WO2005123672A2 - Kinase inhibitors - Google Patents

Kinase inhibitors Download PDF

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Publication number
WO2005123672A2
WO2005123672A2 PCT/US2005/020890 US2005020890W WO2005123672A2 WO 2005123672 A2 WO2005123672 A2 WO 2005123672A2 US 2005020890 W US2005020890 W US 2005020890W WO 2005123672 A2 WO2005123672 A2 WO 2005123672A2
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WIPO (PCT)
Prior art keywords
alkyl
group
heteroaryl
unsubstituted
substituted
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Application number
PCT/US2005/020890
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French (fr)
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WO2005123672A3 (en
Inventor
Jerome C. Bressi
Anthony R. Gangloff
David J. Hosfield
Andrew John Jennings
Bheema R. Paraselli
Jeffrey Alan Stafford
Original Assignee
Takeda San Diego, Inc.
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Application filed by Takeda San Diego, Inc. filed Critical Takeda San Diego, Inc.
Priority to US11/570,315 priority Critical patent/US20080153869A1/en
Priority to EP05763319A priority patent/EP1773807A2/en
Priority to JP2007516629A priority patent/JP2008502687A/en
Publication of WO2005123672A2 publication Critical patent/WO2005123672A2/en
Publication of WO2005123672A3 publication Critical patent/WO2005123672A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds that may be used to inhibit kinases as well as compositions of matter and kits comprising these compounds.
  • the present invention also relates to methods for inhibiting kinases as well as treatment methods using compounds according to the present invention.
  • the invention relates to inhibitors of enzymes that catalyze phosphoryl transfer and/or that bind ATP/GTP nucleotides, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions.
  • the inhibitors and compositions comprising them are useful for treating or modulating disease in which phosphoryl transferases, including kinases, may be involved, symptoms of such disease, or the effect of other physiological events mediated by phosphoryl transferases, including kinases.
  • the invention also provides for methods of making the inhibitor compounds and methods for treating diseases in which one or more phosphoryl transferase, including kinase, activities is involved.
  • Phosphoryl transferases are a large family of enzymes that transfer phosphorous-containing groups from one substrate to another.
  • IUBMB Nomenclature Committee of the International Union of Biochemistry and Molecular Biology
  • Kinases are a class of enzymes that function in the catalysis of phosphoryl transfer.
  • the protein kinases constitute the largest subfamily of structurally related phosphoryl transferases and are responsible for the control of a wide variety of signal transduction processes within the cell.
  • Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain.
  • the protein kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, histidine, etc.). Protein kinase sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S.K.; Hunter, T., FASEB J.
  • Lipid kinases constitute a separate group of kinases with structural similarity to protein kinases.
  • Protein and lipid kinases can function in signaling pathways to activate or inactivate, or modulate the activity of (either directly or indirectly) the targets.
  • targets may include, for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors.
  • Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases and disease conditions, including, for example, inflammation, cancer, allergy/asthma, diseases and conditions of the immune system, disease and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis.
  • Protein kinases play a critical role in this regulatory process.
  • a partial non-limiting list of such kinases includes abl, Aurora-A, Aurora-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, c-Src, CDK1, CDK2, CDK4, CDK6, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Flt-1, Fps, Frk, Fyn, Hck, IGF- 1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PY
  • MAPK mitogen activated protein kinase
  • Aurora kinases are serine/threonine protein kinases that have been implicated in human cancer, such as colon, breast and other solid tumors.
  • Aurora-A also sometimes referred to as AIK
  • Aurora-A is believed to be involved in protein phosphorylation events that regulate the cell cycle.
  • Aurora-A may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities.
  • Aurora-A, Aurora-B, Aurora-C have been found to be overexpressed (See, Bischoff et al., EMBO J., 17:3052-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646 (1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)).
  • the protein kinases specifically but not limited to Aurora-A, Aurora-B and Aurora-C are especially attractive targets for the discovery of new therapeutics due to their important role in cancer, diabetes, Alzheimer's disease and other diseases.
  • the present invention relates to compounds that have activity for inhibiting kinases.
  • the present invention also provides compositions, articles of manufacture and kits comprising these compounds.
  • a pharmaceutical composition is provided that comprises a kinase inhibitor according to the present invention as an active ingredient.
  • Pharmaceutical compositions according to the invention may optionally comprise 0.001 % ⁇ 100 of one or more kinase inhibitors of this invention.
  • compositions may be administered or coadministered by a wide variety of routes, including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the compositions may also be administered or coadministered in slow release dosage forms.
  • the invention is also directed to kits and other articles of manufacture for treating disease states associated with kinases.
  • a kit comprising a composition comprising at least one kinase inhibitor of the present invention in combination with instructions.
  • the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also comprise packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • an article of manufacture is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • the compounds, compositions, kits and articles of manufacture are used to inhibit kinases.
  • the compounds, compositions, kits and articles of manufacture are used to treat a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state.
  • a compound is administered to a subject wherein kinases activity within the subject is altered, preferably reduced.
  • a prodrug of a compound is administered to a subject that is converted to the compound in vivo where it inhibits kinases.
  • a method of inhibiting kinases comprises contacting kinases with a compound according to the present invention.
  • a method of inhibiting kinases comprises causing a compound according to the present invention to be present in a subject in order to inhibit kinases in vivo.
  • a method of inhibiting kinases comprises administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits kinases in vivo.
  • the compounds of the present invention may be the first or second compounds.
  • a therapeutic method comprises administering a compound according to the present invention.
  • a method of inhibiting cell proliferation comprises contacting a cell with an effective amount of a compound according to the present invention.
  • a method of inhibiting cell proliferation in a patient comprises administering to the patient a therapeutically effective amount of a compound according to the present invention.
  • a method of treating a condition in a patient which is known to be mediated by kinases, or which is known to be treated by kinase inhibitors comprising administering to the patient a therapeutically effective amount of a compound according to the present invention.
  • a method is provided for using a compound according to the present invention in order to manufacture a medicament for use in the treatment of disease state which is known to be mediated by kinases, or which is known to be treated by kinase inhibitors.
  • a method for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: causing a compound according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
  • a method for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a first compound to a subject that is converted in vivo to a second compound such that the second compound is present in the subject in a therapeutically effective amount for the disease state.
  • the compounds of the present invention may be the first or second compounds.
  • a method for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a compound according to the present invention to a subject such that the compound is present in the subject in a therapeutically effective amount for the disease state.
  • the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well know in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers.
  • pharmaceutically acceptable ionized forms e.g., salts
  • solvates e.g., hydrates
  • prodrugs may also be administered which are altered in vivo and become a compound according to the present invention.
  • the various methods of using the compounds of the present invention are intended, regardless of whether prodrug delivery is specified, to encompass the administration of a prodrug that is converted in vivo to a compound according to the present invention.
  • certain compounds of the present invention may be altered in vivo prior to inhibiting kinases and thus may themselves be prodrugs for another compound.
  • Such prodrugs of another compound may or may not themselves independently have kinase inhibitory activity.
  • Alicyclic means a moiety comprising a non-aromatic ring structure.
  • Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quatemerized or oxidized and the sulfur atoms can be optionally oxidized.
  • alicyclic moieties include, but are not limited to moieties with C3 - C8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.
  • C3 - C8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene
  • Aliphatic means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.
  • Alkoxy means an oxygen moiety having a further alkyl substituent.
  • the alkoxy groups of the present invention can be optionally substituted.
  • Alkyl represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with oxygen (See
  • oxaalkyl or nitrogen atoms (See “aminoalkyl”) between the carbon atoms.
  • C x alkyl and C ⁇ . ⁇ alkyl are typically used where X and Y indicate the number of carbon atoms in the chain.
  • C 1-6 alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like).
  • 1 and 6 carbons e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-
  • Alkyl represented along with another radical means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C 6-1 o)aryl(C 1- )alkyl includes, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like).
  • Alkylene unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical.
  • Cx alkylene and C ⁇ .y alkylene are typically used where X and Y indicate the number of carbon atoms in the chain.
  • Alkylidene means a straight or branched saturated or unsaturated, aliphatic radical connected to the parent molecule by a double bond.
  • Cx alkylidene and C ⁇ . ⁇ alkylidene are typically used where X and Y indicate the number of carbon atoms in the chain.
  • amino means a nitrogen moiety having two further substituents where, for example, a hydrogen or carbon atom is attached to the nitrogen.
  • representative amino groups include -NH 2 , -NHCH , -N(CH 3 ) 2 , -NH .io-alkyl, -N(C 1-10 - alkyl) 2/ -NHaryl, -NHheteroaryl, -N(aryl) 2 , -N(heteroaryl) 2 , and the like.
  • the two substituents together with the nitrogen may also form a ring.
  • the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Aminoalkyl means an alkyl, as defined above, except where one or more substituted or unsubstituted nitrogen atoms (-N-) are positioned between carbon atoms of the alkyl.
  • an (C 2-6 ) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.
  • "Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
  • Aromatic means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp 2 hybridized and the total number of pi electrons is equal to 4n+2.
  • An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
  • Aryl means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. Cx aryl and C ⁇ . ⁇ aryl are typically used where X and Y indicate the number of atoms in the ring.
  • Bicycloalkyl means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.
  • Bicycloaryl means a bicyclic ring assembly wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic.
  • C bicycloaryl and C x- ⁇ bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring.
  • “Bridging ring” as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where two ring atoms that are common to both rings are not directly bound to each other.
  • Non-exclusive examples of common compounds having a bridging ring include borneol, norbornane, 7- oxabicyclo[2.2.1]heptane, and the like.
  • One or both rings of the bicyclic system may also comprise heteroatoms.
  • Carbamoyl means the radical -OC(O)NR a R b where R a and R b are each independently two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
  • Carbocycle means a ring consisting of carbon atoms.
  • Carbocyclic ketone derivative means a carbocyclic derivative wherein the ring contains a -CO- moiety.
  • Carbonyl means the radical -CO-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.
  • Carboxy means the radical -CO 2 -. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
  • Cyano means the radical -CN.
  • Cycloalkyl means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly.
  • Cx cycloalkyl and C ⁇ . ⁇ cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • C 3-10 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, and the like.
  • Cycloalkylene means a divalent saturated or partially unsaturated, monocyclic or polycyclic ring assembly. C cycloalkylene and C ⁇ . ⁇ cycloalkylene are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
  • fused ring refers to a ring that is bonded to another ring to form a compound having a bicyclic structure when the ring atoms that are common to both rings are directly bound to each other.
  • Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like.
  • Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, and the like.
  • "Halo" means fluoro, chloro, bromo or iodo.
  • Halo-substituted alkyl as an isolated group or part of a larger group, means “alkyl” substituted by one or more "halo" atoms, as such terms are defined in this Application.
  • Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C 1- )alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like).
  • Heterobicycloalkyl means bicycloalkyl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
  • hetero(C 9-12 )bicycloalkyl as used in this application includes, but is not limited to, 3-aza- bicyclo[4.1.0]hept-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl , 3-aza-bicyclo[3.1.0]hex-3-yl, and the like.
  • Heterocyclo alkylene means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.
  • Heteroaryl means a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The nitrogen atoms can be optionally quatemerized and the sulfur atoms can be optionally oxidized.
  • Heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.
  • Heteroaryl also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring.
  • bicyclic or tricyclic heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2- b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[l,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, imidazo[l,2-a]pyrimidine, imidazo[l,2-c]pyrimidine, imidazo[l,5
  • the bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused.
  • the heteroaryl groups of this invention can be substituted or unsubstituted.
  • Heterobicycloaryl means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
  • hetero(C 8-1 o)bicycloaryl as used in this Application includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and the like.
  • Heterocycloalkyl means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, O, or S.
  • heterocycloalkyl examples include piperidyl, 4- morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the like.
  • "Hydroxy" means the radical -OH.
  • Iminoketone derivative means a derivative comprising the moiety -C(NR)-, wherein R comprises a hydrogen or carbon atom attached to the nitrogen.
  • “Isomers” mean any compound having an identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space.
  • stereoisomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers.”
  • a carbon atom bonded to four nonidentical substituents is termed a “chiral center.”
  • a compound with one chiral center has two enantiomeric forms of opposite chirality.
  • a mixture of the two enantiomeric forms is termed a "racemic mixture.”
  • a compound that has more than one chiral center has 2 n ⁇ enantiomeric pairs, where n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog.
  • Niro means the radical -NO 2 .
  • Oxaalkyl means an alkyl, as defined above, except where one or more oxygen atoms (-O-) are positioned between carbon atoms of the alkyl.
  • an (C 2-6 )oxaalkyl refers to a chain comprising between 2 and 6 carbons and one or more oxygen atoms positioned between the carbon atoms.
  • Oxoalkyl means an alkyl, further substituted with a carbonyl group.
  • the carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts of inhibitors of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobro ic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • Prodrug means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention.
  • the prodrug itself may or may not also have kinase inhibitory activity.
  • an inhibitor comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
  • esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.
  • an inhibitor comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
  • Protected derivatives means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
  • Substituted or unsubstituted means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
  • isopropyl is an example of an ethylene moiety that is substituted by -CH 3 .
  • a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted.
  • substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, (C 1-1 o)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
  • Sulfinyl means the radical -SO-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
  • Sulfonyl means the radical -SO2-. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
  • “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • Thiocarbonyl means the radical -CS-. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.
  • Treatment means any administration of a compound of the present invention and includes: (1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology) .
  • a Ci alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom.
  • a alkyl comprises methyl (i.e., -CH 3 ) as well as -CR a RbR c where R a , Rb, and R c may each independently be hydrogen or any other substituent where the atom attached to the carbon is a heteroatom or cyano.
  • CF 3 , CH OH and CH CN are all alkyls.
  • kinase inhibitors of the present invention comprise one of the following formula:
  • J, K, L, and Y are each independently selected from the group consisting of C and
  • N is selected from the group consisting of CH and N;
  • X and Z are each independently selected from the group consisting of C, N, O and
  • R 3 , , and R 5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - 1 o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C 1 - 1 o)alkyl, (C 3-12 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C l o)alkyl, heteroaryl(C ⁇ - 5 )alkyl, (C 9-12 )bicycloaryl, hetero(C -12 )bicycloaryl, carbonyl(C 1- )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1- )alkyl, sulfinyl(C 1- )alkyl, imino(C ⁇ -3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy,
  • kinase inhibitors of the present invention comprise the formula:
  • J, K, L and M each comprise a carbon ring atom.
  • J, K and L each comprise a carbon ring atom and M is nitrogen.
  • at least one of X, Y and Z optionally comprise a nitrogen ring atom.
  • Y can be N.
  • X and Y optionally comprise substituents that form a second ring fused to the ring comprising X and Y.
  • W and X can comprise substituents that form a second ring fused to the ring comprising W andX.
  • the ring formed by J, K, L and M can comprise substituents that form a ring fused to the ring formed by J, K, L and M.
  • X and Y comprise substituents that form a second ring fused to the ring comprising X and Y, and the ring formed by J, K, L and M comprises substituents that form a ring fused to the ring formed by J, K, L and M.
  • the fused ring can comprise a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring.
  • the fused ring can be an alicyclic ring, such as, for example a substituted or unsubstituted pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline or triazine.
  • kinase inhibitors of the present invention comprise the formula:
  • J, K, L, W and Y are each independently selected from the group consisting of C and N;
  • M is selected from the group consisting of CH and N;
  • V 1; V 2 , V 3 , and V 4 are each independently selected from the group consisting of C and N when the respective atom is part of a ring double bond and are independently selected from the group consisting of C, N, O and S when the respective atom is not part of a double bond;
  • R , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, perhalo(Cr 10 )alkyl, amino, nitro, cyano, thio, sulfonamide, (C 1 - 1 o)alkyl, (C 3-12 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 - ⁇ o)alkyl, heteroaryl(C 1 - 5 )alkyl, (C 9-12 )bicycloary
  • R 12 , R 1 and R 1 may optionally each be independently selected from the group consisting of hydrogen, F, Br, Cl, -OCH 3 , -SO 2 Me, -SO 2 NH 2 , -SO 2 NHMe, -SO 2 NHCH 2 CH 2 OH, -SO 2 NMe 2 , -NHSO 2 (3-fluorophenyl), perhalo(C ⁇ o )alkyl, -OCF 3 , -CF 3 , (C ri o)alkyl, hydroxy- (C 1 - 1 o)alkyl, aryl, aryl-(C 1 - 1 o)alkyl, heteroaryl, aminosulfonyl, alkyls
  • R ⁇ 2) R 13 and R 1 may each optionally be independently selected from the group consisting of hydrogen, (C 1-6 )alkyl, hydroxy, hydroxy-(C 1-6 )alkyl, carboxamide, mono-(C 1-6 )alkyl aminocarbonyl, substituted aryl-(C 1-6 )alkyl, heteroaryl, heterocyclo, heteroaryl-(C 1-6 )alkyl, (C 1-6 )alkoxy, aryloxy, heteroaryloxy, amino, mono- or di-(C 1-6 )alkyl-amino, (C 1-6 )alkyl aminocarbonyl, mono- or di-(C 1-6 )alkyl-amino (C 1-6 )alkoxycarbonyl, mono- or di-(C 1- 6 )alkyl-amino (C 1-6 )alkyl aminocarbonylamino, mono- or di-(C 1- )
  • Y is N and R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, (C 1-6 )alkyl, hydroxy, hydroxy-(C 1-6 )alkyl, carboxamide, mono-(C 1-6 )alkyl aminocarbonyl, substituted aryl-(C 1-6 )alkyl, heteroaryl, heterocyclo, heteroaryl-(C 1-6 )alkyl, heterocyclyl-(C 1-6 )alkyl, heteroaryloxy, heterocyclyloxy, mono- or di-(C 1-6 )alkyl-amino (C 1-6 )alkyl aminocarbonyl, mono- or di-(C 1-6 )alkyl-amino ( .
  • kinase inhibitors of the present invention comprise one of the following formula: wherein: R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - 1 o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C 1 - 1 o)alkyl, (C 3-1 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 - 10 )alkyl, heteroaryl(Cr 5 )alkyl, (C 9-12 )bicycloaryl, hetero(C -12 )bicycloaryl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1- )alkyl, sulfonyl(C ⁇ -3 )alkyl, sulfinyl(C 1-3 )alkyl, imino(C
  • R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - 1 o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C 1 - 1 o)alkyl, (C 3 - 12 )cycloalkyl, hetero(C - 12 )cycloalkyl, aryl(C 1 - 1 o)alkyl, heteroaryl(C 1 - 5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1- )alkyl, sulfinyl(C 1-3 )alkyl, imino(C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, ary
  • kinase inhibitors of the present invention comprise the following formula:
  • R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - 1 o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C 1 - 10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 - 1 o)alkyl, heteroaryl(Cr 5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, imino(C 1 .
  • R 7 is hydrogen or a substituent convertible in vivo to hydrogen
  • R 14 is selected from the group consisting of hydrogen, (C 1-12 )alkyl, alkoxy, thio, hydroxy, (C 3-12 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, hetero(C 3 - 12 )cycloalkoxy, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy,
  • kinase inhibitors of the present invention comprise the following formula:
  • R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - 10 )alkyl, amino, nitro, cyano, thio, sulfonamide, (C 1 - 1 o)alkyl, (C 3-1 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 - 1 o)alkyl, heteroaryl(C 1 - 5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1- )alkyl, sulfinyl(C 1-3 )alkyl, imino(C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy
  • kinase inhibitors of the present invention comprise one of the following formula: wherein: i, V 2 , V 3 , and V 4 are each independently selected from the group consisting of C, N, O and S; R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - 1 o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C 1 - 10 )alkyl, (C 3- ⁇ 2 )cycloalkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C 1 - 10 )alkyl, heteroaryl(C 1 - 5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sul
  • kinase inhibitors of the present invention comprise one of the following formula:
  • W, X, and Y are each independently selected from the group consisting of C and
  • R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - ⁇ o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C 1 - 10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C ⁇ - 1 o)alkyl, heteroaryl(C 1 - 5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C ⁇ -3 )alkyl, sulfinyl(C ⁇ -3 )alkyl, imino(C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryl
  • R 12 and R 1 or R 13 and R 1 may optionally be taken together to form a substituted or unsubstituted fused ring.
  • the fused ring is an alicyclic ring.
  • the fused ring is a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring.
  • R 16 and the ring substituent nearest R 16 may optionally be taken together to form a substituted or unsubstituted fused ring.
  • R 14 and R 16 can be taken together to from an unsubstituted or substituted ring.
  • the fused ring thus formed is an alicyclic ring.
  • the fused ring thus formed is a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring.
  • R 16 and R 1 can be selected from the group consisting of hydrogen and ( - ⁇ ) alkyl.
  • R 1 is H.
  • R 16 and R 17 are both independently selected from the group consisting of hydrogen and (C ⁇ _ ⁇ ) alkyl.
  • R 16 and R 17 are both hydrogen.
  • kinase inhibitors of the present invention comprise one of the following formula:
  • J, K, L, and Y are each independently selected from the group consisting of C and
  • kinase inhibitors of the present invention comprise one of the following formula:
  • kinase inhibitors include, but are not limited to: 3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indol-2-ol; 5-fluoro-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indol-2-ol; 2-hydroxy-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indole-5-carbonitrile; (Z)-N',2-dihydroxy-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indole-5-carboxamidine; N-(2-hydroxy-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indol-5- yl)methanesulfonamide; 2-hydroxy-N-methyl-3-(lH-pyrrolo[2,3-b]pyridin-6
  • the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or prodrug thereof.
  • the compound optionally comprises a substituent that is convertible in vivo to a different substituent such as a hydrogen.
  • the compounds of the present invention may optionally be solely or predominantly in the enol tautomer in its active state. It is further noted that the compound may be present in a mixture of stereoisomers, or the compound comprises a single stereoisomer.
  • compositions comprising, as an active ingredient, a compound according to any one of the above embodiments and variations.
  • the composition may be a solid or liquid formulation adapted for oral administration.
  • the pharmaceutical composition may be a tablet.
  • the pharmaceutical composition may be a liquid formulation adapted for parenteral administration.
  • the pharmaceutical composition comprising a compound according to each of the above variations wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, mtraarticularly, and intrathecally.
  • the invention also provides a kit comprising a compound or composition according to any one of the above embodiments and variations, and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.
  • the kit comprises the compound or composition in a multiple dose form.
  • the present invention provides an article of manufacture comprising a compound or composition according to any one of the above embodiments and variations, and packaging materials.
  • the packaging material comprises a container for housing the compound or composition.
  • the container optionally comprises a label indicating a disease state for which the compound or composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound or composition.
  • the article of manufacture optionally comprises the compound or composition in a multiple dose form.
  • the present invention provides a method of inhibiting kinase comprising contacting kinase with a compound or composition according to any one of the above embodiments and variations.
  • the inhibition arises from a favorable conformation adopted by the compound in its enol form, and the conformation arises from an intramolecular hydrogen bonding of the enol hydrogen and an adjacent nitrogen atom of the compound.
  • the inhibition arises from a favorable conformation adopted by the compound in its enol form, and the inhibition arises from a hydrogen bonding interaction between the enol tautomer and an active site residue of the kinase.
  • a method of inhibiting kinase comprising causing a compound or composition according to any one of the above embodiments and variations to be present in a subject in order to inhibit kinase in vivo.
  • the present invention also provides a method of inhibiting kinase comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits kinase in vivo, the second compound being a compound according to any one of the above embodiments and variations.
  • the present invention provides a therapeutic method comprising administering a compound or composition according to any one of the above embodiments and variations to a subject.
  • a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising causing a compound or composition according to any one of the above embodiments and variations to be present in a subject in a therapeutically effective amount for the disease state.
  • the present invention also provides a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising administering a first compound to a subject that is converted in vivo to a second compound according to any one of the above embodiments and variations wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
  • a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising administering a compound or composition according to any one of the above embodiments and variations, wherein the compound or composition is present in the subject in a therapeutically effective amount for the disease state.
  • a method for treating cancer comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a composition of the present invention.
  • the cancer is selected from the group consisting of squamous cell carcinoma, astrocytoma,
  • Kaposi's sarcoma Kaposi's sarcoma, glioblastoma, non small-cell lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.
  • a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: causing a compound or composition according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
  • a method for treating inflammation, inflammatory bowel disease, psoriasis, or transplant rejection comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to the present invention.
  • the present invention provides a method of preventing or treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound according to any one of the compounds or compositions of the present invention wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
  • a method of preventing or treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a compound or composition of the present invention, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.
  • a method for preventing or treating dementia related diseases and Alzheimer's Disease comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiments.
  • the dementia related diseases are selected from the group consisting of Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Guam, HIV dementia, diseases with associated neurofibrillar tangle pathologies, predemented states, vascular dementia, dementia with Lewy bodies, Frontotemporal dementia and dementia pugilistica.
  • a method for preventing or treating amyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome, Huntington's Disease, Parkinson's Disease, postencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma and other chronic neurodegenerative diseases, Bipolar Disease, affective disorders, depression, schizophrenia, cognitive disorders, hair loss and contraceptive medication comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiments.
  • a method for preventing or treating mild Cognitive Impairment, Age-Associated Memory Impairment, Age-Related Cognitive Decline, Cognitive Impairment No Dementia, mild cognitive decline, mild neurocognitive decline, Late-Life Forgetfulness, memory impairment and cognitive impairment and androgenetic alopecia comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound or composition according to any one of the above embodiments.
  • a method for preventing or treating dementia related diseases, Alzheimer's Disease and conditions associated with kinases comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound or composition according to the above embodiments.
  • a method for treating arthritis comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiment.
  • a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a first compound to a subject that is converted in vivo to a second compound or composition according to any one of the present invention, wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
  • a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a compound or composition according to any one of the above embodiment, wherein the compound is present in the subject in a therapeutically effective amount for the pathology and/or symptomology.
  • the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or a prodrug thereof (e.g., where the compound comprises a substituent that is convertible in vivo to a different substituent such as hydrogen).
  • the compounds of the present invention may optionally be solely or predominantly in the enol tautomer in its active state.
  • the compounds of the present invention may be present as a mixture of stereoisomers or may be present as a single stereoisomer.
  • the compounds of the present invention may be present and optionally administered in the form of salts, hydrates and prodrugs that are converted in vivo into the compounds of the present invention.
  • the compounds of the present invention possess a free base form
  • the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
  • a pharmaceutically acceptable inorganic or organic acid e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide
  • other mineral acids and their corresponding salts such as sulfate, n
  • Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, man
  • a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • bases include alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N- methylglutamine.
  • aluminum salts of the compounds of the present invention are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N- methylglutamine.
  • aluminum salts of the compounds of the present invention are also included.
  • Organic base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts.
  • Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl
  • N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 °C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
  • Prodrug derivatives of compounds according to the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention.
  • prodrugs can be prepared by reacting a compound with a carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate, ⁇ ra-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods of making prodrugs are described in Saulnier et /.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.
  • Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • a "pharmaceutically acceptable salt”, as used herein, is intended to encompass any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound.
  • the pharmaceutically acceptable salt form may also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body.
  • An example of a pharmacokinetic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound.
  • a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds.
  • the diastereomers may then be separated in order to recover the optically pure enantiomers.
  • Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
  • Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities.
  • diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility.
  • separation/resolution techniques A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • compositions and administration methods may be used in conjunction with the kinase inhibitors of the present invention.
  • Such compositions may include, in addition to the kinase inhibitors of the present invention, conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive agents.
  • the compositions may include active agents in addition to the kinase inhibitors of the present invention.
  • additional active agents may include additional compounds according to the invention, and/or one or more other pharmaceutically active agents.
  • compositions may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used.
  • routes of administration for oral administration, capsules and tablets are typically used.
  • parenteral administration reconstitution of a lyophilized powder, prepared as described herein, is typically used.
  • compositions comprising kinase inhibitors of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermaliy, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
  • kinase inhibitors and compositions comprising them may be administered or coadministered in any conventional dosage form.
  • Co-administration in the context of this invention is intended to mean the administration of more than one therapeutic agent, one of which includes a kinase inhibitor, in the course of a coordinated treatment to achieve an improved clinical outcome.
  • Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; agents for the adjustment of tonicity such as sodium chloride or dextrose, and agents for adjusting the acidity or alkalinity of the composition, such as alkaline or acidifying agents or buffers like carbonates, bicarbonates, phosphates, hydrochloric acid, and organic acids like acetic and citric acid.
  • a sterile diluent such as water for injection,
  • Parenteral preparations may optionally be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
  • methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate.
  • cosolvents such as dimethylsulfoxide (DMSO)
  • surfactants such as TWEEN
  • dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
  • Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
  • a solution, suspension, emulsion or the like may be formed.
  • the form of the resulting composition will depend upon a number of factors, including the intended mode of administration, and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration needed to ameliorate the disease being treated may be empirically determined.
  • compositions according to the present invention are optionally provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds, particularly the pharmaceutically acceptable salts, preferably the sodium salts, thereof.
  • the pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms.
  • Unit-dose forms refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art.
  • Each unit- dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
  • unit-dose forms include ampoules and syringes individually packaged tablet or capsule.
  • Unit-dose forms may be administered in fractions or multiples thereof.
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form.
  • Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pint or gallons.
  • multiple dose form is a multiple of unit-doses that are not segregated in packaging.
  • the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
  • a lubricant such as magnesium stearate, calcium stearate and talc
  • a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like
  • the pharmaceutical composition to be administered may also contain minor amounts of auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • composition or formulation to be administered will, in any event, contain a sufficient quantity of a kinase inhibitor of the present invention to reduce kinases activity in vivo, thereby treating the disease state of the subject.
  • Dosage forms or compositions may optionally comprise one or more kinase inhibitors according to the present invention in the range of 0.005% to 100% (weight/weight) with the balance comprising additional substances such as those described herein.
  • a pharmaceutically acceptable composition may optionally comprise any one or more commonly employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum.
  • compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these formulations are known to those skilled in the art.
  • the compositions may optionally contain 0.01%-100% (weight/weight) of one or more kinase inhibitors, optionally 0.1- 95%, and optionally 1-95%.
  • Salts, preferably sodium salts, of the kinase inhibitors may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
  • the formulations may further include other active compounds to obtain desired combinations of properties.
  • Oral pharmaceutical dosage forms may be as a solid, gel or liquid.
  • solid dosage forms include, but are not limited to tablets, capsules, granules, and bulk powders. More specific examples of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated or film-coated.
  • capsules include hard or soft gelatin capsules. Granules and powders may be provided in non- effervescent or effervescent forms. Each may be combined with other ingredients known to those skilled in the art.
  • kinase inhibitors according to the present invention are provided as solid dosage forms, preferably capsules or tablets.
  • the tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
  • binders examples include, but are not limited to, microcrystallme cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
  • lubricants examples include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
  • diluents examples include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
  • glidants examples include, but are not limited to, colloidal silicon dioxide.
  • disintegrating agents examples include, but are not limited to, crosscarmellose sodium, sodium starch glycolate, alginic acid, com starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • coloring agents examples include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • sweetening agents examples include, but are not limited to, sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray-dried flavors.
  • flavoring agents examples include, but are not limited to, natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
  • wetting agents examples include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • anti-emetic coatings examples include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
  • film coatings examples include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
  • the salt of the compound may optionally be provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • the composition may also be formulated in combination with an antacid or other such ingredient.
  • dosage unit form When the dosage unit form is a capsule, it may optionally additionally comprise a liquid carrier such as a fatty oil.
  • dosage unit forms may optionally additionally comprise various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • Compounds according to the present invention may also be administered as a component of an elixir, suspension, sy p, wafer, sprinkle, chewing gum or the like.
  • a sy p may optionally comprise, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the kinase inhibitors of the present invention may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. For example, if a compound is used for treating asthma or hypertension, it may be used with other bronchodilators and antihypertensive agents, respectively.
  • Examples of pharmaceutically acceptable carriers that may be included in tablets comprising kinase inhibitors of the present invention include, but are not limited to binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.
  • Enteric-coated tablets because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines.
  • Sugar- coated tablets may be compressed tablets to which different layers of pharmaceutically acceptable substances are applied.
  • Film-coated tablets may be compressed tablets that have been coated with polymers or other suitable coating. Multiple compressed tablets may be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in tablets.
  • Flavoring and sweetening agents may be used in tablets, and are especially useful in the formation of chewable tablets and lozenges.
  • liquid oral dosage forms that may be used include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • aqueous solutions examples include, but are not limited to, elixirs and syrups.
  • elixirs refer to clear, sweetened, hydroalcoholic preparations.
  • pharmaceutically acceptable carriers examples include, but are not limited to solvents.
  • solvents include glycerin, sorbitol, ethyl alcohol and symp.
  • syrups refer to concentrated aqueous solutions of a sugar, for example, sucrose. Syrups may optionally further comprise a preservative.
  • Emulsions refer to two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may optionally be oil-in- water or water-in-oil emulsions. Examples of pharmaceutically acceptable carriers that may be used in emulsions include, but are not limited to non-aqueous liquids, emulsifying agents and preservatives.
  • Examples of pharmaceutically acceptable substances that may be used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents.
  • Examples of pharmaceutically acceptable substances that may be used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents may optionally be used in all of the above dosage forms.
  • preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
  • Diluents include lactose and sucrose.
  • Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
  • wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • organic acids that may be used include citric and tartaric acid.
  • Sources of carbon dioxide that may be used in effervescent compositions include sodium bicarbonate and sodium carbonate.
  • Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • Particular examples of flavoring agents that may be used include natural flavors extracted from plants such f its, and synthetic blends of compounds that produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
  • Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the solution e.g., for example, in a polyethylene glycol
  • a pharmaceutically acceptable liquid carrier e.g. water
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Other useful formulations include those set forth in U.S. Pat. Nos. Re 28,819 and 4,358,603.
  • compositions designed to administer the kinase inhibitors of the present invention by parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
  • injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • excipients examples include, but are not limited to water, saline, dextrose, glycerol or ethanol.
  • the injectable compositions may also optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained see, e.g., U.S. Pat. No.
  • Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.
  • suitable carriers include, but are not limited to physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • PBS physiological saline or phosphate buffered saline
  • thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • Examples of pharmaceutically acceptable carriers that may optionally be used in parenteral preparations include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • aqueous vehicles examples include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
  • nonaqueous parenteral vehicles examples include fixed oils of vegetable origin, cottonseed oil, com oil, sesame oil and peanut oil.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations may be added to parenteral preparations, particularly when the preparations are packaged in multiple-dose containers and thus designed to be stored and multiple aliquots to be removed. Examples of antimicrobial agents that may be used include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Examples of isotonic agents that may be used include sodium chloride and dextrose.
  • Examples of buffers that may be used include phosphate and citrate.
  • antioxidants that may be used include sodium bisulfate.
  • Examples of local anesthetics that may be used include procaine hydrochloride.
  • Examples of suspending and dispersing agents that may be used include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
  • Examples of emulsifying agents that may be used include Polysorbate 80 (TWEEN 80).
  • a sequestering or chelating agent of metal ions include EDTA.
  • Pharmaceutical carriers may also optionally include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
  • concentration of a kinase inhibitor in the parenteral formulation may be adjusted so that an injection administers a pharmaceutically effective amount sufficient to produce the desired pharmacological effect.
  • concentration of a kinase inhibitor and/or dosage to be used will ultimately depend on the age, weight and condition of the patient or animal as is known in the art.
  • Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration should be sterile, as is know and practiced in the art.
  • Injectables may be designed for local and systemic administration.
  • a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, preferably more than 1% w/w of the kinase inhibitor to the treated tissue(s).
  • the kinase inhibitor may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the composition is parenterally administered, the carrier and other variables that may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data.
  • concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Hence, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulations.
  • the kinase inhibitor may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease state and may be empirically determined.
  • the kinase inhibitors of the present invention may also be prepared as lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures.
  • the lyophilized powders may also be formulated as solids or gels.
  • Sterile, lyophilized powder may be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation.
  • the lyophilized powder may optionally be prepared by dissolving dextrose, sorbitol, fructose, corn symp, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5 to 15%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • a suitable buffer such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • a kinase inhibitor is added to the resulting mixture, preferably above room temperature, more preferably at about 30-35 °C, and stirred until it dissolves.
  • the resulting mixture is diluted by adding more buffer to a desired concentration.
  • the resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization.
  • the kinase inhibitors of the present invention may also be administered as topical mixtures.
  • Topical mixtures may be used for local and systemic administration.
  • the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
  • the kinase inhibitors may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Pat. Nos.
  • compositions for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.
  • the kinase inhibitors may also be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracistemal or intraspinal application.
  • Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the kinase inhibitor alone or in combination with other pharmaceutically acceptable excipients can also be administered.
  • rectal administration may also be used.
  • pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect.
  • Rectal suppositories are used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
  • Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
  • bases examples include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used.
  • Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration may be manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
  • oral, intravenous and tablet formulations that may optionally be used with compounds of the present invention. It is noted that these formulations may be varied depending on the particular compound being used and the indication for which the formulation is going to be used.
  • ORAL FORMULATION Compound of the Present invention 10-100 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL INTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mg Dextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL TABLET FORMULATION Compound of the Present Invention 1 % Microcrystallme Cellulose 73% Stearic Acid 25% Colloidal Silica 1%. Kits Comprising Kinase Inhibitors
  • the invention is also directed to kits and other articles of manufacture for treating diseases associated with kinases. It is noted that diseases are intended to cover all conditions for which the kinases possesses activity that contributes to the pathology and or symptomology of the condition.
  • a kit comprising a composition comprising at least one kinase inhibitor of the present invention in combination with instmctions.
  • the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also comprise packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • an article of manufacture is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instmctions regarding how to administer the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • a pharmaceutically acceptable material for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container that is employed will depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in
  • the kit includes directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, topical, transdermal and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • kits are a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter that indicates the number of daily doses that has been dispensed.
  • a memory-aid is a battery- powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds.
  • the diastereomers may then be separated in order to recover the optically pure enantiomers.
  • Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
  • Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities.
  • diastereomers can typically be separated by chromatography or by separation resolution techniques based upon differences in solubility.
  • separation resolution techniques based upon differences in solubility.
  • Compounds according to the present invention can also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds are set forth in the definitions section of this Application.
  • the salt forms of the compounds can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
  • N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, r ⁇ et ⁇ -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 °C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, r ⁇ et ⁇ -chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • the N-oxides of the compounds can be prepared from the N-oxide of an appropriate
  • Compounds in an unoxidized form can be prepared from N-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 °C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et ⁇ /.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodmgs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate, ⁇ r ⁇ -nitrophenyl carbonate, or the like).
  • Protected derivatives of the compounds can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, Inc. 1999.
  • Compounds according to the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds according to the present invention can also be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • g grams
  • mg milligrams
  • L liters
  • mL milliliters
  • ⁇ L microliters
  • psi pounds per square inch
  • M molar
  • mM millimolar
  • ⁇ NMR spectra were recorded on a Bmker Avance 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of Hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
  • MS mass spectra
  • compound purity data were acquired on a Waters ZQ LC MS single quadrapole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD).
  • ESI electrospray ionization
  • ELSD evaporative light scattering detector
  • Thin-layer chromatography was performed on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or may be prepared by methods well known to a person of ordinary skill in the art, following procedures described in such standard references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, NY, 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols.
  • Kinase inhibitors according to the present invention may be synthesized according to the reaction scheme shown below. Other reaction schemes could be readily devised by those skilled in the art. It should also be appreciated that a variety of different solvents, temperatures and other reaction conditions can be varied to optimize the yields of the reactions. [0247] In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
  • Kinase inhibitors according to the present invention may be synthesized according to the reaction scheme shown below. Other reaction schemes could be readily devised by those skilled in the art. It should also be appreciated that a variety of different solvents, temperatures and other reaction conditions can be varied to optimize the yields of the reactions.
  • Example 1 was prepared according to the reaction scheme described above. This kinase inhibitor was found to have an IC50 value less than 100,000 nM for AIK and c-KTf .
  • 1H NMR 400 MHz, DMSO-d6) ⁇ ppm 2.22 (s, 3 H), 6.58 (s, 1 H), 6.92-7.09 (m, 3 H), 7.69 (m, 1 H), 10.83 (s, 1 H), 13.75 (s, 1 H).
  • ESI-MS m/z 241.0 (M+H) + .
  • the activity of compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of the activated protein kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by mnning a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands. A. Determination of Inhibition of AIK
  • the inhibitory properties of compounds relative to ATK may be determined by the Direct Fluorescence Polarization detection method (FP) using a Greiner small volume black 384- well-plate format under the following reaction conditions: 50 mM Hepes pH
  • LRRASLG peptide (provided by SYNPEP), 5% DMSO, 2.5uM ATP. Detection of the reaction product is performed by addition of EVLAP binding reagent (Molecular Devices).
  • Reaction product may be determined quantitatively by FP using an Analyst HT plate reader (Molecular Devices) with an excitation wavelength at 485 nm and emission at 530 nm and using a Fluorescein 505 dichroic mirror.
  • the assay reaction may be initiated as follows: 2 ul of (3x) 300 nM Fl-Peptide/
  • IC50 values may be calculated by non-linear curve fitting of the compound concentrations and fluorescent polarization values to the standard IC50 equation. As a reference point for this assay, Staurosporin showed an IC50 of ⁇ 10 nM.
  • the inhibitory properties of compounds relative to c-Kit may be determined by the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method using a small volume black 384-well-plate (Greiner) format under the following reaction conditions: 50 mM Hepes pH 7.3, 10 mM MgC12, 10 mM NaCl, 1 mM DTT, 0.01%
  • reaction product may be performed by addition of
  • Streptavidin-APC Prozyme
  • Eu-Anti-phosphotyrosine antibody Perkin Elmer
  • Reaction product may be determined quantitatively by TR-FRET reading using an Analyst
  • HT plate reader (Molecular Devices) with an excitation wavelength at 330 nm and emission at 615 nm (Europium) compared to 330 nm excitation (Europium) and emission
  • the assay reaction may be initiated as follows: 4 ul of (2.5x) 625 nM Biotin-
  • reaction mixture may then be incubated at room temperature for 30 min, and quenched and developed by addition of 10 ul of (2x) 3.2 nM Eu-Antibody and 25 nM Streptavidin-APC in 50mM Hepes pH 7.3,
  • TR-FRET readings of the resulting reaction mixtures may be measured after a 60-minute incubation at room temperature on the
  • IC50 values may be calculated by non-linear curve fitting of the compound concentrations and ratio metric Eu:APC values to the standard IC50 equation. As a reference point for this assay, Staurosporin showed an IC50 of ⁇ 5 nM.

Abstract

The invention relates to compounds having one of the below formulae that may be used to inhibit kinases as well as compositions of matter and kits comprising these compounds, and methodsusing the compounds.

Description

KINASE INHIBITORS
Field of the Invention
[0001] The invention relates to compounds that may be used to inhibit kinases as well as compositions of matter and kits comprising these compounds. The present invention also relates to methods for inhibiting kinases as well as treatment methods using compounds according to the present invention.
Background of the Invention
[0002] The invention relates to inhibitors of enzymes that catalyze phosphoryl transfer and/or that bind ATP/GTP nucleotides, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating or modulating disease in which phosphoryl transferases, including kinases, may be involved, symptoms of such disease, or the effect of other physiological events mediated by phosphoryl transferases, including kinases. The invention also provides for methods of making the inhibitor compounds and methods for treating diseases in which one or more phosphoryl transferase, including kinase, activities is involved.
[0003] Phosphoryl transferases are a large family of enzymes that transfer phosphorous-containing groups from one substrate to another. By the conventions set forth by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB) enzymes of this type have Enzyme Commission (EC) numbers starting with 2.7.-.- (See, Bairoch A., The ENZYME database in Nucleic Acids Res. 28:204-305 (2000)). Kinases are a class of enzymes that function in the catalysis of phosphoryl transfer. The protein kinases constitute the largest subfamily of structurally related phosphoryl transferases and are responsible for the control of a wide variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The protein kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, histidine, etc.). Protein kinase sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S.K.; Hunter, T., FASEB J. 9:576-596 (1995); Kinghton et al., Science, 253:407-414 (1991); Hiles et al., Cell 70:419-429 (1992); Kunz et al., Cell, 73:585-596 (1993); Garcia-Bustos et al., EMBO J., 13:2352-2361 (1994)). Lipid kinases (e.g. PI3K) constitute a separate group of kinases with structural similarity to protein kinases.
[0004] Protein and lipid kinases regulate many different cell processes including, but not limited to, proliferation, growth, differentiation, metabolism, cell cycle events, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to targets such as proteins or lipids. Phosphorylation events catalyzed by kinases act as molecular on/off switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neuro transmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. Protein and lipid kinases can function in signaling pathways to activate or inactivate, or modulate the activity of (either directly or indirectly) the targets. These targets may include, for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases and disease conditions, including, for example, inflammation, cancer, allergy/asthma, diseases and conditions of the immune system, disease and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis.
[0005] Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of oncogene related protein kinases in human proliferatives disorders. Subsequently, deregulated protein kinase activity, resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including, for example, cancer, CNS conditions, and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest. [0006] Cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death. Protein kinases play a critical role in this regulatory process. A partial non-limiting list of such kinases includes abl, Aurora-A, Aurora-B, Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, c-Src, CDK1, CDK2, CDK4, CDK6, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Flt-1, Fps, Frk, Fyn, Hck, IGF- 1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, Ros, Tiel, Tie2, Trk, Yes and Zap70. In mammalian biology, such protein kinases comprise mitogen activated protein kinase (MAPK) signaling pathways. MAPK signaling pathways are inappropriately activated by a variety of common disease-associated mechanisms such as mutation of ras genes and deregulation of growth factor receptors (Magnuson et al., Seminars in Cancer Biology 5:247-252 (1994)). Therefore the inhibition of protein kinases is an object of the present invention.
[0007] Aurora kinases (Aurora-A, Aurora-B, Aurora-C) are serine/threonine protein kinases that have been implicated in human cancer, such as colon, breast and other solid tumors. Aurora-A (also sometimes referred to as AIK) is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-A may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, Aurora-A, Aurora-B, Aurora-C have been found to be overexpressed (See, Bischoff et al., EMBO J., 17:3052-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646 (1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)). [0008] There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases, specifically but not limited to Aurora-A, Aurora-B and Aurora-C are especially attractive targets for the discovery of new therapeutics due to their important role in cancer, diabetes, Alzheimer's disease and other diseases.
SUMMARY OF THE INVENTION
[0009] The present invention relates to compounds that have activity for inhibiting kinases. The present invention also provides compositions, articles of manufacture and kits comprising these compounds. [0010] In one embodiment, a pharmaceutical composition is provided that comprises a kinase inhibitor according to the present invention as an active ingredient. Pharmaceutical compositions according to the invention may optionally comprise 0.001 %~100 of one or more kinase inhibitors of this invention. These pharmaceutical compositions may be administered or coadministered by a wide variety of routes, including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The compositions may also be administered or coadministered in slow release dosage forms. [0011] The invention is also directed to kits and other articles of manufacture for treating disease states associated with kinases.
[0012] In one embodiment, a kit is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with instructions. The instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also comprise packaging materials. The packaging material may comprise a container for housing the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms. [0013] In another embodiment, an article of manufacture is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with packaging materials. The packaging material may comprise a container for housing the composition. The container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms. [0014] Also provided are methods for preparing compounds, compositions and kits according to the present invention. For example, several synthetic schemes are provided herein for synthesizing compounds according to the present invention. [0015] Also provided are methods for using compounds, compositions, kits and articles of manufacture according to the present invention.
[0016] In one embodiment, the compounds, compositions, kits and articles of manufacture are used to inhibit kinases.
[0017] In another embodiment, the compounds, compositions, kits and articles of manufacture are used to treat a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state.
[0018] In another embodiment, a compound is administered to a subject wherein kinases activity within the subject is altered, preferably reduced.
[0019] In another embodiment, a prodrug of a compound is administered to a subject that is converted to the compound in vivo where it inhibits kinases.
[0020] In another embodiment, a method of inhibiting kinases is provided that comprises contacting kinases with a compound according to the present invention.
[0021] In another embodiment, a method of inhibiting kinases is provided that comprises causing a compound according to the present invention to be present in a subject in order to inhibit kinases in vivo.
[0022] In another embodiment, a method of inhibiting kinases is .provided that comprises administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits kinases in vivo. It is noted that the compounds of the present invention may be the first or second compounds.
[0023] In another embodiment, a therapeutic method is provided that comprises administering a compound according to the present invention.
[0024] h another embodiment, a method of inhibiting cell proliferation is provided that comprises contacting a cell with an effective amount of a compound according to the present invention.
[0025] In another embodiment, a method of inhibiting cell proliferation in a patient is provided that comprises administering to the patient a therapeutically effective amount of a compound according to the present invention.
[0026] In another embodiment, a method of treating a condition in a patient which is known to be mediated by kinases, or which is known to be treated by kinase inhibitors, comprising administering to the patient a therapeutically effective amount of a compound according to the present invention. [0027] In another embodiment, a method is provided for using a compound according to the present invention in order to manufacture a medicament for use in the treatment of disease state which is known to be mediated by kinases, or which is known to be treated by kinase inhibitors.
[0028] hi another embodiment, a method is provided for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: causing a compound according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
[0029] In another embodiment, a method is provided for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound such that the second compound is present in the subject in a therapeutically effective amount for the disease state. It is noted that the compounds of the present invention may be the first or second compounds. [0030] In another embodiment, a method is provided for treating a disease state for which kinases possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound according to the present invention to a subject such that the compound is present in the subject in a therapeutically effective amount for the disease state.
[0031] It is noted in regard to all of the above embodiments that the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well know in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers. Further, unless otherwise specified, recitation of a compound is intended to encompass all possible resonance forms and tautomers. With regard to the claims, the language "compound comprising the formula" is intended to encompass the compound and all pharmaceutically acceptable ionized forms and solvates, all possible stereoisomers, and all possible resonance forms and tautomers unless otherwise specifically specified in the particular claim.
[0032] It is further noted that prodrugs may also be administered which are altered in vivo and become a compound according to the present invention. The various methods of using the compounds of the present invention are intended, regardless of whether prodrug delivery is specified, to encompass the administration of a prodrug that is converted in vivo to a compound according to the present invention. It is also noted that certain compounds of the present invention may be altered in vivo prior to inhibiting kinases and thus may themselves be prodrugs for another compound. Such prodrugs of another compound may or may not themselves independently have kinase inhibitory activity.
DEFINITIONS
[0033] Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings for the purposes of this Application.
[0034] "Alicyclic" means a moiety comprising a non-aromatic ring structure.
Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quatemerized or oxidized and the sulfur atoms can be optionally oxidized. Examples of alicyclic moieties include, but are not limited to moieties with C3 - C8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.
[0035] "Aliphatic" means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.
[0036] "Alkoxy" means an oxygen moiety having a further alkyl substituent. The alkoxy groups of the present invention can be optionally substituted.
[0037] "Alkyl" represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with oxygen (See
"oxaalkyl") or nitrogen atoms (See "aminoalkyl") between the carbon atoms. Cx alkyl and Cχ.γ alkyl are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C1-6 alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g., as in arylalkyl, heteroarylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C6-1o)aryl(C1- )alkyl includes, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like). [0038] "Alkylene", unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical. Cx alkylene and Cχ.y alkylene are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C1-6 alkylene includes methylene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-) 2-butenylene (-CH2CH=CHCH2-),
2-methyltetramethylene (-CH2CH(CH3)CH2CH2-), pentamethylene
(-CH2CH2CH2CH2CH2-) and the like).
[0039] "Alkylidene" means a straight or branched saturated or unsaturated, aliphatic radical connected to the parent molecule by a double bond. Cx alkylidene and Cχ.γ alkylidene are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C1-6 alkylidene includes methylene (=CH2), ethylidene (=CHCH3), isopropylidene (=C(CH3)2), propylidene (=CHCH2CH3), allylidene (=CH-CH=CH ), and the like).
[0040] "Amino" means a nitrogen moiety having two further substituents where, for example, a hydrogen or carbon atom is attached to the nitrogen. For example, representative amino groups include -NH2, -NHCH , -N(CH3)2, -NH .io-alkyl, -N(C1-10- alkyl)2/ -NHaryl, -NHheteroaryl, -N(aryl)2, -N(heteroaryl)2, and the like. Optionally, the two substituents together with the nitrogen may also form a ring. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
[0041] "Aminoalkyl" means an alkyl, as defined above, except where one or more substituted or unsubstituted nitrogen atoms (-N-) are positioned between carbon atoms of the alkyl. For example, an (C2-6) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms. [0042] "Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
[0043] "Aromatic" means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2. An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
[0044] "Aryl" means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. Cx aryl and Cχ.γ aryl are typically used where X and Y indicate the number of atoms in the ring.
[0045] "Bicycloalkyl" means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.
[0046] "Bicycloaryl" means a bicyclic ring assembly wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic. C bicycloaryl and Cx-γ bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring.
[0047] "Bridging ring" as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where two ring atoms that are common to both rings are not directly bound to each other. Non-exclusive examples of common compounds having a bridging ring include borneol, norbornane, 7- oxabicyclo[2.2.1]heptane, and the like. One or both rings of the bicyclic system may also comprise heteroatoms.
[0048] "Carbamoyl" means the radical -OC(O)NRaRb where Ra and Rb are each independently two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
[0049] "Carbocycle" means a ring consisting of carbon atoms.
[0050] "Carbocyclic ketone derivative" means a carbocyclic derivative wherein the ring contains a -CO- moiety.
[0051] "Carbonyl" means the radical -CO-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones. [0052] "Carboxy" means the radical -CO2-. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. [0053] "Cyano" means the radical -CN.
[0054] "Cycloalkyl" means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly. Cx cycloalkyl and Cχ.γ cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. For example, C3-10 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, and the like.
[0055] "Cycloalkylene" means a divalent saturated or partially unsaturated, monocyclic or polycyclic ring assembly. C cycloalkylene and Cχ.γ cycloalkylene are typically used where X and Y indicate the number of carbon atoms in the ring assembly. [0056] "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy. [0057] "Fused ring" as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure when the ring atoms that are common to both rings are directly bound to each other. Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like. Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, and the like. [0058] "Halo" means fluoro, chloro, bromo or iodo.
[0059] "Halo-substituted alkyl", as an isolated group or part of a larger group, means "alkyl" substituted by one or more "halo" atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C1- )alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like). [0060] "Heteroatom" refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur. [0061] "Heteroatom moiety" includes a moiety where the atom by which the moiety is attached is not a carbon. Examples of heteroatom moieties include -N=, -NRC-, -^(0")=, -O-, -S- or -S(O) -, wherein Rc is further substituent.
[0062] "Heterobicycloalkyl" means bicycloalkyl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom. For example hetero(C9-12)bicycloalkyl as used in this application includes, but is not limited to, 3-aza- bicyclo[4.1.0]hept-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl , 3-aza-bicyclo[3.1.0]hex-3-yl, and the like.
[0063] "Heterocyclo alkylene" means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom. [0064] "Heteroaryl" means a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The nitrogen atoms can be optionally quatemerized and the sulfur atoms can be optionally oxidized. Heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole. "Heteroaryl" also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring. These bicyclic or tricyclic heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2- b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[l,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, imidazo[l,2-a]pyrimidine, imidazo[l,2-c]pyrimidine, imidazo[l,5-a]pyrimidine, imidazo[l,5-c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3- c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine, pyrazolo[l,5-a]ρyridine, pyrrolo[l,2- b]pyridazine, ρyrrolo[l,2-c]pyrimidine, pyrrolo[l,2-a]pyrimidine, pyrrolo[l,2-a]pyrazine, triazo[l,5-a]pyridine, pteridine, purine, carbazole, acridine, phenazine, phenothiazene, phenoxazine, l,2-dihydropyrrolo[3,2,l-fø]indore, indolizine, pyrido[l,2-a]indole and 2(lH)-pyridinone. The bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused. The heteroaryl groups of this invention can be substituted or unsubstituted.
[0065] "Heterobicycloaryl" means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom. For example, hetero(C8-1o)bicycloaryl as used in this Application includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and the like. [0066] "Heterocycloalkyl" means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, O, or S. Non-exclusive examples of heterocycloalkyl include piperidyl, 4- morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the like. [0067] "Hydroxy" means the radical -OH.
[0068] "Iminoketone derivative" means a derivative comprising the moiety -C(NR)-, wherein R comprises a hydrogen or carbon atom attached to the nitrogen. [0069] "Isomers" mean any compound having an identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers." A carbon atom bonded to four nonidentical substituents is termed a "chiral center." A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is termed a "racemic mixture." A compound that has more than one chiral center has 2nΛ enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992).
[0070] "Nitro" means the radical -NO2.
[0071] "Oxaalkyl" means an alkyl, as defined above, except where one or more oxygen atoms (-O-) are positioned between carbon atoms of the alkyl. For example, an (C2-6)oxaalkyl refers to a chain comprising between 2 and 6 carbons and one or more oxygen atoms positioned between the carbon atoms.
[0072] "Oxoalkyl" means an alkyl, further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride. [0073] "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
[0074] "Pharmaceutically acceptable salts" means salts of inhibitors of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobro ic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, -chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, -toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid,
4,4'-methylenebis(3-hydroxy-2-ene-l -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like. [0075] Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
[0076] "Prodrug" means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention. The prodrug itself may or may not also have kinase inhibitory activity. For example, an inhibitor comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like. Similarly, an inhibitor comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
[0077] "Protected derivatives" means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
[0078] "Substituted or unsubstituted" means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety. For example, isopropyl is an example of an ethylene moiety that is substituted by -CH3. In general, a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted. Examples of substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, (C1-1o)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
[0079] "Sulfinyl" means the radical -SO-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
[0080] "Sulfonyl" means the radical -SO2-. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
[0081] "Therapeutically effective amount" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
[0082] "Thiocarbonyl" means the radical -CS-. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.
[0083] "Treatment" or "treating" means any administration of a compound of the present invention and includes: (1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology) .
[0084] It is noted in regard to all of the definitions provided herein that the definitions should be interpreted as being open ended in the sense that further substituents beyond those specified may be included. Hence, a Ci alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom. Hence, a alkyl comprises methyl (i.e., -CH3) as well as -CRaRbRc where Ra, Rb, and Rc may each independently be hydrogen or any other substituent where the atom attached to the carbon is a heteroatom or cyano. Hence, CF3, CH OH and CH CN, for example, are all alkyls.
KINASE INHIBITORS
[0085] In one embodiment, kinase inhibitors of the present invention comprise one of the following formula:
Figure imgf000017_0001
wherein: J, K, L, and Y are each independently selected from the group consisting of C and
N; M is selected from the group consisting of CH and N; X and Z are each independently selected from the group consisting of C, N, O and
S; R3, , and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C lo)alkyl, heteroaryl(Cι-5)alkyl, (C9-12)bicycloaryl, hetero(C -12)bicycloaryl, carbonyl(C1- )alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1- )alkyl, sulfinyl(C1- )alkyl, imino(Cι-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or R3 and ^ are taken together to form an unsubstituted or substituted ring, or R and R5 are taken together to form an unsubstituted or substituted ring, with the proviso that R3, R , and/or R5 are absent when J, K and/or L respectively are nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R13 and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-ι )cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or R1 and R1 are taken together to form an unsubstituted or substituted ring, with the provisos that (a) R13 is absent when X is O or S, (b) R13 is absent when X is N and X is part of a double bond, and (c) R1 is absent when Y is N; R16 and R17 are independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(Ci-7)alkyl, -SO^ -^alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1- )alkyl group, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R1 and R16 are taken together to form an unsubstituted or substituted ring, with the provisos that (a) X, Y and Z are not all simultaneously C, (b) X and Z are not O or S when that atom is part of a double bond, and (c) a double bond is present between one of X and Y or Y and Z and a single bond is present between the other of either X and Y or Y and Z.
[0086] In another embodiment, kinase inhibitors of the present invention comprise the formula:
Figure imgf000018_0001
wherein: J, K, L, W, X, Y and Z are each independently selected from the group consisting of C and N; M is selected from the group consisting of CH and N; R3, R , and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C -12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C -12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1- )alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or R3 and R4 are taken together to form an unsubstituted or substituted ring, or R and R5 are taken together to form an unsubstituted or substituted ring, with the proviso that R3, R4, and/or R5 are absent when J, K and/or L respectively are nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R12, R13, and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-1 )cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or R12 and R13 are taken together to form an unsubstituted or substituted ring, or R13 and R14 are taken together to form an unsubstituted or substituted ring, with the proviso that R12, R13 and/or R14 are absent when W, X, and/or Y respectively is N; and R16 and R17 are independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(Ci-7)alkyl, -SO2(C 7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R1 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted, or substituted, or where R14 and R16 are taken together to form an unsubstituted or substituted ring. [0087] In one variation of each of the above embodiments, J, K, L and M each comprise a carbon ring atom. In another variation of each of the above embodiments, J, K and L each comprise a carbon ring atom and M is nitrogen. [0088] In yet another variation, at least one of X, Y and Z optionally comprise a nitrogen ring atom.
[0089] With regard to each of the above embodiments and variations, Y can be N.
[0090] Also with regard to each of the above embodiments and variations, X and Y optionally comprise substituents that form a second ring fused to the ring comprising X and Y.
[0091] In addition, with regard to each of the above embodiments and variations, W and X can comprise substituents that form a second ring fused to the ring comprising W andX.
[0092] Further, with regard to each of the above embodiments and variations, the ring formed by J, K, L and M can comprise substituents that form a ring fused to the ring formed by J, K, L and M.
[0093] In yet another embodiment, X and Y comprise substituents that form a second ring fused to the ring comprising X and Y, and the ring formed by J, K, L and M comprises substituents that form a ring fused to the ring formed by J, K, L and M.
[0094] With regard to the above embodiments and variations wherein a fused ring is formed, the fused ring can comprise a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring. In particular, the fused ring can be an alicyclic ring, such as, for example a substituted or unsubstituted pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline or triazine.
[0095] In another embodiment, kinase inhibitors of the present invention comprise the formula:
Figure imgf000021_0001
Figure imgf000022_0001
wherein: J, K, L, W and Y are each independently selected from the group consisting of C and N; M is selected from the group consisting of CH and N; V1; V2, V3, and V4 are each independently selected from the group consisting of C and N when the respective atom is part of a ring double bond and are independently selected from the group consisting of C, N, O and S when the respective atom is not part of a double bond; R , R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(Cr10)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-ιo)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C -12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that R3, R4, and/or R5 are absent when J, K and/or L respectively are nitrogen; R is hydrogen or a substituent convertible in vivo to hydrogen; R12, R14, R 0, R2o\ R21, R21', R22, R22', R23, and R23' are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-1 )cycloalkyl, hetero(C3-1 )cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-1 )bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, with the provisos that (a) R12, R14, R20, R21, R22, and/or R23 are absent when the atom to which R12, R14, R20, R21, R22, and R23 respectively are bound is O or S, and (b) R20', R21', R22', and/or R23' are absent when the atom to which R21', R22', and R 3' respectively are bound is N, O or S, and; R16 and R1 are independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C1-7)alkyl, -SO2(Ci-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2) -5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
[0096] In one variation of the above embodiment, at least one of Y V2, V3, V , W and Y is N. In another variation, W and/or Y is N. [0097] In regard to each of the above embodiments and variations thereof, R12, R1 and R1 may optionally each be independently selected from the group consisting of hydrogen, F, Br, Cl, -OCH3, -SO2Me, -SO2NH2, -SO2NHMe, -SO2NHCH2CH2OH, -SO2NMe2, -NHSO2(3-fluorophenyl), perhalo(C ιo)alkyl, -OCF3, -CF3, (Crio)alkyl, hydroxy- (C1-1o)alkyl, aryl, aryl-(C1-1o)alkyl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, hydroxy, aryloxy, heteroaryloxy, arylalkyl, heteroaryl(C1-1o)alkyl, cycloalkyl, heterocycloalkyl, HS-, (C1-6)alkylS-, cyano, nitro, cycloalkoxy, (C1-12)alkoxy, -COOH, -CO Me, carboxamide, (C1-12)alkylNHCO-, R9R10N-(C1-12)alkyl aminocarbonyl, R9R1oN-(C1-12)alkoxycarbonyl, hetero-(C1-6)alkylaminocarbonyl, heterocycloalkyl-(C1- 6)alkylCO-, heteroaryl-(Cj-6)alkylCO-, heterocycloalkyl-(C1_6)alkylOCO-, heteroaryl- (C1-6)alkylOCO-, (C1-6)alkylOCO-, diethoxyphosphorylmethyl, imino group, R9R1oN-(C1- 6)alkylsulfonyl, -NH2, -NHCH3, -N(CH3)2, -NH(C1-3)alkyl, -N(C1-3-alkyl)2, R9R10N- (C1-12)alkyl aminocarbonylamino, R9R10N-(C1.6)alkyl alkoxycarbonylamino, heterocycloalkyl-(C1-6)alkyl aminocarbonylamino, heteroaryl-(C1-6)alkyl aminocarbonylamino, (C3-1 )heterocycloalkyl-(C1-6)alkoxycarbonylamino, heteroaryl- (C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)(C1-6 alkyl)amino, R9R1oN-(C1-6)alkyl carbonylamino, [R9R1oN-(C1-6)alkylcarbonyl][(C1- 6)alkyl] amino, R9R10N-(C1-6)alkyl sulfonylamino, [R9R10N-(C1-6)alkylsulfonyl][(C1- 6)alkyl]amino, and -NR9R10 where R and R10 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R9 and R10 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R9 and R10 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted.
[0098] Also in regard to each of the above embodiments and variations thereof, Rι2) R13 and R1 may each optionally be independently selected from the group consisting of hydrogen, (C1-6)alkyl, hydroxy, hydroxy-(C1-6)alkyl, carboxamide, mono-(C1-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heterocyclo, heteroaryl-(C1-6)alkyl, (C1-6)alkoxy, aryloxy, heteroaryloxy, amino, mono- or di-(C1-6)alkyl-amino, (C1-6)alkyl aminocarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonyl, mono- or di-(C1- 6)alkyl-amino (C1-6)alkyl aminocarbonylamino, mono- or di-(C1- )alkyl-amino (C1.6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)((C1. 6)alkyl)amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonylamino, [mono- or di-(Cι_ 6)alkyl-amino (C1-6)alkyl carbonyl][(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl- amino (Cι_ 6)alkyl sulfonylamino, [mono- or di-(C1-6)alkyl-amino(Cι-6)alkylsulfonyl][(Cι- 6)alkyl] amino, mono- or di-(C1-6)alkyl-amino(C1_6)alkylsulfonyl, heteroaryl(C1-6)alkyl aminocarbonyl, heterocyclyl(C1-6)alkyl aminocarbonyl, heteroaryl (C1-6)alkyl aminocarbonylamino, heterocyclyl (C1-6)alkyl aminocarbonylamino, heteroaryl ( . 6)alkoxycarbonylamino, heterocyclyl(C1-6)alkoxycarbonylamino, heteroaryl (Q, 6)alkylcarbonyl, heterocyclyl(C1-6)alkyl carbonyl, heteroaryl (C1-6)alkoxycarbonyl, heterocyclyl(C1-6)alkoxycarbonyl, (C1-6)alkyl sulfonyl (C1-6)alkylaminoalkyl, (C1-6)alkyl sulfonyl-(C1-6)alkyl-aminoalkyl-heteroaryl~, (C1-6)alkoxycarbonyl, halo, cyano, diethoxyphosphorylmethyl, trifluoromethyl and trifluoromethoxy, each substituted or unsubstituted.
[0099] Also in regard to each of the above embodiments and variations thereof, in one further variation, Y is N and R12, R13 and R14 are each independently selected from the group consisting of hydrogen, (C1-6)alkyl, hydroxy, hydroxy-(C1-6)alkyl, carboxamide, mono-(C1-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heterocyclo, heteroaryl-(C1-6)alkyl, heterocyclyl-(C1-6)alkyl, heteroaryloxy, heterocyclyloxy, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonyl, mono- or di-(C1-6)alkyl-amino ( . 6)alkoxycarbonyl, mono- or di-(C1-6)alkyl-amino(C1-6)alkyl aminocarbonylamino, mono- or di-(C1-6)alkyl-amino (C1-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, (( . 6)alkyl carbonyl)((C1-6) alkyl)amino, mono- or di-(Cι.6)alkyl-amino (C1-6)alkyl carbonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl carbonyl] [(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl] [(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl, heteroaiyl (C1-6)alkyl aminocarbonyl, heteroaryl (C1-6)alkyl carbonyl, (C1-6)alkyl sulfonyl (C1-6)alkyl aminoalkyl, (C1-6)alkyl sulfonyl-(C1-6)alkyl-aminoalkyl-heteroaryl-, halo, cyano and trifluoromethyl, each substituted or unsubstituted.
[0100] In a further embodiment, kinase inhibitors of the present invention comprise one of the following formula:
Figure imgf000026_0001
wherein: R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-1 )cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(Cr5)alkyl, (C9-12)bicycloaryl, hetero(C -12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1- )alkyl, sulfonyl(Cι-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that R3, R , and/or R5 are absent when the atom to which R , R4, and R5 respectively are bound is nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R13 and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-ι2)cycloalkyl, hetero(C3-ι2)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted; and R16 and R17 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C1-7)alkyl, -SO2(C1-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring. [0101] In a another embodiment, kinase inhibitors of the present invention comprise the following formula:
Figure imgf000027_0001
wherein: R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C -12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1- )alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R14 is selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted; and R16 and R17 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C 7)alkyl, -SO2(C 7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R1 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
[0102] In yet another embodiment, kinase inhibitors of the present invention comprise the following formula:
Figure imgf000028_0001
wherein: R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Cr5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1.3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R14 is selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted; and R16 and R17 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C1-7)alkyl, -SO2(C 7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R1 together are -(CH2) -5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
[0103] In still another embodiment, kinase inhibitors of the present invention comprise the following formula:
Figure imgf000029_0001
wherein: R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-1 )cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1- )alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R is hydrogen or a substituent convertible in vivo to hydrogen; R14 is selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted; and R16 and R17 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C1-7)alkyl, -SO2(C1-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R1 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
[0104] In a further embodiment, kinase inhibitors of the present invention comprise one of the following formula:
Figure imgf000030_0001
wherein: i, V2, V3, and V4 are each independently selected from the group consisting of C, N, O and S; R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-10)alkyl, (C3-ι2)cycloalkyl, hetero(C3-ι2)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(Cι-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R is hydrogen or a substituent convertible in vivo to hydrogen; R20>
Figure imgf000030_0002
R21, R21', R22, R22', R23, and R23' are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C -12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, with the provisos that (a) R20, R21, R22, and/or R23 are absent when V1; V2, V3, and/or V4 respectively are O or S, and (b) R20\ R21', R2 ', and/or R23' are absent when V1 ; V2, V , and/or V4 respectively are N, O or S; and R16 and R17 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C1-7)alkyl, -SO2(C 7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and Rι7 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R16 is taken together with another substituent to form an unsubstituted or substituted ring.
[0105] In a further embodiment, kinase inhibitors of the present invention comprise one of the following formula:
Figure imgf000031_0001
wherein: W, X, and Y are each independently selected from the group consisting of C and
N; R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-ιo)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-ι2)cycloalkyl, aryl(Cι-1o)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(Cι-3)alkyl, sulfinyl(Cι-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that R3, R4, and/or R5 are absent when J, K and/or L respectively are nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; and Rι2, R13, and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-ι2)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, with the proviso that R12, R13 and/or R1 are absent when W, X, and/or Y respectively is N.
[0106] In regard to each of the above embodiments and variations thereof, R12 and R1 or R13 and R1 may optionally be taken together to form a substituted or unsubstituted fused ring. In one variation, the fused ring is an alicyclic ring. In another variation, the fused ring is a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring. [0107] In regard to each of the above embodiments and variations thereof, R16 and the ring substituent nearest R16 may optionally be taken together to form a substituted or unsubstituted fused ring. For example, R14 and R16 can be taken together to from an unsubstituted or substituted ring. In one particular variation, the fused ring thus formed is an alicyclic ring. In another particular variation, the fused ring thus formed is a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring.
[0108] In a variation of each of the above embodiments and variations thereof, at least one of R16 and R1 can be selected from the group consisting of hydrogen and ( -^) alkyl. In another particular variation, R1 is H. In yet another variation, R16 and R17 are both independently selected from the group consisting of hydrogen and (Cι_δ) alkyl. In still another variation, R16 and R17 are both hydrogen.
[0109] In a further embodiment, kinase inhibitors of the present invention comprise one of the following formula:
is
Figure imgf000032_0001
wherein: J, K, L, and Y are each independently selected from the group consisting of C and
N; M is selected from the group consisting of CH and N; X and Z are each independently selected from the group consisting of C, N, O and S; R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C _12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl ( -^alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1_3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or R3 and R4 are taken together to form an unsubstituted or substituted ring, or R^ and R5 are taken together to form an unsubstituted or substituted ring, with the proviso that R3, R^ and/or R5 are absent when J, K and/or L respectively are nitrogen; R is hydrogen or a substituent convertible in vivo to hydrogen; R13 and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-1 )cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-1 )cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or R13 and R1 are taken together to form an unsubstituted or substituted ring, with the provisos that (a) R13 is absent when X is O or S, (b) R13 is absent when X is N and X is part of a double bond, and (c) R1 is absent when Y is N; R16 is selected from the group consisting of hydrogen, -CONNH , -CSNH2, -CONH2, -CO(Cr7)alkyl, -SO2(Ci-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R1 together are -(CH ) -5- optionally interrupted by one O, S, NH or -N(C1- )alkyl group; R17 is selected from the group consisting of hydrogen and (C1,6)alkyl, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form an unsubstituted or substituted ring, with the provisos that (a) X, Y and Z are not all simultaneously C, (b) X and Z are not O or S when that atom is part of a double bond, and (c) a double bond is present between one of X and Y or Y and Z and a single bond is present between the other of either X and Y or Y and Z.
[0110] In yet a further embodiment, kinase inhibitors of the present invention comprise one of the following formula:
Figure imgf000034_0001
wherein: J, K, L, W, X, Y and Z are each independently selected from the group consisting of C and N; M is selected from the group consisting of CH and N; R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl,
(C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl,
(C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or R3 and R4 are taken together to form an unsubstituted or substituted ring, or R and R5 are taken together to form an unsubstituted or substituted ring, with the proviso that R3, R , and/or R5 are absent when J, K and/or L respectively are nitrogen; R is hydrogen or a substituent convertible in vivo to hydrogen; R12, R13, and R14 are each independently selected from the group consisting of hydrogen, (Cι-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or R12 and R13 are taken together to form an unsubstituted or substituted ring, or R13 and R14 are taken together to form an unsubstituted or substituted ring, with the proviso that R12, R1 and/or R1 are absent when W, X, and/or Y respectively is N; R16 is selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO( -7)alkyl, -SO (Ci-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted; and R1 is selected from the group consisting of hydrogen and (C1-6)alkyl, or where R16 and R1 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(Cι-3)alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1- yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted, or substituted, or where R14 and R16 are taken together to form an unsubstituted or substituted ring. [0111] Particular examples of kinase inhibitors according to the present invention include, but are not limited to: 3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indol-2-ol; 5-fluoro-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indol-2-ol; 2-hydroxy-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indole-5-carbonitrile; (Z)-N',2-dihydroxy-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indole-5-carboxamidine; N-(2-hydroxy-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indol-5- yl)methanesulfonamide; 2-hydroxy-N-methyl-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indole-5-sulfonamide; 3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indol-2-ol; 5-fluoro-3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indol-2-ol; 2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indole-5-carbonitrile; (Z)-N',2-dihydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indole-5- carboxamidine; N-(2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indol-5- yl)methanesulfonamide 2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)-N-methyl-lH-indole-5-sulfonarnide; 3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indol-2-ol; 5-fluoro-3-( 1 H-pyrazolo[3 ,4-b]pyridin-6-yl)- 1 H-indol-2-ol; 2-hydroxy-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indole-5-carbonitrile; (Z)-N',2-dihydroxy-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indole-5- carboxamidine; N-(2-hydroxy-3-( 1 H-pyrazolo [3 ,4-b]pyridin-6-yl)- 1 H-indol-5- yl)methanesulfonamide; 2-hydroxy-N-methyl-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indole-5- sulfonamide; 3-(2-Amino-6-methyl-pyrimidin-4-yl)-lH-indol-2-ol; 3-(3-aminoisoquinolin-l-yl)-lH-indol-2-ol; 3-(3-aminoisoquinolin- 1 -yl)-2 -hydroxy- 1 H-indole-5-carbonitrile; 8-(3-aminoisoquinolin- 1 -yl)-6H-thiazolo[5,4-e]indol-7-ol; N-(3-(3-aminoisoquinolin-l-yl)-2-hydroxy-lH-indol-5-yl)ethanesulfonamide; 2-hydroxy-N-methyl-3-(7-oxo-7,8-dihydro- 1 ,8-naphthyridin-2-yl)- lH-indole-5- sulfonamide; and N-ethyl-2-hydroxy-3-(7-oxo-7,8-dihydro-l,8-naphthyridin-2-yl)-lH-indole-5- sulfonamide.
[0112] It is noted that the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or prodrug thereof. For example, the compound optionally comprises a substituent that is convertible in vivo to a different substituent such as a hydrogen. [0113] It is further noted that the compounds of the present invention may optionally be solely or predominantly in the enol tautomer in its active state. It is further noted that the compound may be present in a mixture of stereoisomers, or the compound comprises a single stereoisomer.
[0114] The invention also provides pharmaceutical compositions comprising, as an active ingredient, a compound according to any one of the above embodiments and variations. In addition, the composition may be a solid or liquid formulation adapted for oral administration. In a further variation, the pharmaceutical composition may be a tablet. In yet another variation, the pharmaceutical composition may be a liquid formulation adapted for parenteral administration.
[0115] In one embodiment, there is provided the pharmaceutical composition comprising a compound according to each of the above variations wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, mtraarticularly, and intrathecally.
[0116] The invention also provides a kit comprising a compound or composition according to any one of the above embodiments and variations, and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.
[0117] In one variation, the kit comprises the compound or composition in a multiple dose form.
[0118] In another embodiment, the present invention provides an article of manufacture comprising a compound or composition according to any one of the above embodiments and variations, and packaging materials.
[0119] In one variation, the packaging material comprises a container for housing the compound or composition. The container optionally comprises a label indicating a disease state for which the compound or composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound or composition.
[0120] In regard to the above embodiments and variations, the article of manufacture optionally comprises the compound or composition in a multiple dose form.
[0121] In yet another embodiment, the present invention provides a method of inhibiting kinase comprising contacting kinase with a compound or composition according to any one of the above embodiments and variations.
[0122] In one variation, the inhibition arises from a favorable conformation adopted by the compound in its enol form, and the conformation arises from an intramolecular hydrogen bonding of the enol hydrogen and an adjacent nitrogen atom of the compound.
[0123] In another variation, the inhibition arises from a favorable conformation adopted by the compound in its enol form, and the inhibition arises from a hydrogen bonding interaction between the enol tautomer and an active site residue of the kinase.
[0124] In still another embodiment, there is provided a method of inhibiting kinase comprising causing a compound or composition according to any one of the above embodiments and variations to be present in a subject in order to inhibit kinase in vivo.
[0125] The present invention also provides a method of inhibiting kinase comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits kinase in vivo, the second compound being a compound according to any one of the above embodiments and variations.
[0126] hi another embodiment, the present invention provides a therapeutic method comprising administering a compound or composition according to any one of the above embodiments and variations to a subject.
[0127] In yet another embodiment, there is provided a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising causing a compound or composition according to any one of the above embodiments and variations to be present in a subject in a therapeutically effective amount for the disease state.
[0128] The present invention also provides a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising administering a first compound to a subject that is converted in vivo to a second compound according to any one of the above embodiments and variations wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
[0129] In addition, there is provided a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state comprising administering a compound or composition according to any one of the above embodiments and variations, wherein the compound or composition is present in the subject in a therapeutically effective amount for the disease state.
[0130] In another embodiment, there is provided a method for treating cancer comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a composition of the present invention. In one embodiment, the cancer is selected from the group consisting of squamous cell carcinoma, astrocytoma,
Kaposi's sarcoma, glioblastoma, non small-cell lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.
[0131] In another embodiment, there is provided a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: causing a compound or composition according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
[0132] In another embodiment, there is provided a method for treating inflammation, inflammatory bowel disease, psoriasis, or transplant rejection, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to the present invention.
[0133] In yet another embodiment, the present invention provides a method of preventing or treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound according to any one of the compounds or compositions of the present invention wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
[0134] In yet another embodiment, there is provided a method of preventing or treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound or composition of the present invention, wherein the compound is present in the subject in a therapeutically effective amount for the disease state. [0135] In a further embodiment, there is provided a method for preventing or treating dementia related diseases and Alzheimer's Disease, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiments. In one particular variation, the dementia related diseases are selected from the group consisting of Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Guam, HIV dementia, diseases with associated neurofibrillar tangle pathologies, predemented states, vascular dementia, dementia with Lewy bodies, Frontotemporal dementia and dementia pugilistica. [0136] In another embodiment, there is provided a method for preventing or treating amyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome, Huntington's Disease, Parkinson's Disease, postencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma and other chronic neurodegenerative diseases, Bipolar Disease, affective disorders, depression, schizophrenia, cognitive disorders, hair loss and contraceptive medication, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiments. [0137] In yet another embodiment, there is provided a method for preventing or treating mild Cognitive Impairment, Age-Associated Memory Impairment, Age-Related Cognitive Decline, Cognitive Impairment No Dementia, mild cognitive decline, mild neurocognitive decline, Late-Life Forgetfulness, memory impairment and cognitive impairment and androgenetic alopecia, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound or composition according to any one of the above embodiments. [0138] In another embodiment, there is provided a method for preventing or treating dementia related diseases, Alzheimer's Disease and conditions associated with kinases, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound or composition according to the above embodiments. [0139] In another embodiment, there is provided a method for treating arthritis comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound or composition according to any one of the above embodiment.
[0140] In another embodiment, there is provided a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound or composition according to any one of the present invention, wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
[0141] In another embodiment, there is provided a method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound or composition according to any one of the above embodiment, wherein the compound is present in the subject in a therapeutically effective amount for the pathology and/or symptomology. [0142] It is noted that the compounds of the present invention may be in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or a prodrug thereof (e.g., where the compound comprises a substituent that is convertible in vivo to a different substituent such as hydrogen).
[0143] It is further noted that the compounds of the present invention may optionally be solely or predominantly in the enol tautomer in its active state.
[0144] It is also noted that the compounds of the present invention may be present as a mixture of stereoisomers or may be present as a single stereoisomer.
Salts, Hydrates, and Prodrugs of Kinase Inhibitors
[0145] It should be recognized that the compounds of the present invention may be present and optionally administered in the form of salts, hydrates and prodrugs that are converted in vivo into the compounds of the present invention. For example, it is within the scope of the present invention to convert the compounds of the present invention into and use them in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases in accordance with procedures well known in the art. [0146] When the compounds of the present invention possess a free base form, the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate and phthalate. It should be recognized that the free base forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base forms for the purposes of the present invention.
[0147] When the compounds of the present invention possess a free acid form, a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N- methylglutamine. Also included are the aluminum salts of the compounds of the present invention. Further base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts. Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D- glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl)-methylamine (tromethamine). It should be recognized that the free acid forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid forms for the purposes of the present invention. [0148] Compounds of the present invention that comprise basic nitrogen-containing groups may be quatemized with such agents as (C1-4) alkyl halides, e.g., methyl, ethyl, iso- propyl and tert-butyl chlorides, bromides and iodides; di (C1- ) alkyl sulfates, e.g., dimethyl, diethyl and diamyl sulfates; ( o-is) alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C1- ) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water- soluble and oil-soluble compounds of the present invention.
[0149] N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, metα-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 °C. Alternatively, the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
[0150] Prodrug derivatives of compounds according to the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention. For example, prodrugs can be prepared by reacting a compound with a carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate, αra-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods of making prodrugs are described in Saulnier et /.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.
[0151] Protected derivatives of compounds of the present invention can also be made. Examples of techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3r edition, John Wiley & Sons, Inc. 1999.
[0152] Compounds of the present invention may also be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
[0153] A "pharmaceutically acceptable salt", as used herein, is intended to encompass any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound. The pharmaceutically acceptable salt form may also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body. An example of a pharmacokinetic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound. While the route of administration of the pharmaceutical composition is important, and various anatomical, physiological and pathological factors can critically affect bioavailability, the solubility of the compound is usually dependent upon the character of the particular salt form thereof, which it utilized. One of skill in the art will appreciate that an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated, while lipid solutions and suspensions, as well as solid dosage forms, will result in less rapid absorption of the compound. PREPARATION OF KINASE INHIBITORS
[0154] Various methods may be developed for synthesizing compounds according to the present invention. Representative methods for synthesizing these compounds are provided in the Examples. It is noted, however, that the compounds of the present invention may also be synthesized by other synthetic routes that others may devise. [0155] It will be readily recognized that certain compounds according to the present invention have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of compounds according to the present invention may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
[0156] Various methods for separating mixtures of different stereoisomers are known in the art. For example, a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds. The diastereomers may then be separated in order to recover the optically pure enantiomers. Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts). Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities. For example, diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility. A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
COMPOSITION COMPRISING KINASE INHIBITORS
[0157] A wide variety of compositions and administration methods may be used in conjunction with the kinase inhibitors of the present invention. Such compositions may include, in addition to the kinase inhibitors of the present invention, conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive agents. Additionally, the compositions may include active agents in addition to the kinase inhibitors of the present invention. These additional active agents may include additional compounds according to the invention, and/or one or more other pharmaceutically active agents.
[0158] The compositions may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used. For oral administration, capsules and tablets are typically used. For parenteral administration, reconstitution of a lyophilized powder, prepared as described herein, is typically used. [0159] Compositions comprising kinase inhibitors of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermaliy, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
[0160] The kinase inhibitors and compositions comprising them may be administered or coadministered in any conventional dosage form. Co-administration in the context of this invention is intended to mean the administration of more than one therapeutic agent, one of which includes a kinase inhibitor, in the course of a coordinated treatment to achieve an improved clinical outcome. Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
[0161] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; agents for the adjustment of tonicity such as sodium chloride or dextrose, and agents for adjusting the acidity or alkalinity of the composition, such as alkaline or acidifying agents or buffers like carbonates, bicarbonates, phosphates, hydrochloric acid, and organic acids like acetic and citric acid. Parenteral preparations may optionally be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material. [0162] When kinase inhibitors according to the present invention exhibit insufficient solubility, methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions. [0163] Upon mixing or adding kinase inhibitors according to the present invention to a composition, a solution, suspension, emulsion or the like may be formed. The form of the resulting composition will depend upon a number of factors, including the intended mode of administration, and the solubility of the compound in the selected carrier or vehicle. The effective concentration needed to ameliorate the disease being treated may be empirically determined.
[0164] Compositions according to the present invention are optionally provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds, particularly the pharmaceutically acceptable salts, preferably the sodium salts, thereof. The pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms, as used herein, refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit- dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes individually packaged tablet or capsule. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pint or gallons. Hence, multiple dose form is a multiple of unit-doses that are not segregated in packaging.
[0165] In addition to one or more kinase inhibitors according to the present invention, the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents. Actual methods of preparing such dosage forms are known in the art, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The composition or formulation to be administered will, in any event, contain a sufficient quantity of a kinase inhibitor of the present invention to reduce kinases activity in vivo, thereby treating the disease state of the subject.
[0166] Dosage forms or compositions may optionally comprise one or more kinase inhibitors according to the present invention in the range of 0.005% to 100% (weight/weight) with the balance comprising additional substances such as those described herein. For oral administration, a pharmaceutically acceptable composition may optionally comprise any one or more commonly employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum. Such compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these formulations are known to those skilled in the art. The compositions may optionally contain 0.01%-100% (weight/weight) of one or more kinase inhibitors, optionally 0.1- 95%, and optionally 1-95%.
[0167] Salts, preferably sodium salts, of the kinase inhibitors may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings. The formulations may further include other active compounds to obtain desired combinations of properties.
Formulations For Oral Administration
[0168] Oral pharmaceutical dosage forms may be as a solid, gel or liquid. Examples of solid dosage forms include, but are not limited to tablets, capsules, granules, and bulk powders. More specific examples of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated or film-coated. Examples of capsules include hard or soft gelatin capsules. Granules and powders may be provided in non- effervescent or effervescent forms. Each may be combined with other ingredients known to those skilled in the art.
[0169] In certain embodiments, kinase inhibitors according to the present invention are provided as solid dosage forms, preferably capsules or tablets. The tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
[0170] Examples of binders that may be used include, but are not limited to, microcrystallme cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
[0171] Examples of lubricants that may be used include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. [0172] Examples of diluents that may be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
[0173] Examples of glidants that may be used include, but are not limited to, colloidal silicon dioxide.
[0174] Examples of disintegrating agents that may be used include, but are not limited to, crosscarmellose sodium, sodium starch glycolate, alginic acid, com starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. [0175] Examples of coloring agents that may be used include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
[0176] Examples of sweetening agents that may be used include, but are not limited to, sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray-dried flavors.
[0177] Examples of flavoring agents that may be used include, but are not limited to, natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
[0178] Examples of wetting agents that may be used include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
[0179] Examples of anti-emetic coatings that may be used include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
[0180] Examples of film coatings that may be used include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
[0181] If oral administration is desired, the salt of the compound may optionally be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.
[0182] When the dosage unit form is a capsule, it may optionally additionally comprise a liquid carrier such as a fatty oil. In addition, dosage unit forms may optionally additionally comprise various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
[0183] Compounds according to the present invention may also be administered as a component of an elixir, suspension, sy p, wafer, sprinkle, chewing gum or the like. A sy p may optionally comprise, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. [0184] The kinase inhibitors of the present invention may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. For example, if a compound is used for treating asthma or hypertension, it may be used with other bronchodilators and antihypertensive agents, respectively.
[0185] Examples of pharmaceutically acceptable carriers that may be included in tablets comprising kinase inhibitors of the present invention include, but are not limited to binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric-coated tablets, because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar- coated tablets may be compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film-coated tablets may be compressed tablets that have been coated with polymers or other suitable coating. Multiple compressed tablets may be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in tablets. Flavoring and sweetening agents may be used in tablets, and are especially useful in the formation of chewable tablets and lozenges. [0186] Examples of liquid oral dosage forms that may be used include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
[0187] Examples of aqueous solutions that may be used include, but are not limited to, elixirs and syrups. As used herein, elixirs refer to clear, sweetened, hydroalcoholic preparations. Examples of pharmaceutically acceptable carriers that may be used in elixirs include, but are not limited to solvents. Particular examples of solvents that may be used include glycerin, sorbitol, ethyl alcohol and symp. As used herein, syrups refer to concentrated aqueous solutions of a sugar, for example, sucrose. Syrups may optionally further comprise a preservative.
[0188] Emulsions refer to two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may optionally be oil-in- water or water-in-oil emulsions. Examples of pharmaceutically acceptable carriers that may be used in emulsions include, but are not limited to non-aqueous liquids, emulsifying agents and preservatives.
[0189] Examples of pharmaceutically acceptable substances that may be used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents.
[0190] Examples of pharmaceutically acceptable substances that may be used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide.
[0191] Coloring and flavoring agents may optionally be used in all of the above dosage forms.
[0192] Particular examples of preservatives that may be used include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
[0193] Particular examples of non-aqueous liquids that may be used in emulsions include mineral oil and cottonseed oil.
[0194] Particular examples of emulsifying agents that may be used include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
[0195] Particular examples of suspending agents that may be used include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
[0196] Particular examples of wetting agents that may be used include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
[0197] Particular examples of organic acids that may be used include citric and tartaric acid.
[0198] Sources of carbon dioxide that may be used in effervescent compositions include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. [0199] Particular examples of flavoring agents that may be used include natural flavors extracted from plants such f its, and synthetic blends of compounds that produce a pleasant taste sensation. [0200] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
[0201] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those set forth in U.S. Pat. Nos. Re 28,819 and 4,358,603.
Injectables, Solutions, and Emulsions
[0202] The present invention is also directed to compositions designed to administer the kinase inhibitors of the present invention by parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
[0203] Examples of excipients that may be used in conjunction with injectables according to the present invention include, but are not limited to water, saline, dextrose, glycerol or ethanol. The injectable compositions may also optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplated herein. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. [0204] Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.
[0205] When administered intravenously, examples of suitable carriers include, but are not limited to physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
[0206] Examples of pharmaceutically acceptable carriers that may optionally be used in parenteral preparations include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
[0207] Examples of aqueous vehicles that may optionally be used include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
[0208] Examples of nonaqueous parenteral vehicles that may optionally be used include fixed oils of vegetable origin, cottonseed oil, com oil, sesame oil and peanut oil. [0209] Antimicrobial agents in bacteriostatic or fungistatic concentrations may be added to parenteral preparations, particularly when the preparations are packaged in multiple-dose containers and thus designed to be stored and multiple aliquots to be removed. Examples of antimicrobial agents that may be used include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. [0210] Examples of isotonic agents that may be used include sodium chloride and dextrose. Examples of buffers that may be used include phosphate and citrate. Examples of antioxidants that may be used include sodium bisulfate. Examples of local anesthetics that may be used include procaine hydrochloride. Examples of suspending and dispersing agents that may be used include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Examples of emulsifying agents that may be used include Polysorbate 80 (TWEEN 80). A sequestering or chelating agent of metal ions include EDTA.
[0211] Pharmaceutical carriers may also optionally include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
[0212] The concentration of a kinase inhibitor in the parenteral formulation may be adjusted so that an injection administers a pharmaceutically effective amount sufficient to produce the desired pharmacological effect. The exact concentration of a kinase inhibitor and/or dosage to be used will ultimately depend on the age, weight and condition of the patient or animal as is known in the art.
[0213] Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration should be sterile, as is know and practiced in the art.
[0214] Injectables may be designed for local and systemic administration. Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, preferably more than 1% w/w of the kinase inhibitor to the treated tissue(s). The kinase inhibitor may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the composition is parenterally administered, the carrier and other variables that may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Hence, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulations.
[0215] The kinase inhibitor may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease state and may be empirically determined.
Lyophilized Powders
[0216] The kinase inhibitors of the present invention may also be prepared as lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. The lyophilized powders may also be formulated as solids or gels. [0217] Sterile, lyophilized powder may be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Briefly, the lyophilized powder may optionally be prepared by dissolving dextrose, sorbitol, fructose, corn symp, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5 to 15%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH. Then, a kinase inhibitor is added to the resulting mixture, preferably above room temperature, more preferably at about 30-35 °C, and stirred until it dissolves. The resulting mixture is diluted by adding more buffer to a desired concentration. The resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization. Each vial may contain a single dosage or multiple dosages of the kinase inhibitor.
Topical Administration
[0218] The kinase inhibitors of the present invention may also be administered as topical mixtures. Topical mixtures may be used for local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration. [0219] The kinase inhibitors may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.
[0220] The kinase inhibitors may also be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracistemal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the kinase inhibitor alone or in combination with other pharmaceutically acceptable excipients can also be administered.
Formulations For Other Routes of Administrations
[0221] Depending upon the disease state being treated, other routes of administration, such as topical application, transdermal patches, and rectal administration, may also be used. For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration may be manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
Examples of Formulations
[0222] The following are particular examples of oral, intravenous and tablet formulations that may optionally be used with compounds of the present invention. It is noted that these formulations may be varied depending on the particular compound being used and the indication for which the formulation is going to be used.
ORAL FORMULATION Compound of the Present invention 10-100 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL INTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mg Dextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL TABLET FORMULATION Compound of the Present Invention 1 % Microcrystallme Cellulose 73% Stearic Acid 25% Colloidal Silica 1%. Kits Comprising Kinase Inhibitors
[0223] The invention is also directed to kits and other articles of manufacture for treating diseases associated with kinases. It is noted that diseases are intended to cover all conditions for which the kinases possesses activity that contributes to the pathology and or symptomology of the condition.
[0224] In one embodiment, a kit is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with instmctions. The instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also comprise packaging materials. The packaging material may comprise a container for housing the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms. [0225] In another embodiment, an article of manufacture is provided that comprises a composition comprising at least one kinase inhibitor of the present invention in combination with packaging materials. The packaging material may comprise a container for housing the composition. The container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instmctions regarding how to administer the composition. The kit may also optionally comprise additional components, such as syringes for administration of the composition. The kit may comprise the composition in single or multiple dose forms. [0226] It is noted that the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container that is employed will depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in rum contained within a box. Typically the kit includes directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, topical, transdermal and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
[0227] One particular example of a kit according to the present invention is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. [0228] Another specific embodiment of a kit is a dispenser designed to dispense the daily doses one at a time in the order of their intended use. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter that indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery- powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken. EXAMPLES:
1. Preparation of Kinase Inhibitors
[0229] Various methods may be developed for synthesizing compounds according to the present invention. Representative methods for synthesizing these compounds are provided in the Examples. It is noted, however, that the compounds of the present invention may also be synthesized by other synthetic routes that others may devise. [0230] It will be readily recognized that certain compounds according to the present invention have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of compounds according to the present invention may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
[0231] Various methods for separating mixtures of different stereoisomers are known in the art. For example, a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds. The diastereomers may then be separated in order to recover the optically pure enantiomers. Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts). Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities. For example, diastereomers can typically be separated by chromatography or by separation resolution techniques based upon differences in solubility. A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
[0232] Compounds according to the present invention can also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds can be prepared using salts of the starting materials or intermediates.
[0233] The free acid or free base forms of the compounds can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
[0234] The N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, røetα-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 °C. Alternatively, the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
[0235] Compounds in an unoxidized form can be prepared from N-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 °C.
[0236] Prodrug derivatives of the compounds can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et α/.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodmgs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate, αrα-nitrophenyl carbonate, or the like).
[0237] Protected derivatives of the compounds can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999. [0238] Compounds according to the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
[0239] Compounds according to the present invention can also be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
[0240] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or thee-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliters); psi (pounds per square inch); M (molar); mM (millimolar); i.v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (ambient temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); Tr (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); DME ( 1 ,2-dimethoxyethane) ; DCM (dichloromethane) ; DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N'-dimethylpropyleneurea); GDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et2O (diethyl ether); EDCI (ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl);FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsiiyl); DMAP (4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); Et (ethyl); tBu (tert-butyl); HPLC (high pressure liquid chromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF (tetra-n-butylammonium fluoride); mCPBA (meta-chloroperbenzoic acid.
[0241] All references to ether or Et2O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions conducted under an inert atmosphere at RT unless otherwise noted.
[0242] Η NMR spectra were recorded on a Bmker Avance 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of Hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
[0243] Low-resolution mass spectra (MS) and compound purity data were acquired on a Waters ZQ LC MS single quadrapole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
[0244] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or may be prepared by methods well known to a person of ordinary skill in the art, following procedures described in such standard references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, NY, 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, NY, 1991; March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, NY; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989. [0245] The entire disclosure of all documents cited throughout this application are incorporated herein by reference.
2. Synthetic Schemes For Kinase inhibitors Of The Present Invention
[0246] Kinase inhibitors according to the present invention may be synthesized according to the reaction scheme shown below. Other reaction schemes could be readily devised by those skilled in the art. It should also be appreciated that a variety of different solvents, temperatures and other reaction conditions can be varied to optimize the yields of the reactions. [0247] In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.
[0248] Kinase inhibitors according to the present invention may be synthesized according to the reaction scheme shown below. Other reaction schemes could be readily devised by those skilled in the art. It should also be appreciated that a variety of different solvents, temperatures and other reaction conditions can be varied to optimize the yields of the reactions.
[0249] In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991. Reaction Scheme
Figure imgf000066_0001
Alkylations with oxindole:
[0250] The oxindole (2.25 mmol) in THF (5 mL) is treated with NaH (2.25 mmol) at 23 °C and allowed to stir for 0.5 h. The electrophile (2.25 mmol) is added and the reaction heated to 80 °C overnight. Alternatively, the oxindole anion can be generated in DMSO using KOH at 23 °C, followed by treatment with electrophile at 23 °C. The reaction is cooled and diluted with EtOAc. The reaction is washed with sat. aq. NH4C1, water and brine, then the organic layer is dried (MgSO4) and concentrated in vacuo. The product from the reaction is purified by, for example, preparative HPLC. [0251] For example, the above reaction scheme, and variations thereof, can be used to prepare the following:
Figure imgf000067_0001
Figure imgf000068_0001
2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)- (Z)-N 2-dihydroxy-3-(3H-imidazo[4,5- 1 H-indole-5-carbonitrile b]pyridin-5-yl)-lH-indole-5-carboxamidine
Figure imgf000068_0002
N-(2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5- 2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)- yl)-lH-indol-5-yl)methanesulfonamide N-methyl- 1 H-indole-5-sulf onamide
Figure imgf000068_0003
3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indol- 5-fluoro-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)- 2-ol lH-indol-2-ol
Figure imgf000068_0004
2~hydroxy-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)- (Z)-N',2-dihydroxy-3-(lH-pyrazolo[3,4- 1 H-indole-5-carbonitrile b]pyridin-6-yl)-lH-indole-5-carboxamidine
Figure imgf000068_0005
N-(2-hydroxy-3-(lH-pyrazolo[3,4-b]pyridin-6- 2-hydroxy-N-methyl-3-(lH-ρyrazolo[3,4- yl)- 1 H-indol-5-yl)methanesulf onamide b]pyridin-6-yl)-lH-indole-5-sulfonamide [0252] In each of the above reaction procedures or schemes, the various substituents may be selected from among the various substituents otherwise taught herein. [0253] Descriptions of the syntheses of particular compounds according to the present invention based on the above reaction scheme are set forth herein.
3. Examples of Kinase Inhibitors
[0254] The present invention is further exemplified, but not limited by, the following examples that describe the synthesis of particular compounds according to the invention.
Example 1: 3-(2-Amino-6-methyl-pyrimidin-4-yl)-lH-indol-2-ol
Figure imgf000069_0001
[0255] Example 1 was prepared according to the reaction scheme described above. This kinase inhibitor was found to have an IC50 value less than 100,000 nM for AIK and c-KTf . 1H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (s, 3 H), 6.58 (s, 1 H), 6.92-7.09 (m, 3 H), 7.69 (m, 1 H), 10.83 (s, 1 H), 13.75 (s, 1 H). ESI-MS: m/z 241.0 (M+H)+.
Example 2: 3-(3-aminoisoquinolin-l-yl)-lH-indol-2-ol
Figure imgf000069_0002
[0256] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (bs, 1H), 10.14 (s, 1 H), 7.37- 7.47 (m, 2 H), 7.12 (bs, 2 H), 6.76-6.85 (m, 4 H), 6.49 (m, 2 H), 5.77 (s, 1 H). ESI-MS: m/z 276.0 (M+H)+
Example 3: 3-(3-aminoisoquinolin- 1 -yl)-2-hydroxy- lH-indole-5-carbonitrile
Figure imgf000070_0001
[0257] 1H NMR (400 MHz, DMSO-d6) δ ppm 14.00 (bs, 1H), 11.06 (s, 1 H), 8.07 (d, 1 H), 7.50 (bs, 2 H), 7.44 (d, 2 H), 7.16-7.24 (m, 2 H), 6.90-7.03 (m, 2 H), 6.17 (s, 1 H). ESI-MS: m/z 301.0 (M+H)+
Example 4 : 8-(3 -aminoisoquinolin- 1 -yl)-6H-thiazolo [5 ,4-e]indol-7-ol
Figure imgf000070_0002
[0258] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.50 (bs, 1H), 10.75 (s, 1 H), 8.88 (s, 1 H), 7.88 (m, 2 H), 7.50 (d, 2 H), 7.42 (m, 1 H), 7.12 (m, 3 H), 6.53 (s, 1 H). ESI-MS: m/z 333.0 (M+H)+ Example 5 : N-(3-(3-aminoisoquinolin- 1 -yl)-2-hydroxy- 1 H-indol-5-yl)ethanesulfonamide
Figure imgf000071_0001
[0259] 1H NMR (400 MHz, DMSO-d6) δ ppm 14.25 (bs, 1H), 11.66 (s, 1 H), 9.28 (s, 1 H), 7.49 (m, 2 H), 7.02 (m, 2 H), 6.82 (m, 2 H), 6.58-6.80 (m, 3 H), 2.90 (q, 2 H), 1.13 (t, 3H). ESI-MS: m/z 383.0 (M+H)+
Example 6: 2-hydroxy-N-methyl-3-(7-oxo-7,8-dihydro- 1 ,8-naphthyridin-2-yl)- 1H- indole-5 -sulf onamide
Figure imgf000071_0002
[0260] 1H NMR (400 MHz, DMSO-D6) δ ppm 2.38 (d, 7=4.80 Hz, 3 H) 6.51 (s, 1 H) 7.11 (d, 7=5.05 Hz, 1 H) 7.23 (d, 7=5.31 Hz, 1 H) 7.38 - 7.49 (m, 2 H) 7.93 - 8.09 (m, 3 H) 11.24 (s, 1 H) 12.41 (s, 1 H) 14.38 (s, 1 H). ESI-MS: m/z 371.2 (M+H)+
Example 7: N-ethyl-2-hydroxy-3-(7-oxo-7,8-dihydro-l,8-naphthyridin-2-yl)-lH-indole- 5-sulfonamide
Figure imgf000071_0003
[0261] 1H NMR (400 MHz, DMSO-D6) δ ppm 0.97 (t, 7=7.20 Hz, 3 H) 2.66 - 2.77 (m, 7=6.82, 6.82, 6.82, 6.82 Hz, 2 H) 6.48 (s, 1 H) 7.12 (d, 7=8.08 Hz, 1 H) 7.33 (t, 7=5.68 Hz, 1 H) 7.43 (d, 7=8.08 Hz, 2 H) 7.92 (s, 1 H) 7.99 (s, 1 H) 8.11 (d, 7=8.59 Hz, 1 H) 11.26 (s, 1 H) 12.56 (s, 1 H) 14.37 (s, 1 H). ESI-MS: m/z 385.2 (M+H)+
4. Biological Testing
[0262] The activity of compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of the activated protein kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by mnning a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands. A. Determination of Inhibition of AIK
[0263] The inhibitory properties of compounds relative to ATK may be determined by the Direct Fluorescence Polarization detection method (FP) using a Greiner small volume black 384- well-plate format under the following reaction conditions: 50 mM Hepes pH
7.3, 10 mM MgCl2, 10 mM NaCl, 1 mM DTT, 0.01% Brij35, 100 nM Fluorescein-
LRRASLG peptide (provided by SYNPEP), 5% DMSO, 2.5uM ATP. Detection of the reaction product is performed by addition of EVLAP binding reagent (Molecular Devices).
Reaction product may be determined quantitatively by FP using an Analyst HT plate reader (Molecular Devices) with an excitation wavelength at 485 nm and emission at 530 nm and using a Fluorescein 505 dichroic mirror.
[0264] The assay reaction may be initiated as follows: 2 ul of (3x) 300 nM Fl-Peptide/
7.5 uM ATP was added to each well of the plate, followed by the addition of 2 ul of (3x) inhibitor (2.5 fold serial dilutions for 11 data points for each inhibitor) containing 15%
DMSO. 2 ul of (3x) 7.5 nM AIK solution may be added to initiate the reaction (final enzyme concentration was 2.5 nM for AIK). The reaction mixture may then be incubated at room temperature for 45 min, and quenched and developed by addition of 20 ul of 1 to 400 diluted TVIAP binding reagent in lx proprietary IJVIAP binding buffer. Fluorescence polarization readings of the resulting reaction mixtures may be measured after a 60-minute incubation at room temperature.
[0265] IC50 values may be calculated by non-linear curve fitting of the compound concentrations and fluorescent polarization values to the standard IC50 equation. As a reference point for this assay, Staurosporin showed an IC50 of <10 nM. B. Determination of Inhibition of c-KIT
[0266] The inhibitory properties of compounds relative to c-Kit may be determined by the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method using a small volume black 384-well-plate (Greiner) format under the following reaction conditions: 50 mM Hepes pH 7.3, 10 mM MgC12, 10 mM NaCl, 1 mM DTT, 0.01%
Brij35, 250 nM Biotin-EGPWLEEEEEAYGWMDF peptide (provided by SYNPEP), 5%
DMSO, lOOuM ATP. Detection of the reaction product may be performed by addition of
Streptavidin-APC (Prozyme) and Eu-Anti-phosphotyrosine antibody (Perkin Elmer).
Reaction product may be determined quantitatively by TR-FRET reading using an Analyst
HT plate reader (Molecular Devices) with an excitation wavelength at 330 nm and emission at 615 nm (Europium) compared to 330 nm excitation (Europium) and emission
665 nm (APC) and using an Europium 400 dichroic mirror.
[0267] The assay reaction may be initiated as follows: 4 ul of (2.5x) 625 nM Biotin-
Peptide / 250 uM ATP was added to each well of the plate, followed by the addition of 2 ul of (5x) inhibitor (2.5 fold serial dilutions for 11 data points for each inhibitor) containing 25% DMSO. 4 ul of (2.5x) c-Kit solution may be added to initiate the reaction
(final enzyme concentration was 0.13 nM for c-Kit). The reaction mixture may then be incubated at room temperature for 30 min, and quenched and developed by addition of 10 ul of (2x) 3.2 nM Eu-Antibody and 25 nM Streptavidin-APC in 50mM Hepes pH 7.3,
30mM EDTA, 0.1% Triton X-100 buffer. TR-FRET readings of the resulting reaction mixtures may be measured after a 60-minute incubation at room temperature on the
Analyst HT.
[0268] IC50 values may be calculated by non-linear curve fitting of the compound concentrations and ratio metric Eu:APC values to the standard IC50 equation. As a reference point for this assay, Staurosporin showed an IC50 of <5 nM.
[0269] The following abbreviations have been used: ATP Adenosine Triphophatase
BSA Bovin Semm Albumin
EDTA Ethylenediaminetetraacetic acid
GSK3 Glycogen synthase kinase 3
MOPS Morpholinepropanesulfonic acid
SPA Scintillation Proximity Assay
[0270] It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds, compositions, kits, and methods of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

What is claimed is:
1. A compound comprising one of the following formula:
Figure imgf000075_0001
wherein: J, K, L, and Y are each independently selected from the group consisting of C and
N; M is selected from the group consisting of CH and N; X and Z are each independently selected from the group consisting of C, N, O and S; R , R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-1 )cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C9-1 )bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1- )alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or R3 and R are taken together to form an unsubstituted or substituted ring, or R^ and R5 are taken together to form an unsubstituted or substituted ring, with the proviso that R , R4, and/or R5 are absent when J, K and/or L respectively are nitrogen; R is hydrogen or a substituent convertible in vivo to hydrogen; R1 and R14 are each independently selected from the group consisting of hydrogen, (Cι-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C -12)cycloalkyl, hetero(C3-1 )cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or R13 and R14 are taken together to form an unsubstituted or substituted ring, with the provisos that (a) R1 is absent when X is O or S, (b) R13 is absent when X is N and X is part of a double bond, and (c) R14 is absent when Y is N; R16 and R17 are independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(Cι-7)alkyl, -SO2(Cι-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R 7 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R1 and R16 are taken together to form an unsubstituted or substituted ring, with the provisos that (a) X, Y and Z are not all simultaneously C, (b) X and Z are not O or S when that atom is part of a double bond, and (c) a double bond is present between one of X and Y or Y and Z and a single bond is present between the other of either X and Y or Y and Z.
2. A compound comprising the formula:
Figure imgf000076_0001
wherein: J, K, L, W, X, Y and Z are each independently selected from the group consisting of C and N; M is selected from the group consisting of CH and N; R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C -1 )cycloalkyl, aryl(C1-10)alkyl, heteroaryl(Ci-5)alkyl, (C9-12)bicycloaryl, hetero(C -1 )bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1- )alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or R3 and R are taken together to form an unsubstituted or substituted ring, or R4 and R5 are taken together to form an unsubstituted or substituted ring, with the proviso that R3, R , and/or R5 are absent when J, K and/or L respectively are nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R12, R13, and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or R12 and R13 are taken together to form an unsubstituted or substituted ring, or R13 and R14 are taken together to form an unsubstituted or substituted ring, with the proviso that R12, R13 and/or R1 are absent when W, X, and/or Y respectively is N; and R16 and R17 are independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C 7)alkyl, -SO2(C 7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R1 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted, or substituted, or where R14 and R16 are taken together to form an unsubstituted or substituted ring.
3. A compound according to claim 2 comprising a formula selected from the group consisting of:
Figure imgf000078_0001
Figure imgf000079_0001
wherein: J, K, L, W and Y are each independently selected from the group consisting of C and N; M is selected from the group consisting of CH and N; Vl5 V2, V3, and V4 are each independently selected from the group consisting of C and N when the respective atom is part of a ring double bond and are independently selected from the group consisting of C, N, O and S when the respective atom is not part of a double bond; R3, R^ and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that R3, R4, and/or R5 are absent when J, K and/or L respectively are nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R12, R14, R20, R20', R21, R21', R22, R22', R23, and R23' are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C -12)cycloalkyl, hetero(C3-1 )cycloalkyl, hetero(C -12)cycloalkoxy, (C9-1 )bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, with the provisos that (a) R12, R14, R2o, R21, R22, and/or R2 are absent when the atom to which R^, Rι4, R20, R21, R22, and R23 respectively are bound is O or S, and (b) R2o\ R21', R22', and/or R2 ' are absent when the atom to which R20', R21', R22', and R2 ' respectively are bound is N, O or S, and; R16 and R17 are independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(d-7)alkyl, -SO2(C1-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
4. A compound according to claim 1 comprising one of the following formula:
Figure imgf000081_0001
wherein: R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(Ci-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3) alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R13 and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C -12)cycloalkyl, hetero(C3- 2)cycloalkyl, hetero(C -i2)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted; and R16 and R17 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(Ci-7)alkyl, -SO2(C 7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R1 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1- )alkyl group, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
5. A compound according to claim 1 comprising one of the following formula:
Figure imgf000082_0001
wherein: R , R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-10)alkyl, (C3-ι2)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1- )alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R1 is selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, hetero.(C -12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted; and R16 and R17 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C 7)alkyl, -SO2(C1-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
6. A compound according to claim 1 comprising one of the following formula:
Figure imgf000083_0001
wherein: R3, R^, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C -12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C -ι2)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R14 is selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted; and R16 and R1 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(Ci-7)alkyl, -SO2(C 7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R1 together are -(CH2)4.5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
7. A compound according to claim 1 comprising one of the following formula:
Figure imgf000084_0001
wherein: R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-i2)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C -12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl(C1.3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R1 is selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted; and R16 and R17 are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH , -CONH2, -CO(C1-7)alkyl, -SO2(C1-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form a unsubstituted or substituted ring.
8. A compound according to claim 1 comprising one of the following formula:
Figure imgf000085_0001
wherein: Vi, V2, V3, and V4 are each independently selected from the group consisting of C, N, O and S; R3, R , and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C -12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R2Q, R20', R21, R21', R22, R22', R23, and R23' are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, with the provisos that (a) R20, R21, R22, and/or R23 are absent when Vi, V2, V3, and or V respectively are O or S, and (b) R20\ R2ι', R22', and/or R2 ' are absent when V], V2, V3, and/or V4 respectively are N, O or S; and Ri and Rπ are each independently selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C 7)alkyl, -SO2(C!-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2)4-5- optionally interrapted by one O, S, NH or -N(C1- )alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R16 is taken together with another substituent to form an unsubstituted or substituted ring.
9. A compound according to claim 2 comprising the formula:
Figure imgf000086_0001
wherein: W, X, and Y are each independently selected from the group consisting of C and
N; R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-ι0)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C .12)bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1- )alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that R3, R4, and/or R5 are absent when J, K and/or L respectively are nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; and R12, R13, and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-ι2)cycloalkyl, hetero(C -12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, with the proviso that R12, R13 and/or R14 are absent when W, X, and/or Y respectively is N.
10. A compound according to claim 1 comprising one of the following formula:
Figure imgf000087_0001
wherein: J, K, L, and Y are each independently selected from the group consisting of C and
N; M is selected from the group consisting of CH and N; X and Z are each independently selected from the group consisting of C, N, O and
S; R3, R , and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-i2)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-s)alkyl, (C9-12)bicycloaryl, hetero(C4-1 )bicycloaryl, carbonyl(C1-3)alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1-3)alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or R and 4 are taken together to form an unsubstituted or substituted ring, or R4 and R5 are taken together to form an unsubstituted or substituted ring, with the proviso that R3, R^ and/or R5 are absent when J, K and/or L respectively are nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; R13 and R1 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-i2)bicycloaryl, hetero(Cg-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or R13 and R14 are taken together to form an unsubstituted or substituted ring, with the provisos that (a) R1 is absent when X is O or S, (b) R13 is absent when X is N and X is part of a double bond, and (c) R1 is absent when Y is N; R16 is selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C 7)alkyl, -SO2(Cι-7)alkyl, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R16 and R17 together are -(CH2)4-5- optionally interrupted by one O, S, NH or -N(Cι-3)alkyl group; R1 is selected from the group consisting of hydrogen and (C1-6)alkyl, or where R16 and R17 together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted, or where R14 and R16 are taken together to form an unsubstituted or substituted ring, with the provisos that (a) X, Y and Z are not all simultaneously C, (b) X and Z are not O or S when that atom is part of a double bond, and (c) a double bond is present between one of X and Y or Y and Z and a single bond is present between the other of either X and Y or Y and Z.
11. A compound according to claim 2 comprising the formula:
Figure imgf000089_0001
wherein: J, K, L, W, X, Y and Z are each independently selected from the group consisting of C and N; M is selected from the group consisting of CH and N; R , R4, and R5 are each independently selected from the group consisting of hydrogen, halo, perhalo(C1-1o)alkyl, amino, nitro, cyano, thio, sulfonamide, (C1-1o)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-1o)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C -12)bicycloaryl, carbonyl(C1- )alkyl, thiocarbonyl(C1-3)alkyl, sulfonyl(C1- )alkyl, sulfinyl(C1-3)alkyl, imino(C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or R3 and R4 are taken together to form an unsubstituted or substituted ring, or R4 and R5 are taken together to form an unsubstituted or substituted ring, with the proviso that R3, R , and/or R5 are absent when J, K and/or L respectively are nitrogen; R7 is hydrogen or a substituent convertible in vivo to hydrogen; Ri2> Ri35 and R14 are each independently selected from the group consisting of hydrogen, (C1-12)alkyl, alkoxy, thio, hydroxy, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, hetero(C3-12)cycloalkoxy, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl group, imino group, sulfonyl group and sulfinyl group, halo, cyano, nitro, and trifluoromethoxy, each substituted or unsubstituted, or R12 and R13 are taken together to form an unsubstituted or substituted ring, or R13 and R14 are taken together to form an unsubstituted or substituted ring, with the proviso that R12, R13 and/or R1 are absent when W, X, and/or Y respectively is N; R16 is selected from the group consisting of hydrogen, -CONNH2, -CSNH2, -CONH2, -CO(C1-7)alkyl, -SO2(Cr7)alkyl, (C1.6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted; and R1 is selected from the group consisting of hydrogen and (Cι-6)alkyl, or where R16 and R17 together are -(CH2) -5- optionally interrapted by one O, S, NH or -N(C1-3)alkyl group, or where R16 and R1 together is selected from the group consisting of pyrrolidin-1 - yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted, or substituted, or where R1 and R16 are taken together to form an unsubstituted or substituted ring.
12. A compound according to any one of claims 1, 2, 3, 10 and 11, wherein J, K, L and M each comprise a carbon ring atom.
13. A compound according to any one of claims 1, 2, 3, 10 and 11, wherein J, K and L each comprise a carbon ring atom and M is nitrogen.
14. A compound according to any one of claims 1, 2, 9, 10 and 11, wherein X comprises a nitrogen ring atom.
15. A compound according to any one of claims 1, 2, 3, 9, 10 and 11, wherein Y comprises a nitrogen ring atom.
16. A compound according to any one of claims 1, 2, 10 and 11, wherein Z comprises a nitrogen ring atom.
17. A compound according to any one of claims 1, 2, 9, 10 and 11, wherein X and Y comprise substituents that form a second ring fused to the ring comprising X and Y.
18. A compound according to any one of claims 2, 9 and 11 , wherein W and X comprise substituents that form a second ring fused to the ring comprising W and X.
19. A compound according to any one of claims 1 , 2, 3, 10 and 11 , wherein the ring formed by J, K, L and M comprises substituents that form a ring fused to the ring formed by J, K, L and M.
20. A compound according to any one of claims 1, 2, 10 and 11, wherein X and Y comprise substituents that form a second ring fused to the ring comprising X and Y, and the ring formed by J, K, L and M comprises substituents that form a ring fused to the ring formed by J, K, L and M.
21. A compound according to any one of claims 17-20, wherein the fused ring is a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring.
22. A compound according to any one of claims 17-20, wherein the fused ring is an alicyclic ring.
23. A compound according to any one of claims 17-20, wherein the fused ring is a substituted or unsubstituted heteroaryl selected from the group consisting of pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline and triazine.
24. The compound according to any one of claims 3 and 8, wherein at least one of Vl5
V2, V3 and V4 is N.
25. The compound according to any one of claims 2, 3, 9 and 11, wherein W or Y is N.
26. The compound according to any one of claims 1, 2, 4, 9, 10 and 11, wherein R13 is selected from the group consisting of hydrogen, F, Br, Cl, -OCH , -SO2Me, -SO2NH2, -SO2NHMe, -SO2NHCH2CH2OH, -SO2NMe2, -NHSO2(3-fluorophenyl), perhalo(C1-1o)alkyl, -OCF3, -CF3, (C1-1o)alkyl, hydroxy-(C1 -10)alkyl, aryl, aryl- (C1-1o)alkyl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, hydroxy, aryloxy, heteroaryloxy, arylalkyl, heteroaryl(C1-1o)alkyl, cycloalkyl, heterocycloalkyl, HS-, (C1-6)alkylS-, cyano, nitro, cycloalkoxy, (Cι.ι2)alkoxy, -COOH, -CO2Me, carboxamide, (C1-12)alkylNHCO-, R9R10N-(C1-12)alkyl aminocarbonyl, R9R10N- (C1-12)alkoxycarbonyl, hetero-(C1-6)alkylaminocarbonyl, heterocycloalkyl-(C1-6)alkylCO-, heteroaryl-(C1-6)alkylCO-, heterocycloalkyl-(C1-6)alkylOCO-, heteroaryl-(C1-6)alkylOCO-, (C1-6)alkylOCO-, diethoxyphosphorylmethyl, imino group, R9R1oN-(C1-6)alkylsulfonyl, -NH2, -NHCH3, -N(CH3)2, -NH(C1-3)alkyl, -N(C1-3-alkyl)2, R9R10N-(C1-ι2)alkyl aminocarbonylamino, R9R1oN-(C1.6)alkyl alkoxycarbonylamino, heterocycloalkyl-(Cι. 6)alkyl aminocarbonylamino, heteroaryl-(C1-6)alkyl aminocarbonylamino, (C3-12)heterocycloalkyl-(C1-6)alkoxycaι-bonylamino, heteroaryl- ( ^alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)(C1-6 alkyl)amino, R9R!oN-(C1-6)alkyl carbonylamino, [R9R1oN-(Cι-6)alkylcarbonyl][(Cι. 6)alkyl] amino, R9R1oN-(C1-6)alkyl sulfonylamino, [R9R1oN-(C1-6)alkylsulfonyl][(C1- 6)alkyl]amino, and -NR9R10 where R9 and R10 are independently selected from the group consisting of hydrogen, (Cι-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R9 and Rio together are -(CH2)4-5- optionally intermpted by one O, S, NH or -N(Cι- )alkyl group, or where R and Rio together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted.
27. The compound according to any one of claims 1-7, 9, 10 and 11, wherein Rj4 is selected from the group consisting of hydrogen, F, Br, Cl, -OCH3, -SO2Me, -SO2NH2, -SO2NHMe, -SO2NHCH2CH2OH, -SO2NMe2, -NHSO2(3 -fluorophenyl), perhalo(Cr10)alkyl, -OCF3, -CF3, (Ci-ιo)alkyl, hydroxy-(C1-ι0)alkyl, aryl, aryl- (C1-ιo)alkyl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, hydroxy, aryloxy, heteroaryloxy, arylalkyl, heteroaryl(Cι-1o)alkyl, cycloalkyl, heterocycloalkyl, HS-, (Cι-6)alkylS-, cyano, nitro, cycloalkoxy, (Cι-12)alkoxy, -COOH, -CO2Me, carboxamide, (C1-12)alkylNHCO-, R9R10N-(C1-12)alkyl aminocarbonyl, R9R10N- (C1-12)alkoxycarbonyl, hetero-(C1-6)alkylaminocarbonyl, heterocycloalkyl-(C1-6)alkylCO-, heteroaryl-(C1-6)alkylCO-, heterocycloalkyl-(C1-6)alkylOCO-, heteroaryl-(C1-6)alkylOCO-, (C1-6)alkylOCO-, diethoxyphosphorylmethyl, imino group, R9R1oN-(C1-δ)alkylsulfonyl, -NH2, -NHCH3, -N(CH3)2, -NH(C1-3)alkyl, -N(Cι-3-alkyl)2, R9Rι0N-(CM2)alkyl aminocarbonylamino, R9RιoN-(C1-6)alkyl alkoxycarbonylamino, heterocycloalkyl-(C1- 6)alkyl aminocarbonylamino, heteroaryl-(Cι-6)alkyl aminocarbonylamino, (C3-i2)heterocycloalkyl-(C1-6)alkoxycarbonylamino, heteroaryl- (Cι-6)alkoxycarbonylamino, (Cι-6)alkyl carbonylamino, (( ^alkyl carbonyl)(Cι-6 alkyl)amino, R9R1oN-(C1-6)alkyl carbonylamino, [R9R1oN-(C1-6)alkylcarbonyl][(C1- 6)alkyl]amino, R9Rι0N-(Cι-6)alkyl sulfonylamino, [R9Rι0N-(C1.6)alkylsulfonyl][(Cι- 6)alkyl] amino, and -NR9R10 where R9 and R10 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R and R10 together are -(CH2)4-5- optionally intermpted by one O, S, NH or -N(C1-3)alkyl group, or where R and Rjo together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted.
28. A compound according to any one of claims 1-7 and 9-11, wherein R12, R13 and Ri4 are each independently selected from the group consisting of hydrogen, F, Br, Cl, -OCH3, -SO2Me, -SO2NH2, -SO2NHMe, -SO2NHCH2CH2OH, -SO2NMe2, -NHSO2(3- fluorophenyl), perhalo(C1-1o)alkyl, -OCF3, -CF3, (C1-1o)alkyl, hydroxy-(C1-1o)alkyl, aryl, aryl-(Ci-io)alkyl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, hydroxy, aryloxy, heteroaryloxy, arylalkyl, heteroaryl(Cι-10)alkyl, cycloalkyl, heterocycloalkyl, HS-, (C1-6)alkylS-, cyano, nitro, cycloalkoxy, (C1-12)alkoxy, -COOH, -CO2Me, carboxamide, (C1-12)alkylNHCO-, R9R10N-(C1-12)alkyl aminocarbonyl, R9R1oN-(C1-ι2)alkoxycarbonyl, hetero-(C1-6)alkylaminocarbonyl, heterocycloalkyl-(C1- 6)alkylCO-, heteroaryl-(C1-6)alkylCO-, heterocycloalkyl-(Cι-6)alkylOCO-, heteroaryl- (C1-6)alkylOCO-, (C1-6)alkylOCO-, diethoxyphosphorylmethyl, imino group, R9R10N-(Cι. 6)alkylsulfonyl, -NH2, -NHCH3, -N(CH3)2, -NH(Cι-3)alkyl, -N(C1-3-alkyl)2, R9R10N- (C1-12)alkyl aminocarbonylamino, R R10N-(C1.6)alkyl alkoxycarbonylamino, heterocycloalkyl-(C1-6)alkyl aminocarbonylamino, heteroaryl-(C1-6)alkyl aminocarbonylamino, (C3-12)heterocycloalkyl-(C1-6)alkoxycarbonylamino, heteroaryl- (Cι-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)(Cι-6 alkyl)amino, R9R1oN-(C1-6)alkyl carbonylamino, [R9R1oN-(C1-6)alkylcarbonyl][(C1- 6)alkyl] amino, R9R1oN-(Cι-6)alkyl sulfonylamino, [R9R1oN-(C1-6)alkylsulfonyl][(C1- 6)alkyl]amino, and -NR9R10 where R9 and Rio are independently selected from the group consisting of hydrogen, (C1-6)alkyl, heterocycloalkyl, and heteroaryl, each substituted or unsubstituted, or where R9 and R10 together are -(CH2)4-5- optionally intermpted by one O, S, NH or -N(Cι-3)alkyl group, or where R9 and R^ together is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, and 4-methyl-piperazin-l-yl, each unsubstituted or substituted.
29. A compound according to any one of claims 1-7 and 9-11, wherein R12, R13 and R1 are each independently selected from the group consisting of hydrogen, (C1-6)alkyl, hydroxy, hydroxy-(Cι-6)alkyl, carboxamide, mono-(Cι-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heterocyclo, heteroaryl-(C1-6)alkyl, (C1-6)alkoxy, aryloxy, heteroaryloxy, amino, mono- or di-(C1-6)alkyl-amino, (Cι_6)alkyl aminocarbonyl, mono- or di-(C1- )alkyl-amino (C1-6)alkoxycarbonyl, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonylamino, mono- or di-(Cι-6)alkyl-amino (C1-6)alkoxycarbonylamino, (Cι_ 6)alkyl carbonylamino, ((C1-6)alkyl carbonyl)((C1-6)alkyl)amino, mono- or di-(C1-6)alkyl- amino (Cι-6)alkyl carbonylamino, [mono- or di-(Cι-6)alkyl-amino (Cj_6)alkyl carbonyl] [(C1-6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonylamino, [mono- or di-(Ci-6)alkyl-amino(Ci-6)alkylsulfonyl][(C1-6)alkyl]amino, mono- or di-(C1- 6)alkyl-amino(C1-6)alkylsulfonyl, heteroaryl(C1-6)alkyl aminocarbonyl, heterocyclyl(Cι_6)alkyl aminocarbonyl, heteroaryl (C1-6)alkyl aminocarbonylamino, heterocyclyl (C1-6)alkyl aminocarbonylamino, heteroaryl (C1-6)alkoxycarbonylamino, heterocyclyl(Ci,6)alkoxycarbonylamino, heteroaryl (C1-6)alkylcarbonyl, heterocycly C!. 6)alkyl carbonyl, heteroaryl (C1-6)alkoxycarbonyl, heterocyclyl(Cι-6)alkoxycarbonyl, ( . 6)alkyl sulfonyl (C1-6)alkylaminoalkyl, (Cι-6)alkyl sulfonyl-(C1-6)alkyl-aminoalkyl- heteroaryl-, (C1-6)alkoxycarbonyl, halo, cyano, diethoxyphosphorylmethyl, trifluoromethyl and trifluoromethoxy, each substituted or unsubstituted.
30. A compound according to any one of claims 1-3 and 9-11, wherein Y is N and R12,
Rι3 and Rι are each independently selected from the group consisting of hydrogen,
(Cι.6)alkyl, hydroxy, hydroxy-(C1-6)alkyl, carboxamide, mono-(C1-6)alkyl aminocarbonyl, substituted aryl-(C1-6)alkyl, heteroaryl, heterocyclo, heteroaryl-(Cι-6)alkyl, heterocyclyl-
(Cι-6)alkyl, heteroaryloxy, heterocyclyloxy, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl aminocarbonyl, mono- or di-(Cι-6)alkyl-amino (Cι-g)alkoxycarbonyl, mono- or di- (C1-6)alkyl-amino(Cι_6)alkyl aminocarbonylamino, mono- or di-(C1- )alkyl-amino (Cι-6)alkoxycarbonylamino, (C1-6)alkyl carbonylamino, ((Cι-6)alkyl carbonyl)((Cι-6) alkyl)amino, mono- or di-(Cι-6)alkyl-amino (Cι-6)alkyl carbonylamino, [mono- or di-(Cι. 6)alkyl-amino (C1-6)alkyl carbonyl] [(Ci.6)alkyl]amino, mono- or di-(Ci-6)alkyl-amino ( . 6)alkyl sulfonylamino, [mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl] [(Q. 6)alkyl]amino, mono- or di-(C1-6)alkyl-amino (C1-6)alkyl sulfonyl, heteroaryl (Cι_6)alkyl aminocarbonyl, heteroaryl (Cι-6)alkyl carbonyl, (Cι-6)alkyl sulfonyl (Cι-6)alkyl aminoalkyl, (Cι-6)alkyl sulfonyl-(Cι-6)alkyl-aminoalkyl-heteroaryl-, halo, cyano and trifluoromethyl, each substituted or unsubstituted.
31. A compound according to any one of claims 1 -7 and 9-11, wherein R12 and R13 or R1 and R1 are taken together to form a substituted or unsubstituted fused ring.
32. A compound according to claim 31, wherein the fused ring is an alicyclic ring.
33. A compound according to claim 31 , wherein the fused ring is a substituted or unsubstituted 5 or 6 membered aryl or heteroaryl ring.
34. A compound according to any one of claims 1-7, 10 and 11, wherein Rι and Rι6 are taken together to form a substituted or unsubstituted fused ring.
35. A compound according to claim 34, wherein the fused ring is an alicyclic ring.
36. A compound according to claim 34, wherein the fused ring is an unsubstituted or substituted 5 or 6 membered aryl or heteroaryl ring.
37. A compound according to any one of claims 1-8, 10 and 11, wherein at least one of R16 and R1 is selected from the group consisting of hydrogen and (Ci—e) alkyl.
38. A compound according to any one of claims 1-8, 10 and 11, wherein R17 is H.
39. A compound according to any one of claims 1-8, 10 and 11, wherein R16 and Rι7 are both independently selected from the group consisting of hydrogen and ( —β) alkyl.
40. A compound according to any one of claims 1-8, 10 and 11, wherein Rι6 and R17 are both hydrogen.
41. A compound selected from the group consisting of: 3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indol-2-ol; 5-fluoro-3-(lH-ρyrrolo[2,3-b]pyridin-6-yl)-lH-indol-2-ol; 2-hydroxy-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indole-5-carbonitrile; (Z)-N 2-dihydroxy-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indole-5-carboxamidine; N-(2-hydroxy-3-( lH-pyrrolo[2,3-b]pyridin-6-yl)- lH-indol-5- yl)methanesulfonamide; 2-hydroxy-N-methyl-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)-lH-indole-5-sulfonamide; 3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indol-2-ol; 5-fluoro-3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indol-2-ol; 2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indole-5-carbonitrile; (Z)-N',2-dihydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indole-5- carboxamidine; N-(2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)-lH-indol-5- yl)methanesulfonamide 2-hydroxy-3-(3H-imidazo[4,5-b]pyridin-5-yl)-N-methyl-lH-indole-5-sulfonamide; 3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indol-2-ol; 5-fluoro-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indol-2-ol; 2-hydroxy-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indole-5-carbonitrile; (Z)-N',2-dihydroxy-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indole-5- carboxamidine; N-(2-hydroxy-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)-lH-indol-5- yl)methanesulfonamide; 2-hydroxy-N-methyl-3-( lH-pyrazolo[3 ,4-b]pyridin-6-yl)- lH-indole-5- sulfonamide; 3-(2-Amino-6-methyl-pyrimidin-4-yl)-lH-indol-2-ol; 3-(3-aminoisoquinolin- 1 -yl)- 1 H-indol-2-ol; 3-(3-aminoisoquinolin- 1 -yl)-2-hydroxy- lH-indole-5-carbonitrile; 8-(3-aminoisoquinolin-l-yl)-6H-thiazolo[5,4-e]indol-7-ol; N-(3-(3-aminoisoquinolin-l-yl)-2-hydroxy-lH-indol-5-yl)ethanesulfonamide; 2-hydroxy-N-methyl-3-(7-oxo-7,8-dihydro-l,8-naphthyridin-2-yl)-lH-indole-5- sulfonamide; and N-ethyl-2-hydroxy-3-(7-oxo-7,8-dihydro-l,8-naphthyridin-2-yl)-lH-indole-5- sulfonamide.
42. A compound according to any one of claims 1-41, wherein the compound is in the form of a pharmaceutically acceptable salt, biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or prodmg thereof.
43. A compound according to any one of claims 1-41, wherein the compound is present in a mixture of stereoisomers.
44. A compound according to any one of claims 1-41, wherein the compound comprises a single stereoisomer.
45. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1-44.
46. A pharmaceutical composition according to claim 45, wherein the composition is a solid formulation adapted for oral administration.
47. A pharmaceutical composition according to claim 45, wherein the composition is a liquid formulation adapted for oral administration.
48. A pharmaceutical composition according to claim 45, wherein the composition is a tablet.
49. A pharmaceutical composition according to claim 45, wherein the composition is a liquid formulation adapted for parenteral administration.
50. A pharmaceutical composition comprising a compound according to any one of claims 1-44, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, and intrathecally.
51. A kit comprising: a compound according to any one of claims 1-44, and instmctions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instmctions regarding how to administer the compound.
52. A kit according to claim 51 , wherein the kit comprises the compound in a multiple dose form.
53. An article of manufacture comprising: a compound according to any one of claims 1-44, and packaging materials.
54. An article of manufacture according to claim 53, wherein the packaging material comprises a container for housing the compound.
55. An article of manufacture according to claim 54, wherein the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instmctions regarding how to administer the composition.
56. An article of manufacture according to claim 53, wherein the article of manufacture comprises the compound in a multiple dose form.
57. A method of inhibiting kinase comprising: contacting kinase with a compound according to any one of claims 1-44.
58. A method according to claim 57, wherein the inhibition arises from a favorable conformation adopted by the compound in its enol form, and wherein the conformation arises from an intramolecular hydrogen bonding of the enol hydrogen and an adjacent nitrogen atom of the compound.
59. A method according to claim 57, wherein the inhibition arises from a favorable conformation adopted by the compound in its enol form, and said inhibition arises from a hydrogen bonding interaction between the enol tautomer and an active site residue of the kinase.
60. A method of inhibiting kinase comprising: causing a compound according to any one of claims 1-44 to be present in a subject in order to inhibit kinase in vivo.
61. A method of inhibiting kinase comprising: administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits kinase in vivo, the second compound being a compound according to any one of claims 1-44.
62. A therapeutic method comprising: administering a compound according to any one of claims 1-44 to a subject.
63. A method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: causing a compound according to any one of claims 1-44 to be present in a subject in a therapeutically effective amount for the disease state.
64. A method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound according to any one of claims 1-44 wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
65. A method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound according to any one of claims 1-44, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.
66. A method for treating cancer comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a composition according to any one of 1-44.
67. A method of claim 66, wherein the cancer is selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, non small-cell lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.
68. A method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: causing a compound according to any one of claims 1-44 to be present in a subject in a therapeutically effective amount for the disease state.
69. A method for treating inflammation, inflammatory bowel disease, psoriasis, or transplant rejection, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound according to any one of claims 1-44.
70. A method of preventing or treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound according to any one of claims 1-44 wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
71. A method of preventing or treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound according to any one of claims 1-44, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.
72. A method for preventing or treating dementia related diseases and Alzheimer's Disease, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound according to any one of claims 1-44.
73. A method of claim 72, wherein the dementia related diseases are selected from the group consisting of Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Guam, HIV dementia, diseases with associated neurofibrillar tangle pathologies, predemented states, vascular dementia, dementia with Lewy bodies, Frontotemporal dementia and dementia pugilistica.
74. A method for preventing or treating amyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome, Huntington's Disease, Parkinson's Disease, postencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann- Pick's Disease, stroke, head trauma and other chronic neurodegenerative diseases, Bipolar Disease, affective disorders, depression, schizophrenia, cognitive disorders, hair loss and contraceptive medication, comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound according to any one of claims 1-44.
75. A method for preventing or treating mild Cognitive Impairment, Age- Associated Memory Impairment, Age-Related Cognitive Decline, Cognitive Impairment No Dementia, mild cognitive decline, mild neurocognitive decline, Late-Life Forgetfulness, memory impairment and cognitive impairment and androgenetic alopecia, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound according to any one of claims 1-44.
76. A method for preventing or treating dementia related diseases, Alzheimer's Disease and conditions associated with kinases, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound according to any one of claims 1-44.
77. A method for treating arthritis comprising administration to a mammalian species in need thereof of a therapeutically effective amount of a compound according to any one of claims 1-44.
78. A method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound according to any one of claims 1-44, wherein the second compound is present in a subject in a therapeutically effective amount for the disease state.
79. A method of treating a disease state for which kinase possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound according to any one of claims 1-44, wherein the compound is present in the subject in a therapeutically effective amount for the pathology and/or symptomology.
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