WO2002062789A1 - Pyrazole compounds useful as protein kinase inhibitors - Google Patents

Pyrazole compounds useful as protein kinase inhibitors Download PDF

Info

Publication number
WO2002062789A1
WO2002062789A1 PCT/US2001/051031 US0151031W WO02062789A1 WO 2002062789 A1 WO2002062789 A1 WO 2002062789A1 US 0151031 W US0151031 W US 0151031W WO 02062789 A1 WO02062789 A1 WO 02062789A1
Authority
WO
WIPO (PCT)
Prior art keywords
ring
aliphatic
membered
hydrogen
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2001/051031
Other languages
English (en)
French (fr)
Inventor
David Bebbington
Jean-Damien Charrier
Julian M. C. Golec
Andrew Miller
Ronald Knegtel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to NZ526471A priority Critical patent/NZ526471A/en
Priority to HU0400638A priority patent/HUP0400638A2/hu
Priority to JP2002563142A priority patent/JP4160395B2/ja
Priority to CA002432222A priority patent/CA2432222C/en
Priority to DE60119776T priority patent/DE60119776T2/de
Priority to MXPA03005608A priority patent/MXPA03005608A/es
Priority to IL15640701A priority patent/IL156407A0/xx
Priority to HK04102099.2A priority patent/HK1061389B/en
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Priority to EP01994510A priority patent/EP1345927B1/en
Priority to KR1020037008409A priority patent/KR100909665B1/ko
Publication of WO2002062789A1 publication Critical patent/WO2002062789A1/en
Priority to NO20032736A priority patent/NO20032736L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D403/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—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 present invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, this invention relates to compounds that are inhibitors of Aurora-2 protein kinase. The invention also relates to methods of treating diseases associated with protein kinases, especially diseases associated with Aurora-2, such as cancer.
  • Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway.
  • kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H 2 0 2 ) , cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis. factor ⁇ (TNF- oc) ) , and growth factors (e.g.
  • environmental and chemical stress signals e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H 2 0 2
  • cytokines e.g. interleukin-1 (IL-1) and tumor necrosis. factor ⁇ (TNF- oc)
  • growth factors
  • GM-CSF granulocyte macrophage- colony-stimulating factor
  • FGF fibroblast growth factor
  • An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.
  • Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
  • Aurora-2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 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, the aurora- 2 protein has been found to be overexpressed. See Bischoff et al., EMBO J. , 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol . , 1998, 143, 1635-1646; Kimura et al., J. Biol . Chem. , 1997, 272, 13766-13771.
  • Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of ⁇ and ⁇ isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev. , 10, 508-514 (2000)].
  • GSK-3 has been implicated in various diseases including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol . (2000) 151, 117]..
  • GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins . These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor ⁇ -catenin, the translation initiation factor elF2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPB ⁇ . These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.
  • GSK-3 is a negative regulator of the insulin-induced signal.
  • the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase.
  • the inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J. , 303, 21-26 (1994); Cohen, Biochem . Soc . Trans . , 21, 555-567 (1993); Massillon et al., Biochem J.
  • Alzheimer's disease This disease is characterized by the well-known ⁇ -amyloid peptide and the formation of intracellular neurofibrillary tangles.
  • the neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnormal sites.
  • GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models.
  • inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer's disease.
  • ⁇ -catenin Another substrate of GSK-3 is ⁇ -catenin which is degradated after phosphorylation by GSK-3. Reduced levels of ⁇ -catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death
  • GSK-3 As a result of the biological importance of GSK-3, there is current interest in therapeutically • effective GSK-3 inhbitors. Small molecules that inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham) ] .
  • Z 1 is nitrogen or C-R 8 and Z 2 is nitrogen or CH, wherein at least one of Z 1 and Z 2 is nitrogen;
  • R x and R y are independently selected from T-R 3 or L-Z-R 3 , or R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • Q is selected from -N(R 4 )-, -0-, -S-, -C(R 6 ') 2 -, 1,2- cyclopropanediyl , 1,2-cyclobutanediyl, or 1,3- cyclobutanediyl;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ . 4 alkylidene chain, wherein when Q is -C(R 6' ) 2 -, a methylene unit of said C ⁇ . 4 alkylidene chain is optionally replaced by -0-, -S-, -N(R 4 )-, -CO-, -C0NH-, -NHC0-, -S0 2 -, -S0 2 NH-, -NHS0 2 -, -CO2-, -OC(O)-, -0C(0)NH-, or - HCO 2 -;
  • Z is a C ⁇ _ 4 alkylidene chain
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R s )S0 2 -, -S0 2 N(R 5 )-, -N(R)-, -CO-, -C0 2 -, -N(R 6 )CO-, -N (R 6 ) C (O) O- , -N(R 6 )CON(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N (R 6 ) N (R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-,
  • R 2 and R 2' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are taken together with their intervening atoms to form
  • each R is independently selected from hydrogen or an optionally substituted group selected from Ci- ⁇ aliphatic, C 6 _ ⁇ 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms ; each R 4 is independently selected from -R 7 , -COR 7 ,
  • W is -C(R s ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 S0 2 -,
  • aliphatic as used herein means straight-chain, branched or cyclic C ⁇ -C ⁇ 2 hydrocarbons which are completely saturated or which contain one or more units of unsaturation but which are not aromatic.
  • suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (eyeloalkenyl) alkyl or
  • alkyl alkenyl
  • alkyl alkoxy
  • hydroxyalkyl alkoxyalkyl
  • alkoxycarbonyl used alone or as part of a larger moiety
  • alkenyl and “alkynyl” used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms.
  • cycloalkyl used alone or as part of a larger moiety shall include cyclic C 3 -C ⁇ 2 hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic .
  • haloalkyl means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • halogen means F, Cl, Br, or I.
  • heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
  • nitrogen includes a substitutable nitrogen of a heterocyclic ring.
  • the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl) .
  • carrier means an aliphatic ring system having three to fourteen members.
  • carrier refers to rings that are optionally substituted.
  • carbocycle refers to rings that are optionally substituted.
  • Carbocyclic also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy” , or “aryloxyalkyl” refers to aromatic ring groups having five to fourteen members, such as phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2- anthracyl.
  • aryl also refers to rings that are optionally substituted.
  • aryl may be used interchangeably with the term “aryl ring” .
  • Aryl also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2- anthracyl.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
  • heterocycle includes non-aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, 0, or S.
  • heterocyclic rings examples include 3-1H- benzimidazol-2-one, (l-substituted) -2-oxo-benzimidazol-3- yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyrany1, 3-1etr hydropyrany1, 4- tetrahydropyranyl, [1,3] -dioxalanyl, [1,3] -dithiolanyl, [1,3] -dioxanyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4- morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4- thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1- piperidinyl, 2-
  • heterocyclyl or “heterocyclic”, as it is used herein, is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl , or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring.
  • heterocycle is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl , or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring.
  • heterocyclyl or “heterocyclic” whether saturated or partially unsaturated, also refers to rings that are optionally substituted.
  • heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or
  • heteroarylalkoxy refers to heteroaromatic ring groups having five to fourteen members.
  • heteroaryl rings include 2-furanyl, 3-furanyl, 3-furazanyl, N- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5- oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1- pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 2- pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetra
  • heteroaryl is a group in which a heteroatomic ring is fused to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [3,4-d]pyrimidinyl.
  • heteroaryl also refers to rings that are optionally substituted.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic” .
  • An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents.
  • suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, -R°, -0R°, -SR°, 1, 2-methylene-dioxy, 1, 2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph) , substituted Ph, -O(Ph), substituted -O(Ph), -CH 2 (Ph), substituted -CH 2 (Ph), -CH 2 CH 2 (Ph), substituted -CH 2 CH 2 (Ph), -N0 2 , -CN, -N(R°) 2 , -NR°C(0)R°, -NR°C
  • substituents on the aliphatic group or the phenyl ring of R° include amino, alkylamino, dialkylamino, aminocarbonyl , halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl , alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl .
  • An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents.
  • substituents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
  • substituents on the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl , dialkylaminocarbonyl , alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl , hydroxy, haloalkoxy, or haloalkyl.
  • linker group means an organic moiety that connects two parts of a compound.
  • Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -NH- , -CH 2 -, -C(O)-, -C(0)NH-, or a chain of atoms, such as an alkylidene chain.
  • the . molecular mass of a linker is typically in the range of about 14 to 200, preferably in the range of 14 to 96 with a length of up to about six atoms.
  • linkers include a saturated or unsaturated C ⁇ _ 6 alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by -C(O)-, -C(0)C(0)-, -CONH-, -CONHNH-, -C0 2 -, -OC(0)-, -NHC0 2 -, -0-, -NHCONH-, -OC(0)NH-, -NHNH- , -NHCO-, -S-, -SO-, -S0 2 -, -NH-, -S0 2 NH-, or -NHS0 2 - .
  • alkylidene chain refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation.
  • the optional substituents are as described above for an aliphatic group.
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when, kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Compounds of formula I or salts thereof may be formulated into compositions.
  • the composition is a pharmaceutical composition.
  • the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein kinase, particularly Aurora-2, in a biological sample or in a patient.
  • Compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat or prevent an Aurora-2-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof .
  • Aurora-2-mediated disease or “Aurora-2-mediated condition”, as used herein, means any disease or other deleterious condition in which Aurora is known to play a role.
  • the terms “Aurora-2-mediated disease” or “Aurora-2-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor. Such conditions include, without limitation, colon, breast, stomach, and ovarian cancer.
  • Another aspect of the invention relates to inhibiting Aurora-2 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 inhibitor of formula I, or a composition thereof..
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • GSK-3 -mediated disease or "GSK-3- mediated condition”, as used herein, mean any disease or other deleterious condition or state in which GSK-3 is known to play a role.
  • diseases or conditions include, without limitation, diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDS- associated dementia, amyotrophic lateral sclerosis (AML) , multiple sclerosis (MS) , schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, and baldness.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in ' a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • CDK-2-mediated disease or “CDK-2- mediated condition”
  • CDK-2-mediated disease or “CDK-2- mediated condition”
  • diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor.
  • Such conditions include, without limitation, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such, as rheumatoid arthritis. See Fischer, P.M.
  • Another aspect of the invention relates to inhibiting CDK-2 activity in a biological sample or a patient, which method, comprises administering to the patient a compound of formula I or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing an ERK-2-mediated diseases with an ERK-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • ERK-mediated disease or "ERK- mediated condition”
  • ERK-2-mediated disease or "ERK-2- mediated condition” also mean those diseases or conditions that are alleviated by treatment with a ERK-2 inhibitor.
  • Such conditions include, without limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases.
  • cancer includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral) , lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, and
  • ERK-2 protein kinase and its implication in various diseases has been described [Bokemeyer et al. 1996, Kidney Int . 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al . , 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol . Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol . Cell Biol . 16, 1247; Raingeaud et al . 1996; Chen et al., 1993 Proc . Natl . Acad. Sci .
  • Another aspect of the invention relates to inhibiting ERK-2 activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing an AKT-mediated diseases with an AKT inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • AKT-mediated disease or "AKT- mediated condition”
  • AKT-mediated disease or “AKT- mediated condition” also mean those diseases or conditions that are alleviated by treatment with a AKT inhibitor.
  • AKT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders.
  • AKT also known as protein kinase B
  • the association of AKT, also known as protein kinase B, with various diseases has been described [Khwaja, A., Nature, pp. 33-34, 1990; Zang, Q. Y. , et al, Oncogene, 19 2000; Kazuhiko, ⁇ .
  • Another aspect of the invention relates to inhibiting AKT activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said- compound.
  • Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof .
  • Src-mediated disease or "Src- mediated condition” , as used herein mean any disease or other deleterious condition in which Src is known to play a role.
  • the terms “Src-mediated disease” or “Src- mediated condition” also mean those diseases or conditions that are alleviated by treatment with a Src inhibitor. Such conditions include, without limitation, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget's disease.
  • Src protein kinase and its implication in various diseases has been described [Soriano, Cell , 69 , 551 (1992); Soriano et al .
  • Another aspect of the invention relates to inhibiting Src activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing an Lck-mediated diseases with an Lck inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • Lck-mediated disease or “Lck- mediated condition” , as used herein, mean any disease state or other deleterious condition in which Lck is known to play a role.
  • Lck-mediated disease or “Lck-mediated condition” also mean those diseases or conditions that are alleviated by treatment with an Lck inhibitor.
  • Lck-mediated diseases or conditions include, but are not limited to, autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, and leukemia. The association of Lck with various diseases has been described [Molina et al., Nature, 357, 161 (1992)] .
  • Another aspect of the invention relates to inhibiting Lck activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof .
  • patient includes human and veterinary subjects.
  • biological sample includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • An amount effective to inhibit protein kinase for example, Aurora-2 and GSK-3, is an amount that causes measurable inhibition of the kinase activity when compared to the activity of the enzyme in the absence of an inhibitor. Any method may be used to determine inhibition, such as, for example, the Biological Testing Examples described below.
  • Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions are generally known in the art. They include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial- injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents' that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non- irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal- tract. Suitable topical formulations are readily prepared for each of these areas or organs .
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in- a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons,- and/or other conventional solubilizing or dispersing agents.
  • compositions to treat or prevent the above-identified diseases or disorders.
  • a "pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species .
  • compositions of this invention include, without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pe
  • Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (C ⁇ _ 4 alkyl) 4 salts.
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium and N + (C ⁇ _ 4 alkyl) 4 salts e.g., sodium and potassium
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium and N + (C ⁇ _ 4 alkyl) 4 salts e.g., sodium and potassium
  • the amount of the protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.
  • compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a -variety of -factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of the inhibitor will also depend upon the particular compound in the composition.
  • additional therapeutic agents which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention.
  • additional therapeutic agents which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention.
  • chemotherapeutic agents or other anti-proliferative agents may be combined with the present compounds to treat cancer.
  • agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives .
  • agents for treating diabetes such as insulin or insulin analogues, in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas
  • anti- inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine
  • - immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine
  • neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti- convulsants, ion channel blockers, ril
  • those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor of this invention in a . single composition.
  • R x and R y may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A.
  • Preferred R x /R y rings include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R x /R y ring is optionally substituted.
  • Examples of bicyclic systems , containing Ring A are shown below by compounds I-A through I-BB, wherein Z 1 is nitrogen or C(R 8 ) and Z 2 is nitrogen or C(H) .
  • Preferred bicyclic Ring A systems include I-A, I-B, I-C, I-D, I-E, I-F, I-I, I-J, I-K, I-P, I-Q, I-V, and I-U, more preferably I-A, I-B, I-D, I-E, I-J, I-P, and I-V, and most preferably I-A, I-B, I-D, I-E and I-J.
  • preferred R x groups when present, include hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.
  • Preferred R y groups when present, include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, -C(R 6 ) 2 0-, -CO- or -N(R 4 )-, and R 3 is -R, -N(R 4 ) 2 , or -OR.
  • R y groups include 5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl; C x .
  • alkoxyalkylamino such as methoxyethylamino
  • alkoxyalkyl such as methoxymethyl or methoxyethyl
  • alkyl- or dialkylamino such as ethylamino or dimethylamino
  • alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy
  • acetamido and optionally substituted phenyl such as phenyl or halo-substituted phenyl .
  • the ring formed when R x and R y are taken together may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -0(CH 2 ) 2 . 4 -N(R 4 ) 2 , -0(CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -CON(R 4 ) 2 , -CN, -0 (CH 2 ) 2 . 4 -N (R 4 ) 2 , -O (CH 2 ) 2 - 4 -R, -N0 2 -N(R) 2 , . -NRC0R, -NR 4 S0 2 R, -S0 2 N(R) 2 wherein R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group.
  • R 2 and R 2' may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring, wherein said fused ring is optionally substituted.
  • Preferred substituents on the R 2 /R 2' fused ring include one or more of the following: -halo, -N(R 4 ) 2 , -C ⁇ _ 3 alkyl, -C ⁇ - 3 haloalkyl, -N0 2 , -O (C ⁇ _ 3 alkyl) , -C0 2 (C 1 .
  • preferred R 2 groups include hydrogen, C ⁇ _ 4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl , alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl , dialkylaminoalkyl, phenylaminocarbonyl , and (N- heterocyclyl) carbonyl.
  • R 2 substituents examples include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, C0 2 H, C0 2 CH 3 , CH 2 OH, CH 2 OCH 3 , CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 OCH 2 Ph, CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHCOOC (CH 3 ) 3 ,
  • a preferred R 2 ' group is hydrogen.
  • R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ; R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each, substitutable ring nitrogen of Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ _ 4 alkylidene chain;
  • Z is a C ⁇ - 4 alkylidene chain;
  • L is -0-, -S-, -SO-, -SO 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(0)0-, -N(R 6 )C0N(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N (R 6 ) N (R 6 ) - , -C(0)N(R 6 )-, -0C(O)N(R 6 )-,- -C(R ⁇ ) 2 0-, -C(R ⁇ ) 2 S-,
  • R 2 and R 2' are independently selected from -R, -T-W-R 6 , or R
  • each R is independently selected from hydrogen or an optionally substituted group selected from C ⁇ _ 6 aliphatic, C 6
  • each R ⁇ is independently selected from hydrogen or an optionally substituted C ⁇ - 4 aliphatic group, or two R ⁇ groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
  • Preferred rings formed by R x and R y include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R x /R y ring is optionally substituted.
  • This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula Ila are shown below.
  • More preferred pyrimidine ring systems of formula Ila include Ila-A, Ila-B, Ila-D, Ila-E, Ila-J, Ila-P, and Ila-V, most preferably Ila-A, Ila-B, Ila-D, Ila-E, and Ila-J.
  • the ring formed when R x and R y are taken together may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -0(CH 2 ) 2 . 4 -N(R 4 ) 2 , -0(CH 2 ) 2 -4-R, "OR, -N(R 4 )-(CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -C0N(R 4 ) 2 , -CN, -0(CH 2 ) 2 . 4 -N(R 4 ) 2 , -O (CH 2 ) 2 . 4 -R, , -N0 2 -N(R 4 ) 2 , -NR 4 C0R, -NR 4 S0 2 R, -S0 2 N(R 4 ) 2 wherein R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group.
  • R 2 and R 2 ' groups of formula Ila may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula Ila compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2 ' fused ring of formula Ila include one or more of the following: -halo, -N(R 4 ) 2 , -C ⁇ .4 alkyl, -C ⁇ - 4 haloalkyl, -N0 2 , -0(C ⁇ _ 4 alkyl), -C0 2 (C ⁇ - 4 alkyl) , -CN, -S0 2 (C ⁇ _ 4 alkyl) , -S0 2 NH 2 , -OC(0)NH 2 , -NH 2 S0 2 (C 1 - 4 alkyl) , -NHC (O) (C ⁇ _ 4 alkyl) ,
  • the (Ci- 4 alkyl) is a straight, branched, or cyclic alkyl group.
  • the (Ci- 4 alkyl) group is methyl or ethyl.
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ - 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl , and benzyloxypropyl .
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula Ila When Ring D of formula Ila is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl , indazolyl , benzothiazolyl , cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl .
  • preferred T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R ) 2 , optionally substituted C x . 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )COR, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 , -N(R 4 )S0 2 R, -N(R ⁇ )COCH 2 N(R 4 ) 2 , -N (R ⁇ ) COCH 2 CH 2 N (R 4 ) 2 , and -N(R ⁇ )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membere
  • R 5 substituents include -CI, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (C0 2 1-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 )
  • aliphatic such as -NHMe, -N(C ⁇ _ aliphatic) 2 such as -NMe 2 , OH, -0(C ⁇ - 4 aliphatic) such as -OMe, C ⁇ _ 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2 (C ⁇ - 4 aliphatic) .
  • Preferred formula Ila compounds have one or more, and more preferably all, of the features selected from, the group consisting of:
  • R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit;
  • Ring-D is- a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 5 and R 2' is hydrogen; or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring; and
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 .
  • More preferred compounds of formula Ila have one or more, and more preferably all, of the features selected from the group consisting of: (a) R x and R y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ . 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 ) -.
  • Even more preferred compounds of formula Ila have one or more, and more preferably all, of the features selected from the group consisting of: (a) R x and R y are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;
  • R 1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;
  • R 2 is hydrogen or C ⁇ - 4 aliphatic and R 2' is hydrogen;
  • R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and
  • Ring D is substituted by up to three substituents selected from -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ . 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )C0R,
  • R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. Representative compounds of formula Ila are shown below in Table 1.
  • this invention provides a composition comprising a compound of formula Ila and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ila or a pharmaceutical composition thereof .
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a .
  • compound of formula Ila or a composition comprising said compound comprises administering to the patient a .
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ila or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula Ila or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula Ila or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a CDK-2 -mediated disease with a CDK-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ila or a pharmaceutical composition thereof.
  • Another aspect of the invention relates to inhibiting CDK-2 activity in a patient, which method comprises administering to the patient a compound of formula Ila or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ila or a pharmaceutical composition thereof.
  • Another aspect of the invention relates to inhibiting Src activity in a patient, which method comprises administering to the patient a compound of formula Ila or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2, GSK-3, CDK2, or Src activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2, GSK-3, CDK2 , or Src inhibitor of formula Ila, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2, GSK-3, CDK2, or Src.
  • Each of the aforementioned methods directed to the inhibition of Aurora-2, GSK-3, CDK2, or Src, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula Ila, as described above.
  • R and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of, Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ _ 4 alkylidene chain
  • Z is a Ci- 4 alkylidene chain
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R ⁇ )S0 2 -, -S0 2 N(R 6 )-, • -N(R 6 )-, -CO-, -C0 2 -, -N(R ⁇ )CO-, -N (R 6 ) C (O) O- , -N(R ⁇ )CON(R ⁇ ) -, -N(R 6 )S0 2 N(R 6 )-, -N (R 6 ) N R ⁇ ) - , -C(0)N(R 6 )-, -OC(0)N(R 5 )-, -C(R ⁇ ) 2 0-, -C(R ⁇ ) 2 S-, -C(R ⁇ ) 2 SO-, -C(R ⁇ ) 2 S0 2 -, -C(R ⁇ ) 2 S0 2 N(
  • R 2 and R 2' are independently selected from -R, -T-W-R 6 , or R 2 and R 2' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2' is independently substituted by halo, oxo, -CN, -N0 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2' is independently substituted by R 4 ;
  • each R is independently selected from hydrogen or an optionally substituted group selected from C ⁇ _ 6 aliphatic, C 6 _ ⁇ 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms ; each R 4 is independently selected from -R 7 , -COR 7 ,
  • More preferred pyrimidine ring systems of formula lib include Ilb-A, Ilb-B, Ilb-D, Ilb-E, Ilb-J, Ilb-P, and Ilb-V, most preferably Ilb-A, Ilb-B, Ilb-D, Ilb-E, and Ilb-J.
  • the ring formed when R x and R y are taken together may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -0(CH 2 ) 2 - -N(R 4 ) 2 , -0(CH 2 ) 2 - 4 -R, -OR, -N(R 4 )-(CH 2 ) 2 - 4 -N(R 4 ) 2 , -N(R 4 ) - (CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -CON(R 4 ) 2 , -CN, -0(CH 2 ) 2 - 4 -N(R 4 ) 2 , -0(CH 2 ) 2 _4-R, , -N0 2 -N(R 4 ) 2 , -NRCOR, -NRS0 2 R, -S0 2 N(R 4 ) 2 wherein R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group.
  • R 2 and R 2' groups of formula lib may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula lib compounds having a pyrazole-containing bicyclic ring system:
  • R 2 /R 2 ' fused ring of formula lib include one or more of the following:
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ _ 6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl .
  • a preferred R 2 ' group is hydrogen.
  • preferred Ring D of formula lib is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Ring D of formula lib is bicyclic
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.
  • R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ - 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R)C0R, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 , -N(R)S0 2 R, -N(R ⁇ )C0CH 2 N(R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N(R 4 ) 2 , and -N(R ⁇ )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C .
  • R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (C0 2 1-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 ,
  • - 4 aliphatic such as -OMe, C 1 - 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2 (C ⁇ _ 4 aliphatic) .
  • Preferred formula lib . compounds have one or more, and more preferably all, of the features selected from the group consisting of:
  • R and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit;
  • Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring; and
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 . More preferred compounds of formula lib have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x and R y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 ) -.
  • Even more preferred compounds of formula lib have one or more, and more preferably all, of the features selected from the group consisting of: (a) R x and R y are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring; (b) R 1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; (c) R 2 is hydrogen or C ⁇ _ 4 aliphatic and R 2' is hydrogen;
  • R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and
  • Ring D is substituted by up to three substituents selected from -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ _ s aliphatic group, -OR, -C(0)R, -C0 2 R, -C0NH(R 4 ), -N(R 4 )C0R, -N(R)C0 2 R, -S0 2 N(R 4 ) 2 , --N(R)S0 2 R,
  • R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. Representative compounds of formula lib are shown below in Table 2.
  • this invention provides a composition comprising a compound of formula lib and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula lib or a pharmaceutical composition thereof .
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula lib or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula l b or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula lib or a pharmaceutical composition thereof. This method is especially useful for diabetic patients.
  • Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease.
  • Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula lib or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula lib, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
  • Each of the ⁇ aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out- with a preferred compound of formula lib, as described above.
  • Another embodiment of this invention relates to compounds of formula lie :
  • R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently s ⁇ bstituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ _ 4 alkylidene chain;
  • Z is a Ci- 4 alkylidene chain;
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R ⁇ )S0 2 -, -S0 2 N(R ⁇ )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )C0-, -N (R 6 ) C (O) O- , -N(R 6 )C0N(R 6 ) -, -N(R 6 )S0 2 N(R 6 )-, -N (R 6 ) N (R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R ⁇ ) 2 0-, -C(R ⁇ ) 2 S-,
  • R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are independently selected from -R, -T-W
  • each R is independently selected from hydrogen or an optionally substituted group selected from C ⁇ _6 aliphatic, C 6 - ⁇ o aryl, a- heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms ; each R 4 is independently selected from -R 7 , -COR 7 ,
  • each R 5 is independently selected from -R, halo, -OR,
  • V is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N R 6 ) -co- -C0 2 -, -N(R 6 )CO-, -N(R 6 )C(0)0-, -N R 6 )C0N(R 6 )-, -N(R 6 )S0 2 N(R 6 ) -, -N (R ⁇ ) N (R ⁇ ) - , -C 0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R ⁇ ) 2 S-, -C R ⁇ ) 2 S0-, -C(R 6 ) 2 S0 2 -, -C(R 6 ) 2 S0 2 N(R 6 )-, -C (R 6
  • each R 6 is independently selected from hydrogen or an optionally substituted C ⁇ _ 4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
  • Preferred rings formed by R x and R y include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R x /R y ring is optionally substituted.
  • This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula lie are shown below.
  • More preferred pyrimidine ring systems of formula He include IIc-A, IIc-B, IIc-D, IIc-E, IIc-J, IIc-P, and IIc-V, most preferably IIc-A, IIc-B, IIc-D, IIc-E, and IIc-J.
  • the ring formed when R x and R y of formula He are taken together may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -O (CH 2 ) 2 -4-N(R 4 ) 2 , -0(CH 2 ) 2 .4-R, -OR, -N(R 4 )-(CH 2 ) 2 _ 4 -N(R 4 ) 2 , -N (R 4 ) - (CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -CON(R 4 ) 2 , -CN, -0(CH 2 ) 2 - 4 -N(R 4 ) 2 , -0(CH 2 ) 2 -4-R, , -N0 2 -N(R) 2 , -NR 4 COR, -NR 4 S0 2 R, -S0 2 N(R 4 ) 2 wherein R is hydrogen or an optionally substituted C ⁇ - 6 aliphatic group.
  • the R 2 and R 2' groups of formula He may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula lie compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2 ' fused ring , of formula He include one or more of the following: -halo, -N(R) 2 , -C ⁇ _ 4 alkyl, -C ⁇ _ 4 haloalkyl, -N0 2 , -0(C 1 .
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ _ 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula He is monocyclic
  • preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Ring D of formula He is bicyclic
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl , cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl .
  • T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ _ 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )C0R, -N(R 4 )C0 2 R, -S0 2 N(R) 2 , -N(R 4 )S0 2 R, -N(R 6 )COCH 2 N(R 4 ) 2 , -N (R 6 ) C0CH 2 CH 2 N (R 4 ) 2 , and -N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • R 5 substituents include -CI, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3 , -NHC0CH 2 N (C0 2 t-Bu) CH 3 , -NHC0CH 2 N (CH 3 ) 2 , -NHC0CH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 ,
  • He compounds have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x and R y are taken together with their ⁇ • ⁇ intervening -atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit;
  • Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring; and
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 .
  • More preferred compounds of formula He have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x and R y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ _e aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (d) R 3 is--selected from -R, -halo, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 ) -.
  • Even more preferred compounds of formula He have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x and R y are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;
  • R 1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;
  • R 2 is hydrogen or C ⁇ _ 4 aliphatic and R 2 ' is hydrogen;
  • R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and
  • Ring D is substituted by up to three substituents selected from -halo, -CN, -N0 2 ,
  • -N(R 4 ) 2 optionally substituted C ⁇ . 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )COR, -N(R 4 )C0 2 R, -S0 2 N(R) 2 , -N(R)S0 2 R, -N(R 6 )COCH 2 N(R 4 ) 2 , -N(R 6 )COCH 2 CH 2 N(R 4 ) 2 , or -N(R 6 )COCH 2 CH 2 CH 2 N(R ) 2 , wherein R is -selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • Preferred compounds of formula He include compounds of formula lie' :
  • R x and R y are taken together with their intervening atoms to form a fused benzo ring, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by T-R 3 , or L-Z-R 3 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ _ 4 alkylidene chain;
  • Z is
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )CO-, -N (R 6 ) C (O) 0- , -N(R 6 )CON(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N (R 6 ) N (R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 S0 2 -, -C(R 6 ) 2 S0 2 N(R 6 )-, -C (R
  • each R is independently selected from hydrogen or an optionally substituted group selected from C ⁇ - 6 aliphatic, C 6
  • the ring formed when R x and R y of formula He' are taken together may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -O (CH 2 ) 2 - 4 -N(R 4 ) 2 , -0(CH 2 ) 2 _ 4 -R / -OR, -N(R 4 )-(CH 2 ) 2 -4-N(R 4 ) 2 , -N (R 4 ) - (CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -C0N(R 4 ) 2 , -CN, -0(CH 2 ) 2 - 4 -N(R 4 ) 2 , -0 (CH 2 ) 2 - 4 -R, , -N0 2 -N(R 4 ) 2 , -NR 4 COR, -NR 4 S0 2 R, -S0 2 N(R 4 ) 2 , wherein R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group.
  • the R 2 and R 2' groups of formula He' may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula He' compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2 ' fused ring of formula He' include one or more of the following: -halo, -N(R) 2 , -C3.-4 alkyl, -C x - haloalkyl, -N0 2 , -0(C ⁇ - alkyl), -C0 2 (d- 4 alkyl) , -CN, -S0 2 (C ⁇ _ 4 alkyl) , -S0 2 NH 2 , -OC(0)NH 2 , -NH 2 S0 2 (Ci- 4 alkyl) , -NHC (0) (C ⁇ - 4 alkyl) , -C(0)NH 2 , and -CO (Ci- 4 alkyl) , wherein the (C ⁇ _ 4 alkyl) is a straight, branched, or cyclic alkyl group.
  • the (Ci- 4 alkyl) group is methyl.
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ -6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2' group is hydrogen.
  • Ring D of formula lie' When Ring D of formula lie' is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl .
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl .
  • preferred T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ _ 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )C0R, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 ,
  • R is selected from hydrogen, C ⁇ - 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAC, -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3 , -NHC0CH 2 N (C0 2 t-Bu) CH 3 , -NHC0CH 2 N(CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl) , -NHCO (isobutyl) , -NHC0CH 2 (morpholin-4-
  • He' compounds have one or more, and more preferably all, of the features selected from the group consisting of:
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit;
  • Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring; and (d) R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 . More preferred compounds of formula He' have one or more, and more preferably all, of the features selected from the group consisting of:
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C - ⁇ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is.-O-, -S-, or -N(R 4 )-.
  • Even more preferred compounds of formula He' have one or more, and more preferably all, of the features selected from the group consisting of:
  • R 1 is T-Ring D, wherein T is a valence bond and Ring D is -a 5-6 membered aryl or heteroaryl ring;
  • R 2 is hydrogen or C ⁇ _ 4 aliphatic and R 2' is hydrogen;
  • R 3 is selected from -R, -OR, or -N(R) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and
  • Ring D is substituted by up to three substituents selected from -halo, -CN, -N0 2 , -N(R) 2 , optionally substituted C x . 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ) , -N(R 4 )C0R, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2/ -N(R 4 )S0 2 R, -N(R 6 )COCH 2 N(R 4 ) 2 , -N(R 6 )COCH 2 CH 2 N(R) 2 , or -N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ . 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • R is selected from
  • R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, -5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is optionally substituted by oxo, T-R 3 , or L- Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is optionally substituted by R 4 ,- provided that said fused ring formed by R x and R y is other than benzo;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ - alkylidene chain
  • Z is a Ci- 4 alkylidene chain;
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )C0-, -N (R 6 ) C (O) O- , -N(R 6 )CON(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N (R 6 ) N (R 6 ) - , -C(0)N(R 6 )-, -0C(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 S0-, -C(R 6 ) 2 S0-, -C(R 6 ) 2 S0-
  • R 2 and R 2' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -N0 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is
  • each R 5 is independently selected from -R, halo, -OR,
  • V is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )CO-, -N (R 6 ) C (O) 0- , -N(R 6 )CON(R 6 )-, -N(R s )S0 2 N(R 6 )-, -N(R 6 ) N(R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 S0-, -C(R 6 ) 2 S0 2 -, -C(R 6 ) 2 S0 2 N(R 6 )-, -C (
  • Preferred rings formed by R x and R y of formula lie" include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 1-2 heteroatoms, or a partially unsaturated carbocyclo ring, wherein said R x /R y ring is optionally substituted.
  • This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula He" are shown below.
  • More preferred pyrimidine ring systems of formula He include IIe"-B, IIc-D, IIc-E, IIc-J, IIc-P, and Hc-V, most preferably IIc-B, IIc-D, IIc-E, and IIc- J.
  • R x and R y of formula He may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -0(CH 2 ) 2 . 4 -N(R 4 ) 2 , -0(CH 2 ) 2 . 4 -R, -OR, -N(R 4 )-(CH 2 ) 2 _4-N(R 4 ) 2 , -N(R 4 ) - (CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -C0N(R 4 ) 2/ -CN, -0(CH 2 ) 2 _4-N(R) 2 , -O (CH 2 ) 2 . 4 -R, , -N0 2 -N(R 4 ) 2 , -NR 4 COR, -NR 4 S0 2 R, -S0 2 N(R) 2 wherein R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group.
  • the R 2 and R 2 ' groups of formula He" may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula He" compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2' fused ring of formula He" include one or more of the following: -halo, -N(R 4 ) 2 , -Ci-4 alkyl, -C ⁇ - haloalkyl, -N0 2 , -0(C 1 . 4 alkyl), -C0 2 (C ⁇ - 4 alkyl) , -CN, -S0 2 (C ⁇ - 4 alkyl) , -S0 2 NH 2 , -0C(0)NH 2 , -NH 2 S0 2 (C 1 .
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ - 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula He When Ring D of formula He" is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Ring D of formula He is bicyclic
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl , benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.
  • preferred T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ _ 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )C0R, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 , -N(R 4 )S0 2 R, -N(R 6 )COCH 2 N(R 4 ) 2 , -N (R 6 ) C0CH 2 CH 2 N (R 4 ) 2 , and -N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered
  • R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me,
  • _ 4 aliphatic such as -NHMe, -N(Ci- 4 aliphatic) 2 such as -NMe 2 , OH, -0(C ⁇ - aliphatic) such as -OMe, C ⁇ _ 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2 (C ⁇ _ 4 aliphatic) .
  • Preferred formula He have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 1-2 heteroatoms selected from oxygen, ⁇ sulfur, or nitrogen, or a partially unsaturated
  • each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3
  • each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit, and Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring; and
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 . More preferred compounds of formula He" have one or more, and more preferably all, of the features selected from the group consisting of: (a) R x and R y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D)-, wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, or 5-6 membered heterocyclyl,. phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 )-.
  • Even more preferred compounds of formula He have one or more, and more preferably all, of the features selected from the group consisting of: (a) R x and R y are taken together to form a pyrido, piperidino, or cyclohexo ring, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ; (b) R 1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;
  • R 2 is hydrogen or C ⁇ - 4 aliphatic and R 2' is hydrogen; • .. ..
  • R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ - 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ) , -N(R 4 )COR, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2/ -N(R 4 )S0 2 R, -N(R 6 )COCH 2 N(R 4 ) 2 , -N (R 6 ) COCH
  • R is selected from hydrogen, C ⁇ - 6 ' aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • Representative compounds of formula He are shown below in Table 3.
  • this invention provides a composition comprising a compound of formula He, He', or lie", and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula He, He', or He", or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula He, He', or He", or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula He, He', or He", or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula He, He', or He", or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of
  • Alzheimer's disease Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula He, lie', or He", or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ilc, lie', or He", or a pharmaceutical composition thereof .
  • Another aspect of the invention relates to inhibiting Src activity in a patient, which method comprises administering to the patient a compound of formula He, He', or He", or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing an ERK-2-mediated diseases with an ERK-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula He, He', or He", or a pharmaceutical composition thereof .
  • Another aspect of the invention relates to inhibiting ERK-2 activity in a patient, which method comprises administering to the patient a compound of formula He, He', or He", or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing an AKT-mediated diseases with an AKT inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula He, He', or He", or a pharmaceutical composition thereof .
  • Another aspect of the invention relates to inhibiting AKT activity in a patient, which method comprises administering to the patient a compound of formula He, He', or He", or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2, GSK-3, Src, ERK-2, or AKT activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2, GSK-3, Src, ERK-2, or AKT inhibitor of formula He, He', or He", or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2, GSK-3, Src, ERK-2, or AKT.
  • Each of the aforementioned methods directed to the inhibition of Aurora-2, GSK-3, Src, ERK-2, or AKT, or the treatment of a disease alleviated thereby is preferably carried out with a preferred compound of formula He, He', or He", as described above.
  • Q' is selected from -C(R 6 ') 2 -, 1, 2-cyclopropanediyl, 1,2- cyclobutanediyl, or 1,3-cyclobutanediyl;
  • R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ _ alkylidene chain, wherein when Q' is -C(R 6' ) 2 - a methylene group of said C ⁇ _ 4 alkylidene chain is optionally replaced by -0-, -S- ,
  • Z is a C ⁇ - 4 alkylidene chain
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )C0-, -N (R 6 ) C (O) O- , -N(R 6 )CON(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N(R 6 ) N(R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 S0-, -C(R 6 ) 2 S0 2 -, -C(R 6 ) 2 S0 2 N(R 6 )-, -C (R
  • each R 4 is independently selected from -R 7 , -COR 7 ,
  • Preferred rings formed by R x and R y include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R x /R y ring is optionally substituted.
  • This provides a bicyclic ring, system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula Hd are shown below.
  • More preferred pyrimidine ring systems of formula Hd include Hd-A, Hd-B, Hd-D, Hd-E, Ild-J, Hd-P, and Hd-V, most preferably Hd-A, Hd-B, Hd-D, Hd-E, and Hd-J.
  • R x and R y of formula Hd may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -0(CH 2 ) 2 . 4 -N(R 4 ) 2 , -0(CH 2 )2-4-R, -OR, -N(R 4 )-(CH 2 ) 2 -4-N(R 4 ) 2/ -N (R 4 ) - (CH 2 ) 2 .
  • R 2 and R 2 ' groups of formula Hd may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring.
  • Preferred substituents on the R 2 /R 2 ' fused ring of formula Hd include one or more of the following: -halo, -N(R 4 ) 2 , -Ci- 4 alkyl, -C ⁇ _ 4 haloalkyl, -N0 2 , -0(C 1 .
  • preferred R 2 groups include hydrogen or. a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ . 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula Hd is monocyclic
  • preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Ring D of formula Hd is bicyclic
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl .
  • preferred T-R 5 or V-Z- R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ - 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -C0NH(R 4 ), -N(R 4 )COR, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 , • -N(R 4 )S0 2 R, -N(R 6 )C0CH 2 N(R) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic
  • R 5 substituents include -CI, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe , -CONHEt , -NH 2 , -NHAc , -NHS0 2 Me ,
  • Preferred Q' groups of formula Hd include -C(R 6' ) 2 - or 1,2-cyclopropanediyl, wherein each R 6 ' is independently selected from hydrogen or methyl.
  • a more preferred Q' group is -CH 2 -.
  • He compounds have one or more, and more preferably all, of the features selected from the group consisting of: (a) R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and
  • R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is , independently substituted by R 4 ;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit and wherein said methylene unit is optionally replaced by -0-, -NH-, or -S-;
  • Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring; and (e) R 3 is selected from -R, -halo, -OR, or -N(R ) 2 . More preferred compounds of formula He have one or more, and more preferably all, of the features selected from the group consisting of: (a) R x and R y are- taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit and wherein said methylene unit is optionally replaced by -0-, and Ring D is a
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ . 6 aliphatic, phenyl, a
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 ) -; and
  • Q' is -C(R 6 ') 2 - or 1, 2-cyclopropanediyl, wherein each R 6' is independently selected from hydrogen or methyl.
  • R x and R y are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;
  • R 1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;
  • R 2 is hydrogen or C ⁇ - 4 aliphatic and R 2' is hydrogen;
  • R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ . 6 aliphatic, 5-6 membered -heterocyclyl-, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-;
  • Ring D is substituted by up to three substituents selected from -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ _ 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ) , -N(R 4 )COR,
  • R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;
  • this invention provides a composition comprising a compound of formula Hd and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Hd or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula Hd or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Hd or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula Hd or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula Hd or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula Hd, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
  • R x and R y are independently selected from T-R 3 or L-Z-R 3 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered " bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ - 4 alkylidene chain
  • Z is a Ci- 4 alkylidene chain
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R s )C0-, -N (R 6 ) C (O) O- , -N(R 6 )C0N(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N(R 6 ) N(R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 S0-, -C(R 6 ) 2 S0 2 -, -C(R 6 ) 2 S0 2 N(R 6 )-, -
  • R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or -Impartially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -N0 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ;
  • R x groups of formula Ilia include hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl .
  • R y groups of formula Ilia include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R 6 ) 2 0-, -CO- and R 3 is -R,
  • R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.
  • R 2 and R 2 ' groups of formula Ilia may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula Ilia compounds having a pyrazole-containing bicyclic ring system:
  • R 2 /R 2 ' fused ring of formula Ilia include one or more of the following:
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ . 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula Ilia is monocyclic
  • preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Ring D of formula Ilia is bicyclic
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyi, 1, 8-naphthyridinyl and isoquinolinyl.
  • preferred T-R 5 or V- Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C . 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )C0R, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 , -N(R 4 )S0 2 R, -N(R 6 )C0CH 2 N(R 4 ) 2 , -N (R 6 ) C0CH 2 CH 2 N (R 4 ) 2 , and -N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a. ' 5-6 membered heteroaryl ring, or a 5
  • R 5 substituents include -CI, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (C0 2 t-Bu) CH 3 , -NHC0CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N(CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 ,
  • Suitable formula Ilia compounds have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x is hydrogen, alkyl- or dialkylamino, acetamido, or -a C ⁇ _ 4 aliphatic group; •
  • R y is T-R 3 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4 ) 2 , or -OR;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit;
  • Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and
  • R 2 is -R or -T-W-R 6 and R 2' is hydrogen, or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring.
  • More preferred compounds of formula Ilia have one or more, and more preferably all, of the features selected from the group consisting of :
  • R y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, or -N(R 4 ) 2/ wherein R is selected from hydrogen,
  • R 1 is T- (Ring D) , wherein T is a valence bond
  • Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ -6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (e) L is -0-, -S-, or -N(R 4 )-.
  • R x is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
  • R y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl;
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, -CN, -N0 2 , -N(R) 2 , optionally substituted C ⁇ .
  • R 2 is hydrogen or a substituted or unsubstituted Ci- 6 aliphatic, and L is -0-, -S-, or -NH- .
  • this invention provides a composition comprising a compound of formula Ilia and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which, method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ilia or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula Ilia or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ilia or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ilia or. a pharmaceutical composition thereof.
  • Another aspect of the invention relates to inhibiting Src activity in a patient, which method comprises administering to the patient a compound of formula Ilia or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2, GSK-3, or Src activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2, GSK-3, or Src inhibitor of formula Ilia, or a pharmaceutical composition thereof, in an. amount effective to inhibit Aurora-2, GSK-3, or Src.
  • Each of the aforementioned methods directed to the inhibition of Aurora-2, GSK-3, or Src, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula Ilia, as described above.
  • R x and R y are independently selected from T-R 3 or L-Z-R 3 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ; T is a valence bond or a C ⁇ _ 4 alkylidene chain; Z is a Ci- 4 alkylidene chain;
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )CO-, -N (R 6 ) C (O) O- , -N(R 6 )CON(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N (R 6 ) N (R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 S0-, -C(R 6 ) 2 S0 2 -, -C(R 6 ) 2 S0 2 N(R 6 )-, -C (R
  • each R 6 is independently selected from hydrogen or an optionally substituted C .t aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom. to form a 5-6 membered 0 heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted C ⁇ aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring .
  • R groups of formula IHb include hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group such as- methyl, ethyl, cyclopropyl, or isopropyl.
  • R y groups of formula IHb include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R 6 ) 2 0-, -CO- and R 3 is -R, -N(R 4 ) 2 , or -OR.
  • R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl,.
  • alkoxyalkylamino such as methoxyethylamino
  • alkoxyalkyl such as methoxymethyl or methoxyethyl
  • alkyl- or dialkylamino such as ethylamino or dimethylamino
  • R 2 and R 2 ' groups of formula IHb may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IHb compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2 ' fused ring of formula IHb include one or more of the following: -halo, -N(R) 2 , -Ci-4 alkyl, -C ⁇ - 4 haloalkyl, -N0 2 , ⁇ OfCx ⁇ alkyl), -C0 2 (C ⁇ _ alkyl) , -CN, -S0 2 (C ⁇ - 4 alkyl) ,-• -S0 2 NH 2 , -OC(0)NH 2 , -NH 2 S0 2 (C ⁇ - 4 alkyl) , -NHC (0) (C ⁇ _ 4 alkyl) , -C(0)NH 2 , and -CO (C ⁇ _ 4 alkyl) , wherein the (C ⁇ - 4 alkyl) is a straight, branched, or cyclic alkyl group.
  • the (Ci- 4 alkyl) group is methyl.
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ _ 6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula IHb is monocyclic
  • preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Ring D of formula IHb is bicyclic
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.
  • preferred T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ . 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -C0NH(R 4 ), -N(R 4 )C0R, -N(R)C0 2 R, -S0 2 N(R 4 ) 2 , -N(R 4 )S0 2 R, -N(R 6 )C0CH 2 N(R 4 ) 2/ -N(R 6 ) C0CH 2 CH 2 N(R 4 ) , and -N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2/ wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic
  • R 5 substituents include -CI, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me, -NHS0 2 Et, -NHS02(n-propyl) ,- -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (C0 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N(CH3) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2,
  • aliphatic such as -NHMe, -N(Ci- 4 aliphatic) 2 such as -NMe 2 , OH, -0(C ⁇ _ 4 aliphatic) such as -OMe, C ⁇ _ 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2 (C ⁇ - 4 aliphatic) .
  • Preferred formula IHb compounds have one or more, and more preferably all, of the features selected from the group consisting of :
  • R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group
  • R y is T-R 3 or L-Z-R 3 , wherein is a valence bond or a methylene and R 3 is -R, -N(R 4 ) 2 , or -OR;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit;
  • Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen, or R 2 and . R 2 ' are taken together to form an optionally substituted benzo ring. More preferred compounds of formula HIb have one or more, and more preferably all, of the features selected from the group consisting of:
  • R y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, or -N(R ) 2 , wherein R is selected from hydrogen, C ⁇ -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
  • R 1 is T- (Ring D) , wherein T is a valence bond;
  • Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ . 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and
  • L is -0-, -S-, or -N(R 4 )-.
  • R x is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido
  • R y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl;
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered
  • R 2 is hydrogen or a substituted or unsubstituted C ⁇ -6 aliphatic, and L is -0-, -S-, or -NH- .
  • Representative compounds of formula IHb are shown below in Table 6.
  • this invention provides a composition comprising a compound of formula IHb and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises, administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IHb or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IHb or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3 -mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IHb or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IHb or a pharmaceutical composition thereof. This method is especially useful for diabetic patients.
  • Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease.
  • Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IHb or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula IHb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
  • R x and R y are independently selected from T-R 3 or L-Z-R 3 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ; T is a valence bond or a C ⁇ - 4 alkylidene chain;
  • Z is a C ⁇ - 4 alkylidene chain
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-,- -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )C0-, -N (R 6 ) C (O) O- , -N(R 6 )C0N(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N(R 6 )N(R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-,
  • R 2 and R 2' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -N0 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ;
  • each R 4 is independently selected from -R 7 , -COR 7 , -C0 2 (optionally substituted C x .
  • W is -C(R 6 ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 S0 2 -, -C(R 6 ) 2 S0 2 N(R 6 ) -, -C(R 6 ) 2 N(R 6 )-, -CO-, -C0 2 -,
  • each R 6 is independently selected from hydrogen or an optionally substituted C ⁇ _ 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted C ⁇ _ 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R 7 is independently
  • R x groups of formula IIIc include hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ . 4 aliphatic group such as methyl, ethyl, cyclopropyl, . or isopropyl .
  • R y groups of formula IIIc include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is
  • R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, orpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo
  • R 2 and R 2 ' groups of formula IIIc may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IIIc compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2 ' fused ring of formula IIIc include one or more of the following.- -halo, -N(R 4 ) 2 , -C ⁇ - 4 alkyl, -C ⁇ . 4 haloalkyl, -N0 2 , -0(C ⁇ - 4 alkyl), -C0 2 (C ⁇ - alkyl) , -CN, -S0 2 (C ⁇ _ alkyl) , -S0 2 NH 2/ -OC(0)NH 2 , -NH 2 S0 2 (C 1 - 4 alkyl) , -NHC(O) (C ⁇ - 4 alkyl) , -C(0)NH 2 , and -CO (C ⁇ - 4 alkyl) , wherein the (C x - 4 alkyl) is a straight, branched, or cyclic alkyl group.
  • the (C ⁇ - 4 alkyl) group is methyl.
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ . 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula IIIc When Ring D of formula IIIc is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.
  • preferred T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R) 2 , optionally substituted C ⁇ -6 aliphatic group,' -OR, -C(0)R, -C0 2 R, -CONH(R 4 )., -N(R 4 )C0R, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 ,
  • R is selected from hydrogen, C ⁇ . 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHC0CH 2 NHCH 3 , -NHCOCH 2 N (C0 2 t-Bu) CH 3 , -NHCOCH 2 N(CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N(CH 3 ) 2 , -NHCO (cyclopropyl) , -NHCO (isobutyl) , -NHCOCH 2 (morpholin-4- yl) , -NHCOCH 2 CH 2 (morpholin-4-yl
  • aliphatic such as -NHMe, -N(C ⁇ _ 4 aliphatic) 2 such as -NMe 2 , OH, -0(C ⁇ - 4 aliphatic) such as -OMe, C ⁇ _ 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2 (C ⁇ - 4 aliphatic) .
  • Preferred formula IIIc compounds have one or more, and more pre-ferably all, of the features selected from the group consisting of:
  • R x is hydrogen, alkyl- or dialkylamino, acetamido, or. a C ⁇ - 4 aliphatic group
  • R y is T-R 3 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4 ) 2 , or -OR;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit;
  • Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (e) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen,, or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring. More preferred compounds of formula IIIc have one or more, and more preferably all, of the features selected from the group consisting of:
  • R y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from C ⁇ . 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
  • R 1 is T- (Ring D) , wherein T is a valence bond
  • Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ - ⁇ aliphatic, phenyl, a
  • L is -0-, -S-, or -N(R 4 )-.
  • Even more preferred compounds of formula IIIc have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x is hydrogen methyl, ethyl, propyl, - cyclopropyl, isopropyl, methylamino or acetimido;
  • R y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl;
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted . with one to two groups selected from -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ _ 6 aliphatic group, -OR, -C0 2 R, -CONH(R 4 ) , -N(R 4 )COR, -N(R 4 )S0 2 R, -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , or
  • R 2 is hydrogen or a substituted or unsubstituted C ⁇ - 6 aliphatic, and L is -0-, -S-, or -NH- .
  • this invention provides a composition comprising a compound of formula IIIc and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IIIc or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IIIc or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition thereof.
  • Another aspect of the invention relates to inhibiting Src activity in a patient, which method comprises administering to the patient a compound of formula IIIc or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2, GSK-3, or Src activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2, GSK-3, or Src inhibitor of formula IIIc, or a pharmaceutical composition thereof, in an amount effective to Aurora-2, GSK-3, or Src.
  • Each of the aforementioned methods directed to the inhibition of Aurora-2, GSK-3, or Src, or the treatment of a disease alleviated thereby is preferably carried out with a preferred compound of formula IIIc, as described above.
  • Q' is selected from -C(R 6 ') 2 -, 1, 2-cyclopropanediyl, 1,2- cyclobutanediyl, or 1,3-cyclobutanediyl;
  • R x and R y are independently selected from T-R 3 or L-Z-R 3 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ;
  • T is a valence bond or a C ⁇ _ 4 alkylidene chain, wherein when Q' is -C(R 6' ) 2 - a methylene group of said C ⁇ _ 4 alkylidene chain is optionally replaced by -0-, -S-, -N(R 4 )-, -CO-, -CONH-, -NHCO-, -S0 2 -, -S0 2 NH-, -NHS0
  • R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or. sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -N0 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ;
  • each R is independently selected from hydrogen or an optionally substituted group selected from C ⁇ .
  • each R 4 is independently selected from -R 7 , -COR 7 ,
  • R x groups of formula Hid include hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group such- as methyl, ethyl, cyclopropyl, or isopropyl.
  • R y groups of formula Hid include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R 6 ) 2 0-, -CO- and R 3 is -R, -N(R 4 ) 2 , or -OR.
  • R y groups examples include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.
  • R 2 and R 2 ' groups of formula H d may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula Hid compounds having a pyrazole-containing bicyclic ring . system:
  • Preferred substituents on the R 2 /R 2 ' fused ring of formula Hid include one or more of the following: -halo, -N(R 4 ) 2 , -Ci-4 alkyl, -C x . haloalkyl, -N0 2 , -0(C;- 4 alkyl), -C0 2 (C ⁇ .
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ . 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2' group is hydrogen.
  • Ring D of formula Hid is monocyclic
  • preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyri idinyl, and pyrazinyl .
  • Ring D of formula Hid is bicyclic
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.
  • preferred T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ . 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -C0NH(R 4 ), -N(R)COR, -N(R 4 )C0R, -S0 2 N(R 4 ) 2 , -N(R 4 )S0 2 R, -N(R 6 )C0CH 2 N(R 4 ) 2 , -N(R 6 ) C0CH 2 CH 2 N(R 4 ) 2 , and -N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C .
  • R 5 substituents include -CI, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3/ -NHCOCH 2 N (C0 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH2CH 2 CH 2 N (CH 3 ) 2 ,
  • each R 6' is independently selected from hydrogen or methyl.
  • a more preferred Q' group is -CH 2 -.
  • Preferred formula Hid compounds have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group
  • R y is T-R 3 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4 ) 2 , or -OR;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit and wherein said methylene unit is optionally replaced by -0-, -NH-, or -S-;
  • Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 5 and R 2' is hydrogen, or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring.
  • More preferred compounds of formula Hid have one or more, and more preferably all, of the features selected from the group consisting of:
  • R y is T-R 3 or L-Z-R 3 wherein T is a valence bond - or a methylene and R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
  • R 1 is T- (Ring D) , wherein T is a valence bond;
  • Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ . 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;
  • L is -0-, -S-, or -N(R 4 )-;
  • Q 1 is -C(R 6' ) 2 - or 1, 2-cyclopropanediyl, wherein each R 6' is independently selected from hydrogen or methyl .
  • Even more preferred compounds of formula Hid have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
  • R y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or .
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, -CN, - -N0 2 , -N(R) 2 > optionally substituted -C ⁇ - 6 aliphatic group, -OR, -C0 2 R, -C0NH(R 4 ) , -N(R 4 )COR, -N(R 4 )S0 2 R, -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , or -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 ;
  • R 2 is hydrogen or a substituted or unsubstituted C ⁇ - 6 aliphatic; and L is -0-, -S-, or -NH- ; and
  • this invention provides a composition comprising a compound of formula Hid and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Hid or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula Hid or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Hid or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose n a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula Hid or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula Hid or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula Hid, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
  • Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula Hid, as described above.
  • Z 1 is nitrogen or C-R 8 and Z 2 is nitrogen or CH, wherein one of Z 1 or Z 2 is nitrogen;
  • R x and R y are independently selected from T-R 3 or L-Z-R 3 , or R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocycl
  • Z is a C ⁇ . 4 alkylidene chain
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )CO-, -N(R 6 ) C (0) O- , -N(R 6 )CON(R 6 )-, -N(R ⁇ )S0 2 N(R 6 )-, -N(R 6 )N(R 6 ) - ,--SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )CO-, -N(R 6 ) C (0) O- , -N(R 6 )CON(R 6
  • R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -N0 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ;
  • -C(R 6 ) N-0-, -C(R 6 ) 2 N(R 6 )N(R 6 )-, -C (R 6 ) 2 N (R 6 ) S0 2 N(R 6 ) - , or -C (R 6 ) 2 N (R 6 ) CON (R 6 ) - ;
  • W is -C(R 6 ) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 S0 2 -, -C(R 6 ) 2 S0 2 N(R 6 )-, -C(R 6 ) 2 N(R 6 )-, -CO-, -C0 2 -, -C(R 6 )OC(0)-, -C(R 6 )OC(0)N(R 6 )-, -C (R 6 ) 2 N (R 6 ) CO- , -C(R 6 ) 2 N(
  • Preferred rings formed by R x and R y of formula IVa include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R x /R y ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVa are shown below.
  • More preferred pyridine ring systems of formula IVa include IVa-A, IVa-B, IVa-D, IVa-E, IVa-J, IVa-P, and IVa-V, most preferably IVa-A, IVa-B, IVa-D, IVa-E, and IVa-J. Even more preferred pyridine ring systems of formula IVa are those described above, wherein Z 1 is nitrogen and Z 2 is CH.
  • R x groups of formula IVa include hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.
  • R y groups of formula IVa include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R 6 ) 2 0-, -CO- and R 3 is -R, -N(R 4 ) 2 , or -OR.
  • R y groups examples include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.
  • the ring formed when the R x and R y groups of formula IVa are taken together may be substituted or unsubstituted.
  • Suitable substituents include --R, halo, -0(CH 2 ) 2 . 4 -N(R 4 ) 2 , -0(CH 2 ) 2 . 4 -R, -OR, -N (R 4 ) - (CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -CON(R 4 ) 2 , -CN, -0(CH 2 ) 2 . 4 -N(R 4 ) 2 , -O (CH 2 ) 2 --R, , -N0 2 -N(R 4 ) 2 , -NR 4 C0R, -NR 4 S0 2 R, -S0 2 N(R 4 ) 2 wherein R is hydrogen or an optionally substituted C ⁇ . 6 aliphatic group.
  • R 2 and R 2 ' groups of formula IVa may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IVa compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2 ' fused ring of formula IVa include one or more of the following: -halo, -N(R) 2 , -Ci- 4 alkyl, -C ⁇ _ 4 haloalkyl, -N0 2f -0(C ⁇ .- alkyl), -C0 2 (C ⁇ - 4 alkyl) , -CN, -S0 2 (C ⁇ . alkyl) , -S0 2 NH 2 , -OC(0)NH 2 , -NH 2 S0 2 (C ⁇ _4 alkyl) , -NHC (0) (C x . 4 alkyl) ,
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ _ 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl., and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula IVa When Ring D of formula IVa is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl , indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl .
  • preferred T-R 5 or V-Z- R 5 substituents include -halo, -CN, -N0 2 , -N(R) 2 , optionally substituted C ⁇ _ 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -C0NH(R 4 ), -N(R 4 )C0R, -N(R)C0 2 R, -S0 2 N(R 4 ) 2 ,
  • R is selected from hydrogen, C ⁇ . 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3 ,- -NHCOCH 2 N (C0 2 t-Bu) CH 3 ,-- -NHC0CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2
  • Preferred R 8 groups of formula IVa when present, include R, OR, and N(R 4 ) 2 .
  • Examples of preferred R 8 include methyl, ethyl, NH 2 , NH 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 NH, N(CH 3 ) 2 CH 2 CH 2 0, (piperidin-1-yl) CH 2 CH 2 0, and NH 2 CH 2 CH 2 0.
  • Preferred formula IVa compounds have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group and R y is T-R 3 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4 ) , or -OR; or R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z- R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ; (b) R 1 is T- (Ring D) , wherein T is a valence bond
  • R y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, or -N(R ) 2 , wherein R is selected from hydrogen,
  • R 1 is T- (Ring D) , wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8- 10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ . e aliphatic, phenyl, a
  • R 3 is selected from -R, -halo, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 )-.
  • R x is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and R y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or R x and R y are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or cyclohexo ring, wherein said ring is optionally substituted with -halo, -R, -OR,
  • R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted C ⁇ . 6 aliphatic, -OR,
  • R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ . 6 aliphatic group, and R 2 ' is hydrogen;
  • R 3 is selected from -R, -OR, or -N(R) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and
  • Ring D is substituted by up to three substituents selected from -halo, -CN, -N0 2/ -N(R 4 ) 2 , optionally substituted C ⁇ - ⁇ aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )COR, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 , -N(R 4 )S0 2 R, -N(R 6 )COCH 2 N(R 4 ) 2 , -N(R 6 )COCH 2 CH 2 N(R 4 )2, or -N(R 6 )COCH 2 CH 2 CH2N(R)2, wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • Representative compounds of formula IVa are shown below in Table
  • this invention provides a composition comprising a compound of formula IVa and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IVa or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IVa or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula IVa, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
  • Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IVa, as described above .
  • Another embodiment of this invention relates to compounds of formula IVb: • • •
  • Z 1 is nitrogen or C-R 8 and Z 2 is nitrogen or CH, wherein one of Z 1 or Z 2 is nitrogen;
  • R x and R y are independently selected from T-R 3 or L-Z-R 3 , or R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is- independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, hetero
  • T is a valence bond or a C ⁇ _ 4 alkylidene chain
  • Z is a Ci- 4 alkylidene chain
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )C0-, -N (R 6 ) C (0) 0- , -N(R 6 )CON(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N(R 6 ) N (R 6 ) - ,
  • R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -N0 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ;
  • IVb include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R x /R y ring is optionally substituted.
  • This provides a bicyclic ring system containing a pyrimidine ring.
  • Preferred pyrimidine ring systems of formula IVb are shown below.
  • More preferred pyrimidine ring systems of formula IVb include IVb-A, IVb-B, IVb-D, IVb-E, IVb-J, IVb-P, and IVb-V, most preferably IVb-A, IVb-B, IVb-D, IVb-E, and IVb-J. Even more preferred pyridine ring systems of formula IVb are those described above, wherein Z 1 is nitrogen and Z 2 is CH.
  • R x groups of formula IVb include hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ _ 4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl .
  • R y groups of formula IVb include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R 6 ) 2 0-, -CO- and R 3 is -R, -N(R 4 ) 2 , or -OR.
  • R y groups examples include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.
  • the ring formed when the R x and R y groups of formula IVba are taken together may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -0(CH 2 ) 2 -4-N(R) 2 , -0(CH 2 ) 2 -4-R, -OR, -N (R 4 ) - (CH 2 ) 2-4-N (R 4 ) 2 , -N(R 4 ) - (CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -C0N(R) 2 , -CN, -O (CH 2 ) 2 . 4 -N (R 4 ) 2 , -0 (CH 2 ) 2 . 4 -R, , -N0 2 -N(R 4 ) 2 , -NR 4 C0R, -NRS0 2 R, -S0 2 N(R 4 ) 2 wherein R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group.
  • R 2 and R 2 ' groups of formula IVb may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IVb compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2 ' fused ring of formula IVb include one or more of the following: -halo, -N(R) 2 , alkyl, -C- 4 haloalkyl, -N0 2 , -0(C ⁇ . 4 alkyl), -C0 2 (C 1 . 4 alkyl) , -CN, -S0 2 (C ⁇ - 4 alkyl) , -S0 2 NH 2 , -0C(0)NH 2 , -NH 2 S0 2 (Ci- 4 alkyl) , -NHC (0) (C ⁇ - 4 alkyl) ,
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ _ 6 aliphatic group.
  • preferred R 2 groups include hydrogen, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula IVb When Ring D of formula IVb is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.
  • preferred T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R) 2 , optionally substituted C x . 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )COR, -N(R 4 )C0 2 R, -S0 2 N(R 4 ) 2 , -N(R 4 )S0 2 R, -N(R 6 )COCH 2 N(R 4 ) 2 , -N(R 6 ) COCH 2 CH 2 N(R 4 ) 2 , and -N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic
  • R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAC, -NHS0 2 Me,
  • Preferred R 8 groups of formula IVb when present, include R, OR, and N(R 4 ) 2 .
  • Examples of preferred R 8 include methyl, ethyl, NH 2 , NH 2 CH 2 CH 2 NH, N(CH 3 ) 2 CH 2 CH 2 NH, N(CH 3 ) 2 CH 2 CH 2 0, (piperidin-l-yl)CH 2 CH 2 0, and NH 2 CH 2 CH 2 0.
  • Preferred formula IVb compounds have one or more, and more preferably all, of the features selected from the group consisting of:
  • R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ - aliphatic group and R y is T-R 3 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4 ) 2 , or -OR; or R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is ⁇ independently substituted by oxo, T-R 3 , or L-Z-
  • each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) , wherein T is a valence bond or a methylene unit;
  • Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
  • R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen, or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring.
  • More preferred compounds of formula IVb have one or more, and more preferably all, of the features selected from the group consisting of:
  • R y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R x and R y are taken together with their intervening atoms to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ; (b) R 1 is T- (
  • R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl, a
  • R 3 is selected from -R, -halo, -OR, or -N(R ) 2 , wherein R is selected from hydrogen, C ⁇ _ 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 )-.
  • R x is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and R y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or R x and R y are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or cyclo
  • R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group;
  • R 1 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -N0 2 , -N(R 4 ) 2 , • optionally substituted C ⁇ _ 6 aliphatic, -OR,
  • R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ _ 6 aliphatic group, and R 2 ' is hydrogen;
  • R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen, C ⁇ - 6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and
  • Ring D is substituted by up to three substituents selected from -halo, -CN, -N0 2 , -N(R) 2 , optionally substituted C ⁇ - 6 aliphatic group, -OR, -C(0)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )COR, -N(R)C0 2 R, -S0 2 N(R 4 ) 2 , -N(R)S0 2 R,
  • R is selected from hydrogen, C ⁇ _ 6 aliphatic, phenyl,. a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • this invention provides a composition comprising a compound of formula IVb and a pharmaceutically acceptable carrier.
  • Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition thereof-.
  • Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IVb or a composition comprising said compound.
  • Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition thereof.
  • One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition thereof. This method is especially useful for diabetic patients.
  • Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease.
  • Another method relates to inhibiting the phosphorylation of ⁇ -catenin, which is useful for treating schizophrenia.
  • Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IVb or a composition comprising said compound.
  • Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula IVb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
  • Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IVb, as described above .
  • Another embodiment of this invention relates to compounds of formula IVc: IVc
  • Z 1 is nitrogen or C-R 8 and Z 2 is nitrogen or CH, wherein one of Z 1 or Z 2 is nitrogen;
  • R x and R y are independently selected from T-R 3 or L-Z-R 3 , or R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;
  • R 1 is T- (Ring D) ;
  • Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ; T is a valence bond or a C ⁇ _ 4 alkylidene chain; Z is a C ⁇ -4 alkylidene chain;
  • L is -0-, -S-, -SO-, -S0 2 -, -N(R 6 )S0 2 -, -S0 2 N(R 6 )-, -N(R 6 )-, -CO-, -C0 2 -, -N(R 6 )CO-, -N (R 6 ) C (0) 0- , -N(R 6 )CON(R 6 )-, -N(R 6 )S0 2 N(R 6 )-, -N(R 6 )N(R 6 ) - , -C(0)N(R 6 )-, -OC(0)N(R 6 )-, -C(R 6 ) 2 0-, -C(R 6 ) 2 S-,
  • R 2 and R 2 ' are independently selected from -R, -T-W-R 6 , or R 2 and R 2' are taken together with their intervening atoms to form
  • each R is independently selected from hydrogen or an optionally substituted group selected from C ⁇ 6 aliphatic, C 6 '
  • each R 7 is independently selected from hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
  • Preferred rings formed by R x and R y of formula IVe- include a 5-, -6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R x /R y ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVe are shown below.
  • More preferred pyridine ring systems of formula IVe include IVc-A, IVc-B, IVc-D, IVc-E, IVc-J, IVc-P, and IVc-V, most preferably IVc-A, IVc-B, IVc-D, IVc-E, and IVc-J. Even more preferred pyridine ring systems of formula IVe are those described above, wherein Z 1 is nitrogen and Z 2 is CH
  • R x groups of formula IVe include hydrogen, alkyl- or dialkylamino, acetamido, or a C ⁇ - 4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.
  • R y groups of formula IVe include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R 6 ) 2 0-, -CO- and R 3 is -R, -N(R 4 ) 2 , or -OR.
  • R y groups examples include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as ' dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.
  • the ring formed when the R x and R y groups of formula IVe are taken together may be substituted or unsubstituted.
  • Suitable substituents include -R, halo, -0(CH 2 ) 2 . 4 -N(R 4 ) 2 , -0(CH 2 ) 2 . 4 -R, -OR, -N (R 4 ) - (CH 2 ) 2 .
  • R x /R y ring substituents include -halo, -R, -OR, -COR, -C0 2 R, -CON(R 4 ) 2 , -CN, -0(CH 2 ) 2 -4-N(R 4 ) 2 , -O (CH 2 ) 2 . 4 -R, , -N0 2 -N(R 4 ) 2 , -NR 4 COR, -NR 4 S0 2 R, -S0 2 N(R 4 ) 2 wherein R is hydrogen or an optionally substituted C ⁇ _ 6 aliphatic group.
  • R 2 and R 2 ' groups of formula IVe may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.
  • Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IVe compounds having a pyrazole-containing bicyclic ring system:
  • Preferred substituents on the R 2 /R 2' fused ring of formula IVe include one or more of the following: -halo, -N(R 4 ) 2 , -Ci-4 alkyl, -C ⁇ - 4 haloalkyl, -N0 2 , -0(C ⁇ - alkyl), -C0 2 (Ci-4 alkyl) , -CN, -S0 2 (d- 4 alkyl) , -S0 2 NH 2 , -OC(0)NH 2 , -NH 2 S0 2 (C 1 . 4 alkyl) , -NHC(O) (d- 4 alkyl) ,
  • (C ⁇ _ 4 alkyl) is a straight, branched, or cyclic alkyl group.
  • the (Ci- 4 alkyl) group is methyl.
  • preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C ⁇ _ 6 aliphatic group.
  • preferred R 2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.
  • a preferred R 2 ' group is hydrogen.
  • Ring D of formula IVe When Ring D of formula IVe is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl , indazolyl , benzothiazolyl , cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.
  • preferred T-R 5 or V-Z-R 5 substituents include -halo, -CN, -N0 2 , -N(R 4 ) 2 , optionally substituted Ci- ⁇ aliphatic group, -OR, -C(0)R, -C0 2 R, -C0NH(R 4 ), -N(R 4 )C0R, -N(R)C0 2 R, -S0 2 N(R 4 ) 2 ,
  • R is selected from hydrogen, Ci-e aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
  • R ⁇ substituents include -CI, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc , -NHS0 2 Me, -NHS0 2 Et, -NHS0 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (C0 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N(CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 ,
  • -NHCO cyclopropyl ) , -NHCO (isobutyl ) , -NHCOCH 2 (morpholin-4 - yl), -NHCOCH 2 CH 2 (morpholin-4-yl) , -NHCOCH 2 CH 2 CH 2 (morpholin- 4-yl), -NHC0 2 (t-butyl) , -NH(d_ 4 aliphatic) such as -NHMe, -N(Ci-- 4 aliphatic) 2 such as -NMe 2 , OH, -0(C ⁇ - 4 aliphatic) such as -OMe, C ⁇ _ 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2 (d- 4 aliphatic) .
  • -NH(d_ 4 aliphatic) such as -NHMe, -N(Ci-- 4 aliphatic
  • R 8 groups of formula IVe when present, include R, OR, and N(R 4 ) 2 .
  • R 8 include methyl, ethyl, NH 2 , NH 2 CH 2 CH 2 NH, N(CH 3 ) 2 CH 2 CH 2 NH, N(CH 3 ) 2 CH 2 CH 2 0, (piperidin-l-yl)CH 2 CH 2 0, and NH 2 CH 2 CH 2 0.
  • Preferred formula IVe compounds have one or more, -and more preferably all, of the features selected from the group consisting of:
  • R x is hydrogen, alkyl- or dialkylamino, acetamido, or a - 4 aliphatic group and R y is T-R 3 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4 ) 2 , or -OR; or R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z- R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ; (b) R 1 is T- (Ring D) , wherein T is a valence bond
  • R y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from hydrogen,
  • R x and R y are taken together with their intervening atoms to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R x and R y is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4 ;

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Molecular Biology (AREA)
  • Obesity (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Biotechnology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
PCT/US2001/051031 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors Ceased WO2002062789A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
IL15640701A IL156407A0 (en) 2000-12-21 2001-12-19 Pyrazole derivatives and pharmaceutical compositions containing the same
JP2002563142A JP4160395B2 (ja) 2000-12-21 2001-12-19 プロテインキナーゼインヒビターとして有用なピラゾール化合物
CA002432222A CA2432222C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
DE60119776T DE60119776T2 (de) 2000-12-21 2001-12-19 Pyrazolverbindungen als protein-kinase-inhibitoren
MXPA03005608A MXPA03005608A (es) 2000-12-21 2001-12-19 Compuestos de pirazol utiles como inhibidores de la proteina cinasa.
NZ526471A NZ526471A (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
KR1020037008409A KR100909665B1 (ko) 2000-12-21 2001-12-19 단백질 키나제 억제제로서 유용한 피라졸 화합물 및 이를 포함하는 약제학적 조성물
HK04102099.2A HK1061389B (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
EP01994510A EP1345927B1 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
HU0400638A HUP0400638A2 (hu) 2000-12-21 2001-12-19 Pirazolvegyületek mint proteinkináz inhibitorok és ezeket tartalmazó gyógyszerkészítmények
NO20032736A NO20032736L (no) 2000-12-21 2003-06-16 Pyrazolforbindelser nyttige som proteinkinaseinhibitorer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US25788700P 2000-12-21 2000-12-21
US60/257,887 2000-12-21
US28694901P 2001-04-27 2001-04-27
US60/286,949 2001-04-27

Publications (1)

Publication Number Publication Date
WO2002062789A1 true WO2002062789A1 (en) 2002-08-15

Family

ID=26946273

Family Applications (8)

Application Number Title Priority Date Filing Date
PCT/US2001/051031 Ceased WO2002062789A1 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049139 Ceased WO2002066461A1 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049401 Ceased WO2002057259A2 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/050312 Ceased WO2002068415A1 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049140 Ceased WO2002050065A2 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/051120 Ceased WO2002059111A2 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049585 Ceased WO2002050066A2 (en) 2000-12-21 2001-12-20 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049594 Ceased WO2002059112A2 (en) 2000-12-21 2001-12-20 Pyrazole compounds useful as protein kinase inhibitors

Family Applications After (7)

Application Number Title Priority Date Filing Date
PCT/US2001/049139 Ceased WO2002066461A1 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049401 Ceased WO2002057259A2 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/050312 Ceased WO2002068415A1 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049140 Ceased WO2002050065A2 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/051120 Ceased WO2002059111A2 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049585 Ceased WO2002050066A2 (en) 2000-12-21 2001-12-20 Pyrazole compounds useful as protein kinase inhibitors
PCT/US2001/049594 Ceased WO2002059112A2 (en) 2000-12-21 2001-12-20 Pyrazole compounds useful as protein kinase inhibitors

Country Status (27)

Country Link
US (16) US6653300B2 (https=)
EP (10) EP1355905B1 (https=)
JP (19) JP4210520B2 (https=)
KR (8) KR100875091B1 (https=)
CN (6) CN100406454C (https=)
AP (2) AP1588A (https=)
AR (4) AR042398A1 (https=)
AT (9) ATE327989T1 (https=)
AU (7) AU2002255452B2 (https=)
BR (2) BR0116493A (https=)
CA (8) CA2432223C (https=)
CY (1) CY1106297T1 (https=)
DE (8) DE60119776T2 (https=)
DK (3) DK1353916T3 (https=)
ES (7) ES2265446T3 (https=)
HU (5) HUP0400638A2 (https=)
IL (8) IL156408A0 (https=)
MX (8) MXPA03005608A (https=)
MY (1) MY140377A (https=)
NO (5) NO328537B1 (https=)
NZ (8) NZ526472A (https=)
PL (2) PL210414B1 (https=)
PT (3) PT1355905E (https=)
RU (1) RU2355688C2 (https=)
SI (2) SI1355905T1 (https=)
TW (2) TWI290551B (https=)
WO (8) WO2002062789A1 (https=)

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026665A1 (en) * 2001-09-26 2003-04-03 Bayer Pharmaceuticals Corporation 2-phenylamino-4-(5-pyrazolylamino)-pyrimidine derivatives as kinase inhibitors, in particular, src kinase inhibitors
WO2003028720A1 (en) * 2001-09-26 2003-04-10 Pharmacia Italia S.P.A. Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
WO2004048365A1 (en) * 2002-11-21 2004-06-10 Chiron Corporation 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
US6982260B1 (en) 1999-11-22 2006-01-03 Warner-Lambert Company Quinazolines and their use for inhibiting cyclin-dependent kinase enzymes
JP2006514619A (ja) * 2002-11-14 2006-05-11 サイクラセル・リミテッド ピリミジン化合物
US7122542B2 (en) 2003-07-30 2006-10-17 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
WO2006115452A1 (en) * 2005-04-27 2006-11-02 Astrazeneca Ab Use of pyrazolyl-pyrimidine derivatives in the treatment of pain
US7226923B2 (en) 2004-09-24 2007-06-05 Hoffman-La Roche Inc. Phthalazinone derivatives
US7285569B2 (en) 2004-09-24 2007-10-23 Hoff Hoffmann-La Roche Inc. Tricycles, their manufacture and use as pharmaceutical agents
US7297700B2 (en) 2005-03-24 2007-11-20 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
JPWO2005087710A1 (ja) * 2004-03-15 2008-01-24 武田薬品工業株式会社 アミノフェニルプロパン酸誘導体
US7329672B2 (en) 2002-02-01 2008-02-12 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
WO2008044045A1 (en) 2006-10-12 2008-04-17 Astex Therapeutics Limited Pharmaceutical combinations
WO2008044041A1 (en) 2006-10-12 2008-04-17 Astex Therapeutics Limited Pharmaceutical combinations
US7414131B2 (en) 2003-12-24 2008-08-19 Renovis, Inc. Bicycloheteroarylamine compounds as ion channel ligands and uses thereof
WO2008111441A1 (ja) 2007-03-05 2008-09-18 Kyowa Hakko Kirin Co., Ltd. 医薬組成物
US7462639B2 (en) 2005-04-14 2008-12-09 Hoffmann-La Roche Inc. Aminopyrazole derivatives
US7517886B2 (en) 2002-07-29 2009-04-14 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7524852B2 (en) 2002-06-07 2009-04-28 Kyowa Hakko Kogyo Co., Ltd. Bicyclic pyrimidine derivatives
US7528142B2 (en) 2005-11-03 2009-05-05 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
US7531536B2 (en) 2000-12-21 2009-05-12 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7550598B2 (en) 2004-08-18 2009-06-23 Takeda Pharmaceutical Company Limited Kinase inhibitors
US7557207B2 (en) 2004-11-24 2009-07-07 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
US7557106B2 (en) 2002-06-20 2009-07-07 Vertex Pharmaceuticals Incorporated Substituted pyrimidines useful as protein kinase inhibitors
US7572809B2 (en) 2005-12-19 2009-08-11 Hoffmann-La Roche Inc. Isoquinoline aminopyrazole derivatives
US7572914B2 (en) 2003-12-19 2009-08-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
US7713973B2 (en) 2004-10-15 2010-05-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
US7745451B2 (en) 2005-05-04 2010-06-29 Renovis, Inc. Tetrahydronaphthyridine and tetrahydropyrido[4,3-d]pyrimidine compounds and compositions thereof useful in the treatment of conditions associated with neurological and inflammatory disorders and dysfunctions
WO2010031056A3 (en) * 2008-09-15 2010-08-05 The Regents Of The University Of California Methods and compositions for modulating ire1, src, and abl activity
US7793137B2 (en) 2004-10-07 2010-09-07 Cisco Technology, Inc. Redundant power and data in a wired data telecommunincations network
US7915263B2 (en) 2006-08-31 2011-03-29 Banyu Pharmaceutical Co., Ltd. Aminopyridine derivatives having aurora A selective inhibitory action
EP2383268A1 (en) 2005-02-04 2011-11-02 AstraZeneca AB Pyrazolylaminopyridine derivatives useful as kinase inhibitors
EP2388259A1 (en) 2005-10-28 2011-11-23 AstraZeneca AB 4- (3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer
US8114870B2 (en) 2005-09-30 2012-02-14 Miikana Therapeutics, Inc. Method of treating disease states using substituted pyrazole compounds
US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
US8153630B2 (en) 2004-11-17 2012-04-10 Miikana Therapeutics, Inc. Kinase inhibitors
US8173647B2 (en) 2007-02-06 2012-05-08 Gordana Atallah PI 3-kinase inhibitors and methods of their use
WO2012059932A1 (en) 2010-11-01 2012-05-10 Aurigene Discovery Technologies Limited 2, 4 -diaminopyrimidine derivatives as protein kinase inhibitors
US8211929B2 (en) 2004-12-30 2012-07-03 Exelixis, Inc. Pyrimidine derivatives as kinase modulators and method of use
US8217035B2 (en) 2006-01-20 2012-07-10 Novartis Ag Pyrimidine derivatives used as PI-3-kinase inhibitors
US8222256B2 (en) 2006-07-05 2012-07-17 Exelixis, Inc. Methods of using IGFIR and ABL kinase modulators
US8278450B2 (en) 2007-04-18 2012-10-02 Takeda Pharmaceutical Company Limited Kinase inhibitors
US8354420B2 (en) 2010-06-04 2013-01-15 Genentech, Inc. Aminopyrimidine derivatives as LRRK2 inhibitors
US8399472B2 (en) 2005-06-08 2013-03-19 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8633207B2 (en) 2010-09-01 2014-01-21 Ambit Biosciences Corporation Quinazoline compounds and methods of use thereof
US8637537B2 (en) 2011-08-25 2014-01-28 Genentech, Inc. Serine/threonine kinase inhibitors
US8815882B2 (en) 2010-11-10 2014-08-26 Genentech, Inc. Pyrazole aminopyrimidine derivatives as LRRK2 modulators
US8815877B2 (en) 2011-12-22 2014-08-26 Genentech, Inc. Serine/threonine kinase inhibitors
US8865894B2 (en) 2012-02-24 2014-10-21 Novartis Ag Oxazolidin-2-one compounds and uses thereof
US8957068B2 (en) 2011-09-27 2015-02-17 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9040547B2 (en) 2011-09-22 2015-05-26 Pfizer Inc. Pyrrolopyrimidine and purine derivatives
US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
US9434719B2 (en) 2013-03-14 2016-09-06 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9593082B2 (en) 2005-06-08 2017-03-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
CN116354938A (zh) * 2021-12-28 2023-06-30 沈阳药科大学 一类喹唑啉衍生物与其类似物的制备方法及应用

Families Citing this family (329)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660731B2 (en) * 2000-09-15 2003-12-09 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7473691B2 (en) * 2000-09-15 2009-01-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
EP1317450B1 (en) * 2000-09-15 2006-11-22 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US20020111353A1 (en) * 2000-12-05 2002-08-15 Mark Ledeboer Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
US20030125344A1 (en) * 2001-03-23 2003-07-03 Bayer Corporation Rho-kinase inhibitors
US7034026B2 (en) 2001-04-10 2006-04-25 Merck & Co., Inc. Inhibitors of Akt activity
US7105667B2 (en) * 2001-05-01 2006-09-12 Bristol-Myers Squibb Co. Fused heterocyclic compounds and use thereof
US7138404B2 (en) * 2001-05-23 2006-11-21 Hoffmann-La Roche Inc. 4-aminopyrimidine derivatives
US7115617B2 (en) 2001-08-22 2006-10-03 Amgen Inc. Amino-substituted pyrimidinyl derivatives and methods of use
US6939874B2 (en) 2001-08-22 2005-09-06 Amgen Inc. Substituted pyrimidinyl derivatives and methods of use
SE0104140D0 (sv) 2001-12-07 2001-12-07 Astrazeneca Ab Novel Compounds
US20030187026A1 (en) 2001-12-13 2003-10-02 Qun Li Kinase inhibitors
AU2002361846A1 (en) * 2001-12-21 2003-07-15 Bayer Pharmaceuticals Corporation Quinazoline and quinoline derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents
AU2003235798A1 (en) 2002-01-10 2003-07-24 F. Hoffmann-La Roche Ag Use of a gsk-3beta inhibitor in the manufacture of a medicament for increasing bone formation
EP1472245A2 (en) * 2002-02-06 2004-11-03 Vertex Pharmaceuticals Incorporated Heteroaryl compounds useful as inhibitors of gsk-3
EP1485100B1 (en) 2002-03-15 2010-05-05 Vertex Pharmaceuticals Incorporated Azinylaminoazoles as inhibitors of protein kinases
DE60327999D1 (de) 2002-03-15 2009-07-30 Vertex Pharma Azolylaminoazine als inhibitoren von proteinkinasen
AU2003218215A1 (en) 2002-03-15 2003-09-29 Vertex Pharmaceuticals, Inc. Azolylaminoazines as inhibitors of protein kinases
US7223738B2 (en) 2002-04-08 2007-05-29 Merck & Co., Inc. Inhibitors of Akt activity
JP2005536517A (ja) * 2002-07-23 2005-12-02 スミスクライン ビーチャム コーポレーション キナーゼインヒビターとしてのピラゾロピリミジン
EP1739087A1 (en) * 2002-08-02 2007-01-03 Vertex Pharmaceuticals Incorporated Pyrazole compositions useful as inhibitors of gsk-3
DK1532145T3 (da) * 2002-08-02 2007-01-15 Vertex Pharma Pyrazolpræparater der er anvendelige som inhibitorer af GSK-3
BR0314098A (pt) * 2002-09-05 2005-07-19 Aventis Pharma Sa Derivados da aminoindazóis a tìtulo de medicamentos e composições farmacêuticas que os contêm
FR2844267B1 (fr) * 2002-09-05 2008-02-15 Aventis Pharma Sa Nouveaux derives d'aminoindazoles a titre de medicaments et compositions pharmaceutiques les renfermant
AU2003255482A1 (en) * 2002-10-02 2004-04-23 Merck Patent Gmbh Use of 4 amino-quinazolines as anti cancer agents
MXPA05003607A (es) 2002-10-04 2005-11-17 Prana Biotechnology Ltd Compuestos neurologicamente activos.
KR100490893B1 (ko) * 2002-10-11 2005-05-23 (주) 비엔씨바이오팜 2-메톡시-1,3,5-트리아진 유도체, 그 제조방법 및 이를 포함하는 항바이러스용 약학적 조성물
US7309701B2 (en) 2002-11-19 2007-12-18 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them
US7462613B2 (en) 2002-11-19 2008-12-09 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them
FR2847253B1 (fr) * 2002-11-19 2007-05-18 Aventis Pharma Sa Nouveaux derives de pyridazinones a titre de medicaments et compositions pharmaceutiques les renfermant
WO2004072029A2 (en) * 2003-02-06 2004-08-26 Vertex Pharmaceuticals Incorporated Pyrazolopyridazines useful as inhibitors of protein kinases
US7157455B2 (en) * 2003-02-10 2007-01-02 Hoffmann-La Roche Inc. 4-Aminopyrimidine-5-one derivatives
WO2004087679A1 (en) * 2003-04-01 2004-10-14 Aponetics Ag 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases
ATE401080T1 (de) * 2003-06-02 2008-08-15 Astrazeneca Ab (3-((chinazolin-4-yl)amino)-1h-pyrazol-1- yl)acetamid derivate und verwandte verbindungen als aurora kinase inhibitoren zur behandlung von proliferativen erkrankungen wie krebs
JP4869068B2 (ja) * 2003-06-19 2012-02-01 スミスクライン ビーチャム コーポレーション 化合物
TWI372050B (en) * 2003-07-03 2012-09-11 Astex Therapeutics Ltd (morpholin-4-ylmethyl-1h-benzimidazol-2-yl)-1h-pyrazoles
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
NZ544472A (en) 2003-07-03 2009-04-30 Myriad Genetics Inc Compounds and therapeutical use thereof
GB0315966D0 (en) * 2003-07-08 2003-08-13 Cyclacel Ltd Compounds
PL2256106T3 (pl) 2003-07-22 2015-08-31 Astex Therapeutics Ltd Związki 3,4-pochodne 1h-pirazolu i ich zastosowanie jako kinazy zależne od cyklin (cdk) i modulatory kinazy syntazy glikogenu-3 (gsk-3)
EP1648875A1 (en) * 2003-07-30 2006-04-26 Cyclacel Limited 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors
US7417726B2 (en) * 2003-09-19 2008-08-26 Applied Biosystems Inc. Normalization of data using controls
US20060024690A1 (en) * 2003-09-19 2006-02-02 Kao H P Normalization of data using controls
US20050221357A1 (en) * 2003-09-19 2005-10-06 Mark Shannon Normalization of gene expression data
WO2005030131A2 (en) * 2003-09-23 2005-04-07 Replidyne, Inc Bis-quinazoline compounds for the treatment of bacterial infections
WO2005040159A1 (en) 2003-10-17 2005-05-06 Astrazeneca Ab 4-(pyrazol-3-ylamino) pyrimidine derivatives for use in the treatment of cancer
AU2004297235A1 (en) * 2003-12-04 2005-06-23 Vertex Pharmaceuticals Incorporated Quinoxalines useful as inhibitors of protein kinases
RU2006124559A (ru) * 2003-12-09 2008-01-20 Вертекс Фармасьютикалз Инкорпорейтед (Us) Производные нафтиридина и применение указанных производныхых в качестве модуляторов мускариновых рецепторов
JP2007522233A (ja) * 2004-02-11 2007-08-09 アムジエン・インコーポレーテツド バニロイド受容体リガンド及び治療におけるそれらの使用
US20080050314A1 (en) * 2004-02-26 2008-02-28 Bayer Healthcare Ag Diagnostics and Therapeutics for Diseases Associated With Glycogen Synthase Kinase 3 Beta (Gsk3b)
WO2005099688A2 (en) * 2004-04-07 2005-10-27 Takeda Pharmaceutical Company Limited Cyclic compounds
EP1742921A2 (en) * 2004-04-21 2007-01-17 AstraZeneca AB Pyrazole derivatives useful for the treatment of cancer
WO2005105788A1 (en) * 2004-04-23 2005-11-10 Takeda San Diego, Inc. Indole derivatives and use thereof as kinase inhibitors
EP1751136B1 (en) * 2004-05-07 2014-07-02 Amgen Inc. Nitrogenated heterocyclic derivatives as protein kinase modulators and use for the treatment of angiogenesis and cancer
ES2540987T3 (es) * 2004-05-14 2015-07-15 Millennium Pharmaceuticals, Inc. Métodos para preparar inhibidores de la aurora cinasa
US20050255485A1 (en) * 2004-05-14 2005-11-17 Livak Kenneth J Detection of gene duplications
EP1905773B1 (en) * 2004-05-14 2012-07-18 Millennium Pharmaceuticals, Inc. Compounds and methods for inhibiting mitotic progression by inhibition of aurora kinase
AU2012200416B2 (en) * 2004-05-14 2014-07-31 Millennium Pharmaceuticals, Inc. "Compounds and methods for inhibiting mitotic progression by inhibition of Aurora kinase"
JP4993604B2 (ja) * 2004-05-14 2012-08-08 バーテックス ファーマシューティカルズ インコーポレイテッド ピロリルピリミジンｅｒｋプロテインキナーゼインヒビターのプロドラッグ
JP2007538102A (ja) * 2004-05-20 2007-12-27 バイエル・フアーマシユーチカルズ・コーポレーシヨン 糖尿病の処置に有用な５−アニリノ−４−ヘテロアリールピラゾール誘導体
KR20070034519A (ko) * 2004-05-27 2007-03-28 이 아이 듀폰 디 네모아 앤드 캄파니 광감성 중합체 보호층용 현상제
EP1765325A4 (en) * 2004-07-01 2009-08-12 Synta Pharmaceuticals Corp HETEROARYL COMPOUNDS SUBSTITUTED IN 2
CN101031551A (zh) * 2004-07-06 2007-09-05 安吉永生物制药公司 针对癌症治疗的肝细胞生长因子/c－met活性的喹唑啉调节剂
CN101031550B (zh) * 2004-09-30 2015-05-27 泰博特克药品有限公司 抑制hiv的5-碳环-或杂环取代的嘧啶类
RU2405778C2 (ru) * 2004-09-30 2010-12-10 Тиботек Фармасьютикалз Лтд. 5-гетероциклилпиримидины, ингибирующие вич
ATE542802T1 (de) * 2004-09-30 2012-02-15 Tibotec Pharm Ltd Hiv-inhibierende 5-substituierte pyrimidine
EP1813609B1 (en) * 2004-10-29 2013-06-19 Msd K.K. Novel aminopyridine derivatives having selective aurora-a inhibitory effect
US7491720B2 (en) 2004-10-29 2009-02-17 Banyu Pharmaceutical Co., Ltd. Aminopyridine derivatives having Aurora A selective inhibitory action
US7767680B2 (en) 2004-11-03 2010-08-03 Vertex Pharmaceuticals Incorporated Ion channel modulators and methods of use
US20060128710A1 (en) * 2004-12-09 2006-06-15 Chih-Hung Lee Antagonists to the vanilloid receptor subtype 1 (VR1) and uses thereof
JP2008525422A (ja) * 2004-12-23 2008-07-17 ファイザー・プロダクツ・インク 抗癌剤として有用な複素芳香族誘導体
EP1833819A1 (en) 2004-12-30 2007-09-19 Astex Therapeutics Limited Pyrazole compounds that modulate the activity of cdk, gsk and aurora kinases
CA2592900A1 (en) 2005-01-03 2006-07-13 Myriad Genetics Inc. Nitrogen containing bicyclic compounds and therapeutical use thereof
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
DE602006010979D1 (de) 2005-01-19 2010-01-21 Rigel Pharmaceuticals Inc Prodrugs aus 2,4-pyrimidindiamin-verbindungen und ihre verwendungen
AR054425A1 (es) 2005-01-21 2007-06-27 Astex Therapeutics Ltd Sales de adicion de piperidin 4-il- amida de acido 4-(2,6-dicloro-benzoilamino) 1h-pirazol-3-carboxilico.
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
DE602006010991D1 (de) * 2005-01-26 2010-01-21 Schering Corp 3-(indazol-5-yl)-(1,2,4)triazinderivate und verwandte verbindungen als proteinkinaseinhibitoren zur behandlung von krebs
CA2598076A1 (en) * 2005-02-16 2006-08-24 Astrazeneca Ab Chemical compounds
PT1853588E (pt) * 2005-02-16 2008-08-25 Astrazeneca Ab Compostos químicos
CA2600144A1 (en) * 2005-03-15 2006-09-28 Irm Llc Compounds and compositions as protein kinase inhibitors
JP2008534481A (ja) * 2005-03-23 2008-08-28 アストラゼネカ アクチボラグ インスリン様増殖因子−１受容体活性の阻害剤としての２−アゼチジニル−４−（１ｈ−ピラゾール−３−イルアミノ）ピリミジン
SI1869032T1 (sl) * 2005-04-05 2008-12-31 Astrazeneca Ab Pirimidinski derivati za uporabo kot sredstva proti raku
GB0507347D0 (en) * 2005-04-12 2005-05-18 Astrazeneca Ab Chemical compounds
AU2006241825A1 (en) 2005-04-28 2006-11-09 Mitsubishi Tanabe Pharma Corporation Cyanopyridine derivative and use thereof as medicine
US20080207594A1 (en) 2005-05-04 2008-08-28 Davelogen Aktiengesellschaft Use of Gsk-3 Inhibitors for Preventing and Treating Pancreatic Autoimmune Disorders
CN101218229A (zh) * 2005-05-05 2008-07-09 阿斯利康(瑞典)有限公司 吡唑基-氨基取代的嘧啶及其在癌症治疗中的应用
EP1899323A2 (en) * 2005-05-16 2008-03-19 AstraZeneca AB Pyrazolylaminopyrimidine derivatives useful as tyrosine kinase inhibitors
US8193206B2 (en) 2005-06-14 2012-06-05 Taigen Biotechnology Co., Ltd. Pyrimidine compounds
JP5118029B2 (ja) 2005-06-14 2013-01-16 タイゲン バイオテクノロジー カンパニー，リミテッド ピリミジン化合物
EP1746096A1 (en) 2005-07-15 2007-01-24 4Sc Ag 2-Arylbenzothiazole analogues and uses thereof in the treatment of cancer
AU2006279376B2 (en) * 2005-08-18 2011-04-14 Vertex Pharmaceuticals Incoporated Pyrazine kinase inhibitors
WO2007023382A2 (en) * 2005-08-25 2007-03-01 Pfizer Inc. Pyrimidine amino pyrazole compounds, potent kinase inhibitors
EP2258358A3 (en) 2005-08-26 2011-09-07 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
EP1928437A2 (en) 2005-08-26 2008-06-11 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
CN101316587B (zh) * 2005-09-30 2013-04-03 迈卡纳治疗股份有限公司 取代的吡唑化合物
EP1940389A2 (en) 2005-10-21 2008-07-09 Braincells, Inc. Modulation of neurogenesis by pde inhibition
US20070112017A1 (en) 2005-10-31 2007-05-17 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
NZ567858A (en) * 2005-11-01 2011-08-26 Array Biopharma Inc Pyridine compounds useful as Glucokinase activators
CA2629781A1 (en) * 2005-11-16 2007-05-24 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
US8546404B2 (en) 2005-12-13 2013-10-01 Merck Sharp & Dohme Compounds that are ERK inhibitors
EP1968579A1 (en) 2005-12-30 2008-09-17 Astex Therapeutics Limited Pharmaceutical compounds
WO2007081978A2 (en) * 2006-01-11 2007-07-19 Angion Biomedica Corporation Modulators of hepatocyte growth factor / c-met activity
MX2008010635A (es) * 2006-02-16 2008-10-28 Schering Corp Derivados de pirrolidina como inhibidores de cinasa regulada por señales extracelulares.
US20100216734A1 (en) 2006-03-08 2010-08-26 Braincells, Inc. Modulation of neurogenesis by nootropic agents
PE20080145A1 (es) * 2006-03-21 2008-02-11 Janssen Pharmaceutica Nv Tetrahidro-pirimidoazepinas como moduladores de trpv1
WO2007113254A1 (en) 2006-03-30 2007-10-11 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 5-amido substituted pyrimidines
JP5255559B2 (ja) * 2006-03-31 2013-08-07 アボット・ラボラトリーズ インダゾール化合物
ES2400375T3 (es) 2006-04-07 2013-04-09 Novartis Ag Combinación que comprende A) un compuesto de pirimidilaminobenzamida y B)un inhibidor de cinasa THR315LLE
KR20080109096A (ko) 2006-04-14 2008-12-16 프라나 바이오테크놀로지 리미티드 연령 관련 황반 변성（에이엠디）의 치료 방법
AU2007244183B2 (en) * 2006-04-27 2012-05-10 Msd K.K. Novel aminopyridine derivative having aurora-a-selective inhibitory activity
AU2007249399A1 (en) 2006-05-09 2007-11-22 Braincells, Inc. Neurogenesis by modulating angiotensin
WO2007134077A2 (en) 2006-05-09 2007-11-22 Braincells, Inc. 5 ht receptor mediated neurogenesis
BRPI0713378A8 (pt) 2006-06-27 2018-01-02 Takeda Pharmaceutical composto, pró-droga, modulador da função do receptor gpr40, agente farmacêutico uso do composto, e, método de produção de uma forma opticamente ativa de um composto
WO2008001101A2 (en) * 2006-06-29 2008-01-03 Astex Therapeutics Limited Pharmaceutical combinations
EP2049119A2 (en) 2006-06-29 2009-04-22 Astex Therapeutics Limited Pharmaceutical combinations of 1-cyclopropyl-3-[3-(5-morphoolin-4-ylmethyl-1h-benzoimidazol-2-yl)-1h-1-pyrazol-4-yl]-urea
WO2008001886A1 (en) * 2006-06-30 2008-01-03 Kyowa Hakko Kirin Co., Ltd. Aurora inhibitor
JP2009541480A (ja) * 2006-06-30 2009-11-26 アストラゼネカ アクチボラグ 癌の治療において有用なピリミジン誘導体
JP2010500300A (ja) 2006-08-08 2010-01-07 サノフィ−アベンティス アリールアミノアリール−アルキル−置換イミダゾリジン−２，４−ジオン、それらの製造法、それらの化合物を含有する薬剤、およびそれらの使用
US7718648B2 (en) * 2006-08-09 2010-05-18 Millennium Pharmaceuticals, Inc. Pyridobenzazepine compounds and methods for inhibiting mitotic progression
US7744164B2 (en) * 2006-08-11 2010-06-29 Schluimberger Technology Corporation Shield of a degradation assembly
EP2068872A1 (en) 2006-09-08 2009-06-17 Braincells, Inc. Combinations containing a 4-acylaminopyridine derivative
US20100184806A1 (en) 2006-09-19 2010-07-22 Braincells, Inc. Modulation of neurogenesis by ppar agents
EP2223925A1 (en) * 2006-10-09 2010-09-01 Takeda Pharmaceutical Company Limited Kinase inhibitors
WO2008053812A1 (en) * 2006-10-27 2008-05-08 Mitsubishi Tanabe Pharma Corporation Cyanopyridine derivative and medicinal use thereof
MX2009004807A (es) * 2006-11-02 2009-06-15 Vertex Pharma Aminopiridinas y aminopirimidinas utiles como inhibidores de proteina cinasa.
CL2007003244A1 (es) 2006-11-16 2008-04-04 Millennium Pharm Inc Compuestos derivados de pirimido[5,4-d][2]benzazepina; composicion farmaceutica que comprende a dicho compuesto; y uso del compuesto para el tratamiento del cancer.
NZ577768A (en) * 2006-12-19 2012-01-12 Vertex Pharma Aminopyrimidines useful as inhibitors of protein kinases
JP5185283B2 (ja) * 2006-12-29 2013-04-17 テイボテク・フアーマシユーチカルズ Ｈｉｖ阻害６−置換ピリミジン
EP2114902B1 (en) * 2006-12-29 2014-09-17 Janssen R&D Ireland Hiv inhibiting 5,6-substituted pyrimidines
ATE526328T1 (de) * 2007-03-09 2011-10-15 Vertex Pharma Als inhibitoren von proteinkinasen geeignete aminopyrimidine
MX2009009592A (es) 2007-03-09 2009-11-10 Vertex Pharma Aminopiridinas utiles como inhibidores de proteinas cinasas.
MX2009009590A (es) * 2007-03-09 2009-11-10 Vertex Pharma Aminopirimidinas utiles como inhibidores de proteinas cinasas.
CA2682195A1 (en) * 2007-03-20 2008-09-25 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
WO2008117050A1 (en) * 2007-03-27 2008-10-02 Astrazeneca Ab Pyrazolyl-amino-substituted pyrazines and their use for the treatment of cancer
AU2008240313A1 (en) * 2007-04-13 2008-10-23 Aj Park Aminopyrimidines useful as kinase inhibitors
BRPI0810411B8 (pt) 2007-04-18 2021-05-25 Pfizer Prod Inc derivados de sulfonil amida para o tratamento de crescimento celular anormal, seu sos, bem como composição farmacêutica
WO2008129255A1 (en) * 2007-04-18 2008-10-30 Astrazeneca Ab 5-aminopyrazol-3-yl-3h-imidazo [4,5-b] pyridine derivatives and their use for the treatment of cancer
AU2008247592A1 (en) 2007-05-02 2008-11-13 Vertex Pharmaceuticals Incorporated Thiazoles and pyrazoles useful as kinase inhibitors
JP5389786B2 (ja) 2007-05-02 2014-01-15 バーテックス ファーマシューティカルズ インコーポレイテッド キナーゼ阻害として有用なアミノピリミジン
CN101679387A (zh) * 2007-05-02 2010-03-24 沃泰克斯药物股份有限公司 可用作激酶抑制剂的氨基嘧啶类化合物
US20100137398A1 (en) * 2007-05-04 2010-06-03 Novartis Ag Use of hdac inhibitors for the treatment of gastrointestinal cancers
UA99459C2 (en) * 2007-05-04 2012-08-27 Астразенека Аб 9-(pyrazol-3-yl)- 9h-purine-2-amine and 3-(pyraz0l-3-yl)-3h-imidazo[4,5-b]pyridin-5-amine derivatives and their use for the treatment of cancer
MX2009012719A (es) * 2007-05-24 2010-02-04 Vertex Pharma Tiazoles y pirazoles utiles como inhibidores de cinasa.
KR101294731B1 (ko) * 2007-06-04 2013-08-16 삼성디스플레이 주식회사 어레이 기판, 이를 갖는 표시패널 및 이의 제조방법
AU2008262291A1 (en) * 2007-06-11 2008-12-18 Miikana Therapeutics, Inc. Substituted pyrazole compounds
EP2178563A2 (en) * 2007-07-06 2010-04-28 OSI Pharmaceuticals, Inc. Combination anti-cancer therapy comprising an inhibitor of both mtorc1 and mtorc2
WO2009007753A2 (en) * 2007-07-11 2009-01-15 Astrazeneca Ab 4- (3-aminopyrazole) -pyrimidine derivativee and their use as tyrosine kinase inhibitors for the treatment of cancer
KR20100038108A (ko) * 2007-07-25 2010-04-12 브리스톨-마이어스 스큅 컴퍼니 트리아진 키나제 억제제
WO2009013545A2 (en) * 2007-07-26 2009-01-29 Astrazeneca Ab Chemical compounds
TW200906818A (en) * 2007-07-31 2009-02-16 Astrazeneca Ab Chemical compounds
CN101790532B (zh) * 2007-07-31 2013-11-20 沃泰克斯药物股份有限公司 5-氟-1H-吡唑并[3，4-b]吡啶-3-胺及其衍生物的制备方法
EP2025674A1 (de) 2007-08-15 2009-02-18 sanofi-aventis Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
WO2009027736A2 (en) * 2007-08-27 2009-03-05 Astrazeneca Ab 2,4 diaminopyrimid'lnes for the treatment of myeloproliferative disorders and cancer
AU2008305294B2 (en) 2007-09-21 2012-11-29 Array Biopharma Inc. Pyridin-2 -yl-amino-1, 2, 4 -thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus
JP5372943B2 (ja) 2007-10-11 2013-12-18 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー 新規ｓＥＨ阻害剤およびそれらの使用
WO2009078999A1 (en) 2007-12-17 2009-06-25 Janssen Pharmaceutica N.V. Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of trpv1
US20090270418A1 (en) * 2008-01-09 2009-10-29 Marianne Sloss Pyrazole pyrazine amine compounds as kinase inhibitors, compositions thereof and methods of treatment therewith
EP2242745A1 (de) * 2008-02-07 2010-10-27 Sanofi-Aventis Neue phenyl-substituierte imidazolidine, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
WO2009105500A1 (en) 2008-02-21 2009-08-27 Schering Corporation Compounds that are erk inhibitors
AU2009216062B2 (en) * 2008-02-22 2013-02-07 Msd K.K. Novel aminopyridine derivatives having Aurora A selective inhibitory action
AU2008355098B2 (en) 2008-04-21 2012-11-15 Gpcr Therapeutics, Inc Heterocyclic compounds
WO2010011411A1 (en) 2008-05-27 2010-01-28 The Trustees Of Columbia University In The City Of New York Systems, methods, and media for detecting network anomalies
KR20110017445A (ko) * 2008-06-11 2011-02-21 아스트라제네카 아베 암 및 골수증식성 장애의 치료에 유용한 트리시클릭 2,4-디아미노-ｌ,3,5-트리아진 유도체
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
AR073354A1 (es) * 2008-07-31 2010-11-03 Genentech Inc Compuestos de pirimidina, composiciones farmaceuticas y su uso en el tratamiento del cancer.
WO2010027921A1 (en) * 2008-09-03 2010-03-11 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical formulations comprising the same
JP2012501654A (ja) * 2008-09-05 2012-01-26 アビラ セラピューティクス， インコーポレイテッド 不可逆的インヒビターの設計のためのアルゴリズム
CN102227422A (zh) * 2008-09-30 2011-10-26 阿斯利康(瑞典)有限公司 杂环jak激酶抑制剂
US8759362B2 (en) * 2008-10-24 2014-06-24 Purdue Pharma L.P. Bicycloheteroaryl compounds and their use as TRPV1 ligands
WO2010056758A1 (en) * 2008-11-12 2010-05-20 Yangbo Feng Quinazoline derivatives as kinase inhibitors
WO2010056847A2 (en) 2008-11-13 2010-05-20 Taigen Biotechnology Co., Ltd. Lyophilization formulation
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
PA8851101A1 (es) 2008-12-16 2010-07-27 Lilly Co Eli Compuesto amino pirazol
US8524707B2 (en) * 2008-12-19 2013-09-03 Nerviano Medical Sciences S.R.L. Bicyclic pyrazoles as protein kinase inhibitors
RU2535032C2 (ru) 2008-12-22 2014-12-10 Милленниум Фармасьютикалз, Инк. Сочетание ингибиторов аврора киназы и анти-cd 20 антител
WO2010072155A1 (zh) * 2008-12-26 2010-07-01 复旦大学 一种嘧啶类衍生物及其制备方法和用途
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
AR075633A1 (es) * 2009-02-27 2011-04-20 Ambit Biosciences Corp Compuestos moduladores de jak quinasa y sus metodos de uso
CA2660962A1 (en) 2009-03-31 2010-09-30 Astellas Pharma Inc. Novel pharmaceutical composition for treatment of schizophrenia
US8399663B2 (en) 2009-04-03 2013-03-19 Astellas Pharma Inc. Salt of 1,3,5-triazine-2,4,6-triamine derivative
JO3635B1 (ar) 2009-05-18 2020-08-27 Millennium Pharm Inc مركبات صيدلانية صلبة وطرق لانتاجها
AU2010259023A1 (en) * 2009-06-08 2012-01-12 Nantbioscience, Inc. Triazine derivatives and their therapeutical applications
KR101460095B1 (ko) * 2009-06-08 2014-11-10 캘리포니아 캐피탈 에쿼티, 엘엘씨 트리아진 유도체와 이들의 치료적 용도
WO2010144394A1 (en) * 2009-06-09 2010-12-16 Abraxis Bioscience, Llc Benzyl substituted triazine derivatives and their therapeutical applications
KR101457027B1 (ko) 2009-06-09 2014-10-31 캘리포니아 캐피탈 에쿼티, 엘엘씨 트리아진 유도체와 이들의 치료적 용도
BRPI1011320A2 (pt) * 2009-06-09 2016-06-21 California Capital Equity Llc derivados de estiril-triazina e suas aplicações terapêuticas
AU2010258825B2 (en) * 2009-06-09 2014-08-21 Nantbio, Inc. Ureidophenyl substituted triazine derivatives and their therapeutical applications
EP2443106A1 (en) * 2009-06-18 2012-04-25 Cellzome Limited Heterocyclylaminopyrimidines as kinase inhibitors
US8637525B2 (en) 2009-07-31 2014-01-28 Bristol-Myers Squibb Company Compounds for the reduction of beta-amyloid production
TWI468402B (zh) * 2009-07-31 2015-01-11 必治妥美雅史谷比公司 降低β－類澱粉生成之化合物
MX2012001729A (es) 2009-08-26 2012-06-13 Sanofi Sa Nuevos hidratos cristalinos de fluoroglicosido heteroaromatico, productos farmaceuticos que comprenden estos compuestos, y su empleo.
NZ620174A (en) * 2009-09-16 2016-08-26 Celgene Avilomics Res Inc Protein kinase conjugates and inhibitors
KR101923049B1 (ko) * 2009-11-13 2018-11-28 인튜어티브 서지컬 오퍼레이션즈 인코포레이티드 여분의 닫힘 메커니즘을 구비한 단부 작동기
US9180127B2 (en) 2009-12-29 2015-11-10 Dana-Farber Cancer Institute, Inc. Type II Raf kinase inhibitors
EP2519664A4 (en) 2009-12-30 2014-03-12 Avila Therapeutics Inc LIGAND-RELATED COVALENTS MODIFYING A PROTEIN
SA111320200B1 (ar) * 2010-02-17 2014-02-16 ديبيوفارم اس ايه مركبات ثنائية الحلقة واستخداماتها كمثبطات c-src/jak مزدوجة
CA2788774A1 (en) 2010-02-19 2011-08-25 Millennium Pharmaceuticals, Inc. Crystalline forms of sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5h-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate
WO2011107494A1 (de) 2010-03-03 2011-09-09 Sanofi Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung
US20130059830A1 (en) * 2010-05-20 2013-03-07 Fa-Xiang Ding Novel prolylcarboxypeptidase inhibitors
US8927547B2 (en) 2010-05-21 2015-01-06 Noviga Research Ab Pyrimidine derivatives
WO2011157827A1 (de) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-on-derivate als inhibitoren von lipasen und phospholipasen
US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
TW201221505A (en) 2010-07-05 2012-06-01 Sanofi Sa Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament
TW201215387A (en) 2010-07-05 2012-04-16 Sanofi Aventis Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
WO2012013728A1 (en) 2010-07-29 2012-02-02 Oryzon Genomics S.A. Arylcyclopropylamine based demethylase inhibitors of lsd1 and their medical use
WO2012030918A1 (en) * 2010-09-01 2012-03-08 Ambit Biosciences Corporation Adenosine a3 receptor modulating compounds and methods of use thereof
EP2611794A1 (en) * 2010-09-01 2013-07-10 Ambit Biosciences Corporation 4-azolylaminoquinazoline derivatives and methods of use thereof
ES2579942T3 (es) 2010-09-01 2016-08-17 Ambit Biosciences Corporation Pirazolilaminoquinazolina ópticamente activa y composiciones farmacéuticas y métodos de uso de la misma
CN103270030B (zh) * 2010-09-01 2016-01-20 埃姆比特生物科学公司 吡唑基氨基喹唑啉的氢溴酸盐
US20130296363A1 (en) * 2010-09-01 2013-11-07 Ambit Biosciences Corporation Quinoline and isoquinoline derivatives for use as jak modulators
EP2611793A1 (en) * 2010-09-01 2013-07-10 Ambit Biosciences Corporation 2-cycloquinazoline derivatives and methods of use thereof
EP2683702B1 (de) 2011-03-08 2014-12-24 Sanofi Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
US8828995B2 (en) 2011-03-08 2014-09-09 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
EP2683701B1 (de) 2011-03-08 2014-12-24 Sanofi Mit benzyl- oder heteromethylengruppen substituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
US8871758B2 (en) 2011-03-08 2014-10-28 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120052A1 (de) 2011-03-08 2012-09-13 Sanofi Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
EP2683698B1 (de) 2011-03-08 2017-10-04 Sanofi Mit adamantan- oder noradamantan substituierte benzyl-oxathiazinderivate, diese verbindungen enthaltende arzneimittel und deren verwendung
EP2683699B1 (de) 2011-03-08 2015-06-24 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
US8895547B2 (en) 2011-03-08 2014-11-25 Sanofi Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
EP2683705B1 (de) 2011-03-08 2015-04-22 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
DK2688883T3 (en) 2011-03-24 2016-09-05 Noviga Res Ab pyrimidine
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2760862B1 (en) 2011-09-27 2015-10-21 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
CA2856291C (en) 2011-11-17 2020-08-11 Dana-Farber Cancer Institute, Inc. Inhibitors of c-jun-n-terminal kinase (jnk)
ES2655177T3 (es) * 2012-02-17 2018-02-19 Abbvie Inc. Diaminopirimidinas útiles como inhibidores del virus respiratorio sincitial (VRS) humano
TWI485146B (zh) * 2012-02-29 2015-05-21 Taiho Pharmaceutical Co Ltd Novel piperidine compounds or salts thereof
KR20140138293A (ko) 2012-03-16 2014-12-03 액시킨 파마수티컬스 인코포레이티드 3,5-다이아미노피라졸 키나아제 억제제
US20130303519A1 (en) 2012-03-20 2013-11-14 Millennium Pharmaceuticals, Inc. Methods of treating cancer using aurora kinase inhibitors
JP6378171B2 (ja) 2012-04-24 2018-08-22 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ Ｄｎａ−ｐｋ阻害剤
EP2855451B1 (en) * 2012-05-24 2017-10-04 Cellzome Limited Heterocyclyl pyrimidine analogues as tyk2 inhibitors
JP6280546B2 (ja) 2012-06-26 2018-02-14 デル マー ファーマシューティカルズ ジアンヒドロガラクチトール、ジアセチルジアンヒドロガラクチトール、ジブロモズルシトール、又はこれらの類似体若しくは誘導体を用いた、遺伝子多型又はａｈｉ１の調節不全若しくは変異を有する患者におけるチロシンキナーゼインヒビター抵抗性悪性腫瘍を処置するための方法
SG11201500005SA (en) * 2012-07-10 2015-01-29 Ares Trading Sa Pyrimidine pyrazolyl derivatives
MY183976A (en) * 2012-09-19 2021-03-17 Taiho Pharmaceutical Co Ltd Pharmaceutical composition for oral administration with improved dissolution and/or absorption
CN103059002B (zh) * 2012-12-31 2015-04-22 中山大学 具有Aurora激酶抑制活性的嘧啶衍生物及其制备方法以及应用
CN103191120B (zh) * 2012-12-31 2015-11-25 刘强 一种嘧啶衍生物在制备预防和/或治疗和/或辅助治疗肿瘤的药物中的用途
CN103202843B (zh) * 2012-12-31 2015-04-29 刘强 一种嘧啶衍生物在制备预防和/或治疗和/或辅助治疗癌症的药物中的用途
CN103910716A (zh) * 2013-01-07 2014-07-09 华东理工大学 2,4-二取代-环烷基[d]嘧啶类化合物及其用途
SI3527563T1 (sl) 2013-03-12 2022-01-31 Vertex Pharmaceuticals Incorporated Inhibitorji DNA-PK
EP3842424B1 (en) 2013-03-15 2024-12-11 The Trustees of Columbia University in the City of New York Map kinase modulators and uses thereof in the tretament of tauopathies
WO2014153509A1 (en) 2013-03-22 2014-09-25 Millennium Pharmaceuticals, Inc. Combination of catalytic mtorc 1/2 inhibitors and selective inhibitors of aurora a kinase
WO2015003355A2 (en) * 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
CN105764501A (zh) 2013-07-26 2016-07-13 现代化制药公司 改善比生群治疗效益的组合物
WO2015028848A1 (en) * 2013-09-02 2015-03-05 Piramal Enterprises Limited Bicyclic heterocyclic compounds as multi-kinase inhibitors
NZ631142A (en) 2013-09-18 2016-03-31 Axikin Pharmaceuticals Inc Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
RU2675270C2 (ru) 2013-10-17 2018-12-18 Вертекс Фармасьютикалз Инкорпорейтед Сокристаллы и содержащие их фармацевтические композиции
EP3057955B1 (en) 2013-10-18 2018-04-11 Syros Pharmaceuticals, Inc. Heteroaromatic compounds useful for the treatment of prolferative diseases
US10047070B2 (en) 2013-10-18 2018-08-14 Dana-Farber Cancer Institute, Inc. Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)
HRP20201384T1 (hr) 2014-01-01 2020-11-27 Medivation Technologies Llc Spojevi i postupci njihove upotrebe
US10258585B2 (en) 2014-03-13 2019-04-16 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
ES2967693T3 (es) 2014-03-13 2024-05-03 Neuroderm Ltd Composiciones del inhibidor de la dopa descarboxilasa
MX2016012574A (es) * 2014-03-28 2017-09-26 Calitor Sciences Llc Compuestos heteroarilo sustituidos y metodos de uso.
NZ725860A (en) 2014-04-04 2019-08-30 Iomet Pharma Ltd Indole derivatives for use in medicine
US20170165230A1 (en) 2014-04-09 2017-06-15 Christopher Rudd Use of gsk-3 inhibitors or activators which modulate pd-1 or t-bet expression to modulate t cell immunity
CN105367555B (zh) * 2014-08-07 2019-06-25 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
EP3929190B1 (en) 2014-10-13 2024-12-25 Yuhan Corporation Compounds and compositions for modulating egfr mutant kinase activities
US9546163B2 (en) 2014-12-23 2017-01-17 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
AU2015371251B2 (en) 2014-12-23 2020-06-11 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US10227343B2 (en) * 2015-01-30 2019-03-12 Vanderbilt University Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
HK1246645A1 (zh) 2015-03-27 2018-09-14 达纳-法伯癌症研究所股份有限公司 细胞周期蛋白依赖性激酶的抑制剂
AU2016247858B2 (en) 2015-04-17 2020-10-15 Ludwig Institute For Cancer Research Ltd. PLK4 inhibitors
JP6692836B2 (ja) 2015-05-28 2020-05-13 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Ｊａｋキナーゼ阻害剤としてのナフチリジン化合物
JP2018135268A (ja) * 2015-06-05 2018-08-30 大日本住友製薬株式会社 新規ヘテロアリールアミノ−３−ピラゾール誘導体およびその薬理学上許容される塩
JP2018524292A (ja) 2015-07-21 2018-08-30 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． オーロラキナーゼインヒビターと化学療法剤の投与
EP3347018B1 (en) 2015-09-09 2021-09-01 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
WO2017044434A1 (en) 2015-09-11 2017-03-16 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
EA201800367A1 (ru) * 2015-12-10 2019-02-28 ПиТиСи ТЕРАПЬЮТИКС, ИНК. Способы лечения болезни хантингтона
CN105399695B (zh) * 2015-12-11 2019-04-19 浙江大学 三嗪类化合物及其制备方法和用途
CN105384702B (zh) * 2015-12-11 2018-04-10 浙江大学 三取代均三嗪类化合物及其制备方法
CN105503754B (zh) * 2015-12-11 2017-11-17 浙江大学 2‑氨基‑4‑苄基‑6‑吗啉‑1,3,5‑三嗪及其制备和应用
WO2017102091A1 (en) 2015-12-18 2017-06-22 Bayer Pharma Aktiengesellschaft Heteroarylbenzimidazole compounds
MA43821A (fr) 2016-03-14 2018-11-28 Afferent Pharmaceuticals Inc Pyrimidines et variantes de celles-ci, et leurs utilisations
MA44489A (fr) 2016-03-25 2019-01-30 Afferent Pharmaceuticals Inc Pyrimidines et variants de celles-ci, et leurs utilisations
MX377180B (es) 2016-04-28 2025-03-07 Theravance Biopharma R&D Ip Llc Compuestos de pirimidina como inhibidores de la quinasa jak.
WO2017207534A1 (en) 2016-06-03 2017-12-07 Bayer Pharma Aktiengesellschaft Substituted heteroarylbenzimidazole compounds
RU2758669C2 (ru) 2016-09-27 2021-11-01 Вертекс Фармасьютикалз Инкорпорейтед Способ лечения рака с применением сочетания днк-поражающих агентов и ингибиторов днк-пк
US10858319B2 (en) 2016-10-03 2020-12-08 Iomet Pharma Ltd. Indole derivatives for use in medicine
US10968227B2 (en) * 2016-11-08 2021-04-06 Vanderbilt University Isoquinoline ether compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
CN108239071B (zh) * 2016-12-27 2020-12-04 沈阳药科大学 酰胺及硫代酰胺类衍生物及其制备方法和应用
FR3064275B1 (fr) 2017-03-21 2019-06-07 Arkema France Procede de chauffage et/ou climatisation d'un vehicule
EA201992764A1 (ru) 2017-05-30 2020-04-29 Басф Се Пиридиновые и пиразиновые соединения
EP3634953B1 (en) 2017-06-05 2024-01-03 PTC Therapeutics, Inc. Compounds for treating huntington's disease
MX2019015580A (es) 2017-06-28 2020-07-28 Ptc Therapeutics Inc Metodos para tratar la enfermedad de huntington.
CN111182898B (zh) 2017-06-28 2024-04-16 Ptc医疗公司 用于治疗亨廷顿氏病的方法
WO2019000682A1 (zh) * 2017-06-30 2019-01-03 北京泰德制药股份有限公司 Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途
CN110582489B (zh) 2017-06-30 2023-10-27 北京泰德制药股份有限公司 Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途
US10323023B2 (en) 2017-06-30 2019-06-18 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
EP3675860B1 (en) * 2017-08-28 2023-03-08 Zhihong, Chen Substituted pyrimidines, pharmaceutical compositions and therapeutic methods thereof
WO2019046316A1 (en) * 2017-08-28 2019-03-07 Acurastem Inc. PIKFYVE KINASE INHIBITORS
HRP20221221T1 (hr) 2017-10-27 2022-12-09 Theravance Biopharma R&D Ip, Llc Pirimidinski spoj kao inhibitor jak kinaze
KR20200090198A (ko) * 2017-11-23 2020-07-28 바이오메드 엑스 게엠베하 트로포미오신 수용체 키나제 A(TrkA) 저해제로서의 피리미딘 유도체
EP3720560A4 (en) * 2017-12-06 2022-01-05 Ludwig Institute for Cancer Research Ltd METHOD OF TREATMENT OF CANCER WITH PLK4 INHIBITORS
KR20200143376A (ko) 2018-03-13 2020-12-23 샤이어 휴먼 지네틱 테라피즈 인크. 혈장 칼리크레인 억제제로서의 치환된 이미다조피리딘 및 이의 용도
EA202092001A1 (ru) 2018-03-27 2021-01-29 ПиТиСи ТЕРАПЬЮТИКС, ИНК. Соединения для лечения болезни гентингтона
US12187701B2 (en) 2018-06-25 2025-01-07 Dana-Farber Cancer Institute, Inc. Taire family kinase inhibitors and uses thereof
HRP20240935T1 (hr) 2018-06-27 2024-11-22 Ptc Therapeutics, Inc. Heterociklični i heteroaril spojevi za liječenje huntingtonove bolesti
EP3814360B8 (en) 2018-06-27 2024-11-06 PTC Therapeutics, Inc. Heteroaryl compounds for treating huntington's disease
WO2020005877A1 (en) 2018-06-27 2020-01-02 Ptc Therapeutics, Inc. Heteroaryl compounds for treating huntington's disease
KR102919209B1 (ko) 2018-08-10 2026-01-28 다이아핀 테라퓨틱스, 엘엘씨 트리-펩타이드 그리고 대사, 심장혈관 및 염증성 장애의 치료
JP2022510980A (ja) * 2018-11-30 2022-01-28 江▲蘇▼豪森▲薬▼▲業▼集▲団▼有限公司 ヘテロ芳香族誘導体調節因子、その製造方法及び使用
JP7660063B2 (ja) 2018-12-28 2025-04-10 ダナ－ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼ７のインヒビターおよびそれらの使用
TW202106681A (zh) 2019-04-24 2021-02-16 美商施萬生物製藥研發Ｉｐ有限責任公司 用於治療皮膚疾病之嘧啶jak抑制劑
EP3958969B1 (en) 2019-04-24 2024-01-10 Theravance Biopharma R&D IP, LLC Ester and carbonate pyrimidine compounds as jak kinase inhibitors
JP7649257B2 (ja) 2019-05-13 2025-03-19 ピーティーシー セラピューティクス， インコーポレイテッド ハンチントン病を処置するための化合物
US12428395B2 (en) 2019-08-01 2025-09-30 Sperogenix Therapeutics Limited Heterocyclic compounds as kinase inhibitor and uses thereof
CN114667289B (zh) 2019-09-18 2025-08-26 武田药品工业有限公司 杂芳基血浆激肽释放酶抑制剂
EP4031547B1 (en) 2019-09-18 2024-07-17 Takeda Pharmaceutical Company Limited Plasma kallikrein inhibitors and uses thereof
CN110483493A (zh) * 2019-09-19 2019-11-22 广东工业大学 一种二唑类衍生物及其制备方法和应用
KR20220140515A (ko) 2020-01-13 2022-10-18 버지 애널리틱스, 인크. 치환된 피라졸로-피리미딘 및 그의 용도
US11213502B1 (en) 2020-11-17 2022-01-04 Neuroderm, Ltd. Method for treatment of parkinson's disease
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease
US11331293B1 (en) 2020-11-17 2022-05-17 Neuroderm, Ltd. Method for treatment of Parkinson's disease
TW202237119A (zh) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Ａｌｋ﹘５抑制劑和彼之用途
EP4308564A1 (en) * 2021-03-17 2024-01-24 Takeda Pharmaceutical Company Limited Polycyclic inhibitors of plasma kallikrein
KR20230160350A (ko) * 2021-03-24 2023-11-23 아토스 테라퓨틱스, 인크. 키나제-관련 질환의 치료를 위한 소분자
CN117355304A (zh) * 2021-03-26 2024-01-05 住友制药肿瘤公司 Alk-5抑制剂及其用途
CA3213359A1 (en) * 2021-03-26 2022-09-29 Bettina FRANZ Alk-5 inhibitors and uses thereof
MX2023013225A (es) 2021-05-11 2024-01-15 Oric Pharmaceuticals Inc Inhibidores de la cinasa 4 similar a polo.
US11932648B2 (en) 2021-06-28 2024-03-19 Blueprint Medicines Corporation CDK2 inhibitors
KR102692529B1 (ko) * 2021-07-01 2024-08-08 한국원자력의학원 Mastl-pp2a를 표적화하는 암의 예방 또는 치료용 약학적 조성물
CN114276302B (zh) * 2022-01-11 2023-07-25 山东百启生物医药有限公司 一种制备2,4-二氨基喹唑啉衍生物的方法
CN116813595B (zh) * 2022-03-28 2025-07-18 上海医药工业研究院有限公司 喹唑啉类衍生物、其制备方法、药物组合物及应用
WO2024003773A1 (en) 2022-07-01 2024-01-04 Pfizer Inc. 2,7-naphthyridine compounds as mastl inhibitors
CN117736198A (zh) * 2022-09-21 2024-03-22 科辉智药生物科技(深圳)有限公司 大环含氮冠醚化合物及其作为蛋白激酶抑制剂的应用
CN115403568B (zh) * 2022-09-21 2023-09-29 中山大学 一种喹唑啉类Aurora A共价抑制剂及其制备方法和应用
US20240317777A1 (en) * 2023-02-23 2024-09-26 Accutar Biotechnology Inc. Novel macrocyclic aminopyrazole compounds as cdk2 inhibitors
US12161612B2 (en) 2023-04-14 2024-12-10 Neuroderm, Ltd. Methods and compositions for reducing symptoms of Parkinson's disease
WO2026024674A1 (en) 2024-07-22 2026-01-29 Genesis Therapeutics, Inc. Methods of treating skp2-associated cancers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021955A1 (en) * 1998-10-08 2000-04-20 Astrazeneca Ab Quinazoline derivatives
WO2000039101A1 (en) * 1998-12-24 2000-07-06 Astrazeneca Ab Pyrimidine compounds
WO2001060816A1 (en) * 2000-02-17 2001-08-23 Amgen Inc. Kinase inhibitors

Family Cites Families (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2585906A (en) 1952-02-12 Quaternary salts of pyrimdjines
US18436A (en) * 1857-10-20 And saml
US3133081A (en) 1964-05-12 J-aminoindazole derivatives
US3935183A (en) 1970-01-26 1976-01-27 Imperial Chemical Industries Limited Indazole-azo phenyl compounds
BE754242A (fr) 1970-07-15 1971-02-01 Geigy Ag J R Diamino-s-triazines et dinitro-s-triazines
US3755332A (en) * 1971-07-01 1973-08-28 Ciba Geigy Corp Substituted 4 indazolaminoquinolines
US3998951A (en) 1974-03-13 1976-12-21 Fmc Corporation Substituted 2-arylquinazolines as fungicides
DE2458965C3 (de) 1974-12-13 1979-10-11 Bayer Ag, 5090 Leverkusen 3-Amino-indazol-N-carbonsäure-Derivate, Verfahren zu ihrer Herstellung sowie sie enthaltende Arzneimittel
MA18829A1 (fr) 1979-05-18 1980-12-31 Ciba Geigy Ag Derives de la pyrimidine,procedes pour leur preparation,compositions pharmaceutiques contenant ces composes et leur utilisation therapeutique
DOP1981004033A (es) * 1980-12-23 1990-12-29 Ciba Geigy Ag Procedimiento para proteger plantas de cultivo de la accion fitotoxica de herbicidas.
SE8102194L (sv) 1981-04-06 1982-10-07 Pharmacia Ab Terapeutiskt aktiv organisk forening och farmaceutisk beredning innehallande denna
SE8102193L (sv) 1981-04-06 1982-10-07 Pharmacia Ab Terapeutiskt aktiv organisk forening och dess anvendning
JPS58124773A (ja) 1982-01-20 1983-07-25 Mitsui Toatsu Chem Inc ５−メチルチオピリミジン誘導体とその製造法と農園芸用殺菌剤
EP0136976A3 (de) 1983-08-23 1985-05-15 Ciba-Geigy Ag Verwendung von Phenylpyrimidinen als Pflanzenregulatoren
DE3725638A1 (de) 1987-08-03 1989-02-16 Bayer Ag Neue aryloxy (bzw. thio)aminopyrimidine
JPH0532662A (ja) 1990-11-09 1993-02-09 Nissan Chem Ind Ltd 置換ピラゾール誘導体および農園芸用殺菌剤
US5714493A (en) * 1991-05-10 1998-02-03 Rhone-Poulenc Rorer Pharmaceuticals, Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US5710158A (en) 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5597920A (en) 1992-04-30 1997-01-28 Neurogen Corporation Gabaa receptor subtypes and methods for screening drug compounds using imidazoquinoxalines and pyrrolopyrimidines to bind to gabaa receptor subtypes
JPH0665237A (ja) 1992-05-07 1994-03-08 Nissan Chem Ind Ltd 置換ピラゾール誘導体および農園芸用殺菌剤
WO1995009851A1 (en) 1993-10-01 1995-04-13 Ciba-Geigy Ag Pharmacologically active pyrimidineamine derivatives and processes for the preparation thereof
WO1996014843A2 (en) 1994-11-10 1996-05-23 Cor Therapeutics, Inc. Pharmaceutical pyrazole compositions useful as inhibitors of protein kinases
IL117659A (en) 1995-04-13 2000-12-06 Dainippon Pharmaceutical Co Substituted 2-phenyl pyrimidino amino acetamide derivative process for preparing the same and a pharmaceutical composition containing same
CA2230896A1 (en) 1995-09-01 1997-03-13 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
US5935966A (en) 1995-09-01 1999-08-10 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
GB9523675D0 (en) 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds
US6716575B2 (en) 1995-12-18 2004-04-06 Sugen, Inc. Diagnosis and treatment of AUR1 and/or AUR2 related disorders
ID19609A (id) 1996-07-13 1998-07-23 Glaxo Group Ltd Senyawa-senyawa heterosiklik
JPH10130150A (ja) 1996-09-05 1998-05-19 Dainippon Pharmaceut Co Ltd 酢酸アミド誘導体からなる医薬
GB9619284D0 (en) 1996-09-16 1996-10-30 Celltech Therapeutics Ltd Chemical compounds
US6251911B1 (en) 1996-10-02 2001-06-26 Novartis Ag Pyrimidine derivatives and processes for the preparation thereof
WO1998016502A1 (en) 1996-10-11 1998-04-23 Warner-Lambert Company ASPARTATE ESTER INHIBITORS OF INTERLEUKIN-1β CONVERTING ENZYME
DE19710435A1 (de) * 1997-03-13 1998-09-17 Hoechst Ag Verwendung von Pyrimidinderivaten zur Prävention von Krebs allein oder in Kombination mit anderen therapeutischen Maßnahmen
EP1033910A4 (en) 1997-10-10 2004-11-24 Cytovia Inc DIPEPTIDE APOPTOSE INHIBITORS AND THEIR USE
US6267952B1 (en) 1998-01-09 2001-07-31 Geltex Pharmaceuticals, Inc. Lipase inhibiting polymers
JP2000026421A (ja) 1998-01-29 2000-01-25 Kumiai Chem Ind Co Ltd ジアリ―ルスルフィド誘導体及び有害生物防除剤
BR9908004A (pt) 1998-02-17 2001-12-18 Tularik Inc Composto, composição e método para prevençãoou supressão de uma infecção viral
CN1297354A (zh) 1998-03-16 2001-05-30 西托维亚公司 二肽卡斯帕酶抑制剂及其用途
YU76100A (sh) 1998-06-02 2003-12-31 Osi Pharmaceuticals Inc. Pirolo(2,3-d) pirimidin preparati i njihova primena
KR100581199B1 (ko) * 1998-06-19 2006-05-17 카이론 코포레이션 글리코겐 신타제 키나제 3의 억제제
WO2000003901A1 (de) * 1998-07-16 2000-01-27 Continental Teves Ag & Co. Ohg Verfahren und vorrichtung zum ermitteln von kritischen fahrzuständen bei im fahrbetrieb befindlichen fahrzeugen
CA2339188A1 (en) 1998-08-21 2000-03-02 Dupont Pharmaceuticals Company Isoxazolo¬4,5-d|pyrimidines as crf antagonists
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
GB9828640D0 (en) 1998-12-23 1999-02-17 Smithkline Beecham Plc Novel method and compounds
HUP0105092A3 (en) 1999-01-13 2003-12-29 Warner Lambert Co 1-heterocycle substituted diarylamines and medicaments containing them
GB9905075D0 (en) * 1999-03-06 1999-04-28 Zeneca Ltd Chemical compounds
WO2000059509A1 (en) 1999-03-30 2000-10-12 Novartis Ag Phthalazine derivatives for treating inflammatory diseases
WO2000078757A1 (en) 1999-06-17 2000-12-28 Shionogi Bioresearch Corp. Inhibitors of il-12 production
GB9914258D0 (en) 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
MXPA02001565A (es) 1999-08-13 2005-07-14 Vertex Pharma Inhibidores de cinasas c-jun n-terminal (jnk) y de otras cinasas proteicas.
WO2001025220A1 (en) 1999-10-07 2001-04-12 Amgen Inc. Triazine kinase inhibitors
TR200201431T2 (tr) 1999-11-30 2002-09-23 Pfizer Products Inc. İmünosupresanlar olarak faydalı 2,4-diaminopirimidin bileşikleri
KR100840727B1 (ko) 1999-12-02 2008-06-23 오에스아이 파마슈티컬스, 인코포레이티드 아데노신 ａ1, ａ2ａ 및 ａ3 수용체 특이 화합물 및 그의 사용방법
MY125768A (en) 1999-12-15 2006-08-30 Bristol Myers Squibb Co N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
US6376489B1 (en) 1999-12-23 2002-04-23 Icos Corporation Cyclic AMP-specific phosphodiesterase inhibitors
US20020065270A1 (en) 1999-12-28 2002-05-30 Moriarty Kevin Joseph N-heterocyclic inhibitors of TNF-alpha expression
CA2394727A1 (en) 1999-12-28 2001-07-05 Pharmacopeia, Inc. Pyrimidine and triazine kinase inhibitors
HUP0202332A2 (en) 2000-02-05 2002-10-28 Vertex Pharma Pyrazole compositions useful as inhibitors of erk
GB0004887D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004890D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
AU2001251165A1 (en) 2000-04-03 2001-10-15 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease
JP2004501083A (ja) 2000-04-18 2004-01-15 アゴーロン・ファーマシューティカルズ・インコーポレイテッド プロテインキナーゼを阻害するためのピラゾール
JP3890184B2 (ja) * 2000-05-15 2007-03-07 Ｎｅｃパーソナルプロダクツ株式会社 電源装置及びその電力制御方法、情報処理機器
ATE394102T1 (de) 2000-06-28 2008-05-15 Astrazeneca Ab Substituierte chinazolin-derivate und deren verwendung als aurora-2-kinase inhibitoren
CN1498224A (zh) 2000-07-21 2004-05-19 ���鹫˾ 用作丙型肝炎病毒ns3-丝氨酸蛋白酶抑制剂的新型肽
IL154016A0 (en) 2000-08-31 2003-07-31 Pfizer Prod Inc Pyrazole derivatives and their use as protein kinase inhibitors
US6660731B2 (en) 2000-09-15 2003-12-09 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
EP1317450B1 (en) 2000-09-15 2006-11-22 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
ATE335737T1 (de) 2000-09-15 2006-09-15 Vertex Pharma Isoxazole und ihre verwendung als erk-inhibitoren
US7473691B2 (en) 2000-09-15 2009-01-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6610677B2 (en) 2000-09-15 2003-08-26 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6613776B2 (en) 2000-09-15 2003-09-02 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
WO2002024667A1 (en) 2000-09-20 2002-03-28 Merck Patent Gmbh 4-amino-quinazolines
US6641579B1 (en) 2000-09-29 2003-11-04 Spectrasonics Imaging, Inc. Apparatus and method for ablating cardiac tissue
DE10061863A1 (de) 2000-12-12 2002-06-13 Basf Ag Verfahren zur Herstellung von Triethylendiamin (TEDA)
AU2002228922A1 (en) 2000-12-12 2002-06-24 Cytovia, Inc. Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US6716851B2 (en) 2000-12-12 2004-04-06 Cytovia, Inc. Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators or caspases and inducers of apoptosis and the use thereof
NZ526472A (en) * 2000-12-21 2004-04-30 Vertex Pharma Pyrazole compounds useful as protein kinase inhibitors
MY130778A (en) 2001-02-09 2007-07-31 Vertex Pharma Heterocyclic inhibitiors of erk2 and uses thereof
EP1373257B9 (en) 2001-03-29 2008-10-15 Vertex Pharmaceuticals Incorporated Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases
MXPA03009378A (es) 2001-04-13 2004-01-29 Vertex Pharma Inhibidores de cinasas c-jun n-terminales (jnk) y otras proteinas cinasas.
US20030096813A1 (en) 2001-04-20 2003-05-22 Jingrong Cao Compositions useful as inhibitors of GSK-3
AU2002308748A1 (en) 2001-05-16 2002-11-25 Vertex Pharmaceuticals Incorporated Heterocyclic substituted pyrazoles as inhibitors of src and other protein kinases
US6825190B2 (en) 2001-06-15 2004-11-30 Vertex Pharmaceuticals Incorporated Protein kinase inhibitors and uses thereof
WO2003004492A1 (en) 2001-07-03 2003-01-16 Vertex Pharmaceuticals Incorporated Isoxazolyl-pyrimidines as inhibitors of src and lck protein kinases
WO2003026664A1 (en) * 2001-09-26 2003-04-03 Bayer Corporation 2-phenylamino-4- (5-pyrazolylamino) -pyramidine derivatives as kinase inhibitors, in particular, src kinase inhibitors
US6569499B2 (en) 2001-10-02 2003-05-27 Xerox Corporation Apparatus and method for coating photoreceptor substrates
DE60236322D1 (de) 2001-12-07 2010-06-17 Vertex Pharma Verbindungen auf pyrimidin-basis als gsk-3-hemmer
WO2003078423A1 (en) 2002-03-15 2003-09-25 Vertex Pharmaceuticals, Inc. Compositions useful as inhibitors of protein kinases
EP1485100B1 (en) 2002-03-15 2010-05-05 Vertex Pharmaceuticals Incorporated Azinylaminoazoles as inhibitors of protein kinases
AU2003218215A1 (en) 2002-03-15 2003-09-29 Vertex Pharmaceuticals, Inc. Azolylaminoazines as inhibitors of protein kinases
DE60327999D1 (de) 2002-03-15 2009-07-30 Vertex Pharma Azolylaminoazine als inhibitoren von proteinkinasen
US20030207873A1 (en) 2002-04-10 2003-11-06 Edmund Harrington Inhibitors of Src and other protein kinases
AU2003237121A1 (en) 2002-04-26 2003-11-10 Vertex Pharmaceuticals Incorporated Pyrrole derivatives as inhibitors of erk2 and uses thereof
MY141867A (en) 2002-06-20 2010-07-16 Vertex Pharma Substituted pyrimidines useful as protein kinase inhibitors
CA2491895C (en) 2002-07-09 2011-01-18 Vertex Pharmaceuticals Incorporated Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases
DK1532145T3 (da) 2002-08-02 2007-01-15 Vertex Pharma Pyrazolpræparater der er anvendelige som inhibitorer af GSK-3
CA2622352C (en) 2005-09-30 2014-05-27 Miikana Therapeutics, Inc. Substituted pyrazole compounds
NZ577768A (en) 2006-12-19 2012-01-12 Vertex Pharma Aminopyrimidines useful as inhibitors of protein kinases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021955A1 (en) * 1998-10-08 2000-04-20 Astrazeneca Ab Quinazoline derivatives
WO2000039101A1 (en) * 1998-12-24 2000-07-06 Astrazeneca Ab Pyrimidine compounds
WO2001060816A1 (en) * 2000-02-17 2001-08-23 Amgen Inc. Kinase inhibitors

Cited By (113)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6982260B1 (en) 1999-11-22 2006-01-03 Warner-Lambert Company Quinazolines and their use for inhibiting cyclin-dependent kinase enzymes
US7531536B2 (en) 2000-12-21 2009-05-12 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
EP1820503A2 (en) 2001-09-26 2007-08-22 Pfizer Italia S.r.l. Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
WO2003026666A1 (en) * 2001-09-26 2003-04-03 Bayer Pharmaceuticals Corporation 2-phenylamino-4- (5-pyrazolylamino)-pyrimidine derivatives as kinase inhibitors, in particular, as src kinase inhibitors
WO2003028720A1 (en) * 2001-09-26 2003-04-10 Pharmacia Italia S.P.A. Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
WO2003026665A1 (en) * 2001-09-26 2003-04-03 Bayer Pharmaceuticals Corporation 2-phenylamino-4-(5-pyrazolylamino)-pyrimidine derivatives as kinase inhibitors, in particular, src kinase inhibitors
US7511136B2 (en) 2001-09-26 2009-03-31 Pfizer Italia S.R.L. Aminoindazole derivatives active as kinase inhibitors
EP1820503A3 (en) * 2001-09-26 2008-05-21 Pfizer Italia S.r.l. Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them
EA007430B1 (ru) * 2001-09-26 2006-10-27 Фармация Италия С.П.А. Производные аминоиндазола, активные в качестве ингибиторов киназ, способ их получения и содержащая их фармацевтическая композиция
US7485724B2 (en) 2002-02-01 2009-02-03 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7589200B2 (en) 2002-02-01 2009-09-15 Rigel Pharmaceuticals, Inc. 5-Fluoro-4N-phenyl-4-pyrimidineamine compounds
US10709703B2 (en) 2002-02-01 2020-07-14 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7820819B2 (en) 2002-02-01 2010-10-26 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US10682350B2 (en) 2002-02-01 2020-06-16 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7655797B2 (en) 2002-02-01 2010-02-02 Rigel Pharmaceuticals, Inc. Intermediates for making 2,4-pyrimidinediamine compounds
US7329672B2 (en) 2002-02-01 2008-02-12 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7329671B2 (en) 2002-02-01 2008-02-12 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7332484B2 (en) 2002-02-01 2008-02-19 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US9913842B2 (en) 2002-02-01 2018-03-13 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7642351B2 (en) 2002-02-01 2010-01-05 Rogel Pharmaceuticals, Inc. 2,4-Pyrimidinediamine compounds and their uses
US9018204B1 (en) 2002-02-01 2015-04-28 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US8334296B2 (en) 2002-02-01 2012-12-18 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7803939B2 (en) 2002-02-01 2010-09-28 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US9416112B2 (en) 2002-02-01 2016-08-16 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7435814B2 (en) 2002-02-01 2008-10-14 Rigel Pharmaceuticals, Inc. 2,4-Pyrimidinediamine compounds and their uses
US7557210B2 (en) 2002-02-01 2009-07-07 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US9346765B2 (en) 2002-02-01 2016-05-24 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US8835430B2 (en) 2002-02-01 2014-09-16 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7498435B2 (en) 2002-02-01 2009-03-03 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7550460B2 (en) 2002-02-01 2009-06-23 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7524852B2 (en) 2002-06-07 2009-04-28 Kyowa Hakko Kogyo Co., Ltd. Bicyclic pyrimidine derivatives
US7557106B2 (en) 2002-06-20 2009-07-07 Vertex Pharmaceuticals Incorporated Substituted pyrimidines useful as protein kinase inhibitors
US7517886B2 (en) 2002-07-29 2009-04-14 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7825116B2 (en) 2002-07-29 2010-11-02 Rigel Pharmaceuticals, Inc. N2, N4-bis-aryl-5-fluoro-2,4-pyrimidinediamines
US7812029B1 (en) 2002-07-29 2010-10-12 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
JP2006514619A (ja) * 2002-11-14 2006-05-11 サイクラセル・リミテッド ピリミジン化合物
WO2004048365A1 (en) * 2002-11-21 2004-06-10 Chiron Corporation 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
EP2316831A1 (en) * 2002-11-21 2011-05-04 Novartis AG 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer
US7423148B2 (en) 2002-11-21 2008-09-09 Chiron Corporation Small molecule PI 3-kinase inhibitors and methods of their use
US7767669B2 (en) 2002-11-21 2010-08-03 Novartis Ag Small molecule PI 3-kinase inhibitors and methods of their use
EA013811B1 (ru) * 2002-11-21 2010-08-30 Новартис Вэксинес Энд Дайэгностикс, Инк. 2,4,6-тризамещённые пиримидины, являющиеся ингибиторами фосфотидилинозитол(pi)-3-киназы, и их применение при лечении рака
JP2006514118A (ja) * 2002-11-21 2006-04-27 カイロン コーポレイション ホスホチジルイノシトール（ｐｉ）３−キナーゼインヒビターとしての２，４，６−三置換ピリミジン、および癌の処置におけるその使用
US7560466B2 (en) 2003-07-30 2009-07-14 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7122542B2 (en) 2003-07-30 2006-10-17 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US9751893B2 (en) 2003-07-30 2017-09-05 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US8178671B2 (en) 2003-07-30 2012-05-15 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2, 4-pyrimidinediamine compounds
US7582648B2 (en) 2003-07-30 2009-09-01 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7452879B2 (en) 2003-07-30 2008-11-18 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7572914B2 (en) 2003-12-19 2009-08-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
US7414131B2 (en) 2003-12-24 2008-08-19 Renovis, Inc. Bicycloheteroarylamine compounds as ion channel ligands and uses thereof
JPWO2005087710A1 (ja) * 2004-03-15 2008-01-24 武田薬品工業株式会社 アミノフェニルプロパン酸誘導体
US7550598B2 (en) 2004-08-18 2009-06-23 Takeda Pharmaceutical Company Limited Kinase inhibitors
US7226923B2 (en) 2004-09-24 2007-06-05 Hoffman-La Roche Inc. Phthalazinone derivatives
US7285569B2 (en) 2004-09-24 2007-10-23 Hoff Hoffmann-La Roche Inc. Tricycles, their manufacture and use as pharmaceutical agents
US7793137B2 (en) 2004-10-07 2010-09-07 Cisco Technology, Inc. Redundant power and data in a wired data telecommunincations network
US8288536B2 (en) 2004-10-15 2012-10-16 Takeda Pharmaceutical Company Limited Kinase inhibitors
US7713973B2 (en) 2004-10-15 2010-05-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
US8153630B2 (en) 2004-11-17 2012-04-10 Miikana Therapeutics, Inc. Kinase inhibitors
US7851480B2 (en) 2004-11-24 2010-12-14 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
US7557207B2 (en) 2004-11-24 2009-07-07 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
US8211929B2 (en) 2004-12-30 2012-07-03 Exelixis, Inc. Pyrimidine derivatives as kinase modulators and method of use
EP2383268A1 (en) 2005-02-04 2011-11-02 AstraZeneca AB Pyrazolylaminopyridine derivatives useful as kinase inhibitors
US7297700B2 (en) 2005-03-24 2007-11-20 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US7462639B2 (en) 2005-04-14 2008-12-09 Hoffmann-La Roche Inc. Aminopyrazole derivatives
WO2006115452A1 (en) * 2005-04-27 2006-11-02 Astrazeneca Ab Use of pyrazolyl-pyrimidine derivatives in the treatment of pain
US8859545B2 (en) 2005-05-04 2014-10-14 Evotec Ag Tetrahydronaphthyridine and tetrahydropyrido[4,3-D]pyrimidine compounds and compositions thereof useful for the treatment of inflammatory and respiratory diseases
US7745451B2 (en) 2005-05-04 2010-06-29 Renovis, Inc. Tetrahydronaphthyridine and tetrahydropyrido[4,3-d]pyrimidine compounds and compositions thereof useful in the treatment of conditions associated with neurological and inflammatory disorders and dysfunctions
US9732073B2 (en) 2005-06-08 2017-08-15 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US10421752B2 (en) 2005-06-08 2019-09-24 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US11198689B2 (en) 2005-06-08 2021-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US9593082B2 (en) 2005-06-08 2017-03-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US11827628B2 (en) 2005-06-08 2023-11-28 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US9248190B2 (en) 2005-06-08 2016-02-02 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8399472B2 (en) 2005-06-08 2013-03-19 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8415365B2 (en) 2005-06-08 2013-04-09 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8114870B2 (en) 2005-09-30 2012-02-14 Miikana Therapeutics, Inc. Method of treating disease states using substituted pyrazole compounds
US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
EP2388259A1 (en) 2005-10-28 2011-11-23 AstraZeneca AB 4- (3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer
US7528142B2 (en) 2005-11-03 2009-05-05 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
US7572809B2 (en) 2005-12-19 2009-08-11 Hoffmann-La Roche Inc. Isoquinoline aminopyrazole derivatives
US8217035B2 (en) 2006-01-20 2012-07-10 Novartis Ag Pyrimidine derivatives used as PI-3-kinase inhibitors
US8563549B2 (en) 2006-01-20 2013-10-22 Novartis Ag Pyrimidine derivatives used as PI-3 kinase inhibitors
US11667611B2 (en) 2006-02-24 2023-06-06 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8222256B2 (en) 2006-07-05 2012-07-17 Exelixis, Inc. Methods of using IGFIR and ABL kinase modulators
US7915263B2 (en) 2006-08-31 2011-03-29 Banyu Pharmaceutical Co., Ltd. Aminopyridine derivatives having aurora A selective inhibitory action
WO2008044045A1 (en) 2006-10-12 2008-04-17 Astex Therapeutics Limited Pharmaceutical combinations
WO2008044041A1 (en) 2006-10-12 2008-04-17 Astex Therapeutics Limited Pharmaceutical combinations
US8173647B2 (en) 2007-02-06 2012-05-08 Gordana Atallah PI 3-kinase inhibitors and methods of their use
WO2008111441A1 (ja) 2007-03-05 2008-09-18 Kyowa Hakko Kirin Co., Ltd. 医薬組成物
US8278450B2 (en) 2007-04-18 2012-10-02 Takeda Pharmaceutical Company Limited Kinase inhibitors
WO2010031056A3 (en) * 2008-09-15 2010-08-05 The Regents Of The University Of California Methods and compositions for modulating ire1, src, and abl activity
CN102264728B (zh) * 2008-09-15 2015-02-04 加利福尼亚大学董事会 用于调节ire1、src和abl活性的方法和组合物
US9382230B2 (en) 2008-09-15 2016-07-05 The Regents Of The University Of California Methods and compositions for modulating Ire1, SRC and ABL activity
CN102264728A (zh) * 2008-09-15 2011-11-30 加利福尼亚大学董事会 用于调节ire1、src和abl活性的方法和组合物
US8815885B2 (en) 2008-09-15 2014-08-26 The Regents Of The University Of California Methods and compositions for modulating IRE1, SRC, and ABL activity
US8354420B2 (en) 2010-06-04 2013-01-15 Genentech, Inc. Aminopyrimidine derivatives as LRRK2 inhibitors
US8633207B2 (en) 2010-09-01 2014-01-21 Ambit Biosciences Corporation Quinazoline compounds and methods of use thereof
WO2012059932A1 (en) 2010-11-01 2012-05-10 Aurigene Discovery Technologies Limited 2, 4 -diaminopyrimidine derivatives as protein kinase inhibitors
US8815882B2 (en) 2010-11-10 2014-08-26 Genentech, Inc. Pyrazole aminopyrimidine derivatives as LRRK2 modulators
US8637537B2 (en) 2011-08-25 2014-01-28 Genentech, Inc. Serine/threonine kinase inhibitors
US9040547B2 (en) 2011-09-22 2015-05-26 Pfizer Inc. Pyrrolopyrimidine and purine derivatives
US8957068B2 (en) 2011-09-27 2015-02-17 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US8815877B2 (en) 2011-12-22 2014-08-26 Genentech, Inc. Serine/threonine kinase inhibitors
US9458177B2 (en) 2012-02-24 2016-10-04 Novartis Ag Oxazolidin-2-one compounds and uses thereof
US8865894B2 (en) 2012-02-24 2014-10-21 Novartis Ag Oxazolidin-2-one compounds and uses thereof
US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
US10202371B2 (en) 2012-11-12 2019-02-12 Novartis Ag Oxazolidin-2-one-pyrimidine derivatives and the use thereof as phosphatidylinositol-3-kinase inhibitors
US10112931B2 (en) 2013-03-14 2018-10-30 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9434719B2 (en) 2013-03-14 2016-09-06 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9688672B2 (en) 2013-03-14 2017-06-27 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
CN116354938A (zh) * 2021-12-28 2023-06-30 沈阳药科大学 一类喹唑啉衍生物与其类似物的制备方法及应用
WO2023123883A1 (zh) * 2021-12-28 2023-07-06 沈阳药科大学 一类喹唑啉衍生物与其类似物的制备方法及应用
CN116354938B (zh) * 2021-12-28 2024-02-20 沈阳药科大学 一类喹唑啉衍生物与其类似物的制备方法及应用

Also Published As

Publication number Publication date
DE60119776D1 (de) 2006-06-22
JP2008260767A (ja) 2008-10-30
HUP0400638A2 (hu) 2004-06-28
JP2004519479A (ja) 2004-07-02
JP4160389B2 (ja) 2008-10-01
ES2265450T3 (es) 2007-02-16
DE60126828T2 (de) 2007-11-08
CN100406454C (zh) 2008-07-30
ES2375491T3 (es) 2012-03-01
US20090312543A1 (en) 2009-12-17
WO2002057259A3 (en) 2003-04-24
CA2432222A1 (en) 2002-08-15
HUP0400908A3 (en) 2010-03-29
NO20032736D0 (no) 2003-06-16
DE60120219D1 (de) 2006-07-06
CN1487933A (zh) 2004-04-07
EP1345927A1 (en) 2003-09-24
US6664247B2 (en) 2003-12-16
IL156389A0 (en) 2004-01-04
DE60119777D1 (de) 2006-06-22
MXPA03005608A (es) 2003-10-06
TWI290551B (en) 2007-12-01
MXPA03005607A (es) 2003-10-06
WO2002066461A1 (en) 2002-08-29
DE60119774D1 (de) 2006-06-22
RU2003122209A (ru) 2005-02-10
NO20032704D0 (no) 2003-06-13
NZ526474A (en) 2005-10-28
NO328501B1 (no) 2010-03-01
KR100909665B1 (ko) 2009-07-29
US20040214814A1 (en) 2004-10-28
HUP0400639A3 (en) 2010-03-29
US7625913B2 (en) 2009-12-01
JP4160392B2 (ja) 2008-10-01
MXPA03005612A (es) 2003-10-06
DK1355905T3 (da) 2007-06-18
MXPA03005610A (es) 2003-10-06
AU2002234047A1 (en) 2002-07-01
JP2008247921A (ja) 2008-10-16
PL363244A1 (en) 2004-11-15
EP1345929B1 (en) 2006-05-17
AU2001297619B2 (en) 2006-06-08
EP1355905A1 (en) 2003-10-29
AR040925A1 (es) 2005-04-27
HUP0400842A2 (hu) 2004-07-28
NO20032736L (no) 2003-08-18
SI1353916T1 (sl) 2007-02-28
KR20030061463A (ko) 2003-07-18
AU2006201267B2 (en) 2010-07-29
HK1062433A1 (en) 2004-11-05
JP4234435B2 (ja) 2009-03-04
US7087603B2 (en) 2006-08-08
JP2004517894A (ja) 2004-06-17
WO2002059111A2 (en) 2002-08-01
EP1345925B1 (en) 2006-05-17
DE60123283T2 (de) 2007-04-12
NO20032671L (no) 2003-08-18
US7982037B2 (en) 2011-07-19
JP2009155352A (ja) 2009-07-16
ES2280313T3 (es) 2007-09-16
KR100947185B1 (ko) 2010-03-15
CN100408573C (zh) 2008-08-06
IL209827A0 (en) 2011-02-28
JP2009286805A (ja) 2009-12-10
WO2002059112A3 (en) 2003-02-06
PT1345922E (pt) 2006-09-29
US20140187772A1 (en) 2014-07-03
AU2002255452B2 (en) 2006-06-08
HK1060346A1 (en) 2004-08-06
JP2008189687A (ja) 2008-08-21
AP1588A (en) 2006-03-06
NO20032703D0 (no) 2003-06-13
MXPA03005609A (es) 2003-10-06
CA2432223A1 (en) 2002-09-06
CY1106297T1 (el) 2011-10-12
HK1059776A1 (en) 2004-07-16
IL156368A0 (en) 2004-01-04
US6653300B2 (en) 2003-11-25
KR20030061465A (ko) 2003-07-18
JP5249842B2 (ja) 2013-07-31
EP1345928B1 (en) 2007-02-14
NO330527B1 (no) 2011-05-09
US20040157893A1 (en) 2004-08-12
EP1353916A2 (en) 2003-10-22
ES2265452T3 (es) 2007-02-16
JP2008189682A (ja) 2008-08-21
EP1702920B1 (en) 2011-10-12
US20030004164A1 (en) 2003-01-02
US20030055068A1 (en) 2003-03-20
ES2272567T3 (es) 2007-05-01
DE60123283D1 (de) 2006-11-02
BR0116411A (pt) 2003-11-11
JP2005097322A (ja) 2005-04-14
WO2002050065A3 (en) 2002-10-24
NO20032704L (no) 2003-08-21
EP1355905B1 (en) 2007-02-21
CA2432131A1 (en) 2002-08-01
JP2008201808A (ja) 2008-09-04
AP2003002825A0 (en) 2003-09-30
CN1486310A (zh) 2004-03-31
AR042169A1 (es) 2005-06-15
AU2006201267A1 (en) 2006-04-27
ATE353890T1 (de) 2007-03-15
US7427681B2 (en) 2008-09-23
US6727251B2 (en) 2004-04-27
JP4210520B2 (ja) 2009-01-21
JP4160395B2 (ja) 2008-10-01
DE60119775T2 (de) 2007-05-10
AU2002231166B2 (en) 2008-02-21
PL210066B1 (pl) 2011-11-30
US8304414B2 (en) 2012-11-06
DE60126828D1 (de) 2007-04-05
NO328537B1 (no) 2010-03-15
KR20030061857A (ko) 2003-07-22
NZ526475A (en) 2005-06-24
US20030022885A1 (en) 2003-01-30
HK1061389A1 (en) 2004-09-17
JP2013213068A (ja) 2013-10-17
ATE326463T1 (de) 2006-06-15
ATE326461T1 (de) 2006-06-15
US20080287444A1 (en) 2008-11-20
EP1702920A1 (en) 2006-09-20
US7531536B2 (en) 2009-05-12
AR042398A1 (es) 2005-06-22
DE60126658T2 (de) 2007-11-22
CA2432872A1 (en) 2002-06-27
ATE354573T1 (de) 2007-03-15
EP1345926A2 (en) 2003-09-24
CN100340555C (zh) 2007-10-03
WO2002059112A2 (en) 2002-08-01
HK1060349A1 (en) 2004-08-06
IL156407A0 (en) 2004-01-04
CN1486312A (zh) 2004-03-31
AU2002246754B2 (en) 2006-06-08
CA2432872C (en) 2008-09-23
US6656939B2 (en) 2003-12-02
NO20032670D0 (no) 2003-06-12
CA2432799C (en) 2008-08-19
KR20030061466A (ko) 2003-07-18
NZ526469A (en) 2005-10-28
WO2002050066A3 (en) 2003-01-23
CA2432132A1 (en) 2002-08-01
ATE528303T1 (de) 2011-10-15
US20030105090A1 (en) 2003-06-05
CA2432799A1 (en) 2002-06-27
DE60126658D1 (de) 2007-03-29
PT1355905E (pt) 2007-05-31
WO2002068415A1 (en) 2002-09-06
TW200716617A (en) 2007-05-01
EP1345925A2 (en) 2003-09-24
HK1062565A1 (zh) 2004-11-12
CN1549812A (zh) 2004-11-24
KR100843114B1 (ko) 2008-07-02
US20030036543A1 (en) 2003-02-20
IL156369A0 (en) 2004-01-04
HK1060557A1 (en) 2004-08-13
ES2265446T3 (es) 2007-02-16
JP2004517927A (ja) 2004-06-17
MXPA03005605A (es) 2003-10-06
NO20032671D0 (no) 2003-06-12
KR20030061858A (ko) 2003-07-22
IL156389A (en) 2011-01-31
EP1353916B1 (en) 2006-09-20
CN100436452C (zh) 2008-11-26
CN102250071A (zh) 2011-11-23
WO2002059111A3 (en) 2003-01-09
WO2002057259A2 (en) 2002-07-25
US20030004161A1 (en) 2003-01-02
CA2432223C (en) 2008-05-20
NZ526470A (en) 2006-03-31
AP2003002816A0 (en) 2003-06-30
HK1060347A1 (en) 2004-08-06
CA2432303A1 (en) 2002-08-29
US20130096128A1 (en) 2013-04-18
PL363246A1 (en) 2004-11-15
US20030078275A1 (en) 2003-04-24
US8697698B2 (en) 2014-04-15
NO20032670L (no) 2003-08-15
EP1345922A1 (en) 2003-09-24
MXPA03005611A (es) 2003-10-06
US6653301B2 (en) 2003-11-25
JP2004518743A (ja) 2004-06-24
ATE326460T1 (de) 2006-06-15
DK1345922T3 (da) 2006-09-18
AR042397A1 (es) 2005-06-22
EP2264028A1 (en) 2010-12-22
EP1345927B1 (en) 2006-05-17
HUP0400641A2 (hu) 2004-06-28
SI1355905T1 (sl) 2007-08-31
BR0116493A (pt) 2003-09-30
MXPA03005606A (es) 2003-10-06
ATE326462T1 (de) 2006-06-15
JP2004516292A (ja) 2004-06-03
WO2002050066A2 (en) 2002-06-27
NZ526472A (en) 2004-04-30
NZ526471A (en) 2005-08-26
CA2432303C (en) 2010-04-13
HUP0400639A2 (hu) 2004-06-28
KR20030061468A (ko) 2003-07-18
DE60119777T2 (de) 2007-05-03
JP2004517926A (ja) 2004-06-17
EP1345928A2 (en) 2003-09-24
TWI313269B (en) 2009-08-11
DE60119776T2 (de) 2007-05-16
CA2432222C (en) 2008-07-29
HUP0400641A3 (en) 2010-03-29
ATE340172T1 (de) 2006-10-15
CA2432132C (en) 2008-07-29
NO20032703L (no) 2003-08-19
PT1353916E (pt) 2007-01-31
CA2432129C (en) 2008-08-26
HUP0400908A2 (hu) 2004-07-28
JP2004518703A (ja) 2004-06-24
KR100875091B1 (ko) 2008-12-22
ATE327989T1 (de) 2006-06-15
US6989385B2 (en) 2006-01-24
IL156408A0 (en) 2004-01-04
RU2355688C2 (ru) 2009-05-20
PL210414B1 (pl) 2012-01-31
JP2004516291A (ja) 2004-06-03
CA2432131C (en) 2008-07-08
WO2002050065A2 (en) 2002-06-27
KR100889246B1 (ko) 2009-03-19
DE60119775D1 (de) 2006-06-22
MY140377A (en) 2009-12-31
NZ526473A (en) 2005-06-24
KR20030061467A (ko) 2003-07-18
JP2008222719A (ja) 2008-09-25
EP1345929A2 (en) 2003-09-24
AU3116602A (en) 2002-07-01
KR20030061464A (ko) 2003-07-18
US20050038023A1 (en) 2005-02-17
ES2266095T3 (es) 2007-03-01
US20040132781A1 (en) 2004-07-08
IL156369A (en) 2011-02-28
DE60120219T2 (de) 2007-04-12
US20040167141A1 (en) 2004-08-26
EP1345922B1 (en) 2006-05-31
CN1486311A (zh) 2004-03-31
NZ526468A (en) 2004-03-26
EP1345926B1 (en) 2006-05-17
DK1353916T3 (da) 2007-01-29
JP2008247920A (ja) 2008-10-16
DE60119774T2 (de) 2007-05-16
CA2432129A1 (en) 2002-07-25

Similar Documents

Publication Publication Date Title
US6664247B2 (en) Pyrazole compounds useful as protein kinase inhibitors
AU2001297619A1 (en) Pyrazole compounds useful as protein kinase inhibitors
AU2002255452A1 (en) Pyrazole compounds useful as protein kinase inhibitors
RU2332415C2 (ru) Производные пиразола, полезные в качестве ингибиторов протеинкиназы
AU2002246899A1 (en) Pyrazole compounds useful as protein kinase inhibitors
AU2002246731A1 (en) Pyrazole compounds useful as protein kinase inhibitors
AU2002245198A1 (en) Pyrazole compounds useful as protein kinase inhibitors
HK1059776B (en) Pyrazole compounds useful as protein kinase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2003/04471

Country of ref document: ZA

Ref document number: 200304471

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2002246899

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 156407

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 526471

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2432222

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/005608

Country of ref document: MX

Ref document number: 2002563142

Country of ref document: JP

Ref document number: 1020037008409

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 869/KOLNP/2003

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2001994510

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 01822105X

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 1200300629

Country of ref document: VN

WWP Wipo information: published in national office

Ref document number: 1020037008409

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2001994510

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 526471

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 526471

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 2001994510

Country of ref document: EP