ANTAGONISTS FOR TREATMENT OF CD11/CD18 ADHESION RECEPTOR MEDIATED DISORDERS

Abstract: Compounds of the general structure D-L-B-(AA), for example (A), that are useful for treating Mac-1 or LFA-1-mediated disorders such as inflammatory disorders, allergies, and autoimmune diseases are provided.

Description: ANTAGONISTS FOR TRFATMENT OF CD11/CD18 AD ESION RECEPTOR MEDIATED DISORDERS Field of the Invention This invention relates to methods and therapeutic compositions for treating mammals, preferably humans, who suffer from or are susceptible to (CD11/CD18) adhesion receptor mediated disorders, especially leukocyte LFA-1 mediated disorders In particular, it relates to methods for ameliorating or modulating immune responses such as those caused by inflammation, autoimmune responses and host-graft rejection, as exemplified by psoriasis, rheumatoid arthritis, asthma, multiple sclerosis, rejection following transplanted grafts and the like. Background of the Invention Inflammation Human peripheral blood is composed principally of red blood cells, platelets and white blood cells or leukocytes The family of leukocytes are further classified as neutrophils, lymphocytes (mostly B- and T-cell subtypes), monocytes, eosrnophils and basophils Neutrophils, eosrnophils and basophils are sometimes referred to as "granulocytes" or "polymorphonuclear (PMN) granulocytes" because of the appearance of granules in their cytoplasm and their multiple nuclei Granulocytes and monocytes are often classified as "phagocytes" because of their ability to phagocytose or ingest micro-organisms and foreign mater referred to generally as "antigens" Monocytes are so called because of their large single nucleus and these cells may in turn become macrophages Phagocytes are important m defending the host against a variety of infections and together with lymphocytes are also mvolved in inflammatory disorders The neutrophil is the most common leukocyte found m human peripheral blood followed closely by the lymphocyte In a microhter of normal human peripheral blood, there are about 6,000 leukocytes, of which about 4,000 are neutrophils, 1500 are lymphocytes, 250 are monocytes, 150 are eosrnophils and 25 are basophils Durmg an inflammatory response peripheral blood leukocytes are recruited to the site of inflammation or injury by a series of specific cellular mteractions (see Fig 1) The initiation and mamtenance of immune functions are regulated by intercellular adhesive mteractions as well as signal transduction resulting from mteractions between leukocytes and other cells Leukocyte adhesion to vascular endothehum and migration from the circulation to sites of inflammation is a critical step in the inflammatory response (Fig 1) T-cell lymphocyte immune recognition requires the interaction of the T-cell receptor with antigen (m combination with the ma j or histocompabbility complex) as well as adhesion receptors, which promote attachment of T-cells to antigen-presenting cells and transduce signals for T-cell activation The lymphocyte function associated antιgen-1 (LFA-1) has been identified as the major mtegrm that mediates lymphocyte adhesion and activation leading to a normal immune response, as well as several pathological states (Sprmger, T A , Nature 346425-434 (1990)) Intercellular adhesion molecules (ICAM) -1, -2, and -3, members of the immunoglobulin superfamily, are ligands for LFA-1 found on endothehum, leukocytes and other cell types The binding of LFA-1 to ICAMs mediate a range of lymphocyte functions including lymphokine production of helper T-cells in response to antigen presenting cells, T-lymphocyte mediated target cells lysis, natural killing of tumor cells, and immunoglobulin production through T-cell-B-cell interactions. Thus, many facets of lymphocyte function involve the interaction of the LFA-1 integrin and its ICAM ligands. These LFA-1 :IC AM mediated interactions have been directly implicated in numerous inflammatory disease states including; graft rejection, dermatitis, psoriasis, asthma and rheumatoid arthritis. While LFA-1 (CDlla/CD18) on lymphocytes plays a key role in chronic inflammation and immune responses, other members of the leukocyte integrin family (CDllb/CD18, CDllc/CD18 and CDlld/CD18) also play important roles on other leukocytes, such as granulocytes and monocytes, particularly in early response to infective agents and in acute inflammatory response. The primary function of polymorphonuclear leukocytes, derived from the neutrophil, eosinophil and basophil lineage, is to sense inflammatory stimuli and to emigrate across the endothelial barrier and carry out scavenger function as a first line of host defense. The integrin Mac-l(CDllb/CD18) is rapidly upregulated on these cells upon activation and binding to its multiple ligands which results in the release of oxygen derived free radicals, protease's and phospholipases. In certain chronic inflammatory states this recruitment is improperly regulated resulting in significant cellular and tissue injury. (Harlan, J. M., Acta Med Scand Siψpl., 715:123 (1987); Weiss, S., New England ]. of Med.. 320:365 (1989)). LFA-1 ( CDlla CD18) and Mac-1 (CDllb/CD18) The (CD11/CD18) family of adhesion receptor molecules comprises four highly related cell surface glycoproteins; LFA-1 (CDlla/CD18), Mac-1 (CDllb/CD18), pl50.95 (CDllc/CD18) and (CDlld/CD18). LFA-1 is present on the surface of all mature leukocytes except a subset of macrophages and is considered the major iymphoid integrin. The expression of Mac-1, pl50.95 and CDlld/CD18 is predominantly confined to cells of the myeloid lineage (which include neutrophils, monocytes, macrophage and mast cells). Functional studies have suggested that LFA-1 interacts with several ligands, including ICAM-1 (Rothleinet al, ]. Immunol. 137:1270-1274 (1986), ICAM-2, (Staunton et al., Nature 339:361-364 (1989)), ICAM-3 (Fawcett et al, Nature 360:481-484 (1992); Vezeux et al, Nature 360:485-488, (1992); de FougeroUes and Springer, /. Exp. Med. 175:185-190 (1990)) and Telencephalin (Tian et al., /. Immunol 158:928-936 (1997)). The CD11/CD18 family is related structurally and genetically to the larger integrin family of receptors that modulate cell adhesive interactions, which include; embryogenesis, adhesion to extracellular substrates, and cell differentiation (Hynes, R. O., Cell 48:549-554 (1987); Kishimotoet al, Adv. Immunol 46:149-182 (1989); Kishimotoet al, Cell 48:681-690 (1987); Ruoslahtiet al, Science 238:491-497 (1987). Integrins are a class of membrane-spanning heterodimers comprising an subunit in noncovalent association with a β subunit. The β subunits are generally capable of association with more than one α subunit and the heterodimers sharing a common β subunit have been classified as subfamilies within the mtegrm population (Larson and Sprmger, "Structure and function of leukocyte integrins," Immunol Rev 114181-217 (1990)) The mtegrm molecules of the CD11/CD18 family, and their cellular ligands, have been found to mediate a variety of cell-cell mteractions, especially m inflammation These proteins have been demonstrated to be critical for adhesive functions m the immune system (Kishimotoet al , Adv Immunol 46 149-182 (1989)) Monoclonal antibodies to LFA-1 have been shown to block leukocyte adhesion to endothehal cells (Dustm et al , ] Cell Biol 107321-331 (1988), Smithef al , J Chn Invest 83 2008-2017 (1989)) and to inhibit T-cell activation (Kuypers et al , Res Immunol , 140:461 (1989)), conjugate formation required for anπgen-specrfic CTL killing (Kishimotoer al , Adv Immunol 46 149- 182 (1989)), T cell proliferation (Davignonet al , } Immunol 127590-595 (1981)) and NK cell killing (Krenskyet al , J Immunol 131 611-616 (1983)) ICAMs ICAM-1 (CD54) is a cell surface adhesion receptor that is a member of the immunoglobulin protem super-family (Rothlemet al , / Immunol 13 1270-1274 (1986), Stauntonef al , Cell 52925-933 (1988) Members of this superfamily are characterized by the presence of one or more Ig homology regions, each consisting of a disulfide-bndged loop that has a number of anti-parallel β-pleated strands arranged in two sheets Three types of homology regions have been identified, each with a typical length and havmg a consensus sequence of ammo acid residues located between the cystemes of the disulfide bond (Williams, A F et al Ann Rev Immunol 6 381-405 (1988), Hunkapillar, T et al Adv Immunol 44 1-63 (1989) ICAM-1 is expressed on a variety of hematopoietic and non-hematopoietic cells and is upregulated at sites of inflammation by a variety of inflammatory mediators (Dustm et al , / Immunol , 137256-254 (1986)) ICAM-1 is a 90,000- 110,000 M r glycoprotein with a low messenger RNA levels and moderate surface expression on unstimulated endothehal cells LPS, IL-1 and TNF strongly upregulate ICAM-1 mRNA and surface expression with peak expression at approximately 18-24 hours (Dustmet al , J Cell Biol 107321-331 (1988), Stauntonet al , ail 52 925-933 (1988)) ICAM-1 has five extracellular Ig like domams (designated Domains 1, 2, 3, 4 and 5 or Dl, D2, D3, D4 and D5) and an intracellular or cytoplasmic domain The structures and sequence of the domams is described by Staunton et al (Cell 52 925-933 (1988)) ICAM-1 was defmed originally as a counter-receptor for LFA-1 (Sprmger et al , Ann Rev Immunol, 5 223-252 (1987), MarhnCe/Z 51 813-819 (1987), Simmonsef al , Nature 331 624-627 (1988), StauntonNαfwre 339 61-64 (1989), Stauntonet al Cell 52 925-933 (1988)) The LFA-l/ICAM-1 interaction is known to be at least partially responsible for lymphocyte adhesion (Dusrmef al , } Cell Biol 107321-331 (1988), Mentzeret al , J Cell Phystol 126 285-290 (1986)), monocyte adhesion (Amaoutef al , } Cell Phystol 137305 (1988), Mentzeref al , J Cell Physiol 130410-415 (1987), te Veldeet al , Immunology 61 261-267 (1987)), and neutrophil adhesion (Loet al , J Immunol 143(10) 3325-3329 (1989), Smithef al , J Chn Invest 83 2008-2017 (1989)) to endothehal cells Through the development of function blocking monoclonal antibodies to ICAM-1 additional ligands for LFA- 1 were identified, ICAM-2 and ICAM-3 (Simmons, Cancer Surveys 24, Cell Adhesion and Cancer, 1995) that mediate the adhesion of lymphocytes to other leukocytes as well as non-hematopoiehc cells Interactions of LFA-1 with ICAM-2 are thought to mediate natural killer cell activity (Helander et al , Nature 382265-267 (1996)) and ICAM-3 bmdmg is thought to play a role m lymphocyte activation and the initiation of the immune response (Simmons, ibid) The precise role of these ligands m normal and aberrant immune responses remains to be defmed Disorders Mediated by T Lymphocytes Function blockmg monoclonal antibodies have shown that LFA-1 is important m T- lymphocyte-mediated killing, T-helper lymphocyte responses, natural killing, and antibody- dependent killing (Sprmger et al , Ann Rev Immunol 5 223-252 (1987)) Adhesion to the target cell as well as activation and signaling are steps that are blocked by antibodies agamst LFA-1 Many disorders and diseases are mediated through T lymphocytes and treatment of these diseases have been addressed through many routes Rheumatoid arthritis (RA) is one such disorder Current therapy for RA mcludes bed rest, application of heat, and drugs Sahcylate is the currently preferred treatment drug, particularly as other alternatives such as immunosuppressive agents and adrenocorticosteroids can cause greater morbidity than the underlymg disease itself Nonsteroidal anti-inflammatory drugs are available, and many of them have effective analgesic, arti-pyretic and anti-inflammatory activity m RA patients These include cyclosporm, indomethacin. phenylbutazone, phenylacetic acid derivatives such as ibuprofen and fenoprofen, naphthalene acetic acids (naproxen), pyrrolealkanoic acid (tomeπn), mdoleacetic acids (suhndac), halogenated anthranilic acid (meclofenamate sodium), piroxicam, and drflumsal Other drugs for use m RA mclude anti-malaπals such as chloroqume, gold salts and peniαllamine These alternatives frequently produce severe side effects, mcludmg retinal lesions and kidney and bone marrow toxicity Immunosuppressive agents such as methotrexate have been used only m the treatment of severe and unremitting RA because of their toxicity Corucosteroids also are responsible for undesirable side effects (e g , cataracts, osteoporosis, and Cushrng's disease syndrome) and are not well tolerated m many RA patients Another disorder mediated by T lymphocytes is host re j ection of grafts after transplantation Attempts to prolong the survival of transplanted allografts and xenografts, or to prevent host versus graft rejection, both m experimental models and m medical practice, have centered mamly on the suppression of the immune apparatus of the host/ recipient This treatment has as its aim preventive immunosuppression and/ or treatment of graft re j ection Examples of agents used for preventive immunosuppression mclude cytotoxic drugs, anti-metabolites, corhcosteroids, and anti-lymphocytic serum Nonspecific immunosuppressive agents found particularly effective in preventive immunosuppression (azathioprine, bromocryptme, methylprednisolone, predmsone, and most recently, cyclosporm A) have significantly improved the clinical success of transplantation The nephrotoxicity of cyclosporm A after renal transplantation has been reduced by co-administration of steroids such as prednisolone, or prednisolone m conjunction with azathioprrne In addition, kidneys have been grafted successfully using anti-lymphocyte globulin followed by cyclosporm A Another protocol being evaluated is total lymphoid irradiation of the recipient prior to transplantation followed by mmimal immunosuppression after transplantation Treatment of rejection has involved use of steroids, 2-amιno-6-aryl-5-substιtuted pyrimidines, heterologous anti-lymphocyte globulin, and monoclonal antibodies to various leukocyte populations, mcludmg OKT-3 See generally / Pediatrics, 111 1004-1007 (1987), and specifically U S Pat No 4,665,077 The principal complication of immunosuppressive drugs is infections Additionally, systemic immunosuppression is accompanied by undesirable toxic effects (e g , nephrotoxicity when cyclosporm A is used after renal transplantation) and reduction in the level of the hemopoietic stem cells Immunosuppressive drugs may also lead to obesity, poor wound healing, steroid hyperglycemia, steroid psychosis, leukopema, gastrointestinal bleeding, lymphoma, and hypertension In view of these complications, transplantation immunologists have sought methods for suppressing immune responsiveness in an antigen-specific manner (so that only the response to the donor alloanbgen would be lost) In addition, physicians specializing in autoimmune disease strive for methods to suppress autoimmune responsiveness so that only the response to the self- antigen is lost Such specific immunosuppression generally has been achieved by modifying either the antigemcity of the tissue to be grafted or the specific cells capable of mediating rejection In certam mstances, whether immunity or tolerance will be induced depends on the manner m which the antigen is presented to the immune system Pretreating the allograft tissues by growth m tissue culture before transplantation has been found m two murme model systems to lead to permanent acceptance across MHC barriers Lafferty et al , Transplantation, 22 138-149 (1976), Bowen et al , Lancet, 2 585-586 (1979) It has been hypothesized that such treatment results m the depletion of passenger lymphoid cells and thus the absence of a stimulator cell population necessary for tissue lmmunogenicity Lafferty et al , Annu Rev Immunol , 1 143 (1983) See also Lafferty et al , Science, 188:259-261 (1975) (thyroid held m organ culture), and Gores et al , ] Immunol , 13 1482-1485 (1986) and Faustman et al , Proc Natl Acad So U S A , 78 5156-5159 (1981) (islet cells treated with murme anti-la anbsera and complement before transplantation) Also, thyroids taken from donor animals pretreated with lymphocytotoxic drugs and gamma radiation and cultured for ten days in vitro were not re j ected by any normal allogeneic recipient (Gose and Bach, / Exp Med , 149 1254-1259 (1979)) All of these techniques involve depletion or removal of donor lymphocyte cells In some models such as vascular and kidney grafts, there exists a correlation between Class II matchmg and prolonged allograft survival, a correlation not present m skm grafts (Pescovitz et al , J Exp Med , 160:1495-1508 (1984), Conti et al , Transplant Proc , 19: 652-654 (1987)) Therefore, donor-recipient HLA matchmg has been utilized Additionally, blood transfusions prior to transplantation have been found to be effective (Opelz et al , Transplant Proc , 4: 253 (1973), Persijn et al , Transplant Proc , 23:396 (1979)) The combmation of blood transfusion before transplantation, donor-recipient HLA matchmg, and immunosuppression therapy (cyclosporm A) after transplantation was found to improve significantly the rate of graft survival, and the effects were found to be additive (Opelz et al , Transplant Proc , 172179 (1985)) The transplantation response may also be modified by antibodies directed at immune receptors for MHC antigens (Bluestone et al , Immunol Rev 90 5-27 (1986)) Further, graft survival can be prolonged m the presence of antigraft antibodies, which lead to a host reaction that m turn produces specific immunosuppression (Lancaster et al , Nature, 315: 336-337 (1985)) The immune response of the host to MHC antigens may be modified specifically by us g bone marrow transplantation as a preparative procedure for organ grafting Thus, anti-T-cell monoclonal antibodies are used to deplete mature T-cells from the donor marrow moculum to allow bone marrow transplantation without incurring graft-versus-host disease (Mueller-Ruchholtz et al , Transplant Proc , 8 537-541 (1976)) In addition, elements of the host's lymphoid cells that remain for bone marrow transplantation solve the problem of lmmunorncompetence occurrmg when fully allogeneic transplants are used As shown m Fig 1, lymphocyte adherence to endothehum is a key event m the process of inflammation There are at least three known pathw ays of lymphocyte adherence to endoin lium, dependmg on the activation state of the T-cell and the endothehal cell T-cell immune recognition requires the contribution of the T-cell receptor as well as adhesion receptors, which promote attachment of - cells to antigen-presentmg cells and transduce regulatory signals for T-cell acnvation The lymphocyte function associated (LFA) antιgen-1 (LFA-1, CDlla/CD18, αLβ2 where CCL IS CiJlla and β2 is CD18) has been identified as the ma j or mtegrm receptor on lymphocytes mvolved m these cell adherence mteractions leadmg to several pathological states ICAM-1, die endothehal cell lmmunoglobuhn-like adhesion molecule, is a known ligand .or LFA-1 and is implicated directly m graft rejection, psoriasis, and arthritis LFA-1 is required for a range of leukocyte functions, mcludmg lymphokme production of helper T-cells m response to antigen-presenting cells, killer T-cell-mediated target cell lysis, and immunoglobulin production through T-cell/ B-cell mteractions Activation of antigen receptors on T-cells and B-cells allows LFA-1 to bmd its ligand with higher affinity Monoclonal antibodies (MAbs) directed agamst LFA-1 led to the initial identification and investigation of the funcbon of LFA-1 (Davignon et al , ] Immunol , 127590 (1981)) LFA-1 is present only on leukocytes (Krenskey et al , J Immunol , 131:611 (1983)), and ICAM-1 is distributed on activated leukocytes, dermal fibroblasts, and endothehum (Dustm et al , ] Immunol 137:245 (1986)) Previous studies have investigated the effects of anti-CDlla MAbs on many T-cell- dependent immune functions in vitro and a limited number of immune responses in vivo In vitro, anti-CDlla MAbs inhibit T-cell acbvation (Kuypers et al , Res Immunol 140:461 (1989)), T-cell- dependent B-cell proliferation and differentiation (Davignon et al , supra, Fischer et al , J Immunol , 136:3198 (1986)), target cell lysis by cytotoxic T-lymphocytes (Krensky et al , supra), formabon of immune conjugates (Sanders et al , J Immunol , 1372395 (1986), Mentzer et al , ]_Immunol , 135 9 (1985)), and the adhesion of T-cells to vascular endothehum (Lo et al , / Immunol , 1433325 (1989)) Also, the antibody 5C6 directed agamst CDllb/CD18 was found to prevent rntra-islet mfiltrabon by both macrophages and T cells and to inhibit development of insulin-dependent diabetes melhtis m mice (Hutchings et al , Nature, 348 639 (1990)) The observation that LFA-1 ICAM-1 mterachon is necessary to optimize T-cell function in vitro, and that anti-CDlla MAbs induce tolerance to protein antigens (Ben j amin et al , Eur ] Immunol , 18:1079 (1988)) and prolongs tumor graft survival m mice (Heagy et al , Transplantation, 37 520-523 (1984)) was the basis for testing the MAbs to these molecules for prevention of graft rejection m humans Experiments have also been carried out in primates For example based on experiments m monkeys it has been suggested that a MAb directed against ICAM-1 can prevent or even reverse kidney graft rejection (Cosimi et al , "Immunosuppression of Cynomolgus Recipients of Renal Allografts by R6 5, a Monoclonal Anbbody to Intercellular Adhesion Molecule-1," m Sprmger et al (eds ), Leukocyte Adhesion Molecules New York Sprmger, (1988), p 274, Cosimi et l , } Immunology, 1444of4-4612 (1990)) Furthermore, the in vivo administration of anti-CDlla MAb to cynomolgus monkeys prolonged skm allograft survival (Berlm et al , Transplantation, 53 840-849 (1992)) The first successful use of a rat anh-murine CDlla anbbody (25-3, IgGl) m children with inherited disease to prevent the rejection of bone-marrow-mismatched haploidentical grafts was reported by Fischer et al , Lancet, 2 1058 (1986) Minimal side effects were observed See also Fischer et .;,' , Blood, 77 249 (1991), van Dijken et al , Transplantation, 49:882 (1990), and Per, z et al , Bone Marrow Transplantation, 4 379 (1989) Furthermore, the antibody 25-3 was effective m controlling steroid-resistant acute graft-versus-host disease m humans (Stoppa et al , Transplant Ini , 4:3-7 (1991)) However, these results were not reproducible m leukemic adult grafting with this MAb (Mararunchi et al , Bone Marrow Transplant, 4 147-150 (1989)), or with an anb-CD18 MAb, directed against the invariant cham of LFA-1, m another pilot study (Baume et al , Transplantation, 47 472 (1989)) Furthermore, a rat anti-muπne CDlla MAb, 25-3, was unable to control the course of acute rejection m human kidney transplantation (LeMauff et al , Transplantation, 52 291 (1991)) A review of the use of monoclonal antibodies m human transplantation is provided by Dantal and Souhllou, Current Opinion in Immunology, 3 740-747 (1991) An earlier report showed that brief treatment with either anti-LFA-1 or anb-ICAM-1 MAbs mmimally prolonged the survival of primarily vascularized heterotopic heart allografts m mice (Isobe et al , Science, 255 1125 (1992)) However, combined treatment with both MAbs was required to achieve long-term graft survival m this model Independently, it was shown that treatment with anti-LFA-1 MAb alone potently and effectively prolongs the survival of heterotopic (ear-pinnae) nonpπmarily vascularized mouse heart grafts using a maximum dose of 4 mg/kg/day and treatment once a week after a daily dose (Nakakura et al , } Heart Lung Transplant , 11 223 (1992)) Nonpπmaπly vascularized heart allografts are more lmmunogenic and more resistant to prolongation of survival by MAbs than primarily vascularized heart allografts (Warren et al , Transplant Proc , 5:717 (1973), Trager et al , Transplantation, 47587 (1989)) The latter reference discusses treatment with L3T4 antibodies usmg a high initial dose and a lower subsequent dose Another study on treating a sclerosis-type disease m rodents usmg similar antibodies to those used by Nakakura et al , supra, is reported by Yednock et al , Nature, 356:63-66 (1992) Additional disclosures on the use of anb-LFA-1 antibodies and ICAM-1, ICAM-2, and ICAM-3 and their antibodies to treat LFA-1 -mediated disorders mclude WO 91/18011 published 11/28/91, WO 91/16928 published 11/14/91, WO 91/16927 published 11/14/91, Can Pat Appln 2,008,368 published 6/13/91, WO 90/03400, WO 90/15076 published 12/13/90, WO 90/10652 published 9/20/90, EP 387,668 published 9/19/90, WO 90/08187 published 7/26/90, WO 90/13281, WO 90/13316, WO 90/13281, WO 93/06864, WO 93/21953, WO 93/13210, WO 94/11400, EP 379,904 published 8/1/90, EP 346,078 published 12/13/89, U S Pat No 5,002,869, U S Pat No 5,071,964, U S Pat No 5,209,928, U S Pat No 5,223,396, U S Pat No 5,235,049, U S Pat No 5,284,931, U S Pat No 5,288,854, U S Pat No 5,354,659, Australian Pat Appln 15518/88 published 11/10/88, EP 289,949 published 11/9/88, and EP 303,692 published 2/22/89, EP 365,837, EP 314,863, EP 319,815, EP 468, 257, EP 362,526, EP 362, 531, EP 438,310 Other disclosures on the use of LFA-1 and ICAM peptide fragments and antagonists iclude, U S Pat No 5,149,780, U S Pat No 5,288,854, U S Pat No 5,340,800, U S Pat No 5,424,399, U S Pat No 5,470,953, WO 90/03400, WO 90/13316, WO 90/10652, WO 91/19511, WO 92/03473, WO 94/11400, WO 95/28170, JP 4193895, EP 314,863, EP 362,526 and EP 362,531 The above methods successfully utilizing anti-LFA-1 or anti-ICAM-1 antibodies, LFA-1 or ICAM-1 peptides, fragments or peptide antagonists represent an improvement over traditional immunosuppressive drug therapy These studies demonstrate that LFA-1 and ICAM-1 are appropriate targets for antagonism There is a need m the art to better treat disorders that are mediated by LFA-1 mcludmg autoimmune diseases, graft vs host or host vs graft rejection, and T- cell inflammatory responses, so as to minimize side effects and sustain specific tolerance to self- or xenoanfagens There is also a need m the art to provide a non-pephde or peptidomimetic antagonist to the LFA-1 ICAM-1 interaction At least one peptidomimetic antagonist of the LFA-1 ICAM-1 interaction has shown promise m various in vitro assays 2-Bromobenzoyltryptophan exhibits ICso's of about 2μM and lOμM respectively in human LFA- 1:ICAM-1 receptor binding and human T-cell adhesion assays described herein. Recently, aminobenzoic acid derivatives of fluorene have been described in U.S. Patent 5,472,973 is useful anti-inflammatory agents. A representative compound is: Objects of the Invention Accordingly, it is an object of this invention to provide compositions and therapeutic methods for modulating adhesion between intracellular adhesion molecules (e.g. ICAM-1, -2 and - 3) and the leukocyte integrin family of receptors. It is an object to antagonize CD11/CD18 receptors associated with leukocytes, especially Mac-1 and LFA-1 -mediated disorders with minimal side effects. It is an object to control inappropriate inflammatory responses and prevent damage to healthy tissue. More specifically, it is an object to treat LFA-1-mediated disorders including: psoriasis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), dermatitis, meningitis, encephalitis, uveitis, allergic conditions such as eczema and asthma, conditions involving infiltration of T-cells and chronic inflammatory responses, skin hypersensitivity reactions (including poison ivy and poison oak); atherosclerosis, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, juvenile onset diabetes, and immune responses associated with delayed hypersensitivity mediated by cytokines and T-lymphocytes typically found in tuberculosis, sarcoidosis, polymyosihs, granulomatosis and vascuhtis, pernicious anemia, diseases mvolvmg leukocyte diapedesis, CNS inflammatory disorder, multiple organ m j ury syndrome secondary to septicaemia or trauma, autoimmune hemolyhc anemia, myasthemia gravis, antigen- antibody complex mediated diseases, all types of transplantations, mcludmg graft vs host or host vs graft disease, HIV and rhinovrrus infection, pulmonary fibrosis, and the like These and other objects will become apparent to one of ordinary skill m the art Summary of the Invention These objects are accomplished by providmg a method and antagonist compositions for modulating adhesion between intracellular adhesion molecules (e g ICAM-1, -2 and -3) and the leukocyte mtegrm family of receptors The method and antagonists are especially useful for treating CD11/CD18, especially Mac-1 and LFA-1-medιated disorders m a mammal, especially a human, comprising administering to the mammal a therapeutically effective amount of the antagonist Suitable leukocyte mtegrm antagonists, especially Mac-1 and LFA-1 antagonists of this invention are represented by Structural Formula I below Preferably, the LFA-1 antagonist is a specific antagonist of the leukocyte mtegrm CDlla(αL)/CD18(β2) Such antagonists are especially useful to treat chronic LFA-1 mediated disorders Preferably, these LFA-1 antagonists are used to treat psoriasis, alopecia, organ transplant, inflammatory bowel disease (IBD), rheumatoid arthπbs (RA), systemic lupus erythematosis (SLE), type-1 diabetes, multiple sclerosis (MS), asthma, graft verses host (GVH) disease, scleredoma, endometriυsus and vihligo Optionally, certain compounds embraced by Formula I are also capable of antagonizmg Mac-1 CDllb(αjvl)/CD18(β2j bmdmg to ICAM-1 and additional ligands mcludmg ιC3b, fibrmogen and Factor X These compounds are therefore useful for inhibiting adhesion of neutrophils and leukocytes expressmg both or either LFA-1 and Mac-1 m both chronic and leukocyte/ neutrophil mediated disorders More specifically these disorders mclude, lschemic reperfusion mjury mediated by neutrophils such as acute myocardial infarction, res mosis following PTCA, invasive procedures such as cardiopulmanary bypass surgery, cerebral edema, stroke, traumatic bram mjury, multiple sclerosis, systemic lupus erythematosis, hemorragic shock, burns, ischemic kidney disease, multi- organ failure, wound healing and scar formation, atherosclerosis as well as organ failure post- transplant The antagonist is represented by formula I Where D is a mono-, bi-, or tricyclic saturated, unsaturated, or aromatic ring, each ring having 5-, 6- or 7 atoms in the ring where the atoms in the ring are carbon or froml-4 heteroatoms selected from; nitrogen, oxygen, and sulfur, where any sulfur ring atom may optionally be oxidized and any carbon ring atom may form a double bond with O, NR and CR R , each ring nitrogen substituted with R and any ring carbon substituted with R . Optionally, D is an aromatic homocycle or aromatic heterocycle containing 1-3 heteroatoms selected from the group N, S and O, the homo- or hetero-cycles selected from: where Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are CH, CR d or M, Z 1 is O, S, NH or NR n and n is 0-3. More specifically, D may be: 1) a 5-member aromatic heterocycle or het selected from; and 2) a 9-member aromatic heterobicycle selected from; 3) a 6-member aromatic hetero- or homocycle selected from; and L is a bivalent linking group selected from — LΛ— L 2 — L 1 — 1 1 3 1 2 , 1 L L L L and L^L 4 L 3 — L 2 — L 1 , where: L 1 may be oxo (O), S(0) , C{=0), C(=N-R n ), C(=CR 1 R 1 '), C(R 1 R 1 ), C(R 1 ), C, het, N(R n ) or N; L 2 may be oxo (O), S(0) g , C(=0), C(=N-0-R°), C(=CR 2 R 2 '), C(R 2 R 2 '), C(R 2 ), C, het, N(R n ) or N; L 3 may be oxo (O), S(0) g , C(=0), C(=N-0-R°), C(=CR 3 R 3 '), C(R 3 R 3 ') C(R 3 ), C, het, N(R n ) or N; L 4 is absent or may be oxo (O), S(O) , C(=0), C(=N-O-R 0 ), C(=CR R 4 '), C(R 4 R 4 ), C(R 4 ), C, NR n or N; and L 5 is absent or may be oxo (O), S(O) , C(=0), C(=N-R n ), C(R 5 R 5 '), C(=CR 5 R 5 ), C(R 5 ), C, NR or N; 1 3 1 3 provided that only one of L -L may be het and that when one of L - L 1 5 is het the other L -L may be absent. 1 1' 2 2' 3 3' 4 4' 5 5' a c R , R , R , R , R , R , R , R , R and R each are independently selected from R , R 2 2' and U-Q-V-W. Opuonally, R and R separately or together may form a saturated, unsaturated or aromatic fused ring with B through a substituent R^ on B, the fused ring containing 5, 6 or 7 atoms in the ring and optionally containing 1-3 heteroatoms selected from the group O, S and N. where 3 3' 4 any S or N may optionally be oxidized. Optionally, R and R separately or together and R and 4' R separately or together may form a saturated, unsaturated or aromatic fused ring with D through a substituent R on D, the fused ring containing 5, 6 or 7 atoms in the ring and optionally containing 1-3 heteroatoms selected from the group O, S and N, where any S or N may optionally be oxidized. Also optionally, each R -R , or NR together with any other R - R or NR may form a 5, 6 or 7 member homo- or heterocycle either saturated, unsaturated or aromatic optionally containing 1-3 additional heteroatoms selected from N, O and S, each cycle substituted with 0-3 R , where s is 0-2, and where any carbon or sulfur ring atom may optionally be oxidized. More specifically, the bivalent linker L may be: -(CR 6 R 6 ) -Ai-(CR 8 R 8 ') -, o p -(CR 6 R 6 ) -het-(CR 8 R 8 ) -, o p -(CR 6 =CR 7 ) -Ai-(CR 8 R 8 ') -and q P -(CR 6 R 6 ) -Ai-( CR 8 =CR 9 ) -, o r where Ai is selected from where o is 0-1, p is 0-1, q is 0-1 and r is 0-1. het is any mono-, bi-, or tiicyclic saturated, unsaturated, or aromatic ring where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, the 5-membered ring having from 0 to 2 double bonds and the 6- or 7- membered ring having from 0 to 3 double bonds and where any carbon or sulfur atoms in the ring may optionally be oxidized, and where any nitrogen heteroatom may optionally be ςdaternized and where any ring may contain from 0-3 R . Optionally L is a bivalent linking group selected from the group: -C 3 -C 5 -alkyl-, -C3-C5-alkenyl-, -CH C(=0)NH-, -CH NH-C(=0)-, -O-CH -C(=0)-, -CH -CH - C(=0)-, -CH=CH-C(=0)NH-CH 2 -, -CH=CH-C(=0)NH-CH-(CH )-, -CH(OH)-CH -0-, -CH(OH)- CH ? -N(CH 3 )-, -CH(OH)-CH -CH -, -CH -CH -CH(OH)-, -O-CH -CH(OH)-, -O-CH -CH(OH)- CH 2 -, -0-CH 2 -CH 2 -CH(OH)-, -O-CH^CH^O-, -CH -CH -CH -O-, -CH -CH(OH)-CH -O-, -CH^ CH -O-, -CH-(CH )-NH-C(=0)-, -CH 2 -NH-S0 2 -, -NH-S0 2 -CH 2 -, -CH 2 -S0 2 NH-, -S0 2 NH-CH 2 -, - C(=0)-NH-C(=0)-, -NH-C(=0)-NH-, -NH-C(=0)-NH-CH 2 -, -CH 2 -NH-C(=0)-NH-, -C(=0)-NH- CH 2 -C(=0)-NH -, -NH-C(=0)-0- and -0-C(=0)-NH-. Optionally, specific D-L combinations are selected from: B is selected from the group where is a fused hetero- or homocyclic ring containing 5, 6 or 7 atoms, the ring being unsaturated, partially saturated or aromatic, the heteroatoms selected from 1-3 O, S and N. Y is selected from CH and N and n is 0-3. G is selected from hydrogen and C -C alkyl, optionally G taken together with T may form a C -C cycloalkyl optionally substituted with -V-W. 3 6 T is selected from the group 1) a naturally occurring α-amino-acid side chain or derivatives thereto and U-Q-V-W. U is an optionally substituted bivalent radical selected from the group; C -C alkyl, C -C alkyl-Q, C -C alkenyl-Q, and C -C alkynyl-Q, where the substituents on any 1 6 0 6 2 6 2 6 alkyl, alkenyl or alkynyl are 1-3 R . Q is absent or is selected from the group; -O-, -S(O) -, -SO -N(R n )-, -N(R°)-, -N(R n )-C(=0)-, -N(R n )-C(=0)-0-, -N(R n )-SO -, -C(=0)-, -C(=0)-0-, -het-, -C(=0)-N(R n )-, -PO(OR C )0- and -P(0)0-, where s is 0-2 and het is a mono- or bicyclic 5, 6, 7, 9 or 10 member heterocyclic ring, each ring containing 1-4 heteroatoms selected from N, O and S, where the heterocyclic ring may be saturated, partially saturated, or aromatic and any N or S being optionally oxidized, the heterocyclic ring being substituted with 0-3 R . V is absent or is an optionally substituted bivalent grou; selected from C -C alkyl, C - 1 6 3 C cycloalkyl, C -C alkyl-C -C aryl, and C -C alky-het, where the substituents on any alkyl are 1- 8 0 6 6 10 0 6 a d 3 R and the substituents on any aryl or het are 1-3 R . W is selected from the group; hydrogen, -OR°, -SR m , -NR n R n , -NH-C(=0)-0-R C , -NH- C(=0)-NR n R n , -NH-C(=0)-R C , -NH-SO -R s , -NH-SO -NR n R n ', -NH-SO -NH-C(=0)-R C , -NH- C(=0)-NH-S0 2 -R s , -C(=0)-NH-C(=0)-0-R c , -C(=0)-NH-C(=0)-R C , -C(=0)-NH-C(=0)-NR n R n , - C(=0)-NH-SO -R s , -C(=0)-NH-SO -NR n R n ', -C(=S)-NR n R n ', -SO -R S , -SO -0-R S , -SO -NR n R n ,- SO -NH-C(=0)-0-R C , -SO -NH-C(=0)-NR n R n , -SO -NH-C(=0)-R C , -0-C(=0)-NR n R n , -0-C(=0)- R C , -0-C(=0)-NH-C(=0)-R C , -0-C(=0)-NH-SO -R S and -O-SO -R S . R is selected from -C(=0)-R z , -C(=0)-H, -CH (OH) and -CH 0-C(=0)-C -C alkyl. 2 2 1 6 R a is R a or R a substituted with 1-3 R a . R is selected from the group; hydrogen, halo(F. Cl, Br, I), cyano, isocyanate, carboxy, carboxy-C -C alkyl, amino, amino-C -C alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C -C alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl. imidazolyl and indolyl. R a is selected from the group C -C alkyl-Q-C -C alkyl, C -C alkenyl-Q-C -C alkyl, u 10 0 6 0 10 0 6 C 0 -C ιo alkynyl-Q-C o -C 6 alkyl, C^C^ycloalkyl-Q-C^C.alkyl, C 3 -C 10 cycloalkenyl-Q-C 0 -C 6 alkyl, C 1 -C 6 alkyl-C 6 -C 12 aryl-Q-C o -C 6 alkyl, C 6 -C ιo aryl-C ι -C 6 alkyl-Q-C () -C 6 alkyl, C o -C 6 alkyl-het-Q-C 0 - C alkyl, C -C alkyl-Q-het-C -C alkyl, het-C -C alkyl-Q-C -C alkyl, C -C alkyl-Q-C -C aryl 6 U 6 O b O b 0 6 0 6 6 12 and Q-C -C alkyl. 1 6 3 R c is selected from hydrogen and substituted or unsubstituted; C -C alkyl, C - C 1() alkenyl, C^C^alkynyl, C 3 -C 11 cydoalkyl, C^-C^cycloalkenyl, C^C^lkyl-C^C^aryl. C fi - C aryl-C -C alkyl, C -C alkyl-het, het-C -C alkyl, C -C aryl and het, where the substituents on 1U l b 1 6 1 6 6 12 any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl or het are 1-3 R . R is selected from R" and R . R is selected from the group OH, OCF OR C , SR m , halo(F, Cl. Br, I), CN, isocyanate, NO , CF . C -C alkyl-NR n R n ', C -C alky l-C(=0)-NR n R n ', C -C alkyl-C(=0)-R a , C -C alkyl, C - 3 0 6 0 6 0 6 1 8 1 C alkoxy, C -C alkenyl, C -C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, C -C alky 1-phenyl, o 1 o 2 o 3 6 3 6 1 6 phenyl-C -C alkyl, C -C alkyloxycarbonyl, phenyl-C„-C alkyloxy, C -C alkyl-het, het-C - 1 6 1 6 0 6 1 6 1 C alkyl, SO -het, -O-C -C aryl, -SO -C -C aryl, -SO^-C -C alkyl and het, where any alkyl, 6 2 6 12 2 6 12 2 1 6 alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino. 3 1 6 1 6 R m is selected from S-C -C alkyl, C(=0)-C -C alkyl, C(=0)-NR n R n ', C -C alkyl, halo(F, 1 6 1 6 1 6 Cl, Br, I)-C -C alkyl, benzyl and phenyl. 1 6 R n is selected from the group R C , NH-C(=0)-0-R C , NH-C(=0)-R C , NH-C(=0)-NHR C , NH- SO -R S , NH-SO -NH-C(=0)-R C , NH-C(=0)-NH-SO -R S , C(=0)-0-R C , C(=0)-R C , C(=0)-NHR C , C(=0)-NH-C(=0)-0-R C , C(=0)-NH-C(=0)-R c , C(=0)-NH-SO -R S , C(=0)-NH-SO -NHR S , SO -R S , SO -0-R S , SO -N(R C ) SO -NH-C(=0)-0-R C , SO -NH-C(=0)-0-R c and SO -NH-C(=0)-R c . R is selected from hydrogen, hydroxy and substituted or unsubstituted C -C alkyl, C - C^alkoxy, C^C^alkenyl, C 2 -C lo alkynyl, C^C^cycloalkyl, C 3 -C ι() cycloalkenyl, C^C^lkyl-C^ C^aryl, C 6 -C ιo aryl-C ι -C 6 alkyl, C^C^aryl-C^C^lkyloxy, C ι -C 6 alkyl-het, het-C ι -C 6 alkyl, C - C aryl, het, C -C alkylcarbonyl, C -C alkoxycarbonyl, C -C cycloalkylcarbonyl, C - 12 1 6 1 8 3 8 3 C cycloalkoxycarbonyl, C -C aryloxycarbonyl, C -C . , arylalkoxy car bony 1, 8 6 11 7 11 heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C -C alkylsulfonyl and C -C arylsulfonyl, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl, het or heteroaryl are 1-3 R . Optionally, R and R taken together with the common nitrogen to which they are attached may from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, indolinyl, isoindoHnyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl, where the substituents are 1-3 R . R is selected from hydrogen and substituted or unsubstituted C -C alkyl, C - C alkylcarbonyl, C -C alkenyl, C -C alkynyl, C -C cycloalkyl and benzoyl, where the substituents 6 2 6 2 6 3 8 on any alkyl are 1-3 R and the substituents on any aryl are 1-3 R . R P is selected from the group; OH, halo(F, Cl. Br, I), CN, isocyanate, OR C , SR m , SOR C , NO , CF . R C , NR n R n ', N(R n )-C(=0)-0-R C , N(R n )-C(=0)-R C , C -C alkyl-SO ^ -R C , C n -C alkyl-SO - 3 0 6 2 0 6 2 NR n R n , C(=0)-R C , 0-C(=0)-R c , C(=0)-0-R c and C(=0)-NR n R n ', where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl or het are 1-3 R . R s is a substituted or unsubstituted group selected from; C -C alkyl, C -C alkenyl, C - 1 8 2 8 2 C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, C -C alkyl-phenyl, phenyl-C -C alkyl, C - 8 3 o ό 6 0 6 0 6 0 C alkyl-het and het-C -C alkyl, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl or het are 1-3 R R z is a substituted or unsubstituted group selected from, hydroxy, C -C alkoxy, C - 12 cycloalkoxy, C 8 -C arcycloalkoxy, C -C aryloxy, C - C alkylcarbonyloxyalkyloxy, C -C alkoxycarbonyloxyalkyloxy, C -C alkoxycarbonylalkyloxy, C -C cycloalkylcarbonyloxyalkyloxy, ^ ς '^ i n cycloalkoxycarbonyloxyalkyloxy, C - C cycloalkoxycarbonylalkyloxy, C -C aryloxycarbonylalkyloxy, C - 10 8 12 8 C aryloxycarbonyloxyalkyloxy, C -C arylcarbonyloxyalkyloxy, C - C alkoxyalkylcarbonyloxyalkyloxy, (R )(R )N(C -C alkoxy) a where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituentson any aryl or het are 1-3 R and pharmaceutically acceptable salts thereof Brief Description of the Drawings FIGURE 1 A cartoon illustrating lymphocyte recruitment to a site of infection is provided Lymphocyte rolling and adhesion to ICAM expressmg cells (leukocytes, endothehum, epithelium ) is shown FIGURE 2 A cartoon illustrating the human ICAM-1 LFA-1 receptor bmdmg assay (protem/protem assay) is provided Inhibition of the CDlla/CD18-ICAM-l mterachon is quantitated by addmg known amounts of inhibitors to the protem/protem assay system described m Example 3 FIGURE 3 A cartoon illustrating the human T Cell Adhesion Assay described m Example 4 is provided FIGURE 4 A cartoon illustrating the human T cell proliferation assay is provided. Cell proliferation is measured by tritiated thymidine uptake. FIGURE 5 A cartoon illustrating the human one way mixed lymphocyte response is provided. Cell proliferation is measured by tritiated thymidine uptake. Description of the Preferred Embodiments A . Definitions The term "LFA-1-mediated disorders" refers to pathological states caused by cell adherence interactions involving the LFA-1 receptor on lymphocytes. Examples of such disorders include T-cell inflammatory responses such as inflammatory skin diseases including psoriasis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); adult respiratory distress syndrome; dermatitis; meningitis; encephalitis; uveitic; allergic conditions such as eczema and asthma and other conditions involving infiltration of T-cells and chronic inflammatory responses; skin hypersensitivity reactions (including poison ivy and poison oak); atherosclerosis; leukocyte adhesion deficiency; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, type 1 diabetes, juvenile onset diabetes, and immune responses associated with delayed hypersensitivity mediated by cyio rnes and T-lymphocytes typically ound in tuberculosis, sarcoidosis, polymyositis, granulornatosis and vasculitis; pernicious anemia; diseases involving leukocyte diapedesis; CNS inflammatory disorder, multiple organ injury syndrome secondary to septicaemia or trauma; autoimmune haemolytic anemia; myethemia gravis; antigen- antibody complex mediated diseases; all types of transplantations, including graft vs. host or host vs. graft disease; etc. "Treating" such diseases includes therapy, prophylactic treatment, prevention of rejection of grafts, and induction of tolerance of grafts on a long-term basis. The term "graft" as used herein refers to biological material derived from a donor for transplantation into a recipient. Grafts include such diverse material as, for example, isolated cells such as islet cells, tissue such as the amniotic membrane of a newborn, bone marrow, hematopoietic precursor cells, and organs such as skin, heart, liver, spleen, pancreas, thyroid lobe, lung, kidney, tubular organs (e.g., intestine, blood vessels, or esophagus), etc. The tubular organs can be used to replace damaged portions of esophagus, blood vessels, or bile duct. The skin grafts can be used not only for burns, but also as a dressing to damaged intestine or to close certain defects such as diaphragmatic hernia. The graft is derived from any mammalian source, including human, whether from cadavers or living donors. Preferably the graft is bone marrow or an organ such as heart and the donor of the graft and the host are matched for HLA class II antigens. The term "mammal" refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal herein is human. The term "mammalian host" as used herein refers to any compatible transplant recipient. By "compatible" is meant a mammalian host that will accept the donated graft. Preferably, the host is human. If both the donor of the graft and the host are human, they are preferably matched for HLA class II antigens so as to improve histocompatibility. The term "donor" as used herein refers to the mammalian species, dead or alive, from which the graft is derived. Preferably, the donor is human. Human donors are preferably volunteer blood-related donors that are normal on physical examination and of the same major ABO blood group, because crossing major blood group barriers possibly prejudices survival of the allograft. It is, however, possible to transplant, for example, a kidney of a type O donor into an A, B or AB recipient. The term "transplant" and variations thereof refers to the insertion of a graft into a host, whether the transplantation is syngeneic (where the donor and recipient are genetically identical), allogeneic (where the donor and recipient are of different genetic origins but of the same species), or xenogeneic (where the donor and recipient are from different species). Thus, in a typical scenario, the host is human and the graft is an isograft, derived from a human of the same or different genetic origins. In another scenario, the graft is derived from a species different from that into which it is transplanted, such as a baboon heart transplanted into a human recipient host, and including animals from phylogenically widely separated species, for example, a pig heart valve, or animal beta islet cells or neuronal cells transplanted into a human host. The term "LFA-1 antagonist" as used herein generally refers to a benzoyl-amino acid (AA) derivative or a peptidomimetic thereof that acts as a competitive inhibitor of the CDlla and/ or CD18 interaction with ICAM-1, soluble forms of ICAM-1 and bound or soluble forms of ICAM-2, ICAM-3 and telencephalin. The term "immunosuppressive agent" as used herein for adjunct therapy refers to substances that act to suppress or mask the immune system of the host into which the graft is being transplanted. This would include substances that suppress cytokine production, down regulate or suppress self-antigen expression, or mask the MHC antigens. Examples of such agents include 2- amino-6-aryl-5-substituted pyrimidines (see U.S. Pat. No. 4,665,077, supra, the disclosure of which is incorporated herein by reference), azathioprine (or cyclophosphamide, if there is an adverse reaction to azathioprine); bromocryptine; glutaraldehyde (which masks the MHC antigens, as described in U.S. Pat. No. 4,120,649, supra); anti-idiotypic antibodies for MHC antigens and MHC fragments; cyclosporin A; steroids such as glucocorticosteroids, e.g., prednisone, methylprednisolone, and dexamethasone; cytokine or cytokine receptor antagonists including anti- interferon-β, or -a antibodies; anti-tumor necrosis factor-a antibodies; anti-tumor necrosis factor-β antibodies; anti-interleukin-2 antibodies and anti-IL-2 receptor antibodies; anti-L3T4 antibodies; heterologous anti-lymphocyte globulin; pan-T antibodies, preferably anti-CD3 or anti-CD4/CD4a antibodies; soluble peptide containing a LFA-3 binding domain (WO 90/08187 published 7/26/90), streptokinase; TGF-β; stieptodornase; RNA or DNA from the host; FK506; RS-61443; deoxyspergualin; rapamycin; T-cell receptor (Cohen et al, U.S. Pat. No. 5,114,721); T-cell receptor fragments (Offner et al, Science, 251:430-432 (1991); copending U.S. Ser. No. 07/853,362 filed March 18, 1992, the disclosure of which is incorporated herein by reference; Howell, WO 90/11294; Ianeway, Nature, 341:482 (1989); and Vandenbark, WO 91/01133); and T-cell receptor antibodies (EP 340,109) such as T10B9. These agents are administered at the same time or at separate times from the CDlla or CD18 antagonists as used in this invention, and are used at the same or lesser dosages than as set forth in the art. The preferred adjunct immunosuppressive agent will depend on many factors, including the type of disorder being treated including the type of transplantation being performed, as well as the patient's history, but a general overall preference is that the agent be selected from cyclosporin A, a glucocorticosteroid (most preferably prednisone or methylprednisolone), OKT-3 monoclonal antibody, azathioprine, bromocryptine, heterologous anti-lymphocyte globulin, or a mixture thereof. "Increasing tolerance of a transplanted graft" by a host refers to prolonging the survival of a graft in a host in which it is transplanted, i.e., suppressing the immune system of the host so that it will better tolerate a foreign transplant. The term "alkyl" means a branched or unbranched, saturated aliphatic hydrocarbon radical, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. Unless otherwise specified the term also encompasses unsaturated alkyls defined as "cycloalkyl", "alkenyl" and "alkynyl" below. Examples of preferred alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl, and the like. The term "Cn-C6 alkyl" and similar terms containing "Co" means a covalent bond when the number of carbons is zero (Co) or Ci-C alkyl. If necessary to prevent a dangling valence the term "Co" may include a hydrogen atom. A preferred "Ci-C^ alkyl" group is methyl. The term "substituted C n -C m alkyl" where and n are integers identifying the range of carbon atoms contained in the alkyl group, denotes the above alkyl groups that are substituted by the groups listed or if no groups are listed one, two or three halogen, hydroxy, protected hydroxy, amino, protected amino, C1-C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino or C1-C4 alkoxy groups. The substituted alkyl groups may be substituted once , twice or three times with the same or with different substituents. Examples of the above substituted alkyl groups include but are not limited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2- carbamoyloxyethyl and the like. A preferred group of examples within the above "C -Cι 2 substituted alkyl" group includes the substituted methyl group, e.g. a methyl group substituted by the same substituents as the "substituted C n -C m alkyl" group. Examples of the substituted methyl group mclude groups such as hydroxymethyl, protected hydroxymethyl (e.g. tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, bromomethyl and iodomethyl. The terms "Cι-Cι 2 alkyloxy" or "C1-C12 alkoxy" are used interchangeably herein and denote groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. The terms "Cι~Cι 2 acyloxy" or "C[-Cι 2 alkanoyloxy" are used interchangeably and denote herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, and the like. The terms "C1-Q12 alkylcarbonyl", "C1-C12 alkanoyl" and "C1-C12 acyl" are used interchangeably herein encompass groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like. The term "cycloalkyl" as used herein refers to a mono-, bi-, or tiicyclic saturated or unsaturated ring, each ring having from 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms. Optionally any ring carbon may be oxidized to from a carbonyl. The term "alkenyl" means a branched or unbranched hydrocarbon radical having the number of carbon atoms designated containing one or more carbon-carbon double bonds, each double bond being independently cis, trans, or a nongeometric isomer. The term "alkynyl" means a branched or unbranched hydrocarbon radical having the number of carbon atoms designated containing one or more carbon-carbon triple bonds. The terms "C1-C12 alkylthio" and "C1-C12 substituted alkylthio" denote C1-C12 alkyl ar >d C1-C12 substituted alkyl groups, respectively, attached to a sulfur which is in turn the point of attachment for the alkylthio or substituted alkylthio group to the group or substituent designated. The term "aryl" when used alone means a homocyclic aromatic radical whether or not fused having the number of carbon atoms designated. Preferred aryl groups include phenyl, napthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang's Handbook of Chemistry (Dean, J. A., ed.) 13 th ed. Table 7-2 [1985]). The term "substituted phenyl" or "substituted aryl" denotes a phenyl group or aryl group substituted with one, two or three substituents chosen from the groups listed or those selected from; halogen(F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, C -C6alkyl, Cι-C6alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl N-(methylsulfonylamino) or other groups specified. Examples of the term "substituted phenyl" includes but is not limited to a mono- or di(halo)phenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4- fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4- hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyρhenyl, the protected-hydroxy derivatives thereof and the like; a nitiophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4- cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4- dimethylphenyl, 2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyI, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3- ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4- trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4-carboxyphenyl; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4- (protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N- methylsulfonylamino))phenyl. Also, the term "substituted phenyl" represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxy phenyl, 3-chlovo-4- hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2- hydroxy-4-chlorophenyl and the like. Preferred substituted phenyl groups include the 2- and 3- trifluoromethy'nhenyl, the 4-hydroxyphenyl, the 2-aminomethylphenyl and the J-(N- (methylsulfonylamino))phenyl groups. The term "arylalkyl" means one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl radical having the number of carbon atoms designated including but not limited to; benzyl, napthylmethyl, phenethyl, benzhydryl (diphenylmethyl), trityl, and the like. \ preferred arylalkyl group is the benzyl group. The term "substituted Cό-Cioaryl-C -Cgalkyl" denotes a C -Cgalkyl group substituted at any carbon with a C6-Cιoaryl g rou p bonded to the alkyl group through any aryl ring position and substituted on the Ci-Cgalkyl portion with one, two or three groups chosen from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, amino, protected amino, Ci-Cyacyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, C^-Cgalkylthio, N-(methylsulfonylamino) or Ci-Gjalkoxy. Optionally the aryl group may be substituted with one, two, or three groups chosen from halogen, hydroxy, protected hydroxy, nitro, C -C6alkyl, C -Gjalkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, or an N-(methylsulfonylamino) group. As before, when either the C^-Csalkyl portion or the aryl portion or both are disubstituted, the substituents can be the same or different. Examples of the term "substituted Cβ-Cioaryl-Ci-Csalkyl" include groups such as 2- phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl, 2,6-dihydroxy-4-phenyl(n-hexyl), 5-cyano-3- methoxy-2-phenyl(n-pentyl), 3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl, 6-(4- methoxyphenyl)-3-carboxy(n-hexyl), 5-(4-aminomethyl phenyl)-3-(aminomethyl)(n-pentyl), and the like. The term "carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4- methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl,4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-ρhenylprop-2- yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2- trichloroethyl, b-(trimethylsilyl)ethyl, b- (di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, l-(trimethylsilylmethyl)prop-l-en-3-yl, and hke moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the benzodiazepinedione molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject the carboxy-protected benzodiazepinedione molecule to strong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Rar.ey nickel. (Such harsh removal conditions are also to be avoided when removing amino- prctecting groups and hydroxy-protecting groups, discussed below.) Preferred carboxylic acid protecting groups are the allyl and p-nitrobenzyl groups. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents of the benzodiazepinedione. Further examples of these groups are found in E. Haslaπi, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981, Chapter 5. The term "protected carboxy" refers to a carboxy group substituted with one of the above carboxy-protecting groups. As used herein the term "amide-protecting group" refers to any group typically used in the peptide art for protecting the peptide nitrogens from undesirable side reactions. Such groups include p-methoxyphenyl, 3,4-dimethoxybenzyl, benzyl, O-nitrobenzyl, di-(p- methoxyphenyl)methyl, triphenylmethyl, (p-methoxyphenyl)diphenylmethyl, diphenyl-4- pyridylmethyl, m-2-(picolyl)-N '-oxide, 5-dibenzosuberyl, trimethylsilyl, t-butyl dimethylsilyl, and the like. Further descriptions of these protecting groups can be found in "Protective Groups in Organic Synthesis", by Theodora W. Greene, 1981, John Wiley and Sons, New York. Unless otherwise specified, the terms "heterocyclic group" or "heterocyclic" or "HET", "het" or "heterocyclyl" are used interchangeably as used herein refer to any mono-, bi-, or tricyclic saturated, unsaturated, or aromatic ring having the number of atoms designated where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur (Lang's Handbook of Chemistry, supra). Typically, the 5- membered rmg has 0 to 2 double bonds and the 6- or 7-membered rmg has 0 to 3 double bonds and the nitrogen, carbon or sulfur atoms in the rmg may optionally be oxidized ( e g NO , C=0 and SO ) and any nitrogen heteroatom may optionally be quaternized Included m the definition are any bicyclic groups where any of the above heterocyclic rmgs are fused to a benzene rmg Heterocyclics m which oxygen and sulfur are the heteroatom are preferred when the heterocycly forms all or a part of "D" in Formula I The following rmg systems are examples of the heterocyclic (whether substituted or unsubstituted) radicals denoted by the term "heterocyhc" or het thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thia triazolyl, oxatriazolyl, pyπdyl, pyπmidyl, pyrazmyl, pyπdazinyl, thiazinyl, oxazmyl, tπazinyl, thiadiazmyl, oxadiazinyl, dithiazrnyl, dioxazinyl, oxathiazmyl, tetrazmyl, thiatriazrnyl, oxatriazmyl, dithiadiazmyl, lmidazolmyl, dihydropyπmidyl, tetrahydropyπmidyl, tetrazolo[l,5-b]pyπdazmyl and purmyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and mdolyl Heterocyclic 5-membered rmg systems contammg a sulfur or oxygen atom and one to three nitrogen atoms are also suitable for use m the instant invention Fxamples of such preferred groups mclude thiazolyl, in particular thιazol-2-yl and thιazol-2-yι N-oxide, thiadiazolyl, m particular l,3,4-thιadιazol-5-yl and l,2,4-thιadιazol-5-yl, oxazolyl, preferably oxazol-2-yl, and oxadiazolyl, such as l,3,4-oxadιazol-5-yl, and l,2,4-oxadιazol-5-yl A group of further preferred examples of 5-membered rmg systems with 2 to 4 nitrogen atoms mclude imidazolyl, preferably ιmιdazol-2-yl, triazolyl, preferably l,3,4-trιazol-5-yl, l,2,3-trιazol-5-yl, l,2,4-trιazol-5-yl, and tetrazolyl, preferably lH-tetrazol-5-yl A preferred group of examples of benzo-fused derivatives are benzoxazol-2-yl, benzthιazol-2-yl and benzιmιdazol-2-yl Further suitable specific examples of the above heterocyhc rmg systems are 6-membered rmg systems contammg one to three nitrogen atoms Such examples mclude pyndyl, such as pyπd-2-yl, pyπd-3-yl, and pyπd-4-yl, pyπmidyl, preferably pyπmιd-2-yl and pyrιmιd-4-yl, tπazinyl, preferably l,3,4-tπazιn-2-yl and l,3,5-tπazιn-4-yl, pyπdazinyl, m particular pyπdazrn-3- yl, and pyrazmyl The pyπdine N-oxides and pyπdazme N-oxides and the pyndyl, pyπmιd-2-yl, pyrιmιd-4-yl, pyπdazmyl and the l,3,4-tπazιn-2-yl radicals, are a preferred group The substituents for the optionally substituted heterocyclic rmg systems, and further examples of the 5- and 6-membered rmg systems discussed above can be found m W Druckheimer et al , U S Patent No 4,278,793 Another preferred group of "heterocyclics" or "het" mclude, l,3-thιazol-2-yl, 4- (carboxymethyl)-5-methyl-l,3-thιazol-2-yl, 4-(carboxymethyl)-5-methyl-l,3-thιazol-2-yl sodium salt, l,2,4-thιadιazol-5-yl, 3-methyl-l,2,4-thιadιazol-5-yl, l,3,4-tiιazol-5-yl, 2-methyl-l,3,4-trιazol-5- yl, 2-hydroxy-l,3,4-trιazol-5-yl, 2-carboxy-4-methvl-l,3,4-trιazol-5-yl sodium salt, 2-carboxv-4- methy 1-1, 3,4- tπazol-5-yl, l,3-oxazol-2-yl, l,3,4-oxadιazol-5-yl, 2-methyl-l,3,4-oxadιazol-5-yI, 2- (hydroxymethyl)-l,3,4-oxadιazol-5-yl, l,2,4-oxadιazol-5-yl, l,3,4-thιadιazol-5-yl, 2-thιol-l,3,4- thιadιazol-5-yl, 2-(methylthιo)-l,3,4-thιadιazol-5-yl, 2-ammo-l,3,4-thιadιazol-5-yl, lH-tetrazol-5-yl, l-methyl-lH-tetrazol-5-yl, l-(l-(dιmethylammo)eth-2-yl)-lH-tetiazol-5-yl, l-(carboxymethyl)-lH- tetrazol-5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl sodium salt, l-(methylsulfonιc aαd)-lH-tetiazol- 5-yl, l-(methylsulfonιc acιd)-lH-tetrazol-5-yl sodium salt, 2-methyl-lH-tetrazol-5-yl, 1,2,3-trιazol- 5-yl, l-methyl-l,2,3-trιazol-5-yl, 2-methyl-l,2,3-trιazol-5-yl, 4-methyl-l,2,3-trιazol-5-yl, pyπd-2-yl N-oxide, 6-methoxy-2-(n-oxιde)-pyπdaz-3-yl, 6-hydroxypyndaz-3-yl, l-methylpyπd-2-yl, 1- methylρyπd-4-yl, 2-hydroxypyrιmιd-4-yl, l,4,5,6-tetτahydro-5,6-dιoxo-4-methyl-as-trιazm-3-yl, l,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dιoxo-as-trιazm-3-yl, 2,5-dιhydro-5-oxo-6-hydroxy- astrιazm-3-yl, 2,5-dιhydro-5-oxo-6-hydroxy-as-trιazm-3-yl sodium salt, 2,5-dmydro-5-oxo-6- hydroxy-2-methyl-astrιazm-3-yl sodium salt, 2,5-dιhydro-5-oxo-6-hydroxy-2-methyl-as-trιazm-3- yl, 2,5-dιhydro-5-oxo-6-methoxy-2-methyl-as-trιazm-3-yl, 2,5-dιhydro-5-oxo-as-tiιazm-3-yl, 2,5- dιhydro-5-oxo-2-methyl-as-trιazm-3-yl, 2,5-dιhydro-5-oxo-2,6-dιmethyl-as-trιazm-3-yl, tetrazolo[l,5-b]pyπdazm-6-yl and 8-ammotetrazolo[l,5-b]-pyπdazm-6-yl An alternative group of "heterocyclics" mcludes, 4-(carboxymethyl)-5-methyl-l,3-thιazol-2- yl, 4-(carboxymethyl)-5-methyl-l,3-thιazol-2-yl sodium salt, l,3,4-trιazol-5-yl, 2-methyl-l,3,4- trιazol-5-yl, lH-tetrazol-5-yl, l-merhyl-lH-tetrazol-5-yl, l-(ι- ιmethylamιno)eth-2-yl)-lH-tetrazol- 5-yl, l-(carboxymetfιyl)-lH-tetrazol-5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl sodium salt, 1- (methylsulfomc acιd)-lH-tetrazol-5-yl, l-(methylsulfonιc acιd)-lH-tetrazol-5-yl sodium salt, 1,2,3- tiιazol-5-yl, l,4,5,6-tetrahydro-5,6-dιoxo-4-methyl-as-tπazιn-3-yl, l,4,5,6-tetrahydro-4-(2- formylmethyl)-5,6-dιoxo-as-trιazm-3-yI, 2,5-dιhydro-5-oxo-6-hydroxy-2-methyl-as-trιazιn-3-yl sodium salt, 2,5-dιhydro-5-oxo-6-hydroxy-2-methyl-as-trιazιn- A, tetrazolo[l,5-b]pyπdazιn-6-yl, and 8-ammotetrazolo[l,5-b]pyπdazm-6-yl Bivalent radicals L, whether branched or unbranched, derived from alkanes, alkenes, alkadienes, alkynes, alkadiynes, and arenes optionally contammg O, N and/or S atoms, or homo- and heterocycles either aromatic or aliphatic, are designated by adding a free valence "-" to both ends of the corresponding monovalent radical Atoms bearing the free valences may mclude any C, O, N or S "Pharmaceutically acceptable salts" mclude both acid and base addition salts "Pharmaceutically acceptable acid addition salt" refers to those salts which retam the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with morganic acids such as hydrochloric acid, hydrobromic acid, sulfuπc acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloahphatic, aromatic, arahphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycohc acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succrnic acid, fumaπc acid, tartaπc acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranihc acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, tiimerhamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine. The term "prodrug" as used herein means a derivative or precursor of a parent drug molecule that enhances pharmaceutically desirable characteristics or properties (e.g. transport, bioavailablity, pharmacodynamics, etc.) and that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active parent drug. Examples of carboxylic prodrugs include precursors such as aldehydes, alcohol's on amines or derivatives such as esters B. Uses The LFA-1 and/ or Mac-1 antagonists of this invention are useful for therapeutic use in those diseases and conditions for which inhibition or modulation of the LFA-1 and/ or Mac-1 interaction with ICAM, especially ICAM-1, is indicated. Such diseases and conditions include: T- cell inflammatory responses such as inflammatory skin diseases including psoriasis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); adult respiratory distress syndrome; dermatitis; meningitis; encephalitis; uveitis; allergic conditions such as eczema and asthma, psoriasis and other conditions involving infiltration of T-cells and chronic inflammatory responses; skin hypersensitivity reactions (including poison ivy and poison oak), allergic contact dermatitis; atherosclerosis; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, juvenile onset diabetes, and immune responses associated with delayed hypersensitivity mediated by cytokines and T-lymphocytes typically found in tuberculosis, sarcoidosis, polymyositis, granulomatosis and vascuhtis; pernicious anemia; diseases involving leukocyte diapedesis; CNS inflammatory disorder, multiple organ injury syndrome secondary to septicaemia or trauma; autoimmune haemolytic anemia; myasthenia gravis; antigen-antibody complex mediated diseases; all types of transplantations, including graft vs. host or host vs. graft disease, HIV infection and the like. Other leukocyte mediated diseases for which the mstant competitive inhibitors may be used mclude hemorrhagic shock, ischemia/ reperfusion m j ury, bypass surgery, burns, stroke, post CABG surgery, vasculibs, cerebral edema (broader, restenosis, AMI and non Q wave MI C. Preferred Embodiments 1 CDlla/ CD18 ICAM-1 Competitive Inhibitors One embodiment of the invention comprises a compound represented by Formula I capable of inhibiting bmdmg of the leukocyte LFA-1 receptor to its nabve in vivo hgand(s), especially ICAM-1 Preferred inhibitors mclude compounds represented by structural Formula I Referrmg to Formula I the following important structural feature s of the instant pepbdiomimetic LFA-1 inhibitors can be identified a The negatively charged acidic moiety R or prodrug form thereof, b The substituent T, a naturally occurrmg ammo acid side chain and derivatives thereof, c The amide nιtiogen(N) and substituents (R ) d The substituted "benzoyl" rmg B, e substituents of the B rmg, namely R , f The spacer or Imkmg moiety L g The distal aromatic moiety D, and h substituents of D, namely R (a) The negatively charged acidic moiety R The preferred negatively charged acidic moiety R is the carboxyl group (-COOH) or a prodrug thereof Generally the carboxyl group R and prodrug forms thereof is designated COR Suitable R 's mclude Cj-Csalkoxy, Ci-Cgdialkyl-aminocarbonylmethoxy and Cό-Cio rylCj- Cgdialkylammocarbonylmethoxy Other suitable prodrugs R includes the following groups — O-CH 2 -CH 3 — O-CH 2 -CH 2 -CH 2 -CH 3 / / / O O I I II — O-CH 2 -O— C -CH 2 -CH 3 — O-CH 2 -O— C-CH 2 -CH 2 -CH 3 (b) The substituent T or U-Q-V-W T of formula I is usually the sidecham of any α-amino acid, preferably the L configuration, or a homolog or derivative thereof Preferably T will contam a hydrogen bond donating group such as CONH 2 , NHCOH, NH 2 , OH or NH T will frequently be a 1-4 carbon alkane contammg an amide, carbamate, ureido, sulfonamide and an optionally substituted phenyl or heterocycle The heterocycle will usually be a 5 or 6 member rmg with 1 or 2 hetero atoms selected from N, O and S Such heterocycles mclude furan, thiophene, pyrrole, pyπdme and piperidine substituents mclude halogens such as chloro and fluro, nitro, cyano, alkyl and halo substituted alkyl, substituted or unsubstituted amides, ammes, carbamates sulfonamides, ureidos and the like Examples of T will also mclude a lower alkyl, cycloalkyl, alkenyl or alkynyl substituted with an aromatic rmg, especially a heteroaryl or C -C .aryl, substituted with 0-3 R Suitable 6 14 aromatic rings include any mono-, bi-, or tπcychc saturated, unsaturated, or aromatic rmg having three to seven atoms m the rmg, where at least one rmg is a 5-, 6- or 7-membered ring contammg from zero to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, optionally substituted with R Optionally the aromatic rmgs may be linked through a CJ-C4 alkyl Preferred ring's are substituted phenyl and het as defined above optionally substituted with R More preferred optionally substituted aromatic rmg 's are selected from the group, and where R . is Al 0-3 R or U-V-W Other optionally prefered substituents T are U-Q-V-W defmed below Specifically, T may preferably be -C -C alkyl-Q-V-W, where Q is -N(R n )-, -C(=0)-, -N(R n )C(=0)-, -C(=0)-N(R n )-, - 1 6 N(R n )C(=0)-N(R n )-, -N(R n )C(=0)-0-, -0-C(=0)-N(R n )-, -N(R n )S(=0) 2 -, -S(=0) 2 -N(R n )-, -C(=0)-0- or -O-, V may be het or absent and W is provided rn Table 1 Generally, each of U, Q, V and W are independently selected accordmg to the Table 1 below U, Q and V may also each mdependently be absent (1 e one or more of U, Q, V may be a covalent bond) Table 1 Where any alkyl, alkenyl or alkynyl is substituted with 0-3 R and any aryl or het are substituted with 0-3 R , and where R ,R ,R ,R ,R ,R ,R and R are defined above. More specifically, each of U, Q, V and W may be independently selected according to Table 2 below. Table 2 (c) the substituents (R ) for amide nitrogen N are lower alkyl or hydrogen and preferably hydrogen. (d) The substituted "benzoyl" ring B is preferably selected from the group: is a fused hetero- or homocyclic ring containing 5, 6 or 7 atoms, the ring being unsaturated, partially saturated or aromatic, the heteroatoms selected from 1-3 O, S or N, Y is selected from CH or N, r- is 0-3. Preferably B is a para-substituted benzoyl group. (e) substituents of B (R p ) are defined above. Preferably when B is a para-substituted benzoyl group 'ά e remaining positions on B are substituted with one or more halo (F, Cl, Br) or lower alkyl groups. (f) The linking group L The length of the bivalent radical L appears to be important to optimal biological activity. By length is meant the distance between the "B" or benzoyl moiety (eg from the para position on B), including the amide or amide isostere bonded to the benzoyl moiety, and the distal group D. Preferably L is 3, 4 or 5 methylene (-CH 2 -) equivalents in length depending on the atoms in L and 1 3 4 5 1-5 the nature of D. Thus L is composed of L -L and optionally L and L . Each L is independently selected from oxo (-0-), S(O) , C(=0), CR 1"5 R 1 "5 , CR 1"5 , het, NR n or N, where s is 1-5 l'-5' 0-2. For example, functional groups in L (in addition to -CH 2 - or CR R ) include one or more of the following: — c I I- — N 1 — -o- • s- — C 1 = 0 H H o 1 0 I I — s— — s I I - -c II— ~ — N= 0 s NH which may be located within the linker L (e.g. forming amides, imides, amidines, guanidinos, ureidos, carbamates, ethers, thioethers, ketones, sulfoxides, sulfonamides and the like) or combined in any combination, provided only that the compounds so produced are stable in aqueous solution and do not exceed the above stated length requirements. For example, preferred functional groups in L, other than a C -C alkyl, are: ethers, diethers, ketones, alcohols, esters, 3 5 amides, ureidos, carbamates, carbonates, sulfonamides, sulfoxides, sulfones, and combinations thereof. Preferred lengths for L are from 0 to 4 while most preferred lengths are 1 or 3 methylene equivalents. In counting atoms comprising L, only those atoms sequentially linking the benzoyl moiety B and the distyl group D are counted except when a homo- or heterocycle (eg het) comprises L in which case the fewest number of atoms separating these moieties are counted. Preferred exemplary L bivalent linking groups include: -C3-C5-alkyl-, -C3-C5-alkenyl-, - CH C(=0)NH-, -CH NH-C(=0)-, -O-CH -C(=0)-, -CH -CH -C(=0)-, H=CH-C(=0)NH-CH -, - CH=CH-C(=0)NH-CH-(CH )-, -CH(OH)-CH -O-, -CH(OH)-CH -CH -, -CH -CH -CH(OH)-, -O- CH -CH(OH)-, -O-CH -CH(OH)-CH -, -O-CH -CH -CH(OH)-, -O-CH -CH -O-, -CH -CH -CH - 2 2 ' 2 2 2 / 2 2 2 2 2 O-, -CH -CH(OH)-CH -O-, -CH -CH -O-, -CH(OH)-CH -O-, -CH-(CH )-NH-C(=0)-, -CH 2 -NH- S0 2 -, -NH-S0 2 -CH 2 -, -CH 2 -S0 2 NH-, -S0 2 NH-CH 2 -, -C(=0)-NH-C(=0)-, - H-C(=0)-NH-,-NH- C(=0)-NH-CH 2 -, -CH 2 -NH-C(=0)-NH-, -C(=0)-NH-CH 2 -C(=0)-NH -, -NH-C(=0)-0- and -O- C(=0)-NH-. Preferred exemplary L bivalent linking groups containing a heterocycle include: Any carbon in the bivalent linking groups may optionally be substituted with a halogen, especially fluorine. (g) The distal moiety D may be a mono-, bi-, or tricychc saturated, unsaturated, or aromatic rmg, each rmg havmg 5-, 6- or 7 atoms m the rmg where the atoms the rmg are carbon or from 1- 4 heteroatoms selected from, nitiogen, oxygen, and sulfur, each rmg substituted with 0-3 R Optionally, D is an aromatic homocycle or aromatic heterocycle contammg 1-3 heteroatoms selected from the group N, S and O, the homo- or hetero-cycles selected from where Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are CH, CR d or N, Z 1 is O, S, NH or NR n and n is 0-3 More specifically, D may be 1) a 5-member aromatic heterocycle selected from, 2) a 9-member aromatic heterobicycle selected from; 3) a 6-member aromatic hetero- or homocycle selected from; Compounds containing tlie foregoing preferred 5-member aromatic heterocycle and 9- member aromatic heterobicycle, 1 and 2 above, as aromatic groups D are preferred as LFA-1 specific antagonists, while the 6-member aromatic hetero- or homocycles of 3 above are preferred as D groups suitable for inhibiting both LFA-1 and Mac-1. In this latter case D is preferably substituted with a hydroxyl or precursor thereof. (h) Preferred substituents of D are one or more groups selected from; OH, NH^ S0 2 NH , S0 2 CH 3 , CH3, CH 2 OH, CN, CH3-C(=0)NH-, NH C(=0)-, NHCONH^ CF3, Cj-C6 alkoxy and halo(F, Cl, Br and I). Exemplary preferred compounds of this invention include: 46 D Methods of Making One method of producing LFA-1 antagonists involves chemical synthesis of the "peptide" or peptidomimetic. This can be accomplished using methodologies well known to those skilled in the art (see Stewart and Young, Solid Phase Peptide Synthesis Pierce Chemical Co Rockford, IL (1984), see also U S Patent No 's 4,105,603, 3,972,859, 3,842,067, and 3,862,925)) It will be appreciated from mspechon of the compounds shown above that they all contam one or more amide or peptide bonds and thus may be considered pephdomimetics Peptidomimetics of the mvenbon may also be conveniently prepared usmg solid phase peptide synthesis (Merrifield, / Am Chem Soc , 85 2149 (1964), Houghten, Proc Natl Acal Sa USA 825132 (1985)) Solid phase synthesis begms at the carboxy- termmus of the putative peptide by coupling a protected ammo acid to a suitable resm (e g chloromethylated polystyrene resm) as shown m Figures 1-1 and 1-2, on pages 2 and 4 of Stewart and Young supra After removal of the α-ammo protecting group with, for example, tiifluoroacetic acid (TFA) in methylene chloride and neutralizing m, for example TEA, the next α-ammo- and sidecham protected ammo acid m the synthesis is added The remammg α-ammo- and, if necessary, side-cham-protected ammo acids are then coupled sequentially m the desired order by condensation to obtam an mtermediate compound connected to the resm Alternatively, some ammes and acids may be coupled to one another formmg a peptide prior to addition of the peptide to the growmg solid phase peptide cham The condensation between two ammo acids can be carried out accordmg to the usual condensation methods such as the azide method, mixed acid anhydride method, DCC (N,N'- dicyclohexylcarbodumide) or DIPC (N,N'-dusopropylcarbodιιmιde)methods, active ester method (p-nitrophenyl ester method, BOP [benzotrιazole-1-yl-oxy-tπs (dimethyJamino) phosphonium hexafluorophosphate] method, N-hydroxysuccmic acid lmido ester method, etc , and Woodward reagent K method Common to chemical syntheses of peptides is the protection of any reachve side-cham groups of the ammo acids with suitable protecting groups Ultimately these protectmg groups are removed after the desired polypeptide cham has been sequentially assembled Also common is the protection of the α-ammo group on an ammo acid or a fragment while that entity reacts at the carboxyl group followed by the selective removal of the α-ammo-protecbng group to allow subsequent reaction to take place at that location Accordmgly, it is common in peptide synthesis that an mtermediate compound is produced which contains each of the ammo acid residues located m the desired sequence m the peptide cham with various of these residues havmg side-cham protecting groups attached These protectmg groups are then commonly removed substantially at the same time so as to produce the desired resultant product following removal from the resm Suitable protective groups for protecting the α-and ε- ammo side cham groups are exemplified by benzyloxycarbonyl (CBZ), lsonicotinyloxycarbonyl (iNOC), O- chlorobenzyloxycarbonyl (2-C1-CBZ), p-nitrobenzyloxycarbonyl [Z(N0 2 ], p- methoxybenzyloxycarbonyl [Z(OMe)], t-butoxycarbonyl, (BOC), t-amyloxycarbonyl (AOC), lsoborrnyloxycarbonyl, adamatyloxycarbonyl, 2-(4-bιphenyl)-2-propyl-oxycarbonyl (BPOC), 9- fluorenylmethoxycarbonyl (FMOC), methylsulfo-nyiethoxycarbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulphenyl (NPS), diphenylphosphinothioyl (Ppt), dimethylophosphinothioyl (Mpt) and the like. Protective groups for the carboxy functional group are exemplified by; benzyl ester (OBzl), cyclohexyl ester (Chx), 4-nitrobenzyl ester (ONb), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic), and the like. It is often desirable that specific amino acids such as arginine, cysteine, and serine possessing a functional group other than amino and carboxyl groups are protected by a suitable protective group. For example, the guanidino group of arginine may be protected with nitro, p- toluenesulfonyl, benzyloxycarbonyl, adamantyloxycarbonyl, p-methoxybenzenesulfonyl, 4- methoxy-2, 6-dimethylbenzenesulfonyl (Mds), 1,3,5-trimethylphenysulfonyl (Mts), and the like. The thiol group of cysteine may be protected with p-methoxybenzyl, tiiphenylmethyl, acetylaminomethyl ethylcarbamoyle, 4-methylbenzyl, 2, 4, 6-trimethy-benzyl (Tmb) etc., and the hydroxyl group of serine can be protected with benzyl, t-butyl, acetyl, tetrahydropyranyl and the like. Stewart and Young supra provides detailed information regarding procedures for preparing peptides. Protection of α-amino groups is described on pages 14-18, and side-chain blockage is described on pages 18-28. A table of protecting groups for amine, hydroxyl and sulfhydryl functions is provided on pages 149-151. After the desired -miino acid sequence has been completed, the intermediate peptide is removed from the resin support by treatment with a reagent, such as liquid HF and one or more sulfur-containing scavengers, which not only cleaves the peptide from the resin, but also cleaves all the remaining side-chain protecting groups. Following HF cleavage, the peptide residue is washed with ether, and extracted from the resin by washing with aqueous acetonitrile and acetic acid. Preferably in order to avoid alkylation of residues in the polypeptide, (for example, alkylation of methionine, cysteine, and tyrosine residues) a thio-cresol and cresol scavenger mixture is used. Other General Procedures The peptidomimetic compounds of this invention may also be conveniently prepared by the methods for peptide synthesis described in monographs such as ("Principles of Peptide Synthesis, M. Bodanszky, Springer- Verlag, 2nd Ed., 1993; "Synthetic Peptides: A Users Guide", G. A. Grant, Ed, W. H. Freeman and Co., 1992; and references sited therein), or by other methods generally known to one skilled in the art. The synthesis of compounds of this invention that are peptidomimetic in nature (i.e. contain other than standard amide bond linkages between two or more amino acids) may be prepared by extension of the methods described in Examples 6 and by the general synthetic methods described in "Comprehensive Organic Transformations", R. C. Larock, VCH Publishers, 1989, and by methods generally known to one skilled in the art. For compounds of Claim 1 where the amide linkages (-C(=0)-NH-) are replaced with amide isostere (Ai) linkages such as; (-C(=S)-NH-), (-S(=0) 2 -NH-), -CH -NH-, -CH 2 -S-, -CH 2 -0-, - CH -CH 2 -, -CH=CH- (cis and trans), -C(=0)-CH -, -CH(OH)-CH -, -CH(CN)-NH-, -0-C(=0)-NH- and -CH 2 -SO-, amide bond replacmg methods known in the art are employed The following references describe preparation of amide isostere Imkages which mclude these alternative-linking moieties Spatola, A F , Vega Data 1(3) "Peptide Backbone Modifications" (General Review) (Mar 1983), Spatola, A F , m "Chemistry and biochemistry of Ammo Acids Peptides and Proteins", B Weinstein, ed , Marcel Dekker, New York, P 267 (1983), Morley Trends Pharm Sci pp 463-468, Hudson et al hit } Pept Prot Res 14 177-185 (1979) (-CH NH-, -CH?CH -), Spatola et al , Life Sci 38 1243-1249 (1986) (-CH 2 -S-), Hann / Chem Soc Perkin Trans I 307-314 (1982) (-CH=CH-, cis and trans), Almquist et al , } Med Chem 23 1392-1398 (1980) (-C(=0)-CH2-), Jennings-White et al , Tetrahedron Lett 23 (1982) (-C(=0)-CH2-), Szelke et al , EP Apphcabon No 45665 (1982) Chem Abs 9739405 (1982) (-CH(OH)-CH2), Holladay et al , Tetrahedron Lett 244401-4404 (1983) (-C(OH)-CH 2 - ), Hruby Life Sci 31 189-199 (1982) (-CH2S-), Cho et al , Science 261 1303-1305 (1993) (-0-C(=0)-NH- ), Sherman et al , Biochem Biophys Res Comm 162(3) 1126-1132 (1989) (-C(=S)-NH-), Calcagm et al , bit, J Peptide Protein Res 34 319-324 (1989) (-S(=0)2-NH-), TenBrmk, / Org Chem 52418-422 (1987) -CH2-O- Scheme I illustrates one synthetic approach which provides access to unnatural ammo acid sidechains particularly for substituent T of Formula I The method provides for α-alkylation of the "glycine" sidecham usmg a solid phase approach on a commercially available machine, such as an Argonaut Nautilus 2400 Scheme I The following representative "R" groups can be introduced into the LFA-1 antagonists by the alkylation scheme above When "R" of Scheme I is an alkyl amine, prepared from the amino acids lys. orn or DAP A, reduction of the representative nitriles above or prepared from the protected (e.g. FMOC) aminoalkyl halide, synthetic routs are available to make derivatives of T including urea's, carbamates, • mides and sulfonamides by known procedures. Scheme II illustrates a solid phase approach for producing these derivatives of T. Scheme II "Key Intermediate' Urea's made according to Scheme II can be synthesized from representative commercially available isocyanates, RNCO's, including the following: Other representative substituted aryl isocyanates suitable for use in the above scheme include: These and other isocyanates may be used to produce carbamates when the "R" in Scheme I is an alcohol (e.g. ser) according to scheme Scheme Ila below. Scheme Ila Carbamates (of the opposite orientation to Scheme Ila), amides and sulfonamides synthesized according to Scheme II can be made from representative commercially available ROCOCl's, RCOCl's and RSO Cl's including the following: Scheme III illustrates a general synthetic route for alkyl linkers, L, for dichloro-substituted benzoyl-amino acids or derivitaves thereof. The key intermediate in this approach is the iodo, dichloro-benzoyl-AA (4). Scheme III Lil Pyridine Key intermediate (4) is coupled to a variety of alkynes to produce alkyl linkers of various length. For example a 3 carbon linker can be made by coupling (4) to alkyne intermediate (5) prepared according to Scheme Ilia. Scheme Ilia (5) Scheme IV illustrates the synthesis of both substituted or unsubstituted alkane and substituted alkyne linkers. Scheme IV l .H„ 5% Rh/Al,0 3 2.TFA A 4 carbon linker can be made by coupling (4) to alkyne intermediate (6) prepared according to Scheme V. Scheme V l.CH,ONHCH,-HCl EDC,HO —Bt.DIPEA — - 2.Isobutylene. H 2 S0 4 l. HV10%Pd-C 2. DfBAL Scheme VI illustrates the synthesis of unsubstituted alkane and alkyne Imkers Scheme VI Schemes Via and Vlb illustrate the synthesis of substitute'! and unsubstituted alkane and alkene Imkers of 3-5 carbons long Scheme Via TFA, Et j SiH Scheme Vlb Scheme VII illustrates the synthesis of a 3-carbon alkyl Imker where "B" is a dimethyl substituted benzoyl LFA-1 antagonist. Scheme Vil HC≡CMgBr Scheme VIII illustrates the synthesis of a 3-5 atom diether Imker where n is 1-3 Intermediate phenol (7) may also be used m the synthesis of monoethers described below B (CH^n Br K 2 C0 3 ,DMF 1.Resorcinol,K,C0 3 2.Pd(PPh 3 ) 4 ,rnorpholine Scheme IX illustrates the synthesis of a 3-5 atom monoether linkers where n is 1-3. Intermediate phenol (7) above is employed in this method. Scheme IX Scheme X illustrates the synthesis of a 5 atom alkyl linkers where the distyl group "D" is a 1 -member aromatic ring. Preferred rings include thiophene, furan, thiazole and oxazole, where Z 2 3 4 O or S and Y , Y or Y is selected from N or CH. Scheme X l .H.,5%Rh/Al,0 3 2.TFA Scheme XI illustrates the synthesis of 3 atom aminoalcohol linkers where the distyl group "D" is phenyl or het. Scheme XI Beta hydroxy amines are produced via the reaction of a primary or secondary amine with epoxides. Epoxides are easily prepared by known methods (i.e. oxidation of alkenes). Rl = phenyl, alkyl, etc. R2: = a'ι possible C-termini R3 = H o, alkyl Scheme XII illustrates the synthesis of 3-5 atom oxadiazole linkers where the distyl group "D" is phenyl or het. Scheme XII Oxadiazoles are prepared from the combination of hydroxyamidine with an activated carboxylic acid under dehydrating conditions. Hydroxyamidines are conveniently prepared via reaction of a nitrile with hydroxy lamine. to prepare compounds such as: Scheme XIII illustrates the synthesis of 5 atom aminotetiazoles linkers where the distyl group "D" is phenyl or het. Scheme XIII The key step in the preparation of aminotetrazoles is the reaction of a 5-halo-l- phenyltetrazole with an amine. Aminotetiazoles are formed from the reaction of N- bromosuccinimide and sodium azide with phenylisocyanide under phase transfer conditions. Deprotection and coupling at the carboxylate to add the left side amino acid is carried out as described previously for other compounds. E. Modes or Carrying Out the Invention Superior immunosuppressive efficacy is seen with a treatment regimen that uses early induction with a high dose of LFA-1 antagonist followed by extended treatment with a lower dose of antagonist. Typically, the LFA-1 antagonist used in the method of this invention il formulated by mixing it at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of antagonist, but preferably ranges anywhere from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment. The LFA-1 antagonist for use here is preferably sterile LFA-1 antagonist ordinarily will be stored as a solid composition, although lyophilized formulations or aquous solutions are acceptable The antagonist composition will be formulated, dosed, and admmistered m a fashion consistent with good medical practice Factors for consideration m this context mclude the particular disorder bemg treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners The "therapeutically effective amount" of LFA-1 antagonist to be admmistered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the LFA-1-medιated disorder, mcludmg treating rheumatoid arthritis, multiple sclerosis, asthma, psoriasis (topically or systemically), reducmg inflammatory responses, mducmg tolerance of lmmunoshmulants, preventing an immune response that would result m re j ection of a graft by a host or vice-versa, or prolongmg survival of a transplanted graft Such amount is preferably below the amount that is toxic to the host or renders the host significantly more susceptible to infections As a general proposition, the initial pharmaceutically effective amount of the LFA-1 antagonist admmistered parenterally per dose will be in the range of about 0 1 to 20 mg/kg of patient body weight per day, with the typical initial range of LFA-1 antagonist used bemg 0 3 to 15 mg/kg/ day The LFA-1 antagonist is admmistered by any suitable means, mcludmg oral, topical, transdermal, parenteral, subcutaneous, mtraperitoneal, mtiapulmonary, and mtianasal, and, if desired for local immunosuppressive treatment, rntralesional administration (mcludmg perfusmg or otherwise contacting the graft with the antagonist before transplantation) Parenteral infusions mclude intramuscular, intravenous, intraarterial, mtraperitoneal, or subcutaneous administration A preferred administration method for psoriasis is topical m close proximity to the affected area The LFA-1 antagonist need not be, but is optionally formulated with one or more agents currently used to prevent or treat the disorder in question For example, m rheumatoid arthritis, the LFA-1 antagonist may be given in conjunction with a glucocorbcosteroid In addition, T-cell receptor peptide therapy is suitably an adjunct therapy to prevent clinical signs of autoimmune encephalomyelitis (Offner et al , supra ) For transplants, the LFA-1 antagonist may be admmistered concurrently with or separate from an immunosuppressive agent as defmed above, e g , cyclosporm A, to modulate the immunosuppressant effect The effective amount of such other agents depends on the amount of LFA-1 antagonist present m the formulation, the type of disorder or treatment, and other factors discussed above The various autoimmune disorders described above are treated with LFA-1 antagonists in such a fashion as to induce immune tolerance to the self antigen under attack as a result of the disorder In this regard, autoimmune disorders resemble host versus graft re j ection and are treated with LFA-1 antagonists in analogous fashion However, rn these disorders the patient is already mounting an immune response to the target antigen, unlike the case with transplants prior to grafting. Thus, it is desirable to first induce and maintain a- transient state of immunosuppression by conventional methods in such patients, e.g. by the conventional use of cyclosporin A or other conventional immunosuppressive agents (alone or together with LFA-1 antagonist), or to monitor the patient until the occurrence of a period of remission (an absence or substantial lessening of pathological or functional indicia of the autoimmune response). The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. All literature citations are incorporated by reference. Examples Example 1 Preparation and Purification of full-length LFA-1 from 293 Cells Construction of LFA-1 cDNA expression vector A plasmid with both the human CDlla (ajj and CD18 (β2) sequences, each with a separate CMV promoter for expression in 293 cells, was constructed as follows. The plasmid, pRKCDlδ, containing the full length CD18 cDNA, was cut with restriction enzymes Hpal and Avr II. The plasmid, pRKCDlla, containing the full length CDlla cDNA, was treated with the enzyme Taq I methylase to methylate one of the two Xmn I sites, then cut with Xmn I and Spe I. The fragment from the pRKCDlδ digest containing the CD18 coding sequence, the CMV promoter, the antibiotic resistance gene and other plasmid sequences was hgated to the fragment from the pRKCDlla digest containing the CDlla coding sequence and the CMV promoter. The Spe I and Avr II sticky ends are compatible and were hgated together. The Hpa I and Xmn I ends are both blunt and were ligated together to generate the pRK LFA a+b plasmid. Generation of LFA-1 expressing 293 cell line A cell line expressing human LFA-1 was generated by cotransfecting 293 cells with a plasmid (pRK LFA a+b) containing the full-length cDNAs for the aL (CDlla) and b2 (CD18) subunits together with pRSVneo, which encodes the G418 resistance marker under the control of the RSV promoter, using previously described methods. (Bodary, Napier and McLean, J Biol. Chem, 264, 32, 18859-18862, 1989) Upon growth in the presence of 0.8mg/ml of G418 for 20 days a population of drug resistant cells was selected for LFA-1 expression, using two color FACS (fluoresence activated cell sorting,) with monoclonal antibodies directed against the a L subunit (Fluorescein isothiocyanate labeled monoclonal antibody clone 25.3, catalogue # 0860, AMAC, Inc.) or the b2 subunit-complex (Phycoerythrin labeled MHM23.) (MHM23 antibody reference: Hildreth JEK, and August JT, J Immunol, 134, 3272-3280, 1985) After three rounds of FACS a clonal population was isolated (clone 19) and receptor number was determined to be approximately 106 LFA-1 per cell by Scatchard analysis. This cell line was grown under serum free suspension culture conditions to generate cell pellets for the purification of LFA-1. Cell Extraction (All procedures are at 0-4 C.) The frozen 293 cell pellet was suspended in 5 volumes of 0.3 M sucrose/ 20 mM HEPES/5 mM CaCl2/5 mM MgCl2/2 mg/ml aprotinin pH 7.4 using a Polytion homogenizer (Brinkman) at approximately 8000 rpm. Once a uniform suspension was obtained, the cells were homogenized at approximately 20,000 rpm for 1 min. Phenylmethane sulfonyl fluoride (PMSF, 100 mM in isopropanol) was then added to the homogenate to a final concentration of 1 mM, and the homogenate was centrifuged at 21,000 x g for 40 min. The supernatant was discarded and the pellet suspended in a volume of 1% Triton X-100 (ultrapure)/0.15 M NaCl/20 mM HEPES/5 mM CaCl2/5 mM MgCl2/20 mg/ml aprotinin/ 1 mM PMSF pH 7.4 equal to the volume of sucrose buffer above. The cells were homogenized briefly at about 8000 rpm with the Polytion then placed on a rocker for 30 min. The extract was centrifuged as above and the supernatant saved. Lentil Lectin Column Approximately 3 to 4 column volumes of cell extract were loaded at 15 cm/hr onto a lentil lectin Sepharose column (Pharmacia) equilibrated in 0.1% Triton X-100/0.15 M NaCl/ 20 mM HEPES/5 mM CaCl2/5 mM M Cl2 pH 7.4. Once the sample was loaded, the column was washed with equilibration buffer until the A280 nm reached baseline. LFA-1 was eluted with 0.5 M a- methyl mannoside in equilibration buffer. To maximize recovery, elution was stopped when the LFA-1 started to appear, the column was left overnight in elution buffer then elution was resumed. Q Sepharose Column The lentil eluate was diluted with an equal volume of 0.1% Triton X-100/ 20 mM HEPES/5 mM CaCl2/5 mM MgCl2 pH 7.4 and loaded at 15 cm/hr onto a Q Sepharose High Performance column (Pharmacia) equilibrated in the same buffer. After the sample was loaded, the column was washed with equilibration buffer until the A28O nm approached baseline, then with 1 % octyl glucoside/20 mM HEPES/5 mM CaCl2/5 mM MgC-2 pH 7.4 until the Triton X-100 was removed. The LFA-1 was eluted with a 10 column volume 0 to 0.3 M NaCl gradient in the same buffer. Fractions were analyzed by SDS PAGE and the peak fractions pooled and stored frozen at -70 ~ C. Example 2 ICAM-1-immunoadhesin Plasmid for expression of a human ICAM-1-immunoadhesin A plasmid for the expression of a human ICAM-1 immunoadhesin was constructed and named pRK.δdlCAMGalg. This plasmid contains; a CMV (cytomegalovirus) promoter and enhancer region, an SP6 promoter for making riboprobes, the five immunoglobulin-like domains of ICAM-1, a six amino acid cleavage site recognized by Genenase (a genetically engineered form of subtilisin), the Fc region from human IgG, an SV40 early polyadenylation site, an SV40 origin of replication, a bacterial origin of replication, and a bacterial gene coding for ampicillin resistance. This plasmid was constructed using fragments from two other plasmids. The first plasmid, pRKICAMm.2, is a plasmid for the expression of full-length ICAM-1. The following two primers were used to generate a fragment containing the five immunoglobulin-like domains of ICAM-1 by PCR : 1) a 17bp forward primer which is homologous to a portion of the vector sequence 5' of the ICAM-1 coding sequence -5' TGC CTT TCT CTC CAC AG 3 1 and 2) a 48bp reverse primer which is homologous to 7 amino acids at the 3' end of Ig-like domain 5 and contains sequence coding for a protease cleavage site - 5' GG TGG GCA CAG AGT GTA GTG CGC AGC CTC ATA CCG GGG GGA GAG CAC A 3'. The PCR reaction used 0.2μg of pRKICAMm.2, 1 μl forward primer, at 10 OD/ml, 2μl reverse primer, at 10 OD/ml, 0.2 mM each dATP, dCTP, dGTP, and dTTP, 0.5 mM additional Mgθ2, lx VENT polymerase buffer (New England Biolabs), and 1 μl VENT polymerase, at 2 units/ μl (New England Biolabs). The reaction was denatured at 98° C for 5' then cycled 20 times through the following temperatures: 98° C 1", 98° C 10", 60° C 1", 60° C V, 72° C 1", 72° C 1' . The reaction was extended for 20' at 72°C before being held at 4° C overnight. This reaction produces a 1579bp fragment which was purified using Qiaquick-spin PCR purification kit (Qiagen) and digested with restriction enzymes Clal and Dralll (New England Biolabs). The resulting 1515bp fragment was gel purified on a 5% acrylamide gel in lx TBE, electroeluted in O.lx TBE, and purified on SpinBind columns (FMC). This insert fragment contains the first 5 immunoglobulin domains of ICAM-1 and the Genenase cleavage site. The second plasmid, trkcfcgen, is a plasmid for the expression of the TrkC immunoadhesin containing the same portease cleavage site. This plasmid was digested with Clal (New England Biolabs) completely. This material was then digested with Dralll (New England Biolabs) using sub optimal amounts of the enzyme such that a series of partially cut fragments was generated. The desired 5378bp fragment was isolated on a 0.6% GTG Agarose (FMC) gel run in lx TBE (BRL) and electroeluted in 0.1X TBE. The material was extracted first with butanol, then phenol, then chloroform and precipitated with 0.1 volume 3M NaAcetate, pH 7.0 and 2.5 volumes of EtOH. This vector fragment contains all of the plasmid features listed above except the first 5 immunoglobulin domains of ICAM-1 and the protease cleavage site. The two fragments described above were combined in an insertvector ratio of 3:1 using approximately 50 ng of vector in lx ligase buffer and 2 μl ligase at 400 units/ μl (New England Biolabs) for 2 hrs. at room temperature. Half of the reaction was transformed into MM294 competent cells by standard methods. Generation of ICAM-1-immunoadhesin expressing 293 cell line A cell line expressing the ICAM-1-immunoadhesin was generated by transfecting 293 cells with a cDNA encoding the five immunoglobulin domains of human ICAM-1 upstream from the human Fc sequence (ρRK.5dICAMGaIg,) together with pRSVneo, as previously described for the LFA-1 cell line. Upon selection in 0.8mg/ml G418 individual clones of drug resistant cells were isolated. Culture supernatants from these clones were assayed for expression of the human ICAM- 1-immunoadhesin by ELISA, using polyclonal antibodies directed against the human Fc (Caltag catalogue # HI 0507, HI 0700.) A clonal cell line expressing approximately lmg/ml of ICAM-1 - immunoadhesin, as measured by Fc ELISA, was found to react with a monoclonal antibody (AMAC clone 84H10, catalogue # 0544) directed against human ICAM-1. This cell line was grown under serum free culture conditions and culture supernatant was harvested for purification of the ICAM- 1-ιmmunoadhesιn Example 3 ICAM-1:LFA-1 Receptor Binding Assay (protein/protein assay) A cartoon illustrating the forward format of the human ICAM-1 LFA-1 Receptor Bmdmg Assay (PPFF) is provided m Figure 2 Competitive inhibition of the CDlla/CD18-ICAM-l interaction is quantitated by addmg known amounts of inhibitors accordmg to the two protem/protem assay systems described below Forward Format LFA-1 ICAM-1 Assay (PPFF) Purified full-length recombmant human LFA-1 protem is diluted to 2 5μg/ml m 0 02M Hepes, 015M NaCl, and ImM MnCl2 and 96-well plates (50μl/well) are coated overnight at 4°C The plates are washed with wash buffer (0 05% Tween 20 m PBS) and blocked for lh at room temperature with 1% BSA m 0 02M Hepes, 0 15M NaCl, and ImM MnCl2 Plates are washed 50μl/well inhibitors, appropriately diluted m assay buffer (05% BSA m 0 02M Hepes, 0 15M NaCl, and ImM MnC12), are added to a 2X fmal concentration and mcubated for lh at room temperature 50μl/well of purified recombmant human 5 domam ICAM-Ig, diluted to 50ng/ml m assay buffer, is added and mcubated 2h at room temperature Plates are washed and bound ICAM-Ig is detected with Goat anti-HuIgG(Fc)-HRP for lh at room temperature Plates are washed and developed with lOOμl/well TMB substrate for 10-30' at room temperature Colorimetric development is stopped with lOOμl/well 1M H3PO4 and read at 450nM on a platereader An alternative protem/protem assay system described below also quanbtates competitive inhibition of the CDlla/CD18-ICAM-l mteracbon PLM2 Antibody Capture LFA-1 ICAM-1 Assay (PLM2) A non-function blockmg monoclonal antibody agamst human CD18, PLM-2 (as described by Hildreth, et al , Molecular Immunology, Vol 26, No 9, pp 883-895, 1989), is diluted to 5μg/ml m PBS and 96-well flat-bottomed plates are coated with lOOμl/well overnight at 4°C The plates are blocked with 05% BSA m assay buffer (0 02M Hepes, 0 15M NaCl, and ImM MnCl2) lh at room temperature Plates are washed with 50mM Tris pH 75, 0 1M NaCl, 0 05% Tween 20 and ImM MnC12 Purified full-length recombmant human LFA-1 protem is diluted to 2μg/ml assay buffer and lOOμl/well is added to plates and mcubated lh at 37°C Plates are washed 3X 50μl/well inhibitors, appropriately diluted m assay buffer, are added to a 2X fmal concentration and mcubated for 30' at 37°C 50μl/well of purified recombmant human 5 domam ICAM-Ig, diluted to 161ng/ml (for a fmal concentration of 80ng/ml) m assay buffer, is added and mcubated 2h at 37°C Plates are washed and bound ICAM-Ig is detected with Goat anh-HuIgG(Fc)-HRP for lh at room temperature Plates are washed and developed with lOOμl/well TMB substrate for 5-10' at room temperature. Colorimetric development is stopped with lOOμl/well 1M H3PO4 and read at 450nM on a platereader. Example 4 Human T-cell Adhesion Assay (cell attachment assay) A cartoon illustrating the human T cell adhesion colorimetric assay is provided in Figure 3. The T-cell adhesion assay is performed using a human T-lymphoid cell line HuT 78. Goat anti- HuIgG(Fc) was diluted to 2μg/ml in PBS and 96-well plates were coated with 50μl/well @ 37°C for lh. Plates were washed with PBS and blocked for lh @ room temperature with 1% BSA in PBS. 5 domain ICAM-Ig was diluted to lOOng/ml in PBS and 50μl/well was added to the plates O/N @ 4°C. HuT 78 cells were centrifuged at 100 g and the cell pellet was treated with 5mM EDTA for ~5' at 37°C in a 5% C02 incubator. Cells were washed in 0.14M NaCl, 0.02M Hepes, 0.2% Glucose and O.lmM MnC12 (assay buffer) and centrifuged. The cells were resuspended in assay buffer to 3.0 x 10 6 c/ml. Inhibitors were diluted in assay buffer to a 2X final concentration and pre-incubated with HuT 78 cells for 30' at room temperature. lOOμl/well of cells and inhibitors were added to the plates and incubated at room temperature for lh. lOOμl/well PBS was added and the plates were sealed and centrifuged inverted at 100 g for 5'. Unattached cells were flicked out of the plate and excess PBS was blotted on a paper towel. 60μl/well p-nitrophenyl n-acetyl-β-D-glucosaminide (0.257g to 100ml citrate buffer) was added to the plate and incubated for 1.5h at 37°C. The enzyme reaction was stopped with 90μl/well 50mM Glycine/5mM EDTA and read on a platereader at 405nM. HUT 78 cell adhesion to 5dICAM-Ig is measured using the p-nitrophenyl n-acetyl-β-D- glucosaminide method of Landegren, U. (1984) /. Immunol Methods 57, 379-388 Example 5 T-Cell Proliferation assay (co-stimulation assay) A cartoon illustrating the human T cell proliferation assay is provided in Figure 4. This assay is an in vitro model of lymphocyte proliferation resulting from activation, induced by engagement of the T-cell receptor and LFA-1, upon interaction with antigen presenting cells (Sprmger, Nature 346:425 (1990)). Microtiter plates (Nunc 96 well ELISA certified) were precoated overnight at 4°C with 50μl of 2μg/ml of goat anti-human Fc (Caltag H10700) and 50μl of 0.07μg/ml monoclonal antibody to CD3 (Immunotech 0178) in sterile PBS. The next day coat solutions were aspirated. Plates were then washed twice with PBS and lOOμl of 17 ng/ml 5d-ICAM-l-IgG were added for 4 hours at 37°C. Plates were washed twice with PBS prior to addition of CD4+ T cells. Lymphocytes from peripheral blood were separated from heparinized whole blood drawn from healthy donors. An alternative method was to obtain whole blood from healthy donors through leukophoresis. Blood was diluted 1:1 with saline, layered, and centrifuged at 2500 x g for 30 minutes on LSM (6.2g Ficoll and 9.4g sodium diztrizoate per 100ml) (Organon Techmca, NJ) Monocytes were depleted usmg a myeloid cell depletion reagent method (Myeloclear, Cedarlane Labs, Hornby, Ontario, Canada) PBLs were resuspended m 90% heat-mactivated Fetal Bovme serum and 10% DMSO, ahquoted, and stored m liquid nitrogen After thawing, cells were resuspended m RPMI 1640 medium (Gibco, Grand island, NY) supplemented with 10% heat-mactivated Fetal Bovme serum (Intergen, Purchase, NY), ImM sodium pyruvate, 3mM L-glutamme, ImM nonessential ammo acids, 500μg/ml penicillin, 50μg/ml streptomycin, 50μg/ml gentamycm (Gibco) Purification of CD4+ T cells were obtamed by a negative selection method (Human CD4 Cell Recovery Column Kit #CL110-5 Accurate) 100,000 purified CD4+ T cells (90% purity) per microtiter plate well were cultured for 72 hours at 37°C m 5% CO2 in lOOμl of culture medium (RPMI 1640 (Gibco) supplemented with 10% heat inactivated FBS (Intergen), 0 ImM non-essential ammo acids, InM Sodium Pyruvate, 100 units/ml Penicillin, 100 μg/ml Streptomycin, 50μg/ml Gentamicm, lOmM Hepes and 2mM Glutamme) Inhibitors were added to the plate at the initiation of culture Proliferabve responses m these cultures were measured by addition of lμCi/well tritiated thymidme durmg the last 6 hours before harvesting of cells Incorporation of radioactive label was measured by liquid scintillation counting (Packard 96 well harvester and counter) Results are expressed m counts per mmute (cpm) Example 6 In vitro Mixed Lymphocyte Culture Model A cartoon depicting the mixed lymphocyte response assay is provided m Figure 5 This mixed lymphocyte culture model, which is an in vitro model of transplantation (A J Cunningham, "Understanding Immunology, Transplantation Immunology pages 157-159 (1978), exammes the effects of various LFA-1 antagonists m both the proliferahve and effector arms of the human mixed lymphocyte response Isolation cf Cells Mononuclear cells from peripheral blood (PBMC) were separated from hepariruzed whole blood drawn from healthy donors Blood was diluted 1 1 with saline, layered, and centrifuged at 2500 x g for 30 mmutes on LSM (6 2g Ficoll and 9 4g sodium diztrizoate per 100ml) (Organon Techmca, NJ) An alternative method was to obtam whole blood from healthy donors through leukophoresis PBMCs were separated as above, resuspended m 90% heat- machvated Fetal Bovme serum and 10% DMSO, ahquoted, and stored m liquid nitrogen After thawing, cells were resuspended m RPMI 1640 medium (Gibco, Grand Island, NY) supplemented with 10% heat-macbvated Fetal Bovme serum (Intergen, Purchase, NY), ImM sodium pyruvate, 3mM L-glutamme, ImM nonessential ammo acids, 500μg/ml penicillin, 50μg/ml streptomycin, 50μg/ml gentamycm (Gibco) Mixed Lymphocyte Response (MLR) One way human mixed lymphocyte cultures were estabhshed m 96-well flat-bottomed microtiter plates Briefly, 1 5 x 10^ responder PBMCs were co- cultured with an equal number of allogeneic irradiated (3000 rads for 3 mmutes, 52 seconds) stimulator PBMCs in 200μl of complete medium LFA-1 antagonists were added at the initiation of cultures Cultures were mcubated at 37°C in 5% CO2 for 6 days, then pulsed with lμCi/well of ^H- thymidme (6 7 Ci/mmol, NEN, Boston, MA) for 6 hours Cultures were harvested on a Packard cell harvester (Packard, Canberra, Canada) [^H] TdR mcorporahon was measured by liquid scintillation counting Results are expressed as counts per mmute (cpm) Example 7 Compound Synthesis and Activity Abbreviations used m the following section Wang resm = p- alkoxybenzyl alcohol resm, Fmoc = 9- fluorenylmethyloxycarbonyl, Fmoc-OSu = 9- fluorenylmethyloxycarbonyl- N- hydroxysuccinimide, Boc = t- butyloxycarbonyl, B0C 2 O = t- butyloxycarbonyl anhydride, DMA = dimethylacehmide, DMF = dimethylformamide, BOP = (benzotrιazol-1-yloxy) tris (dimethyl-ammo) phosphonium hexafluorophosphate, Hobt = 1-hydroxybenztrιazole, NMM = 4-methylmorphohne, TFA = tiifluoroacetic acid, DCM = dichloromethane, MeOH = methanol, HOAc = acetic acid, HC1 = hydrochloric acid, H2SO4 = sulfuπc acid, K2CO3 = potassium carbonate, PI1 3 P = triphenylphosphine, THF = tetrahydrofuran, EtOAc = ethyl acetate, DIPEA = dusopropylethylamme, NaHCθ 3 = sodium bicarbmate, NMP = N-methyl pyrrohdmone, DIPC = dnsopropylcarbodumide, ACN = acetomtrile, HBTU = 2-(lH-benzotrιazole-l-yl)-l, 1, 3, 3-tetramethyluronιum hexafluorophosphate, NCS = N- chlorosuccnumide, Na2 » EDTA = ethylenediammetetraacehc acid sodium salt, TBAF = terrabutyl ammonium fluoride, EDC = l-(3-dιmethylammopropyl)-3-ethylcarbodumιde*HCl, DEAD = diethyl azocarboxylate, TEA = triethylamrne, MgS0 4 = magnesium sulfate, TES = triethylsilane, Et2θ = diethyl ether, BBr3 = boron tribromide General synthetic methods Method Gl The appropriate Boc protected molecule was dissolved in a solution of TFA in DCM (1 1) After 20 mmutes, the reaction was concentrated in vacuo The resulting oil was dissolved m toluene and then concentrated in vacuo twice Method G2 The appropriate amme was dissolved m Et 2 0 and washed twice with a 10% solution of K2CO3 m H2O and once with brme The orgamc layer was then dried over MgS0 4 , filtered and concentrated in vacuo The product was then used with out further purification Method G3 3 equivalents of the appropriate carboxyhc acid was coupled to 1 equivalent of the appropriate amme usmg 3 equivalents EDC and 1 equivalent of Hobt m DMA The reaction was monitored by TLC (9/1 DCM/ MeOH) Upon completion, the mixture was concentrated in vacuo The resulting oil was re suspended m Et∑O and washed twice with 0 1 N H 2 SO 4 , twice with saturated NaHCθ3, and once with brme The organic layer was then dried over MgS0 4 , filtered and concentrated in vacuo The product was then used with out further purification Method G4 1 equivalent of the appropriate methyl ester was dissolved m THF/H 2 O (3/1) and 3 equivalents of LιOH*H2θ was added The reaction was monitored by TLC (9/1 DCM/ MeOH) Upon completion, the mixture was acidified carefully to pH 2 with concentrated HC1 and then concentrated in vacuo The resulting solid was re suspended m Et 2 θ and washed twice with 0 1 N H2SO4 and once with brme The organic layer was then dried over MgS0 , filtered and concentrated in vacuo Method G5 1 equivalent of the appropriate ammo acid and 25 equivalents of NaHCθ 3 were dissolved m THF/H2O (3/1) Once the solution becomes clear, 1 5 equivalents of Fmoc-OSu was added The reaction was monitored by TLC (9/1 DCM/ MeOH) Upon completion, the mixture was concentrated in vacuo until only the aqueous phase remained The aqueous solution was then extracted twice with Et2θ and then acidified carefully to pH 2 with concentrated HC1 to precipitate out the product The aqueous layer and product was then extracted with EtOAc The organic layer was then partitioned once with brme and dried over MgS0 4 , filtered and concentrated in vacuo The resulting product was used without further purification Method G6 1 equivalent of fluorenylmethanoϊ and 2 5 equivalents of Hobt was dissolved m NMP The mixture was cooled to 0°C with stirring Once cool, 1 equivalent of DIPC was added over 5 mmutes with starring followed by portion wise additions of 1 equivalent of 2- bromoterephthahc acid and then 001 equivalents of 4- pyrrohdinopyridine The mixture was stirred at 0°C for 2 hours, warmed to room temperature and stirred for 4 hours, and then recooled to 0°C and quenched with the drop wise addition of H 2 0 After stirring for 1 hour, the mixture was partitioned with EtOAc The organic layer was then partitioned twice with dilute HC1, once with brme and dried over MgSθ4, filtered and concentrated in vacuo The crude product (a 9 1 mixture of correct versus incorrect isomer) was purified usmg flash sihca chromatography usmg 3/1 hexanes/ EtOAc and 3% HO Ac Method G7 The appropriate methoxy contammg compound was dissolved m DCM and cooled to -5°C m an ice/ acetone bath under nitrogen 2 equivalents of BBr 3 was added drop wise as a solution m DCM over 30 mmutes The reaction was warmed to room temperature and stirred until complete by TLC (DCM/2% HOAc/2% MeOH) The solution was poured onto ice, and the ice was allowed to melt The mixture was then partitioned twice with EtOAc and the combmed orgamc layers were dried over MgSθ4 The filtrate was then passed over a plug of silica gel and concentrated in vacuo Method G8 1 equivalent of dimethyl 2- chloroterephthalic acid was mono hydrolyzed by Method G9 to afford the correct mono protected diacid The mono ester was then t- butyl esterified by Method G10 The methyl ester was then removed by Method G4 to yield the carboxylic acid (Compound A) Method G9 The diester was dissolved in DCM and cooled to -5°C in an ice/ acetone bath under nitrogen. 1 equivalent of BBr 3 was added drop wise as a solution in DCM over 30 minutes. The reaction was warmed to room temperature and stirred until complete by TLC (DCM/2% HOAc/2% MeOH). The solution was poured onto ice, and the ice was allowed to melt. The mixture was then partitioned with EtOAc and concentrated in vacuo. This product was dissolved in H2O with the addition of saturated NaHCθ3 until the pH remained above 8. This solution was partitioned one time with and equal volume of DCM to remove unreacted diester. The basic solution was acidified at 0°C. with concentrated HCl to pH = 1-1.5, and precipitate was extracted twice with equal volumes of EtOAc. The oraganics were partitioned once with brine and dried over MgS0 4 , filtered and concentrated in vacuo. Product was 7:1 of the correct regioisomer by HPLC. Method G10 The monoester was dissolved in DCM was transferred to pre-weighed Parr flask containing a stirring bar. The flask was cooled to -5°C with a dry ice/ alcohol bath under nitrogen. Once cool, -30 equivalents of isobutylene was pumped into solution with stirring. 2.1 equivalents of concentrated sulfuric acid was added and the flask was sealed with a wired rubber stopper and allowed to warm to room temperature with stirring. The solution was stirred until clarification (1-2 days). Once the solution was clear, it was cooled to 0°C in an ice bath. The stopper was removed and the excess isobutylene was blown off with nitrogen bubbling. Saturated NaHCθ3 was added to neutralize the acid and the mixture was concentrated in vacuo until no DCM remained. The solution was then partitioned into EtOAc. The oraganics were partitioned twice with dilute HCl, twice with saturated NaHC0 3 , once with brine, dried over MgS0 4 , filtered and concentiated in vacuo. The resulting product was used with no further purification. Method Gil The t- butyl ester product was dissolved in DCM and an equal volume of TFA was added. After 30 minutes the reaction was concentrated in vacuo and twice redissolved and concentrated from toluene. The product was used without further purification. Method G12 Compound A was coupled to 3- chloro benzylamine by Method G3. The t- butyl ester was removed by Method Gil to yield the carboxylic acid (Compound B). Method G13 Compound A was coupled to 3- methoxy benzylamine, Method G38, by Method G3. This product was converted to the methyl ester by Method G15. The methoxy group was demethylated to the phenol by Method G7. The methyl ester was saponified to the carboxylic acid by Method G4 and the final product (Compound C) was used without further purification. Method G14 1 equivalent of 4- bromo 2- chloro benzoic acid was converted to the methyl ester by Method G15 and the bromine was converted to the nitiile by Method G16. After saponification by Method G4, the nitiile was reduced to the amme and Fmoc protected by Method G17 The fmal product (Compound D) was purified by flash silica chromatography (95/5 DCM/MeOH) and verified by electrospray mass spectrometry Method G15 The appropriate carboxylic acid was dissolved in dry MeOH and 10 equivalents of HCI/dioxane was added and the mixture was stirred overnight to yield the methyl ester product The solution was concentrated in vacuo and twice redissolved and concentrated from toluene The fmal product was purified by flash silica chromatography (95/5 DCM/MeOH) and verified by electrospray mass spectrometry Method G16 0 6 equivalents of Zmc cyamde and 0 04 equivalents of tetrakιs(trιphenylphosphme) palladιum(O) were placed m a round bottom flask an purged for 30 mmutes with circulating nitrogen The methyl ester was dissolved m anhydrous DMF and degassed for 30 mmutes with nitrogen Upon completion of degassmg, the methyl ester solution was added to the zmc cyanide and palladium via cannula and stirred over night at 80°C Upon completion of the reaction, the solution was concentrated in vacuo and redissolved m EtOAc The oraganics were partitioned twice with dilute HCl, twice with saturated NaHC0 3 , once with brme, dried over MgS0 4 , filtered and concentrated in vacuo The product was purified by flash silica chromatography (DCM) and verified by electrospray mass spectrometry Method G17 1 equivalent of the nitiile was dissolved m THF and cooled to 0°C m an ice bath Once cool, 4 equivalents of super hydride was added quickly via cannula to the nitiile After 5 mmutes, the reaction was poured onto ice contammg 5 equivalents of sulfuπc acid a d stirred until all of the ice melts Two volumes of THF was added to the solution and the pH was carefully ad j usted to 8 with portion wise additions of NaHCθ3 1 5 equivalents of Fmoc-OSu was added The reaction was momtored by TLC (9/1 DCM/MeOH) Upon reaction completion, the mixture was concentrated in vacuo until only the aqueous phase remamed The aqueous solution was then extracted twice with Et^O and then acidified carefully to pH 2 with concentrated HCl to precipitate out the product The aqueous layer and product was then extracted with EtOAc The orgamc layer was then partitioned once with brme and dried over MgSθ4, filtered and concentiated in vacuo Method G18 1 equivalent of the appropriate hydroxy carboxylic acid, 22 equivalents off-butyldimethyl silyl chloride and 3 equivalents of imidizole were dissolved DMF and stirred at room temperature The reaction was monitored by TLC (9/1 DCM/MeOH) Upon reaction completion, the mixture was concentrated in vacuo The resulting oil was re suspended m Et 2 0 and washed twice with saturated NaHCθ3, and once with brme The organic layer was then dried over MgS0 4 , filtered and concentrated in vacuo The product was then used with out further purification Method G19 To resm that has been ri sed twice with DMA, a solution consisting of 20% piperidine m DMA was added After 20 mmutes, the resm was filtered and rinsed 5 times with DMA Method G20 3 equivalents of the appropriate carboxylic acid was coupled with 3 equivalents of BOP, 1 equivalent of HOBt, , and 6 equivalents of NMM in DMA for 30 mmutes The coupling was monitored by the Kaiser nrnhydπn test If the Kaiser test was positive, the appropriate carboxylic acid was coupled agam m the same manner Method G21 The molecule was cleaved from the rmsed and dried resm m a solubon consisting of 5% trusopropylsilane m TFA for 1 hour The crude molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder Method G22 3 equivalents of the appropriate amme was coupled with 3 equivalents of BOP, 1 equivalent of HOBt, , and 6 equivalents of NMM m DMA for 60 mmutes Method G23 The resm was washed successively with DMA, DCM, 20% HO Ac m DCM, MeOH and DMF 2 equivalents of the appropriate aldehyde was dissolved in a minimal volume of 1 % HO Ac m DMF and added to the freshly rmsed resm After 5 mmutes, 2 equivalents of sodium cyanoborohydride m DMF was added, and the resm was bubbled overmght The resm was then washed with DMF, 20% DIPEA m DCM, DCM and MeOH The coupling was monitored by the Kaiser nrnhydrin test If the Kaiser test was positive, the appropriate aldehyde was coupled agam m the same manner Method G24 3 equivalents of the appropriate carboxylic acid (R) was coupled with 3 equivalents of HBTU, and 3 equivalents of DIPEA, in DMA The reaction was followed by TLC Upon completion, the mixture was diluted with EtOAc The organic layer was partitioned with dilute sulfuπc acid, saturated NaHCθ3, dried over MgS0 4 , filtered and concentrated in vacuo The resulting methyl ester product was then used with out further purification Method G25 The methyl ester of the appropriate carboxylic acid was made by Method G15 and the phenol was converted to the t- butyl ester by Method G10 1 equivalent of the resulting product was dissolved m a 1 2 mixture of THF and EtOH, and 3 equivalents of lithium chloride and 3 equivalents of sodium borohydπde was added and the reaction was stirred overnight The reaction was quenched with H2O and concentrated in vacuo The residue was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc The combmed organic layers were dried over MgS0 4 , filtered and concentrated in vacuo The crude alcohol was purified usmg silica gel flash chromatography (9 1 hexane/Et2θ) Method G26 A solution of 1 equivalent of the alcohol and 1.1 equivalents of PhjP in THF was cooled to - 10°C in an ice-ethanol bath. While stirring, a solution of 1.1 equivalents of the phenol and 1.1 equivalents of DEAD in THF was added drop wise. The cold bath was removed and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and the resulting residue was taken up in a minimal amount of DCM and filtered through a plug of silica gel, using DCM as eluent. After concentrating this solution in vacuo, the residue was purified using silica gel flash chromatography (8/2/0.5 hexane/DCM/Et2θ) to provide the pure ether. Method G27 1 equivalent of the alcohol was dissolved in acetone and cooled to -10°C. 1.1 equivalents of Jones reagent was added and the reaction was stirred at room temperature for 2 hours. The reaction was filtered through a plug of silica gel and concentrated in vacuo. The residue was partitioned between EtOAc and H 2 0. The residue was partitioned between EtOAc and H 2 O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSθ 4 , filtered and concentrated in vacuo. The yellow solid was triturated with Et2θ to remove impurities, providing pure ketone. Method G28 1 equivalent of the appropriate dihydiuxynaphthalene was dissolved in pyridine. 4 equivalents of solid sodium hydride was added followed by 2 equivalents of the bromide and 0.4 equivalents of cuprous chloride. The resulting mixture was stirred vigorously and heated in an oil bath at 100°C for two days. After concentrating in vacuo., the residue was partitioned between EtOAc and 1M HCl. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS0 , filtered and concentrated in v.icuo. The residue was triturated with Et2θ. After filtering the mixture and concentrating the filtrate, the resulting residue was purified using silica gel flash chromatography (5:4:1 hexane/DCM/Et2θ). Method G29 To a stirred -78°C solution of 1 equivalent of the appropriate methyl ester in dry toluene was added a solution of 1.5 M DIBAL in toluene (1.7 equivalents) drop wise. The reaction mixture was stirred for an additional 2 hours at -78°C or until TLC showed clean formation of product, with only a trace of starting material. The reaction was quenched by slowly adding cold (-78°C) MeOH. The resulting white emulsion was slowly poured into ice-cold 1 N HCl and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSθ4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography (9:1 hexane/Et∑O) to provide the pure aldehyde. Method G30 1 equivalent of the amido alcohol made by Method G28 and 1.5 equivalents of Ph 3 P were dissolved in THF and cooled to -5°C. 1.5 equivalents of DEAD was added drop wise and the reaction was stirred at room temperature overnight. After concentrating the reaction in vacuo, the residue was taken up in a minimal amount of DCM and purified by flash chromatography (9 1 hexane/Et 2 0) to provide pure oxazolme Method G31 To a stirred -78°C solution of 1 equivalent of the bromide in THF was added 1 6 M n-BuLi (1 05 equivalents) drop wise After 0 5 hour, 1 1 equivalents of the aldehyde m THF was added via cannula at -78°C and the reaction was stirred at -78°C After 2 hours, the reaction was quenched with 2 equivalents cold (-78°C) HOAc m THF The mixture was warmed to room temperature, concentrated in vacuo, and the oily residue partitioned between Et 2 0 and H 2 0 The aqueous layer was extracted with Et2θ The combmed organic layers were dried over MgSθ 4 , filtered and concentrated in vacuo The residue was purified usmg silica gel flash chromatography (73 hexane/Et 2 0) Method G32 The oxazolme alcohol was dissolved a 13 1 mixture of ethanol and sulfuπc acid, then heated at reflux for 3 days The reaction was concentrated in vacuo, and the residue was partitioned between E12O and H2O The aqueous layer was extracted with Et 2 θ The combmed organic layers were dried over MgS0 4 , filtered and concentrated in vacuo The residue was purified usmg silica gel flash chroma tography(l 1 hexane/Et 2 0) to give the pure ethyl ester Method G33 To freshly rmsed resm was added, 2 2 equivalents of DIPEA and 22 equivalents of the appropriate isocyanate (R) m 1, 2- dichloroethane were added and the resm agitated overnight The resm was then washed with 10% piperidine in NMP, THF, 30% HOAc m DCM and MeOH Method G34 1 equivalent of 4- benzyloxy benzyl alcohol resm (Wang resm) was washed with DMA and DCM To the resm was added 3 equivalents of the appropriate Fmoc protected ammo acid, 3 equivalents of DIPC and 0 5 equivalents of DMAP DCM The resm was agitated for 2 hours, rinsed with DCM and DMA The resm was then treated with 10% acetic anhydride m DCM for 5 mmutes The resm was washed with DCM and MeOH and then dried in vacuo Method G35 The resm was washed with DCM and chloroform A fresh 0 14M solution of tetrakis (tπphenylphosphine) palladιum(O) m 2 5% NMM, 5% HOAc m chloroform was added to the resm After agitating for 1 hour, the resm was checked by the Kaiser nmhydrm test If the Kaiser test was negative, a new solution of Pd(0) was made and the reaction done agam until a positive Kaiser test results The resm was rinsed with DCM, MeOH and DCM Method G36 The deprotected resm was treated for 1 hour with a solution of 10 equivalents of benzophenone imme and 1 3 equivalents of HOAc m DMA to form the glycme benzophenone imme After rmsmg with DMA the resm was heated with 3 5 equivalents of 2-f-butyhmmo-2- dιethvlamιno-1, 3- dimethylperhydro- 1, 2, 3- diazaphosphorrne for 1 hour 3 equivalents of the appropriate alkylahng agent was added and the reaction agitated for 2 hours The resm was dramed and washed with NMP, 20% DIPEA m DCM, DCM, 10% HOAc in DCM and DCM The benzophenone was removed with a solution of 10 equivalents of hydroxylamine'HCl in THF/H2O for 3 hours The resm was the rmsed with H2O, THF 20% DIPEA m DCM and DCM Method G37 10 equivalents of 2-bromoterephthahc acid, 20 equivalents of HBTU, 20 equivalents of Hobt and 22 equivalents of DIPEA were dissolved in DMA and strrred for 15 mmutes yielding the bisachvated 2-bromoterephthahc acid ester To this solution was added 15 equivalents of 3- hydroxy benzylamine, Method G38, and 15 equivalents of DIPEA yielding the active ester of Compound E The reaction was stirred for 30 mmutes and then it was added to the resm which was then agitated over night Method G38 1 equivalent of 3-cyanophenol was placed m a Parr bottle with EtOH, 0 02 equivalents of HCl and 10% (w/w) of 10% Pd on carbon The vessel was placed m the Parr shaker, charged with 50 psi H2, and shaken for 12 hours The reaction filtered through a pad of cehte and diluted 1 10 with Et2θ Upon standing over night, fme white needles form The product was filtered, washed with EtαO and dried m vacuo The resulting hydrochloride salt was then used with out further purification Method G39 The resm was washed with DCM and chloroform A fresh 0 14M solution of tetrakis (tπphenylphosphine) palladιum(O) m 2 5% NMM, 5% HOAc m chloroform was added to the resm After agitating for 2 hours, the resm was dramed and rinsed with DCM and DMA The resm was then treated with 10% DIPEA m DMA for 10 mmutes, followed by several DMA washes and then with a 5% solution of diethyldithiocarbamic acid m DMA for 15 mmutes The resm was then rmsed with DMA, DCM, MeOH and DCM Method G40 Resm was suspended m ACN and cooled to 0°C Once cool, 3 equivalents of PI13P and 3 equivalents of NCS was added and the resm was agitated for 5 mmutes 6 equivalents of the appropriate aniline was added to the resm and the resm was agitated as it was warmed to room temperature After an additional 10 mmutes at room temperature, the reaction was quenched with 3 equivalents of HOAc and the resm washed with 10% HOAc m ACN, DCM and MeOH Method G41 The resm was preactivated with 3 equivalents of HBTU, 3 equivalents of Hobt and 6 equivalents of DIPEA m DMA for 10 mmutes 2 equivalents of the appropriate amme was added, and the resm agitated for 30 mmutes The procedure was repeated agam The resm was rmsed with DMA and DCM Method G42 The resm was rmsed with DMA, DCM and dichloroethane 1 1 equivalents of the appropriate sulfonyl chloride and 3 equivalents of DIPEA were added m dichloroethane and the resm was agitated for 12 hours The reaction can be followed by the Kiaser nmhydrm test and the procedure repeated until a negative Kiaser test results The resm was washed with dichloroethane, and DCM Method G43 The resm was rinsed with DMA, DCM and dichloroethane 1 1 equivalents of the appropriate chloroformate and 3 equivalents of DIPEA were added m dichloroethane and the resm was agitated for 12 hours The reaction can be followed by the Kiaser nmhydrm test and the procedure repeated until a negative Kiaser test results The resm was washed with dichloroethane, and DCM Method G44 1 equivalent of the appropriate amme was dissolved a 3 2 THF/H 2 O solution 1 1 equivalents of solid NaHCθ3 and 1 1 equivalents of B0C2O were added and the solution was stirred overmght The reaction was concentrated, and the residue was partitioned between H2O and Et 2 θ The aqueous layer was extracted with Et2θ and the combmed organic layers were dried over MgSθ4 and concentrated in vacuo to a solid Recrystallizabon out of Et ∑ O/hexane provided pure product Method G45 1 equivalent of the appropriate phenol was dissolved m DCM contammg 2 6 equivalents of 2, 6-lutidιne and the mixture was cooled to -78°C After addmg 1 25 equivalents of tiiflic anhydride the stirring reaction was al'owed to warm to room temperature overnight The reaction was then concentrated, and the residue was partitioned between Et 2 0 and H 2 O The aqueous layer was extracted with Et^O and the combmed organic layers were dried over MgS0 4 and concentrated in vacuo The residue was purified by silica gel flash chromatography (9 1 hexane/Et 2 θ) to provide the pure triflate Method G46 To a starring solution of 1 equivalent of the triflate m a 2/1 mixture of DMF/ MeOH was added 0 15 equivalents of 1, 3-bιs(dιphenylphosphrno)-propane and 2 5 equivalents of TEA Carbon monoxide gas was bubbled through this solution for 15 mmutes, then 0 15 equivalents of Pd(OAc)2 was added and the reaction was stirred at 70°C for 5-7 hours under an atmosphere of CO (usmg a balloon filled with CO) The reaction was then concentrated in vacuo, and the residue was partitioned between Et2θ and H2O The aqueous layer was extracted twice with Et∑O and the combmed organic layers were dried over MgS0 4 , filtered through a plug of silica gel and concentrated in vacuo The residue was purified by silica gel flash chromatography (9 1 0 02 hexane/DCM/Et2θ) to provide the pure methyl ester Method G47 1 equivalent of the appropriate Boc-aniline was dissolved m methanol and the solution saturated with HCl The reaction was heated at 50°C for 3h, then concentrated in vacuo The pale yellow solid was heated m 35% H2SO4 until complete dissolution occurred Upon coolmg the mixture by the addition of ice H2O the amme bisulfate precipitated The reaction flask was cooled m an ice bath and the mixture stirred vigorously while 1 1 equivalent of sodium nitrite m H2O was added drop wise The reaction was stirred at 0°C for another 1 5 hours After diluting the reaction with H2O, the reaction was heated at 80°C for 10 hours The reaction was cooled to room temperature and extracted with EtOAc The combmed organic layers were dried over MgSθ4 and concentrated in vacuo The residue was purified by sihca gel flash chromatography (14 6 1 hexane/DCM/Et2θ) to provide the pure phenol Method G48 1 equivalent of the appropriate methyl benzoate was dissolved m DCM and 1 5 equivalents of a 1 0M solution of BBr 3 was added After starring the reaction overmght, the reaction was quenched with ice and stirred for an additional 1 5 hours The reaction was extracted three times with Et2θ and the combmed organic layers were dried over MgSθ4 and concentrated in vacuo The residue was taken up m a minimal amount of saturated NaHCθ 3 The product was precipitated from this aqueous solution by the addition of concentrated HCl and then extracted mto Et2θ he combmed organic layers were dried over MgSθ 4 and concentrated in vacuo to provide pure benzoic Method G49 1 equivalent of the appropriate carboxylic acid was dissolved m DMF 1 1 equivalents of solid NaHCθ3 and 5 equivalents of allyl bromide were added and the resulting mixture was stirred at 45°C overnight The reaction was then concentrated, and the residue was partitioned between Et2θ and H2O The aqueous layer was extiacted three times with Et∑O and the combmed organic layers were dried over MgS0 4 and concentrated in vacuo The residue was purified by sihcε. gel flash chromatography (73 hexane/Et2θ) to provide the pure allyl ester Method G50 To a solution of 1 equivalent of the appropriate allyl ester m THF was added 0 1 equivalents of tetrakis (trrphenylphosphine) palladιum(O) and 10 equivalents of morphohne The reaction was starred for 1 5 hours, then concentrated in vacuo The residue was taken up m DCM, extiacted three times with IN HCl, dried over MgS0 4 and concentrated in vacuo The residue was triturated with 1 1 hexane/Et 2 0, filtered through a plug of glass wool and concentrated in vacuo to provide the pure benzoic acid Method G51 1 equivalent of the phenol was dissolved m DMF and 2 05 equivalents of K2CO3 and 4 equivalents of 1, 3-dιbromopropane were added The reaction was stirred overnight while heating the reaction flask in an oil bath mamtamed at 50°C After concentrating the mixture in vacuo , the residue was partitioned between Et 2 0 and H 2 0 The aqueous layer was extiacted three times with Et2θ and the combmed orgamc layers were dried over MgS0 4 and concentrated in vacuo The residue was purified by silica gel flash chromatography (95 5 hexane/Et 2 0) to provide the pure bromide Method G52 1 equivalent of the appropriate hydroxy phenol and 1 equivalent of K 2 CO3 were added to a solution of 0 5 equivalents of the bromide DMF After stirring overnight, the reaction was concentrated in vacuo The residue was partitioned between Et2θ and H2O The aqueous layer was extracted three times with Et2θ and the combmed organic layers were dried over MgS0 4 and concentrated in vacuo The residue was purified by sihca gel flash chromatography (18 1 DCM/EtαO) to provide the pure phenol Method G53 To a nitrogen purged glass pressure tube was added 1 equivalent of the appropriate bromide, 5 equivalents of n-butyl vmyl ether, 15 equivalents of TEA, 0 1 equivalents of 1, 3- bιs(dιphenylphosphrne)propane, 1 equivalent of thallium acetate, 0 09 equivalents of palladium acetate, and DMF The tube was capped and heated to 100°C overnight The reaction was cooled and the catalyst filtered off The mixture was diluted with EtOAc and washed with H2O, and dried over M^0 The crude product was purified on silica (4/1 hexane/DCM) This was ui'-solved m THF and 4N HCl m dioxane and stirred overmght The solvents were evaporated and the product purified on silica (4/1 hexane/ EtOAc) to give pure product Method G54 1 equivalent of the appropriate Boc-anihne was dissolved m methanol and the solution saturated w>ih HCl The reaction was heated at 50°C for 3h, then concentiated in vacuo T\o pale yellow sohd was heated m 35% H2SO4 until complete dissolution occurred Upon cooling the mixture by the addition of ice H2O the amme bisulfate precipitated The reaction flask was cooled m an ice bath and the mixture stirred vigorously while 1 1 equivalents of sodium nitrite m H2O was added drop wise The reaction was starred at 0°C for another 1 5 hours An aqueous solution of 10 equivalents of KI was added, followed immediately with 17 equivalents Cul The reaction was stirred at room temperature for 14 hours, then extracted 3 times with Et 2 θ The combmed orgamc layers were washed with IM NaHCθ3, brme, and dried over MgS0 4 , then concentrated in vacuo The residue was purified by silica gel flash chromatography (95 5 hexane/ Et 2 θ) to provide the pure iodide Method G55 23 equivalents of lithium iodide was added to 1 equivalent of methyl- 2, 6-dιchloro- 4- lodobenzoate m pyπdme, and the mixture heated at reflux for 8 hours The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and IN HCl The aqueous layer was extracted three times with EtOAc, and the combmed organic layers were washed with IM NaHC0 3 , dried over MgSθ4 and concentrated in vacuo The residue was dissolved in NMM and the solution concentiated in vacuo. The residue was taken up in DCM and then washed three times with IN HCl. The organic layer was dried over MgS0 and concentiated in vacuo to provide the benzoic acid in high enough purity to be used without further purification. Method G56 1.3 equivalents of DIPEA was added to a heterogeneous mixture of 1 equivalent of 3- hydroxybenzoic acid, 1.3 equivalents of N, O-dimethylhydroxylamine hydrochloride, 1.3 equivalents of HOBt and 1.3 equivalents of EDC stirring in DMF. All solids eventually dissolved as the mixture was stirred at room temperature for 28 hours. After concentrating the mixture, the residue was partitioned between Et∑O and H 2 0. The aqueous layer was extiacted three times with Et 2 0 and the combined organic layers were dried over MgS0 4 , and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Et 2 0) to provide the pure hydroxamate. Method G57 To a stirred -78°C solution of 1 equivalent of the appropriate protected hydroxamate in THF was added a solution of 1.2 equivalents of 1.5 M DIBAL in toluene drop wise. The reaction mixture was stirred for an additional 3 hours at -78°C or until TLC showed clean formation of product, with only a trace of starting material. The reaction was quenched by adding to a separatory funnel containing Et2θ and 0.35M NaHS0 4 . The layers were separated. The aqueous layer was extracted three times with ethyl ether. The combined organic layers were washeα twice with IN HCl, saturated aqueous NaHCθ3, and over MgS0 4 , filtered through a plug of silica gel, and concentrated in vacuo. No further purification of the aldehyde was necessary. Method G58 A solution of 1 equivalent of the appropriate aldehyde in THF was cooled to -78°C and 1.1 eq livalents of 0.5M ethynylmagnesium bromide/THF was added. After stirrmg the reaction at room temperature for 3 hours, it was diluted with Et θ and washed twice with 10% citric acid. The combined aqueous layers were back-extracted once with Et ∑ O. The combined organic layers were washed twice with saturated aqueous NaHCθ3, dried over MgS0 4 and concentrated in vacuo. The residue was purified by sihca gel flash chromatography (4:1 to 3:2 hexane/Et 2 0) to provide the pure alkyne. Method G59 1 equivalent of the aryl iodide was dissolved in EtOAc and the solution was degassed by passing N2 through a pipette and into the solution for 10 minutes. 1.25 equivalents of the alkyne was added, followed by 0.02 equivalents of dichlorobis(tiiphenylphosphine)palladium(II), 0.04 equivalents of Cul and 5 equivalents TEA. The reaction was stirred for 14 hours, diluted with EtOAc, washed twice with 5% Na 2 » EDTA, brine and then dried over MgSθ 4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient elution, using Et 2 0 to EtOAc) to provide the pure aryl alkyne. Method G60 1 equivalent of the aryl alkyne was dissolved in MeOH and the solution was degassed by passmg N2 through a pipette and mto the solution for 10 mmutes The 5% RI1/AI2O3 was added, one balloon-full of hydrogen was passed through the solution, and the reaction was stirred under an atmosphere of H2 (usmg a balloon) for 7 hours, after which the reaction was filtered through a pad of cehte and concentrated in vacuo The residue was purified by silica gel flash chromatography (gradient elution, usmg Et2θ to EtOAc) to provide the pure product Method G61 2 equivalents of the appropriate protected ammo acid and 2 equivalents of PI13P was suspended m DCM 22 equivalents of NCS was added and the mixture was stirred for 30 mmutes 1 equivalent of the aniline contammg resm and 1 1 equivalents of NMM was suspended m DCM and the clear acid solution added The resm was agitated for 2 hours, rinsed with DCM, DMA and DCM The procedure was repeated agam Method G62 The appropriate benzaldehyde was converted to its correspondmg hydantom by Method G63 and then hydrolyzed to the ammo acid by Method G64 The pure racemic ammo acid was then protected by Method G5 Method G63 1 equivalent of the appropriate benzaldehyde, 2 equivalents of potassium cyamde and 4 equivalents of ammonium carbonate were refluxed m 50% EtOH for 2 5 hours After cool g to 0°C, the solution was acidified to pH 2 will concentrated HCl After standing m the refrigerator over ght, the crystals were filtered and washed with H 2 O and recrystalized from boilmg H 2 0/EtOH Method G64 The pure hydantom was refluxed m 10% NaOH overnight After coolmg, activated carbon was added and the solution filtered through cehte The solution was acidified to pH 7 with concentrated HCl and allowed to stand m the refrigerator overnight The resulting crystals were filtered, washed with H2O and dried overnight in vacuo to give pure racemic ammo acid Method G65 4-bromo-2-chlorobenzoιc acid was converted to the t-butyl ester by Method G10 t- Butylvinyl ether was coupled to the bromide by Method G53 to give 4-acetyl-2-chlorobenzoιc acid t- butyl ester The ketone was reduced to the alcohol by Method G66 and the racemic mixture resolved by Method G67 to give pure S isomer Phthalamide was coupled to the alcohol by Method G68 and the product hydrolyzed by Method G69 to give the amme Method G66 2 equivalents of the appropriate ketone was dissolved in MeOH and 1 equivalent of NaBFL was added After stirrmg for 1 hour, the reaction was quenched with concentrated HCl and concentrated in vacuo The residue was partitioned between Et 2 θ and H 2 O The organics were dried over MgS0 4 and concentiated in vacuo The alcohol can be used without further purification Method G67 1 equivalent of the alcohol mixture was dissolved in dnsopropyl ether and 2 equivalents of vmylacetate and Amano hpase P (lOOmg) were added The suspension was stirred overmght and then concentrated in vacuo The residue was purified by silica get flash chromatography (5/1 EtOAc/ hexane) to give pure R and S isomers Method G68 A solution of 1 equivalent of the alcohol and 3 equivalents of PI13P m THF was cooled to - 10°C m an lce-EtOH bath While stirrmg, a solution of 3 equivalents of the amme and 3 equivalents of DEAD in THF was added drop wise The cold bath was removed and the reaction was stirred at room temperature overnight The reaction was concentrated in vacuo and the resulting residue was taken up a mmimal amount of DCM and filtered through a plug of sihca gel, usmg DCM as eluent After concentrating this solution in vacuo, the residue was purified usmg silica gel flash chromatography (8/2/0 5 hexane/ DCM/ E1.2O) to provide product Method G69 1 equivalent of the phthalamide was dissolved m EtOH and THF followed by addition of 8 equivalents of hydrazme hydrate The reaction was starred at room temperature for 1 5 hours, then at 50°C for 1 hour The solution was cooled, filtered and the sohds washed with EtOAc The clear solution was concentrated in vacuo and the residue purified by sihca gel flash chromatography (94/4 DCM/MeOH) to give pure amme Method G70 1 equivalent of the appropriate commercially available ketone, 5 equivalents of hydroxy lamme hydrochloride and 10 equivalents of sodium acetate were combmed m MeOH and stirred overnight The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and saturated NaHCθ3 The organic layer was washed once with brme, dried over MgSθ4 and concentrated in vacuo The product was purified by silica gel flash chromatography (EtiO) to give pure oxime Method G71 1 equivalent of the appropriate benzaldehyde was treated with 25 equivalents of the appropriate R'MgBr in THF at -20°C under an N2 atmosphere After warmmg to room temperature, the reaction was poured mto a slurry of 0 1 N sulfuπc acid and ice, and the product extracted with EtOAc After partitionmg and washmg with brme, the organic phase was dried over MgS0 4 and concentrated in vacuo to give crude product Oxidation to the ketone was carried out m dioxane with 1 1 equivalents of 2, 3-dιchloro-5, 6-dιcyano-l, 4-benzoquιnone for 48 hours Reaction contents were filtered, and the filtrate concentiated in vacuo The residue was purified by silica gel flash chromatography (hexane/EtOAc 1 1) to yield the product as a yellow solid Method G72 The resin with the S-tiityl or O-tiityl protecting group was washed three times with DCM. It was then washed three times for 10 minutes with a solution consisting of 1% TFA 1% TES in DCM. It was then washed 3 times with DCM. The resin was then checked by placing a small amount of resin into a test tube and treating it with concentrated TFA. If no yellow color appears the removal was complete. If a yellow color appears, the above procedure was repeated until a clear test was achieved. Method G73 The resin containing the appropriate free hydroxyl was washed three times with DCM. A solution of 10% DIPEA in DCM was added to the resin and a 0.3 M solution of phosgene in toluene was added to the resin. The reaction was allowed to proceed for 10 minutes at room temperature, after which it was drained and washed three times with DCM. A 0.3 M solution in DCM of the appropriate amine was added to the resin and it was allowed to react overnight. The resin was then drained and washed three times with DCM. Method G74 The appropriate resin was washed three times with DCM and then treated with a 0.3 M solution of the appropriate chloroformate (R) in 0.33 M DIPEA in NMP overnight. The coupling was monitored by the Kaiser ninhydrin test. If the Kaiser test was positive, the appropriate chloroformate was coupled again in the same manner. The resin was then washed three times with NMP and then three times with DCM. Method G75 The appropriate 2, 6- disubstituted phenol (2, 6- dichlorophenol for Compound F, 2, 6- dimethylphenol for Compound H and 2, 6- difluorophenol for Compound I) was alkylated by Method G76. The resulting phthalimide was hydrolyzed and protected by Method G77. The phenol was then converted to the triflate by Method G78 and carbonylated by Method G79 to give the desired double protected compound. Method G76 A round bottom flask was equipped with an efficient overhead starrer and charged with concentrated H2SO4 (2.7 x volume of H2O) and H2O and cooled to ~-5°C with an ethanol ice bath. Once cool, 1 equivalent of the appropriate disubstituted phenol and 1 equivalent of N- (hydroxymethyl)phrhalimide were added with vigorous stirring. The reaction was kept cool for 4 hours and then allowed to warm to room temperature overnight with constant stirring. The reaction generally proceeds to a point where there was just a solid in the round bottom flask. At this point EtOAc and H2O were added and stirred into the solid. Large chunks were broken up and then the precipitate was filtered and washed with more EtOAc and H 0. The product was then used without further purification after drying overnight in a vacuum desiccator. Method G77 1 equivalent of the product from Method G76 and (22 5ml x #g of starting material) of methanol was added to a round bottom flask equipped with a H 2 O condenser and stirrmg bar 1 2 equivalents of hydrazme mono hydrate was added and the mixture was refluxed for 4 hours After coolmg to room temperature, (45ml x #g of starting material) of concentrated HCl was carefully added Upon completion of the addition, the mixture was refluxed agam overnight (> 8 hours) The reaction was cooled to 0°C and the precipitated by- product filtered off The filtrate was then concentrated in vacuo The residue was then Boc protected by Method G44 with the exception that the product was recrystalized from hot methanol and H 2 O Method G78 1 equivalent of the appropriate phenol and 1 5 equivalents of 2, 6- lubdme was dissolved, with mild heating if necessary, in DCM m a round bottom flask Once the starting material has completely dissolved, the mixture was cooled to -78°C under N2 with a dry ice ethanol bath Once cool, 2 5 equivalents of tiifhc anhydride was added and the reaction was allowed to slowly come to room temperature with stirrmg The reaction was monitored by TLC and was generally done m 4 hours Upon completion, the reaction was concentiated in vacuo and the residue partitioned between EtOAc and H2O The organic layer was washed twice with 0 IN H2SO4, twice with saturated once with brme, dried over MgS0 and concentrated in vacuo The ie'.idue was then purified on silica gel usmg DCM as eluent Method G79 1 equivalent of triflate was dissolved m DMF and MeOH m the glass msert of a high pressure Parr bomb The starting material was then degassed while stirrmg with CO for 10 mmutes 0 15 equivalents palladmm(II) acetate and 0 15 equivalents of 1, 3- bιs(dιphenylphosphιno) p-opane were then added and the mixture was then degassed while stirrmg with CO for another 10 mmutes 2 5 equivalents of dnsopropyl ethyl amme was added and the Parr bomb assembled After properly assemblmg the bomb, it was charged with 300 psi CO gas and heated to 70°C with stirrmg overmght The bomb was then cooled and vented The mixture was transferred to a round bottom flask and concentrated in vacuo The residue was then purified on sihca gel usmg DCM with 1% acetone and 1 % TEA as eluent Method G81 1 equivalent of the appropriate alkene and 1 5 equivalents of KOH were dissolved m H2O an appropriately sized Parr shaker flask A small amount (approximately lOOmg per 50 mmol of alkene) of 5% Pd/C catalyst was added and the flask was charged with 50 psi H 2 and shaken overmght The mixture was then filtered through Cehte and concentrated in vacuo The resulting product was used without further purification Method G80 1 equivalent of the appropriate ethyl ester and 1 5 equivalents of KOH was dissolved m H2O and refluxed for three hours After completion, the reaction was concentrated in vacuo and the product used without further purification Method G82 1 2 equivalents of NaH (60% mineral oil dispersion) was suspended m benzene and cooled to 0°C with and ice H 2 0 bath 1 2 equivalents of triethyl phosphonoacetate was added slowly and the reaction was allowed to stir until the solution becomes clear 1 equivalent of the appropriate ketone (R) was added slowly and the reaction was stirred for 4 hours Upon completion, the reaction was partitioned with toluene and H2O The aqueous layer was back extiacted The combmed orgamc layers were dried over MgS0 4 and concentrated in vacuo The residue was purified by silica gel flash chromatography (85 15 hexane/ EtOAc) Method G83 1 2 equivalents of NaH (60% mineral oil dispersion) was suspended m benzene and cooled to -10°C with and a dry ice H 0 bath 1 2 equivalents of triethyl 2- phosphonopropionate was added slowly and the reaction was allowed to stir until the solution becomes clear 1 equivalent of the appropriate aldehyde (R) was added slowly and the reaction was stirred for 4 hours Upon completion, the reaction was partitioned with toluene and H 2 0 The aqueous layer was back extracted The combmed orgamc layers were dried over MgSθ 4 and concentiated in vacuo The residue was purified by sihca gel flash chromatography (85 15 hexane/ EtOAc) Method G84 1 equivalent of the appropriately protected toluene was dissolved m acetic anhydride and HOAc, then cooled m an ice-salt bath (-5°C) before concentiated H 2 SO 4 was added A solution of Crθ3 (26 equivalents) in acetic anhydride and HOAc was added drop wise and the reaction was stirred for 3 5 hours at -5°C The reaction was poured mto ice H 0 and stirred for 30 mm The mixture was extracted three times with ethyl ether The combmed organic layers were washed with saturated NaHC0 3 and brme, then dried over MgS0 and concentrated in vacuo to an oil Toluene was added to the oil and the solution concentiated in vacuo agam This was repeated to obtam a crystalline solid The sohd was dissolved m methanol and concentrated HCl and heated at reflux for 12 hours The reaction was concentrated in vacuo and the residue was purified by silica gel flash chromatography (9 1 hexane/ Et2θ) to provide the pure aldehyde Method G85 1 equivalent of the appropriate alcohol was dissolved in DMF and cooled to -5°C m an ice- salt H2O bath 1 4 equivalents lithium bιs(trιmethylsιlyl)amιde m THF was added drop wise The reaction was stirred for 0 5 hour, then 1 equivalent of methyl iodide was added and the reaction was stirred overnight under an atmosphere of nitrogen The reaction was partitioned between ethyl ether and 10% citric acid The aqueous layer was extiacted with ethyl ether, the combmed organic layers were washed with saturated NaHC0 3 and brme, then dried over MgS0 4 and concentrated in vacuo to an oil The residue was purified bv silica gel flash chromatography (9 1 hexane/ Et2θ) to provide the pure methyl ether Method G86 Commercially available nitioterephthalic acid was converted to its diethyl ester by Method G87 The ratio group was replaced by a benzyl mercaptan by Method G88 and deprotected by AlBr3 usmg Method G89 The thiol was then alkylated with bromoacetaldehyde diethyl acetal by Method G90 and then dehydrated by Method G91 The diethyl ester was treated with LiOH, Method G4, and then coupled by Method G3 to 3-hydroxy benzyl amme, Method G38 The fmal ethyl ester was removed by Method G4 Method G87 1 equivalent of the appropriate commercially available carboxylic acid was dissolved m toluene with an excess of ethanol and 0 6 equivalents of H2SO 4 and the mixture refluxed for 4 days Upon completion, the reaction was concentrated in vacuo and partitioned between EtOAc and H2O The organic layer was washed with saturated NaHCθ 3 , brme, dried over M Sθ 4 and concentrated in vacuo The product was used without further purification Method G88 1 25 equivalents of 95% NaH was suspended m DMF and cooled under N 2 to -5°C with an ice bath 1 25 equivalents of benzyl mercaptan was added drop wise and the solution was allowed to stir for 40 mmutes 1 equivalent of the appropriate aryl nitro compcund was added over 20 mmutes and the mixture was stirred for an additional 30 mmutes After verifying that reaction was complete, the solution was poured onto ice and stirred until all the ice melts The aqueous solution was partitioned three tames with EtOAc and the combmed organic layers were washed with brme, dried over MgSθ4 and concentrated in vacuo The residue was purified by sihca gel flash chromatography (1 4 hexane/ EtOAc) to provide product Method G89 1 equivalent of benzyl protected material and 2 2 equivalents of AlBft were refluxed m toluene for 3 hours at which tame H2O and enough EtOAc was added to partataon the mixture The orgamc layer was washed three times with H2O, brme, dried over MgSθ 4 and concentrated in vacuo The residue was purified by silica gel flash chromatography (4 1 hexane/ EtOAc) to provide product Method G90 1 equivalent of the thiol was dissolved m DMF and 2 equivalents of K 2 CO3 was added 1 1 equivalents of bromoacetaldehyde diethyl acetal was added slowly over 20 mmutes and then 0 1 equivalent of Nal was added portion wise The reaction was stirred for 2 hours and then partitioned between EtOAc and H2O The organic layer was washed three times with H 2 O, brme, dried over MgSθ4 and concentrated in vacuo The residue was purified by silica gel flash chromatography (9 1 hexane/ EtOAc) to provide product Method G91 1 equivalent (by weight) of the appropriate diethyl acetal and 2 equivalents (by weight) of poly phosphoric acid were dissolved in chlorobenzene. The reaction was monitored by TLC. Upon completion of the reaction, the mixture was concentrated in vacuo and then partitioned between EtOAc and saturated NaHCθ3. The organic layer was washed twice more with saturated NaHCθ3, brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by sihca gel flash chromatography (4:1 hexane/EtOAc) to provide product. Method G92 1 equivalent of the appropriate carboxylic acid was dissolved in DCM and cooled to 0°C with an ice H 2 0 bath. Once cool, 3 drops of DMF and 1.5 equivalents of oxalyl chloride were added. The reaction was stirred at 0°C for 1.5 hours and then for 0.5 hour at room temperature. At this time, the reaction was concentrated in vacuo and used immediately. Method G93 1 equivalent of bis-N-carboxybenzoyl-cystine dibenzyl ester was dissolved in HOAC/H2O (9/1) and treated with chlorine gas for 10 minutes. The reaction was concentrated in vacuo, dissolved in toluene and concentrated in vacuo again to yield a white solid. This product was dissolved in DCM and 0.5 equivalents of the appropriate amine (R) was added. The reaction was stirred for 30 minutes and then diluted with EtOAc and partitioned with 0.1N H 2 SO 4 and then brine. The organic layer was dried over MgSθ4 and concentrated in vacuo. The residue was purified by sihca gel flash chromatography (EtOAc/hexane 1:1) to yield pure product. The protecting groups were removed by Method G38 and the product used without further purification. Specific Example methods Method SI Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N- -Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35 The appropriate isocyanate (R) was coupled by Method G33. The completed molecule was worked up by Method G21. Method S2 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiobutyric acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-γ-Alloc-L- diaminobutyric acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35 The appropriate isocyanate (R) was coupled by Method G33. The completed molecule was worked up by Method G21. Method S3 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Ornithine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-δ-Alloc-L- Omithine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35 The appropriate isocyanate (R) was coupled by Method G33. The completed molecule was worked up by Method G21. Method S4 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Lysine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resin). The resin was made by Method G34 using commercially available N- -Fmoc-N-ε-AUoc-L-lysine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35 The appropriate isocyanate (R) was coupled by Method G33. The completed molecule was worked up by Method G21. Method S5 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 usmg commercially available N-α-Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13 was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S6 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiobutyric acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-γ-Alloc-L- diaminobutyric acid The Fmoc group was cleaved by Method G19. Compound C, Method G13 was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S7 Compounds were synthesized using standard Fmoc sohd phase methods on Fmoc- L- Ornithine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-δ-Alloc-L- Ornithine. The Fmoc group was cleaved by Method G19. Compound C, Method G13 was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S8 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Lysine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-ε-AUoc-L-lysine. The Fmoc group was cleaved by Method G19. Compound C, Method G13 was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S9 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- nipecotic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S10 Compounds were synthesized using .standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- isonipecotic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method Sll Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- 3-aminomethyl benzoic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S12 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N- -Fmoc-N-β- AIloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- 4-aminomethyl benzoic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S13 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- β alanine was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S14 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- glycine was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Me od G21. Method S15 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- Ornirhine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-cx- Fmoc-N-δ-AUoc-L-Ornithine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- nipecotic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S16 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- Omithine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α- Fmoc-N-δ-AUoc-L-Ornithine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- lsonipecohc acid was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S17 Compounds were synthesized usmg standard Fmoc solid phase methods on commercially available Fmoc- L- Ornithine (alloc)- p- alkoxybenzyl alcohol resm (0 5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resm) The resm was made by Method G34 usmg commercially available N-α- Fmoc-N-δ-AUoc-L-Ornithine The Fmoc group was cleaved by Method G19 Compound C, Method G13, was coupled by Method G20 The Alloc group was removed by Method G35 Commercially available Fmoc- pipecolmic acid was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S18 Compounds were synthesized usmg standard Fmoc solid phase methods on commercially available Fmoc- L- Ornithine (alloc)- p- alkoxybenzyl alcohol resm (0 5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resm) The resm was made by Method G34 usmg commercially available N-α- Fmoc-N-δ-Alloc-L-Ornithme The Fmoc group was cleaved by Method G19 Compound C, Method G13, was coupled by Method G20 The Alloc group was removed by Method G35 Commercially available Fmoc- 3-aminomethyl oenzoic acid was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S19 Compounds were synthesiz d usmg standard Fmoc solid phase methods on commercially available Fmoc- L- Ornithine (alloc)- p- alkoxybenzyl alcohol resm (0 5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resm) The resm was made by Method G34 usmg commercially available N-α- Fmoc-N-δ-AUoc-L-Ormthine The Fmoc group was cleaved by Method G19 Compound C, Method G13, was coupled by Method G20 The Alloc group was removed by Method G35 Commercially avadable Fmoc- 4-amιnomethyl benzoic acid was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S20 Compounds were synthesized usmg standard Fmoc solid phase methods on commercially available Fmoc- L- Ornithine (alloc)- p- alkoxybenzyl alcohol resm (0 5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resm) The resm was made by Method G34 usmg commercially available N-α- Fmoc-N-δ-Alloc-L-Orruthine The Fmoc group was cleaved by Method G19 Compound C, Method G13, was coupled by Method G20 The Alloc group was removed by Method G35 Commercially available Fmoc- β alanme was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S21 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- Ornithine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α- Fmoc-N-δ-AlIoc-L-Ornithine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- glycine was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S22 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-N-γ- Alloc-L-diaminobutyric acid- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-cx-Fmoc-N-γ- AlIoc-L-diaminobutyric acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- nipecotic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S23 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-N-γ- Alloc-L-diaminobutyric acid- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-γ- Alloc-L-diaminobu lyric acid. The Fmoc group was cleaved by Method G19. Compound C, Metho G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- isonipecotic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S24 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-N-γ-Alloc-L- diaminobutyric acid- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-γ-AUoc-L- diaminobutyric acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- pipecolinic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S25 Compounds were synthesized using standard Fmoc solid phase methods on N-cx-Fmoc-N-γ- Alloc-L-diaminobutyric acid- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-ct-Fmoc-N-γ- Alloc-L-diaminobutyric acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- 3-aminomethyl benzoic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S26 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-N-γ- Alloc-L-diaminobutyric acid- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-γ- Alloc-L-diaminobutyric acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- 4-aminomerhyl benzoic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S27 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-N-γ- Alloc-L-diaminobutyric acid- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-cx-Fmoc-N-γ- Alloc-L-diaminotπityric acid. The Fmoc group was cleaved by Method G19. Compound C, Me .od G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- β alanine was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S28 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-N-γ- Alloc-L-diaminobutyric acid- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-γ- Alloc-L-diaminobutyric acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- glycine was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S29 Compounds were synthesized usmg standard Fmoc solid phase methods on Fmoc- L- Lysme (alloc)- p- alkoxybenzyl alcohol resm (0 5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resm) The resm was made by Method G34 usmg commercially available N-α-Fmoc-N-ε-Alloc-L-lysme The Fmoc group was cleaved by Method G19 Compound C, Method G13, was coupled by Method G20 The Alloc group was removed by Method G35 Commercially available Fmoc- nipecotic acid was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S30 Compounds were synthesized usmg standard Fmoc solid phase methods on Fmoc- L- Lysme (alloc)- p- alkoxybenzyl alcohol resm (0 5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resm) The resm was made by Method G34 usmg commercially available N-α-Fmoc-N-ε-Alloc-L-lysme The Fmoc group was cleaved by Method G19 Compound C, Method G13, was coupled by Method G20 The Alloc group was removed by Method G35 Commercially available Fmoc- lsorupecotic acid was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S31 Compounds were synthesized usmg standard Fmoc solid phase methods on Fmoc- L- Lys e (alloc)- p- alkoxybenzyl alcohol resm (0 5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resm) The resm was made by Method G34 usmg commercially available N-α-Fmoc-N-ε-Alloc-L-lysme The Fmoc ^roup was cleaved by Method G19 Compound C, Method G13, was coupled bj Method G20 The Alloc group was removed by Method G35 Commercially available Fmoc- pipecolmic acid was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S32 Compounds were synthesized usmg standard Fmoc solid phase methods on Fmoc- L- Lysme (alloc)- p- alkoxybenzyl alcohol resm (05 mmol/g) (Fmoc- L- Lys(alloc)- Wang resm) The resm was made by Method G34 usmg commercially available N-α-Fmoc-N-ε-Alloc-L-lysme The Fmoc group was cleaved by Method G19 Compound C, Method G13, was coupled by Method G20 The Alloc group was removed by Method G35 Commercially available Fmoc- 3-aminomethyl benzoic acid was coupled by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxyhc acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S33 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Lysine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-ε-AUoc-L-lysine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- 4-aminomethyl benzoic acid was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S34 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Lysine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-ε-AUoc-L-lysine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- β alanine was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S35 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Lysine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-ε-Alloc-L-lysine. The ÷~moc group was cleaved by Method G19. Compound C, Method G13, was coupi^d by Method G20. The Alloc group was removed by Method G35. Commercially available Fmoc- glycine was coupled by Method G20. The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S36 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate chloroformate (R) was coupled by Method G74. The completed molecule was worked up by Method G21. Method S37 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- tryptophan(Boc)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Compound D, Method G14, was coupled by Method G20. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S38 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Compound D, Method G14, was coupled by Method G20. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S39 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- asparagine(Trt)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Compound D, Method G14, was coupled by Method G20. The Fmoc group was cleaved by Method G19. The appropriate carboxyhc acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S40 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- tryptoρhan(Boc)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. 4- amino 2- merhylbenzoic acid was coupled oy Method G20. The appropriate carboxylic acid (R) was silyl protected, Method G18, and the acid chloride generated by Method G92 and coupled in DCM over night to the amine. After washing the resin with DCM and THF, 3 equivalents of tetrabutylammonium fluoride in THF was added. After 20 minutes, the resin was washed with THF, H2O and dilute HOAc. The completed molecule was worked up by Method G21. Method S41 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- amino acid- Wang resins (0.5 mmol/g) (R). The Fmoc group was cleaved by Method G19. 4- amino 2- merhylbenzoic acid was coupled by Method G20. The 3- hydroxy phenylacetic acid was silyl protected, Method G18, and the acid chloride generated by Method G92 and coupled in DCM over night to the amine. After washing the resin with DCM and THF, 3 equivalents of TBAF in THF was added. After 20 minutes, the resin was washed with THF, H2O and dilute HOAc. The completed molecule was worked up by Method G21. Method S42 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 4- amino 2-chloro benzoic acid was coupled by Method G20. Fmoc- glycine was coupled to the aniline by Method G61. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S43 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 4- amino 2-chloro benzoic acid was coupled by Method G20. Fmoc- L- alanine was coupled to the aniline by Method G61. The Fmoc group was cleaved by Method G19. The appropriate carboxyhc acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S44 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 4- amino 2-chloro benzoic acid was coupled by Method G20. Fmoc- L- phenylglycine was coupled to the aniline by Method G61. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S45 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 4- amino 2-chloro benzoic acid was coupled by Method G20. Fmoc- L- glutamine was coupled to the aniline by Method G61. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S46 Compounds were synthesized using standard Tmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 4- amino 2-chloro benzoic acid was coupled by Method G20. 3- chloro benzaldehyde was converted to Fmoc- 3- chloro- phenylglycine by Method G62, and coupled to the aniline by Method G61. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S47 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- diaminopropionic acid(alloc)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Compound D, Method G14, was coupled by Method G20. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S48 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- Lysine(Boc)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Compound D, Method G14, was coupled by Method G20. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S49 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 4- amino 2-chloro benzoic acid was coupled by Method G20. 3- methoxy benzaldehyde was converted to Fmoc- 3- chloro- phenylglycine by Method G62, and coupled to the aniline by Method G61. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S50 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 4- amino 2-chloro benzoic acid was coupled by Method G20. Fmoc- meta tyrosine was coupled to the aniline by Method G61. The Fmoc group was cleaved by Method G19. The appropriate carboxylic acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21. Method S51 3-hydroxy aniline was coupled to coinmercially available Boc- d- serine by Method G3. The Boc group was removed by Method Gl and this amine was coupled to Compound A, Method G8. The t-butyl ester was removed by Method Gil and the acid coupled to the appropriate amino acid O-t-butyl ester (R) by Method G3. The final f-butyl ester was removed by Method Gil, and the completed molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S52 The Boc group on Compound F, Method G75, was removed by Method G2 and furylacrylic acid was coupled to the amine after free basing, Method G2, by Method G3. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to the appropriate deprotected commercially available Fmoc protected amino acid Wang resin (0.5 mmol/g) (R). The completed molecule was worked up by Method G21. Method S53 The methyl ester of Compound F, Method G75, was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available L- asparagine f-butyl ester. The Boc group was removed by Method Gl and the appropriate carboxylic acid (R) was coupled by Method G3. After removing the final t-butyl ester by Method Gil, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S54 The Boc group on Compound F, Method G75, was removed by Method 2G1 and furylacrylic acid was coupled to the amine after free basing, Method G2, by Method G3. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester The Boc group was removed by Method Gl and the appropriate carboxylic acid (R) was coupled by Method G3 After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder Method S55 The Boc group on Compound I, Method G75, was removed by Method Gl and 3- hydroxybenzoic acid was coupled to the amme after free basmg, Method G2, by Method G3 The methyl ester was removed by Method G55 and the resultmg acid coupled by Method G20 to commercially available L- tryptophan methyl ester After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder Method S56 The Boc group on Compound H, Method G75, was removed by Method Gl and 3- hydroxy benzoic acid was coupled to the amme after free basmg, Method G2, by Method G3 The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available ammo acid methyl ester (R) After saponification, Method G4, the molecule was purified by reverse phase HPLv_ verified by electrospray mass spectrometry and lyophilized to a powder Method S57 The Boc group on Compound H, Method G75, was removed by Method Gl and furylacrylic acid was coupled to the amme after free basmg, Method G2, by Method G3 The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to the appropriate commercially available ammo acid methyl ester (R) The Boc group was removed by Method Gl if needed and after saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder Method S58 The Boc group on Compound H, Method G75, was removed by Method Gl and 3-(2- thienyi)acryhc acid was coupled to the amine after free basmg, Method G2, by Method G3 The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to the appropriate commercially available ammo acid methyl ester (R) The Boc group was removed by Method Gl if needed and after saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder Method S59 The Boc group on Compound H, Method G75, was removed by Method 2G1 and furylacrylic acid was coupled to the amme after free basmg, Method G2, by Method G3 The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester The Boc group was removed by Method Gl and the appropriate carboxylic acid (R) was coupled by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder. Method S60 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Lysine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-ε-Alloc-L-lysine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate aldehyde (R) was coupled by Method G23. The completed molecule was worked up by Method G21. Method S61 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiopropionic acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Dapa(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-β- Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate aldehyde (R) was coupled by Method G23. The completed molecule was worked up by Method G21. Method S62 The appropriate amine (R) was coupled to Compound A, Method G8, by Method G3. The f- butyl ester was removed by Method Gil. The resulting acid was coupled by Method G3 to resin made by Method G34 using commercially available N-α-Fmoc-N-β-AUoc-L-diaminopropionic acid where the Fmoc group had been removed by Method G19. The completed molecule was worked up by Method G21. Method S63 The appropriate amine (R) was coupled to Compound A, Method G8, by Method G3. The f- butyl ester was removed by Method Gil. The resulting acid was coupled by Method G3 to commercially available Fmoc- L- asparagine(Trt)- Wang resin (0.5 mmol/g) where the Fmoc group had been removed by Method G19. The completed molecule was worked up by Method G21. Method S64 The Boc group on Compound F, Method G75, was removed by Method Gl and reduced furylacrylic acid, Method G81, was coupled to the amine after free basing, Method G2, by Method G3. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester. The Boc group was removed by Method Gl and thiophene 2- carboxylic acid was coupled by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S65 The Boc group on Compound F, Method G75, was removed by Method Gl. 2- acetylfuran was converted to the methyl acrylic acid ethyl ester by Method G82 and after saponification by Method G80 was coupled to the amine after free basing, Method G2, by Method G3. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester. The Boc group was removed by Method Gl and thiophene 2- carboxylic acid was coupled by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S66 The Boc group on Compound F, Method G75, was removed by Method Gl. After 2- acetylfuran was converted to the methyl acrylic acid ethyl ester by Method G82, saponified by Method G80 and reduced by Method G81, it was coupled to the amine after free basing, Method G2, by Method G3. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester. The Boc group was removed by Method Gl and thiophene 2- carboxyhc acid was coupled by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass s ectrometry and lyophilized to a powder. Method S67 The Boc group on Compound F, Method G75, was removed by Method Gl. Furylaldehyde was converted to the methyl acrylic acid ethyl ester by Method G83 and after saponification by Method G80 was coupled to the amine after free basing, Method G2, by Method G3. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester. The Boc group was removed by Method Gl and thiophene 2- carboxylic acid was coupled by Method G3. After saponification, Method G4 the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S68 The Boc group on Compound F, Method G75, was removed by Method Gl. After furylaldehyde was converted to the methyl acrylic acid ethyl ester by Method G83, saponified by Method G80 and reduced by Method G81, it was coupled to the amine after free basing, Method G2, by Method G3. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester. The Boc group was removed by Method Gl and thiophene 2- carboxyhc acid was coupled by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S69 Compounds were synthesized using standard Fmoc sohd phase methods on the appropriate commercially available Fmoc- L- amino acid- Wang resin (0.5 mmol/g) (R). The Fmoc group was cleaved by Method G19. The commercially available 2, 6 dimethyl terephthalic acid was coupled by Method G20. 3- hydroxy benzylamine, Method G38, was coupled by Method G20. The completed molecule was worked up by Method G21 and correct stereochemistry was assigned by activity. Method S70 Compounds were synthesized on resin made by Method G34 using commercially available N-a-Fmoc-N-b-Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. The commercially available 2, 6 dimethyl terephthalic acid was coupled by Method G20. 3- hydroxy benzylamine, Method G38, was coupled by Method G20. The Alloc group was removed by Method G35 and the appropriate carboxyhc acid (R) was coupled by Method G20. The completed molecule was worked up by Method G21 and correct stereochemistry was assigned by activity. Method S71 The Boc group on Compound F, Method G75, was removed by Method Gl and the appropriate carboxyhc acid (R) was coupled to the amine after free basing, Method G2, by Method G3. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester. The Boc group was removed by Method Gl and thiophene 2- carboxylic acid was coupled by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S72 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- tryptophan(Boc)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 2- bromo terephthalic acid was protected with an Fmoc group by Method G6 and the resulting product was coupled by Method G20. The appropriate amine (R) was coupled by Method G22. The completed molecule was worked up by Method G21. Method S73 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- alanine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 2- bromo terephthalic acid was protected with an Fmoc group by Method G6 and the resulting product was coupled by Method G20. The appropriate amine (R) was coupled by Method G22. The completed molecule was worked up by Method G21. Method S74 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiobutyric acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-γ-Alloc-L- diaminobutyric acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate commercially available sulfonyl chloride (R) was coupled by Method G42. The completed molecule was worked up by Method G21. Method S75 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-N- δ-Alloc-L-Ornithine- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-δ-Alloc-L- Ornithine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate commercially available sulfonyl chloride (R) was coupled by Method G42. The completed molecule was worked up by Method G21. Method S76 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Lysine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-ε-Alloc-L-lysine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate commercially available sulfonyl chloride (R) was coupled by Method G42. The completed molecule was worked up by Method G21. Method S77 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- diamiobutyric acid (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Daba(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-γ- Alloc-L- diaminobutyric acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate commercially available chloroformate (R) was coupled by Method G43. The completed molecule was worked up by Method G21. Method S78 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-N- δ-Alloc-L-Ornithine- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Orn(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-δ-Alloc-L- Ornitliine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate commercially available chloroformate (R) was coupled by Method G43. The completed molecule was worked up by Method G21. Method S79 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Lysine (alloc)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Lys(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-ε-Alloc-L-lysine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The Alloc group was removed by Method G35. The appropriate commercially available chloroformate (R) was coupled by Method G43. The completed molecule was worked up by Method G21. Method S80 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- asparagine(Trt)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 2- bromo terephthalic acid was protected with an Fmoc group by Method G6 and the resulting product was coupled by Method G20. The appropriate amine (R) was coupled by Method G22. The completed molecule was worked up by Method G21. Method S81 Compounds were synthesized on resin made by Method G34 using commercially available N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was cleaved by Method G19. Commercially available 2- bromo terephthalic acid was protected with an Fmoc group by Method G6 and the resulting product was coupled by Method G20. The appropriate amine (R) was coupled by Method G22. The completed molecule was worked up by Method G21. Method S82 Compounds were synthesized using standard Fmoc solid phase methods on the appropriate commercially available Fmoc- amino acid p- alkoxybenzyl alcohol resin (R) (Wang resin) (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The completed molecule was worked up by Method G21. Method S83 Compounds were synthesized using standard Fmoc solid phase methods on the appropriate commercially available Fmoc- amino acid p- alkoxybenzyl alcohol resin (P) (Wang resin) (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Compound B, Method G12, was coupled by Method G20. The completed molecule was worked up by Method G21. Method S84 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- tryptophan(Boc)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. Commercially available 4-amino 2-chlorobenzoic acid was coupled by Method G20. The resin was treated with an excess of 0.5M 4- nitrophenyl chloroformate and 0.5M DIPEA for 45 mmutes. After twice washing the resin with THF/ DCM, an excess of the appropriate amine (R) in 0.5M DIPEA/ DMF was added and the resin bubbled for 20 minutes. The completed molecule was worked up by Method G21. Method S85 The appropriate amino acid (R) was converted to its methyl ester by Method G15. After free basing the amine by Method G2, Compound C, Method G13, was coupled to the amino acid methyl ester by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder. Method S86 3-hydroxyacetophenone was converted to the oxime by Method G70 and then hydrogenated by Method G38 to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After removal of the f-butyl ester by Method GH, the acid was coupled to commercially available L-asparagine f-butyl ester by Method G24. The final f-butyl ester was removed by Method Gil and the completed molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S87 3-hydroxyacetophenone was converted to the oxime by Method G70 and then hydrogenated by Method G38 to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After removal of the f-butyl ester by Method Gil, the acid was coupled to commercially available L-tryptophan methyl ester by Method G24. The final methyl ester was removed by Method G4 and the completed molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S88 3-hydroxybenzaldehyde and ethyl magnesium bromide were converted lo the ketone by Method G71. The ketone was then converted to the oxime by Method G70 and then hydrogenated by Method G38 to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After removal of the f-butyl ester by Method Gil, the acid was coupled to commercially available L-asparagine f-butyl ester by Method G24. The final f-butyl ester was removed by Method Gil and the completed molecule was purified by reverse phase HFLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S89 3-hydroxybenzaldehyde and ethyl magnesium bromide were converted to the ketone by Method G71. The ketone was then converted to the oxime by Method G70 and then hydrogenated by Method G38 to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After removal of the f-butyl ester by Method Gil, the acid was coupled to commercially available L-tryptophan methyl ester by Method G24. The final methyl ester was removed by Method G4 and the completed molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S90 3-hydroxybenzaldehyde and N-propyl magnesium bromide were converted to the ketone by Method G71. The ketone was then converted to the oxime by Method G70 and then hydrogenated by Method G38 to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After removal of the f-butyl ester by Method Gil, the acid was coupled to commercially available L-asparagine f-butyl ester by Method G24. The final f-butyl ester was removed by Method Gil and the completed molecule was purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder Method S91 3-hydroxybenzaldehyde and N-propyl magnesium bromide were converted to the ketone by Method G71 The ketone was then converted to the oxime by Method G70 and then hydrogenated by Method G38 to give the amme This amme was then coupled to Compound A, Method G8, by Method G24 After removal of the f-butyl ester by Method GH, the acid was coupled to commercially available L-tryptophan methyl ester by Method G24 The fmal methyl ester was removed by Method G4 and the completed molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder Method S92 The appropriate sulfonamide was synthesized by Method G93 usmg ammonia as the amme (R) and this product converted to the methyl ester by Method G15 Compound C, Method G13, was coupled to the sulfonamide methyl ester by Method G3 The fmale methyl ester was removed by Method G4 The completed molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder Method S93 Compounds were synthesized on commercially available Fmoc- L- asparagrne(Trt)- Wang resm (05 mmol/g) The Fmoc group was removed by Method G19 The product of Method G65, with the exception that it was not resolved by Method G67, was Fmoc protected by Method G5 and the f-butyl ester removed by Method Gil This product was coupled to the resm by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled % ->v Method G20 The completed molecule was worked up by Method G21 Method S94 Compounds were synthesized on commercially available Fmoc- L- asparagrne(Trt)- Wang resm (0 5 mmol/g) The Fmoc group was removed by Method G19 The Method S isomer of Method G65 was Fmoc protected by Method G5 and the f-butyl ester removed by Method Gil This product was coupled to the resm by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S95 Compounds were synthesized on commercially available Fmoc- L- alanme- Wang resm (0 5 mmol/g) The Fmoc group was removed by Method G19 The S isomer of Method G65 was Fmoc protected by Method G5 and the f-butyl ester removed by Method Gil This product was coupled to the resm by Method G20 The Fmoc group was removed by Method G19 and the appropriate carboxylic acid (R) was coupled by Method G20 The completed molecule was worked up by Method G21 Method S96 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- tryptophan(Boc)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. The appropriate commercially available di- acid (R) coupled by Method G20. 3- hydroxy benzylamine, Method G38, was coupled by Method G20. The completed molecule was worked up by Method G21 and correct stereochemistry was assigned by activity. Method S97 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- L- asparagine(Trt)- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. The appropriate commercially available di- acid (R) coupled by Method G20. 3- hydroxy benzylamine, Method G38, was coupled by Method G20. The completed molecule was worked up by Method G21 and correct stereochemistry was assigned by activity. Method S98 The product of Method G86 was coupled by Method G20 to the appropriate commercially available Fmoc- amino acid Wang resin (R) after removing the Fmoc group by Method G19. The completed molecule was worked up by Method G21 and correct stereochemistry was assigned by activity. Method S99 3- hydroxymandelic acid was converted to its corresponding alcohol by Method G25 and coupled to the methyl ester of 4- hydroxy 2- chlorobenzoic acid, Method G15, by Method G26. The methyl ester removed by Method G4 and the carboxylic acid was coupled to L- asparagine f- butyl ester by Method G3. The final f- butyl ester was removed by Method Gil and the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S100 3- hydroxymandelic acid was converted to its corresponding alcohol by Method G25 and coupled to the methyl ester of 4- hydroxy 2- chlorobenzoic acid, Method G15, by Method G26. The methyl ester removed by Method G4 and the carboxylic acid was coupled to L- alanine f- butyl ester by Method G3. The final f- butyl ester was removed by Method Gil and the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S101 The methyl ester of 3-(3-hydroxyphenyl) propionic acid was made by Method G15 and converted to the aldehyde by Method G29. The oxazoline of 4- bromo 2-chloro benzoic acid was made by Method G30. The aldehyde was coupled to the bromide by Method G31 and the oxazoline converted to the ethyl ester by Method G32. After saponification by Method G4, the carboxylic acid was coupled to L- alanine methyl ester by Method G3. After saponification by Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S102 The methyl ester of 3-(3-hydroxyphenyl) propionic acid was made- by Method G15 and converted to the aldehyde by Method G29. The oxazoline of 4- bromo 2-chloro benzoic acid was made by Method G30. The aldehyde was coupled to the bromide by Method G31 and the oxazoline converted to the ethyl ester by Method G32. The allylic alcohol was oxidized to the ketone by Method G27 and the ethyl ester was saponified by Method G4. The carboxylic acid was coupled to L- alanine methyl ester by Method G3; and after saponification by Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S103 The methyl ester of 4-hydroxy-2-chloro-benzoic acid was formed by Method G15. 1, 2- dibromoethane was coupled to the phenol by Method G51. The appropriate hydroxy phenol (R) was coupled by Method G52 and the methyl ester removed by Method G4. L- alanine- O-f-butyl ester was coupled be Method G3. The f-butyl ester was removed by Method Gil and the completed compound was purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder. Method S104 4-amino-2, 6-dichlorophenol was Boc protected by Meuirjd G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the phenol by Method G47 and then the methyl ester removed by Method G48. The resulting carboxylic acid was then converted to its allyl ester by Method G49 (Compound G). 3- hydroxymandelic acid was converted to its corresponding alcohol by Method G25 and coupled to the phenol (Compound G) by Method G26. And the allyl ester removed by Method G50. The resulting benzoic acid was coupled to commercially available L- asparagine-O-f-butyl ester by Method G3. The f-butyl ester was removed by Method Gil without TES. The completed molecule was then concentrated in v cuo, purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder. Method S105 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the phenol by Method G47 and then the methyl ester removed by Method G48. The resulting carboxylic acid was then converted to its allyl ester by Method G49 (Compound G). 1, 3-dibromopropane was coupled to the phenol (Compound G) by Method G51. The 3-hydroxy phenol was coupled by Method G52 and the methyl ester removed by Method G4. The allyl ester removed by Method G50. The resulting benzoic acid was coupled to commercially available L-asparagine-O-f-butyl ester by Method G3. The f-butyl ester was removed by Method Gil without TES. The completed molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder. Method S106 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the phenol by Method G47 and then the methyl ester removed by Method G48. The resulting carboxylic acid was then converted to its allyl ester by Method G49 (Compound G). 1, 2-dibromopropane was coupled to the phenol (Compound G) by Method G51. The 3-hydroxy phenol was coupled by Method G52 and the methyl ester removed by Method G4. The allyl ester removed by Method G50. The resulting benzoic acid was coupled to commercially available L-asparagine-O-f-butyl ester by Method G3. The f-butyl ester was removed by Method Gil without TES. The completed molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S107 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the phenol by Method G47 and then the methyl ester removed by Method G48. The resulting carboxylic acid was then converted to its allyl ester by Method G49 (Compound G). 1, 2-dibromopropane was coupled to the phenol (Compound G) by Method G51. The 3-hydroxy phenol was coupled by Method G52 and the methyl ester removed by Method G4. The allyl ester removed by Method G50. The resulting benzoic acid was coupled to commercially available L-alanine-O-f-butyl εster by Method G3. The f-butyl ester was removed by Method Gil without TES. The completed molecule was then concentiated in vacuo, purified by reverse phase HPLC, verified by electiospray mass spectaOmetry and lyophilized to a powder. Method S108 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54 and then the methyl ester removed by Method G55. This benzoic acid was then coupled to L-asparagine-O-f- butyl ester by Method G3. 3-hydroxy benzoic acid was converted to the hydroxamate by Method G56. The hydroxyl was protected as the f-butyl ether by Method G10 and the hydroxamate converted to the aldehyde by Method G57. The aldehyde was coupled to ethynyl magnesium bromide by Method G58 and the resulting product coupled to the above aryl iodide by Method G59. The alkyne was then reduced to the alkane by Method G60. The f-butyl ester and ether were removed by Method Gil without TES. The completed molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder. Method S109 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54 and then the methyl ester removed by Method G55. This benzoic acid was then coupled to L-asparagine-O-f- butyl ester by Method G3. 3-hydroxybenzoic acid was converted to the hydroxamate by Method G56. The hydroxyl was protected as the f-butyl ether by Method G10 and the hydroxamate converted to the aldehyde by Method G57. The aldehyde was coupled to ethynyl magnesium bromide by Method G58 and the resulting product coupled to the above aryl iodide by Method G59. The alkyne was then reduced to the alkane by Method G60. The f-butyl ester and ether were removed by Method Gil. The completed molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S110 3, 5-dimethyl-4-hydroxybenzaldehyde was coupled to ethynyl magnesium bromide by Method G58 and this product was coupled to 3-iodoanisole by Method G59. The alkynol was hydrogenated to the alkane by Method C?>8 except the product was purified by silica flash chromatography (3/6/1 hexane/ DCM/ Et∑O) to provide pure aryl alcohol. The alcohol was silyl protected by Method G18. The phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxyhc acid methyl ester by Method G46. The methyl ether and ester were removed by Method G55. The acid was coupled to L-asparagine-O-f-butyl ester by Method G3. The f-butyl ester was removed by Method Cl 1 without TES and the silyl ether was removed in the same reaction by adding 3 equivalents of TBAF. The completed molecule was then concentiated in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method Sill 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54 and then the methyl ester removed by Method G55. This benzoic acid was then coupled to L-asparagine-O-f- butyl ester by Method G3. 3'-Hydroxyacetophenone was converted to the f-butyl ether using Method G10. G58 resulting alkyne coupled to the aryl iodide using Method G59. The alkyne was hydrogenated to the alkane using Method G60. Reductive removal of the benzylic alcohol, as well as cleavage of the f-butyl ether and ester groups was accomplished using Method Gil (containing excess TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S112 2, 6-Dichloro-4-methyl phenol was converted to the triflate according to Method G45. This triflate was carbonylated to the methyl ester using Method G46 and then converted to the aldehyde by Method G84. The aldehyde was treated with ethynyl magnesium bromide by Method G58 and the resulting alkyne coupled to 3-iodoρhenol using Method G59. The alkyne was hydrogenated to the alkane using Method G60 and the methyl ester was cleaved using Method G55. The resulting carboxylic acid was coupled to L-asparagine-O-f-butyl ester using Method G3. Cleavage of the f- butyl ester group was accomplished using Method Gil (containing no TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S113 2, 6-Dichloro-4-methyl phenol was converted to the triflate according to Method G45. This triflate was carbonylated to the methyl ester using Method G46 and then converted to the aldehyde by Method G84. 3-Iodophenol was silylated according to Method G18 to give O-f-butyl- dimethylsilyl-3-iodophenol. The aldehyde was treated with ethynyl magnesium bromide by Method G58 and the resulting alkyne coupled to O-f-butyl-dimethylsilyl-3-iodoρhenol using Method G59. The alkyne was hydrogenated to the alkane using Method G60. The resulting alcohol was converted to the methyl ether by Method G85 and the methyl ester was cleaved using Method G55. The resulting carboxyhc acid was coupled to L- asparagine O-f-butyl ester using Method G3. The f-butyl ester was removed by Method Gil without TES and the silyl ether was removed in the same reaction by adding 3 equivalents of TBAF. The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S114 2, 6-Dichloro-4-methyl phenol was converted to the triflate according to Method G45. This triflate was carbonylated to the methyl ester using Method G46 and then converted to the aldehyde by Method G84. 3-Iodophenol was silylated according to Method G18 to give O-f-butyl- dimethylsilyl-3-iodophenol. The aldehyde was treated with ethynyl magnesium bromide by Method G58 and the resultmg alkyne coupled to O-f-butyl-dimethylsilyl-3-iodophenol using Method G59. The alkyne was hydrogenated to the alkane using Method G60 and the methyl ester was cleaved using Method G55. The resulting carboxylic acid was coupled to N-β-alloc-L-α, β- diaminopropionic acid methyl ester using Method G3 (adding an equivalent of DIPEA). The silyl ether was removed by Method Gil without TES with the addition of 3 equivalents of TBAF. The methyl ester was saponified using Method G4. The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder. Method S115 2, 6-Dichloro-4-methyl phenol was converted to the triflate according to Method G45. This triflate was carbonylated to the methyl ester using Method G46 and then converted to the aldehyde by Method G84. 3-Iodophenol was silylated according to Method G18 to give O-f-butyl- dimethylsilyl-3-iodophenol. The aldehyde was treated with ethynyl magnesium bromide by Method G58 and the resulting alkyne coupled to O-f-butyl-dimethylsilyl-3-iodophenol using Method G59. The alkyne was hydrogenated to the alkane using Method G60 and the methyl ester was cleaved using Method G55. The resulting carboxylic acid was coupled to N-ε-Boc-L-lysine methyl ester using Method G3 (adding an equivalent of DIPEA). The methyl ester was saponified using Method G4 and the Boc group was removed by Method Gil without TES and the silyl ether was removed in the same reaction by adding 3 equivalents of TBAF The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S116 3-Hydroxy benzoic acid was converted to the N-methoxy-N-methylamide using Method G56. The hydroxyl was protected as the f-butyl ether by Method G10. The N-methoxy-N- methylamide was reduced to the aldehyde by Method G57. The aldehyde was treated with ethynyl magnesium bromide by Melhod G58. 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54. The resulting aryl iodide was then coupled to the above alkyne by Method G59. The alkyne was hydrogenated to the alkane using Method G60. The methyl ester was cleaved using Method G55. The carbov/lic acid was coupled to N-β-alloc-L-α, β-diaminopropionic acid methyl ester using Method G3 (adding an equivalent of DIPEA). The methyl ester was saponified using Method G4. The f-butyl ether was cleaved by using Method Gil (containing no TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S117 3-Hydroxybenzoic acid was converted to the N-methoxy-N-methylamide using Method G56. The hydroxyl was protected as the f-butyl ether by Method G10. The N-methoxy-N- methylamide was reduced to the aldehyde by Method G57. The aldehyde was treated with ethynyl magnesium bromide by Method G58. 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54. The resulting aryl iodide was then coupled to the above alkyne by Method G59. The alkyne was hydrogenated to the alkane usmg Method G60. The resulting alcohol was converted to the methyl ether by Method G85 and the methyl ester was cleaved using Method G55. The resulting carboxylic acid was coupled to L- asparagine-O-f-butyl ester using Method G3. Ill Cleavage of the f-butyl ester group was accomplished using Method Gil (containing no TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S118 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54. 3- Chlorobenzaldehyde was treated with ethynyl magnesium bromide by Method G58, and the resulting alkyne coupled to the above aryl iodide by Method G59. The alkyne was hydrogenated to the alkane using Method G60. The methyl ester was cleaved using Method G55. The carboxylic acid was coupled to N-β-alloc-L-α, β-diaminopropionic acid methyl ester using Method G3 (adding an equivalent of DIPEA). The methyl ester was saponified using Method G4. The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electiospray mass spectrometry and lyophilized to a powder. Method S119 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The tiiflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54. 3- Chlorobenzaldehyde was treated with ethynyl magnesium bromide by Method G58, and the resulting alkyne coupled to the above aryl iodide by Method G59. The alkyne was hydrogenated to the alkane using Method G60. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diamrnopropionic acid methyl ester. The Boc group was removed by Method Gl and thiophene 2- carboxyhc acid was coupled by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S120 3-Hydroxybenzoic acid was converted to the N-methoxy-N-methylamide using Method G56. The hydroxyl was protected as the f-butyl ether by Method G10. The N-methoxy-N- methylamide was reduced to the aldehyde by Method G57. The aldehyde was treated with ethynyl magnesium bromide by Method G58. 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The triflate was converted to a carboxylic acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54. The resulting aryl iodide was then coupled to the above alkyne by Method G59. The alkyne was hydrogenated to the alkane using Method G60. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available β- Boc- diaminopropionic acid methyl ester. The Boc group was removed by Method Gl and thiophene 2- carboxylic acid was coupled by Method G3. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S121 4-amino-2, 6-dichlorophenol was Boc protected by Method G44 and the phenol converted to its corresponding triflate by Method G45. The tiiflate was converted to a carboxyhc acid methyl ester by Method G46. The Boc aniline was converted to the iodide by Method G54. 3- Chlorobenzaldehyde was treated with ethynyl magnesium bromide by Method G58, and the resulting alkyne coupled to the above aryl iodide by Method G59. The alkyne was hydrogenated to the alkane using Method G60. The methyl ester was removed by Method G55 and the resulting acid coupled by Method G20 to commercially available N-ε-Boc-L-lysine methyl ester using Method G3 (adding an equivalent of DIPEA). The methyl ester was saponified using Method G4 and the Boc group was removed by Method Gil (containing no TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder. Method S122 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc- glycine- Wang resin (0.5 mmol/g). The Fmoc group was cleaved by Method G19. The α glycme α carbon was alkylated with the appropriate commercially available biomide or chloride by Method G36 resulting in the corresponding racemic amino acid. Compound E was coupled to the resin by Method G37 and the completed molecule was worked up by Method G21. Method S123 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- Aspartic acid ( 'lyl)- p- alkoxybenzyl alcohol resin (0.5 mmol/g). The resin was made by Mc iliod G34 using commercially available N-α-Fmoc-β-Allyl-L-aspartic acid. The Fmoc group was cleaved by Method G19. Compound E was coupled to the resin by Method G37. The Allyl group was removed by Method G39. The appropriate aniline (R) was coupled by Method G40. The completed molecule was worked up by Method G21. Method S124 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- aspartic acid (allyl)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- asp(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-β-Allyl-L-aspartic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The allyl group was removed by Method G39. The appropriate amine (R) was coupled by Method G41. The completed molecule was worked up by Method G21. Method S125 Compounds were synthesized using standard Fmoc solid phase methods on Fmoc- L- glutamic acid (allyl)- p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- glu(alloc)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-β-Allyl-L-glutamic acid. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The allyl group was removed by Method G39. The appropriate amine (R) was coupled by Method G41. The completed molecule was worked up by Method G21. Method S126 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-O- trityl-L-serine-p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- Ser(trityl)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-O-tiityl-L-serine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The tiityl group was removed by Method G72. The appropriate amine (R) was coupled by Method G73. The completed molecule was worked up by Method G21. Method S127 Compounds were synthesized using standard Fmoc solid phase methods on N-α-Fmoc-O- trityl-L-threonine-p- alkoxybenzyl alcohol resin (0.5 mmol/g) (Fmoc- L- thr(tiityl)- Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-O-tiityl-L-serine. The Fmoc group was cleaved by Method G19. Compound C, Method G13, was coupled by Method G20. The tiityl group was removed by Method G72. The appropriate amine (R) was coupled by Method G73. The completed molecule was worked up by Method G21. Examples 1-39 Examples 1-39 were synthesized by Method SI. Example # R group 1 2-isopropylphenyl isocyanate 2 phenethyl isocyanate 3 1-napthyl isocyanate 4 (S)-(-)-a-methylbenzyl isocyanate 5 cyclohexyl isocyanate 6 ethoxycarbonyl isocyanate 7 isopropyl isocyanate 8 rrans-2-phenylcyclopropyl isocyanate 9 1-adamantyl isocyanate 10 phenyl isocyante 11 4-(methylthio)phenyl isocyanate 12 3-(methylthio) phenyl isocyanate 13 3-ethoxycarbonylphenyl isocyanate 14 4-ethoxycarbonylphenyl isocyanate 15 4-fluorophenyl isocyanate 16 2-fluorophenyl isocyanate 17 2-(trifluoromethoxy)phenyl isocyanate 18 3-fluorophenyl isocyanate 19 3-bromophenyl isocyanate 20 4-methoxyphenyl isocyanate 21 4-isopropyIphenyl isocyanate 22 3-(2-hydroxy)ethyl phenyl isocyanate 23 4-ethylphenyl isocyanate 24 2-nitioρhenyl isocyanate 25 3-nitrophenyl isocyanate 26 4-nitroρhenyl isocyanate 27 3-cyanophenyl isocyanate 28 4-trifluoromethyl isocyanate 29 3-trifluoromethyl isocyanate 30 2-trifluoromethyl isocyanate 31 3-methylphenyl isocyanate 32 4-chlorophenyl isocyanate 33 3-chlorophenyl isocyanate 34 3-chloro-4-methylphenyl isocyanate 35 3-ethylphenyl isocyanate 36 allyl isocyanate 37 (S)-(-)-a-methylbenzyl isocyanate 38 cyclohexyl isocyanate 39 trans-2-phenylcyclopropyl isocyanate Examples 40-43 Examples 40-43 were synthesized by Method S2 Example # R group 40 benzyl isocyanate 41 ethoxycarbonyl isocyanate 42 2-chloro-6-methylphenyl isocyanate 43 ethoxycarbonyl isocyanate Examples 44-62 Examples 44-62 were synthesized by Method S3 Example # R group 44 phenethyl isocyanate 45 isopropyl isocyanate 46 cyclohexyl isocyanate 47 3-ethoxycarbonylphenyl isocyanate 48 4-ethoxycarbonylphenyl isocyanate 49 4-fluorophenyl isocyanate 50 2-fluorophenyl isocyanate 51 3-fluorophenyl isocyanate 52 4-methoxyphenyl isocyanate 53 4-ιsopropylphenyl isocyanate 54 3-(2-hydroxyethyl)phenyl isocyanate 55 2-nιtiophenyl isocyanate 56 4-mtiophenyl isocyanate 57 3-cyanophenyl isocyanate 58 3-methylphenyl isocyanate 59 4-chlorophenyl isocyanate 60 3-chloro-4-methylphenyl isocyanate 61 2-chloro-6-methylphenyl isocyanate 62 4-ethylphenyl isocyanate Examples 63-71 Examples 63-71 were synthesized by Method S4. Example # R group 63 phenethyl isocyanate 64 isopropyl isocyanate 65 benzyl isocyanate 66 propyl isocyanate 67 ethoxycarbonyl isocyanate 68 ethyl 2-isocyanato-4-methylv -i ierate 69 (S)-(-)-a-methylbenzyl isocyanate 70 benzensulf onyl isocyanate 71 benzyl isocyanate Examples 72-95 Examples 72-95 were synthesized by Method S5. Example # R group 72 3-methylindene-2-carboxylic acid 73 3-methylbenzofuran-2-carboxylic acid 74 4-Oxo-4, 5, 6, 7-terrahydro-benzofuran-3-carboxylic acid 75 1, 2, 5-Trimethyl-lH-pyrrole-3-carboxylic acid 76 4-Methyl-[l, 2, 3]thiadiazole-5-carboxylic acid 77 4-Phenyl-[l, 2, 3]thιadιazole-5-carboxyhc acid 78 3-chloro-2thιophenecarboxyhc acid 79 3, 5-Dιmethyl-ιsoxazole-4-carboxyhc acid 80 3-methyl-2-furoιc acid 81 3-bromothιophene-2-carboxyhc acid 82 2-furoιc acid 83 3-furoιc acid 84 2-thιophene carboxylic acid 85 3- thiophenecarboxyhc acid 86 5- chloro 2- thiophene carboxyhc acid 87 5- bromo 2- thiophene carboxyhc acid 88 mdole 5- carboxylic acid 89 mdole 4- carboxyhc acid 90 mdole 6- carboxylic acid 91 benzoic acid 92 cyclohexyl carboxyhc acid 93 acetic acid 94 isonipecohc acid 95 pipecolmic acid Examples 96-113 Examples 96-113 were synthesized by Method S6 Example # R group 96 3, 4, 5-trimethoxybenzoic acid 97 propionic acid 98 cyclopropyl carboxyhc acid 99 tiimerhyl acetic acid 100 1, 2, 5-Trιmethyl-lH-pyrrole-3-carboxyhc acid 101 3-Chloro-4-methanesulfonyl-thiophene-2-carboxyhc acid 102 4-Methyl-[l, 2, 3]thιadιazole-5-carboxylιc acid 103 4-Phenyl-[l, 2, 3]thιadιazole-5-carboxyhc acid 104 4-Bromo-2-ethyI-5-methyl-2H-pyrazoIe-3-carboxylic acid 105 3-chlorothiophene-2-carboxylic acid 106 3, 5-Dimethyl-isoxazole-4-carboxylic acid 107 5-Methyl-2-phenyl-2H-[l, 2, 3]tiiazole-4-carboxylic acid 108 3-methyl-2-furoic acid 109 3-bromothiophene-2-carboxylic acid 110 benzoic acid 111 cyclohexyl carboxylic acid 112 acetic acid 113 none Examples 114-126 Examples 114-126 were synthesized by Method S7. Example # R group 114 trimethyl acetic acid 115 3-Chloro-benzo[b thiophene-2-carboxylic acid 116 3-chlorothiophene-2-carboxy lie acid 117 3, 5-Dimethyl-isoxazole-4-carboxylic acid 118 3-bromothiophene-2-carboxy lie acid 119 3-methylindene-2-carboxylic acid 120 4-Oxo-4, 5, 6, 7-tetrahydro-benzofuran-3-carboxyhc acid 121 3-Chloro-4-methanesulfonyl-thiophene-2-carboxylic acid 122 4-Methyl-[l, 2, 3]thiadiazole-5-carboxylic acid 123 4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxy lie acid 124 benzoic acid 125 cyclohexane carboxyhc acid 126 acetic acid Examples 127-144 Examples 127-144 were synthesized by Method S8. Example # R group 127 3, 4, 5-trimethoxybenzoic acid 128 isovaleric acid 129 propionic acid 130 cyclopropyl carboxylic acid 131 4-acetyl-3, 5-dimethyl-2-pyrrolecarboxylic acid 132 3-meth ϋndene-2-carboxylic acid 133 4-Oxo-4, 5, 6, 7-tetrahydro-benzofuran-3-carboxyhc acid 134 1, 2, 5-Trimethyl-lH-pyrrole-3-carboxylic acid 135 3-Chloro-4-methanesulfonyl-thiophene-2-carboxyhc acid 136 4-Methyl-[l, 2, 3]thiadiazole-5-carboxylic acid 137 4-Phenyl-[l, ?.. 3]thiadiazole-5-carboxylic acid 138 4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid 139 3-chlororhiophene-2-carboxylic acid 140 3, 5-Dimethyl-isoxazole-4-carboxylic acid 141 5-Methyl-2-phenyl-2H-[l, 2, 3]tiiazole-4-carboxylic acid 142 3-bromothiophene-2-carboxylic acid 143 benzoic acid 144 cyclohexyl carboxylic acid Examples 145-147 Examples 145-147 were synthesized by Method S9. Example # R group 145 propionic acid 146 acetic acid 147 none Examples 148-150 Examples 148-150 were synthesized by Method S10. Example # R group 148 propionic acid 149 butyric acid 150 acetic acid Examples 151-154 Examples 151-154 were synthesized by Method Sll. Example # R group 151 propionic acid 152 butyric acid 153 acetic acid 154 none Examples 155-158 Examples 155-158 were synthesized by Method S12. Example # R group 155 propionic acid 156 butyric acid 157 acetic acid 158 none Examples 159-161 Examples 159-161 were synthesized by Method S13. Example # R group 159 propionic acid 160 acetic acid 161 none Examples 162-163 Examples 162-163 were synthesized by Method S14. Example # R group 162 acetic acid 163 none Examples 164-167 Examples 164-167 were synthesized by Method S15. Example # R group 164 propionic acid 165 butyric acid 166 acetic acid 167 none Examples 168-171 Examples 168-171 were synthesized by Method S16 Example # R group 168 propionic acid 169 butyric acid 170 acetic acid 171 none Example 172 Example 172 was synthesized by Method S17 Examples 173-176 Examples 173-176 were synthesized by Method S18 Example # R group 173 propionic acid 174 butyric acid 175 acetic acid 176 none Examples 177-180 Examples 177-180 were synthesized by Method S19 Example # R group 177 propionic acid 178 butyric acid 179 acetic acid 180 none Examples 181-184 Examples 181-184 were synthesized by Method S20. Example # R group 181 propionic acid 182 butyric acid 183 acetic acid 184 none Examples 185-188 Examples 185-188 were synthesized by Method S21. Example # R group 185 propionic acid 186 butyric acid 187 acetic acid 188 none Examples 189-192 Examples 189-192 were synthesized by Method S22. Example # R group 189 propionic acid 190 butyric acid 191 acetic acid 192 none Examples 193-196 Examples 193-196 were synthesized by Method S23. Example # R group 193 propionic acid 194 butyric acid 195 acetic acid 196 none Example 197 Example 197 was synthesized by Method S24. Examples 198-201 Examples 198-201 were synthesized by Method S25. Example # R group 198 propionic acid 199 butyric acid 200 acetic acid 201 none Examples 202-205 Examples 202-205 were synthesized by Method S26. Example # R group 202 propionic acid 203 butyric acid 204 acetic acid 205 none Examples 206-209 Examples 206-209 were synthesized by Method S27. Example # R group 206 propionic acid 207 butyric acid 208 acetic acid 209 none Examples 210-213 Examples 210-213 were synthesized by Method S28. Example # R group 210 propionic acid 211 butyric acid 212 acetic acid 213 none Examples 214-217 Examples 214-217 were synthesized by Method S29 Example # R group 214 propionic acid 215 butyric acid 216 acetic acid 217 none Examples 218-221 Examples 218-221 were synthesized by Method S30 Example # R group 218 propionic acid 219 butyric acid 220 acetic acid 221 none Examples 222-223 Examples 222-223 were synthesized by Method S31. Example # R group 222 acetic acid 223 none Examples 224-225 Examples 224-225 were synthesized by Method S32. Example # R group 224 propionic acid 225 none Examples 226-227 Examples 226-227 were synthesized bv Method S33 Example # R group 226 acetic acid 227 none Examples 228-229 Examples 228-229 were synthesized by Method S34 Example # R group 228 acetic acid 229 none Example 230 Example 230 was synthesized by Method S35 Examples 231-237 Examples 231- 237 were synthesized by Method S36. Example # R group 231 propyl chloroformate 232 benzyl chloroformate 233 isopropyl chloroformate 234 methyl chloroformate 235 ethyl chloroformate 236 butyl chloroformate 237 3- butenyl chloroformate Examples 238-240 Examples 238 ■240 were synthesized by Method S37. Example # R group 238 3- hydroxy benzoic acid 239 2- hydroxy cinnamic acid 240 3- hydroxy benzoic acid Examples 241-245 Examples 241- 245 were synthesized by Method S38. Example # R group 241 3- hydroxy benzoic acid 242 2- hydroxy cinnamic acid 243 3- chloro benzoic acid 244 indole 5- carboxylic acid 245 3- (2- thienyl)acrylic acid Examples 246-253 Examples 246-253 were synthesized by Method S39. Example # R group 246 3- chlorobenzoic acid 247 3 - (2 - thienyl)acrylic acid 248 2 - furanacrylic acid 249 3- hydroxy benzoic acid 250 indole 5-carboxylic acid 251 benzofuran 5-carboxylic acid 252 benzofuran 4-carboxylic ;«cid 253 indole 6-carboxylic acid Examples 254 Examples 254 were synthesized by Method S40. Examples 255-256 Examples 255-256 were synthesized by Method S41. Example # R group 255 L - Ala 256 L - Thr Example 257 Example 257 was synthesized by Method S42 Examples 258-259 Examples 258-259 were synthesized by Method S43 Example # R group 258 2-thιophene carboxyhc acid 259 3-hydroxybenzoιc acid Examples 260-261 Examples 260-261 were synthesized by Method S44 Example # R group 260 3-hydroxybenzoιc acid 261 2-thιophene carboxyhc acid Examples 262-263 Examples 262-263 were synthesized by Method S45 Example # R group 262 benzoic acid 263 2-thiophene carboxylic acid Examples 264-265 Examples 264-265 were synthesized by Method S46. Example # R group 264 3-hydroxybenzoic acid 265 2-thiophene carboxylic acid Examples 266-267 Examples 266-267 were synthesized by Method S47. Example # R group 266 3-(2-thienyl)-acrylic acid 267 furylacrylic acid Example 268 Example 268 was synthesized by Method S48. Example 269 Example 269 was synthesized by Method S49. Examples 270-271 Examples 270-271 were synthesized by Method S50. Example # R group 270 3- hydroxybenzoic acid 271 2- thiophene carboxylic acid Example 272 Example 272 was synthesized by Method S51. Examples 273-275 Examples 273-275 were synthesized by Method S52. Example # R group 273 L- Ala 274 L- Asn 275 L- diamrnopropionic acid (alloc) Example 276 Example 276 was synthesized by Method S53 Examples 277-282 Examples 277-282 were synthesized by Method S54 Example # R group 277 thiophene 2- carboxyhc acid 278 2- furoic acid 279 2- pyrazmecarboxyhc acid 280 3- methyl thiophene 2- carboxylic acid 281 3- methyl 2- furoic acid 282 3- chloro thiophene 2- carboxyhc acid Example 283 Example 283 was synthesized by Method S55 Examples 284-285 Examples 284-285 were synthesized by Method S56. Example # R group 284 L- Ala 285 L- Asn Examples 286-287 Examples 286-287 were synthesized by Method S57. Example # R group 286 L- diamrnopropionic acid (alloc) 287 L- Lys Examples 288-289 Examples 288-289 were synthesized by Method S58. Example # R group 288 L- diamrnopropionic acid (alloc) 289 L- Lys Example 290 Example 290 was synthesized by Method S59 Examples 291-292 Examples 291-292 were synthesized by Method S60 Example # R group 291 2- furaldehyde 292 3- methyl 2- furaldehyde Examples 293-294 Examples 293-294 were synthesized by Method S61 Example # R group 293 2- furaldehyde 294 3- methyl 2- furaldehyde Examples 295-296 Examples 295-296 were synthesized by Method S62 Example # R group 295 6- aminomethyl benzofuran 296 4- aminomethyl benzofuran Example 297 Example 297 was synthesized by Method S63 Example 298 Example 298 was synthesized by Method S64 Example 299 Example 299 was synthesized by Method S65 Example 300 Example 300 was synthesized by Method S66 Example 301 Example 301 was synthesized by Method S67. Example 302 Example 302 was synthesized by Method S68. Examples 303-305 Examples 303-305 were synthesized by Method S69. Example # R group 303 L- Asn 304 L- diamrnopropionic acid (alloc) 305 L- lys Example 306 Example 306 was synthesized by Method S70 Example 307 Example 307 was synthesized by Method S71 Examples 308-309 Examples 308-309 were synthesized by Method S72 Example # R group 308 3- hydroxy benzylamme 309 3-(3-hydroxyphenyl)propargylamιne Examples 310-312 Examples 310-312 were synthesized by Method S73 Example # R group 310 3- flouro benzylamme 311 benzylamme 312 3-(3-hydroxyphenyl)propargylamιne Examples 313-315 R Examples 313-315 were synthesized by Method S74 Example # R group 313 N-acetylsulfanilyl chloride 314 2-bromobenzenesulfonyl chloride 315 2-thιophenesulfonyl chloride Examples 316-317 Examples 316-317 were synthesized by Method S75 Example # R group 316 2-thιophenesulfonyl chloride 317 8-quιnohnesulfonyl chloride Examples 318-322 Examples 318-322 were synthesized by Method S76. Example # R group 318 benzenesulfonyl chloride 319 N-acetylsulfanilyl chloride 320 2-thiophenesulfonyl chloride 321 2-bromobenzenesulfonyl chloride 322 2-acetamido-4-methyl-5-thiazolesulfonyl chloride Examples 323-328 Examples 323-328 were synthesized by Method S77. Example # R group 323 isobutyl chloroformate 324 allyl chloroformate 325 butyl chloroformate 326 ethyl chloroformate 327 isopropyl chloroformate 328 propyl chloroformate Examples 329-333 Examples 329-333 were synthesized by Method S78. Example # R group 329 isobutyl chloroformate 330 cyclopropyl chloroformate 331 ethyl chloroformate 332 methyl chloroformate 333 2, 2, 2-trichloroethyl chloroformate Examples 334-337 Examples 334-337 were synthesized by Method S79. Example # R group 334 butyl chloroformate 335 propyl chloroformate 336 ethyl chloroformate 337 methyl chloroformate Example 338 Example 338 was synthesized by Method S80. Example 339 Example 339 was synthesized by Method S81. Examples 340-354 Examples 340-354 were synthesized by Method S82. Example # R group 340 L-Ala 341 L-Thr 342 L-Trp 343 L - aza Trp 344 L - Ser(OBzl) 345 L- Asn 346 L-Lys 347 L-His 348 L - Lys(N- e- Ac) 349 L-Gln 350 L-diaminopropionic(alloc) acid 351 L-diaminobutyric(alloc) acid 352 L-lys(alloc) 353 L-orn(alloc) 354 L- Tyr Examples 355-357 Examples 355-357 were synthesized by Method S83. Example # R group 355 L - Ala 356 L - His 357 L - Asn Example 358 Example 358 was synthesized by Method S84. Examples 359-362 Examples 359-362 were synthesized by Method S85. Example # R group 359 1-amino-l -cyclopropane carboxylic acid 360 m-tyrosine 361 o-hydroxytyrosine 362 L-iodotyrosine Example 363 Example 363 was synthesized by Method S86. Example 364 Example 364 was synthesized by Method S87. Example 365 Example 365 was synthesized by Method S88. Example 366 Example 366 was synthesized by Method S89. Example 367 Example 367 was synthesized by Method S90. Example 368 Example 368 was synthesized by Method S91. Example 369 Example 369 was synthesized by Method S92. Examples 370-371 Examples 370-371 were synthesized by Method S93. Example # R group 370 3 - hydroxybenzoic acid 371 benzoic acid Examples 372-375 Examples 372-375 were synthesized by Method S94 Example # R group 372 furylacrylic acid 373 3-(2-thιenyl)-acryhc acid 374 3 - hydroxybenzoic acid 375 benzoic acid Examples 376-377 Examples 376-377 were synthesized by Method S95 Example # R group 376 3 - hydroxybenzoic acid 377 3-(2-thienyl)-acryhc acid Example 378 Example 378 was synthesized by Method S96 Example 379 Example 379 was synthesized by Method S97. Examples 380-383 Examples 380-383 were synthesized by Method S98. Example # R group 380 L- Trp 381 L- Asn 382 L- dapa(alloc) 383 L- Lys Example 384 Example 383 was synthesized by Method S99. Example 385 Example 385 was synthesized by Method SI 00. Example 386 Example 386 was synthesized by Method S101. Example 387 Example 387 was synthesized by Method SI 02. Example 388 Example 388 was synthesized by Method S103. Example 389 Example 389 was synthesized by Method S104. Example 390 Example 390 was synthesized by Method S105. Example 391 Example 391 was synthesized by Method S106. Example 392 Example 392 was synthesized by Method SI 07. Example 393 Example 393 was synthesized by Method S108. Example 394 Example 394 was synthesized by Method SI 09. Example 395 Example 395 was synthesized by Method S110. Example 396 Example 396 was synthesized by Method Sill. Example 397 Example 397 was synthesized by Method S112. Example 398 Example 398 was synthesized by Method S113. Example 399 Example 399 was synthesized by Method S114. Example 400 Example 400 was synthesized by Method S115. Example 401 Example 401 was synthesized by Method S116. Example 402 Example 402 was synthesized by Method SI 17. Example 403 Example 403 was synthesized by Method S118. Example 404 Example 404 was synthesized by Method S119. Example 405 Example 405 was synthesized by Method S120. Example 406 Example 406 was synthesized by Method S121. Examples 407-416 Examples 407-416 were synthesized by Method S122. Example # R group 407 3-methoxybenzyl bromide 408 3-bromobenzyl bromide 409 3, 5-dimethoxybenzyl bromide 410 5-bromovaleronitrile 411 6-bromochexanenitrile 412 3-nitrobenzyl bromide 413 3-cyanobenzyl bromide 414 5-bromomerhyl-furan-2-carboxyhc acid ethyl ester 415 5-bromomethyl-furan-2-carboxylic acid ethyl ester 416 3-bromomethyl benzamide Examples 417-423 Examples 417-413 were synthesized by Method S123. Example # R group 417 1-aminonaphthalene 418 2-cyanoaniline 419 3-cyanoaniline 420 2-fluoroaniIine 421 3-fluoroaniline 422 4-fluoroaniline 423 3-methoxyaniline Examples 424-436 Examples 424-436 were synthesized by Method S124. Example # R group 424 2-(aminomethyl)pyridine 425 3-fluorobenzylamine 426 benzylamme 427 allylamine 428 phenethyl amme 429 histamine 430 4-fluorobenzylamme 431 3-methoxyphenethylamιne 432 4-ammobenzylamme 433 2-ammobenzylamme 434 2-[l, 3]Dιoxan-5-yl-ethylamme 435 piperonylamme 436 anihne Examples 437-440 Examples 437-440 were synthesized by Method S125 Example # R group 437 •-oamyl amme 438 4-(amrnomethyl)pyπdιne 439 2-[l, 3]Dιoxan-5-yl-ethylamme 440 anihne Examples 441-443 Examples 441-443 were synthesized by Method S126 Example # R group 441 o- toluidme 442 allyl amme 443 propyl amine Examples 444-459 Examples 444 459 were synthesized by Method S127. Example # R group 444 propylamine 445 3-(aminomethyl)pyridine 446 4-(aminomethyl)pyridine 447 2- methylbenzylamine 448 3- methylbenzylamine 449 4- methylbenzylamine 450 (S)-(-)-a-methylbenzylamine 451 2-(aminomethyl)pyridine 452 2- fluoro benzylamine 453 3- fluoro benzylamine 454 4- fluoro benzylamine 455 3- chloro benzylamine 456 4- chloro benzylamine 457 4- methoxy benzylamine 458 1- naphthalenemethylamine 459 benzylamine Table 3 provides biological assay data for the compounds prepared by the methods described above. Data is provided for two assay formats: the forward format of LFA/ICAM assay (PPFF) and the PLM2 antibody capture format of LFA/ICAM assay (PLM2). Table 3 PPFF and PLM2 assay data for exemplary compounds Example # PPFF(μM) PLM2(μM) 1 0.149 0.028 2 0.035 3 0.069 0.038 0.013 0.045 0.004 0.021 9 0.033 10 0.003 11 0.065 12 0.029 13 0.064 14 0.024 15 0.010 16 0.011 17 0.036 18 0.010 19 0.037 20 0.029 21 0.023 22 0.019 23 0.072 24 0.012 25 0.019 26 0.021 27 0.008 28 0.092 29 0.055 30 0.064 31 0.014 32 0.047 33 0.023 34 0.078 35 0.069 36 0.013 37 0.038 38 0.013 39 0.021 40 0.076 41 0.098 42 0.046 43 0.098 44 0.095 45 0.059 46 0.066 47 0.070 48 0.046 49 0.038 50 0.052 51 0.056 52 0.050 53 0.094 54 0.014 55 0.047 56 0.052 57 0.036 58 0.080 59 0.066 60 0.078 61 0.052 62 0.046 63 0.062 64 0.055 65 0.044 66 0.072 67 0.046 68 0.071 69 0.084 70 0.088 71 0.040 72 0.063 73 0.063 74 0.087 75 0.011 76 0.010 77 0.017 78 0.031 9 0.033 80 0.005 81 0.008 82 0.004 83 0.006 5 84 0.001 85 0.003 86 0.012 8 0.009 88 0.005 10 89 0.004 90 0.021 91 0.004 92 0.066 93 0.024 15 4 0.002 95 0.006 96 0.070 97 0.042 98 0.033 ° " 0.046 100 0.031 101 0.022 1° 2 0.025 103 0.044 25 104 0.044 105 0.004 106 0.026 107 0.087 108 0.021 30 109 0.026 110 0.052 111 0.007 112 0.036 113 0.086 S5 4 0.018 115 0.073 116 0.026 11 7 0.045 US 0.031 11 9 0.077 : 10 0.064 1 2 1 0.055 1 2 0.050 123 0.054 124 0.035 125 0.058 126 0.033 127 0.017 128 0.035 129 0.029 130 0.036 131 0.025 132 0.057 133 0.020 134 0.053 135 0.021 136 0.029 137 0.039 138 0.071 139 0.064 1 40 0.023 1 4 1 0.068 142 0.074 143 0.031 I 44 0.093 145 0.004 146 0.004 147 0.004 48 0.004 1 49 0.004 150 0.004 151 0.004 152 0.004 153 0.003 15 4 0.003 155 0.006 156 0.009 157 0.007 158 0.004 159 0.017 160 0.004 161 0.004 162 0.004 163 0.005 164 0.012 165 0.015 166 0.018 167 0.017 168 0.012 169 0.006 170 0.007 171 0.011 I 72 0.037 173 0.010 174 0.004 175 0.005 176 0.011 177 0.006 178 0.011 179 0.009 180 0.011 181 0.016 182 0.011 183 0.013 184 0.016 185 0.016 186 0.015 187 0.017 188 0.018 189 0.018 190 0.016 191 0.016 1 92 0.029 1 93 0.014 I 94 0.012 195 0.016 196 0.019 197 0.017 198 0.019 199 0.029 200 0.018 201 0.013 202 0.023 203 0.037 204 0.025 205 0.082 206 0.023 207 0.062 208 0.021 209 0.053 210 0.022 211 0.019 212 0.016 213 0.035 214 0.028 215 0.027 216 0.022 217 0.031 218 0.018 219 0.018 220 0.016 221 0.042 222 0.021 223 0.035 224 0.026 225 0.029 226 0.025 227 0.034 228 0.018 229 0.026 230 0.016 231 0.003 232 0.005 2 3 0.001 234 0.044 23 0.002 236 0.004 237 0.003 238 0.099 239 0.180 0.053 240 0.085 241 0.053 242 0.054 243 0.082 244 0.077 0.078 245 0.058 0.164 246 0.067 0.059 247 0.022 0.034 248 0.027 0.026 249 0.030 0 0.034 251 0.038 252 0.060 253 0.014 -54 0.094 0.036 255 0.042 256 0.076 257 0.042 258 0.038 259 0.049 260 0.071 261 0.052 262 0.075 263 0.066 264 0.093 26 5 0.045 266 0.046 267 0.021 268 0.019 269 0.046 270 0.055 271 0.086 272 0.080 273 0.016 274 0.006 275 0.006 276 0.012 277 0.003 278 0.002 279 0.004 280 0.007 281 0.004 282 0.024 283 0.092 284 0.093 0.079 285 0.064 286 0.014 287 0 043 288 0.023 289 0.074 290 0.009 291 0.007 292 0.015 293 0.083 294 0.100 295 0.047 296 0.017 297 0.028 298 0.009 299 0.016 300 0.074 301 0.025 302 0.023 303 0.005 304 0.003 305 0.015 306 0.004 307 0.004 308 0.061 309 0.057 310 0.082 311 0.079 312 0.089 313 0.069 314 0.028 315 0.037 316 0.030 317 0.055 318 0.031 319 0.023 320 0.007 321 0.020 322 0.011 323 0.036 324 0.042 325 0.056 326 0.042 327 0.070 328 0.074 329 0.033 330 0.009 331 0.027 332 0.057 333 0.090 334 0.072 335 0.096 336 0.066 337 0.079 338 0.060 339 0.020 540 0.014 0.006 341 0.031 342 0.057 0.004 343 0.030 344 0.183 0.053 345 0.019 0.004 346 0.071 347 0.044 0.004 348 0.090 0.023 349 0.042 350 0.027 0.005 351 0.067 0.032 352 0.042 353 0.074 354 0.008 355 0.100 0.094 356 0.068 357 0.057 0.023 358 0.230 0.032 359 0.016 360 0.018 361 0.018 362 0.005 363 0.014 0.010 364 0.087 0.035 365 0.024 366 0.062 367 0.020 368 0.043 369 0.019 370 0.055 0.025 371 0.055 0.037 372 0.013 373 0.021 374 0.021 375 0.040 36 0.078 0.061 3^ 0.016 0.051 378 0.007 379 0.010 380 0.096 381 0.035 382 0.012 3δ 0.060 384 0.046 0.018 385 0.070 0.048 386 0.030 387 0.098 0.043 388 0.050 389 0.054 0.010 390 0.079 391 0.007 392 0.025 393 0.003 394 0.012 395 0.006 396 0.062 397 0.005 398 0.015 399 0.002 400 0.007 4 °1 0.002 402 0.004 403 0.009 404 0.002 405 0.001 406 0.022 407 0.045 408 0.071 4 9 0.054 410 0.065 411 0.055 4 1 2 0.074 413 0.051 0.045 «4 0.087 415 0.059 416 0.036 417 0.086 418 0.056 419 0.079 420 0.015 421 0.056 422 0.083 423 0.032 424 0.038 425 0.082 426 0.057 427 0.044 428 0.029 429 0.094 430 0.070 431 0.070 432 0.070 433 0.046 434 0.050 435 0.074 436 0.011 437 0.083 0.034 438 0.082 439 0.089 440 0.068 441 0.015 442 0.006 443 0.010 444 0.041 445 0.029 446 0.020 447 0.085 448 0.094 449 0.071 450 0.061 451 0.030 452 0.040 453 0.056 454 0.046 455 0.071 456 0.064 457 0.036 458 0.083 459 0.058

Claims: WHAT IS CLAIMED IS 1) A method of treating or ameliorating an immune or inflammatory response or disorder m a mammal mediated through the CD11/CD18 family of cellular adhesion molecules comprismg admmistratmg to the mammal a therapeutically effective amount of a compound represented by structural formula (I) where D is a mono-, bi-, or tricychc saturated, unsaturated, or aromatic rmg, each rmg havmg 5-, 6- or 7 atoms m the rmg where the atoms m the rmg are carbon or from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, where any carbon or sulfur rmg atom may optionally be oxidized, each rmg substituted with 0-3 R , L is a bivalent lmkmg group selected from the group L 3 — L 2 — L 1 -L 4 — L 3 - "- u and L 5 — L 4 — L 3 — L 2 — L 1 — where L 1 is selected from oxo (-0-), S(O) , C(=0), CR 1 R 1 , CR 1 , het, NR n and N, L 2 is selected from oxo (-0-), S(O) , C(=0), C(=N-0-R°), CR 2 R 2 , CR 2 , het, NR n and N, L 3 is selected from oxo (-0-), S(O) , C(=0), C(=N-0-R°), CR 3 R 3 , CR 3 , het, NR n and N, L 4 is absent or is selected from oxo (-0-), S(O) , C(=0), C(=N-0-R°), CR 4 R 4 , CR 4 , NR n and N, and L is absent or is selected from oxo (-0-), S(O) , C(=0), CR 5 R 5 , CR 5 , NR n and N, provided that only one of L - L may be het and that when one of L - L is het the other L - L may be absent, where R 1 , R 1 , R 2 , R 2 , R 3 , R 3 , R 4 , R 4 , R 5 and R 5 each are independently selected from R a , R C and U-Q- V-W, 2 2' optionally, R and R separately or together may form a saturated, unsaturated or aromatic fused rmg with B through a substituent R^ on B, the fused rmg contammg 5, 6 or 7 atoms m the rmg and optionally contammg 1-3 heteroatoms selected from the group O, S and N, where any S or N may optionally be oxadized, 3 3' 4 4' optionally, R and R separately or together and R and R separately or together may form a saturated, unsaturated or aromatic fused rmg with D through a substituent R on D, the fused rmg containing 5, 6 or 7 atoms m the rmg and optionally contammg 1-3 heteroatoms selected from the group O, S and N, where any S or N may optionally be oxidized, also optionally, each R -R , NR or N m L - L together with any other R - R , NR or N m L - 5 L may form a 5, 6 or 7 member homo- or heterocycle either saturated, unsaturated or aromatic optionally contammg 1-3 additional heteroatoms selected from N, O and S, where any carbon or sulfur rmg atom may optionally be oxidized, each cycle substituted with 0-3 R , and where s is 0-2, B is selected from the group where is a fused hetero- or homocychc rmg contammg 5, 6 or 7 atoms, the ring bemg unsaturated, partially saturated or aromatic, the heteroatoms selected from 1-3 O, S and N, Y is selected from CH and NR , 1 G is selected from hydrogen and C -C alkyl, optionally G taken together with T may form a C - 1 6 3 C cycloalkyl optionally substituted with -V-W, 6 T is selected from the group a naturally occurrmg α-ammo-acid side cham, and U-Q-V-W, TJ is an optionally substituted bivalent radical selected from the group C -C alkyl, 1 6 C 0 -C 6 alkyl-Q, C -C alkenyl-Q, and 2 6 C 2 -C 6 alkynyl-Q where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R , Q is absent or is selected from the group -O-, -s ( o) s -, -S0 2 -N(R n )-, -N(R n )-, -N(R n )-C(=0)-, -N(R n )-C(=0)-N(R n )-, -N(R n )-C(=0)-0-, -N(R n )-S0 2 -, -C(=0)-, -C(=0)-0-, -het-, -C(=0)-N(R n )-, -0-C(=0)-N(R n )-, -PO(OR C )0- and -P(0)0-, where s is 0-2 and het is a mono- or bicychc 5, 6, 7, 9 or 10 member heterocyclic rmg, each rmg contammg 1-4 heteroatoms selected from N, O and S, where the heterocyclic rmg may be saturated, partially saturated, or aromatic and any N or S bemg optionally oxidized, the heterocyclic rmg bemg substituted with 0-3 R , V is absent or is an optionally substituted bivalent group selected from C -C alkyl, I D C -C cycloalkyl, 3 8 C -C alkyl-C -C aryl, and 0 6 6 10 y C -C alky-het, 0 6 where the substituents on any alkyl are 1-3 R and the substituents on any aryl or het are 1- 3 R d ; w is selected from the group hydrogen, OR°, SR m NR n R n ', NH-C(=0)-0-R C , NH-C(=0)-NR n R n , NH-C(=0)-R C , NH-SO -R S , 2 NH-SO -NR n R n , 2 NH-SO -NH-C(=0)-R NH-C(=0)-NH-SO -R C(=0)-NH-C(=0)-0-R , C(=0)-NH-C(=0)-R , C(=0)-NH-C(=0)-NR n R n , C(=0)-NH-SO -R C(=0)-NH-SO - ■NR n R n , C(=S)-NR n R n ', S0 2 -R S , SO -0-R S , 2 SO ^ -NR n R n , 2 SO -NH-C(=0)-0-R C , SO -NH-C(=0)-NR n R n , SO -NH-C(=0)-R 0-C(=0)-NR n R n , 0-C(=0)-R , 0-C(=0)-NH-C(=0)-R C , 0-C(=0)-NH-SO -R and O-SO -R 2 R is selected from C(=0)-R z , C(=0)-H, CH (OH) and CH 2 0-C(= C)-C ■C alkyl; 6 ,a . R " is R " or R" subsitiuted with 1-3 R α ; where R is selected from the group hydrogen, halo(F. Cl, Br, I), cyano, isocyanate, carboxy, carboxy-C -C alkyl, amino, amino-C -C alkyl, 1 8 y aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C -C alkoxy, 1 6 mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl. imidazolyl and indolyl; a " R is selected from the group C 0 -C ιo alkyI-Q-C o -C 6 alkyl, C o -C ιo alkenyl-Q-C o -C 6 alkyl, C 0 -C 10 alkynyl-Q-C o -C 6 alkyl, C -C cycloalkyl-Q-C -C alkyl, ά 11 U o C -C cycloalkenyl-Q-C -C alkyl, C^C^lkyl-C^C^aryl-Q-C^C^lkyl, C 6 -C 10 aryl-C 1 -C 6 alkyl-Q-C () -C 6 alkyl, C -C alkyl-het-Q-C -C alkyl, U o U o C -C alkyl-Q-het-C -C alkyl, het-C o -C 6 alkyl-Q-C o -C 6 alkyl, C 0 -C 6 alkyl-Q-C 6 -C 12 aryl and -Q-C -C alky; 1 6 R c is selected from hydrogen and substituted or unsubstituted C Λo aIkyl C -C alkenyl, 2 10 y C -C alkynyl, 2 10 y y C -C cycloalkyl, C -C cycloalkenyl, C ι -C 6 alkyl-C 6 -C ι2 aryl, C 6- C 10 aryl"C l- C 6 alky1 ' C -C . alkyl-het, 1 6 het-C -C alkyl, 1 6 C -C aryl and 6 12 het, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R a and the substituents on any aryl or het are 1-3 R ; R is selected from R" and R ; R is selected from the group OH, OCF 3 , OR SR m , halo(F, Cl. Br, I), CN, isocyanate, N0 2 , CF 3' C -C alkyl-NR n R n . 0 6 C -C alkyl-C(=0)-NR n R n 0 6 C -C alkyl-C(=0)-R 0 6 Chalky!, C ι -C 8 alkoxy, C 2 ~C 8 alkeny1 ' C 2 -C 8 alkynyl, C -C cycloalkyl, 3 6 C -C cycloalkenyl, 3 6 C -C alkyl-phenyl, phenyl-C -C alkyl, 1 6 C -C alkyloxycarbonyl, phenyl-C -C alkyloxy, 0 6 C -C alkyl-het, 1 6 het-C -C alkyl, 1 6 SO -het, 2 -0-C 6 -C ι2 aryl, -S0 2 -C 6 -C 12 aryl, -SO -C -C alkyl and 2 1 6 y het, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1- 2 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino; 3 1 6 1 6 R is selected from S-C -C alkyl, 1 6 C(=0)-C 1 -C 6 alkyl, C(=0)-NR n R n ', C j -C .alkyl, halo(F, Cl, Br, I)-C -C alkyl, 1 6 benzyl and phenyl; -.n R is selected from the group R ^ NH-C(=0)-0-R c NH-C(=0)-R C , NH-C(=0)-NHR C , NH-SO -R S , NH-SO -NH-C(=0)-R NH-C(=0)-NH-SO -R S , C(=0)-0-R C , C(=0)-R c , C(=0)-NHR C , C(=0)-NH-C(=0)-0-R C , C(=0)-NH-C(=0)-R C , C(=0)-NH-SO -R S , C(=0)-NH-SO -NHR S , S0 2 -R S , SO -0-R s , 2 S0 2 -N(R C ) 2 , SO -NH-C(=0)-0-R C , SO -NH-C(=0)-0-R C and SO -NH-C(=0)-R C ; lected from hydrogen, hydroxy and substituted or unsubstituted C -C alkyl 1 11 J C -C .. alkoxy, 1 11 J C 2 "C 10 alkenyI ' C 2 "C 10 alkynyI ' C -C^cycloalkyl, ^- ' '^ 1 n c y c l° a ^enyl, C l- C 6 alkyl - C 6- C 12 aryl C 6 -C ιo aryl-C ι -C 6 arkyl, C -C aryl-C -C alkyloxy, 6 10 ' 0 6 y y C -C alkyl-het, 1 6 3 het-C -C alkyl, 1 6 J C 6 -C 12 aryl, het, C -C alkylcarbonyl, C -C alkoxycarbonyl, 1 8 C -C cycloalkylcarbonyl, 3 8 C -C cycloalkoxycarbonyl, 3 8 C -C aryloxycarbonyl, C -C arylalkoxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C -C alkylsulf onyl and C -C arylsulf onyl, 6 10 where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl, het or heteroaryl are 1-3 R ; R and R taken together with the common nitrogen to which they are attached may from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinoIinyl, thiazolidinyl and azabicyclononyl, where the substituents are 1-3 R ; R is selected from hydrogen and substituted or unsubstituted C ι -C 6 alkyl, C -C alkylcarbonyl, 1 6 C -C alkenyl, 2 6 2 -C 6 alkynyl, C -C cycloalkyl and 3 8 benzoyl, where the substituents on any alkyl are 1-3 R and the substituents on any aryl are 1-3 R"; R" is selected from the group OH, halo(F, Cl. Br, I), CN, isocyanate, OR C , SR m SOR C , N0 2 , CF 3' R c , NR n R n ', NR n C(=0)-0-R C , NR n C(=0)-R C , C 0 -C 6 alkyl-SO 2 -R C , C -C alkyl-SO -NR n R n , 0 6 2 C(=0)-R C , 0-C(=0)-R C , C(=0)-0-R C and C(=0)-NR n R n , where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl or het are 1-3 R ; R s is a substituted or unsubstituted group selected from C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C -C cycloalkyl, 3 8 C -C cycloalkenyl, 3 6 C -C alkyl-phenyl, phenyl-C -C alkyl, C -C alkyl-het and 0 6 het-C -C alkyl, 0 6 where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl or het are 1-3 R ; R z is a substituted or unsubstituted group selected from hydroxy, C -C alkoxy, C -C^cycloalkoxy, C -C aralkoxy, C -C arcycloalkoxy, C 6 -C 1Q aryloxy, C -C alkylcarbonyloxyalkyloxy, C -C alkoxycarbonyloxyalkyloxy, C -C alkoxycarbonylalkyloxy, C -C cycloalkvlcarbonyloxyalkyloxy, 5 10 C -C cycloalkoxycarbonyloxyalkyloxy, C -C cycloalkoxycarbonylalkyloxy, C -C aryloxycarbonylalkyloxy, 8 12 C -C aryloxycarbonyloxyalkyloxy, 8 12 C -C arylcarbonyloxyalkyloxy, 8 12 C -C alkoxyalkylcarbonyloxyalkyloxy, 5 10 (R n )(R n )N(C ι -C ιo alkoxy)-, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the sαbstituents on any aryl or het are 1-3 R and pharmaceutically acceptable salts thereof. 2) The method of Claim 1 wherein D is an aromatic homocycle or aromatic heterocycle containing 1-3 heteroatoms selected from the group N, S and O, the homo- or heterocycles selected from the group where Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are selected from the group CH, CR d and N, Z is selected from the group O, S, N and NR , n is 0-3, R is selected from the group OH, OCF OR C , SR m , halo(F, Cl. Br, I), CN, isocyanate, NO . CF . C -C alkyl-NR n R n , C - 3 2 3 0 6 0 C alkyl-C(=0)-NR n R n , C -C alkyl-C(=0)-R a , C -C alkyl, C -C o alkoxy, C -C alkenyl, C - 6 0 6 1 8 1 8 2 8 2 C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, C -C alkyl-phenyl, phenyl-C -C alkyl, o 3 6 3 6 1 6 1 6 C -C alkyloxycarbonyl, phenyl-C -C alkyloxy, C -C alkyl-het, het-C -C alkyl, SO -het, - O-C -C aryl, -SO -C -C aryl, -SO -C -C alkyl and het, where any alkyl, alkenyl or 6 12 2 6 12 2 1 6 alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino; 3 1 6 1 6 R is R or R subsitiuted with 1-3 R ; where a ' R is selected from the group hydrogen, halo(F. Cl, Br, I), cyano, isocyanate, carboxy, carboxy-C -C alkyl, amino, amino-C -C alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, 1 8 formyloxy, azido, nitro, imidazoyl, ureido, thioureido, rhiocyanato, hydroxy, C -C alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl. imidazolyl and indolyl; a " R is selected from the group C 0 "C 10 al yl"Q"C 0 "C 6 alky1 ' C 0 - C 10 al en y I -Q- C 0 - C 6 alk y 1 ' C 0 -C ιo alkynyl-Q-C o -C 6 alkyl, C 3 -C 11 cycloalkyl-Q-C o -C 6 alkyl, C^C^cycloalkenyl-Q-C^C^lkyl, C^C^lkyl-C^ C i2 aryl-Q-C o -C 6 alkyl, C^C^aryl-C^C^lkyl-Q-C^C^lkyl, C^C^lkyl-het-Q-C^ C alkyl, C -C alkyl-Q-het-C -C alkyl, het-C -C alkyl-Q-C -C alkyl, C -C alkyl-Q-C - 6 y 0 6 0 6 0 6 ' 0 6 ^ 0 6 6 C aryl and -Q-C -C alky; 12 y 1 6 y Q is absent or is selected from the group -O-, -S(O) -, -SO -N(R n )-, -N(R n )-SO -, -N(R n )-C(=0)-, -C(=0)-N(R n )-, -N(R n )-C(=0)-0-, - 0-C(=0)-N(R n )-, -N(R n )-C(=0)-N(R n )-, -C(=0)-, -N(R n )-, -C(=0)-0-, -0-C(=0)-, -het-, - PO(OR )0- and -P(0)0-, where s is 0-2; het is a mono- or bicyclic 5, 6, 7, 9 or 10 member heterocychc ring, each ring containing 1-4 heteroatoms selected from N, O and S, where the heterocychc ring may be saturated, partially saturated, or aromatic and any N or S being optionally oxidized, the heterocychc ring being substituted with 0-3 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino; 3 1 6 1 6 R c is selected from hydrogen and substituted or unsubstituted C l "C 10 al yL C 2 ~C 10 aIkeny1 ' C 2 "C ιo aLkyny1 ' C^C^cycloalkyl, C^C^cycloalkenyl, C^ C 6 alkyl-C 6 -C aryl, C^C^aryl-C^C alkyl, C -C alkyl-het, het^-C alkyl, 6 -C 12 aryl and het, where the substituents are 1-3 hydroxy. halo(F, Cl, Br, I), CF , C -C alkyl, C - 3 1 6 1 C alkoxy, nitro and amino; 6 R is selected from S-C -C alkyl, C(=0)-C -C alkyl, C(=0)-NR n R n ', C -C alkyl, halo(F, Cl, Br, I)-C -C alkyl, 1 6 1 6 1 6 1 6 benzyl and phenyl; R is selected from the group R C , NH-C(=0)-0-R C , NH-C(=0)-R C , NH-C(=Q)-NHR C , NH-SO -R S , NH-SO -NH-C(=0)- R C , NH-C(=0)-NH-S0 -R S , C(=0)-0-R C , C(=0)-R , C(=0)-NHR C , C(=0)-NH-C(=0)-0-R C , C(=0)-NH-C(=0)-R°, C(=0)-NH-SO -R S , C(=0)-NH-SO -NHR S , SO -R S , SO -0-R S , SO -N(R C ) SO -NH-C(=0)-0-R C , SO -NH-C(=0)-0-R C and SO -NH-C(=0)-R C ; R is selected from hydrogen, hydroxy and substituted or unsubstituted C^cycloalkenyl, C^C^lkyl-C^C^aryl, C^C^aryl-C^C^lkyl, C^C^aryl-C^ C alkyloxy, C -C alkyl-het, het-C -C alkyl, C -C aryl, het, C -C, alkylcarbonyl, C - 6 1 6 1 6 6 12 1 6 1 C alkoxycarbonyl, C -C cycloalkylcarbonyl, C -C cycloalkoxycarbonyl, C - 8 3 o 3 8 6 C aryloxycarbonyl, C-C arylalkoxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C -C alkylsulfonyl and C -C arylsulf onyl, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl, heteroaryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino; 3 1 6 1 6 R and R taken together with the common nitrogen to which they are attached may from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyLindolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4- tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl, where the substituents are 1-3 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino; 3 1 6 1 6 R s is a substituted or unsubstituted group selected from C -C alkyl, C -C alkenyl, C -C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, C -C alkyl- 1 8 2 8 2 o 3 8 3 6 0 6 phenyl, phenyl-C -C alkyl, C -C alkyl-het and het-C -C alkyl, where the substituents are 1-3 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino; L is selected from the group -(CR 6 R 6 ) -Ai-(CR 8 R 8 ) -, -(CR 6 R 6 ) -het-(CR 8 R 8 ') -, -(CR 6 =CR 7 ) -Ai-(CR 8 R 8 ') - and - o p o p q p (CR 6 R 6 ) -Ai-( CR 8 =CR 9 ) -, o r where Ai is selected from R 3 R 3' OH R n 9 ? H R{ R 2' R ' R1 ' R 2 R 2 R 2' R n R 2 R n OH OH where o is 0-1, p is 0-1, q is 0-1 and r is 0-1; R 1 , R 1 , R 2 , R 2 , R 3 , R 3 , R 6 , R 6 , R 7 , R 8 , R 8 and R 9 each are mdependently selected from R a , R C and U-W; U is an optionally substituted bivalent radical selected from the group C -C alkyl-, C -C alkyl-Q-, C -C alkenyl-Q-, and C -C alkynyl-Q-, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R ; W is selected from the group hydrogen, OH, O-C -C alkyl, SH, SR m , NR n R n ', NH-C(=0)-0-R c , NH-C(=0)-NR n R n , 1 6 NH-C(=0)-R C , NH-SO -R S , NH-SO -NR n R n ', NH-SO -NH-C(=0)-R C , NH-C(=0)-NH-SO - R S , C(=0)-NH-C(=0)-0-R C , C(=0)-NH-C(=0)-R C , C(=0)-NH-C(=0)-NR n R n , C(=0)-NH- SO -R S , C(=0)-NH-SO -NR n R n , C(=S)-NR n R n ', SO -R s , SO -0-R S , SO -NR n R n , SO - 2 ' 2 ' 2 2 2 2 NH-C(=0)-0-R C , SO -NH-C(=0)-NR n R n ', SO -NH-C(=0)-R C , 0-C(=0)-NR n R n , 0-C(=0)- R C , 0-C(=0)-NH-C(=0)-R C , 0-C(=0)-NH-SO -R S and O-SO -R S ; G is hydrogen; T is U-W; R is C(=0)-OH and pharmaceutically acceptable salts thereof. 3) The method of Claim 2 wherein D is selected from 1) a 5-member aromatic heterocycle selected from the group 2) a 9-member aromatic heterobicycle selected from the group 3) a 6-member aromatic hetero- or homocycle selected from the group and L is .^ bivalent linking group selected from the group -C3-C5-alkyl-, -C3-C5-alkenyl-, -CH C(=0)NH-, -CH NH-C(=0)-, -0-CH 2 -C(=0)-, - CH 2 -CH 2 -C(=0)-, -CH=CH-C(=0)NH-CH -, -CH=CH-C(=0)NH-CH-(CH )-, -CH(OH)-CH -O-, -CH(OH)-CH 2 -CH 2 -, - CH -CH -CH(OH)-, - O-CH -CH(OH)-, - O-CH -CH(OH)-CH -, - O-CH -CH -CH(OH)-, -O-CH -CH -O-, 2 2 -CH -CH -CH -O-, 2 2 2 -CH -CH(OH)-CH -O-, -CH -CH -O-, 2 2 -CH-(CH )-NH-C(=0)-, -CH 2 -NH-S0 2 -, -NH-S0 2 -CH 2 -, -CH 2 -S0 2 NH-, -S0 2 NH-CH 2 -, -C(=0)-NH-C(=0)-, -NH-C(=0)-NH-, -NH-C(=0)-NH-CH 2 -, -CH 2 -NH-C(=0)-NH-, -C(=0)-NH-CH 2 -C(=0)-NH -, -NH-C(=0)-0- and -0-C(=0)-NH-, and pharmaceutically acceptable salts thereof. 4) The method of Claim 3 wherein the compound is represented by where D-L- is selected from where Y , Y and Y are selected from the group CH, CR and N; Z is selected from the group O, S, NH and NR ; n is 0-3; 1 2 3 a c R , R and R each are independently selected from R , R and U-W; U is an optionally substituted bivalent radical selected from the group C -C alkyl-, C -C alkyl-Q-, C -C alkenyl-Q-, and C -C, alkynyl-Q-, where the substitiiits 1 6 0 6 2 6 2 6 on any alkyl, alkenyl or alkynyl are 1-3 R ; Q is absent or is selected from the group -O-, -S(O) -, -SO -N(R n )-, -N(R n )-, -N(R n )-C(=0)-, -N(R n )-C(=0)-N(R n )-, -N(R n )-C(=0)-0-, -0-C(=0)-N(R n )-, -N(R n )-SO -, -C(=0)-, -C(=0)-0-, -het-, -C(=0)-N(R n )-, -PO(OR C )0- and - P(0)0-, where s is 0-2; het is a mono- or bicyclic 5, 6, 7, 9 or 10 member heterocyclic ring, each ring containing 1-4 heteroatoms selected from N, O and S, where the heterocyclic ring may be saturated, partially saturated, or aromatic and any N or S being optionally oxidized, the heterocyclic ring being substituted with 0-3 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, 3 1 6 C -C alkoxy, nitro and amino; 1 6 W is selected from the group hydrogen, OH, O-C -C alkyl, SH, SR m , NR n R n ', NH-C(=0)-0-R C , NH-C(=0)-NR n R n ', 1 6 NH-C(=0)-R C , NH-SO -R S , NH-SO -NR n R n ', NH-SO -NH-C(=0)-R C , NH-C(=0)-NH-SO - R S , C(=0)-NH-C(=0)-0-R C , C(=0)-NH-C(=0)-R C , C(=0)-NH-C(=0)-NR n R n ', C(=0)-NH- SO -R S , C(=0)-NH-SO -NR n R n , C(=S)-NR n R n , SO -R S , SO -0-R S , SO^-NR n R n ', SO - NH-C(=0)-0-R C , SO -NH-C(=0)-NR n R n , SO -NH-C(=0)-R C , 0-C(=0)-NR n R n ', 0-C(=0)- R C , 0-C(=0)-NH-C(=0)-R C , 0-C(=0)-NH-SO -R S and O-SO -R S ; R a is R 3 ' or R a " a ' substituted with 1-3 R ; where R is selected from the group hydrogen, halo(F. Cl, Br, I), cyano, carboxy, carboxy-C -C alkyl, amino, amino-C - C alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, 8 nitro, imidazoyl, ureido, thioureido, thiocyauato, hydroxy, C -C alkoxy, mercapto, 1 6 sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl. imidazolyl and indolyl; a " R is selected from the group C 0 "C 10 aIkyl"Q"C 0 "C 6 alkyl C 0 - C 10 alkenyI - Q - C 0 ~C 6 alky Q C w alk Y^-Q- C 0 - β alk y 1 ' C - . cycloalkyl-Q-C -C,alkyl, C -C n cycloalkenyl-Q-C n -C alkyl, C. -C,alkyl-C - o il U o J lU U o l o o C i2 aryl-Q-C 0 -C 6 alkyl, C^^aryl-C^C^lkyl-Q-C^alk l, C^C^lkyl-het-Q-C^ C alkyl, C -C alkyl-Q-het-C -C alkyl, het-C^-C alkyl-Q-C Λ -C alkyl, C -C alkyl-Q-C - 6 0 6 0 6 0 6 0 6 0 6 6 C ^ aryl and -Q-C -C alky; 12 J 1 6 y R c is selected from hydrogen and substituted or unsubstituted C l ~C 10 aIkyL C 2 - C 10 al en y 1 ' C 2- C 10 aIk y n y l C 3 -C ιι cycloalk y l, C 3 -C 1() cycloalkenyl, C C 6 alkyl-C 6 -C 12 aryl, C 6 -C 1() aryl-C ι -C 6 alkyl, C 1 -C 6 alkyl-het, het-C ι -C 6 alkyl, ^-C^aryl and het, where the substituits are 1-3 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C - 3 1 6 1 C alkoxy, nitro and amino; 6 R is selected from the group OH, OCF 3 , OR C , SR , halo(F, Cl. Br, I), CN, NO CF C -C alkyl-NR n R n ', C -C alkyl- C(=0)-NR n R n , C 0 -C 6 alkyl-C(=O)-R a , C -C alkyl, C -C alkoxy, C -C alkenyl, C - C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, C -C, alkyl-phenyl, phenyl-C -C, alkyl, o 3 6 3 6 1 6 1 6 C -C alkyloxycarbonyl, phenyl-C -C alkyloxy, C -C alkyl-het, het-C -C alkyl, SO -het, - 1 6 0 6 1 6 1 6 2 O-C -C aryl, -SO -C -C aryl, -SO -C -C alkyl and het, where any alkyl, alkenyl or 6 1-. 2 6 12 2 1 6 alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitio and amino; 3 1 6 1 6 R is selected from S-C -C alkyl, C(=0)-C -C alkyl, C(=0) NR n R n ', C - alkyl, halo(F, Cl, Br, I)-C -C, alkyl, l o 1 6 1 6 1 6 benzyl and phenyl; R is selected from the group R C , NH-C(=0)-0-R C , NH-C(=0)-R c , NH-C(=0)-NHR C , NH-SO -R s , NH-SO -NH-C(=0)- R C , NH-C(=0)-NH-S0 -R S , C(=0)-0-R c , C(=0)-R c , C(=0)-NHR c , C(=0)-NH-C(=0)-0-R C , C(=0)-NH-C(=0)-R c , C(=0)-NH-S0 -R S , C(=0)-NH-SO -NHR S , SO -R S , SO -0-R S , SO - N(R C ) 2 , S0 2 -NH-C(=0)-0-R c , SO -NH-C(=0)-0-R c and SO -NH-C(=0)-R C ; R is selected from hydrogen, hydroxy and substituted or unsubstituted C f C li al yL C 1 - C 11 lkoχ y' c 2 - c 10 aIken y 1 ' C 2 -C 1() alkynyl, C 3 -C ιι cycloalkyl, C^ C^cycloalkenyl, C^C^lkyl-C^C^aryl, C ^aryl-C^alkyl, C^ary^- C alkyloxy, C -C alkyl-het, het-C -C alkyl, C -C aryl, het, C -C alkylcarbonyl, C - C alkoxycarbonyl, C -C cycloalkylcarbonyl, C -C cycloalkoxycarbonyl, C - C aryloxycarbonyl, ( ~ 7 ~ ( ~ ι i ary^^oxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C -C alkylsulfonyl and C -C arylsulfonyl, where any alkyl, alkenyl or alkynyl may 1 6 6 10 optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), ratio, ammo and ammocarbonyl and the substituents on any aryl, heteroaryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and ammo, 3 1 6 1 6 R and R taken together with the common nitiogen to which they are attached may from an optionally substituted heterocycle selected from morpholmyl, piperazmyl, thiamorpholinyl, pyrrolidinyl, ιmιdazohdιnyl,ιndolιnyl, isoindohnyl, 1,2,3,4- tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-ιsoqurnohnyl, thiazohdinyl and azabicyclononyl, where the substitiiits are 1-3 hydroxy, halo(F, Cl, Br, I), CF C -C alkyl, C -C alkoxy, nitro 3 1 6 1 6 and ammo, R s is a substituted or unsubstituted group selected from C -C alkyl, C -C alkenyl, C -C alkynyl, C -C cycloalkyl, C -C, cycloalkenyl, C -C alkyl- 1 8 2 o 2 8 3 8 3 6 0 6 phenyl, phenyl-C -C alkyl, C -C alkyl-het and het-C -C, alkyl, where the substitiiits are 1- 0 6 0 6 0 6 3 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and ammo, 3 1 6 1 6 T is U-W, and pharmaceutically acceptable salts thereof 5) The method of Claim 4 wherein Y , Y and Y are selected from CH and CR , Z is selected from NR , O and S, 1 2 3 a R , R and R each are mdependently R , R is R or R substituted with 1-3 R , where R is selected from the group hydrogen, halo(F Cl, Br, I), cyano, carboxy, carboxy, ammo, ammo, ammocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, lmidazoyl, ureido, thioureido, rhiocyanato, hydroxy, C -C alkoxy, mercapto, sulfonamido, phenoxy, phenyl, 1 6 benzamido, morpholmo, morpholmyl, piperazmyl, piperidmyl, pyrrolmyl imidazolyl and indolyl, R is hydrogen or a substituted or unsubstituted group selected from C 0 "C 10 al yl"het ' C l "C 10 aIkyl C 2 - C 10 aIken y 1 ' C 2 - C 10 aIk y n y 1 ' 3 -C ιι cycloalk y l, C^ C Λ „cycloalkenyl-C ^ -C, alky 1, C ^ , -C, alky 1-C -C aryl and C -C aryl-C -C alkyl, where the 10 y ■ 0 6 - 1 6 6 12 - y 6 10 J J subsbtuits are 1-3 hydroxy, halo(F, Cl, Br, I), CF C -C alkyl, C -C alkoxy, nitio and ammo; R is selected from the group ,m OH, OCF . OR , SR , halo(F, Cl. Br, I), CN, NO . CF . C -C,alkyl-C(=0)-R , C -C o alkyl, 3 2 3 0 6 1 8 C -C alkoxy, C -C alkenyl, C -C alkynyl, C -C cycloalkyl, phenyl-C -C alkyl, C - 1 8 2 8 2 8 3 6 1 6 1 C alkyloxycarbonyl, -O-C -C aryl and -SO -C -C aryl, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino; 3 1 6 1 6 ,m . R is selected from S-C -C alkyl, C(=0)-C -C alkyl, C(=0)-NH , C -C alkyl, halo(F, Cl, Br, I)-C -C alkyl, 1 6 1 6 2 1 6 1 6 benzyl and phenyl; R is selected from the group R a ", NH-C(=0)-0-R a , NH-C(=0)-R a ", NH-C(=0)-NHR a ", NH-SO -R S , NH-SO -NH- C(=0)-R , NH-C(=0)-NΗ-SO -R S , C(=0)-0-R a ", C(=0)R a ', C(=0)-NHR a ", C(=0)-NH- C(=0)-0-R a , C(=0)-NH-C(=0)-R a , C(=0)-NH-SO -R S , C(=0)-NH-SO -NHR S , SO -R S , SO -0-R s , SO -N(R) , SO -NH-C(=0)-0-R ", SO -NH-C(=0)-0-R a " and SO -NH-C(=0)- R a "; R is selected from hydrogen, hydroxy and substituted or unsubstituted C-C,„ alkyl, C -C alkoxy, C ^ -C ^ ^ alkenyl, C -C alkynyl, C ^ -C ^ cycloalkyl, C - 1 11 y 1 11 y 2 10 y 2 10 3 lr y 3 C^cycloalkenyl, C^C^lkyl-C^C^aryl, C^C^aryl-C^C^lkyl, C^C^aryl-C^ C alkyloxy, C -C alkyl-het, het-C -C, alkyl, C -C ^aryl, het, C -C alkylcarbonyl, C - 6 1 6 1 6 6 12 1 6 1 C alkoxycarbonyl, C -C cycloalkylcarbonyl, C -C cycloalkoxycarbonyl, C - 8 3 8 3 8 6 C aryloxycarbonyl, ^-T^ i i ar yl a ^oxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C -C alkylsulfonyl and C -C arylsulfonyl, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitio, amino and aminocarbonyl and the substituents on any aryl, heteroaryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro and amino; 3 1 6 1 6 R and R taken together with the common nitiogen to which they are attached may from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl,indolinyl, isoindolinyl, 1,2,3,4- tetrahydro-quinolinyl, 1, 2,3,4- tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl, where the substituits are 1-3 hydroxy, halo(F, Cl, Br, I), CF , C -C alkyl, C -C alkoxy, nitro 3 1 6 1 6 and amino; R s is a substituted or unsubstituted group selected from C -C alkyl, C -C alkenyl, C -C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, C -C alkyl- l o o 2 8 3 8 3 6 0 6 phenyl, phenyl-C -C alkyl, C -C alkyl-het and het-C -C alkyl, where the substituits are 1- U 6 0 6 0 6 3 hydroxy, halo(F, Cl, Br, I), CF C -C alkyl, C -C alkoxy, nitro and amino; T is U-W, 3 1 6 1 6 where U is an optionally substituted bivalent radical selected from the group C -C alkyl-Q-, C -C alkenyl-Q-, and C -C alkynyl-Q-, where the substituits on any alkyl, 1 -. 6 2 6 alkenyl or alkynyl are 1-3 R ; Q is absent or is sek÷ ϊed from the group -S0 2 -N(R n )-, N(R n )-, -N(R n )-C(=0)-, -N(R n )-C(=0)-0- , -N(R n )-SO -, -C(=0)-N(R n )- C(=0)-0-, -C(=0)-0-, -C(=0)- and -C(=0)-N(R n )-; W is selected from the group hydrogen, OH, ϋ-C^C^lkyl, SH, SR m , NR n R n ', NH-C(=0)-0-R ", NH-C(=0)-NR n R n , NH-C(=0)-R a , NH-SO -R S , NH-SO -NR n R n ', NH-SO -NH-C(=0)-R ", NH-C(=0)-NH- SO -R S , C(=0)-NH-C(=0)-0-R a , C(=0)-NH-C(=0)-R a ", C(=0)-NH-C(=0)-NR n R n , C(=0)-NH-S0 2 -R S , C(=0)-NH-S0 2 -NR n R n ', C(=S)-NR n R n ', SO -R S , SO -O-R 5 , SO^ NR n R n ', S0 2 -NH-C(=0)-0-R a , S0 2 -NH-C(=0)-NR n R n ', SO -NH-C(=0)-R a ", 0-C(=0)- NR n R n ', 0-C(=0)-R a ", 0-C(=0)-NH-C(=0)-R a ", 0-C(=0)-NH-SO -R s and O-SO -R S ; and pharmaceutically acceptable salts thereof. 6) A method of treating mammal having an immune disorder mediated through the CD11/CD18 family of adhesion receptors comprising the step of administering a pharmacologically effective amount of a compound represented by the formula: where D is selected from the group where Y is selected from the group NR , CH and CR ; Y , Y , Y and Y are selected from the group CH and CR ; 1 n Z is selected from the group NR , O and S; n is 0-3; L is selected from the group substituted or unsubstituted C -C alkylene, C -C cycloalkylene, 3 6 C -C alkylene-NR -(C=0)-C -C alkylene, 0 3 0 3 C -C alkyIene-(C=0)-NR n -C -C alkylene, 0 3 0 3 C -C alkylene-O-C -C alkylene, C -C alkylene-NR -C n -C alkylene, 0 3 0 3 C -C alkylene-(C=0)-C -C alkylene, C 0 -C 3 alkylene-S(O) 02 -C 0 -C 3 alkylene, C -C alkylene-NR -SO -C -C alkylene, C -C alkylene-SO -NR -C -C alkylene, C -C alkylene-CR 1 =CR 2 -C -C alkylene, C -C alkylene-C=C-C -C alkylene and C -C alkylene-het-C -C alkylene 0 3 0 3 1 2 3 where the substituents are selected from the group one to three R , R and R ; Y L is selected from the group substituted or unsubstituted C -C alkylene, C -C alkylene-NR n -(C=0)-C -C alkylene, C -C alkylene-(C=0)-NR n -C -C alkylene, C -C alkylene-O-C -C alkylene, C -C alkylene-NR n -C -C alkylene, 0 2 0 2 ' C -C alkylene-(C=0)-C -C alkylene, C 0 -C 3 alkylene-S(O) 02 -C 0 -C 3 alkylene, C -C alkylene-SO -NR n -C -C alkylene and 0 3 2 0 3 C -C alkylene-aryl-C -C alkylene 1 2 3 where the substituents are selected from the group one to three R , R and R ; 1 2 3 R , R and R are selected from the group hydrogen, C -C alkyl-hydroxy, 1 8 halo(F, Cl, Br, I), halo(F, Cl, Br, I)-C -C alkyl, 1 8 cyano, isocyanate, carboxy, carboxy-C -C alkyl, 1 6 amino, amino-C -C alkyl, 1 8 amino-di(C -C alkyl), 1 8 aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C -C, alkoxy, 1 6 mercapto, sulfonamido, phenoxy, phenyl, and benzamido; R is selected from the group hydrogen, halo(F. Cl, Br, I), cyano, isocyanate, carboxy, carboxy-C -C alkyl, amino, amino-C -C alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C -C alkoxy, mercapto, sulfonamido, C -C alkylsulfonyl, 1 6 het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl. imidazolyl and indolyl; R c is selected from hydrogen and substituted or unsubstituted c ι- c ιo alk l C 2 -C 1() alkenyl, C 2 "C 10 alkynyL C -C cycloalkyl, C -C cycloalkenyl, - C 6 alk I - C 6- C 12 aryI ' C 6 -C 1o aryl- C1 -C 6 alkyl, C -C alkyl-het, 1 6 het-C -C alkyl, 1 6 C 6 -C 12 aryl, C 1 -C 10 alkyl-O- C -C alkenyl-O-, C 2 -C 1() alkynyl-0-, C 3 "C ll CyCl ° alkyl" ° " C -C cycloalkenyl-O-, C -C alkyl-C, -C aryl-O-, 1 6 ' 6 12 ' C-C „aiyl-C -C alkyl-O-, 6 10 ' 1 6 ' C -C alkyl-het-O-, het-C -C, alkyl-O-, 0 6 C 6 -C 12 aryl-0- C^C^alkyl-NR 11 -, C 2 -C ιo alkenyl-NR n -, C -C alkynyl-NR n -, 2 10 ' ' C -C cycloalkyl-NR n -, C -C cycloalkenyl-NR -, C -C, alkyl-C ,-C„ aryl-NR n -, 1 6 ' 6 12 ' C -C, „aryl-C -C, alkyl-NR n -, 6 10 ' 1 6 ' C -C alkyl-het-NR n -, 1 6 het-C -C alkyl-NR n -, 0 6 C -C aryl-NR - and 6 12 ' het, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R a and the substituents on any aryl or het are 1-3 R ; het is selected from the group and where R^ and R are independently selected from the group OH, CN, N0 2 , halo(F, Cl. Br, I), OR n SR n SOR n , CF 3' R C , NR n R n , NR n C(=0)-0-R n , NR n C(=0)-R n . C -C alkyl-SO -R 0 6 ' 2 C -C alkyl-SO -NR n R n , 0 6 2 C(=0)-R , 0-C(=0)-R n , C(=0)-0-R n and C(=0)-NR n R n , R is a chemical bond when het is a divalent linking group; R and R are independently selected from the group hydrogen, hydroxy, C -C alkyl, 1 o halo(F, Cl, Br, I)-C-C, alkyl, 1 6 C -C, alkyl-het, 1 6 ' het-C -Calkyl, 1 6 C-C aryl, and 6 12 ' het; R z is a substituted or unsubstituted group selected from hydroxy, C 1 -C 11 alkoxy, C-C cycloalkoxy, C -C aralkoxy, C -C arcycloalkoxy, C 6 "C 10 aryl ° Xy ' C -C alkoxycarbonyloxyalkyloxy, C -C alkoxycarbonylalkyloxy, C -C cycloalkylcarbonyloxyalkyloxy, C -C cycloalkoxycarbonyloxyalkyloxy, C -C cycloalkoxycarbonylalkyloxy, C -C aryloxycarbonylalkyloxy, 8 12 C -C aryloxycarbonyloxyalkyloxy, 8 12 C -C arylcarbonyloxyalkyloxy, 8 12 C -C alkoxy alky lcarbonyloxyalkyloxy, ,n. /T1 n (R^^' JN^-C^alkox )-, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl or het are 1-3 R ; Q is absent or is C-C alkyl substituted with a group selected from -N(R n )-, -N(R n )-C(=0)-, -N(R n )-C(=0)-0-, -N(R n )-C(=0)-N(R n )-, -N(R n )-S0 2 -, -C(=0)-, -0-C(=0)-N(R n )-, -C(=0)-N(R n )-, V is absent or is an optionally substituted bivalent group selected from C -C alkylene, 1 11 ' C -C alky lene-O-C -C alkylene, 0 3 0 3 C -C alkenylene, C -C alkylene-O-C -C alkenylene, C -C cycloalkylene, 3 8 C,-C aryl-C -C alkylene, 6 10 ' 0 6 ' C -C alkyl-C -C arylene and 0 6 ' 6 10 ' C -C alky-het; U o where the substituents on any alkyl are 1-3 R and the substituents on any aryl or het are 1- 3 R d ; W is a C -C -alkyl substituted with a group selected from R a , NH-C(-0)-NR n R n , NH-C(=0)-R C , C(=0)-R C , C(=0)-NH-C(=0)-R C , C(=0)-NH-C(=0)-NR n R n ', C(=0)-NH-S0 - R C , C(=0)-NH-SO -NR n R n , C(=0)NR n R n ', NH-C(=0)-R C and c R and pharmaceutically acceptable salts thereof. 7) The method of Claim 6 wherein the compound selected from the group and where D is selected from the group 1 2 3 4 5 H where Y , Y , Y , Y and Y are selected from the group CH and CR ; Z is selected from the group NR , O and S; n is 0-3; L is selected from the group substituted or unsubstituted C -C alkylene, 2 5 C -C cycloalkylene, 3 6 C -C alkylene-NR n -(C=0)-C -C alkylene, C -C alkylene-(C=0)-NR n -C -C alkylene, C -C alkylene-O-C -C alkylene, C -C alkylene-NR n -C -C alkylene, C -C alkylene-(C=0)-C -C alkylene, C 0 -C 3 alkylene-S(O) 02 -C 0 -C 3 alkylene, C -C alkylene-NR n -SO -C -C alkylene, C -C alkylene-SO -NR n -C -C alkylene, C n -C alkylene-Ol 1 =CR 2 -C n -C-alkylene, 0 3 0 3 C -C alkylene-C=C-C -C alkylene and C -Calkylene-het-C -C alkylene 0 3 ' 0 3 ' where the substituits are selected from the group one to three R 1 , „ R2 and R ; Y L is selected from the group substituted or unsubstituted C -C alkylene, C -C alkylene-NR n -(C=0)-C -C alkylene, C -C alkylene-(C=0)-NR n -C -C alkylene, C -C alkylene-O-C -C alkylene, 0 2 ' 0 2 ' C -C alkylene-NR n -C -C alkylene, 0 2 ' 0 2 ' C -C alkylene-(C=0)-C -C alkylene, 0 -C 3 alkylene-S(O) 02 -C 0 -C 3 alkylene, C -C alkylene-SO -NR n -C -C alkylene and 0 3 ' 2 0 3 ' C -C alkylene-aryl-C -C alkylene 1 2 3 where the substituits are selected from the group one to three R , R and R ; 1 2 3 R , R and R are selected from the group hydrogen, C -C alkyl-hydroxy, 1 8 halo(F, Cl, Br, I), halo(F, Cl, Br, I)-C -C alkyl, 1 8 cvano, isocyanate, carboxy, carboxy-C -C alkyl, ammo, amino-C -C alkyl, 1 8 ' amino-di(C -C alkyl), aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C -C alkoxy, 1 6 mercapto, sulfonamido, phenoxy, phenyl, and benzamido; R is selected from the group hydrogen, halo(F. Cl, Br, I), carboxy, amino, amino-C -C alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, imidazoyl, ureido, hydroxy, C -C alkoxy, 1 6 sulfonamido, het, phenoxy and phenyl, R c is selected from hydrogen and substituted or unsubstituted c ι- c ιo aIky1 ' 2 -C 1Q alkenyl, C -C alkynyl, 2 10 ' ' C -C cycloalkyl, C -C cycloalkenyl, Cι -C 6 alkyl-C 6 -C 12 aryl, C 6- C 10 aryl - C l- C 6 alkyl C -C alkyl-het, het-C -C alkyl, 1 6 ' C 6 -C 12 aryl, c ι "c ιo alkyl" ° " ' C 2 -C 1() alkenyl-0-, C 2 "C 10 alkynyl" ° " ' C -C cycloalkyl-O-, C -C cycloalkenyl-O-, C^C^lkyl-C^C^aryl-O- C 6 -C 10 aryl-C ι -C 6 alkyl-O- C -C alkyl-het-O-, 1 6 het-C -C alkyl-O-, 0 6 C 6 -C 12 aryl-0- C^C^alkyl-NR 1 ,n C^-C^alkenyl-NR 1 2 10 " C -C ι n alkynyl-NR n -, " 2 ~10 " C V α -C ι l ι * C ycloalkyl-NR n - C -C cycloalkenyl-NR -, C ι -C 6 alkyl-C 6 -C 12 aryl-NR n -, C 6 -C ιo aryl-C ι -C 6 alkyl-NR n -, C -C,alkyl-het-NR n -, 1 6 ' het-C -C alkyl-NR n -, 0 6 C -C aryl-NR - and het, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl or het are 1-3 R ; het is selected from the group R^ and R are independently selected from the group OH, CN, N0 2 , halo(F, Cl. Br, I), OR n SR n , SOR n , CF 3' R c , NR n R n ', NR n C(=0 ■0-R n ', NR n c(=o -R n : C^alkyl- S0 2 -R n , C -C alkyl-SO -NR n R n , 0 6 2 C(=0)-R n , 0-C(=0)-R n , C(=0)-0-R n and C(=0)-NR n R n , R is a chemical bond when het is a divalent linking group; R and R are independently selected from the group hydrogen, hydroxy, C -C alkyl and 1 6 ' halo(F, Cl. Br, I)-C -C alkyl; 1 6 V is absent or is an optionally substituted bivalent group selected from C -C, alkylene, 1 6 C -C alkylene-O-C -C alkylene, C -C alkenylene, C -C alkylene-O-C -C alkenylene, 0 2 ' 2 4 ' C -C cycloalkylene, 3 8 C -C alkyl-C -C arylene and 0 6 6 10 C -C alky-het; U o a d where the substituents on any alkyl are 1-3 R and the substituents on any aryl or het are 1-3 R ; W is selected from the group hydrogen, NH-C(=0)-NR n R n ' . NH-C(=0)-R^, C(=0)-NH-C(=0)-R" C(=0)-NH-C(=0)-NR n R n , C(=0)-NH-S0 - R ^ C(=0)-NH-SO -NR n R n , C(=0)NR n R n , NH-C(=0)-R L and R ; and pharmaceutically acceptable salts thereof. 8) The method of Claim 6 wherein the compound is selected from the group and where 1 2 3 4 5 R , R , R , R ,and R are selected from the group hydrogen, C -C alkyl-hydroxy, halo(F, Cl, Br, I), halo(F, Cl, Br, I)-C -C alkyl, 1 8 amino, amino-C -C alkyl, 1 8 aminocarbonyl-C -C alkyl, amino-di(C -C alkyl), 1 8 carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, ureido, hydroxy, C -C, alkoxy, 1 6 sulfonamido, phenyl and phenoxy, R is selected from the group hydrogen, halo(F. Cl Br, I), cyano, isocyanate, carboxy, amino, amino-C -C alkyl, 1 8 ' aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, imidazoyl, ureido, hydroxy, C -C alkoxy, 1 6 sulfonamido, phenoxy and phenyl, R c is selected from hydrogen and substituted or unsubstituted C -C alkyl, 1 10 ' C 2 "C 10 alkenyl C 2 "C 10 alkynyI ' 3 -C cycloalkyl, ^ ^ i ^ cycloalkenyl, C l "C 6 alkyl - C 6- C 12 aryI ' C 6- C 10 aryl - C l- C 6 alky1 ' C -C alkyl-het, het-C -C, alkyl, 1 6 C 6 -C 12 aryl, C^alkyl-O-, C 2 -C 1() alkenyl-0-, C 2 -C 10 alkynyI-O-, C 3 -C cycloalkyl-O-, C -C cycloalkenyl-O-, C^C^lkyl-C^C^aryl-O- C 6- C 10 aryI - C l- C 6 aIkyl -°- C -C alkyl-het-O-, 1 6 het-C -C, alkyl-O-, U 6 C 6 -C 12 aryl-0- C^C^alkyl-NR 1 C 2 -C ιo alkenyl-NR n - C 2 -C 1() alkynyl-NR n - C 3 -C cycloalkyl-NR n - C -C cycloalkenyI-NR n - C -C, alkyl-C, -C aryl-NR r 1 6 6 12 ' C -C aryl-C -C,alkyl-NR n -, 6 10 ' 1 6 ' C -C alkyl-het-NR 11 -, 1 6 het-C -C alkyl-NR n -, 0 6 C -C aryl-NR n - and 6 12 ' het, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R and the substituents on any aryl or het are 1-3 R ; R are independently selected from the group OH, C -C, alkyl, I o halo(F, CI. Br, I), N0 2 , cyano, OR n , SR SOR CF 3' R C , NR n R n ', NR n C(=0)-0-R n , NR n C(=0)-R n , C -C,alkyl-SO -R 0 6 ' 2 C -C,alkyl-SO -NR n R n , 0 6 2 C(=0)-R n , 0-C(=0)-R n , C(=0)-0-R n and C(=0)-NR n R n , het is selected from the group R and R are independently selected from the group hydrogen, hydroxyl, C -C aikyl and 1 6 halo(F, Cl. Br, I)-C -C alkyl; 1 6 halo is selected from the group F and Cl; Z is selected from the group NR , O and S; n is 0-3; and pharmaceutically acceptable salts thereof . 9) The method of Claim 6 wherein the adhesion receptor is selected from LFA-1 (CDlla/ CD18) and Mac-1 (CDllb/CD18). 10) The method of Claim 9 wherein the adhesion receptor is LFA-1. 11) The method of Claim 6 wherein the immune disorder is selected from the group; rejection of or by a transplanted graft, psoriasis, rheumatoid arthritis, asthma and multiple sclerosis. 12) The method of Claim 6 further comprising administering an effective amount of an immunosuppressive agent to the mammal. 13) The method of Claim 6 further comprising administering an effective amount of a VLA- 4 antagonist to the mammal. 14) The method of Claim 10 wherein the disorder is selected from psoriasis and asthma and the therapeutically effective amount of the LFA-1 antagonist is administered orally, topically, transdermally, inter-pulmonary or inter-nasal. 15) The method of Claim 6 wherein the mammal is a human.

Inventors: BURDICK DANIEL J, BURDICK, DANIEL, J.
Applicants: BURDICK DANIEL J, GENENTECH INC, BURDICK, DANIEL, J., GENENTECH, INC.
Application year: 1999
Main classification: A61K31
IPC codes: A61K31, A61P11, A61P17, A61P25, A61P29, A61P37, A61P43, C07D207, C07D209, C07D211, C07D231, C07D249, C07D261, C07D285, C07D307, C07D333, C07D409