EP2139329A1 - Hétérocycles à base d'imidazo novateurs - Google Patents

Hétérocycles à base d'imidazo novateurs

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Publication number
EP2139329A1
EP2139329A1 EP08742312A EP08742312A EP2139329A1 EP 2139329 A1 EP2139329 A1 EP 2139329A1 EP 08742312 A EP08742312 A EP 08742312A EP 08742312 A EP08742312 A EP 08742312A EP 2139329 A1 EP2139329 A1 EP 2139329A1
Authority
EP
European Patent Office
Prior art keywords
compound
compounds
disease
inhibitors
sodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08742312A
Other languages
German (de)
English (en)
Other versions
EP2139329A4 (fr
Inventor
David J. Calderwood
Kristine E. Frank
Patrick Betschmann
Eric C. Breinlinger
Richard W. Dixon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Priority claimed from US11/728,919 external-priority patent/US20080242862A1/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP2139329A1 publication Critical patent/EP2139329A1/fr
Publication of EP2139329A4 publication Critical patent/EP2139329A4/fr
Withdrawn legal-status Critical Current

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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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Definitions

  • Protein phosphorylation is important for the regulation of many cellular processes including cell cycle progression and division, signal transduction, and apoptosis.
  • the phosphorylation is usually a transfer reaction of the terminal phosphate group from ATP to the protein substrate.
  • the specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine (S/T) kinases.
  • the phosphorylation reactions, and counteracting phosphatase reactions, on the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals, regulation of cellular functions, and activation or deactivation of cellular processes.
  • a cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell. Given the importance and diversity of protein kinase function, it is not surprising that alterations in phosphorylation are associated with many diseases such as cancer, diabetes, inflammation, and hypertension.
  • the present invention provides novel compounds that inhibit one or more S/T kinase or receptor or non-receptor tyrosine kinase.
  • the compounds of the present invention affect cytokine inhibitory activity.
  • Cytokine mediated diseases and cytokine inhibition, suppression and antagonism are used in the context of diseases or conditions in which excessive or unregulated production or activity of one or more cytokine occurs.
  • cytokines are tumour necrosis factor alpha (TNFoc), interleukin-1 (IL-I), interleukin-6 (EL-6) and interleukin-8 (IL-8).
  • TNFoc tumour necrosis factor alpha
  • IL-I interleukin-1
  • EL-6 interleukin-6
  • IL-8 interleukin-8
  • the p38 MAP kinase (p38, also known as CSBP or SAPK) signaling pathway has been reported to be responsible for the expression of pro-inflammatory cytokines (such as TNF, EL-I, IL-6, EL-8) that are elevated in many inflammatory and auto-immune diseases (see J. C. Lee, Nature Reviews Drug Discovery 2003, 2, 717-726 and references cited therein).
  • This pathway has been shown to be activated by cellular stressors, such as osmotic shock, UV light, free radicals, bacterial toxins, viruses, cytokines, chemokines and in response, mediates the expression of several cytokines including, but not limited to, TNF, IL-I, IL-6 and EL-8.
  • both EL-I and TNFoc are transcribed in response to p38 activation.
  • Subsequent translation and secretion of these and other cytokines initiates a local or systemic inflammatory response in adjacent tissue and through infiltration of leukocytes. While this response is a normal part of the physiological response to cellular stress, acute or chronic cellular stress leads to the excess or unregulated expression of pro-inflammatory cytokines. This, in turn, leads to tissue damage, often resulting in pain and debilitation, (see G. Panayi, N Engl J Med 2001, 344(12), 907 ; J. Smolen Nature Reviews Drug Discovery 2003, 2, 473 and references cited therein).
  • the four known isoforms of p38 MAP kinase each showing different expression levels, tissue distributions and regulation, support the concept that they are involved in the etiology of many diseases.
  • susceptible neoplasm used in present application includes human cancers such as malignant melanoma, colorectal carcinoma, gastric carcinoma, breast carcinoma and non-small cell lung carcinoma.
  • inhibition of p38 kinase may be effective in treatment of certain viral conditions such as influenza (J. Immunology, 2000, 164, 3222), rhinovirus (J. Immunology, 2000, 165, 5211) and HEV (Proc. Nat. Acad. ScL, 1998, 95, 7422).
  • influenza J. Immunology, 2000, 164, 3222
  • rhinovirus J. Immunology, 2000, 165, 5211
  • HEV HEV
  • the invention is a compound of formula (1)
  • the invention is a compound of formula (2)
  • the invention is a compound of formula (3)
  • Protein kinases are a broad and diverse class, of over 500 enzymes, that include oncogenes, growth factors receptors, signal transduction intermediates, apoptosis related kinases and cyclin dependent kinases. They are responsible for the transfer of a phosphate group to specific tyrosine, serine or threonine amino acid residues, and are broadly classified as tyrosine and Serine/Threonine kinases as a result of their substrate specificity.
  • S/T kinases are a large sub-family of protein kinases that specifically transfer a phosphate group to a terminal hydroxyl moiety of specific serine or threonine residues (Hanks et al, (1988) Science, 241: 42-52).
  • a number of S/T kinase family members are involved in inflammatory signaling, tumor growth or cellular transformation.
  • the mitogen-activated protein kinases are S/T kinases that act as intermediates within the signaling cascades of Toll like receptors (TLRs), such as TLR4, growth/survival factors, such as EGF, and death receptors, such as the TNF receptor.
  • TLRs Toll like receptors
  • MAPKs such as extracellular signal-regulated kinases (ERK1-2), p38 ⁇ , c-Jun N-terminal kinase (JNK) or MAPKAP-K2 (MK2) have been shown to transduce signaling in cells, such as monocytes/macrophages, resulting in the extracellular production of pro-inflammatory cytokines, such as TNF.
  • ERK1-2 extracellular signal-regulated kinases
  • JNK c-Jun N-terminal kinase
  • MK2 MAPKAP-K2
  • the p38 MAP kinase (p38, also known as CSBP or SAPK) signaling pathway has been reported to be responsible for the expression of pro-inflammatory cytokines (such as TNF, IL-I, IL-6, IL-8) that are elevated in many inflammatory and auto-immune diseases (see J. C. Lee, Nature Reviews Drug Discovery 2003, 2, 717-726 and references cited therein).
  • This pathway has been shown to be activated by cellular stressors, such as osmotic shock, UV light, free radicals, bacterial toxins, viruses, cytokines, chemokines and in response, mediates the expression of several cytokines including, but not limited to, TNF, IL-I, IL-6 and IL-8.
  • both IL-I and TNF ⁇ are transcribed in response to p38 activation. Subsequent translation and secretion of these and other cytokines initiates a local or systemic inflammatory response in adjacent tissue and through infiltration of leukocytes. While this response is a normal part of the physiological response to cellular stress, acute or chronic cellular stress leads to the excess or unregulated expression of pro-inflammatory cytokines. This, in turn, leads to tissue damage, often resulting in pain and debilitation, (see G. Panayi, N Engl J Med 2001, 344(12), 907 ; J. Smolen Nature Reviews Drug Discovery 2003, 2, 473 and references cited therein).
  • the four known isoforms of p38 MAP kinase (p38 ⁇ , ⁇ , ⁇ , ⁇ ) each showing different expression levels, tissue distributions and regulation, support the concept that they are involved in the etiology of inflammatory, auto-immune and other diseases.
  • PTKs Protein tyrosine kinases
  • endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas).
  • Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • RTKs Receptor Tyrosine Kinases
  • the receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254, 1990).
  • RTKs The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61 :203-212).
  • receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity and receptor trans-phosphorylation.
  • Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, differentiation, metabolic effects, and changes in the extracellular microenvironment; see Schlessinger and Ullrich, 1992, Neuron 9:1-20).
  • Non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. Over twenty-four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack and LEVlK) have been identified. The Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.
  • the invention provides a method for inhibiting p38 in a human subject suffering from a disorder in which p38 activity is detrimental, comprising administering to the human subject a compound of Formula 1, 2 or 3 such that p38 activity in the human subject is inhibited and treatment is achieved.
  • autoimmune diseases and disease associated with chronic inflammation have been linked to activation of p38 MAP kinase and overexpression or dysregulation of inflammatory cytokines.
  • the present compounds are useful in the treatment of inflammatory disorders including, but not limited to rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy and systemic lupus erythematosus.
  • COPD chronic obstructive pulmonary disease
  • the compounds of the invention are also useful in the treatment of cardiovascular disorders, such as acute myocardial infarction, acute coronary syndrome, chronic heart failure, myocardial infaction, atherosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction.
  • cardiovascular disorders such as acute myocardial infarction, acute coronary syndrome, chronic heart failure, myocardial infaction, atherosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction.
  • central nervous system disorders such as meningococcal meningitis, Alzheimer's disease and Parkinson's disease.
  • the compounds of the invention are also useful in the treatment of an ocular condition, a cancer, a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, an cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), Abetalipoprotemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failue, adenocarcinomas, aerial ectopic beats, ADDS dementia complex, alcohol-indced hepatitis, allergic conjun
  • such compounds may be useful in the treatment of disorders such as ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome (ARDS), proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity,
  • these compounds can be used as active agents against hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease)
  • cysts such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • Compounds of Formula 1 , 2 or 3 of the invention can be used alone or in combination with another therapeutic agent to treat such diseases.
  • the compounds of the invention can be used alone or in combination with an additional agent, e.g., a therapeutic agent, said additional agent being selected by the skilled artisan for its intended purpose.
  • the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the compound of the present invention.
  • the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition e.g., an agent that affects the viscosity of the composition.
  • the combinations which are to be included within this invention are those combinations useful for their intended purpose.
  • the agents set forth below are illustrative for purposes and not intended to be limited.
  • the combinations, which are part of this invention can be the compounds of the present invention and at least one additional agent selected from the lists below.
  • the combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
  • Preferred combinations are non-steroidal anti-inflammatory drug(s) also referred to as NSAIDS which include drugs like ibuprofen.
  • Other preferred combinations are corticosteroids including prednisolone; the well known side-effects of steroid use can be reduced or even eliminated by tapering the steroid dose required when treating patients in combination with the p38 inhibitors of this invention.
  • Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of Formula 1 , 2 or 3 of the invention can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-I, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF.
  • CSAIDs cytokine suppressive anti-inflammatory drug(s)
  • S/T kinase inhibitors of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).
  • cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).
  • Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists like chimeric, humanized or human TNF antibodies, HUMIRA® (US Patent 6,090,382), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFRlgG (ENBRELTM) or p55TNFRlgG (Lenercept), and also TNF ⁇ converting enzyme (TACE) inhibitors; similarly IL-I inhibitors (Interleukin-1 -converting enzyme inhibitors, IL-IRA etc.) may be effective for the same reason.
  • TNF antagonists like chimeric, humanized or human TNF antibodies, HUMIRA® (US Patent 6,090,382), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFRlgG (ENBRELTM) or p55TNFRl
  • Yet other preferred combinations are the other key players of the autoimmune response which may act parallel to, dependent on or in concert with IL- 18 function; especially preferred are IL-12 antagonists including IL-12 antibodies or soluble IL-12 receptors, or IL-12 binding proteins. It has been shown that EL- 12 and IL- 18 have overlapping but distinct functions and a combination of antagonists to both may be most effective. Yet another preferred combination are non- depleting anti-CD4 inhibitors. Yet other preferred combinations include antagonists of the co- stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.
  • a compound of Formula 1 , 2 or 3 of the invention may also be combined with agents, such as methotrexate, 6-MP, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/ hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone,
  • IL-I ⁇ converting enzyme inhibitors T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (EnbrelTM and p55TNFRIgG (Lenercept)), sEL-lRI, sIL-lRII, sIL-6R), antiinflammatory cytokines (e.g.
  • IL-4, IL-IO, IL-I l, IL- 13 and TGF ⁇ celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, su
  • Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula 1, 2 or 3 of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-I receptor antagonists; anti-IL-l ⁇ monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-I, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL- 16, EMAP-
  • IL- l ⁇ converting enzyme inhibitors include IL- l ⁇ converting enzyme inhibitors; TNFQC converting enzyme inhibitors; T-cell signalling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6- mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-lRI, sIL-lRII, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, IL-I l, IL-13 and TGF ⁇ ).
  • TNFQC converting enzyme inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6- mercaptopurines; angiotensin converting enzyme inhibitors; soluble
  • TNF antagonists for example, anti-TNF antibodies, HUMIRA® (US Patent 6,090,382), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM)) inhibitors and PDE4 inhibitors.
  • a compound of Formula 1, 2 or 3 can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5 -aminosalicylic acid; olsalazine; and agents which interfere with synthesis or action of proinflammatory cytokines such as IL-I, for example, IL- l ⁇ converting enzyme inhibitors and EL- Ira; T cell signaling inhibitors, for example, tyrosine kinase inhibitors 6-mercaptopurines; DL-I l; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; te
  • Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound of Formula 1, 2 or 3 can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon- ⁇ la (AVONEX®; Biogen); interferon- ⁇ lb (BETASERON®; Chiron/Berlex); interferon ⁇ -n3) (Interferon Sciences/Fujimoto), interferon- ⁇ (Alfa Wassermann/J&J), interferon ⁇ IA-IF (Serono/Inhale Therapeutics), Peginterferon ⁇ 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine; antibodies to or
  • a compound of Formula 1 , 2 or 3 can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CDl 9, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • cell surface molecules such as CD2, CD3, CD4, CD8, CDl 9, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • a compound of Formula 1 , 2 or 3 may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNF ⁇ or IL-I (e.g.
  • agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere
  • IRAK, NDC, IKK), DL- l ⁇ converting enzyme inhibitors TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-lRI, sIL-lRJI, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-IO, IL- 13 and TGF ⁇ ).
  • TACE inhibitors TACE inhibitors
  • T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptor
  • Formula 1, 2 or 3 can be combined to include interferon- ⁇ , for example, IFN ⁇ la and IFN ⁇ lb; Copaxone, corticosteroids, caspase inhibitors, for example inhibitors of caspase-1, EL-I inhibitors, TNF inhibitors, and antibodies to CD40 ligand and CD80.
  • interferon- ⁇ for example, IFN ⁇ la and IFN ⁇ lb
  • Copaxone corticosteroids
  • caspase inhibitors for example inhibitors of caspase-1
  • EL-I inhibitors EL-I inhibitors
  • TNF inhibitors TNF inhibitors
  • CD40 ligand and CD80 antibodies to CD40 ligand and CD80.
  • a compound of Formula 1, 2 or 3 may also be combined with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THCCBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA- 715, anti-BL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-Rl, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists
  • Non-limiting examples of therapeutic agents for angina with which a compound of Formula 1, 2 or 3 of the invention can be combined include the following: aspirin, nitroglycerin, isosorbide mononitrate, metoprolol succinate, atenolol, metoprolol tartrate, amlodipine besylate, diltiazem hydrochloride, isosorbide dinitrate, clopidogrel bisulfate, nifedipine, atorvastatin calcium, potassium chloride, furosemide, simvastatin, verapamil HCl, digoxin, propranolol hydrochloride, carvedilol, lisinopril, spironolactone, hydrochlorothiazide, enalapril maleate, nadolol, ramipril, enoxaparin sodium, heparin sodium, valsartan, sotalol hydrochloride, fenofi
  • Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a compound of Formula 1 , 2 or 3 can be combined include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, etanercept, and infliximab.
  • Non-limiting examples of therapeutic agents for asthma with which a compound of Formula 1, 2 or 3 can be combined include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hydrochloride, flunisolide/
  • Non-limiting examples of therapeutic agents for COPD with which a compound of Formula 1, 2 or 3 can be combined include the following: albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlo ⁇ heniramine/hydrocodon
  • Non-limiting examples of therapeutic agents for HCV with which a compound of Formula 1, 2 or 3 can be combined include the following: Interferon-alpha-2a, Interferon-alpha- 2b, Interferon-alpha conl, Interferon-alpha-nl, pegylated interferon-alpha-2a, pegylated interferon-alpha-2b, ribavirin, peginterferon alfa-2b + ribavirin, ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497 and any compounds that are used to treat HCV through intervention with the following targets: HCV polymerase, HCV protease, HCV helicase, and HCV IRES (internal ribosome entry site).
  • Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis with which a compound of Formula 1, 2 or 3 can be combined include the following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, gamma interferon, methylprednisolone sod succ, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone HCl, potassium chloride, triamcinolone acetonide, tacrolimus anhydrous, calcium, interferon-alpha, methotrexate, mycophenolate mofetil and interferon-gamma
  • Non-limiting examples of therapeutic agents for myocardial infarction with which a compound of Formula 1 , 2 or 3 can be combined include the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, quinapril HCl/mag carb, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirof ⁇ ban HCl m-hydrate, diltiazem hydrochloride, cap
  • Formula 1, 2 or 3 can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc/bismut
  • Non-limiting examples of therapeutic agents for psoriatic arthritis with which a compound of Formula 1 , 2 or 3 can be combined include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide
  • Non-limiting examples of therapeutic agents for restenosis with which a compound of Formula 1, 2 or 3 can be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.
  • Formula 1 , 2 or 3 can be combined include the following: hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HCl, methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine phosphate/apap, tramadol hcl/acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HCl, diclofenac sodium/miso
  • Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of Formula 1, 2 or 3 can be combined include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids, for example, prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for example Cellcept®.
  • NSAIDS for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin
  • COX2 inhibitors for example, celecoxib,
  • a compound of Formula 1, 2 or 3 may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as EL-I, for example, caspase inhibitors like IL- l ⁇ converting enzyme inhibitors and IL- Ira.
  • agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as EL-I, for example, caspase inhibitors like IL- l ⁇ converting enzyme inhibitors and IL- Ira.
  • a compound of Formula 1 , 2 or 3 may also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors; or molecules that target T cell activation molecules, for example, CTLA-4-IgG or anti-
  • a compound of Formula 1, 2 or 3 can be combined with IL-I l or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg antibody), or anti-receptor receptor antibodies, for example, anti-EL-6 receptor antibody and antibodies to B-cell surface molecules.
  • IL-I l or anti-cytokine antibodies for example, fonotolizumab (anti-IFNg antibody), or anti-receptor receptor antibodies, for example, anti-EL-6 receptor antibody and antibodies to B-cell surface molecules.
  • a compound of Formula 1, 2 or 3 may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example, anti-TNF antibodies, HUMIRA® (US Patent 6,090,382), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM)).
  • LJP 394 assay for example, anti-TNF antibodies, HUMIRA® (US Patent 6,090,382), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM)).
  • a “therapeutically effective amount” is an amount of a compound of Formula 1 , 2 or 3 or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition.
  • a therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.
  • Physiologically acceptable salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or (-)-amino acids or mixtures thereof), and the like.
  • These salts can be prepared by methods known to those skilled in the art.
  • Certain compounds of Formula 1 , 2 or 3 which have acidic substituents may exist as salts with pharmaceutically acceptable bases.
  • the present invention includes such salts. Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art.
  • Certain compounds of Formula 1 , 2 or 3 and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of Formula 1, 2 or 3 and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • Certain compounds of Formula 1, 2 or 3 may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of Formula 1, 2 or 3 and mixtures thereof.
  • Certain compounds of Formula 1, 2 or 3 may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of compounds of Formula 1 , 2 or 3 and mixtures thereof.
  • Certain compounds of Formula 1, 2 or 3 may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of Formula 1, 2 or 3 and mixtures thereof.
  • pro-drug refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • pro-drug a compound of the present invention wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial
  • Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A prodrug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • Exemplary pro-drugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., -(CH 2 )C(O)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Ci-C 4 )alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, (C 4 - C 9 )l-(alkanoyloxy)ethyl, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alk
  • exemplary pro-drugs release an alcohol of Formula 1, 2 or 3 wherein the free hydrogen of the hydroxyl substituent (e.g., R 1 contains hydroxyl) is replaced by (C r C 6 )alkanoyloxymethyl, l-((C r C 6 )alkanoyloxy)ethyl, l-methyl-l-((Ci-C 6 )alkanoyloxy)ethyl, (Q- C 6 )alkoxycarbonyloxymethyl, N-(Ci -C 6 )alkoxycarbonylamino-methyl, succinoyl, (C r Q)alkanoyl, ⁇ -amino(Ci-C 4 )alkanoyl, arylactyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl wherein said ⁇ -aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, P(O)
  • heterocyclic or “heterocyclyl”, as used herein, include non-aromatic, ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system) and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heterocyclic rings azepines, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinesyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.
  • heteroaryl as used herein, include aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • azaindole benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furans, imidazoles, imidazopyridine, indole, indolinyl, indazoles, isoindolinyl, isoxazoles, isothiazoles, oxadiazoles, oxazoles, purine, pyrans, pyrazines, pyrazoles, pyridines, pyrimidines, pyrroles, pyrrolo[2,3-d]pyrimidine, pyrazolo[3,4-d]pyrimidine), quinolines, quinazolines, triazoles, thiazoles, thiophenyl, tetrahydroindole, tetrazole
  • substituted heterocyclic or heterocyclyl or “substituted heteroaryl”
  • substituted heterocyclic or heterocyclyl or “substituted heteroaryl”
  • the heterocyclic group is substituted with one or more substituents that can be made by one of ordinary skill in the art and results in a molecule that is a kinase inhibitor.
  • preferred substituents for the heterocycle of this invention are each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylheterocycloalkoxy, alkyl, alkylcarbonyl, alkylester, alkyl-O-C(O)-, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-nitrile, alkynyl, amido groups, amino, aminoalkyl, aminocarbonyl, carbonitrile, carbonylalkoxy, carboxamido, CF 3 , CN, -C(O)OH, - C(O)H, -C(O)-C(CH 3 ) 3 , -OH, -C(O)O-alkyl, -C(O)O-cycl
  • Z 105 for each occurrence is independently a covalent bond, alkyl, alkenyl or alkynyl; and Z for each occurrence is independently selected from an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, alkyl-phenyl, alkenyl-phenyl or alkynyl-phenyl;
  • E is a direct bond, O, S, S(O), S(O) 2 , or NR f , wherein R f is H or alkyl and R d and R 6 are independently H, alkyl, alkanoyl or SO 2 -alkyl; or R d , R 6 and the nitrogen atom to which they are attached together to form a five- or six-membered heterocyclic ring.
  • heterocycloalkyl is a heterocyclic group that is linked to a compound by an aliphatic group having from one to about eight carbon atoms.
  • a preferred heterocycloalkyl group is a morpholinomethyl group.
  • aliphatic or “an aliphatic group” or notations such as “(C 0 -C 8 )” include straight chained or branched hydrocarbons which are completely saturated or which contain one or more units of unsaturation, and, thus, includes alkyl, alkenyl, alkynyl and hydrocarbons comprising a mixture of single, double and triple bonds. When the group is a C 0 it means that the moiety is not present or in other words, it is a bond.
  • alkyl means Ci-C 8 and includes straight chained or branched hydrocarbons, which are completely saturated. Preferred alkyls are methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
  • alkenyl and alkynyl means C 2 -C 8 and includes straight chained or branched hydrocarbons which contain one or more units of unsaturation, one or more double bonds for alkenyl and one or more triple bonds for alkynyl.
  • aromatic groups include aromatic carbocyclic ring systems (e.g. phenyl and cyclopentyldienyl) and fused polycyclic aromatic ring systems (e.g. naphthyl, biphenylenyl and 1,2,3,4-tetrahydronaphthyl).
  • cycloalkyl means C 3 -Ci 2 monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons that is completely saturated or has one or more unsaturated bonds but does not amount to an aromatic group.
  • Preferred examples of a cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • acyloxy groups are -OC(O)R.
  • alkenyl groups alkoxy group (which itself can be substituted, such as -O-CrC ⁇ -alkyl-OR, -O-C r C 6 -alkyl-N(R) 2 , and OCF 3 ), alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy, alkyl groups (which itself can also be substituted, such as -C r C 6 -alkyl-OR, -Ci-C 6 -alkyl-N(R) 2 , and -CF 3 ), alkylamino, alkylcarbonyl, alkylester, alkylnitrile, alkylsulfonyl, amino, aminoalkoxy, CF 3 , COH, COOH, CN, cycloalkyl, dialkylamino, dial
  • One or more compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
  • a therapeutically effective dose refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described herein.
  • Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • parenteral delivery including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • parenteral delivery including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • parenteral delivery including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafiuoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafiuoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. 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.
  • the compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD: 5W) consists of VPD diluted 1 :1 with a 5% dextrose in water solution.
  • This co- solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethysulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art.
  • the therapeutically effective dose can be estimated initially from cellular assays.
  • a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes the IC 50 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half- maximal inhibition of a given protein kinase activity).
  • the IC 50 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half- maximal inhibition of a given protein kinase activity).
  • Such information can be used to more accurately determine useful doses in humans.
  • the most preferred compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that are safely achievable in plasma.
  • a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED 50 (effective dose for 50% maximal response).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g. Fingl et al, 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pi).
  • the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of protein kinase using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using the MEC value.
  • Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the j udgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • Tablets can be prepared, for example, from the following ingredients.
  • Magnesium stearate 3 The active compound, the lactose and some of the starch can be de-aggregated, blended and the resulting mixture can be granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate can be blended with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound. c) Enteric coated tablets
  • Tablets can be prepared by the method described in (b) above.
  • the tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1). d) Suppositories
  • suppositories for example, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein.
  • additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization.
  • the compounds of the invention can be administered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate.
  • the additional pharmaceutical agents include, but are not limited to, anti-edemic steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-ILl agents, antihistamines, PAF-antagonists, COX-I inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF-IR inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin inhibitors and immunosuppressants.
  • the compounds of the invention and the additional pharmaceutical agents act either additively or synergistically.
  • the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deletrious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone.
  • combinations with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present invention.
  • the present invention also comprises the use of a compound of Formula 1 , 2 or 3 as a medicament.
  • a further aspect of the present invention provides the use of a compound of Formula 1, 2 or 3 or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly human beings.
  • the present invention also provides a method of treating vascular hyperpermeability, inappropriate neovascularization, proliferative diseases and/or disorders of the immune system which comprises the administration of a therapeutically effective amount of a compound of Formula 1 , 2 or 3 to a mammal, particularly a human being, in need thereof.
  • the potency of compounds of Formula 1 , 2 or 3 can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., a synthetic peptide (Z. Songyang et al., Nature. 373:536-539) by a test compound relative to control. p38 kinase assay
  • Active p38 ⁇ enzyme can be purchased from Upstate Biotechnology Inc. (UBI).
  • Anti- phospho-MBP specific antibody can be purchased from UBI and Europium (Eu)-cryptate labeled by Cis-Bio International.
  • SAXL streptavidine linked XL
  • Biotin- MBP-peptide Biot-Ahx-VHFFKNIVTPRTPPPSQGKGAEGQR-OH
  • HTRF reader RUBYstar was can be acquired from BMG Labtech. The kinase assay is performed using the homogenous time-resolved fluorescence (HTRF) method (Mabile, 1991; Mathis, 1993).
  • HTRF homogenous time-resolved fluorescence
  • the assay mixture contains 7.8 nM p38 ⁇ , 0.5 ⁇ M biotin-MBP- peptide, 0.1 mM ATP and compound (to a final 5% DMSO) in a buffer containing 20 mM MOPS pH 7.2, 10 mM MgCl 2 , 5 mM EGTA, 5 mM ⁇ -phosphoglycerol, 1 mM Na 3 VO 4 , 0.01% Triton-X- 100, 1 mM DTT.
  • the reaction is carried out at room temperature in 96 half-well black plates (Corning). At designated time point, EDTA (to a final 0.1 M) is added to quench the reaction.
  • the products are detected by addition of the revelation reagents (to a final 11 ng anti-phospho- MBP-Eu antibody and 0.34 ⁇ g SAXL).
  • the plates are incubated in dark at 4 0 C overnight, and read in the HTRF reader RUBYstar.
  • the ratio between the signal at 620 nm and 665 nm at various inhibitor concentrations is used to calculate the IC 50 .
  • kinase assays were performed using the homogenous time-resolved fluorescence (HTRF) method (Mabile, et al.; Mathis, et al.).
  • IKK ⁇ and IKK ⁇ (made in house) assay contained either 6.7 nM IKK ⁇ or 1.7 nM IKK ⁇ , 0.5 ⁇ M biotin-I ⁇ B ⁇ -peptide (Cell Signaling), 0.01 mM ATP and compound in IKK buffer (20 mM MOPS pH 7, 10 mM MgCl 2 , 5 mM EGTA, 5 mM ⁇ -phosphoglycerol, 1 mM Na 3 VO 4 , 0.01% Triton-X-100, 1 mM DTT, 5% DMSO).
  • HTRF homogenous time-resolved fluorescence
  • p38 ⁇ and CDK2 (UBI) assays contained either 7.8 nM p38 ⁇ or 2.7 nM CDK2/cyclin A, and 0.5 ⁇ M biotin-MBP -peptide, 0.1 mM ATP and compound in the KK Buffer.
  • p38 ⁇ assay contained 0.3 nM p38 ⁇ , and 0.1 ⁇ M biotin-MBP-protein (UBI), 0.1 mM ATP and compound in the DCK Buffer.
  • JNKl, JNK2 and JNK3 assays contained either 11.1 nM INKl, 7.6 nM JNK2, or 2.4 nM JNK3, 1 ⁇ M biotin-ATF2-peptide (Cell Signaling), 0.01 mM ATP and compound in the IKK Buffer.
  • KDR (make in house) assay contained 4.0 nM KDR, 2 ⁇ M biotin-FGFR-peptide, 0.1 mM ATP and compound in a buffer containing 50 mM HEPES, pH 7.1 , 10 mM MgCl 2, 2 mM MnCl 2 , 2.5 mM DTT, 0.01% BSA, 0.1 mM Na 3 VO 4 and 5% DMSO.
  • JAKl (make in house) assay contained 3.6 nM JAKl, 2 ⁇ M biotin-FGFR-peptide, 0.001 mM ATP and compound in a buffer containing 50 mM MOPSO, pH 6.5, 10 mM MgCl 2 , 2 mM MnCl 2, 2.5 mM DTT, 0.01% BSA, 0.1 mM Na 3 VO 4 and 5% DMSO. All assays were carried out at RT for 60 min and stopped by addition of EDTA. The products were detected by addition of revelation reagents containing Europium labeled phospho-specific antibodies and SAXL. The plates were incubated in dark at 4 0 C overnight, and read in the HTRF reader RUBYstar (BMG). Reference:
  • THP-I cells from ATCC are serum-starved and seeded at a density of 2 x 10 5 /well in 100 ⁇ L of low serum RPMI media (0.5% FBS). 50 ⁇ l samples of compounds in appropriate serial dilutions are added to the wells. Compound stocks and dilutions in 100% DMSO are prepared such that final concentration of DMSO in RPMI media is 0.5%. Cells and compounds or controls are pre-incubated for 1 hour in a 37 0 C incubator.
  • LPS Cytokine release and P-Hsp27 induction is stimulated by LPS treatment.
  • LPS (Sigma, L- 4516) is reconstituted to a concentration of 1 mg/ml in endotoxin free dIH 2 O, diluted in RPMI media such that 50 ⁇ l/well is added to each well for a final concentration of l ⁇ g/ml (excepting negative control wells). Plates with cells, compound and LPS are incubated at 37 0 C for 45 minutes. This time point needs recalibration when new THP-I cells are thawed.
  • P-Hsp27 phosphorylated Hsp27 protein
  • plates are vacuum filtered to remove media and compounds.
  • Cells are washed twice with buffer (UBI, Assay Buffer #1, 43- 010) using vacuum filtration. Then, 100 ⁇ l of cell lysis buffer (Biorad, 171-304011) is added per well and the plate is covered and shaken for 20 mins at 4 0 C to lyse cells. Lysates are directly transferred to a flat bottom 96 well plate for analysis or stored frozen at -20 0 C until analysis.
  • Lysates are diluted 1 :2 with assay buffer #1 and analysed by the Luminex method on a Bio-Plex machine following manufacturers directions (UBI, Phospho-HSP27 Beadmates kit, 46-607).
  • Luminex method on a Bio-Plex machine following manufacturers directions (UBI, Phospho-HSP27 Beadmates kit, 46-607).
  • UBI Phospho-HSP27 Beadmates kit, 46-607
  • cytokine release plates are spun after incubation with LPS for 5 min at 1000 rpm and 100 ⁇ l of supernatant media is directly transferred to a 2 nd 96 well plate. Test plate with cells is returned to incubator O/N to be assayed for toxicity the next day (see below).
  • Supernatant is stored at -20 0 C until analysis.
  • Supernatant media sample plates are analyzed in a standard ELISA format following manufacturers instructions (R&D, huTNF ⁇ ELISA assay kit).
  • Toxicity analysis is done after the overnight incubation with compound. 50 ⁇ l of a 2.5mg/ml solution of MTT (Sigma, M 2128) is added to cells. Plate is incubated at 37 0 C for 3 hrs. 50 ⁇ l of 20% SDS is then added to solubilize the formazen dye. Plates are incubated at 37°C for an additional 3hrs and OD570 is measured on a spectrophotometer. Materials:
  • Tubes used for drawing blood are 3.2% Buffered Sodium Citrate from Monoject, Mansfield, MA, Catalog Number 340486.
  • Dilution Plates and Assay Plates were from Corning, COSTAR Catalogs Numbers 3365 and 3599, respectively.
  • Dimethyl sulphoxide (DMSO) was from Sigma, St. Louis, MO, Catalog Number D2650.
  • RPMI Media 1640 and HEPES Buffer Solution (IM) are from Invitrogen GIBCO Cell Culture Systems, Carlsbad, CA, Catalog Numbers 11875 and 15630.
  • Lipopolysaccharides from Escherichia coli 0127:B8 (LPS) was from Sigma, Catalog Number L4516.
  • Tumor Necrosis Factor Alpha (TNF- ⁇ /TNFSFlA) ELISA kits were from R&D Systems, Inc., Minneapolis, MN, Catalog Number PDTAOOC.
  • Blood is drawn from healthy donors into sodium citrate tubes within 1 hour of assay.
  • Drugs were prepared in Dimethyl sulphoxide (DMSO) and serial dilute (1:3) with DMSO in Dilution Plate(s) to give 8 dilution points for each compound tested. Further dilution (1 :100) of drug was made into RPMI Media 1640, 2OmM HEPES.
  • RPMI Media 1640, 2OmM HEPES Into wells of 96-well Assay Plate(s), 100 ⁇ L/well of diluted drug or control (1% DMSO in RPMI Media 1640, 2OmM HEPES) and 80 ⁇ L of blood is applied and pre-incubated for 30 minutes in an incubator set at 37 degrees centigrade.
  • Tumor Necrosis Factor Alpha is then stimulated with the addition of Lipopolysaccharides from Escherichia coli 0127:B8 (LPS, 50 ng/ml) for 3.5 hours at 37 degrees centigrade. Plates are spun at 183 g (1000 rpm in Beckman/Coulter Allegra 6KR centrifuge) for 10 minutes. Cell-free supernatant (75 ⁇ L/well) was collected and TNF- ⁇ is measured by commercial ELISA kit, following protocol of manufacturer. Potency of drug to inhibit TNF- ⁇ in vitro is determined the percent reduction of measured TNF- ⁇ in wells with drug compared to control wells without drug. Results are represented as IC 50 values. Reference: Current Protocols in Immunology (2005) 7.18B-7.18B12. LPS-induced TNF production in vivo Materials:
  • LPS Lipopolysaccharide
  • Methylcellulose (Sigma, cat # M7027)
  • TNF ⁇ Rat Tumor Necrosis Factor ⁇ (TNF ⁇ ) ELISA kit (R&D Systems cat # RTAOO)
  • test compound is prepared into vehicle (5% PEG 200, in 0.5% Methylcellulose) at the desired concentrations for dosing (1, 3, 10, 30,100 mg/kg).
  • Lewis rats are pre-dosed with the compound(s) either intraperitoneally (i.p.) or orally (p.o.) at 0.002 ml/gram body weight one-two hours prior to the LPS challenge.
  • Negative control includes rats treated with vehicle (5% PEG 200, in 0.5% Methylcellulose) at the desired concentrations for dosing (1, 3, 10, 30,100 mg/kg).
  • Lewis rats are pre-dosed with the compound(s) either intraperitoneally (i.p.) or orally (p.o.) at 0.002 ml/gram body weight one-two hours prior to the LPS challenge.
  • Negative control includes rats treated with vehicle (5% PEG 200, in 0.5% Methylcellulose
  • the compound concentration is also determined in the serum.
  • the average concentration of TNF ⁇ in the vehicle treated group is taken as a maximal
  • the mean TNF ⁇ levels in the compound treated groups are expressed as a percent of the maximal response.
  • the percent of maximal TNF ⁇ responses at various doses or serum concentrations of the compound(s) are further analyzed using a four parameter curve fit of logarithmically transformed data (Graphpad Prism 4 software) to generate ED 5O and EC 5O .
  • step i a suitably substituted ⁇ -bromoketone 1 is reacted with an optionally substituted 2-amino heterocycle 2.
  • step i a suitably substituted ⁇ -bromoketone 1 is reacted with an optionally substituted 2-amino heterocycle 2.
  • This reaction is typically conducted in an organic solvent (such as ACN, EtOH or DMF) at temperatures at or below reflux (such as 80 0 C).
  • the product 3 is typically isolated from the reaction mixture as a solid by concentrating the mixture and then is used crude after extractive work up with a suitable organic solvent (such as IPA, DCM or EtOAc) or is purified either by crystallizing or triturating in an organic solvent (such as DCM, EtOH or EtOAc) or by flash silica gel chromatography.
  • a suitable organic solvent such as IPA, DCM or EtOAc
  • Compounds 3 can be used as is or first undergo functional group manipulation using methods known to one skilled in the art (see, for example, Larock, R.C.
  • an alkyl group may be introduced via an iron-mediated addition of a Grignard reagent using conditions such as those described in Furstner et ah, J Am Chem Soc, 2002, 124, 13856-13863.
  • an alkyl group is introduced by reaction with an alkylidenephosphorane (see, for example, Taylor, E.C. and Martin, S.F, J Am Chem Soc, 1974, 96, 8095-8102.
  • Coupling of compounds 3 with a substituted pyrimidine such as heterocycles 4 to produce compounds 5 as shown in step ii (Scheme 1) is frequently conducted with palladium- mediated arylation using a catalyst/ligand system such as Pd(OAc) 2 /PPh 3 or PdCl 2 (PPh 3 ) 2 (see, for example, Pivsa-Art, et ah, Bull Chem Soc Japan, 1998, 71, 467-473).
  • This reaction is typically carried out with a base (such as Cs 2 CO 3 , CsOAc, or KOAc) at elevated temperatures (for example, 80-100 0 C) in a solvent such as DMF or NMP.
  • Oxidation as shown in step iii is typically accomplished by treating a solution of 5 in an organic solvent (such as DCM and/or MeOH) with an oxidant (such as an aqueous solution of Oxone ® or m-CBPA) at room temperature to produce 6 (see, for example, Kennedy, RJ. and Stock, A.M. J Org Chem, 1960, 25, 1901-1906 or Zanatta, et al, Synthesis 2003, (6), 894-898).
  • Displacement of the sulfone leaving group of 6 with a primary amine to provide 7 as shown in step iv (Scheme 1) can be accomplished by a variety of methods known to one skilled in the art.
  • compounds 6 are reacted with the desired primary amine in an organic solvent (such as dioxane, toluene, or DMSO), with or without a hindered organic base (such as TEA), at elevated temperatures (see, for example, Clark, et al., J Med Chem, 2004, 47, 2724-2727).
  • organic solvent such as dioxane, toluene, or DMSO
  • hindered organic base such as TEA
  • the compounds 7 can then be isolated and purified using standard techniques (such as crystallization, flash column chromatography, or reverse-phase liquid chromatography).
  • Example #1 4- ⁇ 4- [2-(2,4-Difluorophenyl)-8-methylimidazo [ 1 ,2-a] pyrazin-3-yl] -pyrimidin-2- ylamino ⁇ -2-methyl-butan-2-ol
  • Step A 8-Chloro-2-(2,4-difluorophenyl)-imidazo[l,2- ⁇ ]pyrazine
  • the product was partitioned between DCM (9 x 1000 mL) and filtered from the insoluble material to aid extraction process.
  • the organic extracts were combined and stirred with 2.5N HCl (4 x 75OmL).
  • the organic layer was finally washed with 2.0N NaOH (500 mL) and water (2 x 500 mL), dried over MgSO 4 , and filtered through a Florisil ® pad (3 inch diameter x 3 inch depth) to remove origin material.
  • the Florisil ® pad was washed with repeated amounts of solvent until no product was detected by TLC. The organic solvent was removed in vacuo to yield a yellow solid.
  • the reaction mixture was allowed to warm to ambient temperature over about 1 hour and then stirred overnight.
  • the reaction was concentrated and the residue was stirred with water (1000 mL) and EtOAc (1000 mL) for about 15 min.
  • the mixture was filtered through a Celite ® pad to remove salts.
  • the Celite ® pad was scraped and stirred with EtOAc (3 x 250 mL).
  • the basic aqueous phase was separated and extracted with EtOAc (3 x 250 mL).
  • the organic layers were combined, washed with water (3 x 350 mL), dried over MgSO 4 , and filtered through a Florisil ® pad to remove origin material.
  • Step C 2-(2,4-Difluorophenyl)-8-methyl-3-(2-methylsulf anylpyrimidin-4-yl)-imidazo [ 1 ,2- ⁇ jpyrazine
  • the reaction was returned to heating at about 100 0 C and a solution of 4- iodo-2-(methylthio)pyrimidine (20.56 g, 81.6 mmol) in DMF (40 mL) was added via addition funnel over about 4 h.
  • the reaction was heated at about 100 0 C for about 16 hours after the addition ended then cooled to ambient temperature and concentrated under reduced pressure.
  • the resulting solid was dissolved in DCM (500 mL) and washed with 1 N HCl (5 x 200 mL) then washed with 0.5 N NaOH (200 mL) and filtered through Celite ® to break the resulting emulsion.
  • the layers were separated and the organic layer was dried over MgSO 4 , filtered, and concentrated under reduced pressure.
  • the resulting residue was filtered through a silica gel plug using EtOAc then concentrated under reduced pressure and dissolved in DCM (200 mL).
  • the DCM solution was purified by silica gel chromatography (330 g column) using a gradient of DCM:ACN (1 :0 for 4 min, cut to 4: 1 and held for 40 min, ramped to 1 : 1 over 20 min and held until product finished eluting). All product-containing fractions (including those with triphenylphosphine oxide) were combined and concentrated under reduced pressure until heavy precipitate present in a dark liquid. Then IPA was added and further concentrated under reduced pressure to remove DCM. The resulting suspension was filtered, washing with IPA followed by petroleum ether (b.p.
  • Step D 2-(2,4-Difluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methylimidazo[l,2- ⁇ ]pyrazine
  • Step E 4- ⁇ 4- [2-(2,4-Difluorophenyl)-8-methy limidazo [ 1 ,2-a] pyrazin-3-yl] -pyrimidin-2- ylamino ⁇ -2-methyl-butan-2-ol
  • Example #2 l- ⁇ 4-[2-(2,4-Difluorophenyl)-8-ethylimidazo[l,2-a]pyrazin-3-yI]-pyrimidin-2- ylamino ⁇ -2-methylpropan-2-ol
  • Step A 8-Chloro-2-(2,4-difluorophenyl)-imidazo[l,2- ⁇ ]pyrazine
  • the product was partitioned between DCM (9 x 1000 mL) and filtered from the insoluble material to aid extraction process.
  • the organic extracts were combined and stirred with 2.5N HCl (4 x 75OmL).
  • the organic layer was finally washed with 2.0N NaOH (500 mL) and water (2 x 500 mL), dried over MgSO 4 , and filtered through a Florisil ® pad (3 inch diameter x 3 inch depth) to remove origin material.
  • the Florisil ® pad was washed with repeated amounts of solvent until no product was detected by TLC. The organic solvent was removed in vacuo to yield a yellow solid.
  • the crude material was purified by silica gel chromatography (330 g column) using a gradient of DCM:ACN (1:0 for 4 min, ramped to 4:1 over 1 min, held for 35 min, ramped to 1:1 over 20 min and held for additional 5 min).
  • the column fractions enriched in product were combined, concentrated under reduced pressure, triturated with IPA (75 mL), sonicated for 5 min then filtered, washing with additional IPA (10 mL) followed by petroleum ether (b.p.
  • Step E l- ⁇ 4-[2-(2,4-Difluorophenyl)-8-ethylimidazo[l,2-a]pyrazin-3-yl]-pyrimidin-2- ylamino ⁇ -2-methylpropan-2-ol
  • Example #3 1- ⁇ 4- [8-Cyclopropylmethyl-2-(2,4-difluorophenyl)-imidazo [ 1 ,2-a] pyrazin-3-yl] - pyrimidin-2-yIamino ⁇ -2-methylpropan-2-ol
  • Step A 8-Chloro-2-(2,4-difluorophenyl)-imidazo[l,2- ⁇ ]pyrazine
  • the product was partitioned between DCM (9 x 1000 mL) and filtered from the insoluble material to aid extraction process.
  • the organic extracts were combined and stirred with 2.5N HCl (4 x 75OmL).
  • the organic layer was finally washed with 2.0N NaOH (500 mL) and water (2 x 500 mL), dried over MgSO 4 , and filtered through a Florisil ® pad (3 inch diameter x 3 inch depth) to remove origin material.
  • the Florisil ® pad was washed with repeated amounts of solvent until no product was detected by TLC. The organic solvent was removed in vacuo to yield a yellow solid.
  • the reaction mixture was concentrated in vacuo, diluted with DCM, and washed with sequentially with H 2 O, saturated aqueous NaCl, and H 2 O (250 mL each).
  • the organic layer was dried with MgSO 4 , filtered through Celite ® , and concentrated in vacuo.
  • the crude material was purified by silica gel chromatography (330 g column) using a gradient of DCMiEtOAc (1 :0 for 60 min, ramped to 1 : 1 over 60 min, held for 5 min).
  • the product-containing column fractions were combined, concentrated under reduced pressure, and crystallized from hot EtOAc.
  • the resulting needles were isolated by filtration, washing with petroleum ether (b.p.
  • Step D 8-(Cyclopropylmethyl)-2-(2,4-difluorophenyI)-3-(2-(methanesulfonyl)pyrimidin-4- yl)imidazo [ 1 ,2-a] pyrazine
  • the crude material was purified by silica gel chromatography using a gradient of DCM: EtOAc (1 :1 for 20 min, ramped to 0: 1 over 20 min and held for additional 20 min). Fractions enriched in product were crystallized from hot ACN. The resulting solid was filtered, washing with ACN and petroleum ether (b.p. 30-60 0 C), and dried in a vacuum oven at about 70 0 C for about 5 hours to give 10.0 g (70%) of the title compound.
  • Step E 1- ⁇ 4- [8-Cyclopropylmethyl-2-(2,4-difluorophenyl)-imidazo [ 1 ,2-a] pyrazin-3-yl]- pyrimidin-2-ylamino ⁇ -2-methylpropan-2-ol
  • the product-containing fractions were concentrated under reduced pressure to yield a white solid. Additionally, ⁇ 3 g of a mixture of product and starting material was recovered and treated with 1- amino-2-methylpropan-2-ol (Tyger, 0.505 g, 5.66 mmol) in ACN (50 mL). The reaction mixture was heated at about 80 °C for about 5 hours then concentrated under reduced pressure to provide yellow solid. The yellow solid was purified by silica gel chromatography (12O g column) using a gradient of DCM/MeOH (1:0 for 10 min, ramped to 4:1 over 10 min, held for 10 min). The product-containing fractions were concentrated under reduced pressure then combined with the white solid from the first column by dissolving in MeOH.

Abstract

La présente invention concerne des composés imidazopyrazine novateurs utiles comme inhibiteurs de kinase qui, en tant que telles, seraient utiles dans le traitement de certaines affections et maladies, spécialement les affections et maladies inflammatoires et les troubles et affections prolifératifs, par exemple les cancers.
EP08742312A 2007-03-27 2008-03-27 Hétérocycles à base d'imidazo novateurs Withdrawn EP2139329A4 (fr)

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US11/728,919 US20080242862A1 (en) 2007-03-27 2007-03-27 Novel imidazo based heterocycles
PCT/US2008/004007 WO2008118485A1 (fr) 2007-03-27 2008-03-27 Hétérocycles à base d'imidazo novateurs

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WO2007028051A2 (fr) * 2005-09-02 2007-03-08 Abbott Laboratories Nouveaux heterocycles a base imidazo

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US3988338A (en) * 1974-04-24 1976-10-26 Wisconsin Alumni Research Foundation 4-Substituted amino-2-substituted thio-pyrrolo-[2,3-d]pyrimidine derivatives
EP0963371B1 (fr) * 1997-02-25 2003-05-02 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Benzimidazoles substitues comme inhibiteurs non nucleosidiques de transcriptase inverse
EP1431299B1 (fr) * 2001-09-04 2007-05-23 Sumitomo Chemical Company, Limited IMIDAZO(1,2-a)PYRIMIDINES ET COMPOSITIONS FONGICIDES LES CONTENANT

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JP2010522753A (ja) 2010-07-08

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