1,3,4-THIADIAZOLES AND 1,3,4-OXADIAZOLES AS alpha v beta 3 ANTAGONISTS

Abstract: This invention relates to 1,3,4-thiadiazoles and 1,3,4-Oxadiazoles of formula (I), which are useful as antagonists of alpha v beta 3 and related integrin receptors, to pharmaceutical compositions containing such compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion and the treatment of angioginic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions, including their enantiomeric, diastereomeric, pharmaceutically acceptable salt or prodrug forms thereof wherein R<1> is selected from formulas (a), (b), (c), (d), (e), (f) or (g); U, V, G, W, X, R<20> are as defined in the application.

Description: Title 1, 3, 4-Thiadiazoles and 1, 3, 4-Oxadiazoles as α β3 Antagonists Field of the Invention The present invention relates generally to 1,3,4- thiadiazoles and 1, 3, 4-0xadiazoles which are useful as antagonists of the v β 3 and related integrin receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion and the treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions. Background of the Invention Angiogenesis or neovascularization is critical for normal physiological processes such as embryonic development and wound repair (Folkman and Shing, J. Biol. Chem. 1992, 261_: 10931-10934 ; D'Amore and Thompson, Ann. Rev. Physiol. 1987, 49:453-464) . However, angiogenesis occurs pathologically, for example, in ocular neovascularization (leading to diabetic retinopathy, neovascular glaucoma, retinal vein occlusion and blindness) , in rheumatoid arthitis and in solid tumors (Folkman and Shing, J. Biol. Chem., 1992, 2_67_: 10931-10934; Blood and Zetter, Biochim. Biophys. Acta., 1990, 1032:89-118) . Tumor dissemination, or metastasis, involves several distinct and complementary components, including the penetration and transversion of tumor cells through basement membranes and the establishment of self-sustaining tumor foci in diverse organ systems. To this end, the development and proliferation of new blood vessels, or angiogenesis, is critical to tumor survival. Without neovascularization, tumor cells lack the nourishment to divide and will not be able to leave the primary tumor site (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934) . Inhibition of angiogenesis in animal models of cancer has been shown to result in tumor growth suppression and prevention of metastatic growth. Many angiogehic inhibitors have been directed toward blocking initial cytokine-dependent induction of new vessel growth, e.g. antibodies to endothelial cell growth factors. However, these approaches are problematic because tumor and inflammatory cells can secrete multiple activators of angiogenesis (Brooks et al., Cell, 1994, 7_9: 1157-116 ) . Therefore, a more general approach that would allow inhibition of angiogenesis due to a variety of stimuli would be of benefit . The integrin α v β 3 is preferentially expressed on angiogenic blood vessels in chick and man (Brooks et al., Science, 1994, 264 : 569-571; Enenstein and Kramer, J. Invest. Dermatol., 1994, 103: 381-386). Integrin α v β3 is the most promiscuous member of the integrin family, allowing endothelial cells to interact with a wide variety of extracellular matrix components (Hynes, Cell, 1992, (59:11-25). These adhesive interactions are considered to be critical for angiogenesis since vascular cells must ultimately be capable of invading virtually all tissues. While integrin α v β 3 promotes adhesive events important for angiogenesis, this receptor also transmits signals from the extracellular environment to the intracellular compartment (Leavesley et al., J. Cell Biol., 1993, 121:163-170, 1993). For example, the interaction between the α v β 3 integrin and extracellular matrix components promotes a calcium signal required for cell motility. During endothelium injury, the basement membrane zones of blood vessels express several adhesive proteins, including but not limited to von Willebrand factor, fibronectin, and fibrin. Additionally, several members of the integrin family of adhesion receptors are exptessed on the surface of endothelial, smooth muscle and on other circulating cells. Among these integrins is v /β 3 , the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrin) , vitronectin, thrombospondin, and osteopontin. These integrins initiate a calcium-dependent signaling pathway that can lead to endothelial cell, smooth muscle cell migration and, therefore, may play a fundamental role in vascular cell biology. Recently, an antibody to the α v β 3 integrin has been developed that inhibits the interaction of this integrin with agonists such as vitronectin (Brooks et al., Science, 1994, 264:569-571) . Application of this antibody has been shown to disrupt ongoing angiogenesis on the chick chorioallantoic membrane (CAM) , leading to rapid regression of histologically distinct human tumor transplanted onto the CAM (Brooks et al . , Cell, 1994, 7_9: 1157 ^ -1164) . In this model, antagonists of the α v β 3 integrin induced apoptosis of the proliferating angiogenic vascular cells, leaving pre-existing quiescent blood vessels unaffected. Thus, v β 3 integrin antagonists have been shown to inhibit angiogenesis. Based on this property, therapeutic utility of such agents is expected in human diseases such as cancer, rheumatoid arthritis and ocular vasculopathies (Folkman and Shing, J. Biol. Chem., 1992, 2^7_: 10931-10934) . Increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands 1 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 α- and β- subunits. Integrin subfamilies contain a common β- subunit combined with different α-subunits to form adhesion receptors with unique specificity. The genes for eight distinct β-subunits have been cloned and sequenced to date. Two members of the βl subfamily, α4/βland α5/βl have been implicated in various inflammatory processes. Antibodies to α4 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, 147:4207-4210). Additional studies with monoclonal anti-α4 'antibodies provide evidence that α4/βl 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, 356:63-66). Anti-α4 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al . , J. Immunol., 1991, 147:4178-4184) . The α v /β 3 heterodimer is a member of the β 3 integrin subfamily and has been described on platelets, endothelial cells, melanoma, smooth muscle cells, and osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826; Horton, Int. J. Exp. Pathol., 1990, 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 thrombosponden in a manner mediated by the RGD sequence. A key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. Studies with monoclonal antibodies have implicated the α v /β 3 receptor in this process and suggest that a selective v /β 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). European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula: Copending, commonly assigned U.S. Patent Application Serial Number 08/337,920 filed 11/10/94 discloses integrin inhibitors of the general formula shown below: PCT Patent Application WO 94/08577 published 4/28/94 discloses fibrinogen antagonists, including the isoxazole-containing compound below: 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: European Patent Application Publication Number 478328 relates to compounds having the general formula: R »1 π _-(CH 2 )m PCT Patent Application 9307867 relates to compounds having the general formula: 2 W European Patent Application Publication Number 512831 relates to compounds having the general formula; X-(CH 2 ) m -Y-(CH 2 ) k - -Z Copending commonly assigned US patent application USSN 08/455,768) (filed 5/31/95, Voss et al.) discloses compounds having the general formula: which are useful as α v β 3 antagonists. None of the above references teaches or suggests the compounds of the present invention which are described in detail below. 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 angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other 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 α v /β 3 or vitronectin receptor. The compounds of the present invention inhibit the binding of vironectin to α v /β 3 and inhibit cell adhesion. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of angiogenic disorders. 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, ocular vasculopathies, thrombosis, inflammatory bowel disease and other autoimmune diseases. Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including, but not limited to, angiogenic disorders. Detailed Description of the Invention This invention relates to novel compounds of the Formula I: -u—V—/ \ W-X-CfOlR 20 N—N (I) including their enantiomeric, diastereomeric, pharmaceutically acceptable salt or prodrug forms thereof wherein: R l is : A and B are independently CH 2 , 0 or -N(R 12 )-; A 1 and B 1 are independently CH or -N(R 10 )-; D is NH, 0, or S; E-F is -C(R 2 )=C(R 3 )-, -N=C(R 2 )-, -C(R 2 )=N-, -N=N-, or - CH(R 2 )CH(R 3 )-; G is selected from 0 or S; R 2 and R 3 are independently selected from: H, C 1 -C 4 alkoxy, NR n R 12 , =NR 12 , halogen, N0 2 , CN, CF 3 , Cι-C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, Cg-Cio aryl, C 7 -C 11 arylalkyi. C 2 -C 7 alkylcarbonyl, or C -C 11 arylcarbonyl; alternatively, R 2 and R 3 can be taken together to be a 5-7 membered carbocyclic or 5-7 membered heterocyclic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 R 7 ; U is selected from: - ( CH 2 ) n -, -(CH 2 ) n N(R 12 ) (CH 2 )m-, -(CH 2 ) n NHNH(CH 2 ) m -, -N(R 10 )C(=O)-, or -C(=0)N(R 10 )-; V is selected from: -(CH 2 ) n -, - (C 3. -C 6 alkylene) -Q-, substituted with 0-3 groups independently selected from R 13 , -(C 2 -C 7 alkenylene) -Q-, substituted with 0-3 groups independently selected from R 13 , -(C 2 -C 7 alkynylene) -Q-, substituted with 0-3 groups independently selected from R 13 , - (phenyl) -Q-, said phenyl substituted with 0-2 groups independently selected from R 13 , - (piperidinyl) -Q-, said piperidinyl substituted , with 0-2 groups independently selected from R i3 , - (pyridyl) -Q-, said pyridyl substituted with 0-2 groups independently selected from R 13 , or - (pyridazinyl) -Q-, said pyridazinyl substituted with 0-2 groups independently selected from . R 13 or R 7 ; Q is selected from: -(CH 2 ) n O(CH 2 ) m -, -(CH 2 ) n N(R 12 ) (CH 2 ) m -, -N(R 10 )C(=0)-, or -C(=0)N(R 10 )-; W is selected from : - (CH 2 ) q C ( =0) N ( R 10 ) - , -SCH 2 C ( =O ) N ( R!0 ) - , or -C ( =0)-N(R lO )-(CH 2 ) q -; X is selected from: -(CH 2 ) q -CH(R 8 )-CH(R 9 )-, - (CH 2 ) q -CH (CH 2 R 9 ) - or -CH 2 - R 5 is selected from: H, Ci-Cβ alkyl, C 2 -C 6 alkenyl, C - Q alkynyl, C 3 -C 7 cycloalkyl, C 7 -C 14 bicycloalkyl, hydroxy, Cχ-Cg alkoxy, Cχ-C 6 alkylthio, Cχ-C 6 alkylsulfinyl, Ci-Cς alkylsulfonyl, nitro, C 1 -C 6 alkylcarbonyl, C 6 ~Cχo aryl, -N(R lj -)R 12 ; halo, CF 3 , CN, Cχ-C 6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl; R 6 is selected from: H, Cχ-C 4 alkyl, hydroxy, C -C 4 alkoxy, nitro, Cχ-Cβ alkylcarbonyl, -N(R )R 12 , cyano, halo, -S(0)mR 10 , C0 2 R 10 , OR 10 , Cς to Cχo aryl optionally substituted with 1-3 groups selected from halogen, Cχ-C 6 alkoxy, C -C δ alkyl, CF 3 , S(0) m Me, or -NMe 2 ; methylenedioxy when R 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, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl, or morpholinyl; R 7 is selected from: H, Cχ-Cχo alkyl, hydroxy, Cχ-Cχo alkoxy, nitro, Cχ~ Cχo alkylcarbonyl, -N(R 1] -)R 12 , cyano, halo, C0 2 R 10 , OR!0; R 8 is selected from: CONR^R 11 , -C0 2 R 10 , Cχ-Cχo alkyl , substituted with 0-3 R 6 , C 2 -Cχ 0 alkenyl, substituted with 0-3 R 6 , C 2 -C 10 alkynyl, substituted with 0-3 R 6 , C 3 -C 8 cycloalkyl, substituted with 0-3 R 6 , C 5 -C 6 cycloalkenyl, substituted with 0-3 R 6 , aryl, substituted with 0-3 R 6 , a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl; R 9 is selected from: H, hydroxy, Cχ-Cχo alkoxy, nitro, N(R 10 )R 11 , -N(R 16 )R 17 , Cχ-C 10 alkyl substituted with 0-3 R 6 , aryl substituted with 0-3 R 6 , heteroaryl substituted with 0-3 R 6 or Cχ-Cχo alkylcarbonyl; R 10 is selected from H or Cχ-Cχo alkyl substituted with 0-2 R 5 ; R 11 is selected from hydrogen, hydroxy, Cx to Cs alkyl, C 3 -C 6 alkenyl, C 3 to Cxx cycloalkyl, C 4 to C x cycloalkylmethyl, Cχ-Cg alkoxy, benzyloxy, Q to Cχo aryl, heteroaryl, heteroarylalkyl, C7 to Cxx arylalkyi, adamantylmethyl, or Cχ-Cχo alkyl substituted with 0-2 R 5 ; alternatively, R 10 and R 11 when both are substituents on 'the same nitrogen atom (as in -NR 10 R 1:L ) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1, 2 , 3, 4-tetrahydro-l- quinolinyl, 1, 2, 3, 4-tetrahydro-2-isoquinolinyl, 1- piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl; said heterocycle being optionally substituted with 1-3 groups selected from: Cχ-C 6 alkyl, C 6 ~Cχo aryl, heteroaryl, C 7 -Cχχ arylalkyi, C -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, Cχ-Cβ alkoxycarbonyl, C 7 ~Cχ arylalkoxycarbonyl, Cχ-C 6 alkylsulfonyl or Cg-Cχo arylsulfonyl; R 12 is selected from: H, Cχ-Cg alkyl, Cχ-C 4 alkoxycarbonyl, Cχ-Cg alkylcarbonyl, Cχ-C 6 alkylsulfonyl, aryl (Cχ-C 4 alkyl) sulfonyl, arylsulfonyl, aryl, het'eroarylcarbonyl, or heteroarylalkylcarbonyl, wherein said aryl groups are substituted with 0-3 substituents selected from the group consisting of: Cχ-C alkyl, Cχ-C alkoxy, halo, CF 3 , and N0 2 ; R 13 is selected from H, Cχ-Cχo alkyl, C 2 -Cχo alkenyl, C 2 -Cχo alkynyl, Cχ-Cχo alkoxy, aryl, heteroaryl or Cχ-C 10 alkoxycarbonyl, C0 2 R 10 or -C (=0) N (R 10 ) R 11 ; R 16 is selected from: -C(=0)-0-R 18a , -C(=0)-R 18b , -S0 2 -R 18a , -S0 2 -N(18 b ) 2 ; R 17 is selected from H or Cχ-C alkyl; R 18a is selected from: Cχ-C 8 alkyl substituted with 0-2 R 19 , C 2 -C 8 alkenyl substituted with 0-2 R 19 , C 2 -C 8 alkynyl substituted with 0-2 R 19 , C 3 -C 8 cycloalkyl substituted with 0-2 R 19 , aryl substituted with 0-4 R 19 , aryl(Cχ-C 6 alkyl)- substituted with 0-4 R 19 , a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, isoxazolyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H- indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R l9 ; Cχ-C 6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, isoxazolyl, 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 l9 ; R 18b is selected from R 18a or H; R 19 is selected from: H, halogen, CF 3 , CN, N0 2 , NR 1:L R 12 , Cχ-C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -Cχχ cycloalkyl, C 4 ~C χ cycloalkylalkyl, aryl, aryl(Cχ-C 6 alkyl)-, Cχ-Cg alkoxy, or Cχ-C 4 alkoxycarbonyl; R 20 is selected from: hydroxy; Cx to Cχo 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-, dimethyla inoethoxy- , diethylaminoethoxy- , (5-methyl-l, 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 21 is selected from Cχ-C 8 alkyl, C 2 -C6 alkenyl, C3~C χ . cycloalkyl, C ~Cχχ cycloalkylmethyl, Cs-Cχo aryl, C7~Cχχ arylalkyi, or Cχ-Cχo alkyl substituted with 0-2 R 5 , m is 0-2 n i s 0-2 P is 0-2 q i s 0- 1 and r is 0-2 with the following provisos: (1) n, m and q are chosen such that the number of atoms connecting R 1 and Y is in the range of 8-14; and (2) when V is - (phenyl) -Q-, then either: U is not a direct bond (i.e., U is not -(CH2)n~ where n = 0) or Q is not a direct bond (i.e., Q is not -(CH2)n ~ where n = 0). A preferred embodiment of the invention are compounds of formula (I) as defined above wherein R l V is selected from: XCH 2 ) n -, -(Cχ-Cδ alkylene) -Q-, substituted with 0-3 groups independently selected from R 13 , -(C 2 -C 7 alkenylene) -Q-, substituted with 0-3 groups independently selected from R 13 , -(C 2 -C7 alkynylene) -Q-, substituted with 0-3 groups independently selected from R 13 , - (phenyl) -Q-, said phenyl substituted with 0-2 groups independently selected from R 13 , - (pyridyl) -Q-, said pyridyl substituted with 0-2 groups independently selected from R 13 , or - (pyridazinyl) -Q-, said pyridazinyl substituted with 0-2 groups independently selected from R 13 or R ; The most preferred compounds of the invention are: 2 (S) -Phenylsulfonylamino-3- [2- [2- [3- [ (N-imidazolin-2- yl) amino] propyl] -1, 3, -thiadiazol-5- yl] acetyl] aminopropionic acid 2 (S)-(3-methylphenylsulfonyl)amino-3-[2-[2- [3-[ (N- imidazolin-2-yl) amino] propyl] -1,3, 4-thiadiazol-5- yl] acetyl] aminopropionic acid 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [N- (pyridin-2- yl) amino]butyl] -1, 3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) - (2, 4, 6-Trimethylphenylsulfonyl) amino-3- [ [2- [4- [N- (pyridin-2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) - (1-Naphthalenesulfonyl) amino-3- [ [2- [4- [N- (pyridin- 2-yl) amino]butyl] -1, 3, -thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) -Benzyloxycarbonylamino-3- [ [2— [ — [ (N-imidazolin-2- yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) - (2, 4, 6-Trimethylphenylsulfonyl) amino-3- [ [2- [4- [ (N- imidazolin-2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) - (l-Naphthalenesulfonyl)amino-3-[ [2-[4-[ (N- imidazolin-2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 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 α v β 3 - The compounds of the present invention inhibit the binding of vitronectin to α v β 3 and inhibit cell adhesion. The present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. The compounds of Formula I of the present invention are useful for the treatment (including prevention) of angiogenic disorders. The term "angiogenic disorders" as used herein includes conditions involving abnormal neovascularization, such as tumor metastasis and ocular neovascularization, including, for example, diabetic retinopathy, neovascular glaucoma, age-related macular degeneration, and retinal vein occlusion, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above . The compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, thromboembolic disorders, restenosis, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, inflammatory bowel disease and other autoimmune diseases. The compounds of Formula I of the present invention may also be useful for wound healing. The term "thromboembolic disorders" as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above. The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples. 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 synergi'stic 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 1 therapeutic effect. The term anti-coagulant agents (or coagulation inhibitory agents) , as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as Coumadin™) and heparin. The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti-inflammatory drugs (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, NY) , as Feldane™. 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 α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al . , U.S. Patent No. 5,187,157 and European Patent Application Publication Number 293 881 A2 , the disclosures of which 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, California. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by referenςe herein, in their entirety. Anistreplase is commercially available as Eminase™. 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. 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 nitronection or fibrinogen to α v β 3 . Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving α v β 3 - The compounds of the present invention may also be used in diagnostic assays involving α v β 3 - The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. When any variable (for example but not limited to, R 2 , R 4 , R 6 , R 7 , R 8 , R 12 ,and R 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 4 , then said group may optionally be substituted with up to two R 4 and R 4 at each occurrence is selected independently from the defined list of possible R 4 . Also, by way of example, for the group -N(R 5a ) 2 . each of the two R 5a substituents on N is independently selected from the defined list of possible R 5a . Similarly, by way of example, for the group -C(R 7 ) 2 -, each of the two R 7 substituents on C is independently selected from the defined list of possible R 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 or piperidinyl unless specified otherwise, said piperazinyl or piperidinyl group may be bonded to the rest of the compound of Formula I via any atom in such piperazinyl or piperidinyl 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 substituent is keto (i.e., =0) , 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, "Cχ-Cχo" denotes alkyl having 1 to 10 carbon atoms) ; "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, and cyclobutyl; 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 "alkylehe", "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 1 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, Cχ-C 6 alkoxy, Cχ-C 6 alkyl, CF 3 , S(0) m CH 3 , -N(CH 3 ) 2 , Cχ-C 4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; the term "arylalkyi" 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, 0 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 octahyq oisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5- thiadiazinyl, 2H, 6H-1 , 5, 2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2#-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H- indolyl, lH-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aff-carbazole, carbazole, β-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 the prodrug forms of the compounds of the present invention 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-l, 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- . 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 Remington' s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference. The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety. 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: Boc tert-butyloxycarbonyl Boc 2 0 di-tert-butyl dicarbonate Cbz benzyloxycarbonyl DEC 1- ( 3-dimethylaminopropyl ) -3- ethylcarbodiimide hydrochloride DIEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N, N-dimethyl formamide EtOAc ethyl acetate EtOH ethyl alcohol PLE Pig liver esterase pyr pyridine TBTU 2- (lH-Benzotriazol-1-yl) -1, 1,3,3- tetramethyluronium tetrafluoroborate TFA ' trifluoroacetic acid THF tetrahydrofuran Compounds of Formula I wherein the central heterocycle is a 1, 3, -thiadiazole ring can be conveniently prepared by cyclization of N,N'- diacyl ydrazine in the presence of Lawessen reagent (M. P. Cava, et al, Tetrahedron Lett. 1985, 41, 5061) or P2S5(stelle, et al, J. Prakt. Chem 1904, 69, 145). Scheme I illustrates one synthetic sequence which will provide the 1, 3, 4-thiadiazoles of this invention. An appropriately substituted ester is treated with hydrazihe monohydrate to afford the hydrazide which is then converted to N, N ' -diacylhydrazine on reaction with an acid chloride in aqueous THF using NaHC03 as base. The N, N ' -diacylhydrazine thus obtained is then cyclized to afford the 1, 3, -thiadiazole . Subsequent hydrolysis of the ester using conventional methods known to one skilled in the art of organic synthesis gives the desired acid. Coupling of the resulting acid to appropriately substituted a- or / 5-amino esters affords an intermediate which can be deprotected to give compounds of Formula I . The coupling is carried out using any of the many methods for the 1 formation of amide bonds known to one skilled in the art of organic synthesis. These methods include but are not limited to conversion of the acid to the corresponding acid chloride, or use of standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method,' carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p-nitrophenyl ester, N-hydroxysuccinic imido ester) method, carbonyldiimidazole method, phosphorus reagents such as B0P-C1. Some of these methods (especially the carbodiimide) can be enhanced by the addition of 1- hydroxybenzotriazole . Scheme I 1 ^ NHH 2 2NHH 2 2--HH 22 00 R1 u ζ co 2 Et ► ^ o ζ CONHNH. (CH 2 )qC0 2 ϊ Lawesson's Reagent _]_ THF, reflux X hy w // y qC0 2 R N-N LiOH.H 2 0 \ , aq. THF >-tX ; x // qC0 2 H N-N Alternately, as depicted in Scheme la and lb, the above sequence can be carried out on an ester bearing a suitable functional group or protected functional group which can be converted into R l at a suitable stage of the synthesis of the target molecules. Scheme la CONHNH 2 NHNHC(0) (CH 2 )qC0 2 Me Lawesson's Reagent °2 1 V ^i \1ι I// q q 'C0 2 Me THF, reflux N-N S cheme lb ^S/ C0 2 Et NH 2 NH 2 H 2 0 ^^ , C ONHNH 2 MeOH C1C(0)(CH 2 ) q C0 2 Me ^ ^ CONHNHC(0)(CH 2 )qC0 2 Me THF-H 2 0/NaHCO, Lawesson's Reagent THF, reflux N - N 3) TFA/CH 2 C1 2 Additional 1, 3, 4-thiadiazolyl acids useful as starting materials for the preparation of compounds of Formula I, wherein W is -SCH2C (=0) N (R 10 ) - can be prepared by substitution of a suitably substituted 1, 3, 4-thiadiazolyl sulfone with an acid thiol as shown in Scheme Ic using literature methods or modifications thereof. (Fujii et al, J. Pharm. Soc. Japan 1954, 74, 1056; Young et al, J. Am. Chem. Soc. 1955, 77, 400) . Scheme Ic CONHNHCS 2 CH 2Ph R' \ ca . PTS, C 5 H 6 /reflux oX(T ' -S^Ph // N-N or cone. H2SO4 The appropriately substituted racemic b-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, _5_8_, 299) . Racemic b-substituted-b-amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2- azetidinone followed by treatment with anhydrous ethanol' (Scheme I, Method 2) or by reductive amination of b-keto esters as is described in WO9316038. (Also see Rico et al., J. Org. Chem. 1993, 5_^, 7948-51.) Enantiomerically pure b-substituted-b-amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt-Eistert homologation of the corresponding a-amino acids as shown in Scheme II, Method 3 (see Meier, and Zeller, Angew, Chem. Int. Ed. Engl. 1975, 1_4, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31_, 5153; Greenlee, J. Med. Chem. 1985, _2_8, 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 b-amino acid derivatives may be found in patent application WO 9307867, the disclosure of which is hereby incorporated by reference. Scheme I I Method 1 HC^Cv^, CC^H 0 1 ) N OAc H,N COjMe R° A' H. 2 ) MeOH , HCI Method 2 1 ) ( K) ? CuLi H 2 N. X CC^Et 0 HN N 'Α R 8 2 ) EtOH, HCI Method 3 BocH V: CC5H Method RorHR yy^. enantioselective BocHN. ^^\ BocHN γX. C Q> Me ^ Y CO,Me R 8 hydrogenation R 8 The synthesis of N 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) Synthesis of compounds of Formula I wherein the central heterocycle is a 1, 3, 4-oxadiazole ring, e.g. G=0, is shown in Scheme III. Cyclization of an appropriately substituted N, N ' -diacylhydrazine in the presence of POCI3 according to the method of Klingsberg ( J. Am. Chem. Soc. 1958, 80, 5788) gives the intermediate 1, 3, 4-oxadiazolyl ester. This ester can be converted to compounds of Formula I using the methods described herein. Scheme III R' NH 2 NH 2 Η 2 0 Xk R C0 2 Et ^ CONHNH 2 C1C(0)(CH 2 ) q C0 2 R ^ υ CONHNHC(0)(CH 2 )qC0 2 R THF-H 2 0 NaHCQ 5 POCI 3 , CH 3 CN, reflux Alternately, the 1 , 3 , 4 -oxadiazoles may be prepared from an ester bearing an appropriate functional group such as nitro or vinyl group which can be converted into R 1 at an appropriate stage of the -synthesis of the target molecules. Componds of formula I wherein G=0 and W is - SCH2C (=0) N (R-O) - may be prepared from an appropriately substituted acylhydrazine adopting the method described by Confalone(J. Am. Che. Soc. 1983, 105, 902), as depicted in Scheme IV. Scheme IV. .. NH 2 NH 2 -H 2 O R ι^ ,. ] \ ζ cθ 2 Et ► U \ /χθNHNH 2 3 ) . X ( CH 2 ) n- lC0 2 H The detailed processes for preparing the compounds of Formula I are illustrated by the following Examples. It is, however, understood that this invention is not limited to the specific details of these examples. Melting points are uncorrected. Proton nuclear magnetic resonance spectra (^H NMR) were measured in chloroform-d (CDCI3) unless otherwise specified and the peaks are reported in parts per million (ppm) downfield from tetramethylsilane (TMS) . The coupling patterns are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; qt, quintet; m, multiplet. Example 43 2 (S) -Phenylsulfonylamino-3- [2- [2- [3- [ (N-imidazolin-2- yl) amino] propyl] -1,3, 4-thiadiazol-5- yl] acetyl] aminopropionic acid Part A. 4-nitrobutyrylhydrazine Methyl 4-nitrobutyrate (5.5g, 37.5mmol) and hydrazine monohydrate ( 1.88g, 37.5mmol) were mixed in methanol (30ml) . The resulting solution was stirred at rt for 50hrs, and then evaporated under reduced pressure. The oily residue was pure enough for next reaction. X NMR (300MHz) δ2.08 (qt , 2H) , 2.20(t, 2H) , 4.50(t, 2H); MS(HH3-CI) Calc. for (M+l)+:148. Found: 148. Part B.N- ( 4-Nitrobutyryl ) -N ' (methoxycarbonylacetyl ) hydrazine To a suspesion of 4- nitrobutyrylhydrazine ( 5.5g, 37.5mmol) in aqueous THF (80ml, 1:1 v/v) containing sodium bicarbonate (4. lg, 48.8mmol), cooled with ice-water, was added methyl malonyl chloride ( 6. lg, 44.8mmol) dropwise. After addition, the ice-water bath was removed and the mixture was stirred at rt for 2hrs. The THF was evaporated under reduced pressure and the product as a solid powder was then collected by filtration and dried. (7.9g, 85% yield). 1 ti NMR(300MHz) 82.10 (qt, 2H) , 2.25(t, 2H), 3.34(s, 2H) , 3.62(s,3H), 4.79(t, 2H) , 10.02(s l , IH) , 10.10(s, IH) ; MS(NH3-DCI) Calc. for(M+NH4) + : 265. Found: 265. Part C. Methyl 2- [2- (3-nitropropyl) -1, 3, 4-thiadiazoI-5- yl] acetate A mixture of N- (4-nitrobutyryl) -N ' - (methoxycarbonylacetyl) hydrazine (2. Og, δ.lmmol) and Lawesson's reagent (1.8g, 4.4mmol) in anhydrous THF (30ml) was gently refluxed for lhr. The solution was then evaporated to dryness and the residue was dissolved in ethyl acetate and washed with saturated NaHC03, brine, then dried. Evaporation followed by chromatography using a mixture of ethyl acetate and hexane (1:1. v:v) as eluent gave the product as an oil(l.lg, 56% yield). 3-H NMR(300MHz) 52.60 (qt, 2H) , 3.24(t, 2H) , 3.80(s, 3H) , 4.10(s, 2H) , 4.60(t, 2H) ; MS(NH3-CI) Calc. for (M+l) + : 246. Found: 246. Part D. 2- [2- ( 3-nitropropyl) -1, 3, 4-thiadiazol-5- yl] acetic acid Methyl 2- [2- (3-nitropropyl) -1, 3, 4-thiadiazol-5- yl] acetate ( 1.05g, 4.3mmol) was dissolved in aqueous THF(30ml, 1:1, v:v) containing 450mg ( 10.7mmol) of LiOH.H20. The solution was stirred at rt for 8hrs, and then acidified with 6N HCI to a PH of around 2.0. The solution was evaporated to dryness and the residue was washed with acetone. After removal of acetone, the product was dried(800mg, 81% yield). X NMR(300MHz, DMSO) δ2.34(qt, 2H) , 3.16(t, 2H) , 4.18(s, 2H), 4.68(t, 2H) ; MS(NH3-CI) Calc. for (M+l)+: 232. Found: 232. Part E. Methyl N -Cbz- -2 , 3-diaminopropionate HCI salt . N 2 -Cbz-L-2, 3-diaminopropionic acid (10 mmol, 2.39 g) was dissolved in 20 mL methanol and 20 mL 4 N HCI 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 6 ) : d 8.38 (b, 3H) ; 7.96 (d, IH) ; 7.38 (m, 5H) ; 5 . 05 ( s , 2H) ; 4 . 44 (m, IH) ; 3 . 66 ( s , 3H) ; 3 . 14 (m, 2H) . Part F: Methyl N -Cbz-N 3 -Boc- -2 , 3-diaminopropionate . To a solution of methyl N 2 -Cbz- (S) -2, 3- diaminopropionate HCI 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, NaHC0 3 and brine, dried (MgS0 4 ), and concentrated. Crystallization from ether/petroleum ether gave 5.2 g (92%) product. NMR (DMSO-d 6 ) : d 7.60 (d, IH) ; 7.35 (m, 5H) ; 6.88 (t, IH) ; 5.02 (s, 2H) ; 4.14 (m, IH) ; 3.60 (s, 3H) ; 3.28 (m, 2H) ; 1.37 (s, 9H) . Part G: Methyl N 3 -Boc- (S) -2, 3-diaminopropionate Formic acid salt. A mixture of methyl N 2 -Cbz-N 3 -Boc- (S) -2 , 3- diaminopropionate. (14 mmo, 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 6 ) : δ8.20(s, IH) ; 6.90 (t, IH) ; 5.36 (b, 3H) ; 3.61 9s, 3H) ; 3.51 (t, IH) ; 3.18 (t, 2H) ; 1.38 (s, 9H) . Part H. Methyl N 2 -phenylsulfonyl-N 3 -Boc- (S) -2, 3- , diaminopropionate . To a mixture of methyl N 3 -Boc- (S) -2 , 3- diaminopropionate HCO 2 H salt (3.8g, 14.7mmol) and diisoproppylethylamine (3.3g, 32.3mmol) in CH2CI2 (60ml) , cooled with ice-water, was added phenylsulfonyl chloride (2.86g, 16.2mmol). After stirring at rt for 24hrs, the resulting reaction mixture was diluted with ethyl acetate (150ml) , washed with dilute citric acid, saturated NaHC03 and brine, and then dried. Concentration afforded the product as a foam(5.0g, 95% yield). X NMR (300MHz) δl .52 (s, 9H) , 3.46(m, 2H) , 3.56(s, 3H) , 4.00 ( , IH) , 5.00 (m, IH) , 5.74(d, IH) , 7.56(m, 3H) , 7.82 (m, 2H) ; MS(NH3-CI) Calc. for (M+l) + : 359. Found: 359. Part I. Methyl N 2 -phenylsulfonyl- (S) -2, 3- diaminopropionate HCI salt Methyl N 2 -phenylsulfonyl-N 3 -Boc- (S) -2, 3- diaminopropionate (4.5g, 12.6mmol) was dissolved in dioxane(8ml) and then 4N HCI in dioxane(δml) was added. The resulting solution was stirred at rt for 5hrs and then evaporated to give a foam(3.7g, 100% yield). X NMR(300MHz, DMS0-d6) 52.78 (m, 2H) , 3.56(s, 3H) , 3.68(m, IH) , 5.70(d, IH) , 7.46(m, 3H) , 7.68 (m, 2H) ; MS(ESI) Calc. for (M+l) + : 259. Found: 259(free base). Part J. Methyl 2 (S) -phenylsulfonyl-3- [2- [2- (3- nitropropyl) -1, 3, 4-thiadiazol-5- yl] acety] diaminopropionate . To a mixture of 2- [2- (3-nitropropyl) -1, 3, 4- thiadiazol-5-yl] acetic acid(510mg, 2.2mmol), methyl N 2 -phenylsulfonyl- (S) -2, 3-diaminopropionate HCI salt(650mg, 2.2mmol) and triethylamine (1.35ml, 8.8mmol) in DMF (12ml), cooled with ice-water, was added TBTU(700g, 2.2mmol). After stirring for 3hrs, the reaction ^ mixture was diluted with ethyl acetate and washed with dilute citric acid, dilute NaHC03 and brine successively, then dried. Concentration followed by chromatography using a mixture of ethyl acetate and hexane as the eluent gave the product as an amorphous solid(645mg, 62% yield) . J -H NMR (300MHz) δ2.58 (qt, 2H) , 3.26(t, 2H) , 3.54(m, IH) , 3.58(s, 3H) , 3.70(m, IH) , 4.02(m, IH) , 4.08(s, 2H) , 4.58(t, 2H) , 5.76(d, IH) , 7.08(s, IH) , 7.5 (m, 3H) , 7.80(m, 2H) ; MS(NH3-CI) Calc. for (M+l)+: 472. Found: 472. Part K. Methyl 2 (S) -phenylsulfonyl-3- [2- [2- (3- aminopropyl) -1, 3, 4-thiadiazol-5 yl] acety] diaminopropionate AcOH salt. Methyl 2 (S) -phenylsulfonyl-3- [2- [2- (3- nitropropyl) -1, 3, 4-thiadiazol-5- yl] acetyl] iaminopropionate (400mg, 0.85mmol) was dissolved in a mixed solvent of methanol and acetic acid(12ml, 1:1, v:v) and Ptθ2 (40mg) was added. The resulting mixture was hydrogenated in a shaking bottle for 30hrs, and then was filtered through a short column of Zeliot. The filtrate was concentrated and the residue dried to give an oily product (410mg, 96% yield). X NMR(300MHz, DMSO-dδ) δ2.76 (qt , 2H) , 3.08(t, 2H) , 3.20(t, 2H) , 3.34(s, 3H) , 3.38 ( , 2H) , 3.90(m, 3H) , 7.58 (m, 3H) , 7.749m, 2H) , 8.749s, IH) ; MS(NH3~CI) Calc. for (M+l) + : 442. Found: 442. Part L. Methyl 2 (S) -phenylsulfonyl-3- [2- [2- [3- [ (N- imidazolin-2-yl) amino] propyl] -1,3, 4-thiadiazol-5 -yl] acety] diaminopropionate . A solution of methyl 2 (S) -phenylsulfonyl-3- [2- [2- (3-nitropropyl) -1,3, 4-thiadiazol-5- yl] acetyl] diaminopropionate (425mg, 0.85mmol) and 2- methylthio-2-imidazoline hydriode (207mg, 0.85mmol) in pyridine (10ml) was heated at 70°C for 5hrs . The solution was then concentrated and the residue was chromatographed using a mixture of methylene chloride and methanol as the eluent to afford an oily pruduct (250mg, 58% yield) .3-H NMR (300MHz, CD30D)δ2'.08 (qt, 2H) , 3.18(t, 2H) , 3.30(m, 3H) , 3.40(s, 3H), 3.54(dd, IH) , 3.66(s, 4H) , 4.00(s, 2H) , 4.10(dd, IH), 7.52 (m, 3H) , 7.80(m, 2H) ; MS(ESI) Calc. for (M+l) + : 510. Found: 510. Part M. 2 (S) -phenylsulfonyl-3- [2- [2- [3- [ (N-imidazolin- 2-yl) amino] ropyl] -1,3, 4-thiadiazol-5 -yl] acety] diaminopropionic acid HCI salt. Methyl 2 (S) -phenylsulfonyl-3- [2- [2- [3- [ (N-imidazolin- 2-yl) amino] propyl] -1,3, 4-thiadiazol-5 yl] acety] diaminopropionate (230mg, 0.45mmol) was dissolved in 4N HCI (9ml) and the solution was stirred at rt for 40hrs, then concentrated under reduced pressure to dryness to afford the product as an amorphous solid(200mg, 91% yield). Further puriofication via reverse phase HPLC using a mixture of acetonitrile and 0.1% TFA in water as the eluent gave the. test sample. 3-H NMR(300MHz, DMSO-D6) 51.96 (qt, 2H) , 3.08(t, 2H) , 3.24 (m, 3H) , 3.40(m, IH) , 3.90(m, 3H) , 7.56(m, 3H) , 7.58 (m, 2H) , 8.22(d, IH) , 8.46(t, IH) , 8.56(t, IH) ; MS(ESI) Calc. for (M+l) + : 496. Found: 496, Example 44 2 (S) - (3-methylphenylsulfonyl) amino-3- [2- [2- [3- [ (N- imidazolin-2-yl) amino] propyl] -1,3, 4-thiadiazol-5- yl] acetyl] aminopropionic acid Part A. Methyl N 2 -3-methylphenylsulfonyl-N 3 -Boc- (S; 2 , 3-diaminopropionate . To a mixture of methyl N 3 -Boc- (S) -2 , 3- diaminopropionate HCO 2 H salt (3.8g, 14.7mmol) and diisoproppylethylamine (3.3g, 32.3mmol) in CH2CI2 (60ml) , cooled w ^ ith ice-water, was added 3-methylsulfonyl chloride (3. lg, 16.2mmol). After stirring at rt for 24hrs, the resulting reaction mixture was diluted with ethyl acetate (150ml) , washed with dilute citric acid, saturated NaHC03 and brine, and then dried. Concentration afforded the product as a foam(5.1g, 95% yield). H NMR(300MHz, CDCI3) δl .58 (s, 9H) , 2.30(s, 3H) , 2.72 ( , IH) , 2.98 (m, IH) , 4.10(m, IH) , 5,80(s, IH) , 7.40(d, J=5, 2H) , 7.50 (m, IH) , 7.56(s, IH) , 8.40(d, J=6, IH) ; MS(NH3-CI) Calc. for (M+l) + : 373. Found: 373. Part B. ( Methyl N 2 -3-methylphenylsulfonyl- (S) -2, 3- diaminopropionate HCI salt Methyl N 2 -3-methylphenylsulfonyl-N 3 -Boc- (S) -2, 3- diaminopropionate (4.5g, 12. lmmol) was dissolved in dioxane(8ml) and then 4N HCI in dioxane(8ml) was added. The resulting solution was stirred at rt for 5hrs and then evaporated to give a foam(3.7g, 100% yield). ^H NMR(300MHz, DMSO-d6) δ2.40 (s, 3H) , 2.86(m, IH) , 3.10(m, IH) , 3.40(s, 3H) , 4.28 ( , IH) , 7.48(d,J=5 2H) , .60 (m, IH) , 7.62(s, IH) 8.39(s, broad, 2H) , 8.62(d, J=6, IH) ; MS (ESI) Calc. for (M+l) + : 273. Found: 273 (free base). Part C. Methyl 2 (S) - (3-methylphenyl) sulfonylamino-3- [2- [2- (3-nitropropyl) -1, 3, 4-thiadiazol-5 yl] acety] aminopropionate . To a mixture of 2- [2- (3-nitropropyl) -1 , 3, 4- thiadiazol-5-yl] acetic acid(430mg, 1.86mmol) , methyl N 2 -3-methylphenylsulfonyl- (S) -2, 3-diaminopropionate HCI salt(630mg, 2.0mmol) and triethylamine (1. Iml, 8.2mmol) in DMF (10ml), cooled with ice-water, was added TBTU(660mg, 2.0mmol). After stirring for 3hrs, the reaction mixture was diluted with ethyl acetate and washed with dilute citric acid, dilute NaHC03 and brine successively, then dried. Concentration followed by chromatography using a mixture of ethyl acetate and hexane as the eluent gave the product as an amorphous solid(360mg, 40% yield) . X NMR (300MHz) δ2.40 (s, 3H) , 2.58(qt, 2H) , 3.269t, 2H) , 3.52(s, 3H) , 3.62 (m, 2H) , 4.06(m, IH) , 4.10(s, 2H) , 4.59(t, 2H) , 7.36(m, 2H) , 7.60 (m, 2H) ; MS(NH3~CI) Calc. for (M+l)+: 486. Found: 486. Part D. Methyl 2 (S) - (3-methylphenyl) sulfonylamino-3- [2- [2- (3-aminopropyl) -1, 3, 4-thiadiazol-5- yl] acety] aminopropionate AcOH salt. Methyl 2 (S) - (3-methylphenyl) sulfonylamino-3- [2- [2- (3-nitropropyl) -1, 3, 4-thiadiazol-5- yl] acetyl] aminopropionate (140mg, 0.29mmol) was dissolved in a mixed solvent of methanol and acetic acid(20ml, 1:1, v:v) and Ptθ2(30mg) was added. The resulting mixture was hydrogenated in a shaking bottle for 24hrs, and then was filtered through a short column of Zeliot. The filtrate was concentrated and the residue dried to give an oily product (120mg, 91% yield). J -H NMR(300MHz, DMSO-d6) δl .90 (qt, 3H) , 2.56(s, 3H) , 2.78(t, 2H) , 3.10(t, 2H) , 3.28(s, 3H) , 3.36(m, 2H) , 3.84 (m, 3H) , 7.30 ( , 2H) , 7.42 (m, IH) , 7.74(d, IH) , 8.58 (s, IH) ; MS(ESI) Calc. for (M+l) + : 456. Found: 456. Part E. Methyl 2 (S) - ( 3-methylphenyl) sulfonylamino-3- [2- [2- [3- [ (Ximidazolin-2-yl) amino] propyl] -1, 3, 4- thiadiazol-5-yl] acety] aminopropionate. A solution of methyl 2(S)-(3- methylphenyl) sulfonylamino-3- [2- [2- (3-nitropropyl) - 1,3, 4-thiodiazol-5-yl] acetyl] aminopropionate (130mg, 0.29mmol) and 2-methylthio-2-imidazoline hydriode (78mg, 0.32mmol) in pyridine (5ml) was heated at 70°C for 5hrs . The solution was then concentrated and the residue was chromatographed using a mixture of methylene chloride and methanol as the eluent to afford an oily pruduct (90mg, 59% yield). X NMR(300HMz, DMSO- d6)δl.90(qt, 3H) , 2.56(s, 3H) , 3.04(t, 2H) , 3.20(m, 2H) , 3.28(s, 3H) , 3.58(m, 2H) , 3.56(m, 4H) , 3.84(m, 3H) , 7.30 (m, 2H) , 7. 2 (m, IH) , 7.74(d, IH) , 8.24(s, IH) , 8.46(s, IH) ; MS(ESI) Calc. for (M+l)+: 524. Found: 524. Part F. 2 (S) - (3-methylphenyl) sulfonylamino-3- [2- [2- [3- [ (N-imidazolin-2-yl) amino] propyl] -1,3, 4-thiadiazol-5 -yl] acety] aminopropionic acid HCI salt. Methyl 2 (S) - (3-methylphenyl) sulfonylamino-3- [2- [2- [3- [ (N-imidazolin-2-yl) amino] propyl] -1,3, 4-thiadiazol-5 -yl] acety] aminopropionate (80mg, 0.15mmol) was dissolved in 4N HCI (6ml) and the solution was stirred at rt for 36hrs, then concentrated under reduced pressure to dryness, affording the product as an amorphous solid (75mg, 97% yield). Further puriofication via reverse phase HPLC using a mixture of acetonitrile and 0.1% TFA in water as the eluent gave the test sample. X NMR(300MHz, DMSO-D6) δ2.96 (qt , 2H) , 2.60(s, 3H) , 3.08(t, 2H) , 3.20 (m, 3H) , 3.40 ( , IH) , 3.58(s, 4H) , 3.94 ( , 3H) , 7.30 (m, 3H) , 7.42 (m, IH) , 7.58 (m, 2H) , 8.20(d, IH) , 8.38(t, IH) , 8.50 ( , IH) ; MS(ESI) Calc. for (M+1 + : 510. Found: 510. Example 176 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [N- (pyridin-2- yl) amino]butyl] -1, 3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt Part A. Pent-4-enoyl hydrazide A mixture of pent-4-enoic acid ethyl ester (12.. lg, 94.5mmol) and hydrazine monohydrate (4.6ml, 94.5mmol) in methanol (75ml) was stirred at rt for 48hrs. The volatile portion of the reaction mixture was then removed. The product was obtained as an oil(9.5g, 94% yield). J -H NMR (300MHz) δl .56 (m, 2H) , 2.30(t, 2H) , 5.20 (m, 2H) , 5.80(m, IH) ; MS(NH3-CI) Calcd. for (M+l)+: 115. Found: 115. Part B. N- (Pent-4-enoic) -N ' - (methoxycarbonylcarbonyl ) hydrazine To a solution of pent-4-enoic hydrazine (10.8g, 94.5mmol) in aqueous THF(80ml, 1:1, v:v) containing NaHC03 ( 11.9g, 141.7mmol) cooled in an ice-water bath was added methyl oxalyl chloride (13.0ml, 141.7mmol) dropwise. After addition, the mixture was stirred in the ice-water bath for additional 30mins, and then at rt overnight. The THF was removed under reduced pressure, and the aqueous residue was extracted with ethyl acetate. The ethyl acetate solution was washed with brine and then dried over Na2S0 . Concentration afforded the product as an oil(12.3g, 65% yield). X NMR(300MHz)δl.60(qt, 2H) , 2.44(t, 2H) , 3.96(s, 3H) , 5.10(m, 2H) , 5.80 (m, IH) ; MS(NH3-CI) Calcd. for (M+l)+: 201. Found: 201. Part C. Methyl [2- (but-3-enyl) -1,3, 4-thiadiazol-5- yl] carboxylate N- (Pent-4-enoic) -N ' - (methoxycarbonylcarbonyl) hydrazine (2.13g, 10.6mmol) was dissolved in anhydrous THF (20ml) and then was heated to gentle refluxing. Lawesson reagent (2.15g, 5.3mmol) was introduced and stirring was continued under such conditions for 3hrs. The solvent was removed under reduced pressure and the residue was dissloved in ethyl acetate, washed with saturated NaHC03 and brine, then dried over a2S04. After removal of ethyl acetate, the residue was chromatographed using a mixture of ethyl acetate and hexane as the eluent to give the product as a white solid(1.5g, 73% yield). ^H NMR(300MHz)δ2.60 (qt, 2H) , 3.32(t, 2H) , 4.06(s, 3H) , 5.14 (m, 2H) , 5.84 (m, IH) ; MS(NH3-CI) Calcd. for (M+l) + : 199. Found: 199. Part C. Methyl [2- (4-hydroxybutyl) -1, 3, 4-thiadiazol-5- yl] carboxylate Methyl [2- (but-3-enyl) -1, 3, 4-thiadiazol-5- yl] carboxylate (420mg, 2.13mmol) was dissolved in anhydrous THF (5ml) and then cooled with an ice-water bath to 0°C. 9-BBN(290mg, 2.34mmol) dissolved in THF (5ml) was introduced and the resulting reaction mixture was kept stirring at 0°C for 3hrs, then at rt for 5hrs. NaOAc(lg) dissolved in water (5ml) was added, followed by introduction of 1ml of 30% H2O2. After stirred further at rt for 2hrs, the mixture was extracted with ethyl acetate. The extract was washed with brine and then dried over Na2Sθ4. Concentration followed by chromatography using ethyl acetate as the eluent yielded the product as a white- powder (420mg, 92% yield ) . 1 H NMR (300MHz) δl .64 (m, 2H) , 1.90(m, 2H) , 3.24(t, 2H) , 3.76(q, 2H) , 3.82(t, IH) , 4.06(s, IH) ; MS(NH3-CI) Calcd. for (M+l)+: 217. Found: 217. Part D. Methyl [2- (4-oxobutyl) -1, 3, 4-thiadiazol-5- yl] carboxylate Methyl [2- [4-hydroxybutyl) -1, 3, -thiadiazol-5- yl] carboxylate (210mg, 0.97mmol) was dissloved in CH2CI2, followed by introduction of PCC(314mg, l^Smmol 1 ). The mixture was stirred at rt for 5hrs, and then was filtered through a short column of silica gel. The filtrate was concentrated and the residue was chromatographed using a mixture of ethyl acetate and hexane as the eluent to give llOmg of the product (53% yield) as a white solid. ^-H NMR (300MHz) δ2.20 (qt , 2H) , 2.66(t, 2H), 3.26(t, 2H) , 4.04(s, 3H) , 9.72(s, IH) ; MS(NH3-CI) Calcd. for (M+l)+: 215. Found: 215. Part E. Methyl [2- [4- [N-Boc-N- (pyridin-2- yl) amino] butyl] -1,3, 4-thiadiazol-5-yl] carboxylate Methyl [2- (4-oxobutyl ) -1, 3, -thiadiazol-5- yl] carboxylate (lOOmg, 0.47mmol) and 2- aminopyridine (48mg, 0.52mmol) were dissolved in anhydrous toluene (4ml) and then were heated at 70°C for 2hrs, during which time a small amount of pulverised molecular sieve was added. HOAc(30ul, 0.52mmol) and NaB(0Ac)3H were added. Stirring was continued at rt for lδhrs. NaOAc(300mg) dissolved in 10ml of water was added and the mixture was diluted with another 10ml of water after being stirred for additional 2hrs . The solution was extracted with CH2CI2 and the extract was concentrated and dried. The oily product obtained above was then dissolved in dry CHCl3(5ml), and cooled in an ice-water bath, followed by addition of triethylamine (0.13ml, 0.94mmol), Boc2θ(153mg, 0.71mmol) and a catalytic amount of DMAP . The mixture was stirred at rt for 24hrs, and then diluted with ethyl acetate. The solution was washed with dilute citric acid, saturated NaHCθ3 and brine successively, and then dried over a2Sθ4. Concetration followed by chromatography using a mixture of ethyl acetate and hexane as the eluent afforded the product as an oil(85mg, 46% yield in two steps). X NMR (300MHz) δl .50 (s, 9H) , 1.79(qt, 2H) , 1.84(qt, 2H) , 3.20(t, 2H) , 4.00(t, 2H) , 4.04(s, 3H), 7.00(m, IH) , 7.60 (m, 2H) , 8.38 (m, IH) ; MS(NH3-CI) Calcd. for (M+l) + : 393. Found: 393. Part E. [2- [4- [N-Boc-N- (pyridin-2-yI) amino] butyl] -1,3, 4-thiadiazol-5-yl] carboxylic acid Methyl [2- [4- [N-Boc-N- (pyridin-2- yl) amino] butyl] -1, 3, 4-thiadiazol-5- yl] carboxylate (80mg, 0.20mmol) dissolved in 0.2ml of DMSO was mixed with PLE(50mg) and buffer solution l (PH=7.00, 4ml) and the mixture was vigorously stirred at rt for 18hrs, and then was evaporated under high vaccum. The resulting solid was extracted with ethyl acetate and the extract was concentrated to give an oil(60mg, 78% yield). X NMR (300MHz) δl .52 (s, 9H) , 1.80(qt, 2H) , 1.86(qt, 2H) , 3.22(t, 2H) , 4.00(t, 2H) , 7.10 (m, IH) , 7.6 (m, 2H) , 8.30 (m, IH) ; MS(ESI) Calcd. for (M+l) + : 379. Found: 379. Part F. t-butyl 2 (S) -benzyloxycarbonylamino-3- aminopropionate Cone. H2S04(8ml) was added to dioxane ( 120ml) in a Parr Bottle cooled with dry ice, followed by addition of 2 (S) -benzyloxycarbonylamino-3-aminopropionic acid(6.8δg, 26.8mmol) and pre-condensed isobutylene (130ml, excess). The mixture in the Parr bottlle was then shaked at rt for 70hrs. After removal of isobutylene under reduced pressure, the resulting solution was poured into a NaOH solution containing NaOH (17.4g) and ether (400ml) cooled in an ice water bath while stirred vigorously. The etheral layer was separated and the aqueous layer was extracted with ether. The combined etheral solution was washed with IN HaOH twice and then dried over Na2S04. Concetration gave the product as a solid(6.3g, 75% yield). X NMR(300MHz)δl.44 (s, 9H) , 3.10(m,2H), 4.26(m, IH) , 5.12(s, 2H) , 5.80(d, IH) , 7.36(m, 5H) ; MS(NH3-CI) Calcd. for (M+l) + : 293. Found: 293. Part G. t-Butyl 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [N-Boc-N- (pyridin-2-yl) aminojbutyl] -1, 3, 4-thiadiazol-5- yl] carbonyl] aminopropionate To a mixture of [2- [ 4- [N-Boc-N- (pyridin-2- yl) amino] butyl] -1,3, 4-thiadiazol-5-yl] carboxylic acid (50mg, 0.13mmol), t-butyl 2(S)- benzyloxycarbonylamino-3-aminopropionate (40mg, 0,13mmol) and triethylamine (40ul, 0.29mmol) in EtOAc(4ml), was added PyBop(75mg, 0.13mmol). After stirring for 4hrs at rt, the reaction mixture was diluted with ethyl acetate and washed with dilute citric acid, dilute NaHC03 and brine successively, then dried. Concentration followed by chromatography using a mixture of ethyl acetate and hexane as the eluent gave the product as an amorphous solid(30mg, 35% yield) . ^H NMR(300MHz)δl.46(s, 9H) , 1.50(s, 9H) , 1.80 (m, 4H) , 3.19(t, 2H) , 3.87 (m, 2H) , 4.00(t, 2H) , 4.44 (m, IH) , 5.12(s, 2H) , 5.68(d, IH) , 7.00 (m, IH) , 7.36(m, 5H) , 7.60(m, 2H) , 8.40 ( , IH) ; MS(ESI) Calc. for (M+l) + : 655. Found: 655. Part H. 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [N- (pyridin 2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt t-Butyl 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [N-Boc- N- (pyridin-2-yl) amino] butyl] -1,3,4- thiadiazol-5- yl] carbonyl] aminopropionate (30mg, 0.046mmo'l) was dissolved in CH2Cl2(5ml) containing 0.25ml of TFA. The solution was stirred at rt for 24hrs and then concetrated, affording an oily product (20mg, 87% yield) . Further purification by reverse HPLC using a mixture of acetonitrile and 0.1% TFA in water gave the sample for testing. X NMR (300MHz) δl .68 (qt , 2H) , 1.84(qt, 2H), 3.20(t, 2H) , 3.36(m, 2H) , 3.64(t, 2H) , 4.25 (m, IH), 5.02(s, 2H) , 6.84(t, IH) , 7.04(d, IH) , 7.54 (m, 5H) , 7.70 (m, IH) , 7.90 (m, 2H) , 8.80 (m, IH) , 9.20(t, IH) ; MS(ESI) Calc. for (M+l) + : 499. Found: 499. Example 178 2 (S) - (2, 4, 6-Trimethylphenylsulfonyl) amino-3- [ [2- [4- [N- (pyridin-2-yl) amino] butyl] -l,3,4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt Part A. 2-N-Mesitylenesufonyl-L-asparigine L-Asparagine ( 8.5g, 56.8mmol) was dissolved in water(23ml) containing triethylamine ( 19.8ml ) . Thi mixture was then diluted with dioxane (40ml) . To the resulting mixture was added slowly 2-mesitylenesulfonyl chloride ( 14.85g) dissolved in dioxane (50ml) , causing a little exothermic. After addition, the mixure was stirred further at rt for 24hrs. The reaction mixture was evaporated to remove most of the organic solvent, and then basified with 2N HaOH. The basic solution was extracted with CH2C12 (50mlX2 ) and filtered. The filtrate was acidified with concentrated HCI. The solid formed was collected by filtration (13. Og, 73%yield) . X NMR(300MHz,CDCl3)δ2.24 (s, 3H) , 2.30(dd, IH) , 2.43(dd, IH) , 2.54(s, 6H) , 4.00 (m, IH) , 6.86(s, IH) , 7.00(s, 2H) , 7.32(s, IH) , 7.80(d, IH) ; MS(ESI) Calc. for (M+l)+: 315. Found: 315. Part B. 2 (S) -(2,4, 6-Trimethylphenylsulfonyl) amino-3- aminopropionic acid , Bromine (1.04ml, 20.1ml) was added to a solution of 4N NaOH (34ml) cooled in an ice-water bath. The orange solution was stirred in the ice bath for additional 15mins and then 2-N-Mesitylenesufonyl-L- asparigine (5.3g, 16.8mmol) was added in portions. Stirring was continued in the ice bath for 15 mins and then at 1 65°C for 1 hr. The resulting solution was cooled in an ice bath and acidified with cone. HCI to PH ~6. The solid was collected through filtration (4 , 7g, 97% yield). 1-H NMR(300MHz, DMSO-d6) δ2.20 (s, 3H) , 2.4δ(s, 6H) , 2.76(t, IH) , 2.92 (m, IH) , 3.04(m, IH) , 6.98(s, IH) , 7.00(s, 2H) ; MS(ESI) Calc. for (M+l) + : 287. Foupd: 287. Part C. t-Butyl 2(S)-(2,4,6 trimethylphenylsulfonyl) amino-3-aminopropionate Cone. H2S04 (7.7ml) was added to dioxane ( 120ml) in a Parr Bottle cooled with dry ice, followed by addition of 2 (S) - (2, 4 , 6-trimethylphenylsulfonyl) amino- 3-aminopropionic acid(8,02g, 28mmol) and pre-condensed isobutylene (136ml, excess). The mixture in the Parr bottlle was then shaked at rt for 70hrs. After removal of isobutylene under reduced pressure, the resulting solution was poured into a NaOH solution containing NaOH (11.9g) and ether (400ml) cooled in an ice water bath while stirred vigorously. The etheral layer was separated and the aqueous layer was extracted with ether. The combined etheral solution was washed with IN HaOH twice and then dried over Na2S04. Concetration gave the product as a solid (7.7g, 81% yield). X NMR(300MHz)δl.56(s, 9H) , 2.20(s, 3H) , 2.48(s, 6H) , 2.76(t, IH) , 2.92 (m, IH) , 3.04 (m, IH) , 6.98(s, IH) , 7.00(s, 2H) ; MS(NH3-CI) Calcd. for (M+l) + : 343. Found: 343. Part D. t-Butyl 2 (S) - (2,4, 6-trimethylphenylsulfonyl) amino-3- [2- [4- [N-Boc-N- (pyridin-2-yl) amino] butyl] - 1,3, 4-thiadiazol-5-yl] carbonyl] aminopropionate To a mixture of [2- [ 4- [N-Boc-N- (pyridin-2- yl) amino] butyl] -1,3, 4-thiadiazol-5-yl] carboxylie acid (135mg, 0.36mmol), t-butyl 2(S)-(2,4,6- trimethylphenylsulfonyl) amino-3-aminopropionate (120mg, 0.36mmol) and triethylamine (0.25 ml, 1.8 mmol) in DMF (8 ml), was added PyBop(210 mg, 0.36 mmol). After stirring for 4 hrs at rt, the reaction mixture was diluted with ethyl acetate and washed with dilute citric acid, dilute NaHCθ3 and brine successively, then dried. Concentration followed by chromatography using a mixture of ethyl acetate and hexane as the eluent gave the product as an amorphous solid(150 mg, 64% yield). ^H NMR(300MHz, CDCI3 ) δl .32 ( s , 9H) , 1.50(s, 9H) , 1.82 (m, 4H) , 2.2'4(s, 3H) , 2.64(s, 6H) , 3.20(t, 2H) , 3.66(m, IH) , 3.80 ( , IH) , 4.00(m, 3H) , 5.60(d, IH) , 6.90(s, 2H) , 7.00(m, IH) , 7.60 (m, 2H) , 8.40 (m, IH) ; MS(ESI) Calc. for (M+l) + : 703. Found: 703. Part E. '2 (S) - (2, 4, 6-Trimethylphenylsulfonyl) amino-3- [ [2- [4- [N- (pyridin-2-yl) amino]butyl] -1, 3, 4- thiadiazol-5-yl] carbonyl] aminopropionic acid TFA salt t-Butyl 2(S)-(2,4,6 trimethylphenylsulfonyl) amino-3- [ [2- [4- [N-Boc-N- (pyridin-2-yl) amino] butyl] - 1,3, 4-thiadiazol-5-yl] carbonyl] aminopropionate (60mg, 0.091mmol) was dissolved in CH2Cl2(5ml) containing 0.25ml of TFA. The solution was stirred at rt for 24hrs and then concetrated, affording an oily product (42mg, 90% yield) . Further purification by reverse HPLC using a mixture of acetonitrile and 0.1% TFA in water gave the sample for testing. 3-H NMR(300MHz, DMSO- d6)δl.64(qt, 2H) , 1.80(qt, 2H),2.12(s, 3H) , 2.46(s, 6H), 3.18(t, 2H), 3.30 ( , 2H) , 3.50 (m, 2H) , 3.98(m, IH), 6.80(s, 2H), 6.84(t, IH) , 7.00(d, IH) , 7.86(m, 2H), 8.02(d, IH), 8.76(s, IH) , 6.94(t, IH) ; MS (ESI) Calc. for (M+l) + : 547. Found: 547. Example 179 2 (S) - (1-Naphthalenesulfonyl) amino-3- [ [2- [4- [N- (pyridin- 2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt This compound was analogously prepared to Example 176. X NMR (300MHz, DMSO-d6) δl .64 (qt , 2H) , 1.80(qt, 2H) , 3.18(t, 2H) , 3.34(m, 2H) , 3.44 ( , 2H) , 3.90(m, IH) , 6.80(t, IH) , 7.00(d, IH) , 7.50 ( , 3H) , 7.88 ( , 3H) , 8.06(d, d, 2H) , 8.56(d, 2H) , 8.76(s, IH) , 8.84(t, IH) ; MS(ESI) Calc. for (M+l)+: 555. Found: 555. Example 321 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [ (N-imidazolin-2- yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt Part A. Methyl [2- (4-triazobutyl) -1, 3, 4-thiadiazol-5- , yl] carboxylate Mesyl chloride (0.26 mL, 3.34 mmol) was added slowly to a solution of methyl [2- ( 4-hydroxybutyl) -1, 3, 4- thiadiazol-5- yl] carboxylate (600 mg, 2.78 mmol) and triethylamine (0.77ml, 5.56 mmol) in CH2CI2 cooled in a ice-water bath. After addition, the resulting mixture was stirred for additional 30 mins. The reaction mixture was diluted with ethyl acetate and then washed with aqueous citric acid, saturated NaHC03 and brine. Concentration and chromatography with a mixture of ethyl acetate and hexane gave the mesylate as an oil (530mg) . The mesylate was dissolved in DMF (10ml). Sodium triazide(585 mg, 9.0 mmol) was added. The mixture was heated at 40 _C for 4 hrs . After dilution with ethyl acetate, the organic solution was washed with saturated NaHCθ3, brine and then dried over Na2S0 . Concetration and Chromatography with a mixture of ethyl aceate and hexane gave 450 mg of the product as an oil (67% yield). X NMR(300MHz, CDCI3 ) δl .74 (m, 2H) , 1.96(m, 2H) , 3.24(t, 2H) , 3.38(t, 2H),4.06(s, IH) ; MS(NH3-CI) Calcd. for (M+l)+: 242. Found: 242. Part B. [2- (4-triazobutyl) -1, 3, 4-thiadiazol-5- yl] carboxylic acid Methyl [2- [4-triazobutyl] -1, 3, 4-thiadiazol-5- yl] carboxylate (300 mg, 1.24 mmol) was mixed with PLE- A(200 mg) and buffer solution ( PH=7.00, 10 ml). The mixture was vigorously stirred at rt for 36 hrs, and then evaporated under high vaccum to dryness. The residue was extracted with methanol and the extract was concentrated to give the aciod as an oil (190 mg, 70% yield). *H NMR(300MHz, DMSO-d6) δl .58 (m, 2H) , 1.76(m, '2H), 3.00(t, 2H) , 3.40(t, 2H) ; MS(ESI) Calcd. for (M+l)+: 228. Found: 228. Part C. t-Butyl 2 (S) -benzyloxycarbonylamino-3- [ [2- (4- triazobutyl) -1, 3, 4-thiadiazol-5- yl ] carbonyl ] aminopropionate To a mixture of [2- (4-triazobutyl) -1, 3, 4- thiadiazol-5-yl] carboxylic acid(270 mg, 1.2 mmol), t- butyl 2 (S) -benzyloxycarbonylamino-3-aminopropionate (350 mg, 0,13mmol) and triethylamine ( 40ul, 1.2 mmol) in DMF(10 ml), was added PyBop(700 mg, 1.2 mmol). After stirring for 4hrs at rt, the reaction mixture was diluted with ethyl acetate and washed with dilute citric acid, dilute NaHC03 and brine successively, then dried. Concentration followed by chromatography using a mixture of ethyl acetate and hexane as the eluent gave the product as an amorphous solid (440 mg, 90% yield). ^H NMR(300MHz, CDCI3 ) δl .40 (s , 9H) , 1.74(m, 2H) , 1.85(m, 2H), 3.20(t, 2H) , 3.26(t, 2H) , 3.88(m, 2H) , 4.10(m, IH), 5.12(S, 2H) , 5.80(s, IH) , 7.38(m, 5H) , 7.68(s, IH) ; MS (ESI) Calc. for (M+l) + : 604. Found: 604. Part D. l t-Butyl 2 (S) -benzyloxycarbonylamino-3- [ [2- (4- aminobutyl) -1,3, 4-thiadiazol-5- yl] carbonyl ] aminopropionate A solution of t-Butyl 2 (S) -benzyloxycarbonylamino- 3- [ [2- (4-triazobutyl) -1, 3, 4-thiadiazol-5- yl] carbonyl] aminopropionate (240 mg, 0.48 mmol), triphenylphosphme (125 mg, 0.46 mmol) in THF(10 ml) was heated to reflux for 3 hrs and then stirred at rt overnight. Water (10 mg, 0.55 mmol) was injected and the reaction mixture was stirred at rt for additional 24 hrs. Concentration followed by chromatography with a mixture >of CH2CI2, methanol and ammonium hydroxide gave the product as an oil(150 mg, 66% yield). X NMR(300MHz, DMSO-dδ) δl .28 ( s, 9H) , 1.40 (m, 2H) , 1.70 (m, 2H) , 2.54(t, 2H) , 3.10(t, 2H) , 3.72 (m, IH) , 3.84(m, IH) , 4.20 (m, IH) , 5.00(s, 2H) , 7.30 (m, 5H) , 7.76(d, IH) ; MS(ESI) Calc. for (M+l)+: 478. Found: 478. Part E. t-Butyl 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [ (N-imidazolin-2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionate A mixture of t-Butyl 2 (S) benzyloxycarbonylamino -3- [ [2- (4-triazobutyl) -1, 3, 4-thiadiazol-5- yl] carbonyl] aminopropionate (100 mg, 0.21 mmol) and 2- imidazolidinethione hydrogen iodide (61 mg, 0.25 mmol) in pyridine (5 mL) was stirred at 70 _C for 3 hrs. Concentration and chromatography with a mixture of CH2CI2 and methanol as the eluent gave the product as an amorphous solid(60 mg, 53% yield). 1 H NMR(300MHz, DMSO-d6)δl.28(s, 9H) , 1.5 (m, 2H) , 1.76(m, 2H) , 3.10(t, 2H) , 3.42(m, 2H) , 3.60(m, 2H) , 4.20 (m, IH) , 5.00(s, 2H) , 7.30(m, 5H) , 7.78(d, IH) , 8.20(t, IH) , 9.20(t, IH) ; MS.(ESI) Calc. for (M+l)+: 546. Found: 546. Part E, 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [ (N- imidazolin-2-yl) amino] butyl] -1,3, 4-thiadiazol- 5-yI] carbonyl] aminopropionic acid TFA salt t-Butyl, 2 (S) -benzyloxycarbonylamino-3- [ [2- [4- [ (N- imidazolin-2-yl) amino] butyl] -l,3,4-thiadiazol-5- yl] carbonyl] aminopropionate ( 100 mg, 0.18 mmol) was dissolved in CH2CI2 containg 0.25 mL of TFA. The solution was stirred at rt for 24 hrs. Concentration gave the product(80 mg, 89% yield). X NMR(300MHz, DMSO-d6) . δl.56(m, 2H) , 1.86(m, 2H) , 3.16(m, 4H) , 3.54 (m, IH) , 3.5δ(s, 4H) , 3.66(m, IH) , .10 (m, IH) , 5.00(s, 2H) , 7.30(m, 5H) , 7.76(d, IH) , 8.16(t, IH) , 9.10(t, IH) ; MS(ESI) Calc. for (M+l) + : 491. Found: 491. Example 327 2 (S)- (2,4, 6-Trimethylphenylsulfonyl)amino-3-[ [2- [4- [ (N- imidazolin-2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt This compound was analogously synthesized to Example 321. !H NMR (300MHz, DMSO-d6) 1.54 (m, 2H) , 1.76(m, 2H) , 2.20(s, 3H), 2.60(s, 6H) , 3.10(m, 4H) , 3.42(m, IH) , 3.60 (m, IH), 3.62(s, 4H) , 4.20 (m, IH) , 6.96(s, 2H) , 7.40(d, 2H) 7.7δ(d, IH) , 8.20(t, IH) , 9.20(t, IH) ; MS(ESI) Calc. for (M+l) + : 538. Found: 538. Example 330 2 (S) - (1-Naphthalenesulfonyl) amino-3- [ [2- [4- [ (N- imidazolin-2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt This compound was analogously synthesized to Example 321. X NMR(300MHz, DMSO-d6 ) δl .56 (m, 2H) , 1.74 (m, 2H) , 3.14 (m, 4H), 3.38(m, IH) , 3.48(m, IH) , 3.56(s, 4H) , 4.08 (m, IH), 7.60 (m, 4H) , 7.98(d, IH) , 8.06(d, IH) , 8.16(m, 2H) , 8.58(d, IH) , 8.70(d, IH) , 9.12(t, IH) ; MS(ESI) Calc. for (M+l) + : 546. Found: 546. Table 1 Ex. R--U __} n R 8 R9 MS No. tetrahydropyrimidin 3 1 H H 1 -2-ylamιno tetrahydropyrimidin 3 1 H NHCbz 2 -2-ylammo tetrahydropyrimidin 3 1 H NHtBOC 3 -2-ylamιno tetrahydropyrimidin 3 1 H NHC0 2 -nBu 4 -2-ylamιno tetrahydropyrimidin 3 1 H NHCθ2Et 5 -2-ylammo tetrahydropyrimidin 3 1 H NHC02Me 6 -2-ylamιno tetrahydropyrimidin 3 1 H NHCO(CH 2 ) n Ph 7 -2-ylamιno tetrahydropyrimidin 3 1 H NHCOtBu -2-ylamιno tetrahydropyrimidin 3 1 H NHCO-n-C5hχχ 9 -2-ylamιno tetrahydropyrimidin 3 1 H NHCO-n-C4Hg 10 -2-ylamιno tetrahydropyrimidin 3 1 H NHCOCH2CH3 11 -2-ylammo tetrahydropyrimidin 3 1 H NHCOCH3 12 -2-ylamιno tetrahydropyrimidin 3 1 H NHSO2CH3 13 -2-ylammo tetrahydropyrimidin 3 1 H NHSO2CH2CH3 14 -2-ylamιno tetrahydropyrimidin 3 1 H NHSθ2n-Bu 15 -2-ylammo Ex. R!-U R 8 R 9 MS No. tetrahydropyrimidin 3 H NHSθ2Ph 16 -2-ylamιno tetrahydropyrimidin 3 H NHSO2C6H4 (4-CH3) 17 -2-ylammo tetrahydropyrimidin 3 1 H NHS0 2 Bn 18 -2-ylamιno tetrahydropyrimidin 3 1 H NHCO(2-pyrιdyl) 19 -2-ylamιno tetrahydropyrimidin 3 1 H NHCO(3-pyπdyl) 0 -2-ylamιno tetrahydropyrimidin 3 1 H NHCO(4-pyndyl) 1 -2-ylamιno tetrahydropyrimidin 3 1 H NHCOCH2 (2-pyrιdyl) 2 -2-ylammo tetrahydropyrimidin 3 1 H NHCOCH2 ( 3-pyπdyl ) 3 -2-ylammo tetrahydropyrimidin 3 1 H NHCOCH2 (4-pyrιdyl) 4 -2-ylammo tetrahydropyrimidin 3 1 H HCO2CH2 (2-pyrιdyl) 5 -2-ylamιno tetrahydropyrimidin 3 1 H NHCO2CH2 (3-pyπdylj 26 -2-ylammo tetrahydropyrimidin 3 1 H NHCO2CH2 (4-pyrιdyl) 27 -2-ylamιno ιmι azolιn-2- 3 1 H H 28 ylamino 29 ιmιdazOlιn-2- 3 1 H NHCbz ylamino ιmιdazolιn-2- 3 1 H NHtBOC 30 ylammo ιmιdazolιn-2- 3 1 H NHC0 2 -nBu 31 ylamino ιmιdazolm-2- 3 1 H NHC0 2 Et 32 ylammo ιmιdaz'olιn-2- 3 1 H NHCθ2Me 33 ylamino ιmιdazolm-2- 3 1 H NHCO(CH 2 ) n Ph 34 ylamino ιmιdazolιn-2- 3 1 H NHCOtBu 35 ylamino Ex. R 1 -U R 8 R 9 MS No. ιmιdazolιn-2- 3 1 H NHCO-n-C5Hχχ 36 ylammo ιmιdazolιn-2- 3 1 H NHCO-n-C 4 H9 37 ylamino ιmιdazolm-2- 3 1 H NHCOCH2CH3 38 ylamino ιmιdazolm-2- 3 1 H NHCOCH3 39 ylamino ιmιdazolm-2- 3 1 H NHSO2CH3 40 ylamino imidazolin-2- 3 1 H NHSO2CH2CH3 41 ylamino imidazolin-2- 3 1 H NHSθ2n-Bu 42 yla ino imidaz.olin-2- 3 1 H NHS02Ph 496 43 yla ino imidazolin-2- 3 1 H NHSO2C6H4 (3-CH3) 510 44 ylamino imidazolin-2- 3 1 H NHS02Bn 45 ylamino imidazolin-2- 3 1 H NHCO(2-pyridyl) 46 ylamino imidazolin-2- 3 1 H NHCO (3-pyridyl) 47 yla ino imidazolin-2- 3 1 H NHCO (4 -pyridyl) 48 ylamino imidazolin-2- 3 1 H NHCOCH2 (2-pyridyl) 49 ylamino imidazolin-2- 3 1 H NHCOCH2 ( 3-pyridyl ) 50 ylamino imidazolin-2- 3 1 H NHCOCH2 ( 4 -pyridyl ) 51 ylamino ιmidazolin-2- 3 1 H NHCO2CH2 (2-pyridyl) 52 ylamino imidazolin-2- 3 1 H NHC0 2 CH 2 ( 3-pyridyl ) 53 ylamino imidazolin-2- 3 1 H NHCO2CH2 (4-pyridyl) 54 ylamino tetrahydropyrimidin H H 55 -2-ylamino Ex. R 1 -U m n R8 R9 MS No. tetrahydropyrimidin 0 H NHCbz 56 -2-ylamino tetrahydropyrimidin 0 H NHtBOC 57 -2-ylamino tetrahydropyrimidin 0 H NHC0 2 -nBu 58 -2-ylamino tetrahydropyrimidin 0 H NHCθ2Et 59 -2-ylamino tetrahydropyrimidin 0 H NHC02Me 60 -2-ylamino tetrahydropyrimidin 0 H NHCO(CH2) n Ph 61 -2-ylamino tetrahydropyrimidin 0 H NHCOtBu 62 -2-ylamino tetrahydropyrimidin 0 H NHCO-n-C5Hχχ 63 -2-ylamino tetrahydropyrimidin 4 0 H NHCO-n-C 4 H9 64 -2-ylamιno tetraihydropyrimidm 4 0 H NHCOCH2CH3 65 -2-ylamιno tetrahydropyrimidin 4 0 H NHCOCH3 66 -2-ylamιno tetrahydropyrimidin 4 0 H NHSO2CH3 67 -2-ylamιno tetrahydropyrimidin 4 0 H NHSO2CH2CH3 68 -2-ylamιno tetrahydropyrimidin 4 0 H NHSθ2n-Bu 69 -2-ylamιno tetrahydropyrimidin 4 0 H NHSθ2Ph 70 -2-ylam no tetrahydropyrimidin 4 0 H NHSO2C6H4 (4-CH3) 71 -2-ylammo tetrahydropyrimidin 4 0 H NHSθ2Bn 72 -2-ylammo tetrahydropyrimidin 4 0 H NHCO(2-pyndyi; 73 -2-ylamιno tetrahydropyrimidin 4 0 H NHCO(3-pyrιdyl) 74 -2-ylammo tetrahydropyrimidin 4 0 H NHCO(4-pyrιdyi; 75 -2-ylammo Ex^ R l_u m n R° R- MS No. tetrahydropyπmidin 4 0 H NHCOCH2 (2-pyπdyl) 76 -2-ylamino tetrahydropyrimidm 4 0 H NHCOCH2 (3-pyπdyl) 77 -2-ylammo tetrahydropyrimi .dm 4 0 H NHCOCH2 ( -pyridyl ) 78 -2-ylamιno tetrahydropyrimi .dm 4 0 H NHCO2CH2 ( 2-pyrιdyl ) 79 -2-ylam no tetrahydropyrimi .dm 4 0 H NHCO2CH2 (3-pyπdyl) 80 -2-ylammo tetrahydropyrimi .dm 4 0 H NHCθ2CH2(4-pyrιdyl) 81 -2-ylammo ιmιdazolm-2- 4 0 H H 82 ylamino ιmιdazolm-2- 4 0 NHCbz 83 ylamino ιmιdazolm-2- 4 0 NHtBOC 84 ylamino ιmιdazolm-2- 4 0 NHC0 2 -nBu 85 ylammo ιmιdazolm-2- 4 0 NHC02Et 86 ylamino imidazolin-2- 4 0 H NHCθ2Me 87 ylamino imidazolin-2- 4 0 H NHC0(CH2) n Ph 88 ylamino imidazolin-2- 4 0 H NHCOtBu 89 ylamino imidazolin-2- 4 0 H NHCO-n-C5Hχχ 90 ylamino imidazolin-2- 4 0 H NHCO-n-C 4 H9 91 ylamino imidazolin-2- 4 0 H NHCOCH2CH3 92 ylamino imidazolin-2- 4 0 H NHCOCH3 93 yla ino imidazolin-2- 4 0 H NHSO2CH3 94 ylamino imidazolin-2- 4 0 H NHSO2CH2CH3 95 ylamino Ex. X-U m n R» R- MS No. imidazolin-2- 4 0 H NHSθ2n-Bu 96 ylamino imidazolin-2- 4 0 H NHSθ2Ph 97 ylamino imidazolin-2- 4 0 H NHSO2C6H4 (4-CH3) 98 ylamino imidazolin-2- 4 0 H NHSθ2Bn 99 ylamino imidazolin-2- 4 0 H NHCO(2-pyridyl) 100 ylamino imidazolin-2- 4 0 H NHCO(3-pyridyl) 101 ylamino imidazolin-2- 4 0 H NHCO (4-pyridyl) 102 ylamino imidazolin-2- 4 0 H NHCOCH2 (2-pyridyl) 103 ylamino imidazolin-2- 4 0 H NHCOCH2 (3-pyridyl) 104 ylamino imidazolin-2- 4 0 H NHCOCH2 ( 4 -pyridyl ) 105 ylamiho imidazolin-2- 4 0 H NHCO2CH2 (2-pyridyl) 106 ylamino imidazolin-2- 4 0 H NHCO2CH2 (3-pyridyl) 107 ylamino imidazolin-2- 4 0 H NHCO2CH2 (4-pyridyl) 108 ylamino tetrahydropyrimidin 3 0 H H 109 -2-ylamino tetrahydropyrimidin 3 0 H NHCbz 110 -2-ylamino tetrahydropyrimidin 3 0 H NHtBOC 111 -2-ylamino tetrahydropyrimidin 3 0 H NHC0 2 -nBu 112 -2-ylamino tetrahydropyrimidin 3 0 H NHCθ2Et 113 -2-ylamino tetrahydropyrimidin 3 0 H NHCθ2Me 114 -2-ylamino tetrahydropyrimidin 3 0 H NHC0 ( CH2 ) n Ph 115 -2-ylamino Ex. R 1 -U m n R 8 R 9 MS No. 116 tetrahydropyrimidin 3 0 H NHCOtBu -2-ylamino 117 tetrahydropyrimidin 3 0 H NHCO-n-C5Hχχ -2-ylamino 118 tetrahydropyrimidin 3 0 H NHCO-n-C 4 H9 -2-ylamino 119 tetrahydropyrimidin 3 0 H NHCOCH2CH3 -2-ylamino 120 tetrahydropyrimidin 3 0 H NHCOCH3 -2-ylamino 121 tetrahydropyrimidin 3 0 H NHSO2CH3 -2-ylamino 122 tetrahydropyrimidin 3 0 H NHSO2CH2CH3 -2-ylamino 123 tetrahydropyrimidin 3 0 H NHS02n-Bu -2-ylamino 124 tetrahydropyrimidin 3 0 NHS02P -2-ylamino 125 tetrahydropyrimidin 3 0 H NHSO2C6H (4-CH3) -2-ylamino 126 tetrahydropyrimidin 3 0 H NHSθ2Bn -2-ylamino 127 tetrahydropyrimidin 3 0 H NHCO(2-pyridyl) -2-ylamino 128 tetrahydropyrimidin 3 0 NHC0(3-pyridyl) -2-ylamino 129 tetrahydropyrimidin 3 0 NHCO (4 -pyridyl) -2-ylamino 130 tetrahydropyrimidin 3 0 H NHCOCH2 ( 2-pyridyl ) -2-ylamino 131 tetrahydropyrimidin 3 0 NHCOCH2 (3-pyridyl) -2-ylamino 132 tetrahydropyrimidin 3 0 H NHCOCH2 ( 4 -pyridyl ) -2 -ylamino 133 tetrahydropyrimidin 3 0 H NHCO2CH2 (2-pyπdyl) -2-ylammo 134 tetrahydropyrimidin 3 0 H NHC02CH 2 (3-pyrιdyl) -2-ylammo 135 tetrahydropyrimidin 3 0 H NHCO2CH2 (4 -pyridyl) -2-ylammo Ex. R 1 -U m n R 8 R 9 MS No. 136 ιmιdazolm-2- 3 0 H H ylammo 137 ιmιdazolm-2- 3 0 H NHCbz ylamiho 138 ιmιdazolm-2- 3 0 H NHtBOC ylammo 139 ιmιdazolm-2- 3 0 H NHC0 2 -nBu ylammo 140 ιmιdazolm-2- 3 0 H NHCθ2Et ylammo 141 ιmιdazolm-2- 3 0 H NHC02Me ylamino 142 ιmιdazolm-2- 3 0 H NHC0(CH2) n Ph ylammo 143 ιmιdazolm-2- 3 0 H NHCOtBu ylammo 144 ιmιdazolm-2- 3 0 H NHCO-n-C5Hχχ ylammo 145 ιmιdazolm-2- 3 0 H NHC0-n-C4H9 ylammo 146 ιmιdazolm-2- 3 0 H NHCOCH2CH3 ylammo 147 ιmιdazolm-2- 3 0 H NHCOCH3 ylammo 148 ιmιdazolm-2- 3 0 H NHSO2CH3 yla mo 149 ιmιdazolm-2- 3 0 H NHSO2CH2CH3 ylammo 150 ιmιdazolm-2- 3 0 H NHSθ2n-Bu ylammo 151 ιmιdazolm-2- 3 0 H NHS02Ph ylammo 152 ιmιdazolm-2- 3 0 H NHSO2C6H4 (4-CH3) ylamino 153 ιmιdazolm-2- 3 0 H NHSθ2Bn ylammo 154 ιmιdazolιn-2- 3 0 H NHCO(2-pyrιdyl) ylammo 155 ιmιdazolm-2- 3 0 H NHCO(3-pyrιdyl) ylammo E_x R l_ 0 R 8 R 9 MS No . i 156 imidazolin-2- 3 0 H NHCO (4-pyridyl) ylamino 157 imidazolin-2- 3 0 H NHCOCH2 (2-pyridyl) ylamino 158 imidazolin-2- 3 0 H NHCOCH2 (3-pyridyl) ylamino 159 imidazolin-2- 3 0 H NHCOCH2 ( 4 -pyridyl ) ylamiήo 160 imidazolin-2- 3 0 H NHCO2CH2 ( 2-pyridyl ) yla ino 161 imidazolin-2- 3 0 H NHCO2CH2 ( 3-pyridyl ) ylamino 162 imidazolin-2- 3 0 H NHCO2CH2 ( 4 -pyridyl ) ylamino 163 4 , 1, 3-oxadiazin-2- 4 0 H NHCbz ylamino 164 4, 1, 3-oxadiazin-2- 4 0 H NHCθ2-n-Bu ylamino 165 4 , 1, 3-oxadiazin-2- 4 0 H NHSθ2Ph ylamino 166 4 , 1, 3-oxadiazin-2- 4 0 H NHSθ2-n-Bu ylamino 167 4, 1, 3-roxadiazin-2- 3 1 H NHCbz ylamino 168 4 , 1, 3-oxadiazin-2- 3 1 H NHC02-n-Bu ylamino 169 4, 1, 3-oxadiazin-2- 3 1 H HSθ2Ph ylamino 170 4 , 1, 3-oxadiazin-2- 3 1 H NHSθ2-n-Bu ylamino 172 pyridin-2-ylamino 3 1 NHCbz 173 pyridin-2-ylamino 3 1 H NHCθ2-n-Bu 174 pyridin-2-ylamino 3 1 NHS02Ph 175 pyridin-2-ylamino 3 1 H NHSθ2-nBu 176 pyridin-2-ylamino 4 0 499 NHCbz Ex. R -U R« R- MS No. 177 pyridin-2-ylamino NHCθ2-n-Bu 178 pyridin-2-ylamino 4 0 547 (2, 4, 6-trimethylph- enylsulfonyl) amino 179 pyridin-2-ylamino 555 ( 1-naphthalenesul- fonyl) amino 180 pyridin-2-ylamino 33 00 H NHCbz 181 pyridin-2-ylamino 33 00 H NHCθ2-n-Bu 182 pyridin-2-ylamino 3 Ό NHS02?h 183 pyridin-2-ylamino 33 00 H NHSθ2-nBu 184 imidazol-2-ylamino 3 1 H NHCbz 185 imidazol-2-ylamino 3 1 H NHC02-n-Bu 186 imidazol-2-ylamino 3 1 H NHSθ2Ph 187 imidazol-2-ylamino 3 1 H NHSθ2-nBu 188 imidazol-2-ylamino 4 4 0 NHCbz 189 imidazol-2-ylamino 4 4 0 NHCθ2~n-Bu 190 imidazol-2-ylamino 4 0 NHSθ2Ph 191 imidazol-2-ylamino 4 0 NHSθ2~nBu 192 imidazol-2-ylamino 3 0 NHCbz 193 imidazol-2-ylamino 3 3 0 0 H NHCθ2-n-Bu 194 imidazol-2-ylamino 3 3 0 0 H NHS02Ph 195 imidazol-2-ylamino 3 0 NHSθ2~nBu 196 thiazpl-2-ylamino 3 1 NHCbz Ex. R 1 -U m R 9 MS No. 197 2-aminopyridin-6-yl H NHCθ2-n-Bu 198 2-aminopyridin-6-yl NHSθ2Ph 199 2-aminopyridin-6-yl NHSθ2-nBu 200 2-aminopyridin-6-yl 4 0 H NHCbz 201 2-aminopyridin-6-yl 4 0 H NHCθ2~n-Bu 202 2-aminopyridin-6-yl 4 0 H NHS02Ph 203 2-aminopyridin-6-yl 4 0 H NHSθ2-nBu 204 2-aminopyridin-6-yl 3 0 H NHCbz 205 2-aminopyridin-6-yl 3 0 H NHC02~n-Bu 206 2-amihopyridin-6-yl 3 0 H NHS0 2 Ph 207 2-aminopyridin-6-yl 3 0 H NHSθ2-nBu 208 2-aminopyridin-3-yl 2 0 H NHCbz 209 2-aminopyridin-3-yl 2 0 H NHCθ2-n-Bu 210 2-aminopyridin-3-yl 2 0 H NHSθ2Ph 211 2-aminopyridin-3-yl 2 0 H NHS02-nBu 212 2-aminothiazol-4-yl 3 1 H NHCbz 213 2-aminothiazol-4-yl 3 1 H NHC02-n-Bu 214 2-aminothiazol-4-yl 3 1 H NHSθ2Ph 215 2-aminothiazol-4-yl 3 1 H NHSθ2~nBu 216 2-aminothiazol-4-yl 4 0 H NHCbz Ex . R 1 - U m n R 8 R 9 MS No . 217 2-aminothiazol-4-yl 4 0 H NHCθ2-n-Bu 218 2-aminothiazol-4-yl 4 0 H NHS02Ph 219 2-aminopyridin-6-yl 4 0 H NHSθ2-nBu 220 2-aminothiazol-4-yl 3 0 H NHCbz 221 2-aminothiazol-4-yl 3 0 H NHCθ2-n-Bu 222 2-aminothiazol-4-yl 3 0 H NHSθ2Ph 223 2-aminothiazol-4-yl NHSθ2~nBu 224 2-aminothiazol-4-yl H NHCbz 2-aminothiazol-4- -yl 3 1 H NHC02-n-Bu 226 1, 3, 4-thiadiazol- -2- 3 1 H ylamino NHS02Ph 227 1, 3, 4-thiadiazol- -2- 3 1 H ylamino NHSθ2~nBu 228 1, 3, 4-thiadiazol- -2- 4 0 H ylamino NHCbz 229 1, 3, 4-thiadiazol- -2- 4 0 H ylamino NHCθ2-n-Bu 230 1, 3, 4-thiadiazol- -2- 4 0 H ylamino NHSθ2P 231 1, 3, 4-thiadiazol- -2- 4 0 H ylamino NHSθ2~nBu 232 1, 3, 4-thiadiazol- -2- 3 0 H ylamino NHCbz 233 1, 3, 4-thiadiazol- -2- 3 -0 H ylamino NHCθ2-n-Bu 234 1,3, 4-thiadiazol- -2- 3 0 H ylamino NHS02Ph 235 1, 2, 4-thiadiazol- -5- 3 0 H ylamino NHSθ2~nBu 236 1,2, 4-thiadiazol- -5- 3 1 H ylamino NHCbz Ex. R 1 -U m n R 8 R 9 MS No. 237 1,2, 4-thiadiazol-5- 3 1 H NHCθ2-n-Bu ylamino 238 1, 2, 4-thiadiazol-5- 3 1 H NHSθ2Ph ylam^no 239 1, 2, 4-thiadiazol-5- 3 1 H NHSθ2~nBu ylamino 240 1,2, 4-thiadiazol-5- 4 0 H ylamino NHCbz 241 1,2, 4-thiadiazol-5- 4 0 H NHCθ2~n-Bu ylamino 242 1,2, 4-thiadiazol-5- 4 0 H NHS02Ph ylamino 243 1, 2, 4-thiadiazol-5- 4 0 H NHSθ2~nBu ylamino 244 1,2, 4-thiadiazol-5- 3 0 H ylamino NHCbz 245 1, 2, 4-thiadiazol-5- 3 0 H NHC02-n-Bu ylamino 246 1,2, 4-thiadiazol-5- 3 0 H ylamino NHS02Ph 247 isoxazol-3-ylamino 3 0 H NHSθ2-nBu 248 isoxazol-3-ylamino 3 1 H NHCbz 249 isoxazol-3-ylamino 3 1 H NHC02-n-Bu 250 isoxazol-3-ylamino 3 1 H NHS02Ph 251 isoxazol-3-ylamino 3 -1 H NHSθ2-nBu 252 isoxazol-3-ylamino 4 0 H NHCbz 253 isoxazol-3-ylamino 4 0 H NHC02-n-Bu 254 isoxazol-3-ylamino 4 0 H NHS02Ph 255 isoxazol-3-ylamino 4 0 H NHSθ2~nBu 256 isoxazol-3-ylamino 3 0 H NHCbz Ex. R x -U m n R 8 R 9 MS No. 257 isoxazol-3-ylamino 3 0 H NHCθ2-n-Bu 258 isoxazol-3-ylamino 3 ~ 0 H NHSθ2Ph 259 oxazol-2-ylamino 3 0 H NHSθ2-nBu 260 oxazol-2-ylamino 3 1 H NHCbz 261 oxazol-2-ylamino 3 1 H NHCθ2~n-Bu 262 oxazol-2-ylamino 3 1 H NHS02Ph 263 oxazol-2-ylamino 3 1 H NHSθ2-nBu 264 oxazol-2-ylamino 4 0 H NHCbz 265 oxazol-2-ylamino 4 0 H NHCθ2-n-Bu 266 oxazol-2-ylamino 4 0 H NHSθ2Ph 267 oxazol-2-ylamino 4 0 H NHSθ2-nBu 268 oxazol-2-ylamino 3 0 H NHCbz 269 oxazol-2-ylamino 3 0 H NHCθ2-n-Bu 270 oxazol-2-ylamino 3 0 H NHSθ2Ph 271 oxazol-2-ylamino 3 0 H NHSθ2-nBu 272 1,2, 5-thiadiazol-3- 3 1 H ylamino NHCbz 273 1,2, 5-thiadiazol-3- 3 1 H ylamino NHCθ2-n-Bu 274 1,2, 5-thiadiazol-3- 3 1 H ylamino NHS02Ph 275 1,2, 5-thiadiazol-3- 3 1 H ylamino NHSθ2-nBu 276 1,2, 5-thiadiazol-3- 4 0 H ylamino NHCbz Ex. R 1 -U m n R 8 No. R 9 MS 277 1, 2, 5-thiadiazol-3- 4 0 H ylammo NHCθ2-n-Bu 278 1,2, 5-thiadiazol-3- 4 0 H ylamlno NHSθ2Ph 279 1,2, 5-thiadiazol-3- 4 0 H ylamino NHSθ2~nBu 280 1,2, 5-thiadiazol-3- 3 0 H ylamino NHCbz 281 1,2, 5-thiadiazol-3- 3 0 H ylamino NHCθ2-n-Bu 282 1, 2, l 5-thiadiazol-3- 3 0 H ylamino NHSθ2Ph 283 1, 2, 5-thiadiazol-3- 3 0 H ylammo NHSθ2-nBu 284 imidazolin-2- 2 2 H ylamino NHCbz 285 imidazolin-2- 2 2 H ylamino NHCθ2-n-Bu 286 imidazolin-2- 2 2 H ylamino NHS02Ph 287 imidazolin-2- 2 2 H ylamino NHS02-nBu 288 tetrahydropyrimidin 2 2 H -2-ylamino NHCbz 289 tetrahydropyrimidin 2 2 H NHCθ2-n-Bu -2-ylamino 290 tetrahydropyrimidin 2 2 H -2-ylamino NHSθ2Ph 291 tetrahydropyrimidin 2 2 H -2-ylamino NHSθ2-nBu 292 benzimidazol-2- 4 0 H ylamino NHCbz 293 benzthiazol-2- 4 0 H ylamino NHCbz 294 1, 2-pyrazol-3- 4 0 H ylamino NHCbz 295 1, 2, 4-trιazol-5- 4 0 H ylamino NHCbz 296 imidazol-4-ylamino 4 0 H NHCbz Ex. - R 1 -U m n R 8 MS No. R 9 297 1, 3, 4-oxadiazol-2- 4 0 H ylamino NHCbz 298 1, 2, 4-thiadiazol-5- 4 0 H ylamino NHCbz 299 1, 2, 4-thiadiazol-3- 4 0 H ylamino NHCbz 300 1, 2, 5>-oxadiazol-3- 4 0 H ylamino NHCbz 301 1, 2, 4-oxadiazol-5- 4 0 H ylamino NHCbz 302 1, 2, 4-oxadiazol-3- 4 0 H ylamino NHCbz 303 2-iminopyrrolidin- 3 1 H 5-yl NHCbz 304 2-imihopyrrolidin- 3 1 H 5-yl NHS0 2 Ph 305 2-iminopyrrolidin- 3 0 H 5-yl NHCbz 306 2-iminopyrrolidin- 3 0 H 5-yl NHS0 2 Ph 307 2-iminopyrrolidin- 2 1 H 5-yl NHCbz 308 2-iminopyrrolidin- 2 1 H 5-yl NHS0 2 Ph 309 2-iminopiperidin-6- 3 1 H yi NHCbz 310 2-imιnopιperidin-6- 3 1 H NHS0 2 Ph yi 311 2-iminopiperidin-6- 3 0 H yi NHCbz 312 2-iminopiperidin-6- 3 0 H NHS0 2 Ph yi 313 2-iminopiperidin-6- 2 1 H yi NHCbz 314 2-iminopiperidin-6- 2 1 H NHS0 2 Ph yi 315 2-iminoa zepin-7-yl NHCbz 316 2-iminoazepin-7 -yl NHS0 2 Ph Ex . R x -U m R- MS No . 317 2-iminoazepin-7-yl 3 0 H NHCbz 318 2-iminoazepin-7-yl 3 0 H NHS0 2 Ph 319 2-iminoazepin-7-yl 2 1 H NHCbz 320 2-iminoazepin-7-yl 2 1 H NHS0 2 Ph 321 imidazplin-2- 4 0 H 491 ylamino NHCbz 322 benzthiazol-2- 4 0 n-Bu ylamino H 323 1, 2-pyrazol-3- 4 0 n-Bu ylamino H 324 1,2, 4-triazol-5- 4 0 n-Bu ylamino H 325 imidazol-4-ylamino 4 0 n-Bu H 326 1, 3, 4-oxadiazol-2- 4 0 n-Bu ylamino H 327 imidazolin-2- 4 0 H 53i ylamino (2,4, 6-trimethylp enylsulfonyl ) am 328 1,2, 4-thiadiazol-3- 4 0 n-Bu ylamino H 329 1, 2, 5-oxadiazol-3- 4 0 n-Bu ylamino H 330 imidazolin-2- 4 0 H 546 ylamino ( 1-naphthalenesul phonylamino 331 1, 2, 4-oxadiazol-3- n-Bu ylamino Table 2 Ex . R x -U R 8 R 16 MS No. 501 tetrahydropyrimidin 3 1 H H -2-ylamino 502 tetrahydropyrimidin 3 1 H NHCbz -2-ylamino 503 tetrahydropyrimidin 3 1 H NHtBOC -2-ylamino 504 tetrahydropyrimidin 3 1 H NHC0 2 -nBu -2-ylamino 505 tetrahydropyrimidin 3 1 H NHC02Et -2-ylamino 506 tetrahydropyrimidin 3 1 H NHCθ2Me -2-ylamino 507 tetrahydropyrimidin 3 1 H NHCO(CH2) n Ph -2-ylamino 508 tetrahydropyrimidin 3 1 H NHCOtBu -2-ylamino 509 tetrahydropyrimidin 3 1 H NHCO-n-C5Hχχ -2-ylamino 510 tetrahydropyrimidin 3 1 H NHCO-n-C4H9 -2-y amino 511 tetrahydropyrimidin 3 1 H NHCOCH2CH3 -2-ylamino 512 tetrahydropyrimidin 3 1 H NHCOCH3 -2-ylamino 513 tetrahydropyrimidin 3 1 H NHSO2CH3 -2-ylamino 514 tetrahydropyrimidin 3 1 H NHSO2CH2CH3 -2-ylamino 515 tetrahydropyrimidin 3 1 H NHS02n-Bu -2-ylamino Ex. R 1 -U m R« R 16 MS No . 516 tetrahydropyrimidin H NHSθ2Ph -2-ylamino 517 tetrahydropyrimidin H HSO2C6H4 (4-CH3) -2-ylamino 518 tetrahydropyrimidin 3 1 H NHSθ2Bn -2-ylamιno 519 tetrahydropyrimidin 3 1 H NHCO ( 2-pyπdyl ) -2-ylamιno 520 tetr'ahydropyπmidm 3 1 H NHCO(3-pyrιdyl) -2-ylammo 521 tetrahydropyrimidin 3 1 H NHC0(4-pyrιdyl) -2-ylammo 522 tetrahydropyrimidin 3 1 H NHCOCH2 (2-pyπdyl) -2-ylamιno 523 tetrahydropyrimidin 3 1 H NHC0CH2 (3-pyrιdyl) -2-ylamιno 524 tetrahydropyrimidin 3 1 H NHC0CH2 (4-pyrιdyl) -2-ylammo 525 tetrahydropyrimidin 3 1 H NHCO2CH2 (2-pyrιdyl) -2-ylammo 526 tetrahydropyrimidin 3 1 H NHCO2CH2 (3-pyrιαyl) -2-ylammo 527 tetrahydropyrimidin 3 1 H NHCO2CH2 ( 4 -pyridyl ) -2-ylammo 528 ιmιdazolm-2- 3 1 H H ylammo 529 mιdazolm-2- 3 1 H NHCbz ylaiino 530 ιmιdazolm-2- 3 1 H NHtBOC ylammo 531 ιmιdazolιn-2- 3 1 H NHC0 2 -nBu ylamino 532 ιmιdazolm-2- 3 1 H NHCθ2Et ylamino 533 ιmιdazolm-2- 3 1 H NHC02Me ylammo 534 ιmιdazolm-2- 3 1 H NHCO(CH2) n Ph ylamino 535 ιmιdazolιn-2- 3 1 H NHCOtBu ylamino Ex. R 1 -U m n R 8 R 16 MS No. 536 ιmιdazolιn-2- 3 1 H NHC0-n-C5Hχχ ylamino 537 ιmιdazolm-2- 3 1 H NHCO-n-C4Hg ylammo 538 ιmιdazolm-2- 3 1 H NHCOCH2CH3 ylammo 539 ιmιdazolιn-2- 3 1 H NHCOCH3 ylammo 540 ιmιdazolιn-2- 3 1 H NHSO2CH3 yla mo 541 imidazolin-2- 3 1 H NHSO2CH2CH3 ylamino 542 imidazolin-2- 3 1 H NHSθ2n-Bu ylamino 543 imidazolin-2- 3 1 H NHS02Ph ylamino 544 imidazolin-2- 3 1 H NHSO2C5H (4-CH3) ylamino 545 imidazolin-2- 3 1 H NHSθ2Bn ylamino 546 imidazolin-2- 3 1 H NHC0(2-pyridyl) ylamino 547 imidazolin-2- 3 1 H NHC0(3-pyridyl) ylamino 548 imidazolin-2- 3 1 H NHC0(4-pyridyl) ylamino 549 imidazolin-2- 3 1 H NHC0CH (2-pyridyl) ylamino 550 imidazolin-2- 3 1 H NHCOCH2 (3-pyridyl) ylamino 551 imidazolin-2- 3 1 H NHCOCH2 (4-pyridyl) ylamino 552 imidazolin-2- 3 1 H NHCO2CH2 (2-pyridyl) ylamino 553 imidazolin-2- 3 1 H NHCO2CH2 (3-pyridyl) ylamj.no 554 imidazolin-2- 3 1 H NHCO2CH2 (4-pyridyl) ylamino 555 tetrahydropyrimidin 4 0 H H -2-ylamino Ex. R x -U m n R 8 R 16 MS No. 556 tetrahydropyrimidin 4 0 H NHCbz -2-ylamino 557 tetrahydropyrimidin 4 0 H NHtBOC -2-ylamino 558 tetrahydropyrimidin 4 0 H NHC0 2 -nBu -2-ylamino 559 tetrahydropyrimidin 4 0 H NHC02Et -2-ylamino 560 tetrahydropyrimidin 4 0 H NHCθ2Me -2-ylamino 561 tetrahydropyrimidin 4 0 H NHC0 ( CH2 ) n Ph -2-ylamino 562 tetrahydropyrimidin 4 0 H NHCOtBu -2-ylamino 563 tetrahydropyrimidin 4 0 H NHC0-n-C5Hχχ -2-ylamino 564 tetrahydropyrimidin 4 0 H NHCO-n-C4H9 -2-ylamino 565 tetrahydropyrimidin 4 0 H NHCOCH2CH3 -2-ylamino 566 tetrahydropyrimidin 4 0 H NHCOCH3 -2-ylamino 567 tetrahydropyrimidin 4 0 H NHSO2CH3 -2-ylamino 568 tetrahydropyrimidin 4 0 H NHSO2CH2CH3 -2-ylamino 569 tetrahydropyrimidin 4 0 H NHSθ2n-Bu -2-ylamino 570 tetrahydropyrimidin 4 0 H NHS02Ph -2-ylamino 571 tetrahydropyrimidin 4 0 H NHSO2C6H4 (4' -2-ylamino 572 tetrahydropyrimidin 4 0 H NHS02Bn -2-ylamino 573 tetrahydropyrimidin 4 0 H NHC0 ( 2-pyridyl ) -2-ylamino 574 tetrahydropyrimidin 4 0 H NHC0 ( 3-pyridyl ) -2-ylamino 575 tetrahydropyrimidin 4 0 H NHCO ( 4 -pyridyl ) -2-ylamino Ex. R 1 -U m R 16 MS No. 576 tetrahydropyrimidin 4 0 NHCOCH2 ( 2-pyridyl ) -2-ylamino 577 tetrahydropyrimidin 4 0 H NHCOCH2 ( 3-pyridyl ) -2-ylamino 578 tetrahydropyrimidin 4 0 H NHCOCH2 ( 4 -pyridyl ) -2-ylamino 579 tetrahydropyrimidin 4 0 H NHCO2CH2 ( 2-pyrιdyl ) -2-ylamino 580 tetrahydropyrimidin 4 0 H NHCO2CH2 ( 3-pyridyl ) -2-ylamino 581 tetrahydropyrimidin 4 0 H NHCO2CH2 ( -2-ylamino 582 imidazolin-2- 4 0 H H ylamino 583 imidazolin-2- 4 0 H NHCbz ylamino 584 imidazolin-2- 4 0 H NHtBOC ylamino 585 imidazolin-2- 4 0 H NHC0 2 -nBu ylamino 586 imidazolin-2- 4 0 H NHC02Et ylamino 587 ιmιdazolm-2- 4 0 H NHC02Me ylamino 588 ιmιda zolm-2- 4 0 H NHC0(CH2)n p h ylamino 58 9 ιmιdazolιn-2- 4 0 H NHCOtBu ylamino 590 ιmιdazolιn-2- 4 0 H NHC0-n-C5Hχχ ylammo 591 ιmιdazolm-2- 4 0 H NHCO-n-C4Hg ylammo 592 ιmιdazolm-2- 4 0 H NHCOCH2CH3 ylamino 593 ιmιdazolm-2- 4 0 H NHCOCH3 ylamino 594 ιmιdazolm-2- 4 0 H NHSO2CH3 ylam no 595 ιmιdazolm-2- 4 0 H NHSO2CH2CH3 ylam o Ex . R x -U m R 8 R 16 MS No . 596 ιmιdazolm-2- 4 0 H NHSθ2n-Bu ylammo 597 ιmιdazolm-2- 4 0 H NHSθ2Ph ylamino 598 ιmιdazolm-2- 4 0 H HSO2C6H4 (4-CH3) ylammo 599 ιmιdazolm-2- 4 0 H NHS02Bn ylamino 600 ιmιdazolm-2- 4 0 H NHCO(2-pyrιdyl) yla mo 601 ιmιdazolm-2- 4 0 H NHC0(3-pyrιdyl) ylammo 602 ιmιdazolm-2- 4 0 H NHCO(4-pyrιdyl) ylam o 603 ιmιdazolm-2- 4 0 H NHCOCH2 (2-pyrιdyl) ylammo 604 ιmιdazolιn-2- 4 0 H NHCOCH2 (3-pyrιdyl) ylamino 605 ιmιdazolm-2- 4 0 H NHCOCH2 (4-pyrιdyl) ylamino 606 ιmιdazolιn-2- 4 0 H NHCO2CH2 (2-pyπdyl) ylammo 607 ιmιdazolm-2- 4 0 H NHCO2CH2 (3-pyπdyl) ylamino 608 ιmιo^azolm-2- 4 0 H NHCO2CH2 ( 4 -pyridyl ) ylammo 609 tetrahydropyrimidin 3 0 H H -2-ylamιno 610 tetrahydropyrimidin 3 0 H NHCbz -2-ylamino 611 tetrahydropyrimidin 3 0 H NHtBOC -2-ylamino 612 tetrahydropyrimidin 3 0 H NHC0 2 -nBu -2-ylamino 613 tetrahydropyrimidin 3 0 H NHC02Et -2-ylamino 614 tetrahydropyrimidin 3 0 H NHC02Me -2-ylamino 615 tetrahydropyrimidin 3 0 H NHCO ( CH 2 ) n Ph -2-ylamino Ex. R 1 -U m R s R 16 MS No. 616 tetrahydropyrimidin 3 0 H NHCOtBu -2-ylamino 617 tetrahydropyrimidin 3 0 H NHC0-n-C5Hχχ -2-ylamino 618 tetrahydropyrimidin 3 0 H NHCO-n-C4Hg -2-ylamino 619 tetrahydropyrimidin 3 0 H NHCOCH2CH3 -2-ylamino 620 tetrahydropyrimidin 3 0 H NHCOCH3 -2-ylamino 621 tetrahydropyrimidin 3 0 H NHSO2CH3 -2-ylamino 622 tetrahydropyrimidin 3 0 H NHSO2CH2CH3 -2-ylamino 623 tetrahydropyrimidin 3 0 H NHSθ2n-Bu -2-ylamino 624 tetrahydropyrimidin 3 0 NHSθ2Ph -2-ylamino 625 tetrahydropyrimidin 3 0 H NHS02C 6 H4 (4- -2-ylamino 626 tetrahydropyrimidin 3 0 H NHSθ2Bn -2-ylamino 627 tetrahydropyrimidin 3 0 H NHCO ( 2-pyridyl ) -2-ylamino 628 tetrahydropyrimidin 3 0 H NHCO ( 3-pyridyl ) -2-ylamino 629 tetrahydropyrimidin 3 0 H NHCO ( 4 -pyridyl ) -2-ylamino 630 tetrahydropyrimidin 3 0 H NHCOCH2 ( 2-pyridyl ) -2-ylamino 631 tetrahydropyrimidin 3 0 H NHCOCH2 ( 3-pyridyl ) -2-ylamino 632 tetrahydropyrimidin 3 0 H NHCOCH2 ( 4 -pyridyl ) -2-ylamino 633 tetrahydropyrimidin 3 0 H NHCO2CH2 (2-pyridyl) -2-ylamino 634 tetrahydropyrimidin 3 0 H NHCO2CH2 (3-pyridyl) -2-ylamino 635 tetrahydropyrimidin 3 0 H NHCO2CH2 ( 4 -pyridyl ) -2-ylamino 636 imidazolin-2- 3 0 H H ylamino 637 imidazolin-2- 3 0 H NHCbz ylamino 638 imidazolin-2- 3 0 H NHtBOC ylamino 639 imidazolin-2- 3 0 H NHC0 2 -nBu ylamino 640 imidazolin-2- 3 0 H NHC02Et ylam^no 641 imidazolin-2- 3 0 H NHC02Me ylamino 642 imidazolin-2- 3 0 H NHCO(CH2) n Ph ylamino 643 imidazolin-2- 3 0 H NHCOtBu ylamino 644 imidazolin-2- 3 0 H NHCO-n-C5Hχχ ylamino 645 imidazolin-2- 3 0 H NHCO-n-C4Hg ylamino 646 imidazolin-2- 3 0 H NHCOCH2CH3 ylamino 647 imidazolin-2- 3 0 H NHCOCH3 ylamino 648 imidazolin-2- 3 0 H NHSO2CH3 ylami'no 649 imidazolin-2- 3 0 H NHSO2CH2CH3 ylamino 650 imidazolin-2- 3 0 H NHS02n-Bu ylamino 651 imidazolin-2- 3 0 H NHSθ2Ph ylamino 652 imidazolin-2- 3 0 H NHSO2C6H4 (4-CH3) ylammo 653 imidazolin-2- 3 0 H NHS02Bn ylamino 654 imidazolin-2- 3 0 H NHCO(2-pyridyl) ylamino 655 imidazolin-2- 3 0 H NHCO(3-pyridyl) ylamino Ex . R 1 -U m R 8 Rl6 MS No . 656 imidazolin-2- 3 0 H NHCO(4-pyridyl) ylamino 657 imidazolin-2- 3 0 H NHCOCH2 (2-pyridyl) ylamino 658 imidazolin-2- 3 0 H NHCOCH2 (3-pyridyl) ylamino 659 imidazolin-2- 3 0 H NHCOCH 2 ( 4 -pyridyl ) ylamino 660 imidazolin-2- 3 0 H NHCO2CH2 (2-pyridyl) ylamino 661 imidazolin-2- 3 0 H NHCO2CH2 (3-pyridyl) ylamino 662 imidazolin-2- 3 0 H NHCO2CH2 (4-pyridyl) ylaπiino 663 pyridin-2-ylamino 3 1 H NHCbz 664 pyridin-2-ylamino 3 1 H NHCθ2-n-Bu 665 pyridin-2-ylamino 3 1 H NHS02Ph 666 pyridin-2-ylamino 3 1 H NHSθ2-nBu 667 pyridin-2-ylamino 4 0 H NHCbz 668 pyridin-2-ylamino 4 0 H NHC02-n-Bu 669 pyridin-2-ylamino 4 0 H NHS02Ph 670 pyridin-2-ylamino 4 0 H NHSθ2-nBu 671 pyridin-2-ylamino 3 0 H NHCbz 672 pyridin-2-ylamino 3 0 H NHCθ2~n-Bu 673 pyridin-2-ylamino 3 0 H NHSθ2Ph 674 pyri 1 din-2-ylamino 3 0 H NHSθ2~nBu 675 imidazol-2-ylamino 3 1 H NHCbz Ex. R x -U > 16 MS No. 676 imidazol-2-ylamino NHCθ2-n-Bu 677 imidazol-2-ylamino NHSθ2P 678 imidazol-2-ylamino 3 1 H NHSθ2~nBu 679 imidazol-2-ylamino 4 0 H NHCbz 680 imidazol-2-ylamino 4 0 H NHCθ2-n-Bu 681 imidazol-2-ylamino 4 0 H NHSθ2Ph 682 imidazol-2-ylamino 4 Ό H NHS02-nBu 683 imidazol-2-ylamino 3 0 H NHCbz 684 imidazol-2-ylamino 3 0 H NHCθ2-n-Bu 685 imidazol-2-ylamino 3 0 H HSθ2Ph 686 imidazol-2-ylamino 3 0 H NHSθ2-nBu 687 thiazol-2-ylamino 3 1 H NHCbz 688 2-aminopyridin-6-yl 3 1 H NHCθ2-n-Bu 689 2-aminopyridin-6-yl 3 1 H NHSθ2Ph 690 2-aminopyridin-6-yl 3 1 H NHS0 2 -nBu 691 2-aminopyridin-6-yl 4 0 H NHCbz 692 2-aminopyridin-6-yl 4 0 H NHCθ2~n-Bu 693 2-aminopyridin-6-yl 4 0 H NHSθ2Ph 694 2-aminopyridin-6-yl 4 0 H NHSθ2~nBu 695 2-aminopyridin-6-yl 3 0 H NHCbz Ex. R x -U m n R 8 R 16 MS No. 696 2-aminopyridin-6-yl 3 0 H NHC02-n-Bu 697 2-aminopyridin-6-yl 3 0 H NHS02Ph 698 2-aminopyridin-6-yl 3 0 H NHS02~nBu 699 2-aπtinopyridin-3-yl 2 0 H NHCbz 700 2-aminoρyridin-3-yl 2 0 H NHC02-n-Bu 701 2-aminopyridin-3-yl 2 0 H NHSθ2Ph 702 2-aminopyridin-3-yl 2 0 H NHSθ2-nBu 703 2-aminothiazol-4-yl 3 1 H NHCbz 704 2-aminothiazol-4-yl 3 1 H NHCθ2~n-Bu 705 2-aminothiazol-4-yl 3 1 H NHS02Ph 706 2-aminothiazol-4-yl 3 1 H NHSθ2-nBu 707 2-aminothiazol-4-yl 4 0 H NHCbz 708 2-aminothiazol-4-yl 4 0 H NHCθ2-n-Bu 709 2-aminothiazol-4-yl 4 0 H NHS02Ph 710 2-am . inopyridin-6-yl 4 0 H NHSθ2-nBu 711 2-aminothiazol-4-yl 3 0 H NHCbz 712 2-aminothiazol-4-yl 3 0 H NHCθ2-n-Bu 713 2-aminothiazol-4-yl 3 0 H NHSθ2Ph 714 2-aminothiazol-4-yl 3 0 H NHS02-nBu 715 2-aminothiazol-4-yl 3 1 H NHCbz Ex. R x -U m n R 8 R 16 MS No. 716 2-aminothiazol-4-yl 3 1 H NHCθ2-n-Bu 717 1, 3, l 4-thiadiazol-2- 3 1 H NHSθ2Ph ylamino 718 l,3,4-thiadiazol-2- 3 1 H NHSθ2~nBu ylamino 719 1, 3, 4-thiadiazol-2- 4 0 H NHCbz ylamino 720 1, 3, 4-thiadiazol-2- 4 0 H NHCθ2-n-Bu ylamino 721 1, 3,4-thiadiazol-2- 4 0 H NHS02Ph ylamino 722 1, 3, 4-thiadiazol-2- 4 0 H NHSθ2~nBu ylamino 723 1,3, 4-thiadiazol-2- 3 0 H NHCbz ylamino 1,3, 4-thiadiazol-2- 3 0 H NHCθ2-n-Bu ylamino 1, 3, 4-thiadiazol-2- 3 0 H NHSθ2Ph ylamino 1,2, 4-thiadiazol-5- 3 0 H NHSθ2-nBu ylamino 1 , 2, 4-thiadiazol-5- 3 1 H NHCbz ylamino 1,2, 4-thiadiazol-5- 3 1 H NHCθ2-n-Bu ylamino 1, 2, 4-thiadiazol-5- 3 1 H NHS02Ph ylamino 1,2, 4-thiadiazol-5- 3 1 H NHSθ2-nBu ylamino 1,2, 4-thiadiazol-5- 4 0 H NHCbz ylamino 1, 2 4-thiadiazol-5- 4 0 H NHCθ2-n-Bu ylamino 1, 2, 4-thiadiazol-5- 4 0 H NHS02Ph ylamino 1,2, 4-thiadiazol-5- 4 0 H NHSθ2-nBu ylamino 1,2, 4-thiadiazol-5- 3 0 H NHCbz ylamino Ex. X-ϋ ,16 MS No. 736 1,2, 4-thiadiazol-5- 3 0 H NHC02-n-Bu ylamino 737 1, 2, 4-thiadiazol-5- 3 0 H NHSθ2Ph ylamino 73E isoxazol-3-ylamino 3 0 H NHSθ2~nBu 739 isoxazol-3-ylamino 3 1 H NHCbz 740 isoxazol-3-ylamino 3 1 H NHCθ2~n-Bu 741 isoxazol-3-ylamino 3 1 H NHSθ2P 742 isoxazol-3-ylamino 3 1 H NHS02~nBu 743 isoxazol-3-ylamino 4 0 H NHCbz 744 isoxazol-3-ylamino 4 0 H NHCθ2-n-Bu 745 isoxazol-3-ylamino 4 0 H NHS02Ph 746 isoxazol-3-ylamino 4 0 H NHSθ2-nBu 747 isoxazol-3-ylamino 3 0 H NHCbz 748 isoxazol-3-ylamino 3 0 H NHCθ2-n-B 749 isoxazol-3-ylamino 3 0 H NHS02Ph 750 oxazol-2-ylamino 3 0 H NHSθ2-nBu 751 oxazol-2-ylamino 3 1 H NHCbz 752 oxazol-2-ylamino 3 1 H NHCθ2-n-B 753 oxazol-2-ylamino 3 1 H NHSθ2Ph 754 oxazol-2-ylamino 3 1 H NHSθ2~nBu 755 oxazol-2-ylamino 4 0 H NHCbz Ex . R x -U R 8 R 6 MS No . 756 oxazol-2-ylamino 4 0 H NHCθ2-n-Bu 757 oxazol-2-ylammo 4 0 H NHS02Ph 758 oxazol-2-ylamino 4 0 H NHSθ2-nBu 759 oxazol-2-ylamino 3 0 H NHCbz 760 oxazol-2-ylamino 3 0 H NHCθ2-n-Bu 761 oxazol-2-ylamino 3 0 H NHSθ2Ph 762 oxazol-2-ylamino 3 0 H NHSθ2-nBu 763 1,2, 5-thiadiazol-3- 3 1 H NHCbz ylamino 764 1,2, 5-thiadiazol-3- 3 1 H NHCθ2-n-Bu ylamino 765 1, 2, 5-thiadiazol-3- 3 1 H NHSθ2Ph ylamino 766 1,2, 5-thiadiazol-3- 3 1 H NHSθ2-nBu ylamino 767 1,2, 5-thiadiazol-3- 4 0 H NHCbz ylamino 768 1, 2, 5-thiadiazol-3- 4 0 H NHCθ2-n-Bu ylaimino 769 1,2, 5-thiadiazol-3- 4 0 H NHSθ2Ph ylamino 770 1,2, 5-thiadiazol-3- 4 0 H NHSθ2-nBu ylamino 771 l,2,5-thiadiazol-3- 3 0 H NHCbz ylamino 772 1, 2, 1 5-thiadiazol-3- 3 0 H NHCθ2-n-B ylamino 773 1,2, 5-thiadiazol-3- 3 0 H NHS02Ph ylamino 774 l,2,5-thiadiazol-3- 3 0 H NHSθ2-nBu ylamino 775 imidazolin-2- 2 2 H NHCbz ylamino Ex. R 1 -U m n R 8 R 16 MS No. 776 imidazolin-2- 2 2 H NHCθ2-n-Bu ylamino 777 imidazolin-2- 2 2 H NHSθ2Ph ylamino 778 imidazolin-2- 2 2 H NHSθ2~nBu ylamino 779 tetrahydropyrimidin 2 2 H NHCbz -2-ylamino 780 tetrahydropyrimidin 2 2 H NHCθ2-n-Bu -2-ylamino 781 tetrahydropyrimidin 2 2 H HSθ2Ph -2-ylamino 782 tetrahydropyrimidin 2 2 H NHSθ2-nBu -2-ylamino 783 benzimidazol-2- 4 0 H NHCbz ylamino 784 benzthiazol-2- 4 0 H NHCbz ylamino 785 l,2-pyrazol-3- 4 0 H NHCbz ylamino 786 1 , 2 , 4-triazol-5- 4 0 H NHCbz ylaiηino 787 imidazol-4-ylamino 4 0 H NHCbz 788 1, 3, 4-oxadiazol-2- 4 0 H NHCbz ylamino 789 1, 2, 4-thiadiazol-5- 4 0 H NHCbz ylamino 790 1,2, 4-thiadiazol-3- 4 0 H NHCbz ylamino 791 1, 2, 5-oxadiazol-3- 4 0 H NHCbz ylamino 792 1,2, 4-oxadiazol-5- 4 0 H NHCbz ylamino 793 1,2, 4-oxadiazol-3- 4 0 H NHCbz ylamino 794 2-iminopyrrolidin- 3 1 H NHCbz 5-yl 795 2-iminopyrrolidin- 3 1 H NHS0 2 Ph 5-yl Ex. R x -U m R 8 R16 MS No. 796 2-iminopyrrolidin- 3 0 H NHCbz 5-yl 797 2-iminopyrrolidin- 3 0 H NHS0 2 Ph 5-yl 798 2-iminopyrrolidin- 2 1 H NHCbz 5-yl 799 2-iminopyrrolidin- 2 1 H NHS0 2 Ph 5-yl 800 2-iminopiperidin-6- 3 1 H NHCbz i , 801 2-iminopiperidin-6- 3 1 H NHS0 2 Ph yi 802 2-iminopiperidin-6- 3 0 H NHCbz yi 803 2-iminopiperidin-6- 3 0 H NHSθ2Ph yi 804 2-iminopiperidin-6- 2 1 H NHCbz yi i 805 2-iminopiperidin-6- 2 1 H NHS0 2 Ph yi 806 2-iminoazepin-7-yl 3 1 H NHCbz 807 2-iminoazepin-7-yl 3 1 H NHS0 2 Ph 808 2-iminoazepin-7-yl 3 0 H NHCbz 809 2-iminoazepin-7-yl 3 0 H NHSθ2Ph 810 2-iminoazepin-7-yl 2 1 H NHCbz 811 2-iminoazepin-7-yl 2 1 H NHS0 2 Ph 812 benzimidazol-2- 4 0 n-Bu H ylamino 813 benzthiazol-2- 4 0 n-Bu H ylamino 814 l,2-pyrazol-3- 4 0 n-Bu H ylamino 815 1,2, 4-triazol-5- 4 0 n-Bu H ylamino Ex . X-ϋ m ___ H n R ] ^ 88 R R 1 16 6 MS No . 816 imidazol-4 -ylamino 4 0 n- -Bu H 817 1, 3, 4-oxadiazol-2- 4 0 n- -Bu H ylamino 818 1,2, 4-thiadiazol-5- 4 0 n- -Bu H ylaψino 819 1,2, 4-thiadiazol-3- 4 0 n- -Bu H ylamino 820 1, 2, 5-oxadiazol-3- 4 0 n- -Bu H ylamino 821 1, 2, 4-oxadiazol-5- 4 0 n- -Bu H ylamino 822 1,2, 4-oxadiazol-3- 4 0 n- -Bu H ylamino Table 3 Ex. -U No. 1001 ιmιdazolιn-2-ylammo 0 0 H H 1002 ιmιdazolιn-2-ylammo 0 o H H 1003 ιmιdazolm-2-ylammo 0 0 H NHCbz 1004 ιmιdazolιn-2-ylammo 0 0 H NHCbz 1005 ιmιdazolm-2-ylammo 0 s H NHCbz 1006 ιmιdazolm-2-ylammo 0 s H NHCbz 1009 tetrahydropyrimidm- 0 o H H 2-ylammo 1010 tetrahydropyπmidin- 0 o H NHCbz 2-ylammo 1011 tetrahydropyrimidm- 0 0 H H 2-ylammo 1012 tetrahydropyrimidm- 0 0 H NHCbz 2-yj t ammo 1013 tetrahydropyπmidin- 0 s H NHCbz 2-ylammo 1014 tetrahydropyrimidm- 0 s H NHCbz 2-ylammo 1015 tetrahydropyrimidm- 0 0 H NHCbz 2-ylammo 1017 ιmιdazolm-2-ylammo 2 0 o H NH-n-Bu 1018 ιmιdazolm-2-ylammo 3 0 o H NH-π-Bu 1019 ιmιdazolm-2-ylammo 2 0 s H NH-n-Bu 1020 ιmιdazolιn-2-ylamιno 3 0 s H NH-n-Bu 1023 tetrahydropyπmidm- 2 0 0 H NH-n-Bu 2-ylammo 1024 tetrahydropyrimidm- 3 0 O H NH-n-Bu 2-ylammo 1025 tet ahydropyrimidin- 2 0 s H NH-n-Bu 2-ylammo Ex. R x -U m n G No. 1026 tetrahydropyrimidin- 3 0 S H NH-n-Bu 2-ylammo 1027 tetrahydropyrimidm- 2 0 S H NH-n-Bu 2-ylammo 1028 tetrahydropyrimid - 3 0 0 H NH-n-Bu 2-ylammo 1029 ιmιdazolm-2-ylamιno 2 0 0 H NHSθ2Ph(o-CH3 1030 ιmιdazolιn-2-ylammo 3 0 0 H NHS02Ph(o-CH3 1031 ιmιdazolm-2-ylammo 2 0 S H NHS02Ph(o-CH3 1032 ιmιdazolιn-2-ylammo 3 0 S H NHSθ2Ph(o-CH3) 1033 ιmιdazolm-2-ylammo 2 0 0 H NHS02Ph (m-CH3) 1034 ιmιdazolm-2-ylammo 3 0 0 H NHSθ2Ph(m-CH3) 1035 ιmιdazolιn-2-ylammo 2 0 S H NHS02Ph(m-CH3) 1036 ιmιdazolιn-2-ylammo 3 0 s H NHS02Ph(m-CH3) 1037 ιmιdazolm-2-ylammo 2 2 0 0 H NHS02Ph(p-CH 3 ) 1038 ιmιdazolm-2-ylammo 3 0 0 H NHSθ2Ph(p-CH3) 1039 ιmιdazolm-2-ylammo 2 0 s H NHSθ2Ph (P-CH3) 1040 ιmιdazolm-2-ylammo 3 0 s H NHS02Ph(p-CH3) 1041 ιmιdazolm-2-ylammo 2 0 0 H Sθ2Ph(o-Cl) 1042 ιmιdazolιn-2-ylamιno 3 0 0 H Sθ2Ph(o-Cl) 1043 ιmιdazolm-2-ylammo 2 0 0 H Sθ2Ph(m-Cl) 1044 ιmιdazolm-2-ylammo 3 0 0 H Sθ2Ph(m-Cl) 1045 ιmιdazolm-2-ylammo 2 0 0 H Sθ2Ph(p-Cl) 1046 ιmιdazolm-2-ylammo 3 0 0 H Sθ2Ph(p-Cl) 1047 tetrahydropyrimid - 2 0 0 H Sθ2Ph(p-Cl) 2-ylamιno 1048 tetrahydropyrimidin- 3 0 0 H Sθ2Ph(p-Cl) 2-yl,ammo 1049 tetrahydropyrimidm- 2 0 0 H Sθ2Ph(m-Cl) 2-ylamιno 1050 tetrahydropyrimidin- 3 0 0 H Sθ2Ph(m-Cl) 2-ylammo 1051 tetranydropyrimidm- 2 0 0 H Sθ2Ph (p-Cl) 2-ylammo 1052 tetrahydropyπmidm- 3 0 0 Sθ2Ph(p-Cl) 2-ylammo 1053 ιmιdazolm-2-ylammo 2 0 0 H NHPh(m-F) 1054 ιmιdazolm-2-ylammo 3 0 0 H NHPh(m-F) 1055 tetrahydropyπmidm- 2 0 0 H NHPh(m-F) 2-ylammo 1056 tetrahydropyrimidin- 3 0 0 H NHPh(m-F) 2-ylammo 1057 ιmιdazolm-2-ylammo 2 0 0 H NHPh(p-F) Ex. R x -U m n G * No. ! 1058 ιmιdazolm-2-ylammo 3 0 0 H NHPh(p-F) 1059 tetrahydropyrimidin- 2 2 0 0 H NHPh(p-F) 2-ylammo 1060 tetrahydropyrimidin- 3 NHPh(p-F) 2-ylammo 1061 ιmιdazolm-2-ylammo 2 0 0 H NHPh(m-Br) 1062 ιmιdazolm-2-ylammo 3 0 0 H NHPh(m-Br) 1063 tetrahydropyrimidin- 2 0 0 H NHPh(m-Br) 2-ylamιno 1064 tetrahydropyrimidin- 3 o NHPh(m-Br) 2-ylammo 1065 ιmιdazolm-2-ylamιno 0 0 NHSθ2Ph(p-Br) 1066 ιmιdazolm-2-ylammo 3 0 0 NHS02Ph(p-Br) 1067 tetrahydropyrimidin- 2 0 0 NHSθ2Ph(p-Br) 2-ylammo 1068 tetrahydropyrimidin- 3 NHS02Ph(p-Br) 2-ylammo 1069 imiρ.azolin-2-ylamino 2 O H NHSθ2Ph(m- OCH3) 1070 imidazolin-2-ylamino O H NHSθ2Ph(m- OCH3) 1071 tetrahydropyrimidin- 2 O H NHSθ2Ph(m- 2-ylamino OCH3) 1072 tetrahydropyrimidin- 3 O H NHS02Ph(m- 2-ylamino OCH3) 1073 imidazolin-2-ylamino 2 O H NHS02Ph(p- OCH3) 1074 imidazolin-2-ylamino 0 H NHSθ2Ph(p- OCH3) 1075 tetrahydropyrimidin- O H NHSθ2Ph(p- 2-ylamino OCH3) 1076 tetrahydropyrimidin- O H NHSθ2Ph(p- 2-ylamino OCH3) 1077 imidazolin-2-ylamino O H NHSθ2Bn 1078 imidazolin-2-ylamino 0 H NHSθ2Bn 1079 tetrahydropyrimidin- o H NHSθ2Bn 2-ylamino 1080 tetrahydropyrimidin- NHSθ2Bn 2-ylamino 1081 imidazolin-2-ylamino 0 H NHS02Et 1082 imidazolin-2-ylamino 0 H NHSθ2Et 1083 tetrahydropyrimidin- 0 H NHS02Et 2-ylamino 1084 tetrahydropyrimidin- H NHS02Et 2-ylamino 1085 imidazolin-2-ylamino 0 H NHS02-n-Pr Ex. Rl- Q R No. 1086 imidazolin-2-ylamino 0 " 0 H NHS02-n-Pr 1087 tetrahydropyrimidin- 0 o H NHS02-n-Pr 2-ylamino 1088 tetrahydropyrimidin- 0 o H NHSθ2~n-Pr 2-ylamino 1089 imidazolin-2-ylamino 0 0 H NHSθ2-n- (C5HH) 1090 imidazolin-2-ylamino 3 0 0 NHS0 2 -n- (C5H11) 1091 tetrahydropyrimidin- 0 0 NHSθ2-n- 2-ylamino (C5H11) 1092 tetrahydropyrimidin- 0 0 NHSθ2-n- 2-ylamino (C 5 Hχχ) 1093 imidazolin-2-ylamino 0 0 H NHC02Et 1094 imidazolin-2-ylamino 0 0 H NHC02Et 1095 tetrahydropyrimidin- 0 0 H NHCθ2Et 2-ylamino 1096 tetrahydropyrimidin- 3 NHCθ2Et 2-ylamino 1097 imidazolin-2-ylamino 2 0 0 H NHCθ2-n-C5Hχχ 1098 imidazolin-2-ylamino 0 0 H NHC02- -C5Hχχ 1099 tetrahydropyrimidin- 2 0 0 H NHC02-n-C5Hχχ 2-ylamino 1100 tetrahydropyrimidm- HC02-n-C5H x i 2-ylammo 1101 ιmιdazolm-2-ylammo 0 O H NHCbz 1102 tetrahydropyrimidm- 0 0 H NHCbz 2-ylammo 1103 ιmιdazolm-2-ylammo 0 0 H NHCθ2-n- -Bu 1104 tetrahydropyπmidin- 0 0 H NHCθ2-n- -Bu 2-ylammo 1105 ιmιdazol -2-ylammo 0 0 H NHS0 2 Ph 1106 tetrahydropyrimidm- 0 O H NHSθ2Ph 2-ylamιno 1107 ιmιdazolm-2-ylamιno 0 0 H NHSθ2-n- -Bu 1108 tetrahydropyrimidm- 0 O H NHSθ2-n- -Bu 2-ylammo 1109 ιmιdazolm-2-ylammo 0 S H NHCbz 1110 tetrahydropyrimidm- 0 s H NHCbz 2-ylammo 1111 ιmιdazolm-2-ylammo 0 s H NHSO2B 1112 tetrahydropyrimidm- 0 s H NHSO2BU 2-ylammo 1113 ιmιdazolm-2-ylammo 2 0 o Me H 1114 ιmιdazolm-2-ylammo 0 o Me H Ex. R 1_U m n G Rδ_ R9 No. 1115 tetrahydropyrimidin- 2 0 0 Me H 2-ylamιno 1116 tetrahydropyrimidin- 3 0 Me H 2-ylammo 1117 ιmιda zolm-2-ylammo 3 0 S Me H 1118 tetrahydropyrimidin- 3 0 S Me H 2-ylam no 1119 ιm dazolm-2-ylammo 0 o Me NHCbz 1120 ιmιdazolm-2-ylammo 0 o Me NHCbz 1121 tetrahydropyrimidin- 0 o Me NHSθ2-n- -Bu 2-ylammo 1122 tetrahydropyrimidm- Me NHSθ2-n- -Bu 2-ylammo 1123 ιmιda zolιn-2 -ylamιno 0 Et H 1124 ιmιdazolm-2 -ylammo 3 0 Et H 1125 tetrahydropyrimidin- 2 0 Et H 2-ylammo 1126 tetrahydropyrimidin- 3 Et 2-ylammo 1127 ιmιdazolm-2-ylammo 0 s Et H 1128 tetrahydropyrimidin- 3 0 s Et H 2-ylammo 1129 ιmιdazolm-2-ylammo 2 0 0 Ph H 1130 ιmιdazolm-2-ylammo 3 0 0 Ph H 1131 tetrahydropyrimidin- 2 0 0 Ph H 2-ylammo 1132 tetrahydropyrimidin- 3 Ph 2-ylammo 1133 ιmιdazolm-2-ylamιno Ph 1134 tetrahydropyrimidin- 3 Ph 2-ylammo 1135 ιmιdazolιn-2-ylammo 2 Bn 1136 ιmιda zolm-2-ylammo O Bn H 1137 tetrahydropyrimidm- 0 Bn H 2-ylammo 1138 tetrahydropyπmidm- Bn 2-yl.amιno 1139 ιmιdazolm-2-ylammo 3 0 s Bn H 1140 tetrahydropyrimidm- 3 0 s Bn H 2-ylammo 1141 ιmιda zolm-2-ylammo 2 0 0 H NHCbz 1142 ιmιdazolιn-2-ylammo 3 0 0 H NHCbz 1143 tetrahydropyrimidm- 2 0 0 H NHCbz 2-ylammo 1144 tetrahydropyrimidin- 3 3 0 0 NHCbz 2-ylammo Ex. R 1 -U m n G R- No. 1145 ιmιdazolm-2-ylammo 2 0 0 H NHSθ2-n-Bu 1146 lmida zolιn-2-ylamιno 3 0 0 H NHSθ2-n-Bu 1147 tetrahydropyrimidm- 2 0 0 H NHSθ2-n-Bu 2-ylammo 1148 tetrahydropyrimidm- NHS02-n-Bu 2-ylammo 1149 ιmιdazolιn-2-ylammo s H NHCbz 1150 tetrahydropyrimidin- s H NHCbz 2-ylammo 1151 ιmιdazolm-2-ylammo s H NHSθ2-n-Bu 1152 tetrahydropyrimidin- 3 s H NHSθ2-n-Bu 2-ylammo 1153 ιmιdazolm-2-ylamιno 2 0 H NHCbz 1154 ιmιdazolm-2-ylamιno 3 0 H NHCbz 1155 tetrahydropyrimidin- 2 0 H NHCbz 2-ylammo 1156 tetrahydropyrimidin- 3 NHCbz 2-ylammo 1157 ιmιdazolιn-2-ylammo 2 o H NHS02-n-Bu 1158 ιmιdazolm-2-ylamιno 0 H NHSθ2-n-Bu 1159 tetrahydropyπmidm- 0 H NHSθ2-n-Bu 2-ylammo 1160 tetrahydropyrimidm- H NHSθ2-n-Bu 2-ylammo 1161 ιmιdazolm-2-ylammo s H NHCbz 1162 tetr'ahydropyπmidm- s H NHCbz 2-ylammo 1163 ιmιdazolιn-2-ylammo 3 s H NHS02-n-Bu 1164 tetrahydropyrimidin- 3 s H NHSθ2-n-Bu 2-ylammo 1165 ιmιdazolm-2-ylammo 3 0 Me NHCbz 1166 tetrahydropyrimidin- 3 0 Me NHSO2BU 2-ylammo 1167 ιm dazolιn-2-ylammo 3 0 Bn NHCbz 1168 tetrahydropyrimidin- 3 0 Bn NHCbz 2-ylammo 1169 ιmιdazolm-2-ylamιno 3 0 Me NHSθ2-n-Bu 1170 tetrahydropyrimidin- 3 0 Me NHCbz 2 -ylammo 1171 ιmιdazolιn-2-ylammo 3 Bn NHSθ2-n-Bu 1172 tetrahydropyrimidin- 3 0 0 Bn NHCbz 2-ylamino 1173 (4-oxoimidazolin-2- 2 0 0 H NHCBz yl) amino Ex. R x -U m n G No. R R 1174 ( 4-oxoimidazolin-2- 3 0 0 H NHCBz yl ) amino 1175 ( 4-oxoimidazolin-2- 2 0 0 H NHCθ2-n- -Bu yl) amino 1176 (4-pxoimidazolin-2- 3 0 0 H NHC02-n- -Bu yl) amino 1177 ( 4-oxoimidazolin-2- 2 0 0 H NHS02Ph yl) amino 1178 (4-oxoimidazolin-2- 3 0 0 H NHSθ2Ph yl) amino 1179 (4-oxoimidazolin-2- 2 0 0 H NHSθ2~n- -Bu yl) amino 1180 (4-oxoimidazolin-2- 3 0 0 H NHSθ2-n- -Bu , yl) amino 1181 (4- 3 0 0 H NHCbz oxotetrahydropyrimid in-2-yl ) amino 1182 (4- 3 0 O NHCθ2-n-Bu oxotetrahydropyrimid in-2-yl) amino 1183 (4- 3 0 0 H NHS02Ph oxotetrahydropyrimid ;Ln-2-yl) amino 1184 (4- 3 0 0 H NHSθ2-n-Bu oxotetrahydropyrimid in-2-yl) amino 1185 ( 4-oxoimidazolin-2- 3 0 S H NHCbz yl) amino 1186 (4-oxoimidazolin-2- 3 0 S H NHS02-n-Bu yl) amino 1187 (4- 3 0 s H NHCbz oxotetrahydropyrimid in-2-yl) amino 1188 (4- 3 0 H NHS02-n-Bu oxotetrahydropyrimid in-2-yl ) amino 1189 (4-oxoimidazolin-2- 3 0 0 Me H yl) amino 1190 (4- 3 0 Me H oxotetrahydropyrimid j Ln-2-yl) amino 1191 ( 4-oxoimidazolin-2- 3 0 0 Bn H yl) amino R!-U m n Q PL (4- 3 0 0 Bn oxotetrahydropyrimid in-2-yl) amino 1193 ( 4-oxoimidazolin-2- 0 0 Me NHCbz yl) amino 1194 (4- 0 0 Me NHSθ2-n-Bu oxotetrahydropyrimid in-2-yl) amino 1195 ( 4-oxoimidazolin-2- 0 0 H NHCbz yl) amino 1196 (4- 0 0 H NHCbz oxotetrahydropyrimid in-2-yl) amino 1197 imidazolin-2- 0 0 H NHCbz ylaminocarbonyl 1198 imidazolin-2- 0 0 H NHCbz ylaminocarbonyl 1199 tetrahydropyrimidin- 0 0 H NHS02-n-Bu 2-ylaminocarbonyl 1200 tet ahydropyrimidin- 0 0 H NHS02-n-Bu 2-ylaminocarbonyl 1201 imidazolin-2- 0 0 H NHCbz ylaminocarbonyl 1202 tetrahydropyrimidin- 0 0 H NHSθ2-n-Bu 2-ylaminocarbonyl 1203 imidazolin-2- 0 0 H NHC02-n-Bu ylaminocarbonyl 1204 imidazolin-2- 0 0 H NHC02~n-Bu ylaminocarbonyl 1205 tetrahydropyrimidin- 0 0 H NHSθ2Ph 2-ylaminocarbonyl 1206 tetrahydropyri idin- 0 0 H HS02P 2-ylaminocarbonyl 1207 imidazolin-2- 0 0 Me NHCbz ylaminocarbonyl 1208 tetrahydropyrimidin- 0 0 Me NHSθ2-n-Bu 2-ylaminocarbonyl 1209 imidazolin-2- 0 0 Bn H ylaminocarbonyl 1210 tetrahydropyrimidin- 0 0 Bn H 2-ylaminocarbonyl 1211 imidazolin-2- 0 0 Me H ylaminocarbonyl Ex. R ! -U n G R No. R! 1212 tetrahydropyrimidin- 0 0 Me H 2-ylaminocarbonyl 1213 imidazolin-2- 0 0 H NHCbz ylaminocarbonyl 1214 tetrahydropyrimidin- 0 0 H NHCbz 2-ylaminocarbonyl 1215 imidazolin-2- 0 0 H NHS02-n-Bu ylaminocarbonyl 1216 tetrahydropyrimidin- 0 0 H NHS02-n-Bu 2- l ylaminocarbonyl 1217 imidazolin-2- 2 0 S Me H ylaminocarbonyl 1218 tetrahydropyrimidin- 2 0 s Bn H 2-ylaminocarbonyl 1219 imidazolin-2- 2 0 s H NHCbz ylaminocarbonyl 1220 tetrahydropyrimidin- 2 0 s H NHSθ2-n-Bu 2-ylaminocarbonyl 1221 imidazolin-2-ylamino 2 1 0 H NHCbz 1222 imidazolin-2-ylamino 3 1 0 H NHCbz 1223 tetrahydropyrimidin- 2 1 0 H NHCbz i 2-ylamino 1224 tetrahydropyrimidin- 3 NHCbz 2-ylamino 1225 imidazolin-2-ylamino 2 1 0 H NHSθ2~n-Bu 1226 imidazolin-2-ylamino 3 1 0 H NHSθ2-n-Bu 1227 tetrahydropyrimidin- 2 1 0 H NHSθ2-n-Bu 2-ylamino 1228 tetrahydropyrimidin- 3 1 0 H NHSθ2-n-Bu i 2-ylamino 1229 imidazolin-2-ylamino 2 1 s H NHCbz 1230 imidazolin-2-ylamino 3 1 s H NHCbz 1231 tetrahydropyrimidin- 2 1 s H NHCbz 2-ylamino 1232 tetrahydropyrimidin- 3 H NHCbz 2-ylamino 1233 imidazolin-2-ylaπιino 2 1 0 Me H 1234 imidazolin-2-ylamino 3 1 0 Me H 1235 tetrahydropyrimidin- 2 1 0 Bn H 2-ylamino 1236 tetrahydropyrimidin- 3 1 0 Bn 2-ylamino Ex. R -U m n G No. 1237 imidazolin-2-ylamino 2 1 s Me H 1238 tetrahydropyrimidin- 2 1 s Bn H 2-ylamino 1239 imidazolin-2-ylamino 2 1 0 Me NHCbz 1240 tetrahydropyrimidin- 2 1 0 Me NHCbz 2-ylamino 1241 imidazolin-2-ylamino 2 1 0 H NHCbz 1242 tetrahydropyrimidin- 2 1 0 H NHCbz 2-ylamino 1243 imidazolin-2-ylamino 3 1 0 H NHCbz 1244 tetrahydropyrimidin- 3 1 0 H NHCbz 2-ylamino 1245 pyridin-2-ylamino 2 1 0 H NHCbz 1246 imidazol-2-ylamino 2 1 0 H NHCbz 1247 1,2, 4-thiadiazol-5- 2 1 0 H NHCbz ylamino 1248 isoxazol-3-ylamino 2 1 0 NHCbz 1249 oxazol-2-ylammo 2 1 0 H NHCbz 1250 1,2, 5-thιadιazol-3- 2 1 0 H NHCbz ylammo 1251 benzιmιdazol-2- 2 1 0 H NHCbz ylammo 1252 benzthιazol-2- 2 1 0 H NHCbz ylaiino 1253 1, 2-pyrazol-3- 2 1 0 H NHCbz ylammo 1254 1,2, 4-trιazol-5- 2 1 0 H NHCbz ylammo 1255 ιmιdazol-4-ylammo 2 1 0 H NHCbz 1256 1,3, 4-oxadιazol-2- 2 1 0 H NHCbz ylam o 1257 1,2, 4-thιadιazol-5- 2 1 0 H NHCbz ylammo 1258 1,2, 4-thιadιazol-3- 2 1 0 H NHCbz ylamino 1259 1,2, 5-oxadιazol-3- 2 1 0 H NHCbz ylam o 1260 1,2, 4-oxadιazol-5- 2 1 0 H NHCbz ylam o 1261 1,2, 4-oxadιazol-3- 2 1 0 H NHCbz ylam o 1262 pyrιdιn-2-ylammo 3 0 0 H NHCbz 1263 ιmιdazol-2-ylammo 3 0 0 H NHCbz 1264 1,2, -thιadιazol-5- 3 0 0 H NHCbz ylamino Ex. R x -U m n G Rδ_ R9 No. 1265 ιsoxazol-3-ylammo 3 0 0 H NHCbz 1266 oxazol-2-ylammo 3 0 0 H NHCbz 1267 1,2, 5-thιadιazol-3- 3 0 0 H NHCbz ylammo 1268 benzιmιdazol-2- 3 0 0 H NHCbz yla mo 1269 benzthιazol-2- 3 0 0 H NHCbz ylammo 1270 1, 2-pyrazol-3- 3 0 0 H NHCbz ylamino 1271 1, 2, 4-trιazol-5- 3 0 0 H NHCbz ylammo 1272 ιmιdazol-4-ylammo 3 0 0 H NHCbz 1273 1, 3, 4-oxadιazol-2- 3 0 0 H NHCbz ylaiino 1274 1,2, 4-thιadιazol-5- 3 0 0 H NHCbz ylammo 1275 1,2, 4-thιadιazol-3- 3 0 0 H NHCbz ylam o 1276 1,2, 5-oxadιazol-3- 3 0 0 H NHCbz ylamino 1277 1, 2, 4-oxadιazol-5- 3 0 0 H NHCbz ylammo 1278 1, 2, 4-oxadιazol-3- 3 0 0 H NHCbz ylammo 1279 pyrιdm-2-ylammo 2 0 0 H NHCbz 1280 ιmιdazol-2-ylammo 2 0 0 H NHCbz 1281 1, 2, 4-thιadιazol-5- 2 0 0 H NHCbz ylammo 1282 ιsoxazol-3-ylammo 2 0 0 H NHCbz 1283 oxazol-2-ylamιno 2 0 0 H NHCbz 1284 1, 2, 5-thιadιazol-3- 2 0 0 H NHCbz ylamino 1285 benzιmιdazol-2- 2 0 0 H NHCbz ylamino 1286 benzthιazol-2- 2 0 0 H NHCbz ylammo 1287 1, 2-pyrazol-3- 2 0 0 H NHCbz ylamino 1288 l,2,4-tπazol-5- 2 0 0 H NHCbz ylamino 1289 ιmιdazol-4-ylammo 2 0 0 H NHCbz 1290 1, 3, 4-oxadιazol-2- 2 0 0 H NHCbz ylammo 1291 1,2, 4-thιadιazol-5- 2 0 0 H NHCbz ylamino 1292 1,2, 4-thιadιazol-3- 2 0 0 H NHCbz ylammo Ex R!-U m n G R R9 No . 1293 1,2, 5-oxadιazol-3- 2 0 0 H NHCbz ylammo 1294 1,2, 4-oxadιazol-5- 2 0 0 H NHCbz ylammo 1295 1,2, 4-oxadιazol-3- 2 0 0 H NHCbz ylamino Utility The compounds of Formula I of the present invention possess activity as antagonists of mtegrms such as, for example, the α v β 3 or vitronectin receptor, α v β 5 or cx 5 βl. and as such have utility in the treatment and diagnosis of cell adhesion, angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis. The mtegrm antagonist activity of the compounds of the present invention is demonstrated using assays which measure the bmdmg of a specific mtegrm to a native ligand, for example, using the ELISA assay described below for the bmdmg of vitronectin to the v β 3 receptor. The compounds of the present invention possess selectivity for the α v β 3 receptor relative to the GPIIb/IIIa receptor as demonstrated by their lack of activity in standard assays of platelet aggregation, such as the platelet aggregation assay described below. One of the major roles of integrins in vivo is to mediate cellular interactions with adjacent cells. Cell based adhesion assays can be used to mimic these interactions in vi tro . A cell based assay is more representative of the in vivo situation than an ELISA since the receptor is maintained in membranes in the native state. The compounds of the present invention have activity in cell-based assays of adhesion, for example as demonstrated in using the cell adhesion assays described below. The compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, osteoporosis, rheumatoid arthritis, autoimmune disorders, bone degradation, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoarthritis, atherosclerosis, metastasis, wound healing, inflammatory bowel disease and other angiogenic disorders. The compounds of Formula I have the ability to suppress/inhibit angiogenesis in vivo, for example, as demonstrated using animal models of ocular neovascularization. The compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit integrin-ligand binding. These may be provided in a commercial kit comprising a compound of this invention. As used herein "μg" denotes microgram, "mg" denotes milligram, "g" denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar and "nm" denotes nanometer. "Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, MO. The utility of the compounds of the present invention may be assessed by testing in one or more of the following assays as described in detail below: Purified α v β 3 (human placenta) - Vitronectin ELISA, C v β 3 ~Vitronectin Binding Assay, Human Aortic Smooth Muscle Cell Migration Assay, In Vivo Angiogenesis Model, Pig Restenosis Model, Mouse Retinopathy Model. A compound of the present invention is considered to be active if it has an IC 50 or Kx value of less than about 10 μM for the inhibition of α v β 3 -Vitronectin Binding Assay, with compounds preferably having Kx values of less than about 0.1 μM. Compounds of the present invention are active in the α v β 3 ~Vitronectin Binding Assay as well as in cell-based assays of integrimi adhesion mediated by the α v β 3 ~receptor . Purified α v { 3 (human placenta) - Vitronectin ELISA The v β 3 receptor was isolated from human placental extracts prepared using octylglucoside . The extracts were passed over an affinity column composed of anti-α v β 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 α v β 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 α v β 3 with no detectable levels of v β5 according to the gel (α v β 3 ) and according to effects of blocking antibodies for the α v β 3 or α v βs in the ELISA. A submaximal concentration of biotinylated vitronectin was selected based on cone, response curve with fixed receptor cone, and variable concentrations of biotinylated vitronectin. c / fo-Vitronectin Binding Assay The purified receptor is diluted with coating buffer (20 mM Tris HCI, 150 mM NaCI, 2.0 mM CaCl 2 , 1.0 mM MgCl 2 -6H 2 0, 1.0 mM MnCl 2 -4H 2 0) and coated (100 μL/well) on Costar (3590) high capacity binding plates overnight at 4°C. The coating solution is discarded and the plates washed once with blocking/binding buffer (B/B buffer, 50 mM Tris HCI, 100 mM NaCI, 2.0 mM CaCl 2 ,1.0 mM MgCl 2 • 6H 2 0, 1.0 mM MnCl 2 -4H 2 0). Receptor is then blocked (200 μL/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 μL) and either inhibitor (11 μL) or B/B buffer w/1.0% BSA (11 μL)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 μL/well) in B/B buffer containing 1.0% BSA. The plates are washed twice with B/B buffer and alkaline phosphatase substrate (100 μL) is added. Color is developed at room temperature. Color development is stopped by addition of 2N NaOH (25 μL/well) and absorbance is read at 405 nm. The IC 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 4° C. The following day, the cells were harvested, washed and loaded with a fluorescent dye. Compounds and cells were added together and then were immediately added to the coated plate. After incubation, loose cells are removed from the plate, and the plate (with adherent cells) is counted on a fluorometer. The ability of test compounds to inhibit cell adhesion by 50% is given by the IC 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 α v β 3 , α v β 5 and αsβx integrin interactions. Platelet Aggregation Assay Venous blood was obtained from anesthetized mongrel dogs or from healthy human donors who were drug- and aspirin-free for at least two weeks prior to blood collection. Blood was collected into citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 150 x g (850 RPM in a Sorvall RT6000 Tabletop Centrifuge with H-1000 B rotor) at room temperature, and platelet-rich plasma (PRP) was removed. The remaining blood was centrifuged for 15 minutes at 1500 x g (26,780 RPM) at room temperature, and platelet-poor plasma (PPP) was removed. Samples were assayed on a PAP-4 Platelet Aggregation Profiler, using PPP as the blank (100% transmittance) . 200 μL of PRP (5x108 platelets/mL) were added to each micro test tube, and transmittance was set to 0%. 20 μL of ADP (10 μM) was added to each tube, and the aggregation profiles were plotted (% transmittance versus time). Test agent (20 μL) was added at different concentrations prior to the addition of the platelet agonist. Results are expressed as % inhibition of agonist-induced platelet aggregation. Human Aortic Smooth Muscle Cell Migration Assay A method for assessing α v β 3 ~mediated smooth muscle cell migration and agents which inhibit α v β 3 -mediated smooth muscle cell migration is described in Liaw et al., J. Clin . Invest . (1995) 95: 713-724). In Vivo Angiogenesis Model A quantitative method for assessing angiogenesis and antiangiogenic agents is described in Passaniti et al., Labora tory Investiga tion (1992) 67: 519-52δ Pig Restenosis Model A method for assessing restenosis and agents which inhibit restenosis is described in Schwartz et al., J. Am . College of Cardiology (1992) 19: 267-274. Mouse Retinopathy Model A method for assessing retinopathy and agents which inhibit retinopathy is described in Smith et al., Invest. Ophthal . & Visual Science (1994) 35: 101-111. Dosage and Formulation The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, the α v β 3 integrin, 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 antiplatelet agent such as aspirin, piroxicam, or ticlopidine which are agonist-specific, or an anti-coagulant such as warfarin or heparin, or a thrombin inhibitor such as a boropeptide, hirudin or argatroban, or a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof. The compounds of the invention, or compounds of the invention in combination with other therapeutic agents, can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage of the novel cyclic compounds of this invention administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to 10 milligrams per kilogram of body weight. Dosage forms (compositions suitable for administration) contain from about 0.1 milligram to about 100 milligrams of active ingredient per 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 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 Remington ' s Pharma ceuti cal Sciences, Mack Publishing Company, a standard reference text in this field. Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 10 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate. Soft 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 10 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 10 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. The combination products of this invention, such as the novel α v β 3 antagonist compounds of this invention in combination with an anti-coagulant agent such as warfarin or heparin, or an anti-platelet agent such as aspirin, piroxicam or ticlopidine, or a thrombin inhibitor such as a boropeptide, hirudin or argatroban, or a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof, can be in any dosage form, such as those described above, and can also be administered in various ways, as described above . In a preferred embodiment, the combination products of the invention are formulated together, in a single dosage form (that is, combined together in one capsule, tablet, powder, or liquid, etc.). When the combination products are not formulated together in a single dosage form, the α v β 3 antagonist compounds of this invention and the anti-coagulant agent, antiplatelet agent, thrombin inhibitor, and/or thrombolytic agent may be administered at the same time (that is, together) , or in any order, for example the compounds of this invention are administered first, followed by administration of the anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent. When not administered at the same time, preferably the administration of the compound of this invention and any anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent occurs less than about one hour apart, more preferably less than about 30 minutes apart, even more preferably less than about 15 minutes apart, and most preferably less than about 5 minutes apart. Preferably, administration of the combination products of the invention is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that the α v β 3 antagonist compounds of this invention and the anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent are both administered in the same fashion (that is, for example, both orally) , if desired, they may each be administered in different fashions (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) . The dosage of the combination products of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above. As discussed above, where two or more of the foregoing therapeutic agents are combined or co-administered with the compounds of this invention, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect which would be obtained as a result of addition of further agents in accordance with the present invention. Particularly when provided as a single dosage form, the potential exists for a chemical interaction between the combined active ingredients (for example, a novel compound of this invention and an anti-coagulant such as warfarin or heparin, or a novel compound of this invention and an anti-platelet agent such as aspirin, piroxicam or ticlopidine, or a novel compound of this invention and a thrombin inhibitor such as a boropeptide, hirudin or argatroban, or a novel compound of this invention and a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof) . For this reason, the preferred dosage forms of the combination products of this invention are formulated such that although the active ingredients are combined in a single dosage form, the physical contact between the active ingredients is minimized (that is, reduced) . In order to minimize contact, one embodiment of this invention where the product is orally administered provides for a combination product wherein one active ingredient is enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the 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. Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient. These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure. Pharmaceutical kits useful in, for example, the inhibition of thrombus formation, the prevention of blood clots, and/or the treatment of thromboembolic disorders, which comprise a therapeutically effective amount of a compound according to the method of the present invention along with a therapeutically effective amount of an anti-coagulant agent such as warfarin or heparin, or an antiplatelet agent such as aspirin, piroxicam or ticlopidine, or a thrombin inhibitor such as a boropeptide, hirudin or argatroban, or a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof, in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as exemplified by the UNIVIAL™ two-part container (available from Abbott Labs, Chicago, Illinois), as desired. The compounds according to the method of the invention and the anti-coagulant agent, anti-platelet agent, thrombin inhibitor, thrombolytic agent, and/or combinations thereof, may be separate, or combined into a single dosage form as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

Claims: Claims What is claimed is: 1. A compound of the formula wherein: including their enantiomeric, diastereomeric, pharmaceutically acceptable salt or prodrug forms thereof wherein: R l is selected from: A and B are independently CH 2 , 0 or -N(R 12 )-; A 1 and B 1 are independently CK 2 or -N(R 10 )-; D is NH, O, or S; E-F is -C(R 2 )=C(R 3 )-, -N=C(R 2 )-, -C(R 2 )=N-, -N=N-, or CH(R 2 )CH(R 3 )-; G is selected from 0 or S; R 2 and R 3 are independently selected from: H, Cχ-C 4 alkoxy, NR n R 12 , =NR 12 , halogen, N0 2 , CN, CF 3 , Cχ~ Cg alkyl, C 3 ~C alkenyl, C 3 -C 7 cycloalkyl, C 4 ~Cχχ cycloalkylalkyl, Cg-Cχo aryl, C 7 -Cχχ arylalkyi C 2 -C 7 alkylcarbonyl, or C 7 -Cχχ arylcarbonyl; alternatively, R 2 and R 3 can be taken together to be a 5-7 membered carbocyclic or 5-7 membered heterocyclic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 R 7 ; U is selected from: "(CH 2 ) n -, -(CH 2 ) n N(R l2 ) (CH 2 ) m -, -(CH 2 )nNHNH(CH 2 ) m -, -N(R l °)C(=0)-, or -C(=0)N(R 10 )-; V is selected from: - ( CH 2 ) n-, -(Cχ-Cg alkylene) -Q-, substituted with 0-3 groups independently selected from R 13 , -(C 2 -C 7 alkenylene) -Q-, substituted with 0-3 groups independently selected from R i3 , - (C 2 -C 7 alkynylene) -Q-, substituted with 0-3 groups independently selected from R 13 , - (phenyl) -Q-, said phenyl substituted with 0-2 groups independently selected from R i3 , - (piperidinyl) -Q-, said piperidinyl substituted with 0-2 groups independently selected from R l3 , - (pyridyl) -Q-, said pyridyl substituted with 0-2 groups independently selected from R 13 , or - (pyridazinyl) -Q-, said pyridazinyl substituted with 0-2 groups independently selected from R 13 or R 7. Q is selected from: - ( CH 2 ) n -, -(CH 2 ) n 0(CH 2 ) m -, -(CH 2 ) n N(R 12 ) (CH 2 ) m -, -N (R l °)C(=0)-, or -C(=0)N(R l °)-; W is selected from: -(CH 2 ) q C(=0)N(R l °)-, -SCH 2 C(=0)N(R l °)-, or -C(=0)-N(R l °)-(CH 2 ) q -; X is selected from: -(CH 2 ) q -CH(R 8 )-CH(R 9 )-, - (CH 2 ) q -CH (CH 2 R 9 ) - or -CH 2 - r R 5 is selected from: H, Cχ-Cg alkyl, C -Cg alkenyl, C 2 - Cg alkynyl, C 3 -C 7 cycloalkyl, C 7 -Cχ 4 bicycloalkyl, hydroxy, Cχ-Cg alkoxy, Cχ-Cg alkylthio, Cχ-Cg alkylsulfinyl, Cχ-Cg alkylsulfonyl, nitro, Cχ-Cg alkylcarbonyl, Cg-C 10 aryl, -N(R n )R 12 ; halo, CF 3 , CN, Cχ-Cg alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl; R 6 is selected from: H, Cχ-C 4 alkyl, hydroxy, Cχ-C 4 alkoxy, nitro, Cχ-Cg alkylcarbonyl, -N(R H )R 2 , cyano, halo, -S(0)mR 10 , C0 2 R 10 , OR l °, Cβ to Cχo aryl optionally substituted with 1-3 groups selected from halogen, Cχ-Cg alkoxy, Cχ-Cg alkyl, CF 3 , S(0) m Me, or -NMe ; methylenedioxy when R 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, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl, or morpholinyl; R 7 is selected from: H, Cχ-Cχo alkyl, hydroxy, Cχ-Cχo alkoxy, nitro, Cχ~ Cχo alkylcarbonyl, -N(R H )R i2 , cyano, halo, C0 2 R l °, OR l °; R 8 is selected from: CONR I °R H , -CO 2 R 10 , Cχ-Cχo alkyl, substituted with 0-3 R 6 , C 2 -Cχo alkenyl, substituted with 0-3 R 6 , c 2 -C χo alkynyl, substituted with 0-3 R 6 , C 3 -C 8 cycloalkyl, substituted with 0-3 R 6 , C 5 -Cg cycloalkenyl, substituted with 0-3 R 6 , aryl, substituted with 0-3 R 6 , a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl; R 9 is selected from: H, hydroxy, Cχ-Cχo alkoxy, nitro, N(R i °)R H , -N(R 16 )R l7 , Cχ-C 10 alkyl substituted with 0-3 R 6 , aryl substituted with 0-3 R 6 , heteroaryl substituted with 0-3 R 6 or Cχ-Cχo alkylcarbonyl; R i ° is selected from H or Cχ-Cχo alkyl substituted with 0-2 R 5 ; R H is selected from hydrogen, hydroxy, Cx to Cg alkyl, C 3 -C alkenyl, C 3 to Cxx cycloalkyl, C to Cxx cycloalkylmethyl, Cχ-Cg alkoxy, benzyloxy, Cg to Cχo aryl, heteroaryl, heteroarylalkyl, C 7 to Cxx arylalkyi, adamantylmethyl, or Cχ-Cχo alkyl substituted with 0-2 R 5 ; alternatively, R 10 and R 11 when both are substituents on the same nitrogen atom (as in -NR l0 R iX ) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1, 2, 3, 4-tetrahydro-l- quinolinyl, 1, 2, 3, 4-tetrahydro-2-isoquinolinyl, 1- piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl; said heterocycle being optionally substituted with 1-3 groups selected from: Cχ-Cg alkyl, Cg-Cχo aryl, heteroaryl, C 7 ~Cχχ arylalkyi, Cχ-Cg alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, Cχ-Cg alkoxycarbonyl, C 7 -Cχχ arylalkoxycarbonyl, Cχ-Cg alkylsulfonyl or Cg-Cχo arylsulfonyl; R i2 is selected from: H, Cχ-Cβ alkyl, Cχ-C 4 alkoxycarbonyl, Cχ-Cg alkylcarbonyl, Cχ-Cg alkylsulfonyl, aryl (Cχ-C 4 alkyl) sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, or heteroarylalkylcarbonyl, wherein said aryl groups are substituted with 0-3 substituents selected from the group consisting of: Cχ-C 4 alkyl, Cχ-C 4 alkoxy, halo, CF 3 , and N0 ; R i3 is selected from H, Cχ-Cχo alkyl, C 2 ~Cχo alkenyl, C 2 ~Cχo alkynyl, Cχ-Cχo alkoxy, aryl, heteroaryl or Cχ-C 10 alkoxycarbonyl, C0 2 R 10 or -C(=O)N(R 10 )R π ; R i6 is selected from: -C(=0)-0-R l8a , -C(=0)-R i8b , -S0 2 -R l8a , -S0 2 -N(18b) 2 ; R l7 is selected from H or Cχ-C 4 alkyl; R l8a j_ s selected from: Cχ-C 8 alkyl substituted with 0-2 R 19 , C 2 -C 8 alkenyl substituted with 0-2 R i9 , C 2 -C 8 alkynyl substituted with 0-2 R i9 , C 3 -C 8 cycloalkyl substituted with 0-2 R i9 , aryl substituted with 0-4 R i9 , aryl(Cχ-Cg alkyl)- substituted with 0-4 R i9 , a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, isoxazolyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H- indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 RX Cχ-Cg alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, isoxazolyl, 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 9 ; R l8b is selected from R l8a or H; R i9 is selected from: H, halogen, CF 3 , CN, N0 2 , NR n R 12 , Cχ-C 8 alkyl, C 2 ~C alkenyl, C 2 -Cg alkynyl, C -Cχχ cycloalkyl, C 4 ~Cχχ cycloalkylalkyl, aryl, aryl (Cχ-Cg alkyl)-, Cχ-Cg alkoxy, or Cχ-C 4 alkoxycarbonyl; R 20 is selected from: hydroxy; Cx to Cχo 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 21 is selected from Cχ-Cg alkyl, C 2 -C 6 alkenyl, C 3 ~Cχχ. cycloalkyl, C 4 -Cχχ cycloalkylmethyl, Cg-Cχo aryl, c 7 ~ c χχ arylalkyi, or Cχ-Cχo alkyl substituted with 0-2 R 5 ; m i s 0-2 n i s 0-2 P is 0-2 q i s 0- 1 and r is 0 -2 with the following provisos: (1) n, m and q are chosen such that the number of atoms connecting R l and Y is in the range of 8-14; and (2) when V is - (phenyl) -Q-, then either: U is not a direct bond (i.e., U is not CH2)n- where n = 0) or Q is not a direct bond (i.e., Q is not -(CH2)n~ where n = 0). Claim 2 is a compound of claim 1 wherein R l is V is selected from: -(CH 2 ) n -, -(Cχ-Cg alkylene) -Q-, substituted with 0-3 groups independently selected from R 13 , -(C 2 -C 7 alkenylene) -Q-, substituted with 0-3 groups independently selected from Rl 3 , -(C 2 -C 7 alkynylene) -Q-, substituted with 0-3 groups independently selected from R 13 , - (phenyl) -Q-, said phenyl substituted with 0-2 groups independently selected from R 13 , - (pyridyl) -Q-, said pyridyl substituted with 0-2 groups independently selected from R 13 , or - (pyridazinyl) -Q-, said pyridazinyl substituted with 0-2 groups independently selected from R l or R 7; 3. Claim 3 is a compound of claim 2 selected from the group consisting of: 2 (S) -Phenylsulfonylamino-3- [2- [2- [3- [ (N-imidazolin-2- yl) amino] propyl] -1,3, -thiadiazol-5- yl] acetyl] aminopropionic acid 2 (S) - (3-methylphenylsulfonyl) amino-3- [2- [2- [3- [ (N- imidazolin-2-yl) amino] propyl] -1,3, 4-thiadiazol-5- yl] acetyl] aminopropionic acid 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [N- (pyridin-2- yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) -(2,4, 6-Trimethylphenylsulfonyl) amino-3- [ [2- [4- [N- (pyridin-2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) - (1-Naphthalenesulfonyl) amino-3- [ [2- [4- [N- (pyridin- 2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) -Benzyloxycarbonylamino-3- [ [2- [4- [ (N-imidazolin-2- yl) amino] butyl] -1,3, -thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S) - (2, 4, 6-Trimethylphenylsulfonyl) amino-3- [ [2- [4- [ (N- imidazolin-2-yl) amino] butyl] -1, 3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 2 (S)-(l-Naphthalenesulfonyl)amino-3-[ [2-[4-[ (N- imidazolin-2-yl) amino] butyl] -1,3, 4-thiadiazol-5- yl] carbonyl] aminopropionic acid TFA salt 4. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt from thereof. 5. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 2 or a pharmaceutically acceptable salt form thereof. 6. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 3 or a pharmaceutically acceptable salt form thereof. 7. A method in 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 Claim 1. 8. 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 Claim 2. 9. 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 Claim 3. 10. A method of treating thromboembolic disorders selected from thrombus or embolus formation, harmful platelet aggrgation, 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 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 threapeutically effective amount of a compound of Claim 2. 12. A method of treating thromboembolic disorders selected from thrombus or embolus formation, harmful platelet aggregaion, 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 3.

Inventors: CONFALONE PASQUALE N, JIN FUQIANG, CONFALONE, PASQUALE, N., Jin, Fuqiang
Applicants: DU PONT PHARM CO, DU PONT PHARMACEUTICALS COMPANY
Application year: 1998
Main classification: C07D417
IPC codes: A61K31, A61P1, A61P3, A61P7, A61P9, A61P11, A61P17, A61P19, A61P29, A61P35, A61P37, C07D413, C07D417