WO2005007099A2 - Inhibiteurs de la pkb utilises comme agents antitumoraux - Google Patents

Inhibiteurs de la pkb utilises comme agents antitumoraux Download PDF

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WO2005007099A2
WO2005007099A2 PCT/US2004/021834 US2004021834W WO2005007099A2 WO 2005007099 A2 WO2005007099 A2 WO 2005007099A2 US 2004021834 W US2004021834 W US 2004021834W WO 2005007099 A2 WO2005007099 A2 WO 2005007099A2
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substituted
unsubstituted
alkyl
aryl
heterocyclyl
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PCT/US2004/021834
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WO2005007099A3 (fr
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Joel Kawakami
Matthew Duncton
Dan Sherman
Hai-Ying He
Alexander Kiselyov
Bronek Pytowski
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Imclone Systems Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing 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
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the PKB kinase in the chimaera is constitutively active because the N-terminal myristic acid targets the protein to the plasma membrane in the absence of the PH domain. Id.
  • Another direct tumorigenic mechanism of PKB is based on the over-expression of specific PKB isoforms in transformed cells. For example, PKBb has been found to be amplified in human pancreatic adenocarcinoma and ovarian carcinomas, while upregulation of PKBg has been associated with carcinomas of the breast and prostate.
  • R is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, -NH 2 , -NH(CrC 4 )alkyl, -N[(Ci-C 4 )alkyl] 2 , - SO alkyl, -SO 2 aryl, alkylcarbonyl, alkoxycarbonyl,
  • the present invention encompasses biaryl compounds with two six membered rings fused wherein at least one six membered ring is substituted.
  • the compounds of the invention are useful in the inhibition of PKB kinase, the treatment of cancer, or the inhibition of tumor growth.
  • the compounds of the invention encompass substituted or unsubstituted qumoxalinyl or, pyridopyrazmyl compounds.
  • the invention also encompasses methods for treating cancer by administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • alkyl refers to a saturated hydrocarbon radical having 1 to 8 carbon atoms.
  • the alkyl group may be straight, branched, substituted or unsubstituted.
  • Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.
  • alkenyl refers to a non-aromatic hydrocarbon radical, which may be straight chain or branched, substituted or unsubstituted, having from 2 to 8 carbon atoms and at least one carbon to carbon double bond.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propargyloxy, or vinyloxy.
  • cycloalkyl refers to a cyclic hydrocarbon radical having 3 to 8 carbon atoms, which may be substituted or unsubstituted.
  • the cycloalkyl group may have at least one carbon to carbon double bond.
  • aryl refers to carbocyclic aromatic groups including, but not limited to, phenyl, naphthyl, or anthracyl.
  • aryl also refers to any bicyclic group in which a cycloalkyl or heterocyclyl ring is fused to a benzene ring, examples include, but are not limited to, benzimidazolyl, benzofliranyl, benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, benzopyranyl, benzothiazolyl, benzothienyl, benzotriazole, benzoxazolyl, indolinyl, indolizinyl, indolyl, isoindolyl, isoquinolinyl, or quinolinyl.
  • heteroaryl includes, but is not limited to, azepinyl, benzimidazoyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, isoimidazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiadiazoyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, or 1,2,4-triazolyl.
  • a heteroaryl group can be unsubstituted or substitued.
  • aralkyl refers to a straight-chain alkyl, alkenyl, or alkynyl group wherein one of the hydrogen atoms bonded to a terminal carbon is replaced with an aryl moiety.
  • Typical aralkyl groups include, but are not limited to, benzyl, benzylidene, benzylidyne, benzenobenzyl, naphthenobenzyl, and the like.
  • heterooaralkyl refers to a straight-chain alkyl, alkenyl, or alkynyl group wherein one of the hydrogen atoms bonded to a terminal carbon is replaced with a heteroaryl moiety.
  • aryloxy group refers to an -O-aryl or -O-heteroaryl, wherein aryl or heteroaryl is as defined above.
  • the term “carbamoyl” refers to a radical -CON(R)- or -(R)NCO-, wherein R wherein R is further defined herein.
  • the term “urea” or “urealyl” refers to a radical -RNHCONR-, wherein R may be the same or different is further defined herein.
  • the term “carbamic acid” or “carbamyl” refers to a radical -RNHCOO-, wherein R is further defined herein.
  • a "suitable substituent” means a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them.
  • substituents include, but are not limited to: Ci-Cg alkyl; C 2 -C 8 alkenyl; C 2 -C 8 alkynyl; C 6 aryl; C 2 -C 5 heteroaryl; C 3 -C 7 cycloalkyl; Ci-Cs alkoxy; C 6 aryloxy; -CN; -OH; oxo; halo; -CO 2 H; -NH 2 ; -NH(C 1 -C 8 alkyl); -N(C ⁇ -C 8 alkyl) 2 ; -NH(C 6 aryl); -N(C 6 aryl) 2 ; -CHO; -CO(C ⁇ -C 8 alkyl); -CO(C 6 aryl); -CO 2 (C 1 -C 8 alkyl); and -CO 2 (C 6 aryl).
  • halo or halogen includes fluorine, chlorine, bromine, or iodine, including fluoro, chloro, bromo, and iodo.
  • chiral centers are present in the compounds of the present invention, the individual isomers, i.e., enantiomers, diastereomers, etc. and mixtures thereof (e.g., racemates, etc.) are intended to be encompassed by the formulae depicted herein. Also included are individual polymorphs of each compound of the present invention.
  • Example 12 (600 mg, 1.76 mmol) was suspended in 9 ml ethyl acetate. To this was added SnCl 2 (1.6 g, 7.04 mmol). The reaction mixture was heated to reflux and stirred for 2 hours. The cooled reaction solution was poured into a mixture of 100 ml saturated NaHCO 3 solution and ice. The resulting emulsion was filtered through celite and the organic and aqueous layers were separated.
  • 2,3-Dithiophen-2-yl-5-hydroxyquinoxaline 2,3-Dithiophen-2-yl-5- methoxyquinoxaline (3 g, 9.3 mmol) was taken up in 20 ml 40% HBr and 20 ml glacial acetic acid, heated to 120°C and stirred for 18 hours. The cooled reaction mixture was partitioned between ice water and ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO , filtered, concentrated and purified with a flash column chromatography using 25% ethyl acetate in hexane as the eluant (1.92g, 67%).
  • Example 32 (30 mg, 0.08 mmol) and triethylaniine (13 L, 0.09 mmol) were dissolved in dichloromethane and treated with ethyl isocyanate (7 L, 0.09 mmol). This mixture was stirred for 30 minutes after which it was poured into water and extracted with more dichloromethane. The combined organic layers were washed with brine, dried over
  • N-(2,3-Di-thiophen-6-quinoxalinyl)-benzymaticamide In a 10 ml sized vial equipped with a magnetic stirrer, the 6-Amino-2,3-di-thiophen-2-yl-quinoxaline (50 mg, 0.162 mmol), 2.3 ml of dichloromethane and triethylaniine (27 ⁇ M, 0.194 mmol) were added followed by benzymaticoyl chloride (19 ⁇ M, 0.162 mmol). The reaction was stirred at r.t. overnight.
  • Example 43 Compound 43 Preparation of 2,3,7-Tri-thiophen-2-yl-pyrido[2,3-b]pyrazine PdCl 2 (Ph 3 P) 2 (15 mg, 0.02 mmol) was added in one portion to a stirred solution of 7-bromo-2J-di-tbiophen-2-yl-pyrido[2J-b]pyrazine (124 mg, 0.34 mmol) in 1,4-dioxane (4 ml) ar it under argon.
  • the compound was prepared using the method described for 2,3,7-tri-thiophen-2- yl-pyrido[2,3-b]pyrazine using pyridyl-3 -boronic acid (55 mg, 0.38 mmol) in place of 2- thiophene boronic acid.
  • the compound was purified by column chromatography (silica gel) using hexane/EtOAc (1:1) as an eluent.
  • the solid was then purified further using MP-TsOH (Argonaut Technologies) using the procedure below.
  • a cartridge containing 0.5 g of MP-TsOH (Argonaut Technologies) was conditioned by washing with CH C1 2 (1 x 4 ml).
  • PdCl (dppf) 25 mg, 0.03 mmol was added to a stirred solution of 7-bromo-2,3- di-thiophen-2-yl-pyrido[2,3-b]pyrazine (0.37 g, 1.0 mmol) in 1,4-dioxane (8 ml) at rt under argon. The mixture was stirred for 5 min then 4-hydroxyphenylboronic acid (0J5 g, 1.1 mmol) was added in one portion, followed by a solution of K CO 3 (0.28 g, 2.0 mmol) in H 2 O (2 ml). The mixture was heated to reflux and stirred overnight.
  • hydrochloride salt HCl in 1,4-dioxane (0.5 M; 0.25 mmol, 0.13 mmol [0.5 M HCl in 1,4-dioxane prepared by addition of 1 ml 4M HCl in 1,4-dioxane to 7 ml of 1,4-dioxane]) was added to a hot solution of 7-[4-(3-mo ⁇ holin-4-yl-propoxy)-phenyl]-2,3-di-thiophen-2-yl- pyrido[2,3-b]pyrazine (65 mg, 0.13 mmol) in MeOH (15 ml). After cooling, the mixture was concentrated in vacuo to leave a solid.
  • the compound was prepared using the method described for 7- ⁇ 4-[2-(2-methoxy- ethoxy)-ethoxy]-phenyl ⁇ -2J-di-thiophen-2-yl-pyrido[2J-b]pyrazine using l-bromo-2- methoxy-ethane (70 mg, 0.5 mmol) in place of l-bromo-2-(methoxy-ethoxy)-ethane.
  • the compound was purified by column chromatography (silica gel) using hexane/EtOAc (4:1 to 3:2) as an eluent to give the title compound (60 mg, 54%) as a solid.
  • EtOAc/MeOH/ ⁇ H 4 OH (90:9:1) as an eluent to give an impure solid.
  • the solid was dissolved in DMSO and purified by MP-TsOH (0.5 g TsOH; Argonaut Technologies) ion exchange chromatography washing the MP-TsOH with MeOH (2 x 4 ml) and eluting with 2M NH 3 /EtOH.
  • MP-TsOH 0.5 g TsOH; Argonaut Technologies
  • ion exchange chromatography washing the MP-TsOH with MeOH (2 x 4 ml) and eluting with 2M NH 3 /EtOH.
  • Final purification by preparative thin-layer chromatography using EtOAc/MeOH/NH 4 OH (180:19:1) as an eluent gave the title compound (20 mg, 38%) as a solid.
  • the compound was prepared using the method described for 7-[4-(3-pyrrolidin-l-yl- propoxy)-phenyl]-2,3-di-thiophen-2-yl-pyrido[2,3-b]pyrazine using dimethyl-(2- piperazin-l-yl-ethyl)-amine (30 mg, 0.18 mmol) in place of pyrrolidine. After purification by MP-TsOH the compound was further purified by preparative thin-layer chromatography using EtOAc MeOH/NH 4 OH (90:9:1) as an eluent to give the title compound (20 mg, 23%) as a solid.
  • PdCl (dppf) (82 mg, 0.1 mmol) was added to a mixture of 7-bromo-2,3-di-thiophen-2-yl- pyrido[2,3-b]pyrazine (1.5 g, 4.0 mmol) in 1,4-dioxane (32 ml) at room temperature under argon. The mixture was stirred for 5 min then 3-hydroxyphenyl boronic acid (0.6 g, 4.4 mmol) was added in one portion followed by a solution of K CO 3 (1.1 g, 8.0 mmol) in H O (8 ml). The mixture was heated to reflux and stirred overnight.
  • Example 59 Compound 59 Preparation of 7- ⁇ 3-[2-(2-Methoxy-ethoxy)-ethoxy]-phenyl ⁇ -2,3-di-thiophen-2-yl- pyrido[2,3-b] ⁇ yrazine
  • the compound was prepared using the method described for 7- ⁇ 4-[2-(2-Methoxy- ethoxy)-ethoxy]-phenyl ⁇ -2,3-di-thiophen-2-yl-pyrido[2J-b]pyrazine using 3-(2,3-di- thiophen-2-yl-pyrido[2,3-b]pyrazin-7-yl)-phenol in place of 4-(2,3-di-thiophen-2-yl- pyrido[2,3-b]pyrazin-7-yl)-phenol.
  • the compound was prepared using the method described for 7-[4-(3-chloro-propoxy)- phenyl]-2,3-di-thiophen-2-yl-pyrido[2,3-b]pyrazine using 3-(2,3-di-thiophen-2-yl- pyrido[2,3-b]pyrazin-7-yl)- ⁇ henol (0.75 g, 2.0 mmol), K 2 CO 3 (0.84 g, 6.0 mmol) and toluene-4-sulfonic acid 3-chloro-propyl ester (0.75 g, 3.0 mmol) in DMF (20 ml).
  • Imidazole (61 mg, 0.9 mmol) was added in one portion to a mixture of NaH (60% in mineral oil; 40 mg, 1.0 mmol) in DMF (5 ml) at room temperature under argon. The mixture was stirred for 45 min then 7-[3-(3-iodo-propoxy)-phenyl]-2,3-di-thiophen-2-yl- pyrido[2,3-b]pyrazine (100 mg, 0.18 mmol) in DMSO (1 ml) was added and the mixture heated to 80 °C for 4 hr. After cooling, the mixture was poured in to H 0 (100 ml) and extracted with EtOAc ( 3 x 50 ml).
  • PdCl 2 (Ph 3 P) 2 (0.7 g, 1.0 mmol) was added in one portion to a mixture of 7-bromo-2,3-di- thiophen-2-yl- ⁇ yrido[2,3-b]pyrazine (3.7 g, 10 mmol) in 1,4-dioxane (80 ml) at room temperature under argon. After 5 min 5-formyl-2-thiophene boronic acid (1.7 g, 11 mmol) was added in one portion followed by a solution of K 2 CO 3 (2.8 g, 20 mmol) in H 2 O (20 ml) then the mixture was heated to reflux overnight.
  • the combined organic extracts were dried (MgSO 4 ), filtered and concentrated in vacuo to leave a crude oil.
  • the oil was purified by preparative thin-layer chromatography using EtOAc/MeOH/NH 4 OH (90:9:1) as an eluent to give a solid.
  • the compound was purified further by MP-TsOH ion exchange chromatography (0.5 g MP-TsOH; Argonaut Technologies) washing with MeOH (2 x 4 ml) then eluting with 2M NH3/EtOH.
  • Example 76 Compound 76
  • Example 78 Compound 78
  • Example 84 Compound 84
  • Example 102 Compound 102
  • Example 103 Compound 103
  • Example 105 Compound 105
  • Example 106 Compoimd 106
  • Example 108 Compound 108
  • Example 121 Compound 121
  • Example 123 Compound 123
  • Example 125 Compound 125
  • Example 126 Compound 126
  • Example 127 Compound 127
  • Example 145 Compound 145
  • the kinase reaction was started by the addition of 10 ⁇ l mixture of 10 ⁇ M ATP and 75 nCi/ul 33 P-ATP and incubated at room temperature for 45 minutes. The reaction was stopped by adding 50 ⁇ l/well of 125 mM EDTA and the plates were washed 5x in 300 ⁇ l of PBS containing 0.05% Tween-20. 100 ⁇ l of scintillant were added to each well and the incorporated 33 P-ATP was measured by scintillation counting. See the tables above for the results of the in vitro activity assay.

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Abstract

L'invention concerne des composés biaryle comprenant deux noyaux à six chaînons fondus, un noyau à six chaînons au moins étant substitué par un noyau thiophényle ou furanyle. Lesdits composés sont utilisés dans l'inhibition de la kinase PKB, le traitement du cancer, ou l'inhibition de la croissance tumorale.
PCT/US2004/021834 2003-07-10 2004-07-09 Inhibiteurs de la pkb utilises comme agents antitumoraux WO2005007099A2 (fr)

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US60/486,339 2003-07-10

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Cited By (41)

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EP1785423A1 (fr) * 2005-11-11 2007-05-16 Zentaris GmbH Pyridopyrazines et leur utilisation en tant que modulateurs de kinases
WO2007054556A1 (fr) 2005-11-11 2007-05-18 Æterna Zentaris Gmbh Nouvelle pyridopyrazine et son utilisation pour la modulation de kinases
EP1790342A1 (fr) * 2005-11-11 2007-05-30 Zentaris GmbH Dérivés de pyridopyrazine et leur utilisation comme modulateurs de transduction de signal
US7544677B2 (en) 2004-08-23 2009-06-09 Merck & Co., Inc. Inhibitors of Akt activity
US7576209B2 (en) 2006-12-06 2009-08-18 Merck & Co., Inc. Inhibitors of Akt activity
US7589068B2 (en) 2005-02-14 2009-09-15 Merck & Co., Inc. Inhibitors of Akt activity
US7705014B2 (en) 2005-04-12 2010-04-27 Merck Sharp & Dohme Corp. Inhibitors of AKT activity
WO2011093365A1 (fr) * 2010-01-27 2011-08-04 協和発酵キリン株式会社 Composé hétérocyclique azoté
US8008317B2 (en) 2005-06-10 2011-08-30 Merck Sharp & Dohme Corp. Inhibitors of akt activtiy
WO2011135376A1 (fr) 2010-04-30 2011-11-03 Astex Therapeutics Limited Inhibiteurs de pyrazolyl-quinazoline kinase
WO2012071414A2 (fr) * 2010-11-22 2012-05-31 Board Of Regents Of The University Of Nebraska Composés de quinoxaline et leurs utilisations
US8217042B2 (en) 2005-11-11 2012-07-10 Zentaris Gmbh Pyridopyrazines and their use as modulators of kinases
EP2508184A1 (fr) 2011-04-06 2012-10-10 Æterna Zentaris GmbH Dérivés de pyridopyrazine et leur utilisation
JP2013503896A (ja) * 2009-09-03 2013-02-04 バイオエナジェニックス Ｐａｓｋの阻害用複素環式化合物
WO2013061077A1 (fr) 2011-10-28 2013-05-02 Astex Therapeutics Limited Nouveaux composés
WO2013061081A1 (fr) 2011-10-28 2013-05-02 Astex Therapeutics Limited Benzopyrazines anticancéreuses par le biais de l'inhibition de fgfr kinases
WO2013061074A1 (fr) 2011-10-28 2013-05-02 Astex Therapeutics Limited Quinolines comme modulateurs de la fgfr kinase
WO2013061080A1 (fr) 2011-10-28 2013-05-02 Astex Therapeutics Limited Pyridopyrazines anti-cancéreuses par l'inhibition de kinases de fgfr
JP2014506933A (ja) * 2011-03-02 2014-03-20 バイオエナジェニックス Ｐａｓｋの阻害のための複素環化合物
WO2014106763A1 (fr) * 2013-01-07 2014-07-10 Vichem Chemie Kutató Kft. Pyridopyrazines utilisés en tant qu'agents antinéoplasiques
WO2014121885A1 (fr) 2013-02-07 2014-08-14 Merck Patent Gmbh Dérivés de quinoxaline substitués et leur utilisation à titre de modulateurs allostériques positifs du mglur4
US8916561B2 (en) 2011-03-02 2014-12-23 Bioenergenix, Llc Substituted quinoxaline compounds for the inhibition of PASK
US9073902B2 (en) 2011-01-05 2015-07-07 Bioenergenix, Llc Substituted quinoxaline carboxylic acid compounds for the inhibition of PASK
WO2015144803A1 (fr) 2014-03-26 2015-10-01 Astex Therapeutics Ltd Dérivés de quinoxaline utiles en tant que modulateurs de la kinase fgfr
US9290478B2 (en) 2010-11-29 2016-03-22 Astex Therapeutics Ltd Substituted quinoxalines as FGFR kinase inhibitors
US9303030B2 (en) 2012-05-30 2016-04-05 Astex Therapeutics Limited Compounds
US9447098B2 (en) 2012-05-30 2016-09-20 Astex Therapeutics Ltd Pteridines as FGFR inhibitors
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US9493426B2 (en) 2013-04-26 2016-11-15 Astex Therapeutics Limited Quinazolinone derivatives useful as FGFR kinase modulators
WO2017050864A1 (fr) 2015-09-23 2017-03-30 Janssen Pharmaceutica Nv Nouveaux composés
JP2017514809A (ja) * 2014-04-18 2017-06-08 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． キノキサリン化合物及びその使用
US10085982B2 (en) 2014-03-26 2018-10-02 Astex Therapeutics Ltd Combinations
WO2019109069A1 (fr) 2017-12-01 2019-06-06 Board Of Regents Of The University Of Nebraska Composés de quinoxaline et leurs utilisations
US10323018B2 (en) 2015-01-20 2019-06-18 Millennium Pharmaceuticals, Inc. Quinazoline and quinoline compounds and uses thereof
US10478494B2 (en) 2015-04-03 2019-11-19 Astex Therapeutics Ltd FGFR/PD-1 combination therapy for the treatment of cancer
US10736900B2 (en) 2014-03-26 2020-08-11 Astex Therapeutics Ltd Combinations of an FGFR inhibitor and an IGF1R inhibitor
US10898482B2 (en) 2015-02-10 2021-01-26 Astex Therapeutics Ltd Pharmaceutical compositions comprising N-(3,5-dimethoxyphenyl)-N'-1 methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine
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