US20080207613A1 - Selective Kinase Inhibitors - Google Patents

Selective Kinase Inhibitors Download PDF

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US20080207613A1
US20080207613A1 US10/585,916 US58591605A US2008207613A1 US 20080207613 A1 US20080207613 A1 US 20080207613A1 US 58591605 A US58591605 A US 58591605A US 2008207613 A1 US2008207613 A1 US 2008207613A1
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alkyl
arh
hetaryl
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alkylhetaryl
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Michelle Leanne Styles
Jun Zeng
Herbert Rudolf Treutlein
Andrew Frederick Wilks
Marcel Robert Kling
Christopher John Burns
Xianyong Bu
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YM Biosciences Australia Pty Ltd
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Cytopia Research Pty Ltd
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Definitions

  • the present invention relates to the field of inhibitors of protein tyrosine kinases in particular the JAK family of protein tyrosine kinases.
  • Protein kinases are a family of enzymes that catalyse the phosphorylation of specific residues in proteins. In general protein kinases fall into several groups; those which preferentially phosphorylate serine and/or threonine residues, those which preferentially phosphorylate tyrosine residues and those which phosphorylate both tyrosine and Ser/Thr residues. Protein kinases are therefore key elements in signal transduction pathways responsible for transducing extracellular signals, including the action of cytokines on their receptors, to the nuclei, triggering various biological events. The many roles of protein kinases in normal cell physiology include cell cycle control and cell growth, differentiation, apoptosis, cell mobility and mitogenesis.
  • Protein kinases include, for example, but are not limited to, members of the Protein Tyrosine Kinase family (PTKs), which in turn can be divided into the cytoplasmic PTKs and the receptor PTKs (RTKs).
  • the cytoplasmic PTKS include the SRC family, (including BLK; FGR; FYN; HCK; LCK; LYN; SRC; YES and YRK; the BRK Family (including: BRK; FRK, SAD; and SRM); the CSK family (including: CSK and CTK); the BTK family, (including BTK; ITK; TEC; MKK2 and TXK), the Janus kinase family, (including: JAK1, JAK2, JAK3 and Tyk2), the FAK family (including, FAK and PYK2); the Fes family (including FES and FER), the ZAP70 family (including ZAP70 and SYK); the ACK family (including ACK1 and ACK2); and the Ab
  • the RTK family includes the EGF-Receptor family (including, EGFR, HER2, HER3 and HER4); the Insulin Receptor family (including INS-R, and IGF1-R); the PDGF-Receptor family (including PDGFR ⁇ , PDGFR ⁇ , CSF1R, KIT, FLK2); the VEGF-Receptor family (including; FLT1, FLK1 and FLT4); the FGF-Receptor family (including FGFR1, FGFR2, FGFR3 and FGFR4); the CCK4 family (including CCK4); the MET family (including MET and RON); the TRK family (including TRKA, TRKB, and TRKC); the AXL family (including AXL, MER, and SKY); the TIE/TEK family (including TIE and TIE2/TEK); the EPH family (including EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB
  • the serine/threonine specific kinases comprise a number of distinct sub-families, including the extracellular signal regulated kinases, (p42/ERK2 and p44/ERK1); c-Jun NH2-terminal kinase (JNK); cAMP-responsive element-binding protein kinases (CREBK); cAMP-dependent kinase (CAPK); mitogen-activated protein kinase-activated protein kinase (MAPK and its relatives); stress-activated protein kinase p38/SAPK2; mitogen- and stress-activated kinase (MSK); protein kinases, PKA, PKB and PKC inter alia.
  • JNK extracellular signal regulated kinases
  • JNK cAMP-responsive element-binding protein kinases
  • CREBK cAMP-dependent kinase
  • CAPK cAMP-dependent kinase
  • MEK mitogen-
  • the genomes of a number of pathogenic organisms possess genes encoding protein kinases.
  • the malarial parasite Plasmodium falciparum and viruses such as HPV and Hepatitis vows appear to bear kinase related genes.
  • Diseases where aberrant kinase activity has been implicated include: diabetes; restenosis; atherosclerosis; fibrosis of the liver and kidney; ocular diseases; myelo- and lymphoproliferative disorders; cancer such as prostate cancer, colon cancer, breast cancer, head and neck cancer, leukemia and lymphoma; and, auto-immune diseases such as Atopic Dermatitis, Asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Crouzon syndrome, achondroplasia, and thanatophoric dysplasia.
  • the JAK family of protein tyrosine kinases (PTKs) play a central role in the cytokine dependent regulation of the proliferation and end function of several important cell types of the immune system.
  • JAK homology domains The high degree of conservation of these JAK homology (JH) domains suggests that they are each likely to play an important role in the cellular processes in which these proteins operate.
  • JAK homology domains are arbitrary, and may or may not define functional domains. Nonetheless, their delineation is a useful device to aid the consideration of the overall structural similarity of this class of proteins.
  • JH1 and JH2 The feature most characteristic of the JAK family of PTKs is the possession of two kinase-related domain (JH1 and JH2) (Wilks et al, 1991).
  • the putative PTK domain of JAK1 (JH1) contains highly conserved motifs typical of PTK domains, including the presence of a tyrosine residue at position 1022 located 11 residues C-terminal to sub-domain VII that is considered diagnostic of membership of the tyrosine-specific class of protein kinases
  • Alignment of the human JAK1 PTK domain (255 amino acids), with other members of the PTK class of proteins revealed homology with other functional PTKs (for example, 28% identity with c-fes (Wilks and Kurban, 1988) and 37% homology to TRK (Kozma et al, 1988)).
  • the JH1 domains of each of the JAK family members posses an interesting idiosyncrasy within the highly conserved sub-domain VIII motif (residues 1015 to 1027 in JAK2) that is believed to lie close to the active site, and define substrate specificity.
  • the phenylalanine and tyrosine residues flanking the conserved tryptophan in this motif are unique to the JAK family of PTKs.
  • the JH1 domains of each of the members of the JAK family are typical PTK domains. Furthermore, there is high sequence identity in the JAK family particularly in and around the ATP binding site ( FIG. 1 ).
  • JAK family of protein tyrosine kinases in the cytokine dependent regulation of the proliferation and end function of several important cell types means that agents which inhibit JAK are useful in the prevention and chemotherapy of disease states dependent on these enzymes.
  • Potent and specific inhibitors of each of the currently known four JAK family members will provide a means of inhibiting the action of those cytokines that drive immune pathologies, such as asthma and as immunosuppressive agents for, amongst others, organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, and leukemia/lymphoma.
  • a cytokine receptor chain such as the Interleukin-4 receptor or the Interferon ⁇ receptor
  • a member or members of the JAK family of PTKs
  • a member(s) of the STAT family of transcription factor a sequence specific DNA element to which the activated STAT will bind.
  • JAKs In addition to the diseases listed in Tables 1 and 2, inhibitors of JAKs could be used as immunosuppresive agents for organ transplants and autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis, Type I diabetes, autoimmune thyroid disorders, Alzheimer's disease and other autoimmune diseases. Additionally, treatment of cancers such as prostate cancer by JAK inhibitors is indicated.
  • JAK3 expression appears to be limited to hematopoetic cells. This is consistent with its essential role in signaling through the receptors for IL-2, IL4, IL-7, IL-9 and IL-15 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors.
  • Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor gamma chain (gamma c) gene that encodes a shared, essential component of the receptors of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15.
  • XSCID X-linked severe combined immunodeficiency
  • Prolonged immunomodulation through inhibition of JAK3 signalling should have great therapeutic potential as long as JAK3 inhibition was achieved selectively and not accompanied by inhibition of other kinase-dependent signalling processes.
  • the high degree of sequence identity held in common by members of the JAK family of kinases raises the possibility that a compound which inhibits Jak3 would also inhibit other members of the family with detrimental long term consequences.
  • prolonged inhibition of Jak2 is likely to lead to erythropenia and thrombocytopenia, since the receptors for both crythropoietin and thrombopoietin use only JAK2 for intracellular transmission of signals.
  • a PTK catalyses the transfer of a phosphate group from a molecule of ATP to a tyrosine residue located on a protein substrate.
  • the inhibitors known in the art are usually competitive with either the ATP or the protein substrate of the kinase (Levitzki 2000). Since the concentration of ATP in a cell is normally very high (millimolar), compounds that are competitive with ATP many lack in vivo activity since it is unlikely that said compounds can reach the concentrations within the cell that are necessary to displace the ATP from its binding site.
  • the present inventors have found that a group of compounds based upon a disubstituted heterocyclic scaffold which include an alkylating group such as a Michael acceptor are irreversible and selective inhibitors of the enzyme Janus Kinase 3 and as will find applications in therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, and other indications when immunosuppression would be desirable. Furthermore, it is believed that these compounds may find application in therapeutic treatments for proliferative diseases and cancers such as Leukemia and Lymphoma where JAK3 is hyperactivated and in diseases such as Alzheimer's disease.
  • an alkylating group such as a Michael acceptor
  • the present invention provides a compound of the general formula I
  • the present invention consists in a composition comprising a carrier and at least one compound of the first aspect of the invention.
  • the present invention consists in a method of treating a tyrosine kinase-associated disease state, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention.
  • the present invention provides the use of the compounds of the first aspect or the compositions of the second aspect in the preparation of medicaments for the treatment of JAK3-associated disease states.
  • the present invention provides for a method of suppressing the immune system of a subject, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention.
  • FIG. 1 shows the amino acid sequence alignment of selected Jak Kinases
  • FIG. 2 shows a model of the Jak3 kinase ATP binding pocket displaying the Cysteine residue.
  • the present invention provides a compound of the general formula I
  • the compound is selected from compounds of the general formula II.
  • the compounds of formula I may irreversibly inhibit JAK 3.
  • the strength of binding of reversible inhibitors of an enzyme is measured by the IC 50 value which is a reflection of the equilibrium constant of the interaction between the inhibitor and the active site of the enzyme.
  • Irreversible inhibitors display an apparent IC 50 because once the inhibitor is bound it will not leave the active site and the measured IC 50 will therefore improve (i.e. number will decrease) over time.
  • the compound of example 20 exhibits an “IC 50 ” of ⁇ 40 nM after 20 minute incubation with enzyme (prior to addition of ATP) whereas the “IC50” drops to 7 nM after 90 min pre-incubation.
  • the compound of formula I selectively inhibits JAK 3 with respect to JAK 1 or JAK 2.
  • selectively inhibits is defined to mean that the apparent IC 50 of the compound for JAK 3 is more than ten-fold lower (i.e. more potent) than the IC 50 for JAK 1 or JAK 2.
  • the compounds of this invention include all conformational isomers (eg. cis and trans isomers).
  • the compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
  • This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
  • the compounds of formula I may also exist as tautomers. This invention relates to the wee of all such tautomers and mixtures thereof.
  • This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula I.
  • This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of protein kinases, such as JAK comprising administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.
  • the compound can be used as a purified isomer or as a mixture of any ratio of isomers. It is however preferred that the mixture comprises at least 70%, 80%, 90%, 95%, or 99% of the preferred isomer.
  • the compound is selected from the compounds set out in the Examples. More preferably, the compound is selected from the compounds set out in Table 3.
  • the present invention consists in a composition comprising a carrier and at least one compound of the first aspect of the invention.
  • the present invention consists in a method of treating a tyrosine kinase-associated disease state, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention.
  • the disease state involves JAK1, JAK2, JAK3 or TYK2.
  • the disease state is selected from the group consisting of Atopy, such as Allergic Asthma, Atopic Dermatitis (Eczema), and Allergic Rhinitis; Cell Mediated Hypersensitivity, such as Allergic Contact Dermatitis and Hypersensitivity Pneumonitis; Rheumatic Diseases, such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjögren's Syndrome, Scleroderma, Polymyositis, Ankylosing Spondylitis, Psoriatic Arthritis; Other autoimmune diseases such as Type I diabetes, autoimmune thyroid disorders, and Alzheimer's disease; Viral Diseases, such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV), Human Papilloma Virus (HFV), Cancer, such as Leukemia, Lymphoma and Prostate
  • Atopy such as Alle
  • tyrosine kinase-associated disease state refers to those disorders which result from aberrant tyrosine kinase activity, in particular JAK activity and/or which are alleviated by inhibition of one or more of these enzymes.
  • the present invention provides the use of the compounds described in the preparation of medicaments for the treatment of JAK3-associated disease states.
  • the present invention provides for a method of suppressing the immune system of a subject, the method comprising administering a therapeutically effective amount of at least one compound of the first aspect of the invention or a therapeutically effective amount of a composition of the second aspect of the invention.
  • the method of suppressing the immune system is for the treatment of disease states selected from lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, and Alzheimer's disease.
  • disease states selected from lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, and Alzheimer's disease.
  • the method of suppressing the immune system is to modify the immune system response to a transplant into a subject.
  • the transplant is an organ transplant or tissue transplant.
  • compositions comprising at least one of the compounds of the formula I or II capable of treating a JAK3-associated disorder in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent.
  • the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • the compounds of the formula I or II may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • suitable means for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable
  • the compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
  • the subjects treated in the above methods, in whom which JAK3 inhibition is desired are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.
  • terapéuticaally effective amount means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspenions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such an those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixture of these.
  • Suitable emulsifying agents may be naturally-occurring gum, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty adds such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
  • topical application shall include mouthwashes and gargles.
  • the compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes arm formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines, both natural and synthetic. Methods to form liposomes are known in the art.
  • the pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.
  • the combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
  • Examples of other therapeutic agents include the following:
  • cyclosporins e.g., cyclosporin A
  • CTLA4-Ig antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD401g and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, aspirin, acetaminophen, leflunomide, deoxyspergualin, azathioprine and cycl
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/Kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • Compounds of the general formula I are generally prepared from dihaloheterocycle.
  • the synthesis may begin with a nucleophilic aromatic substitution to generate a monoamino-monohalo intermediate.
  • the nucleophilic aromatic substitution is typically carried out by addition of an amine to the di-halogenated heterocycle in a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, toluene or xylene.
  • a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, toluene or xylene.
  • the reaction is typically performed at elevated temperature in the presence of excess amine or a non-nucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.
  • the amino substituent may be introduced through a transition metal catalysed amination reaction.
  • Typical catalysts for such transformations include Pd(OAc) 2 /P(t-Bu) 3 , Pd 2 (dba) 3 /BINAP and Pd(OAc) 2 /BINAP. These reactions are typically out in solvents such as toluene or dioxane, in the presence of bases such as caesium carbonate or sodium or potassium tert-butoxide at temperatures ranging from room temperature to reflux.
  • the amines employed in the first step of the synthesis of these compounds are obtained commercially or are prepared using methods well known to those skilled in the art.
  • the synthesis typically begs with a cross-coupling reaction between dihaloheterocycle and a suitably functionalised coupling partner.
  • Typical coupling partners are boronic acids or esters (Suzuki coupling: see for example Miyaura and Suzuki 1995), stannanes (Stille coupling: see for example Stille 1986), Grignard reagents (Kumada coupling: Kumada, Tamao and Sumitani 1988) or organozinc species (Negishi coupling: Negishi 2002).
  • the Suzuki coupling is the preferred coupling method and is typically performed in a solvent such as DME, THF, DMF, ethanol, propanol, toluene, or 1,4-dioxane in the presence of a base such as potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate.
  • a base such as potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate.
  • the reaction may be carried out at elevated temperatures and the palladium catalyst employed may be selected from Pd(PPh 3 ) 4 , Pd(OAc) 2 , [PdCl 2 (dppf)], Pd 2 (dba) 3 /P(t-Bu) 3 .
  • the synthesis begins with the requisite hetaryl carboxylic acid bearing a halo group.
  • Amide derivatives of the acid may be readily formed by coupling an amine with the acid using coupling reagents such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diisopropylcarbodiimide or carbonyldiimidazole in solvents such as dichloromethane, tetrahydrofuran or 1,4-dioxane.
  • the acid can be converted to the respective acid chloride using thionyl chloride, oxalyl chloride, bis(trichloromethyl)carbonate or cyanuric chloride, or to the mixed anhydride species using, for example, t-butyl chloroformate, using procedures well known to those skilled in the art.
  • the acid chloride or mixed anhydride derivatives can then be reacted with the desired amine preferably in the presence of a base such as triethylamine, diisopropylethylamine or solid phase equivalent in a solvent such as dichloromethane, tetrahydrofuran, dioxane or ethyl acetate at ambient or elevated temperatures, to generate the amide.
  • the acid chloride may also react with the required amine under aqueous conditions preferably in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide or sodium carbonate to generate the desired amide.
  • Thioamides may be prepared from the amides formed above by methods well-known to those skilled in the art and include reaction of the amide with Lawesson's reagent in a solvent such as toluene at elevated temperature.
  • the second step of the synthesis involves a nucleophilic aromatic substitution reaction of the monohalo intermediate with a benzimidazole or azabenzimidazole.
  • the reaction is typically performed using a salt of the benzimidazole or azabenzimdazole in solvents such as THF, DMF, DMA, NMP, toluene, or xylene from room temperature to reflux.
  • the benzimidazole or azabenzimidazole salt is prepared by reaction with a metal hydride such as sodium or potassium hydride or by reaction with capture carbonate.
  • a metal-catalysed coupling reaction can be used to introduce the benzimidazole or azabenzimidazole ring.
  • Typical metal catalysts include Pd(OAc) 2 /dppf, PdCl 2 /dppe, Pd 2 (OAc) 2 /P(t-Bu) 3 , (CuOTf) 2 .PhH.
  • the reaction is typically performed using a base such as caesium carbonate, rubidium carbonate, potassium carbonate, sodium tert-butoxide or potassium phosphate in a solvent such as xylene, toluene, or DMF from room temperature to reflux.
  • auxiliary reagents such as phase transfer agents (e.g. cetrimonium bromide) or copper complexing agents (e.g. phenanthroline) may also be employed in the reaction.
  • reaction sequence outlined above may be reversed beginning with coupling of the benzimidazole or azabenzimidazole to the dihaloheterocycle using the methods outlined above, followed by introduction of the second substituent onto the heterocyclic nucleus using the procedures outlined above.
  • An alternative route to compounds of the general formula I involves a copper mediated reaction between a benzimidazole or azabenzimdazole and an organometallic reagent (see for example Finet, 2002).
  • organometallic reagents are boronic acids.
  • the thiol reactive moiety (depicted as part of the substituents Z) present in compounds of the general formula I of the invention may be already present in the functionalities employed in the synthetic processes described above or may be introduced at the final stage of the synthetic procedure.
  • the thiol reactive moiety may be introduced in compounds bearing a free hydroxyl or amino substituent by coupling with a suitable acid.
  • coupling reagents such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diisopropylcarbodiimide or carbonyldiimidazole in solvents such as dichloromethane, tetrahydrofuran or 1,4-dioxane.
  • suitable mixed anhydride species of the acid formed using, for example, t-butyl chloroformate, using procedures well known to those skilled in the art, or a suitable acid chloride derivative
  • a base such as triethylamine, diisopropylethylamine or solid phase equivalent in a solvent such as dichloromethane, tetrahydrofuran, dioxane or ethyl acetate at ambient or elevated temperatures, to generate the desired compound.
  • Example 26 The mixture of regioisomers derived from Example 26 (270 mg, 1 mmol) was hydrogenated following the procedure outlined in Example 10. The crude product was chromatographed eluting with CH 2 Cl 2 -MeOH (98:2 ⁇ 95:5) to separate the 6-isomer (84 mg) from the less polar fractions and the 5-isomer from the polar fractions. (122 mg).
  • JAK kinase domains were produced in the following manner:
  • the kinase domain of human JAK1 was amplified from U937mRNA using the polymerase chain reaction with the following primers:
  • JAK1 PCR products were cloned into the pFastBac HTb expression vector (Gibco) via the Xho I and Kpn I sites.
  • the JAK1 plasmid was then transformed into competent DH10Bac cells (Gibco), and the recombinant baculovirus produced prepared for transfection into Sf9 insect cells.
  • the kinase domain of humanJAK2 was amplified from U937mRNA using the polymerase chain reaction with the following primers:
  • JAK2 PCR products wore cloned into the pFastBac HTc expression vector (Gibco) via the Sal I and Not I sites.
  • the JAK2 plasmid was the transformed into competent DH10Bac cells (Gibco), and the recombinant baculovirus produced prepared for transfection into Sf9 insect cells.
  • the kinase domain of humanJAK3 was amplified from U937mRNA using the polymerase chain reaction with the following primers:
  • JAK3 PCR products were cloned into the pFastBac HTb expression vector (Gibco) via the Xho I and Kpn I sites.
  • the JAK3 plasmid was then transformed into competent DH10Bac cells (Gibco), and the recombinant baculovirus produced prepared for transfection into Sf9 insect cells.
  • the kinase domain of humanTYK2 was amplified from A549 mRNA using the polymerase chain reaction with the following primers:
  • TYK2 PCR products were cloned into pBlueBecHis2A (Invitrogen) via the EcoRI site.
  • the recombinant TYK2 baculovirus produced was prepared for transfected into Sf9 insect cells.
  • JAK kinase domains were purified by affinity chromatography on a Probond (Invitrogen) nickel chelate affinity column.
  • Kinase assays were performed either in a 96 well capture-based ELISA assay or in 384 well Optiplates (Packard) using an Alphascreen Protein Tyrosine Kinase kit. In either case using approximately 1.5 ⁇ g of affinity purified PTK domain in the presence of 50 mM HEPES, pH 7.5, 10 mM MgCl 2 , 150 mM NaCl and 10 ⁇ M-1 mM ATP.
  • the biotinylated substrate biotin-EGPWLEEEEEAYGWMDF-NH 2 was used as substrate.
  • tyrosine phosphorylation was quantitated following transfer to an avidin coated ELISA plate using peroxidase-linked anti-phospho-tyrosine antibody PY20.
  • Alphascreen assay Alphascreen phosphotyrosine acceptor beads followed by streptavidin donor beads were added under subdued light.
  • the ELISA plates were read on a BMG Fluorostar, the Alphascreen plates were read on a Packard Fusion Alpha.
  • Inhibitors were added to the assays fifteen minutes prior to the addition of ATP. Inhibitors were added in aqueous DMSO, with DMSO concentrations never exceeding 1%.
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Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080085909A1 (en) * 2006-02-17 2008-04-10 Pharmacopeia Drug Discovery, Inc. Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US20080085898A1 (en) * 2006-10-04 2008-04-10 Pharmacopeia, Inc. 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
US20080119496A1 (en) * 2006-11-16 2008-05-22 Pharmacopeia Drug Discovery, Inc. 7-Substituted Purine Derivatives for Immunosuppression
US20080214580A1 (en) * 2006-10-04 2008-09-04 Pharmacopeia, Inc. 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US20080287468A1 (en) * 2005-04-05 2008-11-20 Pharmacopeia, Inc. Purine and imidazopyridine derivatives for immunosuppression
US20090069289A1 (en) * 2006-10-04 2009-03-12 Pharmacopeia, Inc. 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US20090137588A1 (en) * 2007-10-19 2009-05-28 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US20090275529A1 (en) * 2008-05-05 2009-11-05 Reiss Allison B Method for improving cardiovascular risk profile of cox inhibitors
US20100016296A1 (en) * 2007-10-19 2010-01-21 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US20100029610A1 (en) * 2008-06-27 2010-02-04 Avila Therapeutics, Inc. Heteroaryl Compounds and Uses Thereof
US20100249092A1 (en) * 2008-06-27 2010-09-30 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US8563568B2 (en) 2010-08-10 2013-10-22 Celgene Avilomics Research, Inc. Besylate salt of a BTK inhibitor
WO2014013014A1 (en) 2012-07-18 2014-01-23 Fundació Privada Centre De Regulació Genòmica (Crg) Jak inhibitors for activation of epidermal stem cell populations
US8796255B2 (en) 2010-11-10 2014-08-05 Celgene Avilomics Research, Inc Mutant-selective EGFR inhibitors and uses thereof
US8975249B2 (en) 2010-11-01 2015-03-10 Celgene Avilomics Research, Inc. Heterocyclic compounds and uses thereof
US9056839B2 (en) 2012-03-15 2015-06-16 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
US9108927B2 (en) 2012-03-15 2015-08-18 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
US9126950B2 (en) 2012-12-21 2015-09-08 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9145387B2 (en) 2013-02-08 2015-09-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9187487B2 (en) 2011-05-17 2015-11-17 Principia Biopharma, Inc. Azaindole derivatives as tyrosine kinase inhibitors
US9238629B2 (en) 2010-11-01 2016-01-19 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9364476B2 (en) 2011-10-28 2016-06-14 Celgene Avilomics Research, Inc. Methods of treating a Bruton's Tyrosine Kinase disease or disorder
US9415049B2 (en) 2013-12-20 2016-08-16 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9492471B2 (en) 2013-08-27 2016-11-15 Celgene Avilomics Research, Inc. Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase
US9573958B2 (en) 2012-08-31 2017-02-21 Principia Biopharma, Inc. Benzimidazole derivatives as ITK inhibitors
US9908884B2 (en) 2009-05-05 2018-03-06 Dana-Farber Cancer Institute, Inc. EGFR inhibitors and methods of treating disorders
WO2018041989A1 (en) 2016-09-02 2018-03-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing and treating refractory celiac disease type 2
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor
US10793551B2 (en) 2017-10-19 2020-10-06 Effector Therapeutics Inc. Benzimidazole-indole inhibitors of Mnk1 and Mnk2
WO2020201362A2 (en) 2019-04-02 2020-10-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting and preventing cancer in patients having premalignant lesions
WO2020212395A1 (en) 2019-04-16 2020-10-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of jak inhibitors for the treatment of painful conditions involving nav1.7 channels
US11351168B1 (en) 2008-06-27 2022-06-07 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
WO2023222565A1 (en) 2022-05-16 2023-11-23 Institut National de la Santé et de la Recherche Médicale Methods for assessing the exhaustion of hematopoietic stems cells induced by chronic inflammation

Families Citing this family (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6878206B2 (en) 2001-07-16 2005-04-12 Applied Materials, Inc. Lid assembly for a processing system to facilitate sequential deposition techniques
TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
ES2445208T3 (es) 2002-07-29 2014-02-28 Rigel Pharmaceuticals, Inc. Compuestos de 2,4-pirimidindiamina para uso en métodos para tratar o prevenir enfermedades autoinmunitarias
KR101201603B1 (ko) 2003-07-30 2012-11-14 리겔 파마슈티칼스, 인크. 자가면역 질환의 치료 또는 예방에 사용하기 위한2,4-피리미딘디아민 화합물
CA2545425C (en) * 2003-12-03 2013-09-24 Cytopia Research Pty Ltd Azole-based kinase inhibitors
DE602005019556D1 (de) 2004-04-13 2010-04-08 Icagen Inc Polycyclische pyrazine als kaliumionenkanal-modulatoren
US7491732B2 (en) 2005-06-08 2009-02-17 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US20070203161A1 (en) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
DE602006017574D1 (de) * 2005-07-26 2010-11-25 Vertex Pharma Als protein-kinase-inhibitoren nutzbare benzimidazole
EP3332807B1 (en) 2005-10-26 2023-02-22 Novartis AG Use of anti il-1beta antibodies
ES2481671T3 (es) 2005-11-21 2014-07-31 Novartis Ag Inhibidores de mTOR en el tratamiento de tumores endocrinos
GB0601744D0 (en) 2006-01-27 2006-03-08 Novartis Ag Organic compounds
US8962643B2 (en) 2006-02-24 2015-02-24 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
TW200812587A (en) * 2006-03-20 2008-03-16 Synta Pharmaceuticals Corp Benzoimidazolyl-pyrazine compounds for inflammation and immune-related uses
JP2009530409A (ja) * 2006-03-23 2009-08-27 シンタ ファーマシューティカルズ コーポレーション 炎症及び免疫関連使用用のベンゾイミダゾリル−ピリジン化合物
EP2089369B1 (en) 2006-10-19 2011-02-02 Rigel Pharmaceuticals, Inc. 2,4 -pyrimidinediamine derivatives as inhibitors of jak kinases for the treatment of autoimmune diseases
DK2848610T3 (da) * 2006-11-15 2017-11-06 Ym Biosciences Australia Pty Hæmmere af kinaseaktivitet
AU2013273769B2 (en) * 2006-11-15 2016-05-12 Ym Biosciences Australia Pty Ltd Inhibitors of Kinase Activity
WO2008060301A1 (en) * 2006-11-16 2008-05-22 Pharmacopeia , Llc 7-substituted purine derivatives for immunosuppression
RU2009148597A (ru) 2007-05-29 2011-07-10 Новартис АГ (CH) Новые показания к применению при лечении антителами против il-1-бета
CL2008001933A1 (es) 2007-06-29 2009-09-25 Millennium Pharm Inc Compuestos derivados de pirimidina, inhibidores de la raf quinasa; compuestos intermediarios; procedimiento de preparacion; composicion farmaceutica; y su uso para tratar trastornos proliferativos, cardiacos, neurodegenerativos, inflamatorios, oseos, inmunologicos enfermedad viral, entre otros.
EP2167497A2 (en) 2007-06-29 2010-03-31 Sunesis Pharmaceuticals, Inc. Heterocyclic compounds useful as raf kinase inhibitors
US8415358B2 (en) 2007-09-17 2013-04-09 Neurosearch A/S Pyrazine derivatives and their use as potassium channel modulators
US20100233716A1 (en) 2007-11-08 2010-09-16 Pierre Saint-Mezard Transplant rejection markers
AU2008343173A1 (en) * 2007-12-19 2009-07-09 Aj Park Pyrazolo [1,5-a] pyrimidines useful as JAK2 inhibitors
US8268834B2 (en) 2008-03-19 2012-09-18 Novartis Ag Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
KR20170051521A (ko) 2008-04-16 2017-05-11 포톨라 파마슈티컬스, 인코포레이티드 ｓｙｋ 또는 ＪＡＫ 키나제 억제제로서의 ２,６－디아미노-피리미딘－５－일－카르복스아미드
US8063058B2 (en) 2008-04-16 2011-11-22 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
US8258144B2 (en) 2008-04-22 2012-09-04 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
JP5595389B2 (ja) 2008-06-20 2014-09-24 ジェネンテック， インコーポレイテッド トリアゾロピリジンｊａｋ阻害剤化合物と方法
JP5512665B2 (ja) 2008-06-20 2014-06-04 ジェネンテック， インコーポレイテッド トリアゾロピリジンｊａｋ阻害剤化合物と方法
WO2011006119A2 (en) 2009-07-09 2011-01-13 The Scripps Research Institute Gene expression profiles associated with chronic allograft nephropathy
TW201111385A (en) * 2009-08-27 2011-04-01 Biocryst Pharm Inc Heterocyclic compounds as janus kinase inhibitors
US8791100B2 (en) 2010-02-02 2014-07-29 Novartis Ag Aryl benzylamine compounds
US8247436B2 (en) 2010-03-19 2012-08-21 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
SG184989A1 (en) * 2010-04-30 2012-11-29 Cellzome Ltd Pyrazole compounds as jak inhibitors
UA112517C2 (uk) 2010-07-06 2016-09-26 Новартіс Аг Тетрагідропіридопіримідинові похідні
JP2014501705A (ja) 2010-11-01 2014-01-23 ポートラ ファーマシューティカルズ， インコーポレイテッド Ｓｙｋ調節剤としてのベンズアミドおよびニコチンアミド
TW201300360A (zh) 2010-11-01 2013-01-01 Portola Pharm Inc 做為ｊａｋ激酶調節劑之菸鹼醯胺
WO2012061415A1 (en) 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Oxypyrimidines as syk modulators
US8889684B2 (en) * 2011-02-02 2014-11-18 Boehringer Ingelheim International Gmbh Azaindolylphenyl sulfonamides as serine/threonine kinase inhibitors
WO2012135160A1 (en) 2011-03-28 2012-10-04 Pathway Therapeutics Inc. (alpha- substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5 -triazinyl benzimidazoles, pharmaceutical compositions containing them, and these compounds for use in treating proliferative diseases
CN102267980B (zh) * 2011-06-04 2012-11-21 山西大学 2，6-二苯并咪唑基吡啶的制备方法
EA201490164A1 (ru) 2011-06-27 2014-04-30 Новартис Аг Твердые формы и соли производных тетрагидропиридопиримидина
CA2841111A1 (en) 2011-07-08 2013-01-17 Novartis Ag Novel pyrrolo pyrimidine derivatives
CN103987699A (zh) 2011-10-21 2014-08-13 诺华股份有限公司 作为pi3k调节剂的喹唑啉衍生物
BR112014012396B1 (pt) 2011-11-23 2020-08-25 Portola Pharmaceuticals, Inc inibidores de pirazina quinase, composição, método in vitro para inibição de quinase syk ou via de transdução de sinal, uso dos referidos inibidores e kit
WO2013082282A1 (en) 2011-12-02 2013-06-06 lNOVARTIS AG Anti-il-1beta (interleukin-1beta) antibody-based prophylactic therapy to prevent complications leading to vaso-occlusion in sickle cell disease.
EP2790705B1 (en) 2011-12-15 2017-12-06 Novartis AG Use of inhibitors of the activity or function of pi3k
EP2794594A1 (en) 2011-12-22 2014-10-29 Novartis AG Quinoline derivatives
LT2794600T (lt) 2011-12-22 2018-02-26 Novartis Ag 2,3-dihidro-benzo[1,4]oksazino dariniai ir giminingi junginiai kaip fosfoinozitido-3 kinazės (pi3k) inhibitoriai, skirti gydymui, pavyzdžiui, reumatoidinio artrito
US9034885B2 (en) 2012-01-13 2015-05-19 Acea Biosciences Inc. EGFR modulators and uses thereof
US9586965B2 (en) 2012-01-13 2017-03-07 Acea Biosciences Inc. Pyrrolo[2,3-d]pyrimidine compounds as inhibitors of protein kinases
US9464089B2 (en) 2012-01-13 2016-10-11 Acea Biosciences Inc. Heterocyclic compounds and uses thereof
EP2802568A1 (en) 2012-01-13 2014-11-19 Acea Biosciences, Inc. Heterocyclic compounds and uses as anticancer agents.
CN104704129A (zh) 2012-07-24 2015-06-10 药品循环公司 与对布鲁顿酪氨酸激酶(btk)抑制剂的抗性相关的突变
EP2903970A4 (en) 2012-10-08 2016-11-30 Portola Pharm Inc SUBSTITUTED PYRIMIDINYL KINASE INHIBITORS
CA2892045C (en) 2012-11-21 2022-05-31 Ptc Therapeutics, Inc. Substituted reverse pyrimidine bmi-1 inhibitors
TW201422625A (zh) 2012-11-26 2014-06-16 Novartis Ag 二氫－吡啶并－□衍生物之固體形式
EP3007689B1 (en) 2013-01-10 2018-03-07 Pulmokine, Inc. Non-selective kinase inhibitors
AU2014208964B2 (en) 2013-01-23 2016-09-01 Astrazeneca Ab Chemical compounds
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
JP6564771B2 (ja) 2013-07-11 2019-08-21 エイシア バイオサイエンシーズ インコーポレイテッド キナーゼ阻害剤としてのピリミジン誘導体
UY35675A (es) 2013-07-24 2015-02-27 Novartis Ag Derivados sustituidos de quinazolin-4-ona
NZ748260A (en) 2013-08-30 2020-01-31 Ptc Therapeutics Inc Substituted pyrimidine bmi-1 inhibitors
WO2015179773A1 (en) 2014-05-22 2015-11-26 The Scripps Research Institute Tissue molecular signatures of kidney transplant rejections
MY184292A (en) 2013-09-22 2021-03-30 Sunshine Lake Pharma Co Ltd Substituted aminopyrimidine compounds and methods of use
CN106132403B (zh) 2013-10-11 2020-04-28 普尔莫凯恩股份有限公司 喷雾干燥制剂
US10584115B2 (en) * 2013-11-21 2020-03-10 Ptc Therapeutics, Inc. Substituted pyridine and pyrazine BMI-1 inhibitors
US9512084B2 (en) 2013-11-29 2016-12-06 Novartis Ag Amino pyrimidine derivatives
EA032075B1 (ru) 2014-04-24 2019-04-30 Новартис Аг Производные аминопиразина в качестве ингибиторов фосфатидилинозитол-3-киназы
BR112016024484A2 (pt) 2014-04-24 2017-08-15 Novartis Ag derivados de aminopiridina como inibidores de fosfatidilinositol 3-quinase
CA2945257A1 (en) 2014-04-24 2015-10-29 Novartis Ag Pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors
US10443100B2 (en) 2014-05-22 2019-10-15 The Scripps Research Institute Gene expression profiles associated with sub-clinical kidney transplant rejection
US11104951B2 (en) 2014-05-22 2021-08-31 The Scripps Research Institute Molecular signatures for distinguishing liver transplant rejections or injuries
TWI679205B (zh) 2014-09-02 2019-12-11 日商日本新藥股份有限公司 吡唑并噻唑化合物及醫藥
GB201518456D0 (en) * 2015-10-19 2015-12-02 Galapagos Nv Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory, autoimmune and/or proliferative diseases
TWI712604B (zh) 2016-03-01 2020-12-11 日商日本新藥股份有限公司 具jak抑制作用之化合物之結晶
EP4108659A1 (en) 2016-06-07 2022-12-28 Jacobio Pharmaceuticals Co., Ltd. Novel heterocyclic derivatives useful as shp2 inhibitors
CA3041679A1 (en) 2016-10-27 2018-05-03 Lawrence S. ZISMAN Combination therapy for treating pulmonary hypertension
AU2018239542C1 (en) 2017-03-23 2021-02-11 Jacobio Pharmaceuticals Co., Ltd. Novel heterocyclic derivatives useful as SHP2 inhibitors
CN111212837A (zh) 2017-04-07 2020-05-29 艾森医药公司 吡咯并嘧啶激酶抑制剂的药用盐、物理形态和组合物及其制备方法
MX2019013862A (es) 2017-05-23 2020-01-20 Mei Pharma Inc Terapia de combinacion.
CA3072476A1 (en) 2017-08-14 2019-02-21 Mei Pharma, Inc. Combination therapy
AU2018355487B2 (en) 2017-10-27 2023-09-21 Shanghai Yao Yuan Biotechnology Co., Ltd. Compositions and methods of modulating the immune response by activating alpha protein kinase 1
US10751339B2 (en) 2018-01-20 2020-08-25 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use
BR112021023054A2 (pt) 2019-05-23 2022-03-29 Novartis Ag Formas cristalinas de um inibidor de btk
CN112358468B (zh) * 2020-11-10 2022-03-22 德州德药制药有限公司 一种工业化合成azd9291的方法
CN112980809B (zh) * 2021-03-17 2023-04-11 云南中烟工业有限责任公司 一种烟草法尼基焦磷酸合酶基因及其应用
WO2023083330A1 (zh) * 2021-11-12 2023-05-19 百极优棠(广东)医药科技有限公司 Drak2抑制剂及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329380B1 (en) * 1999-06-30 2001-12-11 Merck & Co., Inc. SRC kinase inhibitor compounds
US6498165B1 (en) * 1999-06-30 2002-12-24 Merck & Co., Inc. Src kinase inhibitor compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4492708A (en) * 1982-09-27 1985-01-08 Eli Lilly And Company Antiviral benzimidazoles
US5990146A (en) * 1997-08-20 1999-11-23 Warner-Lambert Company Benzimidazoles for inhibiting protein tyrosine kinase mediated cellular proliferation
US6080747A (en) * 1999-03-05 2000-06-27 Hughes Institute JAK-3 inhibitors for treating allergic disorders
WO2001052892A2 (en) * 2000-01-24 2001-07-26 Genzyme Corporation Jak/stat pathway inhibitors and the uses thereof
CA2486187C (en) * 2002-05-23 2013-02-19 Cytopia Pty Ltd. Kinase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329380B1 (en) * 1999-06-30 2001-12-11 Merck & Co., Inc. SRC kinase inhibitor compounds
US6498165B1 (en) * 1999-06-30 2002-12-24 Merck & Co., Inc. Src kinase inhibitor compounds

Cited By (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080287468A1 (en) * 2005-04-05 2008-11-20 Pharmacopeia, Inc. Purine and imidazopyridine derivatives for immunosuppression
US7884109B2 (en) * 2005-04-05 2011-02-08 Wyeth Llc Purine and imidazopyridine derivatives for immunosuppression
US20080085909A1 (en) * 2006-02-17 2008-04-10 Pharmacopeia Drug Discovery, Inc. Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US7989459B2 (en) 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US20080085898A1 (en) * 2006-10-04 2008-04-10 Pharmacopeia, Inc. 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
US20080214580A1 (en) * 2006-10-04 2008-09-04 Pharmacopeia, Inc. 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US20090069289A1 (en) * 2006-10-04 2009-03-12 Pharmacopeia, Inc. 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7919490B2 (en) 2006-10-04 2011-04-05 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7915268B2 (en) 2006-10-04 2011-03-29 Wyeth Llc 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
US7902187B2 (en) 2006-10-04 2011-03-08 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US20080119496A1 (en) * 2006-11-16 2008-05-22 Pharmacopeia Drug Discovery, Inc. 7-Substituted Purine Derivatives for Immunosuppression
US20090137588A1 (en) * 2007-10-19 2009-05-28 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US9296704B2 (en) 2007-10-19 2016-03-29 Celgene Avilomics Research, Inc. Substituted pyrimidines as protein kinase inhibitors
US9393246B2 (en) 2007-10-19 2016-07-19 Celgene Avilomics Research, Inc. 4,6-disubstituted pyrimidines as kinase inhibitors
US20100016296A1 (en) * 2007-10-19 2010-01-21 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US7982036B2 (en) 2007-10-19 2011-07-19 Avila Therapeutics, Inc. 4,6-disubstitued pyrimidines useful as kinase inhibitors
US8748606B2 (en) 2007-10-19 2014-06-10 Celgene Avilomics Research, Inc. 4,6-diaminopyrimidines useful as kinase inhibitors
US7989465B2 (en) 2007-10-19 2011-08-02 Avila Therapeutics, Inc. 4,6-disubstituted pyrimidines useful as kinase inhibitors
US20110224432A1 (en) * 2007-10-19 2011-09-15 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US20110230494A1 (en) * 2007-10-19 2011-09-22 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US8329901B2 (en) 2007-10-19 2012-12-11 Celgene Avilomics Research, Inc. 4,6-disubstitued pyrimidines useful as kinase inhibitors
US9040541B2 (en) 2007-10-19 2015-05-26 Celgene Avilomics Research, Inc. 4,6-disubstituted pyrimidines useful as kinase inhibitors
US8445498B2 (en) 2007-10-19 2013-05-21 Celgene Avilomics Research, Inc. 4,6-disubstituted pyrimidines useful as kinase inhibitors
US20090275529A1 (en) * 2008-05-05 2009-11-05 Reiss Allison B Method for improving cardiovascular risk profile of cox inhibitors
US9296737B2 (en) 2008-06-27 2016-03-29 Celgene Avilomics Research, Inc. Substituted 2,4-diaminopyrimidines as kinase inhibitors
US10596172B2 (en) 2008-06-27 2020-03-24 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
US8609679B2 (en) 2008-06-27 2013-12-17 Celgene Avilomics Research, Inc. 2,4-diaminopyrimidines useful as kinase inhibitors
US11351168B1 (en) 2008-06-27 2022-06-07 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
US8710222B2 (en) 2008-06-27 2014-04-29 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US8450335B2 (en) 2008-06-27 2013-05-28 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US10828300B2 (en) 2008-06-27 2020-11-10 Celgene Car Llc Substituted 2,4-diaminopyrimidines as kinase inhibitors
US9409921B2 (en) 2008-06-27 2016-08-09 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines as kinase inhibitors
US8338439B2 (en) 2008-06-27 2012-12-25 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US20100029610A1 (en) * 2008-06-27 2010-02-04 Avila Therapeutics, Inc. Heteroaryl Compounds and Uses Thereof
US10010548B2 (en) 2008-06-27 2018-07-03 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
US9987276B2 (en) 2008-06-27 2018-06-05 Celgene Car Llc Substituted 2,4-diaminopyrimidines as kinase inhibitors
US9212181B2 (en) 2008-06-27 2015-12-15 Celgene Avilomics Research, Inc. Substituted 2,4-diaminopyrimidines as kinase inhibitors
US20100249092A1 (en) * 2008-06-27 2010-09-30 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
WO2010123870A1 (en) * 2009-04-20 2010-10-28 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US9908884B2 (en) 2009-05-05 2018-03-06 Dana-Farber Cancer Institute, Inc. EGFR inhibitors and methods of treating disorders
US8563568B2 (en) 2010-08-10 2013-10-22 Celgene Avilomics Research, Inc. Besylate salt of a BTK inhibitor
US9604936B2 (en) 2010-08-10 2017-03-28 Celgene Car Llc Besylate salt of a BTK inhibitor
US10081606B2 (en) 2010-11-01 2018-09-25 Celgene Car Llc Heteroaryl compounds and uses thereof
US9238629B2 (en) 2010-11-01 2016-01-19 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US10434101B2 (en) 2010-11-01 2019-10-08 Celgene Car Llc Heterocyclic compounds and uses thereof
US8975249B2 (en) 2010-11-01 2015-03-10 Celgene Avilomics Research, Inc. Heterocyclic compounds and uses thereof
US11096942B2 (en) 2010-11-01 2021-08-24 Celgene Car Llc Heterocyclic compounds and uses thereof
US9867824B2 (en) 2010-11-01 2018-01-16 Celgene Car Llc Heterocyclic compounds and uses thereof
US9375431B2 (en) 2010-11-01 2016-06-28 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidine compounds useful as kinase inhibtors
US9765038B2 (en) 2010-11-01 2017-09-19 Celgene Car Llc Heteroaryl compounds and uses thereof
US9409887B2 (en) 2010-11-10 2016-08-09 Celgene Avilomics Research, Inc. Mutant-selective EGFR inhibitors and uses thereof
US9868723B2 (en) 2010-11-10 2018-01-16 Celgene Car Llc Mutant-selective EGFR inhibitors and uses thereof
US8796255B2 (en) 2010-11-10 2014-08-05 Celgene Avilomics Research, Inc Mutant-selective EGFR inhibitors and uses thereof
US9187487B2 (en) 2011-05-17 2015-11-17 Principia Biopharma, Inc. Azaindole derivatives as tyrosine kinase inhibitors
US9364476B2 (en) 2011-10-28 2016-06-14 Celgene Avilomics Research, Inc. Methods of treating a Bruton's Tyrosine Kinase disease or disorder
US11292772B2 (en) 2012-03-15 2022-04-05 Celgene Car Llc Salts of an epidermal growth factor receptor kinase inhibitor
US10946016B2 (en) 2012-03-15 2021-03-16 Celgene Car Llc Solid forms of an epidermal growth factor receptor kinase inhibitor
US9540335B2 (en) 2012-03-15 2017-01-10 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
US9539255B2 (en) 2012-03-15 2017-01-10 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
US10005738B2 (en) 2012-03-15 2018-06-26 Celgene Car Llc Salts of an epidermal growth factor receptor kinase inhibitor
US10570099B2 (en) 2012-03-15 2020-02-25 Celgene Car Llc Salts of an epidermal growth factor receptor kinase inhibitor
US9056839B2 (en) 2012-03-15 2015-06-16 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
US10004741B2 (en) 2012-03-15 2018-06-26 Celgene Car Llc Solid forms of an epidermal growth factor receptor kinase inhibitor
US9108927B2 (en) 2012-03-15 2015-08-18 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
WO2014013014A1 (en) 2012-07-18 2014-01-23 Fundació Privada Centre De Regulació Genòmica (Crg) Jak inhibitors for activation of epidermal stem cell populations
US9573958B2 (en) 2012-08-31 2017-02-21 Principia Biopharma, Inc. Benzimidazole derivatives as ITK inhibitors
US9549927B2 (en) 2012-12-21 2017-01-24 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9126950B2 (en) 2012-12-21 2015-09-08 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9796700B2 (en) 2013-02-08 2017-10-24 Celgene Car Llc ERK inhibitors and uses thereof
US9504686B2 (en) 2013-02-08 2016-11-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9980964B2 (en) 2013-02-08 2018-05-29 Celgene Car Llc ERK inhibitors and uses thereof
US9561228B2 (en) 2013-02-08 2017-02-07 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9145387B2 (en) 2013-02-08 2015-09-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9492471B2 (en) 2013-08-27 2016-11-15 Celgene Avilomics Research, Inc. Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase
US9415049B2 (en) 2013-12-20 2016-08-16 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor
US10202364B2 (en) 2014-08-13 2019-02-12 Celgene Car Llc Forms and compositions of an ERK inhibitor
WO2018041989A1 (en) 2016-09-02 2018-03-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing and treating refractory celiac disease type 2
US10793551B2 (en) 2017-10-19 2020-10-06 Effector Therapeutics Inc. Benzimidazole-indole inhibitors of Mnk1 and Mnk2
WO2020201362A2 (en) 2019-04-02 2020-10-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting and preventing cancer in patients having premalignant lesions
WO2020212395A1 (en) 2019-04-16 2020-10-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of jak inhibitors for the treatment of painful conditions involving nav1.7 channels
WO2023222565A1 (en) 2022-05-16 2023-11-23 Institut National de la Santé et de la Recherche Médicale Methods for assessing the exhaustion of hematopoietic stems cells induced by chronic inflammation

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