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  • 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
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
  • C07C255/17—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and doubly-bound oxygen atoms bound to the same acyclic carbon skeleton
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
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  • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
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  • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
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  • 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
  • C07D239/26—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07—ORGANIC CHEMISTRY
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  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
  • C07D277/24—Radicals substituted by oxygen atoms
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  • 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
  • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

• the present invention relates to a novel family of protein kinase inhibitors, to the processes for preparation of compounds and their intermediates, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative, inflammatory, infectious, or autoimmune diseases, disorders, or conditions in which protein kinase activity is implicated.
• Protein kinases are a large group of intracellular and transmembrane signaling proteins in eukaryotic cells (Manning G. et al, (2002) Science, 298: 1912-1934). These enzymes are responsible for transfer of the terminal (gamma) phosphate from ATP to specific amino acid residues of target proteins. Phosphorylation of specific amino acid residues in target proteins can modulate their activity leading to profound changes in cellular signaling and metabolism. Protein kinases can be found in the cell membrane, cytosol and organelles such as the nucleus and are responsible for mediating multiple cellular functions including metabolism, cellular growth and differentiation, cellular signaling, modulation of immune responses, and cell death.
• Serine kinases specifically phosphorylate serine or threonine residues in target proteins.
• tyrosine kinases including tyrosine receptor kinases, phosphorylate tyrosine residues in target proteins.
• Tyrosine kinase families include: Tec, Src, Abl, Jak, Csk, Fak, Syk, Fer, Ack, and the receptor tyrosine kinase subfamilies including EGFR, FGFR, VEGFR, RET and Eph.
• Kinases exert control on key biological processes related to health and disease. Furthermore, aberrant activation or excessive expression of various protein kinases are implicated in the mechanism of multiple diseases and disorders characterized by benign and malignant proliferation, as well as diseases resulting from inappropriate activation of the immune system (Kyttaris V.C., Drug Des. Devel. Then, 2012, 6:245-50 and Fabbro D. et al. Methods Mol. Biol., 2012, 795:1-34).
• inhibitors of select kinases or kinase families are expected to be useful in the treatment of cancer, vascular disease, autoimmune diseases, or inflammatory conditions including, but not limited to: solid tumors, hematological malignancies, thrombus, arthritis, graft versus host disease, lupus erythematosus, psoriasis, colitis, illeitis, multiple sclerosis, uveitis, coronary artery vasculopathy, systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergy, dermatomyositis, pemphigus, and the like.
• Tec kinases are a family of non-receptor tyrosine kinases predominantly, but not exclusively, expressed in cells of hematopoietic origin (Bradshaw J.M. Cell Signal. 2010, 22:1175-84).
• the Tec family includes Tec, Bruton's tyrosine kinase (Btk), inducible T- cell kinase (Itk), resting lymphocyte kinase (Rlk/Txk), and bone marrow-expressed kinase (Bmx/Etk).
• Btk is important in B-cell receptor signaling and regulation of B-cell development and activation (W.N. Khan et al.
• Btk is activated by Src-family kinases and phosphorylates PLC gamma leading to effects on B-cell function and survival. Additionally, Btk is important in signal transduction in response to immune complex recognition by macrophage, mast cells and neutrophils. Btk inhibition is also important in survival of lymphoma cells (Herman SEM., Blood, 2011 , 117:6287-6289) suggesting that inhibition of Btk may be useful in the treatment of lymphomas. As such, inhibitors of Btk and related kinases are of great interest as anti-inflammatory as well as anti-cancer agents. Btk is also important for platelet function and thrombus formation suggesting that Btk-selective inhibitors may prove to be useful antithrombotic agents (Liu J., Blood, 2006, 108:2596-603).
• Bmx another Tec family member which has roles in inflammation, cardiovascular disease, and cancer (Cenni B. et al. Int. Rev. Immunol., 2012, 31 : 166-173) is also important for self-renewal and tumerogenic potential of glioblastoma stem cells (Guryanova OA et al. Cancer Cell 2011 ,19: 498-511). As such, Bmx inhibitors are expected to be useful in the treatment of various diseases including cancer, cardiovascular disease and inflammation.
• the SRC family of tyrosine kinases includes cSRC, Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk, and Yes.
• cSRC is critically involved in signaling pathways involved in cancer and is often over-expressed in human malignancies (Kim L.C. et al. (2009) Nat. Rev. Clin. Oncol. 6(10):587-9). cSRC is involved in signaling downstream of growth factor receptor tyrosine kinases and regulates cell cycle progression suggesting that cSRC inhibition would impact cancer cell proliferation. Furthermore, Src inhibitors or downregulation of Hck sensitize tumor cells to immunotoxins (Lui X.F., Mol. Cancer Ther. 2013, Oct. 21).
• SRC family members may be useful in treatments designed to modulate immune function.
• SRC family members including Lck, regulate T-cell receptor signal transduction which leads to gene regulation events resulting in cytokine release, survival and proliferation.
• inhibitors of Lck may be useful immunosuppressive agents with potential application in graft rejection and T-cell mediated autoimmune disease (Martin et al., Expert Opin. Ther. Pat. 2010, 20:1573-93).
• the Src family member HCK is implicated in regulation of cytokine production suggesting that inhibition of this kinase may be useful in treatment of inflammatory disease (Smolinska M.J. et al., J. Immunol. 2011 ; 187:6043-51).
• Src family kinase Fgr is critical for activation of mast cells and IgE-mediated anaphylaxis suggesting that this kinase is a potential therapeutic target for allergic diseases (Lee J.H. et al., J. Immunol. 2011 ,187:1807-15)
• the present invention relates to a novel family of kinase inhibitors.
• Compounds of this class have been found to have inhibitory activity against members of the Tec or Scr protein kinase families.
• One aspect of the present invention is directed to a compound of Formula I:
• R is selected from the group consisting of:
• heteroaryl wherein the alkyl, heteroalkyi, carbocyclyl, heterocyclyl, aryl, or heteroaryl are optionally substituted;
• R 1 is selected from the group consisting of:
• heterocyclyl or 6) halogen, wherein the alkyl, heteroalkyi, carbocyclyl, or heterocyclyl are optionally substituted;
• W is selected from
• R 2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
• X 1 and X 2 are independently selected from hydrogen or halogen; m is an integer from 0 to 4;
• Another embodiment of the present invention includes compounds of Formula I, wherein Z is
• Another embodiment includes compounds of Formula I, wherein Y is
• Preferred embodiment includes compounds of Formula I, wherein R 1 is hydrogen.
• Another embodiment of the present invention includes compounds of Formula I, wherein R is selected from the group consisting of:
• R is selected from the group consisting of:
• heteroaryl wherein the alkyl, heteroalkyi, carbocyclyl, heterocyclyl, aryl, or heteroaryl are optionally substituted;
• W is selected from the group consisting of: -OCH 2 R 2 , or -CH 2 OR 2 , wherein R 2 is selected from subst tuted or unsubstituted aryl, substituted or
• Another embodiment of the present invention includes compounds of Formula II, wherein R is
• Another embodiment of the present invention includes compounds of Formula II, wherein W is
• Another aspect of the present invention provides intermediates and their synthesis related to a process of production of compounds of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
• the present invention relates to a process for preparing a compound of Formula I, or Formula II, wherein the process comprises:
• Another aspect of the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula I, Formula II, or a pharmaceutically acceptable salts, solvates, solvates of salts, sterecisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
• the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt, solvate, solvates of salts, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites thereof, for use in therapy.
• the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of subjects suffering from a protein kinase mediated diseases or conditions.
• Another aspect of the present invention provides a use of the compound of Formula I or Formula II, as an inhibitor of protein kinase, more particularly, as an inhibitor of members of the Src, or Tec family of kinases.
• a further aspect of the present invention provides a use of the compound of Formula I or Formula II, as an inhibitor of protein kinase, more particularly, as an inhibitor of members of the Src, or Tec family of kinases.
• the present invention relates to the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt, or solvate thereof, in the production of a medicament for use in the treatment of subjects suffering from a protein kinase mediated disease or condition.
• a further aspect of the present invention provides a pharmaceutically acceptable salt, or solvate thereof, for use in manufacturing of a pharmaceutical composition for use in treatment of proliferative, inflammatory, infectious, or autoimmune diseases.
• Another aspect of the present invention provides a compound, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition as defined in present invention, for use in the treatment of a proliferative disorder, inflammatory or autoimmune disease.
• the proliferative disorder, inflammatory or autoimmune disease is cancer. More particular, is a human cancer.
• a further aspect of the present invention provides the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a proliferative disorder, such as cancer.
• Another aspect of the present invention provides a compound of Formula I, or Formula II, or a pharmaceutically acceptable salts, solvates, solvates of salts, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites thereof, for use in the treatment of a proliferative, inflammatory, infectious, or autoimmune diseases disorder, or state in combination with an agent selected from: an estrogen receptor modulator; an androgen receptor modulator; a retinoid receptor modulator; a cytotoxic agent; an anti-proliferative agent comprises: adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, or platinum derivatives; an anti-inflammatory agent comprises: corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, or sulfasalazine; a pre
• the medicament is for the treatment of a proliferative disorder or disease state in combination with a death receptor agonist.
• Another aspect of the present invention provides a compound, or pharmaceutically acceptable salts, or solvates thereof, or a pharmaceutical composition as defined in present invention, for use in the treatment of diseases, or disorders selected from: cancer, myeloproliferative disorders, lung fibrosis, hepatic fibrosis, cardiovascular diseases: cardiac hypertrophy, cardiomyopathy, restenosis; thrombosis, heart attacks, or stroke; alopecia, emphysema; atherosclerosis, psoriasis, or dermatological disorders, lupus, multiple sclerosis, macular degeneration, asthma, reactive synoviotides, viral disorders; CNS disorders; auto-immune disorders: glomerulonephritis, or rheumatoid arthritis; hormone-related diseases, metabolic disorders; inflammatory diseases; infectious or fungal diseases, malaria, or parasitic disorders.
• diseases or disorders selected from: cancer, myeloproliferative disorders, lung fibrosis, hepatic fibrosis, cardiovascular diseases:
• Another aspect of the present invention provides a compound, or pharmaceutically acceptable salts, or solvates thereof, or a pharmaceutical composition as defined in present invention, for use in the manufacture of a medicament for use in the treatment of: arthritis, tenosynovial giant cell tumour, pigmented vilionoduiar synovitis, or other reactive synoviotides, bone metastases formation, or progression, acute myeloid leukemia, or human cancer, or select subsets of cancer, for example breast tumours, or gastric cancer by inhibition of kinase activity.
• the present invention relates to a method of treating a disease or condition associated with protein kinase activity, said method comprising administering to a subject a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
• the present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or solvate thereof, or a pharmaceutical composition as defined herein.
• the proliferative disorder is a cancer.
• Another aspect of the present invention provides a method of modulating kinase function, the method comprising contacting a cell with a compound of the present invention in an amount sufficient to modulate the enzymatic activity of a given kinase or kinases, from Src, or Tec family kinases, thereby modulating the kinase function.
• a further aspect of the present invention provides a method of inhibiting cell proliferation, or survival in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or solvate thereof.
• the present invention provides a method of producing a protein kinase inhibitory effect in a cell or tissue, said method comprising contacting the cell or tissue with an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof.
• the present invention provides a method of producing a protein kinase inhibitory effect in vivo, said method comprising administering to a subject an effective amount of a compound, or a pharmaceutically acceptable salt, or solvate thereof.
• the administration may be by any suitable route of administration, such as parenteral or oral.
• the dosage unit may be any suitable amount, for example, the dosage unit for parenteral or oral administration may contain from 50 mg to 5000 mg of a compound of Formula I, or Formula II, or a pharmaceutical acceptable salt, or solvate thereof.
• the compound of the present invention may be administered 1 to 4 times a day. A dosage of between 0.01-100 mg/kg body weight/day of the compound of the present invention can be administered to a patient receiving these compositions.
• the compounds of the present invention may be used alone or in combination with one or more other therapeutic agents.
• the combination may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of treatment.
• Such combination products employ the compounds of this invention, within the dose range described hereinbefore and the other pharmaceutically active agent within its approved dose range.
• Another aspect of the present invention provides a method of modulating the target kinase function.
• the method comprising:
• the present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt, or solvate thereof, as defined herein.
• probe comprising a compound of Formula I, or Formula II, labeled with a detectable label, or an affinity tag.
• the probe compriiies a residue of a compound of Formula I, or Formula II, covalently conjugated to a detectable label.
• detectable labels include, but are not limited to, a fluorescent moiety, a chemiluminescent moiety, a paramagnetic contrast agent, a metal chelate, a radioactive isotope-containing moiety, or biotin.
• the present invention relates to novel kinase inhibitors. These compounds are found to have activity as inhibitors of protein kinases, including members of the Src, or Tec kinase families.
• compositions which comprises an effective amount of a compound of the present invention with at least one pharmaceutically acceptable diluent, carrier, or excipient.
• pharmaceutically effective amount refers to an amount of the composition for the prevention and treatment of humans or animals that is effective in treating of disease, disorder, or condition associated with protein kinase activity.
• a pharmaceutical composition which comprises a compound of Formula I, Formula II, or a pharmaceutically acceptable salt, solvate, solvate of salt, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite thereof, or mixtures of the compounds of the present invention, in association with at least one pharmaceutically acceptable diluent, carrier, or excipient.
• the pharmaceutical compositions may be in a conventional pharmaceutical form suitable for oral administration (e.g., tablet, capsule, granules, powder, liquid solution, suspension, or syrup); parenteral administration ((including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intra-arterial, intra-cerebral, intraocular injection, or infusion); suppository (rectal or vaginal); bronchial, nasal, topical, buccal, sub-lingual, transdermal, or those in a form suitable for administration by inhalation or insufflations, including powders and liquid aerosol administration, drop infusion preparations, eye lotion, or by sustained release systems.
• the compounds may be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
• the choice of the core excipients is extremely important.
• Several aspects of the finished dosage form must be considered such as the nature of the active pharmaceutical ingredient (API), the intended delivery method of the API (immediate release, modified, sustained, extended, delayed release etc), and the manufacturing process.
• API active pharmaceutical ingredient
• compositions comprising a compound of Formula I, or Formula II (or combinations of the inventive compounds), according to the present invention, and at least one pharmaceutically acceptable excipient, such as a binder, a disintegrating agent, a lubricant, a diluents, a solubilizing agent, an emulsifier, a coating agent, a cyclodextrin or buffer, for use in formulation of suitable release dosage forms: "prolonged release”, “extended release”, “modified release”, “delayed release”, “sustained release” or “immediate release”, "orally disintegrating tablets", or "sustained release parenteral depot” pharmaceutical compositions.
• a pharmaceutically acceptable excipient such as a binder, a disintegrating agent, a lubricant, a diluents, a solubilizing agent, an emulsifier, a coating agent, a cyclodextrin or buffer
• controlled release pharmaceutical compositions there are different dosage forms with plurality of "controlled release” pharmaceutical compositions, particularly “prolonged release”, “extended release”, “modified release”, “delayed release”, or “sustained release” compositions.
• Examples for controlled release pharmaceutical compositions are immediate release pharmaceutical compositions, enteric coated pharmaceutical compositions, pulsed release pharmaceutical compositions, or sustained release pharmaceutical compositions.
• An oral controlled release pharmaceutical composition means a pharmaceutical composition including at least one active pharmaceutical ingredient which is formulated with at least one pharmaceutically acceptable film forming polymer and optionally with at least one pharmaceutically acceptable excipient, where the pharmaceutical composition shows a pH-dependent, or a pH-independent reproducible release profile.
• oral controlled release pharmaceutical composition is defined to mean oral pharmaceutical compositions, which when administered releases the active ingredient at a relatively constant rate and provide plasma concentrations of the active ingredient that remain substantially invariant with time within the therapeutic range of the active ingredient over a 24-hour period and encompasses "prolonged release", “extended release”, “modified release”, “delayed release”, or “sustained release” compositions.
• modified release means that the escape of the drug from the tablet has been modified in some way. Usually this is to slow the release of the drug so that the medicine doesn't have to be taken too often and therefore improves compliance.
• the other benefit from modifying release is that the drug release is controlled and there are smaller peaks, and troughs in blood levels therefore reducing the chance of peak effects, and increasing the likelihood of therapeutic effectiveness for longer periods of time.
• continuous release means that a term applied to a drug that is designed to deliver a dose of a medication over an extended period.
• the most common device for this purpose is a soft, soluble capsule containing minute pellets of the drug for release at different rates in the Gl tract, depending on the thickness and nature of the oil, fat, wax, or resin coating on the pellets.
• Another system consists of a porous plastic carrier impregnated with the drug and a surfactant to facilitate the entry of Gl fluids that slowly leach out of the drug.
• Ion exchange resins that bind to drugs and liquids containing suspensions of slow-release drug granules are also used to provide medication over an extended period.
• pulsatile release means that a drug is delivered in one or more doses that fluctuate between a maximum and minimum dose over a predetermined time intervals. This can be represented by a dose release profile, having one or more distinct peaks or valleys. However, two or more pUsed releases may produce an overlapping, overall, or composite release profile that appears, or effectively is constant.
• the need for pulsatile release may include the desire to avoid drug degradation in the stomach or first pass metabolism. Pulsatile release can be achieved via coating of multiparticulates with pH dependent and/or barrier membrane coating systems, followed by blending of the multiparticulates to achieve desired release profiles.
• delayed release refers to the onset of release in relationship to administration of the drug. “Delayed” means that the release of drug is postponed, and begins, or is triggered some period of time after administration (e.g., the lag time), typically a relatively long period of time, e.g. more than one hour.
• immediate release is defined to mean oral pharmaceutical compositions, which when administered releases the active ingredient within a small period of time, typically less than 45 minutes after administration.
• Oral formulation for immediate release drug delivery system is a conventional type of drug delivery system, which is designed to disintegrate, and release their pharmaceutically active ingredient with no rate controlling features, such as special coatings and other techniques.
• ODT Orally Disintegrating Tablets
• ODT refers to the tablet that have a disintegration time less than 60 seconds, with good mouth feel and friability that did not exceed 1%.
• Orally Disintegrating Tablet (ODT) allows to improve patient compliance, in particular with pediatric, geriatric, and institutionalized patients, or patients with chemotherapy-induced nausea.
• Oral dosage forms which may be employed with the present invention include: tablets, granules, spheroids, or pellets in a capsule, or in any other suitable solid form.
• a “depot formulation” may be formulated to provide slow absorption of the molecules of Formula I, or Formula II, or combinations thereof, or pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof from the site of administration, often keeping therapeutic levels of the molecule or an active metabolite, in the patient's system for days or weeks at a time.
• a “depot formulation” may provide convenience for a patient in need of chronic medication by a delivering molecule of the present invention without exposure to the Gl tract.
• a “depot formulation” may provide better compliance due to the infrequent dosing regimen and convenience. Additional characteristics of a "depot formulation” that will enhance patient compliance are good local tolerance at the injection site and ease of administration.
• the dosage form will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated, or prevented, the route of administration, and the form of the drug. In general a daily dosage form 0.01 to 2000 mg of the compound is recommended for an adult human patient, and this may be administered in a single dose, or in divided doses.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound, which produces a therapeutic effect.
• the time of administration and/or amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type, and stage, general physical condition, responsiveness to a given dosage form, and type of medication), route of administration, etc.
• pharmaceutically acceptable is employed herein to refer to those ligands, materials, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem, or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
• a pharmaceutically acceptable material such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
• Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation, including the active ingredient, and not injurious or harmful to the patient.
• materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, or sucrose; starches, such as corn starch, potato starch, and substituted or unsubstituted ⁇ -cyclodextrin; cellulose, or its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, or cellulose acetate; powdered tragacanth; malt; gelatin; talc; or other excipients, such as cocoa butter, or suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, or soybean oil; glycols, such ias propylene glycol; polyols, such as glycerin, sorbitol, mannitol, or polyethylene glycol; esters, such as ethyl oleate, or ethyl laurate; agar; buffering agents, such as magnesium hydroxide, such
• pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form, with a suitable organic or inorganic acid, and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
• halo or halogen refers to chlorine, bromine, fluorine, or iodine. Fluorine is a preferred halogen.
• compositions of the present invention are obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
• the compounds ot the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
• These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
• a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
• Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, or aluminum salts, and the like.
• Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., 7977,"Pharmaceutical Salts").
• affinity tag means a ligand or group, linked either to a compound of the present invention, or to a protein kinase domain, that allows the conjugate to be extracted from a solution.
• alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups, such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
• Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, cyclopropylmethyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
• alkenyl and alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length, and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
• Representative alkenyl groups include vinyl, propen-2-yl, crotyl, isopenten-2-yl, 1 ,3-butadien-2-yl), 2,4- pentadienyl, or 1 ,4-pentadien-3-yl.
• Representative alkynyl groups include ethynyl, 1- and 3-propynyl, or 3-butynyl.
• alkyl substituents are lower alkyl groups, e.g., having from 1 to 6 carbon atoms.
• alkenyl and alkynyl preferably refer to lower alkenyl, or alkynyl groups, e.g., having from 2 to 6 carbon atoms.
• alkylene refers to an alkyl group with two open valencies (rather than a single valency), such as -(CH 2 ) MO - and substituted variants thereof.
• alkoxy refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
• An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxy.
• alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, thereby forming an ether.
• amide and “amido” are art-recognized as an amino-substituted carbonyl and include a moiety that can be represented by the general formula:
• R 9 , R 10 are as defined above.
• Preferred embodiments of the amide will not include imides, which may be unstable.
• amine and “amino” are art-recognized, and refer to both unsubstituted and substituted amines, and salts thereof, e.g., a moiety that can be represented by the general formula: wherein R 9 , R 10 and R 0 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) P -R 8 , or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R 8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, or a polycyclyl; and p is zero, or an integer from 1 to 8.
• R 9 or R 10 can be a carbonyl, e.g., R 9 , R 10 , and the nitrogen together do not form an imide.
• R 9 or R 10 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) P -R 8 .
• the amino group is basic, meaning the protonated form has a pK a > 7.00.
• aralkyl refers to an alkyl group substituted with an aryl group, for example -(CH 2 ) P -Ar.
• heteroaryl refers to an alkyl group substituted with a heteroaryl group, for example -(CH 2 ) -Het.
• aryl as used herein includes 5-, 6-, and 7-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
• aryl also includes polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjoining rings, wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, or heterocyclyls.
• Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, anthracene, or phenanthrene.
• carrier refers to a non-aromatic substituted or unsubstituted ring in which each atom of the ring is carbon.
• carrier also include polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjoining rings, wherein at least one of the rings is carbocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, or heterocyclyls.
• carbocyclic groups include cyclopentyl, cyclohexyl, 1-cyclohexenyl, or 3- cyclohexen-1- yl, or cycloheptyl.
• carbonyl is art-recognized and includes such moieties as can be represented by the general formula:
• X is a bond, or represents an oxygen, or a sulfur
• R 11 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) P -R 8 , or a pharmaceutically acceptable salt.
• X is oxygen, and R 11 is not hydrogen, the formula represents an "ester”.
• X is oxygen, and R 11 is hydrogen, the formula represents a "carboxylic acid”.
• heteroaryl includes substituted or unsubstituted aromatic 5- to 7-membered ring structures, more preferably 5- to 6-membered rings, whose ring structures include one to four heteroatoms.
• heteroaryl also includes polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjoining rings, wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, or heterocyclyls.
• Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, isoxazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine or pyrimidine, and the like.
• heteroatom means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, or sulfur.
• heterocyclyl refers to substituted or unsubstituted non-aromatic 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms.
• heterocyclyl or “heterocyclic group” also include polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjoining rings, wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, or heterocyclyls.
• Heterocyclyl groups include, for example, tetrahydrofuran, tetrahydropyran, piperidine, piperazine, pyrrolidine, morpholine, lactones, or lactams.
• Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, or combinations thereof.
• polycyclyl or “polycyclic”, refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls), in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings".
• rings e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls
• Each of the rings of the polycycle can be substituted or unsubstituted.
• the term "probe” means a compound of the invention, which is labeled with either a detectable label, or an affinity tag, and which is capable of binding, either covalently, or non-covalently to a protein kinase domain.
• the probe When, for example, the probe is non-covalently bound, it may be displaced by a test compound.
• the probe When, for example, the probe is bound covalently, it may be used to form cross-linked adducts, which may be quantified and inhibited by a test compound.
• substituted refers to moieties having substituents replacing a hydrogen on one, or more atoms of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted”, is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic or heterocyclic, aromatic or non-aromatic substituents of organic compounds.
• the permissible substituents can be one or more and the same, or different for appropriate organic compounds.
• the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
• Substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phcsphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will
• Compounds of the present invention also include isotopes of atoms present in the intermediates and/or final compounds.
• Isotopes include those atoms having the same atomic number, but different mass numbers.
• isotopes of hydrogen include deuterium, or tritium.
• the compounds of the present invention are inhibitors of protein kinase activity.
• An aspect of the present invention provides a compound of Formula I, or Formula II, or combinations thereof, or a pharmaceutically acceptable salt, or solvate, solvate of salt, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite thereof, for use in therapy.
• the compounds of the present invention are suitable for producing a protein kinase inhibitory effect in vivo, and thus, are suitable for the treatment of diseases or conditions in which one or more of the protein kinase targets are implicated.
• the protein kinase is selected from the following group: Tec, Src, Abl, Jak, Csk, Fak, Syk, Fer, or Ack kinases, and receptor protein kinases.
• the protein kinases are from Tec, or Src kinase family.
• the compounds are suitable for inhibition of a proliferative disorder mediated by Tec kinase targets. In other embodiment, the compounds are suitable for inhibition of a proliferative disorder mediated by Src kinase targets.
• An aspect of the present invention provides a method of inhibiting protein kinase activity in a cell, the method comprising administering to said cell compound of Formula I or Formula II, or combinations thereof, or a pharmaceutically acceptable salt, solvate, solvate of salt, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite thereof.
• the present invention provides a method of inhibiting protein kinase in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein.
• a further aspect of the present invention provides a method of inhibiting protein kinase activity in a human or animal subject, the method comprising administering to said subject an effective amount of a compound of Formula I or Formula II, or combinations thereof, as defined herein or a pharmaceutically acceptable salt, or solvate thereof.
• the compounds of the present invention are suitable for the treatment of diseases or conditions in which one or more of the protein kinase targets outlined above are implicated.
• proliferative disorder is used herein in a broad sense to include any disorder that requires control of deleterious cell proliferation , for example cancers or other disorders associated with uncontrolled cellular proliferation such as dermatological disorders such as psoriasis, certain viral disorders; certain cardiovascular diseases such as restenosis, or cardiomyopathy; certain CNS disorders; auto-immune disorders such as glomerulonephritis, or rheumatoid arthritis; hormone-related diseases; metabolic disorders; thrombosis stroke, alopecia, emphysema, inflammatory diseases, or infectious diseases such fungal diseases, or parasitic disorders such as malaria.
• dermatological disorders such as psoriasis, certain viral disorders; certain cardiovascular diseases such as restenosis, or cardiomyopathy; certain CNS disorders; auto-immune disorders such as glomerulonephritis, or rheumatoid arthritis; hormone-related diseases; metabolic disorders; thrombosis stroke, alopecia, emphysema,
• the compounds of the present invention may induce apoptosis, or maintain stasis within the desired cells as required.
• protein kinase mediated disease is used herein associated with abnormal cellular responses triggered by protein kinase-mediated events.
• aberrant activation or excessive expression of various protein kinases is implicated in the mechanism of multiple diseases and disorders characterized by benign, or malignant proliferation.
• These diseases include, but are not limited to allergies, or asthma, Alzheimer's disease, autoimmune diseases, bone diseases, cancer, cardiovascular diseases, inflammatory diseases, hormone-related diseases, metabolic diseases, neurological, or neurodegenerative diseases.Thus, inhibitors of kinase families are expected to be suitable in the treatment of cancer, vascular disease, autoimmune diseases, or inflammatory conditions including, but not limited to: solid tumors, hematological malignancies, thrombus, arthritis, graft versus host disease, lupus erythematosus, psoriasis, colitis, illeitis, multiple sclerosis, uveitis, coronary artery vasculopathy, systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergy, or dermatomyositis.
• the compound of Formula I, Formula II, combinations thereof, or pharmaceutically acceptable salts, solvates, solvates of salts, stereoisomers, tautomers, isotopes, prodrugs, complexes, or biologically active metabolites thereof is acting by inhibiting one or more of the host cell kinases involved in cell proliferation, cell survival, viral replication, cardiovascular disorders, neurodegeneration, autoimmunity, a metabolic disorder, stroke, alopecia, an inflammatory disease, or an infectious disease.
• the proliferative disorder is cancer.
• the cancer may be selected from the group consisting of: chronic lymphocytic leukaemia (CLL), lymphoma, leukaemia, breast cancer, lung cancer, prostate cancer, colon cancer, melanoma, pancreatic cancer, ovarian cancer, squamous carcinoma, carcinoma of head, or neck, endometrial cancer, or oesophageal carcinoma.
• CLL chronic lymphocytic leukaemia
• lymphoma lymphoma
• leukaemia breast cancer
• lung cancer prostate cancer
• colon cancer melanoma
• pancreatic cancer pancreatic cancer
• ovarian cancer squamous carcinoma, carcinoma of head, or neck
• endometrial cancer or oesophageal carcinoma.
• the infectious disease includes diseases that are caused by protozoal infestations in humans and animals.
• Such veterinary and human pathogenic Protozoas are preferably intracellular active parasites of the phylum Apicomplexa or Sarcomastigophora, especially Trypanosoma, Plasmodia, Leishmania, Babesia, or Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia, or Trichomonadia.
• the compounds of the present invention are particularly suitable for the treatment of Malaria tropica, caused by Plasmodium falciparum, Malaria tertiana, caused by Plasmodium vivax, or Plasmodium ovale, or for the treatment of Malaria quartana, caused by Plasmodium malariae.
• Toxoplasmosis caused by Toxoplasma gondii
• Coccidiosis caused for instance by Isospora belli
• intestinal Sarcosporidiosis caused by Sarcocystis suihominis
• dysentery caused by Entamoeba histolytica
• Cryptosporidiosis caused by Cryptosporidium parvum
• Chagas disease caused by Trypanosoma cruzi
• sleeping sickness caused by Trypanosoma brucei rhodesiense or gambiense
• the cutaneous or visceral as well as other forms of Leishmaniosis.
• the present invention is also suitable for the treatment of animals infected by veterinary pathogenic Protozoa, like Theileria parva, the pathogen causing bovine East coast fever, Trypanosoma congolense, or Trypanosoma vivax, Trypanosoma brucei pathogens causing Nagana cattle disease in Africa, Trypanosoma brucei evansi causing Surra, Babesia bigemina, the pathogen causing Texas fever in cattle and buffalos, Babesia bovis the pathogen causing European bovine Babesiosis as well as Babesiosis in dogs, cats and sheep; Sarcocystis ovicanis and Sarcocystis ovifelis pathogens causing Sarcocystiosis in sheep, cattle and pigs; Cryptosporidia pathogens causing Cryptosporidioses in cattle and birds; Eimeria and Isospora species, pathogens causing Coccidiosis in rabbits, cattle, sheep
• the compounds of the present invention is particularly preferred for use in the treatment of Coccidiosis or Malaria infections, or for the preparation of a drug, or feed stuff for the treatment of these diseases. These treatments can be prophylactic or curative.
• the protein kinase inhibitor as defined above may be combined with at least one other anti-malaria agent.
• the present compound described may further be used for viral infections, or other infections caused by Pneumocystis carinii.
• Tec kinases is a family of non-receptor tyrosine kinases predominantly, but not exclusively, expressed in cells of hematopoietic origin.
• the Tec family comprises: Tec, Bruton's tyrosine kinase (Btk), inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk/Txk), and bone marrow-expressed kinase (Bmx/Etk).
• Btk is activated by Src-family kinases and phosphorylates PLC gamma leading to effects on B-cell function and survival. Additionally, Btk is important in signal transduction in response to immune complex recognition by macrophage, mast cells and neutrophils. Btk inhibition is also important in survival of lymphoma cells (Herman SEM. Blood, 201 1 , 1 17:6287-6289) suggesting that inhibition of Btk may be useful in the treatment of lymphomas. Bmx, another Tec family member are expected to be suitable in the treatment of various diseases including cancer, cardiovascular disease or inflammation.
• the compound of Formula I, Formula II, combinations thereof, or pharmaceutically acceptable salts, solvates, solvates of salts, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites thereof is acting as inhibitor of cell kinases, as anti-inflammatory, anticancer, or as antithrombotic agents.
• These compounds may be used alone, or in combination with one of more agents for the treatment of cancer, inflammatory diseases, or thrombi.
• the compounds of the present invention can also be used in combination with one or more chemotherapeutic agents, used particularly in treatment of cancer, or other neoplasms.
• the compounds of Formula I, F ormula II, combinations thereof, or pharmaceutically acceptable salts, solvates, solvates of salts, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites thereof, object of the present invention can be used in combination with:
• Anti-proliferative agents such as adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, or platinum derivatives
• anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, or sulfasalazine;
• Angiogensis inhibitors comprising sorafenib, sunitinib, pazopanib, or everolimus;
• Immunomodulatory or immunosuppressive agents comprising: cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, or sulfasalazine;
• PPAR- ⁇ agonists such as thiazolidinediones; PPAR- ⁇ agonists;
• Agents for the treatment of anemia comprising erythropoiesis, stimulating agents, vitamins, or iron supplements;
• Anti-emetic agents including 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptor antagonists, H1 histamine receptor antagonists, cannabinoids, benzodiazepines, anticholinergic agents, or steroids;
• Modulators of the immune system including interferon-alpha, Bacillus Calmette- Guerin (BCG), or ionizing radition (UVB) that can induce the release of cytokines, such as the interleukins, TNF, or induce release of death receptor ligands, such as TRAIL;
• BCG Bacillus Calmette- Guerin
• UVB ionizing radition
• TRAIL death receptors
• TRAIL agonists such as the humanized antibodies HGS-ETR1 , or HGS-ETR, in combination, or sequentially with radiation therapy;
• Neurotrophic factors comprising acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, or riluzole;
• Anti-Parkinsonian agents comprising anticholinergic agents, dopaminergic agents, including dopaminergic precursors, monoamine oxidase B inhibitors, COMT inhibitors, or dopamine receptor agonists;
• Agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, or statins;
• Agents for treating liver disease comprising: corticosteroids, cholestyramine, or interferons;
• Anti-viral agents including nucleoside reverse transcriptase inhibitors, non nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, chemokine receptor antagonists, polymerase inhibitors, viral proteins synthesis inhibitors, viral protein modification inhibitors, neuraminidase inhibitors, fusion or entry Inhibitors; 23.
• Agents for treating blood disorders such as corticosteroids, anti-leukemic agents, or growth factors;
• agents for treating immunodeficiency disorders such as gamma globulin, adalimumab, etarnecept, or infliximab; or
• HMG-CoA reductase inhibitors comprising torvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, or pitavastatin.
• an effect against a proliferative disorder mediated by a kinase within the scope of the present invention may be demonstrated by the ability to inhibit a purified kinase in vitro, or to inhibit cell proliferation, or survival in an in vitro cell assay, for example in Btk Kinase Inhibitior Assay and Splenic Cell Proliferation Assay.
• the present invention includes the transdermal, rectal, parenteral, or oral administration of compounds of Formula I, or Formula II, or combinations thereof, or a pharmaceutical acceptable salt, solvate, solvate of salt, stereoisomer, tautomer, isotope, prodrug, complex or biologically active metabolite thereof, to a human or animal subject.
• the dosage unit for the administration may contain any suitable amount of a compound of Formula I, Formula II, combinations thereof (or a pharmaceutical acceptable salt or solvate thereof, or combinations thereof), for example, from 10 mg to 5000 mg.
• the dosage unit for the oral administration may contain from 50mg to 500mg per human subject.
• the compound of Formula I, or Formula II, combinations thereof, or a pharmaceutical acceptable salt or solvate thereof, of the present invention may be administered 1 to 4 times a day.
• a dosage may be any suitable therapeutically effective amount, for example, between 0.01-100 mg/kg body weight/day of the compound of the present invention can be administered to a patient receiving these compositions.
• the dose can vary within wide limits and is to be suited to the individual conditions in each individual case. For the above uses the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. Preferably a dose of 1 to 50 mg/kg body weight/day may be used.
• suitable dosage rates for larger mammals are of the orde r of from about 10 mg to 3 g/day, administered orally once, or divided doses such as 2 to 4 times a day, or in sustained release form.
• suitable dosage rates for topical delivery depending on the permeability of the skin, the type and the severity of the disease, on the type of formulation, and frequency of application, different concentrations of active compounds within the medicament can be sufficient to elicit a therapeutic effect by topical application.
• the concentration of an active compound pharmaceutically acceptable salts, solvates, solvates of salts, stereoisomers, tautomers, isotopes, prodrugs, complexes or biologically active metabolites thereof, within a medicament according to the present invention is in the range of between 1 pmol/L and 100 mmol/L.
• intermediate 5-b (8.9 g, 37.5 mmol) in toluene (20 ml) was added intermediate 6-b (5.0 g, 45.0 mmol), and PTSA (713 mg, 3.7 mmol).
• the reaction was stirred at reflux using a Dean-Stark apparatus overnight, and then cooled to room temperature.
• a saturated aqueous solution of NaHC0 3 and ethyl acetate were added, the organic layer was separated, and the aqueous phase was extracted twice with ethyl acetate.
• the combined organic extracts were washed with brine, dried over MgS0 4 , filtered, and concentrated under reduced pressure to provide Intermediate 7-a as a beige solid.
• Step 1 Intermediate 24-b To a suspension of NaH (250 mg, 6.2 mmol) in THF (16 ml) cooled to 0°C was added diethyl cyanomethylphosphonate (0.3 g, 7.4 mmol) drop wise followed by a solution of intermediate 24-a (1.0 g, 5.7 mmol) in THF (62 ml). After the addition was completed the reaction was warmed to room temperature and stirred overnight. Water and ethyl acetate were added, the organic layer was separated, washed with brine, dried over MgS0 4 , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography provided Intermediate 24-b as a colorless oil.
• Step 2 Intermediate 25-b To a solution of Intermediate 25-a (240 mg, 0.5 mmol) in tert-butanol (2.6 ml) was added a 1.0 M solution of potassium tert-butoxide in tert-butanol (590 ⁇ , 0.59 mmol). The reaction was stirred for 30 minutes at 80°C, then cooled to room temperature, and poured in a saturated aqueous solution of ammonium chloride. Ethyl acetate was added, the organic layer was separated, washed with brine, dried over MgS0 , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography provided Intermediate 25-b as a beige solid.
• Fluorescence polarization-based kinase assays were performed in 384 well-plate format using histidine tagged recombinant human full-length Bruton Agammaglobulinemia Tyrosine Kinase (Btk), and a modified protocol of the KinEASETM FP Fluorescein Green Assay supplied from Millipore®. Kinase reaction were performed at room temperature for 60 minutes, in presence of 250 ⁇ substrate, 10 ⁇ ATP, and variable test article concentrations. The reaction was stopped with EDTA/kinease detection reagents. Phosphorylation of the substrate peptide was detected by fluorescence polarization, measured with a Tecan 500 instrument.
• Btk histidine tagged recombinant human full-length Bruton Agammaglobulinemia Tyrosine Kinase
• Kinase reaction were performed at room temperature for 60 minutes, in presence of 250 ⁇ substrate, 10 ⁇ ATP, and variable test article concentrations. The reaction was stopped with
• the ICso was calculated using Graph Pad Prisms®, using a non linear fit curve.
• the Km for ATP on each enzyme was experimentally determined and the Ki values calculated using the Cheng-Prusoff equation (see Cheng Y, Prusoff WH. (1973) Relationship between the inhibition constant (K1), and the concentration of inhibitor which causes 50% inhibition (l 50 ) of an enzymatic reaction”. Biochem Pharmacol 22 (23): 3099-108).
• hBTK kinase is diluted in buffer and all compounds were prepared to 50x final assay concentration in 100% DMSO. This working stock of the compound was added to the assay well as the first component in the reaction, followed by the remaining components as detailed in the assay protocol iisted above. The reaction was initiated by the addition of the MgATP mix. The kinase reaction was performed at room temperature for 40 minutes, in presence of 250 ⁇ substrate, 10 mM MgAcetate, [y-33P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required) and variable test article concentrations. The ATP concentrations in the assays were with 15 ⁇ of the apparent. The reaction was stopped by the addition of 3% phosphoric acid solution.
• Splenocytes were obtained from 6 week old male CD1 mice (Charles River Laboratories Inc.). Mouse spleens were manually disrupted in PBS and filtered using a 70um cell strainer followed by ammonium chloride red blood cell lysis. Cells were washed, resuspended in Splenocyte Medium (HyClone RPMI supplemented with 10% heat- inactivated FBS, 0.5X non-essential amino acids, 10 mM HEPES, 50 uM beta mercaptoethanol), and incubated at 37°C, 5% C0 2 for 2h, to remove adherent cells.
• Splenocyte Medium HyClone RPMI supplemented with 10% heat- inactivated FBS, 0.5X non-essential amino acids, 10 mM HEPES, 50 uM beta mercaptoethanol
• Suspension cells were seeded in 96 well plates, at 50,000 cells per well, and incubated at 37°C, 5% C0 2 for 1 h.
• Splenocytes were pre-treated in triplicate with 10,000 nM curves of Formula I, compounds for 1h, followed by stimulation of cell proliferation with 2.5ug/ml anti-IgM F(ab') 2 (Jackson Immuno Research) for 72h.
• Cell proliferation was measured by Cell Titer-Glo Luminescent Assiiy (Promega).
• EC 50 values (50% proliferation in the presence of compound, as compared to vehicle treated controls) were calculated from dose response compound curves using GraphPad Prism Software.

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