WO2012168733A1 - 8-amino-imidazo[1,2-a]pyrazines substituées en tant qu'agents antibactériens - Google Patents

8-amino-imidazo[1,2-a]pyrazines substituées en tant qu'agents antibactériens Download PDF

Info

Publication number
WO2012168733A1
WO2012168733A1 PCT/GB2012/051303 GB2012051303W WO2012168733A1 WO 2012168733 A1 WO2012168733 A1 WO 2012168733A1 GB 2012051303 W GB2012051303 W GB 2012051303W WO 2012168733 A1 WO2012168733 A1 WO 2012168733A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
mmol
heteroaryl
aryl
Prior art date
Application number
PCT/GB2012/051303
Other languages
English (en)
Inventor
Gabriel Waksman
Alethea TABOR
James SAYER
Karin WALLDEN
Original Assignee
Ucl Business Plc
Birkbeck College
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 Ucl Business Plc, Birkbeck College filed Critical Ucl Business Plc
Publication of WO2012168733A1 publication Critical patent/WO2012168733A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to 2- or 3-substituted 8-amino-imidazo[1 ,2-a]pyrazines and derivatives thereof and methods of making such compounds.
  • the present invention also relates to the use of these compounds as antibacterial agents and their use in methods of treating or preventing bacterial infection. Background to the Invention
  • Gram-negative bacteria such as Helicobacter pylori, Legionella pneumophilia, Brucella suis, Bartonella henselae and Bordetella pertussis, can cause serious infections in both animals and plants and many resources have been devoted to developing pharmaceutical agents to kill such bacteria.
  • these bacterial populations in a host can develop resistance to these pharmaceutical agents and survive, resulting in inefficient treatments which do not kill the bacteria in question.
  • microorganisms have evolved a number of macromolecular secretion machineries to translocate proteins and nucleoprotein complexes from the bacterial cytosol to the host cell.
  • Five types of secretion systems (l-V) have so far been identified, with a diverse range of functions including: the transfer of plasmid DNA from one cell to another (the major mechanism for the spread of antibiotic resistance genes between pathogenic bacteria); the secretion of proteins toxic to host cells; and the secretion of effector molecules required for the propagation of the microorganism within the host cell.
  • Type IV secretion systems are vital for the pathogenicity of these important gram-negative bacteria.
  • H. pylori utilizes the Type IV secretion system to translocate the toxic protein CagA into gastric epithelial cells, and in doing so induces a number of changes in the host cell.
  • T4SS mediate transfer of plasmid DNAs from one cell to another and, as such, are the primary cause for the spread of antibiotics resistance genes.
  • Type IV secretion systems require ATP as an energy source to drive this transport and therefore require a class of ATPases known as VirB1 1 ATPases, which are associated with the inner membrane.
  • Z is O or NH
  • Ri is selected from substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
  • R 2 and R 3 is H, and the other one of R 2 and R 3 is selected from substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
  • L is a direct bond or is selected from: NH
  • R 4 and R 5 are independently selected from H, alkyl, halo, alkoxy, alkylthio, hydroxy, cyano, amino and nitro;
  • Z is O or NH
  • R is selected from substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
  • R 2 and R 3 is H, and the other one of R 2 and R 3 is selected from substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
  • L is a direct bond or is selected from:
  • n 0 1 2, 3, 4, 5 or 6;
  • R 4 and R 5 are independently selected from H, alkyl, halo, alkoxy, alkylthio, hydroxy, cyano, amino and nitro;
  • Ri is selected from substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
  • R 2 and R 3 is H, and the other one of R 2 and R 3 is selected from substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
  • L is a direct bond or is selected from:
  • R 4 and R 5 are independently selected from H, alkyl, halo, alkoxy, alkylthio, hydroxy, cyano, amino and nitro;
  • a third aspect of the invention there is provided a compound as defined according to the second aspect or a pharmaceutically acceptable salt thereof for use in treating or preventing bacterial infection.
  • a method of treating or preventing bacterial infection in a subject by administering a therapeutically effective amount of a compound according to the second aspect or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • a fifth aspect of the invention there is provided a use of a compound of the second aspect in the manufacture of a medicament for treating or preventing bacterial infection or inhibiting the spread of antibiotic resistance genes.
  • the bacterial infection may be infection with Helicobacter pylori, Legionella pneumophilia, Brucella suis, Bartonella henselae or Bordetella pertussis. Inhibition of conjugation applies to all bacterial Gram-negative pathogens.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the second aspect, optionally one or more other active ingredients pharmaceutically acceptable carrier.
  • a seventh aspect of the invention there is provided a method of making a compound of the second aspect which comprises reacting a compound of Formula (II):
  • X is a leaving group, for example a halo group (eg chloro), and R 2 and R 3 are as defined above, with a compound of the formula: wherein Ri , L and Z are as above.
  • a seventh aspect of the invention there is further provided a method of making a compound of the second aspect which comprises reacting a compound of Formula (II):
  • X is a leaving group, for example a halo group (eg chloro), and R 2 and R 3 are as defined above, with a compound of the formula: wherein R-i and L are as above.
  • Ri , R 3 , L and Z are as above.
  • a method of making the compounds of the second aspect in which R 3 is substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl, comprising:
  • Ri , R 3 and L are as above.
  • a ninth aspect there is provided a method of making a compound of the second aspect in which R 2 is substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl, comprising:
  • Ri , R 2 , L and Z are as above.
  • a ninth aspect there is also provided a method of making the compounds of the second aspect in which R 2 is substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl, comprising:
  • Ri , R 2 and L are as above.
  • a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
  • a compound refers to one or more compounds or at least one compound.
  • the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • alkyl denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 or more carbon atoms.
  • alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, / ' - propyl, n-butyl, / ' -butyl, i-butyl or pentyl, isopentyl, neopentyl and hexyl.
  • alkyl may refer to lower alkyl groups of CrC 6 .
  • substituted alkyi denotes an alkyi group containing one or more substituents selected from the group consisting of alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, alkyi amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydr
  • alkylene as used herein means a divalent unbranched or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having 1 or more carbon atoms inclusive, for example lower alkylene groups of Ci-C 6 , unless otherwise indicated.
  • alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methylethylene, 3-methylpropylene, 2-ethylethylene, pentylene, hexylene, and the like.
  • haloalkyl denotes an unbranched or branched chain alkyi group as defined above wherein 1 , 2, 3 or more hydrogen atoms are substituted by a halogen. Examples are 1 -fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1 -iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1- chloroethyl, 1-bromoethyl, 1 -iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2- iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl.
  • fluoroalkyl refers to a "haloalkyl” wherein the halogen is fluorine.
  • cydoalkyl denotes a saturated carbocyclic ring containing 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the cydoalkyl group may be substituted with one or more substituents as defined above with reference to substituted alkyi.
  • alkenyl denotes an unsubstituted hydrocarbon chain radical having 2 or more carbon atoms, preferably 2 to 6 carbon atoms and having one or two olefinic double bonds, for example C 2 -C 6 . Examples are vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl).
  • the alkenyl group may be substituted with one or more substituents as defined above with reference to substituted alkyl.
  • alkynyl denotes an unsubstituted hydrocarbon chain radical having 2 or more carbon atoms, preferably 2 to 6 carbon atoms and having one or where possible two triple bonds. Examples are ethynyl, 1 -propynyl, 2-propynyl, 1 - butynyl, 2-butynyl or 3-butynyl.
  • the alkynyl group may be substituted with one or more substituents as defined above with reference to substituted alkyl.
  • alkoxy denotes an unsubstituted unbranched or branched chain alkyloxy group wherein the "alkyl” portion is as defined above such as methoxy, ethoxy, n-propyloxy, / ' -propyloxy, n-butyloxy, / ' -butyloxy, i-butyloxy, pentyloxy and hexyloxy including their isomers.
  • haloalkoxy group as used herein means an O-haloalkyl group, wherein haloalkyl is as defined above.
  • haloalkoxy groups include, but are not limited to, 2,2,2-trifluoroethoxy, difluoromethoxy and 1 ,1 , 1 ,3,3, 3-hexafluoro-iso- propoxy.
  • thioalkyl or “alkylthio” as used herein refers to a group -SR where R is an alkyl group as defined herein such as methylthio, ethylthio, n-propylthio, i-propylthio and n-butylthio including their isomers.
  • alkoxyalkyi refers to the radical R'R"-, wherein R' is an alkoxy radical as defined herein, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the alkoxyalkyi moiety will be on the alkylene radical.
  • hydroxyalkyl denotes the radical R'R" where R' is an hydroxy radical and R" is alkylene as defined herein and the attachment point of the hydroxyalkyl radical will be on the alkylene radical.
  • acylating agent refers to a reagent which is capable of transferring an acyl moiety as defined previously to another functional group capable of reacting with the acylating agent.
  • an alkylcarbonyl is introduced by reaction with an anhydride or an acyl halide.
  • anhydride refers to compounds of the general structure RC(0)-0-C(0)R wherein R is as defined in the previous paragraph.
  • acyl halide refers to the group RC(0)X wherein X is bromo or chloro.
  • an alkoxycarbonyl is introduced by reaction with an alkoxycarbonyl chloride.
  • heterocyclylalkyl as used herein means a radical R'R" where R' is an alkylene radical and R" is a heterocyclyl radical as defined herein.
  • heterocyclylalkyl radicals include, but are not limited to, tetrahydropyran-2-ylmethyl, 2- piperidinylmethyl, 3-piperidinylmethyl, morpholin-1 -ylpropyl, and the like.
  • alkylamino as used herein means a radical-NR'R", wherein R' is hydrogen and R" is an alkyl radical as defined herein.
  • dialkylamino as used herein means a radical-NR'R", wherein R' and R" are alkyl radicals as defined herein.
  • alkylamino radicals include, but are not limited to, methylamino, ethylamino, cyclopropylmethylamino, dicyclopropylmethylamino, dimethylamino, methylethylamino, diethylamino, di(1 -methylethyl)amino, and the like.
  • aryl denotes an optionally substituted monocyclic or polycyclic-aromatic group comprising carbon and hydrogen atoms.
  • suitable aryl groups include, but are not limited to, phenyl and naphthyl (e.g. 1 -naphthyl or 2-naphthyl).
  • Suitable substituents for aryl are selected from the group consisting of Ci-6 alkyl, Ci -6 alkenyl, Ci -6 alkynyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, Ci -6 alkylthio, arylthio, alkoxycarbonyl, amino, substituted amino for example alkylamino, CONR'R", carbamoyl, carbamate, ureido, amidino, imino, aryl, nitro, halogen and cyano.
  • Optionally substituted phenyl in R-i or R 2 or R 3 can be for example 2- phenoxyphenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,3- dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4- dimethylphenyl, 3,5-dimethylphenyl, 2,3,4-trimethylphenyl, 3,4,5-trimethylphenyl, 2,3,4,5,6-pentamethylphenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 2,3- dicyanophenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 3,4- dicyanophenyl, 3,5-dicyanophenyl, 3,6-dicyanophenyl, 2-methoxyphenyl, 3- methoxyphenyl
  • heteroaryl or “heteroaromatic” as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of said heteroaryl radical will be on said aromatic ring.
  • heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character.
  • heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms including but not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinone, pyrrolyl, pyrazolyl, imidazolyl, triazolinyl, thiophenyl and oxadiaxolinyl which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarb
  • heterocyclylalkyl as used herein means a radical -R'R" where R' is an alkylene radical and R" is a heterocyclyl radical as defined herein.
  • heterocyclylalkyl radicals include, but are not limited to, 2-piperidinylmethyl, 3- piperidinylmethyl, morpholin-1 -ylpropyl, and the like.
  • heterocycle or “heterocyclic” as used herein means a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms and one or more N, S, or O heteroatoms.
  • a heterocyclic group can have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring as long as the ring is not rendered aromatic by their presence.
  • heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino.
  • a heterocyclic group can be unsubstituted or substituted with one to three suitable substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl and dialkylcarbamoyl.
  • amino refers to-NH 2 ,-NHR and-NR 2 respectively and R is alkyl as defined above.
  • the two alkyl groups attached to a nitrogen in a dialkyl moiety can be the same or different.
  • aminoalkyl refers to NH2(CH 2 )n-, RHN(CH 2 ) n -, and R2N(CH 2 ) n - respectively wherein n is 1 or more and R is alkyl as defined above.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • halo encompasses fluoro, chloro, bromo, and iodo.
  • alkylthio or "thioalkyl” means an -S-alkyl group, wherein alkyl is as defined above such as meththio, ethylthio, n-propylthio, /-propylthio, n-butylthio, hexylthio, including their isomers.
  • alkylsulfinyl as used herein means the radical-S(0)R', wherein R' is alkyl as defined herein. Examples of alkylaminosulfonyl include, but are not limited to methylsulfinyl and /so-propylsulfinyl.
  • alkylsulfonyl as used herein means the radical-S(0) 2 R', wherein R' is alkyl as defined herein.
  • alkylaminosulfonyl include, but are not limited to methylsulfonyl and /so-propylsulfonyl.
  • sulfonylating agent refers to a reagent which is capable of transferring an alkyl sulfonyl moiety as defined previously to another functional group capable of reacting with the sulfonating agent such as a sulfonyl chloride Cl-S0 2 - .
  • the present inventors have identified compounds of Formula (I) as being inhibitors of the bacterial ATPase VirB1 1 and its homologs, and thus being useful as antibacterial agents.
  • the compounds when used as antibacterial agents reduce the spread of antibiotic resistance.
  • R 2 is H; and R 3 is selected from substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl. In another embodiment, R 2 is selected from substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl; and R 3 is H.
  • R 4 and R 5 are independently selected from H, lower alkyl, halo (e.g. chloro, fluoro or bromo), alkoxy, alkylthio, hydroxy, cyano, amino and nitro.
  • R 4 and R 5 are each hydrogen.
  • Z is NH
  • the amino substituent may be in the ortho, meta or para position. In another embodiment, the amino substituent is in the para position. In the embodiment where L is the amino substituent may be in the ortho, meta or para position. In another embodiment, the amino substituent is in the para position.
  • R-i is unsubstituted or substituted alkyl.
  • Ri is unsubstituted or substituted aryl. In another embodiment, Ri is unsubstituted or substituted heteroaryl.
  • Ri is substituted aryl substituted with a poly(ethylene) glycol or PEG moiety.
  • the PEG moiety may be coupled to the aryl group via a linker.
  • the linker is a carbamate linker.
  • the present invention encompasses any linker, for example but not limited to an amide, ester, carbonate, imidate, alkyl, alkenyl or alkynyl linker.
  • the PEG moiety is coupled directly to the aryl group.
  • the PEG moiety may itself be substituted.
  • the PEG moiety may be substituted with an alkenyl, alkynyl or maleido group.
  • the PEG moiety may comprise one or more PEG monomers, for example two PEG monomers, three PEG monomers or four PEG monomers.
  • the PEG moiety may comprise (PEG)i, (PEG) 2 , (PEG) 3 or (PEG) 4 .
  • the compound is not selected from the group consisting of:
  • the compound is not selected from the compounds of Table 1 :
  • the compound is selected from the group consisting of:
  • the compound is selected from the compounds in Table 2. In an embodiment, any one of the compounds of Table 2 may be used in treating or preventing bacterial infection.
  • R-i, R 2 and R 3 in the following methods are as defined above. All starting materials in the following general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art. Solvents and reagents were obtained from commercial sources and were used as received unless otherwise stated. Dry solvents were dried over anhydrous columns. Moisture levels were usually ⁇ 15 ppm by Karl Fischer titration. Brine refers to a saturated solution of sodium chloride. Anhydrous magnesium sulfate (MgS0 4 ) or sodium sulfate (Na 2 S0 4 ) were used as drying agents after reaction workup, as indicated. Pet Ether refers to the fraction of light petroleum ether boiling in the range 40-60 °C.
  • solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1 ,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; nitriles, such as acetonitrile and benzonitrile; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, /V,/V-dimethylformamide, and ⁇ /,/V-dimethylacetamide sulfoxides, such as dimethyl sulfoxide and sulfolane; or mixed solvents thereof.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1 ,2-dichloroethane
  • ethers such as diethyl ether, diisopropyl
  • the synthesis of the amino alcohol was achieved via a-bromination of the aryl ketone with pyridinium tribromide. This was followed by substitution of the a-bromine with an azide, giving the azidoketone which was then reduced to give the corresponding azido-alcohol. Hydrogenation to give the amino alcohol was performed at atmospheric pressure, with the exception of the thiophene analogue which required 3 bar pressure to go to completion. Coupling with 2,3- dichloropyrazine in 1 ,4-dioxane afforded the pyrazinyl-amino alcohol in good yields. Swern oxidation to the ketone was followed by acid-induced cyclisation to form the 3- aryl-8-chloroimidazo[1 ,2-a]pyrazine.
  • palladium catalysts which may be suitable include but are not limited to: palladium metal, palladium- carbon, palladium (II) acetate, tris(dibenzylideneacetone)dipalladiumchloroform, [1 ,2- bis(diphenylphosphino)ethane]palladium dichloride, bis(tri-o-toluylphosphine)palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine) palladium or dichloro[1 ,1 '-bis(diphenylphosphino)ferrocene]palladium.
  • Pd(dba) 2 is Pd(dba) 2 .
  • Examples 1 to 6 were prepared according to this general method.
  • Melting points were recorded on a Gallenkamp Melting Point Apparatus and are uncorrected.
  • Proton nuclear magnetic resonance ( 1 H NMR) were recorded using Bruker AV400 (400 MHz), AV500 (500 MHz) and AV600 (600MHz) spectrometers as indicated.
  • Carbon nuclear magnetic resonance ( 13 C NMR) were recorded using Bruker AV400 (100 MHz), AV500 (125 MHz) and AV600 (150MHz) spectrometers as indicated.
  • Spectra were obtained using CDCI 3 , CD 3 OD, CD 2 CI 2 and DMSO-c/ 6 as solvents and chemical shifts are quoted on the ⁇ scale in units of ppm using TMS as an internal standard.
  • Infra-Red (IR) spectroscopy was carried out using a PerkinElmer Spectrum 100 FT-IR Spectrometer using thin films. Absorption maxima (v max ) are reported in wavenumbers (cm "1 ).
  • HPLC High Performance Liquid Chromatography
  • LCMS Liquid Chromatography Mass Spectrometry
  • NaHC0 3 sodium hydrogen carbonate
  • compositions The present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, together with a pharmaceutically acceptable carrier for said compound. Also, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, further comprising other pharmacologically active agent(s).
  • Pharmaceutically acceptable salts of a compound of Formula (I) include the acid addition salts (including disalts) thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, palmoate, phosphat
  • a pharmaceutically acceptable salt of a compound of Formula (I) may be readily prepared by mixing together solutions of the compound of Formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • Pharmaceutically acceptable salts of the compounds of the invention include both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, c/ 6 -acetone, c/ 6 -DMSO.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • the compounds of Formula (I) may exist in one or more crystalline forms. These polymorphs, including mixtures thereof are also included within the scope of the present invention.
  • the compounds of Formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • Oral Administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as, for example, tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include, for example, suspensions, solutions, syrups and elixirs.
  • Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents. H (6), 981-986 by Liang and Chen (2001 ).
  • the drug may make up from about 1 wt% to about 80 wt% of the dosage form, more typically from about 5 wt% to about 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from about 1 wt% to about 25 wt%, preferably from about 5 wt% to about 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface-active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents may comprise from about 0.2 wt% to about 5 wt% of the tablet, and glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from about 0.25 wt% to about 10 wt%, preferably from about 0.5 wt% to about 3 wt% of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line. 25(2), 1-14 (2001 ). The use of chewing gum to achieve controlled release is described in WO00/35298. Parenteral Administration
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from about 3 to about 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from about 3 to about 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of Formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject(TM), Bioject(TM), etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • a suitable propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from about 1 ⁇ g to about 20mg of the compound of the invention per actuation and the actuation volume may vary from about 1 ⁇ to about 10 ⁇ .
  • a typical formulation may comprise a compound of Formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from about 1 to about 100 ⁇ g of the compound of Formula (I).
  • the overall daily dose will typically be in the range about 50 ⁇ g to about 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in. W091/1 1 172, WO94/02518 and W098/55148.
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the compounds of the invention is typically in the range of about 0.05 mg to about 500 mg depending, of course, on the mode of administration, preferred in the range of about 0.1 mg to about 400 mg and more preferred in the range of about 0.5 mg to about 300 mg.
  • oral administration may require a total daily dose of from about 1 mg to about 300 mg, while an intravenous dose may only require from about 0.5 mg to about 100 mg.
  • the total daily dose may be administered in single or divided doses. These dosages are based on an average human subject having a weight of about 65 kg to about 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the reaction was then allowed to slowly warm to RT over a period of 2 1 ⁇ 2 h.
  • the reaction was quenched with H 2 0 (50 mL) and organics extracted followed by washing with 2.0 M HCI (2 x 40 mL), sat. NaHC0 3 (1 x 40 mL), H 2 0 (1 x 40 mL) and brine (1 x 40 mL). Drying (MgS0 4 ), filtration and concentration gave a yellow solid (2.31 , 8.37 mmol, 90.0%).
  • Steps 1 to 6 were carried out as per Steps 1 to 6 of Example
  • Step 1 was carried out as per Step 1 of Example 2 Step 2
  • Step 1 was carried out as per Step 1 of Example 3.
  • Step 2 is carried out as per Step 1 of Example 3.
  • Step 1 was carried out as per Step 1 of Example 4 Step 2
  • Steps 1 and 2 were carried out as per Steps 1 and 2 of Example 8 to give compound JS18.
  • Tris(dibenzylideneacetone)dipalladium(0) ( ⁇ 1 mg, 1 .1 ⁇ ), 2-Dicyclohexylphosphino- 2'-(/V,/V-dimethylamino)biphenyl ( ⁇ 1 mg, 2.5 ⁇ ) and Sodium-ie f-butoxide ( ⁇ 12.5 mg, 130 ⁇ ) were added to a flask and dissolved in 5 ml anhydrous toluene.
  • JS1 1 1 (648 mg, 2.58 mmol), 2-amino-3-chloropyrazine (334.4 mg, 2.58 mmol) and NaHC0 3 (271.0 mg, 3.23 mmol) in ie f-butanol (15 ml) were stirred under reflux for 40 h. The solvent was removed and the resulting residual was taken up in CH 2 CI 2 and washed H 2 0 and brine, dried (MgS0 4 ), filtered and solvent removed. Flash chromatography (Pet Ether; 3:1 to 1 :1 to 1 :3 Pet Ether/EtOAc) afforded the title compound as an orange solid (341 .9 mg, 1 .21 mmol, 47.1 %).
  • JS1 14 (100 mg, 0.355 mmol), /V-(4-aminophenyl)-4-methylbenzenesulfonamide (1 1 1 .8 mg, 0.426 mmol), Pd(dba) 2 (2.0 mg, 1 mol%), DavePhos (4.2 mg, 3 mol%) and Cs 2 C0 3 (162.0 mg, 0.497 mmol) were stirred in anhydrous 1 ,4-dioxane under reflux for 40 h. After LCMS confirmed the presence of the product mass, the reaction was cooled to RT and solvent removed. The resulting residue was taken up in CH 2 CI 2 and washed with sat. aq.
  • Tris(dibenzylideneacetone)dipalladium(0) ( ⁇ 2 mg, 2.2 ⁇ mol), 2-dicyclohexylphosphino- 2'-(N,N-dimethylamino)biphenyl ( ⁇ 3 mg, 7.6 ⁇ ) and sodium-tertbutoxide ( ⁇ 7 mg, 73 ⁇ ) were added to a flask and dissolved in 5 ml anhydrous toluene.
  • 2-(8- chloroimidazo[1 ,2-a]pyrazin-2-yl)quinoline (HK006, 15 mg, 53 ⁇ ) and N-(4- aminophenyl)-4-methylbenzenesulfonamide (15 mg, 57 ⁇ ) were added under argon atmosphere.
  • the main fraction was collected in three split subfractions; only the first subfraction was furtherly used; 1 H-NMR, but not LCMS showed that the other subfractions were not appropriate.
  • the product was dried under high vacuum after evaporation of the solvent (coevaporation with dichloromethane). 0.8 mg (1 .6 ⁇ , yield: 3%) of the solid product were obtained with minor to moderate impurities and characterized by 1 H-NMR and an IC50 assay. Further characterization of the product was impeded by problems to dissolve the compound, occurrence of new relatively significant impurities and the small amount of the sample.
  • Benzene-1 ,4-diamine (3.14 g, 29.0 mmol), was dissolved in anhydrous CH 2 CI 2 (100 ml), triethylamine (1 .62 ml, 1 1.61 mmol) added and the mixtures cooled on ice. MeS0 2 CI (0.449 ml, 5.81 mmol) was added drop wise and the reaction was stirred at RT for 16 h. The mixture was then diluted with CH 2 CI 2 and washed sat. aq. NaHC0 3 . The aqueous layer was then extracted with CH 2 CI 2 (4x) as well as EtOAc (4x).
  • JS169 (18 mg, 0.049 mmol) was dissolved in anhydrous pyridine (1 ml) and the mixture was cooled on ice. 4-methylbenzene-1-sulfonyl chloride (1 1 .3 mg, 0.059 mmol) was added and the deep yellow/orange solution was stirred under Ar at RT for 16 h.
  • JS1 1 (See Step 1 of Example 7) (1 .12 g, 4.01 mmol) was dissolved in anhydrous DMSO (16 ml). NaSMe (337 mg, 4.81 mmol) was added portion wise and the reaction was stirred at 100 °C for 16 h. The mixture was then cooled to RT, diluted with brine and extracted with CH 2 CI 2 . The organic layer was washed with H 2 0 (5x) and brine (1 x), dried (MgS0 4 ), filtered and solvent removed in vacuo.
  • JS130 (1.7662 g, 6.07 mmol) was dissolved in anhydrous CH 2 CI 2 (50 ml) and the mixture was cooled on ice.
  • mCPBA (5.231 g, 30.3 mmol) was added in one portion and the reaction continued to stir at RT for 5 h.
  • the reaction was partitioned with NaHC0 3 and extracted with CH 2 CI 2 (3x); the combined organic extracts were then washed with brine, dried (MgS0 4 ), filtered and concentrated in vacuo. Flash chromatography (CH 2 CI 2 ; 2% to 5% EtOAc) afforded the title compound as a yellow solid (1 .098 g, 3.398 mmol, 56.0%).
  • NaH was pre-activated by stirring NaH (60% in Mineral Oil; 12.4 mg, 0.310 mmol) in anhydrous hexanes (3 ml) for 20 min, removing the solvent using a syringe and drying the contents under high vacuum.
  • DMF 0.5 ml
  • JS168 81 .4 mg, 0.310 mmol
  • JS132 50 mg, 0.155 mmol
  • DMF 1 .5 ml
  • JS206 (556.5 mg, 5.57 mmol) was dissolved in anhydrous toluene (140 ml).
  • JS129 (see Example 23) (1 .509 g, 6.68 mmol) and molecular sieves (4A, 10 sieves) were added and the reaction was stirred under reflux for 16 h. The solvent was removed and the reaction purified via flash chromatography (Toluene; 2:1 Toluene/EtOAc) to afford the title compound as a white solid (663 mg, 2.22 mmol, 39.9%).
  • NaH was pre-activated by stirring NaH (60% in Mineral Oil; 88.7 mg, 2.215 mmol) in anhydrous hexanes (25 ml) for 20 min, removing the solvent using a syringe and drying the contents under high vacuum.
  • DMF (6 ml) was added followed by JS207 (660 mg, 2.215 mmol) in DMF (8 ml) and the mixture was stirred at RT for 20 min.
  • JS132 (357.7 mg, 1 .107 mmol) in DMF (20 ml) was added and the resulting dark brown solution was heated at 100 °C under Argon for 18 h.
  • NaH was pre-activated by stirring NaH (60% in Mineral Oil; 70.6 mg, 1 .765 mmol) in anhydrous hexanes (50 ml) for 20 min, removing the solvent using a syringe and drying the contents under high vacuum.
  • DMF 5 ml
  • JS121 529 mg, 1.765 mmol
  • JS132 285 mg, 0.882 mmol
  • DMF 13 ml
  • JS136 (993 mg, 4.39 mmol) was dissolved in anhydrous toluene (92 ml).
  • JS129 (750.6 mg, 3.66 mmol) was added and the reaction was stirred under reflux for 16 h. The reaction was cooled to RT and adsorbed onto silica and purification via flash chromatography (Pet Ether; 2:1 to 1 :1 to 1 :2 Pet Ether/EtOAc) afforded the title compound as a white solid (1 .1306 g, 2.81 mmol, 76.7%).
  • NaH was pre-activated by stirring NaH (60% in Mineral Oil; 71 .0 mg, 1 .774 mmol) in anhydrous hexanes (25 ml) for 20 min, removing the solvent using a syringe and drying the contents under high vacuum.
  • DMF 5 ml
  • JS138 715 mg, 1.774 mmol
  • DMF 8 ml
  • JS132 286.5 mg, 0.887 mmol
  • JS179 (317.9 mg, 0.492 mmol) was dissolved in anhydrous CH 2 CI 2 (15 ml) and cooled on ice. TFA (15 ml) was added and the reaction was stirred at RT for 3 h. Removal of the solvent, with the aid of toluene, followed by flash chromatography (CH 2 CI 2 ; 5% to 10% MeOH/CH 2 CI 2 ).
  • the VirB1 1 protein was produced in the E. coli strain BL21 Star(DE3) (Invitrogen) as described previously. The protein concentration was estimated spectroscopically using a NanoDrop (Thermo Scientific) and a calculated extinction coefficient at 280 nm, based on the amino acid composition. The ATPase activity of VirB1 1 was measured, with and without a specific amount of compound present, using an in vitro ATPase colorimetric assay kit (Innova Biosciences). The assay was performed in 96-well ELISA microplates (Greiner Bio-One), using a multipipett robot. All measurements were made in duplicate.
  • a volume of 49 ⁇ _ of a substrate/buffer solution (200 mM tris(hydroxymethyl)aminomethane (TRIS), pH 7.5; 5 mM MgCI 2 ; 250 ⁇ ATP; and 10% DMSO) was added to each assigned well, followed by the addition of 1 ⁇ _ of compound (at 0.5; 5 or 50 mM to achieve the final concentrations of 5; 50 and 500 ⁇ in the reaction, respectively) in DMSO (or 1 ⁇ _ DMSO to controls).
  • the solutions were mixed carefully by pipetting.
  • the reaction was started by the addition of 50 ⁇ _ of 0.106 ⁇ VirB1 1 to each well (except the negative control, see text below), and the reaction plate was directly transferred to 37 °C for 30 min of incubation.
  • the reaction was stopped by the addition of the Gold mix according to the standard protocol of the kit.
  • the absorbance at 620 nm was measured after 30 min at room temperature.
  • the percentage of absorbance relative non-inhibited VirB1 1 was calculated, after subtracting the absorbance value of the negative control.
  • the protein was added after the Gold mix, as described in the standard protocol of the kit, which when used as a blank corrects for all free P, not produced by the enzyme during the 30 min incubation at 37 °C.
  • VirB1 1 A known inhibitor of VirB1 1 (Microbiology, (2006), 152, 2919-2930, denoted CHIR02) was used as a control inhibitor. A selection of the compounds were assayed as above at additional concentrations ranging between 5 and 200 ⁇ from which IC50 values were calculated, assuming a linear relationship between P, production and absorbance. IC50 was defined as the concentration of compound that produces 50% inhibition. Evaluation of compounds as VirB1 1 ATPase inhibitors
  • the VirB1 1 protein was produced recombinantly in Escherichia coli and purified to high purity as described previously.
  • the ATPase activity of VirB1 1 was measured by monitoring the release of inorganic phosphate (P,) using an in vitro ATPase assay.
  • Examples 1 to 12 were evaluated by performing the ATPase assay with and without compound present at concentrations of 500 ⁇ (or 250 ⁇ ), 50 ⁇ and 5 ⁇ (Fig. 1 ). At the highest concentration, precipitation appeared in the reaction wells of compounds 1 , 2, 5, 8, 9 and 1 1 , which interfered with the measurements. Despite this, a clear inhibitory effect could be seen of the compounds 1 , 3, 4, 5, 6, 1 1 and 12 of which 4, 5, 8, 1 1 and 12 clearly reduced the ATPase activity at 50 ⁇ . IC 50 values, logP and logS values were then measured for a selection of the compounds 1 to 23 (Table 3).

Abstract

La présente invention concerne des imidazo[1,2-a]pyrazines de formule (I) et leur utilisation en tant qu'agents antibactériens.
PCT/GB2012/051303 2011-06-10 2012-06-08 8-amino-imidazo[1,2-a]pyrazines substituées en tant qu'agents antibactériens WO2012168733A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1109763.1A GB201109763D0 (en) 2011-06-10 2011-06-10 Compounds
GB1109763.1 2011-06-10

Publications (1)

Publication Number Publication Date
WO2012168733A1 true WO2012168733A1 (fr) 2012-12-13

Family

ID=44357536

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2012/051303 WO2012168733A1 (fr) 2011-06-10 2012-06-08 8-amino-imidazo[1,2-a]pyrazines substituées en tant qu'agents antibactériens

Country Status (2)

Country Link
GB (1) GB201109763D0 (fr)
WO (1) WO2012168733A1 (fr)

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016162318A1 (fr) 2015-04-08 2016-10-13 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire, et leurs produits intermédiaires
WO2017072039A1 (fr) 2015-10-26 2017-05-04 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire
WO2017093180A1 (fr) 2015-12-01 2017-06-08 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire
WO2017144341A1 (fr) 2016-02-23 2017-08-31 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés en tant que produits de lutte antiparasitaire
WO2017174414A1 (fr) 2016-04-05 2017-10-12 Bayer Cropscience Aktiengesellschaft Dérivés de naphtaline utilisés comme agents de lutte contre les nuisibles
EP3241830A1 (fr) 2016-05-04 2017-11-08 Bayer CropScience Aktiengesellschaft Derivés de bicycles condensés hétérocycliques utilisés comme pesticides
WO2018015289A1 (fr) 2016-07-19 2018-01-25 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2018033455A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2018050825A1 (fr) 2016-09-19 2018-03-22 Bayer Cropscience Aktiengesellschaft Dérivés pyrazolo[1,5-a]pyridine et leur utilisation en tant qu'agents de lutte antiparasitaire
EP3305786A2 (fr) 2018-01-22 2018-04-11 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène bicycliques condensés en tant que pesticides
WO2018065288A1 (fr) 2016-10-07 2018-04-12 Bayer Cropscience Aktiengesellschaft Dérivés de 2-[2-phényl-1-(sulfonylméthyl)vinyl]-imidazo[4,5-b]pyridine et composés apparentés utilisés comme pesticides en protection des plantes
WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
CN108299252A (zh) * 2018-04-04 2018-07-20 梯尔希（南京）药物研发有限公司 一种去甲肾上腺素磺酸类代谢物的合成方法
WO2018138050A1 (fr) 2017-01-26 2018-08-02 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2018197257A1 (fr) 2017-04-24 2018-11-01 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2019162174A1 (fr) 2018-02-21 2019-08-29 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2020126954A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyrazine
WO2020126952A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Dérivés d'imidazopyrazine en tant qu'agents antibactériens
WO2020126953A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyrazine en tant qu'antibactériens
WO2020126956A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Dérivés d'imidazopyrazine en tant qu'agents antibactériens
WO2020127075A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Dérivés d'imidazopyrazine en tant qu'antibactériens
WO2020173861A1 (fr) 2019-02-26 2020-09-03 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2020173860A1 (fr) 2019-02-26 2020-09-03 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
EP3896065A1 (fr) 2015-08-07 2021-10-20 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène condensés 2-(het)aryl-substitués en tant que pesticides
WO2021219578A1 (fr) * 2020-04-29 2021-11-04 F. Hoffmann-La Roche Ag Dérivés antibactériens de 8-phénylamino-3-(pyrazol-4-yl)imidazo[1,2-a]pyrazine
WO2021244997A1 (fr) * 2020-06-01 2021-12-09 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyrazne
WO2021249896A1 (fr) * 2020-06-09 2021-12-16 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyrazine
WO2021249893A1 (fr) * 2020-06-08 2021-12-16 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazo-pyrazine
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2023285497A1 (fr) * 2021-07-15 2023-01-19 F. Hoffmann-La Roche Ag Dérivés d'imidazole et leur utilisation en tant qu'antibiotiques
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008079460A2 (fr) * 2006-09-05 2008-07-03 Emory University Inhibiteurs de kinase pour la prévention ou le traitement d'une infection pathogène et procédé d'utilisation de ceux-ci
WO2009024585A2 (fr) * 2007-08-21 2009-02-26 Biofocus Dpi Limited Composés d'imidazopyrazine
WO2010069684A1 (fr) * 2008-12-17 2010-06-24 Biomarin Iga, Ltd. Composés destinés au traitement de la dystrophie musculaire de duchenne

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008079460A2 (fr) * 2006-09-05 2008-07-03 Emory University Inhibiteurs de kinase pour la prévention ou le traitement d'une infection pathogène et procédé d'utilisation de ceux-ci
WO2009024585A2 (fr) * 2007-08-21 2009-02-26 Biofocus Dpi Limited Composés d'imidazopyrazine
WO2010069684A1 (fr) * 2008-12-17 2010-06-24 Biomarin Iga, Ltd. Composés destinés au traitement de la dystrophie musculaire de duchenne

Cited By (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016162318A1 (fr) 2015-04-08 2016-10-13 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire, et leurs produits intermédiaires
EP3896065A1 (fr) 2015-08-07 2021-10-20 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène condensés 2-(het)aryl-substitués en tant que pesticides
EP3896066A2 (fr) 2015-08-07 2021-10-20 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène condensés 2-(het)aryl-substitués en tant que pesticides
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017072039A1 (fr) 2015-10-26 2017-05-04 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017093180A1 (fr) 2015-12-01 2017-06-08 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
US11866435B2 (en) 2015-12-22 2024-01-09 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017144341A1 (fr) 2016-02-23 2017-08-31 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés en tant que produits de lutte antiparasitaire
WO2017174414A1 (fr) 2016-04-05 2017-10-12 Bayer Cropscience Aktiengesellschaft Dérivés de naphtaline utilisés comme agents de lutte contre les nuisibles
EP3241830A1 (fr) 2016-05-04 2017-11-08 Bayer CropScience Aktiengesellschaft Derivés de bicycles condensés hétérocycliques utilisés comme pesticides
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018015289A1 (fr) 2016-07-19 2018-01-25 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2018033455A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018050825A1 (fr) 2016-09-19 2018-03-22 Bayer Cropscience Aktiengesellschaft Dérivés pyrazolo[1,5-a]pyridine et leur utilisation en tant qu'agents de lutte antiparasitaire
WO2018065288A1 (fr) 2016-10-07 2018-04-12 Bayer Cropscience Aktiengesellschaft Dérivés de 2-[2-phényl-1-(sulfonylméthyl)vinyl]-imidazo[4,5-b]pyridine et composés apparentés utilisés comme pesticides en protection des plantes
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US11566026B2 (en) 2016-12-22 2023-01-31 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
US11339149B2 (en) 2016-12-22 2022-05-24 Incyte Corporation Heterocyclic compounds as immunomodulators
US10800768B2 (en) 2016-12-22 2020-10-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
US11787793B2 (en) 2016-12-22 2023-10-17 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018138050A1 (fr) 2017-01-26 2018-08-02 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2018197257A1 (fr) 2017-04-24 2018-11-01 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
EP3305786A2 (fr) 2018-01-22 2018-04-11 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène bicycliques condensés en tant que pesticides
WO2019162174A1 (fr) 2018-02-21 2019-08-29 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US11124511B2 (en) 2018-03-30 2021-09-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
CN108299252A (zh) * 2018-04-04 2018-07-20 梯尔希（南京）药物研发有限公司 一种去甲肾上腺素磺酸类代谢物的合成方法
US10906920B2 (en) 2018-05-11 2021-02-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US11414433B2 (en) 2018-05-11 2022-08-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US20230012368A1 (en) * 2018-12-17 2023-01-12 Hoffmann-La Roche Inc. Novel imidazopyrazine derivatives
WO2020126954A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyrazine
WO2020126952A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Dérivés d'imidazopyrazine en tant qu'agents antibactériens
CN113164771A (zh) * 2018-12-17 2021-07-23 豪夫迈·罗氏有限公司 咪唑并吡嗪衍生物作为抗菌剂
WO2020127075A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Dérivés d'imidazopyrazine en tant qu'antibactériens
WO2020126956A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Dérivés d'imidazopyrazine en tant qu'agents antibactériens
WO2020126953A1 (fr) * 2018-12-17 2020-06-25 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyrazine en tant qu'antibactériens
WO2020173860A1 (fr) 2019-02-26 2020-09-03 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2020173861A1 (fr) 2019-02-26 2020-09-03 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
WO2021219578A1 (fr) * 2020-04-29 2021-11-04 F. Hoffmann-La Roche Ag Dérivés antibactériens de 8-phénylamino-3-(pyrazol-4-yl)imidazo[1,2-a]pyrazine
WO2021244997A1 (fr) * 2020-06-01 2021-12-09 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyrazne
WO2021249893A1 (fr) * 2020-06-08 2021-12-16 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazo-pyrazine
WO2021249896A1 (fr) * 2020-06-09 2021-12-16 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyrazine
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
WO2023285497A1 (fr) * 2021-07-15 2023-01-19 F. Hoffmann-La Roche Ag Dérivés d'imidazole et leur utilisation en tant qu'antibiotiques
US11858912B2 (en) 2021-07-15 2024-01-02 Hoffmann-La Roche Inc. Heterocyclic compounds

Also Published As

Publication number Publication date
GB201109763D0 (en) 2011-07-27

Similar Documents

Publication Publication Date Title
WO2012168733A1 (fr) 8-amino-imidazo[1,2-a]pyrazines substituées en tant qu'agents antibactériens
US10526291B2 (en) Potent dual BRD4-kinase inhibitors as cancer therapeutics
US9381192B2 (en) Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof
US20200407328A1 (en) Brd4-kinase inhibitors as cancer therapeutics
JP5150878B2 (ja) キナーゼ阻害剤
JP5876503B2 (ja) 呼吸合胞体ウイルスの抗ウイルス剤としてのイミダゾピリジン
CN108290860B (zh) 作为plasmepsin v抑制剂的亚氨基四氢嘧啶酮衍生物
JP2019508462A (ja) 癌治療用の４，６−ジヒドロピロロ［３，４−ｃ］ピラゾール−５（１Ｈ）−カルボニトリル誘導体
HUE035612T2 (en) 1 H-pyrazolo [3,4-b] pyridines and their therapeutic use
CA2890981A1 (fr) Composes heterocycliques substitues par amide, utiles comme modulateurs d'il-12, il-23 et/ou de reponses a l'ifn?
WO2015173683A1 (fr) Pyrazolopyridines et pyrazolopyrimidines
EP2888242B1 (fr) 4-pyridones substituées et leur utilisation comme inhibiteurs de l'activité de l'élastase neutrophile
US11858897B2 (en) Substituted 6,11-dihydro-5H-benzo[b]carbazoles as inhibitors of ALK and SRPK
AU2008252380A1 (en) Quinazolin-oxime derivatives as Hsp90 inhibitors
KR20150031318A (ko) 효소의 억제
KR20190104632A (ko) 트라이사이클릭 자이라제 억제제
TW201625620A (zh) 作為蛋白去乙醯酶抑制劑及雙蛋白去乙醯酶蛋白激酶抑制劑之雜環氧肟酸及其使用方法
CA3134814A1 (fr) Ligands de pseudokinase tyk2
CA2779951A1 (fr) Derives d'imidazopyridine
WO2017083756A1 (fr) Composés hétérocycliques pour le traitement de maladies
TW200530245A (en) Pyrrolo pyrimidine derivatives useful for treating proliferative diseases
CN114907350B (zh) 一类含氮稠环类化合物、制备方法和用途
JP7110335B2 (ja) プロテインキナーゼ阻害剤として有用なピリドキナゾリン誘導体
US20110015395A1 (en) Pyrazole compounds with inhibitory activity against ros kinase
EP2920169A1 (fr) Dérivés d'imidazopyridine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12726851

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12726851

Country of ref document: EP

Kind code of ref document: A1