WO2006091862A2 - Cytokine inhibitors and their use in therapy - Google Patents

Cytokine inhibitors and their use in therapy Download PDF

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Publication number
WO2006091862A2
WO2006091862A2 PCT/US2006/006682 US2006006682W WO2006091862A2 WO 2006091862 A2 WO2006091862 A2 WO 2006091862A2 US 2006006682 W US2006006682 W US 2006006682W WO 2006091862 A2 WO2006091862 A2 WO 2006091862A2
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substituted
unsubstituted
alkyl
independently
phenyl
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PCT/US2006/006682
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WO2006091862A3 (en
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Erik Boman
Susanna Conde Ceide
Russell Dahl
Justin Ernst
Jeffrey Kahl
Antonio Garrido Montalban
Zhinjun Wang
Christopher Larson
Eddine Saiah
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Kemia, Inc.
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Publication of WO2006091862A2 publication Critical patent/WO2006091862A2/en
Publication of WO2006091862A3 publication Critical patent/WO2006091862A3/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to low molecular weight compounds and compositions thereof, useful as cytokine inhibitors, and their preparation.
  • the invention further relates to methods of prevention and treatment of cytokine-mediated disorders, in particular inflammatory disorders, pain and cancer.
  • the invention also relates to pharmaceutical compositions and dosing regimens.
  • the invention relates to the use of cytokine inhibitors, optionally in conjunction with other therapies, for treatment of cancer, more particularly glioma, glioblastoma, osteosarcoma and bone metastases.
  • the present invention relates to methods of treating, modifying and managing pain, more particularly neuropathic pain, which comprise the administration of a cytokine inhibitor alone or in combination with known therapeutics.
  • Tumor necrosis factor- ⁇ TNF- a or TNFa
  • IL- 1 interleukin- 1
  • RA rheumatoid arthritis
  • IL-cds IL-I and TNF-cds 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.
  • TNF- ⁇ also referred to as TNFa
  • IL-Ib interleukin- I ⁇
  • IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias [Treon, et al, Current Opinion in Hematology, 5, 42 (1998)]. Cytokines including IL- 1 , TNFa and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts [Bruserud, Leukemia Res. 20, 65 (1996)]. Clinical studies have linked TNFa production and/or signaling to a number of diseases including advanced cancer [MucWierzgon et al. J. Biol.
  • lymphoid malignancies [Levy et al. Crit. Rev. Immunol., 16, 31 (1996)] impaired wound healing in infection, inflammation, and cancer [Buck et al. Am. J. Pathol. 149, 195 (1996)], and myelodysplastic syndromes [Raza et al. Int. J. Hematol. 63, 265 (1996)].
  • cytokine inhibitors show potential in the treatment of malignancies .
  • Cytokines are also known to play a role in the production of pain, such as nociceptive pain, neuropathic pain, visceral pain, headaches, post-operative pain and the like.
  • nociceptive pain is elicited when noxious stimuli such as inflammatory chemical mediators are released following tissue injury, disease, or inflammation and are detected by normally functioning sensory receptors (nociceptors) at the site of injury [Koltzenburg, M. Clin. J. of Pain 16:S131-S138 (2000)].
  • Nociceptors are distributed throughout the periphery of tissue and are sensitized by inflammatory mediators such as prostaglandin, substance P, bradykinin, histamine, and serotonin, as well as by intense, repeated, or prolonged noxious stimulation.
  • inflammatory mediators such as prostaglandin, substance P, bradykinin, histamine, and serotonin
  • cytokines and growth factors e.g., nerve growth factor
  • Sensitization of peripheral nociceptors plays an important role in clinical pain states such as hyperalgesia and allodynia.
  • Medications presently used during the treatment of pain in general include calcium channel blockers, muscle relaxants, nonnarcotic analgesics, opioid analgesics, and systemic corticosteroids.
  • patients rarely obtain complete pain relief.
  • cytokine- mediated diseases including inflammation, cancer and pain. While some cytokine protein therapeutics have been developed, they suffer from bioavailability and stability problems. In particular, there is a need for low molecular weight compounds that inhibit TNFa and/or IL-Ib production.
  • the present invention provides low molecular weight compounds and pharmaceutical compositions thereof.
  • compounds of the invention are useful as cytokine release inhibitory agents.
  • compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.
  • the invention provides methods of preventing or treating disorders mediated by cytokines which comprise administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein.
  • cytokine-mediated disorders include rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, and non-
  • Exemplary cytokine-mediated disorders also include acute or chronic pain, such as but not limited to neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Horton's disease, varicose ulcers, neuralgias, musculoskeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, vertebral pain, post-surgery pain, herniated intervertebral disc-induced sciatica, cancer-related pain, vascular pain, visceral pain, childbirth-related pain, or HIV-related pain.
  • acute or chronic pain such as but not limited to neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Horton's disease, varicose ulcers, neuralgias, musculoskeletal pain, osteo-traumatic pain, fractures, al
  • cytokine-mediated disorders are stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure such as heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary artery bypass; hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, such as for example, acute venous thrombosis, pulmonary embolism, thrombosis during pregancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), clot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary o
  • Cytokine-mediated disorders further include allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection and respiratory tract inflammation. Also included are psoriasis, eczema, atopic dermatitis, contact dermatitis, or acne.
  • cytokine-mediated disorders are Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral meningitis, bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF syndrome, MELAS syndrome, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, or epilepsy.
  • the cytokine-mediated disorders include bone resorption diseases, such as osteopetrosis, osteoporosis, or osteoarthritis. Also included are diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), obesity, anorexia nervosa, or bulimia nervosa.
  • bone resorption diseases such as osteopetrosis, osteoporosis, or osteoarthritis.
  • diabetes systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), obesity, anorexia nervosa, or bulimia nervosa.
  • the cytokine-mediated disease can be sepsis, HIV infection, hepatitis C virus (HCV) infection , malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, including but not limited to breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, or follicular lymphoma, Castleman's disease, or drug resistance.
  • HCV hepatitis C virus
  • the cytokine mediated disorder is a neutrophil-mediated disorder, such as, for example, bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, hemodialysis, leukopheresis, granulocyte transfusion associated syndromes, or necrotizing enterocolitis.
  • ARDS adult respiratory distress syndrome
  • Combination therapy with cytokine inhibitors provides a beneficial therapeutic effect, particularly an additive or over-additive effect or an overall reduction of side effects of therapy.
  • a beneficial therapeutic effect is desirable in the treatment of cytokine-mediated disorders as described herein, and in particular in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis.
  • another aspect the of the invention provides methods of treating a cytokine-mediated disorder including administering one or more, typically one, of the ingredients (hereafter referred to as ingredient A) described herein together with one or more, typically one, cytokine inhibitor of the invention.
  • ingredient A typically one
  • a combination of any two or more ingredients A are administered with a cytokine inhibitor of the invention.
  • An additive or over-additive effect of the pharmaceutical combinations according to the invention provides for dose reduction, side-effect reduction and/or interval extension when compared to monotherapy with the individual compounds A or with the cytokine inhibitors.
  • 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.
  • ingredient A being an injectable, especially a biological agent, other benefits of adding the cytokine inhibitor may be seen. For example, cost reduction by way of interval and/or dose reduction.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDS include acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen,
  • Angiogenesis inhibitors may serve as ingredient A, such as VEGF inhibitors, taxol, pentoxyfylline and/or thalidomide.
  • 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.
  • 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.
  • ingredient A also within the scope of the invention for ingredient A are steroids, such as glucocorticoids, and vitamin D3 and analogs thereof (cholecalciferols), alone (the latter being used mostly for psoriasis) or in combination.
  • Steroids include budesonide, dexamethasone, fluocinonide, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, clobetasone, deflazacort, fluocinolone acetonide, fluticasone, triamcinolone acetonide, mometasone and diflucortolone.
  • vitamin D3 derivatives are calcipotriol, tacalcitol, maxacalcitol, and tacalitol, the calciotropic hormones, lce,25-dihydroxyvitamin D3, and parathyroid hormone-related peptide.
  • cytokine inhibitors of the invention Many types of immunomodulatory, immunosuppressive or cytostatic drugs can be used in combination with the cytokine inhibitors of the invention.
  • exemplary agents include hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, pimecrolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine, cyclophosphamide, macrolides, ascomycin, hydroxyurea, 6-thioguanine, (Orfanos C E., 1999, Cutis 64(5):347-53); alefacept, leflunomide, infliximab, etanercept, efalizumab, anti-CD4, anti-CD25, peptide T,
  • agents or therapies which act on other targets or immune mediated products are suitable as the ingredient A.
  • agents or therapies which act on other targets or immune mediated products are suitable as the ingredient A.
  • PTKs protein tyrosine kinases
  • EGFR epidermal growth factor receptor
  • E-selectin inhibitors and therapies widely used for psoriasis such as anthralin, coal tar, phototherapies including ultraviolet B (UVB) or psoralen ultraviolet A (PUVA), photodynamic therapy and laser therapy.
  • UVB ultraviolet B
  • PUVA psoralen ultraviolet A
  • Retinoid therapy can also be used as ingredient A.
  • bexarotene, acitretin, etretinate and tazarotene, and hydroxyurea, 6-thioguanine and phototherapies are suitable additional ingredients.
  • 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.
  • combinations comprising ingredient A and one or more cytokine inhibitors of the invention, typically in therapeutically effective amounts, for use as pharmaceutical compositions with anti-cytokine activity.
  • combinations comprising ingredient A and a cytokine inhibitor can be used for preparing a pharmaceutical composition for the treatment and/or prevention of a cytokine-mediated disease or condition.
  • the pharmaceutical preparations, containing as the active substance one or more compound combinations comprising ingredient A and the cytokine inhibitor further include the pharmaceutically acceptable derivatives thereof, and may be optionally combined with conventional excipients and/or carriers.
  • the pharmaceutical combinations of ingredient A and the cytokine inhibitor according to the invention may be administered in any conventional dosage form in any conventional manner, including any of the routes described herein.
  • 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.
  • the pharmaceutical combinations of ingredient A and the cytokine inhibitor according to the invention 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 cytokine inhibitor may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition.
  • the ingredient A and/or the cytokine inhibitor may be used in the combination as a salt, solvate, tautomer and/or prodrug and as a single stereroisomer or mixtures of stereoisomers, including racemates.
  • the proportions in which the two components, ingredient A and the cytokine inhibitor, may be used in the combinations according to the invention are variable.
  • Ingredient A and the cytokine inhibitor are optionally present in the form of their solvates or hydrates.
  • 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 cytokine inhibitor, and are within the skill in the art.
  • UVB ultraviolet B
  • PUVA psoralens ultraviolet A
  • a typical combination for treating psoriasis is the cytokine inhibitor compound in combination with immunomodulatory and/or immunosuppresive drugs which include cyclosporin, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti- CD80, anti-CD25, peptide T, LFA3TIP, anti LFA3-IgCl, anti-CDll, DAB 389 , CTLA- 4Ig, E-selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, and those disclosed in Griffiths, Christopher E. M., 1998 Hospital Medicine, 59 No 7, and the obvious variants thereof.
  • immunomodulatory and/or immunosuppresive drugs which include cyclosporin, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti- CD80, anti-CD25, peptide T, LFA3TIP, anti LFA3-IgCl, anti-CDll,
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound 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 treating psoriasis is the cytokine inhibitor compound with cyclosporine, especially because of cyclosporine's efficiency for induction of remission.
  • Another embodiment of the invention comprises administration in the following sequence: induction with cytokine inhibitor and cyclosporine, followed by continuation with cytokine inhibitor after decrease of dosing and discontinuation of cyclosporine.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with retinoids.
  • Retinoids provide minimal efficacy with potential Cyt P450 interactions and risk of teratogenicity, and this would be alleviated by continuation therapy with the cytokine inhibitor.
  • Yet another typical combination for treating psoriasis is the cytokine inhibitor compound, in combination with ingredients A selected from steroids, vitamin D analogs, retinoids and dithranol. In some such combination treatments, the steroids and retinoids can be administered topically.
  • a more typical combination for treating psoriasis is a cytokine inhibitor compound with vitamin D derivatives, most typically calcipotriol or tacalcitol.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with macrolides, most typically with ascomycin analogues, administered topically, and even more typically with those available orally such as pimecrolimus.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with cell adhesion molecules inhibitors, such as anti LFA3, or anti LFAl. This includes adhesion molecule blockage by recombinant fusion proteins like alefacept, anti LF A3 -IgCl, or by anti-CD 11 monoclonal antibodies, efalizumab, and the obvious variants thereof.
  • Cell adhesion molecules inhibitors appear to provide an acceptable response rate with limited tolerability problems.
  • Combination with a cytokine inhibitor 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 cytokine inhibitor and CAM inhibitors, followed by maintenance treatment with the cytokine inhibitor alone and retreatment with CAM inhibitors in case of significant relapse.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound 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.
  • topical or general antisense inhibitors of TNFa such as ICAM-I ISIS 2302 in combination with a cytokine inhibitor compound.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound with anti-CD4, anti-CD80 (IDEC-114 or ABX-IL8), DAB-IL-2, DAB 389 -IL-2, CTLA4-Ig, ILlO, the IL-2 receptor inhibitors such as daclizumab (anti-TAC), or basiliximab.
  • DMARDs Disease Modifying Antirheumatic Drugs
  • SAARDs Slow Acting Antirheumatic Drugs
  • a typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs, such as, for example, hydroxychloroquine, D-penicillamine, sulfasalazine, auranofm, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, lefmnomide, methotrexate, azathioprine or cyclophosphamide.
  • immunosuppressive immunomodulatory
  • cytostatic drugs such as, for example, hydroxychloroquine, D-penicillamine, sulfasalazine, auranofm, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, si
  • cytokine inhibitor compound Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with angiogenesis inhibitors, such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha- interferon.
  • angiogenesis inhibitors such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha- interferon.
  • cytokine inhibitor compound in combination with inhibitors of cell adhesion, such as inhibitors of LFA-I or inhibitors of ICAM-I.
  • a more typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with anti-TNF antibodies or TNF-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.
  • the cytokine inhibitor is combined with infliximab alone or infliximab and methotrexate.
  • Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound in combination with IL-I receptor antagonists, such as Kineret®.
  • cytokine inhibitor compound 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,
  • NSAIDs including acetaminophen, aspir
  • cytokine inhibitor compound Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with steroids, such as betamethasone, dexamethasone, methylprednisolone, prednisolone, and deflazacort.
  • steroids such as betamethasone, dexamethasone, methylprednisolone, prednisolone, and deflazacort.
  • the following groups of drugs combined with the cytokine inhibitor may be effective: steroids such as budesonide, 5-AS A drugs like mesalamine, immunosuppressants, biological agents and adhesion molecule inhibitors.
  • steroids such as budesonide, 5-AS A drugs like mesalamine, immunosuppressants, biological agents and adhesion molecule inhibitors.
  • a typical combination for treating Crohn's disease is the cytokine inhibitor compound with one or more of the following: steroids including all those listed herein, 5-ASA drugs, methotrexate and azathioprine.
  • Another typical combination for treating Crohn's disease is the cytokine inhibitor compound combined with IL-I receptor antagonists, such as Kineret®.
  • cytokine inhibitor compound with anti-TNF antibodies or TNF- 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.
  • TNF- 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.
  • the cytokine inhibitor is administered with infliximab alone or combined with methotrexate.
  • cytokine inhibitor compound combined with IL-10, ISIS 2302 (anti ICAM 1), or Antegren (VCAM receptor antagonist).
  • 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 patient in need thereof a pharmaceutically effective amount of the cytokine inhibitor.
  • This administration may be of benefit given either prophylactically to patients at risk or therapeutically for patients who have developed complications related to these pathways.
  • Methods of treating a disorder relating to blood coagulation or fibrinolysis also include administering to a subject in need thereof a pharmaceutically effective amount of a cytokine inhibitor of the invention in combination with one or more anticoagulant or fibrinolytic agents.
  • the latter agents 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.
  • tissue plasminogen activator rtPA
  • streptokinase SK
  • urokinase UK
  • proUK proUK
  • heparin heparin
  • enoxoparin dalteparin
  • coumarin anticoagulants aspirin, dipyrimidamole
  • aggrennox ticlopidine
  • abciximab abciximab
  • RheoPro integrilin
  • a method of treating a cancer which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein.
  • a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein.
  • the method further comprises treating the mammal with surgery, radiation, cryotherapy, or one or more antiproliferative agents or a combination thereof.
  • the antiproliferative agent is an alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotic, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, DNA antagonist, farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, endothelin A receptor antagonist, retinoic acid receptor agonist, immunomodulator, hormonal or antihormonal agent, photodynamic agent, angiogenesis inhibitor, or a tyrosine kinase inhibitor.
  • the alkylating agent is busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, or chlorambucil.
  • platinum agents examples include spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin.
  • the antimetabolite is azacytidine, trimetrexate, floxuridine, deoxycoformycin, 2- chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irotulven (MGI Pharma), methotrexate, tomudex, ethynylcytidine (Taiho), fludarabine, gemcitabine, raltitrexed, or capecitabine.
  • the topoisomerase inhibitor is amsacrine, exatecan mesylate (Daiichi), epirubicin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl-lO-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-11), or topotecan.
  • the antitumor antibiotic is dactinomycin (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menarini), plicamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonaf ⁇ de.
  • antimitotic agents are colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Warner- Lambert), synthadotin (BASF), cemadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (Eli Lilly), vinflunine (Fabre), hydravin (Prescient NeuroPharma), a
  • the aromatase inhibitor is aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole.
  • the thymidylate synthase inhibitor is pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche), or 5, 10-methylenetetrahydro folate (BioKeys).
  • the DNA antagonist is trabectedin (PliarmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics).
  • the farnesyltransferase inhibitor is arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).
  • Examples of pump inhibitors are zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG).
  • Examples of histone acetyltransferase inhibitors include tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG).
  • the metalloproteinase inhibitor is neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech).
  • the ribonucleoside reductase inhibitor is gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health).
  • the endothelin A receptor antagonist is atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
  • the retinoic acid receptor agonist is fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD- 1550 (Ligand).
  • the immuno-modulator is an interferon, interferon a-2a (e.g., Roferon-A, Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CD 154 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), ⁇ -alethine (Dovetail), melanoma vaccine (CTL Imrnuno), vasocare (Vasogen), rituximab (Genentech/Biogen pou), or p21 RAS vaccine (GemVax).
  • interferon a-2a
  • the hormonal agent is an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutaniide, or leuporelin.
  • the hormonal agent is an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methyl
  • the photodynamic agent is talaporfm (Light Sciences), Pd-bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin.
  • the angiogenesis inhibitor is neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Pfizer).
  • tyrosine kinase inhibitors include imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKline), panitumumab (Abgenix), IMC-ICl 1 (Im
  • the anti-proliferative agent is melphalan, carmustine, cisplatin, 5- fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, or paclitaxel (Taxol ® ).
  • the cancer is osteosarcoma
  • epithelial cell-derived neoplasia epit
  • the cancer is acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gas
  • the cancer is leukemia, erythroblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non- hodgkin's lymphoma or follicular lymphoma. In some embodiments, the cancer is follicular lymphoma, acute myelogenous leukemia, multilple myeloma or non- hodgkin's lymphoma.
  • the cancer is brain cancer, glioma, glioblastoma, meningioma, astrocytoma, medulloblastoma, neuroblastoma or retinoblastoma. In some such embodiments, the cancer is glioma or glioblastoma. [0041] In yet other embodiments, the cancer is osteosarcoma, Kaposi's sarcoma, chondosarcoma, Ewing's sarcoma or myoblastoma. In some such embodiments, the cancer is osteosarcoma bone cancer.
  • the cancer is breast, lung, kidney or prostate cancer metastasis.
  • the neoplasm is bone metastasis.
  • a method of treating, modifying or managing pain which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein.
  • a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein.
  • the composition further comprises an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, ⁇ - adrenergic receptor agonist, ⁇ -adrenergic receptor antagonist, ketamine, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, NSAID, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, hyperbaric oxygen, ⁇ 2 ⁇ ligand, NMDA receptor antagonist, or a combination of any two or more thereof.
  • the antidepressant is nortriptyline, amitriptyline, imipramine, doxepin, clomipramine, fluoxetine, sertraline, nefazodone, venlafaxine, trazodone, or bupropion.
  • the anti-hypertensive is nifedipine, terazosin, prazosin, losartan, verapamil, telmisartan, fosinopril, bosentan, or olmesartan.
  • the anxiolytic is fluoxetine, paroxetine, sertraline, or venlafaxine.
  • Examples of calcium channel blockers include nifedipine, verapamil and clonidine.
  • the ⁇ -adrenergic receptor agonist is clonidine or midodrine.
  • the ⁇ -adrenergic receptor antagonist is terazosin, prazosin, or doxasozin.
  • the anesthetic is procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine, or ropivacaine.
  • opioid analgesic include hydromorphone, oxycodone, morphine sulfate, meperidine, and fentanyl transdermal patch.
  • the NSAID is a COX-2 inhibitor, salicylic acid acetate, ⁇ buprofen, ketoprofen, naproxen sodium, ketorolac, diclofenac, indometacin, or acetaminophen.
  • the COX-2 inhibitor is rofecoxib, celecoxib, or valdecoxib.
  • the corticosteroid is prednisone, dexamethasone or hydrocortisone.
  • the anticonvulsant is carbamazepine, oxcarbazepine, gabapentin, pregabalin, phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, tiagabine, famotodine, phenobarbital, diphenylhydantoin, mephenytoin, ethotoin, mephobarbital, primidone, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, clobazam, sulthiame, dilantin, diphenylan, or L-5-hydroxytryptophan.
  • the NMDA receptor antagonist is dextromethorphan, dextrorphan, ketamine, memantine, amantadine, agmatine, aptiganel, gavestinel, selfotel, 7-chlorokynurate, remacemide, riluzole, pyrroloquinoline quinone or cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, hi others
  • the ⁇ 2 ⁇ ligand is gabapentin, pregabalin, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl- cyclohexylmethyl)-4H-[l,2,4]-oxadiazol-5-one and C-[l-(lH-tetrazol-5-ylmethyl)- cycloheptylj-methylamine, (3S,4S)-(l
  • the composition further comprises acetylsalicylic acid, diclofenac, ibuprofen, indometacin, flufenamic acid, mefenamic acid, morphine, pethidine, methadone, fentanyl, buprenorphine, tramadol, gabapentin, pregabalin, carbamazepine, lamotrigin, topiramate, phenyloin, levitiracetam, procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine, ropivacaine, amitryptiline, paroxetine, citalopram, bupropione, duxoletine, ketamine, memantine, 2,3- benzodiazepines, or a combination of any two or more thereof.
  • the pain is acute pain, chronic pain, pain resulting from soft tissue and peripheral damage from acute trauma; neuropathic pain; post-stroke pain; pain from neuralgia, acute herpetic neuralgia, postherpetic neuralgia, occipital neuralgia, HIV related neuralgias, AIDS related neuralgias, trigeminal neuralgia, or segmental or intercostal neuralgia; pain associated with osteoarthritis or rheumatoid arthritis; musculo-skeletal pain; spinal pain, central nervous system pain; lower back pain, pain from sciatica, dental pain, myofascial pain syndromes, episiotomy pain, or gout pain; deep and visceral pain; muscle pain, eye pain, inflammatory pain, orofacial pain; abdominal pain, or gynecological pain; somatogenic pain; pain associated with nerve and root damage; pain associated with limb amputation, tic douloureux, neurom
  • the musculo-skeletal pain is pain associated with strains, sprains or broken bones.
  • the central nervous system pain is pain due to spinal cord or brain stem damage.
  • the deep and visceral pain is heart pain, hi others, the orofacial pain is odontalgia.
  • the gynecological pain is dysmenorrhoea, labor pain and pain associated with endometriosis, hi others, the pain associated with nerve and root damage, is pain associated with peripheral nerve disorders.
  • the peripheral nerve disorder is nerve entrapment or brachial plexus avulsions
  • the headache is migraine with aura, migraine without aura, vascular headaches, acute or chronic tension headache, sinus headache or cluster headache.
  • the chronic non-neuropathic pain is pain associated with HIV, arthralgia, vasculitis or fibromyalgia.
  • the complex regional pain syndrome is type I or type II.
  • the pain is nociceptive pain or neuropathic pain.
  • the nociceptive pain is associated with chemical or thermal burn, cut of the skin, contusion of the skin, osteoarthritis, rheumatoid arthritis, systemic lupus erthrematosis (SLE), or tendonitis, or is myofascial pain.
  • the neuropathic pain is post-stroke pain; complex regional pain syndrome; sympathetic maintained pain syndrome; pain associated with diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, fibromyalgia, chronic fatigue syndrome, radiculopathy, luetic neuropathy; spinal cord injury pain; pain related to cancer or metastases; phantom limb pain; or painful neuropathic condition induced by a drug.
  • the cancer is osteosarcoma, colorectal cancer, brain cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body; leukemia; lymphoma; or angiogenesis including neoplasia.
  • the metastases are breast, lung, kidney or prostate cancer metastases.
  • Cytokine inhibitors useful in the methods of the invention are exemplified by Formulas IA, IB, IC and II and are described in U.S. application 10/939,324, filed 9/10/2004, and U.S. Application No. 60/656,196, filed February 24, 2005, which are each incorporated herein by reference in their entirety: Q
  • the cytokine inhibitors comprise: a targeting moiety 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 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 a target protein; an orienting moiety 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 ⁇ - ⁇ or edge-to-face aromatic interaction with a target protein.
  • Ethanesulfonic acid (5-tert-butyl-2-methoxy-3- ⁇ 3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl ⁇ -phenyl)-amide;
  • 6-Hydroxy-nicotinic acid 3-[5-tert-butyl-2-methoxy-3-(propane-l-sulfonylatnino)- phenylcarbamoyl]-lH-indazol-5-yl ester;
  • references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • isotopically labeled compounds are within the scope of the invention.
  • substituted refers to a functional group as defined below 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.
  • substituted groups have 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include, but are not limited to: 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; thiols; alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl sulfide groups; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; is
  • 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 alkyl, alkenyl, and alkynyl groups as defined below.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n- ⁇ ropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • 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 any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 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.
  • 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 any of the groups listed above, for example, methyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
  • Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkylene brige, 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 2 carbon atoms.
  • Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexyl, 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 norbomyl 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 any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
  • 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.
  • Alkenyl groups include straight and branched chain alkyl and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • 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 carbon atoms.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienylgroups.
  • 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.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups include monocyclic, bicyclic and polycyclic ring systems.
  • 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.
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups.
  • 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.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with groups such as those listed above.
  • 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.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • 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, the heterocyclyl group contains 1, 2, 3, or 4 heteroatoms.
  • heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 10, 12, or 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.
  • a heteroatom such as, but not limited to, quinuclidyl.
  • 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.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, pyrazolidinyl, tetrahydropyranyl, thiomorpholinyl, pyranyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl
  • Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various groups as defined above, including, but not limited to, alkyl, oxo, carbonyl, amino, alkoxy, cyano, and/or halo.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • the heteroaryl group includes 1, 2, 3, or 4 heteroatoms and has 5 to 20, 5 to 15, or 5 to 10 ring members.
  • the heteroaryl groups have 5, 6, 7, 8, or 9 ring members.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl (thienyl), benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • heteroaryl groups includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substituents are referred to as "substituted heteroaryl groups".
  • Representative substituted heteroaryl groups may be substituted one or more times with various groups as defined above, including, but not limited to, amino, oxo, alkoxy, alkyl, cyano, and/or halo.
  • 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.
  • Representative heterocyclyl alkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • 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.
  • Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an alkyl group as defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • carboxylate refers to a -COOH group.
  • carboxylic ester refers to -COOR 30 groups.
  • R 30 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e.,
  • R 31 and R 32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
  • Urethane groups include N- and 0-urethane groups, i.e., -
  • R 33 and R 34 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • amine refers to -NHR 35 and -NR 36 R 37 groups, wherein R 35 , R 36 and R 37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • sulfonamido includes S- and N-sulfonamide groups, i.e.,
  • R 38 and R 39 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • thiol refers to -SH groups
  • sulfides include -SR 40 groups
  • sulfoxides include -S(O)R 41
  • sulfones include -SO 2 R 42 groups
  • sulfonyls include -SO 2 OR 43 .
  • R 40 , R 41 , R 42 , and R 43 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • urea refers to -NR 44 -C(O)-NR 45 R 46 groups.
  • R 46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • amidine refers to -C(NR 47 )NR 48 R 49 and -NR 47 C(NR 48 )R 49 groups, wherein R 47 , R 48 , and R 49 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • guanidine refers to -NR 50 C(NR 51 )NR 52 R 53 groups, wherein R 50 , R 51 , R 52 and R 53 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • R 54 , R 55 , R 56 and R 57 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • imide refers to -C(O)NR 58 C(O)R 59 groups, wherein R 58 and R 59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the term "imine” refers to -CR 60 (NR 61 ) and -N(CR 60 R 61 ) groups, wherein R 60 and R 61 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 not both R 60 and R 61 are H simultaneously.
  • 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 trifiuoracetate.
  • a reagent such as, but not
  • N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloro acetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, A- 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-
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4- ⁇ icolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4- ⁇ icolyl thioether
  • substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals
  • carboxy protecting groups are Ci to C 8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as
  • 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, triazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • Stereoisomers of compounds include all chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure, unless the specific stereochemistry or isomeric form is specifically indicated.
  • 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.
  • Pharmaceutically acceptable salts of the invention compounds are considered within the scope of the present invention.
  • 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).
  • 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, mal
  • the compound of the invention when it 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 + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia, organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine).
  • alkali and earth alkali metals e.g. Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+
  • ammonia e.g., organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e
  • prodrugs Certain compounds within the scope of the invention 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 1985, 112, 309; Bodor, N., “Novel Approaches in Prodrug Design," Drugs of the Future 1981, 6, 165; 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
  • cancer refers to any of various malignant neoplasms characterized by the proliferation of cells that can invade surrounding tissue and metastasize to new body sites.
  • a neoplasm, or tumor is an abnormal, unregulated, and disorganized proliferation of cell growth.
  • a neoplasm is malignant, or cancerous, if it has properties of destructive growth, invasiveness and metastasis.
  • Invasiveness refers to the local spread of a neoplasm by infiltration or destruction of surrounding tissue, typically breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body's circulatory system.
  • Metastasis typically refers to the dissemination of tumor cells by lymphotics or blood vessels.
  • Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance. Bone tissues are one of the most favored sites of metastases of malignant tumors, occurring in about 30% of all the cancer cases. Among malignant tumors, cancers of the lung, breast, prostate or the like are particularly known to be likely to metastasize to bone.
  • Both benign and malignant tumors are classified according to the type of tissue in which they are found.
  • fibromas are neoplasms of fibrous connective tissue
  • melanomas are abnormal growths of pigment (melanin) cells.
  • Malignancies of epithelial glandular tissue such as are found in the breast, prostate, and colon, are known as adenocarcinomas.
  • Malignant growths of connective tissue e.g., muscle, cartilage, lymph tissue, and bone, are called sarcomas. Lymphomas and leukemias are malignancies arising among the white blood cells.
  • nociceptive pain includes, but is not limited to, pain associated with chemical or thermal burns, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.
  • neurode includes, but is not limited to, a functional disturbance or pathological change in the peripheral nervous system and is characterized clinically by sensory or motor neuron abnormalities.
  • the term mononeuropathy indicates that a single peripheral nerve is affected, while the term polyneuropathy indicates that several peripheral nerves are affected.
  • Deafferentation indicates a loss of the sensory input from a portion of the body, and can be caused by interruption of either peripheral sensory fibres or nerves from the central nervous system.
  • Neuropathic pain thus reflects injury or impairment of the nervous system, and is defined herein as pain initiated or caused by a primary lesion or dysfunction in the nervous system. In particular, neuropathic pain can be caused by injury or dysfunction of the peripheral nervous system.
  • the etiology of a neuropathy can be known or unknown.
  • Known etiologies include complications of a disease or toxic state such as diabetes (which is the most common metabolic disorder causing neuropathy), or irradiation, ischemia or vasculitis. It is understood that the methods of the invention can be used to treat chronic pain of these or other chronic neuropathies of known or unknown etiology.
  • neuropathic pain includes, but is not limited to, CRPS (Complex Regional Pain Syndrome) type I, CRPS type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer and metastases related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine, velcade and thalidomide.
  • the neuropathic pain can result from a mononeuropathy, polyneuropathy, complex regional pain syndromes or dea
  • Visceral pain is conventionally viewed as a variant of somatic pain, but may differ in neurological mechanisms. Certain clinical characteristics are peculiar to visceral pain: (i) it is not evoked from all viscera and not always linked to visceral injury; (ii) it is often diffuse and poorly localized, due to the organization of visceral nociceptive pathways in the central nervous system (CNS), particularly the absence of a separate visceral sensory pathway and the low proportion of visceral afferent nerve fibers; (iii) it is sometimes referred to other nonvisceral structures; and (iv) it is
  • Headaches can be classified as primary and secondary headache disorders.
  • the pathophysiology of the two most common primary disorders i.e., migraine and tension-type headache, is complex and not fully understood.
  • nociceptive input to the CNS may be increased due to the activation and sensitization of peripheral nociceptors, and the barrage of nociceptive impulses results in the activation and sensitization of second- and third-order neurons in the CNS.
  • central sensitization plays a role in the initiation and maintenance of migraine and tension-type headache [Johnson, B. W. Pain Mechanisms: Anatomy, Physiology and Neurochemistry, Chapter 11 in Practical Management of Pain ed. P. Prithvi Raj. (3 rd Ed., Mosby, Inc. St Louis, 2000)].
  • a "cytokine inhibitor" within the context of this invention is a compound which at a concentration of 10 ⁇ M inhibits induced cytokine release from a cell by about 50% or greater than 50%.
  • 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.
  • LPS lipopolysaccharide
  • IL-Ib IL-Ib
  • 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 halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder (i.e., inflammation, cancer or pain).
  • successful treatment may include an alleviation of symptoms or halting the progression of the disease, as measured by a reduction in the growth rate of a tumor, a halt in the growth of the tumor, a reduction in the size of a tumor, partial or complete remission of the cancer, or increased survival rate or clinical benefit.
  • 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 halts of further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder.
  • a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, pain symptoms, or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the pain symptoms.
  • a therapeutically effective amount of a cytokine inhibitor 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 ratio of doses between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
  • Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies.
  • the compounds and pharmaceutical formulations of the present invention may be administered before, during, or after surgical procedure and/or radiation therapy.
  • the compounds of the invention can also be administered in conjunction with other anti-inflammatory agents, anticancer agents and other agents described herein.
  • the cytokine inhibitors disclosed herein 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. Additional treatments comprise treatment by surgery, radiation, or cryotherapy, while treatment with additional active ingredients comprises the use of antiproliferative agents. Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e.g., carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects of each drug.
  • Additional treatments comprise treatment by surgery, radiation, or cryotherapy
  • additional active ingredients comprises the use of antiproliferative agents.
  • Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e.g., carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects of each drug.
  • the specific amount of the additional active agent will depend on the specific agent used, the type of cancer being treated or managed, the severity and stage of the cancer, and the amount(s) of cytokine inhibitors and any optional additional active agents concurrently administered to the mammal.
  • the additional active ingredients that can be used in combination with the cytokine inhibitors of the present invention are used at dosages well known in the art.
  • inhibition in the context of neoplasia, cancer, tumor growth or tumor cell growth, may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition is referred to herein as prevention or chemoprevention.
  • prevention in the context of cancer includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinically evident stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or arresting or reversing the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia.
  • antiproliferative agents includes agents that prevent the development, maturation, or spread of cells, by acting directly on the cell, e.g., by cytostatic or cytocidal effects, and not indirectly through mechanisms such as biological response modification.
  • antiproliferative agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be employed for treatment with compounds of the present invention for treatment of cancer by combination drug chemotherapy.
  • Exemplary antiproliferative agents can be categorized as alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, endothelin A receptor antagonists, retinoic acid receptor agonists, immunomodulators, hormonal or antihormonal agents, photodynamic agents, angiogenesis inhibitors, tyrosine kinase inhibitors, and the like. Some antiproliferative agents operate through multiple or unknown mechanisms and can thus be classified into more than one category.
  • the alkylating agents are believed to act by alkylating and cross- linking guanine and possibly other bases in DNA, arresting cell division.
  • exemplary alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cisplatin, and various nitrosoureas.
  • a disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skin, gastro-intestinal mucosa, and fetal tissue.
  • Suitable alkylating-type agents include, but are not limited to, busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, and chlorambucil.
  • Suitable platinum agents that may be used in the present invention include, but are not limited to spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin.
  • Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids.
  • Suitable antimetabolite agents include, but are not limited to azacytidine, trimetrexate, floxuridine, deoxycoformycin, 2-chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex, ethynylcytidine (Taiho), fludarabine, gemcitabine, raltitrexed, or capecitabine.
  • azacytidine trimetrexate, floxuridine, deoxycoformycin, 2-chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision
  • topoisomerase agents that may be used in the present invention include, but are not limited to amsacrine, exatecan mesylate (Daiichi), epirubicin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl-lO-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR- 3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-I l), or topotecan.
  • amsacrine exatecan me
  • Suitable antibiotic-type antiproliferative agents include, but are not limited to dactinomycin (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menarini), plicamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonafide.
  • Suitable antimitotic antiproliferative agents include, but are not limited to colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Warner-Lambert), synthadotin (BASF), cemadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (El
  • Suitable aromatase inhibitors that may be used in the present invention include, but are not limited to aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole.
  • Suitable thymidylate synthase inhibitors include, but are not limited to, pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche), or 5,10- methylenetetrahydrofolate (BioKeys).
  • Suitable DNA antagonists that may be used in the present invention include, but are not limited to trabectedin (PharmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics).
  • Suitable farnesyltransferase inhibitors include, but are not limited to arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).
  • Suitable pump inhibitors that may be used in the present invention include, but are not limited to zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG).
  • Suitable histone acetyltransferase inhibitors that may be used in the present invention include, but are not limited to tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG).
  • Suitable metalloproteinase inhibitors that may be used in the present invention include, but are not limited to neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech).
  • Suitable ribonucleoside reductase inhibitors contemplated for use in the present invention include, but are not limited to, gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health).
  • Suitable endothelin A receptor antagonists that may be used in the present invention include, but are not limited to atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
  • retinoic acid receptor agonists include compounds which are natural and synthetic analogues of retinol (Vitamin A). The retinoids bind to one or more retinoic acid receptors to initiate diverse processes such as reproduction, development, bone formation, cellular proliferation and differentiation, apoptosis, hematopoiesis, immune function and vision.
  • Suitable retinoic acid receptor agonists that may be used in the present invention include, but are not limited to fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD-1550 (Ligand).
  • Suitable immunomodulators that may be used in the present invention include, but are not limited to interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CDl 54 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP -25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), ⁇ -alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen pou), or p21 RAS vaccine (GemVax).
  • Suitable hormonal agents include, but are not limited to an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutamide, or leuporelin.
  • an estrogen dexamethasone
  • a conjugated estrogen prednisone
  • ethinyl estradiol
  • Suitable photodynamic agents that may be used in the present invention include, but are not limited to talaporfm (Light Sciences), Pd- bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin.
  • Suitable angio genesis inhibitors include, but are not limited to neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Sugen).
  • Suitable tyrosine kinase inhibitors include, but are not limited to imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKline), panit
  • Additional anti-proliferative agents which may be used in combination with cytokine inhibitors of the present invention include melphalan, carmustine, cisplatin, 5-fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, paclitaxel (Taxol ® ), and the like.
  • the cytokine inhibitors of the invention can be used together with additional active ingredients or agents.
  • the additional active agents are capable of relieving pain, inhibiting inflammatory reactions, providing a sedative effect or an antineuralgic effect, or ensuring patient comfort.
  • additional active agents include, but are not limited to, opioid analgesics, non-narcotic analgesics, antiinflammatories, cox-2 inhibitors, ⁇ - adrenergic receptor agonists or antagonists, ketamine, anesthetic agents, NMDA antagonists, ⁇ 2 ⁇ ligands, immunomodulatory agents, immunosuppressive agents, antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, corticosteroids, hyperbaric oxygen, other therapeutics known to relieve pain, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, prodrugs or pharmacologically active metabolites thereof.
  • Opioids can be used to treat severe pain.
  • opioid analgesics include, but are not limited to, oxycodone (OxyContinTM), morphine sulfate (MS ContinTM, DuramorphTM, AstramorphTM), meperidine (DemerolTM), and fentanyl transdermal patch (DuragesicTM) and other known conventional medications [See, e.g., Physicians' Desk Reference, 594-595, 2851 and 2991 (57 th ed., 2003)].
  • Oxycodone (OxyContinTM) is a long-acting form of an opioid and may be used in initial and later stages of CRPS.
  • Morphine sulfate may be used for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate is sold in the United States under the trade name MS ContinTM, DuramorphTM, or AstramorphTM [See, e.g., Physicians' Desk Reference, 594-595 (57 th ed., 2003)].
  • Fentanyl transdermal patch (DuragesicTM) is a potent narcotic analgesic with much shorter half-life than morphine sulfate.
  • Meperidine (DemerolTM) and hydromorphone (DilaudidTM) may also be used for pain management [See, e.g., Physicians' Desk Reference, 2991 (57 th ed., 2003)].
  • Non-narcotic analgesics and antiinflammatories are preferably used for treatment of pain during pregnancy and breastfeeding.
  • Anti -inflammatories such as non-steroidal anti-inflammatory drugs (NSAIDs) and cox-2 inhibitors typically inhibit inflammatory reactions and pain by decreasing the activity of cyclo- oxygenase, which is responsible for prostaglandin synthesis.
  • NSAIDs may provide pain relief in the early stage of pain syndrome.
  • antiinflammatories include, but are not limited to, salicylic acid acetate (AspirinTM), ibuprofen (MotrinTM, AdvilTM), ketoprofen (OruvailTM), rofecoxib (VioxxTM), naproxen sodium (AnaproxTM, NaprelanTM, NaprosynTM), ketorolac (AcularTM), and other known conventional medications.
  • a specific cox-2 inhibitor is celecoxib (CelebrexTM) [See, e.g., Physicians' Desk Reference, 1990, 1910-1914 and 2891 (57 th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 511, 667 and 773 (23 rd ed., 2002)].
  • Antidepressants increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. Some antidepressants also have sodium channel blocking ability to reduce the firing rate of injured peripheral afferent fibers.
  • antidepressants include, but are not limited to, nortriptyline (PamelorTM), amitriptyline (ElavilTM), imipramine (Tofranill), doxepin (SinequanTM), clomipramine (AnafranilTM), fluoxetine (ProzacTM), sertraline (ZoloftTM), nefazodone (SerzoneTM), venlafaxine (EffexorTM), trazodone (DesyrelTM), bupropion (WellbutrinTM) and other known conventional medications [See, e.g., Physicians' Desk Reference, 329, 1417, 1831 and 3270 (57 th ed., 2003)].
  • Anticonvulsant drugs may also be used in embodiments of the invention.
  • anticonvulsants include, but are not limited to, carbamazepine, oxcarbazepine, gabapentin (NeurontinTM), phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, and tiagabine [See, e.g., Physicians' Desk Reference, 2563 (57 th ed., 2003)].
  • Corticosteroids e.g., prednisone, dexamethasone or hydrocortisone
  • orally active class Ib anti-arrhythmic agents e.g., mexiletine
  • calcium channel blockers e.g., nifedipine
  • beta-blockers e.g., propranolol
  • ⁇ -blockers e.g., phenoxybenzamine
  • oc2-adrenergic agonists e.g., clonidine
  • cytokine inhibitor See, e.g., Physicians' Desk Reference, 1979, 2006 and 2190 (57 th ed., 2003)].
  • Administration of the cytokine inhibitors of the invention and the optional additional active agents to a patient 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 cytokine inhibitors is oral.
  • 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, 594-597 (57 th ed., 2003)].
  • the cytokine inhibitor and the additional active agents are administrated simultaneously by coformulation.
  • the specific amount of the additional active agent will depend on the specific agent used, the type of pain being treated or managed, the severity and stage of pain, and the amount(s) of cytokine inhibitors and any optional additional active agents concurrently administered to the patient.
  • Hydromorphone (DilaudidTM) is typically administered in an initial dose of about 2 mg orally, or about 1 mg intravenously to manage moderate to severe pain [See, e.g., Physicians' Desk Reference, 2991 (57 th ed., 2003)].
  • Morphine sulphate (DuramorphTM, AstramorphTM, MS ContinTM) is typically administered in an initial dose of about 2 mg IV/SC/IM, depending on whether a patient has already taken narcotic analgesics [See, e.g., Physicians' Desk Reference, 594-595 (57 th ed., 2003)].
  • Oxycodone is a long-acting form of an opioid and may be used in initial and later stages of pain syndrome.
  • Oxycodone (OxyContinTM) is usually administered in an amount of about 10-160 mg twice a day [See, e.g., Physicians' Desk Reference, 2851 (57 th ed., 2003)].
  • Meperidine (DemerolTM) is typically administered in an amount of about 50-150 mg PO/IV/IM/SC every 3-4 hours.
  • a typical pediatric dose of meperidine (DemerolTM) is 1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC every 3-4 hours [See, e.g., Physicians' Desk Reference, 2991 (57 th ed., 2003)].
  • Fentanyl transdermal patch (DuragesicTM) is available as a transdermal dosage form.
  • a typical adult dose is about 25 mcg/h (10 cm ), 50 mcg/h (20 cm 2 ), 75 mcg/h (75 cm 2 ), or 100 mcg/h (100 cm 2 ) [See, e.g., Physicians' Desk Reference, 1775 (57 th ed., 2003)].
  • Non-narcotic analgesics and antiinflammatories such as NSAIDs and cox-2 inhibitors may be used to treat patients suffering from mild to moderate pain.
  • Ibuprofen MotrinTM, AdvilTM
  • Naproxen sodium may also be used for relief of mild to moderate pain in an amount of about 275 mg thrice a day or about 550 mg twice a day [See, e.g., Physicians' Desk Reference, 1417,2193 and 2891 (57 th ed., 2003)].
  • Antidepressants e.g., nortriptyline (PamelorTM) may also be used in the practice of the invention to treat patients suffering from chronic and/or neuropathic pain.
  • the oral adult dose is typically in an amount of about 25-100 mg, and usually does not exceed 200 mg/d.
  • a typical pediatric dose is about 0.1 mg/kg PO as initial dose, increasing, as tolerated, up to about 0.5-2 mg/d.
  • Amitriptyline (EtrafonTM) is typically used for neuropathic pain in an adult dose of about 25-100 mg PO [See, e.g., Physicians' Desk Reference, 1417 and 2193 (57 th ed., 2003)].
  • Anticonvulsants such as gabapentin (NeurontinTM) may also be used to treat patients suffering from chronic and neuropathic pain.
  • gabapentin is orally administered in an amount of about 100-1,200 mg three times a day [See, e.g., Physicians' Desk Reference, 2563 (57 th ed., 2003)].
  • Carbamazepine (TegretolTM) is used to treat pain associated with true trigeminal neuralgia.
  • the oral adult dose is typically in an amount of about 100 mg twice a day as initial dose, increasing, as tolerated, up to about 2,400 mg/d [See, e.g., Physicians' Desk Reference, 2323-25 (57 th ed., 2003)].
  • the additional active agents can act additively or, more typically, synergistically with the cytokine inhibitor.
  • a cytokine inhibitor is administered concurrently with one or more second active agents in the same pharmaceutical composition.
  • a cytokine inhibitor is administered concurrently with one or more second active agents in separate pharmaceutical compositions, hi still another example, a cytokine inhibitor is administered prior to or subsequent to administration of a second active agent.
  • the invention contemplates administration of a cytokine inhibitor and a second active agent by the same or different routes of administration, e.g., oral and parenteral.
  • the second active agent when a cytokine inhibitor is administered concurrently with a second active agent that potentially produces adverse side effects including, but not limited to, toxicity, can advantageously be administered at a dose that falls below the threshold that elicits the adverse side effect.
  • cytokine inhibitors or combinations of cytokine inhibitors and additional active agents may be adjusted depending on conditions of 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.
  • Administration of the cytokine inhibitors and the additional active agents to a mammal 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 cytokine inhibitors described herein is oral.
  • 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)].
  • the cytokine inhibitor and the additional active agents are administrated simultaneously by coformulation.
  • the additional active agent can be administered orally, intravenously, intramuscularly, subcutaneously, mucosally, or transdermally and once or twice 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.
  • a cytokine inhibitor and an additional active agent are administered to a mammal, more typically a human, in a sequence and within a time interval such that the cytokine inhibitor can act together with the other agent to provide an increased benefit than if they were administered otherwise.
  • 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.
  • the cytokine inhibitor and the additional active agent(s) exert their effects at times which overlap.
  • Each additional active agent can be administered separately, in any appropriate form and by any suitable route.
  • the cytokine inhibitor is administered before, concurrently or after administration of the additional active agent(s).
  • the cytokine inhibitor 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 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the cytokine inhibitor and the additional active agents are administered concurrently.
  • the cytokine inhibitor and the additional active agents are administered concurrently by coformulation.
  • the cytokine inhibitor 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.
  • the cytokine inhibitor and the optional additional active agent(s) are cyclically administered to 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 reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, reduce the dose levels of the cytokine inhibitor and/or the optional active agent(s), and/or improve the efficacy of the treatment.
  • the cytokine inhibitor and the optional additional active agent(s) 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 cytokine inhibitor and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 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.
  • the cytokine inhibitor 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.
  • the cytokine inhibitor is used at doses lower than other protocols such as daily dosing.
  • 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.
  • the cytokine inhibitor 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.
  • Courses of treatment can be administered concurrently to a mammal, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the cytokine inhibitor can work together with the additional active agents.
  • 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.
  • the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
  • compositions which may be prepared by mixing one or more cytokine inhibitory compounds as described herein, 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 treat, or prevent a variety of disorders associated with excess cytokine production.
  • the compositions of the invention may be used to create
  • compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injections.
  • dosage forms are given by way of example and should not be construed as limiting the instant invention.
  • 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.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
  • suitable coating materials known in the art.
  • 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.
  • suspensions may include oils.
  • 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.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri- glycerides.
  • the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above.
  • these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • 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.
  • 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.
  • 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
  • Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide.
  • 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 including compounds 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.
  • 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.
  • the compounds may be formulated in oily solutions or as a gel.
  • any suitable propellant may be used including compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
  • 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.
  • 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.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention to the body.
  • 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.
  • Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • the compounds used in this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
  • the compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye.
  • the compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
  • Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer.
  • the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
  • the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
  • Gelling agents can also be used, including, but not limited to, gellan and xanthan gum.
  • sterile ophthalmic ointment formulations the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations maybe 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.
  • 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).
  • 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.
  • 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.
  • the formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below.
  • the pharmaceutical formulations may also be formulated for controlled release or for slow release.
  • 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.
  • cytokine inhibitors used in the instant invention are described below.
  • a first group of compounds are represented by Formula IA,
  • G is a C 3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R 1 , R 2 or R 3 ;
  • X is C(O), C(S) or CH 2 ;
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C 6-10 aryl, -(Cj -3 alkyl)-(C 6-10 aryl), -(Y)-(C 0-3 alkyl)-(C 6-10 aryl), or -(Y)-(C 0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R 4 or R 5
  • each Z is independently F, Cl, -OR, -NR 2 , -SR, -NHCONHR, or -NHCOR;
  • L is a covalent bond or a saturated or unsaturated branched or unbranched Ci -10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0) m ; and wherein L is optionally substituted with 1-2 oxo groups and one or of F, Cl, Br, or I;
  • each m is independently 0, 1 or 2;
  • Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C 1-6 alkoxy, Ci -6 alkyl-S(O) m , or phenyl- S (O) m , wherein the cycloalkyl, aryl, heterocyclyl, Ci -6 alkoxy, Ci -6 alkyl-S(O) ra , or phenyl-S(O) m is each optionally substituted with one or more R 27 ;
  • each R is independently hydrogen or substituted or unsubstituted Ci -6 alkyl; each R' is independently hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted (C 0-4 alkyl)-(C 6 . 10 aryl) or substituted or unsubstituted (C 0-4 alkyl)-(5-10 member heterocyclyl);
  • each R 1 is independently F, Cl, Br, I, cyano, -C(O)R 5 -C(O)NR 2 , -C(O)OR, -OR, -NR'R', -SiR 3 , - S(O) m R, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-10 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing I 5 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m ;
  • each R 2 , R 4 and R 5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C 1-6 alkyl, substituted or unsubstituted C 6-I0 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) 1n R", -NR 5 SO 2 R", -NR' C(O)NR' R', - NR'C(S)NR'R ⁇ -NR 5 C(O)OR' or -SO 2 NR' 2 ;
  • each R" is independently substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 0-4 alkyl-C 6 . 10 aryl or substituted or unsubstituted (C 0-4 alkyl)-(5-10 member heterocyclyl);
  • each R 3 is independently substituted or unsubstituted C 6-1O 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, S(0) m , substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted C 5-I2 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted straight or branched Ci -8 alkyl, R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )-, R 26 C( ⁇ CH 2 ) m N(R 21 )-, substituted or unsubstituted C 2-8 alkenyl, or substituted or unsubstituted C 2-8 alky
  • each R 6 is a C 1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R 26 ;
  • each R 26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co- 4 alkyl)amino, wherein the Co- 4 alkyl is optionally partially or folly halogenated;
  • R 20 is substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 0-6 alkyl-phenyl, substituted or unsubstituted C 0-6 alkyl-heterocyclyl, OR' or NR' 2 ;
  • R 21 is hydrogen or C 1-4 branched or unbranched alkyl optionally partially or fully halogenated
  • each R 22 , R 23 and R 24 is independently hydrogen, substituted or unsubstituted Ci -1 O alkyl, wherein the C 1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C 0-6 alkyl-phenyl, substituted or unsubstituted C 0-6 alkyl-heterocyclyl; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring;
  • each R 27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NR' 2 , -C(O)OR', -OR', -NR'R ⁇ -SiR' 3 , - S(O) m R ⁇ substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-1O alkenyl, substituted or unsubstituted C 2-10 alkynyl, substituted or unsubstituted C 3-1O cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m ;
  • the compound at a concentration of 10 ⁇ M inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
  • pyrazolyl pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzof ⁇ ranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[l,4]oxazine-3-only, benzodioxolyl, benzo[l,3]dioxol-2
  • pyrrolidinyl tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomo ⁇ holinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
  • G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one.
  • 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 phthalimi
  • 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.
  • G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or C 6-10 aryl.
  • Ar is substituted with at least one R 4 or R 5 .
  • Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl or imidazolyl.
  • Ar is indazolyl, phenyl, tetrahydronapthyl or naphthyl.
  • Ar is -(C 1-3 alkyl)-(C 6-10 aryl), -(Y)-(C 0-3 alkyl)-(C 6- i 0 aryl), or -(Y)-(C 0-3 alkyl)-(5-10 member heteroaryl).
  • Ar is substituted with at least one R 4 or R 5 .
  • Y is -CZ 2 - and each Z is independently F, -OR or -CHR.
  • Y is -CF 2 -.
  • Y is -CHR or -CHZ- and Z is -OR.
  • Y is -CHOH-.
  • Y is -O- or -CH 2 -.
  • the C 6-10 aryl is phenyl or naphthyl, and/or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
  • Ar is -(C 1-3 alkyl)-(C 6-10 aryl).
  • one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(0) m .
  • L is a covalent bond, a C 1 -Cg alkoxy, -C(O)O-, -NH- or -O-.
  • R 27 is C 1-6 alkyl, C 1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C 1-3 alkyl)amino, mono- or di- (phenyl-d- 3 alkyl)amino, C 1-6 alkyl-S(O) m , phenyl-C 1-3 -alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkyl or C 1-6 alkoxy.
  • Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl.
  • R 27 is -C(O)OR', -NR'R', substituted or unsubstituted straight or branched C 1-10 alkyl, substituted or unsubstituted C 7-2 O 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, S(0) m .
  • Q is pyrimidinyl and R 27 is -NR'R' or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) m .
  • Q is pyridinyl
  • R 27 is -NR'R', substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) n ,.
  • each R 1 is independently
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1-3 alkyl groups;
  • each R 1 is independently C 3-10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3- io 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, C 1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, hydroxy, cyano, Ci -3 alkoxy which is optionally partially or fully halogenated and NHiC(O) or mono- or di-(C
  • each R 2 is independently -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) 1n R", -NR 5 SO 2 R", -NR 5 C(O)NR 5 R', -NR 5 C(S)NR 5 R 5 , -NR 5 C(O)OR 5 or -SO 2 NR' 2 .
  • each R 2 is independently -NR 5 2 , -NO 2 , -C(O)NR 5 2 , - NR 5 SO 2 R 5 ', -NR 5 C(O)NR 5 R', -NR 5 C(S)NR 5 R 5 , -NR 5 C(O)OR 5 or -SO 2 NR' 2 .
  • each R 3 is independently
  • 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
  • Ci -3 alkyl groups C 1-4 alkyl or alkylene-phenyl-C(0)-Co- 4 alkyl or alkylene, Cj -4 alkyl or alkylene-C(O)-C 0- 4 alkyl or alkylene, C 1-4 alkyl or alkylene - ⁇ henyl-S(O) m -C 0-4 alkyl or alkylene;
  • R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )- or R 26 C(O)(CH 2 ) m N(R 21 )-;
  • branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C 1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or
  • each R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 17 , R 19 , and R 25 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C 0-4 alkyl)amino, wherein the Co -4 alkyl is optionally partially or fully halogenated; each R 11 and R 16 is independently hydrogen or C 1-4 branched or unbranched alkyl optionally partially or folly halogenated; and
  • R 18 is independently hydrogen or C 1-4 branched or unbranched alkyl optionally independently substituted with oxo or R 25 .
  • each R 3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or folly halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, foryl, tetrahydroforyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzoforanyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothioforanyl
  • each R 3 is independently phenyl, pyridazinyl or pyridyl, each of which is optionally partially or folly halogenated and optionally substituted with C 1-6 branched or unbranched alkyl which is optionally partially or folly halogenated, hydroxy, oxo, cyano, C 1 - 3 alkoxy optionally partially or folly halogenated, nitro, amino, mono- or di-(C 1-3 alkyl)amino; C 1-6 alkyl or C 1-6 alkoxy, each optionally partially or folly halogenated or optionally substituted with R 17 , amino, OR 18 , C 1-5 mono- or di-alkylamino optionally substituted with R 9 ; R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )- or R 26 C(O)(CH 2 ) m N
  • cytokine inhibitors of a first group of compounds having Formula IB are provided.
  • G is a C 3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R 1 , R 2 or R 3 ;
  • X is C(O), C(S) or CH 2 ;
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C 6-10 aryl, -(C 1-3 alkyl)-(C 6 .io aryl), -(Y)-(C 0-3 alkyl)-(C 6- io aryl), or -(Y)-(C 0-3 alkyl)-(5- 10 member heteroaryl), each of which is optionally substituted with one or more R
  • each Z is independently F, Cl, -OR, -NR 2 , -SR, -NHCONHR, or -NHCOR;
  • L is a covalent bond or a saturated or unsaturated branched or uribranched C 1-1O 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 oxo 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, C 1-6 alkoxy, Ci -6 alkyl-S(O) m , or phenyl-S(O) m , wherein the cycloalkyl, aryl, heterocyclyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) m , or phenyl-S(O) m is each optionally substituted with one, or more R 27 ; provided that if R 4 and R 5 are absent, -L-Q is not -H;
  • each R is independently hydrogen or substituted or unsubstituted Cj -6 alkyl
  • each R' is independently hydrogen, substituted or unsubstituted C 1 - S alkyl, substituted or unsubstituted (Co -4 alkyl)-(C 6 . 1 o aryl) or substituted or unsubstituted (C 0-4 alkyl)-(5-10 member heterocyclyl);
  • each R 1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR 2 , -C(O)OR, -OR, -NR'R', -SiR 3 , - S(O) 1n R, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-I0 alkenyl, substituted or unsubstituted C 2-10 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m ;
  • each R 2 , R 4 and R 5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) 1n R", -NR 5 SO 2 R", -NR 5 C(O)NR 5 R', - NR 5 C(S)NR 5 R', -NR 5 C(O)OR' or -SO 2 NR' 2 ;
  • each R" is independently substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 0-4 alkyl-Ce-io aryl or substituted or unsubstituted (Co -4 alkyl)-(5-10 member heterocyclyl); each R 3 is independently substituted or unsubstituted C 6- Io ary.
  • heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) m , substituted or unsubstituted C 3-I2 cycloalkyl, substituted or unsubstituted C 5-12 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted straight or branched C 1-8 alkyl, R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )-, R 26 C(O)(CH 2 ) m N(R 21 )-, substituted or unsubstituted C 2-8 alkenyl, or substituted or unsubstituted C 2-8 alkynyl, wherein one or more methylene groups of the Ci -8
  • each R 6 is a C 1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R ;
  • each R 26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C 0-4 alkyl)amino, wherein the C 0-4 alkyl is optionally partially or fully halogenated;
  • R 20 is substituted or unsubstituted Q -1O alkyl, substituted or unsubstituted C 0-6 alkyl-phenyl, substituted or unsubstituted C 0-6 alkyl-heterocyclyl, OR' or NR' 2 ;
  • R 21 is hydrogen or C 1-4 branched or unbranched alkyl optionally partially or fully halogenated
  • each R , R and R is independently hydrogen, substituted or unsubstituted C 1-I0 alkyl, wherein the C MO alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co -6 alkyl-phenyl, substituted or unsubstituted Co -6 alkyl-heterocyclyl; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring;
  • each R 27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NR' 2 , -C(O)OR', -OR', -NR'R', -SiR' 3 , - S(O) 01 R', substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2- Io alkynyl, substituted or unsubstituted C 3-1O cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) m .
  • the compound at a concentration of 10 ⁇ M inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
  • 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- on
  • 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.
  • G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one.
  • 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,
  • G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomo ⁇ holinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
  • G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, piperidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or C 6-10 aryl.
  • Ar is substituted with at least one R 4 or R 5 .
  • Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronapthyl, indanyl, indenyl, or imidazolyl.
  • Ar is indazolyl, phenyl, naphthyl, or tetrahydronaphthyl.
  • Ar is -(C 1-3 alkyl)- (C 6-10 aryl), -(Y)-(C 0-3 alkyl)-(C 6-10 aryl), Or -(Y)-(C 0-3 alkyl)-(5-10 member heteroaryl).
  • Ar is substituted with at least one R 4 or R 5 .
  • Y is -CHR or -CHZ- and Z is -OR.
  • Y is -CH 2 -.
  • the C 6-10 aryl is phenyl or naphthyl or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
  • Ar is -(Cj -3 alkyl)-(C 6 .io aryl).
  • one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(O) n ,.
  • L is a covalent bond, a C 1 -C 9 alkoxy, - C(O)O-, -NH- or -O-.
  • Q is optionally substituted with R 27 .
  • the first group of compounds of Formula IB Q is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, ⁇ yrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2 5 3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b] ⁇ yridinyl, or imidazo[
  • R 27 is C 1-6 alkyl, C 1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C 1-3 alkyl)amino, mono- or di- (phenyl-C 1-3 alkyl)amino, C 1-6 alkyl-S(O) m , phenyl-d- 3 -alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkyl or C 1-6 alkoxy.
  • Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino.
  • Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl.
  • R 27 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched C 1-I0 alkyl, substituted or unsubstituted C 7-20 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, S(0) m .
  • Q is pyrimidinyl and R 27 is -NR'R'or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) m .
  • Q is pyridinyl
  • R 27 is -NR'R' or substituted or unsubstituted Cj -6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m .
  • each R 1 is independently:
  • Ci -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 1-3 alkoxy optionally partially or fo
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1-3 alkyl groups;
  • C 2 _ 6 branched or unbranched alkyl-C(O), C 2-6 branched or unbranched- S, C 2-6 branched or unbranched-S(O), C 2-6 branched or unbranched-S(O) 2 ;
  • each R 1 is independently C 3-1O branched or unbranched alkyl optionally partially or folly halogenated, and optionally substituted with one to three C 3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, foryl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C 1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, hydroxy, cyano, Cj -3 alkoxy which is optionally partially or fully halogenated and NH 2 C(O) or mono- or di-
  • each R 2 is independently -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) 1n R", -NR 5 SO 2 R", -NR'C(0)NR'R ⁇ -NR'C(S)NR'R', -NR 5 C(O)OR' or -SO 2 NR' 2 .
  • R 2 is independently -NR' 2 , -NO 2 , -C(0)NR' 2 , -NR 5 SO 2 R", - NR 5 C(O)NR 5 R', -NR 5 C(S)NR 5 R 5 , -NR 5 C(O)OR' or -SO 2 NR' 2 .

Abstract

The present invention relates to low molecular weight compounds and compositions thereof, useful as cytokine inhibitors, and their preparation. The invention further relates to methods of prevention and treatment of cytokine-mediated disorders, in particular inflammatory disorders, pain and cancer. The invention also relates to pharmaceutical compositions and dosing regimens. In particular, the invention relates to the use of cytokine inhibitors, optionally in conjunction with other therapies, for cancer, more particularly glioma, glioblastoma, osteosarcoma and bone metastases. Additionally, the present invention relates to methods of treating, modifying and managing pain, more particularly neuropathic pain, which comprise the administration of a cytokine inhibitor alone or in combination with known therapeutics.

Description

CYTOKINE INHIBITORS AND THEIR USE IN THERAPY
FIELD OF THE INVENTION
[0001] The present invention relates to low molecular weight compounds and compositions thereof, useful as cytokine inhibitors, and their preparation. The invention further relates to methods of prevention and treatment of cytokine-mediated disorders, in particular inflammatory disorders, pain and cancer. The invention also relates to pharmaceutical compositions and dosing regimens. In particular, the invention relates to the use of cytokine inhibitors, optionally in conjunction with other therapies, for treatment of cancer, more particularly glioma, glioblastoma, osteosarcoma and bone metastases. Additionally, the present invention relates to methods of treating, modifying and managing pain, more particularly neuropathic pain, which comprise the administration of a cytokine inhibitor alone or in combination with known therapeutics.
BACKGROUND OF THE INVENTION
[0002] Tumor necrosis factor-α (TNF- a or TNFa) and interleukin- 1 (IL- 1 ) are proinflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses. Overproduction of cytokines such as IL-I and TNF-cds 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). An accepted therapeutic approach for potential drug intervention in these conditions is the reduction of proinflammatory cytokines such as TNF-α (also referred to as TNFa) and interleukin- Iβ (IL-Ib).
[0003] Recently, a functional link between chronic inflammation and cancer has been suggested (F. Balkwill et al, Nature, 431, 405-406 (2004); F. Balkwill et al, Lancet, 357, 539-545 (2001); L.M. Coussens et al, Nature, 420, 860-867 (2002)). Multiple pro-inflammatory mediators are probably involved, and NF-KB and TNFa have been suggested (E. Pikarsky et al, Nature, 431, 461-466 (2004); F.R. Greten, Cell, 118, 285-296 (2004)). For example, IL-I and TNFa stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8 [R. B. Kimble et al., Endocrinol., 136, pp. 3054-61 (1995)]. IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias [Treon, et al, Current Opinion in Hematology, 5, 42 (1998)]. Cytokines including IL- 1 , TNFa and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts [Bruserud, Leukemia Res. 20, 65 (1996)]. Clinical studies have linked TNFa production and/or signaling to a number of diseases including advanced cancer [MucWierzgon et al. J. Biol. Regulators Homeostatic Agents, 10, 25 (1996)] lymphoid malignancies [Levy et al. Crit. Rev. Immunol., 16, 31 (1996)], impaired wound healing in infection, inflammation, and cancer [Buck et al. Am. J. Pathol. 149, 195 (1996)], and myelodysplastic syndromes [Raza et al. Int. J. Hematol. 63, 265 (1996)]. Thus, cytokine inhibitors show potential in the treatment of malignancies .
[0004] Cytokines are also known to play a role in the production of pain, such as nociceptive pain, neuropathic pain, visceral pain, headaches, post-operative pain and the like. For example, nociceptive pain is elicited when noxious stimuli such as inflammatory chemical mediators are released following tissue injury, disease, or inflammation and are detected by normally functioning sensory receptors (nociceptors) at the site of injury [Koltzenburg, M. Clin. J. of Pain 16:S131-S138 (2000)]. Nociceptors are distributed throughout the periphery of tissue and are sensitized by inflammatory mediators such as prostaglandin, substance P, bradykinin, histamine, and serotonin, as well as by intense, repeated, or prolonged noxious stimulation. In addition, cytokines and growth factors (e.g., nerve growth factor) can influence neuronal phenotype and function [Besson, J. M. Lancet 353:1610-15 (1999)]. Sensitization of peripheral nociceptors plays an important role in clinical pain states such as hyperalgesia and allodynia. Medications presently used during the treatment of pain in general include calcium channel blockers, muscle relaxants, nonnarcotic analgesics, opioid analgesics, and systemic corticosteroids. However, patients rarely obtain complete pain relief. [0005] Thus, a need exists for therapeutics useful in the treatment of cytokine- mediated diseases, including inflammation, cancer and pain. While some cytokine protein therapeutics have been developed, they suffer from bioavailability and stability problems. In particular, there is a need for low molecular weight compounds that inhibit TNFa and/or IL-Ib production.
SUMMARY OF THE INVENTION
[0006] The present invention provides low molecular weight compounds and pharmaceutical compositions thereof. In particular, compounds of the invention are useful as cytokine release inhibitory agents. There are further provided methods for the preparation of such compounds and their use in the prevention and treatment of various disorders mediated by cytokines, in particular inflammatory diseases, cancer and pain.
[0007] In accordance with one aspect of the invention, there are provided the following compounds:
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-(memylsulfonamido)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)naphthalen- 1 -yl)-2-oxoacetamide; N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2- (dimethylamino)pyridin-4-ylamino)naphthalen- 1 -yl)-2-oxoacetamide; 5-tert-butyl-N-cyclopropyl-3-(2-(4-(2-(dimethylamino)pyridin-4-ylamino)naρhthalen- l-yl)-2-oxoacetamido)-2-methoxybenzamide; 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)ρyridin-4-ylamino)naphthalen- 1 -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-(niethylainino)pyridm-3 -yl)naphthalen- 1 - yl)-2-oxoacetamide;
5-tert-butyl-2-methoxy-3-(2-(4-(6-(methylamino)pyridin-3-yl)naphthalen-l-yl)-2- oxoacetamido)benzamide;
5-tert-butyl-N-ethyl-2-methoxy-3 -(2-(4-(6-(methylamino)pyridin-3 -yl)naphthalen- 1 - yl)-2-oxoacetamido)benzamide;
5-tert-butyl-N-cyclopropyl-2-methoxy-3-(2-(4-(6-(methylamino)pyridin-3- yl)naphthalen- 1 -yl)-2-oxoacetamido)benzamide;
(S)-N-(5-tert-butyl-2-methoxy-3-(propylsulfonamido)ρhenyl)-2-(4-(2,3- dihydroxypropoxy)naphthalen- 1 -yl)-2-oxoacetamide;
2-(5-tert-butyl-2-methylfuran-3-yl)-N-(4-(2-chloropyrimidin-4-ylamino)naphthalen-l- yl)-2-oxoacetamide;
2-(5-tert-butyl-2-methylfuran-3 -yl)-2-oxo-N-(4-(pyrimidin-4-ylamino)naphthalen- 1 - yl)acetamide;
N-(5-tert-butylisoxazol-3-yl)-2-(4-(2,3-dihydroxypropoxy)naphthalen-l-yl)-2- oxoacetamide;
2-(5-tert-butyl-2-niethylfuran-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-morpholinopyrimidin-4- ylamino)naphthalen- 1 -yl)-2-oxoacetamide;
2-(5-tert-butyl-3 -methylfuran-2-yl)-N-(4-(2-morpholinoethoxy)naphthalen- 1 -yl)-2- oxoacetamide;
2-(5-(4-chlorophenyl)-2-(trifluoromethyl)fbran-3-yl)-N-(4-(2- morpholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(ρyrrolidin-
1 -yl)ρyrimidin-4-ylamino)naphthalen-l -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-oxoacetaraide;
2-(4-(2-aminopyrimidin-4-ylamino)naρhthalen- 1 -yl)-N-(5-tert-butyl-2-methoxy-3 -
(methylsulfonamido)phenyl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyrimidin-4- ylamino)naphthalen- 1 -yl)acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyridm-4- ylamino)naphthalen- 1 -yl)acetamide; or a pharmaceutically acceptable salt, solvate, tautomer, or prodrug thereof.
[0008] In another aspect, the invention provides compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.
[0009] In yet another aspect, the invention provides methods of preventing or treating disorders mediated by cytokines which comprise administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein. Exemplary compounds include those listed above. Such cytokine-mediated disorders include rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, and non-articular inflammatory conditions, such as intervertbral disk syndrome conditions, bursitis, tendonitis, tenosynovitis or fibromyalgic syndrome. Exemplary cytokine-mediated disorders also include acute or chronic pain, such as but not limited to neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Horton's disease, varicose ulcers, neuralgias, musculoskeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, vertebral pain, post-surgery pain, herniated intervertebral disc-induced sciatica, cancer-related pain, vascular pain, visceral pain, childbirth-related pain, or HIV-related pain.
[0010] Other cytokine-mediated disorders are stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure such as heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary artery bypass; hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, such as for example, acute venous thrombosis, pulmonary embolism, thrombosis during pregancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), clot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial or venous cannulae, cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leukopenia or thrombocytopenia; or atherosclerosis. Yet others are allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, or surgery or trauma-induced proliferative vitreoretinopathy. Cytokine-mediated disorders further include allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection and respiratory tract inflammation. Also included are psoriasis, eczema, atopic dermatitis, contact dermatitis, or acne. Yet other cytokine- mediated disorders are Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral meningitis, bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF syndrome, MELAS syndrome, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, or epilepsy. In another aspect of the invention, the cytokine-mediated disorders include bone resorption diseases, such as osteopetrosis, osteoporosis, or osteoarthritis. Also included are diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), obesity, anorexia nervosa, or bulimia nervosa. Additonally, the cytokine-mediated disease can be sepsis, HIV infection, hepatitis C virus (HCV) infection , malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, including but not limited to breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, or follicular lymphoma, Castleman's disease, or drug resistance.
[0011] In some embodiments of the invention, the cytokine mediated disorder is a neutrophil-mediated disorder, such as, for example, bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, hemodialysis, leukopheresis, granulocyte transfusion associated syndromes, or necrotizing enterocolitis.
[0012] Combination therapy with cytokine inhibitors 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 as described herein, and in particular in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis. Thus, another aspect the of the invention provides methods of treating a cytokine-mediated disorder including administering one or more, typically one, of the ingredients (hereafter referred to as ingredient A) described herein together with one or more, typically one, cytokine inhibitor of the invention. Ia some embodiments, a combination of any two or more ingredients A are administered with a cytokine inhibitor of the invention. An additive or over-additive effect of the pharmaceutical combinations according to the invention provides for dose reduction, side-effect reduction and/or interval extension when compared to monotherapy with the individual compounds A or with the cytokine inhibitors. 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 the cytokine inhibitor may be seen. For example, cost reduction by way of interval and/or dose reduction.
[0013] A variety of ingredients A are contemplated for use in the combinations of the invention. For example, non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of inflammation, pain and fever, may be used. Such NSAIDS include acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, combinations of any two or more thereof, and the like.
[0014] Angiogenesis inhibitors may serve as ingredient A, such as VEGF inhibitors, taxol, pentoxyfylline and/or thalidomide.
[0015] 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. [0016] Also within the scope of the invention for ingredient A are steroids, such as glucocorticoids, and vitamin D3 and analogs thereof (cholecalciferols), alone (the latter being used mostly for psoriasis) or in combination. Steroids include budesonide, dexamethasone, fluocinonide, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, clobetasone, deflazacort, fluocinolone acetonide, fluticasone, triamcinolone acetonide, mometasone and diflucortolone. Among vitamin D3 derivatives are calcipotriol, tacalcitol, maxacalcitol, and tacalitol, the calciotropic hormones, lce,25-dihydroxyvitamin D3, and parathyroid hormone-related peptide.
[0017] Many types of immunomodulatory, immunosuppressive or cytostatic drugs can be used in combination with the cytokine inhibitors of the invention. Exemplary agents include hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, pimecrolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine, cyclophosphamide, macrolides, ascomycin, hydroxyurea, 6-thioguanine, (Orfanos C E., 1999, Cutis 64(5):347-53); alefacept, leflunomide, infliximab, etanercept, efalizumab, anti-CD4, anti-CD25, peptide T, LFA3TIP, ICAM-I ISIS 2302, 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 psoralen ultraviolet A (PUVA), photodynamic therapy and laser therapy.
[0018] Retinoid therapy can also be used as ingredient A. Thus, for example, bexarotene, acitretin, etretinate and tazarotene, and 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). [0019] 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.
[0020] In another aspect, there are provided the above-mentioned combinations comprising ingredient A and one or more cytokine inhibitors of the invention, typically in therapeutically effective amounts, for use as pharmaceutical compositions with anti-cytokine activity. Moreover, combinations comprising ingredient A and a cytokine inhibitor can be used for preparing a pharmaceutical composition for the treatment and/or prevention of a cytokine-mediated disease or condition. The pharmaceutical preparations, containing as the active substance one or more compound combinations comprising ingredient A and the cytokine inhibitor further include the pharmaceutically acceptable derivatives thereof, and may be optionally combined with conventional excipients and/or carriers.
[0021] For therapeutic use, the pharmaceutical combinations of ingredient A and the cytokine inhibitor according to the invention 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.
[0022] The pharmaceutical combinations of ingredient A and the cytokine inhibitor according to the invention 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 cytokine inhibitor may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. The ingredient A and/or the cytokine inhibitor may be used in the combination as a salt, solvate, tautomer and/or prodrug and as a single stereroisomer or mixtures of stereoisomers, including racemates.
[0023] The proportions in which the two components, ingredient A and the cytokine inhibitor, may be used in the combinations according to the invention are variable. Ingredient A and the cytokine inhibitor are optionally present in the form of their solvates or hydrates. Depending on the choice of ingredient A and the invention cytokine inhibitor, 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 cytokine inhibitor, and are within the skill in the art.
[0024] In psoriasis, known combination treatments have been effective and are used as rotation therapy for maintenance of remission or if refractory to usual systemic products. Most of the combinations are with different modes of action either to improve efficacy or to reduce side effects by reduction of the dosage. See Van de Kerkhof, P. 1997 Clinics in Dermatology, 15:831-834, which illustrates the use 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 cyclosporin and retinoids.
[0025] A typical combination for treating psoriasis is the cytokine inhibitor compound in combination with immunomodulatory and/or immunosuppresive drugs which include cyclosporin, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti- CD80, anti-CD25, peptide T, LFA3TIP, anti LFA3-IgCl, anti-CDll, DAB389, CTLA- 4Ig, E-selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, and those disclosed in Griffiths, Christopher E. M., 1998 Hospital Medicine, 59 No 7, and the obvious variants thereof. Another typical combination for treating psoriasis is the cytokine inhibitor compound 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 treating psoriasis is the cytokine inhibitor compound with cyclosporine, especially because of cyclosporine's efficiency for induction of remission. Another embodiment of the invention comprises administration in the following sequence: induction with cytokine inhibitor and cyclosporine, followed by continuation with cytokine inhibitor after decrease of dosing and discontinuation of cyclosporine. Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with retinoids. Retinoids provide minimal efficacy with potential Cyt P450 interactions and risk of teratogenicity, and this would be alleviated by continuation therapy with the cytokine inhibitor. Yet another typical combination for treating psoriasis is the cytokine inhibitor compound, in combination with ingredients A selected from steroids, vitamin D analogs, retinoids and dithranol. In some such combination treatments, the steroids and retinoids can be administered topically. A more typical combination for treating psoriasis is a cytokine inhibitor compound with vitamin D derivatives, most typically calcipotriol or tacalcitol. Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with macrolides, most typically with ascomycin analogues, administered topically, and even more typically with those available orally such as pimecrolimus. Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with cell adhesion molecules inhibitors, such as anti LFA3, or anti LFAl. This includes adhesion molecule blockage by recombinant fusion proteins like alefacept, anti LF A3 -IgCl, or by anti-CD 11 monoclonal antibodies, efalizumab, and the obvious variants thereof. Cell adhesion molecules inhibitors appear to provide an acceptable response rate with limited tolerability problems. Combination with a cytokine inhibitor 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 cytokine inhibitor and CAM inhibitors, followed by maintenance treatment with the cytokine inhibitor alone and retreatment with CAM inhibitors in case of significant relapse. [0026] Another typical combination for treating psoriasis is the cytokine inhibitor compound 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 as ICAM-I ISIS 2302 in combination with a cytokine inhibitor compound. Another typical combination for treating psoriasis is the cytokine inhibitor compound with anti-CD4, anti-CD80 (IDEC-114 or ABX-IL8), DAB-IL-2, DAB389-IL-2, CTLA4-Ig, ILlO, the IL-2 receptor inhibitors such as daclizumab (anti-TAC), or basiliximab. (See Tutrone, "Biologic Therapy for Psoriasis, A Brief History, I, " Biologic Therapy for Psoriasis, 2001, 68, 331; Ben- Bassat, "Biological activity of tyrosine kinase inhibitors: Novel agents for psoriasis therapy," Current Opinion in Investigational Drugs, 2001, 2(11), 1539; Salim, et. al., "Targeting interleukin-2 as a treatment for psoriasis," Current Opinion in Investigational Drugs, 2001, 2(11), 1546).
[0027] Any of the above mentioned combinations within the scope of the invention may be tested by animal models known in the art. Reference in this regard maybe 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 treating rheumatoid arthritis is the cytokine inhibitor compound combined with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs, such as, for example, hydroxychloroquine, D-penicillamine, sulfasalazine, auranofm, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, lefmnomide, methotrexate, azathioprine or cyclophosphamide. Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with angiogenesis inhibitors, such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha- interferon. Yet another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound in combination with inhibitors of cell adhesion, such as inhibitors of LFA-I or inhibitors of ICAM-I.
[0030] A more typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with anti-TNF antibodies or TNF-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 the cytokine inhibitor is combined with infliximab alone or infliximab and methotrexate. Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound in combination with IL-I receptor antagonists, such as Kineret®. Yet another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound 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 treating rheumatoid arthritis is the cytokine inhibitor compound combined with steroids, such as betamethasone, dexamethasone, methylprednisolone, prednisolone, and deflazacort. [0031 ] Any of the above mentioned combinations within the scope of the invention maybe tested by animal models known in the art. (See Wooley, P. H. 1998, Animal models of arthritis, in Klippel J. H., Dieppe, P. A., (eds.) Rheumatology, second edition, 5.8.1, Mosby, London, Philadelphia, St. Louis, Sydney, Tokio).
[0032] In Crohn's disease, the following groups of drugs combined with the cytokine inhibitor may be effective: steroids such as budesonide, 5-AS A drugs like mesalamine, immunosuppressants, biological agents and adhesion molecule inhibitors. A typical combination for treating Crohn's disease is the cytokine inhibitor compound with one or more of the following: steroids including all those listed herein, 5-ASA drugs, methotrexate and azathioprine. Another typical combination for treating Crohn's disease is the cytokine inhibitor compound combined with IL-I receptor antagonists, such as Kineret®. Yet another typical combination for treating Crohn's disease is the cytokine inhibitor compound with anti-TNF antibodies or TNF- 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 the cytokine inhibitor is administered with infliximab alone or combined with methotrexate. Another typical combination for treating Crohn's disease is the cytokine inhibitor compound combined with IL-10, ISIS 2302 (anti ICAM 1), or Antegren (VCAM receptor antagonist).
[0033] It has been found that cytokine inhibitors possess inhibitory effects on the procoagulant and profibrinolytic responses during human endotoxemia. 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 patient in need thereof a pharmaceutically effective amount of the cytokine inhibitor. This administration may be of benefit given either prophylactically to patients at risk or therapeutically for patients who have developed complications related to these pathways.
[0034] Methods of treating a disorder relating to blood coagulation or fibrinolysis also include administering to a subject in need thereof a pharmaceutically effective amount of a cytokine inhibitor of the invention in combination with one or more anticoagulant or fibrinolytic agents. The latter agents 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 either alone or combined is within the skill in the art. In some embodiments of the methods, the disorder is caused by a clot, thrombosis or embolism.
[0035] In another aspect of the invention, there is provided a method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein. Further embodiments of inventive methods are described below and in U.S. Application No. 60/679,294, filed May 9, 2005, the entire contents of which is incorporated by reference herein.
[0036] In some embodiments of the invention, the method further comprises treating the mammal with surgery, radiation, cryotherapy, or one or more antiproliferative agents or a combination thereof.
[0037] In some such embodiments, the antiproliferative agent is an alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotic, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, DNA antagonist, farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, endothelin A receptor antagonist, retinoic acid receptor agonist, immunomodulator, hormonal or antihormonal agent, photodynamic agent, angiogenesis inhibitor, or a tyrosine kinase inhibitor. In some embodiments, the alkylating agent is busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, or chlorambucil. Examples of platinum agents include spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin. In some embodiments, the antimetabolite is azacytidine, trimetrexate, floxuridine, deoxycoformycin, 2- chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irotulven (MGI Pharma), methotrexate, tomudex, ethynylcytidine (Taiho), fludarabine, gemcitabine, raltitrexed, or capecitabine. In others, the topoisomerase inhibitor is amsacrine, exatecan mesylate (Daiichi), epirubicin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl-lO-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-11), or topotecan. In yet others, the antitumor antibiotic is dactinomycin (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menarini), plicamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonafϊde. Examples of antimitotic agents are colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Warner- Lambert), synthadotin (BASF), cemadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (Eli Lilly), vinflunine (Fabre), hydravin (Prescient NeuroPharma), auristatin PE (Teikoku Hormone), azaepothilone B (BMS), ixabepilone (BMS), tavocept (BioNumerik), BMS 184476 (BMS), combrestatin A4 disodium phosphate (OXiGENE), BMS 188797 (BMS), dolastatin- 10 (NIH), taxoprexin (Protarga), cantuzumab mertansine (GlaxoSmithKline), docetaxel, vinorelbine, or vincristine. In some embodiments, the aromatase inhibitor is aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole. In others, the thymidylate synthase inhibitor is pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche), or 5, 10-methylenetetrahydro folate (BioKeys). In yet others, the DNA antagonist is trabectedin (PliarmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics). In still others, the farnesyltransferase inhibitor is arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer). Examples of pump inhibitors are zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG). Examples of histone acetyltransferase inhibitors include tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG). In some embodiments, the metalloproteinase inhibitor is neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech). In others, the ribonucleoside reductase inhibitor is gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health). In yet others, the endothelin A receptor antagonist is atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca). In still others, the retinoic acid receptor agonist is fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD- 1550 (Ligand). In some embodiments, the immuno-modulator is an interferon, interferon a-2a (e.g., Roferon-A, Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CD 154 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), β-alethine (Dovetail), melanoma vaccine (CTL Imrnuno), vasocare (Vasogen), rituximab (Genentech/Biogen Idee), or p21 RAS vaccine (GemVax). In others, the hormonal agent is an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutaniide, or leuporelin. In yet others, the photodynamic agent is talaporfm (Light Sciences), Pd-bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin. In still others, the angiogenesis inhibitor is neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Pfizer). Examples of tyrosine kinase inhibitors include imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKline), panitumumab (Abgenix), IMC-ICl 1 (ImClone), sorafenib (Bayer) or trastuzumab (Genentech). In some embodiments, the anti-proliferative agent is melphalan, carmustine, cisplatin, 5- fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, or paclitaxel (Taxol®).
[0038] In some embodiments of the invention, the cancer is osteosarcoma,
Kaposi's sarcoma, colorectal cancer, brain cancer, epithelial cell-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, Hp cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell cancer, basal cell cancer, prostate cancer, renal cell carcinoma, leukemia, lymphoma, erythroblastoma, glioblastoma, glioma, meningioma, astrocytoma, myoblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplasia syndrome, non- Hodgkins lymphoma, or follicular lymphoma. In some such embodiments, the cancer is acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioma, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiatied carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, or Wilm's tumor.
[0039] In some embodiments, the cancer is leukemia, erythroblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non- hodgkin's lymphoma or follicular lymphoma. In some embodiments, the cancer is follicular lymphoma, acute myelogenous leukemia, multilple myeloma or non- hodgkin's lymphoma.
[0040] In other embodiments, the cancer is brain cancer, glioma, glioblastoma, meningioma, astrocytoma, medulloblastoma, neuroblastoma or retinoblastoma. In some such embodiments, the cancer is glioma or glioblastoma. [0041] In yet other embodiments, the cancer is osteosarcoma, Kaposi's sarcoma, chondosarcoma, Ewing's sarcoma or myoblastoma. In some such embodiments, the cancer is osteosarcoma bone cancer.
[0042] In some embodiments, the cancer is breast, lung, kidney or prostate cancer metastasis. In some such embodiments, the neoplasm is bone metastasis.
[0043] In yet another aspect of the invention, there is provided a method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein. Further embodiments of inventive methods are described below and in U.S. Application No. 60/665,129, filed March 24, 2005, the entire contents of which is incorporated by reference herein.
[0044] In some embodiments of the invention, the composition further comprises an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, α- adrenergic receptor agonist, α-adrenergic receptor antagonist, ketamine, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, NSAID, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, hyperbaric oxygen, α2δ ligand, NMDA receptor antagonist, or a combination of any two or more thereof. In some such embodiments, the antidepressant is nortriptyline, amitriptyline, imipramine, doxepin, clomipramine, fluoxetine, sertraline, nefazodone, venlafaxine, trazodone, or bupropion. In others, the anti-hypertensive is nifedipine, terazosin, prazosin, losartan, verapamil, telmisartan, fosinopril, bosentan, or olmesartan. In yet others, the anxiolytic is fluoxetine, paroxetine, sertraline, or venlafaxine. Examples of calcium channel blockers include nifedipine, verapamil and clonidine. hi other embodiments, the α-adrenergic receptor agonist is clonidine or midodrine. In yet others, the α-adrenergic receptor antagonist is terazosin, prazosin, or doxasozin. hi some embodiments, the anesthetic is procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine, or ropivacaine. Examples of opioid analgesic include hydromorphone, oxycodone, morphine sulfate, meperidine, and fentanyl transdermal patch. In some embodiments, the NSAID is a COX-2 inhibitor, salicylic acid acetate, ϊbuprofen, ketoprofen, naproxen sodium, ketorolac, diclofenac, indometacin, or acetaminophen. In some such embodiments, the COX-2 inhibitor is rofecoxib, celecoxib, or valdecoxib. hi yet others, the corticosteroid is prednisone, dexamethasone or hydrocortisone. In others, the anticonvulsant is carbamazepine, oxcarbazepine, gabapentin, pregabalin, phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, tiagabine, famotodine, phenobarbital, diphenylhydantoin, mephenytoin, ethotoin, mephobarbital, primidone, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, clobazam, sulthiame, dilantin, diphenylan, or L-5-hydroxytryptophan. In some embodiments, the NMDA receptor antagonist is dextromethorphan, dextrorphan, ketamine, memantine, amantadine, agmatine, aptiganel, gavestinel, selfotel, 7-chlorokynurate, remacemide, riluzole, pyrroloquinoline quinone or cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, hi others, the α2δ ligand is gabapentin, pregabalin, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl- cyclohexylmethyl)-4H-[l,2,4]-oxadiazol-5-one and C-[l-(lH-tetrazol-5-ylmethyl)- cycloheptylj-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (lα,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3- aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-rnethyl-nonanoic acid and (3S,5R)-3-amino-5-methyl-octanoic acid. In yet other embodiments, the composition further comprises acetylsalicylic acid, diclofenac, ibuprofen, indometacin, flufenamic acid, mefenamic acid, morphine, pethidine, methadone, fentanyl, buprenorphine, tramadol, gabapentin, pregabalin, carbamazepine, lamotrigin, topiramate, phenyloin, levitiracetam, procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine, ropivacaine, amitryptiline, paroxetine, citalopram, bupropione, duxoletine, ketamine, memantine, 2,3- benzodiazepines, or a combination of any two or more thereof.
[0045] In some embodiments of the invention, the pain is acute pain, chronic pain, pain resulting from soft tissue and peripheral damage from acute trauma; neuropathic pain; post-stroke pain; pain from neuralgia, acute herpetic neuralgia, postherpetic neuralgia, occipital neuralgia, HIV related neuralgias, AIDS related neuralgias, trigeminal neuralgia, or segmental or intercostal neuralgia; pain associated with osteoarthritis or rheumatoid arthritis; musculo-skeletal pain; spinal pain, central nervous system pain; lower back pain, pain from sciatica, dental pain, myofascial pain syndromes, episiotomy pain, or gout pain; deep and visceral pain; muscle pain, eye pain, inflammatory pain, orofacial pain; abdominal pain, or gynecological pain; somatogenic pain; pain associated with nerve and root damage; pain associated with limb amputation, tic douloureux, neuroma, or vasculitis; diabetic neuropathy pain, chemotherapy-induced-neuropathy; atypical facial pain, neuropathic lower back pain, or arachnoiditis; allodynia, pain associated with hyperalgesia, burn pain, idiopathic pain, pain caused by chemotherapy; psychogenic pain, pain from brachial plexus avulsion, pain associated with restless leg syndrome; pain associated with gallstones; pain caused by chronic alcoholism, hypothyroidism, uremia or vitamin deficiencies; neuropathic or non-neuropathic pain associated with carcinoma, cancer pain, phantom limb pain, functional abdominal pain; headache; temperomandibular pain or maxillary sinus pain; pain resulting from ankylosing spondylitis; pain caused by increased bladder contractions; complex regional pain syndrome, or sympathetic maintained pain syndrome; pain associated with reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, chronic fatigue syndrome, radiculopathy, or luetic neuropathy; painful neuropathic condition induced from a drug, post operative pain, scar pain, or chronic non-neuropathic pain.
[0046] In some such embodiments, the musculo-skeletal pain is pain associated with strains, sprains or broken bones. In others, the central nervous system pain is pain due to spinal cord or brain stem damage. In yet others, the deep and visceral pain is heart pain, hi others, the orofacial pain is odontalgia. In some embodiments, the gynecological pain is dysmenorrhoea, labor pain and pain associated with endometriosis, hi others, the pain associated with nerve and root damage, is pain associated with peripheral nerve disorders. In some such embodiments, the peripheral nerve disorder is nerve entrapment or brachial plexus avulsions, hi some other embodiments, the headache is migraine with aura, migraine without aura, vascular headaches, acute or chronic tension headache, sinus headache or cluster headache. In yet other embodiments, the chronic non-neuropathic pain is pain associated with HIV, arthralgia, vasculitis or fibromyalgia. In some embodiments, the complex regional pain syndrome is type I or type II.
[0047] In some embodiments, the pain is nociceptive pain or neuropathic pain.
In some such embodiments, the nociceptive pain is associated with chemical or thermal burn, cut of the skin, contusion of the skin, osteoarthritis, rheumatoid arthritis, systemic lupus erthrematosis (SLE), or tendonitis, or is myofascial pain. In others, the neuropathic pain is post-stroke pain; complex regional pain syndrome; sympathetic maintained pain syndrome; pain associated with diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, fibromyalgia, chronic fatigue syndrome, radiculopathy, luetic neuropathy; spinal cord injury pain; pain related to cancer or metastases; phantom limb pain; or painful neuropathic condition induced by a drug. In some such embodiments, the cancer is osteosarcoma, colorectal cancer, brain cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body; leukemia; lymphoma; or angiogenesis including neoplasia. In other embodiments, the metastases are breast, lung, kidney or prostate cancer metastases.
[0048] Cytokine inhibitors useful in the methods of the invention are exemplified by Formulas IA, IB, IC and II and are described in U.S. application 10/939,324, filed 9/10/2004, and U.S. Application No. 60/656,196, filed February 24, 2005, which are each incorporated herein by reference in their entirety:
Figure imgf000026_0001
Q
IA IB IC
Figure imgf000026_0002
H, wherein the variables G, X, Ar, L, Q, Ring and X' are as defined in the Detailed Description of the Invention.
[0049] In another aspect of the invention, the cytokine inhibitors comprise: a targeting moiety 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 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 a target protein; an orienting moiety 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 a target protein.
[0050] In some embodiments, the cytokine inhibitor is
1 H-Indazole-3 -carboxylic acid (5-tert-butyl-2-p-tolyI-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- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-hydroxy-3-morpholin-4-ylnietliyl-phenyl)-2-[4-(2-inorpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-hydroxy-3-methyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-3-methyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-3-chloro-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-etlioxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
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-ρ-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- 1 -yl] -2-oxo-acetylamino } -benzamide;
N-[5-tert-ButyI-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)-naplithalen- 1 -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- 1 -yl]-2-oxo-acetamide;
1 -Bicyclo[2.2.1 ]hept-2-yl-5-phenylamino-3-p-tolyl- 1 ,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-yI-3-p-toIyl-5-p-tolylamino-l,3-dihydro-imidazo[4,5- b]pyridin-2-one; N-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2,2-difluoro-2-[4-(2-morpholin-4-yl- ethoxy)-naρhthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-N'-naphthalen-l-yl-oxalamide;
N-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
2-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -ylamino)- 1 -[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -ethanol;
1 -(3-tert-Butyl-phenyl)-4-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-
[1 ,2,4]triazolidine-3,5-dione;
4-(3 -tert-Butyl-phenyl)- 1 -[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -
[l,2,4]triazolidine-3,5-dione;
(E)-3-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbanioyl)-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl] -acrylic acid methyl ester;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholm-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-metrioxy-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-[4-(2-piperidin-
1 -yl-pyrimidm-4-yloxy)-naphthalen- 1 -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-etriyl)-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-ρhenyl)-2H-pyrazol-3-yl]-2-[4-(2-morρholin-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-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-(4-niethoxy- naphthalen- 1 -yl)-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3-chloro-benzoyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-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-oxo-acetamide;
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-l-yl]-2- oxo-acetamide;
N-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenyl)-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-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-ρyrazol-3-yl)- acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[3-£luoro-4-(2-morpholin-4-yl-ethoxy)- phenyl]-acetamide;
(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-(2,2-dimethyl-propyl)-amine;
2-(4-Benzyloxy-phenyl)-N-(5-tert-butyl-2-p-tolyl-2H-pyrazoI-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-ρyrazol-3-yl]-2-[4-(2-morρholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
5-tert-Butyl-2-methoxy-3-(l-naphthalen-l-yl-3,5-dioxo-[l,2,4]triazolidin-4-yl)- benzamide;
2-(4-Bromo-naphthalen- 1 -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-inetlioxy-pb.enyl)-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-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-dimethylamino-ρyrimidin-4-ylamino)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2-oxo-2- {4-[2-(l -oxo-1 λ4-thiomorpholin-
4-yl)-ethoxy] -naphthalen- 1 -yl } -acetamide;
5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-acetylamino}-thiophene-2-carboxylic acid methyl ester;
N-[5-tert-Butyl-2-(3-methanesulfonyl-ρhenyl)-2H-ρyrazol-3-yl]-2-hydroxy-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-acetaniide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-((2R,6R)-2,6-dimethyl- morpholin-4-yl)-ethoxy]-naphthalen-l-yl}-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-niethoxy-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)-hydroxyimino]-
2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-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]-benzamide;
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-morρholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
5-tert-Butyl-N-cyclopropyl-3-{2-hydrazono-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetylamino } -2-methoxy-benzamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-(4-methoxy-naphthalen-l-yl)- propionamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-phenyl-acetamide;
N-(5-tert-Butyl-3-niethanesulfonylamino-2-methoxy-phenyl)-2-hydrazono-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
2,3-Dihydro-indole- 1 -carboxylic acid (5-tert-butyl-2-p-tolyl-2H-ρyrazol-3-yl)-amide;
N-(3 ,4-Dimethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naρhthalen- 1 -yl] -2-oxo- acetamide;
N-(5-tert-Butyl-2-cyclohexyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yI-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- 1 -yl)- acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-moφholin-4-yl-ethoxy)- naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-niethoxy-phenyl)-2-[4-(2-diethylamino- 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-[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-ethanesulfonylamino-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl] -benzamide; 2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-oxo-N-m-tolyl-acetamide;
N-(2,5-Dimethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
Pyrrolidine-l-carboxylic acid (5-tert-butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-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- 1 -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-l-yl]-2-oxo- acetylamino } -benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-methoxy-2-(4-methoxy-naphthalen-l- yl)-propionamide;
5-tert-Butyl-2-methoxy-N-[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-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4- yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
N'-[l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l-[4-(2-morρholin-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- yl]-acetylamino}-thiophene-2-carboxylic acid amide;
Ethanesulfonic acid (5-tert-butyl-2-methoxy-3- {3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl } -phenyl)-amide;
5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetylamino}-benzamide; 5-Fluoro-lH-indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)- amide;
N-[5-tert-Butyl-2-methoxy-3-(2-methoxy-acetylamino)-phenyl]-2-[4-(2-morpholin-4- yl-ethoxy)-naphthalen-l-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-morpholin-4- yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
3-tert-Butyl-l-(3,4-dichloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2-oxo-2-[4-(2-thiomorpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;
5-Nitro-lH-pyrazole-3-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- pyriniidin-4-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide; l-(2-Amino-4-tert-butyl-6-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino} -ρhenyl)-pyridinium;
N-(5-tert-Butyl-2-isopropoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl] -2-oxo-acetaniide;
N-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2,5-bis-trifluoromethyl-benzamide;
2-(tert-Butyl-dimethyl-silanyloxy)-N-(5-tert-butyl-2-p-tolyl-2H-ρyrazol-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)-naphthalen- 1 -yl]-acetamide;
5-tert-Butyl-2-methoxy-3 -[2-(4-methoxy-naphthalen- 1 -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)- naρhthalen-l-yl]-2-oxo-acetylamino}-benzamide;
(E)-3-(5-tert-Butyl-3-ethanesulfonylamino-2-methoxy-phenylcarbamoyl)-3-[4-(2- morpholin-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-morpholin-4-yl-pyrimidin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetamide;
2-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetamide;
N-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2-(2,4-dimethoxy-plienyl)-acetamide;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid methyl ester;
3-tert-Butyl-5- {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetylaniino}-pyrazole-l-carboxylic acid adamantan-1-ylamide;
3-tert-Butyl-5-phenyl-l-(4-trifluoromethyl-phenyl)-l,6-dihydro-imidazo[4,5- c]pyrazole;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2,4,5-trioxo-imidazolidin-l-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-morpholin-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-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-(2,6-dimethyl-morpholin-4-yl)- ethyl] -naphthalen- 1 -yl} -2-oxo-acetamide;
N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
3-tert-Butyl-5-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-pyrazole-l-carboxylic acid tert-butylamide; l-(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-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
3-tert-Butyl-5-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-pyrazole-l-carboxylic acid amide;
N-Allyl-5-tert-butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetylamino} -benzamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;
3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-l-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-pyrrole-2,5-dione;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimmo]-N-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
3 -tert-Butyl-5-o-tolyl- 1 -p-tolyl- 1 ,6-dihydro-imidazo [4,5-c]pyrazole;
N-(5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl)-2-[(E)-hydroxyitnino]-2-phenyl- acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-2-phenyl-acetamide;
N-(3-Acetylamino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide; lH-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-morpholin-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-l-yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-N-[4-(2-morpholin-4-yl-pyrimidin-4- yloxy)-naphthalen-l-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-l-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- 1 -yl]-2-oxo~acetamide;
N-(5-tert-Butyl-2,3-dimethoxy-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4- yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl)-2-(2-cliloro-ρhenyl)-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2- {4-[2-(4-methyl-piperazin- 1 -yl)-ethyl]- naphthalen- 1 -yl } -2-oxo-acetamide;
N-(5-tert-Butyl-3-niethanesulfonylammo-2-m.eth.oxy-phenyl)-2-(lH-indol-3-yl)-2- oxo-acetamide;
N-(5-tert-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-pyrimidm-2-yl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-ρ-tolyl-2H-ρyrazol-3-yl)-2-o-tolyl-acetamide;
5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-acetylamino}-thiophene-2-carboxylic acid methylamide;
N-[5-tert-Butyl-2-(3,5-dichloro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-((2R,6S)-2,6-dimethyl-morpholin-
4-yl)-ethoxy] -naphthalen- 1 -yl } -2-oxo-acetamide;
3-tert-Butyl- 1 ,5-diphenyl- 1 ,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-imidazol-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-ethoxy)- naphthalen- 1 -yl] -acetamide; l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-
4-yloxy} -naphthalen- 1 -yl)-imidazolidine-2,4,5-trione;
N-[5-tert-Butyl-2-(3-chloro-ρhenyl)-2H-ρyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide; 5-Methoxy-lH-indazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)- amide;
N-[5-tert-Butyl-2-(6-chloro-pyridazm-3-yl)-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-morpholin-4-yl-ethoxy)- naphthalen-l-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-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo- acetylamino}-phenyl)-methanesulfonyl-amino] -acetic acid ethyl ester;
N-(5-tert-Butyl-4-methyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
N-[5-tert-Butyl-2-(2,5-dichloro-phenyl)-2H-ρyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2-[4-(2-[l,4]oxazeρan-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-l- yl]-2-oxo-acetamide;
3-Isopropyl-5-phenyl-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]ρyrazole;
3,5-Di-tert-butyl-l-p-tolyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
5-tert-Butyl-N-cyclopentyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetylamino}-benzamide;
2-[5-tert-Butyl-2-(3-fluoro-4-methyl-ρhenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4- yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-2-oxo-acetamide;
1 ,3-Di-tert-butyl-5-phenyl- 1 ,6-dihydro-imidazo[4,5-c]pyrazole; 4-(4-Bromo-naphthalen- 1 -yl)- 1 -(3 -tert-butyl-phenyl)-[ 1 ,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;
1 -tert-Butyl-5-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -ylamino]-3 -p-tolyl- 1,3- dihydro-imidazo[4,5-b]pyridin-2-one;
2-[5-tert-Butyl-2-(3-fluoro-phenyl)-2H-ρyrazol-3-yl]-2-[(Z)-hydroxyimino]-N-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 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-ρyrazol-3-yl]-N-[4-(2-morρholin-4-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
5-tert-Butyl-N-cyclopropylmethyl-2-methoxy-3-[2-(4-methoxy-naphthalen-l-yl)-2- oxo-acetylamino]-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-morpholin-4-yl- ethoxy)-naphthalen-l -yl]-2-oxo-acetamide;
N-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-2-[4-(2-morρholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-oxo-2-[4-(2- piperazin- 1 -yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-3-meth.anesulfonylammo-2-methoxy-phenyl)-2-[4-(2-morρholin-4-yl- pyridin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid isopropyl ester; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-dimethylamino-pyrimidin-4-yloxy)- naphthalen- 1 -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- 1 -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-moφholin-4-yl-ethoxy)-naphthalen- l-yl]-2-oxo-acetylamino}-benzamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-[l,4]oxazepan-
4-yl-ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
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-morpholin-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-ρyrazol-3-yl]-2-[4-(2-morpholin-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-l-yl]-2~oxo-acetamide;
4-{2-[4-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylaminooxalyl)- naphthalen-1-yloxy] -ethyl }-ρiρerazine-l -carboxylic acid ethyl ester;
2-Hydroxy-N-(5-isopropyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide; l-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-m.orpholin-4-yl-pyrimidin-4- ylamino)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-3-(2-diniethylamino-acetylainino)-2-methoxy-phenyl]-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{6-[4-(2-morpholin-4-yl-ethoxy)-naρhthalen-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-morpholin-4-yl-ethoxy)- naphthalen- 1 -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- 1 -yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-[2-(3-Amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
2-[5-tert-Butyl-2-(3-chloro-phenyl)-2H-pyrazol-3-yl]-N-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
1 ,5-Diphenyl-l ,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-[l,354]thiadiazol-2-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-niorpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-3-{2-hydroxy-2-[4-(2-morpholin-4-yl-pyriniidin-4-yloxy)- naphthalen- 1 -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-morρholin-4-yl-ethoxy)-naphthalen-l-yl]-2- oxo-acetamide;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-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-l-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- 1 -yl] -acrylamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-[4-(2-imidazol- 1 -yl-ethoxy)~naphthalen-
1 -yl]-2-oxo-acetamide;
N-(4-Bromo-3 -trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 - 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-methanesulfonylaniino-2-methoxy-phenyl)-2-[8-chloro-4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-niethoxy-ρhenyl)-2-[4-(2-chloro-etlioxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid dimethylamide; l-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- imidazolidine-2,4,5-trione;
N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl] -2 -oxo-acetamide;
1 -Benzoyl-3 -(5-tert-butyl-2-methoxy-phenyl)-urea;
N'-[l-(5-tert-Butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-meth-(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-niorpholin-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-diethylammo-3-methanesulfonylamino-phenyl)-2-[4-(2-morpliolin-
4-yl-ethoxy)-naρhthalen- 1 -yl]-2 -oxo-acetamide; N-(5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl)-2-[4-(2-morρholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-(4-methoxy- naphtlialen- 1 -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]-benzamide;
2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-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-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2- dimethylamino-pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl)-2-phenyl-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-(2-moφholin-
4-yl-pyrimidin-4-yloxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-{4-[2-(2,6-dimetliyl- morpholin-4-yl)-ethoxy]-naphthalen-l-yl}-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl)-2-(4-methoxy-naphthalen- 1 -yl)-acetamide;
3-tert-Butyl-l-cyclohexyl-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
3-tert-Butyl-5-(4-fluoro-phenyl)- 1 -p-tolyl- 1 ,6-dihydro-imidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-methoxy-3-{4-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-3,5- dioxo-[ 1 ,2,4]triazolidin- 1 -yl} -phenyl)-methanesulfonamide;
N-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2-oxo-2- {4-[2-(3-oxo-ρiperazin- 1 -yl)- ethyl]-naphthalen-l-yl}-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-2-[4-(3-pyridm-4-yl-propoxy)- naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-metlioxy-phenyl)-2-[(Z)-hydroxyiniino]-
2-[4-(2-morpholin-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-plienyl)-2-[4-(2-iinidazol-l-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-[5-tert-Butyl-2-(3,5-dimethyl-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-niorpholin-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-l-yl-2-oxo-acetamide;
N'-[l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester;
5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetylamino} -benzamide;
N-[54ert-Butyl-2-(3-nitro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-rnorpholin-4-yl-ethoxy)- naphthalen-l-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-l-yl]-2-oxo-acetamide;
3-tert-Butyl-5-{2-[4-(2-morpholin-4-yl-etlioxy)-naphthalen-l-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-l-yl]-2-oxo-acetamide;
N'-[l-(5-tert-Butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2-morpholin-4- yl-ethoxy)-naphtb.alen-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- 1 -sulfonylamino)-benzamide;
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-methanes-ulfonylamino-2-methoxy-phenyl)-2-[7-fluoro-4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-pyridin-4-ylamino)- naphthalen- 1 -yl] -2-oxo-acetamide;
3-tert-Butyl-l-(4-chloro-ρhenyl)-5-phenyl-l,6-dihydro-iniidazo[4,5-c]pyrazole;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-methoxy-naphthalen-l-yl)-2-oxo- acetamide;
2-[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-2-[(Z)-hydroxyimino]-N-
[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-methoxy-naphthalen-l-yl)-2-oxo-acetamide;
N-[5-(l,l-Dimethyl-propyl)-2-ρ-tolyl-2H-pyrazol-3-yl]-2-hydroxy-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-acetamide;
N-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-dimethylamino- pyrimidin-4-ylamino)-naρhthalen-l-yl]-2-oxo-acetamide;
N-(2-Chloro-5-trifluoromethyl-phenyl)-2-[4-(2-morpholm-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[2,3-dichloro-4-(2- morpholin-4-yl-ethoxy)-phenyl]-2-oxo-acetarnide;
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-
1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-2-naρhthalen-l-yl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-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-l-carboxylic acid ethyl ester;
5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)-naplithalen-
1 -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-l-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- 1 -yl]-imidazolidine-2,4,5-trione;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(2,3-difluoro-phenyl)-acetamide;
N-[5-tert-Butyl-3-(carbamoylmethyl-methanesulfonyl-amino)-2-methoxy-phenyl]-2- naphthalen- 1 -yl-2-oxo-acetaniide;
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-Ammo-phenyl)-5-tert-butyl-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- 1 -yl]-2-oxo- acetylamino}-phenyl)-carbamic acid phenyl ester;
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-2-isobutoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl] -2 -oxo-acetamide;
N-(4-tert-Butyl-phenyl)-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-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 amide; 1 -(5-tert-Butyl-2-methoxy-ρhenyl)-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-acetainide;
N-[5-tert-Butyl-2-(2,3-dimethyl-ρhenyl)-2H-pyrazol-3-yl]-2-[4-(2-morρholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpliolin-4-yl-ethoxy)- naphthalen- 1 -yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-N-[4-(2-morρholin-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- 1 -yl] -2-oxo-acetamide;
N'- [ 1 -(5-tert-Butyl-2-methyl-2H-pyrazol-3 -ylcarbamoyl)- 1 -[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;
Nl-[l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl)-l-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl] -meth-(Z)-ylidene] -hydrazinecarboxamide;
N-[5-tert-Butyl-2-(3-methoxy-ρhenyl)-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- 1 -yl] -2-oxo- acetylamino}-N-pyridin-2-yl-benzamide;
N-[5-tert-Butyl-3-(3,3-dimethyl-ureido)-2-methoxy-ρhenyl]-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-l-yl]-imidazolidine-2,4,5-trione;
N-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2-hydroxy-2-phenyl-propionaniide;
2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-N-quinolin-3-yl-acetamide; l-(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-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-methoxy-2-(4-methoxy-naphthalen-l- 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-l-yl)-ethoxy]-naphthalen-l-yl}-N-(5-tert-butyl-3- methanesulfonylammo-2-methoxy-phenyl)-2-oxo-acetamide;
2-(lH-Indol-3-yl)-N-[4-(2-morpliolin-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-yl- ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
2-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-N-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(3,4-dichloro-phenyl)-2H-ρyrazol-3-yl]-2-[4-(2-morρholin-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- 1 -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; lH-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- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-meth-(E)-ylidene]-hydrazinecarboxamide;
N-(5-tert-Butyl-2-ρ-tolyl-2H-ρyrazol-3-yl)-N'-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -oxalamide;
N-(5-tert-ButyI-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-inethylamino- pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2- morpholin-4-yl-ethoxy)-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-ρ-tolyl-2H-pyrazol-3-yl)-2-{4-[2-(2,6-dimethyl-morρholin-4-yl)- ethoxy]-naphthalen-l -yl} -2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[8-fluoro-4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-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-l-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-(ρropane-l-sulfonylamino)-ρhenyl]-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-
1 -yl]-imidazolidine-2,4,5-trione; l-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-3'-(carbamic acid ethyl ester)-urea ;
N-(5-tert-Butyl-3 -methanesulfonylamino-2-methoxy-ρhenyl)-2-oxo-2- {4-[2-(3 -oxo- piperazin- 1 -yl)-ethoxy]-naphthalen- 1 -yl} -acetamide;
2- {4-[2-(4-Acetyl-piperazin-l -yl)-ethyl]-naphthalen- 1 -yl} -N-(5-tert-butyl-2~p-tolyl-
2H-pyrazol-3-yl)-2-oxo-acetamide;
N-(5-tert-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- 1 -yl} -acetamide;
2-(5-tert-Butyl-2-m-tolyl-2H-ρyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-morphoIin-
4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
N-[5-tert-Butyl-2-(3-ureido-ρhenyl)-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-l-yl]-acetamide;
N-[5-tert-Butyl-2-methoxy-3-(3-oxo-piperazine-l-carbonyl)-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-l-carboxylic acid propylamide;
5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-pyrimidin-4- yloxy)-naphthalen- 1 -yl]-2-oxo-acetylamino } -benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-{4-[2-(4-methyl-ρiperazin-l-yl)- ethoxy]-naphthalen-l-yl}-2-oxo-acetamide;
N-(3-Amino-5-tert-butyI-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-morpholin-4-yl-ethoxy)-naphthalen- 1 -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-ρyrazol-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl]-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(3-phenoxy-phenyl)-acetamide;
N-(5-Isopropyl-2-metliyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naρhthalen-l-yl]-2- oxo-acetamide;
7-Isopropyl-9-ρhenyl-2-phenylamino-7,9-dihydro-purin-8-one;
(5-tert-Butyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetylamino}-phenyl)-carbamic acid pyridin-3-ylmethyl ester;
N-(5-tert-Butyl-3-metlianesulfonylaniino-2-methoxy-phenyl)-2-[4-(2-ethylamino- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(3,5-Di-tert-butyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
2-Amino-N-(5-tert-butyl-2-ρ-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-morpholin-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-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4- yloxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-(2,3-dichloro-pb.enyl)-2H-pyrazol-3-yl]-2-[4-(2-niorpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-[3,5-Bis-(l,l-dimethyl-propyl)-2-hydroxy-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
4-{2-[4-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylaminooxalyl)- naρhthalen-l-yloxy]-ethyl}-piperazine-l-carboxylic acid tert-butyl ester;
3-tert-Butyl-l-naphthalen-2-yl-5-phenyl-lJ6-dib.ydro-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-morpholin-4-yl-ethoxy)-naphthalen-
1 -yl] -2-oxo-acetylamino } -benzamide; N-(5-tert-Butyl-3-diethylaminomethyl-2-hydroxy-phenyl)-2-[4-(2-morρholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
6-Hydroxy-nicotinic acid 3-[5-tert-butyl-2-methoxy-3-(propane-l-sulfonylatnino)- phenylcarbamoyl]-lH-indazol-5-yl ester;
N-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-2-[4-(2-morpholin-4-yl-pyrimidin-4- ylamino)-naρhthalen~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-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-niethoxy-phenyl)-2-[4-(4-morpholin-4-yl- pyrimidin-2-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
1 ,3 ,5-Triphenyl- 1 ,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- acetylamino}-thiophene-2-carboxylic acid methylamide;
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-morρholin-4-yl- pyrimidin-4-ylamino)-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-(Z)-ylidene]-hydrazinecarboxylic acid ethyl ester;
4-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-l-(2,3-dimethyl-phenyl)-
[ 1 ,2,4]triazolidine-3 ,5-dione;
N-(4-Fluoro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naprithalen-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-Morρholin-4-yl-ethoxy)-naphthalen-l -yl carbamoyl] -pyrrole- 1 -carboxylic acid tert-butyl ester;
N-(2,5-Di-tert-butyl-phenyl)-2-[4-(2-morpholm-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo- acetamide;
2-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-N-((lS,2R)-2-prienyl- 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-
1 -yl] -2-oxo-acetamide;
N-[2-(4-Bromo-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3 - [4-(2-morpholin-4-yl-pyrimidin-4-yloxy)- naphthalen-l-yl]-irnidazolidine-2,4,5-trione;
5-tert-Butyl-2-methoxy-N-methyl-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-2-oxo-acetyIamino}-benzamide;
N-(5-tert-Butyl-2-methoxy-3-piperidin-l-ylmethyl-prienyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-prienyl)-2-naphthalen-l-yl-2-oxo-acetamide;
N-(2,5-Di-tert-butyl-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 4-methoxy-phenyl ester;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-naphthalen-l-yl-2-oxo-acetamide;
5-tert-Butyl-N-ethyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-acetylamino}-2-methoxy-benzamide;
4- {2-[4-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -ylaminooxalyO-naphthalen- 1 -yl] -ethyl } - piperazine-1 -carboxylic acid tert-butyl ester;
5-tert-Butyl-N-ethyl-2-hydroxy-3-{2-[4-(2-morpholm-4-yl-ethoxy)-naphthalen-l-yl]-
2-oxo-acetylamino}-benzamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-naphthalen-l-yl-acetamide;
N-(5-tert-Butyl-2-ethoxy-3-methanesulfonylamino-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naρhthalen- 1 -yl]-2-oxo-acetamide; N'-[l-(5-tert-Butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-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-tert-Butyl-N-ethyl-2-methoxy-3 - {2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -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-isoxazol-3-yl)-2-[4-(2-dimethylamino-pyrimidin-4-ylamino)- naphthalen- 1 -yl] -2-oxo-acetamide;
5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-pyridin-4-ylammo)-naphthalen-l-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- 1 -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- 1 -yl]-2-oxo-acetamide;
6-Bromo- 1 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)-naρhthalen-l-yl]-acetamide;
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-2-[4-(2-dimethylamino-pyrimidin-4- ylamino)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-thiophen-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naρhthalen-l-yl]-2- oxo-acetamide;
N-[5-tert-Butyl-2-(4-chloro-plienyl)-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-niethoxy-phenylcarbamoyl)-l-[4-(2-morpholin-4- yl-ethoxy)-naplithalen-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-benzamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-{4-[2-(4-methyl- piperazin- 1 -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- 1 -yl]-imidazolidin-2-one;
N-(5-tert-Butyl-thiophen-3-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morρholin-4-yl- ethoxy)-naphthalen- 1 -yl] -acetamide;
5-tert-Butyl-N-cyclopropyl-3-[2-[(Z)-hydroxyimino]-2-(4-methoxy-naphthalen-l-yl)- acetylamino] -2-methoxy-benzamide;
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-ρyrazol-3-yl]-2-[(Z)-hydroxyimino]-2-[4-
(2-morpholin-4-yl-ethoxy)-naρhthalen- 1 -yl] -acetamide;
N-[2-Methoxy-5-(l-methyl-l-phenyl-ethyl)-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-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-l-yl]-2-oxo-acetamide;
5-tert-Butyl-3-{2-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)-naρhtlialen-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- 1 - yl]-2-oxo-acetylamino}-benzamide;
2-(5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl)-2-[(Z)-hydroxyimino]-N-[4-(2-morpholin-
4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
3-tert-Butyl-l-(2,3-dichloro-phenyl)-5-phenyl-l,6-dihydro-imidazo[4,5-c]pyrazole;
N-(3,5-Di-tert-butyl-2-methoxy-phenyl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-
1 -yl]-2-oxo-acetamide;
5-tert-Butyl-3-{2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l- yl]-acetylamino}-thiophene-2-carboxylic acid dimetliylamide;
N-(5-tert-Butyl-2-methoxy-3-methyl-phenyl)-2-[(Z)-hydroxyimino]-2-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -acetamide;
N'-[l-(5-tert-Butyl-3-cyclopropylcarbamoyl-2-methoxy-phenylcarbamoyl)-l-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-meth-(E)-ylidene]-hydrazinecarboxylic acid ethyl ester;
N-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-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-(255-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;
1 H-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] -naphthal en- 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-l-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]-acetamide;
N-(5-tert-Butyl-3-niethanesulfonylamino-2-methoxy-phenyl)-2-[(Z)-hydroxyimino]-
2-[4-(2-morpholin-4-yl-pyrimidin-4-yloxy)-naphthalen-l-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- 1 -yl]-2-oxo- acetylamino}-pyrazole-l-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-ρyrazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]- 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)-naphthalen- 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-Butyl-isoxazol-5-yl)-2-[(Z)-hydroxyimino]-2-[4-(2-morpholin-4-yI-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- 1 -sulfonylamino)-phenyl] -2-[4-(2-morpholin-
4-yl~ethoxy)-naphthalen- 1 -yl] -2-oxo-acetamide;
7-Bicyclo[2.2.1]hept-2-yl-9-ρhenyl-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-tert-Butyl-2-methoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-benzamide; N-(5-tert-Butyl-2-methyl-2H-ρyrazol-3-yl)-2-[2,3-dimethyl-4-(2-morpholin-4-yl- ethoxy)-phenyl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-(3-fluoro-phenyl)-acetamide;
1 -(5-tert-Butyl-2-methoxy-3-benzamide)-3-(2,3-dimethylphenyl)-3 '-(carbamic acid ethyl ester)-urea;
2-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-oxo-N-(3-trifluoromethyl-phenyl)- acetamide;
7-Benzyl-9-ρhenyl-2-phenylamino-7,9-dihydro-purin-8-one;
2,5-Dihydro-lH-pyrrole-2-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)- amide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-metb.oxy-phenyl)-2-oxo-2-{4-[2-(5-oxo-
[l,4]diazepan-l-yl)-ethoxy]-naphthalen-l-yl}-acetamide;
N-[5-tert-Butyl-2-(3-cyano-phenyl)-2H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-methoxy-3-phenylacetylamino-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
2-(2-Chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholin-4-yl-pyrimidm-4-yloxy)- naphthalen-l-yl]-2-oxo-acetamide; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-piperidin-l-yl-pyrimidin-4-yloxy)- naphthalen-l-yl]-irnidazolidine-2,4,5-trione;
2-(2-Benzyl-5-tert-butyl-2H-pyrazol-3-yl)-2-hydroxy-N-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-acetaniide;
5-tert-Butyl-3-{2-[4-(2-dimethylamino-pyrimidin-4-ylamino)-naphthalen-l-yl]-2- oxo-acetylaniino}-thiophene-2-carboxylic acid amide;
N'-[l-(5-tert-Butyl-3-ethylcarbamoyl-2-niethoxy-phenylcarbamoyl)-l-[4-(2- morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -meth-(E)-ylidene] -hydrazinecarboxylic acid ethyl ester;
N-(3-Methanesulfonylamino-5-trifluoromethyl-phenyl)-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-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)-naρhthalen-l-yl]-2-oxo- acetamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-oxo-2-{4-[2-((S)-l-phenyl-ethylamino)- 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)-naphthalen- 1 -yl] -2-oxo-acetamide;
N'-[ 1 -(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)- 1 -[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-ρyrazol-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- 1 -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-ρyrazol-3-yl]-2-[4-(2-morpholin-4-yl- ethoxy)-naphthalen- 1 -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-l-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-furan-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-l-yl]-2-oxo-acetamide;
5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-pyridin-4- ylamino)-naphthalen- 1 -yl] -2-oxo-acetylamino } -b enzamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-ρhenyl)-2-oxo-2-{4-[6-
(tetrahydro-pyran-4-ylamino)-pyridm-3-yl]-naphthalen-l-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-morpholin-4-yl- pyridin-3-yl)-naphthalen- 1 -yl]-2-oxo-acetamide;
N-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-[4-(6-morpholin-4-ylmethyl-ρyridin-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- 1 - yl]-2-oxo-acetamide;
4-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-2-oxo-acetylamino]-phenoxy}-pyridine-
2-carboxylic acid methylamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-niethoxy-phenyl)-2-{4-[2-(5-methoxy-
1 H-indol-3 -yl)-ethylamino] -naphthalen- 1 -yl } -2-oxo-acetamide;
N-[5-tert-Butyl-3-(carbamoylmethyl-methanesulfonyl-amino)-2-methoxy-phenyl]-2-
[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-dimethylamino- pyridin-3-yl)-naphthalen- 1 -yl] -2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(6-niethylaniino- pyridin-3-yl)-naphthalen-l-yl]-2-oxo-acetamide;
N-[5-tert-Butyl-2-methoxy-3 -(propane- 1 -sulfonylamino)-phenyl]-2-[4-(2- dimethylamino-pyridin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2-dimethylamino- pyridin-4-ylamino)-naphthalen- 1 -yl]-2-oxo-acetamide;
5-tert-Butyl-N-cyclopropyl-3-{2-[4-(2-dimethylamino-pyridin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetylamino}-2-methoxy-benzamide;
N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-dimethylamino-pyridin-4-ylamino)- naphthalen- 1 -yl] -2-oxo-acetamide;
5-tert-Butyl-3- {2-[4-(2-dimethylamino-pyridin-4-ylamino)-naphthalen- 1 ~yl]-2-oxo- acetylamino}-thiophene-2-carboxylic acid amide;
N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(3-ethyl-isoxazol-
5-yl)-naphthalen- 1 -yl] -2-oxo-acetamide; N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(6-methylamino-pyridin-3-yl)-naphthalen-l- yl]-2-oxo-acetamide;
5-tert-Butyl-2-methoxy-3-{2-[4-(6-methylamino-pyridin-3-yl)-naphthalen-l-yl]-2- oxo-acetylamino} -benzamide;
5-tert-Butyl-N-ethyl-2-methoxy-3 - {2-[4-(6-methylamino-pyridin-3 -yl)-naphthalen- 1 - yl]-2-oxo-acetylamino}-benzamide;
5-tert-Butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(6-methylamino-pyridin-3-yl)- naphthalen-l-yl]-2-oxo-acetylamino}-benzamide;
N-[5-tert-Butyl-2-methoxy-3-(propane-l-sulfonylamino)-phenyl]-2-[4-((S)-2,3- dihydroxy-propoxy)-naphthalen- 1 -yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(2-chloro-pyrimidin-4-ylamino)- naphthalen-1 -yl]-2-oxo-acetamide;
2-(5-tert-Butyl-2-niethyl-foran-3-yl)-2-oxo-N-[4-(pyrimidin-4-ylamino)dihydro- naphthalen- 1 -yl] -acetamide;
N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(2,3-dihydroxy-propoxy)-naphthalen-l-yl]-2-oxo- acetamide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-2-oxo-N-[4-(pyrimidin-2-ylamino)-naphthalen- l-yl]-acetamide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(2-morpholm-4-yl-pyriniidin-4-yloxy)- naphthalen- 1 -yl] -2-oxo-acetaniide;
2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(2-morpholin-4-yl-pyrimidin-4-ylamino)- naphthalen-1 -yl]-2-oxo-acetamide;
2-(5-tert-Butyl-3-methyl-furan-2-yl)-N-[4-(2-morpholin-4-yl-ethoxy)-naρhthalen-l- yl]-2-oxo-acetamide;
2-[5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-yl]-N-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-l-yl]-2-oxo-acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(pyrrolidin-
1 -yl)pyrimidin-4-ylamino)naphthalen- 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-
(methylsulfonarnido)phenyl)-2-oxoacetarnide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyrimidin-4- ylamino)naphthalen- 1 -yl)acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyridin-4- ylamino)naρhthalen- 1 -yl)acetamide; or a pharmaceutically acceptable salt, solvate, tautomer, or prodrug thereof.
DETAILED DESCRIPTION QF THE INVENTION
[0051 ] The following terms are used throughout as defined below.
[0052] 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.
[0053] In general, "substituted" refers to a functional group as defined below 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. In some embodiments, substituted groups have 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include, but are not limited to: 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; thiols; alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl sulfide groups; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; and nitriles.
[0054] 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 alkyl, alkenyl, and alkynyl groups as defined below.
[0055] Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-ρropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
[0056] 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 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 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. 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 any of the groups listed above, for example, methyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
[0057] Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkylene brige, 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 2 carbon atoms. Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexyl, 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 norbomyl 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 any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
[0058] 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.
[0059] Alkenyl groups include straight and branched chain alkyl 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 carbon atoms. Examples include, but are not limited to vinyl, -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.
[0060] Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienylgroups. [0061] 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.
[0062] 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 carbon atoms. Examples include, but are not limited to -OCH, -C=C(CH3), -C=C(CH2CH3), -CH2C=CH, -CH2C=C(CH3), and -CH2CsC(CH2CH3), among others.
[0063] 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 6-10 carbon atoms in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono- substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with groups such as those listed above.
[0064] 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. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. [0065] 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, the heterocyclyl group contains 1, 2, 3, or 4 heteroatoms. In some embodiments, heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 10, 12, or 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, pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, pyrazolidinyl, tetrahydropyranyl, thiomorpholinyl, pyranyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, quinazolinyl, benzotriazolyl, 2,3- dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl groups. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various groups as defined above, including, but not limited to, alkyl, oxo, carbonyl, amino, alkoxy, cyano, and/or halo.
[0066] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, the heteroaryl group includes 1, 2, 3, or 4 heteroatoms and has 5 to 20, 5 to 15, or 5 to 10 ring members. In other embodiments, the heteroaryl groups have 5, 6, 7, 8, or 9 ring members. Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl (thienyl), benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Although the phrase "heteroaryl groups" includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substituents are referred to as "substituted heteroaryl groups". Representative substituted heteroaryl groups may be substituted one or more times with various groups as defined above, including, but not limited to, amino, oxo, alkoxy, alkyl, cyano, and/or halo.
[0067] 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. Representative heterocyclyl alkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
[0068] 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.
[0069] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an 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 include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
[0070] The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
[0071] The term "carboxylate" as used herein refers to a -COOH group.
[0072] 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.
[0073] 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).
[0074] Urethane groups include N- and 0-urethane groups, i.e., -
NR33C(O)OR34 and -OC(O)NR33R34 groups, respectively. R33 and R34 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
[0075] The term "amine" 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.
[0076] 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).
[0077] The term "thiol" refers to -SH groups, while sulfides include -SR40 groups, sulfoxides include -S(O)R41, 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.
[0078] 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.
[0079] The term "amidine" refers to -C(NR47)NR48R49 and -NR47C(NR48)R49 groups, wherein R47, 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.
[0080] The term "guanidine" refers to -NR50C(NR51)NR52R53 groups,, 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.
[0081] The term "enamine" refers to -C(R54)=C(R55)NR56R57 and
-NR54C(R55)=C(R56)R57 groups, 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.
[0082] The term "imide" refers to -C(O)NR58C(O)R59 groups, 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. [0083] 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 not both R60 and R61 are H simultaneously.
[0084] 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 trifiuoracetate.
[0085] N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloro acetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, A- 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, o;o;-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).
[0086] Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-ρicolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
[0087] Representative carboxy protecting groups are Ci to C8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valerytoxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1 -(propionyloxy)- 1 -ethyl, 1 -(pivaloyloxyl)- 1 -ethyl, 1 -methyl- 1 -(propionyloxy)- 1 - 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- 1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1 -ethoxycarbonyloxy-1 -ethyl, l-cyclohexyloxycarbonyloxy-l -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 dimethylaminocarbonylniethyl, diethylaminocarbonylmethyl and the like; (5- (alkyl)-2-oxo-l,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)alkylJ such as (5- phenyl-2-oxo-l,3-dioxolen-4-yl)methyl and the like.
[0088] "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, triazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
Figure imgf000071_0001
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 of the invention are within the scope of the present invention.
[0089] Stereoisomers of compounds include all chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure, unless the specific stereochemistry or isomeric form is specifically 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. [0090] 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).
[0091] Certain compounds within the scope of the invention 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 1985, 112, 309; Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future 1981, 6, 165; 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.
[0092] The term "cancer" refers to any of various malignant neoplasms characterized by the proliferation of cells that can invade surrounding tissue and metastasize to new body sites. A neoplasm, or tumor, is an abnormal, unregulated, and disorganized proliferation of cell growth. A neoplasm is malignant, or cancerous, if it has properties of destructive growth, invasiveness and metastasis. Invasiveness refers to the local spread of a neoplasm by infiltration or destruction of surrounding tissue, typically breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body's circulatory system. Metastasis typically refers to the dissemination of tumor cells by lymphotics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance. Bone tissues are one of the most favored sites of metastases of malignant tumors, occurring in about 30% of all the cancer cases. Among malignant tumors, cancers of the lung, breast, prostate or the like are particularly known to be likely to metastasize to bone.
[0093] Both benign and malignant tumors are classified according to the type of tissue in which they are found. For example, fibromas are neoplasms of fibrous connective tissue, and melanomas are abnormal growths of pigment (melanin) cells. Malignant tumors originating from epithelial tissue, e.g., in skin, bronchi, and stomach, are termed carcinomas. Malignancies of epithelial glandular tissue such as are found in the breast, prostate, and colon, are known as adenocarcinomas. Malignant growths of connective tissue, e.g., muscle, cartilage, lymph tissue, and bone, are called sarcomas. Lymphomas and leukemias are malignancies arising among the white blood cells.
[0094] Unless otherwise indicated, the term "nociceptive pain" includes, but is not limited to, pain associated with chemical or thermal burns, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.
[0095] Unless otherwise indicated, the term "neuropathy" includes, but is not limited to, a functional disturbance or pathological change in the peripheral nervous system and is characterized clinically by sensory or motor neuron abnormalities. The term mononeuropathy indicates that a single peripheral nerve is affected, while the term polyneuropathy indicates that several peripheral nerves are affected. Deafferentation indicates a loss of the sensory input from a portion of the body, and can be caused by interruption of either peripheral sensory fibres or nerves from the central nervous system. Neuropathic pain thus reflects injury or impairment of the nervous system, and is defined herein as pain initiated or caused by a primary lesion or dysfunction in the nervous system. In particular, neuropathic pain can be caused by injury or dysfunction of the peripheral nervous system. The etiology of a neuropathy can be known or unknown. Known etiologies include complications of a disease or toxic state such as diabetes (which is the most common metabolic disorder causing neuropathy), or irradiation, ischemia or vasculitis. It is understood that the methods of the invention can be used to treat chronic pain of these or other chronic neuropathies of known or unknown etiology.
[0096] Unless otherwise indicated, the term "neuropathic pain" includes, but is not limited to, CRPS (Complex Regional Pain Syndrome) type I, CRPS type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer and metastases related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine, velcade and thalidomide. The neuropathic pain can result from a mononeuropathy, polyneuropathy, complex regional pain syndromes or deafferentation.
[0097] Visceral pain is conventionally viewed as a variant of somatic pain, but may differ in neurological mechanisms. Certain clinical characteristics are peculiar to visceral pain: (i) it is not evoked from all viscera and not always linked to visceral injury; (ii) it is often diffuse and poorly localized, due to the organization of visceral nociceptive pathways in the central nervous system (CNS), particularly the absence of a separate visceral sensory pathway and the low proportion of visceral afferent nerve fibers; (iii) it is sometimes referred to other nonvisceral structures; and (iv) it is
O
7^ associated with motor and autonomic reflexes, such as nausea [Johnson, B. W., Pain Mechanisms: Anatomy, Physiology and Neurochemistry, Chapter 11 in Practical Management of Pain ed. P. Prithvi Raj. (3rd Ed., Mosby, Inc. St Louis, 2000); and Cervero, F. and Laird J. M. A., Lancet 353:2145-48 (1999)].
[0098] Headaches can be classified as primary and secondary headache disorders. The pathophysiology of the two most common primary disorders, i.e., migraine and tension-type headache, is complex and not fully understood. Recent studies indicate that nociceptive input to the CNS may be increased due to the activation and sensitization of peripheral nociceptors, and the barrage of nociceptive impulses results in the activation and sensitization of second- and third-order neurons in the CNS. Thus, it is likely that central sensitization plays a role in the initiation and maintenance of migraine and tension-type headache [Johnson, B. W. Pain Mechanisms: Anatomy, Physiology and Neurochemistry, Chapter 11 in Practical Management of Pain ed. P. Prithvi Raj. (3rd Ed., Mosby, Inc. St Louis, 2000)].
[0099] 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.
[0100] "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 halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder (i.e., inflammation, cancer or pain). For example, within the context of cancer, successful treatment may include an alleviation of symptoms or halting the progression of the disease, as measured by a reduction in the growth rate of a tumor, a halt in the growth of the tumor, a reduction in the size of a tumor, partial or complete remission of the cancer, or increased survival rate or clinical benefit. [0101] 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 halts of further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder. For example in the context of pain, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, pain symptoms, or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the pain symptoms.
[0102] A therapeutically effective amount of a cytokine inhibitor 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 ratio of doses 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.
[0103] Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies. For example, the compounds and pharmaceutical formulations of the present invention may be administered before, during, or after surgical procedure and/or radiation therapy. Alternatively, the compounds of the invention can also be administered in conjunction with other anti-inflammatory agents, anticancer agents and other agents described herein.
[0104] In the context of cancer, the cytokine inhibitors disclosed herein 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. Additional treatments comprise treatment by surgery, radiation, or cryotherapy, while treatment with additional active ingredients comprises the use of antiproliferative agents. Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e.g., carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects of each drug. The specific amount of the additional active agent will depend on the specific agent used, the type of cancer being treated or managed, the severity and stage of the cancer, and the amount(s) of cytokine inhibitors and any optional additional active agents concurrently administered to the mammal. For example, the additional active ingredients that can be used in combination with the cytokine inhibitors of the present invention are used at dosages well known in the art.
[0105] The term "inhibition," in the context of neoplasia, cancer, tumor growth or tumor cell growth, may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition is referred to herein as prevention or chemoprevention.
[0106] The term "prevention" in the context of cancer includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinically evident stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or arresting or reversing the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia.
[0107] In general, surgery and radiation therapy are employed as potentially curative therapies for humans under 70 years of age who present with clinically localized disease and are expected to live at least 10 years.
[0108] The phrase "antiproliferative agents" includes agents that prevent the development, maturation, or spread of cells, by acting directly on the cell, e.g., by cytostatic or cytocidal effects, and not indirectly through mechanisms such as biological response modification. There are large numbers of antiproliferative agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be employed for treatment with compounds of the present invention for treatment of cancer by combination drug chemotherapy.
[0109] Exemplary antiproliferative agents can be categorized as alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, endothelin A receptor antagonists, retinoic acid receptor agonists, immunomodulators, hormonal or antihormonal agents, photodynamic agents, angiogenesis inhibitors, tyrosine kinase inhibitors, and the like. Some antiproliferative agents operate through multiple or unknown mechanisms and can thus be classified into more than one category.
[0110] The alkylating agents are believed to act by alkylating and cross- linking guanine and possibly other bases in DNA, arresting cell division. Exemplary alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cisplatin, and various nitrosoureas. A disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skin, gastro-intestinal mucosa, and fetal tissue. Suitable alkylating-type agents that may be used in the present invention include, but are not limited to, busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, and chlorambucil.
[0111] Suitable platinum agents that may be used in the present invention include, but are not limited to spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin. [0112] Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids. Suitable antimetabolite agents that may be used in the present invention include, but are not limited to azacytidine, trimetrexate, floxuridine, deoxycoformycin, 2-chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex, ethynylcytidine (Taiho), fludarabine, gemcitabine, raltitrexed, or capecitabine.
[0113] Suitable topoisomerase agents that may be used in the present invention include, but are not limited to amsacrine, exatecan mesylate (Daiichi), epirubicin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl-lO-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR- 3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-I l), or topotecan.
[0114] Suitable antibiotic-type antiproliferative agents that may be used in the present invention include, but are not limited to dactinomycin (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menarini), plicamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonafide.
[0115] Suitable antimitotic antiproliferative agents that may be used in the present invention include, but are not limited to colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Warner-Lambert), synthadotin (BASF), cemadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (Eli Lilly), vinfhmine (Fabre), hydravin (Prescient NeuroPharma), auristatin PE (Teikoku Hormone), azaepothilone B (BMS), ixabepilone (BMS), tavocept (BioNumerik), BMS 184476 (BMS), combrestatin A4 disodium phosphate (OXiGENE), BMS 188797 (BMS), dolastatin-10 (NIH), taxoprexin (Protarga), cantuzumab mertansine (GlaxoSmithKline), docetaxel, vinorelbine, or vincristine.
[0116] Suitable aromatase inhibitors that may be used in the present invention include, but are not limited to aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole.
[0117] Suitable thymidylate synthase inhibitors that may be used in the present invention include, but are not limited to, pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche), or 5,10- methylenetetrahydrofolate (BioKeys).
[0118] Suitable DNA antagonists that may be used in the present invention include, but are not limited to trabectedin (PharmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics).
[0119] Suitable farnesyltransferase inhibitors that may be used in the present invention include, but are not limited to arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).
[0120] Suitable pump inhibitors that may be used in the present invention include, but are not limited to zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG).
[0121] Suitable histone acetyltransferase inhibitors that may be used in the present invention include, but are not limited to tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG). [0122] Suitable metalloproteinase inhibitors that may be used in the present invention include, but are not limited to neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech).
[0123] Suitable ribonucleoside reductase inhibitors contemplated for use in the present invention include, but are not limited to, gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health).
[0124] Suitable endothelin A receptor antagonists that may be used in the present invention include, but are not limited to atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
[0125] Yet another group of antiproliferative agents which may be used in combination with cytokine inhibitors of the present invention includes retinoic acid receptor agonists. The family of retinoic acid receptor agonists includes compounds which are natural and synthetic analogues of retinol (Vitamin A). The retinoids bind to one or more retinoic acid receptors to initiate diverse processes such as reproduction, development, bone formation, cellular proliferation and differentiation, apoptosis, hematopoiesis, immune function and vision. Retinoids are required to maintain normal differentiation and proliferation of almost all cells and have been shown to reverse/suppress carcinogenesis in a variety of in vitro and in vivo experimental models of cancer, see (Moon et al., Ch. 14 Retinoids and cancer. In The Retinoids, Vol. 2. Academic Press, Inc. 1984). Suitable retinoic acid receptor agonists that may be used in the present invention include, but are not limited to fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD-1550 (Ligand).
[0126] Suitable immunomodulators that may be used in the present invention include, but are not limited to interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CDl 54 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP -25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), β-alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen Idee), or p21 RAS vaccine (GemVax).
[0127] Suitable hormonal agents that may be used in the present invention include, but are not limited to an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutamide, or leuporelin.
[0128] Suitable photodynamic agents that may be used in the present invention include, but are not limited to talaporfm (Light Sciences), Pd- bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin.
[0129] Suitable angio genesis inhibitors that may be used in the present invention include, but are not limited to neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Sugen).
[0130] Suitable tyrosine kinase inhibitors that may be used in the present invention include, but are not limited to imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKline), panitumumab (Abgenix), IMC-ICl 1 (ImClone), sorafenib (Bayer) or trastuzumab (Genentech).
[0131] Additional anti-proliferative agents which may be used in combination with cytokine inhibitors of the present invention include melphalan, carmustine, cisplatin, 5-fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, paclitaxel (Taxol®), and the like.
[0132] In the context of pain treatment, the cytokine inhibitors of the invention can be used together with additional active ingredients or agents. Typically, the additional active agents are capable of relieving pain, inhibiting inflammatory reactions, providing a sedative effect or an antineuralgic effect, or ensuring patient comfort. Examples of the additional active agents include, but are not limited to, opioid analgesics, non-narcotic analgesics, antiinflammatories, cox-2 inhibitors, α- adrenergic receptor agonists or antagonists, ketamine, anesthetic agents, NMDA antagonists, α2δ ligands, immunomodulatory agents, immunosuppressive agents, antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, corticosteroids, hyperbaric oxygen, other therapeutics known to relieve pain, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, prodrugs or pharmacologically active metabolites thereof.
[0133] Opioids can be used to treat severe pain. Examples of opioid analgesics include, but are not limited to, oxycodone (OxyContin™), morphine sulfate (MS Contin™, Duramorph™, Astramorph™), meperidine (Demerol™), and fentanyl transdermal patch (Duragesic™) and other known conventional medications [See, e.g., Physicians' Desk Reference, 594-595, 2851 and 2991 (57th ed., 2003)]. Oxycodone (OxyContin™) is a long-acting form of an opioid and may be used in initial and later stages of CRPS. Morphine sulfate may be used for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate is sold in the United States under the trade name MS Contin™, Duramorph™, or Astramorph™ [See, e.g., Physicians' Desk Reference, 594-595 (57th ed., 2003)]. Fentanyl transdermal patch (Duragesic™) is a potent narcotic analgesic with much shorter half-life than morphine sulfate. Meperidine (Demerol™) and hydromorphone (Dilaudid™) may also be used for pain management [See, e.g., Physicians' Desk Reference, 2991 (57th ed., 2003)].
[0134] Non-narcotic analgesics and antiinflammatories are preferably used for treatment of pain during pregnancy and breastfeeding. Anti -inflammatories such as non-steroidal anti-inflammatory drugs (NSAIDs) and cox-2 inhibitors typically inhibit inflammatory reactions and pain by decreasing the activity of cyclo- oxygenase, which is responsible for prostaglandin synthesis. NSAIDs may provide pain relief in the early stage of pain syndrome. Examples of antiinflammatories include, but are not limited to, salicylic acid acetate (Aspirin™), ibuprofen (Motrin™, Advil™), ketoprofen (Oruvail™), rofecoxib (Vioxx™), naproxen sodium (Anaprox™, Naprelan™, Naprosyn™), ketorolac (Acular™), and other known conventional medications. A specific cox-2 inhibitor is celecoxib (Celebrex™) [See, e.g., Physicians' Desk Reference, 1990, 1910-1914 and 2891 (57th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 511, 667 and 773 (23rd ed., 2002)].
[0135] Antidepressants increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. Some antidepressants also have sodium channel blocking ability to reduce the firing rate of injured peripheral afferent fibers. Examples of antidepressants include, but are not limited to, nortriptyline (Pamelor™), amitriptyline (Elavil™), imipramine (Tofranill), doxepin (Sinequan™), clomipramine (Anafranil™), fluoxetine (Prozac™), sertraline (Zoloft™), nefazodone (Serzone™), venlafaxine (Effexor™), trazodone (Desyrel™), bupropion (Wellbutrin™) and other known conventional medications [See, e.g., Physicians' Desk Reference, 329, 1417, 1831 and 3270 (57th ed., 2003)].
[0136] Anticonvulsant drugs may also be used in embodiments of the invention. Examples of anticonvulsants include, but are not limited to, carbamazepine, oxcarbazepine, gabapentin (Neurontin™), phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, and tiagabine [See, e.g., Physicians' Desk Reference, 2563 (57th ed., 2003)].
Ri [0137] Corticosteroids (e.g., prednisone, dexamethasone or hydrocortisone), orally active class Ib anti-arrhythmic agents (e.g., mexiletine), calcium channel blockers (e.g., nifedipine), beta-blockers (e.g., propranolol), α-blockers (e.g., phenoxybenzamine), and oc2-adrenergic agonists (e.g., clonidine) can also be used in combination with a cytokine inhibitor [See, e.g., Physicians' Desk Reference, 1979, 2006 and 2190 (57th ed., 2003)].
[0138] Administration of the cytokine inhibitors of the invention and the optional additional active agents to a patient 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 cytokine inhibitors is oral. 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, 594-597 (57th ed., 2003)]. Alternatively, the cytokine inhibitor and the additional active agents are administrated simultaneously by coformulation.
[0139] The specific amount of the additional active agent will depend on the specific agent used, the type of pain being treated or managed, the severity and stage of pain, and the amount(s) of cytokine inhibitors and any optional additional active agents concurrently administered to the patient.
[0140] Hydromorphone (Dilaudid™) is typically administered in an initial dose of about 2 mg orally, or about 1 mg intravenously to manage moderate to severe pain [See, e.g., Physicians' Desk Reference, 2991 (57th ed., 2003)]. Morphine sulphate (Duramorph™, Astramorph™, MS Contin™) is typically administered in an initial dose of about 2 mg IV/SC/IM, depending on whether a patient has already taken narcotic analgesics [See, e.g., Physicians' Desk Reference, 594-595 (57th ed., 2003)]. No intrinsic limit to the amount that can be given exists, as long as a patient is observed for signs of adverse effects, especially respiratory depression. Various IV doses may be used, commonly titrated until a desired effect is obtained. For patients not using long-term agents, as little as 2 mg IV/SC may be sufficient. Larger doses are typically required for patients taking long-term narcotic analgesics. Morphine sulphate is also available in oral form in immediate-release and timed-release preparations. The long-acting oral form may be administered twice per day. An immediate-release form may be needed for periods of pain break-through, with the dose dependent on previous use. Oxycodone (OxyContin™) is a long-acting form of an opioid and may be used in initial and later stages of pain syndrome. Oxycodone (OxyContin™) is usually administered in an amount of about 10-160 mg twice a day [See, e.g., Physicians' Desk Reference, 2851 (57th ed., 2003)]. Meperidine (Demerol™) is typically administered in an amount of about 50-150 mg PO/IV/IM/SC every 3-4 hours. A typical pediatric dose of meperidine (Demerol™) is 1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC every 3-4 hours [See, e.g., Physicians' Desk Reference, 2991 (57th ed., 2003)]. Fentanyl transdermal patch (Duragesic™) is available as a transdermal dosage form. Most patients are administered the drug in 72 hour dosing intervals; however, some patients may require more frequent dosing intervals as low as about 48 hours. A typical adult dose is about 25 mcg/h (10 cm ), 50 mcg/h (20 cm2), 75 mcg/h (75 cm2), or 100 mcg/h (100 cm2) [See, e.g., Physicians' Desk Reference, 1775 (57th ed., 2003)].
[0141] Non-narcotic analgesics and antiinflammatories such as NSAIDs and cox-2 inhibitors may be used to treat patients suffering from mild to moderate pain. Ibuprofen (Motrin™, Advil™) is orally administered in an amount of 400-800 mg three times a day [See, e.g., Physicians' Desk Reference, 1900-1904 (57th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 511, 667 and 773 (23rd ed., 2002)]. Naproxen sodium (Anaprox™, Naprelan™, Naprosyn™) may also be used for relief of mild to moderate pain in an amount of about 275 mg thrice a day or about 550 mg twice a day [See, e.g., Physicians' Desk Reference, 1417,2193 and 2891 (57th ed., 2003)].
[0142] Antidepressants, e.g., nortriptyline (Pamelor™), may also be used in the practice of the invention to treat patients suffering from chronic and/or neuropathic pain. The oral adult dose is typically in an amount of about 25-100 mg, and usually does not exceed 200 mg/d. A typical pediatric dose is about 0.1 mg/kg PO as initial dose, increasing, as tolerated, up to about 0.5-2 mg/d. Amitriptyline (Etrafon™) is typically used for neuropathic pain in an adult dose of about 25-100 mg PO [See, e.g., Physicians' Desk Reference, 1417 and 2193 (57th ed., 2003)].
[0143] Anticonvulsants such as gabapentin (Neurontin™) may also be used to treat patients suffering from chronic and neuropathic pain. Typically, gabapentin is orally administered in an amount of about 100-1,200 mg three times a day [See, e.g., Physicians' Desk Reference, 2563 (57th ed., 2003)]. Carbamazepine (Tegretol™) is used to treat pain associated with true trigeminal neuralgia. The oral adult dose is typically in an amount of about 100 mg twice a day as initial dose, increasing, as tolerated, up to about 2,400 mg/d [See, e.g., Physicians' Desk Reference, 2323-25 (57th ed., 2003)].
[0144] The additional active agents can act additively or, more typically, synergistically with the cytokine inhibitor. In one example, a cytokine inhibitor is administered concurrently with one or more second active agents in the same pharmaceutical composition. In another example, a cytokine inhibitor is administered concurrently with one or more second active agents in separate pharmaceutical compositions, hi still another example, a cytokine inhibitor is administered prior to or subsequent to administration of a second active agent. The invention contemplates administration of a cytokine inhibitor and a second active agent by the same or different routes of administration, e.g., oral and parenteral. In certain embodiments, when a cytokine inhibitor 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 elicits the adverse side effect.
[0145] Specific dosages of cytokine inhibitors or combinations of cytokine inhibitors and additional active agents may be adjusted depending on conditions of 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.
[0146] Administration of the cytokine inhibitors and the additional active agents to a mammal 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 cytokine inhibitors described herein is oral. 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 (57th ed., 2003)]. Alternatively, the cytokine inhibitor and the additional active agents are administrated simultaneously by coformulation.
[0147] The additional active agent can be administered orally, intravenously, intramuscularly, subcutaneously, mucosally, or transdermally and once or twice 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.
[0148] In one embodiment of the invention, a cytokine inhibitor and an additional active agent are administered to a mammal, more typically a human, in a sequence and within a time interval such that the cytokine inhibitor can act together with the other agent to provide an increased benefit than 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 one embodiment, the cytokine inhibitor and the additional active agent(s) 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 cytokine inhibitor is administered before, concurrently or after administration of the additional active agent(s).
S7 [0149] In various examples, the cytokine inhibitor 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 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In other examples, the cytokine inhibitor and the additional active agents are administered concurrently. In yet other examples, the cytokine inhibitor and the additional active agents are administered concurrently by coformulation.
[0150] In other examples, the cytokine inhibitor 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.
[0151] In certain examples, the cytokine inhibitor and the optional additional active agent(s) are cyclically administered to 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 reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, reduce the dose levels of the cytokine inhibitor and/or the optional active agent(s), and/or improve the efficacy of the treatment.
[0152] In other examples, the cytokine inhibitor and the optional additional active agent(s) 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 cytokine inhibitor and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 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.
[0153] In yet other examples, the cytokine inhibitor 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 cytokine inhibitor is used at doses lower than other protocols such as daily dosing. 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 cytokine inhibitor 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.
[0154] Courses of treatment can be administered concurrently to a mammal, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the cytokine inhibitor 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.
[0155] The invention also provides for pharmaceutical compositions which may be prepared by mixing one or more cytokine inhibitory compounds as described herein, 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 treat, or prevent a variety of disorders associated with excess cytokine production. The compositions of the invention may be used to create
SQ formulations and prevent or treat a variety of disorders associated with excess cytokine production, e.g., diseases and pathological conditions involving inflammation, pain or cancer. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injections. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.
[0156] 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 anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
[0157] 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.
[0158] 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.
[0159] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri- glycerides.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Delivery of aerosols including compounds 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. The compounds used in this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye. The compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations maybe 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.
[0169] 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). [0170] 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.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] Examples of cytokine inhibitors used in the instant invention are described below. A first group of compounds are represented by Formula IA,
Figure imgf000096_0001
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl 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), 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, C6-10 aryl, -(Cj-3 alkyl)-(C6-10 aryl), -(Y)-(C0-3 alkyl)-(C6-10 aryl), or -(Y)-(C0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5;
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-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0)m; and wherein L is optionally substituted with 1-2 oxo groups and one or of F, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl- S (O)m, wherein the cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, Ci-6 alkyl-S(O)ra, or phenyl-S(O)m is each optionally substituted with one or more R27;
each R is independently hydrogen or substituted or unsubstituted Ci-6 alkyl; each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6.10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R1 is independently F, Cl, Br, I, cyano, -C(O)R5 -C(O)NR2, -C(O)OR, -OR, -NR'R', -SiR3, - S(O)mR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing I5 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-I0 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", -NR5SO2R", -NR' C(O)NR' R', - NR'C(S)NR'R\ -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6.10 aryl or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-1O 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, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-I2 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched Ci-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(θχCH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)1n;
91 each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or folly halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted Ci-1O alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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 C1-10 alkyl, substituted or unsubstituted C2-1O alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-1O 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, S(0)m;
provided however that when Ar is -(Y)-(C6-10 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. [0175] 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%.
[0176] 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, benzofαranyl, 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.
[0177] 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, benzo[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.
[0178] 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 C6-10 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.
[0179] In certain embodiments of compounds having Formula IA, Ar is -(C1-3 alkyl)-(C6-10 aryl), -(Y)-(C0-3 alkyl)-(C6-i0 aryl), or -(Y)-(C0-3 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 C6-10 aryl is phenyl or naphthyl, and/or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl. In yet other such embodiments Ar is -(C1-3 alkyl)-(C6-10 aryl).
[0180] 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(0)m. In others, L is a covalent bond, a C1-Cg alkoxy, -C(O)O-, -NH- or -O-.
[0181] 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
phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl, ρyrrolo[2,3-b]pyridinyl, ρyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b]ρyridinyl, or imidazo[4,5-b]pyridinyl, tetrahydropyranyl, tetrahydro furanyl, 1,3- dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or Ci-5 alkoxyalkyl, phenylamino; C1-6 alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R27 is C1-6 alkyl, C1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C1-3 alkyl)amino, mono- or di- (phenyl-d-3 alkyl)amino, C1-6 alkyl-S(O)m, phenyl-C1-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy.
[0182] In some other embodiments of the first group of compounds of
Formula IA, Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R27 is -C(O)OR', -NR'R', substituted or unsubstituted straight or branched C1-10 alkyl, substituted or unsubstituted C7-2O 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, S(0)m. 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, S(O)m. In yet other such embodiments, Q is pyridinyl, and R27 is -NR'R', substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)n,.
[0183] In some embodiments of the first group of compounds of Formula IA, when R4 and R5 are absent, -L-Q is not -H.
[Ol 84] 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, Ci-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)m, CHOH, C=O, C=S or NH;
C3-10 branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three C1-5 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, C1-3 alkoxy optionally partially or fully halogenated, NH2C(O) or mono- or di-(C1-3 alkyl)aminocarboxyl; and wherein the C3-1O branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(O)1n;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
cyano, F, Cl, Br, or I;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
silyl containing three C1-4 independently branched or unbranched alkyl groups optionally partially or folly halogenated;
C2-6 branched or unbranched alkyl-C(O), C2-6 branched or unbranched- S, C2-6 branched or unbranched-S(O), C2-6 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(O)m and wherein said alkynyl group is optionally independently substituted with 0-2 oxo 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 C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms.
[0185] In other 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- io cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, Ci-3 alkoxy which is optionally partially or fully halogenated and NHiC(O) or mono- or di-(C1-3 alkyl)aminocarbonyl. For example, each R1 is independently C3-10 branched or unbranched alkyl.
[0186] 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", -NR5C(O)NR5R', -NR5C(S)NR5R5, -NR5C(O)OR5 or -SO2NR'2. Alternatively, each R2 is independently -NR 5 2, -NO2, -C(O)NR 5 2, - NR5SO2R5', -NR5C(O)NR5R', -NR5C(S)NR5R5, -NR5C(O)OR5 or -SO2NR'2.
[Ol 87] In some embodiments of the first group of compounds of Formula IA, each R3 is independently
hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5- pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl Ci-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(Ci-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(Ci_3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-Ci-5 alkyl(Ru)N, carboxy-mono- or di-(C1-5 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, C1-6 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-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), C1-5 alkyl amino-S(O)2, mono- or di-(C1-3 alkyl)amino-C1-5 alkyl, R12-C1-5 alkyl, R13-C1-5 alkoxy, RH-C(O)-Ci-5 alkyl, R15-C1-5 alkyl(R16)N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, C=O, C=S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three Ci-3 alkyl groups; C1-4 alkyl or alkylene-phenyl-C(0)-Co-4 alkyl or alkylene, Cj-4 alkyl or alkylene-C(O)-C0-4 alkyl or alkylene, C1-4 alkyl or alkylene -ρhenyl-S(O)m-C0-4 alkyl or alkylene;
C1-6 alkyl or C1-6 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 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)-, 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(0)m, 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or
benzoyl or naphthoyl; and wherein
each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, and R25 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or fully halogenated; each R11 and R16 is independently hydrogen or C1-4 branched or unbranched alkyl optionally partially or folly halogenated; and
R18 is independently hydrogen or C1-4 branched or unbranched alkyl optionally independently substituted with oxo or R25.
[0188] In some such embodiments, each R3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or folly halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, foryl, tetrahydroforyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzoforanyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothioforanyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or folly halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or folly halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(Ci-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8-C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-Ci-5 alkyl(Rn)N, or carboxy-mono- or di-(C1-5 alkyl)amino. In others, each R3 is independently phenyl, pyridazinyl or pyridyl, each of which is optionally partially or folly halogenated and optionally substituted with C1-6 branched or unbranched alkyl which is optionally partially or folly halogenated, hydroxy, oxo, cyano, C1 -3 alkoxy optionally partially or folly halogenated, nitro, amino, mono- or di-(C1-3 alkyl)amino; C1-6 alkyl or C1-6 alkoxy, each optionally partially or folly halogenated or optionally substituted with R17, amino, OR18, C1-5 mono- or di-alkylamino optionally substituted with R 9; 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. [0189] In some embodiments of the first group of compounds of Formula IA,
X is C=O.
[0190] In another aspect of the invention, there are provided cytokine inhibitors 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:
G is a C3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl 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), 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, C6-10 aryl, -(C1-3 alkyl)-(C6.io aryl), -(Y)-(C0-3 alkyl)-(C6-io aryl), or -(Y)-(C0-3 alkyl)-(5- 10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5;
each Y is independently -CHZ-, -CZ2-, -CHR-, -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 uribranched C1-1O 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 oxo 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, C1-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one, or more R27; provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted Cj-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-S alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6.1o aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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)1nR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-I0 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", -NR5SO2R", -NR5C(O)NR5R', - NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-Ce-io aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl); each R3 is independently substituted or unsubstituted C6-Io ary.> substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)m, substituted or unsubstituted C3-I2 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R ;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted Q-1O alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R , R and R is independently hydrogen, substituted or unsubstituted C1-I0 alkyl, wherein the CMO alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)01R', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-Io alkynyl, substituted or unsubstituted C3-1O 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, S(O)m.
[0191] In some embodiments of the first group of compounds of Formula IB, the compound at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
[0192] In certain embodiments of the first group of compounds of Formula IB,
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, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
[0193 ] In other embodiments of the first group of compounds of Formula IB,
G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one.
I l l Alternatively, 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. In others, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomoφholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. In yet other embodiments, G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
[0194] In certain embodiments of the first group of compounds of Formula IB,
Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, piperidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or C6-10 aryl. In some such embodiments, Ar is substituted with at least one R4 or R5. In others, Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronapthyl, indanyl, indenyl, or imidazolyl. For example, Ar is indazolyl, phenyl, naphthyl, or tetrahydronaphthyl. In other embodiments, Ar is -(C1-3 alkyl)- (C6-10 aryl), -(Y)-(C0-3 alkyl)-(C6-10 aryl), Or -(Y)-(C0-3 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 C6-10 aryl is phenyl or naphthyl or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl. Alternatively, Ar is -(Cj-3 alkyl)-(C6.io aryl). [0195] In some embodiments of the first group of compounds of Formula IB, one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(O)n,. Alternatively, L is a covalent bond, a C1-C9 alkoxy, - C(O)O-, -NH- or -O-.
[0196] 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 IB Q is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, ρyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[253-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b]ρyridinyl, or imidazo[4,5-b]pyridinyl; tetrahydropyranyl, tetrahydrofuranyl, 1,3- dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C1-5 alkoxyalkyl, phenylamino; C1-6 alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R27 is C1-6 alkyl, C1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C1-3 alkyl)amino, mono- or di- (phenyl-C1-3 alkyl)amino, C1-6 alkyl-S(O)m, phenyl-d-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy. Alternatively, Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In yet other embodiments, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R27 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched C1-I0 alkyl, substituted or unsubstituted C7-20 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, S(0)m. 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, S(O)m. In yet other embodiments, Q is pyridinyl, and R27 is -NR'R' or substituted or unsubstituted Cj-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m.
[0197] In some embodiments of the first group of compounds of Formula IB each R1 is independently:
C3-Io branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-1O cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl Ci-3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O5 S(O)m, CHOH, C=O, C=S or NH;
C3-10 branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three Ci-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, C1-3 alkoxy optionally partially or folly halogenated, NH2C(O) or mono- or di-(C1-3 alkyl)aminocarboxyl; and wherein the C3-1O branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
cyano, F, Cl, Br, or I;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
silyl containing three C1-4 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), C2-6 branched or unbranched-S(O)2;
C2-6 branched or unbranched alkynyl optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(O)m and wherein said alkynyl group is optionally independently substituted with 0-2 oxo 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 C1-4 branched or unbranched alkyl amino optionally substituted by one or more halogen atoms.
[0198] In other embodiments of the first group of compounds of Formula IB, each R1 is independently C3-1O branched or unbranched alkyl optionally partially or folly halogenated, and optionally substituted with one to three C3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, foryl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, Cj-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(Cj-3 alkyl)aminocarbonyl. For example, each R1 is independently C3.10 branched or unbranched alkyl.
[0199] In certain embodiments of the first group of compounds of Formula IB, 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(0)NR'R\ -NR'C(S)NR'R', -NR5C(O)OR' or -SO2NR'2. In others, R2 is independently -NR'2, -NO2, -C(0)NR'2, -NR5SO2R", - NR5C(O)NR5R', -NR5C(S)NR5R5, -NR5C(O)OR' or -SO2NR'2.
[0200] In some embodiments of the first group of compounds of Formula IB each R3 is independently
hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5- pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, Ci-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(Ci_3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(Ci-3 alkyl)aminocarbonyl, C1-5 alkyl-C(0)-Ci-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-Ci-5 alkyl(Rn)N, carboxy-mono- or di-(C1-5 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, C1-6 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-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), C1-5 alkylamino-S(O)2, mono- or di-(Ci.3 alkyl)amino-Ci-5 alkyl, R12-C1-5 alkyl, R13-C1-5 alkoxy, R14-C(O)-C1-5 alkyl, R15-C1-5alkyl(R16)N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, C=O, C=S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups; C1-4 alkyl or alkylene-phenyl-C(0)-Co-4 alkyl or alkylene, C1-4 alkyl or alkylene-C(O)-C0-4 alkyl or alkylene, C1-4 alkyl or alkylene -phenyl-S(O)m-C0-4 alkyl or alkylene;
C1-6 alkyl or C1-6 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 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)-, 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 branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(0)m, 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, 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; and wherein
each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, R25 and R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated; each R11 and R16 is independently hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated;
R18 is independently hydrogen or Ci-4 branched or unbranched alkyl optionally independently substituted with oxo or R25.
[0201] 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-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothioraranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(Ci-3 alkyl)amino - S(O)2, R7-Ci-5 alkyl, R8-C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-C1-5 alkyl(Rn)N, or carboxy-mono- or di-(C1-5 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 C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, nitro, amino, mono- or di-(C1-3 alkyl)amino; C1-6 alkyl or C1-6 alkoxy, each optionally partially or rally halogenated or optionally substituted with R17, amino, OR18, C1-5 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)raN(R21)- For example, each R3 can be phenyl or tolyl. [0202] In certain embodiments of the first group of compounds of Formula IB,
X is C=O.
[0203] Where features or aspects of the invention are described in terms of
Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is 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.
[0204] 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 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) maybe 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 1 - Exemplary Combinations of Ar and G for the First Group of Compounds of Formulas IA and IB
Figure imgf000122_0001
Figure imgf000123_0001
TABLE 1 Continued
Figure imgf000124_0001
Figure imgf000125_0001
TABLE 2 - Exemplary Combinations of L and Q for AU Groups of Compounds of Formulas IA, IB, IC and II
Figure imgf000126_0001
Figure imgf000127_0001
[0205] There is provided in accordance with another aspect of the invention, a second group of cytokine inhibitors having Formula IA:
Figure imgf000128_0001
IA
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-10 carbocyclyl, a 5-8 membered monocyclic heterocyclyl, or a 8-11 membered bi cyclic heterocyclyl 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 -(Y)-(C0-3 alkyl)-(bicyclic aryl), or -(Y)-(C0-3 alkyl)- (bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or 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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(O)1n; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or ρhenyl-S(O)m is each optionally substituted with one or more R , and provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (Co-4 alkyl)-(5-10 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 C1-I0 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-I0 alkynyl, substituted or unsubstituted C3-1O cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N5 O, S(O)m;
each R , R4 and R is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2; -NR'2, -NO2, -S(O)mR", -NR5SO2R", -NR5C(O)NR5R', - NR'C(S)NR'R\ -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently H, substituted or unsubstituted C6-10 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, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or folly halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl, OR' orNR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R , R and R is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
each R27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(0)NR'2, -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)nJR.', substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-I0 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, S(0)m; provided however 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.
[0206] In certain embodiments of compounds of Formula IA5 the compound at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
[0207] In certain embodiments of the second group of compounds of Formula
IA, G is
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, cyclopropyl, 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, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
[0208] In other embodiments, G is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one. Alternatively, G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzoforanyl, 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. In others, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. In yet other embodiments, G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidmyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
[0209] In certain 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. In others, Y is -C(O)-, -C(N(NRC(O)OR))- or -C(N(OR))-. Alternatively, Ar is -C(O)-(bicyclic aryl) or -C(NOR)-(bicyclic aryl) and the the bicyclic aryl can be naphthyl, dihydronapthyl, tetrahydronaphthyl, indanyl, indenyl or azulenyl. In other embodiments, Ar is -(Y)- (C0-3 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.
[0210] In certain embodiments of the second 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(0)m. Alternatively, L is a covalent bond, a C1-Cg alkoxy, -C(O)O-, -NH- or -0-. [0211 ] In certain embodiments of the second 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]ρyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b]pyridinyl, or imidazo[4,5-b]pyridinyl; tetrahydropyranyl, tetrahydrofuranyl, 1,3- dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperazinonyl, oxazepinyl, diazepanonyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C1-5 alkoxyalkyl, phenylamino; C1-6 alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R27 is C1-6 alkyl, C1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C1-3 alkyl)amino, mono- or di- (phenyl-C1-3 alkyl)amino, C1-6 alkyl-S(O)m, phenyl-C1-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy.
[0212] In other embodiments of the second group of compounds of Formula
IA, Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In yet other embodiments, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R27 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched C1-Jo alkyl, substituted or unsubstituted C7-2O 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, S(O)m. For example, 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, S(O)n,. Alternatively, Q is pyridinyl, and R27 is -NR'R', substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)m.
[0213] In certain embodiments of the second group of compounds of Formula
IA5 each R1 is independently:
C3-1O 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or (Ii-(C1-S alkyl)aminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl Ci-3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)m, CHOH, C=O, C=S or NH;
C3-10 branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three C1-5 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, C1-3 alkoxy optionally partially or fully halogenated, NH2C(O) or mono- or Oi-(C1-3 alkyl)arninocarboxyl; and wherein the C3-1O branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
cyano, F, Cl, Br, or I;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
silyl containing three C1-4 independently branched or unbranched alkyl groups optionally partially or folly halogenated;
C2-6 branched or unbranched alkyl-C(O), C2-6 branched or unbranched- S, C2-6 branched or unbranched-S(O), C2-6 branched or unbranched-S(O)2;
C2-6 branched or unbranched alkynyl optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(O)m 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, morphoHno, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms. Alternatively, 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, C1-6 branched or unbranched alkyl which is optionally partially or folly halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, Ci-3 alkoxy which is optionally partially or folly halogenated and NH2C(O) or mono- or di-(Ci-3 alkyl)aminocarbonyl. For example, n each R1 is independently C3-10 branched or unbranched alkyl. [0214] In certain embodiments of the second 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)mR", -NR5SO2R", -NR5C(O)NR5R', -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2. Alternatively, R2 is independently -NR'2, -NO2, -C(O)NR'2, -NR5SO2R'5, -NR'C(0)NR'R', -NR5C(S)NR5R5, -NR5C(O)OR5 or ~SO2NR'2.
[0215] In certain embodiments of the second group of compounds of Formula
IA, each R3 is independently
hydrogen or phenyl, naphthyl, or heterocyelyl, 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-S alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(Ci_3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- Ci-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-C1-5 alkyl(Rπ)N, carboxy-mono- or di-(C1-5 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, cyclopentanothiopliene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclic ring is optionally, independently substituted with 1 to 3 groups selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyano, 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 (Ji-(C1-3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), C1-5 alkylamino-S(O)2, mono- or di-(d.3 alkyl)amino-C1-5 alkyl, R12-C1-5 alkyl, RB-C1-5 alkoxy, R14-C(O)-C1-5 alkyl, R15-Ci-5alkyl(R16)N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, 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 C1-3 alkyl groups;
C1-4 alkyl or alkylene-phenyl-C(O)-C0-4 alkyl or alkylene, C1-4 alkyl or alkylene-C(0)-Co-4 alkyl or alkylene, C1-4 alkyl or alkylene -phenyl-S(0)m-Co-4 alkyl or alkylene;
C1-6 alkyl or C1-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, or C1-S mono- or di-alkylamino optionally substituted with R19; cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, which are optionally partially or folly 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)-, 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 branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(0)m, 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or
benzoyl or naphthoyl; and wherein
each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, and R25 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
each R11 and R16 is independently hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
R18 is independently hydrogen or Ci-4 branched or unbranched alkyl optionally independently substituted with oxo or R25.
[0216] In some such embodiments of the second 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, pyrirnidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydroforyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzoforanyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothioforanyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or Ui-(C1-3 alkyl) aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-Ci-5 alkyl, mono- or di-(C1-3 alkyl)amino -Ci-5 alkyl, amino-S(O)2, di-(Ci-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8-C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-C1-5 alkyl(Ru)N, or carboxy-mono- or di-(C1-5 alkyl)amino. In other such embodiments, R3 is phenyl, pyridazinyl or pyridyl, each of which is optionally partially or folly halogenated and optionally substituted with C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or folly halogenated, nitro, amino, or mono- or di-(C1-3 alkyl)amino;C1-6 alkyl or C1-6 alkoxy, each optionally partially or folly halogenated or optionally substituted with R17, amino, OR18, C]-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)-.
[0217] In some embodiments of the second group of compounds of Formula
IA, X is C=O.
[0218] In certain embodiments of the second group of compounds of Formula
IA, Ar is -(Y)-naρhthyl-, Y is -C(O)-, or -C(=N0H)- 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(=N0H)- and G is phenyl or pyridyl. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched C1-10 alkyl and each R3 can be independently R23R24N-C(O)-,
R -C(O)-NR -, or OR . hi some such embodiments, each R is independently -NR5SO2R", -Cl, -Br, -F, -C(O)-NR'2; substituted or unsubstituted straight or branched C1-6 alkyl, -NR'2, or -OR'.
[0219] In other embodiments of the second group of compounds of Formula
IA5 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 C1-10 alkyl each R3 can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted C1-6 branched or unbranched alkyl or substituted or unsubstituted C1-4 alkoxy.
[0220] 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 again illustrates combinations of L and Q.
TABLE 3. Exemplary Combinations of Ar and G for the Second Group of Compounds of Formula IA
Figure imgf000141_0001
TABLE 3 Continued
Figure imgf000142_0001
[0221] There is provided in accordance with another aspect of the invention, a second group of compounds having Formula IB:
H
G.
SX" ^Ar-L-Q
IB
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C-(Y)- wherein G' is a C3-1O 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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0)m; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently O, 1 or 2; Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-O alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27;and provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-1o aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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 C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted Cs-8 cycloalkenyl, substituted or unsubstituted C7-20 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, S(0)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-1O aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(0)NR'2, -NR'2, -NO2, -S(O)mR", -NR5SO2R", -NR5C(O)NR5R', - NR5C(S)NR5R5, -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4
Figure imgf000144_0001
aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 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, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-g alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH5 or S(0)m;
each R6 is a Cj-6 branched or unbranched alkyl optionally partially or folly halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or folly halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl, OR' orNR'a;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or folly halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-1O alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)1nR', substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-I0 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)m. [0222] In certain embodiments of the second group of compounds of Formula
IB, the compound at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
[0223] 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, 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, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
[0224] 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, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomoφholinyl, thiazolidinyl, 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.
[0225] 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))-.
[0226] 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, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl or benzoisothiazolyl dioxide.
[0227] hi certain embodiments of the second group of compounds of Formula
IB, one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(O)m. Alternatively, L is a covalent bond, a C1-C9 alkoxy, -C(O)O-, -NH- or -O-.
[0228] In certain embodiments of the second group of compounds of Formula
IB, Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, ρyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b]pyridinyl, or irnidazo[4,5-b]pyridinyl; tetrahydropyranyl, tetrahydrofuranyl, 1,3- dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperazinonyl, oxazepinyl, diazepanonyl, 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 C1-3 alkyl or C1-5 alkoxyalkyl, phenylamino; C1-6 alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R27 is C1-6 alkyl, C1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C1-3 alkyl)amino, mono- or di- (phenyl-C1-3 alkyl)amino., Ci-6 alkyl-S(O)m, phenyl-C1-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy.
[0229] In other embodiments of compounds of Formula IB, Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In yet others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. hi some such embodiments, R27 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched C1-10 alkyl, substituted or unsubstituted C7-20 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, S(O)m. For example, 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, O5 S(O)m. Alternatively, Q is pyridinyl, and R27 is -NR'R', substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m.
[0230] In certain embodiments of the second group of compounds of Formula
IB, 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or folly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)m, CHOH, C=O, C=S or NH;
C3-1O branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three C1-5 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, Cj-6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C1-3 alkoxy optionally partially or fully halogenated, NH2C(O) or mono- or di-(C1-3 alkyl)arninocarboxyl; and wherein the C3-10 branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
cyano, F, Cl, Br, or I;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; silyl containing three C1-4 independently branched or unbranched alkyl groups optionally partially or folly halogenated;
C2-6 branched or unbranched alkyl-C(O), C2-6 branched or unbranched- S, C2-6 branched or unbranched-S(O), C2-6 branched or unbranched-S(O)2;
C2-6 branched or unbranched alkynyl optionally partially or folly halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(O)m 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms.
[0231] In other embodiments, each R1 is independently C3-10 branched or unbranched alkyl optionally partially or folly halogenated, and optionally substituted with one to three C3-1O cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, foryl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C1-6 branched or unbranched alkyl which is optionally partially or folly halogenated, C3-S cycloalkyl, C5-S cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or folly halogenated and NH2C(O) or mono- or di-(Ci-3 alkyl)aminocarbonyl. For example, each R1 is independently C3-10 branched or unbranched alkyl.
[0232] In certain embodiments of the second group of compounds of Formula
IB, each R2 is independently -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)mR", -NR5SO2R", -NR' C(O)NR' R', -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2. In others, each R2 is independently -NR'2, -NO2, -C(0)NR'2, - NR5SO2R", -NR'C(O)NR'R', -NR5C(S)NR1R5, -NR5C(O)OR' or -SO2NR'2.
[0233] In certain embodiments of the second group of compounds of Formula
IB, each R3 is independently hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5- pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(Ci-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-5 3UCyI-C(O)-C1-4 alkyl, amino-Ci-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- C1-5 alkoxy, R9-C(O)-C1-5 alkyl, Rlo-C1-5 alkyl(Rπ)N, carboxy-mono- or di-(C1.5 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyano, C 1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, heteroaryloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH2C(O), a mono- or (Ii-(C1-3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), C1-5 alkylamino-S(O)2, mono- or (Ii-(C1-3 alkyl)amino-CMalkyl, R12-Ci-5 alkyl, R13-C1-5 alkoxy, R14-C(O)-C1-5 alkyl, R15-Ci-5 alkyl(R16)N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or folly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or folly halogenated, cyano, hydroxyl C1-3 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 C1-3 alkyl groups;
C1-4 alkyl or alkylene-phenyl-C(0)-Co-4 alkyl or alkylene, C1-4 alkyl or alkylene-C(O)-C0-4 alkyl or alkylene, C1-4 alkyl or alkylene -phenyl-S(O)m-C0-4 alkyl or alkylene;
C1-S alkyl or C1-6 alkoxy, each optionally partially or folly 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 folly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or folly halogenated wherein one to three ring methylene groups are replaced independently by O, S(0)m, CHOH, C=O5 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 branched or unbranched carbon chain optionally partially or folly halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m, and wherein said alkynyl group is optionally independently substituted with 0-2 oxo 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 C1-4 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or rally halogenated;
each R11 and R16 is independently hydrogen or C1-4 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.
[0234] In some such embodiments, each R3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or folly 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Ci-5 alkyl, naphthyl Ci_5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(0)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8-Ci-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-C1-5 alkyl(Rπ)N, or carboxy-mono- or di-(C1-5 alkyl)amino. In other such embodiments, R3 is phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, nitro, amino, or mono- or di-(C1-3 alkyl)amino; C1-6 alkyl or Ci-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, C1-5 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)-.
[0235] In some embodiments of the second group of compounds of Formula
IB, X is C=O.
[0236] In certain embodiments of the second group of compounds of Formula
IB, Ar is naphthyl, G is G' -(Y)-, Y is -C(O)- or -C(=NOH)- and G' is selected from phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is naphthyl, G is G'-(Y)-, Y is -C(O)- or -C(=NOH)- and G' is phenyl or pyridinyl, substituted by one or more R1, R2 or R3. hi some such embodiments, each R is independently a substituted or unsubstituted straight or branched C1-10 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 C1-6 alkyl, -NR'2, or -OR'.
[0237] 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 fϊiranyl, substituted by one or more R1, R2 or R3. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched C1-10 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 C1-6 branched or unbranched alkyl, or substituted or unsubstituted C1-3 alkoxy.
[0238] Similar to Tables 1 and 3 above, Table 4 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 4 - Exemplary Combinations of Ar and G for the Second Group of Compounds of Formula IB
Figure imgf000156_0001
Figure imgf000157_0001
TABLE 4 Continued
Figure imgf000158_0001
Figure imgf000159_0001
[0239] There is provided in accordance with another aspect of the invention, a third group of compounds having Formula IA:
Figure imgf000160_0001
IA
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-5 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(0)or C(S);
Ar is -(Y)-(C0-3 alkyl)-(phenyl), or -(Y)-(C0-3 alkyl)-(monocyclic heteroaryl), wherein Ar is optionally substituted with one or more R4 or R5;
I SQ Y is -C(O)- , -C(N(NRC(O)OR))-, -C(N(NRR))-, -C(N(NC(O)NRR))- or -C(N(OR))-,
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 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 oxo groups and one or more of F, Cl, Br, or I;
each m is independently O, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, Cj-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, on
Ci-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R ; provided that if R4 and R5 are absent, -L-Q is not — H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-io aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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 C2-10 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1JR.", -NR5SO2R", -NR'C(0)NR'R\ - NR'C(S)NR'R\ -NR5C(O)OR' or -SO2NR'2; each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-I0 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, S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)fflN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R2 ;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-1O alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl, OR' orNR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; each R27 is independently F5 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 C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-1O alkynyl, substituted or unsubstituted C3-1O 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, S(O)m;
provided however that when Ar is phenyl and G is N-(substituted or unsubstituted ρhenyl)-pyrazolyl, the pyrazolyl is additionally substituted with one or more R1, R2 or R3.
[0240] In certain embodiments of the third group of compounds 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%.
[0241 ] In certain embodiments of the third group of compounds of Formula
IA5 G is cyclopropyl, cyclobutyl or cyclopentyl, In others, G is cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, or thienyl.
[0242] In some embodiments of the third group of compounds of Formula IA,
Ar is -(Y)-(C0-3 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)-(C0-3 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. [0243] In certain embodiments of the third 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 covalent bond, a C1-Cg alkoxy, -C(O)O-, -NH- or -0-.
[0244] In certain embodiments of the third 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]ρyrimidinyl, purinyl, pyrrolo[2,3~b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b]pyridinyl, or imidazo[4,5-b]pyridinyl; tetrahydropyranyl, tetrahydrofuranyl, 1,3- dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperazinonyl, oxazepinyl, diazepanonyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C1-5 alkoxyalkyl, phenylamino; C1-6 alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R27 is C1-6 alkyl, C1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C1-3 alkyl)amino, mono- or di- (phenyl-C1-3 alkyl)amino, Ci-6 alkyl-S(O)m, phenyl-C1-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy.
[0245] In other embodiments, Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In yet others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R27 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched C1-10 alkyl, substituted or unsubstituted C7-20 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, S(0)m. For example, 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, S(O)m. Alternatively, Q is pyridinyl, and R27 is -NR'R', substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)m.
[0246] In certain embodiments of the third group of compounds of Formula
IA5 each R1 is independently:
C3-IO branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-1O cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, Cs-S cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C]-3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)m, CHOH, C=O, C=S or NH;
C3-1O branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three C1-5 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, C1-6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C1-3 alkoxy optionally partially or fully halogenated, NH2C(O) or mono- or di-(C1-3 alkyl)aminocarboxyl; and wherein the C3-10 branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
cyano, F, Cl, Br, or I;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
silyl containing three C1-4 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), C2-6 branched or unbranched-S(O)2;
C2-6 branched or unbranched alkynyl 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 C1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, m'trile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms.
[0247] In some other embodiments of the third 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-s cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl. For example, each R1 is independently C3-10 branched or uribranched alkyl.
[0248] In certain embodiments of the third 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)mR", -NR5SO2R", -NR' C(O)NR5R', -NR'C(S)NR'R', -NR5C(O)OR' or -SO2NR'2. Alternatively, each R2 is independently -NR'2, -NO2, -C(O)NR'2, - NR5SO2R", -NR'C(0)NR'R5, -NR'C(S)NR'R', -NR5C(O)OR5 or -SO2NR'2.
[0249] m some embodiments of the third group of compounds of Formula IA, each R3 is independently
hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5- pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or Oi-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- C1-5 alkoxy, R9-C(O)-d-5 alkyl, R10-C1-5 alkyl(Rπ)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, foryl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, C1-6 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-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), C1-5 alkylamino-S(O)2, mono- or di-(Ci-3 alkyl)amino-Ci.5 alkyl, R12-C1-5 alkyl, R13-C1-5 alkoxy, R14-C(O)-C1-5 alkyl, R15-C1-5 alkyl(R16)N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or folly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or folly halogenated, cyano, hydroxyl C1-3 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 C1-3 alkyl groups; C1-4 alkyl or alkylene-phenyl-C(0)-Co-4 alkyl or alkylene, C1-4 alkyl or alkylene-C(0)-Co-4 alkyl or alkylene, C1-4 alkyl or alkylene -phenyl-S(O)m-C0-4 alkyl or alkylene;
C1-6 alkyl or C1-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, or Ci-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 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)-, 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 branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(0)m, 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or
benzoyl or naphthoyl; and wherein
each R7, R8, 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-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated; each R11 and R16 is independently hydrogen or C1-4 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.
[0250] In some such embodiments of the third 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(Ci-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl)amino -Ci-5 alkyl, amino-S(O)2, di-(Ci-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8-C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-C1-5 alkyl(Rπ)N, or carboxy-mono- or di-(C1-5 alkyl)amino. In others, R3 is phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, nitro, amino, or mono- or di-(C1-3 alkyl)amino; C1-6 alkyl or C1-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, C1-5 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)-. [0251 ] In some embodiments of the third group of compounds of Formula IA,
X is C=O.
[0252] In certain embodiments of the third group of compounds of Formula
IA, Ar is -(Y)-phenyl-, Y is -C(O)-, or -C(=NOH)- and G is selected from pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In others, Ar is -(Y)-phenyl-, Y is -C(O)-, or -C(=NOH)-, and G is pyrazolyl, thienyl or isoxazolyl. In some such embodiments, each R1 is independently a substituted or unsubstituted straight or branched C1-10 alkyl. In these embodiments, each R3 can be independently phenyl or pyridinyl, optionally substituted with one, two, or three -F, -Cl, substituted or unsubstituted C1-6 branched or unbranched alkyl or substituted or unsubstituted CM alkoxy.
[0253] Similar to Tables 1, 3 and 4 above, Table 5 illustrates combinations of
Ar and G for the third group of compounds having Formula IA. Table 2 above again illustrates combinations of L and Q that may be employed for the third group of compounds having Formula IA.
TABLE 5 - Exemplary Combinations of Ar and G for the Third Group of Compounds of Formula IA
Figure imgf000172_0001
TABLE 5 Continued
Figure imgf000173_0001
TABLE 5 Continued
Figure imgf000174_0001
TABLE 5 Continued
Figure imgf000175_0001
TABLE 5 Continued
Figure imgf000176_0001
TABLE 5 Continued
Figure imgf000177_0001
TABLE 5 Continued
Figure imgf000178_0001
Atty. Dkt. No. 060621-1907
[0254] There is provided in accordance with another aspect of the invention, a third 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:
X is C(O) or C(S);
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;
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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 carbon chain, wherein one or more methylene groups are optionally independently Atty. Dkt. No. 060621-1907
replaced by heteroatoms selected from O, NR or S(O)m; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl- S(O)nJ, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1- 6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; and provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6-1o aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R1 is independently F, Cl, Br, I* cyano, -C(O)R, -C(O)NR2, -C(O)OR, -NR'R', -OR, -SiR3, - S(O)mR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-1O cycloalkyl, substituted or unsubstituted Cs-8 cycloalkenyl, substituted or unsubstituted C7-20 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, S(O)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched Ci-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", -NR5SO2R", -NR'C(O)NR'R\ -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2; Atty. Dkt. No. 060621-1907
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-1o aryl or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted Cβ-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, S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-I2 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)1n;
each R is a Ci-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R ;
each R is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted Ci-10 alkyl, wherein the Ci-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; Atty. Dkt. No. 060621-1907
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 C1-J0 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-I0 alkynyl, substituted or unsubstituted C3,io 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, S(O)m;
provided however 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.
[0255] In certain embodiments of the third group of compounds of Formula IB, the compound at a concentration of 10 μM inhibits induced TNFa-release from a ceil by about 50% or greater than 50%.
[0256] In some embodiments of the third group of compounds of Formula IB, G' is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, imidazolyl, furanyl, thienyl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, pyrimidinyl, or pyrazinyl. In others, G' is phenyl, naphthyl, pyrazolyl, cyclopropyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
[0257] 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))-.
[0258] In some embodiments of the third group of compounds of Formula IB, Ar is phenyl, pyrazoly, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, or pyrimidinyl. Atty. Dkt. No. 060621-1907
[0259] In other embodiments of the third group of compounds of Formula IB, one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(O)m. Alternatively, L is a covalent bond, a C1-C9 alkoxy, -C(O)O-, -NH- or - O-.
[0260] In certain embodiments of the third group of compounds of Formula IB, 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-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl, or imidazo[4,5-b]pyridinyl; tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3- dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperazinonyl, oxazepinyl, diazepanonyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C1-5 alkoxyalkyl, phenylamino; Q-O alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R27 is C1-6 alkyl, C1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-Cd.3 alkyl)amino, mono- or di-^henyl-d^ alkyi)amino, C1-6 alkyl-S(O)m, phenyl-Ci-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or Ci-6 alkoxy.
[0261] In other embodiments of the third group of compounds of Formula IB, Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In yet others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. hi some such embodiments, R 7 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched C1-Jo alkyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 Atty. Dkt. No. 060621-1907
heteroatoms independently selected from N, O, S(O)m. For example, 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, S(O)1n. Alternatively, Q is pyridinyl, and R27 is -NR'R', substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)m.
[0262] In certain embodiments of the third group of compounds of Formula IB, each R1 is independently:
C3-1O branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-io cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di- (C1-3 alkyl)aminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)1n, CHOH, C=O, C=S or NH;
C3-1O branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three C1-S branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, Atty. Dkt. No. 060621-1907
imidazolyl, pyrazolyl, thienyl, fϊiryl, isoxazolyl, isothiazolyl; each of the aforementioned being optionally, partially or fully halogenated, C1-6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C1-3 alkoxy optionally partially or fully halogenated, NH2C(O) or mono- or di-(C1-3 alkyl)aminocarboxyl; and wherein the C3-10 branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
cyano, F, Cl, Br, or I;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
silyl containing three C1-4 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), C2-6 branched or unbranched-S(O)2;
C2-6 branched or unbranched alkynyl optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(O)m 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms.
[0263] In other embodiments of the third group of compounds of Formula IB, each R is independently C3-10 branched or unbranched alkyl optionally partially or fully Atty. Dkt. No. 060621-1907
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, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di- (Ci-3 alkyl)aminocarbonyl. For example, each R1 is independently C3-10 branched or unbranched alkyl.
[0264] In certain embodiments of the third group of compounds of Formula IB , each R2 is independently -OR', -OR6, -C(O)R', -C(O)OR', -C(0)NR'2, -NR'2, -NO2, -S(O)mR", -NR5SO2R", -NR1C(O)NR5R', -NR5C(S)NR5R', -NR5C(O)OR5 or -SO2NR'2. alternatively, each R2 is independently -NR'2, -NO2, -C(O)NR' 2, - NR5SO2R'5, -NR5C(O)NR5R', -NR5C(S)NR5R5, -NR5C(O)OR' or -SO2NR'2.
[0265] In certain embodiments of the third group of compounds of Formula IB,
R3 is independently
hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin- dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl Cj-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, Atty. Dkt. No. 060621-1907
Ci-5 EIlCyI-C(O)-C1-4 alkyl, amino-Ci-s alkyl, mono- or di-(C1-3 alkyl)amino -C1-S alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8-C1-5 alkoxy, R9-C(O)-d-5 alkyl, R10-C1-5 alkyl(Rn)N, carboxy-mono- or di-(C1-5 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, C1-6 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-(C1-3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), C1-5 alkylamino-S(O)2, mono- or di-(Cμ3 alkyl)amino-C1-5 alkyl, R12-C1-5 alkyl, R13-Ci-5 alkoxy, R14-C(O)-C1-5 alkyl, R15-C1-5 alkyl(R16)N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three Ci-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl Cj-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)n,, CHOH, C=O, C=S or NH; Atty. Dkt. No. 060621-1907
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl, bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-4 alkyl or alkylene-phenyl-C(0)-Co-4 alkyl or alkylene, Ci-4 alkyl or alkylene-C(0)-Co-4 alkyl or alkylene, C1-4 alkyl or alkylene -phenyl-S(O)m-C0-4 alkyl or alkylene;
C1-6 alkyl or C1-6 alkoxy, each optionally partially or folly halogenated or optionally substituted with R17, amino, OR18, or Cj.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 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)-, R22O-, R23R24NC(O)-, R26(CH2)ffiC(O)N(R21)- or R26C(O)(CH2)mN(R21)-;
C2-6 alkenyl substituted by R23R24NC(O)-;
C2-6 alkynyl branched or unbranched carbon chain optionally partially or folly halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m, 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or
benzoyl or naphthoyl; and wherein Atty. Dkt. No. 060621-1907
each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, and R25 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
each R11 and R16 is independently hydrogen or C1-4 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.
[0266] In some such embodiments of the third group of compounds of Formula
IB, 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-S alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(Cχ.3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di- (C1-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(Ci.3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8-C1-5 alkoxy, R9-C(O)-C1-5 alkyl, Rlo-C1-5 alkyl(Rn)N, or carboxy-mono- or di-(C1-5 alkyl)amino. hi other such embodiments, R3 is phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, Atty. Dkt. No. 060621-1907
oxo, cyano, C1-3 alkoxy optionally partially or folly halogenated, nitro, amino, or mono- or di-(C1-3 alkyl)amino; C1-6 alkyl or C1-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, C]-5 mono- or di-alkylamino optionally substituted with R19; R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)- or R2δC(O)(CH2)mN(R21)-.
[0267] In certain embodiments of the third group of compounds of Formula IB, X is C=O.
[0268] 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 C1-10 alkyl. Li these, each R3 can be independently R23R24N-C(O)-, R20-C(O)-NR21-, or OR22. Alternatively, each R2 is independently -NR5SO2R", -Cl, -Br, -F, -C(O)-NR'2, substituted or unsubstituted straight or branched C1-6 alkyl, -NR'2, or -OR'.
[0269] 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 C1-10 alkyl. In these, each R3 can be independently substituted or unsubstituted C1-6 alkyl, pyridinyl or phenyl, optionally substituted with one to three -F, -Cl, substituted or unsubstituted C1-6 branched or unbranched alkyl, or substituted or unsubstituted C1-3 alkoxy.
[0270] 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 again Atty. Dkt. No. 060621-1907
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 Formula IB
Figure imgf000192_0001
TABLE 6 Continued
Figure imgf000193_0001
TABLE 6 Continued
Figure imgf000194_0001
[0271] 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:
Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine-trione, triazolidin-dione, or triazine-dione;
G is a C3-1O carbocyclyl, C4-12 carbocyclylalkyl, 5-8 membered monocyclic heterocyclyl or heterocyclylalkyl, 8-11 membered bicyclic heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl rings contain 1 or more heteroatoms selected from O, N or S; and G is substituted by one or more R1, R2 or R3;
Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzothiazolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C6-Io aryl5 or -(Ci-3 alkyl)-(C6-io aryl), wherein Ar is optionally substituted with one or more R4 or R5;
L is a covalent bond or a saturated or unsaturated branched or unbranched Cwo carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(O)1n; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl-S(O)m, wherein each of the cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl-S(O)m is optionally substituted with one or more R27; and provided that if R4 and R5 are absent, -L-Q is not -H; each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6-1o aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR5 -OR, -NR'R', -SiR3, - S(O)mR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(0)NR'2, -NR'2, -NO2, -S(O)1nR", -NR5SO2R", -NR' C(O)NR5R', - NR'C(S)NR'R\ -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (C0-4 alkyl)-(5-l O member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-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, S(O)1n, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Cj-8 alkyl, C2-8 alkenyl, or C2.g alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or folly halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or folly halogenated;
R20 is substituted or unsubstituted C1-Jo alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl, OR' orNR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or folly halogenated; and
each R , R and R is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; and
each R27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NJf2, -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)1nR', substituted or unsubstituted C1-I0 alkyl, substituted or unsubstituted C2-10 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, S(O)m.
[0272] In certain embodiments of compounds of Formula IC, the compound at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%. [0273] In certain embodiments of compounds of Formula IC, G is
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, cyclopropyl, 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, tertraliydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
[0274] In other embodiments of compounds of Formula IC, G is phenyl, naphthyl, cyclopropyl, 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, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimidyl. In still others, 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, dihydropyratiyl, oxocanyl, heptacanyl, thioxanyl or dithianyl. For example, G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
[0275] In certain embodiments of compounds of Formula IC, Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C6-10 aryl. In some such embodiments, Ar is substituted with at least one R4 or R5. Alternatively, Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indanyl, indenyl or imidazolyl. For example, Ar is indazolyl, phenyl, naphthyl, or tetrahydronaphthyl.
[0276] In some embodiments of compounds of Formula IC, one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(O)m. Alternatively, L is a covalent bond, a C1-Cg alkoxy, -C(O)O-, -NH- or -O-.
[0277] In certain embodiments of compounds of Formula IC, 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]ρyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b]ρyridinyl, or imidazo[4,5-b]pyridinyl; tetrahydropyranyl, tetrahydrofuranyl, 1,3- dioxolanone, 1,3-dioxanone, 1 ,4-dioxanyl, morpholino, thiomoφholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperazinonyl, oxazepinyl, diazepanonyl, 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 C1-3 alkyl or C1-5 alkoxyalkyl, phenylamino; C1-6 alkyl-S(O)m or phenyl-S(O)m. In some such embodiments, R27 is C1-6 alkyl, C1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C1-3 alkyl)amino, mono- or di- (phenyl-C1-3 alkyl)amino, C1-6 alkyl-S(O)m, phenyl-C1-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy.
[0278] In other embodiments of compounds of Formula IC, Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In yet others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R27 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched C1-1O alkyl, substituted or unsubstituted C7-2O 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, O5 S(O)n,. For example, 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, S(O)n,. Alternatively, Q is pyridinyl, and R27 is -NR'R', substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)n,.
[0279] In certain embodiments of compounds of Formula IC, 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl, or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)1n, CHOH, C=O, C=S orNH;
C3-10 branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three C1-5 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, C1-6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C1-3 alkoxy optionally partially or fully halogenated, NH2C(O) or mono- or di-(C1-3 alkyl)aminocarboxyl; and wherein the C3-1O branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(OV,
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three Ci-3 alkyl groups;
cyano, F5 Cl, Br, I;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
silyl containing three C1-4 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), C2-6 branched or unbranched~S(O)2;
C2-6 branched or unbranched alkynyl optionally partially or folly halogenated, wherein one or more methylene groups are optionally replaced by O, NH and S(O)m 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms.
[0280] In other embodiments of compounds of Formula IC, each R1 is independently C3-10 branched or unbranched alkyl optionally partially or folly halogenated, and optionally substituted with one to three C3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, foryl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C1-6 branched or unbranched alkyl which is optionally partially or folly halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or folly halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl. For example, each R1 is independently C3-10 branched or unbranched alkyl.
[0281] In certain embodiments of compounds of Formula IC, each R2 is independently -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", -NR5SO2R", -NR5C(O)NR5R', -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2. Alternatively, each R2 is independently -NR'2, -NO2, -C(O)NR'2, -NR5SO2R", -NR5C(O)NR5R', -NR5C(S)NR5R', -NR5C(O)OR5 or -SO2NR'2.
[0282] In certain embodiments of compounds of Formula IC, each R3 is independently
hydrogen, phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or folly 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)arninocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-C^ alkyl, mono- or di-(Ci.3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-CC^ alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R1^C1-5 alkyl(Ru)N, carboxy-mono- or di-(C1-5 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, C1-6 branched or unbranched alkyl which is optionally partially or folly halogenated, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, heteroaryloxy, nitro, amino, mono- or di-(C3-3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), C1-5 alkylamino-S(O)2, mono- or (Ii-(Ci-3 alkyl)amino-C1-5 alkyl, R12-C1-5 alkyl, R13-C1-5 alkoxy, R14-C(O)-C1-5 alkyl, R15-C1-5 alkyl(R16)N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or folly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, 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 C1-3 alkyl groups;
C1-4 alkyl or alkylene-ρhenyl-C(O)-C0-4 alkyl or alkylene, C1-4 alkyl or alkylene-C(0)-Co-4 alkyl or alkylene, C1-4 alkyl or alkylene -phenyl-S(0)m-Co-4 alkyl or alkylene;
C1-6 alkyl or C1-6 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 Ci-3 alkyl groups optionally partially or fully halogenated wherein one to three ring methylene groups are replaced independently by O, S(0)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)-; Q.2-6 alkynyl 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)m, 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or
benzoyl or naphthoyl; and wherein
each R7, R8, 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-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
each R11 and R16 is independently hydrogen or C1-4 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.
[0283] In some such embodiments of compounds of Formula IC, 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(Ci-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or (Ii-(C1-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-Ci-4 alkyl, amino-Q.5 alkyl, mono- or (H-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-C1-5 alkyl(Ru)N, or carboxy-mono- or di-(C1-5 alkyl)amino. In other such embodiments R3 is phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, nitro, amino, or mono- or di-(C1-3 alkyl)amino; C1-6 alkyl or C1-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, C1-5 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)-.
[0284] 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, [1 ,2,4]triazolidine-3,5-dione-l,4-diyL or 2H-[l,2,4]triazine-3,5-dione-4,6-diyl.
[0285] 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 again 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
Figure imgf000207_0001
Figure imgf000208_0001
TABLE 7 Continued
Figure imgf000208_0002
Figure imgf000209_0001
[0286] In another aspect of the invention there are provided compounds having Formula II:
Figure imgf000210_0001
II
stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-1O carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl 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 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')-(C0-3 alkyl)-(C6-1o aryl), each being optionally substituted with one or more R4 groups;
Y' is absent or is -O- or -NH-;
L is a covalent bond or saturated or unsaturated branched or unbranched C1-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(O)n,; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently 0, 1 or 2; Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 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 Ci-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl or substituted or unsubstituted -(C0-4 alkyl)-(C6-io aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR, -NR'R', -OR, -SiR3, - S(O)1nR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-1O cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-20 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, S(0)m;
each R2 and R4 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-Io aryl5 substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(0)NR'2, -NR'2, -NO2, -S(O)mR", -NR5SO2R", -NR' C(O)NR' R', - NR'C(S)NR'R', -NR5C(O)OROr -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (Co- 4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently H, substituted or unsubstituted C6-1O 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, S(O)1n, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Cj-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(OU
R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or folly halogenated;
R20 is C1-10 branched or unbranched alkyl optionally partially or fully halogenated, phenyl, pyridinyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, C1-6 branched or unbranched alkyl optionally substituted by carbonylamino-, mono- or di-Q.3 alkyl or amino-mono or di-C1-3 alkyl; or wherein said C1-6 alkyl is optionally partially or folly halogenated and optionally interrupted by one or more O, N or S; phenyl; pyridine; mono- or di-Co-4 branched or unbranched alkyl optionally partially or folly halogenated; or alkylamino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; and
each R27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(0)NR'2, -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 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, S(0)m. [0287] In certain embodiments of compounds of Formula II, the compound at a concentration of 10 μM inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
[0288] In certain embodiments of compounds of Formula II, 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, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
[0289] In other embodiments of compounds of Formula II, G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one, or 4H- benzo[l,4]oxazine-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, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimidyl. In still others, G is 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. In certain embodiments, G is phenyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
[0290] In certain embodiments of compounds of Formula II, Ar is indazolyl, isoindolyl, pyrazolyl, imidazolyl, or imidazolonyl. In some such embodiments, Ar is substituted with at least one R4. Alternatively, Ar is indazolyl, 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 R4.
[0291] In yet other embodiments of compounds of Formula II, Ar is -(Y')-(C0-
3 alkyl)-(C6-10 aryl). In some such embodiments, Ar is substituted with at least one R4. In others, the C6-1O aryl is phenyl or naphthyl. Alternatively, Y' is -NH-.
[0292] In certain embodiments of compounds of Formula II, 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 bond, a C1-C9 alkoxy, -C(O)O-, -NH- or -O-.
[0293] In some embodiments of compounds of Formula II, Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthytpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, ρyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b]pyridinyl, or imidazo[4,5-b]ρyridinyl; tetrahydropyranyl, tetrahydrofuranyl, 1,3- dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanolol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; Ci-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C1-5 alkoxyalkyl, phenylamino; C1-6 alkyl-S(O)m or phenyl-S(O)ra . In some such embodiments, R27 is C1-6 alkyl, C1-6 alkoxy, hydroxy amino, substituted or unsubstiruted 5-10 member heterocyclyl, mono- or di-(C1-3 alkyl)amino, mono- or di- (phenyl-C1-3 alkyl)amino, C1-6 alkyl-S(O)m, phenyl-C1-3-alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or Ci-6 alkoxy.
[0294] In other embodiments of compounds of Formula II, Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or or morpholino. In yet others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In some such embodiments, R27 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched Ci-10 alkyl, substituted or unsubstiruted C7-20 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, S(O)m. For example, 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, S(O)m. Alternatively, Q is pyridinyl, and R27 is -NR'R', substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m.
[0295] In certain embodiments of compounds of Formula II, each R1 is independently
C3-10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-io 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, Ci-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently by O, S(O)n,, CHOH, C=O, C=S or NH;
C3-1O branched or unbranched alkenyl optionally partially or fully halogenated, and optionally substituted with one to three Ci-5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thienyl, furyl, isoxazolyl, isothiazolyl; each of the aforementioned being optionally, partially or fully halogenated, C1-6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxyl, cyano, C1-3 alkoxy optionally partially or folly halogenated, NH2C(O) or mono- or di-(d-3 alkyl)aminocarboxyl; the C3-IQ branched or unbranched alkenyl is optionally interrupted by one or more O, N or S(OU
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
cyano, F, Cl, Br, or I;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; silyl containing Cj-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 o unbranched-S(O), C2-6 branched or unbranched-S(O)2
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, 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, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms.
[0296] In other embodiments of compounds of Formula II, 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which is optionally partially or fully halogenated and NH2C(O) or mono- or di-(C1-3 alkyl)aminocarbonyl. For example, each R1 is independently C3-10 branched or unbranched alkyl.
[0297] In certain embodiments of compounds of Formula II, each R3 is independently
hydrogen or phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5- pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl, indazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C!-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, amino-Cϊ-5 alkyl, mono- or di-(C1-3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- C1-5 alkoxy, R9-C(O)-C1-5 alkyl, R10-C1-5 alkyl(Rπ)N, carboxy-mono- or di-(C1-5 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, C1-6 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-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, C1-4 alkyl-C(O), C1-5 alkylamino-S(O)2, mono- or di- (C1-3 alkyl)amino-C1-5 alkyl5 R12-C1-5alkyl, R13-CI-5 alkoxy, R14-C(O)-C1-5 alkyl, R15- C1-5 alkyl(R16)N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, which are optionally partially or folly halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxyl C1-3 alkyl or aryl; or an analogue of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl wherein one to three ring methylene groups are replaced independently 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 C1-3 alkyl groups;
C1-4 branched or uribranched alkyl-phenyl-C(0)-Co-4 branched or unbranched alkyl, CM branched or unbranched alkyl-C(0)-Co-4 branched or unbranched alkyl, C1-4 branched or unbranched alkyl-phenyl-S(O)m-C0-4 branched or unbranched alkyl;
Cj-6 branched or uribranched alkyl or C1-6 branched or unbranched alkoxy each is optionally partially or fully halogenated or optionally substituted with
R17;
C1-6 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(0)m, CHOH5 C-O, C=S or NH; R20C(O)N(R21)-, R22-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)- or
R26C(O)(CH2)mN(R21)-;
C2-6 alkenyl substituted by R 223jτR>2244>NC(0)-;
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 oxo groups, pyrrolidinyl, pyrrolyl, one or more C1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or
benzoyl or naphthoyl; and wherein
each R7, R8, 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-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
each R11 and R16 is independently hydrogen or C1-4 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.
[0298] In some such embodiments of compounds of Formula II, 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, hydroxy, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy, nitro, amino, mono- or di-(C1-3 alkyl)amino, phenylamino, naphthylamino, heterocyclylamino, NH2C(O), a mono- or di-(C1-3 alkyl)aminocarbonyl, Ci-5 alkyl-C(0)-Cj,4 alkyl, amino-Cj-s alkyl, mono- or di-(Ci_3 alkyl)amino -C1-5 alkyl, amino-S(O)2, di-(C1-3 alkyl)amino - S(O)2, R7-C1-5 alkyl, R8- C1-5 alkoxy, R9-C(O)-Ci-5 alkyl, R10-C1-5 alkyl(Rπ)N, or carboxy-mono- or di-(C1-5 alkyl)amino. In others, R3 is 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, oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, nitro, amino, or mono- or di-(C1-3 alkyl)arnino; C1-6 alkyl or C1-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R17, amino, OR18, C1-5 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 is phenyl or tolyl.
[0299] In certain embodiments of compounds of Formula II, X' is NR' ,
CR'=N or CR'=CR'.
[0300] 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 again 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
Figure imgf000222_0001
[0301] In yet another aspect of the invention, there are provided cytokine inhibitors comprising: a targeting moiety (ZM)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 a 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 a target protein.
[0302] In this aspect of the invention, cytokine inhibitors 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%.
[0303] 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.
[0304] 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, norbornyl, and the like. [0305] 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 cytokine inhibitor 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.
[0306] In other embodiments, the cytokine inhibitors 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.
[0307] In certain embodiments of the cytokine inhibitors of the invention, the pocket-expanding moiety is not a substituted 5-member heterocyclyl ring if the cytokine inhibitor is PEM-CHR"C(O)NH-QM, wherein R" is H or C1-6 alkyl, optionally partially or fully halogenated. In other embodiments, the targeting moiety is not a substituted tricyclic heterocyclyl ring having a nitrogen atom ring member bonded to the amide carbonyl of the targeting moiety.
[0308] Cytokine inhibitors 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 U.S. Application No. 60/656,196, filed February 24, 2005.
[0309] 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.
[0310] 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
[0311 ] The following abbreviations are used throughout the application with respect to chemical terminology:
Ac: Acetyl
AcN: Acetonitrile
AcOH: Acetic acid aq. Aqueous
BINAP: 2,2 ' -Bis(diphenylphosphino)- 1 , 1 ' -binaphthyl
Bu: Butyl
DIEA: N,N-Diisopropylethylamine
Dba: Dibenzylidene acetone
DCM: Dichloromethane
DMAP: 4-Dimethylaminopyridine
DMF: N,N-Dimethylformamide
DMSO: Dimethylsulfoxide dppb: l,4-Bis(diphenylphosphino)-butane
EDCI: 1 -(3 -Dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride
EtOAc: Ethyl acetate
EtOH: Ethanol
Hex: Hexanes
HOBt: 1 -Hydroxybenzotriazole
HPLC: High Pressure Liquid Chromatography IC50 value: The concentration of an inhibitor that causes a 50 % reduction in a measured activity.
LC-MS: Liquid chromatography- mass spectroscopy
MeOH: Methanol
NMR: Nuclear Magnetic Resonance
PyBOP: Benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate rt: Room temperature
TEA: Triethylamine
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
[0312] Compounds are named according to standard IUPAC nomenclature using the automatic naming application in Chemdraw Ultra 9.0 (Cambridgesoft, Cambridge, MA).
Example 1: Synthesis of naphthalene ketoamide derivatives A. [4-(2-Dimethylamino-pyridin-4-ylamino)-naphthalen-l-yl] Derivatives.
Figure imgf000226_0001
[0313] DimethyI-(4-nitro-l-oxy-pyridin-2-yl)-amine. 2-Chloro-4-nitro- pyridine 1 -oxide (300 mg, 1.72 mmol) was dissolved in THF (3 ml) and EtOH (3 ml). A 2M solution of dimethylamine in THF (2 ml, 3.95 mmol) was added and the reaction mixture was stirred at 9O0C for 5 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (50- 100% EtO Ac/Hex), yielding 280 mg of target material. 1H-NMR 500 MHz (CD3OD): δ 8.30 (d, J= 7 Hz, IH), 7.80 (d, J= 3 Hz, IH), 7.72 (dd, J= 3 Hz, 3 Hz, IH), 3.10 (s, 6H). [0314] N2,N2-Dimethyl-pyridine-2,4-diamine (l). The compound obtained in the previous reaction (100 mg, 0.55 mmol) was dissolved in MeOH (5 ml) and hydrogenated overnight under 1 atm H2 in the presence of a catalytic amount of Raney nickel. The solution was filtered and concentrated to yield 83 mg of target compound 1. 1H-NMR 500 MHz (CD3OD): δ 7.61 (d, J= 6 Hz, IH), 6.00 (d, J= 8 Hz, IH), 5.85 (d, J= 2 Hz5 IH), 2.99 (s, 6H).
Figure imgf000227_0001
[0315] [4-(2-Dimethylamino-pyridin-4-ylamino)-naphthalen-l-yl]-oxo- acetic acid methyl ester (2). N2,N2-Dimethyl-pyridine-2,4-diamine 1 (40 mg, 0.291 mmol) was dissolved in toluene (5 ml) and dioxane (5 ml). (4-Bromo-naphthalen-l- yl)-oxo-acetic acid methyl ester (prepared as described previously in U.S. Application No. 10/939,324) (77 mg, 0.263 mmol) was added, followed by addition OfPd(OAc)2 (10 mg), BINAP (20 mg) and CsCO3 (283 mg, 0.873 mmol). The reaction mixture was stirred at 95°C overnight and then concentrated. The residue was purified by silica gel column chromatography (30-100 % EtO Ac/Hex), yielding 120 mg of target material 2. CaIc. mass: 349.4, obs. mass: 349.5.
[0316] Other [(pyridin-4-ylamino)-naphthalen-l-yl]-oxo-acetic acid methyl ester derivatives were prepared by these methods using related starting starting materials.
Figure imgf000227_0002
[0317] General deprotection and coupling procedure. Deprotection. The methyl ester 2 (67 mg, 0.2 mmol) was dissolved in DCM and a IM solution OfBBr3 in DCM was added (0.6 ml). The reaction was stirred at 0°C for 35 min., then quenched by the addition of water. The mixture was diluted with MeOH and concentrated in vacuo to yield 40 mg deprotected material.
[0318] Coupling. The carboxylate (20 mg, 0.059 mmol) and primary amine
(G-NH2) (0.119 mmol) (prepared by the methods described in U.S. Application No. 10/939,324) were dissolved in DMF (1 ml) and PyBOP (92 mg, 0.177 mmol), HOBt (27 mg, 0.177 mmol) and DIEA (0.05 ml) were added. The reaction mixture was stirred at it for 2 hours then purified by LC-MS (10-100% AcN/H2O) yielding the target products, e.g., 3-7.
[0319] N-[5-tert-Butyl-2-methoxy-3-(propane-l -sulfonylamino)-phenyl]-2-[4-
(2-dimethylamino-pyridin-4-ylamino)-naphthalen-l -yl]-2-oxo-acetamide (3): CaIc. mass: 617.8, obs. mass: 617.9.
[0320] N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-(2- dimethylamino-pyridin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide (4): CaIc. mass: 589.7, obs. mass: 589.9.
[0321] 5-tert-Butyl-N-cyclopropyl-3-{2-[4-(2-dimethylamino-pyridin-4- ylamino)-naphthalen-l-yl]-2-oxo-acetylamino}-2-methoxy-benzamide (5): CaIc. mass: 579.7, obs. mass: 579.9.
[0322] N-(5-tert-Butyl-2-methoxy-phenyl)-2-[4-(2-dimethylamino-ρyridin-4- ylamino)-naρhthalen-l-yl]-2-oxo-acetamide (6): CaIc. mass: 496.6, obs. mass: 496.8.
[0323] 5-tert-Butyl-3- {2-[4-(2-dimethylamino-pyridin-4-ylamino)- naphthalen-l-yl]-2-oxo-acetylamino}-thiophene-2-carboxylic acid amide (7): CaIc. mass: 515.6, obs. mass: 515.8.
B. [4-(6-methylamino-pyridin-3-yl)-naphthalen-l-yl] Derivatives
Figure imgf000228_0001
[0324] 5-tert-Butyl-2-methoxy-3-nitro-benzamide (8). To a solution of 5-t- butyl-2-methoxy-3-nitrobenzoic acid (prepared as described previously in U.S. Application No. 10/939,324) (1.985 g, 7.84 mmol) in 50 ml DCM was added oxalyl chloride (3.5 ml, 39.2 mmol). After stirring at rt for 2 hours the reaction mixture was evaporated to dryness. The resulting acid chloride was dissolved in 40 ml DCM, followed by addition of DIEA (4 ml, 23.5 mmol) and a solution of 0.5 N NH3 in dioxane (47 ml, 23.5 mmol). Stirring was continued overnight at rt, and DCM was added to the reaction mixture. After aq. sodium NaHCO3 work-up, column purification was carried out on ISCO Optix (3x40 g silica gel column) using 0-40%B (10% MeOH in DCM). 1.796 g pure product 8 was isolated as a pale yellow solid.
Figure imgf000229_0001
[0325] 3-[2-(4-Bromo-naphthaIen-l-yI)-2-oxo-acetyIamino]-5-tert-butyI-2- methoxy-benzamide (9). Nitro-compound 8 (1.031 g, 4.07 mmol) was reduced with Pd/C and H2 in 40 ml MeOH at rt for 3 hours. After filtration, the MeOH was removed and the crude reduced intermediate was dissolved in 25 ml DCM. DIEA (2.6 ml, 12.21 mmol) was added. In another flask, (4-bromo-naphthalen-l-yl)-oxo-acetic acid (prepared as described previously in U.S. Application No. 10/939,324) (1.36 g, 4.88 mmol) was dissolved in 30 ml DCM and oxalyl chloride (2.2 ml, 20.35 mmol) was added, followed by addition of a catalytic amount of DMF. The reaction mixture was stirred at rt for 2 hours before evaporation of the solvent. The resulting crude acid chloride was dissolved in 15 ml DCM, and the above amine solution was added. After stirring for 40 hours at rt, DCM was added. Aqueous NaHCO3 work-up followed by ISCO column purification (3x40g silica gel column, 0-40% (50% EtOAc/DCM) gave 1.08 g of product 9 as a yellow solid.
Figure imgf000230_0001
10
[0326] (5-Bromo-pyridin-2-yl)-methyl-amine. 2,5-Dibromopyridine (6 g,
25 mmol) in 40 ml 33% MeNH2 in EtOH (325 mmol) was heated at 8O0C for 60 hours. After evaporation, the solid residue was suspended in DCM, and extracted with 1 N HCl. The combined aq. phases were neutralized with 2 N NaOH (pH=10-l 1), and then back extracted with DCM. The combined DCM phases were washed with water, and dried over sodium sulfate. Concentration afforded 4.457 g of the target bromo amine product as an off-white solid.
[0327] Methyl-(5-tributylstannanyl-pyridin-2-yl)-amine (10). A solution of the bromo amine compound obtained above (2,805 g, 15 mmol) in 150 ml dry THF under N2 atmosphere was cooled to -780C. A 1.7M solution of t-BuLi (19.4 ml, 33 mmol) in heptane was added dropwise. Lithiation was continued at the same temperature for 30 min before addition of a solution of tri-n-butyltin chloride (8.9 ml, 33 mmol) in 15 ml dry THF. The reaction was stirred at -780C for 2 hours, and then quenched by addition of 5% AcOH in THF. The temperature was allowed to rise slowly to rt. After removal of the solvent by evaporation, the residue was dissolved in EtO Ac/water, and then worked up with aq. NaHCO3. The organic phase was dried over sodium sulfate, concentrated and then subjected to ISCO column (10x40 g column) purification first with DCM (30 min), then with 1 :3 EtOAc/hex → 1 : 1 EtO Ac/hex (30 min) to give 2.44 g product 10 as a white soft solid.
Figure imgf000230_0002
[0328] 5-tert-Butyl-2-methoxy-3-{2-[4-(6-methylamino-pyridin-3-yl)- naphthalen-l-yl]-2-oxo-acetylamino}-benzamide (11). A solution of bromoketoamide 9 (1.633 g, 3.378 mmol), tin derivative 10 (1.61 g, 4.05 mmol) and Pd catalyst (490 mg, 14% mol) in 10 ml dry toluene and 30 ml dry dioxane was heated at 1100C for 24 hours under N2. After evaporation, DMF was added. The red solution was subjected to HPLC reverse phase purification after filtration (gradient: 25-95% AcNTH2O over 12 min). The fractions containing product were collected. The organic solvent was removed under reduced pressure. Solid NaHCO3 was added to the suspension followed by addition of EtOAc. The organic phase was separated, and the aqueous layer was extracted one more time with EtOAc. The combined organic phases were dried over sodium sulfate. Concentration gave 727 mg free base. The free base was then dissolved in DCM, and 2 ml of 4 N HCl in dioxane was added. The DCM was evaporated. Dry dioxane was added. The suspension was frozen and lyophilized to give the target compound 11 (755 mg HCl salt) as an orange fine powder.
C. [4-(3-ethyl-isoxazol-5-yl)-naphthalen-l-yl] Derivatives
Figure imgf000231_0001
12
[0329] 2-(4-Bromo-naphthalen-l-yl)-N-(5-tert-butyl-3- methanesulfonylaniino-2-methoxy-phenyl)-2-oxo-acetamide (12). (4-Bromo- naphthalen-l-yl)-oxo-acetic acid (prepared as described previously in U.S. Application No. 10/939,324) (5 g, 18 mmol) was added to a round bottom flask and diluted with 60 ml of DCM. The reaction was cooled to 00C and oxalyl chloride (3.1 ml, 36 mmol) was added, followed by a few catalytic drops of DMF. The reaction was allowed to stir at room temperature for 1 hour. After an hour the reaction was concentrated and dried under high vacuum. To this flask was added a solution of N- (3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (prepared as described previously in U.S. Application No. 10/939,324) (4.9 g, 18 mmol) in DCM (60 ml). The reaction mixture was cooled to O0C and TEA (7.5 ml, 54 mmol) was then added slowly to the reaction. The reaction mixture was left to stir at rt for 12 hours. The reaction was then diluted with DCM and extracted with sat. NaHCO3, 1 N HCl5 washed with brine, dried over MgSO4, filtered and concentrated to give 8.1 g (84% yield) of the target compound 12 as a yellow solid.
Figure imgf000232_0001
12 13
[0330] N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-(4- ethynyl-naphthalen-l-yl)-2-oxo-acetamide (13). 2-(4-Bromonaphthalen- 1 -yl)-iV-(5- tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxoacetamide 12 (0.30 g, 0.56 mmol) was dissolved in TEA (10 ml) in a screw-capped vessel. Ethynyltrimethylsilane (0.10 g, 1.00 mmol) was added and the solution was purged with nitrogen. Copper iodide (0.10 mmol) and Pd2(dba)3 (0.10 mmol) were added and the solution was heated at 8O0C for 28 hours. After cooling, the solution was filtered and concentrated. The residue was stirred in a 20% TFA/DCM solution for 10 min. After evaporation, the mixture was chromatographed on silica gel (DCM/EtOAc) to furnish the desired product 13 (0.15 g).
Figure imgf000232_0002
13 14
[0331 ] N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-
(3-ethyl-isoxazol-5-yl)-naphthalen-l-yl]-2-oxo-acetamide (14). 1 -Nitropropane (0.03 g, 0.40 mmol) and phenylisocyanate (0.06 g, 0.50 mmol) were dissolved in dry toluene (10 ml). To this solution, 5 drops of TEA were added with stirring. After 10 min, N-(5 -tert-butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4- ethynylnaphthalen-l-yl)-2-oxoacetamide 13 (0.10 g, 0.20 mmol) was added in one portion. After stirring this mixture at rt for 30 min, the solution was heated at 1000C for 20 h. The mixture was cooled, filtered, and purified by LC-MS to afford the isoxazole product 14 (0.01 g, 10%).
D. [4-(2-(pyrrolidin-l-yl)pyrimidin-4-yIamino)-naphthalen-l-yl] Derivatives
Figure imgf000233_0001
[0332] 5-bromo-2-chloropyrimidin-4-amine. 5-bromo-2,4- dichloropyrimidine (5 g, 22 mmol) was added to a round bottom flask and dissolved with approx. 100 ml of THF. An excess amount (25 ml) of a 30 % solution of ammonium hydroxide in water was added to the reaction. The reaction was allowed to stir at room temperature for 12 hours. The THF was evaporated and the reaction was extracted with 50 ml EtOAc. The organic layers were collected and evaporated to give the target compound in greater than 90% purity and approximately 90 % yield.
[0333] 5-bromo-2-(pyrrolidin-l-yl)pyrimidin-4-amine. The compound obtained above (3.75 g, 18.2 mmol) was dissolved in approximately 100 ml AcN. Pyrrolidine (2.58 g, 36.4 mmol) was added to the reaction. The reaction mixture was heated to 80°C and allowed to stir for 12 hours. The reaction was concentrated to give the target compound.
[0334] 2-(pyrrolidin-l-yl)pyrimidin-4-amine (15). The compound obtained above (2.5 g, 10.2 mmol) was diluted with 100 ml of a 1:1 mixture of THF and MeOH. The reaction was purged with N2 and then 2 g of a 10% Palladium on activated carbon was added to the reaction. The reaction was purged with H2 and kept under H2 for 12 hours at room temperature. The reaction was then purged with N2 and the palladium on carbon was filtered off on Celite. The reaction was concentrated to give compound 15 in 85% purity and 80% percent yield. CaIc. mass = 164.2. Obs. mass = 164.7.
Figure imgf000234_0001
[0335] N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-
(4-(2-(pyrrolidin-l-yI)pyrimidin-4-ylainino)naphthalen-l-yl)acetamide (16).
Compound 15 (2 g, 12 mmol), compound 12 (6.4 g, 12 mmol), BINAP (1.5 g, 2.4 mmol), and CsCO3 (7.8 g, 24 mmol) were added to a round bottom flask, to which 30 ml of a 1 : 1 mixture of toluene and dioxane was added. The reaction mixture was purged with N2 and Pd(II)(OAc)2 (270 mg, 1.2 mmol) was added. The reaction vessel was sealed and then heated and stirred at 80°C for 12 hours. The reaction was then concentrated and purified using HPLC to give compound 16 in 98% purity and 15% yield (1.1 g). CaIc. mass = 616.7. Obs. mass = 616.7.
E. [4-(pyridin-4-ylamino)-naphthalen-l-yl] Derivatives
Figure imgf000234_0002
[0336] N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-
(pyridin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide (17). A mixture of ketoamide 12 (50 mg, 0.09 mmol), 4-aminopyridine (13 mg, 0.14 mmol), Pd(OAc)2 (2.0 mg, 10mol%), BINAP (11 mg, 20mol%) and CsCO3 (88 mg, 0.27 mmol) in DMF/dioxane (2 ml, 1 :1) was heated at 150°C under microwave irradiation for 20 min. The mixture was filtered (Celite), the solids washed with DCM, MeOH5 the combined organics evaporated and the residue repeatedly purified via reverse phase LC-MS to give product 17 (14 mg) as a reddish solid. CaIc. mass = 546.6. Obs. mass = 546.7.
F. [4-(6-methoxy-pyridin-3-yl)-naphthaIen~l-yl] Derivatives
Figure imgf000235_0001
[0337] N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-2-[4-
(6-methoxy-pyridin-3-yl)-naphthalen-l-yl]-2-oxo-acetamide (18). A mixture of ketoamide 12 (30 mg, 0.06 mmol), 2-methoxy-5-pyridineboronic acid (10 mg, 0.07 mmol), Pd(dpρb)Cl2 (2 mg, 5mol%) and K2CO3 (25 mg, 0.18 mmol) in toluene/DMF (2 ml, 9:1) was heated at 185°C under microwave irradiation for 10 min. The mixture was filtered (Celite), the solids washed with DCM, MeOH, the combined organics evaporated and the residue purified via reverse phase HPLC (25-90% AcN in H2O) to give product 18 (13 mg) as a yellow solid. CaIc. mass = 561.7. Obs. mass = 561.6.
Example 2: Synthesis of 2-(5-tert-Butyl-2-methyl-furan-3-yl)-2-oxo-acetamide
Derivatives
Figure imgf000235_0002
[0338] 3-(5-tert-Butyl-2-methyl-furan-3-yl)-3-oxo-2-(triphenyl-15- phosphanylidene)-propionitrile. To a round bottomed flask containing 5-tert-butyl- 2-methyl-furan-3-carboxylic acid (0.346 g, 1.9 mmol) was added 50 ml DCM followed by the addition of (triphenyl-15-phosphanylidene)-acetonitrile (0.635 g, 2.0 mmol), EDCI (0.394 g, 2.0 mmol) and DMAP (0.024 g, 0.2 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours and concentrated under vacuum. The crude residue was purified by flash chromatography (0-20% EtOAc/DCM on silica gel) to yield the desired product as a white powder (0.754 g, 81%).
[0339] (5-tert-Butyl-2-methyl-furan-3-yl)-oxo-acetic acid methyl ester. In a 100 ml round bottom flask containing 3-(5-tert-butyl-2-methyl-furan~3-yl)-3-oxo- 2-(triphenyl-l5-phosphanylidene)-propionitrile (1.0 g, 2.2 mmol) was added 15 ml DCM and 50 ml MeOH. The starting material was allowed to fully dissolve in the solvent mixture, after which dimethyl dioxirane (150 ml, 0.1 M in acetone) was added to the reaction. The resulting solution was allowed to stir at rt for 30 min, after which, the reaction mixture was concentrated under vacuum and the crude material purified by flash chromatography (0-20% EtOAc/DCM on silica gel) to afford the desired keto-ester as a white solid (0.449 g, 92%).
[0340] N-(4-Bromo-naphthalen-l-yl)-2-(5-tert-butyl-2-methyl-furan-3-yl)-
2-oxo-acetamide (19). To (5-tert-butyl-2-methyl-furan-3-yl)-oxo-acetic acid methyl ester: (0.52 g, 2.3 mmol) in a 40 ml scintillation vial was added 2.5 ml THF and 2.5 ml 1 N LiOH. The reaction was heated at 5O0C for 1 hr after which, the reaction mixture was concentrated under vacuum and the crude residue was diluted with 5 ml IN HCl. The reaction slurry was then extracted with DCM (3 x 25 ml) and the combined organic layers were washed with brine (10 ml) and dried over MgSO4. The resulting solution was concentrated under vacuum to afford the desired acid. The neat acid was then dissolved in a minimal amount of DCM ~2 ml and oxalyl chloride (5 ml) was added followed by the addition of one drop of DMF. The suspension was stirred at rt for lhr, and concentrated under vacuum. The resulting solid was dissolved in EtOAc (10 ml) and added to 4-bromo-naphthalen-l-ylamine (0.511 g, 2.3 mmol) dissolved in EtOAc (10 ml)/50% NaHCO3 (10 ml) and stirred lhr at rt. The mixture was diluted with EtOAc and washed with NaHCO3. The aqueous layer was extracted twice more with 30 ml EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed under vacuum to afford a dark brown oil. The material was purified by column chromatography (0- 100% EtOAc/DCM) yielding 0.828 g (87%) of compound 19 as a yellow solid.
Figure imgf000237_0001
[0341 ] 2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(2-morρholin-4-yl- pyrimidin-4-ylamino)-naphthalen-l-yl]-2-oxo-acetamide (20). To N-(4-Bromo- naphthalen-l-yl)-2-(5-tert-butyl-2-methyl-furan-3-yl)-2-oxo-acetamide 19 (100 mg, 0.2 mmol) in a 40 ml scintillation vial was added 2-morpholm-4-yl-pyrimidin-4- ylamine (prepared as described before) (36 mg, 0.2 mmol), 10 ml dioxane and (tetrakis-tirphenylphosphine) palladium (20 mg, 0.04 mmol). The reaction vessel was sealed and heated to 80°C for 16 hours, after which, the resulting mixture was concentrated under vacuum. The dark brown residue was taken up in DCM (20 ml) and washed with saturated NaHCO3 (25 ml). The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to afford crude product (dark brown oil). This oil was further purified by flash chromatography (Silica gel 0- 100% EtAc/DCM) to afford 436 mg (36%) of product 20. (CaIc. mass = 513, obs. mass = 514).
[0342] The following compounds were synthesized by essentially the same methods:
[0343] 2-(5-tert-Butyl-2-methyl-furan-3-yl)-N-[4-(2-chloro-ρyrimidin-4- ylamino)-naphthalen-l-yl]-2-oxo-acetamide (21) (calc. mass = 463, obs. mass = 464),
[0344] 2-(5-tert-Butyl-2-methyl-furan-3-yl)-2-oxo-N-[4-(pyrimidin-4- ylamino)naphthalen-l-yl]-acetamide (22) (calc, mass = 428, obs. mass= 429),
[0345] 2-(5-tert-Butyl-2-methyl-furan-3-yl)-2-oxo-N-[4-(ρyrimidin-2- ylamino)-naphthalen-l-yl]-acetamide (23) (calc. mass = 428, obs. mass = 429). Example 3: Inhibition of TNFa production in THP cells
[0346] 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) are 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/L glucose and 0.05 mM 2-mercaptoethanol as suggested by ATCC. For the assay the cells and compounds are diluted in the media above having 1% fetal bovine serum (assay media). Test compound stocks in DMSO are diluted into assay media to 6x the final assay concentration, with a final DMSO concentration of maximally 0.3% in the assay. THP-I cells are plated at lX105/well in 96 well tissue culture plates. Diluted compounds (or DMSO control) are 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 are then incubated 18-20 hours at 37°C/5% CO2. The assay is terminated by centrifuging the plates for 10 min at room temperature. Supernatants are removed to clean culture plates and aliquots are removed for analysis for TNFa by a commercially available ELISA kit (R&D Systems #DY210, Minneapolis, MN). Data is 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 causes a 50% decrease in the maximal TNFa production.
Example 4: Anti-Proliferation Assay
[0347] Human non-small cell lung carcinoma cells A549 (ATCC# CCL-185), are grown at 37°C +/- 0.5°C 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 1Ox 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 +/-0.5°C with 5% CO2. Twenty microliters of 20% Alamar Blue warmed to 37°C +/- 0.5°C is added to each assay well following the incubation period. Alamar Blue metabolism is quantified by the amount of fluorescence intensity 3.5-5.0 hours after addition. Quantification, using an LJL Analyst AD reader (LJL Biosystems), is taken in the middle of the well with high attenuation, a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 575 nm. For some experiments, quantification is performed using a Wallac 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.
[0348] The percent inhibition (% I) for each well is calculated using the following formula:
% I=[(avg. untreated wells-treated well)/(avg. untreated wells)] x 100
[0349] 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.
[0350] 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, Ml 4 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.
[0351] 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.
Example 5: In vivo bone cancer models.
[0352] Method A. Experiments are performed on 39 adult male C3H mice
(The Jackson Laboratory, Bar Harbor, Maine), weighing 18-20 g. After induction of general anesthesia with sodium pentobarbital (50 mg/kg, i.p.), an arthrotomy is performed exposing the condyles of the distal femur. HBSS (Sigma, St. Louis, MO; sham, n = 8) or medium containing 105 osteolytic murine sarcoma cells (20 μl, NCTC 2472; American Type Culture Collection, Rockville, MD; tumor, n = 16) is injected into the intramedullary space of the mouse femur and the injection site sealed with dental amalgam.
[0353] Method B. The experiments use 36 adult male C3H/HeJmice
(Jackson Laboratories, Bar Harbor, Maine), 20-25 g in body weight. The mice are housed in accordance with National Institutes of Health guidelines in a vivarium maintained at 22°C with a 12-hour alternating light-dark cycle, and are given food and water ad libitum. After induction of general anesthesia with sodium pentobarbital (a dose of 50mg/kg, at a concentration of 5 mg/ml, injected intraperitoneally), a superficial incision is made in the skin overlying the patella, using Mora scissors .The patellar ligament is then cut, exposing the condyles of the distal femur. A 30-gauge needle is inserted at the level of the intercondylar notch and into the medullary canal to create an initial core pathway. After the initial core is made, a 29-gauge needle is used to make the final pathway into the bone. A 0.5-mm depression is then made using a halfround bur in a pneumatic dental high speed handpiece, to serve as mechanical retention for the amalgam plug. Then, 20 μL α-minimum essential media (Sigma; sham injection; n = 12) or 20 μL media containing 1 x 105 2472 osteolytic sarcoma cells (American Type Culture Collection, Rockville, Maryland; sarcoma injection; n = 24) is injected using a 29-gauge needle and a 0.25 cc syringe. To prevent leakage of cells outside the bone, the injection site is closed with dental grade amalgam, followed by copious irrigation with filtered water. Wound closure is achieved using autowound clips (Becton Dickinson, San Jose, California). Wound clips are removed at day 5 to prevent interference with behavioral testing.
[0354] For both methods above, cancer cells are introduced on day 0 of the protocol and compound/vehicle dosing is started the same day. After 14 days, cancer progression is evaluated by measurement of bone mineral density using DEXA (dual energy X-ray absorptiometry), measurement of bone loss by Faxitron (solid-state X- ray), histology, histomorphometry (essentially quantitative measurements of bone erosion and tumor progression), or osteoclast staining.
[0355] Alternatively, the animals can be monitored for metastatic growths or metastasis by MRI or other types of scanning or for mortality.
[0356] Other cancer cell lines can also be used, in particular, prostate cancer cells or breast cancer cells. These cells are introduced directly into the bone as above and serve as a model for establishment and growth of metastatic tumors.
Example 6: Xenograft cancer models
[0357] Human cancer cell lines are injected into athymic nude mice. For cells maintained in vitro, tumors are generated by injecting precisely determined numbers of cells into mice. For tumors which are best propagated in vivo, tumor fragments from donor mice are implanted into small numbers of mice for maintenance, or larger numbers of mice for study initiation. A typical efficacy study design involves administering one or more drugs of unknown efficacy to tumor-bearing mice. Additionally, reference chemotherapeutic agents (positive control) and negative controls are similarly administered and maintained. Routes of administration can include subcutaneous (SC), intraperitoneal (IP), intravenous (IV), intramuscular (IM) and oral (PO). Tumor measurements and body weights are taken over the course of the study and morbidity and mortality are recorded. Necropsy, histopathology, bacteriology, parasitology, serology and PCR can also be performed to enhance understanding of disease and drug action.
[0358] Some of the typical human cancer cell lines that can be used in the above xenograft models are: the MDA MB-231, MCF7, MDA-MB-435, and T-47D cell lines for breast cancer; the KM 12, HCT- 15, COLO 205, and HT29 cell lines for colon cancer; the NCI-H460 and A549 cell lines for lung cancer; the CRW22, LNCAP, PCC-3, and DU-145 cell lines for prostate cancer; the LOX-IMVI cell line for melanoma; the SK-O V-3 cell line for ovarian cancer; and the CAKI-I, A498, and SN12C cell lines for renal cancer.
Example 7: Pharmacological assays for pain assessment
[0359] A variety of animal pain models are described in Hogan, Q., Regional
Anesthesia and Pain Medicine 27(4):385-401 (2002). Examples of models are given below. The most commonly used neuropathic pain models are the Bennett, Selzer, and Chung models [Siddall, P. J. and Munglani, R., Animal Models of Pain, pp 377- 384 in Bountra, C, Munglani, R., Schmidt, W. K., eds. Pain: Current Understanding, Emerging Therapies and Novel Approaches to Drug Discovery, Marcel Dekker, Inc., New York, 2003].
A; Neuropathic pain models
[0360] Sciatic nerve ligation procedure. Nerve injury. Mice are anesthetized with a mixture of ketamine (50 mg/kg, i.m.) and medetomidine (1 mg/kg, i.m.). An incision is made just below the hip bone, parallel to the sciatic nerve. The nerve is exposed and any adhering tissue removed from the nerve. A tight ligature with 6-0 silk suture thread around one-third to one-half of the diameter of the sciatic nerve is made (12). Muscles are closed with suture thread and the wound with wound clips. The response of the mice to mechanical stimulation is tested before and up to 15 days after nerve injury. [0361 ] Spinal Nerve Ligation (SNL) (Chung model). L5/L6 SNL is performed as described by Kim and Chung (Kim, S. H. & Chung, J. M. (1992) Pain 5Q, 355-363). Animals are anesthetized with halothane. An incision is made lateral to the lumbar spine. The right L5 and L6 spinal nerves are isolated and tightly ligated distal to the dorsal root ganglion. The incision is closed, and animals are allowed to recover for 10 days. Sham-operated animals re prepared in an identical fashion except that the spinal nerves are not ligated.
[0362] Hyperalgesia model. C3H/HeJ mice receive an intratibial injection of
105 NCTC 2472 cells. Thermal hyperalgesia is seen after recovery (about 7 days) vs. vehicle-injected mice.
B: Bone cancer pain models.
[0363] Method A. Experiments are performed on 39 adult male C3 H mice
(The Jackson Laboratory, Bar Harbor, Maine), weighing 18—20 g. After induction of general anesthesia with sodium pentobarbital (50 mg/kg, i.p.), an arthrotomy is performed exposing the condyles of the distal femur. HBSS (Sigma, St. Louis, MO; sham, n = 8) or medium containing 105 osteolytic murine sarcoma cells (20 μl, NCTC 2472; American Type Culture Collection, Rockville, MD; tumor, n = 16) is injected into the intramedullary space of the mouse femur and the injection site sealed with dental amalgam."
[0364] Method B. The experiments use 36 adult male C3H/HeJmice
(Jackson Laboratories, Bar Harbor, Maine), 20-25 g in body weight. The mice are housed in accordance with National Institutes of Health guidelines in a vivarium maintained at 220C with a 12-hour alternating light-dark cycle, and are given food and water ad libitum. After induction of general anesthesia with sodium pentobarbital (a dose of 50mg/kg, at a concentration of 5 mg/ml, injected intraperitoneally), a superficial incision is made in the skin overlying the patella, using Mora scissors.The patellar ligament is then cut, exposing the condyles of the distal femur. A 30-gauge needle is inserted at the level of the intercondylar notch and into the medullary canal to create an initial core pathway. After the initial core is made, a 29-gauge needle is used to make the final pathway into the bone. A 0.5-mm depression is then made using a halfround bur in a pneumatic dental high speed handpiece, to serve as mechanical retentionfor the amalgam plug. Then, 20 μl ominimum essential media (Sigma; sham injection; n = 12) or 20 μl media containing 1 x 105 2472 osteolytic sarcoma cells (American Type Culture Collection, Rockville, Maryland; sarcoma injection; n = 24) is injected using a 29-gauge needle and a .25 cc syringe. To prevent leakage of cells outside the bone, the injection site is closed with dental grade amalgam, followed by copious irrigation with filtered water. Wound closure is achieved using autowound clips (Becton Dickinson, San Jose, California). Wound clips are removed at day 5 to prevent interference with behavioral testing.
C: Pain Measurements.
[0365] Measurement of Tactile Withdrawal Threshold (Von Frey model).
Tactile withdrawal threshold is determined as described by Chaplan et al. (Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. (1994) J. Neurosci. Methods 53, 55-63. ). Animals are acclimated for 30 min in suspended cages with wire mesh bottoms. The hindpaw is probed with calibrated von Frey filaments (Stoelting) applied perpendicularly to the plantar surface. A positive response is indicated by a sharp withdrawal of the paw. The 50% paw withdrawal threshold is determined by the nonparametric method of Dixon (Dixon, W. J. (1980) Annu. Rev. Pharmacol. Toxicol. 20, 441-462.), in which the stimulus is incrementally increased until a positive response is obtained, then decreased until a negative result is observed. The protocol is repeated until three changes in behavior are determined.
[0366] Measurement of Thermal Withdrawal Latency. The method of
Hargreaves et al. (Hargreaves, K. M., Dubner, R., Brown, F., Flores, C. & Joris, J. (1988) Pain 32, 77-88) is used. Animals re acclimated within Plexiglas enclosures on a clear glass plate maintained at 30°C. A radiant heat source (high-intensity projector lamp) is focused onto the plantar surface of the paw. When the paw is withdrawn, a motion detector halts the stimulus and a timer. A maximal cut-off of 40 sec for rats and 30 sec for mice is used to prevent tissue damage.
[0367] Formalin Test for Measurement of Persistent Pain in Rats.
Animals are injected with compound or vehicle (controls) followed by the injection of formalin into the dorsal surface of the paw. The animal is observed to determine the number of times it flinches the injected paw over a period of 60 minutes. This model allows for the evaluation of anti-nociceptive drugs in the treatment of pain [Abbott, F. et al. Pain 60:91-102 (1995)].
[0368] Hot Plate Test for Measurement of Acute Pain in Rats. Animals are injected with a selective cytokine inhibitory drug or vehicle (controls) and then placed on the hot plate one at a time. Latency to respond to the heat stimulus is measured by the amount of time it takes for the animal to lick one of its paws [Malmberg, A. and Yaksh, T., Pain 60:83-90 (1995)]. This model allows for the evaluation of anti-nociceptive drugs in the treatment of pain. Langerman et al., Pharmacol. Toxicol. Methods 34:23-27 (1995).
[0369] Tail-Flick Test for Measurement of Acute Pain in Rats. Animals are injected with compound or vehicle (controls) and then a light beam is focused on the tail. Latency to respond to the stimulus is measured by the amount of time it takes for the animal to flick its tail. This model allows for the evaluation of anti-nociceptive drugs in the treatment of pain [Langerman et al., Pharmacol. Toxicol. Methods 34:23- 27 (1995)].
[0370] Model for Topical Capsaicin-Induced Thermal Allodynia. A model particularly useful for thermal allodynia is the topical capsaicin-induced thermal allodynia model [Butelman, E. R. et al., J. of Pharmacol. Exp. Therap. 306:1106-1114 (2003]). This model is a modification of the warm water tail withdrawal model [Ko, M. C. et al., J. of Pharmacol. Exp. Therap. 289:378-385 (1999)]. Briefly, monkeys sit in a custom made chair in a temperature-controlled room (20-22°C). Their tails are shaved with standard clippers and tail withdrawal latencies are timed in 0.1 second increments up to a maximum of 20 seconds in both 38°C and 42°C water stimuli to provide a baseline. Following baseline determination, the tail is gently dried and degreased with an isopropyl alcohol pad. Approximately 15 minutes before use, capsaicin is dissolved in a vehicle composed of 70% ethanol and 30% sterile water for a final capsaicin concentration of either 0.0013 or 0.004 M. The solution (0.3 mL) is slowly injected onto a gauze patch, saturating the patch and avoiding overflow. Within 30 seconds of the capsaicin solution being added to the patch, capsaicin patch is fastened to the tail with tape. After 15 minutes, the patch is removed and tail withdrawal testing in both 38°C and 420C water stimuli is performed as described above. Allodynia is detected as a decrease in tail withdrawal latency compared to the baseline measurements. To determine the ability of a compound to decrease allodynia, a single dose of the compound is administered prior to (e.g., 15 minutes prior, 30 minutes prior, 60 minutes prior or 90 minutes prior) the application of the capsaicin patch. Alternatively, the allodynia reversal properties of a compound can be determined by administering a single dose of the compound after application of the capsaicin patch (e.g., immediately after, 30 minutes after, 60 minutes after or 90 minutes after).
[0371] Other methods: Hyperalgesia measurements can use the same two readouts as above (thermal withdrawal latencies and tactile thresholds). Other methods include observations of spontaneous guarding behaviour, rotorod testing, weigh-bearing on limbs, etc.
[0372] 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.
Example 8
[0373] Table 9 lists compounds of the invention prepared using the methods of Examples 1-2 or methods previously disclosed. Each compound was analyzed by LC-MS and displayed the expected molecular ion. Each of the compounds in Table 9 was tested in the TNFa ELISA assay (Example 3) and found to have activity therein, with some compounds having IC50S below 10 μM in this assay.
TABLE 9
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
[0374] 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.
[0375] 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 compound selected from
N-(5-tert-butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4-(2-(5-methoxy- 1 H- 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-l-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)naplithalen-l-yl)-2-oxoacetamide; N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-(4-(2- (dimethylamino)pyridin-4-ylamino)naphthalen- 1 -yl)-2-oxoacetamide; 5-tert-butyl-N-cyclopropyl-3-(2-(4-(2-(dimethylamino)pyridin-4-ylamino)naphthalen- l-yl)-2-oxoacetamido)-2-methoxybenzamide;
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)naphthalen- 1 - yl)-2-oxoacetamide;
5-tert-butyl-2-methoxy-3 -(2-(4-(6-(methylamino)pyridin-3 -yl)naphthalen- 1 -yl)-2- oxoacetamido)benzamide;
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-niethoxy-3-(2-(4-(6-(methylamino)ρyridm-3- yl)naphthalen- 1 -yl)-2-oxoacetamido)benzamide; (S)-N-(5-tert-butyl-2-methoxy-3-(ρropylsulfonamido)phenyl)-2-(4-(2,3- dihydroxyproρoxy)naphthalen- 1 -yl)-2-oxoacetamide;
2-(5-tert-butyl-2-methylforan-3-yl)-N-(4-(2-chloropyrimidin-4-ylamino)naphthalen-l- yl)-2-oxoacetamide;
2-(5-tert-butyl-2-methylfuran-3-yl)-2-oxo-N-(4-(pyrimidin-4-ylainino)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)naphtlialen-l- yl)acetamide;
2-(5-tert-butyl-2-methylfuran-3-yl)-N-(4-(2-morpholinopyrimidin-4- yloxy)naphthalen-l-yl)-2-oxoacetamide;
2-(5-tert-butyl-2-methylfuran-3-yl)-N-(4-(2-morpholinopyrimidin-4- ylamino)naphthalen-l-yl)-2-oxoacetamide;
2-(5-tert-butyl-3 -methylfuran-2-yl)-N-(4-(2-morpholinoethoxy)naphthalen- 1 -yl)-2- oxoacetamide;
2-(5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-yl)-N-(4-(2- morpholinoethoxy)naphthalen- 1 -yl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(2-(pyrrolidin-
1 -yl)pyrimidin-4-ylamino)naphthalen- 1 -yl)acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)ρb.enyl)-2-(4-(4- morpholinophenyl)naphthalen- 1 -yl)-2-oxoacetamide;
N-(5 -tert-butyl-2-methoxy-3 -(methylsulfonamido)phenyl)-2-(4-(6-πietlioxyρyridin-3 - yl)naphthalen- 1 -yl)-2-oxoacetamide;
2-(4-(2-aminopyrimidin-4-ylainino)naphthalen- 1 -yl)-N-(5 -tert-butyl-2-methoxy-3 -
(methylsulfonamido)ρhenyl)-2-oxoacetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyrimidin-4- ylaniino)naphthalen- 1 -yl)acetamide;
N-(5-tert-butyl-2-methoxy-3-(methylsulfonamido)phenyl)-2-oxo-2-(4-(pyridin-4- ylamino)naphthalen- 1 -yl)acetamide; or a pharmaceutically acceptable salt, solvate, tautotner, or prodrug thereof. 2. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
3. A method of treating a disorder mediated by cytokines which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.
4. The method according to claim 3, wherein the cytokine- mediated disorder is rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute pain, chronic pain, stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, atherosclerosis, allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection, respiratory tract inflammation, psoriasis, eczema, atopic dermatitis, contact dermatitis, acne, Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis or other demyelinating diseases, viral meningitis, bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF syndrome, MELAS syndrome, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, epilepsy, diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, obesity, anorexia nervosa, bulimia nervosa, bone resorption diseases, sepsis, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman's disease, or drug resistance.
5. The method of claim 4, wherein the cancer is breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, or follicular lymphoma.
6. The method of claim 4, wherein the non-articular inflammatory condition is intervertebral disk syndrome conditions, bursitis, tendonitis, tenosynovitis, or fibromyalgic syndrome.
7. The method of claim 4, wherein the cardiac failure is heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary artery bypass.
8. The method of claim 4, wherein the disorder related to fibrinolysis is acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation, clot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial or venous cannulae, cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leukopenia or thrombocytopenia.
9. The method of claim 4, wherein the acute or chronic pain is or is associated with neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension or cluster headache, Horton's disease, varicose ulcers, neuralgias, musculoskeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, vertebral pain, herniated intervertebral disc-induced sciatica, post-surgery pain, cancer-related pain, vascular pain, visceral pain, childbirth-related pain, or HIV- related pain.
10. The method of claim 3, wherein the cytokine-mediated disorder is rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute pain, or chronic pain.
11. The method of claim 3, wherein the cytokine-mediated disorder is stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, or atherosclerosis.
12. The method of claim 3, wherein the cytokine-mediated disorder is allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic ■ retinopathy, laser induced optic damage, or surgery or trauma-induced proliferative vitreoretinopathy.
13. The method of claim 3, wherein the cytokine-mediated disorder is allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, SARS infection, silicosis, or respiratory tract inflammation.
14. The method of claim 3 , wherein the cytokine-mediated disorder is psoriasis, eczema, atopic dermatitis, contact dermatitis, or acne,
15. The method of claim 3, wherein the cytokine-mediated disorder is Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis or other demyelinating diseases, viral or bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF syndrome, MELAS syndrome, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, or epilepsy.
16. The method of claim 3, wherein the cytokine-mediated disorder is a bone resorption disease selected from osteopetrosis, osteoporosis, or osteoarthritis.
17. The method of claim 3, wherein the cytokine-mediated disorder is diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, obesity, anorexia nervosa, or bulimia nervosa.
18. The method of claim 3, wherein the cytokine-mediated disorder is sepsis, HFV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman's disease, or drug resistance.
19. The method of claim 3, wherein the cytokine mediated disorder is a neutrophil-mediated disorder.
20. The method of claim 19, wherein the neutrophil-mediated disorder is bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, hemodialysis, leukopheresis, granulocyte transfusion associated syndromes, or necrotizing enterocolitis.
21. A composition comprising a compound of claim 1 and one or more ingredients A, wherein A is an NSAID, immunosuppressive drug, immunomodulatory drug, cytostatic drug, angiogenesis inhibitor, biological agent, steroid, vitamin D3 or analog thereof, retinoid, inhibitor of LFA-I or inhibitor of ICAM.
22. The composition of claim 21 further comprising a pharmaceutically acceptable carrier or excipient.
23. The composition of claim 21 wherein A is budesonide, vitamin D3, 5-ASA drugs, glucocorticoids, betamethasone, dexamethasone, methylprednisolone, prednisolone, deflazacort, methotrexate, fluocinonide, hydrocortisone, halobetasol, clobetasone, fluocinolone acetonide, fluticasone, triamcinolone acetonide, mometasone, diflucortolone, calcipotriol, tacalcitol, maxacalcitol, tacalitol, calciotropic hormones lo!,25-dihydroxyvitarnin D3, parathyroid hormone-related peptide, pimecrolimus, tacrolimus, macrolides, ascomycin, daclizumab, anti-CD4, anti-CD80, anti-CD25, peptide T, LFA3TIP, DAB38C), anti LFA3-IgCl, CTLA-4Ig, protein tyrosine kinase inhibitor, E-selectin inhibitor, alefacept, infliximab, anakinra, IL-I-RA, antibodies or receptor constructs directed against TNFa, IL-6, LFA-I, or C5, etanercept, efalizumab, ICAM-I ISIS 2302, DAB-IL-2, DAB389-IL-2, basiliximab, cyclosporine, azathioprine, hydroxyurea, 6-thioguanine, anti-TAC, hydroxychloroquine, D-penicillamine, sulfasalazine, auranofm, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, sirolimus, mycophenolate mofetil, leflunomide, cyclophosphamide; compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta-IB, alpha-interferon, adalimumab, IL-I receptor antagonist, 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, lornoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, or combinations of any two or more thereof.
24. The composition according to claim 21 wherein A is methotrexate, infliximab, leflunomide, or combinations of any two or more thereof.
25. A method of treating rheumatoid arthritis comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 21, wherein A is an NSAID, immunosuppressive drug, immunomodulatory drug, cytostatic drug, angiogenesis inhibitor, biological agent, steroid, inhibitor of LFA-I or inhibitor of ICAM-I.
26. A method of treating psoriasis comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of claim 1 and one or more ingredients A, optionally combined with conventional excipients and/or carriers, wherein A is selected from retinoids, immunosuppressive drugs, immunomodulatory drugs, biological agents, steroids, Vitamin D analogs, dithranol, or inhibitors of cell adhesion molecules; or A is a therapy selected from ultraviolet B (UVB) or psoralens ultraviolet A (PUVA), each optionally administered with retinoids, methotrexate, or the combination of cyclosporin and retinoids.
27. A method of treating Crohn's disease comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a compound of claim 1 and one or more ingredients A, optionally combined with conventional excipients or carriers, wherein A is selected from steroids, 5-ASA drugs, immunosuppressants, biological agents, or adhesion molecule inhibitors.
28. A method of treating a disorder relating to blood coagulation or fibrinolysis comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of claim 1 in combination with one or more anticoagulant or fibrinolytic agents.
29. The method according to claim 28 wherein the disorder is selected from acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation, clot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial or venous cannulae, cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leucopenia, or thrombocytopenia.
30. The method according to claim 28 wherein the disorder is caused by a clot, thrombosis or embolism.
31. A method of treating cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor, wherein the cytokine inhibitor comprises:
a targeting moiety 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 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 a target protein; an orienting moiety 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 a target protein.
32. A method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IA:
Figure imgf000261_0001
IA
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl 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), 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, C6-10 aryl, -(C1-3 alkyl)-(C6-1o aryl), -(Y)-(Co-3 alkyl)-(C6-10 aryl), or -(Y)-(C0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5;
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 C1-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0)m; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 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 C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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)1nR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)n,;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6^o aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", - NR5SO2R", -NR'C(O)NR'R\ -NR5C(S)NR5R', -NRO(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (Co-4 alkyl)-(5-l O member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 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, S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7. 20 aralkyl, substituted or unsubstituted straight or branched C1-S alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-S alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted Ci-10 alkyl, wherein the C1-Io alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
each R27 is independently F, Cl, Br, I5 cyano, -C(O)R', -C(O)NR'2, -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)mR\ substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-1O 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, S(O)m;
provided however that when Ar is -(Y)-(C6-10 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.
33. A method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IB:
H
X 7\r— L— Q
IB
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-I0 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl 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), 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, C6-io aryl, -(C1-3 alkyl)-(C6-io aryl), -(Y)-(Co-3 alkyl)-(C6-10 aryl), or -(Y)-(C0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5;
each Y is independently -CHZ-, -CZ2-, -CHR-, -C(=CHR)-3 or -CC=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-1O 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 oxo groups and one or more ofF, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)fflJ wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one, or more R27; provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl; each R' is independently hydrogen, substituted or unsubstituted C1-S alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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 C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-1O cycloalkyl, substituted or unsubstituted C5-g cycloalkenyl, substituted or unsubstituted C7- 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, S(O)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-Io aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)mR", - NR5SO2R", -NR'C(O)NR'R\ -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted Ci-g alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (Co-4 alkyl)-(5-l O member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 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, S(O)n,, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7- 2o aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(θχCH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or Ci-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted Ci-1O alkyl, wherein the Ci-1O alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
each R27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NR'* -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)mR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-I0 alkynyl, substituted or unsubstituted C3-1O 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, S(O)m.
34. A method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IA:
Figure imgf000268_0001
IA
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-1O carbocyclyl, a 5-8 membered monocyclic heterocyclyl, or a 8-11 membered bicyclic heterocyclyl 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 -(Y)-(C0-3 alkyl)-(bicyclic aryl), or -(Y)-(C0-3 alkyl)- (bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or 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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-1O carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0)m; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I; each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; and provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-S alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR, -OR5 -NR'R', -SiR3, - S(O)1nR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched Cj-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", - NR5SO2R", -NR'C(0)NR'R', -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (CQ-4 alkyl)-(5-10 member heterocyclyl); each R3 is independently H, substituted or unsubstituted C6-1O aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N3 O, S(O)m, substituted or unsubstituted C3-I2 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-Io alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)JR.', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 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 rrom N, O, S(O)m;
provided however 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.
35. A method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor of formula IB:
H
X Ar- L— Q
IB
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a G'-(Y)- wherein G' is a C3-10 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))-; L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27;and provided that if R4 and R5 are absent, -L- Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1- alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6-1o aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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)1nR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-1O alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-s cycloalkenyl, substituted or unsubstituted C7- 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, S(O)n,;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-1O aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NIf2, -NR'2, -NO2, -S(O)mR", - NR5SO2R", -NR'C(O)NR'R'5 -NR'C(S)NR'R', -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 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, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7- 20 aralkyl, substituted or unsubstituted straight or branched Cj-S alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-s alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-I0 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' orNR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R , R and R is independently hydrogen, substituted or unsubstituted C1-1O alkyl, wherein the CMO alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5^ 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
Figure imgf000274_0001
36. A method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IA:
Figure imgf000274_0002
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-5 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)-(C0-3 alkyl)-(phenyl)5 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))-,
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0)m; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl; each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5- 10 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 C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-S cycloalkenyl, substituted or unsubstituted C7. 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, S(O)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", - NR5SO2R", -NR5C(O)NR5R', -NR5C(S)NR5R5, -NR5C(O)OR5 or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-S alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-1O 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, S(0)m, substituted or unsubstituted C3-^ cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7- 20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R2 ;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0,4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S5 substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-io alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted Cs-8 cycloalkenyl, substituted or unsubstituted C7- 2Q aralkyl, substituted or unsubstituted 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)1n;
provided however 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.
37. A method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor of formula IB:
H
X Ar™L — Q
IB
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C-(Y)- wherein G' is a C3-1O 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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; and provided that if R4 and R5 are absent, - L-Q is not — H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl);
each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR, -NR'R', -OR, -SiR3, - S(O)mR, substituted or unsubstituted C1-10 alkyl, , substituted or unsubstituted C2-10 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)mR", - NR5SO2R", -NR'C(0)NR'R', -NR' C(S)NR5R', -NR5C(O)OR' or -SO2NR'2; each R" is independently substituted or unsubstituted C]-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 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, S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7- 2o aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the Co-4 alkyl is optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-β alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-1O alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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 straight or branched C1-1O alkyl, C2-io alkenyl, or C2_io alkynyl, substituted or unsubstituted C3-1O cycloalkyl, substituted or unsubstituted Cs-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, S(O)m;
provided however that when Ar-L-Q is -N-(substituted or unsubstited phenyl)-ρyrazolyl and G is phenyl, naphthyl, indane or tetrahydronaphthyl, the pyrazolyl is additionally substituted with one or more R4 Or R5.
38. A method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IC:
G—Ring— Ar- L— Q
IC stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine-trione, triazolidin-dione, or triazine-dione;
G is a C3-10 carbocyclyl, C4-12 carbocyclylalkyl, 5-8 membered monocyclic heterocyclyl or heterocyclylalkyl, 8-11 membered bicyclic heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl rings contain 1 or more heteroatoms selected from O, N or S; and G is substituted by one or more R1, R2 or R3; Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzothiazolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C6-Io aryl, or -(C1-3 alkyl)-(C6-10 aryl), wherein Ar is optionally substituted with one or more R4 or R5;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; and provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-i0 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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 C1-I0 alkyl, substituted or unsubstituted C2-I0 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)m;
each R2, R4 and R5 is independently F5 Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", - NR1SO2R", -NR'C(O)NR'R', -NR'C(S)NR'R\ -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted Cj.g alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 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, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-I2 cycloalkenyl, substituted or unsubstituted C7- 2o aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino, wherein the C0-4 alkyl is optionally partially or fully halogenated; R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R 5 R and R is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; and
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)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-io cycloalkyl, substituted or unsubstituted Cs-g 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
Figure imgf000284_0001
39. A method of treating a cancer, which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula II:
Figure imgf000284_0002
II stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof, wherein: G is a C3-Io carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl 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 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 -QT)-(C0-3 alkyl)-(C6-10 aryl), each being optionally substituted with one or more R4 groups;
Y' is absent or is -O- or -NH-;
L is a covalent bond or saturated or unsaturated branched or unbranched C1-1O 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 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 C1-6 alkyl; each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl or substituted or unsubstituted -(C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl); each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR, -NR'R', -OR, -SiR3, - S(O)mR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 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 saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0)m; each R2 and R4 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)mR", -NR5SO2R", -NR'C(O)NR'R', - NR'C(S)NR'R\ -NR5C(O)OROr -SO2NR'2; each R" is independently substituted or unsubstituted C1-S alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0- 4 alkyl)-(5-10 member heterocyclyl); each R3 is independently H, substituted or unsubstituted C6-10 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, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)1n;
R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26; 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;
R20 is C1-10 branched or unbranched alkyl optionally partially or fully halogenated, phenyl, pyridinyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and each R22, R23 and R24 is independently hydrogen, C1-6 branched or unbranched alkyl optionally substituted by carbonylamino-, mono- or di-C1-3 alkyl or amino-mono or di-C1-3 alkyl; or wherein said C1-6 alkyl is optionally partially or fully halogenated and optionally interrupted by one or more O, N or S; phenyl; pyridine; mono- or di-Co-4 branched or unbranched alkyl optionally partially or fully halogenated; or alkylamino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; and each R27 is independently F, Cl5 Br, I, cyano, -C(O)R', -C(0)NR'2, -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)mR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-I0 alkenyl, substituted or unsubstituted C2-10 alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O)m.
40. The method as in any one of claims 31-39, wherein the method further comprises treating the mammal with surgery, radiation, cryotherapy, or one or more anti-proliferative agents or a combination thereof.
41. The method of any one of claims 31-39, wherein the cancer is osteosarcoma, Kaposi's sarcoma, colorectal cancer, brain cancer, epithelial cell- derived neoplasia, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell cancer, basal cell cancer, prostate cancer, renal cell carcinoma, leukemia, lymphoma, erythroblastoma, glioblastoma, glioma, meningioma, astrocytoma, myoblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non- Hodgkins lymphoma, or follicular lymphoma.
42. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor, wherein the cytokine inhibitor comprises:
a targeting moiety 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 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 a target protein;
an orienting moiety 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 a target protein.
43. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IA:
Figure imgf000288_0001
IA
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X is C(O), C(S) or CH2;
G is a C3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bi cyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more RZ5 R2 Or R3;
Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C6-10 aryl, -(C1-3 alkyl)-(C6-10 aryl), -(Y)-(C0-3 alkyl)-(C6-10 aryl), or -(Y)-(C0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5; 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 C1-10 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, Ci-6 alkyl-SCO)m, or phenyl-S(O)m is each optionally substituted with one or more R27;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted Ci-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-1o aryl) or substituted or unsubstituted (Co-4 alkyl)-(5- 10 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 C1-10 alkyl, substituted or unsubstituted C2-1O alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-g cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(0)m; each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-1O aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'* -NR'2, -NO2, -S(O)1nR", - NR5SO2R", -NR'C(0)NR'R\ -NR'C(S)NR'R', -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-1o aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7- 20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-S alkynyl are optionally replaced by O, NH, or S(0)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino optionally partially or fully halogenated;
R is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' orNR'2; R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R , R and R is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, 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 NR, O, S(0)m;
provided however that when Ar is -(Y)-(C6-10 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-ρhenyl-2H-pyrazol-3-yl)-2-(4- chloro-phenyl)-acetamide.
44. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IB:
H
X Ar- L— Q
IB stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X is C(O), C(S) or CH2;
G is a C3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8-11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R1, R2 or R3;
Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C6-10 aryl, -(C1-3 alkyl)-(C6-10 aryl), -(Y)-(C0-3 alkyl)-(C6-10 aryl), or -(Y)-(C0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R4 or R5;
each Y is independently -CHZ-, -CZ2-, -CHR-, -C(=CHR)-, or -CC=C-CO2R)S
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 C1-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0)m; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl5 Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one, or more R27; provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (Co-4 alkyl)-(5-10 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)1nR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-1O cycloalkyl, substituted or unsubstituted C5-S cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)mR", - NR5SO2R", -NR'C(0)NR'R', -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2;
each R'5 is independently substituted or unsubstituted C1-S alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R is independently substituted or unsubstituted C6-10 aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7- 2o aralkyl, substituted or unsubstituted straight or branched C1-S alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or folly halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or folly halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m.
45. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IA:
Figure imgf000295_0001
IA
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X is C(O)or C(S);
G is a C3-I0 carbocyclyl, a 5-8 membered monocyclic heterocyclyl, or a 8-11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R1, R2 or R3;
Ar is -(Y)-(C0-3 alkyl)-(bicyclic aryl), or -(Y)-(C0-3 alkyl)- (bicyclic heteroaryl), wherein the bicyclic heteroaryl is indazolyl, isoindolyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxoazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or 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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-1O 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; and provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-S alkyl, substituted or unsubstituted (Co-4 alkyl)-(C6-1o aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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 C1-10 alkyl, substituted or unsubstituted C2-1O alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-1O cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", - NR5SO2R", -NR5C(O)NR5R', -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2; each R" is independently substituted or unsubstituted C1-S alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl);
each R is independently H, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O3 S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or folly halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
each R27 is independently F5 Cl5 Br, I5 cyano, -C(O)R', -C(O)NR'2, -C(O)OR', -OR', -NR'R', -SiR'3, - S(O)1nR', substituted or unsubstituted C1-1O alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m;
provided however 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.
46. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IB:
H
X Ar- L— Q
IB
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X is C(O) or C(S);
G is a G'-(Y)- wherein G' is a C3-10 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; 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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0)m; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27;and provided that if R4 and R5 are absent, -L- Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1- alkyl, substituted or unsubstituted (C0-4 3IkVl)-(C6-1O aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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)1nR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-1O cycloalkyl, substituted or unsubstituted Cs-8 cycloalkenyl, substituted or unsubstituted C7-2O aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", - NR5SO2R", -NR'C(0)NR'R\ -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-S alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (Co-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted Cs-12 cycloalkenyl, substituted or unsubstituted C7- 20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-S alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or folly halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino optionally partially or fully halogenated; R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' or NR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-S 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 NR, O, S(O)m.
47. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IA:
Figure imgf000301_0001
IA stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X is C(O)or C(S); G is a C3-5 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, morpliolinyl, 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;
Ar is -(Y)-(C0-3 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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, Ci-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-S alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 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)1nR, substituted or unsubstituted Ci-10 alkyl, substituted or unsubstituted C2-I0 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-I0 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m;
each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted CO-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR' 2, -NR' 2, -NO2, -S(O)1nR", - NR5SO2R", -NR'C(0)NR'R', -NR'C(S)NR'R', -NR5C(O)OR' or -SO2NR'2;
each R" is independently substituted or unsubstituted C1^ alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-Io aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-I2 cycloalkenyl, substituted or unsubstituted C7- 20 aralkyl, substituted or unsubstituted straight or branched C1-S alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH5 or S(O)m;
each R is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R 26.
each R is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl- heterocyclyl, OR' orNR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-1O alkyl, wherein the Ci-1O alkyl is optionally interrupted by one or more O5 N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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)1nR', substituted or unsubstituted C1-1O alkyl, substituted or unsubstituted C2-Io alkenyl, substituted or unsubstituted C2-1Q alkynyl group, 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 NR, O, S(O)m;
provided however 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.
48. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IB:
H
X^ Ar- L— Q IB
stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
X is C(O) or C(S);
G is a C-(Y)- wherein G' is a C3-1O 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;
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))-;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0)m; and wherein L is optionally substituted with 1 -2 oxo groups and one or more of F, Cl, Br, or I;
each m is independently 0, 1 or 2;
Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m; or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; and provided that if R4 and R5 are absent, - L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-S alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR, -NR'R', -OR, -SiR3, - S(O)mR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5.8 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(0)m; each R2, R4 and R5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched Cj-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, ~S(O)mR", - NR5SO2R", -NR'C(O)NR'R', -NR5C(S)NR5R', -NR5C(O)OR' or -SO2NR' 2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (C0-4 alkyl)-(5-l O member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-10 aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7- 2o aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a Cj-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted Co-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl- heterocyclyl, OR5 orNR'2; R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co-β alkyl-phenyl, substituted or unsubstituted C0-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
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 C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-1O 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 NR, O, S(0)m;
provided however that when Ar-L-Q is -N-(substituted or unsubstited phenyl)-pyrazolyl and G is phenyl, naphthyl, indane or tetrahydronaphthyl, the pyrazolyl is additionally substituted with one or more R4 or R5.
49. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula IC:
G— Ring— Ar — L-Q
IC stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein:
Ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine-trione, triazolidin-dione, or triazine-dione; G is a C3-IO carbocyclyl, C4-12 carbocyclylalkyl, 5-8 membered monocyclic heterocyclyl or heterocyclylalkyl, 8-11 membered bicyclic heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl rings contain 1 or more heteroatoms selected from O, N or S; and G is substituted by one or more R1, R2 or R3;
Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzothiazolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C6-10 aryl, or -(C1-3 alkyl)-(C6-1o aryl), wherein Ar is optionally substituted with one or more R4 or R5;
L is a covalent bond or a saturated or unsaturated branched or unbranched C1-10 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m is each optionally substituted with one or more R27; and provided that if R4 and R5 are absent, -L-Q is not -H;
each R is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl); each R1 is independently F, Cl5 Br5 1, cyano, -C(O)R5 -C(O)NR2, -C(O)OR5 -OR5 -NR'R', -SiR3, - S(O)1nR5 substituted or unsubstituted Cuo alkyl, substituted or unsubstituted C2-1O alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3.10 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing I5 2, 3, or 4 heteroatoms independently selected from NR5 O5 S(O)m;
each R2, R4 and R5 is independently F5 Cl5 Br5 15 cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-1O aryl, substituted or unsubstituted 5-10 member heteroaryl, - OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)mR", - NR5SO2R", -NR' C(O)NR5R', -NR'C(S)NR'R', -NR5C(O)OR5 or -SO2NR'2;
each R5' is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C0-4 alkyl-C6-10 aryl or substituted or unsubstituted (C04 alkyl)-(5-10 member heterocyclyl);
each R3 is independently substituted or unsubstituted C6-io aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(O)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7- 2o aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-5 substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(O)m;
each R6 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R26; each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C0-4 alkyl)amino optionally partially or fully halogenated;
R20 is substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl- heterocyclyl, OR' orNR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
each R22, R23 and R24 is independently hydrogen, substituted or unsubstituted C1-10 alkyl, wherein the C1-I0 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C0-6 alkyl-phenyl, substituted or unsubstituted Co-6 alkyl-heterocyclyl; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; and
each R27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NR'2, -C(O)OR', -OR', -NR5R', -SiR'3, - S(O)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, 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 NR, O, S(O)m.
50. A method of treating, modifying or managing pain, which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor of Formula II:
Figure imgf000312_0001
II stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof, wherein:
G is a C3-1O carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R , R or R ;
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 -(V)-(Co-3 alkyl)-( C6-10 aryl), each being optionally substituted with one or more R4 groups;
Y' is absent or is -O- or -NH-;
L is a covalent bond or saturated or unsaturated branched or unbranched C1-10 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 oxo 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, C1-6 alkoxy, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the cycloalkyl, aryl, heterocyclyl, Ci-6 alkoxy, C1-6 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 Ci-6 alkyl;
each R' is independently hydrogen, substituted or unsubstituted C1-8 alkyl or substituted or unsubstituted -(CQ-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0-4 alkyl)-(5-10 member heterocyclyl);
each R1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR2, -C(O)OR, -NR'R', -OR, -SiR3, - S(O)mR, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1 , 2, 3, or 4 heteroatoms independently selected from NR, O, S(0)m;
each R2 and R4 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR6, -C(O)R', -C(O)OR', -C(O)NR'2, -NR'2, -NO2, -S(O)1nR", -NR5SO2R", -NR'C(O)NR'R', - NR'C(S)NR'R', -NR'C(0)OR'or -SO2NR'2;
each R" is independently substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted (C0-4 alkyl)-(C6-10 aryl) or substituted or unsubstituted (C0- 4 alkyl)-(5-l O member heterocyclyl);
each R3 is independently H, substituted or unsubstituted C6-1O aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from NR, O, S(0)m, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-12 cycloalkenyl, substituted or unsubstituted C7-20 aralkyl, substituted or unsubstituted straight or branched C1-8 alkyl, R20C(O)N(R21)-, R22O-, R23R24NC(O)-, R26(CH2)mC(O)N(R21)-, R26C(O)(CH2)mN(R21)-, substituted or unsubstituted C2-8 alkenyl, or substituted or unsubstituted C2-8 alkynyl, wherein one or more methylene groups of the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl are optionally replaced by O, NH, or S(0)m;
R6 is a C1-6 branched or unbranched alkyl optionally partially or folly halogenated and optionally substituted with R26;
each R26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co-4 alkyl)amino optionally partially or folly halogenated;
R20 is C1-10 branched or unbranched alkyl optionally partially or folly halogenated, phenyl, pyridinyl, OR' orNR'2;
R21 is hydrogen or C1-4 branched or unbranched alkyl optionally partially or folly halogenated; and
each R22, R23 and R24 is independently hydrogen, C1-6 branched or unbranched alkyl optionally substituted by carbonylamino- mono- or di-Q.3 alkyl or amino-mono or di-Ci-3 alkyl or wherein said C1-6 alkyl is optionally partially or folly halogenated and optionally interrupted by one or more O, N or S, phenyl, pyridine, mono- or di-Co-4 branched or unbranched alkyl optionally partially or folly halogenated and alkylamino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring; and
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)1nR', substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, substituted or unsubstituted C2-10 alkynyl group, substituted or unsubstituted C3-1O 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 NR, O, S(O)m.
51. The method as in any one of claims 42-50, wherein the composition further comprises an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, α-adrenergic receptor agonist, α-adrenergic receptor antagonist, ketamine, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, NSAID, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, hyperbaric oxygen, α2δ ligand, NMDA receptor antagonist, or a combination of any two or more thereof.
PCT/US2006/006682 2005-02-24 2006-02-23 Cytokine inhibitors and their use in therapy WO2006091862A2 (en)

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US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
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