WO2009019518A1 - Composés de pyrimidine ayant un effet inhibiteur du fgfr - Google Patents

Composés de pyrimidine ayant un effet inhibiteur du fgfr Download PDF

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WO2009019518A1
WO2009019518A1 PCT/GB2008/050673 GB2008050673W WO2009019518A1 WO 2009019518 A1 WO2009019518 A1 WO 2009019518A1 GB 2008050673 W GB2008050673 W GB 2008050673W WO 2009019518 A1 WO2009019518 A1 WO 2009019518A1
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group
optionally substituted
compound
alkyl
pharmaceutically acceptable
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PCT/GB2008/050673
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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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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 compounds, 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.
  • 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. al., Cytokine & Growth Factor Reviews 2005, 16, pl39-149). Consequently, 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. et. al., Cytokine & Growth Factor Reviews 2005, 16, pl79-186 and Kwabi-Addo, B. et.
  • 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.
  • R 1 represents a Ci-C ⁇ alkyl optionally substituted by one or more R 13 , a C 3 -C 5 cycloalkyl optionally substituted by one or more R 14 , a C 2 -C 6 alkenyl optionally substituted by one or more R 15 , a 4- to 6-membered heterocyclyl group optionally substituted by one or more R , 1 1 6 a Ci-C ⁇ alkoxy group optionally substituted by one or more R , 1 1 7 a C3-Ci2carbocyclyloxy group optionally substituted by one or more
  • R 18 a 5- to 6-membered heterocyclyloxy group optionally substituted by one or more R 19 , a -S(O) x R 5 group, a -S(O) 2 NR 6 R 7 group, or
  • R 2 represents hydrogen or a Ci-C ⁇ alkyl group optionally substituted by one or more substituents selected from Ci-C ⁇ alkoxy, cyano, hydroxyl, amino (-NH 2 ), mono-Ci-C3alkyamino and di-(Ci-C3alky)amino;
  • R 4 represents hydrogen, a Ci-C ⁇ alkyl group optionally substituted with Ci-C ⁇ alkoxy, hydroxyl, amino (-NH 2 ), mono-Ci-C3alkyamino and di-(Ci-C3alky)amino, a Ci-C ⁇ alkenyl group optionally substituted with Ci-C 3 alkoxy, a Ci-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
  • A represents a C 2 -alkylene optionally substituted by one or more R 20 , a Ci-alkyleneoxy optionally substituted by one or more R 21 , or a oxyCi-alkylene optionally substituted by one or more R 22 ;
  • B represents a 5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the aromatic ring being optionally substituted by one or more R 23 and optionally wherein two or more adjacent R 23 together with the atoms to which they are attached form a partially or fully unsaturated 4- to 6-membered ring;
  • R 5 represents a Ci-C ⁇ alkyl, C 3 -Cecycloalkyl or -CH 2 Ar wherein Ar represents a 5- or
  • 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the aromatic ring being optionally substituted by one or more R 24 and optionally wherein two or more adjacent R 24 together with the atoms to which they are attached form a partially or fully unsaturated 4- to 6-membered ring; -A-
  • R 6 and R 7 each independently represent hydrogen, Ci-C 4 alkyl or C ⁇ -Cecycloalkyl, or R 6 and R 7 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 6 and R 7 independently may be optionally substituted on carbon by one or more substituents R 25 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 26 ;
  • R 8 and R 9 each independently represent hydrogen, Ci-C 4 alkyl or C ⁇ -Cecycloalkyl, or R 8 and R 9 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 8 and R 9 independently may be optionally substituted on carbon by one or more substituents R 27 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 28 ; R 10 and R 11 each independently represent hydrogen, Ci-C 4 alkyl or C ⁇ -Cecycloalkyl, or
  • R 10 and R 11 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 10 and R 11 independently may be optionally substituted on carbon by one or more substituents R 29 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 30 ;
  • R 12 represents Ci-C ⁇ alkyl or C ⁇ -Cecycloalkyl;
  • R 13 , R 14 , R 15 , R 20 , R 21 , R 22 , R 36 and R 38 each independently is -NR 32 R 33 , -C(O)NR 34 R 35 , cyano, hydroxyl or a group selected from d-C 6 alkyl, d-C 6 alkoxy, C3-C6cycloalkyl, Ci-C ⁇ alkylthio wherein said group may be optionally substituted by one or more R 31 ;
  • R 16 and R 17 each independently is selected from R 36 and a 5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, wherein the aromatic ring is optionally substituted by one or more substituents selected from R 37 ;
  • R 18 , R 19 , R 37 and R 42 each independently is R 38 , -SO 2 NR 39 R 40 , nitro, carboxyl or a group selected from a C 2 -Cealkenyl, Ci-C ⁇ alkoxycarbonyl, Ci-C ⁇ alkylcarbonyl, Ci-Cealkylcarbonylamino, phenylcarbonyl, -S(O) m Ci-C 6 alkyl wherein said group may be optionally substituted by one or more R 41 ;
  • R 23 and R 24 each independently is R 42 , -OS(O) 2 Ci-C 6 alkyl or a group selected from phenyl, benzyl, benzyloxy wherein said group may be optionally substituted by one or more R 43 ;
  • R 25 , R 27 , R 29 , R 31 , R 41 , R 43 , R 44 , R 46 and R 48 each independently is selected from halogen, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, amino (-NH 2 ), mono- and di- Ci-Cealkyamino, cyano, hydroxyl and trifluoromethyl;
  • R 26 , R 28 , R 30 , R 45 , R 47 and R 49 each independently is selected from Ci-C 6 alkyl, benzyl, Ci-C ⁇ alkoxycarbonyl, Ci-C ⁇ alkylcarbonyl, phenylcarbonyl,
  • R 32 and R 33 each independently represent hydrogen, Ci-C 4 alkyl or C ⁇ -Cecycloalkyl, or R 32 and R 33 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 32 and R 33 independently may be optionally substituted on carbon by one or more substituents R 44 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 45 ; R 34 and R 35 each independently represent hydrogen, Ci-C 4 alkyl or C ⁇ -Cecycloalkyl, or R 34 and R 35 together with the nitrogen atom to which they are attached form a 4- to
  • each R 34 and R 35 independently may be optionally substituted on carbon by one or more R 46 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 47 ;
  • R 39 and R 40 each independently represent hydrogen, Ci-C 4 alkyl or C ⁇ -Cecycloalkyl, or R 39 and R 40 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 39 and R 40 independently may be optionally substituted on carbon by one or more R 48 and wherein if said heterocycle contains an -NH- moiety that nitrogen may be optionally substited by a group selected from R 49 ; m is 0, 1 or 2; x is 0, 1 or 2; y is 0, 1 or 2; and wherein (i) when R 1 is an optionally substituted C 2 -C6alkenyl, 4- to 6-membered heterocyclyl group, Ci-C ⁇ alkoxy group, 5- to 6-membered heterocyclyloxy, -S(O) x R 5 , -S(O) 2 NR 6 R 7 or -A-B group,
  • R 3 represents a Ci-Csalkyl group optionally substituted by one or more substituents selected from d-C 3 alkoxy, cyano, hydroxyl, amino (-NH 2 ), mono-Ci-C3alkylamino and di-(Ci-C3alkyl)amino, a C 3 -C 5 cycloalkyl group optionally substituted by one or more substituents selected from Ci-C3alkyl and Ci-C3alkoxy, a 3- to 5-membered saturated heterocyclyl group optionally substituted with by one or more substituents selected from Ci-C3alkyl, Ci-C3alkoxy and C3Cycloalkyl, a 5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, a mono-Ci-C 3 alkylaminocarbonyl group, a di-(Ci-C 3 alkyl)aminocarbonyl group, a Ci-
  • R 3 represents a d-C 5 alkyl group optionally substituted by one or more substituents selected from Ci-C3alkoxy, cyano, hydroxyl, amino (-NH 2 ), mono-Ci-C3alkylamino and di-(Ci-C3alkyl)amino, a C 3 -C 5 cycloalkyl group optionally substituted with Ci-C 3 alkoxy, a 3- to 5-membered saturated heterocyclyl group optionally substituted with by one or more substituents selected from Ci-C 3 alkyl, Ci-C3alkoxy and C3Cycloalkyl, a -CONH 2 group, a -CO 2 H group; 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.Cealkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, /-propoxycarbonyl, butoxycarbonyl, /-butoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl, /-pentoxycarbonyl, neopentoxycarbonyl and hexoxycarbonyl.
  • Examples of "Ci-C ⁇ alkoxy” include methoxy, ethoxy, n-propoxy, /-propoxy, n-butoxy, /-butoxy, t-butoxy, pentoxy, /-pentoxy, neopentoxy, hexoxy).
  • Examples of "Ci.C ⁇ alkoxy” include methoxy, ethoxy, n-propoxy and /-propoxy.
  • Example of "Ci-C ⁇ alkylthio” include methylthio, ethylthio, n-propylthio, /-propylthio, n-butylthio, /-butylthio, t-butylthio, pentylthio,
  • Ci.Cealkylcarbonylamino include formamido, acetamido and propionylamino.
  • S(O) m Ci.C6alkyl examples include Ci-Cealkylthio, Ci-C ⁇ alkylsulphinyl and Ci-C ⁇ alkylsulphonyl, for example methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
  • Ci-Cealkylthio Ci-C ⁇ alkylsulphinyl
  • Ci-C ⁇ alkylsulphonyl for example methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
  • Ci.Cealkylcarbonyl include methylcarbonyl (acetyl), ethylcarbonyl (propionyl), propylcarbonyl, /-propylcarbonyl, butylcarbonyl, /-butylcarbonyl, t-butylcarbonyl, pentylcarbonyl, /-pentylcarbonyl, neopentylcarbonyl and hexylcarbonyl.
  • Examples of "C 2 -C 6 alkenyl” include vinyl, allyl, 1-propenyl, butenyl and isobutenyl.
  • Examples of "Ci-C ⁇ alkynyl” include acetylenyl and propargyl. Examples of "mono- and di-
  • Ci.Cealkylamino include methylamino, ethylamino, n-propylamino, /-propylamino, n-butylamino, /-butylamino, t-butylamino, n-pentylamino, /-pentylamino, neopentylamino, hexylamino, dimethylamino, 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 fluoro, 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 heterocyclic group” is a saturated, partially saturated or unsaturated, 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, g ⁇ mm ⁇ -butyrolactone, alpha-pyran, g ⁇ mm ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolan, dithiolan, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, thiomorpholine S,S-dioxide, diazepan, oxazine, tetrahydro-oxazinyl, is
  • a "5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur” is a fully unsaturated, aromatic monocyclic ring containing 5 or 6 atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which may, unless otherwise specified, be carbon or nitrogen linked.
  • Suitable "5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur” include furyl, imidazolyl, isothiazolyl, isoxazolyl, oxaxolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl and triazolyl rings.
  • a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH 2 - group can optionally be replaced by a
  • Carbocyclyl is a monocyclic ring containing 3 to 6 atoms or a bicyclic ring containing 9 or 10 atoms.
  • Examples of “carbocyclyl” include cycloalkyl and aryl rings.
  • Carbocyclyl include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or
  • a "C 3 .C 6 Cycloalkyl” is a saturated monocyclic ring containing 3 or 6 atoms.
  • Examples of “C 3 -C 6 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • a "C3-Ci2carbocyclyloxy group” and “5- to 6-membered heterocyclyloxy” denotes an
  • R is either a 3- to 10-membered carbocyclyl group or a 5- to 6-membered heterocyclyl group as defined above.
  • a "C ⁇ aryloxy group” and "5- to 6-membered heteroaryloxy” denotes an -OR group wherein R is a 6-membered aromatic ring, for example phenyl, or a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur for example furyl, imidazolyl, isothiazolyl, isoxazolyl, oxaxolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl or triazolyl.
  • R is a 6-membered aromatic ring, for example phenyl, or a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur for example furyl, imidazolyl, isothiazo
  • C2-alkylene denotes a two carbon saturated linking group.
  • an unsubstituted C2-alkylene group is a -CH 2 CH 2 - linking group.
  • a "Ci-alkyleneoxy” denotes a two atom saturated linking group comprising one carbon and one oxygen atom.
  • an unsubstituted Q-alkyleneoxy group is a
  • Ci-alkylene denotes a two atom saturated linking group comprising one carbon and one oxygen atom.
  • an unsubstituted Ci-alkyleneoxy group is a -OCH 2 - linking group (and for example the group -A-B is -OCH 2 -B).
  • B represents a 5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least two adjacent substituents and wherein the two or more adjacent substituents together with the atoms to which they are attached form a partially or fully unsaturated 4- to 6-membered ring
  • examples of B include indole, indoline, benzothiophen, benzofuran, benzimidazole and benzodioxole.
  • 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 6 and R 7 , or R 8 and R 9 , or R 10 and R 11 , or R 32 and R 33 , or R 34 and R 35 , or R 39 and R 40 represent a saturated heterocycle
  • the heterocycle comprises only one heteroatom
  • the heteroatom present is the nitrogen atom to which R 6 and R 7 , or R 8 and R 9 , or R 10 and R 11 , or R 32 and R 33 , or R 34 and R 35 , or R 39 and R 40 are attached.
  • 4- to 6-membered saturated heterocycles include pyrrolidinyl, piperidinyl and morpholinyl.
  • Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
  • R 1 represents a Ci-C ⁇ alkoxy group optionally substituted by one or more R 17 ; a C3-Ci2carbocyclyloxy group optionally substituted by one or more
  • R 18 or a 5- to 6-membered heterocyclyloxy group optionally substituted by one or more R 19 .
  • R 1 represents a Ci-C ⁇ alkoxy group optionally substituted by one or more R 17 ; a C ⁇ aryloxy group optionally substituted by one or more R 18 ; or a 5- to 6-membered heteroaryloxy group optionally substituted by one or more R 19 .
  • R 1 represents a Ci-C ⁇ alkoxy group optionally substituted by one or more substituents selected from Ci-C 6 alkoxy.
  • R 1 represents a Ci-C ⁇ alkoxy group.
  • R 1 represents a Ci-C ⁇ alkoxy group. In another embodiment of the invention, R 1 represents a z ' -propoxy group. In another embodiment of the invention, R 1 represents a a Ci-C ⁇ alkyl optionally substituted by one or more R 13 .
  • R 1 represents a Ci-C ⁇ alkyl group substituted by one or more substituents selected from Ci-C ⁇ alkoxy (which may be optionally substituted by one or more substituents selected from halogen, d-C ⁇ alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, amino (-NH 2 ), mono- and di-Ci-C ⁇ alkylamino, cyano, hydroxyl and trifiuoromethyl) and hydroxyl.
  • Ci-C ⁇ alkoxy which may be optionally substituted by one or more substituents selected from halogen, d-C ⁇ alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, amino (-NH 2 ), mono- and di-Ci-C ⁇ alkylamino, cyano, hydroxyl and trifiuoromethyl
  • R 1 represents a C 3 -CsCyC loalkyl optionally substituted by one or more R 14 .
  • R 1 represents a 4- to 6-membered heterocyclyl group optionally substituted by one or more R 16 .
  • R 1 represents -A-B wherein
  • A represents a C2-alkylene optionally substituted by one or more R 20 , a Ci-alkyleneoxy optionally substituted by one or more R 21 , or a oxyCi-alkylene optionally substituted by one or more R 22 ;
  • B represents a 5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the aromatic ring being optionally substituted by one or more R 23 and optionally wherein two or more adjacent R 23 together with the atoms to which they are attached form a partially or fully unsaturated 4- to
  • R 1 represents -A-B wherein A represents a C2-alkylene optionally substituted by one or more R 20 , or a oxyCi-alkylene optionally substituted by one or more R 22 ; and B represents a 5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the aromatic ring being optionally substituted by one or more R 23 and optionally wherein two or more adjacent R 23 together with the atoms to which they are attached form a partially or fully unsaturated 4- to 6-membered ring.
  • R 1 represents -A-B wherein A represents a C2-alkylene optionally substituted by one or more R 20 , or a oxyCi-alkylene optionally substituted by one or more R 22 ; and B represents a phenyl ring or a pyridin-4-yl ring each optionally substituted by one or more R 23 and optionally wherein two or more adjacent R 23 together with the atoms to which they are attached form a partially or fully unsaturated 4- to 6-membered ring.
  • R 1 represents -A-B wherein A represents a C2-alkylene optionally substituted by one or more R 20 , or a oxyCi-alkylene optionally substituted by one or more R 22 ; and B represents a phenyl ring optionally substituted by one or more R 23 and optionally wherein two or more adjacent R 23 together with the atoms to which they are attached form a partially or fully unsaturated 4- to 6-membered ring.
  • R 1 represents -A-B wherein A represents a C2-alkylene optionally substituted by one or more R 20 ; and B represents a phenyl ring or a pyridin-4-yl ring each optionally substituted by one or more R 23 and optionally wherein two or more adjacent R 23 together with the atoms to which they are attached form a partially or fully unsaturated 4- to 6-membered ring.
  • R 1 represents -A-B wherein A represents an oxyCi-alkylene optionally substituted by one or more R 22 ;
  • R 1 represents -A-B wherein
  • A represents a -CH 2 CH 2 - or a -OCH 2 -;
  • B represents a phenyl ring or a pyridin-4-yl ring each optionally substituted by one or more R 23 and optionally wherein two or more adjacent R 23 together with the atoms to which they are attached form a partially or fully unsaturated 4- to 6-membered ring.
  • R 1 represents -A-B wherein A represents a -CH 2 CH 2 - or a -OCH 2 -; and B represents a phenyl ring optionally substituted by one or more substituents selected from d-C 6 alkyl, d-C 6 alkoxy, Ci-C 6 alkoxycarbonyl, Ci-Cealkylcarbonylamino, phenyl, -NR 32 R 33 , -C(O)NR 34 R 35 , (each of which may be optionally substituted by one or more substituents selected from halogen, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, amino (-NH 2 ), mono- and di-Ci-C ⁇ alkylamino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, carboxyl and hydroxyl, and optionally wherein two or more adjacent substituents together with the atoms to which they are attached form a partially or fully unsaturated 4-
  • A represents a -CH 2 CH 2 - or a -OCH 2 -;
  • B represents a phenyl ring or a pyridin-4-yl ring each optionally substituted by one or more substituents selected from Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkoxycarbonyl, Ci-Cealkylcarbonylamino, phenyl, -NR 32 R 33 , -C(O)NR 34 R 35 , (each of which may be optionally substituted by one or more substituents selected from halogen, d-C 6 alkyl, d-C 6 alkoxy, amino (-NH 2 ), mono- and di-Ci-C ⁇ alkylamino, hydroxyl and trifluoromethyl), halogen, cyano, carboxyl and hydroxyl, and optionally wherein two or more adjacent substituents together with the atoms to which they are attached form a partially or fully unsaturated
  • R 32 and R 33 each independently represent hydrogen, C 1 -C 4 , particularly Ci-C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-buty ⁇ ) or C ⁇ -Cecycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 61 and R 62 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl, morpholiny or piperidinyl); and
  • R 34 and R 35 each independently represent hydrogen, C 1 -C 4 , particularly Ci-C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-buty ⁇ ) or C ⁇ -Cecycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 63 and R 64 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl, morpholiny or piperidinyl).
  • Ci-C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-buty ⁇
  • C ⁇ -Cecycloalkyl cyclopropyl, cyclobutyl, cyclopentyl and cyclohe
  • R 1 represents -A-B wherein A represents a -CH 2 CH 2 - or a -OCH 2 -; and B represents a phenyl ring or a pyridin-4-yl ring each optionally substituted by one or more substituents selected from d-C ⁇ alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkoxycarbonyl, Ci-Coalkylcarbonylamino, phenyl, -NR 32 R 33 , -C(O)NR 34 R 35 , (each of which may be optionally substituted by one or more substituents selected from halogen, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, amino (-NH 2 ), mono- and di-Ci-C ⁇ alkylamino, hydroxyl and trifluoromethyl), halogen, cyano, carboxyl and hydroxyl; and wherein R 32 and R 33 each independently represent hydrogen, C 1 -C 4 , particularly
  • R 63 and R 64 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl, morpholiny or piperidinyl).
  • R 1 represents a Ci-C ⁇ alkyl group substituted by one or more substituents selected from hydroxyl and Ci-C ⁇ alkoxy which may be optionally substituted by one or more substituents selected from halogen, Ci-C ⁇ alkyl and Ci-C ⁇ alkoxy, a Ci-C ⁇ alkoxy group optionally substituted by one or more substituents selected from Ci-C ⁇ alkoxy and cyclopropyl, a phenyloxy group optionally substituted by one or more substituents selected from Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy and cyclopropyl, or -A-B wherein A represents a C2-alkylene or oxyCi-alkylene, and B represents a phenyl or pyridin-4yl ring wherein the phenyl or the pyridin-4yl ring may be optionally substituted by one or more R 23 .
  • R 1 represents a hydroxymethyl, methoxypropyl, ethoxypropyl, phenylethyl, 2-(3-methoxyphenyl)ethyl,
  • R 1 represents a 2-(3-methoxyphenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, z ' -propoxy, (3,5-dimethoxyphenyl)methoxy, 2-(3-hydroxyphenyl)ethyl, or a (3-fluorophenyl)methoxy group.
  • R 2 represents hydrogen or a Ci-C ⁇ alkyl 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 a Ci-Csalkyl group; a
  • R 3 represents a Ci-Csalkyl group; a C 3 -C 5 cycloalkyl group.
  • R 3 represents methyl, ethyl, propyl, z ' -propyl, cyclopropyl, cyclobutyl or -CONH 2 .
  • R 3 represents methyl, ethyl, propyl, z ' -propyl or cyclopropyl or cyclobutyl. In a further aspect of the invention R 3 represents methyl, cyclopropyl or cyclobutyl. In a further aspect of the invention R 3 represents methyl, cyclopropyl. In a further aspect of the invention R 3 represents methyl. In a further aspect of the invention R 3 represents cyclopropyl. In a further embodiment of the invention R 4 hydrogen, a Ci-C ⁇ alkyl group; a
  • R 4 represents hydrogen, methyl or methoxy. In a further aspect R 4 represents hydrogen.
  • R 1 represents a Ci-C ⁇ alkyl optionally substituted by one or more R 13 , a C 3 -C 5 cycloalkyl optionally substituted by one or more R 14 , a 4- to 6-membered heterocyclyl group optionally substituted by one or more R 16 , a Ci-C ⁇ alkoxy group optionally substituted by one or more R 17 , a C ⁇ -aryloxy group optionally substituted by one or more R 18 , a 5- to 6-membered heteroaryloxy group optionally substituted by one or more R 19 , or -A-B; wherein A represents a C2-alkylene optionally substituted by one or more R 20 , a Ci-alkyleneoxy optionally substituted by one or more R 21 , or a oxyCi-alkylene optionally substituted by one or more R 22 ; and B represents a 5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the aromatic
  • R 1 represents a Ci-C ⁇ alkyl optionally substituted by one or more R 13 , a 4- to 6-membered heterocyclyl group optionally substituted by one or more R 16 , a Ci-C ⁇ alkoxy group optionally substituted by one or more R 17 , a C 6 -aryloxy group optionally substituted by one or more R 18 , a 5- to 6-membered heteroaryloxy group optionally substituted by one or more R 19 , or -A-B; wherein A represents a C2-alkylene optionally substituted by one or more R 20 , a Q-alkyleneoxy optionally substituted by one or more R 21 , or a oxyCi-alkylene optionally substituted by one or more R 22 ; and B represents a 5- or 6-membered aromatic ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and
  • R 3 represents methyl, ethyl, propyl, i-propyl, cyclopropyl or cyclobutyl; and R 4 represents hydrogen.
  • R 1 represents a Ci-C ⁇ alkyl group substituted by one or more substituents selected from hydroxyl and Ci-C ⁇ alkoxy which may be optionally substituted by one or more substituents selected from halogen, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, amino (-NH 2 ), mono- and di- Ci-Cealkylamino, cyano, hydroxyl and trifluoromethyl, a Ci-C ⁇ alkoxy group optionally substituted by one or more R 17 , a C 6 -aryloxy group optionally substituted by one or more R 18 , a 5- to 6-membered heteroaryloxy group optionally substituted by one or more R 19 , or -A-B; wherein A represents a C2-alkylene optionally substituted by one or more R 20 , a Ci-alky
  • R 3 represents methyl, ethyl, propyl, i-propyl, cyclopropyl or cyclobutyl; and R 4 represents hydrogen.
  • R 1 represents a Ci-C ⁇ alkyl group substituted by one or more substituents selected from hydroxyl and Ci-C ⁇ alkoxy which may be optionally substituted by one or more substituents selected from halogen, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, amino (-NH 2 ), mono- and di- Ci-Cealkylamino, cyano, hydroxyl and trifluoromethyl, a Ci-C 6 alkoxy group optionally substituted by one or more R 17 , a C ⁇ -aryloxy group optionally substituted by one or more R 18 , a 5- to 6-membered heteroaryloxy group optionally substituted by one or more R 19 , or -A-B; wherein A represents a C2-alkylene optionally substituted by one or more R 20 , or a oxyCi-
  • R 2 represents hydrogen
  • R 3 represents methyl, ethyl, propyl, i-propyl, cyclopropyl or cyclobutyl; and R 4 represents hydrogen.
  • R 4 represents hydrogen.
  • R 1 represents a Ci-C 3 alkyl group substituted by one or more substituents selected from hydroxyl and Ci-C 3 alkoxy which may be optionally substituted by one or more substituents selected from halogen, Ci-C 3 alkyl and Ci-C 3 alkoxy, a Ci-C 3 alkoxy group optionally substituted by one or more substituents selected from Ci-C 3 alkoxy and cyclopropyl, a phenyloxy group optionally substituted by one or more substituents selected from Ci-C 3 alkyl, Ci-C 3 alkoxy and cyclopropyl, or -A-B wherein A represents a C2-alkylene, and B represents a phenyl ring wherein the phenyl ring may be optionally substituted by one or more R 23 ;
  • R 2 represents hydrogen or methyl
  • R 3 represents methyl, ethyl, propyl, i-propyl or cyclopropyl; and R 4 represents hydrogen.
  • R 1 represents a Ci-C 3 alkyl group substituted by one or more substituents selected from hydroxyl and Ci-C 3 alkoxy which may be optionally substituted by one or more substituents selected from halogen, Ci-C 3 alkyl and Ci-C 3 alkoxy, a Ci-C 3 alkoxy group optionally substituted by one or more substituents selected from Ci-C 3 alkoxy and cyclopropyl, a phenyloxy group optionally substituted by one or more substituents selected from Ci-C 3 alkyl, Ci-C 3 alkoxy and cyclopropyl, or -A-B wherein A represents a C2-alkylene, and B represents a pyridine -4-yl ring wherein the pyridin-4-yl ring may be optionally substituted by one or more R 23 ; R 2 represents hydrogen or methyl;
  • R 3 represents methyl, ethyl, propyl, i-propyl or cyclopropyl; and R 4 represents hydrogen.
  • R 3 represents methyl, ethyl, propyl, i-propyl or cyclopropyl; and R 4 represents hydrogen.
  • R 1 represents a Ci-C 3 alkyl group substituted by one or more substituents selected from hydroxyl and Ci-C 3 alkoxy which may be optionally substituted by one or more substituents selected from halogen, Ci-C 3 alkyl and Ci-C 3 alkoxy, a Ci-C 3 alkoxy group optionally substituted by one or more substituents selected from Ci-C 3 alkoxy and cyclopropyl, a phenyloxy group optionally substituted by one or more substituents selected from Ci-C 3 alkyl, Ci-C 3 alkoxy and cyclopropyl, or -A-B wherein A represents an oxyCi-alkylene, and B represents a phenyl ring or a pyridin-4-yl ring wherein the phenyl or pyridin-4-yl ring may be optionally substituted by one or more R 23 ; R 2 represents hydrogen or methyl;
  • R 3 represents methyl, ethyl, propyl, i-propyl or cyclopropyl; and R 4 represents hydrogen.
  • R 1 represents a hydroxymethyl, methoxypropyl, ethoxypropyl, phenylethyl,
  • R 4 represents hydrogen, or a pharmaceutically acceptable salt thereof.
  • R 1 represents a 2-(3-methoxyphenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, z ' -propoxy,
  • R 2 represents hydrogen; R 3 represents methyl; and R 4 represents hydrogen, or a pharmaceutically acceptable salt thereof.
  • 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.
  • X and Y each independently represents a leaving group (e.g. halogen or sulfanyl such as methanesulfanyl or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy), Z represents hydrogen or a halogen, and R 4 is as defined hereinbefore for a compound of formula (I) to give a compound of formula (IV)
  • a leaving group e.g. halogen or sulfanyl such as methanesulfanyl or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy
  • Z represents hydrogen or a halogen
  • R 4 is as defined hereinbefore for a compound of formula (I) to give a compound of formula (IV)
  • 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 7V,7V-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
  • 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 (IX) may be prepared by (a) reacting a compound of formula (VII)
  • R 4 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 (V)
  • 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.
  • 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.
  • reaction may conveniently be carried out in a suitable solvent such as 1- methylpyrrolidinone, dimethylacetamide or a compound of formula (XIII) 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 (XIII) 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.
  • 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
  • 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.
  • 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-[(3-fluorophenyl)methoxy]-2H-pyrazol-3-yl]-N-[(5-methyl-l,2-oxazol-3- yl)methyl]pyrimidine-2,4-diamine
  • 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: (1) carcinoma, including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon, thyroid and skin;
  • 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 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 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 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 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.
  • a compound of the invention is expected to possess a wide range of anti-cancer 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.
  • a compound of the invention will possess anti-cancer activity against these cancers.
  • 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 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, heptafluoroalkane 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
  • 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.
  • 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-acceptable 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.
  • 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.
  • 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.
  • 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-tumour agents may include one or more of the following categories of anti-tumour agents:- (i) other 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 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin,
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, 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
  • 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-l-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 Heparanas
  • anti-invasion agents for example c-Src kinase
  • 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 platelet-
  • 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 A- (4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline
  • 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 0 C;
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium (0); BINAP (+/-)-2,2'-bis(diphenylphosphino)-l,l '-binaphthyl;
  • NEt 3 triethylamine and (xii) "Gilson HPLC” refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 20mm/ 100 and 50mm/250 in water-CH ⁇ CN with 0.1% TFA, 1OmM ammonium acetate ,or 0.1% formic acid as mobile phase, obtained from Waters Corporation 34, Maple street, Milford, MA,USA.
  • 5-propan-2-yloxy-2H-pyrazol-3-amine used as starting material, can be prepared according to the literature (Sato, Tadahisa; Mizukawa, Hiroki; Kawagishi, Toshio. Preparation of 3- alkoxy-5 -amino- lH-pyrazoles as intermediates for photographic magenta couplers
  • 2-Methylsulfonylpyrimidin-4-ol used as starting material was prepared as follows :- 2-Thiouracil (84g, 0.66mol, leq) was dissolved in aqueous sodium hydroxide (26g, 0.68mol, 1.05eq in 8OmL water). The solution was diluted with MeOH (16OmL). Iodomethane (47mL, 0.75mol, 1.15eq) was added dropwise. The temperature was kept between 35-4O 0 C. A precipitate formed and the mixture was heated at 4O 0 C for 1 h.
  • 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 (70ml) and the mixture stirred at room temperature for 30 mins.
  • Ethyl 3-(3,5-dimethoxyphenyl)propanoate (8.66g, 36.34mmol, leq) in toluene (60ml) was added and the reaction was refluxed 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 (50ml).
  • 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 refluxed for 24h and then cooled to room temperature.
  • 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) the sequence of which was specific for FGFRl kinase.
  • Assay plates were incubated at room temperature for 1.5h, before the reaction was stopped with the addition of buffer [comprising: 10OmM HEPES - pH7.5, 0.033% Brij-35, 0.22% Caliper Coating Reagent #3, 88mM EDTA, 5% DMSO]. Stopped assay plates were then read using the Caliper LabChip® LC3000 (which uses microfludics to measure a shift in mobility between fluorescent labelled peptide and the FGFRl kinase - phosphorylated form of this peptide). The mean data values for each compound concentration, untreated control wells and 100% inhibition control wells were used to determine the IC50 for each test compound. The IC50 is the concentration of compound, which inhibits FGFRl kinase activity by 50% in the context of this assay.
  • 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
  • Cos-1 cells were harvested at 90-95% confluence for cell trans fection. For each 96-well plate, 24ul Lipofectamine 2000 was added to 809ul OptiMEM and incubated at room temperature for 5 minutes.
  • 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.
  • 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%.
  • Cos-1 cells were harvested at 90-95% confluence for cell trans fection.
  • 24 ⁇ l Lipofectamine 2000 was added to 809ul OptiMEM and incubated at room temperature for 5 minutes.
  • 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 following day,_compounds from dry weight samples were dissolved in 100% DMSO to give 1OmM concentration.
  • 40 ⁇ l of the compound was dispensed into the wells of each quadrant across the 384 Labcyte plate (inclusive of a positive control (100% DMSO), a negative control (lO ⁇ M) and a reference compound (25OnM)).
  • the 384 Labcyte plate was then transferred to the Hydra to dilute the compounds 1:100 into the remaining wells of the quadrant.
  • 70 ⁇ l of media was aspirated from the assay plate using the Quadra before the plate was transferred onto the ECHO 550.
  • the 384 Labcyte compound plate was also transferred onto the ECHO 550.
  • Compound transfer to the assay plate on the ECHO 550 was at concentration ranges 1) 10 ⁇ M, 2) 3 ⁇ M, 3) l ⁇ M, 4) 0.3 ⁇ M, 5) O.l ⁇ M, 6) 0.01.
  • 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.
  • Media was removed from the wells using vacuum aspiration; cells were fixed by adding 50 ⁇ l 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 200 ⁇ l 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.
  • the permeabilisation solution was then removed and the cells washed once more with 200 ⁇ l / well PBS/A before the addition of 40 ⁇ l 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. Following incubation at room temperature for 1 hour, the antibody solution was removed and the wells were washed once with 200ul / well PBS/A.
  • PBS/A phosphate buffered saline

Abstract

L'invention concerne des composés de pyrimidine de formule (I) : ou des sels pharmaceutiques de ces composés. L'invention concerne également des procédés destinés à leur préparation, des compositions pharmaceutiques les contenant, un procédé de préparation des compositions pharmaceutiques, et leur utilisation en thérapie, par exemple dans le traitement d'une maladie proliférative telle que le cancer et en particulier dans une maladie médiée par un effet inhibiteur du FGFR.
PCT/GB2008/050673 2007-08-09 2008-08-07 Composés de pyrimidine ayant un effet inhibiteur du fgfr WO2009019518A1 (fr)

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