WO2007146712A2 - Therapy using cytokine inhibitors - Google Patents

Abstract

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.

Description

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 antiinflammatory cytokines. For example, IL-4, IL-10, and IL-13 are potent activators of B 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-I, TNF, and chemokines (CA. 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. [0004] Tumor necrosis factor-o; (TNF- en) and interlcukin-1 (IL-I) are proinflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses. Overproduction of cytokines such as IL-I and TNF-αis 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, CA. 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-α 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-o; (also referred to as TNFa) and interleukin-1/3 (IL-Ib) 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-I, 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-I. 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-bome 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 endartcrectomy, 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 (19pl3.1-13.3)), 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, 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 πsk for a cytokinc-mcdiated 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-I. 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 descπbed 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-I, 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 p38 activity The methods compose contacting p38 with an amount of a compound, such as a cytokine inhibitor, effective to inhibit p38 activity, the phosphorylation of p38, 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 p38 activity or phosphorylation of p38 is at least 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 πsk for, a cytokine- mediated disorder as described herein. In some embodiments of the invention wherein the p38 is in a subject, the method further includes administration of additional therapeutic ingredients (hereafter referred to as ingredient A) to the subject, as descπbed herein.

[0010] In another aspect of the invention, there are provided methods of reducing the activity of a pro-inflammatory mediator. The methods compπse 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 acthity pπor to the administration of the compound, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof. Tn 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 πsk for a cytokme-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 proinflammatory 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 descπbed 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 compπse administeπng 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- 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/1. 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 more thereof, and wherein the cytokine inhibitor is as descπbed 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 descπbed 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 descπbed herein, for example a cytokine inhibitor, together with one or more, typically one, of the ingredients A descπbed herein. In some embodiments, the methods are for treating cytokme-mediated disorders or conditions. In some embodiments, a combination of any two or more ingredients A are administered with a compound as descπbed 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 descπbed 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 vaπety 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, pam and fever, may be used. Such NSAIDs include acetaminophen, aspiπn, lbuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflumsal, etodolac, fenoprofen calcium, flurbiprofen, lndomethacm, ketoprofen, carprofen, mdoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulmdac, tolmetin, meloxicam, rofecoxib, celecoxib, etoπcoxib, valdecoxib, 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 1-B, CTLA-4, and other antibodies or receptor constructs directed against TNFa, IL1-6, LFA-I , 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 (ulobctasol), 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, lα,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, auranofm, 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, DAB₃₈₉, CTLA-4Ig, 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, 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-I or ICAM-I.

[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 ω 3 -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, 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 ιngredient(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 m 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 cyclospoπne and retinoids.

[0025] A typical combination for reducing the number or seventy of the clinical signs of psoriasis includes a compound described herein in combination with immunotherapy drugs which include cyclospoπne, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T, LFA3T1P, DAB₃₈₉, CTLA-41g, E-selectin inhibitors, alefacept, infliximab, etanercept, efahzumab, 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 descπbed 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 seventy of the clinical signs of psoπasis is a compound as descπbed herein with cyclospoπnc, especially because of cyclosporin's efficiency for induction of remission. Another embodiment of the invention compπses administration in the following sequence induction with a 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 macro lides, most typically with ascomycin analogues, administered topically, and even more typically with those available orally such as pimecroϋmus. 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 LF A3, and/or anti LFAl. This includes adhesion molecule blockage by recombinant fusion proteins like alefacept, anti LFA3- IgCl, or by anti-CD 11 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 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, DAB₃₈₉-IL-2, CTLA4-Ig, ILl O, 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(1 1), 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, dapsonc, chlorambucil, mercaptopurinc, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprinc 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, interferon beta-IB 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-I or inhibitors of ICAM-I .

[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-I, IL-6, ICAM-I, 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 drags 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 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-I 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-I , IL-6, ICAM-I , 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-IO, alicaforscn (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 HDL₂, while in others it is HDL₃. 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, 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, pravastatin (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; ω3-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-Al-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 me/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 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 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-I levels. The methods comprise administering to a subject at risk for increased PAI-I 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-I -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. [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. Pn 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 (LIPlTOR, TORVAST), fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LlVALO, 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; ω3-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%. [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 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.

[0043] In another aspect of the invention, there are provided methods of decreasing the HbAIc 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 HbAIc value above about 8%, above about 7.5%, or above about 7%. In others, the HbAIc 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 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/1, above about 150 pmol/1, above about 200 pmol/1, above about 250 pmol/1, above about 300 pmol/1, above about 350 pmol/1, above about 400 pmol/1, or above about 500 pmol/1. In others, the subject has a postprandial insulin level of above about 400 pmol/1, above about 500 pmol/1, above about 600 pmol/1, above about 700 pmol/1, or above about 800 pmol/1. hi 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 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. Li 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 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, hi 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. [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 hei'ein, 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, 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. [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 α-glucosidase inhibitor, a cholesterol lowering agent, a PPARδ 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-I 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 β-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-I, -2, or -3 activator, a thyroid hormone β agonist, a COX-2 inhibitor, a monoamine reuptake inhibitor, a mGlu5 receptor antagonist, an acyl-estrogen, a FAS inhibitor, an ACC2 inhibitor, a corticotropin- rel easing hormone agonist, a galanin antagonist, a BRS3 agonist, a PTP-IB 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, IDI lOl, 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 α-glucosidase inhibitor, or a glucose transporter inhibitor. In others, ingredient A is a cholesterol lowering agent, or a PPARδ 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 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-I 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, radafaxme, orlistat, cetihstat, oxyntomodulin, or oleoyl-estrone.

[0052] Typical examples of ingredients A, and combinations of any two or more thereof, that may be combined with compounds descπbed 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) γ agonists, such as glitazones (e.g.isaghtazone; pioglitazone; rosightazone; πvoglitazone, netoglitazone), naveglitazar, farghtazar, metaglidasen, GW6779542, CS038, MBX2044, AZD6610, PLX204, LBM642, AMG131, AVE0847, AVE5376, ONO5129, TAK654, CLX0921, and the like); (ii) biguanides such as metformin and phenformm;

[0054] (b) insulin or insulin mimetics, such as insulin aspart, insulin glulisine, insulin glargme, insulin lispro, insulin detemir, NN5401, NN9101, NN344, AT1391, DTYOOl, betaRx, insulin zinc suspension (lente and ultralente); insuhntropm (by "msulm" is meant a polypeptide or its equivalent useful in regulation of blood glucose levels. A general descπption 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 deπvatives of msulm 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, glybuπde, glimepinde, gliclazide, ghpentide; gliquidone; ghsolamidc; tolazamide, and tolbutamide; [0056] (d) oglucosidase 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) PPARα agonists such as fenofibric acid derivatives (ciprofibrate, gemfibrozil, clofibrate, fenofibrate and benzafibrate), GW677954, CS038, ABT335, LY674, GFT14, PLX204, Kl 11 , naveglitazar, LBM642, GW590735, NS220, AVE5376, AVE8134, DRFl 0945, ONO5129, KRPlOl , 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) PPARδ 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-I receptor antagonists or inverse agonists, for example rimonabant, surinabant,, AVEl 625, 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, WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499, 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, dexfenfluramine, phentermine, DOVl 02677, zimeldine, and sibutramine; [0062] (3) adrenoceptor agonists, including /33-adrenoreceptor agonists, such as solabregon, YMl 78, 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 SLx4090;

[0065] (6) melanin-concentrating hormone (MCH) receptor antagonists, including

MCHlR 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 NPYl antagonists, for example, BIBP3226, Jl 15814, BIBO3304, LY357897, CP671906, GI264879A, 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, GI264879A, 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(28,31)]NPY 24-36, and PYY(3-36)NH₂, cyclo-(28/32)-Ac-[Lys28- Glu32]-(25-36)-pNPY, TASP-V, 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)-I agonists, including GLP-I, GLP-I analogs and derivatives, such as exenatide, exenatide-LAR, liraglutide, CJCl 134PC, LY548806, 716155, and AVEOOlO;

[0070] (11) mclanocortin (MC) agonists, including MC4 agonists and MC4R agonists, such as Melanotan II, PTl 5, BL3020, AP 1030, or those described in PCT Application Nos. WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844, WO 02/12166, WO 02/1 1715, 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 NOXBl 1, CYT009GhrQb,

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 OB3, 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, GI181771 ,

JMV180, A71378, A71623, SR146131, UCL2000, and A71378, and those described in U.S. Pat. No. 5,739,106; [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 SUNl 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, RO0730699, TS021, ALS20426, vidagliptin, GRC8200, MP513, PHXl 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

GSKl 89254A, 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, fiuvoxamine, escitalopram, sibutramine, venlafaxine, vilazodone, DOV21947, LUAA21004, BGC201259, NS2359, UK416244, DOV102677, SEP225289, OPC14523, SLV314, WLlOl 1, WLl 017, 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 ; [0080] (21) dopamine agonists, for example dopamine D2 agonists, such as, ropinirole, bifeprunox, aripiprazole, pergolide, talipexole, ACP 104, quinagolide, nolomirole, NHOOl, SLV308, piribedil, lisuride, bromocriptine, aplindore, tesofensine, and preclamol;

[0081] (22) norepinephrine (NE) transport inhibitors, such as lisdexamfetamine, atomoxetine, duloxetine, SLE381, 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 SGLOOlO;

[0084] (25) 110-hydroxy steroid dehydrogenase-1 (/ϊ-HSD-1) inhibitors, such as

INCBl 3739, and AMG221;

[0085] (26) cholesterol ester transfer protein (CETP) inhibitors, such as torcetrapib, CETiI, 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-3B

(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, tofimilasL UKl 69003, 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, argatroban, SCH530348, cilostazol, YSPSL, parogrelil, asasantin, DG041, prasugrel, ramatroban, cangrelor, epoprostenol, beraprost, aspirin, Kl 34, 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, CHF 1521, 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, CYT006AngQb, TAK491, eprosartan, VNP489, CGP63170, fϊmesartan, 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)-l-propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123;

[0093] (34) thyroid hormone β 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, PMIOOl, 6444784, SVT2016, nimesulfide, CS706, cimicoxib, LR3001, LAS34475, P54, rofecoxib, celecoxib, and arcoxia;

[0095 j (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

ADXl 0059, AFQ-056, 2-mcthyl-6-(phenylethynyl)-p>τidine (MPEP), (3-[(2-methyl-l,3- thiazol-4-yl)ethynyl]pyridine) (MTEP) and those compounds described in Anderson et al. (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- IB (PTP-IB) 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 II;

[00108] (49) human agouti-related proteins (AGRP);

[00109] (50) neuromedin U receptor agonists;

[00110] (51) topiramate, oxyntomodulin, tagatose, CP741952, zonisamide,

IDI lOl, 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. 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, 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:

N Ar-L — Q I

I G_{\ /}N^

^H X Ar L Q _G__Rmg__Ar__^L^Q

IA IB IC

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 π-π 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:

Formula 111 wherein G, L , L , Ar, L³, 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:

Formula IV wherein G, L¹, B, D, E, L², 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.

[00125] In this aspect of the invention, the compounds have the structure

PEM-TM-OM-L-AM.

[00126] 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. lH-Indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;

3-tert-Butyl-5-phenyl-l-p-tolyl-l,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-l- 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; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl- pyrimidin-4-yloxy)-naphthalen-l-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-phcnyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;

N-(5-tert-Butyl-3-chloro-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl]-2-oxo-acet amide;

N-(5-tert-Butyl-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 -yl] -2-oxo-acetamide;

5-tert-Butyl-N-cyclopropyl-2-methoxy-3- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetylamino } -benzamide;

N-[5-tert-Butyl-2-methoxy-3-(piperidine-l-carbonyl)-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

5-tert-Butyl-2-hydroxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino} -benzoic acid;

N-(2-Benzenesulfonyl-5-tert-butyl-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-yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide; l-Bicyclo[2.2.1]hept-2-yl-5-phenylamino-3-p-tolyl-l,3-dihydro-imidazo[4,5-b]pyridin-2- one;

3-p-Tolyl-5-p-tolylamino-l,3-dihydro-imidazo[4,5-b]pyridin-2-one; l-Bicyclo[2.2.1]hept-2-yl-3-p-tolyl-5-p-tolylamino-l,3-dihydro-imidazo[4,5-b]pyridin-2- one;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2,2-difluoro-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-N'-naphthalen- 1 -yl-oxalamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-moipholin-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 -yl]-acetamide;

2-(5-tert-Butyl-2-p-tolyl-2H-pyτazol-3-ylamino)-l-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-ethanol; l-(3-tert-Butyl-phenyl)-4-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-

[l,2,4Jtriazolidinc-3,5-dionc;

4-(3-tert-Butyl -phenyl)- 1 -[4-(2-morpholin-4~yl-ethoxy)-naphthalcn-l -yl]-

[1 ,2,4]triazolidine-3,5-dione;

(E)-3-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl] -acrylic acid methyl ester;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2,5- dioxo-2,5-dihydro-pyrrol-l-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-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;

N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-[4-(2-piperidin- 1 - yl-pyrimidin-4-yloxy)-naphthalen-l-yl]-acetamide;

3-tert-Butyl-l-p-tolyl-5-(3-trifluoromethyl-phenyl)-l,6-dihydro-imidazo[4,5-c]pyrazole; l-(2-Morpholin-4-yl-ethyl)-lH-indazole-3-carboxylic acid (5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-amide;

N-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-2-(2,4,6-trimethyl-phenyl)- acetamide;

1-Phenyl-cyclopropanecarboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;

N-[5-tert-Butyl-2-(2,5-difluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxG-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-(4-methoxy-naphthalen- l-yl)-2-oxo-acetamide; N-[5-tert-Butyl-2-(3-chloro-benzoyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(3-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxoacetamide;

4-[(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylcarbamoyl)-methyl]-piperidine-l-carboxylic acid tert-butyl ester;

N-[3-(Benzenesulfonyl-carbamoylmethyl-amino)-5-tert-butyl-2-methoxy-phenyl]-2- naphthalen- 1 -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)-naphthalen-l-ylj-succinamic acid methyl ester;

2-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-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-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetamide;

5-tert-Butyl-2-(3-chloro-phenyl)-2H-pyrazole-3-carboxylic acid [4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -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)- naphthalen- 1 -yl]-acetamide;

N-[5-tert-Butyl-2-(4-sulfamoyl-phenyl)-2H-pyrazol-3-ylJ-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

5-tert-Butyl-2-methoxy-3-(l-naphthalen-l -yl-3,5-dioxo-[ 1 ,2,4]triazolidin-4-yl)- benzamide;

2-(4-Bromo-naρhthalen-l-yl)-N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-2-oxo- acetamide;

5-tert-Butyl-2-hydroxy-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-hydroxy-2-(4-methoxy-naphthalen-l-yl)- acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l-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-ylamino)- naphthalen-l-yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-{4-[2-(l-oxo-l λ⁴-thiomorpholin-4- yl)-ethoxy]-naphthalcn-l-yl}-acetamidc;

5-tert-Butyl-3- {2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalcn-l-yl]- acetylamino}-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-l-yl]-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-((2R,6R)-2,6-dimethyl-moφholin-4- yl)-ethoxy]-naphthalen- 1 -ylj -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-l-yl]-2-oxo-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydrox>imino]-2-[4-

(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl]-2-oxo-acetamide;

5-tert-Butyl-N-cyclopropyl-2-methoxy-3-[2-(4-methoxy-naphthalen-l-yl)-2-oxo- acetylamino]-benz amide;

4-tert-Butyl-N-[4-(2-piperidin-l-yl-ethoxy)-naphthalen-l-yl]-benzamide;

N-(2-Acetyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;

5-tert-Butyl-N-cyclopropyl-3-{2-hydrazono-2-[4-(2-morpholiπ-4-y!-ethoxy)-naphthaleii- l-yl]-acetylamino}-2-methoxy-benzamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-(4-methoxy-πaphthaltin-l-yl)- propionamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-phenyl-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-l -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-l-yl]-2-oxo- acetamide;

N-(5-tert-Butyl-2-cyclohexyl-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-(3,5-difluoro-phenyl)-acetamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalen-l-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-πiethoxy-phenyl)-2-[4-(2-diethylaπiino- 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-[l,4]diazepan-l-yl)- ethyl] -naphthalen- 1 -yl } -acetamide;

5-tert-Butyl-N-ethyl-2-methoxy-3-[2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetylamino]- benzamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-

3-yl] -naphthalen- 1 -yl } -acetamide;

5-tert-Butyl-3-cthancsulfonylamino-2-methoxy-N-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -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-l-yl]-2-oxo- acetamide;

Pyrrolidine- 1 -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-tert-butyl-2-methoxy-phenyl)-acetamide:

N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-oxo-2-{4-[2-((S)-l-phenyl-ethylamino)- pyrimidm-4-ylamino]-naphthalen-l-yl}-acetamide;

5-tert-Butyl-3-[l-(2,3-dimethyl-phenyl)-3,5-dioxo-[l,2,4]triazolidin-4-yl]-2-methoxy- benzamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-naphthalen-2-yl-acetamide; 5-tert-Butyl -2-methoxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -2-oxo- acetylamino}-benzamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-methoxy-2-(4-methoxy-naphthalen- 1 -yl)- propionamide;

5-tert-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-ylmethyl]-3-nitro- benzamide;

N-(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-benzamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2,5-difluoro-phenyl)-acetamide;

N-(3,5-Di-tert-butyl-2-methoxy-phcnyl)-2-[(Z)-hydroxyimino]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen-l-yl]-acetamide;

N'-[l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide;

N-[2-(4-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;

5-tert-Butyl-3-{2-[(Z)-methoxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-ylj- acetylamino}-thiophene-2-carboxylic acid amide;

Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2,5-dioxo-2,5-dihydro-pyrrol-l-yl}-phenyl)-amide;

5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetylamino } -benzamide;

5-Fluoro-l H-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-moφholin-4-yl- ethoxy)-naphthal en- 1 -yl] -2-oxo-acetamide;

7-Bicyclo[2.2.1]hept-2-yl-9-p-tolyl-2-p-tolylamino-7,9-dihydro-purin-8-one;

N-(5-tert-Butyl-2-isopropoxy-3-methanesulfonylamino-phenyl)-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(3₅4-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

3-tert-Bijtyl-l-(3,4-dichloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-[4-(2-thiomoφholin-4-yl-ethoxy)- naphthalen-1 -yl]-acetamide;

S-Nitro-lH-pyrazole-S-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide; N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-dimethylamino- pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;

1 -(2-Amino-4-tert-butyl-ό- {2-[4-(2-moφholin-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-l-yl]-

2-oxo-acetamide;

N-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2,5-bis-trifluoromethyl-benz amide;

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)-hydroxyimino]-2-[4-(2-morpholin-4- yl-ethoxy)-naphthalcn-l-yl]-acetamide;

5-tert-Butyl-2-methoxy-3-[2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetylamino]- 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)- naphthaien-l-yl]-2-oxo-acetylamino}-benzamide;

(E)-3-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenylcarbamoyl)-3-[4-(2- moφholin-4-yl-ethoxy)-naphthalen-l-yl]-acrylic acid methyl ester; l-Isopropyl-3-phenyl-5-phenylamino-l ,3-dihydro-imidazo[4,5-b]pyridin-2-one;

N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-moφholin-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-l-yl]-acetamide;

2-(5 -tert-Butyl-2-methoxy-phenyl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 -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-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid methyl ester;

3-tert-Butyl-5-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- pyrazole-l-carboxylic acid adamantan-1-ylamide;

3-tert-Butyl-5-phenyl-l-(4-trifluoromethyl-phenyl)-l,6-dih3'dro-imidazo[4,5-c]pyrazole;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2,4,5- trioxo-imidazolidin- 1 -yl} -phenyl)-methanesulfonamide; 3-tert- Butyl- l-(3-chloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

5-tert-Butyl-3- {2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 -yl] -2-oxo-acetylamino) - thiophene-2-carboxylic acid amide;

2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-N-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-1 -yl]-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-(2,6-dimethyl-moφholin-4-yl)-ethyl]- naphthalen- 1 -yl} -2-oxo-acetamide;

N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalcn-l-yl]-2- oxo-acetamide;

N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-acetamide;

3-tert-Butyl-5-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-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-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;

3-tert-Butyl-5-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid amide;

N-Allyl-5-tert-butyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetylamino}-benzamide;

N-(5-tert-Butyl-isoxazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;

3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-l-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl]-pyπrole-2,5-dione;

2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-moφholin-4- yl-ethoxy)-naphthalen-l-yl]-acetamide;

3-tert-Butyi-5-o-tolyl-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(E)-hydroxyimino]-2-phenyl-acetaπiide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-phenyl-acetamide;

N-(3-Acetylamino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide; 1 H-Indazole-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-l-yl]-3-nitro- benzamide;

5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-moφholin-4-yl-pyrimidin-4-yloxy)- naphthalen-l-yl]-acetylamino}-thiophene-2-carboxylic acid amide;

N-[3-(4-Acetyl-piperazine-l-carbonyl)-5-tert-butyl-2-methoxy-phenyl]-2-[4-(2- 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 -yl]-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-l-yl]-2-oxo-N-(2-phenyl-cyclopropyl)- acetamide;

N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl] -2-oxo-acetamide;

N-(5-tert-Butyl-2,3-dimethoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen-l-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-[2-(4-methyl-piperazin-l-yl)-ethyl]- naphthalcn-l-yl}-2-oxo-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-(lH-indol-3-yl)-2-oxo- acetamide;

N-(5-teτt-Butyl-2-methoxy-phenyl)-2-[4-(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-l-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 Diethylamide;

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; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-((2R,6S)-2,6-dimethyl-morpholin-4- yl)-ethoxy]-naphthalen-l-yl}-2-oxo-acetamide;

3-tert-Butyl-l,5-diphenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-imidazol-l-yl-ethyl)-naphthalen-l-yl]-

2-oxo-acetamide;

3-tert-Butyl-5-(3-chloro-phenyl)-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(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)- naphthalcn- 1 -yl] -acctamidc; l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4- yloxy}-naphthalen-l -yl)-imidazolidine-2,4,5-trione;

N-[5-tert-Butyl-2-(3-chloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;

S-Methoxy-lH-indazole-S-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-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-

1 -yl] -2-oxo-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2-methoxy-phenyl)-acetamide;

5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)- naphthalen- 1 -yl] -2-oxo-acetylamino } -benzamide;

[(5-tert-Butyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-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- moφholin-4-yl-ethoxy)-naphthalen-l-yl]-acetamide;

N-[5-tert-Butyl-2-(2,5-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-[1.4]oxazepan-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;

1 -(5-tert-Butyl-2-methoxy-3-benzamide)-3-(4-methoxy-phenyl)-3'-(carbamic acid ethyl ester)-urea; N-[5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-(4-methoxy-naphthalen-l-yl)- acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-4-chloro-benzamide;

N-(2-Bromo-5-trifluoromethyl-phenyl)-2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-

2-oxo-acetamide;

3-Isopropyl-5-phenyl-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

3,5-Di-tert-butyl-l -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-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-moφholin-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-l-yl)-l-(3-tert-butyl-phenyl)-[l,2,4]triazolidine-3,5-dione;

N-[5-tert-Butyl-2-(morpholine-4-carbonyl)-thiophen-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

3-tert-Butyl-5-(3-methoxy-phenyl)-l-p-tolyl-l,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; l-tert-Butyl-5-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-ylamino]-3-p-tolyl-l,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- moφholin-4-yl-ethoxy)-naρhthal en- 1 -yl] -acetamide;

5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -ylmethyl] -amide;

2-[5-tert-Butyl-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- acetylaminoj-benzamide;

N-[5-tert-Butyl-3-(3,3-diethyl-ureido)-2-methoxy-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide; N-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-[4-(2-piperazin-l- yl-ethoxy)-naphthalen- 1 -yl] -acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl- pyridin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;

(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-cthoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phcnyl)-carbamic acid isopropyl ester; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-dimethylamino-pyrimidin-4-yloxy)- naphthalen-l-yl]-imidazolidine-2,4,5-trione;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl- pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;

4-(3-tert-Butyl-l-p-tolyl-l,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 -yl] -2-oxo-acetamide;

5-tert-Butyl-N,N-diethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetylamino } -benz amide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-[l,4]oxazepan-4-yl- ethoxy)-naphthalen- 1 -ylj -2-oxo-acctamidc;

N-(3-tert-Butyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l -yl]-2-oxo- acetamide;

5-tert-Butyl-N-ethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- acetylamino} -benzamide;

N-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen-l-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-tolyl-2H-pyrazol-3-yl)-2-[4-(2-dimethylamino-ethoxy)-naphthalen-

1 -yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-[4-(2-piperidin-l-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl]-acetamide; N-[5-tert-Butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

Indazole-1-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amide;

N-[3,5-Bis-(l,l-dimethyl-propyl)-2-methoxy-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide; l-Benzyl-3-tert-butyl-5-phenyl-l ,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-l-yloxy]-ethyl}-piperazine-l-carboxylic acid ethyl ester;

2-Hydroxy-N-(5-isopropyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetamide;

1 -Bicyclo[2.2.1 ]hept-2-yl-3-phenyl-5-phenylamino-l ,3-dihydro-imidazo[4,5-b]pyridin-2- one;

N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl-pyrimidin-4- ylamino)-naphthalen-l-yl]-2-oxo-acetamide;

N-[5-tert-Butyl-3-(2-dimethylamino-acetylamino)-2-methoxy-phenyl]-2-[4-(2-morpholin-

4-yl-ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;

N-(5-tert-Butyl-2-methoxy-3-{6-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-3,5- dioxo-2,5-dihydro-3H-[l ,2,4]triazin-4-yl}-phenyl)-methanesulfonamide;

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;

(R)-N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-dimethylamino- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;

N-[2-(3-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-moφholin-4-yl- ethoxy)-πaphthalen- 1 -yl]-acetamide;

2-[5-tert-Butyl-2-(3-chloro-phenyl)-2H-ρyrazol-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; N-(5-tert-Butyl-[l,3,4]thiadiazol-2-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-acetamide;

N-(5-tert-Butyl-3-{2-hydroxy-2-[4-(2-moφholin-4-yl-pyrimidin-4-yloxy)-naphthalen-l- yl] -ethylamino } -2-methoxy-phenyl)-methanesulfonamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-4-chloro-benzamide;

N-(5-tert-Butyl-2-ethoxy-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l -yl]-2- oxo-acetamide;

(5-tert-Butyl-2-methoxy-3- {2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetylamino}-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-1 -yl]-acetamide;

2-Amino-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-naphthalen-l-yl-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acrylamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-imidazol-l-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;

N-(4-Bromo-3-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-

2-oxo-acetamide;

4-(4-Benzyloxy-phenyl)-l-(3-tert-butyl-phenyl)-[l,2,4]triazolidine-3,5-dione;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[8-chloro-4-(2- moφholin-4-yl-ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-chloro-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;

5-tert-Butyl-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- thiophene-2-carboxylic acid dimethylamide; l-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]- imidazolidine-2.4,5-trione;

N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l -yl]-

2-oxo-acetaiiiide; l-Benzoyl-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

N'-[l-(5-tert-Butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2-moφholin-4- yl-ethoxy)-naphthalen-l-yl]-mcth-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester; 3-tert-Butyl-5-(3-fluoro-phenyl)-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

2-[3-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-l-yl]-2-oxo-acetamide;

(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid p-tolyl ester;

N-(5-tert-Butyl-2-diethylamino-3-methanesulfonylamino-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-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 - yl]-acetamide;

N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-(4-methoxy- naphthalen-l-yl)-2-oxo-acetamide;

Propane- 1 -sulfonic acid (5-tert-butyl-2-methoxy-3-{4-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-3,5-dioxo-[l,2,4]triazolidin-l-yl}-phenyl)-amide;

3-Amino-5-tert-butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- ylmethyl]-benz amide;

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-l- yl]-2H-[l,2,4]triazine-3,5-dione;

N-[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-l-sulfonylamino)-phenyl]-2-[4-(2-dimethylamino- pyrimidin-4-ylaniino)-naphthalen- 1 -yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-phenyl-acetamide;

N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl- pyrimidin-4-yloxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-{4-[2-(2,6-dimethyl- morpholin-4-yl)-ethoxy]-naphthalen- 1 -yl} -2-oxo-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(4-methoxy-naphthalen-l-yl)-acetamide;

3-tert-Butyl-l-cyclohexyl-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole; 3-tert-Butyl-5-(4-fluoro-phenyl)-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(5-tert-Butyl-2-methoxy-3 - {4- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-3 , 5- dioxo-[ 1 ,2,4]triazolidin- 1 -yl} -phenyl)-methanesulfonamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazin-l-yl)-ethyl]- naphthalen- 1 -yl } -acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-[4-(3-pyridin-4-yl-propoxy)- naphthalen- 1 -yl]-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-

(2-moφholin-4-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen-l-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-l-carboxylic acid tert-butyl ester;

N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-imidazol- 1 -yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(3,5-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morphoiin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)- naphthalen- 1 -yl] -2-oxo-acetamide;

N-{5-tert-Butyl-3-[carbamoylmethyl-(propane-l-sulfonyl)-amino]-2-methoxy-phenyl}-2- naphthalen- 1 -yl-2-oxo-acetaniide;

N'-[ 1 -(5-tert-Butyl-2-niethyl-2H-pyrazol-3-ylcarbamoyl)- 1 -[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-meth-(Z)-ylidcne]-hydrazinecarboxylic acid ethyl ester;

5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-acetylamino}-benzamide;

N-[5-tert-Butyl-2-(3-nitro-phenyl)-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-[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- {2- [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetylamino } - pyrazole-1-carboxylic acid cyclohexylamide; 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-l-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;

5-tert-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-3-(propane-l- sulfonylamino)-benz amide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-(4-methoxy-naphthalen-l-yl)- acetamide;

(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-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-l-yl]-2-oxo-acetamide;

N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-moφholin-4-yl-pyridin-4-ylamino)-naphthalen-l- yl] -2 -oxo-acetamide;

3-tert-Butyl-l-(4-chloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yi)-2-(4-methoxy-naphthaien-l-yi)-2-oxo- acetamide;

2-[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[(Z)-hydroxyimino]-N-[4-(2- moφholin-4-yl-ethoxy)-naphthalen-l-yl]-acetamide;

N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetamide;

N-[5-(l,l-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-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-

2-oxo-acetamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[2,3-dichloro-4-(2- moφholin-4-yl-ethoxy)-phenyl]-2-oxo-acetamide;

N-(3-Methanesulfonylamino-2-methoxy-5-methyl-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

4-{2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl)-naphthalen-l-yl]-ethyl}- piperazine-1-carboxylic acid ethyl ester;

(l-Benzyl-lH-benzoimidazol-2-yl)-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-amine; N-(3,5-Di-tert-butyl-2-hydroxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-naphthalen-l-yl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl-pyrimidin-4-ylamino)- naphthalen- 1 -yl]-2-oxo-acetamide;

4-{2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl)-naphthalen-l-yloxy]-ethyl}- piperazine-1-carboxylic acid ethyl ester;

5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)-naphthalen-l- yl]-2-oxo-acetylamino}-benzamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-(l-methyl-lH-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- 1 -yl] - acetylamino } -benzamide;

N-[2-(4-Acetyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide; l-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- 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- naphthalen- 1-yl -2-oxo-acetamide;

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[2-methyl-4-(2-morpholin-4-yl-ethoxy)- phenyl]-2-oxo-acetamide;

N-[2-(4-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;

(5-tert-Butyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid phenyl ester;

N-(5-ttat-Butyl-2-meth>l-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl]-acetamide;

N-(5-tert-Butyl-2-isobutoxy-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide; N-(4-tert-Butyl-pheπyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-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-l-yl]- acetylamino}-thiophene-2-carboxylic acid amide;

1 -(5-tert-Butyl-2-methoxy-phenyl)-3 -[4-(2-chloro-pyrimidin-4-yloxy)-naphthalen- 1 -yl] - imidazolidine-2,4,5-trione;

(S)-N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-acetamide;

N-[5-tert-Butyl-2-(2,3-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;

N-[5-tert-Butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;

2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-

1 -yl] -2-oxo-acetamide;

2-[(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- 1 -yl] -acetamide;

N-(5-tert-Butyl-2-phenyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;

N'-[ 1 -(5-tcrt-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l -[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;

N'-[ 1 -(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l -[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-meth-(Z)-ylidene]-hydrazinecarboxamide;

N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-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-l-yl]-2-oxo- acetylamino}-K-pyridin-2-yl-benzamide;

N-[5-tert-Butyl-3-(3,3-dimethyl-ureido)-2-methoxy-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

5-tert-Butyl-3-{2-[7-chloro-4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino } -2-methoxy-benzamide; N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-m-tolyl-acetamide; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-pyrrolidin-l-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl]-imidazolidine-2,4,5-trione;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-propionamide;

2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-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-[5-tert-Butyl-3-(3-isopropyl-ureido)-2-methoxy-phenylJ-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-methoxy-2-(4-methoxy-naphthalen- 1 -yl)- acetamide;

N-(3-Amino-5-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-

2-oxo-acetamide;

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl] -2-oxo-acetamide;

3-Methyl-l,5-diphenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(5-tert-Butyl-isoxazol-3-yl)-2-hydroxy-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-acetamide;

N-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-2-(2-phenyl-cyclopropyl)- acetamide;

2- {4-[2-(4-Acetyl-piperazin- 1 -yl)-ethoxy]-naphthalcn- 1 -yl} -N-(5-tert-butyl-3- methanesulfonylamino-2-methoxy-phenyl)-2-oxo-acetamide;

2-(lH-Indol-3-yl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(3-fluoro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-y]-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;

2-(3-Amino-5-tcat-butyl-2-methoxy-phenyl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-

1 -yi]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(3,4-dichloro-phenyl)-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-pyrimidin-4-yloxy)-naphthalen-l- 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-l-yl]-2-oxo-acetamide; lH-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; lH-Indazole-3-carboxylic acid [5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]- amide;

1 H-Indazole-3-carboxylic acid [5-tert-butyl-2-(4-hydroxy-phenyl)-2H-pyrazol-3-yl]- amide;

N'-[l-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-l-[4-(2- moφholin-4-yi-ethoxy)-naphthaien-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-N'-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- l-yl]-oxal amide;

N-(5-tert-Butyl-3-methanesulfonylamino-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)-naphthalen-l-yl]-acetamide;

5-tert-Butyl-N-cyclopropyl-3-[2-[(E)-hydroxyimino]-2-(4-methoxy-naphthalen-l-yl)- acetylamino]-2-methoxy-benzamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-(2,6-dimethyl-morpholin-4-yl)- ethoxy] -naphthal en- 1 -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-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(3-fluoro-phenyl)-acetamide;

5-tert-Butyl-N-furan-2-ylmethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2~oxo-acetylamino } -benzamide;

N-[5-tert-Butyl-2-(3-trifluoromethyl-benzoyl)-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-l-sulfonylamino)-phenyl]-2-[4-(2-morpholin-4-yl- pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide; l-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen-l- yl]-imidazolidine-2,4,5-trione;

1 -(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 - yl]-3'-(carbamic 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- 1 -yl } -acetamide;

2- {4- [2-(4-Acetyl-piperazin- 1 -yl)-ethyl] -naphthalen- 1 -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)- ethoxy]-naphthalen-l-yl}-acet amide;

2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-morpholin-4- yl-ethoxy)-naphthalen-ϊ-yl]-acetamide;

N-[5-tert-Butyl-2-(3-ureido-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-[(Z)-methoxyimino]-2-[4-

(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 -yl] -acetamide;

N-[5-tert-Butyl-2-methoxy-3-(3-oxo-piperazine-l-carbonyl)-phenyl]-2-[4-(2-mθφholin-

4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

3-tert-Butyl-5-{2-[4-(2-moφholin-4-yl-cthoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid propylamide;

5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen-l-yl]-2-oxo-acetylamino}-benzamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-(4-methyl-piperazin-l-yl)-ethoxy]- naphthalen- 1 -yl} -2-oxo-acetamide;

N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl] -2-oxo-acetamide;

5-tert-Butyl-2-methoxy-3-{2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino } -N-propyl-benzamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-(4-methoxy-phenyl)-acetamide; N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-moφholin-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-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;

7-Isopropyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

(5-tert-Butyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetylamino}-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- acetamide;

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-l-yl]-acetamide;

2-[5-tert-Butyl-2-(3,4-difluoro-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-moφholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-methylamino-pyrimidin-4-ylamino)- naphthalen- 1 -yl] -2-oxo-acetamide;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-moφholin-4-yl-pyrimidin-4-yloxy)- naphthalen- 1 -yl] -2-oxo-acetamide;

N-[5-tert-Butyl-2-(2,3-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;

N-[3,5-Bis-(l,l-dimethyl-propyl)-2-hydroxy-phenyl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-1-yl] -2-oxo-acetamide;

4-{2-[4-(5-tert-Butyl-3-methanesulfonylamino-2-mcthoxy-phenylaminooxalyl)- naphthalen-l-yloxy]-ethyl}-piperazine-l-carboxylic acid tert-butyl ester;

3-tert-Butyl-l-naphthalen-2-yl-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

2-Biphenyl-4-yl-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-acetamide;

5-tert-Butyl-N-isopropyl-2-methoxy-3 - {2- [4-(2-moφholin-4-yl-ethoxy)-naphthalen- 1 - yl] -2-oxo-acetylamino } -benzamide;

N-(5-tert-Butyl-3-diethylaminomethyl-2-hydroxy-phenyl)-2-[4-(2-moφholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide; 6-Hydroxy-nicotinic acid 3-[5-tert-butyl-2-methoxy-3-(propane-l -sulfonylamino)- phenylcarbamoyl]-l H-indazol-5-yl ester;

N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrirnidin-4- ylamino)-naphthalen-l-yl]-2-oxo-acetamide;

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4- ylamino)-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-l-yl]-2-oxo-acetamide;

N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-

1 -ylj^-oxo-acctamidc; l ,3,5-Triphenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-cyclohexyl-acetamide;

2-[5-tert-Butyl-2-(2-chloro-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-2-oxo-acetamide;

7-Cyclohexylmethyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetyIamino}- thiophene-2-carboxylic acid Diethylamide;

5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetylamino} -benzamide;

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-acetamide;

N'-[ 1 -(5-tert-Butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl)-l -[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(Z)-ylidcnc]-hydrazinecarboxylic acid ethyl ester;

4-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-l-(2,3-dimcthyl-phenyl)-[l,2,4]triazolidine-

3,5-dione;

N-(4-Fluoro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-

2-oxo-acetamide; l-Benzyl-3-phenyl-5-phenylamino-l,3-dihydro-imidazo[4,5-b]pyridin-2-one;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-naphthalen-2-yl-acetamide:

2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-ylcarbamoyl]-pyτrole-l-carboxylic acid tert-butyl ester;

N-(2,5-Di-tert-butyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide; 2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-N-((l S,2R)-2-phenyl- cyclopropyl)-acetamide;

2-Oxo-2,3 -dihydro-benzoimidazole- 1 -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-l- yl]-2-oxo-acetamide;

N-[2-(4-Bromo-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen-l-yl]-imidazolidine-2,4,5-trione;

5-tert-Butyl-2-methoxy-N-methyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetylamino}-benzamide;

N-(5-tert-Butyl-2-methoxy-3-piperidin-l-ylmethyl-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-naphthalen-l-yl-2-oxo-acetamide;

N-(2,5-Di-tert-butyl-2H-pyrazol-3-yi)-2-[4-(2-morpholin-4-yI-ethoxy)-naphthalen-l-yl]-

2-oxo-acetamide;

(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 4-methoxy-phenyl ester;

N-(3 -Amino-5-tert-butyl-2-methoxy-phenyl)-2-naphthalen- 1 -yl-2-oxo-acetamide;

5-tert-Butyl-N-ethyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalcn- 1 -yl] -acetylamino} -2-methoxy-benzamide;

4.{2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl)-naphthalen-l-yl]-ethyl}- piperazine-1 -carboxylic acid tert-butyl ester;

5-tert-Butyl-N-ethyl-2-hydroxy-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-naphthalen- 1 -yl-acetamide;

N-(5-tert-Butyl-2-ethoxy-3-methanesulfonylamino-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;

N'-[ 1 -(5-tert-Butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl)- 1 -[4-(2-morphoIin-4- yl-ethoxy)-naphthalm-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide,

2-{4-[2-(4-Acetyl-piperazin-l-yl)-ethoxy]-naphthalen-l-yl}-N-(5-tert-butyl-2-p-tolyl-2H- pyrazol-3-yl)-2-oxo-acetamide; 5-tcrt-Butyl-N-ethyl-2-methoxy-3-{2-[4-(2-morphoHn-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetylamino} -benzamide;

5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino} -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-isoxazo]-3-yl)-2-[4-(2-dimethylamino-pyrimidin-4-ylamino)-naphthalen- l-yl]-2-oxo-acetamide;

5-tert-Butyl-3- {2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)-naphthalen- 1 -yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid amide;

2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-N-m-tolyl-acetamide;

5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetylamino}- thiophene-2-carboxylic acid methyl ester;

N'-[l-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-l-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-meth-(Z)-ylidene]-hydrazinecarboxamide;

N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-pyridin-

4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;

N-(5-Isopropyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- 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- l-yl]-2-oxo-acetamide;

6-Bromo-l H-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-l-yl]- acetylamino}-2-methoxy-benzamide;

N-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-

(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-acetamide;

N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-dimethylamino-pyrimidin-4- ylamino)-naphthalen- 1 -ylJ-2-oxo-acetainIde;

N-(5-tert-Butyl-thiophen-3-yl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acet amide; N-[5-tert-Butyl-2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;

N'-[l-(5-tert-Butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2-moφholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide;

N-[5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;

5-tert-Butyl-3-{2-[7-chloro-4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-N-cyclopropyl-2-methoxy-benz amide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-{4-[2-(4-methyl- piperazin- 1 -yl)-ethoxy]-naphthalen- 1 -yl } -2-oxo-acetamide;

1 -(5-tcrt-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3 -[4-(2-moφholin-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-l-yl]-acetamide;

5-tert-Butyl-N-cyclopropyl-3-[2-[(Z)-hydroxyimino]-2-(4-methoxy-naphthalen-l-yl)- acetylamino]-2-methoxy-benz amide;

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(4-morpholin-4-yl-pyrimidin-2- ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[(Z)-hydroxyimino]-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;

N-[2-Methoxy-5-(l -methyl- l-phenyl-ethyl)-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;

2-[5-tert-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-{2-[4-(2-moφholin-4-yl-pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid amide;

5-tert-Butyl-N-isobutyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-

2-oxo-acetylamino}-benz amide;

2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-moφholin-4- yl-ethoxy)-naphthalen- 1 -yl]-acetamide;

3-tert-Butyl-l-(2,3-dichloro-plienyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;

N-(3,5-Di-tert-butyl-2-methoxy-phenyl)-2-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l- yl] -2-oxo-acetamide; 5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-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-l-yl]-acetamide;

N^l-[l-(5-tert-Butyl-3-cyclopropylcarbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;

N-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-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-l-carbonyl)-2-methoxy-phenyl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;

2-(2,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-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; lH-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-[l ,4]diazepan-l-yl)- ethoxy] -naphthalen- 1 -yl } -acetamide;

3-tert-Butyl-l-p-tolyl-5-(4-trifluoromethyl-phenyl)-l,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-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid isopropylamide;

N-(5-tert-Butyl-[l,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)-hydroxyimino]-2-[4-

(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen- 1 -yl] -acetamide;

N-[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-l-yl]-2-oxo-acetylamino}- pyrazole-1-carboxylic acid phenylamide; 2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;

N-(5-tert-Butyl-2-o-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;

N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-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-l-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-acetamide;

N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(3-hydroxy-propoxy)-naphthalen-l-yl]-2-oxo- acetamide;

N-(3-tert-Butyi-isoxazol-5-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetamide; lH-Indole-3-carboxylic acid (5-tert-butyl-2-methoxy-phenyl)-amide;

N-[5-tert-Butyl-2-methoxy-3-(propane-l-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-l-yl]-benz amide;

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; l-(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-lH-pyrrole-2-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-p>τazol-3-yl)- amide; 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-l-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-moφholin-4-yl-ethoxy)- naphthalcn- 1 -yl] -acetami de;

5-tert-Butyl-3-{2-[4-(2-dimethylamino-pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid amide;

N'-[l-(5-tert-Butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2-moφholin-4- yl-ethoxy)-naphthalen-l-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-l-ylmethyl-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;

2-(l-Methyl-lH-indol-3-yl)-N-[4-(2-moφholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;

N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2- (4-[2-((S)- 1 -phcnyl-cthylamino)-pyrimidin-

4-ylamino]-naphthalen- 1 -yl} -acetamide;

N-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalcn-l-yl]-2-oxo-acetamide;

N'-[l-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-l-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;

N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-morpholin-4- yl-ethoxy)-naphthalen-l-yl]-acetamide;

N-(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-isobutyramide; N-[5-tert-Butyl-2-(4-methyl-benzoyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(2-chloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;

N-[5-tert-Butyl-2-(3-chloro-4-methyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;

2-(4-Bromo-phenyl)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-acetamide;

2-(5-tert-Butyl-2-methyl-furan-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-fur an-3-yl)-2-oxo-acetylamino]-naphthalen-l- ylamino}-phenoxy)-pyridine-2-carboxylic acid methylamide;

N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-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-l-yl]-2-oxo-acetylamino}-benzamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-{4-[6-(tetrahydro- pyran-4-ylamino)-pyridin-3 -yl] -naphthalen- 1 -yl } -acetamide;

3-[2-(4-Bromo-naphthalen-l-yl)-2-oxo-acetylamino]-5-tert-butyl-N-cyclopropyl-2- methoxy-benzamide;

N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-moφholin-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- l-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-pyrazol-3-yl)-2-oxo-2-(4-pyridin-3-yl-naphthalen-l-yl)- acetamide;

2-(4-Chloro-3-trifluoromethyl-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-

2-oxo-acetamide;

4-{4-[2-(4-CMoro-3-trifluoromethvl-phenyl)-2-oxo-acetylamino]-phenoxy}-pyridiHe-2- carboxylic acid methylamide;

1907 N-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-(5-methoxy-lH-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-

(dimethylamino)pyridin-3-yl)naphthalen- 1 -yl)-2-oxoacetamide;

N-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)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-oxoacetamide;

N-(5-tert-Butyl-2-mcthoxy-3-(methylsulfonamido)phenyl)-2-(4-(2-

(dimcthylamino)pyridin-4-ylamino)naphthal en- 1 -yl)-2-oxoacet amide;

5-tert-Butyl-N-cyclopropyl-3-(2-(4-(2-(dimethylamino)pyridin-4-ylamino)naphthalen-l- yl)-2-oxoacetamido)-2-niethoxybenzamide;

N-(5-tert-Butyl-2-methoxyphenyl)-2-(4-(2-(dimethylamino)pyridin-4- ylamino)naphthalen- 1 -yl)-2-oxoacetamide;

5-tert-Butyl-3-(2-(4-(2-(dimethylamino)pyridin-4-ylamino)naphthalen-l-yl)-2- oxoacetamido)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-(methylamino)pyridin-3-yl)naphthalcn-l-yl)-

2-oxoacet amide;

5-tert-Butyl-2-methoxy-3-(2-(4-(6-(methylamino)pyridin-3-yl)naphthalen-l-yl)-2- oxoacetamido)benzamidc;

5-tert-Butyl-N-ethyl-2-methoxy-3-(2-(4-(6-(methylamino)pyridin-3-yl)naphthalen-l-yl)-

2-oxoacetamido)benzamide;

5-tert-Butyl-N-cyclopropyl-2-methoxy-3-(2-(4-(6-(methylamino)pyridin-3-yl)naphthalen- l-yl)-2-oxoacetamido)benzamide:

(S)-N-(5-tert-Butyl-2-methoxy-3-(propylsulfonamido)phenyl)-2-(4-(2,3- dihydroxypropoxy)naphthalen- 1 -yl)-2-oxoacetamide;

2-(5-tert-Butyl-2-methylfixran-3-yl)-N-(4-(2-chloropyriinidin-4-ylamino)naphthalen-l- yl)-2-oxoacetamide; 2-(5-tert-Butyl-2-methylfuran-3-yl)-2-oxo-N-(4-(pyrimidin-4-ylamino)naphthalen-l- yl)acetamide;

N-(5-tert-Butylisoxazol-3-yl)-2-(4-(2,3-dihydroxypropoxy)naphthalen-l-yl)-2- oxoacetamide;

2-(5-tert-Butyl-2-methylfuran-3-yl)-2-oxo-N-(4-(pyrimidin-2-ylamino)naphthalen-l- yl)acetamide;

2-(5-tert-Butyl-2-methylfuran-3 -yl)-N-(4-(2-morpholinopyrimidin-4-yloxy)naphthalen- 1 - yl)-2-oxoacetamide;

2-(5-tert-Butyl-2-methylfuran-3-yl)-N-(4-(2-moφholinopyrimidin-4-ylamino)naphthalen-

1 -yl)-2-oxoacetamide;

2-(5-tert-Butyl-3-mcthylfuran-2-yl)-N-(4-(2-morpholinoethoxy)naphthalen-l-yl)-2- oxoacetamide;

2-(5-(4-Chlorophenyl)-2-(tri£luorome%l)furan-3-yl)-N-(4-(2- moφholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamide;

N-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(pyrrolidin-l- yl)pyrimidin-4-ylamino)naphthaien- 1 -yl)acetamide;

N-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(4- morpholinophenyl)naphthalen- 1 -yl)-2-oxoacetamide;

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-ylamino)naphthalen-l-yl)-N-(5-tert-butyl-2-methoxy-3-

(methylsulfonamido)phenyl)-2-oxoacetamide;

N-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)phcnyl)-2-oxo-2-(4-(pyrimidin-4- ylamino)naphthalen- 1 -yl)acctamidc;

N-(5-tcrt-Butyl-2-methoxy-3-(methylsulfbnamido)phenyl)-2-oxo-2-(4-(pyridin-4- ylamino)naphthalen- 1 -yl)acetamide;

5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methyl-N-(4-(pyridin-4- ylmethoxy)phenyl)nicotinamide;

5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benxamidυ)-2-methyl-N-(4-(2- moφholinoethoxy)phenyJ)nicotinamide;

5-(3-Fluoro-5-morpholinobenzamido)-2-methyl-N-(4-(2- moφholinoethoxy)phenyl)nicotinamide; 5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-N-(4-methoxyphenyl)-2- methylnicotinamide;

5-(3-Fluoro-5-morpholinobenzamido)-N-(4-methoxyphenyl)-2-methylnicotinamide;

5-(5-tert-Butyl-2-methoxybenzamido)-2-methyl-N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide;

5-(3-Fluoro-5-morpholinobenzamido)-2-methyl-N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide;

5-(5-tert-Butyl-2-methoxy-3-nitrobenzamido)-2-methyl-N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide;

5-(3-Acetamido-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)nicotinamide;

5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methyl-N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide;

Methyl 3-tert-butyl-5-(6-methyl-5-(4-(pyridin-2-ylmethoxy)phenylcarbamoyl)pyridin-3- ylcarbamoyl)benzoate;

5-tert-Butyl-N¹-(6-methyl-5-(4-(pyridin-2-ylmethoxy)phenylcarbamoyl)pyridin-3- yl)isophthalamide;

5-tert-Butyl-N ^] -methyl-N³-(6-methyl-5-(4-(pyridin-2- ylmethoxy)phenylcarbamoyl)pyridin-3-yl)isophthal amide;

N-(6-(Cyclopropylmethylamino)pyridin-3-yl)-5-(3-fluoro-5-moφholinobenzamido)-2-

(trifluoromethyl)nicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-N-(6-(isobutylamino)pyridin-3-yl)-2- methylnicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-N-(6-(isobutylamino)pyridin-3-yl)-N- methoxy-2 -methylnicotinamide;

5-(3-tert-Butyl-5-cyanobenzamido)-N-(6-(isobutylamino)pyridin-3-yl)-2- methyl ni coti nami de;

N¹-(5-(3-tert-Butylphenylcarbamoyl)-2-mcthylpyridin-3-yl)-N⁴-(tetrahydro-2H-pyraii-4- yl)terephthalamide;

N⁵-(5-tert-Butyl-3-cyano-2-methoxyphenyl)-2-methyl-N³-(4-(pyridin-2- ylmethoxy)phenyl)pyridine-3,5-dicarboxamide; 5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methyl-N-(4-(pyridin-3- ylmethoxy)phenyl)nicotinaπiide;

5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-N-(6-methoxypyridin-3- yl)-2-methylnicotinamide;

5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-N-(4-(5-fluoro-2- moφholinopyrimidin-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-N¹-methyl-N³-(6-methyl-5-(4-(pyridin-4- ylmethoxy)phenylcarbamoyl)pyridin-3-yl)isophthalamide;

5-(3-Bromo-5-tert-butyl-2-methoxybenzamido)-2-πiethyl-N-(4-(2- morpholinoethoxy)phenyl)nicotinamide;

5-(3-tert-Butyl-5-cyanobenzamido)-2-methyl-N-(4-(pyridin-4- ylmethoxy)phenyl)nicotinamide;

5-(3-Bromo-5-tert-butyl-2-methoxybenzamido)-2-methyl-N-(4-(pyridin-4- ylmethoxy)phenyl)nicotinamide;

5-tert-Butyl-N¹-methyl-N³-(6-methyl-5-(4-(tetrahydro-2H-pyran-4- ylcarbamoyl)phenylcarbamoyl)pyridin-3-yl)isophthalamide;

5-(5-tert-Butyl-3-cyano-2-methoxybcnzamido)-2-methyl-N-(4-(pyridin-4- ylmethoxy)phenyl)nicotinamidc;

N⁵-(5-tcrt-Butyl-2-methoxyphenyl)-2-methyl-N³-(4-(pyridin-2- ylmethoxy)phenyl)pyridine-3,5-dicarboxamide;

N⁵-(5-tert-Butyl-3-carbamoyl-2-methoxyphenyl)-2-methyl-N³-(4-(pyridin-2- ylmethoxy)phenyl)pyridine-3,5-dicarboxamide;

N⁵-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-methyl-N³-(4-(pyridin-4- ylniethoxy)phenyl)pyridine-3,5-dicarboxamide;

N⁵-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)plienyl)-2-methyl-N³-(4-(pyridin-2- ylmethoxy)phenyl)pyridine-3,5-dicarboxamide;

5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methyl-N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide; 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)benzamido)-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-methylnicotinaniide;

5-(3-tert-Butyl-5-cyanobenzamido)-N-(4-methoxyphenyl)-2-methylnicotinamide;

2-Methyl-5-(3-morpholino-5-(trifluorometliyl)benzamido)-N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide;

2-Methyl-5-(3-(piperidin-l-yl)-5-(trifluoromethyl)benzamido)-N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide;

2-Methyl-N-(4-(pyridin-2-ylmethoxy)phenyl)-5-(3-(pyrrolidin-l-yl)-5-

(trifluoromethyl)benzamido)nicotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-2-methyl-N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-2 -methyl -N-(4-(pyridin-2- ylmethoxy)phenyl)nicotinamide;

5-(3-Fluoro-5-moipholinobenzamido)-2-methyl-N-(6-((tetrahydrofuran-2- yl)methylamino)pyridin-3-yl)nicotinamide;

N-(6-(Cyclohexylmethylamino)pyridin-3-yl)-5-(3-fluoro-5-morpholinobenzaniido)-2- methylnicotinamide;

5-(3-Fluoro-5-moφholinobenzamido)-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; 5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-N-(4-methoxyphenyl)-2- methylnicotinamide;

5-(3-Fluoro-5-morpholinobenzamido)-2-methyl-N-(4-(pyridin-3- ylmethoxy)phenyl)nicotinamide;

N-(4-(3,5-Dimethoxybenzyloxy)phenyl)-5-(3-fluoro-5-moφholinobenzamido)-2- methylnicotinamide;

5-(3-Fluoro-5-morpholinobenzamido)-2-methyl-N-(4-(4-

(methylsulfonyl)benzyloxy)phenyl)nicotinamide;

5-(3-Fluoro-5-morpholinobcnzamido)-N-(4-(pyridin-2-ylmethoxy)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)benzamido)nicotinamide;

N-(6-(Cyclopropylmethylamino)pyridin-3-yl)-2-methyl-5-(3-morpholino-5-

(trifluoromethyl)benzamido)nicotinamide;

2-Methyl-5-(3-moφholino-5-(trifluoromethyl)benzamido)-N-(6-((tetrahydrofuran-2- yl)methylamino)pyridin-3-yl)ni cotinamide;

2-Methyl-5-(3-morpholino-5-(trifluoromethyl)benzamido)-N-(6-(tctrahydro-2H-pyran-4- ylamino)pyridin-3-yl)ni cotinamide;

N-(6-(Cyclohexylmethylamino)pyridin-3-yl)-2-methyl-5-(3-morpholino-5-

(trifluoromethyl)benzamido)nicotinamide;

2-Methyl-5-(3-moφholino-5-(trifluoromethyl)benzamido)-N-(6-((tetrahydro-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-moφholinobenzamido)-2-methyl-N-(6-(tetrahydro-2H-pyran-4- ylamino)pyridin-3-yl)nicotinamide;

N-(6-(Cyclopropylamino)pyridin-3-yl)-5-(3-fluoro-5-moφholinobenzamido)-2- methylni cotinamide;

5-(3-Fluoro-5-moφholinobenzamido)-2-methyl-N-(6-((tetrahydro-2H-pyτan-4- yl)methylamino)pyridin-3-yl)ni cotinamide; 5-(3-Fluoro-5-morpholinobenzamido)-N-(6-(isopropylamino)pyridin-3-yl)-2- methylnicotinamide;

5-(3-Fluoro-5-moφholinobenzamido)-N-(6-(isobutylamino)pyridin-3-yl)-2- methylnicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-N-(6-(isopropylamino)pyridin-3-yl)-2- methylnicotinamide;

N-(6-(Cyclopropylamino)pyridin-3-yl)-5-(3-fluoro-5-(pyrrolidin-l-yl)benzamido)-2- methylnicotinamide;

N-(6-(Cyclopropylmethylamino)pyridin-3-yl)-5-(3-fluoro-5-(pyrrolidin-l-yl)benzamido)-

2-methylnicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-2-methyl-N-(6-(tetrahydro-2H-pyran-4- ylamino)pyridin-3 -yl Nicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-2-methyl-N-(6-((tetrahydro-2H-pyran-4- yl)methyl ami no)pyri din-3 -yl)ni co tinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-2-methyl-N-(6-((tetrahydrofuran-2- yl)methylamino)pyridin-3-yl)nicotinamide;

N-(6-(Cyclohexylmethylamino)pyridin-3 -yl)-5-(3 -fluoro-5-(pyrrolidin- 1 -yl)benzamido)-

2-methylnicotinamide;

5-(3-Fluoro-5-moφholinobenzamido)-N-(6-(isopropylamino)pyridin-3-yl)-N-methoxy-2- methylni cotinamide;

5-(3-Fluoro-5-morpholinobenzamido)-N-(6-(isobutylamino)pyridin-3-yl)-N-methoxy-2- methylnicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-N-(6-(isopropylamino)ρyridin-3-yl)-N- methoxy-2-methylni cotinamide;

N-(6-(Cyclopropylmethylamino)pyridin-3-yl)-5-(3-fluoro-5-(pyrrolidin-l-yl)benzamido)-

N-methoxy-2 -methylnicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-N-methoxy-2-methyl-N-(6-(tetrahydro-2H- pyran-4-ylamino)pyridin-3-yl)ni cotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-N-methoxy-2-methyl-N-(6-((tetrahydro-2H- pyran-4-yl)methylamino)pyridin-3-yl)nicotinamide;

5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-N-methoxy-2-methyl-N-(6-((tetrahydrofαran-

2-yl)methylamino)pyridin-3-yl)ni cotinamide; 5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-N-(6-(isopropylamino)pyridin-3-yl)-2- methylnicotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-N-(6-(isobutylamino)pyridin-3-yl)-2- methylnicotinamide;

N-(6-(Cyclopropylamino)pyridin-3-yl)-5-(3-fluoro-5-(piperidin-l-yl)benzamido)-2- methylnicotinamide;

N-(6-(Cyclopropylmethylamino)pyridin-3-yl)-5-(3-fluoro-5-(piperidin-l-yl)benzamido)-

2-methylnicotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-2-methyl-N-(6-(tetrahydro-2H-pyran-4- ylamino)pyridin-3-yl)nicotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-2-methyl-N-(6-((tetrahydro-2H-pyran-4- yl)methylamino)pyridin-3-yl)nicotinamide;

5-(3-Fluoro-5-(piperidin-l -yl)benzamido)-2-methyl-N-(6-((tetrahydrofuran-2- yl)methylamino)pyridin-3-yl)nicotinamide;

N-(6-(Cyclohexy]methylamino)pyridin-3-yl)-5-(3-fluoro-5-(piperidin-l-yl)benzamido)-2- methylni cotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-N-(6-(isopropylamino)pyridin-3-yl)-N- methoxy-2 -methylni cotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-N-(6-(isobutylamino)pyridin-3-yl)-N-methoxy-

2-methylnicotinamide;

N-(6-(Cyclopropylmethylamino)pyridin-3-yl)-5-(3-fluoro-5-(piperidin-l-yl)benzamido)-

N-methoxy-2-methylnicotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-N-methoxy-2-methyl-N-(6-(tetrahydro-2H- pyran-4-ylamino)pyridin-3-yl)nicotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-N-methoxy-2-methyl-N-(6-((tetrahydro-2H- pyran-4-yl)methylamino)pyridin-3-yl)nicotinamide;

5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-N-methoxy-2 -methyl -N-(6-((tetrahydrofuran-

2-yl)methylamino)pyridin-3-yl)nicotinamide;

5-tert-Butyl-N¹-(5-(6-(isopropylamino)pyridin-3-3dcarbamoyl)-6-methylp>τidin-3-yl)-N³- mcthylisophthalamide;

5-tert-Butyl-N¹-(5-(6-(isobutylamino)pyridin-3-ylcarbamoyl)-6-methylpyridin-3-yl)-N³- methyli sophthalamide; 5-tert-Butyl-N¹-(5-(6-(cyclopropylamino)pyridin-3-ylcarbamoyl)-6-methylpyridin-3-yl)-

N³-methylisophthal amide;

5-tert-Butyl-N^I-(5-(6-(cyclopropylmethylamino)pyridin-3-ylcarbamoyl)-6-methylpyridin-

3-yl)-N³-methylisophthal amide;

5-tert-Butyl-N¹-methyl-N³-(6-methyl-5-(6-((tetrahydrofuran-2-yl)methylamino)pyridin-3- ylcarbamoyl)pyridin-3-yl)isophthal amide;

5-(3-tert-Butyl-5-cyanobenzamido)-N-(6-(isopropylamino)pyridin-3-yl)-2- methylnicotinamide;

5-(3-tert-Butyl-5-cyanobenzamido)-N-(6-(cyclopropylamino)pyridin-3-yl)-2- methylnicotinamide;

5-(3-tert-Butyl-5-cyanobenzamido)-N-(6-(cyclopropylmethylamino)pyridin-3-yl)-2- methylnicotinamide;

5-(3-tert-Butyl-5-cyanobenzamido)-2-methyl-N-(6-(tetrahydro-2H-pyran-4- ylamino)pyridin-3-yl)nicotinamide;

5-(3-tert-Butyl-5-cyanobenzamido)-2-methyl-N-(6-((tetrahydrofuran-2- yl)methylamino)pyridin-3-yl)nicotinamide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-2-methoxy-3-(methylsulfonamido)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

5-tert-Butyl-N¹-methyl-N³-(4-methyl-3-(5-(ncopentylcarbamoyl)isoxazol-3- yl)phenyl)isophthalamide;

3-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-Acetamido-5-tert-butylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamidc;

Methyl 3-tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3- yl)phenylcarbamoyl)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; tert-Butyl (3-(5-(5-tert-butyl-2-memoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methylcarbamate;

5-tert-Butyl-2-methoxy-N-(4-methyl-3-(5-(pivalamidomethyl)isoxazol-3- yl)phenyl)b enzamide;

5-tert-Butyl-N-(3-(5-((3,3-dimethylbutanamido)methyl)isoxazol-3-yl)-4-methylphenyl)-

2-methoxybenzamide;

N-(3-(5-(Benzamidomethyl)isoxazol-3-yl)-4-methylphenyl)-5-tert-butyl-2- methoxybenzamide;

N-((3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methyl)fiiran-2-carboxamide;

N-((3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylρhenyl)isoxazol-5- yl)methyl)picolinamide;

N-((3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methyl)nicotinamide;

N-((3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)isoxazol-5- yl)methyl)isonicotinamide;

5-tert-Butyl-2-methoxy-N-(4-methyl-3-(5-(morpholine-4-carbonyl)-lH-pyrazol-3- yl)phenyl)b enzamide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)- lH-pyrazole-5-carboxamide;

3-(5-(3 -tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-neopcntyl- 1 H-pyrazole-5- carboxamide;

5-(3-(3-tert-Butyl-5-cyanobenzamido)plienyl)-l-methyl-N-neopentyl-lH-ρyrazole-3- carboxamide;

5-(3-(3-Fluoro-5-morpholinobenzamido)phenyl)-l-isopropyl-N-neopentyl-lH-pyrazole-

3 -carboxamide;

5-(3-(5-tert-Butyl-3-cyano-2-methoxybenzamido)phenyl)-l-methyl-N-neopentyl-lH- pyrazole-3 -carboxamide;

5-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-N-neopentyl- 1.3,4- oxadiazole-2-carboxamide:

3-(5-(3-Fluoro-5-morphoHnobenzamido)-2-πiethylpyridin-3-yl)-N-neopentyl-lH- pyrazole-5-carboxamide; 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-l-methyl-N-neopentyl- lH-pyrazole-5-carboxamide;

5-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylpyridin-3-yl)-l-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-πiethylphenyl)-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-ncopentylisoxazole-5- carboxamide;

3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2-(pyridin-4- yl)ethyl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-morpholInobenzamido)-2-methylphenyI)-N-(pyridin-3- ylmethyl)Isoxazole-5-caτboxamide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4- yl)isoxazole-5-carboxamide; 3-(5-(3-Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-Cyano-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-Cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-

((tetrahydrofiiran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-(piperazin-l-ylmethyl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-(2-(4-methylpiperazin-l-yl)ethoxy)benzamido)-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- ylmethyl)isoxazole-4-carboxamide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-neopentyl-lH-pyrazole-5- carboxamide;

3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-neopentyl-lH-pyrazole-5- carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydro-2H-pyran-4- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-moφholinobenzamido)-2-methylphcnyl)-N-((tetrahydro-2H-pyran-4- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-moφholinobenzamido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4- yl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2-(pyrrolidin-l- yl)cthyl)isoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-((tetrahydrofiαran-2- yl)mcthyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-(pyridin-3-ylmethyl)isoxazole-

5-carboxamide;

3-(2-Methyl-5-(3-morpholinobenzamido)phenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-Methyl-5-(3-moφholinobenzamido)phenyl)-N-(pyridin-3-ylmethyl)isoxazole-5- carboxamide;

3-(5-(3-Cyanobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

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 (adamantan-l-ylmethyl)-amide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydro-2H-pyran-4- yl)mcthyl)- 1 H-pyrazole-5-carboxamide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)- 1 H-pyrazole-5-carboxamide;

3-(5-(5-tert-Butyl-2-methoxybenzamido)-2-methylphenyl)-N-(cyclohexylmethyl)-lH- pyrazole-5-carboxamide;

5-[5-(5-tert-Butyl-2-methoxy-benzoylamino)-2-methyl-phenyl]-2H-pyrazole-3-carboxylic acid (adamantan-1 -yl-methyl)-amide;

3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-((tetrahydro-2H-pyran-4- yl)methyl)-lH-pyrazole-5-carboxamide;

3-(2-Methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-Methoxybenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-Chlorobenzamido)-2-methylphcnyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3,5-bis(Trifluoromcthyl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-Fluorobenzamido)-2-methylphenyI)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-moφholinobenzamido)-2-methylphenyl)-N-((tetrahj'droniran-2- yl)methyl)- 1 H-pyrazole-5-carboxamide;

3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-

1 H-pyrazole-5-carboxamide; 3-(5-(3-Fluoro-5-morpholinobenzamido)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)-

1 H-pyrazole-5-carboxamide;

N-(Cyclohexylmethyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2-metliylphenyl)-lH- pyrazole-5-carboxamide;

5-[5-(3-Fluoro-5-morpholin-4-yl-benzoylamino)-2-methyl-phenyl]-2H-p>τazole-3- carboxylic acid (adamantan-l-ylmethyl)-amide;

N-(Cyclohexylmethyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

3-[5-(3-Fluoro-5-moφholin-4-yl-benzoylamino)-2-methyl-phenyl]-isoxazole-5- carboxylic acid (adamantan-l-ylmethyl)-amide;

3-(5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-neopcntylisoxazole-5- carboxamide;

3-(5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

N-Benzyl-3-(5-(3-tcrt-butyl-5-cyanobenzamido)-2-methylphenyl)-N-methylisoxazole-5- carboxamide;

N-Benzyl-3-(5-(5-tert-butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N- methylisoxazole-5-carboxamide;

N-Benzyl-3-(5-(3-fluoro-5-moφholinobenzamido)-2-methylphenyl)-N-methylisoxazole-

5-carboxaniide;

3-(5-(3-Fluoro-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(3-moφholino-5-(trifluoromethyl)benzamido)phenyl)-N- neopentylisoxazole-5-carboxamide;

3-(2-Methyl-5-(3-morpholino-5-(trifluoromethyl)benzamido)phenyl)-N-(pyridin-3- 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-moφholino-5-(trifluoromethyl)benzamido)pheny])-N-(tetrahydro-2H- pyran-4-yl)isoxazole-5-carboxamide;

3-(2Mmethyl-5-(3-moφholino-5-(trifluoromethyl)benzamido)phenyl)-N-

((tetrahydroftιran-2-yl)methyl)isoxazole-5-carboxamide; 3-(5-(4-tert-Butylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-Methyl-5-(3-(piperidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(3-(piperidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N- neopentylisoxazole-5-carboxamide;

3-(2-Methyl-5-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N- neopentylisoxazole-5-carboxamide;

3-(2-Methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2- carboxamido)phenyl)-N-neopentylisoxazole-5-carboxamide;

N-(3,4-Dimethoxybenzyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl)-N- methylisoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(3-(4-methylpiperazin-l-yl)-5-(trifiuoromethyI)benzamido)phenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-fluoro-5-(4-methylpiperazin-l-yl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3,3-Dimethyl-2,3-dihydrobenzofuran-5-carboxamido)-2-methylplienyl)-N- neopentylisoxazole-5-carboxamide;

3-(2-Methyl-5-(3-(piperidin-l-yl)-5-(trifluoromethyl)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-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-

((tetrahydroftiran-2-yl)metliyl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-

((tetrahydronαran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-Biphcnyl-3-ylcarboxamido-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-moφholinobenzamido)-2-niethylphenyl)-N-methylisoxazole-5- carboxamide; N-Ethyl-3-(5-(3-fluoro-5-morpholinobenzaniido)-2-methylphenyl)isoxazole-5- carboxamide;

3-(5-(3-Fluoro-5-moφholinobenzamido)-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-moφholinobenzamido)-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-neopentylisoxazole-5-carboxamide;

3-(2-Methyl-5-(5-(piperidin-l-yl)nicotinamido)phenyl)-N-neopentylisoxazole-5- carboxamide;

3-(2-Methyl-5-(5-(pyrrolidin-l-yl)nicotinamido)phenyl)-N-neopentylisoxazole-5- carboxamide;

3-(2-Methyl-5-(5-moφholinonicotinamido)phenyl)-N-neopentylisoxazole-5- carboxamide;

3-(2-Methyl-5-(5-(pyrrolidin-l-yl)nicotinamido)phenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(5-(piperidin-l-yl)nicotinamido)phenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(5-(pyrrolidin-l-yl)nicotinamido)phenyl)-N-(tetrahydro-2H-pyran-4- yl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(5-(piperidin-l-yl)nicotinamido)phenyl)-N-(tetrahydro-2H-pyran-4- yl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(5-morpholinonicotinamido)phenyl)-N-((tetrahydroniran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(2,3- dimcthoxybenzyl)-N-methylisoxa7ole-5-carboxamide:

3-(5-(3-lsopropylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(2- methoxybenzyl)-N-methylisoxazole-5-carboxamide; 3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(3- methoxybenzyl)-N-methylisoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(3,5- dimethoxybenzyl)-N-methylisoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-((l- ethylpyτrolidin-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-((tetrahydrofuran-

2-yl)methyl)isoxazole-5-carboxamide;

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-methoxybenzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-moφholinobenzamido)-2-methylphenyl)-N-(3- methoxybenzyl)isoxazole-5-carboxamide;

N-(2,3-Dimethoxybenzyl)-3-(5-(3-fluoro-5-moφholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

N-((l-Ethylpyrrolidin-2-yl)methyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

N-Benzyl-3-(5-(3-fluoro-5-moφholinobenzamido)-2-methylphenyl)isoxazole-5- carboxamide;

N-(3,5-Dimethoxybenzyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

N-(Benzo[d][l,3]dioxol-5-ylmethyl)-3-(5-(3-fluoro-5-morpholinobenzamido)-2- methylphenyl)isoxazole-5-carboxamide;

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-methylphenyl)-N-neopentylisoxazole-5- carboxamidc;

3-(5-(3-Acetylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5-carboxamide;

3-(5-(3-Cyano-5-moφholinobenzamido)-2-methylphenyl)-N-(3- methoxybenzyl)isoxazole-5-carboxamide;

3-(5-(3-(2-Methoxypropan-2-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide; 3-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-((l-ethylpyrrolidin-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-((l-ethylpyrrolidin-2- yl)methyl)isoxazole-5-carboxamide;

N-((l-Ethylpyrrolidin-2-yl)methyl)-3-(2-methyl-5-(3-moφholino-5-

(trifluoromethyl)benzaπiido)phenyl)isoxazole-5-carboxamide;

3-(5-(3-(2-Ethoxypropan-2-yl)benzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-(l- methylpiperidin-4-yl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-(l-methylpiperidin-4- yl)isoxazole-5-carboxamide;

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-(trifluoroniethyl)benzamido)phenyl)-N-((l- methylpiperidin-4-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-((l-methylpiperidin-4- yl)methyl)isoxazole-5-carboxamide;

3-(5-(5-tert-Butyl-3-cyano-2-methoxybenzamido)-2-methylphenyl)-N-((l- methylpiperidin-4-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-moφholinobenzamido)-2-methylphenyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-(piperidin-l-yl)benzamido)-2-methylphcnyl)-N-((tetrahydrofuran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-((tetrahydrofiαran-2- yl)methyl)isoxazole-5-carboxamidc;

2-Methoxyethyl 3-tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3- yl)phenylcarbamoyl)phenylcarbamate;

Methyl 3-tert-butyl-5-(4-methyl-3-(5-(neopentylcarbamoyl)isoxazol-3- yl)phenylcarbamoyl)benzoate;

3-(5-(3-tert-Butyl-5-(2-methylthiazol-4-yl)benzamido)-2-raethylphenyi)-N- neopentylisoxazole-5-carboxamide; 3-(5-(3-Fluoro-5-thiomorphoKnobenzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-thiomoφholinobenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-(2,6-Dimethylmorpholino)-5-fluorobenzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-(l,4-oxazepan-4-yl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-(l-Hydroxy-2,2-dimethylpropyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-Amino-5-tert-butylbenzamido)-2-methylphenyl)-N-neopentylisoxazole-5- carboxamide;

3-(5-(3-lsobutylbenzamido)-2-methylphenyl)-N-((tetrahydrofliran-2-yl)methyl)isoxazole-

5-carboxamide;

3-(2-Methyl-5-(3-neopentylbenzamido)phenyl)-N-((tetrahydroniran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-(2,6-Dimethylmorpholino)-5-fluorobenzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-(l,4-oxazepan-4-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-thiomorpholinobenzamido)-2-methylphenyl)-N-((tetrahydroftiran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-(2,6-Dimethylmoφholino)-5-fluorobenzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-Fluoro-5-(l,4-oxazepan-4-yl)benzamido)-2-methylphenyl)-N-((tetrahydrofuran-

2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-((tetrahydronαran-2- yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-(hydroxymethyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxainide;

3-(2-Methyl-5-(3-neopentylbenzamIdo)phenyl)-N-neopentylisoxazole-5-carboxamide;

3-(2-Methyl-5-(2-morpholinoisonicotinamido)phenyl)-N-neopentylisoxazole-5- carboxamide; 3 -(2-Methyl-5-(2-(pyrrolidin- 1 -yl)isonicotinamido)phenyl)-N-neopentylisoxazole-5- carboxamide;

3-(2-Methyl-5-(2-(piperidin-l-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-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-(pyridin-2-ylmethyl)isoxazole-

5-carboxamide;

3-(5-(3-Fluoro-5-(pyrrolidin-l-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- ylmethyl)isoxazole-5-carboxamide;

3-(2-Methyl-5-(3-(pyridin-2-yl)benzamido)pheπyl)-N-((tetrahydroflιran-2- yl)niethyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-morpholinobenzamido)-2-methylphenyl)-N-(pyridin-2- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-(piperidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-2- ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-Cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-(pyridin-2- ylmethyl)isoxazole-5-carboxamide;

3-{5-[3-Fluoro-5-(l-oxo-l λ -thiomorpholin-4-yl)-benzoylamino]-2-methyl-phenyl}- isoxazole-5-carboxylic acid (2,2-dimethyl-propyl)-amide;

N-(( 1 -Methyl- 1 ,2, 5,6-tetrahydropyridin-3 -yl)methyl)-3 -(2-methyl-5-(3 -(pyrrolidin- 1 -yl)-

5-(trifluoromethyl)benzamido)phenyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N- ncopcntylisoxazole-S-carboxamide;

3-(5-(3-tert-Butyl-5-(morpholinomethyl)bcnzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide; 3-(5-(3-tert-Butyl-5-(pyrrolidin-l-ylmethyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-(piperidin-l-ylmethyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-(morpholinomethyl)benzamido)-2-methylphenyl)-N-

((tetrahydrofuran-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-l-ylmethyl)benzamido)-2-methylphenyl)-N- neopentylisoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-(pyrrolidin-l-ylmethyl)benzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-(pipcridin-l-ylmethyl)benzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-((dimethylamino)methyl)benzamido)-2-methylphenyl)-N-

((tetrahydroftiran-2-yl)methyl)isoxazole-5-carboxaniide;

3-(5-(3-tert-Butyl-5-(piperazin-l-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-N¹-(2-(dimethylamino)ethyl)-N³-(4-methyl-3-(5-

(neopentylcarbamoyl)isoxazol-3-yl)phenyl)isophthal amide;

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-l-yl)methyl)bcnzamido)-2-methylphenyl)-N-

(pyτidin-3-ylmethyl)isoxazole-5-carboxamidc;

3-(5-(3-tert-Butyl-5-(moφholinomcthyl)benzamido)-2-metliylphenyl)-N-(pyridin-3- ylmethyl)isoxazole-5-carboxamide;

3 -(5-(3 -tcrt-Butyl-5-((4-(2-hydroxyethyl)piperazm- 1 -yl)methyl)benzamido)-2- mcthylphenyl)-N-((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-(((3 S,5R)-3 ,5-dimethylpiperazin- 1 -yl)methyl)benzamido)-2- methylphenyl)-N-((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide; 3-(5-(3-((4-Acetylpiperazin-l-yl)methyl)-5-tert-butylbenzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-((3-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-

((tetrahydrofuran-2-yl)methyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-cyclohexylisoxazole-5- carboxamide;

3-(5-(3-Cyano-5-(pyrrolidin-l-yl)benzamido)-2-methylphenyl)-N-cyclohexylisoxazole-5- carboxamide;

3-(5-(3-tert-Butyl-5-cyanobenzamido)-2-methylphenyl)-N-(piperidin-l-yl)isoxazole-5- carboxamide;

3 -(5-(3 -Cyano-S-Cpyrrolidin- 1 -yl)benzamido)-2-methylphenyl)-N-(piperidin-l - yl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-cyanobcnzamido)-2-methylphenyl)-N-morpholinoisoxazole-5- carboxamide;

3 -(5-(3 -Cyano-5-(pyrrolidin- 1 -yl)benzamido)-2-methylphenyl)-N-morpholinoisoxazole-

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- tert-butyl-3-cyano-2-methoxybenz amide;

3-tert-Butyl-5-cyano-N-(4-methyl-3-(5-(2,2,6,6-tetramethylmorpholinc-4- carbonyl)isoxazol-3-yl)phenyl)benz amide;

5-tert-Butyl-3-cyano-2-methoxy-N-(4-methyl-3-(5-(2,2,6,6-tetramethylmorpholine-4- carbonyl)isoxazol-3-yl)phenyl)benz amide;

3-(5-(3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N- cyclohexylisoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-

((6-(trifluoromethyl)pyridin-3-yl)methyl)isoxazole-5-carboxamide;

3-tert-Butyl-N-(4-methyl-3-(5-(piperidine-l -carbonyl)isoxazol-3-yl)phenyl)-5-((4- methylpipcrazin- 1 -yl)methyl)benzamide; 3-(5-(3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-

(piperidin- 1 -yl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N-

(pyridin-4-ylmethyl)isoxazole-5-carboxamide;

3-(5-(3-tert-Butyl-5-((4-methylpiperazin-l-yl)methyl)benzamido)-2-methylphenyl)-N- cyclopentylisoxazole-S-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-IB 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 pretrearment 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 6 A and 6B show the effects of a compound as described herein on the particle size distribution and on HDL₂ and HDL₃ levels of Syrian Golden Hamsters, upon once daily administration of the compound for 14 days (as determined by NMR and ultracentrifugation methods, respectively). [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 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

[00143] 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. [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- hepty!, 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 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[3.3.1]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 substitucnts 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(CH₃), -CH=C(CH₃)₂, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃), -C(CH₂CH₃)=CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others. Representative substituted alkeny] 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. [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 -C≡CH, -CsC(CH₃), -CsC(CH₂CH₃), -CH₂C≡CH, -CH₂C=C(CH₃), and -CH₂C≡C(CH₂CH₃), among others. Representative substituted alkynyl groups maybe 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-, A-, 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. 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, O, 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[l,4]dioxinyl, and benzo[l,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[l,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyπdinyl, pteπdinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydromdolyl, dihydrobenzodioxmyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotπazolyl, 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 morphohnyl 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 πng compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, tπazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyπmidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyπdyl), lndazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, tπazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyπdyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, lsoquinohnyl, 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 πng 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-prop>lmorpholinyt. furan-2-yI methyl, furan-3-yl methyl, ρyndine-3-yl methyl, tctrahydrofuran-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. [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 alkcnylcnc refers to divalent alkene groups.

[00163] The term "carboxylate" as used herein refers to a -COOH group. [00164] The term "carboxylic ester" as used herein refers to -COOR³⁰ groups. R³⁰ 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)NR³¹R³², and -NR³¹C(O)R³² groups, respectively. R³¹ and R³² 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)NH₂) and formamide groups (-NHC(O)H).

[00166] Urethane groups include N- and O-urethane groups, i.e., -NR³³C(O)OR³⁴ and -OC(O)NR R groups, respectively. R³³ and R³ 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 -NHR³⁵ and -

NR³⁶R³⁷ groups, wherein R³⁵, R³⁶ and R³⁷ 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 NH₂, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[00168] The term "sulfonamido" includes S- and N-sulfonamide groups, i.e.,

-SO₂NR³⁸R³⁹ and -NR³⁸SO₂R³⁹ groups, respectively. R³⁸ and R³⁹ 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 (-SO2NH₂).

[00169] The term "thiol" refers to -SH groups, while sulfides include -SR⁴⁰ groups, sulfoxides include -S(O)R⁴¹ groups, sulfones include -SO₂R⁴² groups, and sulfonyls include -SO₂OR⁴³. R⁴⁰, R⁴¹, R⁴², and R⁴³ are each independently a substituted or unsubstituted alkyl, cycloalkyl. alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00170] The term "urea" refers to -NR⁴⁴-C(O)-NR⁴⁵R⁴⁶ groups. R⁴⁴, R⁴⁵, and R⁴⁶ 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(NR⁴⁷)NR⁴⁸R⁴⁹ and -NR⁴⁷C(NR⁴⁸)R⁴⁹, wherein R⁴', R⁴⁸, and R⁴⁹ 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 -NR⁵⁰C(NR⁵¹)NR⁵²R⁵³, wherein R⁵⁰, R⁵¹,

R⁵² and R⁵³ 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(R⁵⁴)=C(R⁵⁵)NR⁵⁶R⁵⁷ and

-NR⁵⁴C(R⁵⁵)=C(R⁵⁶)R⁵⁷, wherein R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ 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)NR⁵⁸C(O)R⁵⁹, wherein R⁵⁸ and R⁵⁹ 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 -CR⁶⁰(NR⁶¹) and -N(CR⁶⁰R⁶¹) groups, wherein

R⁶⁰ and R⁶¹ 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 R⁶⁰ and R⁶¹ 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 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.

[00177] 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, oi,Q!-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-mcthyl derivatives such as hemithio, dithio and aminothio acetals; and others. [00179] Representative carboxy protecting groups are Cj to Cg 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, cyclop entylmethyl, 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, l-(propionyloxy)-l -ethyl, l-(pivaloyloxyl)-l -ethyl, 1 -methyl- 1- (propionyloxy)-! -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-l- ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1 -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-l,3-dioxolen-4-yl)methyl, and the like; and (5-phenyl-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-l,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 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:

[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 7/2:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future 6:165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (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⁺, Mg²⁺, Zn²⁺), 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 <!mg/l represent low cardiovascular risk, while levels >3mg/I 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 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-α, 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 HDL₂ (large, buoyant HDL, densityl.063-1.125 g/rnl) and HDL₃ (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. Typically, 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 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 HDL₂ and HDL₃, 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/1, 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 AIc, HbIc , HbAIc or HgAIc) 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 HbAIc. While diabetic subject treatment goals vary, many include a target range of HbAIc values. A diabetic with good glucose control has a HbAl c level that is close to or within the reference range. The International Diabetes Federation and American College of Endocrinology recommends HbAIc values below 6.5%, while the range recommended by the American Diabetes Association extends to 7%. A very high HbAIc 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 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 Fe²⁺, carbon monoxide and bilirubin via the intermediate compound biliverdm. 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 hence fibrinolysis (the physiological breakdown of blood clots). PAI-I 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-I 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 μM 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-Ib 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 I. References describing cytokine-mediated processes and disorders.

al.,

rte tis empora n onopouos et a., nn eum s

62:1116

Arthropod-Borne SL Raung et al., Biochem Biophys Res Commun Encephalitis 2005 ll(327):399-406 et

45(7): 2314-23

Corticosteroid Resistant HT Holgatc ct al., Lancet 2006 368: 780-93 Asthma

Degenerative Joint PH Marks et al., Arthroscopy 2005 21(11):1342- Disease 7 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-l l

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-£

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 Pomerance 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 J 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-l 1 ; N Koike et al., Transplantation 2004 77(2):286-92

Lefkowitz et al., Med Hypotheses 2005 65(4):716-21

J Physiol 2003 194(2):215-24; R Vassal, et al., Chest 2002 124(1):413-414; P Pantelidis et al., Respir Res 2001 2(6):365-72; M KoIb et al., J Clin Invest 2001 107(12):1529-36

Renal Cancer S JJtemoto et al., Oncol Rep 2003 10(6): 1947-55

[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 "therapeutically 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, but are not limited to, Creatine Kinase with Muscle and/or Brain subunits (CKMB), D- Dimer, F 1.2, 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 LD₅₀ and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and the ED₅₀ is the dose therapeutically effective in 50% of the population. The LD₅₀ and ED₅₀ 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, synergist! cally 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. Ln 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 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, intrastemal, 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 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 antioxidants 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 maybe 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. [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 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.

[00215] 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 dichlorodifluorom ethane, 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.

[00216] 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, 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 withm the scope of this invention The compounds used in this invention can be incorporated into vaπous types of ophthalmic formulations for delivery to the eye (e.g., topically, lntracamerally, 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, stenle ophthalmic suspension or solution. Ophthalmic solution foπnulations 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, methyl cellulose, 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 stenle ophthalmic ointment foπnulations, 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 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.

[00223] 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.

[00225] 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 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 (57^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 1 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 11 hours apart, at about 1 1 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. [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 1 month to about 2 months, to about 3 months, to about 4 months, to 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 descπbed 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 descπbed 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 descπbed 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 peπod 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 [00237] Examples of compounds used in the instant invention are described below.

A first group of compounds are represented by Formula IA,

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, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List II.

LIST II: Definition of variables for the first group of compounds of Formula IA.

G is a C₃-₁₀ carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl containing one or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R¹, R² or R³;

X is C(O), C(S) or CH₂;

Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide,

aryl, -(C_1-3 alkyl)-(C6-₁o aryl), -(Y)-(Co-3 alkyl)-(C₆-i₀ aryl), or -(Y)-(C₀^₃ alkyl)-(5- 10 member heteroaryl), each of which is optionally substituted with one or more R or R ; each Y is independently -CHZ-, -CZ₂-, -CHR-, -O-, -C(=CHR)-, or -C(=C-CO₂R)-; each Z is independently F, Cl, -OR, -NR₂, -SR, -NHCONHR, or -NHCOR;

L is a covalent bond or a saturated or unsaturated branched or unbranched Ci-io carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(O)_m; and wherein L is optionally substituted with 1-2 0x0 groups and one or more of F, Cl, Br, or I; each m is independently 0, 1 or 2; Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci_-6 alkoxy, C₁^ alkyl-S(O)_m, or phenyl-S(O)_m, wherein the cycloalkyl, aryl, heterocyclyl, C₁^ alkoxy, C₁^ alkyl-S(O)_m, or phenyl-S(O)_m is each optionally substituted with one or more R²⁷; each R is independently hydrogen or substituted or unsubstituted Cue alkyl; each R' is independently hydrogen, substituted or unsubstituted Cμg alkyl, substituted or unsubstituted (C0-4 alkyl)-(Cβ-io aryl) or substituted or unsubstituted (Co-4 alkyl)-(5-lO member heterocyclyl); each R" is independently substituted or unsubstituted C₁-_S alkyl, substituted or unsubstituted (C0-4 alkyl)-C6-io ^aryl or substituted or unsubstituted (Co-4 alkyl)-(5-lO member heterocyclyl); each R¹ is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR₂, -C(O)OR, -OR, -NR'R', -SiR₃, - S(O)_mR, substituted or unsubstituted Ci_{- 10} alkyl, substituted or unsubstituted C_2-1O alkenyl, substituted or unsubstituted C_2-1O alkynyl, substituted or unsubstituted C_3-IO cycloalkyl, substituted or unsubstituted Cs_-S 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, O, or S(O)_m; each R , R and R is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C_1-6 alkyl, substituted or unsubstituted Cβ-io aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR⁶, -C(O)R', -C(O)OR', -C(O)NR'₂, -NR'_2j -NO₂, -S(O)_1nR", -NR¹SO₂R", -NR'C(O)NR'R', -NR'C(S)NR'R\ -NR¹C(O)OR' or -SO₂NR'₂; each R³ is independently substituted or unsubstituted Cβ-io aryl, substituted or unsubstituted saturated or unsaturated 3-1 1 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)_m, substituted or unsubstituted C3-1₂ cycloalkyl, substituted or unsubstituted Cs_-12 cycloalkenyl, substituted or unsubstituted C_7-2O aralkyl, substituted or unsubstituted straight or branched C_M alkyl, R²⁰C(O)N(R²¹)-, R²²O-, R²³R²⁴NC(O)-, R²⁵(CH₂)_mC(O)N(R²ⁱ)-, R²⁶C(O)(CH₂)_mN(R²¹)-, substituted or unsubstituted C₂^g alkenyl, or substituted or unsubstituted C_2-g alkynyl, wherein one or more methylene groups of the Ci-s alkyl, Co-s alkenyl, or C₂^ alkynyl are optionally replaced by O, NH, or S(O)_m; each R⁶ is a C_1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R²⁶; each R⁷, R^s, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁷, R¹⁹, and R²⁵ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co_^) alkyl)amino, wherein the Co_-4 alkyl is optionally partially or fully halogenated; each R¹ ' and R is independently hydrogen or C₁.₄ branched or unbranched alkyl optionally partially or fully halogenated; and

R ⁸ is independently hydrogen or Cj_₄ branched or unbranched alkyl optionally independently substituted with oxo or R²⁵.

R²⁰ is substituted or unsubstituted C_MO alkyl, substituted or unsubstituted Co-₆ alkyl- phenyl, substituted or unsubstituted Co-₆ alkyl-heterocyclyl, OR' or NR'₂;

R²¹ is hydrogen or C_M branched or unbranched alkyl optionally partially or fully halogenated; each R ², R²³ and R is independently hydrogen, substituted or unsubstituted Ci_-1O alkyl, wherein the Ci-io alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted Co-β alkyl-heterocyclyl; or R ³ and R taken together optionally form a heterocyclic or heteroaryl ring; each R²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-₄ alkyl)amino, wherein the C₀-₄ alkyl is optionally partially or fully halogenated; each R²⁷ 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_M0 alkyl, substituted or unsubstituted C₂-io alkenyl, substituted or unsubstituted C₂-₁0 alkynyl, substituted or unsubstituted C₃-₁₀ cycloalkyl, substituted or unsubstituted C₅.₈ cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)_m; provided however that when Ar is -(Y)-(Ce-_Io aryl) and G is N-(substituted or unsubstituted phenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R¹, R² or R³; and IA is not N-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-2-(4-chloro- phenyl)-acetamide. [00238] In certain embodiments of the first group of Formula IA, the compound at a concentration of 10 μM 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[l,4]oxazine-3-only, benzodioxolyl, benzo[l,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, thiomoφholinyl, 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[l,4]oxazin-3-onyl, benzodioxolyl, bcnzo[l ,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 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 Cβ-io aryl. In some such embodiments, Ar is substituted with at least one R⁴ or R⁵. 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 -(Ci_-3 alkyl)-(C₆.₁₀ aryl), -(Y)-(C_0-3 alkyl)-(C_6-10 aryl), Or -(Y)-(C_0-3 alkyl)-(5-10 member heteroaryl). In some such embodiments, Ar is substituted with at least one R⁴ or R⁵. In some such embodiments, Y is -CZ₂- and each Z is independently F, -OR or -CHR. For example, Y is -CF₂-. In others, Y is -CHR or -CHZ- and Z is -OR. Thus, for example, Y is -CHOH-. Alternatively, Y is -O- or -CH₂-. In still other such embodiments, the Cβ-io 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 -(Ci_-3 alkyl)-(C6-io 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 O, NR or S(O)_m. In others, L is a covalcnt bond, a Ci-C₉ alkoxy, -C(O)O-, -NH- or -O-.

[00244] As noted above, Q, other than -H or -NR'R', is optionally substituted with

R²⁷. 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, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3- bjpyridinyl, 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, thiomoφholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, Cue alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to Ci_-3 alkyl or Ci_-5 alkoxyalkyl, phenylamino; Ci .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- bjpyridinyl, 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, thiomoφholino sulfoxide, thiomoφholino sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, Ci_-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C i-3 alkyl or C ₁.5 alkoxyalkyl, phenylamino; Ci_-6 alkyl-S(O)_m or phenyl-S(O)_m. In some such embodiments, R²⁷ is Cj_-6 alkyl, Ci-e alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C]_3 alkyl)amino, mono- or di- (phenyl-Ci-3 alkyl)amino, Ci_-6 alkyl-S(O)_m, phenyl-C].₃-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, Ci-₆ alkyl or Ci_₆ alkoxy.

[00246] In some other embodiments of the first group of compounds of Formula

IA, Q is hydrogen, phenyl, thiomoφholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In others, Q is mσφholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R" is -C(O)OR', -NR'R', substituted or unsubstituted straight or branched Ci_-10 alkyl, substituted or unsubstituted C_7-2O aralkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S(O)_n,. Alternatively, Q is pyrimidinyl and R²⁷ 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, O, or S(O)_m. In yet other such embodiments, Q is pyridinyl, and R²⁷ is -NR'R', substituted or unsubstituted C₁^ alkyl, or substituted or unsubstituted saturated or unsaturated 3-1 1 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)_n,.

[00247] In some embodiments of the first group of compounds of Formula IA, when R⁴ and R⁵ are absent, -L-Q is not -H.

[00248] In some embodiments of the first group of compounds of Formula IA, each R¹ is independently

C₃.₁₀ branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3.10 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^ branched or unbranched alkyl which is optionally partially or fully halogenated, C3.8 cycloalkyl, C5.8 cycloalkenyl, hydroxy, cyano, Cμ₃ alkoxy which is optionally partially or fully halogenated and NH₂C(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 Ci .3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl Ci_₃ alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyelopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O₅ S(O)_n,, CHOH, C=O₅ C=S or NH;

C₃-_Io 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 being optionally, partially or fully halogenated, Ci_-6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C[.₃ alkoxy optionally partially or fully halogenated, NH₂C(O) or mono- or (Ii-(C_1-3 alkyl)aminocarboxyl; and wherein the C_3-I0 branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(0)_m; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three Ci_-3 alkyl groups; cyano, F, Cl, Br, or I; methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; silyl containing three Ci_-4 independently branched or unbranched alkyl groups optionally partially or fully halogenated;

C₂-₆ branched or unbranched alkyl-C(O), C₂-6 branched or unbranched-S, C₂-6 branched or unbranched-S(O), C₂.ή branched or unbranched- S (O)₂;

C₂-₆ branched or unbranched alkynyl group optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(0)_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_]-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

R¹ is independently C₃.io branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C₃.i₀ cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, ϊsoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogens, Ci_-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C_3-8 cycloalkyl, Cs_-8 cycloalkenyl, hydroxy, cyano, C^₃ alkoxy which is optionally partially or fully halogenated and NH₂C(O) or mono- or di- (C₁O alkyl)aminocarbonyl. For example, each R¹ is independently C₃_io branched or unbranched alkyl.

[00250] In some embodiments of the first group of compounds of Formula IA, each R² is independently -OR', -OR⁶, -C(O)R', -C(O)OR', -C(O)NR'₂, -NR'₂, -NO₂, -S(O)_1nR", -NR⁵SO₂R", -NR' C(O)NR⁵R', -NR'C(S)NR'R', -NR¹C(O)OR' or -SO₂NR'₂. Alternatively, each R² is independently -NR'₂, -NO₂, -C(O)NR'₂, -NR⁵SO₂R", -NR⁵C(O)NR⁵R⁵, -NR' C(S)NR⁵R', -NR⁵C(O)OR' or -SO₂NR'₂.

[00251] In some embodiments of the first group of compounds of Formula IA, each R³ 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, Ci-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C_1-S alkyl, naphthyl C_1-S alkyl, hydroxy, oxo, cyano, Cu alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or CU-(C_1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH₂C(O), a mono- or CU-(Ci_-3 alkyl)aminocarbonyl, Ci-s alkyl-C(0)-Ci_₄ alkyl, amino-Ci-s alkyl, mono- or di-(C]_₃ alkyl)amino -C_1-5 alkyl, amino-S(O)₂, di-(C_1-3 alkyl)amino - S(O)₂, R⁷-Ci_-5 alkyl, R⁸-C_1-5 alkoxy, R⁹-C(O)-C_1-5 alkyl, R¹⁰-Ci_-5 alkyl(R^π)N, carboxy-mono- or di-(Ci_-5 alkyl)amino; a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopynmidine, 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, thiaxolyl, oxazolyl, triazolyl, isothiazolyl, Ci_-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyano, C₁.₃ alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, heteroaryloxy, nitro, amino, mono- or di-(Ci_₃ alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH₂C(O), a mono- or di-(Ci_₃ alkyl)aminocarbonyl,

alkyl-C(O), Ci_-5 alkylamino-S(0)₂, mono- or di-(Ci_-3 alkyl)amino-Ci_-5 alkyl, R^l2-Ci_₅ alkyl, R¹³^₅ alkoxy, R^l4-C(O)-Ci-₅ alkyl, R^ls-Ci._s alkyl(R¹⁶)N; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bi cycloheptanyl, 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 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 O, S(O)_m, CHOH, C=O, C=S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three C ₁-₃ alkyl groups;

C[_₄ alkyl or alkylene-phenyl-C(0)-Co-₄ alkyl or alkylene, C_M alkyl or alkyl ene-C(0)-Co-₄ alkyl or alkylene, C_1-4 alkyl or alkylene -phenyl-S(0)_m-Co-₄ alkyl or alkylene;

Ci-6 alkyl or Ci-β alkoxy, each optionally partially or fully halogenated or optionally substituted with R¹⁷, amino, OR¹⁸, or C₁.₅ mono- or di-alkylamino optionally substituted with R¹⁹; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, which are optionally partially or fully halogenated and optionally substituted with one to three C_1-3 alkyl groups optionally partially or fully halogenated wherein one to three ring methylene groups are replaced independently by O, S(O)_m, CHOH, C=O, C=S or NH; R²⁰C(O)N(R²¹)-, R²²O-, R²³R²⁴NC(O)-, R²⁶(CH₂)_mC(O)N(R²¹)- or R²⁶C(O)(CH₂)_mN(R²¹)-,

C₂-6 alkenyl substituted by R²³R²⁴NC(O)-,

C₂-₆ alkynyl group branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)_1n, and wherein said alkynyl group is optionally independently substituted with 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more C₁-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, pipeπdinyl, piperazinyl, imidazolyl, phenyl, pyπdmyl, tetrazolyl, or Ci_-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or benzoyl or naphthoyl; and wherein each R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁷, R¹⁹, and R²⁵ is independently cyano, morpholino, pipeπdinyl, piperazinyl, imidazolyl, phenyl, pyπdinyl, tetrazolyl, or mono or di-(Co_₄ alkyl)amino, wherein the Co ₄ alkyl is optionally partially or fully halogenated; each R¹¹ and R¹⁶ is independently hydrogen or Ci_-4 branched or unbranched alkyl optionally partially or fully halogenated; and

R¹⁸ is independently hydrogen or C₁-₄ branched or unbranched alkyl optionally independently substituted with oxo or R²⁵.

[00252] In some such embodiments, each R³ 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-pyrrohdin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl. isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnohnyl, pteπndinyl, phthalazinyl, naphthylpyπdinyl, quinoxalinyl, qumazolmyl, puπnyl, mdazolyl. Ci-e branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C_M alkyl, naphthyl C ₁.₅ alkyl, hydroxy, oxo, cyano, C_M alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di- (C_{1 3} alkyl)ammo, phenylammo, naphthylammo, heterocyclylamino, NH₂C(O), a mono- or di-(C].₃ alkyl)aminocarbonyl, Ci_-5 alkyl-C(O)-C_M alkyl, amino-Ci.₅ alkyl, mono- or CU-(C_{1 -3} alkyl)ammo -Ci_-5 alkyl, amino-S(O)₂, O₁-(C_1-3 alkyl)amino - S(O)₂, R⁷-Ci_-5 alkyl, R^s-Ci_₅ alkoxy, R⁹-C(O)-C_]-5 alkyl, R¹⁰-Ci_₅ alkyl(R^u)N, or carboxy-mono- or di-(C,_-5 alkyl)amino In others, each R³ is independently phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with Ci_-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, 0x0, cyano, Ci_-3 alkoxy optionally partially or fully halogenated, nitro, amino, mono- or di-(Ci_-3 alkyl) amino; Ci_-6 alkyl or Ci_-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R¹⁷, ammo, OR¹⁸, Ci ₅ mono- or di-alkylamino optionally substituted with R¹⁹; R²⁰C(O)N(R²¹)-, R²²O-, R²³R²⁴NC(O)-, R²⁶(CH₂)_mC(O)N(R²¹)- or R²⁶C(O)(CH₂)_mN(R²¹)-. For example, R³ 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", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ 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", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, Rⁿ, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List II;

X is C(O)or C(S),

Ar is -(Y)-(Co-I alkyl)-(bicychc aryl). or -(Y)-(Co_-3 alkyl)-(bicychc hctcroaryl), wherein the bicyclic heteroaryl is indazolyl, isomdolyl, quinolmyl. isoquinohnyl, phthalazinyl, dihydroindolyl, benzofuranyl. benzoxazolyl, benzoisoxazolyl. dihydrobenzoisoxoazolyl, dihydroisomdolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or benzoisothiazolyl dioxide, and wherein Ar is optionally substituted with one or more R⁴ or R⁵;

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 R⁴ and R 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, R² or R³.

[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 R⁵. hi 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 R⁴ or R⁵. 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_I-)0 alkyl and each R³ can be independently R²³R²⁴N-C(O)-, R²⁰-C(O)- NR²¹-, or OR²². In some such embodiments, each R² is independently -NR¹SO₂R", -Cl, -Br, -F, -C(O)-NR^J _2, substituted or unsubstituted straight or branched Q.6 alky], -NR'₂, or -OR'. [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 R¹ is independently a substituted or unsubstituted straight or branched Ci_-10 alkyl each R³ can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted Ci_-6 branched or unbranched alkyl or substituted or unsubstituted Ci^ 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", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ 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", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^s, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ 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[l,4]oxazine-3-onyl, benzodioxolyl, benzo[l,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 R¹, R² or R³;

X is C(O)or C(S); Ar is -(Y)-(Co-₃ alkyl)-(phenyl), or -(Y)-(C₀-₃ alkyl)-(monocyclic heteroaryl), wherein Ar is optionally substituted with one or more R⁴ or R⁵;

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 R⁴ and R⁵ 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, R² or R³.

[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 arc 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)-(C_0-3 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 R⁴ or R⁵. 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 R⁵. 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 -CO=NOH)-, and G is pyrazolyl, thienyl or isoxazolyl. In some such embodiments, each R¹ is independently a substituted or unsubstituted straight or branched Ci-io alkyl. In these embodiments, each R³ can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted C₁^ branched or unbranched alkyl or substituted or unsubstituted Cμ 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", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^{1 1}, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ arc as defined in List V.

LIST V: Definition of variables for the first group of compounds of Formula IB.

G, X, Ar, Y, L, m, Q, R, R', R", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List II. provided that if R⁴ and R⁵ 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 IB, 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 IB, the following additional embodiments are provided.

[00266] In some embodiments of the first group of compounds of Formula IB, Ar is -(C₃ alkyl)-(C₆_₁₀ aryl), -(Y)-(C_0-3 alkyl)-(C₆_₁₀ aryl), or -(Y)-(C_0-3 alkyl)-(5-10 member heteroaryl). In some such embodiments Ar is substituted with at least one R⁴ or R⁵. In others, Y is -CHR or -CHZ- and Z is -OR. For example, Y is -CH₂-. In still other such embodiments, the C₆._]0 aryl is phenyl or naphthyl or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl. Alternatively, Ar is -(C₁^₃ alkyl)- (C_6-IO aryl). [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, Y₃ L₁ m, Q, R, R', R", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^{1 1}, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List VI.

LIST VT: Definition of variables for the second group of compounds of Formula IB.

L , m Q R R ' R " R ¹ R², R³ , R⁴, R⁵ , R ⁶ R⁷, R⁸ , R⁹ , R^{1 0}, R ^{1 1} ,R^{1 2}, R ¹³ ,R ¹⁴ ,R ¹⁵ ,R ¹⁶ ,R ¹⁷

R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List II;

G is a G'-(Y)- wherein G' is a C₃_κ) carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl other than indolyl containing 1 or more heteroatoms selected from O, N or S, wherein G' is substituted by one or more R¹, R² or

R³;

X is C(O) or C(S);

Ar is bicyclic aryl or 8-11 membered bicyclic heteroaryl containing 1 or more heteroatoms selected from O, N or S, wherein Ar is optionally substituted with one or more R⁴ or R⁵;

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 R⁴ and R⁵ 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 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.

[00269] In some embodiments of the second group of compounds of Formula IB,

G' is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3 -one, pyrazolyl, pyrrolyl, imidazolyl, lmidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyπdmyl, pyπdonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzo furanyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H- benzo[l,4]oxazine-3-only, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl; pyrrolidinyl, tetrahydro furanyl, tetrahydrothiophenyl, pipeπdinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopipeπdinyl, pyrroHnyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thia/olidinyl, 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[l,4]oxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimidyl. Alternatively, G' is pyrrolidinyl, tctrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, lsoxazohnyl, thiazolinyl, imidazolinyl tertrahydropyridinyl, homopipendmyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazohdinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. In yet 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, bcnzothiazolyl, 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 C-(Y)-, Y is -C(O)- or -C(=NOH)- and G' is phenyl or pyridinyl, substituted by one or more R¹, R² or R³. In some such embodiments, each R¹ is independently a substituted or unsubstituted straight or branched C_1-1O alkyl. In these, each R³ can be independently R²³R²⁴N-C(O)-, R²⁰-C(O)-NR²¹-, or OR²². In others such embodiments each R² is independently -NR⁵SO₂R", -Cl, -Br, -F, -C(O)-NR'₂, substituted or unsubstituted straight or branched C₁^ alkyl, -NR'₂, or -OR'.

[00274] In other embodiments of the second group of compounds of Formula IB,

Ar is -naphthyl- and G is G' -(Y)-, wherein Y is selected from -C(O)- and -C(=NOH)- and G' is pyrazolyl, isoxazolyl or furanyl, substituted by one or more R¹, R² or R³. In some such embodiments, each R¹ is independently a substituted or unsubstituted straight or branched Cj_-1O alkyl. In these, each R³ can be independently substituted or unsubstituted Ci-₆ alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted Ci-₆ branched or unbranched alkyl, or substituted or unsubstituted C₁.₃ alkoxy.

[00275] There is provided in accordance with another aspect of the invention, a third 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", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ 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", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List II;

G is a G'-(Y)- wherein G' is a C₃-₁₀ cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl other than l,l,4,4-tetramethyl-l,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 R¹, 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 R⁵;

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 R⁴ and R⁵ 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 R⁴ or R⁵.

[00276] As before, with respect to variables that are identically defined between the first group of compounds of Foπnula 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, pyra/olyl, 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 R¹, R² or R³. In some such embodiments, each R¹ is independently a substituted or unsubstituted straight or branched C_1-1O alkyl. In these, each R³ can be independently R²³R²⁴N-C(O)-, R²⁰-C(O)-NR²¹-, or OR²². Alternatively, each R² is independently -NR³SO₂R", -Cl, -Br, -F, -C(O)-NR'₂, substituted or unsubstituted straight or branched C₁^ 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 pyrazolyl, isoxazolyl or furanyl, substituted by one or more R¹, R² or R³. In some such embodiments, each R¹ is independently a substituted or unsubstituted straight or branched Ci_-I0 alkyl. In these, each R³ can be independently substituted or unsubstituted Cue alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted C_{1 -6} branched or unbranched alkyl, or substituted or unsubstituted C₁^ alkoxy.

[00282] There is provided in accordance with another aspect of the invention, compounds having Formula IC:

G—Ring— Ar- L— Q 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", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^u, R¹², R¹³, R¹⁴, R¹⁵, R^I6,R¹⁷, R¹⁸, R¹⁹, R²⁰, R^2J, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List VIII.

LIST VIII: Definition of variables for compounds of Formula IC.

Ar, Y, L, m, Q, R, R', R", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^{1 1}, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List II;

Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine- trione, triazolidin-dione, or triazine-dione;

G is a C₃.₁0 carbocyclyl, C₄-_I2 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 O, N or S; and G is substituted by one or more R¹, R² or R³;

[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-l ,4-diyl, maleimide- 1,4-diyl, imidazolidin-2-one-l,3-diyl, imidazolidine-2,4,5-trione-l,3-diyl, [l,2,4]triazolidine-3,5- dione- 1,4-diyl, or 2H-[ 1,2,4 jtriazine-3,5-dione-4,6-diyl. [00286] In another aspect of the invention there are provided compounds having

Formula II:

II stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof, wherein the variables G, X', Ar, Y', L, m, Q, R, R', R", R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹,

R^zυ, R^Z1, r,2

R%5 τ R>26 , and R" are as defined in List IX.

LIST IX: Definition of variables for the compounds of Formula II.

G, L, m, Q, R, R', R", R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are as defined in List II;

X' is CR'=CR', CR'=N, NR', CR'₂, O 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)-(C6-io aryl), each being optionally substituted with one or more R⁴ groups;

Y' is absent or is -O- or -NH-; each R³ is independently H, substituted or unsubstitutcd 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, O, or S(O)_m, substituted or unsubstituted C_3-J₂ cycloalkyl, substituted or unsubstituted C_5-12 cycloalkenyl, substituted or unsubstituted C₇_₂o aralkyl, substituted or unsubstituted straight or branched C_1-8 alkyl, R²⁰C(O)N(R²¹)-, R²²O-, R²³R²⁴NC(O)-, R²⁶(CH₂)_mC(O)N(R²¹)-, R²⁶C(O)(CH₂)_mN(R²¹)-, substituted or unsubstituted C_2-8 alkenyJ, or substituted or unsubstituted C_2-g alkynyl, wherein one or more methylene groups of the Ci-g alkyl, C₂-g alkenyl, or C_2-8 alkynyl are optionally replaced by O, NH₅ or S(O)_n,,

[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 embodiments of the first group of compounds of Formula IA are also provided for the compounds of Formula II. 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 mdazolyl, isoindolyl, pyrazolyl, imidazolyl, or imidazolonyl. In some such embodiments, Ar is substituted with at least one R⁴. Alternatively, Ar is mdazolyl, optionally substituted with one or more R⁴. In yet other embodiments, Ar is phenyl or naphthyl In some such embodiments, Ar is substituted with at least one R .

[00289] In yet other embodiments of compounds of Formula II, Ar is -(Y')-(Co-₃ alkyl)-(C6-io aryl). In some such embodiments, Ar is substituted with at least one R⁴. In others, the Ce io 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, pyπdinyl, pynmidmyl, pyrazinyl, pyπdazinyl, pyrrolyl, pyrrolidmyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, lsoxazolyl, thiazolyl, oxazolyl, tπazolyl, tetrazolyl, isothiazolyl, quinolyl, isoqumolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pteπndinyl, phthalazinyl, naphthylpyπdinyl, quinoxalinyl, quinazolinyl, puπnyl, indazolyl, Ci ₆ branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C₁-_S alkyl, naphthyl Ci_₅ alkyl, hydroxy, oxo, cyano,

alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(Ci 3 alkyl)amino, phenyl amino, naphthylamino, heteroc>clylamino, NH₂C(O), a mono- or di-(Ci_-3 alkyl)ammocarbonyl₃ Ci ₅ alkyl-C(O)-C|-₄ alkyl, amino-Ci_-5 alkyl, mono- or di-(Ci 3 alkyl)amino -Cj 5 alkyl, amino-S(Q)_2ϊ di-(Ci_₃ alkyl)amino - S(O)₂. R⁷-C_1-5 alkyl, R⁸-Ci_-5 alkoxy, R⁹-C(O)-d _s alkyl, R^-Ci-s alky^R'^N, carboxy-mono- or di-(Ci-5 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 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, Cj_-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-(Ci_₃ alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH₂C(O), a mono- or di-(C_1-3 alkyl)aminocarbonyl, Ci_-4 alkyl-C(O), Ci_-5 alkylamino-S(O)₂, mono- or di-(Ci_-3 alkyl)amino-Ci-5 alkyl, R^!2-Ci-s alkyl, Rⁱ³-Ci_₅ alkoxy, R¹⁴-C(O)-Ci_₅ alkyl, R¹⁵-Ci_-5 alkyl(R¹⁶)N; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bi cyclohexanyl, 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_]-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 O, S(O)_n,, CHOH, C=O, C=S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three C_1-3 alkyl groups;

C i-4 branched or unbranched alkyl -phenyl-C(0)-Co-4 branched or unbranched alkyl, Cj_-4 branched or unbranched alkyl-C(0)-Co-₄ branched or unbranched alkyl, C₁^ branched or unbranched alkyl-phenyl-S(O)_m-C_0-4 branched or unbranched alkyl; C_1-G branched or unbranched alkyl or C],₆ branched or unbranched alkoxy each is optionally partially or fully halogenated or optionally substituted with R¹⁷;

C[_₆ branched or unbranched alkyl optionally substituted with OR¹⁸; amino or C₁-C₅ branched or unbranched mono- or di-alkylamino optionally substituted with R¹⁹; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, which are optionally partially or fully halogenated and optionally substituted with one to three C₁.₃ alkyl groups optionally partially or fully halogenated wherein one to three ring methylene groups are replaced independently by O, S(O)_m, CHOH, C=O, C=S or NH;

R²⁰C(O)N(R²¹)-, R²²-, R²³R²⁴NC(O)-, R²⁶(CH₂)_mC(O)N(R²¹)- or R²⁶C(O)(CH₂)_raN(R²¹)-;

C_2-6 alkenyl substituted by R²³R²⁴NC(O)-;

C₂-6 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 O, NH and S(O)_n, or S and wherein said alkynyl group is optionally independently substituted with 0-2 0x0 groups, pyrrolidinyl, pyrrolyl, one or more Ci_-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or Ci_-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 arc 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. TABLE 1 - Exemplary Combinations of Ar and G for the First Group of Compounds of Formulas IA and IB

TABLE 1 - Continued

[00293] Table 2 sets forth various combinations of substituents from all groups of compounds of Formulas IA, IB, IC and II. Thus, e.g., combination 1477 describes those embodiments in which L is -O- 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-(CH₂)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), CH₂) 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 CH₂, Ar is indolyl and G is phenyl, etc. TABLE 2 - Exemplary Combinations of L and Q for All Groups of Compounds of Formulas IA, IB, IC and II

[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_-3 alkyl)-(bicyclic aryl).

TABLE 3 - Continued

[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. TABLE 4 — Exemplary Combinations of Ar and G for the Third Group of Compounds of Formula IA.

TABLE 4 - Contin.ued

TABLE 4 - Con.tinued

[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

TABLE 5 - Continued

[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 IB. Table 2 above illustrates combinations of L and Q that may be employed for the third group of compounds having Formula IB.

TABLE 6 - Exemplary Combinations of Ar and G for the Third Group of compounds of F

TABLE 6 - Continued

TABLE 6 - Continued

[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.

TABLE 7 - Continued

[00299] Similar to Tables 1 and 3 - 7 above, Table 8 illustrates combinations of Ar and G for the compounds having Formula II. Table 2 above illustrates combinations of L and Q that may be employed for compounds having Formula II.

TABLE 8 — Exemplary Combinations of Ar and G for the Compounds of Formula II

[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 π-π 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 μM 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, 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.

[00305] 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.

[00306] 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 Ci_-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. [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. PCT7US2006/006682, filed February 23, 2006.

[00308] In accordance with another aspect, there are provided compounds useful in the methods of the invention having Formula III:

Formula III

stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein the variables A, Ar, G, L¹, L², L³, Q, R¹, R², R³, 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, NR₂, or a C_1-3 alkyl or -0(C_1-3 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 R¹, R² or R³;

L¹ is -C(O)NH-;

L² is -C(O)NR-, or -C(O)NOR-; provided that if one of L¹ and L² is attached to the pyridine ring via nitrogen, the other of L¹ and L² is not attached to the pyridine ring via nitrogen;

L³ is a covalent bond, O, NR, C(O), C(O)NR, or a substituted or unsubstituted Ci_-5 alkyl, C₂-5 alkenyl, C_2-5 alkynyl, NR(C_1-5 alkyl) or 0(Cj_-5 alkyl) group;

Q is hydrogen, or a substituted or unsubstituted alkyl, aryl or heterocyclyl group; each R¹ is independently F, Cl, Br, I, -NR₂, -CN. or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heterocyclylalkyl group; each R² is independently F, Cl, Br, I, -CN, -NO₂, a substituted or unsubstituted alkyl group, -OR', -C(O)R', -C(O)OR', -C(O)NR'₂, -NR'₂, -NR' C(O)R", -NR¹C(O)OR', -NR'SO₂R", -NR'C(O)NR"₂, -NR'C(S)NR"₂, -S(O)_mR", or -SO₂NR'₂; each R³ is independently a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or an -0(Cj,₄ alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted Ci^ 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 O, 1 or 2.

[00309] All of the following compounds arc contemplated by Formula III:

iiiA HiB me

HID HIE

[00310] As those of skill in the art will appreciate, unless otherwise noted, all orientations of divalent linkers such as L¹, L² and L³ are contemplated for use in compounds of the invention.

[0031 1] In some embodiments, the compound of Formula III is

iiiA iim me [00312] In some embodiments of compounds of Formula III, A is F, CH₃, or

-CF₃. In others, G is a phenyl, pyrimidyl or pyridyl group, for example, G may be

[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

[00314] In some other embodiments of compounds of Formula III, L^J is a covalent bond, O, NR, C(O)NH, or a substituted or unsubstituted O(Ci-₃ alkylene) or NR(C_r3 alkylene) group, for example, L³ is a covalent bond, O, NH, C(O)NH, OCH₂, OCH₂CH₂, NHCH₂, or NHCH₂CH₂.

[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, cyclopenty], cyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl group.

[00316] In some embodiments of compounds of Formula III, R¹ is F, -CN, -NR₂, or a substituted or unsubstituted C₁.₄ alkyl, C_3-9 cycloalkyl, heterocyclyl, or heterocyclylalkyl group. For example, R¹ is F, -CN, -N(Ci_-3 alkyl)₂ wherein each C_1-J alkyl group is independently substituted or unsubstituted, or a substituted or unsubstituted isopropyl, tert-butyl, iso-butyl, sec-butyl, cyclohexyl, thiazolyl, CH₂-thiazolyI, CH₂CH₂-IhIaZoIyI, pyrrolidinyl, CH₂-pyrrolidinyl, CH₂CH₂-pyrrolidinyl, piperidyl, CH₂-piperidyl, CH₂CH₂~piρeridyl, morpholinyl, CH₂-moipholinyl, CH₂CH₂-morphoJinyl, thiomorpholinyl, CH₂-thiomorpholinyl, CH₂CH₂-thiomoφholinyl, piperazinyl, CH₂-piperazinyl, CH₂CH₂-piperazinyl, oxazepanyl, CH₂-oxazepanyl, or CH₂CH₂-oxazepanyl group. [00317] In other embodiments, R² is a substituted or unsubstituted Ci_-4 alkyl group,

F, Br, Cl, -CN, -NO₂, -C(O)OR', -C(O)NR'_2> -NRC(O)R", -NRC(O)OR", -NR⁵SO₂R", -NR'C(O)NR'₂, or -SO₂NRS. For example, R² is F, -CF₃, -CN, -NO₂, -0(C_1-6 alkyl), -C(O)O(C,_-6 alkyl), -C(O)NH₂, -C(O)NH(C_1-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(Cj_-6 alkyl), -NHC(0)(aryl), -NHC(O)(aralkyl), -NHSO₂(C_1-6 alkyl), -NHSO₂(aryl), -NHSO₂(aralkyl), -SO₂NH(C]_-6 alkyl), -SO₂NH(aryl), or -SO₂NH(aralkyl), wherein each Ci_-6 alkyl, aryl, or aralkyl group is substituted or unsubstituted.

[00318] In yet other embodiments, R³ is a substituted or unsubstituted C₁^ alkyl or

-0(Ci-₄ alkyl) group, or is a partially or fully halogenated -0(C_{1 2} alkyl) group.

[00319] In some embodiments of compounds of Formula III, G is is phenyl and R¹ is F, -CN, -N(C U3 alkyl)₂ wherein each C₁^ 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, R² is a substituted or unsubstituted Ci ₄ alkyl group, F, Br, -CN, -NO₂, -0(Ci_-6 alkyl), -C(O)O(Cj_-6 alkyl), -C(O)NH₂, -C(O)NH(C_1-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(C_1-6 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO₂(Ci_-6 alkyl), -NHSO₂(aryl), -NHSO₂(aralkyl), -SO₂NH(Ci_-6 alkyl), -SO₂NH(aryl) or -SO₂NH(aralkyl), wherein each Ci_-6 alkyl, aryl, or aralkyl group is substituted or unsubstituted. For example, R² may be F, -CF3, -CN, -C(O)NH₂, -C(O)NH(C_1-6 alkyl), -NHSO₂(C_1-6 alkyl), or -SO₂NH(C_1-6 alkyl), wherein each Ci_-6 alkyl group is substituted or unsubstituted. In certain of these embodiments. R³ is a substituted or unsubstituted Ci_-4 alkyl or -0(Ci_-4 alkyl) group, or is a partially or fully halogenated -0(C_1-2 alkyl) group.

[00320] In some embodiments of compounds of Formula III, -L -Q is -H, -OMe,

-C(O)NH₂,

H H ' ^H • ^• H ^•

[00323] Table 10 sets forth various combinations of substituents L and Q of

Formula III. Thus, e.g., combination 1766 describes those embodiments in which L³ is OCH₂, 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 L³ 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, L³ is OCH₂, and Q is 2-pyridyl. Each Ar, G, L , and Q group in the tables is understood to be optionally substituted as described herein. Moreover, each value of A (F, Cl, Br, I, NR₂, or a C_1-3 alkyl or -O(C].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 NR₂, G is phenyl and Ar is pyridin-2,5-diyl, etc.

Table 10 - Exemplary combinations of L and Q for Formula III.

[00324] In one embodiment, the compound of Formula III at a concentration of

10 μM 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. [00326] In this aspect of the invention, compounds have the structure PEM-TM-

OM-L-AM. At a concentration of 10 μM 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 C₂-₄ alkyl groups, for example substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec-butyl groups; substituted or unsubsituted C₃.₉ 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 hctcroarylene. Thus, e.g., the linker moiety may be a ben/amide or a pyridylamide. [00331 ] The anchoring moiety may include an O 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 C₁-_S alkylene, or the like.

[00333] Another group of compounds useful in the methods of the invention are compounds of Formula IV:

Formula IV stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; wherein the variables X, Y, A, B, D, E, G, L¹, L², Q, R¹, R², R³, 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, NR₂, or a C^ alkyl or -O(Cι-3 alkyl) group, wherein the alkyl group Is optionally partially or fully halogenated;

B, D and E are each independently N, NR, O, S or CR; wherein B, D, and E are selected such that the ring containing B, D, and E is aromatic; G is an aryl or heteroaryl group, wherein G is substituted by one or more R¹, R² or R³; L¹ is -C(O)NH-;

L² is -(CRy_n-C(OMCRU-, -(CRS)_n-NR-(CR',^-, -(CR'₂)_n-C(O)NR-(CR'₂)_p-, -(CR'₂)_n-C(O)NRNR-(CR'₂)_p-, or -(CR'₂)_n-O-C(O)NR-(CR'₂)_p-;

Q is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, 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; each R² is independently F, Cl, Br, I, -CN, -NO₂, a substituted or unsubstituted alkyl or heterocyclylalkyl group, -OR', -C(O)R', -C(O)OR', -C(0)NR'₂, -NR'₂, -NRC(O)R", -NR'C(0)0R", -NR⁵SO₂R", -NR'C(O)NR'₂, -NR'C(S)NR'₂, -S(O)_mR", or -SO₂NR'₂; each R³ is independently a substituted or unsubstituted C_M alkyl, alkenyl, or alkynyl group, or an -0(Ci_-4 alkyl) group, wherein the alkyl group is optionally partially or fully halogenated; each R is independently hydrogen or a substituted or unsubstituted Ci .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 O, 1 or 2; and n and p are each independently O, 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, L¹ is TM, the 6-member ring is OM, the 5-member heteroaryl is L, and -L²-Q is AM, [00335] All of the following compounds are contemplated by Formula IV:

IVC-IO IVC-Il IVC-12

[00336] As those of skill in the art will appreciate, all orientations of divalent linkers such as L and L 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:

Formula IVD

[00337] In others, the compound of Formula IV has the structure IVE or IVF:

IVE IVF [00338] In some embodiments of compounds of Formula IV, B is N. In others, D is NH, O or S. In still others, E is CH or O. In some other embodiments of compounds of Formula I, A is F, -CH₃, or -CF₃.

[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

[00340] In some embodiments of compounds of the invention, including compounds of Formula IV or IVD, L² is -C(O)-(CR'₂)_P-, -(CH₂)_n-C(O)NR-(CH₂)_p-, or -(CH₂)_n-C(O)NRNR-(CH₂)_p-. For example, L² is -C(O) -, -C(O)CH₂-, -C(O)CH₂CH₂-, -C(O)CH₂CH₂CH₂- -C(O)NHNH-, -C(O)N(CH₃)NH-, -C(O)N(CH₃)NH-CH₂-, -C(O)N(CH₃)NH-CH₂CH₂-, -C(O)N(CH₃)NH-CH₂CH₂CH₂-, -C(O)NHNH-CH₂-, -C(O)NHNH-CH₂CH₂- Or -C(O)NHNH-CH₂CH₂CH₂-, C(O)NH-, -C(O)N(CH₃)-, -C(O)N(CH₃)-CH₂- -C(O)N(CH₃)-CH₂CH₂-, -C(O)N(CH₃)-CH₂CH₂CH₂- -C(O)NH-CH₂-, -C(O)NH-CH₂CH₂- or -C(O)NH-CH₂CH₂CH₂-.

[00341] In others, the compound is

[00342] In still others, the compound is

and Q is a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclyl group. [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]octanyl, 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.

[00344] In yet other embodiments of compounds of the invention, including compounds of Formula IV or IVD, R is F, -CN, -NR₂, or a substituted or unsubstituted Ci-₄ alkyl, C₃.₉ cycloalkyl, aryl, heterocyclyl, or heterocyclylalkyl group. In some such embodiments, R¹ is F, -CN, -N(Cu alkyl)₂ wherein each C₁^ 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, CH₂-thiazolyl, CH₂CH₂-thiazolyl, pyrrolidinyl, CH₂-pyrrolidinyl, CH₂CH₂-pyrrolidinyl, piperidyl, CH₂-piperidyl, CH₂CH₂-piperidyl, morpholinyl, CH₂-morpholinyl, CH₂CH₂-moφholinyl, thiomorpholinyl, CH₂-thiomorpholinyl, CH₂CH₂-thiomorpholinyl, piperazinyl, CH₂-piperazinyl, CH₂CH₂-piρerazinyl, oxazepanyl, CH₂-oxazepanyl, or CH₂CH₂-oxazepanyl group.

[00345] Also contemplated are compounds of the invention, including compounds of Formula IV or IVD, wherein R² is a substituted or unsubstituted C_1-4 alkyl or heterocyclylalkyl group, F, Cl, -CN, -NO₂, -OR', -C(O)OR', -C(O)NIT₂, -NRC(O)R", -NRC(O)OR", -NR⁵SO₂R", -NITC(O)NIT₂, or -SO₂NR'₂. In some such embodiments, the alkyl group is substituted with NRR. In others, the heterocyclylalkyl group is a substituted or unsubstituted -(C ₁.₃ alkyl)-pyrrolidinyl, -(C_1-S alkyl)-piperidyl, -(Ci-₃ alkyl)-piperazinyl, or -(C₃ alkyl)-morpholinyl group. In still other embodiments, R² is F, -CF₃, -CN, -NO₂, -0(C₆ alkyl), -C(O)O(C_1-6 alkyl), -C(O)NH₂, -C(O)NH(C_1-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralky!)₅ -NHC(O)(Ci_-6 alkyl), -NHC(O)(aiyl), -NHC(θXaralkyl), -NHSO₂(C_-6 alkyl), -NHSO₂(aryl), -NHSO₂(aralkyl), -SO₂NH(Ci_-6 alkyl), -SO₂NH(aryl), or -SO₂NH(aralkyl), wherein each C^ alkyl, aryl, or aralkyl group is substituted or unsubstituted. [00346] In still other embodiments of compounds of the invention, including compounds of Formula IV or IVD, R³ is a substituted or unsubstituted C_M alkyl or -O(Ci-₄ alkyl) group, or is a partially or fully halogenated -0(Ci_-2 alkyl) group.

[00347] In some embodiments of compounds of the invention, including compounds of Formula IV or IVD, G is phenyl and R¹ is F, Cl, -CN, -N(Ci_-3 alkyl)₂ wherein each Ci_-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, R¹ 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 C_M alkyl or heterocyclylalkyl group, F, -CN, -NO₂, -0(Ci_-6 alkyl), -C(O)O(C_L6 alkyl), -C(O)NH₂, -C(O)NH(Ci_-6 alkyl), -C(O)NH(aryl), -C(O)NH(aralkyl), -NHC(O)(Ci_-6 alkyl), -NHC(O)(aryl), -NHC(O)(aralkyl), -NHSO₂(Ci- ₆ alkyl), -NHSO₂(aryl), -NHSO₂(aralkyl), -SO₂NH(Ci_-6 alkyl), -SO₂NH(aryl) or -SO₂NH(aralkyl), wherein each Ci_-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, -(Ci_-3 alkyl)-piperidyl, -(Ci_-3 alkyl)-piperazinyl, or -(Ci_-3 alkyl)-morpholinyl group. Typically, R² is F, -CF₃, -CN, -C(O)NH₂, -C(O)NH(Ci_-6 alkyl), -NHSO₂(Ci_-6 alkyl), or -SO₂NH(Ci_-6 alkyl), wherein each Ci_-6 alkyl is substituted or unsubstituted. In some such embodiments, R³ is a substituted or unsubstituted Ci_-4 alkyl or -O(Cu alkyl) group, or is a partially or fully halogenated -Q(Ci_-2 alkyl) group.

[00348] In some embodiments of compounds of the invention, — L -Q is

[00349] In some such embodiments, G is a phenyl or a pyridyl group. [00350] In some embodiments of compounds of the invention such as compounds of Formula IV, the compound is

[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 substiruents 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-diyl and G is phenyl.

Table 1 1 - Exemplary combinations of the B,D, E containing aromatic ring and G for Formula IV.

[00352] Table 12 sets forth various combinations of substituents L² and Q of

Formula IV. Thus, e.g., combination 1692 describes those embodiments in which L 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" and Q. For example, combination 1047 from Table 1 1 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, L² is -C(O)- and Q is t-butyl. Each G and Q in the tables is understood to be optionally substituted as described herein. Moreover, each value of A (-F, Cl, Br, I, NR₂, or C₁^ alkyl or -O(C]^)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, L² is -C(O)- and Q is t-butyl, as well as those where A is -CH₃, L² is -C(O)- and Q is t-butyl, etc.

Table 12 - Exemplary combinations of L² and Q for Formula IV.

[00353] In some embodiments, the compound of Formula IV at a concentration of

10 μM 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 linker moiety, L, attached to a different atom of the orienting moiety than the targeting moiety, wherein the linker moiety comprises a 5-membεred 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 μM, 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 m 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 as substituted or unsubstituted C_2^t alkyl groups, for example substituted or unsubstituted isopropyl, tert-butyl, isobutyl, or sec-butyl groups; substituted or unsubsituted C₃..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]octan-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 unsubstituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydropyranyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, ethyl, n-propyl, isopropyl, n-butyl, 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. [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-I cells (see Prichett et al. J. Inflammation, 1995, 45, 97). THP-I cells (ATCC TIB 202, American Type Culture Collection, Rockville, MD) were maintained at 37°C, 5% CO₂ in RPMI 1640 media with 10% fetal bovine serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g/1 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-I cells were plated at lxlO⁵/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% CO₂ for 30 minutes prior to the addition of LPS (Sigma) to a final concentration of 1 μg/ml. Cells were then incubated 18-20 hours at 37°C/5% CO₂. 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 IC₅₀ 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 IC₅₀S below 10 μM 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 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, 1 13. 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/1 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 μl/mouse; 100 μg/mouse collagen; lOOμg/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 μl/mouse; 100 μg/mouse collagen; lOOμg/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 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 μl 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 inflammation, pannus formation and bone resorption. Percent inhibition of paw weight and AUC is calculated using the following formula:

% Inhibition A - B/A * 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 TNF^ΛARE 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: O=(O-I) polymorphonuclear (PMN) cells per hpf (PMN/hpf); l=(2-10) PMN/hpf within mucosa; 2=(11-20) 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 mucosae. Chronic inflammatory score: O=(O-IO) mononuclear leukocytes (ML) per hpf (ML/hpf) within mucosa; 1 -(11-20) 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 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 TNF^ΔARE 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, 1 1 , 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 4 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 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

[00372] 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 μl) 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 μl 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. 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°C and 5% CO₂.

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 -70⁰C until analysis.

[00374] TNF-α, IL- 1/3, IL-6 or other cytokines are analyzed using validated ELISA methods.

[00375] Individual and mean group effects on the IL-lβ 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 ct 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 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).

[003791 Psoriasis disease assessment. Efficacy of psoriasis treatment can be monitored by changes in clinical signs and symptoms of the disease, including Psoπasis Area and Seventy 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 psoπasis, and psoriasis plaque thickness. Skin biopsies are studied for the effects of the drug on lymphocytes within psoπatic 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 marmosets (Crook et 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 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 -20⁰C 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 HDL₂ and HDL₃ 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 arc 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 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. Cardiovasc Res, 68 (2005) 415 - 424) including TNFa (Monraats et al. FASEB J 2005; 19: 1998-2004) and MCP-I, 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. [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) >!0 kg/m². Doses of inhibitor are administered sufficient to result in an increase of M 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 1 l.lmmol/1 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 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/1. 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 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 (μU/ml) / 405

[00398] In this equation, one should use the constant 22.5 instead of 405 if the glucose is reported in mmol/1. 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 I. 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]. 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. [00406] Figure 13 shows the effects of a compound as descπbed 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 descπbed herein on the mean PAI-I levels of human subjects, upon once daily administration of the compound for 6 weeks.

[00408] Figure 15 shows the effects of a compound as descπbed 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 +/- 0.5⁰C and 5% CO₂ 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 μL of 10x stock compound solutions is added to 40 μL 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 μL of media into each assay well. Assay plates are incubated for 72-80 hours at 37°C +/-0.5⁰C with 5% CO₂. Twenty microliters of 20% Alamar Blue warmed to 37°C +/- 0.5⁰C 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 expeπments, quantification is performed using a Wallac Victor² 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. [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-I ovarian teratocarcinoma, HT29 colorectal adenocarcinoma, H 1299 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, HTl 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, M 14 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. [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.

Claims

CLAIMSWhat is claimed is:

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

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 Il

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L², L³, A, Ar, and Q are as defined in List X; f) Formula IV

wherein variables G, X, Y, L¹, 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 π-π 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; 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-I .

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, 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

wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; b) Formula IB

H

X Ar -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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L , L³, A, Ar, and Q are as defined in List X; f) Formula IV

wherein variables G, X, Y, L¹, 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 π-π 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-membercd 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).

6. The method of claim 5, wherein 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.

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

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 proinflammatory 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; 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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L², L³, A, Ar, and Q are as defined in List X; f) Formula IV

wherein variables G, X, Y, L¹, 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 π-π 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-membcred 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).

12. The method of claim 11 , wherein the pro-inflammatory stimulus results from the presence of TNFa, IL-I, 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-I, 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

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 V₅ Vl, or VIl; 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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L , L², L , A, Ar, and Q are as defined in List X; f) Formula IV

wherein variables G, X, Y, L¹, 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 π-π 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; 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

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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L², L³, A, Ar, and Q are as defined in List X; f) Formula IV

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 π-π 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; or a stereoisomer, tautomer, solvate, prodrug, or pharmaceutically 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

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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L², L³, A, Ar, and Q are as defined in List X; f) Formula IV

wherein variables G, X, Y, L¹, 1/, 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 π-π 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; 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 HDL₂.

22. The method of claim 17, wherein the HDL is HDL₃.

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.

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

wherein variables G, X, Ar, L, and Q are as defined in Lists II, III, or IV; b) Formula IB

H

^G\ /^N\

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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L², L³, A, Ar, and Q are as defined in List X; f) Formula IV

wherein variables G, X, Y, L¹, 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 π-π 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; 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-Al -level of the subject relative to the level prior to the administration of the compound, wherein the compound is selected from: a) Formula IA

wherein variables G, X, Ar, L, and Q are as defined in Lists 11, 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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L², L³, A, Ar, and Q are as defined in List X; f) Formula IV

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 π-π 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; 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%.

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

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, L₅ 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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L², L , A, Ar, and Q are as defined in List X; F) Formula IV

wherein variables G, X, Y, L¹, 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 π-π 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; or a stereoisomer, 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.

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-I 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

wherein variables G, X, Ar, L, and Q arc as defined in Lists 11, III, or IV; b) Formula IB

H

λ Ar L Li 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

wherein variables G, X', Ar, L, and Q are as defined in List IX; e) Formula III

wherein variables G, L¹, L², L³, A, Ar, and Q are as defined in List X; f) Formula IV

wherein variables G, X, Y, L¹, 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-expandmg 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 oπenting moiety, OM, compπsing a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said oπenting moiety capable of forming a π-π or edge-to-face aromatic interaction with the target protein, h) a compound compπsing a targeting moiety, TM, compπsing 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 compπsing 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 oπenting moiety, OM, compπsing a pyπdyl πng and attached to a different atom of the targeting moiety than the pocket-expandmg moiety, wherein the onenting moiety is capable of forming hydrophobic interactions with the target protein, and an anchoπng moiety, AM, indirectly attached to the oπenting moiety by a linker moiety, L, wherein the anchoπng moiety is capable of forming at least 1 hydrogen bond interaction with an ATP -binding pocket of the target protein, i) a compound compπsing: a targeting moiety, TM, compπsing 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-expandmg moiety compπsing 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 oπenting moiety, OM, compπsing a 6-membered aryl or heteroaryl nng and attached to the NH of the targeting moiety, wherein the oπenting 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).

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