WO2008036277A1 - Pyraz0l0(l,5-a) (1, 3, 5) triazine and pyrazolo (1, 5-a) pyrimidine derivatives useful as protein kinase inhibitors - Google Patents
Pyraz0l0(l,5-a) (1, 3, 5) triazine and pyrazolo (1, 5-a) pyrimidine derivatives useful as protein kinase inhibitors Download PDFInfo
- Publication number
- WO2008036277A1 WO2008036277A1 PCT/US2007/020231 US2007020231W WO2008036277A1 WO 2008036277 A1 WO2008036277 A1 WO 2008036277A1 US 2007020231 W US2007020231 W US 2007020231W WO 2008036277 A1 WO2008036277 A1 WO 2008036277A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- phenyl
- pyrazolo
- triazin
- diaza
- Prior art date
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- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title abstract description 6
- 239000003909 protein kinase inhibitor Substances 0.000 title abstract description 6
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 title description 2
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 238000000034 method Methods 0.000 claims abstract description 14
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- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
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- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 238000005710 macrocyclization reaction Methods 0.000 description 1
- ZZCRRKKIXDTWPD-UHFFFAOYSA-N methyl 5-[2-(3-aminoanilino)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl]pentanoate Chemical compound N=1C(NC=2C=C(N)C=CC=2)=NC2=C(CCCCC(=O)OC)C=NN2C=1NC1CC1 ZZCRRKKIXDTWPD-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- CZGIEJXGCLWRPY-UHFFFAOYSA-N n,1-dimethylpyrrolidin-3-amine Chemical compound CNC1CCN(C)C1 CZGIEJXGCLWRPY-UHFFFAOYSA-N 0.000 description 1
- AVAWMINJNRAQFS-UHFFFAOYSA-N n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)C1CCNC1 AVAWMINJNRAQFS-UHFFFAOYSA-N 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 1
- PKUBGLYEOAJPEG-UHFFFAOYSA-N physcion Natural products C1=C(C)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O PKUBGLYEOAJPEG-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- JUXWUYWPUDKPSD-UHFFFAOYSA-N pyrazolo[1,5-a][1,3,5]triazine Chemical compound N1=CN=CN2N=CC=C21 JUXWUYWPUDKPSD-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000036964 tight binding Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- ZMCBYSBVJIMENC-UHFFFAOYSA-N tricaine Chemical compound CCOC(=O)C1=CC=CC(N)=C1 ZMCBYSBVJIMENC-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
Classifications
-
- 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
- C07D487/12—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 three hetero rings
- C07D487/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61P25/28—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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- 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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- PYRAZOLO (1 , 5-A) (1 , 3 , 5) TRIAZINE AND PYRAZOLO (1 , 5-A) PYRIMIDINE DERIVATIVES USEFUL AS PROTEIN KINASE INHIBITORS
- the present invention relates to chemical compounds that are useful, for example, as protein kinase inhibitors for treating cancer, neurological disorders, autoimmune disorders, and other diseases, and methods of using such compounds.
- CK2 an essential serine/threonine protein kinase, until recently has not been considered as a possible target in cancer chemotherapy, but a wide variety of cancers exhibit elevated levels of CK2 activity that correlate with the aggressiveness of tumor growth. Furthermore, decreasing CK2 activity, through use of small molecules, dominant negative overexpression of kinase inactive mutants, anti-sense methods, or small interfering RNAs, decreases cellular proliferation, increases the level of apoptosis in cancer cells, and eradicates the PC3 human prostate cancer cells from tumor-bearing mice.
- Existing C2 inhibitors such as emodin, coumarins, TBB (triazole), quinazolines, DRB and quercetin, however, while useful for laboratory studies, lack the qualities of a clinically useful chemotherapeutic agent.
- One aspect of the present invention provides a new class of protein kinase inhibitors based upon macrocyclic pyrazolo[l,5-a][l,3,5]triazine and pyrazolo[l,5-a]pyrimidine compounds, methods of using them, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof.
- pharmaceutically acceptable prodrugs Such compounds, prodrugs, metabolites, polymorphs, and pharmaceutically acceptable salts thereof are collectively referred to as "agents.”
- the invention also relates to pharmaceutical compositions comprising an effective amount of an agent with one or more pharmaceutically acceptable carriers.
- inventive agents and pharmaceutical compositions containing such agents are useful in treating various diseases including but not limited to those associated with uncontrolled or un-wanted cellular proliferation such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular diseases.
- Preferred agents modulate and/or inhibit the activity of CK2 protein kinase.
- the pharmaceutical compositions containing such agents are useful in treating diseases mediated by kinase activity, such as cancer.
- the invention relates generally to compounds of Formula (I), as well as prodrugs, pharmaceutically active metabolites, polymorphs, and pharmaceutically acceptable salts thereof:
- Rl is alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
- R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl
- R3 groups are independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl,aryl, heteroaryl, or halo:
- X is CH or N.
- the invention also relates to methods of treating proliferative diseases such as cancer, auto immune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular diseases, comprising administration of effective amounts of an agent of the invention to a subject in need of such treatment.
- proliferative diseases such as cancer, auto immune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular diseases.
- the invention further relates to methods of modulating and/or inhibiting the protein kinase activity of CK2 by administering a compound of Formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable salt of such compound or metabolite thereof.
- Alkyl refers to straight or branched hydrocarbon chains containing from 1 to 8 carbon atoms
- alkylene and “alkynyl” refer to the corresponding chains containing a double- or triple bond, respectively.
- Alkyl, alkylene, and alkynyl groups may be optionally substituted with one or more substituents selected from the group consisting of mercapto, nitro, cyano, azido and halo.
- Heteroaryl refers to 5- and 6-membered aromatic rings having one or more heteroatoms selected independently from N, O, and S.
- Rl is aryl, preferably substituted aryl, more preferably substituted phenyl.
- Rl is N- alkyl-N-alkylpyrrolidinyl-carbonyl-phenyl (e.g., N-methyl-N-(l -methyl -pyrrolidinyl)-carbonyl)- phenyl, as in compound Hg) or N-alkyl-N-alkylaminoalkyl (e.g., N-methyl-N-ethylaminoethyl, as in compound 11 s) are particularly useful.
- each R2 and R3 group is hydrogen
- (C) is alkyl
- n 4
- X is N.
- inventive agents may be prepared by synthetic schemes described below.
- Triazine-based compounds of Formula (I) for example, can be prepared according to Scheme 1:
- salts and/or solvates of compounds of the present invention may also be used.
- Such salts include those formed from, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, fumaric, acetic, propionic, succinic, glycolic, maleic, tartaric, citric, malonic, and methanesulfonic acids.
- Certain compounds may include a chiral center, in which case each enantiomer as well as the corresponding racemate is encompassed in the present invention.
- the present invention also is directed to pharmaceutical formulations that include the inventive compounds, regardless of the intended mode of administration.
- Therapeutic dosages of compounds of the present inventions can be readily determined by methods well-known in the art.
- CK2 protein kinase activity was measured through use of a spectrophotometric PK/LDH coupled assay to detect ATP turnover.
- Full Length His-tagged Human CK2 was cloned, expressed, and purified from an E. coli expression system.
- the peptide substrate for CK2 phosphorylation was RRRDDDSDDD (Genscript Corporation, Piscataway, NJ, USA).
- a typical CK2 enzymatic assay contained ⁇ 20 nM human CK2, 100 ⁇ M peptide substrate, 50 mM Tris- HCl pH 8.0, 100 mM NaCl, 10 mM MgC12, 200 ⁇ M EDTA, 5 mM 2-mercaptoethanol, 1 mM phosphoenol pyruvate, 150 ⁇ M NADH, 0.5% PK/LDH Mix (Sigma #P-0294), 2.5% DMSO and 50 ⁇ M ATP. Inhibitor compounds were suspended in 100% DMSO and added to achieve various concentrations at a constant DMSO proportion of 2.5% by volume.
- CK2 enzyme Prior to the addition of ATP to initiate the phosphorylation reaction, CK2 enzyme was pre-incubated with inhibitors and other assay components for 5 min. Progress of the reaction was continuously monitored by the change in UV/Vis absorbance at 340 nm. Reaction rates were plotted versus inhibitor concentration and Ki values were fitted with the assumption of competitive inhibition and use of a Km value of 10 ⁇ M. In the case of very potent binding, tight-binding methods were employed to determine Ki. The results are recorded in Tables 1 and 2.
- HCT-116 and PC-3 cells were cultured at 37°C with 5% CO2 and in 10% fetal bovine serum with McCoy's 5 A modified medium and F- 12 K medium respectively.
- Cells were plated on 96 well plates at a density of 2,000-4,000/well in the volume of 100 ⁇ L medium. After overnight incubation, 50 ⁇ L more medium containing various amount of CK2 inhibitors were added into each well to give final inhibitor concentrations ranging from 0.01 to 20 ⁇ M in 1% dimethylsulfoxide.
- the control wells contained 1% dimethylsulfoxide only in their medium.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Transplantation (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Communicable Diseases (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES07838443T ES2400450T3 (en) | 2006-09-18 | 2007-09-18 | Pyrazolo [1,5-a] [1,3,5] triazine and pyrazolo [1,5-a] pyrimidine derivatives for use as protein kinase inhibitors |
CN2007800342168A CN101522683B (en) | 2006-09-18 | 2007-09-18 | Pyraz0l0(l,5-A) (1, 3, 5) triazine and pyrazolo (1, 5-A) pyrimidine derivatives useful as protein kinase inhibitors |
CA2663791A CA2663791C (en) | 2006-09-18 | 2007-09-18 | Pyrazolo (1, 5-a) (1, 3, 5) triazine and pyrazolo (1, 5-a) pyrimidine derivatives useful as protein kinase inhibitors |
AU2007297675A AU2007297675B2 (en) | 2006-09-18 | 2007-09-18 | Pyrazolo(l,5-a) (1, 3, 5) triazine and pyrazolo (1, 5-a) pyrimidine derivatives useful as protein kinase inhibitors |
KR1020097005501A KR101418619B1 (en) | 2006-09-18 | 2007-09-18 | Pyrazolo(1,5-a)(1,3,5)triazine and pyrazolo(1,5-a)pyrimidine derivatives useful as protein kinase inhibitors |
JP2009528344A JP5232786B2 (en) | 2006-09-18 | 2007-09-18 | Pyrazolo (1,5-a) (1,3,5) triazine and pyrazolo (1,5-a) pyrimidine derivatives useful as protein kinase inhibitors |
BRPI0718459-0A BRPI0718459A2 (en) | 2006-09-18 | 2007-09-18 | PIRAZOLE (1,5-A) (1,3,5) TRIAZINE AND PIRAZOLE (1,5-A) PYRIMIDINE DERIVATIVES USEFUL AS PROTEIN KINASE INHIBITORS |
EP07838443A EP2064214B1 (en) | 2006-09-18 | 2007-09-18 | Pyrazolo[l,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives useful as protein kinase inhibitors |
HK10100383.3A HK1135688A1 (en) | 2006-09-18 | 2010-01-13 | Pyrazolo (1,5-a)(1,3,5) triazine and pyrazolo (1,5-a) pyrimidine derivatives useful as protein kinase inhibitors |
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US84531406P | 2006-09-18 | 2006-09-18 | |
US60/845,314 | 2006-09-18 | ||
US11/856,476 US7517882B2 (en) | 2006-09-18 | 2007-09-17 | Protein kinase inhibitors |
US11/856,476 | 2007-09-17 |
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US (2) | US7517882B2 (en) |
EP (1) | EP2064214B1 (en) |
JP (1) | JP5232786B2 (en) |
KR (1) | KR101418619B1 (en) |
CN (1) | CN101522683B (en) |
AU (1) | AU2007297675B2 (en) |
BR (1) | BRPI0718459A2 (en) |
CA (1) | CA2663791C (en) |
ES (1) | ES2400450T3 (en) |
HK (1) | HK1135688A1 (en) |
TW (1) | TWI472530B (en) |
WO (1) | WO2008036277A1 (en) |
Cited By (1)
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WO2016142855A3 (en) * | 2015-03-09 | 2016-11-03 | Aurigene Discovery Technologies Limited | Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives as cdk inhibitors |
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US7517882B2 (en) * | 2006-09-18 | 2009-04-14 | Polaris Group | Protein kinase inhibitors |
CN102056925A (en) * | 2008-04-07 | 2011-05-11 | Irm责任有限公司 | Compounds and compositions as kinase inhibitors |
CN103930427B (en) * | 2011-09-30 | 2016-03-09 | 昂科迪塞恩股份有限公司 | Large ring FLT3 kinase inhibitor |
JP2016510797A (en) * | 2013-03-15 | 2016-04-11 | オンコデザイン エス.ア. | Macrocyclic salt-inducible kinase inhibitor |
CN103570728B (en) * | 2013-11-12 | 2015-12-30 | 山东大学 | Also [1,5-a] pyridine derivatives and preparation method thereof and the application of a kind of substituted pyrazolecarboxylic |
KR20190034225A (en) * | 2016-07-28 | 2019-04-01 | 티피 테라퓨틱스, 인크. | Macrocyclic kinase inhibitor |
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WO2004104007A1 (en) * | 2003-05-22 | 2004-12-02 | Pharmacia Italia S.P.A. | Pyrazolo-quinazoline derivatives,process for their preparation and their use as kinase inhibitors |
EP1752457A1 (en) * | 2004-06-02 | 2007-02-14 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound |
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- 2007-09-18 JP JP2009528344A patent/JP5232786B2/en not_active Expired - Fee Related
- 2007-09-18 EP EP07838443A patent/EP2064214B1/en not_active Not-in-force
- 2007-09-18 ES ES07838443T patent/ES2400450T3/en active Active
- 2007-09-18 KR KR1020097005501A patent/KR101418619B1/en active IP Right Grant
- 2007-09-18 BR BRPI0718459-0A patent/BRPI0718459A2/en not_active Application Discontinuation
- 2007-09-18 AU AU2007297675A patent/AU2007297675B2/en not_active Ceased
- 2007-09-18 WO PCT/US2007/020231 patent/WO2008036277A1/en active Application Filing
- 2007-09-19 TW TW96134833A patent/TWI472530B/en not_active IP Right Cessation
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2009
- 2009-03-03 US US12/396,919 patent/US20090247501A1/en not_active Abandoned
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WO2004048384A1 (en) * | 2002-11-27 | 2004-06-10 | Nad Ag | N,n-bridged, nitrogen-substituted carbacyclic indolocarbazoles as protein kinase inhibitors |
WO2004104007A1 (en) * | 2003-05-22 | 2004-12-02 | Pharmacia Italia S.P.A. | Pyrazolo-quinazoline derivatives,process for their preparation and their use as kinase inhibitors |
EP1752457A1 (en) * | 2004-06-02 | 2007-02-14 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2016142855A3 (en) * | 2015-03-09 | 2016-11-03 | Aurigene Discovery Technologies Limited | Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives as cdk inhibitors |
CN107530329A (en) * | 2015-03-09 | 2018-01-02 | 奥瑞基尼探索技术有限公司 | Pyrazolo [1,5 a] [1,3,5] triazine and pyrazolo [1,5 a] pyrimidine derivatives as CDK inhibitor |
CN107530329B (en) * | 2015-03-09 | 2021-10-08 | 奥瑞基尼探索技术有限公司 | Pyrazolo [1, 5-a ] [1, 3, 5] triazine and pyrazolo [1, 5-a ] pyrimidine derivatives as CDK inhibitors |
US11186576B2 (en) | 2015-03-09 | 2021-11-30 | Aurigene Discovery Technologies Limited | Pyrazolo[1,5-A][1,3,5]triazine and pyrazolo[1,5-A]pyrimidine derivatives as CDK inhibitors |
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CA2663791A1 (en) | 2008-03-27 |
AU2007297675B2 (en) | 2012-09-20 |
JP5232786B2 (en) | 2013-07-10 |
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HK1135688A1 (en) | 2010-06-11 |
AU2007297675A1 (en) | 2008-03-27 |
CN101522683B (en) | 2013-02-27 |
TWI472530B (en) | 2015-02-11 |
US20090247501A1 (en) | 2009-10-01 |
ES2400450T3 (en) | 2013-04-10 |
US20080070893A1 (en) | 2008-03-20 |
TW200837065A (en) | 2008-09-16 |
BRPI0718459A2 (en) | 2013-12-03 |
EP2064214A1 (en) | 2009-06-03 |
JP2010503690A (en) | 2010-02-04 |
US7517882B2 (en) | 2009-04-14 |
CA2663791C (en) | 2015-11-03 |
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EP2064214B1 (en) | 2013-01-30 |
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