[go: up one dir, main page]

WO2000012089A1 - Nouveaux inhibiteurs d'angiogenese - Google Patents

Nouveaux inhibiteurs d'angiogenese Download PDF

Info

Publication number
WO2000012089A1
WO2000012089A1 PCT/US1999/005297 US9905297W WO0012089A1 WO 2000012089 A1 WO2000012089 A1 WO 2000012089A1 US 9905297 W US9905297 W US 9905297W WO 0012089 A1 WO0012089 A1 WO 0012089A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzoimidazol
alkyl
aryl
phenyl
heterocyclyl
Prior art date
Application number
PCT/US1999/005297
Other languages
English (en)
Inventor
Mark T. Bilodeau
Randall W. Hungate
April M. Cunningham
Timothy J. Koester
Original Assignee
Merck & Co., 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 Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP2000567206A priority Critical patent/JP2002523459A/ja
Priority to EP99912408A priority patent/EP1109555A4/fr
Priority to CA002341409A priority patent/CA2341409A1/fr
Priority to AU30789/99A priority patent/AU760020B2/en
Priority to US09/786,004 priority patent/US6465484B1/en
Publication of WO2000012089A1 publication Critical patent/WO2000012089A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphospate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Accordingly, inhibitors of these tyrosine kinases are useful for the prevention and treatment chemotherapy of proliferative diseases dependent on these enzymes. For example, a method of treatment described herein relates to neoangiogenesis. Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.
  • VEGF Vascular endothelial growth factor binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1.
  • KDR mediates the mitogenic function of VEGF
  • Flt-1 appears to modulate non- mitogenic functions such as those associated with cellular adhesion.
  • Inhibiting KDR thus modulates the level of mitogenic VEGF activity.
  • Vascular growth in the retina leads to visual degeneration culminating in blindness.
  • VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy.
  • Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased p0 2 levels in mice that lead to neovascularization.
  • Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.
  • VEGF vascular endothelial growth factor
  • monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities.
  • These monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells.
  • VEGF-binding construct of Flk-1 Viral expression of a VEGF-binding construct of Flk-1, the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors.
  • Embryonic stem cells which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors.
  • KDR or Flt-1 are implicated in pathological neoangiogenesis, and these are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., diabetic retinal vascularization, as well as various forms of cancer.
  • Cancers which are treatable in accordance with the present invention demonstrate high levels of gene and protein expression.
  • cancers include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
  • Raf-activating oncogenes e.g., K-ras, erb-B
  • the present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, atherosclerosis, diabetic retinopathy or inflammatory diseases, in mammals.
  • X is N or C
  • Rj&R 3 are independently H, C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a :
  • R 2 is independently H, C,_ 6 alkyl, C 5 . 10 aryl, C3-.6 cycloalkyl,
  • R 4 &R 5 are independently H, C 0 alkyl, C3-6 cycloalkyl, C ⁇ 6 alkoxy C 2 . ⁇ o alkenyl, C 2-10 alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl,
  • C 1-6 alkoxyNR 7 R 8 halo, N0 2 , OH, -NH 2 or C 5 .
  • 10 heteroaryl said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a , or R4 and R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from R a .
  • R a is H, C 0 alkyl, halogen, N0 2 , R, NHC,. 6 alkylR ⁇ , OR, -NR
  • R is H, C j . 6 alkyl or C 1 -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C,. 10 alkyl, C3-6 cycloalkyl, COR,
  • X is N or C
  • Rj is H, C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C 6 alkyl, C 5 _ 10 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 is H, Cj., 0 alkyl, C3-6 cycloalkyl, C N6 alkoxy C 2 . 10 alkenyl, C 2 - ⁇ o alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, C ⁇ - 6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R is H, or C,. 6 alkyl, OR, halo, NH 2 or N0 2 ;
  • R is H, C J . JO alkyl, halogen, N0 2 , OR, -NR NR 7 R 8 , R 7 R 8) C 5 . 10 aryl, C 5 . 10 heteroaryl or C 3 . 10 heterocyclyl;
  • R is H, or C,_ 6 alkyl, C ⁇ -6 alkylR 9 ;
  • RQ is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl;
  • R7&R8 are independently H, C M0 alkyl, C3-6 cycloalkyl, COR, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • composition which is comprised of a compound represented by the formula I:
  • R,, R 2 , R 3 , R 4 and R 5 are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
  • Also included is a method of treating or preventing a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included is a method of treating or preventing cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.
  • Also included in the present invention is a method of treating or preventing diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis.
  • a method of treating or preventing ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
  • a method of treating or preventing retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization.
  • Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology.
  • a method of treating or preventing age-related macular degeneration is also included.
  • alkyl refers to a monovalent alkane
  • hydrocarbon (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.
  • Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:
  • the alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
  • substituted alkyl when substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of R a , described herein.
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present.
  • Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of R a , when a substituted alkenyl group is provided.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of R a , when a substituted alkynyl group is provided.
  • Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
  • Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted with 1-3 groups of R a as defined herein.
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • heterocycle, heteroaryl, heterocyclyl or heterocyclic represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • the heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of R a .
  • Examples of such heterocyclic elements, inclusive of all possible isomers, include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, iso
  • alkoxy refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
  • halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
  • prodrug refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process.
  • exemplary prodrugs include acyl amides of the amino compounds of this inventon such as amides of alkanoic(C ⁇ _ 6 )acids, amides of aryl acids (e.g., benzoic acid) and alkane(C. perennial 6 )dioic acids.
  • Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant tyrosine kinase enzyme activity. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), etc.
  • X is N or C
  • R,&R 3 are independently H, C M0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • Ro is independently H, C,_ 6 alkyl, C 5 . 10 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 &R 5 are independently H, C,_ 10 alkyl, C3-6 cycloalkyl, C,_ 6 alkoxy C 2- ⁇ o alkenyl, C 2- ⁇ o alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, C ⁇ -6 alkoxyNR 7 R 8 , halo, N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, .
  • alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a , or R4 a ⁇ j R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from R a .
  • R a is H, C 0 alkyl, halogen, N0 2 , R, NHC,. 6 alkylR 9 , OR, -NR,
  • R is H, C,. 6 alkyl or C ⁇ -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C M o alkyl, C3-6 cycloalkyl, COR, C 5 _ ⁇ 0 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • Still another aspect of this invention is described wherein . is C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, C 5 . 10 heteroaryl, or C 3 . 10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is C M0 alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • R a is H, C LI O alkyl, halogen, C 1-6 alkylR 9 , CN, R, OR, NR, RNR 7 R 8 , NR 7 R 8 , R 7 R 8 and all other variables are as described above.
  • R,&R 3 are independently H, C M0 alkyl, C 5 . 10 aiyl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 is independently H, C,. 6 alkyl, C 3-6 cycloalkyl, OH, or halogen;
  • R 4 &R 5 are independently H, C,. 10 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl, C ⁇ -6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ; and all other variables are as described above.
  • Another preferred subset of compounds of the present invention is realized when:
  • R 1 &R 3 are independently C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 is H or C,. 6 alkyl
  • R 4 is piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, is
  • X is N or C
  • R is H, C 0 alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C,. 6 alkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, C 1-6 alkoxyNR 7 R 8 , or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 5 is H, C,. 6 alkyl, OR, halo, NH 2 or N0 2 ;
  • R a is H, C 0 alkyl, halogen, N0 2 , R, OR, -NR, NR 7 R 8j R 7 R 8 , C 5 . 10 aryl, C 5 . 10 heteroaryl or C 3 . 10 heterocyclyl,
  • R is H, or C,_ 6 alkyl, C ⁇ -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl;
  • R7&R8 are independently H, C M0 alkyl, C3-6 cycloalkyl, COR, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • R4 is C J . JO alkyl, C 3-6 cycloalkyl, C 5 .j 0 aryl, C 5 . 10 heteroaryl, or C 3 . 10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is C J . JO alkyl, C 5 .j 0 aryl, C 3 .j 0 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is H, C J . J O alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C,_ 6 alkyl, C 3-6 cycloalkyl, OH, or halogen;
  • R 4 is H, C J . JO alkyl, C 3 . 6 cycloalkyl, C 5 ., 0 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl, Cj -6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ; and all other variables are as described above.
  • Rj is C 5 _i 0 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H or Cj. 6 alkyl
  • R 4 is C J . JO alkyl, C 5 ., 0 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from
  • X & W are independently N or C
  • R j &R 3 are independently H, C J . J0 alkyl, C 3-6 cycloalkyl, C 5 .j 0 aryl, halo, OH, C 3 _i 0 heterocyclyl, or C 5 .j 0 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 9 is independently H, Cj. 6 alkyl, C 5 ., 0 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R is independently H, Cj. 10 alkyl, C3-6 cycloalkyl, Cj. 6 alkoxy C 2 _ ⁇ o alkenyl, C 2- ⁇ o alkynyl, C 5 .j 0 aryl, C 3 .j 0 heterocyclyl, Cj. 6 alkoxyNR 7 R 8 , halo, N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • Rio is H, or Cj. 6 alkyl, Cj. 6 alkylR 9 , C 5 . 10 aryl, C 3 . 10 heterocyclyl, NHC j . 6 alkylR 9; said alkyl (where R is C j . 6 alkyl), aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R is H, C J . JO alkyl, halogen, N0 2 , OR, -NR RNR 7 R 8 , NR 7 R 8 ,
  • R 7 R 8 CN, C 5 ., 0 aryl, C 5 . 10 heteroaryl or C 3 .j 0 heterocyclyl;
  • R is H, Cj. 6 alkyl or Cj. 6 alkylR 9 ;
  • R 9 is C 5 .jo aryl, C 3 .j 0 heterocyclyl, or C 5 .] 0 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C 0 alkyl, C3-6 cycloalkyl, COR,
  • C 5 _jo aryl, C 3 .j 0 heterocyclyl, or C 5 .j 0 heteroaryl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • R 10 is H, C,., 0 alkyl, Cj -6 alkylR 9 , C 5 .j 0 aryl, C 5 . 10 heteroaryl, or C 3 .j 0 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Examples of the compounds of this invention are:
  • the invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with a carrier.
  • pharmaceutically acceptable salts and “hydrates” refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, abso ⁇ tion, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which are also important in the selection are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • a counterion e.g., an alkali metal cation such as sodium or potassium.
  • suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality.
  • the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
  • salts also include acid addition salts.
  • the compound can be used in the form of salts derived from inorganic or organic acids or bases. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • any variable e.g., aryl, heterocyle, Rl, etc
  • the compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.
  • the compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
  • the carrier employed may be, for example, either a solid or liquid.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
  • oral solid dosage forms examples include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500mg.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
  • the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
  • dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors.
  • An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses.
  • An example of a suitable parenteral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection.
  • An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day.
  • An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.
  • the compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds.
  • the non-limiting examples that follow are illustrations of the compounds of the instant invention and are not meant to limit the invention in any way.
  • Nitroaniline 5 (0.213 g, 0.665 mmol) and palladium on carbon (10%, 100 mg) were stirred in 8 mL 3: 1 EtOH/AcOH. The reaction was put under a balloon of H 2 . After 2 h the reaction was filtered through a plug of celite and the filtrate was concentrated to dryness. The resulting residue was dissolved in 1.5 mL trimethylorthoformate and heated to 120 ° C for 30 min. The solution was cooled concentrated to dryness and purified by flash column chromatography (2 x 15 cm silica gel, 1 : 1 hexane/ethyl acetate) which provided 6.
  • Benzimidazole 7 (0.025g, 0.087 mmol) and N-(2- chloroethyl)piperidine hydrochloride (11 mg, 0.059 mmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL). Cesuim carbonate (0.085g, 0.26 mmol) was added and the resulting mixture was heated to 50 °C. After 2 h additional and N-(2-chloroethyl)pi ⁇ eridine hydrochloride (11 mg, 0.059 mmol) was added. After 1 h the reaction was allowed to cool, quenched with water and extracted with ethyl acetate (3x).
  • the bromochloronitropyridine was dissolved in 15mL of anhydrous l-methyl-2-pyrrolidinone.
  • Aniline (3.580 mL, 0.0393 mol) was added followed by the addition of N,N-diisopropylethylamine (13.69 mL, 0.0786 mol) and the solution was heated to 120 °C. After 1.5 hr., the solution was cooled to ambient temperature and diluted with water. The product was extracted using ethyl acetate and washed with brine. The organic layer was then dried over sodium sulfate, filtered, concentrated, and dried in vacuo.
  • Bromoaromatic 10 (30 mg, 0.102 mmol), 4- methoxyphenylboronic acid (17 mg, 0.112 mmol) was dissolved in 0.75 mL dioxane followed by the addition of 204 ⁇ L of 2M sodium carbonate.
  • the vessel was flushed with argon followed by the addition of tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) and 0.56 mL water.
  • the vessel was flushed again with argon and heated to 80 °C for 2.5 hr.
  • the solution was cooled to room temperature and diluted with water.
  • the product was extracted with ethyl acetate and washed with brine, followed by drying over sodium sulfate.
  • the organic layer was concentrated, and the product dried in vacuo.
  • the crude mixture was purified by flash column chromatography (2.5 x 8 cm silica gel, 8:2 hexane:ethyl
  • Nitroaniline 11 (1.333 g, 4.15 mmol), Zn dust(6.239 g, 95.40 mmol), and 10 mL acetic acid were mixed under argon. The solution was heated to 60 °C for 1 hr until the solution turned light green. The zinc was removed using vacuum filtration with celite and washed with acetic acid. The filtrate was concentrated and 20 mL of trimethylorthoformate was added. The solution was heated to 100 °C for 2 hr followed by cooling to ambient temperature. The solution was concentrated and the crude mixture was purified by flash column chromatography(5 x 16 cm silica gel, 6:4 ethylacetate:hexane) affording 12.
  • the aqueous layer was extracted a second time with dichloromethane w/ 3% 1-butanol.
  • the organic layers were washed with saturated sodium bicarbonate, and dried over sodium sulfate.
  • the organic layers were conentrated at aspirator pressure to remove ethyl acetate and methylene chloride; the 1-butanol and residual DMF were removed under high pressure.
  • the product was purified using flash column chromatography(silica gel 2.5 x 32.5 cm, 10:1 methylene chloride :methanol). Excess trifluoroacetic acid was added to the product to create the resulting salt, and the mixture was triturated using ether.
  • Bromoaromatic 4 (7.10 g, 24.1 mmol) and powdered zinc (36.2 g, 554 mmol, 23 equiv) were stirred in 80 mL glacial acetic acid. The mixture was heated to 60 °C. After lh the reaction was cooled and filtered through a plug of celite and concentrated to dryness. The resulting residue was dissolved in 60 mL of formic acid and heated to 100 °C overnight. The reaction was cooled and concentrated to dryness. Purification by flash column chromatography (6x25 cm silica, 55:45 hexanes/EtOAc) afforded 5.88 g benzimidazole 15 (89% yield). !
  • Benzimidazole 15 (2.91 g, 10.7 mmol), diboron pinacol ester (2.97 g, 11.7 mmol) and potassium acetate (3.14 g, 32.0 mmol) were stirred in 20 mL anhydrous DMF under Ar.
  • PdCl 2 (dppf) (0.26 g, 0.32 mmol) was added, solution was degassed and heated to 80 °C. After 20h the reaction was quenched with 125 mL of water and 50 mL of saturated aqueous NaCl and was extracted 3 x with EtOAc. The combined extracts were dried over Na 2 S0 4 , filtered and concentrated to afford 2.77 g of unpurified boronate.
  • l-Phenyl-5-pyridin-4-yl-lH-benzoimidazole (12) (8.82 g, 32.5 mmol) was dissolved in 120 mL of CH 2 C1 2 .
  • the resulting solution was cooled to 0°C and to it was added mCPBA (11.2 g, 65.0 mmol). After stirring for 2.5 days an additional portion of mCPBA (3.0 g, 17 mmol) was added. After an additional 24 h the reaction solution was loaded directly onto a column (8 x 20 cm) pre-wetted with CH 2 C1 2 .
  • N-3-chloropiperidine HC1 54 mg, .275 mmol
  • cesium carbonate 164 mg, .504 mmol
  • 4 mL anhydrous N,N- dimethylformamide 4 mL
  • the vessel was placed in 60 °C oil bath with stirring under argon.
  • the reaction was heated to 80 °C after 1 day, and was stopped after 4 days after no further progression.
  • the solvent was removed via high vacuum rotary evaporation, the residue was diluted with MeOH, and filtered through a 0.7 ⁇ M syringe filter.
  • VEGF RECEPTOR KINASE ASSAY VEGF receptor kinase activity is measured by incorporation of radio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY) substrate.
  • the phosphorylated pEY product is trapped onto a filter membrane and the incoporation of radio-labeled phosphate quantified by scintillation counting.
  • the intracellular tyrosine kinase domains of human KDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519-524) were cloned as glutathione S-transferase (GST) gene fusion proteins. This was accomplished by cloning the cytoplasmic domain of the KDR kinase as an in frame fusion at the carboxy terminus of the GST gene.
  • GST glutathione S-transferase
  • Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf 1) insect cells (Invitrogen) using a baculo virus expression vector (pAcG2T, Pharmingen).
  • EDTA 0.05% triton X-100, 10 % glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride.
  • Millipore #MAFC NOB GF/C glass fiber 96 well plate.
  • reaction mix containing 5 ⁇ l of 10 X reaction buffer, 5 ⁇ l 25 mM ATP/10 ⁇ Ci [ 33 P]ATP (Amersham), and 5 ⁇ l 10 X substrate.
  • VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells.
  • Human umbilical vein endothelial cells (HUVECs) in culture proliferate in response to VEGF treatment and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation.
  • quiescent HUVEC monolayers are treated with vehicle or test compound 2 hours prior to addition of VEGF or basic fibroblast growth factor (bFGF).
  • the mitogenic response to VEGF or bFGF is determined by measuring the incorporation of [ 3 H]thymidine into cellular DNA.
  • HUVECs frozen as primary culture isolates are obtained from Clonetics Corp. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and are used for mitogenic assays at passages
  • IPX Growth factors Solutions of human VEGF 165 (500 ng/ml; R&D Systems) and bFGF (10 ng/ml; R&D Systems) are prepared in Assay Medium.
  • HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4000 cells per 100 ul Assay Medium per well in 96-well plates. Cells are growth-arrested for 24 hours at 37°C in a humidified atmosphere containing 5% C0 2 .
  • Growth-arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% [v/v] DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37°C/5% C0 2 for 2 hours to allow test compounds to enter cells.
  • I are inhibitors of VEGF and thus are useful for the inhibition of neoangiogenesis, such as in the treatment of occular disease, e.g., diabetic retinopathy and in the treatment of cancers, e.g., solid tumors.
  • the instant compounds inhibit VEGF-stimulated mitogenesis of human vascular endothelial cells in culture with IC 50 values between 150-650 nM. These compounds also show selectivity over related tyrosine kinases (e.g. FGFR1 and the Src family).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention se rapporte à des composés qui inhibent les tyrosine-kinases, à des compositions qui contiennent des composés inhibiteurs de tyrosine-kinases et à des procédés d'utilisation d'inhibiteurs de tyrosine-kinases pour traiter, chez les mammifères, les affections/maladies dépendant des tyrosine-kinases telles que l'angiogenèse, le cancer, l'athérosclérose, la rétinopathie diabétique ou les maladies auto-immunes.
PCT/US1999/005297 1997-09-26 1999-03-11 Nouveaux inhibiteurs d'angiogenese WO2000012089A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2000567206A JP2002523459A (ja) 1998-08-31 1999-03-11 新規血管形成阻害剤
EP99912408A EP1109555A4 (fr) 1998-08-31 1999-03-11 Nouveaux inhibiteurs d'angiogenese
CA002341409A CA2341409A1 (fr) 1998-08-31 1999-03-11 Nouveaux inhibiteurs d'angiogenese
AU30789/99A AU760020B2 (en) 1998-08-31 1999-03-11 Novel angiogenesis inhibitors
US09/786,004 US6465484B1 (en) 1997-09-26 1999-03-11 Angiogenesis inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14388198A 1998-08-31 1998-08-31
US09/143,881 1998-08-31

Publications (1)

Publication Number Publication Date
WO2000012089A1 true WO2000012089A1 (fr) 2000-03-09

Family

ID=22506085

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/005297 WO2000012089A1 (fr) 1997-09-26 1999-03-11 Nouveaux inhibiteurs d'angiogenese

Country Status (5)

Country Link
EP (1) EP1109555A4 (fr)
JP (1) JP2002523459A (fr)
AU (1) AU760020B2 (fr)
CA (1) CA2341409A1 (fr)
WO (1) WO2000012089A1 (fr)

Cited By (133)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1132381A1 (fr) * 2000-03-08 2001-09-12 Cermol S.A. Derivés d'esters d'acide propionique et compositions pharmaceutiques les contenant
WO2003074515A1 (fr) * 2002-03-01 2003-09-12 Smithkline Beecham Corporation Diamino-pyrimidines et leurs utilisations en tant qu'inhibiteurs de l'angiogenese
WO2004014899A1 (fr) * 2002-08-08 2004-02-19 Smithkline Beecham Corporation Composes de benzimidazole-1-yl-thiophene utilises en cancerotherapie
FR2846656A1 (fr) * 2002-11-05 2004-05-07 Servier Lab Nouveaux derives d'imidazopyridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2005021537A1 (fr) 2003-08-21 2005-03-10 Osi Pharmaceuticals, Inc. Inhibiteurs de c-kit pyrazolyle-amidyle-benzimidazolyle n-substitues
WO2005042518A3 (fr) * 2003-10-21 2005-06-09 Amgen Inc Composes heterocycliques substitues et leurs procedes d'utilisation
WO2005075470A1 (fr) 2004-01-28 2005-08-18 Smithkline Beecham Corporation Composes thiazole
JP2006513162A (ja) * 2002-11-01 2006-04-20 パラテック ファーマシューティカルズ インコーポレイテッド 転写因子調節化合物およびその使用方法
WO2006060318A2 (fr) 2004-11-30 2006-06-08 Amgen Inc. Heterocycles substitues et leurs procedes d'utilisation
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
US7105530B2 (en) 2000-12-21 2006-09-12 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
WO2006108103A1 (fr) * 2005-04-05 2006-10-12 Pharmacopeia, Inc. Derives de purine et d'imidazopyridine en vue d'une immunosuppression
WO2007089445A2 (fr) 2006-01-27 2007-08-09 Amgen Inc. Combinaisons d'inhibiteurs d'ang2 et de vegf
JP2007217427A (ja) * 2000-09-01 2007-08-30 Chiron Corp アザ複素環式誘導体およびその治療的使用
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
WO2008079291A2 (fr) 2006-12-20 2008-07-03 Amgen Inc. Hétérocycles substitués et leurs méthodes d'utilisation
WO2008078091A1 (fr) 2006-12-22 2008-07-03 Astex Therapeutics Limited Composés hétérocycliques bicycliques servant d'inhibiteurs des fgfr
WO2008086014A2 (fr) 2007-01-09 2008-07-17 Amgen Inc. Dérivés de bis-aryl amide et procédés d'utilisation
WO2008103277A2 (fr) 2007-02-16 2008-08-28 Amgen Inc. Cétones d'hétérocyclyle contenant de l'azote et procédés d'utilisation
US7442709B2 (en) 2003-08-21 2008-10-28 Osi Pharmaceuticals, Inc. N3-substituted imidazopyridine c-Kit inhibitors
US7465807B2 (en) 2003-10-16 2008-12-16 Smithkline Beecham Corporation Process for preparing benzimidazole thiophenes
US7531542B2 (en) 2005-05-18 2009-05-12 Wyeth Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor
US7534796B2 (en) 2005-02-18 2009-05-19 Wyeth Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor
US7538113B2 (en) 2005-02-18 2009-05-26 Wyeth 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7582634B2 (en) 2005-02-18 2009-09-01 Wyeth 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7582636B2 (en) 2005-05-26 2009-09-01 Wyeth Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor
US7595330B2 (en) 2005-09-06 2009-09-29 Smithkline Beecham Corporation Benzimidazole thiophene compounds
US7615643B2 (en) 2006-06-02 2009-11-10 Smithkline Beecham Corporation Benzimidazole thiophene compounds
US7696210B2 (en) 2004-06-17 2010-04-13 Wyeth Gonadotropin releasing hormone receptor antagonists
US7714130B2 (en) 2004-06-17 2010-05-11 Wyeth Processes for preparing gonadotropin releasing hormone receptor antagonists
US7825145B2 (en) 2001-06-18 2010-11-02 Biodiem Ltd Antimicrobial and radioprotective compounds
US7884109B2 (en) 2005-04-05 2011-02-08 Wyeth Llc Purine and imidazopyridine derivatives for immunosuppression
US7902187B2 (en) 2006-10-04 2011-03-08 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7915268B2 (en) 2006-10-04 2011-03-29 Wyeth Llc 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
US7919490B2 (en) 2006-10-04 2011-04-05 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
EP2341067A1 (fr) 2003-07-18 2011-07-06 Amgen, Inc Agents de liaison spécifiques pour facteur de croissance des hépatocytes
US7989459B2 (en) 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US7989631B2 (en) 2006-02-10 2011-08-02 Amgen Inc. Hydrate forms of AMG706
US8071614B2 (en) 2007-10-12 2011-12-06 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8076354B2 (en) 2007-10-12 2011-12-13 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
WO2011161217A2 (fr) 2010-06-23 2011-12-29 Palacký University in Olomouc Ciblage du vegfr2
US8131527B1 (en) 2006-12-22 2012-03-06 Astex Therapeutics Ltd. FGFR pharmacophore compounds
WO2012129344A1 (fr) 2011-03-23 2012-09-27 Amgen Inc. Doubles inhibiteurs tricycliques fusionnés de cdk 4/6 et de flt3
EP2578583A1 (fr) 2006-07-14 2013-04-10 Amgen Inc. Dérivés hétérocycliques condensés et procédés d'utilisation
US8436031B2 (en) 2004-04-23 2013-05-07 Paratek Pharmaceuticals, Inc. Transcription factor modulating compounds and methods of use thereof
EP2589610A1 (fr) 2007-08-21 2013-05-08 Amgen, Inc Protéines de liaison d'antigène de c-fms humain
US8481531B2 (en) 2009-04-15 2013-07-09 Astex Therapeutics Ltd Bicyclic heterocyclyl derivatives as FGFR kinase inhibitors for therapeutic use
US8513276B2 (en) 2006-12-22 2013-08-20 Astex Therapeutics Limited Imidazo[1,2-a]pyridine compounds for use in treating cancer
WO2013132044A1 (fr) 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Thérapie combinée d'anticorps contre le csf -1r humain et ses utilisations
US8648199B2 (en) 2005-12-23 2014-02-11 Amgen Inc. Process for making a solid-state form of AMG 706
WO2014036022A1 (fr) 2012-08-29 2014-03-06 Amgen Inc. Composés quinazolinones et leurs dérivés
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8722687B2 (en) 2009-04-15 2014-05-13 Astex Therapeutics Ltd Imidazo [1,2-A]pyridine derivatives as FGFR kinase inhibitors for use in therapy
US8796244B2 (en) 2008-06-13 2014-08-05 Astex Therapeutics Ltd Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
WO2016112111A1 (fr) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Facteurs et cellules pour l'induction d'os, de moelle osseuse et de cartilage
EP3170824A1 (fr) 2008-01-15 2017-05-24 Amgen, Inc Dérivés de 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylméthyl)-1,6-naphthyridin-5(6h)-one en tant qu'inhibiteurs de c-met
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
WO2018119183A2 (fr) 2016-12-22 2018-06-28 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
WO2018217651A1 (fr) 2017-05-22 2018-11-29 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019051291A1 (fr) 2017-09-08 2019-03-14 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019213526A1 (fr) 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019213516A1 (fr) 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019217691A1 (fr) 2018-05-10 2019-11-14 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
WO2019232419A1 (fr) 2018-06-01 2019-12-05 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US10501438B2 (en) 2015-08-11 2019-12-10 Neomed Institute Aryl-substituted dihydroquinolinones, their preparation and their use as pharmaceuticals
US10501459B2 (en) 2015-10-21 2019-12-10 Neomed Institute Substituted imidazo[1,2-a]pyridines as bromodomain inhibitors
WO2019241157A1 (fr) 2018-06-11 2019-12-19 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
US10519151B2 (en) 2016-01-28 2019-12-31 Neomed Institute Substituted [1,2,4]triazolo[4,3-A]pyridines, their preparation and their use as pharmaceuticals
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
WO2020050890A2 (fr) 2018-06-12 2020-03-12 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2020102730A1 (fr) 2018-11-16 2020-05-22 Amgen Inc. Synthèse améliorée d'un intermédiaire clé du composé inhibiteur de kras g12c
WO2020106647A2 (fr) 2018-11-19 2020-05-28 Amgen Inc. Polythérapie comprenant un inhibiteur de krasg12c et un ou plusieurs principes pharmaceutiquement actifs supplémentaires pour le traitement de cancers
WO2020106640A1 (fr) 2018-11-19 2020-05-28 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2020132653A1 (fr) 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
WO2020132651A1 (fr) 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2020132649A1 (fr) 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
WO2020132648A1 (fr) 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
US10703740B2 (en) 2015-08-12 2020-07-07 Neomed Institute Substituted benzimidazoles, their preparation and their use as pharmaceuticals
WO2020180770A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétérocyclyle bicycliques et leurs utilisations
WO2020180768A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétéroaryle bicycliques et leurs utilisations
US10836742B2 (en) 2015-08-11 2020-11-17 Neomed Institute N-substituted bicyclic lactams, their preparation and their use as pharmaceuticals
WO2021026099A1 (fr) 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021026098A1 (fr) 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021026100A1 (fr) 2019-08-02 2021-02-11 Amgen Inc. Dérivés de pyridine en tant qu'inhibiteurs de kif18a
WO2021026101A1 (fr) 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021081212A1 (fr) 2019-10-24 2021-04-29 Amgen Inc. Dérivés de pyridopyrimidine utiles en tant qu'inhibiteurs de kras g12c et de kras g12d dans le traitement du cancer
WO2021091967A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2021091956A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2021092115A1 (fr) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Composés hétéroaryles bicycliques et leurs utilisations
WO2021091982A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2021097212A1 (fr) 2019-11-14 2021-05-20 Amgen Inc. Synthèse améliorée de composé inhibiteur de kras g12c
WO2021097207A1 (fr) 2019-11-14 2021-05-20 Amgen Inc. Synthèse améliorée de composés inhibiteurs de kras g12c
WO2021108683A1 (fr) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2021142026A1 (fr) 2020-01-07 2021-07-15 Revolution Medicines, Inc. Dosage d'inhibiteurs de shp2 et méthodes de traitement du cancer
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
US11236091B2 (en) 2019-05-21 2022-02-01 Amgen Inc. Solid state forms
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
WO2022140427A1 (fr) 2020-12-22 2022-06-30 Qilu Regor Therapeutics Inc. Inhibiteurs de sos1 et utilisations associées
US11426404B2 (en) 2019-05-14 2022-08-30 Amgen Inc. Dosing of KRAS inhibitor for treatment of cancers
US11465998B2 (en) 2019-04-25 2022-10-11 Regents Of The University Of Minnesota Therapeutic compounds and methods of use thereof
WO2022235866A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024081916A1 (fr) 2022-10-14 2024-04-18 Black Diamond Therapeutics, Inc. Méthodes de traitement de cancers à l'aide de dérivés d'isoquinoline ou de 6-aza-quinoléine
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025137507A1 (fr) 2023-12-22 2025-06-26 Regor Pharmaceuticals, Inc. Inhibiteurs de sos1 et leurs utilisations

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10021246A1 (de) * 2000-04-25 2001-10-31 Schering Ag Substituierte Benzoesäureamide und deren Verwendung als Arzneimittel
GB0402137D0 (en) * 2004-01-30 2004-03-03 Smithkline Beecham Corp Novel compounds
GB0402809D0 (en) * 2004-02-09 2004-03-10 Glaxo Group Ltd Chemical compounds
EP2099789A4 (fr) * 2006-12-04 2012-02-15 Boehringer Ingelheim Int Inhibiteurs de la réplication du vih

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2637731A (en) * 1949-06-02 1953-05-05 American Cyanamid Co Imidazopyridines
US3819640A (en) * 1972-08-07 1974-06-25 Degussa Aza-benzimidazoles and process for their production
US4144341A (en) * 1975-05-28 1979-03-13 Merck & Co., Inc. Imidazo pyridine-2-ones and pharmaceutical compositions and methods of treatment utilizing same
US4859672A (en) * 1986-10-29 1989-08-22 Rorer Pharmaceutical Corporation Pyrido[2,3-d]pyrimidinone and imidazo[4,5-b]pyrimidinone
EP0385850A2 (fr) * 1989-03-03 1990-09-05 Laboratoires Upsa Nouveaux dérivés de benzimidazoles et azabenzimidazoles, leurs procédés de préparation, intermédiaires de synthèse, compositions pharmaceutiques les contenant, utiles notamment pour le traitement des maladies cardiovasculaires, et les ulcères duodénaux
US5010086A (en) * 1990-02-28 1991-04-23 Sterling Drug Inc. Imidazopyridines, compositions and use
US5360809A (en) * 1992-03-26 1994-11-01 Neurosearch A/S Imidazole compounds and their use as calcium channel blockers
US5446159A (en) * 1993-09-17 1995-08-29 Lonza, Ltd. Process for preparing imidazopyridine derivatives
US5501850A (en) * 1992-02-13 1996-03-26 Merck Patent Gesellschaft Mit Beschrankter Haftung Use of benzimidazole derivatives as light protection filters
US5514682A (en) * 1992-05-15 1996-05-07 Merck Sharp & Dohme Limited Fused imidazole and triazole derivatives as 5-HT1 receptor agonists
US5637724A (en) * 1995-06-05 1997-06-10 Neurogen Corporation Substituted aryl and cycloalkyl imidazolones; a new class of GABA brain receptor ligands
US5665709A (en) * 1990-11-01 1997-09-09 The Regents Of The University Of Michigan Polysubstituted benzimidazole nucleosides as antiviral agents

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593997A (en) * 1995-05-23 1997-01-14 Pfizer Inc. 4-aminopyrazolo(3-,4-D)pyrimidine and 4-aminopyrazolo-(3,4-D)pyridine tyrosine kinase inhibitors
IL131582A0 (en) * 1997-03-19 2001-01-28 Basf Ag Pyrrolo [2,3d] pyrimidines and their use as tyrosine kinase inhibitors
CA2291709A1 (fr) * 1997-05-30 1998-12-03 Merck & Co., Inc. Nouveaux inhibiteurs d'angiogenese

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2637731A (en) * 1949-06-02 1953-05-05 American Cyanamid Co Imidazopyridines
US3819640A (en) * 1972-08-07 1974-06-25 Degussa Aza-benzimidazoles and process for their production
US4144341A (en) * 1975-05-28 1979-03-13 Merck & Co., Inc. Imidazo pyridine-2-ones and pharmaceutical compositions and methods of treatment utilizing same
US4859672A (en) * 1986-10-29 1989-08-22 Rorer Pharmaceutical Corporation Pyrido[2,3-d]pyrimidinone and imidazo[4,5-b]pyrimidinone
EP0385850A2 (fr) * 1989-03-03 1990-09-05 Laboratoires Upsa Nouveaux dérivés de benzimidazoles et azabenzimidazoles, leurs procédés de préparation, intermédiaires de synthèse, compositions pharmaceutiques les contenant, utiles notamment pour le traitement des maladies cardiovasculaires, et les ulcères duodénaux
US5010086A (en) * 1990-02-28 1991-04-23 Sterling Drug Inc. Imidazopyridines, compositions and use
US5665709A (en) * 1990-11-01 1997-09-09 The Regents Of The University Of Michigan Polysubstituted benzimidazole nucleosides as antiviral agents
US5501850A (en) * 1992-02-13 1996-03-26 Merck Patent Gesellschaft Mit Beschrankter Haftung Use of benzimidazole derivatives as light protection filters
US5360809A (en) * 1992-03-26 1994-11-01 Neurosearch A/S Imidazole compounds and their use as calcium channel blockers
US5514682A (en) * 1992-05-15 1996-05-07 Merck Sharp & Dohme Limited Fused imidazole and triazole derivatives as 5-HT1 receptor agonists
US5446159A (en) * 1993-09-17 1995-08-29 Lonza, Ltd. Process for preparing imidazopyridine derivatives
US5637724A (en) * 1995-06-05 1997-06-10 Neurogen Corporation Substituted aryl and cycloalkyl imidazolones; a new class of GABA brain receptor ligands

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1109555A4 *

Cited By (200)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001066526A1 (fr) * 2000-03-08 2001-09-13 Cermol S.A. Derives esters d'acide dimethylpropionique et compositions pharmaceutiques les contenant
EP1132381A1 (fr) * 2000-03-08 2001-09-12 Cermol S.A. Derivés d'esters d'acide propionique et compositions pharmaceutiques les contenant
JP2007217427A (ja) * 2000-09-01 2007-08-30 Chiron Corp アザ複素環式誘導体およびその治療的使用
US7105530B2 (en) 2000-12-21 2006-09-12 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US7858626B2 (en) 2000-12-21 2010-12-28 Glaxosmithkline Llc Pyrimidineamines as angiogenesis modulators
US8114885B2 (en) 2000-12-21 2012-02-14 Glaxosmithkline Llc Chemical compounds
US7262203B2 (en) 2000-12-21 2007-08-28 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US7223757B2 (en) 2001-03-28 2007-05-29 Bristol-Myers Squibb Company Tyrosine kinase inhibitors
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
US7825145B2 (en) 2001-06-18 2010-11-02 Biodiem Ltd Antimicrobial and radioprotective compounds
US8569363B2 (en) 2001-06-18 2013-10-29 Biodiem Ltd. Antimicrobial and radioprotective compounds
US8158664B2 (en) 2001-06-18 2012-04-17 Biodiem Ltd. Antimicrobial and radioprotective compounds
US9045452B2 (en) 2001-06-18 2015-06-02 Biodiem Ltd. Antimicrobial and radioprotective compounds
US7338959B2 (en) 2002-03-01 2008-03-04 Smithkline Beecham Corporation Diamino-pyrimidines and their use as angiogenesis inhibitors
WO2003074515A1 (fr) * 2002-03-01 2003-09-12 Smithkline Beecham Corporation Diamino-pyrimidines et leurs utilisations en tant qu'inhibiteurs de l'angiogenese
JP2006505522A (ja) * 2002-08-08 2006-02-16 スミスクライン ビーチャム コーポレーション チオフェン化合物
WO2004014899A1 (fr) * 2002-08-08 2004-02-19 Smithkline Beecham Corporation Composes de benzimidazole-1-yl-thiophene utilises en cancerotherapie
RU2296758C2 (ru) * 2002-08-08 2007-04-10 Смитклайн Бичем Корпорейшн Производные тиофена
AU2003265348B2 (en) * 2002-08-08 2007-08-16 Smithkline Beecham Corporation Thiophene compounds
JP2006513162A (ja) * 2002-11-01 2006-04-20 パラテック ファーマシューティカルズ インコーポレイテッド 転写因子調節化合物およびその使用方法
US7098220B2 (en) 2002-11-05 2006-08-29 Les Laboratoires Servier Imidazopyridine derivatives, preparation method and pharmaceutical compositions containing same
CN100335480C (zh) * 2002-11-05 2007-09-05 瑟维尔实验室 咪唑并吡啶衍生物、它们的制备方法以及含有它们的药物组合物
EA008446B1 (ru) * 2002-11-05 2007-06-29 Ле Лаборатуар Сервье Соединения имидазопиридина, способ их получения и фармацевтические композиции, которые их содержат
FR2846656A1 (fr) * 2002-11-05 2004-05-07 Servier Lab Nouveaux derives d'imidazopyridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2004043957A1 (fr) * 2002-11-05 2004-05-27 Les Laboratoires Servier Derives d’imidazopyridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP2341067A1 (fr) 2003-07-18 2011-07-06 Amgen, Inc Agents de liaison spécifiques pour facteur de croissance des hépatocytes
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
US7767673B2 (en) 2003-08-21 2010-08-03 Osi Pharmaceuticals, Inc. N-substituted imidazopyridine c-Kit inhibitors
US7442709B2 (en) 2003-08-21 2008-10-28 Osi Pharmaceuticals, Inc. N3-substituted imidazopyridine c-Kit inhibitors
WO2005021537A1 (fr) 2003-08-21 2005-03-10 Osi Pharmaceuticals, Inc. Inhibiteurs de c-kit pyrazolyle-amidyle-benzimidazolyle n-substitues
US7465807B2 (en) 2003-10-16 2008-12-16 Smithkline Beecham Corporation Process for preparing benzimidazole thiophenes
WO2005042518A3 (fr) * 2003-10-21 2005-06-09 Amgen Inc Composes heterocycliques substitues et leurs procedes d'utilisation
US7560568B2 (en) 2004-01-28 2009-07-14 Smithkline Beecham Corporation Thiazole compounds
EP1711496A4 (fr) * 2004-01-28 2009-02-11 Smithkline Beecham Corp Composes thiazole
WO2005075470A1 (fr) 2004-01-28 2005-08-18 Smithkline Beecham Corporation Composes thiazole
US8436031B2 (en) 2004-04-23 2013-05-07 Paratek Pharmaceuticals, Inc. Transcription factor modulating compounds and methods of use thereof
US7696210B2 (en) 2004-06-17 2010-04-13 Wyeth Gonadotropin releasing hormone receptor antagonists
US7714130B2 (en) 2004-06-17 2010-05-11 Wyeth Processes for preparing gonadotropin releasing hormone receptor antagonists
WO2006060318A2 (fr) 2004-11-30 2006-06-08 Amgen Inc. Heterocycles substitues et leurs procedes d'utilisation
US7538113B2 (en) 2005-02-18 2009-05-26 Wyeth 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7582634B2 (en) 2005-02-18 2009-09-01 Wyeth 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7534796B2 (en) 2005-02-18 2009-05-19 Wyeth Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor
US7884109B2 (en) 2005-04-05 2011-02-08 Wyeth Llc Purine and imidazopyridine derivatives for immunosuppression
JP2008534689A (ja) * 2005-04-05 2008-08-28 ファーマコペイア， インコーポレイテッド 免疫抑制のためのプリン及びイミダゾピリジン誘導体
WO2006108103A1 (fr) * 2005-04-05 2006-10-12 Pharmacopeia, Inc. Derives de purine et d'imidazopyridine en vue d'une immunosuppression
US7531542B2 (en) 2005-05-18 2009-05-12 Wyeth Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor
US7582636B2 (en) 2005-05-26 2009-09-01 Wyeth Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor
US7786127B2 (en) 2005-09-06 2010-08-31 Glaxo SmithKline LLC Benzimidazole thiophene compounds
US7595330B2 (en) 2005-09-06 2009-09-29 Smithkline Beecham Corporation Benzimidazole thiophene compounds
US8648199B2 (en) 2005-12-23 2014-02-11 Amgen Inc. Process for making a solid-state form of AMG 706
WO2007089445A2 (fr) 2006-01-27 2007-08-09 Amgen Inc. Combinaisons d'inhibiteurs d'ang2 et de vegf
US7989631B2 (en) 2006-02-10 2011-08-02 Amgen Inc. Hydrate forms of AMG706
US7989459B2 (en) 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US9266834B2 (en) 2006-03-15 2016-02-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US7615643B2 (en) 2006-06-02 2009-11-10 Smithkline Beecham Corporation Benzimidazole thiophene compounds
EP3093289A1 (fr) 2006-07-14 2016-11-16 Amgen, Inc Dérivés [1,2,4]triazolo[4,3-a]pyridiniques utiles en tant qu'inhibiteurs du récepteur du facteur de croissance des hépatocytes
EP2578583A1 (fr) 2006-07-14 2013-04-10 Amgen Inc. Dérivés hétérocycliques condensés et procédés d'utilisation
US7919490B2 (en) 2006-10-04 2011-04-05 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7915268B2 (en) 2006-10-04 2011-03-29 Wyeth Llc 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
US7902187B2 (en) 2006-10-04 2011-03-08 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
WO2008079291A2 (fr) 2006-12-20 2008-07-03 Amgen Inc. Hétérocycles substitués et leurs méthodes d'utilisation
US8131527B1 (en) 2006-12-22 2012-03-06 Astex Therapeutics Ltd. FGFR pharmacophore compounds
US8895745B2 (en) 2006-12-22 2014-11-25 Astex Therapeutics Limited Bicyclic heterocyclic compounds as FGFR inhibitors
WO2008078091A1 (fr) 2006-12-22 2008-07-03 Astex Therapeutics Limited Composés hétérocycliques bicycliques servant d'inhibiteurs des fgfr
US8513276B2 (en) 2006-12-22 2013-08-20 Astex Therapeutics Limited Imidazo[1,2-a]pyridine compounds for use in treating cancer
WO2008086014A2 (fr) 2007-01-09 2008-07-17 Amgen Inc. Dérivés de bis-aryl amide et procédés d'utilisation
WO2008103277A2 (fr) 2007-02-16 2008-08-28 Amgen Inc. Cétones d'hétérocyclyle contenant de l'azote et procédés d'utilisation
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
EP2592093A1 (fr) 2007-08-21 2013-05-15 Amgen, Inc Protéines de liaison d'antigène de c-fms humain
EP3330292A1 (fr) 2007-08-21 2018-06-06 Amgen, Inc Protéines de liaison d'antigène de c-fms humain
EP2589610A1 (fr) 2007-08-21 2013-05-08 Amgen, Inc Protéines de liaison d'antigène de c-fms humain
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9132122B2 (en) 2007-09-14 2015-09-15 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US8076354B2 (en) 2007-10-12 2011-12-13 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8859582B2 (en) 2007-10-12 2014-10-14 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8071614B2 (en) 2007-10-12 2011-12-06 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8859583B2 (en) 2007-10-12 2014-10-14 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
EP3170824A1 (fr) 2008-01-15 2017-05-24 Amgen, Inc Dérivés de 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylméthyl)-1,6-naphthyridin-5(6h)-one en tant qu'inhibiteurs de c-met
US8796244B2 (en) 2008-06-13 2014-08-05 Astex Therapeutics Ltd Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8722687B2 (en) 2009-04-15 2014-05-13 Astex Therapeutics Ltd Imidazo [1,2-A]pyridine derivatives as FGFR kinase inhibitors for use in therapy
US8481531B2 (en) 2009-04-15 2013-07-09 Astex Therapeutics Ltd Bicyclic heterocyclyl derivatives as FGFR kinase inhibitors for therapeutic use
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
US9226930B2 (en) 2009-05-12 2016-01-05 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
WO2011161217A2 (fr) 2010-06-23 2011-12-29 Palacký University in Olomouc Ciblage du vegfr2
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
EP2937349A1 (fr) 2011-03-23 2015-10-28 Amgen Inc. Doubles inhibiteurs tricycliques fusionnés de cdk 4/6 et flt3
WO2012129344A1 (fr) 2011-03-23 2012-09-27 Amgen Inc. Doubles inhibiteurs tricycliques fusionnés de cdk 4/6 et de flt3
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
WO2013132044A1 (fr) 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Thérapie combinée d'anticorps contre le csf -1r humain et ses utilisations
WO2014036022A1 (fr) 2012-08-29 2014-03-06 Amgen Inc. Composés quinazolinones et leurs dérivés
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US11103506B2 (en) 2014-01-21 2021-08-31 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US12048696B2 (en) 2014-01-21 2024-07-30 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
WO2016112111A1 (fr) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Facteurs et cellules pour l'induction d'os, de moelle osseuse et de cartilage
US10836742B2 (en) 2015-08-11 2020-11-17 Neomed Institute N-substituted bicyclic lactams, their preparation and their use as pharmaceuticals
US10501438B2 (en) 2015-08-11 2019-12-10 Neomed Institute Aryl-substituted dihydroquinolinones, their preparation and their use as pharmaceuticals
US11365186B2 (en) 2015-08-12 2022-06-21 Epigenetix, Inc. Substituted benzimidazoles, their preparation and their use as pharmaceuticals
US11981657B2 (en) 2015-08-12 2024-05-14 Epigenetix, Inc. Substituted benzimidazoles, their preparation and their use as pharmaceuticals
US10703740B2 (en) 2015-08-12 2020-07-07 Neomed Institute Substituted benzimidazoles, their preparation and their use as pharmaceuticals
US10501459B2 (en) 2015-10-21 2019-12-10 Neomed Institute Substituted imidazo[1,2-a]pyridines as bromodomain inhibitors
US10519151B2 (en) 2016-01-28 2019-12-31 Neomed Institute Substituted [1,2,4]triazolo[4,3-A]pyridines, their preparation and their use as pharmaceuticals
US10532042B2 (en) 2016-12-22 2020-01-14 Amgen Inc. KRAS G12C inhibitors and methods of using the same
EP4001269A1 (fr) 2016-12-22 2022-05-25 Amgen Inc. Dérivés de benzoisothiazole, isothiazolo[3,4-b]pyridine, quinazoline, phthalazine, pyrido[2,3-d]pyridazine et pyrido[2,3-d]pyrimidine en tant qu'inhibiteurs de kras g12c pour le traitement de cancer du poumon, du pancréas ou de l'intestin
US11285135B2 (en) 2016-12-22 2022-03-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2018119183A2 (fr) 2016-12-22 2018-06-28 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US10519146B2 (en) 2017-05-22 2019-12-31 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11905281B2 (en) 2017-05-22 2024-02-20 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2018217651A1 (fr) 2017-05-22 2018-11-29 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
EP3974429A1 (fr) 2017-05-22 2022-03-30 Amgen Inc. Précurseurs d'inhibiteurs de kras g12c
WO2019051291A1 (fr) 2017-09-08 2019-03-14 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US11306087B2 (en) 2017-09-08 2022-04-19 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
US10640504B2 (en) 2017-09-08 2020-05-05 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
EP4141005A1 (fr) 2017-09-08 2023-03-01 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
EP4403175A2 (fr) 2017-09-08 2024-07-24 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US11993597B2 (en) 2017-09-08 2024-05-28 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
US11766436B2 (en) 2018-05-04 2023-09-26 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11090304B2 (en) 2018-05-04 2021-08-17 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019213516A1 (fr) 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019213526A1 (fr) 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US11045484B2 (en) 2018-05-04 2021-06-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019217691A1 (fr) 2018-05-10 2019-11-14 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
US10988485B2 (en) 2018-05-10 2021-04-27 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019232419A1 (fr) 2018-06-01 2019-12-05 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US11096939B2 (en) 2018-06-01 2021-08-24 Amgen Inc. KRAS G12C inhibitors and methods of using the same
EP4268898A2 (fr) 2018-06-11 2023-11-01 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
WO2019241157A1 (fr) 2018-06-11 2019-12-19 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
WO2020050890A2 (fr) 2018-06-12 2020-03-12 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US11285156B2 (en) 2018-06-12 2022-03-29 Amgen Inc. Substituted piperazines as KRAS G12C inhibitors
US12083121B2 (en) 2018-06-12 2024-09-10 Amgen Inc. Substituted piperazines as KRAS G12C inhibitors
EP4234546A2 (fr) 2018-11-16 2023-08-30 Amgen Inc. Synthèse améliorée d'un intermédiaire clé du composé inhibiteur de kras g12c
US11299491B2 (en) 2018-11-16 2022-04-12 Amgen Inc. Synthesis of key intermediate of KRAS G12C inhibitor compound
WO2020102730A1 (fr) 2018-11-16 2020-05-22 Amgen Inc. Synthèse améliorée d'un intermédiaire clé du composé inhibiteur de kras g12c
US11053226B2 (en) 2018-11-19 2021-07-06 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11439645B2 (en) 2018-11-19 2022-09-13 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2020106647A2 (fr) 2018-11-19 2020-05-28 Amgen Inc. Polythérapie comprenant un inhibiteur de krasg12c et un ou plusieurs principes pharmaceutiquement actifs supplémentaires pour le traitement de cancers
US11918584B2 (en) 2018-11-19 2024-03-05 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US12280056B2 (en) 2018-11-19 2025-04-22 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2020106640A1 (fr) 2018-11-19 2020-05-28 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2020132651A1 (fr) 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2020132653A1 (fr) 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
US11236069B2 (en) 2018-12-20 2022-02-01 Amgen Inc. KIF18A inhibitors
WO2020132649A1 (fr) 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
US12054476B2 (en) 2018-12-20 2024-08-06 Amgen Inc. KIF18A inhibitors
WO2020132648A1 (fr) 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2020180770A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétérocyclyle bicycliques et leurs utilisations
WO2020180768A1 (fr) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Composés hétéroaryle bicycliques et leurs utilisations
US11465998B2 (en) 2019-04-25 2022-10-11 Regents Of The University Of Minnesota Therapeutic compounds and methods of use thereof
US11426404B2 (en) 2019-05-14 2022-08-30 Amgen Inc. Dosing of KRAS inhibitor for treatment of cancers
US11827635B2 (en) 2019-05-21 2023-11-28 Amgen Inc. Solid state forms
US11236091B2 (en) 2019-05-21 2022-02-01 Amgen Inc. Solid state forms
WO2021026100A1 (fr) 2019-08-02 2021-02-11 Amgen Inc. Dérivés de pyridine en tant qu'inhibiteurs de kif18a
WO2021026099A1 (fr) 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021026101A1 (fr) 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021026098A1 (fr) 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021081212A1 (fr) 2019-10-24 2021-04-29 Amgen Inc. Dérivés de pyridopyrimidine utiles en tant qu'inhibiteurs de kras g12c et de kras g12d dans le traitement du cancer
WO2021091967A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2021091956A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2021091982A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2021092115A1 (fr) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Composés hétéroaryles bicycliques et leurs utilisations
WO2021097207A1 (fr) 2019-11-14 2021-05-20 Amgen Inc. Synthèse améliorée de composés inhibiteurs de kras g12c
WO2021097212A1 (fr) 2019-11-14 2021-05-20 Amgen Inc. Synthèse améliorée de composé inhibiteur de kras g12c
WO2021108683A1 (fr) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2021142026A1 (fr) 2020-01-07 2021-07-15 Revolution Medicines, Inc. Dosage d'inhibiteurs de shp2 et méthodes de traitement du cancer
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
WO2022140427A1 (fr) 2020-12-22 2022-06-30 Qilu Regor Therapeutics Inc. Inhibiteurs de sos1 et utilisations associées
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235866A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024081916A1 (fr) 2022-10-14 2024-04-18 Black Diamond Therapeutics, Inc. Méthodes de traitement de cancers à l'aide de dérivés d'isoquinoline ou de 6-aza-quinoléine
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025137507A1 (fr) 2023-12-22 2025-06-26 Regor Pharmaceuticals, Inc. Inhibiteurs de sos1 et leurs utilisations

Also Published As

Publication number Publication date
AU3078999A (en) 2000-03-21
AU760020B2 (en) 2003-05-08
JP2002523459A (ja) 2002-07-30
EP1109555A4 (fr) 2001-11-21
EP1109555A1 (fr) 2001-06-27
CA2341409A1 (fr) 2000-03-09

Similar Documents

Publication Publication Date Title
US6465484B1 (en) Angiogenesis inhibitors
US6162804A (en) Tyrosine kinase inhibitors
AU760020B2 (en) Novel angiogenesis inhibitors
AU744939B2 (en) Novel angiogenesis inhibitors
US6235741B1 (en) Angiogenesis inhibitors
WO1998054093A1 (fr) Nouveaux inhibiteurs d'angiogenese
US7696223B2 (en) Pyrrolo- and Thiazolo-pyridine compounds, and methods of use thereof
US6180643B1 (en) Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
EP2328871B1 (fr) Modulateurs de la voie hedgehog
AU2006223070B2 (en) Benzazole derivatives, compositions, and methods of use as B-secretase inhibitors
EP1097147A1 (fr) Nouveaux inhibiteurs de l'angiogenese
KR20160135283A (ko) 5-치환된 인다졸-3-카르복스아미드 및 이의 제조 및 용도
WO2000043393A1 (fr) Inhibiteurs d'angiogenese
EA019507B1 (ru) Конденсированные азотсодержащие гетероциклы и содержащие их композиции в качестве ингибиторов киназы
WO2003051366A2 (fr) Inhibiteurs de kinase
WO1998022457A9 (fr) Agents anti-inflammatoires a base de pyrrole condense a substitution aryle et heteroaryle
US20050075334A1 (en) Novel compounds
US6380203B1 (en) Angiogenesis inhibitors
EP1463505A2 (fr) Derives de la 3-(phenyl-alkoxy)-5-(phenyl)-pyridine et composes similaires avec activite inhibiteur de kinase pour le traitement du cancer.
US6228871B1 (en) Angiogenesis inhibitors
AU2011244844A1 (en) Benzazole derivatives, compositions, and methods of use as B-secretase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

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

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

Ref document number: 2341409

Country of ref document: CA

Ref country code: CA

Ref document number: 2341409

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1999912408

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 30789/99

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 09786004

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1999912408

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1999912408

Country of ref document: EP