AU2007257959A1 - Therapy using cytokine inhibitors - Google Patents

Description

WO 2007/146712 PCT/US2007/070547 THERAPY USING CYTOKINE INHIBITORS FIELD OF THE INVENTION [0001] The present invention relates to methods of treating, preventing, modifying and managing cytokine-mediated disorders or related disorders, which comprise the administration of a compound, such as a cytokine inhibitor, alone or in combination with known therapeutics. The invention also relates to pharmaceutical compositions and dosing regimens using the disclosed compounds. In particular, the invention relates to the use of compounds as disclosed herein, optionally in conjunction with other therapies, for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, and cancer. BACKGROUND OF THE INVENTION [0002] The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Some cytokines promote inflammation and are called pro-inflammatory cytokines, whereas other cytokines suppress the activity of pro-inflammatory cytokines and are referred to as anti inflammatory cytokines. For example, IL-4, IL-10, and IL-13 are potent activators ofB lymphocytes, but are also potent anti-inflammatory agents. They are anti-inflammatory cytokines by virtue of their ability to suppress genes for pro-inflammatory cytokines such as IL-1, TNF, and chemokines (C.A. Dinarello, Chest. 2000, 118, 503-508). [0003] Unregulated activities of these mediators can lead to the development of serious inflammatory conditions. For example, autoimmune diseases arise when immune system cells (lymphocytes, macrophages) become sensitized against the "self'. Lymphocytes as well as macrophages are usually under control in this system. However, a misdirection of the system toward the body's own tissues may happen in response to still unexplained triggers. One hypothesis is that lymphocytes recognize an antigen which mimics the "self' and a cascade of activation of different components of the immune system takes place, ultimately leading to tissue destruction. Genetic predisposition has also been postulated to be responsible for autoimmune disorders.

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WO 2007/146712 PCT/US2007/070547 [0004] Tumor necrosis factor-a (TNF- a) and interleukin-1 (IL-1) are pro inflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses. Overproduction of cytokines such as IL-I and TNF-a is believed to underlie the progression of many inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure, and psoriasis among others (Dinarello, C.A. et al., Rev. Infect. Diseases 1984, 6, 51; Salituro et al., Curr. Med. Chem. 1999, 6, 807; Henry et al., Drugs Fut. 1999, 24,1345). Recent data from clinical trials support the use of protein antagonists of cytokines, for example soluble TNF-a receptor fusion protein (etanercept) (Moreland et al., Ann. Intern. Med. 1999, 130, 478) or the monoclonal TNFa antibody (infliximab), for the treatment of rheumatoid arthritis, Crohn's disease, juvenile chronic arthritis and psoriatic arthritis (Rankin et al., Br. J. Rheumatol. 1995, 34, 334; Galadari et al. Int J Dermatol. 2003, 42,231; Reimold, Am J Med Sci. 2003, 325(2), 75). Thus, the reduction of pro-inflammatory cytokines such as TNF-a (also referred to as TNFa) and interleukin-lf3 (IL-lb) has become an accepted therapeutic approach for potential drug intervention in these conditions. SUMMARY OF THE INVENTION [0005] In one aspect of the invention, there is provided a method of treating a disorder mediated by one or more cytokines, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compoundas described herein, for example, a cytokine inhibitor. In some embodiments, the cytokine is selected from TNFa, IL-1, IL-6, IL-8, GM-CSF, and IFN-gamma, or a combination of any two or more thereof. In others, the cytokine is TNFa or IL-1. In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein. [0006] In some embodiments of the invention, the disorder is or results from abnormal bleeding, an abscess, actinic reticuloid syndrome, acute confusional migraine, acute confusional senile dementia, acute hepatocellular injury, acute tubular necrosis, adenohypophyseal diseases, adenovirus infections, adhesions, adhesive capsulitis, adnexitis, agammaglobulinemia, allergy, alopecia, fibrosing alveolitis, amyloidosis, angioplasty, angor pectoris, antiphospholipid syndrome, arteriosclerotic dementia, arteritis temporal, arthropod-borne encephalitis, asphyxia, atopic hypersensitivity, atrial 2 WO 2007/146712 PCT/US2007/070547 fibrillation, beaver fever, biliary cirrhosis, bone loss, bronchiolitis, cancer of endocrine gland, cancer of larynx, candidiasis, small cell lung carcinoma, cardiac hypertrophy, cardiac surgery, cardiomegaly, carditis, carotid angioplasty, carotid endarterectomy, carotid stents, carotid ulcer, celiac disease, cirrhosis, colitis, colitis granulomatous, coronary artery bypass graft, coronary artery bypass surgery, cortical cataracts, corticosteroid-resistant asthma, degenerative joint disease, dermatitis, diarrhea, erectile neuropathy, erectile vasculopathy, (particularly diabetic erectile neuropathy and vasculopathy) dry eye, dyslipidemia (including hyperlipidemia (increased lipids), hypercholesterolemia (increased cholesterol), hyperglyceridemia (increased glycerides), hypertriglyceridemia (increased triglycerides), hyperlipoproteinemia (increased lipoproteins), hyperchylomicronemia (increased chylomicrons), combined hyperlipidemia (increased LDL and triglycerides), familial hypercholesterolemia (hypercholesterolemia due to a defect on chromosome 19 (19p13.1-13.3)), hypolipoproteinemia (decreased lipoproteins), hypocholesterolemia (decreased cholesterol), abetalipoproteinemia (decreased beta lipoproteins), and Tangier disease (decreased high density lipoprotein)), dyspnea, edema, end-stage renal disease, epstein-barr virus infections, fever, follicular thyroid carcinoma, gastroenteritis, heart attack, heart bypass surgery, heart surgery, heart transplantation, hepatitis A, hepatitis B, hepatitis C, chronic hepatitis, insulin resistance, kidney failure, kidney transplantation, adult chronic leukemia, liver cirrhosis, liver transplantation, meningitis, bacterial meningitis, myeloproliferative disorders, myopathies, myositis, neonatal-onset multisystem inflammatory disease, nephritis, neuromuscular disorders, neuropathy, obliterative bronchiolitis, oral cancer, percutaneous coronary intervention, periodontal bone loss, peripheral nerve disorders, neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, posterior capsular opafication, pruritus (including ocular, skin and general pruritus), pulmonary fibrosis, renal cancer, renal dialysis, scleroderma, septic arthritis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, sympathetic opthalmia, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's granulomatosis. [0007] In another aspect of the invention, there are provided methods of reducing levels of a cytokine in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to reduce a level of a cytokine relative to the level prior to administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, 3 WO 2007/146712 PCT/US2007/070547 solvate, prodrug, or pharmaceutically acceptable salt thereof In some embodiments, the reduction in cytokine levels is at least 10%, at least 30%, at least 50%, or at least 90%. In some embodiments the subject suffers from, or is at risk for a cytokine-mediated disorder, as described herein. In some embodiments, the cytokine is selected from TNFa, IL-I, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof In others, the cytokine is TNFa or IL-1. In some embodiments, the cytokine level is measured in the subject or samples from the subject, e.g., tissue or bodily fluids such as the subject's blood. In others, cytokine level is measured in the subject's synovium. In still others, the cytokine level is measured in the subject's skin. In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein. [0008] In yet another aspect of the invention, there are provided methods of reducing the level of a cytokine released from a cell in response to a pro-inflammatory stimulus. The methods comprise exposing a cell to an amount of a compound, such as a cytokine inhibitor, effective to reduce the level of cytokine released from the cell in response to a pro-inflammatory stimulus relative to the level of released cytokine prior to contacting the cell with the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof In some embodiments, the reduction in cytokine levels is at least 10%, at least 30%, at least 50%, or at least 90%. In some embodiments, the pro-inflammatory stimulus results from the presence of TNFa, IL-1, IL-6, IL-8, GM-CSF, IFN-gamma, LPS, or a combination of any two or more thereof In other embodiments, the cytokine level is the level of TNFa, IL-1, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof In some embodiments of the invention, the method further includes exposing the cell to additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein. [0009] In yet another aspect of the invention, there are provided methods of inhibiting p3 8 activity. The methods comprise contacting p38 with an amount of a compound, such as a cytokine inhibitor, effective to inhibit p38 activity, the phosphorylation of p 3 8, or both, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof In some embodiments, the inhibition of p 3 8 activity or phosphorylation of p38 is at least 4 WO 2007/146712 PCT/US2007/070547 10%, at least 30%, at least 50%, or at least 90%. In some other embodiments, the p38 is in a subject. In some embodiments, the subject suffers from, or is at risk for, a cytokine mediated disorder as described herein. In some embodiments of the invention wherein the p3 8 is in a subject, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A) to the subject, as described herein. [0010] In another aspect of the invention, there are provided methods of reducing the activity of a pro-inflammatory mediator. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to reduce the activity of a pro-inflammatory mediator relative to the activity prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof In some embodiments, the reduction in pro-inflammatory mediator activity is at least 10%, at least 30%, at least 50%, or at least 90%. In certain embodiments, the subject suffers from or is at risk for a cytokine-mediated disorder as described herein. In some embodiments, the reduction in activity results from a decrease in circulating levels of a pro-inflammatory mediator relative to the circulating levels prior to administration of the compound. In some such embodiments, the decrease in circulating pro-inflammatory mediator level is at least 10%, at least 30%, at least 50%, or at least 90%. In some such embodiments, the pro-inflammatory mediator is a prostaglandin or a leukotriene, or a combination of two or more thereof. In some other embodiments, the reduction in activity results from an inhibition of the production of a pro-inflammatory mediator. In some such embodiments, the inhibition of pro inflammatory mediator production is at least 10%, at least 30%, at least 50%, or at least 90%. In some such embodiments, the pro-inflammatory mediator is a prostaglandin, leukotriene, COX-2, NO-synthase, or a combination of any two or more thereof. In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein. [0011] In another aspect of the invention, there are provided methods of reducing the circulating levels of C-Reactive Protein or Rheumatoid Factor, or both. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to reduce the circulating levels of C 5 WO 2007/146712 PCT/US2007/070547 Reactive Protein or Rheumatoid Factor, or both, in the subject's blood relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the circulating C-Reactive Protein levels before administration are higher than about 2.87 mg/l. In some embodiments, the reduction in circulating level is at least 10%, at least 30%, at least 50%, or at least 90%. In some embodiments, the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In certain embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein, for example, the method further includes administration of methotrexate. [0012] In yet another aspect of the invention, there are provided methods of reducing at least one indicium of rheumatoid arthritis. The methods comprise administering to a subject exhibiting one or more indicia of rheumatoid arthritis, an amount of a compound, such as a cytokine inhibitor, effective to reduce at least one of the indicia to a level below that which exists prior to the administration of the compound, wherein the indicia are selected from erythrocyte sedimentation rate (ESR), number of painful and tender joints, level of joint pain, Ritchie articular index, duration of morning stiffness, joint immobility, joint swelling, and/or circulating C-reactive protein level, and wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein. [0013] Also provided are methods of reducing the number or severity of the clinical signs of psoriasis. The methods comprise administering to a subject exhibiting one or more clinical signs of psoriasis an amount of a compound, such as a cytokine inhibitor, effective to reduce the number or severity of clinical signs of psoriasis relative to those present in the subject prior to the administration of the compound, wherein the clinical signs of psoriasis are the percentage of total body surface area (BSA) affected by psoriasis, psoriasis plaque thickness, level of lymphocytes within psoriatic lesions, epidermal thickness, T-cell infiltration, pathological epidermal hyperplasia, cell-mediated immunity reactions, tetanus antibody response, lymphocyte subpopulations, or any two or 6 WO 2007/146712 PCT/US2007/070547 more thereof, and wherein the cytokine inhibitor is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments of the invention, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A), as described herein. [0014] Combination therapy with other therapeutic ingredients A in the methods of the invention provides a beneficial therapeutic effect, particularly an additive or over additive effect or an overall reduction of side effects of therapy. Such a beneficial therapeutic effect is desirable in the treatment of cytokine-mediated disorders and other methods as described herein. Thus, in one aspect, the invention provides methods that further include administering to a subject one or more, typically one, compound as described herein, for example a cytokine inhibitor, together with one or more, typically one, of the ingredients A described herein. In some embodiments, the methods are for treating cytokine-mediated disorders or conditions. In some embodiments, a combination of any two or more ingredients A are administered with a compound as described herein. An additive or over-additive (e.g., synergistic) effect of the pharmaceutical combinations according to the invention provides for dose reduction, side-effect reduction and/or interval extension when compared to the individual compounds of the invention alone, or ingredient A alone. The effects mentioned above are observed both when the two substances are administered simultaneously in a single formulation and when they are administered successively in separate formulations. In the case of ingredient A being an injectable, especially a biological agent, other benefits of adding a compound as described herein, e.g., a cytokine inhibitor, may be seen, such as, for example, cost reduction by way of interval and/or dose reduction. [0015] A variety of ingredients A are contemplated for use in the combinations of the invention. For example, non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of inflammation, pain and fever, may be used. Such NSAIDs include acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, 7 WO 2007/146712 PCT/US2007/070547 nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and the like, or a combination of two or more thereof. [0016] Angiogenesis inhibitors may serve as ingredient A, such as VEGF inhibitors, taxol, pentoxyfylline and/or thalidomide. [0017] Biological agents shall be understood to mean any natural or artificial/synthetic biological molecule or fragment thereof as known in the art, such as antibodies, proteins, fusion proteins, receptors, nucleic acids, lipids, carbohydrates, and the like. Therefore, ingredient A includes biological agents, such as etanercept, infliximab, alefacept, adalimumab, efalizumab, anakinra, IL-IRA, alpha-interferon, interferon beta I-B, CTLA-4, and other antibodies or receptor constructs directed against TNFa, ILl-6, LFA-1, or C5. [0018] Also within the scope of the invention for ingredient A are steroids, such as glucocorticoids, and vitamin D3 and analogs thereof (cholecalciferols), alone (the latter being used mostly for psoriasis) or in combination. Steroids include budesonide, dexamethasone, fluocinonide, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, prednisone, clobetasone, deflazacort, fluocinolone acetonide, fluticasone, triamcinolone acetonide, mometasone and diflucortolone. Among vitamin D3 derivatives are calcipotriol, tacalcitol, maxacalcitol, and tacalitol, the calciotropic hormones, la,2,5-dihydroxyvitamin D3, and parathyroid hormone-related peptide. [0019] Many types of immunomodulatory, immunosuppressive or cytostatic drugs can be used in combination with cytokine inhibitors as described herein. Exemplary agents include hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, pimecrolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine, cyclophosphamide, macrolides, ascomycin, hydroxyurea, 6 thioguanine, (Orfanos C E., 1999, Cutis 64(5), 347); alefacept, leflunomide, infliximab, etanercept, efalizumab, anti-CD4, anti-CD25, peptide T, LFA3TIP, alicaforsen, DAB 38 , CTLA-41g, anti-CD80, for example IDEC- 114 or ABX-IL8, DAB-IL-2, IL-10, anti-TAC, basiliximab and daclizumab. In addition, agents or therapies which act on other targets or immune mediated products are suitable as the ingredient A. These include, for example, 8 WO 2007/146712 PCT/US2007/070547 inhibitors of protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (EGFR), E-selectin inhibitors, and therapies widely used for psoriasis such as anthralin, coal tar, phototherapies including ultraviolet B (UVB) or psoralens ultraviolet A (PUVA), photodynamic therapy and laser therapy. [0020] Retinoid therapy can also be used as ingredient A. Thus, for example, bexarotene, acitretin, etretinate, tazarotene, hydroxyurea, 6-thioguanine and phototherapies are suitable additional ingredients. (Orfanos C E., 1999, Cutis 64(5), 347; see also Saurat J H., 1999, J.Am.Acad.Derm. 41(3 Pt 2), S2). [0021] Ingredients A useful in the invention further include small molecule inhibitors directed against enzymes involved in signal transduction pathways or to cell adhesion molecules like LFA-1 or ICAM-1. [0022] Statins and HMG-CoA reductase inhibitors may also be employed as ingredients A including, e.g., atorvastatin (LIPITOR, TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR), or simvastatin (ZOCOR, LIPEX). Other ingredients A contemplated for use in methods of the invention include fibrates, such as bezafibrate (e.g., BEZALIP), ciprofibrate (e.g., MODALIM), clofibrate, clinofibrate, gemfibrozil (e.g., LOPID), or fenofibrate; cholesterol absorption inhibitors, such as, ezetimibe (e.g., ZETIA); nicotinic acid; bile acid sequestrants, such as cholestyramine (QUESTRAN) and colestipol (COLESTID); and/or plant sterol-containing products and 03-fatty acids. Also contemplated are the combination of two or more of the above, for example the combination of ezetimibe/simvastatin (VYTORIN or INEGY). Combination therapy with the above ingredients A is contemplated for use in any method of the invention including treatment of the cytokine-mediated disorders and conditions as well as in the methods described in the related applications, U.S. Application No. 10/939,324, International Application PCT/US2006/042679, International Application PCT/US2006/048803, and International Application No. PCT/US2006/006682, each of which is herein incorporated by reference in its entirety. [0023] In another aspect, there are provided the above-mentioned combinations comprising ingredient A and one or more compounds, as described herein, for example, 9 WO 2007/146712 PCT/US2007/070547 cytokine inhibitors, typically in therapeutically effective amounts, for use as pharmaceutical compositions with anti-cytokine activity. Moreover, combinations comprising ingredient A and a compound as described herein can be used for preparing a pharmaceutical composition for the treatment and/or prevention of a cytokine-mediated disorder or condition. The pharmaceutical preparations, containing as the active substance one or more compound combinations comprising ingredient(s) A and the compound(s) as described herein further include the pharmaceutically acceptable derivatives thereof, and may be optionally combined with a conventional excipient, carrier, or combination thereof [0024] In psoriasis, known combination treatments have been effective and are used as rotation therapy for maintenance of remission or if the subject is refractory to usual systemic products. Most of the combinations are with different modes of action either to improve efficacy or to reduce side effects by reduction of the dosage. See Van de Kerkhof, P. 1997 Clinics in Dermatology, 15, 831, which showed the effect of topical steroids or vitamin D with systemic agents. Two combinations which are widely accepted include ultraviolet B (UVB) or psoralens ultraviolet A (PUVA) each optionally administered with retinoids, methotrexate, or the combination of cyclosporine and retinoids. [0025] A typical combination for reducing the number or severity of the clinical signs of psoriasis includes a compound described herein in combination with immunotherapy drugs which include cyclosporine, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T, LFA3TIP, DAB 38 9 , CTLA-41g, E-selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, and those disclosed in Griffiths, Christopher E. M., 1998 Hospital Medicine, 59 No 7, and variants thereof Another typical combination for reducing the number or severity of the clinical signs of psoriasis is a compound as described herein with methotrexate (MTX). It is expected this combination will be effective because of the good tolerability of MTX in the short term and because of the acceptability if maintenance of remission is obtained with good quality of life. Another typical combination for reducing the number or severity of the clinical signs of psoriasis is a compound as described herein with cyclosporine, especially because of cyclosporine's efficiency for induction of remission. Another embodiment of the invention comprises administration in the following sequence: induction with a 10 WO 2007/146712 PCT/US2007/070547 compound described herein and cyclosporine, followed by continuation with the compound after decrease of dosing and discontinuation of cyclosporine. Another typical combination for treating psoriasis is a compound described herein in combination with retinoids. Retinoids provide minimal efficacy with potential Cyt P450 interactions and risk of teratogenicity, and this would be alleviated by continuation of therapy with the compound. Yet another typical combination for reducing the number or severity of the clinical signs of psoriasis is a compound described herein, in combination with ingredients A selected from steroids, such as glucocorticosteroids, vitamin D analogs, retinoids and dithranol. In some such combination treatments, the steroids and retinoids can be administered topically. A more typical combination for reducing the number or severity of the clinical signs of psoriasis is a compound as described herein with vitamin D derivatives, most typically calcipotriol or tacalcitol. Another typical combination for reducing the number or severity of the clinical signs of psoriasis is a compound described herein in combination with macrolides, most typically with ascomycin analogues, administered topically, and even more typically with those available orally such as pimecrolimus. Another typical combination for reducing the number or severity of the clinical signs of psoriasis is a compound described herein in combination with cell adhesion molecule inhibitors, such as anti LFA3, and/or anti LFA1. This includes adhesion molecule blockage by recombinant fusion proteins like alefacept, anti LFA3 IgCl, or by anti-CD1 1 monoclonal antibodies, efalizumab, and the obvious variants thereof. Cell adhesion molecule inhibitors appear to provide an acceptable response rate with limited tolerability problems. Combination with a compound described herein could avoid the disadvantage of their injectable form, with CAM inhibitors being used intermittently. Another embodiment of the invention comprises administration in the following sequence: induction with compound as described herein and CAM inhibitors, followed by maintenance treatment with the compound alone and retreatment with CAM inhibitors in case of significant relapse. [0026] Another typical combination for reducing the number or severity of the clinical signs of psoriasis is a compound as described herein with another anti-TNFa ingredient. A typical embodiment is one wherein the other anti-TNFa ingredient is selected from infliximab or etanercept, typically infliximab. Infliximab is believed to have a higher rate of response for induction of remission, which recently was suggested to be maintained on the long term. Within the scope of the invention is the use of topical or 11 WO 2007/146712 PCT/US2007/070547 general antisense inhibitors of TNFa, such alicaforsen in combination with a cytokine inhibitor compound. Another typical combination for reducing the number or severity of the clinical signs of psoriasis is a compound described herein with anti-CD4, anti-CD80 (IDEC-114 or ABX-IL8), DAB-IL-2, DAB 3 89 -IL-2, CTLA4-Ig, ILl0, the IL-2 receptor inhibitors such as daclizumab (anti-TAC), or basiliximab. (See Tutrone, "Biologic Therapy for Psoriasis, A Brief History, I, " Biologic Therapy for Psoriasis, 2001, 68, 331; Ben-Bassat, "Biological activity of tyrosine kinase inhibitors: Novel agents for psoriasis therapy," Current Opinion in Investigational Drugs, 2001, 2(11), 1539; Salim, et. al., "Targeting interleukin-2 as a treatment for psoriasis," Current Opinion in Investigational Drugs, 2001, 2(11), 1546). [0027] Any of the above mentioned combinations within the scope of the invention may be tested by animal models known in the art. Reference in this regard may be made to: Schon, Michael P. 1999 Animal models of Psoriasis--What can we learn from them, The Society for Investigative Dermatology--Reviews, 112. No. 4, 405. [0028] In rheumatoid arthritis, combination of immunosuppressive or immunomodulatory agents is a long and well established therapeutic paradigm. Combination partners may be selected from various therapeutic entities. Their identification is either based on empirical data supported by evolving knowledge about the underlying mechanisms or based on a well defined mode of action. These agents are generally referred to as Disease Modifying Antirheumatic Drugs (DMARDs) or Slow Acting Antirheumatic Drugs (SAARDs). Apart from the combinations listed below, combination of the cytokine inhibitor, with one or more agents classified as DMARD/SAARD or NSAID and/or steroids, are contemplated in this invention. [0029] A typical combination for reducing at least one of the indicia of rheumatoid arthritis is a compound as described herein combined with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs, such as, for example, hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine or cyclophosphamide. Another typical combination for reducing at least one of the indicia of rheumatoid arthritis is a compound as described herein combined with angiogenesis inhibitors, such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, 12 WO 2007/146712 PCT/US2007/070547 interferon beta-I B and alpha-interferon. Yet another typical combination for reducing at least one of the indicia of rheumatoid arthritis is a compound as described herein in combination with inhibitors of cell adhesion, such as inhibitors of LFA- 1 or inhibitors of ICAM-1. [0030] Another typical combination for reducing at least one of the indicia of rheumatoid arthritis is a compound as described herein combined with anti-TNFa antibodies or TNFa-receptor antagonists such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or biological agents directed against targets such as CD-4, LFA-1, IL-6, ICAM-1, C5, or IL-I receptor. In another embodiment a compound as described herein is combined with infliximab alone or infliximab and methotrexate. Another typical combination for reducing at least one of the indicia of rheumatoid arthritis is a compound as described herein in combination with IL-I receptor antagonists, such as anakinra (KINERET). Yet another typical combination for reducing at least one of the indicia of rheumatoid arthritis is a compound as described herein combined with NSAIDs, including acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and the like. Another typical combination for reducing at least one of the indicia of rheumatoid arthritis is a compound as described herein combined with steroids, such as glucocorticosteroids, for example, betamethasone, dexamethasone, methylprednisolone, prednisolone, and deflazacort. [0031] Any of the above mentioned combinations within the scope of the invention may be tested by animal models known in the art. (See Wooley, P. H. 1998, Animal models of arthritis, in Klippel J. H., Dieppe, P. A., (eds.) Rheumatology, second edition, 5.8.1, Mosby, London, Philadelphia, St. Louis, Sydney, Tokio). [0032] In Crohn's disease, the following groups of drugs combined with a compound as described herein may be effective: steroids such as budesonide, 5-ASA drugs like mesalamine, immunosuppressants, biological agents and adhesion molecule inhibitors. A typical combination for treating Crohn's disease is a compound as described 13 WO 2007/146712 PCT/US2007/070547 herein with one or more of the following: steroids including all those listed herein, 5 ASA, methotrexate and azathioprine. Another typical combination for treating Crohn's disease is a compound described herein combined with IL-1 receptor antagonists, such as anakinra (KINERET). Yet another typical combination for treating Crohn's disease is a compound described herein with anti-TNFa antibodies or TNFa-receptor antagonists, such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA 4, or biological agents directed against targets such as CD-4, LFA-1, IL-6, ICAM-1, or C5. In another embodiment a compound described herein is combined with infliximab and methotrexate. More typically, the compound is a cytokine inhibitor and is combined with infliximab. Another typical combination for treating Crohn's disease is a compound described herein combined with IL- 10, alicaforsen (anti ICAM 1), or antegren (VCAM receptor antagonist). [0033] In another aspect of the invention, there are provided methods of increasing HDL-levels of a subject. The methods comprise administering to a subject an amount of a compound, such as a cytokine inhibitor, effective to increase the HDL-level of the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a p38 inhibitor. In certain embodiments, the subject suffers from or is at risk for a cytokine mediated disorder as described herein. In some embodiments, the HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/ml, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. For example, the HDL level prior to administration is less than about 55 mg/dl. In some embodiments, the HDL is HDL 2 , while in others it is HDL 3 . In other embodiments, the subject has an LDL level less than about 150 mg/ml. [0034] In some embodiments of methods for increasing HDL-levels in a subject, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, 14 WO 2007/146712 PCT/US2007/070547 relative to a subject who is at risk of a vascular event who has not been administered the compound. In still other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. [0035] In some embodiments, the methods of increasing HDL-levels in a subject additionally comprise administration of statins or HMG-CoA reductase inhibitors, such as, atorvastatin (LIPITOR, TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR), or simvastatin (ZOCOR, LIPEX); fibrates, such as, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate, or clinofibrate; bile acid sequestrants, such as, cholestyramine (QUESTRAN); cholesterol absorption inhibitors, such as colestipol (COLESTID), or ezetimibe (ZETIA); niacin; plant sterol-containing products; c3-fatty acids ; or combinations of two or more thereof, for example ezetimibe/simvastatin (VYTORIN or INEGY). In some embodiments, the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. For example, the HDL level of the subject is increased by at least about 12%. [0036] In another aspect, there are provided methods of increasing Apo-A 1-levels of a subject. The methods comprise administering to a subject an amount of a compound, such as a cytokine inhibitor, effective to increase the Apo-Al -level of the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the Apo-Al -level is increased by at least about 5% or by at least about 10%. In some other embodiments, the subject's HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. In other embodiments, the HDL level prior to administration is less than about 55 mg/dl; or the subject's LDL level prior to administration is less than about 150 mg/ml. In some embodiments, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. For example, the vascular event can be a 15 WO 2007/146712 PCT/US2007/070547 cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the cytokine inhibitor. In other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. For example, the HDL level of the subject is increased by at least about 12%. [0037] In another aspect, there are provided methods of decreasing or preventing from increasing the systolic or diastolic blood pressure of a subject in need thereof. The methods comprise administering to a subject an amount of a compound effective to decrease or to prevent from increasing the systolic or diastolic blood pressure of the subject relative to the blood pressure prior to the administration of the compound, wherein the compound is as described herein or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the blood pressure is the systolic blood pressure. In others, the blood pressure is the diastolic blood pressure. In some embodiments, the subject's systolic blood pressure prior to administration is above 140 mm Hg, and the diastolic blood pressure prior to administration of the compound is above 90 mm Hg. In others, the diastolic blood pressure prior to administration of the compound is higher than 85 mm Hg. In some embodiments, the decrease in systolic or diastolic blood pressure, or both, is at least about 5 mm Hg, at least about 3 mm Hg or at least about 2 mm Hg. In some other embodiments, the subject's HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl. In other embodiments, the HDL level prior to administration is less than about 55 mg/dl; or the subject's LDL level prior to administration is less than about 150 mg/ml. In some embodiments, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. For example, the vascular event may be a cardiovascular event or a cerebrovascular event. In some embodiments, the present methods produce a reduction of the occurrence or severity of the vascular event in the subject, relative to a subject who is at risk of a vascular event 16 WO 2007/146712 PCT/US2007/070547 who has not been administered a compound described herein. In other embodiments, the subject is suffering from or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the HDL level of the subject may be increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. For example, the HDL level of the subject is increased by at least about 12%. In other embodiments the HDL level of the subject may be increased by about 5% to about 20%. [0038] Compounds disclosed herein, such as cytokine inhibitors, may be used in combination therapy with one or more anti-hypertensive agents, for example, ACE inhibitors, calcium channel blockers, aldosterone antagonists, angiotensin II antagonists, diuretics, benzothiazepine derivatives, beta blocking agents, dihydropyridine derivatives, potassium-sparing agents, urologicals, sulfonamides, or thiazides. Examples include benazepril, , enalapril, lisinopril, quinapril, captopril, ramipril, spironolactone, olmesartan, valsartan, , telmisartan, valsartan, losartan, irbesartan, diltiazem, verapamil, trandolapril, , atenolol, bisoprolol, metoprolol, toprol, tenoretic, amlodipine, nifedipine, felodipine, nisoldipine, triamterene, furosemide, lasix, prazosin, propanolol, hydrochlorothiazide, or combinations of two or more thereof. [0039] In another aspect, there are provided methods of decreasing or preventing an elevation in PAI-1 levels. The methods comprise administering to a subject at risk for increased PAI- 1 levels (for example in a subject suffering from, or at risk of obesity, metabolic syndrome or inflammatory conditions) an amount of a compound effective to decrease or prevent an elevation in the PAI-l-level of the subject relative to the level in the untreated subject, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. [0040] In another aspect, there are provided methods of decreasing or preventing an elevation in VEGF-levels. The methods comprise administering to a subject at risk of increased VEGF levels (for example in a subject suffering from, or at risk for cancer or inflammation) an amount of a compound effective to decrease or prevent an elevation in the VEGF-level of the subject relative to the level in an untreated subject, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. 17 WO 2007/146712 PCT/US2007/070547 [0041] In yet another aspect of the invention, there are provided methods of decreasing the triglyceride-level of a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the triglyceride-level of the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the triglyceride-level prior to administration is above 500 mg/dl, above 200 mg/dl, or above 150 mg/dl. For example, the triglyceride-level prior to administration is above 200 mg/dl. In certain embodiments, the subject suffers from or is at risk for a cytokine-mediated disorder as described herein. In other embodiments, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. In some embodiments of the invention, the method additionally comprises administration of statins or HMG-CoA reductase inhibitors, such as, atorvastatin (LIPITOR, TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR), or simvastatin (ZOCOR, LIPEX); fibrates, such as, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate, or clinofibrate; bile acid sequestrants, such as, cholestyramine (QUESTRAN); cholesterol absorption inhibitors, such as colestipol (COLESTID), or ezetimibe (ZETIA); niacin; plant sterol-containing products; A3-fatty acids ; or combinations of two or more thereof, for example ezetimibe/simvastatin (VYTORIN or INEGY). In other embodiments, the subject is suffering from, or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the subject is a primate, particularly a human. In some embodiments of the invention, the triglyceride level of the subject is reduced by at least about 10%. In others, the triglyceride level of the subject is reduced by at least about 20%. 18 WO 2007/146712 PCT/US2007/070547 [0042] In yet another aspect of the invention, there are provided methods of decreasing the fasting glucose-level in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the fasting glucose-level in a subject relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the glucose level prior to the administration is above about 130 mg/dl. In others, the glucose level is decreased by about 5%, about 10%, about 20% or about 30%. In certain embodiments, the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In others, the subject suffers from, or is at risk of suffering from diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or combinations of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular evcnt. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. [0043] In another aspect of the invention, there are provided methods of decreasing the HbAI c value in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the HbAic value in the subject relative to the level prior to the administration of the compound, wherein the cytokine inhibitor is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some such embodiments, the subject has a HbAl c value above about 8%, above about 7.5%, or above about 7%. In others, the HbAl c level is decreased to between about 4% and about 6.5%. In certain embodiments, the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In other embodiments, the subject 19 WO 2007/146712 PCT/US2007/070547 suffers from, or is at risk of suffering from, diabetes, insulin resistance or metabolic syndrome. In some embodiments, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or combinations of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. [0044] In yet another aspect of the invention, there are provided methods for decreasing the insulin level in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the insulin-level in the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some such embodiments, the subject has a fasting insulin level prior to administration of above about 100 pmol/l, above about 150 pmol/l, above about 200 pmol/l, above about 250 pmol/l, above about 300 pmol/l, above about 350 pmol/l, above about 400 pmol/l, or above about 500 pmol/l. In others, the subject has a postprandial insulin level of above about 400 pmol/l, above about 500 pmol/l, above about 600 pmol/l, above about 700 pmol/1, or above about 800 pmol/l. In some embodiments, the insulin level is reduced by about 10%, about 20%, about 30%, or about 40%. In certain embodiments, the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In yet other embodiments, the subject suffers from, or is at risk of suffering from diabetes, insulin resistance or metabolic syndrome. In some embodiments of the invention, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or a combination of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular 20 WO 2007/146712 PCT/US2007/070547 event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. [0045] In another aspect of the invention, there are provided methods for decreasing the HOMA Insulin Resistance Index in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to decrease the HOMA Insulin Resistance Index in the subject relative to the Index prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some such embodiments, the Insulin Resistance Index is reduced to below about 2.5, below about 2.0, or below about 1.8. In some embodiments, the Insulin Resistance Index is reduced by about 10%, about 20%, or about 30%. In certain embodiments, the subject is in need of a decreased HOMA Insulin Resistance Index because, e.g., the subject suffers from, or is at risk for a cytokine mediated disorder as described herein. In others, the subject suffers from, or is at risk of suffering from diabetes, insulin resistance or metabolic syndrome. In some embodiments of the invention, the method further comprises administration of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, repaglinide, nateglinide, metformin, miglitol, acarbose, exendin, pramlintide, insulin, or a combination of two or more thereof. In some embodiments of the invention, the subject is at risk of a vascular event, for example, one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischernic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and/or a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. 21 WO 2007/146712 PCT/US2007/070547 [0046] In yet another aspect of the invention, there are provide methods of increasing the indirect bilirubin-level in a subject. The methods comprise administering to a subject, such as a subject in need thereof, an amount of a compound, such as a cytokine inhibitor, effective to increase the indirect bilirubin-level in the subject relative to the level prior to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the indirect bilirubin level is increased to about 0.4 mg/dl, to about 0.5 mg/dl, to about 0.6 mg/dl, or to about 0.7 mg/dl. In others, the indirect bilirubin level is increased by about 10%, about 20%, or about 30%. In other embodiments, the bilirubin level is increased without causing jaundice. In certain embodiments, the subject is in need of increased indirect bilirubin-level because, e.g., the subject suffers from, or is at risk for a cytokine-mediated disorder as described herein. In some embodiments of this aspect of the invention, the subject is at risk of a vascular event, for example, the vascular event is one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis. In other embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound. [0047] In some embodiments, compounds described herein possess inhibitory effects on the procoagulant and profibrinolytic responses during human endotoxemia. In another aspect, the invention therefore also provides a method of anticoagulant and fibrinolytic therapy for a disease or condition relating to blood coagulation or fibrinolysis, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound as described herein, for example, a cytokine inhibitor. This administration may be of benefit given either prophylactically to subjects at risk or therapeutically to subjects who have developed complications related to these pathways. [0048] Compounds disclosed herein, such as cytokine inhibitors, may be used in combination therapy with one or more other anticoagulant or fibrinolytic agents. These include recombinant tissue plasminogen activator (rtPA), streptokinase (SK), urokinase (UK). proUK, heparin, enoxoparin, dalteparin, coumarin anticoagulants, aspirin, 22 WO 2007/146712 PCT/US2007/070547 dipyrimidamole, aggrennox, ticlopidine, clopidogrel (Plavix), abciximab, RheoPro, integrilin, aggrestat, and the like. Particular dosages, formulations and methods of administration of the anticoagulant and fibrinolytic agents are known in the art. In view of the present disclosure it is within the skill in the art to determine appropriate dosages, formulations and methods of administration for the combinations of the compounds of the invention and the anti-coagulant or fibrinolytic agents for particular applications.. [0049] In another aspect of the invention, there is provided a method comprising administering to a subject a combination of a compound, as described herein, for example, a cytokine inhibitor, and one or more ingredients A, in an amount effective to control, treat or prevent obesity or obesity-related conditions or disorders in a subject in need thereof, wherein ingredient A is selected from agents useful in the treatment of obesity or an obesity-related condition or disorder. In some such embodiments, the obesity-related disorder is selected from overeating, binge eating, bulimia, diabetes, elevated plasma insulin concentrations, insulin resistance, metabolic syndrome, dyslipidemias, hyperlipidemia, lipodystrophy, osteoarthritis, arthritis deformans, lumbodynia, emmeniopathy, obstructive sleep apnea, cholelithiasis, gallstones, nonalcoholic steatohepatitis, heart disease, abnormal heart rhythms and abnormal heart arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, coronary artery disease, angina pectoris, hypertension, sudden death, stroke, cerebral infarction, cerebral thrombosis, transient ischemic attack, polycystic ovary disease, craniopharyngioma, Pickwickian syndrome, fatty liver, Prader-Willi Syndrome, Frohlich's syndrome, GH-deficiency, normal variant short stature, Turner's syndrome, pediatric acute lymphoblastic leukemia, infertility, hypogonadism in males, hirsutism in females, gastrointestinal motility disorders, respiratory disorders, cardiovascular disorders, inflammation, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, endometrial cancer, breast cancer, prostate cancer, colon cancer or kidney cancer. In other embodiments of the invention, the subject desires to lose body weight relative to the subject's body weight prior to administration of the combination. In some embodiments, the method additionally comprises treatment of the subject with lipoplasty, gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion or vertical banded gastroplasty. 23 WO 2007/146712 PCT/US2007/070547 [0050] In some embodiments of this aspect of the invention, both compound(s) as described herein and ingredient A are administered orally. In others, both compound and ingredient A are administered intravenously, subcutaneously or by inhalation. In still others, compound is administered orally and the ingredient A is administered intravenously, subcutaneously, or by inhalation. Alternatively, compound may be administered intravenously, subcutaneously, or by inhalation and the ingredient(s) A may be administered orally. [0051] Examples of agents useful in the treatment of obesity or an obesity-related condition or disorder as ingredients A include an insulin sensitizer, an insulin or insulin mimetic, a sulfonylurea, an c-glucosidase inhibitor, a cholesterol lowering agent, a PPAR6 agonist, a CB receptor ligand, a serotonergic agent, an adrenoceptor agonist, a pancreatic lipase inhibitor, an ApoB/MTP inhibitor, a MCH receptor antagonist, an amylin and/or calcitonin receptor agonist, an NPY antagonist, an orexin antagonist, a GLP-1 agonist, an MC agonist, a ghrelin antagonist, a leptin agonist, a CCK agonist, a PYY agonist, a CNTF, a GH secretagogue, a GH secretagogue receptor modulator, a DP IV inhibitor, a H3 antagonist or inverse agonist, a 5HT agonist, a serotonin transport or reuptake inhibitor, a dopamine agonist, a NE transport inhibitor, a DAG inhibitor, a glucose transporter inhibitor, a f-HSD- 1 inhibitor, a CETP inhibitor, a squalene synthase inhibitor, a glucocorticoid antagonist, a PDE inhibitor, an anti-platelet agent, an ACE inhibitor, an All receptor antagonist, a UCP- 1, -2, or -3 activator, a thyroid hormone 0 agonist, a COX-2 inhibitor, a monoamine reuptake inhibitor, a mGlu5 receptor antagonist, an acyl-estrogen, a FAS inhibitor, an ACC2 inhibitor, a corticotropin releasing hormone agonist, a galanin antagonist, a BRS3 agonist, a PTP- 1 B inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, a phosphate transporter inhibitor, a urocortin binding protein antagonist, a urocortin ligand, a human agouti-related protein, a neuromedin U receptor agonist, topiramate, oxyntomodulin, tagatose, CP741952, zonisamide, ID1101, BDC03, S2367, AOD9604, fluasterone, GT389255, QCBT16, MK0916, MK0493, MK0364, PD6735, c2735, adiponectin, or a combination of two or more thereof In some such embodiments, ingredient A is an insulin sensitizer, an insulin or insulin mimetic, a sulfonylurea, an a-glucosidase inhibitor, or a glucose transporter inhibitor. In others, ingredient A is a cholesterol lowering agent, or a PPAR8 agonist. In still others, ingredient A is a CB receptor ligand, a serotonergic agent, an adrenoceptor agonist, a pancreatic lipase inhibitor, an ApoB/MTP inhibitor, a 24 WO 2007/146712 PCT/US2007/070547 DP-IV inhibitor, a H3 antagonist or inverse agonist, a 5HT agonist, a serotonin transport or reuptake inhibitor, a dopamine agonist, a NE transport inhibitor, a CETP inhibitor, a squalene synthase inhibitor, a PDE inhibitor, or an acyl-estrogen. In other embodiments, ingredient A is a MCH receptor antagonist, an NPY antagonist, an orexin antagonist, a GLP-1 agonist, an MC agonist, a ghrelin antagonist, a leptin agonist, a CCK agonist, a PYY agonist, a CNTF, a GH secretagogue, or a GH secretagogue receptor modulator. In some embodiments, ingredient A is rimonabant, sibutramine, fluoxetine, phentermine, bupropion, radafaxine, orlistat, cetilistat, oxyntomodulin, or oleoyl-estrone. [0052] Typical examples of ingredients A, and combinations of any two or more thereof, that may be combined with compounds described herein, for the treatment or prevention of obesity, diabetes and/or obesity-related disorders, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: [0053] (a) insulin sensitizers including (i) peroxisome proliferator activated receptors (PPAR) y agonists, such as glitazones (e.g.isaglitazone; pioglitazone; rosiglitazone; rivoglitazone, netoglitazone), naveglitazar, farglitazar, metaglidasen, GW6779542, CS038, MBX2044, AZD6610, PLX204, LBM642, AMG131, AVE0847, AVE5376, ONO5129, TAK654, CLX0921, and the like); (ii) biguanides such as metformin and phenformin; [0054] (b) insulin or insulin mimetics, such as insulin aspart, insulin glulisine, insulin glargine, insulin lispro, insulin detemir, NN5401, NN9101, NN344, AT1391, DTYOO 1, betaRx, insulin zinc suspension (lente and ultralente); insulintropin (by "insulin" is meant a polypeptide or its equivalent useful in regulation of blood glucose levels. A general description of such insulins is provided in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press (1990). Such insulins can be fast acting, intermediate acting, or long acting. Various derivatives of insulin exist and are useful in this invention. Such compositions can be administered by any standard route, including oral, nasal, pulmonary, or transdermal administration.); [0055] (c) sulfonylureas, such as acetohexamide; chlorpropamide; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide; 25 WO 2007/146712 PCT/US2007/070547 [0056] (d) a-glucosidase inhibitors, such as alglucosidase alfa, voglibose, celgosivir, miglitol, acarbose, and the like; [0057] (e) cholesterol lowering agents such as (i) 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pitavastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, lovastatin and other statins); (ii) bile acid absorbers/sequestrants, such as colesevelam, colestipol, cholestyramine, dialkylaminoalcyl derivatives of a cross-inked dextran, and the like; (ii) nicotinyl alcohol, nicotinic acid or a salt thereof; (iii) PPARa agonists such as fenofibric acid derivatives (ciprofibrate, gemfibrozil, clofibrate, fenofibrate and benzafibrate), GW677954, CS038, ABT335, LY674, GFT14, PLX204, K111, naveglitazar, LBM642, GW590735, NS220, AVE5376, AVE8134, DRF10945, ON05129, KRP101, GW641597, and DRF4832; (iv) inhibitors of cholesterol absorption such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, and the like, and acyl CoA cholesterol acyltransferase (ACAT) inhibitors such as SMP797, K604, and SR-45023A, (v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics; [0058] (f) PPARS agonists, such as GW677954, CS068, RWJ800025, GW501516, and CKD501; and [0059] (g) other therapeutic agents, including anti-obesity and anti-diabetic agents, such as [0060] (1) cannabinoid (CB) receptor ligands, such as CB-1 receptor antagonists or inverse agonists, for example rimonabant, surinabant,, AVE1625, CP945598, and SLV-319, and those disclosed in U.S. Pat. Nos. 6,344,474, 6,028,084, 5,747,524, 5,596,106, 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, PCT Application Nos. WO 96/33159, WO 98/33765, W098/43636, W098/43635, WO 01/09120, W098/31227, W098/41519, W098/37061, WOOO/10967, WOOO/10968, W097/29079, W099/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, W002/076949, and WO 03/007887, WO 02/076949; and EPO Application No. EP-658546, EP-656354, EP-576357; [0061] (2) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluranine, phentermine, DOV102677, zimeldine, and sibutramine; 26 WO 2007/146712 PCT/US2007/070547 [0062] (3) adrenoceptor agonists, including 03-adrenoreceptor agonists, such as solabregon, YM178, amibregon, tesofensince, fenfluramine, amphetamine, phenmetrazine, phentermine, and N5984; [0063] (4) pancreatic lipase inhibitors, such as orlistat, cetilistat, and GT389255; [0064] (5) apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, such as ISIS301012, ISIS301012, JTT130, and SLx409O; [0065] (6) melanin-concentrating hormone (MCH) receptor antagonists, including MCH1R and MCH2R antagonists, for example, 856464, and AMG076, and those described in U.S. Patent Application Publication Nos. 2005/0009815, 2005/0026915, 2004/0152742, 2004/0209865; PCT Patent Application Publication Nos. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, and WO 02/51809; and Japanese Patent Application No. JP 13226269; [0066] (7) neuropeptide Y (NPY) antagonists, such as NPY1 antagonists, for example, BIBP3226, J115814, B1B03304, LY357897, CP671906, G1264879A, and those disclosed in U.S. Pat. No. 6,001,836 and PCT Application Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; NPY5 antagonists, for example, S2367, FMS586, GW569180A, GW594884A, GW587081, GW548118., FR226928, FR240662, FR252384, 1229U91, G1264879A, CGP71683A, LY377897, PD160170, SR120562A, SR120819A and JCF104, and those disclosed in U.S. Pat. Nos. 6,124,331, 6,140,354, 6,191,160, 6,214,853, 6,258,837, 6,313,298, 6,337,332, 6,329,395, 6,326,375, 6,335,345, and 6,340,683, European Patent Nos. EP-01010691, and EP-01044970, and PCT Application Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; [0067] (8) peptide YY (PYY) agonists, such as PYY, PYY 3-36, peptide YY analogs, and PYY agonists, for example, AC162352, N-Acetyl [Leu(28,3 1)]NPY 24-36, and PYY(3-36)NH 2 , cyclo-(28/32)-Ac-[Lys28- Glu32]-(25-36)-pNPY, TASP-V, 27 WO 2007/146712 PCT/US2007/070547 pancreatic peptide (PP), 122U91, and those disclosed in U.S. Pat. Publication No. 2002/0141985 and PCT Application Publication No. WO 2005/077094, WO 03/026591, WO 03/057235, and WO 03/027637; [0068] (9) orexin antagonists, such as orexin-1 receptor antagonists, for example SB334867-A, and those disclosed in PCT Application Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838; [0069] (10) glucagon-like peptide (GLP)-1 agonists, including GLP-1, GLP-1 analogs and derivatives, such as exenatide, exenatide-LAR, liraglutide, CJCI 134PC, LY548806, 716155, and AVE0010; [0070] (11) melanocortin (MC) agonists, including MC4 agonists and MC4R agonists, such as Melanotan II, PT15, BL3020, AP1030, or those described in PCT Application Nos. WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, WO 02/12178, WO 03/007949, WO 02/068388, WO 02/068387, WO 02/067869, WO 03/040117, WO 03/066587, WO 03/068738, WO 03/094918, and WO 03/031410; [0071] (12) ghrelin receptor antagonists, such as NOXB 11, CYTO09GhrQb, TZP300, EP01492, and those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250; [0072] (13) leptin agonists, including recombinant human leptin and recombinant methionyl human leptin, and leptin derivatives, such as 0B3, and those disclosed in U.S. Pat. Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, 6,777,388 and 6,936,439, and PCT Application Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, WO 96/23520, WO 96/05309, WO 96/40912; WO 97/06816, WO 00/20872, WO 97/18833, WO 97/38014, WO 98/08512, WO 98/284427, U.S. patent publications 2004/0072219, 2003/049693, 2003/0166847, and 2003/0092126; [0073] (14) cholecystokinin (CCK) agonists, such as ARR15849, G1181771, JMV18O, A71378, A71623, SR146131, UCL2000, and A71378, and those described in U.S. Pat. No. 5,739,106; 28 WO 2007/146712 PCT/US2007/070547 [0074] (15) ciliary neurotrophic factors (CNTF), including CNTF, CNTF modulators, and CNTF derivatives, such as Axokine and NT501, and those disclosed in U.S. Pat. Nos. 6,680,291 and 6,767,894 and in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813; [0075] (16) growth hormone (GH) secretagogues, growth hormone secretagogue receptor modulators, such as SUN1 1031, RC1291, tesamorelin, sermorelin, examorelin, NN703, hexarelin, MK677, SM-130686, CP-424,391, L-692,429 and L-163,255; [0076] (17) dipeptidyl peptidase IV (DP-IV or DPP-IV) inhibitors, such as denagliptin, sitagliptin, SYR322, R00730699, TSO21, ALS20426, vidagliptin, GRC8200, MP513, PHX1 149, PSN9301, TA6666, saxagliptin, SSR162369, R1438, KRP104, 825964, and the compounds disclosed in PCT Application Nos. WO 03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181; [0077] (18) histamine receptor-3 (H3) antagonists/inverse agonists, such as GSK189254A, A331440, ABT239, ABT834, BP294, thioperamide, 3-(lH-imidazol-4 yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394, and those described and disclosed in PCT Application Nos. WO 02/15905; [0078] (19) 5-hydroxytryptamine (5HT) agonists, for example 5HT2C (serotonin receptor 2C) agonists, such as lorcaserin, vabicaserin, APD356, and those disclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; and 5HT6 agonists, such as PRX07034; [0079] (20) serotonin transport or serotonin reuptake inhibitors such as nefazodone, citalopram, dapoxetine, duloxetine, desvenlafaxine, fluvoxamine, escitalopram, sibutramine, venlafaxine, vilazodone, DOV21947, LUAA21004, BGC201259, NS2359, UK416244, DOV102677, SEP225289, OPC14523, SLV314, WL1011, WL1017, zimeldine, fluoxetine, paroxetine, fenfluramine, imipramine and sertraline, and those disclosed in U.S. Pat. No. 6,365,633, and PCT Application Nos. WO 01/27060 and WO 01/162341; 29 WO 2007/146712 PCT/US2007/070547 [0080] (21) dopamine agonists, for example dopamine D2 agonists, such as, ropinirole, bifeprunox, aripiprazole, pergolide, talipexole, ACP 104, quinagolide, nolomirole, NHOO1, SLV308, piribedil, lisuride, bromocriptine, aplindore, tesofensine, and preclamol; [0081] (22) norepinephrine (NE) transport inhibitors, such as lisdexamfetamine, atomoxetine, duloxetine, SLE3 81, desvenlafaxine, amfebutamone, sibutramine, venlafaxine, DOC21947, radafaxine, bupropion, DOV216303, reboxetine, AD337, NS2359, DOV102677, SEP225289, Xen2174, indeloxazine, protriptyline, and S33005; [0082] (23) diacylglycerol acyltransferase (DAG) inhibitors, such as BAY744113; [0083] (24) glucose transporter inhibitors, for example, sodium glucose cotransporter (SGLT) inhibitors, such as, KGT1251, 189075, AVE2268, and SGLOO1O; [0084] (25) 1 1#-hydroxy steroid dehydrogenase-1 (#-HSD-1) inhibitors, such as INCB13739, and AMG221; [0085] (26) cholesterol ester transfer protein (CETP) inhibitors, such as torcetrapib, CETil, JTT705, BAY605521,and JTT302; [0086] (27) squalene synthase inhibitors, for example, lapaquistat; [0087] (28) glucocorticoid antagonists, for example, mifepristone, Org34517, and Org34850; [0088] (29) phosphodiesterase (PDE) inhibitors, including phosphodiesterase-31B (PDE3B) inhibitors, for example, tetomilast, tadalafil, atopik, vardenafil, tipelikast, HT0712, QAD171A, SK3530, oglemilast, acanafil, cilostazol, roflumilast, parogrelil, udenafil, EHT0202, dasantafil, MEM1414, SLx2101, CC10004, 256066, cilomilast, vinpocetine, ibudilast, pimobendan, ND7001, LAS37779, K123, UK357903, ND1251, tofimilast, UK169003, senazodan, trapidil, arofylline, theophylline, doxofylline, olprinone, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast; [0089] (30) antiplatelet agents, such as, limaprost, clopidogrel, felbinac, cptifibatide, NCX4016, ticagrelor, tirofiban, abcixmab, sarpogrelade, DA697B, 30 WO 2007/146712 PCT/US2007/070547 argatroban, SCH530348, cilostazol, YSPSL, parogrelil, asasantin, DG041, prasugrel, ramatroban, cangrelor, epoprostenol, beraprost, aspirin, K134, triflusal, YY280, xemilofiban, ozagrel, alprostadil alfadex, TP9201, procainamide, AT1015, Z335, BGC728, glyrofam, EF5077, SH529, and ME3229; [0090] (31) angiotensin converting enzyme (ACE) inhibitors, such as peridopril, enalapril, ramipril, fosinopril, quinapril, lisinopril, imidapril, benazepril, ilepatril, captopril, trandolapril, temcapil, cilazapril, MC4232, CHF1521, omapatrilat, spirapril, moexipril, zofenopril, delapril, alacepril, S5590, and fasidotril; [0091] (32) angiotensin II (All) receptor antagonists, for example, losartan, candesartan, temisartan, coaprovel, imidapril, azilsartan, valsartan, irbesartan, olmesartan, CYTO06AngQb, TAK491, eprosartan, VNP489, CGP63170, fimcsartan, pratosartan, and saralasin; [0092] (33) uncoupling protein (UCP)- 1, 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)- 1 -propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123; [0093] (34) thyroid hormone 0 agonists, such as thyroid hormone, levothyroxine, KB2115, 3,5-diiodothyropropionic acid, liothyronine, methimazole, and those disclosed in PCT Patent Application No. WO 02/15845, and Japanese Patent Application No. JP 2000256190; [0094] (35) cyclo-oxygenase (COX)-2 inhibitors such as etoricoxib, GW406381, meloxicam, lumiracoxib, diclofenac, valdecoxib, parecoxib, PMI001, 6444784, SVT2016, nimesulfide, CS706, cimicoxib, LR3001, LAS34475, P54, rofecoxib, celecoxib, and arcoxia; [0095] (36) monoamine reuptake inhibitors, such as those disclosed in PCT Application No. WO 01/27068, and WO 01/62341; [0096] (37) metabotropic glutamate 5 (mGlu5) receptor antagonists, such as ADX10059, AFQ-056, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), (3-[(2-methyl-1,3 thiazol-4-yl)ethynyl]pyridine) (MTEP) and those compounds described in Anderson et al. 31 WO 2007/146712 PCT/US2007/070547 (2003) J. Eur. J. Pharmacol. 473:35-40; Cosford et al. (2003) Bioorg. Med. Chem. Lett. 13(3):351-4; and Anderson et al. (2002) J. Pharmacol. Exp. Ther. 303:1044-1051; [0097] (38) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); [0098] (39) fatty acid synthase (FAS) inhibitors, such as Cerulenin, and C75; [0099] (40) acetyl-CoA carboxylase-2 (ACC2) inhibitors; [00100] (41) corticotropin-releasing hormone agonists; [00101] (42) galanin antagonists; [00102] (43) bombesin receptor subtype 3 (BRS3) agonists; [00103] (44) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; [00104] (45) fatty acid transporter inhibitors; [00105] (46) dicarboxylate transporter inhibitors; [00106] (47) phosphate transporter inhibitors; [00107] (48) urocortin binding protein antagonists and urocortin ligands, such as urocortin 11; [00108] (49) human agouti-related proteins (AGRP); [00109] (50) neuromedin U receptor agonists; [00110] (51) topiramate, oxyntomodulin, tagatose, CP741952, zonisamide, ID1101, BDC03, S2367, AOD9604, fluasterone, GT389255, QCBT16, MK0916, MK0493, MK0364, PD6735, c2735, and adiponectin. [00111] Examples of other anti-obesity agents that can be employed in combination with compounds described herein are disclosed in "Patent focus on new anti obesity agents," Exp. Opin. Ther. Patents, 10: 819-831 (2000); "Novel anti-obesity drugs," Exp. Opin. Invest. Drugs, 9: 1317-1326 (2000); and "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity, Exp. Opin. 32 WO 2007/146712 PCT/US2007/070547 Ther. Patents, 11: 1677-1692 (2001). The role of neuropeptide Y in obesity is discussed in Exp. Opin. Invest. Drugs, 9: 1327-1346 (2000). Cannabinoid receptor ligands are discussed in Exp. Opin. Invest. Drugs, 9: 1553-1571 (2000). [00112] Obesity and weight loss treatments also include surgery. Typically the weight loss surgical procedure is liposuction or lipoplasty. Surgical obesity treatments include gastric bypass, laparoscopic adjustable gastric binding, biliopancreatic diversion or vertical banded gastroplasty. [00113] In another aspect, there is provided a method comprising administering a compound, such as a cytokine inhibitor, and one or more ingredients A to a subject in need thereof, in an amount effective to increase or enhance the effectiveness of the ingredient A when used alone, wherein ingredient A is selected from agents useful in the treatment of obesity or an obesity-related condition or disorder, and wherein the compound is as described herein, or is a mixture of any two or more thereof and/or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. In some embodiments, the effectiveness enhancement is obtained by allowing administration of lower dosages of one or more of the ingredient A used in combination as relative to the use of either agent alone. [00114] In another aspect of the invention, there is provided a method comprising administering to a subject a compound as described herein, for example, a cytokine inhibitor, and an ingredient A, in an amount effective to reduce the risk of metabolic disorders in a subject in need thereof relative to the subject's risk prior to administration of the compound and ingredient A, wherein ingredient A is selected from agents useful in the treatment of obesity or an obesity-related condition or disorder. In some embodiments, the reduction in risk of metabolic disorders is obtained by reducing the body weight of the subject, relative to the subject's body weight prior to administration of the combination of the cytokine inhibitor and ingredient(s) A. [00115] For therapeutic use, the pharmaceutical combinations of ingredient A and compound(s) described herein may be administered in any conventional dosage form in any conventional manner, including any of the routes described herein. Accordingly, routes of administration include, but are not limited to, intravenous, intramuscular, 33 WO 2007/146712 PCT/US2007/070547 subcutaneous, intrasynovial, by infusion, sublingual, transdermal, oral, topical and by inhalation. Typical modes of administration are oral, topical or intravenous. [00116] The pharmaceutical combinations of ingredient A and the compound as described herein may be administered separately, or in a combination formulation with other ingredients or adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, or provide like advantages. Such combination therapies typically utilize lower dosages of the conventional therapeutics, and avoid the possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Pharmaceutical combinations of ingredient A and the compound may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. The ingredient A and/or the compound may be used in the combination as a salt, solvate, tautomer and/or prodrug and as a single stereoisomer or mixtures of stereoisomers, including racemates. [00117] The proportions in which the two components, ingredient A and the compound as described herein, may be used in the combinations according to the invention are variable. Ingredient A and the compound are optionally present in the form of their solvates or hydrates. Depending on the choice of the ingredient A and the compound as described herein, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies. Determination of ratios by weight is dependent on the particular ingredient A and the compound, and are within the skill in the art. [00118] Some compounds useful in the invention are exemplified by Formulas IA, IB, IC and II and are described in US application 10/939,324, filed September 10, 2004, and International Application No. PCT/US2006/006682, filed February 23, 2006, which are each incorporated herein by reference in their entirety: GN Ar-L-HQ G N H X Ar-L-Q G-Ring-Ar-L-Q IA IB IC 34 WO 2007/146712 PCT/US2007/070547 x' G / Ar-L--Q N II, wherein the variables G, X, Ar, L, Q, Ring and X' are as defined in the Detailed Description of the Invention. [00119] Other compounds useful in the invention comprise: a targeting moiety, TM comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety, PEM directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a n-n or edge-to-face aromatic interaction with the target protein; wherein the compound is optionally a cytokine inhibitor. [00120] Other compounds contemplated in the methods of the invention are described in International Application No. PCT/US2006/042679, filed November 1, 2006, which is incorporated herein by reference in its entirety, and are exemplified by Formula III:

GL

1 L2 L3 N' A Formula III 35 WO 2007/146712 PCT/US2007/070547 wherein G, L', L 2 , Ar, L , Q, and A are as described in the Detailed Description of the Invention for Formula III. [00121] Yet other compounds useful in the methods of the invention comprise: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, such as, for example, a benzamide or pyridylamide, and wherein the anchoring moiety is capable of forming at least one hydrogen bond interaction with an ATP-binding pocket of the target protein; wherein the compound is optionally a cytokine inhibitor. [00122] In this aspect of the invention, compounds have the structure PEM-TM OM-L-AM. [00123] Still other compounds contemplated in the methods of the invention are described in International Application No. PCT/US2006/048803, filed December 20, 2006, which is incorporated herein by reference in its entirety, and are exemplified by Formula IV: G E Y A Formula IV 36 WO 2007/146712 PCT/US2007/070547 wherein G, L', B, D, E, L 2 , Q, X, Y and A are as described in the Detailed Description of the Invention for Formula IV. [00124] Additional compounds useful in the invention comprise: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety- (L), wherein the anchoring moiety is capable of forming at least one hydrogen bond interaction with an ATP-binding pocket of the target protein; wherein the compound is optionally a cytokine inhibitor. [001251 In this aspect of the invention, the compounds have the structure PEM-TM-OM-L-AM. [001261 Compounds contemplated in the methods of the invention include representative examples of Formulas I, II, III and IV, as set forth in List I. List I: Examples of compounds of Formulas I, II, III and IV. 1H-Indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide; 3-tert-Butyl-5-phenyl-1-p-tolyl-1,6-dihydro-imidazo[4,5-c]pyrazole; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 yl]-2-oxo-acetamide; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1-yl]-2-oxo-acetamide; 37 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2- [4-(2-morpholin-4-yl pyrimidin-4-yloxy)-naphthalen- Il-yl] -2-oxo-acetamide; N.-(5-tert-Butyl-2-hydroxy-3-morpholin-4-ylmethyl-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-hydroxy-3 -methyl-phenyl)-2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-3 -methyl-phenyl)-2- [4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yll-2-oxo-acetamide; N-(5-tert-Butyl-3 -chloro-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen 1 -yll-2-oxo-acetamide; N-(5-tert-B utyl-2-methoxy-3 -trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[7-chloro-4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yll -2-oxo-acetamide; 5-tert-Butyl-N-cyclopropyl-2-methoxy-3 - f 2- 4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-2-oxo-acetylamino I -benzamide; N-[5-tert-Butyl-2-methoxy-3 -(piperidine- 1 -carbonyl)-phenyl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-2-hydroxy-3 - f{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetylaminol4-benzoic acid; N-(2-Benzenesulfonyl-5-tert-butyl-2H-pyrazol-3 -yl)-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- l-yl] -2-oxo-acetamide; 2-(5-tert-B utyl-2-p-tolyl-2H-pyrazol-3 -yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-2-oxo-acetamide; 1 -Bicyclo [2.2.1 lhept-2-y1-5-phenylamino-3 -p-tolyl- 1,3-dihydro-imidazo[4,5-b]pyridin-2 one; 3-p-Tolyl-5-p-tolylamino- 1,3 -dihydro-imidazo[4,5-blpyridin-2-one; 1 -Bicyclo [2.2. 1 lhept-2-yl-3 -p-tolyl-5-p-tolyl amino- 1,3 -dihydro-imidazo [4,5-b]pyri din-2 one: .N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2,2-difluoro-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-acetamide; N-(5-tcrt-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-N t -naphthalen- 1 -yl-oxalamide; 38 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-[(Z)-hydroxyimino] -2-[4-(2-morpholin-4 yl-ethoxy)-naphthalen- 1 -yl]-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-[(Z)-methoxyimino--2-[4.-(2-morpholin-4 yl-ethoxy)-naphthalen- 1 -yll-acetamide; 2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -ylamino)- 1 -[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl] -ethanol; 1 -(3-tert-Butyl-phenyl)--4-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- Il-yl] [ 1,2,4Jtri azolidinc-3,5-dionc; 4-(3-tert-Butyl-phenyl)- 1 -[4-(2-morpholin-4-yl-ethoxy)-naphthalcn-1 -yl] [ 1, 2,4]triazolidine-3,5-di one; (E)-3-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenylcarbamoyl)-3 -[4-(2 morpholin-4-yl-ethoxy)-naphthalen- Il-yl] -acrylic acid methyl ester; N-(5-tert-Butyl-2-methoxy-3- {3- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl] -2,5 dioxo-2 ,5-dihydro-pyrrol- 1-yl }-phenyl)-methanesulfonamide; N-(5-tert-Butyl-2-methoxy-3- {3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl] -2,5 dioxo-pyrrolidin- 1-yl }-phenyl)-methanesulfonamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2- [4-(2-morpholin-4-yl ethoxy)-naphthalen- 1-yl] -acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-[4-(2-pipeidinl- 1 yl-pyrimidin-4-yloxy)-naphthalen-1 -yl]--acetamide; 3-tert-Butyl-1 -p-tolyl-5-(3-trifluoromethyl-phenyl)- 1,6-dihydro-imidazo[4, 5-cipyrazole; 1-(2-Morpholin-4-yl-ethyl)-1 H-indazole-3-carboxylic acid (5-tert-butyl-3 methanesulfonylamino-2-methoxy-phenyl)-amide; N-[4-(2-Morpholin-4-yl-ethoxy)-naphthal en-I -yl] -2-oxo-2-(2,4,6-trimcthyl-phenyl) acetamide; 1 -Phenyl-cyclopropanecarboxylic acid (5-tert--butyl-2-p-tolyl-2H-pyrazol-3 -yl)-amide; N-15-tert-Butyl-2-(2, 5-difluoro-phenyl)-2H-pyrazol-3-yl] -2-[4-(2-rnorpholin-4-yI ethoxy) -naphthal en-i -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalel- l-yl]-2 oxo-acetamide; N-(5-tert-Butyl-3-methanesufonylamino-2-methoxy-phenfly)-2-(4-mthoxy-laphthalefl 1 -yl)-2-oxo-acetamide; 39 WO 2007/146712 PCT/US2007/070547 N-[5-tert-Butyl-2-(3 -chloro-benzoyl)-2H-pyrazol-3-yI ]-2-[4-(2-morpholin-4-yl-ethoxy) naphthal en-i1 -yl]-2-oxo-acetamide; N-[5-tert-Butyl-2-(3 -methanesulfonyl-phenyl)-2H-pyrazol-3-yl j-2- [4-(2-morpholin-4-yl etho xy)-naphthal en-i -yl]-2-oxo-acetamnide; 4-[(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -ylcarbamoyl)-methyl] -piperidine-l1-carboxylic acid tert-butyl ester; N-f 3-(B enzenesulfonyl-carbamoylmethyl-amnino)-5-tert-butyl-2-methoxy-phenyl]-2 naphthalen-l -yl-2-oxo-acetamide; N-(3 -tert-Butyl-isoxazol-5-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-2-oxo acetamide; N-(5-tert-Butyl-3 -ethanesulfonylamino-2-methoxy-phenyl)-3 -[4-(2-morpholin-4-yl ethoxy)-naphthal en-i -ylJ-succinamic acid methyl ester; 2-(2-Benzyl-5 -tert-butyl-2H-pyrazol-3 -yI)-N-[4-(2-morpholin-4-yI-ethoxy)-naphthalen- 1 yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino) naphthalen-1 -yl]-2-oxo-acetamide; 5-tert-Butyl-2-(3 -ehloro-phenyl)-2H-pyrazole-3 -carboxylic acid [4-(2-morpholin-4-yl ethoxy)-naphthalen- l-yl] -amide; 2-(3 -Bromo-4-methoxy-phenyl)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl)-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[3-fluoro-4-(2-morpholin-4-yl-ethoxy) phenyl]-acetamide; (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-(2,2-dimethyl-propyl)-amine; 2-(4-Benzyloxy-phenyl)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl)-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-hydroxy-2-[4-(2-morpholin-4-yl-ethoxy) naphtha] en- I -yl]-acetamide; N-f 5-tert-Butyl-2-(4-sulfamoyl-phenyl)-2H-pyrazol-3 -ylJ -2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamnide; 5-tert-Butyl-2-methoxy-3 -(1 -naphthalen-1 -yl-3 ,5-dioxo-[ 1 )2,4]triazolidin-4-yl) benzamide; 2-(4-Bromo-naphthalen- I -yl)-N-(5-teit-butyl-2-rnethyl-2H-pyrazol-3-yl)-2-okxo acetamide; 5-tert-B-utyl-2-hydroxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetyl amino I}-benzamide; 40 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-hydroxy-2-(4-methoxy-naphthalen- l-yl) acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-pheny)-2- [4-(6-morpholin-4 ylmethyl-pyridin-3 -yl)-naphthalen-1 -yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2- [4-(2-methylamino-pyrimidin-4-ylamino) naphthalen- 1 -yl]-2-oxo-acetamide; N-(5 -tert-Butyl-2 -methoxy-phenyl)-2- [4-(2 -dimethylamino-pyrimidin-4-yl amino) naphthalen-1 -yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-oxo-2- {4-[2-( 1-oxo- 1 \-thiomorpholin-4 yl)-ethoxy]-naphthalen-I -yl} -acetamide; 5-tert-Butyl-3 - (2- [(Z)-hydroxyiminoJ-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-ylJ acetylamnino }-thiophene-2-carboxylic acid methyl ester; N-[5-tert-Butyl-2-(3-methanesulfonyl-phenyl)-2H-pyrazol-3 -yl] -2-hydroxy-2-[4-(2 morpholin-4-yl-ethoxy)-naphthalen- I -yl]-acetamnide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2- {4-[2-((2R,6R)-2,6-dimethyl-morpholin-4 yl)-ethoxy]-naphthaien- l -yll -2-oxo-acetamide; N-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-2-[4-(6-morpholin-4-ylmethyl-pyridin-3 -yl) naphthalen- 1 -yl] -2-oxo-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[7-chloro-4-(2 morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4 (2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide; N-(5-tert-Butyl-2-methoxy-pheny)-2-L4-(6-morpholin-4-ylmethyl-pyridin-3-y) naphthalen- I -yl]-2-oxo-acetamide; 5-tert-Butyl-N-cyclopropyl-2-m ethoxy-3-[2-(4-methoxy-naphthalen- 1 -yl)-2-oxo acetylamnino]-benzamide; 4-tert-Butyl-N-[4-(2-piperidin- 1 -yl-ethoxy)-naphthalen- Il-yl] -benzamide; N-(2-Acetyl-5-tert-butyl-2H-pyrazol-3 -yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthal en-i yl]-2-oxo-acetamide; 5-tert-Butyl-N-cyclopropyl-3 - f{2-hydrazono-2-[4-(2-morpholin-4-y1-ethoxy)-naphthalen 1 -yll-acetylamino }-2-methoxy-benzamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-(4-methoxy-naphthalen- Il-yl) propionamide; 41 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -y1)-2-oxo-2-pheny1-acetamide; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-hydrazono-2-[4-(2. morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-acetamide; 2,3-Dihydro-indole- 1-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl)-amide; N-(3 ,4-Dimethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-2-oxo acetamide; N-(5-tert-Butyl-2-cyclohexyl-2H-pyrazol-3-yl)--2- [4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -y]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-(3 ,5-difluoro-phenyl)-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalen- 1-yl)-acetamide; N-(5-tert-Butyl-isoxazol-3 -yl)-2- [(Z)-hydroxyimino]-2- [4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl]-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-diethylamino ethoxy)-naphthalen- l-yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2- {4- [2-(3-oxo-[ 1,4ldiazepan- l-yl) ethyl] -nap-hthaien- 1l-yl I -acetamide; 5-tert-Butyl-N-ethyl-2-methoxy-3-[2-(4-methoxy-naphthalen- 1 -yl)-2-oxo-acetylamino] benzamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2- f{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin 3-yl] -naphthalen- Il-yl I -acetamide; 5-tert-Butyl.-3-cthancsulfonylamino-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy) naphthalen- Il-yl] -benzamidc; 2-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-2-oxo-N-m-tolyl-acetamidc; N-(2,5-Dimethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- Il-yl] -2-oxo acetamide; Pyrrolidine-l1-carboxylic acid (5-tert-butyl-2-methoxy-3 - 2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1-yl]-2-oxo-acetylamino }-phenyl)-amide; 2-(4-Bromo-phenyl)-N-(5-tcrt-butyl-2-methoxy-phenyl)-acetamide N(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2 -oxo-2- f4-[2-((S)- 1-phenyl-ethylamino) pyrimidin-4-ylamino]-naplithalen- l-yl} -acetamide;, 5-tert-Butyl-3 -[1 -(2,3-dimethyl-phenyl)-3 ,5-dioxo-[ 1,2,4]triazolidin-4-yl]-2-methoxy benzamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-naphthalen-2-yl-acetamide; 42 WO 2007/146712 PCT/US2007/070547 5-tert-Butyl -2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl] -2-oxo acetylamino} -benzamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-methoxy-2-(4-methoxy-naphthalen- l-yl) propionamide; 5-tert-Butyl-2-methoxy-N- 14-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -ylmethyl]-3 -nitro benzamnide; N-(5-tert-Butyl-2-methoxy-3 - {2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetylamnino} -phenyl)-benzamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-(2, 5-difluoro-phenyl)-acctamide; N-(3 ,5-Di-tert-butyl-2-methoxy-phcnyl)-2- [(Z)-hydroxyimino] -2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1 -yl]-acetamide; N'- [1-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -ylcarbamoyl)- 1 -[4-(2-morpholin-4-yI-ethoxy) naphthalen- 1-yl]-meth-(E)-ylidene]j-hydrazinecarboxamnide; N-[2-(4-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3 -yl]-2-hydroxy-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- l-yl] -acetamnide; 5-tert-Butyl-3 - {2-[(Z)-methoxyimino]-2- [4-(2-morphoiin-4-yl-ethoxy)-naphthalen- i-yi]j acetylamino }-thiophene-2-carboxylic acid amnide; Ethanesulfonic acid (5-tert-butyl-2-methoxy-3 - 3 -[4-(2-morpholin-4-yl-ethoxy) naplithalen- l-yl] -2, 5-dioxo-2,5-dihydro-pyrrol- l-yl} -phenyl)-amide; 5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- l-yl] -2-oxo-acetylamino }-benzamide; 5-Fluoro- 1H-indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl)-amide; N-[ 5-tert-Butyl-2-methoxy-3 -(2-methoxy-acetylamino)-phenyl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthal en- l-yl] -2-oxo-acetamide; 7-Bicyclo [2.2. 1 ]hept-2-yl-9-p-tolyl-2-p-tolyl amino-7,9-dihydro-purin-8 -one; N-(5-tert-Butyl-2-isopropoxy-3 -methanesulfonylamino-phenyl)-2- [4-(2-morpholin-4-yl ethoxy)-naphthal en-i -yl]-2-oxo-acetamnide; N-[ 5-tert-Butyl-2-(3 ,4-dimethyl-phenyl)-2H-pyvrazol-3-yl]-2- [4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 3-tert-Butyl- 1 -(3,4-dichloro-phenyl)-5-phenyl- I ,6-dihydro-imidazo[4,5-c]pyrazole; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-oxo-2- [4-(2-thiomorpholin-4-yl-ethoxy) naphthalen-1I -ylj-acetamide; 5 -Nitro- 1 H-pyrazole-3 -carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl)-amide; 43 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-3 -methanesulfonyl amino-2-methoxy-phenyl)-2- [4-(2-dimethylamino pyrimidin-4-ylamino)-naphthal en-i -yl]-2-oxo-acetamnide; 1 -(2-Amino-4-tert-butyl-6- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-2-oxo acetylamino) -phenyl)-pyridinium; N-(5-tert-Butyl-2-isopropoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- Il-ylJ 2-oxo-acetamide; N-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen- 1 -ylJ-2,5-bis-trifluoromethyl-benzamide; 2-(tert-Butyl-dimethyl-silanyloxy)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(4 methoxy-phenyl)-acetamide; N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2- [(Z)-hydroxyiminoJ -2-[4-(2-morpholin-4 yl-ethoxy)-naphthalcn-1 -yl]-acetamide; 5 -tert-Butyl-2-methoxy-3 -[2-(4-methoxy-naphthalen- 1 -yl)-2-oxo-acetyl amino] benzamide; N-(5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-oxo-2-phenyl-acetamide; 5 -tert-Butyl-2-methoxy-N-(2-methoxy-ethyl)-3- {2-[4-(2-morpholin-4-yl-ethoxy) naphthaen- i-yl] -2-oxo-acetylamino} -benzamide; (E)-3 -(5 -tert-Butyl-3 -ethanesulfonylamino-2-methoxy-phenylcarbamoyl)-3- [4-(2 morpholin-4-yl-ethoxy)-naphthalen- I -yl]-acrylic acid methyl ester; 1 -Isopropyl-3 -phenyl-5 -phenylamino- 1, ,3-dihydro-imidazo [4,5-b]pyridin-2 -one; N-(5-tert-Butyl-isoxazol-3 -yl)-2-14-(2-morpholin-4-yl-pyrimidin-4-ylamino)-naphthalen 1 -yl]-2-oxo-acetamide; 2-(2-Benzyl-5 -tert-butyl-2H-pyrazol-3 -yl)-2- [(Z)-hydroxyimino]-N-[4-(2-morpholin-4 yl-cthoxy)-naphthalen-1 -ylJ-acetamide; 2-(5 -tert-Butyl-2-methoxy-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl] -2 oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-(2,4-dimethoxy-phenyl)-acetamide; (5-tert-Butyl-2-methoxy-3 -{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetylamino) -phenyl)-carbam-ic acid methyl ester; 3-tert-Butyl-5- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl] -2-oxo-acetylamino } pyrazole- 1 -carboxylic acid adamantan- 1 -ylamide; 3 -tert-Butyl-5 -phenyl- 1 -(4-trifluoromethyl-phenyl)- 1 ,6-dihydro-imidazo[4, 5-c]pyrazole; N-(5-tert-Butyl-2-methoxy-3 - f{3 -[4-(2-morpholin-4-yl-ethoxy)-naphthalen- Il-yl]-2,4, 5 trioxo-imidazolidin- 1 -yl I -phenyl)-methanesulfonamide; 44 WO 2007/146712 PCT/US2007/070547 3-tert-Butyl- 1 -(3 -chloro-phenyl)-5-phenyl- 1 ,6-dihydro-imidazo[4, 5-cipyrazole; 5-tert-Butyl-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yl] -2-oxo-acetylaminol thiophene-2-carboxylic acid amide; 2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-N-[4-(2-morpholin-4-yl-ethoxy) naphthal en-i -yl]-acetamide; ,N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)- 2 - {4-[2-(2,6-dimethy-morpholin-4-y1)-ethy1] naphthalen- l-yl} -2-oxo-acetamide; N-(5-tert-Butyl-2H-pyrazol-3 -yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalcn-I -yl] -2 oxo-acetamide; N-[5 -tert-Butyl-2-methoxy-3 -(propane- I -sulfonylamino)-phenyl] -2-[4-(2-morpholin-4-yl ethoxy)-naphthal en- I -yl]-acetamide; 3-tert-Butyl-5- f{2-[4-(2-morpholin-4-yI-ethoxy)-naphtha en- I -yl]-2-oxo-acetylamino} pyrazole-1 -carboxylic acid tert-butylamide; 1 -(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3 -(2,3 -dichlorophenyl)-3 '-(carbamic acid ethyl ester)-urea ; 2-(3 ,5-Difluoro-phenyl)-N- [4-(2-morphoiin-4-yl-ethoxy)-naphtha en- 1 -yl-2-oxo acetamide; 3 -tert-Butyl-5 - f{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1l-yl] -2-oxo-acetyl amino} pyrazole-1 -carboxylic acid amide; N-Allyl-5-tert-butyl-2-methoxy-3 - {2- [4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1l-yl] -2 oxo-actylamino I}-b enzamide; N-(5-tert-Butyl-isoxazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl] -acetamide; 3-(5 -tert-Butyl-2-methyl-2H-pyrazol-3 -yl)- I - [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-pyrrole-2, 5-dione; 2-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-2-[(Z)-hydroxyimino] -N-[4-(2-morpholin-4 yl-ethoxy)-naphthalen-1 -yl]-acetamide; 3-tert-Butyl-5-o-tolyl- 1 -p-tolyl- 1,6-dihydro-imidazo [4, 5-clpyrazole; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yi)-2-[(E)-hydroxyiminoj-2-phenyl-acetamide; N-(5-tort-Butyl-2-methoxy-phenyl)-2-hydroxy-2-pheny1-acetamide N-(3-Acetylamino-5-ter-t-butyl-2-methoxyr-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; 45 WO 2007/146712 PCT/US2007/070547 1 H-Jndazole-3-carboxylic acid (5-tert-butyl-3 -methanesulfonylamino-2-methoxy phenyl).-amide; 5-tert-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -3 -nitro benzarnide; 5-tert-Butyl-3 - f{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-y1-pyrimidin-4-yloxy) naphthalen- 1-yl]-acetylamino }-thiophene-2-carboxylic acid amide; N-[3-(4-Acetyl-piperazine-l1-carbonyl)-5-tert-butyl-2-methoxy-phenyl] -2- [442 morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 2-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-N-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy) naphthalen- 1 -ylJ-2-oxo-acetamide; N-(5-tert-Butyl-4-methyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-[(Z)-hydroxyimino] -2-[4-(2 morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide; 2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen- 1l-yll -2-oxo-N-(2-phenyl-cyclopropyl) acetamide; N-(5-tert-Butyl-isoxazol-3 -yl)-2-[4-(6-morpholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 yl] -2-oxo-acetamide; N-(5-tert-Butyl-2 ,3 -dimethoxy-phenyl)-2-[(Z)-hydroxyimino] -2-14-(2-morpholin-4-yl ethoxy)-naphthal en- 1l-yl] -acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2-chloro-phenyl)-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2- {4-12-(4-methyl-piperazin- I -yl)-ethyl] naphthalcn- 1-yl}-2-oxo-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-(l1H-indol-3 -yl)-2-oxo acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-14-(2-morpholin-4-yl-pyridin-4-ylamino) naphthalen- 1-yl]-2-oxo-acetamide; N-(4-tert.-Butyl-6-trifluoromethyl-pyrimidin-2-yl)-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1-yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-o-tolyl-acetamide; 5-tert-Butyl-3 - 2-[(Z)-hydroxyimino]-2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl] acetylamino} -thiophene-2-carboxylic acid methylamide; ,N- [5-tert-Butyl-2-(3 ,5-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 46 WO 2007/146712 PCT/US2007/070547 iN-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2- {4- [2-((2R,6S)-2,6-dimethyl-morpholin-4 yl)-ethoxy]-naphthalen-1 -yl}-2-oxo-acetamnide; 3-tert-Butyl- 1,5-diphenyl- 1,6-dihydro-imidazo[4,5-c]pyrazole; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-[4-(2-imidazol- 1-yl-ethyl)-naphthalen- l-yl] 2-oxo-acetamide; 3 -tert-Butyl-5-(3-chloro-phenyl)-l1-p-tolyl- 1,6-dihydro-imidazo [4, 5-c]pyrazole; iN-(5-tert-Butyl-2-methoxy-3 -phenylmethanesulfonylamino-phenyl)-2- [4-(2-morpholin-4 yl-ethoxy)-naphthalen- 1-yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-oxo-2-[4-(2-pyridin-4-yl-cthoxy) naphthalen- 1 -ylJ -acctamide; 1 -(5-tert-Butyl-2-methoxy-phenyl)-3 -(4- {2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4 yloxy} -naphtha] en- I -yI)-imidazolidine-2,4, 5-tri one; N-[ 5-tert-Butyl-2-(3-chloro-phenyl)-2H-pyrazol-3 -yl] -2-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl]-2-oxo-acetamide; 5-Methoxy- 1H-indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) amide; N-[5-tert-Butyl-2-(6-chloro-pyridazin-3-yl)-2H-pyrazol-3-yl -2-r4-(2-morpholin-4-yl ethoxy)-naphthalen- 1-yl]-2-oxo-acetamnide; N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen 1 -yl]-2-oxo-acetamnide; N-(5-tcrt-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2-methoxy-phenyl)-acetamide; 5-tert-Butyl-N-cyclopropyl-2-mcthoxy-3- {2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino) naphthalen- Il-yl] -2-oxo-acetylamino }-benzamide; [(5-tert-Buty -2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetylamino } -phenyl)-methanesulfonyl-amino] -acetic acid ethyl ester; N-(5-tert-Butyl-4-methyl-2-m-tolyl-2H-pyrazol-3 -yl)-2-[(Z)-hydroxyimino]-2-[4-(2 morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-acetamide; N-[5-tert-Buty1-2-(2, 5-dichloro-phenyl)-2H-pyrazol-3-yl] -2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- I -ylJ-2-oxo-acetamide; N-(5-tert-Butyl-2-p-toly1-2H-pyrazol-3 -yl)-2-[zl-(2-I 1 4]oxazepan-4-yl-ethoxy) naphthalen- 1 -ylJ-2-oxo-acetamide; 1 -(5-tert-Butyl-2-methoxy-3 -benzamide)-3 -(4-methoxy-phenyl)-3 '-(carbamic acid ethyl ester)-urea; 47 WO 2007/146712 PCT/US2007/070547 N-[5-tert-Butyl-2-(4-methoxy-pheny1)-2H-pyrazo1-3-y1]-2-(4-methoxy-naphthalen byl) acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-4-chloro-benzamide; N-(2-Bromo-5-trifluoromethyl-phenyl)-2- r4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl] 2-oxo-acetamide; 3-Isopropyl-5-phenyl-l1-p-tolyl- 1,6-dihydro-imidazo [4,5-cipyrazole; 3 ,5-Di--tert-butyl- 1 -p-tolyl- 1,6-dihydro-imidazo [4,5-c]pyrazole; 5-tert-Butyl-N-cyclopentyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-.ethoxy)-naphthalen- 1 yl] -2-oxo-acetylamino} -benzamide; 2-[5-tert-Butyl-2-(3-fluoro-4-methyl-pheny])-2H-pyraz-ol-3 -yl]-N- [4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-(4-methoxy-phenyl)-2-oxo-acetamide; 1,3 -Di-tert-butyl-5-phenyl- 1 ,6-dihydro-imidazo [4,5-c]pyrazole; 4-(4-Bromo-naphthalen- Il-yl)-l -(3 -tert-butyl-phenyl)-[ 1 ,2,4ltriazolidine-3 ,5-dione; N- r5-tert-Buty1-2-(morpholine-4-carbony1)-thiophen-3 -yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 3 -tert-Butyl-5 -(3 -methoxy-phenyl)- I -p-tolyl- 1, 6-dihydro-imidazo[4,5-c]pyrazole; N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy) naphthalen-1 -yl] -2-oxo-acetamide; 1 -tert-Butyl-5-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -ylamino] -3 -p-tolyl- 1,3 dihydro-imidazo [4,5-b]pyridin-2-one; 2-[5-tert-Butyl-2-(3-fluoro-phenyl)-2H-pyrazol-3-yl] -2-[(Z)-hydroxyimino] -N -[4-(2 morpholin-4-yl-ethoxy)-naphthalen- 1l-yl] -acetamide; 5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid [4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -ylmethyll -amide; 2-[5-tert-B utyl-2-(3 -fluoro-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3 -[2-(4-methoxy-naphthalen- 1 -yl)-2-oxo acetylaminol-benzamide; N-[5-tert-Butyl-3 -(3,3 -diethyl-ureido)-2-methoxy-phenyl]-2- r4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamnide; N-[5-tert-Butyl-2-(4--fluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl] -2-oxo-acetamide; 48 WO 2007/146712 PCT/US2007/070547 N-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-2-oxo-acetamide; N-(5-tert-Buty1-3-methanesulfonylamino-2-methoxy-pheny1)-2-oxo-2-[4-(2-piperazin- 1 yl-ethoxy)-naphthalen-I -yll -acetamide, N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2 -morpholin-4-yl pyridin-4-ylamino)-naphthalen-1 -yl]-2--oxo-acetamide; (5-tert-Butyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-cthoxy)-naphthalen-I -ylJ-2-oxo acetylaminol}-phcnyl)-carbamnic acid isopropyl ester; 1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-dimethylamino-pyrimidin-4-yloxy) naphthal en- Il-yl] -imidazolidine-2 ,4,5-tri one; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl pyrimidin-4-ylamino)-naphthalen- 1-yl]-2-oxo-acetamide; 4-(3-tert-Butyl-l1-p-tolyl- 1,6-dihydro-imidazo [4,5-c]pyrazol-5-yl)-2-methoxy-phenol;, N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-(3 ,4-dichloro-phenyl)-acetamide; N[3 -(3-Allyl-ureido)-5-tert-butyl-2-methoxy-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -y1]-2-oxo-acetamide; 5-tert-Butyl-N,N-diethyl-2-methoxy-3 -{2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-2-oxo-acetylamino } benzamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-[ 1,4]oxazepan-4-yl ethoxy)-naphthalen-1 -yl]-2-oxo-acctamidc; N-(3 -tert-Butyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -ylJ-2-oxo acetamide; 5-tert-Butyl-N-ethyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yll acetylaminol -benzamide; N-[5-tert-Butyl-2-(6-methyl-pyridin-3 -yl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1I -yl]-2-oxo-acetamide; N- [5-tert-Butyl-2-(4-ureido-phenyl)-2H-pyrazol-3-yl] -2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-m-toly1-2H-pyrazo1-3 -yl)-2-[4-(2-dimethylamino-ethoxy)-naphthalen I -yl]-2-oxo-acetamnidc; N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-f4-(2-piperidin- I .-yl-pyrimidin-4-yloxy) naphthalen- 1 -yl]-acetamide; 49 WO 2007/146712 PCT/US2007/070547 N- [5-tert-Butyl-2-(3 -fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl] -2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; Indazole-l1-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl)-amide; N- [3,5-Bis-( 1,1 -dimethyl-propyl)-2-methoxy-phenyl] -2-[4-(2-rnorpholin-4-yl-ethoxy) naphthalen-1 -yl]-2-oxo-acetamide; 1 -Benzyl-3 -tert-butyl-5-phenyl- 1,6-dihydro-imidazo [4, 5-c]pyrazole; 2-(5-tert-Butyl-2-methoxy-3 -nitro-phenyl)-N- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl] -2-oxo-acetamide; 4- {2- [4-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylaminooxalyl) naphthalen- 1 -yloxy] -ethyl) -piperazine- 1 -carboxylic acid ethyl ester; 2-Hydroxy-N-(5-isopropyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholi-4-y-ethoxy) naphthalen-1 -yl]-acetamide; 1 -Bicyclo [2.2. 1 ]hept-2-yl -3 -phenyl-5 -phenyl amino- 1,3 -dihydro-imidazo [4,5 -b]pyridin-2 one; N-(3 -Amino-5-tert-butyl-2-methoxy-phenyl)-2- [4-(2-morpholin-4-yl-pyrimidin-4 ylamino)-naphthalen- l-yi] -2-oxo-acetamide; N-r5-tert-Butyl-3 -(2-dimethylamino-acetylamino)-2-methoxy-phenyl]-2- [4-(2-morpholin 4-yl-ethoxy)-naphthalen- l-yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-3- {6-14-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl]-3 ,5 dioxo-2,5-dihydro-3H-[ 1,2,4ltriazin-4-yl }-phenyl)-methanesulfonamide; N-5tr-uy--ehl2-przl3y 1[-2mrhoi--lehx)nptae yl]-2-oxo-acetamide; (R)-N-(5-tert-Butyl-2-p-toly-2H-pyrazo-3-y)-2-hydroxy-2-phenly-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-dimethylamilo ethoxy)-naphthalen- 1-yl]-2-oxo-acetamide; 2-(5-tert-Buty1-2-methy1-2H-pyrazo1-3-yl)-N-[4-(2-morpholil-4-yl-ethoxy)-naphthalefl yl]-2-oxo-acetamide; N-[2-(3-Amino-phenyl)-5-tert-butyl-24-pyrazol-3 -yl] -2-hydroxy-2- [4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-acetamide; 2-[5 -tert-B utyl-2-(3-chloro-phenvl)-2H-pyrazol-3 -yl] -N-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; 1 ,5-Diphenyl- 1 ,6-dihydro-imidazo[4,5-c]pyrazole; 50 WO 2007/146712 PCT/US2007/070547 N.-(5-tert-Butyl- [1,3 ,4Jthiadiazol-2-yl)-2- [(Z)-hydroxyimino] -2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1I-yl]-acetamide; N-(5-tert-Butyl-3- {2-hydroxy-2- [4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 yl] -ethylamino)}-2-methoxy-phenyl)-methanesulfonamnide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-4-chloro-benzamide; N-(5-tert-Butyl-2-ethoxy-phenyl)-2-r4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yll- 2 oxo-acetamide; (5-tert-Butyl-.2-methoxy-3 -{2- [4-(2-morpholin--4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetyl amino I -phenyl)-carbamic acid 2-methoxy-ethyl ester; (R)-N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-methoxy-2-phenyl-acetamide; 2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3 -yl)-2-hydroxy-N-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1I -ylJ-acetamide; 2-Amino-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-y)-2-naphthal en-i -yI-acetamide; N-(5-tert-Butyl-3 -methanesulfonylarnino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1-yl]-acrylamide; N-(5-tert-Butyl-2-p-tolyi-2H-pyrazol-3-yl)-2-[4-(2-imidazol- 1-yl-ethoxy)-naphthalen- 1 yl]-2-oxo-acetwmide; N-(4-Bromo-3-trifluoromethyl-phenyl)-2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1Nyl] 2-oxo-acetamide; 4-(4-Benzyloxy-phenyl)-l1-(3 -tert-butyl-phenyl)-[ 1,2,4lltriazolidine-3 ,5-dione; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[8-chloro-4-(2 morpholin-4-yl-ethoxy)-naphthalen- i-yil]-2-oxo-acetamide; N-(5 -tert-Butyl-3-mcthanesulfonylamnino-2-methoxy-phenyl)-2- [4-(2-chloro-ethoxy) naphthalen- 1 -yl]-2-oxo-acctamide; 5 -tert-Butyl-3 - f{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalcn- 1 -yl] -2-oxo-acetyl amino} thiophene-2-carboxylic acid dimethylamide; 1 -(5-tert-Butyl-isoxazol-3 -yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-ylJ imidazolidine-2,4,5-trione; N-(4-Chloro-3 -trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthal en- l-yl] 2-oxo-acetai-nide; 1 -Benzoyl-3-(5-tert-butyl-2-methoxy-phenyl)-urea; N'-[ 1 -(5-tert-Butyl-3 -ethyl earbamoyl-2-methoxy-phenylcarbam oyl)- I -[4-(2-morpholin-4 yl-ethoxy)-naphthalen- 1-yl]-meth-(Z)-ylidene] -hydrazinecarboxylic acid ethyl ester; 51 WO 2007/146712 PCT/US2007/070547 3 -tert-Butyl-5-(3-fluoro-phenyl)- 1-p-tolyl- 1,6-dihydro-imidazo [4, 5-clpyrazole; 2-13-Bromo-4-(2-morpholin-4-yl-ethoxy)-phenyl]-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol 3 -yl)-acetamide; 2-(2-Chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl] 2-oxo-acetamide; N- [5-tert-Butyl-2-(3-chloro-benzenesulfonyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1 -yl]-2-oxo-acetamide; (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-carb amic acid p-tolyl ester; N-(5-tert-Butyl-2-diethylamino-3 -methanesulfonylam ino-phenyl)-2-[4-(2-morpholin-4 yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-14-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yI]-acetamide; N-[5-tert-Butyl-2-methoxy-3 -(propane-i1 -sulfonylamino)-phenyl]-2-(4-methoxy naphthalen- 1 -yl)-2-oxo-acetamide: Propane- I -sulfonic acid (5-tert-butyl-2-methoxy-3 -{4-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1-yl]-3, 5-dioxo-I1 ,2,4]triazolidin- i-yl }-phenyl)-amide; 3 -Amino- 5-tert-butyl-2-methoxy-N- [4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 ylmethyl]-benzamide; 2- [4-(2-Morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-2-oxo-N-(3 -trifluoromethyl-phenyl) acetamide; 4-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-6-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-2H-[ 1 ,2,4ltriazine-3,5-dione; N-h 5-tert-Butyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3 -yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; N-[5-tert-Butyl-2-methoxy-3 -(propane- I -sulfonylamino)-phenyl]-2-[4-(2-dimethylamino pyrimidin-4-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamnide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-phenyl-acetamide; N-[5-tert-Butyl-2-methoxy-3 -(propane- I -sulfonylamino)-pheny1-2-114-(2-morpholin-4-yl pyrimidin-4-yloxy)-naphthalen- I -yl]-2-oxo-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamnino-2-methoxy- henyl)-2- {4-[2-(2,6-dimethyl morpholin-4-yl)-ethoxy]-naphthalen- l-yl} -2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(4-methoxy-naphthalen- 1-yl)-acetamide; 3-tert-Butyl-1 -cyclohexyl-5-phenyl- 1,6-dihydro-imidazo [4, 5-clpyrazole; 52 WO 2007/146712 PCT/US2007/070547 3-tert-Butyl-5-(4-fluoro-phenyl)- 1 -p-tolyl- 1 ,6-dihydro-imidazo [4, 5-c]pyrazole; N-(5-tert-Butyl-2-methoxy-3 - {4- [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yll-3 ,5 dioxo-[ 1 ,2,4]triazolidin- Il-ylj -phenyl)-methanesulfonamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-oxo-2- { 4- [2-(3-oxo-piperazin- 1 -yl)-ethyll naphthalen- 1 -yl) -acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2- [4-(3-pyridin-4-yl-propoxy) naphthal en-i1 -yl]-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino] -244 (2-morpholin-4-yl-ethoxy)-5,6,7, 8-tetrahydro-naphthalen- Il-yl] -acetamide; N-[5-tert-Butyl-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3 -yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -ylcarbamoyl)-2,5-dihydro-pyrrole- 1 -carboxylic acid tert-butyl ester; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-imidazol- Il-yl ethoxy)-naphthalen-1I -yl] -2-oxo-acetamide; N-[5-tert-Butyl-2-(3 ,5.-dimethyl-phenyi)-2H-pyrazol-3 -yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yll-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyridin-4-ylamino) naphthalen-1I -yl] -2-oxo-acetamide; N- f 5-tert-Butyl-3 - [carbamoylmethyl-(propane- 1 -sulfonyl)-amino]-2-methoxy-phenyl } -2 naphthalen- 1 -yl-2-oxo-acetamide; N'-[ 1 -(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)- 1 -[4-(2-morpholin-4-yl-ethoxy) naphthalen- l-yl] -meth-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester; 5-tert-Butyl-N-cyclopropyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-acetylamino} -benzamide; N- [5-tert-Butyl-2-(3 -nitro-phenyl)-2H-pyrazo] -3-yI]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-[3 -chloro-4-(2-morpholin-4-yl-ethoxy) phenyl]-2-oxo-acetamide; N-(3-Benzenesulfonylamino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 3 -tert-Butyl-5- f{2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetylamino} pyrazole- 1-carboxylic acid cyclohexylamide; 53 WO 2007/146712 PCT/US2007/070547 N-[5-tert-Butyl-2-methoxy-3-(2,2,2-trifluoro-ethanesulfonylamino)-phenyl]-2-[4-(2 morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; N'-[ 1 -(5-tert-Butyl-3 -carbamoyl-2-methoxy-phenylcarbamoyl)- 1 -[4-(2-morpholin-4-yl ethoxy)-naphthalen-1-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester; 5-tert-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-3-(propane- 1 sulfonylamino)-benzamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-(4-methoxy-naphthalen-1-yl) acetamide; (5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo acetylamino}-phcnyl)-carbamic acid 2-dimethylamino-ethyl ester; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[7-fluoro-4-(2-morpholin 4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetamide; N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)-naphthalen-1 y1]-2-oxo-acetamide; 3-tert-Butyl-1-(4-chloro-phenyl)-5-phenyl-1,6-dihydro-imidazo[4,5-c]pyrazole; N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yi)-2-(4-methoxy-naphthalen-1 -yi)-2-oxo acetamide; 2-[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[(Z)-hydroxyimino]-N-[4-(2 morpholin-4-yl-ethoxy)-naphthalen-1-yl]-acetamide; N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-methoxy-naphthalen-1-yl)-2-oxo-acetamide; N-[5-(1,1 -Dimethyl-propyl)-2-p-tolyl-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-morpholin-4 yl-ethoxy)-naphthalen-1-yl]-acetamide; N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-dimethylamino pyrimidin-4-ylamino)-naphthalen-1-yl]-2-oxo-acetamide; N-(2-Chloro-5-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl] 2-oxo-acetamide; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[2,3-dichloro-4-(2 morpholin-4-yl-ethoxy)-phenyl]-2-oxo-acetamide; N-(3-Methanesulfonylamino-2-methoxy-5-methyl-phenyl)-2-[4-(2-morpholin-4-y ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 4- {2- [4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl)-naphthalen- 1 -yl]-ethyl} piperazine-1-carboxylic acid ethyl ester; (1-Benzyl-1H-benzoimidazol-2-yl)-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amine; 54 WO 2007/146712 PCT/US2007/070547 N-(3 ,5-Di-tert-butyl-2-hydroxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-naphthalen-1 -yl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy) naplithal en- 1l-yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino) naphthalen- 1 -yll-2-oxo-acetamide; 4- {2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl)-naphthalen- 1 -yloxy] -ethyl} piperazine-1-carboxylic acid ethyl ester; 5-tert-Butyl-2-methoxy-3 - { 2- [4-(2-morpholin-4-yl-pyrimidin-4-ylamino)-naphthalen-1 yl] -2-oxo-acetylamino I -benzamnide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-( 1-methyl- I H-indol-3 yl)-2-oxo-acetamide; 4-Phenyl-piperidine-4-carboxylic acid (5-tert-butyl-2-methoxy-phenyl)-amide; 5-tert-Butyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- I -yl] acetylamnino I -benzamide; N-[2-(4-Acetyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-mor-pholin-4-yl-ethoxy) naphthalen- 1 -yl] -2-oxo-acetamide; 1 -(5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-3 -[4-(2-morpholin-4-yl -ethoxy)-naphthalen- 1 yl]-imidazolidine-2,4, 5-trione; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-(2,3 -difluoro-phenyl)-acetamide; N-[5-tert-Butyl-3 -(carbamoylmethyl-methanesulfonyl-amino)-2-methoxy-phenyl] -2 naphthalcn- I1-yl-2-oxo-acetamnide; N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[2-methyl-4-(2-morpholin-4-yl-ethoxy) phenyl]-2-oxo-acetamnide; N-[2-(4-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-cthoxy) naphthalen- 1 -yl]-2-oxo-acetamide; (5-tert-Butyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthal en- I -yl]-2-oxo acetylamino}-phenyl)-carbamic acid phenyl ester; N-(5-tert-But;1-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethioxy)-naphthalen- 1 yi]-acetamide, N-(5-tert-Butyl-2-isobutoxy -phenyl)-2-[4-(2-morpholin-4-yl-dthoxy)-naphthalen- 1 -yl]- 2 oxo-acetamide; 55 WO 2007/146712 PCT/US2007/070547 N-(4-tert-Buty] -phenyl )-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 byl] -2-oxo acetamide; N-[ 5-tert-Butyl-2-(3 -methyl-benzoyl)-2H-pyrazol-3 -yl]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-3 - {2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- Il-yl] acetylamino }-thiophene-2-carboxylic acid amide; 1 -(5-tert-Butyl-2-methoxy-phenyl)-3 -[4-(2-chloro-pyrimnidin-4-yloxy)-naphthalen- l-yl] imidazolidine-2,4,5-trione; (S)-N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-acetamide; N-15-tert-Butyl-2-(2,3 -dimethyl-phenyl)-2H-pyrazol-3 -yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1 -ylJ-2-oxo-acetamide; N-[5-tert-Butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-yl] -2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- l-yl] -2-oxo-acetamide; 2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3 -yl)-N- [4-(2-morpholin-4-yl-ethoxy)-naphthalen 1 -yl]-2-oxo-acetamide; 2-f (Z)-Hydroxyimino] -N-(3-methanesulfonylamino-2-methoxy-5-methyl-phenyl)-2-[4 (2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-acetamide; N-[5-tert-Butyl-2-(morpholine-4-carbonyl)-thiophen-3 -yl] -2-[(Z)-hydroxyimino] -2-[4-(2 morpholin-4-yl-ethoxy)-naphthalen- l-yl] -acetamide; N-(5-tert-Butyl-2-phenyl-2H-pyrazol-3 -yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 ylJ-2-oxo-acetamide; N'-I1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)- 1-[4-(2-morpholin-4-yl-ethoxy) naphthalen- l-yl] -meth-(E)-ylidencJ -hydrazinecarboxylic acid ethyl ester;

N

t -[ 1-(5-tert-Butyl-2-methyl-211-pyrazol-3-ylcarbamoyl)- 1-[4-(2-morpholin-4-yl-ethoxy) naphthalen- l-yl] -meth-(Z)-ylidene]-hydrazinecarboxamide; N-[5-tert-Butyl-2-(3 -methoxy-phenyl)-2H-pyrazol-3 -yI]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1-yl]-2-oxo-acetamide; 5-tert-Butyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l1-yl]-2-oxo acetylamino} -N.\ -pyridin-2-yl-benzamide; N-[5-tert-Butyl-3 -(3,3 -dimethyl-ureido)-2-methoxy-phenyl]-2-[4-(2-morpholin-4- '1 cthoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-3 - {2-[7-chloro-4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetylamino I -2-methoxy-benzamide; 56 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-m-tolyl-acetamide; 1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-pyrrolidin-1I-yl-pyrimidin-4-yloxy) naphthalen- 1 -yl]-imidazolidine-2,4,5-trione; N-(5-tert-Butyl-2-p-toyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-propionamide; 2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen- I -yll-2-oxo-N-quinolin-3-yl-acetamide; 1 -(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3 -yl)-3- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-imidazolidine-2 ,4,5-trione; (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-(3-trifluoromethyl-benzyl)-amine; N- [5-tert-Butyl-2-methoxy-3 -(morpholine-4-carbonyl)-phenyl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; N-j[5-tert-Buty1-3 -(3-isopropyl-ureido)-2-methoxy-phenylJ -2-j14-(2-morpholin-4-yl ethoxy)-naphthalen-I -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-methoxy-2-(4-methoxy-naphhialen-l -yl) acetamide; N-(3 -Amino-5-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l -yl] 2-oxo-acetamnide; N-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-2-r4-(2-morpholin-4-yl-pyrimidin-4-yloxy) naphthalen-1 -yl] -2-oxo-acetamide; 3-Methyl-i ,5-diphenyl- 1,6-dihydro-imidazo[4,5-clpyrazole; N-(5-tert-Butyl-isoxazol-3-yl)-2-hydroxy-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-acetamide; N-[4-(2-Morpholin-4-y1-ethoxy)-naphthalen- 1 -yll-2-oxo-2-(2-phenyl-cyclopropyl) acetamide; 2- {4-[2-(4-Acetyl-piperazin- 1-yl)-ethoxy]-naphthalen-I -yl} -N-(5-tert-butyl-3 methanesulfonylamino-2-methoxy-phenyl)-2-oxo-acetamide; 2-(1 H-Indol -3-yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamnide; N-[5-tert-Butyl-2-(3-fluoro-pheny)-2H-pyrazol-3 -yl]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; 2-(3 -Aino-5-tert-butyl-2-methoxy-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen 1 -yl]-2-oxo-acetamide; N-[5-tert-Butyl-2-(3 ,4-cichloro-phenyl)-2H-pymazol-3-yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 57 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-i soxaz-ol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 yl] -2-oxo-acetamide; N-[5-tert-Butyl-2-(2,5-dimethyl-phenyl)-2H-pyrazol-3 -yl] -2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1-yl]-2-oxo-acetamide; N-(5--tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-5, 6,7,8-tetrahydro-naphthalen- 1-yll-2-oxo-acetamide; 1 H-Indazole-3 -carboxylic acid (5-tert-butyl-2-pyridin-2-yl-2H-pyrazol-3 -yl)-amide; N-(4-Chloro-3 -trifluoromethyl-phenyl)-2-(4-methoxy-naphthalen- 1 -yl)-2-oxo-acetamide; N- [5-(l 1 -Dimethyl-butyl)-2-p-tolyl-2H-pyrazol-3 -yl] -2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; 1 H-Indazole-3 -carboxylic acid [5 -tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl] amnide; 1 H-Indazole-3 -carboxylic acid [5-tert-butyl-2-(4-hydroxy-phenyl)-2H-pyrazol-3 -yl] amide; N'-[l1-(5-ter-t-Butyl-3 -methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1- [4-(2 morpholin-4-yil-ethoxy)-naphthaen-1 -yl]-meth-(E)-ylidene]-hydrazinecarboxamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-N-f4-(2-morpholin-4-yl-ethoxy)-naphthalen 1 -yl]-oxalamnide; N-(5-tert-Butyl-3 -methanesulfonylamnino-2-methoxy-phenyl)-2-[4-(2-methylamino pyrimidin-4-ylamino)-naphthalen- 1-yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholin-4 yl-cthoxy)-naphthal en-i -yl]-acetamide; 5-tert-Butyl-N-cyclopropyl-3 -[2-[(E)-hydroxyimino] -2-(4-methoxy-naphthalen- 1-yl) acetylamino]-2-methoxy-benzamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2- f{4-[2-(2, 6-dimethyl-morpholin-4-yl) ethoxy] -naphthal en- Il-yl } -2-oxo-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[8-fluoro-4-(2-morpholin 4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamnide; N(5-tert-Butyl-2-p-tolyi-2H-pyrazol-3 -yl)- 2 -(3 -fluoro-phenyl)-acetamid e; 5-tert-Butyl-N-furan-2-yhnethyl-2-methoxy-3 - f{2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- I -yl]-2-oxo-acetylamino I -benzamide; N-f 5-ter-t-Butyl-2-(3-trifluoromethyl-benzoyl)-2H-pyrazol-3 -yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamnide; 58 WO 2007/146712 PCT/US2007/070547 N-[5-tert-Butyl-2-methoxy-3 -(propane-i -sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl pyrimidin-4-ylamino)-naphthalen-1 -yl]-2-oxo-acetamide; 1 -(5-tert-Butyl-isoxazol-3-yl)-3 -[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 yll -imidazolidine-2,4,5-trione; 1 -(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-3'-(carbamnic acid ethyl ester)-urea ; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2- {4-[2-(3 -oxo piperazin- 1-yl)-ethoxy]-naphthalen- l-yl }-acetamide; 2- {4- [2-(4-Acetyl-piperazin- 1-yl)-ethyll -naphthalen- l-yl }-N-(5-tert-butyl-2-p-tolyl-2H pyrazol-3-yl)-2-oxo-acetamide; N-(5-tcrt-Butyl-2-phenylacetyl-2H-pyrazol-3 -yl)-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2- {4-[2-(3-oxo-piperazin- l-yl) ethoxyl -naphthal en- l-yl }-acetamide; 2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3 -yl)-2-[(Z)-hydroxyimino]-N- [4-(2-morpholin-4 yl-ethoxy)-naphthalen- 1-yl]-acetamide; N-[5-tert-Butyl-2-(3 -ureido-phenyl)-2H-pyrazol-3 -yll -2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- l-yl] -2-oxo-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2- [(Z)-methoxyiminol -2-[4 (2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- l-yl] -acetamide; N-[5-tert-Butyl-2-methoxy-3-(3-oxo-piperazine- 1 -carbonyl)-phenyll -2- [4-(2-morpholin 4-yl-ethoxy)-naphthalen- 1-yl]-2-oxo-acetamnide; 3-tert-Butyl-5- {2-[4-(2-morpholin-4-yl-cthoxy)-naphthalen-1 -ylJ-2-oxo-acetylamino } pyrazole-l1-carboxylic acid propylamide; 5-tert-Butyl-N-cycl opropyl-2-mnethoxy-3 - 2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy) naphthalen- 1-yl]-2-oxo-acetylamino }-benzamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)- 2 - {4- [2-(4-methyl-piperazin- 1-yl)-ethoxy] naphthalen- 1l-yl} -2-oxo-acetamide; N-(3-Amino-5-tert-butvl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy) naphthalen- I -yl]-2-oxo-acetamide; 5-tert-Butyl-2-methoxy-3 - f{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1l-yl] -2-oxo acetylamnino I -N-propyl-benzamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-hydroxy-2-(4-methoxy-phenyl)-acetamide; 59 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-2-[(Z)-hydroxyiminol -2-[4--(2-morpholin-4 yl-ethoxy)-naphthalen- 1-yl] -acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)- 2 -(3 -phenoxy--phenyl)-acetamide; N-(5-Isopropyl-2-methyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- Il-yl] -2 oxo-acetamnide; 7-Isopropyl-9-phenyl-2-phenylamnino-7,9-dihydro-purin-8-one; (5-tert-Butyl-2-methoxy-3 - f{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetylaminol}-phenyl)-carbamic acid pyridin-3 -ylmethyl ester; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-ethylamino ethoxy)-naphthalen- l-yl] -2-oxo-acetamide; N-(3 ,5-Di-tert-butyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo acetamnidc; 2-Amino-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-naphthalen-2-yl-acetamide; N-[5-tert-Butyl-2-(3 -fluoro-4-methyl-phenyl)-2H-pyrazol-3 -yl]-2-hydroxy-2-[4-(2 morpholin-4-yl-ethoxy)-naphthalen-1 -yl] -acetamide; 2-[5-tert-Butyl-2-(3 ,4-difluoro-phenyl)-2H-pyrazol-3-yl] -N-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1 -yl]-2-oxo-acetamide; N-(3 -Amino-5-tert-butyl-2-methoxy-phenyl)-2 -[4-(2-methylamino-pyrimidin-4-yl amino) naphthalen- Il-yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy) naphthalen- I -yl] -2-oxo-acetamide; N-[5-tert-Butyl-2 -(2,3 -dichloro-phenyl)-2H-pyrazol-3 -yl] -2- [4-(2-morpholin-4-yl ethoxy)-naphthalen- I -yl] -2-oxo-acetamide; N-[3 ,5-Bis-(, 1, -dimethyl-propyl)-2-hydroxy-phenyl] -2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- Il-yl] -2-oxo-acctamidc; 4- { 2- [4-(5 -tert-Butyl-3 -methanesulfonylamino-2-mcthoxy-phcnylaminooxalyl) naphthalen- I -yloxy] -ethyl I -piperazine- 1 -carboxylic acid tert-butyl ester; 3 -tert-Butyl- 1 -naphthalen-2-yl -5-phenyl- 1, 6-dihydro-imidazo [4,5-c] pyrazole; 2-Biphenyl-4-yl-N-(5-tert-butyl-2-p-tolyl-2H-p yrazol-3 -yl)-acetami de; 5-tert-Butyl-N -isopropyl-2-methoxy-3 - { 2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- I1 yl] -2-oxo-acetylamino I -b enzamide; N-(5 -tert-Butyl-3 -diethylaminomethyl-2-hydroxy-phenyl)-2- [4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamnide; 60 WO 2007/146712 PCT/US2007/070547 6-Hydroxy-nicotinic acid 3 -[5-tert-butyl-2-methoxy-3 -(propane-i -sulfonylamino) phen-ylcarbar-noyl]-1 H-indazol-5-yl ester; N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3 -yl)-2- [4-(2-morpholin-4-yl-pyrimidin-4 ylamino)-naphthalen-1 -yl]-2-oxo-acetamide;, N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4 ylamnino)-naphthalen-1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2--methoxy-phenyl)-2-[4-(4-morpholin-4-yl pyrimidin-2-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide; N-(3 -Amino-5-tert-butyl-2-methoxy-phenyl)-2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen 1 -ylJ-2-oxo-acctamnidc; 1,3 ,5-Triphenyl- 1,6-dihydro-imidazo[4,5-cJpyrazole; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-cyclohexyl-acetamnide; 2-[ 5-tert-Butyl-2-(2-chloro-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl]-2-oxo-acetamnide; 7-Cyclohexylmethyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one; 5-tert-Butyl-3 - f{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl 3-2-oxo-acetylamino} thiophene-2-carboxylic acid methylamide; 5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3 - f{2-r4-(2-morpholin-4-yl-ethoxy) naphthalen-I -yl] -acetylamino} -benzamnide; N-[5-tert-Butyl-2-(3 -methoxy-phenyl)-2H-pyrazol-3-yl] -2-[4-(2-morpholin-4-yl pyrimidin-4-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamnide; N'-[ I1 -(5-tert-Butyl-3 -carbamoyl-2-methoxy-phenylcarbamnoyl)-I 1-[4-(2-morpholin-4-yl ethoxy)-naphthalen- l-yl] -meth-(Z)-ylidcncJ -hydrazinecarboxylic acid ethyl ester; 4-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-l -(2 ,3-dimethiyl-phenyl)-[ 1,2,4]triazolidine 3,5-dione; N-(4-Fluoro-3 -trifluoromethyl -phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -ylJ 2-oxo-acetamide; 1 -Benzyl-3 -phenyl-5-phenylamino- 1,3-dihydro-imidazo[4,5-b]pyridin-2-one; N-(5-tert-Butyl-2-methoxy-phenyl)-2-naphthalen-2-yl-acetanide 2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1I-ylcarbamoyl]-py ole-i -carboxylic acid tert-butyl ester; N-(2,5-Di-tert-butyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-2-oxo acetamide; 61 WO 2007/146712 PCT/US2007/070547 2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-N-((1 S,2R)-2-phenyl cyclopropyl)-acetamide; 2-Oxo-2,3 -dihydro-benzoimidazole-l1-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol 3 -yl)-amide; N-(2-Methoxy-5-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-2-oxo-acetamide; N-[2-(4-Bromo-phenyl)-5-tert-butyl-2H-pyrazol-3 -yl]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- I yl] -2-oxo--acetamide; 1 -(5-tert-Butyl-2-methoxy-phenyl)-3 -[4-(2-morpholin-4-yl-pyrimidin-4-yloxy) naphthalen-1I -ylJ -imidazolidine-2,4,5-trione; 5-tert-Butyl-2-methoxy-N-methyl-3 - f{2-14-(2-morpholin-4-yl-ethoxy)-naphthalen- Il-yl]-2 oxo-acetyl amino I}-benzamide; N-(5-tert-Butyl-2-methoxy-3-piperidin- 1 -ylmethyl-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1l-yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-naphthalen- 1 -yl-2-oxo-acetamide; N-(2,5-Di-tert-butyl-2H-pyrazol-3 -yi)-2-[4-(2-morpholin-4-yi-ethoxy)-naphthalen- Il-yl] 2-oxo-acetamide; (5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carb amic acid 4-methoxy-phenyl ester; N-(3 -Amino-5-tert-butyl-2-methoxy-phenyl)-2-naphthalen- 1-yl-2-oxo-acetamnide; 5-tert-Butyl-N-ethyl-3 - {2-[(Z)-hydroxyimino]-2-[4-(2-mor-pholin-4-yl-ethoxy) naphthalcn- l-yl] -acetylamino} -2-methoxy-benzamide; 4- {2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 I-ylaminooxalyl)-naphthalen- l-yl] -ethyl } pip erazine- 1 -carboxylic acid tert-butyl ester; 5-tert-Butyl-N-ethyl-2-hydroxy-3 - {2-[4-(2-morpholin-4-yI-ethoxy)-naphthalen-I -yl] -2 oxo-acetylaminol}-benzamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-naphthalen- 1 -yI-acetamide; N-(5-tert-Buty1-2-ethoxy-3-methanesulfonylamino-pheny)-2-I4-(2-morpholin-4-yl ethoxy)-naphthalen- Il-yI] -2-oxo-acetamnide; N-[ 1 -(5-tert-Butyl-3 -ethyl carbamoyl-2-methoxy-phenylcarbamoyl)- 1 -[4-(2-morpholin-4 yl-ethox y)-naphthalen- Il-yl] -meth- 'E)-ylidene] -hydrazinecarboxainide;, 2- f{4-[2-(4-Acetyl-piperazin- 1 -yl)-ethoxy]-naphthalen- l-yl} -N-(5-tert-butyl-2-p-tolyl-2H pyrazol-3-y1)-2-oxo-acetamide;, 62 WO 2007/146712 PCT/US2007/070547 5-tcrt-Butyl-N-ethyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1l-yl] -2 oxo-acetylamino -benzamide; 5-tert-Butyl-2-methoxy-3 - f{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1l-yl] -2-oxo acetylaminol-benzoic acid; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-hydroxy-2- [4-(2 morpholin-4-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen- l-yl] -acetamide; N-(5-tert-Butyl-isoxazol-3 -yl)-2-[4-(2-dimethylamino-pyrimidin-4-ylamino)-naphthalen 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-3 - 2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)-naphthalen- l-yl] -2-oxo acetyl amino I -thiophene-2 -carboxylic acid amide; 2- [4-(2-Morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-2-oxo-N-m-tolyl-acetamide; 5-tert-Butyl-3 - 2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-ylJ-2-oxo-acetylamino } thiophene-2-carboxylic acid methyl ester; N'-[l1-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1- [4-(2 morpholin-4-yl-ethoxy)-naphthalen- l-yll -meth-(Z)-ylidene]-hydrazinecarboxamide; N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3 -yl]-2-[4-(2-morphoiin-4-yi-pyridin 4-ylamino)-naphthalen-1 -yl]-2-oxo-acetamide; N-(5-Isopropyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-2--oxo--acetamide; N-(5-tert-Butyl-isoxazol-3 -yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl] -2-oxo acetamide; N-(2-Benzoyl-5-tert-butyl-2H-pyrazol-3 -yl)-2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen 1 -ylJ-2-oxo-acetamide; 6-Bromo-l1H-indazole-3 -carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide; 5-tert-Butyl-N-ethyl-3 - 2-hydrazono-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl] acetylamino }-2-methoxy-benzamide; N-(5-tert-Butyl-3 -ethanesul fonylamino-2-methoxy-pheny1)-2-[(Z)-hydroxyiminoJ -2-L4 (2-morpholin-4-yl-ethoxy)-naphthalen-I -yl]-acetamide; N-(3-Amino-5-tert-buty1-2-methoxy-phenv1)-2-I4-(2-dimethylamino-pyrimidin-4 ylamino)-naphthalen- I -y1]-2-oxo-acetarnide; N-(5-tert-Butyl-thiophen-3 -yl)-2-[4-(2-mor-pholin-4-yl-ethoxy)-naphthalen- I -yll -2-oxo acetamide;, 63 WO 2007/146712 PCT/US2007/070547 N-[5-tert-Butyl-2-(4-chloro-phenyI)-2H-pyrazo-3-y]-2- [4-(2-morpholin--4-yl-ethoxy) naphthalen- I -yl]-2-oxo-acetamide; N'-[ 1 -(5-tert-Butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl)- 1 -[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-meth-(E)-ylidene] -hydrazinecarboxamide; ,N-[5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3 -yil]-2-f4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-3 - f{2-f 7-chloro-4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1l-yl] -2-oxo acetylamino } -N-cyclopropyl-2-methoxy-benzamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2- f{4-[2-(4-methyl piperazin- 1 -. yl)-ethoxy]-naphthalen-I -yll}-2-oxo-acetamide; 1 -(5-tcrt-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3 -[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl] -imidazolidin-2-one; N-(5-tert-Butyl-thiophen-3 -yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl] -acetamide; 5-tert-Butyl-N-cyclopropyl-3 -[2-[(Z)-hydroxyimino]-2-(4-methoxy-naphthalen- 1l-yl) acetyiamino]-2-methoxy-benzamide; N-(5-tert-Butyl-2-methyl-2H-pyrazol-3 -yl)-2-[4-(4-morpholin-4-yl-pyrimidin-2 ylamino)-naphthalen- 1 -yll-2-oxo-acetamide; N-15-tert-Butyl-2-(3 -methoxy-phenyl)-2H-pyrazol-3 -yl]-2-[(Z)-hydroxyimino]-2-[4-(2 morpholin-4-yl-ethoxy)-naphthalen-1 -yl] -acetamnide; N-[2-Methoxy-5-( 1-methyl- I -phenyl-ethyl)-phenyl] -2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl] -2-oxo-acetamide; 2-[5-tcrt-Butyl-2-(3 ,4-dimethyl-phenyl)-2H-pyrazol-3 -yl]-N-[4-(2-morpholin-4-yl ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 5-tert-Butyl-3 - f{2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)-naphthalen- 1 -yl]-2-oxo acetylamino} -thiophene-2-carboxylic acid amide; 5-tert-Butyl-N-isobutyl-2-methoxy-3- {2-[4-(2-morpholin-4-yI-ethoxy)-naphthalen- 1-yll 2-oxo-acetylamino }-benzamide; 2-(5-tert-Butyl-2-p-tolyl-2H-pyTazol-3 -yl)-2-[(Z)-hydroxyimino]-N-[4-(2-morpholin-4 yl-ethoxy)-naphthalen- 1-yl]-acetamide; 3-tert-Butyl-l1-(2,3-dichloro-phenyl)-5-phenyl- 1,6-dihydro-imidazo[4,5-c]pyrazole; N-(3 ,5-Di-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl] -2-oxo-acetamide; 64 WO 2007/146712 PCT/US2007/070547 5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl] acetylamino} -thiophene-2-carboxylic acid dimethylamide; N-(5-tert-Butyl-2-methoxy-3-methyl-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4 yl-ethoxy)-naphthalen-1-yl]-acetamide; N'-[1-(5-tert-Butyl-3-cyclopropylcarbamoyl-2-methoxy-phenylcarbamoyl)- 1-[4-(2 morpholin-4-yl-ethoxy)-naphthalen-1-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester; N-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-2-oxo-acetamide; N-[5-tert-Butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1-yl]-2-oxo-acetamide; N-[5-tert-Butyl-3-(imidazole-1-carbonyl)-2-methoxy-phenyl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1-yl]-2-oxo-acetamide; 2-(2,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-2 oxo-acetamide; N-[5-tert-Butyl-2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1-yl]-2-oxo-acetamide; 1H-Indazole-3-carboxylic acid (5-tert-butyl-2-methoxy-phenyl)-amide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-{4-[2-(5-oxo-[1,4]diazepan-1-yl) ethoxy]-naphthalen-1-yl}-acetamide; 3-tert-Butyl-1-p-tolyl-5-(4-trifluoromethyl-phenyl)-1,6-dihydro-imidazo[4,5-c]pyrazole; N-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1-yl]-2-oxo-acetamide; 3-tert-Butyl-5- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetylamino} pyrazole-1-carboxylic acid isopropylamide; N-(5-tert-Butyl-[1,3,4]thiadiazol-2-yl)-2-hydroxy-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1-yl] -acetami de; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-bydroxyimino]-2-[4 (2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1-yl] -acetamide; N-f[2-(3 -Amino-phenyl)-5-tert-butyl-2H-pyrazol-3 -yl] -2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; 3-tert-Butyl-5- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetylamino} pyrazole- 1 -carboxylic acid phenylamide; 65 WO 2007/146712 PCT/US2007/070547 2-(5-tert-Butyl-2-m ethyl-furan-3 -yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]- 2 oxo-acetamide; N-(5-tert-Butyl-2-o-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 yl]-2-oxo-acetamide; N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl] acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-(3-methoxy-phenyl)-acetamide; 5-tert-Butyl-3 -{2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 -yl]-2-oxo acetylamino}-thiophene-2-carboxylic acid amide; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-hydroxy-2-[4-(2 morpholin-4-yl-ethoxy)-naphthalcn- 1 -yl]-acetamide; N-[5-tert-Butyl-2-(2,4-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1 -yl]-2-oxo-acetanide; N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(3-hydroxy-propoxy)-naphthalen- 1-yl] -2-oxo acetamide; N-(3-tert-Butyl-isoxazol-5-y)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1-yl] -acetamide; 1H-Indole-3-carboxylic acid (5-tert-butyl-2-methoxy-phenyl)-amide; N-[5-tert-Butyl-2-methoxy-3-(propane- 1 -sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1-yl]-2-oxo-acetamide; 7-Bicyclo[2.2. 1 ]hept-2-yl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2,4-dichloro-phenyl)-acetamide; 5-tcrt-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide; N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[2,3-dimethyl-4-(2-morpholin-4-yl-ethoxy) phenyl]-2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-(3-fluoro-phenyl)-acetamide; 1-(5-tert-Butyl-2-methoxy-3-benzamide)-3-(2,3-dimethylphenyl)-3'-(carbamic acid ethyl ester)-urea; 2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-oxo-N-(3-trifluoromethyl-phenyl) acetamide; 7-Benzyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one; 2,5-Dihydro-1H-pyrrole-2-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) amide; 66 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-{4-[2-(5-oxo [1,4]diazepan-1-yl)-ethoxy]-naphthalen-1-yl}-acetamide; N-[5-tert-Butyl-2-(3-cyano-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-3-phenylacetylamino-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1 -yl]-2-oxo-acetamide; 2-(2-Chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy) naphthalen- 1 -yl]-2-oxo-acetamide; 1-(5-tert-Butyl-2-methoxy-phenyl)-3 - [4-(2-piperidin- 1 -yl-pyrimidin-4-yloxy)-naphthalen 1 -yl]-imidazolidine-2,4,5-trione; 2-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-2-hydroxy-N-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl]-acetamide; 5-tert-Butyl-3- {2-[4-(2-dimethyl amino-pyrimidin-4-ylamino)-naphthalen- 1 -yl]-2-oxo acetyl amino)-thiophene-2-carboxylic acid amide; N'-[1-(5-tert-Butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl)-1-[4-(2-morpholin-4 yl-ethoxy)-naphthalen-1-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester; N-(3-Methanesulfonylamino-5-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-hydroxy-3-piperidin-1-ylmethyl-phenyl)-2-[4-(2-morpholin-4-yl ethoxy)-naphthalen-1-yl]-2-oxo-acetamide; 2-(1-Methyl-1H-indol-3-yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-{4-[2-((S)-1-phenyl-ethylamino)-pyrimidin 4-ylamino]-naphthalen- l-yl} -acetamide; N-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy) naphthalen-1 -yl]-2-oxo-acetamide; N'- [1 -(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenylcarbamoyl)- 1- [4-(2 morpholin-4-yl-ethoxy)-naphthalen-1-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester; N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylJ-2-hydroxy-2-[4-(2-morpholin-4 yl-ethoxy)-naphthalen-1-yl]-acetamide; N-(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo acetylamino}-phenyl)-isobutyramide; 67 WO 2007/146712 PCT/US2007/070547 N-15-tert-Butyl-2-(4-methyl-benzoyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy). naphthal en- I -yl]-2-oxo-acetamide; N-[5-tert-Buty-2-(2-chloro-pheny)-2H-pyrazo-3 -yl]-2-[4-(2-morpholin-4-yl--ethoxy) naphthalen- 1 -yl]-2-oxo-acetamide; N-[5-tert-Buty1-2-(3-chloro-4-methyl-phenyl)-2H-pyrazo1.-3-y]-2-[4-(2-morphoin4yb ethoxy)-naphthalen-1 -yll-2-oxo-acetamide; 2-( 4 -Bromo-phenyl)-N-(5-tert-butyl-2-p-tolylb2H-pyrazol-3-yl)-acetamide; 2-(5-tert-Butyl-2-methyl-ftiran-3 -yl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3 -yl) naphthalen-1 -yl]-2-oxo-acetamide; 4-(4- {4-[2-(5-tert-Butyl-2-methyl-furan-3 -yl)-2-oxo-acetylamino]-naphthalen- 1 ylamino} -phenoxy)-pyridine-2-carboxylic acid methyl amide; N-[5 -tert-Buty1-2-methoxy-3 -(propane- 1 -sul fonyl amino)-phenyl] -2- [4-(2-morpholin-4-yl pyridin-4-ylamino)-naphthalen- 1-yl]-2-oxo-acetamide; 5-tert-Butyl-N-cyclopropyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-pyridin-4-ylamino) naphthalen- 1-yl]-2-oxo-acetylamino }-benzamide; N-(5-tert-Butyl-3--methanesulfonylamino-2-mefthoxy-phenyl)-2-oxo-2- {4-[6-(tetrahydro pyran-4-ylamino)-pyridin-3-yl]-naphthalen-1 -yl}-acetamnide; 3 -[2-(4-Bromo-naphthalen- 1 -yl)-2-oxo-acetyl amino] -5-tert-butyl-N-cyclopropyl-2 methoxy-benzamnide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-morpholin-4-yl pyridin-3-yl)-naphthalen- 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen- 1 -yl]-2-oxo-acetamide; N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-(4-pyridin-3-yl naphthalen- 1 -yl)-acetamide; N-(5-tert-Butyl-2-methyl-2H-pyra7zol-3-yl)-2-oxo-2-(4-pyridin-3 -yl-naphthalen- Il-yl) acetamide; 2-(4-Chloro-3-trifluoromethyl-phenyl)-N- [4-(2-morpholin-4-yl-ethoxy)-naphthalen-I -yl] 2-oxo-acetamide; 4- {4-[2-(4-Chloro-3-trifluorometh;1-phenyl)-2-oxo-acetylamino]-phenoxy} -pyridine-2 carboxylic acid methylamide; 1907 68 WO 2007/146712 PCT/US2007/070547 N-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4-(2-(5-methoxy-l1H-indol 3-yl)ethylamino)naphthalen- 1 -yl)-2-oxoacetamide; N-(3 -(N-(2-Amino-2-oxoethyl)methylsulfonamido)-5-tert-butyl-2-methoxyphenyl)-2-(4 (2-morpholinoethoxy)naphthalen- 1-yl)-2-oxoacetamide; N-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4-(6 (dimethylamnino)pyridin-3-yl)naphthalen- 1 -yl)-2-oxoacetamide; N-(5-tert-Butyl--2-methoxy-3 -(methylsulfonamrido)phenyl)-2-(4-(6-(methylamino)pyridin 3-yl)naphthalen- 1 -yl)-2-oxoacetamide; N-(5-tert-Butyl-2-methoxy-3 -(propylsulfonamido)phenyl)-2-(4-(2 (dimethylamino)pyridin-4-ylamino)naphthalcn- 1 -yl)-2-oxoacetamnide; N-(5-tert-Butyl-2-mcthoxy-3-(methylsulfonamido)phenyl)-2-(4-(2 (dimethylamino)pyridin-4-ylamnino)naphtha en- I -yl)-2-oxoacetamide; 5-tert-Butyl-N-cyclopropyl-3 -(2-(4-(2-(dimethylamino)pyridin-4-ylamino)naphthalen- 1 yl)-2-oxoacetamido)-2-methoxyb enzamide; N-(5-teirt-Butyl-2-methoxyphenyl)-2-(4-(2-(dimethylamino)pyridin-4 ylamnino)naphthaien- 1 -yl)-2-oxoacetamide; 5-tert-Butyl-3 -(2-(4-(2-(dimethylamino)pyridin-4-ylamino)naphthalen- 1l-yl)-2 oxoacetamnido)thiophene-2-carboxamide; N-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4-(3 -ethylisoxazol-5 yl)naphthalen- 1 -yl)-2-oxoacetamide; N-(5-tert-Butyl-2-methoxyphenyl)-2-(4-(6-(methylamnino)pyridin-3-yl)naphthalen- Il-yl) 2-oxoacetamnide; 5-tert-Butyl-2-methoxy-3 -(2-(4-(6-(methylamnino)pyridin-3-yl)naphthalen- Il-yI)- 2 oxoacetamido)benzamide; 5-tcrt-Butyl-N-ethyl-2-methoxy-3-(2-(4-(6-(methylamino)pyridin-3-yl)naphthalen- 1l-yl) 2-oxoacetamido)benzamide; 5-tert-Butyl-N-cyclopropyl-2-methoxy-3-(2-(4-(6-(methylamino)pyridin-3-yl)naphthalen 1 -yl)-2-oxoacetamido)benzamide; (S)--N-(5-tert-Butyl-2-nethoxy-3-(propyisulfonarnido)phenyl)-2-(4-(2,3 dihydroxypropoxy)n-aphthalen- 1 -yl)-2-oxoacetamide; 2-(5-tert-Butyl-2-methylfuran-3-yl)-N-(4-(2-chloropyrimidin-4-ylamino)naphthalen- 1 yl)-2-oxoacetamide;, 69 WO 2007/146712 PCT/US2007/070547 2-(5-tert-lButyl-2-methylfuran-3-yl)-2-oxo-N-(4-(pyrimidin-4-ylamino)naphthalen- 1 yl)acetamide; N-(5-tert-Butylisoxazol-3-yl)-2-(4-(2,3-dihydroxypropoxy)naphthalen- l-yl)-2 oxoacetamide; 2-(5-tert-Butyl-2-methylfiuran-3-y1>-2-oxo-N-(4-(pyrimidin-2-ylamino)naphthalen- 1 yl)acetamide; 2-(5-tert-Butyl-2-methylfiiran-3 -yl)-N-(4-(2-morpholinopyrimidin-4-yloxy)naphthalen- 1 yl)-2-oxoacetamide; 2-(5-tert-Butyl-2-methylfuran-3 -yl)-N-(4-(2-morpholinopyrimidin-4-ylamino)naphthalen 1 -yl)-2-oxoacetamnide; 2-(5-tert-B-utyl-3-mcthylfuran-2-yl)-N-(4-(2-morpholinoethoxy)naphthalen-I -yly- 2 oxoacetamide; 2-(5-(4-Chl orophenyl)-2--(trifluoromethyl)furan-3-yl)-N-(4-(2 morpholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamnide; N-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(pyrrolidin- 1 yl)pyrimidin-4-ylamino)naphthaien- I -yl)acetamide; N-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4-(4 morpholinophenyl)naphthalen- 1 -yl)-2-oxoacetamnide; N-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4-(6-methoxypyridin-3 yl)naphthalen- 1 -yl)-2-oxoacetamide; 2-(4-(2 -Aminopyrimidin-4-ylamnino)naphthal en- I -yl)-N-(5-tert-butyl-2-methoxy-3 (methylsulfonamnido)phenyl)-2-oxoacetamnide; N-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)phcnyl)-2-oxo-2-(4-(pyimidin-4 ylamino)naphthalen- 1 -yl)acctamidc; N-(5-tcrt-Butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyridin-4 ylamino)naphthalen- 1 -yl)acetamide; 5-(5-tert-flutyl-2-methoxy-3 -(methylsulfonamido)benzamido)-2-methyl-N-(4-(pyridin-4 ylmethoxy)phenyl)nicotinamide; 5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)benzamido)-2-mthyl-N-(4-(2 morpholinoethoxy)phenyl)nicotinamide; 5-(3--Fluoro-5-morpholinobenzamido)-2-methyl-N-(4-(2 morpholinoethoxy)phenyl)nicotinamide; 70 WO 2007/146712 PCT/US2007/070547 5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-N-(4-methoxypheny1-2 methylnicotinamide; S-(3 -Fluoro-5-morpholinobenzamido)-N-(4-methoxyphenyl)-2-methylnicotinamide; 5-(5-tert-Butyl-2-methoxybenzamido)-2-methyl-N-(4-(pyridin-2 Ylmethoxy)phenyl)nicotinamnide; 5-(3-Fluoro-5-morpholinobenzamnido)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamide; 5-(5-tert-Butyl-2-methoxy-3 -nitrobenzamnido)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamnide; 5-(3 -Acetamnido-5-tert-butyl-2-methoxybenzamido)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamide; 5-(3 -(Dimethylamino)benzamido)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamnide; 5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamnido)benzamido)-2-methyl-N-(4-(pyridin-2 ylmethoxy~phenyl)nicotinamide; Methy 13-tert-butyl-5-(6-methy1-5-(4-(pyridin-2-ylmethoxy~phenyicarbamoyil)pyridin-3 ylcarbamoyl)benzoate; 5-tert-Butyl-N'-(6-methyl-5-(4-(pyridin-2-ylmethoxy)phenylcarbamoyl)pyridin-3 yl)isophthalamide; 5-tert-Butyl-N 1 -methyl-N 3 -(6-methyl-5-(4-(pyridin-2 ylmethoxy)phenylcarbamoyl)pyridin-3 -yl)isophthalamide; N-(6-(Cyclopropylmethylamino)pyridin-3-yl)-5-(3-fluoro-5-morpholinobenzamido)- (trifluoromethyl)nicotinamide; 5-(3-Fluoro-5-(pyrrolidin- 1 -yl)benzamido)-N-(6-(isobutylamino)pyridin-3-yl)-2 methylnicotinamide; 5-(3-Fluoro-5-(pyrrolidin- 1 -yl)benzamnido)-N-(6-(isobutylamnino)pyri din-3-yl)-N mcthoxy-2--methylnicotinamide; 5-(3 -tert-Butyl-5-cyanobenzamido)-N-(6-(isobutylamino)pyridin-3-yl)-2 methylnicotinamide; N'(-3tr-uypeycrany)2mtyp~dn3y)Nttavr-Hprn4 yl)tecphthalamide; N -(5-tert-Butyl-3 -cyano-2-methoxyphenyl)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)pyridine-3 ,5-dicarboxamide; 71 WO 2007/146712 PCT/US2007/070547 5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamnido)-2-methyl-N-(4-(pyridin-3 ylmethoxy)phenyl)nicotinamide; 5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-N-(6-methoxypyridin-3 yl)-2-methylnicotinamnide; 5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)benzamnido)-N-(4-(5-fluoro-2 morpholinopyrimidin-4-yloxy)phenyl)-2-methylnicotinamide; 5-(3-tert-Butyl-5-cyanobenzamido)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamide; 5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)benzamido)-N-(4-carbamoylphenyl)-2 methylnicotinamide; 5-tert-Butyl-N'-methyl-N 3 -(6-methyl-5-(4-(pyridin-4 ylmethoxy)phenyl carbamoyl)pyridin-3-yl)isophthalamide; 5-(3 -Bromo-5-tert-butyl-2-methoxybenzamido)-2-methyl-N-(4-(2 morpholinoethoxy)phenyl)nicotinamide; 5-(3 -tert-Butyl-5-cyanobenzamnido)-2-methyl-N-(4-(pyridin-4 yimethioxy)phenyl)nicotinamide; 5-(3 -Bromo-5-tert-buty1-2-methoxybenzamido)-2-methy1-N-(4-(pyridin-4 ylmethoxy)phenyl)nicotinamnide; 5-tert-Butyl-N 1 -methyl-N 3 -(6-methyl-5-(4--(tetrahydro-2H-pyran-4 ylcarbamoyl)phenylcarb amoyl)pyridin-3-yl)isophthalamide; 5-(5-tert-Butyl-3-cyano--2-methoxybcnzamido)-2-methyl-N-(4-(pyridin-4 ylmethoxy)phenyl)nicotinamnidc;

N

5 -(5-tcrt-Butyl-2-methoxyphenyl)-2-methyl-N 3 -(4-(pyridin-2 ylmethoxy)phenyl)pyridine-3 ,5-dicarboxamide;

N

5 -(5-tert-Butyl-3 -carbamoyl-2-methoxyphenyl)-2-methyl-N 3 -(4-(pyridin-2 ylmethoxy)phenyl)pyridine-3,5-dicarboxamide; N (-etBtl2mtoy3(ehlufnaiopey)2mty- (-prdn4 ylmethoxy)phenyl)pyridine-3 ,5-dicarboxamnide;

N

5 -(5-tert-Buty1-2-methoxy-3-(methylsulfonamido)pheny)-2-methy-N 3-(4-(pyridin-2-. ylmethoxy)phenyl)pyiidine-3,5-dicarboxamnide; 5-(5-tert-Butyl-3 -cyano-2-methoxybenzamido)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamide; 72 WO 2007/146712 PCT/US2007/070547 5-(3 -tert-Butyl-5-cyanobenzamido)-2-methyl-N- (4-(quinolin-4 Ylmethoxy)phenyl)nicotinamide, 5-(5-tert-Butyl-3 -cyano-2-methoxybenzamido)--2-methyl-N-(4-(quinolin-4 ylmethoxy)phenyl)nicotinamide; 5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)benzamnido)-2-methyl-N-(4-(quinolin 4-ylmethoxy)phenyl)nicotinamide; N-(4-(Benzyloxy)phenyl)-5-(5-tert-butyl-3 -cyano-2-methoxybenzamido)-2 methylnicotinamide; N-(4-(Benzyloxy)phenyl)-5-(3 -tert-butyl-5-cyanobenzamido)-2-methylnicotinamide; 5-(3 -tert-Butyl-5-cyanobenzamido)-N-(4-methoxyphenyl)-2-methylnicotinamide; 2-Methyl-5-(3 -morpholino-5-(trifluoromethyl)benzamido)-N-(4-(pyridin-2 ylmethoxy)phenyl)ni cotinamide; 2-Methyl-5-(3 -(piperidin- 1-yl)-5-(trifluoromethyl)benzamido)-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamnide; 2-Methyl-N-(4-(pyridin-2-ylmethoxy)phenyl)-5-(3 -(pyrrolidin- l-yl).-5 (trifluoromethyl)benzamnido)nicotinamide; 5-(3 -Fluoro-5-(piperidin- 1-yl)b enzamido)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamide; 5-(3-Fluoro-5-(pyrrolidin- 1-yl)benzamnido)-2-methyl-N-(4-(pyridin-2 ylmethoxy)phenyl)nicotinamnide; 5-(3-Fluoro-5-morpholinobenzamido)-2-methyl-N-(6-((tetrahydrofuran-2 yl)methylamino)pyridin-3-yl)nicotinamide; N-(6-(Cyclohexylmethylamino)pyridin-3 -yl)-5-(3-fluoro-5-morpholinobenzamido)-2 methylnicotinamide; 5-(3-Fluoro-5-morpholinobenzamido)-N-(6-(2-methoxyethylamino)pyridin-3 -yl)- 2 methylnicotinamide; N-(6-(Cyclopropylmethylamino)pyridin-3 -yl)- 5

-(

3 -fluoro-5-morpholinobenzamido)-2 methylnicotinamide; Methyl 3 -((4-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2 methylnicotinamido)phenoxy)methyl)benzoate; 5-(5-tert-Butyl-3 -cyano-2-methoxybenzamido)-N-(4-(3 ,5-dimethoxybenzyloxy)phenyl) 2-methylnicotinamide; 73 WO 2007/146712 PCT/US2007/070547 5-(5-tert-Butyl-3 -cyano-2-methoxybenzamido)-N-(4-methoxypheny)-2 methylnicotinamnide; 5-(3 -Fluoro-5-morpholinobenzamido)-2-methyl-N-(4-(pyridin3 ylmethoxy)phenyl)nicotinamide; N-(4-(3 ,5-Dimethoxybenzyloxy)phenyl)-5 -(3-fluoro-5-morpholinobenzamido)-2 methylnicotinamide; 5-(3-Fluoro-5-morpholinobenzamido)-2-methyl-N-(4-(4 (methylsulfonyl)benzyloxy)phenyl)nicotinamide; 5-(3-Fluoro--5-morpholinobenzamido)-N-(4-(pyridin-2-ylm ethoxy)phenyl)-2 (trifluoromethyl)nicotinamide; 5-(3-Fluoro-5-morpholinobenzamido)-N-(6-((tetrahydrofuran-2-yl)methylamino)pyridin 3 -yl)-2-(trifluoromethyl)ni cotinamide; ,N-(6-(Cyclopropylamino)pyridin-3-yl)-2-methyl-5-(3 -morpholino-5 (trifluoromethyl)benzamiido)nicotinamnide; N-(6-(Cyclopropylmethylamino)pyridin-3 -yl)-2-methyl-5-(3 -morpholino-5 (trifluoromethyi)benzamido)nicotinamnide; 2-Methyl-5-(3 -morpholino-5-(trifluoromethyl)benzamido)-N-(6-((tetrahydrofuran-2. yl)methylamnino)pyridin-3-yl)nicotinamide; 2-Methyl-5-(3 -morpholino-5-(trifluoromethy1)benzamido)-N-(6-(ttrahydro-2H-pyran-4 ylamino)pyridin-3 -yl)nicotinamide; N-(6-(Cyclohexylmethylamino)pyridin-3-yl)-2-methyl-5-(3-morpholino-5 (trifluoromethyl)benzamido)nicotinamide; 2-Methyl-5-(3-morpholino-5-(trifluoromethy1)benzamido)-N-(6-((tetra1hydro-2H-pyran-4 yl)methylamino)pyridin-3-yl)nicotinamide; 5-(5-tert-Butyl-3 -cyano-2-methoxybenzamido)-2-methyl-N-(4-(pyridin-3 ylmethoxy)phenyl)nicotinamide; 5-(3 -Fluoro-5-morpholinobenzamido)-2-methyl-N-(6-(tetrahydro-2H-pyran-4 ylamino)pyridin-3 -yl)nicotinamide; iN-(6-(Cyclopropylamino)pyridin-3 -yl)- 5

-(

3 -fluoro-5-morpholinobenzamido)-2 methylnicotinamide;, 5-(3-Fluoro-5-morpholinobenzamido)-2-methy1-N-(6-((tetrahydro-2-pyra-4 yl)methylamino)pyridin-3 -yl)nicotinamide; 74 WO 2007/146712 PCT/US2007/070547 5

-(

3 -Fluoro-5-morpholinobenzamido)-N-(6-(isopropylamino)pyridin-3-yl)-2 methylnicotinamide; 5-(3 -Fluoro-5-morpholinobenzamido)-N.(6(isobutylamino)pyridin-3-yl)-2 methylnicotinamide; 5-(3 -Fluoro-5-(pyrrolidin- 1-yl)benzamido)-N-(6-(isopropylamino)pyridin-3-yl)-2 methylnicotinamide; N-(6--(Cyclopropylamino)pyridin-3 -yl)-5--(3--fluoro-5-(pyrrolidin- I -yl)benzamido)-2 methylnicotinamide; N-(6-.(Cyclopropylmethylamino)pyridin-3 -yl)-5-(3 -fluoro-5-(pyrrolidin- 1-yl)benzamido) 2-methylnicotinamide; 5-(3-Fluoro-5-(pyrrolidin- 1-yl)benzamido)-2-methyl-N-(6-(tetrahydro-2H-pyran-4 ylamino)pyridin-3 -yI)nicotinamide; 5-(3 -Fluoro-5 -(pyrroli din- 1 -yl)benzamido)-2-methyl-N-(6-((tetrahydro-2Hpyran-4 yl)methylamino)pyridin-3-yI)nicotinamide; 5-(3 -Fluoro -5-(pyrrolidin- 1-yl)benzamido)-2-methyl-N-(6-((tetrahydrofijran-2 yIlrnethyiamino)pyridin-3 -yl)nicotinamide; N-(6-(Cyclohexylmethylamino)pyridin-g -yl)-5-(3-fluoro-5-(pyrrolidin- 1-yl)benzamido) 2-methylnicotinamide; 5-(3 -Fluoro-5-morpholinobenzamido)-N-(6-(isopropylamino)pyridin-3-yl)-N-methoxy-2 methylnicotinamide; 5-(3 -Fluoro-5-morpholinobenzamido)-N-(6-(isobutylamino)pyridin-3-yl)-N-methoxy-2 methylniicotinamide; 5-(3 -Fluoro-5-(pyrrolidin- 1-yl)benzamido)-N-(6-(isopropyl amino)pyridin-3-yl)-N methoxy-2-methylni cotinamide; N-(6--(Cyclopropylmethylamino)pyridin-3 -yl)-5-(3 -fluoro-5-(pyrrolidin- 1 -yl)benzamido) N-methoxy-2-methylnicotinamide; 5-(3 -Fluoro-5-(pyrrolidin- 1-yI)benzamido)-N-methoxy-2-methy1-N(6(tetrahydro-2H pyran-4-ylamino)pyridin-3 -yl)nicotinamide: 5-(3 -Fluoro-5-(pyrrolidin- 1-yl)benzamido)-'NT-methoxy-2-methyl-N-(6-((tctrahvdro-2H pyran-4-yI)methyl amino)pyridin-3 -yl)nicotinamidc-; 5-(3 -Fluoro-5-(pyrrolidin-l1-yl)benzamido)-' N--methoxy-2-methy1-N-(6-((tetrahydrofiuran 2-yl)m ethyl amino)pyridin-3 -yl)nicotinamide; 75 WO 2007/146712 PCT/US2007/070547 5-(3 -Fluoro-5-(piperidin- I -yl)benzamido)-N-(6-(isopropylamino)pyridin-3-y1>2 methylnicotinamide; 5-(3-Fluoro-5-(piperidin- 1 -yl)benzamido)-N-(6-(isobutylamino)pyridin-3-yl)-2 methyinicotinamide; N-(6-(Cyclopropyl amino)pyridin-3 yl)y5-(3 -fluoro-5 -(piperi din- 1 -yl)benzamido)-2 methylnicotinamide;

N-(

6 -(Cyclopropylmethylamino)pyridin-3 -yl)-5-(3-fluoro-5-(piperidin- 1 -yl)benzamido) 2-methylnicotinamide; 5-(3-Fluoro-5-(piperidin- 1 -yl)benzamido)-2-methyl-N-(6-(tetrahydro2Hpyran-4 ylamnino)pyridin-3 -yl)nicotinamnide; 5-(3 -Fluoro-5--(piperidin- 1 -yI)benzamido)-2-methyl-N-(6-((tetrahydro2H-pyran-4 yl)methylamino)pyridin-3 -yl)nicotinamide; 5-(3-Fluoro-5-(piperidin- I -yl)benzamido)-2-methyl-N-(6-((tetaydrofuran-2 yl)methylamino)pyridin-3-yl)nicotinamide; N-(6-(Cycloh exylmethylamino)pyridin-3 -yl)-5 -(3 -fluoro-5 -(piperi din- 1 -yl)benzamido)-2 rnethylni cotinamide; 5-(3 -Fluoro-5-(piperidin- 1 -yl)benzamido)-N-(6-(isopropylamino)pyridin-3-yl)-N methoxy-2-methylnicotinamide; 5-(3 -Fluoro-5-(piperidin- 1 -yl)benzamido)-N-(6-(isobutylamino)pyridin-3-yl)-N-methoxy 2-methylnicotinamide;

N-(

6 -(Cyclopropylmethylamnino)pyridin-3-yl)-5-(3 -fluoro-5-(piperidin- 1 -yl)benzamnido) N-methoxy-2-methylnicotinamide; 5-(3-Fluoro-5-(piperidin- 1 -yl)benzamnido)-N-methoxy-2-methylN-(6(tetrahydro-2H pyran- 4 -ylamino)pyridin-3-yl)nicotinanide; 5-(3-Fluoro-5-(piperidin- 1 -yl)benzamido)-N-methoxy-2-mehy[-N-(6((tetrahydro-2H pyran-4-yl)methylamino)pyridin-3-yl)nicotinamide; 5-(3 -Fluoro-5-(piperidin- 1 -yl)benzamido)-N-methoxy-2-methyN(((tetrahydrofuran 2 -yl)methylamino)pyridin-3-yl)nicotinamide; 5-tert-Butyl-N' -(5-( 6 -(isopropylamnino)pyridin-3-ylcarbamoy1)&6methylpyridin-3 -y1)-N 3 methylisophthalamide, 5-tert-Butyl-N -( 5 -(6-(isobutylamino)pyridin-3-ylcarbamnoyl)-6-methylpyridin-3 -yl)-N 3 methyli sophthalamide; 76 WO 2007/146712 PCT/US2007/070547 5-tert-Butyl-N'-(5-(6-(cyclopropylamino)pyridin-3-ylcarbamoy1)-6-methylpyridin-3-y) N 3 -methylisophthalamide; 5-tert-Buty1-N 1 -(5-(6-(cyclopropylmethyamino)pyridin-3-ylcarbamnoyl)--6-methylpyridin 3 .yl).N 3 methylisophthalamide; 5-etBtlN-ehlN-6-ehl5(-(erhdourn2y ehlmn~yii ylcarbamoyl)pyridin-3 -yl)isophthalamide; 5-(3 -tert-Butyl-5-cyanobenzamido)-N-(6-(isopropylamino)pyridin-3-yI)-2 methylnicotinamide; 5-(3 -tert-Butyl-5-cyanobenzamido)-N-(6-(cyclopropylamnino)pyridin-3 -yl)-2 methylnicotinamide; 5-(3 -tert-Butyl-5-cyanobenzamnido)-N-(6-(cyclopropylmethylamino)pyridin-3 -yl)-2 methylnicotinamide; 5-(3-tert-Butyl-5caoezmd)2mty N(-ttayr-Hprn4 ylamino)pyridin-3 -yl)nicotinamide; 5

-(

3 -tert-Butyl-5-cyanobenzamido)-2-methy1-N-(6((tetrahydrofturan-2 yl)methylamnino)pyridin-3 -yl)nicotinamide; 3 -( 5

-(

5 -tert-Butyl-2-methoxybenzamido)2-methylpheny)N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)benzamido)-2-methylphenyl)yN neopentylisoxazole-5-carboxamide; 5-tert-Butyl-N'1 -methyl--N 3 -(4-methyl-3 -(5-(ncopentylcarbamoyl)isoxazol-3 yl)phenyl)isophthalamide; 3 -(5-(3 -tert-Butyl-5-cyanobenzamido)-2-methylpheny1)-N-neopentylisoxazole-5 carboxamide: 3 -(5-(3 -Acetamnido-5-tert-butylbenzamnido)-2-methylphenyyNneopentylisoxazole-5 carboxamnidc; Methyl 3 -tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazo-3 yI)phenylcarbanioyl)phenylcarbamate; 5-(3 -(5-tert-Butyl-2-methoxybenzamido)phenyl)N(pyridin-3-ylmethyl)isoxazole-3 carboxamide; 5-(3 -(5-tert-Butyl-2-methoxybenzamido)phenyl)-N- pyridin-2-ylmethyl)isoxazole-3 carboxamide; 77 WO 2007/146712 PCT/US2007/070547 tert-Butyl (3 -(5-(5 -tert-buty1-2-methoxybenzamido)-2-methylpheny1}isoxazop5 yl)methylearbamate; 5-tert-Butyl-2-methoxy-N-(4-methyl-3 -(5-(pivalamidomethyl)isoxazol-3 yl)phenyl)benzamide; 5-tert-Butyl-N-(3 -(5-((3 ,3-dimethylbutanamido)methyl)isoxazol-3 -yl)-4-methylphenyl) 2-methoxybenzamnide; N-(3--(5-(Benzamidomethyl)isoxazol-3 -yl)-4-methylphenyl)-5-tert-butyl-2 methoxybenzamide;

N-((

3

-(

5 -(5-tert-Butyl-2-methoxybenzamido)-2mcthylphenyl)isoxazol -5 yl)methyl)ftiran-2-carboxamide; N-((3 -(5-(5 -tert-Buty1-2-methoxybenzamnido)-2-methylphenyl)isoxazo15 yl)methyl)picolinamide; N-((3 -(5-(5-ter-t-Buty1-2-methoxybenzamido)-2-methylpheny1)isoxazolps yl)methyl)nicotinamide; N-((3 -(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5 yl)methyi)isonicotinamide; 5-tert-Butyl-2-methoxy-N-(4-methyl-3 -(5-(morpholine-4-carbony1l 1 H-pyrazol-3 yl)phenyl)benzamide; 3 -(5-(5-tert-Butyl-2-methoxybenzamido)-2-methypheny)N(tetraydro2Hpyran4.yl) 1 H-pyrazole-5-carboxamide; 3-(5-(3 -tert-Butyl-5-cyanobenzamido)-2-methylphenyl-N-neopentyl I H-pyrazole-5 carboxamide; 5-(3-(3 -tert-Butyl-5--cyanobenzamnido)phenyl)-l1-mcthyl-N-neopentyl- 1H-pyrazole-3 carboxamide; 5-(3-(3 -Fluoro-5-morpholinobenzamido)phenyl)-l1-isopropyl-N-neopentyl-l1H-pyrazole 3 -carboxamide; 5-(3 -(5-tert-Butyl-3-cyano-2-methoxybenzamido)phenyl) 1 -methyl-N-neopentyl-l1H pyrazole-3 -carboxamnide; 5-(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylpridin-3 -y1)-N-neopenty1- 1,3,4 oxadiazole-2-carboxamide; 3-(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylpyridin-3 -yl)-N-neopentyl- 1H pyrazolc-5-carboxamide; 78 WO 2007/146712 PCT/US2007/070547 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3 -yl)- I-methyl-N-neopentyl 1H-pyrazole-5-carboxamide; 5-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3 -yl)- I-methyl-N-neopentyl 1 H-pyrazole-3-carboxamide; 3-(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylpyridin-3 -yl)-N-neopentylisoxazole-5 carboxamide; N-Benzyl-3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)isoxazole-5 carboxamide; N-Benzyl-3-(5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)benzamido)-2 methylphenyl)isoxazole-5-carboxamide; 3 -(5-(5 -tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methylphenyl)-N (pyridin-2-ylmethyl)isoxazole-5-carboxamide; 3 -(5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)benzamido)-2-methylphenyl)-N (pyridin-3-ylmethyl)isoxazole-5-carboxamide; 3 -(5-(5-tert-Butyl-2-methoxy-3 -(methylsulfonamido)benzamido)-2-methylphenyl)-N (pyridin-4-ylmethyl)isoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-neopentylisoxazole-5 carboxamide; 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(2 morpholinoethyl)isoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(2-(pyridin-4 yl)ethyl)isoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(2-(pyridin-3 yl)ethyl)isoxazole-5-carboxamide; 3 -(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5 carboxamide; 3 -(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2-(pynidin-4 yl)ethyl)isoxazole-5-carboxamide; 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4 yl)isoxazole-5-carboxamide; 79 WO 2007/146712 PCT/US2007/070547 3

-(

5

-(

3 -Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5 carboxamide; 3-(5-(3-Cyano-5-(piperidin- 1 -yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5 carboxamide; 3-(5-(3-Cyano-5-(pyrrolidin- 1 -yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5 carboxamide; 3-(5-(3 -tert-Butyl-5-((4-methylpiperazin- 1 -yl)methyl)benzamido)-2-methylphenyl)-N ((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3 -(5-(3 -tert-Butyl-5-(piperazin- 1 -ylmethyl)benzamido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3 -(5-(5-tert-Butyl-3 -cyano-2-(2--(4-methylpiperazin- 1 -yl)ethoxy)benzamnido)-2 methylphenyl)-N-neopentylisoxazole-5-carboxamide; 5-tert-Butyl-3 -cyano-2-methoxy-N-(4-methyl-3 -(5-(3 -phenylpropanoyl)isoxazol-3 yl)phenyl)benzamide; 3 -(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(pyridin-3 ylrnethi~yl)isoxazole-4-carboxamide 3 -(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl>N-neopentyl. 1 H-pyrazole-5 carboxamide; 3 -(5-( 3 -Fluoro-5-morpholinobenzamido)-2-methylphenylyN-neopentyl- 1 H-pyrazole-5 carboxamide; 3-(5-(5-tert-Butyl-3 -cyano-2-methoxybenzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 3 -( 5 -(5-ter-Butyl-2-methoxybenzamido-2-methylphenyl)-N-((tetrahydro2pyan-4 yl)methyl)isoxazole-5-carboxamide; 3-(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-((tetrahydro2l-pyran.4 yl)methyl)isoxazole-5-carboxamide; 3 -(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4 yl)isoxazole-5--carboxamide; 3-(5-(3 -Fluoro-5-morpholinobenzamnido)-2-methylpheny)-N-(2-(pyrroidin- I y1)cthyI)isoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydrofiiran-2 yl)methyl)isoxazole-5-carboxamide; 80 WO 2007/146712 PCT/US2007/070547 3 -(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylpheny1)-N-((tetrahydrofijran-2 yl)methyl)isoxazole-5-carboxamide; 3 -(5-( 3 -tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-(pyridin-3-ylmethyl)isoxazole 5- carb oxam ide; 3

-(

2 -Methyl-5-(3-morpholinobenzamido)phenyl)-bNbneopentylisoxazole-5carboxamide; 3-(2-Methy1-5-(3-morpholinobenzamido)pheny)-N-(pyridin-3 -ylmethyl)isoxazole-5 carboxamide; 3-.(5-(3 -Cyanobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5carboxamide; 3 -(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N (cyclohexylmethyl)isoxazole-5-carboxamide; 3 -[5-(5-tert-Butyl-2-methoxy-benzoylamino)-2-mcthyl-phenyl] -isoxazole-5-carboxylic acid (adamnantan- 1-ylmethyl)-amide; 3 -(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydro-2H-pyran-4 yl)mcthyl)- 1H-pyrazole-5-carboxamide; 3 -(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2 yl)methyl)- 1 H-pyrazole-5-carboxamide; 3-(-5tr-Btl2mtoxbnaio-2mty1ey -- ccoexlehl-H pyrazole-5-carboxamide; 5-15-(5-tert-Butyl-2-methoxy-benzoylamnino)-2-methyl-phenyl] -2H-pyrazole-3 -carboxylic acid (adamantan- 1 -yl-methyl)-amide; 3 -(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-((tetrahydro2Hpyran-4 yl)methyl)-1 H-pyrazole-5-carboxamide; 3-(2-Methyl-5-(3 -(trifluoromethyl)benzamido)phenyl)-N-neopentylisoxazoles.. carboxamide; 3 -(5-(3 -Methoxybenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide; 3 -(5-(3 -Chlorobenzamido)-2-methylphcnyl)-N-neopentylisoxazole-s-carboxamide; 3 -(5-(3 ,5-bis(Trifluoromcthyl)benzamido)-2-methylphenyl)-N-neopentylisoxazoles.. carboxamide; 3-(5-(3 -Fluorobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide; 3-(5-(3-Fluoro-5-morpholinobcnzamnido)-2-i cthylphenyl)-N-((tctrahydrofuran-2 yl)methyl)- 1H-pyrazole--5-carboxamide;, 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2-(pyrrolidin- 1 -yl)ethyl) 1 H-pyrazole-5-carboxamide; 81 WO 2007/146712 PCT/US2007/070547 3 -(5-(3 -Fluoro-5-morpholinobenzamido)-2-methypheny)-N-(tetrahydro-2H-pyrali4y) 1 1-J-prazole-5-carboxamide; N-(Cyclohexylmethyl)-3-(5-(3 -fluoro-5-morpholinobenzamido)-2-methylphenyl)- 1 H pyrazole-5-carboxamide; 5

-[

5 -(3-Fluoro-5-morpholin-4-yl-benzoylamino)-2-methyl-phenyl]-2H-pyTazole-3 carboxylic acid (adamanitan- 1-ylmethyl)-amide; N-(Cyclohexylmethyl)-3 -(5-(3 -fluoro-5-morpholinobenzamido)-2 methylphenyl)isoxazole-5-carboxamide; 3 -[5-(3 -Fluoro-5-morpholin-4-yl-b enzoylamino)-2-methyl-phenyl]-isoxazole-5 carboxylic acid (adamantan-1 -ylmethyl)-amide; 3 -(5-(3 -Fluoro-5-(pyrrolidin- 1-yl)benzamido)-2-methylphenyl)-N-neopcntylisoxazole-5 carboxamide; 3 -(5-(3 -Fluoro -5 -(piperidin- 1 -yl)b enzamido)-2-methylphenyl)-N-neopentyli sox azole-5 carboxamide; N-Benzyl-3 -(5-(3 -tert-butyl-5-cyanobenzamido)-2-methypheny)-N-methyisoxazole-5 carboxarnide; N-Benzyl-3 -(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N methylisoxazol e-5-carboxamide; N-B enzyl-3 -(5-(3 -fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-methylisoxazole 5-carboxamide; 3-(5-(3 -Fluoro-5-(piperidin- 1-yl)benzamido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3 -(2-Methyl-5-(3 -morpholino-5-(trifluoromethy1)benzamido)pheny)-N neopentylisoxazole-5-carboxamide; 3 -(2-Methyl-5-(3 -morpholino-5-{trifluoromethy1)benzamido)pheny1)-N-(pyvridin3 ylmethyl)isoxazole-5-carboxamide; 3 -(5-(3 -tert-Butylbenzamido)-2-methylphenyl)-N-neopcntylisoxazole-5-carboxamide; 3 -(5-(3 -tert-Butylbenzamido)-2-methylphenyl)-N-(pyridin-3 -ylmethyl)isoxazole-5 carboxamide; 3 -(2-Methyl-5-(3-morpholino-5-(trifluoromethyl)benzamido)phenyl-N-(te rahydro-2H py-ran-4-yl)isoxazole-5-carboxamide; 3-(2Mmethyl-5-(3-morpholino-5-(trifluoromethyl)benzamido)phenyl)-N ((tetrahydrofuran-2-yI)methyl)isoxazole-5-carboxamide 82 WO 2007/146712 PCT/US2007/070547 3 -(5-( 4 -tert-Butylbenzamnido)-2-methylphenyl-N-neopentylisoxazoles5carboxamide; 3-(2-Methyl-5-(3-(piperidin- 1-yl)-5-(trifluoromethyl)benzamnido)phenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3-(2-Methyl-5-(3-(pyrrolidin- 1-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3-(2-Methyl-5-(3-4piperidin- 1-yl)-5-(trifluoromethyl)benzamido)phenyl)-N neopentylisoxazole-5-carboxamide; 3-(2-Methyl-5-(3 -(pyrrolidin- 1-yl)-5-(trifluoromethyl)benzamnido)phenyl)-N neopentylisoxazole-5-carboxamide; 3 -(2-Methyl-5-(5, 5,8, 8-tetramnethyl-5,6,7,8 -tetrahydronaphthalene-2 carboxamido)phenyl)-N-neopentylisoxazole-5-carboxamide; N-(3 ,4-Dimethoxybenzy)-3-(5-(3--fluoro-5-morpholinobenzamido)-2-methylphenyl)-N methylisoxazole-5-carboxamide; 3 -(5-(3 -Fluoro-5-(pyrrolidin- 1 -yl)benzamido)-2-methylphenyl)-N-(pyri din-3 ylmethyl)isoxazole-5-carboxamide-, 3 -(2-Metlhyi-5-(3I-(4-mcethylpiperazin- 1-yl)-5-(trifiuoromethyi)b enzamnido)phenyl)-N neopentylisoxazole-5-carboxamide; 3-(5-(3 -fluoro-5-(4-methylpiperazin- 1 -yl)benzamnido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 3-(5-(3 ,3-Dimethyl-2,3-dihydrobenzofiiran-5-carboxamido)-2-methylphenyl).N neopentylisoxazole-5-carboxamide; 3-(2-Methyl-5-(3 -(piperidin- 1 -yl)-5-(trifluoromethyi)benzamido)phenyl)-N-(tetrahydro 2H-pyran-4-yl)isoxazole-5-carboxamide; 3 -(2-Methyl-5-(3 -(pyrrolidin- 1-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-(tetrahydro 2H-pyran-4-yl)isoxazole-5-carboxamide; 3 -(2-Methyl-5-(3 -(piperidin- I -yi)-5-(trifluoromethyl)benzamido)phenyl)-N ((tetrahydrofiiran-2-yl)methyl)isoxazole-5-carboxamide; 3-(2-Methyl-5-(3-(pyrrolidin- I -yl)-5-(trifluoromethyl)benzamido)phenyl)-N ((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3-5Bpey--labxmd--ehlhnl--epnyioaoe5croaie 3-(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-mthylisoxazole-5 carboxamide; 83 WO 2007/146712 PCT/US2007/070547 N-Ethyl-3 -(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)isoxazole-5 carboxamide; 3 -(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-propylisoxazole-5 carboxamide; 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2,2,3 ,3,3 pentafluoropropyl)isoxazole-5-carboxamide; 3-(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2,2,2 trifluoroethyl)isoxazole-5-carboxamide; 3 -(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N -(3,3,3 trifluoropropyl)isoxazole-5-carboxamide; 3 -( 2 -Methyl-5-(5-phenylnicotinamido)phenyl)-N-neopentylisoxazoles5carboxamide; 3 -(2-Methyl--5-(5 -(pip eridin- 1 -yl)nicotinamnido)phenyl)-N-neopentylisoxazole-5 carboxamide; 3 -(2-Methyl-5-(5-(pyrrol idin- 1 -yl)nicotinamido)phenyl)-N-neopentylisoxazole-5 carboxamide; 3 -(2-Methyi-5-(5-morpholinonicotinamido)phenyl)-N-neopentylisoxazole-5 carboxamide; 3-(2-Methyl-5-(5-(pyrrolidin- 1 -yl)nicotinamido)phenyl)-N-((tetrahydrofuran-2 yl)methyl)isoxazole-5-carboxamide; 3-(2-Methyl-5-(5-(piperidin- 1 -yl)nicotinamido)phenyl)-N-((tetrahydrofuran-2 yl)methyl)isoxazole-5-carboxamide; 3 -(2-Methyl-5-(5-(pyrroidin- 1 -yl)nicotinamido)phenyl)-N-(tetrahydro-2H-pyran-4 yl)isoxazole-5-carboxamide; 3 -(2-Methyl-5-(5-(piperidin- 1 -yl)nicotinamnido)phenyl)-N-(tetrahydro-2H-pyran-4 yl)isoxazole-5-carboxamnide; 3 -( 2 -Methyl-5-(5-morpholinonicotinamido)phenyl)-N-((tetrahydrofuran-2 yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(2,3 dimethoxybenzyl)-N-methylIisoxazole-5-carboxamide; 3 -(5-(3'-Isopropylbenzamido)-2-methylphenyl)- '-neopentylisoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(2 methoxybenzyl)-N-methylisoxazole-5-carboxamide 84 WO 2007/146712 PCT/US2007/070547 3 -(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(3 methoxybenzyl)-N-methylisoxazole-5-carboxamide; 3 -( 5

-(

5 -tert-Buty1-3-cyano-2-methoxybenzamido)-2-methylpheny)N(3 ,5 dimethoxybenzyl)-N-methylisoxazole-5-carboxamide; 3

-(

5

-(

5 -tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)>N.(( 1 ethylpyrrolidin-2-yl)methyl)isoxazole-5-carboxamide; 3-(5 -(5 -tert-Butyl-3 -cyano-2-methoxybenzamido)-2-methylpheny)-N-((tetrahydrofflran 2-yl)methyl)isoxazole-5-carboxamnide; 3 -(5-(5 -tert-Butyl-3 -cyano-2-methoxybenzamido)-2-methylphcnyl)-N-(3 methoxybenzyl)isoxazole-5-carboxamide; 3 -(5-(5-tert-Butyl-3 -cyano-2-methoxybenzamnido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3 -(5-(3 -Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(3 methoxybenzyl)isoxazole-5 -carboxamide; N-(2,3 -Dimethoxyb enzyl)-3 -(5-(3-fluoro-5-mor-pholinobenzamido)-2 methylphenyl'isoxazole-5-carboxamide; N-((1 -Ethylpyrrolidin-2-yl)methyl)-3 -(5-(3 -fluoro-5-morpholinobenzamnido)-2 methylphenyl)isoxazole-5-carboxamide; N-B enzyl-3 -(5-(3 -fluoro-5-morpholinobenzamnido)-2-methylphenyl)isoxazoles.

carboxamide; N-(3 ,5-Dimethoxybenzyl)-3 -(5-(3 -fluoro-5-morpholinobenzamnido)-2 methylphenyl)isoxazole-5-carboxamide; N-(Benzo[d] [ 1,3]dioxol-5-ylmethyl)-3 -(5(3 -fluoro-5-morpholinobenzamnido)-2 methylphenyl)isoxazole-5-carboxamnide; 3 -(5-(5-tert-Butyl-3 -cyano-2-methoxybenzamido)-2-methylphenyl)-N-(2,3 dimethoxybenzyl)isoxazole-5-carboxamide; 3-(5-(3 -(2-Hydroxypropan-2-yl)benzamido)-2-metylpheny)-N-neopentylisoxazoles5 carboxamide; 3-(5-(3-Acetylbenzamnido)-2-mcthylphenyl)-N-neopentylisoxazole-5-carboxamide; 3 -(5-(3-.Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-(3 methoxybenzyl)isoxazole-5-carboxamide; 3-(5-(3-( 2 -Methoxypropan-2-y1)benzamido)-2-methylpheny>Nneopentylisoxazoles5 carboxamide; 85 WO 2007/146712 PCT/US2007/070547 3 -(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-(( I -ethylpyrrolidin-2 yl)methyl)isoxazole-5-carboxamide; 3 -(5-(3-Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-(( 1 -ethylpyrrolidin-2 yI)m ethyl)isoxazole-5-carboxamide; N-((1 -Ethylpyrrolidin-2-yl)methyl)-3-(2-methyl-5-(3-morpholino-5 (trifluoromethyl)benzamnido)phenyl)isoxazole-5-carboxamide; 3

-(

5

-(

3 -(2-Fthoxypropan-2-y)benzamido)-2-methylpheny)-N-neopentylisoxazole-5 carboxamide; 3-(5-(5-tert-Butyl-3 -cyano-2-methoxybenzamido)-2-methylphenyl)-N-( 1 methylpiperidin-4-yl)isoxazole-5-carboxamide; 3 -(5-(3 -Cyano-5-morpholinobenzamnido)-2-methylphenyl)-N-( 1 -methylpiperidin-4 yl)isoxazole-5-carboxamnide; 3 -(2-Methyl-5-(3 -morpholino-5-(trifluoromethyl)benzamido)phenyl)-N-( 1 methylpiperidin-4-yl)isoxazole-5-carboxamide; 3 -(2-Methyl-5-(3 -morpholino-5-(trifluoromethyl)benzamido)phenyl)-N-(( 1 rnethyi'piperidin-4-yl)methyl)isoxazoie-5-carboxamide; 3 -(5-(3 -Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-((1 -methylpiperidin-4 yl)methyl)isoxazole-5-carboxamide; 3-(5-(5-tert-Buty1-3-cyano-2-methoxybenzamido)-2methylpheny1)-N{( 1 methylpiperidin-4-yl)methyl)isoxazole-5-carboxamide; 3 -(5-(3-Cyano-5-morpholinobenzamido)-2-methylpheny1)-N((tetrahydrofran2 yl)methyl)isoxazole-5-carboxamide; 3 -(5 -(3 -Cyano-5-(piperi din- 1 -yl)benzamido)-2-methylphcnyl)-N-((tetrahydrofuran-2 y1)methy1)isoxazole-5-carboxamide; 3 -(5-(3-Cyano-5-(pyrrolidin- 1 -yl)benzamido)-2-methylphenyl)-N-((tetrahydrofuran-2 yl)methyl)isoxazole-5-carboxamidc; 2-Methoxyethyl 3 -tert-butyl-5-(4-methyl-3 -(5-(neopentylcarbamoyl)isoxazol-3 yl)phenylcarbainoyl)phenylcarbamate; Methyl 3-tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3 yl)phenylearbamoyl)benzoate;, 3-(5-(3 -tert-Butyl-5-(2-methylthiazol-4-yl)benzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 86 WO 2007/146712 PCT/US2007/070547 3 -(5-(3-Fluoro-5-thiomorpholinobenzamido)-2-methylpheny)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3 -(5-(3-Fluoro-5-thiomorpholinobenzamido)-2-methylphenyl)Nneopentylisoxazole-5 carboxamide; 3 -(5-( 3

-(

2

,

6 -Dimethylmorpholino)-5-fluorobenzamido)-2-methylphenyl).N neopentylisoxazole-5-carboxamide; 3-(5-(3 -Fluoro-5-(1 ,4-oxazepan-4-yl)benzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 3 -(5-(3 -(1 -Hydroxy-2,2-dimethylpropy1)benzamido)-2-methylphenyl>N neopentylisoxazole-5-carboxamide; 3 -(5(3 -Amino-5-tert-butylbenzaindo)-2-methylpheny)-N-neopentylisoxazoles.

carboxamide; 3-(5-(3 -lsobutylbenzamido)-2-methylphenyl)-N-((tetrahydroftiran-2-yl)methyl)isoxazole 5-carboxamide; 3 -(2-Methyl.5-(3 -neopentylbenzamido)phenyl)-N-((tetrahydrofijran-2 yI'methyl'isoxazole-5-carboxamide; 3-(-3(,-iehlopoio-- oobnaio--ehlhnl--prdn3 ylmethyl)isoxazole-5-carboxamide; 3-(5-(3-Fluoro-5-( 1,4-oxazepan-4-yl)benzamnido)-2-methylphenyl)-N-(pyridin3 ylmethyl)isoxazole-5-carboxamide; 3-(5-(3 -Fluoro-5-thiomorpholinobenzamido)-2-methylphenyl)-N-((tetrahydrofflran-2 yl)methyl)isoxazole-5-carboxamide; 3-(5-(3 -(2,6-Dimethylmorpholino)-5-fluorobenzamido)-2-methylphenylyN ((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3 -(5-(3 -Fluoro-5-( 1, 4 -oxazepan-4-yl)benzamido)-2-methylphenyl)-N-((tetrahydrofiiran 2-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3 -tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-((tetrahydroftiran-2 yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-tcrt-Butyl-5-(hydroxymiethyl)benzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxar-nide, 3-(2-Methyl-5-(3-neopenty lbenzamido)phenyl)-N-neopentylisoxazole-5-carboxamide; 3

-(

2 -Methyl-5-( 2 -rnorpholinoisonicotinamido)phenyl)-N-neopentylisoxazoles5 carboxamide; 87 WO 2007/146712 PCT/US2007/070547 3 -(2-Methyl-5-(2-(pyrrolidin- 1-yl)isonicotinamido)phenyl)-N-neopentylisoxazole-5 carboxamide; 3 -(2-Methyl-5-(2-(piperidin- 1-yl)isonicotinamido)phenyl)-N-neopentylisoxazole-5 carboxamide; 3 -( 5 -(3-Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3-(5-(3 -Cyano-5-(piperidin- 1-yl)benzamido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3-(5-(3 -Cyano-5-(pyrrolidin- 1-yl)benzamido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3 -(5-(3 -tert-Butyl-5-cyanobenzamido)-2-methylphenyl)yN-pyridin2ylmethyl)isoxazole. 5-carboxamide; 3 -(5-(3 -Fluoro-5-(pyrrolidin- 1-yl)benzamido)-2-methylphenyl)-N-(pyridin-2 ylmethyl)isoxazole-5-carboxamide; 3 -(2-Methyl-5-(3 -(pyrrolidin- 1 -yl)-5-.(trifluoromethyl)benzamido)phenyl)-N-(pyridin-2 ylrnethyl)isoxazole-5-carboxamide; 3 -(2-Methyl-5-(3 -(pyridin-2-yl)benzamido)pheny1)-N-((tetrahydrofiaran-2 yl)methyl)isoxazole-5-carboxamide; 3 -(5-(3-Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-(pyridin-2 ylmethyl)isoxazole-5-carboxamide; 3-(5-(3-Cyano-5-(piperidin- 1-yl)benzamido)-2-methylphenyl)-N-(pyridin-2 ylmethyl)isoxazole-5-carboxamide; 3-(5-(3 -Cyano-5-(pyrrolidin- 1-yl)benzamido)-2-methylphenyl)-N-(pyridin-2 ylmethyl)isoxazole-5-carboxamide; 3-f {5-[3-Fluoro-5-( 1 -oxo-l1 X-thiomorpholin-4-yl)-benzoylamino] -2-methyl-phenyl } isoxazole-5-carboxylic acid (2,2-dimethyl-propyl)-amide; N-(( 1-Methyl-i ,2, 5,6-tetrahydropyridin-3 -yl)methyl)-3 -(2-methyl-5-(3 -(pyrrolidin- l-yl) 5-(trifluoromethyl)benzamido)phenyl)isoxazole-5-carboxamide; 3 -(5-(3 -tc rt-Butyl-5-((4-methylpiperazin-l1-vl)methyl)benzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 3 -(5-(3-tert-Butyl-5-(morpholinomethyl)benzamido)-2-methy lphenyl)neopentylisoxazole-5-carboxamide; 88 WO 2007/146712 PCT/US2007/070547 3 -(5-(3-tert-Butyl-5-(pyrrolidin-1 -ylmethyl)benzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 3 -(5-(3-tert-Butyl-5-(piperidin- 1 -ylmethyl)benzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 3

-(

5

-(

3 -tert-Butyl-5-(morpholinomethyl)benzamido)-2-methylphenyl)-N ((tetrahydrof'uran-2-yl)methyl)isoxazole-5-carboxamide; 3 -(5-( 3 -tert-Butyl-5-((dimethylamino)methyl)benzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-(piperazin- 1 -ylmethyl)benzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; 3 -(5-(3 -tert-Butyl-5-(pyrrolidin- 1 -ylmethyl)benzamido)-2-methylphenyl)-N ((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-(pipcridin-1 -ylmethyl)benzamido)-2-methylphenyl)-N ((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3 -(5-(3 -tert-Butyl-5-((dimethylamino)methyl)benzamido)-2-methylphenyl)-N ((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-(piperazin- 1 -ylmethyl)benzamido)-2-methylphenyl)-N ((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3 -tert-Butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3 yl)phenylcarbamoyl)benzoic acid; 5-tert-Butyl-N-(2-(dimethylamino)ethyl)-N 3 -(4-methyl-3-(5 (neopentylcarbamoyl)isoxazol-3-yl)phenyl)isophthalamide; 3-(5-(3 -tert-Butyl-5-(piperidin- 1 -ylmethyl)benzamido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-((4-methylpiperazin-1-yl)methyl)benzamido)-2-methylphenyl)-N (pyridin-3-ylmethyl)isoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-(morpholinomcthyl)benzamido)-2-methylphenyl)-N-(pyridin-3 ylmethyl)isoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)benzamido)-2 methylphenyl)-N-((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-(((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)benzamido)-2 methylphenyl)-N-((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 89 WO 2007/146712 PCT/US2007/070547 3 -(5-(3 -((4-Acetylpiperazin- 1 -yl)methyl)-5-tert-butylbenzamido)-2-methylphenyl)-N ((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-((3 -methylpiperazin- 1 -yl)methyl)benzamido)-2-methylphenyl)-N ((tetrahydrofiaran-2-yl)methyl)isoxazole-5-carboxamide; 3

-(

5

-(

3 -tert-Butyl-5-cyanobenzamido)-2-methylphenylyN-cyclohexylisoxazole.5 caboxamide; 3-(5-(3-Cyano-5-(pyrrolidin- 1 -yl)benzamido)-2-methylphenyl)-N-cyclohexylisoxazole-s carboxamide; 3-(5..(3 -tert-Butyl-5-cyanobenzamido)-2-methylphenylyN-(piperidin- 1 -yl)i soxazole-5 carboxamide; 3 -(5-(3 -Cyano-5-(pyrroli din- 1 -yl)benzamido)-2-methylphenyl)-N-(piperidin- 1 yl)isoxazole-5-carboxamide; 3 -(5-(3 -tert-Butyl-5-cyanobcnzamido)-2-methylphenyl-N-morpholinoisoxazole-5 carboxamide; 3 -(5-(3 -Cyano-5 -(pyrroli din- 1 -yl)benzamido)-2-methylpheny)-N-morphoinoisoxazole 5-carboxamide; 3 -(5-(3-(8-Oxa-3-aza-bicyclo [3.2.1] octan-3 -yl)-5-fluorobenzamido)-2-methylphenyl)-N neopentylisoxazole-5-carboxamide; N-(3 -(5-(8-Oxa-3 -aza-bicyclo[3 .2.1 ]octane-3-carbonyl)isoxazol-3 -yl)-4-methylphenyl)-3 tert-butyl-5-cyanobenzamide; N-(3-(5-(8-Oxa-3 -aza-bicyclo[3 .2.1] octane-3-carbonyl)isoxazol-3 -yl)-4-methylphenyl)-5 ter-t-butyl-3 -cyano-2-methoxybenzamide; 3 -tert-Butyl-5-cyano-N-(4-methyl-3-(5-(2,2,6,6-tetramethylmorpholinc-4 carbonyl)isoxazol-3-yl)phenyl)benzamide; 5-tert-Butyl-3 -cyano-2-methoxy-N-(4-methyl-3 -(5-(2,2,6,6-tetramethylmorpholine-4 carbonyl)isoxazol-3 -yl)phenyl)benzamide; 3 -(5-(3 -tert-Butyl-5-((4-methylpiperazin- 1-yl)methyl)benzamido)-2-methylphenyl)-N cyclohexylisoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-((4-methylpiperazin-1 -yI)m ethyl)benzamido)-2-methylphenyl)-N ((6-(trifluoromethyl)pyridin-3-y)methy1)isoxazole-5-carboxamide. 3-tert-But;1-N -(4-methyl-3 -(5-(piperidine- I -carbonyl)isoxazol-3 -yl)phenyl)-5-((4 methylpiperazin- 1-yl)methyl)benzamide; 90 WO 2007/146712 PCT/US2007/070547 3-(5-(3-tert-Butyl-5-((4-methylpiperazin-I -yl)methyl)benzamido)-2-methylphenyl)-N (piperidin- 1 -yl)isoxazole-5-carboxamide; 3-(5-(3-tert-Butyl -5-((4-methylpiperazin- 1 -yl)methyl)benzamido)-2-methylphenyl)-N (pyridin-4-ylmethyl)isoxazole-5-carboxamide; 3-(5-(3 -tert-Butyl-5-((4-methylpiperazin- 1 -yl)methyl)benzamido)-2-methylphenyl)-N cyclopentylisoxazole-5-carboxamide; and pharmaceutically acceptable salts thereof. BRIEF DESCRIPTION OF THE FIGURES [00127] Figure 1 shows the effects of a compound as described herein on the ankle diameter in collagen induced arthritis in rats, upon once daily administration of the compound for 7 days. [00128] Figure 2 shows individual and mean group effects on the IL-lB response of lymphocytes to ex vivo LPS challenge after oral dosing of a compound described herein. The effects are expressed as the response after treatment versus pretreatment for each dose group, reflecting the inhibition of cytokines in the circulating leukocytes after oral dosing with a compound as described herein. (* Statistically significant effect (p <0.01)). [00129] Figure 3 shows the effects of a compound as described herein on the HDL cholesterol levels of cynomolgus monkeys, upon once daily administration of the compound for 90 days. [00130] Figure 4 shows the effects of a compound as described herein on the triglyceride levels of cynomolgus monkeys, upon once daily administration of the compound for 90 days. [00131] Figure 5 shows the effects of a compound as described herein on the HDL cholesterol levels of Wistar rats, upon once daily administration of the compound for 90 days. [00132] Figures 6A and 6B show the effects of a compound as described herein on the particle size distribution and on HDL 2 and HDL 3 levels of Syrian Golden Hamsters, upon once daily administration of the compound for 14 days (as determined by NMR and ultracentrifugation methods, respectively). 91 WO 2007/146712 PCT/US2007/070547 [00133] Figure 7 shows the quantification of the accelerated atherosclerosis in the vessel wall, based on the quantification of the staining of the cross sections at the 14 day time point, using the monocyte/macrophage marker AIA31240. Theis area was expressed as total area of AIA31240 positive area (upper panel) as wel as the percentage of the total area showing AIA31240 positivity (lower panel). [00134] Figure 8 shows the effects of a compound as described herein on the mean CRP-levels of human subjects with starting CRP levels > 0.3 mg/dl, upon once daily administration of the compound for 6 weeks, compared with placebo. (* p < 0.05 versus baseline (paired t-test)). [00135] Figure 9 shows the effects of a compound as described herein on the mean HDL levels of of human subjects, upon once daily administration of the compound for 6 weeks. [00136] Figure 10 shows the effects of a compound as described herein on the mean HDL levels of of human subjects, upon once daily administration of the compound in combination with statins for 6 weeks (p-values derived from Wilcoxon Rank-Sum test). [00137] Figure 11 shows the effects of a compound as described herein on the mean HDL particle size of human subjects, upon once daily administration of the compound for 6 weeks (particle size determined using NMR; p-values based on Wilcoxon Rank-Sum test). [00138] Figure 12 shows the effects of a compound as described herein on the mean ApoAl levels of human subjects, upon once daily administration of the compound for 6 weeks. [00139] Figure 13 shows the effects of a compound as described herein on the mean indirect bilirubin levels of human subjects, upon once daily administration of the compound for 6 weeks. [00140] Figure 14 shows the effects of a compound as described herein on the mean PAI-I levels of human subjects, upon once daily administration of the compound 92 WO 2007/146712 PCT/US2007/070547 for 6 weeks PAI-I (Mean individual absolute change from Baseline to Week 6; P values relative to placebo based on Wicoxon Rank Sum test). [00141] Figure 15 shows the effects of a compound as described herein on the diastolic and systolic blood pressure of human subjects, upon once daily administration of the compound for 6 weeks (Horizontal line denotes mean; p-values based on Wilcoxon Rank-Sum test). [00142] Figure 16 shows the effects of a compound as described herein on the mean VEGF levels of human subjects, upon once daily administration of the compound for 6 weeks (mean individual absolute change from Baseline to Week 6). DETAILED DESCRIPTION OF THE INVENTION [001431 The following terms are used throughout as defined below. [00144] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Hence, isotopically labeled compounds are within the scope of the invention. [00145] In general, "substituted" refers to an organic group as defined below (e.g., an alkyl group)in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sufides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitriles (i.e. CN); and the like. 93 WO 2007/146712 PCT/US2007/070547 [00146] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below. [00147] Alkyl groups include straight chain and branched alkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups further include cycloalkyl groups as defined below. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2 dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above. [00148] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 10 or 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like. In some embodiments, polycyclic cycloalkyl groups have three rings. Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above. [00149] Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkylene bridge, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms are located on adjacent carbon atoms, or 2 to 4 94 WO 2007/146712 PCT/US2007/070547 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 1 or 2 carbon atoms. Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2. 1.1 ]hexane, or tricyclic, such as, for example, adamantyl. Representative bridged cycloalkyl groups include bicyclo[2.1.1 ]hexyl, bicyclo[2.2. 1 ]heptyl, bicyclo[3.2.1 ]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3. I]nonyl, bicyclo[3.3.2]decanyl, adamantyl, noradamantyl, bornyl, or norbornyl groups. Substituted bridged cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted adamantyl groups, which may be substituted with substituents such as those listed above. [00150] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above. In some embodiments, cycloalkylalkyl groups have from 4 to 20 carbon atoms, 4 to 16 carbon atoms, and typically 4 to 10 carbon atoms. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group. Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above. [00151] Alkenyl groups include straight and branched chain and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkenyl groups include cycloalkenyl groups having from 4 to 20 carbon atoms, 5 to 20 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7 or 8 carbon atoms. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH 3 ), -CH=C(CH 3

)

2 ,

-C(CH

3

)=CH

2 , -C(CH 3

)=CH(CH

3 ), -C(CH 2

CH

3

)=CH

2 , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above. 95 WO 2007/146712 PCT/US2007/070547 [00152] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above. [00153] Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples include, but are not limited to -CFCH, -C-C(CH 3 ), -CWC(CH 2

CH

3 ), -CH 2 C=CH, -CH 2

C=C(CH

3 ), and

-CH

2

C=C(CH

2

CH

3 ), among others. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above. [00154] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups include monocyclic, bicyclic and polycyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6 substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above. [00155] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. 96 WO 2007/146712 PCT/US2007/070547 In some embodiments, aralkyl groups contain 7 to 20 carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above. [00156] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, 0, and S. In some embodiments, heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 15 ring members. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups". Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl,azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, 97 WO 2007/146712 PCT/US2007/070547 naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above. [00157] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, 0, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Although the phrase "heteroaryl groups" includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups". Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above. [00158] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group. Representative heterocyclyl alkyl groups include, but are not limited to, 4-ethyl morpholinyl, 4-propyhmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above. 98 WO 2007/146712 PCT/US2007/070547 [00159] Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl, or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above. [00160] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above. [00161] The terms "aryloxy" and "arylalkoxy" refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above. [00162] Alkyl, alkenyl, and alkynyl groups may be divalent as well as monovalent. The valency of an alkyl, alkenyl, or alkynyl group will be readily apparent from the context to those of skill in the art. For example, the alkyl group in an aralkyl group is divalent. In some embodiments, divalency is expressly indicated by appending the suffix "ene" or "ylene" to terms defined herein. Thus, for example, "alkylene" refers to divalent alkyl groups and alkenylene refers to divalent alkene groups. [00163] The term "carboxylate" as used herein refers to a -COOH group. 99 WO 2007/146712 PCT/US2007/070547 [00164] The term "carboxylic ester" as used herein refers to -COOR 3 0 groups. R3" is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. [00165] The term "amide" (or "amido") includes C- and N-amide groups, i.e.,

-C(O)NR

3

'R

32 , and -NR 3

C(O)R

3 2 groups, respectively. R 3 1 and R 32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H). [00166] Urethane groups include N- and O-urethane groups, i.e., -NR 33

C(O)OR

3 4 and -OC(O)NR3 R groups, respectively. R 33 and R 3 4 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. [00167] The term "amine" (or "amino")as used herein refers to -NHR 35 and NR 36R groups, wherein R3, R36 and R 37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is NH 2 , methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino. [00168] The term "sulfonamido" includes S- and N-sulfonamide groups, i.e., -S0 2

NRMR

3 9 and -NR 3 8

SO

2

R

39 groups, respectively. R 38 and R 3 9 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO 2

NH

2 ). [00169] The term "thiol" refers to -SH groups, while sulfides include -SR 40 groups, sulfoxides include -S(O)R4' groups, sulfones include -SO 2 R42 groups, and sulfonyls include -SOOR 43 . R 40 , R 4 , R 4 2 , and R4 3 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. 100 WO 2007/146712 PCT/US2007/070547 [00170] The term "urea" refers to -NR 4

-C(O)-NR

45

R

46 groups. R44, R 45 , and R 46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein. [00171] The term "amidine" refers to -C(NR 47

)NR

4 8R 49 and -NR 47

C(NR

48

)R

4 9 , wherein R47, R 48 , and R are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00172] The term "guanidine" refers to -NR C(NR )NR2 R", wherein R", R",

R

52 and R 53 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00173] The term "enamine" refers to -C(R )=C(R 55

)NR

56 R1 7 and 54 55 56 5'"456 5 -NR C(R )=C(R )R %,wherein R 54 , R 55 , R 5 and R 5 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00174] The term "imide" refers to -C(O)NR C(O)R 5 9 , wherein Rs' and R 9 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00175] The term "imine" refers to -CR 60

(NR

61 ) and -N(CR 6 0

R

61 ) groups, wherein

R

60 and R 6 1 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R 60 and R 6 ' are not both simultaneously hydrogen. [00176] The term "protected" with respect to hydroxyl groups, amine groups, carboxy groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups. Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures, such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as 101 WO 2007/146712 PCT/US2007/070547 those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1 -ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoroacetate. [001771 N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2--nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5 dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1 methylethoxycarbonyl, ca-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9 methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethylsilyl, and the like. Typical N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). [00178] Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others. 102 WO 2007/146712 PCT/US2007/070547 [00179] Representative carboxy protecting groups are C 1 to C 8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl, and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl, and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups, and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl, and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valerytoxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-1 -ethyl, 1-(pivaloyloxyl)-1-ethyl, 1-methyl-1 (propionyloxy)-I-ethyl, pivaloyloxymethyl, propionyloxymethyl, and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl, and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl, and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1 -methoxycarbonyl- I ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, I -ethoxycarbonyloxy-1-ethyl, 1 -cyclohexyloxycarbonyloxy- 1-ethyl, and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl, and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl, and the like; alkanoylaminoalkyl, such as acetylaminomethyl, and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl, and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, and the like; (5-(alkyl)-2 oxo-1,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl, and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen 4-yl)methyl, and the like. [00180] Those of skill in the art will appreciate that compounds of the invention may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the invention 103 WO 2007/146712 PCT/US2007/070547 encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms. [00181] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, triazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

-H

N N N N N H [00182] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of compounds as described herein are within the scope of the present invention. [00183] Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention. [00184] Certain compounds within the scope of Formulas IA, IB, IC, II, III and IV are derivatives referred to as "prodrugs". The expression "prodrug" denotes a derivative of a known direct acting drug, e.g.. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology 112:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future 6:165-182 (198 1); and 104 WO 2007/146712 PCT/US2007/070547 Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design ofProdrugs (H. Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992. The preceding references and all references listed herein are hereby incorporated in their entirety by reference. [00185] Pharmaceutically acceptable salts of the invention compounds are considered within the scope of the present invention. When the compound of the invention has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the invention has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na*, Li+, K+, Ca2+, Mg 2 +, Zn 2 +), ammonia, organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine), or basic amino acids (e.g., arginine, lysine and ornithine). [00186] C-reactive protein (CRP) is a plasma protein, and an acute phase protein produced by the liver. CRP is a member of the class of acute phase reactants as its levels rise dramatically during inflammatory processes occurring in the body. CRP is used mainly as a marker of inflammation. Measuring and charting C-reactive protein values can prove useful in determining disease progress or the effectiveness of treatments. Blood, usually collected in a serum-separating tube, is analysed in a medical laboratory or at the point of testing. Various analytical methods are available for CRP determination, such as ELISA, immunoturbidimetry, rapid immunodiffusion and visual agglutination. Research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes, hypertension and cardiovascular disease. It is thought that CRP levels <lmg/l represent low cardiovascular risk, while levels >3mg/l represent high risk. [00187] Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing 105 WO 2007/146712 PCT/US2007/070547 vasculature). As its name implies, VEGF activity is restricted mainly to cells of the vascular endothelium, although it does have effects on a limited number of other cell types (e.g., stimulation monocyte/macrophage migration). In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF also enhances microvascular permeability and is sometimes referred to as vascular permeability factor. Once released, VEGF may elicit several responses. It may cause a cell to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of cancer. VEGF is also released in rheumatoid arthritis in response to TNF-o, increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries). [00188] Lipoproteins are complexes which contain both a lipid and protein. Most of the lipids in plasma are present as lipoproteins and are transported as such. Lipoproteins are characterized by their flotation constants (e.g., densities). Various classes of lipoproteins exist and include high density lipoproteins (HDL) and low density lipoproteins (LDL). The HDL fraction comprises two major fractions, namely HDL 2 (large, buoyant HDL, density1.063-1.125 g/ml) and HDL 3 (small, dense HDL, density 1.125-1.21 g/ml). LDLs are particularly rich in cholesterol esters. Traditionally, high levels of LDL and/or low levels of HDL are associated with coronary artery disease. Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dl) have protective value against cardiovascular diseases. Low concentrations of HDL (below 40 mg/dl for men, below 50 mg/dl for women) are a positive risk factor for atherosclerotic diseases. A near optimal level of LDL is considered to be between 100 to 129 mg/dl, with levels below 100 mg/dl considered optimal, while very high LDL levels (above 190 mg/dl) correspond to the highest increased risk of heart disease. [00189] Assessment of these levels is associated with assessing the risk of cardiovascular and/or cerebrovascular disease. Lipoproteins levels and triglyceride levels are measured and assessed using routine methods known in the art. Commercially available kits and assays may be used to evaluate the level of HDL-C, LDL-C and the level of triglycerides in a subject. T pically, cholesterol analysis is performed by two methods, namely an NMR based method and an ultracentrifugation method. The first method is based on NMR analysis of the lipid environment to determine the size classes and utilizes deconvolution to determine the number of particles in each class. The second 106 WO 2007/146712 PCT/US2007/070547 method, based on density gradient ultracentrifugation, measures the amount of cholesterol across a range of densities and utilizes deconvolution to determine the amount of cholesterol in each fraction (HDL, including HDL 2 and HDL 3 , LDL, IDL, VLDL). [00190] Apolipoprotein A-I (ApoA-I) is the major protein component of HDL in plasma. The protein promotes cholesterol efflux from tissues to the liver for excretion and helps to clear cholesterol from arteries. [00191] Glucose, or "blood sugar", is normally present in humans at concentrations of about 80-120 mg/dl and is the principal source of carbohydrate energy for man and many other organisms. Excess glucose is stored in the body (especially in the liver and muscles) as glycogen, a starch-like substance which is, essentially, polymerized glucose. Glycogen is metabolized into glucose as needed to meet bodily requirements. [00192] Glucose normally stimulates both the secretion and biosynthesis of insulin. In addition to this glucose-stimulated insulin secretion, however, there exists a basal insulin secretion, namely the biological process by which insulin is released into the circulation in the absence of stimulation by levels of glucose, or other agents that promote insulin secretion, that are elevated above their "fasting" or non-fed levels. The values for fasting and post-prandial (after a meal) insulin are about 14 to 145 pmol/l, and 100 to 300 pmol/1 respectively in healthy people, with perhaps 3-to 4-fold higher levels in insulin resistant people. [00193] Glycosylated (or glycated) hemoglobin (hemoglobin Alc, Hblc , HbAl c or HgAl c) is a form of hemoglobin used primarily to identify the plasma glucose concentration over time. The normal range (that found in healthy subjects) is 4% to 5.9%. People with diabetes mellitus often have higher levels of HbAlc. While diabetic subject treatment goals vary, many include a target range of HbAlc values. A diabetic with good glucose control has a HbAI c level that is close to or within the reference range. The International Diabetes Federation and American College of Endocrinology recommends HbAlc values below 6.5%, while the range recommended by the American Diabetes Association extends to 7%. A very high HbA Ic represents poor glucose control. [00194] Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin 107 WO 2007/146712 PCT/US2007/070547 resistance in fat cells results in hydrolysis of stored triglycerides, which elevates free fatty acids in the blood plasma. Insulin resistance in muscle reduces glucose uptake whereas insulin resistance in liver reduces glucose storage, with both effects serving to elevate blood glucose. High plasma levels of insulin and glucose due to insulin resistance often leads to metabolic syndrome and type 2 diabetes. Metabolic syndrome, also known as Syndrome X, metabolic syndrome X, insulin resistance syndrome, is a combination of medical disorders, having at least three of the following symptoms and features: fasting hyperglycemia (including diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance or insulin resistance), high blood pressure, central obesity (also known as visceral adiposity), decreased HDL cholesterol, and elevated triglycerides. [00195] Insulin resistance can be detected by the following indications: as an increased level of blood insulin, increased blood level of glucose in response to oral glucose tolerance test (OGTT), decreased level of phosphorylated protein kinase B (AKT) in response to insulin administration, and the like. Insulin resistance may be caused by decreased sensitivity of the insulin receptor-related signaling system in cells and/or by loss of beta cells in the pancreas through apoptosis. There is also evidence that insulin resistance can be characterized as having an underlying inflammatory component. [00196] Bilirubin is formed when red blood cells die and their hemoglobin is broken down within the macrophages to heme and globins. The heme is further degraded to Fer, carbon monoxide and bilirubin via the intermediate compound biliverdin. Since bilirubin is poorly soluble in water, it is carried to the liver and bound to albumin. Bilirubin is made water-soluble in the liver by conjugation with glucuronic acid. Conjugated bilirubin, or bilirubinglucuronide, moves into the bile canaliculi of the liver and then to the gall bladder. Bilirubin is found in blood either in the conjugated form (also called direct bilirubin), or in the unconjugated form (also called indirect bilirubin). The reference range for total bilirubin is 0.3 - 1.0 mg/dl. For direct bilirubin, it is 0.1 - 0.3 mg/dl, while for indirect bilirubin it is 0.2 - 0.7 mg/dl. In diseases where too much hemoglobin is broken down or the removal of bilirubin does not function properly, the accumulating bilirubin in the body causes jaundice. Usually the concentration of total bilirubin in the blood must exceed 2-3 mg/dl for the coloration to be easily visible. [00197] Plasminogen activator inhibitor-1 is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and 108 WO 2007/146712 PCT/US2007/070547 hence fibrinolysis (the physiological breakdown of blood clots). PAI-1 is present in increased levels in various disease states, for example in obesity and metabolic syndrome. It has been linked to the increased occurrence of thrombosis in patients with these conditions. In inflammatory conditions in which fibrin is deposited in tissues, PAI-1 appears to play a significant role in the progression to fibrosis (pathological formation of connective tissue). Presumably, lower PAI levels would lead to less suppression of fibrinolysis and conversely a more rapid degradation of the fibrin. [00198] A "cytokine inhibitor" within the context of this invention is a compound which at a concentration of 10 tM inhibits induced cytokine release from a cell by about 50% or greater than 50%. For example, induction of TNFa release can be achieved by, but not limited to, treatment of a cell or cell line with lipopolysaccharide (LPS) or IL-1b and is inhibited by compounds described herein. [00199] The association of disorders with imbalances in specific cytokine levels is well known in the art, as documented by the references in List I. LIST 1. References describing cytokine-mediated processes and disorders. Disorder Reference Abnormal bleeding K Fassbender et al., J Neurol Neurosurg Psychiatry 2001 70(4):534-7; JW Semple et al., Transfus Apher Sci. 2003 28(3):237-342 Abscess CE Lloyd et al., Metabolism 2003 52(9):1218-25 Actinic Reticuloid J Hildesheim et al., J Invest Dermatol. 2004 Syndrome 122(2):497-502 Acute Confusional F Perini et al., Headache, 2005 45(7):926-31 Migraine Acute Confusional Senile I Ferrer et al., Curr Alzheimer Res 2005 2(1):3 Dementia 18 Acute hepatocellular L Nagy et al. Exp Biol Med 2003 228:882-890 injury Acute tubular necrosis K Furuichi et al., Nephrol Dial Transplant 2002 17(3):399-407 109 WO 2007/146712 PCT/US2007/070547 Disorder Reference Adenohypophyseal H Kanasaki et al., Biol Reprod 200 62(6):1486 Diseases 94 Adenovirus Infections Q Liu et at, Gene Ther. 2003 10(11):935-40 Adhesions J Yu et al., J Biol Chem. 2004 279(48):50446-54 Adhesive Capsulitis I Voloshin et al., Arthroscopy 2005 21(9):1076 Adnexitis T Guvenal et al, Eur Soc Hum Rep Emb 2001 16(8):1732-1735 Agammaglobulinemia C Ibanez et al., BioDrugs 2005 19(1):59-65 Agnogenic Myeloid RA Mesa, mt J Hematol 2002 76 Suppi 2:296 Metaplasia 304 Allergy KJ Escott et al., Br J Phamacol 2000 131 173 176 Alopecia MP Philpott et al., Br J Dermatol 1996 135(6):942-8 Alveolitis Fibrosing H Matsuoka et al., Am J physiol Lung Ccl Mo( Physiol 2002 283(l):L7 03-L S 12 Amyloidosis K Migita et al., Rheumatology (Oxford) 2005 44(4):443-8 Angioplasty N Ohashi et al., Arterioscler Thromb Base Biol 2000 20(12):2521-6 Angor Pectoris AS Gabriel et al., J Intern Med 2000 248(1):61-6 Antiphospholipid T. Koike et al., Lupus 2005 14: 799-801 Syndrome Arteriosclerotic Dementia {A De Luigi et al., Neurobiol Dis 2002 11(2):208 14 Arteritis Temporal AP Andonopoulos et al., Ann Rheum Dis 2003 62:1116 ~Arthropod-Bome SL Raung et al., Biochem Biophys Res Commun Encephalitis 2005 11(327):399-406 110 WO 2007/146712 PCT/US2007/070547 Disorder Reference Asphyxia K Okazaki et al., Biol Neonate 2006 89(3):183-9 Atopic Hypersensitivity WS Wong, Curr Opin Pharmacol 2005 5(3):264 71 Atrial Fibrillation S Sanada et al., Circulation 2001 104(6):705-10; J. 01gmn et al., W02007/053685 Beaver Fever E Maciorkowska et al., Med Wieku Rozwoj 2005 TX(4):665-673 Biliary Cirrhosis K Fernandez-Martinez t al., Exp Toxicol Pathol 2006 [ahead of print]; TK Mao, et al., Hepatology 2005 42(4):802-8 Bone Loss MA Karsdal et al., J Biol Chem 2003 278(45):44975-87; M Matsumoto t al., J Biol Chem 2000 275(40):31155-61; M Matsumoto et al., J Biol Chem 2004 279(44):45969-79 Bronchiolitis AS Farivar et al., J Heart Lung Transplant 2004 23(8):985-92 Cancer of Endocrine M Moscova et al., Cancer Res 2006 66(3):1376 Gland 83 Cancer of Larynx J Westermarck et al., Cancer Res 2000 60(24):7156-62 Candidiasis S Nagafuchi et al., Immunol Lett 2005 99(1):130-5; R Deva et al., J Immunol 2003 171(6):3047-55 Carcinoma Small Cell AK Greenberg et al., Am J Respir Cell Mol Biol ~Lung 2002 26(5):558-64 Cardiac Hypertrophy L Xu et al., J Mol Cell Cardiol 2005 38(5):735 43 Cardiac Surgery TA Khan et al., J Thorac Cardiovasc Surg 2004 127(3):806-11 111 WO 2007/146712 PCT/US2007/070547 Disorder Reference Cardiomegaly S Wenzel et al., Eur J Heart Fail 2005 7(4):453 60 Carditis DA Neumann et al., Clin Immunol Immunopathol 1993 68(2):181-90 Carotid Angioplasty N Ohashi et al. Arterioscier Thromb Basc Biol 2000 20(12):2521-6 Carotid Endarterectomy E Profiamo et al., J Cardiovasc Surg (Torino) 2003 44(2):237-42 Carotid Stents M Kotani et al., Cardiovasc Res 2003 57(4):265 76 Carotid Ulcer K Yoshida et al., Circulation 2003 108(14):1746 52 Celiac Disease L Palova-Jelinkova et al., J Immunol 2005 175(1 0):7038-45 Cirrhosis YP Zhang et al., World J Gastroenterol 2006 12(9): 1392-6 Colitis E Hollenbach et al., FASEB J 2004 18(13):1550 2 Colitis Granulomatous D Hommes et al., Gastrocntrology 2003 122(1):7-14 Coronary Artery Bypass D Talmor et al., Circ Res 2000 86(9):1004-7 Graft Coronary Artery Bypass D Talmor et al., Circ Res 2000 86(9):1004-7 Surgery Cortical Cataracts J Zhou et al., Invest Opthalmol Vis Sci 2004 45(7): 2314-23 Corticosteroid Resistant HT Holgatc et al, Lancet 2006 368: 780-93 Asthma Degenerative Joint PH Marks et al., Arthroscopy 2005 21(11):1342 Disease 7 112 WO 2007/146712 PCT/US2007/070547 Disorder Reference Dermatitis J Hildesheim et al., J Invest Dermatol. 2004 122(2):497-502; Y Takanami-Ohnishi et al., J Biol Chem 2002 277(40):37896-903 Diabetic Erectile MR Nangle et al., Int J Impotence Res. 2006 18: Neuropathy 258-263 Diabetic Erectile MR Nangle et al., Int J Impotence Res. 2006 18: Vasculopathy 258-263 Diarrhea MA Khan et al., Immunology 2004 112(4):651 60 Dry Eye SC Pflugfelder et al., Curr Eye Res 1999 19(3):201-11 Dyspnea H Lou et al., Am J Physiol Heart Circ Physiol 2005 288(4):H1925-30 Edema K Issbrucker et al., FASEB J 2003 17(2):262-4 End-Stage Renal Disease SR Khan, Clin Exp Nephrol 2004 8(2):75-88 Epstein-Barr Virus U Dirmeier et al., Cancer Res 2003 63(11):2982 Infections 9 Fever BL Fiebich et al., J Neurochem 2000 75(5):2020-8 Follicular Thyroid M Pomdrance et al., J Pathol 2006 209: 298-306 Carcinoma Gastroenteritis JM Kim et al., Eur J Immunol 2005 35(9):2648 57 Heart attack YH Liu et al., J Card Fail 2005 11(1):74-81 Heart Bypass Surgery TA Khan et al., J Thorac Cardiovasc Surg 2004 127(3):806-11; N Koike et al., Transplantation 2004 77(2):286-92 Heart Surgery TA Khan et al., J Thorac Cardiovasc Surg 2004 127(3):806-11; N Koike et al., Transplantation 2004 77(2):286-92 113 WO 2007/146712 PCT/US2007/070547 Disorder Reference Heart Transplantation TA Khan et al., J Thorac Cardiovasc Surg 2004 127(3):806-11; N Koike et al., Transplantation 2004 77(2):286-92 Hepatitis JP Moorman et al., Respir Res 2005 6:105; C Tam et al., J Virol 2002 76(19):9763-72; A Dolganiuc et al., Gastroenterology 2004 127(5):1513-24 Hepatitis A JP Moorman et al., Respir Res 2005 6:105; C Tam et al., J Virol 2002 76(19):9763-72; A Dolganiuc et al., Gastroenterology 2004 127(5):1513-24 Hepatitis B JP Moorman et al., Respir Res 2005 6:105; C Tarn et al., J Virol 2002 76(19):9763-72; A Dolganiuc et al., Gastroenterology 2004 127(5):1513-24 Hepatitis C JP Moorman et al., Respir Res 2005 6:105; C Tam et al., J Virol 2002 76(19):9763-72; A Dolganiuc et al., Gastroenterology 2004 127(5):1513-24 Hepatitis Chronic C Bureau et al., J Biol Chem 2001 276(25):23077-83 Insulin Resistance YH Shen et al., J Biol Chem 2006 281(12):7727 36; A Bloch-Damti et al., Antioxid Redox Signal 2005 7 (11-12):1553-67; A Kushiyama et al., J Biol Chem 2005 280(51):42016-25 Kidney Failure T Kita et al., Shock 2004 21(6):532-42 Kidney Transplantation K Furuichi et al., Nephrol Dial Transplant 2002 17(3):399-407; A Djamali et al., Transplantation 2005 79(12):1645-57 Leukemia Adult Chronic A Sainz-Perez et al., Leukemia 2006 20(3):498 504 114 WO 2007/146712 PCT/US2007/070547 Disorder Reference Liver Cirrhosis HS Lee et al., J Biomed Sci 2003 10(6 Pt 2):757 65 Liver Transplantation T Liang et al., Liver Transpl 2005 11(12):1527 32 Meningitis D Constantin et al., J Neurochem 2004 89(5):1166-74 Meningitis Bacterial D Constantin et al., J Neurochem 2004 89(5):1166-74 Myeloproliferative E Katsoulidis et al., Cancer Res 2005 Disorders 65(19):9029-37 Myopathies A Migliore et al., Eur Rev Med Pharmacol Sci 2005 9(6):373-8; DL Lefkowitz et al., Med Hypotheses 2005 65(4):716-21; Lc Gosselin et al., Med Sci Sprots Exere 2004 36(1):44-51; IE Lundberg ct al., Rheum Dis Clin North Am 2002 28(4):799-822 Myositis GJ Hengstman et al., Eur Neurol 2003 50(1):10 5, H Sprott et al., Rheumatology (Oxford) 2004 43(4):524-6 Neonatal-Onset R Goldbach-Mansky et al., New Eng J Med Multisystem 355(6): 581 Inflammatory Disease Nephritis JR Timoshanko et al., Curr Drug Targets Inflamm Allergy 2005 4(3):353-62 Neuromuscular Disorders K Kancyama et al., Oral Surg Oral Med Pathol Oral Radiol Endod 2005 99(3):276-84; N Ogura et al., J Oral Pathol Med 2005 34(6):657-63; DL Lefkowitz et al., Med Hypotheses 2005 65(4):716-21 115 WO 2007/146712 PCT/US2007/070547 Disorder Reference Neuropathy JM Gonzalez-Clemente et al., Clin Endocrinol (Oxf) 2005 63(5):525-9 Obliterative Bronchiolitis AS Farivar et al., J. Heart Lung Transplant, 2004 23(8): 985-92 Oral cancer NL Rhodus et al., Mol Carcinog 2005 44(2):77 82 Percutaneous Coronary N Ohashi et al., Arterioscler Thromb Base Biol Intervention 2000 20(12):2521-6 Periodontal Bone Loss KL Kirkwood ct al., J Pharmacol Exp Ther 2007 320:56-63 Peripheral Nerve JM Gonzalez-Clemente et al., Clin Endocrinol Disorders (Oxf) 2005 63(5):525-9 Neuropathy JM Gonzalez-Clemente et al., Clin Endocrinol (Oxf) 2005 63(5):525-9 Peritoneal Dialysis I Daniels et al., Clin Diagn Lab Immunol 1999 6(6):878-84 Pleural disease CL Chung et al., Chest 2005 128(2):690-7 Pneumonitis RT Sadikot J Immunol 2006 176(8):4923-30 Polymyositis P Efthimiou et al., Ann Rheum Dis 2006 [ahead of print] Posterior Capsular S. Menko, W02006/128152 Opafication Pruritus M Kato et al., W02006/062069 Pulmonary fibrosis LK Lundblad et al., Am J Respir Crit Care Med 2005 171(12):1605-6; L Wang et al., J Cell Physiol 2003 194(2):215-24; R Vassall et al. Chest 2002 124(1):413-414; P Pantelidis et al., Respir Res 2001 2(6):365-72; M Kolb et al., J Clin Invest 2001 107(12):1529-36 Renal Cancer S Ikemoto et al., Oncol Rep 2003 10(6):1947-55 116 WO 2007/146712 PCT/US2007/070547 Disorder Reference Renal Dialysis G Tripepi et al., J Am Soc Nephrol 2005 Suppl 1:S83-8 Scleroderma H Ihn et al., J Invest Dermatol 2005 125(2):247 55; Z Tutuncu et al., Clin Exp Rheumatol 2002 20(6 Suppl 28):S146-51; AF Alexis et al., J Cutan Med Surg 2006 25[ahead of print] Septic Arthritis J Anguita et al., J Immunol 2002 168(12):6352-7 Sjogren's Syndrome Atzeni F et al., Autoimmun Rev 2005 4(3):144 52 Spondylitis Ankylosing J Braun et al., Rheumatology (Oxford) 2004 43(9):1072-84 Still's Disease Z Tutuncu et al., Clin Exp Rheumatol 2002 20(6 Supply 28):S146-51; J Cutan Med Surg 2006 25[ahead of print] Sympathetic Ophthalmia GN Palexas et al. Scand J Immunol 1992 11 Supply , 173-5 Toxemia D Klintman et al., Ann Surg 2005 242(6):830-8 Tuberculosis S Haraguchi et al., AIDS Res Ther 2006 3(1):8[ahead of print] Urticaria G Chodorowska et al., Ann Univ Mariae Curie Sklodowska [Med] 2003 58(2):50-6; S Piconi et al., Int Arch Allergy Immunol 2002 128(1):59 66; B Hermes et al., J Allergy Clin Immunol 1999 103(2 Pt 1):307-14 Viral Hepatitis JP Moorman ct al., Respir Res 2005 6:105; C Tam ct al., J Virol 2002 76(19):9763-72; A Dolganiuc et al., Gastroenterology 2004 127(5):1513-24; C Burea et al, J Biol Chem 2001 276(25):23077-83 117 WO 2007/146712 PCT/US2007/070547 Disorder Reference Wegener's D Huugen et al., Am J Pathol 2005 167(l):47-58 Granulomatosis [00200] "Treating" within the context of the instant invention, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder. As used herein, a therapeuticallyy effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder or disease, or slows or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder. As will be apparent to those of skill in the art, it is to be expected that the therapeutically effective amount of a compound disclosed herein may vary depending on the indication being treated, e.g., the therapeutically effective amount of a compound described herein would likely be different for treating subjects suffering from, or at risk for, cytokine-mediated disorders relative to the therapeutically effective amount of the compound for treating subjects suffering from, or at risk of, a different disorder, e.g., vascular event(s), diabetes, insulin resistance, or metabolic syndrome. Similarly, it is also to be expected that, for example, the therapeutically effective amount of a compound for decreasing CRP-levels in a subject would likely be different from the therapeutically effective amount for raising HDL-levels in a subject. [00201] A subject is any animal that can benefit from the administration of a compound as described herein. In some embodiments, the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse. Typically, the subject is a human. [00202] Subjects who are at risk for a cardiovascular and/or cerebrovascular event are also subjects who manifest at least one symptom indicative of a vascular disorder/event. Symptoms that are indicative of a coronary-related vascular event, for example, include chest pain, abnormal electrocardiograms, elevated levels of ischemic markers, necrosis markers, or thrombin/fibrin generation markers. Such markers include, 118 WO 2007/146712 PCT/US2007/070547 but are not limited to, Creatine Kinase with Muscle and/or Brain subunits (CKMB), D Dimer, F1.2, thrombin anti-thrombin (TAT), soluble fibrin monomer (SFM), fibrin peptide A (FPA), myoglobin, thrombin precursor protein (TPP), platelet monocyte aggregate (PMA) and troponin (cTn). Subjects who are at risk also include subjects having a history of a thrombotic event (e.g., disorder), including coronary heart disease (CHD), stroke, or transient ischemic attacks (TIA). A history of CHD can include, for example, a history of MI, coronary revascularization procedure, angina with ischemic changes, or a positive coronary angiogram (e.g., showing greater than about 50% stenosis of at least one major coronary artery). [00203] A therapeutically effective amount of a compound as described herein used in the present invention may vary depending upon the route of administration and dosage form. Effective amounts of invention compounds typically fall in the range of about 0.001 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 10 mg/kg/day. Typically, the compound or compounds used in the instant invention are selected to provide a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 5 0 and ED 50 . The LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population. The LD 5 o and

ED

50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals. [00204] The instant compounds can be used in the methods and compositions of the invention either alone or together with additional treatments or active ingredients or a combination thereof The additional active agents can act additively or, more typically, synergistically with the inventive compound. In one example, the inventive compound is administered concurrently with one or more second active agents in the same pharmaceutical composition. In another example, the inventive compound is administered concurrently with one or more second active agents in separate pharmaceutical compositions. In still another example, the inventive compound is administered prior to or subsequent to administration of a second active agent. The invention contemplates administration of the inventive compound and a second active agent by the same or different routes of administration, e.g., oral and parenteral. In certain embodiments, when the inventive compound is administered concurrently with a second active agent that 119 WO 2007/146712 PCT/US2007/070547 potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited. [00205] Specific dosages of compounds or combinations of compounds as described herein and additional active agents may be adjusted depending on condition of the subject, the disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the dosage forms described below containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention. [00206] The invention also provides for pharmaceutical compositions and medicaments which may be prepared by mixing one or more compounds of Formula IA, IB, 1C, II, III, and/or IV and optionally additional active ingredients, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat disorders associated with excess cytokine production. The compounds and compositions of the invention may be used to prepare formulations and medicaments that prevent or treat a variety of disorders associated with excess cytokine production as disclosed herein, e.g., diseases and pathological conditions involving inflammation, metabolic disease, pain, cancer, etc. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injections. The following dosage forms are given by way of example and should not be construed as limiting the instant invention. [00207] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at 120 WO 2007/146712 PCT/US2007/070547 least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art. [00208] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. [00209] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations. [00210] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. 121 WO 2007/146712 PCT/US2007/070547 [00211] For injection, the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. [00212] For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives. [00213] Compounds used in the invention may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate. Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation. [00214] Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or 122 WO 2007/146712 PCT/US2007/070547 polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. A nonaqueous suspension (e.g., in a fluorocarbon propellant) can also be used to deliver compounds used in the invention. [002151 Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Delivery of aerosols of the present invention using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound. [002163 For nasal administration, the pharmaceutical formulations and medicaments may be a spray, nasal drops or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. For administration in the form of nasal drops, the compounds may be formulated in oily solutions or as a gel. For administration of nasal aerosol, any suitable propellant may be used including compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent. [00217 Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds used in the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required. Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, 123 WO 2007/146712 PCT/US2007/070547 polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof [00218] Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the inventive compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. [00219] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention. The compounds used in this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye. The compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution fonnulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the invention compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can be optionally incorporated. [00220] Intrathecal administration, via bolus dosage or constant infusion, allows the local administration of a compound to a region of the spinal cord, such as the dorsal 124 WO 2007/146712 PCT/US2007/070547 horn regions, delivering the compound directly to the subarachnoid space containing the CSF (cerebrospinal fluid). [00221] Central delivery to the spinal cord regions can also be performed by epidural injection to a region of the spinal cord exterior to the arachnoid membrane. Enhancing permeation of the active compound through meningeal membranes may be achieved by using hypertonic dosing solutions that increase permeability of meningeal membranes, or by addition of permeation enhancers, such as, but not limited to, liposomal encapsulation, surfactants, or ion-pairing agents. [00222] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. [002231 The formulations of the invention may be designed to be short-acting, fast releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release. [00224] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers. [002253 Administration of compounds described herein and the additional active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. A typical route of administration for the compounds described 125 WO 2007/146712 PCT/US2007/070547 herein is oral or topical. Typical routes of administration for the additional active agents or ingredients of the invention are known to those of ordinary skill in the art [See, e.g., Physicians' Desk Reference ( 5 7 th ed., 2003)]. Alternatively, the compound and the additional active agents are administrated simultaneously by coformulation. [00226] The additional active agent can be administered orally, intravenously, intramuscularly, subcutaneously, mucosally, or transdermally and once, twice or more daily in an amount of from about 1 to about 3,500 mg, from about 5 to about 2,500 mg, from about 10 to about 500 mg, or from about 25 to about 250 mg. [00227] In some embodiments of the invention, one or more compounds as described herein and an additional active agent are administered to a subject such as a mammal, more typically a human, in a sequence and within a time interval such that the compound can act together with the other agent to provide an enhanced benefit relative to the benefits obtained if they were administered otherwise. For example, the additional active agents can be coadminstered by coformulation, administered at the same time or administered sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In some embodiments, the compound as described herein and the additional active agents exert their effects at times which overlap. Each additional active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the compound is administered before, concurrently or after administration of the additional active agents. [00228] In various examples, the compound as described herein and the additional active agents are administered less than about I hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about II hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In other examples, the compound as described herein and the additional active agents are administered concurrently. In yet other examples, the compound as described herein and the additional active agents are administered concurrently by coformulation. 126 WO 2007/146712 PCT/US2007/070547 [00229] In other examples, the compound as described herein and the additional active agents are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart. [00230] In certain examples, the compound as described herein and optionally the additional active agents are cyclically administered to a subject such as a mammal. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and/or third agent for a period of time and repeating this sequential administration. Cycling therapy can provide a variety of benefits, e.g., reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one or more of the therapies, and/or improve the efficacy of the treatment. [00231] In other examples, the compound as described herein and optionally the additional active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of a compound as described herein and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle, about 30 minutes every cycle, or about 15 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles. [00232] In yet other examples, the compound described herein is administered in metronomic dosing regimens, either by continuous infusion or frequent administration without extended rest periods. Such metronomic administration can involve dosing at constant intervals without rest periods. Typically the compound as described herein is used at lower doses. Such dosing regimens encompass the chronic daily administration of relatively low doses for extended periods of time. In typical examples, the use of lower doses can minimize toxic side effects and eliminate rest periods. In certain cases, the compound as described herein is delivered by chronic low-dose or continuous infusion ranging from about 24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3 weeks to about I month to about 2 months, to about 3 months, to about 4 months, to 127 WO 2007/146712 PCT/US2007/070547 about 5 months, to about 6 months. The scheduling of such dose regimens can be optimized by the skilled artisan. [00233] Courses of treatment can be administered concurrently to a subject, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the compound as described herein can work together with the additional active agents. For example, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day. [00234] The present disclosure also provides medical devices incorporating compounds described herein. A representative device includes a vascular stent coated or impregnated with compound(s) described herein. The device can be configured to be inserted into a blood vessel where it can release a compound(s) as described herein to help reduce or prevent vascular inflammation. [00235] Other embodiments include medical devices that include compounds as described herein, or a combination of compounds described herein with additional ingredients A, as described herein. Compounds described herein can be coated on the surface of the medical device or the device can be saturated with the compounds such that the compounds are released from the device, for example over a period of time. Exemplary medical devices including compounds disclosed herein include, but are not limited to, vascular medical devices such as vascular stents. [00236] Stents and methods for making and using stents coated or impregnated with therapeutic agents are well-known in the art: see, e.g., U.S. Application No. US20050181977 and U.S. Application No. US20050129729. 128 WO 2007/146712 PCT/US2007/070547 [00237] Examples of compounds used in the instant invention are described below. A first group of compounds are represented by Formula IA, N Ar-L-Q H IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, X, Ar, Y, L, m, Q, R, R', R", R1, R 2 , RR 4 , R, R, R, R, R , R R, R", R ,R"4, R , R ,R , 1 19 20 21 22 23 24 25 26 2 R18, R19, R RR , R R R R2, and R are as defined in List II. LIST II: Definition of variables for the first group of compounds of Formula IA. G is a C 3

.

10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl containing one or more heteroatoms selected from 0, N or S; 1 2 3 wherein G is substituted by one or more R , R or R X is C(O), C(S) or CH 2 ; Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazoly dioxide, C 6

.

10 aryl, -(CI- 3 alkyl)-(C 61 oi aryl), -(Y)-(CO.3 alkyl)-(C 6

-

10 aryl), or -(Y)-(CO.

3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R 5 ; each Y is independently -CHZ-, -CZ 2 -, -CHR-, -0-, -C(=CHR)-, or -C(=C-C0 2 R)-; each Z is independently F, Cl, -OR, -NR 2 , -SR, -NHCONHR, or -NHCOR; L is a covalent bond or a saturated or unsaturated branched or unbranched C 1 io carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from 0, NR or S(O),m; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I; each m is independently 0, 1 or 2; 129 WO 2007/146712 PCT/US2007/070547 Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C 1

.

6 alkoxy, CI- 6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C 1

.

6 alkoxy, C 1

.

6 alkyl-S(O)m,, or phenyl-S(O)m is each optionally substituted with one or more R 27; each R is independently hydrogen or substituted or unsubstituted C 1

.

6 alkyl; each R' is independently hydrogen, substituted or unsubstituted C 1

-

8 alkyl, substituted or unsubstituted (Co 4 alkyl)-(C- 10 aryl) or substituted or unsubstituted (Ca 4 alkyl)-(5- 10 member heterocyclyl); each R" is independently substituted or unsubstituted C 1 .s alkyl, substituted or unsubstituted (Co 4 alkyl)-C- 10 aryl or substituted or unsubstituted (Co 4 alkyl)-(5-1 0 member heterocyclyl); each R' is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR 2 , -C(O)OR, -OR, -NR'R', -SiR 3 , - S(O)mR, substituted or unsubstituted C 1

-

10 alkyl, substituted or unsubstituted C 2 -ia alkenyl, substituted or unsubstituted C 2

-

10 alkynyl, substituted or unsubstituted C 3

-

10 cycloalkyl, substituted or unsubstituted C 5

_

8 cycloalkenyl, substituted or unsubstituted C 7 . 20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, 0, or S(O)m; each R 2, R4 and R is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C 1

.

6 alkyl, substituted or unsubstituted C 6

-

10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR 6, -C(O)R', -C(O)OR', -C(O)NR' 2 ,

-NR'

2 , -NO 2 , -S(O)mR", -NR'SO 2 R", -NR'C(O)NR'R', -NR'C(S)NR'R', -NR'C(O)OR' or -SO 2

NR'

2 ; each R 3 is independently substituted or unsubstituted C 6 -io aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, 0, or S(O)m, substituted or unsubstituted C 3 -1 2 cycloalkyl, substituted or unsubstituted C 5

-

12 cycloalkenyl, substituted or unsubstituted C 7 -2o aralkyl, substituted or unsubstituted straight or branched C Is alkyl, R 20 C(O)N(R')-, R 2 O-. R 23 R2 4 NC(O)-, R (CH 2 )mC(O)N(R 2 )-, R 26

C(O)(CH

2 )mN(R )-, substituted or unsubstituted C 2 -S alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the

C

18 alkyl, C 28 alkenyl, or C 2 -s alkynyl are optionally replaced by 0, NH, or S(O)m; 130 WO 2007/146712 PCT/US2007/070547 each R6 is a C 1

-

6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R 26 ; 7 9 10 12 13 14 is 17 192 each R , R', R , R , R , RD, R , R , R , R ', and R 2 s is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C 04 alkyl)amino, wherein the Co- alkyl is optionally partially or fully halogenated; each R 11 and R 16 is independently hydrogen or Ci- 4 branched or unbranched alkyl optionally partially or fully halogenated; and

R

1 8 is independently hydrogen or C 14 branched or unbranched alkyl optionally independently substituted with oxo or R 25 . R 2 is substituted or unsubstituted C 1 Io alkyl, substituted or unsubstituted CO 6 alkyl phenyl, substituted or unsubstituted Co- 6 alkyl-heterocyclyl, OR' or NR' 2 ;

R

21 is hydrogen or C 14 branched or unbranched alkyl optionally partially or fully halogenated; each R , R2 and R2 is independently hydrogen, substituted or unsubstituted C 1

.

10 alkyl, wherein the C 1

_

1 0 alkyl is optionally interrupted by one or more 0, N or S, substituted or unsubstituted Co.

6 alkyl-phenyl, substituted or unsubstituted Co 0 6 alkyl-heterocyclyl; or

R

23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring; each R 26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co 4 alkyl)amino, wherein the Co 4 alkyl is optionally partially or fully halogenated; each R 2 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NR' 2 , -C(O)OR', -OR', NR'R', -SiR' 3 , - S(O)mR', substituted or unsubstituted C 1 .10 alkyl, substituted or unsubstituted C 2

-

10 alkenyl, substituted or unsubstituted C 2

-

10 alkynyl, substituted or unsubstituted C 3

-

1 o cycloalkyl, substituted or unsubstituted Cs_8 cycloalkenyl, substituted or unsubstituted C 7

-

20 aralkyl, substituted or unsubstituted 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, 0, or S(O)m; provided however that when Ar is -(Y)-(C 6 10 aryl) and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R 1 , R 2 or R 3 ; and IA is not N-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-2-(4-chloro phenyl)-acetamide. 131 WO 2007/146712 PCT/US2007/070547 [00238] In certain embodiments of the first group of Formula IA, the compound at a concentration of 10 pM inhibits induced TNFa-release from a cell by about 50% or greater than 50%. [00239] In some embodiments of the first group of compounds of Formula IA, G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one; pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H benzo[ 1,4]oxazine-3 -only, benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl; pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. [00240] In other embodiments of the first group of compounds of Formula IA, G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one. In yet others, G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, benzo[I.4]oxazin-3-onyl, benzodioxolyl, bcnzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimidyl. Alternatively, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, 132 WO 2007/146712 PCT/US2007/070547 tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. In other embodiments, G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl. [00241] In certain embodiments of the first group of compounds of Formula IA, Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or C 6 -io aryl. In some such embodiments, Ar is substituted with at least one R 4 or R 5 . Alternatively, Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl or imidazolyl. In still other such embodiments, Ar is indazolyl, phenyl, tetrahydronapthyl or naphthyl. [00242] In certain embodiments of compounds having Formula IA, Ar is -(C 1

.

3 alkyl)-(C6io aryl), -(Y)-(CO.

3 alkyl)-(C 6 -io aryl), or -(Y)-(CO.

3 alkyl)-(5-10 member heteroaryl). In some such embodiments, Ar is substituted with at least one R 4 or R . In some such embodiments, Y is -CZ 2 - and each Z is independently F, -OR or -CHR. For example, Y is -CF 2 -. In others, Y is -CHR or -CHZ- and Z is -OR. Thus, for example, Y is -CHOH-. Alternatively, Y is -0- or -CH 2 -. In still other such embodiments, the C 6

.

10 aryl is phenyl or naphthyl, and/or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl. In yet other such embodiments Ar is -(C 1

.

3 alkyl)-(C 6 .10 aryl). [00243] In some embodiments of the first group of compounds of Formula IA, one or more methylene groups of L are independently replaced by hetero atoms selected from 0, NR or S(O)m. In others, L is a covalent bond, a C 1

-C

9 alkoxy, -C(O)O-, -NH- or -O-. [00244] As noted above, Q, other than -H or -NR'R', is optionally substituted with 27 R . In certain embodiments of the first group of compounds of Formula IA Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, 133 WO 2007/146712 PCT/US2007/070547 pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3 b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl, or imidazo[4,5-b]pyridinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3 dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C 1

.

6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to

C

1

.

3 alkyl or C 1 .5 alkoxyalkyl, phenylamino; C 1

.

6 alkyl-S(O)m or phenyl-S(O)m. [00245] In other embodiments of the first group of compounds of Formula IA, Q is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3 b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl, or imidazo[4,5-b]pyridinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3 dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C1.

alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1.

3 alkyl or C 1

.

5 alkoxyalkyl, phenylamino; C 1

.

6 alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R is C 1

.

6 alkyl, C 1

.

6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C 1

.

3 alkyl)amino, mono- or di (phenyl-C 1

.

3 alkyl)amino, C 1 . alkyl-S(O)m, phenyl-C 1

.

3 -alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1.

6 alkyl or C1_ 6 alkoxy. [00246] In some other embodiments of the first group of compounds of Formula !A, Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinony1, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R 27 is -C(O)OR', -NR'R', substituted or unsubstituted straight or branched CI 10 alkyl, substituted or unsubstituted C- 20 aralkyl, or substituted or unsubstituted saturated or 134 WO 2007/146712 PCT/US2007/070547 unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, 0, or S(O)m. Alternatively, Q is pyrimidinyl and R 27 is -NR'R' or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, 0, or S(O)m. In yet other such embodiments, Q is pyridinyl, and R 27 is -NR'R', substituted or unsubstituted C1.

6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, 0, S(O)m. [00247] In some embodiments of the first group of compounds of Formula IA, when R 4 and R 5 are absent, -L-Q is not -H. [00248] In some embodiments of the first group of compounds of Formula IA, each R 1 is independently

C

3 .io branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3

.

10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C1.

6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3

.

8 cycloalkyl, C 5

.

8 cycloalkenyl, hydroxy, cyano, C1- 3 alkoxy which is optionally partially or fully halogenated and NH 2 C(O) or mono- or di (Ci 3 alkyl)aminocarbonyl; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1.3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1.

3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by 0, S(O)m, CHOH, C=0, C=S or NH;

C

3

-

10 branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three C 1

.

5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl; each of the aforementioned 135 WO 2007/146712 PCT/US2007/070547 being optionally, partially or fully halogenated, C 1

.

6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C 1 3 alkoxy optionally partially or fully halogenated,

NH

2 C(O) or mono- or di-(C 1 3 alkyl)aminocarboxyl; and wherein the C3 1 0 branched or unbranched alkenyl is optionally interrupted by one or more 0, N or S(O)m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1 3 alkyl groups; cyano, F, Cl, Br, or I; methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; silyl containing three C 1 4 independently branched or unbranched alkyl groups optionally partially or fully halogenated;

C

2

.

6 branched or unbranched alkyl-C(O), C 2

.

6 branched or unbranched-S,

C

2

.

6 branched or unbranched-S(O), C 2

.

6 branched or unbranched-S(0) 2 ;

C

2

-

6 branched or unbranched alkynyl group optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by 0, NH and S(O)m and wherein said alkynyl group is optionally independently substituted with 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more C-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C 1 4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms. [00249] In other embodiments of the first group of compounds of Formula IA, each R' is independently C 3 10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3

.

10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogens, C 1 -6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3

.

8 cycloalkyl, C 5 8 cycloalkenyl, hydroxy, cyano, C 1 3 alkoxy which is optionally partially or fully halogenated and NH 2 C(O) or mono- or di 136 WO 2007/146712 PCT/US2007/070547

(C-

3 alkyl)aminocarbonyl. For example, each R1 is independently C 3 10 branched or unbranched alkyl. [00250] In some embodiments of the first group of compounds of Formula IA, each R2 is independently -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O)mR", -NR'SO 2 R", -NR'C(O)NR'R', -NR'C(S)NR'R', -NR'C(O)OR' or -SO 2

NR'

2 . Alternatively, each R2 is independently -NR' 2 , -NO 2 , -C(O)NR' 2 , -NR'SO 2 R", -NR'C(O)NR'R', -NR'C(S)NR'R', -NR'C(O)OR' or -SO 2

NR'

2 . [00251] In some embodiments of the first group of compounds of Formula IA, each R 3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C 1

-

6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C 15 alkyl, naphthyl C 1 5 alkyl, hydroxy, oxo, cyano, C 1 3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C 1 3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH 2 C(O), a mono- or di-(Cp 3 alkyl)aminocarbonyl,

C-

5 alkyl-C(O)-Ci 4 alkyl, amino-C 1 5 alkyl, mono- or di-(C 1 3 alkyl)amino -C.

5 alkyl, amino-S(O) 2 , di-(Cp 3 alkyl)amino - S(O) 2 , R 7

-C

5 alkyl, R 8

-C

1 5 alkoxy, R 9

-C(O)-C

1 5 alkyl, R' 0

-C

1 5 alkyl(R 11 )N, carboxy-mono- or di-(CI.s alkyl)amino; a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused 137 WO 2007/146712 PCT/US2007/070547 heterocyclic ring is optionally, independently substituted with 1 to 3 groups selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, C 1

.

6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyano, C 1

.

3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, heteroaryloxy, nitro, amino, mono- or di-(C.

3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH 2 C(O), a mono- or di-(CI-3 alkyl)aminocarbonyl, Ci 4 alkyl-C(O), C 1 5 alkylamino-S(O) 2 , mono- or di-(C.

3 alkyl)amino-C 1 5 alkyl, R1 2

-C

1 s alkyl, R 13

-C

1 s alkoxy, R"1-C(O)-C _ 5 alkyl, R"-C 5 alkyl(R 16 )N; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three CI.

3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C 1 3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are independently replaced by 0, S(O)m, CHOH, C=0, C=S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three C 1 3 alkyl groups;

C

14 alkyl or alkylene-phenyl-C(O)-Co 4 alkyl or alkylene, C 14 alkyl or alkylene-C(O)-Co 4 alkyl or alkylene, C 14 alkyl or alkylene -phenyl-S(O)m-C.

4 alkyl or alkylene;

CI

6 alkyl or C 1

.

6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R' 7 , amino, OR' , or C 15 mono- or di-alkylamino optionally substituted with R 1 9 ; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, which are optionally partially or fully halogenated and optionally substituted with one to three C 1 s alkyl groups optionally partially or fully halogenated wherein one to three ring methylene groups are replaced independently by 0, S(O)m, CHOH, C=O, C=S or NH; 138 WO 2007/146712 PCT/US2007/070547 R C(O)N(R 21 )-, R 22 0-, R2R24NC(O)-, R 26

(CH

2 )mC(O)N(R 2 )- or R C(O)(CH 2 )mN(R 2 1)

C

2 6 alkenyl substituted by R R 24NC(O)-;

C

2 6 alkynyl group branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by 0, NH or S(O)m, and wherein said alkynyl group is optionally independently substituted with 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more CiA branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or benzoyl or naphthoyl; and wherein 8 9 10 12 13 14 15 17 1 each R', R', R', R", R , R , R", R", R", and R is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(CO 4 alkyl)amino, wherein the Co 4 alkyl is optionally partially or fully halogenated; each R" and R1 6 is independently hydrogen or Ci 4 branched or unbranched alkyl optionally partially or fully halogenated; and R1 8 is independently hydrogen or CiA branched or unbranched alkyl optionally independently substituted with oxo or R 2 . [00252] In some such embodiments, each R 3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C 1

.

6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl

C

1

.

5 alkyl, naphthyl C 1 .5 alkyl, hydroxy, oxo, cyano, C 1

.

3 alkoxy optionally partially or 139 WO 2007/146712 PCT/US2007/070547 fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di

(C-

3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH 2 C(O), a mono or di-(C- 3 alkyl)aminocarbonyl, C 1 5 alkyl-C(O)-C4 alkyl, amino-C 1 5 alkyl, mono- or di-(C 1 3 alkyl)amino -C 1 5 alkyl, amino-S(O) 2 , di-(C 1 3 alkyl)amino - S(0)2, R 7

-C

5 alkyl,

R

8

-C

15 alkoxy, R 9

-C(O)-C

1 5 alkyl, R'K-Cj 5 alkyl(R")N, or carboxy-mono- or di-(CIs alkyl)amino. In others, each R 3 is independently phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with C1- 6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C1 3 alkoxy optionally partially or fully halogenated, nitro, amino, mono- or di-(C 1 3 alkyl)amino; C 1

.

6 alkyl or C 1

.

6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R", amino, OR 18 , C 15 mono- or di-alkylamino optionally substituted with R"; R2C(O)N(R')-, R"0-, R R2NC(O)-,

R

26

(CH

2 )mC(O)N(R 2 1 )- or R 26

C(O)(CH

2 )mN(R 2 )-. For example, R 3 can be phenyl or tolyl. [00253] In some embodiments of the first group of compounds of Formula IA, X is C=O. [00254] There is provided in accordance with another aspect of the invention, a second group of compounds having Formula IA, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, X, Ar, Y, L, m, Q, R, R', R", R', R 2 , R 3 , R 4 , R', R , R , R 8 , R 9 , R , R", 12 13 14 15 16 17 1 19 20 21 22 23 24 25 26 27 R , R , R , R", R ,R , R8, R19, Ro, R , R , R2, R2, R R2, and R are as defined in List III. LIST III: Definition of variables for the second group of compounds of Formula IA. G, L, m, Q, R, R', R", R, R 2 , R 3 , R 4 , R', R , R , R , R 9 , R 0

,R

1 1 , R", R , R 4 , R, 16 17 18 19 20 21 22 23 24 25 267 Rp ,R , R ,R ,R,R ,R ,R ,R 2, and R2 are as defined in List II; X is C(O)or C(S); Ar is -(Y)-(Co 0 alkyl)-(bicyclic aryl), or -(Y)-(COb 3 alkyl)-(bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or 140 WO 2007/146712 PCT/US2007/070547 benzoisothiazolyl dioxide, and wherein Ar is optionally substituted with one or more R4 or Rs. Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-; provided, however, that if R 4 and R 5 are absent, -L-Q is not -H and that when Ar is -(Y) (bicyclic aryl) and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R1, R 2 or R 3 [00255] With respect to variables that are identically defined between the first and second groups of compounds of Formula IA, all of the embodiments of the first group of compounds are also provided for the second group of compounds of Formula IA. To the extent that the variables differ between the first and second groups of compounds of Formula IA, the following additional embodiments are provided. [00256] In some embodiments of the second group of compounds of Formula IA, Ar is -(Y)-(CO- 3 alkyl)-(bicyclic aryl), and the bicyclic aryl is naphthyl, tetrahydronaphthyl, dihydronaphthyl, indenyl, indanyl or azulenyl. In some such embodiments, Ar is substituted with at least one R4 or R 5 . In others, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. Alternatively, Ar is -C(O)-(bicyclic aryl) or -C(NOR)-(bicyclic aryl) and the the bicyclic aryl can be naphthyl, dihydronapthyl, tetrahydronaphthyl, indanyl, indenyl or azulenyl. In other embodiments, Ar is -(Y)-(CO.

3 alkyl)-(bicyclic heteroaryl). In some such embodiments, Ar is substituted with at least one R 4 or R 5 . In others, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. In yet others, Ar is -C(O)-(bicyclic heteroaryl) or -C(NOR)-(bicyclic heteroaryl). For example, the bicyclic heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl. [00257] In certain embodiments of the second group of compounds of Formula IA, Ar is -(Y)-naphthyl-, Y is -C(O)-, or -C(=NOH)- and G is selected from phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is -(Y)-naphthyl-, Y is -C(O)-, or -C(=NOH)- and G is phenyl or pyridyl. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched C.-,o alkyl and each R 3 can be independently R 2

R

2 4N-C(O)-, R 20

-C(O)

NR

2 ' -, or OR 2 . In some such embodiments, each R 2 is independently -NR'SO 2 R", -C], -Br, -F, -C(O)-NR' 2 , substituted or unsubstituted straight or branched C 1

-

6 alkyl, -NR' 2 , or -OR'. 141 WO 2007/146712 PCT/US2007/070547 [00258] In other embodiments of the second group of compounds of Formula IA, Ar is -(Y)-naphthyl-, Y is -C(O)-, or -C(=NOH)-, and G is pyrazolyl, thienyl or isoxazolyl. In some such embodiments, each R 1 is independently a substituted or unsubstituted straight or branched Ci- 1 0 alkyl each R 3 can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted C 1 - branched or unbranched alkyl or substituted or unsubstituted C 1 4 alkoxy. [00259] There is provided in accordance with another aspect of the invention, a third group of compounds having Formula IA, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, X, Ar, Y, L, m, Q, R, R', R", R', R 2 , R 3 , R 4 , R', R', R', R', R', R1 0 , R", R 1 ,R, R ,R 1 R 4,5R', 'R ,R, R, R 2 , R, R 24 , R 2 , R 2 , and R 27 are as defined in List IV. LIST IV: Definition of variables for the third group of compounds of Formula IA. L, m,Q, R, R', R", R', R 2 , R , R 4 , R', R , R , R 8 , R 9 , R 0 , R", R , R", R , R1 5 , R ,R",

R

18 , R' 9 , R 20 , R 2 1 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are as defined in List II; G is a C 3

.

5 cycloalkyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, imidazolonyl, isoxazolyl, furanyl, thienyl, pyridonyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[1,4]oxazine-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is substituted by one or more R', R 2 or R3; X is C(O)or C(S); 142 WO 2007/146712 PCT/US2007/070547 Ar is -(Y)-(CO.

3 alkyl)-(phenyl), or -(Y)-(CO- 3 alkyl)-(monocyclic heteroaryl), wherein Ar is optionally substituted with one or more R4 or R 5 ; Y is -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-, provided, however, that if R 4 and R 5 are absent, -L-Q is not -H; and that when Ar is phenyl and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R1, R 2 or R 3 . [00260] As before, with respect to variables that are identically defined between the first and third groups of compounds of Formula IA, all of the embodiments of the first group of compounds are also provided for the third group of compounds of Formula IA. To the extent that the variables differ between the first and third groups of compounds of Formula IA, the following additional embodiments are provided. [00261] In certain embodiments of the third group of compounds of Formula IA, G is cyclopropyl, cyclobutyl or cyclopentyl. In others, G is cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, or thienyl. [00262] In some embodiments of the third group of compounds of Formula IA, Ar is -(Y)-(CO.

3 alkyl)-(phenyl) and Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-, In some such embodiments, Ar is substituted by at least one R or R . In others, Ar is -C(O)-(phenyl). In yet other embodiments, Ar is -(Y)-(Co.

3 alkyl)-(monocyclic heteroaryl), and the monocyclic heteroaryl is pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyrimidinyl or pyridazinyl. In some such embodiments, Ar is substituted by at least one R4 or R 5 . Alternatively, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. In yet others, Ar is -C(O)-(monocyclic heteroaryl) or -C(N(OR)) (monocyclic heteroaryl). For example, the monocyclic heteroaryl can be pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyrimidyl, or pyridazinyl. [00263] In certain embodiments of the third group of compounds of Formula IA, Ar is -(Y)-phenyl-, Y is -C(O)-, or -C(=NOH)- and G is selected from pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is -(Y)-phenyl-, Y is -C(O)-, or -C(=NOH)-, and G is pyrazolyl, thienyl or isoxazolyl. In some such embodiments, each R' is independently a substituted or unsubstituted straight or branched Cjo alkyl. In these embodiments, each R 3 can be independently phenyl or 143 WO 2007/146712 PCT/US2007/070547 pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted C 1 6 branched or unbranched alkyl or substituted or unsubstituted C 1 4 alkoxy. [00264] In another aspect of the invention, there are provided compounds of a first group of compounds having Formula IB: H X Ar-L-Q IB stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, X, Ar, Y, L, m, Q, R, R', R", RI, R 2 , RR 4 , R, R, R 7 , R,R 9 , Ri , R,'Rl , R ,R,'R,R", 18 19 20 21 2 3 2 5 26 27 R 'R , R , R1, R2, R2, R24, R2, RandR areas defined inListV. LIST V: Definition of variables for the first group of compounds of Formula IB. 1 2 3 4 5 6 7 8 9 0 11 12 13 14 G, X, Ar, Y, L, m, Q, R, R', R", R , R2, R3, R , R', R , R , R, R9, R1 , R, R ,R R 15 16 17 18 19 20 21 22 23 24 25 2 R ,R ,R ,R 9, R , R R R R R , R26, and R 27 are as defined in List II. provided that if R 4 and R 5 are absent, -L-Q is not -H. [00265] As before, with respect to variables that are identically defined between the first groups of compounds of Formula IA and Formula 13, all of the embodiments of the first group of compounds of Formula IA are also provided for the first group of compounds of Formula IB. To the extent that the variables differ between the first groups of compounds of Formula IA and 13, the following additional embodiments are provided. [00266] In some embodiments of the first group of compounds of Formula IB, Ar is -(CIa alkyl)-(C 6 .10 aryl), -(Y)-(Co-3 alkyl)-(C 6 -io aryl), or -(Y)-(CO.

3 alkyl)-(5-1 0 member heteroaryl). In some such embodiments Ar is substituted with at least one R4 or

R

5 . In others. Y is -CHR or -CHZ- and Z is -OR. For example, Y is -CH 2 -. In still other such embodiments, the C 6

.

10 aryl is phenyl or naphthyl or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl. Alternatively, Ar is -(C.

3 alkyl)

(C

6

.

1 0 aryl). 144 WO 2007/146712 PCT/US2007/070547 [00267] There is provided in accordance with another aspect of the invention, a second group of compounds having Formula IB, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, X, Ar, Y, L, m, Q, R, R', R", R , R 2 , R 3 , R 4 , R', R', R', R 8 , R 9 , R' 0 , R", R12 13 14 15 16 17 18 19 20 21 22 23 26275 R, R ,RR ,RRRR, R , R R ,R 2 4 , R R26, and R2 are as defined in List VI. LIST VI: Definition of variables for the second group of compounds of Formula IB. 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 L, m, Q, R, R', R", R, R, R,R,R,R,R,R',R,RR",R R , R ,R ,R ,R 18 19 20 21 22 23 24 25 26 R , R ,R,R R ,R,R , , and R 2 7 are as defined in List II; G is a G'-(Y)- wherein G' is a C 3

-

10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl other than indolyl containing 1 or more heteroatoms selected from 0, N or S, wherein G' is substituted by one or more R', R 2 or X is C(O) or C(S); Ar is bicyclic aryl or 8-11 membered bicyclic heteroaryl containing 1 or more heteroatoms selected from 0, N or S, wherein Ar is optionally substituted with one or more R 4 or R 5 ; Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR)) or -C(N(OR))-; provided that if R 4 and R 5 are absent, -L-Q is not -H. [00268] As before, with respect to variables that are identically defined between the first group of compounds of Formula IA and the second group of compounds of Formula IB, all of the embodiments of the first group of compounds of Formula IA are also provided for the second group of compounds of Formula TB. To the extent that the variables differ between the first group of compounds of Formula IA and the second group of compounds of Formula TB, the following additional embodiments are provided. [00269] In some embodiments of the second group of compounds of Formula IB, G' is 145 WO 2007/146712 PCT/US2007/070547 phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one; pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyI, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H benzo[ 1,4]oxazine-3 -only, benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl; pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. [00270] In other embodiments of the second group of compounds of Formula IB, G' is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one. In others, G' is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimidyl. Alternatively, G' is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. In yet 146 WO 2007/146712 PCT/US2007/070547 other embodiments, G' is phenyl, naphthyl, pyrazolyl, cyclopropyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl. [00271] In certain embodiments of the second group of compounds of Formula IB, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. [00272] In certain embodiments of the second group of compounds of Formula IB, Ar is naphthyl, dihydronapthyl, tetrahydronaphtyl, indenyl or azulenyl. Alternatively, Ar is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, indolyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobcnzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl or benzoisothiazolyl dioxide. [00273] In certain embodiments of the second group of compounds of Formula IB, Ar is naphthyl, G is G'-(Y)-, Y is -C(O)- or -C(=NOH)- and G' is selected from phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is naphthyl, G is G'-(Y)-, Y is -C(O)- or -C(=NOH)- and G' is phenyl or pyridinyl, substituted by one or more R1, R 2 or R 3 . In some such embodiments, each R' is independently a substituted or unsubstituted straight or branched C1I 10 alkyl. In these, each R 3 can be independently R 23

R

24 N-C(O)-, R- 20 C(O)-NR-, or OR 22 . In others such embodiments each R 2 is independently -NR'SO 2 R", -Cl, -Br, -F, -C(O)-NR' 2 , substituted or unsubstituted straight or branched C 1

.

6 alkyl, -NR' 2 , or -OR'. [00274] In other embodiments of the second group of compounds of Formula 113, Ar is -naphthyl- and G is G'-(Y)-, wherein Y is selected from -C(O)- and -C(=NOH)- and 1 2 3 G' is pyrazolyl, isoxazolyl or furanyl, substituted by one or more R1, R or R . In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched Ci-ia alkyl. In these, each R 3 can be independently substituted or unsubstituted C1- 6 alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted C 16 branched or unbranched alkyl, or substituted or unsubstituted C- 3 alkoxy. [00275] There is provided in accordance with another aspect of the invention, a third group of compounds having Formula lB, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein 147 WO 2007/146712 PCT/US2007/070547 the variables G, X, Ar, Y, L, m, Q, R, R', R", R', R2, R', R', R', R6, R7, R8, R9, R10, R",

R

12 , R 13 , R R 1 5 , R1 6 R, , R 8

,R

9

,R

20 R, R, R, R 24 R, R 2 6 , and R 27 are as defined in List VII. LIST VII: Definition of variables for the third group of compounds of Formula IB. L, m, Q, R, R', R", R', R 2 , R 3 , R 4 , RS, R, R 7 , RS, R, R1, R" R 2

R

13

R'

4 R , R ' 6 R , 18 19 20 21 22 23 24 215 26 2 R18, R , R ,RR RR R, R, ,andR 2 areas defined in List II; G is a G'-(Y)- wherein G' is a C 3

-

1 o cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl other than 1,1,4,4-tetramethyl- 1,2,3,4-tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl other than furan-2-yl, thienyl other than thien-2-yl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzpyrazolyl, or homopiperidinyl; wherein G' is substituted by one or more R', R2 or R3; X is C(O) or C(S); Ar is phenyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, furanyl, thienyl, pyrimidinyl, pyrazinyl; wherein Ar is optionally substituted with one or more R4 or R 5 ; Y is independently -C(O)-, -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-; provided, however, that if R 4 and R 5 are absent, -L-Q is not -H, and that when Ar-L-Q is -N-(substituted or unsubstituted phenyl)-pyrazolyl and G is phenyl, naphthyl, indane or tetrahydronaphthyl, the pyrazolyl is additionally substituted with one or more R or R 5 . [00276] As before, with respect to variables that are identically defined between the first group of compounds of Formula IA and the third group of compounds of Formula IB, all of the embodiments of the first group of compounds of Formula IA are also provided for the third group of compounds of Formula IB. To the extent that the variables differ between the first group of compounds of Formula IA and the second group of compounds of Formula IB, the following additional embodiments are provided. [00277] In some embodiments of the third group of compounds of Formula IB, G' is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, 148 WO 2007/146712 PCT/US2007/070547 pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl, thienyl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, pyrimidinyl, or pyrazinyl. In others, G' is phenyl, naphthyl, pyrazolyl, cyclopropyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl. [00278] In certain embodiments of the third group of compounds of Formula IB, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. [00279] In some embodiments of the third group of compounds of Formula IB, Ar is phenyl, pyrazoly, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, or pyrimidinyl. [00280] In some embodiments of the third group of compounds of Formula IB, Ar is phenyl, G is G'-(Y)-, Y is -C(O)- or -C(=NOH)- and G' is selected from phenyl, pyridinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is phenyl, G is G'-(Y)-, Y is -C(O)- or -C(=NOH)- and G' is phenyl or pyridinyl, substituted by one or more R', R 2 or R 3. In some such embodiments, each R 1 is independently a substituted or unsubstituted straight or branched Cio alkyl. In these, each R 3 can be independently R 23

R

24 N-C(O)-, R 20 -C(O)-NR 2 1-, or OR 22 . Alternatively, each R 2 is independently -NR'SO 2 R", -Cl, -Br, -F, -C(O)-NR' 2 , substituted or unsubstituted straight or branched C1.

6 alkyl, -NR' 2 , or -OR'. [00281] In other embodiments of the third group of compounds of Formula IB, Ar is phenyl and G is G'-(Y)-, wherein Y is selected from -C(O)- and -C(=NOH)- and G' is 1 2 3 pyrazolyl, isoxazolyl or furanyl, substituted by one or more R1, R2 or R . In some such embodiments, each R' is independently a substituted or unsubstituted straight or branched CpIo alkyl. In these, each R 3 can be independently substituted or unsubstituted C1.

6 alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted C] - branched or unbranched alkyl, or substituted or unsubstituted C- 3 alkoxy. [00282] There is provided in accordance with another aspect of the invention, compounds having Formula IC: G-Ring-Ar-L-Q 149 WO 2007/146712 PCT/US2007/070547 IC stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, Ring, Ar, Y,L,m,Q,R,R',R",R,R 2

,R

3 ,RtR 5

,R

6

,R

7

,R

8

,R

9 ,R ' 0 ,R','R, R, R, R", R 1,R" , R19, R20, R2, R , R2, R24, R25 R26, and R are as defined in List VIII. LIST VIII: Definition of variables for compounds of Formula IC. Ar, Y, L, m, Q, R, R', R", R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 1 ", R", R' 2 , R, R ,R' 5 , 16 17 1 19 20 21 2 2 3 4 2 26 27 R ,R" , R19, R2, R , R , R2, R24 R2, R2, and R are as defined in List II; Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine trione, triazolidin-dione, or triazine-dione; G is a C 3

-

1 carbocyclyl, C 4 12 carbocyclylalkyl, 5-8 membered monocyclic heterocyclyl or heterocyclylalkyl, 8-11 membered bicyclic heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl rings contain 1 or more heteroatoms selected from 0, N or S; and G is substituted by one or more R', R 2 or R 3 ; [00283] As before, with respect to variables that are identically defined between the first group of compounds of Formula IA and compounds of Formula IC, all of the embodiments of the first group of compounds of Formula IA are also provided for the compounds of Formula IC. To the extent that the variables differ between the first group of compounds of Formula IA and the compounds of Formula IC, the following additional embodiments are provided. [00284] In other embodiments of compounds of Formula IC, G is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one. For example, G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl. [00285] In certain embodiments of compounds of Formula IC, Ring is maleimide, succinimide or triazine-dione. In others, Ring is succinimid-1,4-diyl, maleimide-1,4-diyl, imidazolidin-2-one-1,3-diyl, imidazolidine-2,4,5-trione-1,3-diyl, [1,2,4]triazolidine-3,5 dione- 1,4-diyl, or 2H-[ 1,2,4]triazine-3,5-dione-4,6-diyl. 150 WO 2007/146712 PCT/US2007/070547 [00286] In another aspect of the invention there are provided compounds having Formula II: X' G / Ar-L-Q N II stereolsomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, X', Ar, Y', L, m, Q, R, R', R", R , R 2 , R 3 , R 4 , R, R , R', R', R 9 , R 1 0 , R 1 , R 2 , R 3 , R 4 , R 1 5 , R ,6R", R8, R 19 , 20 21 22 23 24 25 2 R2, R , R , R2,R R , R26, and R 2 7 are as defined in List IX. LIST IX: Definition of variables for the compounds of Formula I. 1 2 4 5 6 7 8 9 10 11 12 13 14 15 16 17 G, L, m, Q, R, R', R", R', R2, R4, R', R , R , R', R', R , R , R , R , R", R ,R R18, R9, R 20 , R 2 1 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are as defined in List II; X' is CR'=CR', CR'=N, NR', CR' 2 , 0 or S; Ar is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl, indole, or the structure -(Y')-(CO.

3 alkyl)-(C 6

.-

10 aryl), each being optionally substituted with one or more R4 groups; Y' is absent or is -0- or -NH-; each R 3 is independently H, substituted or unsubstituted C 6

.

1 o aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, 0, or S(O)m, substituted or unsubstituted C 3 12 cycloalkyl, substituted or unsubstituted C 512 cycloalkenyl, substituted or unsubstituted C 7

-

20 aralkyl, substituted or unsubstituted straight or branched Cs alkyl, R 20 C(O)N(R)-, R 2 O-, R 2

R

2 NC(O)-. R (CH 2 )mC(O)N(R )-, R C(O)(CH 2 )mN(R 21 -, substituted or unsubstituted C 2 -8 alkenyl, or substituted or unsubstituted C 2 -8 alkynyl, wherein one or more methylene groups of the C-s alkyl, C 2 -s alkenyl, or C 2

-

8 alkynyl are optionally replaced by 0, NH, or S(O)m. [00287] As before, with respect to variables that are identically defined between the first group of compounds of Formula IA and the compounds of Formula II, all of the 151 WO 2007/146712 PCT/US2007/070547 embodiments of the first group of compounds of Formula IA are also provided for the compounds of Formula I. To the extent that the variables differ between the first group of compounds of Formula IA and the compounds of Formula II, the following additional embodiments are provided. [00288] In certain embodiments of compounds of Formula II, Ar is indazolyl, isoindolyl, pyrazolyl, imidazolyl, or imidazolonyl. In some such embodiments, Ar is substituted with at least one R 4 . Alternatively, Ar is indazolyl, optionally substituted with one or more R 4 . In yet other embodiments, Ar is phenyl or naphthyl. In some such embodiments, Ar is substituted with at least one R 4 . [00289] In yet other embodiments of compounds of Formula II, Ar is -(Y')-(CO.

3 alkyl)-(C 61 oi aryl). In some such embodiments, Ar is substituted with at least one R 4 . In others, the C 6

-

10 aryl is phenyl or naphthyl. Alternatively, Y' is -NH-. [00290] In certain embodiments of compounds of Formula II, each R3 is independently hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C 1

-

6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1 5 alkyl, naphthyl C 1 s alkyl, hydroxy, oxo, cyano, C1 3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(CI3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH 2 C(O), a mono- or di-(C 3 alkyl)aminocarbonyl,

C

1 5 alkyl-C(O)-C, 4 alkyl, amino-C- 5 alkyl, mono- or di-(CI 3 alkyl)amino -C>s alkyl, amino-S(O) 2 , di-(C 1 3 alkyl)amino - S(O) 2 , R!7C 5 alkyl, Rg-C- 5 alkoxy, R 9 -C(O)-Cp 5 alkyl, R 1 4-C 15 alkyl(R")N, carboxy-mono- or di-(C 1 s alkyl)amino; 152 WO 2007/146712 PCT/US2007/070547 a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclic ring is optionally, independently substituted with 1 to 3 groups selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, C1.

6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyano, C 1

.

3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, heteroaryloxy, nitro, amino, mono- or di-(C- 3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH 2 C(O), a mono- or di-(C 1

.

3 alkyl)aminocarbonyl, C 1 4 alkyl-C(O), C 1 5 alkylamino-S(O) 2 , mono- or di-(C 1

.

3 alkyl)amino-C 1 5 alkyl, R 12 -CIs alkyl, R 13

-CI

5 alkoxy, R 1 4

-C(O)-C

1

.

5 alkyl, R 15

-C

5 alkyl(R" 6 )N; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C 1 3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C 1

.

3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by 0, S(O)m, CHOH, C=0, C=S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three C 1

.

3 alkyl groups;

C

1 4 branched or unbranched alkyl-phenyl-C(O)-Co 4 branched or unbranched alkyl, C 14 branched or unbranched alkyl-C(O)-CO 4 branched or unbranched alkyl, C 14 branched or unbranched alkyl-phenyl-S(O)m-C 0 4 branched or unbranched alkyl; 153 WO 2007/146712 PCT/US2007/070547

C-

6 branched or unbranched alkyl or C 1 .6 branched or unbranched alkoxy each is optionally partially or fully halogenated or optionally substituted with R 17 ;

C

1

.

6 branched or unbranched alkyl optionally substituted with OR 18 ; amino or C-C 5 branched or unbranched mono- or di-alkylamino optionally substituted with R1 9 ; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, which are optionally partially or fully halogenated and optionally substituted with one to three CI - 3 alkyl groups optionally partially or fully halogenated wherein one to three ring methylene groups are replaced independently by 0, S(O)m, CHOH, C=O, C=S or NH; R"C(O)N(R")-, R2-, R R 24NC(O)-, R26(CH 2 )mC(O)N(R)- or

R

2 6

C(O)(CH

2 )mN(R3)-;

C

2

-

6 alkenyl substituted by R 23

R

24 NC(O)-;

C

2

.

6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by 0, NH and S(O)m or S and wherein said alkynyl group is optionally independently substituted with 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more C 1

.

4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C 1

.

4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or benzoyl or naphthoyl. [00291] In certain embodiments of compounds of Formula II, X' is NR', CR'=N or CR'=CR'. [00292] Where compounds are described in terms of Markush groups or other groupings of alternatives, those skilled in the art will recognize that the compounds are also thereby described in terms of any individual member or subgroup of members of the Markush group or other group. By way of illustration and not limitation, Table 1 sets forth various combinations of substituents from the first group of compounds of Formula IA and the first group of compounds of Formula IB as described herein. Thus, e.g., combination 1004 describes those embodiments in which Ar is indolyl and G is phenyl. 154 WO 2007/146712 PCT/US2007/070547 TABLE 1 - Exemplary Combinations of Ar and G for the First Group of Compounds of Formulas IA and IB G 73 E Ara g . 6 indolyl 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 isoindolyl 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 imidazolyl 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 benzimidazolyl 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 pyrazolyl 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 pyrazolinyl 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 pyrrolyl 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 pyrrolinyl 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 pyridinyl 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 pyridazinyl 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 guinolinyl 1101 1102 1103 1104 1105;1106 1107 11081109 1110 isoquinolinyl 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 phthalazinyl 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 dihydroindolyl 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 benzoisoxazolyl 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 dihydrobenzo- 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 isoxazolyl I__ dihydroisoindoly1 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 benzoisothiazolyl 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 benzoisothiazolyl 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 dioxide C6o ary 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200

-(C

3 alkyl)-(C "" 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 aryl) -(Y (C- alkyl)- 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220

(C&

10 aryl)____

-(Y)-(CO

3 alkyl) (5-10 member 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 heteroaryl) naphthyl 1231 - 1232 1233 1234 1235 1236 1237 1238 1239 1240 TABLE 1 - Continued G Ar indolyl 1241 1242 1243 1244 1245 1246 isoindolyl 1247 1248 1249 1250 1251 1252 imidazolyl 1253 1254 1255 1256 1257 )1258 benzimidazolyl 1259 1260 1261 1262 1263 1264 pyrazolyl 1265 1266 1267 1268 1269 1270 pyrazolinyl 1271 1272 r 1273 1274 1275 1276 pyrrolyl 1277 1278 1279 1280 1281 122 Lyrrolinyl____1283 1284 1285 1286 1287 1288 155 WO 2007/146712 PCT/US2007/070547 G 7 7 Ar pyridinyl 1289 1290 1291 1292 1293 1294 pyridazinyl 1295 1296 1297 1298 1299 1300 quinolinyl 1301 1302 1303 1304 1305 1306 isouinolinyl1307 1308 1309 1310 1311 312 phthalazinyl 1313 1314 1315 1316 1317 1318 dihydroindolyl 1319 1320 1321 1322 1323 1324 benzoisoxazolyl 1325 1326 1327 1328 1329 1330 dihydrobenzoisoxazolyl 1331 1332 1333 1334 1335 1336 dihydroisoindolyl 1337 1338 1339 1340 1341 1342 benzoisothiazolyl 1343 1344 1345 1346 1347 1348 benzoisothiazolyl dioxide 1349 135011351 1352 1353 1354 C6 10 aryl 1355 135611357 1358 1359 1360

-(C-

3 alkyl)-(Cr 10 aryl) 1361 1362 1363 1364 1365 1366 -(Y)C alkyl)-(COa) 1367 1368 1369 1370 1371 1372 -(Y)-(Co-3 alkyl)-(5-10 member heteroaryl) 1373 1374 1375 1376 1377 1378 naphthyl 1379 1380 1381 1382 1383 1384 [00293] Table 2 sets forth various combinations of substituents from all groups of compounds of Formulas IA, IB, IC and 11. Thus, e.g., combination 1477 describes those embodiments in which L is -0- and Q is heterocyclyl. Further, those skilled in the art will understand that a combination of substituents or variables is permissible only if such a combination results in a chemically stable compound, and that any combination from Table 1, describing Ar and G, may be combined with any combination from Table 2, describing L and Q. For example, combination 1045 from Table 1 and combination 1509 from Table 2 describe those embodiments of Formula IA in which Ar is pyrazolyl, G is naphthyl, L is-O-(CH 2

)

2 -, and Q is heterocyclyl. Each Ar, G, L, and Q group in the tables is understood to be optionally substituted as described herein. Moreover, each value of X (C(O), C(S), CH 2 ) may be combined with any combination from Table 1 or Table 2 or any pair of combinations from the two tables. Thus, e.g., it will be understood that combination 1004 describes those embodiments in which X is C(O), Ar is indolyl and G is phenyl, as well as those where X is CH- 2 , Ar is indolyl and G is phenyl, etc. 156 WO 2007/146712 PCT/US2007/070547 TABLE 2 - Exemplary Combinations of L and Q for All Groups of Compounds of Formulas IA, IB, IC and II L C bond 1385 1386 1387 1388 1389 1390 1391 1392

-CH

2 - 1393 1394 1395 1396 1397 1398 1399 1400 (CH2)r 1401 1402 1403 1404 1405 1406 1407 1408 -(CH2) 3 - 1409 1410 1411 1412 1 -(CH2) 14 1417 1418 141

-(CR

2 )4- 1417 1418 1419 1420 1421 j1422 1423 1424

-(CH

2

)

5 - 1425 1426 1427 1428 1429 1430 1431 1432 -(CH2) 6 1433 1434 1435 1436 1437 1438 1439 1440 -(CH2)r 1441 1442 1443 1444 1445 1446 1447 1448

-(CH

2

)

8 - 1449 1450 1451 1452 1453 1454 1455 1456 -(CH2)r 1457 1458 1459 1460 1461 1462 1463 1464 -(CH2)1- 1465 1466 1467 1468 1469 1470 1471 1472 -0- 1473 1474 1475 1476 1477 1478 1479 1480 -S(O).- 1481 1482 1i4-83 1484 1485 1486 1487 1488 -NR- 148-9 1490 1491 1492 1493 1494 1495 1496 -0-CR 2 - 1497 1498 1499 1500 1501 1502 1503 1504 -0(C4 2

)

2 - 1505 1506 1507 1508 1509 1510 1511 1512

-N(R)-CR

2 - 1513 1514 1515 1516 1517 1518 1519 15201 -N(g~ - 1521 1522 1523 1524 1525 1526 1527 1528 S0 -CH 2 - 1529 f1530 1531 j 1532 [1533 1534 1535 1536 S(0)-(CH 2

)

2 - 11537 1538 j1539 [1540 1541 1542 15439 1544 [00294] Similar to Table 1 above, Table 3 illustrates combinations of Ar and G for the second group of compounds having Formula IA. Table 2 above illustrates combinations of L and Q, which can be employed for the second group of compounds having Formula IA. Any combination from Table 3 may be combined with any combination from Table 2, as all such combinations are within the scope of the invention. TABLE 3 -- Exemplary Combinations of Ar and G for the Second Group of Compounds of Formula IA, wherein Ar is -(Y)-(CO 0 3 alkyl)-(bicyclic aryl). G I indazo1444>14451 1546 1547 1448 ______ ~ 1454 1553 144 155 S2 1456_ isoinolvi___ 556 157 1460_ 160 146145~63 164 __________ __ __ ____ 148169 1470 I__ I 147 I~~~ -_ _ _-_ ; _ _ A17 45 177 178 I 14 -Ni 148 491 6 1587 9159 1590 1591 1592 1963 1594 phh lai 1594 15719 dihydroinoy 19 98 14 99 1 601 102 1 603 1604 benzofuranyl 1605 1606 [1608 1609 1610 1111 1612 16 1614 157 WO 2007/146712 PCT/US2007/070547 G Ar C 4 benzoxazolyl 1615 1616 1617 1618 1619 1620 1621 1622 1623 1624 benzoisoxazolyl 1625 1626 1627 162811629 1630 1631 1632 1633 1634 dihydrobenzo ioozl 1635 1636 1637 13 169 64 14111642 1643 1644 isoxoazolyl_____ _____+ dihydroiso ihdoyl~ 1645 1646 11647 16481 1649 1650 1651 1652 1653 16541 indolyl _____ ____ benzimidazolyl 1655 1656 1657 1658 59 1660 1661 1662 1663 1664 benzothienyl 1665 1666 1667 1668 1669 16701671 1672 1673 1674 benzothiazolyl 16751 1676 1677 1678 1679 16801 benzoisothiazoll 1685 1686 168711688 1689 16901691 1692 1693 94 benzoisothiazolyl 1695 1696 1697 1698 1699 170011701 1702 1703 1704 dioxide naphthyl L 1705 17061 1707 1708 1709 1710 1711 1712 1713 1714 TABLE 3 - Continued G 7-J -f Ar indazolyl 1715 1716 1717 1718 1719 1720 isoindolyl 1721 1722 1723 1724 1725 1726 1uinolinyl 1727 1728 1729 1730 1731 1732 isouinoinyl 1 17 3 1734 1735 1736 1737 1738 phthalazinyl 1739 1740 1741 1742 1743 1744 dihydroindolyl 1745 1746 1747 1748 1749 1750 benzofuranyl 1751 1752 1753 1754 1755 1756 bezoxazolyl 1 1757 1758 1759 1760 1761 1762 benzoisoxazoly) 1763 1764 1765 1766 1767 1768 dih1drobe6zoisoxoazolyl 1769 1770 1771 1772 1773 1774 dihydroiso 10doly 1775 1776 1777 1778 1779 1780 benzimidazolyl 1781 1782 1783 1784 1785 1786 benzothienyl 1787 1788 1789 1790 1791 1792 benzotiazolyl 1793 1794 1795 1796 1797 1798 benzoisothazolyl 1799 1800 1801 1802 1803 1804 benzoisothiazolyl dioxide 1805 1806 1807 88 1809 1810 napimidyl 181 182 1813 1814 1815 1816 [00295] Similar to Tables 1 and 3 above, Table 4 illustrates combinations of Ar and G for the third group of compounds having Formula IA. Table 2 above illustrates combinations of L and Q that may be employed for the third group of compounds having Formula IA. 158 WO 2007/146712 PCT/US2007/070547 TABLE 4 - Exemplary Combinations of Ar and G for the Third Group of Compounds of Formula IA. G Ar 7- N o N1 ~ -~ aY)-(phenyL) 2495 2496 2497 2498 2499 2500 2501 2502 2503 2504 2505 -(Co 3 alkyl)- 2506 2507 2508 2509 2510 2511 2512 2513 2514! 2515 2516

-(V)-(CO

3 alkyl)- 2517 2518 2519 2520 2521 2522 2523 2524 2525 2526 2527 (imidazolyl) -(Y)-(Co 3 alkyl)- 2528 2529 2530 2531 2532 2533 2534 2535 2536 2537 2538 (pyrazolinyl) ______

-(Y)-(CO

3 alkyl)- 2539 2540 2541 2542 2543 2544 2545 2546 2547 2548 2549 -()-( aky)- 2550 2551 2552 2553 2554 2555 2556 2557 2558 2559 2560 (pyrroinyl)

-()-(CO

3 alkyl)- 2561 2562 2563 2564 2565 2566 2567 2568 2569 2570 2571 _(pyridinyl)___

-(Y)-(CO

3 alkyl)- 2572 2573 2574 2575 2576 2577 2578 2579 2580 2581 2582 (pyrimidinyl)

-(V)-(CO.

3 alky2)- 9583 2584 2585 2586 2587 2588 2589 2590 2591 2592 2593 L(pyri azinyl) I-- _ ~L b I~ _ _ _ TABLE 4 - Contin.ued G 21 7- 7. 7 Ar ,C, -(Y)-(CO.3 alkyl)-(phenyl) 2594 2595 2596 2597 2598 2599 2600 2601 2602 2603 2604 -(Y)-(CII.3 alkyl) (pyrazolyl) 2605 2606 2607 2608 2609 261 0i 2611 2612 2613 2614 2615 -(Y)-(CO.3 alkyl) (imidazolyl) 2616 2617 2618 2619 2620 2621 2622 2623 2624 2625 2626 -(Y)-(CO.3 alkyl) (pyrazolinyl) 2627 2628 2629 2630 2631 2632 2633 2634 2635 2636 2637 -(Y)-(Co.

3 alkyl)- I (pyrrolyl) 2638 2639 2640 2641 2642 2643 2644 2645 2646 2647 2648

-(Y)-(C.

3 alkyl)- 5 (pyrrolinyl) 2649 2650 2651 2652 2653 26541 2655 2656 26571 26581 2659!

-(Y)-(CO

3 alkyl) (pyridiny) 2660. 2661 2662 26631 2664 2665 2666 26671 26681 266912670 -(Y)-(Co 3 alkyl) (pyrimidinyl) 2671 2672 2673 2674 2675 2 2672677 2678 2679 2680 2681 -(Y)-(Co- alkyl) (pyridazinyl) 2682 2683 2684 2685 2686 2687 2688 2689 2690 2691 2692 159 WO 2007/146712 PCT/US2007/070547 TABLE 4 - Continued Ar28 2 2 2 2 ( (COalky)- 2693 2694 2695 2696 2697 2698 2699 2700 2701 2702 2703 aky C) Iph nyl) 2748 2 4 27 2751 2752 27 75 -V(C( alkyl)- 25 7026 7226 7426 7626 7826 2704 2705 2706 2707 2708 2709 2710 2711 2712 2713 2714 -- (CO 3 akYI)- 2715 2716 2717 2718 2719 2720 2721 2722 2723 2724 2725 (inidazolyl)

-(Y)-(CO

3 akyI)- 2726 2727 2728 2729 2730 2731 2732 2733 2734 2735 2736 alkyl)-(henyl)

-(Y)-(CO

3 alkyl)- 2737 2738 2739 2740 2741 2742 2743 2744 2745 2746 2747

-(Y)--(C-

3 alkyI)- 2748 2749 2750 2751 2752 2753 2754 2755 2756 2757 2758 (pyrrolinyl)

-(Y)-(C

03 alkyl)- 21 -(Y-(C-3 lky)- 2759 2760 2761 2762 2763 2764 2765 2766 2767 2768 2769

-(Y)-(CO

3 alkyl)- 2770 2771 2772 2773 2774 2775 2776 2777 2778 2779 2780 (pyrimidinyl) _ -(Y)-(Co 3 alkyl)- 2781 2782 2783 2784 2785 2786 2787 2788 2789 2790 2791 (pyridazinyl) I I I I I i -(Y)-(C aly)- 24 (pL) - ro n;1) alky)-(henl) 7922793 2794 2795 2796 2797 2798 2799 2800 2801 2802 -(Y-(C~alyl). 2032804 2805 2806 2807 2808 2809 2810 2811 2812 2813

-(Y-(C

3 akyI- 2142815 2816 2817 2818 2819 2820 2821 2822 2823 2824

-(Y-(C

3 akyI- 2252826 2827 2828 2829 2830 2831 2832 2833 2834 2835

-(Y-(C

3 aky1- 2362837 2838 2839 2840 2841 2842 2843 2844 28451 28461 24:2848 24 , 25 2851 2852 28531 2854 25 8625 284 1 251 2 SJ S 2859 2860alky)-2261 2862 2863, 2864126 86 8726 (pyridinyl) 51i5 8O 85 8687 88

KY~(C

0 alyl) 2869: 28701 28711 2872 28731 28741 2875 28761 287 2878'27 py d 0 ~ inyl). 2880 2881 2882f 28831 28841 2885 2886 2887 2888 2889129 160 WO 2007/146712 PCT/US2007/070547 TABLE 4 - Continued G Ar N 0 a)-( heny) 2891 2892 2893 2894 2895 2896 28971 2898 2899 2900 2901 alkyl)-(phemny___ __

-(Y)-(CO-

3 ~2902 2903 2904 2905 2906 2907 2908 2909 2910 2911 2912 (pyrazolyl) ___ -(-(Calkyl)- 2913 2914 2915 2916 2917 2918 2919 2920 2921 2922 2923 (iraidazolyl)___ -(Y)-(CO-alkYI)- 2924 2925 2926 2927 2928 2929 2930 2931 2932 2933 2934

-(Y)-(C

3 alkyl)- 2935 2936 2937 2938 2939 2940 2941 2942 2943 2944 2945 (pyrrolyl)

-()-(C

0

-

3 akyI)- 2946 2947 2948 2949 2950 2951 2952 2953 2954 2955 2956 (pyrroinyl) I_

-(-(CO

3 alkyl)- 2957 2958 2959 2960 2961 2962 2963 2964 2965 2966 2967 (pyridinyl) I

-(Y)-(C

03 Ilkyl)- 2968 2969 2970 2971 2972 2973 2974 2975 2976 2977 2978 (pyrimidinyl) __

-(Y)-(CO

3 alkyl)- 2979 2980 2981 2982 2983 2984 2985 2986 2987 2988 2989 (pyridazinyl) -__ _______ __ TABLE 4 - C.ontinued G 70 Ar w -(Y)-(CO_3 alkyl)-(phenyl) 2990 2991 2992 2993 2994 2995 2996 2997 2998 2999 3000 -(Y)-(CO.3 alkyl) (pyrazolyl) 3001 3002 3003 3004 3005 3006 3007 3008 3009 3010 3011, -(Y)-(CO.3 alkyl) (imidazolyl) 3012 3013 3014 3015 3016 3017 3018 3019 3020 3021 3022 -(Y)-(CO- alkY l) (pyrazolinyl) 3023 3024 3025 3026 3027 3028 3029 3030 3031 3032 3033 -(Y)-(CO- alkyl)-II (pyrrolyl) 3034 3035 3036 3037 3038 3039 3040 3041 3042 3043 3044

-(Y)-(CO.

3 alkyl)- ] (pyrrolinyl) 3045 3046 3047 3048 3049 3050 3051 3052 3053 3054 3055 'Y" 3045_ 304 _

-(Y)-(CO.

3 alkyl) (pyridiny 30561 30571 3058 30591 3060 3061 30621 3063 30164 3065 3066 -(Y)-(CO 3 alkyl)- I (pyrimidinyl) 3 0 6 7 j 30687 30697 3070 31 '2 3073 3074 3075 3076 3077

-(Y)(CO

3 alkyl)- ; 34 088 (pyridazinyl) f 30781 3079 3080 308 3082 3083 3084 30851 3086 3087 3088 161 WO 2007/146712 PCT/US2007/070547 TABLE 4 - Con.tinued G 7 Ar

-(Y)-(C,

3 alkyl)-(pheny') 3089 3090 3091 3092 3093 3094 3095 -(Y)-(CO.3 alky)-(pyrazolyl) 3096 3097 3098 3099 3100 3101 3102 -(Y)-(Co.3 alkyl)-(imidazolyl) 3103 3104 3105 3106 3107 3108 3109

-(Y)-(CO.

3 aIkyI)-(pyrazoinyl) 3110 3111 3112 3113 3114 3115 3116

-(Y)-(CO.

3 alkyI)-(pyrrolyI) 3117 3118 3119 3120 3121 3122 3123

-(Y)-(CO.

3 al ky)-(pyrrolinyl) 3124 3125 3126 3127 3128 3129 3130

-(Y)-(CO

3 alkyl)-(pyridinyl) 3131 3132 3133 3134 3135 3136 3137 -(Y)-(Co.

3 alkyl)-(pyrimidinyl) 3138 3139 3140 3141 3142 3143 144 4Y)-(CO- 3 aIkyI)-(pyrid zinyl) 3145 314 3147 3148 3149 3150 3151 [00296] Similar to Tables 1, 3 and 4 above, Table 5 illustrates combinations of Ar and G for the second group of compounds having Formula IB. Table 2 above illustrates combinations of L and Q that may also be employed for the second group of compounds having Formula IB. TABLE 5 - Exemplary Combinations of Ar and G for the Second Group of Compounds of Formula IB G L 0 6 bicyclic aryl 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 cyc1 cmetereary 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 indolyl 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 isoindolyl 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 imidazolyl 2023 2024 2025 2026 2027 12028 j2029 2030 12031 20321 benzimidazol 2033 12034 2035 2036 2037 2038 2039 2040 2041 2042 pyrazoy 2043 2044 12045 12046 12047 2048 2049 2050 2051 05 pyrazfoliny 2053 2054 2055 12056 1205~ 2058 2059 2060 12061 12062J - F - ; .i - N02 7 + N r 2063 2064 2065 1206 206- 2068 o2069 2072 pyr+iy 20 73 20O7-4 2 07-5 2076 207~ 2078 12079 2080 21081 28 -P iy 8- -, 206 08 pydin yl 2083 2084 2085 1986 1987 2088 12089 12090 2091 1202

.-

11 21e0m1er01d pyridaziny 2003 2094 2095 2096 2097 2098 2099 210 201 212 quinolinyl 2103 2104 2105 2106 2107 2108 2109 2110 211 2112 [ p y r o l l p 0 6 3 2 0 6 2 0 5 2 6 6 0 6 7 2 0 6 2 0 9 20 7 .2 7 2 0 7 2 isoquinolinyl 2113 2114 215 2116 217 2118 219 210 2121 2 16 2910 _ 2097 22102 162 WO 2007/146712 PCT/US2007/070547 G9 Ar phthalazinyl 2123 2124 2125 |2126 2127 2128 2129 23 1123 dihydroindolyl 2133 2134 2135 |2136 2137 2138 2139 24 1124 benzoisoxazolyl 2143 2144 12145 |2146 2147 2148 2149 25 1125 dihydrobenzo- 2153 2154 2155 2156 2157 2158 2159 26 1126 dihydroisoindolyl 2163 2164 12165 |2166 2167 2168 2169 27 1127 benzoisothiazolyl 2173 2174 2175 |2176 2177 2178 2179 28 1128 b noisothiazolyl 2183 2184 2185 2186 2187 2188 21892101922 22150 2251 22 21 09 219 TABLE 5 - Continued G' Ar bicyclic aryl20 25 2622720 8-11 membered bicyclic heteroaryl 229212112221324 indolyl 21 26 -2721 2922 isoindolyl 22 22 2322 2522 imidazolyl 22 27 2 128 2 12 230 2 131 2132 benzimidazolyl 1 33 234 25 1 36 2 23 221 4 pyrazolyl229242212424324 pyrazolinyl 245 246 247 248 249 2501 pyrrolyl -252222522422526 pyrrolinyl 22 57 2 158 2 159 2 160216112162 pyridazinyl 2269 2 2271 27 23 7 quinolinyl225272272727928 isoquinolinyl 21 266 267 28 269 221 7 phthalaziny20l291 29 dihydroindolvl 29 24 25F29 29129 benoiaziso 1 2 276 21 27821z79l 201 doihidobenzosoxaly do xide 21832218432123 2 4 215 226 227 2208 n y [2193 2194 2 29 210 29 11 23321 2 2 0 2 2 01 1 2 1 1 222 228 2292323|23 bicylic ryl2203 2204| 2205 2206 2207 2208 bicylichteroryl 2209 2210| 2211 2212 2213| 224 indolyl2245 2216| 2217 2218 2219 2220 isoinolyl2221 2252 2223 2224 2225 2226 imidaolyl2227 2228| 2229 2230 2231 2232 benzmidaolyl2233 2234| 2235 2236 2237 2238 pyraolyl2239 2240| 2241 2242 2243 2274 pyrazlinyl2245 2246| 2247 2248 2249 2250 pyrrolyl2251 2252 2283 2254 2255 2256 pyrroinyl2257 2258 2259 2260 2261 2262 pyriinyl2263 2264 2265 2266 2267 2268 ~iyrdazny12269 2230 2271 2272 2273 2274 guinoinyl2275 2276' 2277 2278 2279 2280' dihydroisndol 2231 232 2295 2296 2297 2316' benzoisoxhisolyl 2299 23184 23019 2320 2303 23042 benzoisothiiazolyl ~dioxide 2323, 2324, 2325~ 2326 2327'2328 ~naphthy1 2329[ 2330| 2331 2332 23331 2334i 163 WO 2007/146712 PCT/US2007/070547 [00297] Similar to Tables 1 and 3 - 5 above, Table 6 illustrates combinations of Ar and G for the third group of compounds having Formula LB. Table 2 above illustrates combinations of L and Q that may be employed for the third group of compounds having Formula LB. TABLE 6 - Exemplary Combinations of Ar and G for the Third Group of compounds of Formula IB G G - ;,. 0 -l - N N 9 \Ar5 phenyl 3152 3153 3154 3155 3156 3157 3158 3159, 3160 3161 3162 pyrimidinyl 3163 3164 3165 3166 3167 3168 3169 3170 3171 3172 3173 pyrazolyl 3174 3175 3176 3177 3178 3179 3180 3181 3182 3183 3184 thiazolyl 3185 3186 3187 3188 3189 3190 3191 3192 3193j 3194 3195 thiadiazolyl 3196 3197 3198 3199 3200 3201 3202 3203 3204 3205 3206 oxazolyl 3207 3208 3209 3210 3211 3212 3213 3214 3215 3216 3217 isoxazolyl 3218 3219 3220 3221 3222 3223 3224 3225 3226 3227 3228 oxadiazolyl 3229 3230 3231 3232 3233 3234 3235 3236 3237 3238 3239 isothiazolyl 3240 3241 3242 3243 3244 3245 3246 3247 3248 3249 3250 pyrrolinyl 3251 32521 3253 3254 3255 3256 3257 3258 3259 3260 3261 pyridazinyl 3262 3263 3264 3265 3266 3267 3268 3269 3270 3271 3272 pyrrolyl 3273 3274 3275 3276 3277 3278 3279 3280 3281 3282 3283 imidazolyl 3284 3285 3286 3287 3288 3289 3290 3291 3292 3293 3294 furanyl 3295 3296 3297 3298 3299 3300 3301 3302 3303 3304 3305 thienyl 3306 3307 3308 3309 3310 3311 3312 3313 3314 3315 3316 pyrimidinyl 3317 3318 3319 3320 3321 3322 3323 3324 3325 3326 3327 pyrazinyl 3328 3329 3330 3331 33321 3333 3334 3335 3336f 3337 3338 TABLE 6 - Continued G Ar phenyl 3339 3340 3341 3342 3343 3344 3345 3346 3347 3348 3349 pyrimidinyl 3350| 3351 3352 3353 335413354 3356 3357 3358 3359 3360 pyrazolyl 3 3 6 1 3362 3363 3364 3365 33661 33671 3368 3369 3370 3371 thiazolyl 3372 3373 33741 3375 3376 3377' 33 78 3 37 9 3380 3381 3382 thiadiazolyl 3383 3384 33851 3386 3387 3388 3389 3396 3391 3392 3393 oxazolv 3394 3395 3396 3397 3398 3399 3400 3401 3402 3403 3404 isoxazolyl 3405 3406 340'1 34081 34091 3410 3411 3412 34131 34141 3415 oxadiazol 3416 34 17 3 4 1 8 34191 3420 3421 34221 3423 34241 3425 34261 isothiazolyl 342' 34281 3429 34301 3431 34321 3 3434 3435 ' 3436 343/1 pyrrolinyl 3438 3439 3440 34411 3442 34431 3444 3445 346 4 3447 3448 pyridazinyl 3449 3450 34511 3452 3453 3454 3455 3456 3457 3458 3459' rroly 13460 3461! 3462 3463 3464 3465 3466 3467 3468 34691 3470 imidazolyl 3471 3472 3473 3474 3475 3476 3477 3478 3479 3480 3481 furanyl 3482! 3483 3484 34851 3486 348 34883489! 3490 3491 3492 164 WO 2007/146712 PCT/US2007/070547 Ar thienyl 3493 3494| 3495 3496 3497 3498 13499 3500 3501 3502 3503 pyrimidinyl 35041 3505 1 3506 3507 3508 3509 3510 3511, 3512 135 -13 3514 pyrazinyl 135151 35161 3517 3518 35191 3520 3521 35221 35231 3524 3525, TABLE 6 - Continued \ G Ar phenyl 3526 3527 3528 3529 13530 3531 pyrimidinyl 3532 3533 3534 3535 3536 3537 pyrazolyl 3538 3539 3540 541 3542 3543 thiazolyl 35434 345 3546 3547 3548 3549 thiadiazolyl 3550 3550 3550 3553 35 354 3555 oxazolyl 3556 3557 3558 3 5 5 3 5 6 3561 isoxazolyl 3562 3563 3564 3565 |3566 3567 oxadiazolyl 3568 3569 3570 3-5-71 |3572 3573 isothiazolyl 3574 3575 3576 3577 3578 3579 pyrrolinyl 3580 3581 3582 3583 3584 3585 pyridazinyl 3586 3 587 3588 3589 3590 3591 pyrrolyl 3592 3593 3594 13595 3596 3597 imidazolyl 3598 3599 3600 3601 3602 3603 furanyl 3604 3605 3606 3607 3608 3609 thienyl 3610 3611 3612 3613 3614 3615 py 3617 3618 3619 3620 3621 pyraziny 3622 3623 3624 3625 3626 3627 [00298] Similar to Tables 1 and 3 - 6 above, Table 7 illustrates combinations of Ar and G for the compounds having Formula IC. Table 2 above illustrates combinations of L and Q that may be employed for compounds having Formula IC. TABLE 7 - Exemplary Combinations of Ar and G for the Compounds of Formula IC. G indazolyl 3628 3629 36303631 3632 3633 356 363 3 637 165 WO 2007/146712 PCT/US2007/070547 G Ar 5 - 7 indoly1 363836934 361 34 363 - 67 isoindoly 1 3648 34 l35 35 6435 6635 imidazoly1 3658 35 60 61136 63 36 6536 66 benzi-midazolyJ 3668 36 6037 672 3673 6437 6637 pyrazolyl 3678 j7 8 8 8 63 38 65'6638 pyrazolinyl 3688 __8 39 61 39 3 9 6439 36639 pyrll3698 39 70130 72 30 74370 7630 pyrrolinyl 3708 30 7031 1 7431 7631 pyridinyl 371837932 T2 322 __23_72T25T26 77 pyriaziyl 7283639 3640 3641 3642 3733 3644 3645376 77 quinoli Y 3 364379 3650 36511 3652 3653 3654 3645534134 isoginolnyl 7483659 3660 3661 3662 13663 3664 365 7635 phthlaznyl 7583669 37670 37671 37672 3767 37674 376575 636 benzfurnyl 7783679 3680 3681 _3682 3683 3684 3685376 78 benzxazly] 7883689 3690 3691 3692 3693 3694 3695376 79 benoioxzoyl i 98 3699 37i800 37-01 37-02 3703 3704 3705386 801 dihyrobezo- 8083709 3710 3711 3712 3713 3714 37 1 81 3 319 3720 3721 3722 3723 3724 3725 pyrzioaz yl 372838933 381 3R 2 _ 833 T84-85336 87 oi s zolyl 338 339 3640 3641 342 3643 3644 3845 3646 3647 C6oindaryl 3848 349 350 3651 3652 3653 3854 355 3656 3657 -imaolkYl 1 3858 359 3660 3661 3662 3863 3664 3865 366 3667 bazini l 368 369 370 3671 36j-872 __3673 36_874 375 3676 3677 imazolyl 378 379 380 381 3821 3683 6841 3885 3686 3687 ylyl1 3688 389 3690 391 13921 36931 36941 3695 3696 3697 so i dolyI1 3698 399 3700 71 302 3703 37041 3705 3706 3707 309 101 3711 312 3 15 3716 3717 p31 1 320 3211 322 3723 3724 3725' 3726 3727 prazyl 13728 119,3729 3730 3731 3732 3733 3734 3735 3736 3737 quinolinyl 3738 3739 3740 3741 3742 3743 3744 3745 3746 3747 isoquinolinyl 3748 3749 3750 3751 37521 3 3 54 3755 3756 3757 phthalazinyl 3758 3759 3760 3761 3762 dihydroindolyl 3768 3769 3770 3771 3772 373174 75376 ''7 benzofuranyl 3778 3779 3780 3781 3782 j38 7438 7638 benzoxazolyl 3788 3789 3790 3791 3792 39 7439 7639 benzoisoxazolyl 3798 3799 3800 3801 3802 30 8430 8630 dihydrobenzo- 3808 3809 3810 3811 3812 dihydroisoindolyl 3818 3819 3820 3821 3822 benzoisothiazolyl 3828 3829 3830 3831 3832 benzoisothiazolyl 3838 3839 3840 3841 3842 34 8434 8634

C~

1 ory1384 389 380 351 852 3853 3854 3855 3856 3857

-(C~

3 aky1-(C 10 858385 380 361 862 3863 3864 3865 3866 3867 aryl)~38713873 3874 3805 3876 387 naphtliyl 368 3869338014__383873816__3817 3823L|3824-325o382n382d 383 33G83 8633 ndaphthl 388389 380 381 3821 | 387 38 7 4 F 3895 3876 38977 inaol 88389_88_81_38 3883 3884' 3885 3886 38871 indolyl F3888|13889, 3890 3891_ 38239339_39_89_I9 tisoindolvi _____3898' 3899: 3900 3901 3902 3903 39041 3905 3906 3907, imiidazolyl -39081 3909 3910 39111 3912 3913 39141 39151 3916 394 benzimidazolyl 3918, 3919 3920 3921'b 3922 39231 3924~ 3925j 3926, 3927 [pyrazolyl 3928, 3929, 3930{ 3931 3932k 3933! 3934, 3935 3936 3937 pyrazolinyl 3938 3939, 39401 3941 F 3942 3943 3944; 3945 3946, 3947| pyrrolyl 39481 3949j 3950j 3951| 3952 3953 3954| 3955 3956{ 397 Ipyrrolinyl 39581 39591 396013961 39621 39631 3964| 3965 39661 3967, ~pyridinyl L3968L 39691 39701 3971; 39721 3973J 3974{ 3975 3976' 3977i 166 WO 2007/146712 PCT/US2007/070547 G . Ar . pyridazinyl 3978 3979 3980 3981 3982 3983 3984 3985 3986 3987 quinolinyl 3988 3989 3990 3991 3992 3993 3994 3 3996 3997 isoquinolnyl 3998 3999 4000 4001 4002 40031 4004 4005 4006 4007 phthalazinyl 4008 4009 4010 4011 4012 4013 4014 4015 4016 4017 dihydroindolyl 4018 4019 4020 4021 4022 4023 4024 4025 4026 4027 benzofuranyl 4028 4029 4030 4031 4032 4033 4034 4035 4036 4037 benzoxazolyl 4038 4039 4040 4041 4042 4043 4044 4045 4046 4047 benzoisoxazolyl 4048 4049 4050 4051 4052 4053 4054 4055 4056 4057 dihydrobenzoisoxazolyl 4058 4059 4060 4061 4062 4063 4064 4065 4066 4067 dihydroisoindolyl 4068 4069 4070 4071 4072 4073 4074 4075 4076 4077 benzoisothiazolyl 4078 4079 4080 4081 082 83 4084 4085 4086 4087 benzoisothiazolyl dioxide 088 4089 4090 4091 4092 4093 4094 4095 4096 4097 C6 aryl 14098 4099 4100 4101 41021 4103 4104 4105 4106 4107 -(C.3a~yI-(Cioarl) 4008 40091 4010 4011 40121 40131 4014 4015 4016 4017 lithy 14118 4119 41201 4121 4122 4123 4124 4125 4126 4127 [00299] Similar to Tables 1 and 3 - 7 above, Table 8 illustrates combinations of Ar and C" for the compounds having Formula 11. Table 2 above illustrates combinations of L and Q that may be employed for compounds having Formula 11, TABLE 8 - Exemplary Combinations of Ar and G for the Compounds of Formula II G Ar r: 7' N 0 M a -E 0 V Phenyl40 438 439 440 441 442 443 444 445 44644 nahtl40 448 449 450 451 4024 53 454 455 45645 Ar 15 415 145 -4 N16 41546 405840594060 461 462 463 4 0 isoginoine 6-7468 4069 470 471 472 473 -- 474 475 476 47 tethdo 417 4128 4129 4130 4131 4132 4133 4134 4135 4136 pyrenyl 4137 4138 14139 !4140 !4141 4142 4143 1 4 1944 j4145 41496 naphthyl 4147 4148 4149 41200 4121 4122 4123 4124 41255 41261 guinolinyl 4109 410 4 1 2 413 414 415 416 isoquinoline 4167 4168 4169 4170 4171 412 1 34 4175 4176 tetrahydronaplitl 4177 4178 4179 4180 4181 4182 4314184 45446 pyridinyl 48 1848 4 9 1149 1349 1549 4pyridaziny 417 1418 1499 4200 4201 4202 4203 42041425 4206 quinolinvi 2 4 o 4 ot 2 0 4 1 4224__ __ phthalazinyl 4240 4241 4242 4243 4244 4245 426 tetrahydroquinoline 43 2843 __ __ __ __ tetrahydroisoquinoline 44 2844 2045 2245 45 2545 1benzimidazole (2745 29(20-46 2246 46 2546 bezofuran 4267 4268 4269 4270 4271 4272 4273 4274 4275 4276 idnl41671416 4169_ 4170 4171 417_413 417 475 17 42 2- 48 14279 14280 4281 4282 4283 4284 4285 4286 167 WO 2007/146712 PCT/US2007/070547 G Ar E U0 indenyl 4287 14288 4289 4290 4291 4292 4293 4294 4295 4296 -(Y')-(COI- alkyl)-(C6 aryl) 4297 4298 4299 4300 430114302 4303 4304 4305 4306 [00300] In yet another aspect, there are provided compounds useful in the invention comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a it-it or edge-to-face aromatic interaction with the target protein; wherein the compound is optionally a cytokine inhibitor. [00301] In this aspect of the invention, the compounds have the structure PEM-TM-OM. At a concentration of 10 pM such compounds typically inhibit induced TNFa-release from a cell by about 50% or greater than 50%. [00302] The targeting moiety can hydrogen bond to residues at the binding site of the target protein and may further include additional hydrogen bond donor or acceptor groups that also form hydrogen bonds to the target protein. Targeting moieties include amide and thioamide groups, methyl amide and thioamide groups, carbamates, 168 WO 2007/146712 PCT/US2007/070547 hydroxymethyl amides, alpha-ketoamides, diamides, and the like. Cyclic targeting moieties are also contemplated such as imidazolinone, imidazoline dione and trione. [00303] The pocket-expanding moiety is of sufficient size to force a conformational change in the target protein, resulting in an expanded binding pocket therein. Such moieties include, for example, pyrazolyl, oxazolyl, phenyl, or the like, each substituted by bulky moieties. Bulky moieties fill a large volume of space in comparison to, for example, a methyl group and include groups such as t-butyl, norbomyl, and the like. [00304] The orienting moiety, by binding to a hydrophobic pocket on the target protein, provides the proper orientation of the targeting moiety and pocket-expanding moiety for binding of the compound to its target protein. The planar hydrophobic moieties which make up the orienting moiety have either few or no polar groups. Such moieties include, for example, phenyl, naphthyl, indazolyl, and the like. [003051 In other embodiments, the compounds further comprise a hydrophilic moiety having at least one functionality selected from the group consisting of a hydrogen bond donor, hydrogen-bond acceptor, basic heteroatom, or acidic heteroatom, wherein the hydrophilic moiety is indirectly attached to the hydrophobic orienting moiety and is capable of forming a hydrogen bond with the backbone of the protein. Typically the hydrophilic moiety is attached to the orienting moiety by a linker chain of atoms of from about 2 to about 10 angstroms in length. The hydrophilic moiety binds in or near an ATP-binding pocket on the target protein, forming at least one hydrogen bond with a residue of the ATP-binding pocket. Hydrophilic moieties include morpholinyl, piperazinyl, and pyrimidinyl groups, among others. Such moieties may be attached to the orienting moiety by, for example, oxy, ethylene, methyleneoxy and ethyleneoxy chains. [003061 In certain embodiments of the compounds of the invention, the pocket expanding moiety is not a substituted 5-member heterocyclyl ring if the compound is PEM-CHR"C(O)NH-OM, wherein R" is H or C1- 6 alkyl, optionally partially or fully halogenated. In other embodiments, the targeting moiety is not a substituted tricyclic heterocyclyl ring having a nitrogen atom ring member bonded to the amide carbonyl of the targeting moiety. 169 WO 2007/146712 PCT/US2007/070547 [00307] Compounds of this aspect of the invention may be readily synthesized by techniques well known to those of skill in the art, as described in U.S. Application No. 10/939,324, filed September 10, 2004, and International Application No. PCT/US2006/006682, filed February 23, 2006. [00308] In accordance with another aspect, there are provided compounds useful in the methods of the invention having Formula III: G L Ar Q N A Formula III stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein the variables A, Ar, G, L',

L

2 , L 3 , Q, R', R 2 , R 3 , R, R', R", and m are as defined in List X. LIST X: Definition of variables for compounds of Formula III. A is F, Cl, Br, I, NR 2 , or a CI- 3 alkyl or -O(C.

3 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; Ar is a substituted or unsubstituted aryl or heteroaryl group; G is an aryl or heteroaryl group, wherein G is substituted by one or more R', R 2 or R3; L' is -C(O)NH-; L2 is -C(O)NR-, or -C(O)NOR-; provided that if one of Li and L 2 is attached to the pyridine ring via nitrogen, the other of L' and L 2 is not attached to the pyridine ring via nitrogen;

L

3 is a covalent bond, 0, NR, C(O), C(O)NR, or a substituted or unsubstituted CI-s alkyl,

C

2

-

5 alkenyl, C 2

-

5 alkynyl, NR(C 1

-

5 alkyl) or O(C 15 alkyl) group; Q is hydrogen, or a substituted or unsubstituted alkyl, aryl or heterocyclyl group; each R' is independently F, Cl, Br, I, -NR2, -CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heterocyclylalkyl group; 170 WO 2007/146712 PCT/US2007/070547 each R 2 is independently F, Cl, Br, I, -CN, -NO 2 , a substituted or unsubstituted alkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NR'C(O)R", -NR'C(O)OR',

-NR'SO

2 R", -NR'C(O)NR" 2 , -NR'C(S)NR" 2 , -S(O)mR", or -SO 2

NR'

2 ; each R 3 is independently a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or an -O(C 1 4 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted C 1 _ alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; and each m is independently 0, 1 or 2. [00309] All of the following compounds are contemplated by Formula III: HAr-L 3 _Q 0 Ar-L-Q -Ar-L 3 .Q G G R G N AT"R ~ NAN A NA IIIA HIB IIIC R -_ -Ar-L -Q RO, -Ar-L 3 -Q G N 0 GN N N 0 N _- A N A ID HIE [00310] As those of skill in the art will appreciate, unless otherwise noted, all orientations of divalent linkers such as L', L 2 and L 3 are contemplated for use in compounds of the invention. [003111 In some embodiments, the compound of Formula III is HAr-L 3 -Q 0 Ar-L 3 -Q /Ar-L 3 -Q H RN O 0 RN G NO G N R GO G N I N 0 H L- H 0 N A N A or N A IIA IIB IIIC 171 WO 2007/146712 PCT/US2007/070547 [00312] In some embodiments of compounds of Formula III, A is F, -CH 3 , or

-CF

3 . In others, G is a phenyl, pyrimidyl or pyridyl group, for example, G may be R' RR

R

2 ,or

R

3 R R 3 [00313] In some embodiments of compounds of Formula III, Ar is a substituted or unsubstituted phenyl, pyridyl, or pyrimidinyl group. For example, Ar may be NK N [00314] In some other embodiments of compounds of Formula III, L 3 is a covalent bond, 0, NR, C(O)NH, or a substituted or unsubstituted O(C 1

-

3 alkylene) or

NR(C-

3 alkylene) group, for example, L 3 is a covalent bond, 0, NH, C(O)NH, OCH 2 ,

OCH

2

CH

2 , NHCH 2 , or NHCH 2

CH

2 . [00315] In yet other embodiments, Q is H or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, pyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, quinolyl, pyrrolidinyl, piperidyl, or piperazinyl group. For example, Q is a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl group. [00316] In some embodiments of compounds of Formula III, R' is F, -CN, -NR 2 , or a substituted or unsubstituted C 14 alkyl, C 3 9 cycloalkyl, heterocyclyl, or heterocyclylalkyl group. For example, R' is F, -CN, -N(C 1 3 alkyl) 2 wherein each C13 alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted isopropyl, tert-butyl, iso-butyl, sec-butyl, cyclohexyl, thiazolyl,

CH

2 -thiazolyl, CH 2

CH

2 -thiazolyl, pyrrolidinyl, CH 2 -pyrrolidinyl, CH 2

CH

2 -pyrrolidinyl, piperidyl, CH 2 -piperidyl, CH 2

CH

2 -piperidyl, morpholinyl, CH 2 -morpholinyl,

CH

2

CH

2 -morpholinyl, thiomorpholinyl, CH 2 -thiomorpholinyl, CH 2

CH

2 -thiomorpholinyl, piperazinyl, CH 2 -piperazinyl, CH 2

CH

2 -piperazinyl, oxazepanyl, CH 2 -oxazepanyl, or

CH

2

CH

2 -oxazepanyl group. 172 WO 2007/146712 PCT/US2007/070547 [00317] In other embodiments, R 2 is a substituted or unsubstituted C 1 - alkyl group, F, Br, Cl, -CN, -NO 2 , -C(O)OR', -C(O)NR' 2 , -NRC(O)R", -NRC(O)OR", -NR'SO 2 R",

-NR'C(O)NR'

2 , or -SO 2

NR'

2 . For example, R 2 is F, -CF 3 , -CN, -NO 2 , -O(C 1 6 alkyl), -C(O)O(CI-6 alkyl), -C(O)NH 2 , -C(O)NH(CI-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl),

-NHC(O)(C

1 o alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl),

-NHSO

2 (CI-6 alkyl), -NHS0 2 (aryl), -NHSO 2 (aralkyl), -SO 2

NH(C

1

.

6 alkyl), -SO 2 NH(aryl), or -SO 2 NH(aralkyl), wherein each C 1

.

6 alkyl, aryl, or aralkyl group is substituted or unsubstituted. [00318] In yet other embodiments, R 3 is a substituted or unsubstituted Cia alkyl or -O(CIA alkyl) group, or is a partially or fully halogenated -O(C 1 2 alkyl) group. [00319] In some embodiments of compounds of Formula III, G is is phenyl and R 1 is F, -CN, -N(C 1 3 alkyl) 2 wherein each C 1 3 alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, oxazepanyl, isopropyl, tert-butyl, isobutyl, sec-butyl, or cyclohexyl group. In some such embodiments, R 2 is a substituted or unsubstituted

C

1 4 alkyl group, F, Br, -CN, -NO 2 , -O(C 1 6 alkyl), -C(O)O(C 1

.

6 alkyl), -C(O)NH 2 , -C(O)NH(CI-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(C -6 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO 2

(C

1

.

6 alkyl), -NHS O2(aryl), -NHS O2(aralkyl),

-SO

2

NH(C

1 6 alkyl), -SO 2 NH(aryl) or -SO 2 NH(aralkyl), wherein each C 1

.

6 alkyl, aryl, or aralkyl group is substituted or unsubstituted. For example, R 2 may be F, -CF 3 , -CN,

-C(O)NH

2 , -C(O)NH(C 1

.

6 alkyl), -NHSO 2

(C

1 6 alkyl), or -SO 2

NH(C-

6 alkyl), wherein each C1-6 alkyl group is substituted or unsubstituted. In certain of these embodiments. R 3 is a substituted or unsubstituted CiA alkyl or -O(Ci 4 alkyl) group, or is a partially or fully halogenated -O(C 1 2 alkyl) group. 173 WO 2007/146712 PCT/US2007/070547 [00320] In some embodiments of compounds of Formula III, -L -Q is -H, -OMe,

-C(O)NH

2 , NN- N N H H , H H H H N NN 0 O O O' N/O O N H NO, or [00321] In some such embodiments, G is a phenyl group. [00322] Where compounds are described in terms of Markush groups or other groupings of alternatives, those skilled in the art will recognize that the compounds are also thereby described in terms of any individual member or subgroup of members of the Markush groups or other groupings. By way of illustration and not limitation, Table 9 sets forth various combinations of substituents from the formulas described herein. Thus, e.g., combination 1031 describes those embodiments of Formula III in which G is phenyl and Ar is pyridyl. Table 9 - Exemplary Combinations of G and Ar for Formula III. G 4 Ar 2

P

aryl 1001 1002 1003 1004 1005 1006 1007 heteroaryl 1008 1009 1010 1011 1012 1013 1014 phenyl 1015 1016 1017 1018 1019 1020 1021 pyrimidyl 1022 1023 1024 1025 1026 1027 1028 pyridyl 1029 1030 1031 1032 1033 1034 1035 pyridin-2,5-diyl 1036 1037 1038 1039 1040 1041 , 1042 174 WO 2007/146712 PCT/US2007/070547 [00323] Table 10 sets forth various combinations of substituents L 3 and Q of Formula II. Thus, e.g., combination 1766 describes those embodiments in which L 3 is

OCH

2 , and Q is 2-pyridyl. Further, those skilled in the art will understand that only combination of substituents that result in a chemically stable compound are possible and will understand and how to select such combinations. Those skilled in the art will further appreciate that any combination from Table 9, describing G and Ar, may be combined with any combination from Table 10, describing L 3 and Q. For example, combination 1038 from Table 9 and combination 1766 from Table 10 describe those embodiments of Formula III in which G is phenyl, Ar is pyridin-2,5-diyl, L 3 is OCH 2 , and Q is 2-pyridyl. Each Ar, G, L 3 , and Q group in the tables is understood to be optionally substituted as described herein. Moreover, each value of A (F, Cl, Br, I, NR 2 , or a C 1 3 alkyl or -O(C 1 3 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated) may be combined with any combination from Table 9 or Table 10 or any pair of combinations from the two tables. Thus, e.g., it will be understood that combination 1038 describes those embodiments in which A is Br, G is phenyl and Ar is pyridin-2,5-diyl, as well as those where A is NR 2 , G is phenyl and Ar is pyridin-2,5-diyl, etc. Table 10 - Exemplary combinations of L 3 and Q for Formula III. L3 H 1230 1231 1232 1233 1234 1235 1236 1237 1238 alkyl 1248 1249 1250 1251 1252 1253 1254 1255 1256 aryl 1266 1267 1268 1269 1270 1271 1272 1273 1274 heterocyclyl 1284 1285 1286 1287 1288 1289 1290 1291 1292 cycloalkyl 1302 1303 1304 1305 1306 1307 1308 1309 1310 phenyl 1320 1321 1322 1323 1324 1325 1326 1327 1328 pyridyl 1338 1339 1340 1341 1252 1343 1344 1345 1346 pyrimidinyl 1356 1357 138 139 130 131 132 133 134 morpholinyl 1374 1375 1376 1377 1378 1379 1380 1381 12 thiomorpholinyl 1392 1393 1394 1395 1396 137 1398 1399 10 tetrahydrofuranyl 1410 1411 1412 1413 1414 1415 1416 1417 1418 tetrahydropyranyl 1428 1429 140 141 142 143 134 145 146 quinolyl 1446 1447 1448 1449 1450 1451 1452 1453 14 pyrrolidinyl 14 1465 1466 1467 1468 1469 1470 1471 piperidyl 1482 1483 1484 1485 1486 1487 1488 1489 140 pieraziylfrnl11 41111 4311 4511 4711 tcrayd:(,,,'-:-tnI1338 1339 113401 14341 143421 143 14344 143451 14346 quinlyl1356 1357 1358 13549 ,1360 1361 1362 1433 134 pyrrlidnyl 1374 1375 1376 1377 1378 1379 1380 1381_ 1382 pipeidyl1410 1481 1412 1413 1414 1415 1416 1487 1418 piperazinyl 1500 1501 1502 1503 1504 1505 1506 1507 1508 methyl 1518 1519 1520 1521 1522 1523 1524 1525 1526 175 WO 2007/146712 PCT/US2007/070547 L 3 Q > ethyl 1536 1537 1538 1539 1540 1541 1542 1543 1544 n-propyl 1554 1555 1556 1557 1558 1559 1560 1561 1562 isopropyl 1572 1573 1574 1575 1576 1577 1578 1579 1580 n-butyl 1590 1591 1592 1593 1594 1595 1596 1597 1598 isobutyl 1608 1609 1610 1611 1612 1613 1614 1615 1616 sec-butyl 1626 1627 1628 1629 1630 1631 1632 1633 1634 t-butyl 1644 1645 1646 1647 1648 1649 1650 1651 1652 neopentyl 1662 1663 1664 1665 1666 1667 1668 1669 1670 cyclopropyl 1680 1681 1682 1683 1684 1685 1686 1687 1688 cyclobutyl 1698 1699 1700 1701 1702 1703 1704 1705 1706 cyclopentyl 1716 1717 1718 1719 1720 1721 1722 1723 1724 cyclohexyl 1734 1735 1736 1737 1738 1739 1740 1741 1742 2-pyridyl 1752 1753 1754 1755 1756 1757 1758 1759 1760 3-pyridyl 1770 1771 1772 1773 1774 1775 1776 1777 1778 4-pyridyl 1788 1789 1790 1791 1792 1793 1794 1795 1796 [00324] In one embodiment, the compound of Formula III at a concentration of 10 pAM inhibits induced TNFa-release from a cell by about 50% or greater than 50%. [00325] Other compounds useful in the methods of the invention comprise: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, and wherein the anchoring moiety is capable of forming at least one hydrogen bond interaction with an ATP-binding pocket of the target protein; wherein the compound is optionally a cytokine inhibitor. 176 WO 2007/146712 PCT/US2007/070547 [00326] In this aspect of the invention, compounds have the structure PEM-TM OM-L-AM. At a concentration of 10 pM such compounds typically inhibit induced TNFa-release from a cell by about 50% or greater than 50%. [00327] The targeting moiety can hydrogen bond to residues at the binding site of the target protein. Targeting moieties include amide and thioamide groups, methyl amide and thioamide groups, and the like. The target protein is a protein to which the compound binds in a specific manner. [00328] The pocket-expanding moiety is of sufficient size to force a conformational change in the target protein, resulting in an expanded binding pocket therein. Such moieties include 6-membered aryl and heteroaryl moieties, for example, phenyl, pyridyl, or the like, substituted by bulky moieties. Bulky moieties fill a large volume of space in comparison to, for example, a methyl group and include groups such as substituted or unsubstituted C2A alkyl groups, for example substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec-butyl groups; substituted or unsubsituted C 3

.

9 cycloalkyl groups, for example substituted or unsubstituted cyclohexyl or norbornyl groups; or substituted or unsubstituted heterocyclyl groups, such as substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidyl, or thiomorpholinyl groups. [00329] The orienting moiety, by binding to a hydrophobic pocket on the target protein, provides the proper orientation of the targeting moiety and pocket-expanding moiety for binding of the compound to its target protein. Such moieties include, for example, a pyridyl group, substituted by small hydrophobic moieties, exemplified by halogens, methyl, trifluoromethyl, and the like. [00330] The linker moiety, L, may include a hydrogen bond donor, a hydrogen bond acceptor, or acceptor or both a hydrogen bond donor and acceptor that form hydrogen bond(s) with the target protein. For example, the linker moiety may comprise an amide NH and carbonyl. The linker moiety further includes a planar aromatic ring such as an arylene or heteroarylene. Thus, e.g., the linker moiety may be a benzamide or a pyridylamide. 177 WO 2007/146712 PCT/US2007/070547 [00331] The anchoring moiety may include an 0 or N atom which may form a hydrogen bond to the target protein. In some embodiments the anchoring moiety includes an ether oxygen or an amine NH, and in others it comprises a carbonyl oxygen. [00332] In other embodiments, the compounds further comprise a hydrophilic moiety having at least one functionality selected from a hydrogen-bond donor, hydrogen bond acceptor, basic heteroatom, or acidic heteroatom, wherein the hydrophilic moiety is attached to the anchoring moiety and is capable of forming a hydrogen bond with the backbone of the target protein. Typically the hydrophilic moiety is attached to the anchoring moiety by a chain of atoms of from about 2 to about 10 angstroms in length. The hydrophilic moiety binds in or near an ATP-binding pocket on the target protein, forming at least one hydrogen bond with a residue in or near the ATP-binding pocket. Hydrophilic moieties include morpholinyl, pyridyl, and pyrimidyl groups, among others. Such moieties may be attached to the anchoring moiety by, for example, a bond, a C1s alkylene, or the like. [00333] Another group of compounds useful in the methods of the invention are compounds of Formula IV: B' L2-Q G LE Y A Formula IV stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein the variables X, Y, A, B, D, F, G, L L 2 , Q, R', R 2 , R', R, R', R", m, n, and p are defined as in List XI. LIST XI: Definition of variables for compounds of Formula IV. X and Y are each independently CH or N; A is F, Cl, Br, I, NR 2 , or a C1- alkyl or -O(C 3 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; B, D and E are each independently N, NR, 0, S or CR; wherein B, D, and E are selected such that the ring containing B, D, and E is aromatic; 178 WO 2007/146712 PCT/US2007/070547 G is an aryl or heteroaryl group, wherein G is substituted by one or more R 1 , R 2 or R 3 ; Ll is -C(O)NH-;

L

2 is -(CR' 2 )n-C(O)-(CR' 2 )p-, -(CR' 2 )n-NR-(CR' 2 )p-, -(CR' 2 )n-C(O)NR-(CR' 2 )p-,

-(CR'

2

),-C(O)NRNR-(CR'

2 )p-, or -(CR' 2 ),-O-C(O)NR-(CR'2)p-; Q is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group; each R 1 is independently F, Cl, Br, I, -NR 2 , -CN, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclylalkyl group; each R 2 is independently F, Cl, Br, 1, -CN, -NO 2 , a substituted or unsubstituted alkyl or heterocyclylalkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NRC(O)R", -NR'C(O)OR", -NR'SO 2 R", -NR'C(O)NR' 2 , -NR'C(S)NR' 2 , -S(O)mR", or -SO 2

NR'

2 ; each R 3 is independently a substituted or unsubstituted Ci alkyl, alkenyl, or alkynyl group, or an -O(C1A alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted C 1

.

6 alkyl group; each R' is independently hydrogen, or a substituted or unsubstituted alkyl, aralkyl, heterocyclyl, or heterocyclylalkyl group; each R" is independently a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl group; each m is independently 0, 1 or 2; and n and p are each independently 0, 1, 2 or 3. [00334] Thus, in some embodiments, compounds of Formula IV are also cytokine inhibitors having the formula PEM-TM-OM-L-AM. For example, in some embodiments, G is PEM, Ll is TM, the 6-member ring is OM, the 5-member heteroaryl is L, and -L 2 -Q is AM. 179 WO 2007/146712 PCT/US2007/070547 [00335] All of the following compounds are contemplated by Formula IV: 11 -0 N-NR G-L' G-L', G-L, 1

L

2 -Q X L 2 -Q L 2 _Q Y AY AY A IVA-I IVA-2 IVA-3 G-G-L-L N L G-L

L

2 -Q Q L 2 Y A X YA YA tVA-4 IVA-5 IVA-6 R R NR R J NL L NL2 -Q N L -Q GL N L Q Y- A Y A Y IVA-7 IVA-8 IVA-9 R 0 NRS G-L' I G 2 GL', 1 : G-L 1 I) 2-L 2 -Q 12-Q x R x- R X,- R Y '[A Y - A Y A IVA-10 IVA-11 IVA-12 R R R NN N G-L G-L 1 G-L S 0 L 2 -Q ii~ N L 2 -Q j S L 2 -Q R Y A Y Y A IVH-1 IVB-2 IVB-3 R QN Y' A Y AY A IVH-4 IVB-5 IVB-6 R R R N N N 0 L 2 - N L 2 - - S L 2 A X,~ Y AA Y A IVB-7 WVB-8 I VB-9 R R R, R R, ~R ~ L-Q GL-~ 2 -Q S 2 -Q xY A Y A Y A IVB-10 IVB-11 IVB-12 180 WO 2007/146712 PCT/US2007/070547 -N RN-N -- N G-Li L2 G-LL2 G-L L

N.L

2 -Q L 2 _Q NL 2 -Q X,- R X R X , R IVC-1 IVC-2 IVC-3 - -N RN-N G-LN L 2 -Q G-L N L2 N L 2 -Q X AX Y A Y A IVC-4 IVC-5 IVC-6 R R R GLG-L RNI G-L N. N L-Q N. N L 2 -Q N N L 2 .Q Yx A Y A Y A IVC-7 IVC-8 IVC-9 R R R G-L 01 RN G-' S I L2- L2-I L 2 -Q Y, A Y A Y Ay IVC-10 IVC-11 IVC-12 [00336] As those of skill in the art will appreciate, all orientations of divalent linkers such as L' and L 2 are contemplated for use in compounds in this aspect of the invention. Thus, in some embodiments, the compound of Formula IV is the compound of Formula IVD: H 0 L 2 -Q Y I E 0 x Formula IVD [003371 In others, the compound of Formula IV has the structure IVE or IVF:

G_L

2 -0 GL 2 -Q GIIN E Gy N E H or 0 IVE IVF 181 WO 2007/146712 PCT/US2007/070547 [00338] In some embodiments of compounds of Formula IV, B is N. In others, D is NH, 0 or S. In still others, E is CH or 0. In some other embodiments of compounds of Formula I, A is F, -CH 3 , or -CF 3 . [00339] In some embodiments of compounds of the invention, including compounds of Formula IV or IVD, G is a phenyl, pyrimidyl or pyridyl group. In other embodiments, G is a phenyl or pyridyl group, For example, G is R1 R1 R1 R4 -~ N N I I R2 R26 ' R2 or N

R

3

R

3 3 [00340] In some embodiments of compounds of the invention, including compounds of Formula IV or IVD, L 2 is -C(O)-(CR' 2 )p-, -(CH 2

).-C(O)NR-(CH

2 )p-, or

-(CH

2 )n-C(O)NRNR-(CH 2 )p-. For example, L 2 is -C(O) -, -C(O)CH 2 -, -C(O)CH 2

CH

2 -,

-C(O)CH

2

CH

2

CH

2 -, -C(O)NHNH-, -C(O)N(CH 3 )NH-, -C(O)N(CH 3

)NH-CH

2 -,

-C(O)N(CH

3

)NH-CH

2

CH

2 -, -C(O)N(CH 3

)NH-CH

2

CH

2

CH

2 -, -C(O)NHNH-CH 2 -,

-C(O)NHNH-CH

2

CH

2 - or -C(O)NHNH-CH 2

CH

2

CH

2 -, C(O)NH-, -C(O)N(CH 3 )-,

-C(O)N(CH

3

)-CH

2 -, -C(O)N(CH3)-CH 2

CH

2 -, -C(O)N(CH 3

)-CH

2

CH

2

CH

2 -,

-C(O)NH-CH

2 -, -C(O)NH-CH 2

CH

2 - or -C(O)NH-CH 2

CH

2

CH

2 -. [00341] In others, the compound is GrL E HN Y A [00342] In still others, the compound is G,--L N G -- E H N - \\ Y A and Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group. 182 WO 2007/146712 PCT/US2007/070547 [00343] In other embodiments of compounds of the invention, including compounds of Formula IV or IVD, Q is H, or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, pyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, 8-oxa-3-aza bicyclo[3.2.1 Joctanyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidyl, or piperazinyl group. For example, Q is a substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidyl, morpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, or neopentyl group. [003441 In yet other embodiments of compounds of the invention, including compounds of Formula IV or IVD, R' is F, -CN, -NR 2 , or a substituted or unsubstituted

C

1 4 alkyl, C 3

.

9 cycloalkyl, aryl, heterocyclyl, or heterocyclylalkyl group. In some such embodiments, R 1 is F, -CN, -N(CI.

3 alkyl) 2 wherein each C1.

3 alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted isopropyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, phenyl, 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl, thiazolyl, CH 2 -thiazolyl, CH 2

CH

2 -thiazolyl, pyrrolidinyl, CH 2 -pyrrolidinyl,

CH

2

CH

2 -pyrrolidinyl, piperidyl, CH 2 -piperidyl, CH 2

CH

2 -piperidyl, morpholinyl,

CH

2 -morpholinyl, CH 2

CH

2 -morpholinyl, thiomorpholinyl, CH 2 -thiomorpholinyl,

CH

2

CH

2 -thiomorpholinyl, piperazinyl, CH 2 -piperazinyl, CH2CH 2 -piperazinyl, oxazepanyl, CH 2 -oxazepanyl, or CH 2

CH

2 -oxazepanyl group. [003451 Also contemplated are compounds of the invention, including compounds of Formula IV or IVD, wherein R 2 is a substituted or unsubstituted C 1 4 alkyl or heterocyclylalkyl group, F, Cl, -CN, -NO 2 , -OR', -C(O)OR', -C(O)NR' 2 , -NRC(O)R", -NRC(O)OR", -NR'SO 2 R", -NR'C(O)NR' 2 , or -SO 2

NR'

2 . In some such embodiments, the alkyl group is substituted with NRR. In others, the heterocyclylalkyl group is a substituted or unsubstituted -(C1-3 alkyl)-pyrrolidinyl, -(CI.

3 alkyl)-piperidyl,

-(C.

3 alkyl)-piperazinyl, or -(C.

3 alkyl)-morpholinyl group. In still other embodiments, R2 is F, -CF 3 , -CN, -NO2, -O(C 1

.

6 alkyl), -C(O)O(Ci- 6 alkyl), -C(O)NH 2 , -C(O)NH(C.

6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(Cf- 6 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHS 0 2 (C1-6 alkyl), -NHSO 2 (aryl), -NHSO 2 (aralkyl), -SO 2 NH(Cj-6 alkyl), -SO 2 NH(aryl), or -SO 2 NH(aralkyl), wherein each C 1

.

6 alkyl, aryl, or aralkyl group is substituted or unsubstituted. 183 WO 2007/146712 PCT/US2007/070547 [00346] In still other embodiments of compounds of the invention, including compounds of Formula IV or IVD, R 3 is a substituted or unsubstituted Ci- alkyl or -O(CiA alkyl) group, or is a partially or fully halogenated -O(Ci- 2 alkyl) group. [00347] In some embodiments of compounds of the invention, including compounds of Formula IV or IVD, G is phenyl and R 1 is F, Cl, -CN, -N(C 1

.

3 alkyl) 2 wherein each C 1

.

3 alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted morpholinyl, thiomorpholinyl, 8-oxa-3-aza bicyclo[3.2.1]octan-3-yl, pyrrolidinyl, piperidyl, oxazepanyl, isopropyl, tert-butyl, iso butyl, sec-butyl, or cyclohexyl group. For example, R' is F, Cl, a substituted or unsubstituted morpholinyl, 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl, pyrrolidinyl, piperidyl, oxazepanyl, tert-butyl, or cyclohexyl group. In some such embodiments, R2 is a substituted or unsubstituted CIA alkyl or heterocyclylalkyl group, F, -CN, -NO 2 , -O(C 1

.

6 alkyl), -C(O)O(CI- 6 alkyl), -C(O)NH 2 , -C(O)NH(C1-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(Ci-6 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHS0 2 (Ci 6 alkyl), -NHSO 2 (aryl), -NHSO 2 (aralkyl), -SO 2

NH(C

1

-

6 alkyl), -SO 2 NH(aryl) or

-SO

2 NH(aralkyl), wherein each C 1

-

6 alkyl, aryl, or aralkyl group is substituted or unsubstituted. In some such embodiments, the alkyl group is substituted with NRR. In others, the heterocyclylalkyl group is a substituted or unsubstituted -(CI.

3 alkyl) pyrrolidinyl, -(C1-3 alkyl)-piperidyl, -(C1-3 alkyl)-piperazinyl, or -(C1-3 alkyl)-morpholinyl group. Typically, R 2 is F, -CF 3 , -CN, -C(O)NH 2 , -C(O)NH(C 1

.

6 alkyl), -NHSO 2

(C

1

.

6 alkyl), or -SO 2

NH(C

1

.

6 alkyl), wherein each C 1

-

6 alkyl is substituted or unsubstituted. In some such embodiments, R 3 is a substituted or unsubstituted CIA alkyl or -O(C 1 4 alkyl) group, or is a partially or fully halogenated -O(CI- 2 alkyl) group. 184 WO 2007/146712 PCT/US2007/070547 [00348] In some embodiments of compounds of the invention, -L 2 -Q is 0 0 0 0 N N' N N H H N HN 0 0N N NR H N NR N NK N N H H R H ' N 00 HH H H 00 H0 0: A N H H H' 0 0 0 AXN Nj 0 NN R 00 H H 0 0 HH A N K N <N H R N, H N -N -NI R' H ' H R ,or A XNRR [00349] In some such embodiments, G is a phenyl or a pyridyl group. 185 WO 2007/146712 PCT/US2007/070547 [00350] In some embodiments of compounds of the invention such as compounds of Formula IV, the compound is N.--O O.--N H

L

2 -Q H

L

2 -Q G N G N Y A Y A ,or N-NH H L 2 -Q G N 0 Y A [00351] Where compounds are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the compounds are also thereby described in terms of any individual member or subgroup of members of the Markush group or other groupings. By way of illustration and not limitation, Table 11 sets forth various combinations of substituents of Formulas IV and IVD as described herein. Thus, e.g., combination 1047 describes those embodiments in which the 5 membered B, D, E containing aromatic ring is pyrazol-3,5-diy and G is phenyl. Table 11 - Exemplary combinations of the B,D, E containing aromatic ring and G for Formula IV. G Ring D O0 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 H 1014 1015 1016 1017 1018 1019 1020 186 WO 2007/146712 PCT/US2007/070547 G Gu Ring 1021 1022 1023 1024 1025 1026 1027 B S 1028 1029 1030 1031 1032 1033 1034 B D 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 N0 XI /1049 1050 1051 1052 1053 1054 1055 0,N 1056 1057 1058 1059 1060 1061 1062 H N N 1063 1064 1065 1066 1067 1068 1069 [00352] Table 12 sets forth various combinations of substituents L 2 and Q of Formula IV. Thus, e.g., combination 1692 describes those embodiments in which L 2 is -C(O)- and Q is t-butyl. Further, those skilled in the art will understand that a combination of substituents is permissible only if such a combination results in a chemically stable compound, and that any combination from Table 11, describing the B, D, E containing ring and G, may be combined with any combination from Table 12, describing L 2 and Q. For example, combination 1047 from Table 11 and combination 1692 from Table 12 describe those embodiments of Formulas IV and IVD in which the 5-membered B, D, E containing aromatic ring is pyrazol-3,5-diyl, G is phenyl, L 2 is -C(O)- and Q is t-butyl. Each G and Q in the tables is understood to be optionally 187 WO 2007/146712 PCT/US2007/070547 substituted as described herein. Moreover, each value of A (-F, Cl, Br, I, NR 2 , or C 1

.

3 alkyl or -O(C 1

.

3 )alkyl group) may be combined with any combination from Table 11 or Table 12 or any pair of combinations from the two tables. Thus, e.g., it will be understood that combination 1692 describes those embodiments in which A is -F, L 2 is -C(O)- and Q is t-butyl, as well as those where A is -CH 3 , L 2 is -C(O)- and Q is t-butyl, etc. 188 WO 2007/146712 PCT/US2007/070547 - - -N - - - 00 "0 '11 N1 D 'I , t-- C m-C - - 'I =- -C' r- - - - - .- In M I- I - kn -- kr m- - . - k- ' -- W) m C; r-4 CD oc cN 'I CA CI - t IN W I I - - ,- .- - '- - -- -- - 0 T r CD C l c I N CD 00 N' 'I- ~ - O n r - O rq N NCA m0 m- m I- fl0 ~ O -- -- - - -- - -- - Cd~~-- -d- - - - - -- O) -- - - -X 4R ~)~J(xJ kn ml'N0 - 1 C.ON r-kl mI 0 r- Lc'N'. C N 00 w T 14D cO N W)'I 00 = M' .0 O ,4 -- - - ------ 00 IC. 0 0 c I - - -- K cd C)A 189 WO 2007/146712 PCT/US2007/070547 -H(HD)N(O)D-mJ cC C n - 0 - ,n , - - - - lC -HNIIN(O)D -r 000m0 ' Y C DC mO V -) r 00r c n 00 r lV -ZHDZHDZH(O)D- \D\. , r, -oNcl 00 m ~C ,C - - - - - - -- - - - - - <= 0 0 N00\0 -CA : Zo: rqC -Z~~ ~ --- kn c- - N --- 00 - 11 C V HD(O)D-\1\M\ -r x 0 0 l o 0 C (= D F,- - - - - - - - - - - C14C n m -- - -- - - - -n m rl~ 0 - r.O ON 00 j 00 00 e N C', ON C', 0 r- r C-00 0 00N\NO ON Z kn- M n - - - -)- M Cl Cl d(ZHD)~ ~ ~ ~ ~ NNNO --u N Nc v) 0 00 00 00; O4 ON ON ON 0m r- - -- - oc oo - C Cl _d(zHD)"I(O)D-l(ZHD>- \co \no G - r- o NONOrN -n M - ,- r- - kn M - - - MlC Cl v 00 C l M C OND ol ' IT r- CD~ m o 00- ' C) 00 \.O00O OON 0\0 rq 'n -0 -,- r - l Cl 0 Vn 00 r-- Ln ON ClmN n O 0 d(Z' c,4 I r- 1=1 M 1 0 I c NO) n O00 r- - - - r - - oo - C Ml 1rN a, ~ O O - 0 mO r V 1 00 - "; r, r, r- 00 0000CNON CO CN C - - ,- ,- - -- - -- -- - -Cll 00 l 00l0 kn 00 Cl~~c cOl-N00 C: 00 N' - N 00 0 0 ON 't ON 00 1-r- m c ~o 0 - ,I - N C Lf 00- i w> 0 00 00 ONO ONONOOC 0 -.- ~~~c - - - - - Cl C O 00tl000~~Cl00~~7l -~->0 ~ O 0.-~t O C ~00. 1 Cfl~fN N 000O O O O 0 190 WO 2007/146712 PCT/US2007/070547 [00353] In some embodiments, the compound of Formula IV at a concentration of 10 pM inhibits induced TNFa-release from a cell by about 50% or greater than 50%. [00354] Also provided are compounds useful in the invention comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with a target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with a target protein; a tinker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety (L), wherein the anchoring moiety is capable of forming at least one hydrogen bond interaction with an ATP-binding pocket of the target protein, wherein the compound is optionally a cytokine inhibitor. [00355] In this aspect of the invention, compounds have the structure PEM-TM OM-L-AM. At a concentration of 10 pM, such compounds typically inhibit induced TNFa-release from a cell by about 50% or greater than 50%. [00356] The targeting moiety can hydrogen bond to residues at the binding site of the target protein. Typically the targeting moiety is an amide group. [00357] The pocket-expanding moiety is of sufficient size to force a conformational change in the target protein, resulting in an expanded binding pocket therein. Such moieties include 6 membered aryl and heteroaryl groups, for example, phenyl, pyridyl, or the like, substituted by bulky moieties. Bulky moieties fill a large volume of space in comparison to, for example, a methyl group, and include groups such 191 WO 2007/146712 PCT/US2007/070547 as substituted or unsubstituted C2A alkyl groups, for example substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec-butyl groups; substituted or unsubsituted C 3 9 cycloalkyl groups, for example substituted or unsubstituted cyclohexyl or norbornyl groups; or substituted or unsubstituted heterocyclyl groups, such as substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidyl, 8-oxa-3-aza-bicyclo[3.2.1 joctan-3-yl, oxazepanyl, thiazolyl, or thiomorpholinyl groups. [00358] The orienting moiety, by binding to a hydrophobic pocket on the target protein, provides the proper orientation of the targeting moiety and pocket-expanding moiety for binding of the compound to its target protein. Such moieties include, for example, phenyl, pyridyl or pyridazinyl, substituted by small hydrophobic moieties, exemplified by halogens, methyl, trifluoromethyl, and the like. [00359] Typically, the linker moiety, L, comprises an oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl group. [00360] In some embodiments, the anchoring moiety is a hydrogen bond acceptor. In other embodiments, the anchoring bond moiety comprises both a hydrogen bond donor and acceptor. For example, the anchoring moiety may comprise a substituted or unsubstituted amide, hydrazide or urethane group, and may further comprise a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group, such as substituted or unsub stituted phenyl, 2-pyridyl, 3 -pyridyl, 4-pyridyl, tetrahydropyranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, ethyl, n-propyl, isopropyl, n-butyt, sec-butyl, tert-butyl, isobutyl, or neopentyl group. [00361] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure. For example, the entire contents of each of the following priority documents are in corporated by reference in their entirety: U.S. Provisional Application No. 60/812,268, filed June 9 2006, U.S. Provisional Application No. 60/833,078, filed July 24, 2006, and U.S. Provisional Application No. 60/835,270, filed August 3, 2006. 192 WO 2007/146712 PCT/US2007/070547 [00362] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention. EXAMPLES Example 1: Inhibition of TNFa production in THP cells [00363] The inhibition of cytokine production can be observed by measuring inhibition of TNFa in lipopolysaccharide-stimulated THP-l cells (see Prichett et al. J. Inflammation, 1995, 45, 97). THP-1 cells (ATCC TIB 202, American Type Culture Collection, Rockville, MD) were maintained at 37"C, 5% CO 2 in RPMI 1640 media with 10% fetal bovine serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g/l glucose and 0.05 mM 2-mercaptoethanol as suggested by ATCC. For the assay, the cells and compounds were diluted in the media above except with 1% fetal bovine serum (assay media). Test compound stocks in DMSO were diluted into assay media to 6x the final assay concentration, with a final DMSO concentration of less than 0.3% in the assay. THP-1 cells were plated at 1x10 5 /well in 96 well tissue culture plates. Diluted compounds (or DMSO control) were added and allowed to preincubate with the cells at 37"C, 5% CO 2 for 30 minutes prior to the addition of LPS (Sigma) to a final concentration of 1 tg/ml. Cells were then incubated 18-20 hours at 37'C/5% CO 2 . The assay was terminated by centrifuging the plates for 10 min at room temperature. Supernatants were removed to clean culture plates and aliquots were removed for analysis for TNFa by a commercially available ELISA kit (R&D Systems #DY210, Minneapolis, MN). Data was analyzed by non-linear regression using PRISM 4 software from Graphpad Software (San Diego, CA). The calculated ICso is the concentration of the test compound that caused a 50% decrease in the maximal TNFa production. [00364] Each of the compounds in List 1 was tested in the TNFa ELISA assay and was found to have activity therein, with most compounds having IC 5 os below 10 PM in this assay. Example 2: Inflammation models [00365] Methods for the testing of systemic lupus erythematosus (SLE) in susceptible mice are known in the art (Knight et al., J. Exp. Med., 1978, 147, 1653; Reinersten et al., New Eng. J. Med., 1978, 299, 515). Myasthenia Gravis (MG) is tested 193 WO 2007/146712 PCT/US2007/070547 in SJL/J female mice by inducing the disease with soluble AchR protein from another species (Lindstrom et al., Adv. Immunol., 1988, 42, 233). Arthritis is induced in a susceptible strain of mice by injection of Type II collagen (Stuart et al., Ann. Rev. Immunol., 1984, 42, 233). A model by which adjuvant arthritis is induced in susceptible rats by injection of mycobacterial heat shock protein has been described (Van Eden et al., Nature, 1988, 331, 171). Thyroiditis is induced in mice by administration of thyroglobulin as described (Maron et al., J. Exp. Med., 1980, 152, 1115). Insulin dependent diabetes mellitus (IDDM) occurs naturally or can be induced in certain strains of mice such as those described by Kanasawa et al., Diabetologia, 1984, 27, 113. EAE in mouse and rat serves as a model for MS in human. In this model, the demyelinating disease is induced by administration of myelin basic protein (see Paterson, Textbook of Immuopathology, Mischer et al., eds., Grune and Stratton, New York, 1986, pp. 179-213; McFarlin et al., Science, 1973, 179, 478: and Satoh et al., J. Immunol., 1987, 138, 179). Examples are described in more detail below. [00366] Collagen Induced Arthritis model in mice. Immunization of for example, DBA/l mice with murine type II collagen induces a chronic relapsing polyarthritis that provides a strong model for human autoimmune arthritis. The model is described, for example, by Courtenay et al., Nature, 1980, 282, 666; Kato et al., Ann. Rheum. Dis., 1996, 55, 535; and Myers et al., Life Sci., 1997, 61,1861-1878, each of which is incorporated herein by reference. Briefly, mice are quarantined for at least three days. On day 0, the mice are weighed and separated into treatment groups. The non diseased control group animals receive no adjuvant (10 mice), in contrast to diseased mice (20 mice/treatment group). The mice are anesthetized, shaved at the base of tail, and injected (id) with adjuvant (50 pl/mouse; 100 pg/mouse collagen; 100pg/mouse M. tuberculosis H37Ra), using a 1 ml syringe fitted with a 26 G needle. On day 21, the adjuvant is prepared by emulsifying (in an homogenizer) a 1:1 combination of collagen and M. tuberculosis H37Ra. The adjuvant is injected (id) (50 pl/mouse; 100 pg/mouse collagen; 10Opg/mouse M. tuberculosis H37Ra) using 1 ml syringe fitted with a 26 G needle. On days 22-27 the macroscopic signs of arthritis are scored daily. Each paw receives a score: 0 = no visible effects of arthritis; 1 = edema and/or erythema of one digit; 2 = edema and/or erythema of two joints; 3 = edema and/or erythema of more than two joints; or 4 = severe arthritis of the entire paw and digits. The Arthritic Index is calculated by addition of all the individual paw scores, and recorded (maximum arthritic 194 WO 2007/146712 PCT/US2007/070547 index = 16). On day 28 the mouse weights are recorded and the macroscopic signs of arthritis are scored. The mice are sorted into treatment groups (10 mice/group) based upon their arthritic index. Each treatment group is designed to have a similar average Arthritic Index and a similar range of arthritic indices. The dosing regimen by oral route is initiated. On day 29-42 the mice are dosed and any adverse effects of test agent administration are recorded. The macroscopic signs of arthritis for each paw are scored daily. On day 43 the macroscopic signs of arthritis are scored, the mice are exsanguinated and their blood is collected in heparinized tubes. The hindlimbs and/or forelimbs are removed and immersed in four volumes of 10% buffered formalin. The paws are evaluated for decalcification and histology. Livers are removed and their weights are recorded. [00367] Collagen Induced Arthritis model in rats. Female Lewis rats, (Charles River ref #7218419), weighing 125-150 g on arrival (8/group for arthritis, 4/group for normal control), are housed 4/cage, and are acclimated for 4-8 days after arrival. Acclimated animals are anesthetized with Isoflurane and given collagen injections (DO). On day 6 they are anesthetized again for the second collagen injection. Collagen is prepared by making a 4 mg/ml solution in 0.01 N acetic acid. Equal volumes of collagen and Freund's incomplete adjuvant are emulsified by hand mixing until a bead of this material holds its form when placed in water. Each animal receives 300 1ti of the mixture each time spread over 3 subcutaneous sites on its back. Caliper measurements of normal (pre-disease) right and left ankle joints are collected on day 9. On days 10-11, the onset of arthritis occurs and the rats are randomized into treatment groups. Animals to be given vehicle or compound doses are enrolled and qd (24 hr. intervals) dosing is initiated for days 1-6 using a volume of 5 ml/kg for oral solutions. The rats are weighed on days 1-7 of arthritis; caliper measurements of ankles are taken every day. The final body weights are collected on day 7 of arthritis. On day 7, the animals are anesthetized for whole blood draw to exsanguinate (serum can be used for clinical chemistry) and then euthanized. Both hind paws and knees are removed, the hind paws are weighed and then (with knees) placed in formalin and processed for microscopy. Following 1-2 days in fixative and 4-5 days in decalcifier, the ankle joints are cut in half longitudinally, the knees are cut in half in the frontal plane, processed, embedded, sectioned and stained with toluidine blue. The arthritic ankles and knees are given scores of 0 (normal) -5 (severe effects) for 195 WO 2007/146712 PCT/US2007/070547 inflammation, pannus formation and bone resorption. Percent inhibition of paw weight and AUC is calculated using the following formula: % Inhibition= A - B/A x 100 with A = (Mean Disease Control - Mean Normal) and B = (Mean Treated - Mean Normal). [00368] Figure 1 shows the effects of a compound as described herein on the ankle diameter in collagen induced arthritis in rats upon once daily administration of the compound for 7 days. [00369] Inflammatory Bowel and Crohn's Disease Models. To evaluate the effectiveness of test compounds in Crohn's disease, the TNFAARE transgenic mouse model of Crohn's disease (originally described by Kontoyiannis et al., Immunity, 1999, 10, 387) is used (the DSS model can also be used in a similar fashion). The animals develop an IBD phenotype with similarity to Crohn's disease starting between 4 and 8 weeks of age. Test compounds are administered at either 3 weeks of age (to test prevention of disease) or 6 weeks of age (to test stabilization, prevention of progression or reversal of disease symptoms), and animals are scored by weight and histologically as described herein. Test compositions are administered either weekly or twice weekly, or can be administered continuously, for example, using an osmotic pump. Alternatively, oral delivery formulations can also be applied. The studies are continued for up to 7 weeks or more once initiated. Animals can be monitored for bowel disease according to a standard scale as described in Kontoyiannis et al., 2002, supra. Paraffin-embedded intestinal tissue sections of ileum are histologically evaluated in a blinded fashion according to the following scale: Acute and chronic inflammation are assessed separately in a minimum of 8 high power fields (hpf) as follows --acute inflammatory score: 0=(0-1) polymorphonuclear (PMN) cells per hpf (PMN/hpf); 1=(2-10) PMN/hpf within mucosa; 2=(1 1-20) PMN/hpf within mucosa; 3=(21-30) PMN/hpf within mucosa or (11-20) PMN/hpf with extension below muscularis mucosae; and 4=>30 PMN/hpf within mucosa or >20 PMN/hpf with extension below muscularis mucosac. Chronic inflammatory score: 0=(0-10) mononuclear leukocytes (ML) per hpf (MLihpf) within mucosa; I1(1-20) ML/hpf within mucosa; 2=(21-30) ML/hpf within mucosa or (11-20) ML/hpf with extension below muscularis mucosae; 3=(31-40) ML/hpf within mucosa or (21-30) ML/hpf with extension below muscularis mucosae or follicular hyperplasia; and 4=>40 196 WO 2007/146712 PCT/US2007/070547 ML/hpf within mucosa or >30 ML/hpf with extension below muscularis mucosae or follicular hyperplasia. Total disease score per mouse is calculated by summation of the acute inflammatory or chronic inflammatory scores for each mouse. [00370] Efficacy in the TNFAAE model of Crohn's disease is shown by any of: i) a failure to develop disease symptoms when administered to animals beginning at 3 weeks of age; ii) lessened severity of disease symptoms appearing when administered starting at 3 weeks of age, relative to control animals; iii) failure to progress to more severe disease or progression at a lower rate relative to control animals when administered beginning at 6 weeks of age; iv) reversal of symptoms at any of 7, 8, 9, 10, 11, 12, or 14 weeks when administered to an animal beginning at 6 weeks of age. In particular, treatment is considered effective if the average histopathological disease score is lower in treated animals (by a statistically significant amount) than that of a vehicle control group. Treatment is also considered effective if the average histopathological score is lower by at least 0.5 units, at least 1.0 units, at least 1.5 units, at least 2.0 units, at least 2.5 units, at least 3.0 units, or by at least 3.5 units relative to the vehicle-only control group. Alternatively, the treatment is effective if the average histopatholigical score remains at or is lowered to 0 to 0.5 throughout the course of the therapeutic regimen. [00371] Other models of IBD include, for example, the DSS (dextran sodium sulfate) model of chronic colitis in BALB/c mice. The DSS model was originally described by Okayasu et al., Gastroenterology, 1990, 98, 694 and was modified by Kojouharoff et al., Clin Exp. Immunol. 1997, 107, 353 (see also WO 2004/041862, incorporated herein by reference). BALB/c mice weighing 21-22 g are treated to induce chronic colitis by the administration of DSS in their drinking water at 5% w/v in cycles of 7 days of treatment and 12 days recovery interval without DSS. The 4h recovery period can be extended from 12 to 21 days to represent a chronic inflammation status, rather than the acute status modeled by shorter recovery. After the last recovery period, treatment with a compound of the invention is initiated. Weekly administration is recommended initially, but can be adjusted by one of skill in the art as necessary. At intervals during treatment, animals are killed, the intestine is dissected and histopathological scores are assessed as described herein or as described in Kojouharoff et al., 1997, supra. Other animal models of inflammatory bowel disease include the chronic intestinal inflammation induced by rectal instillation of 2,4,6-Trinitrobenzene sulfonic acid (TNBS; method 197 WO 2007/146712 PCT/US2007/070547 described by Neurath et al., J. Exp. Med., 1995, 182, 1281; see also U.S. Patent No. 6,764,838, incorporated herein by reference). Histopathological scoring can be performed using the same standard described above. Example 3: Clinical Inflammatory Disease Assessments [003721 Ex-vivo LPS challenge endotoxemia model. Ex-vivo treatment of blood from patients treated with anti-inflammatory compounds with endotoxin represents a safe, well-defined model of acute inflammation in humans. It is also an excellent tool to study the mechanisms contributing to inflammatory responses in man in vivo. Given the importance of the balance of inflammatory and anti-inflammatory cytokines and other factors in the etiology of inflammatory diseases such as rheumatoid arthritis and Crohn's disease, evaluation of cytokine inhibitors in a human LPS model could prove beneficial in elucidating potential effects of anti-inflammatory compounds in human inflammatory processes. [00373] Compounds described herein are administered orally at different doses to human volunteers. After 1 to 24 hours, blood samples are collected via venepuncture into vacutainer tubes and heparinized. Prior to the stimulation assay, a monocyte count is performed for each individual's undiluted heparinized whole blood sample (Cell Dyn 3500 SL). For this purpose a small volume (100-200 pl) is aspirated directly form the whole blood sample into the analyzer. For each sample, for each subject the following stimulation assays are performed: a. Unstimulated control (only vehicle) and b. Stimulated: 10 ng/ml LPS (final concentration). The stimulation assays are performed within one hour after withdrawal of the whole blood samples. The stimulation assay procedure is as follows. 1. Dilute the whole blood sample 1 + 1 with RPMI- 1640 medium; mix gently by inversion. 2. Pipette the diluted whole blood into each of the two separate sterile tubes (one for each condition). 3. Add to each tube 200 pl of the appropriate LPS stock (or blank) to yield the above-listed final LPS concentrations. Mix gently by inversion. 4. From each tube, add gently 0.5 ml per well into multiple (e.g., eight) master block wells. 198 WO 2007/146712 PCT/US2007/070547 5. Any empty wells should be filled with 0.5 ml of PBS buffer. 6. Cover the master blocks with their specific covers. 7. Incubate for 24 hours at 37 0 C and 5% Co 2 . 8. At the end of the incubation period, centrifuge the blocks at 1000 x g for 10 minutes at room temperature. 9. Collect the supernatants and pool the appropriate wells into their appropriate polypropylene tubes (expected yield at 1+1 whole blood dilution: 40-60% of volume). 10. Mix and aliquot into separate tubes; one for each cytokine to be analyzed (target supernatant volume per aliquot: 0.5 ml). 11. Store samples at -70'C until analysis. [00374] TNF-a, IL-1, IL-6 or other cytokines are analyzed using validated ELISA methods. [00375] Individual and mean group effects on the IL-iB response of lymphocytes to ex vivo LPS challenge after oral dosing of a compound as described herein is shown in Figure 2. The effects are expressed as the response after treatment versus pretreatment for each dose group, reflecting the inhibition of cytokines in the circulating leukocytes after oral dosing with a compound as described herein. (* Statistically significant effect (p <0.01)). [00376] Rheumatoid Arhritis disease assessment. Rheumatoid arthritis is clinically scored on the basis of several clinically accepted scales, such as those described in U.S. Patent No. 5,698,195, which is incorporated herein by reference, and Aletaha et al., Clin. Exp. Rheumatol.2005, 23 (suppl. 39), S 100. Disease activity and change effected with treatment can be evaluated using the disease activity score (DAS) and/or the chronic arthritis systemic index (CASI), see Carotti et al., 2002, Ann. Rheum. Dis. 61:877-882, and Salaffi et al., 2000, Rheumatology 39: 90-96. Briefly, clinical response studies can assess the following parameters: A. Number of tender joints ; B. Number of swollen joints (Both tenderness and swelling are evaluated for each joint separately); and C. Visual analog pain scale (0-10 cm). Clinical response is assessed using a subjective reporting system as follows: Without any difficulty, With some difficulty, With much difficulty, or Unable to do. . The visual analog scale for pain is a straight line with the 199 WO 2007/146712 PCT/US2007/070547 left end of the line representing no pain and the right end of the line representing the worst pain. Patients are asked to mark on the line where they think their pain is. [00377] Additionally, blood chemistry analysis determines levels of CRP, Rheumatoid Factor, cytokines and other biomarkers. [00378] Crohn's Disease assessment: Crohn's Disease Activity Index. The CDAI is a patient assessment form incorporating both objective and subjective information. Using established criteria the physician calculates the CDAI score. CDAI scores > 150 indicate active disease with a poorer prognosis than scores < 150. (See Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's disease activity index., National Cooperative Crohn's Disease Study. Gastroenterology 1976; 70: 439 444; Winship DH, Summers RW, Singleton JW, et al. National Cooperative Crohn's Disease Study: study design and conduct of the study. Gastroenterology 1979; 77: 829 842). [00379] Psoriasis disease assessment. Efficacy of psoriasis treatment can be monitored by changes in clinical signs and symptoms of the disease, including Psoriasis Area and Severity Index, (PASI) scores, physician's global assessment (PGA) of the patient compared with the baseline condition. A decrease in PASI score indicates a therapeutic effect. Psoriatic disease activity can also be determined based on Overall Lesion Severity (OLS) scale, percentage of total body surface area (BSA) affected by psoriasis, and psoriasis plaque thickness. Skin biopsies are studied for the effects of the drug on lymphocytes within psoriatic lesions. Histological analysis of skin biopsies can be performed to look for reduction in epidermal thickness and T-cell infiltration and reversal of pathological epidermal hyperplasia. Immunological activity can be monitored by testing for the effects of treatment on cell-mediated immunity reactions (delayed hypersensitivity), tetanus antibody responses, and lymphocyte subpopulations (flow cytometry). Example 4: Cardiovascular and metabolic disease models [00380] Lipid determinations. The anti-atherosclerotic activity of compounds may be demonstrated by determining the amount of agent required to alter plasma lipid levels, for example HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain animals, for example marnosets (Crook et 200 WO 2007/146712 PCT/US2007/070547 al. Arteriosclerosis 10, 625, 1990) or Golden Syrian Hamsters (Goulinet et al., J. Lipid Res., 34, 943, 1993), and others, that possess a plasma lipoprotein profile similar to that of humans. [00381] Blood chemistry evaluation in Marmosets. Adult marmosets are assigned to treatment groups so that each group has a similar mean.+/-SD for total, HDL, and/or LDL plasma cholesterol concentrations. After group assignment, the marmosets are dosed daily with compound as a dietary admix or by intragastric intubation for from one to eight days. Control marmosets receive only the dosing vehicle. Plasma total, LDL VLDL and HDL cholesterol values may be determined at any point during the study by obtaining blood from an antecubital vein and separating plasma lipoproteins into their individual subclasses by density gradient centrifugation, and by measuring cholesterol concentration as previously described (Crook et al. Arteriosclerosis 10, 625, 1990). [00382] Blood chemistry evaluation in cynomolgous monkeys. Sixteen male and 16 female cynomolgous monkeys are assigned to four dose groups. A compound is formulated in a suitable vehicle at low, medium, and high concentrations. The three dosages of the compound and vehicle alone are administered once daily by oral gavage for 90 consecutive days to all male and female monkeys in the corresponding dose group. Blood samples (4 to 6 ml) are collected from the femoral vessel at days 0, 28, and 90. The blood samples are processed for serum, and clinical chemistry values, including, for example, HDL cholesterol, triglyceride and total bilirubin levels, which are determined by standard methods. [00383] Figure 3 shows the effects of a compound as described herein on the HDL cholesterol levels of cynomolgus monkeys, upon once daily administration of the compound for 90 days. [00384] Figure 4 shows the effects of a compound as described herein on the triglyceride levels of cynomolgus monkeys, upon once daily administration of the compound for 90 days. [00385] Blood chemistry evaluation in Wistar rats. Eighty male and 80 female Wistar rats are assigned to four dose groups. A compound is formulated in a suitable vehicle at low, medium, and high concentrations. The three dosages of the compound 201 WO 2007/146712 PCT/US2007/070547 and vehicle alone are administered once daily by oral gavage for 90 consecutive days to all male and female rats in the corresponding dose group. Blood samples (2 to 3 ml) are collected via the orbital sinus at days 0, 28, and 90. The blood samples are processed for serum, and clinical chemistry values, including, for example, HDL cholesterol levels, which are determined by standard methods. [00386] Figure 5 shows the effects of a compound as described herein on the HDL cholesterol levels of Wistar rats, upon once daily administration of the compound for 90 days. [00387] Blood chemistry evaluation in Golden Syrian Hamsters. Female Golden Syrian Hamsters (6-8 weeks old) were quarantined for 72 hours and then assigned to treatment groups. A sample bleed was taken by retro-orbital bleed on day 0,prior to dosing, and processed to 1 ml serum in pre-chilled EDTA-treated tubes. Each serum sample was aliquoted to 0.5 ml and 0.3 ml volumes and stored at -20'C until shipment. Subsequently the test compound or vehicle was administered orally (typically 5 ml/kg, for a dose of 30 mg/kg). Once daily dosing at those doses was continued on days 1-13. On day 2, day 6 or 13, terminal bleeds were taken several hours after the final oral dose, and the sera were processed, aliquoted and stored as before. Lipid analysis and clinical chemistry panel analysis was performed on all bloodsamples. [00388] Figures 6A and 6B show the effects of a compound as described herein on the particle size distribution and on HDL 2 and HDL 3 levels of Syrian Golden Hamsters, upon once daily administration of the compound for 14 days (as determined by NMR and ultracentrifugation methods respectively). [00389] Rabbit Atherosclerosis Assay. Anti-atherosclerotic effects of the compounds may be determined by the amount of compound required to reduce the lipid deposition in rabbit aorta. Male New Zealand White rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (meal-fed once per day). Rabbits are bled from the marginal ear vein and total plasma cholesterol values are determined from these samples. The rabbits are then assigned to treatment groups so that each group has a similar mean.+/-SD for total plasma cholesterol concentration, HDL cholesterol concentration, triglyceride concentration and/or cholesteryl ester transfer protein activity. After group assignment, rabbits are dosed daily with compound given as a dietary admix 202 WO 2007/146712 PCT/US2007/070547 or on a small piece of gelatin based confection. Control rabbits receive only the dosing vehicle, be it the food or the gelatin confection. The cholesterol/coconut oil diet is continued along with the compound administration throughout the study. Plasma cholesterol values may be determined at any point during the study by obtaining blood from the marginal ear vein. After 3-5 months, the rabbits are sacrificed and the aortae are removed from the thoracic arch to the branch of the iliac arteries. The aortae are cleaned of adventitia, opened longitudinally and then analyzed unstained or stained with Sudan IV as described by Holman et. al. (Lab. Invest. 1958, 7, 42-47). The percent of the lesioned surface area is quantitated by densitometry using an Optimas Image Analyzing System (Image Processing Systems). Reduced lipid deposition is indicated by a reduction in the percent of lesioned surface area in the compound-receiving group in comparison with the control rabbits. [00390] Cuff induced accelerated atherosclerosis. The compounds are tested in a mouse model for restenosis and accelerated atherosclerosis based on cuff placement around the femoral artery in ApoE3 Leiden mice (Lardenoye et al. Circ Res. 2000, 87(3):248-53). The model is highly regulated by inflammatory factors (Pires et al. Cardiovase Res, 68 (2005) 415 - 424) including TNFa (Monraats et al. FASEB J 2005;19:1998-2004) and MCP-1, as has been demonstrated by Egashira et al (Circ Res 2002; 90: 1167-72). Cuff placement in ApoE3 Leiden mice receiving a mild hypercholesterolemic diet results in a rapid adhesion and infiltration of monocytes, followed by a rapid induction of neointima formation, and in the induction in foam cell accumulation within the cuffed vessel segment. [00391] Briefly, male ApoE3 Leiden mice (age 12 weeks) are fed a mildly hypercholesterolemic diet for 3 weeks prior to surgical cuff placement. After 3 weeks mice are divided in 3 groups, matched for plasma cholesterol levels. The mice either receive daily (from day- 1 on) a control gavage solution or a gavage solution containing test compound (typically at a concentration of 30 mg/kg). On day 0 surgery is performed, i.e. a non-constricting cuff (2-3 mm in length) is placed around both the femoral arteries of the mice. Mice are sacrificed after 2 days for analysis of monocyte adhesion and infiltration, and additional mice are sacrificed after 2 weeks for histomorphometric analysis to quantify the (inhibition of) accelerated atherosclerotic lesions and neointima formation. 203 WO 2007/146712 PCT/US2007/070547 [00392] Figure 7 shows the quantification of the accelerated atherosclerosis in the vessel wall, based on the quantification of the staining of the cross sections at the 14 day time point, using the monocyte/macrophage marker AIA31240. Theis area was expressed as total area of AIA31240 positive area (upper panel) as wel as the percentage of the total area showing AIA31240 positivity (lower panel). Example 5: Clinical Cardiovascular and Metabolic Disease Assessments [00393] Anti-obesity assay. The ability of compounds to cause weight loss may be assessed in obese human subjects with body mass index (BMI) 20 kg/m 2 . Doses of inhibitor are administered sufficient to result in an increase of > 5% in HDL cholesterol levels. BMI and body fat distribution, defined as waist (W) to hip (H) ratio (WHR), are monitored during the course of the 3-6 month studies, and the results for treatment groups compared to those receiving placebo. [00394] Diagnostic methods for glucose and insulin disorders. Glucose tolerance testing (GTT). During a glucose tolerance test, which may be used to diagnose diabetes mellitus, a fasted subject takes a 75 gram oral dose of glucose. Blood glucose levels are then measured over the following 2 hours. Interpretation is based on WHO guidelines, but glycemia greater than or equal to 11.1mmol/l at 2 hours or greater than or equal to 7.0mmol/L fasting is diagnostic for diabetes mellitus. OGTT can be normal or mildly abnormal in simple insulin resistance. Often, there are raised glucose levels in the early measurements, reflecting the loss of a postprandial (after the meal) peak in insulin production. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip", which is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response. [00395] Hyperinsulinemic euglycemic clamp. The standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so called because it measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. The procedure takes about 2 hours. Through a peripheral vein, insulin is infused at 10-120 mU per m 2 per minute. In order to compensate for the insulin infusion, glucose 20% is infused to maintain blood sugar levels between 5 and 5.5 mmol/l. The rate of glucose infusion is determined by checking the blood sugar levels every 5-10 minutes. Low dose insulin infusions are more useful for assessing the response of the liver whereas high dose insulin infusions are useful for 204 WO 2007/146712 PCT/US2007/070547 assessing peripheral (i.e. muscle and fat) insulin action. The rate of glucose infusion during the last 30 minutes of the test determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the subject is insulin-sensitive. Very low levels (4.0 mg/min or lower) indicate that the body is resistant to insulin action. Levels between 4.0 and 7.5 mg/min are not definitive and suggest "impaired glucose tolerance," an early sign of insulin resistance. [00396] Given the complicated nature of the "clamp" technique (and the potential dangers of hypoglycemia in some subjects), alternatives have been sought to simplify the measurement of insulin resistance. The first was the Homeostatic Model Assessment (HOMA) [ Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9], and a more recent method is QUICKI (quantitative insulin sensitivity check index). Both employ fasting insulin and glucose levels to calculate insulin resistance, and both correlate reasonably with the results of clamping studies. [00397] Using a fasting blood sample, insulin resistance is quantified using the following formula: IR= Glucose (mg/dl)) x Insulin (pU/ml) / 405 [00398] In this equation, one should use the constant 22.5 instead of 405 if the glucose is reported in mmol/l. This model correlates well with estimates using the euglycemic clamp method. [00399] HOMA IR values between 1.7 and 2.5 are seen in subjects with normal glucose tolerance [Tripathy D, Carlsson M, Almgren P, Isomaa Bo, Taskinen MR, Tuomi T, Groop LC: Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study. Diabetes 49:975-980, 2000; Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M: Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes 47:1643-1649, 1998; Juan F. Ascaso, MD, Susana Pardo, MD, Jose T. Real, MD, Rosario . Lorente, MD, Antonia Priego, MD and Rafael Carmena, MD Diagnosing Insulin Resistance by Simple Quantitative Methods in Subjects With Normal Glucose Metabolism, Diabetes Care 26: 3320-3325, 2003]. 205 WO 2007/146712 PCT/US2007/070547 Example 6: Analysis of biomarkers in clinical samples. [00400] Patients with low HDL-C and elevated TG levels, with or without concomitant lipid-lowering therapy (e.g., statins, bile acid sequestrants, or cholesterol absorption inhibitors), are treated with a compound as described herein, administered orally once daily for 6 weeks. A fasting lipid panel (total cholesterol, HDL-C, LDL-C, TG), CRP and general laboratory parameters (CBC, general chemistry panel) are assessed at baseline, every two weeks during dosing and 4 weeks after the end of dosing. At Week 1, patients have a general chemistry panel assessed. Weight, and waist and hip circumference are assessed at each visit, other than Week 1. Lipid/metabolic, inflammatory, and prothrombotic biomarkers are assessed at Baseline, Week 2, Week 4, Week 6 and Follow-up. Urinalysis and coagulation parameters are assessed at baseline and at the end of dosing. [00401] Figure 8 shows the effects of a compound as described herein on the mean CRP-levels of human subjects with starting CRP levels > 0.3 mg/dl, upon once daily administration of the compound for 6 weeks, compared with placebo. (* p < 0.05 versus baseline (paired t-test)). [00402] Figure 9 shows the effects of a compound as described herein on the mean HDL levels of human subjects, upon once daily administration of the compound for 6 weeks. [00403] Figure 10 shows the effects of a compound as described herein on the mean HDL levels of human subjects, upon once daily administration of the compound in combination with statins for 6 weeks (p-values derived from Wilcoxon Rank-Sum test). [00404] Figure 11 shows the effects of a compound as described herein on the mean HDL particle size of human subjects, upon once daily administration of the compound for 6 weeks. (Particle size determined using NMR; p-values based on Wilcoxon Rank-Sum test). [00405] Figure 12 shows the effects of a compound as described herein on the mean ApoAl levels of human subjects, upon once daily administration of the compound for 6 weeks. 206 WO 2007/146712 PCT/US2007/070547 [00406] Figure 13 shows the effects of a compound as described herein on the mean indirect bilurubin levels of human subjects, upon once daily administration of the compound for 6 weeks. [00407] Figure 14 shows the effects of a compound as described herein on the mean PAI-1 levels of human subjects, upon once daily administration of the compound for 6 weeks. [00408] Figure 15 shows the effects of a compound as described herein on the diastolic and systolic blood pressure of human subjects, upon once daily administration of the compound for 6 weeks (Horizontal line denotes mean, p-values based on Wilcoxon Rank-Sum test). [00409] Figure 16 shows the effects of a compound as described herein on the mean VEGF levels of human subjects, upon once daily administration of the compound for 6 weeks (mean individual absolute change from Baseline to Week 6). Example 7: Cancer models [00410] Proliferation assay. Human non-small cell lung carcinoma cells A549 (ATCC# CCL-185), are grown at 37'C +/- 0.5'C and 5% CO 2 in DMEM supplemented with 10% FBS, 2 mM glutamine, 1% penicillin, and 1% streptomycin. Anti-proliferation assays are performed in 384-well plates. 6.6 piL of 1Ox stock compound solutions is added to 40 piL of culture media in assay wells. The tumor cells are liberated from the culture flask using a solution of 0.25% trypsin. Cells are diluted in culture media such that 3000 or 6000 cells are delivered in 20 pL of media into each assay well. Assay plates are incubated for 72-80 hours at 37'C +/-0.5'C with 5% CO 2 . Twenty microliters of 20% Alamar Blue warmed to 37'C +/- 0.5'C is added to each assay well following the incubation period. Alamar Blue metabolism is quantified by the amount of fluorescence intensity 3.5-5.0 hours after addition. Quantification, using an LJL Analyst AD reader (LJL Biosystems), is taken in the middle of the well with high attenuation, a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 575 nm. For some experiments, quantification is performed using a Wallac Victor 2 reader. Measurements are taken at the top of the well with stabilized energy lamp control; a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 590 nm. No significant differences between plate readers are measured. 207 WO 2007/146712 PCT/US2007/070547 [00411] The percent inhibition (% I) for each well is calculated using the following formula: % I=[(avg. untreated wells-treated well)/(avg. untreated wells)] x 100 [00412] The average untreated well value (avg. untreated wells) is the arithmetic mean of 40 wells from the same assay plate treated with vehicle alone. Negative inhibition values result from local variations in treated wells as compared to untreated wells. [00413] The anti-cancer effect that can be demonstrated with the tumor cell lines refered to herein can be similarly demonstrated using other cancer cell lines, such as, for example, NSC lung carcinoma, MCF7 mammary adenocarcinoma, PA-1 ovarian teratocarcinoma, HT29 colorectal adenocarcinoma, H1299 large cell carcinoma, U-2 OS osteogenic sarcoma, U-373 MG glioblastoma, U-118 MG glioblastoma, U-138 MG glioblastoma, LN-229 glioma, Hep-3B hepatocellular carcinoma, BT-549 mammary carcinoma, T-24 bladder cancer, C-33A cervical carcinoma, HT-3 metastatic cervical carcinoma, SiHa squamous cervical carcinoma, CaSki epidermoid cervical carcinoma, NCI-H292 mucoepidermoid lung carcinoma, NCI-2030, non small cell lung carcinoma, HeLa, epithelial cervical adenocarcinoma, KB epithelial mouth carcinoma, HT1 080 epithelial fibrosarcoma, Saos-2 epithelial osteogenic sarcoma, PC3 epithelial prostate adenocarcinoma, SW480 colorectal carcinoma, CCL-228, MS-751 epidermoid cervical carcinoma, LOX IMVI melanoma, MALME-3M melanoma, M14 melanoma, SK-MEL-2 melanoma, SK-MEL-28 melanoma, SK-MEL-5 melanoma, UACC-257 melanoma, or UACC-62 melanoma cell lines. The specificity can be tested by using cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytes, and bone marrow cells as control cells. [00414] As will be recogonized by those of skill in the art, many more cancer cell lines, such as those available from American Type Culture Collection (ATCC) (P.O. Box 1549 Manassas, VA 20108, USA), can be used similarly. 208 WO 2007/146712 PCT/US2007/070547 [00415] The compounds of the invention can be assayed by one or more of the above methods and have or are expected to have activity in one or more of the above assays. [00416] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth. [00417] Compounds are named according to standard IUPAC nomenclature using the automatic naming application Autonom 2000 (MDL Information Systems, San Leandro, CA), or the automatic name generating tool provided in Chemdraw Ultra (CambridgeSoft, Cambrige, MA), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. [00418] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims. 209

Claims (48)

1. A method of treating a disorder mediated by one or more cytokines, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; b) Formula IB H X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; c) Formula IC G-Ring-Ar-L--Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II Ar-L-Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III G0 Ar LQ L N- A wherein variables G, L', L 2 , L', A, Ar, and Q are as defined in List X; 210 WO 2007/146712 PCT/US2007/070547 f) Formula IV O L 2 _Q GE' x~ Y A wherein variables G, X, Y, L', L 2 , A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a ir-7r or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and 211 WO 2007/146712 PCT/US2007/070547 an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i).

2. The method of claim 1, wherein the cytokine is selected from TNFa, IL- 1, IL-6, IL-8, GM-CSF, and IFN-gamma or a combination of any two or more thereof.

3. The method of claim 2, wherein the cytokine is TNFa or IL-1.

4. The method of claim 1, wherein the disorder is or results from abnormal bleeding, an abscess, actinic reticuloid syndrome, acute confusional migraine, acute confusional senile dementia, acute hepatocellular injury, acute tubular necrosis, adenohypophyseal diseases, adenovirus infections, adhesions, adhesive capsulitis, adnexitis, agammaglobulinemia, allergy, alopecia, fibrosing alveolitis, amyloidosis, angioplasty, angor pectoris, antiphospholipid syndrome, arteriosclerotic dementia, 212 WO 2007/146712 PCT/US2007/070547 arteritis temporal, arthropod-borne encephalitis, asphyxia, atopic hypersensitivity, atrial fibrillation, beaver fever, biliary cirrhosis, bone loss, bronchiolitis, cancer of endocrine gland, cancer of larynx, candidiasis, small cell lung carcinoma, cardiac hypertrophy, cardiac surgery, cardiomegaly, carditis, carotid angioplasty, carotid endarterectomy, carotid stents, carotid ulcer, celiac disease, cirrhosis, colitis, colitis granulomatous, coronary artery bypass graft, coronary artery bypass surgery, cortical cataracts, corticosteroid-resistant asthma, degenerative joint disease, dermatitis, diarrhea, erectile neuropathy, erectile vasculopathy, dry eye, dyslipidemia, dyspnea, edema, end-stage renal disease, epstein-barr virus infections, fever, follicular thyroid carcinoma, gastroenteritis, heart attack, heart bypass surgery, heart surgery, heart transplantation, hepatitis A, hepatitis B, hepatitis C, chronic hepatitis, insulin resistance, kidney failure, kidney transplantation, adult chronic leukemia, liver cirrhosis, liver transplantation, meningitis, bacterial meningitis, myeloproliferative disorders, myopathies, myositis, neonatal-onset multisystem inflammatory disease, nephritis, neuromuscular disorders, neuropathy, obliterative bronchiolitis, oral cancer, percutaneous coronary intervention, periodontal bone loss, peripheral nerve disorders, neuropathy, peritoneal dialysis, pleural disease, pneumonitis, polymyositis, posterior capsular opafication, pruritus, pulmonary fibrosis, renal cancer, renal dialysis, scleroderma, septic arthritis, Sjogren's syndrome, ankylosing spondylitis, Still's disease, sympathetic opthalmia, toxemia, tuberculosis, urticaria, viral hepatitis, or Wegener's granulomatosis.

5. A method comprising administering to a subject an amount of a compound effective to reduce a level of a cytokine relative to the level prior to administration of the compound, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; 213 WO 2007/146712 PCT/US2007/070547 b) Formula IB H X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; c) Formula IC G-Ring-Ar-L--Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II X' Ar-L--Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III G'- L Ar Q N A wherein variables G, L', L 2 , L', A, Ar, and Q are as defined in List X; f) Formula IV D LO L 2 -Q G E Y A wherein variables G, X, Y, L', L 2 , A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; 214 WO 2007/146712 PCT/US2007/070547 a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a 7r-7 or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least I hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; 215 WO 2007/146712 PCT/US2007/070547 a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least I hydrogen bond interaction with an ATP-binding pocket of the target protein; or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i).

6. The method of claim 5, wherein the cytokine is selected from TNFa, IL-1, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof.

7. The method of claim 5, wherein the cytokine is TNFa or IL-1.

8. The method of claim 5, wherein the cytokine level is measured in the subject's blood.

9. The method of claim 5, wherein the cytokine level is measured in the subject's synovium.

10. The method of claim 5, wherein the cytokine level is measured in the subject's skin.

11. A method comprising exposing a cell to an amount of a compound effective to reduce the level of cytokine released from the cell in response to a pro inflammatory stimulus relative to the level of released cytokine prior to contacting the cell with the compound, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; 216 WO 2007/146712 PCT/US2007/070547 b) Formula IB H X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; c) Formula IC G-Ring--Ar-L-Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II Gf / Ar-L--Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III G LAr Q N A wherein variables G, L', L2, L3, A, Ar, and Q are as defined in List X; f) Formula IV .-- D O L 2 -Q G E Y A wherein variables G, X, Y, L', L 2 , A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; 217 WO 2007/146712 PCT/US2007/070547 a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a n-n or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; 218 WO 2007/146712 PCT/US2007/070547 a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i).

12. The method of claim 11, wherein the pro-inflammatory stimulus results from the presence of TNFa, IL-1, IL-6, IL-8, GM-CSF, IFN-gamma, LPS, or a combination of any two or more thereof

13. The method of claim 11, wherein the cytokine level is the level of TNFa, IL-1, IL-6, IL-8, GM-CSF, IFN-gamma, or a combination of any two or more thereof.

14. A method comprising contacting p38 with an amount of a compound effective to inhibit p38 activity, the phosphorylation of p38, or both, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; b) Formula IB H X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; c) Formula IC G-Ring-Ar--L-Q 219 WO 2007/146712 PCT/US2007/070547 wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II X' G1 7 Ar-L-Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III G- LLAr-L< G 'Ar Q I L N A wherein variables G, L', L2, L', A, Ar, and Q are as defined in List X; f) Formula IV D L1 L2_-Q G E X / Y A wherein variables G, X, Y, L , L2, A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a n-n or edge-to-face aromatic interaction with the target protein; 220 WO 2007/146712 PCT/US2007/070547 h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; 221 WO 2007/146712 PCT/US2007/070547 or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i)..

15. The method of claim 14, wherein the p38 is in a subject.

16. A method comprising administering to a subject an amount of compound effective to reduce the circulating levels of C-Reactive Protein or Rheumatoid Factor, or both, in the subject's blood relative to the level prior to the administration of the compound, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; b) Formula IB H G N Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; c) Fonnula IC G-Ring-Ar-L-Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II GJ / Ar--L---Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; 222 WO 2007/146712 PCT/US2007/070547 e) Formula III G' 4 LAr LQ N A wherein variables G, L', L 2 , L', A, Ar, and Q are as defined in List X; f) Formula IV LO L 2 _Q G E X Y A 1 2 wherein variables G, X, Y, L , L , A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a a-n or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; 223 WO 2007/146712 PCT/US2007/070547 an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; or a stereoisomer, tautomer, solvate, prodrug, or phanaceutically acceptable salt any one or more of (a) - (i).

17. A method comprising administering to a subject an amount of a compound effective to increase the HDL-level of the subject relative to the level prior to the administration of the compound, wherein the compound is selected from: . a) Formula IA N Ar-L-Q H 224 WO 2007/146712 PCT/US2007/070547 wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; b) Formula IB H X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; c) Formula IC G-Ring-Ar-L-Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II G /Ar-L-Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III G LLAr Q N A wherein variables G, L', L 2 , L 3 , A, Ar, and Q are as defined in List X; f) Formula IV .-- D O L 2 -Q G E~ Y A wherein variables G, X, Y, L', L 2 , A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; 225 WO 2007/146712 PCT/US2007/070547 a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a n-n or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; 226 WO 2007/146712 PCT/US2007/070547 a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i).

18. The method of claim 17, wherein the compound is a p38 inhibitor.

19. The method of claim 17, wherein the HDL level prior to administration is less than about 70 mg/dl, less than about 65 mg/dl, less than about 60 mg/dl, less than about 55 mg/dl, less than about 50 mg/dl, less than about 45 mg/dl or less than about 40 mg/dl.

20. The method of claim 17, wherein the HDL level prior to administration is less than about 55 mg/dl.

21. The method of claim 17, wherein the HDL is HDL 2 .

22. The method of claim 17, wherein the HDL is HDL 3 .

23. The method of claim 17, wherein the subject has an LDL level less than about 150 mg/ml.

24. The method of claim 17, wherein the subject is at risk of a vascular event.

25. The method of claim 24, wherein the vascular event is one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.

26. The method of claim 24, wherein the vascular event is a cardiovascular event or a cerebrovascular event. 227 WO 2007/146712 PCT/US2007/070547

27. The method of claim 24, wherein a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the cytokine inhibitor.

28. The method of claim 17, wherein the subject is suffering from or is at risk of suffering from diabetes, Insulin resistance, or metabolic syndrome.

29. The method of claim 17, the method additionally comprising administration of atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate, clinofibrate, cholestyramine , colestipol, ezetimibe, niacin, or a combination of two or more thereof.

30. The method of claim 17, wherein the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%.

31. The method of claim 17, wherein the HDL level of the subject is increased by at least about 12%.

32. A method comprising administering to a subject exhibiting one or more indicia of rheumatoid arthritis, an amount of a compound effective to reduce at least one of the indicia to a level below that which exists prior to the administration of the compound, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists IT, III, or TV; b) Formula IB H G X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; 228 WO 2007/146712 PCT/US2007/070547 c) Formula IC G-Ring-Ar-L-Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II X1 X >/ Ar-L--Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III G Ar Q N A wherein variables G, L', L 2 , L', A, Ar, and Q are as defined in List X; f) Formula IV B-D O L 2 -Q G E Y A wherein variables G, X, Y, L', L2, A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, 229 WO 2007/146712 PCT/US2007/070547 said orienting moiety capable of forming a n-7c or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; 230 WO 2007/146712 PCT/US2007/070547 or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i).

33. The method of claim 32, wherein the indicia are selected from erythrocyte sedimentation rate (ESR), number of painful and tender joints, level of joint pain, Ritchie articular index, duration of morning stiffness, joint immobility, joint swelling, or circulating C-reactive protein level.

34. A method comprising administering to a subject an amount of a compound effective to increase the Apo-A 1-level of the subject relative to the level prior to the administration of the compound, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; b) Formula IB H X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; c) Formula IC G-Ring-Ar-L-Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II X' G -Ar-L--Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; 231 WO 2007/146712 PCT/US2007/070547 e) Formula III G Ar Q N A wherein variables G, L', L 2 , L', A, Ar, and Q are as defined in List X; f) Formula IV .- D LO L 2 _Q Xs / Y A wherein variables G, X, Y, L', L 2 , A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a n-n or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; 232 WO 2007/146712 PCT/US2007/070547 an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i).

35. The method of claim 34, wherein the Apo-Al-level of the subject is increased by at least about 5%, or by at least about 10%

36. The method of claim 34, wherein the HDL level of the subject is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. 233 WO 2007/146712 PCT/US2007/070547

37. A method comprising administering to a subject an amount of a compound effective to decrease or to prevent from increasing the systolic or diastolic blood pressure of the subject relative to the blood pressure prior to the administration of the compound, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; b) Formula IB H X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII1 c) Formula IC G-Ring-Ar-L--Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II G /> Ar-L-Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III G- L:r LkQ G k Ar Q N A wherein variables G, L', L 2 , L 3 , A, Ar, and Q are as defined in List X; 234 WO 2007/146712 PCT/US2007/070547 f) Formula IV .-- D Li O L 2 _Q G E x~ Y A wherein variables G, X, Y, L 1 , L 2 , A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an amide group having an amide NH-, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a n-ir or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and 235 WO 2007/146712 PCT/US2007/070547 an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; or a stercoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i).

38. The method of claim 37, wherein the blood pressure is the systolic blood pressure.

39. The method of claim 37, wherein the subject's systolic blood pressure prior to administration is above 140 mm Hg, and the subject's diastolic blood pressure prior to administration is above 90 mm Hg.

40. The method of claim 37, wherein diastolic blood pressure prior to administration of the compound is higher than 85 mm Hg. 236 WO 2007/146712 PCT/US2007/070547

41. The method of claim 37, wherein the decrease in systolic or diastolic blood pressure, or both, is at least about 5 mm Hg, at least about 3 mm Hg or at least about 2 mm Hg.

42. The method of claim 37, wherein the subject is at risk of a vascular event.

43. The method of claim 42, wherein the vascular event is one or more of thrombotic disorder, myocardial infarction, angina, stroke, transient ischemic attack, thrombotic re-occlusion subsequent to a coronary intervention procedure and a disorder in which at least one major coronary artery exhibits greater than 50% stenosis.

44. The method of claim 42, wherein the vascular event is a cardiovascular event or a cerebrovascular event.

45. The method of claim 42, wherein a reduction of the occurrence or severity of the vascular event occurs, relative to a subject who is at risk of a vascular event who has not been administered the compound.

46. The method of claim 42, wherein the subject is suffering from or is at risk of suffering from diabetes, Insulin resistance, or metabolic syndrome.

47. A method comprising administering to a subject at risk of increased PAI-1 levels an amount of a compound effective to decrease or prevent an elevation of the PAI-1-level of the subject relative to the level in the untreated subject, wherein the compound is selected from: a) Formula IA N Ar-L-Q H wherein variables G, X, Ar, L, and Q are as defined in Lists 11, 111, or IV; 237 WO 2007/146712 PCT/US2007/070547 b) Formula IB H G X Ar-L-Q wherein variables G, X, Ar, L, and Q are as defined in Lists V, VI, or VII; c) Formula IC G-Ring-Ar-L-Q wherein variables G, Ring, Ar, L, and Q are as defined in List VIII; d) Formula II X' G /Ar-L--Q N wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III G L LAr Q N A wherein variables G, L', L2, L', A, Ar, and Q are as defined in List X; f) Formula IV ..--- D G E Y A 12 wherein variables G, X, Y, L', L , A, B, D, E and Q are as defined in List XI; g) a compound comprising: a targeting moiety, TM, comprising at least an aide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; 238 WO 2007/146712 PCT/US2007/070547 a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with the target protein; and an orienting moiety, OM, comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a r-7r or edge-to-face aromatic interaction with the target protein; h) a compound comprising: a targeting moiety, TM, comprising an amide group having an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a pyridyl ring and attached to a different atom of the targeting moiety than the pocket-expanding moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; and an anchoring moiety, AM, indirectly attached to the orienting moiety by a linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; i) a compound comprising: a targeting moiety, TM, comprising an amide NH and carbonyl, the targeting moiety capable of forming one or more hydrogen bonds with a target protein; a pocket-expanding moiety, PEM, directly attached to the carbonyl of the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non-planar hydrophobic moiety, wherein the non-planar moiety is capable of forming hydrophobic interactions with the target protein; an orienting moiety, OM, comprising a 6-membered aryl or heteroaryl ring and attached to the NH of the targeting moiety, wherein the orienting moiety is capable of forming hydrophobic interactions with the target protein; 239 WO 2007/146712 PCT/US2007/070547 a linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membered heteroaryl moiety and the attachment point on the heteroaryl moiety is a carbon atom; and an anchoring moiety, AM, attached to the orienting moiety by the linker moiety, L, wherein the anchoring moiety is capable of forming at least 1 hydrogen bond interaction with an ATP-binding pocket of the target protein; or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt any one or more of (a) - (i).

48. The method of any one of claims 1-47, wherein the compound is selected from List I. 240