MXPA00009117A - Antagonists for treatment of cd11/cd18 adhesion receptor mediated disorders - Google Patents

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 THE TREATMENT OF MEDIATED DISORDERS BY THE ADHESION RECEIVER CD11 / CD18 Field of Invention This invention relates to methods and therapeutic compositions for the treatment of mammals, preferably humans, suffering from or are susceptible to disorders mediated by the adhesion receptor (CD11 / CD18), especially disorders mediated by the leukocyte LFA-1. In particular, it relates to methods for decreasing or modulating immune responses such as those caused by inflammation, autoimmune responses, and rejection of host grafts, as exemplified by psoriasis, rheumatoid arthritis, asthma, multiple sclerosis, rejection following grafts. transplanted and similar.

Antecedent-bes of the Invention.

Inflammation Peripheral human blood is composed mainly of red blood cells, platelets and Ref: 123156 white blood cells or leukocytes. The family of leukocytes is also classified as neutrophils, lymphocytes (mainly subtypes of T and B cells), monocytes, eosinophils and basophils. Neutrophils, eosinophils and basophils are sometimes referred to as "granulocytes" or "polymorphonuclear granulocytes (PMN)" due to the appearance of granules in their cytoplasm and their multiple nuclei. Granulocytes and monocytes are often classified as "phagocytes" due to their capacity for phagocytosis or microorganisms of intake and foreign matter generally referred to as "antigens". Monocytes are so named because of their large single nucleus and these cells can in turn become macrophages. Phagocytes are important in defending a host against a variety of infections and together with lymphocytes, they are also involved in inflammatory disorders. Neutrophils are the most common leukocyte found in peripheral human blood followed closely by lymphocytes. In a microliter of normal peripheral human blood, there are about 6000 leukocytes, of which about 4000 are neutrophils, 1500 are lymphocytes, 250 are monocytes, 150 are eosinophils and 25 are basophils.

During an inflammatory response, peripheral blood leukocytes are recruited at the site of inflammation or wound by a series of specific cellular interactions (see Figure 1). The initiation and maintenance of immune functions is regulated by intercellular adhesive interactions as well as signal transduction resulting from the interactions between leukocytes and other cells. The adhesion of the leukocyte to the vascular endothelium and the migration of the circulation to sites of inflammation is a critical stage in the inflammatory response (figure 1). The immune recognition of the T cell lymphocyte requires the interaction of the T cell receptor with the antigen (in combination with the major histocompatibility complex) as well as adhesion receptors, which promote the placement of T cells to cells that present antigens and transduce signals for the activation of T cells. Antigen 1 associated with lymphocyte function (LFA-1) has been identified as the main integrin that mediates the adhesion and activation of lymphocytes that lead to a normal immune response, as well as various pathological states (Springer, T: A :, Na tu re 346: 425-434 (1990).) Intercellular adhesion molecules (ICAM) -1, -2 and -3, members of the immunoglobulin superfamily, are ligands of LFA-1 found in the endothelium, leukocytes and other cell types The binding of LFA-1 to ICAMs mediates a range of lymphocyte functions that include the production of T-cell lymphokines. They help in response to the present antigen cells, lysis of target cells mediated by T lymphocytes, natural death of tumor cells, and production of immunoglobulin through B cell-T cell interactions. Thus, many facets of lymphocyte function they involve the interaction of integrin LFA-1 and its ICAM ligands. These LFA-1: ICAM-mediated interactions have been directly implicated in numerous states of inflammatory disorders including graft rejection, dermatitis, psoriasis, asthma, and rheumatoid arthritis.

While LFA-1 (CDlla / CD18) in 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 in other leukocytes, such as granulocytes and monocytes, particularly in the early response to infectious agents and in the acute inflammatory response.

The primary function of polymorphonuclear leukocytes, derived from the neutrophil, eosinophilic and basophilic lineage, is to sensitize the inflammatory stimuli and migrate through the endothelial barrier and carry out a sequestering function as a first line of defense of the host. The Mac-1 integrin (CDllb / CD18) is rapidly over-regulated on this cell by activating and binding to its multiple ligands which results in the release of free radicals derived from oxygen, proteases and phospholipases. In certain chronic inflammatory states, these recruitments are improperly regulated resulting in significant tissue and cell damage. (Harán, J.M., Ac taMed Sca n Suppl., 715: 123 (1987); eiss, S., New Engl and J. of Med., 320: 365 (1989)).

LFA-1 (CDlla / CD18) and Mac-1 (CDllb / CD18) The family (CD11 / CD18) of adhesion receptor molecules comprises 4 highly related cell surface glycoproteins; LFA-1 (CDlla / CD18), Mac-1 (CDl lb / CD18), pl50.95 (CDllc / CD18) and (CDlld / CDl8). LFA-1 is present on the surface of all mature leukocytes except that a subset of macrophages is considered the major lymphoid integrin. The expression of Mac-1, pl50.95 and (CDllc / CD18) is confined mainly to the cells of the myeloid lineage (which includes neutrophils, monocytes, macrophages and mastoid cells). Functional studies have suggested that LFA-1 interacts with various ligands, including ICAM-1 (Rothlein et al., J. Imm un ol. 137: 1270-1274 (1986), ICAM-2, (Stauton et al., Na ture 339: 361-364 (1989)), ICAM-3 (Fa cett et al., Na t ure 360: 481-484 (1992); Vezeux et al., Na t u re 360: 485-488, (1992); from Fougerolles and Springer, J. Exp. Med. 175: 185-190 (1990)) and Telencephalin (Tian et al., J. Immunol 158: 928-936 (1997)).

The CD11-CD18 family is structurally and genetically related to a larger family of receptor integrins that modulate the adhesive interactions of cells, which includes; embryogenesis, adhesion to extracellular substrates and cell differentiation (Hynes, RO, Cell 48: 549-554 (1987); Kishimoto et al., Adv. Immunol. 46: 149-182 (1989); Kishimoto et al., Cell 48 : 681-690 (1987); Ruoslahti et al., Science 238: 491-497 (1987).

Integrins are a class of membrane-extending heterodimers that comprise a subunit a in a non-covalent association with a β subunit. The β subunits are generally capable of association with more than one subunit and the heterodimers that share a common β subunit have been classified as subfamilies within the integrin population (Larson and Springer, "Structure and function of leukocyte integrins", Immunol. Rev. 114: 181-217 (1990)).

The integrin molecules of the CD11 / CD18 family; and its cellular ligands, have been found to mediate a variety of cell-cell interactions especially in inflammation. These proteins have been shown to be critical for adhesive functions in the immune system (Kishimoto et al., Adv. Immunol., 46: 149-182 (1989)). Monoclonal antibodies to LFA-1 have been shown to block the adhesion of leukocytes to endothelial cells (Dustin et al., J. Cell Biol. 107: 321-331 (1988; Smith et al., J. Clin. Invest. 83: 2008-2017 (1989)) and inhibit the activation of T cells (Kuypers et al., Res. Immunol., (1989)), the formation of conjugates required to eliminate the antigen-specific CTL (Kishimoto et al. ., Adv. Immunol., 46: 149-182 (1989)), the proliferation of T cells (Davignon et al., J. Immunol., 127: 590-595 (1981)) and the elimination of NK cells (Krensky et al. ., J. Immunol. 131: 611-616 (1983)).

ICAMs ICAM-1 (CD54) is a cell surface adhesion receptor that is a member of the immunoglobulin protein superfamily (Rothlein et al., J. Immunol., 137: 1270-1274 (1986); Staunton et al., Cell 52: 925-933 (1988)). The members of this superfamily are characterized by the presence of one or more regions of Ig homology, each consisting of a disulfide-bridged circuit having various strands of antiparallel ß-folds placed in two sheets. Three types of homology regions have been identified, each with a typical length and having a consensus sequence of amino acid residues located between the disulfide bond cysteines (Williams, AF 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 (Dustin et al., J. Immunol., 137: 254-256 (1986)). ICAM-1 is a 90,000-110,000 Mr glycoprotein with low levels of messenger RNA and moderate surface expression on unstimulated endothelial cells. LPS, IL-1 and TNF strongly upregulate ICAM-1 RNA and surface expression with a peak expression at approximately 18-24 hours (Dustin et al., J. Cell Biol. 107: 321-331 ( 1988), Staunton et al., Cell 52: 925-933 (1988)). ICAM-1 has five extracellular domains such as Ig (domains designated 1,2,3,4 and 5 or D1, D2, D3, D4 and D5) and an intracellular or cytoplasmic domain. The structures and sequence of the domains are described by Staunton et al. (Cell 52: 925-933 (1988)).

ICAM-1 was originally defined as a counterreceptor for LFA-1 (Springer et al., Ann. Rev. Immunol, 5: 223-252 (1987); Marlin Cell 51: 813-819 (1987); Simmons et al. ., Nature 331: 624-627 (1988), Staunton Nature 339: 61-64 (1989), Staunton et al., Cell 52: 925-933 (1988)). The LFA-I / ICAM-1 interaction is known to be at least partially responsible for the adhesion of lymphocytes (Dustin et al., J Cell, Biol. 107: 321-331 (1988); Mentzer et al., J Cell. Physiol. 126: 285-290 (1986)), the adhesion of monocytes (Amaout et al., J. Cell Physiol., 137: 305 (1988); Mentzer et al., J. Cell. Physiol 130: 410-415 (1987); and the adhesion of neutrophils (Lo et al., J. Ir.-r.unol., 143 (10): 3325-3329 (1989); Smith et al., J. Cl in. Invest., 83: 2008-2017 (1989)) to endothelial cells. Through the development of the blocking function of monoclonal antibodies to ICAM-1, additional ligands were identified for LFA-1, ICAM-2 and ICAM-3 (Simmons, Cán cer Surveys 24, Cell Adhesion and Cancer, 1995). they mediate the adhesion of lymphocytes to other leukocytes as well as non-hematopoietic cells. The interactions of LFA-1 with ICAM-2 are thought to mediate the natural cellular clearance activity (Helander et al., Na t ure 382: 265-267 (1996)) and the ICAM-3 link is thought to play a role role in the activation of lymphocytes and in the initiation of the immune response (Simmons, ibid). The precise role of these ligands in aberrant and normal immune responses remains to be defined.

Disorders mediated by T lymphocytes Functional blocking monoclonal antibodies have shown that LFA-1 is a mediated eliminator of T lymphocytes, with response to T lymphocytes that help, natural elimination, and antibody-dependent elimination (Springer et al., Ann Rev. Immunol 5 : 223-252 (1987)). Adhesion to target cells as well as activation and signaling are steps that are blocked by antibodies against LFA-1.

Many disorders and diseases are mediated through T lymphocytes and the treatment of these diseases has been directed through various routes. Rheumatoid arthritis (RA) is one such disorder. Current therapy for RA includes bed rest, heat application and medications. Salicylate is the currently preferred medication particularly for the treatment, since other alternatives such as immuno-depressant agents and adrenocorticosteroids can cause greater morbidity than the underlying disease by itself. Non-steroidal anti-inflammatory drugs are available, and many of them have effective analgesic, antipyretic and anti-inflammatory activity in patients with RA. These include cyclosporin, indomethacin, phenyl butazone, derivatives of phenyl acetic acid such as ibuprofen and fenoprofen, naphthalene acetic acids (naproxen), pirrolalcanóico acid (tometin), indoleacetic acids (sulindac), halogenated anthranilic acid (meclofenamate sodium), piroxicam and diflunisal. Other medications for use in RA include antimalarials such as chloroquine, gold salts and penicillamine. These alternatives frequently produce severe side effects, including retinal and kidney injuries and spinal cord toxicity. Immuno depressant agents such as methotrexate have been used only in the treatment of non-remitting and severe RA due to their toxicity. Corticosteroids are also responsible for undesirable side effects (eg cataracts, osteoporosis and Cushing's disease syndrome) and are not well tolerated in many patients with RA.

Another disorder mediated by T lymphocytes is the rejection of the host to grafts after transplantation. Efforts to prolong the survival of transplanted allografts and xenografts, or to avoid host rejection against grafting, both in experimental models and in medical practice, have focused mainly on the elimination of the host / recipient immune system. This treatment has as its support, preventive immunosuppression and / or the treatment of graft rejection. Examples of the agents used for preventive immunosuppression include cytotoxic drugs, antimetabolites, corticosteroids, and antilymphocyte serum. Non-specific immunosuppressive agents that are particularly effective in preventive immunosuppression (azathioprine, bromocriptine, methylprednisolone, prednisone, and more recently cyclosporin A) have significantly improved the clinical success of transplants. The nephrotoxicity of ciclosporin A after renal transplantation has been reduced by the co-administration of steroids such as prednisolone or prednisolone in conjunction with azathioprine. In addition, kidneys have been successfully grafted using anti-lymphocyte globulin followed by cyclosporin A. Another protocol being evaluated is total irradiation of lymphoid from the recipient before transplantation followed by minimal immunosuppression after transplantation. The treatment of rejection has involved the use of steroids, pyrimidine 2 amino 6 aryl 5 subtituted, heterologous globulin antilymphocytes, and monoclonal antibodies for various populations of leukocytes, including OKT-3. See generally J. Pediatrics, 111: 1004-1007 (1987), and specifically U.S. Patent No. 4,665,077.

The main complication of immunosuppressive drugs are infections.

Additionally, systemic immunosuppression is accompanied by undesirable toxic effects (eg, nephrotoxicity when cyclosporin A is used after a kidney transplant) and reduction in the level of hemopoietic stem cells. Immunosuppressive medications can also lead to obesity, poor wound healing, steroid hyperglycemia, steroid psychosis, leukopenia, gastrointestinal bleeding, lymphoma and hypertension.

In view of these complications, transplant immunologists have sought methods to eliminate the immune response in a specific form of antigens (so that only the alloantigen response of the donor would be lost). In addition, physicians who specialize in autoimmune diseases, fight for methods to suppress the autoimmune response so that only the response of the self antigen is lost. Such specific immunosuppression has generally been achieved by modifying either the antigenicity of the tissue to be grafted or the specific cells capable of mediating rejection. In certain cases, whether the immunity or tolerance is induced depends on the way in which the antigen occurs in the immune systems. The pretreatment of tissues alloyed by growth in tissue culture before transplantation has been found in two murine model systems to lead to permanent acceptance through MHC barriers. Lafferty et al. , Tran splan ta t on, 22: 138-149 (1976); Bowen et al. , La n ce t, 2: 585-586 (1979). It is hypothesized that such treatments result in the suppression of transient lymphoid cells and thus the absence of a cell population stimulator necessary for tissue immunogenicity. Lafferty et al. , Ann u. Rev. Imm unol. , 1: 143 (1983). See also Lafferty et al., Science, 188: 259-261 (1975) (sustained thyroid in organ culture) and Gores et al., J. Immunol., 137: 1482-1485 (1986) and Faustman et al. , Proc. Nati Acad. Sci. U.S.A., 78: 5156-5159 (1981) (islet cells treated with anti-Ia murine antisera and supplemented before transplantation). Also, thyroid taken from donor animals pretreated with lymphocytotoxic drugs and gamma radiation and cultured for ten days in vitro, were not rejected by any normal allogeneic recipient (Gose and Bach, J. Exp. Med., 149: 1254-1259 (1979 )). All these techniques involve the elimination or separation of the lymphocyte cells from the donor.

In some models such as kidney and vascular grafts, there is a correlation between class II coupling and prolonged allograft survival, a correlation that is not present in skin grafts (Pescovitz et al., J. Exp. Med. ., 160: 1495-1508 (1984); Coni et al., Transplant, Proc., 19: 652-654 (1987)). Therefore, the HLA donor recipient coupling has been used. Additionally, blood transfusions prior to transplantation have been found effective (Opelz et al., Transplant Proc., 4: 253 (1973); Persijn et al., Transplant Proc., 23: 396 (1979)). The combination of blood transfusion before transplantation, the coupling of the HLA donor vessel, and immunosuppressive therapy (cyclosporin A) after transplantation was found to significantly improve the rate of graft survival, and the effects were found to they were additive (Opelz et al., Transplant, Proc., 17: 2179 (1985)).

The response to transplantation can also be modified by antibodies directed to immune receptors for MHC antigens (Bluestone et al., Immunol Rev. 90: 5-27 (1986)). In addition, graft survival can be prolonged in the presence of anti-graft antibodies, which leads to a host reaction which in turn produces a specific immune immunosuppression (Lancaster et al., Nature, 315: 336-337 (1985)). The immune response of the host to the MHC antigens can be modified specifically by using a bone marrow transplant as a preparative procedure for organ grafting. Thus, anti-T cell monoclonal antibodies are used to remove mature T cells from the donor medulla inoculum to allow bone marrow transplantation without incurring graft-versus-host disease (Muller-Ruchholt z et al., Tra n spl ant Proc., 8: 537-541 (1976)). In addition, the elements of host lymphoid cells that remain for bone marrow transplantation resolve the immunocompetency problem that occurs when fully allogeneic transplants are used.

As shown in Figure 1, the adherence of the lymphocyte to the endothelium is a key event in the inflammation process. There are at least three known trajectories of lymphocyte adhesion to the endothelium, depending on the activation state of the T cell and the endothelial cell. The immune recognition of T cells, requires the contribution of the T cell receptor as well as adhesion receptors, which promotes the placement of cells to cells that present antigens and transduce regulatory signals for the activation of T cells. Antigen 1 (LFA ) associated with lymphocyte function (LFA-1 CDlla / CD18, aLß2: where aL is CDlla and β2 is CD18) has been identified as the main integrin receptor in the lymphocytes involved in these cell adhesion interactions that lead to diverse pathological states. ICAM-1, the adhesion molecule as endothelial cell immunoglobulin, is a known ligand for LFA-1 and is directly involved in the rejection of grafts, psoriasis and arthritis.

LFA-1 is required for a range of leukocyte functions that include the production of T cell lymphokine that aids in response to antigen presenting cells, lysis of target cells mediated with T cell eliminators, and production of immunoglobulin through cell interactions T / cell B. Activation of antigen receptors on T cells and B cells allows LFA-1 to bind to its ligand with higher affinity.

Monoclonal antibodies (Mabs) directed against LFA-1 lead to the initial identification and investigation of the function of LFA-1 (Davignon et al., J. Immunol., 127: 590 (1981)). LFA-1 is present only in leukocytes (Krenskey et al., J. Immunol., 131: 611 (1983)), and ICAM-1 is distributed in activated leukocytes, dermal fibroblasts, and endothelium (Dustin et al., J. Immunol., 137: 245 (1986)).

Previous studies have investigated the effects of anti-CDlla MAbs on many immune functions dependent on T cells in vitro and a limited number of immune responses in vivo. In vitro, the anti-CDlla MAbs inhibit the activation of T cells (Kuypers et al., Res. Immunol., 140: 461 (1989)), The proliferation of B cells dependent on T cells and differentiation (Davignon et al. , supra, E'ischer et al., J. Immunol., 136: 3198 (1986)), the lysis of target cells by cytotoxic T lymphocytes (Krensky et al., supra), the formation of immune conjugates (Sanders et al. ., J. Immunol 137: 2395 (1986), Mentzer et al., J. Immunol 135: 9 (1985)), and the adhesion of T cells to vascular endothelium (Lo et al., J. Immunol., 143: 3325 (1989)). Also, the 5C6 antibody directed against CDllb / CD18, was found to prevent intra-macroscopic infiltration of macrophages and T cells, to inhibit the development of insulin-dependent diabetes mellitus in mice (Hutchings et al., Nature, 348: 639 (1990)).

The observation that the LFA-1: ICAM-1 interaction is necessary to optimize the function of T cells in vitro, and that the anti-CDlla MAbs induces tolerance in protein antigens (Benjamín et al., Eur. J Immunol., 18: 1079 (1988)) and prolongs the survival of tumor grafts in mice (Heagy et al., Transplantation, 37: 520-523 (1984)), was the basis for the test that the MAbs of the molecules prevent the rejection of grafts in humans.

Experiments on primates have also been carried out. For example, based on simian experiments, it has been suggested that a MAb directed against ICAM-1 can prevent or even reverse rejection of the kidney graft (Cosimi et al., "Immunosuppression of Cynomolgus Recipients of renal Allografts. by R6.5, a Monoclonal Antibody to Intercellular Adhesion Molecule-l, "in Springer et al. (eds), LeuJocyte Adhesion Molecules New York: Springer, (1988), p.274, Cosimi et al., J. Immunology, 144: 4604-4612 (1990)). In addition, in vivo administration of an anti-CDlla MAb to cynomologous simians prolonged the survival of the allograft in the skin (Berlin et al., Transplantation, 53: 840-849 (1992)).

The first successful use of a CDLA anti-mouse antibody (25-3; IgG1) in children with inherited disease to avoid rejection of haploidentical grafts not coupled to bone marrow, was reported by Fisher et al., Lancet, 2: 1058 (1986). Minimal side effects were observed. See also Fisher et al., Blood, 77: 249 (1991); van Dijken et al., Transplantation, 49: 882 (1990); and Pérez et al., Bone Marrow Transplantation, 4: 379 (1989). In addition, antibody 25-3 was effective in controlling acute steroid-resistant graft-versus-host disease in humans (Stoppa et al., Transplant. Int., 4: 3-7 (1991)).

However, these results were not reproducible in grafts of leukemic adults with this MAb (Maraninchi et al., Bone Marrow Transplant, 4: 147-150 (1989)), or with anti-CD18 MAb, directed against the non-variant chain of LFA-1, in another pilot study (Baume et al., Transplantation, 47: 472 (1989)). In addition, an anti-murine rat CDlla MAb, 25-3, was unable to control the course of acute rejection in a human kidney transplant (LeMauff et al., Transplantation, 52: 291 (1991)).

A review of the use of monoclonal antibodies in transplantation in humans is provided by Dantal and Soulillou, Current Opinion in Immunology, 3: 740-747 (1991).

A previous report showed that brief treatment with anti-LFA-1 or anti-ICAM-1 MAbs, minimally prolongs the survival of primary vascularized heterotopic heart allografts in mice (Isobe et al., Science, 255: 1125 (1992)). However, combined treatment with both MAbs was required to achieve long-term graft survival in this model.

Independently, it has been shown that treatment with anti-LFA-1 MAb alone, potently and effectively prolongs the survival of non-primarily vascularized mouse heart grafts., heterotopic (from the pinna) using a maximum dose of 4 mg / kg. per day and treatment once a week after a daily dose (Nakakura et al., J. Heart Lung Transplant., 11: 223 (1992)). Non-primary vascularized heart allografts are more immunogenic and more resistant to prolongation of survival by MAbs than primary vascularized heart allografts (Warren et al., Transplant, Proc., 5: 717 (1973)).; Trager et al., Transplantation, 47: 587 (1989)). The last reference discusses treatment with L3T4 antibodies using a high initial dose and a subsequent lower dose.

Another study in the treatment of a sclerosis-like disease in rodents using antibodies similar to those used by Nakakura et al., Supra, is reported by Yednock et al., Nature, 356: 63-66 (1992).

Further descriptions on the use of anti-LFA-1 and ICAM-1, ICAM-2 and ICAM-3 antibodies and their antibodies to treat LFA-1 mediated disorders include WO 91/18011 published 11/28/91, WO 91 / 16928 published 11/14/91, WO 91/16927 published 11/14/91, Can Pat. Appln. 2008368 published 6/13/91, WO 90/03400, WO 90/15076 published 12/13/90, WO 90/10652 published 9/20/90, EP 387668 published 9/19/90, WO 90/08187 published 7 / 26/90, WO 90/13281, WO 90/13281, WO 93/06864, WO 93/21953, WO 93/13210, WO 94/11400, EP 379904 published 8/1/90, EP 346,078 published 12/13 / 89, US Pat. No. 5002869, U.S. Pat. No. 5071964, U.S. Pat No. 5209928, U.S. Pat. No. 5223396, U.S. Pat. No. 5235049, U.S. Pat. No. 5284931, U.S. Pat. No. 5288854, U.S. Pat. No. 5354659, Australian Pat. Appln. 15518/88 published 11/10/88, EP 289949 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 362,531, EP 438,310.

Other descriptions regarding the use of LFA-1 and fragments of ICAM peptides and antagonists include the American patents; U.S. Pat. No. 5,149,780, U.S. Pat. No. 5,288,854, U.S. Pat. Do not. ,340,800, U.S. Pat. No. 5,424,399, U.S. Pat. No. 5,470,953, and patents 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 utilize anti-LFA-1 or anti-ICAM-1 antibodies, LFA-1 or ICAM-1 peptides, peptide fragments or antagonists which represent an improvement over traditional immunosuppressant drug therapy. These studies demonstrate that LFA-1 and ICAM-1 are appropriate targets for antagonism. There is a need in the art to better treat disorders that are mediated by LFA-1 including autoimmune diseases, host rejection against graft and graft versus host, and inflammatory responses to T cells, so as to minimize side effects and sustain a tolerance specific to xenoantgens or autoantigens. There is also a need in the art to provide a non-peptide antagonist or peptide identical to the LFA-1: ICAM-1 interaction.

At least one peptide mimetic antagonist of the LFA-1: ICAM-1 interaction has shown promise in several in vitro trials. 2-bromobenzoyltriptophane shows IC50s of around 2μM and lOμM respectively in human LFA-1: ICAM-1 receptors that bind and in human T cell adhesion assays described herein.

Recently, the aminobenzoic acid derivatives of fluorene have been described in US Pat. No. 5,472,973 as useful anti-inflammatory agents. A representative compound is: Objectives 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 family of leukocyte integrin receptors.

It is an object to antagonize the receptors CD11 / CD18 associated with leukocytes, especially disorders mediated by Mac-1 and LFA-1 with minimal side effects.

It is an object to col inappropriate inflammatory responses and avoid damage to healthy tissue.

More specifically, it is an object to treat disorders mediated by LFA-1 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 T cell infiltration and chronic inflammatory responses, hypersensitivity reactions of the skin (including poison ivy and poison oak); arteriosclerosis, 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 attack diabetes, and immune responses associated with delayed hypersensitivity mediated by cytosines, T lymphocytes typically found in tuberculosis, sarcoidosis, polyunsit im, granulomatosis, and vasculitis; pernicious anemia, diseases that involve leukocyte diapedesis; Inflammatory disorder of CNS, multiple organ damage syndrome, secondary to sepsis or trauma; autoimmune hemolytic anemia; myasthenia gravis; diseases mediated by the antigen-antibody complex; all types of transplants, including graft versus host or host against graft, HIV infection and rhinovirus, pulmonary fibrosis and the like.

These and other objects will be apparent to someone skilled in the art.

Brief Description of the Invention These objects are achieved by providing a method and antagonist compositions for modulating adhesion between intracellular adhesion molecules (eg, ICAM-1, -2 and -3) and the family of leukocyte integrin receptors. The method and antagonists are especially useful for treating disorders mediated by CD11 / CD18, especially Mac-1 and LFA-1 in a mammal, especially a human, which comprises administering to a mammal a therapeutically effective amount of the antagonist. Suitable leukocyte integrin antagonists, especially the 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 integrin CDlla (aL) / CD18 (β2). Such antagonists are especially useful for treating chronic disorders mediated by LFA-1. Preferably, these LFA-1 antagonists are used to treat psoriasis, alopecia, organ transplantation, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes, multiple sclerosis (MS). , asthma, graft-versus-host disease (GVH), sclerodoma, endometriosis and vitiligo. Optionally, certain compounds grouped by formula 1 are also capable of antagonizing the binding of Mac-1 CDllb (aM) / CD18 (ß2) to ICAM-1 and additional ligands including iC3b, fibrinogen and factor X. These compounds are thus useful for inhibiting the adhesion of neutrophils and leukocytes that express both LFA-1 and Mac-1 in chronic and acute leukocyte / neutrophil-mediated disorders. More specifically, these disorders include; ischemic damage by neutrophil-mediated reperfusion such as acute myocardial infarction, restenosis following PTCA, invasive procedures such as direct cardiopulmonary surgery, cerebral edema, infarction, traumatic brain injury, multiple sclerosis, systemic lupus erythematosus, hemorrhagic shock, burns, ischemic kidney disease, multi-organ failure, wound healing and scar formation, atherosclerosis as well as organ failure after a transplant.

The antagonist is represented by formula I (i) where D is a mono, bi or tricyclic saturated, unsaturated or aromatic ring, each ring has 5, 6 or 7 atoms in the ring where the atoms in the ring are carbon or from 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein any sulfur ring atom may optionally be oxidized and any carbon ring atom may form a double bond with O, NRn and CR1R1 'each ring nitrogen substituted with Rn and any carbon of the ring substituted with Rd.

Optionally, D is an aromatic homocycle or aromatic heterocycle containing from 1-3 heteroatoms selected from the group N, S and O, the homo or heterocycles selected from: where Y1, Y2, Y3, Y4 and Y5 are CH, CRd or N, ZX is 0, S, NH or NRn and n is 0-3.

More specifically, D can be: 1) a 5-membered aromatic heterocycle or hetero selected from; 2) a 9-membered aromatic heterocycle selected from; 3) a hetero or 6-membered aromatic homocycle selected from; L is a bivalent linking group selected from -L3 -! - 2 -: --- 1- -L5-L4-L3-L2- - 1-, where L1 can be oxo (0), S (0) S, C (= 0), C (= N-Rn), C (= CR1R1 '), CÍR ^ 1'), C (RX), C, het, N (Rn) or N; L2 can be oxo (O), S (0) s, C (= 0), C (= N-0-R °), C (= CR R2 '), C (R2R2'), C (R2), C, het, N (Rn) or N; L3 can be oxo (0), S (0) s, C (= 0), C (= N-0-R °), C (= CR3R3 '), C (R3R3') C (R3), C, het, N (Rn) or N; Is it absent or can it be oxo (0), S (0) S,? 4p l C (= 0), C (= N-0-R °), C (= CR "R4), C (R4R (R4) C, NRn or N L5 is absent or can be oxo (0), S (0) S, C (= 0), C (= N-Rn), C (R5R5 '), C (= CR5R5'), C (R5), C , NRn or N; with the proviso that only one of Lx-L3 can be het and that when one of Lx-L3 is het the other L1-L4 may be absent.

R1, R1 ', R2, R2', R3, R3 ', R4, R4', R5 and R5 'are each independently selected from Ra, Rc and U-Q-V-W. Optionally R2 and R2 'separately or together can form a saturated, unsaturated or aromatic fused ring with B through a substituent Rp on B, the fused ring contains 5.6 or 7 ring atoms and optionally contains 1-3 selected heteroatoms from group 0, S and N. Where either S or N may be optionally oxidized. Optionally, R3 and R3 separately or together and R4 and R4 separately or together can form a saturated, unsaturated or aromatic fused ring with D through a substituent Rd on D, the fused ring contains 5.6 or 7 ring atoms and optionally contains 1 to 3 heteroatoms selected from the group 0, S and N, wherein either S or N may optionally be oxidized. Also optionally, each of R1-R5 or NRn together with any other R1-R5 or NRn, can form a 5-6 or 7-membered hetero or heterocycle whether saturated, unsaturated or aromatic optionally containing 1-3 additional heteroatoms selected from N, 0 and S, each cycle substituted with 0-3Rd, wherein S is 0-2, and wherein any carbon or sulfur ring atom may be optionally oxidized.

More specifically, the bivalent ligation L can be - (CR ° R °) 0-Ai- (CR ° R °) p-, - (CRDR °) 0-het- (CR ° R °) p-, - (CR6 = CR7) q-Ai- (CR8R8 ') p-, and - (CR6R6' or-Ai- CR = CR3) r-, where Ai is selected from where 0 is 0-1, p is 0-1 and r is 0-1 het is any mono, bi or tricyclic saturated, unsaturated or aromatic ring wherein 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 ring of 5 members have from 0 to 2 double bonds and the 6 or 7 member ring has from 0 to 3 double bonds and wherein any carbon or sulfur atoms in the ring may be optionally oxidized, and wherein any nitrogen heteroatom may optionally be Quaternized and where any ring can contain from 0-3 Rd.

Optionally, L is a bivalent linking group selected from the group: C3-C5alkyl-, C3-C5alkenyl-, -CH2C (= 0) NH-, CH2NH-C (= 0) -, -0-CH2-C (= 0) -, -CH2-CH2-C (= 0) -, CH = CH-C (= 0) NH-CH2-, -CH = CH-C (= 0) NH-CH- (CH3) -, CH (OH) -CH2-0-, - CH (OH) -CH2-N (CH3) -, -CH (OH) -CH2-CH2-, -CH2-CH2-CH (OH) -, -0-CH2-CH (OH) -, -0-CH2 -CH (OH) -CH2-, -O-CH2-CH2-CH (OH) -, -0-CH2-CH2-0-, CH2-CH2-CH2-O-, -CH2-CH (OH) -CH2 -O-, -CH2-CH2-O-, CH- (CH3) -NH-C (= 0) -, -CH2-NH-SO2-, -NH-S02-CH2-, CH2-SO2NH-, -SO2NH -CH2-, -C (= 0) -NH-C (= 0) -, -NH-C (= 0) -NH-, -NH-C (= 0) -NH-CH2-, -CH2-NH -C (= 0) -NH-, -C (= 0) -NH-CH2-C (= 0) -NH-, -NH-C (= 0) -0- Y -OC (= 0) -NH -.

Optionally, the specific combinations D-L are selected from: B is selected from the group where is a hetero or homocyclic fused ring containing 5,6 or 7 atoms, the ring is unsaturated, partially saturated or aromatic, heteroatoms selected from 1-3 0, S and N.

Yi is selected from CH and N and n is 0-3 G is selected from hydrogen and Ci-Cß alkyl, optionally G is taken together with T and can form a C3-C6 cycloalkyl optionally substituted with -V-W.

T is selected from group 1, an a-amino acid of natural presence of side chain or derivatives thereof and U-Q-V-W.

U is an optionally substituted bivalent radical selected from the group C 1 -C 6 alkyl-C 0 -C 6 -Q alkyl, C 2 -C 6 -alkenyl and C 2 -C 8 alkynyl-Q? wherein the substituents in any alkyl, alkenyl or alkynyl are 1-3 Ra.

Q is absent or selected from the group; -O-, -S (0) s-, -S02-N (Rn) -, -N (Rn) -, -N (Rn) -C (= 0) -, N (Rn) -C (= 0 ) -O-, -N (Rn) -S02-, -C (= 0) -, -C (= 0) -0-, -het-, -C (= 0) -N (Rn) -, - PO (ORc) 0- and -P (0) 0-, where s is 0-2 and het is a mono or bicyclic ring of 5,6,7,9 or 10 heterocyclic members, each ring contains 1-4 heteroatoms selected from N, 0 and S, wherein the heterocyclic ring can be saturated, partially saturated or aromatic and any of N or S are optionally oxidized, the heterocyclic ring is substituted with 0-3 Rh.

V is absent or is an optionally substituted divalent group selected from Ci-Ce alkyl, C3-Cs cycloalkyl, aryl CQ-C6 alkyl -Ce- • 10 and C0-C6 alkyl-het. wherein the substituents on any alkyl are 1-3Ri the substituents on any aryl or het are 1-3 W is selected from the group hydrogen, -OR °, SRm, -NRnRn ', -NH-C (= 0) -0-Rc, -NH-C (= 0) -NRnRn', -NH-C (= 0) -Rc, -NH-S02-Rs, -NH-S02-NRnRn ', -NH-S02-NH-C (= 0) -Rc, -NH-C (= 0) -NH-S02-Rs, -C (= 0) -NH-C (= 0) -0-Rc, -C (= 0) -NH-C (= 0) -Rc, -C (= 0) -NH-C (= 0) -NRnRn ', C (= 0) -NH-S02-Rs, -C (= 0) -NH-S02-NRnRn', -C (= S) -NRnRn ', -S02-Rs, -S02-0-Rs, -S02-NRnRn ', -S02-NH-C (= 0) -0-Rc, -S02-NH-C (= 0) -NRnRn', -S02-NH-C (= 0) -Rc, -0 -C (= 0) - NR) nnpRnn ', -0-C (= 0) -Rc, -OC (= 0) -NH-C (= 0) -Rc, -0- C (= 0) -NH -S02-Rs and -0-S02-R £ R is selected from -C (= 0) -R2, -C (= 0) -H, CH2 (0H) and alkyl -CH20-C (= 0) -C? -C6 • Ra is Ra 'or Ra "substituted with l-3Ra'.

Ra is selected from the group hydrogen, halo (F, Cl, Br, I), cyano, isocyanate, carboxy, carboxyCi-Cn alkyl, amino, amino-Ci-Cβ-alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl , formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanate, hydroxy, C? -C6 alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, hyperazinyl, piperinidyl, pyrrolinyl, imidazolyl and indolyl .

Ra "is selected from the group alkylCo-C10-Q-C0-C6alkyl, alkenylC0-C? Or Q-alkylCo-C6, alkynyl C0-C? 0-Q-alkylCo-C6, cycloalkylC3-Cn-Q-alkylC0-C6 , C3-C- or C-C-C6-C6alkyl, Ci-C6-C6-C6-C6-C-C-C6-C6alkyl, C6-C6alkyl, C6-C6-C-C6-C6alkyl, C6-C6-C6-C-C6alkyl -C6, alkylCo-C6-Q-het-C0-C6alkyl, alkyl-het-C0-C6-Q -alkylC0-C6, alkylC0-C6-Q-arylC6-Ci2 and alkyl d-C6-Q.

Rc is selected from hydrogen and Ci-C ?alkyl, C C-C? Al alkenyl, C2-C alqu alkynyl, C3-Cn cycloalkyl, C3-C ciclocycloalkenyl or C?-C6 alkyl, C6-C aryl? 2, C6-C? 0 aryl, C?-C6 alkyl, C--C alquilo-alkyl, C?-C6-het alkyl, C6_C? Ar aryl and het, substituted or unsubstituted, wherein the substituents on "any alkyl" , alkenyl or alkynyl are 1-3 Ra and the substituents in any aryl or het are 1-3 Rd Rd is selected from Rp and Rh Rh is selected from the group OH, OCF3, ORc, SRm, halo (F, Cl, Br, I), CN, isocyanate, N02, CF3, C0-C6 alkyl-NRnRn ', C0-C6 alkyl (= 0) -NRnRn ', C0-C6 alkyl (= 0) -Ra, C? -C8 alkyl, C? -C8 alkoxy, C2-Cs alkenyl, C2-Cs alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl. Ci-Cß alkyl phenyl, Ci-Cß alkyl phenyl, C alquilo alkyloxycarbonyl? -, C 0 -C 6 -alkyloxy phenyl, C 1 -C 6 -alkyl, C?-C6-alkyl, -hetS02, aryl-0-C6-C ?2, aryl -S02-C6-C12, alkyl -S02-C ?- C6 and het, wherein any alkyl, alkenyl or alkynyl can be optionally substituted with 1-3 groups selected from OH, halo (F, Cl, Br, I), nitro amino and aminocarbonyl and the substituents in any aryl or het are 1 -2-hydroxy, halo (F, Cl, Br, I), C? -C6 alkyl, C? -C6 alkoxy, nitro and amino.

Rm is selected from SC? -C6alkyl, C (= 0) -C? -C6alkyl, C (= 0) -NRnRn ', alkylC? -C6, halo (F, Cl, Br, I) -C? -C6 alkyl , benzyl and phenyl.

Rn is selected from the group Rc, NH-C (= 0) -0-Rc, NH-S02-Rs, NH-S02-NH-C (= 0) -Rc, NH-C (= 0) -NH-S02 -Rs, C (= 0) -0-Rc, C (= 0) -Rc, C (= 0) -NHRc, C (= 0) -NH-C (= 0) -0-Rc, C (= 0) -NH-C (= 0) -Rc, C (= 0) -NH-S02-Rs, C (= 0) -NH-S02-NHRs, S02-Rs, S02-0-Rs, S02-N (RC) 2, S02-NH-C (= 0) -0-Rc, S02-NH-C (= 0) -0-Rc and S02-NH-C (= 0) -Rc.

Rn is selected from the group of hydrogen, hydroxy and Ci-Cn alkyl, Ci-Cp alkoxy, C2-C? Alkenyl, Ci-Cio alkynyl, C3-Cn cycloalkenyl, C3-C10 cycloalkenyl / Ci-Ce-aryl C6 alkyl- C12, C 1 -C 6 aryl C 1 -C 6 alkyl, C 6 -C 0 aryl 0 C 0 -C 6 alkyloxy, C 1 -C 6 -alkyl, C 1 -C 6 alkyl, C 6 -Ci 2 aryl, het, C 1 -C 7 alkylcarbonyl, C 1 -C 8 alkoxycarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 1 -C 8 aryloxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkysulfonyl, heteroarylsulphonyl, C 1 -C 6 alkylsulphonyl and arylphosphoryl Ce-Cio , substituted or unsubstituted, wherein the substituents on any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl het or heteroaryl are 1-3 Rd.

Optionally Rn and Rn 'taken together with the common nitrogen to which they are placed can be from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl and pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tet rahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl wherein the substituents are 1-3 Ra.

R ° is selected from hydrogen and substituted or unsubstituted C 6 -C alkyl, alkylcarbonyl Ci-Cβ, C2-Cd alkenyl, C2-Cd alkynyl, C3-C8 cycloalkyl and benzoyl, wherein the substituents on any alkyl are 1-3 Ra and the substituents on any aryl are 1-3 Rp.

Rp is selected from the group OH, halo (F, Cl. Br, I), CN, isocyanate, ORc, SRm, SORc, N02, CF3, Rc, NRnRn ', N (Rn) -C (= 0) -0- Rc, N (Rn) -C (= 0) -Rc, C0-C6-SO2-Rc alkyl, C0-C6-SO2-NRnRn 'alkyl, C (= 0) -Rc, 0-C (= 0) - Rc, C (= 0) -0-Rc and C (= 0) -NRnRn ', wherein the substituents are any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd .

Rs is a substituted or unsubstituted group selected from C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C6 cycloalkenyl, C0-C6 alkyl-phenyl, C0-C6 alkyl-phenyl, alkyl-het Co-Cß and C0-C6-het alkyl, wherein the substituents on any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd.

Rz is a substituted or unsubstituted group selected from hydroxy, Ci-Cn alkoxy, C3-C12 cycloalkoxy, C8-C2 aralkoxy, C8-C2 arcycloalkoxy, C ar-Cι aryloxy, C 3 -C 10 alkylcarbonyloxykyloxy, C 3 -C 10 alkoxycarbonyloxykyloxy , C3-C10 alkoxycarbonylalkyl, C5-C10 cycloalkylcarbonyloxyalkyloxy, C5-C10 cycloalkoxycarbyalkyloxyC1, C5-C10 cycloalkoxycarbonylalkyl, C8-C2 aryloxycarbonylalkyl, C8-C2 aryloxycarbonyloxyalkyloxy, C8-C2 arylalkylcarbonyloxy, C5-C10 alkoxyalkylcarbonyloxyalkyloxy. (Rn) (Rn ') N (C1-C10 alkoxy) wherein the substituents of any alkyl, alkenyl alkynyl are 1-3 the substituents on any aryl or het are 1-3 Rd and the pharmaceutically acceptable salts thereof Brief Description of the Drawings FIGURE 1 A drawing illustrating a recruitment of lymphocytes to a site of infection is provided. Shows lymphocyte rolling and adhesion to ICAM expressing cells (leukocytes, endothelium, epithelium).

FIGURE 2 A drawing illustrating the binding assay of the human receptor ICAM-1: LFA-1 (protein / protein assay) is provided. The inhibition of the CDlla / CD18-ICAM-1 interaction is quantified by adding known amounts of inhibitors to the protein / protein assay system described in Example 3.

FIGURE 3 A drawing illustrating the human T cell adhesion assay described in example 4 is provided.

FIGURE 4 A drawing illustrating a human T cell proliferation assay is provided. Cell proliferation is measured by titrated admission of thymidine.

FIGURE 5 A drawing illustrating the mixed one-way human lymphocyte response is provided. Cell proliferation is measured by titrated admission of thymidine.

Detailed Description of the Preferred Modalities.

A. Definitions The term "disorders mediated by LFA-1" refers to pathological conditions caused by cell adhesion interactions that involve the LFA-1 receptor in 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); respiratory pain syndrome in adults; dermatitis; meningitis; encephalitis; uveitis; allergic conditions such as eczema and asthma and other conditions that involve T cell infiltration and chronic inflammatory responses; hypersensitivity reactions in the skin (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 syndrome, type 1 diabetes, diabetes juvenile and immune responses associated with delayed hypersensitivity mediated by cytosines and T lymphocytes typically found in tuberculosis, sarcoidosis, polymyositis, granulomatosis, and vasculitis; pernicious anemia; diseases that involve leukocyte diapedesis; Inflammatory disorder of CNS, secondary syndrome of multiple organ damage, aseptisemia or trauma; autoimmune hemolytic anemia; myasthenia gravis; diseases mediated by the antigen-antibody complex; all types of transplants including graft versus host or host versus graft; etc.

"Treatment" of such diseases includes therapy, prophylactic treatment, prevention of graft rejection and induction of graft tolerance on a long-term basis.

The term "graft" as used herein refers to a biological material derived from a donor for transplantation in a container. The grafts include various materials such as for example, isolated cells such as islet cells, tissues such as the amniotic membrane of a newborn, bone marrow, hematopoietic precursor cells, and organs such as skin, heart, liver, vessel, pancreas, thyroid lobe, lung, kidney, tubular organs (eg intestine, blood vessels or esophagus), etc. The tubular organs can be used to replace damaged portions of the esophagus, blood vessels or bile duct. Skin grafts can be used not only for burns but also as a dressing for the damaged bowel or to close certain defects such as diaphragmatic hernia. The graft is derived from any mammalian source including human, either from cadavers or living donors. Preferably the graft is bone marrow or an organ such as the heart, and the donor of the graft and the host are matched by HLA class II antigens.

The term "mammal" refers to any animal classified as a mammal including humans, domestic and farm and zoo animals, sports animals, or pets such as dogs, horses, cats, cows, etc. preferably the mammal here is a human .

The term "mammalian host" as used herein, refers to any compatible transplant vessel. By "compatible" means a mammalian host that will accept the donated graft. Preferably, the host is a human. If the donor of the graft and the host are human, they preferably correspond to the HLA class II antigens to improve histocompatibility.

The term "donor" as used herein, refers to mammalian species, dead or alive, from which the graft is derived. Preferably, the donor is human. Human donors are preferably blood-related, voluntary donors that are normal on a physical examination and of the same ABO blood group, since by crossing larger blood group barriers, it possibly harms the survival of the allograft. It is however possible to transplant for example a kidney of a type 0 donor into a container A, B or AB.

The term "transplant" and variations thereof, refers to the insertion of a graft in a host, whether the syngeneic transplantation (where the donor and recipient are genetically identical), allogeneic (where the donor and the recipient they are of different genetic origins but of the same species), or xenogenic (where the donor and the recipient are of different species). Thus, in a typical scenario, the host is human and the graft is an isograft derived from a human or from the same or different genetic origins. In another scenario, the graft is derived from a species different from that to which it is transplanted, such as a monkey heart transplanted into a recipient human host and including animals of widely separated species phylogenetically, for example, a pig heart valve or animal islet beta cells or neuronal cells transplanted to a human host.

The term "LFA-1 antagonist" as used generally herein, refers to a benzoylamino acid derivative (AA) or a mimetic peptide thereof that acts as a competitive inhibitor of the CDlla and / or CD18 interaction with ICAM-1. , soluble forms of ICAM-1 and soluble or linked forms of ICAM-2, ICAM-3 and telencephalie.

The term "immunosuppressive agent" as used herein for adjunctive therapy, refers to substances that act on or suppress or mask the immune system of a host within which the graft is being transplanted. This would include substances that suppress the production of cytokines, regulate to diminish or suppress the expression of autoantigens, or mask the MHC antigens. Examples of such agents include the substituted 2-amino 6-aryl-5 pipmidines (see US Pat. No. 4,650,777, the description of which is incorporated herein by reference), azathioprine (or cyclophosphamide if there is an adverse reaction to azathioprine ); bromocript ina; glutaraldehyde (which masks the MHC antigens, as described in U.S. Patent No. 4120649, supra); anti-idiotypic antibodies for MHC antigens and MHC fragments; cyclosporin A; steroids such as glucocorticosteroids for example, prednisone, methylprednisolone and dexamethasone; cytokine or cytosine receptor antagonists including the anti-interferon-β or antibodies to; anti-tumor necrosis factor-a antibodies; ß Antitumor necrosis factor antibodies; anti-interleukin-2 antibodies and anti-IL-2 receptor antibodies; anti-L374 antibodies; anti-lymphocyte heterologous globulin; pan-T antibodies, preferably anti-CD3 or anti-CD4 / CD4a antibodies; soluble peptides containing an LFA-3 binding domain (WO 90/08187 published 7/26/90), streptokinase; TGF-β; streptodornase; RNA or host DNA; FK506; RS-61443; deoxyspergualine; rapamycin; T-cell receptor (Chen et al., U.S. Pat. No. 5114721); T-cell receptor fragments (Offner et al., Science, 251: 430-432 (1991); co-pending patent application US Ser. No. 07/853362 filed on March 18, 1992, the description of which is incorporated here for reference, Howell, WO 90/11294, Ianeway, Nature, 341: 482 (1989), and Vandenbark, WO 91/01133); and T cell receptor antibodies (EP 340109) such as T10B9. These agents are administered at the same time or at separate times from the CDlla or CD18 antagonists as are used in this invention and are used in doses equal to or less than those established in the art.

The preferred immunosuppressive agent herein will depend on many factors including the type of disorder being treated including the type of transplant being performed as well as the patient's history, but a general overall preference is that the agent be selected from cyclosporine A, a icosteroid glucocort (more preferably prednisone or met ilprednisolone), monoclonal antibody OKT-3, azathioprine, bromocriptine, heterologous antilymphocyte globulin or a mixture thereof.

The "increased tolerance of a transplanted graft" by a host refers to prolonging the survival of a graft in a host in which it has been transplanted, that is, suppressing the host's immune system so that it will better tolerate a foreign transplant.

The term "alkyl" means a saturated, branched or unbranched aliphatic hydrocarbon radical having a specified number of carbon atoms and if no number is specified, it has up to 12 carbon atoms. Unless otherwise specified, the term also groups unsaturated alkyls defined as cycloalkyl, alkenyl and alkynyl below. Examples of the preferred alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tertbutyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl , 2, 2-dimethylbutyl, n-heptyl, 2-methylhexyl and the like. The term "Co-Cβ alkyl" and similar terms containing Co, means a covalent bond when the number of carbons is zero (Co) or Ci-Cß alkyl. If it is necessary to avoid a hanging valence, the term "Co" may include a hydrogen atom. A preferred "Ci-Ce alkyl" group is methyl.

The term "substituted Cn-Cm alkyl" where n and m are integers that identify the range of carbon atoms contained in the alkyl group, denotes the above alkyl groups which are substituted by the groups listed or if there are no groups listed, 2 or 3 halogens, hydroxy, protected hydroxy, amino, aminoprotected, C 1 -C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino or C 4 -C 4 alkoxy groups. The substituted alkyl groups can be substituted once, twice or three times with the same or different substituents.

Examples of the alkyl groups substituted above include but are not limited to cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, alkyloxycarbonylmethyl, allyloxycarbonyl aminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, T-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2-4 dichloro (n-butyl), 2-amino (isopropyl), 2-carbamoyloxyethyl, and the like. A preferred group of examples within the C? -C? 2 substituted alkyl group includes the substituted methyl group, for example, a methyl group substituted by the same substituents as the "substituted Cn-Cm alkyl group". Examples of the substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (for example tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, bromomethyl and iodomethyl.

The terms "C 1 -C 2 alkyloxy" or "C 1 -C 2 alkoxy" are used interchangeably herein and denote groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and similar groups.

The terms "acyloxy C? -C? 2" or "C? -C? 2 alkanoyloxy" are used interchangeably and denote groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.

The terms "alkylcarbonyl C _.- C? 2" "Ci-C12 alkanoyl" and "Ci-C12 acyl" are used interchangeably herein and embrace groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.

The term "cycloalkyl" as used herein, refers to a saturated or unsaturated mono-, bi- or tricyclic ring, each ring having from 3 to 14 carbon atoms and preferably from 3 to 7 carbon atoms. Optionally any ring carbon can be oxidized from a carbonyl.

The term "alkenyl" means a branched or unbranched hydrocarbon radical having a number of designated carbon atoms containing one or more carbon-carbon double bonds, each double bond being independently cis, trans or a non-geometric isomer.

The term "alkynyl" means a branched or unbranched hydrocarbon radical having a number of designated carbon atoms containing one or more triple carbon-carbon bonds.

The terms "C 1 -C 12 alkylthio" and "C 1 -C 12 substituted alkylthio" denote C 1 -C 12 alkyl and C 1 -C 12 substituted alkyl groups respectively, placed at a sulfur which in turn is the point of attachment for the group alkylthio or substituted alkylthio to the designated group or substituent.

The term "aryl" when used alone, means a homocyclic aromatic radical whether or not it is molten having a designated carbon atom number. Preferred aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl and the like (see for example La ng 's Ha n dbook of Ch emi s try (Dean, JA, ed.) 13 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 selected from the groups listed or those selected from allogeneic (F, Cl, Br, I), hydroxy, protected hydroxy , cyano, nitro, C?-C6 alkyl, Ci-Cß alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl N- (dimethylsulfonylamino) or other specified groups.

Examples of the term "substituted phenyl" include but are not limited to a mono or dihalophenyl 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 dihydroxyphenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2-4-dihydroxy phenyl, the hydroxy-protected derivatives thereof and the like; a nitrophenyl 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-methylphenylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-isopropylphenyl, 4-ethylphenyl, 3-n-propylphenyl and the like; a mono- or di-alkoxyphenyl group for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-isopropoxyphenyl, 4-t-butoxyphenyl, 3-ethoxy-4-methoxyphenyl and the like; 3 or 4 trifluoromethylphenyl; a dicarboxy phenyl or mono or phenyl group (protected carboxy) such as 4-caboxyphenyl; a mono or di (hydroxymethyl) phenyl or phenyl (protected hydroxymethyl) such as 3- (hydroxymethyl) phenyl or 3,4-di (hydroxymethyl) phenyl; a mono or di-aminomethyl phenyl or (aminomethyl protected) phenyl such as 2-aminomet ilphenyl or 2,4-aminomethyl protected 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-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3- hydroxy 4-nitophenyl, 2-hydroxy-4-chlorophenyl and the like. Preferred substituted phenyl groups include 2 and 3 trifluoromethylphenyl, 4-hydroxyphenyl, 2-aminomethylphenyl and the groups 3- (N- (methylsulfonylamino)) phenyl.

The term "arylalkyl" means one, two or three aryl groups having a designated number of carbon atoms, placed on an alkyl radical having the number of carbon atoms designated including but not limited to benzyl, naphthylmethyl, phenethyl, benzylhydril (diphenylmethyl), trityl and the like. A preferred arylalkyl group is the benzyl group.

The term "C6-C? 0-aryl-C? -C8 substituted alkyl" denotes a substituted Ci-C? Alkyl group in any carbon with a C6-C? Aryl group or linked to the alkyl group through any aryl ring and substituted position. in the C? -C8 alkyl portion with one, two or three groups chosen from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, amino, protected amino, C? -C acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, alkylthio Ci- Ce, N-methylsulphonylamino or C 1 -C 4 alkoxy. Optionally, the aryl group may be substituted with one, two or three selected groups of halogen, hydroxy, protected hydroxy, nitro, C 1 -C 4 C 1 -C 4 alkoxy, carboxy, protected carboxy, carboxymethyl, carboxymethyl protected, hydroxymethyl, hydroxymethyl protected , aminomethyl, protected aminomethyl or an N-methylsulphonylamino group. As before, when the C? -C8 alkyl portion or the aryl moiety or both are disubstituted, the substituents may be the same or different.

Examples of the term "C 1 -C 8 -C 6 -alkyl or substituted alkyl" 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), (4-aminomethyl phenyl) 3- (aminomethyl) (n-pentyl) and the like.

The term "carboxy protective 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 the reactions are carried out on other functional groups in the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-t rimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4 -met ilenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzydichloride, 2, 2 ', 4,4'-tetramethoxybenzhydryl, tertbutyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4', 4 '-trimethoxytrityl, 2-phenylprop-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, 1- (trimethylsilyl-yl-yl) prop-1-en-3-yl and similar varieties. The carboxy-protective group species employed are not critical as long as the derivatized carboxylic acid is stable in the subsequent reaction condition over other positions of the benzodiazepinedione molecule and can be separated at an appropriate point without breaking the remainder of the molecule. In particular it is important not to subject the carboxy-protected benzodiazepinedione molecule to strong nucleophilic bases or to reducing conditions employing highly activated metal catalysts such as Raney nickel. (Such severe separation conditions can also be avoided when separating the aminoprotective groups and the hydroxyprotective groups discussed below). Preferred carboxylic acid protecting groups are the allyl and p-nitrobenzyl groups. Similar carboxy protective groups used in the cephalosporin, penicillin and peptide arts can also be used to protect substituents of benzodiazepinedione carboxy groups. Additional examples of these groups are found in E. Haslam, "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 art of peptides to protect nitrogens peptides from undesirable side reactions. Such groups include p-methoxyphenyl, 3,4-dimethoxybenzyl, benzyl, O-nitrobenzyl, di- (p-methoxyphenyl) methyl, t-rifenylmethyl, (p-methoxyphenyl) diphenylmethyl, diphenyl 4-pyridylmethyl, m-2- ( picolyl) -N'-oxide, 5-dibenzosuberyl, trimethylsilyl, t-butyl dimethylsilyl and the like. Additional descriptions of these protective 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 to refer to any saturated mono, bi or tricyclic ring or unsaturated or aromatic having a designated number of atoms wherein 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 n g 's Ha n dbook of Ch em i s t ry, s upra). Typically, the 5-membered rings have 0 to 2 double bonds and the 6- or 7-membered rings have 0 to 3 double bonds and the nitrogen atoms, carbon or sulfur in the ring may optionally be oxidized (for example NO2, C = 0 and S02) and any nitrogen heteroatom may optionally be quaternized. Included in the definition are any bicyclic group wherein any of the above heterocyclic rings are fused to a benzene ring. Heterocyclics in which oxygen and sulfur are L heteroatoms are preferred when the heterocyclic forms all or part of "D" in formula 1.

The following ring systems are examples of the heterocyclic radicals (either substituted or unsubstituted) denoted by the term "heterocyclic" or het: thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl , oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, t iatriazinilo, oxatriazinyl, dit iadiazinilo, imidazolinyl, dihydropyrimidyl, tetrahidropirinidilo, tetrasolo (1, 5-b) pyridazinyl and purinyl, as well as the benzo-molten derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotrizolyl, benzoimidazolyl and indolyl.

Ring systems of 5 heterocyclic members, containing a sulfur or oxygen atom and from one to three nitrogen atoms are also suitable for use in the present invention. Examples of such preferred groups include thiazolyl in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl in particular 1,3-thiadiazol-5-yl and 1, 2,4-thiadiazol-5-yl , oxazolyl preferably oxazol-2-yl and oxadiazolyl such as 1, 3, 4-oxadiazol-5-yl and 1, 2,4-oxadiazol-5-yl. A group of preferred additional examples of 5-membered ring systems with 2 to 4 nitrogen atoms include imidazolyl preferably imidazol-2-yl, triazolyl preferably 1,3-, 4-triazol-5-yl, 1,2,3-triazole -5-yl, 1, 2,4-t-riazol-5-yl and tetrazolyl preferably lH-tetrazol-5-yl. A preferred group of examples of benzofused derivatives are benzoxasol-2-yl, benzothiazol-2-yl and benzimidazol-2-yl.

Additional appropriate specific examples of the above heterocyclic ring systems are 6-membered ring systems containing from 1 to 3 nitrogen atoms. Such examples include pyridyl such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; pyrimidyl preferably pyrimid-2-yl and pyrimid-4-yl; triazinyl preferably 1, 3, 4 -tria zin-2-yl and 1, 3, 5-triazin-4-yl; pyridazinyl in particular pyridazin-3-yl and pyrazinyl. The N pyridine oxides and the N pyridazine oxides and the pyridyl pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl radicals are a preferred group.

Substituents for the optionally substituted heterocyclic ring systems, and additional examples of the 5 and 6 member ring systems discussed above, can be found in W. Druckheimer et al., U.S. Patent No. 4278793.

Another preferred group of "heterocyclics" or "het" include 1,3-thiazol-2-yl, 4- (carboxymethyl) -5-methyl-1,3-thiazol-2-yl, sodium salt of 4- (carboxymethyl) ) 5-methyl-1,3-thiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-l, 2,4-thiadiazol-5-yl, 1,3-triazole-5 -yl, 2-methyl-1, 3, 4-triazol-5-yl, 2-hydroxy-1,3,4-t-riazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazole-5- ilo sodium salt, 2-carboxy 4-methyl-1,3-, 4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1, 3 , 4-oxadiazol-5-yl, 2- (hydroxymethyl) -1,4,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl , 2-thiol 1, 3, 4-thiadiazol-5-yl, 2- (methylthio) 1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, lH- tetrazol-5-yl, 1-met yl-lH-tetra zol-5-yl, 1- (1- (dimethylamino) het-2-yl) -lH-tetrazol-5-yl, 1- (carboxymethyl) -lH -tetrazol-5-yl, sodium salt of 1- (carboxymethyl) -lH-tetrazol-5-yl, 1- (methylsulfonic acid) -lH-tetrazol-5-yl, sodium salt of l- (methyl acid) sulphonic) -lH-tetrazol-5-yl, 2-methyl-lH-tetrazol-5-yl, 1, 2, 3-t-riazol-5-yl, 1-methyl-1, 2, 3-t-riazol-5 -yl, 2-methyl-1, 2, 3-triazol-5-yl, 4-methyl-1, 2, 3-t ria-zol-5-yl, pyridi-2-yl-N-oxide,. 6-methoxy-2- (n-oxide) pyridaz-3-yl, 6-hydroxypyridaz-3-yl, 1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1 4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl; 1, 4, 5, 6-tetrahydro-4- (formylmethyl) 5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-t riazin-3 ilo, sodium salt of 2-5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl, sodium salt of 2-5-dihydro-5-oxo-6-hydroxy-2-methyl- as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2- methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-2-methyl-as-tria zin-3-yl , 2,5-dihydro-5-oxo-2, 6-dimethyl-as-triazin-3-yl, tetrazolo (1,5-b) pyridazin-6-yl and 8-aminotetrazolo (1,5-b) pyridazin -6-ilo.

An alternative group of heterocyclics includes 4- (carboxymethyl) -5-methyl-1,3-thiazol-2-yl, sodium salt of 4- (carboxymethyl) -5-methyl-1,3-thiazol-2-yl, , 3,4-triazol-5-yl, 2-methyl-1,3-triazol-5-yl, lH-tetrazol-5-yl, 1-methyl-lH-tetrazol-5-yl, 1- (1 ( dimethylamino) het-2-yl) lH-tetrazol-5-yl, 1- (carboxymethyl) lH-tetrazol-5-yl, sodium salt of 1-carboxymethyl-lH-tetrazol-5-yl, l- (methylsulfonic acid) lH-tetrazol-5-yl, l- (methylsulfonic acid) lH-tetrazol-5-yl sodium salt, 1, 2, 3-t-riazol-5-yl, 1, 4, 5, 6-tetrahydro 5, 6-dioxo-4-methyl-as-tria zin-3-yl, 1,4,5,6-tetrahydro-4- (2-formylmethyl) 5,6-dioxo-as-triazin-3-yl 2, 5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-met yl-as-triazin- 3-yl, tetrazolo (1,5-b) pyridazin-6-yl and 8-aminotetrazolo (1,5-b) pyridazin-6-yl.

The bivalent radicals L, whether branched or unbranched, derived from alkanes, alkenes, alkadienes, alkynes, alkandiines and lodes optionally containing 0, N and / or S atoms and homo and heterocycles, whether aromatic or aliphatic, are designated by the addition of a free valence "-" for both ends of the corresponding monovalent radical. The atoms that support the free valencies can include any of C, O, N or S.

"Pharmaceutically acceptable salts" include acid and basic addition salts, "pharmaceutically acceptable acid addition salt" refers to those salts that retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable , formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids can be selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, acid citric acid, aspartic acid, ascorbic acid, g acid luthmic, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

"Pharmaceutically acceptable basic addition salts" includes those derived from bases or inorganics such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.

Particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of secondary primary 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, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, phenamine resins and the like . Particularly preferred non-toxic organic 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, bioavailability, pharmacodynamics, etc.) and that requires spontaneous or enzymatic biotransformation within the organism to release the active parent drug. Examples of carboxylic prodrugs include precursors such as aldehydes, alcohols or 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 the inhibition or modulation of the interaction of LFA-1 and / or Mac-1 with ICAM, especially ICAM-1, are indicated. Such diseases and conditions include: inflammatory responses to T cells such as inflammatory skin diseases including psoriasis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); syndrome with respiratory damage in adults; dermatitis; meningitis; encephalitis; uveitis; allergic conditions such as eczema and asthma, psoriasis, and other conditions that involve T cell infiltration and chronic inflammatory responses; hypersensitivity reactions to the skin (including poison ivy and poison oak), allergic contact dermatitis; arterosclerosis; 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 attack diabetes, and immune responses associated with cytosine-mediated delayed hypersensitivity and T lymphocytes typically foin tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; pernicious anemia; diseases that involve leukocyte diapedesis; Inflammatory CNS disorder, multiple organ damage syndrome secondary to sepsis or trauma; autoimmune hemolytic anemia; myasthenia gravis; diseases mediated by the antibody antigen complex; all types of transplants, including graft-versus-host or host-graft diseases, HIV infection and the like. Other leukocyte-mediated diseases for which current competitive inhibitors may be used include: hemorrhagic shock, ischemia / reperfusion injury, live connection surgery, burns, infarction, post-CABG surgery, vasculitis, cerebral edema (wider restenosis, AMI and MI of wave not Q.

C. Preferred modes 1. CDlla / CD18 competitive inhibitors: 1CAM-1 One embodiment of the invention comprises a comporepresented by formula I, capable of inhibiting the binding of the leukocyte receptor LFA-1 to its native ligand in vi, especially ICAM-1. Preferred inhibitors include compo represented by structural formula I: With reference to formula I, 'the following important structural features of the current peptide mimetic inhibitors LFA-1 can be identified: to. the acid portion negatively charged R or a form of promedication thereof; b. the T substituent, an amino acid that naturally occurs side chain and derivatives thereof; c. the amide nitrogen (N) and substituents (Rn): d. the substituted "benzoyl" ring B; and. substituents of ring B, nominally Rp; F. the spacer or link portion L. g. The distal aromatic D portion; and h. Substituents of D, nominally Rd. (a) the acid portion negatively charged R The preferred negatively charged acid portion R is the carboxyl group (-COOH) or a prodrug thereof. Generally the carboxyl group R and forms of prodrug thereof are designated CORz. Suitable Rzs include C? _8 alkoxy, dialkyl aminocarbonylmethoxy C?-8 and diakylaminocarbonylmethoxy C?-8 aryl C6-C? O. • Other appropriate prodrugs Rz include the following groups: O O II II -O-CH 2 -O- C -CH 2 -CH 3 -O-CH 2 -O-C-CH 2 -CH 2 -CH 3 (b) Substituent T or U-Q-V-W The T of formula I is usually the side chain of some a-amino acid, preferably the L-configuration, or a homolog derived therefrom. Preferably T will contain a hydrogen bond donor group such as CONH2, NHCOH, NH2, OH or NH. T will frequently be a 1-4 carbon alkane containing an amide, carbamate, ureido, sulfonamide, and an optionally substituted phenyl or heterocycle. The heterocycle will usually be a 5- or 6-membered ring with 1 or 2 heteroatoms selected from N, O and S. Such heterocycles include furan, thiophene, pyrrole, pyridine and piperidine. Substituents include halogen such as chloro and fluoro, nitro, cyano, alkyl and alkyl substituted by halo, substituted or unsubstituted amides, amines, carbamate sulfonamides, ureides and the like.

Examples of T will also include a lower alkyl, cycloalkyl, alkenyl or alkynyl substituted by an aromatic ring, especially a heteroaryl or C6-C? Ar aryl, substituted with 0-3 Rd. Suitable aromatic rings include any saturated, unsaturated or aromatic mono-, bi-, or tricyclic ring having from 3 to 7 ring atoms, wherein at least one ring is a 5, 6 or 7 membered ring containing from zero to four heteroatoms selected from the group nitrogen, oxygen and sulfur, optionally substituted with Rd.

Optionally, the aromatic rings can be linked through a C -C alkyl. Preferred rings are substituted phenyl and het as defined above optionally substituted with Rd. The most preferred optionally substituted aromatic rings are selected from the group; . where R is Al 0 -. 0-3Rd or U -V- Other optionally preferred substituents T are U-Q-V-W defined below. Specifically, T may preferably be Ci-Ce-C6-C? 4 Q-VW alkyl, wherein Q is -N (Rn) -, -C (= 0) -, -N (Rn) C (= 0) - , -C (= 0) -N (Rn) -, -N (Rn) C (= 0) -N (Rn) -, - (Rn) C (= 0) -0-, -0-C (= 0) -N (Rn) -, -N (Rn) S (= 0) 2-, - S (= 0) 2-N (Rn), C (= 0) -0- or -0-; V can be het or be absent and W is provided in table 1.

Generally, each of U, Q, V and W are independently selected in accordance with Table 1 below. U, Q and V can also each independently be absent (this is one or more of U, Q, V can be a covalent bond).

Table 1 Wherein any alkyl, alkenyl or alkynyl is substituted with Ra of 0-3 and any aryl or het is substituted with Rd of 0-3, and wherein Ra, Rc, R, Rm, Rn, Rn ', R °, and Rs are as defined above. More specifically, each of U, Q, V and W can be independently selected in accordance with Table 2 below.

Table 2 (c) The substituents (Rn) for the N-amide nitrogen are lower alkyl or hydrogen and preferably hydrogen. (d) The substituted "benzoyl" ring B is preferably selected from the group: It is a hetero- or homocyclic fused ring containing 5, 6 or 7 atoms, the ring is unsaturated, partially saturated or aromatic, the heteroatoms are selected from 1-3 0, S or N, Yi is selected from CH or N, n is 0-3. Preferably B is para-substi tuted benzoyl group. (e) The substituents of B (R) are defined above. Preferably, when B is a para-substi tuted benzoyl group, the remaining positions on B are substituted with one or more halo groups (F, Cl, Br) or lower alkyl. (f) The linking group L The length of the bivalent radical L appears to be important for optimal biological activity. By length is meant the distance between the B or benzoyl portion (e.g. from the para position on B), including the amide or amide isostere linked to the benzoyl portion, and the distal group D, preferably L are 3, 4 or 5 methylene (-CH2-) equivalents in length depending on the atoms in L and the nature of D. Thus, L is composed of L1-L3 and optionally L4 and L5. Each of L1-5 is independently selected from oxo (-0-), S (0) s, C (= 0), CR1"5Rlr" 5 ', CR1"5, het, NRn, or N, where s is 0-2 For example, the functional groups in L (in addition to -CH2- or CR1 ~ 5R1 '~ 5') include one or more of the following: which can be located within the linker L (for example by forming amides, imides, amidines, guanidines, ureides, carbamates, ethers, thioethers, ketones, sulfoxides, sulfonamides and the like) or combined in any combination, with the proviso that the compounds thus produced are stable in aqueous solution and do not exceed the length requirements stated above. For example, preferred functional groups in L, other than C3-C5 alkyl, are: ethers, diethers, ketones, alcohols, esters, amides, ureides, carbamates, carbonates, sulfonamides, sulfoxides, sulfone and combinations thereof. The preferred lengths for L are from 0 to 4 while the most preferred lengths are 1 or 3 equivalents of methylene. By counting the atoms comprising L, only those atoms that are sequentially linked to the benzoyl moiety and the distal B group are counted except when a homo or heterocycle (eg het) comprises L in which case the smallest number of atoms that separate These portions are counted.

Preferred bivalent linking groups L include: C3-C5-alkyl, C3-C5-alkenyl, -CH2C (= 0) NH-, CH2NH-C (= 0) -, -O-CH2C (= 0) -, CH2CH2C (= 0) -, -CH = CH-C (= 0) NH- CH2-, -CH = CH-C (= 0) NH- CH- (CH3) -, CH (OH) -CH2- O-, -CH (0H) CH2-CH2-, CH2-CH2-CH (OH) -, -O-CH2-CH (OH) -, -O-CH2-CH (OH) -CH2-, -0- CH2-CH2-CH (OH) -, -O-CH2-CH2-O-, -CH2-CH2-CH2-0-, CH2-CH (OH) -CH2-O-, -CH2-CH2-O-, -CH (OH) -CH2-O-, CH (CH3) -NH-C (= 0) -, -CH2-NH-S02-, -NH-S02-CH2-, CH -S02-NH-, -SO2 -NH-CH2-, -C (= 0) -NH-C (= 0) -, -NH-C (= 0) -NH, -NH-C (= 0) -NH-CH2-, -CH2- NH-C (= 0) -NH-, C (= 0) -NH-CH2-C (= 0) -NH, -NH-C (= 0) -0- and -OC (= 0) -NH- .

Preferred bivalent linking groups L containing a heterocycle include: Any carbon in the bivalent linking groups may be optionally substituted with a halogen especially fluorine. g) the distal portion D can be a mono-, bi, or tricyclic saturated, unsaturated, or aromatic ring, each ring having 5, 6 or 7 ring atoms wherein the ring atoms are carbon or from 1-4 heteroatoms selected from; nitrogen, oxygen and sulfur, each ring substituted with 0-3 Rd.

Optionally, D is an aromatic homocycle or aromatic heterocycle containing from 1-3 heteroatoms selected from the group N, S and O, the homo- or heterocycles selected from: wherein Y1, Y3, Y3, Y4, and Y5 are CH, CRd or N, Z1 is O, S, NH or NRn and n is 0-3.

More specifically, D can be 1) an aromatic heterocycle of members selected from; A 9-member aromatic heterobicycle selected from; 3) a hetero or 6-membered aromatic homocycle selected from Compounds containing the above preferred 5-membered aromatic heterocycles and the 9-membered aromatic heterobicycles, 1 and 2 above, as aromatic groups D are preferred as specific antagonists of LFA-1, while hetero aromatic heterocycles or 6-membered aromatic heterocycles. 3 above, they are preferred as appropriate D groups to inhibit both LFA-1 and Mac-1. In the 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, NH2, SO2NH2, SO2CH3, CH3, CH2OH, CN, CH3-C (= 0) NH-, NH2C (= 0) -, NHCONH2, CF3, C6-6 alkoxy and halo (F, Cl, Br, and I).

Exemplary preferred compounds of this invention include: D Manufacturing methods A method for producing the LFA-1 antagonists involves the chemical synthesis of the "peptide" or peptide mimetic. This can be achieved 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 Nos. 4,105,603; 3,972,859; 3,842,067; and 3,862,925)).

It will be appreciated from the inspection of the compounds shown above, that they all contain one or more amide or peptide bonds and can thus be considered as peptide mimetics. The peptide mimetics of the invention can also be conveniently prepared using peptide solid phase synthesis (Merrifield, J. Am. Cem. Soc, 85: 2149 (1964); Houghten, Proc. Na ti. Aca d. Sci. USA 82: 5132 (1985)). Solid phase synthesis begins at the carboxy terminus of the putative peptide by coupling a protected amino acid to an appropriate resin (eg chloromethylated polystyrene resin) as shown in Figures 1-1 and 1-2, on pages 2 and 4 from Stewart and Young above. After removal of the a-amino protecting group with, for example, trifluoroacetic acid (TFA) in methylene chloride and neutralizing it in, for example TEA, the following a-amino- and the protected amino acid in the side chain in the synthesis. The remaining a-amino and, if necessary, the protected amino acids in the side chain are then coupled sequentially in the desired order by condensation, to obtain an intermediate compound connected to the resin. Alternatively, some amines and acids can be coupled to one another by forming a peptide prior to the addition of the peptide to the growing solid phase peptide chain.

The condensation between two amino acids can be carried out according to the usual condensation methods such as the azide method, mixed acid anhydride method, DCC (N, N'-dicyclohexylcarbodiimide) or DIPC (N, N '-diisopropylcarbodiimide) method. , active ester method (p-nitrophenyl ester method, BOI [benzotriazol-1-yl-oxy-tris (dimethylamino) phosphoniohexafluorophosphate] method, N-hydroxysuccinic acid imido ester method, etc., and the reagent method Woodward K Common to the chemical synthesis of the peptides, is the protection of any reactive side chain group of amino acids with appropriate protecting groups. Finally, these protective groups are removed after the desired chain of polypeptides has been assembled sequentially. It is also common, the protection of the a-amino group on an amino acid or a fragment while that entity reacts in the The carboxyl group followed by the selective removal of the a-amino protecting group, to allow the subsequent reaction to take place in that location. In this way, it is common in the synthesis of peptides that a compound The intermediate is produced and contains each of the amino acid residues located in the desired sequence in the peptide chain with several of these residues having side chain protecting groups placed. These Protective groups are then commonly removed substantially at the same time they produce the desired resultant product following the removal of the resin.

Appropriate protecting groups to protect the side chain groups a and e-amino -i *, a_ are exemplified by benzyloxycarbonyl (CBZ), isonicotinyloxycarbonyl (iNOC), 0-chlorobenzyloxycarbonyl (2-C1-CBZ), p-nitrobenzyloxycarbonyl [Z (N02], p-methoxybenzyloxycarbonyl [Z (Ome)], t -butoxycarbonyl, (BOC), t-amyloxycarbonyl (AOC), isobornyloxycarbonyl, adamantyloxycarbonyl, 2- (4-biphenyl) -2-propyl-oxycarbonyl (BPOC), 9-fluorenylmethoxycarbonyl (FMOC), methylsulfo-nylethoxycarbonyl (MsC), trifluoroacetyl , phthalyl, formyl, 2-nitrophenylsulfonyl (NPS), diphenylphosphinothioyl (Ppt), dimethyl-phosphinothioyl (Mpt) and the like.

The protecting groups for the carboxy functional group are exemplified by; benzyl ester (Obzl), cyclohexyl ester (Chx), 4-nitrobenthenyl 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 the amino and carboxyl groups be protected by an appropriate protecting group. For example, the guanidino group of arginine can be protected with nitro, p-toluenesulfonyl, benzyloxycarbonyl, adamantyloxycarbonyl, p-methoxybenzenesulfonyl, 4-methoxy-2, ddimethylbenzenesulfonyl (Mds), 1,3,5-trimethylphenylsulfonyl (Mts) and the like . The thiol group of cysteine can be protected with p-methoxybenzyl, triphenylmethyl, acetylaminomethyl ethylcarbamoyl, 4-methylbenzyl, 2,4,6-trimethyl-enebenzyl (Tmb) etc., and the hydroxyl group of serine can be protected with benzyl, t- butyl, acetyl, tetrahydropyranyl and the like.

Stewart and Young's upra provides detailed information with reference to the procedures for preparing peptides. The protection of the a-amino groups is described on pages 14-18 and blocking of the side chain is described on pages 18-28. A table of protective groups for amine, hydroxyl and sulfhydryl functions is given on pages 149-151.

After the desired amino 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 to the peptide of the resin, but also part all the remaining side chain protective groups. After partition with HF, the peptide residue is washed with ether, and extracted from the resin when washing with aqueous acetonitrile and acetic acid. Preferably, in order to avoid the alkylation of residues in the polypeptide, (for example the alkylation of methionine, cysteine and tyrosine residues), a sequestering mixture of cresol and thio-cresol is used.

Other General Procedures The idomimetic peptide compounds of this invention can also be conveniently prepared by the peptide synthesis methods described in the monographs such as ("Principles of peptide synthesis, M. Bodanszky, Springer-Verlag, 2nd Ed., 1993;" Synthe tic Peptides: A Users Guide ", GA Grant, Ed, WH Freeman and Co., 1992, and the reference cited therein), or by other methods generally known to those skilled in the art The synthesis of the compounds of this invention which are peptidomimetic in nature (that is, they contain ligatures different from that of the normal amide bond between two or more amino acids) can be prepared by the extension of the methods described in Examples 6 and by the synthetic general methods described in "transformations" detailed organic ", RC Larock, VCH Publishers, 1989, and by the methods generally known to someone skilled in the art.

For the compounds of claim 1, wherein the amide bonds (-C (= 0) -NH-), are substituted with ligands of an amide isostere (Ai) such as; (-C (= S) -NH-), (-S (= 0) 2-NH-), -CH2-NH-, -CH2-S-, -CH2-0-, -CH2-CH2-, - CH = CH-, (cis and trans), -C (= 0) -CH2-, -CH (CN) -NH-, -0-C (= 0) -NH- and -CH2-S0-, are used methods of amide bond substitution known in the art. The following references describe the preparation of amide isostere ligatures which include these alternative ligature portions: Spatola, A.F., Vega Data 1 (3): "Peptide Backbone Modifications" (General Review) (Mar 1983), Spatola A.F., in "Chemistry and biochemistry of Amino Acids Peptides and Proteins", B. Weinstein, ed., Marcel Dekker, New York, P. 267 (1983); Morley Trends Pharm. Sci. Pp. 463-468; Hudson et al. Int, J. Pept. Prot. Res. 14: 177-185 (1979) (-CH2NH-, CH2CH2-) Spatola et al., Life Sci. 38: 1243-1249 (1986) (CH2-S-); Hann J. Che; n. Soc. Perkin. Trans. I 307-314 (1982) (-CH = CH-, cis and trans); Almquist et al., J. Med. Chem. 23: 1392-1398 (1980) (-C (= 0) -CH2-); Jennings-White et al., Tetrahedron Lett 23: (1982) (-C (= 0) -CH2-); Szelke et al., EP Application No. 45665 (1982) Chem Abs: 9739405 (1982) (-CH (OH) -CH2); Holladay et al., Tetrahedron Lett 24: 4401-4404 (1983) (-C (OH) -CH2-); 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-); Calcagni et al., Int. J. Peptide Protein Res. 34: 319-324 (1989) (-S (= 0) 2-NH-); TenBrink, J. Org. Chem. 52: 418-422 (1987) -CH2-0-.

Scheme 1 illustrates a synthetic approach which provides access to the unnatural amino acid side chains, particularly for the T substituent of formula 1. The method provides the a-alkylation of the "glycine" side chain using a solid phase approach on a commercially available machine such as an Argonaut Nautilus 2400.

Scheme I Br HO OH =? -OH HBTU. HOBt H0H --- H DIPEA t ~ NH3a ^ 95% TF Ou-OÍ » The following representative "R" groups can be introduced into the LFA-1 antagonists by the above alkylation scheme: When "R" of scheme 1 is an alkyl amine, prepared from amino acids lys. Orn or DAPA, the reduction of the representative nitriles above or prepared from the protected aminoalkyl halide (for example FMOC), synthetic routes are available for making T derivatives including urea carbamates, amides and sulfonamides by known methods.

Scheme II illustrates a solid phase approach to produce these derivatives of T.

Scheme II The urea made in accordance with scheme II, can be synthesized from commercially available representative isocyanates, RNCO, including the following: . / 'and Other representative substituted aryl isocyanates suitable for use in the above scheme include: These and other isocyanates can be used to produce carbamates when the "R" in scheme I is an alcohol (eg, be) according to the scheme below. Scheme lia The carbamates (of the opposite orientation to the Ha scheme), amides and sulfonamides synthesized according to scheme II can be made from representative R0C0C1, RC0C1, and RS02C1 commercially available including the following: Scheme III illustrates a general synthetic route for the alkyl linkers, L, for dichloro-substituted benzoyl amino acids or derivatives thereof. The key intermediary in this approach is iodine, dichlorobenzoyl, AA (4).

Scheme lll Lil Piridina The key intermediate (4) is coupled to a variety of alkynes to produce alkyl ligatures of varying length. For example, a 3-carbon linker can be made by coupling (4) the alkyne intermediate (5) prepared according to the Illa scheme.

Scheme Illa (5) Scheme IV illustrates the synthesis of substituted or unsubstituted alkane and substituted alkyne ligatures.

Scheme IV l.H ,, 5% RhAI, 03 2.TFA A bond of 4 carbons can be made by coupling (4) the alkyne intermediate (6) prepared in accordance with scheme V.

Scheme V l. H 10% P -C 2. DÍBAL Scheme VI illustrates the synthesis of unsubstituted alkane and alkyne linkers.

Scheme VI The Vía and VIb schemes illustrate the synthesis of substituted and unsubstituted alkane and alkene linkers of 3-5 carbons in length.

Scheme Via TFA. EtjSiH Scheme Vlb Scheme VII illustrates the synthesis of a 3-carbon alkyl linker wherein B is a benzoyl antagonist LFA-1 substituted with dimethyl.

Scheme VI I Scheme VIII illustrates the synthesis of a diether linker of 3-5 atoms where n is 1-3. The intermediate phenol (7) can also be used in the synthesis of the monoethers described below.

Scheme VIII / A. Br (CH2) n ^ Br K2CO, .DMF Scheme IX illustrates the synthesis of the monoether linkers of 3-5 atoms where n is 1-3. The intermediate phenol (7) above is used in this method. Scheme IX Scheme X illustrates the synthesis of 5-atom alkyl linkers wherein the distyl group "D" is a 5-membered aromatic ring. Preferred rings include thiophene, furan, thiazole and oxazole, wherein Z1 is 0 or S and Y2, Y3 or Y4 are selected from N or CH.

Scheme X HC = CMgBr _ .H2,5% Rh / AI203 2.TFA Scheme XI illustrates the synthesis of 3-atom amino alcohol linkers where the distyl group "D" is phenyl or het.

Scheme XI Beta hydroxy amines are produced by the reaction of a primary or secondary amine with epoxides. Epoxides are easily prepared by known methods (ie, oxidation of alkenes). l = phenyl. alkyl etc 2 = all possible terminations in C R5 = H or alkyl Scheme XII illustrates the synthesis of oxadiazole linkers of 3-5 atoms where the distyl group "D" is phenyl or het.

Scheme XII The oxadiazoles are prepared from the combination of hydroxyamidine with an activated carboxylic acid under dehydrating conditions. The hydroxyamidines are conveniently prepared by means of a reaction of a nitrile with hydroxylamine. to prepare compounds such as Scheme XIII illustrates the synthesis of amino tetrazole linkers of 5 atoms wherein the distyl group "D" is phenyl or het.

Scheme XIII The key step in the preparation of the amino tetrazoles is the reaction of a 5-halo-1-phenyltetrazole with an amine. Amino tetrazoles are formed from the reaction of N-bromo succinimide and sodium azide with phenyl isocyanate under phase transfer conditions.

The deprotection and coupling in the carboxylate to add the left-side amino acid is carried out as previously described for other compounds.

E. Modes for carrying out the invention The superior immunosuppressive efficacy is observed with a treatment regimen that uses early induction with a high dose of LFA-1 antagonist followed by prolonged treatment with a lower dose of antagonist.

Typically, the LFA-1 antagonist used in the method of this invention is formulated by mixing at room temperature at the appropriate pH, and to the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are nontoxic to containers in the dose and concentrations used. The pH of the formulation depends mainly on the particular use and the concentration of the antagonist, but preferably it is in the range of from about 3 to about 8. The formulation in an acetate buffer at a pH of 5 is an appropriate embodiment.

The LFA-1 antagonist to be used herein is preferably sterile. The LFA-1 antagonist will ordinarily be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable.

The antagonist composition will be formulated, dosed and administered in a manner consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the delivery site of the agent, the method of administration, the administration programming, and other factors known to medical practitioners. The "therapeutically effective amount" of LFA-1 antagonist to be administered is governed by such considerations, and is the minimum amount necessary to avoid, diminish, or treat disorders mediated by LFA-1, including the treatment of rheumatoid arthritis, multiple sclerosis , asthma, psoriasis, (topically or systemically), reduce inflammatory responses, induce tolerance of immune stimulants, prevent an immune response that would result in the rejection of a graft by a host or vice versa, or prolong the survival of a transplanted graft. Such amount is preferably below the amount that is toxic to the host or it turns out that the host is significantly more susceptible to infections.

As a general proposition, the initial pharmaceutically effective amount of the LFA-1 antagonist administered parenterally per dose, will be in the range of about 0.1 to 20 mg / kg of the patient's body weight per day, with a typical initial interval of LFA- antagonist. 1 used between 0.3 to 15mg / kg / day.

The LFA-1 antagonist is administered by any appropriate means, including oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary and intranasal and, if desired, by local immunosuppressive treatment, intralesional administration (including perfusion or otherwise graft contact). with the antagonist before the transplant). Parenteral infusions include intramuscular, intravenous, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. A preferred method of administration for psoriasis is topical in 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, in rheumatoid arthritis the LFA-1 antagonist can be given in conjunction with a glucocorticosteroid. In addition, peptide therapy of T cell receptors is appropriately an adjunct therapy to avoid the clinical signs of encephalon autoimmune myelitis (Offner et al., Supra). For transplants, the LFA-1 antagonist can be administered concurrently with or separated from an immunosuppressive agent as defined above, for example, cyclosporin A, to modulate the immunosuppressive effect. The effective amount of such other agents depends on the amount of LFA-1 antagonist present in 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 a form such that they induce immune tolerance to autoantigen under attack as a result of the disorder. In this regard, autoimmune disorders resemble host rejection against graft and are treated with LFA-1 antagonists in an analogous manner. However, in these disorders the patient is already mounting an immune response to the target antigen, unlike the case with transplants before placing the graft. Thus, it is desirable to first induce and maintain a transient immunosuppression state by conventional methods in such patients, for example, by the conventional use of cyclosporin A or other conventional immunosuppressive agents (together or only with LFA-1 antagonist) or to observe the patient up to that the occurrence of a remission period (the absence or substantial decrease of pathological or functional signs of the autoimmune response).

The invention will be more fully understood with reference to the following examples. These 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 LF? -1 from 293 cells Construction of the expression vector CADÍJ of the LFA-1 A plasmid with human CDlla (aL) and CD18 (ß2) sequences, each with a separate CMV promoter for expression in 293 cells, was constructed as follows. The plasmid pRKCD18, which contained the full length CD18 cDNA, was cut with the restriction enzymes Hpai and Avr II. The plasmid, pRKCDlla, which contained the full length of the CDlla cDNA, was treated with the enzyme taq 1 methylase to methylate one of the two Xmn 1 sites, then cut with Xmn ly and Spe 1. The digest fragment pRKCDld containing the sequence of cd 18 coding, the CMV promoter, the antibiotic resistance gene and other plasmid sequences were ligated to the fragment from the pRKCDlla digest containing the CDlla coding sequence and the CMV promoter. The sticky ends Spe I and Avr II are compatible and ligated together. The Hpa 1 and Xmn 1 ends are both abrupt and ligated together to generate the plasmid pRKLFAa + b.

Gene was the cell line of the 293 express of the LFA-1.

A human LFA-1 expressing cell line was generated by cotransfecting 293 cells with plasmid (pRK LFA a + b) containing the full-length cDNA for the aL (CDlla) and B2 (CD18) subunits together with pRSVneo, which encodes the resistance marker G418 under the control of the RSV promoter, using the previously described methods. (Bodary, Napier and McLean, J Biol. Chem, 264, 32, 18859-18862, 1989). With growth in the presence of 0.8 mg / ml of G418 for 20 days, a population of drug-resistant cells was selected for the expression of LFA-1, using two color FACS (selection of fluorescence-activated cells), with monoclonal antibodies directed against an L subunit (clone 25.3 of a monoclonal anti-drug labeled with fluorocein isothiocyanate, catalog # 0860, AMAC, Inc.) or b2 subunit complex (MHM23 labeled with phycoerythrin). (MHM23 antibody reference: Hildreth JEK, and August J, Immunol J, 134, 3272-3280, 1985). After three rounds of FACS, a clonal population was isolated (clone 19) and the number of receptors 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.

Ex tra ction of cells (all procedures at 0-4 ° C) The pelleting of frozen 293 cells was suspended in 5 volumes of 0.3M sucrose / 20mM HEPES / 5mM CaCl2 / 2mg / ml aprotinin with pH 7.4 using a polytron homogenizer (Brinkman) at approximately 8000 rpm. Once a uniform suspension was obtained, the cells were homogenized at approximately 20,000 rpm for 1 min. Sulfonyl phenylmethane fluoride (PMSF, 100 mM in isopropanol) was then added to homogenize to a final concentration of lmM, and the homogenate was centrifuged at 21,000 xg for 40 min. The supernatant and suspended pellets were discharged 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 volume of the sucrose buffer solution above. The cells were briefly homogenized around 8000 rpm with the polytron then placed in a washing screen for 30 minutes. The extract was centrifuged as above and the supernatant was saved.

Lentil Lecithin Column Approximately 3 to 4 column volumes of cell extract were loaded at 15cm / hr onto a lentil lecithin sepharose column (Pharmacia) equilibrated in 0.1% Triton X-100 / 0.15 M NaCl / 20mM HEPES / 5mM CaCL2 / 5 mM MgCL2pH 7.4. Once the sample was loaded, the column was washed with an equilibrium buffer solution until the base line A28 or mn- was reached. LFA-1 was eluted with 0.5 M a-methyl mannoside in an equilibrium buffer solution. To maximize recovery, elution was stopped when LFA-1 started to appear, the column was left overnight in an elution buffer and then the elution was started again.

Column Q of Sepharose The lentil eluate was diluted with an equal volume of 0.1% Triton X-100/20 mM NaCl / 20 mM HEPES / 5 mM CaCL2 / 5 mM MgCL2pH 7.4 was loaded at 15 cm / hr on a high performance Sepharose column Q (Pharmacia), balanced in the same buffer solution. After the sample was loaded, the column was washed with an equilibrium buffer until the base line A280 nm was approached, then with 1% octyl glucoside until the Triton X-100 was removed. The LFA-1 was eluted with a volume of 10 columns with gradient NaCl from 0 to 0.3 M in the same buffer. The fractions were analyzed by SDS PAGE and the peak fractions were pooled and stored frozen at -70 ° C.

Example 2 Immunoadhesin-ICAM-1 Plasmids for the expression of a human immunoadhesive ICAM-1.

A plasmid for the expression of a human immunoadhesin ICAM-1 was constructed and named pRK.5DICAMGalg. This plasmid contains; a CMV promoter (cytomegalovirus) and an enrichment region, an SP6 promoter to make riboprobes, the five immunoglobulin-like domains of ICAM-1, a pendant site of 6 amino acids recognized by Genenase (a genetically engineered form of the subtitle ilicin), the Fc region from human IgG, an early SV40 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 of two other plasmids. The first plasmid pRKICAMm.2, is a plasmid for the expression of full-length ICAM-1. The other two primers that were used to generate a fragment containing the five immunoglobulin-like domains of ICAM-1 by PCR: 1), a forward primer 17bp which is homologous to a portion of the 5 'vector sequence of the coding sequence of ICAM-1 -5 'TGC CTT TCT CTC CAC AG 3' and 2) a reverse priming 48bp which is a homologue to amino acids 7 at the 3 'end of IgY-like domain 5 containing the coding of the sequence for a suspended site of protease-5 'GG TGG GCA AGT GTA GTG CGC AGC CTC ATA CCG GGG GGA GAG CAC A 3'. The PCR reaction used 0.2μg of pRKICAMm.2, 1μl of forward priming, at 10 OD / ml, 2μl of inverse priming at 10 OD / ml, 0.2mM each dATP, dCTP, dGTP, and dTTP, MgCl2, 0.5M additional, VENT polymerase buffer solution VENT (New England Biolabs), and VENT lμl polymerase, 2 units / μl (New England Biolabs). The reaction was denatured at 98 ° C for 5 'then a 20-fold cycle was made through the following temperatures: 98 ° C 1", 98 ° C 10", 60 ° C 1", 60 ° C 1', 72 ° C 1", 72 ° C 1 '. The reaction was prolonged by 20 'at 72 ° C before being maintained at 4 ° C overnight. This reaction produces a 1579bp fragment which was purified using a Qiaquick spin PCR purification kit (Qiagen) and digested with Clal and DralII restriction enzymes (New England Biolabs). The resulting 1515bp fragment was gel purified on a 5% acrylamide gel in TBE lx, electroeluted in TBE O.lx, and purified on SpinBin columns (FMC). This insert fragment contains the first five immunoglobulin domains of ICAM-1 and the hanging site of Genenasa.

The second plasmid, the trkcfc gene, is a plasmid for the expression of the immunoadhesin TrkC contains the same pendant protease site. This plasmid was digested with Clal (New England Biolabs) completely. This material was then digested with DralII (New England Biolabs) using suboptimal amounts of the enzyme such that a series of partially cut fragments was generated. The desired 5378 bp fragment was isolated in a run of 0.6% GTG agarose gel (FMC) in TBE lx (BRL) and electroeluted in 0.1X TBE. The material was extracted first with butanol, then with phenol, then with chloroform and precipitated with 3M sodium acetate in 0.1 volume, pH 7.0 and 2.5 volumes of EtOH. This fragment of the vector contains all the plasmid characteristics listed above except the first 5 immunoglobulin domains of ICAM-1 and the penase protease site.

The two fragments described above were combined in an insert: 3: 1 vector ratio using approximately 50 mg of vector in a lx ligase buffer and 2 μl of ligase at 400 units / μl (New England Biolabs) for 2 hours at room temperature . Half of the reaction was transformed into the competent MM294 cells by conventional methods.

Generation was a one or two-year ICAM-1, which expresses the existence of cell 293 A cell line expressing the ICAm-1 immunoadhesin was generated by transfecting 293 cells with a cDNA encoding the five immunoglobulin domains of the human ICAM-1 upstream from the human Fc sequence (pRK.5DICAMGalg) together with the pRSVneo, as previously described for the cell line LFA-1. By selecting at 0.8mg / ml individual clones G418 were isolated from drug resistant cells. The culture supernatants of these clones were tested for the expression of the ICAM-1 immunoadhesin by ELISA, using polyclonal antibodies directed against human Fc (Caltag Catalog # H10507, H10700). 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, catalog # 0544) directed against human ICAM-1. This cell line was grown under serum free culture conditions and the culture supernatant was collected by purification of the ICAM-1 immunoadhesin.

Example 3 ICAM-1 receptor binding assay: LFA-1 (protein / protein assay) A drawing illustrating the forward format of the human receptor binding assay ICAM-1: LFA-1 is given in Figure 2. The competitive inhibition of the CDlla / CD18 -ICAM-1 interaction is quantified by adding known amounts of inhibitors. in accordance with the two protein / protein assay systems described below.

In terms of LFA-1: ICAM-1 in the form of a nt ero (PPFF): The purified full-length recombinant LFA-1 human protein was diluted to 2.5μg / ml in 0.02M Hepes, 0.15M NaCl, and lmM MnCL2 in 96-well plates (50μl per well) and coated overnight at 4 ° C. C. Plates are washed with wash buffer (0.05% Tween 20 in PBS) and blocked for 1 hour at room temperature with 1% BSA in 0.02M Hepes, 0.15M NaCl, and MnCL2 lmM. The plates are washed, and inhibitors of 50μl per well, appropriately diluted in a test buffer solution (0.5% BSA in 0.02M Hepes, 0.15M NaCl, and lmM MnCL2), are added to a final concentration 2X and incubated during a hour at room temperature. 50μl / well of the purified recombinant human ICAM-lg domain, diluted to 50ng / ml in a test buffer and incubated 2 hours at room temperature, are added. The plates are washed and bound ICAM-lg is detected with goat anti-HulgG (Fc) -HPR for 1 hour at room temperature. The plates are washed and developed with 100μl / well of TMB substrate for 10-30 'at room temperature. The colorimetric development is stopped with 100μl / well of H3P04 1M and a reading of 450nM is read in a plate reader.

An alternative protein / protein assay system described below also quantifies the competitive inhibition of the CDlla / CD18-ICAM-1 interaction.

LFA-1 Assay: ICAM-1 Capture of Ani bodies (PLM2): A non-functional blocking monoclonal antibody against human CD18, PLM2, (as described by Hildreth, et al., Mol ecul ar Imm un olygy, Vol. 26, No. 9, pp. 883-895, 1989), Dilute to 5μg / ml in PBS and cover 96-well flat bottom plates with lOOμl / well overnight at 4 ° C. Plates are blocked with 0.5% BSA in assay buffer (0.02 Hepes, 00.15M NaCl, and lmM MnCL2) 1 hour at room temperature. The plates are washed with 50mM Tris pH 7.5, 0.1M NaCl, 0.05% Tween 20 and lmM MnCL2. The purified full-length recombinant human LFA-1 protein, diluted to 2 μg / ml in a test buffer and 100 μl / well are added to the plates and incubated at 37 ° C. The plates are washed 3X. 50μl / well inhibitors, appropriately diluted in a test buffer, are added to a final 2X concentration and incubated for 30'to 37 ° C. 50μl / well of purified recombinant human ICAM-lg domain 5, diluted to 161 ng / ml (for a final concentration of 80ng / ml) in assay buffer, added and incubated 2 hours at 37 ° C. The plates are washed and the ICAM-lg bound with goat ant i-HulgG (Fc) -HPR is detected for 1 hour at room temperature. The plates are washed and developed with a substrate of TNB 100μl / well for 5-10 minutes at room temperature, the colorimetric development is stopped with 100μl / well of H3P04 1M and a reading of 450nM is read in the plate reader.

Example 4 Adhesion test of human T cells (cell placement assay) A drawing illustrating the colorimetric assay of adhesion of human T cells is given in Figure 3. The T cell adhesion assay is carried out using a human T-lymphoid HuT 78 cell line. Anti-HulgG (Fc) was diluted ) goat up to 2μg / ml in PBS and 96 well plates were coated with 50μl / well at 37 ° C for 1 hour. Plates were washed with PBS and blocked for 1 hour at room temperature with 1% BSA in PBS. The ICAM-lg from domain 5 was diluted to 100 ng / ml in PBS and 50μl per well was added to the O / N plates at 4 ° C. The HuT 78 cells were centrifuged at 100g and the cell pellet was treated with 5mM ECTA for about 5 minutes at 37 ° C in a 5% C02 incubator. Cells were washed in 0.14M NaCl, 0.02M Hepes, 0.2% glucose, and 0. ImM MnCL2 (assay buffer) and centrifuged. The cells were resuspended in a buffer assay until 3.0 x 106c / ml. The inhibitors were diluted in a test buffer to a final concentration 2X and preincubated with HuT 78 cells for 30 minutes at room temperature. 100μl / well cells and inhibitors were added to the plates and incubated at room temperature for 1 hour. 100μl / per well of PBS were added and the plates were sealed and centrifuged inverted at 100g for 5 minutes. The unplaced cells were detached from the plate and the excess PBS was dried on a paper towel. 60μl / per well of p-nitrophenyl n-acetyl-β-D-glucosaminide (0.2527g to lOOml of the citrate buffer) was added to the plate and incubated for 1.5h to 37 ° C. The reaction of the enzymes was stopped with 90μl / well of 50mM glycine / 5mM EDTA and reading in the plate reader at 405nM. The adhesion of HUT 78 cells to 5dICAM-lg is measured using the p-nitrophenyl n-acetyl-β-D-glucosaminide method of Landegren, U. (1984) J. Imm an ol. Me th ods 57, 379-388 EXAMPLE 5 T Cell Proliferation Assay (Co-stimulation Assay) A drawing illustrating the proliferation assay of human T cells is provided in Figure 4. This assay is an in vitro model of lymphocyte proliferation resulting from the activation induced by the coupling of the T cell receptor and LFA-1, with the interaction with the antigen presenting cells (Springer, Nature 346: 425 (1990)).

Microtiter plates (96-well Nunc certified with ELISA) were pre-coated overnight at 4 ° C with 50μl of 2μg / ml goat antihuman Fc (Caltag H10700) and 50μl of 0.07μg / ml monoclonal antibody to CD3 (Immunotech 0178) in sterile PBS. The next day the coated solutions were aspirated. The plates were then washed twice with PBS and lOOμl of 17ng / ml of 5d-ICAM .1-IgG were added for 4 hours at 37 ° C. Plates were washed twice with PBS before addition to CD4 + T cells. Peripheral blood lymphocytes were separated from heparinized whole blood removed from healthy donors. An alternative method was to obtain whole blood from healthy donors through leukophoresis. The blood was diluted with 1: 1 saline, layered and centrifuged at 2500xg for 30 minutes on LSM (6.2g of ficol and 9.4g of sodium distrizoate for 100 milliliters) (Organon Technica, NJ). Monocytes were suppressed using a method of myeloid cell suppression reagents (Myeloclear, Cedarlane Labs, Hornby, Ontario, Canada). The PBL were resuspended in 90% heat inactivated fetal bovine serum and 10% DNSO, formed in aliquots and stored in liquid nitrogen. After melting, the cells were resuspended in RPMI 1640 medium (Gibco, Grand Island, NY) supplemented with 10% heat inactivated bovine fetal serum (Intergen, Purchase, NY), sodium pyruvate lmM, L- 3mM glutamine, non-essential amino acids lmM, penicillin 500μg / ml, streptomycin 50μg / ml, gentamicin 50μg / ml (Gibco).

The purification of CD4 + T cells was obtained by a negative selection method (Human CD4 cell recovery column case # CL110-5 accurate). 100,000 purified CD4 + T cells (90% purity) per well microtitre plate, were cultured for 72 hours at 37 ° C in 5% C02 in lOOμl culture medium (RPMI 1640 (Gibco) supplemented with heat-inactivated FBS 10% (Intergen), non-essential amino acids O.lmM, sodium pyruvate lmM, penicillin 100 units / ml, streptomycin lOOμg / ml, gentamicin 50μg / ml, Hepes lOmM and glutamine 2mM). Inhibitors were added to the plate at the beginning of the culture. The proliferative responses in these cultures were measured by the addition of thymidine titrated lμCi / well during the last 6 hours before harvesting the cells. The incorporation of a radioactive label was measured by a liquid scintillation count (Packard 96 well counter and well counter). The results were expressed in accounts per minute (cpm).

EXAMPLE 6 Culture model of mixed lymphocytes in vi tro A drawing detailing the mixed lymphocyte response assay is provided in Figure 5. This mixed lymphocyte culture model, which is a model for transplanting (AJ Cunningham, "Understanding Immunology, Transplantation Immunology pages 157-159 (1978), examines the effects of various LFA-1 antagonists on both the effector and proliferative arms of the mixed human lymphocyte response.

Isolation of cells: peripheral blood mononuclear cells (PBMC) were separated from heparinized whole blood withdrawn from healthy donors. The blood was diluted 1: 1 with saline, layered and centrifuged at 2500 x g for 30 minutes on LSM (6.2 g ficol, 9.4 g sodium distrizoate per 100 ml) (Organon Technica NJ). An alternative method to obtain whole blood from healthy donors through leukophoresis. The PBMCs were separated as above, resuspended in 90% heat-inactivated fetal bovine serum and 10% DMSO, formed in aliquots and stored in liquid nitrogen. After thawing, the cells were resuspended in RPMI 1640 medium (Gibco, Grand Island, NY) supplemented with 10% heat-inactivated fetal bovine serum (Intergen, Purchase, NY), lmM sodium pyruvate, l- 3mM glutamine, non-essential amino acids lmM, penicillin 500μg / ml, sterptomycin 50μg / ml, gentamicin 50μl / ml (Gibco).

Mixed lymphocyte response (MLR): One-way mixed human lymphocyte cultures were established on 96-well flat-bottom microtiter plates, and 1.5 x 105 response PBMCs were cultured with an equal number of allogeneic and radiated stimulator (3000 rads for 3 minutes, 52 seconds) PBMCs in 200μl of complete medium. LFA-1 antagonists were added at the start of cultures. The cultures were incubated at 37 ° C in 5% S02 for 6 days, then pulsed with a 1 μCi / 3H thymidine well (6.7 Ci / mmol, NEN, Boston, MA) for 6 hours. The cultures were harvested in a Packard cell harvester (Packard, Canberra, Canada). The incorporation of [3 H] TdR was measured by a liquid scintillation count. The results are expressed as how many per minute (cpm).

Example 7 Synthesis of the compound and activity The abbreviations used in the following section: wang resin = p-alkoxybenzyl alcohol resin; Fmoc = 9-fluorenylmethyloxycarbonyl; Fmoc-Osu = 9-fluorenylmethyloxycarbonyl- N-hydroxysuccinimide; Boc = t-butyloxycarbonyl; Boc20 = t-butyloxycarbonyl anhydride; DMA = dimethylacetimide; DMF = dimethylformamide; BOP = hexafluorophosphate (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium; Hobt = 1-hydroxybenzotriazole; NMM = 4-methylmorpholine; TFA = trifluoroacetic acid; DCM = dichloromethane; MeOH = methanol; HOAc = acetic acid; HCl = hydrochloric acid; H2S04 = sulfuric acid; K2C03 = potassium carbonate; Ph3P = triphenylphosphine; THF = tetrahydrofuran; EtOAc = ethyl acetate; DIPOEA = diisopropylethylamine; NaHCO3 = sodium bicarbonate; NMP = methyl pyrrolidinone; DIPC = diisopropylcarbodiimide; ACN = acetonitrile; HBTU = 2- (lH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate; NCS = N-chlorosuccinimide; Na2 »EDTA = sodium salt of ethylenediaminetetraacetic acid; TBAF = tetrabutylamine fluoride; EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide by HCl; DEAD = diethyl azocarboxylate; TEA = triethylamine; MgSO4 magnesium sulfate; TES = triethyl silane; Et20 = diethyl ether; BBr3 = boron tribromide.

Synthetic general methods Gl Method The appropriate Boc-protected molecule was dissolved in a solution in a solution of TFA in DCN (1: 1). After 20 minutes, the reaction was concentrated in vacuo. The resulting oil was dissolved in toluene and then concentrated in vacuo twice.

G2 method The appropriate amine was dissolved in Et20 and washed twice with a 10% solution of K2C03 in H20 and once with brine. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The product was then used without further purification.

G3 method 3 equivalents of the appropriate carboxylic acid were coupled to an equivalent of the appropriate amine using 3 equivalents of EDC and one equivalent of Hobt in DMA. The reaction was monitored by TLC (9/1 DCM / MeOH). When finished, the mixture was concentrated in va cuo. The resulting oil was resuspended in Et20 and washed twice with 0.1 N H2SO4, twice with saturated NaHCO3, and once with brine. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The product was then used without further purification.

Method G4 1 equivalent of the appropriate methyl ester was dissolved in THF / H20 (3/1) and 3 equivalents of LiOH »H20 were added. The reaction was monitored by TLC (9/1 DCM / MeOH). Upon completion, the mixture was carefully acidified to a pH of two with concentrated HCl and then concentrated in vacuo. The resulting solid was resuspended in Et20 and washed twice with H2SO4 and once with brine. The organic layer was then dried over MgSO 4, filtered and concentrated in vacuo.

Method 5 1 equivalent of the appropriate amino acid and 2.5 equivalents of NaHCO3 were dissolved in THF / H20 (3/1). Once the solution became clear, 1.5 equivalents of Fmoc-Osu were added. The reaction was monitored by TLC (9/1 DCM / MeOH). Upon completion, the mixture was concentrated until only the aqueous phase remained. The solution was then extracted twice with Et20 and then acidified carefully to a pH of 2 with concentrated HCl to precipitate the product. The aqueous layer and the product were then extracted with EtOAc. The organic layer was partitioned once with brine and dried over MgSO4, filtered and concentrated in vacuo. The product was then used without further purification.

G6 method 1 equivalent of fluoroenilmethanol and 1 equivalent of the appropriate amino acid and 2.5 equivalents of Hobt were dissolved in NMP. The mixture was cooled to 0 ° C without stirring. Once cold, an equivalent of DIPC was added for 5 minutes with stirring followed by portionwise additions of an equivalent of 2-bromoterephthalic acid and then 0.01 equivalents of 4-pyrrolidinopyridine. The mixture was stirred at 0 ° C for 2 hours, allowed to warm to room temperature and stirred for 4 hours, and then re-cooled to 0 ° C and quenched with the dropwise addition of H20. After stirring for 1 hour, the mixture was partitioned with EtOAc. The organic layer was then divided twice with dilute HCl, once with brine and dried over MgSO4, filtered and concentrated in vacuo. The crude product (a 9: 1 mixture of the correct isomer against the wrong one) was purified using flash silica chromatography using 3/1 hexane / EtOAc and 3% HOAc.

G7 method The appropriate methoxy containing the compound was dissolved in DCM and cooled to minus 5 ° C in an ice / acetone bath under nitrogen. Two equivalents of BBr3 were added dropwise as a solution in DCM for 30 minutes. The reaction was allowed to warm to room temperature and was stirred until complete by TLC (DCM / 2% HOAc / 2% MeOH). The solution was emptied on ice, and the ice was allowed to melt. The mixture was then divided twice with EtOAc and the combined organic layers were dried over MgSO4. The filtrate was then passed over a plug of silica gel and concentrated in vacuo.

G8 method 1 equivalent of dimethyl 2-chloroterephthalic acid was monohydrolyzed by the G9 method to result in the correct monoprotected diacid. The monoester was esterified to t-butyl then by the G10 method. The methyl ester was then separated by the G4 method to result in the carboxylic acid (compound A).

G9 method The diester was dissolved in DCM and cooled to minus 5 ° C in an ice / acetone bath under nitrogen. An equivalent of BBr3 was added dropwise as a solution in DCM for 30 minutes. The reaction was allowed to warm to room temperature and was stirred until complete by TLC (DCM / 2% HOAc / 2% MeOH). The solution was emptied on ice, and the ice was allowed to melt. The mixture was then partitioned with EtOAc and concentrated in vacuo. This product was dissolved in H20 with the addition of saturated NaHCO3 until the pH remained above 8. This solution was divided once with an 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 the precipitate was extracted twice with equal volumes of EtOAc. The organic compounds were divided once with brine and dried over MgSO4, filtered and concentrated in vacuo. The product was 7: 1 of the correct regioisomer by HPLC.

G10 Method The monoester was dissolved in DCM and transferred to a pre-weighed Parr flask containing a stir bar. The flask was cooled to minus 5 ° C with a dry ice / alcohol bath under nitrogen. Once cooled, approximately 30 isobutylene equivalents were pumped into the solution with stirring. 2.1 equivalents of concentrated sulfuric acid were added and the flask was sealed with wired rubber fastener 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 fastener was removed and the excess isobutylene moved with bubbling by nitrogen. Saturated NaC03 was added to neutralize the acid and the mixture was concentrated until there was no DCM. The solution was then partitioned with EtOAc. The organics were divided twice with dilute HCl, twice with saturated NaHCO3, once with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting product was used without further purification.

Gil Method 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 redissolved twice and concentrated from toluene. The product was used without further purification.

Method G12 Compound A was coupled to 3-chlorobenzylamine by the G3 method. The t-butyl ester was separated by the Gil method to produce the carboxylic acid (compound B).

Method G13 Compound A was coupled to the 3-methoxy benzylamine, Method G38, by the G3 method. This product was converted to the methyl ester by the G15 method. The methoxy group was demethylated to phenol by the G7 method. The methyl ester was saponified to the carboxylic acid by the G4 method 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 the G15 method and the bromine was converted to the nitrile by the G16 method. After saponification by the G4 method, the nitrile was reduced to the amine and the Fmoc protected by the G17 method. The final product (compound D) was purified by flash silica chromatography (95/5 DCM / MeOH) and verified by electroatomatization mass spectrometry.

Method G15 The appropriate carboxylic acid was dissolved in dry MeOH and 10 equivalents of HCl / dioxane were added and the mixture was stirred overnight to yield the methyl ester product. The solution was concentrated and re-dissolved twice and concentrated from toluene. The final product was purified by flash silica chromatography (95/5 DCM / MeOH) and verified by electroatomization mass spectrometry.

Method G16 0. 6 equivalents of zinc cyanide 0.04 equivalents of tet racis (triphenylphosphine) palladium (0) were placed in a round bottom flask and purged for 30 minutes with circulating nitrogen. The methyl ester was dissolved in anhydrous DMF and degassed for 30 minutes with nitrogen. Upon completion of degassing, the methyl ester solution was added to zinc cyanide and palladium via a cannula and stirred overnight at 80 ° C. At the end of the reaction, the solution was concentrated and re-dissolved in EtOAc. The organics were divided twice with dilute HCl, twice with saturated NaHCO 3, once with brine, dried over MgSO 4, filtered and concentrated in vacuo. The product was purified by flash silica chromatography (DCM) and verified by electroatomization mass spectrometry.

Method G17 1 equivalent of the nitrile was dissolved in THF and cooled to 0 ° C in an ice bath. Once cold, 4 equivalents of the superhydride were quickly added by means of a cannula to the nitrile. After 5 minutes, the reaction was emptied onto ice containing 5 equivalents of sulfuric acid and stirred until all the ice melted. Two volumes of THF were added to the solution and the pH was carefully adjusted to 8 with portionwise additions of NaHCO4. 1.5 equivalents of Fmoc-Osu were added. The reaction was monitored by TLC (9/1 DCM / MeOH). Upon completion of the reaction, the mixture was concentrated in vacuo until only the aqueous phase remained. The aqueous solution was then extracted twice with Et20 and then carefully acidified to a pH of 2 with concentrated HCl to precipitate the product. The aqueous layer and the product were then extracted with EtoAc. The organic layer was then divided once with brine and dried over MgSO 4, filtered and concentrated in vacuo.

Method G18 1 equivalent of the appropriate hydroxycarboxylic acid, 2.2 equivalents of t-butyldimethyl silyl chloride and 3 equivalents of imidazole were dissolved in DMF and stirred at room temperature. The reaction was monitored by TLC (9/1 DCM / MeOH). When finished, the reaction, the mixture was concentrated in va cuo. The resulting oil was resuspended in ET20 and washed twice with saturated NaHCO3 and once with brine. The organic layer was then dried over MgSO 4, filtered and concentrated in vacuo. The product was then used without further purification.

Method G19 To the resin that had been rinsed twice with DMA, a solution consisting of 20% piperidine in DMA was added. After 20 minutes, the resin was filtered and rinsed 5 times with DMA.

G20 method 3 equivalents of the appropriate carboxylic acid were coupled with 3 equivalents of BOP, 1 equivalent of HOBt, and 6 equivalents of NMM in DMA for 30 minutes. The coupling was observed by the Kaiser ninhydrin test. If the Kaiser test was positive, the appropriate carboxylic acid was coupled again in the same way.

Method G21 The molecule was suspended from a rinsed resin and dried in a solution consisting of 5% tisopropylsilane in TFA for 1 hour. The crude molecule was concentrated after it was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

G22 Method 3 equivalents of the appropriate amine were coupled with 3 equivalents of BOP, 1 equivalent of HOBt and 6 equivalents of NMM in DMA for 60 minutes.

Method G23 The resin was washed successively with DMA, DCM, 20% HOAc in DMC, MeOH and DMF. 2 equivalents of the appropriate aldehyde were dissolved in a minimum volume of 1% HOAc in DMF and added to the freshly rinsed resin. After 5 minutes, 2 equivalents of sodium cyano borohydride in DMF were added and the resin was bubbled overnight. The resin was then washed with DMF, 20% DIPEA in DMC, DCM and MeOH. The coupling was observed by the Kaiser ninhydrin test. If the Kaiser test was positive, the appropriate aldehyde was reattached in the same manner.

G24 method 3 equivalents of the appropriate carboxylic acid (R) were 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 sulfuric acid, saturated NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The resulting methyl ester as a product was then used without further purification.

Method G25 The methyl ester of the appropriate carboxylic acid was made by the G15 method and the phenol was converted to the t-butyl ester by the G10 method. An equivalent of the resulting product was dissolved in a 1: 2 mixture of THF and EtOH, and 3 equivalents of lithium chloride and 3 equivalents of boron sodium hydride were added and the reaction was stirred overnight. The reaction was quenched with H20 and concentrated in vacuo. The residue was divided between EtOAc and H20 and the aqueous layer was extracted with EtOAc.

The combined organic layers were dried over MgSO 4, filtered and concentrated in vacuo. The crude alcohol was purified using flash chromatography on silica gel (9: 1 hexane / Et20).

Method G26 A solution of one equivalent of alcohol and 1.1 equivalents of Ph3P in THF was cooled to 10 ° C in an ice / ethanol bath. While stirring, a solution of 1.1 equivalents of phenol and 1.1 equivalents of DEAD in THF were added dropwise. The cold bath was separated and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and the resulting residue was taken up in a minimum amount of DCM and filtered through a plug of silica gel, using DCM as eluent. After concentrating this in va cuo solution, the residue was purified using silica gel flash chromatography (8 2/2/0.5 hexane / DCM / Et20) to give the pure ether.

G27 Method 1 equivalent of the alcohol was dissolved in acetone and cooled to minus 10 ° C. 1.1 equivalents of Jones reagent were 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 H20. The residue was partitioned between EtOAc and H20 and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The yellow solid was triturated with Et20 to remove impurities providing pure ketone.

Method G28 1 equivalent of the appropriate dihydroxynaphthalene, dissolved in pyridine. 4 equivalents of solid sodium hydride were added followed by two equivalents of bromine and 0.4 equivalents of cuprous chloride. The resulting mixture was stirred vigorously and heated in an oil bath at 100 ° C for 2 days. After concentrating in vacuo, the residue was partitioned between EtOAc and 1M HCl.

The aqueous layer was extracted EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with Et20. After filtering the mixture and concentrating the filtrate, the resulting residue was purified using flash chromatography on silica gel (5: 4: 1 hexane / DCM / Et20).

Method G29 To a stirred solution at minus 78 ° C of an equivalent of the appropriate methyl ester, in dry toluene, a solution of DIBAL 1.5 M in toluene (1.7 equivalents) was added dropwise. The reaction mixture was stirred for an additional two hours at minus 78 ° C or until the TLC showed a clean product formation, with only a trace of the starting material. The reaction was quenched by slowly adding cold MeOH (-78 ° C). The resulting white emulsion was slowly emptied into ice cold HCl and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified using flash chromatography on silica gel (9: hexane / Et20) to provide the pure aldehyde.

Method G30 1 equivalent of the amido alcohol made by the G28 method and 1.5 equivalents of the Ph3P were dissolved in THF and cooled to minus 5 ° C. 1.5 equivalents of DEAD were added dropwise and the reaction was stirred at room temperature overnight. After concentrating the reaction in vacuo, the residue was taken up in a chemical amount of DCM and purified by flash chromatography (9: hexane / Et20) to yield pure oxazoline.

Method G31 To a stirred solution at minus 78 ° C of one equivalent of bromine in THF, 1.6 M n-BuLi (1.05 equivalents) was added dropwise. After 0.5 hours, 1.1 equivalents of the aldehyde in THF were added via a cannula at minus 78 ° C and the reaction was stirred at minus 78 ° C. After 2 hours, the reaction was quenched with 2 equivalents of cold HOAc (-78 ° C) in THF. The mixture was warmed to room temperature, concentrated in vacuo and the oily residue was partitioned between Et20 and H20. The aqueous layer was extracted with Et20. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo. The residue was purified using flash chromatography on silica gel (7: 3hexane / Et20).

G32 method The oxazoline alcohol was dissolved in a 13: 1 mixture of ethanol and sulfuric acid, then heated to reflux for 3 days. The reaction was concentrated and the residue was partitioned between Et20 and H20. The aqueous layer was extracted with Et20. The combined organic layers were dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified using flash chromatography on silica gel (1: hexane / Et20) to give the pure ethyl ester.

G33 method To a freshly rinsed resin was added 2.2 equivalents of DIPEA and 2.2 equivalents of the appropriate isocyanate (R) in 1,2-dichloroethane were added and the resin was stirred overnight. The resin was then washed with 10% piperidine in NMP, THF, 30% HOAc in DCM and MeOH.

Method G34 1 equivalent of the 4-benzyloxy benzyl alcohol resin (Wang resin) was washed with DMA and DCM. To the resin was added 3 equivalents of the amino acid protected with appropriate Fmoc, 3 equivalents of DIPC and 0.5 equivalents of DMAP in DCM. The resin was stirred for 2 hours, rinsed with DCM and DMA. The resin was then treated with 10% acetic anhydride in DCM for 5 minutes. The resin was washed with DCM and MeOH and then dried.

Method G35 The resin was washed with DCM and chloroform. A fresh 0.14 M solution of tet racis (triphenylphosphine) palladium (O) in 2.5% NMM, 5% HOAc in chloroform was added to the resin. After stirring for 1 hour, the resin was verified by the Kaiser ninhydrin test. If the Kaiser test was negative, a new Pd (0) solution was made and the reaction made again until a positive Kaiser test was found. The resin was rinsed with DCM, MeOH and DCM.

Method G36 The deprotected resin was treated for 1 hour with a solution of 10 equivalents of benzophenone imine and 1.3 equivalents of HOAc in DMA to form the benzophenone imine of glycine. After rinsing with DMA, the resin was treated with 3.5 equivalents of 2-t-butyl-2-diethylamino-1,3-dimethyl-1, 2, 3-diazaphosphorine for 1 hour. 3 equivalents of the appropriate alkylating agent were added and the reaction was stirred for 2 hours. The resin was drained and washed with NMP, 20% DIPEA in DCM, DCM, 10% HOAc in DCM and DCM. The benzophenone was separated with a solution of 10 equivalents of hydroxylamine HCl in THF / H20 for 3 hours. The resin was rinsed with H20, THF, 20% DIPEA in DCM and DCM.

Method G37 equivalents of 2-bromoterephthalic acid, 20 equivalents of HBTU, 20 equivalents of Hobt and 22 equivalents of DIPEA were dissolved in DMA and stirred for 15 minutes, resulting in the bisactivated ester of 2-bromoterephthalic acid. To this solution were added 15 equivalents of 3-hydroxy benzylamine, Method G38 and 15 equivalents of DIPEA resulting in the active ester of Compound E. The reaction was stirred for 30 minutes and then added to the resin which was stirred overnight .

Method G38 One equivalent of 3-cyanophenol was placed in a Parr bottle with EtOH, 0.02 equivalents of HCl and 10% (w / w) of 10% Pd on carbon. The vessel was placed on the Parr agitator, charged with H2 at 3.5 kg / cm2 (50 psi) and stirred for 12 hours. The reaction was filtered through a pad of celite and diluted with 1:10 Et20. When left overnight, fine white needles were formed. The product was filtered, washed with Et20 and dried in vacuo. The resulting hydrochloride salt was then used without further purification.

Method G39 The resin was washed with DCM and chloroform. A fresh 0.14 M solution of tetracis (triphenylphos fin) palladium (O) in NMM 2.5%, 5% HOAc in chloroform was added to the resin. After stirring for 2 hours, the resin was drained and rinsed with DCM and DMA. The resin was then treated with 10% DIPEA in DMA for 10 minutes, followed by various washes with DMA and then with a 5% solution of diethyldithiocarbamic acid in DMA for 15 minutes. The resin was then rinsed with DMA, DCM, MeOH and DCM.

G40 method The resin was suspended in ACN and cooled to 0 ° C. Once cold, 3 equivalents of Ph3P and 3 equivalents of NCS were added and the resin was stirred for 5 minutes, 6 equivalents of the appropriate aniline were added to the resin and the resin was stirred while warming to room temperature. After an additional 10 minutes at room temperature, the reaction was quenched with 3 equivalents of HOAc and the resin was washed with 10% HOAc in ACN, DCM and MeOH. Method G41 The resin was pre-activated with 3 equivalents of HBTU, 3 equivalents of Hobt and 6 equivalents of DIPEA in DMA for 10 minutes. 2 equivalents of the appropriate amine were added and the resin was stirred for 30 minutes. The procedure was repeated again. The resin was rinsed with DMA and DCM.

Method G42 The resin was rinsed with DMA, DCM and dichloroethane. 1.1 equivalents of the appropriate sulfonyl chloride and 3 equivalents of DIPEA in dichloroethane were added and the resin was stirred for 12 hours. The reaction can be followed by the Kaiser ninhydrin test and the repeated procedure until a negative Kaiser test results. The resin was washed with dichloroethane and DCM.

Method G43 The resin was rinsed with DMA, DCM and dichloroethane. 1.1 equivalents of the appropriate chloroformate were added and 3 equivalents of DIPEA were added in dichloroethane and the resin was stirred for 12 hours. The reaction can be followed by the Kaiser ninhydrin test and the procedure is repeated until a negative Kaiser test results. The resin was washed with dichloroethane and DCM.

Method G44 1 equivalent of the appropriate amine was dissolved in a 3: 2 solution of THF / H20. 1.1 equivalents of solid NaHCO 3 and 1.1 equivalents of Boc 20 were added and the solution was stirred overnight. The reaction was concentrated, and the residue was partitioned between H20 and Et20. The aqueous layer was extracted with Et20 and the combined organic layers were dried over MgSO4 and concentrated to a solid. Recrystallization of Et20 / hexane gave pure product.

Method G45 1 equivalent of the appropriate phenol was dissolved in DCM containing 2.6 equivalents of 2,6-lutidine and the mixture was cooled to -78 ° C. After adding 1.25 equivalents of triflic anhydride, the stirred reaction was allowed to warm to room temperature overnight. The reaction was then concentrated, and the residue was partitioned between Et20 and H20. The aqueous layer was extracted with Et20 and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (9: 1 hexane / Et20) to provide the pure triflate.

Method G46 To a stirred solution of 1 equivalent of the triflate in a 2/1 mixture of DMF / MeOH, 0.15 equivalents of 1,3-bis (diphenylphosphino) -propane and 2.5 equivalents of TEA were added. Gaseous carbon monoxide was bubbled through this solution for 15 minutes, then 0.15 equivalents of Pd (OAc) 2 were added and the reaction was stirred at 70 ° C for 5-7 hours under a CO atmosphere (using a filled balloon with CO). The reaction was then concentrated in vacuo and the residue was partitioned between Et20 and H20. The aqueous layer was extracted twice with Et20 and the combined organic layers were dried over MgSO4, filtered through a plug of silica gel and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (9: 1: 0.02 hexane / DCM / Et20) to give the pure methyl ester.

G47 Method An equivalent of the appropriate Boc-aniline was dissolved in methanol and the solution saturated with HCl. The reaction was heated at 50 ° C for 3 h, then concentrated in vacuo. The pale yellow solid was heated in 35% H2SO4 until complete dissolution occurred. Upon cooling the mixture by the addition of H20 on ice the amine bisulfate was precipitated. The reaction flask was cooled in an ice bath and the mixture was stirred vigorously while 1.1 equivalent of sodium nitrite in H20 was added dropwise. The reaction was stirred at 0 ° C for another 1.5 hours. After diluting the reaction with H20, the reaction was heated at 80 ° C for 10 hours. The reaction was cooled to room temperature and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (14: 6: 1 hexane / DCM / Et20) to provide the pure phenol.

G48 method 1 equivalent of the appropriate methyl benzoate was dissolved in DCM and 1.5 equivalents of a 1.0 M solution of BBr3 was added. After stirring the reaction overnight, the reaction was quenched with ice and stirred for an additional 1.5 hours. The reaction was extracted three times with Et20 and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was taken in a minimum amount of saturated NaHCO 3. The product was precipitated from this aqueous solution by the addition of concentrated HCl and then extracted into Et20. The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide pure benzoic acid.

Method G49 1 equivalent of the appropriate carboxylic acid was dissolved in DMF. 1.1 equivalents of solid NaHCO 3 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 Et20 and H20. The aqueous layer was extracted three times with Et20 and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (7: 3 hexane / Et20) to give the pure allyl ester.

Method G50 To a solution of 1 equivalent of the appropriate allyl ester in THF, 0.1 equivalents of tet racis (triphenylphosphine) palladium (O) and 10 equivalents of morpholine were added. The reaction was stirred for 1.5 hours, then concentrated in vacuo. The residue was taken up in DCM, extracted three times with IN HCl, dried over MgSO4 and concentrated in vacuo. The residue was triturated with filtered 1: 1 hexane / Et20 through a glass wool plug and concentrated to give the pure benzoic acid.

Method G51 1 equivalent of phenol was dissolved in DMF and 2.05 equivalents of K2C03 and 4 equivalents of 1,3-dibromopropane were added. The reaction was stirred overnight while heating the reaction flask and maintaining an oil bath at 50 ° C. After concentrating the mixture in vacuo, the residue was partitioned between Et20 and H20. The aqueous layer was extracted three times with Et20 and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (65: 5 hexane / Et20) to provide the pure bromide.

Method G52 1 equivalent of the appropriate hydroxy phenol and 1 equivalent of K2C03 were added to a solution of 0.5 equivalents of the bromide in DMF. After stirring overnight, the reaction was concentrated in vacuo. The residue was partitioned between Et20 and H20. The aqueous layer was extracted three times with Et20 and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (18: 1 DCM / Et20) to provide the pure phenol.

Method G53 To a pressurized glass tube, purged with nitrogen, 1 equivalent of the appropriate bromide, 5 equivalents of n-butyl vinyl ether, 15 equivalents of TEA, 0.1 equivalents of 1,3-bis (diphenylphosph) propane, 1 equivalent were added. of thallium acetate, 0.09 equivalents of palladium acetate and DMF. The tube was capped and heated at 100 ° C overnight. The reaction was cooled and the catalyst was filtered. The mixture was diluted with EtOAc and washed with H20 and dried over MgSO4. The crude product was purified on silica (4/1 hexane / DCM). This was dissolved in THF and 4N HCl in dioxane and stirred overnight. The solvents were evaporated and the product was purified on silica (4/1 hexane / EtOAc) to give the pure product.

Method G54 1 equivalent of the appropriate Boc-aniline was dissolved in methanol and the solution was saturated with HCl. The reaction was heated at 50 ° C for 3 h, then concentrated in vacuo. The pale yellow solid was heated in 35% H2SO4 until complete dissolution occurred. Upon cooling the mixture by the addition of H20 on ice, the amine bisulfate was precipitated. The reaction flask was cooled in an ice bath and the mixture was stirred vigorously while 1.1 equivalents of sodium nitrile in H20 were added dropwise. The reaction was stirred at 0 ° C for another 1.5 hours. An aqueous solution of 10 equivalents of Kl was added, followed immediately with 17 Cul equivalents. The reaction was stirred at room temperature for 14 hours, then extracted 3 times with Et20. The combined organic layers were washed with 1M NaHCO 3, brine, and dried over MgSO 4 and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (95: 5 hexane / Et20) to provide the pure iodide.

Method G55 2. 3 equivalents of lithium iodide were added to 1 equivalent of methyl 2,6-dichloro-4-iodobenzoate in pyridine, and the mixture was heated to reflux for 8 hours. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and 1N HCl. The aqueous layer was extracted three times with Et20 and the combined organic layers were washed with 1M NaHCO3, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in NMM and the solution was concentrated in vacuo. The residue was taken up in DCM and then washed three times with IN HCl. The organic layer was dried over MgSO4 and concentrated to give the benzoic acid of sufficiently high purity to be used without further purification.

Method G56 1. 3 equivalents of DIPEA were 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 when the mixture was stirred at room temperature for 28 hours. After concentrating the mixture, the residue was partitioned between Et20 and H20. The aqueous layer was extracted three times with Et20 and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Et20) to give the pure hydroxamate.

Method G57 To a stirred solution at -78 ° C of 1 equivalent of the appropriate hydroxamate protected in THF, a solution of 1.2 equivalents of DIBAL 1.5 M in toluene was added dropwise. The reaction mixture was stirred for an additional 3 hours at -78 ° C or until the TLC showed a clean product formation, with only traces of the starting material. The reaction was quenched by adding to a separatory funnel containing Et20 and 0.35 M NaHS04. The layers were separated. The aqueous layer was extracted three times with ethyl ether. The combined organic layers were washed twice with IN HCl, saturated aqueous NaHCO 3 and MgSO 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 equivalents of ethyl magnesium bromide 0.5M / THF were added. After stirring the reaction at room temperature for 3 hours, it was diluted with Et20 and washed twice with 10% citric acid. The combined aqueous layers were extracted once with Et20. The combined organic layers were washed twice with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (4.:1 to 3: 2 hexane / Et20) to give 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 alkyne were added, followed by 0.02 equivalents of dichlorobis (triphenylphosphine) palladium (II), 0.04 equivalents of Cul and 5 equivalents of TEA. The reaction was stirred for 14 hours, diluted with EtOAc, washed twice with Na2. 5% EDTA, brine, and dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution gradient, using Et20 to EtOAc) to give the pure alkyne.

Method G60 1 equivalent of the aryl alkyne was dissolved in MeOH and the solution was degassed by passing N2 through a pipette and into the solution for 10 minutes. 5% Rh / Al203 was added, a balloon filled with hydrogen was passed through the solution, and the reaction was stirred under an atmosphere of H2 (using a balloon) for 7 hours, after which the reaction was filtered through through a pad of celite and concentrated in va c uo. The residue was purified by flash chromatography on silica gel (gradient elution, using Et20 to EtOAc) to give the pure product.

Method G61 2 equivalents of the appropriate protected amino acid and 2 equivalents of Ph3P were suspended in DCM. 2.2 equivalents of NCS were added and the mixture was stirred for 30 minutes. 1 equivalent of resin containing aniline and 1.1 equivalents of NMM were suspended in DCM and the clear acid solution was added. The resin was stirred for 2 hours, rinsed with DCM, DMA and DCM. The procedure was repeated again.

Method G62 The appropriate benzaldehyde was converted to its corresponding hydantoin by Method G63 and then hydrolyzed to the amino acid by the Method G64 The racemic pure amino acid was then protected by Method G5.

Method G63 1 equivalent of the appropriate benzaldehyde, 2 equivalents of potassium cyanide and 4 equivalents of ammonium carbonate were refluxed in 50% EtOH for 2.5 hours. After cooling to 0 ° C, the solution was acidified to a pH of 2 with concentrated HCl. After remaining in the refrigerator overnight, the crystals were filtered and washed with H20 and recrystallized from boiling H20 / EtOH.

Method G64 The pure hydantoin was refluxed in 10% NaOH overnight. After cooling, activated carbon was added and the solution was filtered through celite. The solution was acidified to a pH of 7 with concentrated HCl and allowed to remain in the refrigerator overnight. The resulting crystals were filtered, washed with H20 and dried overnight to give the racemic pure amino acid.

G65 method 4-Bromo-2-chlorobenzoic acid was converted to the t-butyl ester by Method G10. The t-butylvinyl ether was coupled to the bromide by Method G53 to give the t-butyl ester of 4-acetyl-2-chlorobenzoic acid. The ketone was reduced to alcohol by Method G66 and the racemic mixture was resolved by Method G67 to give the pure isomer S. Phthalamide was coupled to alcohol by Method G68 and the product was hydrolyzed by Method G69 to give the amine .

Method G66 2-equivalents of the appropriate ketone were dissolved in MeOH and 1 equivalent of NaBH4 were added. After stirring for 1 hour, the reaction was quenched with concentrated HCl and concentrated in vacuo. The residue was partitioned between Et20 and H20. The organics were dried over MgSO4 and concentrated in vacuo. The alcohol can be used without further purification.

G67 method 1 equivalent of the alcohol mixture was dissolved in diisopropyl ether and 2 equivalents of vinyl acetate and Amano lipase P (100 mg) was added. The suspension was stirred overnight and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5/1 EtOAc / hexane) to give the pure R and S isomers.

Method G68 A solution of 1 equivalent of alcohol and 3 equivalents of Ph3P in THF was cooled to -10 ° C in an ice-EtOH bath. While stirring, a solution of 3 equivalents of the amine and 3 equivalents of DEAD in THF was added dropwise.

The cold bath was removed and the reaction was stirred at room temperature overnight. The reaction was concentrated and the resulting residue was taken up in a minimum 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 flash chromatography on silica gel (8/2 / 0.5 hexane / DCM / Et20) to provide the product.

Method G69 One equivalent of phthalamide was dissolved in EtOH and THF followed by the addition of 8 equivalents of hydrazine hydrate. The reaction was stirred at room temperature for 1.5 hours, then at 50 ° C for 1 hour. The solution was cooled, filtered and the solids were washed with EtOAc. The clear solution was concentrated and the residue was purified by flash chromatography on silica gel (94/4 DCM / MeOH) to give the pure amine.

Method G70 1 equivalent of the commercially available appropriate ketone, 5 equivalents of hydroxylamine hydrochloride and 10 equivalents of sodium acetate, were combined in MeOH and stirred overnight. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and saturated NaHCO 3. The organic layer was washed once with brine, dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography on silica gel (Et20) to give the pure oxime.

Method G71 1 equivalent of the appropriate benzaldehyde was treated with 2.5 equivalents of the appropriate R'MgBr in THF, at -20 ° C under an N 2 atmosphere. After warming to room temperature, the reaction was emptied into a slurry of 0. I N sulfuric acid and ice, and the product was extracted with EtOAc. After dividing and washing with brine, the organic phase was dried over MgSO4 and concentrated to give the crude product. Oxidation to the ketone was carried out in dioxane with 1.1 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone for 48 hours. The reaction contents were filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane / EtOAc 1: 1) to give the product as a yellow solid.

Method G72 The resin with the S-trityl or 0-trityl protecting group was washed three times with DCM. It was then washed 3 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 treated with concentrated TFA. If it did not appear yellow, the elimination was complete. If a yellow color appeared, the above procedure was repeated until a transparent test was reached.

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 resin 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 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 observed by the Kaiser ninhydrin test. If the Kaiser test was positive, the appropriate chloroformate was reattached in the same way. The resin was washed three times with NMP and then three times with DCM.

Method G75 The appropriate phenol 2,6-disubstuitable (2,6-dichlorophenol for Compound F, 2,6-dimethephenol 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 carbonylized by Method G79 to give the desired double protection compound.

Method G76 A round bottom flask was equipped with an efficient dome stirrer and charged with concentrated H2SO4 (2.7 x volume of H20) and H20 and cooled to -5 ° C with an ice and ethanol bath. Once cold, an equivalent of the appropriate disubstituted phenol and 1 equivalent of N- (hydroxymethyl) phthalimide were added with vigorous stirring. The reaction was kept cold 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 only one solid in the round bottom flask. At this point, EtOAc and H20 were added and stirred into the solid. Large pieces were broken and then the precipitate was filtered and washed with more EtOAc and H20. The product was then used without further purification after drying overnight in a vacuum desiccator.

G77 method 1 equivalent of the product of Method G76 and (22.5 ml x #g of the starting material) of methanol were added to a round bottom flask equipped with a H20 condenser and a stir bar. 1.2 equivalents of hydrazine monohydrate were added and the mixture was refluxed for 4 hours. After cooling to room temperature (4.5 ml x #g of starting material) of concentrated HCl, they were carefully added. At the end of the addition, the mixture was refluxed again overnight (> 8 hours). The reaction was cooled to 0 ° C and the precipitated by-product was filtered. The filtrate was then concentrated m va cuo. The residue was protected by Boc by Method G44 except that the product was recrystallized from hot methanol and H20.

G78 method 1 equivalent of appropriate phenol and 1.5 equivalents of 2,6-lutidine was dissolved, with medium heating if needed, in DCM in a round bottom flask. Once the starting material had completely dissolved, the mixture was cooled to -78 ° C under N2 with an ethanol-ice bath. Once cold, 2.5 equivalents of triflic anhydride were added and the reaction slowly allowed to come back at room temperature with stirring. The reaction was observed by TLC and was generally done in 4 hours. Upon completion, the reaction was concentrated in vacuo and the residue was partitioned between EtOAc and H20. The organic layer was washed twice with 0.1 N H2SO4, twice with saturated NaHCO3, once with brine, dried over MgSO4 and concentrated in vacuo. The residue was then purified on silica gel using DCM as eluent.

Method G79 1 equivalent of triflate was dissolved in DMF and MeOH in the glass insert of a high-pressure Parr pump. The starting material was then degassed while stirring with CO for 10 minutes. Then 0.15 equivalents of palladium (II) acetate and 0.15 equivalents of 1,3-bis (diphenylphosphino) propane were added and the mixture was then degassed while stirring with CO for another 10 minutes. 2.5 equivalents of diisopropyl ethyl amine were added and the Parr pump was assembled. After properly assembling the pump, it was charged with CO gas at 21 kg / cm2 (300 psi) and heated to 70 ° C with stirring overnight. The pump cooled and vented later. The mixture was transferred to a round bottom flask and concentrated in vacuo. The residue was then purified on silica gel using 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 in H20 in an appropriately sized Parr shaker flask. A small amount (approximately 100 mg per 50 mmol of alkene) of 5% Pd / C catalyst was added and the flask was charged with 3.5 kg / cm2 (50 psi) and stirred overnight. The mixture was then filtered through celite and concentrated in vacuo. The resulting product was used without further purification.

G80 method 1 equivalent of the appropriate ethyl ester and 1.5 equivalents of KOH were dissolved in H20 and refluxed for 3 hours. After completion, the reaction was concentrated in vacuo and the product was used without further purification.

Method G82 1. 2 equivalents of NaH (60% mineral oil dispersion) was suspended in benzene and cooled to 0 ° C with a water and ice bath. 1.2 equivalents of triethyl phosphonoacetate were added slowly and the reaction was allowed to stir until the solution was clear. 1 equivalent of the appropriate ketone (R) was slowly added slowly and the reaction was stirred for 4 hours. Upon completion, the reaction was partitioned with toluene and H20. The aqueous layer was extracted back. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (85:15 hexane / EtOAc).

Method G83 1.2 equivalents of NaH (60% mineral oil dispersion) were suspended in benzene and cooled to -10 ° C with a H20 bath and dry ice. 1.2 equivalents of triethyl 2-phosphonopropionate were added slowly and the reaction was allowed to stir until the solution became 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 H20. The aqueous layer was extracted back. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (85:15 hexane / EtOAc).

Method G84 1 equivalent of the appropriately protected toluene was dissolved in acetic anhydride and HOAc, then cooled in an ice-water bath (-5 ° C) before concentrated H2SO4 was added. A solution of Cr03 (2.6 equivalents) in acetic anhydride and HOAc was added dropwise and the reaction was stirred for 3.5 hours at -5 ° C. The reaction was poured onto H20 and ice and stirred for 30 minutes. The mixture was extracted three times with ethyl ether. The combined organic layers were washed with satined NaHCO 3 and brineThey were then dried over MgSO4 and concentrated in an oil. Toluene was added to the oil and the solution was concentrated in vacuo again. This was repeated to obtain a crystalline solid. The solid was dissolved in methanol and concentrated HCl and heated to reflux for 12 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (9: 1 hexane / Et20) to provide the pure aldehyde.

G85 method An equivalent of the appropriate alcohol was dissolved in DMF and cooled to -5 ° C in an ice-water-salt bath. 1.4 equivalents of lithium bis (trimethylsilyl) amide in THF were added dropwise. The reaction was stirred for 0.5 hour, then 1 equivalent of methyl iodide was added and the reaction was stirred overnight under a nitrogen atmosphere. The reaction was partitioned between ethyl ether and 10% citric acid. The aqueous layer was extracted with ethyl ether, the combined organic layers were washed with saturated NaHCO 3 and brine, then dried over MgSO 4 and concentrated in vacuo to an oil. The residue was purified by flash chromatography on silica gel (9: 1 hexane / Et20) to give the pure methyl ether.

G86 method The commercially available nitroterephthalic acid was converted to its diethyl ester by the G87 Method. The nitro group was replaced by a benzyl mercaptan by Method G88 and deprotected by AIBr3 using 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-hydroxybenzyl amine, Method G38. The final ethyl ester was removed by Method G4.

G87 method 1 equivalent of the commercially available appropriate carboxylic acid was dissolved in toluene with an excess of ethanol and 0.6 equivalents of H2SO4 and the mixture was refluxed for 4 days. Upon completion, the reaction was concentrated in vacuo and partitioned between EtOAc and H20. The organic layer was washed with saturated NaHCO3, brine and dried over MgSO4 and concentrated in vacuo. The product was used without further purification.

Method G88 1.25 equivalents of 95% NaH in DMF were suspended and cooled under N2 at -5 ° C with an ice bath. 1.25 equivalents of benzyl mercaptan were added dropwise and the solution was allowed to stir for 40 minutes. 1 equivalent of the appropriate nitro-aryl compound was added over 20 minutes and the mixture was stirred for an additional 30 minutes. After verifying that the reaction was finished, the solution was emptied on ice and stirred until all the ice melted. The aqueous solution was partitioned three times with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1: 4 hexane / Et20) to give the product.

Method G89 1 equivalent of benzyl protected material and 2.2 equivalents of AIBr3 in toluene were refluxed for three hours, at which time H20 was added and enough EtOAc for division of the mixture. The organic layer was washed three times with H20, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (4: 1 hexane / EtOAc) to provide product.

G90 method 1 equivalent of thiol was dissolved in DMF and 2 equivalents of K2C03 were added. They added 1. 1 equivalents of bromoacetaldehyde diethyl acetal slowly over 20 minutes and then 0.1 equivalents of Nal were added in portions. The reaction was stirred for 2 hours and then partitioned between EtOAc and H20. The organic layer was washed three times with H20, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (9: 1 hexane / EtOAc) to provide product.

G91 method 1 equivalent (by weight) of the appropriate diethyl acetal and 2 equivalents (by weight) of polyphosphoric acid were dissolved in chlorobenzene. The reaction was monitored by TLC. At the end of the reaction, the mixture was concentrated in vacuo and then partitioned between EtOAc and saturated NaHCO 3. The organic layer was washed twice more with saturated NaHCO 3, brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (4: 1 hexane / EtOAc) to provide product.

G92 Method 1 equivalent of the appropriate carboxylic acid was dissolved in DCM and cooled to 0 ° C with an H20 ice bath. Once cold, 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 hours at room temperature. At this point, the reaction was concentrated in vacuo and used immediately.

G93 Method 1 equivalent of bis-N-carboxybenzoyl-cyan dibenzyl ester was dissolved in HOAc / H20 (9/1) and treated with chlorine gas for 10 minutes. The reaction was concentrated in vacuo, dissolved in toluene and concentrated again to result in a white solid. This product was dissolved in DCM and 0.5 equivalents of the appropriate amine (R) were added. The reaction was stirred for 30 minutes and then diluted with EtOAc and partitioned with 0.1 N H2SO4 and then brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1: 1 hexane / EtOAc) to provide pure product. The protecting groups were separated by Method G38 and the product used without further purification.

Methods of the Specific Examples SI method The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-diaminopropionic acid (alloc) -alcohol p-alkoxybenzyl (0.5 mmol / g) (resin Fmoc-L-Dapa (alloc) -Wang). The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by the Method G19. Compound C, Method G13 was coupled by Method G20. The Alloc group separated by the Method G35. The appropriate isocyanate (R) was coupled by the G33 method. The finished molecule was developed by the G21 Method.

Method S2 The compounds were synthesized using standard Fmoc solid phase methods on the Fmoc-L-diaminobutyric acid (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Daba (alloc) -Wang resin). The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate isocyanate (R) was coupled by the G33 method. The finished molecule was developed by the G21 Method.

Method S3 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate isocyanate (R) was coupled by the G33 method. The finished molecule was developed by the G21 Method.

Method S4 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-lysine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Lys (alloc) -Wang resin). The resin was made by the method G34 using N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate isocyanate (R) was coupled by the G33 method. The finished molecule was developed by the G21 Method.

S5 method The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminopropionic acid (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin resin (Fmoc-L-Dapa (alloc) -Wang resin). The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

S6 method The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminobutyric acid (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Daba (alloc) -Wang resin) . The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

S7 method The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S8 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-lysine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Lys (alloc) -Wang resin). The resin was made by the G34 method using N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S9 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-diaminopropionic acid (alloc) - p-alkoxybenzyl alcohol (0.5 mmol / g) (resin Fmoc-L-Dapa (alloc) -Wang). The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available nipecotic Fmoc-acid was coupled by the G20 Method. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S10 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminopropionic acid (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Dapa (alloc) -Wang resin) ). The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. Fmoc-isonipecotic acid commercially available by the G20 Method was coupled. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Sil Method The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminopropionic acid (alloc) -p-alkoxybenzyl alcohol resin (0.5 mmol / g) (Fmoc-L-Dapa (alloc) -Wang resin). The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. Fmoc-3-aminomethyl benzoic acid commercially available by the G20 Method was coupled. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S12 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminopropionic acid (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin resin (Fmoc-L-Dapa (alloc) -Wang resin). The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. The compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. Fmoc-4-aminomethyl benzoic acid commercially available by the G20 Method was coupled. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S13 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminopropionic acid (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin resin (Fmoc-L-Dapa (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. Commercially available Fmoc-ß alanine was coupled by the G20 Method. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S14 The compounds were synthesized using normal Fmoc solid phase methods on Fmoc-L-diaminopropionic acid (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Dapa (alloc) -Wang resin ). The resin was made by the G34 method using commercially available N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. Commercially available Fmoc-glycine was coupled by the G20 Method. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S15 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-nipecotic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S16 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-isonipecotic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S17 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-pipecolinic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S18 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-3-aminomethyl-benzoic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S19 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-4-aminomethyl benzoic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S20 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-ß-alanine was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S21 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-ornithine (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Orn (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-glycine was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S22 The compounds were synthesized using normal Fmoc solid phase methods on the Na-Fmoc-N-α-Alloc-L-diaminobutyric acid-p-alkoxybenzyl alcohol resin (0.5 mmol / g) (Fmoc-L-Daba resin (alloc)). ) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-α-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-nipecotic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S23 The compounds were synthesized using normal Fmoc solid phase methods on the Na-Fmoc-N-α-Alloc-L-diaminobutyric acid-p-alkoxybenzyl alcohol resin (0.5 mmol / g) (Fmoc-L-Daba resin (alloc)) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-α-Alloc-L-diaminobutyl acid. The Fmoc group was split by Method G19- Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-isonipecotic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S24 The compounds were synthesized using normal Fmoc solid phase methods on the Na-Fmoc-N-α-Alloc-L-diaminobutyl-p-alkoxybenzyl alcohol (0.5 mmol / g) resin resin (Fmoc-L-Daba resin). alloc) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-α-Alloc-L-di-amino butyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-pipecol acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S25 The compounds were synthesized using normal Fmoc solid phase methods on the Na-Fmoc-N-α-Alloc-L-diaminobutyl-p-alkoxybenzyl alcohol (0.5 mmol / g) resin resin (Fmoc-L-Daba resin). alloc) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-α-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-3-aminomet i 1 benzoic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S26 The compounds were synthesized using normal Fmoc solid phase methods on the Na-Fmoc-N-α-Alloc-L-diaminobutyric acid-p-alkoxybenzyl alcohol resin (0.5 mmol / g) (Fmoc-L-Daba resin (alloc)). ) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-α-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-4-aminomethyl benzoic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S27 The compounds were synthesized using normal Fmoc solid phase methods on the Na-Fmoc-N-α-Alloc-L-diaminobutyl-p-alkoxybenzyl alcohol (0.5 mmol / g) resin resin (Fmoc-L-Daba resin). alloc) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-α-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-ß alanine was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S28 The compounds were synthesized using normal Fmoc solid phase methods on the Na-Fmoc-N-α-Alloc-L-diaminobutyric acid-p-alkoxybenzyl alcohol resin (0.5 mmol / g) (Fmoc-L-Daba resin (alloc)). -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-α-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-glycine was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S29 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-lysine (alloc) p-alkoxybenzyl alcohol (0.5 mmol / g) (resin Fmoc-L-Lys (alloc) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-nipecotic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S30 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-lysine (alloc) p-alkoxybenzyl alcohol (0.5 mmol / g) (Fraoc-L-Lys (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-isonipecotic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S31 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-lysine (alloc) p-alkoxybenzyl alcohol (0.5 mmol / g) (Fmoc-L-Lys (alloc) -Wang resin). The resin was made by the method G34 using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by the Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group separated by the Method G35. The commercially available Fmoc-pipecolinic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S32 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-lysine (alloc) p-alkoxybenzyl alcohol (0.5 mmol / g) (resin Fmoc-L-Lys (alloc) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-3-aminomethyl-benzoic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S33 The compounds were synthesized using standard Fmoc solid phase methods on the Fmoc-L-lysine (alloc) alcohol p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Lys (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-4-aminomethyl benzoic acid was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S34 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-lysine (alloc) p-alkoxybenzyl alcohol (0.5 mmol / g) (Fmoc-L-Lys (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmoc-ß alanine was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S35 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-lysine (alloc) p-alkoxybenzyl alcohol (0.5 mmol / g) (Fmoc-L-Lys (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available Fmocillin was coupled by the G20 method. The Fmoc group was separated by the G19 method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S36 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminopropionic acid (alloc) -p-alkoxybenzyl alcohol (0.5 mmol / g) resin resin (Fmoc-L-Dapa (alloc) -Wang resin). The resin was made by the G34 method using N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate chloroformate (R) was coupled by the G74 method. The finished molecule was developed by the G21 Method.

Method S37 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-tryptophan (Boc) -Wang (0.5 mmol / g) resin. The Fmoc group was split by Method G19. Compound D, Method G14 was coupled by the G20 method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S38 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. Compound D, Method G14 was coupled by the G20 method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S39 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-asparagine (Trt) -Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. Compound D, Method G14 was coupled by the G20 method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S40 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-tryptophan (Boc) -Wang (0.5 mmol / g) resin. The Fmoc group was split by Method G19. The 4-amino-2-methylbenzoic acid was coupled by the G20 method. The appropriate carboxylic acid (R) was protected by silyl, Method G18, and the acid chloride generated by Method G92 and coupled in DCM overnight to amine. After washing the resin with DCM and THF, 3 equivalents of tetrabutylammonium fluoride in THF were added. After 20 minutes, the resin was washed with THF, H20 and dilute HOAC. The finished molecule was developed by the G21 Method.

Method S41 Compounds were synthesized using standard Fmoc solid phase methods on commercially available Fmoc-L-amino-Wang (0.5 mmol / g) resins (R). The Fmoc group was split by Method G19. The 4-amino-2-methylenbenzoic acid was coupled by the G20 method. 3-hydroxy phenylacetic acid was protected by silyl, Method G18, and the acid chloride generated by Method G92 and coupled in DCM overnight to amine. After washing the resin with DCM and THF, 3 equivalents of TBAF in THF were added. After 20 minutes, the resin was washed with THF, H20 and dilute HOAc. The finished molecule was developed by the G21 Method.

Method S42 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The commercially available 4-amino-2-chlorobenzoic acid was coupled by the G20 method. The Fmoc-glycine was coupled to the aniline by the G61 Method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S43 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The commercially available α-amino-2-chlorobenzoic acid was coupled by the G20 method. The Fmoc-L-alanine was coupled to the aniline by the G61 Method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S44 The compounds were synthesized using normal methods of solid phase Fmoc on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The commercially available 4-amino-2-chlorobenzoic acid was coupled by the G20 method. Fmoc-L-phenylglycine was coupled to the aniline by Method G61. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S45 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The commercially available 4-amino-2-chlorobenzoic acid was coupled by the G20 method. The Fmoc-L-glutamine was coupled to the aniline by the G61 Method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S46 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The commercially available 4-amino-2-chlorobenzoic acid was coupled by the G20 method. The 3-chloro benzaldehyde was converted to Fmoc-3-chloro-phenylglycine by the G62 method and coupled to the aniline by the G61 method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S47 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-diaminopropionic-Wang (0.5 mmol / g) resin. The Fmoc group was split by Method G19. Compound D, Method G14 was coupled by the G20 method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S48 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-lysine (Boc) -Wang (0.5 mmol / g) resin. The Fmoc group was split by Method G19. Compound D, Method G14 was coupled by the G20 method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S49 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The commercially available 4-amino-2-chlorobenzoic acid was coupled by the G20 method. The 3-methoxy benzaldehyde was converted to Fmoc-3-chloro-phenylglycine by the G62 method and coupled to the aniline by the G61 Method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

S50 method The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The commercially available 4-amino-2-chlorobenzoic acid was coupled by the G20 method. The Fmoc-meta-t-irosine was coupled to the aniline by the G61 Method. The Fmoc group was split by Method G19. The appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S51 The 3-hydroxy aniline was coupled to commercially available Boc-d-serine by Method G3. The Boc group was separated by the Gl Method and this amine was coupled to Compound A, Method G8. The t-butyl ester was separated by the Gil Method and the acid was coupled to the O-t-butyl ester of the appropriate amino acid (R) by the G3 method. The final t-butyl ester was separated by the Gil Method, and the finished molecule was purified by reverse phase HPLC, verified by electro-atomization mass spectrometry and lyophilized to a powder.

Method S52 The Boc group in Compound F, Method G75, was separated by Method G2 and furyl acrylic acid was coupled to the amine after free basification, Method G2, by Method G3. The methyl ester was separated by the G55 method and the resulting acid was coupled by Method G20 to the appropriate Wang resin of commercially available and deprotected Fmoc-protected amino acid (0.5 mmol / g) (R). The finished molecule was developed by the G21 Method.

Method S53 The methyl ester of Compound F, Method G75, was separated by Method G55 and the resulting acid was coupled by the G20 Method to the commercially available t-butyl ester of L-aspargine. The Boc group was separated by the Gl Method and the appropriate carboxylic acid (R) was coupled by the G3 method. After separating the final t-butyl ester by the Gil Method, the molecule was purified by reverse phase HPLC, verified by mass spectrometry by electro-atomization and lyophilized to a powder.

Method S54 The Boc group in Compound F, Method G75, was separated by Method 2G1 and furyl acrylic acid was coupled to the amine after free basification, Method G2, by Method G3. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of the β-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and the appropriate carboxylic acid (R) was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S55 The Boc group in Compound I, Method G75, was separated by Method Gl and the 3-hydroxybenzoic acid was coupled to the amine after a free basification, Method G2, by Method G3.

The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of L-tryptophan. After the saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S56 The Boc group in Compound H, Method G75, was separated by Method Gl and the 3-hydroxybenzoic acid was coupled to the amine after a free basification, Method G2, by Method G3. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the methyl ester of the commercially available amino acid. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S57 The Boc group in Compound H, Method G75, was separated by Method Gl and the furyl acrylic acid was coupled to the amine after free basification, Method G2, by Method G3. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the methyl ester of the commercially available amino acid (R). The Boc group was separated by the Gl Method if needed and after saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S58 5 The Boc group in Compound H, Method G75, was separated by Method Gl and the 3- (2-thienyl) acrylic acid was coupled to the amine after free basification, Method G2, by Method G3.

The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the methyl ester of the commercially available amino acid. The Boc group was separated by the Gl Method if needed and after the Saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S59 The Boc group in Compound H, Method G75, was separated by Method 2G1 and the furyl acrylate was coupled to the amine after a free basification, Method G2, by the G3 Method.

- '%. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl β-diaminopropionic methyl ester. The Boc group was separated by the Gl Method and the appropriate carboxylic acid (R) was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S60 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-lysine (alloc) p-alkoxybenzyl alcohol (0.5 mmol / g) (Fmoc-L-Lys (alloc) -Wang resin). The resin was made by the method G34 using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate aldehyde (R) was coupled by the G23 method. The finished molecule was developed by the G21 Method.

Method S61 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminopropionic acid (alloc) p-alkoxybenzyl alcohol resin (0.5 mmol / g) (Fmoc-L-Dapa (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate aldehyde (R) was coupled by the G23 method. The finished molecule was developed by the G21 Method.

Method S62 The appropriate amine (R) was coupled to Compound A, Method G8, by Method G3. The t-butyl ester was separated by the Gil Method. The resulting acid was coupled by Method G3 to the resin made by Method G34 using commercially available N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid where the Fmoc group had been removed by the G19 method. The finished molecule was developed by the G21 Method.

Method S63 The appropriate amine (R) was coupled to Compound A, Method G8, by Method G3. The t-butyl ester was separated by the Gil Method. The resulting acid was coupled by the G3 Method to the commercially available Fmoc-L-aspargine (Trt) -Wang resin (0.5 mmol / g) where the Fmoc group had been removed by the G19 method. The finished molecule was developed by the G21 Method.

Method S64 The Boc group in Compound F, Method G75, was separated by Method Gl and the reduced furyl acrylic acid, Method G81, was coupled to the amine after free basification, Method G2, by Method G3. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of the β-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and thiophene 2-carboxylic acid was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S65 The Boc group in Compound F, Method G75, was separated by the Gl Method. The 2-acet-ylurane was converted to the ethyl ester of methyl acrylic acid by the G82 method and after saponification by the G80 Method it was coupled to the amine after a free basification, Method G2, by the G3 Method. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of the β-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and thiophene 2-carboxylic acid was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S66 The Boc group in Compound F, Method G75, was separated by the Gl Method. After the 2-acetylfuran was converted to the ethyl ester of methyl acrylic acid by the G82 method, it was saponified by the G80 Method and reduced by the G81 Method, coupled to the amine after a free basification, Method G2, by the G3 Method. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of the β-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and thiophene 2-carboxylic acid was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

S67 method The Boc group in Compound F, Method G75, was separated by the Gl Method. The furyl aldehyde was converted to the ethyl ester of methyl acrylic acid by the G83 method and after saponification by the G80 Method it was coupled to the amine after a free basification, Method G2, by the G3 Method. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of the β-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and thiophene 2-carboxylic acid was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S68 The Boc group in Compound F, Method G75, was separated by the Gl Method. After the furyl aldehyde was converted to the ethyl ester of methyl acrylic acid by the G83 method, saponified by the G80 Method and reduced by the G81 Method, it was coupled to the amine after a free basification, Method G2, by the G3 Method . The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of the β-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and thiophene 2-carboxylic acid was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S69 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-amino-Wang-acid (0.5 mmol / g) (R). The Fmoc group was split by Method G19. The commercially available 2,6-dimethyl terephthalic acid was coupled by the G20 method. The 3-hydroxy benzylamine, Method G38, was coupled by the G20 method. The finished molecule was developed by the G21 Method and the correct stereochemistry was assigned by activity.

Method S70 The compounds were synthesized on the resin made by Method G34 using commercially available N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split by Method G19. The commercially available 2,6-dimethyl terephthalic acid was coupled by the G20 method. The 3-hydroxy benzylamine, Method G38, was coupled by the G20 method. The Alloc group was removed by the G35 Method and the appropriate carboxylic acid (R) was coupled by the G20 Method. The finished molecule was developed by the G21 Method and the correct stereochemistry was assigned by activity.

S71 method The Boc group in Compound F, Method G75, was separated by Method Gl and the appropriate carboxylic acid (R) was coupled to the amine after free basification, Method G2, by Method G3. The methyl ester was separated by the G55 method and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of the β-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and thiophene 2-carboxylic acid was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S72 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-tryptophan (Boc) -Wang resin (0.5 mmol / g). The Fmoc group was split 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 the G20 method. The appropriate amine (R) was coupled by the G22 method. The finished molecule was developed by the G21 Method.

Method S73 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was split 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 the G20 method. The appropriate amine (R) was coupled by the G22 method. The finished molecule was developed by the G21 Method.

Method S74 The compounds were synthesized using Fmoc solid phase methods on the resin of Fmoc-L-diaminobutyric acid (alloc) p-alkoxybenzyl alcohol (0.5 mmol / g) (Fmoc-L-Daba (alloc) -Wang resin). The resin was made by Method G34 using commercially available N-α-Fmoc-N-α-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by Method G20. The Alloc group was eliminated by the G35 Method. The appropriate sulfonyl chloride (R) commercially available was coupled by Method G42. The finished molecule was developed by the G21 Method.

Method S75 Compounds were synthesized using normal Fmoc solid phase methods on the resin of Na-Fmoc-Nd-Alloc-L-Ornit p-alkoxybenzyl alcohol (0.5 mmol / g) (resin Fmoc-L-Orn (alloc) -Wang) . The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate sulfonyl chloride (R) commercially available, was coupled by the G42 method. The finished molecule was developed by the G21 Method.

Method S76 The compounds were synthesized using normal Fmoc solid phase methods on the resin of Fmoc-L-Lysine (alloc) alcohol p-alkoxybenzyl 1 (0.5 mmol / g) (resin Fmoc-L-Lys (alloc) -Wang). The resin was made by the G34 method using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The appropriate sulfonyl chloride (R) commercially available, was coupled by the G42 method. The finished molecule was developed by the G21 Method.

Method S77 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-diaminobutyric acid (alloc) p-alkoxybenzyl alcohol resin (0.5 mmol / g) (Fmoc-L-Daba (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-α-Alloc-L-diaminobutyric acid. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available chloroformate (R) was coupled by the G43 method. The finished molecule was developed by the G21 Method.

S7 method & The compounds were synthesized using normal Fmoc solid phase methods on the resin of Na-Fmoc-Nd-Alloc-L-Ornithine alcohol p-alkoxybenzyl (0.5 mmol / g) (resin Fmoc-L-Orn (alloc) -Wang) . The resin was made by the G34 method using commercially available N-α-Fmoc-N-d-Alloc-L-ornithine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available appropriate chloroformate (R) was coupled by the G43 method. The finished molecule was developed by the G21 Method.

Method S79 The compounds were synthesized using normal Fmoc solid phase methods on the Fmoc-L-Lysine (alloc) alcohol p-alkoxybenzyl alcohol (0.5 mmol / g) resin (Fmoc-L-Lys (alloc) -Wang resin). The resin was made by the G34 method using commercially available N-α-Fmoc-N-e-Alloc-L-lysine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by the G20 method. The Alloc group was separated by the G35 Method. The commercially available appropriate chloroformate (R) was coupled by the G43 method. The finished molecule was developed by the G21 Method.

S80 method The compounds were synthesized using normal Fmoc solid phase methods on the commercially available Fmoc-L-asparagine (Trt) -Wang resin. (0.5 mmol / g). The Fmoc group was split by the Method G19. Commercially available 2-bromo terephthalic acid was protected with a group Fmoc by the G6 Method and the resulting product was coupled by the G20 Method. The appropriate amine (R) was coupled by Method G22. The finished molecule was developed by the G21 Method.

Method S81 The compounds were synthesized on the resin made by Method G34 using commercially available N-α-Fmoc-N-β-Alloc-L-diaminopropionic acid. The Fmoc group was split 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 the G20 method. The appropriate amine (R) was coupled by Method G22. The finished molecule was developed by the G21 Method.

Method S82 The compounds were synthesized using standard Fmoc solid phase methods on the appropriate p-alkoxybenzyl alcohol resin and commercially available Fmoc-amino acid (R) (Wang resin) (0.5 mmol / g). The Fmoc group was split by Method G19. Compound C, Method G13, was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S83 The compounds were synthesized using standard Fmoc solid phase methods on the appropriate resin of commercially available p-alkoxybenzyl alcohol and Fmoc-amino acid (R) (Wang resin) (0.5 mmol / g). The Fmoc group was split by Method G19. Compound B, Method G12, was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S84 The compounds were synthesized using standard Fmoc solid phase methods on Fmoc-L-tryptophan (Boc) -Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The commercially available 4-amino-2-chlorobenzoic acid was coupled by the G20 method. The resin was treated with an excess of 0.5 M 4-nitrophenyl chloroformate and 0.5 M DIPEA for 45 minutes. After washing the resin twice with THF / DCM, an excess of the appropriate amine (R) in 0.5 M DIPEA / DMF was added and the resin was bubbled for 20 minutes. The finished molecule was developed by the G21 Method.

S85 Method The appropriate amino acid (R) was converted to its methyl ester by Method G15. After free basification of 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 mass spectrometry by electroatomization and lyophilized to a powder.

S86 method The 3-hydroxyacetophenone was converted to the oxime by the G70 Method and then hydrogen by the G38 Method to give the amine. This amine was then coupled to Compound A, Method G8, by the Method G24. After removal of the t-butyl ester by the Gil Method, the acid was coupled to a t-butyl ester of L-asparagine commercially available by the Method G24. The final t-butyl ester was separated by the Gil Method and the finished molecule was purified by reverse phase HPLC, verified by mass spectrometry by electroatomization and lyophilized to a powder.

Method S87 The 3-hydroxyacetophenone was converted to the oxime by the method G70 and then hydrogen by the method G38 to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After separation of the t-butyl ester by the Gil Method, the acid was coupled to a methyl ester of L-tryptophan commercially available by the Method G24. The final methyl ester was separated by Method G4 and the finished molecule was purified by reverse phase HPLC, verified by mass spectrometry by electroatomization and lyophilized to a powder.

S88 method 3-Hydroxybenzaldehyde and ethyl magnesium bromide were converted to the ketone by Method G71. The ketone was then converted to the oxime by the G70 Method and then hydrogen by the G38 Method to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After removal of the t-butyl ester by the Gil Method, the acid was coupled to a t-butyl ester of L-asparagine commercially available by the Method G24. The final t-butyl ester was separated by the Gil Method and the finished molecule was purified by reverse phase HPLC, verified by mass spectrometry by electroatomization and lyophilized to a powder.

Method S89 The 3-hydroxybenzaldehyde and ethyl magnesium bromide were converted to the ketone by the Method G71 The ketone was then converted to the oxime by the G70 Method and then hydrogen by the Method G38 to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After separation of the t-butyl ester by the Gil Method, the acid was coupled to a methyl ester of L-tryptophan commercially available by the Method G24. The final methyl ester was separated by Method G4 and the finished molecule was purified by reverse phase HPLC, verified by mass spectrometry by electroatomization and lyophilized to a powder.

Method S90 The 3-hydroxybenzaldehyde and the N-propyl magnesium bromide were converted to the ketone by Method G71. The ketone was then converted to the oxime by the G70 Method and then hydrogen by the G38 Method to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After removal of the t-butyl ester by the Gil Method, the acid was coupled to a t-butyl ester of L-asparagine commercially available by the Method G24. The final t-butyl ester was separated by the Gil Method and the finished molecule was purified by reverse phase HPLC, verified by mass spectrometry by electroatomization and lyophilized to a powder.

Method S91 The 3-hydroxybenzaldehyde and the N-propyl magnesium bromide were converted to the ketone by the Method G71. The ketone was then converted to the oxime by the G70 Method and then hydrogen by the G38 Method to give the amine. This amine was then coupled to Compound A, Method G8, by Method G24. After separation of the t-butyl ester by the Gil Method, the acid was coupled to a methyl ester of L-tryptophan commercially available by the Method G24. The final methyl ester was separated by the Gil Method and the finished molecule was purified by reverse phase HPLC, verified by mass spectrometry by electroatomization and lyophilized to a powder.

Method S92 The appropriate sulfonamide was synthesized by Method G93 using ammonia as the amine (R) and this product was converted to the methyl ester by the G15 Method. Compound C, Method G13, was coupled to the methyl ester of sulfonamide by Method G3. The final methyl ester was removed by Method G4. The finished molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S93 The compounds were synthesized on the commercially available Fmoc-L-asparagine (Trt) -Wang resin (0.5 mmol / g). The Fmoc group was separated by the G19 Method. The product of Method G65, with the exception that it was not solved by Method G67, was Fmoc protected by Method G5 and the t-butyl ester separated by the Gil Method. This product was coupled to the resin by the G20 Method. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S94 The compounds were synthesized on the commercially available Fmoc-L-asparagine (Trt) -Wang resin (0.5 mmol / g). The Fmoc group was separated by the G19 Method. The S-isomer of Method G65 was Fmoc protected by Method G5 and the t-butyl ester separated by the Gil Method. This product was coupled to the resin by the G20 Method. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

S95 Method The compounds were synthesized on the commercially available Fmoc-L-alanine-Wang resin (0.5 mmol / g). The Fmoc group was separated by the G19 Method. The S-isomer of Method G65 was Fmoc protected by Method G5 and the t-butyl ester separated by the Gil Method. This product was coupled to the resin by the G20 Method. The Fmoc group was separated by the G19 Method and the appropriate carboxylic acid (R) was coupled by the G20 method. The finished molecule was developed by the G21 Method.

Method S96 The compounds were synthesized using standard methods of solid phase Fmoc on the commercially available Fmoc-L-tryptophan (Boc) -Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The appropriate commercially available di-acid (R) coupled by the G20 Method. The 3-hydroxy benzylamine, Method G38 was coupled by the G20 Method. The finished molecule was developed by the G21 Method and the correct stereochemistry was assigned by activity.

Method S97 The compounds were synthesized using standard Fmoc solid phase methods on the commercially available Fmoc-L-asparagine (Trt) -Wang resin. (0.5 mmol / g). The Fmoc group was split by the Method G19. The appropriate commercially available di-acid (R) coupled by the G20 Method. The 3-hydroxy benzylamine, Method G38 was coupled by the G20 Method. The finished molecule was developed by the G21 Method and the correct stereochemistry was assigned by activity.

Method S98 The product of Method G86 was coupled by the G20 method to the Wang Fmoc-amino acid suitable commercially available resin (R) after removing the Fmoc group by the G19 Method. The finished molecule was developed by the G21 Method and the 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 the G4 Method and the carboxylic acid were coupled to the t-butyl ester of L-asparagine by the G3 Method. The final t-butyl ester was separated by the Gil Method and the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

S100 method 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 the G4 Method and the carboxylic acid were coupled to the t-butyl ester of L-alanine by Method G3. The final t-butyl ester was separated by the Gil Method and the molecule was purified by reverse phase HPLC, verified by electroatomization 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 was converted to the ethyl ester by Method G32.

After saponification by the G4 Method, the carboxylic acid was coupled to the methyl ester of L-alanine by the G3 Method. After saponification by Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization 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 was converted to the ethyl ester by Method G32. The allyl alcohol was oxidized to the ketone by the G27 Method and the ethyl ester was saponified by the G4 Method. The carboxylic acid was coupled to the methyl ester of L-alanine by Method G3, and after saponification by the G4 Method, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized until a powder Method S103 The methyl ester of 4-hydroxy-2-chloro-benzoic acid was formed by Method G15. 1,2-dibromomethane was coupled to phenol by Method G51. The appropriate hydroxy phenol (R) was coupled by Method G52 and the methyl ester was separated by Method G4. The t-butyl ester O of L-alanine was coupled by Method G3. The t-butyl ester was separated by the Gil Method and the finished compound was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S104 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to phenol by Method G47 and then the methyl ester was separated 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 phenol (Compound G) by Method G26, and the allyl ester was removed by Method G50. The resulting benzoic acid was coupled to the commercially available 0-t-butyl ester of L-asparagine by Method G3. The t-butyl ester was separated by the Gil Method without TES. The finished molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electrophoretic mass spectrometry and lyophilized to a powder.

Method S105 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to phenol by Method G47 and then the methyl ester was separated by Method G48. The resulting carboxylic acid was then converted to its allyl ester by the method G49 (Compound G). 1,3-dibromopropane was coupled to phenol (Compound G) by Method G51. The 3-hydroxy phenol was coupled by Method G52 and the methyl ester separated by Method G4. The allyl ester removed by the G50 Method. The resulting benzoic acid was coupled to the commercially available O-t-butyl ester of L-asparagine by Method G3. The t-butyl ester was separated by the Gil Method without TES. The finished molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S106 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to phenol by Method G47 and then the methyl ester was separated by Method G48. The resulting carboxylic acid was then converted to its allyl ester by the method G49 (Compound G). 1,2-dibromopropane was coupled to phenol (Compound G) by Method G51. The 3-hydroxy phenol was coupled by Method G52 and the methyl ester separated by Method G4. The allyl ester removed by the G50 Method. The resulting benzoic acid was coupled to the commercially available O-t-butyl ester of L-asparagine by Method G3. The t-butyl ester was separated by the Gil Method without TES. The finished molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S107 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to phenol by Method G47 and then the methyl ester was separated by Method G48. The resulting carboxylic acid was then converted to its allyl ester by the method G49 (Compound G). 1,2-dibromopropane was coupled to phenol (Compound G) by Method G51. The 3-hydroxy phenol was coupled by Method G52 and the methyl ester separated by Method G4. The allyl ester removed by the G50 Method. The resulting benzoic acid was coupled to the commercially available O-t-butyl ester of L-alanine by Method G3. The t-butyl ester was separated by the Gil Method without TES. The finished molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S108 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to iodide by the G54 Method and then the methyl ester was separated by Method G55. This benzoic acid was then coupled to the O-t-butyl ester of L-asparagine by the G3 Method. 3-Hydroxybenzoic acid was converted to hydroxamate by Method G56. The hydroxyl was protected as the t-butyl ether by the G10 Method and the hydroxamate was converted to the aldehyde by the G57 Method. The aldehyde was coupled to ethynyl magnesium bromide by Method G58 and the resulting product was coupled to the above aryl iodide by Method G59. The alkyne was then reduced to the alkane by the G60 Method. The t-butyl ester and ether were separated by the Gil Method without TES. The finished molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S109 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to iodide by the G54 Method and then the methyl ester was separated by Method G55. This benzoic acid was then coupled to the O-t-butyl ester of L-asparagine by the G3 Method. 3-Hydroxybenzoic acid was converted to hydroxamate by Method G56. The hydroxyl was protected as the t-butyl ether by the G10 Method and the hydroxamate was converted to the aldehyde by the G57 Method. The aldehyde was coupled to ethynyl magnesium bromide by Method G58 and the resulting product was coupled to the above aryl iodide by Method G59. The alkyne was then reduced to the alkane by the G60 Method. The t-butyl ester and ether were separated by the Gil Method. The finished molecule was then concentrated, purified by reverse phase HPLC, verified by electrospray mass spectrometry and lyophilized to a powder.

SllO method 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 hydrolyzed to the alkane by Method G38 except that the product was purified by flash silica chromatography (3/6/1 hexane / DCM / Et20) to provide pure aryl alcohol. The alcohol was protected by silyl by Method G18. The phenol converted to its corresponding triflate by the Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. The ether and methyl ester were separated by Method G55. The acid was coupled to the O-t-butyl ester of L-asparagine by Method G3. The t-butyl ester was separated by the Gil Method without TES and the silyl ether was removed by the same reaction by adding 3 equivalents of TBAF. The finished molecule was then concentrated in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Slll method The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to iodide by the G54 Method and then the methyl ester was separated by Method G55. This benzoic acid was then coupled to the O-t-butyl ester of L-asparagine by the G3 Method. The 3'-hydroxyacetophenone was converted to the t-butyl ether using the G10 Method. The resulting alkyne of G58 was coupled to the aryl iodide using Method G59. The alkyne was hydrogenated to the alkane using Method G60. The reductive removal of the benzyl alcohol, as well as the partition of the t-butyl ether and ester groups was achieved using the Gil Method (containing excess TES).

The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S112 The 2,6-dichloro-4-methyl phenol was converted to the triflate according to Method G45. This triflate was carbonyllated 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 was coupled to 3-iodophenol using Method G59. The alkyne was hydrogenated to the alkane using Method G60 and the methyl ester was split using Method G55. The resulting carboxylic acid was coupled to the O-t-butyl ester of L-asparagine by Method G3. The partition of the t-butyl ester group was achieved using the Gil Method (without containing TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S113 The 2,6-dichloro-4-methyl phenol was converted to the triflate according to Method G45. This triflate was carbonyllated to the methyl ester using Method G46 and then converted to the aldehyde by Method G84. The 3-iodophenol was silylated according to Method G18 to give O-t-butyl-dimethylsilyl-3-iodophenol. The aldehyde was treated with ethynyl magnesium bromide by Method G58 and the resulting alkyne was coupled to O-t-butyl-dimethylsilyl-3-iodophenol using Method G59. The alkyne was hydrogenated to the alkane using Method G60. The resulting alcohol was converted to the methyl ester by Method G85 and the methyl ester was split using Method G55. The resulting carboxylic acid was coupled to the O-t-butyl ester of L-asparagine by Method G3. The t-butyl ester was removed by the Gil Method without TES and the silyl ester was removed in the same reaction by adding 3 equivalents of TBAF. The crude product was isolated by concentrating on it, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S114 The 2,6-dichloro-4-methyl phenol was converted to the triflate according to Method G45. This triflate was carbonyllated to the methyl ester using Method G46 and then converted to the aldehyde by Method G84. The 3-iodophenol was silylated according to Method G18 to give O-t-butyl-dimethylsilyl-3-iodophenol. The aldehyde was treated with ethynyl magnesium bromide by Method G58 and the resulting alkyne was coupled to O-t-butyl-dimethylsilyl-3-iodophenol using Method G59. The alkyne was hydrogenated to the alkane using Method G60 and the methyl ester was split using Method G55. The resulting carboxylic acid was coupled to the methyl ester of N-β-alloc-L-α, β-diaminopropionic acid using Method G3 (adding one equivalent of DIPEA). The silyl ether was removed by the Gil Method 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 electroatomization mass spectrometry and lyophilized to a powder.

Method S115 The 2,6-dichloro-4-methyl phenol was converted to the triflate according to Method G45. This triflate was carbonyllated to the methyl ester using Method G46 and then converted to the aldehyde by Method G84. The 3-iodophenol was silylated according to Method G18 to give 0-t-butyl-dimethylsilyl-3-iodophenol. The aldehyde was treated with ethynyl magnesium bromide by Method G58 and the resulting alkyne was coupled to O-t-butyl-dimethylsilyl-3-iodophenol using Method G59. The alkyne was hydrogenated to the alkane using Method G60 and the methyl ester was split using Method G55. The resulting carboxylic acid was coupled to the methyl ester of N-e-Boc-L-lysine using the G3 Method (adding an equivalent of DIPEA). The methyl ester was saponified using Method G4 and the Boc group was removed by the Gil Method without TES and 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 electroatomization mass spectrometry and lyophilized to a powder.

Method S116 3-Hydroxybenzoic acid was converted to N-methoxy-N-methylamide using Method G56. The hydroxyl was protected as the t-butyl ether by the G10 Method. The N-methoxy-N-methylamide was reduced to the aldehyde by Method G57. The aldehyde was treated with ethynyl magnesium bromide by Method G58. The 4-amino-2,6-dichlorophenol was protected by Boc by Method G44 and the phenol was converted to its corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Aniline Boc was converted to iodide by the G54 Method. The resulting aryl iodide was then coupled to the previous alkyne by Method G59. The alkyne is hydrogen to the alkane using Method G60. The methyl ester was split using Method G55. The carboxylic acid was coupled to the methyl ester of N-β-alloc-L-a, β-diaminopropionic acid using Method G3 (adding one equivalent of DIPEA). The methyl ester was saponified using Method G4. The t-butyl ether was split using the Gil Method (without containing TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S117 3-Hydroxybenzoic acid was converted to N-methoxy-N-methylamide using Method G56. The hydroxyl was protected as the t-butyl ether by the G10 Method. The N-methoxy-N-methylamide was reduced to the aldehyde by Method G57. The aldehyde was treated with ethynyl magnesium bromide by Method G58. The 4-amino-2,6-dichlorophenol was protected by Boc by Method G44 and the phenol was converted to its corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Aniline Boc was converted to iodide by the G54 Method. The resulting aryl iodide was then coupled to the previous alkyne by Method G59. The alkyne is hydrogen to the alkane using Method G60. The resulting alcohol was converted to methyl ether by Method G85 and the methyl ester was split using Method G55. The carboxylic acid was coupled to the O-t-butyl ester of L-asparagine using Method G3. The partition of the t-butyl ester group was achieved by using the Gil Method (without containing TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S118 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to iodide by the G54 Method. The 3-chlorobenzaldehyde was treated with ethynyl magnesium bromide by Method G58, and the resulting alkyne was coupled to the above aryl iodide by Method G59. The alkyne is hydrogen to the alkane using Method G60. The methyl ester was split by Method G55. The carboxylic acid was coupled to the methyl ester of N-β-alloc-L-a, β-diaminopropionic acid using Method G3 (adding one 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 electroatomization mass spectrometry and lyophilized to a powder.

Method S119 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to iodide by the G54 Method. The 3-chlorobenzaldehyde was treated with ethynyl magnesium bromide by Method G58, and the resulting alkyne was coupled to the above aryl iodide by Method G59. The alkyne is hydrogen to the alkane using Method G60. The methyl ester was removed by Method G55 and the resulting acid was coupled by the G20 Method to the commercially available methyl ester of ß-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and the thiophene 2-carboxylic acid was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S120 3-Hydroxybenzoic acid was converted to N-methoxy-N-methylamide using Method G56. The hydroxyl was protected as the t-butyl ether by the G10 Method. The N-methoxy-N-methylamide was reduced to the aldehyde by Method G57. The aldehyde was treated with ethynyl magnesium bromide by Method G58. The 4-amino-2,6-dichlorophenol was protected by Boc by Method G44 and the phenol was converted to its corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Aniline Boc was converted to iodide by the G54 Method. The resulting aryl iodide was then coupled to the previous alkyne by Method G59. The alkyne is hydrogen to the alkane using Method G60. The methyl ester was removed by Method G55 and the resulting acid was coupled by Method G.20 to the commercially available methyl ester of ß-Boc-diaminopropionic acid. The Boc group was separated by the Gl Method and thiophene 2-carboxylic acid was coupled by the G3 Method. After saponification, Method G4, the molecule was purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S121 The 4-amino-2,6-dichlorophenol was Boc protected by Method G44 and the phenol was converted to the corresponding triflate by Method G45. The triflate was converted to the methyl ester of the carboxylic acid by Method G46. Boc aniline was converted to iodide by the G54 Method. The 3-chlorobenzaldehyde was treated with ethynyl magnesium bromide by Method G58, and the resulting alkyne was 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 was coupled by the G20 Method to the commercially available N-e-Boc-L-lysine methyl ester using Method G3 (adding one equivalent of DIPEA). The methyl ester was saponified using Method G4 and the Boc group was removed by the Gil Method (without containing TES). The crude product was isolated by concentrating in vacuo, purified by reverse phase HPLC, verified by electroatomization mass spectrometry and lyophilized to a powder.

Method S122 Compounds were synthesized using the normal Fmoc solid phase methods on commercially available Fmoc-glycine Wang resin (0.5 mmol / g). The Fmoc group was split by Method G19. The a glycine charcoal was alkylated with the appropriate bromide or chloride commercially available by the method G36 resulting in the corresponding racemic amino acid. Compound E was coupled to the resin by Method G37 and the finished molecule was developed by Method G21.

Method S123 Compounds were synthesized using the normal Fmoc solid phase methods on p-alkoxybenzyl alcohol resin Fmoc-L-aspartic acid (allyl) (0.5 mmol / g). The resin was made by Method G34 using commercially available N-α-Fmoc-β-allyl-L-aspartic acid. The Fmoc group was split 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 the G40 Method. The finished molecule was developed by the G21 Method.

Method S124 Compounds were synthesized using the normal Fmoc solid phase methods on p-alkoxybenzyl alcohol resin Fmoc-L-aspartic acid (allyl) (0.5 mmol / g) (Wang-Fmoc-L-asp (alloc) resin). The resin was made by Method G34 using commercially available N-α-Fmoc-β-allyl-L-aspartic acid. The Fmoc group was split by Method G19. Compound C, Method G13, was coupled by Method G20. The appropriate amine (R) was coupled by Method G41. The finished molecule was developed by the G21 Method.

Method S125 Compounds were synthesized using the normal Fmoc solid phase methods on p-alkoxybenzyl alcohol resin Fmoc-L-glutamic acid (allyl) (0.5 mmol / g) (Wang-Fmoc-L-glu (alloc) resin). The resin was made by Method G34 using commercially available N-α-Fmoc-β-allyl-L-glutamic acid. The Fmoc group was split 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 finished molecule was developed by the G21 Method.

Method S126 Compounds were synthesized using the normal Fmoc solid phase methods on p-alkoxybenzyl alcohol resin N-α-Fmoc-O-trit yl-L-serine (0.5 mmol / g) (Wang-Fmoc-1-Ser (trityl) resin). The resin was made by Method G34 using commercially available N-α-Fmoc-O-trityl-L-serine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by Method G20. The trityl group was removed by Method G72. The appropriate amine (R) was coupled by Method G73. The finished molecule was developed by the G21 Method.

Method S127 Compounds were synthesized using the normal Fmoc solid phase methods on p-alkoxybenzyl alcohol resin Na-Fmoc-O-trityl-L-threonine (0: 5 mmol / g) (Wang-Fmoc-L-thr resin (trityl)) . The resin was made by Method G34 using commercially available N-α-Fmoc-O-trityl-L-serine. The Fmoc group was split by Method G19. Compound C, Method G13 was coupled by Method G20. The trityl group was removed by Method G72. The appropriate amine (R) was coupled by Method G73. The finished molecule was developed by the G21 Method.

Examples 1-39 Examples 1-39 were synthesized by the SI Method.

Example # Group R 1 2-isopropylphenyl isocyanate 2 Phenethyl isocyanate 3 1-naphthyl isocyanate 4 (S) - (-) a-Methylbenzyl isocyanate 5 Cyclohexyl isocyanate 6 Etoxycarbonyl isocyanate 7 isopropyl isocyanate Trans-2-phenylcyclopropyl isocyanate 9 1-adamantyl isocyanate 10 Phenyl isocyanate 11 4- (meth ilt io) phenyl isocyanate 12 3- (meth ilthio) phenyl isocyanate 13 3-ethoxycarbonylphenyl isocyanate 14 4-ethoxycarbonylphenyl isocyanate 4-fluorophenyl isocyanate 16 2-fluorophenyl isocyanate 17 2- (trifluoromethoxy) phenyl isocyanate 18 3-fluorophenyl isocyanate 19 3-bromophenyl isocyanate 4-methoxyphenyl isocyanate 21 4-isopropylphenyl isocyanate 22 3- (2-hydroxy) et phenyl isocyanate 23 4-ethylphenyl isocyanate 24 2-nitrophenyl isocyanate 25 3- nitrophenyl isocyanate 26 4-nitrophenyl isocyanate 27 3-cyanophenyl isocyanate 28 4-t rif loromethyl isocyanate 29 3-trif loromethyl 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 D2.

Example # Group R 40 Benzyl isocyanate 41 Ethoxycarbonyl isocyanate 42 2-chloro-6-met ilphenyl isocyanate 43 Ethoxycarbonyl isocyanate Examples 44-62 Examples 44-62 were synthesized by Method S3.

Example # Group R 44 Fenethyl isocyanate 45 Isopropyl isocyanate 46 Cyclohexyl isocyanate 47 3-ethoxycarbonylphenyl isocyanate 48 4-ethoxycarbonylphenyl isocyanate 49 4-fluorophenyl isocyanate 50 2-f lorophenyl isocyanate 51 3-f lorophenyl isocyanate 52 4-methoxyphenyl isocyanate 53 4-isopropylphenyl isocyanate 54 3- (2-hydroxyethyl) phenyl isocyanate 55 2-nitrophenyl isocyanate 56 4-nitrophenyl 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 Example 63-71 Examples 63-71 were synthesized by Method S4.

Example # Group R 63 Fenetyl isocyanate 64 Isopropyl isocyanate 65 Benzyl isocyanate 66 Propyl isocyanate 67 Ethoxycarbonyl isocyanate 68 Ethyl 2-isocyanato-4-methylvalerate 69 (S) - (-) -a-methylbenzyl isocyanate 70 Benzenesulfonyl isocyanate 71 Benzyl isocyanate Examples 72-95 Examples 72-95 were synthesized by Method S5.

Example # Group R 72 3-met i 1 indene-2-carboxylic acid 73 3-Methylbenzofuran-2-carboxylic acid 74 4-Oxo-4, 5, 6, 7 -ethohydrobenzofuran-3-carboxylic acid 75 I, 2,5-trimethyl-lH-pyrrole-3-carboxylic acid 76 4-methyl- [1, 2, 3] thiadiazole-5-carboxylic acid 77 4-phenyl- [1,2-] thiadiazole-5-carboxylic acid 78 3-chloro-2-thiophenecarboxylic acid 79 Acid 3, 5-dimethyl-isoxazole-4-carboxylic acid 80 3-Met-il-2-furoic acid 81 3-Bromothiophen-2-carboxylic acid 82 2-furoic acid 83 3-furoic acid 84 2-t-Iofenocarboxylic acid 85 Acid 3 -thiophenecarboxylic acid 86-chloro-2-thiophenecarboxylic acid 87 5-bromo-2-thiophenecarboxylic acid Indole-5-carboxylic acid 89 Indole-4-carboxylic acid 90 Indole-6-carboxylic acid 91 Benzoic acid 92 Acid cyclohexylcarboxylic acid 93 Acetic acid 94 Isonipecotic acid 95 Pipecolynic acid Example 96-113 Examples 96-113 were synthesized by the S6 method Example # Group R 96 Acid 3, 4, 5-trimethoxybenzoic acid 97 Propionic acid 98 Cyclopropylcarboxylic acid 99 Trimethylacetic acid 100 l, 2,5-Trimethyl-lH-pyrrole-3-carboxylic acid 101 3-chloro-4-methanesulfonyl-thiophene -2-carboxylic acid 102 4-methyl- [1,2,3] -thiadiazole-5-carboxylic acid 103 4-phenyl- [1,2-] thiadiazole-5-carboxylic acid 104 4-bromo-2 acid -ethyl-5-methyl-2H-pyrazole-3-carboxylic acid 105 3-chlorothiophen-2-carboxylic acid 106 3,5-dimethyl-isoxazole-4-carboxylic acid 107 5-methyl-2-phenyl-2H- acid [1, 2, 3] triazole-4-carboxylic acid 108 3-Methyl-2-furoic acid 109 3-Bromothiophene-2-carbo-organic acid 110 Benzoic acid 111 Cyclohexylcarboxylic acid 112 Acetic acid 113 None Examples 114-126 Examples 114-126 were synthesized by Method S7.

Example # Group R 114 Trimethylacetic acid 115 3-Chloro-benzo [b] thiophene-2-carboxylic acid 116 3-Chlorothiophen-2-carboxylic acid 117 3, 5-dimethyl-isoxazole-4-carboxylic acid 118 Acid 3- bromot iofen-2 -carboxylic acid 119 3-methylindene-2-carboxylic acid 120 4-OXO-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid 121 3-chloro-4-methanesulfonyl-thiophene -2-carboxylic acid 122 4-Methyl- [1,2,3] thiadiazole-5-carboxylic acid 123 4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid 124 Benzoic acid 125 Cyclohexanecarboxylic acid 126 Acetic acid Examples 127-144 Examples 127-144 were synthesized by Method S8.

Example # Group R 127 3, 4, 5-trimethoxybenzoic acid 128 Isovaleric acid 129 Propionic acid 130 Cyclopropylcarboxylic acid 131 4-Acetyl-3,5-dimethyl-2-pyrrolcarboxylic acid 132 3-Methyl-inden-2-carboxylic acid 133 Acid 4-OXO-4, 5, 6, 7-tetrahydro-benzofuran-3-carboxylic acid 1,2,5-Trimethyl-1H-pyrrol-3-carboxylic acid 135 3-Chloro-4-methanesulfonyl-thiophene-2 acid -carboxylic acid 4-methyl- [1,2,3] thiadiazole-5-carboxylic acid 137 4-phenyl- [1,2,3] thiadiazole-5-carboxylic acid 138 4-bromo-2-ethyl- 5-methyl-2H-pyrazole-3-carboxylic acid 139 3-chlorothiophen-2-carboxylic acid 140 Acid 3, 5-dimethyl-isoxazole-4-carboxylic acid 141 5-methyl-2-phenyl-2H- [1, 2 , 3] triazole-4-carboxylic acid 142 3-bromothiophene-2-carboxylic acid 143 Benzoic acid 144 Cyclohexylcarboxylic acid Examples 145-147 Examples 145-147 were synthesized by the Method S9 Example # Group R 145 Propionic acid 146 Acetic acid 147 N ingun Examples 148-150 Examples 148-150 were synthesized by Method S10.

Example # Group R 148 Acid propionic 149 Butyric acid 150 Acetic acid Examples 151-154 Examples 151-154 were synthesized by the Sil Method.

Example # Group R 151 Propionic acid 152 Butyric acid 153 Acetic acid 154 None Example 155-158 Examples 155-158 were synthesized by Method S12.

Example # Group R 155 Propionic acid 156 Butyric acid 157 Acetic acid 158 None Examples 159-161 Examples 159-161 were synthesized by Method S13.

Example # Group R 159 Propionic acid 160 Acetic acid 161 None Examples 162-163 Examples 162-163 were synthesized by Method S14.

Example # Group R 162 Acetic acid 163 None Examples 164-167 Examples 164-167 were synthesized by Method S15. Example # Group R 164 Propionic acid 165 Butyric acid 166 Acetic acid 167 None Examples 168-171 Examples 168-171 were synthesized by Method S16.

Example # Group R 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 # Group R 173 Propionic acid 174 Butyric acid 175 Acetic acid 176 None Examples 177-180 Examples 177-180 were synthesized by Method S19.

Example # Group R 177 Propionic acid 178 Butyric acid 179 Acetic acid 180 None Examples 181-184.

Examples 181-184 were synthesized by Method S20.

Example # Group R 181 Propionic acid 182 Butyric acid 183 Acetic acid 184 None Examples 185-188 Examples 185-188 were synthesized by Method S21.

Example # Group R 185 Propionic acid 186 Butyric acid 187 Acetic acid 188 None Examples 189-192 Examples 189-192 were synthesized by Method S22.

Example # Group R 189 Propionic acid 190 Butyric acid 191 Acetic acid 192 Ni nsuno Examples 193-196 Examples 193-196 were synthesized by Method S23.

Example # Group R 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 # Group R 198 Propionic acid 199 Butyric acid 200 Acetic acid 201 None Examples 202-205 Examples 202-205 were synthesized by Method S26.

Example # Group R 202 Propionic acid 203 Butyric acid 204 Acetic acid 205 None Examples 206-209 Examples 206-209 were synthesized by Method S27.

Example # Group R 206 Propionic acid 207 Butyric acid 208 Acetic acid 209 None Examples 210-213 Examples 210-213 were synthesized by Method S28.

Example # Group R 210 Propionic acid 211 Butyric acid 212 Acetic acid 213 None Examples 214-217 Examples 214-217 were synthesized by Method S29.

Example # Group R 214 Propionic acid 215 Butyric acid 216 Acetic acid 217 None Examples 218-221 Examples 218-221 were synthesized by Method S30.

Example # Group R 218 Propionic acid 219 Butyric acid 220 Acetic acid 221 None Examples 222-223 Examples 222-223 were synthesized by Method S31.

Example # Group R 222 Acetic acid 223 None Examples 224-225 Examples 224-225 were synthesized by Method S32.

Example # Group R 224 Acetic acid 225 None Examples 226-227 Examples 226-227 were synthesized by Method S33.

Example # Group R 226 Acetic acid 227 None Examples 228-229 Examples 228-229 were synthesized by Method S34.

Example # Group R 228 Acetic acid 229 None Example 230 Example 230 was synthesized by the S35 Method Examples 231-237 Examples 231-237 were synthesized by Method S36.

Example # Group R 231 Propyl Chloroformate 232 Benzyl Chloroformate -233 Isopropyl Choroformate 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 # Group R 238 3-Hydroxybenzoic Acid 239 2-Hydroxycinnamic Acid 240 3-Hydroxybenzoic Acid Examples 241-245 Examples 241-245 were synthesized by Method S38.

Example # Group R 241 3-Hydroxybenzoic Acid 242 2-Hydroxycinnamic Acid 243 3-Chlorobenzoic Acid 244 Indole-5-carboxylic acid 245 3- (2-Ethyl) Acrylic Acid Examples 246-253 Examples 246-253 were synthesized by Method S39.

Example # Group R 246 3-chlorobenzoic acid 247 3- (2-thienyl) acrylic acid 248 2-furanacrylic acid 249 3-hydroxybenzoic acid 250 Indole-5-carboxylic acid 251 Benzofuran-5-carboxylic acid 252 Benzofuran-4 acid carboxylic acid 253 Indole-6-carboxylic acid Example 254 Example 254 was synthesized by the S40 Method Examples 255-256 Examples 255-256 were synthesized by Method S41.

Example # Group R 255 L-Wing 256 L-Thr Example 257 Example 257 was synthesized by Method S42 Examples 258-259 Examples 258-259 were synthesized by Method S43.

Example # Group R 258 2-Thiophenecarboxylic Acid 259 3-Hydroxybenzoic Acid Examples 260-261 Examples 260-261 were synthesized by Method S44.

Example # Group R 260 3-hydroxybenzoic acid 261 2-thiophenecarboxylic acid Examples 262-263 ^^ A ßfejgj ^ Examples 262-263 were synthesized by Method S45.

Example # Group R 262 Benzoic acid 263 2-thiophenecarboxylic acid Examples 264-265 Examples 264-265 were synthesized by Method S46 Example # Group R 264 3-Hydroxybenzoic Acid 265 2-T-Iofencarboxylic Acid Examples 266-267 Examples 266-267 were synthesized by Method S47.

Example # Group R 266 3- (2-thienyl) -acrylic acid 267 Furilacrylic acid Example 268 Examples 268 were synthesized by the Method S48 Example 269 Example 269 was synthesized by Method S49 Examples 270-271 Examples 270-271 were synthesized by Method S50.

Example # Group R 270 3-hydroxybenzoic acid 271 2-t iofenocarboxylic acid Example 272 Example 272 was synthesized by the S51 Method Examples 273-275 Examples 273-275 were synthesized by Method S52.

Example # Group R 273 L-Wing 274 L-Asn 275 L-diaminopropionic acid (alloc) Example 276 Example 276 was synthesized by Method S53 Examples 277-282 Examples 277-282 were synthesized by Method S54.

Example # Group R 277 Thiophene-2-carboxylic acid 278 2-furoic acid 279 2-pyrazinecarboxylic acid 280 3-methylthiophen-2-carboxylic acid 281 3-Met il-2-furoic acid 282 3-chlorothiophen-2-carboxylic acid Example 283 Example 283 was synthesized by the S55 Method Examples 284-285 Examples 284-285 were synthesized by Method S56.

Example # Group R 284 L-Wing 285 L-Asn Examples 286-287 Examples 286-287 were synthesized by Method S57.

Example # Group R 286 L-diaminopropionic acid (alloc) 287 L-Lys Examples 288-289 Examples 288-289 were synthesized by Method S58.

Example # Group R 288 L-diaminopropionic acid (alloc; 289 L-Lys Example 290 Example 290 was synthesized by Method S59 Example 291-292 Examples 291-292 were synthesized by Method S60.

Example # Group R 291 2-furaldehyde 292 3-met i1-2 -furaldehyde Examples 293-294 Examples 293-294 were synthesized by Method S61.

Example # Group R 293 2-Furaldehyde 294 3-methyl-2-furaldehyde Examples 295-296 Examples 295-296 were synthesized by Method S62.

Example # Group R 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 the S65 Method Example 300 Example 300 was synthesized by the S66 Method Example 301 Example 301 was synthesized by the S67 Method Example 302 Example 302 was synthesized by Method S68 Examples 303-305 Examples 303-305 were synthesized by Method S69.

Example # Group R 303 L-Asn 304 L-diaminopropionic acid (alloc) 305 L-lys Example 306 Example 306 was synthesized by Method S70 Example 307 Example 307 was synthesized by the S71 Method Examples 308-309 Examples 308-309 were synthesized by Method S72.

Example # Group R 308 3-hydroxybenzylamine 309 3- (3-hydroxyphenyl) propargylamine Examples 310-312 or Examples 310-312 were synthesized by Method S73.

Example # Group R 310 3-fluorobenzyl sheet 311 Benzylamine 312 3- (3-hydroxyphenyl) propargylamine Examples 313-315 Examples 313-315 were synthesized by Method S74.

Example # Group R 313 n-acetylsulfañyl chloride 314 2-bromobenzenesulfonyl chloride * £ w > -. 315 2-Thiophenesulfonyl Chloride Examples 316-317 Examples 316-317 were synthesized by Method S75.

Example # Group R 316 2-thiophenesulfonyl chloride 317 8-quinolinesulfonyl chloride Examples 318-322 Examples 318-322 were synthesized by Method S76.

Example # Group R 318 Benzenesulfonyl chloride 319 N-acetylsulfañyl chloride 320 2-thiophenesulfonyl chloride 321 Bromobenzenesulfonyl chloride 322 2-Acetamido-4-methyl-5-thiazolesulfonyl chloride Examples 323-32 Examples 323-328 were synthesized by Method S77.

Example # R 323 Isobutyl Chloroformate 324 Allyl Chloroformate 325 Butyl Chloroformate 326 Ethyl Chloroformate 327 Isopropyl Choroformate 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-t Ricloroetyl Chloroformate Examples 334-337 Examples 334-337 were synthesized by Method S79.

Example # Group R 334 Butyl Chloroformate 335 Propyl Chloroproma 336 Ethyl Chloropromate 337 Methyl Chloropromate Example 338 Example 338 was synthesized by the S80 Method Example 339 Example 339 was synthesized by the S81 Method Examples 340-354 Examples 340-354 were synthesized by Method S82.

Example # Group R 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 (Ne-Ac) 349 L-Gln 350 L-diaminopropionic acid (alloc) 351 L-diaminobutyric acid (alloc) 352 L-lys (alloc) 353 L-orn (alloc) 354 L-Tyr Examples 355-357 Examples 355-357 were synthesized by Method S83.

Example # Group R 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 # Group R 359 1-amino-1-cyclopropane carboxylic acid 360 m-t irosine 361 o-hydroxytyrosine 362 L-iodotyrosine Example 363 Example 363 was synthesized by Method S86 Example 364 Example 364 was synthesized by the S87 Method Example 365 Example 365 was synthesized by the S88 Method Example 366 Example 366 was synthesized by the S89 Method Example 367 Example 367 was synthesized by the S90 Method Example 368 Example 368 was synthesized by the S91 Method Example 369 Example 369 was synthesized by the S92 Method Example 370-371 Examples 370-371 were synthesized by Method S93.

Example # Group R 370 3-Hydroxybenzoic acid 371 Benzoic acid Examples 372-375 Examples 372-375 were synthesized by Method S94.

Example # Group R 372 Furilacrylic acid 373 3- (2-thienyl) -acrylic acid 374 3-hydroxybenzoic acid 375 Benzoic acid Examples 376-377 Examples 376-377 were synthesized by Method S95.

Example # Group R 376 3-Hydroxybenzoic acid 377 3- (2-thienyl) -acrylic 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 # Group R 380 L-Trp 381 L-Asn 382 L-dapa (alloc) 383 L-Lys Example 384 Example 384 was synthesized by Method S99 Example 385 Example 385 was synthesized by the S100 Method Example 386 Example 386 was synthesized by the Method S101 Example 387 Example 387 was synthesized by the Method S102 Example 388 Example 388 was synthesized by the Method S103 Example 389 OH Example 389 was synthesized by the Method S104.

Example 390 Example 390 was synthesized by the Method S105 Example 391 Example 391 was synthesized by the Method S106 Example 392 Example 392 was synthesized by the Method S107 Example 393 Example 393 was synthesized by the Method S108 Example 394 Example 394 was synthesized by the Method S109 Example 395 Example 395 was synthesized by the Method SllO Example 396 Example 396 was synthesized by the Method Slll Example 397 Example 397 was synthesized by the Method S112 Example 398 Example 398 was synthesized by the Method S113 Example 399 Example 399 was synthesized by the Method S114 Example 400 Example 400 was synthesized by the Method S115 Example 401 Example 401 was synthesized by the Method S116 Example 402 Example 402 was synthesized by the Method S117.

Example 403 Example 403 was synthesized by the Method S118 Example 404 Example 404 was synthesized by the Method S119 Example 405 Example 405 was synthesized by the Method S120 Example 406 Example 406 was synthesized by the Method S121 Examples 407-416 were synthesized by Method S122.

Example # Group R 407 3-methoxybenzyl bromide 408 3-bromobenzyl bromide 409 3,5-Dimethoxybenzyl bromide 410 5-bromovaleronitrile 411 6-bromohexanonitrile 412 3-Nitrobenzyl bromide 413 3-Cyanobenzyl bromide 414 Ethyl ether ester 5- bromomet il-furan-2-carboxylic acid 415 Ethyl ester of 5-bromomet-il-furan-2-carboxylic acid 416 3-bromomethyl benzamide Examples 417-423 Examples 417-423 were synthesized by Method S123.

Example # Group R 417 1 -aminonaphthalene 418 2-cyanoaniline 419 3-cyanoaniline 420 2-fluoroaniline 421 3-fluoroaniline 422 4-fluoroaniline 423 3-methoxyaniline Examples 424-436 Examples 424-436 were synthesized by Method S124.

Example # Group R 424 2- (aminomethyl) pyridine 425 3-fluorobenzylamine 426 Benzylamine 427 Allylamine 428 Phenethylamine 429 Histamine 430 4-fluorobenzylamine 431 3-methoxyphenethylamine 432 4-aminobenzylamine 433 2-aminobenzyl sheet 434 2- [1,3-dioxan- 5-yl-ethylamine 435 Piperonylamine 436 Aniline Examples 437-440 Examples 437-440 were synthesized by Method S125.

Example # Group R 437 Isoamylamine 438 4- (aminomethyl) piperidine 439 2- [1, 3] dioxan-5-yl-ethylamine 440 Aniline Examples 441-443 Examples 441-443 were synthesized by Method S126.

Example # Group R 441 o-toluidine 442 Allylamine 443 Propylamine Examples 444-459 Examples 444-459 were synthesized by Method S127.

Example # Group R 444 Propylamine 445 3- (aminomethyl) pyridine 446 4- (aminomethyl) pyridine 447 2-methybenzene sheet 448 3-methybenzene sheet 449 4 -methenebenzene sheet 450 (S) - (-) -a-met ilbenci lamin 451 2- (aminomethyl) pyridine 452 2-fluorobenzyl lamine 453 3-fluorobenzyl lamin 454 4-fluorobenzyl lamin 455 3-chlorobenzylamine 456 4-chlorobenzyl amine 457 4-methoxybenzylamine 458 1-naphthalenomethylamine 459 Benzylamine Table 3 provides data of the biological assays for the compounds prepared by the methods described above. The data is provided by two assay formats: the LFA / ICAM forward assay format (PPFF) and the PLM2 antibody capture format of the LFA / ICAM assay (PLM2).

Table 3 PPFF and PLM2 test data for exemplary compounds Example * PPFF (μM) PLM2 (μM) 1 0.149 0.028 2 0.035 3 0.069 4 0.038 5 0.013 6 0.045 7 0.004 8 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 0.064 31 0.014 32 0.047 33 0.023 34 0.078 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 79 0.033 80 0.005 81 0.008 82 0.004 83 0.006 84 0.001 85 0.003 86 0.012 87 0.009 88 0.005 89 0.004 90 0.021 91 0.004 92 0.066 93 0.024 94 0.002 95 0.006 96 0.070 97 0.042 98 0.033 99 0.046 100 0.031 101 0.022 102 0.025 103 0.044 104 0.044 105 0.004 106 0.026 107 0.087 108 0.021 109 0.026 110 0.052 111 0.007 112 0.036 113 0.086 114 0.018 115 0.073 116 0.026 117 0.045 118 0.031 119 0.077 120 0.064 121 0.055 122 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 0.064 140 0.023 141 0.068 142 0.074 143 0.031 144 0.093 145 0.004 146 0.004 147 0.004 148 0.004 149 0.004 150 0.004 151 0.004 152 0.004 153 0.003 154 0.003 l OD 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 0.011 172 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 0.016 192 0.029 193 0.014 194 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 0.005 233 0.001 234 0.044 235 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 0.030 250 0.034 251 0.038 252 0.060 253 0.014 254 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 0.093 265 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 0043 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 40 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 0.040 376 0.078 0.061 377 0.016 0.051 378 0.007 379 0.010 380 0.096 381 0.035 382 0.012 383 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 0.007 401 0.002 402 0.004 403 0.009 404 0.002 405 0.001 406 0.022 407 0.045 408 0.071 409 0.054 410 0.065 411 0.055 412 0.074 413 0.051 0.045 414 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 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (15)

Claims

1. A method of treating or alleviating the inflammatory response or disorder in a mammal mediated by the CD11 / CD18 family of cell adhesion molecules, characterized in that it comprises administering a therapeutically effective amount of a compound represented by the structural formula (I) where D is a mono, bi or tricyclic saturated, unsaturated or aromatic ring, each ring has 5, 6 or 7 atoms in the ring where the atoms in the ring are carbon or from one to four heteroatoms selected from nitrogen, oxygen and sulfur, wherein any sulfur or carbon ring atom may optionally be oxidized, each ring substituted with 0-3 of R; L is a bivalent linking group selected from -L3 -! - 2 -! - 1- -L5 -! - 4 -! - 3 -! - 2 -! - 1- where L1 is selected from oxo (-0-), S (0) s, C (= 0), CR1! * 1 ', CR1, het, NRn and N, L2 is selected from oxo (-0-), S (0) s, C (= 0), C (= N-0-R °), CCR2R2 ', CR2R2', CR2, het, NRn and N, it is selected from oxo (-0-), S (0) s, C (= 0), C (= N-0-R °), CR3R3 ', CR3, CR3, het, NRn and N, L4 is absent or selected from oxo (-0-), S (0) s, C (= 0), C (= N-0-R °), CCR R4 ', CR4, NRn and N; and L5 is absent or selected from oxo (-0-), S (0) S / C (= 0), CR5R5 ', CR5, NRn and N, with the proviso that only one of Lx-L3 can be het and when one of Lx-L3 is het the other Lx-L5 can be absent; where R1, R1 ', R2, R2', R3, R3 ', R4, R4', R5 and R5 'are each independently selected from Ra, Rc and ü-Q-V-W, optionally R2 and R2 'separately or together can form a saturated, unsaturated or aromatic fused ring with B through a substituent Rp on B, the fused ring contains 5, 6 or 7 ring atoms and optionally contains 1-3 selected heteroatoms of the group O, S and N, where either S or N can optionally be oxidized; optionally, R3 and R3 separately or together and R4 and R4 separately or together can form a saturated, unsaturated or aromatic fused ring with D through a substituent Rd on D, the fused ring contains 5, 6 or 7 ring atoms and optionally contains 1 to 3 heteroatoms selected from the group 0, S and N, wherein either S or N may optionally be oxidized; also optionally, each of R1-R5, NRn or N in L1-L5 together with any other R1-R5 ', NRn or N in Lx-L5 can form a 5-, 6- or 7-membered hetero or heterocycle, whether saturated, unsaturated or aromatic optionally containing 1-3 additional heteroatoms selected from N, 0 and S, wherein any carbon or sulfur ring atoms may be optionally oxidized, each cycle substituted with 0-3 of Rd; where s is 0-2; B is selected from the group where it is a hetero or homocyclic fused ring containing 5, 6 or 7 atoms, the ring is unsaturated, partially saturated or aromatic, the heteroatoms selected from 1-3 0, S and N, Yi is selected from CH and NRn; n is 0-3; G is selected from hydrogen and Ci-Cß alkyl, optionally G is taken together with T and can form a C3-C6 cycloalkyl optionally substituted with -V-W; T is selected from the group of, an α-amino acid of natural side chain presence, and U-Q-V-; ü is an optionally substituted divalent radical selected from the group C? -C6 alkyl, C0-C6-Q alkyl, C2-C6 alkenyl, and C2-C6-Q alkynyl, wherein the substituents in any alkyl, alkenyl or alkynyl are 1-3 Ra; Q is absent or selected from the group; -0-, -S (0) s-, -S02-N (Rn) -, -N (Rn) -, -N (Rn) -C (= 0) -, -N (Rn) -C (= 0) -N (Rn) -, -N (Rn) -C (= 0) -0-, -N (Rn) -S02-, -C (= 0) -, -C (= 0) -0- , -het-, -C (= 0) -N (Rn) -, -OC (= 0) -N (Rn) -, -P0 (0Rc) 0- and -P (0) 0-, where s is 0-2 and het is a mono or bicyclic ring of 5, 6, 7, 9 or 10 heterocyclic members, each ring contains 1-4 heteroatoms selected from N, O and S, wherein the heterocyclic ring can be saturated, partially saturated or aromatic and any of N, O or S are optionally oxidized, the heterocyclic ring is substituted with 0-3 R; V is absent or is an optionally substituted bivalent group selected from Ci-Cß alkyl, C3-Ce cycloalkyl, Co-C6-aryl-C6-C6 alkyl and C0-C6 alkyl het, wherein the substituents on any alkyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd; is selected from the group of hydrogen, OR °, SRm, NRnRn ', NH-C (= 0) -0-Rc, NH-C (= 0) -NRnRn', NH-C (= 0) -Rc, NH-S02-Rs, NH-S02-NRnRn ', NH-S02-NH-C (= 0) -Rc, NH-C (= 0) -NH-S02-Rs , C (= 0) -NH-C (= 0) -0-Rc, C (= 0) -NH-C (= 0) -Rc, C (= 0) -NH-C (= 0) -NR > nnRr_nr ' C (= 0) -NH-S02-Rs, C (= 0) -NH-S02-NRnRn ', C (= S) -NRnRn', S02-Rs, S02-0-Rs, S02-NRnRn 'S02- NH-C (= 0) -0-Rc S02-NH-C (= 0) -NRnRn ', S02-NH-C (= 0) -Rc, 0-C (= 0) -NRnRn ', O-C (= 0) -Rc, O-C (= 0) -NH-C (= 0) -Rc, O-C (= 0 ') -NH-S02-Rs and 0-S02-Rs; R is selected from C (= 0) -R2, C (= 0) -H, CH2 (0H) and alkyl -CH20-C (= 0) -C? -C6; Ra is R £ or R £ substituted with 1-3 Re where Ra is selected from the group of hydrogen, halo (F, Cl, Br, I), cyano, isocyanate, carboxy, carboxy-Ci-Cnalkyl, amino, amino-C? -C8-alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, zido, nitro, imidazoyl, ureido, thioureido, thiocyanate, hydroxy, Ci-Cβ alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, hyperazinyl, piperinidyl, pyrrolinyl, imidazolyl and indolyl; is selected from the group alkylCo-Cio-Q-C0-C6alkyl, alkenylC0-C? or Q-C0-C6alkyl, C0-C? alkynyl-Q-C0-C6alkyl, C3-C6cycloalkyl-Q-C0-C6alkyl, cycloalkenylC3-C? 0- Q-C 1 -C 6 alkyl, C 1 -C 6 alkyl C 6 -Ci 2 -Q-C 0 -C 6 alkyl, C 6 -C 10 arylC 6 alkyl -C 6 -C 8 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkyl, Q-het-C0-C6alkyl, -alkyl-het-Co-C6-Q-C0-C6alkyl, C0-C6alkyl-Q-arylC6-C? 2 and C? -C6-Qalkyl; select hydrogen and Ci-Cio alkyl, C2-C? alkenyl, C2-C? alkynyl, C3-Cn cycloalkyl, C3-C10 cycloalkenyl, Ci-Cß alkyl. C6-Ci2 aryl, C6-C? aryl, C alquilo-Cß alkyl, C alquilo-C6 alkyl-het, C?-C6-het alkyl, C6-C? ar aryl and het, substituted or unsubstituted, wherein the substituents on any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd; Rd is selected from Rp and Rh; Rh is selected from the group OH, OCF3, ORc, SRm, halo (F, Cl, Br, I), CN, isocyanate, N02, CF3, C0-C6 alkyl-NRnRn ', C0-C6 alkyl (= 0) -NRnRn', alkyl C0-C6-C (= 0) -Ra, Ci-Cß alkyl, Ci-Cg alkoxy, C2-C8 alkenyl, C2-C alqu alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C?-C6 alkyl phenyl, alkyl Ci-Ce phenyl, alkyloxycarbonyl Ci-Cβ, alkyloxy Co-Ce phenyl, alkyl-het C? ~ C6, alkyl Ci-Ce het, -het-S02, aryl-0-C6-Ci2, aryl-S02-C6- C? 2, S02- C-C6 alkyl and het, wherein any alkyl, alkenyl or alkynyl can be optionally substituted with 1-3 groups selected from OH, halo (F, Cl, Br, I), nitro amino and aminocarbonyl and the substituents in any aryl or het are 1-2 hydroxy, halo (F, Cl, Br, I), Ci-Cß alkyl, Ci-Cβ alkoxy, nitro and amino; is selected from SC? -C6alkyl, C (= 0) -C? -C6alkyl, C (= 0) -NRnRn ', alkyl-Ci-Cdr halo (F, Cl, Br, I) -C? -C6 alkyl, benzyl and phenyl; is selected from the group Rc, NH-C (= 0) -0-Rc, NH-S02-Rs, NH-S02-NH-C (= 0) -Rc, NH-C (= 0) -NH-S02- Rs, C (= 0) -0-Rc, C (= 0) -Rc, C (= 0) -NHRC, C (= 0) -NH-C (= 0) -0-Rc, C (= 0) ) -NH-C (= 0) -Rc, C (= 0) -NH-S02-Rs, C (= 0) -NH-S02-NHRs, S02-Rs, S02-0-Rs, S02-N ( Rc) 2, S02-NH-C (= 0) -0-Rc, S02-NH-C (= 0) -0-Rc and S02-NH-C (= 0) -Rc; it is selected from the group of hydrogen, hydroxy and Ci-Cn alkyl, Ci-Cn alkoxy, C2-C al alkenyl, Ci-Cio alkynyl, C3-Cn cycloalkenyl, C3-C10 cycloalkenyl, C6-C6 alkyl, C6-C2 aryl, C6-C aryl? 0- C 1 -C 6 alkyl, C 6 -C 0 aryl 0 C 0 -C 6 alkyloxy, C 1 -C 6 alkyl. $, C 1 -C 4 -alkyl, C 6 -C 2 aryl, het, Ci-Ce alkylcarbonyl, C 1 -C 8 alkoxycarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkoxycarbonyl, aryloxycarbonyl Ce-Cu, arylalkoxycarbonyl-C 7 -C n , heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkysulfonyl, heteroarylsulphonyl, substituted C 1 -C 6 -Cy-sulphonyl and C 1 -Cy-arylsulfonyl, substituted or unsubstituted, wherein the substituents on any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl, het or heteroaryl are 1-3 R; Rn and Rn 'taken together with the common nitrogen to which they are placed can be from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imido zolidini lo, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl wherein the substituents are 1-3 Ra; R ° is selected from hydrogen and Ci-Ce alkyl. Ci-Ce alkylcarbonyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and benzoyl, substituted or unsubstituted, wherein the substituents on any alkyl are 1-3 Ra and the substituents on any aryl are 1-3 Rp; Rp is selected from the group OH, halo (F, Cl, Br, I), CN, isocyanate, 0RC, SRm, SORc, N02, CF3, Rc, NRnRn ', N (Rn) -C (= 0) -0-Rc, (Rn) -C (= 0) -Rc, C0-C6-SO2-Rc alkyl, C0-C6-SO2-NR alkyl nnnRnn ' C (= 0) -Rc, O-C (= 0) -Rc, C (= 0) -0-Rc and C (= 0) -NRnRn ', wherein the substituents are any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd; Rs is a substituted or unsubstituted group selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkenyl, C 1 -C 6 alkyl phenyl, C 1 -C 3 phenyl alkyl, C 6 -C 6 alkyl and C 8 -C 8 alkyl Cß-het, wherein the substituents on any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents on any aryl or het are 1-3 Rd; Rz is a substituted or unsubstituted group selected from hydroxy, Ci-Cn alkoxy, C3-C2 cycloalkoxy, C8-C2 aralkoxy, - ^ & arcicloalcoxi C8-C? 2, aryloxy CSS-Cio, alkylcarbonyloxyalkyloxy C3-C? 0, alcoxicarboniloxialquiloxi C3-C10, alcoxicarbonilalquiloxi C3-C10, cicloalquilcarboniloxialquiloxi C5-C10, cicloalcoxicarboniloxialquiloxi C5-C10, cicloalcoxicarbonilalquiloxi C5-C10, ariloxicarbonilalquiloxi C8-C? 2 , C 8 -C 12 aryloxycarbonyloxyalkyloxy, arylcarbonyloxyalkyloxy C 8 -Cy 2, alkoxyalkylcarbonyloxyalkyloxy C 5 -C 10, (R n) (R n ') N (C 1 -C 10 alkoxy), wherein the substituents of any alkyl, alkenyl or alkynyl are 1-3 Rc the constituents on any aryl or het are 1-3 Rc the pharmaceutically acceptable salts thereof

2. The method according to claim 1, characterized in that D is an aromatic homocycle or aromatic heterocycle containing from 1-3 heteroatoms selected from the group N, S and O, the homo or heterocycles selected from: wherein Y1, Y2, Y3, Y4 and Y5 are selected from the group CH, CRd and N, selected from the group 0, S, NH or NRn n is 0-3, Rd is selected from the group OH, 0CF3, 0RC, SRm, halo (F, Cl, Br, I), CN, isocyanate, N02, CF3, C0-C6 alkyl-NRnRn ', C0-C6 alkyl (= 0) -NRnRn ', C0-C6-C alkyl (= 0) - Ra, C? -C8 alkyl, C? -C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, alkyl -C-C-phenyl, C? -C6 alkyl phenyl, Ci-C? alkyloxycarbonyl, C0-C6 alkyloxy phenyl, Ci-C? alkyl-alkyl, C? -C6 alkyl, -hetS02, aryl -0-C6-C? 2, aryl -S02-C6-Ci2, alkyl -S02-C? -C6 and het, wherein any alkyl, alkenyl or alkynyl may be optionally substituted with 1-3 groups selected from OH, halo (F, Cl, Br, I), nitro amino and aminocarbonyl and the substituents in any aryl or het are 1- 2 hydroxy, halo (F, Cl, Br, I), C 1 -C 6 alkyl, Ci-Cβ alkoxy. nitro and amino Ra is R, a 'or R > a 'replaced with 1-3 Ra; where Ra 'is selected from the group hydrogen, halo (F, Cl, Br, I), cyano, isocyanate, carboxy, carboxyCi-Cn alkyl, amino, amino-Ci-Ce-alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy , formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanate, hydroxy, Ci-Cβ alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, hyperazinyl, piperinidyl, pyrrolinyl, imidazolyl and indolyl; Ra "is selected from the group C0-Cio-Q-C0-C6 alkyl, C0-C alkenyl 0-Q-C0-Cd alkyl / alkynyl Co-C? Or Q-C0-C6alkyl, C3-Cn-Q-cycloalkylCo-C6alkyl , C3-C-cycloalkenyl, or Q-C6-C6alkyl, C6-C6alkyloxy-C6-Ci2-Q-C6-C6alkyl, C6-C6alkyl, or C6alkyl-C6-Q-C6-C6alkyl, C6-C6-C6alkyl C6, C 0 -C 6 -alkyl-het- C 0 -C 6 alkyl, alkyl-het-Co-Ce-Q-C 0 -C 6 alkyl, C 0 -C 6 -alkyl C 6 -C 6 aryl, and C 6 -C 6 alkyl; Q is absent or is selected from the group -O-, -S (0) s-, -S02-N (Rn) -, -N (Rn) -, -N (Rn) -C (= 0) -, - N (Rn) -C (= 0) -O-, -N (Rn) -S02-, -C (= 0) -, -C (= 0) -0-, -het-, -C (= 0 ) -N (Rn) -, -P0 (0Rc) 0- and -P (0) 0-, where s is 0-2 and het is a mono or bicyclic ring of 5,6,7,9 or 10 members heterocyclic, each ring contains 1-4 heteroatoms selected from N, O and S, wherein the heterocyclic ring can be saturated, partially saturated or aromatic and any of N or S are optionally oxidized, the heterocyclic ring is substituted with 0-3 hydroxy , halo (F, Cl, Br, I), CF3, Ci-Cß alkyl. alkoxy-Ci-Ce, nitro and amino; Rc is selected from hydrogen and Ci-Cio alkyl / C2-C? Alkenyl, C2-C alqu alkynyl, C3-Cn cycloalkyl, C3-C10 cycloalkenyl, Ci-Cß alkyl, C6-C? Aryl, C C aryl -Cio, Ci-Cß alkyl, C--C6 alkyl-het, C C-C he-het alkyl, C C-C? 2 aryl and het, substituted or unsubstituted, wherein the substituents are hydroxy, halo (F, Cl, Br, I), CF 3, C 1 -C-alkyl, C 1 -C 6 -alkoxy. nitro and amino; Rm is selected from S-Ci-Cealkyl, C (= 0) -C? -C6alkyl, C (= 0) - NRnRn ', Ci- C-alkyl, halo (F, Cl, Br, I) -C? -C, alkyl, benzyl and phenyl; Rn is selected from the group Rc, NH-C (= 0) -0-Rc, NH-S02-Rs, NH-S02-NH-C (= 0) - Rc, NH-C (= 0) -NH-S02 -Rs, C (= 0) -0-Rc, C (= 0) -Rc, C (= 0) -NHRc, C (= 0) -NH-C (= 0) -0-Rc, C (= 0) -NH- C (= 0) -Rc, C (= 0) -NH-S02-Rs, C (= 0) -NH-S02-NHRs, S02-Rs, S02-0-Rs, S02-N (RC) 2, S02-NH-C (= 0) -0-Rc, S02-NH-C (= 0) -0-Rc and S02-NH-C (= 0) -Rc; Rn 'is selected from the group of hydrogen, hydroxy and C C-Cp alkyl, Ci-Cn alkoxy, C2-C al alkenyl, C alqu-C? Alkynyl, C3-C11 cycloalkenyl, C3-C10 cycloalkenyl, C alquilo alkyl? -C6- aryl? -C12, C 1 -C 6 aryl C 1 -C 6 alkyl, C 6 -C 6 aryl or C 1 -C 6 alkyloxy, C 1 -C 6 alkyl-het, C 6 -C 6 alkyl, C 2 -C aryl, het , Ci- C6 alkylcarbonyl, C? -C8 alkoxycarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxycarbonyl, aryloxycarbonyl C6-Cn, arylalkoxycarbonyl C7-Cn, heteroarylalkoxycarbonyl, ^^^^^^^^ - "heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, Ci-Cß alkylsulfonyl, and C 6 -C 0 arylsulfonyl, substituted or unsubstituted, wherein any alkyl, alkenyl, or alkynyl can be optionally substituted with 1-3 groups selected from OH, halo (F, Cl, Br, I), nitro, amino and aminocarbonyl, and the substituents in either aryl, heteroaryl or het are 1-2 hydroxy, halo (F, Cl, Br, I), CF3, alkyl Ci-? , C 1 -C 6 alkoxy, nitro and amino; Rn 'taken together with the common nitrogen to which they are placed may be from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl and pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2 , 3,4 tet rahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl wherein the substituents are 1-3 hydroxy, halo (F, Cl, Br, I), CF 3, Ci-Ce alkyl, C 1 -C 6 alkoxy, nitro and Not me; Rs is a substituted or unsubstituted group selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkenyl, C 1 -C 6 alkyl phenyl, Co-Ce-phenyl alkyl, alkyl-het Co-Ce and C 0 -C 6 -alkyl, wherein the substituents are 1-3 hydroxy, halo (F, Cl, Br, I), CF 3, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro and amino; L is selected from the group - (CR6R6 ') or -Ai- (CR8R8') p-, - (CR6R6 ', -het- (CR8R8') P-, - (CR6 = CR7) q-Ai- (CR8R8 ') p-, y (CR6R6 ') 0-Ai- (CR8 = CR9) r-, where Ai is selected from where 0 is 0-1, p is 0-1 and r is 0-1; R1, R1 ', R2, R2', R3, R3 ', R4, R4', R5 and R5 'are each independently selected from Ra, Rc and U-Q-V-W; U is an optionally substituted bivalent radical selected from the group C 1 -C 6 alkyl, C 0 -C 6 -alkyl, C 2 -C 2 -alkenyl and C 2 -C 6 -alkynyl, wherein the substituents in any alkyl, alkenyl or alkynyl are 1-3 Ra; is selected from the group hydrogen, -OR °, -SRm, -NRnRn ', -NH-C (= 0) -0-R, -NH-C (= 0) -NRnRn', -NH-C (= 0) -Rc, -NH-S02-Rs, NH-S02-NRnRn ', -NH-S02-NH-C (= 0) -Rc, -NH-C (= 0) - NH-S02-Rs, -C ( = 0) -NH-C (= 0) -0-Rc, -C (= 0) -NH- C (= 0) -Rc, -C (= 0) -NH-C (= 0) -NRnRn ' , -C (= 0) -NH- S02-Rs, -C (= 0) -NH-S02-NRnRn ', -C (= S) -NRnRn', S02-Rs, -S02-0-Rs, - S02-NRnRn ', -S02-NH-C (= 0) -0- Rc, -S02-NH-C (= 0) -NRnRn', -S02-NH-C (= 0) -Rc, -0- C (= 0) -NRnRn ', -0-C (= 0) -Rc, -OC (= 0) -NH-C (= 0) - Rc, -OC (= 0) -NH-S02-Rs and -0-S02-Rs; G is hydrogen; T is U-; R is C (= 0) -OH and pharmaceutically acceptable salts thereof.

3. The method according to claim 2, characterized in that D is selected from 1) a 5-membered aromatic heterocycle or hetero selected from; 2) a 9-membered aromatic heterocycle selected from; 3) a hetero or 6-membered aromatic homocycle selected from; L is a bivalent linking group selected from C3-C5alkyl-, C3-C5alkenyl-, -CH2C (= 0) H-, -CH2NH-C (= 0) -, -0-CH2-C (= 0) -, -CH2-CH2- C (= 0) -, -CH = CH-C (= 0) NH-CH2-, -CH = CH-C (= 0) NH-CH- (CH3) -CH (OH) -CH2-0-, -CH (OH) -CH2-N (CH3) -, -CH (OH) -CH2-CH2-, -CH2-CH2-CH (OH) -, -0-CH2-CH (OH) -, -0- CH2-CH (OH) -CH2-, -0-CH2-CH2-CH (OH) -, -0-CH2-CH2-0-, -CH2-CH2-CH2-0-, -CH2-CH (OH) -CH2-O-, -CH2-CH2-0-, -CH- (CH3) -NH-C (= 0) -, -CH2-NH-S02-, -NH-S02-CH2-, -CH2-S0 NH-, -SO2NH-CH2-, -C (= 0) -NH-C (= 0) -, -NH-C (= 0) -NH-, -NH-C (= 0) -NH-CH2- , -CH2-NH-C (= 0) -NH-, -C (= 0) -NH-CH2-C (= 0) -NH-, -NH-C (= 0) -0- and -OC ( = 0) -NH-, and pharmaceutically acceptable salts thereof.

4. The method according to claim 3, characterized in that the compound is represented by where D-L is selected from and where Y2, Y4 are selected from the group CH, CRd and N, Z1 is selected from the group 0, S, NH and NRn; n is 0-3; R1, R2 and R3 are independently selected from Ra, Rc and U-W; U is an optionally substituted bivalent radical selected from the group Ci-Cß alkyl, C0-C6-Q alkyl, alkenyl lo-C2-C6-Q and C2-C6 alkynyl Q, wherein the substituents in any alkyl, alkenyl or alkynyl are 1-3 Ra; Q is absent or selected from the group; -O-, -S (0) s-, -S02-N (Rn) -, -N (Rn) -, -N (Rn) -C (= 0) -, -N (Rn) -C (= 0) -O-, -N (Rn) -S02-, -C (= 0) -, C (= 0) -0-, -het-, -C (= 0) -N (Rn) -, - PO (ORc) 0- and -P (0) 0-, where s is 0-2; het is a mono or bicyclic ring of 5, 6, 7, 9 or 10 heterocyclic members, each ring contains 1-4 heteroatoms selected from N, 0 and S, wherein the heterocyclic ring can be saturated, partially saturated or aromatic and any of N or S are optionally oxidized, the heterocyclic ring being substituted with 0-3 hydroxy, halo (F, Cl, Br, I), CF 3, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro and amino; W is selected from the group hydrogen, -OR °, -SRm, -NRnRn ', -NH-C (= 0) -0-Rc, -NH-C (= 0) -NRnRn', -NH-C (= 0 ) -Rc, -NH-S02-Rs, -NH-S02-NRnRn ', -NH-S02-NH-C (= 0) -Rc, -NH-C (= 0) -NH-S02-Rs, - C (= 0) -NH-C (= 0) -0-Rc, -C (= 0) -NH-C (= 0) -Rc, -C (= 0) -NH-C (= 0) - NRnRn ', -C (= 0) -NH-S02-Rs, -C (= 0) -NH-S02-NRnRn', -C (= S) -NRnRn, -S02-Rs, -S02-0-Rs , -S02-NRnRn ', -S02-NH-C (= 0) -0-Rc, -SO2-NH-C (= 0) -NRnRn', -S02-NH-C (= 0) -Rc, - OC (= 0) -NRnRn ', -0-C (= 0) -Rc, -0-C (= 0) -NH-C (= 0) -Rc, -OC (= 0) -NH-S02- Rs and -0-S02-Rs; Ra is Ra "substituted with 1-3 Ra '; Ra 'is selected from the group hydrogen, halo (F, Cl, Br, I), cyano, isocyanate, carboxy, carboxyCi-Cn alkyl, amino, amino-Ci-Cs-alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanate, hydroxy, C? -C6 alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, hyperazinyl, piperinidyl, pyrrolinyl, imidazolyl and indolyl; R, a "is selected from the group -Co-Calkyl or Q-C6alkyl / alkenylC0-C? 0-Q-C0-C6alkyl, alkynyl Co-C10-Q-C0-C6alkyl, cycloalkylC3-C? -Q -alkylCo-C6, cycloalkenylC3-C? or Q-C0-C6alkyl, C6alkyl-C6arylC6-C? 2-Q-alkylCo-Ce, arylC6-C? or alkylC? -C6-Q-alkylCo-C6, alkyl-het-C0 -C6-Q-C0-C6alkyl, C0-C6alkyl-Q-het-C0-C6alkyl, -alkyl-C0-C6-Qalkyl-C6alkyl, C0-C6alkyl-Q-arylC6-Ci2 and C? -Calkyl -Q. Rc is selected from hydrogen and Ci-Cio alkyl, C2-C al alkenyl, C2-C alqu alkynyl, C3-Cn cycloalkyl, C3-C10 cycloalkenyl, C?-C6 alkyl, C6-C ?2 aryl, aryl Cβ-Cι, C alquilo-C 6 alkyl, C 1 -C 6 -alkyl-het alkyl, C 6 -C 12 aryl and het, substituted or unsubstituted, wherein the substituents 1-3 hydroxy, halo (F, Cl, Br, I), CF 3, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro and amino; Rd is selected from the group OH, OCF3, ORc, SRm, halo (F, Cl, Br, I), CN, isocyanate, N02, CF3, C0-C6 alkyl-NRnRn ', C0-C6 alkyl (= 0) -NRnRn ', C0-C6-C alkyl (= 0) -Ra, C? -C8 alkyl, C? -C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, alkyl C6-C6-phenyl, C6-C6-phenyl alkyl, C6-C6alkyloxycarbonyl, C0-C6alkyloxy phenyl, C6-C6alkyl, C6-C6alkyl, -hetS02, aryl -0-C6- C? 2, aryl -S02-C6-C12, alkyl -S02-C? -C6 and het, wherein any alkyl, alkenyl or alkynyl can be optionally 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), C 1 -C 6 alkyl, Ci-Ce alkoxy, nitro and amino; Rm is selected from SC? -C6alkyl, C (= 0) -C? -C6alkyl, C (= 0) -NRnRn ', Ci-Ce alkyl, halo (F, Cl, Br, I) -C? -C6 alkyl, benzyl and phenyl; Rn is selected from the group Rc, NH-C (= 0) -0-Rc, NH-S02-Rs, NH-S02-NH-C (= 0) -Rc, NH-C (= 0) -NH-S02 -Rs, C (= 0) -0-Rc, C (= 0) -Rc, C (= 0) -NHRc, C (= 0) -NH-C (= 0) -0-Rc, C (= 0) -NH-C (= 0) -Rc, C (= 0) -NH-S02-Rs, C (= 0) -NH-S02-NHRs, S02-Rs, S02-0-Rs, S02-N (RC) 2, S02-NH-C (= 0) -0-Rc, S02-NH-C (= 0) -0-Rc and SO2-NH-C (= 0) -Rc; Rn 'is selected from the group of hydrogen, hydroxy and alkyl Ci-Cn, alkoxy Ci-Cii, alkenyl C2-C? 0, alkynyl Ci-Cio, cycloalkenyl C3-Cn, cycloalkenyl C3-C10, alkyl d-C6-aryl C6 -C? 2, aryl C6-C? 0- C? -C6 alkyl, C6-C? Aryl or C0-C6 alkyloxy, C12-C6 alkyl-het, C? -C6 alkyl, C6-C2 aryl , het, C 1 -C 6 alkylcarbonyl, C 1 -C 8 alkoxycarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkoxycarbonyl. C 1 -C 9 aryloxycarbonyl, C 1 -C arylaxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkysulfonyl, heteroarylsulfonyl, C 1 -C 6 alkylsulfonyl and C 6 -C 0 arylsulfonyl, substituted or unsubstituted, wherein the substituents on any alkyl, alkenyl or alkynyl can optionally substituted with 1-3 hydroxy, halo (F, Cl, Br, I), CF3, Ci-C6 alkyl, C6-C6 alkoxy, nitro and amino; Rn and Rn 'taken together with the common nitrogen to which they are placed can be from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl and pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4-tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl wherein the substituents are 1-2 hydroxy, halo (F, Cl, Br, I), CF 3, C 1 -C alkyl, C 1 -C 6 alkoxy, nitro and Not me; Rs is a substituted or unsubstituted group selected from Ci-Cβ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C6 cycloalkenyl, C0-C6 alkyl-phenyl, Co-C-phenyl alkyl, C0-C6 alkyl-het and C0-C6-het alkyl, wherein the substituents are 1-3-hydroxy, halo (F, Cl, Br, I), CF3, C?-C6 alkyl, C alco-Cß alkoxy, nitro and amino; 15 T is U-W; Y pharmaceutically acceptable salts thereof.

5. The method according to claim 4, characterized in that and Y are selected from the group CH, CR and N Z1 is selected from the group O, S, NH and NRn; 25 ¿Ü ^^^^ J ^^ n is O- 3; R2 and R- are each independently Rc Ra 'is selected from the group hydrogen, halo (F, Cl, Br, I), cyano, isocyanate, carboxy, carboxyCi-Cn alkyl, amino, amino-C? -8-alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy , formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanate, hydroxy, Ci-Cβ alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, hyperazinyl, piperinidyl, pyrrolinyl, imidazolyl and indolyl; Ra "is hydrogen or a substituent or non-substituent of the selected group of Alkyl-hetC0-C? Or, Ci-Cio alkyl, C2-Cio alkenyl, C2-C20 alkynyl, IOC3-C11 cloalk, C3-C3 cycloalkenyl or C6-C6 alkyl? C6-C6-arylC6-Ci2 and C6-C6alkyl or -C6-C6alkyl, wherein the substituents are 1-3-hydroxy, halo (F, Cl, Br, I), CF3, C6-C6alkyl, C0-alkoxy -C10, nitro and amino; Rd is selected from the group OH, OCF3, ORc, SRm, halo (F, Cl, Br, I), CN, isocyanate, N02, CF3, C0-C6 alkyl-NRnRn ', C0-C6 alkyl (= 0) -NRnRn ', C 0 -C 6 -alkyl (= 0) -R, C 1 -C 8 alkyl, C 1 -C 6 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, alkyl -C6-phenyl, C6-C6-phenyl alkyl, C6-C6-alkyloxycarbonyl, Co-C3-phenyl-alkyloxy, Ci-C3-alkyl, C6-C6-alkyl, -hetS02, aryl-0-C6-C 2, aryl -S02-C6-C12, alkyl -S02-C? -C6 and het, wherein any alkyl, alkenyl or alkynyl can be optionally substituted with 1-3 groups selected from OH, halo (F, Cl, Br , I), nitro amino and aminocarbonyl and the substituents in any aryl or het are 1-2 hydroxy, halo (F, Cl, Br, I), C? -C6 alkyl, Ci-C? Alkoxy, nitro and amino; Rm is selected from SC? -C6alkyl, C (= 0) -C? -C6alkyl, C (= 0) -NRnRn ', alkylC? -C6, halo (F, Cl, Br, I) -C? -C6 alkyl , benzyl and phenyl; Rn is selected from the group NH-C (= 0) -0-Ra '' NH-C (= 0) -Ra NH-C (= 0) - NHRa, NH-S02-Rs, NH-S02-NH-C (= 0) -Ra, NH-C (= 0) -NH- S02-Rs, C (= 0) -O-R6 C (= 0) -R £ C (= 0) -NHR £ C (= 0 ) -NH-C (= 0) -0-R £ C (= 0) -NH-C (= 0) -Ra 'C (= 0) NH-S02-Rs, C (= 0) -NH-S02 -NHRs, S02-Rs, S02-0-Rs, S02- N (R) 2, S02-NH-C (= 0) -0-Ra, SO2-NH-C (= 0) -O-Ra " R is selected from the group of hydrogen, hydroxy and substituted or unsubstituted Ci-Cn alkyl, Ci-C alkoxy, C2-C10 alkenyl, C1-C10 alkynyl, C3-C11 cycloalkenyl, C3-C10 cycloalkenyl, C6-C6 alkyl - aryl C6 ~ C? 2, aryl C6-C? 0- alkyl C? ~ C6, aryl Ce-Cio alkyloxy 15 Co-Cβ, C 1 -C 4 alkyl, C 1 -C 7 alkyl, C 6 -C 2 aryl, het, Ci-Ce alkylcarbonyl, C 1 -C 8 alkoxycarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkoxycarbonyl, aryloxycarbonyl Ce - Cu, arylalkoxycarbonyl C -Cn, Heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C 1 -C 6 alkylsulfonyl and C 1 -C 6 arylsulfonyl, substituted or unsubstituted, wherein the 25 substituents on any alkyl, alkenyl The alkyl or alkynyl can optionally be substituted with 1-3 hydroxy, halo (F, Cl, Br, I), CF 3, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro and amino; Rn and Rn 'taken together with the common nitrogen to which they are placed can be from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl and pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, , 2,3,4-tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl wherein the substituents are 1-2 hydroxy, halo (F, Cl, Br, I), CF3, Ci-C6 alkyl, C6-alkoxy, nitro and not me; Rs is a substituted or unsubstituted group selected from C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C6 cycloalkenyl, C0-C6 alkyl-phenyl, Co-Cß-phenyl alkyl, alkyl-het Co-Cß and C0-C6-het alkyl, wherein the substituents are 1-3-hydroxy, halo (F, Cl, Br, I), CF3, C-C-alkyl, alkoxy-Ci-Ce, nitro and Not me; U is an optionally substituted bivalent radical selected from the group C-C6 alkyl, C0-C6-C-alkyl, C2-C6-Q alkenyl and C-C-Q alkynyl, wherein the substituents in any alkyl, alkenyl or alkynyl are 1-3 Ra; Q is absent or selected from the group; -S02-N (Rn) -, -N (Rn) -, -N (Rn) -C (= 0) -O, -N (Rn) -S02-, -C (= 0) -N (Rn) -, C (= 0) -0-, -C (= 0) -0-, -C (= 0) - and -C (= 0) -H (Rn) -; W is selected from the group hydrogen, -0R °, -SR, -NRnRn ', -NH-C (= 0) -0-Rc, -NH-C (= 0) -NRnRn', -NH-C (= 0 ) -Rc, -NH-S02-Rs, -NH-S02-NRnRn ', -NH-S02-NH-C (= 0) -Rc, -NH-C (= 0) -NH-S02-Rs, - C (= 0) -NH-C (= 0) -0-Rc, -C (= 0) -NH-C (= 0) -Rc, -C (= 0) -NH-C (= 0) - NRnRn ', -C (= 0) -NH-S02-Rs, -C (= 0) -NH-S02-NRnRn', -C (= S) -NRnRn ', -S02-Rs, -S02-0- Rs, -S02-NRnRn ', -S02-NH-C (= 0) -0-Rc, -S02-NH-C (= 0) -NRnRn', -S02-NH-C (= 0) -Rc, -OC (= 0) -NRnRn ', -0-C (= 0) -Rc, -0-C (= 0) -NH-C (= 0) -Rc, -OC (= 0) -NH-S02 -Rs and -0-S02-Rs; and pharmaceutically acceptable salts thereof.

6. A method of treating or alleviating a mediated mammal having a disorder mediated through the CD11 / CD18 family of cell adhesion molecules, characterized in that it comprises the step of administering a pharmacologically effective amount of a compound represented by the formula: where D is selected from the group where Y1 is selected from the group NRn, CH and CRC Y2, and Y5 are selected from the CH and CRC group is selected from the group NRn, 0 and S n is 0-3; Lx is selected from the group of C2-C5 alkylene, C3-C6 cycloalkylene, C0-C3 alkylene-NRn- (C = 0) -C0-C3 alkylene, -C0-C alkylene- (C = 0) -NRn-C0-C3 alkylene, alkylene-Co -C3-0-C0-C3 alkylene, alkylene-Co-C3-NRn-alkylene-Co-C3, alkylene-Co-C3- (C = 0) -alkylene-Co-C3, alkylene-Co-C3-S ( O) o-2-alkylene-Co_C3, C0-C3-alkylene-NRn-S? 2- C0-C3 alkylene, alkylene-Co-C3-S02-NRn-alkylene-Co-C3, alkylene-Co-C3- CR1 = CR2-C0-C3-alkylene, C3-C3-C-alkylene-C-C3-alkylene, and C3-C3-het-alkylene-Co-C3 alkylene wherein the substituents are selected from group one to three of R1, R2 and R3; is selected from the group, substituted or unsubstituted C 1 -C 2 alkylene, C 0 -C 2 alkylene-NR n- (C = 0) -alkylene-Co-C 2, C 0 -C 2 alkylene- (C = 0) -NRn-alkylene-Co-C 2 -alkylene-Co- C2-0-alkylene-Co-C2, C0-C2-alkylene-NRn-alkylene-Co-C2, C0-C2-alkylene- (C = 0) -alkylene-Co-C2, C0-C3-S-alkylene ( O) o-2-alkylene-Co-C3, alkylene-C0-C3-NRn-alkylene-Co-C3 and alkylene-C0-C2-aryl-alkylene-Co-C2 wherein the substituents are selected from group one to three of R1, R2 and R3; R1, R2 and R3 are selected from the group hydrogen-C?-C8-hydroxy halo (F, Cl, Br, I), halo (F, Cl, Br, I) -alkyl-C? -C8, cyano, isocyanate, carboxy, carboxy-C-alkyl? -C6, amino, amino-C-C8-amino, ino-di (C-C8-alkyl), aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, nitro, imide zoyl, ureido, thioureido, thiocyanate, hydroxy, alkoxy-Ci-Cβ, mercapto, sulfonamido, phenoxy, phenyl, and benzamido; select from the group hydrogen, halo (F, Cl, Br, I), cyano, isocyanate, carboxy, carboxy-C-C6-alkyl, amino, amino-C-C8-alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy , azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C6-C6 alkoxy, mercapto, sulfonamido, alkylsulfonyl-Ci-Cß, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl, imidazolyl and indolyl; select from hydrogen and from, replaced or replaced, alkyl-C? -C? o. C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkenyl, C 1 -C 6 alkyl-C 6 -Ci 2 alkyl, C 6 -C 6 alkyl -α-C?-C6 alkyl, C--Cß-het-alkyl, C he-C he-C he-C he-aryl, C Ci-C? 2alkyl, C--C--C--alkyl, C2-C al-alkenyl, alkynyl- C2-C? O_0-, cycloalkyl-C3-Cn-0-, cycloalkenyl-C3-C? O-0-, alkyl-C? -C6-aryl-C6-C? 2-0-, aryl-Ce-Cio -alkyl-Ci-Cβ-O-, C 1 -C 6 -het-0-, het-C 0 -C 6 -alkyl-C 6 -C 2 -alkyl, C -C-alkyl o-NRn-, C2-C-alkenyl or -NRn-, alkynyl-C? -Cio-NRn-, C3-Cn-NRn- cycloalkyl, -C3-C- or -NRn- cycloalkenyl, C-alkyl? -C6-aryl-C6-C? 2-NRn-, aryl-C6-C? Or -alkyl-C? -C6-NRn-, alkyl-Ci-C? -het-NRn-, het-alkyl-C0-C6 -NRn-, aryl-C6-C? 2-NRn- and het, wherein the substituents in any alkyl, alkenyl or alkynyl are 1-3 of Ra and the substituents in any aryl or het are 1-3 Rd; het is selected from the group Rp and Rd are independently selected from the group: OH, CN, N02, halo (F, Cl, Br, I), ORn, SRn, SORn, CF3, Rc, NRnRn ', NRnC (= 0) -0-Rn', NRnC (= 0) -Rn ', alkyl-C0-C6-S02-Rn, alkyl-C0-C6-SO2-NRnRn ', C (= 0) -Rn, 0-C (= 0) -Rn, C (= 0) -0-Rn and C (= 0) -NRnRn ', Rd is a chemical bond where het is a divalent linking group; Rn and Rn 'are independently selected from the group Hydrogen-Ci-Cd alkyl, halo (F, Cl, Br, I) -C 0 -6 alkyl, C 1 -C 6 -het, het-C 1 -C 6 aryl C 6 -Cl 2, and het; Rz is a substituted or unsubstituted group selected from hydroxy, alkoxy-Ci-Cn, cycloalkoxy-C3-Ci2, aralkoxy-C8-Ci2, arcycloalkoxy-C8-Ci2, aryloxy-C6-C? or, alkylcarbonyloxyalkyloxy-C3-C? or, alkoxycarbonyloxyalkyloxy-C3-C? o, alkoxycarbonylalkyl-C-C6-, cycloalkylcarbonyloxyalkyloxy-C5-C6-, cycloalkoxycarbonyloxy-C5-C6- or cycloalkoxycarbonylalkyl-C5-C6-, aryloxycarbonylalkyl-C8-C2-, aryloxycarbonyloxyalkyloxy-C8-Ci2, arylcarbonyloxyalkyloxy-C8- Ci2, alkoxyalkylcarbonyloxyalkyloxy-C5-C? Or, (Rn) (Rn) N (alkoxy-C? -C? O) -, where the substituents in any alkyl, alkenyl or alkynyl are 1-3 Ra and the substituents in any aryl or het are 1-3 Rd; Q is absent or is alkyl I0-C0-C3 with a selected group of N (Rn) -, -N (Rn) -C (= 0) -, -N) Rn) -C- (= 0) -O-, -N (Rn) -C (= 0) -N (Rn) ) -, -N (Rn) -S02-, -C (= 0) -, -OC (= 0) -N (Rn) -, -C (= 0) -N (Rn; V is absent or is an optionally substituted bivalent group selected from alkylene-Ci-Cn, alkylene-Co-C3-0-alkylene-C0-C3, alkylene-C2-C6, alkylene-Co-C2-0-alkylene-C2-C4, cycloalkylene-C3-C8, aryl-C6- C0-C6-C6-alkylene, C0-C6-C6-C6-C6-C6 alkyl, and C0-C6-C6-alkyl; where the substituents in any alkyl are 1-3 Ra and the substituents in any aryl or het are 1-3 Rd; is C0-C3 alkyl substituted with a group selected from Ra, NH-C (= 0) -NRnRn ', NH-C (= 0) -R c, C (= 0) -R c, C (= 0) -NH-C (= 0) -R c, C (= 0) -NH-C (= 0) -NRnRn ', C (= 0) -NH-S02-Rc, C (= 0) -NH-S02-NRnRn', C (= 0) NRnRn ', NH-C (= 0) -Rc and Rc and pharmaceutically acceptable salts thereof.

7. The method of claim 6 wherein the compound is selected from the group where D is selected from the group where Y1, Y2, Y3, Y4 and Y5 are selected from the group CH and CRd; is selected from the group NRn, 0 and S n is 0-3; Lx is selected from the group of C2-C5 alkylene, C3-C6 cycloalkylene, C0-C3 alkylene-NRn- (C = 0) -C0-C alkylene, C0-C3-cyano- (C = O) -NRn-C0-C3 alkylene, alkylene- Co-C3-0-alkylene Co ~ C3, alkyl-Co-C3-NRn-alkylene-Co-C3, alkylene-C0-C3- (C = 0) -alkylene-C0-C3, alkylene-Co ~ C3 -S (O) 0-2 ~ alkylene-Co-C3, C0-C3-alkylene-NRn-S02-C0-C3 alkylene, -C0-C3-S-alkylene-2-NRn-alkylene-Co-C3, alkylene -C0-C3-CR1 = CR2-alkylene-C0-C3, alkylene-Co-C3-C = C-alkylene-C0-C3, and alkylene-Co-C3-het-alkylene-Co-C3 wherein the substituents are selected from group one to three of R1, R2 and R3; is selected from the group, replaced not replaced alkylene-C0-C, alkylene-C0-C2-NRn- (C = 0) -alkylene-C0-C2, alkylene-C0-C2- (C = 0) -NRn-alkylene-C0-C2- alkylene-C0- C2-0-alkylene-Co-C2, alkylene-Co-C2-NRn-alkylene-Co-C2, alkylene-C0-C2- (C = 0) -alkylene-C0-C2, alkylene-Co-C3-S (O) o-2-alkylene-C0-C3, alkylene-Co-C3-NRn-alkylene-Co-C3 and alkylene-Co-C2-aryl-alkylene-Co-C2 wherein the substituents are selected from group one to three of R1, R2 and R3; R1, R2 and R3 are selected from the group hydrogen-C? -C8-hydroxy halo (F, Cl, Br, I), halo (F, Cl, Br, I) -alkyl-C? -C8, cyano, isocyanate, carboxy, carboxy-alkyl-Ci- Cn, amino, amino-C-C8-amino, di-amino (C-C8-alkyl), aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanate, hydroxy , C6-C6 alkoxy, mercapto, sulfonamido, phenoxy, phenyl, and benzamido; select from the group hydrogen, halo (F, Cl, Br, I), carboxy, amino, amino-C-C8-alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, imide zoyl, ureido, hydroxy, alkoxy-C? C6, sulfonamido, het, phenoxy, and phenyl, Rc is selected from hydrogen and, substituted or unsubstituted, a 1 qui 1 o - C i -Cio, C2-C2 alkenyl or C2-C2 alkynyl, C3-C3 cycloalkyl, C3-C3 cycloalkenyl, or C6-C6-aryl-C6 alkyl -Ci2, C6-C6alkyl or C6alkyl, Ci-C4alkyl, hetCalkyl, C6alkyl, Ci-Cioalkyl, Alkenyl -C2-C ?o, alkynyl-C2-C? O_0-, cycloalkyl-C3-Cn-0-, cycloalkenyl-C3-C? O-0-, alkyl-C? -C6-aryl-C6-Ci2-0 -, 25 aryl-C6-C? O-alkyl-C? -C6-0-, - - - - - - - - C - C - C6 - het - 0 -, - C - C6 - C - C6 - C6 - C - 2 - C - alkyl, - C - C - alkyl ? -NRn-, C2-C? -O-NRn-, C2-C? -CN alkynyl-NRn-, C3-Cn-NRn-, cycloalkenyl-C -C? 0 -NRn-, alkyl- cycloalkyl- C6-C6-aryl-C6-Ci2-NRn-, aryl-Ce-Cio-alkyl-Ci-Ce-NR "-, C-C6-het-NRn-, het-C0-C6-alkyl- NRn-, aryl-C6-C? 2-NRn- and het, wherein the substituents in any alkyl, alkenyl or alkynyl are 1-3 of Ra and the substituents in any aryl or het are 1-3 Rd; het is selected from the group Rp and Rd are independently selected from the group: OH, CN, N02, halo (F, Cl, Br, I), ORn, SRn, SORn, CF3, Rc, NRnRn ', NRnC (= 0) -0-Rn', NRnC (= 0) -Rn ', alkyl-C0-C6-SO2-Rn, alkyl-Co-C6-S02-NRnRn ', C (= 0) -Rn, 0-C (= 0) -Rn, C (= 0) -0-Rn and C (= 0) -NRnRn ', Rd is a chemical bond where het is a divalent linking group; Rn and Rn 'are independently selected from the group hydrogen, hydroxy, alkyl-Ci-Ce, and halo (F, Cl, Br, I) - C -C6 alkyl, V is absent or is an optionally substituted bivalent group selected from alkylene-Ci-Ce, C 0 -C 3 alkylene-alkylene-Co-C 3, C 6 alkylene, C 0 -C 2 alkylene-C 2 -C alkylene, C 3 -C 8 cycloalkylene, C 1 -C 8 alkylene C6-arylene-C6-C? O and alkylo-Co-Ce-het; where the substituents in any alkyl are 1-3 Ra and the substituents in any aryl or het are 1-3 Rd; W is selected from the group hydrogen, NH-C (= 0) -NRnRn ', NH-C (= 0) -Rc, C (= 0) -NH-C (= 0) -Rc, C (= 0) -NH-C (= 0) -NRnRn ', C (= 0) -NH-S02-Rc, C (= 0) -NH-S02-NRnRn', C (= 0) NRnRn ', NH-C (= 0) -Rc and Rd; Y pharmaceutically acceptable salts thereof

8. The method according to claim 6, characterized in that the compound is selected from the group where R1, R2, R3, R4 and R are selected from the group hydrogen-C-C8 alkyl-C-C8-hydroxy halo (F, Cl, Br, I), halo (F, Cl, Br, I) -alkyl-C? -C8, amino, amino-C-C8-alkyl, aminocarbonyl-alkyl-Co-C-amino-di (C-C8-alkyl), carboxamido, carbamoyl, carbamoyl loxi, formyl, formyloxy, ureido , hydroxy, alkoxy-Ci-Ce, phenyl, and phenoxy, select from the group hydrogen, halo (F, Cl, Br, I), cyano, isocyanate, caboxy, ammo, amino-alkylo-C? ~ C8, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, imidazoyl, ureido, hydroxy, alkoxy-Ci-Cß, sulfonamido, phenoxy, and phenyl, select from hydrogen and from, replaced or replaced, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 8 alkynyl, C 3 -C 3 cycloalkyl, C 3 -C 6 cycloalkenyl, C 6 -C 6 aryl-C 6 alkyl C 2, C 6 -C 6 alkyl, or C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 -alkyl, C 6 -C 6 aryl, C 1 -C 6 alkyl. or-0-, C2-C- or C-0- alkenyl, C2-C- or C-0- alkynyl, C3-Cn-0- cycloalkyl, C3-C- or C-cycloalkenyl-0-, C-alkyl C6-aryl-C6-C? 2-0-, aryl-C6-C? O-alkyl-C? -C6-0-, alkyl-C? -C6-het-0-, het-alkyl-Co -Cd-O-aryl-C6_Ci2-0-, C-C-alkyl or -NRn-, C2-C-alkenyl-0-NRn-, C2-C alkynyl-0-NRn-, C3-cycloalkyl- Cn-NRn-, C3-C-cycloalkenyl or -NRn-, C6-C6-C6-aryl-C6-C2-NRn-, C6-C6-aryl-C-C6-NRn-alkyl - C 1 -C 6 -het-NR n-, het-C 0 -C 6 -NR n-, C 6 -C 12 -NR n- and het alkyl, wherein the substituents on any alkyl, alkenyl or alkynyl are 1- 3 of Ra and the substituents in any aryl or het are 1-3 Rd; Rc is independently selected from the group OH, alkyl-Ci-Cß, halo (F, Cl, Br, I), N02, Cyan, ORn, SRn, SORn, CF3, Rc, NRnRn ', NRnC (= 0) -0-Rn', NRnC (= 0) -Rn ', alkyl-Co-C6-S02-Rp, alkyl-CO-C6-SO2-NRnRn', C (= 0) -Rn, 0-C (= 0) -Rn, C (= 0) -0-Rn and C (= 0) -NRnRn ', het is selected from the group R and R are independently selected from the group hydrogen, hydroxy, C 1 -C 6 alkyl, and halo (F, Cl, Br, I) - C 1 -C 6 alkyl, halo is selected from the group F and Cl; Z1 is selected from the group NRn, O and S; n is 0-3; and pharmaceutically acceptable salts thereof.

9. The method according to claim 6, characterized in that the adhesion receptor is selected from LFA-1 (CDlla / CDl8) and Mac-1 (CDllb / CD18).

10. The method according to claim 9, characterized in that the adhesion receptor is LFA-1.

11. The method according to claim 6, characterized in that the immune disorder is selected from the group; rejection of or by a host graft, psoriasis, rheumatoid arthritis, asthma, multiple sclerosis.

12. The method according to claim 6, characterized in that it additionally comprises administering an effective amount of an immunosuppressive agent to the mammal.

13. The method according to claim 6, characterized in that it additionally comprises administering an effective amount of a VLA-4 antagonist to the mammal.

14. The method according to claim 10, characterized in that 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 intra-nasally.

15. The method according to claim 6, characterized in that the mammal is a human.