CA2249733A1 - Spirocycle integrin inhibitors - Google Patents

Abstract

This invention relates to novel heterocycles, including (S)-2-phenylsulfonylamino-3-[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionic acid, which are useful as antagonists of the .alpha.v.beta.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.

Description

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, 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 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 W097/33887 PCT~Sg7/04567 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.

w097/33887 pcT~ss7lo4s67 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:

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.

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 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 W O 97/33887 PCTrUS97/04567 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;

W097/33887 PCT~S97/04567 Rl is selected from:
B--N ( ~ N M--N

O NH

\>--U-- I \~ U [~ V-- X~,--V--. ~tJ' I <\ ~ V-- ~ ~ 'N~ V-- N V--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-;

W097/33887 PcT~ss7lo4s67 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 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 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)-;

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, W097l33887 pcT~ss7lo4s67 ~ 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, W O 97/33887 PCTrUS97/04567 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.

W O 97/33887 PCTrUS97/04S67 ~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 WO 97/33887 PCTtUS97tO4567 R10;

~ ~~ CX~ .

- --N~/ ~/ , ~/, NX~ X~ N~/

~ N~/ ~ N~/

~~~ ~/R10a ~, R1 ~~ R1o or --N~/

CA 02249733 l998-og-ll W O 97/33887 PCTrUS97/04567 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--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, W O 97/33887 PCT~USg7/04567 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)-;

W097/33887 . PCT~S97/04567 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 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, 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 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, 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:

W 097/33887 PCTrUS97/04567 Q ls selected from:

~/ ~N~ .

N~

R~ R

Rl~

~ ~ . or ~ O~ ~R10a .

Rl ls selected from:

¢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-~N~ , HN

, or ~V

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 ) -;

W O 97/33887 PCTrUS97/04567 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

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 W097/33887 PCTrUS97/04567 pharmaceutically acceptable salt or prodrug forms thereof wherein:

Q is selected from:

--N~/ ~N~/, ~/

~/ R ~ ~

~ R10~

Rl is selected from:

W 097/33887 PCT~US97/04567 ¢ \~U-- C ~U-- ~ ~U

U ¢ \~ U ~ U

~U [~¢ \~U-- ~¢ \~U

~N~_ R2NH~rN F~2NH~V--~=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 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:

W O 97t33887 PCTrUS97/04567 -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-, W 097/33887 PCTrUS97/04567 (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, 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, 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-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, W O 97/33887 PCTrUS97/04S67 (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-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, W 097/33887 . PCTrUSg7/04567 (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-w097/33887 PCT~S97/04567 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 W O 97/33887 PCTrUS97/04567 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, W097/33887 PCT~S97/04567 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, W097/33887 PCT~S97/04567 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 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 -W O 97133887 PCT~US97/04567 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 W097/33887 PcT~S97/04567 - 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 W O 97/33887 PCT~US97/04567 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 W O 97/33887 PCTrUS97/04567 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.

W O 97/33887 PCT~US97/04~67 ~ 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 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), W097/33887 PCTrUS97/04567 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-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, 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.

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 W O g7/33887 . PCT~US97/04567 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-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).

W 097/33887 pcTrus97lo4s67 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.

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 ~ ~>~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) 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.

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 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.

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 ~ 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 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).

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) 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 Ç?_N~N ~~NH;116 6N HCI

NHBOC 6(fl N~N ~NHR"

NH2 6(9) 7 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).

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) W 097/33887 PCT~US97/04567 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).

W O 97t33887 PCTtUS97/04567 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 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).

W O 97/33887 PCT~US97/04S67 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 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 W O 97t33887 PCTrUS97/04567 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 W O 97/33887 PCT~US97/04567 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%

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 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) W O 97/33887 PCTrUS97/04567 (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 W097/33887 PCT~S97/04567 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 W O 97/33887 PCTrUS97/04567 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 W097l33887 PCT~S97/04567 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 W 097/33887 PCT~US97/04567 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 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 W097/33887 pcT~ss7lo4s67 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 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 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 W097/33887 PCT~S97/04567 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.

W097/33887 PCT~S97/04567 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

W 097/33887 PCTrUS97/04567 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 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--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.

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 W097/33887 PCT~S97/04567 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 W097/33887 PCT~S97/04567 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.

W097/33887 PCT~S97/04S67 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 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 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 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 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.

CA 02249733 l998-09-ll 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) _99_ CA 02249733 l998-09-ll 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) CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04S67 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) CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W 097/33887 PCT~US97/04567 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) CA 02249733 l998-09-ll W 097/33887 PCTrUS97104S67 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) 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) ..

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 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) -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) 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 CA 02249733 l998-09-ll 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 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) 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 CA 02249733 l998-09-ll 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 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 CA 02249733 l998-09-ll 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 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 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 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 CA 02249733 l998-09-ll 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 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) CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W O 97/33887 PCTrUSg7/04567 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 CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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) CA 02249733 l998-09-ll W 097l33887 PCT~US97/04567 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) CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W O 97/33887 PCT~US97104567 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 CA 02249733 l998-09-ll W O 97l33887 PCT~US97/04567 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) CA 02249733 l998-09-ll 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) CA 02249733 l998-09-ll 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) CA 02249733 l998-09-ll W 097/33887 PCT~US97/04567 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) CA 02249733 l998-09-ll 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]

CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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) CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W O 97t33887 PCTtUS97/04567 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

CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W O 97/33887 PCT~US97/04567 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W O 97l33887 PCTrUS97/04~67 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 CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W 097/33887 PCT~US97/04567 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) CA 02249733 l998-09-ll 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 W O 97133887 PCTrUS97/04S67 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 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 CA 02249733 l998-09-ll W 097/33887 PCT~USg7/04567 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) CA 02249733 l998-09-ll W O 97t33887 PCTrUS97/04567 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 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 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) CA 02249733 l998-09-ll 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 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 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) 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 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 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) -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 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 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) 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 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 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 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~

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 CA 02249733 l998-09-ll 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 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) 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 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 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) 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 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 CA 02249733 l998-09-ll 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) 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 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 -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) 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 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 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) 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 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) 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 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 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 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) CA 02249733 l998-09-ll 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) 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 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) 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 CA 02249733 l998-09-ll 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 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 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 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) -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 CA 02249733 l998-09-ll 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) 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 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) 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 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 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 CA 02249733 l998-09-ll W O 97l33887 PCTAUS97/04567 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) 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) CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 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) 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W O 97/33887 PCT~US97/04567 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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) CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97104567 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 CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W 097/33887 PCTtUS97tO4567 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 CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W O 97t33887 PCT~US97/04567 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 CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04S67 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) CA 02249733 l998-09-ll 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) CA 02249733 l998-09-ll W O 97t33887 PCT~US97/04567 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) CA 02249733 l998-09-ll W 097/33887 PCT~US97/04567 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 CA 02249733 l998-09-ll 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) CA 02249733 l998-09-ll 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 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 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 CA 02249733 l998-09-ll W O 97t33887 PCTtUS97/04567 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) CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W O 97l33887 PCT~US97/04567 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) CA 02249733 l998-09-ll W O 97/33887 PCT~US97/04567 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 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 CA 02249733 l998-09-ll W O 97/33887 rCT~US97/04567 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 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 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 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 CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W O 97/33887 PCT~US97/04567 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) 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) CA 02249733 l998-09-ll 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 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 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 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 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 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 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) 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) 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) CA 02249733 l998-09-ll 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 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) 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 CA 02249733 l998-09-ll 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) 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 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) 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 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) CA 02249733 l998-09-ll W 097l33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W O97/33887 PCT~US97104567 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 CA 02249733 l998-09-ll 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W 097/33887 PCTrUS97/04567 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 CA 02249733 l998-09-ll W 097l33887 PCTA~S97/04567 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 CA 02249733 l998-09-ll 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) CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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) CA 02249733 l998-09-ll W O 97/33887 PCTrUS97/04567 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

Claims (7)

WHAT IS CLAIMED IS:

1. A compound of Formula I:

(I) and pharmaceutically acceptable salt forms thereof, wherein:

Q is selected from or ;
A is selected from -N(R10)-, -C(R11)- or -O-;

A1 is selected from -O- or -N(R10)-;

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 R10 or R10a;

R1 is selected from:
, , , , , , , , or R7R6N~ V~ , , , ;

B is independently selected from -CH2-, -O-, -N(R2)-, or -C(=O)-;

B1 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 -C(R4)2C(R5)2-;

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, 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 C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;

R3 isselected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 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, C1-C4 alkoxy, halo, cyano, amino, CF3, or NO2;

R6 is selected from: H, C1-C4 alkyl, or benzyl;

R7 and R8 are independently selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, or heteroaryl(C0-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-;
-N(R6) (CH2)mC(=O)-;

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, 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;

R10 is selected from: H, C22R17, C(=O)R17, C(=O)NR17R20, -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, C(=O)NR17R20, -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;

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(R12)2)qO(C(R12)2)q-, -(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(R12)2)qC(R12)(R14)-C(R12)(R15)-;

alternatively, W and X can be taken together to be ;
R12 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C10 cycloalkylalkyl, (C1-C4 alkyl)carbonyl, aryl, or aryl(C1-C6 alkyl)-;

R13 is selected from H, C1-C6 alkyl, C3-C7 cycloalkylmethyl, or aryl(C1-C6 alkyl)-R14 is selected from:

H, C1-C6 alkylthio(C1-C6 alkyl)-, aryl(C1-C10 alkylthioalkyl)-, aryl(C1-C10 alkoxyalkyl)-, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C6 hydroxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-, heteroaryl(C1-C6 alkyl)-, aryl, heteroaryl, CO2R17 C(=O)R17, or CONR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-1 R16 or 0-2 R11;

R15 is selected from:
H, R16, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C10 alkylaminoalkyl, C1-C10 dialkylaminoalkyl, (C1-C10 alkyl)carbonyl, aryl(C0-C6 alkyl)carbonyl, C1-C10 alkenyl, C1-C10 alkynyl ,C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-, heteroaryl(C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O) R17, CONR17R20, SO2R17, or SO2NR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-2 R11;

Y is selected from:
-COR19, -SO3H, -PO3H, tetrazolyl, -CONHNHSO2CF3, -CONHSO2R17, -CONHSO2NHR17, -NHCOCF3, -NHCONHSO2R17, -NHSO2R1, -OPO3H2, -OSO3H, -PO3H2, -SO3H, -SO2NHCOR17, - SO2NHCO2R17, , , or ;

R16 is selected from:
-N(R20)-C(=O)-O-R17, -N(R20)-C(=O)-R17 -N(R20)-C(=O)-NH-R17, -N(R20)SO2-R17, or -N(R20)SO2-NR20R17;

R17 is selected from:
C1-C10 alkyl, C3-C11 cycloalkyl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl)aryl, heteroaryl(C1-C6 alkyl)-, (C1-C6 alkyl)heteroaryl, arylaryl(C1-C6 alkyl)-, heteroarylaryl(C1-C6 alkyl)-, arylheteroaryl(C1-C6 alkyl)-, heteroarylheteroaryl(C1-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: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;

R18 is selected from:
H, -C(=O)-O-R17 -C(=O)-R17, -C(=O)-NH-R17, -SO2-R17, or - SO2-NR20R17;

R19 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C1-C6 alkoxy)-, C3-C10 alkylcarbonyloxyalkyloxy, C3-C10 alkoxycarbonyloxyalkyloxy, C2-C10 alkoxycarbonylalkyloxy, C5-C10 cycloalkylcarbonyloxyalkyloxy, C5-C10 cycloalkoxycarbonyloxyalkyloxy, C5-C10 cycloalkoxycarbonylalkyloxy, C7-C11 aryloxycarbonylalkyloxy, C8-C12 aryloxycarbonyloxyalkyloxy, C8-C12 arylcarbonyloxyalkyloxy, C5-C10 alkoxyalkylcarbonyloxyalkyloxy, C5-C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10-C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R11)(R12)N-(C1-C10 alkoxy)-;

R20 is 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;

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.

2. A compound of Claim 1 of the Formula I:

(I) and pharmaceutically acceptable salt forms thereof wherein:

Q is selected from:

, ,, , , , , , , , , , , , , , , , , , , , or ;

R1 is selected from:

, , , , , , , , , , ;

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-;

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, 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, or aryl(C1-C6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;

R3 is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 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, 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: C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3, or NO2;

R6 is selected from: H, C1-C4 alkyl, or benzyl;

R7 and R8 are independently selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, or heteroaryl(C0-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-;

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, 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;

R10 is selected from: H, CO2R17, C(=O)R17, C(=O)NR17R20, -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, C(=O)NR17R20, -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;

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(R12)2)qO(C(R12)2)q-, -(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(R12)2)qC(R12)(R14)-C(R12)(R15)-;

alternatively, W and X can be taken together to be ;

R12 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C10 cycloalkylalkyl, (C1-C4 alkyl)carbonyl, aryl, or aryl(C1-C6 alkyl)-;

R13 is selected from H, C1-C6 alkyl, C3-C7 cycloalkylmethyl, or aryl(C1-C6 alkyl)-;

R14 is selected from:
H, C1-C6 alkylthio(C1-C6 alkyl)-, aryl(C1-C10 alkylthioalkyl)-, aryl(C1-C10 alkoxyalkyl)-, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C6 hydroxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-, heteroaryl(C1-C6 alkyl)-, aryl, heteroaryl, CO2R17 C(=O)R17, or CONR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-1 R16 or 0-2 R11;

R15 is selected from:
H, R16, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C10 alkylaminoalkyl, C1-C10 dialkylaminoalkyl, (C1-C10 alkyl)carbonyl, aryl(C0-C6 alkyl)carbonyl, C1-C10 alkenyl, C1-C10 alkynyl ,C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-, heteroaryl(C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17 CONR17R20, SO2R17, or SO2NR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-2 R11;

Y is selected from:
-COR19, -SO3H, -PO3H, tetrazolyl, -CONHNHSO2CF3, -CONHSO2R17, -CONHSO2NHR17, -NHCOCF3, -NHCONHSO2R17, -NHSO2R17, -OPO3H2, -OSO3H, -PO3H2, -SO3H, - SO2NHCOR17, - SO2NHCO2R17, , , or ;
R16 is selected from:
-N(R20)-C(=O)-O-R17 -N(R20)-C(=O)-R17 -N(R20)-C(=O)-NH-R17 -N(R20)SO2-R17, or -N(R20) SO2-NR20R17;

R17 is selected from:

C1-C10 alkyl, C3-C11 cycloalkyl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl)aryl, heteroaryl(C1-C6 alkyl)-, (C1-C6 alkyl)heteroaryl, arylaryl(C1-C6 alkyl)-, heteroarylaryl(C1-C6 alkyl)-, arylheteroaryl(C1-C6 alkyl)-, heteroarylheteroaryl(C1-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: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;

R18 is selected from:
H, -C(=O)-O-R17, -C(=O)-R17, -C(=O)-NH-R17, -SO2-R17, or - SO2-NR20R17;

R19 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C1-C6 alkoxy)-, C3-C10 alkylcarbonyloxyalkyloxy, C3-C10 alkoxycarbonyloxyalkyloxy, C2-C10 alkoxycarbonylalkyloxy, C5-C10 cycloalkylcarbonyloxyalkyloxy, C5-C10 cycloalkoxycarbonyloxyalkyloxy, C5-C10 cycloalkoxycarbonylalkyloxy, C7-C11 aryloxycarbonylalkyloxy, C8-C12 aryloxycarbonyloxyalkyloxy, C8-C12 arylcarbonyloxyalkyloxy, C5-C10 alkoxyalkylcarbonyloxyalkyloxy, C5-C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10-C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R11)(R12)N-(C1-C10 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;

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.

3. A compound of Claim 1 of the Formula I and pharmaceutically acceptable salt forms thereof wherein:

Q is selected from:

, , , , , , , , , , , , , , or , R1 is selected from:

, , , , , , , , , , , , , , IMG>, , , , , , , , , , , , ,,, , , , ,or ;

wherein the above heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH2, halogen, NO2, CN, CF3, C1-C4 alkoxy, C1-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, COR17, C(=O)R17, CONR17R20, -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, -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;

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(R14)-CH(R15)-;

R13 is H or CH3;

R14 is selected from:
H, C1-C10 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:
-N(R20)-C(=O)-O-R17 -N(R20)-C(=O)-R17 -N(R20)-C(=O)-NH-R17 -N(R20)SO2-R17, or -N(R20)SO2-N(R20)R17;

R17 is selected from:
C1-C10 alkyl, C3-C11 cycloalkyl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl)aryl, heteroaryl(C1-C6 alkyl)-, (C1-C6 alkyl)heteroaryl, arylaryl(C1-C6 alkyl)-, heteroarylaryl(C1-C6 alkyl)-, arylheteroaryl(C1-C6 alkyl)-, heteroarylheteroaryl(C1-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: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;

R19 is selected from:
hydroxy, C1-C10 alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-, 1-(methylcarbonyloxy)ethoxy-, 1-(ethylcarbonyloxy)ethoxy-, 1-(t-butylcarbonyloxy)ethoxy-, 1-(cyclohexylcarbonyloxy)ethoxy-, i-propyloxycarbonyloxymethoxy-, t-butyloxycarbonyloxymethoxy-, 1-(i-propyloxycarbonyloxy)ethoxy-, 1-(cyclohexyloxycarbonyloxy)ethoxy-, 1-(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. A compound of Claim 1 of the Formula I and pharmaceutically acceptable salt forms thereof wherein:

Q is selected from:

R1 is selected from:

R2 is selected from: H, C1-C4 alkyl, or benzyl;

U is -NH(CH2)n-;

V is -(CH2)n-;
R10 is selected from: H, CO2R17, C(=O)R17, C(=O)NR17R20, -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, -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;

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(R14)-CH(R15)-;

R13 is H or CH3;

R14 is selected from:
H, C1-C10 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:
-N(R20)-C(=O)-O-R17, -N(R20)-C(=O)-R17, -N(R20)SO2-R17, R17 is selected from:
C1-C10 alkyl, C3-C11 cycloalkyl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl)aryl, heteroaryl(C1-C6 alkyl)-, (C1-C6 alkyl)heteroaryl, arylaryl(C1-C6 alkyl)-, heteroarylaryl(C1-C6 alkyl)-, arylheteroaryl(C1-C6 alkyl)-, heteroarylheteroaryl(C1-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: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;

R19 is selected from:
hydroxy, C1-C10 alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-, 1-(methylcarbonyloxy)ethoxy-, 1-(ethylcarbonyloxy)ethoxy-, 1-(t-butylcarbonyloxy)ethoxy-, 1-(cyclohexylcarbonyloxy)ethoxy-, i-propyloxycarbonyloxymethoxy-, t-butyloxycarbonyloxymethoxy-, 1-(i-propyloxycarbonyloxy)ethoxy-, 1-(cyclohexyloxycarbonyloxy)ethoxy-, 1-(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.

5. A compound of Claim 1 and enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diastereomeric forms thereof, and pharmaceutically acceptable salt 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, (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)-]-1-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)-]-1-oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionic acid, (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)-]-1-oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionic acid, (S)-2-[(2-bromophenyl)sulfonyl]amino-3-[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionic acid, (S)-2-[(2-naphthyl)sulfonyl]amino-3-[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionic acid, (S)-2-[(1-naphthyl)sulfonyl]amino-3-[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2-azaspiro-[4,5]-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-[[[8-(2-imidazolylaminomethyl)-]-1-oxa-2-azaspiro-14,5]-dec-2-en-3-yl]carbonylamino3propionic 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-[4,5]-dec-2-en-3-yl]carbonylamino]propionic acid, (S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino]propionic acid, (S)-2-benzyloxycarbonylamino-3-[[7-benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-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-imidazolylaminomethyl)-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-imidazolylaminomethyl)-1-oxa-2,7-dlazaspiro-[4,4]-non-2-en-3-yl]carbonylamino]propionic acid, (S)-2-[(2,6-dichlorophenyl)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-[(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)-1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino]propionic acid, (S)-2-phenylsulfonylamino-3-[[8-(2-imidazolylaminomethyl)-1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino]propionic acid, (S)-2-benzyloxycarbonylamino-3-[[8-(2-imidazolylaminomethyl)-1-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)-1-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)-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-(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)-1-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-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-E(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)sulfonyllamino-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, (S)-2-benzyloxycarbonylamino-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-[(2,4,6-trimethylphenyl)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-dimethylphenyl)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-dichlorophenyl)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-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-1-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-1-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-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.

6. A method for the treatment of cancer metastasis, diabetic retinopathy, neovascular glaucoma, thrombosis, restenosis, osteoporosis, or macular degeneration which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1-5.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 1-5.