Note: Descriptions are shown in the official language in which they were submitted.
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WO97/33887 PCT~S97/04567
TITLE
Spirocycle Integrin Inhibitors
FTF~T.n OF TH~ INVF~l'ITION
This invention relates to novel heterocycles which
are useful as antagonists of the a~3 integrin and
related cell surface adhesive protein receptors, to
pharmaceutical compositions containing such compounds,
processes for preparing such compounds, and to methods
of using these compounds, alone or in combination with
other therapeutic agents, for the inhibition of cell
adhesion, the treatment of angiogenic disorders,
inflammation, bone degradation, cancer metastasis,
diabetic retinopathy, thrombosis, restenosis, macular
degeneration, and other conditions mediated by cell
adhesion and/or cell migration and/or angiogenesis.
~ ('KGROUNr) OF TH~ INVF~TTON
Angiogenesis or neovascularization is critical for
normal physiological processes such as embryonic
development and wound repair (Folkman and Shing, J.
Biol. Chem. 1992, 267:10931-10934; D'Amore and Thompson,
Ann. Rev. Physiol. 1987, ~:453-464). However,
angiogenesis also occurs pathologically, for example, in
ocular neovascularization (leading to diabetic
retinopathy, neovascular glaucoma, retinal vein
occlusion and blindness), in rheumatoid arthritis and in
solid tumors (Folkman and Shing, J. Biol. Chem., 1992,
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267:10931-10934i Blood and Zetter, Biochim. Biophys.
Acta., 1990, 1032:118-128).
Tumor dissemination, or metastasis, involves
several distinct and complementary components, including
the penetration and transversion of tumor cells through
basement membranes and the establishment of self-
sustaining tumor foci in diverse organ systems. To this
end, the development and proliferation of new blood
vessels, or angiogenesis, is critical to tumor survival.
Without neovascularization, tumor cells lack the
nourishment to divide and will not be able to leave the
primary tumor site (Folkman and Shing, J. Biol. Chem.,
1992, 267:10931-10934).
Inhibition of angiogenesis in animal models of
cancer has been shown to result in tumor growth
suppression and prevention of metastatic growth (Herblin
et al., Exp. Opin. Ther. Patents, 1994, 1-14). Many
angiogenic inhibitors have been directed toward blocking
initial cytokine-dependent induction of new vessel
growth, e.g. antibodies to endothelial cell growth
factors. However, these approaches are problematic
because tumor and inflammatory cells can secrete
multiple activators of angiogenesis (Brooks et al.,
Cell, 1994, 79:1157-1164). Therefore, a more general
approach that would allow inhibition of angiogenesis due
to a variety of stimuli would be of benefit.
The integrin av~3 is preferentially expressed on
angiogenic blood vessels in chick and man (Brooks et
al., Science, 1994, 264:569-571i Enenstein and Kramer,
J. Invest. Dermatol., 1994, 103:381-386). Integrin a~3
is the most promiscuous member of the integrin family,
allowing endothelial cells to interact with a wide
variety of extracellular matrix components (Hynes, Cell,
1992, 69:11-25). These adhesive interactions are
considered to be critical for angiogenesis since
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vascular cells must ultimately be capable of invading
virtually all tissues.
While integrin av~3 promotes adhesive events
important for angiogenesis, this receptor also transmits
signals from the extracellular environment to the
intracellular compartment (Leavesley et al., J. Cell
Biol., 1993, L21:163-170~ 1993). For example, the
interaction between the av~3 integrin and extracellular
matrix components promotes a calcium signal required for
cell motility.
During endothelium injury, the basement membrane
zones of blood vessels express several adhesive
proteins, including but not limited to von Willebrand
factor, fibronectin, and fibrin. Additionally, several
members of the integrin family of adhesion receptors are
expressed on the surface of endothelial, smooth muscle
and on other circulating cells. Among these integrins
is av~3~ the endothelial cell, fibroblast, and smooth
muscle cell receptor for adhesive proteins including von
Willebrand factor, fibrinogen (fibrin), vitronectin,
thrombospondin, and osteopontin. These integrins
initiate a calcium-dependent signaling pathway that can
lead to endothelial cell, smooth muscle cell migration
and, therefore, may play a fundamental role in vascular
cell biology.
Recently, an antibody to the av~3 integrin has been
developed that inhibits the interaction of this integrin
with agonists such as vitronectin (Brooks et al.,
Science, 1994, 264:569-571). Application of this
antibody has been shown to disrupt ongoing angiogenesis
on the chick chorioallantoic membrane (CAM), leading to
rapid regression of histologically distinct human tumor
transplanted onto the CAM (Brooks et al., Cell, 1994,
79:1157-1164). In this model, antagonists of the av~3
integrin induced apoptosis of the proliferating
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angiogenic vascular cells, leaving pre-existing
quiescent blood vessels unaffected. Thus, av~3 integrin
antagonists have-been shown to inhibit angiogenesis and
are recognized as being useful as therapeutic agents for
the treatment of human diseases such as cancer,
restenosis, thromoembolic disorders, rheumatoid
arthritis and ocular vasculopathies (~olkman and Shing,
J. Biol. Chem., 1992, 267:10931-10934).
Inc~easing numbers of other cell surface receptors
have been identified which bind to extracellular matrix
ligands or other cell adhesion ligands thereby mediating
cell-cell and cell-matrix adhesion processes. These
receptors belong to a gene superfamily called integrins
and are composed of heterodimeric transmembrane
glycoproteins containing a- and ~-subunits. Integrin
subfamilies contain a common ~-subunit combined with
different a-subunits to form adhesion receptors with
unique specificity. The genes for eight distinct
~subunits have been cloned and sequenced to date.
The av~3 heterodimer is a member of the ~3 integrin
subfamily and has been described on platelets,
endothelial cells, melanoma, smooth muscle cells, and
osteoclasts (Horton and Davies, J. Bone Min. Res. 1989,
4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-
1826; Horton, Int. J. Exp. Pathol., 1990, 7i:741-759).
Like GPIIb/IIIa, the vitronectin receptor binds a
variety of RGD-containing adhesive proteins such as
vitronectin, fibronectin, VWF, fibrinogen, osteopontin,
bone sialo protein II and thrombosponden in a manner
mediated by the RGD sequence. A key event in bone
resorption is the adhesion of osteoclasts to the matrix
of bone. Studies with monoclonal antibodies have
implicated the av~3 receptor in this process and suggest
that a selective av~3 antagonist would have utility in
blocking bone resorption ~Horton et al., J. Bone Miner.
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Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner.
Res., 1992, 7:335-343).
PCT Patent Application Publication Number
WO95/14683, published June 1, 1995 discloses isoxazoline
and isoxazole fibrinogen receptor antagonists of general
formula shown below:
R1s
R _ 9\,~ W--X Y
R1--U--V 'N--O
Copending, commonly assigned U.S. Patent
Application Serial Number 08/455,768 filed 5/31/95
discloses integrin inhibitors of the general formula
shown below:
R15
R14~5 ~X Y
R1--U--V 'N--O
PCT Patent Application Publication Number
20 WO95/32710, published December 7, 1995 discloses
compounds for inhibition of osteoclast-mediated bone
resorption of general formula shown below:
X-Y-Z-Aryl-A-B
wherein Aryl is a 6-membered aromatic ring system.
None of the above references discloses or suggests
the spirocyclic compounds of the present invention which
are described in detail below.
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SU~/IMA~Y OF THF INVF~JTION
The present invention provides novel nonpeptide
compounds which bind to integrin receptors thereby
altering cell-matrix and cell-cell adhesion processes.
The compounds of the present invention are useful for
the inhibition of cell adhesion and the treatment of
angiogenic disorders, inflammation, bone degradation,
cancer metastases, diabetic retinopathy, thrombosis,
restenosis, macular degeneration, and other conditions
mediated by cell adhesion and/or cell migration and/or
angiogenesis.
One aspect of this invention provides novel
compounds of Formula I (described below) which are
useful as antagonists of the a~3 integrin, which is also
referred to as the vitronectin receptor. The compounds
of the present invention inhibit the binding of
vitronectin or other RGD-containing ligands to a~3 and
inhibit cell adhesion. The present invention also
includes pharmaceutical compositions containing such
compounds of Formula I, and methods of using such
compounds for the inhibition of angiogenesis, and/or for
the treatment of disorders mediated by angiogenesis.
Another aspect of the present invention comprises
agents that inhibit the binding of vitronectin to the
a~3 receptor for the treatment (including prevention) of
thrombosis which do not significantly alter hemostatic
balance and do not significantly inhibit platelet
aggregation and do not significantly inhibit
coagulation. Also the compounds of the current
invention can be used for the treatment or prevention of
restenosis.
The present invention also provides novel
compounds, pharmaceutical compositions and methods which
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may be used in the treatment or prevention of other
diseases which involve cell adhesion processes,
including, but not limited to, rheumatoid arthritis,
asthma, allergies, adult respiratory distress syndrome,
graft versus host disease, organ transplantation, septic
shock, psoriasis, eczema, contact dermatitis,
osteoporosis, osteoarthritis, atherosclerosis,
metastasis, wound healing, diabetic retinopathy, ocular
vasculopathies, thrombosis, inflammatory bowel disease
and other autoimmune diseases.
Also included in the present invention are
pharmaceutical kits comprising one or more containers
containing pharmaceutical dosage units comprising a
compound of Formula I, for the therapeutic inhibition of
cell adhesion, the treatment of angiogenic disorders,
inflammation, bone degradation, cancer metastasis,
diabetic retinopathy, thrombosis, restenosis, macular
degeneration, and other conditions mediated by cell
adhesion and/or cell migration and/or angiogenesis.
DF~TATT,~n D~SCRTPTION OF TH~ INVF~TION
The present invention provides novel nonpeptide
compounds of Formula I (described below) which bind to
integrin receptors thereby altering cell-matrix and
cell-cell adhesion processes. The compounds of the
present invention are useful for the inhibition of cell
adhesion and the treatment of angiogenic disorders,
inflammation, bone degradation, cancer metastases,
diabetic retinopathy, thrombosis, restenosis, macular
degeneration, and other conditions mediated by cell
adhesion and/or cell migration and/or angiogenesis, in a
mammal.
One aspect of this invention provides novel
compounds of Formula I which are useful as antagonists
--7--
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of the a~3 or vitronectin receptor. The compounds of
the present invention inhibit the binding of vitronectin
and other RGD-containing ligands to a~3 and inhibit cell
adhesion. The present invention also includes
pharmaceutical compositions containing such compounds of
Formula I, and methods o~ using such compounds for the
inhibition of angiogenesis, and/or for the treatment of
angiogenic disorders.
[1] The present invention comprises spirocyclic
compounds of Formula I:
Rl-Q-W-X-Y
(I)
including stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, or pharmaceutically
acceptable salt or prodrug forms thereof wherein:
Q is selected from
--z~ ~ or _ z~ ~ N(
A is selected from -N(Rl~)-, -C(Rll)- or -O-;
Al is selected from -O- or -N(Rl~)-;
Z is a spiro-fused 4-7 membered ring system (including
the sprio atom) containing 0-2 heteroatoms selected
from O, S, or N, said ring system optionally being
substituted on carbon with keto, or being
substituted on carbon or nitrogen independently
with 0-2 R9 or Rl~ or RlOa;
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Rl is selected from:
B--N ( ~ N M--N
O NH
\>--U-- I \~ U [~ V-- X~,--V--
. ~tJ' I <\ ~ V-- ~ ~ 'N~ V-- N V--
NR7 NR7 NR7
R7R6N_V_ R C NR -V .R8R7N--C--V-- R8R7N--Il NR6 V
B is independently selected from -CH2-, -O-, -N(R2)-, or
-C ( =O) - i
Bl is independently selected from -CH2- or -N(R3)-;
D is -N(R2~ O-, -S-, -C(=O)- or -SO2-;
E-F is -C(R4)=C(R5)-, -N=C(R4)-, -C(R4)=N-, or
15-C(R4)2C(R5) 2-i
J, K, L and M are independently selected from -C(R4)-,
-C(R5)- or -N-, provided that at least one of J, K,
L and M is not -N-;
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R2 is selected from: H, C1-C6 alkyl, (C1-C6
alkyl)carbonyl, (C1-C6 alkoxy)carbonyl; (C1-C6
alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7
cycloalkyl, C4-C11 cycloalkylalkyl, aryl,
heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl C1-C6 alkyl, (C1-C6
alkyl)carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl,
arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6
alkyl)sulfonyl, aryloxycarbonyl, aryl(C1-C6
alkoxy)carbonyl, wherein said aryl groups are
substituted with 0-2 substituents independently
selected from the group consisting of Cl-C4 alkyl,
C1-C4 alkoxy, halo, CF3, and nitro;
R3 isselected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-
Cll cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, or
heteroaryl(C1-C6 alkyl)-;
R4 and R5 are independently selected from: H, C1-C4
alkoxy, NR2R3, halogen, NO2, CN, CF3, C1-C6 alkyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C4-C11
cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, ~C1-C6
alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl;
alternatively, when substituents on adjacent atoms, R4
and R5 can be taken together with the carbon atoms
to which they are attached to form a 5-7 membered
carbocyclic or 5-7 membered heterocyclic aromatic
or non-aromatic ring system, said carbocyclic or
heterocyclic ring being optionally substituted with
0-2 groups independently selected from: C1-C4
alkyl, Cl-C4 alkoxy, halo, cyano, amino, CF3, or
NO2i
-10-
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W097/33887 PCT~S97tO4567
R6 is selected from: H, C1-C4 alkyl, or benzyl;
R7 and R~ are independently selected from: H, Cl-C6
alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl,
aryl, aryl(C1-C6 alkyl)-, or heteroaryl(CO-C6
alkyl)-;
U is selected from:
-N(R6) (CH2)n~~
-N(R6) (CH2)mO~,
-N(R6) (CH2)mN(R7)-
-N (R6 ) (CH2 ) nS (O) p~
-N(R6) C (=O) (cH2) n~i
1 5 - N ( R6 ) ( CH2 ) mC ( =O ) - i
V is selected from:
- (CH2)n~~
~ (CH2)mO~ (CH2)n~~
~(cH2)mN(R7)(cH2) n~
- (CH2) nS (O)p(CH2) n~~
~ (CH2)mN(R7)C(=o) (CH2)n~~
- (CH2)nC(=o)N(R7) (CH2) n~~
~ (CH2)nC(=O) (CH2)n~;
R9 is selected from H, Cl-C4 alkyl, C1-C4 alkoxy, aryl,
aryl(C1-C6 alkyl)-, (Cl-C4 alkoxy)carbonyl, (C1-C4
alkyl)carbonyl, Cl-C4 alkylsulfonyl, or C1-C4
alkylaminosulfonyl;
R10 is selected from: H, Co2Rl7~ C(=o)Rl7, C(=o)NRl7R20,
-So2R17, -So2NRl7R2o~ C1-C6 alkyl substituted with O-
1 R15, C3-C6 alkenyl substituted with O-1 R15, C3-C7
cycloalkyl substituted with O-1 R15, C4-Cl1
cycloalkylalkyl substituted with O-1 R15, aryl
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WO97/33887 PCT~S97/04567
substituted with 0-1 R15 or 0-2 R11, or aryl(C1-C6
alkyl)- substituted with 0-1 R15 or 0-2 R11;
R1Oa is selected from: Co2Rl7~ C(=o)R17, C(=o)NR17R20,
S -So2R17, -So2NRl7R2o~ C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7
cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl
substituted with 0-1 R15 or 0-2 R11, or aryl(C1-C6
alkyl)- substituted with 0-1 R15 or 0-2 R11;
R11-is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl,
aryl(C1-C6 alkyl)-, (C1-C4 alkoxy)carbonyl, (C1-C4
alkyl)carbonyl, C1-C4 alkylsulfonyl, or C1-C4
alkylaminosulfonyl
W is selected from:
C1-C4 alkylene,
-(c(Rl2)2)qo(c(Rl2)2)q~~
-(C(R12)2)qC(=0)(C(R12)2)q~~
~ (C(R12)2)qC(=O)N(R13)~~
-c(=o)-N(Rl3)-(c(~l2)2)q-;
X is -(c(Rl2)2)qc(Rl2)(Rl4)-c(Rl2)(Rl5)
alternatively, W and X can be taken together to be
~--(CH2)qC(=O)--N~ N--R18
_~w
R12 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl, C3-C7 cycloalkyl, C4-C1O cycloalkylalkyl,
(C1-C4 alkyl)carbonyl, aryl, or aryl(C1-C6 alkyl)-;
-12-
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Rl3 is selected from H, Cl-C6 alkyl, C3-C7
cycloalkylmethyl, or aryl(Cl-C6 alkyl)-
Rl4 ls selected from:
H, Cl-C6 alkylthio(Cl-C6 alkyl)-, aryl(Cl-Cl0
alkylthioalkyl)-, aryl(Cl-Clo alkoxyalkyl)-, Cl-Clo
alkyl, Cl-Clo alkoxyalkyl, Cl-C6 hydroxyalkyl,
C2-C10 alkenyl, C2-Clo alkynyl, C3-Clo cycloalkyl,
C3-Clo cycloalkylalkyl, aryl(Cl-C6 alkyl)-,
heteroaryl(Cl-C6 alkyl)-, aryl, heteroaryl, Co2Rl7/
C(=o)Rl7, or CONRl7R20, provided that any of the
above alkyl, cycloalkyl, aryl or heteroaryl groups
may optionally be substituted independently with 0-
1 R16 or 0-2 Rll;
Rl5 is selected from:
H, R16, Cl-Clo alkyl, Cl-C10 alkoxyalkyl,
Cl-C10 alkylaminoalkyl, Cl-ClO dialkylaminoalkyl,
(Cl-C10 alkyl)carbonyl, aryl(CO-C6 alkyl)carbonyl,
Cl-C10 alkenyl, Cl-Clo alkynyl ,C3-Clo cycloalkyl,
C3-C10 cycloalkylalkyl, aryl(Cl-C6 alkyl)-,
heteroaryl(Cl-C6 alkyl)-, aryl, heteroaryl, Co2Rl7,
C(=o)Rl7, CoNRl7R20, So2Rl7, or So2NRl7R2o~ provided
that any of the above alkyl, cycloalkyl, aryl or
heteroaryl groups may optionally be substituted
independently with 0-2 Rll;
Y is selected from:
-CORl9, -SO3H, -PO3H, tetrazolyl, -CONHNHSO2CF3,
-CoNHso2Rl7~ -CoNHso2NHRl7~ -NHCOCF3, -NHCoNHSo2Rl7,
-NHSo2Rl7, -OPO3H2, -OSO3H, -PO3H2, -SO3H,
-So2NHCoRl7, -So2NHCo2Rl7,
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~ N ~ ~ CF3 ~ ~
R16 is selected from:
-N(R20)-c(=
-N(R20)-c(=o)-Rl7
-N(R20) -C (=O) -N~-R17
-N(R2~)So2-Rl7~ or
-N(R20)So2-NR20Rl7
Rl7 is selected from:
Cl-C10 alkyl, C3-Cll cycloalkyl, aryl(Cl-C6 alkyl)-,
(Cl-C6 alkyl)aryl, heteroaryl(Cl-C6 alkyl)-, (Cl-C6
alkyl)heteroaryl, arylaryl(Cl-C6 alkyl)-,
heteroarylaryl(Cl-C6 alkyl)-, arylheteroaryl(Cl-C6
alkyl)-, heteroarylheteroaryl(Cl-C6 alkyl)-,
heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with
0-3 substituents independently selected from the
group consisting of: Cl-C4 alkyl, Cl-C4 alkoxy,
aryl, halo, cyano, amino, CF3, and NO2;
Rl3 is selected from:
H,
-C ( =o ) -o-Rl7 ~
-C(=o)-Rl7~
-C ( =0 ) -N~-Rl7 ~
-So2-Rl7~ or
-SO2-NR20R17;
Rl9 is selected from:
hydroxy,
Cl-C10 alkyloxy,
-14-
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C3-C11 cycloalkyloxy,
aryloxy,
aryl(C1-C6 alkoxy)-,
C3-C10 alkylcarbonyloxyalkyloxy,
C3-C10 alkoxycarbonyloxyalkyloxy,
C2-C10 alkoxycarbonylalkyloxy,
Cs-Clo cycloalkylcarbonyloxyalkyloxy,
C5-Clo cycloalkoxycarbonyloxyalkyloxy,
Cs-Clo cycloalkoxycarbonylalkyloxy,
C7-C11 aryloxycarbonylalkyloxy,
C8-C12 aryloxycarbonyloxyalkyloxy,
C8-C12 arylcarbonyloxyalkyloxy,
Cs-Clo alkoxyalkylcarbonyloxyalkyloxy,
Cs-Clo (5-alkyl-1,3-dioxa-cyclopenten-2-one-
yl)methyloxy,
C10-Cl~ (5-aryl-1,3-dioxa-cyclopenten-2-one-
yl)methyloxy, or
(R11)(R12)N-(C1-C1o alkoxy)-;
R20 is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl,
C~-Cll cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, or
heteroaryl(C1-C6 alkyl)-;
m is 1-2i
n is 0-2;
p is 0-2i
q is 0-2; and
r is 0-2i
provided that:
n, q, and r are chosen such that the number of in-chain
atoms between R1 and Y is in the range of 8-18.
-15-
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~2~ Preferred compounds of the invention as described
above are spirocyclic compounds of Formula I:
R1-Q-W_x_y
(I)
including stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, or pharmaceutically
acceptable salt or prodrug forms thereof wherein:
Q is selected from
-16-
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R10;
~ ~~ CX~ .
- --N~/ ~/ , ~/,
R10
NX~ X~ N~/
~ N~/ ~ N~/
~~~ ~/R10a
~,
R10
R1 ~~ R1o or --N~/
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Rl is selected from:
N ( ~N M--N
~ \~u- < ' \~u L/,/ \~u
(~H .~NH K=J
H
~U ~ ~U ~ V
.1 Nll <~ ~ V-- R2NH~'V--
NR7 NR7 NR7
R C NR -V . R8R7N--C--V_ R8R7N--Il NR6 V--
D iS -N(R2)-, -O-, -S-, -C(=O)- or - SO2-;
E-F is -C(R4)=C(R5)-, -N=C(R4)-, -C(R4)=N-, or
-C(R4)2C(R5)2-i
J, K, L and M are independently selected from -C (R4)-,
-C(R5)- or -N-, provided that at least one of J, K,
L and M is not -N-;
R2 iS selected from: H, Cl-C6 alkyl, (Cl-C6
alkyl)carbonyl, (Cl-C6 alkoxy)carbonyl; (Cl-C6
alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7
cycloalkyl, C4-Cll cycloalkylalkyl, aryl,
heteroaryl(Cl-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(Cl-C6 alkyl)-, (Cl-C6
alkyl)carbonyl, arylcarbonyl, Cl-C6 alkylsulfonyl,
-18-
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arylsulfonyl, aryl(Cl-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(Cl-C6
alkyl)sulfonyl, aryloxycarbonyl, or aryl(Cl-C6
alkoxy)carbonyl, wherein said aryl groups are
substituted with 0-2 substituents independently
selected from the group consisting of Cl-C4 alkyl,
Cl-C4 alkoxy, halo, CF3, and nitro;
R3 is selected from: H, Cl-C6 alkyl, C3-C7 cycloalkyl,
C4-Cll cycloalkylalkyl, aryl, aryl(Cl-C6 alkyl)-, or
heteroaryl (Cl-C6 alkyl)-;
R4 and R5 are independently selected from: H, Cl-C4
alkoxy, NR2R3, halogen, NO2, CN, CF3, Cl-C6 alkyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C4-Cll
cycloalkylalkyl~ aryl, aryl(Cl-C6 alkyl)-, (Cl-C6
alkyl)carbonyl, (Cl-C6 alkoxy)carbonyl,
arylcarbonyl, or
alternatively, when substituents on adjacent atoms, R4
and R5 can be taken together with the carbon atoms
to which they are attached to form a 5-7 membered
carbocyclic or 5-7 membered heterocyclic aromatic
or non-aromatic ring system, said carbocyclic or
heterocyclic ring being optionally substituted with
0-2 groups independently selected from: Cl-C4
alkyl, Cl-C4 alkoxy, halo, cyano, amino, CF3, or
NO2;
R6 is selected from: H, Cl-C4 alkyl, or benzyl;
R7 and R8 are independently selected from: H, Cl-C6
alkyl, C3-C7 cycloalkyl, C4-Cll cycloalkylalkyl,
aryl, aryl(Cl-C6 alkyl)-, or heteroaryl(C0-C6
alkyl)-;
-19-
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U is selected from:
-N(R6) (cH2) n~~
-N(R6) (cH2)mo-~
~N(R6)(CH2)mN(R7)-
-N(R6) ~CH2)nS(O)p-
- N ( R6 ) C ( =0 ) ( CH2 ) n~ i
V is selected from:
- (CH2)n~~
- (CH2)mO- (CH2)n~~
- - (CH2 ) mN (R7 ) (cH2 ) n~
~ (CH2)nS(O)p(CH2)n
- (CH2 ) mN (R7 ) C ( =0 ) (CH2 ) n~
- (CH2)nC(=o)N(R7) (CH2)n~~
- (CH2)nC (=O) (CH2) n~;
R9 is selected from H, Cl-C4 alkyl, Cl-C4 alkoxy, aryl,
aryl(C1-C6 alkyl)-, (Cl-C4 alkoxy)carbonyl, ~C1-C4
alkyl)carbonyl, C1-C4 alkylsulfonyl, or C1-C4
alkylaminosulfonyl;
R10 is selected from: H, Co2Rl7, C (=O) R17, C (=O) NRl7R20,
-So2R17, -So2NRl7R2o~ C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7
cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl
substituted with 0-1 R15 or 0-2 R11, or aryl(C1-C6
alkyl)- substituted with 0-1 R15 or 0-2 Rl1;
R10a is selected from: Co2R17, C(=o)R17, C(=C)NR17R20,
-So2R17, -So2NRl7R2o~ C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7
cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl
-20-
CA 02249733 1998-09-11
W097/338X7 PCT~S97/04567
substituted with 0-1 Rls or 0-2 Rll, or aryl(Cl-C6
alkyl)- substituted with 0-1 Rl5 or 0-2 Rll;
Rll is selected from H, Cl-C4 alkyl, Cl-C4 alkoxy, aryl,
aryl(Cl-C6 alkyl)-, (Cl-C~ alkoxy)carbonyl, (Cl-C4
alkyl)carbonyl, Cl-C4 alkylsulfonyl, or Cl-C4
alkylaminosulfonyl;
W is selected from:
Cl-C4 alkylene,
-(C(Rl2)2)qO(C(Rl2
~(C(R12)2)qC(=O) (C(R12)2)q-~
- (C(R12)2)qC(=O)N(R13)-,
-C(=o)-N(R13) - (C(R12)2)q~;
X is -(C(Rl2)2)qC(Rl2)(Rl4)-c(Rl2)(Rl5)_;
alternatively, W and X can be taken together to be
~- (CH2)qc(=o)-N N- R18
~
R12 is selected from H, Cl-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C3-C7 cycloalkyl,
C4-C10 cycloalkylalkyl, (Cl-C4 alkyl)carbonyl, aryl,
or aryl(Cl-C6 alkyl)-;
R13 is selected from H, Cl-C6 alkyl, C3-C7
cycloalkylmethyl, or aryl(Cl-C6 alkyl)-
Rl4 is selected from:
H, Cl-C6 alkylthio(Cl-C6 alkyl)-, aryl(Cl-Clo
alkylthioalkyl)-, aryl(Cl-C10 alkoxyalkyl)-, Cl-Clo
alkyl, Cl-Clo alkoxyalkyl, Cl-CO hydroxyalkyl,
C2-C10 alkenyl, C2-C1Q alkynyl, C3-C10 cycloalkyl,
-21-
CA 02249733 1998-09-11
W097/33887 pcT~ss7lo4s67
C3-Cl0 cycloalkylalkyl, aryl(Cl-C6 alkyI)-,
heteroaryl(Cl-C6 alkyl)-, aryl, heteroaryl, Co2Rl7/
C(=o)Rl7, or CoNRl7R20, provided that any of the
above alkyl, cycloalkyl, aryl or heteroaryl groups
may optionally be substituted independently with 0-
1 R16 or 0-2 Rll;
Rl5 is selected from:
H, Rl6, Cl-Clo alkyl, Cl-Cl0 alkoxyalkyl,
Cl-Cl0 alkylaminoalkyl, Cl-Clo dialkylaminoalkyl,
(Cl-Cl0 alkyl)carbonyl, aryl(C0-C6 alkyl)carbonyl,
Cl-Cl0 alkenyl, C~-C10 alkynyl ,C3-Clo cycloalkyl,
C3-Cl0 cycloalkylalkyl, aryl(Cl-C6 alkyl)-,
heteroaryl(Cl-C6 alkyl)-, aryl, heteroaryl, Co2Rl7~
C(=o)Rl7, CoNRl7R20, So2Rl7, or So2NRl7R2o~ provided
that any of the above alkyl, cycloalkyl, aryl or
heteroaryl groups may optionally be substituted
independently with 0-2 Rll;
Y is selected from:
-CORl9, -SO3H, -PO3H, tetrazolyl, -CONHNHSO2CF3,
-CoNHSo2Rl7, -CoNHso2NHRl7~ -NHCOCF3, -NHC3NHSo2Rl7,
-NHSo2Rl7, -OPO3H2, -OSO3H, -PO3H2, -SO3H,
-So2NHCOR17, -So2NHC02R17~
N,N~ ~ \~ CF3
H H HO ~
Rl6 is selected from:
-N(R20)-c(=o)-o-Rl7
-N(R20)-c(=o)-Rl7
-N(R20) -C (=O) -NH-R17
-N(R20)So2-Rl7~ or
-22-
CA 02249733 1998-09-11
W097/33887 PCT~Ss7/04s67
-N(R20) S02_NR20R17;
Rl7 is selected from:
Cl-C10 alkyl, C3-Cll cycloalkyl, aryl(Cl-C6 alkyl)-,
(Cl-C6 alkyl)aryl, heteroaryl~Cl-C6 alkyl)-, (Cl-C6
alkyl)heteroaryl, arylaryl(Cl-C6 alkyl)-,
heteroarylaryl(Cl-C6 alkyl)-, arylheteroaryl(Cl-C6
alkyl)-, heteroarylheteroaryl(Cl-C6 alkyl)-,
heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with
0-3 substituents independently selected from the
group consisting of: Cl-C4 alkyl, Cl-C4 alkoxy,
aryl, halo, cyano, amino, CF3, and N02;
R18 is selected from:
H,
-C(=o)-o-Rl7
-C ( =0 ) -Rl7
-C ( =0 ) -NH-R17
-So2-Rl7~ or
-S02-NR20Rl7;
Rl9 is selected from:
hydroxy,
Cl-C10 alkyloxy,
C3-Cll cycloalkyloxy,
aryloxy,
aryl(Cl-C6 alkoxy)-,
C3-Clo alkylcarbonyloxyalkyloxy,
C3-C10 alkoxycarbonyloxyalkyloxy,
C2-C10 alkoxycarbonylalkyloxy,
Cs-Clo cycloalkylcarbonyloxyalkyloxy,
C5-Clo cycloalkoxycarbonyloxyalkyloxy,
Cs-Clo cycloalkoxycarbonylalkyloxy,
C7-Cll aryloxycarbonylalkyloxy,
-23-
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W O 97/33887 . PCT~US97/04567
C8-C12 aryloxycarbonyloxyalkyloxy,
C8-C12 arylcarbonyloxyalkyloxy,
C5-C10 alkoxyalkylcarbonyloxyalkyloxy,
Cs-Clo (5-alkyl-1,3-dioxa-cyclopenten-2-one-
yl)methyloxy,
C10-Cl4 (5-aryl-1,3-dioxa-cyclopenten-2-one-
yl)methyloxy, or
(R11)(R12)N-(C1-C1o alkoxy)-;
R20 selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-
C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, or
heteroaryl(C1-C6 alkyl)-;
m is 1-2;
n is 0-2;
p is 0-2;
q is 0-2; and
r is 0-2;
~0 provided that:
n, q, and r are chosen such that the number of in-
chain atoms ~etween R1 and Y is in the range of 8-
18.
[3] Further preferred compounds of the invention as
described above are compounds of the Formula I including
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, or pharmaceutically
acceptable salt or prodrug forms thereof wherein:
-24-
CA 02249733 1998-09-11
W 097/33887 PCTrUS97/04567
Q ls selected from:
~/ ~N~ .
N~
R~ R
Rl~
~ ~ . or ~ O~ ~R10a .
R10
Rl ls selected from:
CA 02249733 1998-09-11
WO 97133887 PCTIUS97/04567
¢N>-- . C /~U , ~N>--
H ¢S ~
¢ ~>--U ~ U 1~ U--
u N~ U- ~ ~U
~¢ \>--U ~ \>--U_ 1~ ,~_U--
Ç¢ \>-U ~¢ \>-U ~¢ \>-U--
U- N~ \>--U ~ >--U
1~¢ ~>--U_ N~ \>--U ~ \~V
N~ \>--U Nl~,¢ \>--U I~N~
~Sr~V ~ ~u ~¢ \~U-
R2NH R2NH
~N~ , HN
, or ~V
- 2 6 -
CA 02249733 1998-09-11
W097l33887 PCT~S97/04567
wherein the above heterocycles are optionally
substituted with 0-2 substituents selected from the
group consisting of: NH2, halogen, N02, CN, CF3, Cl-C4
alkoxy, Cl-C6 alkyl, and C3-C7 cycloalkyl;
R2 is selected from: H, C1-C4 alkyl or benzyl;
U is -NH(CH2)n~;
V is -(CH2)n~;
R10 is selected from: H, Co2Rl7~ C~=o)Rl7, CoNRl7R20,
-So2R17, -So2NR17R20, C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7
cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl
substituted with 0-1 R15 or 0-2 R11, or aryl(C1-C6
alkyl)- substituted with 0-1 R15 or 0-2 R11;
R10a is selected from: Co2R17, C(=o)R17, CoNR17R20,
-So2Rl7~ -So2NR17R20, C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 Rl5, C3-C7
cycloalkyl substituted with 0-1 Rl5, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl
substituted with 0-1 R15 or 0-2 R11, or aryl(C1-C6
alkyl)- substituted with 0-1 R15 or 0-2 R11;
R11 is selected from H, Cl-C4 alkyl, C1-C4 alkoxy, aryl,
aryl(C1-C6 alkyl)-, (C1-C4 alkoxy)carbonyl, (C1-Cg
alkyl)carbonyl, C1-C4 alkylsulfonyl, or C1-C4
alkylaminosulfonyl;
W iS -C (=O) -N (R13 ) -;
CA 02249733 1998-09-11
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X iS -CH(R14)-CH(R15)-;
R13 iS H or CH3i
Rl4 is selected from:
H, Cl-Clo alkyl, aryl, or heteroaryl, wherein said
aryl or heteroaryl groups are optionally
substituted with 0-3 substituents independently
selected from the group consisting of: Cl-C4 alkyl,
Cl-C4 alkoxy, aryl, halo, cyano, amino, CF3, and
NO2i
Rl5 is H or Rl6;
Y is -C(=O)Rl9i
R16 is selected from:
-N(R20)-c(=
-N(R20) -C (=O) -R17
-N(R20)-C(=o)-NH-Rl7,
-N(R2~)So2-Rl7, or
-N(R20) So2-N(R2o)Rl7i
Rl7 is selected from:
Cl-Clo alkyl, C3-Cll cycloalkyl, aryl(Cl-C6 alkyl)-,
(Cl-C6 alkyl)aryl, heteroaryl(Cl-C6 alkyl)-, (Cl-C6
alkyl)heteroaryl, arylaryl(Cl-C6 alkyl)-,
heteroarylaryl(Cl-C6 alkyl)-, arylheteroaryl(Cl-C6
alkyl)-, heteroarylheteroaryl(Cl-C6 alkyl)-,
heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with
0-3 substituents independently selected from the
group consisting of: Cl-C4 alkyl, Cl-C4 alkoxy,
aryl, halo, cyano, amino, CF3, and NO
-28-
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Rl9 is selected from:
hydroxy,
Cl-C10 alkoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
l-(methylcarbonyloxy)ethoxy-,
l-(ethylcarbonyloxy)ethoxy-,
l-(t-butylcarbonyloxy)ethoxy-,
l-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
l-(i-propyloxycarbonyloxy)ethoxy-,
l-(cyclohexyloxycarbonyloxy)ethoxy-,
l-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-
yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-,
or
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R20 is H or CH3; and
n is 0-1.
[4] Still further preferred compounds of the above
invention as described above are compounds of the
Formula I including stereoisomeric forms thereof, or
mixtures of stereoisomeric forms thereof, or
-29-
CA 02249733 1998-09-11
W097/33887 PCTrUS97/04567
pharmaceutically acceptable salt or prodrug forms
thereof wherein:
Q is selected from:
--N~/ ~N~/, ~/
~/ R ~ ~
R10
~ R10~
R10
Rl is selected from:
-30-
CA 02249733 1998-09-11
W 097/33887 PCT~US97/04567
¢ \~U-- C ~U-- ~ ~U
U ¢ \~ U ~ U
~U [~¢ \~U-- ~¢ \~U
~N~_ R2NH~rN F~2NH~V--
R2NH R2NH
~=N ~=N
~V ~V--
~ ,or ~ V -
R2 is selected from: H, Cl-C4 alkyl, or benzyl;
U is -NH(cH2)n-;
V is ~ (cH2)n-i
~0 R10 is selected from: H, Co2Rl7, C(=o~Rl7, C(=o)NRl7R20,
-So2Rl7, -So2NRl7R2~, Cl-C6 alkyl substituted with 0-
1 Rl5, C3-C6 alkenyl substituted with 0-1 Rl5, C3-C7
cycloalkyl substituted with 0-1 Rl5, C4-Cll
cycloalkylalkyl substituted with 0-1 Rl5, aryl
CA 02249733 1998-09-11
W097/33887 PCT~S97/04567
substituted with 0-1 R15 or 0-2 R11, or aryl(C1-C6
alkyl)- substituted with 0-1 R15 or 0-2 R11;
R1Oa is selected from: Co2Rl7~ C(=o)R17, CoNR17R20,
-So2R17, -SC2NR17R20, C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7
cycloalkyl substituted with 0-1 Rl5, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl
substituted with 0-1 Rl5 or 0-2 R11, or aryl(C1-C6
alkyl)- substituted with 0-1 R15 or 0-2 Rl1;
R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl,
aryl(C1-C6 alkyl)-, (C1-C4 alkoxy)carbonyl, (C1-C4
alkyl)carbonyl, C1-C4 alkylsulfonyl, or C1-C4
alkylaminosulfonyl
W is -C(=o)-N(R13)-;
X is -CH(Rl4)-CH(R15)-;
R13 is H or CH3;
R14 is selected from:
H, Cl-C1o alkyl, aryl, or heteroaryl, wherein said
aryl or heteroaryl groups are optionally
substituted with 0-3 substituents independently
selected from the group consisting of: C1-C4 alkyl,
C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and
NO2;
R15 is H or R16;
Y is -C(=O)R19;
R16 is selected from:
CA 02249733 1998-09-11
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-N(R20)-C(=o)-o-R17,
-N(R20)-C(=o)-R17
-N(R2~)So2-Rl7~
Rl7 is selected from:
Cl-C10 alkyl, C3-Cll cycloalkyl, aryl(Cl-C6 alkyl)-,
(Cl-C6 alkyl)aryl, heteroaryl(Cl-C6 alkyl)-, (Cl-C6
alkyl)heteroaryl, arylaryl(Cl-C6 alkyl)-,
heteroarylaryl(Cl-C6 alkyl)-, arylheteroaryl(Cl-C6
alkyl)-, heteroarylheteroaryl(Cl-C6 alkyl)-,
heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted wlth
0-3 substituents independently selected from the
group consisting of: Cl-C4 alkyl, Cl-C4 alkoxy,
aryl, halo, cyano, amino, CF3, and NO
Rl9 is selected from:
hydroxy,
Cl-Clo alkoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
l-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
l-(t-butylcarbonyloxy)ethoxy-,
l-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
l-(i-propyloxycarbonyloxy)ethoxy-,
l-(cyclohexyloxycarbonyloxy)ethoxy-,
l-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
~ 35 (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
CA 02249733 1998-09-11
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(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-
yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-,
or
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R20 is H or CH3; and
n is 0-1.
[5] Specifically preferred compounds of the above
invention are compounds including enantiomeric or
diasteriomeric forms thereof, or mixtures of
enantiomeric or diastereomeric forms thereof, or
pharmaceutically acceptable salt or prodrug forms
thereof, selected from the group consisting of:
(S)-2-phenylsulfonylamino-3-[[[8-(2-
pyridinylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-benzyloxycarbonylamino-3-[[[8-(2-
pyridinylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-
[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2-
azaspiro-[4,5]-dec-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(3,5-dimethylisoxazol4-yl)sulfonyl]amino-3-
[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2-
azaspiro-[4,5]-dec-2-en-3-
yl]carbonylamino]propionic acid,
-34-
CA 02249733 1998-09-11
W 097/33887 PCT~US97/04567
(S)-2-phenylsulfonylamino-3-[[[8-[(6-aminopyridin-
2-yl)methyl]-]-1-oxa-2,8-diazaspiro-[4,5~-dec-
2-en-3-yl]carbonylamino]propionic acid,
(S)-2-phenylsulfonylamino-3-[[[8-[(6-aminopyridin-
2-yl)methyl]]-1-oxa-2,8-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino~propionic acid,
(S)-2-phenylsulfonylamino-3-[[[8-(2-
pyridinylaminomethyl)-]-l-oxa-2-azaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-phenylsulfonylamino-3-[[[8-[2-(4,5-
dihydroimidazol-2-yl)aminomethyl]-]-1-oxa-2-
azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]-
propionic acid,
(S)-2-[(2-methylphenyl)sulfonyl]amino-3-[[[8-(2-
pyridinylaminomethyl)-]-l-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acld,
(S)-2-[(2-chloro-4-methylphenyl)sulfonyl]amino-3-
[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2-
azaspiro-[4,5]-dec-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(4-biphenyl)sulfonyl]amino-3-[[[8-(2-
pyridinylaminomethyl)-]-l-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2-bromophenyl)sulfonyl]amino-3-[[[8-(2-
pyridinylaminomethyl)-]-l-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[[8-(2-
pyridinylaminomethyl)-]-l-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
CA 02249733 1998-09-11
W097/33887 PCT~S97/04567
(S)-2-[(1-naphthyl)sulfonyl]amino-3-[[[8-(2-
pyridinylaminomethyl)-]-1-oxa-2-azaspiro-
[4,53-dec-2-en-3-yl]carbonylamino]propionic
acid.
(S)-2-phenylsulfonylamino-3-~[[8-(2-
imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-benzyloxycarbonylamino-3-[[[8-(2-
imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-
[[[8-(2-imidazolylaminomethyl)-]-1-oxa-2-
azaspiro-[4,5]-dec-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[[8-
(2-imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl]amino-3-[[[8-
(2-imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino-
3-l[[8-(2-imidazolylaminomethyl)-~-1-oxa-2-
azaspiro-[4,5]-dec-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[[8-(2-
imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[biphenylsulfonyl]amino-3-[[[8-(2-
imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
-36-
CA 02249733 1998-09-11
W 097/33887 PCT~US97/04567
[4,5]-dec-2-en-3-yl]carbonylamino]propionic
acid,
(S~-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl-
8-(2-imldazolylaminomethyl)-1-oxa-2,7-
diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[7-
benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-
l-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-~[7-
benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-
l-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-
l-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-
l-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino-
3-[[7-benzyloxycarbonyl-8-(2-
imidazolylaminomethyl)-1-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-
1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-
l-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
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(S)-2-phenylsulfonylamino-3-[[8-~2-
imidazolylaminomethyl)-l-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-benzyloxycarbonylamino-3-[[8-(2-
imidazolylaminomethyl)-l-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[8-
(2-imidazolylaminomethyl)-1-oxa-2,7-
diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[8-(2-
imidazolylaminomethyl)-l-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl]amino-3-[[8-(2-
imidazolylaminomethyl)-l-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino-
3-[[8-(2-imidazolylaminomethyl)-1-oxa-2,7-
diazaspiro-~4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[8-(2-
imidazolylaminomethyl)-l-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[biphenylsulfonyl]amino-3-~[8-(2-
imidazolylaminomethyl)-1-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl-
8-(2-pyridinylaminomethyl)-1-oxa-2,7-
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W097/338~7 PCT~S97/04567
diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[7-
benzyloxycarbonyl-8-(2-pyridinylaminomethyl)-
1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-pyridinylaminomethyl)-
1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-pyridinylaminomethyl)-
1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-pyridinylaminomethyl)-
1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino-
3-[[7-benzyloxycarbonyl-8-(2-
pyridinylaminomethyl)-1-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino]propionic
acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-pyridinylaminomethyl)-
1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl~carbonylamino]propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(2-pyridinylaminomethyl)-
1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl-
8-(4,5-dihydroimidazol-2-yl)aminomethyl-1-oxa-
2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
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(S)-2-benzyloxycarbonylamino-3-[[7-
benzyloxycarbonyl-8-(4,5-dihydroimidazol-2-
yl)aminomethyl-l-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino]propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(4,5-dihydroimidazol-2-
yl)aminomethyl-l-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(4,5-dihydroimidazol-2-
yl)aminomethyl-l-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(4,5-dihydroimidazol-2-
yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino-
3-[[7-benzyloxycarbonyl-8-(4,5-
dihydroimidazol-2-yl)aminomethyl-1-oxa-2,7-
diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-(4,5-dihydroimidazol-2-
yl)aminomethyl-l-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino]propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[7-
benzyloxycarbonyl-8-8-(4,5-dihydroimidazol-2-
yl)aminomethyl-l-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino]propionic acid,
(S)-2-phenylsulfonylamino-3-[[8-(4,5-
dihydroimidazol-2-yl)aminomethyl-1-oxa-2,7-
diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[8-(4,5-
dihydroimidazol-2-yl)aminomethyl-1-oxa-2,7-
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diazaspiro-[4,4~-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[8-
(4,5-dihydroimidazol-2-yl)aminomethyl-1-oxa-
2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[8-
(4,5-dihydroimidazol-2-yl)aminomethyl-1-oxa-
2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl]amino-3-[[8-
(4,5-dihydroimidazol-2-yl)aminomethyl-1-oxa-
2,7-diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino-
3-[[8-(4,5-dihydroimidazol-2-yl)aminomethyl-1-
oxa-2,7-diazaspiro-[4,4~-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[8-(4,5-
dihydroimidazol-2-yl)aminomethyl-1-oxa-2,7-
diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[8-(4,5-
dihydroimidazol-2-yl)aminomethyl-1-oxa-2,7-
diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid, and
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[8-
(2-benzimidazolyl~aminomethyl-1-oxa-2,7-
diazaspiro-[4,4]-non-2-en-3-
yl]carbonylamino]propionic acid.
In the present invention it has been discovered
that the compounds of Formula I above are useful as
inhibitors of cell-matrix and cell-cell adhesion
processes. The present invention includes novel
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compounds of Formula I and methods for using such
compounds for the prevention or treatment of diseases
resulting from abnormal cell adhesion to the
extracellular matrix which comprises administering to a
host in need of such treatment a therapeutically
effective amount of such compound of Formula I.
In the present invention it has also been discovered
that the compounds of Formula I above are useful as
inhibitors of a~3. The compounds of the present
invention inhibit the binding of vitronectin to av~3 and
inhibit cell adhesion.
The present invention also provides pharmaceutical
compositions comprising a compound of Formula I and a
pharmaceutically acceptable carrier.
The compounds of Formula I of the present
invention are useful for the treatment (including
prevention) of angiogenic disorders. The term
"angiogenic disorders" as used herein includes
conditions involving abnormal neovascularization, such
as tumor metastasis and ocular neovascularization,
including, for example, diabetic retinopathy,
neovascular glaucoma, age-related macular degeneration,
and retinal vein occlusion, comprising administering to
a mammal in need of such treatment a therapeutically
effective amount of a compound of Formula I described
above.
The compounds of Formula I of the present invention
may be useful for the treatment or prevention of other
diseases which involve cell adhesion processes,
including, but not limited to, inflammation, bone
degradation, thromboembolic disorders, restenosis,
rheumatoid arthritis, asthma, allergies, adult
respiratory distress syndrome, graft versus host
disease, organ transplantation rejection, septic shock,
psoriasis, eczema, contact dermatitis, osteoporosis,
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osteoarthritis, atherosclerosis, inflammatory bowel
disease and other autoimmune diseases. The compounds of
Formula I of the present invention may also be useful
for wound heallng.
The term "thromboembolic disorders" as used
herein includes conditions involving platelet activation
and aggregation, such as arterial or venous
cardiovascular or cerebrovascular thromboembolic
disorders, including, for example, thrombosis, unstable
angina, first or recurrent myocardial infarction,
ischemic sudden death, transient ischemic attack,
stroke, atherosclerosis, venous thrombosis, deep vein
thrombosis, thrombophlebitis, arterial embolism,
coronary and cerebral arterial thrombosis, myocardial
infarction, cerebral embolism, kidney embolisms,
pulmonary embolisms, or such disorders associated with
diabetes, comprising administering to a mammal in need
of such treatment a therapeutically effective amount of
a compound of Formula I described above.
The compounds of the present invention may be used
for other ex vivo applications to prevent cellular
adhesion in biological samples.
The compounds of the present invention can also be
administered in combination with one or more additional
therapeutic agents selected from: anti-coagulant or
coagulation inhibitory agents, such as heparin or
warfarin; anti-platelet or platelet inhibitory agents,
such as aspirin, piroxicam, or ticlopidine; thrombin
inhibitors such as boropeptides, hirudin or argatroban;
or thrombolytic or fibrinolytic agents, such as
plasminogen activators, anistreplase, urokinase, or
streptokinase.
The compounds of Formula I of the present
invention can be ~mi ni stered in combination with one or
more of the foregoing additional therapeutic agents,
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thereby to reduce the doses of each drug required to
achieve the desired therapeutic effect. Thus, the
combination treat-ment of the present invention permits
the use of lower doses of each component, with reduced
adverse, toxic effects of each component. A lower
dosage minimizes the potential of side effects of the
compounds, thereby providing an increased margin of
safety relative to the margin of safety for each
component when used as a single agent. Such combination
therapies may be employed to achieve synergistic or
additive therapeutic effects for the treatment of
thEomboembolic disorders.
By "therapeutically effective amount" it is meant
an amount of a compound of Formula I that when
administered alone or in combination with an additional
therapeutic agent to a cell or m~m~l iS effective to
prevent or ameliorate the thromboembolic disease
condition or the progression of the disease.
By "administered in combination" it is meant that
the compound of Formula I and one or more additional
therapeutic agents are administered concurrently to the
mammal being treated. When administered in combination
each component may be administered at the same time or
sequentially in any order at different points in time.
Thus, each component may be administered separately but
sufficiently closely in time so as to provide the
desired therapeutic effect.
The term anti-coagulant agents (or coagulation
inhibitory agents), as used herein, denotes agents that
inhibit blood coagulation. Such agents include warfarin
(available as COUMADIN~) and heparin.
The term anti-platelet agents (or platelet inhibitory
agents), as used herein, denotes agents that inhibit
platelet function such as by inhibiting the aggregation,
adhesion or granular secretion of platelets. Such
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agents include the various known non-steroidal anti-
inflammatory drugs such as aspirin, ibuprofen, naproxen,
sulindac, indomethacin, mefenamate, droxicam,
diclofenac, sulfinpyrazone, and piroxicam, including
pharmaceutically acceptable salts or prodrugs thereof.
Other suitable anti-platelet agents include ticlopidine,
including pharmaceutically acceptable salts or prodrugs
thereof. Ticlopidine is also a preferred compound since
it is known to be gentle on the gastro-intestinal tract
in use. Still other suitable platelet inhibitory agents
include thromboxane-A2-receptor antagonists and
thromboxane-A2-synthetase inhibitors, as well as
pharmaceutically acceptable salts or prodrugs thereof.
The phrase thrombin inhibitors (or anti-thrombin
agents), as used herein, denotes inhibitors of the
serine protease thrombin. By inhibiting thrombin,
various thrombin-mediated processes, such as
thrombin-mediated platelet activation (that is, for
example, the aggregation of platelets, and/or the
granular secretion of plasminogen activator inhibitor-l
and/or serotonin) and/or fibrin formation are disrupted.
Such inhibitors include boroarginine derivatives and
boropeptides, hirudin and argatroban, including
pharmaceutically acceptable salts and prodrugs thereof.
Boroarginine derivatives and boropeptides include
N-acetyl and peptide derivatives of boronic acid, such
as C-terminal a-aminoboronic acid derivatives of lysine,
ornithine, arginine, homoarginine and corresponding
isothiouronium analogs thereof. The term hirudin, as
used herein, includes suitable derivatives or analogs of
hirudin, referred to herein as hirulogs, such as
disulfatohirudin. Boropeptide thrombin inhibitors
include compounds described in Kettner et al., U.S.
Patent No. 5,187,157 and European Patent Application
Publication Number 293 881 A2, the disclosures of which
-
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are hereby incorporated herein by reference. Other
sui~able boroarginine derivatives and boropeptide
thrombin inhibitors include those disclosed in PCT
Application Publication Number 92/07869 and European
Patent Application Publication Number 471 651 A2, the
disclosures of which are hereby incorporated herein by
reference, in their entirety.
The phrase thrombolytics (or fibrinolytic)
agents (or thrombolytics or fibrinolytics), as used
herein, denotes agents that lyse blood clots (thrombi).
Such agents include tissue plasminogen activator,
anistreplase, urokinase or streptokinase, including
pharmaceutically acceptable salts or prodrugs thereof.
Tissue plasminogen activator (tPA) is commercially
available from Genentech Inc., South San Francisco,
California. The term anistreplase, as used herein,
refers to anisoylated plasminogen streptokinase
activator complex, as described, for example, in
European Patent Application No. 028,489, the disclosures
of which are hereby incorporated herein by reference
herein, in their entirety. The term urokinase, as used
herein, is intended to denote both dual and single chain
urokinase, the latter also being referred to herein as
prourokinase.
~ministration of the compounds of Formula I
of the invention in combination with such additional
therapeutic agent, may afford an efficacy advantage over
the compounds and agents alone, and may do so while
permitting the use of lower doses of each. A lower
dosage minimizes the potential of side effects, thereby
providing an increased margin of safety.
The compounds of the present invention are also
useful as standard or reference compounds, for example
as a quality standard or control, in tests or assays
involving the binding of vitronectin or fibrinogen to
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- Such compounds may be provided in a commercial
kit, for example, for use in pharmaceutical research
involving a~3. The compounds of the present invention
may also be used in diagnostic assays involving a~3.
The compounds herein described may have asymmetric
centers. Unless otherwise indicated, all chiral,
diastereomeric and racemic forms are included in the
present invention. Many geometric isomers of olefins,
C=N double bonds, and the like can also be present in
the compounds described herein, and all such stable
isomers are contemplated in the present invention. It
will be appreciated that compounds of the present
invention that contain asymmetrically substituted carbon
atoms may be isolated in optically active or racemic
forms. It is well known in the art how to prepare
optically active forms, such as by resolution of racemic
forms or by synthesis, from optically active starting
materials. All chiral, diastereomeric, racemic forms
and all geometric isomeric forms of a structure are
intended, unless the specific stereochemistry or isomer
form is specifically indicated.
When any variable (for example but not limited to,
R2, R4, R6, R7, R8, Rl2,and Rl4, n, etc.) occurs more
than one time in any constituent or in any formula, its
definition on each occurrence is independent of its
definition at every other occurrence. Thus, for
example, if a group is shown to be substituted with 0-2
R4, then said group may optionally be substituted with
up to two R4 and R4 at each occurrence is selected
independently from the defined list of possible R4.
Also, by way of example, for the group -N(R5a)2, each of
- the two R5a substituents on N is independently selected
from the defined list of possible R5a. Similarly, by
way of example, for the group -C(R7)2-, each of the two
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R7 substituents on C is independently selected from the
defined list of possible R7.
When a bond to a substituent ls shown to cross the
bond connecting two atoms in a ring, then such
substituent may be bonded to any atom on the ring. When
a bond joining a substituent to another group is not
specifically shown or the atom in such other group to
which the bond joins is not specifically shown, then
such substituent may form a bond with any atom on such
other group.
When a substituent is listed without indicating the
atcm via which such substituent is bonded to the rest of
the compound of Formula I, then such substituent may be
bonded via any atom in such substituent. For example,
when the substituent is piperazinyl, piperidinyl, or
tetrazolyl, unless specified otherwise, said
piperazinyl, piperidinyl, tetrazolyl group may be bonded
to the rest of the compound of Formula I via any atom in
such piperazinyl, piperidinyl, tetrazolyl group.
Combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds. By stable compound or stable structure it is
meant herein a compound that is sufficiently robust to
survive isolation to a useful degree of purity from a
reaction mixture, and formulation into an efficacious
therapeutic agent.
The term ~'substituted", as used herein, means that
any one or more hydrogen on the designated atom is
replaced with a selection from the indicated group,
provided that the designated atom's normal valency is
not exceeded, and that the substitution results in a
stable compound. When a substitent is keto (i.e., =O),
then 2 hydrogens on the atom are replaced.
As used herein, "alkyl" is intended to include both
branched and straight-chain saturated aliphatic
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hydrocarbon groups havlng the specified number of carbon
atoms (for example, "Co-Clo" denotes alkyl having 0 to 10
carbon atomsi thus, C0 denotes a direct bond between the
groups linked by the Co group); "haloalkyl" is intended
to include both branched and straight-chain saturated
aliphatic hydrocarbon groups having the specified number
of carbon atoms, substituted with 1 or more halogen (for
example -CVFw where v = 1 to 3 and w = 1 to ~2v+1));
~lalkoxy'' represents an alkyl group of indicated number
of carbon atoms attached through an oxygen bridge;
"cycloalkyl" is intended to include saturated ring
groups, including mono-,bi- or poly-cyclic ring systems,
such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, and ~m~ntyl; and
"biycloalkyl" is intended to include saturated bicyclic
ring groups such as [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
[2.2.2]bicyclooctane, and so forth. "Alkenyl" is
intended to include hydrocarbon chains of either a
straight or branched configuration and one or more
unsaturated carbon-carbon bonds which may occur in any
stable point along the chain, such as ethenyl, propenyl
and the like; and "alkynyl" is intended to include
hydrocarbon chains of either a straight or branched
configuration and one or more triple carbon-carbon bonds
which may occur in any stable point along the chain,
such as ethynyl, propynyl and the like.
The terms "alkylene", "alkenylene", "phenylene",
and the like, refer to alkyl, alkenyl, and phenyl
groups, respectively, which are connected by two bonds
to the rest of the structure of Formula I. Such
"alkylene", "alkenylene", "phenylene", and the like, may
alternatively and equivalently be denoted herein as
"-(alkyl)-~ (alkyenyl)-" and "-(phenyl)-", and the
- 35 like.
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~ Halo" or "halogen" as used herein refers to
fluoro, chloro, bromo and iodo; and "counterion~ is used
to represent a small, negatively charged species such as
chloride, bromide, hydroxide, acetate, sulfate and the
like.
As used herein, "aryl" or "aromatic residue" is
intended to mean phenyl or naphthyl; the term
~arylalkyl" represents an aryl group attached through an
alkyl bridge.
As used herein, "carbocycle" or "carbocyclic
residue" is intended to mean any stable 3- to 7-
membered monocyclic or bicyclic or 7- to 14-membered
bicyclic or tricyclic or an up to 26-membered polycyclic
carbon ring, any of which may be saturated, partially
unsaturated, or aromatic. Examples of such carbocyles
include, but are not limited to, cyclopropyl,
cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl,
indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or
"heterocyclic" is intended to mean a stable 5- to 7-
membered monocyclic or bicyclic or 7- to 10-membered
bicyclic heterocyclic ring which may be saturated,
partially unsaturated, or aromatic, and which consists
of carbon atoms and from 1 to 4 heteroatoms
independently selected from the group consisting of N, O
and S and wherein the nitrogen and sulfur heteroatoms
may optionally be oxidized, and the nitrogen may
optionally be quaternized, and including any bicyclic
group in which any of the above-defined heterocyclic
rings is fused to a benzene ring. The heterocyclic ring
may be attached to its pendant group at any heteroatom
or carbon atom which results in a stable structure. The
heterocyclic rings described herein may be substituted
on carbon or on a nitrogen atom if the resulting
compound is stable. Examples of such heterocycles
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include, but are not limited to, pyridyl (pyridinyl),
pyrimidinyl, furanyl (furyl), thiazolyl, thienyl,
~ pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,
benzofuranyl, benzothiophenyl, indolyl, indolenyl,
isoxazolinyl, isoxazolyl, quinolinyl, isoquinolinyl,
benzimidazolyl, piperidinyl, 4-piperidonyl,
pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,
tetrahydrofuranyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl or
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-
thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl,
pyranyl, isobenzofuranyl, chromenyl, xanthenyl,
phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl,
pyrazolyl, isothiazolyl, isoxazolinyl, isoxazolyl,
oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl,
indolyl, lH-indazolyl, purinyl, 4H-quinolizinyl,
isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,
4aH-carbazole, carbazole, ~-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl,
phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl,
isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, imidazolinyl, pyrazolidinyl,
pyrazolinyl, piperidinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl or
oxazolidinyl. Also included are fused ring and spiro
compounds containing, for example, the above
heterocycles.
As used herein, the term "heteroaryl" refers to
aromatic heterocyclic groups. Such heteroaryl groups
are preferably 5-6 membered monocyclic groups or 8-10
membered fused bicyclic groups. Examples of such
heteroaryl groups include, but are not limited to
pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl),
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thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl,
pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl,
quinolinyl, or isoquinolinyl.
As used herein, "prodrugs" refer to any covalently
bonded carriers which release the active parent drug
according to Formula I in vivo when such prodrug is
administered to a mammalian subject. Prodrugs of the
compounds of Formula I are prepared by modifying
functional groups present in the compounds in such a way
tha-t the modifications are cleaved, either in routine
manipulation or in vivo, to the parent compounds.
Prodrugs include compounds of Formula I wherein
hydroxyl, amino, sulfhydryl, or carboxyl groups are
bonded to any group that, when administered to a
mammalian subject, cleaves to form a free hydroxyl,
amino, sulfhydryl, or carboxyl group respectively.
Examples of prodrugs include, but are not limited to,
acetate, formate and benzoate derivatives of alcohol and
amine functional groups in the compounds of Formula I,
and the like.
As used herein, "pharmaceutically acceptable salts"
refer to derivatives of the disclosed compounds wherein
the parent compound of Formula I is modified by making
acid or base salts of the compound of Formula I.
Examples of pharmaceutically acceptable salts include,
but are not limited to, mineral or organic acid salts of
basic residues such as amines; alkali or organic salts
of acidic residues such as carboxylic acids; and the
like.
The pharmaceutically acceptable salts of the
compounds of Formula I include the conventional non-
toxic salts or the quaternary ammonium salts of the
compounds of Formula I formed, for example, from non-
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CA 02249733 1998-09-11
W O 97/33887 PCT~US97/04567
toxic inorganic or organic acids. For example, such
conventional non-toxic salts include those derlved from
- inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitric and the like; and
the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, sulfanillc, 2-acetoxybenzoic, fumaric,
toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the
present invention can be synthesized from the compounds
of Formula I which contain a basic or acidic moiety by
conventional chemical methods. Generally, the salts are
prepared by reacting the free base or acid with
stoichiometric amounts or with an excess of the desired
salt-forming inorganic or organic acid or base in a
suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids
of Formula I with an appropriate amount of a base, such
as an alkali or alkaline earth metal hydroxide e.g.
sodium, potassium, lithium, calcium, or magnesium, or an
organic base such as an amine, e.g.,
dibenzylethylenediamine, trimethylamine, piperidine,
pyrrolidine, benzylamine and the like, or a quaternary
ammonium hydroxide such as tetramethylammonium hydroxide
and the like.
As discussed above, pharmaceutically acceptable
salts of the compounds of the invention can be prepared
by reacting the free acid or base forms of these
compounds with a stoichiometric amount of the
appropriate base or acid, respectively, in water or in
an organic solvent, or in a mixture of the two;
- 35 generally, nonaqueous media like ether, ethyl acetate,
CA 02249733 1998-09-11
W O 97/33887 PCTrUS97/04567
ethanol, isopropanol, or acetonitrile are preferred.
Lists of suitable salts are found in Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing
Company, Easton, PA, 1985, p. 1418, the disclosure of
which is hereby incorporated by reference.
The disclosures of all of the references cited
herein are hereby incorporated herein by reference in
their entirety.
Svnthe~is
The compounds of the present invention can be
prepared in a number of ways well known to one skilled
in the art of organic synthesis. The compounds of the
present invention can be synthesized using the methods
described below, together with synthetic methods known
in the art of synthetic organic chemistry, or variations
thereon as appreciated by those skilled in the art.
Preferred methods include, but are not limited to, those
described below. All references cited herein are hereby
incorporated in their entirety herein by reference.
Compounds of Formula I wherein Q includes an
isoxazoline ring as one ring of the spirocycle can be
conveniently prepared by dipolar cycloaddition of
nitrile oxides with appropriate dipolarophiles (for
reviews of l,3-dipolar cycloaddition chemistry, see 1,3-
Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, New
York, 1984; Kanemasa and Tsuge, Heterocvcles 1990, 30,
719). The requisite nitrile oxides are in turn prepared
from commercially available precursors or appropriately
substituted aldehydes via the intermediate oximes.
Scheme 1 illustrates one synthetic sequence which
will provide compounds of Formula I of this invention.
-54-
CA 02249733 1998-09-11
WO 97/33887 PCTrUS97/04567
Scheme 1
HO/~ Cl~c02E~ CH Cl ~ ~COzEt
1(a)
r =0-2
Swern Oxidation O CO2Et l. Reductive a~ n~liu~
H~ 2. (BOC)20/CH2C12
1 (b)
~,~E~ ~ H ~
BOP~CI r\~H ~C02R
2 Rls ~B~r /\ 1~ R15
1(e)
R= Me or tBu
1. LiOH /~ ~CO2H
2 TFA ~HN/~r /\o_N R15
N 1(9)
Treatment of a methylenecycloalkylmethanol with
ethyl chlorooximidoacetate in a suitable solvent, such
as tetrahydrofuran or dichloromethane, in the presence
of a mild base, such as sodium bicarbonate or
CA 02249733 1998-09-11
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triethylamine, provides a spirocycle intermediate, l(a).
Alternately, the cycloaddition can be carried out by
thermal decomposition of diethyl nitromalonate in
refluxing mesitylene by the method of Shimizu et al.
(Bull Chem. Soc. Jpn., 1985, 58, 2519-2522). The
hydroxyl group in l(a) can be subsequently oxidized to
the corresponding aldehyde by any of a number of known
methods for carrying out this transformation, i.e., (See
Manacuso & Swern, Synthesis, 1981, 165; Tidwell,
Synthesis, 1990, 857; D.B. Dess & J.C. Martin, J. Org.
Chem., 1983, 48, 4155; op cit. J. Amer. Chem. Soc.,
19gl, 72, 77; R.E. Ireland & L. Liu, J. Org. Chem,
1993, 58, 2899). Reductive amination of the resulting
aldehyde with an appropriate aminoheterocycle, such as
2-aminopyridine, can be achieved using sodium
triacetoxyborohydride (Abdel-Magid, A. F.; Maryanoff, C.
A. ~ynlett, 1990, 9, 537) to provide a secondary amine.
Optional protection of the nitrogen as its BOC
derivative yields l(c). Subsequent hydrolysis of the
ethyl ester using conventional methods known to one
skilled in the art of organic synthesis gives the
corresponding acid l(d). Coupling of compound l(d) to
an appropriately substituted ~- or ~-amino ester, l(e)
affords compounds of formula l(f).
The coupling is carried out using any of the many
methods for the formation of amide bonds known to one
skilled in the art of organic synthesis. These methods
include but are not limited to conversion of the acid to
the corresponding acid chloride or fluoride, or use of
standard coupling procedures such as the azide method,
mixed carbonic acid anhydride (isobutyl chloroformate)
method, carbodiimide (dicyclohexylcarbodiimide,
diisopropylcarbodiimide, or water-soluble carbodiimides)
method, active ester (p-nitrophenyl ester, N-
-56-
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W O 97/33887 PCT~US97/04567
hydroxysuccinic imido ester) method, carbonyldiimidazole
method, or coupling with phosphorus reagents such as
BOP-Cl. Some of these methods (especially the
carbodiimide) can be enhanced by the addition of 1-
- 5 hydroxybenzotriazole. Deprotection of compound l(f) is
carried out using standard methods of removal of carboxy
and amino protecting groups to provide target compounds
of formula l(g).
Additional compounds of formula I can be prepared
as shown in Scheme 2. Cycloaddition product, l(a) can be
converted to the corresponding amino compound by
conversion to azide 2(a) using diphenylphosphoryl azide
under Mitsunobu conditions (Mitsunobu, O. Synthesis
15 1981, 1) and reduction of the resulting azide with
triphenylphosphine (Staudinger, H.; Meyer, J . Helv.
Chim. Acta. 1919, 2, 635) Protection of the resulting
amino group as its BOC derivative provides intermediate
2(b). Alternately, the amine function can be introduced
prior to cycloaddition by conversion of the starting
methylenecycloalkylmethanol to the corresponding
tosylate, displacement of the tosyl group with sodium
azide, reduction to the amine and treatment with di-t-
butyldicarbonate. Subsequent 1,3 dipolarcycloaddition
provides 2(a). Ester hydrolysis and amide coupling as
described above provides compounds of formula 2(d).
~ydrolysis of the ester, removal of the BOC protecting
group and treatment of the free amine with an
appropriate heterocyclic isothiouronium salt, such as
those listed in the scheme, provides compounds of
Formula 2(f).
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Scheme 2
/~ (PhO)2pN3 ~CO2Et
HO ~r \o N DEAD N3 ~/ o_N
A 1(a) 2(a)
r=0-2
HO ~ ~. Ph3P
1. TosCI ~ /THF/H20
2. NaN~/DMF\ ~/2. (BOC)20
3. Ph3P
4. (BOC)20 ~
5. EtO2CC(=NOH)CI' CO2Et LiOH ~X ~CO2H
BOCNH ~J o--N 2(c)
2(b) O
BOP~IBOCNH~o~N R1s
R= Me or tBu
1 ester l~ huly~s ~ H R15
2(-)
o
HET-SMe 1 X--H~ H R15
1 00~C 2(f)
HET = (~ N~ f o H
Compounds of Formula I, wherein Rl is a 7-
azabenzimidazol-2-yl, group can also be prepared from
cycloaddition product l(a) as depicted in Scheme 3.
-58-
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W O 97/33887 PCTrUS97/04567
Jones oxidation of the primary hydroxyl group provides
acid 3(a) which is condensed with 2,3-diaminopyridine to
provide the 7-azabenzimidazole derivative, 3(b). This
intermediate is converted to compounds of the invention
by the steps of ester hydrolysis, coupling to compounds
of formula l(e) and deprotection described in detail
above.
Scheme 3
HO/~ 2 CrO3 _~C02Et
1(~) 0~C 3~a)
r =0-2
NH2
~NH2 ~ ~>~CO2Et LiOH
100 ~C H 3(b)
~CO2H BOP-CI
3(c) NHR16
R= Me or tBu
H>~ N ~C02R
3(d)
~H>~ NHH16
3(e)
-59-
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W O 97/33887 . PCTrUS97/04567
The appropriately substituted racemic ~-amino acids
may be purchased commercially or, as is shown in Scheme
4, Method 1, prepared from the appropriate aldehyde,
malonic acid and ammonium acetate according to the
procedure of Johnson and Livak (J. Am. Chem. Soc. 1936,
~, 299). Racemic ~-substituted-~-amino esters may be
prepared through the reaction of dialkylcuprates or
alkyllithiums with 4-benzoyloxy-2-azetidinone followed
by treatment with anhydrous ethanol (Scheme 4, Method 2)
or by reductive amination of ~-keto esters as is
des~ribed in W09316038. (Also see Rico et al., J. Org.
Chem. 1993, 58, 7948-51.) Enantiomerically pure ~-
substituted-~-amino acids can be obtained through the
optical resolution of the racemic mixture or can be
prepared using numerous methods, including: Arndt-
Eistert homologation of the corresponding a-amino acids
as shown in Scheme 4, Method 3 (see Meier, and Zeller,
~naew, Chem. Tnt. ~ nal. 1975, 1~, 32; Rodriguez, et
al. Tetr~he~ron T,ett 1990, 31, 5153; Greenlee, ~. Me~.
Chem. 1985, 2~, 434 and references cited within); and
through an enantioselective hydrogenation of a
dehydroamino acid as is shown in Scheme 4, Method 4 (see
Asymmetric Synthesis, Vol. 5, (Morrlson, ed.) Academic
Press, New York, 1985). A comprehensive treatise on the
preparation of ~-amino acid derivatives may be found in
patent application WO 93/07867, the disclosure of which
is hereby incorporated by reference.
-60-
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W O 97/33887 PCTAJS97/04567
Scheme 4
M~alod 1 R~
HO2CyC02H J~ 1)NH40Ac, H2N~CO M
R4 R8 H 2) MeOH, Ha R~
Me~od 2
Ph 0 1) (Ra)2CuLi H2N~--CO2Et
O HN 2) EtOH, HCI R8
Me~od 3
BocHN~CO2H ) , B~CHN'~CHN ) g . H2N~CO2Me
Me~od 4
B~CHN~CO2Me _, ,b ~ q~ B~CHN~;~CO2Me
R8 1,j~r~_ ,~ ' R8
The synthesis of N2-substituted diaminopropionic
acid derivatives can be carried out via Hoffman
rearrangement of a wide variety of asparagine
derivatives as described in Synthesis, 266-267, (1981)
or by manipulation of the commercially available 3-
amino-2-benzyloxycarbonylaminopropionic acid.
Additional dipolarophiles useful for the
preparation of the compounds of this invention are
either commercially available or may be prepared by
numerous methods. Synthesis of representative examples
and their conversion into compounds of Formula I are
illustrated in the following schemes.
Heating a neat mixture of 8-aza-1,4-
dioxaspiro(4,5)decane and 2,6-dibromopyridine provides
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W O 97/33887 PCTrUS97/04567
bromopyridine intermediate 5(a) as shown in Scheme 5.
Hydrolysis of the acetal protecting group gives the
ketone, 5(b) which can then undergo olefination to
compound 5(c). The olefination can be carried out by a
number of methods known to one skilled in the art. (For
suitable olefination methods, see S. H. Pine et al .,
Sy~thesis 1991, 165; Bull. Chem Soc. Jpn., 1980, ~,
1698; or J. Org. Chem. 1968, 33, 780.) The alkene is
then subjected to the 1,3-dipolar cycloaddition
conditions described above to provide the spirocyclic
system, 5(d). Amination with potassium amide in liquid
ammonia followed by protection of the resulting amine as
its BOC derivative gives compound 5(e). This
intermediate is then carried on to compounds of Formula
5(g) using the steps previously described.
-62-
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w097/33887 PCT~S97/04567
Scheme 5
Ç;~ ~~~ neat ~ N~
Br Br 5(a)
aq. HOAc ~ N~eo Ph3PCH3+ Br
1 00~C ~>= N KOtBu/THF
Br 5(b)
~ N3 EtCOzC(=NOH)C~ N~CO2Et
Br 5~c) CH2Ci2 5~d)
1. KNH2Jliq- NH3 ~N~YCO2Et 1. LiOH
~= O_ N 2. BOP-CI
2. (BOC)20 gOCNH 5(e)H2N~CO2tBu
NHR16
~ N~ H~HR16 TCFHA2cl2
BOCNH
5(f)
~ N~ ~r CO2H
H2N 5(9)
Preparation of the analogous (4,4) spiro system is
outlined in Scheme 6. Hydrogenation of commercially
-63-
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W 097/33887 PCTrUS97/04567
available 1-benzyl-3-hydroxypyrolidine and selective
reprotection of the amine as the t-butylcarbamate
provides 6(a). Oxidation of the hydroxyl to the ketone
6(b) by Swern oxidation or other standard methods
followed by olefination as described above provides
alkene 6(c). This alkene is then subjected to 1,3-
dipolar cycloaddition as previously described to provide
the spirocycle 6(d). Ester hydrolysis and coupling to a
suitable ~-amino ester gives 6(e). Removal of the BOC
protecting group and treament with 2-bromo-6-t-
butoxycarbonylaminopyridine (Aust. J. Chem. 1982, 35,
2025) gives intermediate 6(f). Finally, deprotection
provides compounds of this invention of Formula 6(g).
-64-
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W O 97/33887 rCTrUS97/04567
Scheme 6
OH1. Pd(OH)2 OH ~
cycloh~x~ne
EtOH c~ Swern
N r.xidr tic n N
2. (BOC)20 N
Bn MeOH BOC BOC
6(a) 6(b)
CH2
Ph3PCH3~Br- ~ EtO2CC(=NOH)CI BOC--N
KOtBu/THF N TE~ CH2C12 \--~C02Et
BOC --N
6(c) 6(d)
1. LiOH
2. BOP-CI BOC _N~ CO2M 1 TFA
H2N ~ CO2Me 6(e) BOCNH N Br
NHR16
Ç?_N~N ~~NH;116 6N HCI
NHBOC 6(fl
N~N ~NHR"
NH2 6(9)
--65-
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WO 97/33887 PCT~US97/04567
A further class of spirocycles useful in the
present lnvention is prepared as outlined in Scheme 7.
Reduction of N-Cbz 4-hydroxyproline with borane-dimethyl
sulfide complex in tetrahydrofuran provides diol 7(a).
The primary hydroxyl is then selectively protected as
its t-butyldimethylsilyl ether, 7(b). Oxidation of the
remaining secondary alcohol using methods described
above provides ketone 7(c) which can be converted to
alkene 7(d) by olefination. Compound 7(d) then
undergoes l,3-dipolarcycloaddition to provide spirocycle
7(e). Deprotection of the silyl ether by treatment with
fluoride ion followed by Swern oxidation of the
resulting alcohol provides aldehyde 7(f). Reductive
amination with 2-aminopyridine followed by Boc
protection of the resulting secondary amine yields 7(g).
Ester hydrolysis, coupling to the desired 2,3-
diaminopropionate derivative and deprotection gives
7(h). Alternately prior to deprotection the Cbz group
can be selectively removed and alternate Rl~ groups
introduced using standard methods known to one skilled
in the art to provide compounds 7(i).
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WO 97/33887 PCT/US97104567
Scheme 7
pH
BH~Me 2S ~OH
HOOC "~ (t j TBDMSCI ~OH
Nl THF HOCH2' N l r
Cbz Cbz TBDMSOCH2'' ~ N~
r = 1-2 7(a) 7(bC)bz
Swern , (~ r, ~ CH2
~ TBDMSOcH2' N TBDMSOCH2''
oxidabon I N
Cbz Cbz
7(c) 7(d)
EtOOC(=NOH)CI N ~ c~2Et 1 . TBAF ~N--~CO2Et
CEHAcl TBDMSOCH2~r o,N oxidation r o,N
7(e) 7(~)
1. Na(AcO)3BH Cbz C02Et 1. LiOH
DCE N ~\ / 1~ 2. BOP-CI
2 (BOC) O ~<O,N \ R15
3 H2/Pd/BaSO4
1. LiOH 10 5. 6N HCI
2. BOP-CI R~ o
H2N~ ~ O~ N ~co2H
~, N ~ N ~ C02H
7(h)
--67--
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Compounds of Formula I wherein Q includes a 1,2,4-
oxadiazoline as one ring of the spriocycle are prepared
as shown in Scheme-8. Protection of 4-
methylenecyclohexylmethanol as its t-butyldimethylsilyl
ether followed by ozonolysis of the double bond provides
ketone B(a). Treatment of compound 8(a) with a
suitable amine provides an imine 8(b) which can undergo
1,3-dipolarcycloaddition with a nitrile oxide to provide
spirocycle 8(c). Further elaboration as described above
would provide additional compounds of the present
invention of Formula 8(h).
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Scheme 8
~c 1. TBDMS-CI ~ = Rl0a
HO (~ 2. o3 TBDMSO (\~J
r =0-2 8~a)
R10a
~c NR10a TEA A~N~I~CO2Et
TBDMSO (\~/ 2. TBAF HO/~\o_N
8(b) r 8(c)
R10a
Swem o ~ N~CO2Et 1 RedUctive
Oxidation ~o_N 2. (BOC)2O/CH2Cl2
~d)
R10a R10a~
~CO2Et BO/~<
R10a 0
BOP-CI \ ll
NHR16 ~B~ ~H--~ 16
1 (e)
R= Me or tEu
R10a 0
1. LiOH ~ ~H~HR~6
--69--
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w097/33887 PCT~S97/04567
Additional spirocyclic compounds useful in the
present invention can be prepared as outlined in Scheme
9 wherein 1,3-dipolarcycloaddition is carried using
ethyl diazoacetate (E. Keller et al., Tetrahedron, 1993,
4g, 8899) to provide spirocycle 9(b) (Rl~ = H). The
nitrogen of the resulting pyrazole ring may be
optionally functionalized using standard methodology
prior to carrying out the remaining steps leading to
compounds of formula 9(g).
-70-
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Scheme 9
HO/~-- ~ /~= diox~e
r =0-2 9(a) 2. NaH, Rl~X
3. T8AF
~CO2Et o CO2Et 1 Reducbve
HO ~/ N'N Oxidabon ~Y
r R10 H (\~/ N1ON 2. (Boc)2olcH2ci2
9(b) R
9(c)
~ LiOH
EIOP-CI BNo~H R1s
9(t)
1 (o)
R= Me or tBu
2 TFA ~;~H/~ R15
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W097/33887 PCT~S97/04567
Fully saturated spirocycles are obtained by 1,3-
dipolarcycloadditon of a-methoxycarbonylnitrones to an
appropriately substituted alkene as illustrated in
Scheme 10. (Y. Inouye et al., Bull Chem. Soc. Jpn,
1979, 52, 3763; J. Hara et al., ibid., 1981, ~, 3871).
CA 02249733 l998-09-ll
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Scheme 10
MeO2C
~ TBDMS-CI /--\ ~
HO ~e T8DMSO/~e1 R~ N ~O
10(a) 2. TBAF
r=0-2
~CO2Et o CO2Et 1- Reducbve
HO O' O~dabon ~
r H ~/ o_NRl~a 2. (BOC)2O/CH2cl2
1 0(b)
1 O(c)
~;~ B~CO2Et B~,CO2LI
10(d) 10(~)
BOP-C BN/o~H ~r
1(~) 10(f)
R=MeortBu
1. LiOH /~ ~COzH
2. TFA ~H/~o_NR10a R15
N 1 0(9)
The detailed processes for preparing the compounds
of Formula I are illustrated by the following Examples.
It is, however, understood that this invention is not
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limited to the specific details of these examples.
Melting points (mp) are uncorrected. Proton nuclear
magnetic resonance spectra (N~) were measured in
chloroform-d (CDCl3) unless otherwise specified and the
5 peaks are reported in parts per million (ppm) downfield
from tetramethylsilane (TMS). The coupling patterns are
reported as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; bs, broad singlet;
bm, broad multiplet. Infrared spectra are reported in
10 reciprocal centimeters (cm ). All final compounds gave
satisfactory nmr and HRMS data and were analyzed to be
>98% pure by reverse phase analytical HPLC.
~x~mnl~.s
~x~Tnnle 1081
(S)-2-h~n~yloxycarhonvl~mino-3-~8- (2-
Dyri~linyl~mino)~n~thvl -l-ox~-2-~.spiro-~4,5l--lec-2-en-3-
20 yllc~rhor~ mi nol~roDi onic ~ci~l
~t~ ~(8-hv(lroxvmethvl)-l-ox~-2-~ pi ro-r4,5~--lec-2-
en-3-yllc~rhoxyl~te 1 ( A )
Method A: 4-Methylenecyclohexylmethanol (2.52g, 20mmol,
25 Wiley Organics, 63% purity) and sodium bicarbonate
(8.4g, 100mmol) in 45ml of 2:1 THF:H20 was cooled in an
ice bath. Ethyl chlorooximidoacetate (5.00g, 33ITunol) in
30ml 2:1 THF:H~0 was then added, and the mixture stirred
at room temperature for 18 hours. The mixture was then
30 diluted with ethyl acetate and washed with water. The
aqueous layer was extracted with one more portion of
ethyl acetate. The organic layers were combined, dried
(MgSO4), filtered, concentrated and the residue purified
by flash chromatography (silica gel column/l:l
35 EtOAc:Hexane) to afford l(a) as a colorless oil (57.6%
--74--
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W097/33887 PCT~S97/04567
yield). HRMS calcd. for Cl2H1gNO4 ([M+H]+~: 242.139233;
found: 242.140376.
- Method B: A mixture of 4-Methylenecyclohexylmethanol
(lOg, mol, Wiley Organics, 63% purity, 0.051 mol) and
diethylnitromalonate (14 ml, 0.08 mol) in 100 ml
mesitylene was refluxed for 4-5 hrs under a nitrogen
atmosphere with stirring. The resulting yellow solution
was evaporated on a rotary evaporator in vacuo and the
residue purified by flash chromatography (silica
gel/70:30 Hexane/ethyl acetate) to provide 6.4 g of l(a)
(52%) as 3/2 mixture of diastereomers by nmr.
~thvl ~(8-form,vl)-1-oxa-2-azasDiro-~4,5l-dec-2-en-3-
yllcarboxylate: l(b) : Oxalyl chloride (0.70ml, 8mmol)
in 5ml CH2Cl2 was cooled to -78~C in dry ice-acetone bath
and treated with dimethylsulfoxide (0.74ml, 10.4mmol) in
10ml CH2Cl2 and stirred at -78~C for 15 minutes.
Intermediate l(a) (992mg, 4mmol) in 10ml CH2Cl2 was then
added, and the mixture stirred at -78~C for 1 hour.
Triethylamine (2.0g, 20mmol) in 5 ml CH2Cl2 was then
added, and the mixture stirred at -78~C for 15 minutes.
The bath was removed and the mixture allowed to warm up
over a 30 minute period, diluted with CH2Cl2 (5Oml) and
washed with water followed by brine. The organic layer
was separated, dried over anhydrous magnesium sulfate,
filtered and concentrated to afford 0.68g of l(b) as a
clear oil. HRMS calcd. for C12Hl7NO4 ([M+H]+):
240.123583; found: 240.123665.
Ethvl ~8-~(N-t-butoxvcarbonyl)-(N-2-
~vridinyl)aminomethvll-1-oxa-2-azas~iro-~4,51-dec-2-en-
3-vllcarboxvlate l(c): The intermediate l(b) (1.068g, 4
~ mmol crude) and acetic acid (240mg, 4mmol) in 15ml 1,2-
- dichloroethane were treated with sodium
~ 35 triacetoxyborohydride (1.19g, 5.6mmol), and the mixture
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W 097/33887 PCTrUS97/04567
stirred at room temperature for 18 hours. The mixture
was diluted with ethyl acetate and washed with sat.
sodium bicarbonate and then brine. The organic layer
was separated, dried over anhydrous magnesium sulfate,
filtered and concentrated to afford 1.32g of amine as
an oil. HRMS calcd. for Cl7H23N3O3 ([M+H]+): 318.181767;
found: 318.183254.
The crude amine and triethylamine (1.0g, 10mmol) in 20ml
dichloromethane were treated with di-t-butyldicarbonate
(2.18g, 10mmol), and stirred at room temperature for 18
hours. The mixture was diluted with dichloromethane and
washed with water and brine. The organic layer was
separated, dried over anhydrous magnesium sulfate,
filtered, concentrated and the residue purified by flash
chromatography (silica gel/1:3 EtOAc:Hexane) to afford
845mg of l(c) as a colorless oil (50.6% yield from
l(a)). HRMS calcd. for C22H3lN3Os ([M+H]+): 418.234197;
found: 418.233666.
~8-~tN-t -Rl ]toxvc~rhonvl~-(N-2-Dvri~i~yl) ~mi nom~thyll-1-
ox~-2-~z~sDi ro-~4,5l-~ec-2-en-3-vllc~rhoxylic ~ci~ 1(~):
The intermediate l(c~ (209mg, 0.5mmol) in 4.5ml of 2:1
THF:H2O was treated with lithium hydroxide monohydrate
(25mg, 0.6mmol) and the mixture stirred at room
temperature for 18 hours. The mixture was quenched with
0.6ml of 1 N HCl and extracted with ethyl acetate
(2x25ml). The organic layer was separated, dried over
anhydrous magnesium sulfate, filtered, concentrated to
afford l99mg of l(d) as a colorless foam. HRMS calcd.
for C20H27N305 ([M+H]+): 390.202896; found: 390.202306.
Methvl (S~-2-h~nzyloxvc~rho~yl~mino-3-~8-~N-(t-
hutoxyc~rho~vl~-N~ Dvri~inyl~minolmethyl-l-ox~-2-
~7~Diro-~4~51-~ec-2-en-3-yllc~rbonvl~minolpropion~te
l(f) (Rl5 = NHCbz, R = Me): The intermediate l(d)
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(199mg, 0.5mmol crude), l(e) (Rl 5 = NHCbz, R = Me,
14~mg, 0.5mmol) and BOP Reagent (265 mg, 0.6 mmol) in
3ml DMF were treated with 4-N-methylmorpholine (152 mg,
1.5 mmol) in 2ml DMF and the mixture stirred at room
temperature for 18 hours. The mixture was diluted with
ethyl acetate and washed with sat. sodium blcarbonate,
water and then brine. The organic layer was separated,
dried over anhydrous magnesium sulfate, filtered,
concentrated and the residue purified by flash
chromatography (silica gel column/l:l EtOAc:Hexane
followed by 10:1:10 EtOAc:EtOH:Hexane) to afford 213mg
of l(f) (Rl5 = NHCbz, R = Me) as a white solid (68.3%
yield from l(c)). HRMS calcd. for C32H4lN5Og ([M+H]+):
624.303339; found: 624.303031.
(S)-2-henzvloxycarbonylamino-3-~8-(2-
~vridinylamino)metbyl-l-oxa-2-azas~iro-~4,5l-dec-2-en-3-
yllcarhonvlaminQlDro~ionic ~cid l(g) (Rl5 = NHCbz): The
intermediate l(f) (205mg, 0.33mmol crude) in 4ml of 1:1
MeOH:H2O was treated with lithium hydroxide monohydrate
(2lmg, 0.5mmol) and the mixture stirred at room
temperature for 18 hours. The mixture was neutralised
with 0.5ml of 1 N HCl and extracted with EtOAc. The
organic layer was separated, dried over anhydrous
magnesium sulfate, filtered, concentrated to afford
205mg of the free acid as a white solid. HRMS calcd.
for C3lH3gN5O8 ([M+H]+): 610.287689; found: 610.290115.
Crude acid was treated with 3ml of 4M HCl in dioxane and
stirred at room temperature for 18 hoùrs. The mixture
was concentrated in vacuo and the residue purified by
preparative HPLC (C18/80% CH3CN:20% H20:0.05% TFA) to
afford 132mg of a white solid. The compound was
lyophilyzed from 2ml of 1:1 CH3CN:H2O to afford 107mg of
l(g) (Rl5 = NHCbz) as a white solid (52.0% yield from
l(f)). lH NMR (DMSO-D6; Mixture of diastereoisomers) d
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7.8 ~m, 2H), 7.35 (bs, 5H), 6.8 (m, 2H), 5.11 (s, 2H),
4.44 (s, lH), 3.4 (bm, 2H), 3.2 (m, 2H), 2.8 (s, 2H),2.0
- 1.2 (bm, 8H) ; HRMS calcd. for C26H3lNsO6 ([M+H]+):
510.235259; found: 510.236039.
Similarly prepared from l(d) were the following:
~x~m~le 1111
(S)-2-Dhenylsl]lfo~ylamino-3-~8-(2-
~yri~i~yl~mi nQ) m~t~yl-l-ox~-2-~a.s~iro-~4 5l-~ec-2-en-3-
yllc~rhony]~minolDroDionic ~ci~
lH NMR (DMSO-D6) d 8.8 (bs,lH), 8.23 (t, lH, J = 6),
8.18 (d, lH, J = 9), 7.85-7.40 (m, 5H), 7.03 (d, lH, J =
9), 6.8 (t, lH, J = 7), 3.93 (dd, lH, J = 13, 7), 3.38
(m, lH), 3.19 (bm, 3H), 2.8 (s, 2H), 1.85-1.2 (bm, 8H);
MS calcd. for C24H2gNsO6S ([M+H]+): 516.2; found: 516.1.
~x~m~le 11?1
(S)-2-~(~.5-~im~thylisox~ol-2-yl)sl]lfonvll~mino-3-~8-
(2-Dyri~i~yl~mino~methyl-l-ox~-2-~ ~ .s~i ro-~4,5l-~ec-2-
~n-3-yllc~rhonvl~minolDro~ionic ~ci~
H NMR (DMSO-D6) d 8.8 (bs,lH), 8.54 (d, lH, J = 9),
8.27 (t, lH, J = 6), 7.86 (m, lH), 7.03 (d, lH, J = 9),
3.94 (m, lH), 3.44 (m, lH), 3.19 (bm, 3H), 2.8 (s, 2H),
2.45 (s, 3H), 2.5 (s, 3H), 2.9 - 1.2 (bm, 8H); MS calcd.
for C23H3ON6o7s ([M+H]+): 535.2; found: 535.1.
~x~m~le 3055
(S)-2-~(2,4,6-trimet~ylphenvl).sl]lfonyll~mino-3-~7-
hen~vloxvc~rhonyl-8-(2-imi~zolvl~mino)m~t~yl-1-ox~-2 7-
~i~za.s~iro-~4,4l-non-2-en-3-yllc~rhonyl~minol~ro~ionic
Part A: N-chz-4-~y~roxv-rl-~rolinol: A solutlon of N-
Cbz-4-hydroxy-L-proline (50 gm, 0.188 mol) in
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tetrahydrofuran (400 ml) was cooled to O ~C in an ice
bath under nitrogen and a solution of borane
dimethylsulfide complex (2.OM in THF, 122 ml, 0.244 ~ol)
was added dropwise over lh. The resulting mixture is
- 5 then allowed to stir overnight at room temperature. the
reaction mixture was recooled to O ~C and a second
portion of borane-dimethylsulfide complex was added as
described above. Reaction was again stirred at room
temperature overnight, then cooled to O ~C and quenched
by addition of approximately 200ml of 1:1
methanol/water. Solvents were removed on rotary
evaporator and residue diluted with water and extracted
4X with ethyl acetate. The combined extracts were
washed with saturated aqueous sodium bicarbonate
solution (2X) and brine (lX) then dried over anhydrous
magnesium sulfate, filtered and evaporated to a clear
oil (46.77 g, 99%) which was used without purification
in part B below.
P~rt ~. 1-h~n~vloxyc~rho~yl-2-(S)-t-
hl~tvl~im~t~y1si~yloxym~t~yl-4-~y~roxypyrroli~ine: A
mixture of the compound of Part A above (46.77 g, 0.186
mol), triethylamine (51.8 g, 0.372 mol), and t-
butyldimethylsilylchloride (30.86 g, 0.205 mol) in
methylene chloride (375 ml) was stirred under nitrogen
overnight at room temperature. An additional aliquot of
silyl chloride (5 g, 0.033 mol) was added and stirring
continued for 4-5 h. Reaction mixture was transferred
to a separatory funnel and washed with water (4X) and
brine (lX) then dried over anhydrous sodium sulfate,
filtered and solvent removed in vacuo. The residue was
chromatographed on silica gel (hexane - hexane/ethyl
acetate 8:2 - hexane/ethyl acetate 7:3) to provide the
- silyl ether (47.11 g, 69~)
P~rt C. 1-henzyloxvc~rhony1-2(S)-t-
hutyl~imethv1siLyloxymeth~yl-4-~vrroli~inone: To a
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solution of oxalyl chloride (12.4 ml, 0.142 mol) in
methylene chloride (330 ml) precooled to -70 ~C in an
acetone/dry ice bath was added a solution of anhydrous
dimethylsulfoxide (20.60ml, 0.29 mol) in methylene
chloride (66 ml) dropwise under nitrogen over 30 min at
T < -65~C. The resulting mixture was stirred 15 min,
followed by dropwise addition of a solution of the
compound of part B above in methylene chloride (130 ml)
over 45 min at T c -65~C. The reaction was stirred for
30 min followed by dropwise addition of triethylamine
(119.2 ml, 0.855 mol) over 30 min again at T < -65~C.
The cooling bath was removed and the reaction
temperature was allowed to rise to 5-10~C, and then
quenched by addition of 645 ml of 10% aqueous potassium
hydrogen sulfate solution. The mixture was then
transferred to a separatory funnel and layers separated.
The aqueous was extracted with methylene chloride and
the combined organic layers are washed with 10% citric
acid solution (3X) and brine (lX) then dried over
anhydrous sodium sulfate, filtered and concentrated to a
clear oil (46.8 g, 100%) which was used without
purification in part D below.
p~rt D. l-b~n~yloxyc~rhor~yl-2 (S) -t-
hl]tvl~i~et~ylsi~ylox~methyl-4-methyl~nepyrroli~ine:
Methyltriphenylphosphonium bromide (68,98 g, 0.193 mol)
is added to a suspension of potassium t-butoxide (20.27
g, 0.181 mol~ in anhydrous ether (700 ml) with stirring
at 0~C under nitrogen. The resulting bright yellow
solution is stirred for an additional 15 min. To this
is added a solution of the compound of part D above
(46.8 g, 0.129 mol) in ether (100 ml). The mixture is
allowed to assume room temperature and stirred
overnight. The resulting mixture was cooled in an ice
bath and quenched by addition 700 ml of a saturated
solution of ammonium chloride. The phases were
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separated and aqueous reextracted 2X with ether. The
combined organics were washed with brine and dried over
anhydrous sodium sulfate, filtered and evaporated in
vacuo. The crude product was purified by flash
chromatography (silica gel, hexane-ether 9:1) to provide
the olefin (42.6 g, 91%) as a pale yellow oil.
p~rt E: 7-benzv~ox~yc~rhonvl-8-t-hutyl~im~thvl~ilyloxv-
meth~yl-3-ethoxyc~rhonyl-1-ox~-2 7-~ iro-r4 4l-non-
2-~ne: The compound of part D above (13.04 g, 0.036
mol) was dissolved in methylene chloride (50 ml),
treated with ethyl chlorooximidoacetate (8.18 g., 0.054
mol), and the mixture was cooled to 0~C followed by
dropwise addition of triethylamine (7.53 ml, 0.054 mol).
The reaction was allowed to come to room temperature
over several hours then stirred overnight. An
additional 1.5 eq. of the chlorooxime was then added,
and the mixture was cooled to 0~C and treated with
triethylamine (1.5 eq) as described above. Resulting
mixture was stirred at room temperature for 48 h, then
diluted with additional methylene chloride and washed
with 10% aqueous citric acid (3X), and brine (lX) then
dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo. The crude was charged to silica
gel and eluted first with Hexane/ether(80:20) to provide
unreacted starting material (6.64 g, 51%) and then with
hexane/ethyl acetate (75:25) to provide the two
diastereomers of the product (S,S isomer, 5.54 g, 32%;
S,R isomer, 1.34 g, 8%). Anal. Calcd. for C24H36N2O6Si:
C, 60.48; H, 7.61; N, 5.89. Found: C, 60.46; H, 7.33; N,
5.96.
Part F: 7-henzyloxvc~rho~yl-8-t-hl~tyl~imethylsilylo~y-
meth~yl-3-c~rbo~y-l-ox~-2,7-~i~7~s~iro-~4,4~-non-2-ene:
The compound of Part E above (18.7 g, 0.038 mol) was
dissolved in methanol (200 ml) and treated at room
temperature with a solution of lithium hydroxide
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W097/33~7 PCT~S97/04567
monohydrate (2.4 g, 0.057 mol) in water (50 ml). The
whole was stirred for 5 h and then solvent removed in
vacuo. Water was added and the pH of the solution was
adjusted to 4.4 with 10% aq. citric acid solution. The
resulting mixture was extracted 3X with ethyl acetate
with adjustment of pH back to 4.4 between extractions.
The combined extracts were washed with brine and dried
over anhydrous sodium sulfate, filtered and evaporated.
The residue was dried under vacuum to provide the acid
(16.2 g, 95%) as a foam which was used without
purification in Part G below. MS(esi) m/z 449.4 (M+H)+,
335.2 (M+H-TBMDS)+
Part G: t-BIltyl (S)-2-~(2.4.6-trimeth~ylDh~nvl)slllfonyll-
~mino-3-~7-h~n~vloxvc~rhonvl-8-(t-hl]tyl~im~thvlsilyl-
oxv)m~thyl-1-ox~-2 7-~ spiro-~4 4l-non-2-en-3-
vllc~rhonvl ~mi nol~ro~ionic ~ci~: A mixture of the
compound of Part F above ~10 g, 0.022 mol), t-butyl 3-
amino-2-(2,4,6-trimethylphenylsulfonylamino)propionate
(7.6 g, 0.022 mol), N-methylmorpholine (5.4 ml, (0.049
mol) and Castro's reagent (14.8 g, 0.033 mol) in N,N-
dimethylformamide (100 ml)was stirred under nitrogen at
room temperature overnight. The DMF was removed in
vacuo and the residue diluted with 500 ml water and
extracted 3X with ethyl acetate. The combined extracts
were washed with water (2X), 10% citric acid (lX),
saturated sodium bicarbonate (lX) and brine (lX) then
dried over anhydrous sodium sulfate, filtered and
evaporated. The coupling product was purified by
filtration through a pad of silica gel eluted with
hexane/ethyl acetate (4:1) to provide the product as a
white foam (15 gm, 88%). MS(esi) m/z 773.4 (M+H)+ 795.4
(M+Na)+.
p~rt H: t-sntvl ~S)-2-~(2,4,6-trim~thvl~henvl~ Sl]l fonvll-
~mino-3-r~7-h~n~vloxyc~rhonyl-8-hy~roxymethvl-l-ox~-2~7
~i~z~Diro-~4,4l-non-2-en-3-vllc~rhonyl~minolDro~ionic
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acid: The compound of Part G above (2.8 g, 3.62 mmol)
was dissolved in tetrahydrofuran (12 ml) and treated
with tetra-n-butylammonium floride (5.8 ml of a 1.0 M
solution in THF, 5.8 mmol). The resulting solution was
~ 5 stirred overnight at room temperature. Reaction was
quenched by addition of water and T~F removed on rotary
evaporator. The remaining aqueous was extracted 3X with
ethyl acetate. The combined extracts were washed with
water and brine, dried over anhydrous sodium sulfate,
filtered and evaporated. Chromatography on silica gel
(hexane/ethyl acetate 1:1 followed by methylene
chloride/methanol 95:5) provided the alcohol (2.02 g.,
85%) ms m/z 659.3 (M+H)+.
p~rt I: t-sutyl (S)-2-~(2.4,6-trimethvl~henvl)sulfonvll-
15 ~mi no-3-~7-benzyloxycarbonyl-8-formvl-1-oxa-2,7-
diaz~iro-~4,4l-non-2-en-3-vllc~rbonylaminolDroDionic
acid: A solution of the compound of Part H above (0.8
g, 1.21 mmol) in anhydrous methylene chloride (1 ml) was
added dropwise to a a solution of Dess-Martin
20 periodinane (0.59g, 1.30 mmol) in approxim~tely 4 ml of
dry methylene chloride at room temperature under
nitrogen. The resulting mixture was stirred for 1 hr,
the diluted with ethyl acetate and poured into a
solution of saturated sodium bicarbonate (20 ml)
containing 5 g sodium thiosulfate. This was stirred for
10 min. The phases were separated, aqueous reextracted
with ethyl acetate, and combined organics washed with
saturated sodium bicarbonate, water and brine, then
dried over anhydrous magnesium sulfate, filtered and
evaporated to give the aldehyde as a clear oil (0.74 g,
93%).
Part J: t-Butyl (S)-2-~(2,4,6-trimethvl~henyl)sulfonyll-
amino-3-~7-benzvloxvcarbonyl-8-(imidazol-2-
ylamino)methyl-l-ox~-2,7-diazas~iro-~4,41-non-2-en-3-
yllcarbonyl~minol~ro~ionic acid: To a solution of the
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W O 97/33887 PCT~US97/04567
compound of Part I above (0.73 g, 1.11 mmol) in benzene
was added anhydrous magnesium sulfate (0.588 g, 4.88
mmol) and 2-amino-1-tritylimidazole (0.398 g, 1.22 mmol)
and the whole was refluxed for 4 hrs under nitrogen.
The mixture was cooled to room temperature, filtered
under nitrogen and benzene removed in vacuo. The
residue was taken up in l,2-dichloroethane, treated
under nitrogen at room temperature with sodium
triacetoxyborohydride (0.588 g, 2.78 mmol), and the
whole was stirred overnight. The reaction was quenched
by addition of water and then diluted with ethyl
acetate. Aqueous was reextracted with ethyl acetate,
and combined organic layers were washed with saturated
sodium bicarbonate, water and brine, then dried over
anhydrous magnesium sulfate, filtered and evaporated.
Filtration through silica gel provided the desired
product (0.682 g, 63~) as an off-white foam which was
used without further purification in part K below.
p~rt K: (S)-2- r (2. 4, 6-trim~thvlDh~r~yl ~ sl~l fonyll-~mino-3-
r r7-h~n7~yloxvc~rhor~rl-8-(imi~1~7:ol-2-yl ~mi no)m~thyl-l-
ox~-2,7-~ ;ro- r 4 ~ 4l-non-2-~n-3-yllc~rhonvl~inol-
DroDionic ~ci~: The compound of part J above (0.3 g,
0.31 mmol) was dissolved in 20% acetic acid in methanol
(10 ml) and refluxed for 24 h under nitrogen. The
reaction was cooled to room temperature, methanol
removed by evaporation and residue diluted with ethyl
acetate. This solution was washed with saturated sodium
bicarbonate (2X), water and brine then dried over
anhydrous magnesium su~fate, filtered and evaporated.
Filtration through silica gel (eluted with (i)methylene
chloride/methanol 95:5; (2) methylene
chloride/methanol/conc. ammonium hydroxide 95:5:0/5; (3)
90/10/1) provided the intermediate detritylated t-butyl
ester 0.139 mg, 62%). This was taken up in methylene
chloride (8 ml) and trifluoroacetic acid (2 ml) was
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W097/33887 PCT~S97/04567
added. The solution was stirred for 72 h, then
evaporated and triturated with ether. The resulting
~ solid was purified by prep HPLC (C18, gradient from 100%
A to 100% B: A=90/10/0.05 H2O/CH3CN/TFA; B=90/10/0.05
CH3CN/H2O/TFA) to provide the title compound (0.078g,
50%). MS m/z 690.4 (M+Na)+ 668.4 (M+H)+.
~x~mnle 3063: ~S)-2-~(2,4,6-trimethvlph~yl) Slll fonyll-
~mino-3-~8-(imi~A~ol-2-vl~mino~m~thvl-1-ox~-2 7-
0 (1i;~ Di ro-~4~4l-non-2-~n-3-yllc~rhonyl~minol-vropionic
The compound of Example 3055, Part J, (0.1 g, 0.1 mmol)
was taken up in neat trifluoroacetic acid (3 ml) and the
mixture refluxed for 1.5 h. Reaction was cooled to room
temperature and TFA removed in vacuo. The residue was
purified by prep HPLC using the system described under
Ex. 3055, Part K above to provide the title compound
(0.043 g, 80%). MS m/z 534.4 (M+H)+.
Using the methods described above and modifications
thereof known to one skilled in the art of organic
synthesis, additional compounds of the present invention
can be prepared, including, but not limited to the
representative compounds listed in the Tables below.
Utilitv
The compounds of Formula I of the present invention
possess activity as antagonists of integrins such as,
for example, the a~3 or vitronectin receptor, a~s or
aS~l, and as such have utility in the treatment and
diagnosis of cell adhesion, angiogenic disorders,
inflammation, bone degradation, cancer metastases,
diabetic retinopathy, thrombosis, restenosis, macular
degeneration, and other conditions mediated by cell
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adhesion and/or cell migration and/or angiogenesis. The
integrin antagonist activity of the compounds of the
present invention is demonstrated using assays which
measure the binding of a specific integrin to a native
ligand, for example, using the ELISA assay described
below for the binding of vitronectin to the a~3
receptor.
The compounds of the present invention possess
selectivity for the ~v~3 receptor relative to the
GPIIb/IIIa receptor as demonstrated by their lack of
activity in standard assays of platelet aggregation,
such as the platelet aggregation assay described below.
One of the major roles of integrins in vivo is to
mediate cellular interactions with adjacent cells. Cell
based adhesion assays can be used to mimic these
interactions in vi tro. A cell based assay is more
representative of the in vivo situation than an ELISA
since the receptor is maintained in membranes in the
native state. The compounds of the present invention
have activity in cell-based assays of adhesion, for
example as demonstratéd in using the cell adhesion
assays described below.
The compounds of Formula I of the present invention
may be useful for the treatment or prevention of other
diseases which involve cell adhesion processes,
including, but not limited to, osteoporosis, rheumatoid
arthritis, autoimmune disorders, bone degradation,
rheumatoid arthritis, asthma, allergies, adult
respiratory distress syndrome, graft versus host
disease, organ transplantation, septic shock, psoriasis,
eczema, contact dermatitis, osteoarthritis,
atherosclerosis, metastasis, wound healing, inflammatory
bowel disease and other angiogenic disorders.
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The compounds of Formula I have the ability to
suppress/inhibit angiogenesis in vivo, for example, as
demonstrated using animal models of ocular
neovascularization.
The compounds provided by this invention are also
useful as standards and reagents in determining the
ability of a potential pharmaceutical to inhibit
integrin-ligand binding. These may be provided in a
commercial kit comprising a compound of this invention.
As used herein "~g" denotes microgram, "mg" denotes
milligram, "g" denotes gram, "~L" denotes microliter,
"mL" denotes milliliter, "L" denotes liter, "nM" denotes
nanomolar, "~MN denotes micromolar, "mM" denotes
millimolar, "M" denotes molar and "nm" denotes
nanometer. "Sigma" stands for the Sigma-Aldrich Corp.
of St. Louis, MO.
The utility of the compounds of the present
invention may be assessed by testing in one or more of
the following assays as described in detail below:
Purified av~3 (human placenta~ - Vitronectin ELISA,
av~3-Vitronectin Binding Assay, Human Aortic Smooth
Muscle Cell Migration Assay, In Vivo Angiogenesis Model,
Pig Restenosis Model, Mouse Retinopathy Model. A
compound of the present invention is considered to be
active if it has an ICsO or Ki value of less than about
10 ~M for the inhibition of aV~3-vitronectin Binding
Assay, with compounds preferably having Ki values of
less than about 0.1 ~M. Tested compounds of the present
invention are active in the a~3-Vitronectin Binding
Assay as well as in cell-based assays of integrin
- adhesion mediated by the av~3-receptor.
pl2rifie~ ~y~ (hl~m~n 2~1~c~nt~) - Vltronectin ~T.ISA
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The a~3 receptor was isolated from human placental
extracts prepared using octylglucoside. The extracts
were passed over-an affinity column composed of anti-a~3
monoclonal antibody (LM609) to Affigel. The column was
subse~uently washed extensively at pH 7 and pH 4.5
followed by elution at pH 3. The resulting sample was
concentrated by wheat germ agglutinin chromatography to
provide gave two bands on SDS gel which were confirmed
as a~3 by western blotting.
Affinity purified protein was diluted at different
levels and plated to 96 well plates. ELISA was performed
using fixed concentration of biotinylated vitronectin
(approximately 80 nM/well). This receptor preparation
contains the av~3 with no detectable levels of av~5
according to the gel (av~3) and according to effects of
blocking antibodies for the av~3 or a~s in the ELISA.
A submaximal concentration of biotinylated
vitronectin was selected based on conc. response curve
with fixed receptor conc. and variable concentrations of
biotinylated vitronectin.
~-Vitronectin Binding Assay
The purified receptor is diluted with coating
buffer ~20 mM Tris HCl, 150 mM NaCl, 2.0 mM CaC12, 1.0 mM
MgCl2 6H2O, 1.0 mM MnCl2-4H2O) and coated (100 ~L/well)
on Costar (3590) high capacity binding plates overnight
at 4~C. The coating solution is discarded and the
plates washed once with blocking/binding buffer (B/B
buffer, 50 mM Tris HCl, 100 mM NaCl, 2.0 mM CaC12,1.0 mM
MgCl2 6H2O,l.0 mM MnCl2-4H2O). Receptor is then blocked
(200 ~L/well) with 3.5% BSA in B/B buffer for 2 hours at
room temperature. After washing once with 1.0% BSA in
B/B buffer, biotinylated vitronectin (100 ~L) and either
inhibitor (11 ~L) or B/B buffer w/1.0% BSA (11 ~L)is
added to each well. The plates are incubated 2 hours at
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CA 02249733 l998-09-ll
W097/33887 PCT~S97/04567
room temperature. The plates are washed twice with B/B
buffer and incubated 1 hour at room temperature with
- anti-biotin alkaline phosphatase (100 ~L/well) in B/B
buffer containing 1.0% BSA. The plates are washed twice
with B/B buffer and alkaline phosphatase substrate (100
~L) is added. Color is developed at room temperature.
Color development is stopped by addition of 2N NaOH (25
~L/well) and absorbance is read at 405 nm. The ICso is
the concentration of test substance needed to block 50%
of the vitronectin binding to the receptor.
Intearin Cell-B~.se~ A~esion A~s~y.s
In the adhesion assays, a 96 well plate was coated
with the ligand (i.e., fibrinogen) and incubated
overnight at 4~ C. The following day, the cells were
harvested, washed and loaded with a fluorescent dye.
Compounds and cells were added together and then were
immediately added to the coated plate. After
incubation, loose cells are removed from the plate, and
the plate (with adherent cells) is counted on a
fluorometer. The ability of test compounds to inhibit
cell adhesion by 50% is given by the IC50 value and
represents a measure of potency of inhibition of
integrin mediated binding. Compounds were tested for
their ability to block cell adhesion using assays
specific for av~3, av~s and a5~1 integrin interactions.
Pl~telet Aaarea~tion ~.ss~y
Venous blood was obtained from anesthetized mongrel
dogs or from healthy human donors who were drug- and
aspirin-free for at least two weeks prior to blood
collection. Blood was collected into citrated Vacutainer
tubes. The blood was centrifuged for 15 minutes at 150
x g (850 RPM in a Sorvall RT6000 Tabletop Centrifuge
with H-1000 B rotor) at room temperature, and platelet-
-
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W O 97/33887 PCT~US97/04567
rich plasma (PRP) was removed. The remaining blood was
centrifuged for 15 minutes at 1500 x g (26,780 RPM) at
room temperature, and platelet-poor plasma (PPP) was
removed. Samples were assayed on a PAP-4 Platelet
Aggregation Profiler, using PPP as the blank (100%
transmittance). 200 ~L of PRP (5x108 platelets/mL) were
added to each micro test tube, and transmittance was set
to 0%. 20 ~L of ADP (10 ~M~ was added to each tube, and
the aggregation profiles were plotted (% transmittance
versus time). Test agent (20 ~L) was added at different
concentrations prior to the addition of the platelet
agonist. Results are expressed as % inhibition of
agonist-induced platelet aggregation.
Hl]m~n A~rtic S~ooth Mll.scle Cell ~i~r~t;on Ass~y
A method for assessing a~3-mediated smooth muscle cell
migration and agents which inhibit a~3-mediated smooth
muscle cell migration is described in Liaw et al., J.
Clin. Invest. ~1995) 95: 713-724).
In Vivo ~naio~enesis Mo~el
A quantitative method for assessing angiogenesis and
antiangiogenic agents is described in Passaniti et al.,
Laboratory Investigation (1992) 67: 519-528
Pi~ Restenosi.s Mo~el
A method for assessing restenosis and agents which
inhibit restenosis is described in Schwartz et al., J.
Am. College of Cardiology ~1992) 19: 267-274.
Mollse Retinop~thv Mo~el
A method for assessing retinopathy and agents which
inhibit retinopathy is described in Smith et al.,
Invest. Ophthal. & Visual Science (1994) 35: 101-111.
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W097/33887 PCT~S97/04567
Dosage and Formulation
The compounds of this invention can be administered
by any means that produces contact of the active agent
with the agent's site of action, the a~3 integrin, in
the body of a ~ A 1 . They can be administered by any
conventional means available for use in conjunction with
pharmaceuticals, either as individual therapeutic agents
or in a combination of therapeutic agents, such as a
antiplatelet agent such as aspirin, piroxicam, or
ticlopidine which are agonist-specific, or an
anti-coagulant such as warfarin or heparin, or a
thrombin inhibitor such as a boropeptide, hirudin or
argatroban, or a thrombolytic agent such as tissue
plasminogen activator, anistreplase, urokinase or
streptokinase, or combinations thereof. The compounds
of the invention, or compounds of the invention in
combination with other therapeutic agents, can be
administered alone, but generally administered with a
pharmaceutical carrier selected on the basis of the
chosen route of administration and standard
pharmaceutical practice.
The dosage of the novel cyclic compounds of this
invention administered will, of course, vary depending
upon known factors, such as the pharmacodynamic
characteristics of the particular agent and its mode and
route of administration; the age, health and weight of
the recipient; the nature and extent of the symptoms;
the kind of concurrent treatmenti the frequency of
treatment; and the effect desired. A daily dosage of
active ingredient can be expected to be about 0.001 to
10 milligrams per kilogram of body weight.
Dosage forms ~compositions suitable for
administration) contain from about 0.1 milligram to
~ 35 about 100 milligrams of active ingredient per unit. In
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these pharmaceutical compositions the active ingredient
will ordinarily be present in an amount of about 0.5-95%
by weight based cn the total weight of the composition.
The active ingredient can be ~mi ni stered orally in
solid dosage forms, such as capsules, tablets, and
powders, or in liquid dosage forms, such as elixirs,
syrups, and suspensions. It can also be administered
parenterally, in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and
powdered carriers, such as lactose, starch, cellulose
derivatives, magnesium stearate, stearic acid, and the
like. Similar diluents can be used to make compressed
tablets. Both tablets and capsules can be manufactured
as sustained release products to provide for continuous
release of medication over a period of hours. Compressed
tablets can be sugar coated or film coated to mask any
unpleasant taste and protect the tablet from the
atmosphere, or enteric coated for selective
disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can
contain coloring and flavoring to increase patient
acceptance.
In general, water, a suitable oil, saline, aqueous
dextrose (glucose), and related sugar solutions and
glycols such as propylene glycol or polyethylene glycols
are suitable carriers for parenteral solutions.
Solutions for parenteral administration preferably
contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer
substances. Antioxidizing agents such as sodium
bisulfite, sodium sulfite, or ascorbic acid, either
alone or combined, are suitable stabilizing agents.
Also used are citric acid and its salts and sodium EDTA.
In addition, parenteral solutions can contain
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preservatives, such as benzalkoniu~ chloride, methyl- or
propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in
Remington~s Pharmaceutical Sciences, Mack Publishing
~ 5 Company, a standard reference text in this field.
Useful pharmaceutical dosage-forms for
administration of the compounds of this invention can be
illustrated as follows:
Ca~sllle.s
A large number of unit capsules are prepared by
filling standard two-piece hard gelatin capsules each
with 10 milligrams of powdered active-ingredient, 150
milligrams of lactose, 50 milligrams of cellulose, and 6
milligrams magnesium stearate.
Soft Gel~tin C~psl~
A mixture of active ingredient in a digestable oil
such as soybean oil, cottonseed oil or olive oil is
prepared and injected by means of a positive
displacement pump into gelatin to form soft gelatin
capsules containing 10 milligrams of the active
ingredient. The capsules are washed and dried.
T~hlets
A large number of tablets are prepared by
conventional procedures so that the dosage unit was 10
milligrams of active ingredient, 0.2 milligrams of
colloidal silicon dioxide, 5 milligrams of magnesium
stearate, 275 milligrams of microcrystalline cellulose,
11 milligrams of starch and 98.8 milligrams of lactose.
Appropriate coatings may be applied to increase
palatability or delay absorption.
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The combination products of this invention, such as
the novel a~3 antagonist compounds of this invention in
combination with an anti-coagulant agent such as
warfarin or heparin, or an anti-platelet agent such as
aspirin, piroxicam or ticlopidine, or a thrombin
inhibitor such as a boropeptide, hirudin or argatroban,
or a thrombolytic agent such as tissue plasminogen
activator, anistreplase, urokinase or streptokinase, or
combinations thereof, can be in any dosage form, such as
those described above, and can also be ~i ni stered in
various ways, as described above.
In a preferred embodiment, the combination products
of the invention are formulated together, in a single
dosage form (that is, combined together in one capsule,
tablet, powder, or liquid, etc.). When the combination
products are not formulated together in a single dosage
form, the av~3 antagonist compounds of this invention and
the anti-coagulant agent, anti-platelet agent, thrombin
inhibitor, and/or thrombolytic agent may be administered
at the same time (that is, together), or in any order,
for example the compounds of this invention are
administered first, followed by administration of the
anti-coagulant agent, anti-platelet agent, thrombin
inhibitor, and/or thrombolytic agent. When not
administered at the same time, preferably the
administration of the compound of this invention and any
anti-coagulant agent, anti-platelet agent, thrombin
inhibitor, and/or thrombolytic agent occurs less than
about one hour apart, more preferably less than about 30
minutes apart, even more preferably less than about 15
minutes apart, and most preferably less than about 5
minutes apart. Preferably, administration of the
combination products of the invention is oral. The
terms oral agent, oral inhibitor, oral compound, or the
like, as used herein, denote compounds which may be
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W097/33887 PCT~S97/04567
orally administered. Although it is preferable that the
a~3 antagonist compounds of this invention and the
anti-coagulant agent, anti-platelet agent, thrombin
inhibitor, and/or thrombolytic agent are both
administered in the same fashion (that is, for example,
both orally), if desired, they may each be administered
in different fashions (that is, for example, one
component of the combination product may be administered
orally, and another component may be administered
intravenously). The dosage of the combination products
of the invention may vary depending upon various factors
such as the pharmacodynamic characteristics of the
particular agent and its mode and route of
administration, the age, health and weight of the
recipient, the nature and extent of the symptoms, the
kind of concurrent treatment, the frequency of
treatment, and the effect desired, as described above.
As discussed above, where two or more of the
foregoing therapeutic agents are combined or
co-administered with the compounds of this invention,
generally the amount of each component in a typical
daily dosage and typical dosage form may be reduced
relative to the usual dosage of the agent when
administered alone, in view of the additive or
synergistic effect which would be obtained as a result
of addition of further agents in accordance with the
present invention.
Particularly when provided as a single dosage form,
the potential exists for a chemical interaction between
the combined active ingredients (for example, a novel
compound of this invention and an anti-coagulant such as
warfarin or heparin, or a novel compound of this
invention and an anti-platelet agent such as aspirin,
piroxicam or ticlopidine, or a novel compound of this
invention and a thrombin inhibitor such as a
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w097/338x7 PCT~S97/04567
boropeptide, hirudin or argatroban, or a novel compound
of this invention and a thrombolytic agent such as
tissue plasminogen activator, anistreplase, urokinase or
streptokinase, or combinations thereof). For this
reason, the preferred dosage forms of the combination
products of this invention are formulated such that
although the active ingredients are combined ln a single
dosage form, the physical contact between the active
ingredients is minimi zed (that is, reduced).
In order to minimize contact, one embodiment of
this invention where the product is orally ~mi ni .~tered
provides for a combination product wherein one active
ingredient is enteric coated. By enteric coating one of
the active ingredients, it is possible not only to
minimize the contact between the combined active
ingredients, but also, it is possible to control the
release of one of these components in the
gastrointestinal tract such that one of these components
is not released in the stomach but rather is released in
the intestines. Another embodiment of this invention
where oral ~i ni stration is desired provides for a
combination product wherein one of the active
ingredients is coated with a sustained-release material
which effects a sustained-release throughout the
gastrolntestinal tract and also serves to mi~imize
physical contact between the combined active
ingredients. Furthermore, the sustained-released
component can be additionally enteric coated such that
the release of this component occurs only in the
intestine. Still another approach would involve the
formulation of a combination product in which the one
component is coated with a sustained and/or enteric
release polymer, and the other component is also coated
with a polymer such as a low viscosity grade of
hydroxypropyl methylcellulose (HPMC) or other
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W097/33887 PCT~S97/04567
appropriate materials as known in the art, in order to
further separate the active components. The polymer
coating serves to form an additional barrier to
interaction with the other component.
Dosage forms of the combination products of the
present invention wherein one active ingredient is
enteric coated can be in the form of tablets such that
the enteric coated component and the other active
ingredient are blended together and then compressed into
a tablet or such that the enteric coated component is
compressed into one tablet layer and the other active
ingredient is compressed into an additional layer.
Optionally, in order to further separate the two layers,
one or more placebo layers may be present such that the
placebo layer is between the layers of active
ingredients. In addition, dosage forms of the present
invention can be in the form of capsules wherein one
active ingredient is compressed into a tablet or in the
form of a plurality of microtablets, particles, granules
or non-perils, which are then enteric coated. These
enteric coated microtablets, particles, granules or non-
perils are then placed into a capsule or compressed into
a capsule along with a granulation of the other active
ingredient.
These as well as other ways of minimizing contact
between the components of combination products of the
present invention, whether administered in a single
dosage form or administered in separate forms but at the
same time by the same manner, will be readily apparent
to those skilled in the art, once armed with the present
disclosure.
Pharmaceutical kits useful in, for example, the
inhibition of thrombus formation, the prevention of
~ 35 blood clots, and/or the treatment of thromboembolic
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w097t33887 PCT~S97/04S67
disorders, which comprise a therapeutically effective
amount of a compound according to the method of the
present invention along with a therapeutically effective
amount of an anti-coagulant agent such as warfarin or
heparin, or an antiplatelet agent such as aspirin,
piroxicam or ticlopidine, or a thrombin inhibitor such
as a boropeptide, hirudin or argatroban, or a
thrombolytic agent such as tissue plasminogen activator,
anistreplase, urokinase or streptokinase, or
combinations thereof, in one or more sterile containers,
are also within the ambit of the present invention.
Sterilization of the container may be carried out using
conventional sterilization methodology well known to
those skilled in the art. The sterile containers of
materials may comprise separate containers, or one or
more multi-part containers, as exemplified by the
UNIVIAL~ two-part container (available from Abbott Labs,
Chicago, Illinois), as desired. The compounds according
to the method of the invention and the anti-coagulant
agent, anti-platelet agent, thrombin inhibitor,
thrombolytic agent, and/or combinations thereof, may be
separate, or combined into a single dosage form as
described above. Such kits may further include, if
desired, one or more of various conventional
pharmaceutical kit components, such as for example, one
or more pharmaceutically acceptable carriers, additional
vials for mixing the components, etc., as will be
readily apparent to those skilled in the art.
Instructions, either as inserts or as labels, indicating
quantities of the components to be administered,
guidelines for administration, and/or guidelines for
mixing the components, may also be included in the kit.
Representative compounds of the present invention
are listed in the Tables below.
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Table ~
O Rl4 O
R~ HN ~OH
E~ Bl L Bl4~15
~ .
1001imidazol-2-yl- 1 H H
aminomethyl
1002imidazol-2-yl- 1 HNHC02Bn
aminomethyl
1003imidazol-2-yl- 1 HNHC02CH2C6H4-(2-
aminomethyl CH3)
1004imidazol-2-yl- 1 HNHCo2cH2c6H4-(3
aminomethyl CH3)
1005imidazol-2-yl- 1 HNHco2cH2c6H4
aminomethyl ~4-CH3)
1006imidazol-2-yl- 1 HNHCO2CH2~2-
aminomethyl pyridinyl)
1007imidazol-2-yl- 1 HNHco2cH2(3
aminomethyl pyridinyl)
1008imidazol-2-yl- 1 HNHCo2cH2~4
aminomethyl pyridinyl)
1009imidazol-2-yl- 1 HNHC02CH2(2-
aminomethyl thiazolyl)
1010imidazol-2-yl- 1 HNHC02CH2(4-
aminomethyl thiazolyl)
1011imidazol-2-yl- 1 HNHC02CH2(5-
aminomethyl thiazolyl)
1012imidazol-2-yl- 1 HNHCO2CH2(4-
aminomethyl isoxazolyl)
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W 097/33887 PCTrUS97/04567
1013imidazol-2-yl- 1 H NHCO2CH2(2-
aminomethyl thienyl)
1014imidazol-2-yl-- 1 H NHCo2cH2(5
aminomethyl isoxazolyl)
1015imidazol-2-yl- 1 H NHCO2n-Bu
aminomethyl
1016imidazol-2-yl- 1 H NHCO2i-Bu
aminomethyl
1017imidazol-2-yl- 1 H NHCO2t-Bu
aminomethyl
1018imidazol-2-yl- 1 H NHCOCH2Ph
aminomethyl
1019imidazol-2-yl- 1 H NHCOCH2C6H4_(2-
aminomethyl CH3)
1020imidazol-2-yl- 1 H NHCOCH2C6H4-(3-
aminomethyl CH3)
1021imidazol-2-yl- 1 H NHCOCH2C6H4-(4-
aminomethyl CH3)
1022imidazol-2-yl- 1 H NHCOCH2(2-
aminomethyl pyridinyl)
1023imidazol-2-yl- 1 H NHCOCH2(3-
aminomethyl pyridinyl)
1024imidazol-2-yl- 1 H NHCOCH2(4-
aminomethyl pyridinyl)
1025imidazol-2-yl- 1 H NHCOCH2(2-
aminomethyl thiazolyl)
1026imidazol-2-yl- 1 H NHCOCH2(4-
aminomethyl thiazolyl)
1027imidazol-2-yl- 1 H NHCOCH2(5-
aminomethyl thiazolyl)
1028imidazol-2-yl- 1 H NHCOCH2(4-
aminomethyl isoxazol)
1029imidazol-2-yl- 1 H NHCOCH2(2-
aminomethyl thienyl)
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1030imidazol-2-yl- 1 H NHCOn-Bu
aminomethyl
1031imidazol-2-yl- 1 H NHCOt-Bu
aminomethyl
1032imidazol-2-yl- 1 H NHSO2Ph 505.2
aminomethyl
1033imidazol-2-yl- 1 H NHSO2C6H4-(2-
aminomethyl CH3)
1034imidazol-2-yl- 1 H NHSO2C6H4-(3-
aminomethyl CH3)
1035imidazol-2-yl- 1 H NHSO2C6H4-(4-
aminomethyl CH3)
1036imidazol-2-yl- 1 HNHSO2(2-pyridyl)
aminomethyl
1037imidazol-2-yl- 1 HNHSO2(3-pyridyl)
aminomethyl
1038imidazol-2-yl- 1 HNHSO2(4-pyridyl)
aminomethyl
1039imidazol-2-yl- 1 H NHSO2(2-thiaz-
aminomethyl olyl)
1040imidazol-2-yl- 1 H NHSO2(3-
aminomethyl thiazolyl)
1041imidazol-2-yl- 1 H NHSO2(4-
aminomethyl isoxazolyl)
1042imidazol-2-yl- 1 H NHSO2[4-(3,5-
aminomethyl dimethyl)isoxaz
olyl]
1043imidazol-2-yl- 1 H NHso2c6H4-(2
aminomethyl Br)
1044imidazol-2-yl- 1 H NHSO2C6H4-(3-
aminomethyl Br)
1045imidazol-2-yl- 1 H NHS02C6H4-(4-
aminomethyl Br)
1046imidazol-2-yl- 1 H NHSO2C6H4-(2-F)
aminomethyl
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1047imidazol-2-yl- 1 HNHS02C6H4-(3-F)
aminomethyl
1048imidazol-2-yl- 1 HNHSO2C6H4-(4-F)
aminomethyl
104gimidazol-2-yl- 1 H NHS02~2- 555.2
aminomethyl naphthyl)
1050imidazol-2-yl- 1 H NHSO2(1-
aminomethyl naphthyl)
1051imidazol-2-yl- 1 HNHSO2CH=CHPh
aminomethyl
1052imidazol-2-yl- 1 HNHSO2CH2Ph
aminomethyl
1053imidazol-2-yl- 1 HNHSO2CH2CH=CH-Ph
amlnomethyl
1054imidazol-2-yl- 1 HNHS02-n-Bu
aminomethyl
1055imidazol-2-yl- 1 HNHSO2-i-Bu
aminomethyl
1056imidazol-2-yl- 1 HNHSO2-t-Bu
aminomethyl
1057imidazol-2-yl- 1 HMHSO2NHPh
aminomethyl
1058imidazol-2-yl- 1 HNHSO2NHC6H4-(2-
aminomethyl CH3)
1059imidazol-2-yl- 1 HNHS02NHC6H4-(3-
aminomethyl CH3)
1060imidazol-2-yl- 1 HNHS02NHC6H4-(4-
aminomethyl CH3)
1061imidazol-2-yl- HNHS02NH(2-
aminomethyl pyridyl)
1062imidazol-2-yl- 1 HNHS02NH(3-
aminomethyl pyridyl)
1063imidazol-2-yl- 1 HNHS02NH(4-
aminomethyl pyridyl)
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W O 97/33887 PCTrUS97/04567
1064imidazol-2-yl- 1 H NHSO2NH(2-
aminomethyl thiazolyl)
1065imidazol-2-yl- 1 H NH502NH(4-
aminomethyl thiazolyl)
1066imidazol-2-yl- 1 H NHSO2NH(4-
aminomethyl isoxazolyl)
1067imidazol-2-yl- 1 H NHSO2[4-(3,5-
aminomethyl dimethyl)isoxaz
olyl]
1068imidazol-2-yl- 1 H NHSo2NHC6H4-(2-
aminomethyl Br)
1069imidazol-2-yl- 1 H NHSO2NHC6H4-(3-
aminomethyl Br)
1070imidazol-2-yl- 1 H NHSO2NHC6H4-(4-
aminomethyl Br)
1071imidazol-2-yl- 1 H NHSo2NHC6H4-(3-
aminomethyl F)
1072imidazol-2-yl- 1 H NHSO2NHC6H4-(4-
aminomethyl F)
1073imidazol-2-yl- 1 H NHSO2NH(2-
aminomethyl naphthyl)
1074imidazol-2-yl- 1 H NHSO2NH(1-
aminomethyl naphthyl)
1075imidazol-2-yl- 1 H NH5O2NHCH=CH-Ph
aminomethyl
1076imidazol-2-yl- 1 H NHSO2NHCH2Ph
aminomethyl
1077imidazol-2-yl- 1 H NHSO2NHCH2CH=CH-
aminomethyl Ph
1078imidazol-2-yl- 1 H NHSO2NH-n-Bu
aminomethyl
1079imidazol-2-yl- 1 H NHSO2NH-i-Bu
aminomethyl
1080imidazol-2-yl- 1 H NHSO2NH-t-Bu
aminomethyl
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1081pyridin-2-yl- 1 H NHCO2Bn 510.2
aminomethyl
1082pyridin-2-yl- 1 HNHCo2CH2C6H4-(2
aminomethyl CH3)
1083pyridin-2-yl- 1 HNHco2cH2c6H4
aminomethyl (3-CH3)
1084pyridin-2-yl- 1 HNHco2cH2c6H4
aminomethyl (4-CH3)
1085pyridin-2-yl- 1 HNHCO2CH2(2-
aminomethyl pyridinyl)
1086pyridin-2-yl- 1 HNHCo2cH2(3
aminomethyl pyridinyl)
1087pyridin-2-yl- 1 HNHCo2cH2(4
aminomethyl pyridinyl)
1088pyridin-2-yl- 1 HNHCO2CH2(2-
aminomethyl thiazolyl)
1089pyridin-2-yl- 1 HNHCo2cH2(4
aminomethyl thiazolyl)
1090pyridin-2-yl- 1 HNHCO2CH2(5-
aminomethyl thiazolyl)
1091pyridin-2-yl- 1 HNHCo2cH2(4
aminomethyl isoxazolyl)
1092pyridin-2-yl- 1 HNHCO2CH2(2-
aminomethyl thienyl)
1093pyridin-2-yl- 1 H NHCO2n-Bu
aminomethyl
1094pyridin-2-yl- 1 H NHCO2i-Bu
aminomethyl
1095pyridin-2-yl- 1 H NHCO2t-Bu
aminomethyl
1096pyridin-2-yl- 1 H NHCOCH2Ph
aminomethyl
1097pyridin-2-yl- 1 HNHCOCH2C6H4-(2-
aminomethyl CH3)
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1098pyridin-2-yl- t HNHCOCH2-C6H4-
aminomethyl (3-CH3)
1099pyridin-2-yl- 1 HNHCOCH2C6H4_(4-
aminomethyl CH3)
1100pyridin-2-yl- 1 H NHCoCH2(2-
aminomethyl pyridinyl)
1101pyridin-2-yl- 1 H NHCOCH2(3-
aminomethyl pyridinyl)
1102pyridin-2-yl- 1 H NHCOCH2(4-
aminomethyl pyridinyl)
1103pyridin-2-yl- 1 H NHCOCH2(2-
aminomethyl thiazolyl)
1104pyridin-2-yl- 1 H NHCOCH2(4-
aminomethyl thiazolyl)
1105pyridin-2-yl- 1 H NHCOCH2(5-
aminomethyl thiazolyl)
1106
1107pyridin-2-yl- 1 H NHCOCH2(4-
aminomethyl isoxazolyl)
1108pyridin-2-yl- 1 H NHCOCH2(2-
aminomethyl thienyl)
1109pyridin-2-yl- 1 H NHCOn-Bu
aminomethyl
1110pyridin-2-yl- 1 H NHCOt-Bu
aminomethyl
1111pyridin-2-yl- 1 H NHSO2Ph 516.1
aminomethyl
1112pyridin-2-yl- 1 HNHSO2C6H4-(2-
aminomethyl CH3)
1113pyridin-2-yl- 1 HNHSO2C6H4-(3-
aminomethyl CH3)
1114pyridin-2-yl- 1 HNHSO2C6H4-(4-
aminomethyl CH3)
..
-105-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04~67
1115pyridin-2-yl- 1 HNHSO2~2-pyridyl)
aminomethyl
1116pyridin-2-yl- 1 HNHSO2(3-pyridyl)
aminomethyl
1117pyridin-2-yl- 1 HNHSO2(4-pyridyl)
aminomethyl
1118pyridin-2-yl- 1 H NHSO2(2-
aminomethyl thiazolyl)
1119pyridin-2-yl- 1 H NHSO2(4-
aminomethyl thiazolyl)
1120pyridin-2-yl- 1 H NHSO2(4-
aminomethyl isoxazolyl)
1121pyridin-2-yl- 1 H NHSo2-[4-(3~5- 535.1
aminomethyl dimethyl)isoxaz
olyl]
1122pyridin-2-yl- 1 H NHSO2C6H4-(2-
aminomethyl Br)
1123pyridin-2-yl- 1 H NHSo2c6H4-(3
aminomethyl Br)
1124pyridin-2-yl- 1 H NHSO2C6H4-(4-
aminomethyl Br)
1125pyridin-2-yl- 1 H NHSO2C6H4-(2-F)
aminomethyl
1126pyridin-2-yl- 1 H NHSO2C6H4-(3-F)
aminomethyl
1127pyridin-2-yl- 1 H NHSO2C6H4-(4-F)
aminomethyl
1128pyridin-2-yl- 1 H NHSO2(2-
aminomethyl naphthyl)
1129pyridin-2-yl- 1 H NHS02(1-
aminomethyl naphthyl)
1130pyridin-2-yl- 1 H NHSO2CH=CH-Ph
aminomethyl
1131pyridin-2-yl- 1 H NHSO2CH2Ph
aminomethyl
-106-
CA 02249733 l998-09-ll
W O 97/33887 PCT~US97/04567
1132pyridln-2-yl- 1 H NHSO2-CH2CH=CH-
aminomethyl Ph
- 1133pyridin-2-yl- 1 H NHSO2-n-Bu
aminomethyl
1134pyridin-2-yl- 1 H NHSO2-i-Bu
aminomethyl
1135pyridin-2-yl- 1 H NHSO2-t-Bu
aminomethyl
1136pyridin-2-yl- 1 H NHSO2NHPh
aminomethyl
1137pyridin-2-yl- 1 H NHSO2NHC6H4-(2-
aminomethyl CH3)
113~pyridin-2-yl- 1 H NHSO2NHC6H4-(3-
aminomethyl CH3)
1139pyridin-2-yl- 1 H NHSO2NHC6H4-(4-
aminomethyl CH3)
1140pyridin-2-yl- 1 H NHS02NH(2-
aminomethyl pyridyl)
1141pyridin-2-yl- 1 H NHSO2NH(3-
aminomethyl pyridyl)
1142pyridin-2-yl- 1 H NHSO2NH(4-
aminomethyl pyridyl)
1143pyridin-2-yl- 1 H NHSO2NH(2-
aminomethyl thiazolyl)
1144pyridin-2-yl- 1 H NHS02NH-(4-
aminomethyl thiazolyl)
1145pyridin-2-yl- 1 H NHS02NH(4-
aminomethyl isoxazolyl)
1146pyridin-2-yl- 1 H NHSO2-[4-(3,5-
aminomethyl dimethyl)isoxaz
olyl]
1147pyridin-2-yl- 1 H NHSO2NHC6H4-(2-
aminomethyl Br)
-
-107-
CA 02249733 l998-09-ll
WO 97/33887 PCTrUS97/04567
1148pyridin-2-yl- 1 HNHSo2NHC6H4-(3-
aminomethyl Br)
1149pyridin-2-yl- - 1 HNHSO2NHC6H4-(4-
aminomethyl Br)
1150pyridin-2-yl- 1 HNHSO2NHC6H4-~3-
aminomethyl F)
1151pyridin-2-yl- 1 HNHSO2NHC6H4-(4-
aminomethyl F)
1152pyridin-2-yl- 1 H NHSO2NH(2-
aminomethyl naphthyl)
1153pyridin-2-yl- 1 H NHSO2NH)1-
aminomethyl naphthyl)
1154pyridin-2-yl- 1 HNHSO2NHCH=CH-Ph
aminomethyl
1155pyridin-2-yl- 1 HNHSO2NHCH2Ph
aminomethyl
1156pyridin-2-yl- 1 HNHSO2NHCH2CH=CH-
aminomethyl Ph
1157pyridin-2-yl- 1 HNHSO2NH-n-Bu
aminomethyl
1158pyridin-2-yl- 1 HNHSO2NH-i-Bu
aminomethyl
1159pyridin-2-yl- 1 HNHSO2NH-t-Bu
aminomethyl
1160 tetrahydropyrimidin 1 H NHCOOBn
-2-ylaminomethyl
1161 tetrahydropyrimidin 1 H NHCO2CH2C6H4-
-2-ylaminomethyl (2-CH3)
1162 tetrahydropyrimidin 1 H NHCO2CH2C6H4-
-2-ylaminomethyl (3-CH3)
1163 tetrahydropyrimidin 1 H NHCO2CH2C6H4-
-2-ylaminomethyl (4-CH3)
1164 tetrahydropyrimidin 1 H NHCO2CH2(2-
-2-ylaminomethyl pyridinyl)
-108-
CA 02249733 l998-09-ll
W 097/33887 PCTr~S97/04567
1165 tetrahydropyrimidin 1 H NHCO2CH2(3-
-2-ylaminomethyl pyridinyl)
1166 tetrahydropyrimidin 1 H NHCO2CH2(4-
-2-ylaminomethyl pyridinyl)
1167 tetrahydropyrimidin H NHCO2CH2(2-
-2-ylaminomethyl thiazolyl)
1168 tetrahydropyrimidin 1 H NHCO2CH2(4-
-2-ylaminomethyl thiazolyl)
1169 tetrahydropyrimidin 1 H NHCO2CH2(5-
-2-ylaminomethyl thiazolyl)
1170 tetrahydropyrimidin 1 H NHCO2CH2(4-
-2-ylaminomethyl isoxazolyl)
1171 tetrahydropyrimidin l H NHCO2CH2(2-
-2-ylaminomethyl thienyl)
1172 tetrahydropyrimidin l H NHCO2n-Bu
-2-ylaminomethyl
1173 tetrahydropyrimidin 1 H NHCO2i-Bu
-2-ylaminomethyl
1174 tetrahydropyrimidin 1 H MHCO2t-Bu
-2-ylaminomethyl
1175 tetrahydropyrimidin 1 H NHSO2Ph 521.3
-2-ylaminomethyl
1176 tetrahydropyrimidin 1 H NHSO2C6H4-(2-
-2-ylaminomethyl CH3)
1177 tetrahydropyrimidin 1 H NHSO2C6H4-(3-
-2-yl~minom~thyl CH3)
1178 tetrahydropyrimidin l H NHS02C6H4-(4-
-2-ylaminomethyl CH3)
1179 tetrahydropyrimidin 1 H NHSO2(2-pyridyl)
-2-ylaminomethyl
1180 tetrahydropyrimidin 1 H NH502(3-pyridyl)
-2-ylaminomethyl
1181 tetrahydropyrimidin 1 H NHSO2(4-pyridyl)
~ -2-ylaminomethyl
-109-
CA 02249733 l998-09-ll
W O 97/33887 PCTAUS97/04567
1182 tetrahydropyrimidin 1 H NHSO2(2-
-2-ylaminomethyl thiazolyl)
1183 tetrahydropyrimidin 1 H NHSO2(4-
-2-ylaminomethyl thiazolyl)
1184 tetrahydropyrimidin 1 H NHSO2(4-
-2-ylaminomethyl isoxazolyl)
1185 tetrahydropyrimidin 1 H NHSO2-[4-(3,5-
-2-ylaminomethyl dimethyl)isoxaz
olyl]
1186 tetrahydropyrimidin 1 H NHSO2C6H4-(2-
-2-ylaminomethyl Br)
1187 tetrahydropyrimidin l H NHSO2C6H4-(3-
-2-ylaminomethyl Br)
1188 tetrahydropyrimidin 1 H NHSO2C6H4-(2-F)
-2-ylaminomethyl
1189 tetrahydropyrimidin 1 H NHSO2C6H4-(3-F
-2-ylaminomethyl
1190 tetrahydropyrimidin 1 H NHSO2c6H4-(4-F)
-2-ylaminomethyl
1191 tetrahydropyrimidin 1 H NHSO2(2-
-2-ylaminomethyl naphthyl)
1192 tetrahydropyrimidin ~ H NHSO2~1-
-2-ylaminomethyl naphthyl)
1193 tetrahydropyrimidin 1 HNHSO2CH=CHPh
-2-ylaminomethyl
1194 tetrahydropyrimidin 1 H NHSO2CH2Ph
-2-ylaminomethyl
1195 tetrahydropyrimidin 1 H NHSO2CH2CH=CHPh
-2-ylaminomethyl
1196 tetrahydropyrimidin 1 HNHSO2-n-Bu
-2-ylaminomethyl
1197 tetrahydropyrimidin 1 HNHSO2-i-Bu
-2-ylaminomethyl
1198 imidazolin-2-yl- 1 H NHCOOBn
aminomethyl
-110-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
1199imidazolin-2-yl- 1 HNHCO2CH2C6H4_(2-
aminomethyl CH3)
1200imidazolin-2-yl- 1 HNHCO2CH2C6H4_(3-
aminomethyl CH
1201imidazolin-2-yl- 1 HNHCo2cH2c6H4-(4
aminomethyl CH3)
1202imidazolin-2-yl- 1 HNHCO2CH2(2-
aminomethyl pyridinyl)
1203imidazolin-2-yl- 1 HNHCo2cH2(3
aminomethyl pyridinyl)
1204imidazolin-2-yl- 1 HNHCo2cH2(4
aminomethyl pyridinyl)
1205imidazolin-2-yl- 1 HNHCO2CH2(2-
aminomethyl thiazolyl)
1206imidazolin-2-yl- 1 HNHCo2cH2(4
aminomethyl thiazolyl)
1207imidazolin-2-yl- 1 HNHCo2cH2(5
aminomethyl thiazolyl)
1208imidazolin-2-yl- 1 HNHCo2cH2(4
aminomethyl isoxazolyl)
1209imidazolin-2-yl- 1 HNHCO2CH2(2-
aminomethyl thienyl)
1210imidazolin-2-yl- 1 HNHCO2n-Bu
aminomethyl
1211imidazolin-2-yl- 1 HNHCO2i-~u
aminomethyl
1212imidazolin-2-yl- 1 HNHCO2t-Bu
aminomethyl
1213imidazolin-2-yl- 1 H NHSO2Ph 507.3
aminomethyl
1214imidazolin-2-yl- 1 HNHSo2C6H4-(2-
aminomethyl CH3)
1215imidazolin-2-yl- 1 HNHSO2C6H4-(3-
aminomethyl CH3)
-111-
CA 02249733 l998-09-ll
W 097l33887 PCTrUS97/04567
1216imidazolin-2-yl- 1 H NHSO2C6H4-(4-
aminomethyl CH3)
1217imidazolin-2-yl-- 1 H NHSO2(2-pyridyl)
aminomethyl
1218imidazolin-2-yl- 1 H NHSO2(3-pyridyl)
aminomethyl
1219imidazolin-2-yl- 1 H NHSO2(4-pyridyl)
aminomethyl
1220imidazolin-2-yl- 1 H NHSO2(2-thiaz-
aminomethyl olyl)
1221imidazolin-2-yl- 1 H NHSO2~4-
aminomethyl isoxazolyl)
1222imidazolin-2-yl- 1 H NHSO2-[4-(3,5-
aminomethyl dimethyl)isoxaz
olyl]
1223imidazolin-2-yl- 1 H NHSO2C6H4-(2-
aminomethyl Br)
1224imidazolin-2-yl- 1 H NHSO2C6H4-(3-
aminomethyl Br)
1225imidazolin-2-yl- 1 H NHSo2c6H4-(2-F)
aminomethyl
1226imidazolin-2-yl- 1 H NHSO2C6H4-(3-F)
aminomethyl
1227imidazolin-2-yl- 1 H NHSo2C6H4-(4-F)
aminomethyl
1228imidazolin-2-yl- 1 H NHSO2(2-
aminomethyl naphthyl)
1229imidazolin-2-yl- 1 H NHSO2(1-
aminomethyl naphthyl)
1230imidazolin-2-yl- 1 H NHSO2CH=CHPh
aminomethyl
1231imidazolin-2-yl- 1 H NHSO2CH2Ph
aminomethyl
1232imidazolin-2-yl- 1 H NHSO2CH2CH=CHPh
aminomethyl
-112-
CA 02249733 l998-09-ll
W O 97/33887 PCTAUS97/04567
1233imidazolin-2-yl- 1 H NHSO2-n-Bu
aminomethyl
1234imidazolin-2-yl- 1 H NHSO2-i-Bu
aminomethyl
1235benzimidazol-2-yl- 1 H NHS02Ph
aminomethyl
1236benzimidazol-2-yl- 1 H NHSO2C6H4-(2-
aminomethyl CH3)
1237benzimidazol-2-yl- 1 H NHSO2C6H4-(3-
aminomethyl CH3)
1238benzimidazol-2-yl- 1 H NHSO2C6H4-(4-
aminomethyl CH3)
1239benzimidazol-2-yl- 1 H NHSO2(2-pyridyl)
aminomethyl
1240benzimidazol-2-yl- 1 H NHSO2~3-pyridyl)
aminomethyl
1241benzimidazol-2-yl- 1 H NHSO2(4-pyridyl)
aminomethyl
1242benzimidazol-2-y~- 1 H NHSO2(2-
aminomethyl thiazolyl)
1243benzimidazol-2-yl- 1 H NHSO2(4-
aminomethyl isoxazolyl)
1244benzimidazol-2-yl- 1 H NHSO2-[4-(3,5-
aminomethyl dimethyl)isoxaz
olyl]
1245benzimidazol-2-yl- 1 H NHSO2C6H4-(2-
~mir~ -thyl Br)
1246benzimidazol-2-yl- 1 H NHSO2C6H4-(3-
aminomethyl Br)
1247benzimidazol-2-yl- 1 H NHSO2C6H4-(2-F)
aminomethyl
1248benzimidazol-2-yl- 1 H NHSO2C6H4-(3-F)
aminomethyl
1249benzimidazol-2-yl- 1 H NHSO2C6H4-(4-F)
aminomethyl
-113-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
1250benzimidazol-2-yl- 1 H NHCO2CH2Ph
aminomethyl
1251benzimidazol-2-yl- 1 H NHCO2n-Bu
aminomethyl
1252benzimidazol-2-yl- 1 H NHCO2i-Bu
aminomethyl
12S32-aminopyridin-6- 1 H NHSO2Ph
ylmethyl
12542-aminopyridin-6- 1 H NHSO2C6H4-(2-
ylmethyl CH3)
12552-aminopyridin-6- 1 H NHSO2C6H4-(3-
ylmethyl CH3)
12562-aminopyridin-6- 1 H NHSO2C6H4-(4-
ylmethyl CH3)
12572-aminopyridin-6- 1 HNHSO2(2-pyridyl)
ylmethyl
12582-aminopyridin-6- 1 HNHSO2(3-pyridyl)
ylmethyl
12592-aminopyridin-6- 1 HNHSO2(4-pyridyl)
ylmethyl
12602-aminopyridin-6- 1 H NHSO2(2-
ylmethyl thiazolyl)
12612-aminopyridin-6- 1 H NHSO2(4-
ylmethyl isoxazolyl)
12622-aminopyridin-6- 1 H NHSo2-[4-(3~5- 535.1
ylmethyl dimethyl)isoxaz
olyl]
12632-aminopyridin-6- 1 H NHSO2C6H4-(2-
ylmethyl Br)
12642-aminopyridin-6- 1 H NHSO2C6H4-(3-
ylmethyl Br)
12652-aminopyridin-6- 1 H NHSO2C6H4-(2-F)
ylmethyl
12662-aminopyridin-6- 1 H NHSO2C6H4-(3-F)
ylmethyl
-114-
CA 02249733 l998-09-ll
W 097/33887 PCTAUS97/04567
1267 2-aminopyridin-6- 1 H NHSO2C6H4-(4-F)
ylmethyl
1268 2-aminopyridin-6- 1 H NHCO2CH2Ph
- ylmethyl
1269 2-aminopyridin-6- 1 H NHCO2n-Bu
ylmethyl
1270 2-aminopyridin-6- 1 H NHCO2i-Bu
ylmethyl
1271 7-azabenimidazol-2- 1 H NHSO2Ph
yl
1272 7-azabenimidazol-2- 1 H NHSO2C6H4-~2-
yl CH3)
1273 7-azabenimidazol-2- 1 H NHSO2C6H4-(3-
yl CH3)
1274 7-azabenimidazol-2- 1 H NHSO2C6H4-(4-
yl CH3)
1275 7-azabenimidazol-2- 1 H NHSO2(2-
yl naphthyl)
1276 7-azabenimidazol-2- 1 H NHSO2(1-
yl naphthyl)
1277 7-azabenimidazol-2- 1 H NHSO2~biphenyl)
yl
1278 7-az~h~ni mi dazol-2- 1 H NHSO2C6H4- 569.4
yl ~2,4,6-~CH3)3)
1279 7-azabenimidazol-2- 1 H NHSO2(2-thienyl)
yl
1280 7-azabenimidazol-2- 1 H NHSO2-[4-(3,5-
yl dimethyl)isoxaz
olyl]
1281 7-az~hPnimidazol-2- 1 H NHSO2C6H4-(2-
yl Br)
1282 7-azabenimidazol-2- 1 H NHSO2C6H4-(3-
yl Br)
- 1283 7-azabenimidazol-2- 1 H NHSO2C6H4-(2-F)
yl
-115-
CA 02249733 l998-09-ll
W O 97/33887 . PCTrUS97/04567
1284 7-azabenimidazol-2- 1 H NHSO2C6H4-(3-F)
yl
1285 7-azabenimidazol-2- 1 H NHSO~C6H4-(4-F)
yl
1286 7-azabenimidazol-2- 1 H NHCO2CH2Ph
yl
1287 7-azabenimidazol-2- 1 H NHCO2n-Bu
yl
1288 7-azabenimidazol-2- 1 H NHC02i-Bu
yl
1289 4,5,6,7-tetrahydro- 1 H NHSO2Ph 561.4
benzimidazol-2-yl-
aminomethyl
1290 4,5,6,7-tetrahydro- 1 H NHSO2C6H4-~2-
benzimidazol-2-yl- CH3)
aminomethyl
1291 4,5,6,7-tetrahydro- 1 H NHSO2C6H4-(3-
benzimidazol-2-yl- CH3)
aminomethyl
1292 4,5,6,7-tetrahydro- 1 H NHS02C6H4-(4-
benzimidazol-2-yl- CH3)
aminomethyl
1293 4,5,6,7-tetrahydro- 1 H NHSO2(2-
benzimidazol-2-yl- naphthyl)
aminomethyl
1294 4,5,6,7-tetrahydro- 1 H NHSO2(1-
benzimidazol-2-yl- naphthyl)
aminomethyl
1295 4,5,6,7-tetrahydro- 1 -HNHSO2(biphenyl)
benzimidazol-2-yl-
aminomethyl
1296 4,5,6,7-tetrahydro- 1 H NHSO2C6H4-
benzimidazol-2-yl- (2,4,6-(CH3)3)
aminomethyl
-116-
CA 02249733 l998-09-ll
W 097/33887 PCT~US97/04567
1297 4,5,6,7-tetrahydro- 1 HNHSO2(2-thienyl)
benzimidazol-2-yl-
aminomethyl
-1298 4,5,6,7-tetrahydro- 1 HNHSO2-[4-(3,5-
benzimidazol-2-yl- dimethyl)isoxaz
aminomethyl olyl]
1299 4,5,6,7-tetrahydro- 1 HNHSO2C6H4-(2-
benzimidazol-2-yl- Br)
aminomethyl
1300 4,5,6,7-tetrahydro- 1 HNHSO2C6H4-(3-
benzimidazol-2-yl- Br)
aminomethyl
1301 4,5,6,7-tetrahydro- 1 HNHSO2C6H4-(2-F)
benzimidazol-2-yl-
aminomethyl
1302 4,5,6,7-tetrahydro- 1 HNHSO2C6H4-(3-F)
benzimidazol-2-yl-
aminomethyl
1303 4,5,6,7-tetrahydro- 1 HNHSO2C6H4-(4-F)
benzimidazol-2-yl-
amlnomethyl
1304 4,5,6,7-tetrahydro- 1 HNHCO2CH2Ph
benzimidazol-2-yl-
aminomethyl
1305 4,5,6,7-tetrahydro- 1 H NHCO2n-Bu
benzimidazol-2-yl-
aminomethyl
1306 4,5,6,7-tetrahydro- 1 H NHCO2i-Bu
benzimidazol-2-yl-
aminomethyl
13074-oxo-3,4,5,6- 1 H NHSO2Ph 549 3
tetrahydro-
pyrimidin-2-yl-
~ aminomethyl
-117-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04S67
13084-oxo-3,4,5,6- 1 H NHSo2C6H4-~2-
tetrahydro- CH3)
pyrimidin-2-yl-
aminomethyl
13094-oxo-3,4,5,6- 1 H NHSo2C6H4-(3-
tetrahydro- CH3)
pyrimidin-2-yl-
aminomethyl
13104-oxo-3,4,5,6- 1 H NHS02C6H4-(4-
tetrahydro- CH3)
pyrimidin-2-yl-
aminomethyl
13114-oxo-3,4,5,6- 1 H NHSO2(2-
tetrahydro- naphthyl)
pyrimidin-2-yl-
aminomethyl
13124-oxo-3,4,5,6- 1 H NHSO2(1-
tetrahydro- naphthyl)
pyrimidin-2-yl-
aminomethyl
13134-oxo-3,g,5,6- 1 H NHS02(blphenyl)
tetrahydro-
pyrimidin-2-yl-
aminomethyl
13144-oxo-3,4,5,6- 1 H NHSO2C6H4-
tetrahydro- (2,4,6-(CH3)~)
pyrimidin-2-yl-
aminomethyl
13154-oxo-3,4,5,6- 1 H NHS02(2-thienyl)
tetrahydro-
pyrimidin-2-yl-
aminomethyl
-118-
CA 02249733 l998-09-ll
WO 97/33887 PCT/US97104567
13164-oxo-3,4,5,6- 1 H NHSO2-[4-(3,5-
tetrahydro- dimethyl)isoxaz
pyrimidin-2-yl- olyl]
aminomethyl
13174-oxo-3,4,5,6- 1 H NHSO2C6H4-(2-
tetrahydro- Br)
pyrimidin-2-yl-
aminomethyl
13184-oxo-3,4,5,6- 1 H NHSO2C6H4-(3-
tetrahydro- Br~
pyrimidin-2-yl-
aminomethyl
13194-oxo-3,4,5,6- 1 H NHSO2C6H4-(2-F)
tetrahydro-
pyrimidin-2-yl-
aminomethyl
13204-oxo-3,4,5,6- 1 H NHSO2C6Hq-(3-F)
tetrahydro-
pyrimidin-2-yl-
aminomethyl
13214-oxo-3,4,5,6- 1 H NHSO2C6H4-(4-F)
tetrahydro-
pyrimidin-2-yl-
aminomethyl
13224-oxo-3,4,5,6- 1 H NHCO2CH2Ph
tetrahydro-
pyrimidin-2-yl-
aminomethyl
13234-oxo-3,4,5,6- 1 H NHCO2n-Bu
tetrahydro-
pyrimidin-2-yl-
aminomethyl
-119-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04S67
13244-oxo-3,4,5,6- 1 H NHCO2i-Bu
tetrahydro-
pyrimidin-2-yl- -
aminomethyl
13252-iminoazepin-7- 1 H NHS02Ph
ylmethyl
13261,2-pyrazol-3- H NHSO2Ph
ylaminomethyl
13271,2,4-triazol-5- 1 H NHS02Ph
ylaminomethyl
1328imidazol-4- 1 H NHSO2Ph
-ylaminomethyl
13291,3,4-oxadiazol- 1 H MHSO2Ph
2ylaminomethyl
1330 1,2,4-thiadiazol-5- 1 H NHS02Ph
ylaminomethyl
13311.2.5-oxadiazol-3- 1 H NHS02Ph
yl~mino~thyl
13321.2.4-oxadiazol-5- 1 H NHSO2Ph
ylaminomethyl
13332-iminoazepin-7- 1 H NHS02(4-
ylmethyl isoxazolyl)
13341,2-pyrazol-3- 1 H NHSO2(4-
ylaminomethyl isoxazolyl)
13351,2,4-triazol-5- 1 H NHSO2(4-
yl~min~ thyl isoxazolyl)
1336imidazol-4- 1 H NHSO2(4-
ylaminomethyl isoxazolyl)
13371,3,4-oxadiazol- 1 H NHS02(4-
2ylaminomethyl isoxazolyl)
1338 1,2,4-thiadiazol-5- 1 H NHSO2(4-
ylaminomethyl isoxazolyl)
1339 1.2.5-oxadiazol-3- 1 H NHS02(4-
ylaminomethyl isoxazolyl)
-120-
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W O 97/33887 PCTrUS97104567
13401.2.4-oxadiazol-5- 1 H NHS02(4-
ylaminomethyl isoxazolyl)
13412-iminoazepin-7- 1 H NHS02-[4-(3,5-
ylmethyl dimethyl)isoxaz
olyl]
13421,2-pyrazol-3- 1 H NHS02-[4-(3,5-
ylaminomethyl dimethyl)isoxaz
olyl]
13431,2,4-triazol-5- 1 H NHS02-[4-(3,5-
ylaminomethyl dimethyl)isoxaz
olyl]
1344imidazol-4- 1 H NHSo2-[4-(3~5-
ylaminomethyl dimethyl)isoxaz
olyl]
13451,3,4-oxadiazol- 1 H NHS02-[4-(3,5-
2ylaminomethyl dimethyl)isoxaz
olyl]
1346 1,2,4-thiadiazol-5- 1 H NHS02-[4-~3,5-
ylaminomethyl dimethyl)isoxaz
olyll
13471.2.5-oxadiazol-3- 1 H NHS02-[4-(3,5-
ylaminomethyl dimethyl)isoxaz
olyl]
13481.2.4-oxadiazol-5- 1 H NHS02-[4-(3,5-
ylaminomethyl dimethyl)isoxaz
olyl]
1349imidazol-2-yl- 13-pyridinyl H
aminomethyl
1350pyridin-2- 13-pyridinyl H
ylaminomethyl
1351imidazolin-2-yl- 13-pyridinyl H
aminomethyl
1352 tetrahydropyrimidin 1 3-pyridinyl H
-2-ylaminomethyl
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1353benzimidazol-2-yl- 13-pyridinyl H
aminomethyl
13542-aminopyridin-6- 13-pyridinyl H
ylmethyl
13552-iminoazepin-7- 13-pyridinyl H
ylmethyl
13561,2-pyrazol-3- 13-pyridinyl H
ylaminomethyl
13571,2,4-triazol-5- 13-pyridinyl H
ylaminomethyl
1358imidazol-4- 13-pyridinyl H
ylaminomethyl
13591,3,4-oxadiazol- 13-pyridinyl H
2ylaminomethyl
1360 1,2,4-thiadiazol-5- 13-pyridinyl H
ylaminomethyl
13611.2.5-oxadiazol-3- 13-pyridinyl H
ylaminomethyl
13621.2.4-oxadiazol-5- 13-pyridinyl H
ylaminomethyl
1363imidazol-2-yl- 1(3,4- H
aminomethyl methylene-
dioxy)phenyl
1364pyridin-2- 1(3,4- H
ylaminomethyl methylene-
dioxy)phenyl
1365imidazolin-2-yl- 1(3,4- H
aminomethyl methylene-
dioxy)phenyl
1366 tetrahydropyrimidin 1(3,4- H
-2-ylaminomethyl methylene-
dioxy)phenyl
1367benzimidazol-2-yl- 1(3,4- H
aminomethyl methylene-
dioxy)phenyl
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13682-aminopyridin-6- 1(3,4- H
ylmethyl methylene-
dioxy)phenyl
13692-iminoazepin-7- 1(3,4- H
ylmethyl methylene-
dioxy)phenyl
13701,2-pyrazol-3- 1(3,4- H
ylaminomethyl methylene-
dioxy)phenyl
13711,2,4-triazol-5- 1(3,4- H
ylaminomethyl methylene-
dioxy)phenyl
1372imidazol-4- 1(3,4- H
ylaminomethyl methylene-
dioxy)phenyl
13731,3,4-oxadiazol- 1(3,4- H
2ylaminomethyl methylene-
dioxy)phenyl
1374 1,2,4-thiadiazol-5- 1(3,4- H
ylaminomethyl methylene-
dioxy)phenyl
13751,2,5-oxadiazol-3- 1(3,4- H
ylaminomethyl methylene-
dioxy)phenyl
13761.2.4-oxadiazol-5- 1(3,4- H
ylaminomethyl methylene-
dioxy)phenyl
1377imidazol-2-yl- 13-pyridinyl NHSO2Ph
aminomethyl
1378pyridin-2- 13-pyridinyl NHSO2Ph
ylaminomethyl
1379imidazol-2-yl- 1(3,4- NHSO2Ph
aminomethyl methylene-
dioxy)phenyl
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1380 pyridin-2-ylamino 1(3,4- NHSO2Ph
methylene-
dioxy)phenyl
1381 imidazol-2-yl-amino 1 H NHSO2Ph
1382 pyridin-2-ylamino 1 H NHSO2Ph
1383 imidazolin-2-yl- 1 H NHSO2Ph
amlno
1384 tetrahydropyrimidin 1 H NHSO2Ph
-2-ylamino
1385 benzimidazol-2-yl- 1 H NHSO2Ph
amino
1386 2-aminopyridin-6- 1 H NHSO2Ph
ylmethyl
1387 2-iminoazepin-7-yl 1 H NHSO2Ph
1388 1,2-pyrazol-3- 1 H NHSO2Ph
ylamino
1389 1,2,4-triazol-5- 1 H NHSO2Ph
ylamino
1390 imidazol-4-ylamino 1 H NHSO2Ph
1391 1,3,4-oxadiazol- 1 H NHSO2Ph
2ylaminomethyl
1392 1,2,4-thiadiazol-5- 1 H NHSO2Ph
ylaminomethyl
1393 1.2.5-oxadiazol-3- 1 H NHSO2Ph
ylaminomethyl
1394 1.2.4-oxadiazol-5- 1 H NHSO2Ph
ylaminomethyl
1395 imidazol-2-yl- 1 H NHS02Ph
aminoethyl
1396 pyridin-2- 1 H NHSO2Ph
ylaminoethyl
1397 imidazolin-2-yl- 1 H NHSO2Ph
aminoethyl
1398 tetrahydropyrimidin 1 H NHS02Ph
-2-ylaminoethyl
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1399 benzimidazol-2-yl- 1 H NHSO2Ph
aminoethyl
1400 2-aminopyridin-6- 1 H NHSO2Ph
ylethyl
1401 2-iminoazepin-7- 1 H NHSO2Ph
ylethyl
1402 1,2-pyrazol-3- 1 H NHSO2Ph
ylaminoethyl
1403 1,2,4-triazol-5- 1 H NHS02Ph
ylaminoethyl
1404 imidazol-4- 1 H NHS02Ph
ylaminoethyl
1405 1,3,4-oxadiazol- 1 H NHS02Ph
2ylaminoethyl
1406 1,2,4-thiadiazol-5- 1 H NHSO2Ph
ylaminoethyl
1407 1,2,5-oxadiazol-3- 1 H NHS02Ph
ylaminoethyl
1408 1,2,4-oxadiazol-5- 1 H NHSO2Ph
ylaminoethyl
1409 imidazol-2-yl- 2 H NHSO2Ph
aminomethyl
1410 pyridin-2- 2 H NHS02Ph
ylaminomethyl
1411 imidazolin-2-yl- 2 H NHSO2Ph
aminomethyl
1412 tetrahydropyrimidin 2 H NHS02Ph
-2-ylaminomethyl
1413 benzimidazol-2-yl- 2 H NHSO2Ph
aminomethyl
1414 7-azabenimidazol-2- 2 H NHS02Ph
yl
1415 4,5,6,7-tetrahydro- 2 H NHSO2Ph
benzimidazol-2-yl-
aminomethyl
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14164-oxotetrahydro- 2 H NHSO2Ph
pyrimidin-2-yl-
aminomethyl
14172-aminopyridin-6- 2 H NHSO2Ph
ylmethyl
14182-iminoazepin-7- 2 H NHSO2Ph
ylmethyl
14191,2-pyrazol-3- 2 H NHSO2Ph
ylaminomethyl
14201,2,4-triazol-5- 2 H NHSO2Ph
ylaminomethyl
1421imidazol-4- 2 H NHSO2Ph
ylaminomethyl
14221,3,4-oxadiazol- 2 H NHSO2Ph
2ylaminomethyl
1423 1,2,4-thiadiazol-5- 2 H NHSO2Ph
ylaminomethyl
1424 1.2.5-oxadiazol-3- 2 H NHSO2Ph
ylaminomethyl
1425 1.2.4-oxadiazol-5- 2 H NHSO2Ph
ylaminomethyl
1426 imidazol-2-yl- 0 H NHSO2Ph
aminomethyl
1427 pyridin-2- 0 H NHSO2Ph
ylaminomethyl
1428 imidazolin-2-yl- 0 H NHSO2Ph
aminomethyl
1429 tetrahydropyrimidin 0 H NHSO2Ph
-2-ylaminomethyl
1430 benzimidazol-2-yl- 0 H NHSO2Ph
aminomethyl
1431 7-azabenimidazol-2- 0 H NHSO2Ph
yl
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1432 4,5,6,7-tetrahydro- 0 H NHSO2Ph
benzimidazol-2-yl-
aminomethyl-
- 14334-oxotetrahydro- 0 H NHSO2Ph
pyrimidin-2-yl-
aminomethyl
14342-aminopyrldin-6- 0 H NHSO2Ph
ylmethyl
14352-iminoazepin-7- 0 H NHSO2Ph
ylmethyl
14361,2-pyrazol-3- 0 H NHSO2Ph
ylaminomethyl
14371,2,4-triazol-5- 0 H NHS02Ph
ylaminomethyl
1438imidazol-4- 0 H NHSO2Ph
ylaminomethyl
14391,3,4-oxadiazol- 0 H NHS02Ph
2ylaminomethyl
1440 1,2,4-thiadiazol-5- 0 H NHS02Ph
ylaminomethyl
14411,2,5-oxadiazol-3- 0 H NHS02Ph
ylaminomethyl
14421.2.4-oxadiazol-5- 0 H NHSO2Ph
ylaminomethyl
1443benzimidazol-2- 1 H NHS02(2,4,6- 597 4
ylaminomethyl trimethyl
phenyl)
1444 2- 1 H NHS02(2,4,6- 608.5
quinolinylaminometh trimethyl
yl phenyl~
1445benzimldazol-2- 1 H NHSO2(2,4,6- 611.3
ylaminocarbonyl trimethyl
phenyl)
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1446benzimidazol-2-yl 1 HNHS02(2,4,6- 568.5
trimethyl
phenyl)
1447imidazol-2- 1 HNHSO2(2,4,6- 561.4
ylaminocarbonyl trimethyl
phenyl)
1448imidazol-2- 1 H NHSO2(2- 569.2
ylaminocarbonyl naphthyl)
1449imidazol-2- 1 H NHSO2(2,6- 587.3/
ylaminocarbonyl dichlorophenyl) 589.4
1450pyridin-2- 1 HNHSO2(2,4,6- 547 3
ylaminomethyl trimethyl
phenyl)
1451imidazol-2- 1 HNHSO2(2,4,6- 547.2
ylaminomethyl trimethyl
phenyl)
1452imidazol-2- 1 HNHSO2biphenyl 581.2
ylaminomethyl
1453imidazol-2- 1 HNHSO2[(2,6- 649.1
ylaminomethyl dichloro-4-
phenyl)phenyl]
1454imidazol-2- 1 HNHSO2[(2,6- 609.2
ylaminomethyl dimethyl-4-
phenyl)phenyl]
1455imidazol-2- 1 H NHSO2(2,6- 533.2
ylaminomethyl dimethylphenyl)
1456imidazol-2- 1 HNHSO2(2-chloro- 553.2
ylaminomethyl 6-methylphenyl)
1457imidazol-2- 1 H NHSO2(2,6- 573.1
ylaminomethyl dichlorophenyl)
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Table 2
o Rl4 o
R1_N~H ~OH
E~- Bla L Bl4 B15
~Q
2001 2-aminopyridin-6-yl 0 H H
2002 2-aminopyridin-6-yl 0 H NHCO2Bn
2003 2-aminopyridin-6-yl 0 H NHCO2CH2C6H4-~2-CH
2004 2-aminopyridin-6-yl 0 H NHCO2CH2C6H4-(3-CH3)
2005 2-aminopyridin-6-yl 0 H NHco2cH2c6H4-(4-cH3)
2006 2-aminopyridin-6-yl 0 H NHCO2CH2(2-
pyridinyl)
2007 2-aminopyridin-6-yl 0 H NHCO2CH2(3-
pyridinyl)
2008 2-aminopyridin-6-yl 0 H NHCO2CH2(4-
pyridinyl)
2009 2-aminopyridin-6-yl 0 H NHCO2CH2(2-
thiazolyl)
2010 2-aminopyridin-6-yl 0 H NHCO2CH2(4-
thiazolyl)
2011 2-aminopyridin-6-yl 0 H MHCO2CH2(5-
thiazolyl)
2012 2-aminopyridin-6-yl 0 H NHCO2CH2(4-
isoxazolyl)
2013 2-aminopyridin-6-yl 0 H NHCO2CH2(2-thienyl
2014 2-aminopyridin-6-yl 0 H NHCO2CH2(5-
isoxazolyl)
2015 2-aminopyridin-6-yl 0 H NHCO2n-Bu
2016 2-aminopyridin-6-yl 0 H NHCO2i-Bu
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2017 2-aminopyridin-6-yl 0 H NHCO2t-Bu
2018 2-aminopyridin-6-yl 0 H NHCOCH2Ph
2019 2-aminopyridin-6-yl 0 H NHCOCH2C6H4_(2-CH3)
2020 2-aminopyridin-6-yl 0 H NHCOCH2C6H4-(3-CH3)
2021 2-aminopyridin-6-yl 0 H NHcocH2c6H4-(4-cH3)
2022 2-aminopyridin-6-yl 0 H NHCO(CH2)2Ph
2023 2-aminopyridin-6-yl 0 H NHCOn-Bu
2024 2-aminopyridin-6-yl 0 H NHCOt-Bu
2025 2-aminopyridin-6-yl 0 H NHSO2Ph
2026 2-aminopyridin-6-yl 0 H NHSO2C6H4-(2-CH3)
2027 2-aminopyridin-6-yl 0 H NHSO2C6H4-(3-CH3)
2028 2-aminopyridin-6-yl 0 H NHSO2C6H4-(4-CH3)
2029 2-aminopyridin-6-yl 0 H NHSO2(2-pyridyl)
2030 2-aminopyridin-6-yl 0 H NHSO2(3-pyridyl)
2031 2-aminopyridin-6-yl 0 H NHSO2(4-pyridyl)
2032 2-aminopyridin-6-yl 0 H NHSO2(2-thiaz-olyl)
2033 2-aminopyridin-6-yl 0 H NHSO2(3-thiazolyl)
2034 2-aminopyridin-6-yl 0 H NHSO2(4-isoxazolyl)
2035 2-aminopyridin-6-yl 0 H NHSO2[4-(3,5-
dimethyl)isoxazolyl]
2036 2-aminopyridin-6-yl 0 H NHSO2C6H4-~2-Br)
2037 2-aminopyridin-6-yl 0 H NHSO2C6H4-(3-Br)
2038 2-aminopyridin-6-yl 0 H NHSO2C6H4-(4-Br)
2039 2-aminopyridin-6-yl 0 H NHSO2C6H4-(2-F)
2040 2-aminopyridin-6-yl 0 H NHSO2C6H4-(3-F)
2041 2-aminopyridin-6-yl 0 H NHSO2C6H4-(4-F)
2042 2-aminopyridin-6-yl 0 H NHSO2(2-naphthyl)
2043 2-aminopyridin-6-yl 0 H NHSO2(1-naphthyl)
2044 2-aminopyridin-6-yl 0 H NHSO2CH=CHPh
2045 2-aminopyridin-6-yl 0 H NHSO2CH2Ph
2046 2-aminopyridin-6-yl 0 H NHSO2CH2CH=CH-Ph
2047 2-aminopyridin-6-yl 0 H NHSO2-n-Bu
2048 2-aminopyridin-6-yl 0 H NHSO2-i-Bu
2049 2-aminopyridin-6-yl 0 H NHSO2-t-Bu
2050 2-aminopyridin-6-yl 0 H NHSO2NHPh
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2051 2-aminopyridin-6-yl 0 H NHso2NHc6H4-(2-cH3)
2052 2-aminopyridin-6-yl 0 H NHSO2NHC6H4-(3-CH3)
2053 2-aminopyridin-6-yl 0 H NHSO2NHC6H4-(4-CH3)
2054 2-aminopyridin-6-yl 0 H NHSO2NH(2-pyridyl)
- 2055 2-aminopyridin-6-yl 0 H NHSO2NH(3-pyridyl)
2056 2-aminopyridin-6-yl 0 H NHS02NH(4-pyridyl)
2057 2-aminopyridin-6-yl 0 H NHSO2NH(2-thiazolyl)
2058 2-aminopyridin-6-yl 0 H NHSO2NH(4-thiazolyl)
2059 2-aminopyridin-6-yl 0 H NHSO2NH(4-
isoxazolyl)
2060 2-aminopyridin-6-yl 0 H NHSO2[4-~3,5-
dimethyl)isoxazolyl]
2061 2-aminopyridin-6-yl 0 H NHSO2NHC6H4-(2-Br)
2062 2-aminopyridin-6-yl 0 H NHSO2NHC6H4-(3-Br)
2063 2-aminopyridin-6-yl 0 H NHSO2NHC6H4-(4-Br)
2064 2-aminopyridin-6-yl 0 H NHSO2NHC6H4-(3-F)
2065 2-aminopyridin-6-yl 0 H NHSO2NHC6H4-(4-F)
2066 2-aminopyridin-6-yl 0 H NHSO2NH(2-naphthyl)
2067 2-aminopyridin-6-yl 0 H NHSO2NH(l-naphthyl)
2068 2-aminopyridin-6-yl 0 H NHSO2NHCH=CH-Ph
2069 2-aminopyridin-6-yl 0 H NHSO2NHCH2Ph
2070 2-aminopyridin-6-yl 0 H NHSO2NHCH2CH=CH-Ph
2071 2-aminopyridin-6-yl 0 H NHSO2NH-n-Bu
2072 2-aminopyridin-6-yl 0 H NHSO2NH-i-Bu
2073 2-aminopyridin-6-yl 0 H NHSO2NH-t-Bu
2074 2-aminopyridin-6-yl 1 H NHCO2Bn 497.2
2075 2-aminopyridin-6-yl 1 H NHCO2CH2C6H4_(2-CH3)
2076 2-aminopyridin-6-yl 1 H NHCO2cH2c6H4-(3-cH3)
2077 2-aminopyridin-6-yl 1 H NHco2cH2c6H4-(4-cH3)
2078 2-aminopyridin-6-yl 1 H NHCO2CH2(2-
pyridinyl)
2079 2-aminopyridin-6-yl 1 H NHCO2CH2(3-
- pyridinyl)
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2080 2-aminopyridln-6-yl 1 H ~HCO2CH2(4-
pyridinyl)
2081 2-aminopyridin-6-yl 1 H NHCO2CH2(2-
thiazolyl)
2082 2-aminopyridin-6-yl 1 H NHCO2CH2(4-
thiazolyl)
2083 2-aminopyridin-6-yl 1 H NHCO2CH2(5-
thiazolyl)
2084 2-aminopyridin-6-yl 1 H NHCO2CH2(4-
isoxazolyl)
2085 2-aminopyridin-6-yl 1 H NHCO2CH2(2-thienyl
2086 2-aminopyridin-6-yl 1 H NHCO2n-Bu
2087 2-aminopyridin-6-yl 1 H NHC02i-Bu
2088 2-aminopyridin-6-yl 1 H NHCO2t-Bu
2089 2-aminopyridin-6-yl 1 H NHCOCH2Ph
2090 2-aminopyridin-6-yl 1 H NHCOCH2C6H4-(2-CH3)
2091 2-aminopyridin-6-yl 1 H NHCOCH2-C6H4-(3-CH3)
2092 2-aminopyridin-6-yl 1 H NHCOCH2C6H4_(4-CH3)
2093 2-aminopyridin-6-yl 1 H NHCOCH2(2-pyridinyl)
2094 2-aminopyridin-6-yl 1 H NHCOCH2(3-pyridinyl)
2095 2-aminopyridin-6-yl 1 H NHCOCH2(4-pyridinyl)
2096 2-aminopyridin-6-yl 1 H NHCOCH2(2-thiazolyl)
2097 2-aminopyridin-6-yl 1 H NHCOCH2(4-thiazolyl)
2098 2-aminopyridin-6-yl 1 H NHCOCH2(5-thiazolyl)
2099 2-aminopyridin-6-yl 1 H NHCOCH2(4-
isoxazolyl)
2100 2-aminopyridin-6-yl 1 H NHCOCH2(2-thienyl)
2101 2-aminopyridin-6-yl 1 H NHCOn-Bu
2102 2-aminopyridin-6-yl 1 H NHCOt-Bu
2103 2-aminopyridin-6-yl 1 H NHSO2Ph
2104 2-aminopyridin-6-yl 1 H NHSO2C6H4-(2-CH3)
2105 2-aminopyridin-6-yl 1 H NHSO2C6H4-(3-CH3)
2106 2-aminopyridin-6-yl 1 NHSO2C6H4-(4-CH3)
2107 2-aminopyridin-6-yl 1 H NHSO2(2-pyridyl)
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2108 2-aminopyridin-6-yl 1 H NHSO2(3-pyridyl
2109 2-aminopyridin-6-yl 1 H NHSO2(4-pyridyl)
2110 2-aminopyridin-6-yl 1 H NHSO2(2-thiazolyl)
2111 2-aminopyridin-6-yl 1 H NHSO2(4-thiazolyl)
~ 2112 2-aminopyridin-6-yl 1 H NHSO2(4-isoxazolyl)
2113 2-aminopyridin-6-yl 1 H NHSO2-f4-(3,5-
dimethyl)isoxazolyl]
2114 2-aminopyridin-6-yl 1 H NHSO2C6H4-(2-Br)
2115 2-aminopyridin-6-yl 1 H NHSO2C6H4-(3-Br)
2116 2-aminopyridin-6-yl 1 H NHSO2C6H4-(4-Br
2117 2-aminopyridin-6-yl 1 H NHSO2C6H4-(2-F)
2118 2-aminopyridin-6-yl 1 H NHSO2C6H4-(3-F)
2119 2-aminopyridin-6-yl 1 H NHSO2C6H4-(4-F)
2120 2-aminopyridin-6-yl 1 H NHSO2(2-naphthyl)
2121 2-aminopyridin-6-yl 1 H NHSO2(1-naphthyl)
2122 2-aminopyridin-6-yl 1 H NHSO2CH=CH-Ph
2123 2-aminopyridin-6-yl 1 H NHSO2CH2Ph
2124 2-aminopyridin-6-yl 1 H NHSO2-CH2CH=CH-Ph
2125 2-aminopyridin-6-yl 1 H NHSO2-n-Bu
2126 2-aminopyridin-6-yl 1 H NHSO2-i-Bu
2127 2-aminopyridin-6-yl 1 H NHSO2-t-Pu
2128 2-aminopyridin-6-yl 1 H NHSO2NHPh
2129 2-aminopyridin-6-yl 1 H NHSO2NHC6H4-(2-CH3)
2130 2-aminopyridin-6-yl 1 H NHSO2NHC6H4-(3-CH3)
2131 2-aminopyridin-6-yl 1 H NHSO2NHC6H4-(4-CH
2132 2-aminopyridin-6-yl 1 H NHSO2NH(2-pyridyl)
2133 2-aminopyridin-6-yl 1 H NHSO2NH(3-pyridyl)
2134 2-aminopyridin-6-yl 1 H NHSO2NH(4-pyridyl)
2135 2-aminopyridin-6-yl 1 H NHSO2NH(2-thiazolyl)
2136 2-aminopyridin-6-yl 1 H NHSO2NH-(4-
thiazolyl)
2137 2-aminopyridin-6-yl 1 H NHSO2NH(4-
isoxazolyl)
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2138 2-aminopyridin-6-yl 1 H NH502-[4-(3,5-
dimethyl)isoxazolyl]
2139 2-aminopyridin-6-yl 1 H NHSO2NHC6H4-(2-Br)
2140 2-aminopyridin-6-yl 1 H NHSO2NHC6H4-(3-Br)
2141 2-aminopyridin-6-yl 1 H NHSO2NHC6H4-(4-Br~
2142 2-aminopyridin-6-yl 1 H NHSO2NHC6H4-(3-F)
2143 2-aminopyridin-6-yl 1 H NHSO2NHC6H4-(4-F)
2144 2-aminopyridin-6-yl 1 H NHSO2NH(2-naphthyl)
2145 2-aminopyridin-6-yl 1 H NHSO2NH)1-naphthyl)
2146 2-aminopyridin-6-yl 1 H NHS02NHCH=CH-Ph
2147 2-aminopyridin-6-yl 1 H NHS02NHCH2Ph
2148 2-aminopyridin-6-yl 1 H NHSO2NHCH2CH=CH-Ph
2149 2-aminopyridin-6-yl 1 H NHSO2NH-n-Bu
2150 2-aminopyridin-6-yl 1 H NHSO2NH-i-Bu
21S1 2-aminopyridin-6-yl 1 H NHSO2NH-t-Bu
2152 2-aminoimidazol- 0 HNHCOOBn
5-yl
21532-aminoimidazol- 0 HNHCO2CH2C6H4-(2-CH3)
5-yl
21542-aminoimidazol- 0 HNHCO2CH2C6H4-(3-CH3)
5-yl
21552-aminoimidazol- 0 HNHCO2CH2C6H4-(4-CH3)
5-yl
21562-aminoimidazol- 0 HNHCO2CH2(2-
5-yl pyridinyl)
21572-aminoimidazol- 0 HNHCO2CH2(3-
5-yl pyridinyl)
21582-aminoimidazol- 0 HNHCO2CH2(4-
5-yl pyridinyl)
21592-aminoimidazol- 0 HNHCO2CH2(2-
5-yl thiazolyl)
21602-aminoimidazol- 0 HNHCO2CH2(4-
5-yl thiazolyl)
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21612-aminoimidazol- 0 HNHCO2CH2(5-
5-yl thiazolyl)
21622-aminoimidazol- 0 HNHCO2CH2(4-
5-yl isoxazolyl)
21632-aminoimidazol- 0 HNHCO2CH2(2-thienyl)
5-yl
21642-aminoimidazol- 0 HNHCO2n-Bu
5-yl
21652-aminoimidazol- 0 HNHCO2i-Bu
5-yl
21662-aminoimidazol- 0 HNHCO2t-Bu
5-yl
21672-aminoimidazol- 0 HNHSO2Ph
5-yl
21682-aminoimidazol- 0 HNHSO2C6H4-(2-CH3)
5-yl
21692-aminoimidazol- 0 HNHSO2C6H4-(3-CH3)
5-yl
21702-aminoimidazol- 0 HNHSO2C6H4-(4-CH3)
5-yl
21712-aminoimidazol- 0 HNHSO2(2-pyridyl)
5-yl
21722-aminoimidazol- 0 HNHSO2(3-pyridyl)
5-yl
21732-aminoimidazol- 0 HNHSO2(4-pyridyl)
5-yl
21742-aminoimidazol- 0 HNHSO2(2-thiazolyl)
5-yl
21752-aminoimidazol- 0 HNHSO2(4-thiazolyl)
5-yl
21762-aminoimidazol- 0 HNHSO2(4-isoxazolyl)
5-yl
21772-aminoimidazol- 0 HNHSO2-[4-(3,5-
5-yl dimethyl)isoxazolyl]
-135-
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21782-aminoimidazol- 0 HNHSO2C6H4-(2-Br
S -yl
21792-aminoimidazol- 0 HNHSO2C6H4-(3-Br)
5-yl
21802-aminoimidazol- 0 HNHSO2C6H4-(2-F~
5-yl
21812-aminoimldazol- 0 HNHSO2C6H4-(3-F)
5-yl
21822-aminoimidazol- 0 HNHSO2c6H4-(4-F)
5-yl
21832-aminoimidazol- 0 HNHSO2(2-naphthyl)
5-yl
21842-aminoimidazol- 0 HNHSO2(1-naphthyl)
5-yl
21852-aminoimidazol- 0 HNHSO2CH=CHPh
5-yl
21862-aminoimidazol- 0 HNHSO2CH2Ph
5-yl
21872-aminoimidazol- 0 HNHSO2CH2CH=CHPh
5-yl
21882-aminoimidazol- 0 HNHSO2-n-Bu
5-yl
21892-aminoimidazol- 0 HNHSO2-i-Bu
5-yl
2190 2-aminoimidazol- 1 HNHCOOBn
5-yl
21912-aminoimidazol- 1 HNHCO2CH2C6H4_(2-CH3)
5-yl
21922-aminoimidazol- 1 HNHCO2CH2C6H4_(3-CH3)
5-yl
21932-aminoimidazol- 1 HNHCO2CH2C6H4-(4-CH3)
5-yl
21942-aminoimidazol- 1 HNHCO2CH2(2-
5-yl pyridinyl)
-136-
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21952-aminoimidazol- 1 HNHCO2CH2~3-
5-yl pyridinyl)
21962-aminoimidazol- 1 HNHCo2cH2(4
5-yl pyridinyl)
21972-aminoimidazol- 1 HNHCO2CH2(2-
5-yl thiazolyl)
21982-aminoimidazol- 1 HNHCo2cH2(4
5-yl thiazolyl)
21992-aminoimidazol- 1 HNHCO2CH2(5-
5-yl thiazolyl)
22002-aminoimidazol- 1 HNHCo2cH2(4
5-yl isoxazolyl)
22012-aminoimidazol- 1 HNHCO2CH2(2-thienyl)
5-yl
22022-aminoimidazol- 1 HNHCO2n-Bu
5-yl
22032-aminoimidazol- 1 HNHCO2i-Bu
S -yl
22042-aminoimidazol- 1 HNHCO2t-Bu
5-yl
22052-aminoimidazol- 1 HNHSO2Ph
5-yl
22062-aminoimidazol- 1 HNHSO2C6H4-(2-CH3)
5-yl
22072-aminoimidazol- 1 HNHSO2C6H4-(3-CH3)
5-yl
22082-aminoimidazol- 1 HNHSO2C6H4-(4-CH3)
5-yl
22092-aminoimidazol- 1 HNHSO2(2-pyridyl)
5-yl
22102-aminoimidazol- 1 HNHSO2(3-pyridyl)
5-yl
22112-aminoimidazol- 1 HNHSO2(4-pyridyl)
5-yl
-137-
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22122-aminoimidazol- 1 HNHSO2(2-thiaz-olyl)
5-yl
22132-aminoimidazol- 1 HNHSO2~4-isoxazolyl)
5-yl
22142-aminoimidazol- 1 HNHSo2-[4-(3~5-
5-yl dimethyl)isoxazolyl]
22152-aminoimidazol- 1 HNHSO2C6H4-(2-Br)
5-yl
22162-aminoimidazol- 1 HNHSO2C6H4-(3-Br)
5-yl
22172-aminoimidazol- 1 HNHSO2C6H4-(2-F)
5-yl
22182-aminoimidazol- 1 HNHSO2C6H4-(3-F)
5-yl
22192-aminoimidazol- 1 HNHSO2C6H4-(4-F)
5-yl
22202-aminoimidazol- 1 HNHSO2(2-naphthyl)
5-yl
22212-aminoimidazol- 1 HNHSO2(1-naphthyl)
5-yl
22222-aminoimidazol- 1 HNHSO2CH=CHPh
5-yl
22232-aminoimidazol- 1 HNHSO2CH2Ph
5-yl
22242-aminoimidazol- 1 HNHSO2CH2CH=CHPh
5-yl
22252-aminoimidazol- 1 HNHSO2-n-Bu
5-yl
22262-aminoimidazol- 1 HNHSO2-i-Bu
5-yl
22272-aminoimidazol- 1 HNHSO2Ph
5-yl
22282-aminoimidazol- 1 HNHSO2C6H4-(2-CH3)
5-yl
-138-
CA 02249733 l998-09-ll
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22292-aminoimidazol- 1 HNHSO2C6H4-(3-CH3)
5-yl
22302-aminoimidazol- 1 HNHSO2C6H4-(4-CH3)
5-yl
22312-aminoimidazol- 1 HNHSO2(2-pyridyl)
5-yl
22322-aminoimidazol- 1 HNHSO2(3-pyridyl)
5-yl
22332-aminoimidazol- 1 HNHSO2(4-pyridyl)
S -yl
22342-aminoimidazol- 1 H NHSO2(2-thiazolyl)
5-yl
22352-aminoimidazol- 1 H NHSO2~4-isoxazolyl)
5-yl
2236 2-aminoimidazol- 1 H NHS02-[4-~3,5-
5-yl dimethyl)isoxazolyl]
2237 2-aminoimidazol- 1 H NHSO2C6H4-~2-Br)
5-yl
2238 2-aminoimidazol- 1 H NHSO2C6H4-~3-Br)
5-yl
2239 2-aminoimidazol- 1 H NHSO2C6H4-~2-F)
5-yl
2240 2-aminoimidazol- 1 H NHSO2C6H4-~3-F)
5-yl
2241 2-aminoimidazol- 1 H NHSO2C6H4-(4-F)
5-yl
2242 2-aminoimidazol- 1 H NHCO2CH2Ph
5-yl
2243 2-aminoimidazol- 1 H NHCO2n-Bu
5-yl
2244 2-aminoimidazol- 1 H NHCo2i-Bu
5-yl
2245 2-aminothiazol-4-yl 0 HNHS02Ph
2246 2-aminothiazol-4-yl 0 HNHSO2C6H4-(2-CH3)
2247 2-aminothiazol-4-yl 0 HNHSO2C6H4-~3-CH
-139-
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2248 2-aminothiazol-4-yl O H NHSO2C6H4-(4-CH3)
2249 2-aminothiazol-4-yl 0 H NHSO2(2-pyridyl)
2250 2-aminothiazol-4-yl O H NHSO2(3-pyridyl)
2251 2-aminothiazol-4-yl O H NHSO2(4-pyridyl)
2252 2-aminothiazol-4-yl 0 H NHSO2(2-thiazolyl)
2253 2-aminothiazol-4-yl O H NHSO2(4-isoxazolyl)
2254 2-aminothiazol-4-yl O H NHSO2-[4-~3,5-
dimethyl)isoxazolyl
2255 2-aminothiazol-4-yl O H NHSO2C6H4-(2-Br)
2256 2-aminothiazol-4-yl 0 H NHSO2C6H4-(3-Br)
2257 2-aminothiazol-4-yl 0 H NHSO2C6H4-(2-F)
2258 2-aminothiazol-4-yl O H NHSO2C6H4-(3-F)
2259 2-aminothiazol-4-yl O H NHSO2C6H4-(4-F)
2260 2-aminothiazol-4-yl 0 H NHCO2CH2Ph
2261 2-aminothiazol-4-yl O H NHCO2n-Bu
2262 2-aminothiazol-4-yl 0 H NHCO2i-Bu
2263 2-aminothiazol-4-yl 1 H NHSO2Ph
2264 2-aminothiazol-4-yl 1 H NHSO2C6H4-(2-CH3)
2265 2-aminothiazol-4-yl 1 H NHSO2c6H4-(3-cH3)
2266 2-aminothiazol-4-yl 1 H NHso2c6H4-(4-cH3)
2267 2-aminothiazol-4-yl 1 H NHSO2(2-pyridyl)
2268 2-aminothiazol-4-yl 1 H NHSO2(3-pyridyl)
2269 2-aminothiazol-4-yl 1 H NHSO2(4-pyridyl)
2270 2-aminothiazol-4-yl 1 H NHSO2(2-thiazolyl)
2271 2-aminothiazol-4-yl 1 H NHSO2(4-isoxazolyl)
2272 2-aminothiazol-4-yl 1 H NHSO2-[4-(3,5-
dimethyl)isoxazolyl]
2273 2-aminothiazol-4-yl 1 H NHSO2C6H4-(2-Br)
2274 2-aminothiazol-4-yl 1 H NHSO2C6H4-(3-Br)
2275 2-aminothiazol-4-yl 1 H NHSO2C6H4-(2-F)
2276 2-aminothiazol-4-yl 1 H NHSO2C6H4-(3-F)
2277 2-aminothiazol-4-yl 1 H NHSO2C6H4-(4-F)
2278 2-aminothiazol-4-yl 1 H NHCO2CH2Ph
2279 2-aminothiazol-4-yl 1 H NHCO2n-Bu
2280 2-aminothiazol-4-yl 1 H NHCO2i-Bu
-140-
CA 02249733 l998-09-ll
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22812-aminopyridin-6- 0 H NHSO2Ph
ylmethyl
22822-aminopyridin-6- 0 H NHS02C6H4-(2-CH3)
ylmethyl
22832-aminopyridin-6- 0 H NHS02C6H4-(3-CH3)
ylmethyl
22842-aminopyridin-6- 0 H NHS02C6H4-(4-CH3)
ylmethyl
22852-aminopyridin-6- 0 H NHSO2(2-naphthyl)
ylmethyl
22862-aminopyridin-6- 0 H NHS02(1-naphthyl)
ylmethyl
22872-aminopyridin-6- o H NHS02(biphenyl)
ylmethyl
22882-aminopyridin-6- 0 H NHS02(2,4,6-
ylmethyl trimethylphenyl)
22892-aminopyridin-6- 0 H NHSO2(2-thienyl)
ylmethyl
22gO2-aminopyridin-6- 0 H NHS02-[4-(3,5-
ylmethyl dimethyl)isoxazolyl]
22912-aminopyridin-6- 0 H NHSO2C6H4-(2-Br)
ylmethyl
22922-aminopyridin-6- 0 H NHSO2C6H4-(3-Br)
ylmethyl
22932-aminopyridin-6- 0 H NHSO2C6H4-(2-F)
ylmethyl
22942-aminopyridin-6- 0 H NHS02C6H4-(3-F)
ylmethyl
22952-aminopyridin-6- 0 H NHS02C6H4-(4-F)
ylmethyl
22962-aminopyridin-6- 0 H NHC02CH2Ph
ylmethyl
22972-aminopyridin-6- 0 H NHC02n-Bu
. ylmethyl
-141-
CA 02249733 l998-09-ll
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2298 2-aminopyridin-6- 0 H NHCO2i-Bu
ylmethyl
2299 2-aminopyridin-6- 1 H NHSO2Ph
ylmethyl
2300 2-aminopyridin-6- 1 H NHSo2C6H4-(2-CH3)
ylmethyl
2301 2-aminopyridin-6- 1 H NHSO2C6H4-~3-CH3)
ylmethyl
2302 2-aminopyridin-6- 1 H NHSo2C6H4-(4-CH3)
ylmethyl
2303 2-aminopyridin-6- 1 H NHSO2(2-naphthyl)
ylmethyl
2304 2-aminopyridin-6- 1 H NHSO2(1-naphthyl)
ylmethyl
2305 2-aminopyridin-6- 1 H NHSO2(biphenyl)
ylmethyl
2306 2-aminopyridin-6- 1 H NHSO2(2,4,6-
ylmethyl trimethylphenyl)
2307 2-aminopyridin-6- 1 H NHSO2(2-thienyl)
ylmethyl
2308 2-aminopyridin-6- 1 H NHSo2-[4-(3~5-
ylmethyl dimethyl)isoxazolyl]
2309 2-aminopyridin-6- 1 H ~SO2C6H4-(2-Br)
ylmethyl
2310 2-aminopyridin-6- 1 H NHSO2C6H4-(3-Br)
ylmethyl
2311 2-aminopyridin-6- 1 H NHSO2C6H4-(2-F)
ylmethyl
2312 2-aminopyridin-6- 1 H NHSo2C6H4-(3-F)
ylmethyl
2313 2-aminopyridin-6- 1 H NHS02C6H4-(4-F)
ylmethyl
2314 2-aminopyridin-6- 1 H NHC02CH2Ph
ylmethyl
-142-
CA 02249733 l998-09-ll
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23152-aminopyridin-6- 1 H NHC02n-Bu
ylmethyl
23162-aminopyridin-6- 0 H NHS02Ph
ylcarbonyl
23172-aminopyridin-6- 0 H NHSO2C6H4-(2-CH3)
ylcarbonyl
23182-aminopyridin-6- 0 H NHS02C6H4-(3-CH3)
ylcarbonyl
23192-aminopyridin-6- 0 H NHSO2C6H4-(4-CH3)
ylcarbonyl
23202-aminopyridin-6- 0 H NHSO2(2-naphthyl)
-ylcarbonyl
23212-aminopyridin-6- 0 H NHSO2(1-naphthyl)
ylcarbonyl
23222-aminopyridin-6- 0 H NHSO2(biphenyl)
ylcarbonyl
23232-aminopyridin-6- 0 H NHSO2(2,4,6-
ylcarbonyl trimethylphenyl)
23242-aminopyridin-6- 0 H NHS02(2-thienyl)
ylcarbonyl
23252-aminopyridin-6- 0 H NHSO2-~4-(3,5-
ylcarbonyl dimethyl)isoxazolyl]
23262-aminopyridin-6- 0 H NHSO2C6H4-(2-Br)
ylcarbonyl
23272-aminopyridin-6- 0 H NHSO2C6H4-(3-Br)
ylcarbonyl
23282-aminopyridin-6- 0 H NHSO2C6H4-(2-F)
ylcarbonyl
23292-aminopyridin-6- 0 H NHS02C6H4-(3-F)
ylcarbonyl
23302-aminopyridin-6- 0 H NHSO2C6H4-(4-F)
ylcarbonyl
23312-aminopyridin-6- 0 H NHCO2CH2Ph
ylcarbonyl
-143-
CA 02249733 l998-09-ll
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2332 2-aminopyridin-6- 0 H NHCO2n-Bu
ylcarbonyl
2333 2-aminopyridin-6- 0 H NHCO2i-Bu
ylcarbonyl
2334 2-aminopyridin-6- 1 H NHSO2Ph
ylcarbonyl
2335 2-aminopyridin-6- 1 H NHSo2C6H4-(2-CH3)
ylcarbonyl
2336 2-aminopyridin-6- 1 H NHSO2C6H4-(3-CH3)
ylcarbonyl
2337 2-aminopyridin-6- 1 H NHSO2C6H4-(4-CH3)
ylcarbonyl
2338 2-aminopyridin-6- 1 H NHSO2~2-naphthyl)
ylcarbonyl
2339 2-aminopyridin-6- 1 H NHSO2(1-naphthyl)
ylcarbonyl
2340 2-aminopyridin-6- 1 H NHSO2(biphenyl)
ylcarbonyl
2341 2-aminopyridin-6- 1 H NHSO2(2,4,6-
ylcarbonyl trimethylphenyl)
2342 2-aminopyridin-6- 1 H NHSO2(2-thienyl)
ylcarbonyl
2343 2-aminopyridin-6- 1 H NHSO2-[4-(3,5-
ylcarbonyl dimethyl)isoxazolyl]
2344 2-aminopyridin-6- 1 H NHSO2C6H4-(2-Br)
ylcarbonyl
2345 2-aminopyridin-6- 1 H NHSO2C6H4-(3-~r)
ylcarbonyl
2346 2-aminopyridin-6- 1 H NHSO2C6H4-(2-F)
ylcarbonyl
2347 2-aminopyridin-6- 1 H NHSO2C6H4-(3-F)
ylcarbonyl
2348 2-aminopyridin-6- 1 H NHSo2C6H4-(4-F)
ylcarbonyl
-144-
CA 02249733 l998-09-ll
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2349 2-aminopyridin-6- 1 H NHCO2CH2Ph
ylcarbonyl
2350 2-aminopyridin-6- 1 H NHCO2n-Bu
ylcarbonyl
2351 2-aminoimidazol-5- 1 H NHSO2Ph
ylmethyl
2352 2-aminoimidazol-5- 1 H NHSO2C6H4-(2-CH3)
ylmethyl
2353 2-aminoimidazol-5- 1 H NHSO2C6H4-~3-CH3)
ylmethyl
2354 2-aminoimidazol-5- 1 H NHSO2C6H4-(4-CH3)
ylmethyl
2355 2-aminoimidazol-5- 1 H NHSO2(2-naphthyl)
ylmethyl
2356 2-aminoimidazol-5- 1 H NHSO2(1-naphthyl)
ylmethyl
2357 2-aminoimidazol-5- 1 H NH5O2(biphenyl)
ylmethyl
2358 2-aminoimidazol-5- 1 H NHSO2(2,4,6-
ylmethyl trimethylphenyl)
2359 2-aminoimidazol-5- 1 H NHSO2(2-thienyl)
ylmethyl
2360 2-aminoimidazol-5- 1 H NHSO2-[4-(3,5-
ylmethyl dimethyl)isoxazolyl]
2361 2-aminoimidazol-5- 1 H NHSO2C6H4-(2-Br)
ylmethyl
2362 2-aminoimidazol-5- 1 H NHSO2C6H4-(3-Br)
ylmethyl
2363 2-aminoimidazol-5- 1 H NHSO2C6H4-(2-F)
ylmethyl
2364 2-aminoimidazol-5- 1 H NHSO2C6H4-(3-F)
ylmethyl
2365 2-aminoimidazol-5- 1 H NHSO2C6H4-(4-F)
ylmethyl
-145-
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2366 2-aminoimidazol-5- 1 H NHCO2CH2Ph
ylmethyl
2367 2-aminoimidazol-5- 1 H NHC02n-Bu
ylmethyl
2368 2-amino-1,3,4- 0 H NHSO2Ph
triazol-5-yl-
carbonyl
2369 4-imidazolyl- 0 H NHSO2Ph
carbonyl
2370 2-aminoimidazol-5- 0 H NHSO2Ph
ylmethyl
-146-
CA 02249733 l998-09-ll
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Tabl e 3
~ ~N~OH
E~. ~
~Q- Bl L Bl~ Bl4 Bl5 (M+H)+
3001 2- 0 Cbz H NHSO2Ph
pyridinylamino-
methyl
3002 2- 0SO2Ph H NHSO2Ph
pyridinylamino-
methyl
3003 2- 0CO(CH2)2Ph H NHSO2Ph
pyridinylamino-
methyl
3004 2- 0 Bn H NHSO2Ph
pyridinylamino-
methyl
3005 2- 0 n-Bu H NHSO2Ph
pyridinylamino-
methyl
3006 2- 0COCH2(3- H NHSO2Ph
pyridinylamino- indolyl)
methyl
3007 2- 0 S02- H NHSO2Ph
pyridinylamino- (biphenyl)
methyl
3008 2- 0CO2-n-Bu H NHSO2Ph
pyridinylamino-
methyl
-147-
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3009 2- 0Co2-i-Bu H NHSO2Ph
pyridinylamino-
methyl
3010 2- 0CO2-t-Bu H NHSO2Ph
pyridinylamino-
methyl
3011 2- 0 H H NHSO2Ph
pyridinylamino-
methyl
3012 2- 0-(CH2)4NH2 H NHSO2Ph
pyridinylamino-
methyl
3013 2- 0COPh H NHSO2Ph
pyridinylamino-
methyl
3014 2- 0cyclopropyl- H NHSO2Ph
pyridinylamino- methyl
methyl
3015 2- 0S02-n-Bu HNHS02Ph
pyridinylamino-
methyl
3016 2- 0Cbz HNHS02-(2,4,6- 679.4
pyridinylamino- trimethylphen
methyl yl)
3017 2- 0SO2Ph HNHSO2-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3018 2- 0CO(CH2)2Ph HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3019 2- 0Bn HNHSO2-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
-148-
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3020 2- o n-Bu H NHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3021 2- 0CO2-n-Bu HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3022 2- 0CO2-i-Bu HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3023 2- 0C02-t-Bu HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3024 2- 0 H HNHS02-(2,4,6- 545.5
pyridinylamino- trimethylphen
methyl yl)
3025 2- 0-(CH2)4NH2 HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3026 2- 0COPh HNHSO2-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3027 2- 0SO2-n-Bu HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
302~ 2- 0 Cbz HNHCbz
pyridinylamino-
methyl
3029 2- 0SO2Ph HNHCbz
pyridinylamino-
methyl
3030 2- 0Co(cH2)2ph HNHCbz
pyridinylamino-
methyl
-149-
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3031 2- 0 Bn H NHC~z
pyridinylamino-
methyl
3032 2- 0 n-Bu H NHCbz
pyridinylamino-
methyl
3033 2- 0CO2-n-Bu H NHCbz
pyridinylamino-
methyl
3034 2- 0CO2-i-Bu H NHCbz
pyridinylamino-
methyl
3035 2- 0CO2-t-Bu H NHCbz
pyridinylamino-
methyl
3036 2- 0 H H NHCbz
~-,ridinylamino-
methyl
3037 2- 0-(CH2)4NH2 H NHCbz
py-idinylamino-
methyl
3038 2- 0COPh H NHCbz
pyridinylamino-
methyl
3039 2- 0SO2-n-Bu H NHCbz
pyridinylamino-
methyl
3040 2- 0 Cbz H NHSO2Ph
imidazolylamino-
methyl
3041 2- 0SO2Ph H NHSO2Ph
imidazolylamino-
methyl
-lSO-
CA 02249733 l998-09-ll
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3042 2- 0CO(CH2)2Ph H NHSO2Ph
imidazolylamino-
methyl
3043 2- 0 Bn H NHSO2Ph
imidazolylamino-
methyl
3044 2- 0 n-Bu H NHS02Ph
imidazolylamino-
methyl
3045 2- 0COCH2(3- H NHSO2Ph
imidazolylamino- indolyl)
- methyl
3046 2- 0 so2- H NHS02Ph
imidazolylamino- (biphenyl)
methyl
3047 2- 0 CO2-n-Bu H NHSO2Ph
imidazolylamino-
methyl
3048 2- 0 C02-i-Bu H NHS02Ph
imidazolylamino-
methyl
3049 2- 0 CO2-t-Bu H NHSO2Ph
imidazolylamino-
methyl
3050 2- 0 H H NHSO2Ph 492.3
imidazolylamino-
methyl
3051 2- 0 -(CH2)4NH2 H NHS02Ph
imidazolylamino-
methyl
3052 2- 0 COPh H NHSO2Ph
imidazolylamino-
methyl
-151-
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3053 2- 0cyclopropyl- H NHSO2Ph
imidazolylamino- methyl
methyl
3054 2- oSO2-n-Bu HNHSO2Ph
imidazolylamino-
methyl
3055 2- 0Cbz HNHS02-(2,4,6- 668.4
imidazolylamino- trimethylphen
methyl yl)
3056 2- 0SO2Ph HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3057 2- 0CO(CH2)2Ph HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3058 2- 0Bn HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3059 2- 0n-Bu HNHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3060 2- 0CO2-n-Bu HNHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3061 2- 0CO2-i-Bu HNHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3062 2- 0CO2-t-Bu HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3063 2- 0 H HNHSO2-(2,4,6- 534.4
imidazolylamino- trimethylphen
methyl yl)
-152-
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3064 2- 0-(CH2)4NH2 HNHS02-(2,4,6-
imidazolylamlno- trimethylphen
methyl yl)
3065 2- 0 COPh H NHSO2-(2,4,6-
- imidazolylamino- trimethylphen
methyl yl)
3066 2- 0 SO2-n-Bu H NHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3067 2- 0 Cbz H NHCbz
imidazolylamino-
methyl
3068 2- 0 SO2Ph H NHCbz
imidazolylamino-
methyl
3069 2- 0 CO(cH2)2Ph H NHCbz
imidazolylamino-
methyl
3070 2- 0 Bn H NHCbz
imidazolylamino-
methyl
3071 2- 0 n-Bu H NHCbz
imidazolylamino-
methyl
3072 2- 0 CO2-n-Bu H NHCbz
imidazolylamino-
methyl
3073 2- 0 C02-i-Bu H NHCbz
imidazolylamino-
methyl
3074 2- 0 C02-t-Bu H NHCbz
imidazolylamino-
methyl
-153-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04S67
3075 2- 0 H H NHCbz
imidazolylamino-
methyl
3076 2- 0-~CH2)4NH2 H NHCbz
imidazolylamino-
methyl
3077 2- 0COPh H NHCbz
imidazolylamino-
methyl
3078 2- 0SO2-n-Bu H NHCbz
imidazolylamino-
methyl
30792-imidazolinyl- 0 Cbz H NHSO2Ph
aminomethyl
30802-imidazolinyl- 0SO2Ph H NHSO2Ph
aminomethyl
30812-imidazolinyl- 0CO(cH2)2Ph H NHSO2Ph
aminomethyl
30822-imidazolinyl- 0 Bn H NHSO2Ph
aminomethyl
30832-imidazolinyl- 0 n-Bu H NHSO2Ph
aminomethyl
30842-imidazolinyl- 0COCH2(3- H NHSO2Ph
aminomethyl indolyl~
30852-imidazolinyl- 0 so2- H NHSO2Ph
aminomethyl (biphenyl)
30862-imidazolinyl- 0CO2-n-Bu H NHSO2Ph
aminomethyl
30872-imidazolinyl- 0CO2-i-Bu H NHSO2Ph
aminomethyl
30882-imidazolinyl- 0CO2-t-Bu H NHSO2Ph
aminomethyl
30892-imidazolinyl- 0 H H NHSO2Ph
aminomethyl
-154-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
3090 2-imidazolinyl- 0 -~CH2)4NH2 H NHS02Ph
aminomethyl
3091 2-imidazolinyl- -0 COPh H MHSO2Ph
aminomethyl
3092 2-imidazolinyl- 0cyclopropyl- H NHSO2Ph
aminomethyl methyl
3093 2-imidazolinyl- 0S02-n-Bu H NHSO2Ph
aminomethyl
3094 2-imidazolinyl- 0 Cbz H NHSO2-(2,4,6-
aminomethyl trimethylphen
yl)
3095 -2-imidazolinyl- 0 SO2Ph H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
3096 2-imidazolinyl- 0CO(CH2)2Ph H NHSO2-(2,4,6-
aminomethyl trimethylphen
yl)
3097 2-imidazolinyl- 0 Bn H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
3098 2-imidazolinyl- 0 n-Bu H NHSO2-(2,4,6-
aminomethyl trimethylphen
yl)
3099 2-imidazolinyl- 0CO2-n-Bu H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
3100 2-imidazolinyl- 0C02-i-Bu H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
3101 2-imidazolinyl- 0CO2-t-Bu H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
3102 2-imidazolinyl- 0 H H NHSO2-(2,4,6- 536.3
aminomethyl trimethylphen
yl)
-155-
CA 02249733 l998-09-ll
W097/33887 PCTAUS97/04567
31032-imidazolinyl- 0 -~CH2)4NH2 H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
31042-imidazolinyl- 0 COPh H NHSO2-(2,4,6-
aminomethyl trimethylphen
yl)
31052-imidazolinyl- 0 S02-n-Bu H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
3106 2-imidazolinyl- 0Cbz HNHCbz
aminomethyl
31072-imidazolinyl- 0 SO2Ph H NHCbz
aminomethyl
31082-imidazolinyl- 0 CO(CH2)2Ph H NHCbz
aminomethyl
3109 2-imidazolinyl- 0Bn HNHCbz
aminomethyl
3110 2-imidazolinyl- 0n-Bu HNHCbz
aminomethyl
31112-imidazolinyl- 0 CO2-n-Bu H NHCbz
aminomethyl
31122-imidazolinyl- 0 CO2-i-Bu H NHCbz
aminomethyl
31132-imidazolinyl- 0 C02-t-Bu H NHCbz
aminomethyl
3114 2-imidazolinyl- 0 H HNHCbz
aminomethyl
3115 2-imidazolinyl- 0-(CH2)4NH2 HNHCbz
aminomethyl
3116 2-imidazolinyl- 0COPh HNHCbz
aminomethyl
3117 2-imidazolinyl- 0SO2-n-Bu HNHCbz
aminomethyl
-156-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04S67
3118 2- 0 Cbz H NHS02Ph
benzimidazolyl-
aminomethyl
311~ 2- 0S02Ph H NHS02Ph
benzimidazolyl-
aminomethyl
3120 2- 0CO(CH2)2Ph H NHS02Ph
benzimidazolyl-
aminomethyl
3121 2- 0 Bn H NHS02Ph
benzimidazolyl-
aminomethyl
3122 2- 0 n-Bu H NHS02Ph
benzimidazolyl-
aminomethyl
3123 2- 0COCH2(3- H NHS02Ph
benzimidazolyl- indolyl)
aminomethyl
3124 2- 0 S02- H NHS02Ph
benzimidazolyl- (biphenyl)
aminomethyl
3125 2- 0C02-n-Bu H NHS02Ph
benzimidazolyl-
aminomethyl
3126 2- 0C02-i-Bu H NHS02Ph
benzimidazolyl-
aminomethyl
3127 2- 0C02-t-Bu H NHS02Ph
benzimidazolyl-
aminomethyl
3128 2- 0 H H NHS02Ph
benzimidazolyl-
aminomethyl
-157-
CA 02249733 l998-09-ll
W 097l33887 PCTAUS97/04567
3129 2- 0-(CH2)4NH2 H NHS02Ph
benzimidazolyl-
aminomethyl
3130 2- 0COPh H NHSO2Ph
benzimidazolyl-
aminomethyl
3131 2- 0cyclopropyl- H NHS02Ph
benzimidazolyl- methyl
aminomethyl
3132 2- 0S02-n-Bu HNHS02Ph
benzimidazolyl-
aminomethyl
3133 2- 0Cbz HNHS02-(2,4,6- 718.4
benzimidazolyl- trimethylphen
aminomethyl yl)
3134 2- 0SO2Ph HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3135 2- 0CO(CH2)2Ph HNHS02-(2,4,6-
benzimidazolyi- trimethylphen
aminomethyl yl)
3136 2- 0Bn HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3137 2- 0n-Bu HNHSO2-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3138 2- 0CO2-n-Bu HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3139 2- 0C02-i-Bu HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
-158-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
3140 2- 0CO2-t-Bu H NHSO2-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl - yl)
3141 2- 0 H HNHSO2-(2,4,6- 584.2
benzimidazolyl- trimethylphen
aminomethyl yl)
3142 2- 0-(CH2)4NH2 HNHSO2-~2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3143 2- 0COPh HNHSO2-(2,4,6-
benzimidazolyl- trimethylphen
_ aminomethyl yl)
3144 2- 0SO2-n-Bu HNHSO2-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3145 2- 0 Cbz HNHCbz
benzimidazolyl-
aminomethyl
3146 2- 0SO2Ph HNHCbz
benzimidazolyl-
aminomethyl
3147 2- 0CO~CH2)2Ph HNHCbz
benzimidazolyl-
aminomethyl
3148 2- 0 Bn HNHCbz
benzimidazolyl-
aminomethyl
3149 2- 0 n-Bu HNHCbz
benzimidazolyl-
aminomethyl
3150 2- 0CO2-n-Bu HNHCbz
benzimidazolyl-
aminomethyl
-159-
CA 02249733 l998-09-ll
W 097/33887 PCT~US97/04567
3151 2- 0C02-i-Bu H NHCbz
benzimidazolyl-
aminomethyl
3152 2- 0C02-t-Bu H NHCbz
benzimidazolyl-
aminomethyl
3153 2- 0 H H NHCbz
benzimidazolyl-
aminomethyl
3154 2- 0-(CH2)sNH2 H NHCbz
benzimidazolyl-
aminomethyl
3155 2- 0COPh H NHCbz
benzimidazolyl-
aminomethyl
3156 2- 0S02-n-Bu H NHCbz
benzimidazolyl-
aminomethyl
3157 7-aza-2- 0 Cbz H NHS02Ph
benzimidazolyl
3158 7-aza-2- 0S02Ph H NHS02Ph
benzimidazolyl
3159 7-aza-2- 0CO~CH2)2Ph H NHS02Ph
benzimidazolyl
3160 7-aza-2- 0 Bn H NHS02Ph
benzimidazolyl
3161 7-aza-2- 0 n-Bu H NHS02Ph
benzimidazolyl
3162 7-aza-2- 0COCH2(3- H NHS02Ph
benzimidazolyl indolyl)
31637-aza-2- 0 S02- H NHS02Ph
benzimidazolyl (biphenyl)
31647-aza-2- 0C02-n-Bu H NHS02Ph
benzimidazolyl
-160-
CA 02249733 l998-09-ll
W 097/33887 PCTtUS97tO4567
3165 7-aza-2- 0C02-i-2u H NHS02Ph
benzimidazolyl
3166 7-aza-2- 0C02-t-Bu H NHS02Ph
benzimidazolyl
3167 7-aza-2- 0 H H NHS02Ph
benzimidazolyl
3168 7-aza-2- 0-(CH2)4NH2 H NHS02Ph
benzimidazolyl
3169 7-aza-2- 0COPh H NHS02Ph
benzimidazolyl
3170 7-aza-2- 0cyclopropyl- H NHS02Ph
benzimidazolyl methyl
31717-aza-2- 0S02-n-Bu HNHS02Ph
benzimidazolyl
31727-aza-2- 0 Cbz HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
31737-aza-2- 0S02Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
31747-aza-2- 0Co(CH2)2Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
31757-aza-2- 0 Bn HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
31767-aza-2- 0 n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
31777-aza-2- 0C02-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
31787-aza-2- 0C02-i-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
-
-161-
CA 02249733 l998-09-ll
W O 97l33887 PCTrUS97/04567
3179 7-aza-2- 0CO2-t-Bu H NHSO2-(2,4,6-
benzimidazolyl trimethylphen
yl)
31807-aza-2- 0 H HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
31817-aza-2- 0-(CH2)4NH2 HNHSO2-(2,4,6-
benzimidazolyl trimethylphen
yl)
31827-aza-2- 0COPh HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
31837-aza-2- 0SO2-n-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphen
yl)
31847-aza-2- 0 Cbz HNHCbz
benzimidazolyl
31857-aza-2- 0SO2Ph HNHCbz
benzimidazolyl
31867-aza-2- 0CO(CH2)2Ph HNHCbz
benzimidazolyl
31877-aza-2- 0 Bn HNHCbz
benzimidazolyl
31887-aza-2- 0 n-Bu HNHCbz
benzimidazolyl
31897-aza-2- 0CO2-n-Bu HNHCbz
benzimidazolyl
31907-aza-2- 0CO2-i-Bu HNHCbz
benzimidazolyl
31917-aza-2- 0CO2-t-Bu HNHCbz
benzimidazolyl
31927-aza-2- 0 H HNHCbz
benzimidazolyl
31937-aza-2- 0-(CH2)4MH2 HNHCbz
benzimidazolyl
-162-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04S67
3194 7-aza-2- 0COPh H NHCbz
benzimidazolyl
3195 7-aza-2- 0SO2-n-Bu H NHCbz
benzimidazolyl
3196 tetrahydropyrimi 0 Cbz H NHSO2Ph
din-2-
ylaminomethyl
3197 tetrahydropyrimi 0SO2Ph H NHSO2Ph
din-2-
ylamlnomethyl
3198 tetrahydropyrimi 0CO(CH2)2Ph H NHSO2Ph
din-2-
ylaminomethyl
3199 tetrahydropyrimi 0 Bn H NHS02Ph
din-2-
ylaminomethyl
3200 tetrahydropyrimi 0 n-Bu H NHSO2Ph
din-2-
ylaminomethyl
3201 tetrahydropyrimi 0CoCH2(3- H NHSO2Ph
din-2- indolyl)
ylaminomethyl
3202 tetrahydropyrimi 0 S02- H NHS02Ph
din-2- (biphenyl)
ylaminomethyl
3203 tetrahydropyrimi 0CO2-n-Bu H NHSO2Ph
din-2-
ylaminomethyl
3204 tetrahydropyrimi 0CO2-i-Bu H NHSO2Ph
din-2-
ylaminomethyl
3205 tetrahydropyrimi 0CO2-t-Bu H NHSO2Ph
din-2-
ylaminomethyl
-163-
CA 02249733 l998-09-ll
W097/33887 PCTrUS97/04567
3206 tetrahydropyrimi 0 H H NHSO2Ph
din-2-
ylaminomethyl
3207 tetrahydropyrimi 0 -(CH2)4NH2 H NHSO2Ph
din-2-
ylaminomethyl
3208 tetrahydropyrimi 0COPh H NHSO2Ph
din-2-
ylaminomethyl
3209 tetrahydropyrimi 0 cyclopropyl- H MHSO2Ph
din-2- methyl
ylaminomethyl
3210 tetrahydropyrimi 0 S02-n-Bu H NWS02Ph
din-2-
ylaminomethyl
3211 tetrahydropyrimi 0 Cbz H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3212 tetrahydropyrimi 0 SO2Ph H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3213 tetrahydropyrimi 0 Co(cH2)2Ph H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3214 tetrahydropyrimi 0 Bn H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3215 tetrahydropyrimi 0 n-Bu H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3216 tetrahydropyrimi 0 C02-n-Bu H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
-164-
CA 02249733 l998-09-ll
W 097/33887 PCT~US97104567
3217 tetrahydropyrimi 0 CO2-i-Bu H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3218 tetrahydropyrimi 0 CO2-t-Bu H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3219 tetrahydropyrimi 0 H H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3220 tetrahydropyrimi 0 -(CH2)4NH2 H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3221 tetrahydropyrimi 0 COPh H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3222 tetrahydropyrimi 0 SO2-n-Bu H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3223 tetrahydropyrimi 0Cbz HNiHCbz
din-2-
ylaminomethyl
3224 tetrahydropyrimi 0 S02Ph H NHCbz
din-2-
ylaminomethyl
3225 tetrahydropyrimi 0 CO(CH2)2Ph H NHCbz
din-2-
ylaminomethyl
3226 tetrahydropyrimi 0Bn HNHCbz
din-2-
ylaminomethyl
3227 tetrahydropyrimi 0n-Bu HNHCbz
din-2-
ylaminomethyl
-165-
CA 02249733 l998-09-ll
W O 97/33887 PCT~US97/04567
3228 tetrahydropyrimi 0 CO2-n-Bu H NHCbz
din-2-
ylaminomethyl
3229 tetrahydropyrimi 0 C02-i-Bu H NHCbz
din-2-
ylaminomethyl
3230 tetrahydropyrimi 0 CO2-t-Bu H NHCbz
din-2-
ylaminomethyl
3231 tetrahydropyrimi 0 H H NHCbz
din-2-
ylaminomethyl
3232 tetrahydropyrimi 0 -(CH2)4NH2 H NHCbz
din-2-
ylaminomethyl
3233 tetrahydropyrimi 0 COPh H NHCbz
din-2-
ylaminomethyl
3234 tetrahydropyrimi 0 S02-n-Bu H NHCbz
din-2-
ylaminomethyl
3235 2- 1 Cbz H NHSO2Ph
pyridinylamino-
methyl
3236 2- 1 S02Ph H NHS02Ph
pyridinylamino-
methyl
3237 2- 1CO(CH2)2Ph H NHSO2Ph
pyridinylamino-
methyl
3238 2- 1 Bn H NHSO2Ph
pyridinylamino-
methyl
-166-
CA 02249733 1998-09-11
W 097/33887 PCTrUS97/04567
3239 2- 1n-Bu H NHS02Ph
pyridinylamino-
- methyl
3240 2- 1COCH2(3- H NHS02Ph
pyridinylamino- indolyl)
methyl
3241 2- 1 S02- H NHS02Ph
pyridinylamino- ~biphenyl)
methyl
3242 2- 1 C02-n-Bu H NHS02Ph
pyridinylamino-
methyl
3243 2- 1 C02-i-Bu H NHS02Ph
pyridinylamino-
methyl
3244 2- 1 C02-t-Bu H NHS02Ph
pyridinylamino-
methyl
3245 2- 1 H H NHS02Ph
pyridinylamino-
methyl
3246 2- 1 -(CH2)4NH2 H NHS02Ph
pyridinylamino-
methyl
3247 2- 1 COPh H NHS02Ph
pyridinyla~ino-
methyl
3248 2- 1 cyclopropyl- H NHS02Ph
pyridinylamino- methyl
methyl
3249 2- 1 S02-n-Bu H NHS02Ph
pyridinylamino-
methyl
-167-
CA 02249733 l998-09-ll
W 097l33887 PCT~US97/04567
3250 2- 1 Cbz HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3251 2- 1SO2Ph HNHSO2-(2,~,6-
pyridinylamino- trimethylphen
methyl yl)
3252 2- 1CO(CH2)2Ph HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3253 2- 1 Bn HNHSO2-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3254 2- 1 n-Bu HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3255 2- 1C02-n-Bu HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3256 2- 1C02-i-Bu HNHSO2-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3257 2- 1CO2-t-Bu HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3258 2- 1 H HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3259 2- 1-(CH2)4NH2 HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3260 2- 1COPh HNHS02-(2,4,6-
pyridinylamino- trimethylphen
methyl yl~
-168-
CA 02249733 l998-09-ll
W O 97l33887 PCT~US97/04567
3261 2- 1SO2-n-Bu HNHSO2-(2,4,6-
pyridinylamino- trimethylphen
methyl yl)
3262 2- 1 Cbz HNHCbz
pyridinylamino-
methyl
3263 2- 1SO2Ph HNHCbz
pyridinylamino-
methyl
3264 2- 1CO(CH2)2Ph HNHCbz
pyridinylamino-
methyl
3265 2- 1 Bn HNHCbz
pyridinylamino-
methyl
3266 2- 1 n-Bu HNHCbz
pyridinylamino-
methyl
3267 2- 1C02-n-Bu HNHCbz
pyridinylamino-
methyl
3268 2- lCO2-i-Bu HNHCbz
pyridinylamino-
methyl
3269 2- 1CO2-t-Bu HNHCbz
pyridinylamino-
methyl
3270 2- 1 H HNHCbz
pyridinylamino-
methyl
3271 2- 1-(cH2)4NH2 HNHCbz
pyridinylamino-
methyl
-169-
CA 02249733 l998-09-ll
W 097/33887 PCTAUS97/04567
3272 2- 1COPh H NHCbz
pyridinylamino-
methyl
3273 2- 1SO2-n-Bu H NHCbz
pyridinylamino-
methyl
3274 2- 1 Cbz H NHSO2Ph
imidazolylamino-
methyl
3275 2- 1SO2Ph H NHSO2Ph
imidazolylamino-
methyl
3276 2- 1CO~CH2)2Ph H NHS02Ph
imidazolylamino-
methyl
3277 2- 1 Bn H NHSO2Ph
imidazolylamino-
methyl
3278 2- 1 n-Bu H NHSO2Ph
imidazolylamino-
methyl
327g 2- 1COCH2(3- H NHSO2Ph
imidazolylamino- indolyl)
methyl
3280 2- 1 SO2- H NHSO2Ph
imidazolylamino- (biphenyl)
methyl
3281 2- 1CO2-n-Bu H NHSO2Ph
imidazolylamino-
methyl
3282 2- 1CO2-i-Bu H NHSO2Ph
imidazolylamino-
methyl
-170-
CA 02249733 l998-09-ll
W O 97/33887 . PCT~US97/04567
3283 2- 1C02-t-Bu H NHS02Ph
imidazolylamino-
methyl
3284 2- 1 H H NHSO2Ph
imidazolylamino-
methyl
3285 2- 1-(CH2)4NH2 H NHSO2Ph
imidazolylamino~
methyl
3286 2- 1COPh H NHSO2Ph
imidazolylamino-
methyl
3287 2- 1cyclopropyl- H NHSO2Ph
imidazolylamino- methyl
methyl
3288 2- 1 SO2-n-Bu H NHSO2Ph
imidazolylamino-
methyl
3289 2- 1 Cbz H NHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3290 2- 1 S02Ph H NHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
329i 2- 1 CO(CH2)2Ph H NHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3292 2- 1 Bn H NHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3293 2- l n-Bu H NHS02-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
-171-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
3294 2- 1CO2-n-Bu HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3295 2- 1CO2-i-Bu HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3296 2- 1CO2-t-Bu HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3297 2- 1 H HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3298 2- 1-(CH2)4NH2 HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3299 2- 1COPh HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3300 2- 1SO2-n-Bu HNHSO2-(2,4,6-
imidazolylamino- trimethylphen
methyl yl)
3301 2- 1 Cbz HNHCbz
imidazolylamino-
methyl
3302 2- 1SO2Ph HNHCbz
imidazolylamino-
methyl
3303 2- 1CO(CH2)2Ph HNHCbz
imidazolylamino-
methyl
3304 2- 1 Bn HNHCbz
imidazolylamino-
methyl
-172-
CA 02249733 l998-09-ll
W O 97t33887 PCTrUS97/04~67
3305 2- 1 n-Bu H NHCbz
imidazolylamino-
methyl
3306 2- 1CO2-n-Bu H NHCbz
imidazolylamino-
methyl
3307 2- 1CO2-i-Bu H NHCbz
imidazolylamino-
methyl
3308 2- 1CO2-t-Bu H NHCbz
imidazolylamino-
methyl
3309 2- 1 H H NHCbz
imidazolylamino-
methyl
3310 2- 1-(CH2)4NH2 H NHCbz
imidazolylamino-
methyl
3311 2- 1COPh H NHCbz
imidazolylamino-
methyl
33~2 2- 1SO2-n-Bu H NHCbz
imidazolylamino-
methyl
3313 2-imidazolinyl- 1 Cbz H NHSO2Ph
aminomethyl
3314 2-imidazolinyl- 1 SO2Ph H NHSO2Ph
aminomethyl
3315 2-imidazolinyl- 1 CO(CH2)2Ph H NHSO2Ph
aminomethyl
3316 2-imidazolinyl- 1 Bn H NHSO2Ph
aminomethyl
~ 3317 2-imidazolinyl- 1 n-Bu H NHSO2Ph
aminomethyl
-173-
CA 02249733 1998-09-11
W097/33887 PCTAUS97~04567
33182-imidazolinyl- 1 COCH2(3- H NHSO2Ph
aminomethyl indolyl)
33192-imidazolinyl- 1 so2- H NHSO2Ph
aminomethyl (biphenyl)
33202-imidazolinyl- 1 CO2-n-Bu H NHSO2Ph
aminomethyl
33212-imidazolinyl- 1 CO2-i-Bu H NHSO2Ph
aminomethyl
33222-imidazolinyl- 1 CO2-t-Bu H NHSO2Ph
aminomethyl
33232-imidazolinyl- 1 H H NHSO2Ph
aminomethyl
33242-imidazolinyl- 1 -(CH2)4NH2 H NHSO2Ph
aminomethyl
33252-imidazolinyl- 1 COPh H NHSO2Ph
aminomethyl
33262-imidazolinyl- 1 cyclopropyl- H NHS02Ph
aminomethyl methyl
33272-imidazolinyl- 1 S02-n-Bu H NHS02Ph
aminomethyl
332~2-imidazolinyl- 1 Cbz H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
33292-imidazolinyl- 1 SO2Ph H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
33302-imidazolinyl- 1 CO(cH2)2Ph H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
33312-imidazolinyl- 1 Bn H NHSO2-(2,4,6-
aminomethyl trimethylphen
yl)
33322-imidazolinyl- 1 n-Bu H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
-174-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
33332-imidazolinyl- 1 CO2-n-Bu H NHS02-~2,4,6-
aminomethyl trimethylphen
yl)
33342-imidazolinyl- 1 CO2-i-Bu H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
33352-imidazolinyl- 1 CO2-t-Bu H NHS02-~2,4,6-
aminomethyl trimethylphen
yl)
33362-imidazolinyl- 1 H H NHS02-(2,4,6-
aminomethyl trimethylphen
yl)
33372-imidazolinyl- 1 -(CH2)4NH2 H NHSO2-~2,4,6-
aminomethyl trimethylphen
yl)
33382-imidazolinyl- 1 COPh H NHSO2-(2,4,6-
aminomethyl trimethylphen
yl)
33392-imidazolinyl- 1 SO2-n-Bu H NHSO2-(2,4,6-
aminomethyl trimethylphen
yl)
3340 2-imidazolinyl- 1 Cbz HNHCbz
aminomethyl
33412-imidazolinyl- 1 SO2Ph H NHCbz
aminomethyl
33422-imidazolinyl- 1 CO(CH2)2Ph H NHCbz
aminomethyl
3343 2-imidazolinyl- 1 Bn HNHCbz
aminomethyl
3344 2-imidazolinyl- 1 n-Bu HNHCbz
aminomethyl
33452-imidazolinyl- 1 CO2-n-Bu H NHCbz
aminomethyl
33462-imidazolinyl- 1 CO2-i-Bu H NHCbz
aminomethyl
-175-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
3347 2-imidazolinyl- 1C02-t-Bu H NHCbz
aminomethyl
3348 2-imidazolinyl- 1 H H NHCbz
aminomethyl
334g 2-imidazolinyl- l -(CH2)gNH2 H NHCbz
aminomethyl
3350 2-imidazolinyl- 1COPh H NHCbz
aminomethyl
33512-imidazolinyl- 1 S02-n-Bu H NHCbz
aminomethyl
3352 2- 1 Cbz H NHS02Ph
benzimidazolyl-
aminomethyl
3353 2- 1 S02Ph H NHS02Ph
benzimidazolyl-
aminomethyl
3354 2- 1CO~CH2)2Ph H NHS02Ph
benzimidazolyl-
aminomethyl
3355 2- 1 Bn H NHS02Ph
benzimidazolyl-
aminomethyl
3356 2- 1 n-Bu H NHS02Ph
benzimidazolyl-
aminomethyl
3357 2- 1 COCH2~3- H NHS02Ph
benzimidazolyl- indolyl)
aminomethyl
3358 2- 1 S02- H NHS02Ph
benzimidazolyl- (biphenyl)
aminomethyl
3359 2- 1 C02-n-Bu H NHS02Ph
benzimidazolyl-
aminomethyl
-176-
CA 02249733 l998-09-ll
W O 97/33887 PCTAUS97/04567
3360 2- 1C02-i-Bu H NHS02Ph
benzimidazolyl-
aminomethyl
3361 2- 1CO2-t-Bu H NHSO2Ph
benzimidazolyl-
aminomethyl
3362 2- 1 H H NHSO2Ph
benzimidazolyl-
aminomethyl
3363 2- 1-(CH2)4NH2 H NHSO2Ph
benzimidazolyl-
aminomethyl
3364 2- 1COPh H NHS02Ph
benzimidazolyl-
aminomethyl
3365 2- 1cyclopropyl- H NHSO2Ph
benzimidazolyl- methyl
aminomethyl
3366 2- 1SO2-n-Bu HNHSO2Ph
benzimidazolyl-
aminomethyl
3367 2- 1Cbz HNHSO2-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3368 2- 1SO2Ph HNHS02-(2,g,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3369 2- 1CO(CH2)2Ph HNHSO2-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3370 2- 1Bn HNHSO2-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
-177-
CA 02249733 l998-09-ll
W O 97/33887 PCT~US97/04567
3371 2- 1 n-Bu HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3372 2- 1CO2-n-Bu HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3373 2- 1CO2-i-Bu HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3374 2- 1CO2-t-Bu HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3375 2- 1 H HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3376 2- 1-(CH2)4NH2 HNHSO2-~2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3377 2- 1COPh HNHSO2-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3378 2- 1SO2-n-Bu HNHS02-(2,4,6-
benzimidazolyl- trimethylphen
aminomethyl yl)
3379 2- 1 Cbz HNHCbz
benzimidazolyl-
aminomethyl
3380 2- 1SO2Ph HNHCbz
benzimidazolyl-
aminomethyl
3381 2- 1CO(CH2)2Ph HNHCbz
benzimidazolyl-
aminomethyl
-178-
CA 02249733 l998-09-ll
W 0 97t33887 . PCTtUS97tO4567
3382 2- 1 Bn H NHCbz
benzimidazolyl-
aminomethyl
3383 2- 1 n-Bu H NHCbz
benzimidazolyl-
aminomethyl
3384 2- 1C02-n-Bu H NHCbz
benzimidazolyl-
aminomethyl
3385 2- 1C02-i-Bu H NHCbz
benzimidazolyl-
aminomethyl
3386 2- 1C02-t-~u H NHCbz
benzimidazolyl-
aminomethyl
3387 2- 1 H H NHCbz
benzimidazolyl-
aminomethyl
3388 2- 1-(CH2)~NH2 H NHCbz
benzimidazolyl-
aminomethyl
3389 2- 1COPh H NHCbz
benzimidazolyl-
aminomethyl
3390 2- 1S02-n-Bu H NHCbz
benzimidazolyl-
~mi n~ ~ thyl
3391 7-aza-2- 1 Cbz H NHS02Ph
benzimidazolyl
3392 7-aza-2- 1 S02Ph H NHS02Ph
benzimidazolyl
3393 7-aza-2- 1 CO(CH2)2Ph H NHS02Ph
benzimidazolyl
3394 7-aza-2- 1 Bn H NHS02Ph
- benzimidazolyl
-
-179-
CA 02249733 l998-09-ll
W 097l33887 PCT~US97/04567
3395 7-aza-2- 1n-Bu H NHS02Ph
benzimidazolyl
3396 7-aza-2- 1COCH2(3- H NHS02Ph
benzimidazolyl indolyl)
3397 7-aza-2- 1 S02- H NHS02Ph
benzimidazolyl (biphenyl)
3398 7-aza-2- 1C02-n-Bu H NHS02Ph
benzimidazolyl
3399 7-aza-2- 1C02-i-Bu H NHS02Ph
benzimidazolyl
3400 7-aza-2- 1C02-t-Bu H NHS02Ph
benzimidazolyl
3401 7-aza-2- 1 H H NHS02Ph
benzimidazolyl
3402 7-aza-2- 1-(CH2)4NH2 H NHS02Ph
benzimidazolyl
3403 7-aza-2- 1COPh H NHS02Ph
benzimidazolyl
3404 7-aza-2- 1cyclopropyl- H NHS02Ph
benzimidazolyl methyl
3405 7-aza-2- 1S02-n-Bu H NHS02Ph
benzimidazolyl
3406 7-aza-2- 1 Cbz H NHS02-(2,g,6-
benzimidazolyl trimethylphen
yl)
3407 7-aza-2- 1S02Ph H NHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
3408 7-aza-2- 1CO(CH2)2Ph H NHSO2-12~4~6-
benzimidazolyl trimethylphen
yl)
3409 7-aza-2- 1 Bn H NHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
-180-
CA 02249733 l998-09-ll
W O 97l33887 PCT~US97/04567
3410 7-aza-2- 1 n-Bu H NHSO2-~2,4,6-
benzimidazolyl trimethylphen
yl)
34117-aza-2- 1CO2-n-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphen
yl)
34127-aza-2- 1CO2-i-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
34137-aza-2- 1CO2-t-Bu HNHS02-(2,4,6-
benzimldazolyl trimethylphen
yl)
34147-aza-2- 1 H HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
34157-aza-2- 1-(CH2)4NH2 HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
34167-aza-2- 1COPh HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
34177-aza-2- 1S02-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphen
yl)
34187-aza-2- 1 Cbz HNHCbz
benzlmidazolyl
34197-aza-2- 1SO2Ph HNHCbz
benzimidazolyl
34207-aza-2- 1CO(CH2)2Ph HNHCbz
benzimidazolyl
34217-aza-2- 1 Bn HNHCbz
benzimidazolyl
34227-aza-2- 1 n-Bu HNHCbz
benzimidazolyl
-181-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
3423 7-aza-2- 1C02-n-Bu H NHCbz
benzimidazolyl
3424 7-aza-2- 1C02-i-Bu H NHCbz
benzimidazolyl
3425 7-aza-2- 1C02-t-Bu H NHCbz
benzimidazolyl
3426 7-aza-2- 1 H H NHCbz
benzimidazolyl
3427 7-aza-2- 1-(CH2)4NH2 H NHCbz
benzimidazolyl
3428 7-aza-2- 1COPh H NHCbz
benzimidazolyl
3429 7-aza-2- 1S02-n-Bu H NHCbz
benzimidazolyl
3430 tetrahydropyrimi 1 Cbz H NHS02Ph
din-2-
ylaminomethyl
3431 tetrahydropyrimi 1 S02Ph H NHS02Ph
din-2-
ylaminomethyl
3432 tetrahydropyrimi 1 CO(cH2)2Ph H NHS02Ph
din-2-
ylaminomethyl
3433 tetrahydropyrimi 1 Bn H NHS02Ph
din-2-
ylaminomethyl
3434 tetrahydropyrimi 1 n-Bu H NHS02Ph
din-2-
ylaminomethyl
3435 tetrahydropyrimi 1 CoCH2(3- H NHS02Ph
din-2- indolyl)
ylaminomethyl
3436 tetrahydropyrimi 1 S02- H NHS02Ph
din-2- (biphenyl)
ylaminomethyl
-182-
CA 02249733 l998-09-ll
W 097/33887 PCT~US97/04567
3437 tetrahydropyrimi 1CO2-n-Bu H NHSO2Ph
din-2-
- ylaminomethyl
3438 tetrahydropyrimi 1CO2-i-Bu H NHSO2Ph
din-2-
ylaminomethyl
3439 tetrahydropyrimi 1CO2-t-Bu H NHSO2Ph
din-2-
ylaminomethyl
3440 tetrahydropyrimi 1 H H NHS02Ph
din-2-
ylaminomethyl
3441 tetrahydropyrimi 1-(CH2)4NH2 H NHSO2Ph
din-2-
ylaminomethyl
3442 tetrahydropyrimi 1COPh H NHS02Ph
din-2-
ylaminomethyl
3443 tetrahydropyrimi 1 cyclopropyl- H NHSO2Ph
din-2- methyl
ylaminomethyl
3444 tetrahydropyrimi 1SO2-n-Bu HNHSO2Ph
din-2-
ylaminomethyl
3445 tetrahydropyrimi 1 Cbz HNHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3446 tetrahydropyrimi 1SO2Ph HNHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3447 tetrahydropyrimi 1CO(cH2)2Ph HNHS02-(2,4,6-
din-2- trimethylphen
- ylaminomethyl yl)
-183-
CA 02249733 l998-09-ll
W O 97/33887 PCT~US97104567
3448 tetrahydropyrimi 1 Bn H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3449 tetrahydropyrimi 1 n-Bu H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3450 tetrahydropyrimi 1 C02-n-Bu H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3451 tetrahydropyrimi 1 C02-i-Bu H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3452 tetrahydropyrimi 1 C02-t-Bu H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3453 tetrahydropyrimi 1 H H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3454 tetrahydropyrimi 1 -(CH2)4NH2 H NHS02-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3455 tetrahydropyrimi 1 COPh H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3456 tetrahydropyrimi 1 SO2-n-Bu H NHSO2-(2,4,6-
din-2- trimethylphen
ylaminomethyl yl)
3457 tetrahydropyrimi 1 Cbz HNHCbz
din-2-
ylaminomethyl
3458 tetrahydropyrimi 1 S02Ph H NHCbz
din-2-
ylaminomethyl
-184-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
3459 tetrahydropyrimi 1 CO(CH2)2Ph H NHCbz
din-2-
ylaminomethyl
3460 tetrahydropyrimi 1Bn H NHCbz
din-2-
ylaminomethyl
3461 tetrahydropyrimi 1n-Bu H NHCbz
din-2-
ylaminomethyl
3462 tetrahydropyrimi 1 C02-n-Bu H NHCbz
din-2-
ylaminomethyl
3463 ~etrahydropyrimi 1 C02-i-Bu H NHCbz
din-2-
ylaminomethyl
3464 tetrahydropyrimi 1 C02-t-Bu H NHCbz
din-2-
ylaminomethyl
3465 tetrahydropyrimi 1 H H NHCbz
din-2-
ylaminomethyl
3466 tetrahydropyrimi 1 -(CH2)4NH2 H NHCbz
din-2-
ylaminomethyl
346i tetrahydropyrimi 1COPh H NHCbz
din-2-
ylaminomethyl
3468 imidazol-2- 0C02Me H NHS02-(2,4,6- 592.4
ylaminomethyl trimethylphen
yl)
3469 benzamidazol-2- 0 Bn H NHS02-(2,4,6- 674.3
ylaminomethyl trimethylphen
yl)
-185-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
3470benzamidazol-2- 0CO2Me HNHSO2-(2,4,6- 642.3
ylaminomethyl trimethylphen
yl)
3471benzamidazol-2- 0CO2Bu HNHSO2-~2,4,6- 684.4
ylaminomethyl trimethylphen
yl)
3472imidazol-2- 0CO2CH2~3- HNHSO2-~2,4,6- 669.4
ylaminomethyl pyr) trimethylphen
yl)
3473imidazol-2- 0 H HNHSO2-(2,6- 520.3
ylaminomethyl trimethylphen
yl)
3474imidazol-2- 0 H HNHS02biphenyl 568.3
ylaminomethyl
3475imidazolin-2- 0 Cbz HNHSO2(2- 678.1
ylaminomethyl naphthyl
3476imidazolin-2- 0 H HNHSO2biphenyl 570.2
ylaminomethyl
-186-
CA 02249733 1998-09-ll
W 097l33887 PCT~US97/04567
Tabl e 4
O Rl4 0
R1~
E~- Bl L gl~ ~14 Bl5
~Q-
40012-pyridinylamino- 0 Cbz H NHSO2Ph
methyl
40022-pyridinylamino- ~ S02Ph H NHS02Ph
methyl
40032-pyridinylamino- oCO(CH2)2Ph H NHSO2Ph
methyl
40042-pyridinylamino- 0 Bn H NHS02Ph
methyl
40052-pyridinylamino- 0 n-Bu H NHS02Ph
methyl
40062-pyridinylamino- 0COCH2(3- H NHSO2Ph
methyl indolyl)
40072-pyridinylamino- 0 S02- H NHS02Ph
methyl (biphenyl)
40082-pyridinylamino- 0C02-n-Bu H NHS02Ph
methyl
40092-pyridinylamino- 0CO2-i-Bu H NHSO2Ph
methyl
40102-pyridinylamino- 0C02-t-Bu H NHSO2Ph
methyl
40112-pyridinylamino- 0 H H NHS02Ph
methyl
40122-pyridinylamino- 0-(CH2)4NH2 H NHSO2Ph
methyl
-187-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
4013 2-pyridinylamino- 0 COPh H NHSO2Ph
methyl
4014 2-pyridinylamino- 0cyclopropy H NHSO2Ph
methyl l-methyl
4015 2-pyridinylamino- 0SO2-n-Bu H NHSO2Ph
methyl
4016 2-pyridinylamino- 0 Cbz H NHSO2-(2,4,6-
methyl trimethylphenyl)
4017 2-pyridinylamino- o SO2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
4018 2-pyridinylamino- oCO(CH2)2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
4019 2-pyridinylamino- 0 Bn H NHS02-(2,4,6-
methyl trimethylphenyl)
4020 2-pyridinylamino- 0 n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
4021 2-pyridinylamino- 0CO2-n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
4022 2-pyridinylamino- 0C02-i-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
4023 2-pyridinylamino- 0CO2-t-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
4024 2-pyridinylamino- 0 H H NHSO2-(2,4,6-
methyl trimethylphenyl)
4025 2-pyridinylamino- 0-(CH2)4NH2 H NHSO2-(2,4,6-
methyl trimethylphenyl)
4026 2-pyridinylamino- 0 COPh H NHS02-(2,4,6-
methyl trimethylphenyl)
4027 2-pyridinylamino- 0SO2-n-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
4028 2-pyridinylamino- 0 Cbz H NHCbz
methyl
4029 2-pyridinylamino- oSO2Ph H NHCbz
methyl
-188-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
4030 2-pyridinylamino- 0 CO(CH2)2Ph H NHCbz
methyl
4031 2-pyridinylamino- 0 Bn H NHCbz
methyl
4032 2-pyridinylamino- 0 n-Bu H NHCbz
methyl
4033 2-pyridinylamino- 0 CO2-n-Bu H NHCbz
methyl
4034 2-pyridinylamino- 0 CO2-i-Bu H NHCbz
methyl
4035 2-pyridinylamino- 0 CO2-t-Bu H NHCbz
methyl
4036 2-pyridinylamino- 0 H H NHCbz
methyl
4037 2-pyridinylamino- 0 -(CH2~4NH2 H NHCbz
methyl
4038 2-pyridinylamino- 0 COPh H NHCbz
methyl
4039 2-pyridinylamino- 0 SO2-n-Bu H NHCbz
methyl
4040 2-imidazolylamino- 0 Cbz H NHSO2Ph
methyl
4041 2-imidazolylamino- 0 S02Ph H NHS02Ph
methyl
4042 2-imidazolylamino- 0 CO(CH2)2Ph H NHSO2Ph
methyl
4043 2-imidazolylamino- 0 Bn H NHS02Ph
methyl
4044 2-imidazolylamino- 0 n-Bu H NHSO2Ph
methyl
4045 2-imidazolylamino- 0 COCH2(3- H NHSO2Ph
methyl indolyl)
4046 2-imidazolylamino- 0 S02- H NHSO2Ph
methyl (biphenyl)
-189-
CA 02249733 l998-09-ll
W 097/33887 PCTAUS97/04567
4047 2-imidazolylamino- 0 CO2-n-Bu H NHSO2Ph
methyl
4048 2-imidazolylamino- 0 CO2-i-Bu H NHSO2Ph
methyl
4049 2-imidazolylamino- 0 CO2-t-Bu H NHSO2Ph
methyl
4050 2-imidazolylamino- 0 H H NHSO2Ph
methyl
4051 2-imidazolylamino- 0 -(CH2)4NH2 H NHSO2Ph
methyl
4052 2-imidazolylamino- 0 COPh H NHS02Ph
methyl
4053 2-imidazolylamino- 0 cyclopropy H NHSO2Ph
methyl l-methyl
4054 2-imidazolylamino- 0 SO2-n-Bu H NHSO2Ph
methyl
4055 2-imidazolylamino- 0 Cbz H NHS02-(2,4,6-
methyl trimethylphenyl)
4056 2-imidazolylamino- 0 S02Ph H NHS02-(2,4,6-
methyl trimethylphenyl)
4057 2-imidazolylamino- o CO(CH2)2Ph H NHS02-(2,4,6-
methyl trimethylphenyl)
4058 2-imidazolylamino- 0 Bn H NHS02-(2,4,6-
methyl trimethylphenyl)
4059 2-imidazolylamino- 0 n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
4060 2-imidazolylamino- 0 C02-n-Bu H NHS02-(2,4,6- methyl trimethylphenyl)
4061 2-imidazolylamino- 0 CO2-i-Bu H NHS02-(2,4,6- methyl trimethylphenyl)
4062 2-imidazolylamino- 0 CO2-t-Bu H NHSO2-(2,4,6- methyl trimethylphenyl)
4063 2-imidazolylamino- 0 H H NHS02-(2,4,6-
methyl trimethylphenyl)
-190-
CA 02249733 l998-09-ll
W O 97l33887 PCTAUS97/04567
40642-imidazolylamino- o -(CH2)4NH2 H NHS02-(2,4,6-
methyl trimethylphenyl)
40652-imidazolylamino- 0 COPh H NHSO2-(2,4,6-
methyl trimethylphenyl)
40662-imidazolylamino- 0 SO2-n-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
4067 2-imidazolylamino- 0 Cbz H NHCbz
methyl
40682-imidazolylamino- 0 SO2Ph H NHCbz
methyl
40692-imidazolylamino- 0 CO~CH2)2Ph H NHCbz
methyl
4070 2-imidazolylamino- 0 Bn H NHCbz
methyl
4071 2-imidazolylamino- 0 n-Bu H NHCbz
methyl
40722-imidazolylamino- 0 CO2-n-Bu H NHCbz
methyl
40732-imidazolylamino- 0 CO2-i-Bu H NHCbz
methyl
40742-imidazolylamino- 0 C02-t-Bu H NHCbz
methyl
4075 2-imidazolylamino- 0 H H NHCbz
methyl
4076 2-imidazolylamino- 0 -(CH2)4NH2 H NHCbz
methyl
4077 2-imidazolylamino- 0 COPh H NHCbz
methyl
40782-imidazolylamino- 0 SO2-n-Bu H NHCbz
methyl
40792-imidazolinyl- 0 Cbz HNHSO2Ph
aminomethyl
40802-imidazolinyl- ~ SO2Ph HNHSO2Ph
aminomethyl
-191-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
4081 2-imidazolinyl- 0Cc(cH2)2ph HNHSO2Ph
aminomethyl
4082 2-imidazolinyl- 0Bn HNHSO2Ph
aminomethyl
4083 2-imidazolinyl- 0n-Bu HNHS02Ph
aminomethyl
4084 2-imidazolinyl- 0COCH2(3- HNHS02Ph
aminomethyl indolyl)
4085 2-imidazolinyl- 0S02- HNHSO2Ph
aminomethyl (biphenyl)
4086 2-imidazolinyl- 0CO2-n-Bu HNHSO2Ph
aminomethyl
4087 2-imidazolinyl- 0CO2-i-Bu HNHSO2Ph
aminomethyl
4088 2-imidazolinyl- 0CO2-t-Bu HNHSO2Ph
aminomethyl
4089 2-imidazolinyl- 0 H HNHSO2Ph
aminomethyl
4090 2-imidazolinyl- Q-(CH2)4NH2 HNHSO2Ph
aminomethyl
4091 2-imidazolinyl- 0COPh HNHSO2Ph
aminomethyl
4092 2-imidazolinyl- 0cyclopropy HNHSO2Ph
aminomethyl l-methyl
4093 2-imidazolinyl- 0SO2-n-Bu HNHSO2Ph
aminomethyl
4094 2-imidazolinyl- 0Cbz HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
4095 2-imidazolinyl- ~SO2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
4096 2-imidazolinyl- 0CO(CH2)2Ph HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
4097 2-imidazolinyl- 0Bn HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
-192-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
4098 2-imidazolinyl- 0n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
4099 2-imidazolinyl- 0CO2-n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
4100 2-imidazolinyl- 0Co2-i-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
4101 2-imidazolinyl- 0CO2-t-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
4102 2-imidazolinyl- 0 H HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
4103 2-imidazolinyl- 0-(CH2)4NH2 HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
4104 2-imidazolinyl- 0COPh HNHSO2-(2,4,6-
~ino -thyl trimethylphenyl)
4105 2-imidazolinyl- 0SO2-n-Bu HMHS02-(2,4,6-
aminomethyl trimethylphenyl)
4106 2-imidazolinyl- 0 Cbz HNHCbz
aminomethyl
4107 2-imidazolinyl- 0SO2Ph HNHCbz
aminomethyl
4108 2-imidazolinyl- oCO(CH2)2Ph HNHCbz
aminomethyl
4109 2-imidazolinyl- 0 Bn HNHCbz
aminomethyl
4110 2-imidazolinyl- 0 n-Bu HNHCbz
aminomethyl
4111 2-imidazolinyl- 0CO2-n-Bu HNHCbz
aminomethyl
4112 2-imidazolinyl- 0CO2-i-Bu HNHCbz
aminomethyl
4113 2-imidazolinyl- 0CO2-t-Bu HNHCbz
aminomethyl
4114 2-imidazolinyl- 0 H HNHCbz
aminomethyl
-193-
CA 02249733 l998-09-ll
WO 97/33887 PCTAUS97/04567
41152-imidazolinyl- 0-(CH2)4NH2 H NHCbz
aminomethyl
41162-imidazolinyl- 0COPh H NHCbz
aminomethyl
41172-imidazolinyl- 0SO2-n-Bu H NHCbz
aminomethyl
4118 2-benzimidazolyl- 0 Cbz H NHSO2Ph
aminomethyl
4119 2-benzimidazolyl- 0 S02Ph H NHSO2Ph
aminomethyl
4120 2-benzimidazolyl- 0 CO(CH2)2Ph H NHSO2Ph
aminomethyl
4121 2-benzimidazolyl- 0 Bn H NHSO2Ph
aminomethyl
4122 2-benzimidazolyl- 0 n-Bu H NHSO2Ph
aminomethyl
4123 2-benzimidazolyl- 0 COCH2(3- H NHSO2Ph
aminomethyl indolyl)
4124 2-benzimidazolyl- 0 S02- H NHSO2Ph
aminomethyl (biphenyl)
4125 2-benzimidazolyl- 0 CO2-n-Bu H NHSO2Ph
aminomethyl
4126 2-benzimidazolyl- 0 CO2-i-Bu H NHSO2Ph
aminomethyl
4127 2-benzimidazolyl- 0 CO2-t-Bu H NHSO2Ph
aminomethyl
4128 2-benzimidazolyl- 0 H H NHSO2Ph
aminomethyl
4129 2-benzimidazolyl- 0 -(CH2)4NH2 H NHSO2Ph
aminomethyl
4130 2-benzimidazolyl- 0 COPh H NHSO2Ph
aminomethyl
4131 2-benzimidazolyl- 0 cyclopropy H NHSO2Ph
aminomethyl l-methyl
-194-
CA 02249733 l998-09-ll
W O 97/33887 PCT~US97/04S67
41322-benzimidazolyl- 05O2-n-Bu HNHSO2Ph
aminomethyl
- 41332-benzimidazoly-l- 0Cbz HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
41342-benzimidazolyl- 0SO2Ph HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
41352-benzimidazolyl- 0CO(CH2)2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
41362-benzimidazolyl- 0Bn HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
41372-benzimidazolyl- 0n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
41382-benzimidazolyl- 0CO2-n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
41392-benzimidazolyl- 0CO2-i-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
41402-benzimidazolyl- 0CO2-t-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
41412-benzimidazolyl- 0 H HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
41422-benzimidazolyl- 0-(CH2)4NH2 HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
41432-benzimidazolyl- 0COPh HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
41442-benzimidazolyl- 0SO2-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
4145 2-benzimidazolyl- 0 Cbz H NHCbz
aminomethyl
4146 2-benzimidazolyl- ~ SO2Ph H NHCbz
aminomethyl
4147 2-benzimidazolyl- 0 CO(CH2)2ph H NHCbz
aminomethyl
4148 2-benzimidazolyl- 0 Bn H NHCbz
aminomethyl
-lg5-
CA 02249733 l998-09-ll
W O 97/33887 PCTAUS97104567
4149 2-benzimidazolyl- 0n-Bu H NHCbz
aminomethyl
4150 2-benzimidazolyl- 0 C02-n-Bu H NHCbz
aminomethyl
4151 2-benzimidazolyl- 0 C02-i-Bu H NHCbz
aminomethyl
4152 2-benzimidazolyl- 0 C02-t-Bu H NHCbz
aminomethyl
4153 2-benzimidazolyl- 0 H H NHCbz
aminomethyl
4154 2-benzimidazolyl- 0-(CH2)4NH2 H NHCbz
aminomethyl
4155 2-benzimidazolyl- 0COPh H - NHCbz
aminomethyl
4156 2-benzimidazolyl- 0 S02-n-Bu H NHCbz
aminomethyl
4157 7-aza-2- 0 Cbz H NHS02Ph
benzimidazolyl
4158 7-aza-2- ~ S02Ph H NHS02Ph
benzimidazolyl
4159 7-aza-2- 0 CO(CH2)2Ph H NHS02Ph
benzimidazolyl
4160 7-aza-2- 0 Bn H NHS02Ph
benzimidazolyl
4161 7-aza-2- 0 n-Bu H NHS02Ph
benzimidazolyl
4162 7-aza-2- 0 COCH2(3- H NHS02Ph
benzimidazolyl indolyl)
4163 7-aza-2- 0 S02- H NHS02Ph
benzimidazolyl (biphenyl)
4164 7-aza-2- 0 C02-n-Bu H NHS02Ph
benzimidazolyl
4165 7-aza-2- 0 C02-i-Bu H NHS02Ph
benzimidazolyl
-196-
CA 02249733 l998-09-ll
W O 97l33887 PCTAUS97/04567
4166 7-aza-2- 0CO2-t-Bu HNHSO2Ph
benzimidazolyl
4167 7-aza-2- 0 H HNHSO2Ph
benzimidazolyl
4168 7-aza-2- 0-(CH2)4NH2 HNHSO2Ph
benzimidazolyl
4169 7-aza-2- 0COPh HNHSO2Ph
benzimidazolyl
4170 7-aza-2- 0cyclopropy HNHSO2Ph
benzimidazolyl l-methyl
4171 7-aza-2- 0SO2-n-Bu HNHSO2Ph
benzimidazolyl
4172 7-aza-2- 0 Cbz HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4173 7-aza-2- 0SO2Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4174 7-aza-2- 0CO(CH2)2Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4175 7-aza-2- 0 Bn HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4176 7-aza-2- 0 n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4177 7-aza-2- 0CO2-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4178 7-aza-2- 0CO2-i-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4179 7-aza-2- 0CO2-t-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4180 7-aza-2- 0 H HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4181 7-aza-2- 0-(CH2)sNH2 HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4182 7-aza-2- 0COPh HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
-
-197-
CA 02249733 l998-09-ll
W 097l33887 PCT~US97/04S67
4183 7-aza-2- oSO2-n-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl~
4184 7-aza-2- 0Cbz HNHCbz
benzimidazolyl
4185 7-aza-2- 0SO2Ph HNHCbz
benzimidazolyl
4186 7-aza-2- oCO(CH2)2Ph HNHCbz
benzimidazolyl
4187 7-aza-2- 0Bn HNHCbz
benzimidazolyl
4188 7-aza-2- 0n-Bu HNHCbz
benzimidazolyl
4189 7-aza-2- 0C02-n-Bu HNHCbz
benzimidazolyl
4190 7-aza-2- 0CO2-i-Bu HNHCbz
benzimidazolyl
4191 7-aza-2- 0CO2-t-Bu HNHCbz
benzimidazolyl
4192 7-aza-2- 0 H HNHCbz
benzimidazolyl
4193 7-aza-2- 0-(CH2)4NH2 HNHCbz
benzimidazolyl
4194 7-aza-2- 0COPh HNHCbz
benzimidazolyl
4195 7-aza-2- 0SO2-n-Bu HNHCbz
benzimidazolyl
4196 tetrahydropyrimidin 0 Cbz H NHS02Ph
-2-ylaminomethyl
4197 tetrahydropyrimidin 0 SO2Ph H NHSO2Ph
-2-ylaminomethyl
4198 tetrahydropyrimidin 0 COtCH2)2Ph H NHSO2Ph
-2-ylaminomethyl
4199 tetrahydropyrimidin 0 Bn H NHSO2Ph
-2-ylaminomethyl
-198-
CA 02249733 l998-09-ll
W O 97/33887 PCTAUS97/04567
4200 tetrahydropyrimidin 0 n-Bu H NHSO2Ph
-2-ylaminomethyl
4201 tetrahydropyrimidin 0 COCH2(3- H NHSO2Ph
-2-ylaminomethyl indolyl)
4202 tetrahydropyrimidin 0 S02- H NHSO2Ph
-2-ylaminomethyl (biphenyl)
g203 tetrahydropyrimidin 0 CO2-n-Bu HNHSO2Ph
-2-ylaminomethyl
4204 tetrahydropyrimidin 0 CO2-i-Bu H NHSO2Ph
-2-ylaminomethyl
4205 tetrahydropyrimidin 0 CO2-t-Bu H NHSO2Ph
- -2-ylaminomethyl
4206 tetrahydropyrimidin 0 H H NHSO2Ph
-2-ylaminomethyl
4207 tetrahydropyrimidin 0 -(CH2)4NH2 H NHSO2Ph
-2-ylaminomethyl
4208 tetrahydropyrimidin 0 COPh H NHSO2Ph
-2-ylaminomethyl
4209 tetrahydropyrimidin 0 cyclopropy H NHSO2Ph
-2-ylaminomethyl l-methyl
4210 tetrahydropyrimidin 0 SO2-n-Bu H NHSO2Ph
-2-ylaminomethyl
4211 tetrahydropyrimidin 0 Cbz H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4212 tetrahydropyrimidin 0 SO2Ph H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4213 tetrahydropyrimidin o CO(CH2)2Ph H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4214 tetrahydropyrimidin 0 Bn H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4215 tetrahydropyrimidin 0 n-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4216 tetrahydropyrimidin 0 CO2-n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
-199-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
4217 tetrahydropyrimidin oC02-i-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4218 tetrahydropyrimidin 0CO2-t-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4219 tetrahydropyrimidin 0 H H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4220 tetrahydropyrimidin 0-(CH2)4NH2 H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4221 tetrahydropyrimidin 0COPh H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4222 tetrahydropyrimidin 0SO2-n-Bu H NHS02-(2,g,6-
-2-ylaminomethyl trimethylphenyl)
g223 tetrahydropyrimidin 0 Cbz H NHCbz
-2-ylaminomethyl
4224 tetrahydropyrimidin 0 SO2Ph H NHCbz
-2-ylaminomethyl
4225 tetrahydropyrimidin 0 CO(CH2)2Ph H NHCbz
-2-ylaminomethyl
4226 tetrahydropyrimidin 0 Bn H NHCbz
-2-ylaminomethyl
4227 tetrahydropyrimidin 0 n-Bu H NHCbz
-2-ylaminomethyl
4228 tetrahydropyrimidin 0 CO2-n-Bu HNHCbz
-2-ylaminomethyl
4229 tetrahydropyrimidin 0 CO2-i-Bu HNHCbz
-2-ylaminomethyl
4230 tetrahydropyrimidin 0 CO2-t-Bu HNHCbz
-2-ylaminomethyl
4231 tetrahydropyrimidin 0 H H NHCbz
-2-ylaminomethyl
4232 tetrahydropyrimidin 0 -(CH2)4NH2 H NHCbz
-2-ylaminomethyl
4233 tetrahydropyrimidin 0 COPh H NHCbz
-2-ylaminomethyl
-200-
CA 02249733 l998-09-ll
WO 97l33887 PCTAUS97/04567
4234 tetrahydropyrimidin o S02-n-Bu H NHCbz
-2-ylaminomethyl
4235 2-pyridlnylamino- 1 Cbz H NHS02Ph
methyl
4236 2-pyridinylamino- 1 S02Ph H NHS02Ph
methyl
4237 2-pyridinylamino- 1 CO(CH2)2Ph H NHS02Ph
methyl
4238 2-pyridinylamino- 1 Bn H NHS02Ph
methyl
4239 2-pyridinylamino- 1 n-Bu H NHS02Ph
methyl
4240 2-pyridinylamino- 1 COCH2(3- H NHS02Ph
methyl indolyl)
4241 2-pyridinylamino- 1 S02- H NHS02Ph
methyl (biphenyl)
4242 2-pyridinylamino- 1 C02-n-Bu H NHS02Ph
methyl
4243 2-pyridinylamino- 1 C02-i-Bu H NHS02Ph
methyl
4244 2-pyridinylamino- 1 C02-t-Bu H NHS02Ph
methyl
4245 2-pyridinylamino- 1 H H NHS02Ph
methyl
4246 2-pyridinylamino- l -(CH2)4NH2 H NHS02Ph
methyl
4247 2-pyridinylamino- 1 COPh H NHS02Ph
methyl
4248 2-pyridinylamino- 1 cyclopropy H NHS02Ph
methyl l-methyl
4249 2-pyridinylamino- 1 S02-n-Bu H NHS02Ph
methyl
4250 2-pyridinylamino- 1 Cbz H NHS02-(2,4,6-
methyl trimethylphenyl)
-201-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
42512-pyridinylamlno- 1 SO2Ph HNHS02-(2,4,6-
methyl trimethylphenyl)
42522-pyridinylamino- 1CO(CH2)2Ph HNHS02-~2,4,6-
methyl trimethylphenyl)
42532-pyridinylamino- 1 Bn HNHS02-(2,4,6-
methyl trimethylphenyl)
42542-pyridinylamino- 1 n-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
42552-pyridinylamino- 1 CO2-n-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
42562-pyridinylamino- 1 CO2-i-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
42572-pyridinylamino- 1 CO2-t-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
42582-pyridinylamino- 1 H HNHSO2-(2,4,6-
methyl trimethylphenyl)
42592-pyridinylamino- 1-(CH2)~NH2 HNHS02-(2,4,6-
methyl trimethylphenyl)
42602-pyridinylamino- 1 COPh HNHS02-(2,4,6-
methyl trimethylphenyl)
42612-pyridinylamino- l SO2-n-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
4262 2-pyridinylamino- 1Cbz H NHCbz
methyl
42632-pyridinylamino- 1 SO2Ph HNHCbz
methyl
42642-pyridinylamino- 1CO(CH2)2ph HNHCbz
methyl
4265 2-pyridinylamino- 1Bn H NHCbz
methyl
4266 2-pyridinylamino- 1n-Bu H NHCbz
methyl
4267 2-pyridinylamino- 1CO2-n-Bu H NHCbz
methyl
-202-
CA 02249733 l998-09-ll
W 097/33887 PCTtUS97tO4567
4268 2-pyridinylamino- 1C02-i-Bu H NHCbz
methyl
-4269 2-pyridinylamino- 1C02-t-Bu H NHCbz
methyl
4270 2-pyridinylamino- 1 H H NHCbz
methyl
4271 2-pyridinylamino- 1 -~CH2)4NH2 H NHCbz
methyl
4272 2-pyridinylamino- 1 COPh H NHCbz
methyl
42732-pyridinylamino- 1S02-n-Bu H NHCbz
methy~
42742-imidazolylamino- 1Cbz H NHS02Ph
methyl
42752-imidazolylamino- 1S02Ph H NHS02Ph
methyl
42762-imidazolylamino- 1CO(CH2)2Ph H NHS02Ph
methyl
42772-imidazolylamino- 1Bn H NHS02Ph
methyl
42782-imidazolylamino- 1n-Bu H NHS02Ph
methyl
42792-imidazolylamino- 1COCH2(3- H NHS02Ph
methyl indolyl)
42802-imidazolylamino- 1so2- H NHS02Ph
methyl (biphenyl)
42812-imidazolylamino- 1C02-n-Bu H NHS02Ph
methyl
42822-imidazolylamino- 1C02-i-Bu H NHS02Ph
methyl
42832-imidazolylamino- 1C02-t-Bu H NHS02Ph
methyl
42842-imidazolylamino- 1 H H NHS02Ph
methyl
-203-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
4285 2-imidazolylamino~ CH2)4NH2 H NHS02Ph
methyl
4286 2-imidazolylamlno- 1COPh H NHSO2Ph
methyl
4287 2-imidazolylamino- 1cyclopropy H NHSO2Ph
methyl l-methyl
4288 2-imidazolylamino- 1SO2-n-Bu H NHSO2Ph
methyl
4289 2-imidazolylamino- 1 Cbz H NHS02-(2,4,6-
methyl trimethylphenyl)
4290 2-imidazolylamino- 1SO2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl~
42gl 2-imidazolylamino- 1CO(CH2~2Ph H NHS02-(2,4,6-
methyl trimethylphenyl)
4292 2-imidazolylamino- 1 Bn H NHSO2-(2,4,6-
methyl trimethylphenyl)
4293 2-imidazolylamino- 1 n-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
4294 2-imidazolylamino- 1CO2-n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
4295 2-imidazolylamino- 1C02-i-~3u H NHS02-(2,4,6-
methyl trimethylphenyl)
4296 2-imidazolylamino- 1CO2-t-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
4297 2-imidazolylamino- 1 H H NHSO2-(2,4,6-
methyl trimethylphenyl)
42g8 2-imidazolylamino- 1-(CH2)4NH2 H NHSO2-(2,4,6-
methyl trimethylphenyl)
4299 2-imidazolylamino- 1COPh H NHS02-(2,4,6-
methyl trimethylphenyl)
4300 2-imidazolylamino- 1SO2-n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
4301 2-imidazolylamino- 1Cbz H NHCbz
methyl
-204-
CA 02249733 l998-09-ll
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4302 2-imidazolylamino- 1 SO2Ph H NHCbz
methyl
4303 2-imidazolylamino- 1 COtCH2)2Ph H NHCbz
methyl
4304 2-imidazolylamino- 1 Bn H NHCbz
methyl
4305 2-imidazolylamino- 1 n-Bu H NHCbz
methyl
4306 2-imidazolylamino- 1CO2-n-Bu H NHCbz
methyl
4307 2-imidazolylamino- l CO2-i-Bu H NHCbz
methyl
4308 2-imidazolylamino- 1CO2-t-Bu H NHCbz
methyl
4309 2-imidazolylamino- 1 H H NHCbz
methyl
4310 2-imidazolylamino- 1-(CH2)4NH2 H NHCbz
methyl
4311 2-imidazolylamino- 1COPh H NHCbz
methyl
4312 2-imidazolylamino- 1 SO2-n-Bu H NHCbz
methyl
4313 2-imidazolinyl- 1 Cbz H NHS02Ph
aminomethyl
4314 2-imidazolinyl- 1 S02Ph H NHS02Ph
aminomethyl
4315 2-imidazolinyl- 1 CO(CH2)2Ph H NHS02Ph
aminomethyl
4316 2-imidazolinyl- 1 Bn H NHSO2Ph
aminomethyl
4317 2-imidazolinyl- 1 n-Bu H NHSO2Ph
aminomethyl
4318 2-imidazolinyl- 1 COCH2(3- H NHSO2Ph
aminomethyl indolyl)
-205-
CA 02249733 l998-09-ll
W 097l33887 PCTrUS97/04567
43192-imidazolinyl- 1 SO2- H NHSO2Ph
aminomethyl (biphenyl)
43202-imidazolinyl- lCO2-n-Bu H NHSO2Ph
aminomethyl
43212-imidazolinyl- 1CO2-i-Bu H NHSO2Ph
aminomethyl
43222-imidazolinyl- 1CO2-t-Bu H NHS02Ph
aminomethyl
43232-imidazolinyl- 1 H H NHS02Ph
aminomethyl
43242-imidazolinyl- 1-~CH2)4NH2 H NHSO2Ph
aminomethyl
43252-imidazolinyl- 1COPh H NHS02Ph
aminomethyl
43262-imidazolinyl- 1cyclopropy H NHS02Ph
aminomethyl l-methyl
43272-imidazolinyl- 1S02-n-Bu H NHS02Ph
aminomethyl
43282-imidazolinyl- 1 Cbz H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
43292-imidazolinyl- 1SO2Ph H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
43302-imidazolinyl- 1CO(CH2)2Ph H NHSO2-(2,4,6-
aminomethyl trimethylphenyl~
43312-imidazolinyl- 1 Bn H NHSO2-(2,4,6-
aminomethyl trimethylphenyl)
43322-imidazolinyl- 1 n-Bu H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
43332-imidazolinyl- 1C02-n-Bu H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
43342-imidazolinyl- 1C02-i-Bu H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
43352-imidazolinyl- 1CO2-t-Bu H NHSO2-(2,4,6-
aminomethyl trimethylphenyl)
-206-
CA 02249733 l998-09-ll
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43362-imidazolinyl- 1 H HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
43372-imidazolinyi- 1-(CH2)4NH2 HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
43382-imidazolinyl- 1COPh HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
43392-imidazolinyl- 1SO2-n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
4340 2-imidazolinyl- 1Cbz HNHCbz
aminomethyl
43412-imidazolinyl- 1SO2Ph HNHCbz
aminomethyl
43422-imidazolinyl- 1CO(CH2)2Ph HNHCbz
aminomethyl
43432-imidazolinyl- 1 Bn HNHCbz
aminomethyl
4344 2-imidazolinyl- 1n-Bu HNHCbz
aminomethyl
43452-imidazolinyl- 1CO2-n-Bu HNHCbz
aminomethyl
43462-imidazolinyl- 1CO2-i-Bu HNHCbz
aminomethyl
43472-imidazolinyl- 1CO2-t-Bu HNHCbz
aminomethyl
43482-imidazolinyl- 1 H HNHCbz
aminomethyl
43492-imidazolinyl- 1-(CH2)4NH2 HNHCbz
aminomethyl
4350 2-imidazolinyl- 1COPh HNHCbz
aminomethyl
43512-imidazolinyl- 1SO2-n-Bu HNHCbz
aminomethyl
43522-benzimidazolyl- 1 Cbz HNHSO2Ph
aminomethyl
-207-
CA 02249733 l998-09-ll
W 097l33887 PCTrUS97/04567
4353 2-benzimidazolyl- 1 S02Ph H NHS02Ph
aminomethyl
4354 2-benzimidazolyl- 1 CO(CH2)2Ph H NHS02Ph
aminomethyl
4355 2-benzimidazolyl- 1 Bn H NHS02Ph
aminomethyl
9356 2-benzimidazolyl- 1 n-Bu H NHS02Ph
aminomethyl
4357 2-benzimidazolyl- 1 COCH2(3- H NHS02Ph
aminomethyl indolyl)
4358 2-benzimidazolyl- 1 S02- H NHS02Ph
aminomethyl (biphenyl)
4359 2-benzimidazolyl- 1 C02-n-Bu H NHS02Ph
aminomethyl
4360 2-benzimidazolyl- 1 C02-i-Bu H NHS02Ph
aminomethyl
4361 2-benzimidazolyl- 1 C02-t-Bu H NHS02Ph
aminomethyl
4362 2-benzimidazolyl- 1 H H NHS02Ph
aminomethyl
4363 2-benzimidazolyl- 1 -(CH2)4NH2 H NHS02Ph
aminomethyl
4364 2-benzimidazolyl- 1 COPh H NHS02Ph
aminomethyl
4365 2-benzimidazolyl- 1 cyclopropy H NHS02Ph
aminomethyl l-methyl
4366 2-benzimidazolyl- 1 S02-n-Bu H NHS02Ph
aminomethyl
4367 2-benzimidazolyl- 1 Cbz H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
4368 2-benzimidazolyl- 1 S02Ph H NHS02-~2,4,6-
aminomethyl trimethylphenyl)
4369 2-benzimidazolyl- 1 Co(cH2~2ph H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
-208-
CA 02249733 l998-09-ll
W O 97l33887 PCT~US97/04567
4370 2-benzimidazolyl- 1 Bn H NHSO2-~2,4,6-
aminomethyl trimethylphenyl)
4371 2-benzimidazolyl- 1 n-Bu H NHSO2-~2,4,6-
aminomethyl trimethylphenyl)
4372 2-benzimidazolyl- 1CO2-n-Bu H NHSO2-~2,4,6-
aminomethyl trimethylphenyl)
4373 2-benzimidazolyl- 1CO2-i-Bu H NHSO2-~2,4,6-
aminomethyl trimethylphenyl)
4374 2-benzimidazolyl- 1CO2-t-Bu H NHS02-~2,4,6-
aminomethyl trimethylphenyl)
4375 2-benzimidazolyl- 1 H H NHSO2-~2,4,6-
aminomethyl trimethylphenyl)
4376 2-benzimidazolyl- 1-~CH2)4NH2 H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
4377 2-benzimidazolyl- 1 COPh H NHSO2-~2,4,6-
aminomethyl trimethylphenyl)
4378 2-benzimidazolyl- 1SO2-n-Bu H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
4379 2-benzimidazolyl- 1 Cbz H NHCbz
aminomethyl
4380 2-benzimidazolyl- 1 SO2Ph H NHCbz
aminomethyl
4381 2-benzimidazolyl- 1CO(CH2)2Ph H NHCbz
aminomethyl
4382 2-benzimidazolyl- 1 Bn H NHCbz
aminomethyl
4383 2-benzimidazolyl- 1 n-Bu H NHCbz
aminomethyl
4384 2-benzimidazolyl- 1CO2-n-Bu H NHCbz
aminomethyl
4385 2-benzimidazolyl- 1CO2-i-Bu H NHCbz
aminomethyl
4386 2-benzimidazolyl- 1C02-t-Bu H NHCbz
aminomethyl
-209-
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4387 2-benzimidazolyl- 1 H H NHCbz
aminomethyl
4388 2-benzimidazolyl- 1-~CH2)4NH2 H NHCbz
aminomethyl
4389 2-benzimidazolyl- 1COPh H NHCbz
aminomethyl
4390 2-benzimidazolyl- 1 SO2-n-Bu H NHCbz
aminomethyl
43gl 7-aza-2- 1 Cbz H NHSO2Ph
benzimidazolyl
4392 7-aza-2- 1 S02Ph H NHS02Ph
benzimidazolyl
4393 7-aza-2- 1 CO(CH2)2Ph H NHSO2Ph
benzimidazolyl
4394 7-aza-2- 1 Bn H NHSO2Ph
benzimidazolyl
4395 7-aza-2- 1 n-Bu H NHSO2Ph
benzimidazolyl
4396 7-aza-2- 1 COCH2~3- H NHSO2Ph
benzimidazolyl indolyl)
4397 7-aza-2- 1 S02- H NHSO2Ph
benzimidazolyl (biphenyl)
4398 7-aza-2- 1 C02-n-Bu H NHS02Ph
benzimidazolyl
4399 7-aza-2- 1 CO2-i-Bu H NHSO2Ph
benzimidazolyl
4400 7-aza-2- 1 CO2-t-Bu H NHSO2Ph
benzimidazolyl
4401 7-aza-2- 1 H H NHSO2Ph
benzimidazolyl
4402 7-aza-2- 1 -(CH2)4NH2 H NHSO2Ph
benzimidazolyl
4403 7-aza-2- 1 COPh H NHSO2Ph
benzimidazolyl
-210-
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4404 7-aza-2- 1cyclopropy HNHSO2Ph
benzimidazolyl l-methyl
4405 7-aza-2- 1SO2-n-Bu HNHSO2Ph
benzimidazolyl
4406 7-aza-2- 1Cbz HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4407 7-aza-2- 1SO2Ph HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4~08 7-aza-2- 1CO(CH2)2Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4409 7-aza-2- 1Bn HNHSO2-(2,4,6-
- benzimidazolyl trimethylphenyl)
4410 7-aza-2- 1 n-Bu H NHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4411 7-aza-2- 1CO2-n-Bu H NHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4412 7-aza-2- 1CO2-i-Bu H NHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4413 7-aza-2- 1CO2-t-Bu H NHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4414 7-aza-2- 1 H H NHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4415 7-aza-2- 1-(CH2)4NH2 H NHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4416 7-aza-2- 1 COPh H NHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
4417 7-aza-2- 1SO2-n-Bu H NHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
4418 7-aza-2- 1 Cbz H NHCbz
benzimidazolyl
4419 7-aza-2- 1 SO2Ph H NHCbz
benzimidazolyl
4420 7-aza-2- 1CO(CH2)2Ph H NHCbz
benzimidazolyl
-211-
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4421 7-aza-2- 1 Bn H NHCbz
benzimidazolyl
4422 7-aza-2- 1 n-Bu H NHCbz
benzimidazolyl
4423 7-aza-2- 1C02-n-Bu H NHCbz
benzimidazolyl
4424 7-aza-2- 1C02-i-Bu H NHCbz
benzimidazolyl
4425 7-aza-2- 1C02-t-Bu H NHCbz
benzimidazolyl
4426 7-aza-2- 1 H H NHCbz
benzimidazolyl
4427 7-aza-2- l~(CH2)gNH2 H NHCbz
benzimidazolyl
4428 7-aza-2- 1COPh H NHCbz
benzimidazolyl
4429 7-aza-2- 1S02-n-Bu H NHCbz
benzimidazolyl
4430 tetrahydropyrimidin 1 Cbz H NHS02Ph
-2-ylaminomethyl
4431 tetrahydropyrimidin 1 S02Ph H NHS02Ph
-2-ylaminomethyl
4432 tetrahydropyrimidin 1 CO(CH2)2Ph H NHS02Ph
-2-ylaminomethyl
44i3 tetrahydropyrimidin 1 Bn H NHS02Ph
-2-ylaminomethyl
4434 tetrahydropyrimidin 1 n-Bu H NHS02Ph
-2-ylaminomethyl
4435 tetrahydropyrimidin 1 COCH2(3- H NHS02Ph
-2-ylaminomethyl indolyl)
4436 tetrahydropyrimidin 1 S02- H NHS02Ph
-2-ylaminomethyl (biphenyl)
4437 tetrahydropyrimidin 1 C02-n-Bu H NHS02Ph
-2-ylaminomethyl
-212-
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4438 tetrahydropyrimidin 1 CO2-i-Bu H NH5O2Ph
-2-ylaminomethyl
443g tetrahydropyrimidin 1 C02-t-Bu H NHS02Ph
-2-ylaminomethyl
- 4440 tetrahydropyrimidin 1 H H NHSO2Ph
-2-ylaminomethyl
4441 tetrahydropyrimidin 1 -(CU2)4NH2 H NHSO2Ph
-2-ylaminomethyl
4442 tetrahydropyrimidin 1 COPh H NHSO2Ph
-2-ylaminomethyl
4443 tetrahydropyrimidin 1 cyclopropy HNHSO2Ph
-2-ylaminomethyl l-methyl
4444 tetrahydropyrimidin 1 SO2-n-Bu H NHSO2Ph
-2-ylaminomethyl
4445 tetrahydropyrimidin 1 Cbz H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4446 tetrahydropyrimidin 1 SO2Ph H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4447 tetrahydropyrimidin 1 CO(CH2)2Ph H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4448 tetrahydropyrimidin 1 Bn H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4449 tetrahydropyrimidin 1 n-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4450 tetrahydropyrimidin 1 CO2-n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4451 tetrahydropyrimidin 1 CO2-i-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4452 tetrahydropyrimidin 1 CO2-t-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4453 tetrahydropyrimidin 1 H H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4454 tetrahydropyrimidin 1 -(CH2)~NH2 H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
-213-
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4455 tetrahydropyrimidin 1COPh H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4456 tetrahydropyrimidin 1SO2-n-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
4457 tetrahydropyrimidin 1 Cbz H NHCbz
-2-ylaminomethyl
4458 tetrahydropyrimidin 1 SO2Ph H NHCbz
-2-ylaminomethyl
4459 tetrahydropyrimidin 1 CO(CH2)2Ph H NHCbz
-2-ylaminomethyl
4460 tetrahydropyrimidin 1 Bn H NHCbz
-2-ylaminomethyl
4461 tetrahydropyrimidin 1 n-Bu H NHCbz
-2-ylaminomethyl
4462 tetrahydropyrimidin 1 CO2-n-Bu H NHCbz
-2-ylaminomethyl
4463 tetrahydropyrimidin 1 CO2-i-Bu H NHCbz
-2-ylaminomethyl
4464 tetrahydropyrimidin 1 CO2-t-Bu H NHCbz
-2-ylaminomethyl
4465 tetrahydropyrimidin 1 H H NHCbz
-2-ylaminomethyl
4466 tetrahydropyrimidin 1 ~CH2)4NH2 H NHCbz
-2-ylaminomethyl
4467 tetrahydropyrimidin 1 COPh H NHCbz
-2-ylaminomethyl
-214-
CA 02249733 l998-09-ll
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Table 5
R1 \ ~ R14 o
~ko_N J~
E~ Bl L B10a Bl4 Bl5
~Q-
50012-pyridinylamino- 0Cbz H NHSO2Ph
methyl
50022-pyridinylamino- 0SO2Ph H NHSO2Ph
methyl
50032-pyridinylamino- 0CO(CH2)2Ph H NHSO2Ph
methyl
50042-pyridinylamino- 0Bn H NHS02Ph
methyl
50052-pyridinylamino- 0n-Bu H NHS02Ph
methyl
50062-pyridinylamino- 0COCH2(3- H NHSO2Ph
methyl indolyl)
50072-pyridinylamino- 0S02-(bi H NHSO2Ph
methyl phenyl)
50082-pyridinylamino- oCO2-n-Bu H NHSO2Ph
methyl
50092-pyridinylamino- oCO2-i-Bu H NHSO2Ph
methyl
50102-pyridinylamino- oCO2-t-Bu H NHSO2Ph
methyl
50112-pyridinylamino- o-(CH2)4NH2 H NHS02Ph
methyl
50122-pyridinylamino- 0COPh H NHSO2Ph
methyl
-215-
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50132-pyridinylamino- 0cyclo HNHSO2Ph
methyl propyl-
methyl
50142-pyridinylamino- 0SO2-n-Bu HNHSO2Ph
methyl
50152-pyridinylamino- 0Cbz HNHS02-(2,4,6-
methyl trimethylphenyl)
50162-pyridinylamino- 0SO2Ph HNHS02-~2,4,6-
methyl trimethylphenyl)
50172-pyridinylamino- 0CO(CH2)2Ph H NHS02-(2,4,6-
methyl trimethylphenyl)
50182-pyridinylamino- 0Bn HNHS02-(2,4,6-
methyl trimethylphenyl)
50192-pyridinylamino- 0n-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
50202-pyridinylamino- 0CO2-n-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
50212-pyridinylamino- 0CO2-i-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
50222-pyridinylamino- 0CO2-t-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
50232-pyridinylamino- 0-(CH2)4NH2 HNHS02-(2,4,6-
methyl trimethylphenyl)
50242-pyridinylamino- 0COPh HNHS02-(2,4,6-
methyl trimethylphenyl)
50252-pyridinylamino- 0S02-n-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
5026 2-pyridinylamino- 0 Cbz HNHCbz
methyl
50272-pyridinylamino- 0SO2Ph HNHCbz
methyl
50282-pyridinylamino- oCO(CH2)2Ph H NHCbz
methyl
5029 2-pyridinylamino- 0 Bn HNHCbz
methyl
-216-
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5030 2-pyridinylamino- o n-Bu H NHCbz
methyl
50312-pyridinylamino- o C02-n-Bu H NHCbz
methyl
50322-pyridinylamino- o C02-i-Bu H NHCbz
methyl
50332-pyridinylamino- 0 C02-t-Bu H NHCbz
methyl
50342-pyridinylamino- o -(CH2)4NH2 H NHCbz
methyl
5035 2-pyridinylamino- 0COPh H NHCbz
methyl
50362-pyridinylamino- o S02-n-Bu H NHCbz
methyl
50372-imidazolylamino- 0 Cbz H NHS02Ph
methyl
50382-imidazolylamino- 0 S02Ph H NHS02Ph
methyl
50392-imidazolylamino- 0 CO(CH2)2Ph H NHS02Ph
methyl
50402-imidazolylamino- 0 Bn H NHS02Ph
methyl
50412-imidazolylamino- 0 n-Bu H NHS02Ph
methyl
50422-imidazolylamino- 0 COCH2(3- H NHS02Ph
methyl indolyl)
50432-imidazolylamino- 0 S02-(bi H NHS02Ph
methyl phenyl)
50442-imidazolylamino- 0 C02-n-Bu H NHS02Ph
methyl
50452-imidazolylamino- 0 C02-i-Bu H NHS02Ph
methyl
50462-imidazolylamino- 0 C02-t-Bu H NHS02Ph
methyl
-217-
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5047 2-imidazolylamino- 0 -(CH2)4NH2 H NHSO2Ph
methyl
504~ 2-imidazolylamino- 0 COPh H NHSO2Ph
methyl
50492-imidazolylamino- 0 cyclo H NHSO2Ph
methyl propyl-
methyl
50502-imidazolylamino- 0 SO2-n-Bu H NHSO2Ph
methyl
50512-imidazolylamino- 0 Cbz H NHSO2-(2,4,6-
methyl trimethylphenyl)
50522-imidazolylamino- 0 SO2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
50532-imidazolylamino- o CO(CH2)2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
50542-imidazolylamino- 0 Bn H NHSO2-(2,4,6-
methyl trimethylphenyl)
50552-imidazolylamino- 0 n-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
50562-imidazolylamino- 0 C02-n-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
50572-imidazolylamino- 0 CO2-i-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
50582-imidazolylamino- o CO2-t-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
50592-imidazolylamino- o -(CH2)4NH2 H NHS02-(2,4,6-
methyl trimethylphenyl)
50602-imidazolylamino- 0 COPh H NHSO2-(2,4,6-
methyl trimethylphenyl)
50612-imidazolylamino- 0 SO2-n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
5062 2-imidazolylamino- 0 Cbz H NHCbz
methyl
5063 2-imidazolylamino- 0 SO2Ph H NHCbz
methyl
-218-
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5064 2-imidazolylamino- o CO(CH2)2Ph H NHCbz
methyl
5065 2-imidazolylamino- 0 Bn H NHCbz
methyl
5066 2-imidazolylamino- 0 n-Bu H NHCbz
methyl
50672-imidazolylamino- o C02-n-Bu H NHCbz
methyl
50682-imidazolylamino- 0 CO2-i-Bu H NHCbz
methyl
5069 2-imidazolylamino- C CO2-t-Bu H NHCbz
methyl
5070 2-imidazolylamino- 0-~CH2)4MH2 H NHCbz
methyl
5071 2-imidazolylamino- 0 COPh H NHCbz
methyl
50722-imidazolylamino- 0 SO2-n-Bu H NHCbz
methyl
50732-imidazolinyl- 0 Cbz H NHS02Ph
aminomethyl
50742-imidazolinyl- 0 S02Ph H NHS02Ph
aminomethyl
50752-imidazolinyl- o CO(CH2)2Ph H NHSO2Ph
aminomethyl
50762-imidazolinyl- 0 Bn H NHS02Ph
aminomethyl
50772-imidazolinyl- 0 n-Bu H NHSO2Ph
aminomethyl
50782-imidazolinyl- o COCH2(3- H NHSO2Ph
aminomethyl indolyl)
50792-imidazolinyl- 0 S02-(bi H NHSO2Ph
aminomethyl phenyl)
50802-imidazolinyl- o CO2-n-Bu H NHSO2Ph
aminomethyl
-219-
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50812-imidazolinyl- 0C02-i-Bu HNHS02Ph
aminomethyl
50822-imidazolinyl- oCO2-t-Bu HNHSO2Ph
aminomethyl
50832-imidazolinyl- 0-(CH2)qNH2 HNHSO2Ph
aminomethyl
50842-imidazolinyl- 0COPh HNHSO2Ph
aminomethyl
50852-imidazolinyl- 0cyclo HNHSO2Ph
aminomethyl propyl-
methyl
50862-imidazolinyl- 0S02-n-Bu HNHSO2Ph
aminomethyl
50872-imidazolinyl- 0Cbz HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
50882-imidazolinyl- ~SO2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
50892-imidazolinyl- 0C0(CH2)2Ph H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
50902-imidazolinyl- 0Bn HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
50912-imidazolinyl- 0n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
50922-imidazolinyl- 0CO2-n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
50932-imidazolinyl- oCO2-i-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
50942-imidazolinyl- 0CO2-t-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
50952-imidazolinyl- 0-(CH2)4NH2 HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
50962-imidazolinyl- 0COPh HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
50972-imidazolinyl- 0S02-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
-223-
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509B 2-imidazolinyl- 0 Cbz H NHCbz
aminomethyl
5099 2-imidazolinyl- ~ SO2Ph H NHCbz
aminomethyl
' 5100 2-imidazolinyl- o CO(CH2)2Ph H NHCbz
- aminomethyl
5101 2-imidazolinyl- 0 Bn H NHCbz
aminomethyl
5102 2-imidazolinyl- 0 n-Bu H NHCbz
aminomethyl
5103 2-imidazolinyl- o CO2-n-Bu H NHCbz
aminomethyl
5104 2-imidazolinyl- 0 CO2-i-Bu H NHCbz
aminomethyl
5105 2-imidazolinyl- 0 CO2-t-Bu H NHCbz
aminomethyl
5106 2-imidazolinyl- 0 -~CH2)4NH2 H NHCbz
aminomethyl
5107 2-imidazolinyl- 0COPh H NHCbz
aminomethyl
5108 2-imidazolinyl- 0 SO2-n-Bu H NHCbz
aminomethyl
5109 2-benzimidazolyl- 0 Cbz H NHSO2Ph
aminomethyl
5110 2-benzimidazolyl- 0 SO2Ph H NHSO2Ph
aminomethyl
5111 2-benzimidazolyl- o CO(CH2)2Ph H NHSO2Ph
aminomethyl
5112 2-benzimidazolyl- 0 Bn H NHSO2Ph
aminomethyl
5113 2-benzimidazolyl- 0 n-Bu H NHS02Ph
aminomethyl
5114 2-benzimidazolyl- o COCH2(3- H NHSO2Ph
aminomethyl indolyl)
-221-
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51152-benzimidazolyl- 0S02-(bi HNHS02Ph
aminomethyl phenyl)
51162-benzimidazolyl- 0C02-n-Bu HNHS02Ph
aminomethyl
51172-benzimidazolyl- 0C02-i-Bu HNHS02Ph
aminomethyl
51182-benzimidazolyl- 0C02-t-Bu HNHS02Ph
aminomethyl
51192-benzimidazolyl- 0-(CH2)4NH2 HNHS02Ph
aminomethyl
51202-benzimidazolyl- 0COPh HNHS02Ph
aminomethyl
51212-benzimidazolyl- 0cyclo HNHS02Ph
aminomethyl propyl-
methyl
51222-benzimidazolyl- 0S02-n-Bu HNHS02Ph
aminomethyl
51232-benzimidazolyl- 0Cbz HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
51242-benzimidazolyl- 0S02Ph HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
51252-benzimidazolyl- 0 CO(CH2)2Ph H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
51262-benzimidazolyl- 0Bn HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
51272-benzimidazolyl- 0n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
51282-benzimidazolyl- 0C02-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
51292-benzimidazolyl- CC02-i-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
51302-benzimidazolyl- oC02-t-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
51312-benzimidazolyl- 0-(CH2)gNH2 HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
-222-
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51322-benzlmidazolyl- 0COPh HNH502-(2,4,6-
aminomethyl trimethylphenyl)
51332-benzimidazolyl- 0SO2-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
5134 2-benzimidazolyl- 0 Cbz HNHCbz
aminomethyl
51352-benzimidazolyl- 0SO2Ph HNHCbz
aminomethyl
51362-benzimidazolyl- oCO(CH2)2Ph H NHCbz
aminomethyl
5137 2-benzimidazolyl- 0 Bn HNHCbz
aminomethyl
5138 2-benzimidazolyl- 0 n-Bu HNHCbz
aminomethyl
5139 2-benzimidazolyl- 0 CO2-n-Bu HNHCbz
aminomethyl
5140 2-benzimidazolyl- o CO2-i-Bu H MHCbz
aminomethyl
51412-benzimidazolyl- o C02-t-Bu HNHCbz
aminomethyl
51422-benzimidazolyl- 0 -(CH2)4NH2 HNHCbz
aminomethyl
5143 2-benzimidazolyl- 0 COPh HNHCbz
aminomethyl
51442-benzimidazolyl- 0 S02-n-Bu HNHCbz
aminomethyl
51457-aza-2- 0 Cbz HNHSO2Ph
benzimidazolyl
51967-aza-2- o S02Ph HNHS02Ph
benzimidazolyl
51477-aza-2- o CO(CH2)2Ph HNHSO2Ph
benzimidazolyl
51487-aza-2- 0 Bn HNHSO2Ph
benzimidazolyl
-223-
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WO 97/33887 PCTrUS97/04567
5149 7-aza-2- 0n-Bu HNHS02Ph
benzimidazolyl
5150 7-aza-2- 0COCH2(3- HNHS02Ph
benzimidazolyl indolyl)
5151 7-aza-2- 0S02-(bi HNHS02Ph
benzimidazolyl phenyl)
5152 7-aza-2- 0C02-n-Bu HNHS02Ph
benzimidazolyl
5153 7-aza-2- oC02-i-Bu HNHS02Ph
benzimidazolyl
5154 7-aza-2- 0C02-t-Bu HNHS02Ph
benzimidazolyl
5155 7-aza-2- 0-(CH2)4NH2 HNHS02Ph
benzimidazolyl
51567-aza-2- 0COPh HNHS02Ph
benzimidazolyl
51577-aza-2- 0cyclo HNHS02Ph
benzimidazolyl propyl-
methyl
51587-aza-2- 0S02-n-Bu HNHS02Ph
benzimidazolyl
515g7-aza-2- 0Cbz HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
51607-aza-2- oS02Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
51617-aza-2- 0CO(CH2)2Ph H NHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
51627-aza-2- 0Bn HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
51637-aza-2- 0n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
51647-aza-2- oC02-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
51657-aza-2- 0C02-i-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
-224-
CA 02249733 l998-09-ll
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51667-aza-2- 0C02-t-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
51677-aza-2- 0-(CH2)4NH2 HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
51687-aza-2- 0COPh HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
51697-aza-2- 0SO2-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
51707-aza-2- 0Cbz HNHCbz
benzimidazolyl
51717-aza-2- oSO2Ph HNHCbz
benzimidazolyl
51727-aza-2- oCO(CH2)2Ph H NHCbz
benzimidazolyl
51737-aza-2- 0Bn HNHCbz
benzimidazolyl
51747-aza-2- 0n-Bu HNHCbz
benzimidazolyl
51757-aza-2- oC02-n-Bu HNHCbz
benzimidazolyl
51767-aza-2- oCO2-i-Bu HNHCbz
benzimidazolyl
51777-aza-2- 0CO2-t-Bu HNHCbz
benzimidazolyl
51787-aza-2- 0-(CH2)4NH2 HNHCbz
benzimidazolyl
51797-aza-2- 0COPh HNHCbz
benzimidazolyl
51807-aza-2- 0SO2-n-Bu HNHCbz
benzimidazolyl
5181 tetrahydropyrimidin 0 Cbz H NHSO2Ph
-2-ylaminomethyl
5182 tetrahydropyrimidin 0 SO2Ph H NHSO2Ph
-2-ylaminomethyl
-225-
CA 02249733 l998-09-ll
W O 97l33887 PCTrUS97/04567
51~3 tetrahydropyrimidin o CO(CH2)2Ph H NHS02Ph
-2-ylaminomethyl
5184 tetrahydropyrimidin O Bn H NHSo2Ph
-2-ylaminomethyl
5185 tetrahydropyrimidin O n-Bu H NHS02Ph
-2-ylaminomethyl
5186 tetrahydropyrimidin O COCH2(3- H NHS02Ph
-2-ylaminomethyl indolyl)
5187 tetrahydropyrimidin O S02-(bi H NHS02Ph
-2-ylaminomethyl phenyl)
5188 tetrahydropyrimidin O C02-n-Bu H NHS02Ph
-2-ylaminomethyl
5189 tetrahydropyrimidin O C02-i-Bu H NHS02Ph
-2-ylaminomethyl
5190 tetrahydropyrimidin o C02-t-Bu H NHS02Ph
-2-ylaminomethyl
5191 tetrahydropyrimidin O -(CH2)4NH2 H NHS02Ph
-2-ylaminomethyl
5192 tetrahydropyrimidin O COPh H NHS02Ph
-2-ylaminomethyl
5193 tetrahydropyrimidin O cyclo H NHS02Ph
-2-ylaminomethylpropyl-
methyl
5194 tetrahydropyrimidin O S02-n-Bu H NHS02Ph
-2-ylaminomethyl
5195 tetrahydropyrimidin O Cbz H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5196 tetrahydropyrimidin O S02Ph H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5197 tetrahydropyrimidin o CO(CH2)2Ph H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5198 tetrahydropyrimidin O Bn H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5199 tetrahydropyrimidin O n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl
-226-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97104567
5200 tetrahydropyrimidin oCO2-n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5201 tetrahydropyrimidin 0CO2-i-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5202 tetrahydropyrimidin oCO2-t-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5203 tetrahydropyrimidin o-(CH2)4NH2 H NHS02-(2,g,6-
-2-ylaminomethyl trimethylphenyl)
5204 tetrahydropyrimidin 0COPh H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5205 tetrahydropyrimidin 0SO2-n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5206 tetrahydropyrimidin 0Cbz HNHCbz
-2-ylaminomethyl
5207 tetrahydropyrimidin ~ 502Ph H NHCbz
-2-ylaminomethyl
5208 tetrahydropyrimidin 0CO(CH2)2Ph H NHCbz
-2-ylaminomethyl
5209 tetrahydropyrimidin 0Bn HNHCbz
-2-ylaminomethyl
5210 tetrahydropyrimidin 0n-Bu HNHCbz
-2-ylaminomethyl
5211 tetrahydropyrimidin o CO2-n-Bu HNHCbz
-2-ylaminomethyl
5212 tetrahydropyrimidin o CO2-i-Bu HNHCbz
-2-ylaminomethyl
5213 tetrahydropyrimidin o CO2-t-Bu HNHCbz
-2-ylaminomethyl
5214 tetrahydropyrimidin 0-(CH2)4NH2 HNHCbz
-2-ylaminomethyl
5215 tetrahydropyrimidin 0COPh HNHCbz
-2-ylaminomethyl
5216 tetrahydropyrimidin 05O2-n-Bu HNHCbz
-2-ylaminomethyl
-227-
CA 02249733 l998-09-ll
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52172-pyridinylamino- 1Cbz HNHSO2Ph
methyl
52182-pyridinylamino- 1S02Ph HNHS02Ph
methyl
52192-pyridinylamino- 1CO(CH2)2Ph H NHS02Ph
methyl
52202-pyridinylamino- 1Bn HNHSO2Ph
methyl
52212-pyridinylamino- 1n-Bu HNHSO2Ph
methyl
52222-pyridinylamino- 1COCH2(3- HNHSO2Ph
methyl indolyl)
52232-pyridinylamino- 1S02-(bi HNHS02Ph
methyl phenyl)
52242-pyridinylamino- 1CO2-n-Bu HNHSO2Ph
methyl
52252-pyridinylamino- lCO2-i-Bu HNHSO2Ph
methyl
52262-pyridinylamino- 1CO2-t-Bu HNHSO2Ph
methyl
52272-pyridinylamino- 1-(CH2)4NH2 HNHSO2Ph
methyl
52282-pyridinylamino- 1COPh HNHSO2Ph
methyl
52292-pyridinylamino- 1cyclo HNHSO2Ph
methyl propyl-
methyl
52302-pyridinylamino- 1SO2-n-Bu HNHSO2Ph
methyl
52312-pyridinylamino- 1Cbz HNHSO2-(2,4,6-
methyl trimethylphenyl)
52322-pyridinylamino- 1SO2Ph HNHSO2-(2,4,6-
methyl trimethylphenyl)
52332-pyridinylamino- 1CO(CH2)2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
-228-
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52342-pyridinylamino- 1Bn HNHSO2-(2,4,6-
methyl trimethylphenyl)
52352-pyridinylamino- 1n-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
52362-pyridinylamino- 1CO2-n-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
52372-pyridinylamino- 1CO2-i-Bu HNH502-(2,4,6-
methyl trimethylphenyl)
52382-pyridinylamino- 1CO2-t-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
52392-pyridinylamino- 1-(CH2)4NH2 HNHSO2-(2,4,6-
methyl trimethylphenyl)
52402-pyridinylamino- 1COPh HNHS02-(2,4,6-
methyl trimethylphenyl)
52412-pyridinylamino- 1SO2-n-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
5242 2-pyridinylamino- 1 Cbz HNHCbz
methyl
52432-pyridinylamino- 1SO2Ph HNHCbz
methyl
52442-pyridinylamino- 1CO(CH2)2Ph H NHCbz
methyl
5245 2-pyridinylamino- 1 Bn HNHCbz
methyl
5246 2-pyridinylamino- 1 n-Bu HNHCbz
methyl
52472-pyridinylamino- 1CO2-n-Bu HNHCbz
methyl
52482-pyridinylamino- 1CO2-i-Bu HNHCbz
methyl
52492-pyridinylamino- 1CO2-t-Bu HNHCbz
methyl
52502-pyridinylamino- 1-(CH2)4NH2 HNHCbz
methyl
-229-
CA 02249733 l998-09-ll
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5251 2-pyridinylamino- 1COPh H NHCbz
methyl
52522-pyridinylamino- 1 S02-n-Bu H NHCbz
methyl
52532-imidazolylamino- 1 Cbz H NHS02Ph
methyl
52542-imidazolylamino- 1 S02Ph H NHS02Ph
methyl
52552-imidazolylamino- 1 CO(CH2)2Ph H NHS02Ph
methyl
52562-imidazolylamino- 1 Bn H NHS02Ph
methyl
52572-imidazolylamino- 1 n-Bu H NHS02Ph
methyl
52582-imidazolylamino- 1 COCH2(3- H NHS02Ph
methyl indolyl)
52592-imidazolylamino- 1 S02-(bi H NHS02Ph
methyl phenyl)
52602-imidazolylamino- 1 C02-n-Bu H NHS02Ph
methyl
52612-imidazolylamino- 1 C02-i-Bu H NHS02Ph
methyl
52622-imidazolylamino- 1 C02-t-Bu H NHS02Ph
methyl
52632-imidazolylamino- 1 -(CH2)4NH2 H NHS02Ph
methyl
52642-imidazolylamino- 1 COPh H NHS02Ph
methyl
52652-imidazolylamino- 1 cyclo H NHS02Ph
methyl propyl-
methyl
52662-imidazolylamino- 1 S02-n-Bu H NHS02Ph
methyl
52672-imidazolylamino- 1 Cbz H NHS02-(2,4,6-
methyl trimethylphenyl)
-230-
CA 02249733 l998-09-ll
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52682-imidazolylamino- 1SO2Ph HNHSO2-(2,4,6-
methyl trimethylphenyl)
52692-imidazolylamino- 1CO(CH2)2ph H NHS02-(2,4,6-
methyl trimethylphenyl~
52702-imidazolylamino- 1Bn HNHSO2-(2,4,6-
methyl trimethylphenyl)
52712-imidazolylamino- 1n-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
52722-imidazolylamino- 1CO2-n-8u HNHS02-(2,4,6-
methyl trimethylphenyl)
52732-imidazolylamino- 1C02-i-Bu HNHS02-~2,4,6-
methyl trimethylphenyl)
52742-imidazolylamino- 1CO2-t-Bu HNHS02-~2,4,6-
methyl trimethylphenyl)
52752-imidazolylamino- 1-(CH2)4NH2 HNHSO2-(2,4,6-
methyl trimethylphenyl)
52762-imidazolylamino- 1COPh HNHSO2-~2,4,6-
methyl trimethylphenyl)
52772-imidazolylamino- 1SO2-n-Bu HNHSO2-~2,4,6-
methyl trimethylphenyl)
5278 2-imidazolylamino- 1 Cbz HNHCbz
methyl
52792-imidazolylamino- 1SO2Ph HNHCbz
methyl
52802-imidazolylamino- 1CO~CH2)2Ph H NHCbz
methyl
5281 2-imidazolylamino- 1 Bn HNHCbz
methyl
5282 2-imidazolylamino- 1 n-Bu HNHCbz
methyl
52832-imidazolylamino- 1CO2-n-Bu HNHCbz
methyl
52842-imidazolylamino- 1CO2-i-Bu HNHCbz
methyl
-231-
CA 02249733 l998-09-ll
W O 97l33887 PCTAUS97/04567
5285 2-imidazolylamino- 1 C02-t-Bu H NHCbz
methyl
5286 2-imidazolylamino- 1 -(CH2)4NH2 H NHCbz
methyl
5287 2-imidazolylamino- 1 COPh H NHCbz
methyl
52882-imidazolylamino- 1S02-n-Bu H NHCbz
methyl
52892-imidazolinyl- 1 Cbz H NHS02Ph
aminomethyl
52902-imidazolinyl- 1S02Ph H NHS02Ph
aminomethyl
52912-imidazolinyl- 1C0~CH2)2Ph H NHS02Ph
aminomethyl
52922-imidazolinyl- 1 Bn H NHS02Ph
aminomethyl
52932-imidazolinyl- 1 n-Bu H NHS02Ph
aminomethyl
52942-imidazolinyl- 1COCH2(3- H NHSo2Ph
aminomethyl indolyl)
52952-imidazolinyl- 1S02-(bi H NHS02Ph
aminomethyl phenyl)
52962-imidazolinyl- 1C02-n-Bu H NHS02Ph
aminomethyl
52972-imidazolinyl- 1C02-i-Bu H NHS02Ph
aminomethyl
52982-imidazolinyl- 1C02-t-Bu H NHS02Ph
aminomethyl
52992-imidazolinyl- 1-(CH2)4NH2 H NHS02Ph
~mi n,: -thyl
53002-imidazolinyl- 1COPh H NHS02Ph
aminomethyl
53012-imidazolinyl- 1cyclo H NHS02Ph
aminomethyl propyl-
methyl
-232-
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53022-imidazolinyl- 1SO2-n-Bu HNHSO2Ph
aminomethyl
- 53032-imidazolinyl- 1Cbz HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
53042-imidazolinyl- 1SO2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
53052-imidazolinyl- 1CO(CH2)2Ph H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
53062-imidazolinyl- 1Bn HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
53072-imidazolinyl- 1n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
53082-imidazolinyl- 1CO2-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53092-imidazolinyl- 1CO2-i-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53102-imidazolinyl- 1CO2-t-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53112-imidazolinyl- 1-(CH2)4NH2 HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53122-imidazolinyl- 1COPh HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
53132-imidazolinyl- 1SO2-n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
53142-imidazolinyl- 1Cbz HNHCbz
aminomethyl
53152-imidazolinyl- 1SO2Ph HNHCbz
aminomethyl
53162-imidazolinyl- 1CO(CH2)2Ph H NHCbz
aminomethyl
53172-imidazolinyl- 1Bn HNHCbz
aminomethyl
53182-imidazolinyl- 1n-Bu HNHCbz
aminomethyl
-233-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
53192-imidazolinyl- 1C02-n-Bu H NHCbz
aminomethyl
53202-imidazolinyl- 1C02-i-Bu H NHCbz
aminomethyl
53212-imidazolinyl- 1C02-t-Bu H NHCbz
aminomethyl
53222-imidazolinyl- 1-(CH2)4NH2 H NHCbz
aminomethyl
53232-imidazolinyl- 1COPh H NHCbz
aminomethyl
53242-imidazolinyl- 1S02-n-Bu H NHCbz
aminomethyl
53252-benzimidazolyl- 1Cbz H NHS02Ph
aminomethyl
53262-benzimidazolyl- 1S02Ph H NHS02Ph
aminomethyl
53272-benzimidazolyl- 1CO(CH2)2Ph H NHS02Ph
aminomethyl
53282-benzimidazolyl- 1Bn H NHS02Ph
aminomethyl
53292-benzimidazolyl- 1n-Bu H NHS02Ph
aminomethyl
53302-benzimidazolyl- 1COCH2(3- H NHS02Ph
aminomethyl indolyl)
53312-benzimidazolyl- 1S02-(bi H NHS02Ph
aminomethyl phenyl)
53322-benzimidazolyl- 1C02-n-Bu H NHS02Ph
~mi n~ thyl
53332-benzimidazolyl- 1C02-i-Bu H NHS02Ph
aminomethyl
53342-benzimidazolyl- 1C02-t-Bu H NHS02Ph
aminomethyl
53352-benzimidazolyl- 1-(CH2)gNH2 H NHS02Ph
aminomethyl
-234-
CA 02249733 l998-09-ll
W 0 97/33887 PCTtUS97tO4567
53362-benzimidazolyl- 1COPh HNHS02Ph
aminomethyl
53372-benzimidazol-yl- 1cyclo HNHS02Ph
aminomethyl propyl-
methyl
53382-benzimidazolyl- 1S02-n-Bu HNHS02Ph
aminomethyl
53392-benzimidazolyl- 1Cbz HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53402-benzimidazolyl- 1S02Ph HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
534~2-benzimidazolyl- 1CO(CH2)2Ph H NHS02-(2,4,6-
aminomethyl trimethylphenyl)
53422-benzimidazolyl- 1Bn HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53432-benzimidazolyl- 1n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53442-benzimidazolyl- 1C02-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53452-benzimidazolyl- 1C02-i-Bu HNHS02-(2,4,6-
~mi no~thyl trimethylphenyl)
53462-benzimidazolyl- 1C02-t-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53472-benzimidazolyl- 1-(CH2)4NH2 HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
53482-benzimidazolyl- 1COPh HNH502-(2,4,6-
aminomethyl trimethylphenyl)
53492-benzimidazolyl- 1S02-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
5350 2-benzimidazolyl- 1 Cbz HNHCbz
aminomethyl
53512-benzimidazolyl- 1S02Ph HNHCbz
aminomethyl
53522-benzimidazolyl- 1Co(cH2)2ph H NHCbz
aminomethyl
-235-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04~67
5353 2-benzimidazolyl- 1Bn H NHCbz
aminomethyl
5354 2-benzimidazolyl- 1n-Bu H NHCbz
aminomethyl
53552-benzimidazolyl- 1 C02-n-Bu H NHCbz
aminomethyl
53562-benzimidazolyl- 1 C02-i-Bu H NHCbz
aminomethyl
53572-benzimidazolyl- 1 C02-~-Bu H NHCbz
aminomethyl
53582-benzimidazolyl- 1 -(CH2)4NH2 H NHCbz
aminomethyl
5359 2-benzimidazolyl- 1COPh H NHCbz
aminomethyl
53602-benzimidazolyl- 1 S02-n-Bu H NHCbz
aminomethyl
53617-aza-2- 1 Cbz H NHS02Ph
benzimidazolyl
53627-aza-2- 1 S02Ph H NHS02Ph
benzimidazolyl
53637-aza-2- 1 Co(cH2)2ph H NHS02Ph
benzimidazolyl
53647-aza-2- 1 Bn H NHS02Ph
benzimidazolyl
53657-aza-2- 1 n-Bu H NHS02Ph
benzimidazolyl
53667-aza-2- 1 COCH2(3- H NHS02Ph
benzimidazolyl indolyl)
53677-aza-2- 1 S02-(bi H NHS02Ph
benzimidazolyl phenyl)
53687-aza-2- 1 C02-n-Bu H NHS02Ph
benzimidazolyl
53657-aza-2- 1 C02-i-Bu H NHS02Ph
benzimidazolyl
-236-
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W O 97/33887 PCT~US97/04567
5370 7-aza-2- 1CO2-t-Bu HNHSO2Ph
benzimidazolyl
5371 7-aza-2- 1-(CH2)4NH2 HNHSO2Ph
benzimidazolyl
5372 7-aza-2- 1COPh HNHSO2Ph
benzimidazolyl
5373 7-aza-2- 1cyclo HNHSO2Ph
benzimidazolyl propyl-
methyl
5374 7-aza-2- 1SO2-n-Bu HNHSO2Ph
benzimidazolyl
5375 7-aza-2- 1 Cbz HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
5376 7-aza-2- 1SO2Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
5377 7-aza-2- 1CO(CH2)2Ph HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
5378 7-aza-2- 1 Bn HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
537g 7-aza-2- 1 n-Bu HNHS02-~2,4,6-
benzimidazolyl trimethylphenyl)
5380 7-aza-2- 1CO2-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
5381 7-aza-2- 1CO2-i-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
5382 7-aza-2- 1CO2-t-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
5383 7-aza-2- 1-(CH2)4NH2 HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
5384 7-aza-2- 1COPh HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
5385 7-aza-2- 1SO2-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
53867-aza-2- 1 Cbz HNHCbz
benzimidazolyl
-237-
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5387 7-aza-2- 1SO2Ph H NHCbz
benzimidazolyl
5388 7-aza-2- 1CO(CH2)~Ph H NHCbz
benzimidazolyl
5389 7-aza-2- 1 Bn H NHCbz
benzimidazolyl
5390 7-aza-2- 1 n-Bu H NHCbz
benzimidazolyl
5391 7-aza-2- 1CO2-n-Bu H NHCbz
benzimidazolyl
5392 7-aza-2- 1CO2-i-Bu H NHCbz
benzimidazolyl
5393 7-aza-2- 1CO2-t-BU H NHCbz
benzimidazolyl
5394 7-aza-2- 1-(CH2)4NH2 H NHCbz
benzimidazolyl
5395 7-aza-2- 1COPh H NHCbz
benzimidazolyl
5396 7-aza-2- 1S02-n-Bu H NHCbz
benzimidazolyl
5397 tetrahydropyrimidin 1 Cbz H NHSO2Ph
-2-ylaminomethyl
5398 tetrahydropyrimidin 1 S02Ph H NHSO2Ph
-2-ylaminomethyl
5399 tetrahydropyrimidin 1 CO(CH2)2Ph H NHSO2Ph
-2-ylaminomethyl
5400 tetrahydropyrimidin 1 Bn H NHSO2Ph
-2-ylaminomethyl
5401 tetrahydropyrimidin 1 n-Bu H NHSO2Ph
-2-ylaminomethyl
5402 tetrahydropyrimidin 1 COCH2(3- H NHSO2Ph
-2-ylaminomethyl indolyl)
5403 tetrahydropyrimidin 1 S02-(bi H NHSO2Ph
-2-ylaminomethyl phenyl)
-238-
CA 02249733 l998-09-ll
WO 97/33887 . PCTrUS97/04S67
540q tetrahydropyrimidin 1 CO2-n-Bu H NHSO2Ph
-2-ylaminomethyl
5405 tetrahydropyrimidin 1 CO2-i-Bu H NHSO2Ph
-2-ylaminomethyl
5406 tetrahydropyrimidin 1 CO2-t-Bu H NHSO2Ph
-2-ylaminomethyl
5407 tetrahydropyrimidin 1 -(CH2)4NH2 H NHSO2Ph
-2-ylaminomethyl
5408 tetrahydropyrimidin 1 COPh H NHSO2Ph
-2-ylaminomethyl
5409 tetrahydropyrimidin 1 cyclo H NHSO2Ph
-2-ylaminomethylpropyl-
methyl
5410 tetrahydropyrimidin l SO2-n-Bu H NHSO2Ph
-2-ylaminomethyl
5411 tetrahydropyrimidin 1 Cbz H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5412 tetrahydropyrimidin 1S02Ph H NHS02-(2,4,6-
-2-yl~ln~thyl trimethylphenyl)
5413 tetrahydropyrimidin 1CO(CH2)2Ph H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5414 tetrahydropyrimidin 1 Bn H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5415 tetrahydropyrimidin 1 n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5416 tetrahydropyrimidin 1C02-n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5417 tetrahydropyrimidin 1CO2-i-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5418 tetrahydropyrimidin 1CO2-t-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5419 tetrahydropyrimidin 1-(CH2)4NH2 H NHS02-~2,4,6-
-2-ylaminomethyl trimethylphenyl)
5420 tetrahydropyrimidin 1COPh H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
-239-
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5421 tetrahydropyrimidin 1 SO2-n-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
5422 tetrahydropyrimidin 1 Cbz H NHCbz
-2-ylaminomethyl
5423 tetrahydropyrimidin 1 SO2Ph H NHCbz
-2-ylaminomethyl
5424 tetrahydropyrimidin 1 CO(CH2)2Ph H NHCbz
-2-ylaminomethyl
5425 tetrahydropyrimidin 1 Bn H NHCbz
-2-ylaminomethyl
5426 tetrahydropyrimidin 1 n-Bu H NHCbz
-2-ylaminomethyl
5427 tetrahydropyrimidin 1 CO2-n-Bu HNHCbz
-2-ylaminomethyl
5428 tetrahydropyrimidin 1 CO2-i-Bu HNHCbz
-2-ylaminomethyl
5429 tetrahydropyrimidin 1 CO2-t-Bu HNHCbz
-2-ylaminomethyl
5430 tetrahydropyrimidin 1 -(CH2)4NH2 H NHCbz
-2-ylaminomethyl
5431 tetrahydropyrimidin 1 COPh H NHCbz
-2-yl~i nr -thyl
5432 tetrahydropyrimidin 1 SO2-n-Bu HNHCbz
-2-ylaminomethyl
-240-
CA 02249733 1998-09-11
W O 97/33887 pcTrus97lo4567
T~hle 6
O R14 o
R1 ~--X¢ H J~OH
E~- Bl LBlOa Bl4 ~15
~Q-
60012-pyridinylamino- 0 Cbz H NHSO2Ph
methyl
60022-pyridinylamino- 0SO2Ph H NHSO2Ph
methyl
60032-pyridinylamino- oCO(CH2)2Ph H NHSO2Ph
methyl
60042-pyridinylamino- 0 Bn H NHSO2Ph
methyl
60052-pyridinylamino- 0 n-Bu H NHSO2Ph
methyl
60062-pyridinylamino- 0CoCH2(3- H NHSO2Ph
methyl indolyl)
60072-pyridinylamino- 0 S02- H NHSO2Ph
methyl (biphenyl)
60082-pyridinylamino- 0C02-n-Bu H NHS02Ph
methyl
60092-pyridinylamino- 0C02-i-Bu H NHSO2Ph
methyl
60102-pyridinylamino- 0CO2-t-8u H NHSO2Ph
methyl
60112-pyridinylamino- 0-(CH2)4NH2 H NHSO2Ph
methyl
60122-pyridinylamino- 0COPh H NHSO2Ph
methyl
-241-
CA 02249733 l998-09-ll
WO 97/33887 PCT~US97/04567
6013 2-pyridinylamino- 0 cyclopropyl- H NHSO2Ph
methyl methyl
6014 2-pyridinylamino- 0 SO2-n-Bu H NHSO2Ph
methyl
6015 2-pyridinylamino- 0 Cbz H NHS02-(2,4,6-
methyl trimethylphenyl)
6016 2-pyridinylamino- 0 SO2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl~
6017 2-pyridinylamino- 0 CO(CH2)2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
6018 2-pyridinylamino- 0 ~n H NHSO2-(2,4,6-
methyl trimethylphenyl)
6019 2-pyridinylamino- 0 n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
6020 2-pyridinylamino- 0 C02-n-Bu H NHS02-(2,4,6- methyl trimethylphenyl)
6021 2-pyridinylamino- 0 CO2-i-Bu H NHS02-(2,4,6- methyl trimethylphenyl)
6022 2-pyridinylamino- 0 CO2-t-Bu H NHSO2-(2,4,6- methyl trimethylphenyl)
6023 2-pyridinylamino- 0 -(CH2)4NH2 H NHS02-(2,4,6-
methyl trimethylphenyl)
6024 2-pyridinylamino- 0 COPh H NHS02-(2,4,6-
methyl trimethylphenyl)
6025 2-pyridinylamino- 0 SO2-n-Bu H NHSO2-(2,4,6- methyl trimethylphenyl)
6026 2-pyridinylamino- 0 Cbz H NHCbz
methyl
6027 2-pyridinylamino- 0 SO2Ph H NHCbz
methyl
6028 2-pyridinylamino- 0 CO(CH2)2Ph H NHCbz
methyl
6029 2-pyridinylamino- 0 Bn H NHCbz
methyl
-242-
CA 02249733 l998-09-ll
W 097/33887 PCT~US97/04567
6030 2-pyridinylamino- 0 n-Bu H NHCbz
methyl
60312-pyridinylamino- 0CO2-n-Bu H NHCbz
methyl
- 60322-pyridinylamino- 0CO2-i-Bu H NHCbz
methyl
60332-pyridinylamino- 0CO2-t-Bu H NHCbz
methyl
603~2-pyridinylamino- 0-~CH2)4NH2 H NHCbz
methyl
6035 2-pyridinylamino- 0 COPh H NHCbz
methyl
60362-pyridinylamino- 0SO2-n-Bu H NHCbz
methyl
60372-imidazolylamino- 0 Cbz H NHSO2Ph
methyl
60382-imidazolylamino- 0 S02Ph H NHS02Ph
methyl
603g2-imidazolylamino- 0 CO(CH2)2Ph H NHSO2Ph
methyl
60402-imidazolylamino- 0 Bn H NHSO2Ph
methyl
60412-imidazolylamino- 0 n-Bu H NHS02Ph
methyl
60422-imidazolylamino- 0 COCH2(3- H NHSO2Ph
methyl indolyl)
60432-imidazolylamino- 0 S02- H NHS02Ph
methyl (biphenyl)
60442-imidazolylamino- 0 CO2-n-Bu H NHSO2Ph
methyl
60452-imidazolylamino- 0 C02-i-Bu H NHS02Ph
methyl
60462-imidazolylamino- 0 CO2-t-Bu H NHSO2Ph
methyl
-243-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
60472-imidazolylamino- o-(CH2)~NH2 H NHSO2Ph
methyl
60482-imidazolylamino- 0COPh H NHSO2Ph
methyl
60492-imidazolylamino- 0 cyclopropyl- H NHSO2Ph
methyl methyl
6050 2-imidazolylamino- 0 SO2-n-Bu H NHSO2Ph
methyl
6051 2-imidazolylamino- 0 Cbz H NHSO2-~2,4,6-
methyl trimethylphenyl)
6052 2-imidazolylamino- ~ SO2Ph H NHS02-(2,4,6-
-methyl trimethylphenyl)
6053 2-imidazolylamino- o CO(CH2)2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
6054 2-imidazolylamino- 0 Bn H NHSO2-(2,4,6-
methyl trimethylphenyl)
6055 2-imidazolylamino- 0 n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
6056 2-imidazolylamino- 0 CO2-n-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
6057 2-imidazolylamino- 0 CO2-i-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
6058 2-imidazolylamino- 0 CO2-t-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
6059 2-imidazolylamino- 0 -(CH2)4NH2 H NHS02-(2,4,6-
methyl trimethylphenyl)
60602-imidazolylamino- 0COPh H NHSO2-(2,4,6-
methyl trimethylphenyl)
60612-imidazolylamino- 0SO2-n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
6062 2-imidazoly~amino- 0Cbz H NHCbz
methyl
6063 2-imidazolylamino- 0SO2Ph H NHCbz
methyl
-244-
CA 02249733 l998-09-ll
WO 97l33887 PCTrUS97/04567
6064 2-imidazolylamino- o CO(CH2)2Ph H NHCbz
methyl
6065 2-imidazolylamino- 0 Bn H NHCbz
methyl
~ 6066 2-imidazolylamino- 0 n-Bu H NHCbz
methyl
60672-imidazolylamino- 0 CO2-n-Bu H NHCbz
methyl
60682-imidazolylamino- 0 CO2-i-Bu H NHCbz
methyl
606g 2-imidazolylamino- o CO2-t-Bu H NHCbz
methyl
6070 2-imidazolylamino- o -(CH2)gNH2 H NHCbz
methyl
6071 2-imidazolylamino- 0 COPh H NHCbz
methyl
60722-imidazolylamino- 0 SO2-n-Bu H NHCbz
methyl
60732-imidazolinyl- 0 Cbz H NHSO2Ph
aminomethyl
60742-imidazolinyl- 0 SO2Ph H NHSO2Ph
aminomethyl
60752-imidazolinyl- 0 CO(CH2)2Ph H NHSO2Ph
aminomethyl
60762-imidazolinyl- 0 Bn H NHSO2Ph
aminomethyl
60772-imidazolinyl- 0 n-Bu H NHSO2Ph
~mi no~thyl
60782-imidazolinyl- 0 COCH2(3- H NHS02Ph
aminomethyl indolyl)
60792-imidazolinyl- 0 S02- H NHSO2Ph
aminomethyl (biphenyl)
60802-imidazolinyl- 0 CO2-n-Bu H NHSO2Ph
aminomethyl
-245-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
6081 2-imidazolinyl- 0CO2-i-Bu HNHSO2Ph
aminomethyl
6082 2-imidazolinyl- 0CO2-t-Bu HNHSO2Ph
aminomethyl
6083 2-imidazolinyl- 0-~CH2)4NH2 HNHSO2Ph
aminomethyl
6084 2-imidazolinyl- 0COPh HNHSO2Ph
aminomethyl
6085 2-imidazolinyl- 0 cyclopropyl- H NHSO2Ph
aminomethyl methyl
6086 2-imidazolinyl- 0SO2-n-Bu HNHSO2Ph
aminomethyl
6087 2-imidazolinyl- 0 Cbz HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
6088 2-imidazolinyl- ~ SO2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
6089 2-imidazolinyl- 0CO~CH2)2Ph HNHS02-(2,4,6-
aminomethyl trime~hylphenyl)
6090 2-imidazolinyl- 0 Bn HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
6091 2-imidazolinyl- 0 n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
6092 2-imidazolinyl- 0CO2-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
6093 2-imidazolinyl- 0CO2-i-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
6094 2-imidazolinyl- 0C02-t-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
6095 2-imidazolinyl- 0-(CH2)4NH2 HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
6096 2-imidazolinyl- 0COPh HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
6097 2-imidazolinyl- 0S02-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
-246-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
6098 2-imidazolinyl- 0Cbz H NHCbz
aminomethyl
6099 2-imidazolinyl- 0 S02Ph H NHCbz
aminomethyl
6100 2-imidazolinyl- o CO(CH2)2Ph H NHCbz
aminomethyl
6101 2-imidazolinyl- 0Bn H NHCbz
aminomethyl
6102 2-imidazolinyl- 0n-Bu H NHCbz
aminomethyl
6103 2-imidazolinyl- 0 CO2-n-Bu H NHCbz
aminomethyl
6104 2-imidazolinyl- 0 CO2-i-Bu H NHCbz
aminomethyl
6105 2-imidazolinyl- 0 C02-t-Bu H NHCbz
aminomethyl
6106 2-imidazolinyl- o -(CH2)4NH2 H NHCbz
aminomethyl
6107 2-imidazolinyl- 0COPh H NHCbz
aminomethyl
6108 2-imidazolinyl- 0 SO2-n-Bu H NHCbz
aminomethyl
6109 2-benzimidazolyl- 0 Cbz H NHSO2Ph
aminomethyl
6110 2-benzimidazolyl- 0 SO2Ph H NHSO2Ph
aminomethyl
6111 2-benzimidazolyl- 0 CO(CH2)2Ph H NHSO2Ph
aminomethyl
6112 2-benzimidazolyl- 0 Bn H NHSO2Ph
aminomethyl
6113 2-benzimidazolyl- 0 n-Bu H NHSO2Ph
aminomethyl
6114 2-benzimidazolyl- 0 COCH2(3- H NHSO2Ph
aminomethyl indolyl)
-247-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
61152-benzimidazolyl- 0S02- HNHS02Ph
aminomethyl (biphenyl)
61162-benzimidazolyl- 0C02-n-Bu HNHS02Ph
aminomethyl
61172-benzimidazolyl- 0C02-i-Bu HNHS02Ph
aminomethyl
61182-benzimidazolyl- 0C02-t-Bu HNHS02Ph
aminomethyl
61192-benzimidazolyl- 0-(CH2)4NH2 HNHS02Ph
aminomethyl
61202-benzimidazolyl- 0COPh HNHS02Ph
aminomethyl
61212-benzimidazolyl- 0 cyclopropyl- H NH502Ph
aminomethyl methyl
61222-benzimidazolyl- 0S02-n-Bu HNHS02Ph
aminomethyl
61232-benzimidazolyl- 0Cbz HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
61242-benzimidazolyl- 0S02Ph HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
61252-benzimidazolyl- 0CO(CH2)2Ph HNHS02-(2,4,6-
aminomethyl trimethylphenyl~
61262-benzimidazolyl- 0Bn HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
61272-benzimidazolyl- 0n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
61282-benzimidazolyl- 0C02-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
61292-benzimidazolyl- 0C02-i-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
61302-benzimidazolyl- 0C02-t-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
61312-benzimidazolyl- 0-(CH2)4NH2 HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
-248-
CA 02249733 l998-09-ll
W 097/33887 PCTAUS97/04567
6132 2-benzimidazolyl- 0 COPh H NHSO2-(2,4,6-
aminomethyl trimethylphenyl)
6133 2-benzimidazolyl- 0 SO2-n-Bu H NHSO2-(2,4,6-
aminomethyl trimethylphenyl)
6134 2-benzimidazolyl- 0 Cbz H NHCbz
aminomethyl
6135 2-benzimidazolyl- ~ SO2Ph H NHCbz
aminomethyl
6136 2-benzimidazolyl- 0CO(CH2)2Ph H NHCbz
aminomethyl
6137 2-benzimidazolyl- 0 Bn H NHCbz
aminomethyl
6138 2-benzimidazolyl- 0 n-Bu H NHCbz
aminomethyl
6139 2-benzimidazolyl- 0 C02-n-Bu H NHCbz
aminomethyl
6140 2-benzimidazolyl- 0 C02-i-Bu H NHCbz
aminomethyl
6141 2-benzimidazolyl- 0 C02-t-Bu H NHCbz
aminomethyl
6142 2-benzimidazolyl- 0 -(CH2)4NH2 H NHCbz
aminomethyl
6143 2-benzimidazolyl- 0COPh H NHCbz
aminomethyl
6144 2-benzimidazolyl- 0 SO2-n-Bu H NHCbz
aminomethyl
6145 7-aza-2- 0 Cbz H NHSO2Ph
benzimidazolyl
6146 7-aza-2- 0 S02Ph H NHS02Ph
benzimidazolyl
6147 7-aza-2- oCO(CH2)2Ph H NHSO2Ph
benzimidazolyl
6148 7-aza-2- 0 Bn H NHSO2Ph
benzimidazolyl
-249-
CA 02249733 l998-09-ll
W 097/33887 rcTrusg7/o4567
6149 7-aza-2- 0n-Bu HNHS02Ph
benzimidazolyl
6150 7-aza-2- 0COCH2(3- HNHS02Ph
benzimidazolyl indolyl)
6151 7-aza-2- 0S02- HNHS02Ph
benzimidazolyl (biphenyl)
6152 7-aza-2- 0C02-n-Bu HNHS02Ph
benzimidazolyl
6153 7-aza-2- oC02-i-Bu HNHS02Ph
benzimidazolyl
6154 7-aza-2- 0C02-t-Bu HNHS02Ph
benzimidazolyl
6155 7-aza-2- o-(CH2)4NH2 HNHS02Ph
benzimidazolyl
6156 7-aza-2- 0COPh HNHS02Ph
benzimidazolyl
6157 7-aza-2- 0 cyclopropyl- H NHS02Ph
benzimidazolyl methyl
6158 7-aza-2- 0S02-n-Bu HNHS02Ph
benzimidazolyl
6159 7-aza-2- 0Cbz HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6160 7-aza-2- 0S02Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6161 7-aza-2- oCO(CH2)2Ph HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6162 7-aza-2- 0Bn HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6163 7-aza-2- on-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6164 7-aza-2- 0C02-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6165 7-aza-2- 0 CO2-i-Bu H NHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
-250-
CA 02249733 l998-09-ll
W O 97/33887 PCTrUS97/04567
6166 7-aza-2- oCO2-t-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
6167 7-aza-2- 0-(CH2)4NH2 HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6168 7-aza-2- 0COPh HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl~
6169 7-aza-2- 0S02-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6170 7-aza-2- 0 Cbz H NHCbz
benzimidazolyl
6171 7-aza-2- oSO2Ph H NHCbz
benzimidazolyl
6172 7-aza-2- oCO(CH2)2Ph H NHCbz
benzimidazolyl
6173 7-aza-2- 0 Bn H NHCbz
benzimidazolyl
6174 7-aza-2- 0 n-Bu H NHCbz
benzimidazolyl
6175 7-aza-2- 0CO2-n-Bu H NHCbz
benzimidazolyl
6176 7-aza-2- 0C02-i-Bu H NHCbz
benzimidazolyl
6177 7-aza-2- 0CO2-t-Bu H NHCbz
benzimidazolyl
6178 7-aza-2- 0-(CH2)4NH2 H NHCbz
benzimidazolyl
6179 7-aza-2- 0COPh H NHCbz
benzimidazolyl
6180 7-aza-2- 0S02-n-Bu H NHCbz
benzimidazolyl
6181 tetrahydropyrimidin 0 Cbz H NHSO2Ph
-2-ylaminomethyl
6182 tetrahydropyrimidin ~SO2Ph HNHSO2Ph
-2-ylaminomethyl
-251-
CA 02249733 l998-09-ll
W 097/33887 PCTAUS97/04567
6183 tetrahydropyrimidin o C0(CH2)2Ph H NHS02Ph
-2-ylaminomethyl
6184 tetrahydropyrimidin 0 Bn H NHS02Ph
-2-ylaminomethyl
6185 tetrahydropyrimidin 0 n-Bu H NHS02Ph
-2-ylaminomethyl
6186 tetrahydropyrimidin 0 CoCH2(3- H NHS02Ph
-2-ylaminomethylindolyl)
6187 tetrahydropyrimidin 0 S02- H NHS02Ph
-2-ylaminomethyl(biphenyl)
6188 tetrahydropyrimidin 0 C02-n-Bu H NHS02Ph
-2-ylaminomethyl
618g tetrahydropyrimidin 0 C02-i-Bu H NHS02Ph
-2-ylaminomethyl
6190 tetrahydropyrimidin 0 C02-t-Bu H NHS02Ph
-2-ylaminomethyl
6191 tetrahydropyrimidin 0 -(CH2)4NH2 H NHS02Ph
-2-ylaminomethyl
6192 tetrahydropyrimidin 0 COPh H NHS02Ph
-2-ylaminomethyl
6193 tetrahydropyrimidin 0 cyclopropyl- H NHS02Ph
-2-ylaminomethylmethyl
6194 tetrahydropyrimidin 0 S02-n-Bu H NHS02Ph
-2-ylaminomethyl
6195 tetrahydropyrimidin 0 Cbz H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6196 tetrahydropyrimidin 0 S02Ph H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6197 tetrahydropyrimidin o CO(CH2)2Ph H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6198 tetrahydropyrimidin 0 Bn H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6199 tetrahydropyrimidin 0 n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
-252-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97104567
6200 tetrahydropyrimidin 0 CO2-n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6201 tetrahydropyrimidin 0 CO~-i-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6202 tetrahydropyrimidin 0 CO2-t-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6203 tetrahydropyrimidin o -(CH2)4NH2 H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6204 tetrahydropyrimidin 0 COPh H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6205 tetrahydropyrimidin 0 SO2-n-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6206 tetrahydropyrimidin 0 Cbz H NHCbz
-2-ylaminomethyl
6207 tetrahydropyrimidin 0 SO2Ph H NHCbz
-2-ylaminomethyl
6208 tetrahydropyrimidin o CO(CH2)2Ph H NHCbz
-2-ylaminomethyl
6209 tetrahydropyrimidin 0 Bn H NHCbz
-2-ylaminomethyl
6210 tetrahydropyrimidin 0 n-Bu H NHCbz
-2-ylaminomethyl
6211 tetrahydropyrimidin 0 CO2-n-Bu H NHCbz
-2-ylaminomethyl
6212 tetrahydropyrimidin 0 CO2-i-Bu H NHCbz
-2-ylaminomethyl
6213 tetrahydropyrimidin 0 CO2-t-Bu H NHCbz
-2-ylaminomethyl
6214 tetrahydropyrimidin 0 -(CH2)4NH2 H NHCbz
-2-ylaminomethyl
6215 tetrahydropyrimidin 0 COPh H NHCbz
-2-ylaminomethyl
- 6216 tetrahydropyrimidin 0 SO2-n-Bu H NHCbz
-2-ylaminomethyl
-253-
CA 02249733 l998-09-ll
W 097/33887 PCT~US97/04567
62172-pyridinylamino- 1 Cbz HNHS02Ph
methyl
62182-pyridinylamino- 1S02Ph HNHS02Ph
methyl
62192-pyridinylamino- 1CO(CH2)2Ph HNHS02Ph
methyl
622Q2-pyridinylamino- 1 Bn HNHS02Ph
methyl
62212-pyridinylamino- 1 n-Bu HNHS02Ph
methyl
62222-pyridinylamino- 1COCH2(3- HNHS02Ph
methyl indolyl)
62232-pyridinylamino- 1 S02- HNHS02Ph
methyl (biphenyl)
62242-pyridinylamino- 1C02-n-Bu HNHS02Ph
methyl
62252-pyridinylamino- 1C02-i-Bu HNHS02Ph
methyl
62262-pyridinylamino- 1C02-t-Bu HNHS02Ph
methyl
62272-pyridinylamino- 1-(CH2)4NH2 HNHS02Ph
methyl
62282-pyridlnylamino- 1COPh HNHS02Ph
methyl
62292-pyridinylamino- 1 cyclopropyl- H NHS02Ph
methyl methyl
62302-pyridinylamino- 1S02-n-Bu HNHS02Ph
methyl
62312-pyridinylamino- 1 Cbz HNHS02-(2,4,6-
methyl trimethylphenyl)
62322-pyridinylamino- 1S02Ph HNHS02-(2,4,6-
methyl trimethylphenyl)
62332-pyridinylamino- 1CO~CH2)2Ph HNHS02-(2,4,6-
methyl trimethylphenyl)
-254-
CA 02249733 l998-09-ll
W 097/33887 PCTrUS97/04567
62342-pyridinylamino- 1Bn HNHS02-(2,4,6-
methyl trimethylphenyl)
62352-pyridinylamino- 1n-Bu HNH502-(2,4,6-
methyl trimethylphenyl)
- 62362-pyridinylamino- 1C02-n-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
62372-pyridinylamino- 1CO2-i-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
62382-pyridinylamino- 1CO2-t-Bu HNHSO2-(2,4,6-
methyl trimethylphenyl)
62392-pyridinylamino- 1-(CH2)4NH2 HNHS02-(2,4,6-
methyl trimethylphenyl)
62402-pyridinylamino- 1COPh HNHSO2-(2,4,6-
methyl trimethylphenyl)
62412-pyridinylamino- 15O2-n-Bu HNHS02-(2,4,6-
methyl trimethylphenyl)
6242 2-pyridinylamino- 1 Cbz H NHCbz
methyl
62432-pyridinylamino- 1SO2Ph H NHCbz
methyl
62g42-pyridinylamino- 1CO~CH2)2Ph H NHCbz
methyl
6245 2-pyridinylamino- 1 Bn H NHCbz
methyl
6246 2-pyridinylamino- 1 n-Bu H NHCbz
methyl
62472-pyridinylamino- 1CO2-n-Bu H NHCbz
methyl
62482-pyridinylamino- 1Co2-i-Bu H NHCbz
methyl
62492-pyridinylamino- 1CO2-t-Bu H NHCbz
methyl
62502-pyridinylamino- 1-(CH2)4NH2 H NHCbz
methyl
-255-
CA 02249733 l998-09-ll
W O 97l33887 PCTrUS97/04567
6251 2-pyridinylamino- 1COPh H NHCbz
methyl
6252 2-pyridinylamino- 1 S02-n-Bu H NHCbz
methyl
6253 2-imidazolylamino- 1 Cbz H NHS02Ph
methyl
6254 2-imidazolylamino- 1 S02Ph H NHS02Ph
methyl
6255 2-imidazolylamino- 1CO(CH2)2Ph H NHS02Ph
methyl
6256 2-imidazolylamino- l Bn H NHS02Ph
methyl
6257 2-imidazolylamino- 1 n-Bu H NHS02Ph
methyl
6258 2-imidazolylamino- 1 COCH2(3- H MHS02Ph
methyl indolyl)
6259 2-imidazolylamino- 1 S02- H NHS02Ph
methyl (biphenyl)
6260 2-imidazolylamino- 1 C02-n-Bu H NHS02Ph
methyl
6261 2-imidazolylamino- 1 C02-i-Bu H NHS02Ph
methyl
6262 2-imidazolylamino- 1 C02-t-Bu H NHS02Ph
methyl
6263 2-imidazolylamino- 1-(CH2)4NH2 H NHS02Ph
methyl
6264 2-imidazolylamino- 1 COPh H NHS02Ph
methyl
6265 2-imidazolylamino- 1 cyclopropyl- H NHS02Ph
methyl methyl
6266 2-imidazolylamino- 1 S02-n-Bu H NHS02Ph
methyl
6267 2-imidazolylamino- 1 Cbz H NHS02-(2,4,6-
methyl trimethylphenyl)
-256-
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6268 2-imidazolylamino- 1 SO2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
6269 2-imidazolylamino- 1CO(CH2)2Ph H NHSO2-(2,4,6-
methyl trimethylphenyl)
6270 2-imidazolylamino- 1 Bn H NHSO2-(2,4,6-
methyl trimethylphenyl)
6271 2-imidazolylamino- 1 n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
6272 2-imidazolylamino- 1CO2-n-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
6273 2-imidazolylamino- 1CO2-i-Bu H NHSO2-(2,4,6-
methyl trimethylphenyl)
6274 2-imidazolylamino- 1CO2-t-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
6275 2-imidazolylamino- 1-(CH2)4NH2 H NHSO2-(2,4,6-
methyl trimethylphenyl)
6276 2-imidazolylamino- 1 COPh H NHS02-(2,4,6-
methyl trimethylphenyl)
6277 2-imidazolylamino- 1S02-n-Bu H NHS02-(2,4,6-
methyl trimethylphenyl)
6278 2-imidazolylamino- 1 Cbz H NHCbz
methyl
6279 2-imidazolylamino- 1 SO2Ph H NHCbz
methyl
6280 2-imidazolylamino- 1CO(CH2)2Ph H NHCbz
methyl
6281 2-imidazolylamino- 1Bn H NHCbz
methyl
6282 2-imidazolylamino- 1n-Bu H NHCbz
methyl
6283 2-imidazolylamino- 1C02-n-Bu H NHCbz
methyl
6284 2-imidazolylamino- 1CO2-i-Bu H NHCbz
methyl
-257-
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6285 2-imidazolylamino- 1CO2-t-Bu H NHCbz
methyl
6286 2-imidazolylamino- 1-(CH2)4NH2 H NHCbz
methyl
6287 2-imidazolylamino- 1COPh H NHCbz
methyl
6288 2-imidazolylamino- 1 SO2-n-Bu H NHCbz
methyl
6289 2-imidazolinyl- 1 Cbz H NHSO2Ph
aminomethyl
6290 2-imidazolinyl- 1 SO2Ph H NHSO2Ph
aminomethyl
6291 2-imidazolinyl- 1 CO(CH2)2Ph H NHSO2Ph
aminomethyl
6292 2-imidazolinyl- 1 Bn H NHSO2Ph
aminomethyl
6293 2-imidazolinyl- 1 n-Bu H NHSO2Ph
aminomethyl
6294 2-imidazolinyl- 1 COCH2~3- H NHSO2Ph
aminomethyl indolyl)
6295 2-imidazolinyl- 1 S02- H NHSO2Ph
aminomethyl (biphenyl)
6296 2-imidazolinyl- 1 CO2-n-Bu H NHSO2Ph
aminomethyl
6297 2-imidazolinyl- 1 CO2-i-Pu H NHSO2Ph
aminomethyl
6298 2-imidazolinyl- 1 CO2-t-Bu H NHSO2Ph
aminomethyl
6299 2-imidazolinyl- 1 -(CH2)4NH2 H NHS02Ph
aminomethyl
6300 2-imidazolinyl- 1 COPh H NHSO2Ph
aminomethyl
6301 2-imidazolinyl- 1 cyclopropyl- H NHSO2Ph
aminomethyl methyl
-258-
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63022-imidazolinyl- 1SO2-n-Bu HNHSO2Ph
aminomethyl
63032-imidazolinyl- 1Cbz HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63042-imidazolinyl- lSO2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63052-imidazolinyl- 1CO(CH2)2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63062-imidazolinyl- 1Bn HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63072-imidazolinyl- 1n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63082-imidazolinyl- 1CO2-n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63092-imidazolinyl- 1CO2-i-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63102-imidazolinyl- 1CO2-t-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63112-imidazolinyl- 1-(CH2)~NH2 HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
63122-imidazolinyl- 1COPh HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63132-imidazolinyl- 1SO2-n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
6314 2-imidazolinyl- 1 Cbz H NHCbz
aminomethyl
63152-imidazolinyl- 1SO2Ph HNHCbz
aminomethyl
63162-imidazolinyl- 1CO(CH2)2Ph HNHCbz
aminomethyl
6317 2-imidazolinyl- 1Bn H NHCbz
aminomethyl
6318 2-imidazolinyl- 1n-Bu H NHCbz
aminomethyl
-259-
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6319 2-imidazolinyl- 1C02-n-Bu H NHCbz
aminomethyl
6320 2-imidazolinyl- 1C02-i-Bu H MHCbz
amlnomethyl
6321 2-imidazolinyl- 1C02-t-Bu H NHCbz
aminomethyl
6322 2-imidazolinyl- 1-(CH2)4NH2 H NHCbz
aminomethyl
6323 2-imidazolinyl- 1COPh H NHCbz
aminomethyl
6324 2-imidazolinyl- 1 S02-n-Bu H NHCbz
- aminomethyl
6325 2-benzimidazolyl- 1 Cbz H NHS02Ph
aminomethyl
6326 2-benzimidazolyl- 1 S02Ph H NHS02Ph
aminomethyl
6327 2-benzimidazolyl- 1 CO(CH2)2Ph H NHS02Ph
aminomethyl
6328 2-benzimidazolyl- 1 Bn H NHS02Ph
aminomethyl
6329 2-benzimidazolyl- 1 n-Bu H NHS02Ph
aminomethyl
6330 2-benzimidazolyl- 1 COCH2(3- H NHS02Ph
aminomethyl indolyl)
6331 2-benzimidazolyl- 1 502- H NHS02Ph
aminomethyl (biphenyl)
6332 2-benzimidazolyl- 1 C02-n-Bu H NHS02Ph
aminomethyl
6333 2-benzimidazolyl- 1 C02-i-Bu H NHS02Ph
aminomethyl
6334 2-benzimidazolyl- 1 C02-t-Bu H NHS02Ph
aminomethyl
6335 2-benzimidazolyl- 1 -(CH2)4NH2 H NHS02Ph
aminomethyl
-260-
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63362-benzimidazolyl- 1 COPh HNHSO2Ph
aminomethyl
63372-benzimidazolyl- 1 cyclopropyl- H NHSO2Ph
aminomethyl methyl
63382-benzimidazolyl- 1SO2-n-Bu HNHSO2Ph
aminomethyl
63392-benzimidazolyl- 1 Cbz HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
63402-benzimidazolyl- 1SO2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63412-benzimidazolyl- 1CO(CH2)2Ph HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63422-benzimidazolyl- 1 Bn HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63432-benzimidazolyl- 1 n-Bu HMHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63442-benzimidazolyl- 1C02-n-Bu HNHS02-(2,4,6-
aminomethyl trimethylphenyl)
63452-benzimidazolyl- 1CO2-i-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63462-benzimidazolyl- 1CO2-t-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63472-benzimidazolyl- 1-(CH2)4MH2 HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63482-benzimidazolyl- 1COPh HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
63492-benzimidazolyl- 1SO2-n-Bu HNHSO2-(2,4,6-
aminomethyl trimethylphenyl)
6350 2-benzimidazolyl- 1 Cbz H NHCbz
aminomethyl
63512-benzimidazolyl- 1SO2Ph H NHCbz
aminomethyl
63522-benzimidazolyl- 1CO(CH2)2Ph H NHCbz
aminomethyl
-261-
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6353 2-benzimidazolyl- 1 Bn H NHCbz
aminomethyl
6354 2-benzimidazolyl- 1 n-Bu H NHCbz
aminomethyl
6355 2-benzimidazolyl- 1 C02-n-Bu H NHCbz
aminomethyl
6356 2-benzimidazolyl- 1 C02-i-Bu H NHCbz
aminomethyl
6357 2-benzimidazolyl- 1 C02-t-Bu H NHCbz
aminomethyl
6358 2-benzimidazolyl- 1 -(CH2)4NH2 H NHCbz
aminomethyl
6359 2-benzimidazolyl- 1COPh H NHCbz
aminomethyl
6360 2-benzimidazolyl- 1 S02-n-Bu H NHCbz
aminomethyl
6361 7-aza-2- 1 Cbz H NHS02Ph
benzimidazolyl
6362 7-aza-2- 1 S02Ph H NHS02Ph
benzimidazolyl
6363 7-aza-2- 1 C0~CH2)2Ph H NHS02Ph
benzimidazolyl
6364 7-aza-2- 1 Bn H NHS02Ph
benzimidazolyl
6365 7-aza-2- 1 n-Bu H NHS02Ph
benzimidazolyl
6366 7-aza-2- 1 COCH2(3- H NHS02Ph
benzimidazolyl indolyl)
6367 7-aza-2- 1 S02- H NHS02Ph
benzimidazolyl (biphenyl)
6368 7-aza-2- 1 C02-n-Bu H NHS02Ph
benzimidazolyl
6369 7-aza-2- 1 C02-i-Bu H NHS02Ph
benzimidazolyl
-262-
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6370 7-aza-2- 1CO2-t-Bu HNHSO2Ph
benzimidazolyl
6371 7-aza-2- 1-(CH2)4NH2 HNHSO2Ph
benzimidazolyl
6372 7-aza-2- 1COPh HNHSO2Ph
benzimidazolyl
6373 7-aza-2- 1 cyclopropyl- H NHSO2Ph
benzimidazolyl methyl
6374 7-aza-2- 1SO2-n-Bu HNHSO2Ph
benzimidazolyl
6375 7-aza-2- 1Cbz HNHSO2-~2,4,6-
benzimidazolyl trimethylphenyl)
6376 7-aza-2- 1SO2Ph HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
6377 7-aza-2- 1CO(CH2)2Ph HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
6378 7-aza-2- 1Bn HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
6379 7-aza-2- 1n-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
6380 7-aza-2- 1CO2-n-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
6381 7-aza-2- 1CO2-i-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6382 7-aza-2- 1CO2-t-Bu HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
6383 7-aza-2- 1-(CH2)4NH2 HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6384 7-aza-2- 1COPh HNHSO2-(2,4,6-
benzimidazolyl trimethylphenyl)
6385 7-aza-2- 1SO2-n-Bu HNHS02-(2,4,6-
benzimidazolyl trimethylphenyl)
6386 7-aza-2- 1Cbz HNHCbz
benzimidazolyl
-263-
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6387 7-aza-2- 1SO2Ph H NHCbz
benzimidazolyl
6388 7-aza-2- 1CO(CH2)2Ph H NHCbz
benzimidazolyl
6389 7-aza-2- 1Bn H NHCbz
benzimidazolyl
6390 7-aza-2- 1n-Bu H NHCbz
benzimidazolyl
6391 7-aza-2- 1CO2-n-Bu H NHCbz
benzimidazolyl
6392 7-aza-2- 1CO2-i-BU H NHCbz
benzimidazolyl
6393 7-aza-2- 1CO2-t-Bu H NHCbz
benzimidazolyl
6394 7-aza-2- 1-(CH2)4NH2 H NHCbz
benzimidazolyl
6395 7-aza-2- 1COPh H NHCbz
benzimidazolyl
6396 7-aza-2- 1SO2-n-Bu H NHCbz
benzimidazolyl
6397 tetrahydropyrimidin 1 Cbz H NHSO2Ph
-2-ylaminomethyl
6398 tetrahydropyrimidin 1 SO2Ph H NHSO2Ph
-2-ylaminomethyl
6399 tetrahydropyrimidin 1 CO(CH2)2Ph H NHSO2Ph
-2-ylaminomethyl
6400 tetrahydropyrimidin 1 Bn H NHSO2Ph
-2-ylaminomethyl
6401 tetrahydropyrimidin 1 n-Bu H NHSO2Ph
-2-ylaminomethyl
6402 tetrahydropyrimidin 1 COCH2(3- H NHSO2Ph
-2-ylaminomethylindolyl)
6403 tetrahydropyrimidin 1 S02- H NHSO2Ph
-2-ylaminomethyl(biphenyl)
-264-
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6404 tetrahydropyrimidin 1 C02-n-Bu H NHS02Ph
-2-ylaminomethyl
6405 tetrahydropyrimidin 1 CO2-i-Bu H NHSO2Ph
-2-ylaminomethyl
6406 tetrahydropyrimidin 1 CO2-t-Bu H NHSO2Ph
-2-ylaminomethyl
6407 tetrahydropyrimidin 1 -(CH2)4NH2 H NHSO2Ph
-2-ylaminomethyl
6408 tetrahydropyrimidin 1 COPh H NHS02Ph
-2-ylaminomethyl
6409 tetrahydropyrimidin 1 cyclopropyl- H NHS02Ph
-2-ylaminomethylmethyl
6410 tetrahydropyrimidin 1 SO2-n-Bu H NHSO2Ph
-2-ylaminomethyl
6411 tetrahydropyrimidin 1 Cbz H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6412 tetrahydropyrimidin 1 SO2Ph H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6413 tetrahydropyrimidin 1 CO~CH2)2Ph H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6414 tetrahydropyrimidin 1 Bn H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6415 tetrahydropyrimidin 1 n-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6416 tetrahydropyrimidin 1 CO2-n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6417 tetrahydropyrimidin 1 CO2-i-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6418 tetrahydropyrimidin 1 CO2-t-Bu H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6419 tetrahydropyrimidin 1 -(CH2)4NH2 H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6420 tetrahydropyrimidin 1 COPh H NHSO2-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
-265-
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6421 tetrahydropyrimidin 1 SO2-n-Bu H NHS02-(2,4,6-
-2-ylaminomethyl trimethylphenyl)
6422 tetrahydropyrimidin 1 Cbz H NHCbz
-2-ylaminomethyl
6423 tetrahydropyrimidin 1 SO2Ph H NHCbz
-2-ylaminomethyl
6424 tetrahydropyrimidin 1 CO~CH2)2Ph H NHCbz
-2-ylaminomethyl
6425 tetrahydropyrimidin 1 Bn H NHCbz
-2-ylaminomethyl
6426 tetrahydropyrimidin 1 n-Bu H NHCbz
-2-ylaminomethyl
6427 tetrahydropyrimidin 1 CO2-n-Bu H NHCbz
-2-ylaminomethyl
6428 tetrahydropyrimidin 1 CO2-i-Bu H NHCbz
-2-ylaminomethyl
6429 tetrahydropyrimidin 1 CO2-t-Bu H NHCbz
-2-ylaminomethyl
6430 tetrahydropyrimidin 1 -(CH2)~NH2 H NHCbz
-2-ylaminomethyl
6431 tetrahydropyrimidin 1 COPh H NHCbz
-2-ylaminomethyl
6432 tetrahydropyrimidin 1 SO2-n-Bu H NHCbz
-2-ylaminomethyl
-266-
