WO2009056886A1 - Dérivés de pyrimidine et leur utilisation en tant que modulateurs de l'activité du fgfr - Google Patents

Dérivés de pyrimidine et leur utilisation en tant que modulateurs de l'activité du fgfr Download PDF

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WO2009056886A1
WO2009056886A1 PCT/GB2008/051018 GB2008051018W WO2009056886A1 WO 2009056886 A1 WO2009056886 A1 WO 2009056886A1 GB 2008051018 W GB2008051018 W GB 2008051018W WO 2009056886 A1 WO2009056886 A1 WO 2009056886A1
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compound
pharmaceutically acceptable
acceptable salt
formula
amino
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PCT/GB2008/051018
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English (en)
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Kevin Michael Foote
Maria-Elena Theoclitou
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to pyrimidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
  • Protein kinases are a class of proteins (enzymes) that regulate a variety of cellular functions. This is accomplished by the phosphorylation of specific amino acids on protein substrates resulting in conformational alteration of the substrate protein. The conformational change modulates the activity of the substrate or its ability to interact with other binding partners.
  • the enzyme activity of the protein kinase refers to the rate at which the kinase adds phosphate groups to a substrate. It can be measured, for example, by determining the amount of a substrate that is converted to a product as a function of time. Phosphorylation of a substrate occurs at the active-site of a protein kinase.
  • Tyrosine kinases are a subset of protein kinases that catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. These kinases play an important part in the propagation of growth factor signal transduction that leads to cellular proliferation, differentiation and migration.
  • ATP adenosine triphosphate
  • Fibroblast growth factor has been recognized as an important mediator of many physiological processes, such as morphogenesis during development and angiogenesis.
  • FGF Fibroblast growth factor
  • the fibroblast growth factor receptor (FGFR) family consists of four members with each composed of an extracellular ligand binding domain, a single transmembrane domain and an intracellular cytoplasmic protein tyrosine kinase domain.
  • FGFRs Upon stimulation with FGF, FGFRs undergo dimerisation and transphosphorylation, which results in receptor activation.
  • Receptor activation is sufficient for the recruitment and activation of specific downstream signalling partners that participate in the regulation of diverse process such as cell growth, cell metabolism and cell survival (Reviewed in Eswarakumar, V. P. et.
  • FGF and FGFRs have the potential to initiate and/ or promote tumorigenesis.
  • FGF signalling to human cancer.
  • the elevated expression of various FGFs has been reported in a diverse range of tumour types such as bladder, renal cell and prostate (amongst others).
  • FGF has also been described as a powerful angiogenic factor.
  • the expression of FGFRs in endothelial cells has also been reported.
  • Activatiing mutations of various FGFRs have been associated with bladder cancer and multiple myeloma (amongst others) whilst receptor expression has also been documented in prostate and bladder cancer amongst others (Reviewed in Grose, R.
  • the FGF signalling system is an attractive therapeutic target, particularly since therapies targeting FGFRs and/ or FGF signalling may affect both the tumour cells directly and tumour angiogenesis.
  • D represents CH 2 ;
  • E represents CH 2 or O
  • R N1 represents hydrogen or a Ci-C3alkyl group optionally substituted by one or more substituents selected from Ci-C3alkoxy, cyano, hydroxyl, amino (-NH 2 ), mono-Ci-C 3 alkylamino and di-(Ci-C 3 alkyl)amino;
  • R 1 represents -F, -OH, -CN, a Ci-C 3 alkoxy group optionally substituted by one or more R 8 , or -CONHR 6 ;
  • R 2 represents hydrogen or a Ci-C3alkyl group optionally substituted by one or more substituents selected from Ci-C3alkoxy, cyano, hydroxyl, amino (-NH 2 ), mono-Ci-C 3 alkylamino and di-(Ci-C 3 alkyl)amino;
  • R 3 represents hydrogen
  • R 4 represents hydrogen, a Ci-C ⁇ alkyl group optionally substituted with Ci-C3alkoxy, hydroxyl, amino (-NH 2 ), mono-Ci-C3alkylamino and di-
  • (Ci-C3alkyl)amino a C 2 -C 6 alkenyl group optionally substituted with Ci-C 3 alkoxy, a C 2 -C ⁇ alkynyl group optionally substituted with Ci-C3alkoxy, a C 3 -C 5 cycloalkyl group optionally substituted with Ci-C 3 alkoxy, a Ci-C ⁇ alkoxy group optionally substituted with Ci-C3alkoxy, hydroxyl, amino (-NH 2 ), mono-Ci-C 3 alkylamino and di-(Ci-C3alkyl)amino,
  • R 5 represents hydrogen or a Ci-C3alkoxy group
  • R 6 represents a Ci-C ⁇ alkyl optionally substituted by one or more R 8
  • R 7 represents hydrogen or a Ci-C ⁇ alkyl optionally substituted by one or more R 8
  • R 9 and R 10 each independently represent hydrogen, d-C 4 alkyl or C 3 -C 6 cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle optionally comprising an additional heteratom selected from oxygen, sulphur or nitrogen wherein each R 9 and R 10 independently may be optionally substituted on carbon by one or more substituents R 14 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 15 ; R 11 and R 12 each independently represent hydrogen, d-C 4 alkyl or C 3 -C 6 cycl
  • R 8 , R 14 and R 16 each independently is selected from halogen, Ci-C 3 alkyl, Ci-C 3 alkoxy, C 3 cycloalkyl, Ci-C 3 alkylthio, amino (-NH 2 ), mono- and di- Ci-C 3 alkylamino, cyano, hydroxyl and trifluoromethyl;
  • R 15 and R 17 each independently is selected from Ci-C ⁇ alkyl, benzyl, Ci-C ⁇ alkoxycarbonyl, Ci-C ⁇ alkylcarbonyl, phenylcarbonyl, Ci-C ⁇ alkylsulphonyl and phenylsulphonyl; and either when Q represents CR 5 , Q 1 represents N or CH; or when Q represents N, Q 1 represents CH, or a pharmaceutically acceptable salt thereof.
  • D represents CH 2 ;
  • E represents CH 2 or O;
  • R N1 represents hydrogen or a Ci-C3alkyl group optionally substituted by one or more substituents selected from Ci-C3alkoxy, cyano, hydroxyl, amino (-NH 2 ), mono-Ci-C 3 alkylamino and di-(Ci-C 3 alkyl)amino;
  • R 1 represents -F, -OH, a Ci-C3alkoxy group optionally substituted by one or more R 8 , or -CONHR 6 ;
  • R 2 represents hydrogen or a Ci-C3alkyl group optionally substituted by one or more substituents selected from Ci-C3alkoxy, cyano, hydroxyl, amino (-NH 2 ), mono-Ci-C 3 alkylamino and di-(Ci-C 3 alkyl)amino;
  • R 3 represents hydrogen, -F, or a -CONHR 7 group
  • R 4 represents hydrogen, a Ci-C ⁇ alkyl group optionally substituted with Ci-C3alkoxy, hydroxyl, amino (-NH 2 ), mono-Ci-C3alkylamino and di- (Ci-C3alkyl)amino, a C 2 -C 6 alkenyl group optionally substituted with Ci-C 3 alkoxy, a C 2 -C ⁇ alkynyl group optionally substituted with Ci-C3alkoxy, a C 3 -C 5 cycloalkyl group optionally substituted with Ci-C 3 alkoxy, a Ci-C ⁇ alkoxy group optionally substituted with Ci-C3alkoxy, hydroxyl, amino (-NH 2 ), mono-Ci-C 3 alkylamino and di-(Ci-C3alkyl)amino, -C(O)NR 9 R 10 , -NR 11 R 12 ,
  • R 6 represents a Ci-C ⁇ alkyl optionally substituted by one or more R 8 ;
  • R 7 represents hydrogen or a Ci-C ⁇ alkyl optionally substituted by one or more R 8 ;
  • R 9 and R 10 each independently represent hydrogen, d-C 4 alkyl or C 3 -C 6 cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a A- to 6-membered saturated heterocycle optionally comprising an additional heteratom selected from oxygen, sulphur or nitrogen wherein each R 9 and R 10 independently may be optionally substituted on carbon by one or more substituents R 14 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 15 ;
  • R 11 and R 12 each independently represent hydrogen, Ci-C 4 alkyl or Cs-C ⁇ Cycloalkyl, or R 11 and R 12 together with the nitrogen atom to which they are attached form a A- to 6-membered saturated heterocycle optionally comprising an additional heteratom selected from oxygen, sulphur or nitrogen wherein each R 11 and R 12 independently may be optionally substituted on carbon by one or more substituents R 16 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 17 ;
  • R 13 represents Ci-C ⁇ alkyl or Cs-C ⁇ Cycloalkyl;
  • R 8 , R 14 and R 16 each independently is selected from halogen, Ci-C 3 alkyl, Ci-C 3 alkoxy, Cscycloalkyl, Ci-C 3 alkylthio, amino (-NH 2 ), mono- and di- Ci-C3alkylamino, cyano, hydroxyl and trifluoromethyl;
  • R 15 and R 17 each independently is selected from Ci-C ⁇ alkyl, benzyl, Ci-C ⁇ alkoxycarbonyl, Ci-C ⁇ alkylcarbonyl, phenylcarbonyl, Ci-C ⁇ alkylsulphonyl and phenylsulphonyl; and either when Q represents CR 5 , Q 1 represents N or CH; or when Q represents N, Q 1 represents CH, or a pharmaceutically acceptable salt thereof.
  • alkyl includes both straight and branched chain alkyl groups. References to individual straight chain alkyl groups such as “n-propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” or "/-propyl” are specific for the branched chain version only. Examples of "Ci.C ⁇ alkyl” include methyl, ethyl, n-propyl, /-propyl, butyl, /-butyl, t- butyl, n-pentyl, /-pentyl, neopentyl and hexyl.
  • Examples include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl and t-butyl.
  • examples of "Ci.C ⁇ alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, z ' -propoxycarbonyl, butoxycarbonyl, i- butoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl, z ' -pentoxycarbonyl, neopentoxycarbonyl and hexoxycarbonyl.
  • Examples of "Ci.C ⁇ alkoxy” include methoxy, ethoxy, n-propoxy, z-propoxy, n-butoxy, z ' -butoxy, t-butoxy, pentoxy, z ' -pentoxy, neopentoxy, hexoxy).
  • Examples of "Ci.Csalkoxy” include methoxy, ethoxy, n-propoxy and z ' -propoxy.
  • Ci-C ⁇ alkylthio examples include methylthio, ethylthio, n-propylthio, i- propylthio, n-butylthio, z ' -butylthio, t-butylthio, pentylthio, z ' -pentylthio, neopentylthio and hexylthio.
  • Examples of “Ci.C ⁇ alkylcarbonylamino” include formamido, acetamido and propionylamino.
  • Examples of "S(O) m Ci-C 6 alkyr, "S(O) x Ci.C 6 alkyl” and “S(O) y Ci.C 6 alkyl” wherein m is 0, 1 or 2 include Ci-C ⁇ alkylthio, Ci-C ⁇ alkylsulphinyl and Ci-C ⁇ alkylsulphonyl, for example methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
  • Ci.C ⁇ alkylcarbonyl examples include methylcarbonyl (acetyl), ethylcarbonyl (propionyl), propylcarbonyl, z ' -propylcarbonyl, butylcarbonyl, z ' -butylcarbonyl, t-butylcarbonyl, pentylcarbonyl, z ' -pentylcarbonyl, neopentylcarbonyl and hexylcarbonyl.
  • ⁇ -C ⁇ alkenyl examples include vinyl, allyl, 1-propenyl, butenyl and isobutenyl.
  • C 2 -C 6 alkynyl examples include acetylenyl and propargyl.
  • Examples of "mono- and di-Ci.C ⁇ alkylamino” include methylamino, ethylamino, n-propylamino, i- propylamino, n-butylamino, /-butylamino, t-butylamino, n-pentylamino, /-pentylamino, neopentylamino, hexylamino, dime thy lamino, diethylamino and ethylmethylamino.
  • substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
  • halo refers to fiuoro, chloro, bromo and iodo.
  • amino refers to a -NH 2 group.
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • heterocyclyl examples and suitable values of the term "heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, 7V-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-7V-oxide and quinoline-7V-oxide.
  • a "4- to 6-membered saturated heterocyclic group” is a saturated monocyclic ring containing 4, 5 or 6 atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH 2 - group can optionally be replaced by a -C(O)- and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • Suitable "4- to 6- membered heterocyclic group" which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur” include tetrahydrofuran, tetrahydrofuranone, gamma- butyrolactone, dioxolane, tetrahydropyran, dioxane, thiolan, dithiolan, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine S,S-dioxide, oxetane and azetidine.
  • a “Cs.C ⁇ Cycloalkyl” is a saturated monocyclic ring containing 3 or 6 atoms.
  • Examples of “Cs-C ⁇ Cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 3 represents a 3- to 5-membered saturated heterocyclyl group
  • examples of the 3- to 5-membered saturated heterocyclyl group include oxirane, aziridine, azetidine and pyrrolidine.
  • R 9 and R 10 , or R 11 and R 12 represent a saturated heterocycle
  • the heterocycle comprises only one heteroatom, the heteroatom present is the nitrogen atom to which R 9 and R 10 , or R 11 and R 12 are attached.
  • 4- to 6-membered saturated heterocycles include pyrrolidinyl, piperidinyl and morpholinyl.
  • E represents CH 2 .
  • R N1 represents hydrogen or a Ci-C 3 alkyl group (such as methyl, ethyl, n-propyl, or isopropyl). In a further aspect of the invention, R N1 represents hydrogen or methyl.
  • R N1 represents hydrogen
  • R 1 represents a -F, -CN, -OH, -OMe or a -CONHMe group. In one embodiment of the invention, R 1 represents a -F, -OH, -OMe or a -CONHMe group.
  • R 2 represents hydrogen or a Ci-C3alkyl group (such as methyl, ethyl, n-propyl, or isopropyl).
  • R 2 represents hydrogen or methyl. In a further aspect of the invention, R 2 represents hydrogen. In a further embodiment of the invention, R 3 represents hydrogen, -F or a -CONH 2 group.
  • R 4 hydrogen, a Ci-C ⁇ alkyl group; a C 3 -C 5 cycloalkyl; a Ci-C ⁇ alkoxy group.
  • R 4 represents hydrogen, methyl or methoxy.
  • R 4 represents hydrogen.
  • R 5 represents hydrogen or methoxy.
  • D represents CH 2 ;
  • R 1 represents -F, -CN, -OH, -OMe or a -CONHMe group
  • R 2 represents hydrogen
  • R 3 represents hydrogen, -F or a -CONH 2 group
  • R 4 represents hydrogen; and Q represents N or CR 5 where R 5 is hydrogen or -OMe, or a pharmaceutically acceptable salt thereof.
  • E represents CH 2 or O;
  • R N1 represents hydrogen;
  • R 1 represents -F, -OH, -OMe or a -CONHMe group;
  • R represents hydrogen
  • R 3 represents hydrogen, -F or a -CONH 2 group
  • R 4 represents hydrogen; and Q represents N or CR 5 where R 5 is hydrogen or -OMe, or a pharmaceutically acceptable salt thereof.
  • D represents CH 2 ;
  • E represents CH 2 ;
  • R N1 represents hydrogen
  • R 1 represents -F, -OH, -OMe or a -CONHMe group
  • R represents hydrogen
  • R 3 represents hydrogen, -F or a -CONH 2 group
  • R 4 represents hydrogen
  • Q represents N or CR 5 where R 5 is hydrogen or -OMe, or a pharmaceutically acceptable salt thereof.
  • E represents CH 2 ;
  • R N1 represents hydrogen
  • R 1 represents -OMe or a -CONHMe group
  • R 2 represents hydrogen
  • R 3 represents hydrogen, -F or a -CONH 2 group
  • R 4 represents hydrogen
  • Q represents CR 5 wherein when R 1 is -OMe, R 5 is hydrogen or -OMe, and when R 1 is -CONHMe, R 5 is hydrogen, or a pharmaceutically acceptable salt thereof.
  • D represents CH 2 ;
  • E represents CH 2 or O
  • R N1 represents hydrogen
  • R 1 represents -F, -CN, -OH, -OMe or a -CONHMe group
  • R 2 represents hydrogen or methyl
  • R 4 represents hydrogen
  • Q represents CR 5 where R 5 is hydrogen or -OMe; and either when R ,3a a represents hydrogen, R ,3b represents hydrogen or a -CONH 2 group; or when R 3a represents -F, R 3a represents hydrogen; or a pharmaceutically acceptable salt thereof.
  • D represents CH 2 ;
  • E represents CH 2 or O
  • R N1 represents hydrogen
  • R 1 represents -F, -OH, -OMe or a -CONHMe group
  • R 2 represents hydrogen
  • R 4 represents hydrogen
  • Q represents CR 5 where R 5 is hydrogen or -OMe; and either when R ,3a a represents hydrogen, R ,3b represents hydrogen or a -CONH 2 group; or when R >3a a . represents -F, R ,3a a represents hydrogen; or a pharmaceutically acceptable salt thereof.
  • D represents CH 2 ;
  • E represents CH 2 ;
  • R N1 represents hydrogen
  • R 1 represents -F, -OH, -OMe or a -CONHMe group
  • R 2 represents hydrogen
  • R 4 represents hydrogen; Q represents CR 5 where R 5 is hydrogen or -OMe; and either when R 3a represents hydrogen, R 3b represents hydrogen or a -CONH 2 group; or when R 3a represents -F, R 3a represents hydrogen; or a pharmaceutically acceptable salt thereof.
  • Examples of compounds of the invention include: N'-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-N-(pyridin-2- ylmethyl)pyrimidine-2,4-diamine;
  • the present invention further provides a process for the preparation of a compound of formula (I) as defined herinbefore above, or a pharmaceutically acceptable salt or solvate thereof, which comprises:
  • Step (i) may conveniently be carried out in a suitable solvent such as 2- methoxyethanol, 1-methylpyrrolidinone, butanol or dimethylacetamide at a temperature in the range from 90-200 0 C, optionally with microwave irradiation.
  • the reaction can be carried out in the presence or absence of a suitable acid or base for example an inorganic acid such as hydrochloric acid or sulphuric acid, or an organic acid such as acetic acid or formic acid (or a suitable Lewis acid) or an inorganic base such as sodium carbonate, or an organic base such as 7V,7V-diisopropylethylamine.
  • a suitable acid or base for example an inorganic acid such as hydrochloric acid or sulphuric acid, or an organic acid such as acetic acid or formic acid (or a suitable Lewis acid) or an inorganic base such as sodium carbonate, or an organic base such as 7V,7V-diisopropylethylamine.
  • Optional dehalogenation may conveniently be carried out in a suitable solvent such as ethanol in the presence of a suitable catalyst such as 5-20% palladium on carbon under an atmosphere of hydrogen.
  • a suitable solvent such as ethanol
  • a suitable catalyst such as 5-20% palladium on carbon under an atmosphere of hydrogen.
  • This reaction may conveniently be carried out in the presence of a suitable solvent such as ethanol, butanol, toluene or l-methylpyrrolid-2-one, optionally in the presence of a suitable acid or base for example an inorganic acid such as hydrochloric acid or sulphuric acid, or an organic acid such as acetic acid or formic acid (or a suitable Lewis acid) or an inorganic base such as sodium carbonate, or an organic base such as N,N- diisopropylethylamine and at a temperature in the range from 0 0 C to reflux.
  • a suitable solvent such as ethanol, butanol, toluene or l-methylpyrrolid-2-one
  • a suitable acid or base for example an inorganic acid such as hydrochloric acid or sulphuric acid, or an organic acid such as acetic acid or formic acid (or a suitable Lewis acid) or an inorganic base such as sodium carbonate, or an organic base such as N,N
  • Q 3 is hydrogen or a protecting group, such as an alkyl group or Boc group.
  • the reaction may be conveniently carried out in a solvent, such as ethanol, at temperature range of 60 to 80 0 C.
  • a solvent such as ethanol
  • compounds of formula (V) where E represents O may be prepared by reacting a compound of formula (IX)
  • Q 4 is hydrogen or a protecting group, such as an alkyl group or Boc group.
  • reaction may be conveniently carried out in a solvent, such as dichloromethane, at temperature range of 0 0 C to room temperature.
  • the reaction typically may be carried out in the presence of diisopropylazidocarboxylate and triphenylphosphine.
  • a process for the preparation of a compound of formula (I) as defined hereinbefore above, or a pharmaceutically acceptable salt or solvate thereof which comprises: reacting a compound of formula (XI),
  • the process may conveniently be carried out in a suitable solvent such as 1- methylpyrrolidinone or dimethylacetamide in the presence of a suitable acid such as hydrogen chloride in dioxane at a temperature in the range from 90 to 12O 0 C.
  • a suitable solvent such as 1- methylpyrrolidinone or dimethylacetamide
  • a suitable acid such as hydrogen chloride in dioxane at a temperature in the range from 90 to 12O 0 C.
  • Compounds of Formula (XI) may be prepared by (a) reacting a compound of formula (XII)
  • R is as defined hereinbefore for a compound of formula (I) and X represents a leaving group (e.g. halogen or sulfanyl such as methanesulfanyl or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy), with a compound of formula (III)
  • X represents a leaving group (e.g. halogen or sulfanyl such as methanesulfanyl or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy)
  • Step (a) may conveniently be carried out in a suitable solvent such as diglyme in the presence of a suitable base such as 7V,7V-diisopropylethylamine at a temperature in the range from 120 to 18O 0 C.
  • a suitable solvent such as diglyme
  • a suitable base such as 7V,7V-diisopropylethylamine
  • Step (b) may conveniently be carried out in a suitable solvent such as toluene with a suitable chlorinating agent such as phosphorus oxychloride in the presence of a suitable base such as 7V,7V-diisopropylethylamine at a temperature in the range from 60 to 100 0 C.
  • a suitable solvent such as toluene
  • a suitable chlorinating agent such as phosphorus oxychloride
  • a suitable base such as 7V,7V-diisopropylethylamine
  • A represents a leaving group (such as halogen or sulfanyl such as methanesulfanyl or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy) with a compound of formula (XV)
  • the reaction may conveniently be carried out in a suitable solvent such as 1- methylpyrrolidinone, dimethylacetamide or a compound of formula (XV) used as solvent in the presence of a suitable base such as 7V,7V-diisopropylethylamine or sodium hydride at a temperature in the range from 80 to 200 0 C, optionally with microwave irradiation.
  • a suitable solvent such as 1- methylpyrrolidinone, dimethylacetamide or a compound of formula (XV) used as solvent
  • a suitable base such as 7V,7V-diisopropylethylamine or sodium hydride at a temperature in the range from 80 to 200 0 C, optionally with microwave irradiation.
  • the compound of formula (XIV) may be obtained by:
  • XVI wherein X, Y and A each independently represents a leaving group (such as halogen or sulfanyl such as methanesulfanyl or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy), with a compound of formula (V),
  • Step (1) may conveniently be carried out in a suitable solvent such as ethanol in the presence of a suitable base such as sodium carbonate or 7V,7V-diisopropylethylamine at a temperature in the range from 0 to 25 0 C.
  • a suitable solvent such as ethanol
  • a suitable base such as sodium carbonate or 7V,7V-diisopropylethylamine
  • Step (2) may conveniently be carried out in a suitable solvent such as butanol, hexanol, 1-methylpyrrolidinone or dimethylacetamide in the presence of a suitable base such as 7V,7V-diisopropylethylamine at a temperature in the range from 80 to 12O 0 C.
  • a suitable solvent such as butanol, hexanol, 1-methylpyrrolidinone or dimethylacetamide
  • a suitable base such as 7V,7V-diisopropylethylamine at a temperature in the range from 80 to 12O 0 C.
  • OR >O1 is an alkyl ester (for example as outlined in Example 1) with acetonitrile.
  • the reaction may be conveniently carried out in a solvent, such as toluene, using sodium hydride as a base, at a temperature ranging from room temperature to 110 0 C.
  • a solvent such as toluene
  • sodium hydride as a base
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid; the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • reduction reactions include the reduction of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating or the reduction of a cyano group to an amino group by treatment with lithium aluminium hydride;
  • de-alkylation reactions include the conversion of a methoxy group to a hydroxyl by treatment with boron tribromide;
  • oxidation reactions include oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or/?-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or/?-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates.
  • Certain compounds of formula (I) are capable of existing in tatomeric forms. For example,
  • N'-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-N-(pyridin-2- ylmethyl)pyrimidine-2,4-diamine may also exist as the corresponding tautomer
  • the use of tautomers and mixtures thereof also form an aspect of the present invention.
  • the compounds of formula (I) have activity as pharmaceuticals, in particular as modulators or inhibitors of FGFR activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers:
  • carcinoma including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, thyroid and skin;
  • lymphoid lineage including acute lymphocytic leukaemia, B-cell lymphoma and Burketts lymphoma;
  • tumours of myeloid lineage including acute and chronic myelogenous leukaemias and promyelocytic leukaemia; (4) tumours of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and
  • tumours including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
  • the compounds of the invention are especially useful in the treatment of tumors of the breast and prostate.
  • the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt thereof, as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the invention also provides a method of treating cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined.
  • the invention still further provides a method of modulating FGFR activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined.
  • the compounds defined in the present invention are effective anti-cancer agents which property is believed to arise from their FGFR inhibitory properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by FGFR, i.e. the compounds may be used to produce a FGFR inhibitory effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention provide a method for treating cancer characterised by inhibition of FGFR, i.e. the compounds may be used to produce an anticancer effect mediated alone or in part by the inhibition of FGFR.
  • Such a compound of the invention is expected to possess a wide range of anticancer properties as activating mutations in FGFR have been observed in many human cancers, including but not limited to, melanoma, papillary thyroid tumours, cholangiocarcinomas, colon, ovarian and lung cancers. Thus it is expected that a compound of the invention will possess anti-cancer activity against these cancers. It is in addition expected that a compound of the present invention will possess activity against a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, breast and pancreas.
  • such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the breast and prostate. More particularly such compounds of the invention, or a pharmaceutically acceptable salt thereof, are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with FGFR, especially those tumours which are significantly dependent on FGFR for their growth and spread, including for example, certain tumours of the breast and prostate.
  • a method for producing a FGFR inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
  • a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
  • a method of treating melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein before.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a FGFR inhibitory effect in a warm-blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafiuoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • the compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p_-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
  • compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally-accep table diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
  • compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the size of the dose for therapeutic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a compound of the invention will be administered so that a daily dose in the range, for example, from 0.5 mg to 75 mg active ingredient per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, from 0.5 mg to 30 mg active ingredient per kg body weight will generally be used.
  • a dose in the range for example, from 0.5 mg to 25 mg active ingredient per kg body weight will generally be used.
  • Oral administration is however preferred.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active ingredient.
  • anti cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents :-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fiuorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin- C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblast
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, fiutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5* -reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6- chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5- tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2- methylpyrimidin-4-ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase);
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4- amine (gefitinib, ZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4- amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the plate
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6- methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97,
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669,
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy
  • immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiot
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of B-Raf in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • the alternative and preferred embodiments of the compounds of the invention described herein also apply. Examples
  • temperatures are given in degrees Celsius ( 0 C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
  • chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates;
  • NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz, in DMSOd 6 unless otherwise indicated;
  • DIPEA ⁇ /, ⁇ /-diisopropylethylamine/N-ethyl-N-propan-2-yl- propan-2-amine DCM dichloromethane
  • Acetonitrile (2.29mL, 43.61mmol, 1.2eq) was added to a slurry of sodium hydride (1.75g dispersion in mineral oil, 43.61mmol, 1.2eq) in anhydrous toluene (7OmL) and the mixture stirred at room temperature for 30 mins.
  • Ethyl 3-(3,5-dimethoxyphenyl)propanoate (8.66g, 36.34mmol, leq) in toluene (6OmL) was added and the reaction was refiuxed for 18h. After cooling, the reaction mixture was quenched with water and the solvent was evaporated under reduced pressure. The residue was dissolved in 2M HCl (5OmL).
  • the acidic solution was extracted with ethyl acetate.
  • the organic extracts were combined and washed with water, brine and dried over magnesium sulphate. After filtering, the solvent was evaporated under reduced pressure to yield the crude product as a yellow oil.
  • the oil was purified by silica column chromatography (eluting with DCM) and the desired fractions were combined and evaporated to yield a cream solid (3.76g, 44% yield).
  • To the cream solid (3.72g, 15.96mmol, leq) in ethanol (55mL) was added hydrazine hydrate (852 ⁇ l, 17.56mmol, l.leq). The reaction was refiuxed for 24h before allowing to cool.
  • the reaction was quenched with 1.0 N HCl (100 mL), extracted with diethyl ether (2 x 200 mL), dried and solvent removed in vacuo to yield a yellow gum.
  • the crude material and hydrazine (7.5mL, 154mmol, 3eq) were dissolved in ethanol (300 mL) and heated at reflux for 3 h.
  • the reaction was cooled and the solvent removed in vacuo to yield a viscous yellow gum.
  • To this was added water and the product was extracted with diethyl ether (3 x 200 mL), dried and the organic solvent removed in vacuo to yield light yellow gum.
  • Methyl 3-(3-methoxyphenyl)propanoate used as starting material was prepared as follows :-
  • l-(5-fluoropyridin-2-yl)ethanamine hydrochloride used as starting material can be prepared by the method described in the literature (Wang, Bin; Wang, Tao. 3-(Pyrazol-3- ylamino)pyrimidines as Trk A kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancers.WO2006123113).
  • 2,4-diamine Prepared using an analogous method to example 12, but starting with 5-[(3- fiuorophenyl)methoxy]-lH-pyrazol-3 -amine (97mg, 0.36mmol) to give the title compound (61mg, 40% yield).
  • 2-Chloro-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidin-4-amine used as starting material was prepared as follows:- 2,4-Dichloropyrimidine (2.65g, 17.79mmol, leq), 5-[2-(3-methoxyphenyl)ethyl]-2H- pyrazol-3 -amine (4.Og, 21.35mmol, 1.2eq) and N-ethyl-N-propan-2-yl-propan-2-amine (6.2mL, 35.58mmol, 2eq) were heated in ethanol (8OmL) at 5O 0 C for 5 days.
  • 6-(Aminomethyl)pyridine-2-carboxamide, used as starting material was prepared as follows :- 6-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]pyridine-2-carboxylic acid (7.825g, 31.OOmmol, 1.OOeq) was dissolved in N,N-dimethylacetamide (32OmL) and ammonium chloride (14.885 g, 372.00mmol, 12.0eq) added, followed by N-ethyl-N-propan-2-yl- propan-2-amine (43.12 mL, 248. OOmmol, 8.
  • tert-Butyl N-[(6-carbamoylpyridin-2-yl)methyl]carbamate (7.54g, 30.00mmol, l.OOeq) was placed in a 50OmL round bottomed flask and 2,2,2-trifluoroacetic acid (46.22mL, ⁇ OOmmol, 20.0eq) added. The solution became opaque quickly and after 5 minutes became a fine white suspension. Gas evolution and a slight exotherm (temperature rose to ⁇ 30°C) was noted. The suspension was stirred at room temperature for a further 10 mins. Ethyl acetate (25OmL) was added to give a clear solution.
  • N-Ethyl-N-propan-2-yl-propan-2-amine (0.555 mL, 3.21 mmol, 2eq) was added to 5-(2-(4- methoxypyridin-2-yl)ethyl)-lH-pyrazol-3 -amine (350mg, 1.60 mmol, leq) and 2,4- dichloropyrimidine (239 mg, 1.60 mmol, leq) in ethanol (5mL).
  • the resulting solution was stirred at 50 0 C for 4 days.
  • the reaction mixture was evaporated to dryness and redissolved in EtOAc (20 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL).
  • Acetonitrile (1.078 mL, 20.64 mmol, 1.3eq) was added dropwise to lithium diisopropylamide (10.32 mL, 20.64 mmol, 1.3eq) in THF (10OmL) at -78 0 C over a period of 5 mins under nitrogen. The resulting solution was stirred at -78 0 C for 10 mins.
  • Methyl 3-(4-methoxypyridin-2-yl)propanoate (3.1g, 15.88 mmol, leq) was added in one portion and the reaction was stirred for 30 mins before being allowed to warm to ambient temperature.
  • Methyl 3-(4-methoxypyridin-2-yl)propanoate used as starting material was prepared as follows :- Methyl 3-(4-methoxypyridin-2-yl)prop-2-enoate (3.1g, 16.05 mmol, leq) and palladium on charcoal (310mg, 0.29 mmol, O.leq) in ethanol (20OmL) were stirred under an atmosphere of hydrogen at ambient temperature for 24 h. The reaction mixture was filtered through celite. The mixture was evaporated to dryness and the residue was azeotroped with Et 2 O to afford desired methyl 3-(4-methoxypyridin-2-yl)propanoate (3.04 g, 15.56 mmol, 97 %).
  • Methyl 3-(4-methoxypyridin-2-yl)prop-2-enoate used as starting material was prepared as follows :- Methyl 2-triphenylphosphoranylideneacetate (11.34 g, 33.91 mmol, 1.5eq) was added portionwise to 4-methoxypyridine-2-carbaldehyde (3.1g, 22.61 mmol, leq) in DCM (10OmL) at 2O 0 C over a period of 5 mins. The resulting solution was stirred at 20 0 C for 18 h. The resulting mixture was evaporated to dryness and the crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane.
  • Methyl 3-(3-cyanophenyl)propanoate used as starting material, was prepared as follows:- To a solution of methyl (E)-3-(3-cyanophenyl)prop-2-enoate (12.36g, 66.00mmol) dissolved in DMF (25OmL), was added platinum catalyst (1.24g) and the reaction mixture was stirred under hydrogen overnight. The mixture was filtered through celite, washed with DMF, then evaporated to dryness to give a grey-brown liquid.
  • kinase assays were conducted using ELISA (Enzyme-Linked Immunosorbent Assay) technology. Kinase activity assays were performed in 384-well polypropylene plates (Matrix, 4311) with a total volume of 40 ⁇ l in each well. Each well was coated with 2 ⁇ g of polyEAY substrate (Sigma, P3899) at 4°C overnight. The plates were then washed once with lOO ⁇ l PBS and once with lOO ⁇ l 5OmM HEPES (pH 7.4) prior to the addition of the kinase assay reagents.
  • ELISA Enzyme-Linked Immunosorbent Assay
  • Each kinase reaction contained 0.1 ng His 6 -tagged FGFR kinase domain (FGFR kinase domain (amino acids 458-765, C488A, C584S) N-terminally fused to a His6-tag and TEV cleavage site encoded by the following sequence; [MHHHHHHEFKGSTSLYKKAGSSENLYFQGA].
  • the final alanine denotes the start of the FGFR protein sequence.
  • the resultant protein was expressed and purified based on Mohammadi et al, Cell VoI 86, 577-587 (1996)), 5OmM HEPES (pH 7.4), O.lmM Na 3 VO 4 , O.lmM DTT, 0.05% (v/v) Triton XlOO, 2OmM MgCl 2 , 160 ⁇ M ATP.
  • Various concentrations of test compounds were each added in 5% (v/v) DMSO to yield a final assay DMSO concentration of 1.25% (v/v).
  • the kinase reactions were incubated at room temperature for 45 minutes and stopped by washing the plate three times with lOO ⁇ l PBS plus 0.05% Tween.
  • Data may also be presented as a Percentage inhibition at IuM, this is a calculated value based on the curve fit that was generated experimentally. From the fitted curve plot, the effect of compound at a concentration of IuM was calculated as a percentage inhibition. A percentage inhibition calculated in this way from the shape of the curve is considered to be statistically more accurate compared to a single raw data value measured at a single concentration.
  • kinase assays were conducted using Caliper technology.
  • kinase activity assays were performed in Greiner 384-well low volume plates, with a total reaction volume of 12ul per well. Final concentration of FGFRl active kinase in each reaction well was 7.2nM.
  • the substrate for each assay was a custom peptide with fluorescent tag (13 amino acids in length, 5FAM-KKSRGDYMTMQIG-CONH 2 ) the sequence of which was specific for FGFRl kinase.
  • Inhibition may also be expressed as Percentage inhibition at IuM, which is a calculated value based on the curve fit that was generated experimentally. From the fitted curve plot, the effect of compound at a concentration of IuM was calculated as a percentage inhibition. A percentage inhibition calculated in this way from the shape of the curve is considered to be statistically more accurate compared to a single raw data value measured at a single concentration.
  • inhibition activity of the other family members may also be evaluated, for example FGFR4 inhibition activity may be measured as follows:-
  • kinase assays were conducted using Caliper technology.
  • kinase activity assays were performed in Greiner 384-well low volume plates, with a total reaction volume of 12ul per well. Final concentration of FGFR4 active kinase in each reaction well was 25nM.
  • the substrate for each assay was a custom peptide with fluorescent tag (13 amino acids in length, 5FAM-EEPLYWSFPAKKK-CONH 2 ) the sequence of which was specific for FGFR4 kinase.
  • Percentage inhibition at IuM is a calculated value based on the curve fit that was generated experimentally. From the fitted curve plot, the effect of compound at a concentration of IuM was calculated as a percentage inhibition. A percentage inhibition calculated in this way from the shape of the curve is considered to be statistically more accurate compared to a single raw data value measured at a single concentration.
  • Selective inhibition of the FGFR family members or inhibition of one or more FGFR family members may offer advantage in producing an anti-cancer effect mediated alone or in part by the inhibition of one or more FGFR's.
  • Trk A kinase activity was determined by measuring the kinase's ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA).
  • Trk A kinase activity To measure Trk A kinase activity, the intracellular domain of a HIS-tagged human Trk A kinase (amino acids 442-796 of Trk A, Swiss-Prot Primary Accession Number P04629) was expressed in SF9 cells and purified using standard nickel column chromatography. After incubation of the kinase with a biotinylated substrate and adenosine triphosphate (ATP) for 60 minutes at room temperature, the kinase reaction was stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • reaction was performed in 384 well low volume microtitre plates and the reaction products were detected with the addition of streptavidin coated Donor Beads and phosphotyrosine-specific antibodies coated Acceptor Beads using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature.
  • TRK receptor isoforms are widely expressed in neuronal tissue during development. Compounds which display selectivity for FGFR over TRK may be desirable as they may show lessoned effects on certain tissues. This may amelerioate the potential for toxicity risks and may deliver therapeutic margin benefits.
  • This assay is designed to detect inhibitors of transiently expressed FGFRl phosphorylation by antibody staining of fixed cells detected using ArrayScan technology.
  • Cos-1 cells were routinely passaged in DMEM (Gibco BRL, 41966) plus 3% foetal calf serum (FCS), 1% L-glutamine (Gibco BRL, 25030) to a confluence of 80%. To undertake the assay, Cos-1 cells were harvested at 90-95% confluence for cell transfection.
  • the harvested Cos-1 cells are counted using a coulter counter and diluted further with 1% FCS/DMEM to 2.5 x 10 5 cells/mL. For each 96-well, 8.33mL cells were required.
  • the complexed transfection solution was added to the cell solution and the cells were seeded at 2.5xlO 5 cells/ well in DMEM plus 1% foetal calf serum, 1% L-glutamine in 96 well plates (Costar, 3904) and incubated at 37°C (+5% CO 2 ) in a humidified incubator overnight (24hrs).
  • the plates were dosed with 25 ul compound (diluted from 10 mM stock in DMSO using serum free DMEM) and the plates were returned to a humidified 37°C (+5% CO 2 ) incubator for one hour.
  • Media was removed from the wells using vacuum aspiration; cells were fixed by adding 50ul of 100% methanol to each well and incubated at room temperature for 20 minutes.
  • the fixative solution was then removed and the wells were washed once with 200ul phosphate buffered saline (PBS/A) before permeabilising the cells by the addition of 50ul/ well 0.1% triton/ PBS/A for 20 minutes at room temperature.
  • PBS/A 200ul phosphate buffered saline
  • the permeabilisation solution was then removed and the cells washed once more with 200ul / well PBS/A before the addition of 40ul 1/1000 primary antibody solution (Cell Signalling Technologies #CS3476; mouse anti-phospho FGFRl diluted in PBS/A with 10% FCS + 0.1% Tween20) to each well.
  • 40ul 1/1000 primary antibody solution Cell Signalling Technologies #CS3476; mouse anti-phospho FGFRl diluted in PBS/A with 10% FCS + 0.1% Tween20
  • the Channel 2 (594nm) values obtained from undosed (max) and reference compound (min) wells within a plate are used to set boundaries for 0% and 100% compound inhibition. Compound data is normalized against these values to determine the dilution range of a test compound that gives 50% inhibition of phosphorylated FGFRl .
  • NIH 3T3 ECACC, 93061524 cells were routinely passaged in DMEM (Gibco).
  • NIH 3T3's were seeded at IxIO 4 cells/ well in DMEM plus 10% foetal calf serum, 1% L-glutamine in 96 well plates (Costar, 3904) and incubated at 37°C (+5% CO 2 ) in a humidified incubator. Once the cells had fully adhered (typically following 4-5 hours incubation) the media was removed from each well and the cells gently washed with lOO ⁇ l warm serum free media.
  • NIH 3T3 cells were then stimulated with a final concentration of 3 ng/mL bFGF (Sigma, F0291) for 20 minutes at 37°C. Following stimulation the cells were fixed by adding formaldehyde (4% v/v final concentration) and incubating at room temperature for 20 minutes.
  • the fixative solution was then removed and the wells were washed twice with lOO ⁇ l phosphate buffered saline (PBS/ A) before permeabilising the cells by the addition of 50 ⁇ l/ well 0.1% triton/ PBS/A for 10 minutes at room temperature.
  • the permeabilisation solution was then removed and the cells washed twice more with lOO ⁇ l/ well PBS/A before the addition of 50 ⁇ l/ well anti-phospho p44/42 (Cell Signalling Technology, 9106), diluted 1/500 with PBS/A plus 10% FCS.
  • the anti-phospho p44/42 antibody recognises Erk phosphorylated at threonine 202 and tyrosine 204.
  • IC50 value is the concentration of test compound that inhibits 50% of Erk phosphorylation.
  • This assay is designed to detect inhibitors of transiently expressed FGFRl phosphorylation by antibody staining of fixed cells detected using ArrayScan technology.
  • Cos-1 cells were routinely passaged in DMEM (Gibco BRL, 41966) plus 3% foetal calf serum (FCS), 1% L-glutamine (Gibco BRL, 25030) to a confluence of 80%.
  • FCS foetal calf serum
  • L-glutamine Gibco BRL, 25030
  • the complexed transfection solution was added to the cell solution and the cells were seeded at 2.5xlO 5 cells/ well in DMEM plus 1% foetal calf serum, 1% L-glutamine in 96 well plates (Costar, 3904) and incubated at 37°C (+5% CO 2 ) in a humidified incubator overnight (24hrs).
  • the plates were gently tapped to mix compound in with the cell media and left to incubate at 37 0 C with 5% CO 2 for 1 hour.
  • the Channel 2 (594nm) values obtained from undosed (max) and reference compound (min) wells within a plate are used to set boundaries for 0% and 100% compound inhibition. Compound data was normalized against these values to determine the dilution range of a test compound that gives 50% inhibition of phosphorylated FGFRl .

Abstract

La présente invention concerne des composés de pyrimidine de formule 1 : ou leurs sels pharmaceutiques. L'invention a également pour objet des procédés pour leur préparation, des compositions pharmaceutiques les renfermant, un procédé de préparation des compositions pharmaceutiques et leur utilisation en thérapie, par exemple dans le traitement de maladies prolifératives telles que le cancer et particulièrement de maladies médiées par un effet inhibiteur du FGFR.
PCT/GB2008/051018 2007-11-01 2008-10-30 Dérivés de pyrimidine et leur utilisation en tant que modulateurs de l'activité du fgfr WO2009056886A1 (fr)

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WO2012061337A1 (fr) * 2010-11-02 2012-05-10 Exelixis, Inc. Modulateurs de fgfr2
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US9951047B2 (en) 2014-08-18 2018-04-24 Eisai R&D Management Co., Ltd. Salt of monocyclic pyridine derivative and crystal thereof
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