Isoxazoline and isoxazole fibrinogen receptor antagonists

Abstract

This invention relates to novel isoxazolines and isoxazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex or the vitronectin receptor, 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 platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

Description

FIELD OF THE INVENTION

This invention relates to novel isoxazolines and isoxazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions, including those for intranasal administration, 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 platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

BACKGROUND OF THE INVENTION

Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.

Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.

Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.

Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A.sub.2 synthetase inhibitors or receptor antagonists, which act against thromboxane A.sub.2 ; and hirudin, which acts against thrombin.

Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. Cell (1991) 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.

GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.

In addition to GPIIb/IIIa, increasing 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 .alpha.- and .beta.-subunits. Integrin subfamilies contain a common .beta.-subunit combined with different .alpha.-subunits to form adhesion receptors with unique specificity. The genes for eight distinct .beta.-subunits have been cloned and sequenced to date.

Two members of the .beta.1 subfamily, .alpha.4/.beta.1 and .alpha.5/.beta.1 have been implicated in various inflammatory processes. Antibodies to .alpha.4 prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther-Janssen et al., J. Immunol., 1991, 147:4207). Additional studies with monoclonal anti-.alpha.4 antibodies provide evidence that .alpha.4/.beta.1 may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh et al., J. Immunol., 1991, 146:3419; Bochner et al., J. Exp. Med., 1991 173:1553; Yednock et al., Nature, 1992, 356:63). Anti-.alpha.4 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).

The .alpha..sub.v /.beta..sub.3 heterodimer, commonly referred to as the vitronectin receptor, is another member of the .beta..sub.3 integrin subfamily and has been described in platelets, endothelial cells, melanoma, smooth muscle cells and on the surface of 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, 71:741-759). 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 thrombospondin in a manner mediated by the RGD sequence. Possible roles for .alpha..sub.v /.beta..sub.3 in angiogenesis, tumor progression, and neovascularization have been proposed (Brooks et al., Science, 1994, 264:569-571). A key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. Studies with monoclonal antibodies have implicated the .alpha..sub.v /.beta..sub.3 receptor in this process and suggest that a selective .alpha..sub.v /.beta..sub.3 antagonist would have utility in blocking bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).

Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi.

European Patent Application Publication Number 478363 relates to compounds having the general formula: ##STR1##

European Patent Application Publication Number 478328 relates to compounds having the general formula: ##STR2##

European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula: ##STR3##

PCT Patent Application 9307867 relates to compounds having the general formula: ##STR4##

European Patent Application Publication Number 4512831 relates to compounds having the general formula: ##STR5##

None of the above references teaches or suggests the compounds of the present invention which are described in detail below.

Most peptides and peptidomimetics exhibit very low oral bioavailability due to poor absorption and/or degradation in the GI tract and liver. Therefore, their use is limited to the parenteral route of administration.

Drugs with low bioavailability often have a large variability in pharmacological response due to an associated variability in drug delivery. This large variability in drug delivery may occur when the bioavailability is low because under those conditions, it takes only a small variation in bioavailability to give a large change in plasma drug concentration (W. K. Sietsema, The Absolute Oral Bioavailability of Selected Drug, International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 27 No. 4--1989 (179-211)).

Peptides and peptidomimetics have also generally shown relatively low nasal bioavailability. For example, studies with the luteinizing hormone releasing hormone (LHRH) analog, nafarelin acetate, showed that nasal bioavailability was only .about.2% (S. T. Anik, G. McRae, C. Nerenberg, A. Worden, J. Foreman, J. Hwang, S. Kushinsky, R. E. Jones, and B. Vickery; J. Pharm., Sci. 73: 684-685 (1984)). Thus, the intranasal administration of peptides and peptidomimetics is generally not recommended.

SUMMARY OF THE INVENTION

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 treatment of inflammation, bone degradation, tumors, metastases, thrombosis, and cell aggregation-related conditions in a mammal.

One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

The present invention also includes methods of treating cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula I alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase; or combinations thereof.

The present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of 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, 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 treatment of cell adhesion related disorders, including but not limited to thromboembolic disorders.

DETAILED DESCRIPTION OF THE INVENTION

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 treatment of inflammation, bone degradation, tumors, metastases, thrombosis, and cell aggregation-related conditions in a mammal.

One aspect of this invention provides compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to the platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

This invention relates to novel compounds of the Formula I: ##STR6## or a pharmaceutically acceptable salt or prodrug form thereof. �1! A first embodiment of this invention provides compounds of Formula I: ##STR7## or pharmaceutically acceptable salt or prodrug forms thereof wherein: b is a single or double bond;

R.sup.1 is selected from R.sup.2 (R.sup.3)N(CH.sub.2).sub.q Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2) (CH.sub.2).sub.q Z--, piperazinyl-(CH.sub.2).sub.q Z-- or ##STR8## Z is selected from O, S, S(.dbd.O), or S(.dbd.O).sub.2 ; R.sup.2 and R.sup.3 are independently selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, C.sub.2 -C.sub.7 alkylcarbonyl, C.sub.6 -C.sub.10 arylcarbonyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.6 -C.sub.10 aryloxycarbonyl, aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, C.sub.1 -C.sub.6 alkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl, C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl, C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; U is selected from:

a single bond (i.e., U is not present),

--(C.sub.1 -C.sub.7 alkyl)--,

--(C.sub.2 -C.sub.7 alkenyl)--,

--(C.sub.2 -C.sub.7 alkynyl)--,

--(aryl)-- substituted with 0-3 R.sup.6a, or

--(pyridyl)-- substituted with 0-3 R.sup.6a ;

V is selected from:

a single bond (i.e., V is not present);

--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

--(aryl)--, substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

--(pyridyl)--, substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ; or

--(pyridazinyl)--, substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

W is selected from:

a single bond (i.e., W is not present),

--(C.sub.1 -C.sub.7 alkyl)--,

--(C.sub.2 -C.sub.7 alkenyl)--,

--(C.sub.2 -C.sub.7 alkynyl)--, or

--(C(R.sup.5).sub.2).sub.n C(.dbd.O)N(R.sup.5a)--;

X is selected from:

a single bond (i.e., X is not present);

--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-3 groups independently selected from R.sup.4, R.sup.8 or R.sup.14 ;

--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-3 groups independently selected from R.sup.4, R.sup.8 or R.sup.14 ;

--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-2 groups independently selected from R.sup.4, R.sup.8 or R.sup.14 ; or ##STR9## Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

or (R.sup.2)(R.sup.3)N--(C.sub.1 -C.sub.10 alkoxy)--;

R.sup.4 and R.sup.4b are independently selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, or --N(R.sup..sup.12)R.sup.13 ; R.sup.5 is selected from H, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; R.sup.5a is selected from hydrogen, hydroxy, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 to C.sub.11 arylalkyl, adamantylmethyl or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; alternately, R.sup.5 and R.sup.5a can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, heteroaryl, C.sub.7 -C.sub.11 arylalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.3 -C.sub.7 cycloalkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.7 -C.sub.11 arylalkoxycarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl or C.sub.6 -C.sub.10 arylsulfonyl; R.sup.5b is selected from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; R.sup.6 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O )OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NR.sup.5a C(.dbd.O) R.sup.5a, NR.sup.5a C(.dbd.O) OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O).sub.p R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkylmethyl;

C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

C.sub.7 to C.sub.11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

methylenedioxy when R.sup.6 is a substituent on aryl; or

a 5-10 membered heterocyclic ring containing 1-3N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.7 ;

R.sup.6a is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, NO.sub.2, or NR.sup.12 R.sup.13 ; R.sup.7 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O).sub.p R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, or C.sub.7 -C.sub.11 arylalkyl; R.sup.8 is selected from:

H;

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkynyl, substituted with 0-3 R.sup.6 ;

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;

C.sub.5 -C.sub.6 cycloalkenyl, substituted with 0-2 R.sup.6 ;

aryl, substituted with 0-2 R.sup.6 ;

5-10 membered heterocyclic ring containing 1-3N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.2 -C.sub.7 alkylcarbonyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or

aryl (C.sub.1 -C.sub.10 alkoxy) carbonyl;

R.sup.14 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or C.sub.1 -C.sub.10 alkoxycarbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.5)R.sup.5a ; R.sup.15 is selected from:

H;

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-8 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-6 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxy, substituted with 0-6 R.sup.6 ;

aryl, substituted with 0-5 R.sup.6 ;

5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxycarbonyl substituted with 0-8 R.sup.6 ;

CO.sub.2 R.sup.5 ; or

--C(.dbd.O)N(R.sup.5)R.sup.5a ;

n is 0-4; q is 2-7; r is 0-3; provided that when b is a double bond, only one of R.sup.14 or R.sup.15 is present; provided that n, q, and r are chosen such that the number of in-chain atoms between R.sup.1 and Y is in the range of 8-18. �2! Preferred compounds of this first embodiment are those of Formula II (where W is a single bond (i.e., absent) and U is a single bond (i.e., absent)): ##STR10## wherein: R.sup.1 is selected from R.sup.2 HN(CH.sub.2).sub.q O--, R.sup.2 HN(R.sup.2 N.dbd.)CNH(CH.sub.2).sub.q O--, piperazinyl-(CH.sub.2).sub.q O--, or ##STR11## R.sup.2 is selected from H, aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, C.sub.1 -C.sub.10 alkoxycarbonyl; and/or R.sup.8 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated; and/or R.sup.6 and R.sup.7 are selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, or halo. �3! Further preferred compounds of this first embodiment are those of Formula II (where W is a bond/absent and U is a bond/absent): ##STR12## wherein:

X is selected from:

a single bond (i.e., X is not present);

--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-2 groups independently selected from R.sup.4, R.sup.8 or R.sup.14 ;

--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-2 groups independently selected from R.sup.4, R.sup.8 or R.sup.14 ;

--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-2 groups independently selected from R.sup.4, R.sup.8 or R.sup.14 ; and/or

R.sup.8 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated. �4! Further preferred compounds of this first embodiment are compounds of Formula II wherein: R.sup.1 is ##STR13## V is phenylene or pyridylene; n is 1 or 2; X is --(C.sub.1 -C.sub.2)alkyl-- substituted with 0-2 R.sup.4 Y is selected from:

hydroxy;

C.sub.1 to C.sub.10 alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxmethoxy-;

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-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R.sup.4 is --NR.sup.12 R.sup.13 ; R.sup.12 is H, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, benzyl, benzoyl, phenoxycarbonyl, benzyloxycarbonyl, arylalkylsulfonyl, pyridylcarbonyl, or pyridylmethylcarbonyl; and R.sup.13 is H. �5! Specifically preferred compounds of this first embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from: 5(R,S)-3-��4-(2-piperidin-4-yl)ethoxyphenyl!isoxazolin-5-yl!acetic acid; 5(R,)--N--(butanesulfonyl)-L-{3-�4-(2-piperidin-4-yl)ethoxyphenyl!isoxazolin-5-yl}glycine; 5(R,S)--N--(.alpha.-toluenesulfonyl)-L-{3-�4-(2-piperidin-4-yl)ethoxyphenyl!isoxazolin-5-yl}glycine; 5(R,S)--N--�(benzyloxy)carbonyl!-L-{3-�4-(2-piperidin-4-yl)ethoxyphenyl!isoxazolin-5-yl}glycine; 5(R,S)--N--(pentanoyl)-L-{3-�4-(2-piperidin-4-yl)ethoxyphenyl!isoxazolin-5-yl}glycine; 5(R,S)-3-{�4-(piperidin-4-yl)methoxyphenyl!isoxazolin-5-yl}propanoic acid; 2(R,S)-5(R,S)--N--(butanesulfonyl)amino-{3-�4-(piperidin-4-yl)methoxyphenyl!isoxazolin-5-yl}propanoic acid; 2(R,S)-5(R,S)--N--(.alpha.-toluenesulfonyl)amino-{3-�4-(piperidin-4-yl)methoxyphenyl!isoxazolin-5-yl}propanoic acid; 2(R,S)-5(R,S)--N--�(benzyloxy)carbonyl!amino-{3-�4-(piperidin-4-yl)methoxyphenyl!isoxazolin-5-yl}propanoic acid; 2(R,S)-5(R,S)--N--(pentanoyl)amino-{3-�4-(piperidin-4-yl)methoxyphenyl!isoxazolin-5-yl}propanoic acid. �6! A second embodiment of this invention provides a compound of Formula I: ##STR14## or a pharmaceutically acceptable salt or prodrug form thereof wherein: b is a single or double bond; R.sup.1 is selected from R.sup.2a (R.sup.3)N--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2a (R.sup.3)N(CH.sub.2).sub.p' Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C(CH.sub.2).sub.p",Z--R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, or R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR15## Z is selected from a bond (i.e. is absent), O, S, S(.dbd.O), S(.dbd.O)2; R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.10 alkyl; C.sub.3 -C.sub.6 alkenyl; C.sub.3 -C.sub.11 cycloalkyl; C.sub.4 -C.sub.11 cycloalkylalkyl; C.sub.6 -C.sub.10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.6 alkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl;

heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

provided that only one of R.sup.2 and R.sup.3 may be hydroxy; R.sup.2a is R.sup.2 or R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--; U is selected from:

a single bond (i.e., U is not present),

--(C.sub.1 -C.sub.7 alkyl)--,

--(C.sub.2 -C.sub.7 alkenyl)--,

--(C.sub.2 -C.sub.7 alkynyl)--,

-(aryl)- substituted with 0-3 R.sup.6a, or

-(pyridyl)- substituted with 0-3 R.sup.6a ;

V is selected from:

a single bond (i.e., V is not present);

--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

-(phenyl)-Q-, said phenyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

-(pyridyl)-Q-, said pyridyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ; or

-(pyridazinyl)-Q-, said pyridazinyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7,

Q is selected from:

a single bond (i.e., Q is not present),

--O--, --S(O).sub.m --, --N(R.sup.12)--, --(CH.sub.2).sub.m --, --C(.dbd.O)--,

--N(R.sup.5a)C(.dbd.O)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, --OCH.sub.2 --,

--CH.sub.2 N(R.sup.12)--, --N(R.sup.12)CH.sub.2 --, --CH.sub.2 C(.dbd.O)--, --C(.dbd.O)CH.sub.2 --,

--CH.sub.2 S(O).sub.m --, or --S(O).sub.m CH.sub.2 --,

provided that when b is a single bond, and R.sup.1 -U-V- is a substituent on C5 of the central 5-membered ring of Formula I, then Q is not --O--, --S(O).sub.m --, --N(R.sup.12)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, CH.sub.2 N(R.sup.12)-- or --CH.sub.2 S(O).sub.m --; W is selected from:

--(C(R.sup.4).sub.2).sub.n' --C(.dbd.O)N(R.sup.5a)--, or --C(.dbd.O)--N(R.sup.5a)--(C(R.sup.4).sub.2).sub.n' --

X is selected from:

a single bond (i.e. X is absent)

--(C((R.sup.4).sub.2).sub.n' --C(R.sup.4)(R.sup.8)--C(R.sup.4)(R.sup.4a)-- with the proviso that when n is 0 or 1, then at least one of R.sup.4a or R.sup.8 is other than H or methyl;

Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R.sup.2)(R.sup.3)N--(C.sub.1 -C.sub.10 alkoxy)--; R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl; alternately, two R.sup.4 groups on adjacent carbons may join to form a bond (i.e. a carbon--carbon double or triple bond); R.sup.4a is selected from H, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, N(R.sup.5)R.sup.5a, --N(R.sup.12)R.sup.13, --N(R.sup.16)R.sup.17, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.6, aryl substituted with 0-3 R.sup.6, heteroaryl substituted with 0-3 R.sup.6 or C.sub.1 -C.sub.10 alkylcarbonyl; R.sup.4b is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.7 -C.sub.14 bicycloalkyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl, nitro, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.6 -C.sub.10 aryl, --N(R.sup.12)R.sup.13 ; halo, CF.sub.3, CN, C.sub.1 -C.sub.6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl; R.sup.5 is selected from H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-6 R.sup.4b ; R.sup.5a is selected from hydrogen, hydroxy, C.sub.1 to C.sub.8 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 to C.sub.11 arylalkyl, adamantylmethyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; alternately, R.sup.5 and R.sup.5a when both are substituents on the same nitrogen atom (as in --NR.sup.5 R.sup.5a) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, heteroaryl, C.sub.7 -C.sub.11 arylalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.3 -C.sub.7 cycloalkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.7 -C.sub.11 arylalkoxycarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl or C.sub.6 -C.sub.10 arylsulfonyl; R.sup.5b is selected from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; R.sup.6 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub..sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O) R.sup.5a, NR.sup.5a C(.dbd.O) OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O).sub.m R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, SiMe.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl;

C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

C.sub.7 to C.sub.11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ; methylenedioxy when R.sup.6 is a substituent on aryl; or

a 5-10 membered heterocyclic ring containing 1-3N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.7 ;

R.sup.6a is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, NO.sub.2, or NR.sup.12 R.sup.13 ; R.sup.7 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O)R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; R.sup.8 is selected from:

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkynyl, substituted with 0-3 R.sup.6 ;

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;

C.sub.5 -C.sub.6 cycloalkenyl, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-3 R.sup.6 ;

5-10 membered heterocyclic ring containing 1-3N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl(C.sub.2 -C.sub.10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.7 -C.sub.10 arylcarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, or aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; R.sup.14 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or C.sub.1 -C.sub.10 alkoxycarbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.5)R.sup.5a ; R.sup.15 is selected from:

H; R.sup.6 ; --CO.sub.2 R.sup.5 ; --C(.dbd.O)N(R5)R.sup.5a ;

C.sub.1 -C.sub.10 alkoxycarbonyl substituted with 0-2 R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxy, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-3 R.sup.6 ; or

5-10 membered heterocyclic ring containing 1-3N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

provided that when b is a double bond, only one of R.sup.14 or R.sup.15 is present; R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)--R.sup.18b,

--C(.dbd.O)N(R.sup.18b).sub.2,

--C(.dbd.O)NHSO.sub.2 R.sup.18a,

--C(.dbd.O)NHC(.dbd.O)R.sup.18b,

--C(.dbd.O)NHC(.dbd.O)OR.sup.18a,

--C(.dbd.O)NHSO.sub.2 NHR.sup.18b,

--C(.dbd.S)--NH--R.sup.18b,

--NH--C(.dbd.O)--O--R.sup.18a,

--NH--C(.dbd.O)--R.sup.18b,

--NH--C(.dbd.O)--NH--R.sup.18b,

--SO.sub.2 --O--R.sup.18a,

--SO.sub.2 --R.sup.18a,

--SO.sub.2 --N(R.sup.18b).sub.2,

--SO.sub.2 --NHC(.dbd.O)OR.sup.18b,

--P(.dbd.S) (OR.sup.18a).sub.2,

--P(.dbd.O) (OR.sup.18a).sub.2,

--P(.dbd.S) (R.sup.18a).sub.2,

--P(.dbd.O) (R.sup.18a).sub.2, or ##STR16## R.sup.17 is selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.15 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.10 alkyl)--;

R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)-- substituted with 0-4 R.sup.19,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19,

C.sub.1 -C.sub.6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18a or H; R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -.sub.6 alkynyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.6 alkyl)--, C.sub.1 -C.sub.6 alkoxy, or C.sub.1 -C.sub.4 alkoxycarbonyl; m is 0-2; n is 0-4; r is 0-3; provided that n, are chosen such that the number of atoms connecting R.sup.1 and Y is in the range of 8-18. �7! Preferred compounds of this second embodiment are those compounds of Formula Ia: ##STR17## wherein: Z is selected from a bond (i.e. is absent), O, or S; and/or R.sup.2 is selected from H, aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, or C.sub.1 -C.sub.10 alkoxycarbonyl; and/or W is --(CH.sub.2).sub.n C(.dbd.O)N(R.sup.5a)--; and/or X is --(C(R.sup.4).sub.2).sub.n --C(R.sup.4) (R.sup.8)--CH(R.sup.4)--, with the proviso that when n is 0 or 1, then at least one of R.sup.4a or R.sup.8 is other than H or methyl; and/or R.sup.5 is selected from H or C.sub.1 -C.sub.10 alkyl substituted with 0-6 R.sup.4b ; and/or R.sup.6 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, --NR.sup.5 R.sup.5a, CO.sub.2 R.sup.5, S(O).sub.m R.sup.5, OR.sup.5, cyano, halo;

C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

C.sub.7 to C.sub.11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

methylenedioxy when R.sup.6 is a substituent on aryl; or

a 5-10 membered heterocyclic ring containing 1-3N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.7 ; and/or

R.sup.7 is selected from selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, or halo; and/or R.sup.8 is selected from:

--CONR.sup.5 NR.sup.5a ; --CO.sub.2 R.sup.5 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.11 alkynyl, substituted with 0-3 R.sup.6,

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;

C.sub.5 -C.sub.6 cycloalkenyl, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-2 R.sup.6 ;

5-10 membered heterocyclic ring containing 1-3N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ; and/or

R.sup.12 and R.sup.13 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, or heteroarylalkylcarbonyl,

wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2.

�8! Further preferred compounds of this second embodiment are those compounds of Formula Ia: ##STR18## wherein: Z is selected from a bond (i.e. is absent) or O; and/or W is --(CH.sub.2).sub.n C(.dbd.O)N(R.sup.12)--; and/or X is --C(R.sup.4) (R.sup.8)--C(R.sup.4).sub.2 --. �9! Further preferred compounds of this second embodiment are compounds of Formula Ia, wherein: R.sup.1 is R.sup.2 NHC(.dbd.NR.sup.2)--, R.sup.2 NHC(.dbd.NR.sup.2)NH-- and V is phenylene or pyridylene, or R.sup.1 is ##STR19## and V is a single bond (i.e. V is absent); n is 1 or 2; X is --CHR.sup.8 CH.sub.2 --; Y is selected from:

hydroxy;

C.sub.1 to C.sub.10 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-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R.sup.6 is selected from H, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, --NR.sup.5 R.sup.5a, CO.sub.2 R.sup.5, S(O).sub.m R.sup.5, cyano, halo;

C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

methylenedioxy when R.sup.6 is a substituent on aryl; or

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl;

R.sup.8 is selected from:

--CONR.sup.5 NR.sup.5a ; --CO.sub.2 R.sup.5 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkynyl, substituted with 0-3 R.sup.6,

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-2 R.sup.6 ;

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

R.sup.12 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl, aryl(C.sub.1 -C.sub.4 alkyl)sulfonyl, arylsulfonyl, aryl, pyridylcarbonyl or pyridylmethylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; and R.sup.13 is H. �10!, �35! Specifically preferred compounds of this second embodiment are compounds, or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt or prodrug forms thereof, selected from: 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-phenylpropanoic acid; 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-pentanoic acid; 3(R)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}heptanoic acid; 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(phenylthio)butanoic acid; 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(phenylsulfonamido)butanoic acid; 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino)-4-(n-butylsulfonamido)butanoic acid; 3(S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-(adamantylmethylaminocarbonyl)propanoic acid; 3(S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-(1-azabicyclo�3.2.2!nonylcarbonyl)propanoic acid; 3(S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-(phenethylaminocarbonyl)propanoic acid; 3(R)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino)-3-(3-pyridylethyl)propanoic acid; 3(R)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-(2-pyridylethyl)propanoic acid; 3(R)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-(phenylpropyl)propanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(phenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-methyl-phenyl-sulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(butanesulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(propanesulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(ethanesulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(methyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(ethyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(1-propyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-propyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-(3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(1-(2-methyl)-propyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(2-methyl)-propyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(benzyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-methylbenzyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-methoxybenzyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-chlorobenzyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-bromobenzyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-fluorobenzyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-phenoxybenzyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(methyloxyethyl)-oxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-pyridinylcarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-pyridinylcarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-pyridinyl-carbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(2-pyridinyl)-acetyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(3-pyridinyl)-acetyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(4-pyridinyl)-acetyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-butyloxyphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-thienylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-iodophenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-chlorophenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-2-methoxycarbonylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2,4,6-trimethylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-chlorophenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-fluorophenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-fluorophenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-methoxyphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2,3,5,6-tetramethylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-cyanophenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-chlorophenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-propylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-phenylethylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-isopropylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-phenylpropylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-pyridylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(phenylaminosulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(benzylaminosulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(dimethylaminosulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(phenylaminocarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-fluorophenylaminocarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(1-naphthylaminocarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(benzylaminocarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-bromo-2-thienylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methyl-2-benzothienylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-cyclopropylethoxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{5-(4-formamidinophenyl)-isoxazolin-3-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-bromo-phenylsulfonyl)-2,3-diaminopropionic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-methyl-phenylsulfonyl)-2,3-diaminopropionic acid; N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-diaminopropionic acid; N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid; N.sup.3 -�2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-bromo-phenylsulfonyl)-2,3-diaminopropionic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-bromo-phenylsulfonyl)-2,3-diaminopropionic acid; said enantiomeric and diasteriomeric forms being selected from:

(R,S), (R,S);

(R), (R,S);

(S), (R,S);

(R), (R);

(S), (R);

(R), (S);

(S), (S).

The prodrug forms of the compounds of the second embodiment include the following esters:

methyl;

ethyl;

isopropyl;

methylcarbonyloxymethyl-;

ethylcarbonyloxymethyl-;

t-butylcarbonyloxymethyl-;

cyclohexylcarbonyloxymethyl-;

1-(methylcarbonyloxy)ethyl-;

1-(ethylcarbonyloxy)ethyl-;

1-(t-butylcarbonyloxy)ethyl-;

1-(cyclohexylcarbonyloxy)ethyl-;

i-propyloxycarbonyloxymethyl-;

cyclohexylcarbonyloxymethyl-;

t-butyloxycarbonyloxymethyl-;

1-(i-propyloxycarbonyloxy)ethyl-;

1-(cyclohexyloxycarbonyloxy)ethyl-;

1-(t-butyloxycarbonyloxy)ethyl-;

dimethylaminoethyl-;

diethylaminoethyl-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-;

1-(2-(2-methoxypropyl)carbonyloxy)ethyl-.

�11! Also preferred compounds of the second embodiment are those compounds of Formula Ic: ##STR20## wherein: b is a single or double bond; R.sup.1 is selected from R.sup.2a (R.sup.3)N--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2a (R.sup.3)N(CH.sub.2).sub.p' Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C(CH.sub.2).sub.p" Z--R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, or R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR21## Z is selected from a bond (i.e. is absent), O, or S; R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.6 alkyl; C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; R.sup.2a is R.sup.2 or R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C; U is a single bond (i.e., U is not present), V is selected from:

a single bond (i.e., V is not present);

--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-3 groups independently selected from R6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

-(phenyl)-Q-, said phenyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

-(pyridyl)-Q-, said pyridyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ; or

-(pyridazinyl)-Q-, said pyridazinyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7,

Q is selected from a single bond (i.e., Q is not present), --O--, --S(O).sub.m --, --N(R.sup.12)--, --(CH.sub.2).sub.m --, --C(.dbd.O)--, --N(R.sup.5a)C(.dbd.O)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 N(R.sup.12)--, --N(R.sup.12)CH.sub.2 --, --CH.sub.2 C(.dbd.O)--, --C(.dbd.O)CH.sub.2 --, --CH.sub.2 S(O).sub.m --, or --S(O).sub.m CH.sub.2 --,

provided that when b is a single bond, and R.sup.1 --U--V-- is a substituent on C5 of the central 5-membered ring in Formula I, then Q is not --O--, --S(O).sub.m --, --N(R.sup.12)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, CH.sub.2 N(R.sup.12)-- or --CH.sub.2 S(O).sub.m --;

W is selected from:

--(C(R.sup.4).sub.2)--C(.dbd.O)--N(R.sup.5a)--, or

--C(.dbd.O)--N(R.sup.5a)--(C(R.sup.4).sub.2)--;

X is --C(R.sup.4)(R.sup.8)--CHR.sup.4a ; R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl; R.sup.4a is selected from hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, --N(R.sup.5)R.sup.5a, --N(R.sup.12)R.sup.13, or --N(R.sup.16)R.sup.b 17, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.6, aryl substituted with 0-3 R.sup.6, heteroaryl substituted with 0-3 R.sup.6, or C.sub.1 -C.sub.10 alkylcarbonyl; R.sup.4b is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl, nitro, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.6 -C.sub.10 aryl, --N(R.sup.12)R.sup.13, halo, CF.sub.3, CN, C.sub.1 -C.sub.6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridyl; R.sup.5 is selected from H or C.sub.1 -C.sub.10 alkyl substituted with 0-6 R.sup.4b ; R.sup.5a is selected from hydrogen, hydroxy, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 to C.sub.11 arylalkyl, or adamantylmethyl, C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; alternately, R.sup.5 and R.sup.5a can be taken together to be 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, heteroaryl, C.sub.7 -C.sub.11 arylalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.3 -C.sub.7 cycloalkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl or C.sub.7 -C.sub.11 arylalkoxycarbonyl; R.sup.5b is selected from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; R.sup.6 and R.sup.7 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, or halo; R.sup.12 and R.sup.13 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; R.sup.15 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or C.sub.1 -C.sub.10 alkoxycarbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.5)R.sup.5a ; R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)R.sup.18b,

--C(.dbd.O)N(R.sup.18b).sub.2,

--SO.sub.2 --R.sup.18a, or

--SO.sub.2 --N(R.sup.18b).sub.2 ;

R.sup.17 is selected from: H or C.sub.1 -C.sub.5 alkyl; R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.1 -C.sub.8 alkynyl substituted with 0-2 R.sup.19, C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)-- substituted with 0-4 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

C.sub.1 -C.sub.6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18a or H; R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, heteroaryl, aryl(C.sub.1 -C.sub.6 alkyl)--, or C.sub.1 -C.sub.4 alkoxycarbonyl; n is 0-4; p' is 1-7; p" is 1-7; r is 0-3. �12! Further preferred compounds of the second embodiment of Formula Ic are those compounds of Formula Ib: ##STR22## wherein: R.sup.1 is selected from: R.sup.2 a(R.sup.3)N--, R.sup.2 NH(R.sup.2 N.dbd.)C--, R.sup.2 NH(R.sup.2 N.dbd.)CNH--, R.sup.2a (R.sup.3)N(CH.sub.2).sub.p' Z--, R.sup.2 NH(R.sup.2 N.dbd.)C(CH.sub.2).sub.p" Z--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, or R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR23## n is 0-1; p' is 4-6; p" is 2-4; Z is selected from a bond (i.e. is absent) or O; V is a single bond (i.e., V is not present), -(phenyl)- or -(pyridyl)-; W is selected from:

--(C(R.sup.4).sub.2)--C(.dbd.O)--N(R.sup.5a)--,

--C(.dbd.O)--N(R.sup.5a)--CH.sub.2 --;

X is selected from:

--CH.sub.2 --CH(N(R.sup.16)R.sup.17)--, or

--CH.sub.2 --CH(NR.sup.5 R.sup.5a)--;

Y is selected from:

hydroxy;

C.sub.1 to C.sub.10 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-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)--R.sup.18b,

--S(.dbd.O).sub.2 --R.sup.18a or

--SO.sub.2 --N(R.sup.18b).sub.2 ;

R.sup.17 is selected from H or C.sub.1 -C.sub.5 alkyl; R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.1 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.1 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19, aryl (C.sub.1 -C.sub.6 alkyl)-- substituted with 0-4 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

C.sub.1 -C.sub.6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19.

�13! Further preferred compounds of Formula Ib are those compounds wherein: R.sup.1 is R.sup.2 NH(R.sup.2 N.dbd.)C-- or R.sup.2 HN(R.sup.2 N.dbd.)CNH-- and V is phenylene or pyridylene; or R.sup.1 is ##STR24## and V is a single bond (i.e. V is absent); n is 1 or 2; R.sup.18a is selected from:

C.sub.1 -C.sub.4 alkyl substituted with 0-2 R.sup.19,

C.sub.1 -C.sub.4 alkenyl substituted with 0-2 R.sup.19,

C.sub.1 -C.sub.4 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.7 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.4 alkyl)-- substituted with 0-4 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

C.sub.1 -C.sub.4 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19.

�14! Specifically preferred compounds of Formula Ib are compounds, or pharmaceutically acceptable salt forms thereof, selected from: N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(phenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-methyl-phenyl-sulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(butanesulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(propanesulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(ethanesulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(ethyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(1-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(1-(2-methyl)-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(2-methyl)-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-methylbenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-methoxybenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-chlorobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-bromobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-fluorobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-phenoxybenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(methyloxyethyl)-oxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-pyridinylcarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-pyridinylcarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-pyridinyl-carbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(2-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(3-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(4-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid. N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-butyloxyphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-thienylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(R,S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-iodophenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-2-methoxycarbonylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2,4,6-trimethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S) -yl}-acetyl!-N2-(2-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-fluorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-fluorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-methoxyphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2,3,5,6-tetramethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-cyanophenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-propylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-phenylethylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-isopropylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-phenylpropylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-pyridylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(phenylaminosulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(benzylaminosulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(dimethylaminosulfonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5(R, S) -yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(phenylaminocarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S) -yl)-acetyl!-N2-(4-fluorophenylaminocarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl)-acetyl!-N2-(1-naphthylaminocarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(benzylaminocarbonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-bromo-2-thienylsulfonyl)-2,3-(S)-diaminopropanoic acid; N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R, S)-yl}-acetyl!-N2-(3-methyl-2-benzothienylsulfonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid, N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid, and N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid. N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid. N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5(R)-yl)-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid. N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid. N.sup.3 -�2-{5-(4-formamidinophenyl)-isoxazolin-3(R,S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid; �15! Also specifically preferred are prodrug esters of the specifically preferred compounds of Formula Ib, said esters being chosen from the group consisting of:

methyl;

ethyl;

isopropyl;

methylcarbonyloxymethyl-;

ethylcarbonyloxymethyl-;

t-butylcarbonyloxymethyl-;

cyclohexylcarbonyloxymethyl-;

1-(methylcarbonyloxy)ethyl-;

1-(ethylcarbonyloxy)ethyl-;

1-(t-butylcarbonyloxy)ethyl-;

1-(cyclohexylcarbonyloxy)ethyl-;

i-propyloxycarbonyloxymethyl-;

cyclohexylcarbonyloxymethyl-;

t-butyloxycarbonyloxymethyl-;

1-(i-propyloxycarbonyloxy)ethyl-;

1-(cyclohexyloxycarbonyloxy)ethyl-;

1-(t-butyloxycarbonyloxy)ethyl-;

dimethylaminoethyl-;

diethylaminoethyl-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-;

1-(2-(2-methoxypropyl)carbonyloxy)ethyl-.

�16! A third embodiment of this invention provides a compound of Formula Id: ##STR25## or a pharmaceutically acceptable salt or prodrug form thereof wherein: R.sup.1 is selected from is selected from R.sup.2 (R.sup.3)N--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)--, R.sup.2 (R.sup.3)N(CH.sub.2).sub.q Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C(CH.sub.2).sub.q Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2) (CH.sub.2).sub.q Z--, piperazinyl-(CH.sub.2).sub.q Z--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--, ##STR26## Z is selected from a bond (i.e., is absent), O, S, S(.dbd.O), or S(.dbd.O).sub.2 ; R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.10 alkyl; C.sub.3 -C.sub.6 alkenyl; C.sub.3 -C.sub.11 cycloalkyl; C.sub.4 -C.sub.11 cycloalkylalkyl; C.sub.6 -C.sub.10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; , C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.6 alkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; provided that only one of R.sup.2 and R.sup.3 may be hydroxy; U is selected from:

a single bond (i.e., U is absent)

C.sub.1 -C.sub.7 alkylene,

C.sub.2 -C.sub.7 alkenylene,

C.sub.2 -C.sub.7 alkynylene,

arylene substituted with 0-3 R.sup.6a,, or

pyridylene substituted with 0-3 R.sup.6a ;

V is selected from:

a single bond (i.e., V is absent);

C.sub.1 -C.sub.7 alkylene substituted with 0-6 R.sup.6 or R.sup.7 ;

C.sub.2 -C.sub.7 alkenylene substituted with 0-4 R.sup.6 or R.sup.7 ;

C.sub.2 -C.sub.7 alkynylene substituted with 0-4 R.sup.6 or R.sup.7 ;

phenylene substituted with 0-4 R.sup.6 or R.sup.7 ;

pyridylene substituted with 0-3 R.sup.6 or R.sup.7 ;

pyridazinylene substituted with 0-3 R.sup.6 or R.sup.7 ;

X is selected from:

a single bond (i.e., X is absent);

--(CH.sub.2).sub.n C(.dbd.O)N(R.sup.12)--;

C.sub.1 -C.sub.7 alkylene substituted with 0-6 R.sup.4, R.sup.8 or R.sup.15 ;

C.sub.2 -C.sub.7 alkenylene substituted with 0-4 R.sup.4, R.sup.8 or R.sup.15 ;

C.sub.2 -C.sub.7 alkynylene substituted with 0-4 R.sup.4, R.sup.8 or R.sup.15 ;

Y is selected from:

hydroxy,

C.sub.1 to C.sub.10 alkyloxy,

C.sub.3 to C.sub.11 cycloalkyloxy,

C.sub.6 to C.sub.10 aryloxy,

C.sub.7 to C.sub.11 aralkyloxy,

C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy,

C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy,

C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy,

C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy,

C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy,

C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy,

C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

(R.sup.2) (R.sup.3)N-(C.sub.1 -C.sub.10 alkoxy)-;

R.sup.14 and W are attached to the same carbon and taken together to form a spiro-fused, 5-7 membered ring structure of the formula: ##STR27## D, E, F and G are each independently selected from:

C(R.sup.6a).sub.2 ;

carbonyl;

a heteroatom moiety selected from N, N(R.sup.12), O, provided that no more than 2 of D, E, F and G are N, N(R.sup.12), O, S, or C(.dbd.O);

alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon--carbon double bond;

R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, or --N(R.sup.12)R.sup.13 ; R.sup.6 and R.sup.7 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.12).sub.2, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, OC(.dbd.O)N(R.sup.12).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.12).sub.2, NO.sub.2, NR.sup.12 C(.dbd.O)R.sup.5a, NR.sup.12 C(.dbd.O)OR.sup.5a, NR.sup.12 C(.dbd.O)N(R.sup.12).sub.2, NR.sup.12 SO.sub.2 N(R.sup.12).sub.2, NR.sup.12 SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, SO.sub.2 N(R.sup.12).sub.2, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl;

C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

C.sub.7 to C.sub.11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

methylenedioxy when R.sup.6 is a substituent on aryl;

R.sup.6a is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, NO.sub.2, or NR.sup.12 R.sup.13 ; R.sup.8 is selected from:

H;

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-8 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-6 R.sup.6 ;

C.sub.2 -C.sub.10 alkynyl, substituted with 0-6 R.sup.6 ;

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-6 R.sup.6 ;

C.sub.5 -C.sub.6 cycloalkenyl, substituted with 0-5 R.sup.6 ;

aryl, substituted with 0-5 R.sup.6 ;

5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R.sup.6 ;

R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.2 -C.sub.7 alkylcarbonyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, wherein said aryls or heteroaryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; R.sup.5 and R.sup.5a are selected independently from H, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, C.sub.7 to C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-8 R.sup.4 ; R.sup.15 is selected from:

H;

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-8 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-6 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxy, substituted with 0-6 R.sup.6 ;

aryl, substituted with 0-5 R.sup.6 ;

5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxycarbonyl substituted with 0-8 R.sup.6 ;

CO.sub.2 R.sup.5 ; or

--C(.dbd.O)N(R.sup.12)R.sup.13 ;

n is 0-4; p is 1-3; q is 1-7; r is 0-3; provided that n, p, q and r are chosen such that the number of atoms between R.sup.1 and Y is in the range of 8-17. �47! Also preferred compounds of the second embodiment are those compounds of Formulae Ie or If: ##STR28## or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt form thereof, wherein: R.sup.1 is R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)--, or R.sup.2 (R.sup.3)N--; R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.10 alkyl; C.sub.3 -C.sub.6 alkenyl; C.sub.3 -C.sub.11 cycloalkyl; C.sub.4 -C.sub.11 cycloalkylalkyl; C.sub.6 -C.sub.10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.6 alkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; provided that only one of R.sup.2 and R.sup.3 may be hydroxy; R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl(C.sub.2 -C.sub.10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, or aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)--R.sup.18b,

--C(.dbd.O)N(R.sup.18b).sub.2,

--C(.dbd.O)NHSO.sub.2 R.sup.18a,

--C(.dbd.O)NHC(.dbd.O)R.sup.18b,

--C(.dbd.O)NHC(.dbd.O)OR.sup.18a,

--C(.dbd.O)NHSO.sub.2 NHR.sup.18b,

--C(.dbd.S)--NH--R.sup.18b,

--NH--C(.dbd.O)--O--R.sup.18a,

--NH--C(.dbd.O)--R.sup.18b,

--NH--C(.dbd.O)--NH--R.sup.18b,

--SO.sub.2 --O--R.sup.18a,

--SO.sub.2 --R.sup.18a,

--SO.sub.2 --N(18.sup.b).sub.2,

--SO.sub.2 --NHC(.dbd.O)O18.sup.b,

--P(.dbd.S) (OR.sup.18a).sub.2,

--P(.dbd.O) (OR.sup.18a).sub.2,

--P(.dbd.S) (R.sup.18a).sub.2,

--P(.dbd.O) (R.sup.18a).sub.2, or ##STR29## R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.6 alkenyl substituted with 0-2 R.sup.19,

C.sub.1 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)-- substituted with 0-4 R.sup.19,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19,

C.sub.1 -C.sub.6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18a or H; R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.6 alkyl)--, C.sub.1 -C.sub.6 alkoxy, or C.sub.1 -C.sub.4 alkoxycarbonyl; Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R.sup.2) (R.sup.3)N--(C.sub.1 -C.sub.10 alkoxy)--; m is 0-2; n is 0-2; and p is 1-5. �17! Preferred compounds of this third embodiment are compounds of Formula III: ##STR30## wherein: R.sup.1 is selected from R.sup.2 HN--, H.sub.2 N(R.sup.2 N.dbd.)C--, H.sub.2 N(R.sup.2 N.dbd.)CNH--, R.sup.2 HN(CH.sub.2).sub.q O--, H.sub.2 N(R.sup.2 N.dbd.)CNH(CH.sub.2).sub.q O--, piperazinyl-(CH.sub.2).sub.q O--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--, ##STR31## R.sup.2 and R.sup.3 are selected from H; C.sub.1 -C.sub.6 alkyl; C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or C.sub.1 -C.sub.10 alkoxycarbonyl; R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, or --N(R.sup.12)R.sup.13 ; V is selected from:

a single bond (i.e., V is absent);

C.sub.1 -C.sub.7 alkylene substituted with 0-6 R.sup.6 or R.sup.7 ;

C.sub.2 -C.sub.7 alkenylene substituted with 0-4 R.sup.6 or R.sup.7 ;

C.sub.2 -C.sub.7 alkynylene substituted with 0-4 R.sup.6 or R.sup.7 ;

phenylene substituted with 0-3 R.sup.6 or R.sup.7 ;

pyridylene substituted with 0-3 R.sup.6 or R.sup.7 ;

pyridazinylene substituted with 0-3 R.sup.6 or R.sup.7 ;

X is selected from --(CH.sub.2).sub.n C(.dbd.O)N(R.sup.12)--, C.sub.1 -C.sub.7 alkylene substituted with 0-1 R.sup.4, C.sub.2 -C.sub.7 alkenylene, or C.sub.2 -C.sub.7 alkynylene; Y is selected from:

hydroxy,

C.sub.1 to C.sub.10 alkyloxy,

C.sub.3 to C.sub.11 cycloalkyloxy,

C.sub.6 to C.sub.10 aryloxy,

C.sub.7 to C.sub.11 aralkyloxy,

C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy,

C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy,

C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy,

C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy,

C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy,

C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy,

C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or

C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

Z is selected from O or CH.sub.2 ; D, E, F and G are each independently selected from:

CH.sub.2 ;

carbonyl;

a heteroatom moiety selected from N, NH, O, provided that no more than 2 of D, E, F and G are N, NH, O or S;

alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon--carbon double bond;

R.sup.6 and R.sup.7 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, or halo; R.sup.12 and R.sup.13 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl; n is 0-4; p is 1-3; q is 1-7;

r is 0-3;

provided that n, p, q and r are chosen such that the number of atoms between R.sup.1 and Y is in the range of 8-17. �18! Further preferred compounds of this third embodiment are compounds of Formula II wherein: R.sup.1 is R.sup.2 NHC(.dbd.NR.sup.2)-- and V is phenyl or pyridyl or R.sup.1 is ##STR32## and V is a single bond (i.e. V is absent); n is 1 or 2; X is C.sub.1 -C.sub.4 alkylene substituted with 0-1 R.sup.4 ; Y is selected from:

hydroxy;

C.sub.1 to C.sub.10 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-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R.sup.12 and R.sup.13 are each independently selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylsulfonyl, aryl(C.sub.1 -C.sub.4 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl; and R.sup.13 is H. �19! Specifically preferred compounds of this third embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from: 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro�4.4!nona-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro�4.4!nona-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!dec-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!dec-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!dec-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!dec-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro�4.4!deca-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro�4.4!deca-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!undec-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!undec-2-ene-7,9-dione; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!undec-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!undec-2-ene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro�4.4!undeca-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro�4.4!undeca-2,8-diene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-7,9-dione; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-7,9-dione; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2-azaspiro�4.4!nona-2,8-diene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1oxa-2-azaspiro�4.4!nona-2,8-diene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!dec-2-ene-7,9-dione; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!dec-2-ene-5,7-dione; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!dec-2-ene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!dec-2-ene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2-azaspiro�4.4!deca-2,8-diene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1-oxa-2-azaspiro�4.4!deca-2,8-diene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!undec-2-ene-7,9-dione; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!undec-2-ene-7,9-dione; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!undec-2-ene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!undec-2-ene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(2-carboxyethyl)-1-oxa-2-azaspiro�4.4!undeca-2,8-diene-5-one; 5(R,S)-3-�2-(piperidin-4-yl)ethyl!-8-(3-carboxypropyl)-1-oxa-2-azaspiro�4.4!undeca-2,8-diene-5-one; 5(R,S)-3-(4-amidinophenyl)-8-�2-(benzyloxycarbonylamino)-2-carboxyethyl!-1-oxa-2,8-diazaspiro�4.5!dec-2-ene. �20! A fourth embodiment of this invention provides compounds of Formula I: ##STR33## or pharmaceutically acceptable salt or prodrug forms thereof, wherein: R.sup.1 is selected from:

R.sup.2 (R.sup.3)N(CH.sub.2).sub.q Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C(CH.sub.2).sub.q Z--,

R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)(CH.sub.2).sub.q Z--, piperazinyl-(CH.sub.2).sub.q Z-- or ##STR34## Z is selected from O, S, S(.dbd.O), S(.dbd.O).sub.2 ; R.sup.2 and R.sup.3 are independently selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, C.sub.2 -C.sub.7 alkylcarbonyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, or aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, C.sub.1 -C.sub.6 alkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl, C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl, C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl;

U is optionally present and is selected from C.sub.1 -C.sub.7 alkylene, C.sub.2 -C.sub.7 alkenylene, C.sub.2 -C.sub.7 alkynylene, arylene, or pyridylene; V is selected from:

a single bond (i.e., V is absent);

C.sub.1 -C.sub.7 alkylene substituted with 0-6 R.sup.6 or R.sup.7 ;

C.sub.2 -C.sub.7 alkenylene substituted with 0-4 R.sup.6 or R.sup.7 ;

C.sub.2 -C.sub.7 alkynylene substituted with 0-4 R.sup.6 or R.sup.7 ;

phenylene substituted with 0-4 R.sup.6 or R.sup.7 ;

pyridylene substituted with 0-3 R.sup.6 or R.sup.7 ;

pyridazinylene substituted with 0-3 R.sup.6 or R.sup.7 ;

W is --(aryl)--Z.sup.1 --, wherein said aryl is substituted with 0-6 R.sup.6 or R.sup.7 ; Z.sup.1 is selected from a single bond (i.e., Z.sup.1 is absent), --CH.sub.2 --, O or S;

X is selected from:

a single bond (i.e., X is absent);

C.sub.1 -C.sub.7 alkylene substituted with 0-6 R.sup.4, R.sup.8 or R.sup.15 ;

C.sub.2 -C.sub.7 alkenylene substituted with 0-4 R.sup.4, R.sup.8 or R.sup.15 ; C.sub.2 -C.sub.7 alkynylene substituted with 0-4 R.sup.4, R.sup.8 or R.sup.15 ;

Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; (R.sup.2) (R.sup.3)N--(C.sub.1 -C.sub.10 alkoxy)--; R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, or --N(R.sup.12)R.sup.13 ; R.sup.6 and R.sup.7 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.12).sub.2, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, OC(.dbd.O)N(R.sup.12).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.12).sub.2, NO.sub.2, NR.sup.12 C(.dbd.O)R.sup.5a, NR.sup.12 C(.dbd.O)OR.sup.5a, NR.sup.12 C(.dbd.O)N(R.sup.12).sub.2, NR.sup.12 SO.sub.2 N(R.sup.12).sub.2, NR.sup.12 SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, SO.sub.2 N(R.sup.12).sub.2, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl;

C.sub.6 to C.sub.10 aryl optionally substituted with halogen, alkoxy, alkyl, --CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ; or

C.sub.7 to C.sub.11 arylalkyl said aryl being optionally substituted with halogen, alkoxy, alkyl, --CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

R.sup.8 is selected from:

H;

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-8 R.sup.6 ;

C.sub.1 -C10 alkenyl, substituted with 0-6 R.sup.6 ;

C.sub.1 -C10 alkynyl, substituted with 0-6 R.sup.6 ;

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-6 R.sup.6 ;

C5-C.sub.6 cycloalkenyl, substituted with 0-5 R.sup.6 ;

aryl, substituted with 0-5 R.sup.6 ;

5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R.sup.6 ;

R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.2 -C.sub.7 alkylcarbonyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl (C.sub.1 -C.sub.10 alkoxy) carbonyl; R.sup.14 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or C.sub.1 -C.sub.10 alkoxycarbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.12)R.sup.13 ; R.sup.5 and R.sup.5a are selected independently from H, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, C.sub.7 to C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-8 R.sup.4 ; R.sup.15 is selected from:

H;

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-8 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-6 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxy, substituted with 0-6 R.sup.6 ;

aryl, substituted with 0-5 R.sup.6 ;

5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxycarbonyl substituted with 0-8 R.sup.6 ;

CO.sub.2 R.sup.5 ; or

--C(.dbd.O)N(R.sup.12)R.sup.13 ;

n is 0-4; q is 2-7; r is 0-3; provided that n, q, and r are chosen such that the number of atoms between R.sup.1 and Y is about 8-17. �21! Preferred compounds of this fourth embodiment are those of Formula IV: ##STR35## wherein: R.sup.1 is selected from R.sup.2 HN(CH.sub.2).sub.q O--,

R.sup.2 HN(R.sup.2 N.dbd.C)NH(CH.sub.2).sub.q O--, piperazinyl-(CH.sub.2).sub.q O--, or ##STR36## Z is O; R.sup.2 is selected from H, aryl(C.sub.1 -C.sub.10)alkoxycarbonyl, C.sub.1 -C.sub.10 alkoxycarbonyl;

V is selected from:

a single bond (i.e., V is absent);

C.sub.1 -C.sub.7 alkylene substituted with 0-6 R.sup.6 or R.sup.7 ;

C.sub.2 -C.sub.7 alkenylene substituted with 0-4 R.sup.6 or R.sup.7 ;

C.sub.2 -C.sub.7 alkynylene substituted with 0-4 R.sup.6 or R.sup.7 ;

phenylene substituted with 0-3 R.sup.6 or R.sup.7 ;

pyridylene substituted with 0-3 R.sup.6 or R.sup.7 ;

pyridazinylene substituted with 0-3 R.sup.6 or R.sup.7 ;

Z.sup.1 is selected from a single bond (i.e., Z.sup.1 is absent), O or S; X is selected from:

a single bond (i.e., X is absent);

C.sub.1 -C.sub.7 alkylene substituted with 0-4 R.sup.4, R.sup.8 or R.sup.15 ;

C.sub.2 -C.sub.7 alkenylene substituted with 0-3 R.sup.4, R.sup.8 or R.sup.15 ;

C.sub.2 -C.sub.7 alkynylene substituted with 0-3 R.sup.4, R.sup.8 or R.sup.15 ;

Y selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, or --N(R.sup.12)R.sup.13 ; R.sup.6 and R.sup.7 are selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, or halo; R.sup.8 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2N, O, or S, where said heterocyclic ring may be saturated, partially saturated, or fully unsaturated; R.sup.12 and R.sup.13 are independently selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl; R.sup.14 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or C.sub.1 -C.sub.10 alkoxycarbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.12)R.sup.13 ; R.sup.5 is selected from H or C.sub.1 -C.sub.10 alkyl substituted with 0-6 R.sup.4 ; n is 0-4; q is 2-7; provided that n and q are chosen such that the number of atoms between R.sup.1 and Y is in the range of 8-17. �22! Further preferred compounds of this fourth embodiment are compounds of Formula IV wherein: R.sup.1 is R.sup.2 HN(CH.sub.2).sub.q O-- or ##STR37## V is C.sub.1 -C.sub.3 alkylene; Z.sup.1 is a single bond (i.e. Z.sup.1 is absent) or O; X is C.sub.1 -C.sub.3 alkylene substituted with 0-1 R.sup.4 ; Y is selected from:

hydroxy;

C.sub.1 to C.sub.10 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-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R.sup.12 and R.sup.13 are independently selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl, aryl(C.sub.1 -C.sub.4 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl; R.sup.13 is H. �23! Specifically preferred compounds of this fourth embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:

5(R,S)-4-�3-(piperidin-4-yl)oxymethylisoxazolin-5-yl!hydrocinnamic acid;

5(R,S)-4-�3-(2-aminoethoxymethyl)isoxazolin-5-yl!hydrocinnamic acid;

5(R,S)-4-�3-(3-aminopropyloxymethyl)isoxazolin-5-yl!hydrocinnamic acid;

5(R,S)-4-�3-(piperidin-4-yl)oxymethylisoxazolin-5-yl!phenoxyacetic acid;

5(R,S)-4-�3-(2-aminoethoxymethyl)isoxazolin-5-yl!phenoxyacetic acid;

5(R,S)-4-�3-(3-aminopropyloxymethyl)isoxazolin-5-yl!phenoxyacetic acid.

�24! A fifth embodiment of this invention provides a compound of Formula I: ##STR38## or a pharmaceutically acceptable salt or prodrug form thereof wherein: b is a single or double bond; R.sup.1 is selected from R.sup.2a (R.sup.3)N--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2a (R.sup.3)N(CH.sub.2).sub.q Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C(CH.sub.2).sub.q Z--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR39## Z is selected from a bond (i.e. is absent), O, S, S(.dbd.O), S(.dbd.O).sub.2 ; R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.10 alkyl; C.sub.3 -C.sub.6 alkenyl; C.sub.3 -C.sub.11 cycloalkyl; C.sub.4 -C.sub.11 cycloalkylalkyl; C.sub.6 -C.sub.10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.6 alkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; provided that only one of R.sup.2 and R.sup.3 may be hydroxy; R.sup.2a is R.sup.2 or R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C; U is selected from:

a single bond (i.e., U is not present),

--(C.sub.1 -C.sub.7 alkyl)--,

--(C.sub.2 -C.sub.7 alkenyl)--,

--(C.sub.2 -C.sub.7 alkynyl)--,

-(aryl)- substituted with 0-3 R.sup.6a, or

-(pyridyl)- substituted with 0-3 R.sup.6a ;

V is selected from:

a single bond (i.e., V is not present);

--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

-(phenyl)-, substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

-(pyridyl)-, substituted with 0-2 groups independently selected from R6 or R.sup.7 ; or

-(pyridazinyl)-, substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

W is selected from: ##STR40## X is selected from:

a single bond (i.e. X is absent)

--(C(R.sup.4).sub.2).sub.n --C(R.sup.4) (R.sup.8)--C(R.sup.4) (R.sup.4a)--, with the proviso that when n is 0 or 1, then at least one of R.sup.4a or R.sup.8 is other than H or methyl;

Y is selected from:

hydroxy,

C.sub.1 to C.sub.10 alkyloxy,

C.sub.3 to C.sub.11 cycloalkyloxy,

C.sub.6 to C.sub.10 aryloxy,

C.sub.7 to C.sub.11 aralkyloxy,

C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy,

C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy,

C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy,

C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy,

C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy,

C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy,

C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy,

C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(R.sup.2) (R.sup.3)N--(C.sub.1 -C.sub.10 alkoxy)--;

Z.sup.1 is --C--, --O--, or --NR.sup.22 --; Z.sup.2 is --O--, or --NR.sup.22 --; R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkylene cycloalkyl, or cycloalkylalkylene; alternately, two R.sup.4 groups on adjacent carbons may join to form a bond (i.e. a carbon--carbon double or triple bond); R.sup.4a is selected from H, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, N(R.sup.5)R.sup.5a, --N(R.sup.12)R.sup.13, --N(R.sup.16)R.sup.17,

C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.6, aryl substituted with 0-3 R.sup.6, or C.sub.1 -C.sub.10 alkylcarbonyl;

R.sup.4b is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl, nitro, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.6 -C.sub.10 aryl, --N(R.sup.12)R.sup.13 ; halo, CF.sub.3, CN, C.sub.1 -C.sub.6 alkoxycarbonyl, carboxy, piperidinyl, or pyridyl; R.sup.5 is selected from H, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; R.sup.5a is selected from hydrogen, hydroxy, C, to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, C.sub.7 to C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; alternately, R.sup.5 and R.sup.5a when both are substituents on the same nitrogen atom (as in --NR.sup.5 R.sup.5a) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, heteroaryl, C.sub.7 -C.sub.11 arylalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.3 -C.sub.7 cycloalkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.7 -C.sub.11 arylalkoxycarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl or C.sub.6 -C.sub.10 arylsulfonyl; R.sup.5b is selected from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ; R.sup.6 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O).sub.p R.sup.5, SO.sub.2 NR.sup.5 R.sup.5a, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl;

C.sub.6 to C.sub.11 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

C.sub.7 to C.sub.11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub. 2;

methylenedioxy when R.sup.6 is a substiuent on aryl; or

a 5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.7 ;

R.sup.6a is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, NO.sub.2, or NR.sup.12 R.sup.13 ; R.sup.7 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O).sub.m R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; R.sup.8 is selected from:

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.1 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.1 -C.sub.10 alkynyl, substituted with 0-3 R.sup.6 ;

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;

C.sub.5 -C.sub.6 cycloalkenyl, substituted with 0-3 R.sup.6 ; aryl, substituted with 0-3 R.sup.6 ;

5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, or aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; R.sup.14 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or C.sub.1 -C.sub.10 alkoxycarbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.5)R.sup.5a ; R.sup.15 is selected from:

H;

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.1 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxy, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-3 R.sup.6 ;

5-6 membered heterocyclic ring containing 1-2N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxycarbonyl substituted with 0-2 R.sup.6 ;

--CO.sub.2 R.sup.5 ; or

--C(.dbd.O)N(R.sup.12)R.sup.13 ;

provided that when b is a double bond, only one of R.sup.14 or R.sup.15 is present; R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18 a,

--C(.dbd.O)--R.sup.18b,

--C(.dbd.O)N(R.sup.18b).sub.2,

--C(.dbd.O)NHSO.sub.2 R.sup.18a,

--C(.dbd.O)NHC(.dbd.O)R.sup.18b,

--C(.dbd.O)NHC(.dbd.O)OR.sup.18a,

--C(.dbd.O)NHSO.sub.2 NHR.sup.18b,

--C(.dbd.S)--NH--R.sup.18b,

--NH--C(.dbd.O)--)--R.sup.18a,

--NH--C(.dbd.O)--R.sup.18b,

--NH--C(.dbd.O)--NH--R.sup.18b,

--SO.sub.2 --O--R.sup.18a,

--SO.sub.2 --R.sup.18a,

--SO.sub.2 --N(18.sup.b).sub.2,

--SO.sub.2 --NHC(.dbd.O)O18.sup.b,

--P(.dbd.S) (OR.sup.18a).sub.2,

--P(.dbd.O) (OR.sup.18a).sub.2,

--P(.dbd.S) (R.sup.18a).sub.2,

--P(.dbd.O) (R.sup.18a).sub.2, or ##STR41## R.sup.17 is selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.15 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.10 alkyl)-;

R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)-- substituted with 0-4 R.sup.19,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19,

C.sub.1 -C.sub.6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18a or H; R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, aryl (C.sub.1 -C.sub.6 alkyl)--, C.sub.1 -C.sub.6 alkoxy, or C.sub.1 -C.sub.4 alkoxycarbonyl; R.sup.20 and R.sup.21 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, NR.sup.5 C(.dbd.O)R.sup.5a, NR.sup.12 R.sup.13, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, or C.sub.7 -C.sub.11 arylalkyl; R.sup.22 is selected from C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.15 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.10 alkyl)--; C(.dbd.O)R.sup.5a, CO.sub.2 R.sup.5b, --C(.dbd.O)N(R.sup.5)R.sup.5a, or a bond to X; m is 0-2; n is 0-2; p is 1-2; q is 1-7; r is 0-3; provided that n, q and r are chosen such that the number of atoms connecting R.sup.1 and Y is in the range of 8-17. �25! Preferred compounds of this embodiment are those compounds of Formula Ic: ##STR42## wherein: Z is selected from a bond (i.e. is absent), O, or S; R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.6 alkyl; C.sub.7 -C.sub.10 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; U is a single bond (i.e., U is not present); X is --CHR.sup.4a --; R.sup.5 is selected from H or C.sub.1 -C.sub.10 alkyl substituted with 0-6 R.sup.4b ; R.sup.6 and R.sup.7 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, cyano, or halo; R.sup.12 and R.sup.13 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; R.sup.15 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.1 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or C.sub.1 -C.sub.10 alkoxycarbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.5)R.sup.5a ; R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)R.sup.18b,

--S(.dbd.O).sub.2 --R.sup.18a ;

R.sup.17 is selected from: H or C.sub.1 -C.sub.4 alkyl; R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.1 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.1 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-2 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)-- substituted with 0-2 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R.sup.19 ;

C.sub.1 -C.sub.6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R.sup.19.

�26! Further preferred compounds of this embodiment are compounds of Formula Ib: ##STR43## wherein: R.sup.1 is selected from: R.sup.2 (R.sup.3)N--, R.sup.2 NH(R.sup.2 N.dbd.)C--, R.sup.2 R.sup.3 N(CH.sub.2).sub.p" Z--, R.sup.2 NH(R.sup.2 N.dbd.)CNH(CH.sub.2).sub.p' Z--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR44## n is 0-1; p' is 2-4; p" is 4-6; Z is selected from a bond (i.e. is absent) or O; R.sup.3 is H or C.sub.1 -C.sub.5 alkyl; V is a single bond (i.e., V is not present), or

-(phenyl)-;

X is selected from:

--CH.sub.2 --,

--CHN(R.sup.16)R.sup.17 --, or

--CHNR.sup.5 R.sup.5a ;

Y is selected from:

hydroxy;

C.sub.1 to C.sub.10 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-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R.sup.18a is selected from:

C.sub.1 -C.sub.4 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.4 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.4 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.4 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-2 R.sup.19,

aryl(C.sub.1 -C.sub.4 alkyl)-- substituted with 0-2 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R.sup.19 ;

C.sub.1 -C.sub.6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R.sup.19.

�27! Further preferred compounds of this fifth embodiment are compounds of Formula Ib wherein: R.sup.1 is R.sup.2 NH(R.sup.2 N.dbd.)C-- or R.sup.2 NH(R.sup.2 N.dbd.)CNH-- and V is phenyl or pyridyl; or R.sup.1 is ##STR45## and V is a single bond (i.e. V is absent) n is 1-2; X is selected from:

--CH.sub.2 --,

--CHN(R.sup.16)R.sup.17 --, or

--CHNR.sup.5 R.sup.5a --;

W is selected from: ##STR46## m is 1-3; Y is selected from:

hydroxy;

C.sub.1 to C.sub.10 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-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R.sup.19 is H, halogen, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl, cyclopropylmethyl, aryl, or benzyl; R.sup.20 and R.sup.21 are both H; R.sup.22 is H, C.sub.1 -C.sub.4 alkyl or benzyl. �28! Specifically preferred compounds of this fifth embodiment are compounds of Formula Ib, or pharmaceutically acceptable salt forms thereof, selected from:

2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!piperidine;

2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!azepine;

2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!pyrrolidine;

3-(R,S)-carboxymethyl-4-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!piperazine-2-one;

6-(R,S)-carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!piperidine-2-one;

5-(R,S)-carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!pyrrolidine-2-one;

7-(R,S)-carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!azetidine-2-one;

2-(R,S)-carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!pyrazolidine;

3-(R,S)-carboxymethyl-4-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!morpholine.

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 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 glycoprotein IIb/IIIa (GPIIb/IIIa). The compounds of the present invention inhibit the activation and aggregation of platelets induced by all known endogenous platelet agonists.

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 thromboembolic disorders. 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 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, infammation, bone degradation, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, tumors, metastasis, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases. The compounds of Formula I of the present invention may also be useful for wound healing.

The compounds of the present invention are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal. The compounds of the invention may be used as a medicament for blocking fibrinogen from acting at its receptor site in a mammal.

Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption, and where the aggregated platelets may form thrombi and thromboemboli. The compounds of the present invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.

Extracorporeal circulation is routinely used during cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the extracorporeal circuit. Platelets released from artificial surfaces show impaired homeostatic function. The compounds of the invention may be administered to prevent such ex vivo adhesion.

The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.

Other applications of these compounds include prevention of platelet thrombosis, thromboembolism, and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary and other arteries and after coronary artery bypass procedures. The compounds of the present invention may also be used to prevent myocardial infarction. The compounds of the present invention are useful as thrombolytics for the treatment of thromboembolic disorders.

The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents select 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 administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment 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 thromboembolic 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 mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By "administered in combination" or "combination therapy" 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.TM.) 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 (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam. Piroxicam is commercially available from Pfizer Inc. (New York, N.Y.), as Feldane.TM.. 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 and other inhibitors of thrombin synthesis such as Factor XA. 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-1 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 .alpha.-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. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable 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, Calif. 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. Anistreplase is commercially available as Eminase.TM.. 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.

Administration 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.

GPIIb/IIIa is known to be overexpressed in metastatic tumor cells. The compounds or combination products of the present invention may also be useful for the treatment, including prevention, of metastatic cancer.

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 fibrinogen to platelet GPIIb/IIIa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving GPIIb/IIIa. The compounds of the present invention may also be used in diagnostic assays involving platelet GPIIb/IIIa.

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.dbd.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, R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.12,and R.sup.14, 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 R.sup.4, then said group may optionally be substituted with up to two R.sup.4 and R.sup.4 at each occurrence is selected independently from the defined list of possible R.sup.4. Also, by way of example, for the group --N(R.sup.5a).sub.2, each of the two R.sup.5a substituents on N is independently selected from the defined list of possible R.sup.5a. Similarly, by way of example, for the group --C(R.sup.7).sub.2 --, each of the two R.sup.7 substituents on C is independently selected from the defined list of possible R.sup.7.

When a bond to a substituent is 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 atom 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., .dbd.O), then 2 hydrogens on the atom are replaced.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "C.sub.1 -C.sub.10 " denotes alkyl having 1 to 10 carbon atoms); "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 --C.sub.v F.sub.w where v=1 to 3 and w=1 to (2v+1)); "alkoxy" 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 adamantyl; and "bicycloalkyl" 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)-", "-(alkenyl)-" and "-(phenyl)-", and the like.

"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 optionally substituted with 0-3 groups independently selected from methyl, methoxy, amino, hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; 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, 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, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, .beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 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 monocylic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.

As used herein, the term "chiral amine" refers to any amine containing compound that also contains a chiral center. Such compounds include, by way of example and without limitation, either enantiomer of cinchonidine, ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol, quinidine and pseudoephedrine.

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.

"Prodrugs" are considered to be 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 that 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. Examples of representative carboxyl and amino prodrugs are included under the definition of R.sup.2, R.sup.3, and Y.

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-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived 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, sulfanilic, 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 tetramethylammoinum 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; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Reminaton'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.

Synthesis

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.

The following abbreviations are used herein:

______________________________________Alata. 3-aminopropionic acidBoc tert-butyloxycarbonylBoc.sub.2 O di-tert-butyl dicarbonateBOP benzotriazolyl-N-oxytris(dimethylamino)- phosphonium hexafluorophosphateBSTFA N,O-bis(trimethylsilyl) trifluoromethyl- acetamideCbz benzyloxycarbonylDCC 1,3-dicyclohexylcarbodiimideDEAD diethyl azodicarboxylateDEC 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochlorideDIEA diisopropylethylamineDCHA dicyclohexylamineDCM dichloromethaneDMAP 4-dimethylaminopyridineDMF N,N-dimethylformamideEtOAc ethyl acetateEtOH ethyl alcoholHOBt 1-hydroxybenzotriazoleIBCF iso-butyl chloroformateLAH lithium aluminum hydrideNCS N-chlorosuccinimideNMM N-methylmorpholinePPh.sub.3 triphenylphosphinepyr pyridineTBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3- tetramethyluronium tetrafluoroborateTFA trifluoroacetic acidTHF tetrahydrofuran______________________________________

A convenient method for the synthesis of the compounds of this invention utilizes a dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles to prepare the isoxazoline rings present in compounds of Formula I (for reviews of 1,3-dipolar cycloaddition chemistry, see 1,3-Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, New York, 1984; Kanemasa and Tsuge, Heterocyoles 1990, 3, 719).

Scheme I describes one synthetic sequence to the compounds of the second embodiment of this invention. An appropriately substituted hydroxylamine is treated with NCS in DMF according to the method of Liu, et al. (J. Org. Chem. 1980, 45, 3916). The resulting hydroximinoyl chloride is then dehydrohalogenated in situ using TEA to give a nitrile oxide, which undergoes a 1,3-dipolar cycloaddition to a suitably substituted alkene to afford the isoxazoline. Alternatively, the oxime may be oxidatively chlorinated, dehydrochlorinated and the resulting nitrile oxide trapped by a suitable alkene under phase transfer conditions according to the method of Lee (Synthesis 1982, 508). Hydrolysis of the ester using conventional methods known to one skilled in the art of organic synthesis gives the desired acids. Intermediates containing alkali-sensitive functionality, such as nitrile, may be deesterified with excellent chemoselectivity using sodium trimethylsilanolate according to the procedure of Laganis and Ehenard (Tetrahedron Lett. 1984, 25, 5831). Coupling of the resulting acids to an appropriately substituted .alpha.- or .beta.-amino ester using standard coupling reagents, such as DCC/HOBt, affords a nitrile-amide. The nitrile is then converted to the amidine via the imidate or thioimidate under standard conditions followed by ester saponification (LiOH, THF/H.sub.2 O). ##STR47##

An example of a related method of preparation for compounds within the second embodiment of the present invention is illustrated in Scheme Ia. Conversion of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid to the corresponding amidine, followed by protection as the Boc-derivative and saponification provides 3-(4-Boc-amidinophenyl)isoxazolin-5-ylacetic acid which is coupled with .beta.-amino acid esters as shown. Deprotection provides the desired isoxazolinylacetyl-.beta.-aminoalaninyl esters. Saponification as described above gives the free acids. ##STR48##

A further example of the synthesis of compounds within the second embodiment is shown in Scheme Ib. Cycloaddition of commercially available 4-cyanostyrene and t-butyl-3-oxoproprionate oxime using the method described by Gree et al. (Bioorganic and Med. Chem. Lett. 1994, 253) provides t-butyl �5-(4-cyanophenyl)isoxazolin-3-yl!acetate. Using the procedures described above, this intermediate is converted to compounds of formula I wherein the isoxazoline ring is in the reverse orientation with respect to the compounds prepared via Schemes I and Ia. ##STR49##

Additional isoxazolinyl acetates useful as starting materials for the preparation of compounds of Formula I, wherein V is -(phenyl)-Q- and Q is other than a single bond, can be prepared by cycloaddition of a suitably substituted chloro or bromooxime with an ester of vinyl acetic acid as shown in Scheme Ic using literature methods or modifications thereof. (D. P. Curran & J. Chao, J. Org. Chem. 1988, 53, 5369-71; J. N. Kim & E. K. Ryu, Heterocycles 1990, 31, 1693-97). ##STR50##

The compounds of the present invention where R.sup.2 or R.sup.3 is e.g. alkoxycarbonyl may be prepared by reacting the free amidines, amines or guanidines with an activated carbonyl derivative, such as an alkyl chloroformate. In compounds of the second embodiment, the conversion of the free amines, amidines and guanidines to such acyl-nitrogen groups may optionally be performed prior to coupling an isoxazoline acetic acid with e.g .beta.-amino acids, as illustrated in Scheme Ia.

The compounds of the present invention wherein Y is an oxyalkoxy group, e.g. alkoxycarbonyloxyalkoxy, may be prepared by reacting a suitably protected carboxylic acid of Formula I with an alkoxycarbonyloxyalkyl chloride in the presence of an iodide source, such as tetrabutylammonium iodide or potassium iodide, and an acid scavenger, such as triethylamine or potassium carbonate, using procedures known to those skilled in the art.

The appropriately substituted racemic .beta.-amino acids may be purchased commercially or, as is shown in Scheme II, 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, 58, 299). Racemic .beta.-substituted-.beta.-amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous acid in ethanol (Scheme I, Method 2) or by reductive amination of .beta.-keto esters as is described in WO9316038. (Also see Rico et al., J. Org. Chem. 1993, 5, 7948-51.) Enantiomerically pure .beta.-substituted-.beta.-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 .alpha.-amino acids as shown in Scheme II, Method 3 (see Meier, and Zeller, Angew, Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within); and through an enantioselective hydrogenation of a dehydroamino acid as is shown in Scheme II, Method 4 (see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, New York, 1985). A comprehensive treatise on the preparation of .beta.-amino acid derivatives may be found in patent application WO 9307867, the disclosure of which is hereby incorporated by reference. ##STR51##

The synthesis of N.sup.2 -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).

The appropriately substituted pyrrolidine-, piperidine- and hexahydroazepineacetic acids may be prepared using a number of methods. The pyrrolidines are conveniently prepared using an Arndt-Eistert homologation of the corresponding proline as shown in Scheme III, Method 1 (see Meier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within). The piperidines can be prepared by reduction of the corresponding pyridine as shown in Scheme III, Method 2. The hexahydroazepines are prepared by reduction of the corresponding vinylogous amide using sodium cyanoborohydride as depicted in Scheme III, Method 3. ##STR52##

Many additional appropriately substituted heterocycles are available commercially or can be readily modified by procedures known by one skilled in the art. Appropriately substituted morpholines can be prepared from amino acids via the sequence of steps depicted in Scheme IIIa, method l(see Brown, et. al. J. Chem. Soc. Perkin Trans I 1987, 547; Bettoni, et. al. Tetrahedron 1980, 36, 409; Clarke, F. H. J. Org. Chem. 1962, 27, 3251 and references therein.) N-ethoxycarbonylmethyl-1,2-diazaheterocyles are prepared by condensation of suitably substituted dibromides with benzylhydrazine followed by Mitsunobu reaction with ethyl hydroxyacetate and deprotection as shown in Scheme IIIa, method 2 (see Kornet, et. al. J. Pharm. Sci. 1979, 68, 377.; Barcza, et. al. J. Org. Chem. 1976, 41, 1244 and references therein.) ##STR53##

A general synthetic protocol to the compounds of the first embodiment of this invention is depicted in Scheme IV. Coupling of a suitable Boc-protected amino alcohol to an appropriately substituted phenol under Mitsunobu conditions (see Mitsunobu, Synthesis 1981, 1) is followed by oximation using hydroxylamine hydrochloride in 1:1 ethanol/pyridine. Isoxazoline formation, ester saponification and Boc-deprotection (33% TFA/DCM) then affords the compounds of this invention in good overall yield. ##STR54##

The synthesis of the spiro-fused isoxazolinyl imides of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme V. Dipolar cycloaddition of an oximinoyl chloride with a .alpha.-methylene diester affords an isoxazolinyl diester, which is deesterified using the silanolate method. Dehydration to the anhydride according to Ishihara, et al. (Chem. Pharm. Bull. 1992, 40, 1177-85) followed by imide formation using an appropriately substituted amino ester affords the spirocycle. Alternatively, the imide may be prepared directly from the isoxazoline diester according to Culbertson, et al. (J. Med. Chem. 1990, 33, 2270-75). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR55##

The synthesis of the spiro-fused isoxazolinyl amides of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme VI. Dipolar cycloaddition of an oximinoyl chloride with a .alpha.-methylene lactone affords the isoxazolinyl lactone, which is reacted with an appropriate amino ester to afford the amide (see The Chemistry of the Amides (Zabicky, ed.), p 96, Interscience, New York, 1970; Prelog, et al., Helv. Chim. Acta 1959, 42, 1301; Inubushi, et al., J. Chem. Soc., Chem. Commun. 1972, 1252). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR56##

The synthesis of the spiro-fused isoxazolinyl cycloalkenes of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme VII. Dipolar cycloaddition of an oximinoyl chloride with an appropriately substituted .alpha.-methylene lactone affords the isoxazolinyl lactone. The lactone is then reacted with an appropriate lithium dimethyl alkylphosphonate, followed by PCC oxidation. The resulting diketophosphonate undergoes an intramolecular Wittig reaction in the presence of K.sub.2 CO.sub.3 /18-crown-6 according to the method described by Lim and Marquez (Tetrahedron Lett. 1983, 24, 5559). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR57##

The dipolarophiles used to prepare the compounds of this invention may be prepared by numerous methods. The .omega.-alkenoic ester class of dipolarophile may be purchased commercially or prepared by oxidation of the corresponding .omega.-alkenols by the method of Corey and Schmidt (Tetrahedron Lett. 1979, 399, Scheme VIII, Method 1). The .alpha.-methylene diester and .alpha.-methylene lactone class of dipolarophile may be purchased commercially or can be prepared by numerous methods from the corresponding diester (see Osbond, J. Chem. Soc. 1951, 3464; Ames and Davey, J. Chem. Soc. 1958, 1794; Vig, et al., Ind. J. Chem. 1968, 6, 60; Grieco and Hiroi, J. Chem. Soc., Chem. Commun. 1972, 1317, Scheme VIII, Method 2). The 3-(styryl)propionic ester class of dipolarophile may be prepared by palladium-catalyzed cross coupling of the appropriately substituted bromo- or iodohydrocinnamic acid to a vinylmetal species according to methods cited within Mitchell (Synthesis 1992, 803) and Stille (Angew. Chem. Int. Ed. Engl. 1986, 25, 508, Scheme VIII, Method 3). ##STR58##

Compounds of Formula I wherein b is a double bond can be prepared using one of the routes depicted in Scheme IX. Bromination followed by subsequent dehydrobromination of a suitably substituted methyl 3-(cyanophenyl)isoxazolin-5-ylacetate, prepared as described above, using the method of Elkasaby & Salem (Indian J. Chem. 1980, 19B, 571-575) provides the corresponding isoxazole intermediate. Alternately, this intermediate can be obtained by 1,3-dipolar cycloaddition of a cyanophenylnitrile oxide (prepared from the corresponding chlorooxime as described in Scheme I) with an appropriate alkyne to give the isoxazole directly. Hydrolysis of the ester using conventional methods known to one skilled in the art of organic synthesis gives the acetic acids. Coupling of the resulting acids to an appropriately substituted .alpha.- or .beta.-amino ester using standard coupling reagents, such as TBTU, affords a nitrile-amide. The nitrile is then converted to the amidine via the imidate or thioimidate under standard conditions to give the prodrug esters. Saponification gives the acids. ##STR59##

Compounds of Formula I wherein R.sup.1 is (R.sup.2)(R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)-- and V is phenylene are prepared as illustrated in Scheme X. Cycloaddition of an appropriately N-protected aminophenylaldoxime with vinyl acetic acid, t-butyl ester, using the conditions described above provides t-butyl�3-(4-t-butyloxycarbonylaminophenyl)isoxazolin-5-yl!acetate. Hydrolysis of the ester with lithium hydroxide provides the free acid which can be coupled with a suitably substituted methyl 3-aminopropionate as previously described. After deprotection, the aniline is converted to the corresponding guanidine using the method described by Kim et al. (Tetrahedron Lett. 1993, 48, 7677). A final deprotection step to remove the BOC groups provides guanidino compounds of Formula I. ##STR60##

An example of the preparation of compounds of the second embodiment wherein R.sup.1 -U is a benzamide is illustrated in Scheme XI. Conversion of the 3-(4-cyanophenyl)isoxazolin-5-yl-.beta.-aminoalaninyl esters to the amides can be accomplished by reaction of the nitrile with an appropriate alcohol under acidic conditions. (J. Med. Chem. 1991, 34, 851.) The substituted amides can be accessed by allowing the 3-(4-cyanophenyl)isoxazolin-5-yl-.beta.-aminoalaninyl esters to react with an appropriate halogenated compound (Synthesis, 1978, 303. Saponification as described above gives the free acids. ##STR61##

The compounds of the invention where U is a pyridyl may be prepared by several methods. 2-Amino-4-pyridyl analogs can be easily accessed from readily available 2-bromo-4-pyridylcarboxaldehyde (Corey, E. J et. al. Tetrahedron Lett. 1983, 32, 3291). The desired amino compound can be suitably introduced by displacement of the bromo substituent with a suitable ammonia source or alternatively with sodium azide followed by reduction via standard techniques known to those in the art. 2-Amidino-5-pyridyl analogs can be accessed from 2-bromo-5-pyridylcarboxaldehyde by displacement of the bromide at an appropriate stage in the synthesis with KCN. Conversion of the nitrile to the requisite amidine then affords the desired products. 6-Amino-3-pyridyl analogs can be easily accessed (according to the method described for the preparation of 2-amino-5-pyridyl analogs) from 6-chloro-3-pyridylcarboxaldehyde. This was obtained in part from 6-chloro-3-pyridylcarboxylic acid (Aldrich) via techinques known in the art. 6-Amidino-3-pyridyl analogs can be readily accessed from 6-chloro-3-pyridylcarboxaldehyde via techniques described for 2-amidino-5-pyridylanalogs.

The preparation of quinuclidine carboxaldehyde starting materials may be done as follows. 4-Cyanoquinuclidine prepared by the method of Kanai, T. et al, (Het., 1992, 34, 2137), can be converted to quinuclidine-4-carboxaldehyde by standard conditions and homologated by the method of (Tetrahedron Lett. 1987, 28, 1847) to the desired aldehyde. Conversion of the aldehyde to the oxime followed by chlorination to the chlorooxime should then afford the key quinuclidine chlorooxime which can then be further elaborated to the desired compounds.

The synthesis of spiro-fused isoxazolinyl amines of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme XII. Dipolar cycloaddition of a suitable oxime with a suitably protected methylenecycloamine, prepared by methods known in the literature (De Amici, M.; Fr.o slashed.lund, B.; Hjeds, H.; Krogsgaard-Larson, P. Eur. J. Med. Chem. 1991, 26, 625; Mimura, M., et. al. Chem. Pharm. Bull. 1993, 41, 1971; Labouta, I. M.; Jacobsen, P.; Thorbek, P.; Krogsgaard-Larson, P.; Hjeds, H. Acta Chem. Scand., Ser. B 1982, 36, 669), yields the spirocyclic amine after deprotection. This amine can be functionalized with a serine beta-lactone (Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105) providing an optically active product. Alternatively, the amine can be reacted with a 3-iodo or 3-chloroalanine derivative (I: Marki, W.; Schwyzer, R. Helv. Chim. Acta 1975, 58, 1471; Cl: Bigge, C. F.; Wu J.-P.; Drummond, J. R. Tetrahedron Lett. 1991, 32, 7659; Benoiton, L. Can. J. Chem. 1968, 46, 1549) to give a racemic product. ##STR62## The cycloaddition can also be performed after the introduction of the propionyl side chain as shown in Scheme XIII. ##STR63##

The compounds of Tables 12 and 13 were made using combinatorial synthetic methodology as shown in Scheme XIV. Thus, a resin was derivatized and to it was coupled the protected 2,3-diaminoproprionate. Following deprotection of N.sup.3, the desired isoxazoline carboxylic acid was coupled to N.sup.3. The final product was removed from once the terminal amine of the isoxazoline carboxylic acid was converted to its desired form. ##STR64##

The compounds of this invention and their preparation can be further understood by the following procedures and examples, which exemplify but do not constitute a limit of their invention.

EXAMPLE 1

3-(4-�2-Piperidin-4-yl)ethoxy!phenyl!-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

Part A. Preparation of 2-(4-N-t-Butyloxycarbonylpiperidinyl)ethanol

This material was prepared from 4-piperidine-2-ethanol according to European Patent Application Publication Number 478363 A2.

Part B. 4-�2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy!benzaldehyde

To a solution of 2-(4-N-t-Butyloxycarbonylpiperidinyl)ethanol (7.71 g, 33.6 mmol), 4-hydroxybenzaldehyde (4.11 g, 33.6 mmol) and PPh.sub.3 (8.82 g, 33.6 mmol) in THF (60 mL) at .degree.20.degree. C. was added a solution of DEAD (5.3 mL, 33.7 mmol) in THF (30 mL) over 2 hours. During the addition, a deep red solution resulted, which changed to a golden color upon warming to room temperature overnight (18 hours). At this time the solution was concentrated and redissolved in EtOAc. It was then washed with water, 0.1M HCl, 1M NaOH, sat. NaCl and dried (MgSO.sub.4). Concentration gave a solid (.about.20 g), which was purified using flash chromatography (10-20-30-40-50% EtOAc/hexanes step gradient), affording 7.82 g (70%) of the desired ether after pumping to constant weight; mp 76.4.degree.-79.7.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 9.88 (s 1H), 7.83 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 4.10 (bd, J=12.8 Hz, 2H), 4.04 (t, J=6.6 Hz 2H), 2.69 (bt, 2H), 1.84 (m, 2H), 1.70 (bd J=14.3 Hz, 2H), 1.46 (s, 9H, overlapped with m, 2H), 1.10 (m, 2H).

Part C. 4-�2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy!benzaldoxime

To a solution of 4-�2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy!benzaldehyde (3.16 g, 9.48 mmol) in MeOH (20 mL) was added hydroxylamine hydrochloride (1.27 g, 18.3 mmol) and 2M NaOH (7 mL, 14 mmol). The resulting suspension was stirred overnight at room temperature (18 hours). The mixture was brought to pH 4 using 1M HCl, followed by filtration and water wash. The crystals were dried under vacuum over P205, affording 2.88 g (87%); mp: 114.4.degree.-116.1.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 8.09 (s, 2H), 7.51 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.10 (b, 2H), 4.03 (t, J=6.2 Hz 2H), 2.71 (bt, 2H), 1.73 (m, 4H), 1.46 (s, 9H), 1.19 (m, 2H).

Part D. 4-�2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy!benzaldoximinoyl Chloride

To a solution of 4-�2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy!benzaldoxime (955 mg, 2.74 mmol) in DMF (5 mL) was added NCS (366 mg, 2.74 mmol) in 3 portions. After 3 hours, the solution was diluted with EtOAc and washed with water, sat. NaCl, dried (MgSO.sub.4) and concentrated. The resulting solid was crystallized from ether/hexanes to give 548 mg (52%) of the oximinoyl chloride; mp: 119.3.degree.-119.9.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 8.37 (bs 1H), 7.77 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.12 (bd, J=13.2 Hz, 2H), 4.04 (t, J=6.2 Hz 2H), 2.72 (bt, J=12.1 Hz, 2H), 1.70 (m, 5H), 1.46 (s, 9H), 1.10 (m, 2H).

Part E. Methyl 3-�4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!-(5R,S)-isoxazolin-5-ylacetate

To a solution of 4-�2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy!benzaldoximinoyl chloride (400 mg, 1.045 mmol) and methyl 3-butenoate (200 mg, 2.00 mmol) was added TEA (0.15 mL, 1.1 mmol). The resulting suspension was heated at reflux for 5 hours, cooled to room temperature and diluted with EtOAc. It was then washed with 0.1M HCl, water, sat. NaCl, dried (MgSO.sub.4) and concentrated. The resulting solid was crystallized from DCM/hexanes to give 357 mg (77%) of the isoxazoline; mp: 139.1.degree.-140.9.degree. C.; 1H NMR (300 MHz, CDCl.sub.3) .delta. 7.59 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.08 (m, 1H), 4.10 (bd, J=13.2 Hz, 2H), 4.04 (t, J=5.9 Hz 2H), 3.73 (s, 3H), 3.53 (dd, J=16.5, 10.1 Hz, 1H), 3.10 (dd, J=16.8, 7.1 Hz, 1H), 2.88 (dd, J=16.1, 5.9 Hz, 1H), 2.71 (bt, J=12.8 Hz, 2H), 2.64 (dd, J=15.8, 7.7 Hz, 1H), 1.72 (m, 5H), 1.46 (s, 9H), 1.08 (m, 2H).

Part F. 3-�4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!-(5R,S)-isoxazolin-5-ylacetic Acid

To a solution of methyl 3-�4-{2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!-(5R,S)-isoxazolin-5-ylacetate (47 mg, 0.105 mmol) in THF (2 mL) was added 0.5M LiOH (1 mL, 0.5 mmol). The reaction was stirred at room temperature for 5 hours, then was acidified to pH 3 using 0.1M HCl. The mixture was washed with DCM and the combined organic fraction dried (MgSO.sub.4) and concentrated. The resulting solid was crystallized from EtOAc/hexanes to give 34 mg (74%) of the carboxylic acid; mp: 169.1.degree.-170.6.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.60 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.10 (m, 1H), 4.08 (bd, 2H, overlapped with t, J=5.9 Hz 2H), 3.55 (dd, J=16.5, 10.2 Hz, 1H), 3.11 (dd, J=16.8, 7.0 Hz, 1H), 2.93 (dd, J=16.1, 6.2 Hz, 1H), 2.71 (m, 3H), 2.00 (m, 2H), 1.72 (m, 5H), 1.46 (s, 9H).

Part G. 3-(4-�2-(Piperidin-4-yl)ethoxy!phenyl!-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

To a solution of 3-�4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!-(5R,S)-isoxazolin-5-ylacetic acid (53 mg, 0.12 mmol) in DCM (2 mL) was added TFA (1 mL, 13 mmol). After 1.5 hours, the product was crystallized by the addition of ether, affording 33 mg (60%) of the amino acid; mp: 142.4.degree.-143.1.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.59 (dd, J=8.8, 2.6 Hz, 2H), 6.96 (dd, J=8.8, 2.6 Hz, 2H), 5.03 (m, 1H), 4.10 (m, 2H), 3.55 (ddd, J=16.8, 10.3, 2.2 Hz, 1H), 3.38 (bd, J=12.4 Hz, 2H), 3.16 (ddd, J=17.2, 7.7, 2.2 Hz, 1H), 2.98 (bt, J=13.2 Hz, 2H), 2.69 (m, 2H), 2.01 (bd, J=14.3 Hz, 2H), 1.91 (m, 1H), 1.80 (m, 2H), 1.46 (m, 2H).

EXAMPLE 4

2-�3-(4-�2-(Piperidin-4-yl)ethoxy!phenyl)isox-azolin-5-yl!-2-(S)-(benzyloxycarbonylamino)acetate, Trifluoroacetic Acid Salt

Part A. Benzyl 2-(S)-��(benzyloxy)carbonyl!amino!-3-butenoate

This material was prepared from N-Cbz-L-glutamic acid .alpha.-benzyl ester according to Krol, et al. (J. Org. Chem. 1991, 728).

Part B. Benzyl (2S)-(5R,S)-�3-�4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!isoxazolin-5-yl{�(benzyloxy)carbonyl!amino}!acetate

To a solution of 4-�(2-N-t-butyloxycarbonylpiperidin-4-yl)ethoxy!benzaldoxime (852 mg, 2.44 mmol) and benzyl L-2-��(benzyloxy)carbonyl!amino!-3-butenoate (612 mg, 1.88 mmol) in DCM (10 mL) was added 5% NaOCl (common household bleach, 4 mL, 2.8 mmol). The mixture was rapidly stirred at room temperature for 22 hours, after which time it was diluted with water and DCM. After separation of the layers, the aqueous was washed with DCM (3.times.). The combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo, giving 1.4 g. Purification using flash chromatography (10% EtOAc/hexanes-30% EtOAc/hexanes) then afforded 886 mg (70%) of an oily product as a 2.5:1 mixture of the erythro and threo isomers; .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (m, 2H), 7.34 (m, 5H), 7.23 (m, 5H), 6.87 (d, J=8.8 Hz, 2H), 5.47 (bd, 1H), 5.12 (m, 5H), 4.60 (m, 1H), 4.07 (m, overlapped with 4.03 (t, J=6.1 Hz, 4H)), 3.36 (m, 2H), 2.71 (bt, J=12.7 Hz, 2H), 1.70 (m, 5H), 1.45 (s, 9H), 1.18 (m, 2H); Anal. Calc. for C.sub.38 H.sub.45 N.sub.3 O.sub.8 : C, 67.93; H, 6.76; N, 6.26. Found: C, 67.95; H, 6.77; N, 6.17.

Part C. (2S)-(5R,S)-�3-�4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!isoxazolin-5-yl{�(benzyloxy)carbonyl!amino}!acetic Acid

A solution of benzyl (2S)-(5R,S)-�3-�4-{(2-N-t-butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!isoxazolin-5-yl{�(benzyl-oxy)carbonyl!amino}!acetate (875 mg, 1.302 mmol) in THF (5 mL) was saponified over 5 hours using 0.5M LiOH (3.5 mL) according to Example 1, Part F. To the crude product was added methanol, causing crystallization of one of the diastereomers. Filtration and pumping to constant weight gave 295 mg (39%); mp: 216.1.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6, 80.degree. C.) .delta. 7.50 (d, J 8.9 Hz, 2H), 7.23 (s, 5H), 6.96 (d, J=8.9 Hz, 2H), 6.17 (bs, 1H), 4.99 (m, 3H), 4.07 (t, J=6.1 Hz, 2H), 3.90 (m, 3H), 3.35 (d, J=9.3 Hz, 2H), 2.72 (bt, J=12.4 Hz, 2H), 1.67 (m, 5H), 1.39 (s, 9H), 1.08 (m, 2H). The filtrate was concentrated in vacuo and pumped until constant weight was achieved, giving 200 mg (26%) of the carboxylic acids as a mixture of erythro- and threo-isomers; TLC (silica gel 60, 20% MeOH/CHCl.sub.3) R.sub.f =0.23, Mass Spectrum (ESI, e/z, relative abundance) 582 (M+H).sup.+, 32%; 526 (M--C.sub.4 H.sub.9 +H.sub.2).sup.+, 100%; 482 (M--Boc+H.sub.2).sup.+, 91%).

Part D. (2S)-(5R,S)-�3-�4-{(2-Piperidin-4-yl)ethoxy}phenyl!isoxazolin-5-yl{�(benzyloxy)carbonyl!amino}!acetic Acid (isomer A)

(2S)-(5R,S)-�3-�4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!isoxazolin-5-yl{�(benzyloxy)carbonyl!amino}!acetic acid (23 mg, 0.039 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 15 mg (79%); mp: 302.degree. C. (dec); .sup.1 H NMR (400 MHz, DMSO-d.sub.6, 60.degree. C.) .delta. 7.57 (d, J=8.8 Hz, 2H), 7.30 (s, 5H), 6.99 (d, J=8.8 Hz, 2H), 5.05 (s, 2H, coincident with m, 1H), 4.35 (d, J=4.9 Hz, 1H), 4.09 (t, J=6.1 Hz, 2H), 3.52 (dd, J=17.3, 10.7 Hz, 1H), 3.26 (m, 3H), 2.88 (dt, J=12.7, 2.7 Hz, 2H), 1.88 (bd, J=14.4 Hz, 2H), 1.80 (m, 1H), 1.72 (m, 2H), 1.38 (m, 2H).

Part D'. (2S)-(5R,S)-�3-�4-{(2-Piperidin-4-yl)ethoxy}phenyl!lisoxazolin-5-yl{�(benzyloxy)carbonyl!amino}!acetic Acid, Trifluoroacetic Acid Salt (isomer B)

(2S)-(5R,S)-�3-�4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl!isoxazolin-5-yl{�(benzyloxy)carbonyl!amino}!acetic acid (177 mg, 0.304 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 3 mg (2%) of the TFA salt; mp: >400.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6, 60.degree. C.) .delta. 8.48 (bs, 0.5H), 8.15 (bs, 0.5H), 7.55 (d, J=8.9 Hz, 2H), 7.30 (m, 5H), 6.97 (d, J=8.9 Hz, 2H), 5.05 (s, 2H), 4.96 (m, 1H), 4.33 (m, 1H), 4.07 (t, J=6.3 Hz, 2H), 3.38 (m, 2H), 3.26 (bd, J=12.0 Hz, 2H), 2.87 (m, 2H), 1.86 (bd, J=14.2 Hz, 2H), 1.78 (m, 1H), 1.70 (apparent q, J=6.3 Hz, 2H), 1.36 (bq, J=13.2 Hz, 2H).

EXAMPLE 6

3-(3-�4-(Piperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-yl)propionic Acid, Trifluoroacetic Acid Salt

Part A. Ethyl N-t-Butyloxycarbonylpiperidine-4-carboxylate

To a stirred solution of ethyl isonipecotate (20.01 g, 0.1273 mol) in EtOAc (100 mL) at 0.degree. C. was added dropwise a solution of Boc.sub.2 O (27.76 g, 0.1272 mol) in EtOAc (50 mL). The mixture was allowed to warm to room temperature overnight. After 20 hours, the mixture was washed with water, 0.1M HCl, sat. NaHCO.sub.3, sat. NaCl and dried (MgSO.sub.4). Concentration and pumping under vacuum to constant weight gave 32.54 g (99%) of the desired carbamate as a mobile oil; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 4.13 (q, J=7.0 Hz, 2H), 4.03 (dm, J=13.6 Hz 2H), 2.81 (m, 2H), 2.41 (m, 1H), 1.86 (dm, J=13.6 Hz, 2H), 1.62 (m, 2H), 1.44 (s, 9H), 1.24 (t, J=7.0 Hz, 3H).

Part B. N-t-Butyloxycarbonylpiperidin-4-ylmethanol

To a solution of ethyl N-t-butyloxycarbonylpiperidine-4-carboxylate (32.34 g, 0.1257 mol) in THF (100 mL) at 0.degree. C. was added dropwise 1M LAH in THF (87.9 mL, 0.0879 mol). After 2 hours, excess hydride was quenched by the addition of water (3.2 mL), 2M NaOH (3.2 mL) and water (10 mL). The mixture was filtered, washed with EtOAc and the filtrate washed with water, sat. NaCl, dried (MgSO.sub.4) and concentrated. Pumping to constant weight gave 22.72 g (84%); mp: 79.2.degree.-81.1.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 4.12 (bd, J=12.8 Hz 2H), 3.49 (d, J=6.2 Hz, 2H), 2.68 (dt, J=13.2, 1.8 Hz, 2H), 1.69 (m, 3H), 1.44 (s, 9H, overlapped with m, 1H), 1.14 (m, 2H).

Part C. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldehyde

To N-t-butyloxycarbonylpiperidin-4-ylmethanol (7.87 g, 36.5 mmol), p-hydroxybenzaldehyde (4.46 g, 36.5 mmol) and PPh.sub.3 (9.59 g, 36.5 mmol) in THF (100 mL) at -20.degree. C. was added DEAD (5.75 mL, 36.5 mmol) in THF (50 mL) according to Example 1, Part B, affording 8.14 g (70%); mp: 115.6.degree.-116.8.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 9.86 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.15 (bd, J=13.2 Hz 2H), 3.87 (d, J=6.6 Hz, 2H), 2.74 (dt, J=12.4, 1.8 Hz, 2H), 1.97 (m, 1H), 1.81 (bd, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.27 (dq, J=12.1, 4.0 Hz, 2H).

Part D. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldoxime

A mixture of 4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)benzaldehyde (3.16 g, 9.89 mmol) and hydroxylamine hydrochloride (1.27 g, 18.3 mmol) in 9:1 MeOH/pyridine (30 mL) was heated at reflux for 18 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1M HCl (3.times.), water, sat. CuSO.sub.4 (2.times.), water, sat. NaCl, dried (MgSO.sub.4) and concentrated, giving 3.19 g (96%) of the oxime; mp: 140.1.degree.-141.8.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 8.07 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.14 (bs, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.71 (bt, J=12.4 Hz, 2H), 1.95 (m, 1H), 1.80 (bd, J=12.4 Hz, 2H), 1.45 (s, 9H), 1.26 (m, 2H).

Part E. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldoximinoyl Chloride

4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldoxime (3.19 g, 9.54 mmol) in DMF (10 mL) was reacted with NCS (1.27 g, 9.51 mmol) for 18 hours according to Example 1, Part D to afford the hydroximinoyl chloride (1.17 g, 33%); mp: 178.0.degree.-179.8.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.75 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.17 (bd, J=12.4 Hz, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.74 (dt, J=12.8, 1.8 Hz, 2H), 1.95 (m, 1H), 1.81 (bd, J=12.1 Hz, 2H), 1.46 (s, 9H), 1.27 (dq, J=12.5, 4.0 Hz, 2H).

Part F. Methyl 3-(3-�4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-yl)propionate

4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldoximinoyl chloride (738 mg, 2.00 mmol), methyl 4-pentenoate (230 mg, 2.02 mmol) and TEA (0.28 mL, 2.0 mmol) were heated at reflux for 1 hour according to Example 1, Part E. Crystallization from ether/hexanes afforded 537 mg (60%). mp: 97.9.degree.-99.9.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.57 (d, J=9.0 Hz, 2H), 6.87 (d, J=9.0 Hz,2H), 4.74 (m, 1H), 4.15 (bd, J=13.2 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.67 (s, 3H), 3.40 (dd, J=16.5, 10.2 Hz, 1H), 2.95 (dd, J=16.5, 7.3 Hz, 1H), 2.73 (dt, J=13.2, 1.1 Hz, 2H), 2.52 (t, J=7.3 Hz, 2H), 1.98 (q, J=7.0 Hz, 2H, overlapping m, 1H), 1.81 (bd, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.26 (dq, J=12.4, 3.7 Hz, 2H).

Part G. 3-(3-�4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-yl)propionic Acid

Methyl 3-(3-�4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-yl)propionate (250 mg, 0.560 mmol) was saponified using 0.5M LiOH (2 mL, 1 mmol) in THF (2 mL). The reaction was stirred at room temperature for 3 hours, according to Example 1, Part F. The resulting solid was crystallized from DCM/hexanes to give 163 mg (67%) of the carboxylic acid; mp: 146.5.degree.-147.7.degree. C.; .sup.1 H N (300 MHz, CDCl.sub.3) .delta. 7.57 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.75 (m, 1H), 3.81 (d, J=6.2 Hz, 2H), 3.41 (dd, J=16.5, 10.3 Hz, 1H), 2.95 (dd, J=16.5, 7.3 Hz, 1H), 2.75 (bt, J=12.4 Hz, 2H), 2.57 (t, J=7.3 Hz, 2H), 1.97 (m, 3H), 1.81 (bd, J=12.1 Hz, 2H), 1.45 (s, 9H), 1.24 (m, 2H).

Part H. 3-(3-�4-(Piperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-yl)propionic Acid, Trifluoroacetic Acid Salt

3-(3-�4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-yl)propionic acid (103 mg, 0.238 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 88 mg (83%) of the TFA salt; mp: 179.1.degree.-181.8.degree. C.; .sup.1 H NMR (400 MHz, MeOH-d.sub.4) .delta. 7.60 (d, J=9.0 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 4.73 (m, 1H), 3.94 (d, J=6.1 Hz, 2H), 3.46 (m, 3H), 3.06 (m, 3H), 2.45 (dt, J=7.3, 1.2 Hz, 2H), 2.16 (m, 1H), 2.08 (bd, J=15.4 Hz, 2H), 1.94 (q, J=6.6 Hz, 1H), 1.64 (dq, J=14.2, 4.2 Hz, 2H).

EXAMPLE 7

3-�4-(Piperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

Part A. Methyl 3-�4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-ylacetate

4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldoximinoyl chloride (412 mg, 1.12 mmol), methyl 3-butenoate (200 mg, 2.00 mmol) and TEA (0.18 mL, 1.3 mmol) were heated at reflux for 2 hours according to Example 1, Part E. Crystallization from chloroform/cyclohexane afforded 329 mg (68%). mp: 97.9.degree.-99.9.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.58 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz,2H), 5.04 (m, 1H), 4.15 (bd, J=13.2 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.71 (s, 3H), 3.54 (dd, J=16.8, 10.3 Hz, 1H), 3.08 (dd, J=16.8, 7.3 Hz, 1H), 2.86 (dd, J=16.1, 5.9 Hz, 1H), 2.73 (dt, J=12.8, 1.8 Hz, 2H), 2.62 (dd, J=15.8, 7.7 Hz, 1H), 1.95 (m, 1H), 1.81 (bd, J=13.2 Hz, 2H), 1.45 (s, 9H), 1.25 (dq, J=12.8, 4.4 Hz, 2H).

Part B. 3-�4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-ylacetic Acid

Methyl 3-�4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-ylacetate (329 mg, 0.762 mmol) was saponified using 0.5M LiOH (3 mL, 1.5 mmol) in THF (5 mL). The reaction was stirred at reflux for 4 hours, according to Example 1, Part F to give 72 mg (22%) of the carboxylic acid; mp: 164.0.degree.-164.8.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.58 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 5.07 (m, 1H), 4.15 (bd, J=13.6 Hz, 2H), 3.82 (d, J=6.2 Hz, 2H), 3.53 (dd, J=16.8, 10.3 Hz, 1H), 3.10 (dd, J=16.8, 7.0 Hz, 1H), 2.91 (dd, J=16.1, 5.9 Hz, 1H), 2.73 (dt, J=14.6, 1.8 Hz, 2H), 2.68 (dd, J=16.1, 7.3 Hz, 1H), 1.97 (m, 1H), 1.81 (bd, J=13.2 Hz, 2H), 1.45 (s, 9H), 1.26 (dq, J=12.8, 4.4 Hz, 2H).

Part C. 3-�4-(Piperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

3-�4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl!-(5R,S)-isoxazolin-5-ylacetic acid (72 mg, 0.172 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 64 mg (94%) of the TFA salt; mp: 220.degree. C. (dec); .sup.1 H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.61 (d, J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 5.04 (m, 1H), 3.95 (d, J=5.9 Hz, 2H), 3.56 (dd, J=17.2, 10.2 Hz, 1H), 3.45 (bd, J=12.8 Hz, 2H), 3.18 (dd, J=17.2, 7.3 Hz, 1H), 3.04 (dt, J=10.2, 2.9 Hz, 2H), 2.69 (m, 2H), 2.18 (m, 1H), 2.08 (bd, J=14.6 Hz, 2H) 1.63 (bq, 2H).

EXAMPLE 8

3-�4-(2-Piperidin-4-yl)ethoxyphenyl!-(5R,S) -isoxazolin-5-ylpropionic Acid, Trifluoroacetic Acid Salt

This material was prepared analogously to Example 1, giving the desired material; mp: 114.8.degree.-115.7.degree. C.; .sup.1 H NMR (300 MHz, CD.sub.3 OD) .delta. 7.59 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 4.72 (m, 1H), 4.07 (t, J=5.9 Hz, 2H), 3.47 (dd, J=16.8. 10.2 Hz, 1H), 3.37 (dd, J=16.8, 7.7 Hz, 1H), 2.98 (m, 2H), 2.44 (t, J=7.3 Hz, 2H), 2.01 (bd, J=15.0 Hz, 2H), 1.93 (m, 3H), 1.80 (m, 2H), 1.44 (m, 2H).

EXAMPLE 9

erythro- and-threo-3-�3-�4-�(piperidin-4-yl)methoxy!phenyl!isoxazolin-5-yl{�butanesulfonyl!amino!propionate, Trifluoroacetic Acid Salt

Part A. Dicyclohexylammonium D,L-2-�(Butanesulfonyl)amino!-4-pentenoic acid

To a suspension of D,L-2-amino-4-pentenoic acid (2.54 g, 22.06 mmol) in acetonitrile (35 mL) was added BSTFA (7.3 mL, 27.5 mmol). The suspension was heated at 55.degree. C. for 2 hours, after which time a golden yellow solution resulted. To this solution was added pyridine (2.2 mL, 27.2 mmol) and n-butanesulfonyl chloride (3.0 mL, 23.1 mmol). The mixture was heated at 70.degree. C. for 20 hours, then cooled to room temperature. Concentration in vacuo afforded a brown oil, to which was added 15% KHSO.sub.4 (5 mL). The mixture was stirred for 1 hour and shaken with EtOAc (3.times.). The combined organic extracts were washed with sat. NaCl, dried (MgSO.sub.4), concentrated and the resulting oil dissolved in ether (5 mL). To this solution was added DCHA (4.38 mL, 22.0 mmol), causing immediate precipitation of the dicyclohexylammonium salt. The solid was collected by filtration and pumped to constant weight, giving 8.42 g (92%); mp: 207.1.degree.-208.6.degree. C.; .sup.1 H NMR (400 MHz, MeOH-d.sub.4) .delta. 5.84 (m, 1H), 5.09 (dm, J=17.1 Hz, 1H), 5.04 (dm, J=10.2 Hz, 1H), 3.80 (dd, J=7.1, 5.1 Hz, 1H), 3.18 (m, 2H), 3.02 (m, 2H), 2.49 (m, 2H), 2.06 (m, 4H), 1.78 (m, 8H), 1.55 (m, 12H), 0.94 (t, J=7.3 Hz).

Part B. Methyl D,L-2-�(Butanesulfonyl)amino!-4-pentenoate

To a solution of dicyclohexylammonium D,L-2-�(butanesulfonyl)amino!-4-pentenoate (8.36 g, 20.07 mmol) in MeOH (50 mL) was added HCl-saturated MeOH (50 mL). The resulting suspension was stirred at room temperature for 18 hours, diluted with ether, and filtered. Concentration of the filtrate in vacuo was followed by the addition of ether, a second filtration, and washing of the filtrate with 0.1M HCl, sat. NaHCO.sub.3, sat. NaCl. The solution was dried over anhydrous MgSO.sub.4, concentrated and placed under vacuum until constant weight to give 4.49 g (90%) of the desired ester as a light brown oil; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 5.68 (m, 1H), 5.19 (bd, J=1.5 Hz, 1H), 5.15 (m, 1H), 4.78 (bd, J=8.4 Hz, 1H), 4.20 (dt, J=8.8, 5.8 Hz, 1H), 3.77 (s, 3H), 2.99 (m, 2H), 2.54 (t, J=6.6 Hz, 2H), 1.76 (m, 2H), 1.42 (sextuplet, J=7.3 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H).

Part C. Methyl erythro- and-threo-3-(3-�4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl!isoxazolin-5-yl{�butanesulfonyl!amino})propionate

To a solution of 4-�(N-t-butyloxycarbonylpiperidin-4-yl)methoxy!benzaldoxime (2.680 g, 8.01 mmol), methyl D,L-2-�(butanesulfonyl)amino!-4-pentenoate (2.000 g, 8.02 mmol) and TEA (0.11 mL, 0.79 mmol) in THF (10 mL) was added a 5% solution of NaOCl (common household bleach, 15 mL, 10.5 mmol). The resulting mixture was rapidly stirred at room temperature for 20 hours. The mixture was diluted with EtOAc and water and the layers were separated. The aqueous portion was washed with EtOAc, and the combined organic fraction washed with sat. NaCl and dried over MgSO.sub.4.Concentration in vacuo afforded a light brown oil (4.8 g), which was purified using flash chromatography (0-50% EtOAc/hexanes in 5 steps), giving four components. The least polar of these materials (fractions 8-11) was determined by .sup.1 H NMR to be the starting olefin (1.520 g, 76%). The next component isolated in order of increasing polarity (fractions 12-15) was determined by .sup.1 H NMR to be the starting oxime (1.423 g, 53%). The next component off of the column (fraction 20) was determined to be the faster of the two diastereomers (317 mg). This material had co-eluted with an impurity having a .sup.1 H NMR profile similar to the starting oxime and appeared to be approximately 50% pure. The most polar component isolated (fractions 22-25) was assigned as the second diastereomer (395 mg, 8%); mp: 127.5.degree.-129.3.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.56 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 5.25 (d, J=9.5 Hz, 1H), 4.87 (m, 1H), 4.35 (dt, J=9.2, 3.7 Hz, 1H), 4.15 (bs, 2H), 3.81, (d, J=6.2 Hz, 2H), 3.78 (s, 3H), 3.49 (dd, J=16.5, 10.3 Hz, 1H), 3.05 (t, J=7.7 Hz, 2H), 2.97 (dd, J=16.5, 7.0 Hz, 1H), 2.73 (bt, J=12.1 Hz, 2H), 2.21 (m, 1H), 1.94 (m, 2H), 1.82 (m, 4H), 1.45 (s, 9H), 1.24 (m, 3H), 0.92 (t, J=7.3 Hz, 3H).

Part D. 3-(3-�4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl!isoxazolin-5-yl{�butanesulfonyl!amino})-propionic Acid (More Polar Diastereomer)

A solution of methyl 3-(3-�4-{(butyloxycarbonylpiperidin-4-yl)methoxy)phenyl!isoxazolin-5-yl{�butanesulfonyl!amino})propionate more polar diastereomer (200 mg, 0.344 mmol) in THF (1 mL) was saponified using 0.5M LiOH (1 mL, 0.5 mmol) over 4 hours as per Example 1, Part F. The crude carboxylic acid was crystallized from EtOAc/hexanes, affording 77 mg (39%) of the desired material; mp: 137.3.degree.-139.0.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.55 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.45 (d, J=9.5 Hz, 1H), 4.92 (m, 1H), 4.37 (m, 1H), 4.15 (b, 2H), 3.81, (d, J=6.2 Hz, 2H), 3.47 (dd, J=16.5, 9.9 Hz, 1H), 3.08 (t, J=8.1 Hz, 2H), 3.01 (dd, J=16.5, 7.0 Hz, 1H), 2.74 (bt, J=12.1 Hz, 2H), 2.26 (m, 1H), 2.01 (m, 2H), 1.81 (m, 4H), 1.45 (s, 9H, overlapped with m, 1H), 1.24 (m, 3H), 0.91 (t, J=7.3 Hz, 3H).

Part D'. 3-(3-�4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl!isoxazolin-5-yl{�butanesulfonyl!amino})-propionic Acid (Less Polar Diastereomer)

A solution of the impure methyl 3-(3-�4-{(butyloxycarbonylpiperidin-4-yl)methoxy}phenyl!isoxazolin-5-yl{�butanesulfonyl!amino})propionate less polar diastereomer (309 mg) in THF (5 mL) was saponified using 0.5M LiOH (2 mL, 1 mmol) over 6 hours as per Example 1, Part F. The crude carboxylic acid was purified using flash chromatography (CHCl.sub.3 --5-15% MeOH/CHCl.sub.3 step gradient) followed by crystallization from EtOAc/hexanes, affording 169 mg of the desired material; mp: 155.degree. C. (dec); .sup.1 H NMR (400 MHz, DMSO-d.sub.6, 80.degree. C.) .delta. 7.56 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.80 (m, 1H), 3.96 (bd, J=13.2 Hz, 2H), 3.90 (d, J=6.3 Hz, 2H), 3.77 (bs, 3H), 3.52 (t, J=7.8 Hz, 1H), 3.38 (dd, J=14.4, 10.0 Hz, 1H), 2.98 (t, J=7.8 Hz, 2H), 2.76 (dt, J=12.2, 1.7 Hz, 2H), 1.95 (m, 2H), 1.75 (m, 4H), 1.41 (s, 9H), 1.38 (d, J=7.6 Hz, 1H), 1.25 (m, 4H), 0.88 (t, J=7.3 Hz, 3H).

Part E. 3-(3-�4-{((Piperidin-4-yl)methoxy}phenyl!isoxazolin-5-yl{�butanesulfonyl!amino})propionic Acid, Trifluoroacetic Acid Salt (More polar Diastereomer)

3-(3-�4-�{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl!isoxazolin-5-yl (�butanesulfonyl!amino})propionic acid more polar diastereomer (40 mg, 0.070 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G. Recrystallization from methanol then afforded 4 mg (10%) of the TFA salt; mp: 263.5.degree. C. (dec).

Part E'. 3-(3-�4-{(Piperidin-4-yl)methoxy}phenyl!isoxazolin-5-yl{�butanesulfonyl!amino}!propionic Acid, Trifluoroacetic Acid Salt (Less Polar Diastereomer)

3-(3-�4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl!isoxazolin-5-yl{�butanesulfonyl!amino})propionic acid less polar diastereomer (98 mg, 0.173 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 40 mg of the TFA salt. Recrystallization from methanol then afforded 28 mg (29%) of the pure amino acid; mp: 239.4.degree.-240.7.degree. C.

EXAMPLE 33

4-Carboxymethyl-3-�4-(2-piperidin-4-yl)ethoxyohenyl!-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt

This material was prepared analogously to Example 1, giving the desired material; mp: 141.4.degree. C. (dec); .sup.1 H NMR (400 MHz, CD.sub.3 OD, 60.degree. C.) .delta. 7.60 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 3.84 (d, J=17.3 Hz, 1H), 3.66 (s, 3H), 3.59 (d, J=17.3 Hz, 1H), 3.38 (bd, J=12.9 Hz, 1H), 3.24 (t, J=1.7 Hz, 2H), 3.21 (dm, J=20.3 Hz, 1H), 3.04 (d, J=1.5 Hz, 2H), 3.00 (dt, J=12.9, 2.9 Hz, 2H), 2.02 (bd, J=14.4 Hz, 2H), 1.95 (m, 1H), 1.81 (m, 2H), 1.48 (m, 2H).

EXAMPLE 43

N-�3-(4-Amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(R,S)-3-amino-3-phenylpropanoic Acid

Part A: 4-Cyanobenzaldoxime

This material was prepared from 4-cyanobenzaldehyde according to Kawase and Kikugawa (J. Chem. Soc., Perkin Trans I 1979, 643). To a solution of 4-cyanobenzaldehyde (1.31 g, 10 mmol) in 1:1 EtOH:pyridine (10 mL) was added hydroxylamine hydrochloride (0.70 g, 10 mmol). The resulting solution was stirred at room temperature for 18 h and was concentrated in vacuo to one-half volume. To this solution was added ice water, causing the product to crystallize from solution. Recrystallization from EtOH--water followed by drying over P.sub.2 O.sub.5 afforded 1.46 g (100%) of the desired oxime; mp: 167.8.degree.-169.4.degree. C.

Part B: Methyl 3-(3-Butenoyl)amino-3-phenylpropionate

To a solution of vinylacetic acid (861 mg, 10.0 mmol), methyl 3-amino-3-phenylpropionate hydrochloride (2.37 g, 11.0 mmol) and TEA (1.6 mL, 12 mmol) in DCM (20 mL) at -10.degree. C. was added DEC (2.11 g, 11.0 mmol). The resulting mixture was stirred at -10.degree. C. for 15 hours. The mixture was then washed with water, 0.1M HCl, sat. NaHCO.sub.3, sat. NaCl and dried over anhydrous MgSO.sub.4. Concentration in vacuo followed by pumping until constant weight gave 2.36 g (95%) of the desired amide as a golden oil of suitable purity for further reaction; .sup.1 H NMR (300 MHz, CDCl.sub.3) 87.28 (m, 5H), 6.78 (bd, J=7.7 Hz, 1H), 5.95 (m, 1H), 5.43 (dt, J=8.4, 5.9 Hz, 1H), 5.25 (m, 2H), 3.61 (s, 3H), 3.04 (d, J=7.0 Hz, 2H), 2.88 (dq, J=15.0, 5.9 Hz, 2H).

Part C: Methyl 3(R,S)-{5(R,S)-N-�3-(4-Cyanophenyl)isoxazolin-5-ylacetyl!amino}-3-phenylpropanoate

To a solution of methyl 3-(3-butenoyl)amino-3-phenylpropionate (816 mg, 3.30 mmol) and 4-cyanobenzaldoxime (prepared according to Example 1, Part A, 438 mg, 3.00 mmol) in CH.sub.2 Cl.sub.2 (10 mL) was added a 5% solution of sodium hypochlorite ("Clorox", 5.3 mL, 3.5 mmol). The resulting mixture was stirred rapidly overnight (15 h), the layers separated and the aqueous washed with CH.sub.2 Cl.sub.2. The combined organic was dried (MgSO.sub.4) and concentrated in vacuo. The crude product was then purified using flash chromatography (70% EtOAc/hexanes), affording 731 mg (62%) of the desired isoxazoline as a 1:1 mixture of diastereomers; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.74 (m, 8H), 7.29 (m, 10H), 6.92 (bm, 2H), 5.42 (m, 2H), 5.16 (m, 2H), 3.64 (s, 3H), 3.60 (s, 3H), 3.48 (m, 2H), 3.26 (dd, J=17.3, 7.7 Hz, 1H), 3.15 (dd, J=16.8, 8.1 Hz, 1H), 2.85 (m, 2H), 2.69 (m, 2H).

Part D: Methyl 3(R,S)-{5(R,S)-N-�3-(4-Amidinophenyl)isoxazo-lin-5-ylacetyl!amino}-3-phenylpropanoate

Into a solution of methyl 3(R,S)-{5(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!amino}-3-phenylpropanoate (587 mg, 1.50 mmol) in 10% DCM/methanol (55 mL) was bubbled dry HCl gas for 2 hours. The mixture was stirred for 18 hours, then concentrated in vacuo. The crude imidate was dissolved in methanol (20 mL) and ammonium carbonate added. The resulting mixture was stirred for 18 hours, then filtered. The filtrate was concentrated in vacuo and the residue purified using flash chromatography (CHCl.sub.3 --20% methanol/CHCl.sub.3). Concentration of the appropriate fractions in vacuo followed by placing the residue under vacuum until constant weight afforded 193 mg (32%) of the desired amidines; CIMS (NH.sub.3, e/z, relative abundance): 409 (M+H).sup.+, 100%.

Part E: 3(R,S)-{5(R,S)-N-�3-(4-Amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-phenylpropanoic Acid, Trifluoroacetic Acid Salt

Methyl 3(R, S) -{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-phenylpropanoate (45 mg, 0.113 mmol) was saponified using 0.5M LiOH (0.6 mL, 0.3 mmol) according to Example 1, Part F, affording 28 mg (49%); CIMS (NH.sub.3, e/z, relative abundance): 412 (M+H).sup.+, 100%.

EXAMPLE 43A

5(R,S) -N-�3-(4-Amidinophenyl)isoxazolin-5-ylacetyl!aminopropanoic Acid

Part A: Ethyl 3-(3-Butenoyl aminopropionate

To an ice cold solution of vinylacetic acid (4.39 g, 51.0 mmol), ethyl 3-aminopropionate hydrochloride (8.49 g, 55.3 mmol) and TEA (7.8 mL, 56 mmol) in DCM (50 mL) was added DEC (10.54 g, 55.0 mmol). The resulting mixture was warmed to room temperature overnight (18 h). The mixture was then washed with water, 0.1M HCl, sat. NaHCO.sub.3, sat. NaCl and dried (MgSO.sub.4). Concentration in vacuo followed by pumping until constant weight was achieved gave 6.34 g (67%) of the desired amide as a golden oil of purity suitable for further reaction; .sup.1 H NMR (300 MHz, CDCl.sub.3) 66.26 (bs, 1H), 5.98-5.85 (m, 1H), 5.25-5.17 (m, 2H), 4.16 (q, J=7.0 Hz, 2H), 3.52 (q, J=5.9 Hz, 2H), 2.99 (dt, J=7.0, 1.1 Hz, 2H), 2.53 (t, J=5.9 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H).

Part B: Ethyl 5(R,S) -N-�3-(4-Cyanophenyl)isoxazolin-5-ylacetyl!aminopropanoate

To a solution of ethyl 3-(3-butenoyl)aminopropionate (556 mg, 3.00 mmol) and 4-cyanobenzaldoxime (prepared according to Example 1, Part A, 292 mg, 2.00 mmol) in CH.sub.2 Cl.sub.2 (7 mL) was added a 5% solution of sodium hypochlorite ("Clorox", 4.2 mL, 2.8 mmol). The resulting mixture was stirred rapidly overnight (15 h), the layers separated and the aqueous washed with CH.sub.2 Cl.sub.2. The combined organic was dried (MgSO4) and concentrated in vacuo. The crude product was then purified using flash chromatography (EtOAc), affording 386 mg (58%) of the desired isoxazoline; mp: 102.0.degree.-102.9.degree. C.

Part C: Ethyl 5(R,S) -3-�3-(4-Amidinophenyl)isoxazolin-5-ylacetyl!aminopropanoate

Into a solution of ethyl 5(R,S)-3-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!aminopropanoate (1.65 mg, 5.00 mmol) in 10% DCM/EtOH (165 mL) was bubbled HCl gas for 2 hours. After 18 hours, the solvent was evaporated in vacuo, the residue dissolved in EtOH (100 mL) and ammonium carbonate (14.41 g, 150 mmol) added. The resulting suspension was stirred at room temperature for 18 hours, then filtered and the resulting filtrate concentrated in vacuo. The residue was then crystallized from EtOH/ether, giving 713 mg (41%) of the desired amidine; .sup.1 H NMR (300 MHz, CD.sub.3 OD) .delta. 7.88 (AB quartet, .DELTA.=16.8 Hz, J=8.4 Hz, 4H), 5.13 (m, 1H), 4.12 (q, J=7.3 Hz, 2H), 3.58 (dd, J=17.2, 10.6 Hz, 1H), 3.44 (m, 2H), 3.26 (dd, J=17.2, 7.3 Hz, 1H, coincident with solvent), 2.57 (m, 4H), 1.25 (t, J=7.3 Hz, 2H).

Part H: 5(R,S)-3-�3-(4-Amidino-henyl)isoxazolin-5-ylacetyl!aminopropanoic Acid

To a solution of ethyl 5(R,S)-3-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!aminopropanoate (346 mg, 1.00 mmol) in EtOH (6 mL) was added 0.5M LiOH. Upon mixing, a precipitate of the zwitterionic product began to form. After stirring for 18 hours at room temperature, the solid was collected by filtration, affording 365 mg of the title compound; .sup.1 H NMR (300 MHz, CD.sub.3 OD) .delta. 7.86 (AB quartet, .DELTA.=18.3 Hz, J=8.4 Hz, 4H), 5.21 (m, 1H), 3.57 (dd, J=17.2, 10.6 Hz, 1H), 3.43 (m, 2H), 3.25 (dd, J=17.2, 7.3 Hz, 1H, coincident with solvent), 2.64 (dd, J=14.6, 6.8 Hz, 1H), 2.52 (m, 3H).

EXAMPLE 120a

Methyl 3(R)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-phenethylpropanoate

Part A. Methyl (E)-5-phenyl-2-pentenoate

A solution of hydrocinnamaldehyde (13.42 g, 0.1 mol) and methyl(triphenylphosphoranylidene)acetate (33.44 g, 0.1 mol) in THF was stirred at reflux for 20 hours. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography using hexane:EtOAc::9:1. The desired product was obtained as a clear, pale yellow oil (8.0 g, 0.042 mol, 42%); .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 7.1-6.9 (m, 1H), 5.85 (d, 1H, J=5.8 Hz), 3.75 (s, 3H), 2.8 (t, 2H, J=7.7 Hz), 2.55 (q, 2H, J=7.4 Hz); MS (NH.sub.3 -DCI) 191 (M+H).sup.+.

Part B. Methyl 3-(R)-�N-(1-(R)-1-phenylethyl)amino!-5-phenylpentanoate

A mixture of methyl (E)-5-phenyl-2-pentenoate (5.70 g, 0.03 mol) and R-methylbenzylamine (14.54 g, 0.12 mol) was heated at 110.degree. C. over 94 hours. The cooled reaction mixture was purified by flash chromatography using hexane:EtOAc::8:2 to afford 1.18 g (0.0038 mol, 12%) of the desired product as a clear liquid; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.4-7.0 (m, 11H), 3.9 (q, 1H, J=6.5 Hz), 3.65 (s, 3H), 2.9-2.65 (m, 2H), 2.6-2.35 (m, 3H), 1.75-1.6 (m, 2H), 1.35 (d, 3H, J=6.2 Hz); MS (NH.sub.3 -DCI) 312 (M+H).sup.+.

Part C. Methyl 3-(R)-amino-5-phenylpentanoate . acetic acid salt

A mixture of methyl 3-(R)-�N-(1-(R)-1-phenylethyl)amino!-5-phenylpentanoate (0.72 g, 2.3 mmol), 20% Pd(OH).sub.2 /C (0.38 g), cyclohexene (8.2 mL), glacial HOAc (0.13 mL, 2.3 mmol), and MeOH (15 mL) was heated at reflux under N.sub.2 for 20 hours. After cooling, the catalyst was removed by filtration through a Celite plug, rinsed with MeOH, and the solution concentrated under vacuum. The residue was triturated with hexane to afford 0.46 g (96%) of a white solid, mp=73.degree.-75.degree. C.; .sup.1 H NMR (300 MHz, DMSO) .delta. 8.3 (bs, 2H), 7.35-7.15 (m, 5H), 3.65 (s, 3H), 3.45-3.35 (m, 1H), 2.8-2.6 (m, 4H), 2.0-1.7 (m, 2H); �.alpha.!.sub.D.sup.25 -12.50.degree. (c=0.0032, MeOH).

Part D. Methyl 3(R)-{5(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!amino}-3-phenethylpropanoate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (460 mg, 2.0 mmol) in EtOAc (15 ml) was added methyl 3-(R)-amino-5-phenylpentanoate acetic acid salt (410 mg, 2.0 mmol), TBTU (640 mg, 2.0 mmol), and Et.sub.3 N (0.56 mL, 400 mg, 4.0 mmol). After stirring at room temp for 16 hours, the reaction mixture was concentrated under vacuum then purified by flash chromatography using EtOAc to afford 690 mg (83%) of a colorless oil. .sup.1 H NMR (300 MHz, DMSO) .delta. 8.05 (brs, 1H), 7.95-7.9 (m, 2H), 7.85-7.8 (m, 2H), 7.3-7.25 (m, 2H), 7.2-7.1 (m, 2H), 5.15-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.6 (d, 3H, J=9.9 Hz), 3.3 (d, 2H, J=6.9 Hz), 3.25-3.15 (m, 1H), 2.75-2.35 (m, 6H), 1.8-1.6 (m, 2H); MS (NH.sub.3 -DCI) 420 (M+H).sup.+.

Part E Methyl 3(R)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-phenethylpropanoate

This material was prepared from methyl 3(R)-{5(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!amino}-3-phenethylpropanoate (670 mg, 1.6 mmol) according to Example 43, Part D. The crude product was triturated with cold ether to afford 272 mg (39%) of a white solid of the title compound as a 1:1 mixture of diastereomers, mp=76.degree.-78.degree. C.; .sup.1 H NMR (300 MHz, DMSO) .delta. 8.1-8.0 (m, 1H), 8.0-7.8 (m, 4H), 7.95-7.85 (m, 5H), 7.35-7.2 (m, 5H), 5.1-5.0 (m, 1H), 4.1-4.0 (m, 1H), 3.6 (s, 3H), 3.3-3.15 (m, 2H), 2.7-2.4 (m, 6H), 1.8-1.7 (m, 2H), 1.1-1.0 (m, 2H); Mass Spectrum (NH.sub.3 -ESI,) 437 (M+H).sup.+.

EXAMPLE 120b

Methyl 3(S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-phenethylpropanoate

Part A. Methyl 3-(S)-�N-(1-(R)-1-phenylethyl)amino!-5-phenylpentanoate

A mixture of (E)-methyl-5-phenyl-2-pentenoate (5.70 g, 0.03 mol) and R-methylbenzylamine (14.54 g, 0.12 mol) was heated at 110.degree. C. over 94 hours. The cooled reaction mixture was purified by flash chromatography using hexane:EtOAc::8:2 to afford 1.20 g (0.0039 mol, 13%) of the desired product as a clear liquid; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.35-7.0 (m, 11H), 3.9 (q, 1H, J=6.6 Hz), 3.65 (s, 3H), 2.95-2.8 (m, 1H), 2.75-2.5 (m, 2H), 2.45-2.35 (m, 2H), 1.9-1.65 (m, 2H), 1.3 (d, 3H, J=6.6 Hz); MS (NH.sub.3 -DCI) 312 (M+H).sup.+.

Part B. Methyl 3-(S)-amino-5-phenylpentanoate . acetic acid salt

Methyl 3-(S)-�N-benzyl-N-(1-(R)-1-phenylethyl)amino!heptanoate (0.93 g, 2.9 mmol), 20% Pd(OH).sub.2 /C (0.47 g), cyclohexene (10.1 mL), glacial HOAc (0.17 mL, 2.9 mmol), and MeOH (20 mL) were heated at reflux under N.sub.2 for 48 hours. After cooling, the catalyst was removed by filtration through a Celite plug, rinsed with MeOH, and the solution concentrated under vacuum. The residue was triturated with hexane to afford 0.65 g (80%) of a white solid, mp=86.degree.-88.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.35-7.15 (m, 5H), 5.3 (brs, 2H), 3.65 (s, 3H), 3.35-3.2 (m, 1H), 2.8-2.55 (m, 3H), 2.5-2.4 (m, 1H), 2.0 (s, 3H), 1.8 (q, 2H, J=7.4 Hz); �.alpha.!.sub.D.sup.25 +9.55.degree. (c=0.220, MeOH).

Part C. Methyl 3(S-{5(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!amino}-3-phenethylpropanoate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (700 mg, 2.6 mmol) in EtOAc (15 ml) was added methyl 3-(S)-amino-5-phenylpentanoate acetic acid salt (600 mg, 2.6 mmol), TBTU (830 mg, 2.6 mmol), and Et.sub.3 N (1.09 mL, 790 mg, 7.8 mmol). After stirring at room temperature 16 hours, the reaction mixture was concentrated under vacuum then purified by flash chromatography using EtOAc to afford 420 mg (38%) of a colorless oil. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 8.05-8.0 (m, 1H), 7.95-7.9 (m, 2H), 7.85-7.8 (m, 2H), 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 5.15-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.6-3.55 (m, 3H), 3.3-3.1 (m, 1H), 2.7-2.4 (m, 6H), 1.8-1.6 (m, 2H); MS (NH.sub.3 -DCI) 420 (M+H).sup.+.

Part D. Methyl 3(S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-3-phenethylpropanoate

This material was prepared from methyl 3(S)-{5(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!amino}-3-phenethylpropanoate (360 mg, 0.86 mmol) according to Example 43, Part D. The crude product was triturated with cold ether to afford 230 mg (62%) of an amorphous solid of the title compound as a 1:1 mixture of diastereomers, mp=84.degree.-86.degree. C.; .sup.1 H NMR (300 MHz, DMSO) .delta. 8.1-8.0 (m, 1H), 8.0-7.8 (m, 4H), 7.75-7.7 (m, 1H), 7.3-7.1 (m, 6H), 5.1-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.65 (s, 3H), 3.3-3.1 (m, 1H), 2.7-2.6 (m, 3H), 2.5-2.4 (m, 3H), 1.8-1.65 (m, 2H), 1.1-1.0 (m, 2H); Mass Spectrum (NH.sub.3 -ESI) 437 (M+H).sup.+.

EXAMPLE 189

5(R,S)-(2-Piperidin-4-yl ethyl-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-7,9-dione

Part A. 3-(N-t-Butyloxycarbonylpiperidin-4-yl)propanal

To a suspension of PCC (11.52 g, 53.44 mmol) and sodium acetate (4.38 g, 53.4 mmol) in DCM (60 mL) was added a solution of 3-(N-t-butyloxycarbonylpiperidin-4-yl)propanol (10.00 g, 41.09 mmol) in DCM (20 mL). After 4 hours at room temperature, the mixture was diluted with ether and passed though a short column of fluorisil.RTM. using ether as an eluent. The eluate was concentrated in vacuo and placed under vacuum until constant weight was achieved, affording 8.32 g (84%) of the desired aldehyde as a colorless oil; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 9.76 (t, J=1.5 Hz, 1H), 4.05 (bs, 2H), 2.64 (bt, J=11.7 Hz, 2H), 2.45 (dt, J=7.3, 1.5 Hz, 2H), 1.60 (m, 3H), 1.43 (s, 9H, overlapped with m, 2H), 1.08 (dq, J=12.1, 4.0 Hz, 2H).

Part B. (E,Z)-3-(N-t-Butyloxycarbonylpiperidin-4-yl)propanal Oxime

To a solution of 3-(N-t-butyloxycarbonylpiperidin-4-yl)propanal (3.905 g, 16.18 mmol) in EtOH:pyr=1:1 (20 mL) was added hydroxylamine hydrochloride (1.701 g, 24.48 mmol) and the resulting solution stirred at room temperature for 20 hours. Concentration in vacuo, resulted in an oil, which was dissolved in EtOAc and washed with 0.1M HCl (3.times.), water, sat. CuSO.sub.4 (2.times.), water and brine. The solution was dried over MgSO.sub.4, concentrated in vacuo and placed under vacuum until constant weight was achieved, affording 4.071 g (98%) of a 1:1 mixture of the (E,Z)-oxime as a colorless oil; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.42 (t, J=6.2 Hz, 0.5H), 6.70 (t, J=5.5 Hz, 0.5H), 4.06 (bs, 2H), 2.67 (bt, J=12.8 Hz, 2H), 2.41 (m, 1H), 2.23 (m, 1H), 1.66 (b, 2H), 1.45 (s, 9H, overlapped with m, 4H), 1.08 (m, 2H).

Part C. Methyl (5R,S) -3-{�2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl!-5-carboxymethylisoxazolin-5-yl}acetate

To a solution of (E,Z)-3-(N-t-butyloxycarbonylpiperidin-4-yl)propanal oxime (503 mg, 1.96 mmol) and dimethyl itaconate (620 mg, 3.92 mmol) in DCM (3 mL) was added a 5% solution of sodium hypochlorite (common household bleach, 3 mL, 2 mmol). The resulting mixture was stirred overnight (19 hours) at room temperature. The layers were separated and the aqueous washed with DCM (2.times.). The combined DCM fraction was dried over MgSO.sub.4 and concentrated in vacuo. Purification using flash chromatography (hexanes--10% EtOAc/hexanes--50% EtOAc/hexanes) followed by concentration and pumping to constant weight afforded the desired isoxazoline (510 mg, 63%) as a colorless oil; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 4.06 (bd, J=13.6 Hz, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.57 (d, J=17.6 Hz, 1H), 3.15 (d, J=16.5 Hz), 3.06 (d, J=17.6 Hz, 1H), 2.86 (d, J=16.5 Hz, 1H), 2.65 (bt, J=12.1 Hz, 2H), 2.36 (m, 2H), 1.65 (m, 2H, overlapped with H.sub.2 O, 2H), 1.43 (s, 9H), 1.07 (m, 2H).

Part D. (5R,S)-3-{�2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl!-5-carboxyisoxazolin-5-yl}acetic Acid

To a solution of methyl (5R,S)-3-{�2-(N-t-butyloxycarbonylpiperidin-4-yl)ethyl!-5-carboxymethylisoxazolin-5-yl}acetate (380 mg, 0.921 mmol) was saponified using 0.5M LiOH (5 mL, 2.5 mmol) in THF (5 mL). The reaction was stirred at ambient temperature for 5 hours, according to Example 1, Part F to give 240 mg (68%) of the diacid; mp: 154.4.degree.-154.9.degree. C.; .sup.1 H NMR (300 MHz, MeOH-d.sub.4) .delta. 4.04 (bd, J=13.2 Hz, 2H), 3.52 (d, J=17.8 Hz, 1H), 3.18 (d, J=17.8 Hz, 1H), 2.97 (AB quartet, .DELTA.=32.6, J=16.8 Hz, 2H), 2.72 (b, 2H), 2.39 (m, 2H), 1.71 (bd, J=13.2 Hz, 2H), 1.51 (m, 3H), 1.43 (s, 9H), 1.05 (m, 2H).

Part E. 5(R,S)-2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl-8-�(2-(1,1-dimethylethoxycarbonyl)ethyl!-1-oxa-2,8-diazaspiro�4,4!non-2-ene-7,9-dione

To a solution of (5R,S)-3-{�2-(N-t-butyloxycarbonylpiperidin-4-yl)ethyl!-5-carboxyisoxazolin-5-yl}acetic acid (700 mg, 1.82 mmol) in THF (5 mL) was added DCC (378 mg, 1.83 mmol), and the resulting suspension was stirred for 30 min at room temperature. To this mixture was added a suspension of .beta.-alanine t-butyl ester hydrochloride (372 mg, 2.05 mmol) and TEA (300 .mu.L, 2.15 mmol) in THF (5 mL). The mixture was stirred overnight (18 hours) at room temperature. Following dilution with EtOAc, the mixture was filtered and the filtrate washed with 0.1M HCl, sat. NaHCO.sub.3 and sat. NaCl. It was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight was reached, giving 430 mg (46%) of the crude amide. A portion of this material (420 mg, 0.821 mmol) was dissolved in THF (4 mL). To this solution was added HOSuc (100 mg, 0.869 mmol) followed by DCC (180 mg, 0.872 mmol). The resulting suspension was stirred at room temperature for 18 hours. Following dilution with ether, the mixture was cooled to 0.degree. C. and filtered. The filtrate was dried over anhydrous MgSO.sub.4, concentrated and placed under vacuum until constant weight was reached, giving 430 mg (86%) of the crude active ester. A portion of this material (402 mg, 0.660 mmol) was dissolved in DMF (5 mL) at 0.degree. C. To this solution was added NaH (16 mg, 0.66 mmol). After 3 hours at 0.degree. C., the reaction was quenched with HOAc. After dilution with EtOAc, the mixture was washed with water (4.times.), sat. NaHCO.sub.3, water, 0.1M HCl and sat. NaCl. It was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight was reached, giving 230 mg (70%) of the crude imide. The crude material was purified using flash chromatography (CHCl.sub.3 --5% MeOH/CHCl.sub.3), affording 149 mg (46%) of a colorless oil after concentration of the appropriate fractions and pumping to constant weight; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 4.09 (b, 2H), 3.82 (t, J=7.3 Hz, 2H), 3.54 (d, J=17.2 Hz, 1H), 3.12 (d, J=18.7 Hz, 1H), 2.98 (d, J=17.2 Hz, 1H), 2.83 (d, J=18.7 Hz, 1H), 2.69 (m, 2H), 2.57 (t, J=7.3 Hz, 2H), 2.42 (m, 2H), 1.68 (m, 2H), 1.57 (m, 2H), 1.45 (s, 9H, coincident with m, 1H), 1.11 (m, 2H).

Part F. 5(R,S)-(2-Piperidin-4-yl)ethyl-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro�4,4!non-2-ene-7,9-dione

To a solution of 5(R,S)-2-(N-t-butyloxycarbonylpiperidin-4-yl)ethyl-8-�(2-(1,1-dimethylethoxycarbonyl)ethyl!-1-oxa-2,8-diazaspiro�4,4!non-2-ene-7,9-dione (75 mg, 0.152 mmol) in DCM (1 mL) was added TFA (0.5 mL, 8 mmol). The reaction was stirred at room temperature for 2 hours, then was concentrated in vacuo. Excess TFA was chased by rotary evaporation with toluene (2.times.). Crystallization from MeOH/ether gave 10 mg (15%) of the desired amino acid after pumping to constant weight; mp: 178.0.degree.-179.1.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6, 60.degree. C.) .delta. 12.15 (bs, 1H), 8.26 (bs, 2H), 3.64 (m, 2H), 3.39 (d, J=17.8 Hz, 1H), 3.26 (m, 3H), 2.98 (AB quartet, .DELTA.=71.3 Hz, J=18.3 Hz, 2H), 2.85 (m, 2H), 2.50 (m, 1H, coincident with DMSO-d.sub.5), 2.37 (t, J=7.6 Hz, 2H), 1.84 (bd, J=11.7 Hz, 2H), 1.58 (m, 1H), 1.52 (t, J=7.6 Hz, 2H), 1.29 (m, 2H).

EXAMPLE 275

N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-L-2,3-diaminopropionic acid TFA salt

Part A. 3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetic acid

To a solution of 4-cyanobenzaldoxime (see Ex 43, Part A) (312 g, 2.13 mol) in tetrahydrofuran (3000 ml) at room temperature was added vinyl acetic acid (552 g, 6.41 mol). The yellow solution was cooled in an ice bath and sodium hypochlorite solution (5200 ml) was added in a dropwise fashion over 2h. After stirring overnight at room temperature the reaction was quenched with a 5% citric acid solution and diluted with 200 ml ether. The layers were separated and the aqueous acidified to pH 4 using citric acid. The acid layer was washed twice with 200 ml ether, the ether layers combined and extracted with saturated sodium bicarbonate solution. After acidifying the basic layer with citric acid, the product was extracted into 400 ml ether. The organic phase was washed three times with 150 ml water, once with brine, dried (MgSO.sub.4) and concentrated to give 220g of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid as a white solid. Recrystallization from 25% water/ethanol yielded 165 g of analytically pure material. Anal. Calcd for C.sub.12 H.sub.10 N.sub.2 O.sub.3 : C,62.61; H,4.38; N, 12.17. Found: C, 62.37; H 4.47; N, 11.71. .sup.1 H NMR(300MHz, CDCl.sub.3): .delta. 7.77-7.76 (d, 2H, J=1.8Hz); 7.72-7.71 (d, 2H, J=1.8Hz); 5.22-5.14 (m, 1H); 3.63-3.54 (dd, 1H, J=10.6Hz, 16.8Hz); 3.19-3.11 (dd, 1H, J=7.3Hz, 16.8Hz); 3.00-2.93 (dd, 1H, J=6.2Hz, 16.5Hz); 2.79-2.72 (dd, 1H, J=7.3Hz, 16.5Hz). IR(KBr pellet): 3202, 2244, 1736, 1610, 1432, 1416, 1194, 1152, 928, 840, 562 cm.sup.-1.

Part B. Methyl N.sup.2 -Cbz-L-2,3-diaminopropionate HCl salt

N.sup.2 -Cbz-L-2,3-diaminopropionic acid (10 mmol, 2.39 g) was dissolved in 20 mL methanol and 20 mL 4N HCl in dioxane and the solution was stirred for 4 hours and then concentrated to give a solid. The solid was washed with ether several times to give 2.50 g (87%) product. NMR (DMSO-d.sub.6): .delta. 8.38 (b, 3H); 7.96 (d, 1H); 7.38 (m, 5H); 5.05 (s, 2H); 4.44 (m, 1H); 3.66 (s, 3H); 3.14 (m, 2H).

Part C. Methyl N.sup.2 -Cbz-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5(R, S) -ylacetyl!-L-2,3-diaminopropionate

To a solution of 3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetic acid. (19 mmol, 4.37 g), methyl N.sup.2 -Cbz-L-2,3-diaminopropionate HCl salt (20 mmol, 5.76 g) and triethylamine (60 mmol, 8.36 mL) was added TBTU (20 mmol, 6.42 g) and the solution was stirred for 2 hours. Ethyl acetate was added and the solution was washed with dilute citric acid, brine, NaHCO.sub.3 and brine, dried (MgSO.sub.4), and concentrated. Crystallization from ethyl acetate/ether gave 6.85 g (78%) product. NMR (DMSO-d.sub.6): .delta. 8.16 (t, 1H); 7.92 (d, 2H); 7.82 (d, 2H); 7.68 (d, 1H); 7.36 (m, 5H); 5.04 (m, 3H); 4.20 (m, 1H); 3.64 (s, 3H); 3.50 (m, 2H); 3.26 (m, 2H);2.50 (m, 2H).

Part D. Methyl N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl!-L-2,3-diaminopropionate HCl salt

HCl gas was bubbled into a solution of methyl N.sup.2 -Cbz-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5(R, S) -ylacetyl!-L-2,3-diaminopropionate (2.1 mmol, 1.0 g) for 1 hour and the solution was stirred overnight and concentrated. The residue was dissolved in 30 mL 2M ammonia in methanol and the solution was stirred overnight and concentrated to give 1.2 g crude product.

Part E. N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S) -ylacetyl!-L-2,3-diaminopropionic acid TFA salt

Methyl N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S) -ylacetyl!-L-2,3-diaminopropionate HCl salt (200 mg) was saponified with 1 mL methanol and 1 mL 1N NaOH for 1 hour and acidified with acetic acid. Purification on reversed phase HPLC gave 40 mg product. ESI (M+H).sup.+ : Calcd 334.2; Found 334.2.

EXAMPLE 276

N.sup.2 -Cbz-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S) -ylacetyl!-L-2,3-diaminopropionic acid TFA salt

Part A. Methyl N.sup.2 -Cbz-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl!-L-2,3-diaminopropionate TFA salt

To a solution of the compound of Ex. 275, part D (1.0 mmol, 385 mg) and sodium bicarbonate (5.0 mmol, 400 mg) in 2 mL water, 2 mL acetonitrile and 1 mL DMF was added benzyl chloroformate (1 mmol, 143 .mu.L) and the mixture was stirred for 2 hours at room temperature. The solution was filtered, acidified with TFA and purified on reversed phase HPLC to give 150 mg (25%) product. NMR (DMSO-d.sub.6): .delta. 9.40 (s, 2H); 9.20 (s, 2H); 8.18 (t, 1H); 7.86 (m, 4H); 7.68 (d, 1H); 7.35 (m, 5H); 5.02 (m, 3H); 4.20 (m, 1H); 3.64 (s, 3H); 3.52 (m, 2H); 3.26 (m, 2H); 2.50 (m, 2H).

Part B. N.sup.2 -Cbz-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl!-L-2,3-diaminopropionic acid TFA salt

Methyl N.sup.2 -Cbz-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S) -ylacetyl!-L-2,3-diaminopropionate TFA salt (0.12 mmol, 70 mg) was dissolved in 2 mL methanol and 1 mL 1N NaOH and after 1 hour, the solution was acidified with acetic acid. Purification on reversed phase HPLC gave 50 mg (74%) product. ESI (M+H).sup.+ : Calcd 468.2; Found 468.2.

EXAMPLE 278

N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl!-L-2,3-diaminopropionic acid TFA salt

Part A. Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3(4-amidinophenyl)isoxazolin-5(R, S) -ylacetyl!-L-2,3-diaminopropionate TFA salt

To a solution of the compound of Ex. 275, part E (1.0 mmol, 385 mg) and sodium bicarbonate (2.5 mmol, 200 mg) in 2 mL water, 2 mL acetonitrile and 1 mL DMF cooled in an ice bath was added n-butyl chloroformate (1 mmol, 127 .mu.L). After stirring for 1 hour, the solution was acidified with acetic acid and purified on reversed phase HPLC to give 150 mg (27%) product. NMR (DMSO-d.sub.6): .delta. 9.40 (s, 2H); 9.20 (s, 2H); 8.16 (t, 1H); 7.86 (m, 4H); 7.47 (d, 1H); 5.02 (m, 1H); 4.16 (m, 1H); 3.94 (t, 2H); 3.62 (s, 3H); 3.50 (m, 2H); 3.26 (m, 2H); 2.50 (m, 2H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H). ESI (M+H).sup.+ : Calcd 448.3; Found 448.3.

Part B. N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

Methyl N2-n-butyloxycarbonyl-N3-�3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl!-(S)-2,3-diaminopropionate TFA salt (0.107 mmol, 60 mg) was dissolved in 2 mL methanol and 2 mL 1N NaOH and after 1 hour, the solution was acidified with acetic acid. Purification on reversed phase HPLC gave 53 mg (89%) product. ESI (M+H).sup.+ : Calcd 434.3; Found 434.3.

EXAMPLE 278a

Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate Mesylate salt

Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate (500 mg, 1.03 mmol) was dissolved in 20 mL methanol and methanesulfonic acid (0.335 mL, 5 mmol) was added. The solution was allowed to stand at room temperature overnight and the solvent was removed by concentration. The residue was taken up in 20 mL methanol and the solution was allowed to stand at room temperature overnight. The solvent was removed by concentration and the residue was triturated with 8 mL 2-propanol. The solid product was isolated by filtration and dissolved in 12 mL 2-propanol by warming. After cooling to room temperature, crystalline solid formed. The mixture was allowed to stand in a refrigerator overnight. The crystal was filtered, washed with cold 2-propanol and dried. Yield 230 mg (41%). ES-MS (M+1): calcd 448.3; found 448.3. Analysis for C.sub.22 H.sub.33 N.sub.5 O.sub.9 S: calcd C 48.61, H 6.13, N 12.88; found C 48.38, H 5.91, N 12.65.

EXAMPLE 278b

N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

To a solution of methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate hydrochloride salt (600 mg, 1.24 mmol) in 20 mL MeOH and 20 mL water cooled in an ice bath was added 1N LiOH (1.3 mL, 1.3 mmol) over 5 min and the solution was stirred at room temperature for 5 hours. The solvents were removed by concentration at 25.degree. C. The residue was taken up in 3 mL water, 3 mL acetonitrile, and 0.2 mL TFA. Purification by reversed phase HPLC gave 610 mg (89%) product. ES-MS (M+1): calcd 434.3; found 434.3.

EXAMPLE 298

N.sup.2 -n-Butanesulfonyl-N.sup.3 -�3-(4-amidino-phenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 454 (M+H).sup.+, (100%).

EXAMPLE 299

N.sup.2 -Phenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S) -ylacetyl!-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 474 (M+H).sup.+, (100%).

EXAMPLE 314A

Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(S)-ylacetyl!-(S)-2,3-diaminopropionate TFA salt

Part A: Methyl N.sup.2 -Cbz-N.sup.3 -Boc-L-2,3-diaminopropionate

To a solution of methyl N.sup.2 -Cbz-(S)-2,3-diaminopropionate HCl salt (16.3 mmol, 4.7 g) and di-tert-butyl dicarbonate (16.3 mmol, 3.56 g) in 30 mL chloroform cooled in an ice bath was added triethylamine (34 mmol, 4.7 mL) and the solution was stirred in the ice bath for 1 hour and at room temperature for 3 hours and concentrated. The residue was taken up in ethyl acetate and the solution was washed with dilute citric acid, brine, NaHCO.sub.3 and brine, dried (MgSO.sub.4), and concentrated. Crystallization from ether/petroleum ether gave 5.2 g (92%) product. NMR (DMSO-d.sub.6): .delta. 7.60 (d, 1H); 7.35 (m, 5H); 6.88 (t, 1H); 5.02 (s, 2H); 4.14 (m, 1H); 3.60 (s, 3H); 3.28 (m, 2H); 1.37 (s, 9H).

Part B: Methyl N.sup.3 -Boc-(S)-2,3-diaminopropionate Formic acid salt.

A mixture of methyl N.sup.2 -Cbz-N.sup.3 -Boc-(S)-2,3-diaminopropionate. (14 mmol, 5.0 g), formic acid (42 mmol, 1.6 mL) and 10% Pd/C (500 mg) in 40 mL methanol was stirred at room temperature for 1 hour and filtered through a celite. The filtrate was concentrated and the residue was triturated with ether-petroleum ether to give 3.7 g (100%) solid product. NMR (DMSO-d.sub.6): .delta. 8.20(s, 1H); 6.90 (t, 1H); 5.36 (b, 3H); 3.61 9s, 3H); 3.51 (t, 1H); 3.18 (t, 2H); 1.38 (s, 9H).

Part C: Methyl N.sup.2 -n-butyloxycarhonyl-N.sup.3 -Boc-(S)-2,3-diaminopropionate

To a mixture of methyl N.sub.3 -Boc-(S)-2,3-diaminopropionate HCO.sub.2 H salt (14 mmol, 3.7 g) and NaHCO.sub.3 (40 mmol, 3.4 g) in 10 mL water and 10 mL THF cooled in an ice bath was added slowly butyl chloroformate (16 mmol, 2 mL) over 15 min. After stirring for 1 hour, ethyl acetate was added and the solution was washed with dilute citric acid, brine, NaHCO.sub.3 and brine, dried (MgSO.sub.4), and concentrated to give 4.4 g (100%) oily product. NMR (DMSO-d.sub.6): .delta. 7.37 (d, 1H); 6.84 (t, 1H); 4.10 (m, 1H); 3.96 (t, 2H); 3.60 (s, 3H); 3.26 (m, 2H); 1.52 (m, 2H); 1.38 (s, 9H); 1.36 (m, 2H); 0.88 (t, 3H).

Part D: Methyl N.sup.2 -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt

Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -Boc-(S)-2,3-diaminopropionate (13.9 mmol, 4.4 g) was dissolved in 25 mL methylene chloride and 35 mL TFA and after 1 hour, the solution was concentrated to give an oily product. Yield 4.8 g (100%). NMR (DMSO-d.sub.6): .delta. 8.02 (b, 3H); 7.68 (d, 2H); 4.38 (m, 1H); 3.99 (t, 2H); 3.68 (s, 3H); 3.22 (m, 1H); 3.06 (m, 1H); 1.55 (m, 2H); 1.34 (m, 2H); 0.89 (t, 3H).

Part E: Methyl-N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5(S)-ylacetyl!-(S)-2,3-diaminopropionate

To a solution of 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid (5.2 mmol, 1.2 g) �Chiral starting material was prepared from the racemic compound of Ex. 275, Part A by resolution on a 50.times.2 cm Chiralpak AD column using 0.1% TFA/EtOH at 10.degree. C. to give S-isomer (faster eluting) and R-isomer (slower eluting). Alternately, the isomers were resolved by crystallization of the chinconidine salt of the 5-S isomer of the isoxazolines from acetone, leaving the 5(R) isomer in the mother liquor. The absolute stereochemistry of the crystalline salt was determined by X-ray crystallography to be the 5(S) isoxazoline.! and methyl N.sup.2 -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt (6 mmol, 1.53 g) in 20 ml DMF cooled in an ice bath was added diisopropylethylamine (20 mmol, 3.5 mL) followed by BOP (5.5 mmol, 2.43 g). After stirring at room temperature for 3 hours, ethyl acetate was added and the solution was washed with 0.5N HCl, brine, NaHCO3 and brine, dried (MgSO.sub.4), and concentrated to give 1.9 g (87%) product. NMR (DMSO-d.sub.6): .delta. 8.12 (t, 1H); 7.94 (d, 2H); 7.83 (d, 2H); 7.46 (d, 1H); 5.04 (m, 1H); 4.16 (m, 1H); 3.96 (t, 2H); 3.64 (s, 3H); 3.58 (dd, 1H); 3.40 (m, 2H); 3.20 (dd, 1H); 2.56 (dd, 1H); 2.43 (dd, 1H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H).

Part F: Methyl-N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(S)-ylacetyl!-(S)-2,3-diaminopropionate TFA salt

To a solution of methyl-N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5(S)-ylacetyl!-(S)-2,3-diaminopropionate (4.4 mmol, 1.9 g) in 50 mL methanol was bubbled with HCl gas at 0.degree. C. for 1 hour and the solution was stirred at room temperature for 5 hours and concentrated. The residue was taken up in 20 mL methanol and ammonium carbonate (11 mmol, 1.1 g) was added. The mixture was stirred at room temperature overnight and concentrated. The solid was dissolved in methanol/water/TFA and purification on reversed phase HPLC gave 1.0 g (40%) product. ESI (M+H).sup.+ : Calcd 448.3; Found 448.3.

EXAMPLE 314B

Methyl-N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate TFA salt

Part A: 3-(4-cyanophenyl)-5(R)-ylacetic acid

This material was resolved from 3-(4-cyanophenyl)isoxazolin-5(R,S)-ylacetic acid as described above in the proceudure for Example 314A, Part E.

Part B: Methyl-N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate

This material was synthesized from 3-(4-cyanophenyl)-5(R)-ylacetic acid (4.3 mmol, 1.0 g), Methyl N.sup.2 -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt (5 mmol, 1.27 g), BOP (4.5 mmol, 2 g) and diisopropylethylamine (16 mmol, 2.8 mL) using the same procedure as for XVI. Yield 1.75 g (95%). NMR (DMSO-d.sub.6): .delta. 8.12 (t, 1H); 7.94 (d, 2H); 7.83 (d, 2H); 7.46 (d, 1H); 5.04 (m, 1H); 4.16 (m, 1H); 3.96 (t, 2H); 3.64 (s, 3H); 3.58 (dd, 1H); 3.40 (m, 2H); 3.20 (dd, 1H); 2.56 (dd, 1H); 2.43 (dd, 1H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H).

Part C: Methyl-N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate TFA salt

This compound was synthesized from Methyl-N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate (4.0 mmol, 1.7 g) using the same procedure as for Example 314A, Part G. Yield 1.0 g (45%). ESI (M+H).sup.+ : Calcd 448.3; Found 448.3.

EXAMPLE 317

N.sup.2 -(2-Phenylethylsulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S) -2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 502 (M+H).sup.+, (100%).

EXAMPLE 344

Methyl 3(R)-{5(R,S)-N-�3-(4-Amidinophenyl)isoxazolin-5-ylacetyl!amino}heptanoate

Part A. (E)-Methyl 2-heptenoate

To a solution of diethyl methylphosphonoacetate (19 ml, 104 mmol) in dry THF (800 ml) at -4.degree. C. was added 64 ml of n-BuLi (1.6M in hexane, 102 mmol) dropwise over 45 min. The resulting solution was stirred 1 h at room temp. Valeraldehyle (10.0 ml, 94 mmol) was added and stirred 3.5 h at room temp. The reaction was quenched with 25 ml sat. NH.sub.4 Cl. Solvents were distilled at atmospheric pressure, and the resulting solids were taken up in EtOAc, extracted with water and brine, and dried with Na.sub.2 SO.sub.4. The solvents were again distilled at atmospheric pressure, and the resulting yellow liquid was distilled under house vacuum to yield 7.2 g clear liquid, boiling range under house vacuum 90.degree.-125.degree. C.; HRMS, e/z Calc. for (M+H).sup.+ : 143.1072. Found: 143.1070; IR(film) 1728, 1658 cm-.sup.1.

Part B. N-(1-(R)-1-Phenylethyl)benzamide

A solution of benzoyl chloride (22.5 mL, 0.19 mole) in dichloromethane (10 mL) was added dropwise over 1.5 h to a 0.degree. C. solution of (R)-(+)-.alpha.-methylbenzylamine (25 mL, 0.19 mole), triethylamine (31 mL, 0.22 mole), and 4-DMAP (100 mg), in dichloromethane (1 L). After 1.75 h at 0.degree. C. the mixture was concentrated in vacuo, then diluted with EtOAc. This mixture was extracted with water, 1M HCl, water, and brine, then dried (MgSO.sub.4) and concentrated to yield 43.4 g of a colorless crystalline solid; mp 121.0.degree.-121.5.degree. C.; IR(KBr) 3332, 1636 cm.sup.- ; �.alpha.!.sub.D.sup.25 -2.30.degree. (c=1.002, CH.sub.2 Cl.sub.2); Anal. Calc. for C.sub.15 H.sub.15 NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.88; H, 6.65; N. 6.17.

Part C. N-(1-(R)-1-Phenylethyl)-N-benzylamine

BH.sub.3 /THF (1M in THF, 220 mL, 220 mmol) was added dropwise over 1 h to a 0.degree. C. solution of the above benzamide (20 g, 89 mmol) in dry THF (200 mL). The ice bath was removed, and the mixture was heated to reflux for 40 h. A TLC analysis indicated incomplete reaction, so more BH.sub.3 /THF (1M in THF, 30 mL, 30 mmol) was added, and heating resumed for 22.5 h. After cooling, MeOH (250 mL) was added dropwise cautiously over 5 h. The resulting mixture was boiled for 2 h, then cooled and concentrated in vacuo. Reconcentration from MeOH (2.times.500 mL) and drying under high vacuum gave 19.3 g of an oil containing a small amount of a precipitate. This crude product was stirred with hot 2M HCl (140 mL) to generate a clear solution, then slowly cooled to RT, and ultimately in an ice bath to yield a crystalline solid, as described by Simpkins (Tetrahedron 1990, 46(2), 523). The solid was collected by filtration and rinsed with a small amount of water. After air drying for 3 d, 16.35 g of the hydrochloride salt was obtained; mp 178.5.degree.-179.5.degree. C.; �.alpha.!.sub.D.sup.21 +18.9.degree. (c=4.0, EtOH). The salt was converted to the free base by extraction with Et.sub.2 O and aq. KOH, then Kugelrohr distilled, oven temp. 120.degree.-140.degree. C. (1.1 mm Hg) to give 12.5 g of an oil; �.alpha.!.sub.D.sup.21 +61.2.degree. (c=3.98, EtOH); Anal. Calc. for C.sub.15 H.sub.17 N: C, 85.26; H, 8.11; N, 6.63. Found: C, 84.93; H, 7.75; N, 6.58.

Part D. Methyl 3-(R)-�N-benzyl-N-(1-(R)-1-phenylethyl)amino!heptanoate

Following the asymmetric Michael addition method of Davies (Tetrahedron:Asymmetry 1991, 2(3), 183), n-butyllithium (1.6M in hexanes, 4.4 mL, 7.0 mmol) was added dropwise over 3 min to a 0.degree. C. solution of N-(1-(R)-1-phenylethyl)-N-benzylamine (1.5 g, 7.0 mmol) in dry THF (35 mL). After 30 min, the resulting dark pinkish-red solution was cooled to -78.degree. C., and a solution of methyl 2-heptenoate (0.50 g, 3.5 mmol) in THF (10 mL) was added dropwise over 10 min. After 13 min, the cold reaction was quenched with saturated NH.sub.4 Cl (7 mL). After warming to RT, the mixture was extracted with Et.sub.2 O and brine, dried (MgSO.sub.4), and concentrated in vacuo. The product was purified by chromatography over silica gel, eluting with 0% to 50% EtOAc in hexane. The cleanest major product fractions (apart from a few mixed fractions) were concentrated in vacuo to give 0.91 g of a pale yellow oil which by NMR is a single diastereomer, with the newly generated asymmetric center assigned as 3(R) by analogy with the Davies reference above; .sup.13 C NMR (300 MHz, CDCl.sub.3) .delta. 173.31, 143.40, 141.78, 128.40, 128.27, 128.11, 128.00, 126.91, 126.67, 57.90, 54.22, 51.32, 50.05, 36.83, 33.28, 29.32, 22.72, 19.40, 14.12; �.alpha.!.sub.D.sup.25 +12.96.degree. (c=0.602, MeOH).

Part E. Methyl 3-(R)-aminoheptanoate . acetic acid salt

Methyl 3-(R) -�N-benzyl-N-(1-(R) -1-phenylethyl)amino!heptanoate (0.70 g, 2.0 mmol), 20% Pd(OH).sub.2 /C (0.35 g), cyclohexene (7 mL), glacial HOAc (0.12 mL, 2.1 mmol), and MeOH (14 mL) were heated at reflux under N.sub.2 for 20.5 h. After cooling, the catalyst was removed by filtration thru a Celite plug, rinsed with MeOH, and the solution concentrated in vacuo. Drying overnight under high vacuum yielded 0.43 g of a viscous oil; .sup.13 C NMR (300 MHz, CDCl.sub.3) .delta. 177.64, 171.52, 51.97, 48.22, 37.24, 33.08, 27.50, 23.31, 22.29, 13.76; �.alpha.!.sub.D.sup.25 -10.6.degree. (c=0.602, MeOH).

Part F. Methyl 3(R) -{5(R, S) -N-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!amino}heptanoate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (300 mg, 1.3 mmol) in EtOAc (10 ml) was added methyl 3-(R)-aminoheptanoate acetic acid salt (287 mg, 1.3 mmol), TBTU (420 mg, 1.3 mmol), and Et.sub.3 N (600 .mu.l, 4.3 mmol). After stirring at room temp 2.5 h, the reaction mixture was extracted with 5% KHSO.sub.4, sat NaHCO.sub.3, and brine, then dried with Na.sub.2 SO.sub.4. Evaporation, followed by chromatography over silica gel in 50-100% EtOAc/hexanes yielded 245 mg colorless glass. MS (NH.sub.3 -DCI) Calc. for (M+H).sup.+ : 372, (M+NH.sub.4).sup.+ : 389. Found: 372, 389.

Part G. Methyl 3(R)-{5(R,S) -N-�3-(4-Amidinophenyl)isoxazolin-5-ylacetyl!amino}heptanoate

To a solution of methyl 3(R)-{5(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!amino}heptanoate (179 mg, 0.48 mmol) in 15 ml dry MeOH at 0.degree. C., was added a stream of HCl gas generated from dropping two 20 ml portions of H.sub.2 SO.sub.4 into solid NaCl over 35 min. After stirring 20 h at room temp, the solvent was removed with a rapid stream of N.sub.2. Et.sub.2 O was added and removed with a rapid stream of N.sub.2. The resulting gummy oil was taken up in 15 ml dry MeOH, to which was added (NH.sub.4).sub.2 CO.sub.3 (1.1 g, 11.4 mmol). After stirring 19.5 h at room temp, the solvent was removed with a rapid stream of N.sub.2, and the resulting white solid was purified by chromatography over silica gel, eluting with 0-20% MeOH/CHCl.sub.3. Purified product was taken up in 5% MeOH/CHCl.sub.3 and filtered. Concentration of the filtrate yielded 100 mg white solid. IR(KBr) 3600-2800, 1734, 1676, 1640 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 389.2189. Found: 389.2192.

EXAMPLE 348

Ethyl 3(R)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-5-methylhexanoate . trifluoroacetic acid salt

Part A. (E)-Ethyl 5-methyl-2-hexenoate

Prepared in analogous fashion to methyl 2-heptenoate, using triethyl phosphonoacetate, stirring 17 h at room temp upon addition of isovaleraldehyde. Distillation under house vacuum yielded 72% clear oil, boiling range under house vacuum 80.degree.-130.degree. C.; IR(film) 1724, 1656 cm.sup.-1.

Part B. Ethyl 3-(R)-�N-benzyl-N-(1-(R)-1-phenylethyl)amino!-5-methylhexanoate

Prepared in analogous fashion via the asymmetric Michael addition of Ex. 344, part D above. Yield a viscous pale yellow oil (65%); .sup.13 C NMR (300 MHz, CDCl.sub.3) .delta. 172.83, 143.56, 142.17, 128.27, 128.21, 128.15, 128.03, 126.96, 126.60, 60.10, 58.56, 52.43, 50.09, 43.23, 36.72, 24.76, 23.48, 22.13, 20.20, 14.21; �.alpha.!.sub.D.sup.25 +5.12.degree. (c=0.606, EtOH).

Part C. Ethyl 3-(R)-amino-5-methylhexanoate . acetic acid salt

Prepared as previously described except EtOH was used as solvent. Yield a waxy solid (94%); mp 57.degree.-61.degree. C.; HRMS, e/z Calc. for (M+H).sup.+ : 174.1494. Found: 174.1485.

Part D. Ethyl 3-(R)-amino-5-methylhexanoate . hydrochloric acid salt

The above acetic acid salt (1.1 g, 4.7 mmol) was stirred 4 min in 4M HCl/dioxane (5.0 ml). The resulting solution was triturated with Et.sub.2 O, cooled, and the clear liquid decanted, leaving an orange oil which solidified to 960 mg waxy solid on high vacuum; .sup.1 H NMR (300 MHz, CDCl.sub.3) .differential. 8.49 (br, 3H), 4.20 (q, J=7.3, 2H), 3.70-3.65 (m, 1H), 2.86-2.80 (m, 2H), 1.83-1.80 (m, 2H), 1.58-1.54 (m, 1H), 1.30-1.26 (t, J=7.3, 3H), 0.99-0.91 (m, 6H).

Part E. Ethyl 3(R)-{5(R,S)-N-�3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl!amino}-5-methylhexanoate

To a suspension of 3-�4-(N-t-butoxycarbonylamidino)phenyl!isoxazolin-5-ylacetic acid (78 mg, 0.22 mmol) in EtOAc (5 ml) was added ethyl 3-(R)-amino-5-methylhexanoate hydrochloride salt (47 mg, 0.22 mmol), TBTU (72 mg, 0.22 mmol), and Et.sub.3 N (100 .mu.l, 0.72 mmol). After stirring 6 h at room temp, the reaction mixture was extracted with pH 4 buffer (potassium hydrogen phthalate), sat NaHCO.sub.3, and brine, then dried with Na.sub.2 SO.sub.4. Evaporation, followed by chromatography over silica gel in 100% EtOAc yielded 33 mg colorless glass; .sup.1 H NMR (300 MHz, CDCl.sub.3) .differential. 7.90 (d, J=8.4, 2H), 7.70 (dd, J=8.5, J'=1.9, 2H), 6.32-6.28 (m, 1H), 5.13-5.11 (m, 1H), 4.34-4.33 (m, 1H), 4.17-4.09 (m, 2H), 3.56-3.47 (m, 1H), 3.25-3.17 (m, 1H), 2.71-2.46 (m, 4H), 1.66-1.47 (m, 2H), 1.56 (s, 9H), 1.31-1.23 (m, 4H), 0.92 (dd, J=6.6, J'=1.8, 3H), 0.84 (d, J=6.6, 3H).

Part F. Ethyl 3(R)-�5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino!-5-methyl hexanoate . trifluoroacetic acid salt

The product from Part E above (29 mg, 0.058 mmol) was dissolved in DCM (300 .mu.l), to which was added TFA (100 .mu.l). The resulting solution was stirred at room temp under a CaSO.sub.4 drying tube for 3.5 h, and triturated with Et.sub.2 O. 24 mg white solid were collected by filtration; .sup.1 H NMR (300 MHz, CDCl.sub.3) .differential. 9.4 (br, 1H), 9.0 (br, 1H), 7.8 (s, 4H), 5.0 (m, 1H), 4.2 (m, 1H), 4.0 (q, 2H), 3.6 (m, 1H), 3.3 (m, 2H), 2.4 (m, 3H), 1.6 (m, 1H), 1.4 (m, 1H), 1.2 (m, 4H), 0.8 (m, 6H); HRMS, e/z Calc. for (M+H).sup.+ : 403.2345. Found: 403.2363.

EXAMPLE 350

Methyl 3(R,S)-N-(R,S)-{5-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(phenylthio)butanoate hydrochloric acid salt

Part A. Methyl phenylthioacetoacetate

To a solution of thiophenol (5.00 ml, 48.6 mmol) in DMF (20 ml), K.sub.2 CO.sub.3 (10.09 g, 73 mmol) and methyl chloroacetoacetate (5.93 ml, 48.6 mmol) were added. The reaction mixture was stirred 6 h at 50.degree. C., diluted with EtOAc, and extracted with saturated Na.sub.2 SO.sub.4, water, and brine, then dried (Na.sub.2 SO.sub.4) and concentrated. The resulting oil was chromatographed with 20% EtOAc in Hexane to yield 9.40 g yellow oil; MS (CH4-DCI) Calc. for (M+H).sup.+ : 224. Found: 224; IR(KBr) 2954, 1656, 1438, 626 cm.sup.-1.

Part B. Methyl-3(R,S)-amino-4-phenylthiobutanoate

To a solution of methyl phenylthioacetoacetate (1.00 g, 4.5 mmol) in MeOH (20 ml), ammonium formate (4.26 g, 6.75 mmol) and sodium cyanoborohydride (0.42 g, 6.7 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc and partitioned into 1M HCl. The aqueous layer was then basified to pH=8.0 with NaOH. The desired product was extracted out with EtOAc, washed with water and brine, dried over Na.sub.2 SO.sub.4 and concentrated to yield 0.61 g yellow oil; MS (NH.sub.3 -CI/DDIP) Calc. for (M+H).sup.+ : 226. Found: 226; .sup.1 H NMR (300 MHz, CDCl.sub.3).delta. 7.39 (d, J=7, 2H), 7.32-7.26 (m, 3H), 7.22 (d, J=10, 1H), 3.74 (s, 3H), 3.39-3.31 (m, 1H), 3.13-3.07 (dd, J=13, J'=9, 1H), 2.91-2.83 (dd, J=12, J'=6, 1H), 2.65-2.58 (dd, J=12, J'=6, 1H), 2.46-2.38 (dd, J=16, J'=8, 1H).

Part C. Methyl-3(R,S)-�5(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-ylacetyl!amino!-4-(phenylthio)butanoate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (0.50 g, 2 mmol) in EtOAc (10 ml), methyl-3(R,S)amino-4-(phenylthio)butanoate (0.51 g, 2 mmol), TBTU (0.71 g, 2 mmol), and Et.sub.3 N (1.24 ml, 8.9 mmol) were added. The reaction mixture was stirred 2 h at room temperature, diluted with EtOAc, washed with 5% citric acid, saturated NaHCO.sub.3, and brine, dried over Na.sub.2 SO.sub.4, concentrated, and the resulting oil was chromatographed over silica gel in 100% EtOAc to yield 0.61 g of a yellow glass: MS (NH.sub.3 -CI/DDIP) Calc. for (M+H).sup.+ : 438.1. Found: 438.1; Anal. Calc. for C.sub.32 H.sub.23 N.sub.3 O.sub.4 S.sub.1 : C, 63.31; H, 5.30; N, 9.60; S, 7.33. Found: C, 62.99; H, 5.22; N, 9.53; S, 7.30.

Part D. Methyl 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(phenylthio)butanoate . hydrochloric acid salt

The product from Part C above (0.30 g, 0.68 mmol) was dissolved in dry MeOH (20 ml) at 0.degree. C. To the resulting solution, HCl gas was bubbled in from a generator as described in Example 344, Part G, over a period of 2 h. The generator was removed and the reaction mixture stirred at 0.degree. C. for 18 h, then concentrated and triturated with CHCl.sub.3. The resulting precipitate was collected by filtration and redissolved in dry MeOH (20 ml). To this solution, ammonium carbonate (0.99 g, 10 mmol) was added and the mixture stirred at room temperature for 18 h. The solution was concentrated and recrystallized from DCM/MeOH to yield 0.14 g white solid; HRMS, e/z Calc. for (M+H).sup.+ : 455.1753. Found: 455.175; .sup.1 H NMR (300 MHz, d.sub.6 -DMSO) .delta. 9.44 (br s,1H), 9.18 (br s, 1H), 8.22 (d, J=10, 1H), 7.86 (m, 4H), 7.41-7.25 (m, 4H), 7.2 (m, 1H), 5.03 (m, 1H), 4.2 (m, 1H), 3.59 (s, 3H), 3.29-3.05 (m, 4H), 2.8-2.39 (m, 4H).

EXAMPLE 359

Methyl 3(R,S) -{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(phenylsulfonamido)butanoate . trifluoroacetic acid salt

Part A. Methyl 3-(R,S)-hydroxy-4-aminobutanoate . hydrochloric acid salt

Chlorotrimethylsilane (100 mL, 0.79 mol) was added dropwise over 1.5 h to a stirred 0.degree. C. suspension of 4-amino-3-(R,S)-hydroxybutyric acid (25 g, 0.21 mol) in MeOH (1 L). The resulting clear solution was allowed to slowly warm to room temperature overnight. The solvent was evaporated in vacuo, and the resulting residue was reconcentrated from more MeOH (2.times.500 mL). Drying under high vacuum produced 37 g of a viscous oil; .sup.13 C NMR (300 MHz, d.sub.6 -DMSO) .delta. 171.42, 90.14, 64.67, 51.89, 44.39; Anal. Calc. for C.sub.5 H.sub.16 ClNO.sub.3 : C, 35.41; H, 7.13; N. 8.26; Cl, 20.90. Found: C, 35.18; H, 7.09; N, 8.18; Cl, 20.77.

Part B. Methyl 3-(R,S)-hydroxy-4-(phenylsulfonamido)butanoate

A solution of benzenesulfonyl chloride (7.5 mL, 59 mmol) in dichloromethane (10 mL) was added dropwise over 55 min to a 0.degree. C. solution of the Part A amine salt (10 g, 50 mmol), and Et.sub.3 N (17 mL, 120 mmol) in dichloromethane (110 mL). The mixture was allowed to slowly warm to room temperature, and stirring was continued over the weekend. After solvent removal in vacuo, the mixture was diluted with EtOAc and extracted with H.sub.2 O, 0.1M HCl, and brine. Drying (MgSO.sub.4) and solvent removal in vacuo yielded 14.6 g of a viscous oil; .sup.13 C NMR (300 MHz, CDCl.sub.3) .delta. 172.67, 139.79, 132.78, 129.22, 127.02, 66.77, 52.01, 47.72, 38.31; Anal. Calc. for C.sub.11 H.sub.15 NO.sub.5 S: C, 48.34; H, 5.53; N, 5.13; S, 11.73. Found: C, 48.44; H, 5.61; N, 4.90; S, 11.34.

Part C. Methyl 3-oxo-4-(phenylsulfonamido)butanoate

The Part B alcohol (2.8 g, 10 mmol) was oxidized with Jones reagent under standard conditions. The ketone was purified by chromatography on silica gel, eluting with 0% to 100% EtOAc in hexane, to yield 1.11 g of a waxy solid; mp 94.5.degree.-95.5.degree. C.; .sup.13 C NMR (300 MHz, CDCl.sub.3) .delta. 197.08, 166.80, 139.17, 133.08, 129.29, 127.17, 52.71, 51.91, 46.15; Anal. Calc. for C.sub.11 H.sub.13 NO.sub.5 S: C, 48.70; H, 4.83; N, 5.16; S, 11.82. Found: C, 48.77; H, 4.69; N, 5.08; S, 11.88.

Part D. Methyl 3-(R,S)-3-amino-4-(phenylsulfonamido)butanoate

To a room temperature solution of the Part C ketone (0.71 g, 2.6 mmol) in MeOH (7 mL) and THF (3 mL) was added ammonium formate (2.5 g, 39 mmol) and sodium cyanoborohydride (0.25 g, 3.9 mmol). After 45.5 h, solvent was evaporated, and the residue was diluted with EtOAc (70 mL). This solution was extracted with 1.0M NaOH, H.sub.2 O, and brine. After concentration, the product was purified by chromatography on silica gel, eluting with 0% to 100% EtOAc in hexane, then 1% to 20% MeOH in EtOAc to yield 0.16 g of a viscous oil, which eventually solidified; .sup.1 H NMR (300 MHz, CDCl.sub.3) .differential. 9.79 (br, 2H), 7.84 (d, 2H, J=8 Hz), 7.81 (br, 1H), 7.68-7.53 (m, 3H), 4.05-3.92 (m, 1H), 3.75 (s, 3H), 3.33-3.17 (m, 2H), 2.89-2.72 (m, 2H); HRMS, e/z Calc. for (M+H).sup.+ : 273.0909. Found: 273.0916.

Part E. Methyl 3-(R,S)-{5(R,S)-N-�3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl!amino}-4-(phenylsulfonamido)butanoate

This compound was prepared analogous to Example 348, Part E, stirring 24 h in 5 ml EtOAc and 1 ml DMF. Chromatography in 5% MeOH/CHCl.sub.3 yielded 80% of an orange solid; IR(KBr) 3296, 2338, 1736, 1660, 1618 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 602.2285. Found: 602.2270.

Part F. Methyl 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(phenylsulfonamido)butanoate . trifluoroacetic acid salt

The product from Part E was deprotected analogously to Example 348, Part F, yielding 86% pink solid; IR(KBr) 3312, 3104, 1734, 1670; HRMS, e/z Calc. for (M+H).sup.+ : 502.1760. Found: 502.1761. The more active diastereomer (based on PRP assay) was isolated from the above mixture by SFC HPLC, Chiralpak AD--2.times.25 cm, eluted with 0.1% TFA/25% MeOH/75% CO.sub.2. Under these conditions, the more active diastereomer eluted last.

EXAMPLE 362

Methyl 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(n-butylsulfonamido)butanoate . trifluoroacetic acid salt

Part A. Methyl 3-(R,S)-hydroxy-4-(n-butylsulfonamido)butanoate

This compound was prepared entirely analogously to Ex. 359, Part B, using n-butylsulfonylchloride instead. A colorless, waxy solid of excellent purity was obtained in 65% yield without purification; mp 46.degree.-50.degree. C.; .sup.13 C NMR (300 MHz, CDCl.sub.3) .delta. 172.64, 67.29, 52.56, 51.99, 47.83, 38.40, 25.57, 21.52, 13.55; Anal. Calc. for C.sub.9 H.sub.19 NO.sub.5 S: C, 42.67; H, 7.56; N, 5.53; S, 12.66. Found: C, 42.69; H, 7.59; N, 5.36; S, 12.78.

Part B. Methyl 3-oxo-4-(n-butylsulfonamido)butanoate

The immediately preceeding alcohol was oxidized as described for Example 359, Part C, to give a 57% yield of a colorless solid; mp 53.degree.-55.degree. C.; Anal. Calc. for C.sub.9 H.sub.17 NO.sub.5 S: C, 43.02; H, 6.82; N, 5.57; S, 12.76. Found: C, 42.68; H, 7.03; N, 5.74; S, 13.06.

Part C. Methyl 3(R,S)-3-amino-4-(n-butylsulfonamido)butanoate

This compound was prepared analogous to Example 350, Part B, using the product from Part B above (1.20 g, 4.8 mmol) yielding 0.26 g yellow oil; 1H NMR (300 MHz, CDCl.sub.3) .delta. 3.70 (s, 3H), 3.38 (m, 1H), 3.24-3.13 (m, 1H), 3.02 (m, 4H), 2.58-2.52 (dd, J=16, J'=11, 1H), 1.79 (m, 2H), 1.24 (m, 2H), 0.95 (t, 3H); MS (NH4-DCI) Calc. for (M+H).sup.+ : 271. Found: 271.

Part D. Methyl-3(R,S)-{5(R,S)-N-�3-(4-(N-t-butoxycarbonylamidine)phenyl)isoxazolin-5-ylacetyl!amino}-4-(n-butylsulfonylamidc)butanoate

To a solution 3-�4-(N-t-butoxycarbonylamidine)phenyl!isoxazolin-5-ylacetic acid (0.24 g, 0.83 mmol) in DMF (20 ml), the product from Part C above (0.29 gr, 0.83 mmol), TBTU (0.27 g, 0.83 mmol), and Et.sub.3 N (0.46 ml, 3.3 mmol) was added. After stirring 4 h at room temperature, the reaction mixture was diluted with EtOAc, extracted with pH 4 buffer (potassium hydrogen phthalate), saturated NaHCO.sub.3, brine, then dried (NaSO.sub.4). Concentration, followed by chromatography over silica gel in 100% EtOAc, yielded 1.17 g of a white foam; MS (NH.sub.3 -DCI) Calc. for (M+H).sup.+ : 582.3. Found: 582; IR(KBr) 3312, 2338, 1620, 1144 cm.sup.-1.

Part E. Methyl 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(n-butylsulfonylamido)butanoate . trifluoroacetic acid

To a solution of the product from Part D above (0.22 g, 0.37 mmol) in DCM (10 ml), trifluoroacetic acid (2.2 ml) was added. The reaction mixture was stirred 2 h at room temperature, triturated with Et.sub.2 O, and the resulting precipitate was chromatographed over silica gel in 20% MeOH in CHCl.sub.3 to yield 0.20 g white solid; HRMS, e/z Calc. for (M+H).sup.+ : 482.2073. Found: 482.2090; mp=178.degree.-184.degree. C.

EXAMPLE 365

Methyl {5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(methoxycarbonyl)butanoate . trifluoroacetic acid salt

Part A. Dimethyl 3-aminoglutarate . hydrochloric acid salt

This product was prepared similarly to Example 359, Part A, from .beta.-glutamic acid to yield the diester as a colorless gum in quantitative yield; HRMS, e/z Calc. for (M+H).sup.+ : 176.0923. Found: 176.0933.

Part B. Methyl {5(R,S)-N-�3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl!amino}-4-(methoxycarbonyl butanoate

Prepared analogous to Example 359, Part E, to yield 32% of a white solid; IR(KBr) 3306, 2338, 1738, 1656, 1620 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 505.2298. Found: 505.2283.

Part C. Methyl {5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(methoxycarbonyl)butanoate . trifluoroacetic acid salt

Prepared analogous to Example 348, Part F, yielding 83% white solid; IR(KBr) 3316, 3102, 2340, 1736, 1670 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 405.1774. Found: 405.1775.

EXAMPLE 368

Methyl 3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amino}-4-(methoxycarbonyl)pentanoate . trifluoroacetic acid salt

Part A. Dimethyl 3-(R,S)-aminoadipate . hydrochloric acid salt

This product was prepared as in Example 359, Part A, from .beta.-aminoadipic acid to yield a colorless gum in quantitative yield; HRMS, e/z Calc. for (M+H).sup.+ : 190.1079. Found: 190.1080.

Part B. Methyl-3(R,S)-{5(R,S)-N-�3-(4-(N-t-butoxycarbonylamidine)phenyl)isoxzalin-5-ylacetyl!amino}-4-(methoxycarbonyl)pentanoate

This product was prepared similarly as in Example 362, Part D, using the product from Part B above (0.70 g, 3.1 mmol) instead to yield 1.17 g of a white foam; HRMS, e/z Calc. for (M+H).sup.+ : 519.2454. Found: 519.2459; Anal. Calc. for C.sub.25 H.sub.34 N.sub.4 O.sub.8 : C, 57.90; H, 6.61; N,10.80. Found: C, 57.73; H, 6.51; N, 10.86.

Part C. Methyl-3(R,S)-{5(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-ylacetyl!amine}-4-(methoxyacarbonyl)pentanoate . trifluoroacetic acid salt

This product was prepared as in Example 362, Part E, using the product from Part C above (1.00 g, 1.9 mmol) to yield 0.9 g white solid; HRMS, e/z Calc. for (M+H).sup.+ : 419.1930. Found: 419.1921; mp=214.degree.-215.degree. C. (decomposes).

EXAMPLE 375

Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}piperidine

Part A. Preparation of 2-(Methoxy-2-oxoethyl)piperidine

Pyridylacetic acid hydrochloride (10.00 g, 57.6 mmol) and platinum(IV) oxide (1.00 g, 4.4 mmol) were shaken in a mixture of 75 ml acetic acid, 75 ml methanol, and 10 ml conc. HCl on Parr under 60 psi hydrogen at room temperature overnight. The mixture was then filtered through Celite, and the filtrate evaporated under reduced pressure to yield 8.42 g (75.9%) of the title compound as an off-white solid. MS (NH.sub.3 -CI/DDIP): m/e 158 (M+H).sup.+. .sup.1 H NMR (300 MHz, CDCl.sub.3): .delta. 1.50-1.96 (m, 6H); 2.80 (m, 2H); 3.20-3.60 (m, 3H); 3.76 (s, 3H). .sup.13 C NMR (60 MHz, d.sub.6 -DMSO): .delta. 21.94; 28.05; 37.46; 40.49; 44.12; 57.33; 52.74; 170.39.

Part B. Preparation of 2-(R,S)-2-(Methoxy-2-oxoethyl)-1-{5-(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-yl acetyl!}piperidine

To 2.00 g (8.69 mmol) of 3-(4-cyanophenyl)isoxazolin-5-yl acetic acid in 100 ml anhydrous DMF was added 1.36 g (8.69 mmol) of 2-(methoxy-2-oxoethyl)piperidine, 2.80 g (8.69 mmol) of TBTU, and 6.05 ml (34.7 mmol) of diisopropylethylamine. After stirring for 6 hrs, the reaction mixture was diluted with ethyl acetate and washed with 5% aqueous citric acid solution, water, 5% aqueous NaHCO.sub.3 solution, and saturated NaCl solution. The organic layer was dried over Na.sub.2 SO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to give the crude product as a yellow foam. Purification by flash column chromatography on silica gel using 25-75% ethyl acetate in hexane yielded 1.54 g (48%) of the title compound as a yellow foam. One diastereomer (racemic) was isolated from the mixture. MS (NH.sub.3 -CI/DDIP): m/e 370 (M+H).sup.+. .sup.1 H NMR (300 MHz, CDCl.sub.3): .delta. 1.42-1.76 (m, 6H); 2.60 (m, 2H); 2.77-3.01 (m, 3H); 3.05-3.26 (m, 2H); 3.56-3.70 (m, 4H); 4.50 (m, 1H); 5.20 (m, 1H); 7.69 (d, J=8.4 Hz, 2H); 7.77 (d, J=8.4 Hz, 2H).

Part C. Preparation of 2-(Methoxy-2-oxoethyl)-1-{N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}piperidine, (racemic diastereomer A)

HCl gas was bubbled for 2 hrs through a solution of 1.02 g (2.80 mmol) of the product of part B above in 30 ml of anhydrous MeOH cooled in an ice bath. The reaction flask was then sealed with Teflon tape and warmed to room temperature while stirring overnight. MeOH was evaporated under reduced pressure and then under vacuum to give the intermediate imidate as a yellow foam. MS (ESI): m/e 402 (M+H).sup.+. It was then stirred with 8.07 g (84.0 mmol) of (NH.sub.4).sub.2 CO.sub.3 in 30 ml anhydrous EtOH overnight in a sealed reaction flask. After filtering, the filtrate was evaporated under reduced pressure to give the crude product as a yellow foam, which was then purified by flash column chromatography using 5-17% MeOH in CH.sub.2 Cl.sub.2 to give 0.29 g (26.8%) of the title compound as a yellow solid. MS (ESI): m/e 387 (M+H).sup.+. .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): .delta. 1.57-1.67 (br., 6H); 2.46-2.90 (m, 5H); 3.16 (m, 2H); 3.53-3.64 (m, 4H); 4.36 (br. m, 1H); 5.07 (br. m, 1H); 7.89 (m, 4H); 9.38 (br. s, 3H).

Part D. Preparation of 2-Carboxymethyl-1-{N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}piperidine, (Racemic Isomer A)

To a solution of 0.08 g (0.2 mmol) of the product isolated in Part C above in 5 ml anhydrous THF at ambient temperature was added 0.5 ml (0.5 mmol) of 1.0M solution of NaOTMS in THF. After stirring overnight, solvent was evaporated under reduced pressure to give a yellow solid, which was recrystallized from MeOH and Et.sub.2 O to give 0.05 g (64.9%) of the title compound as a yellow powder. MS (ESI): m/e 373 (M+H).sup.+. .sup.1 H NMR (300 MHz, CD.sub.3 OD): .delta. 1.68 (br., 6H); 2.56 (m, 2H); 2.72 (m, 3H); 2.94 (m, 2H); 3.57 (m, 4H); 4.46 (br., 1H); 5.18 (br., 1H); 7.84 (m, 4H).

EXAMPLE 377

Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}azepine

Part A. Preparation of 2-(R,S)-2-(Ethoxy-2-oxoethyl)-1-(5-(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-yl acetyl!}azepine

From 0.50 g (2.17 mmol) of 3-(4-cyanophenyl)isoxazolin-5-yl acetic acid, using 0.40 g (2.17 mmol) of 2-(ethoxy-2-oxoethyl)azepine, 0.70 g (2.17 mmol) TBTU, and 1.51 ml (8.70 mmol) diisopropylethylamine, 0.73 g (84.6%) of the title compound was obtained following the procedure of Example 375, Part B. MS (NH.sub.3 -CI/DDIP): m/e 398 (M+H).sup.+. .sup.1 H NMR (300 MHz, CDCl.sub.3): .delta. 1.26 (m, 11H); 1.83 (br., 2H); 2.05 (m, 1H); 2.18-2.65 (m, 2H); 2.76-2.85 (m, 1H); 3.04 (m, 2H); 3.62 (s, 1H); 4.08 (m, 2H); 5.22 (m, 1H); 7.68 (d, J=8.4 Hz, 2H); 7.78 (d, J=8.4 Hz, 2H).

Part B. Preparation of 2-(R,S)-2-(Ethoxy-2-oxoethyl)-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}azepine

From 0.73 g (1.84 mmol) of 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-yl acetyl!}azepine, using EtOH as the solvent, 0.42 g (61.6%) of the title compound was obtained following the procedure of Example 375, Part C. MS (NH.sub.3 -CI/DDIP): m/e 415(M+H).sup.+. .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): .delta. 1.18 (m, 3H); 1.38 (m, 2H); 1.70 (m, 4H); 2.08 (br., 2H); 2.66 (m, 2H); 3.02-3.26 (m, 2H); 3.60 (br. m, 2H); 4.05 (m, 2H); 4.58 (m, 1H); 5.10 (m, 1H); 7.90 (m, 4H); 9.38 (br. s, 3H).

Part C. Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}azepine

From 0.16 g (0.35 mmol) of 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S) -N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}azepine and using 0.89 ml (0.89 mmol) of 1.0 M solution of NaOTMS in THF, 0.12 g (82.9%) of the title compound was obtained following the procedure of Example 375, Part D. MS (NH.sub.3 -DCI): m/e 387 (M+H).sup.+.

EXAMPLE 400

Preparation of 3-(R,S)-(Methoxy-2-oxoethyl)-4-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}piperazin-2-one

Part A. Preparation of 3-(R,S)-(Ethoxy-2-oxoethyl)-4-{5-(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-yl acetyl!}piperazin-2-one

From 1.00 g (4.34 mmol) of 3-(4-cyanophenyl)isoxazolin-5-yl acetic acid, using 0.81 g (4.34 mmol) of ethyl 2-piperazin-3-one acetate, 1.39 g (4.34 mol) TBTU, and 3.02 ml (17.40 mmol) diisopropylethylamine, 1.08 g (62.4%) of the title compound was obtained following the procedure of Example 375, Part B. MS (NH.sub.3 -CI/DDIP): m/e 399 (M+H).sup.+. .sup.1 H NMR (300 MHz, CDCl.sub.3): .delta. 1.26 (m, 3H); 2.71-3.65 (br., 9H); 3.87 (br. m, 1H); 4.16 (m, 2H); 5.01 & 5.09 (two t, J=5.0, 5.1 Hz, 1H); 5.20 (m, 1H); 7.00 & 7.12 (two br., 1H); 7.77 (m, 4H).

Part B. Preparation of 3-(R,S)-(Methoxy-2-oxoethyl)-4-{5-(R,S)-N-�3-(4-amidinophenyl)isoxazolin-5-yl acetyl!}piperazin-2-one

From 1.08 g (2.71 mmol) of 3-(R,S)-(ethoxy-2-oxoethyl)-4-{5-(R,S)-N-�3-(4-cyanophenyl)isoxazolin-5-yl acetyl!}piperazin-2-one, 0.30 g (27.6%) of the title compound was obtained, following the procedure of Example 375, Part C. MS (ESI): m/e 402 (M+H).sup.+. .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): .delta. 2.70-3.67 (m, 12H); 3.91 (br., 1H); 4.87 & 4.64 (two m, 1H); 5.06 (m., 1H); 7.88 (m, 4H); 8.16 (br., 1H); 9.40 (br. s, 3H).

EXAMPLE 434

Preparation of (S)-N.sup..alpha. -�3-(4-Amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl!-.alpha.-aspart-N-(2-phenylethyl)amide, trifluoroacetic acid salt

Part A. Preparation of (S)-N.sup..alpha. -(Benzyloxycarbonyl)-.beta.-(O-t-butyl)-.alpha.-aspart-N-(2-phenylethyl)amide

To a solution of (S)-N-(Benzyloxycarbonyl)-.beta.-(O-t-butyl)-aspartic acid (BACHEM-Bioscience Inc) (3.20 g, 9.9 mmol) in DCM (25 mL), was added phenethylamine (1.34 g, 11.1 mmol); followed by DEC (2.10 g, 10.9 mmol). The reaction mixture was stirred overnight at room temperature, affording a pale yellow solution. This solution was washed with water, 1M HCl, 5% NaHCO.sub.3 and sat. NaCl, dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give 4.28 g (100%) of amide, which was of sufficient purity to be carried on to the next step; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.35 (s, 5H), 7.17-7.35 (bm, 5H), 6.52 (bs, 1H), 5.93 (bd, J=8.1 Hz, 1H), 5.10 (s, 2H), 4.46 (bm, 1H), 3.50 (dd, J=13.9, 6.2 Hz, 2H), 2.92 (dd, J=17.0, 4.2 Hz, 1H), 2.78 (t, J=7.1 Hz, 2H), 2.57 (dd, J=17.0, 6.4 Hz, 1H), 1.42 (s, 9H); Mass Spectrum (NH.sub.3 -DCI, e/z, relative abundance) 444, (M+NH.sub.4)+, 100%; 427, (M+H).sup.+, 4%.

Part B. Preparation of (S)-.beta.-(O-t-butyl)-.alpha.-aspart-N-(2-phenylethyl)amide

A solution of (S)-N-(benzyloxycarbonyl)-.beta.-(O-t-butyl)-.alpha.-aspart-N-(2-phenylethyl)amide (4.09 g, 9.58 mmol) in ethyl alcohol (30 mL) was hydrogenated under atmospheric pressure using 10% palladium on carbon catalyst (1.0 g) for 90 minutes. The catalyst was filtered and the filtrate concentrated in vacuo to give 2.80 g of an amber oil, which was purified by flash chromatography (5% MeOH/DCM), affording 2.13 g (76%) of the free amine as a solid product; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.44(bs, 1H), 7.20-7.35 (m, 5H), 3.61 (dd, J=8.4, 3.7 Hz, 1H), 3.52 (dd, J=13.2, 7.0 Hz, 1H), 2.80-2.90 (m, 3H), 2.46 (dd, J=16.7, 8.4 Hz, 1H), 1.58 (bs, 2H), 1.45 (s, 9H); Mass Spectrum (ESI, e/z, relative abundance) 293, (M+H).sup.+, 37%; 237, (M+H--C.sub.4 H.sub.8).sup.+, 100%.

Part C. Preparation of Methyl 3-(4-methoxyiminophenyl)-(5R,S)-isoxazolin-5-ylacetate. Hydrochloride Salt

A suspension of 3-(4-cyanophenyl)-(5R,S)-isoxazolin-5-ylacetic acid (23.1 g, 100 mmol) in 200 mL of anhydrous methanol was chilled in an ice bath and dry HCl gas was bubbled through the reaction mixture until a clear solution was obtained. The total addition time was about three hours. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of about 24 hrs. At this point, the methanolic solution was poured into 600 mL of anhydrous ether, precipitating the product, and the resulting slurry was chilled to -25.degree. C. for 21/2 hours. The slurry was then diluted with an additional 100 mL of chilled anhydrous ether. The precipitate was filtered, washed with two 100 mL portions of chilled anhydrous ether, and suction dried under nitrogen to afford 23.3 g (73%) of the hydrochloride salt; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 12.9 (bs, 1H) 12.2 (bs, 1H), 8.46 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 5.20 (bm, 1H), 4.59 (s, 3H), 3.74 (s, 3H), 3.53 (dd, J=16.8, 10.6 Hz, 1H), 3.15 (dd, J=16.8, 7.7 Hz, 1H), 2.90 (dd, J=16.1, 6.2 Hz, 1H), 2.70 (dd, J=16.1, 7.3 Hz, 1H), 1.77 (bs, 1H); Mass Spectrum (NH.sub.3 -CI/DDIP, e/z, relative abundance) 277, (M+H).sup.+, 100%.

Part D. Preparation of methyl 3-(4-amidinophenyl)-(5R,S)-isoxazolin-5-ylacetate. Hydrochloride Salt

A suspension of methyl 3-(4-methoxyiminophenyl)-(5R,S)-isoxazolin-5-ylacetate hydrochloride (22.9 g, 73.0 mmol) in 500 mL of 1M ammonia in anhydrous methanol was stirred at room temperature for 14 hours during which time all solids dissolved. The solution was concentrated in vacuo to give 22.1 g (100%) of crude hydrochloride salt as a tan solid; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 9.6-9,2 (b), 7.91 (d, J=8.8, 2H), 7.87 (d, J=8.8, 2H), 5.08 (bm, 1H), 3.64 (s, 3H), 3.3-3.1 (m, 2H), 2.8 (m, 2H); Mass Spectrum (ESI, e/z, relative abundance) 264, (M+H).sup.+, 100%.

Part E. Preparation of Methyl 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetate

To a solution of 21.6 g (72.5 mmol) of methyl 3-(4-amidinophenyl)isoxazolin-5-ylacetate (prepared using the procedure of Example 434, Part D) in 350 ml DMF cooled with an ice bath was added 20.2 ml (145 mmol) of triethylamine and 17.4 g (79.8 mmol) of di-tert-butyl dicarbonate. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into 1500 ml water while stirring. A while precipitate formed and was then filtered and dried on the filter under nitrogen to give 19.6 g (74.8%) of the title compound as a white solid. MS (ESI): m/e 362 (M+H).sup.+ ; 306 (M+H-tBu).sup.+. .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): .delta. 1.56 (s, 9H); 2.68 (dd, J=6.1, 6.1 Hz, 1H); 2.90 (dd, J=6.1, 6.1 Hz, 1H); 3.14 (dd, J=6.8, 6.8 Hz, 1H); 3.56 (dd, J=6.8, 6.8 Hz, 1H); 3.74 (s, 3H); 5.14 (m, 1H); 7.70 (d, J=8.4 Hz, 2H); 7.90 (d, J=8.4 Hz, 2H). .sup.13 C NMR (60 MHz, d.sub.6 -DMSO): .delta. 28.46; 39.31; 39.58; 51.98; 77.89; 78.35; 126.91; 128.51; 132.79; 136.24; 156.86; 164.04; 165.76; 170.93.

Part F. Preparation of 3-(4-N-Boc-amidinophenyl)isoxazolin-5ylacetic Acid

To a solution of 18.95 g (52.4 mmol) of methyl 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetate (prepared using the procedure of Example 434, Part E) in 500 ml methanol was added 2.42 g (57.7 mmol) of lithium hydroxide monohydrate in 75 ml water at 22.degree. C. The mixture was stirred at 22.degree. C. for 16 hours and then filtered; the filtrate was then evaporated under reduced pressure to remove methanol. The residual aqueous phase was cooled with an ice bath and acidified with 6N and 1N HCl to pH=4. A white solid precipitated and it was left at -4.degree. C. overnight. The solid was filtered and dried on the filter under nitrogen to give 17.74 g (97.4%) of the title compound as an off-white powder. MS (ESI): m/e 348 (M+H).sup.+ ; 292 (M+H-tBu).sup.+. .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): .delta. 1.50 (s, 9H); 2.68 (d, J=7.0 Hz, 2H); 3.22 (dd, J=7.2, 7.2 Hz, 1H); 3.62 (dd, J=6.8, 7.2 Hz, 1H); 5.04 (m, 1H); 7.78 (d, J=8.4 Hz, 2H); 7.94 (d, J=8.4 Hz, 2H). 13C NMR (60 MHz, d.sub.6 -DMSO): .delta. 28.27; 39.30; 40.44; 78.39; 81.55; 126.87; 129.43; 132.78; 133.87; 156.76; 158.61; 165.58; 171.91.

Part G. Preparation of (S)-N.sup..alpha. -�3-(4-N-Boc-Amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl!-.beta.-(O-t-butyl)-.alpha.-aspart-N-(2-phenylethyl)amide

To a suspension of (S)-.beta.-(O-t-butyl)-.alpha.-aspart-N-(2-phenylethyl)amide (0.30 g, 1.0 mmol), 3-(4-N-Boc-amidinophenyl)-isoxazolin-5-ylacetic acid (0.35 g, 1.0 mmol), and TBTU (0.32 g, 1.0 mmol) in EtOAc (20 mL), was added triethylamine (460 .mu.L, 0.33 g, 1.0 mmol). The reaction mixture was stirred at room temperature for 4.5 hr. It was diluted with EtOAc (20 mL), washed with pH 4 buffer, water, 5% NaHCO.sub.3 and sat. NaCl, dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give 0.58 g of solid. The crude product was purified by flash chromatography (100% EtOAc), affording 0.51 g (81%); .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.89 (t, J=8.1 Hz, 2H), 7.69 (m, 2H), 7.25-7.3 (m, 3H), 7.15-7.25 (m, 4H), 7.04 (d, J=8.4 Hz, 1H), 6.65-6.80 (dt, 1H), 5.10 (bm, 1H), 4.71 (bm, 1H), 3.4-3.7 (bm, 3H), 3.1-3.3 (octet, 1H), 2.75-2.95 (m, 3H), 2.5-2.65 (m, 3H), 1.56 (s, 9H), 1.44 (d, 9H); Mass Spectrum (ESI, e/z, relative abundance) 622, (M+H).sup.+, 100%.

EXAMPLE 435

Preparation of (S)-N.sup..alpha. -�3-(4-Amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl!-.alpha.-aspart-N-(2-phenylethyl)amide, trifluoroacetic acid salt

A solution of (S)-N-�3-(4-N.sup..alpha. -Boc-amidinophenyl)isoxazolin-5-ylacetyl!-.beta.-(O-t-butyl)-.alpha.-aspart-N-(2-phenylethyl)amide (160 mg, 0.26 mmol) in trifluoroacetic acid (10 mL) and DCM (10 mL) was stirred at room temperature for three days. The solution was concentrated in vacuo to give 150 mg of product; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 9.40 (bs, 2H), 9.26 (bs, 2H), 8.33 (t, J=8.6, 1H), 7.85-8.0 (m, 1H), 7.88 (s, 4H), 7.3 (m, 1H), 7.28 (d, J=7.1, 2H), 7.20 (d, J=7.1, 2H), 5.07 (bm, 1H), 4.56 (bm, 1H), 3.5-3.6 (octet, 1H), 3.26 (bt, J=7.0, 2H), 3.2 (m, 1H), 2.70 (bt, J=7.0, 2H), 2.6-2.65 (bm, 2H), 2.4-2.5 (m, 2H); Mass Spectrum (ESI, e/z, relative abundance) 466, (M+H).sup.+, 100%.

EXAMPLE 445a

N.sup.2 -(.beta.-Styrylsulfonyl)-N.sup.3 -�3-(4-amidino-phenyl)isoxazolin-5(R,S) -ylacetyl!-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 500 (M+H).sup.+, (100%).

EXAMPLES 473A and 473B

Resolution of Methyl N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)-5S-ylacetyl!-S-2,3-diaminopropionate trifluoroacetic acid salt and Methyl N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionate trifluoroacetic acid salt

The mixture was initially purified on a Pirkle DNBPG column using 10%HOAc/20%EtOH/70% hexane as the eluting solvent. The column temperature was maintained at 45.degree. C., the flow rate at 1.5 ml/min, and the detector set at 280 nm. The diastereomers were then separated on a chiralcel OD-25.times.2cm column using an eluting solvent of 0.1%TFA/20%MeOH/80%CO.sub.2. The column temperature was maintained at 30.degree. C., the flow rate at 13 ml/min, the pressure at 175 atm, and the detector was set at 280 nm. Injections were made on 23 mg of sample. Over the two columns a total of 300 mg was injected giving 59 mg of the R isomer, Ex. 473A (HRMS calc'd for C.sub.23 H.sub.27 N.sub.5 O.sub.6 S 502.176031 Found: 502.175508) and 85 mg of the S isomer, Ex. 473B (HRMS calc'd for C.sub.23 H.sub.27 N.sub.5 O.sub.6 S 502.176031 Found: 502.176358).

EXAMPLE 473C

N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5S-ylacetyl!-S-2,3-diaminopropionic acid

Part A: Methyl-N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5S-ylacetyl!-S-2,3-diaminopropionate

Into a solution of 3-(4-cyanophenyl)isoxazolin-5-S-ylacetic acid (1.82 g, 7.90 mmol, obtained as described in Es. 314A, part F) in DMF (50 ml) was added methyl-N.sup.2 -3-methylphenylsulfonyl-L-2,3-diaminopropionate HCl salt (2.77 g, 7.90 mmol), TBTU (2.53 g, 7.90 mmol), and Hunigs base (2.75 ml, 15.8 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with EtOAc (500 ml) and washed one time with water (200 ml), one time with sat'd NaHCO.sub.3 (200 ml), one time with 0.1N HCl (200 ml), dried (MgSO.sub.4), filtered, and concentrated. Column chromatography on silica gel using 10% EtOAc/hexane as the eluting solvent gave 1.99 g (52%) of the desired material as an off-white foam. .sup.1 H NMR: (CDCl.sub.3): .delta. 7.81-7.78 (d, 2H, J=8.4Hz); 7.16-7.67 (d, 2H, J=8.8Hz); 7.61-7.58 (m, 2H); 7.39-7.37 (d, 2H, J=5.1Hz); 6.35-6.30 (m, 1H); 5.54-5.52 (d, 1H, J=7.7Hz); 5.18-5.17 (m, 1H); 4.00-3.96 (m, 1H); 3.62-3.50 (m, 3H); 3.57 (s, 3H); 3.27-3.19 (dd, 1H, J-7.7, 17.0Hz); 2.78-2.70 (dd, 1H, J=5.9, 14.8Hz); 2.64-2.57 (dd, 1H, J=6.6, 14.6Hz); 2.42 (s, 3H).

Part B: Methyl-N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5S-ylacetyl!-S-2,3-diaminopropionate hydrochloride

Methyl-N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-cyanophenyl)-5S-ylacetyl!-S-2,3-diaminopropionate was dissolved in 100 ml absolute ethanol at 0.degree. C. and a stream of HCl gas was bubbled through the solution for two hours. The reaction vessel was sealed and after sitting at room temperature for 16 hours the volatiles were removed in vacuo. The residue was then diluted with 100 ml of absolute ethanol, ammonium carbonate (9.6 g, 0.123 mol) was added and after stirring for 16 hours the reaction mixture was filtered and concentrated in vacuo. Column chromatography on silica using a gradient elution from 5%MeOH/CH.sub.2 Cl.sub.2 to 20%MeOH/CH.sub.2 Cl.sub.2 gave 0.762 g (37%) of the desired amidine as a white solid. .sup.1 H NMR (CDCl.sub.3): .delta. 8.23-8.20 (m, 1H); 7.91-7.85 (m, 4H); 7.57-7.54 (m, 2H); 7.49-7.46 (m, 2H); 5.00-4.94 (m, 1H); 4.08-3.86 (m, 1H); 3.59-3.49 (m, 1H); 3.39 (s, 3H); 3.38-3.29 (m, 3H); 2.49 (s, 3H); 2.50-2.45 (m, 2H). HRMS: calc'd for C.sub.23 H.sub.27 N.sub.5 O.sub.6 S 502.176031 found 502.175992. �.alpha.!.sub.D =+48.88.degree. (c=0.180, MeOH).

Part C: N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)5(S)-yl!acetyl-S-2,3-diaminopropionic acid

The compound of Ex 473C, part B (0.077 g., 0.14 mmol) was dissolved in MeOH (4 ml). To the resulting solution was added a solution of lithium hydroxide (0.0066 g., 0.158 mmol) in water (4 ml) and the mixture was stirred overnight at room temperature. The methanol was removed by evaporation in vacuo, and the product precipitated from the aqueous as a white solid (0.026 g., 35%). HRMS calcd for C.sub.22 H.sub.25 N.sub.5 O.sub.6 S: 488.160381; found: 488.160827.

EXAMPLE 473D

Methyl-N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionate hydrochloride

Part A: Methyl-N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-cyanophenyl)-5R-ylacetyl!-S-2,3-diaminopropionate

This compound was synthesized from 3-(4-cyanophenyl)isoxazolin-5-(R)-ylacetic acid (3.07 g, 0.011 mol, obtained as described in Ex. 314B, part B) using the same procedure as for example 473C, part A. Yield 41%. Theory: C 57.02, H 4.99, N 11.56 Found: C 56.83, H 4.87, N 11.45.

Part B: Methyl-N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionate hydrochloride

This compound was synthesized from Methyl-N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionate using the same procedure as for example 473C, part B. Yield 49%. HRMS Calc'd for C.sub.23 H.sub.27 N.sub.5 O.sub.6 S 502.176031 Found: 502.174103.

EXAMPLE 478a

N.sup.2 -2,4,6-trimethylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 H NMR (DMSO-d6) .delta.: 9.37 (s, 2H), 9.06 (s,2H), 8.10 (q,J=6.22Hz, 1H), 7.98 (d,J=9.52Hz, 1H), 7.87 (s,4H),6.98 (d, J=4.40Hz, 2H), 4.99 (m,1H), 3.85 (m, 1H), 3.59-3.0 (m, 4H), 2.55 (s, 6H), 2.41 (m,2H), 2.23 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H).sup.+ 516.3 (100)%, High Res Mass Spectrum (M+H).sup.+ calculated 516.190344, found 516.189999.

EXAMPLE 479a

N.sup.2 -2-chlorophenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid

M.P. 138.degree.-140.degree. C. .sup.1 H NMR (DMSO-d6) .delta.: 9.39 (s, 2H), 9.27 (s, 2H) 8.30 (dd, J=4.40, 9.15Hz 1H), 8.22 (m,1H), 7.96 (d, J=6.95Hz, 1H), 7.88 (s, 4H), 7.65 (m,2H), 7.59 (m 1H), 5.04 (m, 1H), 4.03 (m 1H), 3.58 (m 1H), 3.38 (m, 1H), 3.24 (m, 2H), 2.59 (dd,j=6.22, 14.28Hz, 1H), 2.43 (m,1H)ppm.Mass Spectrum (ESI) m/z (M+H).sup.+ 508.1 (100%) High Res Mass Spectrum (M+H).sup.+ calculated 508.107096, found 508.106929.

EXAMPLE 485a

N.sup..alpha. -2,3,5,6-tetramethylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

M.P. 148.degree.-150.degree. C., .sup.1 H NMR (DMSO-d6) .delta.: 9.38 (s, 2H), 9.29 (s,2H), 8.09 (m, 1H), 7.97 (dd,J=4.40,9.15Hz, 1H), 7.85 (s, 4H), 7.15 (d, J=7.32Hz, 1H), 4.98 (m, 1H), 3.88 (q,J=6.96, 15.75Hz,1H), 3.56 (m, 1H), 3.34-3.08 (m, 4H), 2.43 (s,6H), 2.39 (m, 1H), 2.19 (s,3H), 2.18 (s, 3H) ppm. Mass Spectrum (ESI) m/z (M+H).sup.+ 530.2 (100%); High Res Mass Spectrum (M+H).sup.+ calculated 530.208668; found 530.208357.

EXAMPLE 490a

N.sup.2 -n-Propanesulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionic Acid TFA Salt

Part A: Methyl N.sup.2 -n-Propanesulfonyl-N.sup.3 -Boc-(S)-2,3-diaminopropionate

To a solution of methyl N.sup.3 -Boc-(S)-2,3-diaminopropionate (prepared in Ex 20, Part C, 410 mg, 1.88 mmol) in CH.sub.2 Cl.sub.2 (5 mL) at 0.degree. C. was added propanesulfonyl chloride (0.21 mL, 1.9 mmol) and Et.sub.3 N (0.35 mL, 2.5 mmol) and the resulting mixture allowed to warm to room temperature overnight (18 h). The mixture was washed with 0.1M HCl, sat. NaHCO.sub.3 and brine, dried (MgSO.sub.4), and concentrated to give 530 mg (87%) of the desired sulfonamide as a viscous oil; CIMS (e/z, relative intensity): 342 (M+H).sup.+, 100%.

Part B: Methyl N.sup.2 -n-Propanesulfonyl-(S)-2,3-diaminopropionate Hydrochloride Salt

To neat methyl N.sup.2 -n-propanesulfonyl-N.sup.3 -Boc-(S)-2,3-diaminopropionate (520 mg, 1.60 mmol) was added 4M HCl/dioxane (5 mL, 20 mmol). The resulting solution was stirred at room temperature for 4 h, then it was concentrated in vacuo, giving an oil. Trituration with ether (3.times.10 mL) followed by drying under vacuum afforded 383 mg (92%) of the desired amine; CIMS (e/z, relative intensity): 225 (M+H).sup.+, 100%.

Part C: Methyl N.sup.2 -n-propanesulfonyl-N.sup.3 -�3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionate

To a suspension of 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetic acid (prepared in Example 32, 252 mg, 0.725 mmol), methyl N.sup.2 -n-propanesulfonyl-(S)-2,3-diaminopropionate hydrochloride (189 mg, 0.726 mmol) in DMF (5 mL) was added Et.sub.3 N (0.30 mL, 2.2 mmol) and TBTU (233 mg, 0.726 mmol). The resulting mixture was stirred for 4 h at room temperature, then was diluted with EtOAc (30 mL). It was washed with water (4.times.20 mL), sat. NaHCO.sub.3 (30 mL), sat. NaCl and dried (MgSO.sub.4). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 292 mg (73%) of the desired amide; MS (ESI, e/z, relative intensity): 554 (M+H).sup.+, 100%.

Part D: Methyl N.sup.2 -n-Propanesulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionate TFA Salt

To a solution of methyl N.sup.2 -n-propanesulfonyl-N.sup.3 �3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionate (284 mg, 0.513 mmol) in CH.sub.2 Cl.sub.2 (4 mL) was added TFA (2 mL, 26 mmol). After 2 h at room temperature, the solution was concentrated in vacuo and the residue triturated with ether (3.times.5 mL). The resulting white powder was then placed under vacuum until constant weight was achieved, giving 260 mg (89%) of the desired benzamidine; MS (ESI, e/z, relative intensity): 454 (M+H).sup.+, 100%.

Part E: N.sup.2 -n-Propanesulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionic Acid TFA Salt

To a solution of methyl N.sup.2 -n-propanesulfonyl-N.sup.3 �3-(4-amidinophenyl)isoxazolin-5(R,S) -ylacetyl!-(S)-2,3-diaminopropionate (100 mg, 0.176 mmol) in MeOH (1 mL) was added 0.5M LiOH (0.5 mL, 0.25 mmol) and the reaction stirred at room temperature overnight (18 h). The resulting mixture was concentrated in vacuo, redissolved in water and the pH adjusted to 4 using 1M HCl. Purification on reversed phase HPLC gave 10 mg (10%) of the desired carboxylic acid; MS (ESI, e/z, relative intensity): 440 (M+H).sup.+, (100%).

EXAMPLE 492a

N.sup.2 -p-isopronylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO) .delta.: 9.37 (1H, s), 9.09 (1H, s), 8.15 (2H, m), 8.78 (4H, d, J=1.465Hz), 7.09 (2H, d, J=8.423Hz), 7.44 (2H, m), 4.98 (1H,m), 3.93 (1H, m), 3.59 (2H, m), 3.50 (2H, m), 3.22 (2H, m), 2.98 (1H, m), 2.45 (2H, m), 1.22 (6H, m)ppm; ESI mass spectrum 516.3 (M+H, 100).sup.+ free base.

EXAMPLE 496

Methyl N.sup.2 -(2,2-diphenyl-1-ethenesulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate, trifluoroacetic acid salt

Part A: Methyl N.sup.2 -(2,2-diphenyl-1-ethenesulfonyl)-N.sup.3 -Boc-(S)-2,3-diaminopropionate

To a mixture of methyl N.sup.3 -Boc-(S)-2,3-diaminopropionate (255 mg, 1.17 mmol) and 2,2-diphenylethylenesulfonyl chloride (Hasegawa and Hirooka, J. Chem. Soc. Japan 48, 1513-1518 (1975); 391 mg, 1.40 mmol) in methylene chloride (10 mL) cooled in an ice bath was added triethylamine (0.25 mL, 1.76 mmol). After 22 h, the mixture was concentrated and flash chromatographed (6:4 toluene/ethyl acetate) to provide 240 mg (46%) of product. NMR (CDCl.sub.3) .delta. 7.42-7.20 (10H), 6.81 (s,1H), 5.24 (bd,1H), 4.87 (bs,1H), 3.95 (q,1H), 3.72 (s,3H), 3.50-3.42 (2H), 1.44 (s,9H); mass spec (NH.sub.3 -CI) m/z 466.54 (M+NH4.sup.+, 100%).

Part B: Methyl N.sup.2 -(2,2-diphenyl-1-ethenesulfonyl)-(S)-2,3-diaminopropionate TFA salt

The product of Part A (210 mg, 0.468 mmol) was dissolved in 5 mL of methylene chloride and 3 mL TFA. After 1 hour, the solution was concentrated to give an oily product. (222 mg, 100%). NMR (DMSO-d.sub.6) .delta. 8.02 (bs, 3H),7.40 (m, 5H),7.23 (m, 4H), 7.00 (s, 1H), 4.26 (m, 1H), 3.71 (s, 3H), 3.20 (m, 1H), 2.98 (m, 1H).

Part C: Methyl N.sup.2 -(2,2-diphenyl-1-ethenesulfonyl)-N.sup.3 -�3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate

The product of part B (220 mg, 0.46 mmol) was reacted with 3-(4-N-Boc-amidinophenyl)-isoxazolin-5-ylacetic acid (from Example 434, part F; 160 mg, 0.46 mmol), according to the procedure of example 651, Part A, to provide the title product (215 mg, 68%). NMR (CDCl.sub.3) .delta. 7.84 (m,2H), 7.64 (m,2H), 7.40-7.18 (10H), 6.75 (s,1H), 6.30 (m,1H), 5.30 (m,1H), 5.04 (m,1H), 4.00 (1H), 3.78 (s,3H), 3.62-3.40 (4H), 3.10 (m,1H), 2.70-2.50 (2H), 2.04 (s,1H), 1.58 (s,9H); mass spec (ESI) m/z 690.2 (M+H.sup.+, 100%).

Part D: Methyl N.sup.2 -(2,2-diphenyl-1-ethenesulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate, trifluoroacetic acid salt

The product of part C (210 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and treated with trifluoroacetic acid (1 mL) according to the procedure of example 651, Part B, to provide the title product (150 mg, 80%). NMR (DMSO-d.sub.6) .delta. 9.39 (bs,2H), 9.05 (bs,2H), 8.22 (m,1H), 8.00 (m,1H), 7.85 (s,4H), 7.40 (m,6H), 7.20 (m,4H), 6.89 (s,1H), 5.00 (m,1H), 4.00 (m,1H), 3.70-3.18 (5H), 3.62 (2 s,3H); mass spec (ESI) m/z 590.2 (M+H.sup.+, 100%)

EXAMPLE 511

Methyl N.sup.2 -(N,N-dimethylsulfamoyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate, trifluoroacetic acid salt

Part A: Methyl N.sup.2 -(N,N-dimethyl sulfamoyl)-N.sup.3 -Boc-(S)-2,3-diaminopropionate

To a mixture of methyl N.sup.3 -Boc-(S)-2,3-diaminopropionate (400 mg, 1.80 mmol) and Dimethylsulfamoyl chloride (0.24 mL, 2.20 mmol) in methylene chloride (10 mL) cooled in an ice bath was added triethylamine (0.38 mL, 2.20 mmol). After 18 h, the mixture was concentrated and flash chromatographed (6:4 toluene/ethyl acetate) to provide 283 mg (49%) of product. NMR (CDCl.sub.3) .delta. 5.23 (bd,1H), 4.90 (m,1H), 4.06 (m,1H), 3.80 (s,3H), 3.52 (bt,2H), 2.80 (s,6H), 1.42 (s,9H); mass spec (NH.sub.3 -CI) m/z 343.0 (M+NH.sub.4.sup.+, 100%).

Part B: Methyl N.sup.2 -(N,N-dimethyl sulfamoyl)-(S)-2,3-diaminopropionate TFA salt

The Product of Part A was dissolved in 5 mL of methylene chloride and 3 mL TFA. After 1 hour, the solution was concentrated to give an oily product (294 mg, 100%). NMR (DMSO-d.sub.6) .delta. 6.52 (bs,2H), 4.4-3.9 (2H), 3.8 (bs,3H), 2.93 (bs,6H).

Part C: Methyl N.sup.2 -(N,N-dimethyl sulfamoyl)-N.sup.3 -�3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-L-2,3-diaminopropionate

The product of part B (200 mg, 0.61 mmol) was reacted with 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetic acid (from Example 434, part F; 212 mg, 0.61 mmol), according to the procedure of Example 651, Part A, to provide the title product (203 mg, 61%). NMR (CDCl.sub.3) .delta. 7.78 (m,2H), 7.42 (bt,2H), 7.00 (m,1H), 5.92 (m,1H), 5.04 (m,1H), 3.80 (2 s,3H), 3.64 (m,2H), 3.40 (m,1H), 3.05 (m,1H), 2.80 (2 s,6H), 2.74 (m,1H), 2.60 (m,1H), 2.02 (s,3H), 1.60 (s,9H); mass spec (ESI) m/z 555.1 (M+H.sup.+, 100%).

Part D: Methyl N.sup.2 -(N,N-dimethyl sulfamoyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-L-2,3-diaminopropionate, trifluoroacetic acid salt

The product of part C (183 mg, 0.329 mmol) was dissolved in methylene chloride (3 mL) and treated with trifluoroacetic acid (1 mL) according to the procedure of example 651, Part B, to provide the title product (159 mg, 85%). NMR (DMSO-d.sub.6) .delta. 9.40 (bs,2H), 9.00 (bs,2H), 8.22 (m,1H), 7.82 (s,4H), 5.00 (m,1H), 3.95 (m,1H), 3.68 (2 s,3H), 3.60 (m,2H), 3.20 (m,4H), 2.80 (s,6H); mass spec (ESI) m/z 455.1 (M+H.sup.+, 100%).

EXAMPLE 512

Methyl N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -�3-(4-amidino-2-fluorophenyl)isoxazolin-5-ylacetyl!-S-2,3-diaminopropionate hydrochloric acid salt

Part A: 3-Fluoro-4-methylbenzamide

3-Fluoro-4-methylbenzoic acid (10 g, 65 mmol) was boiled in thionyl chloride (100 mL) under a drying tube for 2.5 h. The excess SOCl.sub.2 was removed by distillation. The oily acid chloride product was diluted with CH.sub.2 Cl.sub.2 (100 mL) and cooled in an ice bath. Conc. aq. NH.sub.3 (20 mL) was added dropwise, and stirring continued at 0.degree. C. for 0.5 h. The CH.sub.2 Cl.sub.2 was removed in vacuo, then the residue was diluted with EtOAc. The mixture was extracted with sat. aq. Na.sub.2 CO.sub.3 (2.times.), H.sub.2 O, and brine, dried (MgSO.sub.4), and concentrated to yield 9.9 g of a pale yellow solid; mp 161.degree.-163.degree. C.; IR(KBr) 3382, 1654 cm.sup.-1 ; Anal. Calc. for C.sub.8 H.sub.8 FNO: C, 62.74;H, 5.27; N, 9.15; F, 12.40. Found: C, 62.66; H, 5.17; N, 9.12; F, 12.28.

Part B: 3-Fluoro-4-methylbenzonitrile

A solution of trichloroacetyl chloride (7.3 mL, 65 mmol) in CH.sub.2 Cl.sub.2 (20 mL) was added dropwise over 0.5 h to a solution/suspension of the Part A amide (9.0 g, 59 mmol) and Et.sub.3 N (17 mL, 120 mmol) in CH.sub.2 Cl.sub.2 (80 mL) at 0.degree. C. After 40 min, the mixture was concentrated in vacuo, then diluted with Et.sub.2 O. This solution was extracted with 1M HCl, sat. aq. NaHCO.sub.3, H.sub.2 O, and brine, then dried (MgSO.sub.4), and concentrated to yield 7.8 g of a tan solid; mp 45.degree.-47.degree. C.; IR(KBr) 2232 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 135.0484. Found: 135.0482.

Part C: 2-Fluoro-4-cyanobenzylbromide

N-Bromosuccinimide (9.6 g, 54 mmol) and the part B substrate (7.3 g, 54 mmol) were heated under reflux in CCl.sub.4 (100 mL) under N.sub.2 with irradiation with a high intensity visible lamp for 2 h. After cooling to ambient temp., the mixture was filtered through a Celite pad and concentrated in vacuo. The crude product was recrystallized from hot cyclohexane (4.times.) to yield 4.5 g of off-white needles; mp 75.degree.-77.degree. C.; IR(KBr) 2236 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 213.9668. Found: 213.9660.

Part D: 2-Fluoro-4-cyanobenzaldehyde

The part C benzyl bromide (3.68 g, 17 mmol), trimethylamine N-oxide dihydrate (7.6 g, 68 mmol), CH.sub.2 Cl.sub.2 (15 mL), and DMSO (30 mL) were stirred at 0.degree. C. for a few h, slowly warming to ambient T overnight. The mixture was diluted with water (30 mL) and brine (30 mL), and extracted with Et.sub.2 O (4.times.). The combined organics were washed with brine, dried (MgSO.sub.4), and concentrated to yield 1.1 g of a yellow solid; IR(KBr) 2238, 1706 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 150.0355. Found: 150.0341.

Part E: 2-Fluoro-4-cyanobenzaldoxime

The part D aldehyde (1.1 g, 7.4 mmol), hydroxylamine hydrochloride (1.0 g, 15 mmol), K.sub.2 CO.sub.3 (1.0 g, 7.4 mmol), water (1 mL), and MeOH (10 mL) were heated under reflux for 2.25 h. After brief cooling, the mixture was diluted with water, and the insoluble product was collected by filtration, then rinsed with more water. Drying under high vacuum provided 0.94 g of a pale yellow amorphous solid; mp 179.degree.-182.degree. C.; IR(KBr) 3256, 2236, 1556 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 165.0464. Found: 165.0455.

Part F: Methyl 3-(4-cyano-2-fluorophenyl)isoxazolin-5-ylacetate

The part E oxime was allowed to react with Clorox and methyl vinylacetate in the usual way to afford the isoxazoline as a yellow solid in 32% yield; mp 92.degree.-94.degree. C.; IR(KBr) 2240, 1746 cm.sup.-1 ; HRMS, e/z Calc. for (M+H).sup.+ : 263.0832. Found: 263.0818. Anal. Calc. for C.sub.13 H.sub.11 FN.sub.2 O.sub.3 : C, 59.54;H, 4.23; N, 10.68; F, 7.24. Found: C, 59.84;H, 4.31; N, 10.53; F, 7.26.

Part G: Methyl N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -�3-(4-tert-butyloxycarbonylamidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminopropionate

The part F intermediate was converted to the title compound by the usual sequence of steps: Pinner amidine synthesis, amidine BOC protection, ester saponification, and condensation with the 2,3-diaminopropionate sulfonamide ester; MS (DCI, NH.sub.3) 620 (M+H), 520.

Part H: Methyl N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -�3-(4-amidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminopropionate hydrochloric acid salt

The BOC group was removed from the part G intermediate by treatment with 4M HCl in dioxane to provide a yellow gum; HRMS, e/z Calc. for (M+H).sup.+ : 520.1666. Found: 520.1675.

EXAMPLE 512A

N.sup.2 -(m-Toluenesulfonyl)-N.sup.3 -�3-(4-amidino-2-fluorophenyl)isoxazolin-(R)-5-ylacetyl-(5)-2,3-diaminopropionate hydrochloric acid salt

Part A: N.sup.2 -(m-Toluenesulfonyl)-N.sup.3 -�3-(4-tert-butyloxycarbonylamidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminopropionate

The intermediate from Example 512, Part G (0.60 g, 0.97 mmol) was saponified using lithium hydroxide hydrate (61 mg, 1.45 mmol) in water (1 mL) and methanol (1 mL) at room temperature for 3 d. The mixture was extracted with ethyl acetate, the aqueous layer was acidified with pH 4 buffer, and it was extracted with ethyl acetate. The extracts were dried and concentrated to 0.427 g of a clear glass. This material was flashed chromatographed using a methanol/chloroform gradient solvent system, starting with chloroform and progressing through 2%, 10%, 15%, and 20% methanol/chloroform to give 0.360 g (57%) of a clear glass. .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 9.09 (br, 1H), 7.88-7.80 (m, 3H), 7.60-7.56 (m, 2H), 7.47-7.42 (m, 2H), 5.00-4.97 (m, 1H), 3.62-3.57 (m, 1H), 3.29-3.16 (m, 4H), 2.58-2.43 (m, 2H), 2.37 (s, 3H), 1.45 (s, 9H). HRMS (FAB, glycerol) Calc. for (M+H).sup.+ : 606.2034. Found: 606.2043.

Part B: N.sup.2 -(m-Toluenesulfonyl)-N.sup.3 -�3-(4-amidino-2-fluorophenyl)isoxazolin-(R)-5-ylacetyl-(5)-2,3-diaminopropionate hydrochloric acid salt

The intermediate from Part A (0.344 g, 0.57 mmol) was dissolved in 4M HCl in dioxane and stirred at room temperature for 21.5 h. The solution was diluted with ether and the precipitated white solid was collected and dried, yielding 0.367 g. This material was subjected to super critical fluid chiral Prep HPLC on a Chiral OG 2 in.times.25 cm column using 0.1% TFA, 25% methanol, 75% carbon dioxide as eluent at a flow rate of 20 mL/min to separate the isoxazoline isomers. The second eluting, (R,S), isomer was obtained as a white solid. .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 12.81 (br, 1H), 9.53 (s, 1.5H), 9.29 (s, 1.5H), 8.17 (m, 2H), 7.95 (t, J=7.7Hz, 1H), 7.86 (d, J=12.0Hz, 1H), 7.40 (d, J=9.5Hz, 1H), 7.60-7.56 (m, 2H), 7.46-7.41 (m, 2H), 4.97-4.93 (m, 1H), 3.88-3.86 (m, 1H), 3.59-3.55 (m, 1H), 3.42-3.14 (m, 3H), 2.52-2.45 (m, 1H), 2.41-2.33 (m, 4H). HRMS (FAB, glycerol) Calc. for (M+H).sup.+ : 506.1510. Found: 506.1494.

EXAMPLE 513

Methyl N.sup.2 -(n-butyloxycarbonyl)-N.sup.3 -�3-(3-amidinopyrid-6-yl)isoxazolin-5-ylacetyl!-S-2,3-diaminopropionate hydrochloric acid salt

Prepared using methods described in Ex. 514 to provide a pale yellow powder; mp 90.degree.-110.degree. C. (dec); HRMS, e/z Calc. for (M+H).sup.+ : 449.2149. Found: 449.2140.

EXAMPLE 514

Methyl N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -3-(3-amidinopyrid-6-yl)isoxazolin-5-ylacetyl!-S-2,3-diaminopropionate hydrochloric acid salt

Part A: 3-cyano-6-pyridaldoxime

5-Cyano-2-picoline (25 g, 0.21 mol) and I.sub.2 were heated under reflux in DMSO (200 mL) for 1 h. After cooling to RT, hydroxylamine hydrochloride (16 g, 0.23 mol), K.sub.2 CO.sub.3 (29 g, 0.21 mol), and water (21 mL) were added. The resulting mixture was heated to 80.degree. C. for 2.5 h, cooled, diluted with water (100 mL) and much acetone, and absorbed onto silica gel by concentration. Chromatography on silica gel, eluting with 0% to 50% EtOAc in hexane, afforded 12.2 g of a tan solid; mp 204.degree.-207.degree. C. (dec); HRMS, e/z Calc. for (M+H).sup.+ : 148.0511. Found: 148.0516.

Part B: Methyl 3-(3-cyanopyrid-6-yl)isoxazolin-5-ylacetate

The oxime of Ex. 514, part A was converted to the isoxazoline as described in Ex. 516, part B in 76% yield as a yellow solid; mp 97.degree.-98.degree. C.; HRMS, e/z Calc. for (M+H).sup.+ : 246.0879. Found: 246.0881. Anal. Calc. for C.sub.12 H.sub.11 N.sub.3 O.sub.3 : C, 58.77;H, 4.52; N, 17.13. Found: C, 58.74; H, 4.51; N, 17.11.

Part C: Methyl 3-(3-t-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-5-ylacetate

The nitrile of Ex. 514, part B was converted to the amidine as described in the method of Ex. 516, parts D & E (except that 0.6 eq. NaOMe was required), and BOC protected in standard fashion to afford, after purification, a yellow solid; mp 143.degree. C. (gas evolves); HRMS, e/z Calc. for (M+H).sup.+ : 363.1668. Found: 363.1675. Anal. Calc. for C.sub.17 H.sub.22 N.sub.4 O.sub.5 : C, 56.35;H, 6.12; N, 15.46. Found: C, 56.35;H, 6.10; N, 15.39.

Part D: Lithium 3-(3-t-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-5-ylacetate

The ester of Ex. 514, part C was saponified and lyophilized as described in the method of Ex. 516, part F to give a colorless amorphous solid quantitatively; mp>230.degree. C.; HRMS, e/z Calc. for conjugate acid (M+H).sup.+ : 349.1512. Found: 349.1527.

Part E: Methyl N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -�3-(3-tert-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl!-(S)-2,3-diaminopropionate

The Part D lithium carboxylate was condensed with methyl N.sup.2 -(m-toluenesulfonyl)-(S)-2,3-diaminopropionate hydrochloride using conditions described above to give a yellow foam. HRMS, e/z Calc for (M+H).sup.+ : 603.2237. Found: 603.2223.

Part F: Methyl N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -�3-(3-amidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl!-(S)-2,3-diaminopropionate hydrochloric acid salt

The protected amidine of Part E was treated with 4M HCl in dioxane to provide a yellow solid; mp 90.degree. C. (dec); HRMS, e/z Calc. for (M+H).sup.+ : 503.1713. Found: 503.1718.

EXAMPLE 514A

N.sup.2 -(m-Toluenesulfonyl)-N.sup.3 -�3-(3-amidinopyrid-6-yl)isoxazolin-(R)-5-ylacetyl!-(S)-2,3-diaminnopropionic acid trifluoroacetic acid salt

Part A: Lithium N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -�3-(3-tert-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl!-(S)-2,3-diaminopropionate

The methyl ester of Example 514, Part E (0.16 g, 0.27 mmol) was saponified by stirring with 0.5M LiOH (0.54 mL, 0.27 mmol) in methanol (2 mL) at room temperature. The mixture was concentrated in vacuo to give 0.16 g (99%) of a tan solid; HRMS, e/z Calc for (M+H).sup.+ : 589.2081. Found: 589.2086.

Part B: N.sup.2 -(m-Toluenesulfonyl)-N.sup.3 -�3-(3-amidinopyrid-6-yl)isoxazolin-(R)-5-ylacetyl!-(S)-2,3-diaminopropionic acid trifluoroacetic acid salt

The lithium salt of Part A was treated with 4M HCl in dioxane to give a tan foam. This material was purified by Prep reverse phase HPLC on a Vydac C18 2.times.25 cm column using a gradient solvent system starting with 0.05% TFA in water progressing to 80:20 0.05% TFA in water: 0.05% TFA in acetonitrile over 50 m, the purified material was subjected to super critical fluid Prep chiral HPLC on a Chiral OG 2 in.times.25 cm column using 0.1% TFA, 25% methanol, 75% carbon dioxide as elutant at a flow rate of 20 mL/min to separate the isoxazoline isomers. The second eluting, (R,S), isomer was resubmitted to reverse phase Prep HPLC as above to give the title compound as a tan solid. .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.31 (dd, J=15.0, 7.0Hz, 1H, partially obscured), 2.37 (s, 3H), 2.48-2.59 (m, 1H, under DMSO), 3.02-3.15 (m, 1H), 3.22 (dd, J=17.6, 10.6Hz, 1H), 3.32-3.42 (m, 1H, under water peak), 3.55 (dd, J=17.6, 10.6 Hz, 1H), 3.82-3.92 (m, 1H), 4.98-5.11 (m, 1H), 7.39-7.49 (m, 2H), 7.54-7.61 (m, 2H), 8.08-8.15 (m, 3H), 8.25 (dd, J=8.4, 2.2Hz, 1H), 9.01 (d, J=1.8Hz, 1H), 9.24 (br s, 2H), 9.53 (br s, 2H), 12.78 (very br s, 1H). MS (ESI) 489 (M+H, 65), 288 (100), 245 (27).

EXAMPLE 515

Methyl N.sup.2 -(n-butyloxycarbonyl)-N.sup.3 -�3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl!-S-2,3-diaminopropionate hydrochloric acid salt

In similar fashion to the method described in Ex. 516, the compound of Ex. 514, part E was coupled with methyl N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropionate hydrochloride using conditions described above, followed by BOC deprotection with 4M HCl/dioxane to yield a pale yellow powder; HRMS, e/z Calc. for (M+H).sup.+ : 449.2149. Found: 449.2154.

EXAMPLE 516

Methyl N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -�3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl!-S-2,3-diaminopropionate hydrochloric acid salt

Part A: 2-Chloro-5-pyridaldoxime

2-Chloro-5-formylpyridine (2.1 g, 15 mmol) was condensed with hydroxylamine hydrochloride in the usual way to give the oxime, 1.5 g, as a yellow crystalline solid; mp 171.degree.-175.degree. C. (dec); HRMS, e/z Calc. for (M+H).sup.+ : 157.0169. Found: 157.0175.

Part B: Methyl 3-(2-chloropyrid-5-yl)isoxazolin-5-ylacetate

Sodium hypochlorite (5% wt, 20 mL) was added dropwise over 1.75 h to a mixture of the part A oxime (1.13 g, 7.2 mmol), methyl vinylacetate (70% purity, 3.0 g, 21 mmol), CH.sub.2 Cl.sub.2 (40 mL), and DMF (4 mL) with stirring at ambient temperature. The CH.sub.2 Cl.sub.2 was evaporated, and the mixture was diluted with EtOAc, extracted with water (5.times.) and brine, then dried (MgSO.sub.4), filtered, and concentrated. Chromatography on silica gel, eluting with 0% to 70% EtOAc in hexane, afforded 1.4 g of a solid; mp 94.degree.-96.degree. C.; HRMS, e/z Calc. for (M+H).sup.+ : 255.0536. Found: 255.0531.

Part C: Methyl 3-(2-cyanopyrid-5-yl)isoxazolin-5-ylacetate

The part B chloropyridine (0.51 g, 2.0 mmol), zinc cyanide (0.23 g, 2.0 mmol), Pd(PPh.sub.3).sub.4 (0.12 g, 0.10 mmol), and DMF (2 mL) were heated to 80.degree. C. under N.sub.2 for 3 days. After cooling and concentration, the mixture was preabsorbed onto silica gel by concentration from CHCl.sub.3. Chromatography on silica gel, eluting with 0% to 90% EtOAc in hexane afforded 0.28 g of a pale yellow solid; mp 115.degree.-116.degree. C.; HRMS, e/z Calc. for (M+H).sup.+ : 246.0879. Found: 246.0880. Anal. Calc. for C.sub.12 H.sub.11 N.sub.3 O.sub.3 : C, 58.77; H, 4.52; N, 17.13. Found: C, 58.68; H, 4.48; N, 16.90.

Part D: Methyl 3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetate formic acid salt

The part C cyanopyridine (0.47 g, 1.9 mmol) and sodium methoxide (prepared in situ from Na metal, 4 mg, 0.2 mmol were stirred in dry MeOH (6 mL) at ambient temperature for 16 h, after which .sup.1 H NMR analysis of a reaction aliquot indicated complete formation of methyl imidate �note 9.25 (s, 1H) and 3.92 (s, 3H)!. Ammonium formate (0.60 g, 9.5 mmol) was added to the reaction mixture, and stirring continued for 7 h. The mixture was absorbed onto silica gel by concentration in vacuo. Chromatography on silica gel, eluting with 0% to 20% MeOH in CHCl.sub.3, and concentration afforded 0.61 g of the amidine as an off-white solid; mp 180.degree.-182.degree. C. (dec); HRMS, e/z Calc. for (M+H).sup.+ : 263.1144. Found: 263.1148.

Part E: Methyl 3-(2-t-butyloxycarbonylamidinopyrid-5-yl)isoxazolin-5-ylacetate

The part D amidine was BOC protected in standard fashion to afford, after silica gel chromatographic purification, a 41% yield of a colorless foam; HRMS, e/z Calc. for (M+H).sup.+ : 363.1668. Found: 363.1682.

Part F: Lithium 3-(2-t-butyloxycarbonylamidinopyrid-5-yl)isoxazolin-5-ylacetate

The part E methyl ester (0.37 g, 1.0 mmol) was saponified by stirring with 0.5M LiOH in MeOH at RT. The MeOH was removed in vacuo, then the aqueous mixture was frozen and lyophilized to produce a pale yellow solid quantitatively; HRMS, e/z Calc. for conjugate acid (M+H).sup.+ : 349.1512. Found: 349.1531.

Part G: Methyl N.sup.2 -(m-toluenesulfonyl)-N.sup.3 -�3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl!-S-2,3-diaminopropionate hydrochloric acid salt

The part F lithium carboxylate was condensed with methyl N.sup.2 -(m-toluenesulfonyl)-2,3-diaminopropionate hydrochloride using conditions described above, followed by standard BOC deprotection with 4M HCl/dioxane to yield a yellow amorphous solid; HRMS, e/z Calc. for (M+H).sup.+ : 503.1713. Found: 503.1707.

EXAMPLE 516A

N.sup.2 -(m-Toluenesulfonyl)-N.sup.3 -�3-(2-amidinopyrid-5-yl)isoxazolin-(R,S)-5-ylacetyl!-(5)-2,3-diaminopropionic acid trifluoroacetic acid salt

The methyl ester of Example 516, Part G (31.4 mg, 54.6 mmol) was dissolved in 6M aqueous hydrochloric acid (1 mL) and the mixture was stirred at room temperature for 44 h. The yellow solution was concentrated and subjected to Prep reverse phase HPLC as described in Example 514 A, Part B to give 25.0 mg (75%) of a white solid. mp 158.5.degree.-161.5.degree. C. .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.31-2.44 (m, 1H), 2.37, 2.38 (singlets, 3H), 2.50-2.60 m, 1H, under DMSO), 3.00-3.10 (m, 0.5H), 3.12-3.36 (m, H), 3.38-3.48 (m, 0.5H), 3.60 (ddd, J=17.2, 10.6, 5.9 z, 1H), 3.85-3.95 (m, 1H), 4.95-5.11 (m, 1H), 7.39-7.45 (m, 2H), 7.52-7.60 (m, 2H), 8.10-8.22 (m, 2H), 8.28-8.40 (m, 2H), 9.06 (s, 1H), 9.37 (br s, 2H), 9.60 (br s, 2H). S (ESI) 489 (M+H, free base, 100), 214 (17).

EXAMPLE 528a

N.sup.2 -o-Bromophenylcarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid

The title compound was obtained as its TFA salt from readily accessible N.sup.2 -amino-3-�(4-tertbutyloxycarbonylamidino)phenylisoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diamino-tertbutylpropionate by common acylation techniques with 2-bromobenzoyl chloride. Removal of the tert-butyl protecting groups with TFA afforded the desired product as colorless crystals. M.P. 172.degree.-174.degree. C.; .sup.1 H NMR (DMSO d6) .delta.: 7.80 (d, J=8Hz,2H), 7.51-7.63 (m,3H), 7.28 (m,2H), 7.12 (dd,1H), 6.61 (m,1H), 5.05 (m,1H), 4.81 (q, 1H), 3.80 (d, 3H), 3.06 (m,1H), 2.53 (m,2H), 1.53 (s, 9H)ppm; ESI mass spectrum 516 (M+H, 100 free base); HRMS calcd. for C.sub.22 H.sub.23 BrN.sub.5 O.sub.5 516.088255, found 516.086811 (free base).

EXAMPLE 536

N.sup.2 -(2,5-Dimethyl-4-chlorobenzenesulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 536 (M+H).sup.+, (100%).

EXAMPLE 540

N.sup.2 -methylphenylcarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid

Obtained as colorless crystals, M.P. 166.degree.-168.degree. C.; .sup.1 H NMR (DMSO d6) .delta.: 9.38 (b, 2H), 9.18 (b,2H), 8.42 (t,1H), 8.20 (m,1H), 7.21 (d, J=10.2Hz, 4H), 5.00 (m, 1H), 4.50 (m, 1H), 3.30-3.73 (m.3H), 2.58-2.65 (dd,1H), 2.41-2.50 (dd, 1H), 2.34 (s,3H)ppm; ESI mass spectrum 452 (M+H, 100 free base); HRMS calcd for C.sub.23 H.sub.26 N.sub.5 O.sub.5 452.193394, found 452.1922251 (free base).

EXAMPLE 540a

N.sup.2 -methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid

Obtained as colorless crystals M.P. 136.degree.-138.degree. C.; .sup.1 H NMR (DMSO d6).delta.: 9.39 (b, 2H), 9.27 (s,2H), 8.18 (m,2H), 7.80 (d, J=7.7Hz, 1H), 7.44 (t,1H), 7.32 (q,2H), 4.96 (m,1H), 3.90 (b, 1H), 3.81 (q, 1H), 3.40-3.60 (m,2H), 3.04 (m,2H), 2.60 (s,2H), 2.24 (dd, J=7.7 and 15.6Hz) ppm; ESI mass spectrum 488 (M+H, 100 free base). HRMS calcd for. C.sub.22 H.sub.25 N.sub.5 SO.sub.6 488.160381, found 488.16292 (free base).

EXAMPLE 548

Preparation of 3-bromothiophene-2-sulfonyl chloride

A solution of chlorosulfonic acid (14.3 g, 0.12 mol) in 35 mL of 1,2-dichloroethane was chilled to -10.degree. C. and protected from moisture. Phosphorus pentachloride (20.8 g, 0.1 mol) was added in small portions while maintaining the temperature between -5.degree. and -10.degree. C. The resulting slurry was stirred at -10.degree. C. for 30 minutes. Then, 3-bromothiophene (16.3 g, 0.1 mol) was added dropwise over a period of 45 minutes, maintaining the temperature between -5.degree. and +5.degree. C. During the addition of the 3-bromothiophene, hydrogen chloride gas was evolved; the reaction mixture became thick and pasty, and difficult to stir. Upon complete addition of the 3-bromothiophene, the reaction temperature was held at 0.degree. C. for two hours. The reaction was then heated to 80.degree. C. and kept there for one hour; during which the solids dissolved, and hydrogen chloride gas was evolved once more. The reaction mixture was chilled in an ice bath, poured over 250 g crushed ice, and stirred for one hour as the ice melted. The resulting two phase system was separated and the aqueous layer washed three times with 125 mL of chloroform. The combined organic phases were dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give 24.1 g (92%) of crude product as a dark amber oil; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.22 (d, J=5.3, 1H), 7.73 (d, J=5.3, 1H); Mass Spectrum (CH.sub.4 -DCI/GC-MS, e/z, relative abundance) 262.8, (M+H).sup.+, 100%; 226.9, (M+H-HCl).sup.+, 89.7%.

EXAMPLE 587A

N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5S-ylacetyl!-S-2,3-diaminopropionic acid

The compound of Example 473C, Part B (0.077 g, 0.14 mmol) was dissolved in MeOH (4 ml), LiOH (0.0066 g, 0.158 mmol) in H.sub.2 O (4 ml) was added and the reaction mixture left to stir overnight. After evaporation of methanol the product precipitated from the aqueous as a white solid (0.027 g, 35% yield). HRMS calc'd for C.sub.22 H.sub.25 N.sub.5 O.sub.6 S: 488.160381 found: 488.160827.

EXAMPLE 602

Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-guanidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate, trifluoroacetic acid salt

Part A: �3-�(4-t-butyloxycarbonylamino)-phenyl!isoxazolin-5-yl!acetic acid: This compound was prepared in 49% yield from 4-t-butyloxycarbonylaminobenzaldoxime and t-butyl vinyl acetate using the procedure described above for Ex. 275, Part A. .sup.1 HNMR(CDCl.sub.3) .delta. 0.99 (t, 3H), 1.35 (m, 2H), 1.50 (s, 9H), 1.61 (m, 2H), 2.60 (dd, J=7.7 and 16.5Hz, 1H) 2.84 (dd, J=5.9 & 16Hz, 1H), 3.06 (dd, J=7.4 & 16.9Hz, 1H), 3.48 (dd, J=10.3 & 16.5Hz, 1H), 4.10 (t, 2H), 5.03 (m, 1H), 6.60 (broad s, 1H), 7.38 (d, J=8.4Hz, 2H), 7.58 (J=8.3Hz, 2H); IR(KBr): 2966, 1734, 1740, 1610, 1578, 1528, 1508, 1458, 1442, 1412, 1392, 1368 1234, 1160, 1058, 916, 878, 828, 772, 612 cm.sup.-1 ; HRMS calcd. for C.sub.20 H.sub.28 N.sub.2 O.sub.5 : 377.207647, Found 377.207278.Standard LiOH saponification conditions then afforded the corresponding carboxylic acid compound as colorless crystals in 88% yield. mp 178.degree.-180.degree. C.; .sup.1 HNMR(CDCl.sub.3) .delta. 1.52 (s, 9H), 2.67 (dd, J=7.8 and 16Hz, 1H), 2.89 (dd, J=8.3 & 16Hz, 1H), 3.06 (dd, J=9.5 & 16.9Hz, 1H), 3.48 (dd, J=10.3 & 16.5 z, 1H), 5.03 (m, 1H).

Part B: Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-�(4-t-butyloxycarbonylamino)phenyl!isoxazolin-5-yl acetyl!-(S)-2,3-diaminopropionate: The compound of Example 602, Part A was condensed with methyl N.sup.2 -tBoc-(S)-2,3-diaminopropionate using the procedure described for Ex. 275, Part C above to provide the desired product. mp 80.degree.-82.degree. C.; .sup.1 HNMR(CDCl.sub.3) .delta. 1.88 (t,3H), 1.30 (m,2H), 1.47 (sm,20H), 2.50 (dd,1H), 2.61 (dd, 1H), 3.07 (dd,1H), 3.40 (dd,1H), 3.63 (t,2H), 3.74 (s,3H), 4.00 (m,2H), 4.38 (m,1H), 5.00 (m,1H), 5.88 (dd,1H), 6.77 (t,1H), 7.58 (d,2H), 7.84 (d,2H), 10.4 (s,1H), 11.6 (s,1H); IR(KBr):3286, 2964, 1722, 1646, 1546, 1414, 1368, 1340, 1312, 1294, 1240, 1156, 1122, 1100, 1058, 1030, 844, 776 cm.sup.-1. Mass spectrum (CI/NH.sub.4) 663 (M+H,20),563 (7), 549 (78), 506 (81),463 (100).

Part C: Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -(3-(4-quanidinophenyl)isoxazolin-5-yl acetyl!-(S)-2,3-diaminopropionate: The compound of Ex 602, part B was treated with TFA in dichloromethane to afford the corresponding aniline as its TFA salt. This intermediate was converted to the corresponding bis-BOC protected quanidino compound in 59% yield using the method of Kim et al. (Tet. Lett. 1993, 48, 7677). Deprotection under standard conditions (TFA/CH.sub.2 Cl.sub.2) provided the title compound as its TFA salt (90%). .sup.1 HNMP(DMSO-d.sub.6) .delta. 1.89 (t,3H), 1.34 (m,2H), 1.57 (m,2H), 2.44 (dd,1H), 2.58 (t,2H), 2.64 (m,1H), 3.17 (m,1H), 3.40 (m,2H), 3.65 (m,1H), 3.70 (s,3H), 4.00 (t,2H), 4.31 (m,1H), 5.02 (m,1H), 6.80 (m,1H), 7.28 (d,2H), 7.64 (broads,3H), 7.68 (d,2H), 7.84 (broad, 1H) ; Mass spectrum(ES) m/z 463 (M+H, 100).

EXAMPLE 606

Methyl N.sup.2 -p-toluylsulfonyl-N.sup.3 -�3-(4-guanidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA Salt

Part A: The methyl di-Boc-quanidino-.alpha.-toluyl ester was prepared according to the procedure for example 602. Deprotection of the Boc-protecting groups then afforded example 606 as the TFA salt. .sup.1 HNMR (DMSO) .delta.: 8.30 (dd, 2H), 8.09 (m, 1H), 7.68 (d, J=8.2Hz, 2H), 7.60 (d, J=8.0Hz, 2H), 7.35 (d, J=8.2Hz, 2H), 7.28 (d, J=8.4Hz, 2H), 4.88 (m, 1H), 4.00 (m, 1H), 3.42 (dt, 1H), 3.38 ((d, 3H), 3.05-3.33 (m, 3H), 2.40 (m, 1H), 2.36 (s, 3H), 2.25 (m,1H)ppm; HR MS calcd. for C.sub.23 H.sub.29 N.sub.6 O.sub.6 S 517.186930; Found 517.186911.

Part B: Lithium hydroxide saponification on the product of part A then afforded example 605 in 39% yield after recrystallization from dichloromethane and ether. 1HNMR (CD.sub.3 OD) .delta.: 8.29 (brd, S, 2H), 8.05 (brd, s, 1H), 7.75 (d, J=8.1Hz, 2H), 7.70 (d, J=8.4Hz, 2H), 7.31 (d, 4H), 5.02 (m, 1H), 3.85 (m, 1H), 3.60 (m, 2H), 3.41 (m, 1H), 3.20 (m, 1H), 2.64 (dd, 1H), 2.43 (dd, 1H), 2.40 (s, 3H);HR MS calcd. for C.sub.22 H.sub.27 N.sub.6 O.sub.6 S 503.171280; Found 503.170531.

EXAMPLE 625

N.sup.2 -p-methylphenylsulfonyl-N.sup.3 -�3-(4-amidinophenylmethyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

Part A: 1-.beta.-nitroethene-4-benzonitrile (Bourgvignon, J. et al., Can, J. Chem., 1985, 63, 2354) (0.9 g, 5.17 mmol) was reduced according to the method of Nakamura, et al. (Chem. Lett., 1985, 523) to afford 0.73 g (80%) of desired product. .sup.1 H NMR (CDCl.sub.3) .delta.: 7.73 (d, J=8.42Hz, 2H), 7.43 (d, J=8.42Hz, 2H), 4.75 (d, J=6.96Hz, 2H), 3.48 (d, J=6.96Hz, 2H) ppm; Mass Spectrum (CH.sub.4 -CI) m/z (M+H).sup.+ 177 (100%).

Part B: 1l-.beta.-nitroethane-4-benzonitrile (1.38 g, 7.8 mmol) was condensed with tert-butyl acrylate (1.4 ml, 9.4 mmol) according to the method of Curran, D. P., et al (J. Org. Chem., 1988, 53, 5369) to afford the crude ester. The ester was difficult to purify so the ester was hydrolyzed in 30 ml of 30% TFA/CH.sub.2 Cl.sub.2 for 48 h. The crude acid was extracted into aqueous NaHCO.sub.3. The aqueous layer was acidified and extracted with CH.sub.2 Cl.sub.2 and dried (MgSO.sub.4) to afford 1.48 g (80%) orange solid. .sup.1 H NMR (CDCl.sub.3) .delta.: 7.97 (brd, 1H), 7.64 (d, J=8.42Hz, 2H), 7.36 (d, J=8.42Hz, 2H), 5.07 (dd, J=6.59, 10.98Hz, 1H), 3.79 (s, 2H), 3.20 (m, 2H) ppm.

Part C: The product of Part B (366 mg, 1.6 mmol) was coupled with methyl-L-N.sup..alpha. -p-toluylsulfonyl-2,3-diaminoproprionate using procedure described in Example 43D. Chromatography on silica gel (2%MeOH/CH.sub.2 Cl.sub.2) afforded 388 mg (50%). mp 141.degree.-144.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.: 7.75-7.65 (m, 2H), 7.60 (d, 2H), 7.45 (d, 2H), 7.30 (dd, 2H), 7.20 (m, 1H), 5.50 (dd, 1H), 4.99 (m, 1H), 4.20-3.99 (m, 1H), 3.90-3.70 (m, 3H), 3.55 (s, 3H), 3.30 (m, 3H), 2.42 (s, 3H)ppm; Mass Spectrum (NH.sub.3 -CI) m/z (M+H).sup.+ 485.2 (100%); IR (KBr) 3276, 1738, 1666, 1538, 1338, 1162, 862, 822 cm.sup.-1.

Part D: The product of Part C (360 mg, 0.74 mmol) was subjected to the Pinner reaction previously described. Chromatography on silica gel (5-15% MeOH/CH.sub.2 Cl.sub.2) afforded 313 mg (75%). mp 133.degree.-137.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.: 9.20 (brd, 2H), 8.26 (t, J=5.86 Hz, 1H), 7.80 (d, J=8.06 Hz, 2H), 7.63 (d, J=8.06 Hz, 2H), 7.51 (d, J=8.06 Hz, 2H), 7.38 (d, J=8.06 Hz, 2H), 4.87-4.73 (m, 1H), 3.98-3.89 (m, 1H), 3.80 (s, 2H), 3.34 (s, 3H), 3.34-3.31 (m, 3H), 3.28 (m, 2H), 2.98 (dd, J=6.23, 17.21 Hz, 1H), 2.37 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H).sup.+ 502.2 (100%).

Part E: To the product of Part D (182 mg, 0.338 mmol) was added 1 ml MeOH, followed by lithium hydroxide (31 mg, 0.74 mmol). The mixture was stirred for 18 h and the solvent was removed in vacuo and water added. HCl was added until a precipitate formed. The solid was filtered off and stirred in 2 ml HCl for 1 h. The acid was removed in vacuo to afford 72 mg of product which contained 15% methyl ester. Purification via standard HPLC techniques then afforded the desire product. .sup.1 H NMR (DMSO-d.sub.6) .delta.: 9.35 (s, 2H), 9.08 (s, 2H), 8.14-8.07 (m, 2H), 7.78 (d, J=7.32 Hz, 2H), 7.66 (dd, J=2.19, 8.42 Hz, 2H), 7.51 (d, J=7.69 Hz, 2H), 7.36 (d, J=8.42 Hz, 2H), 4.86-4.69 (m, 1H), 3.92-3.80 (m, 1H), 3.79 (s, 2H), 3.30-2.90 (m, 4H), 2.49 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H).sup.+ 488.3 (100%).

EXAMPLE 651

Methyl N.sup.2 -benzyloxycarbonyl-N.sup.3 -methyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate, trifluoroacetic acid salt

Part A. Preparation of methyl N.sup.2 -benzyloxycarbonyl-N.sup.3 -methyl-�3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate

To a mixture of 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetic acid (prepared according to the procedure of Example 434, part F; 189 mg, 0.54 mmol), methyl N.sup.3 -methyl-N.sup.2 -Cbz-L-2,3-diaminopropionate (prepared according to Sakai and Ohfune, J. Am. Chem. Soc. 114, 998 (1992); 145 mg, 0.54 mmol) and TBTU (175 mg, 0.54 mmol) in ethyl acetate (10 mL) was added triethylamine (0.15 mL, 1.09 mmol). After stirring for 26 h, the mixture was diluted with ethyl acetate, washed with pH 4 buffer, then with saturated aqueous sodium bicarbonate, then with saturated brine. The organic phase was dried (MgSO.sub.4) and concentrated. The residue was flash chromatographed (ethyl acetate) to provide the product as a colorless glass (279 mg, 86%): NMR (CDCl.sub.3) .delta. 7.88 (m, 2H), 7.69 (m, 2H), 5.79 (bd, 1H), 5.09 (m, 3H), 4.58 (m, 1H), 3.86 (m, 1H), 3.77 (2s, 3H), 3.63 (m, 2H), 3.14 (dd, 1H), 3.01 (2s, 3H), 2.9 (m, 1H), 2.53 (m, 1H), 1.66 (b, 2H), 1.56 (s, 9H); mass spec (ESI) m/z 596.2 (M+H.sup.+, 100%).

Part B. Preparation of Methyl N.sup.2 -benzyloxycarbonyl-N.sup.3 -methyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate, trifluoroacetic acid salt

The product of part A (226 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL) and treated with trifluoroacetic acid (1 mL). After stirring at room temperature for 4 h, the mixture was diluted with ether and stirred. The resulting white solid was collected by filtration to provide the title product as a white solid (201 mg, 87%): NMR (DMSO-d.sub.6) .delta. 9.39 (bs, 2H), 9.19 (bs, 2H), 7.87 (s, 4H), 7.79 (t, 1H), 7.32 (m, 5H), 5.03 (3H), 4.40 (m, 2H), 3.90 (m, 1H), 3.65 (2s, 3H), 2.95 and 2.82 (4s, 3H), 3.6-2.8 (4H); mass spec (ESI) m/z 96.3 (M+H.sup.+, 100%).

EXAMPLE 666

N.sup.2 -(methyl)-N.sup.2 -m-toluylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazoline-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

Part A: Methyl N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5-(R,S)-ylacetyl!-N.sup.2 -m-toluyl-(S)-2,3-diaminopropionate obtained as the precursor to Example 300 was subjected to a selective Mitsonubo-N-methylation of the sulfonamide (Acta. chem. scand. 1994,48,324333), to afford methyl N.sup.2 -(methyl)-N.sup.2 -m-toluyl-N.sup.3 -�3-(4-cyanophenyl)isoaxzolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate as colorless crystals. M.P=148.degree.-149.degree. C. .sup.1 HNMR(CDCl.sub.3) .delta.: 7.77(d, 2H), 7.60(m, 2H), 7.46(m, 2H), 7.41(d, 2H), 6.07(t, 1H), 5.21(m, 1H), 4.80(dd,J=4.8 & 10.6 Hz, 1H), 3.81(m, 1H), 3.56(s, 3H), 3.43(m, 2H), 3.25(dd,J=7.4 & 17.4 Hz, 1H), 2.80(dd,J=8 & 17.1 Hz,1H), 2.77(s, 3H), 2.56(dd, J=7.7 & 15.1 Hz,1H), 2.44(s, 1H) ppm; IR (KBr) 3340, 2224, 1726, 1644, 1610, 1596, 1534, 1440, 1414, 1402, 1366, 1336, 1284, 1258, 1212, 1144, 1012, 934, 918, 896, 844, 812, 784, 690, cm.sup.-1 ESI mass spectrum 499 (M+H, 48), 359(63), 279(53), 198(100). HR MS calcd. for C.sub.24 H.sub.27 N.sub.4 O.sub.6 S 499.165132 found 499.164946.

Part B: The cyano procursor from part A was then subjected to the Pinner amidine reaction conditions as per example 275E to obtain the desired compound as the methyl ester in 60% overall yield. Saponification with 6N HCl followed by HPLC purification �solvent A: CH.sub.3 CN:H.sub.2 O:TFA/2%:98%:0.05%, solvent B: CH.sub.3 CN:H.sub.2 O:TFA/80%:20%:0.05%! afforded the desired amidine acid compound 666 as its TFA salt. .sup.1 HNMR (CDCl.sub.3) .delta.: 9.35(s, 1H), 9.23(s, 1H), 8.20(brd, 2H), 7.89(brd, 4H), 7.57(d,J=8 Hz, 2H), 7.40(d,J=8 Hz, 2H), 5.05(m, 1H), 4.67(m, 1H), 3.50-3.66(m, 3H), 3.20-3.40(m, 2H), 2.80(s, 3H), 2.55(m, 1H), 2.35(m/s, 4H) ppm; ESI mass spectrum 502(M+H, 100), HRMS calcd for C.sub.23 H.sub.27 N.sub.5 SO.sub.6 502.176031 found 502.176612.

EXAMPLE 703

Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazol-5-yl acetyl!-L-2,3-diaminopropionate TFA salt

Part A. Preparation of Methyl 3-(4-cyanophenyl)isoxazo-5-yl acetate

To a suspension of methyl 3-(4-cyanophenyl)-(5R,S)-isoxazolin-5-yl acetate (5.28 g, 21.62 mmol) in chloroform (150 mL) were added N-bromosuccinimide (4.23 g, 23.78 mmol) and AIBN (100 mg) and the mixture was refluxed. Small amounts of AIBN (100 mg-200 mg) were added at one hour intervals until TLC showed a complete reaction. Potassium acetate (17.3 g) and acetic acid (6.5 mL) were added and the reaction mixture was refluxed for 1 hour, cooled, then poured into 1N NaOH (325 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3.times.100 mL). The organic layers were combined and washed with sat. NaCl, dried over Na.sub.2 SO.sub.4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (15% to 35% EtOAc in Hexane) to yield 2.2 g (42%) of an off-white solid as product; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.93 (dd, 2H), 7.76 (dd, 2H), 6.67 (s, 1H), 3.92 (s, 2H), 3.8 (s, 3H).

Part B. Preparation of Methyl 3-(4-methoxyiminophenyl)isoxazo-5-yl acetate HCl salt

A suspension of methyl 3-(4-cyanophenyl)isoxazo-5-yl acetate (2.19 g, 9.04 mmol) in 100 mL of anhydrous methanol was chilled in an ice bath and dry HCl gas was bubbled through the reaction mixture until a solution was obtained. The total addition time was two hours. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of about 24 hrs. At this point, the methanolic solution was poured into 500 mL of anhydrous ether, precipitating the product, and the resulting slurry was chilled to -25.degree. C. for 3 hours. The precipitate was filtered, washed with two 100 mL portions of chilled anhydrous ether, and suction dried under nitrogen to afford 2.3 g (82%) of the hydrochloride salt; .sup.1 H NMR (300 MHz, suspension in CDCl.sub.3) .delta. 8.52 (d, J =8.06 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 6.67 (s, 1H), 4.6 (s, 3H), 3.93 (s, 2H), 3.8 (s, 3H).

Part C. Preparation of Methyl 3-(4-amidinophenyl)isoxazo-5-yl acetate HCl salt

A solution of methyl 3-(4-methoxyiminophenyl)isoxazo-5-yl acetate HCl salt (2.3 g, 7.4 mmol) in 50 mL of anhydrous methanol was chilled in an ice bath and 2M ammonia in methanol (18.5 mL, 37 mmol) was added. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of 24 hrs. The amber solution was then concentrated in vacuo to give 2.2 g (quant. yield) of a yellow foam; .sup.1 H NMR (300 MHz, d.sub.6 -DMSO) .delta. 9.6-9.2 (b), 8.12 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 4.15 (s, 2H), 3.7 (s, 3H).

Part D. Preparation of Methyl 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetate

To a solution of methyl 3-(4-amidinophenyl)isoxazo-5-yl acetate HCl salt (2.2 g, 7.4 mmol) in 30 mL DMF cooled with an ice bath was added triethylamine (2.06 mL, 14.8 mmol) and di-tert-butyl dicarbonate (1.78 g, 8.14 mmol). The reaction mixture was warmed to room temperature and stirred for 64 hrs. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was washed with EtOAc. The organic layers were combined and washed with water, sat. NaCl, dried over Na.sub.2 SO.sub.4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (15% to 25% EtOAc in Hexane) to afford 1.45 g (54%) of product; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.96 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 3.91 (s, 2H), 3.8 (s, 3H), 1.56 (s, 9H).

Part E. Preparation of 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetic acid

To a solution of methyl 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetate (1.45 g, 4.03 mmol) in 30 mL of methanol was added a solution of lithium hydroxide monohydrate (0.195 g, 4.64 mmol) in water (5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and the resulting mixture was cooled using an ice bath. 1N HCl was slowly added to a pH of 3-4 and the resulting acidic aqueous mixture was extracted repeatedly with EtOAc. The organic layers were combined and washed with sat. NaCl, dried over Na.sub.2 SO.sub.4, filtered and concentrated in vacuo to yield 0.97 g (70%) of an off-white powdery solid as product; .sup.1 H NMR (300 MHz, d.sub.6 -DMSO) .delta. 8.07 (d, J=8.79 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.03 (s, 1H), 3.99 (s, 2H), 1.45 (s, 9H).

Part F. Preparation of Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetyl!-L-2,3-diaminopropionate

To a solution of 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetic acid (0.262 g, 0.76 mmol), methyl N.sup.2 -n-butyloxycarbonyl-L-2,3-diaminopropionate HCl salt (0.193 g, 0.76 mmol), and TBTU (0.256 g, 0.8 mmol) in DMF (15 mL) was added triethylamine (0.45 mL, 3.23 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and water. The water layer was washed twice with EtOAc. The organic layers were combined and washed with water, pH 4 buffer, 5% NaHCO.sub.3, and sat. NaCl, dried over Na.sub.2 SO.sub.4, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel (100% EtOAc) to yield 0.315 g (76%) of a slightly amber foam; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.93 (d, J=8.42 Hz, 2H), 7.83 (d, J=8.42 Hz, 2H), 6.6 (s, 1H), 6.57 (bm, 1H), 5.66 (bm, 1H), 4.45 (bm, 1H), 4.05 (m, 2H), 3.77 (s, 5H), 3.7 (m, 2H), 1.57 (s, 9H), 1.56 (m, 2H), 1.35 (m, 2H), 0.9 (t, J=7.32 Hz, 3H).

Part G. Preparation of Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazo-5-yl acetyl!-L-2,3-diaminopropionate TFA salt

A solution of methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetyl!-L-2,3-diaminopropionate (0.215 g, 0.39 mmol) in 1:1 methylene chloride/trifluoroacetic acid (20 mL total) was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the residue chromatographed on silica gel (10% to 30% methanol in chloroform) to yield 0.11 g (50%) of a white solid; .sup.1 H NMR (300 MHz, d.sub.6 -DMSO) .delta. 9.4 (bs, 2H), 9.15 (bs, 2H), 8.45 (t, 1H), 8.11 (d, J=8.42 Hz, 2H), 7.94 (d, J=8.42 Hz, 2H), 7.53 (d, J=8.06 Hz, 1H), 7.01 (s, 1H), 4.21 (m, 1H), 3.95 (t, 2H), 3.81 (s, 2H), 3.62 (s, 3H), 3.55 (m, 1H), 3.34 (m, 1H), 1.5 (m, 2H), 1.3 (m, 2H), 0.87 (t, J=7.32 Hz, 3H); Mass Spectrum (ESI, e/z, relative abundance) 446.3, (M+H).sup.+, 100%.

EXAMPLE 717

N.sup.2 -Phenylmethylsulfonyl-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionic Acid TFA Salt

Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 488 (M+H).sup.+, (100%).

EXAMPLE 816

N.sup.2 -p-toluylsulfonyl-N.sup.3 -�5-(4-amidinophenyl)isoxazolin-3-(R,S)-yl-acetyl!-(S)-2,3-diaminopropionic acid TFA salt

The title compound was prepared in a manner similar to example 829. Saponification of the methyl ester via standard techniques then afforded crude compound 816, which was purified via HPLC �graduant flow, solvent A CH.sub.3 CN(2%):H.sub.2 O(98%):TFA(0.05%), solvent B: CH.sub.3 CN(80%):H.sub.2 O(20%):TFA(0.05%),! to afford colorless crystals of compound 816 as its TFA salt. .sup.1 HNMR(CDCl.sub.3) .delta.: 9.30(brds, 4H), 8.34(t, 1H), 8.12(d,J=9.2Hz, 1H), 7.81(d, J=8.3 Hz, 1H), 7.60(d, J=8.0 Hz, 1H), 5.60(dt, 1H), 3.81(q, 1H), 3.43(dt, 1H), 3.25(m, 1H), 3.20(d, 1H), 3.03(m, 1H), 2.89(m, 1H), 2.50(s, 1H), 2.34(s,3H) ppm; ESI mass spectrum 488(M+H,100), HRMS calcd. for C.sub.22 H.sub.26 N.sub.5 O.sub.6 S 488.160381; found 488.158785.

EXAMPLE 829

Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�5-(4-amidinophenyl)isoxazolin-3-yl acetyl!-(2S)-2,3-diaminopropionate

Part A: t-Butyl �5-(4-cyanophenyl)isoxazolin-3-yl!acetate

Cycloaddition of 4-cyanophenylethylene (MP&D chemical Co.) and tert-butyl-3-oxopropionate oxime was carried out following the procedure of Gree et. al. (Bioorganic & Medicinal Chemistry letters 1994, 253) to provide the desired isoxazoline in 72% yield. .sup.1 HNMR(CDCl.sub.3) .delta.: 1.40 (s, 9H), 3.00 (dd, J=8.3 and 17 Hz, H), 3.35 (dd(AB) J=18 and 8.3 Hz, 2H),3.48 (m, 1H), 5.60 (dd, J=9 and 4.5 Hz, 1H), 7.47 (d, J=8Hz, 2H), 7.65 (d, J=8 Hz, 2H); IR 2235, 1718, 1610 cm.sup.-1. Mass spectrum m/z 287(M+H, 100).

Part B: �5-(4-cyanophenyl)isoxazolin-3-yl! acetic acid

Hydrolysis of the compound of Ex.829, Part A with excess TFA in dichloromethane afforded the acid in 90% yield. .sup.1 HNMR (CDCl.sub.3) .delta. 3.00 (dd, J=8 and 17.2 Hz, 1H), 3.55 (s, 2H), 3.59 (m, 1H), 5.66 (dd, J=8 and 11 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H); IR(KBr) 3325, 2235, 1718, 1605 cm.sup.-1 ; Mass spectrum m/z 231 (M+H, 100).

Part C: Methyl �5-(4-Boc-amidinophenyl)isoxazolin-3-yl!acetate

The compound of Ex. 829, Part B compound was then subjected to the standard Pinner reaction conditions described in Ex. 275, Part D to afford an amidino compound, which, without purification, was subjected to treatment with di-tert-butyldicarbonate in dioxane/water (9:1) and excess triethylamine to afford the desired compound in 28% yield. .sup.1 HNMR(CDCl.sub.3) .delta. 1.54 (s,9H), 2.98 (dd, J=8 and 17 HZ, 1H), 3.49 (s, 2H), 3.53 (m, 1H), 3.71 (s, 3H), 5.63 (dd, J=8 & 11.4 Hz, 1H), 7.38 (d, 8.2 Hz, 2H), 7.82 ((d, 8.2 Hz, 2H); Mass spectrum m/z 362(M+H, 8), 306(18), 262(M+H-Boc, 100).

Part D: �5-(4-Boc-amidinophenyl)isoxazolin-3-yl!acetic acid

Hydrolysis of the ester using standard LiOH conditions afforded the desired acid in 5% yield. .sup.1 HNMR(CDCl.sub.3) .delta. 1.54 (s,9H), 3.00 (dd, J=8 and 17 HZ, 1H), 3.51 (s, 2H), 3.53 (m, 1H), 5.63 (dd, J=8 & 11.4Hz, 1H), 7.38 (d, 8.2 Hz, 2H), 7.82 ((d, 8.2 Hz, 2H); Mass spectrum m/z 348(M+H,12),248(M+H-Boc, 100).

Part E: Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�5-(4-amidino phenyl)isoxazolin-3-yl-acetyl!(S)-2,3-diaminopropionate trifluoroacetate

The compound of Ex. 829, Part D was coupled with methyl-(S)-N.sup.2 -n-butyloxycarbonyl-2,3-diaminopropionate following the procedure described in Ex. 275, Part C to give the Boc protected intermediate in 80% yield. .sup.1 HNMR(CDCl.sub.3) .delta. 0.89 (t, 3H), 1.32 (m, 2H), 1.53 (s, 9H), 1.17 (m, 2H), 2.95 (dd, J=8 and 17 HZ, 1H), 3.33 (s, 2H), 3.46 (m, 1H), 3.60 (m, 2H), 3.73 (s, 3H), 4.00 (m, 2H), 4.31 (m, 1H), 5.60 (dd, J=8 & 11.4 Hz, 1H), 5.70 (bd, 1H), 6.70 (broad, 1H), 7.33 (d, 8.2 Hz, 2H), 7.89 ((d, 8.2 Hz, 2H); Mass spectrum m/z 534 (M+H, 30), 434 (M+H-Boc, 100). Deprotection by treatment of the above Boc-amidine with excess TFA in dichloromethane provided the title compound as the TFA salt. .sup.1 HNMR(CDCl.sub.3 /DMSO-d.sub.6) .delta. 1.88 (t, 3H), 1.30 (m, 2H), 1.53 (m, 2H), 3.00 (dd, J=8 and 17 HZ, 1H), 3.32 (s, 2H), 3.40-3.63 (m, 3H), 3.63 (d, 3H), 3.98 (t, 2H), 4.29 (m, 1H), 5.60 (dd, J=8 & 11 Hz, 1H), 6.80 (d, 1H), 7.50 (d, J=8Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 8.03 (broad s, 1H), 9.05 (broad s, 2H); IR(KBr): 3388, 1718, 1664, 1620, 1528, 1456, 1436, 1384, 1366, 1280, 1254, 1168, 1144, 1074, 980, 882, 778 cm.sup.-1 ; Mass spectrum(ES) m/z 448 (M+H,100).

EXAMPLE 952

Methyl N.sub.2 -m-toluenesulfono-N.sup.3 -�3-(4-N-isopropylamidophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionate

Methyl N.sup.2 -m-toluenesulfono-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionate (prepared as in example 473 part C above) (0.098 g, 0.0002 mol) was stirred with isopropyl alcohol (0.018 ml, 0.0002 mol) and sulfuric acid (5 ml) for 12 hours. The reaction mixture was poured over ice and diluted to three times its' volume with water. The title compound was filtered as a pale brown solid. .sup.1 H NMR (CDCl.sub.3) .delta.: 7.79-7.61(m, 6H); 7.38-7.36(m, 2H); 6.49-6.40(m, 1H); 6.01-5.99(m, 1H); 5.62-5.55(m, 1H); 5.19-5.08(m, 1H); 4.31-4.28(m, 1H); 4.11-3.99(m, 1H); 3.56(s, 3H); 3.72-3.48(m, 4H); 3.24-3.16(dd, 1H, J=7.3, 17.0); 2.41(s, 3H); 1.29-1.27(d, 6H, J=6.59 Hz). MS(ESI) calc'd for C.sub.26 H.sub.32 N.sub.4 SO.sub.7 545.3 found 545.2 (M+H).sup.+l .

EXAMPLE 954

N.sup.2 -3-(n-butylcarbamoyl)-N.sup.3 -�3-(4-amidophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionic acid

Following the procedure outlined for example 1945 above, Methyl N.sup.2 -3-(n-butylcarbamoyl)-N.sup.3 -�3-(4-cyanophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionate (0.87 g, 0.002 mol) gave a 66% yield of N.sup.2 -3-(n-butylcarbamoyl)-N.sup.3 -�3-(4-amidophenyl)isoxazolin-5R-ylacetyl!-S-2,3-diaminopropionic acid. .sup.1 H NMR (CDCl.sub.3) .delta.: 12.7(bs, 1H); 8.12-8.09 and 7.28-7.26(2m, 1H); 8.05 and 7.43(2s, 1H); 7.94-7.92(d, 2H, J=8.54); 7.87(s, 1H); 7.73-7.70(d, 2H, J=8.5 Hz); 6.51-6.49(m, 1H); 5.02-4.95(m, 1H); 3.95-3.90(m, 1H); 3.58-3.47(m, 2H); 3.29-3.13(m, 2H); 2.72-2.38(m, 4H); 1.52-1.46(m, 2H); 1.34-1.25(m, 2H); 0.87-0.85(t, 3H, J=4.3 Hz). MS(ESI): Cacl'd for C.sub.20 H.sub.26 N.sub.4 O.sub.7 435.2 found 435.2(M+H).sup.+.

EXAMPLE 956

N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�3-(4-amidophenyl)-5R-ylacetyl!-S-2,3-diaminopropionic acid

Part A: Methyl N.sup.2 -m-toluenesulfono-N.sup.3 -�3-(4-amidophenyl)-5S-ylacetyl!-S-2,3-diaminopropionate hydrochloride

Methyl N.sup.2 -m-toluenesulfono-N.sup.3 -�3-(4-cyanophenyl)-5R-ylacetyl!-S-2,3-diaminopropionate (0.19 g, 0.00039 mol) was dissolved in 10 ml concentrated sulfuric acid. After stirring for 12 hours the reaction mixture was poured over 10 g of ice and 20 ml of water was added. The white solid was filtered, washed once with water and dried under vacuum overnight to give methyl-N.sup.2 -m-toluenesulfono-N.sup.3 -�3-(4-amidophenyl)-5S-ylacetyl!-S-2,3-diaminopropionate as a white powder. IR(neat) cm.sup.-1 : 3404, 3340, 3274, 3202, 2930, 1710, 1652, 1612, 1526, 1320, 1286, 1238, 1174, 1100, 1086, 1070, 886, 850, 614, 574. MS(ESI): calc'd for C.sub.23 H.sub.26 N.sub.4 O.sub.7 S 503.2 found 503.3(M+H).sup.+.

Part B: N.sup.2 -m-toluenesulfono-N.sup.3 -�3-(4-amidophenyl)-5R-ylacetyl!-S-2,3-diaminopropionic acid

Methyl N.sup.2 -m-toluenesulfono-N.sup.3 -�3-(4-amidophenyl)-5R-ylacetyl!-S-2,3-diaminopropionate hydrochloride (0.146 g, 0.29 mmol) was dissolved in MeOH (5 ml), LiOH (0.013 g, 0.32 mmol) in H.sub.2 O (5 ml) was added and the reaction mixture left to stir overnight. Purification was done by HPLC on a Vyadek column using a gradient of 0.05%TFA/water to 0.05%TFA/acetonitrile over 45 min. The flow was set to 10 ml/min and the detector at 254 nm. The peak eluted at 25 min, the volatiles were evaporated in vacuo, and the solid dried under vacuum. MS(ESI) calc'd for C.sub.22 H.sub.24 N.sub.4 O.sub.7 S: 489.2 found: 489.2.

EXAMPLE 978

Methyl N.sup.2 -m-toluenesulfono-N.sup.3 -�3-(5-amidopyrid-2-yl)isoxazolin-5S-ylacetyl!-S-2,3-diaminopropionate

mp 192.degree.-195.5.degree. C. (dec). .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.28 (dd, J=14.6, 7.0 Hz, 1H), 2.36 (s, 3H), 2.44-2.54 (m, 1H, under DMSO), 3.04-3.15 (m, 1H), 3.20 (dd, J=17.6, 7.3 Hz, 1H), 3.30-3.40 (m, 1H, under water), 3.53 (dd, J=17.6, 10.6 Hz, 1H), 3.80-3.89 (m, 1H), 4.92-5.05 (m, 1H), 7.38-7.48 (m, 2H), 7.54-7.61 (m, 2H), 7.68 (br s, 1H), 7.98 (d, J=8.1 Hz, 1H), 8.04-8.10 (m, 2H), 8.23 (br s, 1H), 8.27 (dd, J=8.1, 2.2 Hz, 1H), 9.06 (d, J=1.5 Hz, 1H), 12.76 (br s, 1H). IR (KBr) 3388, 3314, 3274, 3186, 1712, 1662, 1584, 1546, 1418, 1344, 1160, 934, 794, 712, 688, 620, 576 cm.sup.-1. MS (ESI) 490 (M+H, 100).

EXAMPLE 979

N.sup.2 -�(p-ethyl)phenylsulfonyl!-N.sup.3 -�3-(4-carboxamidophenyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate

.sup.1 HNMR (DMSO) .delta. 8.12(2H,m), 7.94(2H, d, J=8.423 Hz), 7.74(2H, m), 7.70(2H, d, J=8.423 Hz), 7.46(1H, s),7.40(2H, m), 4.94(1H, m), 3.92(1H, m), 3.56(2H, m), 3.37(3H, m), 2.70(2H, m), 2.45(3H, m), 1.22(3H, m) ppm; MS (ESI) m/z 503.3 (M+H).sup.+.

EXAMPLE 996

N.sup.2 -o-toluenesulfonyl-N.sup.3 -�5-(4-amidinophenyl)isoxazolin-3(R,S)-ylformyl!-(S)-2,3-diaminopropionic acid TFA salt

Standard cycloaddition techniques using ethylchlorooximido acetate (Aldrich) and 4-cyanostyrene agfforded the desired precursor ethyl-5-(4-cyanophenyl)isoxazoline carboxylate. Saponification followed by coupling with methyl N.sup.2 -o-toluylsulfonyl-(S)-2,3-diaminopropionate via standard techniques afforded the desired cyanoprecursor. Formation of the amidine via standard Pinner reaction conditions afforded the desired compound as colorless crystals after HPLC purification; M.P. 84.degree.-86.degree. C.; .sup.1 HNMR(DMSO d.sub.6) .delta.: 9.45(b, 1H), 9.35(b, 1H), 8.40(q, 1H), 8.21(dd, 1H), 7.81(t,2H), 7.77(d, J=8.5 Hz, 2H), 7.55(d, J=8.5 Hz, 2H), 7.38-7.49(t, 1H), 7.25(m, 2H), 5.83(m, 1H), 3.89(q, 1H), 3.23-3.71(m, 3H), 2.98(q, 1H), 2.57(s,3H) ppm; ESI mass spectrum 474 (M=H, 100 free base); HRMS calcd for C.sub.21 H.sub.24 N.sub.5 O.sub.6 S 474.144731, found 474.143847.

EXAMPLE 1540

2-(n-Butyloxycarbonylamino)-3-�3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro�4,5!dec-2-en-8-yl!propionic acid bis trifluoroacetic acid salt

Part A: 3-(4-Cyanophenyl)-8-benzyloxycarbonyl-1-oxo-2,8-diazaspiro�4,5!dec-2-ene

The title material was prepared from 4-cyanobenzaldoxime (7.0 g, 48 mmol) and 1-benzyloxycarbonyl-4-methylenepiperidine (De Amici, M.; Fr.o slashed.lund, B.; Hjeds, H. Krogsgaard-Larsen, P. Eur. J. Med. Chem. 1991, 26, 625) (11.0 g, 48 mmol) as described in Example 4, Part B. The crude adduct was purified by flash chromatography using a gradient hexane/ethyl acetate solvent system, starting with hexane and progressing to 65% ethyl acetate/hexane in 5% increments to give 14.4 g (86%) of a pale yellow gum. .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.75 (d, J=8 Hz, 2H), 7.69 (d, J=8 Hz, 2H), 7.37-7.29 (m, 5H), 5.15 (s, 2H), 3.95-3.83 (m, 2H), 3.51-3.44 (m, 2H), 3.09 (s, 2H), 2.00-1.89 (m, 2H), 1.83-1.70 (m, 2H). IR (KBr) 2228, 1698 cm.sup.-1. HRMS (DEP, NH.sub.3) Calc. for (M+H).sup.+ : 376.1661. Found: 376.1646.

Part B: 3-(4-Amidinophenyl)-1-oxo-2,8-diazaspiro�4,5!dec-2-ene dihydrochloric acid salt

The intermediate of Part A (4.18 g, 11.1 mmol) was subjected to standard Pinner conditions to give a crude amidine-amine salt, which was purified by flash chromatography using a graduated solvent system starting with chloroform and progressing to 30% methanol in chloroform to give 1.8 g (48%) of the title compound. .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 9.56 (br s, 1.5H), 9.36 (br s, 1.5H), 7.95 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 4.15-4.14 (m, 1H), 3.43 (s, 2H), 3.36 (s, 4H), 2.05-2.04 (m, 4H). HRMS (DEP, NH.sub.3) Calc. for (M+H).sup.+ : 259.1559. Found: 259.1562.

Part C: Methyl 2-(R,S)-(benyloxycarbonylamino)-3-�3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro �4,5!dec-2-en-8-yl!propionate dihydroiodic acid salt

The intermediate of Part B (1.67 g, 5.0 mmol) was dissolved in dimethylformamide (20 mL) and sodium bicarbonate (1.27 g, 15.1 mmol) was added. A solution of N-benzyloxycarbonyl-3-iodo-L-alanine methyl ester (Marki, W.; Schwyzer, R. Helv. Chim. Acta 1975, 58, 1471) (2.0 g, 5.5 mmol) in dimethylformamide (6 mL) was added and the mixture was stirred at room temperature for 7 d. The solvent was evaporated and the residue was flash chromatographed using a graduated solvent system starting with chloroform and progressing to 20% methanol/chloroform in 5% steps to give 1.78 g of impure material. It was chromatographed a second time as above to give 1.72 g (45%) of pure material. .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 9.16 (br s, 4H), 7.87 (s, 4H), 7.71 (d, J=7.7 Hz, 1H), 7.39-7.30 (m, 5H), 5.10-5.05 (m, 2H), 4.29-4.27 (m, 1H), 3.65 (s, 3H), 3.23 (s, 2H), 2.66-2.60 (m, 4H), 2.46 (m, 2H), 1.75 (m, 4H). IR (KBr) 3300-2950 (br), 1718, 1674 cm.sup.'1. HRMS (FAB, glycerol) Calc for (M+H).sup.+ : 494.2403. Found: 494.2401.

Part D: Methyl 2-(R,S)-amino-3-�3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro�4,5!dec-2-en-8-yl!-propionate trihydrobromic acid salt

The intermediate of Part C (1.2 g, 1.6 mmol) was dissolved in 30% hydrogen bromide in acetic acid (10 mL) and the solution was stirred at room temperature for 17.5 h. The mixture was diluted with ether and filtered. The solid was washed with ether and dried to give 0.872 g (89%) of a gray solid. .sup.1 H NMR (DMSO-d.sub.6 +TFA-d, 300 MHz) .delta. 9.43 (s, 2H), 9.14 (s, 2H), 7.94-7.85 (m, 4H), 4.84 (m, 1H), 3.84 (s, 4H), 3.55-3.42 (m, 6H), 2.16 (br m, 4H). MS (ESI) 360 (M+H).

Part E: Methyl 2-(n-butyloxycarbonylamino)-3-�3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro�4,5!dec-2-en-8-yl!propionate hydrobromic acid salt

n-Butylchloroformate (45 .mu.L, 0.35 mmol) was added to a solution of the intermediate of Part D (0.200 g, 0.33 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dimethylformamide (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was flash chromatographed using a gradient solvent system starting with chloroform and progressing to 20% methanol/chloroform in 5% steps to give 0.249 g of the title compound. MS (ESI) 460 (M+H).

Part F: 2-(n-Butyloxycarbonylamino)-3-�3-(4-amidinophenyl)-1-oxo-2 8-diazaspiro�4.5!dec-2-en-8-yl!propionic acid bis trifluoroacetic acid salt

The intermediate of Part E (229 mg, 0.33 mmol) was dissolved in methanol (7 mL) and water (7 mL) and lithium hydroxide hydrate (33 mg, 0.79 mmol). The mixture was stirred at room temperature for 24 h and additional lithium hydroxide hydrate (18 mg, 0.43 mmol) was added. The mixture was stirred for 24 h and the methanol was evaporated. The aqueous residue was diluted with trifluoroacetic acid (0.15 mL) and the mixture was purified by Prep HPLC as described in Example 514 A, Part B to give 31 mg (11%) of the title compound. .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta. 9.40 (br s, 2H), 9.12 (br s, 2H), 7.91-7.86 (m, 4H), 7.61 (br, 1H), 6.56 (br, 1H), 4.44 (br, 1H), 4.00 (t, J=6.2 Hz, 2H), 3.38 (m, 6H, under water peak), 2.03 (br, 4H), 1.58-1.54 (m, 2H), 1.36-1.34 (m, 2H), 0.90 (t, J=7.4 Hz, 3H). HRMS (FAB, glycerol) Calc. for (M+H).sup.+ : 446.2403. Found: 446.2394.

EXAMPLE 1541

2-(R,S)-(3-methylphenylsulfonylamino)-3-�3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro�4,5!dec-2-en-8-yl!propionic acid bis trifluoroacetic acid salt

Part A: Methyl 2-(R,S)-(m-toluenesulfonylamino)-3-�3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro�4,5!dec-2-en-8-yl!propionate hydrobromic acid salt

m-Toluenesulfonyl chloride (63 mg, 0.33 mmol) was added to a mixture of the intermediate in Example SP1, Part D (0.200 g, 0.33 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dimethylformamide (2 mL) and the mixture was stirred at room temperature for 19 h. Additional m-toluenesulfonyl chloride (14 mg, 0,07 mmol) was added and the mixture was stirred for 24 h. The solution was flash chromatographed using a graduated solvent system starting with chloroform and progressing to 30% methanol/chloroform to give 0.309 g of a tan solid. HRMS (FAB, glycerol) Calc. for (M+H).sup.+ : 514.2124. Found: 514.2137.

Part B: 2-(R,S)-(m-Toluenesulfonylamino)-3-�3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro�4,5!dec-2-en-8-yl!propionic acid bis trifluoroacetic acid salt

The intermediate of Part A (0.277 g, 0.46 mmol) was suspended in 6M hydrochloric acid and the mixture was stirred at room temperature for 2 d. The mixture was concentrated and the residue was purified by Prep HPLC as described in Example 514A, Part B to give 16 mg of the title compound. HRMS (FAB, glycerol) Calc. for (M+H).sup.+ : 500.1968. Found: 500.1956.

EXAMPLE 1552

(R,S)-(2-Piperidin-4-yl)ethyl-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro�4.4!non-2-ene-7,9-dione

This material was prepared using the procedures outlined in Example 189, giving the title compound; mp: 133.4.degree.-135.1.degree. C.; .sup.1 H NMR (400 MHz, CD.sub.3 OD, 55.degree. C.) .delta. 3.59 (t, J=6.8 Hz, 2H), 3.50 (d, J=17.7 Hz, 1H), 3.38 (bd, J=12.9 Hz, 2H), 3.18 (d, J=17.7 Hz, 1H), 2.98 (m, 4H), 2.85 (m, 2H), 2.50 (m, 1H, coincident with DMSO-d.sub.5), 2.45 (m, 2H), 2.31 (t, J=7.1 Hz, 2H), 2.00 (m, 2H), 1.98 (pentuplet, J=7.1 Hz, 2H), 1.40 (m, 2H).

EXAMPLE 1585A

N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-piperidinylmethyl)isoxazolin-5-(R,S)-yl-acetyl!-(S)-2 3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO) .delta. 8.5(1H, brd), 8.2(1H, brd), 8.0(1H, m), 7.4(1H, d), 4.7(1H, m), 3.9(3H, m), 3.6(1H, m), 3.25(2H, m), 3.1(3H, m), 2.9(2H, m), 2.7(1H, m), 2.4(2H, m), 2.2(3H, m), 1.8(2H, m), 1.7(1H, m), 1.5(2H, m), 1.3(4H, m), 0.9(3H, t) ppm; ESI mass spectrum 427.1 (M+H).sup.+ free base.

EXAMPLE 1603

Methyl N.sup.2 -n-butyloycarbonyl-N.sup.3 -�3-(4-piperidinylpropyl)-isoxazolin-5(R,S)-yl-acetyl!-(S)-2,3-diaminopropionate TFA salt

.sup.1 HNMR (CDCl.sub.3) .delta. 6.29(1H, brd), 4.9(lH, m), 4.45(1H, m), 4.05(2H, m), 3.78(3H, s), 3.68(1H, m), 3.5(3H, m), 3.1(1H, m), 2.96(2H, m), 2.78(1H, m), 2.55(2H, m), 2.36(2H, m), 1.95(2H, m), 1.6(6H, m), 1.5(2H, m), 1.35(5H, m), 0.94(3H, m) ppm; ESI mass spectrum 455 (M+H).sup.+ free base.

EXAMPLE 1609

Methyl N.sup.2 -p-toluenesulfonyl-N.sup.3 -�3- (4-piperidinylpropyl)isoxazolin-5-(R S)-yl-acetyl!-(S)-2,3-diaminopropionate TFA salt

.sup.1 HNMR (CDCl.sub.3) .delta.7.7(2H, d), 7.3(2H, d), 7.18(1H, m), 6.4(1H, m), 4.92(1H, m), 4.0(2H,m), 3.7(1H, m), 3.58(3H, d), 3.35(2H, m), 3.1(1H, m), 2.9(2H, m), 2.75(1H, m), 2.55(1H, m), 2.4(6H, m), 1.9(2H, m), 1.6(5H, m), 1.35(2H, m) ppm; ESI mass spectrum 509.3 (M+H).sup.+ free base.

EXAMPLE 1619

N.sup.2 -(2-methylphenylsulfonyl)-N-�3-(4-piperidinylethyl)isoxazolin-5-(R,S)-ylacetyl)-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO).delta.: 8.5(1H, m), 8.18(1H, m), 8.05(1H, m), 7.79(1H, d J=8.057 Hz), 7.51(1H, t, J=6.958 & 7.324 Hz), 7.37(2H, m), 4.65(1H, m), 3.83(1H, m), 3.4(1H, m), 3.27(3H, m), 3.07(1H, m), 2.84(2H, m), 2.68(1H, m), 2.59(3H, s), 2.4(1H, m), 2.32(3H, m), 2.08(1H, m), 1.83(2H, m), 1.45(3H, m), 1.26(2H, m) ppm; ESI mass spectrum 481.4 (M+H, 100).sup.+ free base.

EXAMPLE 1621

N.sup.2 -p-toluenesulfonyl-N.sup.3 -�3-(4-piperidinylethyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO) .delta. 7.73(2H, d), 7.35(2H, d), 4.85(2H, m), 4.05(1H, m), 3.63(1H, m), 3.2(2H, m), 3.0(4H, m), 2.6(1H, m), 2.4(3H, s), 2.42(2H, m), 2.0(2H, m), 1.7(1H, d), 1.6(3H, m), 1.4(3H, m) ppm; ESI mass spectrum 481 (M+H, 100).sup.+ free base.

EXAMPLE 1622

N.sup.2 -(2-bromophenylsulfonyl)-N.sup.3 -�3-(4-piperidinylethyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diamninpropionic acid TFA salt

.sup.1 HNMR (DMSO).delta.: 8.5(1H, brd), 8.2(1H, m), 8.1(1H, m), 7.95(1H, m), 7.8(1H, m), 7.5(2H, m), 4.7(1H, m), 3.9(1H, m), 3.4(1H, m), 3.25(2H, m), 3.2(1H, m), 3.0(1H, m), 2.8(2H, m), 2.7(1H, m), 2.4(2H, m), 2.3(2H, m), 2.2(1H, m), 1.8(2H, m), 1.5(2H, m), 1.2(2H, m) ppm; ESI mass spectrum 545.2 (M+H, 100).sup.+ free base.

EXAMPLE 1623

N.sup.2 -(3,5-dimethylisoxazoylsulfonyl)-N.sup.3 -�3-(4-Diperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO).delta.: 8.5(1H, d), 8.08(1H, m), 4.65(1H, m), 3.9(1H, m), 3.4(1H, m), 3.25(3H, m), 3.15(2H, m), 2.85(2H, m), 2.7(1H, m), 2.52(3H, s), 2.4(1H, m), 2.3(3H, m), 2.2(3H, m), 1.8(2H, brd, d), 1.45(3H, m), 1.25(2H, m) ppm; ESI mass spectrum 486.3 (M+H, 100).sup.+ free base.

EXAMPLE 1624

N.sup.2 -(3 4-dimethylthiazoylsulfonyl)-N.sup.3 -�3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO).delta.: 8.6(1H, d), 8.45(1H, brd), 8.1(1H, m), 4.65(1H, m), 3.9(1H, m), 3.5(4H, m), 3.05(2H, m), 2.9(3H, m), 2.6(3H, s), 2.45(3H, s), 2.4(5H, m), 1.8(2H, brd. d), 1.5(2H, m), 1.2(2H, m) ppm; ESI mass spectrum 502.4 (M+H, 100).sup.+ free base.

EXAMPLE 1625

N.sup.2 -n-butylsulfonyl-N.sup.3 -�3-(4-piperidinylethyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO) .delta. 8.5(1H, m), 8.2(2H, m), 7.55(1H, m), 4.7(1H, m), 3.9(1H, m), 3.4(1H, m), 3.2(3H, brd,d), 3.1(1H, m), 2.98(2H,m), 2.9(4H, m), 2.4(1H, d), 2.3(3H, m), 1.8(2H, brd, d),1.7(2H, m), 1.5(6H, m), 0.9(3H, t) ppm; ESI mass spectrum 447.3 (M+H, 100).sup.+ free base.

EXAMPLE 1627

N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-yl-acetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO) .delta. 8.5(1H, m), 8.2(2H, brd),7.3(1H, m),4.7(1H, m), 4.05(1H, m), 3.9(2H, t), 3.5(1H, m), 3.2(3H, brd,d), 3.0(1H, m), 2.8(2H, m), 2.7(1H, m), 2.4(1H, d), 2.25(3H, m), 1.8(2H, d), 1.6(6H, m), 1.4(7H, m), 0.9(3H, t) ppm; ESI mass spectrum 441.3 (M+H, 100).sup.+ free base.

EXAMPLE 1631

N.sup.2 -p-toluenesulfonyl-N.sup.3 -�3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (CD.sub.3 OD).delta.: 7.7(2H, m), 7.35(2H, m), 4.85(1H, m), 4.05(2H, m), 3.72(1H, m), 3.66(2H, m), 3.56(1H, m), 3.35(2H, m), 3.25(1H, m), 3.14(1H,m), 2.94(2H, m), 2.84(1H, m), 2.55(1H, m), 2.4(3H, m), 2.35(3H, m), 1.95(2H, m), 1.62(3H, m), 1.32(4H, m), ppm; ESI mass spectrum 495.3 (M+H).sup.+ free base.

EXAMPLE 1656

N.sup.2 -m-toluenesulfonyl-N.sup.3 -�3-(4-amidinopiperidinyl)isoxazolin-5-(R S)-ylacetyl!-(S)-2,3-diaminopropionic acid

M.P. 70.degree.-74.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta. 8.13 (m,2H), 7.58(m,2H), 7.44-7.38 (m, 5H), 4.74 (m,1H), 3.88-3.80 (m, 5H), 3.40 (m,1H), 3.14-2.99 (m,4H), 2.74 (m,2H), 2.37 (s,3H), 2.17 (dd, J=7.32, 14.28 Hz), 1.88 (d,J=13.18 Hz, 2H), 1.53 (q, J=11.35 Hz, 2H) ppm; High Res Mass Spectrum calculated (M+H).sup.+ 495.202580;found (M+H).sup.+ 495.200904.

EXAMPLE 1657

N.sup.2 -p-toluenesulfonyl-N.sup.3 -�3-(4-amidinopiperidinyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid

Part A: The isoxazoline acetic acid was prepared starting from 1-t-butylcarbamate-4-piperidine carboxaldehyde (Jacobs, R., et al, EP 532177) through methods previously described. .sup.1 H NMR (CDCl.sub.3) .delta. 4.94 (m, 1H), 4.18-4.05 (m, 2H), 3.18 (dd, J=10.25, 17.20 Hz, 1H), 2.90-2.67 (m, 4H), 2.63 (m, 2H), 1.87 (m, 2H), 1.56-1.45 (s, 9H), 1.46 (s, 9H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+NH.sub.4).sup.+ 330 (100%); IR (KBr) 3100, 1734, 1690, 1648, 1430, 1276, 1168, 758 cm.sup.-1.

Part B: The acid from Part A (360 mg, 1.2 mmol) was coupled with methyl L-N.sup.2 -p-toluylsulfonyl-diaminoproprionate using procedure described in Example 43D. The crude product was chromatographed on silica gel (2% MeOH/CH.sub.2 Cl.sub.2) to afford 270 mg (41%) of a white foam. M.P. 55.degree.-60.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta. 7.72 (d, J=8.06 Hz, 2H), 7.30 (d, J=8.06 Hz, 2H), 6.45 (m, 1H), 5.73 (dd, J=8.42, 16.11 Hz, 1H), 4.90 (m, 1H), 4.13 (m, 2H), 4.01 (m, 1H), 3.58 (s, 3H), 3.60-3.49 (m, 2H), 3.10 (m, 1H), 2.84-2.72 (m, 3H), 2.57 (m, 2H), 2.48 (m, 1H), 2.42 (s, 3H), 1.85 (d, 2H), 1.55-1.46 (brd m, 2H), 1.46 (s, 9H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+NH.sub.4).sup.+ 584 (100%); IR (KBr) brd 3300, 1746, 1688, 1428, 1238, 1164 cm.sup.-1.

Part C: To the product from Part B (230 mg, 0.41 mmol) was added 10 ml of 30% TFA/CH.sub.2 Cl.sub.2 and the mixture was stirred for 3 h. The solvents were removed in vacuo. To the residue was added 2 ml DMF, triethylamine (0.39 ml, 2.8 mmol), and bis-tertbutyloxycarbonyl-3,5-dimethylpyrazole-1-carboxamidine (165 mg, 0.49 mmol) (Kim, et al, Tet. Lett., 1993, 34, 7677) and the mixture was stirred for 24 h. The reaction was partitioned with EtOAc/water. The organic layer was washed successively with water, brine and dried (MgSO.sub.4). Chromatography on silica gel (2% MeOH/CH.sub.2 Cl.sub.2) afforded 203 mg (71%) of a white foam. M.P. 69.degree.-75.degree. C.; .sup.1 H NMR (CDCl3) .delta. 10.18 (brd m, 1H), 7.72 (d, J=8.05 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 6.40 (m,1H), 5.65 (m, 1H), 4.87 (m, 1H), 4.30 (brd, 1H), 4.05 (brd, 1H), 3.60-3.51 (s+m, 5H), 3.09 (m, 3H), 2.78 (m, 3H), 2.42 (s, 3H), 1.89 (m, 2H), 1.73 (m, 2H), 1.63 (brd m, 2H), 1.49 (s, 18H) ppm; Mass Spectrum (ESI) m/z (M+H).sup.+ 709.5 (100%); IR (KBr) 3300-2800, 2210, 1742, 1660, 1600, 1546, 1446, 1332, 1162, 1092 cm.sup.-1.

Part D: To the product from Part C (160 mg, 0.23 mmol) was added 6 ml of 1:1 MeOH/water and lithium hydroxide (28 mg, 0.67 mmol). The mixture was stirred for 18 h and the solvents were removed in vacuo. The residue was taken up in water and acidified with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO.sub.4), filtered and concentrated to afford 118 mg (76%) of the acid. To the acid was added 10 ml 30% TFA/CH.sub.2 Cl.sub.2 and the mixture was stirred 24 h. The solvents were removed and the TFA salt was purified by HPLC to afford 20 mg product. M.P. 134.degree.-140.degree. C.; .sup.1 HNMR (DMSO-d.sub.6) .delta. 7.9 (q,1H), 7.66 (d,j=8.06 Hz, 2H), 7.46 (s, 3H), 7.36 (d,j=8.06 Hz, 2H), 4.72 (m,1H), 3.80 (d, j=13.18 Hz, 2H) 3.61 (m,1H), 3.41-3.18 (m, 5H), 3.13-2.99 (m,3H), 2.75 (m 2H), 2.36 (s,3H), 2.22 (m, 1H), 1.88 (d, j=12.8 Hz, 2H), 1.53 (m, 2H) ppm; Mass spectrum (ESI) m/z 495.2 (100%), high res Mass Spectrum (M+H).sup.+ calculated 495.20258, found 495.202476.

EXAMPLE 1673

N.sup.2 -D-toluenesulfonyl-N.sup.3 -�3-(4-amidinopiperidinylmethyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (DMSO).delta.: 8.1(2H, m), 7.65(2H, d), 7.35(2H, d), 4.7(1H, m), 3.8(3H, m), 3.4(2H, m), 3.1(1H, m), 3.0(3H, m), 2.7(1H, m), 2.4(1H, m), 2.35(3H, s), 2.25(1H, m), 2.2(3H, m),1.85(1H, m),1.7(2H, m), 1.6(1H, m), 1.2(3H, m) ppm; ESI mass spectrum 509.4 (M+H, 100).sup.+ free base.

EXAMPLE 1704

N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(quanidinopropul)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic acid TFA salt

Part A: The title compound was prepared following the �3+2! cycloaddition methodology employed for example 4 from the readily accessible Boc-aminopropylchlorooxime (obtained from a sequence of steps from commerical (Aldrich) aminopropanol (aldehyde obtained via Moffat et. al. J.C.S. Perk. Trans. 1. 1991, 5, 1041-1051)) and butylvinyl ester. LiOH saponification in methanol:water (9:1), then afforded the desired acetic acid compound in 90% yield. .sup.1 HNMR (CDCl.sub.3) .delta.: 4.90(m, 1H), 4.70(brd, s, 1H), 3.08(m, 3H), 2.68(m, 2H), 2.57(dd, 1H), 2.34(t,2H), 1.75(m, 2H), 1.41(s, 9H) ppm; ESI mass spectrum 287(M+H, 100).

Part B: The product from part A was then coupled to methyl N.sup.2 -n-butyloxycarbonyl-(S)-2,3-diaminopropionate via the procedure used in example 4, to obtain Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(Boc-aminopropyl)isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionate in 50% yeild. Treatment with trifluoroaceticacid in dichloromethane, evaporation of solvent then afforded the anilino intermediate as the TFA salt. Standard guanidine formation techniques then afforded the di-Bocguanidinopropyl analog in 90% yield. Removal of the Boc-protecting groups with TFA afforded example 601 as the TFA salt. Alternatively, saponification of the methyl ester followed by removal of the Boc-protecting groups with TFA also afforded the desired product as the TFA salt in 80% overall yield. .sup.1 H NMR (CD.sub.3 OD) .delta.: 4.93(m, 1H), 4.29(brd.m, 1H), 4.02(t, 2H), 3.65(m, 1H), 3.32(m, 1H), 3.21(m, 2H), 3.09(dd, J=10.2 & 17.6 Hz, 1H), 2.79(dd, J=7.32 & 17.1 Hz, 1H), 2.52(dd, J=2.2& 8.8 Hz, 1H), 1.84(m, 2H), 2.39(m, 3H), 1.58(m, 2H), 1.36(m, 2H), 0.9(t,3H,) ppm; HR MS calcd. for ESI mass spectrum 529(M+H, 100) for free base.

EXAMPLE 1756

N.sup.2 -p-toluylsulfonyl-N.sup.3 -�3-(4-piperidinylmethylaminocarbonyl)-isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminopropionic Acid

Part A: To a mixture of tert-butyl vinylacetic acid (11.2 g, 0.079 mol) and ethylchlorooximidoacetate (11.37 g, 0.075 mol,Aldrich) in a mixture of 2:1 THF/water at 0.degree. C. was added sodium bicarbonate (19.9 g, 0.237 mol). The reaction was stirred for 3 d at room temperature, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried with MgSO.sub.4. The crude oil was chromatographed on silica gel (7:1 hexanes/EtOAc) to afford 7.46 g (39%) of product as a colorless oil; .sup.1 H NMR (CDCl.sub.3) .delta. 5.15 (m, 1H), 4.39 (q, J=7.32 Hz, 2H),3.43 (dd,J=10.99, 17.58 Hz, 1H), 3.03 (dd, J=7.69, 17.58 Hz, 1H), 2.81 (dd,J=5.86, 16.11 Hz, 1H), 2.59 (dd,J=7.69, 16.11 Hz, 1H),1.46 (s, 9H), 1.39 (t,J=7.32 Hz, 3H); Mass Spectrum (NH.sub.3 --CI) m/z (M+H).sup.+ 258 (12%), (M+NH.sub.4).sup.+ 275 (100%).

Part B: The ethyl ester (3 g, 0.012 mol) from Part 1A was selectively hydrolyzed with LiOH (0.64 g, 0.015 mol) in 1.5:1 methanol/water at 0.degree. C. for 1.5 h. The methanol was removed in vacuo. The aqueous residue was acidified with 10% citric acid and extracted with EtOAc and dried with MgSO.sub.4. The crude solid was recrystallized with CH.sub.2 Cl.sub.2 /hexanes to afford 2 g (75%) white crystals. mp 83.degree.-86.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta. 5.23 (m, 1H), 3.44 (dd, J=10.98, 17.58 Hz, 1H), 3.05 (dd, J=8.05, 17.95 Hz, 1H), 2.82 (dd, J=5.85, 16.11 Hz, 1H), 2.64 (dd, J=7.32, 16.11 Hz, 1H), 1,46 (s, 9H) ppm; Mass spectrum (NH.sub.3 --CI) m/z (M+NH.sub.4).sup.+ 247 (90%).

Part C: 4-Aminomethyl piperidine (3.8 g, 0.034 mol, Aldrich) was selectively protected in 68% yield with carbobenzoxyimidazole using the method of Sharma, et al. (J. Med. Chem. 1989, 32, 357). To the crude 4-Cbz-aminomethyl piperidine (3 g, 0.012 mol) in 30 ml dioxane at 0.degree. C. was added 13 ml of 1N sodium hydroxide and di-t-butyl dicarbonate (2.7 g, 0.013 mol). The reaction was stirred at room temperature for 48 h. The dioxane was removed in vacuo and the residue was suspended in EtOAc and washed successively with 10% citric acid, sat'd NaHCO.sub.3, brine and dried (MgSO.sub.4). Recrystallization with CH.sub.2 Cl.sub.2 /hexane afforded 1 g of white crystals (24%) mp 91.degree.-96.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta. 7.32 (s, 5H), 5.10(s, 2H), 4.60 (t, 1H), 4.20 (brd, 2H), 3.0 (brd, 2H), 2.75 (brd, 2H), 1.65 (d, 2H), 1.45 (s, 9H), 1.12 (brd, 2H) ppm; Mass spectrum (NH.sub.3 --CI) m/z (M+H)+ 349 (31%), (M+H-56)+ 293 (100%); IR (KBr) 1698, 1530 cm.sup.-1 ; Analysis for C19H28N2O4 calc'd C:65.49, H:8.10, N:8.04; found C:65.78, H:7.82, N:8.06.

Part D: To the compound from part C (94 mg, 2.7 mmol) was added 50 ml EtOH and 100 mg of 10% Pd/C and the mixture was hydrogenated at 40 PSI for 18 h. Filtration and removal of the solvent afforded 569 mg (98%) solid. mp 84.degree.-88.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta. 4.70 (brd, 1H), 3.10 (d, 2H), 3.0 (t, 2H), 2.95 (brd, 2H), 2.64 (t, 2H), 1.70 (d, 2H), 1.46 (s, 9H), 1.20 (m, 2H) ppm; Mass spectrum (NH.sub.3 --CI) m/z (M+H).sup.+ 215 (100%); IR (KBr) 2972-2800, 1694 cm.sup.-1.

Part E: To the acid from Part B (360 mg, 1.6 mmol) in 5 ml EtOAc was added triethylamine (0.67 ml, 4.80 mmol) followed by TBTU (560 mg, 1.73 mmol). After 15 minutes the amine from Part D (370 mg, 1.7 mmol) was added and the reaction was stirred for 24 h. The reaction mixture was washed successively with 10% citric acid, water, sat'd NaHCO.sub.3 , brine and dried (MgSO.sub.4). The residue was chromatogrphed on silica gel (3:2 Hexanes/EtOAc) to afford 0.41 g (61%) white foam. .sup.1 H NMR (CDCl.sub.3) .delta. 5.04 (m, 1H), 4.63 (d, J=13.18 Hz, 2H), 4.53 (d,J=13.18 Hz, 1H), 3.52-3.38 (m, 1H), 3.15-2.99 (m, 4H), 2.77 (m, 2H), 2.59-2.49 (m, 5H),1.78 (t, J=10.0 Hz 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.25 (m, 2H); Mass Spectrum (NH.sub.3 --CI) m/z (M+H)+ 426.3 (29%), (M+H-56)+ 370.2 (43%); IR (KBr) 2976, 2930, 1714, 1632, 1592, 1522, 1476, 1452, 1392, 1366, 1168 cm.sup.-1.

Part F: To the product of Part E (380 mg, 0.89 mmol) was added 10 ml of 30% TFA/CH.sub.2 Cl.sub.2 and stirred for 4 h. The solvents were removed and 10 ml dioxane was added. The mixture was cooled to 0.degree. C. and 2 ml of 1N NaOH was added followed by di-t-butyldicarbonate (0.22 g, 0.98 mmol). The reaction was stirred for 48 h at room temperature. The reaction was concentrated and partitioned with EtOAc and water. The aqueous layer was acidified with 10% citric acid, extracted with EtOAc and dried (MgSO.sub.4). The crude residue was chromatographed on silica gel (10% MeOH/CH.sub.2 Cl.sub.2) to afford 0.23 g (69%) of a white foam. mp 159.degree.-165.degree. C. .sup.1 H NMR (DMSO-d.sub.6) .delta. 6.95 (t, J=5.86 Hz, 1H), 4.87 (m, 1H), 4.33 (d, J=13.18 Hz, 1H), 4.09 (d, J=13.90 Hz, 1H), 3.31 (m, 1H), 3.07 (t, J=12.82 Hz, 1H), 2.99 (dd, J=3.66, 8.05 Hz, 1H), 2.93 (dd, J=3.66, 7.70 Hz, 1H), 2.82 (t, J=5.86 Hz, 2H), 2.69 (t, 12.82 Hz, 1H), 2.39 (m, 1H), 2.27 (dd, J=7.69, 14.6 Hz, 1H), 1.67-1.60 (m, 3H), 1.37 (s, 9H), 1.04 (t, J=13.5 Hz, 1H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+NH.sub.4)+ 387 (100%); IR (KBr) 3352, 1692, 1630, 1588, 1518, 1448, 1210, 1176, 1140 cm.sup.-1.

Part G: The product of Part F (217 mg, 0.59 mmol) was coupled with methyl L-N.sup.2 -p-toluylsulfonyl-diaminoproprionate according to procedure in Example 43D. The crude material was chromatographed on silica gel (2% MeOH/CH.sub.2 Cl.sub.2) to afford 230 mg (63%) foam. .sup.1 H NMR (CDCl.sub.3) .delta.7.72 (d, 2H), 7.30 (d, 2H), 6.40-6.32 (m, 1H), 5.1 (m, 1H), 4.70 (brd, 2H), 4.50 (d, 1H), 3.99 (brd, 1H), 3.65 (s, 3H), 3.50 (m, 2H), 3.15-2.99 (m, 3H), 2.85-2.55 (m 2H), 2.45 (s, 3H), 1.85 (brd, 4H), 1.46 (s, 9H), 1.29 (m, 2H) ppm; Mass Spectrum (ESI) m/z (M+H).sup.+ 624.5 (72%), (M+H-56).sup.+ 568.3 (98%).

Part H: The product of Part G (200 mg, 0.32 mmol) was hydrolyzed with lithium hydroxide (20 mg, 0.48 mmol) in 1:1 MeOH/water for 48 h. The solvents were removed in vacuo and the residue dissolved in water, acidified with 10% citric acid, extracted with EtOAc and dried (MgSO.sub.4). The crude acid was treated with 15 ml of 30% TFA/CH.sub.2 Cl.sub.2 for 24 h. The crude TFA salt was purified via HPLC to give 21 mg (11%) foamy solid. .sup.1 HNMR (DMSO-d.sub.6) .delta. 8.15 (m,1H), 7.73 (m,1H), 7.63 (d,j=8.06 Hz, 2H), 7.35 (d,j=8.05 Hz, 2H), 4.90 (m,1H), 4.37 (d,j=13.5 Hz, 2H), 4.14 (d,j=2 H, j=10.9 Hz), 3.83 (q,j=9 Hz,1H), 3.35 (m,2H), 3.12-2.90 (m,3H), 2.74 (m, 2H), 2.33 (s,3H), 2.50-2.20 (m, 3H), 1.90-1.70 (m,4H), 1.35(m,2H) ppm; High Res Mass Spectrum (M+H).sup.+ calculated 510.202246, found 510.203464.

EXAMPLE 1769

N.sup.2 -p-toluenesulfonyl-N.sup.3 -�3-(N-(4-piperidinylmethyl)-N-(methyl)aminocarbonyl)-isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminoproprionic Acid Trifluoroacetic Acid Salt

Part A: To 4-tertButyloxycarbonyl-piperidinyl-methyl amine described previously (1.93 g, 0.009 mol) in 20 ml CH.sub.2 Cl.sub.2 at 0.degree. C. was added pyridine (1.1 ml, 0.014 mol) followed by slow addition of trifluoroacetic anhydride (1.4 ml, 0.009 mol). The reaction was stirred at 0.degree. C. for 1 h, then it was diluted with CH.sub.2 Cl.sub.2 washed successively with 10% citric acid, water, sat'd NaHCO.sub.3, brine and dried (MgSO.sub.4). Recrystallization from CH.sub.2 Cl.sub.2 /Hexanes afforded 2.4 g (86%) of a bright yellow solid. mp 123.degree.-125.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta. 4.74 (m, 1H), 4.56 (d, J=13 Hz, 1H), 4.0 (d, J=12 Hz, 1H), 3.14 (m, 3H), 2.75 (t, J=13 Hz,1H), 1.82 (d, 3H), 1.45 (s, 9H) 1.28 (m, 2H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+NH.sub.4).sup.+ 328 (100%), (M+NH.sub.4 -56).sup.+ 272.1 (100%); IR (KBr) 3354, 1686, 1526, 1200, 1140 cm.sup.-1.

Part B: To the product of Part A (400 mg, 1.29 mmol) in 2 ml DMF was added NaH (62 mg, 1.6 mmol) After 1 h, methyl iodide (0.1 ml, 1.6 mmol) was added and the reaction was immersed in a 60.degree. C. oil bath for 24 h. The reaction was cooled and partioned between EtOAc and water. The organic layer was washed with water, brine and dried (MgSO.sub.4). The reaction had not gone to completion and was resubjected to the above conditions and after work up afforded 322 mg (77%) yellow oil. The crude trifluoroacetate was placed in 20 ml of 1:1 MeOH/water and K.sub.2 CO.sub.3 (150 mg, 1.1 mmol) was added and the reaction was stirred for 36 h. The solvents were removed in vacuo and the residue partioned with EtOAc/water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and dried (MgSO.sub.4), filtered and concentrated to yield 194 mg (89%) oil. .sup.1 H NMR (CDCl.sub.3) .delta. 3.15 (m, 4H), 2.85 (s, 3H), 2.80 (brd s, 1H), 2.61 (t, J=12 Hz, 2H), 1.63 (d, J=10.6 Hz, 2H), 1.45 (s, 9H), 1.25 (m, 2H), 0.87 (m, 1H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+H).sup.+ 229 (100%), (M+NH.sub.4).sup.+ 246 (15%); IR (KBr) 2924, 1696, 1160 cm.sup.-1.

Part C: The product of Part B (173 mg, 0.76 mmol) was coupled with the acid (from Part B previous example) according to procedure in Example 43D to yield 177 mg (54%) yellow oil. .sup.1 H NMR (CDCl.sub.3) .delta. 5.02 (m, 1H), 4.59-4.50 (brd m, 2H), 3.48 (dd, J=10.62, 17.58 Hz, 1H), 3.15-3.02 (m, 4H), 2.86 (s, 3H), 2.77 (m, 2H), 2.59 (m, 1H), 2.0-1.91 (brd m, 1H), 1.73 (t, J=11.72 Hz, 2H), 1.46 (s, 18H), 1.28 (m, 2H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+H).sup.+ 440.2 (100%), (M+NH.sub.4).sup.+ 457.3 (23%), (M+H-56).sup.+ 384.2 (73%); IR (KBr) 2976, 2932, 1730, 1694, 1634, 1162 cm-.sup.1.

Part D: The product of Part C (170 mg, 0.387 mmol) was deprotected and selectively reprotected as in Part 1F to afford a yellow foam. .sup.1 H NMR (CDCl.sub.3) .delta. 5.10 (m, 1H), 4.60 (m, 1H), 4.50 (m, 1H), 3.50 (m, 1H), 3.12 (m, 4H), 2.80 (s, 3H), 2.78 (m, 1H), 2.70 (m, 2H), 1.90 (brd m, 1H), 1.75 (brd m, 2 H), 1.45 (s, 9H), 1.25 (brd m, 2H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+NH.sub.4).sup.+ 401 (100%).

Part E: The product of Part D (148 mg, 0.386 mmol) was coupled with methyl L-N.sup.2 -p-toluylsulfonyl-diaminoproprionate according to the procedure in Example 43D. The crude material was chromatographed on silica gel (3% MeOH/CH.sub.2 Cl.sub.2) to afford 230 mg clear glass containing minor impurities. .sup.1 H NMR (CDCl.sub.3) .delta. 7.72 (d,2H), 7.33 (d,2H), 6.35 (m, 1H), 5.10 (m,1H), 4.61 (brd m, 1H), 4.45 (brd m, 1H), 3.97 (brd m, 1H), 3.63-3.54 (s+m, 5H), 3.48-3.30 (m, 2H), 3.15 (brd m,4H), 2.85 (s, 3H), 2.75-2.5 (m, 4H), 2.45 (s, 3H), 1.78 (brd m, 2H), 1.46 (s,9H), 1.30 (m, 2H) ppm; Mass Spectrum (ESI) m/z (M+H).sup.+ 638.5 (100%).

Part F: The product of Part E (230 mg, 0.36 mmol) was subjected to hydrolysis and deprotection and purification by HPLC to afford 134 mg (58%) of a white powder. mp 69.degree.-72.degree. C.; .sup.1 HNMR (DMSO-d.sub.6) .delta. 8.35 (brd m, 2H), 8.10 (brd m, 2H), 7.65 (d, J=6.96 Hz, 2H), 7.35 (d, j=8.05 Hz, 2H), 4.83 (m,1H), 4.36 (d,j=13.6 Hz, 1H), 4.12 (d,j=10 Hz, 1H), 4.0-3.5 (m,6H), 3.35 (m,1H), 3.14 (t,j=10.98 Hz, 1H),2.83 (m,1H), 2.59 (s, 3H), 2.55 (m,1H), 2.36 (s, 3H), 2.35 (m,1H), 2.0 (brd m,1H), 1.80-1.74 (brd m, 2H), 1.18 (m, 2H) ppm; Mass Specturm (ESI) m/z (m+H).sup.+ 524.4 (100%); IR (KBr) 3300-2800 brd, 1736, 1632, 1202, 1162 cm.sup.-1.

EXAMPLE 1774

N.sup.2 -p-toluylsulfonyl-N.sup.3 -�3-(4-piperidinylaminocarbonyl)-isoxazolin-5-(R,S)-ylacetyl!-(S)-2,3-diaminoproprionate

Part A: The acid (from Part B described previously, 225 mg, 0.98 mmol) was coupled with 1-tertbutyloxycarbonyl-4-aminopiperidine (Obase, H; et al, J.Het. Chem. 1983, 20, 565) as described in Example 43D. A white foam was obtained in 78% yield. .sup.1 H NMR (CDCl.sub.3) .delta. 6.50 (d, J=8.05 Hz, 1H), 5.13 (m, 1H), 3.43 (dd, J=10.62, 17.95 Hz, 1H), 3.04 (dd, J=7.69, 18.3 Hz, 1H), 2.87 (t, J=12.45 Hz, 2H), 2.76 (dd, J=6.22, 16.11 Hz, 1H), 2.57 (dd, J=6.95, 16.11 Hz, 1H), 1.94 (d, J=9.88 Hz, 2H), 1.46 (s,18H), 1.41 (m, 2H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+H).sup.+ 412.2 (69%), (M+NH.sub.4).sup.+ 429.3 (50%), (M+NH.sub.4 -56).sup.+ 373.2 (100%); IR (KBr) 3424, 2866, 1728, 1692, 1536, 1426, 1368, 1238, 1162 cm.sup.-1.

Part B: The product of Part A (300 mg, 0.73 mmol) was deprotected with TFA and selectively reprotected with di-t-butyldicarbonate to afford 270 mg of a white foam. .sup.1 H NMR (CDCl.sub.3) .delta. 6.64 (d, J=8.05 Hz, 1H), 5.2 (m, 1H), 4.10-3.95 (m, 3H), 3.47 (dd, J=10.99, 17.96 Hz, 1H), 3.08 (dd, J=7.69, 17.95 Hz, 1H), 2.89 (t+dd, 3H), 2.72 (dd, J=6.95, 16.11 Hz, 1H), 1.94 (d, J=12.82 Hz, 2H), 1.46 (s, 9H), 1.46 (brd m, 2H) ppm; Mass Spectrum (NH.sub.3 --CI) m/z (M+NH.sub.4).sup.+ 373 (100%).

Part C: The product of Part B (260 mg, 0.73 mmol) was coupled with methyl L-N.sup.2 -p-toluylsulfonyl-diaminoproprionate according to the procedure in Example 43D. The crude foam was chromatographed on silica gel (2% MeOH/CH.sub.2 Cl.sub.2) to afford 289 mg (65%) of a white foam. .sup.1 H NMR (CDCl.sub.3) .delta. 7.71 (d, J=8.06 Hz, 2H), 7.31 (d, J=8.42 Hz, 2H), 6.65 (dd, J=6.59 Hz, 1H), 6.36 (t, J=5.86 Hz, 1H), 5.15 (m, 1H), 4.10-3.96 (m, 4H), 3.63-3.56 (s+m, 5H), 3.45-3.35 (m, 1H), 3.09 (m,1H), 2.85 (t, J=12.45 Hz, 2H), 2.62 (m, 2H), 2.43 (s, 3H), 1.94 (d, J=12.82 Hz, 2H), 1.45 (s+m, 9+2H) ppm; Mass Spectrum (ESI) m/z (M+H).sup.+ 610.3 (100%).

Part D: The product of Part C (289 mg, 0.47 mmol) was subjected to hydrolysis and deprotection and purification as previously described to afford 224 mg (78%) white powder. mp 88.degree.-91.degree. C.; .sup.1 HNMR (DMSO-d.sub.6) .delta. 8.66-8.57 (d+m, j=7.69 Hz, 2H), 8.30 (brd m, 1H), 8.07 (m, 2H), 7.64 (d,j=8.06 Hz, 2H), 7.35 (d,j=8.06 Hz, 2H), 4.94 (m,1H), 3.96 (m, 1H), 3.87 (q,j=6.95 Hz, 1H), 3.30-3.24 (m,4H), 3.08-2.89 (m,4H), 2.46 (m,1H), 2.37 (s,3H), 2.37 (m,1H), 1.87 (d,j=10.9 Hz,2H), 1.73 (q,j=10.6 Hz,2H) ppm; Mass Spectrum (ESI) m/z (M+H).sup.+ 496.3 (100%); IR (KBr) 3300-2800 brd, 1736, 1666, 1544, 1162 cm.sup.-1.

EXAMPLE 1945

N.sup.2 -3-Methylphenylsulfonyl-N.sup.3 -�3-�2-(piperidin-4-yl)ethyl!isoxazolin-5(R,S)-ylacetyl)-(S)-2,3-diaminopropionic Acid TFA Salt

Part A: Methyl (3-(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetate

To a solution of Methyl Vinylacetate 352 g, 0.35 mol) in CH.sub.2 Cl.sub.2 (175 mL) was added a 5% solution of sodium hypochlorite (210 mL, 0.15 mol). The mixture was stirred rapidly at room temperature and a solution of (3-N-t-butyloxycarbonylpiperidin-4-yl)propanal oxime (Example 189, Part B, 17.60 g, 68.6 mmol) in CH.sub.2 Cl.sub.2 (50 mL) was added over 15 h. The mixture was diluted with water and CH.sub.2 Cl.sub.2, the layers separated, and the aqueous washed with CH.sub.2 Cl.sub.2. The combined organic was dried (MgSO.sub.4), concentrated in vacuo, and the oily residue purified using flash chromatography (10-50% EtOAc/hexanes step gradient), giving 10.35 g (42%) of the desired isoxazoline as a golden oil; Anal. Calcd for C.sub.18 H.sub.30 N.sub.2 O.sub.5 : C, 61.00; H, 8.53; N, 7.90. Found: C, 61.07; H, 8.50; N, 7.80.

Part B: (3-(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetic Acid

To a solution of methyl (3-(2-N-t-butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetate (10.35 g, 29.20 mmol) in THF (100 mL) was added 0.5M LiOH (80 mL, 40 mmol). The resulting solution was stirred at room temperature overnight (18 h) and then concentrated in vacuo to one-half volume.

The pH was adjusted to 4, and the resulting cloudy solution washed with CH.sub.2 Cl.sub.2 (4.times.30 mL). The combined organic was dried (MgSO.sub.4), concentrated in vacuo, and placed under vacuum until constant weight was achieved, affording 9.74 g (98%) of the desired acid; Anal. Calcd for C.sub.17 H.sub.28 N.sub.2 O.sub.5 : C, 59.98; H, 8.29; N, 8.23. Found: C, 60.19; H, 8.42; N, 7.87.

Part C: t-Butyl N.sup.2 -3-Methylphenylsulfonyl-N.sup.3 -(3-(N-t-butyloxycarbonyl-2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionate

To a solution of (3-(2-N-t-butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetic acid (165 mg, 0.485 mmol) and t-butyl N.sup.2 -3-methylphenylsulfonyl-(S)-2,3-diaminopropionate hydrochloride (170 mg, 0.485 mmol) in DMF (5 mL) was added Et.sub.3 N (0.2 mL, 1.4 mmol) followed by TBTU (160 mg, 0.498 mmol). The resulting mixture was stirred for 4 h at room temperature, then was diluted with EtOAc (50 mL). It was washed with water (4.times.20 mL), sat. NaHCO.sub.3 (30 mL), sat. NaCl and dried (MgSO.sub.4). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 271 mg (88%) of the desired amide; MS (ESI, e/z, relative intensity): 637 (M+H).sup.+, 20%, 537 (M+H--C.sub.4 H.sub.9 CO.sub.2).sup.+, 51%.

Part D: N.sup.2 -3-Methylphenylsulfonyl-N.sup.3 -�(3-(2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionic Acid TFA Salt

To a solution of t-butyl N.sup.2 -3-methylphenylsulfonyl-N.sup.3 -�(3-(N-t-butyloxycarbonyl-2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionate (261 mg, 0.410 mmol) in CH.sub.2 Cl.sub.2 (2 mL) was added TFA (2 mL, 26 mmol). After 2 h at room temperature, the solution was concentrated in vacuo and the residue triturated with ether (3.times.5 mL). The resulting white powder was purified using reverse phase HPLC, giving 202 mg (83%) of the desired piperidine; MS (ESI, e/z, relative intensity): 481 (M+H).sup.+, 100%.

EXAMPLE 2103

N.sup.2 -(3,5-dimethylisoxazole-4-sulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionate Trifluoroacetate Salt

Part A: Methyl N.sup.2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N.sup.3 �3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5 (R,S)-ylacetyl!-(S)-2,3-diaminopropionate

Methyl N.sup.2 -(3,5-dimethylisoxazole-4-sulfonyl)-N.sup.3 -Boc-(S)-2,3-diaminopropionate (1.40 mmole) was stirred with 4M HCl/dioxane (10 mL, 40 mmol) at 25.degree. C. After 2.5 h, the volatiles were removed in vacuo, and residual HCl/dioxane was removed by repeated addition of toluene and evaporation. To the residue was added 3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5(R,S) -ylacetic acid (510 mg, 1.47 mmol), TBTU (480 mg, 1.50 mmole) and DMF (15mL). Triethylamine (0.830 mL, 603 mg, 5.97 mmole) was added and the reaction mixture was stirred at 25.degree. C. overnight. The mixture was diluted with water (70 mL) extracted with 3.times. ethyl acetate. The combined organic extracts were washed with 2.times. water, 5% pH 4 potassium hydrogen phthalate buffer (25 mL), 5% aqueous sodium bicarbonate (25 mL) and brine. After drying over MgSO4, removal of volatiles and purification by flash chromatography (ethyl acetate) provided 0.598 g of the desired product in 96% purity, as assessed by analytical HPLC (4.6 mm.times.25 cm C18 reverse phase, 1 mL/min, 0.05% TFA/10-90% AcCN/water gradient over 20 min, product at 12.9 min); .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 7.84 (m, 2H), 7.63 (m, 2H), 6.52 (bm, 1H), 6.07 (bd, 1H), 5.11 (bm, 1H), 4.02 (bm, 1H), 3.66/3.67 (2s, 3H, diastereomers, methyl ester), 3.67-3.45 (m, 3H), 3.15 (m, 1H), 2.60/2.61 (2s, 3H, diastereomers, isoxazole methyl), 2.76-2.55 (m, 2H), 2.38/2.41 (2s, 3H, diastereomers, isoxazole methyl), 1.56 (s, 9H, t-Bu); MS (ESI): m/e 607.2 (M+H).sup.+.

Part B: N.sup.2 -(3,5-Dimethylisoxazole-4-sulfonyl)-�3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diaminopropionate

To a solution of 200 mg (0.329 mmole) of methyl N.sup.2 -(3,5-dimethylisoxazole-4-sulfonyl)-N.sup.3 �3-(4-N-t-butoxycarbonyl-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diamino-propionate in 15 mL of THF/MeOH/water 1:1:1 was added 138 mg (3.29 mmole) of LiOH. After 2 h, analytical HPLC (see conditions in Part A, product at 11.7 min) indicated the reaction was 97% complete. Removal of volatiles and purification by flash chromatography provided 0.164 g 91% pure (see HPLC conditions in Part A) of the desired product as a mixture of free acid and lithium salt (as indicated by 0.55% Li by elemental analysis); .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.02 (d, J=8.0 Hz, 2H), 7.96 (m, 1H), 7.75 (dd, J=1.5, 8.4 Hz, 2H), 5.02 (m, 1H), 3.58-3.08 (m, 5H), 2.55 (s, 3H, isoxazole methyl), 2.60-2.37 (m, 2H), 2.34 (s, 3H, isoxazole methyl), 1.45 (s, 9H, t-Bu); MS (ESI): m/e 593.3 (M+H).sup.+, m/e 493.2 (M-Boc).sup.+.

Part C: N.sup.2 -(3.5-dimethylisoxazole-4-sulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R,S) -ylacetyl!-(S)-2,3-diaminopropionate Trifluoroacetate Salt

A solution of 137 mg (0.231 mmole) of N.sup.2 -(3,5-dimethylisoxazole-4-sulfonyl)-N.sup.3 �3-(4-N-t-butoxycarbonyl-amidinophenyl)isoxazolin-5(R,S)-ylacetyl!-(S)-2,3-diamino-propionate in 4 mL of CH.sub.2 Cl.sub.2 and 2 mL of TFA was stirred for 4 h, then diluted with 60 mL of ether. The precipitate was dried to give 0.103 g of the desired product as a white solid, which was determined to be 96% pure by analytical HPLC (see HPLC conditions in Part A); .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.79 (bs, 1H), 9.72 (bs, 1H), 9.29 (bs, 2H), 8.25 (bs, 1H), 8.16 (m, 1H), 7.87 (s, 4H), 5.02 (bm, 1H), 3.78 (bs, 1H), 3.60-3.08 (m, 4H), 2.54 (s, 3H, isoxazole methyl), 2.34 (s, 3H, isoxazole methyl), 2.62-2.34 (m, 2H); MS (ESI): m/e 493.3 (M+H).sup.+ ; HRMS (FAB): m/e calculated for C.sub.20 H.sub.25 N.sub.6 O.sub.7 S (M+H).sup.+ 493.150544; found 493.148681.

EXAMPLE 2103a

N.sup.2 -(3,5-dimethylisoxazole-4-sulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R) -ylacetyl!-(S)-2,3-diaminopropionate Trifluoroacetate Salt (Alternative Hydrolysis Procedure)

Methyl N.sup.2 -(3,5-dimethylisoxazole-4-sulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R) -ylacetyl!-(S)-2,3-diaminopropionate hydrochloride salt (Part B, replacing ammonium acetate with ammonium chloride, 1.3 g, 2.6 mmol) was stirred in 6N HCl (150 ml) at room temperature for 20 hours. Solvent was evaporated under reduced pressure to give the crude hydrochloride salt as a white solid (1.1 g, 87%). Purification of 0.17 g crude product by preparative HPLC (Vydac C18 reverse phase column; 2.times.25 cm; 10 ml/min flow rate; 254 nM; gradient: from 100% H.sub.2 O with 0.05% TFA to 20% H.sub.2 O and 80% CH.sub.3 CN with 0.05% TFA in 50 minutes) yielded 0.12 g (70.6%) of the title compound as a white powder. Chiral HPLC analysis (SFC, Chiralcel OD; 0.46.times.25 cm; 30.degree. C.; 2.0 ml/min flow rate; 0.1% TFA/22% MeOH/78% CO.sub.2 ; 280 nM; 150 atm) showed >99% d.e. with respect to the (S,S)-diastereomer and >98% chemical purity. MS (ESI): m/e 493 (M+H).sup.+. HRMS (FAB): m/e calculated for C.sub.20 H.sub.24 N.sub.6 O.sub.7 S (M+H).sup.+ 493.150649; Found 493.150544.

EXAMPLE 2103b

N.sup.2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N.sup.3 -�3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionic Acid Methanesulfonate Salt

Part A: Methyl N.sup.2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N.sup.3 �3-(4-(cyanophenyl)isoxazolin-5(R) -ylacetyl!-(S)-2,3-diaminopropionate

To a suspension of 3-(4-cyanophenyl)isoxazolin-5(R)-ylacetic acid (252 mg, 0.725 mmol), methyl N.sup.2 -(3,5-dimethylisoxazole-4-sulfonyl-(S)-2,3-diaminopropionate hydrochloride (28.24 g, 70% purity, 63.0 mmol) in DMF (200 mL) was added TBTU (28.90 g, 90 mmol). The mixture was cooled to 0.degree. C. and Et.sub.3 N (31.4 mL, 225 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature overnight (18 h), then was diluted with EtOAc (500 mL). It was washed with water (4.times.200 mL), sat. NaHCO.sub.3 (100 mL), sat. NaCl (100 mL) and dried (MgSO.sub.4). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 25.06 g (81%) of the desired amide; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 8.77 (bs, 1H), 8.22 (t, J=5.9 Hz, 1H), 5.02 (m, 1H), 3.98 (t, J=7.0 Hz, 1H), 3.55 (dd, J=17.2, 10.6 Hz, 1H), 3.48 (s, 3H), 3.42 (m, 1H), 3.16 (m, 2H), 2.54 (s, 3H, coincident with m, 1H, DMSO-d.sub.5), 2.37 (dd, J=14.6, 7.0 Hz, 1H), 2.33 (s, 3H).

Part B: Methyl N.sup.3 -(3,5-Dimethylisoxazole-4-sulfonyl)-N.sup.3 �3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate Acetate Salt

Into a solution of methyl N.sup.2 -(3,5-dimethyl-isoxazole-4-sulfonyl)-N.sup.3 �3-(4-(cyanophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate (25.06 g, 51.17 mmol) in anhydrous MeOH (750 mL) at 0.degree. C. was bubbled HCl gas for 3 hours. The resulting solution was then allowed to warm to room temperature overnight (18 h), after which the solvent was evaporated in vacuo, to give an oil. The oily residue was triturated with ether (3.times.100 mL) and the resulting solid placed under vacuum until constant weight was achieved. The crude imidate was then dissolved in MeOH (1 L) and ammonium acetate (20.0 g, 259 mmol) added. The resulting mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The residue was then crystallized from EtOH, giving 21.75 g of crude amidine. A portion of this material (8.5 g) was purified using flash chromatography (20% MeOH-EtOAc) to give 3.77 g (33%) of 97.6% pure amidine (analytical HPLC: 4.6 mm.times.25 cm C18 reverse phase, 1 mL/min, 0.05% TFA/10-90% AcCN/water gradient over 20 min); .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.8.26 (bt, 1H), 7.86 (m, 4H), 5.01 (m, 1H), 3.96 (t, J=6.6 Hz, 1H), 3.56 (dd, J=17.2, 10.6 Hz, 1H), 3.48 (s, 3H, coincident with m, 1H), 3.18 (m, 2H), 2.53 (s, 3H, coincident with m, 1H, DMSO-d.sub.5), 2.54 (s, 3H), 2.36 (dd, J=14.6, 7.0 Hz, 1H), 2.32 (s, 3H), 1.74 (s, 3H); MS (ESI): m/e 507.3 (M+H).sup.+.

Part C: N.sup.2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N.sup.3 �3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionic Acid (Enzymatic Hydrolysis)

To a solution of methyl N.sup.2 -(3,5-dimethylisoxazole-4-sulfonyl-N.sup.3 �3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionate HOAc salt (1.866 g, 3.29 mmol) in 0.4N Hepes buffer (pH 7.1, 220 mL, 15 mmol) was added rabbit liver esterase (3.6M crystalline suspension in ammonium sulfate, 2000 units, Sigma). The resulting solution was incubated at 37.degree. C. for 60 hours. Protein was removed from the reaction mixture by ultra filtration (Amicon YM-10 membrane), and the filtrate was then concentrated in vacuo and lyophilized. Purification using a reverse phase silica column (5.times.9.5 cm in water; crude product loaded as an aqueous solution followed by elution with water (1200 mL) and by 500 mL each of 5, 10, 20 and 30% CH.sub.3 CN--H.sub.2 O. Fractions containing the desired product were pooled, acetonitrile was removed and the aqueous solution lyophilized to yield 1.5 g (93%) of pure zwitterion; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.7.93 (t, 1H), 7.76 (s, 4H), 4.98 (m, 1H), 3.17-3.50 (m, 5H,coincident with water), 2.66 (dd, 1H), 2.56 (s, 3H), 2.35 (s, 3H), 2.36 (dd, 1H); MS (ESI): m/e 493.3 (M+H).sup.+.

Part D: N.sup.2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N.sup.3 -(4-amidinophenyl)isoxazolin-5(R)-ylacetyl!-(S)-2,3-diaminopropionic Acid Methanesulfonic Acid Salt

To a solution of the zwitterion (2.75 g, 5.43 mmol) in 50% CH.sub.3 CN--H.sub.2 O (135 mL) was added methanesulfonic acid (0.57 g, 5.97 mmol). The reaction mixture was stirred at room temperature for 1 h, resulting in a clear solution. Solvents were removed in vacuo and the residue placed under vacuum for several hours. The crude mesylate was dissolved in hot acetone and water until the solution was clear (120 mL total volume). After hot filtration the solution was allowed to cool slowly and was then refrigerated for 24 h. The resulting white precipitate was filtered and dried under vacuum, affording 1.72 g (52%) of the title compound; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.9.37 (bs, 2H), 9.03 (bs, 2H), 8.57 (d, J=9.5 Hz, 1H), 8.23 (t, J=5.9 Hz, 1H), 7.88 (s, 4H), 5.03 (m, 1H), 3.91 (m, 2H), 3.57 (dd, J=17.2, 10.6 Hz, 1H), 3.44 (m, 1H), 3.21 (dd, J=17.6, 7.7 Hz, 1H), 3.09 (m, 1H), 2.58 (dd, J=14.6, 6.6 Hz, 1H), 2.54 (s, 3H), 2.38 (dd, J=14.6, 7.3 Hz, 1H), 2.33 (s, 3H, MsOH); MS (ESI): m/e 493.2 (M+H).sup.+ ; Anal. Calcd. for C.sub.21 H.sub.28 N.sub.6 O.sub.10 S.sub.2 : C, 42.85; H, 4.79; N, 14.05; S, 10.89. Found: C, 42.45; H, 4.74; N, 14.05; S, 11.19.

EXAMPLE 2420

Methyl N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylformyl)-(S)-2,3-diaminopropionate TFA salt

.sup.1 HNMR (CDCl.sub.3) .delta. 7.38(1H, brd), 6.95(1H,brd), 5.65(1H, m), 4.98(1H, m), 4,42(1H, m),4.06(2H, m), 3.76(3H, s), 3.65(2H, m), 3.48(2H, m), 3.25(2H, m), 2.95(2H, m), 2.4(2H, m), 1.95(2H, brd), 1.6(5H, m), 1.48(2H, m), 1.35(4H, m), 0.94(3H, m) ppm; ESI mass spectrum 441 (M+H).sup.+ free base.

EXAMPLE 2421

Methyl N.sup.2 -p-toluenesulfonyl-N.sup.3 -�3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylformyl!-(S)-2,3-diaminopropionate TFA salt

.sup.1 HNMR (CDCl.sub.3) .delta.: 7.8(1H, m), 7.68(2H, m), 7.3(3H, m), 5.7(1H, m),4.92(1H, m), 4.1(1H, m), 4.0(1H, m), 3.7(2H, m), 3.55(3H, s), 3.45(3H, m), 2.9(2H, brd), 2.4(3H, s), 2.38(2H, m), 1.9(3H, m), 1.65(2H, m), 1.54(2H, m), 1.35(2H, m) ppm; ESI mass spectrum 495.3 (M+H).sup.+ free base.

EXAMPLE 2422

N.sup.2 -p-toluenesulfonyl-N.sup.3 -3-(4-piperidinylproyl)-isoxazolin-5-(R,S)-ylformyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (CD.sub.3 OD).delta.: 7.7(2H, m), 7.32(2H, m), 4.85(1H, m), 4.1(1H, m), 3.75(1H, m), 3.65(2H, m), 3.32(3H, m), 3.2(2H, m), 2.9(2H, m), 2.4(5H, m), 1.95(2H, m), 1.62(3H, m), 1.35(4H, m),ppm; ESI mass spectrum 481.3 (M+H).sup.+ free base.

EXAMPLE 2423

N.sup.2 -n-butyloxycarbonyl-N.sup.3 -�3-(4-piperidinylproyl)isoxazolin-5-(R,S)-ylformyl!-(S)-2,3-diaminopropionic acid TFA salt

.sup.1 HNMR (CD.sub.3 OD)8: 4.92(1H, m), 4.3(1H, m), 4.05(2H, m), 3.6(2H, m), 3.38(3H, m), 3.15(1H, m), 2.95(2H, m), 2.35(2H, m), 1.95(2H, m), 1.6(5H, m), 1.35(6H, m), 0.95(3H, m) ppm; ESI mass spectrum 427.3 (M+H).sup.+ free base.

EXAMPLE 2500

Methyl N-Boc-(S)-2,3-diaminopropionate

Part A: Methyl N.sup.2 -Cbz-L-2,3-diaminopropionate HCl Salt

To a solution of N.sup.2 -Cbz-L-2,3-diaminopropionic acid (Bachem, 220 g, 0.923 mol) in MeOH (2 L) at 0.degree. C. was added thionyl chloride (76 mL, 1.04 mol) over 20 min. The solution was warmed to room temperature overnight (18 h) and then concentrated to give a solid. The solid was crystallized from CHCl.sub.3 --MeOH to give 172 g (64%) of the desired ester; .sup.1 H NMR (DMSO-d.sub.6) .delta. 8.38 (b, 3H), 7.96 (d, 1H), 7.38 (m, 5H), 5.05 (s, 2H), 4.44 (m, 1H), 3.66 (s, 3H), 3.14 (m, 2H).

Part B: Methyl N.sup.2 -Cbz-N.sup.2 -Boc-L-2,3-diaminopropionate

To a solution of methyl N.sup.2 -Cbz-(S)-2,3-diaminopropionate HCl salt (172 g, 0.596 mol) and di-tert-butyl dicarbonate (129.05 g, 0.591 mol) in CH.sub.2 Cl.sub.2 (2 L) cooled in an ice bath was added a saturated solution of NaHCO.sub.3 (1200 mL, 0.96 mol) and the solution was warmed to room temperature overnight (18 h). The layers were separated and the aqueous washed with CH.sub.2 Cl.sub.2 (2.times.500 mL). The combined organic was washed with brine, dried (MgSO.sub.4), and concentrated. The resulting white solid was triturated with hexanes (3.times.500 mL) and dried under vacuum, giving 195.99 g (93%) of the desired material; .sup.1 H NMR (DMSO-d.sub.6): .delta. 7.60 (d, 1H), 7.35 (m, 5H), 6.88 (t, 1H), 5.02 (s, 2H), 4.14 (m, 1H), 3.60 (s, 3H), 3.28 (m, 2H), 1.37 (s, 9H).

Part C: Methyl N.sup.3 -Boc-(S)-2,3-diaminopropionate

To a solution of methyl N.sup.2 -Cbz-N.sup.3 -Boc-(S)-2,3-diaminopropionate. (54.7 g, 0.155 mol) in EtOH (300 mL) was added 10% Pd/C (4.0 g). The mixture was placed on a Parr apparatus and hydrogenated at 50 p.s.i. overnight (18 h). The catalyst was filtered through Celite.RTM., the filter cake washed with EtOH (3.times.50 mL) and the filtrate was concentrated in vacuo and placed under vacuum to give 32.63 g (96%) of the free base amine as a golden, viscous liquid; .sup.1 H NMR (DMSO-d.sub.6): .delta.8.20(s, 1H), 6.90 (t, 1H), 5.36 (b, 3H), 3.61 9s, 3H), 3.51 (t, 1H), 3.18 (t, 2H), 1.38 (s, 9H).

EXAMPLE 2502

Resolution of 3-(4-cyanophenyl)isoxazolin-5(R,S)-ylacetic Acid by Crystallization

3-(4-Cyanophenyl)isoxazolin-5(S)-ylacetic acid (127 g, 0.55 moles) and (+)-cinchonidine (180.37 g, 0.55 mol) were added to acetone (2.0 L) and stirred at ambien temperature for at least 1.5 hrs. The resulting precipitate (169.21 g) was collected by filtration. The precipitate was dissolved in hot acetone (4.0 L) while stirring. After complete dissolution, the solution was allowed to stand overnight. The crystals formed were collected by filtration and recrystallized with acetone again to yield the 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid/(+)-cinchonidine salt in 33% overall yield and >99% diastereomeric excess. The 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid was liberated from its cinchonidine salt complex by suspending the salt in ethereal HCL (1N), filtering the solid after equilibration and evaporating the ether solution to provide the solid 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid. The R-isomer could be obtained from the mother liquor. Other chiral bases used include ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol, quinidine and pseudoephedrine.

EXAMPLE 2503

General Procedure for the Preparation of Compounds of the Formula (Ie) and (If)

Part A. Z-2,3-diaminopropionic acid (2.5 g, Fluka) was combined with Fmoc-N-Hydroxysuccinimide (1.1 eq., 3.89 g) and NaHCO.sub.3 (3 eq., 2.65 g), in dioxane (24 ml) and H.sub.2 O (21 ml). After stirring at room temperature overnight, the pH was adjusted with Na.sub.2 CO.sub.3 to pH 9. The solution was extracted three times with ethyl ether, then the aqueous layer was acidified with conc. HCl, with stirring. At pH 4-5, a solid precipitated out. This was filtered, rinsed with 1N HCl, and dried. (93% yield).

Part B. Wang resin (2.0 g, 1.16 mmole/g, Advanced Chem Tech) was added to triphenylphosphine (5 eq, 3.0 g) in 20 ml DMF. CBr.sub.4 (5 eq, 3.85 g) was then added and the solution was stirred at room temperature 3 hours. The resin was filtered and rinsed with DMF. Fmoc-Z-2,3-diaminopropionic acid (1.60 g, 1.5 equiv.) was dissolved in 20 ml DMF and the above resin was added, with 1.5 equiv. DIEA (0.60 ml) and 1.0 equiv. CsI (0.60 g) and stirred at room temperature overnight. The resin was filtered and rinsed with DMF and MeOH. Weight gain, IR, elemental analysis, and picric acid determination were used to establish the substitution level of the resin as approx. 0.8 mmole/g.

Part C. The above derivatized resin (150 mg) was deprotected by mixing 10 min. with 20% piperidine/DMF. of The Fmoc-isoxazolin derivative (1.5 eq., 0.18 mmole) was dissolved in 1.5 ml DMF and added to the resin with HBTU (1.5 eq, 68 mg) and DIEA (1.5 eq, 32 ul). The tubes were mixed overnight, then drained, rinsed with DMF and MeOH, and the resin split into two portions. One portion was deprotected with 20% piperidine/DMF and then cleaved to produce the primary amine analogs. The other portion was deprotected with 20% piperidine/DMF and then coupled overnight with bis Boc-S-ethyl isothiourea (2 eq., 37 mg) and DEA (2 eq., 21 ul) in DMF.

Part D. After rinsing, the compounds were cleaved from the resin by mixing with 1:1 TFA:CH.sub.2 Cl.sub.2 for two hours. The filtrate was rotovapped under reduced pressure to an oil, dissolved in 1:1 acetonitrile:H.sub.2 O, and lyophilized. The crude material was analyzed by mass spec and HPLC. They were then purified by reverse phase HPLC (ACN:H.sub.2 O:0.1% TFA, C 18 column).

Using the above methods and variations thereof known in the art of organic synthesis, the additional examples in Tables 1-2, 2A-2D, 3-14 can be prepared.

TABLE 1__________________________________________________________________________ ##STR65##Ex. No. R.sup.2 R.sup.4 Y n R.sup.14 n'__________________________________________________________________________1 H H OH 2 H 02 H NHSO.sub.2 nC.sub.4 H.sub.9 OH 2 H 03 H NHSO.sub.2 CH.sub.2 Ph OH 2 H 04 H NHCO.sub.2 CH.sub.2 Ph OH 2 H 05 H NHCOnC.sub.4 H.sub.9 OH 2 H 06 H H OH 1 H 17 H H OH 1 H 08 H H OH 2 H 19 H NHSO.sub.2 nC.sub.4 H.sub.9 OH 1 H 110 H NHSO.sub.2 CH.sub.2 Ph OH 1 H 111 H NHCO.sub.2 CH.sub.2 Ph OH 1 H 112 H NHCOnC.sub.4 H.sub.9 OH 1 H 113 H NHSO.sub.2 nC.sub.4 H.sub.9 OMe 2 H 014 H NHCO.sub.2 CH.sub.2 Ph OMe 2 H 015 H NHSO.sub.2 nC.sub.4 H.sub.9 OMe 1 H 116 H NHCO.sub.2 CH.sub.2 Ph OMe 1 H 117 H NHSO.sub.2 nC.sub.4 H.sub.9 OEt 2 H 018 H NHCO.sub.2 CH.sub.2 Ph OEt 2 H 019 H NHSO.sub.2 nC.sub.4 H.sub.9 OEt 1 H 120 H NHCO.sub.2 CH.sub.2 Ph OEt 1 H 121 Boc NHSO.sub.2 nC.sub.4 H.sub.9 OH 2 H 022 Boc NHCO.sub.2 CH.sub.2 Ph OH 2 H 023 Boc NHSO.sub.2 nC.sub.4 H.sub.9 OH 1 H 124 Boc NHCO.sub.2 CH.sub.2 Ph OH 1 H 125 Cbz NHSO.sub.2 nC.sub.4 H.sub.9 OH 2 H 026 Cbz NHCO.sub.2 CH.sub.2 Ph OH 2 H 027 Cbz NHSO.sub.2 nC.sub.4 H.sub.9 OH 1 H 128 Cbz NHCO.sub.2 CH.sub.2 Ph OH 1 H 129 H NHSO.sub.2 nC.sub.4 H.sub.9 ##STR66## 2 H 030 H NHSO.sub.2 nC.sub.4 H.sub.9 ##STR67## 2 H 031 H NHSO.sub.2 nC.sub.4 H.sub.9 ##STR68## 2 H 032 H NHSO.sub.2 nC.sub.4 H.sub.9 ##STR69## 2 H 031 H NHSO.sub.2 nC.sub.4 H.sub.9 ##STR70## 2 H 033 H H OH 2 CO.sub.2 Me 034 H H OMe 2 H 035 H NHSO.sub.2 CH.sub.2 Ph OMe 2 H 036 H NHCOnC.sub.4 H.sub.9 OMe 2 H 037 H H OMe 1 H 138 H H OMe 1 H 039 H H OMe 2 H 140 H NHSO.sub.2 CH.sub.2 Ph OMe 1 H 141 H NHCOnC.sub.4 H.sub.9 OMe 1 H 142 H H OMe 2 CO.sub.2 Me 0__________________________________________________________________________ TABLE 2__________________________________________________________________________ ##STR71##Example MSNumber R.sup.2 R.sup.8 Y (M + H).sup.+__________________________________________________________________________43 H Ph OH 41243A H Ph OH HNMR44 H ##STR72## OH45 H ##STR73## OH46 H ##STR74## OH47 H ##STR75## OH48 H ##STR76## OH49 H ##STR77## OH50 H ##STR78## OH51 H ##STR79## OH52 H ##STR80## OH53 H ##STR81## OH54 H ##STR82## OH55 H ##STR83## OH56 H ##STR84## OH57 H ##STR85## OH58 H ##STR86## OH59 H ##STR87## OH60 H ##STR88## OH61 H ##STR89## OH62 H ##STR90## OH63 H ##STR91## OH64 H ##STR92## OH65 H ##STR93## OH66 H ##STR94## OH67 H ##STR95## OH68 H ##STR96## OH69 H Et OH70 H n-Pr OH71 H C CH OH72 H CO.sub.2 H OH73 H CH.sub.2 Ph OH74 H CH.sub.2 CH.sub.2 Ph OH75 H CCH.sub.2 OH76 H ##STR97## OH80 Cbz Ph OH81 Cbz ##STR98## OH82 Boc Ph OH83 Boc ##STR99## OH84 H ##STR100## ##STR101##85 H ##STR102## ##STR103##86 H ##STR104## ##STR105##87 H ##STR106## ##STR107##88 H ##STR108## ##STR109##89 H Ph OMe90 H ##STR110## OMe91 H ##STR111## OMe92 H ##STR112## OMe93 H ##STR113## OMe94 H ##STR114## OMe95 H ##STR115## OMe96 H ##STR116## OMe97 H ##STR117## OMe98 H ##STR118## OMe99 H ##STR119## OMe100 H ##STR120## OMe101 H ##STR121## OMe102 H ##STR122## OMe103 H ##STR123## OMe104 H ##STR124## OMe105 H ##STR125## OMe106 H ##STR126## OMe107 H ##STR127## OMe108 H ##STR128## OMe109 H ##STR129## OMe110 H ##STR130## OMe111 H ##STR131## OMe112 H ##STR132## OMe113 H ##STR133## OMe114 H ##STR134## OMe115 H Et OMe 361116 H n-Pr OMe117 H C CH OMe118 H CO.sub.2 H OMe119 H CH.sub.2 Ph OMe 423120 H CH.sub.2 CH.sub.2 Ph OMe 437121 H CCH.sub.2 OMe122 H ##STR135## OMe126 Cbz Ph OMe127 Cbz ##STR136## OMe128 Boc Ph OMe129 Boc ##STR137## OMe130 H Ph OEt131 H ##STR138## OEt132 H ##STR139## OEt133 H ##STR140## OEt134 H ##STR141## OEt135 H ##STR142## OEt136 H ##STR143## OEt137 H ##STR144## OEt138 H ##STR145## OEt139 H ##STR146## OEt140 H ##STR147## OEt141 H ##STR148## OEt142 H ##STR149## OEt143 H ##STR150## OEt144 H ##STR151## OEt145 H ##STR152## OEt146 H ##STR153## OEt147 H ##STR154## OEt148 H ##STR155## OEt149 H ##STR156## OEt150 H ##STR157## OEt151 H ##STR158## OEt152 H ##STR159## OEt153 H ##STR160## OEt154 H ##STR161## OEt155 H ##STR162## OEt156 H Et OEt157 H n-Pr OEt158 H C CH OEt159 H CO.sub.2 H OEt160 H CH.sub.2 Ph OEt161 H CH.sub.2 CH.sub.2 Ph OEt162 H CCH.sub.2 OEt163 H ##STR163## OEt164 H CH.sub.2 N(Me)Ph OEt165 H CH.sub.2 NEt.sub.2 OEt166 H CH.sub.2 NMe.sub.2 OEt167 Cbz Ph OEt168 Cbz ##STR164## OEt169 Boc Ph OEt170 Boc ##STR165## OEt338 H CO.sub.2 Me OMe mp 160.degree.339 H CO.sub.2 Me H 363340 H CONMe.sub.2 OMe 404341 H ##STR166## OMe 524343 H n-butyl OH344 H n-butyl OMe 389345 H n-butyl OEt346 H isobutyl OH347 H isobutyl OMe 389348 H isobutyl OEt 403349 H CH.sub.2 SPh OH350 H CH.sub.2 SPh OMe 455351 H CH.sub.2 SPh OEt352 H CH.sub.2 OPh OH353 H CH.sub.2 OPh OMe354 H CH.sub.2 OPh OEt355 H CH.sub.2 SO.sub.2 Ph OH356 H CH.sub.2 SO.sub.2 Ph OMe357 H CH.sub.2 SO.sub.2 Ph OEt359 H CH.sub.2 NHSO.sub.2 Ph OMe 502360 H CH.sub.2 NHSO.sub.2 Ph OEt361 H CH.sub.2 NHSO.sub.2 n-Bu OH362 H CH.sub.2 NHSO.sub.2 n-Bu OMe 482363 H CH.sub.2 NHSO.sub.2 n-Bu OEt364 H CH.sub.2 COOH OH 377365 H CH.sub.2 COOMe OMe 405366 H CH.sub.2 COOEt OEt367 H CH.sub.2 CH.sub.2 COOH OH368 H CH.sub.2 CH.sub.2 COOMe OMe 419369 H CH.sub.2 CH.sub.2 COOEt OEt370 H CH.sub.2 NMe.sub.2 OH371 H CH.sub.2 NMe.sub.2 OMe 390372 H CH.sub.2 NMe.sub.2 OEt434 BOC C(O)NH(CH.sub.2).sub.2 C.sub.6 H.sub.5 OtBu 622435 H C(O)NH(CH.sub.2).sub.2 C.sub.6 H.sub.5 OH 466439 H C(O)OC.sub.2 H.sub.5 OEt 419441 H ##STR167## OH 484446 H (CH.sub.2).sub.3 Ph OMe447 H CH.sub.2 -(2-pyr) OMe448 H (CH.sub.2).sub.2 -(2-pyr) OMe449 H (CH.sub.2).sub.2 -(3-pyr) OMe 438450 H (CH.sub.2).sub.2 -(4-pyr) OMe 438452 H C(O)NH(CH.sub.2).sub.2 C.sub.6 H.sub.5 OMe 480453 BOC ##STR168## OMe 635454 H C(O)N(CH.sub.3) OMe (CH.sub.2).sub.2 C.sub.6 H.sub.5455 H ##STR169## OMe457 H C CSiMe.sub.3 OMe 429458 H (CH.sub.2).sub.2 -(3-pyr) OH 424459 H (CH.sub.2).sub.2 -(2-pyr) OH 424460 H (CH.sub.2).sub.3C.sub.6 H.sub.5 OH 437461 H (CH.sub.2)3-C.sub.6 H.sub.5 OMe 451462 H ##STR170## OEt 538463 H ##STR171## OH 510464 H ##STR172## OMe 492465 H ##STR173## OMe 492466 H ##STR174## OMe 510467 H ##STR175## OMe 510468 H ##STR176## OMe 462469 H ##STR177## OMe 448587 H (CH.sub.2).sub.3 -(4-pyr) OH 424611 H CH.sub.2 NHSO.sub.2 NMe.sub.2 OMe 469612 H ##STR178## OMe 416__________________________________________________________________________ TABLE 2A__________________________________________________________________________ ##STR179##Example MSNumber R.sup.1V R.sup.16 Y (M + H).sup.+__________________________________________________________________________275 4-amidinophenyl H OH 334276 4-amidinophenyl benzyloxycarbonyl OH 468277 4-amidinophenyl t-butyloxycarbonyl OH278 4-amidinophenyl n-butyloxycarbonyl OH 434278a 4-amidinophenyl n-butyloxycarbonyl OMe 448278b 4-amidinophenyl n-butyloxycarbonyl OH 439279 4-amidinophenyl ethyloxycarbonyl OH280 4-amidinophenyl methyloxycarbonyl OH290 4-amidinophenyl phenylethylcarbonyl OH 510291 4-amidinophenyl 2,2-dimethyl- OH propylcarbonyl292 4-amidinophenyl n-pentylcarbonyl OH293 4-amidinophenyl n-butylcarbonyl OH294 4-amidinophenyl propionyl OH295 4-amidinophenyl acetyl OH296 4-amidinophenyl methylsulfonyl OH297 4-amidinophenyl ethylsulfonyl OH298 4-amidinophenyl n-butylsulfonyl OH299 4-amidinophenyl phenylsulfonyl OH 474300 4-amidinophenyl 4-methylphenyl- OH 488 sulfonyl301 4-amidinophenyl benzylsulfonyl OH302 4-amidinophenyl 2-pyridylcarbonyl OH303 4-amidinophenyl 3-pyridylcarbonyl OH304 4-amidinophenyl 4-pyridylcarbonyl OH305 4-amidinophenyl 2-pyridylmethyl- OH carbonyl306 4-amidinophenyl 3-pyridylmethyl- OH carbonyl307 4-amidinophenyl 4-pyridylmethyl- OH carbonyl308 4-amidinophenyl 2-pyridylmethoxy- OH carbonyl309 4-amidinophenyl 3-pyridyimethoxy- OH carbonyl310 4-amidinophenyl 4-pyridylmethoxy- OH carbonyl311 4-amidinophenyl H OMe312 4-amidinophenyl benzyloxycarbonyl OMe 482313 4-amudinophenyl t-butyloxycarbonyl OMe314 4-amidinophenyl n-butyloxycarbonyl OMe 448315 4-amidinophenyl ethyloxycarbonyl OMe316 4-amidinophenyl methyloxycarbonyl OMe317 q-amidinophenyl phenylethylsulfonyl OH 502318 4-amidinophenyl 2,2-dimethyl- OMe propylcarbonyl319 4-amidinophenyl n-pentylcarbonyl OMe320 4-amidinophenyl n-butylcarbonyl OMe321 4-amudinophenyl propionyl OMe322 4-amidinophenyl acetyl OMe323 4-amidinophenyl methylsulfonyl OMe 426324 4-amidinophenyl ethylsulfonyl OMe 440325 4-amidinophenyl n-butylsulfonyl OMe326 4-amidinophenyl phenylsulfonyl OMe 488327 4-amidinophenyl 4-methylphenyl- OMe 502 sulfonyl328 4-amidinophenyl benzylsulfonyl OMe 502329 4-amidinophenyl 2-pyridylcarbonyl OMe330 4-amidinophenyl 3-pyridylcarbonyl OMe331 4-amidinophenyl 4-pyridylcarbonyl OMe332 4-amidinophenyl 2-pyridylmethyl- OMe carbonyl333 4-amidinophenyl 3-pyridylmethyl- OMe carbonyl334 4-amidinophenyl 4-pyridylmethyl- OMe carbonyl335 4-amidinophenyl 2-pyridylmethoxy- OMe carbonyl336 4-amidinophenyl 3-pyridylmethoxy- OMe carbonyl337 4-amidinophenyl 4-pyridylmethoxy- OMe carbonyl374 ##STR180## benzyloxycarbonyl OMe 475440 4-(BOCamidino)phenyl benzyloxycarbonyl OMe 582442 4-(BOCamidino)phenyl n-butyloxycarbonyl OMe 594443 4-amidinophenyl 1-naphthylsulfonyl OMe 538444 4-amidinophenyl 2-naphthylsulfonyl OMe 538445 4-amidinophenyl styrylsulfonyl OMe 514445a 4-amidinophenyl styrylsulfonyl OH 500451 ##STR181## n-butyloxycarbonyl OMe 441471 4-amidinophenyl 4-butyloxyphenyl- OMe 560 sulfonyl472 4-amidinophenyl 2-thienylsulfonyl OMe 494473 4-amidinophenyl 3-methylphenyl- OMe 502 sulfonyl474 4-amidinophenyl 4-iodophenyl OMe 614475 4-amidinophenyl 3-trifluoromethyl- OMe 556 phenylsulfonyl476 4-amidinophenyl 3-chlorophenyl- OMe 522 sulfonyl477 4-amidinophenyl 2-methoxycarbonyl- OMe 546 phenylsulfonyl478 4-amidinophenyl 2,4,6-trimethyl- OMe 530 phenylsulfonyl478a 4-amidinophenyl 2,4,6-trimethyl- OH 516 phenylsulfonyl479 4-amidinophenyl 2-chlorophenyl- OMe 522 sulfonyl479a 4-amidinophenyl 2-chlorophenyl- OH 508 sulfonyl480 4-amidinophenyl 2-trifluoromethyl- OMe 556 phenylsulfonyl481 4-amidinophenyl 4-trifluoromethyl- OMe 556 phenylsulfonyl482 4-amidinophenyl 2-fluorophenyl- OMe 506 sulfonyl483 4-amidinophenyl 4-fluorophenyl- OMe 506 sulfonyl484 4-amidinophenyl 4-methoxyphenyl- OMe 518 sulfonyl485 4-amidinophenyl 2,3,5,6-tetramethyl- OMe 544 phenylsulfonyl485a 4-amidinophenyl 2,3,5,6-tetramethyl- OH 530 phenylsulfonyl486 4-amidinophenyl 4-cyanophenyl- OMe 513 sulfonyl487 4-amidinophenyl 4-chlorophenyl- OMe 522 sulfonyl488 4-amidinophenyl 4-ethylphenyl- OMe 516 sulfonyl489 4-amidinophenyl 4-propylphenyl- OMe 530 sulfonyl490 4-amidinophenyl n-propylsulfonyl OMe 454490a 4-amidinophenyl n-propylsulfonyl OH 440491 4-amidinophenyl 2-phenylethyl- OMe 516 sulfonyl492 4-amidinophenyl 4-isopropylphenyl- OMe 530 sulfonyl492a 4-amidinophenyl 4-isopropylphenyl- OH 516 sulfonyl493 4-amidinophenyl 3-phenylpropyl- OMe 530 sulfonyl494 4-amidinophenyl 3-pyridylsulfonyl OMe 489495 4-amidinophenyl 2-pyridylsulfonyl OMe 489496 4-amidinophenyl 2,2-diphenyl-1- OMe 590 ethenylsulfonyl497 4-amidinophenyl 2-pyrimidinyl- OMe sulfonyl498 4-amidinophenyl 4-methyl-2- OMe pyrimidinylsulfonyl499 4-amidinophenyl 4,6-dimethyl-2- OMe pyrimidinylsulfonyl500 4-amidinophenyl 1,2,4-triazol-3- OMe ylsulfonyl501 4-amidinophenyl 1-methyl-1,3,4- OMe triazol-5-ylsulfonyl502 4-amidinophenyl 3,5-dimethyl-4- OMe pyrazolylsulfonyl503 4-amidinophenyl 1-phenyl-4- OMe pyrazolylsulfonyl504 4-amidinophenyl n-butylaminosulfonyl OMe 483505 4-amidinophenyl i-butylaminosulfonyl OMe 483506 4-amidinophenyl t-butylaminosulfonyl OMe 483507 4-amidinophenyl i-propylamino- OMe 469 sulfonyl508 4-amidinophenyl cyclohexylamino- OMe 509 sulfonyl509 4-amidinophenyl phenylaminosulfonyl OMe 503510 4-amidinophenyl benzylaminosulfonyl OMe 517511 4-amidinophenyl dimethylamino- OMe 455 sulfonyl512 4-amidino-2-fluoro- 3-methylphenyl- OMe 520 phenyl sulfonyl512A 4-amidino-2-fluoro- 3-methylphenylsulfonyl OH 506 phenyl514 2-amidino-5-pyridyl 3-methylphenyl- OMe 503 sulfonyl514A 2-amidino-5-pyridyl 3-methylphenylsulfonyl OH 489516 3-amidino-6-pyridyl 3-methylphenyl- OMe 503 sulfonyl516A 3-amidino-6-pyridyl 3-methylphenylsulfonyl OH 489518 4-amidinophenyl 4-fluorophenylamino- OMe 485 carbonyl519 4-amidinophenyl 1-naphthylamino- OMe 517 carbonyl520 4-amidinophenyl benzylaminocarbonyl OMe521 4-amidinophenyl n-butylaminocarbonyl OMe 435522 4-amidinophenyl 4-ethylphenyl- OMe 480 carbonyl523 4-amidinophenyl biphenylcarbonyl OMe 528524 4-amidinophenyl 2-naphthylcarbonyl OMe 502525 4-amidinophenyl (2-chlorophenyl) OMe 516 methoxycarbonyl526 4-amidinophenyl (2-chlorophenyl) OH 502 methoxycarbonyl527 4-amidinophenyl (2-bromophenyl) OMe 562 methoxycarbonyl528 4-amidinophenyl (2-bromophenyl) OH 548 methoxycarbonyl528a 4-amidinophenyl (2-bromophenyl)- OH 516 carbonyl529 4-amidinophenyl n-hexyloxycarbonyl OMe 476530 4-amidinophenyl n-hexyloxycarbonyl OH 460531 4-amidinophenyl isobutyloxycarbonyl OMe 448532 4-amidinophenyl isobutyloxycarbonyl OH 434533 4-amidinophenyl 2-cyclopropylethoxy- OMe 460 carbonyl534 4-amidinophenyl 2-cyclopropylethoxy- OH 446 carbonyl535 4-amidinophenyl 2-cyclopentylethoxy- OMe 488 carbonyl536 4-amidinophenyl 2-cyclopentylethoxy- OH 474 carbonyl537 4-amidinophenyl 4,4,4-trifluoro- OMe 502 butyloxycarbonyl538 4-amidinophenyl 4,4,4-trifluoro- OH 488 butyloxycarbonyl539 4-amidinophenyl n-propylsulfonyl OMe540 4-amidinophenyl 2-methylphenyl- OH 452 carbonyl540a 4-amidinophenyl 2-methylphenyl- OH 488 sulfonyl541 4-amidinophenyl 4-chloro-2,5-dimethyl- OMe 550 phenylsulfonyl541a 4-amidinophenyl 4-chloro-2,5-dimethyl- OMe 536 phenylsulfonyl542 4-amidinophenyl 2,3-dichlorophenyl- OMe 556 sulfonyl543 4-amidinophenyl 2-bromophenyl- OMe 568 sulfonyl544 4-amidinophenyl 3-bromophenyl- OMe 568 sulfonyl545 4-amidinophenyl 4-bromophenyl- OMe 568 sulfonyl546 4-amidinophenyl biphenylsulfonyl OMe 564547 4-amidinophenyl 5-chloro-1,3- OMe 540 dimethyl-4-pyrazolyl548 4-amidinophenyl 3-bromo-2- OMe 574 thienylsulfonyl549 4-amidinophenyl 5-bromo-2- OMe 574 thienylsulfonyl550 4-amidinophenyl 5-�1-methyl-5- OMe 642 trifluoromethyl-3- pyrazolyl!-2- thienylsulfonyl551 4-amidinophenyl 5-(3-isoxazolyl)-2- OMe 561 thienylsulfonyl552 4-amidinophenyl 5-(2-pyridinyl)-2- OMe 571 thienylsulfonyl553 4-amidinophenyl 4-methyl-2- OMe 566 methylcarbonylamino-5- thiazolylsulfonyl554 4-amidinophenyl 2-benzothienyl- OMe 628 sulfonyl555 4-amidinophenyl 2-benzothienyl- OMe 544 sulfonyl556 4-amidinophenyl 3-methyl-2- OMe 558 benzothienylsulfonyl557 4-amidinophenyl 8-quinolinylsulfonyl OMe 539558 4-amidinophenyl 8-quinolinylsulfonyl OH 525559 4-amidinophenyl 2,1,3-benzo- OMe 546 thiadiazol-4-ylsulfonyl560 4-amidinophenyl 2,1,3-benzo- OH 532 thiadiazol-4-ylsulfonyl561 4-amidinophenyl 4-N,N-dimethylamino-1- OMe naphthylsulfonyl562 4-amidinophenyl 4-N,N-dimethylamino-1- OH naphthylsulfonyl563 4-amidinophenyl 2,1,3-benzoxadiazol-4- OMe ylsulfonyl564 4-amidinophenyl 2,1,3-benzoxadiazol-4- OH ylsulfonyl565 4-amidinophenyl 2,2,5,7,8-pentamethyl OMe 3,4-dihydro-2Hbenzo- pyran-6-ylsulfonyl566 4-amidinophenyl 2,2,5,7,8-pentamethyl OH 3,4-dihydro-2Hbenzo- pyran-6-ylsulfonyl567 4-N-methylamidino 3-methylphenylsulfonyl OMe phenyl568 4-N-ethylamidino 3-methylphenylsulfonyl OMe 530 phenyl569 4-N-n-propylamidino 3-methylphenylsulfonyl OMe phenyl570 4-N-benzylamidino 3-methylphenylsulfonyl OMe phenyl571 4-N-n-butylamidino 3-methylphenylsulfonyl OMe 558 phenyl572 4-N-methylamidino 3-methylphenylsulfonyl OH phenyl573 4-N-ethylamidino 3-methylphenylsulfonyl OH 516 phenyl574 4-N-n-propylamidino 3-methylphenylsulfonyl OH phenyl575 4-N-benzylamidino 3-methylphenylsulfonyl OH phenyl576 4-N-n-butylamidino 3-methylphenylsulfonyl OH 544 phenyl577 4-N-methylamidino- n-butyloxycarbonyl OMe phenyl578 4-N-ethylamidinophenyl n-butyloxycarbonyl OMe579 4-N-npropylamidino- n-butyloxycarbonyl OMe phenyl580 4-N-n-butylamidino- n-butyloxycarbonyl OMe 504 phenyl581 4-N-benzylamidino- n-butyloxycarbonyl OMe phenyl582 4-N-methylamidino- n-butyloxycarbonyl OH phenyl583 4-N-ethylamidino- n-butyloxycarbonyl OH phenyl584 4-N-n-propylamidino- n-butyloxycarbonyl OH phenyl585 4-N-n-butylamidino- n-butyloxycarbonyl OH phenyl586 4-N-benzylamidino- n-butyloxycarbonyl OH phenyl589 4-(acetoxyamidino- n-butyloxycarbonyl OMe phenyl590 4-(acetoxyamidino)- n-buty}oxycarbonyl OH phenyl591 4-(acetoxyamidino)- isobutyloxycarbonyl OMe phenyl592 4-(acetoxyamidino)- isobutyloxycarbonyl OH phenyl593 4-(acetoxyamidino)- cyclopropylethoxy- OMe phenyl carbonyl594 4-(acetoxyamidino)- cyclopropylethoxy- OH phenyl carbonyl595 4-(acetoxyamidino)- benzyloxycarbonyl OMe phenyl596 4-(acetoxyamidino)- benzyloxycarbonyl OH phenyl597 4-(acetoxyamidino)- 4-methylphenylsulfonyl OMe phenyl598 4-(acetoxyamidino)- 4-methylphenylsulfonyl OH phenyl599 4-(acetoxyamidino)- 3-methylphenylsulfonyl OMe phenyl600 4-(acetoxyamidino)- 3-methylphenylsulfonyl OH phenyl601 4-guanidinophenyl n-butyloxycarbonyl OH602 4-guanidinophenyl n-butyloxycarbonyl OMe 463603 4-guanidinophenyl benzyloxycarbonyl OH604 4-guanidinophenyl benzyloxycarbonyl OMe605 4-guanidinophenyl 4-methylphenylsulfonyl OH 503606 4-guanidinophenyl 4-methylphenylsulfonyl OMe 517607 4-guanidinophenyl 3-methylphenylsulfonyl OH608 4-guanidinophenyl 3-methylphenylsulfonyl OMe609 4-guanidinophenyl n-butylsulfonyl OH610 4-guanidinophenyl n-butylsulfonyl OMe613 4-amidino-2-fluoro- n-butyloxycarbonyl OMe 466 phenyl614 4-piperidinyl n-butyloxycarbonyl OMe 412615 4-piperidinylmethyl n-butyloxycarbonyl OMe 426616 4-piperidinylpropyl n-butyloxycarbonyl OMe 454617 4-quanidinophenyl n-butyloxycarbonyl OH 449618 4-amidinophenylmethyl benzyloxycarbonyl OMe619 4-amidinophenylmethyl benzyloxycarbonyl OH220 4-amidinophenylmethyl n-butyloxycarbonyl OMe621 4-amidinophenylmethyl n-butyloxycarbonyl OH622 4-amidinophenylmethyl cyclopropylethoxy OMe carbonyl623 4-amidinophenylmethyl cyclopropylethoxy OH carbonyl624 4-amidinophenylmethyl 4-methylphenylsulfonyl OMe625 4-amidinophenylmethyl 4-methylphenylsulfonyl OH 488626 4-amidinophenylmethyl 3-methylphenylsulfonyl OMe627 4-amidinophenylmethyl 3-methylphenylsulfonyl OH628 4-amidinophenylmethyl n-butylsulfonyl OMe629 4-amidinophenylmethyl n-butylsulfonyl OH630 4-amidinophenylmethoxy benzyloxycarbonyl OMe631 4-amidinophenylmethoxy benzyloxycarbonyl OH632 4-amidinophenylmethoxy n-butyloxycarbonyl OMe633 4-amidinophenylmethoxy n-butyloxycarbonyl OH634 4-amidinophenylmethoxy cyclopropylethoxy OMe carbonyl635 4-amidinophenylmethoxy cyclopropylethoxy OH carbonyl636 4-amidinophenylmethoxy 4-methylphenylsulfonyl OMe637 4-amidinophenyimethoxy 4-methylphenylsulfonyl OH638 4-amidinophenylmethoxy 3-methylphenylsulfonyl OMe639 4-amidinophenylmethoxy 3-methylphenylsulfonyl OH640 4-amidinophenylmethoxy n-butylsulfonyl OMe641 4-amidinophenylmethoxy n-butylsulfonyl OH642 4-amidinophenyl 5-chloro-1,3- OMe 526 dimethyl-4-pyrazolyl643 4-amidinophenyl 1-methylimidazol-4- OH 478 ylsulfonyl644 4-amidinophenyl 3,5-dimethyl-1,3- OH 509 thioimidazole-2- ylsulfonyl645 N-t-butyloxycarbonyl-4- 5-(2-pyridinyl)-2- OMe 671 amidinophenyl thienylsulfonyl646 N-t-butyloxycarbonyl-4- 3,5-dimethyl-1,3- OMe 623 amidinophenyl thioimidazole-2- ylsulfonyl647 N-t-butyloxycarbonyl- 3,5-dimethylisoxazol- OMe 607 4-amidinophenyl 4-ylsulfonyl TFA salt, 5(R), N.sup.2 (S) isomer__________________________________________________________________________ TABLE 2B______________________________________ ##STR182##Exam-pleNum- MSber R.sup.1V R.sup.5a R.sup.16 Y (M + H).sup.+______________________________________651 4-amidino- methyl benzyloxycarbony OMe 496 phenyl652 4-amidino- methyl n-butyloxycarbony OMe phenyl653 4-amidino- methyl 3-methylphenyl- OMe phenyl sulfonyl654 4-amidino- methyl benzyloxycarbonyl OH phenyl655 4-amidino- methyl n-butyloxycarbonyl OH phenyl656 4-amidino- methyl 3-methylphenyl- OH phenyl sulfonyl657 4-amidino- methyl 4-methylphenyl- OH phenyl sulfonyl658 4-amidino- methyl 4-methylphenyl- OMe phenyl sulfonyl659 4-amidino- methyl n-butylsulfonyl OH phenyl660 4-amidino- methyl n-butylsulfonyl OMe phenyl______________________________________ TABLE 2C______________________________________ ##STR183##Exam-pleNum- MSber R.sup.1V R.sup.16 R.sup.17 Y (M + H).sup.+______________________________________661 4-amidino- benzyloxycarbonyl methyl OMe phenyl662 4-amidino- benzyloxycarbonyl methyl OH phenyl663 4-amidino- n-butyloxycarbonyl methyl OMe phenyl664 4-amidino- n-butoxycarbonyl methyl OH phenyl665 4-amidino- 3-methylphenyl- methyl OMe phenyl sulfonyl666 4-amidino- 3-methylphenyl- methyl OH 502 phenyl sulfonyl667 4-amidino- 4-methylphenyl- methyl OMe phenyl sulfonyl668 4-amidino- 4-methylphenyl- methyl OH phenyl sulfonyl669 4-amidino- n-butylsulfonyl methyl OMe phenyl670 4-amidino- n-butylsulfonyl methyl OH phenyl______________________________________ TABLE 2D______________________________________ ##STR184##Ex-am-pleNum- MSber R.sup.1V R.sup.16 Y (M + H).sup.+______________________________________701 4-amidinophenyl benzyloxycarbonyl OH702 4-amidinophenyl t-butyloxycarbonyl OH703 4-amidinophenyl n-butyloxycarbonyl OH704 4-amidinophenyl ethyloxycarbonyl OH705 4-amidinophenyl methyloxycarbonyl OH706 4-amidinophenyl phenylethylcarbonyl OH707 4-amidinophenyl 2,2-dimethyl- OH propylcarbonyl708 4-amidinophenyl n-pentylcarbonyl OH709 4-amidinophenyl n-butylcarbonyl OH710 4-amidinophenyl propionyl OH711 4-amidinophenyl acetyl OH712 4-amidinophenyl methylsulfonyl OH713 4-amidinophenyl ethylsulfonyl OH714 4-amidinophenyl n-butylsulfonyl OH715 4-amidinophenyl phenylsulfonyl OH716 4-amidinophenyl 4-methylphenyl- OH sulfonyl717 4-amidinophenyl benzylsulfonyl OH 488718 4-amidinophenyl 2-pyridylcarbonyl OH719 4-amidinophenyl 3-pyridylcarbonyl OH720 4-amidinophenyl 4-pyridylcarbonyl OH721 4-amidinophenyl 2-pyridylmethyl- OH carbonyl722 4-amidinophenyl 3-pyridylmethyl- OH carbonyl723 4-amidinophenyl 4-pyridylmethyl- OH carbonyl724 4-amidinophenyl 2-pyridylmethoxy- OH carbonyl725 4-amidinophenyl 3-pyridylmethoxy- OH carbonyl726 4-amidinophenyl 4-pyridylmethoxy- OH carbonyl727 4-amidinophenyl benzyloxycarbonyl OMe 480728 4-amidinophenyl t-butyloxycarbonyl OMe729 4-amidinophenyl n-butyloxycarbonyl OMe 446730 4-amidinophenyl ethyloxycarbonyl OMe731 4-amidinophenyl methyloxycarbonyl OMe732 4-amidinophenyl phenylethylcarbonyl OMe733 4-amidinophenyl 2,2-dimethyl- OMe propylcarbonyl734 4-amidinophenyl n-pentylcarbonyl OMe735 4-amidinophenyl n-butylcarbonyl OMe736 4-amidinophenyl propionyl OMe737 4-amidinophenyl acetyl OMe738 4-amidinophenyl methylsulfonyl OMe739 4-amidinophenyl ethylsulfonyl OMe740 4-amidinophenyl n-butylsulfonyl OMe741 4-amidinophenyl phenylsulfonyl OMe742 4-amidinophenyl 4-methylphenyl- OMe sulfonyl743 4-amidinophenyl benzylsulfonyl OMe744 4-amidinophenyl 2-pyridylcarbonyl OMe745 4-amidinophenyl 3-pyridylcarbonyl OMe746 4-amidinophenyl 4-pyridylcarbonyl OMe747 4-amidinophenyl 2-pyridylmethyl- OMe carbonyl748 4-amidinophenyl 3-pyridylmethyl- OMe carbonyl799 4-amidinophenyl 4-pyridylmethyl- OMe carbonyl750 4-amidinophenyl 2-pyridylmethoxy- OMe carbonyl751 4-amidinophenyl 3-pyridylmethoxy- OMe carbonyl752 4-amidinophenyl 4-pyridylmethoxy- OMe carbonyl753 4-piperidinylethyl benzylcarbonyl OMe754 4-(BOCamidino)- benzyloxycarbonyl OMe phenyl755 4-(BOCamidino)- n-butyloxycarbonyl OMe phenyl756 4-amidinophenyl 1-naphthylsulfonyl OMe757 4-amidinophenyl 2-naphthylsulfonyl OMe758 4-piperidinylethyl n-butyloxycarbonyl OMe 440759 4-amidinophenyl 2-thienylsulfonyl OMe760 4-amidinophenyl 3-methylphenyl- OMe sulfonyl761 4-amidinophenyl 4-fluorophenyl- OMe sulfonyl762 4-amidinophenyl 4-methoxyphenyl- OMe sulfonyl763 4-amidinophenyl n-propylsulfonyl OMe764 4-amidinophenyl 2-phenylethyl- OMe sulfonyl765 4-amidinophenyl 4-isopropylphenyl- OMe sulfonyl766 4-amidinophenyl 3-phenylpropyl- OMe sulfonyl767 4-amidinophenyl 3-pyridylsulfonyl OMe768 4-amidinophenyl 2-pyridylsulfonyl OMe769 4-amidinophenyl n-butylaminosulfonyl OMe770 4-amidinophenyl i-butylaminosulfonyl OMe771 4-amidinophenyl t-butylaminosulfonyl OMe772 4-amidinophenyl i-propylamino- OMe sulfonyl773 4-amidinophenyl cyclohexylamino- OMe sulfonyl774 4-amidinophenyl phenylaminosulfonyl OMe775 4-amidinophenyl benzylaminosulfonyl OMe776 4-amidinophenyl dimethylamino- OMe sulfonyl777 2-fluoro-4-amidino- 3-methylphenyl- OMe phenyl sulfonyl778 5-amidino-2-pyridyl n-butyloxycarbonyl OMe779 5-amidino-2-pyridyl 3-methylphenyl- OMe sulfonyl780 6-amidino-3-pyridyl n-butyloxycarbonyl OMe781 6-amidino-3-pyridyl 3-methylphenyl- OMe sulfonyl782 4-amidinophenyl phenylaminocarbonyl OMe783 4-amidinophenyl benzylaminocarbonyl OMe784 4-amidinophenyl n-butylaminocarbonyl OMe785 4-amidinophenyl n-bexyloxycarbonyl OMe786 4-amidinophenyl n-hexyloxycarbonyl OH787 4-amidinophenyl isobutyloxycarbonyl OMe788 4-amidinophenyl isobutyloxycarbonyl OH789 4-amidinophenyl 2-cyclopropylethoxy- OMe carbonyl790 4-amidinophenyl 2-cyclopropylethoxy- OH carbonyl791 4-amidinophenyl 2-cyclopentylethoxy- OMe carbonyl792 4-amidinophenyl 2-cyclopentylethoxy- OH carbonyl793 4-amidinophenyl n-propylsulfonyl OMe794 4-amidinophenyl 2-methylphenyl- OMe sulfonyl795 4-amidinophenyl 2-benzothienyl- OMe sulfonyl796 4-amidinophenyl 2-benzothienyl- OMe sulfonyl797 4-amidinophenyl 2,2,5,7,8-pentamethyl OH 3,4-dihydro-2Hbenzo- pyran-6-ylsulfonyl798 4-amidinophenyl 3-methylphenylsulfonyl OH 486______________________________________ TABLE 2E______________________________________ ##STR185##Ex-am-pleNum- MSber R.sup.1V R.sup.16 Y (M + H).sup.+______________________________________801 4-amidinophenyl benzyloxycarbonyl OH802 4-amidinophenyl t-butyloxycarbonyl OH803 4-amidinophenyl n-butyloxycarbonyl OH804 4-amidinophenyl ethyloxycarbonyl OH805 4-amidinophenyl methyloxycarbonyl OH806 4-amidinophenyl phenylethylcarbonyl OH807 4-amidinophenyl 2,2-dimethyl- OH propylcarbonyl808 4-amidinophenyl n-pentylcarbonyl OH809 4-amidinophenyl n-butylcarbonyl OH810 4-amidinophenyl propionyl OH811 4-amidinophenyl acetyl OH812 4-amidinophenyl methylsulfonyl OH813 4-amidinophenyl ethylsulfonyl OH814 4-amidinophenyl n-butylsulfonyl OH815 4-amidinophenyl phenylsulfonyl OH816 4-amidinophenyl 4-methylphenyl- OH 488 sulfonyl817 4-amidinophenyl benzylsulfonyl OH818 4-anudinophenyl 2-pyridylcarbonyl OH819 4-amidinophenyl 3-pyridylcarbonyl OH820 4-amidinophenyl 4-pyridylcarbonyl OH821 4-amidinophenyl 2-pyridylmethyl- OH carbonyl822 4-amidinophenyl 3-pyridylmethyl- OH carbonyl823 4-amidinophenyl 4-pyridylmethyl- OH carbonyl824 4-amidinophenyl 2-pyridylmethoxy- OH carbonyl825 4-amidinophenyl 2-pyridylmethoxy- OH carbonyl826 4-amidinophenyl 4-pyridylmethoxy- OH carbonyl827 4-amidinophenyl benzyloxycarbonyl OMe828 4-amidinophenyl t-butyloxycarbonyl OMe829 4-amidinophenyl n-butyloxycarbonyl OMe 448830 4-amidinophenyl ethyloxycarbonyl OMe831 4-amidinophenyl methyloxycarbonyl OMe832 4-amidinophenyl phenylethylcarbonyl OMe833 4-amidinophenyl 2,2-dimethyl- OMe propylcarbonyl834 4-amidinophenyl n-pentylcarbonyl OMe835 4-amidinophenyl n-butylcarbonyl OMe836 q-amidinophenyl propionyl OMe837 4-amidinophenyl acetyl OMe838 4-amidinophenyl methylsulfonyl OMe839 4-amidinophenyl ethylsulfonyl OMe840 4-amidinophenyl n-butylsulfonyl OMe841 4-amidinophenyl phenylsulfonyl OMe842 4-amidinophenyl 4-methylphenyl- OMe sulfonyl843 4-amidinophenyl benzylsulfonyl OMe844 4-amidinophenyl 2-pyridylcarbonyl OMe845 4-amidinophenyl 3-pyridylcarbonyl OMe846 4-amidinophenyl 4-pyridylcarbonyl OMe847 4-amudinophenyl 2-pyridylmethyl- OMe carbonyl848 4-amidinophenyl 3-pyridylmethyl- OMe carbonyl849 4-amidinophenyl 4-pyridylmethyl- OMe carbonyl850 4-amidinophenyl 2-pyridylmethoxy- OMe carbonyl851 4-amidinopbenyl 3-pyridylmethoxy- OMe carbonyl852 4-amidinophenyl 4-pyridylmethoxy- OMe carbonyl853 4-piperidinylethyl benzylcarbonyl OMe854 4-(BOCamidino)- benzyloxycarbonyl OMe phenyl855 4-(BOCamidino)- n-butyloxycarbonyl OMe phenyl856 4-amidinophenyl 1-naphthylsulfonyl OMe857 4-amidinophenyl 2-naphthylsulfonyl OMe858 4-piperidinylethyl n-butyloxycarbonyl OMe859 4-amidinophenyl 2-thienylsulfonyl OMe860 4-amidinophenyl 3-methylphenyl- OMe sulfonyl861 4-amidinophenyl 4-fluorophenyl- OMe sulfonyl862 4-amidinophenyl 4-methoxyphenyl- OMe sulfonyl863 4-amidinophenyl n-propylsulfonyl OMe864 4-amidinophenyl 2-phenylethyl- OMe sulfonyl865 4-amidinophenyl 4-isopropylphenyl- OMe sulfonyl866 4-amidinophenyl 3-phenylpropyl- OMe sulfonyl867 4-amidinophenyl 3-pyridylsulfonyl OMe868 4-amidinophenyl 2-pyridylsulfonyl OMe869 4-amidinophenyl n-butylaminosulfonyl OMe870 4-amidinophenyl i-butylaminosulfonyl OMe871 4-amidinophenyl t-butylaminosulfonyl OMe872 4-amidinophenyl i-propylamino- OMe sulfonyl873 4-amidinophenyl cyclohexylamino- OMe sulfonyl874 4-amidinophenyl phenylaminosulfonyl OMe875 4-amidinophenyl benzylaminosulfonyl OMe876 4-amidinophenyl dimethylamino- OMe sulfonyl877 2-fluoro-4-amidino- 3-methylphenyl- OMe phenyl sulfonyl878 5-amidino-2-pyridyl n-butyloxycarbonyl OMe879 5-amidino-2-pyridyl 3-methylphenyl- OMe sulfonyl880 6-amidino-3-pyridyl n-butyloxycarbonyl OMe881 6-amidino-3-pyridyl 3-methylphenyl- OMe sulfonyl882 4-amidinophenyl phenylaminocarbonyl OMe883 4-amidinophenyl benzylaminocarbonyl OMe889 4-amidinophenyl n-butylaminocarbonyl OMe885 4-amidinophenyl n-hexyloxycarbonyl OMe886 4-amidinophenyl n-hexyloxycarbonyl OH887 4-amidinophenyl isobutyloxycarbonyl OMe888 4-amidinophenyl isobutyloxycarbonyl OH889 4-amidinophenyl 2-cyclopropylethoxy- OMe carbonyl890 4-amidinophenyl 2-cyclopropylethoxy- OH carbonyl891 4-amidinophenyl 2-cyclopentylethoxy- OMe carbonyl892 4-amidinophenyl 2-cyclopentylethoxy- OH carbonyl893 4-amidinophenyl n-propylsulfonyl OMe894 4-amidinophenyl 2-methylphenyl- OMe sulfonyl895 4-amidinophenyl 2-benzothienyl- OMe sulfonyl896 4-amidinophenyl 2-benzothienyl- OMe sulfonyl897 4-amidinophenyl 2,2,5,7,8-pentamethyl OH 3,4-dihydro-2Hbenzo- pyran-6-ylsulfonyl______________________________________ TABLE 3__________________________________________________________________________ ##STR186##Ex. MSNo. R.sup.2 R.sup.1V FE< p n' Y (M + H).sup.+__________________________________________________________________________171 H ##STR187## C(O)N< 1 1 OH172 H ##STR188## C(O)N< 1 2 OH173 H ##STR189## C(H.sub.2)N< 1 1 OH174 H ##STR190## C(H.sub.2)N< 1 2 OH175 H ##STR191## C(H)C< 1 1 OH176 H ##STR192## C(H)C< 1 2 OH177 H ##STR193## C(O)N< 2 1 OH178 H ##STR194## C(O)N< 2 2 OH179 H ##STR195## C(H.sub.2)N< 2 1 OH180 H ##STR196## C(H.sub.2)N< 2 2 OH181 H ##STR197## C(H)C< 2 1 OH182 H ##STR198## C(H)C< 2 2 OH183 H ##STR199## C(O)N< 3 1 OH184 H ##STR200## C(O)N< 3 2 OH185 H ##STR201## C(H.sub.2)N< 3 1 OH186 H ##STR202## C(H.sub.2)N< 3 2 OH187 H ##STR203## C(H)C< 3 1 OH188 H ##STR204## C(H)C< 3 2 OH189 H ##STR205## C(O)N< 1 1 OH 338190 H ##STR206## C(O)N< 1 2 OH 352191 H ##STR207## C(H.sub.2)N< 1 1 OH192 H ##STR208## C(H.sub.2)N< 1 2 OH193 H ##STR209## C(H)C< 1 1 OH194 H ##STR210## C(H)C< 1 2 OH195 H ##STR211## C(O)N< 2 1 OH196 H ##STR212## C(O)N< 2 2 OH197 H ##STR213## C(H.sub.2)N< 2 1 OH198 H ##STR214## C(H.sub.2)N< 2 2 OH199 H ##STR215## C(H)C< 2 1 OH200 H ##STR216## C(H)C< 2 2 OH201 H ##STR217## C(O)N< 3 1 OH202 H ##STR218## C(O)N< 3 2 OH203 H ##STR219## C(H.sub.2)N< 3 1 OH204 H ##STR220## C(H.sub.2)N< 3 2 OH205 H ##STR221## C(H)C< 3 1 OH206 H ##STR222## C(H)C< 3 2 OH207 Boc ##STR223## C(O)N< 1 1 OH208 Cbz ##STR224## C(O)N< 1 1 OH209 H ##STR225## C(ON< 1 1 ##STR226##210 H ##STR227## C(ON< 1 1 ##STR228##211 H ##STR229## C(ON< 1 1 ##STR230##212 H ##STR231## C(ON< 1 1 ##STR232##213 H ##STR233## C(ON< 1 1 ##STR234##214 H ##STR235## C(ON< 1 1 OEt215 H ##STR236## C(O)N< 1 2 OEt216 H ##STR237## C(H.sub.2)N< 1 1 OEt217 H ##STR238## C(H.sub.2)N< 1 2 OEt218 H ##STR239## C(H)C< 1 1 OEt219 H ##STR240## C(H)C< 1 2 OEt220 H ##STR241## C(O)N< 2 1 OEt221 H ##STR242## C(O)N< 2 2 OEt222 H ##STR243## C(H.sub.2)N< 2 1 OEt223 H ##STR244## C(H.sub.2)N< 2 2 OEt224 H ##STR245## C(H)C< 2 1 OEt225 H ##STR246## C(H)C< 2 2 OEt226 H ##STR247## C(O)N< 3 1 OEt227 H ##STR248## C(O)N< 3 2 OEt228 H ##STR249## C(H.sub.2)N< 3 1 OEt229 H ##STR250## C(H.sub.2)N< 3 2 OEt230 H ##STR251## C(H)C< 3 1 OEt231 H ##STR252## C(H)C< 3 2 OEt232 H ##STR253## C(O)N< 1 1 OEt233 H ##STR254## C(O)N< 1 2 OEt234 H ##STR255## C(H.sub.2)N< 1 1 OEt235 H ##STR256## C(H.sub.2)N< 1 2 OEt236 H ##STR257## C(H)C< 1 1 OEt237 H ##STR258## C(H)C< 1 2 OEt238 H ##STR259## C(O)N< 2 1 OEt239 H ##STR260## C(O)N< 2 2 OEt240 H ##STR261## C(H.sub.2)N< 2 1 OEt241 H ##STR262## C(H.sub.2)N< 2 2 OEt242 H ##STR263## C(H)C< 2 1 OEt243 H ##STR264## C(H)C< 2 2 OEt244 H ##STR265## C(O)N< 3 1 OEt245 H ##STR266## C(O)N< 3 2 OEt246 H ##STR267## C(H.sub.2)N< 3 1 OEt247 H ##STR268## C(H.sub.2)N< 3 2 OEt248 H ##STR269## C(H)C< 3 1 OEt249 H ##STR270## C(H)C< 3 2 OEt250 Boc ##STR271## C(O)N< 1 1 OEt251 Cbz ##STR272## C(O)N< 1 1 OEt373 H ##STR273## C(O)N< 1 2 OH 366__________________________________________________________________________ TABLE 4______________________________________ ##STR274##Ex-am-pleNum-ber R.sup.2 R.sup.1a Z.sup.1 Y______________________________________252 H ##STR275## CH.sub.2 OH253 H NHCH.sub.2).sub.2 CH.sub.2 OH254 H NHCH.sub.2).sub.3 CH.sub.2 OH255 H ##STR276## O OH256 H NHCH.sub.2).sub.2 O OH257 H NHCH.sub.2).sub.3 O OH258 Boc ##STR277## CH.sub.2 OH259 Cbz ##STR278## CH.sub.2 OH260 H ##STR279## CH.sub.2 ##STR280##261 H ##STR281## CH.sub.2 ##STR282##262 H ##STR283## CH.sub.2 ##STR284##263 H ##STR285## CH.sub.2 ##STR286##264 H ##STR287## CH.sub.2 ##STR288##265 H ##STR289## CH.sub.2 OEt266 H ##STR290## CH.sub.2 OEt267 H ##STR291## CH.sub.2 OEt268 H NHCH.sub.2).sub.2 CH.sub.2 OEt269 H NHCH.sub.2).sub.3 CH.sub.2 OEt270 H ##STR292## O OEt271 H NHCH.sub.2).sub.2 O OEt272 H NHCH.sub.2).sub.3 O OEt273 Boc ##STR293## CH.sub.2 OEt274 Cbz ##STR294## CH.sub.2 OEt______________________________________ TABLE 5______________________________________ ##STR295##Example MS(ESI)Number R Y (M + H).sup.+______________________________________375 ##STR296## OH376 ##STR297## OH377 ##STR298## OH 387378 ##STR299## OH379 ##STR300## OH380 ##STR301## OH381 ##STR302## OH382 ##STR303## OH383 ##STR304## OH 415384 ##STR305## OH385 ##STR306## OH386 ##STR307## OH387 ##STR308## OH388 ##STR309## OH389 ##STR310## OH394 ##STR311## OMe 387395 ##STR312## OMe396 ##STR313## OMe397 ##STR314## OMe398 ##STR315## OMe399 ##STR316## OMe400 ##STR317## OMe 402401 ##STR318## OMe402 ##STR319## OMe403 ##STR320## OMe404 ##STR321## OMe405 ##STR322## OMe406 ##STR323## OMe407 ##STR324## OMe408 ##STR325## OMe413 ##STR326## OEt 401414 ##STR327## OEt415 ##STR328## OEt 415416 ##STR329## OEt417 ##STR330## OEt418 ##STR331## OEt419 ##STR332## OEt420 ##STR333## OEt421 ##STR334## OEt422 ##STR335## OEt423 ##STR336## OEt424 ##STR337## OEt425 ##STR338## OEt426 ##STR339## OEt427 ##STR340## OEt432 NHC(CH.sub.3).sub.2 OEt. CH.sub.2 C(O)Y433 N(CH.sub.2 C.sub.6 H.sub.5) OEt (CH.sub.2).sub.2 C(O)Y436 ##STR341## OEt 387437 ##STR342## OEt 387438 ##STR343## OMe 387899 ##STR344## OMe900 ##STR345## OH______________________________________ TABLE 6__________________________________________________________________________ ##STR346## (M + H)Ex. +No. R.sup.2 R.sup.3 R.sup.4a X Y ESI__________________________________________________________________________950 H H 3-methyl- 2-fluoro- OCH.sub.3 521 phenyl- phen-1,4- sulfonyl diyl951 H H 3-methyl- 2-fluoro- OH 507 phenyl- phen-1,4- sulfonyl diyl952 ##STR347## H 3-methyl- phenyl- sulfonylphen-1,4- diyl OCH.sub.3 545953 ##STR348## H 3-methyl- phenyl- sulfonylphen-1,4- diyl OH 532954 H H n-butoxy-phen-1,4- OH 435 carbonyl diyl955 H H 3-methyl-phen-1,4- OCH.sub.3 503 phenyl- diyl sulfonyl956 H H 3-methyl-phen-1,4- OH 489 phenyl- diyl sulfonyl957 H H ##STR349##phen-1,4- diyl OH 527958 H H 4-CF.sub.3 -phen-1,4- OH 543 phenyl- diyl sulfonyl959 H H ##STR350##phen-1,4- diyl OH960 o-CH.sub.3 O- H 3-methyl-phen-1,4- OH benzyl phenyl- diyl sulfonyl961 o-CH.sub.3 O- benzyl H ##STR351##phen-1,4- diyl OH962 o-CH.sub.3 O- benzyl CH.sub.3 ##STR352##phen-1,4- diyl OH963 o-CH.sub.3 O- CH.sub.3 3-methyl-phen-1,4- OH benzyl phenyl- diyl sulfonyl964 H H 2-fluoro-phen-1,4- OH 493 phenyl- diyl sulfonyl965 H H 4-CF.sub.3 -phen-1,4- OH 543 phenyl- diyl sulfonyl966 H H 4-Cl-phen-1,4- OH 509 phenyl- diyl sulfonyl967 H H ##STR353##phen-1,4- diyl OH 525968 3- (CF.sub.3)- benzyl H ##STR354##phen-1,4- diyl OH969 3- (CF.sub.3)- benzyl H ##STR355##phen-1,4- diyl OH970 3- CH.sub.3 3-methyl-phen-1,4- OH (CF.sub.3)- phenyl- diyl benzyl sulfonyl971 3- (CF.sub.3)- benzyl CH.sub.3 ##STR356##phen-1,4- diyl OH972 nBu- H 3-methyl-phen-1,4- OH phenyl- diyl sulfonyl973 nBu- H ##STR357##phen-1,4- diyl OH974 nBu- CH.sub.3 3-methyl-phen-1,4- OH phenyl- diyl sulfonyl975 nBu- CH.sub.3 ##STR358##phen-1,4- diyl OH976 CH.sub.3 CH.sub.3 ##STR359##phen-1,4- diyl OH977 CH.sub.3 CH.sub.3 3-methyl-phen-1,4- OH phenyl- diyl sulfonyl978 H H 3-methyl- 5- OMe 490 phenyl- carboxamido sulfonyl pyrid-2-yl979 H H 4-ethyl-phen-1,4- OH 503 phenyl- diyl sulfonyl__________________________________________________________________________ TABLE 7______________________________________ ##STR360##Ex MSNo. R.sup.1V R.sup.16 Y (M + H).sup.+______________________________________980 4-amidinophenyl H OH981 4-amidinophenyl benzyloxycarbonyl OH982 4-amidinophenyl t-butoxycarbonyl OH983 4-amidinophenyl n-butyloxycarbonyl OH984 4-amidinophenyl ethyloxycarbonyl OH985 4-amidinophenyl methyloxycarbonyl OH986 4-amidinophenyl phenylethylcarbonyl OH987 4-amidinophenyl 2,2-dimethyl- OH propylcarbonyl988 4-amidinophenyl n-pentylcarbonyl OH989 4-amidinophenyl n-butylcarbonyl OH990 4-amidinophenyl propionyl OH991 4-amidinophenyl acetyl OH992 4-amidinophenyl methylsulfonyl OH993 4-amidinophenyl ethylsulfonyl OH994 4-amidinophenyl n-butylsulfonyl OH995 4-amidinophenyl phenylsulfonyl OH996 4-amidinophenyl 4-methylphenyl- OH 474 sulfonyl997 4-amidinophenyl benzylsulfonyl OH998 4-amidinophenyl 2-pyridylcarbonyl OH999 4-amidinophenyl 3-pyridylcarbonyl OH1000 4-amidinophenyl 4-pyridylcarbonyl OH1001 4-amidinophenyl 2-pyridylmethyl- OH carbonyl1002 4-amidinophenyl 3-pyridylmethyl- OH carbonyl1003 4-amidinophenyl 4-pyridylmethyl- OH carbonyl1004 4-amidinophenyl 2-pyridylmethoxy- OH carbonyl1005 4-amidinophenyl 3-pyridylmethoxy- OH carbonyl1006 4-amidinophenyl 4-pyridylmethoxy- OH carbonyl1007 4-amidinophenyl H OMe1008 4-amidinophenyl benzyloxycarbonyl OMe1009 4-amidinophenyl t-butyloxycarbonyl OMe1010 4-amidinophenyl n-butyloxycarbonyl OMe1011 4-amidinophenyl ethyloxycarbonyl OMe1012 4-amidinophenyl methyloxycarbonyl OMe1013 4-amidinophenyl phenylethylcarbonyl OMe1014 4-amidinophenyl 2,2-dimethyl- OMe propylcarbonyl1015 4-amidinophenyl n-pentylcarbonyl OMe1016 4-amidinophenyl n-butylcarbonyl OMe1017 4-amidinophenyl propionyl OMe1018 4-amidinophenyl acetyl OMe1019 4-amidinophenyl methylsulfonyl OMe1020 4-amidinophenyl ethylsulfonyl OMe1021 4-amidinophenyl n-butylsulfonyl OMe1022 4-amidinophenyl phenylsulfonyl OMe1023 4-amidinophenyl 4-methylphenyl- OMe sulfonyl1024 4-amidinophenyl benzylsulfonyl OMe1025 4-amidinophenyl 2-pyridylcarbonyl OMe1026 4-amidinophenyl 3-pyridylcarbonyl OMe1027 4-amidinophenyl 4-pyridylcarbonyl OMe1029 4-amidinophenyl 2-pyridylmethyl- OMe carbonyl1030 4-amidinophenyl 3-pyridylmethyl- OMe carbonyl1031 4-amidinophenyl 4-pyridylmethyl- OMe carbonyl1032 4-amidinophenyl 2-pyridylmethoxy- OMe carbonyl1033 4-amidinophenyl 3-pyridylmethoxy- OMe carbonyl1034 4-amidinophenyl 4-pyridylmethoxy- OMe carbonyl1035 4-piperidinylethyl benzylcarbonyl OMe1036 4-(BOCamidino)- benzyloxycarbonyl OMe phenyl1037 4-(BOCamidino)- n-butyloxycarbonyl OMe phenyl1038 4-amidinophenyl 1-naphthylsulfonyl OMe1039 4-amidinophenyl 2-naphthylsulfonyl OMe1040 4-amidinophenyl styrylsulfonyl OMe1041 4-piperidinylethyl n-butyloxycarbonyl OMe1042 4-amidinophenyl 4-butyloxyphenyl- OMe sulfonyl1043 4-amidinophenyl 2-thienylsulfonyl OMe1044 4-amidinophenyl 3-methylphenyl- OMe sulfonyl1045 4-amidinophenyl 4-iodophenyl OMe1046 4-amidinophenyl 3-trifluoromethyl- OMe phenylsulfonyl1047 4-amidinophenyl 3-chlorophenyl- OMe sulfonyl1048 4-amidinophenyl 2-methoxycarbonyl- OMe phenylsulfonyl1050 4-amidinophenyl 2,4,6-trimethyl- OMe phenylsulfonyl1051 4-amidinophenyl 2-chlorophenyl- OMe sulfonyl1052 4-amidinophenyl 2-trifluoromethyl- OMe phenylsulfonyl1053 4-amidinophenyl 4-trifluoromethyl- OMe phenylsulfonyl1054 4-amidinophenyl 2-fluorophenyl- OMe sulfonyl1055 4-amidinophenyl 4-fluorophenyl- OMe sulfonyl1056 4-amidinophenyl 4-methoxyphenyl- OMe sulfonyl1057 4-amidinophenyl 2,3,5,6-tetramethyl- OMe phenylsulfonyl1058 4-amidinophenyl 4-cyanophenyl- OMe sulfonyl1059 4-amidinophenyl 4-chlorophenyl- OMe sulfonyl1060 4-amidinophenyl 4-ethylphenyl- OMe sulfonyl1061 4-amidinophenyl 4-propylphenyl- OMe sulfonyl1062 4-amidinophenyl n-propylsulfonyl OMe1063 4-amidinophenyl 2-phenylethyl- OMe sulfonyl1064 4-amidinophenyl 4-isopropylphenyl- OMe sulfonyl1065 4-amidinophenyl 3-phenylpropyl- OMe sulfonyl1066 4-amidinophenyl 3-pyridylsulfonyl OMe1067 4-amidinophenyl 2-pyridylsulfonyl OMe1069 4-amidinophenyl 2,2-diphenyl-1- OMe ethenylsulfonyl1070 4-amidinophenyl 2-pyrimidinyl- OMe sulfonyl1071 4-amidinophenyl 4-methyl-2- OMe pyrimidinylsulfonyl1072 4-amidinophenyl 4,6-dimethyl-2- OMe pyrimidinylsulfonyl1073 4-amidinophenyl 1,2,4-triazol-3- OMe ylsulfonyl1074 4-amidinophenyl 1-methyl-1,3,4- OMe triazol-5-ylsulfonyl1075 4-amidinophenyl 3,5-dimethyl-4- OMe pyrazolylsulfonyl1076 4-amidinophenyl 1-phenyl-4- OMe pyrazolylsulfonyl1077 4-amidinophenyl n-butylaminosulfonyl OMe1078 4-amidinophenyl i-butylaminosulfonyl OMe1079 4-amidinophenyl t-butylaminosulfonyl OMe1080 4-amidinophenyl i-propylamino- OMe sulfonyl1081 4-amidinophenyl cyclohexylamino- OMe sulfonyl1082 4-amidinophenyl phenylaminosulfonyl OMe1083 4-amidinophenyl benzylaminosulfonyl OMe1084 4-amidinophenyl dimethylamino- OMe sulfonyl1085 4-amidino-2-fluoro- 3-methylphenyl- OMe phenyl sulfonyl1086 2-amidino-5-pyridyl n-butyloxycarbonyl OMe1088 2-amidino-5-pyridyl 3-methylphenyl- OMe sulfonyl1089 3-amidino-6-pyridyl n-butyloxycarbonyl OMe1090 3-amidino-6-pyridyl 3-methylphenyl- OMe sulfonyl1091 4-amidinophenyl phenylaminocarbonyl OMe1092 4-amidinophenyl 4-fluorophenylamino- OMe carbonyl1093 4-amidinophenyl 1-naphthylamino- OMe carbonyl1094 4-amidinophenyl benzylaminocarbonyl OMe1095 4-amidinophenyl n-butylaminocarbonyl OMe1096 4-amidinophenyl 4-ethylphenyl- OMe carbonyl1097 4-amidinophenyl biphenylcarbonyl OMe1098 4-amidinophenyl 2-naphthylcarbonyl OMe1099 4-amidinophenyl (2-chlorophenyl) OMe methoxycarbonyl1100 4-amidinophenyl (2-chlorophenyl) OH methoxycarbonyl1101 4-amidinophenyl (2-bromophenyl) OMe methoxycarbonyl1102 4-amidinophenyl (2-bromophenyl) OH methoxycarbonyl1103 4-amidinophenyl n-hexyloxycarbonyl OMe1104 4-amidinophenyl n-hexyloxycarbonyl OH1105 4-amidinophenyl isobutyloxycarbonyl OMe1106 4-amidinophenyl isobutyloxycarbonyl OH1107 4-amidinophenyl 2-cyclopropylethoxy- OMe carbonyl1108 4-amidinophenyl 2-cyclopropylethoxy- OH carbonyl1110 4-amidinophenyl 2-cyclopentylethoxy- OMe carbonyl1111 4-amidinophenyl 2-cyclopentylethoxy- OH carbonyl1112 4-amidinophenyl 4,4,4-trifluoro- OMe butyloxycarbonyl1113 4-amidinophenyl 4,4,4-trifluoro- OH butyloxycarbonyl1114 4-amidinophenyl n-propylsulfonyl OH1115 4-amidinophenyl 2-methylphenyl- OMe sulfonyl1116 4-amidinophenyl 4-chloro-2,5-dimethyl- OH 536 phenylsulphonyl1117 4-amidinophenyl 2,3-dichlorophenyl OMe sulfonyl1118 4-amidinophenyl 2-bromophenyl- OMe sulfonyl1119 4-amidinophenyl 3-bromophenyl- OMe sulfonyl1120 4-amidinophenyl 4-bromophenyl- OMe sulfonyl1121 4-amidinophenyl biphenylsulfonyl OMe1122 4-amidinophenyl 5-chloro-1,3- OMe dimethyl-4-pyrazolyl1123 4-amidinophenyl 3-bromo-2- OMe thienylsulfonyl1124 4-amidinophenyl 5-bromo-2- OMe thienylsulfonyl1125 4-amidinophenyl 5-�1-methyl-5- OMe trifluoromethyl-3- pyrazolyl!-2- thienylsulfonyl1127 4-amidinophenyl 5-(3-isoxazolyl)-2- OMe thienylsulfonyl1128 4-amidinophenyl 5-(2-pyridinyl)-2- OMe thienylsulfonyl1129 4-amidinophenyl 4-methyl-2- OMe methylcarbonylamino-5- thiazolylsulfonyl1130 4-amidinophenyl 2-benzothienyl- OMe sulfonyl1131 4-amidinophenyl 2-benzothienyl- OMe sulfonyl1132 4-amidinophenyl 3-methyl-2- OMe benzothienylsulfonyl1133 4-amidinophenyl 8-quinolinylsulfonyl OMe1134 4-amidinophenyl 8-quinolinylsulfonyl OH1135 4-amidinophenyl 2,1,3-benzo- OMe thiadiazol-4-ylsulfonyl1136 4-amidinophenyl 2,1,3-benzo- OH thiadiazol-4-ylsulfonyl1137 4-amidinophenyl 4-N,N-dimethylamino-1- OMe naphthylsulfonyl1138 4-amidinophenyl 4-N,N-dimethylamino- OH haphthylsulfonyl1139 4-amidinophenyl 2,1,3-benzoxadiazol-4- OMe ylsulfonyl1140 4-amidinophenyl 2,1,3-benzoxadiazol-4- OH ylsulfonyl1141 4-amidinophenyl 2,2,5,7,8-pentamethyl OMe 3,4-dihydro-2Hbenzo- pyran-6-ylsulfonyl1143 4-amidinophenyl 2,2,5,7,8-pentamethyl OH 3,4-dihydro-2Hbenzo- pyran-6-ylsulfonyl1144 4-N-methylamidino 3-methylphenylsulfonyl OMe phenyl1145 4-N-ethylamidino 3-methylphenylsulfonyl OMe phenyl1146 4-N-n-propylami- 3-methylphenylsulfonyl OMe dinophenyl1147 4-N-benzylamidino 3-methylphenylsulfonyl OMe phenyl1148 4-N-n-butylamidino 3-methylphenylsulfonyl OMe phenyl1149 4-N-methylamidino 3-methylphenylsulfonyl OH phenyl1150 4-N-ethylamidino 3-methylphenylsulfonyl OH phenyl1151 4-N-n-propylami- 3-methylphenylsulfonyl OH dinophenyl1152 4-N-benzylamidino 3-methylphenylsulfonyl OH phenyl1153 4-N-benzylamidino 3-methylphenylsulfonyl OH phenyl1154 4-N-methylamidino- n-butyloxycarbonyl OMe phenyl1155 4-N-ethylamidino- n-butyloxycarbonyl OMe phenyl1156 4-N-npropylami- n-butyloxycarbonyl OMe dinophenyl1157 4-N-n-butylamidino- n-butyloxycarbonyl OMe phenyl1158 4-N-benzylamidino- n-butyloxycarbonyl OMe phenyl1160 4-N-methylamidino- n-butyloxycarbonyl OH phenyl1161 4-N-ethylamidino- n-butyloxycarbonyl OH phenyl1162 4-N-n-propylami- n-butyloxycarbonyl OH dinophenyl1163 4-N-butylamidino- n-butyloxycarbonyl OH phenyl1164 4-N-benzylamidino- n-butyloxycarbonyl OH phenyl1165 4-(acetoxyamidino)- n-butyloxycarbonyl OMe phenyl1166 4-(acetoxyamidino)- n-butyloxycarbonyl OH phenyl1167 4-(acetoxyamidino)- isobutyloxycarbonyl OMe phenyl1168 4-(acetoxyamidino)- isobutyloxycarbonyl OH phenyl1169 4-(acetoxyamidino)- cyclopropylethoxy- OMe phenyl carbonyl1170 4-(acetoxyamidino)- cyclopropylethoxy- OH phenyl carbonyl1171 4-(acetoxyamidino)- benzyloxycarbonyl OMe phenyl1172 4-(acetoxyamidino)- benzyloxycarbonyl OH phenyl1173 4-(acetoxyamidino)- 4-methylphenylsulfonyl OMe phenyl1174 4-(acetoxyamidino)- 4-methylphenylsulfonyl OH phenyl1175 4-piperidinylethyl n-butloxycarbonyl OMe1176 4-piperidinylethyl benzyloxycarbonyl OMe1177 4-piperidinylethyl n-propyloxycarbonyl OMe1178 4-piperidinylethyl isobutyloxycarbonyl OMe1179 4-piperidinylethyl 2-methylphenylsulfonyl OMe1180 4-piperidinylethyl 3-methylphenylsulfonyl OMe1181 4-piperidinylethyl 4-methylphenylsulfonyl OMe1182 4-piperidinylethyl 2-bromophenylsulfonyl OMe1183 4-piperidinylethyl 2-bromophenylsulfonyl OMe1184 4-piperidinylethyl 2-methoxyphenylsulfonyl OMe1185 4-piperidinylethyl 3-methoxyphenylsulfonyl OMe1186 4-piperidinylethyl 3-trifluoromethylphenyl OMe sulfonyl1187 4-piperidinylethyl n-propylsulfonyl OMe1188 4-piperidinylethyl n-butylsulfonyl OMe1189 4-piperidinylethyl isopropylsulfonyl OMe1190 4-piperidinylethyl isobutylsulfonyl OMe1191 4-piperidinylethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1192 4-piperidinylethyl 2,4-dimethyl- OMe thiazolylsulfonyl1193 4-piperidinylpropyl n-butyloxycarbonyl OMe1194 4-piperidinylpropyl n-propyloxycarbonyl OMe1195 4-piperidinylpropyl benzyloxycarbonyl OMe1196 4-piperidinylpropyl isobutyloxycarbonyl OMe1197 4-piperidinylpropyl 2-methylphenyl- OMe sulfonyl1198 4-piperidinylpropyl 3-methylphenyl- OMe sulfonyl1199 4-piperidinylpropyl 4-methylphenyl- OMe sulfonyl1200 4-piperidinylpropyl 2-bromophenylsulfonyl OMe1201 4-piperidinylpropyl n-butylsulfonyl OMe1202 4-piperidinylpropyl isobutylsulfonyl OMe1203 4-piperidinylpropyl 3,5-dimethyl- OMe isoxazolylsulfonyl1204 4-piperidinylpropyl 2,4-dimethyl- OMe thiazoylsulfonyl1205 4-piperidinylethyl n-butyloxycarbonyl OH1206 4-piperidinylethyl n-propyloxycarbonyl OH1207 4-piperidinylethyl benzyloxycarbonyl OH1208 4-piperidinylethyl isobutyloxycarbonyl OH1209 4-piperidinylethyl 2-methylphenyl- OH sulfonyl1210 4-piperidinylethyl 3-methylphenyl- OH sulfonyl1211 4-piperidinylethyl 4-methylphenyl- OH sulfonyl1212 4-piperidinylethyl 2-bromophenylsulfonyl OH1213 4-piperidinylethyl 3,5-dimethyl- OH isoxazolylsulfonyl1214 4-piperidinylethyl 2,4-dimethyl- OH thiazolylsulfonyl1215 4-piperidinylethyl n-butylsulfonyl OH1216 4-piperidinylethyl isobutylsulfonyl OH1217 4-piperidinylpropyl n-butyloxycarbonyl OH1218 4-piperidinylpropyl n-propyloxycarbonyl OH1219 4-piperidinylpropyl isobutyloxycarbonyl OH1220 4-piperidinylpropyl 2-methylphenyl- OH carbonyl1221 4-piperidinylpropyl 4-methylphenyl- OH carbonyl1222 4-piperidinylpropyl 2-bromophenyl-carbonyl OH1223 4-piperidinylpropyl 3,5-dimethyl- OH isoxazolylsulfonyl1224 4-piperidinylpropyl n-butylsulfonyl OH1225 4-piperidinylpropyl isobutylsulfonyl OH1226 4-amidinopiperi- n-butyloxycarbonyl OMe dinyl1227 4-amidinopiperi- isobutyloxycarbonyl OMe dinyl1228 4-amidinopiperi- n-propyloxycarbonyl OMe dinyl1229 4-amidinopiperi- benzyloxycarbonyl OMe dinyl1230 4-amidinopiperi- n-butylsulfonyl OMe dinyl1231 4-amidinopiperi- isobutylsulfonyl OMe dinyl1232 4-amidinopiperi- n-propylsulfonyl OMe dinyl1233 4-amidinopiperi- 2-methylphenyl- OMe dinyl sulfonyl1234 4-amidinopiperi- 4-methylphenyl- OMe dinyl sulfonyl1235 4-amidinopiperi- benzylsulfonyl OMe dinyl1236 4-amidinopiperi- 3,5-dimethyl- OMe dinyl isoxazolylsulfonyl1237 4-amidinopiperi- 2,4-dimethyl- OMe dinyl thiazolylsulfonyl1238 4-amidinopiperi- 4-methylphenyl- OH dinyl sulfonyl1239 4-amidinopiperi- n-butyloxycarbonyl OH dinyl1240 4-amidinopiperi- isobutyloxycarbonyl OH dinyl1241 4-amidinopiperi- n-propyloxycarbonyl OH dinyl1242 4-amidinopiperi- benzyloxycarbonyl OH dinyl1243 4-amidinopiperi- n-butylsulfonyl OH dinyl1244 4-amidinopiperi- isobutylsulfonyl OH dinyl1245 4-amidinopiperi- 2-methylphenyl- OH dinyl sulfonyl1246 4-amidinopiperi- 3-methylphenyl- OH dinyl sulfonyl1247 4-amidinopiperi- 4-methylphenyl- OH dinyl sulfonyl1248 4-amidinopiperi- 2-bromophenylsulfonyl OH dinyl1249 4-amidinopiperi- 3-bromophenylsulfonyl OH dinyl1250 4-amidinopiperi- 3,5-dimethyl- OH dinyl isoxazolylsulfonyl1251 4-amidinopiperi- 2,4-dimethyl- OH dinyl thiazolylsulfonyl1252 4-amidino- n-butyloxycarbonyl OMe piperidinylmethyl1253 4-amidino- n-propyloxycarbonyl OMe piperidinylmethyl1254 4-amidino- benzyloxycarbonyl OMe piperidinylmethyl1255 4-amidino- n-butylsulfonyl OMe piperidinylmethyl1256 4-amidino- n-propylsulfonyl OMe piperidinylmethyl1257 4-amidino- 2-methylphenyl- OMe piperidinylmethyl sulfonyl1258 4-amidino- 3-methylphenyl- OMe piperidinylmethyl sulfonyl1259 4-amidino- 4-methylphenyl- OMe piperidinylmethyl sulfonyl1260 4-amidino- 2-bromophenylsulfonyl OMe piperidinylmethyl1261 4-amidino- 3-bromophenylsulfonyl OMe piperidinylmethyl1262 4-amidino- 3,5-dimethyl- OMe piperidinylmethyl isoxazolylsulfonyl1263 4-amidino- 4-methylphenyl- OH piperidinylmethyl sulfonyl1264 4-amidino- n-butyloxycarbonyl OH piperidinylmethyl1265 4-amidino- n-propyloxycarbonyl OH piperidinylmethyl1266 4-amidino- benzyloxycarbonyl OH piperidinylmethyl1267 4-amidino- n-butylsulfonyl OH piperidinylmethyl1268 4-amidino- 2-methylphenyl- OH piperidinylmethyl sulfonyl1269 4-amidino- 3-methylphenyl- OH piperidinylmethyl sulfonyl1270 4-amidino- 2-bromophenyl-sulfonyl OH piperidinylmethyl1271 4-aminido- 3-bromophenyl-sulfonyl OH piperidinylmethyl1272 4-amidino- 3,5-dimethyl- OH piperidinylmethyl isoxazolylsulfonyl1273 4-quinuclidinylethyl n-butyloxycarbonyl OH1274 4-quinuclidinylethyl n-propyloxycarbonyl OH1275 4-quinuclidinylethyl benzyloxycarbonyl OH1276 4-quinuclidinylethyl n-butylsulfonyl OH1277 4-quinuclidinylethyl 2-methylphenyl- OH sulfonyl1278 4-quinuclidinylethyl 4-methylphenyl- OH sulfonyl1279 4-quinuclidinylethyl 2-bromophenylsulfonyl OH1280 4-quinuclidinylethyl 3-bromophenylsulfonyl OH1281 4-quinuclidinylethyl 3,5-dimethyl- OH isoxazolylsulfonyl1282 guanidinopropyl n-butyloxycarbonyl OMe1283 guanidinopropyl n-propyloxycarbonyl OMe1284 guanidinopropyl benzyloxycarbonyl OH 4351285 guanidinopropyl n-butylsulfonyl OMe1286 guanidinopropyl 2-methylphenyl- OMe sulfonyl1287 guanidinopropyl 3-methylphenyl- OMe sulfonyl1288 guanidinopropyl 2-bromophenylsulfonyl OMe1289 guanidinopropyl 3-bromophenylsulfonyl OMe1290 guanidinopropyl 3,5-dimethyl- OMe isoxazolylsulfonyl1291 guanidinopropyl benzylsulfonyl OMe1292 guanidinopropyl styrylsulfonyl OMe1293 guanidinopropyl 2-benzothiophene- OMe sulfonyl1294 guanidinopropyl n-butyloxycarbonyl OH1295 guanidinopropyl n-propyloxycarbonyl OH1296 guanidinopropyl benzyloxycarbonyl OH1297 guanidinopropyl n-butylsulfonyl OH1298 guanidinopropyl 2-methylphenyl- OH sulfonyl1299 guanidinopropyl 3-methylphenyl- OH sulfonyl1300 guanidinopropyl 4-mthylphenyl- OH sulfonyl1301 guanidinopropyl 2-bromophenylsulfonyl OH1302 guanidinopropyl 3-bromophenylsulfonyl OH1303 guanidinopropyl 3,5-dimethyl- OH isoxazolylsulfonyl1304 guanidinopropyl 2,4-dimethyl- OH thiazolylsulfonyl1305 guanidinopropyl benzylsulfonyl OH1306 guanidinopropyl styrylsulfonyl OH1307 guanidinopropyl 2-benzothiophene- OH sulfonyl1308 guanidinobutyl n-butyloxycarbonyl OH1309 guanidinobutyl n-butylsulfonyl OH1310 guanidinobutyl phenylsulfonyl OH1311 guanidinobutyl 2-methylphenyl- OH sulfonyl1312 guanidinobutyl 4-methylphenyl- OH sulfonyl1313 guanidinobutyl 2-bromophenylsulfonyl OH1314 guanidinobutyl 3,5-dimethyl- OH isoxazolylsulfonyl1315 guanidinobutyl 2,4-dimethyl- OH thiazolylsulfonyl1316 guanidinobutyl benzylsulfonyl OH1317 guanidinobutyl styrylsulfonyl OH1318 guanidinobutyl 3-fluorophenyl- OH sulfonyl1319 guanidinobutyl n-butyloxycarbonyl OMe1320 guanidinobutyl n-butylsulfonyl OMe1321 guanidinobutyl benzyloxycarbonyl OH 4491322 guanidinobutyl phenylsulfonyl OMe1323 guanidinobutyl 2-methylphenyl- OMe sulfonyl1324 guanidinobutyl 2-bromophenylsulfonyl OMe1325 guanidinobutyl 3-bromophenylsulfonyl OMe1326 guanidinobutyl 3,5-dimethyl- OMe isoxazolyl sulfonyl1327 guanidinobutyl benzylsulfonyl OMe1328 guanidinobutyl n-butyloxycarbonyl OH1329 guanidinobutyl isobutyloxycarbonyl OH1330 guanidinobutyl n-propyloxycarbonyl OH1331 guanidinobutyl phenylsulfonyl OH1332 guanidinobutyl n-butylsulfonyl OH1333 guanidinobutyl 2-methylphenyl- OH sulfonyl1334 guanidinobutyl 3-methylphenyl- OH sulfonyl1335 guanidinobutyl 4-methylphenyl- OH sulfonyl1336 guanidinobutyl 2-bromophenylsulfonyl OH1337 4-piperidinylmethyl- n-butyloxycarbonyl OH aminocarbonyl1338 4-piperidinylmethyl- n-butyloxycarbonyl OMe amino-carbonyl1339 4-piperidinylmethyl- benzyloxycarbonyl OH amino-carbonyl1340 4-piperidinylmethyl- benzyloxycarbonyl OMe amino-carbonyl1341 4-piperidinylmethyl- n-butylsulfonyl OH amino-carbonyl1342 4-piperidinylmethyl- n-butylsulfonyl OMe amino-carbonyl1343 4-piperidinylmethyl- 2-methylphenyl- OH amino-carbonyl sulfonyl1344 4-piperidinylmethyl- 2-methylphenyl- OMe amino-carbonyl sulfonyl1345 4-piperidinylmethyl- 3-methylphenyl- OH amino-carbonyl sulfonyl1346 4-piperidinylmethyl- 4-methylphenyl- OH amino-carbonyl sulfonyl1347 4-piperidinylmethyl- 3-methylphenyl- OMe amino-carbonyl sulfonyl1348 4-piperidinylmethyl- 3,5-dimethyl- OH amino-carbonyl isoxazolylsulfonyl1349 4-piperidinylmethyl- 3,5-dimethyl- OMe amino-carbonyl isoxazolylsulfonyl1350 N-(4-piperidinyl- n-butyloxycarbonyl OH methyl)-N-methyl- aminocarbonyl1351 N-(4-piperidinyl- n-butyloxycarbonyl OMe methyl)-N-methyl- aminocarbonyl1352 N-(4-piperidinyl- benzyloxycarbonyl OH methyl)-N-methyl- aminocarbonyl1353 N-(4-piperidiny- benzoloxycarbonyl OMe methyl)-N-methyl- aminocarbonyl1354 N-(4-piperidinyl- n-butylsulfonyl OH methyl)-N-methyl- aminocarbonyl1355 N-(4-piperidinyl- n-butylsulfonyl OMe methyl)-N- methylamino- carbonyl1356 N-(4-piperidinyl- 2-methylphenyl- OH methyl)-N-methyl- sulfonyl aminocarbonyl1357 N-(4-piperidinyl- 2-methylphenyl- OMe methyl)-N-methyl- sulfonyl aminocarbonyl1358 N-(4-piperidinyl- 3-methylphenyl- OH methyl)-N-methyl- sulfonyl aminocarbonyl1359 N-(4-piperidinyl- 4-methylphenyl- OH methyl)-N-methyl- sulfonyl aminocarbonyl1360 N-(4-piperidinyl- 3-methylphenyl- OMe methyl)-N-methyl- sulfonyl aminocarbonyl1361 N-(4-piperidinyl- 3,5-dimethyl- OH methyl)-N-methyl- isoxazolylsulfonyl aminocarbonyl1362 N-(4-piperidinyl- 3,5-dimethyl- OMe methyl)-N-methyl- isoxazolylsulfonyl aminocarbonyl1363 4-piperidinyl- n-butyloxycarbonyl OH aminocarbonyl1364 4-piperidinyl- 4-methylphenyl- OH aminocarbonyl sulfonyl1365 4-guanidinophenyl 2-methylphenyl- OH sulfonyl1366 4-guanidinophenyl 2-methylphenyl- OMe sulfonyl1367 4-guanidinophenyl 2-bromophenylsulfonyl OH1368 4-guanidinophenyl 2-bromophenylsulfonyl OMe1369 4-guanidinophenyl 3-methylphenyl- OH sulfonyl1370 4-guanidinophenyl 3,5-dimethyl- OH isoxazolylsulfonyl1371 4-guanidinophenyl 3,5-dimethyl- OMe isoxazolylsulfonyl1372 4-guanidinophenyl 2,4-dimethyl- OH thiazolylsulfonyl1373 4-guanidinophenyl 2,4-dimethyl- OMe thiazolylsulfonyl1374 4-guanidinophenyl benzylsulfonyl OH1375 4-guanidinophenyl benzylsulfonyl OMe1376 4-guanidinophenyl styrylsulfonyl OH1377 4-guanidinophenyl styrylsulfonyl OMe1378 4-guanidinophenyl 2-benzothiophene- OH sulfonyl1379 3-guanidinophenyl n-butyloxycarbonyl OH1380 3-guanidinophenyl n-butyloxycarbonyl OMe1381 3-guanidinophenyl n-propyloxycarbonyl OH1382 3-guanidinophenyl 2-bromophenylsulfonyl OH1383 3-guanidinophenyl 2-bromophenylsulfonyl OMe1384 3-guanidinophenyl 2-methylphenyl- OH sulfonyl1385 3-guanidinophenyl 4-methylphenyl- OH sulfonyl1386 3-guanidinophenyl 4-methylphenyl- OMe sulfonyl1387 3-guanidinophenyl n-butylsulfonyl OH1388 3-guanidinophenyl n-butylsulfonyl OMe1389 3-guanidinophenyl styrylsulfonyl OH1390 3-guanidinophenyl benzyloxycarbonyl OH1391 3-guanidinophenyl benzyloxycarbonyl OMe1392 4-amidinophenyl- 2-methylphenyl- OH methyl sulfonyl1393 4-amidinophenyl- 2-methylphenyl- OMe methyl sulfonyl1394 4-amidinophenyl- phenylsulfonyl OH methyl1395 4-amidinophenyl- phenylsulfonyl OMe methyl1396 4-amidinophenyl- 3,5-dimethyl- OH methyl isoxazolylsulfonyl1397 4-amidinophenyl- 3,5-dimethyl- OMe methyl isoxazolylsulfonyl1398 4-amidinophenyl- 2,4-dimethyl- OH methyl thiazolylsulfonyl1399 4-amidinophenyl- 2,4-dimethyl OMe methyl thiazolylsulfonyl1400 4-amidinophenyl- p-tolylsulfonyl OH methyl1401 3-amidinophenyl- n-butyloxycarbonyl OH methyl1402 3-amidinophenyl- n-butyloxycarbonyl OMe methyl1403 3-amidinophenyl- phenylsulfonyl OH methyl1404 3-amidinophenyl- phenylsulfonyl OMe methyl1405 3-amidinophenyl- 3-bromophenylsulfonyl OH methyl1406 3-amidinophenyl- 3-bromophenylsulfonyl OMe methyl1407 3-amidinophenyl- 2-methylphenyl- OH methyl sulfonyl1408 3-amidinophenyl- 2-methylphenyl- OMe methyl sulfonyl1409 3-amidinophenyl- 4-methylphenyl- OH methyl sulfonyl1410 3-amidinophenyl- 4-methylphenyl- OMe methyl sulfonyl1411 3-amidinophenyl- styrylsulfonyl OH methyl1412 3-amidinophenyl- styrylsulfonyl OMe methyl1413 3-amidinophenyl- benzyloxycarbonyl OH methyl1414 3-amidinophenyl- benzyloxycarbonyl OMe methyl1415 3-amidinophenyl- 3,5-dimethyl- OH methyl isoxazolylsulfonyl1416 3-amidinophenyl- 3,5-dimethyl- OMe methyl isoxazolylsulfonyl1417 3-amidinophenyl- 2,4-dimethyl- OH methyl thiazolylsulfonyl1418 3-amidinophenyl- benzylsulfonyl OH methyl1419 4-pyridylethyl n-benzyloxycarbonyl OMe1420 4-pyridylethyl n-benzyloxycarbonyl OH1421 4-pyridylethyl n-butyloxycarbonyl OMe1422 4-pyridylethyl n-butyloxycarbonyl OH1423 4-pyridylethyl 2-methylphenylsulfonyl OH1424 4-pyridylethyl 2-methylphenylsulfonyl OMe1425 4-pyridylethyl 2-bromophenylsulfonyl OH1426 4-pyridylethyl 2-bromophenylsulfonyl OMe1427 4-pyridylethyl 3-methylphenylsulfonyl OH1428 4-pyridylethyl 3,5-dimethyl- OH isoxazolylsulfonyl1429 4-pyridylethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1430 4-pyridylethyl 2,4-dimethyl- OH thiazolylsulfonyl1431 4-pyridylethyl 2,4-dimethyl- OMe thiazolylsulfonyl1432 4-pyridylethyl benzylsulfonyl OH1433 4-pyridylethyl styrylsulfonyl OH1434 4-pyridylethyl styrylsulfonyl OMe1435 4-pyridylethyl 2-benzothiophene- OH sulfonyl1436 3-pyridylethyl n-benzyloxycarbonyl OMe1437 3-pyridylethyl n-benzyloxycarbonyl OH1438 3-pyridylethyl n-butyloxyoxycarbonyl OMe1439 3-pyridylethyl n-butyloxyoxycarbonyl OH1440 3-pyridylethyl 2-methylphenyl- OH sulfonyl1441 3-pyridylethyl 2-methylphenyl- OMe sulfonyl1442 3-pyridylethyl 2-bromophenylsulfonyl OH1443 3-pyridylethyl 2-bromophenylsulfonyl OMe1444 3-pyridylethyl 3-methylphenyl- OH sulfonyl1445 3-pyridylethyl 3,5-dimethyl- OH isoxazolylsulfonyl1446 3-pyridylethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1447 3-pyridylethyl 2,4-dimethyl- OH thiazolylsulfonyl1448 3-pyridylethyl 2,4-dimethyl- OMe thiazolylsulfonyl1449 3-pyridylethyl benzylsulfonyl OH1450 3-pyridylethyl styrylsulfonyl OH1451 3-pyridylethyl styrylsulfonyl OMe1452 3-pyridylethyl 2-benzothiophene- OH sulfonyl1453 2-amino-4- n-benzyloxycarbonyl OMe pyridylethyl1454 2-amino-4- n-benzyloxycarbonyl OH pyridylethyl1455 2-amino-4- n-butyloxyoxycarbonyl OMe pyridylethyl1456 2-amino-4- n-butyloxyoxycarbonyl OH pyridylethyl1457 2-amino-4- 2-methylphenylsulfonyl OH pyridylethyl1458 2-amino-4- 2-methylphenylsulfonyl OMe pyridylethyl1459 2-amino-4- 2-bromophenylsulfonyl OH pyridylethyl1460 2-amino-4- 2-bromophenylsulfonyl OMe pyridylethyl1461 2-amino-4- 3-methylphenylsulfonyl OH pyridylethyl1462 2-amino-4- 3,5-dimethyl- OH pyridylethyl isoxazolylsulfonyl1463 2-amino-4- 3,5-dimethyl- OMe pyridylethyl isoxazolylsulfonyl1464 2-amino-4- 2,4-dimethyl- OH pyridylethyl thiazolylsulfonyl1465 2-amino-4- 2,4-dimethyl- OMe pyridylethyl thiazolylsulfonyl1466 2-amino-4- benzylsulfonyl OH pyridylethyl1467 2-amino-4- benzylsulfonyl OMe pyridylethyl1468 2-amino-4- styrylsulfonyl OH pyridylethyl1469 2-amino-4- styrylsulfonyl OMe pyridylethyl1470 2-amino-4- 2-benzothiophene- OH pyridylethyl sulfonyl1471 6-amino-3- n-benzyloxycarbonyl OMe pyridylethyl1472 6-amino-3- n-benzyloxycarbonyl OH pyridylethyl1473 6-amino-3- n-butyloxyoxycarbonyl OMe pyridylethyl1474 6-amino-3- n-butyloxyoxycarbonyl OH pyridylethyl1475 6-amino-3- 2-methylphenyl- OH pyridylethyl sulfonyl1476 6-amino-3- 2-methylphenyl- OMe pyridylethyl sulfonyl1477 6-amino-3- 2-bromophenylsulfonyl OH pyridylethyl1478 6-amino-3- 2-bromophenylsulfonyl OMe pyridylethyl1479 6-amino-3- 3-methylphenyl- OH pyridylethyl sulfonyl1480 6-amino-3- 3,5-dimethyl- OH pyridylethyl isoxazolylsulfonyl1481 6-amino-3- 3,5-dimethyl- OMe pyridylethyl isoxazolylsulfonyl1482 6-amino-3- 2,4-dimethyl- OH pyridylethyl thiazolylsulfonyl1483 6-amino-3- 2,4-dimethyl- OMe pyridylethyl thiazolylsulfonyl1484 6-amino-3- benzylsulfonyl OH pyridylethyl1485 6-amino-3- benzylsulfonyl OMe pyridylethyl1486 6-amino-3- styrylsulfonyl OH pyridylethyl1487 6-amino-3- styrylsulfonyl OMe pyridylethyl1488 6-amino-4- 2-benzothiophene- OH pyridylethyl sulfonyl1489 2-amidino-4- n-benzyloxycarbonyl OMe pyridylethyl1490 2-amidino-4- n-benzyloxycarbonyl OH pyridylethyl1491 2-amidino-4- n-butyloxyoxycarbonyl OMe pyridylethyl1492 2-amidino-4- n-butyloxyoxycarbonyl OMe pyridylethyl1493 2-amidino-4- 2-methylphenyl- OH pyridylethyl sulfonyl1494 2-amidino-4- 2-methylphenyl- OMe pyridylethyl sulfonyl1495 2-amidino-4- 2-bromophenylsulfonyl OH pyridylethyl1496 2-amidino-4- 2-bromophenylsulfonyl OMe pyridylethyl1497 2-amidino-4- 3-methylphenyl- OH pyridylethyl sulfonyl1498 2-amidino-4 3,5-dimethyl- OH pyridylethyl isoxazolylsulfonyl1499 2-amidino-4- 3,5-dimethyl- OMe pyridylethyl isoxazolylsulfonyl1500 2-amidino-4- 2,4-dimethyl- OH pyridylethyl thiazolylsulfonyl1501 2-amidino-4- 2,4-dimethyl- OMe pyridylethyl thiazolylsulfonyl1502 2-amidino-4- benzylsulfonyl OH pyridylethyl1503 2-amidino-4- benzylsulfonyl OMe pyridylethyl1504 2-amidino-4- styrylsulfonyl OH pyridylethyl1505 2-amidino-4- styrylsulfonyl OMe pyridylethyl1506 2-amidino-4- 2-benzothiophene- OH pyridylethyl sulfonyl1507 6-amidino-3- n-benzyloxycarbonyl OMe pyridylethyl1508 6-amidino-3- n-benzyloxycarbonyl OH pyridylethyl1509 6-amidino-3- n-butyloxyoxycarbonyl OMe pyridylethyl1510 6-amidino-3- n-butyloxyoxycarbonyl OH pyridylethyl1511 6-amidino-3- 2-methylphenyl- OH pyridylethyl sulfonyl1512 6-amidino-3- 2-methylphenyl- OMe pyridylethyl sulfonyl1513 6-amidino-3- 2-bromophenylsulfonyl OH pyridylethyl1514 6-amidino-3- 2-bromophenylsulfonyl OMe pyridylethyl1515 6-amidino-3- 3-methylphenyl- OH pyridylethyl sulfonyl1516 6-amidino-3- 3,5-dimethyl- OH pyridylethyl isoxazolylsulfonyl1517 6-amidino-3- 3,5-dimethyl- OMe pyridylethyl isoxazolylsulfonyl1518 6-amidino-3- 2,4-dimethyl- OH pyridylethyl thiazolylsulfonyl1519 6-amidino-3- 2,4-dimethyl- OMe pyridylethyl thiazolylsulfonyl1520 6-amidino-3- benzylsulfonyl OH pyridylethyl1521 6-amidino-3- benzylsulfonyl Me pyridylethyl1522 6-amidino-3- styrylsulfonyl OH pyridylethyl1523 6-amidino-3- styrylsulfonyl OMe pyridylethyl1524 6-amidino-3- 2-benzothiophene- OH pyridylethyl sulfonyl1525 guanidinoethyl benzyloxycarbonyl OH 421______________________________________ TABLE 8__________________________________________________________________________ ##STR361##Ex. MSNo. R.sup.1V p.sup.1 p.sup.2 R.sup.16 Y M + H__________________________________________________________________________1540 4-amidinophenyl 2 1 n-butyloxycarbonyl OH 4461541 4-amidinophenyl 2 1 3-methylphenylsulfonyl OH 4481542 4-amidinophenyl 1 1 benzyloxycarbonyl OMe1543 4-amidinophenyl 1 1 (2-methylphenyl)- OH methoxycarbonyl1544 4-amidinophenyl 1 1 (3-methylphenyl)- OH methoxycarbonyl1545 4-amidinophenyl 1 2 i-butyloxycarbonyl OMe1546 4-amidinophenyl 1 2 4-methylphenylsulfonyl OH1547 4-amidinophenyl 1 2 2-methylphenylsulfonyl OH1548 4-amidinophenyl 2 1 3,5-dimethylpyrazoyl- OH sulfonyl1549 4-amidinophenyl 2 1 3,5-dimethylisoxazoyl- OH sulfonyl1550 4-amidinophenyl 2 1 i-butylaminosulfonyl OH1551 4-amidinophenyl 2 1 2-bromophenylsulfonyl OH1552 4-piperidinylethyl 1 1 n-propyloxycarbonyl OMe1553 4-piperidinylethyl 1 2 n-butylsulfonyl OH1554 4-piperidlnylethyl 1 2 (3-bromophenyl)- OH methylsulfonyl1555 4-piperidinylethyl 2 1 (3-methylphenyl)- OMe methoxycarbonyl1556 4-piperidinylethyl 2 1 2-phenylethoxycarbonyl OH1557 4-(N-benzylamid- 1 1 n-butyloxycarbonyl OH ino)phenyl1558 4-�N-(2-methylphenyl)- 1 1 3-methylphenylsulfonyl OH methylamidino!phenyl1559 4-�N-(2-bromophenyl)- 1 2 2-bromcphenylsulfonyl OH methylamidino!phenyl1560 4-�N-butylamidino)- 2 1 3,5-dimethylpyrazoyl- OH phenyl sulfonyl1561 4-�N-(2- 2 1 3-methylphenylsulfonyl OH methoxyphenyl)- methylamidino!phenyl1562 4-�N-(3-�trifluoro- 2 1 2,5-dimethylthiazolyl- OH methyl!phenyl)methyl- sulfonyl amidino!phenyl1563 4-amidino-2-fluoro- 1 1 3-methylphenylsulfonyl OH phenyl1564 4-amidino-2-fluoro- 1 2 i-butylaminosulfonyl phenyl1565 4-amidino-2-fluoro- 2 1 3,5-dimethylisoxazoyl- OH phenyl sulfonyl1566 5-amidino-2-pyridyl 1 1 n-butyloxycarbonyl OMe1567 5-amidino-2-pyridyl 1 2 2-methylphenylsulfonyl OH1568 5-amidino-2-pyridyl 1 2 3-methylphenylsulfonyl OMe1569 5-amidino-2-pyridyl 2 1 n-butylsulfonyl OH1570 5-amidino-2-pyridyl 2 1 3,5-dimethylisoxazoyl- OH sulfonyl1571 2-amidino-5-pyridyl 1 1 2-bromophenylsulfonyl OH1572 2-amidino-5-pyridyl 1 1 2-(trifluoromethyl)- OMe phenylsulfonyl1573 2-amidino-5-pyridyl 1 2 n-propylaminocarbonyl OMe1574 2-amidino-5-pyridyl 1 2 4-methylphenylsulfonyl OH1575 2-amidino-5-pyridyl 2 1 2-fluorophenylsulfonyl OH__________________________________________________________________________ TABLE 9__________________________________________________________________________ ##STR362##Example MSNumber R.sup.1V R.sup.16 y (M + H).sup.+__________________________________________________________________________1585 4-piperidinylethyl n-butyloxycarbonyl OMe 4411585A 4-piperidinylmethyl n-butyloxycarbonyl OH 4271586 4-piperidinylethyl benzyloxycarbonyl OMe1587 4-piperidinylethyl n-propyloxycarbonyl OMe1588 4-piperidinylethyl isobutyloxylcarbonyl OMe1589 4-piperidinylethyl 2-methylphenylsulfonyl OMe1590 4-piperidinylethyl 3-methylphenylsulfonyl OMe1591 4-piperidinylethyl 4-methylphenylsulfonyl OMe1592 4-piperidinylethyl 2-bromophenylsulfonyl OMe1593 4-piperidinylethyl 3-bromophenylsulfonyl OMe1594 4-piperidinylethyl 2-methoxyphenyl- OMe sulfonyl1595 4-piperidinylethyl 3-methoxyphenyl- OMe sulfonyl1596 4-piperidinylethyl 3-trifluorornethyl- OMe phenylsulfonyl1597 4-piperidinylethyl n-propylsulfonyl OMe1598 4-piperidinylethyl n-butylsulfonyl OMe1599 4-piperidinylethyl isopropylsulfonyl OMe1600 4-piperidinylethyl isobutylsulfonyl OMe1601 4-piperidinylethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1602 4-piperidinylethyl 2,4-dimethyl- OMe thiazolylsulfonyl1603 4-piperidinylpropyl n-butyloxycarbonyl OMe 4551604 4-piperidinylpropyl n-propyloxycarbonyl OMe1605 4-piperidinylpropyl benzyloxycarbonyl OMe1606 4-piperidinylpropyl isobutyloxycarbonyl OMe1607 4-piperidinylpropyl 2-methylphenyl- OMe sulfonyl1608 4-piperidinylpropyl 3-methylphenyl- OMe sulfonyl1609 4-piperidinylpropyl 4-methylphenyl- OMe 509 sulfonyl1610 4-piperidinylpropyl 2-bromophenylsulfonyl OMe1611 4-piperidinylpropyl n-butylsulfonyl OMe1612 4-piperidinylpropyl isobutylsulfonyl OMe1613 4-piperidinylpropyl 3,5-dimethyl- OMe isoxazolylsulfonyl1614 4-piperidinylpropyl 2,4-dimethyl- OMe thiazoylsulfonyl1615 4-piperidinylethyl n-butyloxycarbonyl OH1616 4-piperidinylethyl n-propyloxycarbonyl OH1617 4-piperidinylethyl benyloxycarbonyl OH1618 4-piperidinylethyl isobutyloxycarbonyl OH1619 4-piperidinylethyl 2-methylphenyl- OH 481 sulfonyl1620 4-piperidinylethyl 3-methylphenyl- OH 481 sulfonyl1621 4-piperidinylethyl 4-methylphenyl- OH 481 sulfonyl1622 4-piperidinylethyl 2-bromophenylsulfonyl OH 5451623 4-piperidinylethyl 3,5-dimethyl- OH 486 isoxazolylsulfonyl1624 4-piperidinylethyl 2,4-dimethyl- OH 502 thiazolylsulfonyl1625 4-piperidinylethyl n-butylsulfonyl OH 4471626 4-piperidinylethyl isobutylsulfonyl OH1627 4-piperidinylpropyl n-butyloxycarbonyl OH 4411628 4-piperidinylpropyl n-propyloxycarbonyl OH1628 4-piperidinylpropyl isobutyloxycarbonyl OH1630 4-piperidinylpropyl 2-methylphenyl- OH carbonyl1631 4-piperidinylpropyl 4-methylphenyl- OH 495 carbonyl1632 4-piperidinylpropyl 2-bromophenyl-carbonyl OH1633 4-piperidinylpropyl 3,5-dimethyl- OH isoxazolylsulfonyl1634 4-piperidinylpropyl n-butylsulfonyl OH1635 4-piperidinylpropyl isobutylsulfonyl OH1636 4-amidinopiperidinyl n-butyloxycarbonyl OMe1637 4-amidinopiperidinyl isobutyloxycarbonyl OMe1638 4-amidinopiperidinyl n-propyioxycarbonyl OMe1639 4-amidinopiperidinyl benzyloxycarbonyl OMe1640 4-amidinopiperidinyl n-butylsulfonyl OMe1641 4-amidinopiperidinyl isobutylsulfonyl OMe1642 4-amidinopiperidinyl n-propyl-sulfonyl OMe1643 4-amidinopiperidinyl 2-methylphenyl- OMe sulfonyl1644 4-amidinopiperidinyl 4-methylphenyl- OMe sulfonyl1645 4-amidinopiperidinyl benzylsulfonyl OMe1646 4-amidinopiperldinyl 3,5-dimethyl- OMe isoxazolylsulfonyl1647 4-amidinopiperidinyl 2,4-dimethyl- OMe thiazolylsulfonyl1648 4-amidinopiperidinyl 4-methylphenyl- OH sulfonyl1649 4-amidinopiperidinyl n-butyloxycarbonyl OH1650 4-amidinopiperidinyl isobutyloxycarbonyl OH1651 4-amidi-nopiperidinyl n-propyloxycarbonyl OH1652 4-amidinopiperidinyl benzyloxycarbonyl OH1653 4-amidinopiperidinyl n-butylsulfonyl OH1654 4-amidinopiperidinyl isobutylsulfonyl OH1655 4-amidinopiperidinyl 2-methylphenyl- OH sulfonyl1656 4-amidinopiperidinyl 3-methylphenyl- OH 495 sulfonyl1657 4-amldinopiperidinyl 4-methylphenyl- OH 495 sulfonyl1658 4-amidinopiperidinyl 2-bromophenylsulfonyl OH1659 4-amidinopiperidinyl 3-bromophenylsulfonyl OH1660 4-amidinopiperidinyl 3,5-dimethyl- OH isoxazolylsulfonyl1661 4-amidinopiperidinyl 2,4-dimethyl- OH thiazolylsulfonyl1662 4-amidino- n-butyloxycarbonyl OMe 427 piperidinylmethyl1663 4-amidino- n-propyloxycarbonyl OMe piperidinylmethyl1664 4-amidino- benzyloxycarbonyl OMe piperidinylmethyl1665 4-amidino- n-butylsulfonyl OMe piperidinylmethyl1666 4-amidino- n-propylsulfonyl OMe piperidinylmethyl1667 4-amidino- 2-methylphenyl- OMe piperidinylmethyl sulfonyl1668 4-amidino- 3-methylphenyl- OMe piperidinylmethyl sulfonyl1669 4-amidino- 4-methylphenyl- OMe piperidinylmethyl sulfonyl1670 4-amidino- 2-bromophenylsulfonyl OMe piperidinylmethyl1671 4-amidino- 3-bromophenylsulfonyl OMe piperidinylmethyl1672 4-amidino- 3,5-dimethyl- OMe piperidinylmethyl isoxazolylsulfonyl1673 4-amidino- 4-methylphenyl- OH 509 piperidinylmethyl sulfonyl1674 4-amidino- n-butyloxycarbonyl OH piperidinylmethyl1675 4-amidino- n-propyloxycarbonyl OH piperidinylmethyl1676 4-amidino- benzyloxycarbonyl OH piperidinylmethyl1677 4-amidino- n-butylsulfonyl OH piperidinylmethyl1678 4-amidino- 2-methylphenyl- OH piperidinylmethyl sulfonyl1679 4-amidino- 3-methylphenyl- OH piperidinylmethyl sulfonyl1680 4-amidino- 2-bromophenyl-sulfonyl OH piperidinylmethyl1681 4-amidino- 3-bromophenyl-sulfonyl OH piperidinylmethyl1682 4-amidino- 3,5-dimethyl- OH piperidinylmethyl isoxazolylsulfonyl1683 4-quinuclidinylethyl n-butyloxycarbonyl OH1684 4-quinuclidinylethyl n-propyloxycarbonyl OH1685 4-quinuclidinylethyl benzyloxycarbonyl OH1686 4-quinuclidinylethyl n-butylsulfonyl OH1687 4-quinuclidinylethyl 2-methylphenyl- OH sulfonyl1688 4-quinuclidinylethyl 4-methylphenyl- OH sulfonyl1689 4-quinuclidinylethyl 2-bromophenylsulfonyl OH1690 4-quinuclidinylethyl 3-bromophenylsulfonyl OH1691 4-quinuclidinylethyl 3,5-dimethyl- OH isoxazolylsulfonyl1692 guanidinopropyl n-butyloxycarbonyl OMe1693 guanidinopropyl n-propyloxycarbonyl OMe1694 guanidinopropyl benzyloxycarbonyl OH 4491695 guanidinopropyl n-butylsulfonyl OMe1696 guanidinopropyl 2-methylphenyl- OMe sulfonyl1697 guanidinopropyl 3-methylphenyl- OMe sulfonyl1698 guanidinopropyl 2-bromophenylsulfonyl OMe1699 guanidinopropyl 3-bromophenylsulfonyl OMe1700 guanidinopropyl 3,5-dimethyl- OMe isoxazolylsulfonyl1701 guanidinopropyl benzylsulfonyl OMe1702 guanidinopropyl styrylsulfonyl OMe1703 guanidinopropyl 2-benzothiophene- OMe sulfonyl1704 guanidinopropyl n-butyloxycarbonyl OH 5291705 guanidinopropyl n-propyloxycarbonyl OH1706 gwnidinopropyl benzyloxycarbonyl OH1707 guanidinopropyl n-butylsulfonyl CH1708 guanidinopropyl 2-methylphenyl- OH sulfonyl1709 guanidinopropyl 3-methylphenyl- OH sulfonyl1710 guanidinopropyl 4-methylphenyl- OH sulfonyl1711 guanidinopropyl 2-bromophenylsulfonyl OH1712 guanidinopropyl 3-bromophenylsulfonyl OH1713 guanidinopropyl 3,5-dimethyl- OH isoxazolylsulfonyl1714 guanidinopropyl 2,4-dimethyl- OH thiazolylsulfonyl1715 guanidinopropyl benzylsulfonyl OH1716 guanidinopropyl styrylsulfonyl OH1717 guanidinopropyl 2-benzothiophene- OH sulfonyl1718 guanidinobutyl n-butyloxycarbonyl OH1719 guanidinobutyl n-butylsulfonyl OH1720 guanidinobutyl phenylsulfonyl OH1721 guanidinobutyl 2-methylphenyl- OH sulfonyl1722 guanidinobutyl 4-methylphenyl- OH sulfonyl1723 guanidinobutyl 2-bromophenylsulfonyl OH1724 guanidinobutyl 3,5-dimethyl- OH isoxazolylsulfonyl1725 guanidinobutyl 2,4-dimethyl- OH thiazolylsulfonyl1726 guanidinobutyl benzylsulfonyl OH1727 guanidinobutyl styrylsulfonyl OH1728 guanidinobutyl 3-fluorophenyl- OH sulfonyl1729 guanidinobutyl n-butyloxycarbonyl OMe1730 guanidinobutyl n-butylsulfonyl OMe1731 guanidinobutyl benzyloxycarbonyl OH 4631732 guanidinobutyl phenylsulfonyl OMe1733 guanidinobutyl 2-methylphenyl- OMe sulfonyl1734 guanidinobutyl 2-bromophenylsulfonyl OMe1735 guanidinobutyl 3-bromophenylsulfonyl OMe1736 guanidinobutyl 3,5-dimethYl- OMe1737 guanidinobutyl benzylsulfonyl OMe1738 guanidinobutyl n-butyloxycarbonyl OH1739 guanidinobutyl isobutyloxycarbonyl OH1740 guanidinobutyl n-propyloxycarbonyl OH1741 guanidinobutyl phenylsulfonyl OH1742 guanidinobutyl n-butylsulfonyl OH1743 guanidinobutyl 2-methylphenyl- OH sulfonyl1744 guanidinobutyl 3-methylphenyl- OH sulfonyl1745 guanidinobutyl 4-methylphenyl- OH sulfonyl1746 guanidinobutyl. 2-bromophenylsulfonyl OH1747 4-piperidinylmethyl- n-butyloxycarbonyl OH aminocarbonyl1748 4-piperidinylmethyl- n-butyloxycarbonyl OMe amino-carbonyl1749 4-piperidinylmethyl- benzyloxycarbonyl OH amino-carbonyl1750 4-piperidinylmethyl- benzyloxycarbonyl OMe amino-carbonyl1751 4-piperidinylmethyl- n-butylsulfonyl OH amino-carbonyl1752 4-piperidinylmethyl- n-butylsulfonyl OMe amino-carbonyl1753 4-piperidinylmethyl- 2-methylphenyl- OH amino-carbonyl sulfonyl1754 4-piperidinylmethyl- 2-methylphenyl- OMe amino-carbonyl sulfonyl1755 4-piperidinylmethyl- 3-methylphenyl- OH amino-carbonyl sulfonyl1756 4-piperidinylmethyl- 4-methylphenyl- OH 510 amino-carbonyl sulfonyl1757 4-piperidinylmethyl- 3-methylphenyl- OMe amino-carbonyl sulfonyl1758 4-piperidinylmethyl- 3-,5-dimethyl- OH amino-carbonyl isoxazolylsulfonyl1759 4-piperidinylmethyl- 3,5-dimethyl- OMe amino-carbonyl isoxazolylsulfonyl1760 N-(4-piperidinyl- n-butyloxycarbonyl OH methyl)-N-methyl- aminocarbonyl1761 N-(4-piperidinyl- n-butyloxycarbonyl OMe methyl)-N-methyl- aminocarbonyl1762 N-(4-piperidinyl- benzyloxycarbonyl OH methyl)-N-methyl- aminocarbonyl1763 N-(4-piperidiny- benzyloxycarbonyl OMe methyl)-N-methyl- aminocarbonyl1764 N-(4-piperidinyl- n-butylsulfonyl OH methyl)-N-methyl- aminocarbonyl1765 N-(4-piperidinyl- n-butylsulfonyl OMe methyl)-N- methylaminocarbonyl1766 N-(4-piperidinyl- 2-methylphenyl- OH methyl)-N-methyl- sulfonyl aminocarbonyl1767 N-(4-piperidinyl- 2-methylphenyl- OMe methyl)-N-methyl- sulfonyl aminocarbonyl1768 N-(4-piperidinyl- 3-methylphenyl- OH methyl)-N-methyl- sulfonyl aminocarbonyl1769 N-(4-piperidinyl- 4-methylphenyl- OH 524 methyl)-N-methyl- sulfonyl aminocarbonyl1770 N-(4-piperidinyl- 3-methylphenyl- OMe methyl)-N-methyl- sulfonyl aminocarbonyl1771 N-(4-piperidinyl- 3,5-dimethyl- OH methyl)-N-methyl- isoxazolylsulfonyl amunocarbonyl1772 N-(4-piperidinyl- 3,5-dimethyl- OMe methyl)-N-methyl- isoxazolylsulfonyl amunocarbonyl1773 4-piperidinyl- n-butyloxycarbonyl OH aminocarbonyl1774 4-piperidinyl- 4-methylphenyl- OH 496 aminocarbonyl sulfonyl1775 4-guanidinophenyl 2-methylphenyl- OH sulfonyl1776 4-guanidinophenyl 2-methylphenyl- OMe sulfonyl1777 4-guanidinophenyl 2-bromophenylsulfonyl OH1778 4-guanidinophenyl 2-bromophenylsulfonyl OMe1779 4-guanidinophenyl 3-methylphenyl- OH sulfonyl1780 4-guanidinophenyl 3.5-dimethyl- OH isoxazolylsulfonyl1781 4-guanidinophenyl 3,5-dimethyl- OMe isoxazolylsulfonyl1782 4-guanidinophenyl 2,4-dimethyl- OH thiazolyl5ulfonyl1783 4-guanidinophenyl 2,4-dimethyl- OMe thiazolylsulfonyl1784 4-guanidinophenyl benzylsulfonyl OH1785 4-guanidinophenyl benzylsulfonyl OMe1786 4-guanidinophenyl styrylsulfonyl OH1787 4-guanidinophenyl styrylsulfonyl OMe1788 4-guanidinophenyl 2-benzothiophene- OH sulfonyl1789 3-guanidinophenyl n-butyloxycarbonyl OH1790 3-guanidinophenyl n-butyloxycarbonyl OMe1791 3-guanidinophenyl n-propyloxycarbonyl OH1792 3-guanidinophenyl 2-bromophenylsulfonyl OH1793 3-guanidinophenyl 2-bromophenylsulfonyl OMe1794 3-guanidinophenyl 2-methylphenyl- OH sulfonyl1795 3-guanidinophenyl 4-methylphenyl- OH sulfonyl1796 3-guanidinophenyl 4-methylphenyl- OMe sulfonyl1797 3-guanidinophenyl n-butylsulfonyl OH1798 3-guanidinophenyl n-butylsulfonyl OMe1799 3-guanidinophenyl styrylsulfonyl OH1800 3-guanidinophenyl benzyloxycarbonyl OH1801 3-guanidinophenyl benzyloxycarbonyl OMe1802 4-amidinophenylmethyl 2-methylphenyl- OH sulfonyl1803 4-amidinophenylmethyl 2-meEhylphenyl- OMe sulfonyl1804 4-amidinophenylmethyl phenylJulfonyl OH1805 4-amidinophenylmethyl phenylsulfonyl OMe1806 4-amidinophenylmethyl 3,5-dimethyl- OH isoxazolylsulfonyl1807 4-amidinophenylmethyl 3,5-dimethy;l- OMe isoxazolylsiulfonyl1808 4-amidinophenylmethyl 2,4-dimethyl- OH thiazolylsulfonyl.1809 4-amidinophenylmethyl 2,4-dimethyl- OMe thiazolylsulfonyl1810 4-amidinophenylmethyl p-toluylsulfonyl OH1811 3-amidinophenylmethyl n-butyloxycarbonyl OH1812 3-amidinophenylmethyl n-butyloxycarbonyl OMe1813 3-amidinophenylmethyl phenylsulfonyl OH1814 3-amidinophenylmethyl phenylsulfonyl OMe1815 3-amidinophenylmethyl 2-bromophenylsulfonyl OH1816 3-amidinophenylmethyl 2-bromophenylsulfonyl OMe1817 3-amidinophenylmethyl 2-methylphenyl- OH sulfonyl1818 3-amidinophenylmethyl 2-methylphenyl- OMe sulfonyl1819 3-amidinophenylmethyl 4-methylphenyl- OH sulfonyl1820 3-amidinophenylmethyl 4-methylphenyl- OMe sulfonyl1821 3-amidinophenylmethyl styrylsulfonyl OH1622 3-amidinophenylmethyl styrylsulfonyl OMe1823 3-amidinophenyimethyl benzyloxycarbonyl OH1824 3-amidinophenylmethyl benzyloxycarbonyl OMe1825 3-amidinophenylmethyl 3,5-dimethyl- OH isoxazolylsulfonyl1826 3-amidinophenylmethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1827 3-amidinophenylmethyl 2,4-dimethyl- OH thiazolylsulfonyl1828 3-amidinophenylmethyl benzylsulfonyl OH1829 4-pyridylethyl n-benzyloxycarbonyl OMe1830 4-pyridylethyl n-benzyloxycarbonyl OH1831 4-pyridylethyl n-butyloxyoxycarbonyl OMe1832 4-pyridylethyl n-butyloxyoxycarbonyl OH1833 4-pyridylethyl 2-methylphenylsulfonyl OH1834 4-pyridylethyl 2-methylphenyl- OMe sulfonyl1835 4-pyridylethyl 2-bromophenylsulfonyl OH1836 4-pyridylethyl 2-bromophenylsulfonyl OMe1837 4-pyridylethyl 3-methylphenyl- OH sulfonyl1838 4-pyridylethyl 3.5-dimethyl- OH isoxazolyilsulfonyl1839 4-pyridylethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1840 4-pyridylethyl 2,4-dimethyl- OH thiazolylsulfonyl1841 q-pyridylethyl 2,4-dimethyl- OMe thiazolylsulfonyl1842 4-pyridylethyl benzylsulfonyl OH1843 4-pyridylethyl styrylsulfonyl OH1844 4-pyridylethyl styrylsulfonyl OMe1845 4-pyridylethyl 2-benzothio.phene- OH sulfonyl1846 3-pyridylethyl n-benzyloxycarbonyl OMe1847 3-pyridylethyl n-benzyloxycarbonyl OH1848 3-pyridylethyl n-butyloxyoxycarbonyl OMe1849 3-pyridylethyl n-butyloxyoxycarbonyl OH1850 3-pyridylethyl 2-methylphenyl- OH sulfonyl1851 3-pyridylethyl 2-methylphenyl- OMe sulfonyl1852 3-pyridylethyl 2-bromophenylsulfonyl OH1853 3-pyridylethyl 2-bromophenylsulfonyl OMe1854 3-pyridylethyl 3-methylphenyl- OH sulfonyl1855 3-pyridylethyl 3,5-dimethyl- OH isoxazolylsulfonyl1856 3-pyridylethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1857 3-pyridylethyl 2,4-dimethyl- OH thiazolylsulfonyl1858 3-pyridylethyl 2,4-dimethyl- OMe thiazolylsulfonyl1859 3-pyridylethyl benzylsulfonyl OH1860 3-pyridylethyl styrylsulfonyl OH1861 3-pyridylethyl styrylsul onyl OMe1862 3-pyridylethyl 2-benzothiophene- OH sulfonyl1863 2-amino-4-pyridylethyl n-benzyloxycarbonyl OMe1864 2-amino-4-pyridylethyl n-benzyloxycarbonyl OH1865 2-amino-4-pyridylethyl n-butyloxyoxycarbonyl OMe1866 2-amino-4-pyridylethyl n-butyloxyoxycarbonyl OH1867 2-amino-4-pyridylethyl 2-methylphenyl- OH sulfonyl1868 2-amino-4-pyridylethyl 2-methylphenyl- OMe sulfonyl1869 2-amino-4-pyridylethyl 2-bromophenylsulfonyl OH1870 2-amino-4-pyridylethyl 2-bromophenylsulfonyl OMe1871 2-amino-4-pyridylethyl 3-methylphenyl- OH sulfonyl1872 2-amino-4-pyridylethyl 3,5-dimethyl- OH isoxazolylsulfonyl1873 2-amino-4-pyridylethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1874 2-amino-4-pyridylethyl 2,4-aimethyl- OH thiazolylsulfonyl1875 2-amino-4-pyridylethyl 2,4-dimethyl- OMe thiazolylsulfonyl1876 2-amino-4-pyridylethyl benzylsulfonyl OH1877 2-amino-4-pyridylethyl benzylsulfonyl OMe1878 2-amino-4-pyridylethyl styrylsulfonyl OH1879 2-amino-4-pyridylethyl styrylsulfonyl OMe1880 2-amino-4-pyridylethyl 2-benzothiophene- OH sulfonyl1881 6-amino-3-pyridylethyl n-benzyloxycarbonyl OMe1882 6-amino-3-pyridylethyl n-benzyloxycarbonyl OH1883 6-amino-3-pyridylethyl n-butyloxyoxycarbonyl OMe1884 6-amino-3-pyridylethyl n-butyloxyoxycarbonyl OH1885 6-amino-3-pyridylethyl 2-methylphenyl- OH sulfonyl1886 6-amino-3-pyridylethyl 2-methylphenyl- OMe sulfonyl1887 6-amino-3-pyridylethyl 2-bromophenylsulfonyl OH1888 6-amino-3-pyridylethyl 2-bromophenylsulfonyl OMe1889 6-amino-3-pyridylethyl 3-methylphenyl- OH sulfonyl1890 6-amino-3-pyridylethyl 3,5-dimethyl- OH isoxazolylsulfonyl1891 6-amino-3-pyridylethyl 3,5-dimethyl- OMe isoxazolylsulfonyl1892 6-amino-3-pyridylethyl 2,4-dimethyl- OH thiazolylsulfonyl1893 6-amino-3-pyridylethyl 2,4-dimethyl- OMe thiazolylsulfonyl1894 6-amino-3-pyridylethyl benzylsulfonyl OH1895 6-amino-3-pyridylethyl benzylsulfonyl OMe1896 6-amino-3-pyridylethyl styrylsulfonyl OH1897 6-amino-3-pyridylethyl styrylsulfonyl OMe1898 6-amino-4-pyridylethyl 2-benzothiophene- OH sulfonyl1899 2-amidino-4- n-benzyloxycarbonyl OMe pyridylethyl1900 2-amidino-4- n-benzyloxycarbonyl OH pyridylethyl1901 2-amidino-4- n-butyloxyoxycarbonyl OMe pyridylethyl1902 2-amidino-4- n-butyloxyoxycarbonyl OH pyridylethyl1903 2-amidino-4- 2-methylphenyl- OH pyridylethyl sulfonyl1904 2-amidino-4- 2-methylphenyl- OMe pyridylethyl sulfonyl1905 2-amidino-g- 2-bromophenylsulfonyl OH pyridylethyl1906 2-amidino-4- 2-bromophenylsulfonyl OMe pyridylethyl1907 2-amidino-4- 3-methylphenyl- OH pyridylethyl sulfonyl1908 2-amidino-4- 3,5-dimethyl- OH pyridylethyl isoxazolylsulfonyl1909 2-amidino-4- 3,5-dimethyl- OMe pyridylethyl isoxazolylsulfonyl1910 2-amidino-4- 2,4-dimethyl- OH pyridylethyl thiazolylsulfonyl1911 2-amidino-4- 2,4-dimethyl- OMe pyridylethyl thiazolylsulfonyl1912 2-amidino-4- benzylsulfonyl OH pyridylethyl1913 2-amidino-4- benzylsulfonyl OMe pyridylethyl1914 2-amidino-4- styrylsulfonyl OH pyridylethyl1915 2-amidino-4- styrylsulfonyl OMe pyridylethyl1916 2-amudino-4- 2-benzothiophene- OH pyridylethyl sulfonyl1917 6-amidino-3- n-benzyloxyearbonyl. OMe pyridylethyl1918 6-amidino-3- n-benzyloxycarbonyl OH pyridylethyl1919 6-amidino-3- n-butyloxyoxycarbonyl OMe pyridylethyl1920 6-amidino-3- n-butyloxyoxycarbonyl OH pyridylethyl1921 6-amidino-3- 2-methylphenyl- OH pyridylethyl sulfonyl1922 6-amidino-3- 2-methylphenyl- OMe pyridylethyl sulfonyl1923 6-amidino-3- 2-bromophenylsulfonyl OH pyridylethyl1924 6-amidino-3- 2-bromophenylsulfonyl OMe pyridylethyl1925 6-amidino-3- 3-methylphenyl- OH pyridylethyl sulfonyl1926 6-amidino-3- 3.5-dimethyl- OH pyridylethyl isoxazolylsulfonyl1927 6-amidino-3- 3,5-dimethyl- OMe pyridylethyl isoxazolylsulfonyl1928 6-amidino-3- 2,4-dimethyl- OH pyridylethyl thiazolylsulfonyl1929 6-amidino-3- 2,4-dimethyl- OMe pyridylethyl thiazolylsulfonyl1930 6-amidino-3- benzylsulfonyl OH pyridylethyl1931 6-amidino-3- benzylsulfonyl Me pyridylethyl1932 6-amidino-3- styrylsulfonyl OH pyridylethyl1933 6-amidino-3- styrylsulfonyl OMe pyridylethyl1934 6-amidino-3- 2-benzothiophene- OH pyridylethyl sulfonyl1935 4-amidino-2-fluoro- 2-methylphenylsulfonyl OH phenyl1936 4-amidino-2-fluoro- 3,5-dimethylisoxazolyl- OH phenyl sulfonyl1937 2-amidino-5-pyridyl 2-methylphenylsulfonyl OH1938 2-amidino-5-pyridyl 2-bromophenylsulfonyl OH1939 2-amidino-5-pyridyl i-butyloxylcarbonyl OMe1940 2-amidino-5-pyridyl 3,5-dimethylisoxazolyl- OH sulfonyl1941 3-amidino-6-pyridyl 2-methylphenylsulfonyl OH1942 3-amidino-6-pyridyl 2-bromophenylsulfonyl OMe1943 3-amidino-6-pyridyl 2,5-dimethylthiazolyl- OH sulfonyl1944 3-amidino-6-pyridyl 3,5-dimethylisoxazolyl- OH sulfonyl1945 4-piperidinylethyl 3-methylphenylsulfonyl OH 4811946 4-(N-2-methoxybenzyl)- 2-methylphenylsulfonyl OMe 622.3 amidinophenyl HCl1947 4-(N-2-methoxybenzyl)- 2-methylphenylsulfonyl OH 608.3 amidinophenyl TFA1948 4-(N-n-butyl)- 2-methylphenylsulfonyl OMe 558.4 amidinophenyl1949 4-(N-n-butyl)- 2-methylphenylsulfonyl OH 544.4 amidinophenyl1950 4-(N-ethyl)- 2-methylphenylsulfonyl OMe 530.3 amidinophenyl1951 4-(N-ethyl)- 2-methylphenylsulfonyl OH 516.3 amidinophenyl1952 4-amidinophenoxymethyl benzyloxycarbonyl OMe1953 4-amidinophenoxymethyl benzyloxycarbonyl OH1954 4-amidinophenoxymethyl n-butyloxycarbonyl OMe1955 4-amidinophenoxymethyl n-butyloxycarbonyl OH1956 4-amidinophenoxymethyl cyclopropylethoxy OMe carbonyl1957 g-amidinophenoxymethyl cyclopropylethoxy OH carbonyl1958 4-amidinophenoxymethyl 4-methylphenylsulfonyl OMe1959 4-amidinophenoxymethyl 4-methylphepylsulfonyl OH1960 4-amidinophenoxymethyl 3-methylphenylsulfonyl OMe1961 4-amidinophenoxymethyl 3-methylphenylsulfonyl OH1962 4-amidinophenoxymethyl n-butylsulfonyl OMe1963 4-amidinophenoxymethyl n-butylsulfonyl OH1964 4-amidinophenoxy benzyloxycarbonyl OMe1965 4-amidinophenoxy benzyloxycarbonyl OH1967 4-amidinophenoxy n-butyloxycarbonyl OMe1969 4-amidinophenoxy n-butyloxycarbonyl OH1970 4-amidinophenoxy cyclopropylethyoxy OMe carbonyl1971 4-amidinophenoxy cyclopropylethoxy OH carbonyl1972 4-amidinophenoxy 4-methylphenylsulfonyl OMe1973 4-amidinophenoxy 4-methylphenylsulfonyl OH1974 4-amidinophenoxy 3-methylphlnylsulfonyl OMe1975 4-amidinophenoxy 3-methylphenylsulfonyl OH1976 4-amidinophenoxy n-butylsulfonyl OMe1977 4-amidinophenoxy D-butylsulfonyl OH1978 4-amidinophenethyl benzyloxycarbonyl OMe1978 4-amidinophenethyl benzyloxycarbonyl OH1980 4-amidinophenethyl n-butyloxycarbonyl OMe1981 4-amidinophenethyl n-butyloxycarbonyl OH1982 4-amidinophenethyl cyclopropylethoxy OMe carbonyl1983 4-amidinophenethyl cyclopropylethoxy OH carbonyl1984 4-amidinophenethyl 4-methylphenylsulfonyl OMe1986 4-amidinophenethyl 4-methylphenylsulfonyl OH1986 4-amidinophenethyl 3-methylphenylsulfonyl OMe1987 4-amidinophenethyl 3-methylphenylsulfonyl OH1988 4-amidinophenethyl n-butylsulfonyl OMe1989 4-amidinophenethyl n-butylsulfonyl OH1990 N-(4-amidinophenyl) benzyloxycarbonyl OMe aminomethyl1991 N-(4-amidinophenyl) benzyloxycarbonyl OH aminomethyl1993 N-(4-amidinophenyl) n-butyloxycarbonyl OMe aminomethyl1994 N-(4-amidinophenyl) n-butyloxycarbonyl OH aminomethyl1995 N-(4-amidinophenyl) cyclopropylethoxy OH aminomethyl carbonyl1996 N-(4-amidinophenyl) 4-methylphenylsulfonyl OMe aminomethyl1997 N-(4-amidinophenyl) 4-methylphenylsulfonyl OH aminomethyl1998 N-(4-amidinophenyl) 3-methylphenylsulfonyl OMe aminomethyl1999 N-(4-amidinophenyl) 3-methylphenylsulfonyl OH aminomethyl2000 N-(4-amidinophenyl) n-butylsulfonyl OMe aminomethyl2001 N-(4-amidinophenyl) n-butylsulfonyl OH aminomethyl2002 4-amidinophenyl benzyloxycarbonyl OMe methylamino2003 4-amidinophenyl benzyloxycarbonyl OH methylamino2004 4-amidinophenyl n-butyloxycarbonyl OMe methylamino2005 4-amidinophenyl n-butyloxycarbonyl OH methylamino2006 4-amidinophenyl cyclopropylethoxy OMe methylamino carbonyl2007 4-amidinophenyl cyclopropy3;ethoxy OH methylamino carbonyl2008 4-amidinophenyl 4-methylphenylsulfonyl OMe methylamino2010 4-amidinophenyl 4-methylphenylsulfonyl OH methylamino2011 4-amidinophenyl 3-methylphenylsulfonyl OMe methylamino2012 4-amidinophenyl n-butylsulfonyl OMe methylamino2013 4-amidinophenyl n-butylsulfonyl OH methylamino2014 N-(4-amidinophenyl) benzyloxycarbonyl OMe aminocarbonyl2015 N-(4-amidinophenyl) benzyloxycarbonyl OH aminocarbonyl2016 N-(4-amidinophenyl) n-butyloxy:carbonyl OMe aminocarbonyl2017 N-(4-amidinophenyl) n-butyloxycarbonyl OH aminocarbonyl2018 N-(4-amidinophenyl) cyclopropylethoxy OMe aminocarbonyl carbonyl2019 N-(4-amidinophenyl) cyclopropylethoxy OH aminocarbonyl carbonyl2020 N-(4-amidinophenyl) 4-methylphenylsulfonyl OMe aminocarbonyl2021 N-(4-amidinophenyl) 4-methylphenylsulfonyl OH aminocarbonyl2022 N-(4-amidinophenyl) 3-methylpYienylsulfonyl OMe aminocarbonyl2023 N-(4-amidinophenyl) 3-methylphenylsulfonyl OH aminocarbonyl2024 N-(4-amidinophenyl) n-butylsulfonyl OMe2025 N-(4-amidinophenyl) n-butylsulfonyl OH aminocarbonyl2027 4-amidinophenyl benzyloxycarbonyl OMe carbonylamino2028 4-amidinophenyl benzyloxycarbonyl OH carbonylamino2029 4-amidinophenyl n-butyloxycarbonyl OMe carbonylamino2030 4-amidinophenyl n-butyloxyc.arbonyl OH carbonylamino2031 4-amidinophenyl cyclopropylethoxy OMe carbonylamino carbonyl2032 4-amidinophenyl cyclopropylethoxy OH carbonylamino carbonyl2033 4-amidinophenyl 4-methylphenylsulfonyl OMe carbonylamino2034 4-amidinophenyl 4-methylphenylsulfonyl OH carbonylamino2035 4-amidinophenyl 3-methylphenylsulfonyl OMe carbonylamino2036 4-amidinophenyl 3-methylphenyl-sulfonyl OH carbonylamino2037 4-amidinophenyl n-butylsulfonyl OMe carbonylamino2038 4-amidinophenyl n-butylsulfonyl OH carbonylamino2039 N-(4-amidinophenyl) benzyioxycarbonyl OMe amino2040 N-(4-amidinophenyl) benzyloxycarbonyl OH amino2041 N-(4-amidinophenyl) n-butyloxycarbonyl OMe amino2042 N-(4-amidinophenyl) n-butyloxycarbonyl OH amino2044 N-(4-amidinophenyl) cyclopropylethoxy OMe amino carbonyl2045 N-(4-amidinophenyl) cyclopropylethoxy OH amino carbonyl2046 N-(4-amidinophenyl) 4-methylphenylsulfonyl OMe amino2047 N-(4-amidinophenyl) 4-methylphenylsulfonyl OH amino2048 N-(4-amidinophenyl) 3-methylphenylsulfonyl OMe amino2049 N-(4-amidinophenyl) 3-methylphenylsulfonyl OH amino2050 N-(4-amidinophenyl) n-butylsulfonyl OMe amino2051 N-(4-amidinophenyl) n-butylsulfonyl OH amino2052 N-(4-amidinophenyl)-N- benzyloxycarbonyl OMe methylamino2053 N-(4-amidinophenyl)-N- benzyloxycarbonyl OH methylamino2054 N-(4-amidinophenyl)-N- n-butyloxycarbonyl OMe methylamino2055 N-(4-amidinophenyl)-N- n-butyloxycarbonyl OH methylamino2056 N-(4-amidinophenyl)-N- cyclopropylethoxy OMe methylamino carbonyl2057 N-(4-amidinophenyl)-N- cyclopropyle.thoxy OH methylamino carbonyl2058 N-(4-amidinophenyl)-N- q-methylphenylsulfonyl OMe methylamino2059 N-(4-amidinophenyl)-N- 4-methylphenylsulfonyl OH methylamino2061 N-(4-amidinophenyl)-N- 3-methylphenylsulfonyl OMe methylamino2062 N-(4-amidinophenyl)-N- 3-methylphenylsulfonyl OH methylamino2063 N-(4-amidinophenyl)-N- n-butylsulfonyl OMe methylamino2064 N-(4-amidinophenyl)-N- n-butylsulfonyl OH methylamino2065 4-amidinobenzoyl benzyloxycarbonyl OMe2066 4-amidinobenzoyl benzyloxycarbonyl OH2067 4-amidinobenzoyl n-butyloxycarbonyl OMe2068 4-amidinobenzoyl n-butyloxycarbonyl OH2069 4-amidinobenzoyl cyclopropylethoxy OMe carbonyl2070 4-amidinobenzoyl cyclopropylethoxy OH carbonyl2071 4-amidinobenzoyl 4-methylphenylsulfonyl OMe2072 4-amidinobenzoyl 4-methylphenylsulfonyl OH2073 4-amidinobenzoyl 3-methylphenylsulfonyl OMe2074 4-amidinobenzoyl 3-methylphenylsulfonyl OH2075 4-amidinobenzoyl n-butylsulfonyl OMe2076 4-amidinobenzoyl n-butylsulfonyl OH2077 4-amidinophenyl benzyloxycarbonyl OMe methylcarbonyl2078 4-amidinophenyl benzyloxycarbonyl OH methylcarbonyl2079 4-amidinophenyl n-butyloxycarbonyl OMe methylcarbonyl2080 4-amidinophenyl n-butyloxycarbonyl OH methylcarbonyl2081 4-amidinophenyl cyclopropylethoxy OMe methylcarbonyl carbonyl2083 4-amidinophenyl cyclopropylethoxy OH methylcarbonyl carbonyl2084 4-amidinophenyl 4-methylphenylsulfonyl OMe methylcarbonyl2085 4-amudinophenyl 4-methylphenylsulfonyl OH methylcarbonyl2086 4-amidinophenyl 3-methylphenylsulfonyl OMe methylcarbonyl2087 4-amidinophenyl 3-methylphenylsulfonyl OH methylcarbonyl2088 4-amidinophenyl n-butylsulfonyl OMe methylcarbonyl2089 4-amidinophenyl n-butylsulfonyl OH methylcarbonyl2090 4-amidinophenyl- benzyloxycarbonyl OMe carbonylmethyl2091 4-amidinophenyl- benzyloxycarbonyl OH carbonylmethyl2092 4-amidinophenyl- n-butyloxycarbonyl OMe carbonylmethyl2093 4-amidinophenyl- n-butyloxycarbonyl OH carbonylmethyl2094 4-amidinophenyl- cyclopropylethoxy OMe carbonylmethyl carbonyl-2095 4-amidinophenyl- cyclopropylethoxy OH carbonylmethyl carbonyl2096 4-amidinophenyl- g-methylphenylsulfonyl OMe. carbonylmethyl2097 4-amidinophenyl- 4-methylphenylsulfonyl OH carbonylmethyl2098 4-amidinophenyl- 3-methylphenylsulfonyl OMe carbonylmethyl2100 4-amidinophenyl- 3-methylphenylsulfonyl OU carbonylmethyl2101 4-amidinophcnyl- n-butylsulfonyl OMe carbonylmethyl2102 4-amidinophenyl- n-butylsulfonyl OH carbonylmethyl2103 4-amidinophenyl 3,5-dimethylisoxazol- OMe HNMR HOAc salt, 5(R),N.sup.2 (S) 4-ylsulfonyl isomer2104 4-amidinophenyl 3,5-dimethylisoxazol- OH 493 TFA salt, 5(R),N.sup.2 (S) 4-ylsulfonyl isomer2105 4-amidinophenyl 3,5-dimethylisoxazol- OMe HNMR HOAc salt, 5(S),N.sup.2 (S) 4-ylsulfonyl isomer2106 4-amidinophenyl 3,5-dimethylisoxazol- OH TFA salt, 5(S),N.sup.2 (S) 4-ylsulfonyl isomer2107 4-amidinophenyl 3,5-dimethylisoxazol- OMe HOAc salt, 5(R),N.sup.2 (R) 4-ylsulfonyl isomer2108 4-amidinophenyl 3,5-dimethylisoxazol- OMe HOAc salt, 5(S),N.sup.2 (R) 4-ylsulfonyl isomer2109 2-guanidinoethyl carbobenzyloxy OH 4352110 5-guanidinovaleryl carbobenzyloxy OH 4772111 4-(N-2- 2-methylphenylsulfonyl OMe 622 methoxybenyzyl)- amidinophenyl.HCl2112 4-(N-2- 2-methylphenylsulfonyl OH 608 methoxybenyzyl)- amidinophenyl.HCl2113 4-(N-n-butyl)- 2-methylphenylsulfonyl OMe 558 amidinophenyl.TFA2114 4-(N-n-butyl)- 2-methylphenylsulfonyl OH 544 amidinophenyl.TFA2115 4-tN-ethyl)- 2-methylphenylsulfonyl OMe 530 amidinophenyl.TFA2116 4-(N-ethyl)- 2-methylphenylsulfonyl OH 516 amidinophenyl.TFA2117 4-amidinophenyl 4-methyl-2-methyl- OH 566 carbonylamino- 5-thiazolylsulfonyl.TFA2118 4-amidinophenyl 5-phenylsulfonyl-2- OMe 634 thienylsulfonyl.TFA2119 4-amidinophenyl 5-phenylsulfonyl-2- OMe 620 thienylsulfonyl.TFA2120 N-t-butyloxycarbonyl-4- 5-phenylsulfonyl-2- OH 720 amidinophenyl thienylsulfonyl.TFA__________________________________________________________________________ TABLE 10__________________________________________________________________________ ##STR363##Ex. MSNo. R.sup.1V R.sup.5a R.sup.16 Y (M + H)__________________________________________________________________________2121 4-piperidinylethyl methyl benzyloxycarbonyl OH2122 4-piperidinylethyl methyl 2-methylphenylsulfonyl OH2123 4-piperidinylethyl methyl 3,5-dimethylisoxazolyl OH sulfonyl2124 4-piperidinylethyl methyl n-butylsulfonyl OH2125 4-piperidinylethyl methyl n-butylsulfonyl OMe2126 4-piperidinylmethyl methyl n-butylsulfonyl OH2127 4-piperidinylmethyl methyl n-butylsulfonyl OMe2128 4-piperidinylmethyl methyl 2-methylphenylsulfonyl OH2129 4-piperidinylmethyl methyl 2-bromophenylsulfonyl OH2130 4-piperidinylmethyl methyl 3-methylphenylsulfonyl OH2131 4-piperidinylmethyl methyl 3-methylphenylsulfonyl OMe2132 4-piperidinylmethyl methyl 3,5-dimethylisoxazolyl OH sulfonyl2133 4-piperidinylmethyl methyl 3,5-dimethylisoxazolyl OMe sulfonyl2134 4-piperidinylmethyl methyl styrylsulfonyl OH2135 4-piperidinylmethyl methyl benzyloxycarbonyl OH2136 4-piperidinylmethyl methyl benzyloxycarbonyl OMe2137 4-piperidinylmethyl methyl n-butyloxycarbonyl OH2138 4-piperidinylmethyl methyl n-butyloxycarbonyl OMe2139 4-piperidinylpropyl methyl n-butylsulfonyl OH2140 4-piperidinylpropyl methyl n-butylsulfonyl OMe2141 4-piperidinylpropyl methyl 2-methylphenylsulfonyl OH2142 4-piperidinylpropyl methyl 2-bromophenylsulfonyl OH2143 4-piperidinylpropyl methyl 3-methylphenylsulfonyl OH2144 4-piperidinylpropyl methyl 3-methylphenylsulfonyl OMe2145 4-piperidinylpropyl methyl 3,5-dimethylisoxazolyl OH sulfonyl2146 4-piperidinylpropyl methyl 3,5-dimethylisoxazolyl OMe sulfonyl2147 4-piperidinylpropyl methyl styrylsulfonyl OH2148 4-piperidinylpropyl methyl benzyloxycarbonyl OH2149 4-piperidinylpropyl methyl benzyloxycarbonyl OMe2150 4-piperidinylpropyl methyl n-butyloxycarbonyl OH2151 4-piperidinylpropyl methyl n-butyloxycarbonyl OMe2152 4-amidinopiperidinyl methyl n-butylsulfonyl OH2153 4-amidinopiperidinyl methyl n-butylsulfonyl OMe2154 4-amidinopiperidinyl methyl 2-methylphenylsulfonyl OH2155 4-amidinopiperidinyl methyl 2-bromophenylsulfonyl OH2156 4-amidinopiperidinyl methyl 3-methylphenylsulfonyl OH2157 4-amidinopiperidinyl methyl 3-methylphenylsulfonyl OMe2158 4-amidinopiperidinyl methyl 3,5-dimethylisoxazolyl OH sulfonyl2159 4-amidinopiperidinyl methyl 3,5-dimethylisoxazolyl OMe sulfonyl2160 4-amidinopiperidinyl methyl styrylsulfonyl OH2161 4-amidinopiperidinyl methyl benzyloxycarbonyl OH2162 4-amidinopiperidinyl methyl benzyloxycarbonyl OMe2163 4-amidinopiperidinyl methyl n-butyloxycarbonyl OH2164 4-amidinopiperidinyl methyl n-butyloxycarbonyl OMe2165 4-amidinopiperidinyl- methyl n-butylsulfonyl OH methyl2166 4-amidinopiperidinyl- methyl n-butylsulfonyl OMe methyl2167 4-amidinopiperidinyl- methyl 2-methylphenylsulfonyl OH methyl2168 4-amidinopiperidinyl- methyl 2-bromophenylsulfonyl OH methyl2169 4-amidinopiperidinyl- methyl 3-methylphenylsulfonyl OH methyl2170 4-amidinopiperidinyl- methyl 3-methylphenylsulfonyl OMe methyl2171 4-amidinopiperidinyl- methyl 3,5-dimethylisoxazolyl OH methyl sulfonyl2172 4-amidinopiperidinyl- methyl 3,5-dimethylisoxazolyl OMe methyl sulfonyl2173 4-amidinopiperidinyl- methyl styrylsulfonyl OH methyl2174 4-amidinopiperidinyl- methyl benzyloxycarbonyl OH methyl2175 4-amidinopiperidinyl- methyl benzyloxycarbonyl OMe methyl2176 4-amidinopiperidinyl- methyl n-butyloxycarbonyl OH methyl2177 4-amidinopiperidinyl- methyl n-butyloxycarbonyl OMe methyl2178 4-amidinophenyl methyl phenylcarbonyl OMe2179 4-amidinophenyl methyl phenylcarbonyl OH2180 4-amidinophenyl methyl 2,6-methylphenylcarbonyl OMe2181 4-amidinophenyl methyl 2,6-methylphenylcarbonyl OH2182 4-amidinophenyl methyl 2-methylphenylcarbonyl OMe2183 4-amidinophenyl methyl 2-methylphenylcarbonyl OH2184 4-amidinophenyl methyl 2-bromophenylcarbonyl OMe2185 4-amidinophenyl methyl 2-bromophenylcarbonyl OH2186 4-amidinophenyl methyl 3-methylphenylcarbonyl OMe2187 4-amidinophenyl methyl 3-methylphenylcarbonyl OH2188 4-amidinophenyl methyl 3,5-dimethyl- OMe isoxazoylcarbonyl2189 4-amidinophenyl methyl 3,5-dimethyl- OH isoxazoylcarbonyl2190 4-piperidinylethyl methyl phenylcarbonyl OMe2191 4-piperidinylethyl methyl phenylcarbonyl OH2192 4-piperidinylethyl methyl 2,6-methylphenylcarbonyl OMe2193 4-piperidinylethyl methyl 2,6-methylphenylcarbonyl OH2194 4-piperidinylethyl methyl 2-methylphenylcarbonyl OMe2195 4-piperidinylethyl methyl 2-methylphenylcarbonyl OH2196 4-piperidinylethyl methyl 2-bromophenylcarbonyl OMe2197 4-piperidinylethyl methyl 2-bromophenylcarbonyl OH2198 4-piperidinylethyl methyl 3-methylphenylcarbonyl OMe2199 4-piperidinylethyl methyl 3-methylphenylcarbonyl OH2200 4-piperidinylethyl methyl 3,5-dimethyl- OMe isoxazoylcarbonyl2201 4-piperidinylethyl methyl 3,5-dimethyl- OH isoxazoylcarbonyl2202 4-piperidinylethyl methyl n-butyloxycarbonyl OH__________________________________________________________________________ TABLE 11______________________________________ ##STR364##Ex-am-ple MSNum- (M +ber R.sup.2 R.sup.8 Y H).sup.+______________________________________2220 H CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7 OH2221 H CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub..sub.9 OH2222 H CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub..sub.11 OH2223 H CH.sub.2 NHCO.sub.2 CH.sub.2 Ph OH2224 H CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph OH2225 H CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9 OH2226 H CH.sub.2 NHSO.sub.2 CH.sub.2 Ph OH2227 H ##STR365## OH2228 H ##STR366## OH2229 H ##STR367## OH2230 H ##STR368## OH2231 n-Bu CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7 OH2232 n-Bu CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub.9 OH2233 n-Bu CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub.11 OH2234 n-Bu CH.sub.2 NHCO.sub.2 CH.sub.2 Ph OH2235 n-Bu CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph OH2236 n-Bu CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9 OH2237 n-Bu CH.sub.2 NHSO.sub.2 CH.sub.2 Ph OH2238 n-Bu ##STR369## OH2239 n-Bu ##STR370## OH2240 n-Bu ##STR371## OH2241 n-Bu ##STR372## OH2242 o-methoxy- CH.sub.2 CH.sub.3 OH benzyl2243 o-methoxy- CHCH.sub.2 OH benzyl2244 o-methoxy- C CH OH benzyl2245 o-methoxy- CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7 OH benzyl2246 o-methoxy- CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub.9 OH benzyl2247 o-methoxy- CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub.11 OH benzyl2248 o-methoxy- CH.sub.2 NHCO.sub.2 CH.sub.2 Ph OH benzyl2249 o-methoxy- CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph OH benzyl2250 o-methoxy- CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9 OH benzyl2251 o-methoxy- CH.sub.2 NHSO.sub.2 CH.sub.2 Ph OH benzyl2252 o-methoxy- benzyl ##STR373## OH2253 o-methoxy- benzyl ##STR374## OH2254 o-methoxy- benzyl ##STR375## OH2255 o-methoxy- benzyl ##STR376## OH2256 o-methoxy- CH.sub.2 CH.sub.3 OH benzyl2257 o-methoxy- CHCH.sub.2 OH benzyl2258 o-methoxy- C CH OH benzyl______________________________________ TABLE 12______________________________________ ##STR377##Ex. MSNo. R.sup.1 R.sup.16 m n (M + H).sup.+______________________________________2280 guanidino benzyloxycarbonyl 2 2 4492281 guanidino benzyloxycarbonyl 1 2 4352282 guanidino benzyloxycarbonyl2283 guanidino benzyloxycarbonyl2284 guanidino benzyloxycarbonyl2285 guanidino benzyloxycarbonyl______________________________________ TABLE 13______________________________________ ##STR378##Ex. MSNo. R.sup.1 R.sup.16 m n (M + H).sup.+______________________________________2400 guanidino benzyloxycarbonyl 2 2 4492401 guanidino benzyloxycarbonyl 3 0 4352402 guanidino benzyloxycarbonyl 5 0 4632403 guanidino benzyloxycarbonyl 3 2 4632404 guanidino benzyloxycarbonyl 4 2 4772405 guanidino benzyloxycarbonyl 2 0 4212406 guanidino benzyloxycarbonyl 4 0 449______________________________________ TABLE 14______________________________________ ##STR379##Ex. MSNo. R.sup.1V R.sup.16 Y (M + H).sup.+______________________________________2420 4-piperidinylpropyl n-butyloxycarbonyl OMe 4412421 4-piperidinylpropyl 4-methylphenylsulfonyl OMe 4952422 4-piperidinylpropyl 4-methylphenylsulfonyl OH 4812423 4-piperidinylpropyl n-butyloxycarbonyl OH 427______________________________________

Utility

The compounds of this invention possess antiplatelet efficacy, as evidenced by their activity in standard platelet aggregation assays or platelet fibrinogen binding assays, as described below. A compound is considered to be active in these assays if it has an IC.sub.50 value of less than about 1 mM. Platelet aggregation and fibrinogen binding assays which may be used to demonstrate the antiplatelet activity of the compounds of the invention are described below.

Platelet Aggregation Assay

Venous blood was obtained from the arm of a healthy human donor who was drug-free and aspirin-free for at least two weeks prior to blood collection. Blood was collected into 10 mL citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 150.times.g at room temperature, and platelet-rich plasma (PRP) was removed. The remaining blood was centrifuged for 15 minutes at 1500.times.g at room temperature, and platelet-poor plasma (PPP) was removed. Samples were assayed on a aggregometer (PAP-4 Platelet Aggregation Profiler), using PPP as the blank (100% transmittance). 200 .mu.L of PRP was added to each micro test tube, and transmittance was set to 0%. 20 .mu.L of various agonists (ADP, collagen, arachidonate, epinephrine, thrombin) were added to each tube, and the aggregation profiles were plotted (% transmittance versus time). The results are expressed as % inhibition of agonist-induced platelet aggregation. For the IC.sub.50 evaluation, the test compounds were added at various concentrations prior to the activation of the platelets.

Ester prodrugs were preincubated (10.sup.-3 M F.C.) with 100 IU/mL Porcine liver esterase (Sigma Chemical Co., St. Louis, Mo., #E-3128) for 2 hours at 37.degree. C. Aliquots are then diluted in 0.1M Tris, pH 7.4, to the desired concentrations. Aliquots of 20 .mu.l of the esterase pretreated prodrugs are added to 200 .mu.l of human platelet rich plasma. Samples were placed in platelet profiler (aggregometer) for 8 minutes at 37.degree. C., followed by the addition of 100 .mu.M Adenosine Diphosphate, (Sigma Chemical Co., St. Louis, Mo., #A-6521), to induce platelet aggregation. Platelet aggregation was allowed to proceed for 5 minutes. Percent inhibition is calculated using percent aggregation in the presence of the test compound divided by percent aggregation of control, times 100. This value is subtracted from 100, yielding percent inhibition. Calculation of IC.sub.50 is performed on a Texas Instruments TI59 with an IC.sub.50 program.

Purified GPIIb/IIIa-Fibrinogen Binding ELISA

The following reagents are used in the GPIIb/IIIa-fibrinogen binding ELISA:

purified GPIIb/IIIa (148.8 .mu.g/mL); biotinylated fibrinogen (.about.1 mg/mL or 3000 nM); anti-biotin alkaline phosphatase conjugate (Sigma no. A7418); flat-bottom, high binding, 96-well plates (Costar Cat. no. 3590); phosphatase substrate (Sigma 104) (40 mg capsules); bovine serum albumin (BSA) (Sigma no. A3294); Alkaline Phosphatase buffer-0.1M glycine-HCl, 1 mM MgCl.sub.2.6H.sub.2 O, 1 mM ZnCl.sub.2, pH 10.4; Binding buffer-20 mM Tris-HCl, 150 mM NaCl, 1 mM CaCl.sub.2.2H.sub.2 O, 0.02% NaN.sub.3, pH 7.0; Buffer A-50 mM Tris-HCl, 100 mM NaCl, 2 mM CaCl.sub.2.2H.sub.2 O, 0.02% NaN.sub.3, pH 7.4; Buffer A+3.5% BSA (Blocking buffer); Buffer A+0.1% BSA (Dilution buffer); 2N NaOH.

The following method steps are used in the GPIIb/IIIa-fibrinogen binding ELISA:

Coat plates with GPIIb/IIIa in Binding buffer (125 ng/100 .mu.L/well) overnight at 4.degree. C. (Leave first column uncoated for non-specific binding). Cover and freeze plates at -70.degree. C. until used. Thaw plate 1 hour at room temperature or overnight at 4.degree. C. Discard coating solution and wash once with 200 .mu.L Binding buffer per well. Block plate 2 hours at room temperature on shaker with 200 .mu.L Buffer A+3.5% BSA (Blocking buffer) per well. Discard Blocking buffer and wash once with 200 .mu.L Buffer A+0.1% BSA (Dilution buffer) per well. Pipet 11 .mu.L of test compound (10.times. the concentration to be tested in Dilution buffer) into duplicate wells. Pipet 11 .mu.L Dilution buffer into non-specific and total binding wells. Add 100 .mu.L Biotinylated fibrinogen (1/133 in Dilution buffer, final concentration=20 nM) to each well. Incubate plates for 3 hours at room temperature on a plate shaker. Discard assay solution and wash twice with 300 .mu.L Binding buffer per well. Add 100 .mu.L Anti-biotin alkaline phosphatase conjugate (1/1500 in Dilution buffer) to each well. Incubate plates for 1 hour at room temperature on plate shaker. Discard conjugate and wash twice with 300 51 Binding buffer per well. Add 100 .mu.L Phosphatase substrate (1.5 mg/mL in Alkaline phosphatase buffer) to each well. Incubate plate at room temperature on shaker until color develops. Stop color development by adding 25 .mu.L 2N NaOH per well. Read plate at 405 nm. Blank against non-specific binding (NSB) well. % Inhibition is calculated as

100-(Test Compound Abs/Total Abs).times.100.

Platelet-Fibrinogen Binding Assay

Binding of .sup.125 I-fibrinogen to platelets was performed as described by Bennett et al. (1983) Proc. Natl. Acad. Sci. U.S.A. 80: 2417-2422, with some modifications as described below. Human PRP (h-PRP) was applied to a Sepharose column for the purification of platelet fractions. Aliquots of platelets (5.times.10.sup.8 cells) along with 1 mM calcium chloride were added to removable 96 well plates prior to the activation of the human gel purified platelets (h-GPP). Activation of the human gel purified platelets was achieved using ADP, collagen, arachidonate, epinephrine, and/or thrombin in the presence of the ligand, .sup.125 I-fibrinogen. The .sup.125 I-fibrinogen bound to the activated platelets was separated from the free form by centrifugation and then counted on a gamma counter. For an IC.sub.50 evaluation, the test compounds were added at various concentrations prior to the activation of the platelets.

The compounds of Formula I of the present invention may also possess thrombolytic efficacy, that is, they are capable of lysing (breaking up) already formed platelet-rich fibrin blood clots, and thus are useful in treating a thrombus formation, as evidenced by their activity in the tests described below. Preferred compounds of the present invention for use in thrombolysis include those compounds having an IC.sub.50 value (that is, the molar concentration of the compound capable of achieving 50% clot lysis) of less than about 1 .mu.M, more preferably an IC.sub.50 value of less than about 0.1 .mu.M.

Thrombolytic Assay

Venous blood was obtained from the arm of a healthy human donor who was drug-free and aspirin free for at least two weeks prior to blood collection, and placed into 10 ml citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 1500.times.g at room temperature, and platelet rich plasma (PRP) was removed. To the PRP was then added 1.times.10.sup.-3 M of the agonist ADP, epinephrine, collagen, arachidonate, serotonin or thrombin, or a mixture thereof, and the PRP incubated for 30 minutes. The PRP was centrifuged for 12 minutes at 2500.times.g at room temperature. The supernatant was then poured off, and the platelets remaining in the test tube were resuspended in platelet poor plasma (PPP), which served as a plasminogen source. The suspension was then assayed on a Coulter Counter (Coulter Electronics, Inc., Hialeah, Fla.), to determine the platelet count at the zero time point. After obtaining the zero time point, test compounds were added at various concentrations. Test samples were taken at various time points and the platelets were counted using the Coulter Counter. To determine the percent of lysis, the platelet count at a time point subsequent to the addition of the test compound was subtracted from the platelet count at the zero time point, and the resulting number divided by the platelet count at the zero time point. Multiplying this result by 100 yielded the percentage of clot lysis achieved by the test compound. For the IC.sub.50 evaluation, the test compounds were added at various concentrations, and the percentage of lysis caused by the test compounds was calculated.

The compounds of Formula I of the present invention are also useful for administration in combination with anti-coagulant agents such as warfarin or heparin, or antiplatelet agents such as aspirin, piroxicam or ticlopidine, or thrombin inhibitors such as boropeptides, hirudin or argatroban, or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof.

The compounds of Formula I of the present invention may also be useful as antagonists of other integrins such as for example, the .alpha..sub.v /.beta..sub.3 or vitronectin receptor, .alpha..sub.4 /.beta..sub.1 or .alpha..sub.5 /.beta..sub.1 and as such may also have utility in the treatment and diagnosis of osteoporosis, cancer metastasis, diabetic retinopathy, rheumatoid arthritis, inflammation, and autoimmune disorders. 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, infammation, bone degradation, 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, inflammatory bowel disease and other autoimmune diseases.

Table A below sets forth the antiplatelet activity of representative compounds of the present invention. The indicated compounds were tested for their ability to inhibit platelet aggregation (using platelet rich plasma (PRP)). The IC.sub.50 value (the concentration of antagonist which inhibits platelet aggregation by 50% relative to a control lacking the antagonist) is shown. In Table 5 the IC.sub.50 values are expressed as: +++=IC.sub.50 of <10 .mu.M; ++=IC.sub.50 of 10-50 .mu.M; +=IC.sub.50 of 50-100 .mu.M (.mu.M=micromolar).

TABLE A______________________________________ Platelet Aggregation Assay Platelet IC.sub.50 (without Aggregation AssayExample Number esterase) IC.sub.50 (with esterase)______________________________________ 1 +++4 (isomer A) ++4 (isomer B) ++ 6 +++ 7 >100 8 +9 (isomer A) +++9 (isomer B) +++ 33 >100 43 +++ 89 +++ 115 +++119A (3R) +++119B (3S) +++120A (3R) +++120B (3S) +++120C (3R) .dagger..dagger. +++ 166 +++ 189 >100 190 + 275 +++ 276 +++ 278 +++ 290 +++ 300 +++ 312 +++314A (2S) .dagger. +++314B (2S) .dagger..dagger. +++ 323 +++ 324 +++ 326 +++327 (2S) +++328 (2S) +++338 (3S) + +++339 (3S) +++340 (3S) + ++341 (3S) +++342 (2S) +++344 (3R) +++ 345 +++347 (3R) .dagger..dagger. +++348 (3R) +++ 350 +++ 359 +++ 362 +++ 365 +++ 368 +++ 373 ++371A +++371B +++374 (2S) + +++375* +++ 377 +++ 394 +++394A .dagger..dagger. +++ 400 +++413* +++ 415 +++ 435 +++ 436 +++ 437 +++ 438 +++ 439 +++ 440 +++ 441 +++ 442 +++443 (2S) +++444 (2S) +++445 (2S) +++ 446 +++449A +++449B +++ 450 +++ 451 +++ 452 +++ 453 +++ 454 +++ 455 +++ 456 ++ 457 +++458A +++458B +++460A +++460B +++ 462 +++ 463 +++ 464 +++ 465 +++ 466 +++ 467 +++ 468 +++ 469 +++ 470 +++ 471 +++ 472 +++ 473 +++473A (2S) .dagger. +++473B (2S) .dagger..dagger. +++ 474 +++ 475 +++ 476 +++ 477 +++ 478 +++ 479 +++ 480 +++ 481 +++ 482 +++ 483 +++ 484 +++ 485 +++ 486 +++ 487 +++ 488 +++ 489 +++ 490 +++ 491 +++ 492 +++ 493 +++ 494 +++ 495 +++ 496 +++ 504 +++ 505 +++ 506 +++ 507 +++ 508 +++ 509 +++ 510 +++ 511 +++ 512 +++ 513 +++ 514 +++ 515 +++ 516 +++ 517 +++ 518 +++ 519 +++ 520 +++ 522 +++ 523 +++ 524 +++ 525 +++ 526 +++ 527 +++ 528 +++ 529 +++ 530 +++ 531 +++ 532 +++ 533 +++ 534 +++ 535 +++ 536 +++ 537 +++ 538 +++ 539 +++ 540 +++ 541 +++ 542 +++ 543 +++ 544 +++ 545 +++ 546 +++ 547 +++ 548 +++ 549 +++ 550 +++ 551 +++ 552 +++ 553 +++ 554 +++ 555 +++ 556 +++587A (2S) .dagger..dagger. +++ 588 +++ 602 +++ 611 +++ 612 +++ 613 +++ 616 +++ 642 +++ 643 +++ 644 +++ 651 +++ 727 +++ 729 +++ 798 +++ 829 +++1284 +++1321 +++1525 +++1694 +++1731 +++2104 +++2109 +++2110 +++2111 +++2112 +++2113 +++2114 +++2115 +++2116 +++2117 +++2118 +++2119 +++2120 +++2280 +++2281 +++2400 +++2401 +++2402 +++2403 +++2404 +++2405 +++2406 +++______________________________________ *Single diastereomer, racemic .dagger. S isomer at C5 of isoxazoline ring .dagger..dagger. R isomer at C5 of isoxazoline ring

The compounds 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, thrombosis, 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, diabetic retinopathy, inflammatory bowel disease and other angiogenic disorders.

The compounds of the formulae (Ie) and (If) possess selectivity as antagonists of integrins such as the .alpha..sub.v /.beta..sub.3 vitronectin receptor. ##STR380## 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 .alpha..sub.v /.beta..sub.3 receptor. 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 would be provided in commercial kits comprising a compound of this invention.

Purified .alpha..sub.v /.beta..sub.3 (human placenta)--Vitronectin ELISA

The .alpha..sub.v /.beta..sub.3 receptor was isolated from human placental extracts prepared using octylglucoside. The extracts were passed over an affinity column composed of anti-.alpha..sub.v /.beta..sub.3 monoclonal antibody (LM609) to Affigel. The column was subsequently 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 .alpha..sub.v /.beta..sub.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 .alpha..sub.v /.beta..sub.3 with no detectable levels of .alpha..sub.v /.alpha..sub.5 according to the gel (.alpha..sub.v /.beta..sub.3) and according to effects of blocking antibodies for the .alpha..sub.v /.beta..sub.3 or .alpha..sub.v /.beta..sub.5 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.

.alpha..sub.v /.beta..sub.3 -Vitronectin Binding Assay

The purified receptor is diluted with coating buffer (20 mM Tris HCl, 150 mM NaCl, 2.0 mM CaCl.sub.2, 1.0 mM MgCl.sub.2.6H.sub.2 O, 1.0 mM MnCl.sub.2.4H.sub.2 O) and coated (100 .mu.l/well) on Costar (3590) high capacity binding plates overnight at 4.degree. 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 CaCl.sub.2, 1.0 mM MgCl.sub.2.6H.sub.2 O, 1.0 mM MnCl.sub.2.4H.sub.2 O). Receptor is then blocked (200 .mu.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 .mu.l) and either inhibitor (11 .mu.l) or B/B buffer w/1.0% BSA (11 .mu.l)is added to each well. The plates are incubated 2 hours at room temperature. The plates are washed twice with B/B buffer and incubated 1 hour at room temperature with anti-biotin alkaline phosphatase (100 .mu.l/well) in B/B buffer containing 1.0% BSA. The plates are washed twice with B/B buffer and alkaline phosphatase substrate (100 .mu.l) is added. Color is developed at room temperature. Color development is stopped by addition of 2N NaOH (25 .mu.l/well) and absorbance is read at 405 nm. The IC.sub.50 is the concentration of test substance needed to block 50% of the vitronectin binding to the receptor.

Integrin Cell-Based Adhesion Assays

In the adhesion assays, a 96 well plate was coated with the ligand (i.e., fibrinogen) and incubated overnight at 40.degree. 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 IC.sub.50 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 .alpha..sub.v /.beta..sub.3, .alpha..sub.v /.beta..sub.5 and .alpha..sub.5 /.beta..sub.1 integrin interactions.

Dosage and Formulation

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent. Finally, the compounds of the invention may also be administered intranasally.

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, glycoprotein IIb/IIIa (GPIIb/IIIa), in the body of a mammal. 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 second antiplatelet agent such as aspirin or ticlopidine which are agonist-specific. They 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 regimen for the compounds of the present invention 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 species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.

We have unexpectedly found that delivery of Example 327 (and it's free acid Example 300) through the nasal route provided very high bioactivity (inhibition of platelet aggregation) that was similar to that observed after administering the same dose intravenously. Also dog to dog variability was very small. For example, nasal and i.v. administration of 0.025 mg/kg gave similar profiles of platelet aggregation inhibition, however comparable effect after oral administration was only seen at doses equal or greater than 0.4 mg/kg. Therefore, the advantages of delivering Example 327 nasally are to enhance bioavailability and reduce variability. The latter is very important due to the steep dose response of these types of compounds.

The active ingredient can be administered intranasally to a mammal at a dosage range of about 0.01 to 0.5 mg/kg while the preferred dosage range is about 0.01-0.1 mg/kg.

Compositions of the active ingredients can be administered intranasally by preparing a suitable formulation of the active ingredient by procedures well known to those skilled in the art. Preferably the formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in REMINGTON'S PHARMACEUTICAL SCIENCES. 17th edition, 1985 a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, jelling agents, or buffering and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.

An example of a nasal solution composition of this invention includes:

______________________________________Active Drug 0.2-2 gSorbitol 0.6 gBenzalkonium chloride 0.002 gHydrochloric acid to adjust pHSodium hydroxide to adjust pHPurified water to 10 mL______________________________________

In this example the active drug can be in one vial and the rest of the formulation can be in another vial. The drug can be reconstituted when needed.

The formulation of this invention may be varied to include: (1) other acids and bases to adjust the pH; (2) other tonicity imparting agents such as glycerin and dextrose; (3) other antimicrobial preservatives such as other parahydroxy benzoic acid esters, sorbate, benzoate, propionate, chlorbutanol, phenylethyl alcohol, and mercurials; (4) other viscosity imparting agents such as sodium carboxy-methylcellulose microcrystalline cellulose, polyvinyl-pyrrolidone, polyvinyl alcohol and other gums; (5) suitable absorption enhancers; (6) stabilizing agents such as antioxidants, like bisulfite and ascorbate, metal chelating agents such as sodium edetate and drug solubility enhancers such as polyethylene glycols.

The above formulation can be administered as drops, sprays, aerosols or by any other intranasal dosage form. Optionally, the delivery system can be a unit dose delivery system. The volume of solution or suspension delivered per dose can be anywhere from 5 to 400 .mu.L, and preferably between 50 and 150 .mu.L. Delivery systems for these various dosage forms can be dropper bottles, plastic squeeze units, atomizers, nebulizers or pharmaceutical aerosols in either unit dose or multiple dose packages.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered 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 may 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 preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Reminaton's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 1-20 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

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 1-20 milligrams of the active ingredient. The capsules are washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 1-20 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.

Injectable

A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5 mL contain 1-20 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

The compounds of the present invention may be administered in combination with a second therapeutic agent selected from: an anti-coagulant agent such as warfarin or heparin; an anti-platelet agent such as aspirin, piroxicam or ticlopidine; a thrombin inhibitor such as a boropeptide thrombin inhibitor, or hirudin; or a thrombolytic agent such as plasminogen activators, such as tissue plasminogen activator, anistreplase, urokinase or streptokinase. The compound of Formula I and such second therapeutic agent can be administered separately or as a physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above.

The compound of Formula I may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.). When the compound of Formula I and the second therapeutic agent are not formulated together in a single dosage unit, the compound of Formula I and the second therapeutic agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent) may be administered essentially at the same time, or in any order; for example the compound of Formula I may be administered first, followed by administration of the second agent (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 Formula I and the second therapeutic agent occurs less than about one hour apart.

A preferable route of administration of the compound of Formula I is oral. Although it is preferable that the compound of Formula I and the second therapeutic agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent) are both administered by the same route (that is, for example, both orally), if desired, they may each be administered by different routes and in different dosage forms (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 compound of Formula I when administered alone or in combination with a second therapeutic agent 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.

Although the proper dosage of the compound of Formula I when administered in combination with the second therapeutic agent will be readily ascertainable by a medical practitioner skilled in the art, once armed with the present disclosure, by way of general guidance, where the compounds of this invention are combined with anti-coagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the anti-coagulant, per kilogram of patient body weight. For a tablet dosage form, the novel compounds of this invention generally may be present in an amount of about 1 to 10 milligrams per dosage unit, and the anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with a second anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the additional anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Further, by way of general guidance, where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, 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 of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be 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. One of the active ingredients may also be coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize 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 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.

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.

The present invention also includes pharmaceutical kits useful, for example, in the inhibition of platelet aggregation, the treatment of blood clots, and/or the treatment of thromboembolic disorders, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, 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.

In the present disclosure it should be understood that the specified materials and conditions are important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.

Claims

1. A compound of Formula I: ##STR381## or a pharmaceutically acceptable salt form thereof wherein: b is a carbon-carbon single or double bond;

R.sup.1 is selected from R.sup.2a (R.sup.3)N--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2a (R.sup.3)N(CH.sub.2).sub.p' Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C(CH.sub.2).sub.p" Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR382## Z is selected from: a bond, O, S, S(.dbd.O), S(.dbd.O).sub.2 ; R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.10 alkyl; C.sub.3 -C.sub.6 alkenyl; C.sub.3 -C.sub.11 cycloalkyl; C.sub.4 -C.sub.11 cycloalkylalkyl; C.sub.6 -C.sub.10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O)MCH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O)MCH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C.sub.1 -C.sub.10 alkoxy)carbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C.sub.1 -C.sub.6 alkyl)carbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; (C.sub.6 -C.sub.10 aryl)carbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C.sub.4 -C.sub.11 cycloalkylcarbonyl)oxy (C.sub.1 -C.sub.4 alkoxy) carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

provided that only one of R.sup.2 and R.sup.3 may be hydroxy;

R.sup.2a is R.sup.2 or R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--;

U is selected from:

a single bond,

--(C.sub.1 -C.sub.7 alkyl)--,

--(C.sub.2 -C.sub.7 alkenyl)--,

(C.sub.2 -C.sub.7 alkynyl)--;

V is selected from:

a single bond;

--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(phenyl)--Q--, said phenyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

--(pyridyl)--Q--, said pyridyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ; or

--(pyridazinyl)--Q--, said pyridazinyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7,

Q is selected from:

a single bond,

--O--, --S(O).sub.m --, --N(R.sup.12)--, --(CH.sub.2).sub.m --, --C(.dbd.O)--, --N(R.sup.5a)C(.dbd.O)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 N(R.sup.12)--, --N(R.sup.12)CH.sub.2 --, --CH.sub.2 C(.dbd.O)--, --C(.dbd.O)CH.sub.2 --, --CH.sub.2 S(O).sub.m --, or --S(O).sub.m CH.sub.2 --,

provided that when b is a single bond, and R.sup.1 --U--V-- is a substituent on C.sub.5 of the central 5-membered ring of Formula I, then Q is not --O--, --S(O).sub.m --, --N(R.sup.12)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, CH.sub.2 N(R.sup.12)-- or --CH.sub.2 S(O).sub.m --;

W is selected from:

--(C(R.sup.4).sub.2).sub.n' C(.dbd.O)N(R.sup.5a)--, or

--C(.dbd.O)--N(R.sup.5a)--(C(R.sup.4).sub.2).sub.n' --;

X is selected from:

--(C(R.sup.4).sub.2).sub.n' --C(R.sup.4)(R.sup.8)--C(R.sup.4)(R.sup.4a)--;

Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R.sup.2) (R.sup.3)N--(C.sub.1 -C.sub.10 alkoxy)--;

R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

alternately, two R.sup.4 groups on adjacent carbon atoms may join to form a bond thereby to form a carbon-carbon double or triple bond between such adjacent carbon atoms;

R.sup.4a is selected from hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, N(R.sup.5)R.sup.5 a, --N(R.sup.12)R.sup.13, --N(R.sup.16)R.sup.17, aryl substituted with 0-3 R.sup.6, or (C.sub.1 -C.sub.10 alkyl)carbonyl

R.sup.4b is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.7 -C.sub.14 bicycloalkyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, nitro, (C.sub.1 -C.sub.6 alkyl)carbonyl, C.sub.6 -C.sub.10 aryl, --N(R.sup.12)R.sup.13 halo, CF.sub.3, CN, (C.sub.1 -C.sub.6 alkoxy)carbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;

R.sup.5 is selected from H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-6 R.sup.4b ;

R.sup.5 a is selected from hydrogen, hydroxy, C.sub.1 to C.sub.8 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 to C.sub.11 arylalkyl, adamantylmethyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;

alternately, R.sup.5 and R.sup.5a when both are substituents on the same nitrogen atom (as in --NR.sup.5 R.sup.5a) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, heteroaryl, C.sub.7 -C.sub.11 arylalkyl, (C.sub.1 -C.sub.6 alkyl)carbonyl, (C.sub.3 -C.sub.7 cycloalkyl)carbonyl, (C.sub.1 -C.sub.6 alkoxy)carbonyl, (C.sub.7 -C.sub.11 arylalkoxy)carbonyl, C.sub.1 -C.sub.6 alkylsulfonyl or C.sub.6 -C.sub.10 arylsulfonyl;

R.sup.5b is selected from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;

R.sup.6 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, (C.sub.1 -C.sub.10 alkyl)carbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O) R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, S(O).sub.m R.sup.5a, SO.sub.2 NR.sup.5 R.sup.5a, SiMe.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl;

C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2;

C.sub.7 to C.sub.11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O)mMe, or --NMe.sub.2 ;

methylenedioxy when R.sup.6 is a substituent on aryl; or

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.7 ;

R.sup.7 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkyl)carbonyl, --N(R.sup.12)R.sup.13, cyano, halo, CF.sub.3, CHO, CO.sub.2 R.sup.5, C(.dbd.O)R.sup.5a, CONR.sup.5 R.sup.5a, OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5b, OR.sup.5a, OC(.dbd.O)NR.sup.5 R.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5, NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5b, NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, NR.sup.5a SO.sub.2 R.sup.5, SO.sub.2 NR.sup.5 R.sup.5a, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl;

R.sup.8 is selected from:

R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkynyl, substituted with 0-3 R.sup.6 ;

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;

C.sub.5 -C.sub.6 cycloalkenyl, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-3 R.sup.6 ;

-- 10membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, (C.sub.1 -C.sub.10 alkoxy)carbonyl, (C.sub.1 -C.sub.10 alkyl)carbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl(C.sub.2 -C.sub.10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl, or aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, wherein said aryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ;

R.sup.14 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or (C.sub.1 -C.sub.10 alkoxy)carbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.5)R.sup.5a ;

R.sup.15 is selected from:

H; R.sup.6 ; --CO.sub.2 R.sup.5 ; --C(.dbd.O)N(R.sup.5)R.sup.5a ;

C.sub.1 -C.sub.10 alkoxycarbonyl substituted with 0-2 R.sup.6 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.1 -C.sub.10 alkoxy, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-3 R.sup.6 ; or

- 10membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

provided that when b is a double bond, only one of R.sup.14 or R.sup.15 is present;

R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)--R.sup.18b,

--C.dbd.O)N(R.sup.18b).sub.2,

--C(.dbd.O)NHSO.sub.2 R.sup.18a,

--C(.dbd.O)NHC(.dbd.O)R.sup.18b,

--C(.dbd.O)NHC(.dbd.O)OR.sup.18a,

--C(.dbd.O)NHSO.sub.2 NHR.sup.18b,

--C(.dbd.S)--NH--R.sup.18b,

--NH--C(.dbd.O)--O--R.sup.18a,

--NH--C(.dbd.O)--R.sup.18b,

--NH--C(.dbd.O)--NH--R.sup.18b,

--SO.sub.2 --O--R.sup.18a,

--SO.sub.2 --R.sup.18a,

--SO.sub.2 --N(R.sup.18b).sub.2,

--SO.sub.2 --NHC(.dbd.O)OR.sup.18b,

--P(.dbd.S) (OR.sup.18a).sub.2,

--P(.dbd.O) (OR.sup.18a).sub.2,

--P(.dbd.S) (R.sup.18a).sub.2,

--P(.dbd.O) (R.sup.18a).sub.2, or ##STR383## R.sup.17 is selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.15 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.10 alkyl)--;

R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)-- substituted with 0-4 R.sup.19,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19,

C.sub.1 -C.sub.6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18 a or H;

R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.6 alkyl)--, C.sub.1 -C.sub.6 alkoxy, heteroaryl, (C.sub.1 -C.sub.6 alkyl)sulfonyl, aryl-sulfonyl, or C.sub.1 -C.sub.4 alkoxycarbonyl;

m is 0-2;

n is 0-4;

n' is 0-4;

p' is 1-7;

p" is 1-7;

r is 0-3;

provided that n' are chosen such that the number of in-chain atoms connecting R.sup.1 and Y is in the range of 8-18.

2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, which is selected from:

methyl-N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate; or

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid.

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2 and a pharmaceutically acceptable carrier.

4. A compound of claim 1 which is:

methyl-N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate acetate salt.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 and a pharmaceutically acceptable carrier.

6. A compound of claim 1 of Formula Ic: ##STR384## wherein: R.sup.1 is selected from R.sup.2a (R.sup.3)N--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2a (R.sup.3)N(CH.sub.2).sub.p' Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C(CH.sub.2).sub.p" Z--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 S)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR385## Z is selected from a bond, O, or S; R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.6 alkyl; C.sub.7 -C.sub.10 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C.sub.1 -C.sub.10 alkoxy)carbonyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O)MCH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

R.sup.2a is R.sup.2 or R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C;

U is a single bond,

V is selected from:

a single bond;

--(C.sub.1 -C.sub.7 alkyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkenyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(C.sub.2 -C.sub.7 alkynyl)--, substituted with 0-3 groups independently selected from R.sup.6 or R.sup.7 ;

--(phenyl)--Q--, said phenyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

--(pyridyl)--Q--, said pyridyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ; or

--(pyridazinyl)--Q--, said pyridazinyl substituted with 0-2 groups independently selected from R.sup.6 or R.sup.7 ;

Q is selected from

a single bond,

--O--, --S(O).sub.m --, --N(R.sup.12)--, --(CH.sub.2).sub.m --, --C(.dbd.O)--, --N(R.sup.5a)C(.dbd.O)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 N(R.sup.12)--, --N(R.sup.12)CH.sub.2 --, --CH.sub.2 C(.dbd.O)--, --C(.dbd.O)CH.sub.2 --, --CH.sub.2 S(O).sub.m --, or --S(O).sub.m CH.sub.2 --,

provided that when b is a single bond, and R.sup.1 --U--V-- is a substituent on C.sub.5 of the central 5-membered ring of Formula Ic, then Q is not --O--, --S(O).sub.m --, --N(R.sup.12)--, --C(.dbd.O)N(R.sup.5a)--, --CH.sub.2 O--, CH.sub.2 N(R.sup.12)-- or --CH.sub.2 S(O).sub.m --;

W is selected from:

--(C(R.sup.4).sub.2)--C(.dbd.O)--N(R.sup.5a)--, or

--C (.dbd.O)--N(R.sup.5a)--(C(R.sup.4).sub.2)--;

X is --C(R.sup.4)(R.sup.8)--CHR.sup.4a --;

R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

R.sup.4a is selected from hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, --N(R.sup.5)R.sup.5a, --N(R.sup.12)R.sup.13, or --N(R.sup.16)R.sup.17, aryl substituted with 0-3 R.sup.6, or (C.sub.1 -C.sub.10 alkyl)carbonyl;

R.sup.4b is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl, nitro, (C.sub.1 -C.sub.6 alkyl)carbonyl, C.sub.6 -C.sub.10 aryl, --N(R.sup.12)R.sup.13, halo, CF.sub.3, CN, (C.sub.1 -C.sub.6 alkoxy)carbonyl, carboxy, piperidinyl, morpholinyl or pyridyl;

R.sup.5 is selected from H or C.sub.1 -C.sub.10 alkyl substituted with 0-6 R.sup.4b ;

R.sup.5a is selected from hydrogen, hydroxy, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 to C.sub.11 arylalkyl, or adamantylmethyl, C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;

alternately, R.sup.5 and R.sup.5a can be taken together to be 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, heteroaryl, C.sub.7 -C.sub.11 arylalkyl, (C.sub.1 -C.sub.6 alkyl)carbonyl, (C.sub.3 -C.sub.7 cycloalkyl)carbonyl, (C.sub.1 -C.sub.6 alkoxy)carbonyl or (C.sub.7 -C.sub.11 arylalkoxy)carbonyl;

R.sup.5b is selected from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b

Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

R.sup.6 and R.sup.7 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, (C.sub.1 -C.sub.10 alkyl)carbonyl , --N(R.sup.12)R.sup.13, cyano, or halo;

R.sup.12 and R.sup.13 are each independently selected from H, C.sub.1 -C.sub.10 alkyl, (C.sub.1 -C.sub.10 alkoxy)carbonyl, (C.sub.1 -C.sub.10 alkyl)carbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl, wherein said aryl groups being optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ;

R.sup.15 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl, heteroaryl or (C.sub.1 -C.sub.10 alkoxy)carbonyl, CO.sub.2 R.sup.5 or --C(.dbd.O)N(R.sup.5)R.sup.5a ;

R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)--R.sup.18b,

--C(.dbd.O)N(R.sup.18b).sub.2,

--SO.sub.2 --R.sup.18a, or

--SO.sub.2 --N(R.sup.18b).sub.2 ;

R.sup.17 is selected from: H or C.sub.1 -C.sub.5 alkyl;

R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)- substituted with 0-4 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

C.sub.1 -C.sub.6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18a or H;

R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, heteroaryl, aryl(C.sub.1 -C.sub.6 alkyl)--, (C.sub.1 -C.sub.4 alkyl)sulfonyl, aryl-sulfonyl, or C.sub.1 -C.sub.4 alkoxycarbonyl;

n is 0-4;

p' is 1-7;

p" is 1-7;

r is 0-3.

7. A compound of claim 6 of Formula Ib: ##STR386## wherein: R.sup.1 is selected from: R.sup.2a (R.sup.3)N--, R.sup.2 NH(R.sup.2 N.dbd.)C--, R.sup.2 NH(R.sup.2 N.dbd.)CNH--, R.sup.2a (R.sup.3)N(CH.sub.2).sub.p' Z--, R.sup.2 NH(R.sup.2 N.dbd.)C(CH.sub.2).sub.p" Z--, R.sup.2 (R.sup.3)NC(O)--, R.sup.2 (R.sup.5 O)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.5 ON.dbd.)C--; ##STR387## n is 0-1; p' is 4-6;

p" is 2-4;

Z is selected from a bond or O;

V is a single bond, --(phenyl)-- or --(pyridyl)--;

W is selected from:

--(C(R.sup.4).sub.2)--C(.dbd.O)--N(R.sup.5a),

--C(.dbd.O)--N(R.sup.5a)--CH.sub.2 --;

X is selected from:

--CH.sub.2 --CH(N(R.sup.16)R.sup.17)--, or

--CH.sub.2 --CH(NR.sup.5 R.sup.5a)--;

Y is selected from:

hydroxy;

C.sub.1 to C.sub.10 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--;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy--;

R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)--R.sup.18b,

--S(.dbd.O).sub.2 --R.sup.18a or

--SO.sub.2 --N(R.sup.18b).sub.2 ;

R.sup.17 is selected from H or C.sub.1 -C.sub.5 alkyl;

R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)- substituted with 0-4 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

C.sub.1 -C.sub.6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19.

8. A compound of claim 6 wherein:

R.sup.1 is R.sup.2 NH(R.sup.2 N.dbd.)C-- or R.sup.2 HN(R.sup.2 N.dbd.)CNH-- and V is phenylene or pyridylene, or

R.sup.1 is ##STR388## and V is a single bond; n is 1 or 2;

R.sup.18a is selected from:

C.sub.1 -C.sub.4 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.4 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.4 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.7 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.4 alkyl)- substituted with 0-4 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

C.sub.1 -C.sub.4 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19.

9. A compound of claim 1, or pharmaceutically acceptable salt forms thereof, selected from:

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R, S) -yl}-acetyl!-N2-(phenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-methyl-phenyl-sulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(butanesulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S) -yl}-acetyl!-N2-(propanesulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S) -yl}-acetyl!-N2-(ethanesulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5 (R. S) -yl}-acetyl!-N2-(methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(ethyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(1-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5 (R, S) -yl}-acetyl!-N2-(2-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5 (R, S) -yl}acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R) -yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5 (R) -yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(1-(2-methyl)-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(2-methyl)-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R) -yl}-acetyl!-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S) -yl}-acetyl!-N2-(4-methylbenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-methoxybenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-chlorobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-bromobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-fluorobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-phenoxybenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5 (R,S) -yl}-acetyl!-N2-(2-(methyloxyethyl)-oxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-pyridinylcarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-pyridinylcarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S) -yl}-acetyl!-N2-(4-pyridinyl-carbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(2-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(3-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-(4-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-butyloxyphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-thienylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(R,S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;

N.sup.3 -�2-(3-(4-formamidinophenyl)-isoxazolin-5(R)-yl)-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-iodophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S) -yl}-acetyl!-N2-(3-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-2-methoxycarbonylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl)-acetyl!-N2-(2,4,6-trimethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-fluorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-t3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-fluorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-methoxyphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2,3,5,6-tetramethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-cyanophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-propylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5 (R,S)-yl}-acetyl!-N2-(2-phenylethylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-isopropylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-phenylpropylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-pyridylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(phenylaminosulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(benzylaminosulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5 (R,S)-yl}-acetyl!-N2-(dimethylaminosulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5 (R,S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5(R, S) -yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5 (R,S)-yl}-acetyl!-N2-(phenylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(4-fluorophenylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(1-naphthylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(benzylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-bromo-2-thienylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(3-methyl-2-benzothienylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl)-acetyl!-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl!-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl)-acetyl!-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-(3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl!-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5(R,S) -yl)-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5(R)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5(R)-yl)-acetyl!-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;

N.sup.3 -�2-{5-(4-formamidinophenyl)-isoxazolin-3(R,S)-yl}-acetyl!-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;

or a propionate ester prodrug form of said compound, wherein the hydrogen of the hydroxy aroup of the diaminopropanoic acid moiety is substituted with a group selected from:

methyl;

ethyl;

isopropyl;

methylcarbonyloxymethyl--;

ethylcarbonyloxymethyl--;

t-butylcarbonyloxymethyl--;

cyclohexylcarbonyloxymethyl--;

1-(methylcarbonyloxy)ethyl--;

1-(ethylcarbonyloxy)ethyl--;

1-(t-butylcarbonyloxy)ethyl--;

1-(cyclohexylcarbonyloxy)ethyl--,

i-propyloxycarbonyloxymethyl--;

cyclohexylcarbonyloxymethyl--;

t-butyloxycarbonyloxymethyl--;

1-(i-propyloxycarbonyloxy)ethyl--;

1-(cyclohexyloxycarbonyloxy)ethyl--;

1-(t-butyloxycarbonyloxy)ethyl--;

dimethylaminoethyl--;

diethylaminoethyl--;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl--;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl--;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl--;

1-(2-(2-methoxypropyl)carbonyloxy)ethyl--.

10. A method of treating thromboembolic disorders selected from thrombus or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerosis, stroke, myocardial infarction, and unstable angina, which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 1.

11. A compound of claim 1, or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt form thereof, selected from:

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(phenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-(3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-methyl-phenyl-sulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(butanesulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-(3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(propanesulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-(3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(ethanesulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(methyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(ethyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(1-propyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-propyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!--N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(1-(2-methyl)-propyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(2-methyl)-propyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!--N.sup.2 -(benzyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-methylbenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-methoxybenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!--N.sup.2 -(4-chlorobenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-bromobenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-fluorobenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-phenoxybenzyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(methyloxyethyl)-oxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3- (4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-pyridinylcarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-pyridinylcarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-pyridinyl-carbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(2-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(3-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-(4-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-butyloxyphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!--N.sup.2 -(2-thienylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!--N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!--N.sup.2 -(4-iodophenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!--N.sup.2 -(3-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-methoxycarbonylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2,4,6-trimethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-fluorophenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-fluorophenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-methoxyphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2,3,5,6-tetramethylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-cyanophenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-propylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-phenylethylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-isopropylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-phenylpropylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-pyridylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(phenylaminosulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(benzylaminosulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(dimethylaminosulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3diaminopropanoic acid;

N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid,

N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid,

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(phenylaminocarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-fluorophenylaminocarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(1-naphthylaminocarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(benzylaminocarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-bromo-2-thienylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methyl-2-benzothienylsulfonyl)-2,3-diaminopropanoic acid,

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid,

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid,

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid,

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-cyclopropylethoxycarbonyl)-2,3-diaminopropanoic acid,

N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-guanidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{5-(4-formamidinophenyl)-isoxazolin-3-yl}-acetyl!-N.sup.2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(2-methyl-phenylsulfonyl)-2,3-diaminopropionic acid;

N.sup.3 -�2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N.sup.3 -�2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N.sup.3 -�2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(3-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;

N.sup.3 -�2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl!-N.sup.2 -(4-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;

or a propionate ester prodrug form of said compound, wherein the hydrogen of the hydroxy group of the propanoic acid moiety is substituted with a aroup selected from:

methyl;

ethyl;

isopropyl

methylcarbonyloxymethyl--;

ethylcarbonyloxymethyl--;

t-butylcarbonyloxymethyl--;

cyclohexylcarbonyloxymethyl--;

1-(methylcarbonyloxy)ethyl--;

1-(ethylcarbonyloxy)ethyl--;

1-(t-butylcarbonyloxy)ethyl--;

1-(cyclohexylcarbonyloxy)ethyl--;

i-propyloxycarbonyloxymethyl--;

cyclohexylcarbonyloxymethyl--;

t-butyloxycarbonyloxymethyl--;

1-(i-propyloxycarbonyloxy)ethyl--;

1-(cyclohexyloxycarbonyloxy)ethyl--;

1-(t-butyloxycarbonyloxy)ethyl--;

dimethylaminoethyl--;

diethylaminoethyl--;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl--;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl--;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl--;

1-(2-(2-methoxypropyl)carbonyloxy)ethyl--,

said enantiomeric and diasteriomeric forms being selected from:

(R,S), (R,S);

(R), (R,S);

(S), (R,S);

(R), (R);

(S), (R)

(R), (S);

(S), (S).

12. A compound of claim 11, or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt form thereof, said enantiomeric and diasteriomeric form being: (R), (S).

13. A prodrug ester of a compound of claim 11, wherein the hydrogen of the hydroxy group of the diaminopropanoic acid moiety is substituted with a group selected from:

methyl;

ethyl;

isopropyl.

14. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claims 1, 6, 9, 11, 12, or 13.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claims 1, 6, 9, 11, 12, or 13 and a pharmaceutically acceptable carrier.

16. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claims 1, 6, 9, 11, 12, or 13.

17. A process for preparing a compound of the formula X ##STR389## wherein: R.sup.4 is selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

R.sup.4a is selected from: H, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, N(R.sup.5)R.sup.5a, --N(R.sup.12)R.sup.13, --N(R.sup.16)R.sup.17, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.6, aryl substituted with 0-3 R.sup.6, or C.sub.1 -C.sub.10 alkylcarbonyl;

R.sup.4b is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.7 -C.sub.14 bicycloalkyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl, nitro, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.6 -C.sub.10 aryl, --N(R.sup.12)R.sup.13 ; halo, CF.sub.3, CN, C.sub.1 -C.sub.6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;

R.sup.5 is selected from H or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;

R.sup.5a is selected from hydrogen, hydroxy, C.sub.1 to C.sub.8 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 to C.sub.11 arylalkyl, adamantylmethyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;

R.sup.6 is selected from H, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, --NR.sup.5 R.sup.5a, CO.sub.2 R.sup.5, S(O).sub.m R.sup.5, OR.sup.5, cyano, halo;

C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

methylenedioxy when R.sup.6 is a substituent on aryl; or

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolyl, isoxazolinyl or morpholinyl;

R.sup.8 is selected from:

--CONR.sup.5 NR.sup.5a ; --CO.sub.2 R.sup.5 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkynyl, substituted with 0-3 R.sup.6,

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-2 R.sup.6 ;

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

R.sup.12 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl, aryl(C.sub.1 -C.sub.4 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylsulfonyl, pyridylcarbonyl or pyridylmethylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; and

R.sup.13 is H.

R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)--R.sup.18b,

--C(.dbd.O)N(R.sup.18b).sub.2,

--SO.sub.2 --R.sup.18a, or

--SO.sub.2 --N(R.sup.18b).sub.2 ;

R.sup.17 is selected from: H or C.sub.1 -C.sub.4 alkyl

R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)- substituted with 0-4 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

C.sub.1 -C.sub.6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18a or H;

R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.6 alkyl)--, C.sub.1 -C.sub.6 alkoxy, or C.sub.1 -C.sub.4 alkoxycarbonyl;

m is 0-2;

n is 0-4;

q is 1-7; and

r is 0-3;

said process comprising the steps of:

deprotecting a compound of the formula IX ##STR390## wherein: R.sup.1 is HR.sup.2 N--C (.dbd.NR.sup.2)--, NC--, HR.sup.2 N--C(.dbd.NHR.sup.2)--NH--, or HR.sup.2 N--;

R.sup.2 and R.sup.3 are independently H, C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.6 alkylcarbonyloxy (C.sub.1 -C.sub.4 alkoxy)carbonyl; C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl wherein the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

Y is selected from C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R.sup.2)(R.sup.3)N-(C.sub.1 -C.sub.10 alkoxy)--;

m is 0-2;

n is 0-4; and

all other substituents are as defined above;

under acidic, basic, catalytic, and/or enzymatic conditions to provide a compound of formula (X) as defined above.

18. A process according to claim 17 further comprising the step of:

contacting a compound of the formula VII ##STR391## with a compound of the formula VIII ##STR392## under peptide bond forming conditions to effect the formation of a peptide bond and form a compound of the formula (IX) wherein all substituents are as defined in claim 17.

19. A process according to claim 18 further comprising the steps of:

contacting a compound of the formula V ##STR393## wherein X is chloro, bromo or iodo, in the presence of a hindered amine base with a compound of the formula VI ##STR394## wherein R is alkyl or other group removable under basic conditions to form a compound of the formula VIIa ##STR395## wherein all other substituents are as defined in claim 18, and hydrolyzing a compound of the formula VIIa under mild basic conditions to form a compound of the formula VII.

20. A process according to claim 18 further comprising the step of:

resolving the two stereoisomers of a compound of the formula VII, wherein R.sup.4 is H, by chemical resolution with an appropriate optically pure chiral amine to form the separated (+) and (-) isomers of a compound of the formula VII.

21. A process according to claim 18 further comprising the step of:

resolving the two stereoisomers of a compound of the formula VII by chiral chromatography to form the separated (+) and (-) isomers of a compound of the formula VII.

22. A process according to claim 18 further comprising the step of:

resolving the two stereoisomers of a compound of the formula VIIa by chiral chromatography to form the separated (+) and (-) isomers of a compound of the formula VIIa.

23. A compound of the formula IX ##STR396## wherein: Y is selected from C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;

R.sup.1 is NC--;

R.sup.4 is selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

R.sup.4a is selected from: H, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, N(R.sup.5)R.sup.5a, --N(R.sup.12)R.sup.13, --N(R.sup.16)R.sup.17, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.6, aryl substituted with 0-3 R.sup.6, or C.sub.1 -C.sub.10 alkylcarbonyl;

R.sup.4b is selected from: H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.7 -C.sub.14 bicycloalkyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl, nitro, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.6 -C.sub.10 aryl, --N(R.sup.12)R.sup.13 ; halo, CF.sub.3, CN, C.sub.1 -C.sub.6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;

R.sup.5 is selected from H or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;

R.sup.5a is selected from hydrogen, hydroxy, C.sub.1 to C.sub.8 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, C.sub.1 -C.sub.6 alkoxy, benzyloxy, C.sub.6 to C.sub.10 aryl, heteroaryl, heteroarylalkyl, C.sub.7 to C.sub.11 arylalkyl, adamantylmethyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.4b ;

R.sup.6 is selected from H, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, --NR.sup.5 R.sup.5a, CO.sub.2 R.sup.5, S(O).sub.m R.sup.5, OR.sup.5, cyano, halo;

C.sub.6 to C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m Me, or --NMe.sub.2 ;

methylenedioxy when R.sup.6 is a substituent on aryl; or

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolyl, isoxazolinyl or morpholinyl;

R.sup.8 is selected from:

--CONR.sup.5 NR.sup.5a ; --CO.sub.2 R.sup.5 ;

C.sub.1 -C.sub.10 alkyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.10 alkenyl, substituted with 0-3 R.sup.6 ;

C.sub.2 -C.sub.1 O alkynyl, substituted with 0-3 R.sup.6,

C.sub.3 -C.sub.8 cycloalkyl, substituted with 0-3 R.sup.6 ;

aryl, substituted with 0-2 R.sup.6 ;

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R.sup.6 ;

R.sup.12 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl, aryl(C.sub.1 -C.sub.4 alkyl)sulfonyl, heteroarylsulfonyl, arylsulfonyl, aryl, pyridylcarbonyl or pyridylmethylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ; and

R.sup.13 is H.

R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C (.dbd.O)--R.sup.18b,

--C(.dbd.O)N(R.sup.18b).sub.2,

--SO.sub.2 --R.sup.18a, or

--SO.sub.2 --N(R.sup.18b).sub.2 ;

R.sup.17 is selected from: H or C.sub.1 -C.sub.4 alkyl

R.sup.18a is selected from:

C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)- substituted with 0-4 R.sup.19,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

C.sub.1 -C.sub.6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18a or H;

R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.6 alkyl)--, C.sub.1 -C.sub.6 alkoxy, or C.sub.1 -C.sub.4 alkoxycarbonyl;

m is 0-2;

n is 0-4;

q is 1-7; and

r is 0-3.

24. A compound of the formulae VII or VIIa wherein:

R is H, alkyl, or other group removable under basic conditions;

R.sup.1 is HR.sup.2 N--C(.dbd.NR.sup.2)--, NC--, HR.sup.2 N--C(.dbd.NHR.sup.2)--NH--, or HR.sup.2 N--;

R.sup.2 is H, C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O)MCH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.6 alkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

R.sup.4 is selected from: H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

m is 0-2;

n is 0-4.

25. A compound of the formulae Ie or If ##STR397## or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt form thereof, wherein:

R.sup.1 is R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)C--, R.sup.2 (R.sup.3)N(R.sup.2 N.dbd.)CN(R.sup.2)--, or R.sup.2 (R.sup.3)N--;

R.sup.2 and R.sup.3 are independently selected from: H; C.sub.1 -C.sub.10 alkyl; C.sub.3 -C.sub.6 alkenyl; C.sub.3 -C.sub.11 cycloalkyl; C.sub.4 -C.sub.11 cycloalkylalkyl; C.sub.6 -C.sub.10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.7 -C.sub.11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.2 -C.sub.7 alkylcarbonyl; C.sub.7 -C.sub.11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.10 alkoxycarbonyl; C.sub.4 -C.sub.11 cycloalkoxycarbonyl; C.sub.7 -C.sub.11 bicycloalkoxycarbonyl; C.sub.7 -C.sub.11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.1 -C.sub.6 alkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; C.sub.6 -C.sub.10 arylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C.sub.4 -C.sub.11 cycloalkylcarbonyloxy(C.sub.1 -C.sub.4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C.sub.1 -C.sub.5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, S(O).sub.m CH.sub.3, --N(CH.sub.3).sub.2, C.sub.1 -C.sub.4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;

provided that only one of R.sup.2 and R.sup.3 may be hydroxy;

R.sup.12 and R.sup.13 are independently H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxycarbonyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 alkylsulfonyl, aryl(C.sub.1 -C.sub.10 alkyl)sulfonyl, arylsulfonyl, aryl(C.sub.2 -C.sub.10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, C.sub.7 -C.sub.11 arylalkyl, C.sub.7 -C.sub.11 arylcarbonyl, C.sub.4 -C.sub.11 cycloalkoxycarbonyl, C.sub.7 -C.sub.11 bicycloalkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, or aryl(C.sub.1 -C.sub.10 alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, and NO.sub.2 ;

R.sup.16 is selected from:

--C(.dbd.O)--O--R.sup.18a,

--C(.dbd.O)--R.sup.18b,

--C(.dbd.O)N(R.sup.18b).sub.2,

--C(.dbd.O)NHSO.sub.2 R.sup.18a,

--C(.dbd.O)NHC(.dbd.O)R.sup.18b,

--C(.dbd.O)NHC(.dbd.O)OR.sup.18a,

--C(.dbd.O)NHSO.sub.2 NHR.sup.18b,

--C(.dbd.S)--NH--R.sup.18b,

--NH--C(.dbd.O)--O--R.sup.18a,

--NH--C(.dbd.O)--R.sup.18b,

--NH--C(.dbd.O)--NH--R.sup.18b,

SO.sub.2 --O--R.sup.18a,

SO.sub.2 --R.sup.18a,

--SO.sub.2 --N(18.sup.b).sub.2,

--SO.sub.2 --NHC(.dbd.O)O18.sup.b,

--P(.dbd.S) (OR.sup.18a).sub.2,

--P(.dbd.O) (OR.sup.18a).sub.2,

--P(.dbd.S) (R.sup.18a).sub.2,

--P(.dbd.O)(R.sup.18a).sub.2, or ##STR398## R.sup.18a is selected from: C.sub.1 -C.sub.8 alkyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkenyl substituted with 0-2 R.sup.19,

C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.19,

C.sub.3 -C.sub.8 cycloalkyl substituted with 0-2 R.sup.19,

aryl substituted with 0-4 R.sup.19,

aryl(C.sub.1 -C.sub.6 alkyl)- substituted with 0-4 R.sup.19,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19,

C.sub.1 -C.sub.6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R.sup.19 ;

R.sup.18b is selected from R.sup.18a or H;

R.sup.19 is selected from H, halogen, CF.sub.3, CN, NO.sub.2, NR.sup.12 R.sup.13, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.6 alkyl)--, C.sub.1 -C.sub.6 alkoxy, or C.sub.1 -C.sub.4 alkoxycarbonyl;

Y is selected from hydroxy, C.sub.1 to C.sub.10 alkyloxy, C.sub.3 to C.sub.11 cycloalkyloxy, C.sub.6 to C.sub.10 aryloxy, C.sub.7 to C.sub.11 aralkyloxy, C.sub.3 to C.sub.10 alkylcarbonyloxyalkyloxy, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyloxy, C.sub.2 to C.sub.10 alkoxycarbonylalkyloxy, C.sub.5 to C.sub.10 cycloalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonyloxyalkyloxy, C.sub.5 to C.sub.10 cycloalkoxycarbonylalkyloxy, C.sub.7 to C.sub.11 aryloxycarbonylalkyloxy, C.sub.8 to C.sub.12 aryloxycarbonyloxyalkyloxy, C.sub.8 to C.sub.12 arylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 alkoxyalkylcarbonyloxyalkyloxy, C.sub.5 to C.sub.10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C.sub.10 to C.sub.14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R.sup.2) (R.sup.3)N-(C.sub.1 -C.sub.10 alkoxy)--;

m is 0-2;

n is 0-2; and

p is 1-5.

26. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 1, a pharmaceutically acceptable excipient, and water.

27. A method of treating thromboembolic disorders, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a compound of claim 1.

28. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 14, a pharmaceutically acceptable excipient, and water.

29. A method of treating thromboeinbolic disorders, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a compound of claim 14.

30. A compound of claim 14 wherein the pharmaceutically acceptable salt form is selected from: hydrochloride, benzenesulfonate, methanesulfonate, or para-toluenesulfonate.

31. A prodrug ester of a compound of claim 14, wherein the pharmaceutically acceptable salt form is selected from: acetate, methanesulfonate, hydrochloride, benzenesulfonate, or para-toluenesulfonate.