CA2432222C - Pyrazole compounds useful as protein kinase inhibitors - Google Patents

Pyrazole compounds useful as protein kinase inhibitors Download PDF

Info

Publication number
CA2432222C
CA2432222C CA002432222A CA2432222A CA2432222C CA 2432222 C CA2432222 C CA 2432222C CA 002432222 A CA002432222 A CA 002432222A CA 2432222 A CA2432222 A CA 2432222A CA 2432222 C CA2432222 C CA 2432222C
Authority
CA
Canada
Prior art keywords
ring
aliphatic
membered
hydrogen
con
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.)
Expired - Fee Related
Application number
CA002432222A
Other languages
French (fr)
Other versions
CA2432222A1 (en
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
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of CA2432222A1 publication Critical patent/CA2432222A1/en
Application granted granted Critical
Publication of CA2432222C publication Critical patent/CA2432222C/en
Anticipated expiration legal-status Critical
Expired - Fee Related 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

Abstract

This invention describes novel pyrazole compounds of formula (IIIC): wherein R1 is T-Ring D, wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; Rx, Ry, R2, and R2' are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer's disease.

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE I)E CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
CECI EST LE TOME DE _2 NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional volumes please contact the Canadian Patent Office.

PYRAZOLE COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS
FIELD OF THE INVENTION
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.

BACKGROUND OF THE INVENTION
The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases.
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. There are a number of 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, H202), cytokines (e.g.
interleukin-1 (IL-1) and tumor necrosis.factor (G (TNF-a)), and growth factors (e.g. granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor .(FGF). 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 a 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] . These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. 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 (3-catenin, the translation initiation factor e1F2B, as well as ATP
citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBOG. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.
In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, 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. 299, 123-128 (1994)].
However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads.to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in.patients with type II
diabetes, GSK-3 is overexpressed [WO 00/38675].
Therapeutic inhibitors of GSK-3 therefore are considered to be useful for treating diabetic patients suffering from an impaired response to insulin.
GSK-3 activity has also been associated with Alzheimer's-disease. This disease is characterized by the well-known (3-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnornial sites.
GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, 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 theneurofibrillary tangles and the progression of Alzheimer's disease.
.Another substrate of GSK-3 is 0-catenin which is degradated after phosphorylation by GSK-3. Reduced levels of (3-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J.
Neuropathol. Exp, 56, 70-78 (1997)].
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)].
For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various'protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported recently as.inhibitors of p38 kinase (WO 00/12497 to Scios). The compounds are reported to be useful for treating conditions characterized by enhanced p38-oc activity and/or enhanced TGF-(3 activity. While p38 activity has been implicated in a wide variety of diseases, including diabetes, p38 kinase is not reported to be a constituent of an insulin signaling pathway that regulates glycogen synthesis or glucose uptake.
Therefore, unlike GSK-3, p38 inhibition would not be expected to enhance glycogen synthesis and/or glucose uptake.
There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases Aurora-2 and GSK-3 are especially attractive targets for the discovery of new therapeutics due to their important roles in cancer and diabetes, respectively.

SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided a compound of formula IIIc:

R2.

NH
HN N
R"
N
I ~
RY N" 'N-R' H
IIIc or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
R' and RY are independently selected from T-R3 or L-Z-R3;
R1 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 Ring D is substituted at any substitutable ring carbon by oxo, T-R5, or V-Z-R5, and at any substitutable ring nitrogen by -Rq;
T is a valence bond or a C3_4 alkylidene chain;
Z is a Cl-Q alkylidene chain;

L is -0-, -S-, -SO-, -SOZ-, -N(R6)SO,-, -S02N(R6)-, -N(R6)-, -CO-, -C0Z-, -N(R6)CO-, -N(R6)C(0)0-, -N(R6)CON(R6) -, -N(R6)S02N(R6) -, -N(R6)N(R6) -, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)20-, -C(R6)ZS-, -C (R6) 2S0-, -C (R6) 2S0z-, -C (R6) 2SO2N (R6) -, -C (R6) 2N (R6) -, -6a--C (R6) 2N (R6) C (0) - , C (R6) 2N (R6) C (0) 0- , -C (R6) =NN (R6) - , -C(R6)=N-O-, -C(R6)zN(R6)N(R6)-, -C(R6)2N(R6)SOZN(R6)-, or -C(R6)2N(R6)CON(R6) -;
R2 and R2' are independently selected from -R, -T-W-R6, or R 2 and R2' 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 carbon on said fused ring formed by R2 and R2' is substituted by halo, oxo, -CN, -NO2r -R', or -V-R6, and any substitutable nitrogen on said ring formed by R2 and R2' is substituted by R4;

R3 is selected from -R, -halo, -OR, -C(=O)R, -COaR, -COCOR, -COCH2COR, -NO2, -CN, -S (O) R, -S (O) 2R, -SR, -N(R4)2, -CON(R7)2, -S02N(R')2, -OC(=O)R, -N(R')COR, -N (R7) C02 (C1_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R') CON (R') Z, -N (R7) SO2N (R') 2, -N (R4) SO2R, or -OC (=O) N (R7) Z;
each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, C6-lo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R', -COR', -CO2 (optionally substituted Cl_6 aliphatic) , -CON (R') 2, or - S02R' ;
each R5 is independently selected from -R, halo, -OR, -C (=0) R, -COzR, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) COz (optionally substituted Cl_6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SOzN(R4)zi -N(R4)SOZR, or -OC(=0)N(R4)2;

-6b-V is -0-, -5-, -SO-, -SO2-, -N(R6)S02-, -SO2N(R6)-, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(O)0-, -N(R6) CON(R6) -, -N(R6) SO2N(R6) -, -N(R6)N(R6) -, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)20-, -C(R6)2S-, -C (R6 ) 2SO-, -C (R6) 2SO2-, -C (R6) 2SO2N (R6) -, -C (R6) 2N (R6) - , -C (R6) 2N (R6) C (0) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN-(R6) -, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SOzN(R6)-, or -C (R6) 2N(R6) CON (R6) -;

W is -C (R6) 20- , -C (R6) ZS-, -C (R6) 2S0-, -C (R6) ZSOZ-, -C(R6)2S02N(R6)-, -C(R6)2N(R6)-, -CO-, -C02-, -C(R6)OC(0)-, -C(R6)OC(0)N(R6)-, -C(R6)zN(R6)CO-, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN(R6) -, -C (R6) =N-O-, -C(R6)2N(R6)N(R6) -, -C(R6)2N(R6)SO2N(R6) =, -C (R6) ZN (R6) CON (R6) -, or -CON (R6) - ;
each R6 is independently selected from hydrogen or an optionally substituted Cl_4 aliphatic group, or two R6 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 R7 is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

-6c-According to another aspect of the present invention, there is provided a compound selected from the group consisting of:

(5-Methyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylamino)-6-phenyl-pyrimidin-4-yl]-amine;
[2-(4-cyanomethylphenylamino)-6-phenyl-pyrimidin=4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2-(pyridin-3-ylmethylamino)-pyrimidin-4-yl]-amine;
[2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(3-Chlorophenyl)amino-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(5-Methyl-2H-pyrazol-3-yl)-[2-(4-sulfamoylphenylamino)-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-amine;
[2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl) -2H-pyrazol-3-yl] -amine;
[2-(Benzimidazol-2-ylamino-)6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine;
[2-(4-Chlorophenyl)amino-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(5-tert-Butyl-2H-pyrazol-3-yl)-[2-(3-chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-amine;

-6d-[2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine;
[5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine;
[2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine;
[2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-[5-(Furan-2-yl)-2H-pyrazol-3-yll-amine;
[2-(4-Chlorophenylamino)-6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Chlorophenyl)amino-5,6-dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(5,6-Dimethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-y1)-amine;
[2-(4-Chlorophenyl)amino-6-methoxymethyl-pyrimidin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(Benzimidazol-2-ylamino)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(6-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine;
(6-Methyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine;
.N4-(5-Cyclopropyl-lH-pyrazol-3-yl)-N2-(1H-indazol-5-yl)-6-methyl-pyrimidine-2,4-diamine; and N2-Benzothiazol-6-yl-N4-(5-cyclopropyl-lH-pyrazol-3-yl)-6-methyl-pyrimidine-2,4-diamine. --6e-According to still another aspect of the present invention, there is provided a method of inhibiting Aurora-2, glycogen synthase kinase-3 (GSK-3), or Src activity in a biological sample comprising the step of contacting said biological sample with a compound as described herein.

According to yet another aspect of the present invention, there is provided a use for inhibiting Aurora-2 activity in a patient of the compound as described herein.

According to a further aspect of the present invention, there is provided a use of a therapeutically effective amount of the compound as described herein for treating an Aurora-2-mediated disease in a patient in need of such a treatment.

According to yet a further aspect of the present invention, there is provided a use for inhibiting glycogen synthase kinase-3 (GSK-3) activity in a patient of the compound as described herein.

According to still a further aspect of the present invention, there is provided a use of a therapeutically effective amount of the compound as described herein for treating a glycogen synthase kinase-3 (GSK-3)-mediated disease in a patient in need of such a treatment.

According to another aspect of the present invention, there is provided a use of a therapeutically effective amount of the compound as described herein for enhancing glycogen synthesis or lowering blood levels of glucose in a patient in need thereof.

-6f-According to yet another aspect of the present invention, there is provided a use of a therapeutically effective amount of the compound as described herein for inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof.

According to another aspect of the present invention, there is provided a use of a therapeutically effective amount of the compound as described herein for inhibiting the phosphorylation of (3-catenin in a patient in need thereof.

According to still another aspect of the present invention, there is provided a use for inhibiting Src activity in a patient of the compound as described herein.

According to yet another aspect of the present invention, there is provided a use of a therapeutically effective amount of the compound as described herein for treating a Src-mediated disease in a patient in need of such a treatment.

-6g-DESCRIPTION OF THE INVENTION
It has now been found that compounds of this invention and pharmaceutical compositions thereof are effective as protein kinase inhibitors, particularly as inhibitors of Aurora-2. These compounds have the general formula I:

R2, ~ NH
HN
R" Z2 ~ A~~
RY Z~' Q-R' I

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Zl is =nitrogen or C-RB and Z2 is nitrogen or CH, wherein at least one of Zl and Z2 is nitrogen;
R" and Ry are independently selected from T-R3 or L-Z-R3, or R" and RY 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;

Q is selected from -N(R4)-, -0-, -S-, -C(R6)2-, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;
R' 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-R5, or V-Z-RS, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C,,_4 alkylidene chain, wherein when Q is -C (R6 ) 2-, a methylene unit of said C1_4 alkylidene chain is optionally replaced by -0-, -S-, -N(R4) -, -CO-, -CONH-, -NHCO-, -SO2-, -SOzNH-, -NHSOz-, -CO2-1 -OC (O) -, -OC (O)NH-, or .-NHCO2-;
Z is a Cl_4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -SO2N(R6)-, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6)CON(R6) -, -N(R6)SO2N(R6) -, -N(R6)N(R6) -, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R.6)20-, -C(R6)2S-, -C (R6) 2S0- , -C (R.6) 2S02- , -C (R6) 2SO2N (R6) - , -C (R6) 2N (R6) - , -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) 2N (R6) CON (R6) - ;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NOz, -R', or -V-R6, and each substitutable ring nitrogen of said.ring =formed by Ra and R 2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=O) R, -C02R, -COCOR, -COCH2COR, -NO2, -CN, -S (O) R, -S (O) 2R, -SR, -N (R4) 21 -CON (R7 ) 2, -S02N (R7 ) 2, -OC (=O) R, -N (R7) COR, -N (R') C02 (C1_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N(R')CON(R')2, -N(R')S02N(R')2, -N(R4)S02R, or -OC(=O)N(R7)2i each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, C6_3.o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R7, -COR', -CO2 (optionally substituted C1_6 aliphatic) , -CON (R') 2i or -S02R';
each RS is independently selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) Z, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted C1_6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)SO2R, or -OC(=O)N(R4)2;
V is -0-, -5-, -SO-, -SO2-, -N(R6)S02-, -SOZN(R6)-, -N (R6) -, -CO-, -CO2-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6)CON(R6) -, -N(R6) S02N(R6) -, -N(R6)N(R6) -, -.C (0)N(R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C (R.6) 2S02N (R.6) -, -C (R.6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R(5) -, -C (R6) 2N (R6) S02N (R6) -, or - C ( R6 ) zN ( R6 ) CON ( R6 ) - ;

W is -C (R6) 20-, -C (R.6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C(R6)2S02N(R6)-, -C(R6)2N(R6)-, -CO-1 -C02-, -C (R6) OC (0) -, -C-(R6) OC (0) N (R6) -, - -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (0) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C(R6)2N(R6)N(R6) -, -C(R6)2N(R6)S02N(R6) -, -C(R6)2N(R6)CON(R6) -, or -CON(R6) -;
each R6 is independently selected from hydrogen or an optionally substituted C1_4 aliphatic group, or two R6 groups on the same nitrogen atom may be taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R" is independently selected from hydrogen or a C,._4 aliphatic group, or two R6' on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring;
each R' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R8 is selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) Z, -CON (R4) 2, -S02N (R4)2 , -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted C11_6 aliphatic),-N (R4) N(R4) 2, -C=NN (R4) 2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)S02R, or -OC(=O)N(R4)2=
As used herein, the following definitions shall apply-unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
The term "aliphatic" as used herein means straight-chain, branched or cyclic Cl-C12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation but which are not aromatic.
For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms "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. The term "cycloalkyl" used alone or as part of a larger moiety shall include cyclic C3-C12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic.
The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I.
The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
Also the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, 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).

The terms "carbocycle", "carbocyclyl", 5-"carbocyclo", or "carbocyclic" as used herein-means an aliphatic ring system having three to fourteen members.
The terms "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted.
The terms "carbocycle", "carbocyclyl", "carbocyclo", or "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.
The term "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. The term "aryl" also refers to rings that are optionally substituted. The term "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. Also included within the scope of the term "aryl", as it is used herein, 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 a.romatic ring.
The term "heterocycle", "heterocyclyl", or "heterocyclic" as used herein 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. Examples of heterocyclic rings include 3-1H-benzimidazol-2-one, (-1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 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-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also included within the scope of the term "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. The term "heterocycle", "heterocyclyl", or "heterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted.
The term "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. Examples of 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-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, or benzoisoxazolyl. Also included within the scope of the term "heteroaryl", as it is used herein, 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.
The term "heteroaryl" also refers to rings that are optionally substituted. The term "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. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, -R , -OR , -SR , 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -O(Ph), substituted -O(Ph), -CH2(Ph), substituted -CHZ(Ph), -CH2CH2(Ph), substituted -CH2CH2 (Ph) , -NO2, -CN, -N (R ) 2, -NR C (O) R , -NR C (O) N (R ) 2, -NR C02R , -NR NR C (0) R , -NR NR C (O) N (R ) 2, -NR NR C02R , -C (O) C (O) R , -C (O) CH2C (O) R , -C02R , -C (O) R , -C (O) N (R ) 2, -OC (O) N (R ) 2, -S (0) aR , -S02N (R ) 2, -S (O) R , -NR SO2N (R ) 2, -NR S02R , -C (=S) N (R ) 2i -C (=NH) -N (R ) 2, - (CH2) YNHC (O) R , - (CH2) yNHC (0) CH (V-R ) (R ) ; wherein each R is independently selected from hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -O(Ph), substituted -O(Ph), -CH2(Ph), or substituted -CH2(Ph); y is 0-6; and V is a linker group. Examples of 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.
Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring include those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following:
=0, =S, =NNHR*, =NN (R*) 2, =N-, =NNHC (0) R*, =NNHCO2 (alkyl) , =NNHS02(alkyl), or =NR*, where each R* is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of 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.
Suitable substituents on the nitrogen of a non-aromatic heterocyclic ring include -R+, -N (R+) 2, -C (O) R+, -C02R+, -C (O) C (O) R+, -C (O) CH2C (O) R+, -S02R+, -S02N (R+) 2, -C (=S) N(R+) 2, -C (=NH) -N (R+) 2, and -NR+S02R+; wherein each R+
is independently selected from hydrogen, an aliphatic group, a substituted aliphatic group, pheny7. (Ph), substituted Ph, -O(Ph), substituted -O(Ph), CH2(Ph), substituted CH2(Ph), or an unsubstituted heteroaryl or heterocyclic ring. Examples of 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.
The term "linker group" or "linker" 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-, -CH2-, -C(O)-, -C(O)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. Examples of linkers include a saturated or unsaturated C1_6 alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by -C (O) -, -C (O) C (O) -, -CONH-, -CONHNH-, -C02-1 -OC (0) -, -NHCO2-, -0-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -S-, -SO-, -SOa-, -NH-1 -SO2NH-, or -NHS02-.
The term "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.
Unless otherwise stated, 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. Unless otherwise stated, 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 13C- or ''4C-enriched carbon are within the scope of this invention.
Compounds of formula I or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, 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 aspec-t 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.
The term "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.

The terms "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. Such 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 0-catenin, which is useful for treating schizophrenia.
Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample', which method comprises contacting the biological sample with a GSK-3 inhibitor of formula I.

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 I 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 I or a pharmaceutical composition thereof.

The terms "CDK-2-mediated disease" or "CDK-2-mediated condition", as used herein, mean any disease or other deleterious condition in which CDK-2 is known to play a role. The terms CDK-2-mediated disease" or "CDK-2-mediated condition" also mean those 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.
and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, S., Wang, C., Wu, K., Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000);
Fry, D.W. and Garrett,. M.D., Current Opinion in Oncologic, Endocrine & Metabolic Investigational Drugs, 2, 40-59 (2000).

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.

The terms "ERK-mediated disease" or "ERK-mediated condition", as used herein mean any disease or other deleterious cond-ition in-which ERK is known to play a role. The terms "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. The term "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 leukemia.

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. USA 90, 10952; Oliver et al., 1995, Proc. Soc.-Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478;
Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 5891.
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.

The terms "AKT-mediated disease" or "AKT-mediated condition", as used herein, mean any disease or other deleterious condition in which AKT is known to play a role. The terms "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. 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, N., et al, The Journal of Neuroscience, 20 2000].
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.
The terms "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., Cell, 64, 693 (1991);
Takayanagi, J. Clin. invest., 104, 137 (1999); Boschelli, Drugs of the Future 2000, 25(7), 717, (2000); Talamonti, J. Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys.
Res. 243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 (1986); Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993) ; Wiener, Clin. Cancer Res., 5, 2164 (1999) ;
Staley, Cell Growth Diff., 8, 269 (1997) ].
Another aspect of the i.nvention 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.
The terms "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. The terms "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.
The term "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.

The term "patient" includes human and veterinary subjects.

The term-"biolog-ical sample", as used herein, 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.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal; intrahepatic, intralesional and intracranial-injection or infusion techniques.
Preferably, 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. Among the acceptable vehicles and solvents-that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, 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. These oi7.
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, Other commonly used 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.
The pharmaceutical 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. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, .such as magnesium stearate, are also typically added.
For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When 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.
Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These 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. Such materials include cocoa butter, beeswax and_polyethylene glycols.
The pharmaceutical 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-* Trade-mark 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.
For topical applications, 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. Alternatively, 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.
For ophthalmic use, 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. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical 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.
In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in 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.
Pharmaceutically acceptable prodrugs of the compounds 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. Examples of 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, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, stilfate, tartrate, thioc.yanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the.invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal' (e.g., magnesium), ammonium and N+(C1_4 alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containin.g groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
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.
Preferably, the 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.
it should also be understood that 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.
Depending upon the particular protein kinase-mediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, in the treatment of cancer other chemotherapeutic agents or other anti-proliferative agents may be combined with the present compounds to treat cancer. These agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, 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-i 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, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents;
agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
Those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen.
Alternatively, those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor of this invention in a.single composition.
Compounds of this invention may exist in alternative 'tautomeric forms, as in tautomers i and ii shown below. Unless otherwise indicated, the representation of either tautomer is meant to include the other.
R2' R2 R2' R2 NH
HN H HN
-.~-Rx ) A ~Z2 Rx :)I A ~Z2 Ry Z "'Q-R1 RY Z1 i'Q-Ri i ii R" and Ry may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A.
Preferred R"/Ry rings include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/Ry ring is optionally substituted. Examples of bicyclic systems,containing Ring A are shown below by compounds I-A through I-BB, wherein Z' is nitrogen or C(R$) and Z2 is nitrogen or C (x) .

R 2' NNH
HN HN3%? HN

~ ( \Z2 I ~\1 1 ~ 0-r'~ ' Z Q-R 1 z .

I-A I-B I-C
HN'3%? HN'~~ HN3%?

I Z2 ~ N Iz 2 I~ Z2 R4' C Z1 ~~5'' Zy I-D I-E I-F
R4 HN1317 H HN"3%? HN3r6?

ZZN z1'.~
O

I-G I-H I-I
HN HN-3Z7 HN'~~
z2 N Z2 UN ~ z2 NZzi~~ Zi-j-y I-J I-K I-L
HN,31? HN,31? HN3r??

I N Z2 N~ I~ Z2 (JZ2 N~ ,-~ , Z N Z Z I-M I-N I-O

HN'37'? HN~ HN-~~
S Z2 (~Z2 1~
Z $ Zk c:x2 Z1-j ~5' I-P I-Q I-R
HN1317 HN3%? HN'~Z?

X IZ2 I Z2 <\ I ~Z2 Z~-jly O ZikN Zi4y I-S I-T I-U
HN'3%? HN'37'? HN377 'N Z2 ~ I\ Z2 S \ Z2 N N

I-V I-W I-X
HN~ HN'31z? HNi~
N~ Z2 NN Z2 C Z2 'N Z1JY 'N Z1'y Zi-j~S' R R ~' I-Y I-Z I-AA
HN'37?

I 1, o ~~
I-BB
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-V1 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.
In the monocyclic Ring A system, preferred Rx groups, when present, include hydrogen, alkyl- or dialkylamino, acetamido, or a C,._4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl. Preferred Ry groups, when present, include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, -C(R6)20-, -CO- or -N (R'4) -, and R3 is -R, -N (R4) 2, or -OR. Preferred Ry groups include 5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl; C1_6 aliphatic, such as methyl, ethyl, cyclopropyl, isopropyl, or 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; and optionally substituted phenyl such as phenyl or halo-substituted phenyl.
In the bicyclic Ring A system, the ring formed when R" and RY are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O(CH2)2-4-N(R4)2, -O(CH2')2-4-R, -OR, -N(R4)-(CH2)2-4-N(R4)2, -N (R4) - (CH2) 2-4-R, -C (=O) R, -CO2R, -COCOR, -NO2, -CN, -S (O) R, -SO2R, -SR, -N (R4) 2i -CON (R4) 2, -SO2N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) CO2 (optionally substituted Cl-6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R, or -OC(=O)N(R4)2, wherein R and R4 are as defined above.
Preferred RX/RY ring substituents include -halo, -R, -OR, -COR, -CO2R, -CON (R4) 2, -CN, -O (CH2) 2_4-N (R4) 2, -O (CH2) 2-4-R, -NO2 -N (R4) 2, : -NR4COR, -NR4SO2R, -SO2N (R4) 2 wherein R is hydrogen or an optionally substituted Cl-6 aliphatic group.
R2 and R2' 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. These are exemplified in the following formula I compounds having a pyrazole-containing bicyclic ring system:
HN N N N ~N

~ 1 N . , ' N.
RY. Zj,~ Q-R and Preferred substituents on the R2/R2' fused ring include one or more of the following: -halo, -N(R4) 2, -Ci_3 alkyl, -C1_3 haloalkyl, -NO2, -O (Cl_3 alkyl) , -C02 (Ci_3 alkyl) , -CN, -SO2 (Cl_3 alkyl) , -SOZNH2, -OC(O)NH2, -NHzS02 (C1_3 alkyl) , -NHC (O) (Cl_3 alkyl) , -C (O) NH2, and -CO (Cl_3 alkyl) , wherein the (C1_3 alkyl) is most preferably me'thyl.
When the pyrazole ring system is monocyclic, preferred R2 groups include hydrogen, C1_4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N-heterocyclyl)carbonyl. Examples of such preferred R2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl,. CO2H, CO2CH3, CH2OH, CH2OCH3, CHZCH2CH2OH, CH2CH2CH2OCH3, CH2CH2CH2OCH2Ph, CH2CH2CH2NH2, CH2CH2CH2NHCOOC (CH3) 3, CONHCH ( CH3 ) 2, CONHCH2CH=CH2, CONHCH2CH2OCH3 , CONHCH2Ph, CONH (cyclohexyl) , CON(Et)2, CON (CH3) CH2Ph, CONH (n-C3H7) , CON ( Et ) CH2CH2 CH3 , CONHCH2CH ( CH3 )2, CON ( n- C3H7) 2, CO ( 3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2, and CO(piperidin-l-yl). A
preferred R2' group is hydrogen.
An embodiment that is particularly useful for treating Aurora-2-mediated diseases relates to compounds of formula IIa:

. R2 R2.
NH
HN
R"

RY ( N.S-R1 IIa or a pharmaceutically acceptable derivative or prodrug thereof, wherein;
R" and RY 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4 ;
R' 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-R5, or V-Z-RS, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C1_4 alkylidene chain;
Z is a C1_4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -SO2N(R6)-, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C (O) N (R6) -, -OC (O) N (R6) -, - -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C (R6) 2SOZN (R6) -, -C (R(5) zN (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (Rg) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C(R6)2N(R6)CON(R6) -;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;
R3 is selected from -R, -halo, -OR, -C (=O) R, -C02R, -COCOR, -COCH2COR, -NO2, -CN, -S(O)R, -S(0)2R, -SR, -N (R4) 2s -CON (R7 ) 2, -S02N (R7 ) 2, -OC (=O) R, -N (R7) COR, -N (R') C02 (C1_6 aliphatic), -N (R4) N (R4) 2, -C=NN=(R4) 2, -C=N-OR, -N (R') CON (R') 2, -N (R') SO2N (R') 2, -N (R4) S02R, or -OC (=0) N (R7 ) z;
each R is independently selected from hydrogen or an optionally substituted group selected from C,._6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R7, -COR', -C02 (optionally substituted Cl_6 aliphatic) , -CON (R') 2, or -S02R;
' each RS is independently selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (0) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=0) R; -N (R4) COR, -N (R4) COZ (optionally substituted C1_6 aliphatic), -N (R.4)-N (R4) 2; -C=NN (R4) 2. -C=N-OR, -N (R4) CON (R.4) a, -N(R4)S02N(R4)2, -N(R4)S02R, or -OC(=O)N(R4)2;
V is -0-, -5-, -SO-, -SO2-, -N(R6)SO2-, -S02N(R6)-, -N (R6) -, -CO-, -CO2-, -N (R6) CO-, -N (R6) C (0) O-, -N(R6)CON(R6) -, -N(R6)S02N(R6) -, -N(R6)N(R 6) -, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2S02-, -C (R6) 2S02N(R6) -, -C (R 6) 2N (R.6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) O-, -C (R6) =NN (R6) -, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, or -C (R6) 2N (R6) CON (R6) - ;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C(R6)2S02N(R.6)-, -C(R6),N(R6)-, -CO-, -C02-, -C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -,. -C (R6) 2N (R6) S02N (R6) -, -C(R6)2N(R6)CON(R6) -, or -CON(R6) -;
each R6 is independently selected from hydrogen or an optionally substituted C1_4 aliphatic group, or two R6 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' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' 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" and Ry include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/Ry ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula IIa are shown below.

R2' NNH HNi'r~ HN3Z?
HN

N N C), N ~
N
~S-R1 IIa-A IIa-B IIa-C
HNI~~ HN.3%? HN31?

N R \N

RN N N N
IIa-D IIa-~E IIa-F
HN03-6? HN13%? HN~~

~N N~ ~N N N
N~ N~ N ~ N
IIa-J IIa-K IIa-L
HN"~ HN131? HN3Z?
S N O N //N N
\N N
N O N ~S' , R4 ~e IIa-P IIa-R IIa-V
HN~~

N
N
N

IIa-W
More preferred pyrimidine ring systems of formula IIa include IIa-A, IIa-B, IIa-D, IIa-E, IIa-J, IIa-P, and IIa-V, most preferably IIa-A, IIa-B, IIa-D, IIa-E, and IIa-J.
The ring formed when R" and Ry are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O (CH2) 2-4-N (R4) Z, -O (CH2) 2-4-R, -OR, -N (R4) - (CH2) 2-4-N (R4) 2. -N (R4) - (CH2) 2-4-R., -C (=O) R, -CO2R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) a, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted C1-6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2.
-N (R4) SO2N (R4) 2, -N (R4) SO2R, 'or -OC (=O) N(R4) 2, wherein R and R4 are as defined above. Preferred R"/Ry ring substituents include -halo, -R, -OR, -COR, -COzR, -CON (R4) 2, -CN, -O (CHZ) 2-4-N (R4) 2, -O (CH2) 2_4-R, , -NO2 -N (R4) 2, -NR4COR, -NR4SO2R, -SO2N (R4) Z wherein R is hydrogen or an optionally substituted C1_6 aliphatic group.
The R2 and R21 groups of formula IIa may be taken together to form a fused ring, thus providing a bicyclic ring syst.em 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 IIa compounds having a pyrazole-containing bicyclic ring system:
I

' NH N \ NN
HN N I
R"
NH NH NH NH
I ~ N -N N N
RY N S-Ri and Preferred substituents on the R2/R2' fused ring of formula IIa include one or more of the following:
-halo, -N (R4) 2, -Cl_4 alkyl, -C1_4 haloalkyl, -N02, -O (Cl_4 alkyl) , -CO2 (C,._4 alkyl) , -CN, -SO2 (C,,_4 alkyl) , -SO2NH2, -OC (0)NH2, -NH2SO2 (Cl_4 alkyl) , -NHC (O) (C1_4 alkyl) , -C (O)NH2, and -CO (C1_4 alkyl) , wherein the (Cl_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Cl_4 alkyl) group is methyl or ethyl.
When the pyrazole ring system of formula IIa is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring D of formula IIa is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIa 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.
On Ring D of formula IIa, preferred T-RS or V-Z-R5 substituents include -halo, -CN, -NO2, -N (R4) 2, optionally substituted C,,_6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH (R'4) , -N (R4) COR, -N (R4) C02R, -SO2N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2r and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, Ci_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me, -NHS02Et, -NHS02(n-propyl), -NHSOz(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( C02 t - Bu ) CH3 , -NHCOCH2N ( CH3 ) 2, -NHCOCH2CH2N ( CH3 ) 2, -NHCOCHaCH2CH2N ( CH3 ) 2 , -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2 (morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholin-4-yl), -NHC02 (t-butyl) , -NH(C1_4 aliphatic) such as -NHMe, -N (C1_4 aliphatic) 2 such as -NMe2, OH, -O (Cl_4 aliphatic) such as -OMe, C1_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1_4 aliphatic).
Preferred formula IIa compounds have one or more, and more preferably all, of the features selected from,the group consisting of:
(a) R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R'- is T-(Ring D), wherein T is a valence bond or a methylene unit;
(c) Ring-D is-a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
(d) R2 is -R or -T-W-R6 and R2' is hydrogen; or R2 and R21 are taken together to form an optionally substituted benzo ring; and (e) R3 is selected from -R, -halo, -OR, or -N (R4) 2.
More preferred compounds of formula IIa have one or more, and more preferably all, of the features selected from the group consisting of:
(a) RX and Ry are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;
(b) R1 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;
(c) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (d) R3 is selected from -R, -halo, -OR, or -N (R4) 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-, -5-, or -N(R4)-.
Even more preferred compounds of formula IIa have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and RY are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;
(b) R1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;

(c) R2 is hydrogen or Cl_4 aliphatic and R2' is hydrogen;

(d) R3 is selected from -R, -OR, or -N (R4) 2, wherein R is selected from hydrogen, CI_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, -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) COZR, -SO2N (R4) 2, -N(R) SOaR, -N (R6) COCH2N (R4) 2, -N (R6) COCHZCH2N (R4) Z, or -N (R6) COCH2CH2CH2N (R4) 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 IIa are shown below in Table 1.

Table 1.

Me Me Me HN ~~'~ H HN ~~'P H ~N H
HN
~ I~N cI{8Ocl I ~ ~ I
N S~
CI
IIa-1 IIa-2 IIa-3 Me Me Me HN _ J~H J~H ,N H

or8,ooMe ~ ~

Et IIa-4 IIa-5 IIa-6 Me Me Me HN" _N H HN * H HNtp H
~
. ( N N N
Ng N S CI N S CI
CI CI
IIa-7 IIa-8 IIa-9 Me Me Me H
'_J~IH
,j~ -f~H IV
HN ~'~ HN /"~ HN" l N S N N ( N \ I F
'~ N ( '~S
N S
~
Iti1e OH F
IIa-10 IIa-11 IIa-12 Me Me Me HN 'rp H H N f-N H HN~N H
N \( OMe \ ( N
OMe N ~I ~
N S N S
OMe IIa-13 - IIa-14 IIa-15 Me Me Me ~JvH ANH -NH
HN IV HN N HN N
N N CI N CI
N S N S~ N S CI
CI
IIa-16 IIa-17 IIa-18 Me Me HN" H HN~~'~ H HN H
N N~/ ccQ
N S

IIa-19 IIa-20 IIa-21 HN H -f~
HN H HN _''~ H

~ ~ -JL 0Me NS ~ COOMe I N S 0'SJ3'OMe IIa-22 IIa-23 IIa-24 HN JNNH HN J:~XH HN J:~XH
O'SJOOMe N i OMe ~ ~ N S COOH N S

IIa-25 IIa-26 IIa-27 HN J:~PPH
HN ~~'~ H HN 'XH

N 4yF ~N SN S N SCI
F CI
IIa-28 IIa-29 IIa-30 H ;~H ~H
HN HN HN
JX

x'ccc N N ~ S N S Me IIa-31 IIa-32 IIa-33 HN HN C02Me HN J~Xll NHAc N N~/ i = N N ~
-J~SJ:N N. I ~ ~
N H N S N S
IIa-34 IIa-35 IIa-36 Me Me ,f~
;~H ~fdq H H
HN~ H HN HN ~'~
i N ~ NSO2Me N ~NHAc ~ .N ~
-J~ ~~ N~S NS ~I
N S

IIa-37 IIa-38 IIa-39 Me Me Me HNJ~-rpH HN -tp H HN ~_ JVH
~ NHAc ~ NHAc 0 IV / C02Me NS ~~ N~S ~~ N~S ~~
OMe rs~,O
(N
O) IIa-40 IIa-41 IIa-42 Me Me Me O HN~~H "~ H HN e~ H
NH
Ac ~ HN N ~, COOH ~ . N ~ NHAc N~ N a N~S -J~ ~~ ~ I ~ ~I
N S MeO N S
IIa-43 IIa-44 IIa-45 Me Me Me HN ~-rp H NH NH
HN HN H
Br N a N I i N ~( N'SO2iPr N S N~S Br ~ NS ~
IIa-46 IIa-47 IIa-48 Me Me Me HN HN" ~H HN, Ct1),,N NH iPr ~ :), N ~ NH Et ' NN~
N - SO ~NS ~.~ O iN~S O
IIa-49 IIa-50 IIa-51 Me Me Me HN ~fx H N H ~jV H
HN HN H
ctLS,ONHAC ~ ~~ ~ N ~ NHAc N NPr ~ - ~~ 00 OH , IIa-52 IIa-53 IIa-54 Me Me Me ~
HN ~-fP H H HN~ H HN' ~H
~
91 I 'N NtSEt ~ N/N~S ~ ~ NHAc ci,cir NH iBu ~ ~S ~ O O HO.N ~ ~ O
H N S
IIa-55 IIa-56 IIa-57 Me Me Me ,-J~H HN,_ J~IH CO
HN +~ HN iV N
~ N NHBoc . N NHAc Csla 'N NHJ
~ d. HN ~N'S ~ - O

IIa-58 IIa-59 IIa-60 Me J:~X H ~,j~ H ~ H
HN H HN ~~'~ HN ~ NHAc N N.Me . N NH2 N
O' O I J-N S ~ N-J
g~ N S
IIa-61 IIa-62 IIa-63 Me 0 Me Me N H N ,N H J-N H
HN H HN O HN H
N N N N 'N .Me N-~S O H N (N'~S OO
N S 'r01 J OMe IIa-64 IIa-65 IIa-66 Me Me Me HN t-tpH 0 HN ~N H Me,x e HN ~tp H H
N N~ c(NJYNHI1) N ~ I %Me r-I H N.Me O NS ~ (O O
~ NS
CNle OH
IIa-67 IIa-68 IIa-69 Me Me ~
HN '~H O HN f''~ H H HN
N ON) N ~ N ~ NH ~~
0 N-Me ~~-~
S Me' Me N S Me OMe S
IIa-70 IIa-71 IIa-72 Me Me Me ~JVH
~ JVH HNIV ~fVH HN N
HNfV
N ~NHAc ~ , N NHAc ~ NNHAc N-J~S ~ ~ HO ~. S
re"'O N -Me MeN,Me Me IIa-73 IIa-74 IIa-75 Me Me H '~H ~H
HN H HN H HN
N N,_Wle NN N ,Me ~LNNHAC N N S~ N S~~
~
F
IIa-76 IIa-77 IIa-78 _ rIH
HN ~IV
N
~IN~S~I

IIa-79 In another embodiment, this invention provides a composition comprising a compound of formula IIa 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 IIa 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 IIa 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 coiYtpound of formula IIa 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 IIa 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 0-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 IIa 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 IIa 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 IIa 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 IIa 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 IIa 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 IIa, 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 IIa, as described above.
Another embodiment of this invention relates to compounds of formula Iib:

R2.
~
NH
HN ~N
RX

DI N
RY N~O-Ri IIb or a pharmaceutically acceptable derivative or prodrug thereof, wherein;
R" and Ry 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" and RY is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4 ;

R' 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-R5, or V-Z-R5, and each substitutable ring nitrogen of, Ring D is independently substituted by -R4;
T is a valence bond or a C1_4 alkylidene chain;
Z is a Cl_4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6)-, -N(R6)-, -CO-, -COZ-, -N(R6)CO-, -N(R6)C(0)O-, -N(R6)CON(R6) -, -N(R6)S02N(R6) -, -N(R6)N( R6) -, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SOZ-, -C (R6) 2S02N (R6) -, -C (R.6) 2N (R.6) -, -C (R6) 2N (R6) C (0) ,-, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C(R6)2N(R6)CON(R6) -;
R2 and R2 ' are independently selected from -R, -T-W-R6, or R2 and R2' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R 2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=0) R, -CO2R, -COCOR, -COCH2COR, -NOZ,- -CN, -S (O) R, -S (0) 2R, -SR, -N (R4) 2, -CON (R') 2, -S02N (R') 2, -OC (=O) R, -N (R') COR, -N (R') CO2 (Cl_6 aliphatic), -N (R4) N (R4 ) 2, -C=NN (R4) a, -C=N-OR, -N (R') CON (R') 2, -N (R') SO2N (R') 2, -N (R4) S02R, or -OC (=O) N (R') Z;
each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R7, -COR', -C02(optionally substituted C1_6 aliphatic), -CON(R')2, or -S02R';
each R5 is independently selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -N02i -CN, -S (0) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) Z, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted C1_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R.4) 2, -N (R4) SOZN (R4) z, -N (R4) S02R, or -OC (=O) N (R4) 2;

V is -0-, -5-, -SO-, -SO2-, -N (R6) SOz-, -S02N(R6) -, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(O)O-, -N (R6) CON (R6) -, -N (R6) SO2N (R6) -, -N (R6) N (R6) -, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2SO-, -C (R6) 2SO2-, -C (R6) 2S02N (R6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (O) 0-, -C (R6) =NN (R6) -, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, or -C (R6) 2N (R6) CON (R6) - ;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2S02-, -C (R6) 2SO2N (R6) -, -C (R6) 2N (R6) -, -CO-, -C02-1 -C (R6) OC (O) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6) -, -C(R6)=N-O-, -C (R6) 2N (R6) N (R6) - , -C (R6) aN (R6) SO2N (R6) -, -C(R6)2N(R6)CON(R6)-, or -CON(R6)-;
each R6 is independently selected from hydrogen or an optionally substituted C1_4 aliphatic group, or two R6 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' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' 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" and RY include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/Ry ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula IIb are shown below.

R2, ' NH HN~ HN~~
HN N

0OR1 -:N , C:),~
N N
~

Iib-A IIb-B Iib-C
HN-~' HN'~~ HN'37'?

I N R N N N N
R4,N N N~~

IIb-D IIb-E IIb-k' HN'~~ HN'37'? HN'~~
N N~ I~N N N
N N~~ N C N
IIb-J IIb-K IIb-L

HN~~ HN'~~ HN'~~
S N O 7 N //N ~N
co \N N.N R4 IIb-P IIb-R IIb-V
HN3??

N
N ~
'N

IIb-W
More preferred pyrimidine ring systems of formula Iib include IIb-A, IIb-B, IIb-D, IIb-E, IIb-J, IIb-P, and IIb-V, most preferably IIb-A, IIb-B, IIb-D, IIb-E, and IIb-J.
The ring formed when R' and RY are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O (CHz) 2-4-N (R4) 2, -O (CHZ) 2-4-R, -OR, -N (R4) - (CH2) 2-4-N (R4) 2, -N (R4) - (CH2) 2-4-R.
-C (=O) R, -CO2R, -COCOR, -NO2, -CN, -S (O) R, -SO2R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) CO2 (optionally substituted C1-6 aliphatic) , -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) SO2N (R4) a, -N (R4) SOzR, or -OC (=O) N(R4) 2, R and R4 are as defined above. Preferred RX/R'' ring substituents include -halo, -R, -OR, -COR, -C02R, -CON(R4)2, -CN, -O (CH2) 2_4-N (R4) 2, -O (CH2) 2_4-R, , -NO2 -N (R4) 2, -NR4COR, -NR4S02R, -S02N(R4)2 wherein R is hydrogen or an optionally substituted C.1_6aliphatic group.
The R2 and R2' 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 IIb compounds having a pyrazole-containing bicyclic ring system:

i N
NH N N ~ N..k-HN N ~ I I
Rx ( ~N 'NNH NNH 'NNH NNH
RY 0-Ri , . . , and .
Preferred substituents on the R2/R2' fused ring of formula IIb include one or more of the following:
-halo, -N (R4) 2i -Cl_4 alkyl, -C1_4 haloalkyl, -N02i -O (Cl_4 alkyl) , -CO2 (C1_4 alkyl) , -CN, -S02 (Cl_4 alkyl) , -SOZNH2, -OC (O) NH2, -NH2SO2 (Cl_4 alkyl) , -NHC (O) (C1_4 alkyl) , -C (0) NH2i and -CO (C,._4 alkyl) , wherein the (C1_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C1_4 alkyl) group is methyl or ethyl.
When the pyrazole ring system of formula Iib is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, 25- heteroaryl, or a C,,_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring D of formula lib is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula Iib 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.
On Ring D of formula lib, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -S02N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred RS substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHS02Et, -NHS02(n-propyl), -NHSO2(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N (C02t-Bu) CH3, -NHCOCHzN (CH3) 2, -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2(morpholin-4-yl), -NHCOCH2CH2CH2 (morpholin-4-yl) , -NHCO2 (t-butyl) , -NH (C1_4 aliphatic) such as -NHMe,=
-N (C1_4 aliphatic) 2 such as -NMe2, OH, -O (C1_4 aliphatic) such as -OMe, C1_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C1_4 aliphatic).
Preferred formula IIb,compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R' is T-(Ring D), wherein T is a valence bond or a methylene unit;
(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
(d) R2 is -R or -T-W-R6 and R2' is hydrogen; or R2 and R2t are taken together to form an optionally substituted benzo ring; and (e) R3 is selected from -R, -halo, -OR, or -N (R4) 2.
More preferred compounds of formula Iib have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and R'' are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;
(b) R' 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;
(c) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C,._6 aliphatic, phenyl, a 5-6 membered hetero=aryl ring, or a 5-6 membered heterocyclic ring;.and (d) R3 is selected from -R, -halo, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, -or -N(R4) -.
Even more preferred compounds of formula IIb have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;
(b) R' is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;
(c) R2 is hydrogen or Cl_4 aliphatic and R2' is hydrogen;

(d) R3 is selected from -R, -OR, or -N(R4) 2, wherein R is selected from hydrogen, C1_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, -NO2, -N (R4) 2, optionally substituted C3,_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -SO2N (R4) 2, -N (R4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 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 lib are shown below in Table 2.
5.

Table 2.

Me Me .f~
NH
HN H HN~-tp H HN " N

N 'N O~ i i~ ~ c~c N O
IIb-l IIb-2 IIb-3 Me _~ " -~H ~'"
HN HN HN
N ~ N ~ N i ~ O ~ ~ --~ ~ ~
N O N O Me N O OMe IIb-4 IIb-5 IIb-6 Me Me Me HN, x H HN j -NN H HNt- 4PP H
OMe oc~o c~o> OMe N N IIb-7 IIb-8 IIb-9 in another embodiment, this invention provides a composition comprising a compound of formula Iib 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 Iib 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 IIb 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 lib 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 IIb 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 (3-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 Iib, 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 IIb, as described above.
Another embodiment of this invention relates to compounds of formula lic:

2' R
:NNH
HN
RX
N
RY I N~N-R1 H
IIc or a pharmaceutically acceptable derivative or prodrug thereof, wherein;
R" and Ry 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 RX and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4 ;
R'= 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-R5, or V-Z-R5, and each .
substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C1_4 alkylidene chain;
Z is a Cl_4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -SOZN(R6) -, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6)CON(R6) -, -N(R6)SO2N(R6) -. -N(R6)N(R6) -C (O) N (R6) -. -OC (O) N (R6) - , -C (R6) 20- , -C (R6) 2S- , -C (R6) 2S0-, -C (R6) 2S02-, -C (R.6) 2SO2N (R6) -,' -C (R6) 2N (R.6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R.6) =N-O- , -C (R6) 2N (R6) N (R6) - , -C (R6) 2N (R6) SO2N (R 6) - , or -C(R6)2N(R6)CON(R6) -;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2' 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 carbori of said fused ring formed by R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C(=O)R, -CO2R, -COCOR, -COCH2COR, -NO2, -CN, -S (O) R, -S (O) zR, -SR, -N (R4) 2, -CON (R7 ) 2, -SO2N (R7 ) 2, -OC (=O) R, -N (R7) COR, -N(R')CO2(Ci_6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N (R7) CON (R') 2, -N (R') S02N (R7 ) 2, -N (R4) S02R, or -OC(=0)N(R7 )2i each R is independently selected from hydrogen or an optionally substituted group selected from CI_6 aliphatic, C6_1.o aryl, a-heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R4 is independently selected from -R7, -COR', -C02 (optionally substituted C,._6 aliphatic), -CON (R') 2, or -S02R 7;

each R5 is independently selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) CO2 (optionally substituted C1_6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)SOaR, or -OC(=O)N(R4)Z;

V is -0-, -5-, -SO-, -SO2-, -N(R6)SO2-, -S02N(R6)-, -N (R6) -, - -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N (R6) CON (R6) -, -N (Rs) SOzN (R6) -, -N (R6) N (R6) -, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C (R6) 2S02N (R6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SOzN (R6) -, or -C (R6) 2N (R6) CON (R6) - ;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2SO-, -C (R6) 2S02-, -C(R6)2S02N(R6) -, -C(R.6)2N(R6) -, -CO-, -C02-, -C (R6) OC (O) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (O) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C(R6)2N(R6)N(R6) -, -C(R6)2N(R6)S02N(R6) -, -C(R6)2N(R6)CON(R6)-, or -CON(R6)-;
each R6 is independently selected from hydrogen or an optionally substituted C,,_4 aliphatic group, or two R6 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' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' 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" and Rx include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/Ry ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula IIc are shown below.

R2' ~NH
HN ~N HN031? HN'~~
()( N N
N'N-R' N, H

IIc-A IIc-B IIc-C
HN137, HN~~ HNO~~

I N R ~N N N
I
N_55J N
R4~N N~~

IIC-D IIC-E IIc-F
HN HN31? HN3rZ?
/ N Nv ~N UN~

NN NNN _~ZY) IIc-J Iic-K IIc-L
HN HN HN3'~

S ~N O 7N //N
D I N
( C ( ~ \N N~

Iic-P IIc-R IiC-V
HN'~~

N
N N
'4 R
IIc-W
More preferred pyrimidine ring systems of formula IIe 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' and Ry of formula IIc are taken together may be substituted or unsubstituted.
Suitable substituents include -R, halo, -O (CH2) 2-4-N (R4) 2, -O (CH2) 2-4-R, -OR, -N (R4) - (CH2) 2-4-N (R4) 2, -N (R4) - (CH2) 2-4-R, -C (=0) R, -CO2R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=0) R, -N (R4) COR, -N (R4) C02 (optionally substituted Ci-6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N (R4) S02N (R4) 2, -N (R4) S02R, or -OC (=O) N(R4) 2, R and R4 are as defined above. Preferred R"/RY ring substituents include -halo, -R, -OR, -COR, -C02R, -CON (R4) 2, -CN, -0 (CH2) 2_4-N (R4) 2, -O (CH2) 2_4-R, , -NO2 -N (R4) 2, -NR4COR, -NR4S02R, -S02N(R4)2 wherein R is hydrogen or an optionally substituted C1_6 aliphatic group.
The R2 and R2' groups of formula IIc 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 IIc compounds having a pyrazole-containing bicyclic ring system:

HN N N \ NN
Rx N
RY N~N-R1 _NNH NH 'NNH NNH
H , and Preferred substituents on the R2/R2' fused ring, of formula lic include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -Cl_4 haloalkyl, -NO2, -0 (Cl_4 alkyl) , -CO2 (C1_4 alkyl) , -CN, -SO2 (C1_4 alkyl) , -SO2NH2, -OC (O) NH2, -NH2SO2 (C1_4 alkyl) , -NHC (O) (Cl_4 alkyl) , -C (O) NH2, and -CO (C,,_4 alkyl) , wherein the (C,._4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C,._4 alkyl) group is methyl.
When the pyrazole ring system of formula Iic is monocyclic, 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 R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen. .
When Ring D of formula lic is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula lic is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[bjfuryl, benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIc, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) CO2R, -SO2N (R4) 2, -N (R'4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include'-C1, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHSO2Et, -NHSO2(n-propyl), -NHSO2(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( CO2 t -Bu ) CH3 , -NHCOCH2N ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2(morpholin-4-yl), -NHCOCH2CH2CH2(morpholin-.
4-yl), -NHCO2(t-butyl), -NH(C1_4 aliphatic) such as -NHMe, -N (Cl_4 aliphatic) 2 such as -NMe2, OH, -O (C1_4 aliphatic) such as -OMe, C1_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1._4, aliphatic).
Preferred formula lic compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry 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' and RY is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and RY is independently substituted by R4;
(b) R' is T- (Ring D), wherein T is a valence bond or a methylene unit;
(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
(d) R2 is -R or -T-W-R6 and R2' is hydrogen; or R2 and RZ1 are taken together to form an optionally substituted benzo ring; and (e) R3 is selected from -R, -halo, -OR, or -N (R4) 2.
More preferred compounds of formula IIc have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;
(b) R:' 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;
(c) R2 is -R and Rz' is hydrogen, wherein R is selected from hydrogen, C:L_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (d) R3 is=-selected from -R, -halo, -OR, or -N(R4)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 (R4) - .
Even more preferred compounds of formula Iic have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;
(b) R' is T-Ring D, wherein T is a valence bond and Ring D is-a 5-6 membered aryl or heteroaryl ring;
(c) R2 is hydrogen or Cl_4 aliphatic and R2' is hydrogen;

(d) R3 is selected from -R, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_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, -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) COZR, -SO2N (R4) 2, -N (R4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2, wherein R is - selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
Preferred compounds of formula Iic include compounds of formula Iic':

R2.
, . .. ... ~ NH .
HN
R"
N
RY N~N-Ri I
H
IIc' or a pharmaceutically acceptable derivative or prodrug thereof, wherein;
R" and Ry are taken together with their intervening atoms to form a fused benzo ring, wherein each substitutable ring carbon of said fused ring formed by RX and Ry is independently substituted by T-R3, or L-Z-R3;
R' 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 heterbatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C1_4 alkylidene chain;
Z is a C1_4 alkylidene chain;

L is -0-, -S-, -SO-, -SOz-, -N(R6)S02-, -S02N(R6)-, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6)CON(R6) -, -N(R6)S02N(R6) -, -N(R6)N(R6) -, -C (O) N (R6) - , '-OC (O) N (R6) -. -C (R6) 20-1 -C (R6) 2S-, -C (R6) 2S0-, -C (R.6) 2S02-, -C (R6) 2SOaN (R6) -, -C (R6) 2N (R6) - ~
-C (R6) 2N (R6) C (0) -, -C (R6) 2N (R6) C (0) O - , - C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) zN (R6) N (R6) - , -C (R6) 2N (R6) SO2N (Rs) -, or -C (R6) 2N (R6) CON (R6) -;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and Rz' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=0) R, -COZR, -COCOR, -COCH2COR, -NOZ, -CN, -S(O)R, -S(O)2R, -SR, -N (R4) zi -CON (R7 ) 2, -S02N (R7 ) 2, -OC,(=O) R, -N (R7) COR, -N (R') CO2 (C1_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R') CON (R') 2, -N (R') SO2N (R') 2, -N (R4) S02R, or -OC(=O)N(R7 )z;

each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R4 is independeritly selected from -R', -COR', -C02 (optionally substituted Cl_6 aliphatic), -CON (R') 2, or -S02R';
each RS is independently selected from -R, halo, -OR, -C (=0) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -SO2R, -SR, -N(R4)2, -CON(R4)a, -S02N(R4)2, -OC(=O)R, -N(R4)COR, -N (R4) C02 (optionally substituted Cl_6 aliphatic) , -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4 ) 2, -N(R4)SO2N(R4)2, -N(R4)S02R, or -OC(=O)N(R4)2;

V is -0-, -5-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6)-, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(0)O-, -N(R6)CON(R6) -, - -N(R6)S02N(R6) -, -N(R6)N(R6) -;

-C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)20-, -C(R6)2S-, -C (R(5) 2S0-, -C (R6) 2SO2-, -C (R6) 2S02N (R6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (0) -, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) zN (R6) CON (R6) -;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C (R6) 2S02N (R6) -, -C (R.6) 2N (R6) -, -CO-, -C02-, -C (R6) OC (O) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (0) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R.6)S02N(R6)-, -C (R6) 2N (R6) CON (R6) - , or -CON (R6) -;
each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 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' is independently selected from hydrogen or an optionally substituted Cz-6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
The ring formed when R" and Ry of formula ITc' are taken together may be substituted or unsubstituted.
Suitable substituents include -R, halo, -O (CH2) 2-4-N (R4) z, -O (CH2) 2-4-R., -OR, -N (R.4) - (CH2) 2-4-N (R4) 2, -N (R4) - (CH2) 2-4-R, -C (=0) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted C,._6 aliphatic), -N (R4) N (R4) 2, -C-NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2.
-N (R4) SO2N (R4) 2, -N (R4) SO2R, or -OC (=O) N(R4) 2, wherein R and R4 are as defined above. Preferred R"/Ry ring substituents include -halo, -R, -OR, -COR, -CO2R, -CON (R4) 2, -CN, -O (CH2) 2_4-N (R4) 2, -O (CH2) 2_4-R, , -NO2 -N (R4) 2, -NR4COR, -NR4SO2R, -SO2N (R4) 2, wherein R is hydrogen or an optionally substituted C,._6 aliphatic group.
The R2 and R2' groups of formula IIc' 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 IIc' compounds having a pyrazole-containing bicyclic ring system:

i NH
HN 'N r/~ N N \ N'~N
RX
Y ~~j - 1 ' NH NH NH NH
J~
R N N R N = ' N N N
H and .
Preferred substituents on the R2/R2' fused ring of formula Iic' include one or more of the following:
-halo, -N (R4) 2, --CZ_4 alkyl, -C1_4 haloalkyl, -NO2, -O (C1_4 alkyl) , -CO2 (Cl_4 alkyl) , -CN, -SO2 (C,,_4 alkyl) , -SO2NH2i -OC (O) NH2, -NH2SO2 (CI_4 alkyl ) , -NHC (O) (Cl_4 alkyl ) , -C (O) NHZ, and -CO (C1_4 alkyl) , wherein the (Cl_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C,._4 alkyl) group is methyl.
When the pyrazole ring system of formula Iic' is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci_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 R2' group is hydrogen.
When Ring D of formula Iic' is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIc' is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benziinidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, b'enzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIe', preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NO2, -N (R4) 2, optionally substituted C3.-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) CO2R, -SO2N (R4) 2, -N (R4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -C1, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me, -NHS02Et, -NHSOz(n-propyl), -NHSO2(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( COz t - Bu ) CH3 , -NHCOCH2N ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2 (morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholin-4-yl) , -NHCO2 (t-butyl) , -NH (C1_4 aliphatic) such as -NHMe, -N (C1_4 aliphatic) 2 such as -NMe2, OH, -O (C1_4 aliphatic) such as -OMe, C1_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1_4 aliphatic).
Preferred formula Iic' compounds have one or more,.and more preferably all, of the features selected from the group corisisting of:
(a) R' is T- (Ring D), wherein T is a valence bond or a methylene unit;
(b) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
(c) R 2 is -R or -T-W-R6 and R 2' is hydrogen; or R 2 and Ra1 are taken together to form an optionally substituted benzo ring; and (d) R3 is selected from -R, -halo, -OR, or -N (R4) 2.
More preferred compounds of formula IIc' have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R' 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;
(b) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (c) R3 is selected from -R, -halo, -OR, or -N (R4) z, wherein R is selected from hydrogen, C1_s aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is.-O-, -S-, or -N ( R4 ) - .
Even more preferred compounds of formula IIc' have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R:' is T-Ring D, wherein T is a valence bond and Ring D is-a 5-6 membered aryl or heteroaryl ring;
(b) R 2 is hydrogen or C,._4 aliphatic and R2' is hydrogen;

(c) R3 is selected from -R, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and (d) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
Other preferred compounds of formula IIc include compounds of formula Iic :

R2, i NH
. HN ~IV
R"
N
, RY N~N-Ri H
IIc or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R" and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, -5-7 membe=red-ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R" and RY is optionally substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is optionally substituted by R4;
provided that said fused ring formed by R" and Ry is other than benzo;

R' 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-R5, or V-Z-Rs, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C,._4 alkylidene chain;-Z is a Cl_4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -SO2N(R6)-, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(O)O-, -N (R6) CON (R6) -, -N (R6) S02N (R6) -, -N (R6) N (R6) -, -C(O)N(R6)-, -OC(O)N(R6)-, '-C(R6)20-, -C(R6)2S-, -C (R6) 2S0-, -C (R6) 2S02-, -C (R6) 2SO2N (R6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) 2N (R6) CON (R6) - J
Rz and R 2 ' are independently selected from -R, -.T-W-R6, or R2 and R2' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4; .

R3 is selected from -R, -halo, -OR, -C (=O) R, -C02R, -COCOR, -COCH2COR, -NO21 -CN, -S (0) R, -S (O) 2R, -SR, -N (R4) 2, -CON (R7 ) 2, -S02N (R7) Z, -OC (=O) R, -N (R7) COR, -N(R')C02(Cl_6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N (R7) CON (R7 ) 2, -N (R7) SO2N (R7) 2, -N (R4) S02R, or -OC(=0)N(R7)2;
each R is independently selected from hydrogen or an optionally substituted group selected from C,,_6 aliphatic, C6_lo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring-atoms;
each R4 is independently selected from -R7, -COR', -CO2 (optionally substituted Cl_6 aliphatic) , -CON (R') 2, or -S02R';
each R'5 is independently selected from -R, halo, -OR, -C (=O) R, -CO2R, -COCOR, -NO2, -CN, -S (O) R, -SO2R, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) CO2 (optionally substituted C3._6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) SO2N (R4) Z, -N (R4) S02R, or -OC (=O) N(R4) 2;

V is -0-, -5-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(0)0-, -N(R6)CON(R6) -, -N(R6)S02N(R6) -, -N(R6)N(R6) -, -C(O)N(R6)-, -OC(O)N(R6)-. -C(R6)20-, -C(R6)2S-, -C (R.6) 2S0-, -C (R.6) 2S02-, =C (R.6) 2SO2N (R6) - , -C (R6) 2N (R6) -, -C (R.6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) - ~ -C (R6) aN (R6) SO2N (R6) -, or -C(R6)2N(R6)CON(R6).-; .

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-1 -C(R(5)2S02N(R6)-, -C(R6)iN(R6)-, -CO-, -C02-, -C (R6) OC (O) -, -C (R6) OC (0) N (R6) -, -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (O) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C(R6)2N(R6)N(R6)-, -C(R.6)2N(R6)S02N(R6)-, - C ( R6 ) 2N ( R6 ) CON (R6-) - , or - CON ( R6 ) - ;
each R6 is independently selected from hydrogen or an optionally substituted C1_4 aliphatic group, or two R6 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' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' 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" and Ry of formula IIc" 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"/Ry ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula Iic" are shown below.
HN'~~ HN'~~ HN'~~

N
I N
C), NN"R4'N N

IIc"-B IIc"-C IIc"-D
HN'37? HN'~~ HN~3rZ'~

%. N I N N N
N~SS' N N N
IIc"-E IIc"-F IIc"-J
HN'377 HN'~~ HN3%?

N N S N
\ IN.~ \ N~
N
IIc"-K IIc"-L IIc"-P
HN'~~ HN3%? HN'~~ c:x~

IIc"-R IIc -V IIc"-W
More preferred pyrimidine ring systems of formula'IIc" include IIc"-B, IIc-D, IIc-E, IIc-J, IIc-P, and IIc-V, most preferably Iic-B, IIc-D, IIc-E, and IIc-J.

The ring formed when R" and Ry of formula Iic"
are taken together may be substituted or unsubstituted.
Suitable substituents include -R, halo, -O (CH2) 2-4-N (R4) 2, -O (CH2) 2-4-R, -OR, -N (R4) - (CH2) 2-4-N (R4) 2, -N (R4) - (CH2) 2-4-R, -C (=0) R, -CO2R, -COCOR, -NO2i -CN, -S (O) R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N (R4) CO2 (optionally substituted Cl_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) SO2N (R4) 2, - -N (R4) SOzR, - or -OC (=O) N(R4) 2, wherein R and R4 are as def ined above. Preferred R"/Ry ring substituents include -halo, -R, -OR, -COR, -C02R, -CON (R4) 2, -CN, -O (CHZ) 2_4-N (R4) 2, -O (CH2) 2_4-R, , -NO2 -N (R4) 2, -NR4COR, -NR4SO2R, -S02N (R4) 2 wherein R is hydrogen or an optionally substituted C1_6 aliphatic group.
The R2 and Rz' groups of formula IIc" 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 IIc"
compounds having a pyrazole-containing bicyclic ring system:

NH
HN N N N \ N ~N
Rx NH NH NH NH
RY NIN-R' N N
H and Preferred substituents on the R2/R2' fused ring 20' of formula IIc include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -Cl_4 haloalkyl, -NO2, -O (C1_4 alkyl), -COz (Cl_4 alkyl) , -CN, -SO2 (C1_4 alkyl) , -SO2NH2, -OC (O) NH2, -NH2S02 (Cl_4 alkyl) , -NHC (O) (C1_4 alkyl) , -C (O)NH2, and -CO (Cl_4 alkyl) , wherein the (Cl_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C,,_4 alkyl) group is methyl.
When the pyrazole ring system of formula IIc"
is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring D of formula IIc" is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula lic" 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.

On Ring D of formula IIc , preferred T-R5 or V-Z-R5 substituents include -halo., -CN, -NO2, -N (R4) 2, -optionally substituted C1_6 aliphatic group, -OR, -C(Q)R, -CO2R, -CONH (R4) ; -N (R4) COR, -N (R4) CO2R, -SO2N (R4) 2, -N (R4) SO2R, . -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHSO2Et, -NHSOz(n-propyl), -NHSO2(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( CO2 t - Bu ) CH3 , -NHCOCH2N ( CH3 ) 2, -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 21 -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2(morpholin-4-yl), -NHCOCH2CH2CH2(morpholin-4-yl) , -NHCO2 (t-butyl) , -NH (Cl_4 aliphatic) such as -NHMe, -N (Cl_4 aliphatic) 2 such as -NMe2, OH, -O (C1_4 aliphatic) .5 such as -OMe,. Cl_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1,_4 aliphatic).
Preferred formula IIc compounds have one or more, and more preferably-all, of the features selected from the group consisting of:
(a) R" and RY 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 6-membered carbocyclo ring; wherein each substitutable ring carbon of said fused ring formed by R" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry=is independently substituted by R4;
(b) R' 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;
(c) R2 is -R or -T-W-R6 and R2 , is hydrogen; or R2 and R2' are taken together to form an optionally substituted benzo ring; and =
(d) R3 is selected from -R, -halo, -OR, or -N (R4) 2.
More preferred compounds of formula Iic have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry 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" and Ry is independently su.bstituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R' 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;
(c) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (d) R3 is selected from -R, -halo, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl,. phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R4)-.
Even more preferred compounds of formula Iic"
have one or more, and more preferably all, of the features selected.from the group consisting of:
(a) R" and RY are taken together to form a pyrido, piperidino, or cyclohexo ring, wherein each substitutable ring carbon of said fused ring formed by R" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R' is T-Ring D, wherein T i's a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;
(c) R2 is hydrogen or C1_4 aliphatic and R2' is hydrogen;

(d) R3 is selected from -R, -OR, or -N (R4) a, wherein R is selected from hydrogen, Cl_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, -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) CO2R, -SO2N (R4) 2, -N (R4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 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 IIc are shown below in Table 3.

Table 3.

Me Me -~ NH
; NH HN;fV NH HN~f~( ' HNN
N N \I N' N- N~ N N cJ
IVIe OH

Iic-1 IIc-2 IIc-3 Me Me Me ~JVH
H HN ~~H HNIV
HN IV

N N ctLNo H H H
IIc-4 IIc-5 IIc-6 Me Me Me J~IH
; JVH HN N ; NH ~IV
HNIV
HN
O(LNJZXOJ N N~ N N
H H H H
IIc-7 IIc-8 IIc-9 Me Me Me HNflx H HN tIPH HN ~~H

N - N i N CI
-.Ll -~ ~ ~ ~ ~ ~ ~ .
N NN N N CE N N
H H H
IIC-lO IIc-11 IIc-12 Me Me Me HN ~~H ~N H N H
HN HN, N 'N i ONZYT
N ~ N N H T H H

OH
IIc-13 IIc-14 IIc-15 Me Me *H H ~H
HN HN HN
~ i cNJZL NN
OH ~ I OH ~ I
N N
H H ' H
ITc-16 IIc-17 Iic-18 H

HN HNJ'H HN J:~IPH
~
OMe ~
~I
N N N N
H H H
IIc-19 IIc-20 IIc-21 , NH
HNJIH HN~'f _ , NH HNnj ' CI
P, N ~ \ N ~ NHAc N :CMe, N-N ~ + N ~J-~ I ~J' H H N N Me N N H H

IIc-22 IIc-23 IIc-24 HN HN HN
N Et N Pr ~ i NN C.OH
~~ N N
H H H
IIc-25 IIc-26 IIc-27 HN JXH HN HN ~XH
N ~ OCOOH
~ ~ ~
N N N N N N
H H H
IIc-28 IIc-29 IIc-30 ~~H H ,_ JVH
HN HN HN
N CN N N .N ~ Me NN S ~ - ~~
N N N N Me H H H
IIc-31 IIc-32 IIc-33 HN HN HN
N ~ N
~O \ S o[5Nc(.COOH
N
H N N H N H~
N N
IIc-34 IIc-35 IIc-36 : JVH ;_ J~1H ; JVH
HN IV H HN IV HN Iv N N
Z~O% i . .N ( ,J" -J~ ( N N N!% -N N N COOMe H H H
IIc-37 IIc-38 IIc-39 -~H J~IPH JVH
HN HN HN
OJ1NIO...COOH '~ ~~ ~ ~I
N N N Et ~
N NMe H H H Me IIc-40 IIc-41 IIc-42 Me ;_ JVH HN J:~tPH HN; JVH
HNIV IV
i ~ i 0N#0%OMe i ~~ (~~
OMe N N
H H H
IIc-43 IIc-44 IIc-45 Me , T1H NH _ J~H
HN tV HN HNN

N cx cx N N N N N N Me H H

IIc-46 Iic-47 IIc=48 Me Me ;,j~ H ;'fq H H
HN "~ ~ HN ~'~ HN N Me O1NOMe H H H CI

IIc-49 IIc-50 IIc-51 Me Me HN J'~XH ~O HN NPH HN tpH
N i ~ a N N i -J- ~.l \~ Me N N N N N N Me H H H
IIc-52 IIc-53 IIc-54 Me Me Me ;_ j~H
HN ~fxH HN * H HNiV
. N NHAc N 'N i ONO(CN
N~N ~( Et N~N ~ I OMe I H H H

IIc-55 IIc-56 IIc-57 Me Me Me ,_ JVH
HN ,i JVH HN, ~ H HNN
V
N N ~ NHAc N o(Ncr.NHBoc H N N N
H H
IIc-58 IIC-59 IIc-60 Me Me Me ;_ H
~NH HN txH HNIV
HN CN i . a O O N
NN -Jk N H H N H
IIc-61 lIc-62 IIc-63 Me Me Me HN
HN.e-JVH , NH H, NH
IV N N N

i N cc CCLNCC IN i ~ NH2 ~ N Me Me N~N ~
H H H
Ilc-64 IIc-65 IIc-66 Me Me Et ~N H HN -~H H CH HN Cr'~ H
HN s H
N ~ N , N
Br - ~ ~ N~N ~ I O CH3 ' ~ N~NN~ ~ Et N N H H
H
IIc-67 IIc-68 IIc-69 ~~

HN HN H HN H
cxNHo N N a N CFN'-J~

IIc-70 IIc-71 IIc-72 HN HN HN '~.
H H
'N crN
i a 'N
~ --t ~ ~ -J~ ~
N N N N N N
H Me H CI
IIc-73 IIc-74 IIc-75 Me HN N H HN H HN H
N C( N i N ~' CN
-Jk ~ ~ ~ ~-J-N' N N N N N

IIc-76 IIc-77 IIc-78 Me Me Me ~~H ;~H ~~H
HN HN _ HN 'N i N ~
cxLNc N~ ~
Bn N N N Bn N N
H H H H
IIc-79 IIc-80 IIc-81 Me Me Me H ~N H 41P H
HN HN
Bn, Bn.N ~ N 1 N N~ ~ Bn.N IIN ~ I
I N N\Cl ~ ~/' ~
N N N N N
H H H H
IIc-82 IIc-83 IIc-84 Me N
,~H NH ' H
HN HN nj ' HN ~'~
~'N N CN N
HN NN N-.~N I. ~'L ~CN
H H N H ~ i IIc-85 IIc-86 IIc-87 F
HN H HN ~tpH HN H

N i,CN C~' ~ i~ CN NNN~ N N~ ~ ~
H H N N
H '~CN
IIc-88 rIc-89 IIc-90 In.another embodiment, this invention provides a composition comprising a compound of formula IIc, Iic', or Iic", 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 Iie, IIc', or IIc", 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 Iic, IIc', or Iic , 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 IIc, IIc', or Iic", 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 IIc, Iic', or IIc", 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 0-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 IIc, Iic', or IIc , 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 coniprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIc, Iic', or Iic", 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 IIc, IIc', or IIc", 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 Iic, Iic', or Iic", 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 IIc, IIc', or Iic", 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 lIc, IIc', or Iic", 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 Iic, Iic', or Iic", 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 IIa, IIc', or IIc", 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 IIc, IIc', or IIc", as described above.
Another embodiment that is particularly useful-for treating Aurora-2-mediated diseases relates to compounds of formula IId:

R2, e NH
HN Rx ~N
( Ry Q'-R1 N~
IId or a pharmaceutically acceptable derivative or prodrug thereof, wherein;
Q' is selected from -C(R6')2-, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;
R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R, and each substitutable ring nitrogen of said ring formed by R" and Ri' is independently substituted by R4 ;
R' 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-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a Cl_4 alkylidene chain,'wherein when Q' is -C (R6' ) z- a methylene group of said C1_4 alkylidene chain is optionally replaced by -0-, -S-, -N(R4) -, -CO-, -CONH-, -NHCO-, -SOz-, -SO2NH-, -NHSOz-, -COz-, -OC (O) -, -OC (O) NH-, or -NHCOz-;
Z is a Cl_4 alkylidene chain;

L is -0-, -S-, -SO-, -SOz-, -N(R) SO2-, -S02N(R6) -, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(O)O-, -N (R6) CON (R6) -, -N (R6) SO2N (R6) -, -N (R6) N (R6) - , -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)z0-, -C(R6)2S-, -C(R6)zS0-, -C(R6)2S02-, -C(R.6)2SO2N(R6-)-', -C(R6)zN(R6)-~
-C (R6) zN (R6) C (O) -, -C (R6) zN (R6) C (O) O-, 'C (R6) =NN (R6) -, -C(R6)=N-O-, -C(R6)zN(R6)N(R6)-, -C(R6)zN(R6)S0zN(R6)-, or - C ( R6 ) zN ( R6 ) CON ( R6 ) - ;
R 2 and Rz' are independently selected from -R, -T-W-R6, or R 2 and Rz' 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 stibstituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R 2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=O) R, -C02R, -COCOR, -COCH2COR, -NO2, -CN, -S (0) R; -S(O)-2R, -SR, -N (R4) 2., -CON (R7 ) 2, -SO2N (R7 ) 2, -OC (=O) R, -N (R7) COR, =N (R') CO2 (Cl_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R') CON (R') z, -N (R') SO2N (R') 2, -N (R4) S02R, or -OC(=O)N(R7 )2i each R is independently selected from hydrogen or an optionally substituted group selected from C,._6 aliphatic, C6_lo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R7, -COR', -C02 (optionally substituted C1_6 aliphatic) , -CON (R') 2, or -S02R';
each R5 is independently selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R:4) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) CO2 (optionally substituted C,._6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SOzN(R4)2, -N(R4)SO2R, or -OC(=0)N(R4)2;

V is -0-, -5-, -SO-, -SO2-, -N(R6) S02-1 -S02N(R6) -, -N(R6)'-, '-CO-, -C02-, -N(R6)CO-, -N(R6)C(0)O-, -N(R6)CON(R6) -, -N(R6) S02N(R6) -, -N(R6)N(R6) -, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S- , -C (R.6) aSO-, -C (R6) 2SO2-, -C (R6) 2S02N (R6) -, -C (R.6) 2N (R6) -, -C (R6) 2N (R6) C (0). - , -C (R6) 2N (R.6) C (0) 0-, -C (R6) =NN (R6) -, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, or -C (R6) 2N(R6) CON (R6) - ;

W is -C (R6) 20-. -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C (R6) 2S02N (R6) -, -C (R.6) 2N (R6) -, -CO-, -CO2-, -C (R6) OC (0) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)S02N(R6) -, -C (R6) 2N (R6) CON (R6) -, or -CON (R6) -;
each R6 is independently se-lected from hydrogen or an optionally substituted CI_4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R6' is independently selected from hydrogen or a C,._4 aliphatic group, or two R6' on the same carbon atom are.
taken together to form a 3-6 membered carbocyclic ring;
and each R' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' 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" and Ry include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/Ry ring is optionally substituted. This provides a bicyclic ring.system containing a pyrimidirie ring.
Examples of preferred pyrimidine ring systems of formula IId are shown below.

R?
R2' NNH HN~ HN'~
HN
N
N~Q'-Ri N

IId-A IId-B IId-C
HN'3'~ HN3%? AN1317 I __ N R %. N N __ N
R4~N N'0&1"~ N"Jy Iid-D ... IId-E - IId-F
HN13r~7 HN.3z? HN3Z?

N N~ ~N N I ~N

N N~~ N~~. \ N_SSJ
IId-J Iid-K IId-L
HN'3%? HNI~~ HN~~
s N O N //N N
CO ~ \IV N N ~,S' R4 IId-P IId-R IId-V
HN0~

N
N
R '4 IId-W
More preferred pyrimidine ring systems of formula IId include IId-A, IId-B, IId-D, IId-E, IId-J, IId-P, and IId-V, most preferably Iid-A, lid-B, IId-D, IId-E, and IId-J.

The ring formed when Rx and Ry of formula IId are taken together may be substituted or unsubstituted.
Suitable substituents include -R, halo, -O (CHa) Z-4-N (R4) 2, -O (CH2) 2-4-R, -OR, -N (R4) - (CH2) 2-4-N (R4) 2 . -N (R4) - (CH2) 2-4-R, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted Cl_6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N (R 4) S02N (R4) 2, -N(R4)S02R;- or -OC(=0)N(R4)2, R-and R4 are as defined above. Preferred R"/RY ring substituents include -halo, -R, -OR, -COR, -C02R, -CON(R4)2, -CN, -O (CH2) 2_4-N (R4) 2, -O (CH2) 2_4-R; , -NO2 -N (R4) 2, -NR4COR, -NR4S02R, -S02N(R4)2 wherein R is hydrogen or an optionally substituted C1_6 aliphatic group.
The R2 and R2' groups of formula lid 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 Iid compounds having a pyrazole-containing bicyclic.ring system:.

NH
N ~N N \ N~N
HN I
RX ~
NH NH NH NH
'( N N ~N N
Y
'1 2 0 R N Q-R I , , and Preferred substituents on the R2/R2' fused ring of formula lid include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -Cl_4 haloalkyl, -NO2, -O (Cl_4 alkyl) , -CO2 (Cl_4 alkyl) , -CN, -SO2 (C1_4 alkyl) , -SO2NH2, -OC (O) NH2i -NH2SO2 (Cl_4 alkyl) , -NHC (O) (Cl_4 alkyl) , -C (0) NH2, and -CO (C1_4 alkyl) , wherein the (Cl_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C1_4 alkyl) group is methyl.
When the pyrazole ring system of formula IId is monocyclic, preferred R2 groups include hydrogen or.a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring,D of formula Iid is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula Iid 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.
On Ring D of formula Iid, preferred T-R5 or V-Z-"
R5 substituents include -halo, -CN, -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR,'-C(O)R, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) CO2R, -SO2N (R4) Z, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, CI_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHS02Et, -NHSO2(n-propyl), -NHS02(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( C0z t -Bu ) CH3 , -NHCOCH2N ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 2, -NHCOCHZCH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCHZ(morpholin-4-yl), -NHCOCHZCH2(morpholin-4-yl), -NHCOCH2CH2CH2(morpholin-4-yl) , -NHC02(t-butyl) , -NH(Cl_4 aliphatic) such as -NHMe, -N (Cl_4 aliphatic) 2 such as -NMe2, OH, -O (C1_4 aliphatic) such as -OMe, C,_4 aliphatic such as methyl, =ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1_4 aliphatic).

Preferred Q' groups of formula Iid include -C (R6') 2- or l, 2-cyclopropanediyl, wherein each R6' is independently selected from hydrogen or methyl. A more preferred Q' group is -CH2-.
Preferred formula IIc compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry are taken together with t.heir 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is,independently substituted by R4;

(b) R1 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-;
(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;
(d) R2 is -R or -T-W-R6 and R 2' is hydrogen; or R2 and R21 are taken together to form an optionally substituted benzo ring; and (e) R3 is selected from -R, -halo, -OR, or -N (R4) 2.
More preferred compounds of formula Iic have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry are=taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;
(b) R' 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 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl.ring;
(c) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyciic ring;
(d) R3 is selected from -R, -halo, -OR, or -N (R4) 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(R4) -; and (e) Q' is -C(R6')2- or 1,2-cyclopropanediyl, wherein each R6' is independently selected from hydrogen or methyl.
Even more preferred compounds of formula IIc have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" and Ry are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;
(b) R' is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;
(c) R2 is hydrogen or C7._4 aliphatic and R2' is hydrogen;

(d) R3 is selected from -R, -OR, or -N (R4) 2i wherein R is selected from hydrogen, C1_6 aliphatic, 5-6 membered=heterocyclyl=, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-;
(e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N (R4) 2, optionally substituted C,:_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) CO2R, -SO2N (R4) 2, -N (R4) Sb2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CHZCHZN (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (f) Q' is -CH2-.
Representative compounds of formula IId are shown below in Table 4.

Table 4.

H
;JV NH HNJ:~XH
HN IV HN N
91 ~
N p I~

IId-1 IId-2 IId-3 Me Me Me HN QH HN rfpH HN~frpH
N N N
S ~ ~ ' 0 'o ~
N . N
N
.. . .. I ~ CI. I CI _ I ~ CI
IId-4 IId-5 IId-6 Me Me Me H -NH ;'j~ H
HN x HN~'~ HN~P
4,-1. N~ N~ ,N Me S ~, N N
Me ~
IId-7 IId-8 IId-9 Me Me Me ~~H
H ~NH HN
HN I'f HN I'( , i ~ N
N
N CI ,N CI N~ ~
N N N \ / 0 ~I
~
CI CI v'CI
IId-l0 IId-11 IId-12 Me ' J~IH
HN 'IV Me Me HN e:v N ; J~IH ; J~H
./HN N
N HNN .
~~~ cx0 N

IId=13 IId-14 IId-15 F
F ~ \
~
HN ~'~ H HN - ~'~ H HN ~H
91 N 'N i NN
N4V ~~~ - .
N~ . .. . . W. N ~~
IId-16 IId-17 IId-18 Me H
etP
HN N
IId-19 In another embodiment, this invention provides a composition comprising a compound of formula IId 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 Iid 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 Iid 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 Iid 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 IId 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 0-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 Iid or a composition comprising said compound.
Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises corritacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula Iid, 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 IId, as described above.

Another embodiment of this invention relates to compounds of formula IIIa:
R2.

)!r~NH
HN Rx Ry ~CNIS-R1 IIIa or a pharmaceutically acceptable derivative or prodrug thereof, wherein:' R" and Ry are independently selected from T-R3 or L-Z-R3;
R' 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-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C,,_4 alkylidene chain;
Z is a Cl_4 alkylidene chain;

L is -0-, -S-, -SO-1 -SO2-, -N(R6)S02-, -SO2N(R6)-, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(O)O-, -N(R6)CON(R6) -, -N (R6) S02N (R6) -, -N(R6)N(R6) -, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20- , -C (R6) 2S-, -C (R6) 2S0- , -C (R6) 2S02- , '-C (R6) 2S02N (R.6) - , -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (0) -, -C (R6) 2N (R6) C (0) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) - , -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) 2N(R6) CON (R6) -;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2' 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 R2' is independently substituted by halo, oxo, -CN, -N02, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=O) R, -C02R, -COCOR, -COCH2COR, -NO2, -CN, -S (0) R, -S (O) 2R, -SR, -N (R4) 2, -CON (R7 ) 2, -S02N (R7 )2, -OC (=O) R, -N (R7) COR, -N(R7)C02(C1_6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N (R7) CON (R') Z, .-N (R7) SO2N (R7 ) 2, -N (R4) S02R, or -OC(=O)N(R7 )2i each R is independently selected from hydrogen or an optionally substituted group selected from C,,_6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 i.s independently selected from -R', -COR', -CO2 (optionally substituted C1_6 aliphatic) ,-CON (R') 2, or -S02R7;

each R5 is independently selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N(R4)2, -CON(R4)2, -S02N(R4)2, -OC(=O)R, -N(R4)COR, -N (R4) C02 (optionally substituted C3._6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)S02R, or -OC(=O)N(R4)2;
V is -0-, -S-1 -SO-, -SO2-, -N(R6)SO2-, -S02N(R6)-, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(O)O-, -N(R6)CON(R6)-, -N(R6)S02N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)20-, -C(R6)2S-, -C (R6) 2S0-, -C (R6) 2S02- , -C (R6) 2SO2N (R6) -, -C (R.6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) - , -C (R.6) 2N (R6) SO2N (R6) -, or -C (R6) 2N (R6) CON (R6) - ;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) ZSO-, -C (R6) 2SO2-, -C (R6) 2S02N (R.6) -, -C (R6) 2N (R6) -, -CO-, -C02-, -C (R6) OC (0) -, "-C (R6) OC (0) N"(R6) -, -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) S02N (R6) -, -C (R6) 2N (R6) CON (R6) - , or -CON (R6) -;
each R6 is independently selected from hydrogen or an optionally substituted C1_4 aliphatic group, or two R6 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' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
Preferred R" groups of formula IIIa include hydrogen, alkyl- or dialkylamino, acetamido, or a C1_4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.
Preferred Ry groups of formula IiIa include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N (R4) -, -C (R6) 20-, -CO- and R3 is -R, -N(R4)2, or -OR. Examples of preferred Ry 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.
The R2 and R2' groups of formula IIIa 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 IIIa compounds having a pyrazole-containing bicyclic ring system:

NH N N ~ N~N
HN N ~ I -RX i NH NH NH NH

Ry C~ N S-R1 , and Preferred substituents on the RZ/R2' fused ring 15, of formula IIIa include one or=more of the following:
-halo, -N (R4) 2, -Ci_4 alkyl, -C1_4 haloalkyl, -NO2, -O (Cl_4 alkyl) , -C02 (Cl_4 a1ky1) , -CN, -S02 (Cl_4 alkyl) , -SO2NH2, -OC (O) NH21 -NH2SO2 (Cl_4 alkyl) , -NHC (O) (Cl_4 alkyl) , -C (O) NH2, and -CO (Cl_4 alkyl) , wherein the (C1_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C,,_4 alkyl) group is methyl.
When the pyrazole ring system of formula IIia is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2j group is hydrogen.
When Ring D of formula IIIa is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIIa 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.
On Ring D of formula IIIa, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NO2, -N (R4) 2, optionally substituted Cl_6 aliphatic group, -OR, -C(O)R, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -SO2N (R4) 2, -N (R4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C,._6 aliphatic, phenyl, a.'5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R.5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHS02Et, -NHS02(n-propyl), -NHSOz(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( CO2 t - Bu ) CH3 , -NHCOCH2N ( CH3 ) Z , -NHCOCH2CH2N ( CH3 ) 2 , -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2 (morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholin-4-yl), -NHC02(t-butyl), -NH(C1_4 aliphatic) such as -NHMe, -N (C1-4 aliphatic) 2 such as -NMe2, OH, -0 (Cl_4 aliphatic) such as -OMe, C,._4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C1_4 aliphatic).
Preferred formula IIIa compounds have one or more, and more preferably all, of the features selected from the group consisting of:

(a) R" is hydrogen, alkyl- or dialkylamino, acetamido, or =a C1_4 al-iphatic group;

(b) Ry is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N (R4) 2, or -OR;
(c) R1 is T- (Ring D), wherein T is a valence bond or a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (e) R2 is -R or -T-W-R6 and R2' is hydrogen, or R2 and R 21 are taken together to form an optionally substituted benzo ring.
More preferred compounds of formula IIIa have one or more, and more preferably all, of the=features selected from the group consisting of:

(a) RY is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected from -R, -OR, or -N(R4)Z, wherein R is selected from hydrogen, C,_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
(b) R' is T- (Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(d) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (e) L is -0-, -S-, or -.N(R4) -.
Even more preferred compounds of formula IIIa have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
(b) Ry 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;
(c) R1 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, -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, " -OR, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) SO2R, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2i and (d) R2 is hydrogen or a substituted or un.substituted Cl_6 aliphatic, and L is -0-, -S-, or -NH-.
Representative compounds of formula IIIa are, shown below in Table 5.

Table 5.

F
~
HN ~~'~ H HN J:~x H HN jr e ~
I QXLS.C%CO2Me NS ~ I e IIIa-i IIIa-2 IIIa-3 HN HN HN
Me N, \ I i Me ,N ~( i ~-~
Me N N S Me N S
IIIa-4 IIIa-5 IIIa-6 Me HN HN HN, IV _ JqH
IV

N ~ ~ z--ccio ~ ~ i ~ ~N N S ~ 0=1) Me,NJ ~ Me IIIa-7 IIIa-8 IIIa-9 Me Me Me HN ~~H HN~~'~ H HN * H
; Ac . N i ~
co ~ Q,~CNONH
N~S (NLS ~ ~~
~~
IIIa-10 IIIa-11 IIIa-12 Me Me Me ~JVH ;_ J~H e jqH
HN IV H HN IV HN N
N NiPr ~N N ~ NHxEt ( 0 ( - Me ' ~ ~ O
N S r N N S' N S
Me'NJ
IIIa-13 IIIa-14 IIIa-15 Me Me Me H
HN_ JVH H HNf-tlp NH HN -' JVH
HNf-tlp .N ~ N~ 'N a H N
N.SfPr 'N ~ I O~SfOEt 0~s N~ N~SO ~ S~ IIIa-16 IIIa-17 IIIa-18 Me Me Me HNtp H HN~N ~j~H H HNex H
'N NHAc N ~ NriBu 51N,0 NHAc M

e ~ ls ~ IIIa-19 IIIa-20 IIIa-21 Me Me Me HN~~'~ H HNf-tlp H HNf-tlp H H
O_.SOCHN I~ I N- ~ ~ Oe N,S ~ ~ iPr N ~ MeO

~ IIIa-22 IIIa-23 IIIa-24 Me Me Me J,H H t-tp HN H NMe2 HN r~ HN H
CrCl ..N .N
-JO ~-J~ N N !1 HN N S ~~
O ~~ MeO,J i CI CI
IIIa-25 IIIa-26 IIIa-27 Me Me Me ;_J~1H
;_JVH HN -f_JVH HNIV
HN fV
IV
~
,N
e 'NJ N O J N Me,N J'N
Me S I i CI
IIIa-28 IIIa-29 IIIa-30 Me Me ~H ~~H J+lH
HN HN H HN N H
~~~ ~~~ \( NO Me N ~ NxEt N N S t=6u N S ~S~ O
Me'NJ OMe IIIa-31 IIIa-32 IIIa-33 Me Me Me _ JVH _ J~IH J~H
HN IV HN IV HN N
MeO
-J, CI 'N e-.Il N SGN N S'YY ~J N S~
O 0 H i~02 o o IIIa-34 IIIa-35 IIIa-36 Me Me Me ~_ JVH
HN HNIV '__ JVH H HN N
~N N N ~ N Et ~
N N ~ C02Me (N~S ~ ~ O ~Ng ~ ~
Me'NJ S02 MeO MeO.

Q
IIIa-37 IIIa-38 IIIa-39 Me Me Me HN~t'~H HNetP H HNNH
"zN ~ OMe .
N N S N N S ~
o,J oJ ~.
OMe OMe ~
IIIa-40 IIIa-41 IIIa-42 Me Me Me ~,f~ ~ H ~ H
HN~'~ H HN ~ HN X
I oi~O
~N S O.J ~.%'NHAc OH NxEt H
NMe2 IIIa-43 IIIa-44 IIIa-45 Me Me Me ; J~H ~~H. ,~H H
HN N H HN H HN
xMe ~~(NN
-J~ O BuO ~ N~S ~ ~ O MeO ~ N~S ~~ O
N S

IIIa-46 IIIa-47 IIIa-48 Me Me Me ,~1 'w~H
HN~~H HN~f'~ H H HN ~~'~ H
Me N i NHAc ~N ~ NxEt H ~N N
HN NS ~ ~ N,S ~ ~ O N ~~~S ~ O

MeO" O
IIIa-49 IIIa-50 IIIa-51 Me Me Me 41PH HN ~N H H HN~~H H
HN
M N=Me N ~~ NHAc M N.Me '. N cJ.NEt Me0 N 01.NA
O I N'~g O
Me Me Me Me IIIa-52 IIIa-53 IIIa-54 Me Me Me t-tp H Me ,f~H ,.j~ H
HN H N=M e HN 1'~ H HN ''~ H
'N ~ N ( J 'N crEt N ~,Me Me2N ~ ~( 0O N N-1.S ~ N 0 N S ~N N S ~~
MeN.J Me%H
e IIIa-55 IIIa-56 IIIa-57 ,~H H
HN HN H HN ~'~ H

H -N crAc ~~~ Et Me ~ N
l, ~~
JOr O N S N S
2N' O S c Me -Me O .
N'Me IIIa-58 IIIa-59 IiIa-60 _PPH
HN J~H ~ NH H
HN ;V HN H ('N Njr-NMe2 ~ N ~ NHAc H ~ N ~ N ~~ Et N-S O
Me0 ~ NtS ~ ~ N C N~S ~ ~ O O
Me Me Me2N O NMe2 IIIa-61 IIIa-62 IIIa-63 In another embodiment, 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 IIIa 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 IIIa 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 IIia 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 IIIa 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.(3-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 IIIa 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 IIIa 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 IIIa 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 IIIa, 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 IiIa, as described above.
Another embodiment of this invention relates to compounds of formula Ilib:

R2~QNH
J'NH
HN RX

N
Ry ~ N~O-W
IIIb or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

R" and Ry are independently selected from T-R3 or L-Z-R3;
R' 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-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C1_4 alkylidene chain;
Z is a C,._4 alkylidene- chain;

L is -0-, -S-, -SO-, -S02-, -N(R6)S02-, -S02N(R6)-, -N(R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6)CON(R6) -, -N(R6)S02N(R6) -, -N(R6)N(R6) -, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)20-, -C(R6)2S-, -C (R6) 2S0-, -C (R6) 2SOa- 1 -C (R6) 2SOaN (R6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) O- , -C (R6) =NN (R6) -, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-. -C(R6)2N(R6)SO2N(R6)-, or -C (R6) 2N (R6) CON (R6) - ;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2' 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 20. R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R 2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=0) R, -C02R, -COCOR, -COCH2COR, -NO2, -CN, -S (O) R, -S (O) 2R, -SR, -N(R4)2, -CON(R7 ) 2, -S02N(R7 )2, -OC(=O)R, -N(R7)COR, -N(R')C02(C1_6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N (R7) CON (R7 ) 2, -N (R7) SO2N (R7 ) 2, -N (R4) S02R, or -OC(=O)N(R7)2;
each R is independently selected from hydrogen or an optionally substituted group selected from Cl_6 aliphatic, C6-loaryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R', -COR', -C02 (optionally substituted Cl_6 aliphatic), -CON (R') 2, or -SO2R';

each R5 is independently selected from -R, halo, -OR, -C (=O) R, -CO2R, -COCOR, -NO2, -CN, -S (0) R, -S02R, -SR, -N (R4) 2, -CON (R'4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted Cl_6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)S02N(R4)2r -N(R4)S02R, or -OC(=O)N(R4)2;
V is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6) -, -N(R6)-, -CO-, -C02-1 -N(R6)CO-, -N(R6)C(0)O-, -N(R6)CON(R6)-, -N(R6)S02N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-, -OC(0)N(R.6)-, =C(R6)20-, --C(R6)2S-, -C (R6) 2S0-, -C (R6) 2SO2 -, -C (R6) 2SO2N (R6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N'(R6) N (R6) -,. -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) 2N(R6) CON(R6) -;

20, W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2S02-, -C(R6)2S02N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-, -C (R6) OC (O) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) - -C (R6) 2N (R.6) SOaN (R.6) -C (R6) 2N (,R6) CON (R6) -, or -CON (R6) -;
each R6 is independently selected from hydrogen or an optionally substituted CI_4 aliphatic group, or two R6 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' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' on the same nitrogen are taken together with the.
nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred R" groups of formula IIib include hydrogen, alkyl- or dialkylamino, acetamido, or a C1_4 aliphatic -group such as- met-hyl, ethyl, cyclopropyl, or isopropyl.
Preferred Ry groups of formula IIIb include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N (R4) -, -C (R6) 20-, -CO- and R3 is -R, -N (R4) 2, or -OR. Examples of preferred Ry 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.
The R 2 and R 2' groups of formula IIib 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 IIIb compounds having a pyrazole-containing bicyclic ring system:

r' .
, NH YN N N N~N
HN N x R N NH NH NH NH
~ ~ N
Ry N O-Ri , , , , and Preferred substituents on the RZ/R2' fused ring of formula IIib include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -C,,_4 haloalkyl, -NO2, -0 (C1_4 alkyl), -CO2 (C2_4 alkyl) , -CN, -SO2 (Cl_4 alkyl) ,- -SO2NH2, -OC (O)NH2, -NH2SO2 (Cl_4 alkyl) , -NHC (O) (Cl_4 alkyl) , -C (O) NH2, and -CO (Cl_4 alkyl ), wherein the (C,._4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C,._4 alkyl) group is methyl. -When the pyrazole ring system of.formula IZIb is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring D of formula IIib is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIib 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.
On Ring D of formula IIIb, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NO2, -N (R4) 2, optionally substituted C,,_6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -S02N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C,._6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHSO2Et, -NHSO2 (n-propyl) ,. -NHSO2.(isopropyl) , = -NHCOEt, -NHCOCH2N~ICH3 , -NHCOCH2N ( C02t-Bu) CH3 , -NHCOCH2N ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl) , -NHCOCH2CH2 (niorpholin-4-yl) , -NHCOCH2CH2CH2(morpholin-4-yl) , -NHCO2 (t-butyl) , -NH (Cl_4 aliphatic) such as -NHMe, -N (C1_4 aliphatic) 2 such as -NMe2i OH, -O (Cl_4 aliphatic) such as -OMe, Cl_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C1_4 aliphatic).
Preferred formula IiIb compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen, alkyl- or dialkylamino, acetamido, or a C1_4 aliphatic group;
(b) Ry is T-R3 or L-Z-R3, wherein T-is a valence bond or a methylene and R3 is -R, -N (R4) 2, or -OR;
(c) R'- is T-(Ring D), wherein T is a valence bond or a methylene unit;

(d) 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-R6 and R 2' is hydrogen, or R2 and R2' are taken together to form an optionally substituted benzo ring.
More preferred compounds of formula IIIb have one or more, and more preferably all, of the features selected from the group consisting of:

(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected from -R, -OR, or -N(R4)a, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
(b) R' is T- (Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(d) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (e) L is -0-, -S-, or -N (R4) Even more preferred compounds of formula IIib have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
(b) Ry 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;

(c) R' 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, -NO2, -N (R4) 2, optionally substituted C,._6 aliphatic group, -OR, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) SO2R, -N (R6) COCH2CH2N (R4) Z, or -N (R6) COCH2CH2 CH2N (R4) 2; and (d) R2 is hydrogen or a substituted or unsubstituted Cl_6 aliphatic, and L is -0-, -S-, or -NH-.
Representative compounds of formula Ilib are shown below in Table 6.

Table 6.

HN H HN HN ~~'~ H
N i ~ ~I ~
N N
I NO \ I ~ O,1LOOCO2Me IIIb-1 IIIb-2 IIIb-3 HN HN HN
Me :xcco N O Me N O

IIIb-4 IIIb-5 IIIb-6 Me HN HN HN ~-X H

~~ ~N N~N &JOO
N O~ O MeMe IIIb-7 IIIb-8 IIIb-9 Me Me - Me _ NH
HN ,_ JVH HN _ 1'IH HN ~IV
Iv N
~ NHAc ~p ~p\ ~ J'p ' &CN i CrIN
III
b-10 IIIb-11 IIIb-12 Me Me Me H
HNr_rpH H HN e-Np HN r- _ J~
~N ~ NyiPr N N IV 0NHEt ~ ! I Me O
N O ~N N O' O

( ~ MeN~ IIIb-13 IIIb-14 IIIb-15 Me Me Me HN_ JVH H HN~N H AP H
IV H HN H
~N rr4 = N;SPr N.g.Et i f N i N I
caN
IIb-16 IIIb-17 IIIb-18 Me Me Me HN~~'P H HN eN H H HNf-4tp H
N NHAc ~ N \ I NHAc Q(NC..NI(IBU IIIb-19 IIIb-20 IIIb-21 Me Me Me HN" _~'~ H HN" _PP H HNt-tp H H
~ N NHAc QNONHAC

i eO IIIb-22 IIIb-23 IIIb-24 Me Me Me w~ H NMe2 HN NH
HN ~''' - ~ -J. ~ ~ NOJ 2 HN~~'~ N
- -J~
N
N O ~NeNLO HNeN O y OJ MeOJ ci ci IIIb-25 IIIb-26 IIIb-27 Me Me Me ~JVH
; JVH HN;IV J~H HN IV
HNIV

~J~ -J ~ -N
r-N N O (% O~ N O ~% ~J N
Me'NJ
Me' N ~
cl IIIb-28 IIIb-29 IIIb-30 In another embodiment, this invention provides a composition comprising a compound of formula IIIb and a pharmaceutically acceptable carrier.
Another aspect of this invention relates to a 5. 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 IlIb 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 IIIb 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 IIIb 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 IIIb 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 (3-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 IIib 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 IIIb, 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 IIIb, as described above.
Another embodiment of this invention relates to compounds of formula IIIc:

R

2, . . . . ... )!NH
HN N
Rx RY I N"N-R1 H
IIIc or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

R" and Ry are independently selected from T-R3 or L-Z-R3;
R' 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-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C,,_4 alkylidene chain;
Z is a C1_4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6)-,-N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(0)O-, -N(R6)CON(R6) -, -N(R6)S02N(R6) -, -N(R6)N(R6) -, -C (0) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2S02-, -C (R6) 2S02N (R.6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) 2N(R6) CON(R6) -;

R2 and R2' are independently selected from -R, -T-W-R6, or Rz and R2' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=O) R, -C02R, -COCOR, -COCH2COR, -NO2, -CN, -S (O) R, -S (O) 2R, -SR, -N (R4) 2, -CON (R7 )2, -SO2N (R7 ) 2, -OC (=O) R, -N (R7) COR, -N (R7) COa (Cl_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) Z, -C=N-OR, -N (R') CON (R') 2, -N (R7) SO2N (R7 ) 2, -N (R4) S02R, or -OC(=O)N(R7 )2i each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, C6_lo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R', -COR', -C02 (optionally substituted C3._6 aliphatic) ,-CON (R') 2, or -S0zR';
each R5 is independently selected from -R, halo, -OR,' -C (=O) R, -CO2R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted Cl_6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)SO2R, or -OC(=0)N(R4)2;
V is -0-, -S-1 -SO-, -S02-, -N(R6)S02-, -S02N(R6) -, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(0)O-, -N(R6) CON(R6) -, -N(R6) S02N(R6) -, -N(R6)N(R6) -, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)20-, -C(R6)2S-, '-C (R6) 2S0-;- -C (R6) 2S02-, -C (R6) 2S02N (R6) -, -C (Rg) 2N (R6) -, -C (R.6) 2N (R6) C (O) - , -C (R6) 2N (R6) C (O) 0-, -C (R6) =NN (R6) - , -C(R6)=N-O-, -C(R6)2N(R.6)N(R6)-, -C(R.6)2N(R6)SO2N(R6)-, or -C(R6) 2N(R6) CON(R6) -;

W is -C (R6) Z0-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C (R6) 2S02N (R6) -, -C (R6) 2N (R6) -, -CO-, -C02-, -C (R6) OC (O) - , -C (R6) OC (O) N (R6) - , -C (R6) 2N (R6) CO-, -C (R.6) 2N (R6) C (O) O-, -C (R.6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) - , -C (R.6) 2N (R6) S02N (R6) - , -C(R6)2N(R6)CON(R6) -, or -CON(R6) -;
each R6 is independently selected from hydrogen or an optionally substituted C1_4 aliphatic group, or two R6 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' is independently selected from hydrogen or an optionally substituted Cl_6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
Preferred R" groups of formula IIIc include hydrogen, alkyl- or dialkylamino, acetamido, or a C1_4 aliphatic group such as methyl, ethyl, cyclopropyl,, or isopropyl.
Preferred Ry groups of formula IIIc include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -5-, or -N(R4) -, -C(R6)20-, -CO- and R3 is -R, -N(R4)2, or -OR. Examples of preferred Ry 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.
The R2 and R2' groups of formula IIic may be taken together to form a fused ring, thusproviding 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:

HN N N ~ NN
R"
y ZN-R NH NH NH NH
R N N N ~N ~N
H and Preferred substituents on the R2/R2' fused ring of formula IIIc include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -Cl_4 haloalkyl, -NO21 -O (Cl_4 alkyl) , -CO2 (Cl_4 alkyl) , -CN, -SO2 (C1_4 alkyl) , -SO2NH2, -OC (O) NHZ, -NH2SO2 (Cl_4 alkyl) , -NHC (0) (Cl_4 alkyl) , -C (O) NH2r and -CO (Cl_4 alkyl) , wherein the (Cl_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C1_4 alkyl) group is methyl.
When the pyrazole ring system of formula IIIc is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring D of formula Ilic is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula Ilic 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.
On Ring D of formula IIIc, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -N02i -N (R4) 2, optionally substituted C:L_6 aliphatic group, -OR, -C(O)R, -C02R, -CONH (R4) ~, -N (R4) COR, -N (R4) C02R, -SO2N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) Z, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C,_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSOaMe, -NHS02Et, -NHS02(n-propyl), -NHS02(isopropyl), -NHCOEt, -NHCOCH2NHCH3 , -NHCOCH2N ( CO2 t -Bu ) CH3 , -NHCOCH2N ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2(morpholin-4-yl), -NHCOCH2CH2CH2(morpholin-4-y1), -NHC02(t-butyl), -NH(C1_4 aliphatic) such-as -NHMe, -N (C3._4 aliphatic) 2 such as -NMe2, OH, -O (Cl_4 aliphatic) such as -OMe, C1_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1_4 aliphatic).
Preferred formula Ilic compounds have one or more, and more-preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen, alkyl- or dialkylamino, acetamido, ora Cl_4 aliphatic group;

(b) Ry is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N (R4) 2, or -OR;
(c) R' is T- (Ring -D) , wherein T is a valence bond or a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (e) R2 is -R or -T-W-R6 and R2' is hydrogen, or R2 and R2' 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:

(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected from -R, -OR, or -N(R4)2, wherein R is selected from C1-6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
(b) R' is T- (Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(d) R2 is -R and R2' 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(R4)-.
Even more preferred compounds of formula IIIc have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
(b) Ry 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;
(c) R' 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, -NOZ,, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -CO2R, -CONH(R4) , -N (R4) COR, -N (R4) SO2R, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2; and (d) R2 is hydrogen or a substituted or unsubstituted C1_6 aliphatic, and L is -0-, -S-, or -NH-.
Representative compounds of formula IIIc are shown below in Table 7.
Table 7.

Me 'IV H rpH
' J~IH
HN HN HN
N N ~
0NC 0NC ~ ~N ~ I Me H H ~i H
IIIc-1 IIIc-2 IIIc-3 Me H NH ,tp HN HN HN
N iICN 'N N i I N'N N'N . N N ~ I CI
H H ~i H

IIIc-4 IIIc-5 IIIc-6 Me Me O ~

;_ JqH ~ JVH ''~~ H
HN N HN N HN ' ~ N ~ N ~ S02NH2 CI
Me0 ~ ~N~N CI M0 ~ ? N-N ~~ e -k ~~
(i ~~ H Me N N
Me0 Me0 H
OMe OMe IIIc-7. IIIc-8 IIIc-9 Me Ph Me f~H HN C~H ,~H
HNN,NN (~N ~~ CI HNN ~ CI
- .I)=NH ' ,.1 ~~
Et N N Me N N Et N N
H H H
IIic-10 IIIc-11 IIIc-12 tBu Ph ~~H eX HH
HN HN HN
~ ~ I N. N ~ I CI
QAO%cJ
~~ H H

IIIc-13 IIIc-14 IIIc-15 ff. Ph Me H H NH
HN HN HN N
~'N N~ ~N N~~ .N CI
~--NH ~ ~-NH ~~
Me N N Me N N Me N N
H H H
IIIc-16 IIIc-17 IIIc-18 Me Me Me HN IV HN HN
i MMe I N ~ I MeO ( N~~
H H
IIIc-19 IIIc-20 IIIc-21 Me Me Me ~_JVH
~tp H HN~N
HN -etp H HN"_ =N N \' ( N N ,= ~
MeO ~-NH MeO' N N N N Me N
H H H
IIIc-22 IIIc-23 IIIc-24 -144-' ~H '~H
HN H HN

J, ~I, I- ~IS
Me N N Me N N
H H
IIIc-25 IIIc-26 In another embodiment, this invention provides a composition comprising-a compound of formula IIIc and a pharmaceutically acceptable carrie"r.
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 effecti-ve 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 0-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.

Another embodiment of this invention relates to compounds of formula IIId:

R2' i NH
HN ~N
R"
I"
Ry N~Q'-R1 D
IIId 5, or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Q' is selected from -C(R6')2-, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, 'or 1,3-cyclobutanediyl;
R" and Ry are independently selected from T-R3 or L-Z-R3;
R' 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-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C,,_4 alkylidene chain, wherein when Q' is -C (R6') 2- a methylene group of said Cl_4 alkylidene chain is optionally replaced by -0-, -S-, -N(R4) -, -CO-, -CONH-, -NHCO-, -SO2-1 -SO2NH-, -NHSO2-, -C02-, -OC(O)-, -OC(O)NH-, or -NHCO2-;
Z is a C1_4 alkylidene chain;
L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6)-, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6) CON(R6) -, -N(R6) SO2N(R6) -, -N(R6)N(R6) -, -C (0) N (R6) -, -OC (O) N (R6) - , -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R.6) 2S02-, -C (R.6) 2S02N (R.6) -, -C (R.6) 2N (R6) -, -C (R6) 2N (R6) C (0) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) 2N (R6) CON (R6) - ;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2 ' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=O) R, -C02R, -COCOR, -COCH2COR, -NO2, -CN, -S (O) R, -S (O) 2R, -SR, -N (R4) 2, -CON (R') 2, -S02N (R7 ) 2, -OC (=O) R, -N (R7) COR, -N (R7) COZ (Cl_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R7) CON (R') 2, -N (R') SO2N (R') 2, -N (R4) S02R, or -OC (=O) N (R7 ) 2i each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R7, -COR', -CO2 (optionally substituted C1_6 aliphatic) , -CON (R') 2, ' or -S02R;
each R5 is independently selected from -R, halo, -OR, -C (=0) R, -C02R, -COCOR, -NO2, -CN, -S (0) R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -S02N(R4)2, -OC(=0)R, -N(R4)COR, -N (R4) C02 (optionally substituted Cl_6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -.N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)S02R, or -OC(=O)N(R4)2;

V is -0-, -S-, -SO-, -SO2-, -N (R6) S02-, -SO2N (R6) -, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O- , -N (R6) CON (R6) -, -N (R6) S02N (R6) -, -N (R6) N (R6) -, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2S02-, -C (R6) 2S02N (R6) -, -C (R.6) 2N (12.6) -, -C(R6)2N(R6)C(O) -, -C(R6)2N(R6)C(0)0-, -C(R6)=NN(R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) S02N (R6) -, or -C (R6) 2N (R6) CON (R6) -;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2S0z-, -C (R6) 2S02N(R6) -, -C (R6) 2N (R6) -, -CO-, -CO2-, -C (R6) OC (O) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C (R.6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, -C (R6) 2N (R6) CON (R6) -, or -CON (R6) -;
each R6 is independently selected from hydrogen or an.
optionally substituted C1_4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the riitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R6' is independently selected from hydrogen or a Cl_4 aliphatic group, or two R6' on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring;
and .30 each R' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
Preferred R" groups of formula IIId include hydrogen, alkyl- or dialkylamino, acetamido, or a C1_4 aliphatic group-such-as methyl, ethyl, cyclopropyl, or isopropyl.
Preferred RY groups of formula IIId include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N (R4) -, -C (R6) 20-, -CO- and R3 is -R, -N(R4)2, or -OR. Examples of preferred RY 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.
The R2 and R2' groups.of formula IIId 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 IIId compounds having a pyrazole-containing bicyclic ring system:

i NH N ~ N
HN N I N 1 ~ N

::H2R1, XNH I ~ NH NH NH
~ ~ , and Preferred substituents on the R2 /R2' fused ring of formula IIId include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -Cl_4 haloalkyl, -NO2, -O (C1_4 alkyl) ,. -CO2 (CI-4 alkyl) , - -CN, -SO2 (CI-4 alkyl) , . -SO2NH2, -OC (O) NH2i -NH2SO2 (C1_4 alkyl) , -NHC (O) (Cl_4 alkyl) , -C (O)NH2, and -CO (Cl_4 alkyl) , wherein the (CI-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (CI-4 alkyl) group is methyl.
When the pyrazole ring system of formula IIId is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring D of formula IIId is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIId 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.
On Ring D of formula IIId, preferred T-R5 or V-Z-RS substituents include -halo, -CN, -NO2, -N(R4)2, optionally substituted C3._6 aliphatic group,'-OR, -C(O)R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) CO2R, -SOzN (R4) 2, -N (R4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R'4) 2i and -N (R6) COCH2CH2CH2N (R4) z, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHSO2Et, -NHSO2(n-p-ropyl), -NHSO2(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( C02 t - Bu ) CH3 , -NHCOCH2N ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 2 , -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCHzCH2(morpholi.n-4-yl), -NHCOCH2CH2CH2(morpholin-4-yl), -NHCO2(t-butyl), -NH(C1_4 aliphatic) such as -NHMe, -N (C,._4 aliphatic)2 such as -NMe2, OH, -O (C,._4 aliphatic) such as -OMe, C,._4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1_4 aliphatic).
Preferred Q' groups of formula IIId include -C (R6') 2- or 1,2-cyclopropanediyl, wherein each R6' is independently selected from hydrogen or methyl. A more preferred Q' group is -CH2-.
Preferred formula IIId compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen, alkyl- or dialkylamino, acetamido, or a C,._4 aliphatic group;

(b) Ry is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N (R4) 2, or -OR;
(c) R' 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-;

(d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (e) R2 is -R or -T-W-R6 and R2 , is hydrogen, or R2 and R2' are taken together to form an optionally substituted benzo ring.
More preferred compounds of formula IIId have one or more, and more preferably all, of the features selected from the group consisting of:

(a) Ry is T-R3 or L-Z-R3 where-in T is -a valence bond or-a;nethylene and R3 is selected from -R, -OR, or -N(R4)2, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
(b) R' is T-(Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(d) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;

(e) L is -0-, -S-, or -N(R4) -; and (f) Q' is -C(R6")2- or 1,2-cyclopropanediyl, wherein each R6' is independently selected from hydrogen or methyl.
Even more preferred compounds of formula IIId have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
(b) Ry 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;
(c) R'- 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 option.ally substituted with one to two groups selected from -halo, -CN, -NO2, -N=(R4) Z; optionally subs-tituted -C1_6 aliphatic group, -OR, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) SO2R, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N ( R4 ) 2 ;
(d) R2 is hydrogen or a substituted or unsubstituted Cl_6 aliphatic; and L is -0-, -S-, or -NH-; and (e) Q' is -CH2-.
Representative compounds of formula IIId are shown below in Table 8.

Table 8.

O~ Ph ~ Ph ;_ JVH ;_ JVH NH
HN N HN N HN N
~~~O CI ~~~O CI ~'N
Me N ~ Me N ~ Me N4','0 _N
IIId-1 IIId-2 IIId-3 C C
Ph ,KpH HN ~H ,_ JVH
HN HN IV
.N N ~N
'.O Me I N~S ~5 ~
Me N Me N ~/
Me IIId-4 IIId-5 IIId-6 Ph p~
p--~H H ;' NH
HN HN HN
( 'N ~N
Me N'~S
~ . Me N ~ ~~~0 ~
Me F Me N I F
IIId-7 IIId-8 IIId-9 Me Me Me ;_ JVH
;_ j~H HNN ; j~H HNIV
HN IV
I ,j~S I j~p \ I ,p Et N ~~ Et N Et N ~~
F
IIId-10 IIId-ll IIId-12 Me Ph Me ; JVH ;_ jVH ~J~1H
HN IV HN IV HN tV
~ -N
Et N Me N'O -O
~ Me N ~
Me Me ( CI I CI

IIId-13 IIId-14 IIId-15 Me p' Me ;_J~IH ;_J~H ;_JVH
HN N HN IV HN IV
\ CI ,,/
MeO ~ N~O I Me eN~p \ N
~ Me N
v'CI CI CI
IIId-16 IIId-17 IIId-18 Me Me Me HN 'X H HN '_ jVH HN ~. J~IH
Me NCI Iv N
~
Me N \~ ~ ,N ,N ~
CI Et N Me N
IIId-19 IIId-20 IIId-21 Me Me Me J- H HN - x HN;NH
HN~ _ p H

~I, Me N \~ Et N Et ZN' IIId-22 IIId-23 IIId-24 In another embodiment, this invention provides a composition comprising a compound of formula IIId 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 IIId 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 IIId 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 IIId 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 IIId 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 0-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 IIId 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 IIId, 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 IIId, as described above.
Another embodiment of this invention relates to compounds of formula IVa:
2' R
NH
HN
R" ~ Z2 RyLz1'S_R1 IVa or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z' is nitrogen or C-R$ and Z2 is nitrogen or CH, wherein one of Z' or Z2 is nitrogen;
R" and Ry are independently selected from T-R3 or L-Z-R3, or R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;

R1 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-R5, or V-Z-RS, and each substitutable ring nitrogen of Ring D is independently substituted by -R;
T is a valence bond or a C,,_4 alkylidene chain;
Z is a C1_4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6)-, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6)CON.(R6)-, -N(R6)SO.2N.(R6).-, -N(R6)N(R6)-, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)20-, -C(R.6)2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C (R6) 2SO2N (R6) -. -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) 2N (R6) CON (R6) - ;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2 ' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=O) R, -C02R, -COCOR, -COCH2COR, -NOZ, -CN, -S (O) R, -S (O) ZR, -SR, -N (R4) 2, -CON (R') 2, -S02N (R7 ) 2, -OC (=O) R, -N (R7) COR, -N (R') CO2 (Cl_6 aliphatic) , -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N(R7)CON(R')2, -N(R')S02N(R7 )2, -N(R4)S02R, or -OC (=O) N (R7 ) 2i each R is independently selected from hydrogen or an optionally substituted group selected from Cl_6 aliphatic, C6_1,0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R', -COR', -CO2 (optionally substituted Cl_6 aliphatic) , -CON (R') 2, or -S02R7;

each R5 is independently selected from -R, halo, -OR, -C (=O) R; -C02R; -COCOR, -NO2, -CN, -S (0) R, -SOzR, -SR, -N(R4)2, -CON(R4)2, -S02N(R4)2, -OC(=O)R, -N(R4)COR, -N (R4) C02 (optionally substituted C1_6 aliphatic), -N(R4)N(R4)2i -C=NN(R4)2, -C=N-OR, -N(R4)CON(R.4)2, -N(R4)S02N(R4)2, -N(R4)S02R, or -OC(=O)N(R4)2;
V is -0-, -5-, -SO-, -S02-, -N (R6) S02-, -SOZN (R6) -, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N (R6) CON (R6) -, -N (R6) S02N (R6) - , -N (R6) N (R6) - , -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2SO-, -C (R.6) 2SO2-, -C (R6) 2S02N (R6) - , -C (R6) 2N (R.6) -, -C(R6)2N(R6)C(0)-, -C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C (R6) 2N (R6) CON (R6) - ;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2S02-, -C (R6) 2S02N (R6) -, -C (R6) 2N (R6) _ , -CO-, -C02-, -C (R6) OC (O) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SOzN (R6) -C(R6)2N(R6)CON(R6) -, or -CON(R6) -;
each R6 is independently selected from hydrogen or an optionally substituted Cz_4.aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R' is independently selected from hydrogen or an optionally substituted C3_6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R8 is selected from -R, halo, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S (O) R,. -SOzR, -SR, -N (R4 ) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted Cl_6 aliphatic),-N (R4) N(R4) 2, -C=NN (R4) 2, -C=N-OR, -N(R4)CON-(R412i --=N(R4)S02N(R4)2, -N(R4)S02R, or -OC (=O) N (R4) a. .
Preferred rings formed by R" and Ry of formula IVa include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVa are shown below.

R2.

NNH HN03Z? HN03%?
HN

~ I I 7iC)I ZiJ
Z1~ S-R1 IVa-A IVa-B IVa-C
HN13IZ7 HN'3%~ HN03~?

z2 R ~N ~Z2 ~Z2 R4 N ZZi'~J" z1,y IVa-D IVa-E IVa-F
HN ~~ HN -~~ HN 37?
~Z2 CIU
~Z2 ~Z2 N~
1 Zi-~ I Zi- Zi- ~ :~5j IVa-J IVa-K IVa-L
HN'3'~ HN3%? HN~3'Z?

Z2 O ~\ Z2 N I 1 Z2 ~ 1JN Z
Z1 o z ~' ' R4 .s~
IVa-P IVa-R IVa-V
HN~~

~ -,-Z2 N Z

IVa-W
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' is nitrogen and Z2 is CH.
Preferred R" groups of formula IVa include hydrogen, alkyl- or dialkylamino, acetamido, or a C1_4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.
Preferred Ry groups of formula IVa include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N (R4) -, -C (R6) 20-, -CO- and R3 is -R, -N (R4) 2r or -OR. Examples of preferred Ry 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.
The ring formed when the Rx and Ry groups of formula IVa are taken together may be substituted or unsubstituted. Suitable-substituents-include=-R, halo, -O (CH2) 2-4-N (R.4) 2t -O (CH2) 2-4-R, -OR, -N (R4) - (CH2) 2-4-N (R.4) 2, -N (R4) - (CH2) 2-4-R, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted Cl-6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) S02N (R4) 2, -N (R4) S02R, or -OC(=O)N(R4)2, R and R4 are as defined above. Preferred R"/Ry ring substituents include -halo, -R, -OR, -COR, -CO2R, -CON (R4) 2, -CN, -O (CH2) 2-4-N (R4) 2, -O (CH2) 2-4-R, , -NO2 -N (R4) 2, -NR4COR, -NR4S02R, -S02N (R4) 2 wherein R is hydrogen or an optionally substituted C31-6 aliphatic group.
The R2 and R2' 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:

NH N N N~N
HN N ~ 1 I
Rx ~2S NH NH NH NH
.~

-Ri , N , , , and Preferred substituents on the R2/R2' fused ring of formula IVa include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -C,,_4 haloalkyl, -NO2, -O (C1_4 alkyl) , -CO2 (C1_4 alkyl) , -CN, -S02 (C,._4 alkyl) , -SO2NH2, -OC (O) NHz, -NH2SO2 (Cl._4 alkyl) , -NHC (O) (C1_4 alkyl) , -C (0) NH2, and -CO (C,._4 alkyl) , wherein the (C1_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Cx_4 alkyl) group is methyl.
When the pyrazole ring system of formula IVa is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci_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 R2' group is hydrogen.
When Ring D of formula IVa is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IVa 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.
On Ring D of formula IVa, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NOz, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -C(O)R, -C02R, . -CONH (R4) , -N (R4) COR, -N (R4) C02R, -S02N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C,._6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered-heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me, -NHSO2Et, -NHS02 (n-propyl) , -NHS02(isopropyl), -NHCOEt, -NHCOCH2NHCH3, ' -NHCOCHZN ( COZ t - Bu) CH3 , = = -NHCOCHzN ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2(morpholin-4-yl), -NHCOCH2CH2CH2(morpholin-4-yl), -NHC02 (t-butyl) , -NH(C1_4 aliphatic) such as -NHMe, -N (Cl_4 aliphatic) 2 such as -NMe2, OH, -O (Cl_4 aliphatic) such as -OMe, C1_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1_4 aliphatic).
Preferred R8 groups of formula IVa, when present, include R, OR, and N(R4)2. Examples of preferred R8 include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3) 2CH2CH2NH, N(CH3) 2CHZCH2O, (piperidin=l-yl) CH2CH2O, and NH2CH2CH2O.
Preferred formula IVa compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) RX is hydrogen, alkyl- or dialkylamino, acetamido, or a Cl_4 aliphatic group and Ry is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N(R4)2, or -OR; or R" and Ry 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 Rx and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R1 is T- (Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D=is a 5-7-membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R2 is -R or -T-W-R6 and R2' is hydrogen, or R2. and R2' are taken together to form an optionally substituted benzo ring.
More preferred compounds of formula IVa have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected from -R, -OR, or -N(R4)2, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) Rl 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;
(c) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;and (d) R3 is selected from -R, -halo, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R4) -. ...

Even more preferred compounds of formula IVa have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and Ry is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethy7., cyclopropyl, isopropyl, t-butyl, alkoxyalkyl amino, *
alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or R" and Ry 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, -COR, -C02R, -CON (R4) 2, -CN, -O (CH2) 2_4-N (R4) 2, -O (CH2) 2_4-R, -NOZ
-N (R4) 2, -NR'COR, -NR4SO2R, or -SO2N (R4) 2, wherein R is hydrogen or an optionally substituted Cl_6 aliphatic group;
(b) R' 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, -NO2, -N(R4)2, optionally substituted C3,_6 aliphatic, -OR, -C (0) R, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -S02N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCHaCH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2;
(c) R2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group, and R2' is hydrogen; and (d) R3 is selected from -R, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_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; -NO2, -N (R4) 2, optionally substituted C1_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) CO2R, -SO2N (R4) 2, -N (R4) SO2R, -N ( R6 ) COCH2N ( R4 ) 2, -N (R6) COCH2CH2N ( R4 ) 2, or -N (R6) COCHZCH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_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 9.

Table 9.

Me ~
H
HN H H HN N H HN ~

\~ Ni4c C \~ S) IN S IS
N S N S ~
IVa-1 IVa-2 IVa-3 Me HN ~~'~ H HN jfr H HN
a5Lo S OOLO N'Ac \ IVa-4 IVa-5 IVa-6 Me ~
HNrlx H H HN HN _ H
i~ N i~ N iN S S
qc ~ I
N S N S
IVa-7 IVa-8 IVa-9 Me HN H HN JtPH H HN H
a S ([ N O NAc 1i a S S S OMe IVa-10 IVa-11 IVa-12 In another embodiment, 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 0-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 TVa, as described above.
Another embodiment of this invention relates to compounds o-f formula IVb:

2' R
i NH
HN
R"

RY Z1 O-Ri IVb or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z' is nitrogen or C-R8 and Z2 is nitrogen or CH, wherein one of Z' or Z2 is nitrogen;
R" and Ry are independently selected from T-R3 or L-Z-R3, or R" and Ry 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" and Ry is- independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
R'= 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-R5, or V-Z-RS, and each substitutable ring nitrogen of Ring D is independently substituted by =-R4; ..
T is a valence bond or a C1_4 alkylidene chain;
Z is a C,,_4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(0)0-, -N(R6)CON(R6) -, -N(R6) S02N(R6) -, -N(R6)N(R6) -, -C (O) N (R6) - , -OC (O) N (R6) - , -C (R6) 20-, -C (R6) ZS- , -C (R6) 2S0-, -C (R6) 2SO2-, -C (R6) 2SO2N (R6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (Rs) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R6) -, or -C(R6)zN(R6)CON(R6) -;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2 ' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -NO2, -R7, or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=O) R, -CO2R, "COCOR, -COCH2COR, -NO2, -CN, -S (O) R, -S (O) 2R, -SR., -N (R4) 2i -CON (R7) 2, -SO2N (R7 ) 2, -OC (=O) R, -N (R7) COR, -N (R7) CO2 (C1_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R') CON (R') 2, -N (R') SO2N (R7 ) 2, -N (R4) S02R, or -OC(=O)N(R7 )2;
each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having.5-10 ring atoms;
each R4 is independently selected from -R', -COR', -COa (optionally = substituted Cl_6 aliphatic),-CON (R') 2, or -S02R';
each R5 is independently selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2i -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) CO2 (optionally substituted Cl_6 aliphatic) , -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)S02N(R4)2, -N(R4)S02R, or -OC(=0)N(R4)2;

V is -0-, -S-, -SO-, -SO2-, -N(R6) S02-, -S02N(R6) -, -N (R6) -, -CO-, -CO2-, -N (R6) CO-, -N (R6) C (0) 0-, -N(R6) CON(R6) -, -N(R6) S02N(R6) -, -N(R6)N(R6) -, -C(O)N(R6) -, -OC(O)N(R6) -, -C(R6)20-, -C(R.6)2S-, -C (R6) ZSO-, -C (R6) 2S02-, -C (R6) 2S02N (R6) -, -C (R.6) 2N (R6) -, -C (R6) ZN (R6) C (0) -, -C (R6) 2N (R6) C (0) 0-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) - , -C (R.6) 2N (R6) SO2N (R6) -, or -C (R6) 2N (R6) CON (R6) - ;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SOZ-, -C(R6)2S 2N(R6)-. -C(R6)2N(R6)-, -CO-, -C02-, -C (R6) OC (O) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C(R6)2N(R6)C(0)0-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) S02N (R6) -, -C(R6)2N(R6)CON(R6)-, or -CON(R6)-;
each R6 is independently selected from hydrogen or an optionally substituted C1_4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R' is independently selected from hydrogen or an optionally substituted C1_6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R8 is selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) CO2 (optionally substituted Cl_6 aliphatic),-N (R4) N(R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) SOzN (R4) 2, -N (R4) S02R, or -OC(=O)N(R4)2.
Preferred rings formed by R" and Ry of formula IVb include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/Ry ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. Preferred pyrimidine ring systems of formula IVb are shown below.

R~~ _ NNH HNr~Z? HN'~Z?
HN
0 + z2 Z2 ~
~~ z'~
~
Z, Z2O-R, ~' IVb-A IVb-B IVb-C
HN'3%? HN-~~ HN'~~

Z2 R \N I \Z2 ~ \Z2 R4' N Z 1'=' Z 1'~~S' Z1,:SS' IVb-D IVb-E IVb-F
HN'3Z~ HN3rZ7 HN'~~
I NI. z2 N~ ( Z2 N I ~z2 N \ z1'~ \ Zi'y \ Z1'~y IVb-J IVb-K IVb-L
HN'3%~ HNO~~ HN~3%?

Z2 O 7 Z2 \N I 1 7 Z2 '~ 1'~S' N Z ~~
z ~s' co z /4 R
IVb-P IVb-R IVb-V
HN'~~

~Zz N Zi IVb-W
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, M-B, IVb-D, IVb-E, and IVb-J. Even more preferred pyridine ring systems of formula IVb are those described above, wherein Z' is nitrogen and Z2 is CH.
Preferred RX groups of formula IVb include hydrogen, alkyl- or dialkylamino, acetamido, or a C1_4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.
Preferred Ry groups of formula IVb include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N (R4) -, -C (R6) 20-, -CO- and R3 is -R, -N(R4)2, or -OR. Examples of preferred RY 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 dialkyl-amino 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" and Ry groups of formula IVba are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O (CH2) 2-4-N (R4) 2, -O (CH2) 2-4-R, -OR, -N (R4) - (CH2) 2-4-N (R4) 2, -N (R4) - (CH2) 2-4-R, -C (=O) R, -C02R, -COCOR, -N021-CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -SOZN (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted Cl-6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SOZN(R4)2, -N(R4)SO2R, or -OC (=O) N(R4) 2, R and R4 are as defined above. Preferred RX/Ry ring substituents include -halo, -R, -OR, -COR, -CO2R, -CON(R4)2, -CN, -O(CH2)2-4-N(R4)2, -O(CH2)2-4-R, , -NO2 -N (R4), , -NR4COR, -NR4SO2R, -SO2N (R4) 2 wherein R is hydrogen or an optionally substituted C,_6 aliphatic group.
The R 2 and R2' 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:
~ \
~
z:z NH ~ N SN', N
HN N ~ ?N
x ::Ri, ~Z2 NNH NH NH NNH
.~
and Preferred substituents on the R2/R2' fused ring of formula IVb include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -Cl_4 haloalkyl, -N02, -O (C1_4 alkyl) , -CO2 (C1_4 a1ky1) , -CN, -SO2 (Cl_4 alkyl) , -SO2NH2, -OC (O) NH2, -NH2SO2 (Cl_4 alkyl) , -NHC (0) (C1_4 alkyl) , -C (O)NH2, and -CO (C,._4 alkyl) , wherein the (C1_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Cl_4 alkyl) group is methyl.
When the pyrazole ring system of formula IVb is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include hydrogen, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A
preferred R2' group is hydrogen.
. When Ring D of formula IVb is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IVb is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyZ, benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IVb, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NO2, -N(R4)2, optionally substituted Cl_6 aliphatic group, -OR, -C(O)R, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -SO2N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2r -N (R6) COCH2CH2N (R4) 2e and -N (R6) COCH2CH2CH2N (R4) 2i wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me, -NHSO2Et, -NHS02(n-propyl.), -NHSO2(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( CO2 t -Bu ) CH3 , -NHCOCH2N ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 21 -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2(morpholin-4-yl), -NHCOCH2CH2CH2(morpholin-4-yl), -NHCO2(t-butyl), -NH(C1_4 aliphatic) such as -NHMe, -N (C1_4 aliphatic) 2 such as -NMe2, OH, -O (Cl_4 aliphatic) such as -OMe, C1_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1_4 aliphatic).
Preferred R8 groups of formula IVb, when present, include R, OR, and N(R4)2. Examples of preferred R$ include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3) 2CH2CH2NH, N(CH3) 2CH2CH2O, (piperidin-1-yl) CH2CH2O, and NH2CH2CH2O.
Preferred formula IVb compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen, alkyl- or dialkylamino, acetamido, or a C,,_4 aliphatic group and Ry is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N (R4) 2, or -OR; or R" and Ry are taken together with their in-tervening 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" and Ry is =independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independentlysubstituted by R4;

(b) Rl is T- (Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R2 is -R or -T-W-R6 and R2' is hydrogen, or R2 and R21 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:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected from -R, -OR, or -N(R4)2, wherein R is selected from hydrogen, C,._6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R'' is T- (Ring D), wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8-membered bicyclic aryl or heteroaryl ring;
(c) R2 is -R and R2' is hydrogen, wherein R is 5 selected from hydrogen,'Cl-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;and (d) R3 is selected from -R, -halo, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1-6 10 aliphatic, or 5-6 membered heterocyclyl, phenyl,.
or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R4) -.
Even more preferred compounds of formula IVb have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and Ry 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 RX and Ry 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, -COR, -CO2R, -CON (R4) 2, -CN, -O (CH2) 2-4-N (R4) 2, -O (CH2) 2-4-R, -NO2 -N (R4) 2, -NR4COR, -NR4S02R, or -S02N (R4) Z, wherein R is hydrogen or an optionally substituted C,,-6 aliphatic group;
(b) R' 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, -NO2, -N (R4) 2, optionally substituted Cl_6 aliphatic,.-OR, -C (0) R, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -S02N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2;
(c) R2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group, and R2' is hydrogen; and (d) R3 is selected from -R, -OR, or -N(R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is.-O-, -S-, or -NH-; and (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N (R4) 2, optionally substituted C3._6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) CO2R, -S02N (R4) 2, -N (R4) SO2R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, Cl_6 aliphatic, phenyl,. a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
Representative compounds of formula IVb are shown below in Table 10.

=181-Table 10.

Me H HN_ H
; J~1H H
_ JV HNN
HNIV
NZ
c a NAc C r cc"~ N 'g N O N O
IVb-1 IVb-2 IVb-3 Me HN '~'~ H HN Jiy H H HN _X H
~~i i Ac ~N ~~

O O OMe IVb-4 IVb-5 IVb-6 Me ~

~jVH H HN J:~PPH HN
HNIV
i NAc i N g ~i ~I S N O
N O N O ~
IVb-7 IVb-8 IVb-9 Me ~
HN f-Np H HN ~''~ H H HN -N H
I N INl i~N ,4c N~I
' , ' ~
~O~ S O~ O~ OMe IVb-10 IVb-il IVb-12 Me H
; JVH HN;fV J~H HN J_X
HN N
C \~ CN a5r%CN ~ ' IVb-13 IVb-14 IVb-15 Me '_J~IH
HN~N

IVb-16 In another embodiment, 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 0-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:

R2, NH
HN
R"
~Z2 .. .. . I ~~
RY Zi' N-Ri H
IVc or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Z' is nitrogen or C-R8 and Z2 is nitrogen or CH, wherein one of Z' or Z2 is nitrogen;
R" and Ry are independently selected from T-R3 or L-Z-R3, or R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
R' 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-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substitia.ted by -R4;
T is a valence bond or a C1_4 alkylidene chain;

Z is a Cl-4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R6)SOZ-, -SO2N(R6)-, -N(R6) -, -CO-, -C02-, -N(R6) CO-, -N (R6) C (O) O-, -N(R6)CON(R6) -, -N(R6)S02N(R6) -, -N(R6)N(R6) -, -C (O) N (R6) -., -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2SO2-, -C (R.6) 2S02N (R6) -, -C (R.6) 2N (R.6) -, -C (R6) 2N (R6) C (O) - , -C (R6) 2N (R6) C (0) O- , -C (R6) =NN (R6) -, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)S02N(R6)-, or -C(R6)2N(R6)CON(R6) -;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2' 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 R2 and R2' is independently substituted by halo, oxo, -CN, -N02i -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;
R3 is selected from -R, -halo, -OR, -C(=O)R, -CO2R, -COCOR, -COCH2COR, -NO2, -CN, -S (O) R, -S (0) 2R, -SR, -N W) 2, -CON (R7 ) 2, -SOZN (R7 ) 2, -OC (=O) R, -N (R7) COR, -N (R') C02 (Cl-6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4.) 2, -C=N-OR, -N (R') CON (R7 ) 2, -N (R7) S02N (R') 2, -N (R4) S02R, or -OC(=O)N(R7 )2i each R is independently selected from hydrogen or an optionally substituted group selected from C1_6 aliphatic, C6=-lo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R', -COR', -C02 (optionally substituted Cl-6 aliphatic), -CON (R') 2, ' or -SO2R;

each R5 is independently selected from -R, halo, -OR, -C (=0) R, -C02R, -COCOR, -N02r -CN, -S (0) R, -SOzR, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) CO2 (optionally substituted C1_6 aliphatic), -N (R4) N (R4) 2., -C=NN (R4') 2, -C=N-OR, -N (R4) CON=(R4) 2, -N(R4)S02N(R4)Z, -N(R4)S02R, or -OC(=O)N(R4)2;

V is -0-, -5-, -SO-, -SO2-, -N(R6)S02-, -S02N(R6)-, -N(R6)-, -CO-, -C02-, -N(R6)CO-, -N(R6)C(0)O-, -N(R6)CON(R6)-, -N(R6)S02N(R6)-, -N(R6)N(R6)-, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2SO-, -C (R6) 2S02-, -C (R6) 2S02N (R6) - , -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) S02N (R6) -, or -C (R6) 2N (R6) CON (R6) -;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) ZSO-, -C (R6) 2S02-, -C (R6) 2SO2N (R6) -. -C (R6) 2N (R6) -, -CO-, -COz-, -C (R6) OC (0) -, -C (R6) OC (O) N (R6) -, -C (R6) 2N (R6) CO-, -C (R6) 2N (R6) C (O) O-, -C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) S02N (R6) -, -C(R6)2N(R6)CON(R6) -, or -CON(R6) -;
each R6 is independently selected from hydrogen or an optionally substituted C,,_4 aliphatic group, or two R6 groups on the same nitrogen atom.are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R' is independently selected from hydrogen or an optionally substituted C,,_6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R 8 is selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=0) R, -N (R4) COR, -N (R4) C02 (optionally substituted C3._6 aliphatic) ,-N (R4) N(R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) SO2N (R4) 2, -N (R4) S02R, or -OC(=O)N(R4)Z.
Preferred rings formed by R" and Ry of formula IVc=include a 5-,.6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVc are shown below.

R2.

NH
HN ~N HN3%? HNI~~
~ ' ~2 Z2 '2 ~ ' ' 0Zi N-Ri z1 ~,' Z1 S' H .S
IVc-A IVc-B IVc-C

HN HN-3 -? HN3~7 ~Z2 R4 N ~Z2 z2 R4~N IZi'~.' Zi~~ Z1' ~

IVc-D IVc-E IVc-F
HN,3%? HN3%? HN3rZ?
C]I ~2 N~z2 CN ~,z2 ~~ 1 Z,-~

~So IVc-J IVc-K IVc-L

HN~ HN3%? HN'~~

\ z2 O('Z2 N I 1 Z2 ' ,'.~ N -~
Z ~S' O Z R4 z ~
IVe-P IVc-R IVc-V
HN ~~

:Jt%zllJ%~sJ.
IVc-W
More preferred pyridine ring systems of formula IVc include IVe-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 IVc are those described above, wherein Z' is nitrogen and Z2 is CH
Preferred RX groups of formula IVe include hydrogen, alkyl- or dialkylamino, acetamido, or a C,,_4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl. -Preferred Ry groups of formula IVe include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -5-, or -N (R4) -, -C (R6) 20-, -CO- and R3 is -R, -N(R4)2, or -OR. Examples of preferred Ry 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.
The ring formed when the R" and Ry groups of formula IVc are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O (CH2) 2-4-N (R4) 2. -O (CH2) 2-a-R, -OR, -N (R.4) - (CH2) 2-4-N (R4) 2, -N (R4) - (CH2) 2_4-R, -C (=O) R, -COZR, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally siubstituted Cl_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) SO2N (R4) 2, -N (R4) S02R, or -OC (=O) N(R4) 2, R and R4 are as defined above. Preferred R"/Ry ring substituents include -halo, -R, -OR, -COR, -C02R, -CON (R4) 2, -CN, -O (CH2) a_4-N (R4) z, -O (CH2) 2_4-R, , -NO2 -N (R4) 2, -NR4COR, -NR4S02R, -SO2N (R4) Z wherein R is hydrogen or an optionally substituted C1_6 aliphatic group.
The R2 and R2' groups of formula IVc 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 IVc compounds having a pyrazole-containing bicyclic ring system:

HN N N 'N N~N

R"RYI Zi Z2 NH NH NH NH
~ N

H , , , , and .

Preferred substituents on the R2/R2' fused ring of formula TVc include one or more of the following:
-halo, -N (R4) z, -CI_4 alkyl, -C3,_4 haloalkyl, -NO2, -0 (C1_4 alkyl) , -CO2 (CI-4 alkyl) , -CN, -SO2 (CI-4 alkyl) , -SO2NH2, -OC (0) NHZ, -NH2SO2 (CI-4 alkyl ) , -NHC (O) (C1_4 alkyl ) , -C (O)NH2,~ and -CO (CI-4 alkyl) , wherein the (Cl_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Cl_4 alkyl) group is methyl.
When the pyrazole ring system of formula IVc is monocyclic, 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 R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring D of formula IVc is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IVc 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.
On Ring D of formula IVc, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NO2, -N (R4) 2, optionally substituted C7._6 aliphatic group, -OR, -C(O)R, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -SO2N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, Cl_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2i ' -NHAc, -NHS02Me, -NHS02Et, -NHS02 (n-propyl) , -NHS02(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( C02 t -Bu ) CH3 , -NHCOCH2N ( CH3 ) 2 , -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2CH2CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2(morpholin-4-yl), -NHCOCH2CH2CH2(morpholin-4-yl), -NHC02 (t-butyl) , -NH(C1_4 aliphatic) such as -NHMe, -N (C1_4 aliphatic) 2 such as -NMe2, OH, -O (Cl_4 aliphatic) such as -OMe, C1_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C1_4 aliphatic).
Preferred R8 groups of formula IVc, when present, include R, OR, and N(R4)2. Examples of preferred R8 include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3) 2CH2CH2NH, N(CH3) 2CH2CH2O, (piperidin-1-yl) CHZCH2O, and NH2CH2CH2O.
Preferred formula IVc compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen, alkyl- or dialkylamino, acetamido, or a C1_4 aliphatic group and Ry is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N (R4) 2, or -OR; or R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R' is T- (Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R2 is -R or -T-W-R6 and R2' is hydrogen, or R2 and R2' are taken together to form an optionally substituted benzo ring.
More preferred compounds of formula IVc have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected fromr-R, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl,, phenyl, or 5-6 membered heteroaryl; or R" and Ry 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 RX and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R' 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;
(c) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;and (d) R3 is selected from -R, -halo, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R4) -.
Even more preferred compounds of formula IVc have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and Ry 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 Rx and Ry 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, -COR, -C02R, -CON (R4) 2, -CN, -O (CH2) 2_4-N (R4) Z, -O (CH2) 2_4-R, -NO2 -N (R4) 2r -NR4COR, -NR4SOZR, or -SO2N (R4) 2, wherein R is hydrogen or an optionally substituted C,,_6 aliphatic group;
(b) R' 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, -NO2, -N (R4) 2, 3.0 optionally -substituted Ci_6 aliphatic, -OR, -C (0) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -SO2N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2;

(c) R2 is hydrogen or a substituted or unsu:bstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group, and R 2 ' is hydrogen; and (d) R3 is selected from -R, -OR, or -N (R4) 2, wherein R is se-lected from hydrogen, Cl_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, -NO2, -N (R4) 2, optionally substituted Cl_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) COzR, -SO2N (R4) 2, -N (R4) S02R, -N (R6) COCHZN (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
Representative compounds of formula IVc are shown below in Table 11.

Table 11.

Me ~ '.j~ H
HN '~H HN _''~ HN XH H
N'S02Me ' N N N
N H H. H N H
IVc-1 IVc-2 IVc-3 Me ,H , HN ~ '~H
H N~H
HN
N -N
N N N
H H H H
IVc-4 IVc-5 IVc-6 Me H
HN rpH HN HN H
crx I~ ~I N'SOMe N NN N Gj- N N"v H H H H
IVc-7 IVc-S IVc-9 Me H J~-X H N H H
HN HN IV
N i~ . -N
N Gj- ~j~ H N
H H H H
IVc-10 IVc-11 IVc-12 In another embodiment, this invention provides a composition comprising a compound of formula IVc 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 IVc 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 IVc 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 IVc 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 IVc 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 0-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 IVc 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 IVc, 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 IVc, as described above.
Another embodiment of this invention relates to compounds of formula IVd:

R2.

_NH
HN N
R"

/
RY Zi Q'-R1 IVd or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z'= is nitrogen or C-R8 and Z2 is nitrogen or CH, wherein one of Z' or Z2 is nitrogen;
Q' is selected from -C(R6')2-, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;
R" and Ry are, independently selected from T-R3 or L-Z-R3, or R" and Ry 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" and RY is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by Rx and Ry is independently substituted by R4;

R' 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-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;
T is a valence bond or a C,._4 alkylidene chain, wherein when Q' is -C (R6') 2- a methylene group of said C1_4 alkylidene chain is optionally replaced by -0-, -S-, -N(R4) -, -CO-, -CONH-, -NHCO-, -SO2-, -SO2NH-, -NHSO2-, -C02-, -OC(O)-, -OC(O)NH-, or -NHCO2-;
Z is a C1_4 alkylidene chain;
L is -0-, -S-, -SO-, -SO2-, -N(R6)S02-, -SO2N(R6)-, -N (R6) -, -CO-, -C02-, -N(R6) CO-, -N (R6) C (O) O-, -N (R6) CON (R6) -, -N (R6) SOzN (R6) -, -N (R6) N (R6) - , -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2S0-, -C (R6) 2S02-, -C (R6) 2S02N (R6) -, -C (R6) 2N(R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (O) O - , - C (R6) =NN (R6) -, -C (R6) =N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SOZN (R6) -, or -C (R6) 2N (R6) CON (R6) - ;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2' 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 R2 and R 2' is independently substituted by halo, oxo, -CN, -NO2, -R', or -V-R6, and each substitutable ring nitrogen of said ring formed by R2 and R2' is independently substituted by R4;

R3 is selected from -R, -halo, -OR, -C (=O) R, -CO2R, -COCOR, -COCH2COR, -NO2, -CN, -S(O)R, -S(0)2R, -SR, -N (R4) 2, -CON (R7 ) 2, -SO2N (R7 ) 2, -OC (=O) R, -N (R') COR, -N(R')C02(Cl-6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N (R7) CON.(R7 )2, -N (R7) SO2N (R7 ) 2, -N (R4) S02R, or -OC(=O)N(R')2;
each R is independently selected from hydrogen or an optionally substituted group selected from C,._6 aliphatic, C6_10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R7, -COR', -CO2 (optionally substituted C,._6 aliphatic) , -CON (R') 2, or -S02R7;

each R5 is independently selected from -R, halo, -OR, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N(R4)2, -CON(R4)2, -S02N(R4)2, -OC(=O)R, -N(R4)COR, -N (R4) CO2 (optionally substituted Cl_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N(R4)SO2N(R4)2, -N(R4)SO2R, or -OC(=O)N(R4)2;

V is -0-, -5-, -SO-, -SO2-, -N (R6) S02-, -S02N(R6) -, -N (R6) -, -CO-, -C02-, -N (R6) CO-, -N (R6) C (O) O-, -N(R6)CON(R6)'-, -N(R6)S02N(R6)-, -N(R6)N(R6)-, -C (O) N (R6) -, -OC (O) N (R6) -, -C (R6) 20-, -C (R6) 2S-, -C (R6) 2SO-, -C (R6) 2S02-, -C (R6) 2SO2N (R6) -, -C (R6) 2N (R6) -, -C (R6) 2N (R6) C (O) -, -C (R6) 2N (R6) C (O) O- , -C (R6) =NN (R6) -, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)S02N(R6)-, or -C (R6) 2N (R6) CON (R6) - ;

W is -C (R6) 20-, -C (R6) 2S-, -C (R6) 2SO-, -C (R6) aS02-, -C (R6) 2SO2N (R6) -, -C (R6) 2N (R6) -, -CO-, -C02-, -C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-', -C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6) -, -C(R6)=N-O-, -C (R6) 2N (R6) N (R6) -, -C (R6) 2N (R6) SO2N (R.6) -, -C(R6)2N(R6)CON(R6) -, or -CON(R6) -;
each R6 is independently selected from hydrogen or an optionally substituted C1_4 aliphatic group, or two R6 groups on the s-ame nitrogen atom are taken-together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R6' is independently selected from hydrogen or a Cl_4 aliphatic group, or two R6' on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring;
each R' is independently selected from hydrogen or an optionally substituted Ci_6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R8 is selected from -R, halo, -OR, -C (=O) R, -CO2R, -COCOR, -NOZ, -CN, -S (O) R, -SO2R, -SR, -N (R4) 2, -CON (R4) 2, -SO2N (R4) 2, -OC (=0) R, -N (R4) COR, -N (R4) CO2 (optionally substituted C1_6 aliphatic),-N (R4) N(R4) 2, =C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) S02N (R4) 2, -N (R4) SO2R, or -OC(=O)N(R4)2.
Preferred rings formed by R" and Ry of formula IVd include a 5-', 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R"/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVa are shown below.

2' R
~NH
HN 'N HN HN3Z?

/I
l1-Z2 \ ~
Z CH2R1 Zi IVd-A IVd-B IVd-C
HN'3'L? HN3L? HN'~~
I - - Z2 R4 NI --Z2 0 I ~ Z2 R4, N Zij~ Z1- Zi- ~ y IVd-D IVd-E IVd-F
HN131? HN3rZ? HN'~~
N'. Z2 N N,Z2 CN NZi'~\ XLz2 Zi~
y IVd-J IVd-K IVd-L
HN'3%? HN'37'? HN3L?
S Z2 ,N I~ Z2 ,CXZ2 ''N
Z Y o Z /4 R
IVd-P IVd-R IVd-V
HN~37?

N I Zi-~
/4 ~
R
IVd-W

More preferred pyridine ring systems of formula IVd include IVd-A, IVd-B, IVd-D, IVd-E, IVd-J, IVd-P, and IVd-V, most preferably IVd-A, IVd-B, IVd-D, IVd-E, and IVd-J. Even more preferred pyridine ring systems of formula IVd include those described above, wherein Z' is nitrogen and Z2 is CH.
Preferred R" groups of formula IVd include hydrogen, alkyl- or dialkylamino, acetamido, or a C,.-4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.
Preferred-Ry groups of formula IVd include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R4) -, -C (R6) 20-, -CO- and R3 is -R, -N (R4) 2, or -OR. Examples of preferred Ry 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.
The ring formed when the R" and RY groups of formula IVd are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O(CH2)2-4-N(R4)2, -O(CH2)2-4-R, -OR, -N(R.4) - (CH2)2-4-N(R4)2, -N (R4) - (CH2) 2-4-R, -C (=O) R, -C02R, -COCOR, -NO2, -CN, -S (O) R, -S02R, -SR, -N (R4) 2, -CON (R4) 2, -S02N (R4) 2, -OC (=O) R, -N (R4) COR, -N (R4) C02 (optionally substituted Cl_6 aliphatic), -N (R4) N (R4) 2, -C=NN (R4) 2, -C=N-OR, -N (R4) CON (R4) 2, -N (R4) S02N (R4) 2, -N (R4) S02R, or -OC (=O) N(R4) 2, R and R4 are as defined above. Preferred R"/Ry ring substituents include -halo, -R, -OR, -COR, -C02R, -CON (R4) Z, -CN, -O (CH2) 2_4-N (R4) 2, -O (CH2) 2_4-R, , -NO2 -N (R4) 2, -NR4COR, -NR'4S02R, -S02N (R4) 2 wherein R is hydrogen or an optionally substituted C,,_6 aliphatic group.
The R2 and R2' groups of formula IVd 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 IVd compounds having a pyrazole-containing bicyclic ring system:

i J'NH ~N N ?-Nf N
RX ~z2 NH NH NH NH
- N
RY ( ~~ Zi Q'-R1, N ~N , . e and 11 Preferred substituents on the R2/R2' fused ring of formula IVd include one or more of the following:
-halo, -N (R4) 2, -C1_4 alkyl, -C1_4 haloalkyl, -NO2, -O (Cl_4 alkyl) , -C02 (C1_4 alkyl) , -CN, -S02 (Cl_4 alkyl) , -SO2NH2, -OC (O) NH2, -NH2SO2 (Cl_4 alkyl) , -NHC (O) (C1_4 alkyl) , -C (O) NH2, and -CO (Cl_4 alkyl) , wherein the (C1_4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Cl_4 alkyl) group is methyl.
. When the pyrazole ring system of formula IVd is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C,,_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen.
When Ring D of formula IVd is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl,-pyrimidinyl, and pyrazinyl.
When Ring D of formula TVd 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.
On Ring D of formula IVd, preferred T-R5 or V-Z-R5 substituents include -halo, -CN, -NO2, -N(R4)2, optionally substituted C1_6 aliphatic group, -OR, -C(O)R, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -SOZN (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4 ) 2, and -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me, -NHSO2Et, -NHS02 (n-propyl) , -NHS02(isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N ( CO2 t -Bu ) CH3 , -NHCOCH2N ( CH3 ) 2, -NHCOCH2CH2N ( CH3 ) 2, -NHCOCH2 CH2 CH2N ( CH3 ) 2, -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH2(morpholin-4-yl), -NHCOCH2CH2 (morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholin-4-yl), -NHC02(t-butyl), -NH(Cl_4 aliphatic) such as -NHMe, -N (C,,_4 aliphatic) 2 such as -NMe2, OH, -O (C1_4 aliphatic) such as -OMe, C,,_4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C1_4 aliphatic).

Preferred R8 groups of formula IVd, when present, include R, OR, and N(R4)2. Examples of preferred R8 include methyl, ethyl, NH2i NH2CH2CH2NH, N(CH3)2CH2CHaNH, N(CH3) 2CH2CH2O, (piperidin-l-yl) CH2CH2O, and NH2CH2CH2O.
Preferred =Q' groups.of -formula IVd =include -C (R6') 2- or 1, 2-cyclopropanediyl, wherein each RV is independently selected from hydrogen or methyl. A more preferred Q' group is -CH2-.
Preferred formula IVd compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen, alkyl- or dialkylamino, acetamido, or a C,_4 aliphatic group and Ry is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N (R4) Z, or -OR; or R" and Ry 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" and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R' 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-;

(c) Ring D is a 5-7 membered inonocyc=lic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R2 is -R or -T-W-R6 and R2' is hydrogen, or R2 and R2' are taken together to form an optionally substituted benzo ring.

More preferred compounds of formula IVd have one or more, and more preferably all, of the features selected from the group consisting of:

(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected from -R, -OR, or -N(R4)2, wherein R is selected from hydrogen, Cl_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R" and Ry 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 RX and Ry is independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said ring formed by R" and Ry is independently substituted by R4;
(b) R' 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;
(c) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring,.or a 5-6 membered heterocyclic ring;
(d) R3 is selected from -R, -halo, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N ( R4 ) - ; and (e) Q' is -C(R6')2- or 1,2-cyclopropanediyl, wherein each R6' is independently selected from hydrogen or methyl.

Even more preferred compounds of formula IVd have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R" is hydrogen methyl, ethyl, propyl, cyclopropyl, =isopropyl, methylamino-or acetamido and Ry 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" and Ry 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, -COR, -COZR, -CON (R4) 2. -CN, -O (CH2) 2-4-N (R4) 2, -O (CH2) 2-4-R, -NO2 -N (R4) 2, -NR4COR, -NR4S02R, or -SO2N (R4) 2, wherein R is hydrogen or an optionally substituted C1-6 aliphatic group;
(b) R'- 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, -NO2, -N (R4) z, optionally substituted C1-6 aliphatic, -OR, -C (O) R, -C02R, -CONH (R4) , -N (R4) COR, -N (R4) COzR, -S02N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) Z, or -N (R6) COCH2CH2CH2N (R4) Z;
(c) R2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Cl-6 aliphatic group, and R2' is hydrogen; and (d) R3 is selected from -R, -OR, or -N (R4) 2, wherein R is selected from hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-;
(e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2i optionally substituted C1_6 aliphatic group, -OR, -C (O) R, -CO2R, -CONH (R4) , -N (R4) COR, -N (R4) C02R, -SO2N (R4) 2, -N (R4) S02R, -N (R6) COCH2N (R4) 2, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2, wherein R is selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (f) Q' is -CH2- .
Representative compounds of formula IVd are shown below in Table 12.

Table 12.

HN ~~'~ H HN J''PH HN JIPH
- N 'QN ~ C N O

IVd-1 IVd-2 IVd-3 Me Me Me ,j~ H
HN C~'~'j~ N H ~ NH HN'~'~
HN

p O
N N
I~CI ~~CI CI

IVd-4 IVd-5 IVd-6 Me Me _ JVH
_ J~H HNf-IV
HN IV
91 INZ 91I I*;;z 91 N OMe N OMe IVd-7 IVd-8 In-another embodiment, this invention provides a composition comprising a compound of formula IVd 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 IVd 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 IVd 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 IVd 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 IVd 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 0-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 IVd 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 IVd, 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 IVd, as described above.
The compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I-VII, the general-methods that follow, and by the preparative examples below.

Scheme I

R2' R2 R21 R
CI 2, R2 HN dqH HN'rpH
R R ~ ..a.. R ' t'-4N b Rx y+ '(~H -~ -~ ~ -~
R N CI H2N Ry ~- N Ci Ry N Q-R1 Reagents: (a) EtOH, Et3N, room temperature; (b) Rl-QH (Q =
S, NH or 0) or R'-CH2-M/catalyst (M is Al or Mg or Sn, catalyst = Pd or Ni ) Scheme I above shows a general route for the preparation of the present compounds. The dichlorinated starting material 1 may be prepared using methods similar to the those reported in J. Indian. Chem. Soc., 61, 690-693 (1984) or in J. Med. Chem., 37, 3828-3833 (1994).
The reaction of 1 with aminopyrazole (or aminoindazole) 2 in a manner as described in Bioorg. Med. Chem. Lett, 10, 11, 1175-1180, (2000) or in J. Het. Chem, 21; 1161-1167, (1984) provides the versatile monochloro intermediate 3.
Conditions for displacing the chioro group of 3 by R1-Q
will.depend on the nature of the Q.linker moiety and are generally known in the field. See, for example, J. Med.
Chem, 38, 14, 2763-2773, (1995) (where Q is an N-Link), or Chem. Pharm. Bull., 40, 1, 227-229, (1992) (S-Link), or J. Het. Chem., 21, 1161-1167, (1984) (0-Link) or Bioorg. Med. Chem. Lett, 8, 20, 2891-2896, (1998) (C-Link).

Scheme II

'_JVH
RX OH Rx C~ R2, R2 X ~.{N ~IV

v a 'N + H R
l- 1-~' Rv N'~Q.Ri H t= ~
R N Q-R 2N Rv N Q-R

Reagents: (a) POC13, Pr3N, 110 C; (b) EtOH, Et3N, room temperature.

Scheme II above shows an alternative route for the preparation of the present compounds. The starting material 4 may be prepared in a manner similar to that described for analogous compounds. See Chem. Heterocycl.
Compd., 35, 7, 818-820 (1999) (where Q is an N-Link), Indian J. Chem. Sect. B, 22, 1, 37-42 (1983) (N-Link), Pestic. Sci, 47, 2, 103-114 (1996) (O-Link), J. Med.
Chem., 23, 8, 913-918 (1980) (S-Link), or Pharmazie, 43, 7, 475-476 (1988) (C-Link). The chlorination of 4 provides intermediate S. See J. Med. Chem., 43, 22, 4288-4312 (2000) (Q is an N-Link), Pestic. Sci, 47, 2, 103-114 (1996) (0-Link), J. Med. Chem., 41, 20, 3793-3803 (1998) (S-Link), or J. Med. Chem., 43, 22, 4288-4312 (2000) (C-Link). Displacement of the 4-Cl group in intermediate 5 with aminopyrazole (or aminoindazole) 2 to provide compounds of this invention may be performed according to known methods for analogous compounds. See J. Med. Chem., 38, 14, 2763-2773 (1995) (where Q is an N-Link), Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997) (0-Link), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000) (S-Link), or J. Med. Chem., 41, 21, 4021-4035 (1998) (C-Link).

Scheme III

Rz R2 ;_ JVH

Rx OH RX C~ R2. R b X ~ ' y ~ ''- + t:~ H R itJ1 Ry N S=Me R N S=Me H2N Ry N
S=Me 2' R2 R

c HN~~H d R 2' ?rPH
~ RX RX HN
t-''~ N 'N
y y~ ~ 1 R N QSOMe R N Q-R
Q-R

Reagents: (a) POC13i (b) EtOH, Et3N, room temperature; (c) Oxone; (d) R'-QH (Q = S, NH or 0) or R'-CH2-M/catalyst (M
is Al or Mg or Sn, catalyst = Pd or Ni ) Scheme III above shows another alternative route for preparing the present compounds. The starting material 6 may be chlorinated to provide intermediate 7.
Displacement of the 4-chloro group in 7 with aminopyrazole (or aminoindazole) 2'gives intermediate 8 which, upon oxidation of the methylsulfanyl group, provides the methylsulfone 9. The methylsulfonyl group of 9 may be displaced readily with R1-QH to give the desired product I. See J. Am. Chem. Soc., 81, 5997-6006 (1959) (where Q is an N-Link)or in Bioorg. Med. Chem.
Lett., 10, 8, 821-826 (2000) (S- Link).

Scheme IV

R2' '_~IH
Rx OH Rx Ci R2, R2 x HN ~N
t--N a N + ~ H b R 'N
CI NS=Me H2 N" X ~ ~~
HO N S=Me CI N S=Me 2' 2 2' c HN ~~H d R -~H e R )_dqH
Rx Rx HN RX HN
'N ('N t Ry N
N~S=Me RY N OSOMe R?' N~Q-R1 Reagents: (a) POC13; (b) EtOH, Et3N, room temperature; (c) RY-H (R = S, NH or O) ; (d) oxone; (e) R1-QH (Q = S, NH or 0) or R'-CH2-M/catalyst (M is Al or Mg or Sn, catalyst =
Pd or Ni ) Scheme IV above shows a general route for the preparation of the present compounds wherein Ry is a group attached to the pyrimidine core via a nitrogen, oxygen or 5 sulfur heteroatom. The starting 4,6-dihydroxy-2-methylsulfanylpyrimidine 10 may be prepared as described in J. Med. Chem., 27, 12, 1621-1629 (1984). The chloro groups of intermediate 11 may be displaced sequentially with aminopyrazole (or aminoindazole) 2 and then with 10 another amine (or alcohol or thiol) following procedures similar to those reported in US Patent 2585906 (ICI, 1949). The methylsulfanyl group of 13 may then be oxidized to provide the methylsulfone 14. Displacement of the methylsulfonyl group of 14 gives the desired product Ii.

Scheme V

R 2' tdqH R 2' t RX CI R2, R2 a RxHN b RX HN Y I + H ~~

R N CI H2N N RS' N C( Ry N' Q-Ri R 2' P H HN t:~X R 2' H

RX CI R2, R2 a RX HN' b RX ~=N + tXH I =N 1=N

Rv ' CI H2N RY CI Rv ' Q-R1 Scheme V above shows general routes for the preparation of compounds of formulae IVa, IVb, IVc., and IVd. Steps (a) and (b) are analogous to the corresponding steps described in Scheme I above. See Indian J. Chem. Sect. B, 34, 9, 1995, 778-790; J. Chem.
Soc., 1947, 899-905; J. Chem. Soc., 34, 9, 1948, 777-782;
and Indian J. Chem., 1967, 467-470.
The synthetic transformations shown in Schemes I-IV above are further illustrated by the following methods.

Scheme VI

a R R6 R6 R6 R~~~N ~ b R~NH2 R CI
N i NH
Me'Al'NH2 Scheme VI above shows a general route for preparing the aryl guanidine intermediate used to prepare compounds where Q is -C(R6')2-. The mono- or bis-alkylation of 19 at step (a) to prepare compound 20 can 5. be -achieved by using methods substantially similar to those described by Jeffery, J. E., et al, J. Chem Soc, Perkin Trans 1, 1996 (21) 2583-2589; Gnecco, D., et al, Org Prep Proced Int, 1996, 28 (4), 478-480; Fedorynski, M. and Jonczyk, A., Org Prep Proced Int, 1995, 27 (3), 355-359; Suzuki, S, et al, Can J Chem, 1994,, 71 (2) 357-361; and Prasad, G., et al, J Org Chem, 1991, (25), 7188-7190. The method of step (b) to prepare compound 21 from compound 20 can be achieved by using methods substantially similar to those described by Moss, R., et al, Tetrahedron Lett, 1995, (48), 8761-8764 and Garigipati, R., Tetrahedron Lett, 1990, (14), 1969-1972.
The aryl guanidine intermediates prepared according to Scheme VI may then be used to prepare the compounds of this invention by the methods described in the above Schemes I-V and by methods known to one skilled in the art.

Scheme VII

O O b NH2 0 + CI a 0H2 0 c CI
NH cXLN

Scheme VII above shows a general method that may be used to prepare compounds of formula II wherein Q

is 1,2-cyclopropanediyl. Compound 26 may then be used to prepare the desired amino-pyrazole compounds using the methods described above at Scheme I step (b).

Method A. To a solution of 2,4-dichloroquinazoline (12.69g, 63mmol) and 3-amino-5-methylpyrazole (6.18g, 63mmol) in ethanol (220mL) is added triethylamine (8.13mL, 63mmol) and the reaction mixture is stirred for 3 hours at room temperature. The pale yellow precipitate is then collected by filtration, washed with cold ethanol and dried under vacuum to give (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
The above-prepared (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (155 mg, 0.6 mmol) and 3-chloroaniline (0.316 mL, 2.99 mmol) are refluxed in tert-butanol (3 mL) over 20 h. The mixture is concentrated in vacuo and the residue is suspended in EtOH/H20 (1mL/3mL). K2C03 (83 mg, 0.6 mmol) is added and the suspension is stirred for 2h at room temperature.
The solid that forms is collected and dried under vacuum to give the product [2-(3-chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method B. Sodium hydride (45 mg, 1.12 mmol) in THF (2 mL) is treated with 3-methoxyphenol (0.94g, 7.6 mmol) and the reaction mixture is stirred until effervescence ceases. The THF is removed in vacuo and the above-prepared (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (150 mg, 0.51 mmol)) is added.
The reaction mixture is stirred at 100 C for 20 h, then poured into aqueous K2C03 and stirred for 2h at room temperature. The solid that forms is collected and re-crystallized from ethanol to give the product [2-(3-methoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method C. To a solution of 4-hydroxy-2-phenoxymethylquinazoline (2 g, 7.93 mmol) in phosphorus oxychloride (lOmL) -is added-t=ripropylamine (3.02 mL, 15.8 mmol) and the reaction mixture is heated for 30 minutes at 110 C. The excess phosphorus oxychloride is evaporated in vacuo, the residue is poured on ice cold aqueous NaHCO3 and extracted with ethyl acetate. The organic layer is washed with brine, dried, filtered and evaporated. The resulting residue is purified on flash chromatography (Si02, hexane /AcOEt gradient) to give 4-chloro-2-phenoxymethylquinazoline.
To a solution of the above 4-chloro-2-phenoxymethylquinazoline (0.5 g, 1.85 mmol) in THF (30 mL) is added 3-amino-5-cyclopropylpyrazole (0.47 g, 3.69 mmol) and the reaction mixture is heated at 65 C for 24 hours. Solvent is evaporated and ethanol is added. A
white solid forms and is collected by filtration and dried under vacuum to give (5-cCyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine.
Method D. To a solution of the above-prepared (2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (123 mg, 0.43 mmol) in THF (5 mL) is added NiC12(dppp) (12 mg, 2.1.10-5 mol), followed by 1M
benzylmagnesium chloride in THF (2.15 mL, 2.15 mmol).
The solution is heated at 50 C for 20 hours and the reaction mixture is then quenched with aqueous NH4C1 and the product extracted in ethyl acetate. The solvent is evaporated and the residue purified by flash chromatography to yield the desired (2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

Method E. A solution of (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (200 mg, 0.77 mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) is refluxed in tert-butanol (3 mL) over a 20 hour period.
Diethylether (10 mL) is added to the mixture and a solid forms that is collected by filtration. This solid is suspended in EtOH/H20 1mL/3mL), then K2C03 (110 mg, 0.8 mmol) is added and the suspension is stirred for 2h at room temperature. A solid forms and is collected and dried under vacuum to give the product [2-(4-acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method F. To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF

(10mL) is added triethylamine (0.357 mL, 2.56 mmol) followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixture is heated at 90 C for 20 h. The reaction mixture is partitioned between ethyl'acetate and aqueous saturated NaHCO3. The organic layer is washed with brine and evaporated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give (2-chloro-5,6,7,8-tetrahyclroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
The above-prepared (2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine is reacted with 2-naphthalene mercaptan as described in Method L to yield the desired (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine.~
Method G. A solution of (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine (110 mg, 0.26 mmol) in a mixture of THF/water (1/1, 10 mL) is treated with 1M LiOH (0.75 mL, 0.75 mmol). The mixture is stirred for 20 hours at room temperature and then neutralized with 1M HC1 (0.75 mL, 0.75 mmol). A solid forms and is collected by filtration to affo-rd the desired [2- (3-carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Method H. A solution of [2-(4-acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (23 mg, 5.54.10-5 mol) in dichloroethane (3 mL) is treated with 1M BBr3 in dichloromethane (222 L, 2.21.10-4 mol). The mixture os heated at 80 C for 4 hours before iM BBr3 in DCM (222 L, 2.21.10-4 mol) is added. The reaction mixture is heated at 80 C for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench residual BBr3. The solvent is evaporated in vacuo and this operation repeated 3 times. 1M HC1(2 mL) is added to the solid residue and the suspension stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture water/EtOH (3/1, 8 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and diethyl ether to give the desired [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method I. To a solution of [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (32 mg, 7.87.10-5 mol) in DMF (1 mL) is added potassium carbonate (65 mg, 4.72.10-4 mol) and the reaction mixture is heated to 80 C. N-(3-,CA 02432222 2007-05-29 chloropropyl)morpholine (39 mg, 2.36.10-4 mol) is then added, and the mixture is stirred at 80 C for 4 hours, cooled to room temperature and the solvent is evaporated.
The resulting residue is purified by flash chromatography to afford the desired [2- (4-acetamidophenylsulfanyl) -7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method J. To a solution of [2-(4-acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (147 mg, 3.38.10-4 mol) in methanol (5 mL) is added Pd/C 10% (40 mg) and the reaction mixture is treated with hydrogen at balloon pressure at 45 C for 20 hours. The catalyst is filtered through a pad of celite which is then washed with dilute HC1. The combined yellow filtrate is evaporated and the resulting solid residue is crystallized from methanol to afford the desired [2-(4-acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-y1]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method K. [2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (182 mg, 4.18.10-4 mol) is dissolved in a mixture EtOH/water/AcOH (25/10/1, 36 mL) and the reaction is heated at 90 C. Iron powder (93 mg) is added and the mixture is stirred at 90 C for 4 hours, cooled to room temperature and filtered through a pad of celite* The pad is washed with methanol and-the combined filtrate is concentrated in vacuo. The residue is purified by'flash chromatography (Si02, DCM/MeOH gradient) to give the desired [2-(4-acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
* Trade-mark Method L. To a solution of 2,4-dichloro-6-phenyl-pyrimidine (300 mg, 1.33 mmol) and 3-amino-5-methylpyrazole (129 mg, 1.33 mmol) in DMF (7 mL) is added triethylamine (195 L, 1.40 mmol) followed by sodium iodide (200 mg, 1:33 mmol) and the reaction mixture is stirred for 15 hours at 90 C. The resulting solution is partitioned between ethyl acetate and water and the organic phase washed with brine, dried over MgSO4 then concentrated in vacuo. The residue is triturated in methanol and the resulting white solid collected by filtration to afford (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (23.6 mg, 62%).
The above prepared (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (60 mg, 0.21 mmol) is combined with 4-acetamidothiophenol (176 mg, 1.05 mmol) in tert-butanol (5 mL) and the mixture heated at reflux for 20 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo.
The resulting residue is purified by flash chromatography (Si02, DCM/MeOH gradient) to afford [2-(4-acetamido-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (74 mg, 85%) Method M. To a suspension of 4,6-dihydroxymercaptopyrimidine (8 g, 55 mmol) in a mixture of EtOH/water (1/1, 140 mL) is added NaOH (2.33 g, 58.3 mmol) followed by 4-methoxybenzyl chloride (7.90 mL, 58.3 mmol). The solution is stirred for 1.5 hours at 60 C
and then at room temperature for a further 6 hours. The resulting white precipitate is collected by filtration to give 4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl)-pyrimidine.

The above-prepared 4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl)-pyrimidine (2.5 g, 9.46 mmol) is suspended in POC13 (20 mL), and tripropylamine (3.60 mL, 18.9 mmol) is added dropwise to the mixture. T he reaction is then heated at 110 C for 4 hours. The brown solution is cooled to room temperature and the solvent is evaporated. The residue is poured on ice cold NaHCO3 and the product is then extracted with ethyl acetate. The organic phase is dried over MgSO4, concentrated in vacuo and the residue is purified by flash chromatography (Si02, hexane/AcOEt gradient) to give 4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine.
To a solution of above-prepared 4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine (915 mg, 3.04 mmol) and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) in BuOH
(20 mL) is added diisopropylethylamine (0.56 mL, 3.19 mmol) followed by sodium iodide (455 mg, 3.04 mmol). The reaction mixture is stirred for 15 hours at 120 C. The solvent is removed in vacuo and the residue is purified by flash chromatography (Si02, hexane/AcOEt gardient) to give [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
The above-prepared [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.38 mmol) in 1-methylpiperazine (10 mL) is heated at 130 C for 15 hours. The solvent is then removed in vacuo and the residue is purified by flash chromatography (Si02, dichloromethane/MeOH gradient) to give the desired product [2-(4-methoxy-benzylsulfanyl-)- 6-(4-methylpiperazin-l-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method N. A solution of [2-(4-acetamido-phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (100 mg, 2.24.10-4 mol) in dichloroethane (5 mL) is treated with 1M BBr3 in DCM (896 L, 8.96.10-4 mol). The mixture is then heated at 80 C
for 4 hours before 1M BBr3 in DCM (896 L, 8.96:10-4 mol) 5'is added. The reaction mixture is then heated at 80 C
for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench any residual BBr3. The solvent is evaporated in vacuo and this evaporation step is repeated 3 times. 1M HC1(8 mL) is added to the solid residue and the suspension is stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture of water/EtOH
(3/1, 24 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and with diethyl ether to give [2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
To a solution of the above-prepared [2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (70 mg, 1.62.10-4 mol) in DMF (3 mL) is added potassium carbonate (134 mg, 9.71.10-4 mol). -The reaction mixture is heated to 80 C
before 1-dimethylamino-3-chloropropane hydrochloride (77 mg, 4.86.10-4 mol) is added. The mixture is stirred at 80 C for 4 hours, cooled to room temperature and the solvent is evaporated: The-residue is purified by flash chromatography to afford the desired product {2-(4-acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylamino-propoxy)-phenyl]-pyrimidin-4-yl}=(5-methyl-2H-pyrazol-3-yl)-amine.
Method O. To a solution of [6-methoxycarbonyl-2-(4-propionylamino-phen.yl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (2g, 4.85 mmol) in THF (100 mL) is added lithium borohydride (0.32 g, 14.5 mmol).

The reaction mixture is stirred at 50 C for 1.5 hours.
The reaction is then quenched with dilute HC1 and extracted with ethyl acetate. The organic layer is successively washed with aqueous saturated NaHCO3 and brine, dried over MgSO4 and evaporated. The solid residue is triturated in ethyl acetate and the resulting white solid is collected by filtration to give the desired product [6-hydroxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method P. To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (5 g, 25.6 mmol) and 3-amino-5-methylpyrazole 2.61 g, 26.9 mmol) in BuOH (60 mL) is added diisopropylethylamine (4.69 mL, 26.9 mmol) followed by sodium iodide (3.84 g, 25.6 mmol). The reaction mixture is stirred for 15 hours at 120 C. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient.) to give' (6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
The above-prepared [6-chloro-2-methylsulf'anyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (2.42 g, 9.46 mmol) is heated in morpholine (10 mL) at 130 C for 15 hours. The solvent is then removed in vacuo and the solid residue is triturated in EtOH and collected by filtration to give [2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
To a suspension of the above-prepared [2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.63 mmol) in MeOH
(10 mL) is added a solution of oxone (3.0 g) in water (10 mL). The reaction mixture is stirred at room temperature for 15 hours and most of the solvent is evaporated. The residue is partitioned between DCM and aqueous saturated NaHCO3. The organic layer is washed with brine, dried, filtered and evaporated. The residue is tritu-rated in MeOH and the resulting white solid is collected by filtration to give [2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
The above-prepared [2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (178 mg, 0.52 mmol) and 4-acetamidothiophenol (176 mg, 1.05 mmol) are refluxed in tert-butanol (5 mL) over 20 h. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography to give the desired product [2-(4-acetamidophenylsulfanyl)-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be' construed as limiting this invention in any manner.

SYNTHETIC EXAMPLES
The following HPLC methods were used in the analysis of the compounds as specified in the Synthetic Examples set forth below. As used herein, the term "Rt"
refers to the retention time observed for the compound using the HPLC method specified.

HPLC-Method A:

Column: C18, 3 um, 2.1 X 50 mm, "Lighting" by Jones Chromatography.
Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA),to 100% acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100% acetonitrile for 1.4 min and return to initial conditions. Total run time 7.0 min. Flow rate: 0.8 mL/min.

HPLC-Method B:

Column: C18, 5 um, 4.6 X 150 mm "Dynamax" by Rainin Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) over 20 min, hold at 100% acetonitrile for 7.0 min and return to initial conditions. Total run time 31.5 min. Flow rate: 1.0 mL/min.

HPLC-Method C:

Column: Cyano, 5 um, 4.6 X 150 mm "Microsorb" by Varian.

Gradient: 99% water (0.1% TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water (0.1% TFA), 50%
acetonitrile (containing 0.1% TFA) over 20 min, hold for 8.0 min and return to initial conditions. Total run time 30 min. Flow rate: 1.0 mL/min.
HPLC-Method D:

Column: Waters (YMC) ODS-AQ 2.Ox50mm, S5, 120A.
Gradient: 90% water (0.2% Formic acid), 10%

acetonitrile (containing 0.1% Formic acid) to 10%
water (0.1% formic acid), 90% acetonitrile (containing 0.1% formic acid) over 5.0 min, hold for 0.8 min and return to initial conditions. Total run time 7.0 min.

Flow rate: 1.0 mL/min.
HPLC-Method E:

Column: 50x2.Omm Hypersil C18 BDS;5 m Gradient: elution 100% water (0.1% TFA), to 5% water (0.1% TFA), 95% acetonitrile (containing 0.1% TFA) over 2.1 min, returning to initial conditions after 2.3 min.
Flow rate: 1 mL/min.

Example 1 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylsulfanyl-quinazolirn-4-yl)-amine (IIa-i): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp >300 C (dec.); 1H NMR (DMSO) S 2.07(3H, s), 5.54(1H, s), 7.38(1H, m), 7.56-7.45(4H, m), 7.65(2H, m) , 7.73 (1H, m), 8.55 (1H, d), 10.43 (1H, s), 12 . 05 (1H, br s); IR (solid) 3259, 3170, 3109, 1618, 1594, 1565, 1525, 1476; MS 334.0 (M+H)+

Example 2 [2-(4-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-2): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 259-260 C; I H NMR (DMSO) S 2.12 (3H, s), 5.40 (1H, s), 7.60 (1H, t), 7.64 (2H, d), 7.76 (3H, d) , 7.92 (1H, t) , 8.70 (1H, d) 11.50 .(1H, br s) ; IR
(solid) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339, 1286, 1219; MS 368.0 (M+H)+
Example 3 [2-(2,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-3): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 258-259 C; 'H NMR (DMSO) S
2.12 (3H, s), 5.40 (1H, s), 7.54 (1H, t), 7.63 (1H, m), 7.68 (1H, d), 7.86 (1H, t), 7.92 (1H, d), 7.96 (1H, d), 8.66 (1H, d) 11.20 (1H,' br s); IR (solid) 1623, 1610, 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0 (M+H)+
Example 4 [2-(4-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-4): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 264-268 C; 'H NMR (DMSO) S 2.04 (3H, s), 3.85 (3H, s), 5.43 (1H, s), 7.12 (2H, d), 7.53 (1H, t), 7.61 (3H, d), 7.84 (3H, t), 8.63 (1H, d), 11. 09 (1H, br s), 12.30 (1H, br s) ; IR-(solid) 1622, 1598, 1552, 1492, 1404, 1340, 1292, 1249, 1219, 1171, 1161; MS
364.1 (M+H)+

Example 5 [2-(2-Ethylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-5): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 205-208 C; 'H NMR (DMSO) S 2.05 (3H, s), 5.19 (1H, s), 7.38 (1H, t), 7.52-7.64 (3H, m), 7.68 (2H, d), 7.9,0 (1H, t), 8.68 (1H, d) ; IR (solid) 3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403, 1344, 1294, 1224, 1162; MS 362.1 (M+H)+

Example 6 {2-[2,4-Bis(trifluoromethyl)phenylsulfarnyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-6): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp >300 C; I H NMR (DMSO) S 1.98 (3H, s), 5.37 (1H, s) , 7.50 (1H, t), 7.59 (2H, d), 7.84 (1H, d), 8.32 (1H, s), 8.40 (2H, s), 8.66 (1H, d), 10.73 (1H, br s); IR (solid) 1628, 1603, 1577, 1548, 1512, 1493, 1448, 1417, 1354, 1275, 1196, 1124; MS 470.1 (M+H)+

Example 7 [2.- (2-Chlorophenylsulfany].) -quinazolin-4-yl] -(5-methyl-2H-pyrazol-3-yl)-amine (IIa-7): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 262-263 C; I H NMR (DMSO) S 2.05 (3H, s) , 5.35 (1H, s) , 7.52 (2H, t) , 7.65 (2H, m) , 7.74 (1H, d), 7.83 (1H, t), 7.88 (1H, d), 8.62 (1H, d), 10.97 (1H, br s); IR (solid) 1621, 1603, 1569, 1544, 1491, 1448, 1400, 1376, 1336, 1288, '1208; MS 368.0 (M+H)+
Example 8 [2-(2,3-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-8): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp >300 C; 'H NMR (DMSO) 2.05 (3H, s), 5.34 (1H, s), 7.50 (2H, m), 7.60 (1H, d), 7.75 (1H, t), 7.88 (2H, m), 8.62 (1H, d), 10.72 (1H, br s); IR (solid) 1632, 1609, 1561, 1532, 1492, 1432, 1400, 1380, 1345, 1298, 1228, 1162, 1125; MS 402.0 (M+H)+

Example 9 [2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-9): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 248-249 C; 1H NMR (DMSO) S 2.05 (3H, s), 5.42 (1H, s), 7.55 (2H, m), 7.66 (3H, m), 7.81 (1H, s), 7.85 (1H, t), 8.62 (1H, d), 11.10 (1H, br s); IR
(solid) 1628, 1611, 1551, 1487, 1432, 1410, 1341, 1292, 1217, 1165; MS 368.0 (M+H)}

Example 10 [2-(1-Methylimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-10): Prepared in a manner similar to the above described Method E to afford an off white solid, mp 255-256 C; I H NMR (DMSO) 2.19 (3H, s), 3.59 (1H, s);'5.51 (1H, s), 7.18 (1H, s), 7.45 (1H, t), 7.57 (1H, s), 7.59 (1H, d), 7.77 (1H, t), 8.57 (1H, d), 10.57 (1H, s), 12.13 (1H, br s); IR (solid) 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292, 1278, 1211; MS 338.2 (M+H)+

Example 11 [2-(2-Hydroxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-11): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 273-275 C; iH NMR (DMSO) S 2.06 (3H, s), 5.41 (1H, s), 6.99 (1H, t), 7.07 (1H, d), 7.50 (1H, t), 7.57-7.62 (2H, m), 7.73 (1H, d), 7.94 (1H, t), 8.71 (1H, d), 10.29 (1H, br s), 11.66 (1H, br s); IR
(solid) 1623, 1597, 1552, 1485, 1442, 1404, 1354, 1341, 1289, 1221, 1165; MS 350.1 (M+H)+

Example 12 [2-(2,4-Difluorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-12): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 256-258 C; 1H NMR (DMSO) 2.10 (3H, s), 5.41 (1H, s), 7.33 (1H, t), 7.51-7.58 (2H, m), 7.65 (1H, d), 7.82-7.91 (2H, m), 8.63 (1H, d), 11.06 (1H, br s); IR (solid) 1626, 1608, 1556, 1482, 1409, 1341, 1288, 1270, 1219, 1162, 1140; MS 370.1 (M+H)+

Example 13 [2-(3,4-Dimethoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-13): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 229-232 C; 1H NMR (DMSO) S

2.05 (3H, s), 3.70 (3H, s), 3.85 (3H, s), 5.39 (1H, s), 6.95 (1H, d), 7.30 (2H, d), 7.60 (1H, t), 7.77 (1H, d), 7.94 (1H, t), 8.72 (1H, d), 11.66 (1H, br s); IR (solid) 1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254, 1237, 1218, - 1161-, 1137; MS 394.1 (M+H) +

Example 14 [2-(3-Methylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-14): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 249-250 C; 'H NMR (DMSO) S 2.06 (3H, s), 2.36 (3H, s), 5.31 (1H, s), 7.45 (2H, d), 7.48-, 7.58 (3H, m), 7.61 (1H, d), 7.88 (1H, t), 8.68 (1H, d), 11.66 (1H, br s); IR (solid) 1617, 1587, 1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1 (M+H)+
Example 15 [2-(2-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-15): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 237-239 C; 1 H NMR (DMSO) S 2.07 (3H, s), 3.71 (3H, s), 5.35 (1H, s), 7.12 (1H, t), 7.23 (1H, d), 7.55 (1H, t), 7.60-7.67 (3H, m), 7.87 (1H, t), 8.66 (1H, d), 11.20 (1H, br s); IR (solid) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251, 1224; MS
364.1 (M+H)+
Example 16 [2-(2-Naphthalenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-16): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 267-270 C; 1H NMR (DMSO) S 2.05 (3H, s), 5.09 (1H, s) , 7.57 (1H, t), 7.62-7.75 (4H, m), 7.90 (1H, t), 8.07 (3H, t), 8.40 (1H, s), 8.66 (1H, d), 11.28 (1H, br s); IR (solid) 1624, 1606, 1550, 1487, 1435, 1407, 1341, 1285, 1216, 1158; MS 384.1 (M+H)+
Example 17 [2-(2,6-Dichiorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-17): Prepared in a manner similar to the above described Method E to afford a pale brown solid, mp >300 C; 1H NMR (DMSO) S 2.11 (3H, s) , 5.49 (1H, s), 7.49 (1H, t), 7.59-7.67 (2H, m), 7.76 (2H, d), 7.81 (1H, d), 8.60 (1H, d), 10.60 (1H, s) ;

IR (solid) 1618, 1599, 1565, 1533, 1486, 1424, 1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0 (M+H)+
Example 18 [2-(3,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-18): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 268-272 C; 1H NMR (DMSO) 2.11 (3H, s), 5.47 (1H, s), 7.56 (1H, t), 7.68-7.72 (2H, m), 7.83 (2H, d), 7.88 (1H, t), 8.05 (1H, d), 8.66 (1H, d); IR (solid) 1628, 1607, 1556, 1488, 1436, 14412, 1399, 1367, 1341, 1288, 1216, 1166; MS 402.0 (M+H)+

Example 19 [2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-19): Prepared in a manner similar to the above described Method E to afford a pale grey solid, mp 192-196 C; 1 H NMR (DMSO) S
1.60 (3H, s), 5.48 (1H, s), 7.44 (2H, m), 7.53 (1H, t), 7.69 (2H, d) , 7.76 (2H, m) , 7.85 (1H, t) , 8.64 (1H, d) , 10.79 (1H, s); IR (solid) 1618, 1606, 1569, 1537, 1487, 1411, 1395, 1369, 1343, 1288, 1273, 1170; MS 374.1 (M+H)+
Example 20 [2-(2-Aminophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-20): Prepared in a manner similar to the above described Method E to afford a bright yellow solid, mp 257-259 C; 'H NMR (DMSO) S 2.11-2.30 (3H, 2xbr s), 6.10 (1H, br s), 7.10-7.80 (7H, m), 8.60 (1H, br s), 9.80 (1H, br s), 10.80 (1H, br s); IR

(solid) 1623, 1591, 1567, 1538, "1496, 1483, *1410, 1351 Example 21 (5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine (IIa-21): Prepared in a manner similar to the above described Method E to afford a yellow solid, mp 233-236 C; 'H NMR (DMSO) 8 0.89 (2H, d), 0.98 (2H, d), 1.67 (1H, m), 5.48 (1H, s), 7.54 -7.73 (7H, m), 7.89 (1H, t), 8.68 (1H, d), 11.60 (1H, br s); IR (solid) 1629, 1606, 1577, 1546, 1509, 1484, 1438, 1413, 1370, 1291, 1219; MS 360.3 (M+H)+

Example 22 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine (IIa-22): Prepared in a manner similar to the above described Method E to afford a white solid, mp 224-225 C;

''H NMR (DMSO) S 0.52 (2H, m), 0.86 (2H, m), 1.67 (1H, m), 3.86 (3H, s), 5.60 (1H, s), 7.45 (1H, t), 7.56 (1H, d), 7.66 (1H,.t), 7.76 (1H, t), 7.93 (1H, d), 8.10 (1H, d), 8.18 (1H, s), 8.57 (1H, d), 10.48 (1H, br s), 12.07 (1H, br s); IR (solid) 1724, 1617, 1593, 1567, 1526, 1478, 1432, 1400, 1361, 1343, 1283, 1260, 1218, 1169, 1128; MS
418 . 3 ( M+H ) +

Example 23 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylsulfanyl)-quinazolin-4-yl]-amine (IIa-23):
Prepared in a manner similar to the above described Method E to afford a white solid, mp 241-243 C; 1H NMR
(DMSO) 8 0.55-0.63 (2H, m), 1.87-1.97 (1H, m), 1.67-1.79 (1H, m), 2.35 (3H, s), 5.72 (1H, s), 7.30-7.60 (6H, m), 7.68-7.78 (1H,m), 8.50-8.60 (1H, d), 10.38 (1H, s), 12-.02 (1H, 5); IR (solid) 1617, 1594, 1568, 1529, 1480, 1401, 1344, 1287, 1176, 758, 665,656; MS (M+H)+

Example 24 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxyphenylsulfanyl)-quinazolin-4-yl]-amine (IIa-24):
Prepared in a manner similar to the above described Method E to afford a white solid, mp 232-234 C; 'H NMR

(DMSO) 5 6.55-0.62 (2H, m), 0.88-0.97 (2H, m), 1.70-1.80 (1H, m), 3.79 (3H, s), 5.79 (1H, s), 7.08 (1H, d), 7.22-7.29 (2H, m), 7.40-7.50 (2H, m), 7.60 (1H, d), 7.79 (1H, t), 8.57 (1H, d), 10.40 (1H, s), 12.04 (1H, s); IR

(solid) 3100, 1618, 1592, 1567, 1527, 1477, 1402, 1345, 1284, 1246, 1231, 1171, 1041, 1,001, 969, 826, 761, 692, 667; MS (M+H)+

Example 25 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethoxyphenylsulfanyl)-quinazolin-4-yl]-aanine (IIa-25):
Prepared in 'a manner similar to the above described Method E to afford a white solid, mp 250-252 C; 'H NMR
(DMSO) 5 0.54-0.60 (2H, m), 0.83-0.91 (2H, m), 1.68-1.77 (1H, m), 3.79 (3H, s), 3.85 (3H, s), 5.79 (1H, s), 7.10.
(1H, d), 7.20-7.26 (2H, m), 7.45 (1H, t), 7.57 (1H, d), 7.77 (1H, t), 8.55 (1H, d), 10.45 (1H, s), 12.04 (1H, m);
IR (solid) 1617, 1593, 1567, 1530, 1504, 1479, 1457, 1439, 1398, 1364, 1347, 1288, 1269, 1250, 1232, 1181, 1169, 1138, 1037, 1020, 997, 972, 882, 846, 804, 764, 750; MS -(M+H)+
Example 26 [2-(3-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIa-26): Prepared from IIa-22 according to Method G to afford a yellow solid, mp >300 C; 'H NMR (DMSO) S 0.53 (2H, d), 0.86 (2H, d) , 1.65 (1H, m) , 5.37 (1H, s) , 7.55 (1H, t), 7.68 (1H, t), 7.81 (1H, d), 7.88 (1H, t), 7.95 (1H, d), 8.15 (1H, d), 8.15 (1H, s), 8.71 (1H, d), 11.32 (1H, br s); IR

(solid) 1702, 1626,' 1609, 1559, 1490, 1412, 1355, 1293, 1222, 1170; MS 404.7(M+H)+

Example 27 (5-Cyclopropyl-2H-pyrazol-3-yl)-(2-(naphtalen-2-ylsulfanyl)-quinazolin-4-yl]-amine (IIa-27): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 285-288 C; -'H NMR (DMSO) 0.25 (2H, br s), 0.52 (2H, br s), 0.87 (1H, m), 5.54 (1H, br s), 7.42 - 7.77 (4H, m), 8.00 (3H, m), 8.30 (1H, br s), 8.56 (1H, br d), 10.42 and 11.88 (1H, 2 x br s); IR
(solid) 1615, 1592, 1562, 1527, 1476, 1398, 1366, 1287, 1240, 1216, 1167, 1158, 1142, 1128, 996, 965; MS
410.7(M+H)+

Example 28 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,4-difluorophenylsulfanyl)-quinazolin-4-yl]-amine (IIa-28):
Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 250-253 C; 'H
NMR (DMSO) b 0.61 (2H, m) , 0.91 (2H, m) , 1.74 (1H, m) , 5.67 (1H, m), 7.24-7.28 (1H, m), 7.44-7.48 (3H, m), 7.53-7.81 (2H, brm), 8.55 (1H, m), 10.47 and 12.10 (1H, 2 x br s) ; IR (solid) 1614, 1598, 1565, 1525, 1479, 1423, 1398, 1366, 1345, 1285, 1267, 1243, 1213, 1168, 1143, 1114, 1026, 995, 968; MS 396.6(M+H)+

Example 29 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine (IIa-29): Prepared in a manner similar to the above described Method F to afford a white solid, mp 244 C; I H NMR (DMSO) $ 0.13 (2H, s) , 0.45. (2H, s) , 0.79 (1H, s), 1.73 (4H, s), 2.42 (2H, s), 2.58 (2H, s), 5.28 (1H, s) , 7.58 (2H, d) , 7.61 (2H, d) , 7.97 (3H, d) , 8.23 (1H, s), 8.56 (1H, s), 11.63 (1H, s); IR (solid) 1594, 1561, 1514, 1477, 1423, 1333, 1279, 1251, 990, 808, 744, 657, 651; MS 414.7(M+H)+

Example 30 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dichlorophenylsulfanyl)-quinazolin-4-yl]-amine (IIa-30):
Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 250-252 C; I H
NMR (DMSO) S 0.60 (2H, d), 0.93 (2H, d), 1.70 (1H, m), 5.54 (1H, s) , 7.47 (2H, m) , 7.57 (1H, d) , 7.76 (1H, t) , 7.86 (2H, d), 8.57 (1H, d), 10.48 (1H, s), 12.04 (1H, s);
IR (solid) 1616, 1601, 1570, 1528, 1486, 1432, 1400, 1367, 1335, 1285, 1246, 1210, 1159, 1146, 1051, 1033, 1021, 997; MS 428.6(M+H)+

Example 31 [2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIa-31): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 235-238 C; 1H NMR (DMSO) 6 0.58 (2H, d), 0.92 (2H, d), 1.75 (1H, m), 5.71 (1H, s), 7.44 (1H, t), 7.50 - 7.63 (4H, m), 7.73 (1H, s), 7.75 (1H, t), 8.57 (1H, d), 10.46 (1H, s), 12.08 (1H, s); IR
(solid) 1616, 1593, 1562,.1528, 1479, 1456, 1406, 1367, 1343, 1286, 1244, 1216, 1176, 1067, 1051, 997; MS
394. 7 (M+H)+
Example 32 [2-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIa-32): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 255-257 C; 1H NMR (DMSO) 0.59 (2H, d), 0.91 (2H, d), 1.71 (1H, m), 5.62 (1H, s), 7.45 (2H, m), 7.57 (1H, m), 7.69 (1H, d), 7.75 (1H, t), 7.85 (1H; d) , 8.56- (1H, d)-, 10.43 (1H, s) , 12:-03 (1H, s) ;
IR (solid) 1619, 1596, 1564, 1529, 1480, 1446, 1398, 1370, 1343, 1289, 1246, 1218, 1165, 1148, 1089, 1054, 1030, 997; MS 394.7(M+H)+

Example 33 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethylphenylsulfanyl)-quinazolin-4-yl]-amine (IIa-33):
Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 255-256 C; 'H
NMR (DMSO) 0.56 (2H, m) , 0.90 (2H, m) , 1.67 (1H, m) , 2.26 and 2.29 (6H, 2 x s), 5.75 (1H, br s), 7.26 (1H, m), 7.35-7.55 (4H,, m), 7.74 (1H, m), 8.54 (1H, br s), 10.44 and 12.06 (2H, 2 x br s) ; IR (solid) 1617, 1596, 1569,.
1526, 1479, 1459, 1404, 1366, 1343, 1287, 1243. 1218, 1167, 1145, 1017, 996, 966; MS 388.3(M+H)+
Example 34 [2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-34) :
Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 201-203 C; I H

NMR (DMSO) $ 0.44 (2H, m) , 0.71 (2H, m) , 1.17 (1H, m) , 5.72 (1H, m), 7.23 (2H; m), 7.51-7.81 (5H, m), 8.59 (1H, m), 10.59, 12.06 and 13.17 (3H, 3 x br s); IR (solid) 1617, 1601, 1572, 1532, 1485, 1402, 1374, 1341, 1290, 1273, 1209, 1168, 1024, 1010, 965; MS 400.2(M+H)+
Example 35 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine (IIa-35): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 245-246 C; 1 H NMR (DMSO) S 0.47 (2H, br s), 0.80 (2H, br s), 1.62 (1H, m), 3.85 (3H, s), 5.69 (1H, br s), 7.46 (1H, m), 7:58 (1H, m), 7.76-7.81 (3H, m), 8.02-8.05 (2H, m), 8.57 (1H, m), 10.48 and 12.11 (2H, 2 x br s); IR (solid) 1721, 1712, 1616, 1596, 1572, 1564, 1523, 1481, 1435, 1404, 1360, 1346, 1277, 1181, 1114, 1106, 996, 971; MS
418.2(M+H)+
1.0 Example 36 [2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIa-36):
Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 239-241 C; I H

NMR (DMSO) 8 0.57 (2H, m) , 0.83 (2H, m), 1.69 (1H, m), 2.02 (3H, s), 5.73 (1H, br s), 7.41 (1H, m), 7.53-7.57 (3H, m)', 7.73-7.75 (3H, m), 8.54 (1H, m), 10.18, 10.39 and 11.98 (3H, 3 x.br s); IR (solid) 1665, 1618, 1607, 1586, 1572, 1564, 1529, 1482, 1387, 1343, 1320, 1287, 1243, 1221, 1162, 1005, 968; MS 417.2(M+H)+.

Example 37 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-1-ylsulfanyl)-quinazolin-4-yl]-amine (IIa-37): Prepared in a manner similar to the above described Method E to afford.an off-white solid, mp 271-273 C; 1 H
NMR (DMSO) 8 0.46-0.47 (2H, m), 0.87-0.89 (2H, m), 1.57 (1H, m), 5.01 (1H, m), 7.42 (1H, m), 7.52-7.54 (3H, m), 7.64 (1H, m), 7.75 (1H, m), 7.98 (1H, m), 8.06 (1H, m), 8.17 (1H, m), 8.28 (1H, m), 8.50 (1H, m), 10.29 (1H, br s), 11.84 (1H, br s); IR (solid) 1615, 1592, 1567, 1528, 1483, 1401, 1362,.1343, 1285, 1242, 1219, 1173, 998, 963;
MS 410.2(M+H)+

Example 38 [2-(4-Acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-38): Prepared in a manner similar to the above described Method E to afford an white s'olid,'mp 268-271 C; 1H NMR (DMSO) S 2.02 (3H, s), 2.09 (3H, s), 5.56 (1H, s), 7.40 (1H, t), 7.55 (3H, m) , 7.75 (3H, d) , 8.55 (1H, d) , 10.21 (1H, s) , 10.40 (1H, s), 12.03 (1H, s); IR (solid) 1662, 1620, 1599, 1572, 1531, 1438, 1397, 1370, 1358, 1341, 1323, 1312, 1278, 1265, 1245, 1216, 1161, 1006, 966; MS 391.2(M+H)+
Example 39 [2-(4-Methanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-39): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 219-222 C; I H
NMR (DMSO) 5 2.15 (3H, s) , 2.61 (3H, s) , 5. 84 (1H, s) , 6.91 (2H, d), 7.22 (2H, d), 7.36 (1H, s), 7.52 (1H, d), 7.69 (1H, s), 8.53 (1H, d), 10.31 (1H, s), 11.96 (1H, s);
IR (solid) 1621, 1602, 1584, 1567, 1528; 1486, 1351, 1287, 1253, 1207, 1179, 1102, 1091, 983; MS 427.0(M+H)+
Example 40 [2-(4-Acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-40): Prepared in a manner similar to the above described Method E to afford a white solid, mp 291-293 C; ~H NMR
(DMSO) $ 2.01 (3H, s), 2.09 (3H, s), 3.87 (3H, s), 5.55 (1H, s), 6.96 (1H, s), 6.99 (1H, d), 7.55 (2H, d), 7.73 (2H, d), 8.45 (1H, d), 10.21 (1H, s), 10.23 (1H, s), 11.99 (1H, s); IR (solid) ; MS 421.2(M+H)+

Example 41 [2-(4-Acetamidophenylsulfanyl)-8-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-aamine (IIa-41): Prepared'in a manner similar to the above described Method E to afford a white solid, mp 262-264 C; 'H NMR (DMSO) 8 1. 94 (2H, quint. ), 2.03 (3H, s) , 2.09 (3H, s), 2.38 (4H, s), 2.45 (2H, t), 3.58 (4H, s), 4.11 (2H, t) , 5.60 (1H,- s) , 7.24 (1H, d) , 7.30 (1H, t) , 7.57 (2H, d), 7.73 (2H, d), 8.07 (1H, d), 10.20 (1H, s), 10.24 (1H, s), 12.02 (1H, br s); IR (solid) 3245, 3045, 2954, 2918, 2845, 1663, 1609, 1586, 1527, 1468, 1391, 1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823 ; MS
534 . 4 (M+H) +

Example 42 [2-(4-Methoxycarbonylphenylsulfanyl)-quiriazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-42): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 257-260 C; 'H
NMR (DMSO) S 1.95 (3H, s) , 3.89 (3H, s) , 5.51 (1H, br s) , 7.39 (1H, br s), 7.51 (1H, br s), 7.70 (1H, br s), 7.81 (2H, d), 8.04 (2H, d), 8.51 (1H, br s), 10.48 (1H, br s), 12.03 (1H, br s); IR (solid) 1718, 1618, 1599, 1568, 1531, 1481, 1434, 1395, 1362, 1342, 1286, 1247, 1216, 1156, 1116, 1018, 1003, 968 ; MS 392.2(M+H)+

Example 43 [2-(4-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-43): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 263-265 C; I H NMR (DMSO) 8 1.98 (3H, s), 5.50 (1H, s), 7.46 (1H, t), 7.60 (1H, d), 7.78 (3H, m) , 8.02 (2H, d) , 8.58 (1H, d) , 10.58 (1H, s) , 12.50 (1H, br s); IR (solid) 1623, 1605, 1574, 1560, 1533, 30. 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131, 1088, 1018; MS 378.2(M+H)}

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional volumes please contact the Canadian Patent Office.

Claims (36)

We claim:
1. A compound of formula IIIc:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

R x and R y are independently selected from T-R3 or L-Z-R3;
R1 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 Ring D is substituted at any substitutable ring carbon by oxo, T-R5, or V-Z-R5, and at any substitutable ring nitrogen by -R4;
T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;

L is -O-, -S-, -SO-, -SO2-, -N(R6)SO2-, -SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-, -N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R(5)-, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-, -C(R6)2N(R6)C(O)O-, -C(R6) =NN(R6)-, -C(R6) =N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, or -C(R6)2N(R6)CON(R6)- ;
R2 and R2' are independently selected from -R, -T-W-R6, or R2 and R2 ' 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 carbon on said fused ring formed by R2 and R2' is substituted by halo, oxo, -CN, -NO2, -R7, or -V-R6, and any substitutable nitrogen on said ring formed by R2 and R2' is substituted by R4;

R3 is selected from -R, -halo, -OR, -C(=O)R, -CO2R, -COCOR, -COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2, -SO2N(R7)2, -OC(=O)R, -N(R7)COR, -N(R7)CO2(C1-6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R7)CON(R7)2, -N(R7)SO2N(R7)2, -N(R4)SO2R, or -OC(=O)N(R7)2;

each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from -R7, -COR7, -CO2 (optionally substituted C1-6 aliphatic) , -CON(R7)2, or - SO2R7 ;

each R5 is independently selected from -R, halo, -OR, -C(=O)R, -CO2R, -COCOR, -NO2, -CN, -S (O) R, -SO2R, -SR, -N(R4)2, -CON(R4)2, -SO2N(R4)2, -OC(=O)R, -N(R4)COR, -N(R4)CO2 (optionally substituted C1-6 aliphatic), -N(R4)N(R4)2, -C=NN(R4)2, -C=N-OR, -N(R4)CON(R4)2, -N(R4)SO2N(R4)2, -N(R4)SO2R, or -OC(=O)N(R4)2;

V is -O-, -S-, -SO-, -SO2-, -N(R6)SO2-, -SO2N(R6)-, -N(R6)-, -CO-, -CO2-, -N(R6)CO-, -N(R6)C(O)O-, -N(R6)CON(R6)-, -N(R6)SO2N(R6)-, -N(R6)N(R6)-, -C(O)N(R6)-, -OC(O)N(R6)-, -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -C(R6)2N(R6)C(O)-, -C(R6)2N(R6)C(O)O-, -C(R6)=NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6)-, or -C(R6)2N(R6)CON(R6)-;

W is -C(R6)2O-, -C(R6)2S-, -C(R6)2SO-, -C(R6)2SO2-, -C(R6)2SO2N(R6)-, -C(R6)2N(R6)-, -CO-, -CO2-, -C(R6)OC(O)-, -C(R6)OC(O)N(R6)-, -C(R6)2N(R6)CO-, -C(R6)2N(R6)C(O)O-, -C(R6) =NN(R6)-, -C(R6)=N-O-, -C(R6)2N(R6)N(R6)-, -C(R6)2N(R6)SO2N(R6) -C(R6)2N(R6)CON(R6)-, or -CON(R6)-;

each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 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 R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
2. ~The compound according to claim 1, wherein said compound has one or more features selected from the group consisting of:

(a) ~R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic group;

(b) ~R y is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N(R4)2, or -OR;

(c) ~R1 is T- (Ring D), wherein T is a valence bond or a methylene unit;

(d) ~Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (e) ~R2 is -R or -T-W-R6 and R2' is hydrogen, or R2 and R2' are taken together to form an optionally substituted benzo ring.
3. ~The compound according to claim 2, wherein:
(a) ~R X is hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic group;

(b) ~R y is T-R3 or L-Z-R3, wherein T is a valence bond or a methylene and R3 is -R, -N(R4)2, or -OR;
(c) ~R1 is T-(Ring D), wherein T is a valence bond or a methylene unit;
(d) ~Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (e) ~R2 is -R or -T-W-R6 and R2' is hydrogen, or R2 and R2' are taken together to form an optionally substituted benzo ring.
4. ~The compound according to claim 2, wherein said compound has one or more features selected from the group consisting of:

(a) ~R y is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected from -R, -OR, or -N(R4)2, wherein R is selected from C1-6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
(b) ~R1 is T- (Ring D), wherein T is a valence bond;
(c) ~Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;

(d) R2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (e) L is -O-, -S-, or -N(R4)-.
5. The compound according to claim 4, wherein:

(a) R y is T-R3 or L-Z-R3 wherein T is a valence bond or a methylene and R3 is selected from -R, -OR, or -N (R4) 2, wherein R is selected from C1-6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

(b) R1 is T-(Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(d) R 2 is -R and R2' is hydrogen, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (e) L is -O-, -S-, or -N(R4)-.
6. The compound according to claim 4, wherein said compound has one or more features selected from the group consisting of:
(a) R x is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;

(b) 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;

(c) R1 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, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -CO2R, -CONH(R4), -N (R4) COR, -N (R4) SO2R, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2; and (d) R 2 is hydrogen or a substituted or unsubstituted C1_6 aliphatic, and L is -O-, -S-, or -NH-.
7. The compound according to claim 6, wherein:
(a) R x is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
(b) 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;

(c) R1 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, -NO2, -N (R4) 2, optionally substituted C1-6 aliphatic group, -OR, -CO2R, -CONH(R4), -N (R4) COR, -N (R4) SO2R, -N (R6) COCH2CH2N (R4) 2, or -N (R6) COCH2CH2CH2N (R4) 2; and (d) R2 is hydrogen or a substituted or unsubstituted C1-6 aliphatic, and L is -O-, -S-, or -NH-.
8. A compound selected from the group consisting of:
(5-Methyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylamino)-6-phenyl-pyrimidin-4-yl]-amine;
[2-(4-cyanomethylphenylamino)-6-phenyl-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2-(pyridin-3-ylmethylamino)-pyrimidin-4-yl]-amine;
[2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(3-Chlorophenyl)amino-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;

(5-Methyl-2H-pyrazol-3-yl)-[2-(4-sulfamoylphenylamino) -6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-amine;
[2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl] -amine;
[2-(Benzimidazol-2-ylamino-)6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine;
[2-(4-Chlorophenyl)amino-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(5-tert-Butyl-2H-pyrazol-3-yl)-[2-(3-chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-amine;

[2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine;
[5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine;
[2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine;
[2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-[5-(Furan-2-yl)-2H-pyrazol-3-yl]-amine;
[2-(4-Chlorophenylamino)-6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Chlorophenyl)amino-5,6-dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(5,6-Dimethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Chlorophenyl)amino-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(Benzimidazol-2-ylamino)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(6-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine;
(6-Methyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine;
N4- (5-Cyclopropyl-1H-pyrazol-3-yl) -N2- (1H-indazol-5-yl)-6-methyl-pyrimidine-2,4-diamine; and N2-Benzothiazol-6-yl-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-pyrimidine-2,4-diamine.
9. A composition comprising a compound according to any one of claims 1-8; and a pharmaceutically acceptable carrier.
10. The composition according to claim 9, further comprising an additional therapeutic agent.
11. A method of inhibiting Aurora-2, glycogen synthase kinase-3 (GSK-3), or Src activity in a biological sample comprising the step of contacting said biological sample with a compound according to any one of claims 1-8.
12. A use for inhibiting Aurora-2 activity in a patient of the composition as defined in claim 9.
13. A use for inhibiting Aurora-2 activity in a patient of the composition as defined in claim 10.
14. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for inhibiting Aurora-2 activity in a patient.
15. A use of a therapeutically effective amount of the composition as defined in claim 9 for treating an Aurora-2-mediated disease in a patient in need of such a treatment.
16. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for treating an Aurora-2-mediated disease in a patient in need of such treatment.
17. The use according to claim 15 or 16, wherein said disease is selected from colon, breast, stomach, or ovarian cancer.
18. The use according to claim 17, further comprising an additional therapeutic agent.
19. The use according to claim 18, wherein said additional therapeutic agent is a chemotherapeutic agent.
20. A use for inhibiting glycogen synthase kinase-3 (GSK-3) activity in a patient of the composition as defined in claim 9.
21. A use for inhibiting glycogen synthase kinase-3 (GSK-3) activity in a patient of the composition as defined in claim 10.
22. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for inhibiting glycogen synthase kinase-3 (GSK-3) activity in a patient.
23. A use of a therapeutically effective amount of the composition as defined in claim 9 for treating a glycogen synthase kinase-3 (GSK-3)-mediated disease in a patient in need of such a treatment.
24. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for treating a glycogen synthase kinase-3 (GSK-3)-mediated disease in a patient in need of such a treatment.
25. The use according to claim 23 or 24, wherein said GSK-3-mediated disease is selected from 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, or baldness.
26. The use according to claim 25, wherein said GSK-3-mediated disease is diabetes.
27. A use of a therapeutically effective amount of the composition as defined in claim 9 for enhancing glycogen synthesis or lowering blood levels of glucose in a patient in need thereof.
28. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for enhancing glycogen synthesis or lowering blood levels of glucose in a patient in need thereof.
29. A use of a therapeutically effective amount of the composition as defined in claim 9 for inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof.
30. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof.
31. A use of a therapeutically effective amount of the composition as defined in claim 9 for inhibiting the phosphorylation of .beta.-catenin in a patient in need thereof.
32. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for inhibiting the phosphorylation of .beta.-catenin in a patient in need thereof.
33. A use for inhibiting Src activity in a patient of the composition as defined in claim 9.
34. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for inhibiting Src activity in a patient.
35. A use of a therapeutically effective amount of the composition as defined in claim 9 for treating a Src-mediated disease in a patient in need of such a treatment.
36. A use of the compound as defined in any one of claims 1 to 8 in the manufacture of a medicament for treating a Src-mediated disease in a patient in need of such treatment.
CA002432222A 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors Expired - Fee Related CA2432222C (en)

Applications Claiming Priority (5)

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
PCT/US2001/051031 WO2002062789A1 (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors

Publications (2)

Publication Number Publication Date
CA2432222A1 CA2432222A1 (en) 2002-08-15
CA2432222C true CA2432222C (en) 2008-07-29

Family

ID=26946273

Family Applications (8)

Application Number Title Priority Date Filing Date
CA2432303A Expired - Fee Related CA2432303C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432129A Expired - Fee Related CA2432129C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432131A Expired - Fee Related CA2432131C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432223A Expired - Fee Related CA2432223C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432222A Expired - Fee Related CA2432222C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432799A Expired - Fee Related CA2432799C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432132A Expired - Fee Related CA2432132C (en) 2000-12-21 2001-12-20 Pyrazole compounds useful as protein kinase inhibitors
CA002432872A Expired - Fee Related CA2432872C (en) 2000-12-21 2001-12-20 Pyrazole compounds useful as protein kinase inhibitors

Family Applications Before (4)

Application Number Title Priority Date Filing Date
CA2432303A Expired - Fee Related CA2432303C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432129A Expired - Fee Related CA2432129C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432131A Expired - Fee Related CA2432131C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432223A Expired - Fee Related CA2432223C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors

Family Applications After (3)

Application Number Title Priority Date Filing Date
CA002432799A Expired - Fee Related CA2432799C (en) 2000-12-21 2001-12-19 Pyrazole compounds useful as protein kinase inhibitors
CA002432132A Expired - Fee Related CA2432132C (en) 2000-12-21 2001-12-20 Pyrazole compounds useful as protein kinase inhibitors
CA002432872A Expired - Fee Related CA2432872C (en) 2000-12-21 2001-12-20 Pyrazole compounds useful as protein kinase inhibitors

Country Status (28)

Country Link
US (16) US6989385B2 (en)
EP (10) EP1353916B1 (en)
JP (19) JP4210520B2 (en)
KR (8) KR100843114B1 (en)
CN (6) CN100408573C (en)
AP (2) AP2003002825A0 (en)
AR (4) AR042398A1 (en)
AT (9) ATE340172T1 (en)
AU (7) AU2002234047A1 (en)
BR (2) BR0116411A (en)
CA (8) CA2432303C (en)
CY (1) CY1106297T1 (en)
DE (8) DE60120219T2 (en)
DK (3) DK1353916T3 (en)
ES (7) ES2375491T3 (en)
HK (8) HK1059776A1 (en)
HU (5) HUP0400641A3 (en)
IL (8) IL156368A0 (en)
MX (8) MXPA03005607A (en)
MY (1) MY140377A (en)
NO (5) NO328537B1 (en)
NZ (8) NZ526468A (en)
PL (2) PL210066B1 (en)
PT (3) PT1353916E (en)
RU (1) RU2355688C2 (en)
SI (2) SI1353916T1 (en)
TW (2) TWI290551B (en)
WO (8) WO2002059111A2 (en)

Families Citing this family (367)

* 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
US7473691B2 (en) * 2000-09-15 2009-01-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6660731B2 (en) * 2000-09-15 2003-12-09 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
AU2001292670A1 (en) * 2000-09-15 2002-03-26 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
MXPA03005001A (en) * 2000-12-05 2003-09-05 Vertex Pharma Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases.
BR0116411A (en) * 2000-12-21 2003-11-11 Vertex Pharma Pyrazole compounds useful as protein kinase inhibitors
AR035791A1 (en) * 2001-03-23 2004-07-14 Bayer Corp COMPOUND N, N-DIHETEROCICLICO OF AMINA, INHIBITOR OF THE RHO-KINASE, ITS USE FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND PROCESS FOR THE PREPARATION OF THE COMPOUND
WO2002083138A1 (en) 2001-04-10 2002-10-24 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
US6939874B2 (en) 2001-08-22 2005-09-06 Amgen Inc. Substituted pyrimidinyl derivatives and methods of use
US7115617B2 (en) 2001-08-22 2006-10-03 Amgen Inc. Amino-substituted pyrimidinyl derivatives and methods of use
EA007430B1 (en) 2001-09-26 2006-10-27 Фармация Италия С.П.А. 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
SE0104140D0 (en) * 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
EP1465610B1 (en) 2002-01-10 2008-12-31 F. Hoffmann-La Roche Ag Use of a gsk-3beta inhibitor in the manufacture of a medicament for increasing bone formation
TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
KR20040084896A (en) * 2002-02-06 2004-10-06 버텍스 파마슈티칼스 인코포레이티드 Heteroaryl compounds useful as inhibitors of gsk-3
AU2003218215A1 (en) 2002-03-15 2003-09-29 Vertex Pharmaceuticals, Inc. Azolylaminoazines as inhibitors of protein kinases
DE60332433D1 (en) * 2002-03-15 2010-06-17 Vertex Pharma AZOLYLAMINOAZINE AS PROTEIN KINASE INHIBITOR
EP1485381B8 (en) * 2002-03-15 2010-05-12 Vertex Pharmaceuticals Incorporated Azolylaminoazine as inhibitors of protein kinases
JP4394960B2 (en) 2002-04-08 2010-01-06 メルク エンド カムパニー インコーポレーテッド Akt activity inhibitor
JPWO2003104230A1 (en) 2002-06-07 2005-10-06 協和醗酵工業株式会社 Bicyclic pyrimidine derivatives
MY141867A (en) * 2002-06-20 2010-07-16 Vertex Pharma Substituted pyrimidines useful as protein kinase inhibitors
JP2005536517A (en) * 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 Pyrazolopyrimidines as 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
BR0313176A (en) * 2002-08-02 2005-06-14 Vertex Pharma Pyrazole compositions useful as gsk-3 inhibitors
SI1532145T1 (en) * 2002-08-02 2007-02-28 Vertex Pharma Pyrazole compositions useful as inhibitors of gsk-3
FR2844267B1 (en) * 2002-09-05 2008-02-15 Aventis Pharma Sa NOVEL DERIVATIVES OF AMINOINDAZOLES AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
AU2003278249B8 (en) 2002-09-05 2010-11-18 Aventis Pharma S.A. Novel aminoindazole derivatives as medicines and pharmaceutical compositions containing same
AU2003255482A1 (en) * 2002-10-02 2004-04-23 Merck Patent Gmbh Use of 4 amino-quinazolines as anti cancer agents
US7692011B2 (en) 2002-10-04 2010-04-06 Prana Biotechnology Limited 8-hydroxy and 8-mercapto quinazolinones
KR100490893B1 (en) * 2002-10-11 2005-05-23 (주) 비엔씨바이오팜 2-methoxy-1,3,5-triazine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same
GB0226583D0 (en) * 2002-11-14 2002-12-18 Cyclacel Ltd Compounds
US7462613B2 (en) 2002-11-19 2008-12-09 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them
US7309701B2 (en) 2002-11-19 2007-12-18 Sanofi-Aventis Deutschland Gmbh Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them
FR2847253B1 (en) * 2002-11-19 2007-05-18 Aventis Pharma Sa NOVEL DERIVATIVES OF PYRIDAZINONES AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
AU2003295776B2 (en) 2002-11-21 2011-05-12 Novartis Vaccines And Diagnostics, Inc. 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer
US7601718B2 (en) * 2003-02-06 2009-10-13 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of protein kinases
US7157455B2 (en) * 2003-02-10 2007-01-02 Hoffmann-La Roche Inc. 4-Aminopyrimidine-5-one derivatives
EP1644338A1 (en) * 2003-04-01 2006-04-12 Aponetics AG 2, 4, 6-trisubstituted pyrimidine derivatives useful for the treatment of neoplastic and autoimmune diseases
JP2006526599A (en) * 2003-06-02 2006-11-24 アストラゼネカ アクチボラグ (3-((Quinazolin-4-yl) amino) -1H-pyrazol-1-yl) acetamide derivatives and related compounds as Aurora kinase inhibitors for the treatment of proliferative diseases such as cancer
ATE532781T1 (en) 2003-06-19 2011-11-15 Glaxosmithkline Llc 5-(ACYLAMINO)INDAZOLE DERIVATIVES AS KINASE INHIBITORS
WO2005003100A2 (en) * 2003-07-03 2005-01-13 Myriad Genetics, Inc. 4-arylamino-quinazolines as activators of caspases and inducers of apoptosis
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
TWI372050B (en) * 2003-07-03 2012-09-11 Astex Therapeutics Ltd (morpholin-4-ylmethyl-1h-benzimidazol-2-yl)-1h-pyrazoles
WO2006074147A2 (en) 2005-01-03 2006-07-13 Myriad Genetics, Inc. Nitrogen containing bicyclic compounds and therapeutical use thereof
GB0315966D0 (en) * 2003-07-08 2003-08-13 Cyclacel Ltd Compounds
PL1651612T3 (en) 2003-07-22 2012-09-28 Astex Therapeutics Ltd 3,4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators
AU2004261484A1 (en) * 2003-07-30 2005-02-10 Cyclacel Limited 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors
CN102358738A (en) 2003-07-30 2012-02-22 里格尔药品股份有限公司 2,4-pyrimidinediamine compounds and uses of treating or preventing autoimmune diseases thereof
US20050221357A1 (en) * 2003-09-19 2005-10-06 Mark Shannon Normalization of gene expression data
US20060024690A1 (en) * 2003-09-19 2006-02-02 Kao H P Normalization of data using controls
US7417726B2 (en) * 2003-09-19 2008-08-26 Applied Biosystems Inc. Normalization of data using controls
US20050124562A1 (en) * 2003-09-23 2005-06-09 Joseph Guiles Bis-quinazoline compounds for the treatment of bacterial infections
CA2542522A1 (en) 2003-10-17 2005-05-06 Astrazeneca Ab 4-(pyrazol-3-ylamino) pyrimidine derivatives for use in the treatment of cancer
JP2007513184A (en) * 2003-12-04 2007-05-24 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 Quinoxaline useful as an inhibitor of protein kinase
EP1709045A1 (en) * 2003-12-09 2006-10-11 Vertex Pharmaceuticals Incorporated Naphthyridine derivatives and their use as modulators of muscarinic receptors
WO2005061519A1 (en) 2003-12-19 2005-07-07 Takeda San Diego, Inc. Kinase inhibitors
TW200530235A (en) 2003-12-24 2005-09-16 Renovis Inc Bicycloheteroarylamine compounds as ion channel ligands and uses thereof
CA2556239A1 (en) 2004-02-11 2005-08-25 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US20080050314A1 (en) * 2004-02-26 2008-02-28 Bayer Healthcare Ag Diagnostics and Therapeutics for Diseases Associated With Glycogen Synthase Kinase 3 Beta (Gsk3b)
JP4875978B2 (en) * 2004-03-15 2012-02-15 武田薬品工業株式会社 Aminophenylpropanoic acid derivatives
WO2005099688A2 (en) * 2004-04-07 2005-10-27 Takeda Pharmaceutical Company Limited Cyclic compounds
US20090227648A1 (en) * 2004-04-21 2009-09-10 Astrazeneca Ab Pyrazole derivatives useful for the treatment of cancer
US20050250829A1 (en) * 2004-04-23 2005-11-10 Takeda San Diego, Inc. Kinase inhibitors
AU2005245386B2 (en) * 2004-05-07 2008-11-27 Amgen Inc. Nitrogenated heterocyclic derivatives as protein kinase modulators and use for the treatment of angiogenesis and cancer
US7793137B2 (en) 2004-10-07 2010-09-07 Cisco Technology, Inc. Redundant power and data in a wired data telecommunincations network
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"
US20050255485A1 (en) * 2004-05-14 2005-11-17 Livak Kenneth J Detection of gene duplications
AU2005243175B2 (en) * 2004-05-14 2011-12-01 Millennium Pharmaceuticals, Inc. Compounds and methods for inhibiting mitotic progression by inhibition of Aurora kinase
BRPI0511124A (en) * 2004-05-14 2007-11-27 Vertex Pharma erk inhibitors prodrugs pyrrolylpyrimidine protein kinase
JP2007538102A (en) * 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 5-anilino-4-heteroarylpyrazole derivatives useful for the treatment of diabetes
KR20070034519A (en) * 2004-05-27 2007-03-28 이 아이 듀폰 디 네모아 앤드 캄파니 Developer for photosensitive polymer protective layer
JP4990766B2 (en) * 2004-07-01 2012-08-01 シンタ ファーマシューティカルズ コーポレーション Disubstituted heteroaryl compounds
AU2005269974A1 (en) * 2004-07-06 2006-02-09 Angion Biomedica Corporation Quinazoline modulators of hepatocyte growth factor / c-Met activity for the treatment of cancer
JP2008510734A (en) * 2004-08-18 2008-04-10 タケダ サン ディエゴ インコーポレイテッド Kinase inhibitor
US7285569B2 (en) 2004-09-24 2007-10-23 Hoff Hoffmann-La Roche Inc. Tricycles, their manufacture and use as pharmaceutical agents
TW200624431A (en) * 2004-09-24 2006-07-16 Hoffmann La Roche Phthalazinone derivatives, their manufacture and use as pharmaceutical agents
TW200626574A (en) * 2004-09-30 2006-08-01 Tibotec Pharm Ltd HIV inhibiting 5-heterocyclyl pyrimidines
BRPI0515935B8 (en) * 2004-09-30 2021-05-25 Janssen Sciences Ireland Uc heterocyclyl- or 5-carbo substituted pyrimidines for inhibition of hiv, and pharmaceutical composition
CN101027288B (en) * 2004-09-30 2013-04-17 泰博特克药品有限公司 HIV inhibiting 5-substituted pyrimidines
US7713973B2 (en) * 2004-10-15 2010-05-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
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
EP1809290A2 (en) 2004-11-03 2007-07-25 Vertex Pharmaceuticals Incorporated Pyrimidine derivatives as ion channel modulators and methods of use
EP1812424A4 (en) * 2004-11-17 2009-07-08 Miikana Therapeutics Inc Kinase inhibitors
CA2584295C (en) 2004-11-24 2014-08-26 Rigel Pharmaceuticals, Inc. Spiro-2, 4-pyrimidinediamine compounds and their uses
US20060128710A1 (en) * 2004-12-09 2006-06-15 Chih-Hung Lee Antagonists to the vanilloid receptor subtype 1 (VR1) and uses thereof
CA2588220A1 (en) * 2004-12-23 2006-06-29 Pfizer Products Inc. Heteroaromatic derivatives useful as anticancer agents
RU2416610C2 (en) * 2004-12-30 2011-04-20 Астекс Терапьютикс Лимитед Pharmaceutical compounds
EP1841760B1 (en) 2004-12-30 2011-08-10 Exelixis, Inc. Pyrimidine derivatives as kinase modulators and method of use
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
DE602006010979D1 (en) 2005-01-19 2010-01-21 Rigel Pharmaceuticals Inc PRODRUGS FROM 2,4-PYRIMIDIN DIAMIN COMPOUNDS AND THEIR USES
AR054425A1 (en) 2005-01-21 2007-06-27 Astex Therapeutics Ltd PIPERIDIN ADDITION SALTS 4-IL-ACID AMID 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
WO2006081230A2 (en) * 2005-01-26 2006-08-03 Schering Corporation 3-(indazol-5-yl)-(1,2, 4) triazine derivatives and related compounds as protein kinase inhibitors for the treatment of cancer
RS52061B (en) 2005-02-04 2012-04-30 Astrazeneca Ab Pyrazolylaminopyridine derivatives useful as kinase inhibitors
WO2006087530A1 (en) * 2005-02-16 2006-08-24 Astrazeneca Ab Chemical compounds
ES2347172T3 (en) * 2005-02-16 2010-10-26 Astrazeneca Ab CHEMICAL COMPOUNDS.
BRPI0608513A2 (en) * 2005-03-15 2010-01-05 Irm Llc compounds and compositions as protein kinase inhibitors
WO2006100461A1 (en) * 2005-03-23 2006-09-28 Astrazeneca Ab 2-AZETIDINYL-4-(lH-PYRAZOL-3-YLAMINO)PYRIMIDINES AS INHIBITORS OF INSULIN-LIKE GROWTH FACTOR-I RECEPTOR ACTIVITY
US7402596B2 (en) * 2005-03-24 2008-07-22 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
ES2310406T3 (en) * 2005-04-05 2009-01-01 Astrazeneca Ab PIRIMIDINE DERIVATIVES FOR USE AS ANTI-TARGET AGENTS.
GB0507347D0 (en) * 2005-04-12 2005-05-18 Astrazeneca Ab Chemical compounds
EP1879894A1 (en) 2005-04-14 2008-01-23 F.Hoffmann-La Roche Ag Aminopyrazole derivatives, their manufacture and use as pharmaceutical agents
WO2006115452A1 (en) * 2005-04-27 2006-11-02 Astrazeneca Ab Use of pyrazolyl-pyrimidine derivatives in the treatment of pain
CA2607727A1 (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
WO2006119504A2 (en) 2005-05-04 2006-11-09 Renovis, Inc. Fused heterocyclic compounds, and compositions and uses thereof
JP2008540391A (en) * 2005-05-05 2008-11-20 アストラゼネカ アクチボラグ Pyrazolylamino substituted pyrimidines and their use in the treatment of cancer
EP1899323A2 (en) * 2005-05-16 2008-03-19 AstraZeneca AB Pyrazolylaminopyrimidine derivatives useful as tyrosine kinase inhibitors
US20070203161A1 (en) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2006133426A2 (en) 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US20060281712A1 (en) 2005-06-14 2006-12-14 Chi-Feng Yen Pyrimidine compounds
US8193206B2 (en) 2005-06-14 2012-06-05 Taigen Biotechnology Co., Ltd. Pyrimidine compounds
EP1746096A1 (en) 2005-07-15 2007-01-24 4Sc Ag 2-Arylbenzothiazole analogues and uses thereof in the treatment of cancer
US7737151B2 (en) * 2005-08-18 2010-06-15 Vertex Pharmaceuticals Incorporated Pyrazine kinase inhibitors
WO2007023382A2 (en) * 2005-08-25 2007-03-01 Pfizer Inc. Pyrimidine amino pyrazole compounds, potent kinase inhibitors
JP2009506069A (en) 2005-08-26 2009-02-12 ブレインセルス，インコーポレイティド Neurogenesis through modulation of muscarinic receptors
EP2258357A3 (en) 2005-08-26 2011-04-06 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
CN101316587B (en) * 2005-09-30 2013-04-03 迈卡纳治疗股份有限公司 Substituted pyrazole compounds
WO2007041358A2 (en) * 2005-09-30 2007-04-12 Miikana Therapeutics, Inc. Substituted pyrazole compounds
US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
AU2006304787A1 (en) 2005-10-21 2007-04-26 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
BRPI0618011A2 (en) * 2005-10-28 2011-08-16 Astrazeneca Ab compound or a pharmaceutically acceptable salt thereof, process for the preparation thereof, pharmaceutical composition, use of a compound or a pharmaceutically acceptable salt thereof, and methods for producing an antiproliferative effect and a pro-apoptotic effect in an animal warm-blooded to treat disease and to produce a jak inhibiting effect on a warm-blooded animal
US20070112017A1 (en) 2005-10-31 2007-05-17 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
ES2372540T3 (en) * 2005-11-01 2012-01-23 Array Biopharma, Inc. GLUCOCINASE ACTIVATORS.
CN101316843B (en) * 2005-11-03 2013-01-02 顶点医药品公司 Aminopyrimidines useful as kinase inhibitors
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
US7572809B2 (en) * 2005-12-19 2009-08-11 Hoffmann-La Roche Inc. Isoquinoline aminopyrazole derivatives
US8399442B2 (en) 2005-12-30 2013-03-19 Astex Therapeutics Limited Pharmaceutical compounds
US20070213319A1 (en) * 2006-01-11 2007-09-13 Angion Biomedica Corporation Modulators of hepatocyte growth factor/c-Met activity
JO2660B1 (en) 2006-01-20 2012-06-17 نوفارتيس ايه جي PI-3 Kinase inhibitors and methods of their use
JP2009528280A (en) 2006-02-16 2009-08-06 シェーリング コーポレイション Pyrrolidine derivatives as ERK inhibitors
US20100216734A1 (en) 2006-03-08 2010-08-26 Braincells, Inc. Modulation of neurogenesis by nootropic agents
PE20080145A1 (en) * 2006-03-21 2008-02-11 Janssen Pharmaceutica Nv TETRAHYDRO-PYRIMIDOAZEPINE AS MODULATORS OF TRPV1
EP2004632B1 (en) 2006-03-30 2014-03-12 Janssen R&D Ireland Hiv inhibiting 5-amido substituted pyrimidines
MX2008012482A (en) * 2006-03-31 2008-10-10 Abbott Lab Indazole compounds.
KR20090023561A (en) 2006-04-07 2009-03-05 노파르티스 아게 Combination comprising a) a pyrimidylaminobenzamide compound, and b) a thr315ile kinase inhibitor
DK2012789T3 (en) 2006-04-14 2013-12-16 Prana Biotechnology Ltd Process for Age-Related Macular Degeneration (AMD)
CA2650572C (en) * 2006-04-27 2013-09-10 Banyu Pharmaceutical Co., Ltd. Novel aminopyridine derivatives having aurora a selective inhibitory action
JP2009536667A (en) 2006-05-09 2009-10-15 ブレインセルス，インコーポレイティド 5HT receptor-mediated neurogenesis
EP2021000A2 (en) 2006-05-09 2009-02-11 Braincells, Inc. Neurogenesis by modulating angiotensin
CN102731451B (en) * 2006-06-27 2015-07-29 武田药品工业株式会社 Fused ring compound
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
JP2009542608A (en) * 2006-06-29 2009-12-03 アステックス・セラピューティクス・リミテッド Pharmaceutical combination
JPWO2008001886A1 (en) * 2006-06-30 2009-11-26 協和発酵キリン株式会社 Aurora inhibitor
AU2007263655A1 (en) * 2006-06-30 2008-01-03 Astrazeneca Ab Pyrimidine derivatives useful in the treatment of cancer
US8222256B2 (en) 2006-07-05 2012-07-17 Exelixis, Inc. Methods of using IGFIR and ABL kinase modulators
RU2009108280A (en) 2006-08-08 2010-09-20 Санофи-Авентис (Fr) Arylamino-arylalkyl-substituted imidazolidine-2,4-dione, methods for their preparation containing these compounds and their use
EP2054413A2 (en) * 2006-08-09 2009-05-06 Millennium Pharmaceuticals, Inc. Pyridobenzazepine compounds and methods for inhibiting mitotic progression
US7635168B2 (en) * 2006-08-11 2009-12-22 Hall David R Degradation assembly shield
JP2008081492A (en) 2006-08-31 2008-04-10 Banyu Pharmaceut Co Ltd New aminopyridine derivative having aurora a selective inhibitory action
US7998971B2 (en) * 2006-09-08 2011-08-16 Braincells Inc. Combinations containing a 4-acylaminopyridine derivative
US20100184806A1 (en) 2006-09-19 2010-07-22 Braincells, Inc. Modulation of neurogenesis by ppar agents
JP2010505962A (en) 2006-10-09 2010-02-25 武田薬品工業株式会社 Kinase inhibitor
EP2223925A1 (en) * 2006-10-09 2010-09-01 Takeda Pharmaceutical Company Limited Kinase inhibitors
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
EP2073807A1 (en) 2006-10-12 2009-07-01 Astex Therapeutics Limited Pharmaceutical combinations
WO2008053812A1 (en) * 2006-10-27 2008-05-08 Mitsubishi Tanabe Pharma Corporation Cyanopyridine derivative and medicinal use thereof
EP2086965B1 (en) * 2006-11-02 2010-02-10 Vertex Pharmaceuticals, Inc. Aminopyridines and aminopyrimidines useful as inhibitors of protein kinases
CL2007003244A1 (en) 2006-11-16 2008-04-04 Millennium Pharm Inc COMPOUNDS DERIVED FROM PIRIMIDO [5,4-D] [2] BENZAZEPINA; PHARMACEUTICAL COMPOSITION THAT INCLUDES SUCH COMPOUND; AND USE OF THE COMPOUND FOR THE TREATMENT OF CANCER.
EP2099787B1 (en) * 2006-12-19 2010-07-21 Vertex Pharmaceuticals, Inc. Aminopyrimidines useful as inhibitors of protein kinases
AU2007341228B2 (en) * 2006-12-29 2013-04-18 Janssen Sciences Ireland Uc HIV inhibiting 5,6-substituted pyrimidines
CA2674178C (en) * 2006-12-29 2015-11-10 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 6-substituted pyrimidines
CA2675558A1 (en) 2007-02-06 2008-08-14 Novartis Ag Pi 3-kinase inhibitors and methods of their use
WO2008111441A1 (en) 2007-03-05 2008-09-18 Kyowa Hakko Kirin Co., Ltd. Pharmaceutical composition
AU2008226461A1 (en) 2007-03-09 2008-09-18 Vertex Pharmaceuticals Incorporated Aminopyridines useful as inhibitors of protein kinases
NZ579485A (en) * 2007-03-09 2012-02-24 Vertex Pharma Aminopyrimidines useful as inhibitors of protein kinases
CA2679884A1 (en) * 2007-03-09 2008-09-18 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as inhibitors of protein kinases
CN101675041A (en) * 2007-03-20 2010-03-17 沃泰克斯药物股份有限公司 Amino-metadiazine compound as kinase inhibitor
WO2008117050A1 (en) * 2007-03-27 2008-10-02 Astrazeneca Ab Pyrazolyl-amino-substituted pyrazines and their use for the treatment of cancer
CA2683785A1 (en) * 2007-04-13 2008-10-23 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
EP2155742A1 (en) * 2007-04-18 2010-02-24 AstraZeneca AB 5-aminopyrazol-3-yl-3h-imidazo [4,5-b]pyridine derivatives and their use for the treatment of cancer
MX2009011090A (en) 2007-04-18 2009-11-02 Pfizer Prod Inc Sulfonyl amide derivatives for the treatment of abnormal cell growth.
MX2009011812A (en) * 2007-05-02 2010-01-14 Vertex Pharma Aminopyrimidines useful as kinase inhibitors.
AU2008247592A1 (en) 2007-05-02 2008-11-13 Vertex Pharmaceuticals Incorporated Thiazoles and pyrazoles useful as kinase inhibitors
AU2008247595A1 (en) * 2007-05-02 2008-11-13 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
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
ATE521609T1 (en) * 2007-05-04 2011-09-15 Astrazeneca Ab AMINOTHIAZOLYLPYRIMIDENE DERIVATIVES AND THEIR USE IN THE TREATMENT OF CANCER
MX2009012719A (en) * 2007-05-24 2010-02-04 Vertex Pharma Thiazoles and pyrazoles useful as kinase inhibitors.
KR101294731B1 (en) * 2007-06-04 2013-08-16 삼성디스플레이 주식회사 Array substrate, display panel having the array substrate and method of manufacturing the array substrate
US20090029992A1 (en) * 2007-06-11 2009-01-29 Agoston Gregory E 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
US8415340B2 (en) * 2007-07-25 2013-04-09 Bristol-Myers Squibb Company Triazine kinase inhibitors
WO2009013545A2 (en) * 2007-07-26 2009-01-29 Astrazeneca Ab Chemical compounds
AU2008282156B2 (en) * 2007-07-31 2014-07-17 Vertex Pharmaceuticals Incorporated Process for preparing 5-fluoro-1H-pyrazolo [3, 4-b] pyridin-3-amine and derivatives thereof
TW200906818A (en) * 2007-07-31 2009-02-16 Astrazeneca Ab Chemical compounds
EP2025674A1 (en) 2007-08-15 2009-02-18 sanofi-aventis Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs
WO2009027736A2 (en) * 2007-08-27 2009-03-05 Astrazeneca Ab 2,4 diaminopyrimid'lnes for the treatment of myeloproliferative disorders and cancer
MX2010002772A (en) 2007-09-21 2010-03-31 Array Biopharma Inc Pyridin-2 -yl-amino-i, 2, 4 -thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus.
JP5372943B2 (en) 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 Novel sEH inhibitors and their use
PE20091102A1 (en) 2007-12-17 2009-07-25 Janssen Pharmaceutica Nv 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
WO2009097995A1 (en) * 2008-02-07 2009-08-13 Sanofi-Aventis Novel phenyl-substituted imidazolidines, method for the production thereof, medicaments containing said compounds and use thereof
EP2260031B1 (en) 2008-02-21 2015-10-07 Merck Sharp & Dohme Corp. Compounds that are erk inhibitors
WO2009104802A1 (en) * 2008-02-22 2009-08-27 Banyu Pharmaceutical Co., Ltd. Novel aminopyridine derivatives having aurora a selective inhibitory action
AU2008355098B2 (en) 2008-04-21 2012-11-15 Gpcr Therapeutics, Inc Heterocyclic compounds
US8844033B2 (en) 2008-05-27 2014-09-23 The Trustees Of Columbia University In The City Of New York Systems, methods, and media for detecting network anomalies using a trained probabilistic model
JP2011522870A (en) * 2008-06-11 2011-08-04 アストラゼネカ アクチボラグ Tricyclic 2,4-diamino-L, 3,5-triazine derivatives useful for the treatment of cancer and myeloproliferative disorders
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
BRPI0911688A2 (en) * 2008-07-31 2015-07-28 Genentech Inc "pyrimidine compounds, compositions and methods of use"
AU2009288200A1 (en) * 2008-09-03 2010-03-11 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical formulations comprising the same
CN102405284B (en) * 2008-09-05 2016-01-20 新基阿维罗米克斯研究公司 The algorithm of design irreversible inhibitor
CN104230901A (en) 2008-09-15 2014-12-24 加利福尼亚大学董事会 Methods and compositions for modulating ire1, src, and abl activity
CA2737217A1 (en) * 2008-09-30 2010-04-08 Astrazeneca Ab Heterocyclic jak kinase inhibitors
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 (en) 2008-12-16 2010-07-27 Lilly Co Eli AMINO PIRAZOL COMPOUND
EP2373664B1 (en) 2008-12-19 2013-06-12 Nerviano Medical Sciences S.r.l. Bicyclic pyrazoles as protein kinase inhibitors
US20100183601A1 (en) 2008-12-22 2010-07-22 Millennium Pharmaceuticals, Inc. Combination of Aurora Kinase Inhibitors and Anti-CD20 Antibodies
US8809343B2 (en) 2008-12-26 2014-08-19 Fudan University Pyrimidine derivative, preparation method and use thereof
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
MY159327A (en) * 2009-02-27 2016-12-25 Ambit Biosciences Corp Jak kinase modulating quinazoline derivatives and methods of use thereof
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 (en) 2009-05-18 2020-08-27 Millennium Pharm Inc Solid pharmaceutical compositions and processes for their production
CA2764823A1 (en) * 2009-06-08 2010-12-16 California Capital Equity, Llc Triazine derivatives and their therapeutical applications
WO2010144338A1 (en) * 2009-06-08 2010-12-16 Abraxis Bioscience, Llc Triazine derivatives and their therapeutical applications
AU2010258964B2 (en) 2009-06-09 2014-09-11 Nantbio, Inc. Benzyl substituted triazine derivatives and their therapeutical applications
WO2010144522A1 (en) * 2009-06-09 2010-12-16 Abraxis Bioscience, Llc Ureidophenyl substituted triazine derivatives and their therapeutical applications
CA2765030C (en) * 2009-06-09 2015-10-27 California Capital Equity, Llc Triazine derivatives and their therapeutical applications
BRPI1011320A2 (en) * 2009-06-09 2016-06-21 California Capital Equity Llc styryl triazine derivatives and their therapeutic applications
US20120172384A1 (en) * 2009-06-18 2012-07-05 Mihiro Sunose Heterocyclylaminopyrimidines as kinase inhibitors
TWI468402B (en) 2009-07-31 2015-01-11 必治妥美雅史谷比公司 Compounds for the reduction of β-amyloid production
US8637525B2 (en) 2009-07-31 2014-01-28 Bristol-Myers Squibb Company Compounds for the reduction of beta-amyloid production
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
RU2012114902A (en) 2009-09-16 2013-10-27 Авила Терапьютикс, Инк. CONJUGATES AND PROTEINKINASE INHIBITORS
KR101923049B1 (en) * 2009-11-13 2018-11-28 인튜어티브 서지컬 오퍼레이션즈 인코포레이티드 End effector with redundant closing mechanisms
CA2784807C (en) 2009-12-29 2021-12-14 Dana-Farber Cancer Institute, Inc. Type ii raf kinase inhibitors
CA2785738A1 (en) 2009-12-30 2011-07-07 Avila Therapeutics, Inc. Ligand-directed covalent modification of protein
SA111320200B1 (en) * 2010-02-17 2014-02-16 ديبيوفارم اس ايه Bicyclic Compounds and their Uses as Dual C-SRC / JAK Inhibitors
JP2013520424A (en) 2010-02-19 2013-06-06 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 Sodium 4-{[9-chloro-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5,4-d] [2] benzoazepin-2-yl] amino} -2-methoxybenzoate Crystal form
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
US20130059830A1 (en) * 2010-05-20 2013-03-07 Fa-Xiang Ding Novel prolylcarboxypeptidase inhibitors
AU2011254550B2 (en) 2010-05-21 2013-11-07 Noviga Research Ab Novel pyrimidine derivatives
CA2797947C (en) 2010-06-04 2019-07-09 Charles Baker-Glenn Aminopyrimidine derivatives as lrrk2 modulators
EP2582709B1 (en) 2010-06-18 2018-01-24 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
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
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, 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
RS57331B1 (en) 2010-07-29 2018-08-31 Oryzon Genomics Sa Arylcyclopropylamine based demethylase inhibitors of lsd1 and their medical use
WO2012030944A2 (en) * 2010-09-01 2012-03-08 Ambit Biosciences Corporation Quinoline and isoquinoline compounds and methods of use thereof
US20130225614A1 (en) * 2010-09-01 2013-08-29 Ambit Biosciences Corporation 4-azolylaminoquinazoline derivatives and methods of use thereof
US20130225615A1 (en) * 2010-09-01 2013-08-29 Ambit Biosciences Corporation 2-cycloquinazoline derivatives and methods of use thereof
CN103298805A (en) * 2010-09-01 2013-09-11 埃姆比特生物科学公司 Quinazoline compounds and methods of use thereof
EP2611502A1 (en) * 2010-09-01 2013-07-10 Ambit Biosciences Corporation Adenosine a3 receptor modulating compounds and methods of use thereof
WO2012030913A1 (en) * 2010-09-01 2012-03-08 Ambit Biosciences Corporation An optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof
JP5872558B2 (en) * 2010-09-01 2016-03-01 アムビト ビオスシエンセス コルポラチオン Pyrazolylaminoquinazoline hydrobromide
WO2012059932A1 (en) 2010-11-01 2012-05-10 Aurigene Discovery Technologies Limited 2, 4 -diaminopyrimidine derivatives as protein kinase inhibitors
HUE046617T2 (en) 2010-11-10 2020-03-30 Genentech Inc Pyrazole aminopyrimidine derivatives as lrrk2 modulators
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
EP2683704B1 (en) 2011-03-08 2014-12-17 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US8901114B2 (en) 2011-03-08 2014-12-02 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
EP2683702B1 (en) 2011-03-08 2014-12-24 Sanofi New substituted phenyl oxathiazine derivatives, method for their manufacture, medicines containing these compounds and their application
EP2683701B1 (en) 2011-03-08 2014-12-24 Sanofi Oxathiazine derivatives substituted with benzyl or heteromethylene groups, method for their preparation, their usage as medicament, medicament containing same and its use
EP2683699B1 (en) 2011-03-08 2015-06-24 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
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
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
CA2830129C (en) 2011-03-24 2016-07-19 Chemilia Ab Novel pyrimidine derivatives
WO2013026914A1 (en) 2011-08-25 2013-02-28 F. Hoffmann-La Roche Ag Serine/threonine pak1 inhibitors
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
WO2013042006A1 (en) 2011-09-22 2013-03-28 Pfizer Inc. Pyrrolopyrimidine and purine derivatives
PE20141581A1 (en) 2011-09-27 2014-11-14 Novartis Ag 3-PIRMIDIN-4-IL-OXAZOLIDIN-2-ONAS AS INHIBITORS OF MUTANT HDI
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013074986A1 (en) 2011-11-17 2013-05-23 Dana-Farber Cancer Institute, Inc. Inhibitors of c-jun-n-terminal kinase (jnk)
CN104011050A (en) 2011-12-22 2014-08-27 霍夫曼-拉罗奇有限公司 2, 4-diamine-pyrimidine derivative as serine/threonine kinase inhibitors
WO2013123401A1 (en) * 2012-02-17 2013-08-22 Abbvie Inc. Diaminopyrimidines useful as inhibitors of the human respiratory syncytial virus (rsv)
UY34632A (en) 2012-02-24 2013-05-31 Novartis Ag OXAZOLIDIN- 2- ONA COMPOUNDS AND USES OF THE SAME
TWI485146B (en) * 2012-02-29 2015-05-21 Taiho Pharmaceutical Co Ltd Novel piperidine compounds or salts thereof
CN104302640A (en) 2012-03-16 2015-01-21 埃克希金医药品有限公司 3,5-diaminopyrazole kinase inhibitors
US20130303519A1 (en) 2012-03-20 2013-11-14 Millennium Pharmaceuticals, Inc. Methods of treating cancer using aurora kinase inhibitors
SG10201704095UA (en) 2012-04-24 2017-06-29 Vertex Pharma Dna-pk inhibitors
EP2855451B1 (en) * 2012-05-24 2017-10-04 Cellzome Limited Heterocyclyl pyrimidine analogues as tyk2 inhibitors
CN104797267A (en) 2012-06-26 2015-07-22 德玛医药 Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof
MX2015000129A (en) * 2012-07-10 2015-04-14 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
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
CN103059002B (en) * 2012-12-31 2015-04-22 中山大学 Pyrimidine derivative with Aurora kinase inhibitory activity and preparation method and application thereof
CN103202843B (en) * 2012-12-31 2015-04-29 刘强 Application of pyrimidine derivative in preparation of drugs capable of prevention and/or treatment and/or adjuvant therapy of cancers
CN103191120B (en) * 2012-12-31 2015-11-25 刘强 A kind of pyrimidine derivatives preparation prevent and/or treat and/or adjuvant therapy of tumors medicine in purposes
CN103910716A (en) * 2013-01-07 2014-07-09 华东理工大学 2,4-disubstituted-cycloalkyl[d]pyrimidine compound and its use
CN107200749B (en) 2013-03-12 2019-09-03 沃泰克斯药物股份有限公司 DNA-PK inhibitor
ES2665619T3 (en) 2013-03-14 2018-04-26 Novartis Ag 3-Pyrimidin-4-yl-oxazolidin-2-ones as mutant HDI inhibitors
WO2014145485A2 (en) 2013-03-15 2014-09-18 The Trustees Of Columbia University In The City Of New York Map kinase modulators and uses thereof
CN105209042B (en) 2013-03-22 2019-03-08 米伦纽姆医药公司 The combination of 1/2 inhibitor of catalytic MTORC and selective aurora A kinase inhibitor
WO2015003355A2 (en) * 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
CN105764501A (en) 2013-07-26 2016-07-13 现代化制药公司 Compositions to improve the therapeutic benefit of bisantrene
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
EP3057953B1 (en) 2013-10-17 2018-08-15 Vertex Pharmaceuticals Incorporated Co-crystals of (s)-n-methyl-8-(1-((2'-methyl-[4,5'-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide and deuterated derivatives thereof as dna-pk inhibitors
ES2676734T3 (en) 2013-10-18 2018-07-24 Syros Pharmaceuticals, Inc. Heteroatomic compounds useful for the treatment of proliferative diseases
JP6491202B2 (en) 2013-10-18 2019-03-27 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド Polycyclic inhibitors of cyclin dependent kinase 7 (CDK 7)
PL3089971T3 (en) 2014-01-01 2021-01-25 Medivation Technologies Llc Compounds and methods of use
PL3116475T3 (en) 2014-03-13 2021-02-08 Neuroderm Ltd Dopa decarboxylase inhibitor compositions
US10258585B2 (en) 2014-03-13 2019-04-16 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
US9399637B2 (en) 2014-03-28 2016-07-26 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
UA121386C2 (en) 2014-04-04 2020-05-25 Айомет Фарма Лтд Indole derivatives for use in medicine
WO2015155738A2 (en) 2014-04-09 2015-10-15 Christopher Rudd Use of gsk-3 inhibitors or activators which modulate pd-1 or t-bet expression to modulate t cell immunity
CN105367555B (en) * 2014-08-07 2019-06-25 广东东阳光药业有限公司 Substituted heteroaryl compound and combinations thereof and purposes
MY191736A (en) 2014-12-23 2022-07-13 Axikin Pharmaceuticals Inc 3,5-diaminopyrazole kinase inhibitors
WO2016105528A2 (en) 2014-12-23 2016-06-30 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
CA2978518C (en) 2015-03-27 2023-11-21 Nathanael S. Gray Inhibitors of cyclin-dependent kinases
EP3283482B1 (en) 2015-04-17 2022-04-06 Ludwig Institute for Cancer Research Ltd Plk4 inhibitors
PT3303348T (en) 2015-05-28 2019-11-15 Theravance Biopharma R&D Ip Llc Naphthyridine compounds as jak kinase inhibitors
JP2018135268A (en) * 2015-06-05 2018-08-30 大日本住友製薬株式会社 Novel heteroaryl amino-3-pyrazole derivative and pharmacologically acceptable salt thereof
EP4019515A1 (en) 2015-09-09 2022-06-29 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
LT3386511T (en) 2015-12-10 2021-08-25 Ptc Therapeutics, Inc. Methods for treating huntington`s disease
CN105503754B (en) * 2015-12-11 2017-11-17 浙江大学 The triazine of 2 amino, 4 benzyl, 6 morpholine 1,3,5 and its preparation and application
CN105399695B (en) * 2015-12-11 2019-04-19 浙江大学 Compound in triazine class and its preparation method and application
CN105384702B (en) * 2015-12-11 2018-04-10 浙江大学 Three substitution s-triazine compounds and preparation method thereof
US10894784B2 (en) 2015-12-18 2021-01-19 Bayer Pharma Aktiengesellschaft Heteroarylbenzimidazole compounds
CA3016773A1 (en) 2016-03-14 2017-09-21 Ronald Charles Hawley Pyrimidines and variants thereof, and uses therefor
CA3018180C (en) 2016-03-25 2024-02-20 Ronald Charles Hawley Pyrimidines and variants thereof, and uses therefor
US10028960B2 (en) 2016-04-28 2018-07-24 Theravance Biopharma R&D Ip, Llc Pyrimidine compounds as JAK kinase inhibitors
WO2017207534A1 (en) 2016-06-03 2017-12-07 Bayer Pharma Aktiengesellschaft Substituted heteroarylbenzimidazole compounds
TW201815418A (en) 2016-09-27 2018-05-01 Vertex Pharma Method for treating cancer using a combination of DNA-damaging agents and DNA-PK inhibitors
US10858319B2 (en) 2016-10-03 2020-12-08 Iomet Pharma Ltd. Indole derivatives for use in medicine
WO2018089546A1 (en) * 2016-11-08 2018-05-17 Vanderbilt University Isoquinoline ether compounds as mglur4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
CN108239071B (en) * 2016-12-27 2020-12-04 沈阳药科大学 Amide and thioamide derivatives, and preparation method and application thereof
FR3064275B1 (en) 2017-03-21 2019-06-07 Arkema France METHOD FOR HEATING AND / OR AIR CONDITIONING A VEHICLE
CR20190580A (en) 2017-05-30 2020-02-10 Basf Se Pyridine and pyrazine compounds
EP3634953B1 (en) 2017-06-05 2024-01-03 PTC Therapeutics, Inc. Compounds for treating huntington's disease
CN111182898B (en) 2017-06-28 2024-04-16 Ptc医疗公司 Methods for treating huntington's disease
EP3645121A4 (en) 2017-06-28 2021-03-17 PTC Therapeutics, Inc. Methods for treating huntington's disease
WO2019000682A1 (en) * 2017-06-30 2019-01-03 北京泰德制药股份有限公司 Rho-associated protein kinase inhibitor, pharmaceutical composition containing rho-associated protein kinase inhibitor, preparation method and use of the pharmaceutical composition
CN117343049A (en) 2017-06-30 2024-01-05 北京泰德制药股份有限公司 Rho-related protein kinase inhibitor, pharmaceutical composition containing Rho-related protein kinase inhibitor, and preparation method and application of Rho-related protein kinase inhibitor
JP7039802B2 (en) 2017-06-30 2022-03-23 ベイジン タイド ファーマシューティカル カンパニー リミテッド Pharmaceutical composition containing RHO-related protein kinase inhibitor, RHO-related protein kinase inhibitor, preparation method and use of the pharmaceutical composition.
WO2019046316A1 (en) * 2017-08-28 2019-03-07 Acurastem Inc. Pikfyve kinase inhibitors
CN111683662B (en) * 2017-08-28 2024-04-02 陈志宏 Substituted pyrimidine compounds, pharmaceutical compositions and methods of treatment
JP7218364B2 (en) 2017-10-27 2023-02-06 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 Pyrimidine compounds as JAK kinase inhibitors
US20200399250A1 (en) * 2017-11-23 2020-12-24 Biomed X Gmbh Pyrimidine Derivatives as Tropomyosin Receptor Kinase A (TRKA) Inhibitors
WO2019113311A1 (en) 2017-12-06 2019-06-13 Ludwig Institute For Cancer Research Ltd Methods of treating cancer with plk4 inhibitors
US20210009590A1 (en) 2018-03-27 2021-01-14 Ptc Therapeutics, Inc. Compounds for treating huntington's disease
CN112367991A (en) * 2018-06-25 2021-02-12 达纳-法伯癌症研究所股份有限公司 TAIRE family kinase inhibitors and uses thereof
EP3814360A1 (en) 2018-06-27 2021-05-05 PTC Therapeutics, Inc. Heteroaryl compounds for treating huntington's disease
EP3814357B1 (en) 2018-06-27 2024-05-01 PTC Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating huntington's disease
AR118768A1 (en) 2019-04-24 2021-10-27 Theravance Biopharma R&D Ip Llc PYRIMIDINE DERIVATIVES AS INHIBITORS OF JAK KINASES
US11439641B2 (en) 2019-04-24 2022-09-13 Theravance Biopharma R&D Ip, Llc Pyrimidine JAK inhibitors for the treatment of skin diseases
JP2022542704A (en) * 2019-08-01 2022-10-06 インテグラル バイオサイエンシーズ プライベート リミテッド Heterocyclic compounds and their use as kinase inhibitors
EP4031547A1 (en) 2019-09-18 2022-07-27 Takeda Pharmaceutical Company Limited Plasma kallikrein inhibitors and uses thereof
CN110483493A (en) * 2019-09-19 2019-11-22 广东工业大学 A kind of diazole analog derivative and its preparation method and application
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease
US11213502B1 (en) 2020-11-17 2022-01-04 Neuroderm, Ltd. Method for treatment of parkinson's disease
US11331293B1 (en) 2020-11-17 2022-05-17 Neuroderm, Ltd. Method for treatment of Parkinson's disease
TW202237119A (en) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Alk-5 inhibitors and uses thereof
EP4308564A1 (en) * 2021-03-17 2024-01-24 Takeda Pharmaceutical Company Limited Polycyclic inhibitors of plasma kallikrein
AU2022243600A1 (en) * 2021-03-26 2023-10-12 Sumitomo Pharma Oncology, Inc. Alk-5 inhibitors and uses thereof
TW202309008A (en) 2021-05-11 2023-03-01 美商歐瑞克製藥公司 Polo like kinase 4 inhibitors
UY39832A (en) 2021-06-28 2023-01-31 Blueprint Medicines Corp CDK2 INHIBITORS
CN116354938B (en) * 2021-12-28 2024-02-20 沈阳药科大学 Preparation method and application of quinazoline derivatives and analogues thereof
CN114276302B (en) * 2022-01-11 2023-07-25 山东百启生物医药有限公司 Method for preparing 2, 4-diaminoquinazoline derivative
WO2024003773A1 (en) 2022-07-01 2024-01-04 Pfizer Inc. 2,7-naphthyridine compounds as mastl inhibitors
CN117736198A (en) * 2022-09-21 2024-03-22 科辉智药生物科技(深圳)有限公司 Macrocyclic nitrogen crown ether compounds and their use as protein kinase inhibitors
CN115403568B (en) * 2022-09-21 2023-09-29 中山大学 Quinazoline Aurora A covalent inhibitor and preparation method and application thereof

Family Cites Families (97)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US18436A (en) * 1857-10-20 And saml
US3133081A (en) * 1964-05-12 J-aminoindazole derivatives
US2585906A (en) 1952-02-12 Quaternary salts of pyrimdjines
US3935183A (en) * 1970-01-26 1976-01-27 Imperial Chemical Industries Limited Indazole-azo phenyl compounds
BE754242A (en) * 1970-07-15 1971-02-01 Geigy Ag J R DIAMINO-S-TRIAZINES AND 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 (en) * 1974-12-13 1979-10-11 Bayer Ag, 5090 Leverkusen 3-Amino-indazole-N-carboxylic acid derivatives, process for their preparation and pharmaceuticals containing them
MA18829A1 (en) 1979-05-18 1980-12-31 Ciba Geigy Ag PYRIMIDINE DERIVATIVES, METHODS FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS AND THEIR THERAPEUTIC USE
DOP1981004033A (en) * 1980-12-23 1990-12-29 Ciba Geigy Ag PROCEDURE TO PROTECT CROP PLANTS FROM PHYTOTOXIC ACTION OF HERBICIDES.
SE8102193L (en) * 1981-04-06 1982-10-07 Pharmacia Ab THERAPEUTIC ACTIVE ORGANIC ASSOCIATION AND ITS USE
SE8102194L (en) * 1981-04-06 1982-10-07 Pharmacia Ab THERAPEUTIC ACTIVE ORGANIC ASSOCIATION AND PHARMACEUTICAL PREPARATION INCLUDING THIS
JPS58124773A (en) 1982-01-20 1983-07-25 Mitsui Toatsu Chem Inc 5-methylthiopyrimidine derivative, its preparation and fungicide for agricultural and horticultural purposes
EP0136976A3 (en) 1983-08-23 1985-05-15 Ciba-Geigy Ag Use of phenyl pyrimidines as plant regulators
DE3725638A1 (en) 1987-08-03 1989-02-16 Bayer Ag NEW ARYLOXY (OR THIO) AMINOPYRIMIDINE
JPH0532662A (en) 1990-11-09 1993-02-09 Nissan Chem Ind Ltd Substituted pyrazole derivative and agricultural and horticultural fungicide
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
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
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 (en) * 1992-05-07 1994-03-08 Nissan Chem Ind Ltd Substituted pyrazole derivative and germicide for agriculture and horticulture
PT672042E (en) 1993-10-01 2006-08-31 Novartis Ag Pharmacologically active pyrimidineamine derivatives and processes for their preparation
ATE262902T1 (en) 1994-11-10 2004-04-15 Millennium Pharm Inc USE OF PYRAZOLE COMPOUNDS TO TREAT GLOMERULONEPHRITIS, CANCER, ATHEROSCLERosis OR RESTENOSIS
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
JPH11512390A (en) 1995-09-01 1999-10-26 シグナル ファーマシューティカルズ，インコーポレイテッド Pyrimidine carboxylate 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
ES2186908T3 (en) 1996-07-13 2003-05-16 Glaxo Group Ltd HETEROCICICLES CONDENSED COMPOUNDS AS INHIBITORS OF PPROTEINA-TIROSINA-QUINASAS.
JPH10130150A (en) 1996-09-05 1998-05-19 Dainippon Pharmaceut Co Ltd Medicine comprising acetic acid amide derivative
GB9619284D0 (en) 1996-09-16 1996-10-30 Celltech Therapeutics Ltd Chemical compounds
JP4205168B2 (en) 1996-10-02 2009-01-07 ノバルティス アクチエンゲゼルシヤフト Pyrimidine derivatives and process for producing the same
KR20000049048A (en) 1996-10-11 2000-07-25 로즈 암스트롱, 크리스틴 에이. 트러트웨인 Aspartate Ester Inhibitors of Interleukin-1Beta Converting Enzyme
EP1033910A4 (en) 1997-10-10 2004-11-24 Cytovia Inc Dipeptide apoptosis inhibitors and the use thereof
US6267952B1 (en) * 1998-01-09 2001-07-31 Geltex Pharmaceuticals, Inc. Lipase inhibiting polymers
JP2000026421A (en) 1998-01-29 2000-01-25 Kumiai Chem Ind Co Ltd Diaryl sulfide derivative and pest controlling agent
CA2321153A1 (en) 1998-02-17 1999-08-19 Timothy D. Cushing Anti-viral pyrimidine derivatives
AU755273B2 (en) 1998-03-16 2002-12-05 Cytovia, Inc. Dipeptide caspase inhibitors and the use thereof
AP1411A (en) 1998-06-02 2005-05-10 Osi Pharm Inc Pyrrolo[2,3d] pyrimidine compositions and their use.
DE69919707T2 (en) 1998-06-19 2005-09-01 Chiron Corp., Emeryville GLYCOGEN SYNTHASE KINASE 3 INHIBITORS
WO2000003901A1 (en) * 1998-07-16 2000-01-27 Continental Teves Ag & Co. Ohg Method and device for detecting the critical driving states in vehicles which are being driven
AU5777299A (en) * 1998-08-21 2000-03-14 Du Pont 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
US7262201B1 (en) * 1998-10-08 2007-08-28 Astrazeneca Ab Quinazoline derivatives
GB9828640D0 (en) 1998-12-23 1999-02-17 Smithkline Beecham Plc Novel method and compounds
GB9828511D0 (en) * 1998-12-24 1999-02-17 Zeneca Ltd Chemical compounds
CZ20012528A3 (en) 1999-01-13 2002-06-12 Warner-Lambert Company 1-Heterocyclically substituted diaryl amines, pharmaceutical compositions based thereon and treatment methods
DE60028740T2 (en) 1999-03-30 2007-05-24 Novartis Ag PHTHALAZINE DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY DISEASES
EP1185528A4 (en) * 1999-06-17 2003-03-26 Shionogi Biores Corp Inhibitors of il-12 production
GB9914258D0 (en) * 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
MY133159A (en) 1999-08-13 2007-10-31 Vertex Pharma Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases
JP2003511378A (en) 1999-10-07 2003-03-25 アムジエン・インコーポレーテツド Triazine kinase inhibitors
CZ20021703A3 (en) 1999-11-30 2003-06-18 Pfizer Products Inc. 2,4-Diaminopyrimidine compounds usable as immunosuppressants
EP1731520A1 (en) 1999-12-02 2006-12-13 OSI Pharmaceuticals, Inc. Pyrrolo[2,3-d]pyrimidine derivatives which are antagonists of adenosine A1, A2A, and A3
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
EP1200422A2 (en) * 2000-02-05 2002-05-02 Vertex Pharmaceuticals Incorporated Pyrazole compositions useful as inhibitors of erk
WO2001060816A1 (en) * 2000-02-17 2001-08-23 Amgen Inc. Kinase inhibitors
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
IL152022A0 (en) 2000-04-03 2003-04-10 Vertex Pharma Compounds useful as protease inhibitors and pharmaceutical compositions containing the same
EP1274706A1 (en) 2000-04-18 2003-01-15 Agouron Pharmaceuticals, Inc. Pyrazoles for inhibiting protein kinases
JP3890184B2 (en) * 2000-05-15 2007-03-07 Ｎｅｃパーソナルプロダクツ株式会社 Power supply device, power control method thereof, and information processing apparatus
SK18102002A3 (en) * 2000-06-28 2003-07-01 Astrazeneca Ab Substituted quinazoline derivatives, their use and a composition comprising said derivatives
CN1518543A (en) 2000-08-31 2004-08-04 �Ʒ� Pyrazole derivatives and their use as protein kinase inhibitors
US7473691B2 (en) * 2000-09-15 2009-01-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
AU2001292670A1 (en) * 2000-09-15 2002-03-26 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
US6610677B2 (en) * 2000-09-15 2003-08-26 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
AU2001290940A1 (en) * 2000-09-15 2002-03-26 Vertex Pharmaceuticals Incorporated Isoxazoles and their use as inhibitors of erk
US6660731B2 (en) * 2000-09-15 2003-12-09 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
AU2001293817A1 (en) 2000-09-20 2002-04-02 Merck Patent Gmbh 4-amino-quinazolines
US6641579B1 (en) * 2000-09-29 2003-11-04 Spectrasonics Imaging, Inc. Apparatus and method for ablating cardiac tissue
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
DE10061863A1 (en) * 2000-12-12 2002-06-13 Basf Ag Preparation of triethylenediamine, useful for making pharmaceuticals and polymers, by reacting ethylenediamine over specific zeolite catalyst
WO2002047690A1 (en) 2000-12-12 2002-06-20 Cytovia, Inc. Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof
BR0116411A (en) * 2000-12-21 2003-11-11 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
CA2441733A1 (en) 2001-03-29 2002-10-10 Vertex Pharmaceuticals Incorporated Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases
DE60214701T2 (en) * 2001-04-13 2007-09-13 Vertex Pharmaceuticals Inc., Cambridge INHIBITORS OF C-JUN-N TERMINAL KINASES (JNK) AND OTHER PROTEIN KINASES
US20030096813A1 (en) * 2001-04-20 2003-05-22 Jingrong Cao Compositions useful as inhibitors of GSK-3
JP4316893B2 (en) * 2001-05-16 2009-08-19 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 Inhibitors of Src and other protein kinases
CA2450769A1 (en) * 2001-06-15 2002-12-27 Vertex Pharmaceuticals Incorporated 5-(2-aminopyrimidin-4-yl) benzisoxazoles as protein kinase inhibitors
US6689778B2 (en) * 2001-07-03 2004-02-10 Vertex Pharmaceuticals Incorporated Inhibitors of Src and Lck protein kinases
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
US6569499B2 (en) * 2001-10-02 2003-05-27 Xerox Corporation Apparatus and method for coating photoreceptor substrates
AU2002364536B2 (en) * 2001-12-07 2008-10-23 Vertex Pharmaceuticals, Inc. Pyrimidine-based compounds useful as GSK-3 inhibitors
EP1485381B8 (en) * 2002-03-15 2010-05-12 Vertex Pharmaceuticals Incorporated Azolylaminoazine as inhibitors of protein kinases
AU2003218215A1 (en) * 2002-03-15 2003-09-29 Vertex Pharmaceuticals, Inc. Azolylaminoazines as inhibitors of protein kinases
DE60332433D1 (en) * 2002-03-15 2010-06-17 Vertex Pharma AZOLYLAMINOAZINE AS PROTEIN KINASE INHIBITOR
WO2003078423A1 (en) * 2002-03-15 2003-09-25 Vertex Pharmaceuticals, Inc. Compositions useful as inhibitors of protein kinases
US20030207873A1 (en) * 2002-04-10 2003-11-06 Edmund Harrington Inhibitors of Src and other protein kinases
US7304061B2 (en) * 2002-04-26 2007-12-04 Vertex Pharmaceuticals Incorporated Heterocyclic inhibitors of ERK2 and uses thereof
MY141867A (en) * 2002-06-20 2010-07-16 Vertex Pharma Substituted pyrimidines useful as protein kinase inhibitors
JP4570955B2 (en) * 2002-07-09 2010-10-27 バーテクス ファーマスーティカルズ インコーポレイテッド Imidazoles with protein kinase inhibitory activity
BR0313176A (en) 2002-08-02 2005-06-14 Vertex Pharma Pyrazole compositions useful as gsk-3 inhibitors
EP2099787B1 (en) 2006-12-19 2010-07-21 Vertex Pharmaceuticals, Inc. Aminopyrimidines useful as inhibitors of protein kinases

Also Published As

Publication number Publication date
EP2264028A1 (en) 2010-12-22
MXPA03005611A (en) 2003-10-06
KR100875091B1 (en) 2008-12-22
AU2006201267A1 (en) 2006-04-27
AU2002246754B2 (en) 2006-06-08
EP1345928A2 (en) 2003-09-24
EP1345929B1 (en) 2006-05-17
HUP0400639A2 (en) 2004-06-28
MXPA03005608A (en) 2003-10-06
TWI290551B (en) 2007-12-01
DE60119774T2 (en) 2007-05-16
WO2002062789A1 (en) 2002-08-15
KR100947185B1 (en) 2010-03-15
DE60119776T2 (en) 2007-05-16
EP1345927B1 (en) 2006-05-17
KR20030061465A (en) 2003-07-18
IL156389A0 (en) 2004-01-04
EP1345929A2 (en) 2003-09-24
KR20030061468A (en) 2003-07-18
EP1355905A1 (en) 2003-10-29
KR20030061857A (en) 2003-07-22
ATE326463T1 (en) 2006-06-15
PL210066B1 (en) 2011-11-30
DE60119775T2 (en) 2007-05-10
DE60123283T2 (en) 2007-04-12
NZ526470A (en) 2006-03-31
US20040167141A1 (en) 2004-08-26
US20130096128A1 (en) 2013-04-18
IL156389A (en) 2011-01-31
WO2002050065A3 (en) 2002-10-24
JP4210520B2 (en) 2009-01-21
CA2432222A1 (en) 2002-08-15
CN1549812A (en) 2004-11-24
TWI313269B (en) 2009-08-11
CA2432129A1 (en) 2002-07-25
HK1059776A1 (en) 2004-07-16
MXPA03005605A (en) 2003-10-06
HUP0400908A2 (en) 2004-07-28
US7531536B2 (en) 2009-05-12
ATE354573T1 (en) 2007-03-15
CN100436452C (en) 2008-11-26
US20030036543A1 (en) 2003-02-20
EP1345922A1 (en) 2003-09-24
NO20032703D0 (en) 2003-06-13
DK1345922T3 (en) 2006-09-18
EP1702920A1 (en) 2006-09-20
JP2008260767A (en) 2008-10-30
CA2432223A1 (en) 2002-09-06
NZ526474A (en) 2005-10-28
WO2002050066A2 (en) 2002-06-27
CA2432799A1 (en) 2002-06-27
ES2265450T3 (en) 2007-02-16
WO2002059111A3 (en) 2003-01-09
EP1345925B1 (en) 2006-05-17
CN1486311A (en) 2004-03-31
EP1345928B1 (en) 2007-02-14
NZ526471A (en) 2005-08-26
US6664247B2 (en) 2003-12-16
KR100843114B1 (en) 2008-07-02
SI1355905T1 (en) 2007-08-31
AU2002255452B2 (en) 2006-06-08
ATE353890T1 (en) 2007-03-15
HUP0400639A3 (en) 2010-03-29
US20030004161A1 (en) 2003-01-02
JP2004517926A (en) 2004-06-17
WO2002059112A2 (en) 2002-08-01
WO2002057259A3 (en) 2003-04-24
US6653301B2 (en) 2003-11-25
AP1588A (en) 2006-03-06
AP2003002816A0 (en) 2003-06-30
US20030004164A1 (en) 2003-01-02
HK1060347A1 (en) 2004-08-06
MXPA03005610A (en) 2003-10-06
CA2432872A1 (en) 2002-06-27
NO20032736D0 (en) 2003-06-16
JP2004518743A (en) 2004-06-24
HK1061389A1 (en) 2004-09-17
IL209827A0 (en) 2011-02-28
CA2432132C (en) 2008-07-29
US20030022885A1 (en) 2003-01-30
NZ526473A (en) 2005-06-24
US20140187772A1 (en) 2014-07-03
DE60126828D1 (en) 2007-04-05
WO2002050065A2 (en) 2002-06-27
DK1355905T3 (en) 2007-06-18
AR040925A1 (en) 2005-04-27
DE60126828T2 (en) 2007-11-08
JP2009155352A (en) 2009-07-16
AU2002231166B2 (en) 2008-02-21
BR0116411A (en) 2003-11-11
HK1060349A1 (en) 2004-08-06
US8697698B2 (en) 2014-04-15
AU3116602A (en) 2002-07-01
HUP0400638A2 (en) 2004-06-28
MY140377A (en) 2009-12-31
EP1702920B1 (en) 2011-10-12
RU2003122209A (en) 2005-02-10
JP2004517927A (en) 2004-06-17
DE60119775D1 (en) 2006-06-22
NO20032736L (en) 2003-08-18
SI1353916T1 (en) 2007-02-28
JP5249842B2 (en) 2013-07-31
CN100408573C (en) 2008-08-06
WO2002050066A3 (en) 2003-01-23
JP2008189687A (en) 2008-08-21
US20030078275A1 (en) 2003-04-24
KR20030061463A (en) 2003-07-18
CN1486310A (en) 2004-03-31
WO2002068415A1 (en) 2002-09-06
DE60126658T2 (en) 2007-11-22
WO2002057259A2 (en) 2002-07-25
US20050038023A1 (en) 2005-02-17
KR20030061858A (en) 2003-07-22
CN1487933A (en) 2004-04-07
CA2432303C (en) 2010-04-13
CA2432131A1 (en) 2002-08-01
US8304414B2 (en) 2012-11-06
ES2265446T3 (en) 2007-02-16
US20030105090A1 (en) 2003-06-05
HUP0400641A2 (en) 2004-06-28
US6727251B2 (en) 2004-04-27
MXPA03005606A (en) 2003-10-06
AR042398A1 (en) 2005-06-22
NO328537B1 (en) 2010-03-15
HK1062433A1 (en) 2004-11-05
US20040157893A1 (en) 2004-08-12
HUP0400842A2 (en) 2004-07-28
MXPA03005607A (en) 2003-10-06
EP1345927A1 (en) 2003-09-24
US6989385B2 (en) 2006-01-24
KR20030061464A (en) 2003-07-18
DE60119774D1 (en) 2006-06-22
DE60119777D1 (en) 2006-06-22
WO2002059111A2 (en) 2002-08-01
NZ526472A (en) 2004-04-30
NO20032671D0 (en) 2003-06-12
ATE528303T1 (en) 2011-10-15
ATE326460T1 (en) 2006-06-15
NO20032670L (en) 2003-08-15
IL156407A0 (en) 2004-01-04
HK1060557A1 (en) 2004-08-13
IL156369A (en) 2011-02-28
CN100340555C (en) 2007-10-03
ES2375491T3 (en) 2012-03-01
EP1345925A2 (en) 2003-09-24
NO20032704L (en) 2003-08-21
PL210414B1 (en) 2012-01-31
KR20030061467A (en) 2003-07-18
JP2004518703A (en) 2004-06-24
TW200716617A (en) 2007-05-01
PT1355905E (en) 2007-05-31
DE60126658D1 (en) 2007-03-29
HK1062565A1 (en) 2004-11-12
EP1355905B1 (en) 2007-02-21
JP2004516291A (en) 2004-06-03
NO20032671L (en) 2003-08-18
CA2432872C (en) 2008-09-23
AP2003002825A0 (en) 2003-09-30
ATE326462T1 (en) 2006-06-15
IL156369A0 (en) 2004-01-04
AU2001297619B2 (en) 2006-06-08
US6656939B2 (en) 2003-12-02
JP4160395B2 (en) 2008-10-01
PL363244A1 (en) 2004-11-15
NZ526468A (en) 2004-03-26
JP2008189682A (en) 2008-08-21
IL156408A0 (en) 2004-01-04
CY1106297T1 (en) 2011-10-12
EP1345926A2 (en) 2003-09-24
DE60120219D1 (en) 2006-07-06
EP1345926B1 (en) 2006-05-17
IL156368A0 (en) 2004-01-04
KR20030061466A (en) 2003-07-18
NZ526469A (en) 2005-10-28
CN102250071A (en) 2011-11-23
AU2006201267B2 (en) 2010-07-29
DE60119776D1 (en) 2006-06-22
JP2005097322A (en) 2005-04-14
ES2280313T3 (en) 2007-09-16
US6653300B2 (en) 2003-11-25
ES2266095T3 (en) 2007-03-01
US20040214814A1 (en) 2004-10-28
US20040132781A1 (en) 2004-07-08
US20030055068A1 (en) 2003-03-20
HUP0400641A3 (en) 2010-03-29
US7087603B2 (en) 2006-08-08
MXPA03005609A (en) 2003-10-06
PT1345922E (en) 2006-09-29
CA2432799C (en) 2008-08-19
US7427681B2 (en) 2008-09-23
CA2432303A1 (en) 2002-08-29
KR100909665B1 (en) 2009-07-29
JP4160389B2 (en) 2008-10-01
JP2008222719A (en) 2008-09-25
JP2008247920A (en) 2008-10-16
JP2009286805A (en) 2009-12-10
US7982037B2 (en) 2011-07-19
NO20032704D0 (en) 2003-06-13
WO2002059112A3 (en) 2003-02-06
DK1353916T3 (en) 2007-01-29
WO2002066461A1 (en) 2002-08-29
CN1486312A (en) 2004-03-31
US20090312543A1 (en) 2009-12-17
JP4160392B2 (en) 2008-10-01
JP2004516292A (en) 2004-06-03
NO330527B1 (en) 2011-05-09
HUP0400908A3 (en) 2010-03-29
HK1060346A1 (en) 2004-08-06
ATE340172T1 (en) 2006-10-15
DE60120219T2 (en) 2007-04-12
ATE326461T1 (en) 2006-06-15
BR0116493A (en) 2003-09-30
NZ526475A (en) 2005-06-24
EP1353916B1 (en) 2006-09-20
US20080287444A1 (en) 2008-11-20
EP1345922B1 (en) 2006-05-31
DE60119777T2 (en) 2007-05-03
ES2272567T3 (en) 2007-05-01
US7625913B2 (en) 2009-12-01
NO328501B1 (en) 2010-03-01
JP2004519479A (en) 2004-07-02
NO20032703L (en) 2003-08-19
PT1353916E (en) 2007-01-31
MXPA03005612A (en) 2003-10-06
ES2265452T3 (en) 2007-02-16
DE60123283D1 (en) 2006-11-02
RU2355688C2 (en) 2009-05-20
JP2008247921A (en) 2008-10-16
JP2013213068A (en) 2013-10-17
EP1353916A2 (en) 2003-10-22
JP4234435B2 (en) 2009-03-04
NO20032670D0 (en) 2003-06-12
CA2432129C (en) 2008-08-26
CA2432131C (en) 2008-07-08
ATE327989T1 (en) 2006-06-15
AR042169A1 (en) 2005-06-15
JP2008201808A (en) 2008-09-04
PL363246A1 (en) 2004-11-15
AU2002234047A1 (en) 2002-07-01
CA2432132A1 (en) 2002-08-01
AR042397A1 (en) 2005-06-22
JP2004517894A (en) 2004-06-17
CN100406454C (en) 2008-07-30
CA2432223C (en) 2008-05-20
KR100889246B1 (en) 2009-03-19

Similar Documents

Publication Publication Date Title
CA2432222C (en) Pyrazole compounds useful as protein kinase inhibitors
AU2002255452A1 (en) Pyrazole compounds useful as protein kinase inhibitors
AU2001297619A1 (en) Pyrazole compounds useful as protein kinase inhibitors
AU2002246899A1 (en) Pyrazole compounds useful as protein kinase inhibitors
AU2002245198A1 (en) Pyrazole compounds useful as protein kinase inhibitors
AU2002246731A1 (en) Pyrazole compounds useful as protein kinase inhibitors

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed

Effective date: 20131219