WO2007027742A2

WO2007027742A2 - SMALL MOLECULE INTEGRIN α2βl/GPIa-IIa ANTAGONISTS

Info

Publication number: WO2007027742A2
Application number: PCT/US2006/033819
Authority: WO
Inventors: Sungwook Choi; Seth E. Snyder; William F. Degrado; Joel S. Bennett
Original assignee: The Trustees Of The University Of Pennsylvania
Priority date: 2005-08-31
Filing date: 2006-08-29
Publication date: 2007-03-08
Also published as: WO2007027742A3

Abstract

Novel compounds inhibiting the integrin α2βl /GPIa-IIa receptor are disclosed. Also disclosed are pharmaceutical compositions containing the compounds, as well as methods of their therapeutic uses. The compounds disclosed are useful, inter alia, as inhibitors of integrin α2βl/GPIa-IIa-mediated activity.

Description

SMALL MOLECULE INTEGRIN α2βl/GPIa-IIa ANTAGONISTS

CROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to U.S. Provisional Patent Application No. 60/712,775, filed August 31, 2005, the entire contents of which are incorporated herein by reference.

GOVERNMENT RIGHTS

[0002] The United States Government may have rights in the invention described herein, which was made in part with funding from the U.S. National Institutes of Health, Grant Nos. POl HL40387-011 and P50 HL54500.

FIELD OF THE INVENTION

[0003] The present invention relates to small molecule inhibitors of the α2βl/GPIa-IIa integrin, as well as methods of production, use, and therapeutic administration thereof.

BACKGROUND OF THE INVENTION

[0004] Recruitment, adhesion, and aggregation of platelets at sites of vascular injury are critical to generation of beneficial blood clotting events. However, excessive accumulation of

platelets, e.g., at sites of ruptured atheriosclerotic plaques, can give rise to the development of acute coronary syndromes, stroke, ischaemic complications of peripheral vascular disease, and other disease states. Fuster, V., Badimon, L., Badimon, J.J. & Chesebro, JH. The Pathogenesis of Coronary Artery Disease and the Acute Coronary Syndromes (1). N. Engl. J. Med. 326, 242- 250 (1992); FaIk, E, Shah, P.K. & Fuster, V. Coronary Plaque Disruption. Circulation 92, 657- 671 (1995). Promise for enhanced clinical management of such vascular diseases has arisen in recent years with progress in understanding of the mechanisms underlying the formation of arterial plaque and thrombosis and of the criticality of the role of platelet activity in the development of cardiovascular disease.

[0005] Tempered by the understanding that antithrombotic treatment should be effective and yet avoid undermining hemostasis, clinicians of cardiovascular disease prevention and treatment have depended on mild therapeutic agents like aspirin and clopidogrel for widespread application. There are a variety of other antithrombotic drugs, including Coumadin and abciximab (ReoPro®), ticlopidine, and others, but there remains an urgent need for newer and safer antithrombotics, to address stroke, deep vein thrombosis (DVT), myocardial infarction, coronary artery disease, cerebrovascular disease, peripheral arterial disease, diabetes mellitus, atrial fibrillation, congestive heart failure, and other vascular disorders. Jackson SP and Schoenwaelder SM. Antiplatelet Therapy: In Search of the 'Magic Bullet'. Nat. Rev. Drug. Discov. 2(10), 775-89 (2003). Review. More versatile and effective and yet selective and safe therapeutic agents are currently the object of extensive research worldwide, especially in light of the increasing prevalence of cardiovascular disease both due to changes in diet and lifestyle and in view of the aging of the population. Special emphasis has been placed on the issue of improving efficacy without compromising safety, since all forms of presently available antithrombotic therapies cannot be administered at potent doses without producing negative physiological conditions, primarily bleeding events.

[0006] Upon vessel injury and attendant removal or damage of the protective endothelial lining, platelets encounter a diverse set of proteins from the connective tissue of the vessel wall. These include collagen and von Willebrand factor (vWf). Platelet adhesion to these proteins and subsequent activation is mediated by a multitude of platelet receptors. Adhesion of platelets to the extracellular matrix triggers a series of signaling events that ultimately result in formation of a hemostatic plug known as a thrombus. Recent findings provide strong evidence that immediately following vessel rapture, the platelet receptor GPVI binds loosely to exposed collagen, which is alone insufficient to induce stable platelet adhesion, but which triggers a tyrosine kinase-based signaling pathway that results in major conformational changes and attendant activation in specific receptors, including integrin α2βl. Emsley J, Knight CG, Farndale RW, Barnes MJ, Liddington RC. Structural Basis of Collagen Recognition by Integrin AlphalBetal. Cell. 101(1), 47-56 (2000).

[0007] Integrin α2βl, also known as platelet GPIa-IIa, was the first collagen receptor to be identified on platelets. Nieuwenhuis HK, Akkerman JW, Houdijk WP, Sixma JJ. Human Blood Platelets Showing No Response to Collagen Fail to Express Surface Glycoprotein Ia. Nature. 318(6045), 470-2 (1985); Santoro SA. Identification of a 160,000 Dalton Platelet Membrane Protein That Mediates the Initial Divalent Cation-dependent Adhesion of Platelets to Collagen. Cell. 46(6), 913-20 (1986). Similar to other members of the integrin family, α2βl links the cytoskeleton of the cell with the extracellular matrix. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 110(6) :673-87. Review (2002). Besides playing an essential role in adhesion to the extracellular matrix, integrins are indispensable for cellular signaling. All integrins are heterodimers, consisting of an α subunit and a β subunit. About half of the known mammalian integrins, including α2βl, have an I-domain inserted into the α subunit. Hynes et al. (2002). In these cases, the I-domain is responsible for binding of the integrin to its natural ligand(s). A specific amino acid sequence in collagen, GFOGER (O = hydroxyproline), promotes stable binding to the I-domain of α2βl OnleyDJ, Knight CG, Tuckwell DS, Barnes MJ, Farndale RW. Micromolar Ca2+ coyicentrations are essential for Mg2+-dependent binding of collagen by the integrin alpha 2beta 1 in human platelets. J Biol Chem. 275 (32) :24560-4 (2000). Binding occurs in a cation dependent manner, supported by either magnesium or manganese Tuckwell D, Calderwood DA, Green LJ, Humphries MJ. Integrin alpha 2 I-domain is a binding site for collagens. J Cell Sd. 108(Pt 4): 1629-37 (1995). A crystal structure of a complex between the I-domain of α2βl and a triple helical peptide containing the GFOGER sequence has been solved. Emsley J Knight CG, Farndale RW, Barnes MJ, Liddington RC. Structural basis of collagen recognition by integrin alpha2betal. Cell. 101(1), 47-56 (2000). A glutamic acid (E) from the middle strand of the triple helix coordinates to metal-ion dependent adhesion site (MIDAS) while other residues of the GFOGER motif from the middle and trailing strands interact with complementary sites on the I-domain surface. a

[0008] Importantly, integrin α2βl has multiple states of activation which can be regulated from inside or outside of the cell Hynes RO. Integiins: bidirectional, allosteric signaling machines. Cell. 110(6): 673-87. Review (2002). For instance, signaling through the platelet receptor GPVI impinges upon the cytoplasmic domain of α2βl, which results in a dramatic conformational change that eventually propagates along the α2βl integrin, ultimately affecting the I-domain at the integrin' s head. Integrin activation is induced by several other platelet agonists, including ADP and thrombin. Jung SM, Moroi M. Platelets interact with soluble and insoluble collagens through characteristically different reactions. J Biol Chem. 273 (24). -14827 -37 (1998). The activated integrin can than bind tightly to collagen. This adhesion can potentially be blocked with either a direct competitor of the collagen/I-domain interaction or with an allosteric regulator, the latter of which precludes activation of the I domain. Two types of small-molecule inhibitors have been developed for a related integrin, αLβ2. Shimaoka M, Salas A, Yang W, Weitz-Schmidt G, Springer TA. Small molecule integrin antagonists that bind to the beta2 subunit I-like domain and activate signals in one direction and block them in the other. Immunity. 19(3):391-402 (2002). The first binds to the I-domain of αLβ2 at a distant site from the MIDAS, blocking activation of its I domain and subsequent binding to ICAM-I. The second binds to the I-like domain of the β subunit, which is located directly beneath the I domain. A direct competitive inhibitor of an I-domain/ligand interaction has not yet been reported.

[0009] Despite the fact that α2βl integrin was discovered more than 15 years ago, its precise role in platelet adhesion and aggregation remains controversial. This is partially due to the overlapping functions of α2βl and GPVI. Chen H, Kahn ML. Reciprocal signaling by integrin and nonintegrin receptors during collagen activation of platelets. MoI Cell Biol. 23(14):4764-77 (2003). Integrin α2βl is essential for platelet adhesion and activation on monomelic type I collagen; it has been demonstrated through platelet analysis that adhesion and thrombus growth on pepsin-solubilized type I collagen under low and high shear flow conditions is absolutely dependent on functional α2βl. Savage B, Ginsberg MH, Ruggeri ZM. Influence of Fibrillar Collagen Structure on the Mechanisms of Platelet Thrombus Fojination Under Flow. Blood. 94(8), 2704-15 (1999); NieswandtB, Brakebusch C, Bergmeier W, Schulte V, BouvardD, Mokhtari-Nejad R, Lindhout T, HeemskerkJW, ZiimgiblH, Fassler R. Glycoprotein VI But Not Alpha2Betal Integrin is Essential For Platelet Interaction With Collagen. EMBOJ. 20(9), 2120- 30 (2001). However, on the more physiologically relevant insoluble collagen (fibrillar collagen), α2βl integrin may be dispensable, at least in the context of hemostasis. Nieswandt B, Watson SP. Platelet-Collagen Interaction: Is GPVI the Central Receptor? Blood. 102(2), 449-6 (2003). Review. For instance, fibrillar collagen-induced aggregation of βl -null mouse platelets is not reduced, despite a slight time delay. Nieswandt B, Brakebusch C, Bergmeier W, Schulte V, BouvardD, Mokhtari-Nejad R, Lindhout T, Heemskerk JW, ZirngiblH, FasslerR. Glycoprotein VI But Not Alpha2B eta 1 Integrin is Essential For Platelet Interaction With Collagen. EMBO J. 20(9), 2120-30 (2001). Furthermore, the βl-null platelets adhere normally to fibrillar collagen under static conditions. Nonetheless, it has been established that adhesion under physiological conditions of blood flow requires a functional α2βl integrin. Siljander PR, MunnixIC, Smethurst PA, Deckmyn H, Lindhout T, Ouwehand WH, Farndale RW, Heemskerk JW. Platelet receptor interplay regulates collagen-induced thrombus formation inflowing human blood. Blood. 103(4):1333-41 (2004).

[0010] Studies of platelets derived from two individuals with an integrin α2βl deficiency have demonstrated a defect in adhesion and spreading on the subendothelium. Nieswandt B, et al. (2001); Ruggeri ZM. Platelets In Atherothrombosis. Nat Med. 8(11), 1227-34 (2002). Review. Indeed, these patients exhibit only modest degree of defect in hemostasis, manifested as only minor bleeding complications. Nieuwenhuis HK, et ah, Nature. 318(6045), 470-2 (1985); Nieuwenhuis HK, Sakariassen KS, Houdijk WP, Nievelstein PF, Sixma JJ Deficiency of Platelet Membrane Glycoprotein Ia Associated With a Decreased Platelet Adhesion to Subendothelium: A Defect in Platelet Spreading. Blood. 68(3), 692-5 (1986). This has important implications for the search for antithrombotic therapies with favorable safety profiles. It suggests that antagonism of α2βl integrin will have a beneficially mild antithrombotic effect; increasing amount of evidence indeed suggests that α2βl may have a greater role in pathological thrombosis relative to normal hemostasis. This observation may reflect the fact that an increased amount of collagen accumulates in diseased blood vessels. For instance, the extracellular matrix around an atheroslerotic lesion is heavily enriched in collagens. Nieswandt B, et al, (2003). Besides providing an adhesive support for platelets, collagen sends potent prothrombotic signals into the cell through interaction with its platelet receptors. Overexpression of α2βl integrin has been linked to cardiovascular disease in humans. KritzikM, Savage B, Nugent DJ, Saritoso S, Ruggeri ZM, Kunicki TJ. Nucleotide polymorphisms in the alpha2 gene define multiple alleles that are associated with differences in platelet alpha2 betal density. Blood. 92(7):2382-8 (1998). Furthermore, recent in vivo data indicates that α2βl -deficient mice have delayed thrombus formation following carotid artery injury. He L, Pappan LK, Grenache DG, Li Z, Tollefsen DM, Santoro SA, Zutter MM. The contributions of the alpha 2 beta 1 integrin to vascular thrombosis in vivo. Blood. 102 (10): 3652-7 (2003). These data reveal a critical role for α2βl in thrombosis. Hence, the α2βl integrin is an important pharmacological target for cardiovascular diseases, and the resulting treatment is expected to be well-tolerated and provide long-term antithrombotic protection.

[0011] Equally significant, the α2βl integrin may be a target for cancer, several types of viral infections, and other pathologies. Overexpression of α2βl in various types of cancer cells, particularly in human melanoma cells and hepatocellular carcinomas, has been linked to tumor metastasis. Han J, Jenq W, Kefalides NA. Integrin Alpha2Betal Recognizes Laminin-2 and Induces C-erb B2 Tyrosine Phosphorylation in Metastatic Human Melanoma Cells. Connect Tissue Res. 40(4), 283-93 (1999). Yang C, ZeisbergM, Lively JC, NybergP, AfdhalN, Kalluri R. Integrin Alphal Betal and Alpha2Betal Are the Key Regulators of Hepatocarcinoma Cell Invasion Across the Fibrotic Matrix Microenvironment. Cancer Res. 63(23), 8312-7 (2003). The α2βl integrin is known to be the primary melanoma cell adhesion molecule for type IV collagen, indicating a key role for that integrin in pathological metastasis Knutson JR, Iida J, Fields GB, McCarthy JB. CD44/Chondroitin Sulfate Proteoglycan and Alpha 2 Beta 1 Integrin Mediate Human Melanoma Cell Migration on Type TV Collagen and Invasion of Basement Membranes. MoI Biol Cell. 7(3), 383-96 (1996). Ligand binding by the α2βl integrin triggers a series of intracellular signaling events that ultimately result in the release of cytokines and proteases, both of which are beneficial for tumor cell progression. Baronas-Lowell D, Lauer-Fields JL, Borgia JA, Sferrazza GF, Al-GhoulM, MinondD, Fields GB. Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by Alpha2Betal Integrin and CD44 Triple-Helical Ligands Derived from Type IV Collagen. J Biol Chem. 279(42), 43503-13 (2004). Furthermore, antagonism of the α2βl integrin suppresses angiogenesis. SengerDR, Perruzzi CA, StreitM, Koteliansky VE, de Fougerolles AR, Detmar M. The Alpha(l)Beta(l) and Alpha(2)Beta(l) Integrins Provide Critical Support For Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis. Am J Pathol. 160(1), 195-204 (2002). This has profound implications since angiogenesis is involved in growth and metastasis of solid tumors, rheumatoid arthritis, diabetes mellitus, diabetic retinopathy, and a variety of other important disease states. Folkman J. Angiogenesis in Cancer, Vascular, Rheumatoid and Other Disease. Nat Med. 1(1), 27-31 (1995). Review; SengerDR, Van de Water L, Brown LF, NagyJA, Yeo KT, Yeo TK, Berse B, Jachnan RW, Dvorak AM, Dvorak HF. Vascular Permeability Factor (VPF, VEGF) in Tumor Biology. Cancer Metastasis Rev. 12(3-4), 303-24 (1993). Review; Ferarra, N. The Role of Vascular Endothelial Growth Factor in Pathological Angiogenesis. Breast Cancer Res Treat. 36(2), 127-37 (1995). Review. Specific blocking of α2βl function halts capillary morphogenesis, the essential antecedent to angiogenesis, whereas blocking of related integrin dimers or monomer subunits does not similarly arrest morphogenesis. Sweeney SM, DiLuIIo G, Slater SJ, Martinez J Iozzo RV, Lauer-Fields JL, Fields GB, San Antonio JD. Angiogenesis in Collagen I Requires Alpha2Betal Ligation of a GFP*GER Sequence and Possibly p38 MAPK Activation and Focal Adhesion Disassembly. J Biol Chem. 278(33), 30516- 24 (2003). Antagonism of the α2βl integrin also curbs haptotactic endothelial cell migration, SengerDR et ah, a critical step in extravasation of tumor cells into secondary tissues.

[0012] It has also recently been shown that human cytomegalovirus (HCMV), which is extremely promiscuous and responsible for significant mortality, requires the presence of α2βl to penetrate a cell. Feire AL, Koss H, Compton T. Cellular Integrins Function as Entry Receptors For Human Cytomegalovirus Via a Highly Conserved Disintegrin-Like Domain. Proc Natl Acad Sd USA. 101(43), 15470-5 (2004). Likewise, integrin α2βl has been strongly implicated in rotavirus cell attachment and entry. Graham KL, Halasz P, Tan Y, Hewish MJ, Takada Y, Mackow ER, Robinson MK, Coulson BS. Integrin-using rotaviruses bind alpha2betal integrin άlpha21 domain via VP 4 DGE sequence and recognize alphaXbeta2 and alphaVbeta3 by using VP7 during cell entry. J Virol. 77(18), 9969-78. (2003). Rotaviruses are leading causes of acute gastroenteritis in human infants and young children and animals around the globe. Id. It has been demonstrated that inhibition of the α2βl integrin forestalls cell binding and infection by rotaviruses. Londrigan SL, Graham KL, Takada Y, Halasz P, Coulson BS. Monkey rotavirus binding to alpha2betal integrin requires the alpha21 domain and is facilitated by the homologous betal subunit. J Virol. 77(17), 9486-501 (2003). Similarly, viruses of the Piconaviridae family, such as Echovirus 1 (Echol), have also been shown to utilize the α2βl integrin during the cell-infection cycle. Triantafilou K & Triantafilou M. A biochemical approach reveals cell-surface molecules utilised by Picornaviridae: Human Parechovirus 1 and Echovirus 1. J Cell Biochem. 80(3), 373-81 (2001). Echo viruses are implicated in numerous human pathologies; for example, certain forms of aseptic meningitis and acute respiratory illness are known to be caused by the Echo-1 virus. See, e.g., Kumar R. Aseptic meningitis: Diagnosis and management. Indian JPediatr. 72(1), 57-63 (2005).

[0013] Inhibition of the α2βl integrin may prove effective in impeding binding and entry of these problematic and medically-significant viruses, and in treatment of cancers and other disease states concerning which α2βl expression and functionality is a significant factor, and previous efforts have been made to provide compounds possessing α2βl integrin inhibitory activity. See Takayanagi, Met at, WO 03/008380. As yet, however, there is an unfulfilled need in these respects.

SUMMARY OF THE INVENTION

[0014] The present invention is directed to "small" molecule inhibitors of the α2βl integrin, as well as to methods of their use for treatment of the range of α2βl -affected disease states. These include, inter alia, vascular conditions, diabetes- or rheumatoid arthritis-related conditions, cancers, and viral infections. The present invention represents a versatile and effective, yet selective and safe therapeutic regime for the treatment of α2βl -affected disease states, conditions, and infections. While not intending to be bound by any theory or theories of operation, it is believed that the compounds of the present invention may effect inhibition of the α2βl integrin by targeting the integrin' s I-domain.

[0015] Li accordance with one embodiment of invention, there are provided novel compounds of the formula I:

wherein:

R¹ is -OR⁵, -NR⁶R⁷; aryl, heteroaryl, or alkyl; R² is aralkyl, heteroaryl, aryl, or alkyl; R³ is alkyl-Z; R⁴ is C(=O)aryl, C(=O)aralkyl, C(=O)aralkoxy, C(=O)aryloxy, S(=O)₂aryl, aryl, alkyl, or heteroaryl;

R⁵ is alkyl, alkenyl, aryl, aralkyl, or heteroaryl; R⁶ and R⁷ are, independently, H or alkyl;

Z is NHC(=O)-R⁸, NHC(=O)-OR⁸, NH₂, NH-R⁸, NHS(=O)₂-R⁸, or C(=O)-O- aralkyl;

R is aryl, heteroaryl, aralkyl or alkyl; or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, or N-oxide thereof.

[0016] In other embodiments, the invention is directed to pharmaceutical compositions comprising a pharmaceutically-acceptable carrier, diluent, or excipient and a compound of the formula I. Other embodiments of the invention provide compositions comprising a stereochemically enriched mixture of compounds of formula I.

[0017] m some preferred embodiments in compounds according to formula I, R₁ is - NH₂, -OCH₃, -OCH₂CH₃, -O(CH₂)₂CH₃, -O(tert-butyl), -0(CH₂)CH=CH₂, -O(CH₂)(phenyl), or - N(CH₂)₃CH₃. R² may preferably be phenyl or -CH₂(phenyl) and phenyl is substituted or unsubstituted. Additionally, in some preferred embodiments R³ is -(CH₂)₂NH(Cbz), - (CH₂)₂NH(Boc), -(CH₂)₂NH(benzenesulfonyl), or -(CH₂)₃NH(Boc). Further, R⁴ may preferably be Cbz, Cbz-halo, Cbz-nitro, methoxy-phenyloxy-carbonyl, or benzylcarbonyl.

[0018] Accordingly, in some preferred embodiments R¹ is -NH₂, -OCH₃, -OCH₂CH₃, - O(CH₂)₂CH₃, -O(tert-butyl), -0(CH₂)CH=CH₂, -O(CH₂)(phenyl), or -N(CH₂)₃CH₃, R² is phenyl or -CH₂(phenyl) and phenyl is substituted or unsubstituted, R³ is -(CH₂)₂NH(Cbz), - (CH₂)₂NH(Boc), -(CH₂)₂NH(benzenesulfonyl), or -(CH₂)₃NH(Boc), and R⁴ is Cbz, Cbz-halo, Cbz-nitro, methoxy-phenyloxy-carbonyl, or benzylcarbonyl.

[0019] Still more preferably, R¹ is -NH₂, -OCH₃, -OCH₂CH₃, -O(CH₂)₂CH₃, -O(tert- butyl), -0(CH₂)CH=CH₂, -O(CH₂)(phenyl), or -N(CH₂)₃CH₃, R² is ~CH₂(phenyl) and phenyl is substituted or unsubstituted, R³ is -(CH₂)₂NH(Cbz) or -(CH₂)₂NH(Boc), and R⁴ is Cbz, Cbz- halo, Cbz-nitro, methoxy-phenyloxy-carbonyl, or benzylcarbonyl.

[0020] In another aspect, there are provided novel compounds of the formula II:

wherein:

R⁹ is aryl, aralkyl, or heteroaryl;

R¹⁰ is -(CH2)_n-NH₂, -(CH₂)_n-NH-alkyl, -(CH₂)_n-NH-aryl, -(CH₂)_n-NH- heteroaryl, -(CH₂)_n-NH-O-alkyl, -(CH₂)_n-NH-O-aryl, -(CH₂)_n-NH-O-heteroaryl, - (CH₂)_n-NH-C(=O)alkyl, -(CH₂)_n-NH-C(=O)aryl, -(CH₂)_n-NH-C(=O)heteroaryl, - (CH₂)_n-NH-C(=O)alkoxy, -(CH₂)_n-NH-C(=O)aralkyl, -(CH₂)_n-NH-S(=O)₂aryl; -(CH₂)_n- NH-S(=O)₂heteroaryl; R¹¹ is H or alkyl;

R is alkyl, aryl, heteroaryl, aryloxy, alkoxy, heteroaryloxy, aralkoxy; Each R¹³ is independently aryl, aryloxy, heteroaryl, arylamino; heteroarylamino; -C(=O)aryl, or -C(=O)heteroaryl n is O, 1, 2, or 3; and z is O, 1, or 2; or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, or N-oxide thereof.

[0021] In other embodiments, the invention is directed to pharmaceutical compositions comprising a pharmaceutically-acceptable carrier, diluent, or excipient and a compound of formula II. Other embodiments of the invention provide compositions comprising a stereochemically enriched mixture of compounds of formula II.

[0022] hi certain preferred embodiments, R⁹ is phenyl or phenalkyl, preferably benzyl. In yet other preferred embodiments, R¹⁰ is -(CH₂)_n-NH-Boc, and each n is the integer 0, 1, 2, or 3, more preferably, 1 or 2. hi still other preferred embodiments, R¹² is phenylmethyloxy. hi other preferred embodiments, R¹³ is benzyl, piperidinyl, or phenoxy.

[0023] In certain other preferred embodiments, R⁹ is phenyl, and R¹³ is benzyl, piperidinyl, or phenoxy. hi yet other preferred embodiments, R⁹ is phenyl, R¹³ is benzyl, piperidinyl, or phenoxy, and z equals 1. hi other preferred embodiments, R⁹ is phenyl, R¹³ is benzyl, piperidinyl, or phenoxy, z equals 1, and R¹⁰ is -(CH₂)_n-NH-Boc. In still other preferred embodiments, R⁹ is phenyl, R¹³ is benzyl, piperidinyl, or phenoxy, z equals 1, R¹⁰ is -(CH₂)_n- NH-Boc, and R¹² is phenylmethyloxy.

[0024] As discussed above, it is known that α2βl receptor activity on platelets is essential for platelet adhesion to collagen under low and high shear flow conditions. Siljander PR et al, Blood. 103(4):1333-41 (2004). This integrin-mediated adhesion, which occurs early in the hemostatic cascade, is critical to subsequent downstream events that lead to the development of a stable thrombus. Furthermore, outside-in signaling through the α2βl integrin plays an important role in thrombus formation. Inoue O, Suzuki-Inoue K, Dean WL, Frampton J, Watson SP. Integrin alpha2betal mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. J Cell Biol. 160(5). -769-80 (2003). Thus, it is expected that α2βl integrin contributes significantly to the formation of arterial plaque and thrombosis and is therefore critical to the development of cardiovascular disease; hence the erstwhile preference for weak antithrombotic medicaments like aspirin and clopidogrel, and reluctant use of stronger compounds that alleviate thrombogenesis but that also provoke disruption of hemostasis. Therefore, in certain other embodiments the invention is directed to a method for treating at least one α2βl -affected vascular disorder or condition, comprising the step of administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of the formulas I or II.

[0_.025] Still other embodiments are directed to methods for treating at least one α2βl- affected vascular disorder or condition, comprising the step of administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of the formulas I or II.

[0026] In another aspect, the invention is directed to methods for treating a subject suffering from or susceptible to one or more of acute coronary syndromes, stroke, ischaemic complications of peripheral vascular disease, deep vein thrombosis (DVT), myocardial infarction, coronary artery disease, cerebrovascular disease, peripheral arterial disease, diabetes mellitus, atrial fibrillation, congestive heart failure, pulmonary embolism, and other vascular- related disorders, comprising the step of administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of the formulas I or II. [0027] It is believed that α2βl activity is closely associated with certain cancers and the processes linked thereto, several types of viral infections, diabetes, rheumatoid arthritis, and numerous other pathologies. Accordingly, the present invention also includes methods for treating cancer-related, diabetes-related, or rheumatoid disease states, comprising the step of administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of the formulas I or II.

[0028] In another aspect, the invention is directed to methods of treatment a subject wherein the subject is suffering from or susceptible to one or more of human melanoma, hepatocellular carcinoma, breast cancer, lung cancer, ovarian cancer, and other cancers and cancer-related disorders.

[0029] In certain other embodiments, the invention is directed to methods of treating one or more of rheumatoid arthritis, diabetes mellitus, diabetic retinopathy, and other diabetes- or rheumatoid-related disorders.

[0030] In still other embodiments, the invention provides methods for effecting treatment of morphogenesis-or matrix reorganization-affected disease states.

[0031] In yet other embodiments, the invention is directed to methods for treating angiogenesis-affected disease states.

[0032] In other aspects, the invention provides methods for treating pathologies that are cell migration-, cell proliferation-, cell colonization- or metastasis-affected.

[0033] In still other aspects the invention provides methods for treating pathologies that are leukocyte infiltration-affected.

[0034] The present invention, in other embodiments, provides methods for treating edema-affected disease states.

[0035] Another aspect of the present invention is directed to methods of treating a subject that is suffering from or susceptible to viral infection.

[0036] A further aspect of the present invention provides methods for treating viral infections that are at least partially attributable to human cytomegalovirus (HCMV), rotaviruses, Piconaviridae viruses or related viruses. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0037] As employed above and throughout the disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings. [0038] "DAP" denotes 2,3-diaminoρropionic acid.

[0039] "EDC" stands for l-CS-DimethylaminopropyO-S-ethylcarbodiimide hydrochloride.

[0040] "HOBT" means 1-Hydroxybenzotriazole hydrate.

[0041] Protective groups are abbreviated according to the system disclosed in Greene, T. W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991, which is incorporated in its entirety herein. For example, "CBZ" or "Cbz" stands for carbobenzyloxy or benzyloxycarbonyl, "Boc" or "BOC" represents t-butoxycarbonyl, "Alloc" denotes allyloxycarbonyl, Bz means benzoyl, and "Fmoc" stands for 9- fluorenylmethoxycarbonyl.

[0042] In the present disclosure the singular forms "a," "an," and "the" include the plural reference unless the context clearly indicates otherwise. Thus, for example, a reference to "an antagonist" includes a plurality of such antagonists, and a reference to "a compound" is a reference to one or more compounds and equivalents thereof known to those skilled in the art, and so forth.

[0043] As used herein, the terms "component," "composition of compounds," "compound," "drug," "pharmacologically active agent," "active agent," "therapeutic," "therapy," "treatment," or "medicament" are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.

[0044] The abbreviations in the specification correspond to units of measure, techniques, properties, or compounds as follows: "min" means minute(s), "g" means gram(s), "mg" means milligram(s), "μg" means microgram(s), "eq" means equivalent(s), "h" means hour(s), "μL" means microliter(s), "mL" means milliliter(s), "mM" means millimolar, "M" means molar, "mmol" or "mmole" means millimole(s), "cm" means centimeters, "SEM" means standard error of the mean, and "IU" means International Units. "IC₅₀ value" or "IC₅₀" means dose of the compound which results in 50% alleviation or inhibition of the observed condition or effect.

[0045] As used herein, "alkyl" refers to an optionally substituted, saturated straight, or branched, hydrocarbon radical having from about 1 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein). [0046] As used herein, "aryl", "arene", and "aromatic" each refer to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system having from about 5 to about 50 carbon atom ring members (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 10 carbon ring atom members being preferred.

[0047] As used herein, "alkenyl" refers to an alkyl radical having from about 2 to about 20 carbon atoms and one or more double bonds (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), wherein alkyl is as previously defined. In some embodiments, it is preferred that the alkenyl groups have from about 2 to about 6 carbon atoms. Alkenyl groups may be optionally substituted.

[0048] As used herein, "aralkyl" refers to alkyl radicals bearing one or more aryl substituents and having from about 6 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), wherein aryl and alkyl are as previously defined. In some preferred embodiments, the alkyl moieties of the aralkyl groups have from about 1 to about 4 carbon atoms. In other preferred embodiments, the alkyl moieties have from about 1 to about 3 carbon atoms. Aralkyl groups may be optionally substituted.

[0049] "Alkylamino" signifies alkyl-(NH)-, wherein alkyl is as previously described. "Arylamino" represents aryl-(NH)-, wherein aryl is as defined herein. "Heteroarylamino" as used herein refers to heteroaryl-(NH)-, wherein heteroaryl is as defined herein. Likewise, "aralkylamino" is used to denote aralkyl-(NH)-, wherein aralkyl is as previously defined. "Alkoxy" as used herein refers to the group R-O- where R is an alkyl group, and alkyl is as previously described. "Aryloxy" as used herein means R-O-, where R is aryl and is as previously defined. "Hetero aryloxy" as used herein means R-O-, where R is heteroaryl and as is defined herein. "Aralkoxy" stands for R-O-, wherein R is an aralkyl group as previously defined. "Alkylsulfonyl" means alkyl-SO₂- , wherein alkyl is as previously defined.

[0050] As used herein, "alkylene" refers to a bivalent alkyl radical having the general formula -(CH₂)_n-, where n is 1 to 10. Non-limiting examples include methylene, trimethylene, pentamethylene, and hexamethylene. Alkylene groups may be optionally substituted.

[0051] As used herein, "heteroaryl" refers to an aryl radical wherein in at least one of the rings, one or more of the carbon atom ring members is independently replaced by a heteroatom group selected from the group consisting of S, O, N, and NH, wherein aryl is as previously defined. Heteroaryl groups having a total of from about 5 to about 14 carbon atom ring members and heteroatom ring members are preferred. Likewise, a "heterocyclic ring" may be an aryl radical wherein one or more of the carbon atom ring members is independently replaced by a heteroatom group selected from the group consisting of S, O, N, and NH. Heterocyclic rings having a total from about 5 to 14 carbon atom ring members and heteroatom ring members are preferred.

[0052] "Halo" and "halogen" each refers to a fluoro, chloro, bromo, or iodo moiety, with fluoro, chloro, or bromo being preferred.

[0053] Typically, substituted chemical moieties include one or more substituents that replace hydrogen. Exemplary substituents include, for example, halo (e.g., F, Cl, Br, I), alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl (-OH), nitro (-NO₂), cyano (-CN), amino (-NH₂), -N-substituted amino (-NHR"), -N,N-disubstituted amino (-N(R")R"), oxo (=0), carboxy (-COOH), -O-C(=O)R", -C(O)R", -OR", -C(=0)0R", -(alkylene)-C(=O)-OR", -NBC(O)R", aminocarbonyl (-C(O)NB₂), -N-substituted aminocarbonyl (-C(O)NHR"), -N,N-disubstituted aminocarbonyl (-C(O)N(R")R"), thiol, thiolato (-SR"), sulfonic acid (-SO₃H), phosphoric acid (-PO₃H), -P(=O)(OR")OR", -S(O)R", -S(O)₂R", -S(O)₂NH₂, -S(O)₂ NHR", -S(O)₂NR⁵⁵R", -NHS(O)₂R", -NR⁵⁵S(O)₂R", -CF₃, -CF₂CF₃, -NHC(O)NHR", -NHC(O)NR⁵⁵R", -NR⁵⁵C(O)NHR", -NR"C(O)NR"R", -NR⁵⁵C(O)R" and the like, hi relation to the aforementioned substituents, each moiety R⁵⁵ can be, independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, for example.

[0054] As used herein, the terms "treatment⁵⁵ or "therapy⁵⁵ (as well as different word forms thereof) includes preventative (e.g., prophylactic), curative, or palliative treatment.

[0055] As employed above and throughout the disclosure the term "effective amount⁵⁵ refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to the treatment of the relevant disorder, condition, or side effect. It will be appreciated that the effective amount of components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration, and the ability of the components (alone or in combination with one or more combination drugs) to elicit a desired response in the individual, but also with factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the patient, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. Dosage regimens may be adjusted to provide the improved therapeutic response. An effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects. As an example, the compounds useful in the methods of the present invention are administered at a dosage and for a time such that the level of activation and adhesion activity of platelets is reduced as compared to the level of activity before the start of treatment.

[0056] "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.

[0057] Within the present invention, the disclosed compounds may be prepared in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound 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. These physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.

[0058] Compounds described herein throughout, can be used or prepared in alternate forms. For example, many amino-containing compounds can be used or prepared as an acid addition salt. Often such salts improve isolation and handling properties of the compound. For example, depending on the reagents, reaction conditions and the like, compounds as described herein can be used or prepared, for example, as their hydrochloride or tosylate salts. Isomorphic crystalline forms, all chiral and racemic forms, N-oxide, hydrates, solvates, and acid salt hydrates, are also contemplated to be within the scope of the present invention.

[0059] Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxy groups often exist in equilibrium with their zwitterionic forms. Thus, any of the compounds described herein throughout that contain, for example, both amino and carboxy groups, also include reference to their corresponding zwitterions.

[0060] "Hydrate" refers to a compound of the present invention which is associated with water in the molecular form, i.e., in which the H-OH bond is not split, and may be represented, for example, by the formula RzH₂O, where R is a compound of the invention. A given compound may form more than one hydrate including, for example, monohydrates (R-H₂O) or polyhydrates (R^*nH₂0 wherein n is an integer > 1) including, for example, dihydrates (R^* 2H₂O), trihydrates (R^* 3H₂O), and the like, or hemihydrates, such as, for example,

R"n_/2H₂θ, R^*n_/3H₂O, R^*n_/4H₂O and the like wherein n is an integer.

[0061] "Solvate" refers to a compound of the present invention which is associated with solvent in the molecular form, i.e., in which the solvent is coordinatively bound, and may be represented, for example, by the formula R^* (solvent), where R is a compound of the invention. A given compound may form more than one solvate including, for example, monosolvates (R^* (solvent)) or polysolvates (R^*n(solvent)) wherein n is an integer > 1) including, for example, disolvates (R'2(solvent)), trisolvates (R^*3(solvent)), and the like, or hemisolvates, such as, for example, Rτi/₂(solvent), R'n_/3(solvent), R'n_/4(solvent) and the like wherein n is an integer.

Solvents herein include mixed solvents, for example, methanol/water, and as such, the solvates may incorporate one or more solvents within the solvate.

[0062] "Acid hydrate" refers to a complex that may be formed through association of a compound having one or more base moieties with at least one compound having one or more acid moieties or through association of a compound having one or more acid moieties with at least one compound having one or more base moieties, said complex being further associated with water molecules so as to form a hydrate, wherein said hydrate is as previously defined and R represents the complex herein described above.

[0063] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ as regards the arrangement of the atoms or groups in space.

[0064] "Racemic" means having the capacity for resolution into forms of opposed optical activity.

[0065] As used herein, the term "partial stereoisomer" refers to stereoisomers having two or more chiral centers wherein at least one of the chiral centers has defined stereochemistry (i.e., R or S) and at least one has undefined stereochemistry (i.e., R or S). When the term "partial stereoisomers thereof is used herein, it refers to any compound within the described genus whose configuration at chiral centers with defined stereochemistry centers is maintained and the configuration of each undefined chiral center is independently selected from R or S. For example, if a stereoisomer has three chiral centers and the stereochemical configuration of the first center is defined as having "S" stereochemistry, the term "or partial stereoisomer thereof refers to stereoisomers having SRR, SRS, SSR, or SSS configurations at the three chiral centers, and mixtures thereof.

[0066] "Prodrug" refers to compounds which are themselves inactive or minimally active for the activity desired, but through biotransformation can be converted into biologically active metabolites. For example, a prodrug of the present invention would include, inter alia, any compound which is convertible in vivo by metabolic means to a compound claimed or described in the present disclosure.

[0067] "N-oxide" refers to compounds wherein the basic nitrogen atom of either a heteroaromatic ring or tertiary amine is oxidized to give a quaternary nitrogen bearing a positive formal charge and an attached oxygen atom bearing a negative formal charge. [0068] When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0069] As used herein, the terms "modulation" or "mediation" refer to the capacity to either enhance or inhibit a functional property of a biological activity or process, for example, receptor binding or signaling activity. Such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway and/or may be manifest only in particular cell types. The modulator is intended to comprise any compound, e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, preferably small molecule, or peptide.

[0070] hi the present disclosure, the term "inhibitor" is intended to comprise any compound or agent, e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, preferably small molecule or peptide, that exhibits a partial, complete, competitive and/or inhibitory effect by inhibiting, suppressing, repressing, or decreasing a specific activity, such as platelet activation or adhesion activity, stabilization of thromboses, metastasis, angiogenesis, or viral infection, hi certain embodiments, the term preferably refers to an inhibitor of human pathological platelet activity, thus diminishing or blocking, preferably diminishing, some or all of the biological effects of pathological platelet activity. In certain other embodiments, the term preferably refers to an inhibitor of angiogenesis, metastasis, morphogenesis, matrix reorganization, cell migration, cell proliferation, cell colonization, or leukocyte infiltration, hi still other embodiments, the term preferably refers to an inhibitor of viral infection.

[0071] The term "administering" means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.

[0072] "Dosage unit" refers to physically discrete units suited as unitary dosages for the particular individual to be treated. Each unit may contain a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect(s) in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention may be dictated by (a) the unique characteristics of the active compound(s) and the particular therapeutic effect(s) to be achieved, and (b) the limitations inherent in the art of compounding such active compound(s).

[0073] The term "vascular system" refers to the vessels and tissue that carry or circulate fluids in the body of an animal, including but not limited to the heart, blood vessels, lymphatic, pulmonary, and portal systems.

[0074] The phrases "vascular disease", "vascular disorder", "vascular condition", "vascular pathology", and the like, refer to bodily states affecting the channels and tissue that carry body fluids, such as, but not limited to stroke, deep vein thrombosis (DVT), myocardial infarction, coronary artery disease, cerebrovascular disease, peripheral arterial disease, diabetes mellitus, atrial fibrillation, and congestive heart failure, acute coronary syndromes, stroke, pulmonary embolism, and ischaemic complications of peripheral vascular disease.

[0075] The term "angiogenesis" refers to the growth, formation, migration, infiltration, or proliferation of blood vessels.

[0076] "Subject" or "patient" refers to an embryonic, immature, or adult animal, including the human species, that is treatable with the compositions, and/or methods of the present invention.

[0077] All units and percents are by weight unless indicated otherwise.

[0078] The present invention is directed to small-molecule inhibitors of the α2βl integral and methods of their use for the treatment of certain vascular disorders and conditions, cancers, diabetes- and arthritis-related conditions, and viral infections. Because the activity of the disclosed compounds of the formulas I and II is attributable to α2βl antagonism and otherwise provides inhibition of particular collagen-induced platelet activity, with respect to treatment of vascular conditions, administration thereof represents an extremely promising and heretofore unachieved strategy for safe antithrombotic therapy and treatment of other disease states associated with the vascular system. For example, it is believed that the present invention described presents a substantial breakthrough in the field of treatment, alleviation, inhibition, and/or prevention of such disorders and conditions, including, but not limited to, stroke, deep vein thrombosis (DVT), myocardial infarction, coronary artery disease, cerebrovascular disease, peripheral arterial disease, atrial fibrillation, and congestive heart failure, acute coronary syndromes, stroke, pulmonary embolism, and ischaemic complications of peripheral vascular disease. In an additional aspect, the present invention represents a promising and distinctive therapy for cancer and cancer-related conditions, including, but not limited to human melanoma, hepatocellular carcinoma, breast, lung, and ovarian cancers, pathological angiogenesis, metastasis, and leukocyte infiltration. In a still further aspect, the invention provides a means of treatment for diabetes- and arthritis-related ailments, such as rheumatoid arthritis, diabetic retinopathy, diabetes mellitus, and related conditions. Administration of the compounds of the formulas I and II also provide medicinal therapy as against infection by the human cytomegalovirus, rotaviruses, or Piconaviridae viruses, or susceptibility thereto.

[0079] In accordance with one embodiment of invention, there are provided novel compounds of the formula I:

wherein:

R¹ is -OR⁵, -NR⁶R⁷; aryl, heteroaryl, or alkyl;

R is aralkyl, heteroaryl, aryl, or alkyl;

R³ is alkyl-Z;

R⁴ is C(=O)aryl, C(=O)aralkyl, C(=O)aralkoxy, C(=O)aryloxy, S(=O)₂aryl, aryl, alkyl, or heteroaryl;

R⁵ is alkyl, alkenyl, aryl, aralkyl, or heteroaryl;

R⁶ and R⁷ are, independently, H or alkyl;

Z is NHC(=O)-R⁸, NHCO=O)-OR⁸, NH₂, NH-R⁸, NHS(=O)₂-R⁸, or C(=O)-O- aralkyl;

[0080] hi other embodiments, the invention is directed to pharmaceutical compositions comprising a pharmaceutically-acceptable carrier, diluent, or excipient and a compound of the formula I. Other embodiments of the invention provide compositions comprising a stereochemically enriched mixture of compounds of formula I. [0081] In certain preferred embodiments of compounds of the formula I, R¹ is -NH₂, - OCH₃, -OCH₂CH₃, -O(CH₂)₂CH₃, -O(tert-butyl), -0(CH₂)CH=CH₂, -O(CH₂)(phenyl), or - N(CH₂)₃CH₃.

[0082] In some preferred embodiments, R² is phenyl or -CH₂(phenyl), and phenyl is substituted or unsubstituted.

[0083] In some other preferred embodiments, R² is phenyl, and phenyl is substituted with fluorine. R³ may be -(CH₃)₂NH(Cbz), -(CH₃)₂NH(Boc), -(CH₃)₂NH-(benzenesulfonyl), or -(CH₃)₃NH(Boc).

[0084] In certain preferred embodiments of compounds of formula I, the compound is selected from the group consisting of:

2-(2,5-Bis-benzyloxycarbonylamino-pentanoylamino)-3-(4-fluoro-phenyl)-propionic acid ethyl ester;

2-(2,5-Bis-benzyloxycarbonylamino-pentanoylamino)-3-phenyl-propionic acid allyl ester; [4-tert-Butoxycarbonylamino- 1 -(I -carbamoyl-2-phenyl-ethylcarbamoyl)-butyl] -carbamic acid benzyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid propyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-(4- fluoro-phenyl)-propionic acid ethyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid allyl ester;

[4-tert-Butoxycarbonylamino- 1 -( 1 -carbamoyl-2-phenyl-ethylcarbamoyl)-butyl] -carb amic acid benzyl ester;

{4-Benzyloxycarbonylamino- 1 -[ 1 -butylcarbamoyl-2-(4-fluoro-phenyl)-ethylcarbamoyl] - butyl} -carbamic acid benzyl ester;

2-(2,5-Bis-benzyloxycarbonylamino-pentanoylamino)-3-phenyl-propionic acid ethyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid methyl ester;

[4-Benzenesulfonylamino-l-(l-carbamoyl-2-phenyl-ethylcarbamoyl)-butyl]-carbamic acid benzyl ester; 2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid benzyl ester;

2-(2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionylamino)-3-phenyl- propionic acid methyl ester;

[4-tert-Butoxycarbonylamino-l-(l-carbamoyl-2-phenyl-ethylcarbamoyl)-butyl]-carbamic acid benzyl ester;

3-Benzyloxycarbonylamino-N-(l-methoxycarbonyl-2-phenyl-ethyl)-succinamic acid benzyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid ethyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-4-methyl- pentanoic acid allyl ester;

[5-Benzyloxycarbonylamino-5-(l-carbamoyl-2-phenyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester;

2-(2-Benzenesulfonylamino-5-tert-butoxycarbonylammo-pentanoylamino)-3-phenyl- propionic acid methyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid tert-butyl ester;

(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-phenyl-acetic acid methyl ester;

2-[5-tert-Butoxycarbonylamino-2-(2-chloro-benzyloxycarbonylamino)-pentanoylamino]- 3-(4-fluoro-phenyl)-propionic acid ethyl ester;

2-[5-tert-Butoxycarbonylamino-2-(4-nitro-benzyloxycarbonylamino)-pentanoylamino]-3- (4-fluoro-phenyl)-propionic acid ethyl ester;

2-(5-tert-Butoxycarbonylamino-2-phenylacetylamino-pentanoylammo)-3-(4-fluoro- phenyl)-propionic acid ethyl ester; and,

2-[5-tert-Butoxycarbonylamino-2-(4-methoxy-phenoxycarbonylamino)-pentanoylamino]- 3-(4-fluoro-phenyl)-propionic acid ethyl ester.

[0085] In another aspect, there are provided novel compounds of the formula II:

wherein:

R⁹ is aryl, aralkyl, or heteroaryl;

R¹⁰ is -(CH₂)_n-NH₂, -(CH₂)_n-NH-alkyl, -(CH₂)_n-NH-aryl, -(CH₂)_n-MΪ- heteroaryl, -(CH₂)_n-NH-O-alkyl, -(CH₂)_n-NH-O-aryl, -(CH₂)_n-NH-O-heteroaryl, - (CH₂)_n-NH-C(=O)alkyl, -(CH₂)_n-NH-C(=O)aryl, -(CH₂)_n-NH-C(=O)heteroaryl, - (CH₂)_n-NH-C(=O)alkoxy, -(CH₂)_n-NH-C(=O)aralkyl, -(CH₂)_n-NH-S(=O)₂aryl; -(CH₂)_n- NH-S(=O)₂heteroaryl;

R^π is H or alkyl;

R is alkyl, aryl, heteroaryl, aryloxy, alkoxy, heteroaryloxy, aralkoxy; Each R¹³ is independently aryl, aryloxy, heteroaryl, arylamino; heteroarylamino; -C(=O)aryl, or -C(=O)heteroaryl n is O, 1, 2, or 3; and z is 0, 1, or 2; or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, or N-oxide thereof.

[0086] Likewise, in other embodiments, the invention is directed to pharmaceutical compositions comprising a pharmaceutically-acceptable carrier, diluent, or excipient and a compound of formula II. Other embodiments of the invention provide compositions comprising a stereochemically enriched mixture of compounds of formula II.

[0087] In certain preferred embodiments, R⁹ is phenyl or phenalkyl, preferably benzyl. In yet other preferred embodiments, R¹⁰ is -(CH₂)_n-NH-Boc, and each n is the integer 0, 1, 2, or 3, more preferably, 1 or 2. hi still other preferred embodiments, R¹² is phenylmethyloxy. In other preferred embodiments, R¹³ is benzyl, piperidinyl, or phenoxy.

[0088] In certain other preferred embodiments, R⁹ is phenyl, and R¹³ is benzyl, piperidinyl, or phenoxy. hi yet other preferred embodiments, R⁹ is phenyl, R¹³ is benzyl, piperidinyl, or phenoxy, and z equals 1. hi other preferred embodiments, R⁹ is phenyl, R¹³ is benzyl, piperidinyl, or phenoxy, z equals 1, and R¹⁰ is -(CH₂)_n-NH-Boc. In still other preferred embodiments, R⁹ is phenyl, R¹³ is benzyl, piperidinyl, or phenoxy, z equals 1, R¹⁰ is -(CH₂)_n- NH-Boc, and R¹² is phenylmethyloxy.

[0089] In certain preferred embodiments of compounds of formula I, the compound is selected from the group consisting of:

[4-Benzyloxycarbonylamino-4-(4-phenoxy-phenylcarbamoyl)-butyl] -carbamic acid tert- butyl ester;

[3-Benzyloxycarbonylamino-3-(4-phenoxy-phenylcarbamoyl)-propyl]-carbamic acid tert- butyl ester;

[4-Benzyloxycarbonylamino-4-(4-phenoxy-phenylcarbamoyl)-butyl]-carbamic acid tert- butyl ester;

[4-Benzyloxycarbonylamino-4-(4-benzyl-phenylcarbamoyl)-butyl]-carbamic acid tert-butyl ester; and,

[4-Benzyloxycarbonylamino-4-(4-piperidin-l-yl-phenylcarbamoyl)-butyl]-carbamic acid tert-butyl ester.

[0090] The compounds employed in the present invention may exist in prodrug form. As used herein, "prodrug" is intended to include any covalently bonded carriers which release the active parent drug, for example, as according to the formulas or compounds employed in the methods of the present invention in vivo when such prodrug is administered to a subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may, if desired, be delivered in prodrug form. Thus, the present invention contemplates methods of delivering prodrugs. Prodrugs of the compounds employed in the present invention, for example, according to the formulas I or II, may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.

[0091] Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid, respectively. Examples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, zjo-propyl, butyl, isobutyl, sec-butyl, tert-bvΛyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.

[0092] As will be readily understood, functional groups present may contain protecting groups during the course of synthesis. Protecting groups are knovmper se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention. Protecting groups that may be employed in accordance with the present invention may be described in Greene, T. W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991.

[0093] In a further aspect, the invention relates to a pharmaceutical composition comprising a compound of the formula and a pharmaceutically acceptable carrier, diluent, or excipient. The applicable carrier, diluent, or excipient may be selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington 's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1985), the disclosure of which is hereby incorporated by reference in its entirety.

[0094] The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers, diluents, or excipients, which may be liquid or solid. The applicable solid carrier, diluent, or excipient may function as, among other things, a binder, disintegrant, filler, lubricant, glidant, compression aid, processing aid, color, sweetener, preservative, suspensing/dispersing agent, tablet-disintegrating agent, encapsulating material, film former or coating, flavors, or printing ink. Of course, any material used in preparing any dosage unit form is preferably pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations. Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol, and rectal systemic. [0095] In powders, the carrier, diluent, or excipient may be a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier, diluent or excipient having the necessary compression properties in suitable proportions and compacted in the shape and size desired. For oral therapeutic administration, the active compound may be incorporated with the carrier, diluent, or excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The amount of active compound(s) in such therapeutically useful compositions is preferably such that a suitable dosage will be obtained. The therapeutic compositions preferably contain up to about 99% of the active ingredient.

[0096] Liquid carriers, diluents, or excipients may be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and the like. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fat. The liquid carrier, excipient, or diluent can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.

[0097] Suitable solid carriers, diluents, and excipients may include, for example, calcium phosphate, silicon dioxide, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, ethylcellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidine, low melting waxes, ion exchange resins, croscarmellose carbon, acacia, pregelatinized starch, crospovidone, HPMC, povidone, titanium dioxide, polycrystalline cellulose, aluminum methahydroxide, agar-agar, tragacanth, or mixtures thereof.

[0098] Suitable examples of liquid carriers, diluents and excipients for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil), or mixtures thereof.

[0099] For parenteral administration, the carrier, diluent, or excipient can also be an oily ester such as ethyl oleate and isopropyl myristate. Also contemplated are sterile liquid carriers, diluents, or excipients, which are used in sterile liquid form compositions for parenteral administration. Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. A dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

[0100] The pharmaceutical forms suitable for injectable use include, for example, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form is preferably sterile and fluid to provide easy syringability. It is preferably stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier, diluent, or excipient may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of a dispersion, and by the use of surfactants. The prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions may be achieved by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0101] Sterile injectable solutions may be prepared by incorporating the active compounds in the required amounts, in the appropriate solvent, with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions may be prepared by incorporating the sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation may include vacuum drying and the freeze drying technique that yields a powder of the active ingredient or ingredients, plus any additional desired ingredient from the previously sterile-filtered solution thereof. [0102] The compounds of the invention may be administered in an effective amount by any of the conventional techniques well-established in the medical field. The compounds employed in the methods of the present invention including, for example, the compounds of formulas I and II, may be administered by any means that results in the contact of the active agents with the agents' site or sites of action in the body of a patient. The compounds may 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. For example, they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients, where medically appropriate.

[0103] Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, buccal tablets, troches, capsules, elixirs, powders, solutions, suspensions, emulsions, syrups, wafers, granules, suppositories, or the like. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. 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. These microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule, possibly along with a granulation of the another active ingredient.

[0104] The dosage of the compounds of the present invention that will be most suitable for prophylaxis or treatment will vary with the form of administration, the particular compound chosen and the physiological characteristics of the particular patient under treatment. Generally, small dosages may be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is reached. Generally speaking, oral administration may require higher dosages.

[0105] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The dose may also be provided by controlled release of the compound, by techniques well known to those in the art.

[0106] The compounds useful in the methods of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by the methods as described below, or variations thereon as appreciated by the skilled artisan. The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.

[0107] The present invention is further defined in the following Examples. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only, and should not be construed as limiting the appended claims From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. EXAMPLES

[0108] Examples 1-5 provide descriptions and schematics depicting the synthesis of compounds of the formula I, including sample embodiments thereof. Examples 6-7 provide schemes for the synthesis of compounds of the formula II. Example 8 is a mass spectrometry and NMR characterization assay of the resulting compounds. Example 9 illustrates an ELISA assay for determining IC₅₀ values of representative compounds. EXAMPLE 1 : Synthesis of Some Preferred Formula I Compounds

[0109] Synthesis of some embodiments was accomplished using standard peptide coupling methods and commercially-available synthetic precursors, as illustrated in the following generalized schematic and as described below:

[0110] Precursor amine compounds (compound A variations, which were sometimes commercially available as HCl salts) and precursor compound B variations were acquired through the commercial vendor Bachem. In the first step, to a round bottomed flask containing: 1) compound A, where (J) was/rø-α-fluorobenzyl, benzyl, phenyl, or isobutyl, and (M) was methoxy, ethoxy, propoxy, prop-2-en-l-oxy, amino, butylamino, benzyloxy, or 2-methyl- propan-2-oxy; 2) compound B, where (L) was -(CH₂)_nNH and n equaled 2, 3 or 4; 3) EDC; and, 4) HOBT (1-Hydroxybenzotriazole hydrate) was added CH₂Cl₂, followed by pyridine. The contents were stirred at room temperature, and then anhydrous DMF was added. After stirring, the contents were diluted with ethyl acetate and than washed with saturated 10% citric acid, saturated sodium bicarbonate and brine respectively. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield a white solid. The solid was recrystallized in ethyl acetate/hexane/methanol to afford a white crystalline solid. The contents of the mother liquor were concentrated and purified using flash column chromatography (60% ethyl acetate/ 40% hexane), giving an additional quantity of product.

[0111] The product from the previous step and Pd/C (10% by weight) were added to a Paar bottle and dissolved in methanol. The bottle was gently rocked at 40⁰C under elevated pressure on a Paar shaker for 1 hour and the MeOH was removed under reduced pressure. The contents were dissolved in ethyl acetate and than filtered through celite to remove excess Pd/C. The ethyl acetate was removed under reduced pressure to give the pure white solid product.

[0112] The free amine from the previous step was added to a round-bottomed flask under argon at O⁰C. To the flask was added dropwise (X)-Cl and ΛζN-diisopropylethylamine (DIPEA), where (X) was 6-chlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, benzyl carbonyl, benzyloxycarbonyl, or 4-methoxyphenoxycarbonyl. The contents were stirred at 0°C for 30 minutes and than at room temperature for an additional 1 hour. The contents were than diluted with ethyl acetate and washed with saturated 10% citric acid, saturated sodium bicarbonate, and brine, respectively. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give an off white solid. The solid was purified using flash column chromatography (50% ethyl acetate/40% hexane), yielding pure white solid product.

[0113] Some embodiments did not require the addition of the (X) functional group at the R₄ position. Therefore, the previous step was only performed during the preparation of those compounds in which R₄ was not hydrogen.

[0114] Removal of the Boc group from the (L) moiety was accomplished as follows: a quantity of Boc-protected compound was placed in a round bottomed flask. A trifluroacetic acid (TFAyCH₂Cl₂ solution (1 : 1 by volume) was added and the contents were stirred at room temperature. The solution was added to a scintillation vial and the solvent was removed. Cold ether was added to the scintillation vial, inducing precipitation. The contents were carefully transferred to a falcon tube and centrifuged. The ether was than discarded. The solid was washed three more times with cold ether and then dried to give a white solid.

[0115] The third and final step - addition of a functional group to the free amine that resulted from the removal of the Boc group - was achieved by adding the product from the previous step to a round bottomed flask along with anhydrous DMF. Contents were cooled to minus 78°C and triethylamine was added dropwise. After stirring, (T)-chloride, where (T) was Cbz or phenylsulfonyl was added dropwise. The temperature was brought to 0°C over a one hour period. After reacting a total of 90 minutes, contents were diluted with ethyl acetate. The organic layer was washed with 10% citric acid, saturated sodium bicarbonate and brine, respectively. Purification was accomplished using flash column chromatography. [0116] In some embodiments, the final product comprised a Boc-protected (L) functional group; accordingly, the steps achieving removal of the Boc group and addition of a functional group to the free amine that resulted from the removal of the Boc group were not performed for these compounds.

EXAMPLE 2: Synthesis of2-(2,5-Bis-benzyloxycarbonylamino-pentanoylamino)-3-(4-fluoro- phenyl)-propionic acid ethyl ester

[0117] Some precursor compound B variations were purchased with Cbz-protected amine groups, and some embodiments retained the Cbz-protected amine groups in their final forms. Accordingly, steps for removing the Cbz groups were omitted during the preparation of some embodiments. The following schematic and description illustrate a particular example of the synthesis of a preferred formula I compound:

[0118] In step 1 , to a round bottomed flask containing Z-D-Ornithine(Z)-OH (1.24 mmol, 0.500 g) (Bachem, Cat. No. C-2965), H-4-F-Phe-OEt HCl (1.31 mmol, 0.326 g) (Bachem, Cat. No. F-3820), EDC (1.37 mmol, 0.262 g) (Cat. No. 39391, Aldrich Chem. Co., Milwaukee, WI) and HOBT (1-Hydroxybenzotriazole hydrate) (1.37 mmol, 0.185 g) (Cat. No. 157260, Aldrich Chem. Co., Milwaukee, WI) was added 8 mL Of CH₂Cl₂ followed by 0.55 niL (5 mmol) of pyridine. Thus, as may be readily appreciated, in the precursor molecules (M) was ethoxy, (J) wasj^ra-fluorobenzyl, and (L) was -(CHa)₃NH-. The contents were stirred at room temperature for 20 minutes and than 1.5 mL of anhydrous DMF was added. After stirring for 5 hours, the contents were diluted with 80 mL of ethyl acetate and than washed with saturated 10% citric acid, saturated sodium bicarbonate and brine respectively. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield a white solid. The solid was recrystallized in ethyl acetate/hexane/methanol to afford a white crystalline solid (0.52 grams). The contents of the mother liquor were concentrated and purified using flash column chromatography (60% ethyl acetate/ 40% hexane), giving an additional 0.2 grams of product (98% combined yield from two recrystallizations). [0119] Because the resulting product represented the final form of the present embodiment, no additional steps were required. Synthesis of Other Preferred Embodiments of Formula I Compounds

[0120] To synthesize other preferred embodiments of compounds represented by the formula I, the steps of Example 1 were replicated using the various commercially-available synthetic precursors and intermediate electrophiles required to produce the desired compounds. Accordingly, precursor molecules with the desired (M), (J), and (L) groups, as well as (T)- chloride molecules, were readily acquired and used to generate the intended end product.

[0121] hi some cases, the desired compound possessed a Boc protective group on the terminal amine in its final form. Accordingly, the second and third steps of the synthesis reaction described supra were omitted. Example 3 depicts the synthesis of one such compound. EXAMPLE 3: Synthesis of 2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino- pentanoylamino)-3-(4-fluoro-phenyl)-propionic acid ethyl ester

[0122] To generate the present embodiment, the first, peptide-coupling step involved the addition of H-4-F-Phe-OEt HCl to Z-D-Ornithine(Boc)-OH (Bachem, Cat. No. C-30702) with EDC and HOBT and CH₂Cl₂ and then pyridine, as follows:

[0123] As the product resulting from the first synthesis step was the complete 2-(2- Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-(4-fluoro-phenyl)- propionic acid ethyl ester molecule, no subsequent steps were performed. EXAMPLE 4: Synthesis of Formula I Variations

[0124] As it is known among those skilled in the art, variations on the disclosed embodiments are synthesized using the same peptide chemistry and substitution steps on the virtually unlimited number of precursor molecules and intermediates, respectively, that are required to obtain the desired intermediates and final products. It is intended that the scope of present invention includes such variations. EXAMPLE 5: Synthesis of3-Benzyloxycarbonylamino-N-(l-methoxycarbonyl-2-phenyl- ethyl)-succinamic acid benzyl ester

[0125] The synthesis of the present embodiment varies from the generalized schematic in one aspect. The precursor compound B molecule did not possess a Boc-protected amine group, and instead possessed a benzyloxycarbonyl moiety at the R₃ position. The synthesis reaction was achieved as depicted and described below.

To a round-bottomed flask was added Z-D-Asp(OBzl)-OH (Bachem, Cat. No. F-4055) (0.350 mmol, 0.125 g), H-Phe-OMe HCl (Bachem, Cat. No. E-2270) (0.285 mmol, 0.083 g), EDC (0.385 mmol, 0.074 g), HOBT (0.385 mmol, 0.052 g) and DIPEA (1.57 mmol, 0.20 g) in 2.5 mL of THF and 0.5 mL DMF. The contents were stirred overnight and than diluted with 50 mL ethyl acetate. The organic layer was washed with saturated 10% citric acid (20 mL), saturated sodium bicarbonate (20 mL) and brine (20 mL) respectively. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give an off white solid. The solid was purified using flash column chromatography (30% ethyl acetate/70% hexane), yielding 0.125 grams (67% yield) of the pure white solid product. EXAMPLE 6: Synthesis of Some Preferred Formula II Compounds

[0126] Synthesis of some preferred embodiments was accomplished as illustrated in the following generalized schematic and as described below:

compound Y

[0127] Precursor amine compounds were obtained from Aldrich Chem. Co. (Milwaukee, WI); precursor compound Y variations were acquired through the commercial vendor Bachem. The first step achieved EDC coupling. To a round-bottomed flask containing: 1. (Q)-NH₂, where (Q) was 4-phenoxyphenyl, 4-benzylphenyl, or 4-piperidin-l-yl-phenyl; 2. compound Y, where (G) was -(CH₂)JMH- and n = 1 or 2, and where (E) was phenylmethoxy; and, 3. EDC (Cat. No. 39391, Aldrich Chem. Co., Milwaukee, WI), was added dichloromethane (CH₂Cl₂). The contents were stirred for 12 hours at room temperature and then diluted with ethyl acetate. The organic layer was washed with 10% citric acid, saturated sodium bicarbonate, and brine, respectively. The organic layer was dried over sodium sulfate and than concentrated under reduced pressure to yield a white/brown solid. This solid was recrystallized from hexane/ethyl acetate to yield a pure white solid.

[0128] The second step accomplished removal of the Boc protective group: a quantity Boc-protected compound was placed in a round bottomed flask; a Trifluroacetic acid (TFA)/CH₂C1₂ solution (1:1 by volume) was added, and the contents were stirred for 1 hour at room temperature. The solution was added to a scintillation vial and the solvent was removed. Cold ether was added to the scintillation vial, inducing precipitation. The contents were carefully transferred to a falcon tube and centrifuged. The ether was than discarded. The solid was washed three more times with cold ether and then dried to yield a white solid.

[0129] Some preferred embodiments of compounds of the formula II (e.g., compounds 27-31, as shown in Table 2) retain the Boc protective group in their final form. Accordingly, the synthesis of these preferred embodiments did not involve the removal of the Boc group via Trifluroacetic acid (TFA)/CH₂C1₂ solution. EXAMPLE 7: Synthesis of[3-Benzyloxycarbonylamino-3-(4-phenoxy-phenylcarbamoyl)- propylj-carbamic acid tert-butyl ester

[0130] The following schematic and description illustrate a particular example of the synthesis of a preferred formula II compound:

[0131] The first step achieved EDC coupling: To a round-bottomed flask containing 4- phenoxyaniline (0.221 g, 1.2 mmol) (Cat. No. P15102, Aldrich Chem. Co., Milwaukee, WI), Z- Ornithine(Boc)-OH (1.3 mmol, 0.476 g) (Cat. No. C-1450, Bachem) and EDC (1.3 mmol, 0.249 g) (Cat. No. 39391, Aldrich Chem. Co., Milwaukee, WI), was added 8 mL of dichloromethane (CH₂Cl₂). The contents were stirred for 12 hours at room temperature and then diluted with 40 mL of ethyl acetate. The organic layer was washed with 10% citric acid, saturated sodium bicarbonate, and brine, respectively. The organic layer was dried over sodium sulfate and than concentrated under reduced pressure to yield a white/brown solid. This solid was recrystallized from hexane/ethyl acetate to yield a pure white solid (first crop: 0.450 g), [3- Benzyloxycarbonylamino-3-(4-phenoxy-phenylcarbamoyl)-propyl]-carbamic acid tert-butyl ester, shown in Table 2 as compound 28. EXAMPLE 8: Characterization of Compounds by Mass Spectrometry and NMR

[0132] Compounds were characterized by use of a VG Micromass 7070H high resolution chemical ionization mass spectrometer interfaced with a Kratos DS-50-S data system for mass spectrometry analysis, and with a Bruker drx-500 spectrometer for NMR characterization.

[0133] For example, Compound 1, as shown in Table 1, was characterized using the described equipment and yielded the following results: ^l H NMR (500MHz, DMSOd₆): δ 1.13 (t, 3H), 1.24-1.48 (m, 4H), 2.86-2.97 (m, 3H), 3.03 (dd, IH), 3.99 (dt, IH), 4.06 (q, 2H), 4.45 (dt, IH), 5.01 (s, 2H), 5.02 (s, 2H), 7.03 (t, 2H), 7.11 (br, IH), 7.22 (t, 3H), 7.27-7.36 (m, 10H), 8.21 (d, IH); EI-MS: m/z (M+Na⁺): 616.244 (calcd), 616.245 (found). [0134] A second example provides the characterization data for Compound 27, shown in Table 2: ^l H NMR (500MHz, DMSOd₆): δ 1.37 (s, 9H), 1.43-1.55 (m, 2H), 1.56-1.70 (m, 2H)₅ 2.95 (dt, 2H), 4.13 (dt, IH), 5.03 (s, 2H), 6.75 (br, IH)₅ 6.96-7.00 (m, 4H)₅ 7.10 (tr IH)₅ 7.20-7.40 (m, 8H), 7.53 (d, IH)₅ 7.65 (d, 2H); EI-MS: m/z (M+Na⁺): 556.242 (calcd), 556.242 (found).

[0135] The other preferred embodiments were evaluated in like fashion. AU characterizations confirmed the fidelity of the synthesis reactions described above and therefore the accuracy of the structural descriptions provided in Tables 1 and 2. EXAMPLE 9: ELISA Assay For Binding of a2βl Integrin I-Domain to Collagen

[0136] Expression of the I-domain was achieved using previously described methods. See, e.g., Knight CG, et al, J Biol Chem. 275(1), 35-40 (2000); Xu Y, et al, J Biol Chem. 275(50), 38981-9 (2000); TuckwellD et al., JCeIl Sd, 108(Pt 4), 1629-37 (1995).

[0137] For compounds of the present invention, the assay for binding of the I-domain of the α2βl integrin to type-I collagen was performed as follows: first, a 96-well plate (Nunc- Immuno Plate, MaxiSorp Surface was coated with 100 μl 10 μg/ml collagen I (from calfskin) (Sigma, Cat. No. C9791) followed by incubation of O/N at 4°C. The plate was washed with assay buffer (HBS supplemented with 0.1% BSA + 0.05% v/v Tween 20+2mM MgCl₂) and blocked by adding 200 μl assay buffer and than incubated for 1 hr at room temperature. At this point, 0.3 μM I-domain was added to 100 μl of the assay buffer and incubated for 3 hr at room temperature. The wells were then washed 3x in 100 μl in assay buffer followed by the addition of 100 μl ExtrAvidin (Sigma, Cat. No. E2886), diluted 1 :8000 in assay buffer. After incubation for 45 min at room temperature, the wells were washed 3x in 100 μl assay buffer and 100 μl ABTS solution (Sigma, Cat. No. A3219) was added. The solution was incubated until a green color appeared, at which point the reaction was stopped by adding 100 μl 1% SDS. Absorbance was read using a spectrophotometer (plate reader; mode no. F-2500, Hitachi) at 405 nm setting, with reference at 690 nm.

[0138] Compounds of the present disclosure, were also assayed for binding of the α2βl I-domain to snake venom jararhagin, a recognized platelet agonist. Paine, M. J. I. et al, J. Biol. Chem. 267, 22869-22876 (1992). This assay was performed in the same fashion as assays with collagen-coated plates, except that type-I collagen was substituted with jararhagin. The IC₅Q values observed for this assay were comparable to the values obtained using assays that utilize collagen-coated plates.

ELISA ASSAYS

[0139] The potencies of the compounds of the present disclosure were determined by testing the ability of a range of concentrations of each compound to inhibit adhesion of the human recombinant α2βl integrin I-domain to soluble collagen under static conditions. Accordingly, the reported IC₅₀ values represent the amount of compound required to reduce adhesion of type I collagen to the recombinant I-domain by 50% (as demonstrated by the assay described in Example 9). While not intending to be bound by any theory or theories of operation, it is believed that the results of these assays demonstrate that the compounds of the present invention effect inhibition of the α2βl integrin by targeting the integrin' s I-domain. RESULTS

[0140] Compounds 1-26, which are preferred embodiments of compounds of formula I, are shown in Table 1.

TABLE l

[0141] Compounds 27-31, which are preferred embodiments of compounds of formula are shown in Table 2.

TABLE 2

[0142] Compounds 1-26, listed in Table 1, and compounds 27-31, as shown in Table 2, were tested in vitro for their ability to inhibit the adhesion of the human recombinant I-domain of the α2βl integrin to soluble collagen under static conditions. These compounds were found to exhibit inhibitory activity. For example, Compound 1 found to possess potent in vitro activity (IC₅₀ = 5 μM), as was Compound 24 (IC₅₀ = 14 μM). Compounds 23, 25, and 26 were also found to possess potent in vitro inhibitory activity (IC₅₀ = 15 μM).

[0143] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0144] The disclosures of each patent, patent application and publication cited or described in this document are hereby incorporated herein by reference, in their entirety.

[0145] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

Claims

What is claimed is:

1. A compound having the formula:

wherein:

R¹ is -OR⁵, -NR⁶R⁷; aryl, heteroaryl, or alkyl;

R² is aralkyl, heteroaryl, aryl, or alkyl;

R³ is alkyl-Z;

R⁴ is C(=O)aryl, C(=O)aralkyl, C(=O)aralkoxy, C(=O)aryloxy, S(=0)₂aryl, aryl, alkyl, or heteroaryl;

R⁵ is alkyl, alkenyl, aryl, aralkyl, or heteroaryl;

R⁶ and R⁷ are, independently, H or alkyl;

Z is NHC(=O)-R⁸, NHC(=O)-OR⁸, NH₂, NH-R⁸, NHS(=O)₂-R⁸, or C(=O)-O-aralkyl;

R⁸ is aryl, heteroaryl, aralkyl or alkyl;

or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, or N-oxide thereof.

2. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

3. A composition comprising a stereocliemically enriched mixture of compounds according to claim 1.

4. A compound according to claim 1, where in R¹ is -NH₂, -OCH₃, -OCH₂CH₃, - O(CH₂)₂CH₃, -O(tert-butyl), -0(CH₂)CH=CH₂, -O(CH₂)(phenyl), or -N(CH₂)₃CH₃.

5. A compound according to claim 1, wherein R² is phenyl or -CH₂(phenyl).

6. A compound according to claim 5, wherein phenyl is substituted with fluorine.

7. A compound according to claim 1, wherein R³ is -(CH₂)₂NH(Cbz), -(CH₂)₂NH(Boc), - (CH₂)₂NH(benzenesulfonyl), or -(CH₂)₃NH(Boc).

8. A compound according to claim 1, wherein R⁴ is Cbz, Cbz-halo, Cbz-nitro, methoxy- phenyloxy-carbonyl, benzylcarbonyl, or benzene sulfonyl.

9. A compound according to claim 1, wherein R⁴ is Cbz, Cbz-halo, Cbz-nitro, methoxy- phenyloxy-carbonyl, or benzylcarbonyl, R³ is -(CH₂)₂NH(Cbz), -(CH₂)₃NH(Boc), or - (CH₂)₂NH(Boc) and R² is -CH₂(phenyl) and phenyl is substituted or unsubstituted.

10. A compound according to claim 9, wherein R is -NH₂, -OCH₃, -OCH₂CH₃, - O(CH₂)₂CH₃, -O(tert-butyl), -0(CH₂)CH=CH₂, -O(CH₂)(phenyl), or -N(CH₂)₃CH₃.

11. A compound according to claim 1 , where in the compound is :

2-(2,5-Bis-benzyloxycarbonylamino-pentanoylammo)-3-(4-fluoro-phenyl)-propionic acid ethyl ester; 2-(2,5-Bis-benzyloxycarbonylamino-pentanoylamino)-3-phenyl-propionic acid allyl ester;

[4-tert-Butoxycarbonylamino-l-(l-carbamoyl-2-plienyl-etliylcarbamoyl)-butyl]-carbamic acid benzyl ester;

2-(2-Benzyloxycarbonylarnino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid propyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylammo-pentanoylamino)-3-phenyl- propionic acid allyl ester;

[4-Benzenesulfonylamino-l-(l-carbamoyl-2-phenyl-ethylcarbamoyl)-butyl]-carbarnic acid benzyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid benzyl ester; 2-(2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionylamino)-3-phenyl- propionic acid methyl ester;

[4-tert-Butoxycarbonylamino-l-(l-carbarnoyl-2-plienyl-ethylcarbarnoyl)-butyl]-carbarnic acid benzyl ester;

3-Benzyloxycarbonylamino-N-(l-methoxycarbonyl-2-phenyl-ethyl)-succmamic acid benzyl ester;

2-(2-Berizyloxycarbonylarnino-5-tert-butoxycarbonylarnino-pentanoylamino)-3-phenyl- propionic acid ethyl ester;

2-(2-Benzyloxycarbonylammo-5-tert-butoxycarbonylamino-pentanoylamino)-4-methyl- pentanoic acid allyl ester;

2-(2-Benzenesulfonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid methyl ester;

2-(2-Benzyloxycarbonylammo-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid tert-butyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-3-phenyl- propionic acid methyl ester,

2-[5-tert-Butoxycarbonylamino-2-(2-chloro-benzyloxycarbonylamino)-pentanoylamino]- 3-(4-fluoro-phenyl)-propionic acid ethyl ester; 2-[5-tert-Butoxycarbonylamino-2-(4-nitro-benzyloxycarbonylamino)-pentanoylamino]-3- (4-fluoro-phenyl)-propionic acid ethyl ester;

2-(5-tert-Butoxycarbonylamino-2-phenylacetylamino-pentanoylamino)-3-(4-fluoro- phenyl)-propionic acid ethyl ester; or,

2-[5-tert-Butoxycarbonylamino-2-(4-rnethoxy-phenoxycarbonylamino)-pentanoylammo]- 3-(4-fluoro-phenyl)-propionic acid ethyl ester;

12. A method for treating at least one integrin α2βl -affected disease state or infection comprising the step of administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound having the formula:

wherein:

R¹ Is -OR⁵ Or-NR⁶R⁷;

R² is aralkyl, aryl, or alkyl;

R³ is alkyl-Z;

R⁴ is C(=O)-O-aralkyl or S(=O)₂aryl; R⁵ is alkyl, alkenyl, or aralkyl;

R and R are, independently, H or alkyl;

Z is NHC(=O)-OR⁸, NHS(=O)₂aryl, or C(=O)-O-aralkyl; and,

R⁸ is aralkyl or alkyl;

13. The method according to claim 12 wherein the subject is administered a therapeutically effective amount of:

2-(2,5-Bis-benzyloxycarbonylamino-pentanoylamino)_-3-(4-fluoro-phenyl)-propionic acid ethyl ester;

2-(2,5-Bis-benzyloxycarbonylamino-pentanoylamino)_-3-phenyl-propionic acid allyl ester;

[4-tert-Butoxycarbonylamino- 1 -( 1 -carbamoyl-2-phenyl-ethylcarbamoyl)-butyl] -carbamic acid benzyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylammo)_-3-phenyl- propionic acid propyl ester;

2-(2-Benzyloxycarbonylammo-5-tert-butoxycarbonylamino-pentanoylamino)_-3-(4-fluoro- phenyl)-propionic acid ethyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)_-3-phenyl- propionic acid allyl ester; [4-tert-Butoxycarbonylamino-l-(l-carbamoyl-2-phenyl-ethylcarbamoyl)-butyl]-carbamic acid benzyl ester;

{4-Benzyloxycarbonylammo-l-[l-butylcarbamoyl-2-(4-fluoro-phenyl)-ethylcarbamoyl]- butyl} -carbamic acid benzyl ester;

2-(2,5-Bis-benzyloxycarbonylamino-pentanoylamino)_-3-phenyl-propionic acid ethyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylarnirio-pentanoylamino)_-3-phenyl- propionic acid methyl ester;

[4-Benzenesulfonylamino- 1 -(I -carbamoyl-2-phenyl-ethylcarbamoyl)-butyl]-carbamic acid benzyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)_-3-phenyl- propionic acid benzyl ester;

2-(2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionylamino).₃-phenyl- propionic acid methyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylammo-pentanoylammo)-₃-phenyl- propionic acid ethyl ester;

2-(2-Benzyloxycarbonylammo-5-tert-butoxycarbonylamino-pentanoylamino)_-4-methyl- pentanoic acid allyl ester; [5-Benzyloxycarbonylamino-5-(l-carbamoyl-2-phenyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester;

2-(2-Benzenesulfonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-₃-phenyl- propionic acid methyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)_-3-plienyl- propionic acid tert-butyl ester;

(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylammo)-phenyl-acetic acid methyl ester;

2-(2-Benzyloxycarbonylamino-5-tert-butoxycarbonylamino-pentanoylamino)-₃-phenyl- propionic acid methyl ester;

2-[5-tert-Butoxycarbonylammo-2-(4-nitro-benzyloxycarbonylammo)-pentanoylamino]-3- (4-fluoro-phenyl)-propionic acid ethyl ester;

2-[5-tert-Butoxycarbonylamino-2-(4-methoxy-phenoxycarbonylamino)-pentanoylamino]- 3-(4-fluoro-phenyl)-propionic acid ethyl ester;

14. The method according to claim 12, wherein the disease state or infection is vascular, cancer-related, diabetes-related, or rheumatoid.

15. The method according to claim 12 wherein the subject is suffering from or susceptible to one or more of acute coronary syndromes, stroke, ischaemic complications of peripheral vascular disease, deep vein thrombosis (DVT), myocardial infarction, coronary artery disease, cerebrovascular disease, peripheral arterial disease, atrial fibrillation, congestive heart failure, pulmonary embolism, and other vascular-related disorders.

16. The method according to claim 12, wherein the subject is suffering from or susceptible to one or more of human melanoma, hepatocellular carcinoma, breast cancer, lung cancer, ovarian cancer, and other cancers and cancer-related disorders.

17. The method according to claim 12, wherein the subject is suffering from or susceptible to one or more of rheumatoid arthritis, diabetes mellitus, diabetic retinopathy, and other rheumatoid- or diabetes-related disorders.

18. The method according to claim 12, wherein the disease state or infection is matrix reorganization-affected.

19. The method according to claim 12, wherein the disease state or infection is angiogenesis- affected.

20. The method according to claim 12, wherein the disease state or infection is cell migration-, cell proliferation-, cell colonization-, or metastasis-affected.

21. The method according to claim 12, wherein the disease state or infection is leukocyte infiltration-affected.

22. The method according to claim 12, wherein the disease state or infection is edema- affected.

23. The method according to claim 12, where in the subject is suffering from or susceptible to viral infection.

24. The method according to claim 12, wherein said viral infection is at least partially attributable to human cytomegalovirus (HCMV), rotaviruses, Piconaviridae viruses, or related viruses.

25. The method according to claim 12 wherein said composition additionally comprises a pharmaceutically acceptable carrier, diluent, or excipient.

26. The method according to claim 12, wherein said composition comprises a stereochemically enriched mixture of compounds of the formula.

27. The method according to claim 12, wherein said subject is human.

28. The method according to claim 12, where said subject is a non-human animal.

29. A compound having the formula:

wherein:

R is aryl, aralkyl, or heteroaryl;

R .1ⁱ0^υ is -(CH₂)_n-NH₂, -(CH₂)_n-NH-alkyl, -(CH₂)_n-NH-aryl, -(CH₂)_n-NH- heteroaryl, -(CH₂)_n-NH-O-alkyl, -(CH₂)_n-NH-O-aryl, -(CH₂)_n-NH-O-heteroaryl, - (CH₂)_n-NH-C(=O)alkyl, -(CH₂)_n-NH-C(=O)aryl, -(CH₂)_n-NH-C(=O)heteroaryl, - (CH2-)_n NH-C(=O)alkoxy, -((CH-2)_nNH-C(=O)aralkyl, -(CH2-)_n NH-SC=O)₂ aryl; -l(CH2)_n- NH-S(=O)₂heteroaryl;

R ^{1 1}is H or alkyl;

R¹² is alkyl, aryl, heteroaryl, aryloxy. alkoxy, heteroaryloxy, aralkoxy,

Each R¹³ is independently aryl, aryloxy, heteroaryl, arylamino; heteroarylamino; -C(-O)ary-, or-C(=O)heteroaryl

n is 0, 1, 2, or 3; and

z is 0, 1, or 2;

or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically aceeptable salt, hydrate, solvate, acid hydrate, or N-oxide thereof.

30. A composition comprising a compound according to claim 29 and a pharmaceutically acceptable carrier, diluent, or excipient.

31. A composition comprising a stereochemically enriched mixture of compounds of claim 2.

32. A compound according to claim 29, where R⁹ is phenyl or a phenalkyl.

33. A compound according to claim 29, where R¹⁰ is -(CH2)_n -NH₂, and each n is the integer 0, 1, 2. or 3.

34. A compound according to claim 29, where R¹⁰ is - (CH2)_n--NH-C(=NH)--NH₂, and n equals 2,

35. A compound according to claim 29, where R^xo is -(CH2)_n-NH-Boc, and n equals 2 or 3.

36. A compound according to claim 29, where R¹² is phenyl, phenylmethyloxy, phenylmethlyamine, phenetyl, phenoxy, orbiphenyl.

37. A compound according to claim 29, where iⁿ³ is phenyl, phenoxy, phenylcarbonyl, phenylamino, benzyl, or piperidinyl.

38. A compound according to claim 38, where z equals 1.

39. A compound according to claim 39, where R¹² is phenyl, phenylmethyloxy, phenylmethlyamine, phenetbyl, phenoxy, or biphenyl.

40. A compound according to claim 40, where R¹⁰ is -(CH₂)_n-NH₂ or -(CH₂)_n-NH-BoO.

41. A compound according to claim 41, where R¹² is phenylmethyloxy

42. A compound according to claim 42, where R¹³ is phenoxy, benzyl, or piperidinyl.

43. A compound according to claim 29, wherein the compound is:

[3-Benzyloxycarbonylamino-3-(4-phenoxy-phenylcarbamoyl)-butyl]-carbamic acid tert- butyl ester;

[4-Benzyloxycarbonylamino-4-(4-phenoxy-phenylcarbamoyl)-butyl]-carbamic acid tert- buty] ester;

[4-Benzyloxycarbonylamino-4-(4-benzyl-phenylcarbamoyl)-nutyl]-carbamic acid tert- butyl ester; or,

[4-Benzyloxycarbonylamino-4- (4-piperidin-l-yl-phenylcarbamoyl)-butyl]-carbamic acid tert-butyl ester. or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, or N-oxide thereof.

44. A method for treating at least one integrin α2βl -affected disease state or infection comprising the step of administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound having the formula:

wherein:

R⁹ is aryl, aralkyl, or heteroaryl

R¹⁰ is -(CH2)_n-NH₂, -{CH₂)_n-NH-alkyl,-(CH₂)_n-(CH-₂)_n-NH-aryl, -(CH2)_n-NH- heteroaryl, -((CH₂)_n-NH-O-alkyl, -(CH₂)_n- NH-O-aryI, -(CH2)_n-NH-O-heteroaryl, - (CH2-)_n NH-C(-O)alkyl, -(CH₂)_n-NH-C(=O)aryl, -(CH₂)n-NH-.C(-O)heteroaryl, - (CH₂)n-NH-C(=O)aIkoxy, -(CH2-)_n NH-C(-O)aralkyl, -(CH2)_n-NH-S(-O)2aryl; -(CH2)_n- NH-S(=0)₂heteτoaryl;

Rⁿ is H or alkyl;

R¹² is alkyl, aryl, heteroaryl, aryloxy, alkoxy, heteroaryloxy, aralkoxy,

each R¹³ is independently aryl, aryloxy, heteroaryl, axylamino; heteroarylamino; -C(«=O)aryl, or-C(=O)heteroaryl n is 0, 1, 2, or 3; and,

z is 0, 1, or 2;

45. The method according to claim 45, where the subject is administered a therapeutically effective amount of:

[4-Benzyloxycarbonylamino-4-(4-phenoxy-phenylcarbamoyl)-butyl]-carbamic acid tert-butyl ester;

[ [4-Benzyloxycarbonylamino-4-(4-phenoxy-phenylcarbamoyl)-butyl]-carbamic tert-butyl ester; or,

[4-Benzyloxycarbonylamino-4-(4-piperidin-l-yl-phenylcarbamoyl}-butyl]- carbamic acid tert-butyl ester.

46. The method according to claim 45 , wherein the disease state or infection is vascular, cancer-related, diabetes-related, or rheumatoid.

47. The method according to claim 47, wherein the subject is suffering from or susceptible to one or more of acute coronaiy syndromes, stroke, ischaemic complications of peripheral vascular disease, deep vein thrombosis (DVT), myocardial infarction, coronary artery disease, cerebrovascular disease, peripheral arterial disease, atrial fibrillation, congestive heart failure, pulmonary embolism, and other vascular-related disorders,

48. The method according to claim 47, wherein the subject is suffering from or susceptible to one or more of human melanoma, hepatocellular carcinoma, breast cancer, lung cancer, ovarian cancer, and other cancers and cancer-related disorders.

49. The method according to claim 47, wherein the subject is suffering from or susceptible to one or more of rheumatoid arthritis, diabetes mellitus, diabetic retinopathy, and other rheumatoid- or diabetes-related disorders.

50. The method according to claim 45, wherein the disease state or infection is matrix reorganization-affected,

51. The method according to claim 45, wherein the disease state or infection is angiogenesis- affected.

52. The method according to claim 45, wherein the disease state or infection is cell migration-, cell proliferation-, cell colonization-, or matastasis-affected.

53. The method according to claim 45, wherein the disease state or infection is leukocyte infiltration-affected.

54. The method according to claim 45, wherein the disease state or infection is edema- affected

55. The method according to claim 45, where in the subject is suffering from or susceptible to viral infection.

56. The method according to claim 45, wherein said viral infection is at least partially attributable to human cytomegalovirus (HCMV), rotaviruses, Piconaviridae viruses, or related viruses.

57. The method according to claim 45, wherein said composition additionally comprises a pharmaceutically acceptable carrier, diluent, or cxcipient.

58. The method according to claim 45, wherein said composition comprises a stereochemically enriched misture of compounds of the formula.

59. The method according to claim 45, wherein said subject is human.

60. The method according to claim 45, where said subject is a non-human animal.