WO2015079251A1 - Composés quinazoléine - Google Patents

Composés quinazoléine Download PDF

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Publication number
WO2015079251A1
WO2015079251A1 PCT/GB2014/053537 GB2014053537W WO2015079251A1 WO 2015079251 A1 WO2015079251 A1 WO 2015079251A1 GB 2014053537 W GB2014053537 W GB 2014053537W WO 2015079251 A1 WO2015079251 A1 WO 2015079251A1
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Prior art keywords
amino
fluoro
oxy
methoxy
methylphenol
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PCT/GB2014/053537
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English (en)
Inventor
Kristin GOLDBERG
Niall HAMILTON
Stuart Jones
Allan Jordan
Amanda Lyons
Rebecca NEWTON
Donald OGILVIE
Bohdan Waszkowycz
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Cancer Research Technology Limited
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Publication of WO2015079251A1 publication Critical patent/WO2015079251A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to certain quinazoline compounds. More specifically, the present invention relates to certain quinazoline compounds that function as inhibitors of RET (rearranged during transfection) kinase enzyme activity. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which RET kinase activity is implicated.
  • Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of a number of molecular targets associated with key metabolic pathways that are known to be associated with malignancy.
  • RET REarranged during Transfection
  • RTK receptor tyrosine kinase
  • GDNF glial derived neurtrophic factor
  • GFRa glycosyl phosphatidylinositol
  • Ligand binding to the corresponding GFRa co-receptor triggers RET dimerization followed by trans-phosphorylation of intracellular signalling cascades.
  • MTC medullary thyroid carcinomas
  • RET inhibition is a secondary pharmacology of this agent, which also targets VEGFR2 (Vascular endothelial growth factor receptor, also known as KDR - kinase insert domain receptor) and EGFR (epidermal growth factor receptor).
  • VEGFR2 Vascular endothelial growth factor receptor
  • EGFR epidermal growth factor receptor
  • the clinical benefit in MTC is considered to be due to RET inhibition but is unfortunately accompanied by significant side effects (rash, hypertension, diarrhoea) due to inhibition of EGFR and/or VEGFR.
  • vandetanib also exhibits off-target activity versus hERG. Collectively all of these unwanted pharmacological activities may compromise its use in advanced MTC and also its extrapolation into earlier clinical settings (e.g. adjuvant).
  • Another object of the present invention is to provide inhibitors of RET kinase enzyme activity that show a greater selectivity for the inhibiton of RET kinase relative to the inhibition of KDR.
  • a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
  • a method of inhibiting RET kinase enzyme activity in vitro or in vivo comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
  • a method of selectively inhibiting RET kinase enzyme activity over KDR enzyme activity in vitro or in vivo comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • a method of inhibiting cell proliferation, in vitro or in vivo comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating a disease or disorder in which RET kinase activity is implicated in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating a proliferative disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy is provided.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer is human cancer.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of RET kinase enzyme activity is provided.
  • the proliferative disorder is cancer, suitably a human cancer (for example medullary thyroid cancer (MTC)).
  • MTC medullary thyroid cancer
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which RET kinase activity is implicated.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.
  • references to "treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.
  • “Treating” or “treatment” of a state, disorder or condition therefore includes: (1 ) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only.
  • (1 -6C)alkyl includes (1 -4C)alkyl, (1 - 3C)alkyl, propyl, isopropyl and f-butyl.
  • phenyl(1 -6C)alkyl includes phenyl(1 -4C)alkyl, benzyl, 1 -phenylethyl and 2-phenylethyl.
  • (m-nC) or "(m-nC) group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkylene is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups.
  • (1 - 6C)alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • (2-6C)alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, for example, as in ethenylene, 2,4-pentadienylene, and the like.
  • (2-6C)alkynylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, for example, as in ethynylene, propynylene, and butynylene and the like.
  • (3-8C)cycloalkyl means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1 ]heptyl.
  • (3-8C)cycloalkenyl means a hydrocarbon ring containing at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-cyclohexen-1 - yl, or cyclooctenyl.
  • (3-8C)cycloalkyl-(1 -6C)alkylene means a (3-8C)cycloalkyl group covalently attached to a (1 -6C)alkylene group, both of which are defined herein.
  • heterocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
  • heterocyclyl includes both monovalent species and divalent species.
  • Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
  • Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocycles contain from about 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
  • Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 ,3-dithiol, tetrahydro-2/-/- thiopyran, and hexahydrothiepine.
  • heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • the oxidized sulfur heterocycles containing SO or S0 2 groups are also included.
  • examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide.
  • heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 ,1 -dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1 -dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl.
  • any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
  • reference herein to piperidino or morpholino refers to a piperidin-1 -yl or morpholin-4-yl ring that is linked via the ring nitrogen.
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131 -133, 1992.
  • bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1 ]heptane, 2-oxa-5-azabicyclo[2.2.1 ]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1 ]octane and quinuclidine.
  • Heterocyclyl(1 -6C)alkyl means a heterocyclyl group covalently attached to a (1 - 6C)alkylene group, both of which are defined herein.
  • heteroaryl or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1 -4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
  • the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non- basic as in the case of an indole or pyrrole nitrogen.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthy
  • Heteroaryl also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur.
  • partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1 ,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2- dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl,
  • Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl groups examples include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • a bicyclic heteroaryl group may be, for example, a group selected from:
  • thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms
  • thiophene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
  • Heteroaryl(1 -6C)alkyl means a heteroaryl group covalently attached to a (1 - 6C)alkylene group, both of which are defined herein.
  • heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
  • aryl includes both monovalent species and divalent species.
  • Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.
  • aryl(1 -6C)alkyl means an aryl group covalently attached to a (1 -6C)alkylene group, both of which are defined herein. Examples of aryl-(1 -6C)alkyl groups include benzyl, phenylethyl, and the like.
  • heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by heterocyclyl.
  • optionally substituted refers to either groups, structures, or molecules that are substituted and those that are not substituted.
  • the term "wherein a/any CH, CH 2 or CH 3 group within a R 1 group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R 1 group is substituted by a relevant stipulated group.
  • X is NH, NRx, O or S, wherein R x is (1 -3C)alkyl;
  • Ri is selected from halo (e.g. fluoro, chloro, or bromo), trifluoromethyl, (1 -4C)alkyl (eg. methyl), (1 -4C)alkoxy or (3-6C)cycloalkyl, wherein an alkyl, alkoxy or cycloalkyl group is optionally substituted with one or more fluoro;
  • R 2 is selected from hydrogen, halo (e.g. fluoro, chloro or bromo), hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, (1 -6C)alkyl (eg. methyl), (3-8C)cycloalkyl, or (1 -4C)alkoxy (e.g. OMe), wherein an alkyl, cycloalkyl or alkoxy group is optionally substituted with one or more fluoro;
  • halo e.g. fluoro, chloro or bromo
  • hydroxyl cyano
  • trifluoromethyl trifluoromethoxy
  • (1 -6C)alkyl eg. methyl
  • 3-8C cycloalkyl
  • (1 -4C)alkoxy e.g. OMe
  • R 3 is selected from hydrogen, halo (e.g. fluoro, chloro or bromo), hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, (1 -6C)alkyl (eg. methyl), (3-8C)cycloalkyl, or (1 -4C)alkoxy (e.g. OMe), wherein an alkyl, cycloalkyi or alkoxy group is optionally substituted with one or more fluoro;
  • halo e.g. fluoro, chloro or bromo
  • hydroxyl cyano
  • trifluoromethyl trifluoromethoxy
  • (1 -6C)alkyl eg. methyl
  • (3-8C)cycloalkyl e.g. methyl
  • (1 -4C)alkoxy e.g. OMe
  • R 4 is selected from hydrogen, halo (e.g. fluoro, chloro or bromo), hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, (1 -6C)alkyl (eg. methyl), (3-8C)cycloalkyl, or (1 -4C)alkoxy (e.g. OMe), wherein an alkyl, cycloalkyi or alkoxy group is optionally substituted with one or more fluoro;
  • halo e.g. fluoro, chloro or bromo
  • hydroxyl cyano
  • trifluoromethyl trifluoromethoxy
  • (1 -6C)alkyl eg. methyl
  • (3-8C)cycloalkyl e.g. methyl
  • (1 -4C)alkoxy e.g. OMe
  • R 5 is selected from hydrogen or a group defined by the formula:
  • L 5 is absent or a linear or branched (1 -4C)alkylene
  • X 5 is absent or -C(0)0-, -0-, -C(O)-, -OC(O)-, -CH(OR 5L )-, -N(R j )-, -N(R 5L )-C(0)-, -N(R 5L )-C(0)0-, -C(0)-N(R 5L )-, -S-, -SO-, -SO2-, -S(0) 2 N(R 5L )-, or -N(R 5L )S0 2 - wherein R 5 i_ is selected from hydrogen or methyl; and
  • Qs is (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl- (1 -4C)alkyl, aryl, aryl-(1 -4C)alkyl, heteroaryl, heteroaryl-(1 -4C)alkyl, heterocyclyl or heterocyclyl-(1 -4C)alkyl;
  • R 6 is selected from hydrogen, or a group defined by the formula:
  • L 6 is absent or a linear or branched (1 -4C)alkylene
  • X 6 is absent or selected from -0-, -C(0)-, -C(0)0-, -0C(0)-, -CH(OR 6 i_)-, -N(R 6L ), -N(R 6L )-C(0)-, -N(R 6L )-C(0)0-, -C(0)-N(R 6L )-, -S-, -SO-, -SO2-, -S(0) 2 N(R 6L )-, or -N(R 6 i_)S0 2 - wherein R 6 L is selected from hydrogen or (1 -3C)alkyl;
  • Q 6 is hydrogen, (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl-(1 -6C)alkyl, aryl, aryl-(1 -6C)alkyl, heteroaryl, heteroaryl-(1 - 6C)alkyl, heterocyclyl, heterocyclyl-(1 -6C)alkyl,
  • Q 6 and RL6 are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • R 6 is optionally substituted (e.g. substituted on L 6 and/or Q 6 ) with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR 6 x, SR 6 x, S(0)R 6X , S(0) 2 R 6 x, C(0)OR 6 x or C(0)NR 6 xR'6x, wherein R 6 x and R' 6 x are independently hydrogen, (1 -8C)alkyl, or R 6 x and R' 6 x are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • R 7 is selected from hydrogen, (1 -6C)alkoxy, or a group defined by the formula: wherein
  • L 7 is absent or a linear or branched (1 -4C)alkylene
  • X 7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR 6L )-, -N(R 7L )-, -N(R 7L )-C(0)-, -N(R 7L )-C(0)0-, -C(0)-N(R 7L )-, -S-, -SO-, -S0 2 -, -S(0) 2 N(R 7L )-, or -N(R 7L )S0 2 - wherein R 7L is selected from hydrogen or (1 -3C)alkyl;
  • Q 7 is hydrogen, (1 -8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl-(1 -6C)alkyl, aryl, aryl-(1 -6C)alkyl, heteroaryl, heteroaryl-(1 -
  • Q 7 and R 7 L are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • R 7 is optionally substituted (e.g. substituted on L 7 and/or Q 7 ) with one or more halo, hydroxyl, nitro, cyano, (1 -8C)alkyl, (1 -8C)alkanoyl , OR 7 x, SR 7 x,
  • R 7 is optionally substituted with one or more groups selected from oxo, (1 -
  • the present invention provides a compound of Formula I is as defined herein, subject to the proviso that said compound is not 6-chloro-2-fluoro-3-((6-methoxy-7-(2- methoxyethoxy)quinazolin-4-yl)amino)phenol, or a pharmaceutically acceptable salt and/or solvate thereof.
  • Particular compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless otherwise stated, each of X, Ri , R 2 , R 3 , R4, R5, Re, R 7 , and any associated substitutent groups has any of the meanings defined hereinbefore or in any of paragraphs (1 ) to (53) hereinafter:-
  • X is NH, N Rx or O, wherein R x is methyl
  • X is NH or NR X , wherein R x is methyl
  • X is N Rx and R x is methyl
  • Ri is selected from halo, trifluoromethyl, (1 -2C)alkyl, (1 -2C)alkoxy or (3-6C)cycloalkyl, wherein an alkyl or cycloalkyl group is optionally substituted with one or more fluoro;
  • Ri is selected from fluoro, chloro, bromo, trifluoromethyl, (1 -4C)alkyl, or (3-6C)cycloalkyl, wherein an alkyl or cycloalkyl group is optionally substituted with one or more fluoro;
  • Ri is selected from fluoro, chloro, bromo, trifluoromethyl, (1 -4C)alkyl (eg. methyl), or (3- 6C)cycloalkyl;
  • Ri is selected from fluoro, chloro, bromo, or (1 -2C)alkyl; wherein an alkyi group is optionally substituted with one or more fluoro;
  • Ri is selected from fluoro, chloro, bromo, or (1 -2C)alkyl
  • Ri is selected from fluoro, chloro, bromo, methyl, ethyl or methoxy;
  • Ri is selected from fluoro, chloro, bromo, methyl, or ethyl
  • Ri is selected from fluoro, chloro, bromo, or methyl
  • Ri is selected from fluoro, chloro, or bromo
  • R 2 is selected from hydrogen, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, (1 - 4C)alkyl, (3-6C)cycloalkyl or (1 -4C)alkoxy, wherein an alkyi, cycloalkyi or aikoxy group is optionally substituted with one or more fluoro;
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, (1 -4C)alkyl, (3-6C)cycloalkyl or (1 -4C)alkoxy, wherein an alkyi, cycloalkyi or aikoxy group is optionally substituted with one or more fluoro;
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, (1 -2C)alkyl, (3-6C)cycloalkyl or (1 -2C)alkoxy, wherein an alkyi, cycloalkyi or aikoxy group is optionally substituted with one or more fluoro;
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, cyano, trifluoromethyl, (1 -2C)alkyl, (3-6C)cycloalkyl or (1 -2C)alkoxy;
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, or (1 -2C)alkyl
  • R 2 is selected from hydrogen, fluoro or (1 -2C)alkyl
  • R 2 is selected from hydrogen, fluoro or methyl
  • R 2 is hydrogen
  • R 3 is selected from hydrogen, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, (1 - 4C)alkyl, (3-6C)cycloalkyl, or (1 -4C)alkoxy, wherein an alkyi, cycloalkyi or aikoxy group is optionally substituted with one or more fluoro;
  • R 3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, cyano, trifluoromethyl, (1 - 2C)alkyl or (1 -2C)alkoxy, wherein an alkyi or aikoxy group is optionally substituted with one or more fluoro;
  • R 3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, cyano, trifluoromethyl, (1 - 2C)alkyl;
  • R 3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, or (1 -2C)alkyl;
  • R 3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, or methyl;
  • R 3 is hydrogen;
  • R 4 is selected from hydrogen, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, ( 1 - 4C)alkyl, (3-6C)cycloalkyl or (1 -4C)alkoxy, wherein an alkyl, cycloalkyi or alkoxy group is optionally substituted with one or more fluoro;
  • R 4 is selected from hydrogen, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, ( 1 - 4C)alkyl, (3-6C)cycloalkyl or ( 1 -4C)alkoxy;
  • R 4 is selected from hydrogen, fluoro, chloro, hydroxy, ( 1 -2C)alkyl, or ( 1 -2C)alkoxy, wherein an alkyl, cycloalkyi or alkoxy group is optionally substituted with one or more fluoro;
  • R 4 is selected from hydrogen, fluoro, chloro, (1 -2C)alkyl or (1 -2C)alkoxy;
  • R 4 is selected from hydrogen, fluoro, chloro, methyl
  • R 5 is selected from hydrogen or a group defined by the formula:
  • X 5 is absent
  • Qs is (1 -6C)alkyl or (3-6C)cycloalkyl
  • R 5 is selected from hydrogen or a group defined by the formula:
  • X 5 is absent
  • Qs is (1 -4C)alkyl or (3-4C)cycloalkyl
  • R 5 is selected from hydrogen or ( 1 -4C)alkoxy
  • R 5 is hydrogen
  • R 6 is selected from hydrogen, or a group defined by the formula:
  • L 6 is absent or a linear or branched (1 -4C)alkylene
  • X 6 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR 6L )-, -N(R 6L ), - N(R 6L )-C(0)-, -N(R 6L )-C(0)0-, -C(0)-N(R 6L )-, -S-, -SO-, -SO2-, -S(0) 2 N(R 6L )-, or -
  • R 6 L is selected from hydrogen or ( 1 -3C)alkyl
  • Q 6 is hydrogen, ( 1 -8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-( 1 -6C)alkyl, phenyl, phenyl-(1 -6C)alkyl, 5 or 6-membered heteroaryl, 5 or 6-membered heteroaryl-(1 -
  • Q 6 and RL6 are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
  • R 6 is optionally substituted (e.g. substituted on L 6 and/or Q 6 ) with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR 6 x, SR 6X , S(0)R 6 x, S(0) 2 R 6 x, C(0)OR 6X or C(0)NR 6 xR' 6 x, wherein R 6 x and R' 6 x are independently hydrogen, (1 -8C)alkyl, or R 6 x and R' 6 x are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
  • R 6 is selected from hydrogen, or a group defined by the formula:
  • L 6 is absent or a linear or branched (1 -4C)alkylene
  • X 6 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR 6L )-, -N(R 6l _), -
  • R 6 L is selected from hydrogen or (1 -2C)alkyl
  • Q 6 is hydrogen, (1 -6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1 -2C)alkyl, phenyl, phenyl-(1 -2C)alkyl, 5 or 6-membered heteroaryl, 5 or 6-membered heteroaryl-(1 - 2C)alkyl, 4, 5 or 6-membered heterocyclyl, or 4, 5 or 6-membered heterocyclyl-(1 -
  • Q 6 and Ri_e are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
  • R 6 is optionally substituted (e.g. substituted on L 6 and/or Q 6 ) with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR 6 x, SR 6X , S(0)R 6 x, S(0) 2 R 6X , C(0)OR 6 x or C(0)NR 6 xR'6x, wherein R 6 x and R' 6 x are independently hydrogen, (1 -8C)alkyl, or R 6 x and R' 6 x are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
  • R 6 is selected from hydrogen, or a group defined by the formula:
  • L 6 is absent or a linear or branched (1 -4C)alkylene
  • X 6 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -N(R 6l _), -N(R 6l _)-C(0)-, -C(0)-N(R 6L )-, -S-, -SO-, -S0 2 -, -S(0) 2 N(R 6L )-, or -N(R 6l _)S0 2 - wherein R 6L is selected from hydrogen or (1 -2C)alkyl;
  • Q 6 is hydrogen, (1 -6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1 -2C)alkyl, phenyl, phenyl-(1 -2C)alkyl, 5 or 6-membered heteroaryl, 5 or 6-membered heteroaryl-(1 - 2C)alkyl, 4, 5 or 6-membered heterocyclyl, or 4, 5 or 6-membered heterocyclyl-(1 - 2C)alkyl,
  • Q 6 and Ri_e are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring; wherein R 6 is optionally substituted (e.g. substituted on L 6 and/or Q 6 ) with one or more (1 -4C)alkyl;
  • R 6 is selected from hydrogen or methoxy
  • R 6 is methoxy
  • R 6 is selected from:
  • L 6 is (1 -3C)alkylene; X 6 is O; and Q 6a is hydrogen, (1 - 8C)alkyl, (3-8C)cycloalkyl, heteroaryl (containing one or more heteroatoms selected from O, S, or N), or heterocyclyl (containing one or more heteroatoms selected from O, S, or N), and where Q 6a is a heteroaryl or heterocyclyl containing an N heteroatom Q 6a is optionally substituted by (1 -6C)alkyl, (1 - 6C)alkanoyl, S(0)R 6 x a , S(0) 2 R6x a , or C(0)NR 6 x a R' 6 x a , wherein R 6 x a and R' 6 x a are independently hydrogen, (1 -6C)alkyl, or R 6 x a and R' 6 x a are linked such that, together with the nitrogen atom to which they are attached,
  • L 6 is (1 -3C)alkylene; X 6 is absent; and Q 6 b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q 6 b is a heteroaryl containing an N heteroatom Q 6 b is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R 6 xb, S(0) 2 R 6 xb, or
  • R 6 xb and R' 6 xb are independently hydrogen, (1 -6C)alkyl, or R 6 xb and R' 6 xb are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 6 is (1 -3C)alkylene; X 6 is absent; and Q 6c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q 6c is a heterocyclyl containing an N heteroatom Q 6c is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R 6 x c , S(0) 2 R 6 xc, or C(0)NR 6 xcR'6Xc, wherein R 6 x c and R' 6 x c are independently hydrogen, (1 -6C)alkyl, or R 6 xc and R' 6 x c are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 6 is (1 -3C)alkylene; X 6 is absent; and Q 6 d is (3- 6C)cycloalkyl optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R 6 x c , S(0) 2 R6Xc, or C(0)NR 6 xcR'6Xc, wherein R 6 x c and R' 6 x c are independently hydrogen, (1 -6C)alkyl, or R 6 x c and R' 6 x c are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 6 is (1 -3C)alkylene; X 6 is N(R 6 i_ e ); and wherein R 6 i_ e hydrogen or (1 -3C)alkyl and Q 6e is hydrogen or (1 -6C)alkyl, or R 6 Le and Q 6e are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring (containing one or more heteroatoms selected from O, S, or N) which heterocyclic ring is optionally substituted by (1 -4C)alkyl, (1 - 4C)alkanoyl, OR 6Xe , SR 6Xe , S(0)R 6Xe , S(0) 2 R 6 x e , or C(0)NR 6 x e R'6Xe, wherein R 6Xe and R' 6 xe are independently hydrogen, (1 -4C)alkyl, or R 6 x e and R' 6 xe are linked such that
  • L 6 is (1 -3C)alkylene
  • X 6 is S(0) m ; wherein m is 0, 1 , or 2, and wherein Q 6 f is (1 -6C)alkyl, wherein Q 6 f is optionally substituted with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR 6Xf , SR 6Xf , S(0)R 6Xf , S(0) 2 R 6X f, or
  • L 6 is (1 -3C)alkylene
  • X 6 is S(0) 2 N(R 6 L g )
  • R 6 i_ g is hydrogen or (1 -3C)alkyl
  • Q 6g is hydrogen or (1 -6C)alkyl
  • R 6 i_ g and Q 6g are are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring (suitably containing one or more heteroatoms selected from O, S, or N) which heterocyclic ring is optionally substituted by (1 - 6C)alkyl, (1 -6C)alkanoyl, OR 6Xg , SR 6Xg , S(0) 2 R 6Xg , or C(0)NR 6Xg R'6 Xg , wherein R 6Xg and R' 6 x g are independently hydrogen or (1 -6C)alkyl;
  • L 6 is (1 -3C)alkylene
  • X 6 is N(R 6 Lh)S(0) 2
  • R 6 Lh and Q 6 h are each independently hydrogen or (1 -8C)alkyl
  • R 6 is optionally further substituted as described herein (if so, suitably on an L 6 group).
  • R 6 is selected from:
  • L 6 is (1 -3C)alkylene;
  • X 6 is O; and
  • Q 6a is hydrogen, (1 - 4C)alkyl;
  • Q 6c is a heterocyclyl containing an N heteroatom
  • Q 6c is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R 6Xc , S(0) 2 R 6Xc , or C(0)NR6XcR'6Xc, wherein R 6Xc and R' 6 xc are independently hydrogen, (1 -6C)alkyl, or R 6Xc and R' 6 xc are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • R 6 is optionally further substituted with one or more (1 -4C)alkyl; (46) R 7 is selected from hydrogen, (1 -6C)alkoxy, or a group defined by the formula: wherein
  • L 7 is absent or a linear or branched (1 -4C)alkylene
  • X 7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR 6 i_)-, -N(R 7L )-, -
  • R 7 L is selected from hydrogen or (1 -2C)alkyl
  • Q 7 is hydrogen, (1 -6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1 -2C)alkyl, aryl, aryl-(1 - 2C)alkyl, heteroaryl, heteroaryl-(1 -2C)alkyl, heterocyclyl, heterocyclyl-(1 -2C)alkyl, or Q 7 and R 7 i_ are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • R 7 is optionally substituted (e.g. substituted on L 7 and/or Q 7 ) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR 7 x, SR 7 x, S(0)R 7 x, S(0) 2 R7x, C(0)OR 7 x or C(0)NR 7 xR'7x, wherein R 7 x and RVx are independently hydrogen, (1 -4C)alkyl, or R 7 x and RVx are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; or
  • R 7 is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, (1 -4C)hydroxyalkyl, C(0)R 7y or NR 7y R'7y, wherein R 7y and R' 7y are independently hydrogen or (1 -6C)alkyl;
  • R 7 is selected from hydrogen, (1 -6C)alkoxy, or a group defined by the formula:
  • L 7 is absent or a linear or branched (1 -4C)alkylene
  • X 7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR 6 i_)-, -N(R 7L )-, - N(R 7L )-C(0)-, -N(R 7L )-C(0)0-, -C(0)-N(R 7L )-, -S-, -SO-, -SO2-, -S(0) 2 N(R 7L )-, or -
  • R 7 L is selected from hydrogen or (1 -2C)alkyl
  • Q 7 is hydrogen, (1 -6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1 -2C)alkyl, phenyl, phenyl-(1 -2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl-(1 - 2C)alkyl, 4, 5 or 6 membered heterocyclyl, 4, 5 or 6 membered heterocyclyl-(1 -2C)alkyl, or Q 7 and R 7 L are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
  • R 7 is optionally substituted (e.g. substituted on L 7 and/or Q 7 ) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR 7 x, SR 7 x, S(0)R 7 x, S(0) 2 R7x, C(0)OR 7 x or C(0)NR 7 xR'7x, wherein R 7 x and RVx are independently hydrogen, (1 -4C)alkyl, or R 7 x and RVx are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring; or R 7 is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, ( 1 -4C)hydroxyalkyl, C(0) R 7Y or NR 7Y R'7y, wherein R 7Y and R' 7Y are independently hydrogen or ( 1 -4C)alkyl;
  • R 7 is selected from hydrogen, ( 1 -4C)alkoxy, or a group defined by the formula:
  • L 7 is absent or a linear or branched (1 -4C)alkylene
  • X 7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR 6 L)-, -N(R 7L )-, - N(R 7L )-C(0)-, -N(R 7L )-C(0)0-, -C(0)-N(R 7L )-, -S-, -SO-, -S0 2 -, -S(0) 2 N(R 7L )-, or - N(R 7L )S0 2 - wherein R 7L is selected from hydrogen or ( 1 -2C)alkyl;
  • Q 7 is hydrogen, ( 1 -6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-( 1 -2C)alkyl, phenyl, phenyl-(1 -2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl-(1 - 2C)alkyl, 4, 5 or 6 membered heterocyclyl, 4, 5 or 6 membered heterocyclyl-(1 -2C)alkyl, or Q 7 and R 7 L are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
  • R 7 is optionally substituted (e.g. substituted on L 7 and/or Q 7 ) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR 7 x, SR 7 x, S(0)R 7 x, S(0) 2 R 7 x, C(0)OR 7 x or C(0)NR 7X R' 7 x, wherein R 7X and R' 7 x are independently hydrogen, (1 -4C)alkyl;
  • R 7 is selected from hydrogen, ( 1 -4C)alkoxy, or a group defined by the formula:
  • L 7 is absent or a linear or branched (1 -4C)alkylene
  • X 7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR 6 L)-, -N(R 7L )-, - N(R 7L )-C(0)-, -N(R 7L )-C(0)0-, -C(0)-N(R 7L )-, -S-, -SO-, -S0 2 -, -S(0) 2 N(R 7L )-, or -
  • R 7L is selected from hydrogen or ( 1 -2C)alkyl
  • Q 7 is hydrogen, ( 1 -6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-( 1 -2C)alkyl, phenyl, phenyl-(1 -2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl-(1 - 2C)alkyl, 4, 5 or 6 membered heterocyclyl, 4, 5 or 6 membered heterocyclyl-(1 -2C)alkyl, or Q 7 and R 7 L are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
  • R 7 is optionally substituted (e.g. substituted on L 7 and/or Q 7 ) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR 7 x, SR 7 x, S(0)R 7 x, S(0) 2 R 7 x, C(0)OR 7 x or C(0)NR 7X R' 7 x, wherein R 7X and R' 7 x are independently hydrogen, (1 -4C)alkyl; or (50) R 7 is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, (1 -4C)hydroxyalkyl, C(0)R 7y or NR 7y R'7y, wherein R 7y and R' 7y are independently hydrogen or (1 -2C)alkyl;R 7 is selected from:
  • L 7 is a linear or branched (1 -3C)alkylene;
  • X 7 is -O;
  • Q 7a is hydrogen, (1 -8C)alkyl, (3-8C)cycloalkyl, heteroaryl (containing one or more heteroatoms selected from O, S, or N), or heterocyclyl (containing one or more heteroatoms selected from O, S, or N), and where Q 7a is a heteroaryl or heterocyclyl containing an N heteroatom Q 7a is optionally substituted by (1 -
  • R 7Xa and R' 7 x a are independently hydrogen, (1 -6C)alkyl, or R 7Xa and R' 7 x a are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; Q 7 b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q 7 b is a heteroaryl containing an N heteroatom Q 7b is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R 7Xb , S(0) 2 R 7 xb, or C(0)NR 7Xb R' 7 xb, wherein R 7Xb and R' 7X b are independently hydrogen, (1 -6C)alkyl, or R 7Xb and R' 7X b are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; and Q 7c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q 7c is a heterocyclyl containing an N heteroatom Q 7c is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R 7Xc , S(0) 2 R 7Xc , or
  • R 7Xc and R' 7Xc are independently hydrogen, (1 -6C)alkyl, or R 7Xc and R' 7Xc are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; and Q 7d is (3-8C)cycloalkyl optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl,
  • R 7Xd and R' 7X d are independently hydrogen, (1 -6C)alkyl, or R 7Xd and R' 7X d are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is N(R 7Le ); wherein R 7Le is hydrogen or (1 -3C)alkyl and Q 7e is hydrogen, (1 -6C)alkyl, or are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring (containing one or more heteroatoms selected from O, S, or N) which heterocyclic ring is optionally substituted by (1 -6C)alkyl, (1 - 6C)alkanoyl, OR 7Xe , SR 7Xe , S(0)R 7Xe , S(0) 2 R 7 xe, or C(0)NR 7Xe R' 7 xe, wherein R 7Xe and R xe are independently hydrogen, (1 -6C)alkyl, or R 7Xe and R' 7Xe are linked such that, together with the nitrogen atom to which they are attached,
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is S(0) m
  • Q 7f is (1 -8C)alkyl, wherein Q 7f is optionally substituted with one or more (1 -8C)alkyl, (1 -8C)alkanoyl, OR 7Xf , SR 7Xf , S(0)R 7Xf , S(0) 2 R 7Xf , or C(0)NR 7Xf R' 7X f, wherein R 7Xf and R' 7X f are independently hydrogen, (1 -8C)alkyl, or R 7Xf and R' 7X f are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is S(0) 2 N(R 7Lg )
  • R 7Lg is hydrogen or (1 -3C)alkyl
  • Q 7g is hydrogen, (1 - 6C)alkyl, or are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring (suitably containing one or more heteroatoms selected from O, S, or N) which heterocyclic ring is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, OR 7Xg , SR 7Xg , S(0) 2 R 7Xg , or C(0)NR 7Xg R' 7Xg , wherein R 7Xg and R' 7Xg are independently hydrogen or (1 - 6C)alkyl;
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is N(R 7L h)S(0) 2 wherein R 7L h is hydrogen or (1 -3C)alkyl and Q 7 h is hydrogen or (1 - 6C)alkyl.
  • R 7 is optionally further substituted as described herein.
  • R 7 is selected from:
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is -O
  • Q 7a is hydrogen or (1 -8C)alkyl
  • L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; Q 7 b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q 7 b is a heteroaryl containing an N heteroatom Q 7b is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R 7Xb , S(0) 2 R 7Xb , or C(0)NR 7X bR' 7X b, wherein R 7Xb and R' 7X b are independently hydrogen, (1 -6C)alkyl, or R 7Xb and R' 7X b are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; ⁇ -O-L7-X7-Q7 C , wherein L 7 is a linear or branched (1 -3C)alkylene;
  • L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; and Q 7d is (3-8C)cycloalkyl optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R 7Xd , S(0) 2 R 7 xd, or C(0)NR 7Xd R' 7 xd, wherein R 7Xd and R xd are independently hydrogen, (1 -6C)alkyl, or R 7Xd and R xd are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is N(R 7Le )
  • R 7Le is hydrogen or (1 -3C)alkyl
  • Q 7e is hydrogen, (1 -6C)alkyl, or are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring (containing one or more heteroatoms selected from O, S, or N) which heterocyclic ring is optionally substituted by (1 -6C)alkyl, (1 - 6C)alkanoyl, OR 7Xe , SR 7Xe , S(0)R 7Xe , S(0) 2 R 7Xe , or C(0)NR 7Xe R' 7X e, wherein R 7Xe and R' 7Xe are independently hydrogen, (1 -6C)alkyl, or R 7Xe and R' 7Xe are linked such that, together with the nitrogen atom to which they
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is
  • N(R 7 Lh)S(0) 2 wherein R 7Lh is hydrogen or (1 -3C)alkyl and Q 7h is (1 -6C)alkyl.
  • R 7 is optionally further substituted as described herein.
  • R 7 is selected from:
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is -O
  • Q 7a is hydrogen or (1 -6C)alkyl
  • L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; Q 7 b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or N); ⁇ -O-L7-X7-Q7 C , wherein L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; and Q 7c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N);
  • L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; and Q 7d is (3-8C)cycloalkyl;
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is N(R 7 Le)
  • R 7 i_ e is hydrogen or (1 -3C)alkyl
  • Q 7e is hydrogen, (1 -6C)alkyl, or are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring (containing one or more heteroatoms selected from O, S, or N);
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is N(R 7 Lh)S(0) 2 wherein R 7 i_h is hydrogen or methyl and Q 7 h is (1 -6C)alkyl;
  • R 7 is optionally further substituted as described herein.
  • R 7 is selected from:
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is -O
  • Q 7a is (1 -6C)alkyl
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is absent
  • Q 7 b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or
  • L 7 is a linear or branched (1 -3C)alkylene; X 7 is absent; and Q 7c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N);
  • L 7 is a linear or branched (1 -3C)alkylene
  • X 7 is N(R 7 i_ e ); wherein R 7 i_ e is hydrogen or (1 -3C)alkyl and Q 7e is hydrogen, (1 -6C)alkyl, or are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring (containing one or more heteroatoms selected from O, S, or N).
  • a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.
  • a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
  • a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S.
  • a heterocyclyl group is a 5- or 6-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3-methyloxetane), pyrrolidinone (e.g. pyrrolidin-2-one)].
  • an aryl group is phenyl
  • X is as defined in any one of paragraphs (1 ) to (6) above. Most suitably, X is NH.
  • Ri is as defined in any one of paragraphs (7) to (15) above. Most suitably, Ri is as defined in paragraphs (12) to (15) above.
  • R 2 is as defined in any one of paragraphs (16) to (23) above. Most suitably, R 2 is as defined in paragraphs (20) to (23) above.
  • R 3 is as defined in any one of paragraphs (24) to (29) above. Most suitably, R 3 is as defined in paragraph (28) or (29) above.
  • R 4 is as defined in any one of paragraphs (30) to (34) above. Most suitably, R 4 is as defined in paragraphs (33) or (34) above.
  • R 5 is as defined in any one of paragraphs (35) to (38) above. Most suitably, R 5 is as defined in paragraph (38) above.
  • R 6 is as defined in any one of paragraphs (39) to (45) above. Most suitably, R 6 is as defined in paragraphs (41 ) to (45) above.
  • R 7 is as defined in any one of paragraphs (46) to (53) above. Most suitably, R 7 is as defined in paragraphs (48) to (53) above.
  • Ri , R 2 , R3, R4, R6 and R7 each have any one of the meanings defined herein;
  • Ri is as defined in any one of paragraphs (7) to (15) above;
  • R 2 is as defined in any one of paragraphs (16) to (23) above;
  • R 3 is as defined in any one of paragraphs (24) to (29) above;
  • R 4 is as defined in any one of paragraphs (30) to (34) above; Re is as defined in any one of paragraphs (39) to (45) above; and
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri is as defined in paragraph (13) above;
  • R 2 is as defined in paragraph (20) above;
  • R 3 is as defined in paragraph (27) above;
  • R 4 is as defined in paragraph (33) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri is as defined in paragraph (15) above;
  • R 2 is as defined in paragraph (23) above;
  • R 3 is as defined in paragraph (29) above;
  • R 4 is as defined in paragraph (34) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • X is NH
  • R 2 is H
  • R 3 is H
  • R 5 is H
  • the compounds have the structural formula lb (a sub-definition of formula I) shown below:
  • Ri , R 4 , R6, and R 7 each have any one of the meanings defined herein;
  • Ri is as defined in any one of paragraphs (7) to (15) above;
  • R 4 is as defined in any one of paragraphs (30) to (34) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri is as defined in paragraph (13) above;
  • R is as defined in paragraph (33) above;
  • Re is as defined in paragraph (41 ) above; and R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri is as defined in paragraph (15) above;
  • R 4 is as defined in paragraph (34) above;
  • R 6 is as defined in paragraph (42) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri , R 3 , R6 and R7 each have any one of the meanings defined herein;
  • Ri is as defined in any one of paragraphs (7) to (15) above;
  • R 3 is as defined in any one of paragraphs (24) to (29) above;
  • R 6 is as defined in any one of paragraphs (39) to (45) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri is as defined in paragraph (13) above;
  • R 3 is as defined in paragraph (27) above;
  • R 6 is as defined in paragraph (41 ) above.
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri is as defined in paragraph (15) above;
  • R 3 is as defined in paragraph (29) above;
  • R 6 is as defined in paragraph (42) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri , R 2 , R3, R4, and R7 each have any one of the meanings defined herein;
  • Ri is as defined in any one of paragraphs (7) to (15) above;
  • R 2 is as defined in any one of paragraphs (16) to (23) above;
  • R 3 is as defined in any one of paragraphs (24) to (29) above;
  • R 4 is as defined in any one of paragraphs (30) to (34) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri is as defined in paragraph (13) above;
  • R 2 is as defined in paragraph (20) above;
  • R 3 is as defined in paragraph (27) above;
  • R 4 is as defined in paragraph (33) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • Ri is as defined in paragraph (15) above;
  • R 2 is as defined in paragraph (23) above;
  • R 3 is as defined in paragraph (29) above;
  • R 4 is as defined in paragraph (34) above;
  • R 7 is as defined in any one of paragraphs (46) to (53) above.
  • X is NH
  • R 2 , R 3 and R 5 are H
  • R 4 is F
  • R 6 is OCH 3
  • the compounds have the structural formula le (a sub-definition of formula I) shown below:
  • R7 is as defined in any one of paragraphs (46) to (53) above.
  • Particular compounds of the invention include those set forth in the Examples, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • Particular compounds of the invention include any one of the following:
  • a particular group of compounds of the invention include any one of the following: 2-Chloro-3-[(6,7-dimethoxyquinazolin-4-yl)amino]-6-methyl-phenol hydrochloride;
  • the various functional groups and substituents making up the compounds of the formula I are typically chosen such that the molecular weight of the compound of the formula I does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • an inorganic or organic acid for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001 ), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.
  • the present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H(D), and 3 H (T);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • O may be in any isotopic form, including 16 0 and 18 0; and the like.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • N-oxides Compounds of the formula I containing an amine function may also form N-oxides.
  • a reference herein to a compound of the formula I that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N- oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • N- oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA m-chloroperoxybenzoic acid
  • the compounds of formula I may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the formula I.
  • the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include
  • Ci- 6 alkyl esters such as methyl, ethyl and ferf-butyl
  • Ci- 6 alkoxymethyl esters such as
  • Ci- 6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters
  • 2-OXO-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and Ci- 6 alkoxycarbonyloxy- Ci- 6 alkyl esters such as methoxycarbonyloxymethyl and 1 - methoxycarbonyloxyethyl esters.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters
  • ester forming groups for a hydroxy group include Ci-i 0 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-i 0 alkoxycarbonyl groups such as ethoxycarbonyl, A/,A/-(Ci ⁇ carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include oc-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci- 4 alkylamine such as methylamine, a (Ci- 4 alkyl) 2 amine such as dimethylamine, A/-ethyl-A/-methylamine or diethylamine, a Ci- 4 alkoxy- C 2 - alkylamine such as 2-methoxyethylamine, a phenyl-Ci- alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a Ci- 4 alkylamine such as methylamine
  • a (Ci- 4 alkyl) 2 amine such as dimethylamine
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-i 0 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, A/-alkylaminomethyl, A/,A/-dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and
  • the in vivo effects of a compound of the formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I. As stated hereinbefore, the in vivo effects of a compound of the formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the present invention excludes any individual compounds not possessing the biological activity defined herein.
  • the compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
  • protecting groups see one of the many general texts on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons).
  • Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyi group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or f-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyi or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a ferf-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyi group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyi or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a f-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a f-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • Resins may also be used as a protecting group.
  • the present invention provides a process for preparing a compound of formula I (as defined herein), the process comprising the steps of:
  • Y or Z is any suitable leaving group; wherein X, Ri , R 2 , R3, R4, R5, R6, R7, each have any one of the meanings defined herein in relation to Formula I and the compound of Formula ⁇ is a compound of Formula I; or
  • one or more of X, Ri , R 2 , R3, R4, R5, Re, R7 of Formula ⁇ are precursors to the corresponding groups in formula I as defiend herein and said compound of Formula ⁇ is thereafter transformed into the compound of Formula I by further reaction to convert one or more precursors of X, Ri , R 2 , R3, R4, R5, Re, R7 in Formula ⁇ into a group X, Ri , R 2 , R3, R4, R5, Re, R7 of Formula I as defined herein (e.g. through deprotection of the relevant group(s) or through substitution of the relevant group(s), e.g. via nucleophilic substitution(s) thereof);
  • Y is any suitable leaving group, and is suitably capable of being substituted during coupling of Intermediate B with intermediate A via the X moiety.
  • Y is suitably a halo group (e.g. fluoro, chloro, bromo, iodo), suitably a halo selected from chloro, bromo, or iodo. Most suitably, Y is chloro.
  • Z is any suitable leaving group, and is suitably capable of being displaced during cyclisation to form a quinazoline following coupling of Intermediate A with intermediate C via the X moiety (and suitably via the cyano group).
  • Z is suitably an optionally substituted amino group.
  • Z may be selected from amino (i.e. NH 2 ), (1 -6C)alkylamino (e.g. NH(Me)), or di(1 - 6C)alkylamino (e.g. N(Me) 2 ). Most suitably, Z is N(Me) 2 .
  • reaction takes place in a suitable solvent, suitably a polar protic or aprotic organic solvent, suitably a solvent selected from acetonitrile, isopropanol, 1 ,4-dioxane, or a mixture of any one or more thereof.
  • a suitable solvent suitably a polar protic or aprotic organic solvent, suitably a solvent selected from acetonitrile, isopropanol, 1 ,4-dioxane, or a mixture of any one or more thereof.
  • reaction takes place in the presence of a suitable acid, for instance, an inorganic acid such as hydrochloric acid (suitably between 0.5 and 2 mole equivalents of said acid, suitable about 1 equivalent, relative to the number of moles of intermediate A).
  • a suitable acid for instance, an inorganic acid such as hydrochloric acid (suitably between 0.5 and 2 mole equivalents of said acid, suitable about 1 equivalent, relative to the number of moles of intermediate A).
  • the relative molar ratio of intermediate A and intermediate B in the reaction is respectively between 1 :2 and 2:1 , and is suitably about 1 :1 .
  • a suitable temperature may be, for example, a temperature above 50°C, suitably above 70°C, more suitably above 80°C, and most suitably above 90°C.
  • a suitable temperature may be, for example, a temperature below 200°C, suitably below 180°C, more suitably below 170°C, and most suitably below 160°C.
  • the reaction takes place over a suitable time period (such as between 10 minutes and 5 hours, or between 15 minutes and 2 hours, most suitably between 25 minutes and 70 minutes).
  • a catalyst suitably a coupling catalyst, suitably a coupling catalyst comprising a palladium or platinum species, most suitably a palladium catalyst.
  • a suitable solvent suitably a polar protic or aprotic organic solvent, suitably a solvent selected from acetonitrile, isopropanol, 1 ,4-dioxane, or a mixture of any one or more thereof, most suitably acetonitrile.
  • the reaction takes place in the presence of a suitable acid, for instance, acetic acid.
  • a suitable acid for instance, acetic acid.
  • the acid may be a solvent or co-solvent in the reaction.
  • the relative molar ratio of intermediate A and intermediate B in the reaction is respectively between 1 :2 and 2:1 , and is suitably about 1 :1 .
  • a suitable temperature may be, for example, a temperature above 50°C, suitably above 70°C, more suitably above 80°C, and most suitably above 90°C.
  • a suitable temperature may be, for example, a temperature below 200°C, suitably below 180°C, more suitably below 170°C, and most suitably below 160°C.
  • the reaction takes place over a suitable time period (such as between 10 minutes and 5 hours, or between 15 minutes and 2 hours, most suitably between 15 minutes and 30 minutes).
  • the source of heat may be microwave radiation.
  • the compound of formula ⁇ may be transformed into a compound of formula I by acid hydrolysis, for instance, in the presence of base or acid, most suitably a base (e.g. an inorganic hydroxide salt, such as lithium hydroxide).
  • base e.g. an inorganic hydroxide salt, such as lithium hydroxide.
  • the compound of formula ⁇ may be transformed into a compound of formula I by substitution of a fluoro substituent group, for instance by reacting the compound of formula ⁇ with an alcohol (e.g. isopropanol or cyclobutanol), suitably in the presence of a base, suitably a base strong enough to deprotonate the alcohol (e.g. sodium hydride), to effect nucleophilic substitution of the fluoro group with the relevant alkoxide of the alcohol.
  • an alcohol e.g. isopropanol or cyclobutanol
  • a base suitably a base strong enough to deprotonate the alcohol (e.g. sodium hydride), to effect nucleophilic substitution of the fluoro group with the relevant alkoxide of the alcohol.
  • Scheme 1 below depicts a generalised scheme illustrating how the compounds of formula I may be synthesised from Intemediate Compounds A and B.
  • X, Ri , R 2 , R3, R4, R5, Re, R7, and any associated substituent groups each have any one of the meanings defined herein.
  • Y is any suitable leaving group, and is suitably capable of being substituted during coupling of Intermediate B with intermediate A via the X moiety. Y is as defined herein.
  • Scheme 2 below depicts an alternative generalised scheme illustrating how the compounds of formula I may be synthesised from Intemediate Compounds A and C.
  • X, Ri , R 2 , R3, R4, R5, Re, R7, and any associated substituent groups each have any one of the meanings defined herein.
  • Z is any suitable leaving group, and is suitably capable of being displaced during cyclisation to form a quinazoline following coupling of Intermediate A with intermediate C via the X moiety (and suitably via the cyano group).
  • Z is as defined herein.
  • Example 216 The biological assays described in Example 216 herein may be used to measure the pharmacological effects of the compounds of the present invention.
  • the compounds of the invention demonstrate an IC 5 o of 1 ⁇ or less in the RET assay described in Example 216, with preferred compounds of the invention demonstrating an IC50 of 200 nM or less and the most preferred compounds of the invention demonstrating an IC50 of 50 nM or less.
  • the ratio of RET activity to KDR activity measured in the RET and KDR assays set out in Example 216 herein is greater than 5, more preferably greater than 10 and most preferably greater than 100.
  • the compounds of formula I suitably possess an activity of less than 5 ⁇ , with the preferred compounds demonstrating an activity of 1 ⁇ or less.
  • the compounds of the invention are compounds of formaul I as defined herein, with the proviso that the compound is not one of compounds 1 to 5 listed above.
  • a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • 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.
  • An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I 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 daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the present invention provides compounds that function as inhibitors of RET. Furthermore, the compounds of the present invention demonstrate an improved selectivity for RET relative to KDR (i.e. they are potent inhibitors of RET and poor inhibitors of KDR).
  • the present invention therefore provides a method of inhibiting RET kinase enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • the present invention also provides a method of selectively inhibiting RET kinase enzyme activity over KDR enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • the present invention also provides a method of treating a disease or disorder in which RET kinase activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • the present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer.
  • the cancer is human cancer.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of RET kinase enzyme activity.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the selective inhibition of RET kinase enzyme activity over KDR enzyme activity.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which RET kinase activity is implicated.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.
  • the medicament is for use in the treatment of human cancers.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of RET kinase enzyme activity.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the selective inhibition of RET kinase enzyme activity over KDR enzyme activity.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which RET kinase activity is implicated.
  • proliferative disorder are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.
  • the anti-proliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (by virtue of their inhibition of RET kinase enzyme activity, and/or the selective inhibition of RET kinase enzyme activity over KDR enzyme activity).
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
  • the proliferative condition to be treated is cancer, for example medullary thyroid cancer (MTC) or non-small cell lung cancer (NSCLC).
  • MTC medullary thyroid cancer
  • NSCLC non-small cell lung cancer
  • the compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcut
  • the antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such 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-fluorouracil 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, 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 5a- reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1 -yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01 /94341 ), A/-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-1 -yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole-5- carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1 -yl)ethoxy]-5-te
  • 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-erbB1 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 A/-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-A/-(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 hepatocyte growth factor family;
  • 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 for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU1 1248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1 - ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linom
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • (ix) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 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; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • (x) 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-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
  • the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
  • 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.
  • a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.
  • a combination for use in the treatment of a proliferative condition such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.
  • a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.
  • Flash chromatography was performed using pre-packed silica gel cartridges (KP- Sil SNAP, Biotage, Hengoed UK). Thin layer chromatography was conducted with 5 ⁇ 10 cm plates coated with Merck Type 60 F254 silica gel to a thickness of 0.25 mm. All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from the Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd., and used without further drying. HPLC grade solvents were obtained from Fisher Chemicals Ltd. or Romil Ltd.
  • LC-MS analyses were performed on a Waters Acquity UPLC system fitted with BEH C18 1 .7 ⁇ columns (2.1 ⁇ 50 mm) and with UV diode array detection (210-400 nm). Positive and negative mass ion detection was performed using a Waters SQD detector. Analyses were performed with either buffered acidic or basic solvents and gradients as detailed below: Low pH:
  • Some compounds were purified by preparative HPLC on a Waters FractionLynx MS autopurification system, with a Waters XBridge 5 ⁇ C18, 100 mm ⁇ 19 mm i.d. column, running at a flow rate of 20 mL/min with UV diode array detection (210 ⁇ 400 nm) and mass- directed collection using both positive and negative mass ion detection.
  • Product contains some bi-product pinacol and starting material impurities but is used in the next step without further purification.
  • the DCM was concentrated down and purified by flash chromatography using 0-50% ethyl acetate/isohexane over 45 minutes. Product containing fractions were concentrated down to give 3-amino-4-methoxy-2- methylphenol as a light pink solid 414mgs.
  • the DCM was concentrated down and purified by flash chromatography eluting with 0-60% ethyl acetate/isohexane over 40 minutes. Product containing fractions were concentrated to give 3-amino-2-methoxyphenol as an off white crystalline solid, 125mgs.

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Abstract

La présente invention concerne des composés quinazoléine de formule I qui fonctionnent comme inhibiteurs de l'activité de l'enzyme RET (réarrangée durant la transfection) kinase: (formule (1) où X, R1, R2, R3, R4, R5, R6 et R7 sont tels que définis ci-inclus. La présente invention concerne également des procédés de préparation de ces composés, des compositions pharmaceutiques les comprenant, et leur utilisation dans le traitement de troubles prolifératifs, tels que le cancer, ainsi que d'autres maladies ou états dans lesquels est impliquée l'activité RET kinase.
PCT/GB2014/053537 2013-11-29 2014-11-28 Composés quinazoléine WO2015079251A1 (fr)

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