio-availability), or the ability to be
detected
in diagnostic applications. For instance, inclusion of one or more D-amino
acids in the sulfonamides of this invention typically increases in vivo
stability.
Stability can be assayed in a variety of ways such as by measuring the half
life
of the proteins during incubation with peptidases or human plasma or serum.
A number of such protein stability assays have been described {see, e.g.,
Verhoef, et al., Eur. J. Drug Metab. Pharmacokinet., 1990,1~.2~:83-93).

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For diagnostic purposes, a wide variety of labels may be linked to the
compounds, which may provide, directly or indirectly, a detectable signal.
Thus, the compounds of the subject invention may be modified in a variety of
ways for a variety of end purposes while still retaining biological activity.
In
addition, various reactive sites may be introduced at the terminus for linking
to
particles, solid substrates, macromolecules, or the like.
Labeled compounds can be used in a variety of in vivo or in vitro
applications. A wide variety of labels may be employed, such as radionuclides
(e.g., gamma-emitting radioisotopes such as technetium-99 or indium-111),
fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors,
enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds,
and the like.. Those of ordinary skill in the art will know of other suitable
labels for binding to the complexes, or will be able to ascertain such using
routine experimentation. The binding of these labels is achieved using
standard techniques common to those of ordinary skill in the art.
In vitro uses include diagnostic applications such as monitoring
inflammatory responses by detecting the presence of leukocytes expressing
VLA-4. The compounds of this invention can also be used for isolating or
labeling such cells. In addition, as mentioned above, the compounds of the
invention can be used to assay for potential inhibitors of VLA-4/VCAM-1
interactions.
For in vivo diagnostic imaging to identify, e.g., sites of inflammation,
radioisotopes are typically used in accordance with well known techniques.
The radioisotopes may be bound to the peptide either directly or indirectly
using intermediate functional groups. For instance, chelating agents such as
diethylenetriaminepentacetic acid (DTPA) and ethylenediaminetetraacetic acid
(EDTA) and similar molecules have been used to bind proteins to metallic ion
radioisotopes.

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The complexes can also be labeled with a paramagnetic isotope for
purposes of in vivo diagnosis, as in magnetic resonance imaging (MRI) or
electron spin resonance (ESR), both of which were well known. In general,
any conventional method for visualizing diagnostic imaging can be used.
Usually gamma- and positron-emitting radioisotopes are used for camera
imaging and paramagnetic isotopes are used for MRI. Thus, the compounds
can be used to monitor the course of amelioration of an inflammatory response
in an individual. By measuring the increase or decrease in lymphocytes
expressing VLA-4 it is possible to determine whether a particular therapeutic
regimen aimed at ameliorating the disease is effective.
The pharmaceutical compositions of the present invention can be used to
block or inhibit cellular adhesion associated with a number of diseases and
disorders. For instance, a number of inflammatory disorders are associated
with integrins or leukocytes. Treatable disorders include, e.g.,
transplantation
rejection (e.g., allograft rejection), Alzheimer's disease, atherosclerosis,
AIDS
dementia, diabetes (including acute juvenile onset diabetes), retinitis,
cancer
metastases, rheumatoid arthritis, acute leukocyte-mediated lung injury (e.g.,
adult respiratory distress syndrome), asthma, nephritis, and acute and chronic
inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and
inflammatory bowel disease (including Crohn's disease and ulcerative colitis).
In preferred embodiments the pharmaceutical compositions are used to treat
inflammatory brain disorders, such as multiple sclerosis (MS), viral
meningitis
and encephalitis.
Inflammatory bowel disease is a collective term for two similar diseases
referred to as Crohn's disease and ulcerative colitis. Crohn's disease is an
idiopathic, chronic ulceroconstrictive inflammatory disease characterized by
sharply delimited and typically transmural involvement of all layers of the
bowel wall by a granulomatous inflammatory reaction. Any segment of the
gastrointestinal tract, from the mouth to the anus, may be involved, although
the disease most commonly affects the terminal ileum and/or colon.

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Ulcerative colitis is an inflammatory response limited largely to the colonic
mucosa and submucosa. Lymphocytes and macrophages are numerous in
lesions of inflammatory bowel disease and may contribute to inflammatory
injury.
Asthma is a disease characterized by increased responsiveness of the
tracheobronchial tree to various stimuli potentiating paroxysmal constriction
of the bronchial airways. The stimuli cause release of various mediators of
inflammation from IgE-coated mast cells including histamine, eosinophilic
and neutrophilic chemotactic factors, leukotrines, prostaglandin and platelet
activating factor. Release of these factors recruits basophils, eosinophils
and
neutrophils, which cause inflammatory injury.
Atherosclerosis is a disease of arteries (e.g., coronary, carotid, aorta and
iliac). The basic lesion, the atheroma, consists of a raised focal plaque
within
the intirna, having a core of lipid and a covering fibrous cap. Atheromas
compromise arterial blood flow and weaken affected arteries. Myocardial and
cerebral infarcts are a major consequence of this disease. Macrophages and
leukocytes are recruited to atheromas and contribute to inflammatory injury.
Rheumatoid arthritis is a chronic, relapsing inflammatory disease that
primarily causes impairment and destruction of joints. Rheumatoid arthritis
usually first affects the small joints of the hands and feet but then may
involve
the wrists, elbows, ankles and knees. The arthritis results from interaction
of
synovial cells with leukocytes that infiltrate from the circulation into the
synovial lining of the joints. See e.g., Paul, Immunology (3d ed., Raven
Press,
1993).
Another indication for the compounds of this invention is in treatment of
organ or graft rejection mediated by VLA-4. Over recent years there has been
a considerable improvement in the efficiency of surgical techniques for
transplanting tissues and organs such as skin, kidney, liver, heart, lung,
*rB

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pancreas and bone marrow. Perhaps the principal outstanding problem is the
lack of satisfactory agents for inducing immunotolerance in the recipient to
the
transplanted allograft or organ. When allogeneic cells or organs are
transplanted into a host (i.e., the donor and donee arP different individuals
from the same species), the host immune system is likely to mount an immune
response to foreign antigens in the transplant (host-versus-graft disease)
leading to destruction of the transplanted tissue. CD8' cells, CD4 cells and
monocytes are all involved in the rejection of transplant tissues. Compounds
of this invention which bind to alpha-4 integrin are useful, inter alia, to
block
alloantigen-induced immune responses in the donee thereby preventing such
cells from participating in the destruction of the transplanted tissue or
organ.
See, e.g., Paul et al., Transplant International 9, 420-425 (1996);
Georczynski
et al., Immunology 87, 573-580 (1996); Georcyznski et al., Transplant.
Immunol. 3, 55-61 {1995); Yang et al., Transplantation 60, 71-76 (1995);
Anderson et al., APMIS 102, 23-27 ( 1994).
A related use for compounds of this invention which bind to VLA-4 is in
modulating the immune response involved in "graft versus host" disease
(GVHD). See e.g., Schlegel et al., J. Immunol. 155, 3856-3865 (1995).
GVHD is a potentially fatal disease that occurs when immunologically
competent cells are transferred to an allogeneic recipient. In this situation,
the
donor's immunocompetent cells may attack tissues in the recipient. Tissues of
the skin, gut epithelia and liver are frequent targets and may be destroyed
during the course of GVHD. The disease presents an especially severe
problem when immune tissue is being transplanted, such as in bone marrow
transplantation; but less severe GVHD has also been reported in other cases as
well, including heart and liver transplants. The therapeutic agents of the
present invention are used, inter alia, to block activation of the donor T-
cells
thereby interfering with their ability to lyse target cells in the host.
A further use of the compounds of this invention is inhibiting tumor
metastasis. Several tumor cells have been reported to express VLA-4 and

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compounds which bind VLA-4 block adhesion of such cells to endothelial
cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J.
Cancer 60, 867-7I (I995); Freedman et al., Leuk. Lymphoma 13, 47-52
( 1994); Okahara et al., Cancer Res. 54, 3233-6 ( 1994).
A further use of the compounds of this invention is in treating multiple
sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease
that affects an estimated 250,000 to 350,000 people in the United States.
Multiple sclerosis is thought to be the result of a specific autoimmune
reaction
in which certain leukocytes attack and initiate the destruction of myelin, the
insulating sheath covering nerve fibers. In an animal model for multiple
sclerosis, marine monoclonal antibodies directed against VLA-4 have been
shown to block the adhesion of leukocytes to the endothelium, and thus
prevent inflammation of the central nervous system and subsequent paralysis
in the animals'6.
Pharmaceutical compositions of the invention are suitable for use in a
variety of drug delivery systems. Suitable formulations for use in the present
invention are found in Remington's Pharmaceutical Sciences, Mace
Publishing Company, Philadelphia, PA, 17th ed. (1985).
In order to enhance serum half life, the compounds may be encapsulated,
introduced into the lumen of liposomes, prepared as a colloid, or other
conventional techniques may be employed which provide an extended serum
half life of the compounds. A variety of methods are available for preparing
liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871,
4,501,728 and 4,837,028 each of which is incorporated herein by reference.
The amount administered to the patient will vary depending upon what is
being administered, the purpose of the administration, such as prophylaxis or
therapy, the state of the patient, the manner of administration, and the like.
In
therapeutic applications, compositions are administered to a patient already

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suffering from a disease in an amount sufficient to cure or at least partially
arrest the symptoms of the disease and its complications. An amount adequate
to accomplish this is defined as "therapeutically effective dose." Amounts
effective for this use will depend on the disease condition being treated as
well
as by the judgment of the attending clinician depending upon factors such as
the severity of the inflammation, the age, weight and general condition of the
patient, and the like.
The compositions administered to a patient are in the form of
pharmaceutical compositions described above. These compositions may be
sterilized by conventional sterilization techniques, or may be sterile
filtered.
The resulting aqueous solutions may be packaged for use as is, or lyophilized,
the lyophilized preparation being combined with a sterile aqueous carrier
prior
to administration. The pH of the compound preparations typically will be
IS between 3 and 1 l, more preferably from 5 to 9 and most preferably from 7
to
8. It will be understood that use of certain of the foregoing excipients,
corners,
or stabilizers will result in the formation of pharmaceutical salts.
The therapeutic dosage of the compounds of the present invention will
vary according to, for example, the particular use for which the treatment is
made, the manner of administration of the compound, the health and condition
of the patient, and the judgment of the prescribing physician. For example,
for
intravenous administration, the dose will typically be in the range of about
20
~cg to about 500 ~cg per kilogram body weight, preferably about 100 ~g to
about 300 ug per kilogram body weight. Suitable dosage ranges for intranasal
administration are generally about 0.1 pg to 1 mg per kilogram body weight.
Effective doses can be extrapolated from dose-response curves derived from in
vitro or animal model test systems.
The following synthetic and biological examples are offered to illustrate
this invention and are not to be construed in any way as limiting the scope of

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this invention. Unless otherwise stated, all temperatures are in degrees
Celsius.
EXAMPLES
In the examples
below, the fo'.lowing
abbreviations have
the following
meanings. If an
abbreviation is
not defined, it
has its generally
accepted
meaning.
aq or aq. - aqueous
AcOH - acetic acid
bd - broad doublet
bm - broad multiplet
bs - broad singlet
Bn - benzyl
Boc - N tert-butoxylcarbonyl
Boc20 - di-tert-butyl dicarbonate
BOP - benzotriazol-1-yloxy-
tris(dirnethylamino)phosphonium
hexafluorophosphate
Cbz - carbobenzyloxy
CHCl3 - chloroform
CH2Clz - dichloromethane
(COCI)Z - oxalyl chloride
d - doublet
dd - doublet of doublets
dt - doublet of triplets
DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC - 1,3-dicyclohexylcarbodiimide
DMAP - 4-N,N-dimethylaminopyridine
DME - ethylene glycol dimethyl ether
DMF - N,N-dimethylformamide
DMSO - dimethylsulfoxide
EDC - 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride
Et3N - triethylamine
Et20 - diethyl ether
EtOAc - ethyl acetate
EtOH - ethanol
eq or eq. - equivalent
Fmoc - N-(9-fluorenylmethoxycarbonyl)
FmocONSu - N (9-fluorenylmethoxycarbonyl)-
succinimide
g - grams

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h - hour
HZO - water
HBr - hydrobromic acid
HCl - hydrochloric acid
HOBT - 1-hydroxybenzotriazoie
hydrate
hr - hour
KZC03 - potassium carbonate
L - liter
m - multiplet
MeOH - methanol
mg - milligram
MgS04 - magnesium sulfate
mL - milliliter
mm - millimeter
1S mM - millimolar
mmol - millimol
mp - melting point
N - normal
NaCI - sodium chloride
NazC03 - sodium carbonate
NaHC03 - sodium bicarbonate
NaOEt - sodium ethoxide
NaOH - sodium hydroxide
NH4C1 - ammonium chloride
NMM - N methylmorpholine
Phe - L-phenylalanine
Pro - L-proline
psi - pounds per square inch
PtOz - platinum oxide
q - quartet
quint. - quintet
rt - room temperature
s - singlet
sat - saturated
t - triplet
t-BuOH - tert-butanol
TFA - trifluoroacetic acid
THF - tetrahydrofuran
TLC or tlc - thin layer chromatography
Ts - tosyl
TsCI - tosyl chloride
TsOH - tosylate
~L - microliter
4S

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In the examples below, all temperatures are in degrees Celcius (unless
otherwise indicated). The following Methods were used to prepare the
compounds set forth below as indicated.
S
Method 1
N Tosylation of the appropriate amino acid was conducted via the method
of Cupps, Boutin and Rapoport J. Org. Chem. 1985, 50, 3972.
Method 2
M t ~ c r Pr ~aration Procedure
Amino acid methyl esters were prepared using the method of Brenner and
Huber Helv. Chim. Acta 1953, 36, 1109.
Method 3
The desired dipeptide ester was prepared by the reaction of a suitable N-
protected amino acid ( 1 equivalent) with the appropriate amino acid ester or
amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate [BOP] (2.0
equivalent), triethylamine (1.1 equivalent), and DMF. The reaction mixture
was stirred at room temperature overnight. The crude product is purified flash
chromatography to afford the dipeptide ester.
Method 4
~jvrdro~enation Procedure I
Hydrogenation was performed using 10% palladium on carbon (10% by
weight) in methanol at 30 psi overnight. The mixture was filtered through a
pad of Celite and the filtrate concentrated to yield the desired amino
compound.

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Method 5
H~~p~,vsis Procedure I
To a chilled (0°C) THF/HZO solution (2:1, 5 - 10 mL) of the
appropriate
ester was added LiOH (or NaOH) (0.95 equivalents). The temperature was
S maintained at 0°C and the reaction was complete in 1-3 hours. The
reaction
mixture was extracted with ethyl acetate and the aqueous phase was
lyophilized resulting in the desired carboxylate salt.
Method 6
F~ er Hvdro ,ysis ProcedLre II
To a chilled {0°C) THF/HZO solution (2: l, 5 - 10 mL) of the
appropriate
ester was added LiOH (1.1 equivalents). The temperature was maintained at
0°C and the reaction was complete in 1-3 hours. The reaction mixture
was
concentrated and the residue was taken up into HZO and the pH adjusted to 2-3
with aqueous HCI. The product was extracted with ethyl acetate and the
combined organic phase was washed with brine, dried over MgS04, filtered
and concentrated to yield the desired acid.
Method 7
Egter Hvdro ,ysis Procey ri a IIt
The appropriate ester was dissolved in dioxane/Hz0 (1:1) and 0.9
equivalents of 0.5 N NaOH was added. The reaction was stirred for 3-16
hours and than concentrated. The resulting residue was dissolved in H20 and
extracted with ethyl acetate. The aqueous phase was lyophilized to yield the
desired carboxylate sodium salt.
Method 8
To the appropriately protected aminophenylalanine analog (11.2 mmol),
dissolved in methylene chloride (25m1) and cooled to -78°C was added
the
desired sulfonyl chloride (12 mmol) followed by dropwise addition of pyridine
(2 mL). The solution was allowed to warm to room temperature and was

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stirred for 48 hr. The reaction solution was transferred to a 2S0 mL
separatory
funnel with methylene chloride (100 mL) and extracted with 1N HCl (SO mL x
3), brine (S0 mL), and water (100 mL). The organic phase was dried
(MgS04) and the solvent concentrated to yield the desired product.
S
Method 9
Reductive amination of Tos-Pro-p-NH2-Phe with the appropriate
aldehyde was conducted using acetic acid, sodium triacetoxyborohydride,
methylene chloride and the combined mixture was stirred at room temperature
overnight. The crude product was purified by flash chromatography.
Method 10
1 S Anhydrous hydrochloride (HCl} gas was bubbled through a methanolic
solution of the appropriate Boc-amino acid ester at 0°C for 15 minutes
and the
reaction mixture was stirred for three hours. The solution was concentrated to
a syrup and dissolved in Et20 and reconcentrated. This procedure was
repeated and the resulting solid was placed under high vacuum overnight.
Method 11
The tert-butyl ester was dissolved in CHzCIz and treated with TFA. The
reaction was complete in 1-3 hr at which time the reaction mixture was
2S concentrated and the residue dissolved in HZO and lyophilized to yield the
desired acid.
Method 12
To a CHZCh solution (S-20 mL) of N-(toluene-4-sulfonyl)-L-proline (1
equivalent), the appropriate amino acid ester hydrochloride (1 equivalent), N-
methylmorpholine (1.1-2.2 equivalents) and 1-hydroxybenzotriazole (2

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equivalents) were mixed, placed in an ice bath and 1-(3-
dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalents) added. The
reaction was allowed to rise to room temperature and stirred overnight. The
reaction mixture was poured into HZO and the organic phase was washed with
S sat. NaHC03, brine, dried (MgS04 or NazS04), filtered and concentrated. The
crude product was purified by column chromatography.
Method 13
To a DMF solution (5-20 mL) of the appropriate N-protected amino acid
( 1 equivalent), the appropriated amino acid ester hydrochloride ( 1
equivalent),
Et3N (1.1 equivalents) and 1-hydroxybenzotriazole (2 equivalents) were
mixed, placed in an ice batch and 1-(3-dimethyiaminopropyl)-3-ethyl
carbodiimide (1.1 equivalents} added. The reaction was allowed to rise to
room temperature and stirred overnight. The reaction mixture was partitioned
between EtOAc and H20 and the organic phase washed with 0.2 N citric acid,
HZO, sat. NaHC03, brine, dried (MgS04 or NazS04}, filtered and concentrated.
The crude product was purified by column chromatography or preparative
TLC.
Method 14
The appropriate sulfonyl chloride was dissolved in CHZCIz and placed in
an ice bath. L-Pro-L-Phe-OMe o HCl ( 1 equivalent) and Et3N ( 1.1 equivalent)
was added and the reaction allowed to warm to room temperature and stirred
overnight under an atmosphere of nitrogen. The reaction mixture was
concentrated and the residue partitioned between EtOAc and Hz0 and the
organic phase washed with sat. NaHC03, brine, dried (MgS04 or NazS04),
filtered and concentrated. The crude product was purified by column
chromatography or preparative TLC.
Method 1 S

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To a solution of L-Pro-L-4-(3-dimethylaminopropyloxy)-Phe-OMe
[prepared using the procedure described in Method 10] ( 1 equivalent) in
CHZC12 was added Et3N (5 equivalents) followed by the appropriate sulfonyl
S chloride {1.1 equivalent). The reaction was allowed to warm to room
temperature and stirred overnite under an atmosphere of nitrogen. The
mixture was concentrated, dissolved in EtOAc, washed with sat. NaHC03 and
0.2 N citric acid. The aqueous phase was made basic with solid NaHC03 and
the product extracted with EtOAc. The organic phase was washed with brine,
dried (MgSO; or NazSO,,), filtered and concentrated. The crude methyl ester
was purified by preparative TLC. The corresponding acid was prepared using
the procedure described in Method 7.
Method 16
To a methanol (10 -15 mL) solution ofthe azlactone, was added NaOAc
( 1 equivalent) and 10% PdIC. This mixture was placed on the hydrogenator at
40 psi H2. After 8 - 16 hours, the reaction mixture was filtered through a pad
of Celite and the filtrate concentrated to yield the dehydrodipeptide methyl
ester. The ester was dissolved in dioxanelH20 (5- 10 mL), to which was
added 0.5 N NaOH {I.OS equivalents). After stirring for I- 3 hours, the
reaction mix was concentrated and the residue was redissolved in Hz0 and
washed with EtOAc. The aqueous phase was made acidic with 0.2 N HCI and
the product was extracted with EtOAc. The combined organic phase was
washed with brine (I x 5 mL), dried (MgS04 or NazSOy), filtered and
concentrated to yield the acid as approximately a 1:1 mixture of
diastereomers.
Method 17
T,~r -B ~tyl .t .r Hydro ;rsis Procedure II
The tert-butyl ester was dissolved in CHZCIZ (5 mL) and treated with TFA
(5 mL). The reaction was complete in 1-3 hours at which time the reaction
mixture was concentrated and the residue dissolved in H,O and concentrated.

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The residue was redissolved in HZO and lyophilized to yield the desired
product.
Example 1 (2)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[(N tert-butoxylcarbonylglycyl)amii'oJ-L-phenylalanine
N (Toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester
(2.00 g, 4.67 mmol) was dissolved 50 mL of dry DMF, with Boc-glycine (1.1
eq, 0.9 g), Et3N (2.2 eq, 1.43 mL), and BOP reagent ( 1.1 eq, 2.27g). The
reaction mixture was stirred at room temperature for 12 hours. EtOAc ( 100
mL) was added. The organic layer was washed with NaHC03 saturated (50
mL), 10°y° citric acid (20 mL), and brine (Sx SO mL). The
organic layer was
dried over MgS04. Upon evaporation of the solvents under reduced pressure,
the crude material was eluted on column chromatography (silica gel;
CHCl3/MeOH 9:1). The desired ester (1.90 g, 3.1 mmol) was isolated in 66%
yield. The ester was then taken up in MeOH:H20 [ 1:1 ] (40 mL), with NaOH
(1.1 eq, 176 mg), for 4 hours at room temperature. EtOAc was added as well
as water. The aqueous layer was collected and acidified with 1N HCl to pH
2.5, and reextracted with EtOAc. The organic layer was dried over MgS04.
Upon filtration and evaporation of the solvents under reduced pressure, the
title compound was isolated in 73% yield, as an oil {1.33g, 2.26 mmol).
NMR data was as follows:
~H NMR (300 MHz, CDCI3): 8 = 8.65 (bs, 1H), 7.70 (d, 2H, J= 7.98 Hz),
7.50 {d, 1 H, J = 7.14 Hz), 7.45 (d, 2H, J = 8.10 Hz), 7.3 2 (d, 2H, J = 7.80
Hz),
7.11 (d, 2H, J = 8.00 Hz), 5.75 (bs, 1 H), 4.82 (m, 1 H), 4.11 (m, 1 H), 3.90
(bs,
2H), 3.38 (m, 1H), 3.21 3.10 (m, 3H), 2.41 (s, 3H), 1.99 (m, 1H), 1.55 (m,
3H), 1.43 (s, 9H).
~3C NMR (75 MHz, CDC13): b = 174.03, 172.19, 169.02, 157.28, 145.03,
137.17, 133.34, 132.58, 130.59, 128.44, 120.65, 81.16, 62.85, 54.05, 50.31,
37.34, 30.69, 28.87, 24.89, 22.14, 14.77.
Mass Spectroscopy: (FAB) 589 (M+H).

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Example 2 (7)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
j(glycyl)aminoj-L-phenylalanine
The product from Example 1 (2) (1.33 g, 2.26 mmol) was taken up in dry
dichloromethane (20 mL) with trifluoroacetic acid ( 1.00 mL) and the reaction
mixture was stirred at room temperature for 12 hours. The solvents were
removed under reduced pressure. The crude material was left on a vacuum
i0 pump overnight, then dissolved in methanol and cooled to 0°C. Ethyl
ether
was added and the product was collected, as a trifluoroacetate salt, in 50%
yield (660 mg, 1.09 mmol).
NMR data was as follows:
'H NMR (300 MHz, CD30D): 8 = 7.51 (d, 2H, J= 8.25 Hz), 7.3 i (d, 2H,
I S J= 8.25 Hz), 7.19 (d, 2H, J= 7.92 Hz), 7.03 (d, 2H, J= 8.25 Hz), 4.43 (m,
1H), 3.87 {m, 1H), 3.63 (s, 2H), 3.13-2.82 (m, 4H), 2.21 (s, 3H), 1.56-1.26
(m,
4H).
'3C NMR (75 MHz, CD30D): 8 = 174.39, 165.97, 146.34, 139.50, 135.38,
135.21, 131.28, 129.57, 121.47, 67.47, 63.86, 51.16, 42.72, 38.39, 32.20,
20 25.87, 22.09, 16.02.
Mass Spectroscopy: (FAB) 489 (M+).
Example 3 (23)
Synthesis of
25 N (Toluene-4-sulfonyt)-L-prolyl-4-
[3-(carboxy)propionamidoj-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester
(455 mg, 1 mmol) was dissolved in DMF (10 mL) with EtiN (1.1 eq, 153 ~L)
30 and succinic anhydride { 1.1 eq, 110 mg). The desired monoester was
isolated
in 53% yield (288 mg, 0.52 mmol) as a foam. The monoester (80 mg, 0.15
mmol) was then hydrolyzed in MeOH: H20 1:1 (5 mL) with NaOH (2.2 eq, 15
mg) for 4 hours at room temperature. EtOAc was added as well as water. The
aqueous layer was collected and acidified with 1N HCl to pH 2.5, and
35 reextracted with EtOAc. The organic layer was dried over MgSOa. Upon

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filtration and evaporation of the solvents under reduced pressure, the diacid
was isolated as a foam.
NMR data was as follows:
'H NMR (300 MHz, CD30D): b = 7.51 (d, 2H, J= 8.31 Hz), 7.28 (d, 2H,
J= 8.34 Hz), 7.19 (d, 2H, J= 8.10 Hz), 6.99 (d, 2H, J= 8.43 Hz), 4.48 (m,
1 H), 3.91 (m, 1 H), 3.17-2.83 (m, 4H), 2.43 (s, 4H), 2.2 I (s, 3H), i .44-
1.29 (m,
4H).
'3C NMR (75 MHz, CD30D): 8 = 176.87, 174.68, 174.53, 173.30, 149.74,
146.31, 139.33, 135.50, 134.24, 131.61, 131.44, 129.53, 121.66, 80.05, 63.81,
55.37, 51.17, 38.25, 32.87, 32.24, 30.55, 25.89, 22.11.
Mass Spectroscopy: (FAB) 532 (M+H).
Example 4 (27)
Synthesis of
N {Toluene-4-sulfonyl)-L-prolyl-4-
[{N tert-butoxylcarbonyl-L-alanyl)amino]-L-phenylalanine
Following the experimental procedure described for Example 1 (2), N-
(toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (0.1 S g,
0.337 mmol) was taken into 5 mL of DMF, with Et3N (2.0 eq, 95 ~L), Boc-L-
alanine ( 1.1 eq, 70 mg), and BOP ( 1.1 eq, 163 mg). The desired methyl ester
was isolated as an oil in 49% yield (102 mg, 0.16 mmol). The ester was then
hydrolyzed with NaOH (1.1 eq, 8 mg) in a I :l MeOH:H,O solution (4 mL).
The monoacid was isolated as an amorphous solid in quantitative yields.
NMR data was as follows:
' H NMR (300 MHz, CDC13): 8 = 9.00 (broad s, 1 H), 7.70 (d, 2H, J =
8.25 Hz), 7.45 (d, 2H, J= 8.37 Hz), 7.32 (d, 2H, J= 8.25 Hz), 7.09 (d, 2H, J=
8.25 Hz), S.bS (bs, 1 H), 4.82 (m, 1 H), 4.35 (bs, 1 H), 4.11 (m, 1 H), 3.38-
3.12
(m, 4H), 2.40 (s, 3H), 1.95 (m, IH), 1.53 (m, 3H), 1.40 (s, 12H).
"C NMR (75 MHz, CDC13): b = 174.71, 172.40, 172.09, 156.72, 144.98,
137.62, 133.43, 132.21, 130.58, 128.48, 120.47, 80.98, 62.87, 54.05, 51.10,
50.31, 37.23, 30.73, 28.88, 24.92, 22.16, 18.89.
Mass Spectroscopy: (FAB) 603 (M+H).

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Example 5 (28)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
((N tert-butoxylcarbonyl-D-alanyl)aminoj-L-phenylalanine
Following the experimental procedure described for Example 1 (2), N
(toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (0.15 g,
0.337 mmol) was taken into 5 mL of DMF, with Et3N (2.0 eq, 95 ~,L), Boc-D-
alanine ( 1.1 eq, 70 mg), and BOP ( 1.1 eq, 163 mg). The desired methyl ester
was isolated as an oil in 33% yield (68 mg, 0.11 mmol). The ester was then
hydrolyzed with NaOH (1.1 eq, S mg) in a 1:1 MeOH:HZO solution (4 mL).
The monoacid was isolated as a film in quantitative yields.
NMR data was as follows:
'H NMR (300 MHz, CDC13): 8 = 8.90 (broad s, 1H), 7.70 (d, 2H, J= 8.25
Hz), 7.45 (d, 2H, J= 8.37 Hz), 7.32 (d, 2H, J= 8.25 Hz), 7.09 (d, 2H, J= 8.25
Hz), 5.65 (bs, 1 H), 4.82 (m, 1 H), 4.3 S (bs, 1 H), 4.11 (m, 1 H), 3.3 8-3.12
(m,
4H), 2.40 (s, 3H), 1.95 (m, 1H), 1.53 (m, 3H), 1.40 (s, 12H).
"C NMR (75 MHz, CDC13): 8 = 174.71, 172.40, 172.09, 156.72, 144.98,
137.62, 133.43, 132.21, 130.58, 128.48, 120.47, 80.98, 62.87, 54.05, 51.10,
50.31, 37.23, 30.73, 28.88, 24.92, 22.16, 18.89.
Mass Spectroscopy: (FAB) 603 (M+H).
Example 6 (29)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
((N tert-butoxylcarbonyl-D-phenylalanyl)amino)-L-phenylalanine
Following the experimental procedure described for Example 1 (2), N
(toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (0.15 g,
0.337 mmol) was taken into 5 mL of DMF, with Et3N (2.0 eq, 95 pL), Boc-L-
phenylalanine (1.1 eq, 99 mg), and BOP (1.1 eq, 163 mg). The desired methyl
ester was isolated as an oil in 16% yield (37 mg, 0.05 mmol). The ester was
then hydrolyzed with NaOH (1.1 eq, 3 mg) in a 1:1 MeOH:HZO solution (2
mL). The monoacid was isolated as an amorphous solid in quantitative yields.
NMR data was as follows:

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'H NMR (300 MHz, CDC13): b = 8.56 (broad s, IH), 7.73 (d, 2H, J = 8.13
Hz), 7.43-7.22 (m, 10 H), 7.09 (d, 2H, J = 7.95 Hz), 5.78 (m, 1 H), 4.87 (m,
1 H), 4.65 (m, 1 H), 4.1 I (m, 1 H), 3.44 (m, 1 H), 3.29-3.01 (m, 4H), 2.43
(s,
3H), 2.08 (m, 1H), 1.60 (m, 3H), 1.33 (s, 9H).
'3C NMR (75 MHz, CDCI3): b = 171.88, 171.44, 170.02, 156.56, 144. 96,
137.23, 136.83, 133.46, 132.78, 130.53, 130.33, 129.92, 129.36, 128.44,
127.64, 120.63, 81.16, 62.84, 53.96, 50.26, 38.91, 37.90, 30.35, 28.81, 24.96,
22.11.
Mass Spectroscopy: (FAB) 679 (M+H).
Example 7 (67)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
{2-(3-(fluorescein)thiouriedoJ acetamido}-L-phenylalanine
The product of Example 2 (7) was treated with NaHC03 and fluorescein
isothiocyanate (isomer I -- obtained from Aldrich Chemical Company) in
EtOH and H20. Acidification of the mixture and isolation of the resulting
precipitate gave the title compound as an amorphous orange solid.
Mass Spectroscopy: (+FAB, 3-nitrobenzyl alcohol) 878 (MH+).
Example 8 (175)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[(N tert-butoxylcarbonylglycyl)amino]-L-phenyiaianine
Methyl Ester
N-(Toluene-4-sulfonyl)-L-prolyl-L-(4-nitro)phenylalanine methyl ester
(2.00 g, 4.48 mmol) was dissolved in MeOH {10 mL) with a catalytic amount
of 10% Pd on C. The hydrogenation reaction was run at room temperature for
12 hours at 40 psi. Upon filtration of the reaction mixture over celite, the
solvent was evaporated under reduced pressure yielding a pink foam in
quantitative yields. The title compound was prepared therefrom and N-Boc
glycine using the procedure described in Method 12.
NMR data was as follows:

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'H NMR (300 MHz, CDC13): 8 = 7.72 (d, 2H, J = 8.13 Hz), 7.45 (d, 2H, J
= 8.49 Hz), 7.35 (d, 2H, J = 8.30 Hz), 7.10 (d, 2H, J = 8.37 Hz), 5.40 (m,
1H),
4.82 {m, 1 H), 4.07 (m, 1 H), 3.91 (s, 2H), 3.76 (s, 3H), 3.40 (m, 1 H), 3.23
(m,
1 H), 3.05 (m, 2H), 2.43 (s, 3H), 2.43 (m, 1 H), 1.46 (m, 12H).
"C NMR (75 MHz, CDC13): 8 = 177.61, 171.97, 171.58, 168.52, 144.93,
137.25, 133.43, 132.55, 131.36, 130.54, 130.33, 128.39, 120.53, 80.50, 62.81,
54.00, 53.08, 50.25, 37.83, 30.42, 28.93, 28.87, 24.81, 22.14.
Mass Spectroscopy: (FAB) 603 (M+H).
Example 9 (306)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
{2-[3-(3-methylphenyl)uriedo]acetamido}-L-phenylalanine
The methyl ester was prepared by the reaction of N-(toluene-4-sulfonyl)-
L-prolyI-L-(4-amino)phenylalanine with 2-(3-m-tolyl-ureido)acetic acid (BOP,
triethyiamine, DMF, stir at room temperature overnight). The crude product
was purified flash chromatography (silica, 9:1 EtOAc:hexane) to afford the
methyl ester. The methyl ester was hydrolyzed using 1M LiOH in THF. The
title compound was isolated following acid/base work-up as a white solid.
NMR data was as follows:
'H NMR (DMSO-db, 400 MHz): b = 12.8 (br s, 1H); 9.96 (s, 1H); 8.70 (s,
1H); 8.04(d, 1H, J = 7.9Hz); 7.68 (d, 2H, J = 8Hz); 7.48 (d, 2H, J = 8.3Hz);
7.39 (d, 2H, J = 8.3Hz); 7.21 (s, 1H); 7.16 (d, 3H, J = 8.56Hz); 7.08 (t, 1H,
J =
7.79Hz); 6.7 (d, 1 H, J = 7.68Hz); 6.38(t, 1 H, J = 5.6Hz); 4.43 (m, 1 H); 4.1
(dd, 1H, J = 3.18, 8.23Hz); 3.89 (d, 2H, J = 5.49Hz); 3.3 (m, 1H); 3.05 (m,
2H); 2.92 (dd,lH, J = 8.34, 13.63Hz); 2.38 (s,3H);2.22 (s,3H); 1.38-1.62 (m,
4H).
IR (KBr, cm-'): 3380, 2990, 1650, 1605, 1540, 1230, 1155, 660, 580, 545.
Mass Spectroscopy: ( (+) FAB, m/e (%)) 644 (100 [M+Na]+); 622 (25
[M+H~+).

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Example 10 (380)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[y-(L-aspartyl)amino]-L-phenylalanine
Substitution of Boc-L-aspartic benzyl ester for Boc-glycine and following
the methods for preparation of Examples 1 {2) and 2 (7), gave the title
compound as a white solid, mp = 163-170°C.
NMR data was as follows:
I 0 ' H NMR (DMSO-db): b = 8.05 (d, 1 H), 7.70 (d, 1 H), 7.45 (dd, 4H), 7.18
(d, 2H), 4.40 (m, 1H), 4.10 (m, 1H), 2.40 (s, 3H), 1.60 (m, 6H)
Mass Spectroscopy: (FAB) (M+H)' 547.
Example 11 ( I4)
Synthesis of
N (Toluene-4-sulfonyl)-L-profyl-4
(a-carboxybenzyloxy)-L-phenylalanine
N (toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester ( 1.32 g, 2.95
mmol) was dissolved in dry DMF (50 mL) at room temperature. To this was
added KzC03 (l.l eq, 440 mg) and ethyl a-bromophenylacetate (1.1 eq, 750
mg). The reaction was stirred for 12 hours at room temperature. Ethyl acetate
( 100 mL) was added, and the organic layer washed several times with brine.
The organic layer was dried over MgSO~. Upon filtration and evaporation of
the solvents under reduced pressure, a residue was isolated which was then
taken up in MeOH: H20 1:1 (30 mL) with NaOH (1.1 eq, 427 mg). The
desired diacid was isolated in 88% yield (754 mg, 1.33 mmol).
NMR data was as follows:
'H NMR (300 MHz, CD30D) : 8 = 7.50 (d, 2H, J= 8.25 Hz), 7. 35 {d,
2H, J = 7.14 Hz), 7.1 S (m, SH), 6.95 (d, 2H, J = 8.13 Hz), 6.71 (d, 2H, J =
8.37 Hz), 5.48 (s, 1H), 4.51 (m, 1H), 3.87 (m, 1H), 3.10-2.79 (m, 4H), 2.15
(s,
3H), 1.45-1.01 {m, 4H).
"C NMR (75 MHz, CD30D): 8 = 174.71, 174.49, 173.98, 158.25, 146.39,
138.08, 135.37, 132.28, 131.74, 130.53, 130.36, 129.60, 129.00, 117.18,
79.95, 63.94, 55.31, 38.00, 32.23, 25.88, 22.32, 15.22.

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Mass Spectroscopy: (FAB) 567 (M+H).
Example 12 (15)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[2-(carboxy)phenyl]-L-phenylalanine
The product of Example 13 (178) was treated with NaOH in dioxane and
water, to give after acidification, extraction, drying with MgSO~, filtration
and
evaporation the title compound as a clear oil.
NMR data was as follows:
'H NMR (CD,OD w/ CD30Na, 300 MHz): b = 7.75 (d, J= 8.2, 2H),
7.44-7.40 (m, SH), 7.29-7.21 (m, SH), 4.47 (t, J= 5.8, 1H), 4.03 (dd, J= 8.5,
J
= 3.4, 1H), 3.37-3.25 (m, 2H), 3.17-3.06 (m, 2H), 1.89-1.80 (m, 1H), 1.64-
1.47 (m, 3H).
"C NMR (CD30D w/ CD30Na, 75 MHz): b = 179.1, 177.5, 173.1,
145.8, 142.4, 141.3, 139.6, 137.8, 134.7, 131.0, 130.6, 130.5, 129.4, 129.1,
128.7, 128.1, 127.6, 63.6, 57.0, 50.7, 38.7, 31.7, 25.2, 21.5.
Mass Spectroscopy: (+FAB, glycerol) 537 (MH+).
Example 13 (178)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[2-(methoxycarbonyl)phenyl]-L-phenylalanine Benzyl Ester
L-4-Iodophenylalanine [Phe(4-I)-OH] was treated with MeOH and HC1
gas, to give after evaporation, HCI o Phe(4-I)-OMe. This product was treated
with N-(toluene-4-sulfonyl)-L-Pro-OH, EDAC, HOBT, and Et3N in DMF, to
give after aqueous workup, N-(toluene-4-sulfonyl)-L-Pro-L-Phe(4-I)-OMe.
This product was treated in THF with Pd(PPh3), and 2-
(methoxycarbonyl)phenylzinc iodide, prepared by the method of Rieke (J.
Org. Chem. 1991, 56, 1445), to give after aqueous workup and flash
chromatography, the title compound as a clear oil.
NMR data was as follows:

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'H NMR (CDC13, 300 MHz): b = 7.81 (d, J=7.7, 1H), 7.72 (d, J=8.2, 2H),
7.54-7.49 (m, 1 H), 7.42-7.16 (m, 9H), 4.93-4.86 (m, 1 H), 4.11-4.07 (m, 1 H),
3.80 (s, 3H), 3.64 (s, 3H), 3.42-3.28 (m, 2H), 3.15-3.08 (m, 2H), 2.43 (s,
3H),
2.09-2.04 (m, 1H), 1.58-1.45 (m, 3H).
"C NMR (CDCl3, 75 MHz): b = 171.3, 170.8, 169.1, 144.3, 141.9, 140. l,
135.0, 132.9, 131.2, 130.8, 130.6, 129.9, 129.7, 129.0, 128.4, 127.8, 127.1,
62.2, 53.3, 52.5, 52.0, 49.7, 37.6, 29.7, 24.2, 21.5.
Mass Spectroscopy: (+FAB, 3-nitrobenzyl alcohol) 565 (MH+).
Example 14 (35)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
{lV j2-(N carbobenzyloxyamino)ethyl]amino}-L-phenylalanine
Following the experimental procedure described for the synthesis of
Example 3 (23), the product from Example 15 (172) (32 mg, 0.051 mmol) was
hydrolyzed in MeOH:HzO 1:1 ( 1 mL), with NaOH ( 1.1 eq, 3 mg). The title
material was isolated in quantitative materials, as a foam.
NMR data was as follows:
'H NMR (300 MHz, CDCl3): b = 7.68 (m, 2H), 7.30 (m, 5H), 7.20 (m,
2H), 4.77 (m, 1H), 4.46 (m, 1H), 4.18 (m, 2H), 3.65 (m, 1H), 3.47 (m, 1H),
3.12 (m, 2H), 2.78 (s, 1.5H), 2.54 (s, 1.5H), 2.42 (s, 3H), 1.26 (m, 3H).
'3C NMR (75 MHz, CDCl3): 8 = 171.47, 170.31, 144.78, 136.42, 135.77,
130.67, 129.88, 129.33, 127.80, 62.44, 60.99, 60.81, 54.00, 53.77, 38.32,
32.19, 31.96, 22.24, 14.76.
Mass Spectroscopy: (FAB) 449 (M+H).
Example 15 ( 172)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
{N [2-(N carbobenzyloxyamino)ethyl]amino}-L-phenylalanine
Methyl Ester
N-(Toluene-4-sulfonyl)-L-prolyl-L-p-amino-phenylalanine methyl ester
(316 mg, 0.7 mmol) was dissolved in a KOAc-HOAc solution in dry methanol

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(10 mL) [pH 6.5], with NaCNBH3 (10.0 eq, 446 mg), and carbobenzyloxy-
glycinal ( l .1 eq). The reaction mixture was stirred at room temperature
overnight , and the solvents were evaporated under reduced pressure. EtOAc
was added and the organic layer washed with brine, dried over MgS04. Upon
S filtration and evaporation of the solvents, the crude material was eluted on
a
preparative plate (Silica gel, EtOAc/hexanes 1:1 ). The desired title compound
was isolated, as a film in S% yield (40 mg, 0.06 mmol).
NMR data was as follows:
'H NMR (300 MHz, CDCl3): b = 7.71 (d, 2H, J = 6.90 Hz), 7.38 (m, SH),
7.26 (m, 2H), 6.93 (d, 2H, J = 7.20 Hz), 6.54 (d, 2H, J = 7.50 Hz), 5.12 (m,
1 H), S.10 (s, 2H), 4.73 (m, 1 H), 4.06 (m, 1 H), 3.75 (s, 3H), 3.41 (m, 4H),
3.26
(m, 1H), 3.14 (m, 2H), 2.99 (m, 1H), 2.43 (s, 3H), 2.04 (m, 1H), 1.53 (m, 3H).
Mass Spectroscopy: (FAB) 623 (M+H).
1 S Example 16 (368)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-L-4
{N [3-(N,N dimethylamino)propyl]-N
[trifluoromethanesulfonyl]amino}-L-phenylalanine
Methyl Ester
N (Toluene-4-sulfonyl)-L-proiyl-L-(4-amino)phenylalanine methyl ester
was reacted with trifluoromethane sulfonyl anhydride in pyridine to produce
the corresponding trifluoromethane sulfonamide. This compound was
2S alkylated on the nitrogen of the trifiuoromethane sulfonamide group under
Mitsunobu conditions using 3-dimethylamino-1-propanol in THF. After
solvent evaporation and aqueous wash the mixture was purified by filtration to
yield the product as a solid, mp = 4S-SS°C.
NMR data was as follows:
'H NMR (CDC13, 400Mhz): b = 7.70 (d, 2H); 7.34 (d, 3H); 7.25 (m, 3H);
4.88 (m, 1H); 4.10 (m, 1H); 3.85 (brd s, 2H); 3.79 (s, 3H); 3.32 (m, 2H); 3.08
(m, 2H); 2.43 (s, 3H); 2.18 (brd s, SH); 1.98 (brd s, 1H); 1.75-1.30 (brd m,
9H).

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IR (ICBr, cm-1): 3400; 2970; 2800; 1750; 1675; 1525; 1450; 1400; 1350;
1225; 1200; 1165; 1150; 1100; 1075; 1000; 950; 825; 675; 600; 550.
Mass Spectroscopy: (+FAB) 663 ( [M+I-I]+ ); 603; 507; 438; 306; 191;
155; 91.
Example 17 (510)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-
L-4-{N,N di[4-(N,IV dimethylamino)benzyl]amino)-
L-phenylalanine
The methyl ester was prepared by reductive amination of N {toluene-4-
sulfonyl)-L-prolyl-L-4-aminobenzyl-L-phenylalanine with 4-N,N-
dimethylaminobenzaldehyde (acetic acid, sodium triacetoxyborohydride,
methylene chloride), stirred at room temperature overnight. The crude product
was purified by flash chromatography to afford the methyl ester which was
hydrolyzed in the manner of Method 6 to provide the title compound.
NMR data was as follows:
'H NMR (DMSO-db, 400 MHz): b = 7.7 (d, 2H, J = 8.34Hz); 7.54 (d, 1H,
J = 5.71 Hz); 7.40 (d, 1H, J = 8.34Hz); 7.02 (d, 4H, J = 8.78Hz); 6.75 (d, 2H,
J
= 8.78Hz); 6.62 (d, 4H, J = 8.78Hz); 6.48 (d, 2H, J = 8.78Hz); 4.39 (s, 4H);
3.92 (dd, 1H, J = 2.85, 9.OHz); 3.78 (m, 1H); 3.33 (s, 12H); 2.86 (m, 4H);
2.39
(s, 3H); 1.62 (m, 1H}; 1.30 (m, 1H); 1.09 (m, 2H).
IR (KBr, cm') 3380, 1610, 1520, 1400, 1350, 1160, 800, 670.
MS ((+) FAB, m/e (%)) 698 (20[M+H]'}.
Anal. Calc'd for C39H,~6NSOSLi 3HZ0: C, 61,76; H, 6.91; N, 9.23. Found:
C,61.73;H,6.91;N,9.15.
Example 18 (138)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[3-(N,N dimethylamino)propoxy]-L-phenylalanine
Triphenylphosphine (24.4 g, 92.9 mmol) and 3-dimethylamino-1-
propanol (8.72 g, 84.5 mmol) were dissolved in THF (200 mL) and cooled in

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an ice bath. Diethyl azodicarboxylate ( 16.2 g, 14.6 mL, 92.9 mmol) was
added dropwise via syringe over 5 minutes and stirred an additional 10
minutes before addition of N Boc-tyrosine methyl ester (24.95 g, 94.5 mmol)
as a solution in I00 mL THF via cannula. The mixture was stirred for 30
minutes at 0°C and 19 hr at room temperature. The mixture was
concentrated
on a rotary evaporator and taken up into Et20 (500 mL). The mixture was
extracted with 0.2N HCl (3 x 350 mL) and the combined acidic extracts were
made basic with solid NaHC03. This mixture was extracted with EtOAc (3 x
300 mL) and the combined extracts were dried (Na2S04), filtered and
evaporated in vacuo to give N Boc-L-4-(3-dimethylaminopropyl-
oxy)phenylalanine methyl ester (26.5 g, 82 %).
N Boc-L-4-(3-N,N dimethylaminopropyloxy)phenylalanine methyl ester
(26.5 g, 69.5 mmol) was dissolved in MeOH (300 mL) and saturated with HC1
gas. The mixture was stirred for 3 hr before removing the volatiles in vacuo
to
give L-4-(3-N,N dimethylaminopropyloxy)phenylalanine methyl ester
dihydrochloride (23.6 g, 90%).
N (Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-4-(3-N,N-
dimethylaminopropyloxy)-phenylalanine methyl ester dihydrochloride using
the procedure described in Method 13 to give N (toluene-4-sulfonyl)-L-prolyl-
L-4-(3-N,N dimethylaminopropyloxy)phenylalanine methyl ester (16.3g,
89%). The title compound was prepared via hydrolysis of the methyl ester
using 0.5 N NaOH in THF/water ( 14.71 g, 99%).
NMR data was as follows:
'H NMR (DMSO-db): b = 7.75 (d, 2H, J= 8.2 Hz), 7.67 (d, 1H, J= 5.6
Hz), 7.42 (d, 2H, J = 8.2 Hz), 7.00 (d, 2H, J = 8.5 Hz), 6.71 (d, 2H, J = 8.5
Hz), 3.98 (m, 2H), 3.90 (t, 2H, J= 6.5 Hz), 3.14-2.97 {4H), 2.40 (s, 3H), 2.32
(t, 2H, J= 7.0 Hz), 2.13 (s, 6H), 1.83-1.75 (3H), 1.45-1.36 (3H).
"C NMR (DMSO-db): b = 173.5, 169.7, 157.2, 144.1, 133.7, 130.9,
130.3, 128.1, 113.9, 65.9, 62.4, 56.0, 55.4, 49.4, 45.5, 36.1, 30.5, 27.3,
23.9,
21.4.

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Mass Spectroscopy: FAB m/e 562 (M+2Na-H).
Example 19 (282)
Synthesis of
N (Toluene-4-sulfonyl)-N methyl-L-serinyl-4-.
[3-(N,IV dimethylaminopropoxyJ-L-phenylalar~ine Methyl Ester
N Methyl-N (toluene-p-sulfonyl)-L-serine (655 mg, 2.4 mmol) was taken
up in DMF (100 mL) with L-4-(3-dimethylamino-propyloxy)phenylalanine
methyl ester hydrochloride salt [see Example 18 (138) for preparation) {1.0 g,
2.4 mmol), HOBT ( 1.1 eq, 356 mg), Et~N (3.2 eq, 1.1 mL), and EDC ( 1.1 eq,
500 mg) following the procedure described in Method 13. The title compound
was isolated in 70% yield (900 mg, 1.7 mmol) as an oil.
NMR data was as follows:
'H NMR (300 MHz, CDCl3): b = 7.68 (d, 2H, J = 8.40 Hz), 7.29 (d, 2H, J
= 8.10 Hz), 7.08 (d, 1 H, J = 7.80 Hz), 7.04 (d, 2H, J = 8.70 Hz), 6.82 (d,
2H, J
= 8.70 Hz), 4.71 (m, 1 H), 4.43 (m, 1 H), 3.94 (t, 2H, J = 6.60 Hz), 3.75 (s,
3H),
3.69 (m, 1 H), 3.51 (m, 1 H), 3.14 (m, 1 H), 2.91 (m, 1 H), 2.59 {s, 3H), 2.45
(m,
2H), 2.42 (s, 3H), 2.20 (s, 6H), 1.87 (m, 2H).
"C NMR (75 MHz, CDC13): b = 172.04, 170.15, 158.66, 144.56, 136.02,
130.72, 130.46, 128.19, 127.87, 115.31, 66.70, 60.86, 60.65, 56.87, 54.01,
53.08, 45.95, 37.39, 31.85, 27.91, 22.13.
Mass Spectroscopy: (FAB) S36 (M+H).
Example 20 (284)
Synthesis of
N (Toluene-4-sutfonyl)-L-(5,5-dimethyl)thiaprolyl-4
[2-(N,IV dimethylamino)ethoxyJ-L-phenylalanine
Triphenylphosphine (1.1 eq) and 3-dimethylamino-1-propanol (1 eq) were
dissolved in THF and cooled in an ice bath. Diethyl azodicarboxylate (1 eq)
was added dropwise via syringe over S min and stirred an additional 10 min
before addition of N Boc-tyrosine methyl ester ( 1.02 eq) as a solution in 100
mL THF via cannula. The mixture was stirred for 30 min at 0 °C and 19
hr at
room temperature. The mixture was concentrated on a rotary evaporator and

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taken up into Et20 (500 mL). The mixture was extracted with 0.2N HCl {3 X
350 mL) and the combined acidic extracts were made basic with solid
NaHC03. This mixture was extracted with EtOAc (3 X 300 mL) and the
combined extracts were dried (Na2S04), filtered and evaporated in vacuo to
S give N Boc-L-4-{3-dimethylaminopropyloxy)phenylalanine methyl ester.
N Boc-L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester (26.5
g, 69.5 mmol) was dissolved in MeOH (300 mL) and saturated with HCl gas.
The mixture was stirred for 3 hr before removing the volatiles in vacuo to
give
L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester dihydrochloride
(23.6 g, 90%).
N (Toluene-4-sulfonyl)-L-(5,5-dimethyl)-thiaproline was coupled to
L-4-(3-dimethylaminopropyloxy)-phenylalanine methyl ester dihydrochloride
using the procedure described in Method 13 to give N (toluene-4-sulfonyl)-L-
(5,5-dimethyl)-L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester
(16.38, 89%). The title compound was prepared via hydrolysis of the methyl
ester using 0.5 N NaOH in THF/water to provide a solid, mp = >200~C (dec.).
NMR data was as follows:
'H NMR (CD~OD, 300 MHz): 8 = .85 (s, 3H), .94 (s, 3H), 1.78 (m, 2H),
2.23 (s, 3H), 2.28 (s, 6H), 2.57 (m, 2H), 2.83 (m, 2H), 3.71-3.74 (m, 2H),
4.22-4.27 (m, 2H), 4.41 {d, 1H, J = 9.1 Hz), 6.58 (d, 2H, J = 8.6 Hz), 6.98
(d,
2H, J = 8.6 Hz), 7.20 (d, 2H, J = 8.3 Hz), 7.54 (d, 2H, J = 8.3 Hz).
'3C NMR (CD30D, 75 MHz): b = 22.2, 25.3, 27.8, 30.5, 39.4, 45.2, 51.9,
56.0, 57.6, 58.2, 67.2, 75.1, 115.8, 129.8, 131.6, 132.1, 132.5, 135.4, 146.7,
159.5, 170.9, 178.2.
Mass Spectroscopy: (FAB+) 586 (M+H).
Anal. HPLC: (Microsorb-MV C18 Rev. Phase, 4.6 x 150mm; Gradient
1:1 CH3CN/Hz0 with O.OS% TFA; flow rate = 1.0 ml/min; 1= 254 nm; sample
vol.= 20 mL ) Run #1: 2.988 min retention time (100.0% purity) Run #2:
3.098 min retention time { 100.0% purity).

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Example 21 (287)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[2-(N,IV dimethylamino)ethoxy]-L-phenylalanine
S
The title compound was prepared as in Exa:.y.~ 20 ( 138), except that 2-
dimethylaminoethanol was used in plac° of 3-dimethylamino-1-propanol.
NMR data was as follows:
'H NMR (DMSO-db): 8 = 7.74 (d, ZH, J = 7.4 Hz), 7.67 (d, 1 H, J = 7.9
Hz), 7.42 (d, 2H, J = 8.0 Hz), 7.01 (d, 2H, J = 7.9 Hz), 6.71 (d, 2H, J = 7.8
Hz), 3.95 (m, 4H), 3.14-2.98 (4H), 2.57 (t, 2H, J = 5.6 Hz), 2.40 (s, 3H),
2.18
(s, 6H), 1.74 (m, 1 H), 1.40 (m, 3H).
"C NMR (DMSO-db): S = 173.5, 169.7, 157.0, 144.1, 133.8, 131.0,
130.9, 130.3, 128.1, 113.9, 66.0, 62.4, 58.0, 55.4, 49.4, 45.9, 36.2, 30.5,
23.9,
1 S 21.4.
Mass Spectroscopy: FAB m/e 504 (M+H).
Example 22 (317)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[2-(N ethyl-N phenylamino)ethoxy]-L-phenylalanine
Methyl Ester
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 2-(N-ethyl,N phenyl)aminoethyl
chloride in refluxing 2-butanone in the presence of potassium carbonate and
sodium iodide. The title compound was prepared using the procedure
described in Method 7.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): S = 1.08 (3H, t, J=8,8Hz); 1.39 (IH, m);
1.5 S (3H, m); 2.19 (3H, s); 2.85-3.0 (2H, m); 3.12 ( 1 H, dd, J=6,10,6Hz);
3.41
(2H, q, J=6,8,6Hz); 3.6 (3H, s); 3.62 (2H, t, J=S,SHz); 4.01 (2H, t, J=S,SHz);
4.04 (1H, t, J=8,8Hz); 4.43 (1H, dd, J=7,6,7Hz); 6.55 (IH, t, J=8,8Hz); 6.65
(2H, d, J=l OHz); 6.8 (2H, d, J=I OHz ); 7.1 (4H, m); 7.38 (2H, d, J=I OHz);
7.64 {2H, d, J=IOHz); 8.1 (IH, d, J=IOHz).

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MS: +FAB, m/z 594 ([MH]+, 45 %), 157 (100%).
Example 23 (321 )
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
(2-(N,1V diisopropylamino)ethoxy]-L-phenylalanine
The methyl ester was prepared via O-alkylation of N (toluene-4-sulfonyi)-
L-prolyl-L-tyrosine methyl ester with 2-diisopropylaminoethyl chloride in
refluxing 2-butanone in the presence of potassium carbonate and sodium
iodide. The title compound was prepared using the procedure described in
Method 7 as a solid, mp = 121-124°C.
NMR data was as follows:
'H NMR (DMSO-d6, 400 Mhz): 8 = 0.9 (12H, d, J=8Hz); 1.25-1.6 (3H,
m); 1.78 (1H, m); 2.38 (3H, s); 2.7 (2H, t , J=8,8Hz); 2.9 (2H, m); 3.0 (2H,
q,
J=S,S,SHz); 3.1 (1H, dd, J=3,4,3Hz); 3.35 (1H, s); 3.78 (1H, t, J=7,7Hz); 3.8
(2H, t, J=S,SHz); 3.95 (1H, d, J=IOHz); 6.5 (1H, d, J=IOHz); 6.65 (1H; d,
J=IOHz); 6.85 (1H, d, 3=IOHz); 6.9 (1H, d, J=IOHz); 7.4 (2H, d, J=IOHz);
7.62 ( 1 H, m); 7.75 (2H, d, J=1 OHz).
MS: +FAB, m/z 560 {[MHJ+, 70 %), 154 (100).
Example 24 (333)
Synthesis of
N (Thiophene-2-sulfonyl)-L-prolyl-4-
[3-(N,N dimethylamino)propoxy]-L-phenylalanine
The title compound was prepared using Method 15 and was isolated as a
white, hygroscopic solid, mp = >200°C.
NMR data was as follows:
. 'H NMR (DMSO-db, 300 MHz): 8 = 8.03 (br s, 1 H); 7.74 (m, 2H); 7.26
(br s, 1H); 7.04 (d, 2H, J = 7.0 Hz); 6.75 (d, 2H, J = 6.0 Hz); 4.16 (m, 1H);
4.06 (m, 1H); 3.85 (m, 2H); 3.33 (m, 1 H); 3.13 - 3.00 (br m, 3H); 2.62 (m,
2H); 2.35 (s, 3H); 1.90 (m, 2H); 1.75 {m, 1H); 1.90 - 1.50 (br m, 3H),

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'3C NMR (DMSO-db, 75 MHz): 8 = 173.4, 169.9, 157.3, 136.1, 134.3,
133.5, 130.8, 130.3, 128.7, 128.7, 114.1, 65.7, 62.5, 55.1, 54.9, 49.7, 43.9,
36.I, 30.6, 25.9, 24.1, 21.6.
Mass Spectroscopy: (PI-FAB) 532, (M)+.
Example 25 (334)
Synthesis of
N (5-Chlorothiophene-2-sulfonyl)-L-prolyl-4
[3-(N,N dimethylamino)propoxy]-L-phenylalanine
The title compound was prepared using Method 15 and was isolated as a
white, hygroscopic solid, mp = >200°C.
NMR data was as follows:
'H NMR {DMSO-db, 300 MHz): 8 = 7.62 (m, 2H); 7.44 (m, 2H); 6.99
(m, 2H); 6.71 (m, 2H); 4.05{m, 1 H); 3.92(m, 3H); 3.26 (m, 1 H); 3.09 - 2.97
(br
m, 3H); 2.30(m, 2H); 2.13 (s, 6H); 1.82 (m, 2H); 1.79 - 1.51 (br m, 4H).
'3C NMR {DMSO-db, 75 MHz): b = 173.3, 169.3, 157.2, 137.3, 134.3,
132.5, 130.9, 130.9, 119.8, 113.9, 65.9, 62.8, 56.0, 55.5, 49.7, 45.5, 36.1,
30.6,
27.2, 24.0, 22.8.
Mass Spectroscopy: (PI-FAB) 588, (M + Na)+.
Example 26 (336)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[2-(N,IV diethylamino)ethoxy]-L-phenylalanine
The methyl ester was prepared via O-alkylation of N (toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 2-diethylaminoethyl chloride
hydrochloride in refluxing 2-butanone in the presence of potassium carbonate
and sodium iodide. The title compound was prepared using the procedure
described in Method 7 as a solid, mp = 105-109°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): 8 = 1.0 (6H, t, J = 8,8Hz); 1.25-1.45 (4H,
m); 1.65 (2H, m); 2.18 (3H, s); 2.26 (2H, t, J = 2,2Hz); 2.65 (4H, q, J =
5,4,SHz); 2.8-3.1 (4H, m); 3.84 {1H, dd, J = 5,4,SHz); 3.9 (2H, t, J = 3,3Hz);

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4.1 (1H, d, J = 8Hz); 6.68 (2H, d, J = IOHz); 6.95 (2H, d, J = IOHz); 7.05
(2H,
d, J = 1 OHz); 7.4 (2H, d, J = 1 OHz); 7.63 ( 1 H, d, J = 4Hz); 7.73 (2H, t, J
=
4,4Hz).
MS: +ESI, m/z 532.4 ([MH]+, I00 %).
Example 27 (340)
Synthesis of
N (2,5-Dichlorothiophene-3-sulfonyl)-L-prolyl
4-[3-(N,lV dimethylamino)propoxy]-L-phenylalanine
The title compound was prepared using Method 15 and was isolated as a
white, hygroscopic solid, mp = >200°C.
NMR data was as follows:
'H NMR (DMSO-db, 300 MHz): 8 = 7.77 (d, I H, J = 6.6 Hz); 7.43 (s,
1 S 1 H); 7.07 (d, 2H, J = 7.4 Hz); 6.76 (d, 2H, J = 7.4 Hz); 4.33 (m, 1 H);
4.15 (m,
1H); 3.89 (t, 2H, J = 6.1 Hz); 3.29 (m, 2H); 2.97 (m, 2H); 2.57 (t, 2H, J =
7.1
Hz); 2.31 (s, 6H); 1.85 (m, 4H); 1.65 (m, 2H).
"C NMR (DMSO-db, 75 MHz): 8 = 173.4, 172.5, 170.0, 157.3, 134.2,
130.8, 130.5, 130.3, 127.7, 126.9, 114.1, 65.8, 61.9, 55.3, 54.9, 49.2, 44.2,
36.2, 30.9, 26.1, 24.3, 21.6.
Mass Spectroscopy: (PI-FAB) 600, (M)'.
Example 28 (341 )
Synthesis of
N (1-Methylpyrazole-4-sulfonyl)-L-prolyl-4-
[3-(N,N dimethylamino)propoxy]-L-phenylalanine
The N methylpyrazole sulfonyl chloride was prepared by adding N
methylpyrazole to chilled (0°C) chlorosulfonic acid. The reaction
mixture
was allowed to warm to room temperature and the heated to 100°C
overnight
under a stream of Nz. The reaction mixture was then cooled to room
temperature and chilled to 0°C. To this solution was added thionyl
chloride
(2.5 eq.) and the reaction was stirred at room temperature for 30 min, then
warmed to 70 °C for two hours. The reaction was cooled to room
temperature
and then chilled in an ice bath. Water and ice were slowly added to the
*rB

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reaction mixture to precipitate a white solid which was collected by
filtration.
The desired sulfonyl chloride was washed with cold water and hexane. The
title compound was prepared using Method 15 and was isolated as a white,
hygroscopic solid, mp = >200°C.
NMR data was as follows:
'H NMR(DMSO-db, 300 MHz): b = 8.44 (s, 1 H); 7.89 (s, 1 H); 7.66 (d,
1 H, J = 5.6 Hz); 7.00 (d, 2H, J = 8.5 Hz); 6.70 (d, 2H, J = 8.6 Hz); 3.89 (m,
4
H), 3.87 (s, 3H); 3.14 - 2.98 (br m, 4H); 2.34 (t, 2H, J = 7.2 Hz); 2.30 (s,
6H);
1.86 (m, 3H); 1.81 - 1.75 (br m, 3H).
~'C NMR(DMSO-db, 75 MHz): b = 172.3, 169.8, 157.2, 138.9, 133.7,
130.9, 130.8, 117.4, 113.9, 65.9, 62.5, 55.9, 55.3, 49.5, 36.0, 30.6, 27.2,
23.9.
Mass Spectroscopy: (PI-FA.B) 530, (M)+.
Example 29 (346)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
(3-(N,IV diethylamino)propoxy(-L-phenylalanine
Methyl Ester
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 3-diethylaminopropyl chloride in
refluxing 2-butanone in the presence of potassium carbonate and sodium
iodide.
NMR data was as follows:
~H NMR (DMSO-db, 400 Mhz): 8 = 1.0 (6H, bs); 1.4-1.6 (4H, m); 1.85
(2H, m); 2.18 {3H, s); 2.5 (2H, bs); 2.5-2.8 (4H, bs); 2.9 (2H, m); 3.1 (1H,
dd,
J = 8,10,8Hz); 3.35 ( 1 H, dd, J = 8,4,8Hz); 3.6 (3H, s); 3.94 (2H, t, J =
6,6Hz);
4.1 ( 1 H, m); 4.48 ( 1 H, dd, J = 8,6,8Hz); 6.8 (2H, d, J = 1 OHz); 7.1 (2H,
d, J =
1 OHz); 7.4 (2H, d, J = l OHz); 7.7 (2H, d, J = l OHz); 8.2 ( 1 H, d, J = l
OHz).
MS: +ESI, m/z 560.5 ([MH]+, 100 %).

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Example 30 (351)
Synthesis of
N (Thiazole-2-sulfonyl)-L-prolyl-4-
[3-(N,IV dimethylamino)propoxy]-L-phenylalanine
The sulfonyl chloride was prepared from the thiol as taught by Roblin and
Clapp, JACS, 72, 4890, 1950. The title compound was prepared using Method
and was isolated as a white, hygroscopic solid, mp = >200°C.
NMR data was as follows:
10 'H NMR (DMSO-db, 300 MHz): 8 = 8.24 (d, 1 H, J = 3.1 Hz); 8.15 (d,
1 H, 3.1 Hz); 7.63 (d, 1 H, J = 5.0 Hz); 6.98 (d, 2H; J = 8.6 Hz); 6.70 (d,
2H, J =
8.6 Hz); 4.24 (m, 1 H); 3.88 (m, 3H); 3.36 (m, 2H); 3.28 - 2.98 (m, 2H); 2.31
(t, 2H, J = 7.0 Hz); 2.12 (s, 6H); 1.83 - 1.79 (br m, 4H); 1.79 (m, 1 H); 1.45
(m,
1 H).
15 '3C NMR (DMSO-db, 75 MHz): 8 = 172.3, 168.9, 162.5, 157.2, 145.5,
131.0, 130.9, 127.5, 113.8, 65.9, 63.3, 56.1, 55.5, 50.1, 45.6, 38.8, 38.5,
35.9,
30.7, 27.3, 24Ø
Mass Spectroscopy: (PI-FAB) 555, (M-H+Na)+.
Example 31 (353)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[3-(N-methyl-N-benzylamino)propoxy]-L-phenylalanine
The title compound was prepared from the product of Example 33 (356)
using the procedure described in Method 7 as a solid, mp = 87-90°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): 8 = 7.75 {d, 2H, J=IOHz); 7.65 (d, 1H, J
= 4Hz); 7.4 (d, 2H, J = 1 OHz); 7.18-7.3 (m, 5H); 6.96 (d, 2H, J = l OHz);
6.65
(d, 2H, J = l OHz); 3.97 (d, 1H, J = 4Hz); 3.91 (t, 2H, J = 4,4Hz); 3.8 (q,
1H, J
= 2,2,2Hz); 3.42 (s, 2H); 2.95-3.1 (m, 4H); 2.42 (t, 2H, J = 8,8Hz); 2.38 (s,
3H); 2.08 (s, 3H); 1.85 (t, 2H, 6,6Hz); 1.7 (m, 1H); 1.3 (bs, 4H).

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Example 32 (354)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[3-(N,N diethylamino)propoxy]-L-phenylalanine
The title compound was prepared from the product of Example 29 (346)
using the procedure described in Method 7 as a solid, mp = 76-82°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): 8 = 1.0 (6H, t, J = 8,8Hz); 1.38 (2H, m);
1.4-1.8 (4H, m); 2.38 (3H, s); 2.45 (2H, t, 3 = 7,7Hz); 2.6 (4H, q, J =
6,5,6Hz);
2.95 (2H, m); 3.05 ( 1 H, dd, J = S,S,SHz); 3.1 S ( 1 H, dd, J = 4,5,4Hz); 3.9
(2H,
t, J = S,SHz); 4.0 ( 1 H, t, J = 6,6Hz); 4.1 ( 1 H, m); 6.7 (2H, d, J = 1
OHz); 6.95
(2H, d, J = 1 OHz); 7.4 (2H, d, J = 1 OHz); 7.7 ( 1 H, d, J = 4Hz); 7.75 (2H,
d, J =
1 OHz).
Example 33 (356)
Synthesis of
N (Toluene-4-sulfonyl~L-prolyl-4-
[3-(N methyl-N benzylamino)propoxy)-L-phenylalanine
Methyl Ester
The title compound was prepared via O-alkylation of N (toluene-4-
sulfonyl)-L-prolyl-L-tyrosine methyl ester with 3-(N-benzyl,N
methyl)aminopropyl chloride in refluxing 2-butanone in the presence of
potassium carbonate and sodium iodide to provide a solid, mp = 60-70°C.
Example 34 {372)
Synthesis of
N (1-Methylimidazole-4-sulfonyl)-L-prolyl-
4-[3-(N,N dimethylamino)propoxyJ-L-phenylalanine
The title compound was prepared using Method 15 and was isolated as a
white, hygroscopic solid, mp = >200°C.
NMR data was as follows:
'H NMR (DMSO-db, 300 MHz): b = 7.86 (s, 1H); 7.82 (s, 1H); 7.63 (d,
1 H, J = 5.6 Hz); 6.96 (d, 2H, J = 8.2Hz); 6.97 (d, 2H, J = 8.2 hz); 4.12 -
4.09

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{br m, 1H); 3.89 (t, 2H, J = 6.5 Hz); 3.70 ( s, 3H); 3.13 (m , 2H); 3.00 (m,
2H);
2.33 (t, 2H, 7.2Hz); 2.13 (s, 6H); 1.82-1.75 (m, 3H), 1.60-1.40 (br m, 3H).
'3C NMR (DMSO-db, 75 MHz): b = 172.8, 169.9, 157.2, 140.7, 136.1,
130.9, 126.6, 113.9, 65.9, 62.9, 56.0, 55.3, 49.7, 45.5, 35.9, 33.9, 30.6,
27.3,
24.0, 21.9.
Mass Spectroscopy: (PI-FAB) 552, (M-H+Na)+.
Example 35 (373)
Synthesis of
N (2-Methylthiadiazole-5-sulfonyl)-L-prolyl-
4-[3-(N,IV dimethylamino)propoxy]-L-phenylalanine
The sulfonyl chloride was prepared from the thiol as taught by Roblin and
Clapp, JACS, 72, 4890, 1950. The title compound was prepared using Method
15 and was isolated the as a white, hygroscopic solid, mp = >200°C.
NMR data was as follows:
'H NMR (DMSO-db, 300 MHz): b = 7.66 (d, 1H, J = 3.2 Hz); 7.02 (d,
2H, J = 8.5 Hz); 6.72 (d, 2H, J = 8.2 Hz); 4.28 (t, 1H; 5.8 Hz); 3.96-3.89 (br
m, 3H); 3.37-3.23 (br m, 2H); 3.02 (m, 1H); 2.95 (m, 1H); 2.82 (s, 3H); 2.39
(t, 2H, J = 7.0 Hz); 2.13 (s, 6H); 1.83 (m, 3H); 1.80-1.40 (m, 3H).
'3C NMR (DMSO-db, 75 MHz): b = 173.2, 170.9, 169.0, 165.9, 157.2,
130.9, 130.8, 113.9, 65.9, 63.1, 56.0, 55.6, 50.1, 45.4, 32.2, 30.9, 27.2,
24.1,
22.3, 15.9.
Mass Spectroscopy: (PI-FAB) 548, (M)'.
Example 36 (393)
Synthesis of
N (Toluene-4-sulfonyl)-L-thiaprolyl-4
[3-(N,IV dimethylamino)propoxy]-L-phenylalanine
The title compound was prepared as in Example 18 (138) except L-
thiaproline is used in place of L-proline.
NMR data was as follows:
'H NMR (300 MHz, CD30D): b = 7.57 (d, 2H, J = 8.40 Hz), 7.20 (d, 2H,
J = 8.10 Hz), 6.92 (d, 2H, J = 8.40 Hz), 6.58 (d, 2H, J = 8.40 Hz), 4.50 (dd,

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I H, J = 4.20, 7.50 Hz), 4.45 (d, I H, J = 10.50 Hz), 4. I 7 (m, 1 H), 3.87
(d, 1 H, J
= 10.50 Hz), 3.76 (t, 2H, J = 6.00 Hz), 3.10 (m, 1 H), 2.99 (m, 2H), 2.80 (m,
IH), 2.55 (m, 2H), 2.35 (m,1H), 2.25 (s, 6H), 2.22 (s, 3H), 1.79 (m, 2H).
'3C NMR (75 MHz, CD30D): 8 = 177.75, 170.46, 159.43, 146.91, 135.93,
132.42, 131.73, 129.80, 115.75, 67.25, 57.90, 57.70, 52.92, 45.30, 38.33,
Example 37 (472)
Synthesis of
N (4-Cyanobenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl
4-[3-(N,1V dimethylamino)propoxy]-L-phenylalanine
Methyl Ester
The title compound was prepared following the procedure outlined for the
34.73, 27.94, 24.74, 22.16.
Mass Spectroscopy: (FAB) 546 (M+H).
preparation of Example 20 (284).
NMR data was as follows:
'H NMR (CDC13): b 7.98-7.95 (d, 2H), 7.83-7.80 (d, 2H), 7.06-7.03 (d,
2H), 6.80-6.77 (d, 2H), 4.80 (m, IH), 4.48 (m, 1H), 3.95 (m, 3H), 3.73 (s,
3H),
3.02 (m, 2H), 2.45 (m, 2H), 2.26 (s, 6H), 1.94 (m, 2H), 1.21 (s, 3H), 1.17 (s,
Example 38 (514}
Synthesis of
N (Toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-
4-[3-(N,1V dimethylamino)propoxy]-L-phenylalanine
3H).
"C NMR (CDC13): b 179.9, 168.2, 158.8, 141.1, 133.7, 130.9, 128.1,
117.9, 115.2, 74.2, 66.7, 56.9, 55.3, 53.9, 53.0, 51.1, 46.0, 38.0, 29.9,
28.0,
24.4.
L-Thiamorpholine-5-carboxylic acid was prepared by the method of
Larsson and Carlson (Acta Chemica Scan. 1994, 4$, S 17-525). N-(Toluene-4-
sulfonyl)-L-thiamorpholine-5-carboxylic acid using the procedure described in
Method 1. The title compound was prepared following the procedure outlined
for the preparation of Example 20 (284).
*rB

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NMR data was as follows:
'H NMR (CD30D): 8 7.53-7.47 (m, 2H), 7.20-7.14 (m, 2H), 7.00-6.85
(m, 2H), 6.58-6.54 (m, 2H), 4.70-4.57 (m, 1H), 4.22-4.14 (m, 1H), 3.77-3.71
(m, 3H), 3.25-3.09 (m, 1H), 2.93-2.59 (m, 4H), 2.44 (rn, 3H), 2.22 (s, 3H),
2.18 (s, 6H), 1.92 (m, 1 H), 1.68 (m, 2H).
'3C 1VMR (CD30D): b 177.9, 177.8, 169.6, 169.4, 159.6, 159.5, 146.3,
146.1, 138.9, 138.9, 132.8, 132.4, 131.8, 130.5, 129.8, 129.2, 126.9, 115.8,
115.7, 67.4, 58.1, 57.8, 57.1, 45.6, 44.9, 38.8, 37.9, 28.2, 28.2, 27.9, 26.6,
26.3, 24.7, 22.1.
Example 39 ( 169)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[2-(carboxy)phenoxy]-L-phenylalanine Methyl Ester
N (Toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester (2.14 g, 5.16
mmol) was added to a suspension of sodium hydride (60% in oil, 1.1 eq, 228
mg) in xylenes (50 mL) at 0°C. The reaction mixture was stirred for 5
minutes and cuprous bromideodimethyl sulfide complex (1.4 eq, 1.48 g) was
added. The reaction mixture was stirred at 23°C for 0.5 hours. 2-Iodo
sodium
benzoate (1.5 eq, 8.06 mmol) was added and the reaction mixture was refluxed
for 12 hours. EtOAc {100 mL) was added, and the organic layer washed with
NH4C1, 10% HCI, and brine, dried over MgS04. The crude material was
eluted on column chromatography (silica gel), with CHCI3:MeOH 9:1, and the
title compound was isolated as an oil.
NMR data was as follows:
'H NMR (300 MHz, CDC13): 8 = 8.16 (broad d, 1H), 7.73 (m, 2H), 7.47
{m, 2H), 7.35 (m, 2H), 7.21 (m, 2H), 7.03 (m, 2H), 6.76 (m, 1H), 4.85 (m,
1 H), 4.07 (m, 1 H), 3.77 (s, 3H), 3.41 (m, 1 H), 3.28 (m, 1 H), 3.09 (m, 2H),
2.44 (s, 3H), 2.05 (m, 1H), 1.55 (m, 3H).
Mass Spectroscopy: (FAB) 567 (M+H).

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Example 40 (309)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
{2-[4-(pyrimidin-2-yl)piperazin-1-yl]ethoxy[-L-phenyialanine
The methyl ester was prepared by Mitsunobu reaction of N (toluene-4-
sulfonyl)-L-prolyl-L-tyrosine methyl ester following the procedure described
for the preparation of Example 20 (284). The title compound was prepared
using the procedure described in Method 7 as a solid, mp = 102-105°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): 8 = 1.35 (4H,s); 1.4 ( 1 H,m); 1.76
(lH,m); 2.38 (3H,s); 2.5 (2H, m); 2.66 (2H, t, J = 8,8Hz); 2.9-3.1 (4H,m);
3.68
(4H, t, J = S,SHz); 3.8 ( 1 H, q; J = 4,6,4Hz); 3.95 ( 1 H, dd, J = 2,10,2Hz);
4.05
(2H, t, 6,6Hz); 6.6 (1H, t, J = S,SHz); 6.7 (2H, d, J = l OHz); 6.96 (2H, d, J
=
1 OHz); 7.4 (2H, d, J = 1 OHz); 7.65 ( 1 H, d, J = 4Hz); 7.74 (2H, d, J = 1
OHz);
8.35 (2H, d, J = SHz).
Example 41 (310)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
(3-(piperidin-1-yl)propoxy]-L-phenylalanine
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 1-(2-chloropropyl)piperidine in
refluxing 2-butanone in the presence of potassium carbonate and sodium
iodide. The title compound was prepared using the procedure described in
Method 7 as a solid, mp = 122-125 °C.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): b = 7.74 (d, 2H, J = IOHz); 7.65 (d, 1H, 3
= 4Hz); 7.4 (d, 2H, J = l OHz); 6.96 (d, 2H, J = l OHz); 6.65 (d, 2H, J =
IOHz);
3.96 (dd, 1H, J = 2,6,2Hz); 3.9 (t, 3H, J = 7,7Hz); 2.95-3.1 (m, 4H); 2.46 (t,
1H, J = 2,2Hz); 2.38 (s, 3H); 2.33 (t, 2H, J = 8,8Hz); 2.24 (m, 2H); 1.78 (m,
3H); 1.45 (t, 4H, J=S,SHz); 1.38 (m, 4H).

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Example 42 (311 )
Synthesis of
N {Toluene-4-sulfonyl)-L-prolyl-4
(2-(pyrrolidin-1-yl)ethoxy(-L-phenylalanine
The methyl ester was prepared via D-alkylation of N (toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 1-(2-chloroethyl)pyrrolidine in
refluxing
2-butanone in the presence of potassium carbonate and sodium iodide. The
title compound was prepared using the procedure described in Method 7 as a
solid, mp = 127-130°C.
NMR data was as follows:
~H NMR (DMSO-db, 400 Mhz): b = 7.73 (d, 2H, J = IOHz); 7.65 (d, 1H, J
= 4Hz); 7.4 (d, 2H, J = l OHz); 6.95 (d, 2H, J = l OHz); 6.65 (d, 2H, J = l
OHz);
3.95 (t, 3H, J = 4,6Hz); 3.7 {q, 1H, J = 2,4,2Hz); 2.95-3.1 (m, 4H); 2.72 (t,
2H,
J = 6,6Hz); 2.48 (m, 3H); 2.38 (s, 3H); 1.74 (m, 1 H); 1.64 (t, 4H, J =
4,4Hz);
1.42 (m, 1H); 1.37 (s, 3H).
Example 43 (316)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
{3-j4-(3-chlorophenyl)piperazin-1-yl(propoxy}-I,-phenylalanine
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 1-(3-chlorophenyl)-4-(3-chloro-
propyl)piperazine in refluxing 2-butanone in the presence of potassium
carbonate and sodium iodide. The title compound was prepared using the
procedure described in Method 7 as a solid, mp = 116-8°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): b = 7.74 (d, 2H, J = IOHz); 7.65 (d, 1H, 3
= 4Hz); 7.4 (d, 2H, J = lOHz); 7.2 (t, 1H, J = 8,8Hz); 6.96 (d, 2H, J = l
OHz);
6.9 (s, 1H); 6.85 (d, 1H, J = lOHz); 6.75 (d, 1H, J = IOHz); 6.7 (d, 2H, J =
IOHz); 3.95 (d, 2H, J = 8Hz); 3.92 (t, 1H, J = 8,8Hz); 3.83 (q, 1H, J =
5,4,5Hz); 3.6 (t, 1H, 5,5Hz); 3.15 (t, 4H, J = 4,4Hz); 2.95-3.1 (m, 4H); 2.5
(m,
3H); 2.45 (t, 2H, J = 8,8Hz); 2.38 (s, 3H); 1.84 (t, 2H, J = 7,7Hz); 1.75 (m,
1H); 1.4 (q, 1H, J = 8,10,8Hz); 1.35 (s, 2H).

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Example 44 {318)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyi-4-
[(1-tert-butoxycarbonylpiperidin-3-yl)methoxy)-
L-phenylalanine Methyl Ester
N (Toluene-4-sulfonyl)-L-prolyl-O-[(1-tert-butoxycarbonyl)-piperidin-3-
yl)methyl]-L-tyrosine methyl ester was prepared via O-alkylation of N
(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with N Boc-3-
piperidinemethyl tosylate in refluxing 2-butanone in the presence of potassium
carbonate and sodium iodide to provide a solid, mp = 60-62°C.
The title compound was prepared from this product using the procedure
described in Method 7 to provide a solid, mp = 82-84°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 MHz): ~= 12.77 (br s, 1H), 8.00 (d, 1H, J =
7.9Hz); 7.68 (d, 2H, J = 8.3Hz); 7.39 (d, ZH, J = 7.9Hz); 7.13 (d, 2H, J =
8.6Hz); 6.81 (d, 2H, 8.6Hz); 4.42 (m, 1 H), 4.10 (m, 1 H), 3.78 (m, 3H); 3.07
(dd, 1 H, J = 9.7, 4.1 Hz); 2.95 (dd, 1 H, J= 19Hz, 5.1 Hz); 2.90 (dd, 1 H, J
=l9Hz); 2.8 (m, 2H); 1.80 (m, 2H); 1.58 (m, 4H); 1.34 (br s 14H).
IR (KBr, cm'): 3400, 2900, 1745, 1700, 1525, 1450, 1350, 1250, 1160,
850, 800, 700, 650, 600.
Mass Spectroscopy: (FAB, m/e {%)) 652 (75, (M+Na')); 530.2 {75); 224
( 100).
Example 45 (322)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[2-(morpholin-4-yl)ethoxy]-L-phenylalanine
The methyl ester was prepared by alkylation of N-(toluene-4-sulfonyl)-L-
prolyl-L-tyrosine methyl ester with N-{2-chloroethyl)rnorpholine (cesium
carbonate, DMF at 60°C under Argon for 72 hrs). The product was
purified
by flash column chromatography (silica, EtOAc) to afford the methyl ester as
an off white foam. The title compound was prepared using the procedure
described in Method 6 as a solid, mp = 99-101 °C.

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NMR data was as follows:
NB contains traces Tos-Pro-Phe (NMR)
'H NMR (DMSO-db, 400 MHz): ~= 7.73 (d, 2H, J = 8.6Hz); 7.62 (d,
1H, J = S.SHz); 7.40 (d, 2H, J = 8.2Hz); 6.69 (d, 2H); 3.95 (m, 3H); 3.8 (m,
1H); 3.55 (m, 4H); 3.1 (m, 3H); 2.62 (t, 2H, J = 4Hz); 2.4 (m, 4H); 2.38 (s,
3H); 1.7 (m, 2H); 1.4 (m, 3H).
IR (ICBr, cm''): 3400, 2950, 2850, 1610, 1510, 1425, 1340, 1245, 1150,
1125, 825, 800, 675, 575, 525.
Mass Spectroscopy: (FAB, m/e (%)) 552 (100, (M+H+)).
Example 46 (325)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[2-(piperidin-1-yl)ethoxyJ-L-phenylalanine
The methyl ester was prepared by Mitsunobu reaction of N (toluene-4-
sulfonyl)-L-prolyl-L-tyrosine methyl ester with piperidineethanol following
the procedure described for the preparation of Example 20 (284). The title
compound was prepared using the procedure described in Method 7 as a solid,
mp = 102-106°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 MHz): ~= 7.73(d, 2H, J = 8Hz); 7.60 (d, 1H, J
= S.SHz); 7.39 (d, 2H, J = 8Hz); 6.96 (d, 2H, J = 8.6Hz); 6.68 (d, 2H, J =
8.6Hz); 3.96 (m; 3H); 3.84 (dd, 1H J = 5.2, 4.8Hz); 2.97-3.10 (m, 4H); 2.56
(t, 2H, J = 5.9Hz); 2.38 (br s, 6H); 1.72 (m, 1 H); 1.34-1.48 (m, l OH).
IR (ICBr, cm-'): 3400, 2900, 1660, 1610, 1510, 1450, 1350, 1150, 875,
675, 600, 550.
Mass Spectroscopy: (FAB, m/e (%)) 542 (100, (M-H~)); 196 (10); 155
(75).

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Example 47 (326)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
{3-(4-(3-chlorophenyl)piperazin-1-yl]propoxy}-
L-phenylalanine Methyl Ester
The methyl ester was prepared via D-alkylation of N (toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 1-(2-chlorophenyl)-4-(3-chloro-
propyl)piperazine in refluxing 2-butanone in the presence of potassium
carbonate and sodium iodide.
NMR data was as follows:
'H NMR (DMSO-d6, 400 Mhz): b = 8.2 (d, IH, J = IOHz); 7.68 (d, 2H, J
= IOHz); 7.4 {d, 2H, J = IOHz); 7.19 (t, 1H, J = 8,8Hz); 7.13 (d, 2H, J =
1 OHz); 6'.9 (s, 1 H); 6.85 (d, 1 H, J = l OHz); 6.82 (d, 2I3, J = l OHz);
6.75 (d,
1 H, J = 1 OHz); 4.45 (q, 1 H, J = 8,5,8Hz); 4.08 (t, 1 H, J = 4,4Hz); 3.94
(t, 2H, J
= S,SHz); 3.3 (s, 3H); 3.12 {bs, 4H); 3.1 (t, 1H, J = 8,8Hz); 2.96 (m, 2H);
2.47
(m, 3H); 2.38 (s, 3H); 1.85 (t, 2H, J = 6,6Hz); 1.57 (m, 3H); 1.4 (m, 1H).
MS: EI, m/z 682/684 ([MH]+, 18 %), 209 (26%).
Example 48 (327)
Synthesis of
N (Toluene-4-sulfoayl)-L-prolyl-4
[2-(azepan-1-yl)ethoxy]-L-phenylalanine
The title compound was prepared from the product of Example 49 (328)
using the procedure described in Method 7 as a solid, mp: 105-107°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): 8 = 7.75 (t, ZH, J = 8,8Hz); 7.45 (d, 1H, J
= 8Hz); 7.4 (t, 2H, J = 8,8Hz); 7.05 (d, 1H, J = lOHz); 6.96 (d, 1H, J =
IOHz);
6.7 (d, 1H, J = IOHz); 4.1 (t, 1H, J = S,SHz); 3.92 (t, 3H, J = 8,8Hz); 3.82
(m,
1H); 3.6 (t, 1H); 2.8 (t, 2H, J = 6,6Hz); 2.66 (d, 4H, J = SHz); 2.5 (d, 3H, J
=
IOHz); 1.76 (t, 1H, 7,7Hz); 1.65 (m, 1H); 1.5 (bs, 6H); 1.43 (t, 2H, J =
8,8Hz);
1.36 (m, 2H); 1.28 (s, 1 H); 1.15 (s, 1 H).

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Example 49 (328)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[2-(azepan-1-yl)ethoxy]-L-phenylalanine Methyl Ester
10
The title compound was prepared via O-alkylation of N (toluene-4-
sulfonyl)-L-prolyl-L-tyrosine methyl ester with 2-(hexamethylene-imino)ethyl
chloride in refluxing 2-butanone in the presence of potassium carbonate and
sodium iodide to provide a solid, mp = 60-65 °C.
Example 50 (347)
Synthesis of
N (Toluene-4-sulfonyl)-L-proiyl-4-
[3-(4-methylpiperazin-1-yl)propoxy]-
L-phenylalanine Methyl Ester
The methyl ester was prepared via O-alkylation of N (toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 3-(N methylpiperazine)propyl chloride
in refluxing 2-butanone in the presence of potassium carbonate and sodium
iodide.
NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): 8 = 8.2 (t, 1H, J = lO,IOHz); 7.7 (t, 2H, J
= 10, l2Hz); 7.4 (d, 2H, J = l OHz); 7.1 (t, 2H, J = 10,10Hz); 6.8 (d, 2H, J =
IOHz); 4.44 (q, 1H, J = 4,6,6Hz); 4.1 (dd, 1H, J = 14,8,8Hz); 3.93 (t, 2H, J =
6,6Hz); 3.6 (s, 3H); 3.08 ( q, 1H, J = 6,4,4Hz); 3.0 (dd, 1H, J = 12,4,4Hz);
2.9
(m, 2H); 2.38 (s, 3H); 2.2-2.35 (m, lOH); 2.12 (s, 3H); 1.8 (t, 2H, J =
6,6Hz);
1.55 (m, 3H); 1.41 (m, 1H).
MS: +ESI, mlz 587 ([MH]+, 100 %).
Example 51 (355)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[3-(4-methylpiperazin-1-yl)propoxy]-L-phenylalanine
The title compound was prepared from the product of Example 50 (347)
using the procedure described in Method 7 as a solid, mp = 80-83 °C.

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NMR data was as follows:
'H NMR (DMSO-db, 400 Mhz): 8 = 7.75 (d, 2H, J = IOHz); 7.63 (d, 1H, J
= 4Hz); 7.4 (d, 2H, J = IOHz); 7.05 (d, 2H, J = l OHz); 6.95 (d, 2H, J = l
OHz);
6.67 (d, 2H, J = l OHz); 4.1 (d, 1 H, J = 8Hz); 3.94 {d, 1 H, J = 8Hz); 3.9
(t, 2H,
S J = S,SHz); 3.8 (bs, 1H); 3.08 {m, 1H); 2.91 (d, 1H, J = IOHz); 2.85 (dd,
2H, J
= 6,18,6Hz); 2.38 (s, 3H); 2.1 S-2.35 i m, 8H); 2.14 (s, 3H); 1.78 (q, 2H, J =
6,8,6Hz); 1.7 (m, 1H); 1.4 (m, 1H); 1.37 (m, 2H).
Example 52 (345)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl
4-N (trifluoromethanesulfonyl)amino
L-phenylalanine Methyl Ester
The title compound was produced by reaction of N-(toluene-4-sulfonyl)-
L-prolyl-(4-amino)phenylalanine methyl ester with trifluoromethanesulfonic
acid anhydride in pyridine to provide a solid, mp = 75-78°C.
Example 53 (370)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl
4-N-(trifluoromethanesulfonyl)amino-L-phenylalanine
The title compound was prepared from the product of Example 52 (345)
using the procedure described in Method 6.
NMR data was as follows:
'H NMR (CDCl3, 400MHz): 8 = 8.08 (s, 1H); 7.7 (d, 2H); 7.56 (d, 1H);
7.34 (d, 2H); 7.22 (s, 2H); 4.85 (m, 1H); 4.16 (m, 1H); 3.40 (m, 3H); 3.09 (m,
2H); 2.44 (s, 3H); 1.86 (m, 1H); 1.50 (m, 3H).
IR (ICBr, cm-1): 3390; 2950; 1750; 1650; 1525; 1425; 1375; 1340; 1200;
1150; 950; 825; 625; 590; 550.
Mass Spectroscopy: (+ESI) 564 ( [M+H]+ ); 530; 462; 406; 362; 342;
335; 157.

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Example 54 (387)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[(N benzylaminocarbony)methoxy]-L-phenylalanine
Methyl Ester
The title compound was prepared by alkylation of N (toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with N benzyl-2-chloroacetamide (potasium
carbonate, sodium iodide, refluxing butanone under Argon overnight). The
product was purified by flash column chromatography (silica, l:l
hexane:EtOAc) to afford the methyl ester as a white solid, mp = 57-
59°C.
Example 55 (389)
Synthesis of
1 S N (Toluene-4-sulfonyl)-L-prolyl-4-
[(benzyloxycarbony)methoxy]-L-phenylalanine
The title compound was prepared from the product of Example 4 (387)
using the procedure described in Method 6 as a solid, mp = 79-81 °C.
NMR data was as follows:
'H NMR (DMSO-db, 400 MHz): ~ = 12.2 (br s, 1 H); 8.60 (t, 1 H); 8.03 (d,
1 H, J = 7.9Hz); 7.70 (d, 2H, J = 6.6Hz); 7.39 (d, 2H, J = 8.4Hz); 7.15 (d,
2H, J
= 8.6Hz); 6.87 (d, 2H, J = 8.6Hz); 4.48 (s, 2H); 4.42 (m, 1 H); 4.31 (d, ZH, J
=
6.3Hz); 4.10 (m, 1H); 3.0-3.2 (m, 2H); 2.8-2.9 (m, 2H); 2.38 (s, 3H); 1.2-1.6
(m, 4H).
IR (KBr, cm'): 3400, 2950, 1725, 1660, 1525, 1510, 1450, 1350, 1240,
1150, 1080, 670, 575, 550.
Mass Spectroscopy: (FAB, m/e (%)) 602 (10, (M+Na-)); 580 (10,
(M+H+)); 131 ( 100).
Example 56 (390)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-
4-[(carboxy)methoxy]-L-phenylalanine
Alkylation of N (toluene-4-sulfonyl)-L-prolyi-L-tyrosine methyl ester
with t-butyl bromoacetate (potasium carbonate, DMF, under Argon for 72 hrs)

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gave N (toluene-4-sulfonyl)-L-prolyl-L-O-(tent-butoxycarbonylmethyl)-
tyrosine methyl ester after purification by flash column chromatography
(silica, 1:1 hexane:EtOAc) to afford a white solid, mp = 55 °C.
S N (Toluene-4-sulfonyl)-L-prolyl-L-O-(tent-butoxycarbonylmethyl)-
tyrosine was prepared from the N (toluene-4-sulfonyl)-L-prolyl-L-O-{tert-
butoxycarbonylmethyl)-tyrosine methyl ester using the procedure described in
Method 6 as a solid, mp = 69-70°C.
The title compound was prepared from N (Toluene-4-sulfonyl)-L-prolyl-
L-O-(tent-butoxycarbonylmethyl)-tyrosine by reaction with formic acid.
Removal. of the formic acid and tituration with ether afforded the desired
compound as a white solid, mp = 70-73 °C.
NMR data was as follows:
'H NMR (DMSO-db, 400 MHz): ~= 12.85 (br s, 2H); 8.01 (d, 1H, J =
7.9Hz); 7.69 (d, 2H, J = 8.3Hz); 7.39 (d, 2H, J = 8.3Hz); 7.13 (d, 2H, J =
8.8Hz); 6.79 (d, 2H, J = 8.6Hz); 4.6 (s, 2H); 4.42 (m, 1 H); 4.10 (m, 1 H);
3.08
{m, 1H); 2.95 (m, 2H); 2.38 (s, 3H); 1.5 (m, 4H).
IR (KBr, cm'): 3350, 2950, 1730, 1625, 1510, 1425, 1340, 1175, 1160,
1075, 825, 675, 575, 550.
Mass Spectroscopy: (FAB, m/e (%)) 513 (100, (M+Na-)), 491 (75,
(M+H')).
Example 57 (407)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
[(aminocwrbonyl]-L-phenylalanine Methyl Ester
The title compound was prepared by alkylation of N-(toluene-4-sulfonyl)-
L-prolyl-L-tyrosine methyl ester with 2-chloroacetamide (potasium carbonate,
sodium iodide, refluxing butanone under Argon for 48 hr). The product was
purified by flash column chromatography (silica, EtOAc, then S% MeOH in
EtOAc) to afford the title compound as a white solid, mp = 60-
64°C.

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Example 58 (408)
Synthesis of
N (Toluene-4-suifonyl)-L-protyl-4
[(aminocarboayl)methoxy]-L-phenylalanine
The title compound was prepared from the product of Example 57 (407)
using the procedure described in Method 6 as a solid, mp = 195-196°C.
NMR data was as follows:
' H NMR (DMSO-db, 400 MHz): ~ = 12.2 (br s, 1 H); 8.02 (d, 1 H, J =
8.lHz); 7.69 (d, 2H, J = 8.3Hz); 7.47, (br s, 1H); 7.40 (d, 2H, J = 7.9Hz);
7.35
(br s, I H); 7.14 (d, 2H, J = 8.6Hz); 6.84 (d, 2H, .1= 8.6Hz); 4.40 (m, I H);
4.35
(s, 2H); 4.11 (dd, 1 H); 3.09 (m, I H); 2.91 (dd, 1 H); 2.39 (s, 3H); I .45-
1.55
(m, 3H); 1.40 (m, 1H).
1R (ICBr, cm-'): 3500, 3350, 3250, 2950, 1725, 1675, 1660, 1560, 1510,
1450, 1400, 1350, 1225, 1200, 1150, 1050, 825, 660, 575, 550.
Mass Spectroscopy: (FAB, m/e (%)) 488 (100, (M-H-)).
Example 59 (409)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4-
[(N tert-butylaminocarbonyl)methoxy]-L-phenylalanine
The methyl ester was prepared by alkylation of N-(toluene-4-sulfonyl)-L-
prolyl-L-tyrosine methyl ester with 2-chloro-N-tert-butylacetamide (potasium
carbonate, sodium iodide, reflux in butanone under Argon overnight). The
product was purified by flash column chromatography (silica, 1:1
hexane:EtOAc) to afford the methyl ester as a white solid. The title compound
was prepared using the procedure described in Method 6 as a solid, mp = 88-
89°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 MHz): ~= 12.2 (br s, 1H); 8.02 (d, 1H, J =
8Hz); 7.68 (d, 2H, J = 8.3Hz); 7.39 (d, 3H, J = 8Hz); 7.14 (d, 2H, J = 8.8Hz);
6.82 (dd, 2H, J = 8.4, 2Hz); 4.4 (m, 1 H); 4.32 (s, 2H); 4.10 (dd, 1 H, J =
2.9,
8Hz); 3.07 (m, 1H); 3.0 (dd, 1H, J = 18.7, 27.SHz); 2.94 (dd, 1H, J = 17.8,
26Hz), 2.39 (s, 3H); 1.5 (m, 3H); 1.4 (m, 1H); 1.29 (s, 9H).

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IR (KBr, cm '): 3400, 2950, 1745, 1675, 1525, 1450, 1350, 1225, 1160,
1075, 825, 675, 575, 540.
Mass Spectroscopy: (FAB, m/e (%)) 544 (100, (M-H-)).
Example 60 (4 i 0)
Synthesis of
N (Toluene-4-sulfonyl)-L-prolyl-4
(2-(4-phenyl-4-hydroxypiperidin-i-yl)ethoxy]-L-phenylalanine
Methyl Ester
The methyl ester was prepared by alkylation of N (toluene-4-sulfonyl)-L-
prolyl)-L-O-(2-chloroethyl)tyrosine methyl ester with 4-hydroxy-4-phenyl
piperidine (potassium carbonate, sodium iodide, in refluxing butanone under
Argon for 72 hr). The product was purified by flash column chromatography
(silica, S% methanol in chloroform) to afford the methyl ester as a white
foam.
The title compound was prepared using the procedure described in Method 6
as a solid, mp = 122-123°C.
NMR data was as follows:
'H NMR (DMSO-db, 400 MHz): ~ = 7.72 (m, 2H); 7.61 (d, 1 H, J =
S.SHz); 7.39 (d, 2H, J = 7.2Hz); 7.28 (m, 2H); 7.17 (m, 1H); 7.04 (d, 1H, J =
8.8Hz); 6.96 (d, 1H, J = 8.6Hz); 6.71 (dd, 2H, J = 2.4, 8.8Hz); 4.75 (s, 1H);
4.1 (m, 1H); 4.0 (m, 2H); 3.9 (q, 1H); 3.8 (q, 1H); 2.8-3.1 (m, 4H,
overlapping
signals); 2.7 (m, 4H, overlapping signals); 2.38 (s, 3H); 1.65 (m, 2H); 1.55
(m,
2H); 1.4 (m, 2H).
IR (KBr, crri'): 3375, 2890, 1660, 1610, 1510, 1390, 1325, 1250, 1160,
1075, 1040, 700, 675, 575, 530.
Mass Spectroscopy: (FAB, m/e (%)) 648 (100, (M+2Li-H)'), 642 (90
(M+Li)+).
Example 61 (375)
Synthesis of
N (Toluene-4-sulfonyl)sarcosyl-
D,L-4-(amidino)phenylalanine
*rB

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N (Toluene-4-sulfonyl)sarcosyl-D,L-4-cyanophenylalanine methyl ester
(see Example 61 (381) (167 mg, 0.388 mmol) was dissolved in pyridine (6
mL) and then H2S gas was bubbled in until saturated. The mixture was stirred
for 19 hours then the volatiles were removed under a stream of Nz. The
residue was taken up into EtOAc (SO mL) and washed with 5% aq KHS04 (2
X 25 mL). The organic solution was dried (Na2S04), filtered and evaporated
in vacuo to give N (toluene-4-sulfonyl)sarcosyl-D,L-4-
thiocarboxamidophenylal anine methyl ester. The thioamide was dissolved in
acetone (10 mL). Iodomethane (1 mL) was added and the mixture was heated
to reflux for lhr. The volatiles were removed in vacuo to give N {toluene-4-
sulfonyl)sarcosyl-D,L-4-methylthioimidatephenylalanine methyl ester
hydroiodide (256 mg, 100%). The thioimidate was dissolved in MeOH (5
mL). Ammonium acetate (52 mg, 0.67 mmol) was added and the mixture was
heated to reflux for 1.5 hr. The solvent was removed in vacuo and the residue
was purified by preparative TLC (90:10:1 CHZC12/MeOH/NH40H) to give N
{toluene-4-sulfonyl)sarcosyl-D,L-4-amidinophenylalanine methyl ester (75
mg, 38%). The title compound was prepared via hydrolysis of the methyl
ester using 0.5 N NaOH in THF/water (66 mg, 87%).
NMR data was as follows:
'H NMR (DMSO-db): 8 = 7.66 (m, 4H), 7.43 (d, 2H, J = 7.7 Hz), 7.29 (d,
2H, J = 8.0 Hz), 4.10 (m, 1H), 3.57 (s, 2H), 3.20-3.06 (m, 2H}, 2.54 {s, 3H),
2.40 (s, 3H).
Mass Spectroscopy: FAB m/e 433 (M+H).
Example 62 (381)
Synthesis of
N (Toluene-4-sulfonyl)sarcosyl
D,L-4-(aminocarbonyl)phenylalanine
N-(Toluene-4-sulfonyl)sarcosine was coupled to 4-cyanophenylalanine
methyl ester hydrochloride (prepared via the method of Wagner, Voight, and
Vieweg Pharmazie 1984, 39, 226-230) to give N-(toluene-4-sulfonyl)sarcosyl-

CA 02290747 1999-11-19
WO 99/06431 PCT1US98/15313
-- 153 --
D,L-4-cyanophenylalanine methyl ester. The compound was prepared vIa
hydrolysis of the methyl ester using 0.5 N NaOH in THF/water.
N (Toluene-4-sulfonyl)sarcosyl-D,L-4-cyanophenylalanine methyl ester
(300 mg, 0.699 mmol) was slurried in EtOH (3mL). NaOH ( l ON, 98 pL) and
HzOZ (475 pL, 5.51 mmol) were added. The mixture was heated to 50 ~C for
16 hr whereupon a white precipitate deposited. The mixture was cooled to
room temp and made acidic with HCI (6N). The mixture was diluted with
water (20 mL) and extracted with chloroform (4 X 25 mL). The organic
extracts were dried (NazS04), filtered and recrystallized from methanol to
give
the compound as a white solid (135 mg, 45%).
NMR data was as follows:
'H NMR (DMSO-db): b = 8,31 (br d, 1 H, J = 3.6 Hz), 7.92 (br s, 1 H), 7.72
(d, 2H, J = 7.8 Hz), 7.62 (d, 2H, J = 7.9 Hz), 7.40-7.21 (SH), 4.47 (m, 1H),
3.59 (m, 2H), 3.15 (m, 1H), 2.94 (m, 1H), 2.53 (s, 3H), 2.39 (s, 3H).
"C NMR (DMSO-db): 8 = 172.9, 168.0, 167.3, 143.7, 141.3, 134.2,
132.8, 130.1, 129.4, 127.8, 127.7, 53.4, 52.4, 36.7, 36.0, 21.3.
Mass Spectroscopy: FAB m/e 434 (M+H).
Other compounds prepared by the methods described above include those
set forth in Table II below as Examples 63-135:
*rB

CA 02290747 1999-11-19
WO 99/Ob431 PCT/US98/15313
-- 154 --
z
a ,''c .~'c ."'c .'~o ,o
O C I ' l C
N T
N C N
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v _ n O_ :r
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W J w
v V
y /
v Z
r Z Z Z
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C
G
4:
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r.
5
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O= x
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F ~ j p J
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~, Z ~
M M .
v
x
CG v _ L; 'v
v
C L" C C

CA 02290747 1999-11-19
WO 99/06431 PCTNS98/15313
-- 155 --
.o
~z
L
o ~ ~ ~ i ~ r'
b
X
~r Cr v y r v/
j, T n n
N
C C ~~ N N
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C C 4 C C C C C

CA 02290747 1999-11-19
WO 99/06431 PCT/US98I15313
-- 156 --
b
n ~ x x x ~
x z ~
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a c_
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n

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 157 --
a a a ~ ~ ~ a a
n ~ %~ i7 n ~ ~ n
x z x ~. .~ x x
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r
z

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
-- 158 --
b b b b b b b b ' b b
n n n n r1 f'~ C')~ n
S. x .:.~ .~ z z
~- ~ ~- 9-9- ~- 'A-9-
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r
z

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/15313
__ 159 -_
b b b "~ b ~ '~ '~ C
C7 n ,'~ !~ .'7 ~ C7 n
x x x x .~ x x
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... ' ..rN
n
Z

CA 02290747 1999-11-19
WO 99/06431 PCT/US98/I5313
-- 160 --
r-
a a ~ a a a a
n n ~'7 %~ ~ n n
x ~ x x x
a e. $. e. B-
c
~;
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vJ ~ V1 i'.. ',,.iN --' f5
z

CA 02290747 1999-11-19
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yv a ? Z'
n Z x n C7 Z w
x
a $. a a ,
W Z ~ ~ W ~. : W n _~ ~ 7C
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WO 99/06431 PCT/US98/15313
-- 162 --
b ~ a a a a
x x
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$ ~- ~ ~- $ ~- $- '$
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b b
x x
$ $
C., : ~- ~''
w w 7C
;C1 70
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S ?
" "
3' =~ 3 ~
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Z
0

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Further to the above, the following additional compounds were prepared
as Examples 136-140:
Example 136
Synthesis of N (Toluene-4-sulfonyi)-L-{5,5-dimethyl)thiaprolyl-4-[3
(N,N-dimethylamino)propoxy]-L-phenylalanine t-bytyl ester
The title compound was prepared as in Example 20 except N-Boc-
tyrosine t-butyl ester was used instead of N-Boc-tyrosine methyl ester.
MS: [(+)ESI), [M+H)' 620.
Example 137
Synthesis of N (Toluene-4-sulfonyl)-L-prolyi-L
(4-(N-methylpiperidinoxy)phenylalanine) tert butyl ester
The title compound was prepared by BOP coupling of Tos-Pro-OH with
Tyr-O-1-methyl piperidine t-butyl ester (prepared by Mitsunobu reaction).
The crude product was purified by flash chromatography (silica, 95:5
EtoAc:Et3N) to afford a white solid (0.615 g, 60%).
MS ({+) ESI, m/z (%)) 586 ( 100 [M+H)')
Anal. Calc'd for C3,H;~N3O6S: C, 63.57; H, 7.40; N, 7.17. Found: C,
63.11;H,7.37;N,6.96.
Example 138
Synthesis of N {Toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-
(4-(N-methyl{piperidinoxy) phenylalanine t-butyl ester
The title compound was prepared following the procedure described in
Example 137 with substitution for the appropriate starting materials.

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Anal. Calc'd for C32H45N3O6Sz~O.2S CHZC12; C, 58.85; H, 7.02; N, 6.43.
Found: C, 58.75; H, 6.92; N, 6.48.
MS (+ESI): 632 [M+H~+
Example 139
Synthesis of N (Toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
tert-butyl ester
The title compound was prepared from the corresponding triflate {which
was prepared from (N (Toluene-4-sulfonyl)-L-prolyl-L-tyrosine tert-butyl
ester as taught by Tilley and coworkers, J. Org. Chem., 55, 906, 1990). The
dipeptide (SOS mg, 0.8 mmol.), a catalytic amount of tetrakis(triphenyl-
hosphine)palladium(0), potassium carbonate (201 mg, 1.5 eq.), phenylboronic
acid (199 mg, 2.0 eq.), and 15 mL of toluene were refluxed for 10 hours with
stirring. Ethyl acetate was added and the organic layer was washed with
water, 1N NaOH, brine and dried over magnesium sulfate. Upon filtration, the
solvent was evaporated under reduced pressure. The crude material was
purified on a preparative plate (1:1 ethyl acetate:hexanes). The silica gel
was
washed several times with acetonitrile and ethyl acetate. The combined
fractions were evaporated and the residue was dried under reduced pressure.
NMR data was as follows:
'H NMR (CDC13, 300 MHz): b = 7.70 (m, 1H); 7.57 (m, 3.SH); 7.45 (m,
3.SH); 7.28 (m, SH); 4.78 (m, 1H); 4.06 (m, 1H); 3.30 (m, 2H); 3.06 (m, 2H);
2.40 (s, 3H); 2.05 (m, 1H); 1.42 (s, 9H).
"C NMR (CDC13): b = 171.02, 169.98, 144.4, 140.78, 139.82, 135.53,
132.82, 129.97, 129.9, 129.41, 128.78, 127.86, 127.04, 126.98, 82.65, 62.15,
53.74, 49.49, 37.43, 29.67, 27.78, 23.92, 21.37.

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Example 140
Synthesis of N (Toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine
The title compound was prepared from the product of Example 139 using
the procedure described in Method 11.
NMR data was as follows:
~H NMR (CD30D, 300 MHz): 8 = 8.05 (m, 1H); 7.71 (d, 2H, J = 8.24
Hz); 7.55 (m, 4H); 7.30 {m, 8H); 4.71 (m, 1H}; 4.09 (m, 1H); 3.30 (m, 3.30);
3.15 (m, 3H}; 2.37 (s, 3H); 1.78 (m, 1H); 1.62 (m, 4H).
"C NMR (CD30D): 8 = 174.27, 145.88, 142.25, 141.23, 137.44, 135.12,
131.19, 131.1 S, 129.98, 129.09, 128.4, 128.17, 128.0, 63.25, 54.69, 50.52,
37.85, 3'1.52, 25.21, 21.43.
Example 141
In vitro Assay For Determining Binding of
Candidate Compounds to VLA-4
An in vitro assay was used to assess binding of candidate compounds to
a4(J, integrin. Compounds which bind in this assay can be used to assess
VCAM-1 levels in biological samples by conventional assays (e.g.,
competitive assays). This assay is sensitive to ICso values as low as about
1 nM.
The activity of a,~~3, integrin was measured by the interaction of soluble
VCAM-1 with Jurkat cells (e.g., American Type Culture Collection Nos. TIB
152, TIB 153, and CRL 8163), a human T-cell line which expresses high
levels of a,~3, integrin. VCAM-1 interacts with the cell surface in an a4p,
integrin-dependent fashion (Yednock, et al. J. Bio. Chem., 1995, ?..ZQ:28740).
Recombinant soluble VCAM-1 was expressed as a chimeric fusion
protein containing the seven extracellular domains of VCAM-1 on the N-

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terminus and the human IgG, heavy chain constant region on the C-terminus.
The VCAM-1 fusion protein was made and purified by the manner described
by Yednock, supra.
Jurkat cells were grown in RPMI 1640 suppiemented with 10% fetal
bovine serum, penicillin, streptomycin and glutamine as described by
Yednock, supra.
Jurkat cells were incubated with 1.5 mM MnCl2 and S ~g/mL 15/7
antibody for 30 minutes on ice. Mn'2 activates the receptor to enhance ligand
binding, and 1 S/7 is a monoclonal antibody that recognizes an
activated/ligand
occupied conformation of a,~~3, integrin and locks the molecule into this
conformation thereby stabilizing the VCAM-1/a,~~i, integrin interaction.
Yednock, et al., supra. Antibodies similar to the 1 S/7 antibody have been
prepared by other investigators (Luque, et al, 1996, J. Bio. Chem. 2?1:11067)
and may be used in this assay.
Cells were then incubated for 30 minutes at room temperature with
candidate compounds, in various concentrations ranging from 66 pM to 0.01
pM using a standard 5-point serial dilution. 15 pL soluble recombinant
VCAM-1 fusion protein was then added to Jurkat cells and incubated for 30
minutes on ice. (Yednock et al., supra.).
Cells were then washed two times and resuspended in PE-conjugated goat
F(ab')Z anti-mouse IgG Fc (Immunotech, Westbrook, ME) at 1:200 and
incubated on ice, in the dark, for 30 minutes. Cells were washed twice and
analyzed with a standard fluorescence activated cell sorter ("FACS") analysis
as described in Yednock, et al., supra.
Compounds having an ICso of less than about lSpM possess binding
affinity to a4(3,.

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When tested in this assay, each of the compounds in Examples 1-135 has
an ICso of 15 ~cM or less.
Example 142
In vitro Saturation Assay For Determining Binding of
Candidate Compounds to a4~3,
The following describes an in vitro assay to determine the plasma levels
needed for a compound to be active in the Experimental Autoimmune
Encephalomyelitis ("EAE") model, described in the next example, or in other
in vivo models.
Log-growth Jurkat cells are washed and resuspended in normal animal
plasma containing 20 pg/mi of the 15/7 antibody (described in the above
example).
The Jurkat cells are diluted two-fold into either normal plasma samples
containing known candidate compound amounts in various concentrations
ranging from 66 pM to 0.01 pM, using a standard 12 point serial dilution for a
standard curve, or into plasma samples obtained from the peripheral blood of
candidate compound-treated animals.
Cells are then incubated for 30 minutes at room temperature, washed
twice with phosphate-buffered saline ("PBS") containing 2% fetal bovine
serum and 1mM each of calcium chloride and magnesium chloride (assay
medium) to remove unbound 1517 antibody.
The cells are then exposed to phycoerythrin-conjugated goat F(ab')z anti-
mouse IgG Fc (Immunotech, Westbrook, ME), which has been adsorbed for
any non-specific cross-reactivity by co-incubation with 5% serum from the
animal species being studied, at 1:200 and incubated in the dark at 4°C
for 30
minutes.

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Cells are washed twice with assay medium and resuspended in the same.
They are then analyzed with a standard fluorescence activated cell sorter
("FACS") analysis as described in Yednock et al. J. Bio. Chem., 1995,
270:28740.
S
The data is then graphed as fluorescence versus dose, e.g., in a normal
dose-response fashion. The dose levels that result in the upper plateau of the
curve represent the levels needed to obtain efficacy in an in vivo model.
This assay may also be used to determine the plasma levels needed to
saturate the binding sites of other integrins, such as the a~/3, integrin,
which is
the integrin most closely related a,~~3, (Palmer et al, 1993, J. Cell Bio.,
123:1289). Such binding is predictive of in vivo utility for inflammatory
conditions mediated by a9~i, integrin, including by way of example, airway
hyper-responsiveness and occlusion that occurs with chronic asthma, smooth
muscle cell proliferation in atherosclerosis, vascular occlusion following
angioplasty, fibrosis and glomerular scarnng as a result of renal disease,
aortic
sten6sis, hypertrophy of synoviai membranes in rheumatoid arthritis, and
inflammation and scarring that occur with the progression of ulcerative
colitis
and Crohn's disease.
Accordingly, the above-described assay may be performed with a human
colon carcinoma cell line, SW 480 (ATTC #CCL228) transfected with cDNA
encoding a9 integrin (Yokosaki et al., 1994, J. Bio. Chem., 269:26691 ), in
place of the Jurkat cells, to measure the binding of the a9~3, integrin. As a
control, SW 480 cells which express other a and ~3, subunits may be used.
Accordingly, another aspect of this invention is directed to a method for
treating a disease in a mammalian patient, which disease is mediated by a9(3,,
and which method comprises administering to said patient a therapeutically
effective amount of a compound of this invention. Such compounds are
preferably administered in a pharmaceutical composition described herein

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above. Effective daily dosing will depend upon the age, weight, condition of
the patient which factors can be readily ascertained by the attending
clinician.
However, in a preferred embodiment, the compounds are administered from
about 20 to 500 pg/kg per day.
Example 143
In vivo Evaluation
The standard multiple sclerosis model, Experimental Autoimmune (or
Allergic) Encephalomyelitis ("EAE"), was used to determine the effect of
candidate compounds to reduce motor impairment in rats or guinea pigs.
Reduction in motor impairment is based on blocking adhesion between
leukocytes and the endothelium and correlates with anti-inflammatory activity
1 S in the candidate compound. This model has been previously described by
Keszthelyi et al., Neurology, 1996, 47:1053-1059, and measures the delay of
onset of disease.
Brains and spinal cords of adult Hartley guinea pigs were homogenized in
an equal volume of phosphate-buffered saline. An equal volume of Freund's
complete adjuvant (100 mg mycobacterium tuberculosis plus 10 ml Freund's
incomplete adjuvant) was added to the homogenate. The mixture was
emulsified by circulating it repeatedly through a 20 ml syringe with a
peristaltic pump for about 20 minutes.
Female Lewis rats (2-3 months old, 170-220 g) or Hartley guinea pigs (20
day old, 180-200 g) were anesthetized with isoflurane and three injections of
the emulsion, 0.1 ml each, were made in each flank. Motor impairment onset
is seen in approximately 9 days.
Candidate compound treatment began on Day 8, just before onset of
symptoms. Compounds were administered subcutaneously ("SC"), orally
("PO") or intraperitoneally ("IP"). Doses were given in a range of lOmg/kg to

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200 mg/kg, bid, for five days, with typical dosing of 10 to 100 mg/kg SC, 10
to 50 mg/kg PO, and 10 to 100 mg/kg IP.
Antibody GGS/3 against a4~3, integrin (Keszthelyi et al., Neurology, 1996,
47:1053-1059), which delays the onset of symptoms, was used as a positive
control and was injected subcutaneously at 3 mg/kg on Day 8 and 11.
Body weight and motor impairment were measured daily. Motor
impairment was rated with the following clinical score:
0 no change
1 tail weakness or paralysis
2 hindlimb weakness
3 hindlimb paralysis
4 moribund or dead
A candidate compound was considered active if it delayed the onset of
symptoms, e.g., produced clinical scores no greater than 2 or slowed body
weight loss as compared to the control.
When tested in this in vivo assay, the compounds of Examples 5, 12, 18
and 20 were active.
Example 144
Asthma Model Example
Inflammatory conditions mediated by a4(i, integrin include, for example,
airway hyper-responsiveness and occlusion that occurs with chronic asthma.
The following describes an asthma model which can be used to study the in
vivo effects of the compounds of this invention for use in treating asthma.
Following the procedures described by Abraham et al, J. Clin. Invest,
93:776-787 (1994) and Abraham et al, Am J. Respir Crit Care Med, 156:696
703 (1997), both of which are incorporated by reference in their entirety,

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compounds of this invention are formulated into an aerosol and administered
to sheep which are hypersensitive to Ascaris suum antigen. Compounds which
decrease the early antigen-induced bronchial response and/or block the late-
phase airway response, e.g., have a protective effect against antigen-induced
late responses and airway hyper-responsiveness ("AHR"), are considered to be
active in this model.
Allergic sheep which are shown to develop both early and late bronchial
responses to inhaled Ascaris suum antigen are used to study the airway effects
of the candidate compounds. Following topical anesthesia of the nasal
passages with 2% lidocaine, a balloon catheter is advanced through one nostril
into the lower esophagus. The animals are then intubated with a cuffed
endotracheal tube through the other nostril with a flexible fiberoptic
bronchoscope as a guide.
Pleural pressure is estimated according to Abraham (1994). Aerosols (see
formulation below) are generated using a disposable medical nebulizer that
provides an aerosol with a mass median aerodynamic diameter of 3.2 pm as
determined with an Andersen cascade impactor. The nebulizer is connected to
a dosimeter system consisting of a solenoid valve and a source of compressed
air (20 psi). The output of the nebulizer is directed into a plastic T-piece,
one
end of which is connected to the inspiratory port of a piston respirator. The
solenoid valve is activated for 1 second at the beginning of the inspiratory
cycle of the respirator. Aerosols are delivered at VT of 500 ml and a rate of
20
breaths/minute. A 0.5% sodium bicarbonate solution only is used as a
control.
To assess bronchial responsiveness, cumulative concentration-response
curies to carbachol can be generated according to Abraham ( 1994). Bronchial
biopsies can be taken prior to and following the initiation of treatment and
24

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hours after antigen challenge. Bronchial biopsies can be preformed according
to Abraham ( 1994).
An in vitro adhesion study of alveolar macrophages can be performed
according to Abraham ( 1994), and a percentage of adherent cells is
calculated.
A solution of the candidate compound in 0.5% sodium bicarbonate/saline
(w/v) at a concentration of 30.0 mg/mL is prepared using the following
procedure:
A. Preparation of 0 S% qodi ~m Bi~a_rbonate / Saline Stock qol ~ ion'
1 Ofd.
Ingredient Gram / 100.0 Final Concentration
mL
Sodium Bicarbonate0.5 g 0.5%
Saline q.s. ad 100.0 q.s. ad 100%
mL
Procedure:
1. Add 0.5g sodium bicarbonate into a 100 mL volumetric flask.
2. Add approximately 90.0 mL saline and sonicate until dissolved.
3. Q.S. to 100.0 mL with saline and mix thoroughly.
Ingredient Gram / 10.0 mL Final Concentration
Candidate Compound0.300 g 30.0 mg/mL
0.5% Sodium q.s. ad 10.0 mL q.s ad 100%
Bicarbonate / Saline
Stock Solution

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Procedure:
1. Add 0.300 g of the candidate compound into a 10.0 mL volumetric
flask.
2. Add approximately 9.7 mL of 0.5% sodium bicarbonate / saline
stock solution.
3. Sonicate until the candidate compound is completely dissolved.
4. Q.S. to 10.0 mL with 0.5% sodium bicarbonate / saline stock
solution and mix thoroughly.
Using a conventional oral formulation, compounds of this invention
would be active in this model.