WO2015079251A1 - Quinazoline compounds - Google Patents

Quinazoline compounds 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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French (fr)
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/en

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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.

Abstract

The present invention relates to quinazoline compounds of formula I that function as inhibitors of RET (rearranged during transfection) kinase enzyme activity: (Formula (I)) wherein X, R1, R2, R3, R4, R5, R6 and R7 are each as defined herein. 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.

Description

QUINAZOLINE COMPOUNDS
FIELD OF THE INVENTION
[0001] 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.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] RET (REarranged during Transfection) is a receptor tyrosine kinase (RTK) that forms part of a macromolecular receptor complex containing dimerized RET receptor, two co- receptors and a bound ligand. The glial derived neurtrophic factor (GDNF) family of ligands bind RET in association with one of four glycosyl phosphatidylinositol (GPI) anchored GDNF family a-receptors (GFRa). Ligand binding to the corresponding GFRa co-receptor triggers RET dimerization followed by trans-phosphorylation of intracellular signalling cascades. These downstream signalling networks play a key role in regulating cell survival, differentiation, proliferation, migration and chemotaxis.
[0004] Activating mutations in RET have been identified in familial and sporadic forms of medullary thyroid carcinomas (MTC) (Santoro & Carlomagno 2006; Schulmberger et al. 2008; Wells & Santoro 2009) and these correlate with aggressive disease progression (Elisei et al. 2008). Clinical benefit has been observed in MTC patients using the small molecule VEGFR2/EGFR inhibitor vandetanib (Wells et al. 201 1 ) which has recently been approved by the FDA & EMEA. 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). 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. Furthermore, 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). [0005] Furthermore, several recent publications (Ju et al, 2012; Lipson et al, 2012; Kohno et al, 2012; Wang et al, 2012; Chao et al, 2012) describe various RET fusion translocations {e.g. KIF5B-RET and CCDC6-RET) present in approximately 1 % of NSCLC (non-small cell lung carcinoma) patient samples, which may offer an important alternative disease segment in which a specific RET inhibitor would offer clinical benefit.
[0006] Therefore, there is a requirement for the development of more selective inhibitors of RET, in particular inhibitors that show less inhibition of KDR. It is anticipated that these more selective inhibitors will produce the desired therapeutic benefits associated with RET inhibition without the side effects associated with significant KDR inhibition. Such inhibitors will offer the potential of better therapy for cancers such as MTC and NSCLC and will widen the scope for the clinical use of RET inhibitors in earlier disease settings.
[0007] It is therefore an object of the present invention to provide further inhibitors of RET kinase enzyme activity.
[0008] 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.
SUMMARY OF THE INVENTION
[0009] According to a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
[0010] According to a further aspect of the present invention, there is provided 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.
[0011] According to a further aspect of the present invention, there is provided 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.
[0012] According to a further aspect of the present invention, there is provided 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.
[0013] According to a further aspect of the present invention, there is provided 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, or a pharmaceutical composition as defined herein.
[0014] According to a further aspect of the present invention, there is provided 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 as defined herein, or a pharmaceutical composition as defined herein.
[0015] According to a further aspect of the present invention, there is provided 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 as defined herein, or a pharmaceutical composition as defined herein.
[0016] According to a further aspect of the present invention, there is provided 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 as defined herein, or a pharmaceutical composition as defined herein.
[0017] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[0018] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.
[0019] According to a further aspect of the present invention, there 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. In a particular embodiment, the cancer is human cancer.
[0020] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of RET kinase enzyme activity.
[0021] According to a further aspect of the present invention, there is provided 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 relative to KDR enzyme activity.
[0022] According to a further aspect of the present invention, there is provided 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.
[0023] According to a further aspect of the present invention, there is provided the 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. [0024] Suitably, the proliferative disorder is cancer, suitably a human cancer (for example medullary thyroid cancer (MTC)).
[0025] According to a further aspect of the present invention, there is provide the 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.
[0026] According to a further aspect of the present invention, there is provided 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.
[0027] According to a further aspect of the present invention, there is provided 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 relative to KDR enzyme activity.
[0028] According to a further aspect of the present invention, there is provided 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.
[0029] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
[0030] According to a further aspect of the present invention, there is provided 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.
[0031] According to a further aspect of the present invention, there are provided novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.
[0032] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0033] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.
[0034] It is to be appreciated that 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.
[0035] 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.
[0036] In this specification the term "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. For example, "(1 -6C)alkyl" includes (1 -4C)alkyl, (1 - 3C)alkyl, propyl, isopropyl and f-butyl. A similar convention applies to other radicals, for example "phenyl(1 -6C)alkyl" includes phenyl(1 -4C)alkyl, benzyl, 1 -phenylethyl and 2-phenylethyl.
[0037] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.
[0038] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus, "(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.
[0039] "(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.
[0040] "(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.
[0041] "(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.
[0042] "(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.
[0043] "(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.
[0044] The term "halo" or "halogeno" refers to fluoro, chloro, bromo and iodo. [0045] The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). The term 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. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or S02 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. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular 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. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1 -yl or morpholin-4-yl ring that is linked via the ring nitrogen.
[0046] By "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, 4th Edition, Wiley Interscience, pages 131 -133, 1992. Examples of 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.
[0047] "Heterocyclyl(1 -6C)alkyl" means a heterocyclyl group covalently attached to a (1 - 6C)alkylene group, both of which are defined herein. [0048] The term "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. The term 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. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, 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. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
[0049] Examples of heteroaryl 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, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1 -b]thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl. "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. Examples of 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,
1 ,2,3,4-tetrahydro-1 ,8-naphthyridinyl, 1 ,2,3,4-tetrahydropyrido[2,3-£>]pyrazinyl and
3,4-dihydro-2H-pyrido[3,2-<b][1 ,4]oxazinyl.
[0050] 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.
[0051] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl. [0052] A bicyclic heteroaryl group may be, for example, a group selected from:
a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;
a thiophene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms; and
a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms.
[0053] Particular examples of 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.
[0054] Particular examples of 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.
[0055] "Heteroaryl(1 -6C)alkyl" means a heteroaryl group covalently attached to a (1 - 6C)alkylene group, both of which are defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
[0056] The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term 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. [0057] The term "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.
[0058] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by heterocyclyl.
[0059] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term "wherein a/any CH, CH2 or CH3 group within a R1 group is optionally substituted" suitably means that (any) one of the hydrogen radicals of the R1 group is substituted by a relevant stipulated group.
[0060] Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
[0061] The phrase "compound of the invention" means those compounds which are disclosed herein, both generically and specifically.
Compounds of the invention
[0062] The present invention provides a compound of Formula I:
Figure imgf000011_0001
Formula I
wherein:
X is NH, NRx, O or S, wherein Rx 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;
R2 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;
R3 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;
R4 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;
R5 is selected from hydrogen or a group defined by the formula:
Figure imgf000012_0001
wherein
L5 is absent or a linear or branched (1 -4C)alkylene;
X5 is absent or -C(0)0-, -0-, -C(O)-, -OC(O)-, -CH(OR5L)-, -N(Rj)-, -N(R5L)-C(0)-, -N(R5L)-C(0)0-, -C(0)-N(R5L)-, -S-, -SO-, -SO2-, -S(0)2N(R5L)-, or -N(R5L)S02- wherein R5i_ 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;
R6 is selected from hydrogen, or a group defined by the formula:
-O-Le-Xe-Qe
wherein
L6 is absent or a linear or branched (1 -4C)alkylene;
X6 is absent or selected from -0-, -C(0)-, -C(0)0-, -0C(0)-, -CH(OR6i_)-, -N(R6L), -N(R6L)-C(0)-, -N(R6L)-C(0)0-, -C(0)-N(R6L)-, -S-, -SO-, -SO2-, -S(0)2N(R6L)-, or -N(R6i_)S02- wherein R6L is selected from hydrogen or (1 -3C)alkyl;
Q6 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,
or Q6 and RL6 are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein R6 is optionally substituted (e.g. substituted on L6 and/or Q6) with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR6x, SR6x, S(0)R6X, S(0)2R6x, C(0)OR6x or C(0)NR6xR'6x, wherein R6x and R'6x are independently hydrogen, (1 -8C)alkyl, or R6x and R'6x are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
R7 is selected from hydrogen, (1 -6C)alkoxy, or a group defined by the formula: wherein
L7 is absent or a linear or branched (1 -4C)alkylene; X7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6L)-, -N(R7L)-, -N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -S02-, -S(0)2N(R7L)-, or -N(R7L)S02- wherein R7L is selected from hydrogen or (1 -3C)alkyl;
Q7 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,
or Q7 and R7L are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein R7 is optionally substituted (e.g. substituted on L7 and/or Q7) with one or more halo, hydroxyl, nitro, cyano, (1 -8C)alkyl, (1 -8C)alkanoyl , OR7x, SR7x,
S(0)R7X, S(0)2R7x, C(0)OR7X or C(0)NR7XR'7x, wherein R7X and R'7x are independently hydrogen, (1 -8C)alkyl, or R7X and R'7x are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; or
R7 is optionally substituted with one or more groups selected from oxo, (1 -
4C)haloalkyl, (1 -4C)hydroxyalkyl, C(0)R7y or NR7yR'7y, wherein R7y and R'7y are independently hydrogen or (1 -8C)alkyl;
or a pharmaceutically acceptable salt and/or solvate thereof.
[0063] In a further aspect, 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.
[0064] 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 , R2, R3, R4, R5, Re, R7, and any associated substitutent groups has any of the meanings defined hereinbefore or in any of paragraphs (1 ) to (53) hereinafter:-
(1 ) X is NH, N Rx or O, wherein Rx is methyl;
(2) X is NH or NRX, wherein Rx is methyl;
(3) X is NH or O;
(4) X is NH;
(5) X is N Rx and Rx is methyl;
(6) X is O;
(7) 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; (8) 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; (9) Ri is selected from fluoro, chloro, bromo, trifluoromethyl, (1 -4C)alkyl (eg. methyl), or (3- 6C)cycloalkyl;
(10) Ri is selected from fluoro, chloro, bromo, or (1 -2C)alkyl; wherein an alkyi group is optionally substituted with one or more fluoro;
(1 1 ) Ri is selected from fluoro, chloro, bromo, or (1 -2C)alkyl;
(12) Ri is selected from fluoro, chloro, bromo, methyl, ethyl or methoxy;
(13) Ri is selected from fluoro, chloro, bromo, methyl, or ethyl;
(14) Ri is selected from fluoro, chloro, bromo, or methyl;
(15) Ri is selected from fluoro, chloro, or bromo;
(16) R2 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;
(17) R2 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;
(18) R2 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;
(19) R2 is selected from hydrogen, fluoro, chloro, bromo, cyano, trifluoromethyl, (1 -2C)alkyl, (3-6C)cycloalkyl or (1 -2C)alkoxy;
(20) R2 is selected from hydrogen, fluoro, chloro, bromo, or (1 -2C)alkyl;
(21 ) R2 is selected from hydrogen, fluoro or (1 -2C)alkyl;
(22) R2 is selected from hydrogen, fluoro or methyl;
(23) R2 is hydrogen;
(24) R3 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;
(25) R3 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;
(26) R3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, cyano, trifluoromethyl, (1 - 2C)alkyl;
(27) R3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, or (1 -2C)alkyl;
(28) R3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, or methyl;
(29) R3 is hydrogen; (30) R4 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;
(31 ) R4 is selected from hydrogen, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, ( 1 - 4C)alkyl, (3-6C)cycloalkyl or ( 1 -4C)alkoxy;
(32) R4 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;
(33) R4 is selected from hydrogen, fluoro, chloro, (1 -2C)alkyl or (1 -2C)alkoxy;
(34) R4 is selected from hydrogen, fluoro, chloro, methyl;
(35) R5 is selected from hydrogen or a group defined by the formula:
Figure imgf000015_0001
wherein
L5 is absent;
X5 is absent; and
Qs is (1 -6C)alkyl or (3-6C)cycloalkyl;
(36) R5 is selected from hydrogen or a group defined by the formula:
Figure imgf000015_0002
wherein
L5 is absent;
X5 is absent; and
Qs is (1 -4C)alkyl or (3-4C)cycloalkyl;
(37) R5 is selected from hydrogen or ( 1 -4C)alkoxy;
(38) R5 is hydrogen;
(39) R6 is selected from hydrogen, or a group defined by the formula:
-O-Le-Xe-Qe
wherein
L6 is absent or a linear or branched (1 -4C)alkylene;
X6 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6L)-, -N(R6L), - N(R6L)-C(0)-, -N(R6L)-C(0)0-, -C(0)-N(R6L)-, -S-, -SO-, -SO2-, -S(0)2N(R6L)-, or -
N(R6L)S02- wherein R6L is selected from hydrogen or ( 1 -3C)alkyl;
Q6 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 -
6C)alkyl, 4, 5 or 6-membered heterocyclyl, or 4, 5 or 6-membered heterocyclyl-(1 - 6C)alkyl,
or Q6 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; wherein R6 is optionally substituted (e.g. substituted on L6 and/or Q6) with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR6x, SR6X, S(0)R6x, S(0)2R6x, C(0)OR6X or C(0)NR6xR'6x, wherein R6x and R'6x are independently hydrogen, (1 -8C)alkyl, or R6x and R'6x are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
(40) R6 is selected from hydrogen, or a group defined by the formula:
-O-Le-Xe-Qe
wherein
L6 is absent or a linear or branched (1 -4C)alkylene;
X6 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6L)-, -N(R6l_), -
N(R6L)-C(0)-, -N(R6L)-C(0)0-, -C(0)-N(R6L)-, -S-, -SO-, -S02-, -S(0)2N(R6L)-, or - N(R6L)S02- wherein R6L is selected from hydrogen or (1 -2C)alkyl;
Q6 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,
or Q6 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 R6 is optionally substituted (e.g. substituted on L6 and/or Q6) with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR6x, SR6X, S(0)R6x, S(0)2R6X, C(0)OR6x or C(0)NR6xR'6x, wherein R6x and R'6x are independently hydrogen, (1 -8C)alkyl, or R6x and R'6x are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
(41 ) R6 is selected from hydrogen, or a group defined by the formula:
-O-Le-Xe-Qe
wherein
L6 is absent or a linear or branched (1 -4C)alkylene;
X6 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -N(R6l_), -N(R6l_)-C(0)-, -C(0)-N(R6L)-, -S-, -SO-, -S02-, -S(0)2N(R6L)-, or -N(R6l_)S02- wherein R6L is selected from hydrogen or (1 -2C)alkyl;
Q6 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,
or Q6 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 R6 is optionally substituted (e.g. substituted on L6 and/or Q6) with one or more (1 -4C)alkyl;
(42) R6 is selected from hydrogen or methoxy;
(43) R6 is methoxy;
(44) R6 is selected from:
■ hydrogen;
■ (1 -3C)alkoxy;
■ -O-Le-Xe-Qea, wherein L6 is (1 -3C)alkylene; X6 is O; and Q6a 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 Q6a is a heteroaryl or heterocyclyl containing an N heteroatom Q6a is optionally substituted by (1 -6C)alkyl, (1 - 6C)alkanoyl, S(0)R6xa, S(0)2R6xa, or C(0)NR6xaR'6xa, wherein R6xa and R'6xa are independently hydrogen, (1 -6C)alkyl, or R6xa and R'6xa are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -O-Le-Xe-Qeb, wherein L6 is (1 -3C)alkylene; X6 is absent; and Q6b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q6b is a heteroaryl containing an N heteroatom Q6b is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R6xb, S(0)2R6xb, or
C(0)NR6xbR'6Xb, wherein R6xb and R'6xb are independently hydrogen, (1 -6C)alkyl, or R6xb and R'6xb are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -O-Le-Xe-Qec, wherein L6 is (1 -3C)alkylene; X6 is absent; and Q6c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q6c is a heterocyclyl containing an N heteroatom Q6c is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R6xc, S(0)2R6xc, or C(0)NR6xcR'6Xc, wherein R6xc and R'6xc are independently hydrogen, (1 -6C)alkyl, or R6xc and R'6xc are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -O-Le-Xe-Qed, wherein L6 is (1 -3C)alkylene; X6 is absent; and Q6d is (3- 6C)cycloalkyl optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R6xc, S(0)2R6Xc, or C(0)NR6xcR'6Xc, wherein R6xc and R'6xc are independently hydrogen, (1 -6C)alkyl, or R6xc and R'6xc are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -O-Le-Xe-Qee, wherein L6 is (1 -3C)alkylene; X6 is N(R6i_e); and wherein R6i_e hydrogen or (1 -3C)alkyl and Q6e is hydrogen or (1 -6C)alkyl, or R6Le and Q6e 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, OR6Xe, SR6Xe, S(0)R6Xe, S(0)2R6xe, or C(0)NR6xeR'6Xe, wherein R6Xe and R'6xe are independently hydrogen, (1 -4C)alkyl, or R6xe and R'6xe are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -O-Le-Xe-Qef, wherein L6 is (1 -3C)alkylene; X6 is S(0)m; wherein m is 0, 1 , or 2, and wherein Q6f is (1 -6C)alkyl, wherein Q6f is optionally substituted with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR6Xf, SR6Xf, S(0)R6Xf, S(0)2R6Xf, or
C(0)NR6XfR'6Xf, wherein R6Xf and R'6Xf are independently hydrogen, (1 -6C)alkyl, or R6Xf and R'6Xf are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -O-Le-Xe-Qeg, wherein L6 is (1 -3C)alkylene; X6 is S(0)2N(R6Lg) ; wherein R6i_g is hydrogen or (1 -3C)alkyl and Q6g is hydrogen or (1 -6C)alkyl, or R6i_g and Q6g 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, OR6Xg, SR6Xg, S(0)2R6Xg, or C(0)NR6XgR'6Xg, wherein R6Xg and R'6xg are independently hydrogen or (1 -6C)alkyl;
■ -O-Le-Xe-Qeh, wherein L6 is (1 -3C)alkylene; X6 is N(R6Lh)S(0)2; wherein R6Lh and Q6h are each independently hydrogen or (1 -8C)alkyl;
wherein R6 is optionally further substituted as described herein (if so, suitably on an L6 group).
(45) R6 is selected from:
■ hydrogen;
■ (1 -3C)alkoxy;
■ -O-Le-Xe-Qea, wherein L6 is (1 -3C)alkylene; X6 is O; and Q6a is hydrogen, (1 - 4C)alkyl;
■ -O-Le-Xe-Qec, wherein L6 is (1 -3C)alkylene; X6 is absent; and Q6c is heterocyclyl
(suitably containing one or more heteroatoms selected from O, S, or N), and where Q6c is a heterocyclyl containing an N heteroatom Q6c is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R6Xc, S(0)2R6Xc, or C(0)NR6XcR'6Xc, wherein R6Xc and R'6xc are independently hydrogen, (1 -6C)alkyl, or R6Xc and R'6xc are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein R6 is optionally further substituted with one or more (1 -4C)alkyl; (46) R7 is selected from hydrogen, (1 -6C)alkoxy, or a group defined by the formula: wherein
L7 is absent or a linear or branched (1 -4C)alkylene;
X7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6i_)-, -N(R7L)-, -
N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -SO2-, -S(0)2N(R7L)-, or - N(R7L)S02- wherein R7L is selected from hydrogen or (1 -2C)alkyl;
Q7 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 Q7 and R7i_ are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein R7 is optionally substituted (e.g. substituted on L7 and/or Q7) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR7x, SR7x, S(0)R7x, S(0)2R7x, C(0)OR7x or C(0)NR7xR'7x, wherein R7x and RVx are independently hydrogen, (1 -4C)alkyl, or R7x and RVx are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; or
R7 is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, (1 -4C)hydroxyalkyl, C(0)R7y or NR7yR'7y, wherein R7y and R'7y are independently hydrogen or (1 -6C)alkyl;
(47) R7 is selected from hydrogen, (1 -6C)alkoxy, or a group defined by the formula:
Figure imgf000019_0001
wherein
L7 is absent or a linear or branched (1 -4C)alkylene;
X7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6i_)-, -N(R7L)-, - N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -SO2-, -S(0)2N(R7L)-, or -
N(R7L)S02- wherein R7L is selected from hydrogen or (1 -2C)alkyl;
Q7 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 Q7 and R7L 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 R7 is optionally substituted (e.g. substituted on L7 and/or Q7) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR7x, SR7x, S(0)R7x, S(0)2R7x, C(0)OR7x or C(0)NR7xR'7x, wherein R7x and RVx are independently hydrogen, (1 -4C)alkyl, or R7x 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 R7 is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, ( 1 -4C)hydroxyalkyl, C(0) R7Y or NR7YR'7y, wherein R7Y and R'7Y are independently hydrogen or ( 1 -4C)alkyl;
(48) R7 is selected from hydrogen, ( 1 -4C)alkoxy, or a group defined by the formula:
-0-L7-X7-Q7
wherein
L7 is absent or a linear or branched (1 -4C)alkylene;
X7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6L)-, -N(R7L)-, - N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -S02-, -S(0)2N(R7L)-, or - N(R7L)S02- wherein R7L is selected from hydrogen or ( 1 -2C)alkyl;
Q7 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 Q7 and R7L 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 R7 is optionally substituted (e.g. substituted on L7 and/or Q7) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR7x, SR7x, S(0)R7x, S(0)2R7x, C(0)OR7x or C(0)NR7XR'7x, wherein R7X and R'7x are independently hydrogen, (1 -4C)alkyl;
(49) R7 is selected from hydrogen, ( 1 -4C)alkoxy, or a group defined by the formula:
-0-L7-X7-Q7
wherein
L7 is absent or a linear or branched (1 -4C)alkylene;
X7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6L)-, -N(R7L)-, - N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -S02-, -S(0)2N(R7L)-, or -
N(R7L)S02- wherein R7L is selected from hydrogen or ( 1 -2C)alkyl;
Q7 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 Q7 and R7L 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 R7 is optionally substituted (e.g. substituted on L7 and/or Q7) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR7x, SR7x, S(0)R7x, S(0)2R7x, C(0)OR7x or C(0)NR7XR'7x, wherein R7X and R'7x are independently hydrogen, (1 -4C)alkyl; or (50) R7 is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, (1 -4C)hydroxyalkyl, C(0)R7y or NR7yR'7y, wherein R7y and R'7y are independently hydrogen or (1 -2C)alkyl;R7 is selected from:
■ hydrogen;
■ (1 -3C)alkoxy;
■ -0-L7-X7-Q7a, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is -O; Q7a 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 Q7a is a heteroaryl or heterocyclyl containing an N heteroatom Q7a is optionally substituted by (1 -
6C)alkyl, (1 -6C)alkanoyl, S(0)R7Xa, S(0)2R7Xa, or C(0)NR7XaR'7xa, wherein R7Xa and R'7xa are independently hydrogen, (1 -6C)alkyl, or R7Xa and R'7xa are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -0-L7-X7-Q7b, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; Q7b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q7b is a heteroaryl containing an N heteroatom Q7b is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R7Xb, S(0)2R7xb, or C(0)NR7XbR'7xb, wherein R7Xb and R'7Xb are independently hydrogen, (1 -6C)alkyl, or R7Xb and R'7Xb are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -0-L7-X7-Q7c, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; and Q7c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q7c is a heterocyclyl containing an N heteroatom Q7c is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R7Xc, S(0)2R7Xc, or
C(0)NR7XcR'7Xc, wherein R7Xc and R'7Xc are independently hydrogen, (1 -6C)alkyl, or R7Xc and R'7Xc are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -0-L7-X7-Q7d, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; and Q7d is (3-8C)cycloalkyl optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl,
S(0)R7Xd, S(0)2R7Xd, or C(0)NR7XdR'7Xd, wherein R7Xd and R'7Xd are independently hydrogen, (1 -6C)alkyl, or R7Xd and R'7Xd are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -0-L7-X7-Q7e, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is N(R7Le); wherein R7Le is hydrogen or (1 -3C)alkyl and Q7e 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, OR7Xe, SR7Xe, S(0)R7Xe, S(0)2R7xe, or C(0)NR7XeR'7xe, wherein R7Xe and R xe are independently hydrogen, (1 -6C)alkyl, or R7Xe and R'7Xe are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -0-L7-X7-Q7f, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is S(0)m; wherein Q7f is (1 -8C)alkyl, wherein Q7f is optionally substituted with one or more (1 -8C)alkyl, (1 -8C)alkanoyl, OR7Xf, SR7Xf, S(0)R7Xf, S(0)2R7Xf, or C(0)NR7XfR'7Xf, wherein R7Xf and R'7Xf are independently hydrogen, (1 -8C)alkyl, or R7Xf and R'7Xf are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -0-L7-X7-Q7g, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is S(0)2N(R7Lg) ; wherein R7Lg is hydrogen or (1 -3C)alkyl and Q7g 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, OR7Xg, SR7Xg, S(0)2R7Xg, or C(0)NR7XgR'7Xg, wherein R7Xg and R'7Xg are independently hydrogen or (1 - 6C)alkyl;
■ -0-L7-X7-Q7h, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is N(R7Lh)S(0)2 wherein R7Lh is hydrogen or (1 -3C)alkyl and Q7h is hydrogen or (1 - 6C)alkyl.
wherein R7 is optionally further substituted as described herein.
R7 is selected from:
■ hydrogen;
■ (1 -3C)alkoxy;
■ -0-L7-X7-Q7a, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is -O; Q7a is hydrogen or (1 -8C)alkyl;
■ -0-L7-X7-Q7b, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; Q7b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q7b is a heteroaryl containing an N heteroatom Q7b is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R7Xb, S(0)2R7Xb, or C(0)NR7XbR'7Xb, wherein R7Xb and R'7Xb are independently hydrogen, (1 -6C)alkyl, or R7Xb and R'7Xb are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; ■ -O-L7-X7-Q7C, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; and Q7c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N), and where Q7c is a heterocyclyl containing an N heteroatom Q7c is optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0) R7Xc, S(0)2R7xc, or C(0)NR7XcR'7xc, wherein R7Xc and R'7xc are independently hydrogen, (1 -6C)alkyl, or R7Xc and R'7xc are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -0-L7-X7-Q7d, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; and Q7d is (3-8C)cycloalkyl optionally substituted by (1 -6C)alkyl, (1 -6C)alkanoyl, S(0)R7Xd, S(0)2R7xd, or C(0)NR7XdR'7xd, wherein R7Xd and R xd are independently hydrogen, (1 -6C)alkyl, or R7Xd and R xd are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
■ -0-L7-X7-Q7e, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is N(R7Le) ; wherein R7Le is hydrogen or (1 -3C)alkyl and Q7e 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, OR7Xe, SR7Xe, S(0)R7Xe, S(0)2R7Xe, or C(0)NR7XeR'7Xe, wherein R7Xe and R'7Xe are independently hydrogen, (1 -6C)alkyl, or R7Xe and R'7Xe are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; or said heterocyclic ring is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, (1 -4C)hydroxyalkyl, C(0) R7y or NR7yR'7y, wherein R7y and R'7y are independently hydrogen or (1 -4C)alkyl;
■ -0-L7-X7-Q7h, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is
N(R7Lh)S(0)2 wherein R7Lh is hydrogen or (1 -3C)alkyl and Q7h is (1 -6C)alkyl.
wherein R7 is optionally further substituted as described herein.
(52) R7 is selected from:
■ hydrogen;
■ (1 -3C)alkoxy;
■ -0-L7-X7-Q7a, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is -O; Q7a is hydrogen or (1 -6C)alkyl;
■ -0-L7-X7-Q7b, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; Q7b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or N); ■ -O-L7-X7-Q7C, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; and Q7c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N);
■ -0-L7-X7-Q7d, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; and Q7d is (3-8C)cycloalkyl;
■ -0-L7-X7-Q7e, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is N(R7Le) ; wherein R7i_e is hydrogen or (1 -3C)alkyl and Q7e 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);
■ -0-L7-X7-Q7h, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is N(R7Lh)S(0)2 wherein R7i_h is hydrogen or methyl and Q7h is (1 -6C)alkyl;
wherein R7 is optionally further substituted as described herein.
(53) R7 is selected from:
■ hydrogen;
■ (1 -3C)alkoxy;
■ -0-L7-X7-Q7a, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is -O; Q7a is (1 -6C)alkyl;
■ -0-L7-X7-Q7b, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; Q7b is heteroaryl (suitably containing one or more heteroatoms selected from O, S, or
N);
■ -O-L7-X7-Q7C, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is absent; and Q7c is heterocyclyl (suitably containing one or more heteroatoms selected from O, S, or N);
■ -0-L7-X7-Q7e, wherein L7 is a linear or branched (1 -3C)alkylene; X7 is N(R7i_e); wherein R7i_e is hydrogen or (1 -3C)alkyl and Q7e 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).
[0065] Suitably, 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.
[0066] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
[0067] Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, 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)].
[0068] Suitably an aryl group is phenyl.
[0069] Suitably, X is as defined in any one of paragraphs (1 ) to (6) above. Most suitably, X is NH.
[0070] Suitably, 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.
[0071] Suitably, R2 is as defined in any one of paragraphs (16) to (23) above. Most suitably, R2 is as defined in paragraphs (20) to (23) above.
[0072] Suitably, R3 is as defined in any one of paragraphs (24) to (29) above. Most suitably, R3 is as defined in paragraph (28) or (29) above.
[0073] Suitably, R4 is as defined in any one of paragraphs (30) to (34) above. Most suitably, R4 is as defined in paragraphs (33) or (34) above.
[0074] Suitably, R5 is as defined in any one of paragraphs (35) to (38) above. Most suitably, R5 is as defined in paragraph (38) above.
[0075] Suitably, R6 is as defined in any one of paragraphs (39) to (45) above. Most suitably, R6 is as defined in paragraphs (41 ) to (45) above.
[0076] Suitably, R7 is as defined in any one of paragraphs (46) to (53) above. Most suitably, R7 is as defined in paragraphs (48) to (53) above.
[0077] In a particular group of compounds of the invention, X is NH and R5 is H, i.e. the compounds have the structural formula la (a sub-definition of formula I) shown below:
Figure imgf000025_0001
Formula la
wherein Ri , R2, R3, R4, R6 and R7 each have any one of the meanings defined herein;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
[0078] In an embodiment of the compounds of formula la:
Ri is as defined in any one of paragraphs (7) to (15) above;
R2 is as defined in any one of paragraphs (16) to (23) above;
R3 is as defined in any one of paragraphs (24) to (29) above;
R4 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
R7 is as defined in any one of paragraphs (46) to (53) above.
[0079] In an embodiment of the compounds of formula la:
Ri is as defined in paragraph (13) above;
R2 is as defined in paragraph (20) above;
R3 is as defined in paragraph (27) above;
R4 is as defined in paragraph (33) above;
Re is as defined in paragraph (41 ) above; and
R7 is as defined in any one of paragraphs (46) to (53) above.
[0080] In an embodiment of the compounds of formula la:
Ri is as defined in paragraph (15) above;
R2 is as defined in paragraph (23) above;
R3 is as defined in paragraph (29) above;
R4 is as defined in paragraph (34) above;
Re is as defined in paragraph (42) above; and
R7 is as defined in any one of paragraphs (46) to (53) above.
[0081] In a particular group of compounds of the invention, X is NH, R2 is H, R3 is H, and R5 is H, i.e. the compounds have the structural formula lb (a sub-definition of formula I) shown below:
Figure imgf000026_0001
Formula lb
wherein Ri , R4, R6, and R7 each have any one of the meanings defined herein;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
[0082] In an embodiment of the compounds of formula lb:
Ri is as defined in any one of paragraphs (7) to (15) above;
R4 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
R7 is as defined in any one of paragraphs (46) to (53) above.
[0083] In an embodiment of the compounds of formula lb:
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 R7 is as defined in any one of paragraphs (46) to (53) above.
[0084] In an embodiment of the compounds of formula lb:
Ri is as defined in paragraph (15) above;
R4 is as defined in paragraph (34) above;
R6 is as defined in paragraph (42) above; and
R7 is as defined in any one of paragraphs (46) to (53) above.
[0085] In a particular group of compounds of the invention, X is NH, R2 is H, R4 is H, and R5 is H, i.e. the compounds have the structural formula Ic (a sub-definition of formula I) shown below:
Figure imgf000027_0001
Formula Ic
wherein Ri , R3, R6 and R7 each have any one of the meanings defined herein;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
[0086] In an embodiment of the compounds of formula Ic:
Ri is as defined in any one of paragraphs (7) to (15) above;
R3 is as defined in any one of paragraphs (24) to (29) above;
R6 is as defined in any one of paragraphs (39) to (45) above; and
R7 is as defined in any one of paragraphs (46) to (53) above.
[0087] In an embodiment of the compounds of formula Ic:
Ri is as defined in paragraph (13) above;
R3 is as defined in paragraph (27) above;
R6 is as defined in paragraph (41 ) above; and
R7 is as defined in any one of paragraphs (46) to (53) above.
[0088] In an embodiment of the compounds of formula Ic:
Ri is as defined in paragraph (15) above;
R3 is as defined in paragraph (29) above;
R6 is as defined in paragraph (42) above; and
R7 is as defined in any one of paragraphs (46) to (53) above.
[0089] In a particular group of compounds of the invention, X is NH, R5 is H and R6 is OCH3, i.e. the compounds have the structural formula Id (a sub-definition of formula I) shown below:
Figure imgf000028_0001
Formula Id
wherein Ri , R2, R3, R4, and R7 each have any one of the meanings defined herein;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
[0090] In an embodiment of the compounds of formula Id:
Ri is as defined in any one of paragraphs (7) to (15) above;
R2 is as defined in any one of paragraphs (16) to (23) above;
R3 is as defined in any one of paragraphs (24) to (29) above;
R4 is as defined in any one of paragraphs (30) to (34) above; and
R7 is as defined in any one of paragraphs (46) to (53) above.
[0091] In an embodiment of the compounds of formula Id:
Ri is as defined in paragraph (13) above;
R2 is as defined in paragraph (20) above;
R3 is as defined in paragraph (27) above;
R4 is as defined in paragraph (33) above;
R7 is as defined in any one of paragraphs (46) to (53) above.
[0092] In an embodiment of the compounds of formula Id:
Ri is as defined in paragraph (15) above;
R2 is as defined in paragraph (23) above;
R3 is as defined in paragraph (29) above;
R4 is as defined in paragraph (34) above; and
R7 is as defined in any one of paragraphs (46) to (53) above.
[0093] In a particular group of compounds of the invention, X is NH, R2, R3 and R5 are H, R4 is F and R6 is OCH3, i.e. the compounds have the structural formula le (a sub-definition of formula I) shown below:
Figure imgf000029_0001
Formula le
wherein Ri is as defined in paragraph (14) above and R7 has any one of the meanings defined herein;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
[0094] In an embodiment of the compounds of formula le, R7 is as defined in any one of paragraphs (46) to (53) above.
[0095] Particular compounds of the invention include those set forth in the Examples, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0096] Particular compounds of the invention include any one of the following:
3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2-methylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,4,6-trimethylphenol;
2-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenol ;
2- Bromo-3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenol;
3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2-ethylphenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,5-dimethylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,6-difluorophenol;
3-((6,7-dimethoxyquinazolin-4-yl)oxy)-2,4-difluorophenol;
2-Chloro-3-[(5-isopropoxyquinazolin-4-yl)amino]phenol;
2-Chloro-3-((5-cyclobutoxyquinazolin-4-yl)amino)phenol;
2-Chloro-3-[(6,7-dimethoxyquinazolin-4-yl)amino]-6-methyl-phenol hydrochloride;
2- Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)phenol;
3- [(6,7-Dimethoxyquinazolin-4-yl)amino]-2-methyl-phenol hydrochloride;
3-((6,7-dimethoxyquinazolin-4-yl)amino)-2,6-dimethylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2-fluorophenol;
3-[(6,7-Dimethoxyquinazolin-4-yl)amino]-4-fluoro-2-methyl-phenol hydrochloride;
3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2,6-difluorophenol hydrochloride;
3-[[7-(2-Hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]-2-methyl-phenol;
Methyl 2-((4-((3-hydroxy-2-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propanoate; 2-Chloro-3-[[7-(2-hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]phenol;
Methyl 2-((4-((2-chloro-3-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propanoate; 4-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-metriylphenol;
Methyl 2-((4-((2-chloro-3-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)acetate hydrochloride;
3- ((6,7-Bis(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
3-((7-methoxy-6-((1 -morpholinopropan-2-yl)oxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
4 luoro-3-((7-Methoxy-6-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-4-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2- ((4-((2-Chloro-3-hydroxyphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetamide;
N-(2-((4-((2-Chloro-3-hydroxyphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide hydrochloride;
4- Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-2-methylphenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2,4-difluorophenol;
4- Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-2-fluorophenol;
2-Chloro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)phenol hydrochloride; 4-Fluoro-3-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-3-((6-methoxy-7-(2-(methylthio)ethoxy)quinazolin-4-yl)amino)phenol;
2- Chloro-3-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)amino)phenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2-methoxyphenol;
2-Methoxy-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol hydrochloride; 2-Chloro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2,4-Difluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
4- Chloro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-3-((6-methoxy-7-((3-methyloxetan-3-yl)methoxy)quinazolin-4-yl)amino)phenol;
4-Chloro-2-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2- Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-fluorophenol;
N-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide;
4-Fluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-3-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)phenol;
N-(2-((4-((6-Chloro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide;
2,4-Difluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)phenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2,6-difluorophenol;
4-Fluoro-3-((6-methoxy-7-((3-methyloxetan-3-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
1 -(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)pyrrolidin-2-one;
3-((7-(Cyclopropylmethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-metriylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2,4-dimetriylphenol;
3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-metriylphenol hydrochloride; 4-Fluoro-3-((6-methoxy-7-((5-methyl-1 ,2,4-oxadiazol-3-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
2,4-Difluoro-3-((6-methoxy-7-((5-methyl-1 ,2,4-oxadiazol-3-yl)methoxy)quinazolin-4- yl)amino)phenol;
2- chloro-4 luoro-3-((6-methoxy-7-((5-methylfuran-2-yl)methoxy)quinazolin-4-yl)amino)phenol; 4-Fluoro-3-((6-methoxy-7-((1 -methyl-1 H-imidazol-5-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-(1 H-lmidazol-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(4-methylpiperazin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
2-Bromo-3-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol hydrochloride;
2- Bromo-3-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol hydrochloride;
5- Fluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol; 3-((6,7- Dimethoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
5-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
4- Fluoro-3-((6-methoxy-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
Ethyl 2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetate; 3-((7-(2,2-Dimethoxyethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
5- Fluoro-3-((6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetic acid; 2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-1 - morpholinoethanone;
2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetaldehyde;
1 - (2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)piperidin-4-ol;
2- ((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetamide; 2((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-N-methyl acetamide; A/it yl-2((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy) acetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/- isopropylacetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/- propylacetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/,A/- dimethylacetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/-isopropyl-N- methylacetamide;
Λ/-(fer Butyl)-2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)- A/-methylacetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/-met yl-A/- propylacetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/,A/- dipropylacetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/- isobutylacetamide;
A/-Butyl2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)- acetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/-(2- hydroxyethyl)acetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/-(2- methoxyethyl)acetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/-(2- hydroxyethyl)-A/-methylacetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/-(2- methoxyethyl)-A/-methylacetamide;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/-(3- methoxypropyl)acetamide;
A/-Cyclobutyl-2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)acetamide;
A/-Cyclopenyl-2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)acetamide;
A/-Cyclo exyl-2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)acetamide; 2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-A/-(tetra y 2 - -pyran-4-yl)acetam ide ;
[0097] 2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-1 - (pyrrolidin-1 -yl)ethanone;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-1 -(piperidin-1 - yl)ethanone;
1 - (Azepan-1 -yl)-2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)ethanone;
2- ((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-1 - morpholinoet anone;
2- ((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-1 -(4- methylpiperazin-1 -yl)ethanone;
1 -(4-Acetylpiperazin-1 -yl)-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethanone;
2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)-1 -(4- met oxylpiperidiin-1 -yl)-et anone;
4-Fluoro-3-((6-met oxy-7-(2-(met ylamino)et oxy)quinazolin-4-yl)amino)-2-met yl phenol;
3- ((7-(2-(Ethylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((7-(2-(isopropylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2-methyl phenol; 3-((7-(2-(feA -Butylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(propylamino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol;
4-Fluoro-3-((7-(2-(isobutylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2-methylphenol
3- ((7-(2-(Butylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methyl phenol;
4- Fluoro-3-((7-(2-((2-hydroxyethyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-((2-methoxyethyl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((7-(2-((3-hydroxypropyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-((3-methoxypropyl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)amino)propanenitrile;
3-((7-(2-(Cyclobutylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; 3-((7-(2-(Cyclopentylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
3- ((7-(2-(Cyclohexylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-((3-methyloxetan-3-yl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-met oxy-7-(2-((2-morpholinoet yl)amino)et oxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(((tetrahydrofuran-2-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-((tetrahydro-2H-pyran-4-yl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-met oxy-7-(2-(((1 -met yl-1 H-imidazol-5-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-met ylphenol;
4-Fluoro-3-((6-met oxy-7-(2-(((1 -met yl-1 H-imidazol-4-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-met ylphenol;
4- Fluoro-3-((6-met oxy-7-(2-(((1 -methyl-1 H-pyrazol-4-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol;
3- ((7-(2-(Azetidin-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(pyrrolidin-1 -yl)ethoxy)-quinazolin-4-yl)amino)-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(piperdin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2-methylphenol;
3- ((7-(2-(Azepan-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)amino)-2-methylphenol;
1 -(4-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)piperazin-1 -yl)ethan-1 -one;
4-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)thiomorpholine 1 ,1 -dioxide
1 -(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)piperidin-4-ol;
4-Fluoro-3-((6-methoxy-7-(2-(4-methoxypiperidin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((7-(2-(Dimethylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
3- ((7-(2-(Diethylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((7-(2-(isopropyl(methyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-(ferf-Butyl(methyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(methyl(propyl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((-7-(2-(Dipropylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; 4-Fluoro-3-((7-(2-((2-hydroxyethyl)(methyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol; 4-Fluoro-3-((6-met oxy-7-(2-((2-met oxyet yl)(met yl)amino)et oxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-(3,4-Dihydroisoquinolin-2(1 H)-yl)et oxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol;
4-Fluoro-3-((7-(2-(2-(hydroxymet yl)piperdin-1 -yl)et oxy)-6-met oxy-quinazolin-4-yl)amino)-2- methylphenol;
4- Fluoro-3-((7-(2-(3-fluoropyrrolidin-1 -yl)et oxy)-6-met oxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-met oxy-7-(2-(3-trifluoromet ylpyrrolidin-1 -yl)et oxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(4-methyl-1 ,4-diazepan-1 -yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-(1 ,4-Oxazepan-4-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(piperazin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2-methylphenol 3-((7-(3-Aminopropoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-(methylamino)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 3-((7-(3-(Dimethylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
3- ((7-(3-(Ethylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((7-(3-(isopropylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2-methylphenol; 4-Fluoro-3-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)-2-methylphenol;
1 -(4-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)propyl)piperazin-1 -yl)ethan-1 -one;
4-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)propyl)thiomorpholine 1 ,1 -dioxide;
1 -(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)propyl)piperidin-4-ol;
4-Fluoro-3-((6-methoxy-7-(3-(4-methoxypiperidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(3-(Azetidin-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro 2-methylphenol; 4-Fluoro-3-((6-methoxy-7-(3-(pyrrolidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(3-(piperidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 3-((7-(3-(Azepan-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; 3-((7-(3-(Diethylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
3- ((7-(3-(Dipropylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; 4-Fluoro-3-((7-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4- Fluoro-3-((6-methoxy-7-(3-((2-methoxyethyl)(methyl)amino)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(3-(feA -Butyl(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol;
4- Fluoro-3-((6-methoxy-7-(3-(methyl(propyl)amino)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(3-(3,4-Dihydroisoquinolin-2(1 /^-yl)propoxy)-6-methoxy
methylphenol;
4- Fluoro-3-((7-(3(2-(hydroxymethyl)piperidin-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((7-(3-(3-fluoropyrrolidin-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-(2-(trifluoromethyl)pyrrolidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((7-(3-(isopropyl(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-(4-methyl-1 ,4-diazepan-1 -yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(3-(1 ,4-Oxezepan-4-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(3-(piperazin-1 -yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 4-Fluoro-3-((6-methoxy-7-(3-(4-methylpiperazin-1 -yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)acetamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)propionamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)isobutyramide;
2-(Dimethylamino)-A/-(2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)acetamide;
3-(Dimethylamino)-A/-(2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)propanamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)methanesulfonamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-1 - methyl- 1 /-/-pyrazole-3-carboxamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-/V- methylacetamide; A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-m
methylcyclopropanecarboxamide;
2- (Dimethylamino)-A/-(2-((4-((6-fluoro-3-hydroxy-2-m
yl)oxy)ethyl)-A/-methylacetamide;
3-(Dimethylamino)-A/-(2-((4-((6-fluoro-3-hydroxy-2-m
yl)oxy)ethyl)-A/-methylpropanamide;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)et yl)-A/- met ylmet anesulfonamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)acetamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)propionamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)isobutyramide;
2-(Dimethylamino)-A/-(3-((4-((6-fluoro-3-hydroxy-2-m
yl)oxy)propyl)acetamide;
3- (Dimethylamino)-A/-(3-((4-((6-fluoro-3-hydroxy-2-m
yl)oxy)propyl)propanamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)methanesulfonamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)ethanesulfonamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-1 - methyl- 1 - -pyrazole-3-carboxamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-/V- methylacetamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-/V- methylcyclopropanecarboxamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-/V- methylisobutyramide;
2- (Dimethylamino)-A/-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazoli yl)oxy)propyl)-A/-methylacetamide;
3- (Dimethylamino)-A/-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazoli^ yl)oxy)propyl)-A/-methylpropanamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-/V- methylmethanesulfonamide; A/-(3-((4-((6 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyqum^
methylethanesulfonamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)propyl)-A/,1 - dimethyl-1 - -pyrazole-3-carboxamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-A/,3- dimethylisoxazole-5-carboxamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)propyl)-A/,1 - dimet yl-1 - -imidazole-2-carboxamide;
3-((6-Met oxy-7-((1 -met ylpiperidin-4-yl)met oxy)quinazolin-4-yl)amino)-2-met ylphenol;
2-C loro-3-((6-met oxy-7-((1 -met ylpiperidin-4-yl)met oxy)quinazolin-4-yl)amino)p enol;
2-C loro-3-((6-met oxy-7-((1 -met ylpiperidin-4-yl)met oxy)quinazolin-4-yl)amino)-6- methylphenol;
4-Fluoro-3-((6-met oxy-7-((1 -met ylpiperidin-4-yl)met oxy)quinazolin-4-yl)amino)-2- methylphenol; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0098] 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;
2- Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)phenol;
3- [(6,7-Dimethoxyquinazolin-4-yl)amino]-2-methyl-phenol hydrochloride;
3-((6,7-dimethoxyquinazolin-4-yl)amino)-2,6-dimethylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2-fluorophenol;
3-[(6,7-Dimethoxyquinazolin-4-yl)amino]-4-fluoro-2-methyl-phenol hydrochloride;
3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2,6-difluorophenol hydrochloride;
3- [[7-(2-Hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]-2-methyl-phenol;
Methyl 2-((4-((3-hydroxy-2-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propanoate; 2-Chloro-3-[[7-(2-hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]phenol;
Methyl 2-((4-((2-chloro-3-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propanoate;
4- Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
Methyl 2-((4-((2-chloro-3-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)acetate hydrochloride;
3-((6,7-Bis(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
3- ((7-methoxy-6-((1 -morpholinopropan-2-yl)oxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
4- fluoro-3-((7-Methoxy-6-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-4-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2-((4-((2-Chloro-3-hydroxyphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetamide;
N-(2-((4-((2-Chloro-3-hydroxyphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide hydrochloride; 4-Chloro-3-((6J-dimethoxyquinazolin-4-yl)amino)-2-methylphenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2,4-difluoroprienol;
4- Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-2-fluoroprienol;
2-Chloro-3-((6-methoxy-7-(pyridin-3-ylmetrioxy)quinazolin-4-yl)amino)prienol hydrochloride; 4-Fluoro-3-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-3-((6-methoxy-7-(2-(methylthio)ethoxy)quinazolin-4-yl)amino)phenol;
2- Chloro-3-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)amino)phenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2-methoxyphenol;
2-Methoxy-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol hydrochloride; 2-Chloro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2,4-Difluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
4- Chloro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-3-((6-methoxy-7-((3-methyloxetan-3-yl)methoxy)quinazolin-4-yl)amino)phenol;
4-Chloro-2-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-fluorophenol;
N-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide;
4-Fluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2- Chloro-3-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)phenol;
N-(2-((4-((6-Chloro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide;
2,4-Difluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)phenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2,6-difluorophenol;
4- Fluoro-3-((6-methoxy-7-((3-methyloxetan-3-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
1 -(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)pyrrolidin-2-one;
3-((7-(Cyclopropylmethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2,4-dimethylphenol;
3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol hydrochloride;
4- Fluoro-3-((6-methoxy-7-((5-methyl-1 ,2,4-oxadiazol-3-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
2,4-Difluoro-3-((6-methoxy-7-((5-methyl-1 ,2,4-oxadiazol-3-yl)methoxy)quinazolin-4- yl)amino)phenol;
2-chloro-4-fluoro-3-((6-methoxy-7-((5-methylfuran-2-yl)methoxy)quinazolin-4-yl)amino)phenol; 4-Fluoro-3-((6-methoxy-7-((1 -methyl-1 H-imidazol-5-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol; 3- ((7-(2-(1 H-lmidazol-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(4-methylpiperazin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
2- Bromo-3-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol hydrochloride;
2-Bromo-3-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol hydrochloride;
5- Fluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
5-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
Ethyl 2-((4-((5 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetate;
3-((7-(2,2-Dimethoxyethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
5- Fluoro-3-((6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetaldehyde;
2- ((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-(tetrahydro- 2 - -pyran-4-yl)acetam ide ;
3- ((2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)amino)propanenitrile;
3-((7-(2-(Cyclobutylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-((3-methyloxetan-3-yl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(((1 -methyl-1 - -imidazol-5-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol;
3-((7-(2-(Azetidin-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)amino)-2-methylphenol;
1 -(4-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)piperazin-1 -yl)ethan-1 -one;
4-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)thiomorpholine 1 ,1 -dioxide;
1 -(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)piperidin-4-ol;
4-Fluoro-3-((6-methoxy-7-(2-(4-methoxypiperidin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((-7-(2-(Dipropylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; 4-Fluoro-3-((7-(2-(2-(hydroxymethyl)piperdin-1 -yl)ethoxy)-6-methoxy-quinazolin-4-yl)amino)-2- methylphenol; 4-Fluoro-3-((7-(2-(3 luoropyrrolidin-1 -yl)et oxy)-6-met oxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-met oxy-7-(2-(4-met yl-1 ,4-diazepan-1 -yl)et oxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((7-(2-(1 ,4-Oxazepan-4-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; 4-Fluoro-3-((6-met oxy-7-(2-(piperazin-1 -yl)et oxy)quinazolin-4-yl)amino)-2-met ylphenol;
3- ((7-(3-Aminopropoxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro-2-met ylphenol;
4- Fluoro-3-((6-met oxy-7-(3-(met ylamino)propoxy)quinazolin-4-yl)amino)-2-met ylphenol;
3- ((7-(3-(Dimet ylamino)propoxy)-6-met oxyquinazolin-4-yl)amino)-4 luoro-2-met ylphenol; 3-((7-(3-(Et ylamino)propoxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro-2-met ylphenol;
4- Fluoro-3-((7-(3-(isopropylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2-methylphenol; 4-Fluoro-3-((6-met oxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)-2-met ylphenol;
1 -(4-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)piperazin-1 -yl)ethan-1 -one;
4-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)thiomorpholine 1 ,1 -dioxide;
1 -(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)piperidin-4-ol;
4-Fluoro-3-((6-methoxy-7-(3-(4-methoxypiperidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(3-(Azetidin-1 -yl)propoxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro 2-met ylphenol;
4- Fluoro-3-((6-methoxy-7-(3-(pyrrolidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 4-Fluoro-3-((6-methoxy-7-(3-(piperidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 3-((7-(3-(Azepan-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; 3-((7-(3-(Diet ylamino)propoxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro-2-met ylphenol;
3- ((7-(3-(Dipropylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((7-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-((2-methoxyethyl)(methyl)amino)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(3-(ferf-Butyl(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol;
4- Fluoro-3-((6-methoxy-7-(3-(methyl(propyl)amino)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((7-(3-(3,4-Dihydroisoquinolin-2(1 H)-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol; 4-Fluoro-3-((7-(3(2-(hydroxymethyl)piperidin-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)am methylphenol;
4-Fluoro-3-((7-(3-(3 luoropyrrolidin-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((7-(3-(isopropyl(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-(piperazin-1 -yl)propoxy)quinazolin-4-yl)^
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-metrioxyquinazolin-7- yl)oxy)ethyl)propionamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-metrioxyquinazolin-7- yl)oxy)ethyl)isobutyramide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-metrioxyquinazolin-7- yl)oxy)ethyl)methanesulfonamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyqm
methyl- 1 - -pyrazole-3-carboxamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-/V- methylacetamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-/V- methylcyclopropanecarboxamide;
A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-/V- methylmethanesulfonamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)propyl)acetamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)propyl)propionamide;
2- (Dimethylamino)-A/-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)propyl)acetamide;
3- (Dimethylamino)-A/-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)propyl)propanamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)propyl)ethanesulfonamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-/V- methylacetamide;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0099] 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.
[00100] 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. In addition, 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.
[00101] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. 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".
[00102] 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.
[00103] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and180; and the like.
[00104] It is also to be understood that certain compounds of the formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.
[00105] It is also to be understood that certain compounds of the formula I may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.
[00106] Compounds of the formula I may exist in a number of different tautomeric forms and references to compounds of the formula I include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by formula I. Examples of 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.
Figure imgf000044_0001
keto enol enolate
[00107] 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. Where a compound contains several amine functions, 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. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, 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.
[00108] 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.
[00109] Accordingly, 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.
[00110] 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.
[00111] 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);
b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);
c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 1 13-191
(1991 );
d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1 -38 (1992);
e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);
f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);
g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and
h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.
[001 12] 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-6alkyl esters such as methyl, ethyl and ferf-butyl, Ci-6alkoxymethyl esters such as
methoxymethyl esters, Ci-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters,
3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- Ci-6alkyl esters such as
cyclopentylcarbonyloxymethyl and 1 -cyclohexylcarbonyloxyethyl esters,
2-OXO-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and Ci-6alkoxycarbonyloxy- Ci-6alkyl esters such as methoxycarbonyloxymethyl and 1 - methoxycarbonyloxyethyl esters.
[001 13] 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
(including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-i0alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-i0alkoxycarbonyl groups such as ethoxycarbonyl, A/,A/-(Ci ^carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, A/,A/-dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(Ci- 4alkyl)piperazin-1 -ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include oc-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
[00114] 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-4alkylamine such as methylamine, a (Ci- 4alkyl)2amine such as dimethylamine, A/-ethyl-A/-methylamine or diethylamine, a Ci-4alkoxy- C2- alkylamine such as 2-methoxyethylamine, a phenyl-Ci- alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
[00115] 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-i0alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and
substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, A/-alkylaminomethyl, A/,A/-dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and
4-(Ci- alkyl)piperazin-1 -ylmethyl.
[00116] 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).
[00117] Though 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.
[00118] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.
Synthesis
[00119] 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.
[00120] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.
[00121] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.
[00122] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.
[00123] For examples of 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.
[00124] Thus, if 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.
[00125] By way of example, 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. Thus, for example, 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.
Alternatively 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.
[00126] 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. Thus, for example, 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. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
[00127] 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.
[00128] Resins may also be used as a protecting group.
[00129] The methodology employed to synthesise a compound of formula I will vary depending on the nature of X, Ri , R2, R3, R4, R5, Re, R7, and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.
[00130] Once a compound of formula I has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:
(i) removing any protecting groups present;
(ii) converting the compound formula I into another compound of formula I;
(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or
(iv) forming a prodrug thereof.
[00131] An example of (ii) above is when a compound of formula I is synthesised and then one or more of the groups of X, Ri , R2, R3, R4, R5, Re, R7, may be further reacted to change the nature of the group and provide an alternative compound of formula I. For example, the compound can be reacted to covert Ri into a substituent group other than hydrogen.
[00132] The resultant compounds of formula I can be isolated and purified using techniques well known in the art.
[00133] The present invention provides a process for preparing a compound of formula I (as defined herein), the process comprising the steps of:
reacting a compound of formula A:
Figure imgf000049_0001
with a compound of formula B:
Figure imgf000049_0002
Formula B
or with a compound of formul
Figure imgf000049_0003
to form a compound of formula Γ:
Figure imgf000049_0004
Formula Γ
wherein Y or Z is any suitable leaving group; wherein X, Ri , R2, R3, R4, R5, R6, R7, each have any one of the meanings defined herein in relation to Formula I and the compound of Formula Γ is a compound of Formula I; or
one or more of X, Ri , R2, R3, R4, R5, Re, R7 of Formula Γ are precursors to the corresponding groups in formula I as defiend herein and said compound of Formula Γ is thereafter transformed into the compound of Formula I by further reaction to convert one or more precursors of X, Ri , R2, R3, R4, R5, Re, R7 in Formula Γ into a group X, Ri , R2, 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);
and optionally thereafter (and if necessary):
(i) transforming the compound of Formula I into another compound of Formula I by, for example, converting one or more of X, Ri , R2, R3, R4, R5, Re, R7 into another group X, Ri , R2, R3, R4, R5, Re, R7 accoridng to formula I defined herein;
(ii) removing any protecting groups present;
(iii) converting the compound formula I into another compound of formula I;
(iv) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or
(v) forming a prodrug thereof.
[00134] 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.
[00135] 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. For instance, Z may be selected from amino (i.e. NH2), (1 -6C)alkylamino (e.g. NH(Me)), or di(1 - 6C)alkylamino (e.g. N(Me)2). Most suitably, Z is N(Me)2.
[00136] Suitably one or more or all of the following features apply in relation to the reaction between the compounds of formulae A and B:
• The 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.
• The 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).
• 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 .
• The reaction takes place at a suitable temperature. 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). · The reaction takes place in the presence of a catalyst, suitably a coupling catalyst, suitably a coupling catalyst comprising a palladium or platinum species, most suitably a palladium catalyst.
[00137] Suitably one or more of the following features apply in relation to the second stage of the reaction between the compounds of formulae A and B:
· The 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, most suitably acetonitrile.
• The reaction takes place in the presence of 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 .
• The reaction takes place at a suitable temperature. 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).
[00138] The source of heat may be microwave radiation.
[00139] The compound of formula Γ 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).
[00140] The compound of formula Γ may be transformed into a compound of formula I by substitution of a fluoro substituent group, for instance by reacting the compound of formula Γ 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.
[00141] Scheme 1 below depicts a generalised scheme illustrating how the compounds of formula I may be synthesised from Intemediate Compounds A and B.
Figure imgf000052_0001
Scheme 1 - Generic reaction scheme for the synthesis of compounds of formula I
[00142] X, Ri , R2, 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.
[00143] Scheme 2 below depicts an alternative generalised scheme illustrating how the compounds of formula I may be synthesised from Intemediate Compounds A and C.
Figure imgf000052_0002
Scheme 2 - Alternative generic reaction scheme for the synthesis of compounds of
formula I [00144] In Scheme 2, X, Ri , R2, 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.
[00145] The compounds of Formula A, B, and C are intermediates from which a variety of compounds of formula I can be made.
[00146] In a further aspect of the invention, there is provided a compound of formula I obtainable by a process as defined herein.
[00147] In a further aspect of the invention, there is provided a compound of formula I obtained by a process as defined herein.
[00148] In a further aspect of the invention, there is provided a compound of formula I directly obtained by a process as defined herein.
[00149] In a further aspect of the present invention there is provided a novel intermediate compound of formula A, B, or C as defined herein.
Biological Activity
[00150] The biological assays described in Example 216 herein may be used to measure the pharmacological effects of the compounds of the present invention.
[00151] Although the pharmacological properties of the compounds of formula I vary with structural change, as expected, the compounds of the invention were found to be active in the RET assays described in Example 216.
[00152] In general, the compounds of the invention demonstrate an IC5o of 1 μΜ 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.
[00153] Suitably 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.
[00154] In the RET cell assay described herein in Example 216, the compounds of formula I suitably possess an activity of less than 5 μΜ, with the preferred compounds demonstrating an activity of 1 μΜ or less.
[00155] The following compounds were tested but did not exhibit the desired activity in the assays described in Example 216:
1 . 3-[(6,7-Dimethoxyquinazolin-4-yl)amino]-2-(trifluoromethyl)phenol;
2. 3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2-ethylphenol;
3. A/-(ferf-Butyl)-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetamide;
4. A/,A/-Diethyl-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-acetamide; and 5. 1 -(3,4-Dihydroisoquinolin-2(1 H)-yl)-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethanone.
[00156] In an embodiment, 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.
Pharmaceutical Compositions
[00157] According to a further aspect of the invention there is provided 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.
[00158] The 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).
[00159] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
[00160] 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.
[00161] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, 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.
[00162] 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.
[00163] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that 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. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, 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. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
Therapeutic Uses and Applications
[00164] 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).
[00165] 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.
[00166] 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.
[00167] 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.
[00168] 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.
[00169] 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.
[00170] 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.
[00171] 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.
[00172] 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.
[00173] 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. In a particular embodiment, the cancer is human cancer.
[00174] 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.
[00175] 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.
[00176] 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.
[00177] 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.
[00178] 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. Suitably, the medicament is for use in the treatment of human cancers.
[00179] 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.
[00180] 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.
[00181 ] 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.
[00182] The term "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. Examples of 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.
[00183] 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).
[00184] 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).
[00185] In a particular embodiment of the invention, the proliferative condition to be treated is cancer, for example medullary thyroid cancer (MTC) or non-small cell lung cancer (NSCLC).
Routes of Administration
[00186] 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).
[00187] 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, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Combination Therapies
[00188] 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:-
(i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) 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;
(iii) 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. Chem., 2004, 47, 6658-6661 ) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase];
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], 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. 54, pp1 1 -29); such 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 insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R1 15777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;
(v) 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 (Avastin™) 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 linomide, inhibitors of integrin ανβ3 function and angiostatin)];
(vi) 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;
(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan;
(viii) 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
(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.
[00189] In a particular embodiment, 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.
[00190] 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.
[00191] According to this aspect of the invention there is provided a combination for use in the treatment of a 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 another anti-tumour agent.
[00192] According to this aspect of the invention there is provided 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.
[00193] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.
[00194] Herein, where the term "combination" is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention "combination" refers to simultaneous administration. In another aspect of the invention "combination" refers to separate administration. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
[00195] According to a further aspect of the invention there is provided 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. EXAMPLES 1-61
Materials, Equipment, and General Experimental Details General experimental
[00196] Flash chromatography was performed using pre-packed silica gel cartridges (KP- Sil SNAP, Biotage, Hengoed UK). Thin layer chromatography was conducted with 5 χ 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.
[00197] All compounds were > 90% purity as determined by examination of both the LC- MS and 1 H NMR spectra unless otherwise indicated. Where CI or Br were present, expected isotopic distribution patterns were observed.
1H NMR
[00198] Proton (1 H) and carbon (13C) NMR spectra were recorded on a 300 MHz Bruker spectrometer. Solutions were typically prepared in either deuterochloroform (CDCI3) or deuterated dimethylsulfoxide (c^-DMSO) with chemical shifts referenced to tetramethylsilane (TMS) or deuterated solvent as an internal standard. 1 H NMR data are reported indicating the chemical shift (δ), the integration (e.g. 1 H), the multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublets etc.) and the coupling constant {J) in Hz (app implies apparent coupling on broadened signals). Deuterated solvents were obtained from the Sigma-Aldrich Chemical Company, Goss or Fluorochem.
Analytical LC-MS.
[00199] LC-MS analyses were performed on a Waters Acquity UPLC system fitted with BEH C18 1 .7 μΜ columns (2.1 χ 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:
Solvent A - Water + 10mM ammonium formate + 0.1 % formic acid
Solvent B - Acetonitrile + 5% water + 0.1 % formic acid High pH:
Solvent A - Water + 10mM ammonium hydrogen carbonate + 0.1 % ammonia solution
Solvent B - Acetonitrile + 0.1 % ammonia solution Gradient:
Figure imgf000062_0001
Preparative HPLC
[00200] Some compounds were purified by preparative HPLC on a Waters FractionLynx MS autopurification system, with a Waters XBridge 5 μηι C18, 100 mm χ 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.
[00201] Purifications were performed using buffered acidic or basic solvent systems as appropriate. Compound retention times on the system were routinely assessed using a 30-50 μΐ test injection and a standard gradient, and then purified using an appropriately chosen focussed gradient as detailed below, based upon observed retention time.
Low pH:
Solvent A - Water + 10mM ammonium formate + 0.1 % formic acid
Solvent B - Acetonitrile + 5% water +0.1 % formic acid
High pH:
Solvent A - Water + 10mM ammonium formate + 0.1 % ammonia solution
Solvent B - Acetonitrile + 5% water + 0.1 % ammonia solution Standard Gradient:
Flow rate
Time % Solvent A % Solvent B
(mL/min)
0 20 90 10
0.3 20 90 10
8.5 20 2 98
12 20 2 98
12.5 0 2 98 Focussed Gradients:
Figure imgf000063_0002
General Methods
Preparation of phenols
Method Phenol- 1
3-Amino-4-chloro-2-methyl-phenol
Figure imgf000063_0001
[00202] To a stirred solution of 3-amino-2-methylphenol (5.35 g, 43.4 mmol) in methane sulfonic acid (30 mL) with ice bath cooling to maintain temperature of 10-12 °C, was added over 2h, N-chlorosuccinimide (6.38 g, 47.8 mmol). The mixture was stirred at -10 °C of 1 h then allowed to warm to rt and stirred overnight. The mixture was slowly poured into 85ml water - the temperature rose to 50 °C and then cone, ammonia solution 32ml was added slowly at less than 60 °C. The pH was then carefully adjusted to pH7 by addition of more cone ammonia solution - a ppt appeared. The slurry was cooled in an ice bath for 1 h and then the solid product filtered off, washed with ice cold water and then dried at 40 °C vac. The solid was then recrystallised from IPA/water, decolourising with charcoal, and after drying at 40 °C vac gave 3-amino-4- chloro-2-methyl-phenol (3.73 g, 23.7 mmol, 54.5%).
[00203] 1 H NMR (DMSO-d6): δ 9.12 (s, 1 H), 6.48 (d, J = 8.4 Hz, 1 H), 6.13 (d, J = 8.4 Hz,
1 H), 4.82 (s, 2H), 1 .95 (s, 3H) Method Phenol-2
3-Amino-2,4-difluoro-phenol
Figure imgf000064_0001
[00204] A mixture of 2,6-difluoro-3-methoxy-aniline (1 g, 6.28 mmol) and pyridinium chloride (2.06 g, 17.8 mmol) in a 25ml RBF was placed into a heating block at 150 °C and heating continued up to 200 °C for 1 h. The flask was removed from the heating block and allowed to cool overnight. Water 25ml was added (solution at pH4) - adjusted to pH 7-8 using sodium bicarbonate solution. A solid pptd out which was filtered off, washed with water and dried at 40 °C vac to give a red solid, 3-amino-2,4-difluoro-phenol (470 mg, 3.24 mmol, 51 .5%) [00205] 1 H NMR (DMSO-d6): δ 9.32 (s, 1 H), 6.65 (m, 1 H), 6.07 (m, 1 H), 5.02 (s, 2H)
[00206] Using method Phenol-2 and the appropriate starting materials the following were prepared:
3-Amino-4-chloro-2-fluorophenol
Figure imgf000064_0002
[00207] Using method Phenol-2 described above 6-chloro-2-fluoro-3-methoxy-aniline was converted to 3-amino-4-chloro-2-fluorophenol (26.5%).
[00208] 1 H NMR (DMSO-d6): δ 9.64 (s, 1 H), 6.8 (dd, J = 2.0 and 8.7 Hz, 1 H), 6.17 (t, J =
8.7 Hz, 1 H), 5.17 (s, 2H).
3-Amino-2-chloro-4-fluorophenol
Figure imgf000064_0003
[00209] Using method Phenol-2 described above 6-fluoro-2-chloro-3-methoxy-aniline was converted to 3-amino-4-fluoro-2-chlorophenol (54%).
[00210] 1 H NMR (DMSO-d6): δ 9.67 (s, 1 H), 6.81 (dd, J = 8.9 and 1 1 .0 Hz, 1 H), 6.12 (dd, J = 4.6 and 8.7 Hz, 1 H), 5.19 (s, 2H).
3-Amino-2, 6-difluorophenol
Figure imgf000065_0001
[00211] Using method Phenol-2 described above 2,4-difluoro-3-methoxy-aniline was converted to 3-amino-2,6-difluorophenol (4.5%).
[00212] 1 H NMR (DMSO-d6): 5 9.65 (s, 1 H), 6.67 (m, 1 H), 6.15 (m, 1 H), 4.38 (s, 2H).
Method phenol-3
3-Amino-2,4-dimethyl-phenol
Step 1
Figure imgf000065_0002
[00213] To a stirred solution of nitro m-xylene (2.7 ml_, 19.85 mmol) in trifluoro acetic acid (20 mL) was added N-bromosuccinimide (7.06 g, 39.7 mmol) and iron (30 mg). The reaction was heated at 65 °C for 4 days and then cooled to rt. Solvent was removed on in vacuo. The residue was taken up in ethyl acetate, washed with sat. sodium bicarbonate 2x, dried with magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate 0-20% in isohexane to give 1 -bromo-2,4-dimethyl-3- nitro-benzene (2.66 g, 1 1 .6 mmol, 58.3%) as a white solid.
[00214] 1 H NMR (CDCI3): δ 7.57 (d, J = 8.4 Hz, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 2.36 (s,
3H), 2.27 (s, 3H).
Step 2
Figure imgf000065_0003
[00215] To a stirred solution of 1 -bromo-2,4-dimethyl-3-nitro-benzene (2.66 g, 1 1 . 6 mmol) in acetic acid (48 mL) was added iron (2.58 g, 46.3 mmol) and the mixture heated at 80 °C for 18h, cooled and filtered. The filtrate was evaporated to dryness in vacuo and the residue basified with aqueous sodium hydroxide and then extracted with ethyl acetate 3x. The organics were dried with magnesium sulfate and the solution evaporated to dryness in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate 0-30% in hexane to give 3-bromo-2,6-dimethyl-aniline (1 .28 g, 6.40 mmol, 55.3%)
Step 3
Figure imgf000066_0001
[00216] Bis(pinacolato)diboron (1 .89 g, 7.45 mmol), 3-bromo-2,6-dimethyl-aniline (1 .24 g, 6.2 mmol) and potassium acetate (1 .82 g, 18.6 mmol) were combined in 1 ,4-dioxane (20 mL) and nitrogen bubbled in below the surface for 5min. Then 1 ,1 -bis(diphenyl-phosphino)ferrocene- palladium(ll)dichloride DCM adduct (328 mg, 0.40 mmol) was added and nitrogen bubbled in below the surface for 5min. The mixture was then heated under nitrogen at 80 °C for 6h and then allowed to cool O/N before being partitioned between DCM and water. The DCM solution was dried with magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/isohexane gradient to give 2,6- dimethyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (1 .2 g, 4.86 mmol, 78.3%)
[00217] 1 H NMR (DMSO-d6): δ 6.81 (s, 1 H), 4.44 (s, 2H), 2.26 (s, 3H), 2.09 (s, 3H), 1 .27
(s, 12H).
Step 4
Figure imgf000066_0002
[00218] 2,6-Dimethyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (1 .14 g, 4.61 mmol) was completely dissolved in THF (20 mL). Water (10 mL) was added followed by sodium perborate (1 .83 g, 1 1 .9 mmol). The mixture was stirred at ambient temperature overnight. Excess THF was removed under vacuo, water was added and the mixture extracted with DCM 3x. Concentration of the DCM gave a brown solid which was purified by flash chromatography eluting with ethyl acetate 0-50% in isohexane to give 3-amino-2,4-dimethyl-phenol (262 mg, 1 .91 mmol, 41 .4%) as a yellow solid.
[00219] 1 H NMR (DMSO-d6): δ 8.54 (s, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 6.02 (d, J = 8.0 Hz, 1 H), 4.36 (s, 2H), 1 .97 (s, 3H), 1 .90 (s, 3H). 3-amino-4-fluoro-2-methylphenol
Step 1
Figure imgf000067_0001
[00220] 1 -Fluoro-3-methyl-2-nitro-benzene (5 g, 32.2 mmol) was mixed with trifluoroacetic acid (21 ml_, 274.2 mmol) and cooled to 0 °C in a salt/ice bath. Sulphuric acid (10.5 ml_, 32.2 mmol) was added portionwise over 10 minutes - the reaction mixture exothermed to 1 °C. The reaction was allowed to cool back to 0 °C and N-bromosuccinimide (8.5 g, 47.8 mmol) was added portionwise over approximately 10 minutes - maintaining the temperature below 2 °C. The mixture was stirred overnight - the ice bath was not removed so the reaction was allowed to slowly warm to ambient temperature. The reaction was poured into ice/water (~500mls) - a solid precipitate could be seen on the top of the ice. The mixture was stirred vigorously for 5 minutes then a mixture of isohexane (230mls) and DCM (20mls) was added and the mixture stirred vigorously for 10 minutes - the layers were separated and the aqueous further extracted with a mixture of isohexane (230mls) and DCM (20mls). The two organic phases were washed separately with 2 x Dl water, 1 x saturated sodium bicarbonate, 1 x brine and then combined and dried over anhydrous sodium sulphate. The organic solution was concentrated down to give crude material, roughly 3:1 ratio of desired product: dibromo Hb δ 8.38 (d) F ~6.6Hz, (TLC 4:1 isohexane/DCM showed no starting material and two spots.)
[00221] The crude material was crystallised from isohexane (100mls) - stirring used on cooling, then cooling and stirring in ice bath. A white solid was filtered off (0.53g).
[00222] 1 H NMR (DMSO-d6): δ 7.99 (dd, J =5.1 and 8.9Hz, 1 H), 7.49 (t, J = 9.2 Hz, 1 H),
2.37 (s, 3H).
[00223] A second crop was obtained on standing, together yielding 2.17g, 27%. Step 2
Figure imgf000067_0002
[00224] 1 -Bromo-4-fluoro-2-methyl-3-nitro-benzene (1 .64 g, 7.0 mmol) was mixed with tin (II) chloride (5.98 g, 31 .5 mmol), methanol (15 mL) and hydrochloric acid (15.47 ml_, 501 mmol) and heated to -40 °C for 4 hours. The reaction was allowed to cool and potassium carbonate was added carefully until pH was adjusted to 12 - ~50mls of water was added during this process. The final aqueous mixture appeared milky. DCM (~100mls) was added and the mixture stirred vigourously for 20 minutes. The layers were separated and the aqueous further extracted with DCM (~150mls). Organics were combined and passed through a hydrophobic frit.The DCM was removed under vacuo to give a white greasy solid. The product purified by flash chromatography over silica eluting with a 0-50% ethyl acetate/isohexane gradient over 30 minutes. Concentration under vacuo gave 3-bromo-6-fluoro-2-methyl-aniline, 1 .24g 81 %.
[00225] 1 H NMR (DMSO-d6): δ 6.85 (dd, J =8.7 and 10.6Hz, 1 H), 6.76 (dd, J =4.8 and
8.7Hz, 1 H), 5.23 (bs, 2H), 2.20 (s, 3H).
Step 3
Figure imgf000068_0001
[00226] 3-Bromo-6-fluoro-2-methyl-aniline (500 mg, 2.45 mmol), bis(pinacolato)diboron (747.8 mg, 2.95 mmol) and potassium acetate (721 .5 mg, 7.35 mmol) were mixed in 1 ,4- dioxane (5 mL) and nitrogen gas was bubbled through for 5 minutes. 1 ,1 -bis(diphenyl- phosphino)ferrocene-palladium(ll)dichloride DCM adduct (130 mg, 0.160 mmol) was added and nitrogen bubbled through again. The mixture was heated under reflux conditions for 4.5 hours. TLC (3:2 isohexane/DCM) showed no starting material - LCMS (alyons746-1 ) showed one main peak R.T 1 .29 minutes, 86% area, MWt. 252.5 M+H. The reaction was allowed to cool - excess dioxane was removed under vacuum and the residue was partitioned between DCM and Dl water. The mixture was passed through a hydrophobic frit. The DCM phase was reduced down in volume and purified by flash chromatography eluting with 0-100% ethyl acetate/isohexane over 45 minutes. Concentration of product containing fractions gave 6-fluoro-2-methyl-3- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline as an oil which solidified to a white solid overnight 502mgs, 76%.
[00227] 1 H NMR (DMSO-d6): δ 6.86 (m, 2H), 4.76 (bs, 2H), 2.29 (s, 3H), 1 .28 (s, 12H).
Step 4
Figure imgf000068_0002
[00228] 6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (21 1 mg, 0.840 mmol) was completely dissolved in THF (4 mL). Water (2 mL) was added followed by sodium perborate (333 mg, 2.16 mmol). The mixture was stirred at ambient temperature overnight. Excess THF was removed under vacuo - some solid appeared. Saturated ammonium chloride was added - a precipitate formed. DCM was added and the mixture stirred vigourously for 15 minutes before passing through a hydrophobic frit. Concentration of the DCM gave 3- amino-4-fluoro-2-methylphenol as a pale pink/brown solid 107mg, 81 %.
[00229] 1 H NMR (DMSO-d6): δ 8.82 (s, 1 H), 6.61 (dd, J = 8.9 and 1 1 .4 Hz, 1 H), 6.0 (dd,
J = 4.4 and 8.9 Hz, 1 H), 4.67 (bs, 2H), 1 .91 (s, 3H). 3-Amino-4-methoxy-2-methylphenol
Step 1
Figure imgf000069_0001
[00230] 3-Methyl-2-nitroanisole (5. g, 29.9 mmol) was dissolved in acetic acid (27 mL) and bromine (1 .69 mL, 32.9 mmol) was added in two portions - slight exotherm. The mixture was stirred overnight at ambient temperature. The reaction mixture was poured into ice (~300mls) and the mixture stirred vigourously until all ice had melted - the mixture turned from orange to white (~2 hours stirring in total). The precipitate was filtered off and washed with water, sucked dry to give 1 -bromo-4-methoxy-2-methyl-3-nitrobenzene as a white solid, dried in the oven overnight at -50 °C under vacuo, 6.71 g.
[00231 ] 1 H NMR (DMSO-d6): δ 7.81 (d, J = 8.7 Hz, 1 H), 7.18 (d, J = 8.7 Hz, 1 H), 3.88 (s,
3H), 2.25 (s, 3H).
Step 2
Figure imgf000069_0002
[00232] 1 -Bromo-4-methoxy-2-methyl-3-nitro-benzene (2. g, 8.13 mmol) was mixed with tin(ll) chloride (6.94 g, 36.6 mmol) , methanol (15 mL) and cone, hydrochloric acid (17.9 mL, 581 mmol) and heated to -40 °C for 4 hours then allowed to stir overnight at ambient temperature. The reaction was allowed to cool and potassium carbonate was added carefully until the pH was adjusted to 12 - ~100mls of water was added during this process. The final aqueous appeared milky. DCM (~250mls) was added and the mixture stirred vigourously for ~1 .5 hours. The layers were separated and the aqueous further extracted with DCM (~250mls). The organic solutions were combined and passed through a hydrophobic frit. The solution was concentrated down and purified by flash chromatography eluting with 0-60% ethyl acetate/isohexane over 35 minutes. The clean fractions were concentrated down to give 3-bromo-6-methoxy-2- methylaniline as a white crystalline solid, 1 .81 g.
[00233] 1 H NMR (DMSO-d6): δ 6.78 (d, J= 8.7 Hz, 1 H), 6.64 (d, J= 8.7 Hz, 1 H), 4.77 (s,
2H), 3.76 (s, 3H), 2.17 (s, 3H).
Step 3
Figure imgf000070_0001
[00234] Nitrogen was bubbled through 1 ,4-dioxane (20 mL) and 3-bromo-6-methoxy-2- methyl-aniline (1 .81 g, 7.54 mmol), bis(pinacolato)diboron (2.3 g, 9.06 mmol), potassium acetate (2.22 g, 22.6 mmol) and 1 ,1 ;bis(diphenyl-phosphino)ferrocene-palladium(ll)dichloride DCM adduct (400 mg, 0.49 mmol) were added and the mixture heated under reflux conditions for 4 hours. The mixture was allowed to cool overnight and excess dioxane removed on the rotavapour. The residue was partitioned between Dl water and DCM, then passed through a hydrophobic frit. The DCM phase was reduced in volume and purified by flash chromatography eluting with 0-100% ethyl acetate/ioshexane over 40 minutes. Product containing fractions were concentrated down to give 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)aniline as a brown solid 1 .73g,
[00235] 1 H NMR (DMSO-d6): δ 6.98 (d, J = 8.2 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H) 3.64 (s,
3H), 2.25 (s, 3H), 1 .28 (s, 12H).
[00236] Product contains some bi-product pinacol and starting material impurities but is used in the next step without further purification.
Step 4
Figure imgf000070_0002
[00237] 6-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (1 .73 g, 3.94 mmol) was completely dissolved in THF (40 mL). Water (20 mL) was added followed by sodium perborate (2.08 g, 13.55 mmol) . The mixture was stirred at ambient temperature overnight. Excess THF was removed under vacuo - some solid. Saturated ammonium chloride (~40mls) and DCM (~100mls) were added and the mixture stirred vigourously for 45 minutes (dark brown in colour) before passing through a hydrophobic frit. 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.
[00238] 1 H NMR (DMSO-d6): δ 8.46 (s, 1 H), 6.46 (d, J = 8.6 Hz, 1 H), 6.03 (d, J = 8.6 Hz, 1 H), 4.43 (s, 2H), 3.66 (s, 3H), 1 .90 (s, 3H).
3-Amino-2-methoxyphenol
Figure imgf000071_0001
[00239] 3-Bromo-2-methoxyaniline (500 mg, 2.47 mmol), bis(pinacolato)diboron (755 mg, 2.97 mmol) and potassium acetate (728 mg, 7.42 mmol) were mixed in 1 ,4-dioxane (8 mL) and nitrogen gas was blown through for 5 minutes. 1 ,1 -Bis(diphenyl-phosphino)ferrocene- palladium(ll)dichloride DCM adduct (173 mg, 0.21 mmol) was added and nitrogen blown through again. The mixture was heated under reflux conditions for 2.5 hours then allowed to cool (black mixture). Dl water and DCM were added (~35mls of each) and the mixture was stirred vigourously for 30 minutes then passed through a hydrophobic frit. The DCM phase was concentrated down to remove excess Dioxane then redissolved in minimum DCM and was purified by flash chromatography eluting with 0-100% ethyl acetate/isohexane over 40 minutes. Product containing fractions were concentrated down to give 2-methoxy-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)aniline as an off-white solid 358mg.
[00240] Ή NMR (DMSO-d6): δ 6.88 (m, 3H), 4.80 (bs, 2H), 3.64 (s, 3H), 1 .29 (s, 12H).
Figure imgf000071_0002
[00241] 2-Methoxy-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (358 mg, 1 .44 mmol) was completely dissolved in THF (10 mL). Water (5 mL) was added followed by sodium perborate (569 mg, 3.7 mmol). The mixture was stirred at ambient temperature overnight. Excess THF was removed under vacuo - some solid. Saturated ammonium chloride (~10mls) and DCM (~50mls) were added and the mixture stirred vigourously for one hour before passing through a hydrophobic frit. 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.
[00242] Ή NMR (DMSO-d6): δ 8.80 (s, 1 H), 6.55 (t, J = 8.1 Hz, 1 H), 6.04 (dd, J = 1 .3 and 8.1 Hz, 1 H), 4.71 (bs, 2H), 3.62 (s, 3H).
Method Phenol-4
Ethylbenzene- 1 , 3-diol
Figure imgf000072_0001
[00243] To a solution of 1 -(2,6-dihydroxyphenyl)ethanone (5 g, 32.86 mmol) in trifluoroacetic acid (100 mL) was added dropwise triethylsilane (15 mL, 93.9 mmol) and the reaction mixture stirred for 3 h under nitrogen. The reaction mixture was carefully poured onto ice/water and extracted (x3) with diethyl ether. The combined extracts were washed (x2) with water and the organic phase was evaporated to dryness (precipitation of solid resulted). The residue was triturated with isohexane and the solid filtered off and washed with isohexane. Recrystallisation from CHCI3/isohexane afforded ethylbenzene-1 , 3-diol, 3.1 g.
[00244] Ή NMR (DMSO-d6): δ 8.96 (s, 2H), 6.72 (t, J = 8.1 Hz, 1 H), 6.24 (d, J = 8.1 Hz,
2H), 2.49 (q, J = 7.4 Hz, 2H, masked by DMSO signal), 1 .00 (t, J = 7.4 Hz, 3H).
Methods for quinazoline intermediates:
Mitsunobu coupling 1
Intermediate M1-1 4-Chloro-7-(2-chloroethoxy)-6-methoxy-quinazoline.
Figure imgf000072_0002
[00245] Diisopropyl azodicarboxylate (0.12 mL, 0.62 mmol) was added to a solution of 4- chloro-6-methoxy-quinazolin-7-ol (100 mg, 0.47 mmol), 2-chloroethanol (0.03 mL, 0.50 mmol) and triphenylphosphine (162 mg, 0.62 mmol) in THF (10 mL). The reaction mixture was heated to 35 °C over the weekend. The reaction was concentrated to dryness then redissolved in DCM (5 mL) and purified by flash chromatography (1 Og silica) with a gradient 20 - 100% EtOAc in hexanes to give 4-chloro-7-(2-chloroethoxy)-6-methoxy-quinazoline (125 mg, 43 mmol, 91 %) as a white solid.
[00246] 1 H NMR (DMSO-d6): δ 8.90 (s, 1 H), 7.51 (s, 1 H), 7.43 (s, 1 H), 4.53 (m, 2H),
4.07 (m, 2H), 4.02 (s, 3H).
Intermediate M1-2. 3-[(4-Chloro-6-methoxy-quinazolin-7-yl)oxymethyl]-5-methyl- 1,2,4- oxadiazole.
Figure imgf000073_0001
[00247] Diisopropyl azodicarboxylate (0.1 mL, 0.49 mmol) was added to a slurry of 4- chloro-6-methoxy-quinazolin-7-ol (80 mg, 0.38 mmol), triphenylphosphine (129.5 mg, 0.49 mmol) and 5-methyl-1 ,2,4-oxadiazole-3-methanol, (45.5 mg, 0.40 mmol) in THF (10 mL). Upon addition of DIAD everything went into solution. The reaction was heated to 35 °C, a precipitate formed slowly over time. The solid was collected by filtration and dried under vacuum to give 3- [(4-chloro-6-methoxy-quinazolin-7-yl)oxymethyl]-5-methyl-1 ,2,4-oxadiazole (66 mg, 0.21 mmol, 55%) as a white solid.
[00248] 1 H NMR (DMSO-d6): δ 8.91 (s, 1 H), 7.67 (s, 1 H), 7.45 (s, 1 H), 5.55 (s, 2H), 4.01
(s, 3H), 2.64 (s, 3H). [00249] The following intermediates were prepared by a similar method:
Intermediate M1-3 4-Chloro-6-methoxy-7-[(3-methylimidazol-4-yl)methoxy] quinazoline.
Figure imgf000073_0002
[00250] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and (1 -methyl-1 H-imidazol-5- yl)methanol.
[00251] 1 H NMR (DMSO-d6): δ 8.91 (s, 1 H), 7.0 (s, 2H), 7.42 (s, 1 H), 7.12 (s, 1 H), 5.40
(s, 2H), 3.98 (s, 3H), 3.65 (s, 3H). Intermediate M1-4 4-Chloro-6-methoxy-7-[(5-methyl-2-furyl)methoxy]quinazoline.
Figure imgf000074_0001
[00252] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and 2-(hydroxymethyl)-5- methylfuran.
LCMS High _pH RT 0.62 min. M+H+ 305
Mitsunobu coupling 2.
[00253] Using polymer supported triphenylphosphine.
Intermediate M2- 1 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline.
Figure imgf000074_0002
[00254] Triphenylphosphine, polymer bound ~1 .6mmol/g (500 mg, 1 .9 mmol) was stirred for 5 minutes in DCM (5 mL). 4-Chloro-6-methoxy-quinazolin-7-ol (150 mg, 0.71 mmol) in MeCN (2 mL), methoxyethanol (0.06 mL, 0.71 mmol) and diisopropyl azodicarboxylate (0.18 mL, 0.93 mmol) were added to the solution. The reaction was stirred at room temperature for 16 hours. The reaction was filtered and the beads washed with MeCN (20 mL) and DCM (20 mL). The reaction mixture was concentrated and purified by flash chromatography using a gradient 0 - 100% EtOAc in hexanes to give product contaminated with reduced DIAD. This material was slurried in ether (20 mL) and filtered to give 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (105 mg, 0.37 mmol, 52%) as a white solid.
[00255] 1 H NMR (DMSO-d6): δ 8.88 (s, 1 H), 7.49 (s, 1 H), 7.41 (s, 1 H), 4.36 (m, 2H),
4.01 (s, 3H), 3.76 (m, 2H), 3.33 (s, 3H) partially obscured by water.
[00256] The following intermediates were prepared by a similar method: Intermediate M2-2. 1-[2-(4-chloro-6-methoxy-quinazolin-7-yl)oxyethyl]pyrrolidin-2-on
Figure imgf000075_0001
[00257] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and 1 -(2- hydroxyet yl)pyrrolidin-2-one.
[00258] 1 H NMR (DMSO-d6): δ 8.89 (s, 1 H), 7.51 (s, 1 H), 7.42 (s, 1 H), 4.35 (t, J = 5.5Hz,
2H), 4.01 (s, 3H), 3.65 (t, J = 5.7 Hz, 2H), 3.52 (t, J = 7.5 Hz, 2H) 2.22 (t, J = 8.4 Hz, 2H), 1 .94 (quin, J = 8.4Hz, 2H).
Intermediate M2-3. 4-chloro-6-methoxy-7-(2-methylsulfanylethoxy)quinazoline.
Figure imgf000075_0002
[00259] Prepared from 4-chloro-6-met oxy-quinazolin-7-ol and 2-met ylt iomet anol.
[00260] 1 H NMR (DMSO-d6): δ 8.88 (s, 1 H), 7.49 (s, 1 H), 7.41 (s, 1 H), 4.37 (m,
4.01 (s, 3H), 3.77 (m, 2H), 2.51 (s, hidden under DMSO).
Intermediate M2-4. 4-[3-(4-chloro-6-methoxy-quinazolin-7-yl)oxypropyl]morpholine.
Figure imgf000075_0003
[00261] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and 4-morpholinepropanol.
Intermediate M2-5. 2-(4-chloro-6-methoxy-quinazolin-7-yl)oxyethyl acetate.
Figure imgf000075_0004
[00262] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and 2-hydroxyethyl acetate. [00263] 1 H NMR (DMSO-d6): δ 8.89 (s, 1 H), 7.52 (s, 1 H), 7.42 (s, 1 H), 4.45 (m,
4.01 (s, 3H), 2.06 (s, 3H).
Alkylation coupling 1.
Intermediate A 1- 1. 4-Chloro-6-methoxy-7-(3-methoxypropoxy)quinazoline.
Figure imgf000076_0001
[00264] 4-Chloro-6-methoxy-quinazolin-7-ol (80 mg, 0.38 mmol), potassium carbonate (157.5 mg, 1 .14 mmol) and 1 -bromo-3-methoxypropane (0.04 mL, 0.38 mmol) were heated in MeCN (3 mL) to 82 °C for 4 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed with EtOAc (50 mL) and discarded. The organics were combined and concentrated. The crude material was purified by flash chromatography using a gradient of 0 - 100% EtOAc in hexanes to give 4-chloro-6-methoxy-7-(3-methoxypropoxy)quinazoline (78 mg, 0.268 mmol, 70%) as a white solid.
[00265] 1 H NMR (DMSO-d6): δ 8.88 (s, 1 H), 7.46 (s, 1 H), 7.41 (s, 1 H), 4.28 (t, J = 6.9 Hz 2H), 4.01 (s, 3H), 3.51 (t, J = 6.9 Hz 2H), 3.27 (s, 3H), 2.06 (t, J = 6.9 Hz 2H).
[00266] The following intermediates were prepared by a similar method:
Intermediate A 1-2 4-Chloro-7-(cyclopropylmethoxy)-6-methoxy-quinazoline
Figure imgf000076_0002
[00267] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and l -(bromomethyl) cyclopropane.
[00268] 1 H NMR (DMSO-d6): δ 8.88 (s, 1 H), 7.42 (s, 2H), 4.09 (d, J = 7.1 Hz, 2H), 4.02
(s, 3H), 0.64 (m, 2H), 0.4 (m, 2H). Intermediate A 1-3 4-Chloro-6-methoxy-7-[(3-methyloxetan-3-yl)methoxy]quinazoline.
Figure imgf000077_0001
[00269] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and (3-methyloxetan-3- yl)methyl methanesulfonate.
[00270] 1 H NMR (DMSO-d6): δ 8.90 (s, 1 H), 7.55 (s, 1 H), 7.43 (s, 1 H), 4.54 (d, J = 6.0
Hz, 2Η), 4.36 and 4.34 (s x 2, 4Η), 4.01 (s, 3Η), 1 .42 (s, 3Η).
Intermediate A 1-4 4-Chloro-6-methoxy-7-(3-pyridylmethoxy)quinazoline.
Figure imgf000077_0002
[00271] Prepared from 4-chloro-6-met oxy-quinazolin-7-ol and 3-(bromomet yl)pyridine ydrobromide.
[00272] 1 Η NMR (DMSO-d6): δ 8.90 (s, 1 Η), 8.75 (d, J = 1 .9 Hz, 1 Η), 8.60 (dd, J = 1 .8 and 4.7 Hz, 1 H), 7.95 (dt, J = 2.0 and 8.1 Hz, 1 H), 7.63 (s, 1 H), 7.48 (dd, J = 4.9 and 7.8 Hz, 1 H), 7.43 (s, 1 H), 5.42 (s, 2H), 4.01 (s, 3H).
Intermediate A 1-5 N-[2-(4-Chloro-6-methoxy-quinazolin-7-yl)oxyethyl]-N-methyl- methanesulfonamide.
Figure imgf000077_0003
[00273] Prepared from 4-chloro-6-met oxy-quinazolin-7-ol and 2- [met yl(met ylsulfonyl)amino]et yl methanesulfonate.
[00274] 1 H NMR (DMSO-d6): δ 8.90 (s, 1 H), 7.53 (s, 1 H), 7.43 (s, 1 H), 4.41 (t, J = 5.3
Hz, 2H), 4.01 (s, 3H), 3.61 (t, J = 5.3 Hz, 2H), 3.0 (s, 3H), 2.92 (s, 3H). Intermediate A 1-6 2-(4-Chloro-6-methoxy-quinazolin-7-yl)oxyacetamide.
Figure imgf000078_0001
[00275] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and 2-bromoacetamide.
[00276] 1 H NMR (DMSO-d6): δ 8.89 (s, 1 H), 7.54 (bs, 1 H), 7.47 (bs, 1 H), 7.44 (s, 1
7.32 (s, 1 H), 4.78 (s, 2H), 4.03 (s, 3H).
Intermediate A 1-7 7-Benzyloxy-4-chloro-6-methoxy-quinazoline.
Figure imgf000078_0002
[00277] Prepared from 4-chloro-6-methoxy-quinazolin-7-ol and benzyl bromide.
[00278] 1 H-NMR (DMSO d6): 8.85 (s, 1 H), 7.58 (s, 1 H), 7.50 (d, 2H), 7.40 (m, 4H), 5.35
(s, 2H), 4.00 (s, 3H).
Preparation of 2-[methyl(methylsulfonyl)amino]ethyl methanesulfonate
Figure imgf000078_0003
[00279] Methane sulfonyl chloride (1 .08 mL, 14 mmol) was added slowly to 2- (methylamino)ethanol (0.53 mL, 6.66 mmol) and triethylamine (2.31 mL, 16.6 mmol) in DCM (25 mL). (Exotherm). The solution was stirred over the weekend. The reaction was diluted with sat. ammonium chloride solution. The organics were isolated, washed with brine and concentrated to give 2-[methyl(methylsulfonyl)amino]ethyl methanesulfonate (1 .24 g, 5.1 mmol, 76.%) as an orange solidwhich was used without further purification.
[00280] 1 H-NMR (DMSO d6): 4.34 (d, J = 5.5 Hz, 2H), 3.42 (d, J = 5.5 Hz, 2H), 3.22 (s,
3H), 2.93 (s, 3H), 2.83 (s, 3H). Preparation of (3-methyloxetan-3-yl)methyl methanesulfonate.
Figure imgf000079_0001
[00281] Methane sulfonyl chloride (0.15 mL, 1 .96 mmol) was added to a solution of 3- methyl-3-oxetanemethanol (0.2 mL, 1 .96 mmol) and triethylamine (0.41 mL, 2.94 mmol) in DCM (10 mL). (Exotherm). The reaction was stirred at room temperature for 4 hours. The reaction was diluted with DCM (10 mL) and washed with sat. ammonium chloride solution. The organics were isolated, washed with brine and concentrated. The crude material was used without further purification.
[00282] 1 H-NMR (CDCI3): 4.53 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 6.2 Hz, 2H), 4.34 (s, 2H), 3.09 (s, 3H), 1 .41 (s, 3H).
Preparation of Example Compounds
Condensation Method C1 (Examples 1 and 2) Example 1 - 2-Chloro-3-[(6,7-dimethoxyquinazolin-4-yl)amino]-6-methyl-phenol
hydrochloride.
Figure imgf000079_0002
[00283] A suspension of 3-amino-2-chloro-6-methylphenol (351 mg, 2.23 mmol) and 4- chloro-6,7-dimethoxy-quinazoline (500 mg, 2.23 mmol) in IPA (10 mL) was heated to reflux for 20h. The mixture was cooled to RT and the solid filtered off, washed with IPA and dried overnight in vacuo at 50 °C to give 2-chloro-3-[(6,7-dimethoxyquinazolin-4-yl)amino]-6-methyl- phenol hydrochloride (713 mg, 1 .86 mmol, 84%) as a beige solid.
[00284] LCMS: Low_pH_2min RT 0.73 min, purity 92% [M+H]+ 346.6. High_pH_2min RT
0.88 min, purity 92% [M+H]+ 346.6.
[00285] 1 HNMR: (DMSO-d6): δ 15.05 (bs, 1 H), 1 1 .52 (s, 1 H), 9.45 (s, 1 H), 8.76 (s, 1 H),
8.27 (s, 1 H), 7.40 (s, 1 H), 7.19 (d, J = 8.0 Hz, 1 H), 6.93 (d, J = 8.1 Hz, 1 H), 4.00 (s, 6H), 2.28 (s, 3H)
[00286] The following compounds were prepared using a similar method: Example 2 - 2-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)phenol was prepared from 4- chloro-6,7-dimethoxy-quinazoline and 3-amino-2-chlorophenol.
[00287] LCMS: Low_pH_2min RT 0.69 min, purity >95% [M+H]+ 332.5. High_pH_2min RT 0.74 min, purity >95% [M+H]+ 332.5.
[00288] 1 HNMR: (DMSO-d6): δ 14.92 (bs, 1 H), 1 1 .44 (s, 1 H), 10.58 (s, 1 H), 8.77 (s, 1 H,
8.21 (s, 1 H), 7.36 (s, 1 H), 7.28 (t, J = 8.14 Hz, 1 H), 7.08 ( dd, J = 8.2 and 1 .4 Hz, 1 H), 6.98 (dd, J = 8.2 and 1 .4), 4.00 and 3.99 (2xs, 6x).
Condensation Method C2 (Examples 3 to 7)
Example 3 - 3-[(6,7-Dimethoxyquinazolin-4-yl)amino]-2-methyl-phenol hydrochloride.
Figure imgf000080_0001
[00289] 4-Chloro-6,7-dimethoxy-quinazoline (75 mg, 0.33 mmol) and 3-amino-2- methylphenol (41 mg, 0.33 mmol) were mixed with acetonitrile (2 mL) and irradiated at 150 °C for 60 minutes. The reaction was allowed to cool and the solid filtered off, washed with acetonitrile (~50mls) and sucked dry under vacuo to give 3-[(6,7-dimethoxyquinazolin-4- yl)amino]-2-methyl-phenol hydrochloride as a brown solid, 81 mg.
[00290] LCMS: Low_pH_2min RT 0.64min, purity >95%, [M+H]+ 312.5. High_pH_2min
RT 0.74min, purity >95% [M+H]+ 312.5.
[00291] 1 HNMR: (DMSO-d6): δ 14.70 (bs, 1 H), 1 1 .37 (s, 1 H), 9.73 (s, 1 H), 8.70 (s, 1 H),
8.27 (s, 1 H), 7.36 (s, 1 H), 7.1 1 (t, J = 8.4 Hz 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 3.99 (s, 6H), 1 .98 (s, 3H,)
[00292] The following compounds were prepared using a similar method:
Example 4 - 3-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,6-dimethyl-phenol was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-2,6-dimethylphenol using microwave heating at 135 °C for 1 h. [00293] LCMS Low_pH_2min RT 0.73 min, purity 92% [M+H]+ 346.6. High_pH_2min RT
0.88 min, purity 92% [M+H]+ 346.6.
[00294] 1HNMR: (DMS0-d6): δ 14.70 (bs, 1H), 11.37 (s, 1H), 9.73 (s, 1H), 8.70 (s, 1H),
8.27 (s, 1H), 7.36 (s, 1H), 7.11 (t, J= 8.4 Hz, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.77 (d, J= 8.0 Hz, 1H), 3.99 (s,6H), 1.98 (s,3H).
Example 5 - 3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2-fluorophenol was prepared from 4- chloro-6,7-dimet oxy-quinazoline and 3-amino-2-fluorop enol using microwave heating at 135 °C for 1 h. The crude product was purified by preparative hplc.
[00295] LCMS: Low_pH_2min RT 0.68 min, purity >95%, [M-H]" 316.5. High_pH_2min
RT 0.74 min, purity >95% [M+H]+ 316.5.
[00296] 1HNMR: (DMSO-d6): δ 9.90 (s, 1H), 9.54 (s, 1H), 8.36 (s, 1H), 7.83 (s, 1H), 7.18
(s, 1H), 7.01 (dt, J=8.18, 1.24 Hz, 1H), 6.90 (m, 2H), 3.94 (s, 6H). Example 6 - 3-[(6,7-Dimethoxyquinazolin-4-yl)amino]-4-f luoro-2-methyl-phenol
hydrochloride was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-4-fluoro-2- methyl-phenol using microwave heating at 100 °C for 1h.
[00297] LCMS: Low_pH_2min RT 0.68min, purity >95% [M+H]+ 330.5. High_pH_2min RT
0.82min, purity >95% [M+H]+ 330.5.
[00298] Ή NMR: (DMSO-d6): δ 11.12 (s, 1H), 9.68 (s, 1H), 8.74 (s, 1H), 8.22 (s, 1H),
7.31 (s, 1 H), 7.04 (t, J= 9.2 Hz, 1 H), 6.88 (dd J= 9.1 , 4.9 Hz, 1 H), 4.01 and 4.00 (2xs, 6H), 2.03 (s, 3H).
Example 7 - 3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2,6-difluorophenol hydrochloride was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-2,6-difluoro-phenol.
[00299] LCMS: Low_pH_2min RT 0.69min, purity 90-95% [M+H]+ 334.5. High_pH_2min
RT 0.62 min, purity 90-95% [M+H]+ 334.5.
[00300] 1H NMR: (DMSO-d6): δ 11.31 (s, 1H), 10.54 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H),
8.19 (s, 1H), 7.33 (s, 1H), 7.18 (dd, J= 9.0 and 2.3 Hz, 1H), 6.98 (m, 1H), 4.01 (s, 3H), 4.00 (s, 3H) Condensation Method C3 (Examples 8 to 49)
Example 8 - 3-[[7-(2-Hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]-2-methyl-phenol.
Figure imgf000082_0001
[00301] A suspension of 3-amino-2-methylphenol (12.5 mg, 0.10 mmol), 2-(4-chloro-6- methoxy-quinazolin-7-yl)oxyethyl acetate (30 mg, 0.10 mmol) and 5-6 N HCI in IPA (0.02 mL, 0.1 1 mmol) in IPA (2 mL) was heated at 100 °C for 30 mins in the microwave. The reaction was evaporated to dryness then partitioned between ethyl acetate and sat. aqueous sodium bicarbonate. The organic solution was washed with brine and concentrated. The crude material was purified by flash chromatography eluting with a gradient of 0 - 10% MeOH in DCM to give 3-[[7-(2-hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]-2-methyl-phenol (5 mg, 0.0132 mmol, 13%) as a light purple solid.
[00302] LCMS: Low_pH_2min RT 0.71 min, purity 85-90% [M+H]+ 342. High_pH_2min RT
0.61 min, purity 90-95% [M+H]+ 342.
[00303] 1 H NMR: (DMSO-d6): δ 9.34 (s, 1 H), 8.24 (s, 1 H), 7.82 (s, 1 H), 7.28 (bs, 1 H),
7.16 (s, 1 H), 7.03 (t, J = 8.6 Hz, 1 H), 6.75 (t, J = 9.9 Hz, 2H), 6.67 (bs, 1 H), 4.14 (t, J = 4.8 Hz, 2H), 3.93 (s, 3H), 3.80 (t, J = 4.4 Hz, 2H), 1 .95 (s, 3H).
[00304] The following compounds were prepared using a similar method: Example 9 - Methyl 2-((4-((3-hydroxy-2-methylphenyl)amino)-7-methoxyquinazolin-6- yl)oxy)propanoate was prepared from methyl 2-(4-chloro-7-methoxy-quinazolin-6- yl)oxypropanoate and 3-amino-2-methylphenol. The crude product was purified by preparative hplc.
[00305] Low_pH_2min RT 0.75 min, purity 90-95% [M+H]+384. High_pH_2min RT 0.88 min purity 90-95% [M+H]+ 384.
[00306] Ή NMR: (DMSO-d6): δ 9.40 (s, 1 H), 9.28 (s, 1 H), 8.25 (s, 1 H), 7.79 (s, 1 H), 7.18
(s, 1 H), 7.03 (t, J = 8.0 Hz, 1 H), 6.75 (t, J = 7.1 Hz, 2H), 5.18 (q, J = 6.8 Hz, 1 H), 3.94 (s, 3H), 3.70 (s, 3H), 1 .94 (s, 3H), 1 .60 (d, J = 6.7 Hz, 3H). Example 10 - 2-Chloro-3-[[7-(2-hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]phenol was prepared from 2-(4-chloro-6-methoxy-quinazolin-7-yl)oxyethyl acetate and 3-amino-2- chlorophenol. The crude product was purified by preparative hplc.
[00307] LCMS: Low_pH_2min RT 0.62 min, purity >95% [M+H]+ 362. High_pH_2min RT 0.66 min, purity >95% [M+H]+ 362.
[00308] 1 H NMR: (DMSO-d6): δ 10.02 (bs, 1 H), 9.44 (s, 1 H), 8.28 (s, 1 H), 7.82 (s, 1 H),
7.18 (m, 2H), 6.98 (dd, J = 8.2 and 1 .5 Hz, 1 H), 6.92 (dd, J = 8.2 and 1 .5Hz, 1 H), 4.94 (t J = 5.2 Hz, 1 H), 4.16 (t J= 5.2 Hz, 2H), 3.94 (s, 3H) 3.80 (d, J = 5.0 Hz, 2H) Example 11 - Methyl 2-((4-((2-chloro-3-hydroxyphenyl)amino)-7-methoxyquinazolin-6- yl)oxy)propanoate was prepared from methyl 2-(4-chloro-7-methoxy-quinazolin-6- yl)oxypropanoate and 3-amino-2-chlorophenol. The crude product was purified by preparative hplc.
[00309] LCMS: Low_pH_2min RT 0.79 min, purity 90-95% [M+H]+ 404. High_pH_2min RT 0.92 min, purity 90-95% [M+H]+ 404.
[00310] 1 H NMR: (DMSO-d6): δ 10.23 (bs, 1 H), 9.36 (s, 1 H), 8.30 (s, 1 H), 7.79 (s, 1 H),
7.21 (s, 1 H), 7.17 (d, J = 8.3 Hz, 1 H), 7.01 (dd, J = 8.2 and 1 .4 Hz, 1 H), 6.92 (dd, J = 8.1 and 1 .4, 1 H), 5.20 (q, J= 6.8 Hz, 1 H), 3.95 (s, 3H), 3.77 (s, 3H), 1 .61 (d, J= 6.8 Hz, 3H). Example 12 - 4-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared from 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline and 3- amino-4-fluoro-2-methyl-phenol.
[0031 1] LCMS: Low_pH_2min RT 0.72 min, purity >95% [M+H]+ 374. High_pH_2min RT
0.84 min, purity >95% [M+H]+ 374.
[00312] 1 H NMR: (DMSO-d6): δ 9.40 (s, 1 H), 9.25 (s, 1 H), 8.25 (s, 1 H), 7.85 (s, 1 H), 7.19
(s, 1 H), 6.95 (t, J = 9.2 Hz, 1 H), 6.77 (dd, J = 9.0 and 4.3 Hz, 1 H), 4.26 (m„ 2H), 3.94 (s, 3H), 3.47 (m, 2H), 3.34 (s, 3H), 1 .99 (s, 3H).
Example 13 - Methyl 2-((4-((2-chloro-3-hydroxyphenyl)amino)-7-methoxyquinazolin-6- yl)oxy)acetate hydrochloride was prepared from methyl 2-(4-chloro-7-methoxy-quinazolin-6- yl)oxyacetate and 3-amino-2-chlorophenol.
[00313] LCMS: Low_pH_2min RT 0.72 min, purity 90-95% [M+H]+ 390. High_pH_2min
RT 0.76 min, purity 85-90% [M+H]+ 390.
[00314] 1 H NMR: (DMSO-d6): δ 1 1 .20 (s, 1 H), 10.56 (s, 1 H), 8.76 (s, 1 H), 8.13 (s, 1 H), 7.34 (s, 1 H), 7.28 (t, J = 8.03 Hz, 1 H), 7.07 (dd, J= 8.27 and 1 .32 Hz, 1 H), 6.99 (dd, J=7.85 and 1 .32 Hz, 1 H), 5.04 (s, 2H), 4.04 (s, 3H), 3.75 (s, 3H).
Example 14 - 3-((6,7-Bis(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared from 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline and 3-amino-2-methylphenol. The crude product was purified by preparative hplc.
[00315] LCMS: Low_pH_2min RT 0.74 min, purity >95% [M+H]+ 400. High_pH_2min RT
0.84 min purity >95% [M+H]+ 400.
[00316] 1 H NMR: (DMSO-d6): δ 9.39 (s, 1 H), 9.31 (s, 1 H), 8.24 (s, 1 H), 7.85 (s, 1 H), 7.17
(s, 1 H), 7.03 (t, J = 7.8 Hz, 1 H), 6.75 (m, 2H), 4.26 (m, 4H), 3.76 (m, 4H), 3.37 (s, 3H), 3.35 (s, 3H), 1 .95 (s, 3H).
Example 15 - 3-((7-methoxy-6-((1-morpholinopropan-2-yl)oxy)quinazolin-4-yl)amino)-2- methylphenol was prepared from 4-[2-(4-chloro-7-methoxy-quinazolin-6- yl)oxypropyl]morpholine and 3-amino-2-methylphenol. The crude product was purified by preparative hplc.
[00317] LCMS: Low_pH_2min RT 0.55 min, purity >95% [M+H]+ 425. High_pH_2min RT
0.87 min, purity >95% [M+H]+ 425.
[00318] 1 H NMR: (DMSO-d6): δ 9.40 (s, 1 H), 9.27 (d, J = 1 1 .77 Hz, 1 H), 8.24 (d, J = 1 .50
Hz, 1 H), 7.84 (d, J = 12.2 Hz, 1 H), 7.15 (d, J = 2.04 Hz, 1 H), 7.04 (t, J = 7.9 Hz, 1 H), 6.69 - 6.82 (m, 2H), 3.92 (d, J = 6. 8 Hz, 3H), 3.48 - 3.61 (m, 4H), 3.02 (q, J = 6.38 Hz, 1 H), 2.58 - 2.67 (m, 4H), 1 .95 (s, 3H), 1 .32 (d, J= 5.96 Hz, 2H), 1 .15 (d, J= 7.79 Hz, 3H).
Example 16 - 2-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol was prepared from 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline and 3-amino-2-chloro- 4-fluoro-phenol. The crude product was purified by preparative hplc.
[00319] LCMS: Low_pH_2min RT 0.71 min, purity >95% [M+H]+ 360.High_pH_2min RT
0.83 min, purity >95% [M+H]+ 360
[00320] 1 H NMR: (DMSO-d6): δ 9.88 (s, 1 H), 8.33 (s, 1 H), 9.43 (s, 1 H), 7.81 (s, 1 H), 7.19
(s, 1 H), 6.96 - 7.05 (m, 1 H), 6.81 - 6.84 (m, 2H), 4.22 - 4.31 (m, 2H), 3.94 (s, 3H), 3.74 (t, J = 4.35 Hz, 2H), 3.34 (s, 3H).
Example 17 - 4-fluoro-3-((7-Methoxy-6-(2-methoxyethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared from 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline and 3- amino-4-fluoro-2-methyl-phenol. The crude product was purified by preparative hplc.
[00321 ] LCMS: Low_pH_2min RT 0.74 min, purity >95% [M+H]+ 374. High_pH_2min RT 0.87min purity >95% [M+H]+ 374.
[00322] 1H NMR: (DMSO-d6): δ 9.40 (s, 1H), 9.21 (s, 1H), 8.26 (s, 1H), 7.86 (s, 1H), 7.18
(s, 1H), 6.95 (t, J= 9.21 Hz, 1H), 6.73 - 6.81 (m, 1H), 4.25 (t, J= 4.47 Hz, 2H), 3.94 (s, 3H), 3.77 (2H, t, J= 4.22 Hz, 2H), 3.36 (s, 3H), 1.99 (s, 3H).
Example 18 - 2-Chloro-4-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4- yl)amino)phenol was prepared from 4-c loro-6-met oxy-7-(2-met oxyet oxy)quinazoline and 3-amino-2-chloro-4-fluoro-phenol. The crude product was purified by preparative hplc.
[00323] LCMS: Low_pH_2min RT 0.75 min, purity >95% [M+H]+ 394. High_pH_2min RT 0.84 min, purity >95% [M+H]+ 394.
[00324] 1H NMR: (DMSO-d6): δ 10.21 (s, 1H), 9.45 (s, 1H), 8.28 (s, 1H), 7.86 (s, 1H),
7.21 (s, 1H), 7.16 (t, J= 9.20 Hz, 1H), 6.92 - 7.00 (m, 1H), 4.27 (t, J = 4.40 Hz, 2H), 3.94 (s, 3H), 3.71 - 3.77 (m, 2H), 3.34 (s, 3H) Example 19 - 2-((4-((2-Chloro-3-hydroxyphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetamide was prepared from 2-(4-chloro-6-methoxy-quinazolin-7-yl)oxyacetamide and 3-amino-2-chlorophenol.
[00325] LCMS: Low_pH_2min RT 0.61 min, purity >95% [M+H]+ 375. High_pH_2min RT
0.61 min, purity 90-95% [M+H]+ 375.
[00326] Ή NMR: (DMSO-d6): δ 9.43 (s, 1H), 8.27 (s, 1H), 7.86 (s, 1H), 7.41 - 7.51 (m,
2H), 7.09 (t, J= 8.01 Hz, 1H), 7.05 (s, 1H), 6.77 - 6.90 (m, 2H), 4.65 (s, 2H), 3.95 (s, 3H).
Example 20 - N-(2-((4-((2-Chloro-3-hydroxyphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)-N-methylmethanesulfonamide hydrochloride was prepared from N-[2-(4- chloro-6-methoxy-quinazolin-7-yl)oxyethyl]-N-methyl-methanesulfonamide and 3-amino-2- chlorophenol.
[00327] Low_pH_2min RT 0.73 min, purity >95% [M+H]+ 453. High_pH_2min RT 0.85 min, purity >95% [M+H]+ 453.
[00328] 1H NMR: (DMSO-d6): δ 11.35 (s, 1H), 10.55 (s, 1H), 8.76 (s, 1H), 8.19 (s, 1H), 7.35 (s, 1H), 7.28 (t, J= 8.04 Hz, 1H), 7.07 (dd, J= 8.22 and 1.39 Hz, 1H), 6.99 (dd, J =7.78 and 1.39 Hz, 1H), 4.37 (t, J= 5.21 Hz, 2H), 4.00 (s, 3H), 3.63 (t, J = 5.24 Hz, 2H), 3.00 (s, 3H), 2.94 (s, 3H). Example 21 - 4-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-2-methylphenol was prepared from 4-c loro-6,7-dimet oxy-quinazoline and 3-amino-6-c loro-2-met yl-phenol using dioxane as solvent. The crude product was purified by preparative hplc.
[00329] LCMS: Low_pH_2min RT 0.75 min, purity >95% [M+H]+ 346.5. High_pH_2min RT 0.86 min, purity >95% [M+H]+ 346.5.
[00330] Ή NMR: (DMSO-d6): δ 9.73 (s, 1 H), 9.37 (s, 1 H), 8.24 (s, 1 H), 7.86 (s, 1 H), 7.21
(d, J = 8.6 Hz, 1 H), 7.17 (s, 1 H), 6.84 (d, J= 8.6 Hz, 1 H), 3.93 (s, 6H), 1 .99 (s, 3H)
Example 22 - 3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2,4-difluorophenol was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-2,6-difluoro-phenol using dioxane as solvent. The crude product was purified by preparative hplc.
[00331] LCMS: Low_pH_2min RT 0.70 min, purity >95% [M+H]+ 334.5. High_pH_2min
RT 0.72 min, purity >95% [M+H]+ 334.5.
[00332] 1 H NMR: (DMSO-d6): δ 9.93 (s, 1 H), 9.43 (s, 1 H), 8.34 (s, 1 H), 7.84 (s, 1 H), 7.21 (s, 1 H), 6.96 (m, 2H), 3.94 (s, 6H)
Example 23 - 4-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-2-fluorophenol was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-4-chloro-2-fluoro-phenol using dioxane as solvent. The crude product was purified by preparative hplc.
[00333] LCMS: Low_pH_2min RT 0.72 min, purity >95% [M+H]+ 350.3. High_pH_2min
RT 0.76 min, purity >95% [M+H]+ 350.3.
[00334] Ή NMR: (DMSO-d6): δ 10.25 (bs, 1 H), 9.46 (s, 1 H), 8.31 (s, 1 H), 7.86 (s, 1 H),
7.23 (dd, J= 9.0 and 2.0 Hz, 1 H), 7.20 (s, 1 H), 6.97 (d, J= 9.0 Hz, 1 H), 3.94 (s, 6H) Example 24 - 2-Chloro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4- yl)amino)phenol hydrochloride was prepared from 4-chloro-6-methoxy-7-(3- pyridylmethoxy)quinazoline and 3-amino-2-chlorophenol.
[00335] LCMS: Low_pH_2min RT 0.70 min, purity >95% [M+H]+ 409. High_pH_2min RT
0.78 min, purity >95% [M+H]+ 409.
[00336] 1 H NMR: (DMSO-d6): δ 1 1 .50 (s, 1 H), 10.58 (s, 1 H), 8.91 (s, 1 H), 8.72 - 8.83 (m,
2H), 8.22 - 8.32 (m, 2H), 7.71 - 7.80 (m, 1 H), 7.50 (s, 1 H), 7.28 (t, J= 8.04 Hz, 1 H), 7.05 - 7.1 1 (m, 1 H), 6.95 - 7.00 (m, 1 H), 5.48 (s, 2H), 4.01 (s, 3H). Example 25 - 4-Fluoro-3-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared from 4-chloro-6-methoxy-7-(3-methoxypropoxy)quinazoline and 3- amino-4-fluoro-2-met yl-phenol.
[00337] LCMS: Low_pH_2min RT 0.79 min, purity >95% [M+H]+ 388. High_pH_2min RT 0.89 min, purity >95% [M+H]+ 388.
[00338] 1 H NMR: (DMSO-d6): δ 9.39 (s, 1 H), 9.24 (s, 1 H), 8.25 (s, 1 H), 7.84 (s, 1 H), 7.16
(s, 1 H),6.95 (t, J =9.5 Hz, 1 H), 6.77 (dd, J = 4.7 and 9.0 Hz, 1 H), 4.21 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.51 (t, J= 6.3 Hz), 2H), 3.27 (s, 3H), 2.04 (t, J= 6.2 Hz, 2H), 1 .99 (s, 3H). Example 26 - 2-Chloro-3-((6-methoxy-7-(2-(methylthio)ethoxy)quinazolin-4- yl)amino)phenol was prepared from 4-chloro-6-met oxy-7-(2-met ylsulfanylet oxy)quinazoline and 3-amino-2-chlorophenol. The crude product was purified by flash chromatography.
[00339] LCMS: Low_pH_2min RT 0.84 min, purity 90-95% [M+H]+ 392. High_pH_2min
RT 0.90 min, purity 90-95% [M+H]+ 392.
[00340] 1 H NMR: (DMSO-d6): 5 9.45 (s, 1 H), 8.29 (s, 1 H), 7.83 (s, 1 H), 7.15 - 7.22 (m,
2H), 6.89 - 7.00 (m, 2H), 4.32 (t, J = 6.50 Hz, 2H), 3.94 (s, 3H), 2.93 (t, J = 6.47 Hz, 2H), 2.21 (s, 3H).
Example 27 - 2-Chloro-3-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)amino)phenol was prepared from 4-chloro-6-methoxy-7-(3-methoxypropoxy)quinazoline and 3-amino-2- chlorophenol.
[00341] LCMS: Low_pH_2min RT 0.78 min, purity >95% [M+H]+ 390. High_pH_2min RT
0.83 min, purity >95% [M+H]+ 390.
[00342] Ή NMR: (DMSO-d6): δ 7.81 (s, 1 H), 7.13 (s, 1 H), 6.90 - 7.01 (m, 1 H), 6.52 - 6.68 (m, 2H), 4.18 (t, J = 6.41 Hz, 2H), 3.92 (s, 3H), 3.51 (t, J = 6.32 Hz, 2H), 3.27 (s, 3H), 2.03 (q, J= 6.32 Hz, 2H).
Example 28 - 3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2-methoxyphenol was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-2-methoxy-phenol.
[00343] LCMS: Low_pH_2min RT 0.65 min, purity 90-95% [M+H]+ 328. High_pH_2min
RT 0.81 min, purity 90-95% [M+H]+ 328.
[00344] 1 H NMR: (DMSO-d6): δ 9.38 (s, 1 H), 9.18 (s, 1 H), 8.32 (s, 1 H), 7.81 (s, 1 H), 7.16
(s, 1 H), 6.89 - 6.99 (m, 2H), 6.77 (dd, J = 6.49 and 2.25 Hz, 1 H), 3.93 (d, J = 1 .0 Hz, 6H,), 3.65 (s, 3H). Example 29 - 2-Methoxy-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol hydrochloride was prepared from 4-c loro-6-met oxy-7-(2-met oxyet oxy)quinazoline and 3- amino-2-met oxy-p enol.
[00345] LCMS: Low_pH_2min RT 0.70min, purity >95% [M+H]+ 372. High_pH_2min RT 0.82 min, purity >95% [M+H]+ 372.
[00346] Ή NMR: (DMSO-d6): δ 1 1 .10 (s, 1 H), 9.74 (s, 1 H), 8.73 (s, 1 H), 8.18 (s, 1 H),
7.33 (s, 1 H), 6.90 - 7.06 (m, 2H), 6.83 (dd, J = 7.87 and 1 .70 Hz, 1 H), 4.32 (t, J = 4.29 Hz, 2H), 3.99 (s, 3H), 3.74 - 3.82 (m, 2H), 3.68 (s, 3H), 3.35 (s, 3H). Example 30 - 2-Chloro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol was prepared from 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline and 3-amino-2- chlorop enol.
[00347] LCMS: Low_pH_2min RT 0.72 min, purity 90-95% [M+H]+ 376. High_pH_2min
RT 0.75 min, purity >95% [M+H]+ 376.
[00348] 1 H NMR: (DMSO-d6): δ 10.21 (s, 1 H), 9.47 (s, 1 H), 8.29 (s, 1 H), 7.83 (s, 1 H),
7.13 - 7.23 (m, 2H), 6.89 - 7.01 (m, 2H), 4.26 (t, J= 4.35 Hz, 2H), 3.94 (s, 3H), 3.74 (t, J= 4.34 Hz, 2H), 3.34 (s, 3H).
Example 31 - 2,4-Difluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4- yl)amino)phenol was prepared from 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline and 3-amino-2,4-difluoro-phenol. The crude product was purified by preparative hplc.
[00349] LCMS: Low_pH_2min RT 0.73 min, purity >95% [M+H]+ 378. High_pH_2min RT
0.73 min, purity >95% [M+H]+ 378.
[00350] Ή NMR: (DMSO-d6): δ 9.65 (s, 1 H), 9.19 (s, 1 H), 8.09 (s, 1 H), 7.60 (s, 1 H), 6.97 (s, 1 H), 6.61 - 6.84 (m, 2H), 4.03 (t, J = 4.26 Hz, 2H), 3.70 (s, 3H), 3.50 (t, J = 4.38 Hz, 2H),
3.34 (s, 3H).
Example 32 - 4-Chloro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared from 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline and 3- amino-4-chloro-2-methyl-phenol. The crude product was purified by preparative hplc.
[00351] LCMS: Low_pH_2min RT 0.77 min, purity >95% [M+H]+ 390. High_pH_2min RT
0.86 min, purity >95% [M+H]+ 390.
[00352] 1 H NMR: (DMSO-d6): δ 9.69 (s, 1 H), 9.37 (s, 1 H), 8.23 (s, 1 H), 7.86 (s, 1 H), 7.16
- 7.24 (m, 2H), 6.84 (d, J= 8.76 Hz, 1 H), 4.26 (t, J = 4.43 Hz, 2H), 3.93 (s, 3H), 3.74 (t, J = 4.34 Hz, 2H), 3.34 (s, 3H), 1 .98 (s, 3H). Example 33 - 2-Chloro-3-((6-methoxy-7-((3-methyloxetan-3-yl)methoxy)quinazolin-4- yl)amino)phenol was prepared from 4-chloro-6-methoxy-7-[(3-methyloxetan-3- yl)methoxy]quinazoline and 3-amino-2-chlorophenol. The crude product was purified by preparative hplc.
[00353] LCMS: Low_pH_2min RT 0.76 min, purity >955 [M+H]+ 402. High_pH_2min RT
0.79 min, purity >95% [M+H]+ 402.
[00354] 1 H NMR: (DMSO-d6): δ 9.46 (s, 1 H), 8.30 (s, 1 H), 7.84 (s, 1 H), 7.25 (s, 1 H), 7.18
(t, J = 7.98 Hz, 1 H), 6.90 - 7.01 (m, 2H), 4.55 (d, J = 5.73 Hz, 2H), 4.34 (d, J = 5.79 Hz, 2H), 4.24 (s, 2H), 3.94 (s, 3H), 1 .42 (s, 3H).
Example 34 - 4-Chloro-2-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4- yl)amino)phenol was prepared from 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline and 3-amino-4-chloro-2-fluoro-phenol. The crude product was purified by preparative hplc.
[00355] LCMS: Low_pH_2min RT 0.74 min, purity >95% [M+H]+ 394. High_pH_2min RT
0.61 min, purity >95% [M+H]+ 394.
[00356] 1 H NMR: (DMSO-d6): δ 10.22 (s, 1 H), 9.45 (s, 1 H), 8.28 (s, 1 H), 7.86 (s, 1 H),
7.21 (s, 1 H), 7.16 (t, J = 9.20 Hz, 1 H), 6.92 - 7.00 (m, 1 H), 4.27 (t, J = 4.37 Hz, 2H), 3.94 (s, 3H), 3.75 (t, J = 4.23 Hz, 2H), 3.34 (s, 3H under H20 peak).
Example 35 - 2-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-fluorophenol was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-2-chloro-4-fluoro-phenol. The crude product was purified by preparative hplc.
[00357] LCMS: Low_pH_2min RT 0.71 min, purity >95% [M+H]+ 350. High_pH_2min RT 0.70 min, purity >95% [M]+ 349.
[00358] Ή NMR: (DMSO-d6): δ 10.23 (s, 1 H), 9.45 (s, 1 H), 8.29 (s, 1 H), 7.86 (s, 1 H),
7.12 - 7.22 (m, 2H), 6.93 - 7.00 (m, 1 H), 3.94 (s, 6H).
Example 36 - N-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)-N-methylmethanesulfonamide was prepared from N-[2-(4-chloro-6-methoxy- quinazolin-7-yl)oxyethyl]-N-methyl-methanesulfonamide and 3-amino-6-fluoro-2-methyl-phenol . The crude product was purified by preparative hplc.
[00359] LCMS: Low_pH_2min RT 0.74 min, purity >95% [M+H]+ 451 . High_pH_2min RT
0.83 min, purity >95% [M+H]+ 451 .
[00360] 1 H NMR: (DMSO-d6): δ 9.40 (s, 1 H), 9.26 (s, 1 H), 8.26 (s, 1 H), 7.87 (s, 1 H), 7.23 (s, 1 H), 6.95 (t, J = 9.32 Hz, 1 H), 6.73 - 6.80 (m, 1 H), 4.31 (t, J = 5.07 Hz, 2H), 3.94 (s, 3.60 (t, J= 5.22 Hz, 2H), 3.00 (s, 3H), 2.92 (s, 3H), 1 .99 (s, 3H).
Example 37 - 4-Fluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared from 4-chloro-6-methoxy-7-(3-pyridylmethoxy)quinazoline and 3- amino-4-fluoro-2-methyl-phenol. The crude product was purified by flash chromatography eluting with a gradient of 10% 7M ammonia in methanol in ethyl acetate: isohexane.
[00361] LCMS: Low_pH_2min RT 0.71 min, purity >95% [M+H]+ 407. High_pH_2min RT
0.83 min, purity 85-90% [M+H]+ 407.
[00362] 1 H NMR: (DMSO-d6): δ 9.41 (s, 1 H), 9.28 (s, 1 H), 8.74 (s, 1 H), 8.55 - 8.62 (m,
1 H), 8.26 (s, 1 H), 7.89 - 7.97 (m, 1 H), 7.88 (s, 1 H), 7.42 - 7.52 (m, 1 H), 7.32 (s, 1 H), 6.95 (t, J = 9.24 Hz, 1 H), 6.73 - 6.82 (m, 1 H), 5.34 (s, 2H), 3.94 (s, 3H), 1 .99 (s, 3H).
Example 38 - 2-Chloro-3-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4- yl)amino)phenol was prepared from 4-[3-(4-chloro-6-methoxy-quinazolin-7- yl)oxypropyl]morpholine and 3-amino-2-chlorophenol.
[00363] LCMS: Low_pH_2min RT 0.56 min, purity 90-95% [M+H]+ 445. High_pH_2min
RT 0.77 min, purity 85-90% [M+H]+ 445.
[00364] Ή NMR: (DMSO-d6): δ 1 1 .32 (s, 1 H), 10.90 (s, 1 H), 10.56 (s, 1 H), 8.74 (s, 1 H), 8.22 (s, 1 H), 7.39 (s, 1 H), 7.27 (t, J = 8.06 Hz, 1 H), 7.04 - 7.10 (m, 1 H), 6.94 - 7.00 (m, 1 H), 4.32 (t, J = 5.79 Hz, 2H), 3.92 - 4.06 (m, 5H), 3.74 - 3.89 (m, 3H), 3.47 - 3.58 (m, 2H), 3.04 - 3.19 (m, 2H), 2.26 - 2.40 (m, 2H).
Example 39 - N-(2-((4-((6-Chloro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)-N-methylmethanesulfonamide was prepared from N-[2-(4-chloro-6-methoxy- quinazolin-7-yl)oxyethyl]-N-methyl-methanesulfonamide and 3-amino-6-chloro-2-methyl-phenol. The crude product was purified by preparative hplc.
[00365] LCMS: Low_pH_2min RT 0.77 min, purity >95% [M+H]+ 467. High_pH_2min RT
0.89 min, purity 90-95% [M+H]+ 467.
[00366] 1 H NMR: (DMSO-d6): δ 9.44 (m, J= 8.51 Hz, 1 H), 8.24 (s, 1 H), 7.89 (s, 1 H), 7.22
(s, 1 H), 7.17 (d, J = 8.64 Hz, 1 H) , 6.82 (d, J = 8.82 Hz, 1 H), 4.31 (t, J = 5.27 Hz, 2H), 3.93 (s, 3H), 3.60 (t, J= 5.15 Hz, 2H), 3.00 (s, 3H), 2.92 (s, 3H), 1 .98 (s, 3H). Example 40 - 2,4-Difluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4- yl)amino)phenol was prepared from 4-chloro-6-methoxy-7-(3-pyridylmethoxy)quinazoline and 3-amino-2,4-difluoro-phenol. The crude product was purified by preparative hplc.
[00367] LCMS: Low_pH_2min RT 0.72 min, purity >95% [M+H]+ 41 1 . High_pH_2min RT 0.77 min, purity >95% [M+H]+ 41 1 .
[00368] Ή NMR: (DMSO-d6): δ 3.95 (s, 3H), 5.35 (s, 2H), 6.85 -7.09 (m, 2H), 7.36 (s,
1 H), 7.44 - 7.52 (m, 1 H), 7.87 (s, 1 H), 7.90 - 7.98 (m, 1 H), 8.34 (s, 2H), 8.55 - 8.63 (m, 1 H), 8.74 (s, 1 H), 9.47 (s, 1 H) Example 41 - 4-Fluoro-3-((6-methoxy-7-((3-methyloxetan-3-yl)methoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared from 4-chloro-6-methoxy-7-[(3-methyloxetan-3- yl)methoxy]quinazoline and 3-amino-6-fluoro-2-methyl-phenol. The crude product wash purified by flash chromatography eluting with a gradient of ethyl acetate 50% to 100% in isohexane.
[00369] LCMS: Low_pH_2min RT 0.76 min, purity 90-95% [M+H]+ 400. High_pH_2min RT 0.88 min, purity 90-95% [M+H]+ 400.
[00370] 1 H NMR: (DMSO-d6): δ 9.41 (s, 1 H), 9.26 (s, 1 H), 8.26 (s, 1 H), 7.86 (s, 1 H), 6.95
(t, J= 9.8 Hz), 6.78 (m, 1 H), 4.55 (d, J= 6.5 Hz, 2H), 4.35 (d, J = 6.5 Hz, 2H), 3.94 (s, 3H), 1 .99 (s, 3H), 1 .42 (s, 3H) Example 42 - 1-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)pyrrolidin-2-one was prepared from 1 -[2-(4-chloro-6-methoxy-quinazolin-7- yl)oxyethyl]pyrrolidin-2-one and 3-amino-6-fluoro-2-methyl-phenol.
[00371] LCMS: Low_pH_2min RT 0.71 min, purity >95% [M+H]+ 427. High_pH_2min RT
0.81 min, purity >95% [M+H]+ 427.
[00372] Ή NMR: (DMSO-d6): δ 9.39 (s, 1 H), 9.25 (s, 1 H), 8.26 (s, 1 H), 7.86 (s, 1 H), 7.21
(s, 1 H), 6.95 (t, J = 9.9 Hz, 1 H), 6.77 (dd, J = 4.6 and 9.0 Hz, 1 H), 4.24 (t, J = 5.2 Hz, 2H), 3.94 (s, 3H), 3.63 (t, J = 5.6 Hz, 2H), 3.53 (t, J = 6.9 Hz, 2H), 2.24 (t, J = 7.9 Hz, 2H), 1 .99 (s, 3H), 1 .94 (quin, J = 7.9 Hz, 2H) Example 43 - 3-((7-(Cyclopropylmethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared from 4-chloro-7-(cyclopropylmethoxy)-6-methoxy-quinazoline and 3-amino-6-fluoro-2-methyl-phenol. The crude product was purified by flash chromatography eluting with a gradient of ethyl acetate 0-100% in isohexane.
[00373] LCMS: Low_pH_2min RT 0.96 min, purity >95% [M+H]+ 370. High_pH_2min RT 0.97 min, purity >95% [M-H]" 368. [00374] Ή NMR: (DMSO-d6): δ 9.38 (s, 1 H), 9.23 (s, 1 H), 8.24 (s, 1 H), 7.83 (s, 1 H), 7.1 1
(s, 1 H), 6.95 (t, J = 9.1 Hz, 1 H), 6.77 (dd, J = 4.6 and 8.9 Hz, 1 H), 3.97 (m, 2H), 3.94 (s, 3H), 1 .99 (s, 3H), 1 .30 (m, 1 H), 0.62 (m, 2H), 0.38 (m, 2H) Example 44 - 3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2,4-dimethylphenol was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-2,4-dimethyl-phenol. The crude product was purified by flash chromatography eluting with a gradient of methanol 0-10% in ethyl acetate.
[00375] LCMS: Low_pH_2min RT 0.69 min, purity >95% [M+H]+ 326.6. High_pH_2min RT 0.84 min, purity >95% [M-H]" 326.6.
[00376] 1 H NMR: (DMSO-d6): 5 9.16 (s, 2H), 8.20 (s, 1 H), 7.85 (s, 1 H), 7.15 (s, 1 H), 6.95
(d, J= 8.3 Hz, 1 H), 6.72 (d, J= 8.3 Hz, 1 H), 3.92 (s, 6H), 2.02 (s, 3H), 1 .95 (s, 3H).
Example 45 - 3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol hydrochloride was prepared from 4-chloro-7-(2-chloroethoxy)-6-methoxy- quinazoline and 3-amino-4-fluoro-2-methyl-phenol.
[00377] LCMS: Low_pH_2min RT 0.79 min, purity >95% [M+H]+ 378. High_pH_2min RT
0.95 min, purity >95% [M+H]+ 378.
[00378] Ή NMR: (DMSO-d6): δ 1 1 .2 (s, 1 H), 9.70 (s, 1 H), 8.74 (s, 1 H), 8.29 (s, 1 H), 7.36 (s, 1 H), 7.04 (t, J = 9.3 Hz, 1 H), 6.90 (dd, J = 4.6 and 9.3 Hz, 1 H), 4.50 (t, J = 5.1 Hz, 2H), 4.09 (t, J = 5.1 Hz, 2H), 4.03 (s, 3H), 2.04 (s, 3H)
Example 46 - 4-Fluoro-3-((6-methoxy-7-((5-methyl-1 ,2,4-oxadiazol-3- yl)methoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared from 3-[(4-chloro-6- methoxy-quinazolin-7-yl)oxymethyl]-5-methyl-1 ,2,4-oxadiazole and 3-amino-4-fluoro-2-methyl- phenol.
[00379] LCMS: Low_pH_2min RT 0.75 min, purity 90-95% [M+H]+ 412. High_pH_2min
RT 0.75 min, purity 90-95% [M=H]+ 412.
[00380] 1 H NMR: (DMSO-d6): δ 9.30 (s, 1 H), 8.26 (s, 1 H), 7.99 (s, 1 H), 7.89 (s, 1 H), 7.35 (s, 1 H), 6.95 (t, J = 9.3 Hz, 1 H), 6.77 (dd, J = 4.6 and 9.3 Hz, 1 H), 5.43 (s, 2H), 3.94 (s, 3H), 1 .99 (s, 3H)
Example 47 - 2,4-Difluoro-3-((6-methoxy-7-((5-methyl-1 ,2,4-oxadiazol-3- yl)methoxy)quinazolin-4-yl)amino)phenol was prepared from 3-[(4-chloro-6-methoxy- quinazolin-7-yl)oxymethyl]-5-methyl-1 ,2,4-oxadiazole and 3-amino-2,4-difluoro-phenol. [00381] LCMS: Low_pH_2min RT 0.77 min, purity >95% [M+H]+ 416. High_pH_2min RT
0.79 min, purity >95% [M=H]+ 416.
[00382] 1 H NMR: (DMS0-d6): δ 9.47 (s, 1 H), 8.35 (s, 1 H), 7.88 (s, 1 H), 7.38 (s, 1 H), 6.96
(m, 2H), 5.42 (s, 2H), 3.95 (s, 3H), 2.64 (s, 3H)
Example 48 - 2-Chloro-4-fluoro-3-((6-methoxy-7-((5-methylfuran-2-yl)methoxy)quinazolin- 4-yl)amino)phenol was prepared from 4-chloro-6-methoxy-7-[(5-methyl-2- furyl)metfioxy]quinazoline and 3-amino-2-chloro-4-fluoro-pfienol. The crude product was purified by preparative hplc.
[00383] LCMS: Low_pH_2min RT 0.85 min, purity 90-95% [M+H]+ 430. High_pH_2min
RT 0.72 min, purity 85-90% [M=H]+ 430.
Example 49 - 4-Fluoro-3-((6-methoxy-7-((1 -methyl-1 H-imidazol-5-yl)methoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared from 4-chloro-6-methoxy-7-[(3-methylimidazol-4- yl)methoxy]quinazoline and 3-amino-4-fluoro-2-methyl-phenol. The crude product was purified by preparative hplc.
[00384] LCMS: Low_pH_2min RT 0.56 min, purity 90-95% [M+H]+ 410. High_pH_2min
RT 0.78 min, purity 90-95% [M=H]+ 410.
[00385] Ή NMR: (DMSO-d6): δ 9.42 (s, 1 H) 9.26 (s, 1 H), 8.227 (s, 1 H), 7.86 (s, 1 H), 7.69 (s, 1 H), 7.40 (s, 1 H), 6.95 (t, J = 9.3 Hz, 1 H), 6.78 (dd, J = 4.6 and 9.3 Hz, 1 H), 5.29 (s, 2H), 3.91 (s, 3H), 3.66 (s, 3H), 1 .99 (s, 3H).
Derivatisation of 7-halo-alkoxy subst guinazolines (Examples 50 and 51)
Example 50 - 3-((7-(2-(1 H-lmidazol-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro- 2-methylphenol
Figure imgf000093_0001
[00386] 3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol hydrochloride (30 mg, 0.08 mmol) and imidazole (54 mg, 0.79 mmol) were dissolved in DMF (2 mL) and heated to 1 1 0 °C for 6 hours. The reaction was concentrated to dryness and purified by preparative HPLC to give 3-((7-(2-(1 H-imidazol- 1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol (12 mg, 0.028 mmol, 35%) as a white solid.
[00387] LCMS: Low_pH_2min RT 0.54 min, purity 90-95% [M+H]+ 410. High_pH_2min RT 0.77 min, purity 90-95% [M=H]+ 410.
[00388] 1 H NMR: (DMSO-d6): δ 9.97 (bs, 1 H), 9.52 (s, 1 H), 8.99 (s, 1 H), 8.41 (s, 1 H),8.07 (s, 1 H), 7.76 (s, 1 H),7.61 (s, 1 H), 7.31 (s, 1 H), 6.94 (t, J = 9.3 Hz, 1 H), 6.90 (dd, J = 4.6 and 9.3 Hz, 1 H), 4.50 (m, 2H), 4.09 (m, 2H), 3.96 (s, 3H), 2.00 (s, 3H). Example 51 - 4-Fluoro-3-((6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared in a similar manner from 3-((7-(2-chloroet oxy)-6- met oxyquinazolin-4-yl)amino)-4-fluoro-2-met ylphenol and 1 -met ylpiperazine.
[00389] LCMS: Low_pH_2min RT 0.56min, purity 90-95% [M-H]" 440, High_pH-2min RT
0.78min purity 85-90% [M-H]" 440.
Preparation of 5-substituted compounds (Examples 52 and 53):
Example 52
Step 1 - N'-(2-Cyano-3-fluorophenyl)-N,N-dimethylformimidamide
Figure imgf000094_0001
[00390] A suspension of 2-amino-6-fluorobenzonitrile (10 g, 73.5 mmol) in N,N- dimethylformamide dimethyl acetal (24.4 mL, 184 mmol) was heated under reflux conditions at 100 °C for 30 mins and then allowed to cool to rt. The yellow solution was transfered to a rbf with dichloromethane and concentrated in vacuo to give N'-(2-cyano- 3-fluorophenyl)-N,N-dimethylformimidamide (13. 9 g, 72.6 mmol, 99%) as a yellow solid, to be used in further reactions without additional purification.
[00391] 1HNMR: (DMSO-d6): δ 10.35 (s, 1 H), 9.23 (d, J = 16 Hz, 1 H), 8.59 (s, 1 H), 7.88 (m, 1 H), 7.69 (m, 2H), 7.48 (m, 1 H), 7.21 (t, J= 8.1 Hz, 1 H), 6.88 (dd, J= 8.5 and 1.6 Hz, 1 H) Step 2 - 2-Chloro-3-((5-fluoroquinazolin-4-yl)amino)phenol.
Figure imgf000095_0001
[00392] 3-amino-2-chlorophenol (665 mg, 5.23 mmol), acetic acid (4 ml_), N'-(2- cyano-3-fluoro-phenyl)-N,N-dimethyl-formamidine (1 g, 5.23 mmol) and acetonitrile (10 imL) were added to a microwave vial. The reaction was irradiated in the microwave for 20 min at 150 °C. The reaction was allowed to cool to room temperature. The resulting solid was collected by filtration and washed with acetonitrile (4 imL) to give 2-chloro-3- ((5-fluoroquinazolin-4-yl)amino)phenol (357 mg, 1 .17 mmol, 33.6%) as a beige solid. [00393] LCMS: Low_pH_2min RT 0.88min, purity >95 [M+H]+ 290.4. High_pH_2min RT 0.88min, purity >95 [M+H]+ 290.4
[00394] 1HNMR: (DMSO-d6): δ 10.35 (s, 1 H), 9.23 (d, J = 16 Hz, 1 H), 8.59 (s, 1 H), 7.88 (m, 1 H), 7.69 (m, 2H), 7.48 (m, 1 H), 7.21 (t, J= 8.1 Hz, 1 H), 6.88 (dd, J= 8.5 and 1.6 Hz, 1 H).
Step 3 - 2-Chloro-3-[(5-isopropoxyquinazolin-4-yl)amino]phenol
Figure imgf000095_0002
[00395] Sodium hydride (69 mg, 1 .73 mmol) and isopropanol (0.92 imL, 12.1 mmol) were stirred for 10 minutes, then 2-chloro-3-[(5-fluoroquinazolin-4- yl)amino]phenol (100 mg, 0.35 mmol) was added and the reaction mixture heated to 150°C for 15 minutes under microwave irradiation to give a yellow solid suspension. The reaction mixture was just acidified with dilute HCI and partitioned between DCM and water. The DCM layer was concentrated down in vacuo and the residue purified by flash chromatography eluting with 0-50% ethyl acetate in isohexane.The appropriate fractions were combined and concentrated in vacuo to give 2-chloro-3-[(5- isopropoxyquinazolin-4-yl)amino]phenol (34.3 mg, 0.099 mmol, 28.6%) 51 H NMR (DMSO-d6, Dec19-2012-ERF_20)- clean and concordant with product structure. [00396] LCMS: Low_pH_2min RT 0.88min, purity >95% [M-H]" 328.5. High_pH_2min RT 1.09 min, purity >95% [M-H]" 328.5
[00397] 1HNMR: (DMS0-d6): δ 10.34 (s, 1H), 10.18 (s, 1H), 8.51 (s, 1H), 7.91 (d, J = 8.47 Hz, 1H), 7.75 (t, J =8.47 Hz, 1H),7.35 (d, J =8.47 Hz, 1H), 7.23 (d, J =8.18 Hz, 1H),7.18 (t, J= 8.18 Hz, 1H), 6.80 (d, J= 8.18 Hz, 1H), 5.05 (m, 1H), 1.49 and 1.47 (6H, s x2).
[00398] The following compound was prepared using a similar method.
Example 53 - 2-Chloro-3-((5-cyclobutoxyquinazolin-4-yl)amino)phenol was prepared from 2-chloro-3-[(5-fluoroquinazolin-4-yl)amino]phenol (prepared above in Example 52) and cyclobutanol.
[00399] LCMS: Low_pH_2min RT 0.98min, purity 90-95% [M-H]" 340.4. High_pH_2min
RT 1.12min, purity 90-95% [M-H]" 340.5.
[00400] 1HNMR: (DMSO-d6): δ 10.17 (s, 1H), 8.54 (s, 1H), 8.03 (dd, J= 8.3 and 1.1 Hz, 1H), 7.74 (t, J= 8.2 Hz, 1H), 7.38 (d, J= 8.3 Hz, 1H), 7.18 (t, J= 8.6 Hz, 1H), 7.02 (d, J= 8.0 Hz, 1H), 6.79 (dd, J= 8.2 and 1.2 Hz, 1H), 5.04 (quin, J= 7.5 Hz, 1H), 5.28 (m, 1H), 2.31 (m, 2H), 1.87 (m, 2H), 1.70 (m, 2H).
Preparation of O-linked compounds (Examples 54 to 61):
Example 54 - 3-((6 J-Dimethoxyquinazolin-4-yl)oxy)-2-methylphenol
Figure imgf000096_0001
[0001] 4-Chloro-6,7-dimethoxy-quinazoline (200 mg, 0.89mmol), potassium carbonate (246.1 mg, 1.78 mmol) and 2-methylresorcinol (331.6 mg, 2.67 mmol) were mixed with MeCN (5 mL) and heated in the microwave at 130 °C for 1 hour. The reaction was cooled and the mixture treated with water and dichloromethane. The aqueous phase was neutralised (HCI then
NaHC03) then extracted with dichloromethane. The combined organics were dried, (MgS04), filtered and evaporated to give a solid that was purified by prep hplc to give 3-((6,7- dimethoxyquinazolin-4-yl)oxy)-2-methylphenol, 15mg.
[0002] LCMS: Low_pH_2min RT 0.93 min, purity >95% [M+H]+ 313.5. High_pH_2min RT 0.95 min, purity >95% [M+H]+ 313.6. [0003] 1 HNMR: (DMSO-d6): δ 9.97 (s, 1 H), 8.51 (s, 1 H), 7.58 (s, 1 H), 7.39 (s, 1 H), 7.08 (t, J =
8.0 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 3.99 (s, 3H), 3.98 (s, 3H), 1 .87 (s, 3H). [0004] Using a similar method the following compounds were prepared:
Example 55 - 3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,4,6-trimethylphenol was prepared from 4- chloro-6,7-dimethoxy-quinazoline and 2,4,6-trimethylresorcinol.
[0005] LCMS: Low_pH_2min RT 1 .06 min, purity >95% [M+H]+ 341 .6. High_pH_2min RT 1 .09 min, purity >95% [M+H]+ 341 .6
[0006] 1 HNMR: (DMSO-d6): δ 8.48 (s, 1 H), 8.29 (s, 1 H), 7.61 (s, 1 H), 7.39 (s, 1 H), 6.87 (s, 1 H), 3.99 (s, 3H), 3.98 (s, 3H), 2.18 (s, 3H), 1 .92 (s, 3H), 1 .90 (s, 3H).
Example 56 - 2-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenol was prepared from 4- chloro-6,7-dimethoxy-quinazoline and 2-chlorobenzene-1 ,3-diol.
[0007] LCMS: Low_pH_2min RT 0.86 min, purity >95% [M+H]+ 333.5. High_pH_2min RT 0.86 min, purity >95% [M+H]+ 333.5.
[0008] 1 HNMR: (DMSO-d6): δ 8.54 (s, 1 H), 7.56 (s, 1 H), 7.41 (s, 1 H), 7.25 (t, J = 8.3 Hz, 1 H), 6.96 (dd, J = 1 .1 and 8.3 Hz, 1 H), 6.90 (dd, J = 1 .1 and 8.2 Hz, 1 H), 4.00 (s, 3H), 3.98 (s, 3H).
Example 57 - 2-Bromo-3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenol was prepared from 4- chloro-6,7-dimethoxy-quinazoline and 2-bromobenzene-1 ,3-diol.
[0009] LCMS: Low_pH_2min RT 0.97 min, purity >95% [M+H]+ 377.5. High_pH_2min RT 0.85 min, purity >95% [M+H]+ 377.5.
[0010] 1 HNMR: (DMSO-d6): δ 10.1 (bs, 1 H), 8.53 (s, 1 H), 7.56 (s, 1 H), 7.40 (s, 1 H), 7.28 (t, J =
8.1 Hz, 1 H), 6.93 (dd, J = 1 .4 and 8.3 Hz, 1 H), 6.88 (dd, J = 1 .4 and 8.1 Hz, 1 H), 4.00 (s, 3H), 3.98 (s, 3H).
Example 58 - 3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2-ethylphenol was prepared from 4-chloro- 6,7-dimethoxy-quinazoline and 2-ethylbenzene-1 ,3-diol.
[0011 ] LCMS: Low_pH_2min RT 1 .01 min, purity >95% [M+H]+ 327.5. High_pH_2min RT 1 .01 min, purity >95% [M+H]+ 327.5.
[0012] 1 HNMR: (DMSO-d6): δ 9.63 (s, 1 H), 8.53 (s, 1 H), 7.56 (s, 1 H), 7.39 (s, 1 H), 7.08 (t, J = 8.1 Hz, 1 H), 6.93 (d, J = 8.1 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 3.99 (s, 3H), 3.97 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz).
[0013] 2-Ethyl benzene-1 ,3-diol was prepared by a method described by Moran et al, Journal of the American Chemical Society, 1991 , Vol. 1 13, # 15 p5707 - 5714. Example 59 - 3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,5-dimethylphenol was prepared from 4- chloro-6,7-dimethoxy-quinazoline and 2,5-dimethyl-1 ,3-benzenediol.
[0014] LCMS: Low_pH_2min RT 1 .01 min, purity >95% [M+H]+ 327.6. High_pH_2min RT 1 .01 min, purity >95% [M+H]+ 327.6
[0015] 1 HNMR: (DMSO-d6): δ 9.53 (s, 1 H), 8.52 (s, 1 H), 7.55 (s, 1 H), 7.38 (s, 1 H), 6.59 (s, 1 H), 6.48 (s, 1 H), 3.99 (s, 3H), 3.97 (s, 3H), 2.21 (s, 3H), 1 .82 (s, 3H).
Example 60 - 3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,6-difluorophenol and Example 61 3- ((6,7-dimethoxyquinazolin-4-yl)oxy)-2,4-difluorophenol were prepared from 4-chloro-6,7- dimethoxy-quinazoline and 2,4-difluoro-1 ,3-benzenediol.
Example 60- 3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,6-difluorophenol.
[0016] LCMS: Low_pH_2min RT 0.98 min, purity >95% [M+H]+ 335.5. High_pH_2min RT 0.89 min, purity >95% [M+H]+ 335.5.
[0017] 1 HNMR: (DMSO-d6): δ 10.3 (bs, 1 H), 8.60 (s, 1 H), 7.58 (s, 1 H), 7.45 (s, 1 H), 7.12 (dt, J = 2.0 and 8.0 Hz, 1 H), 6.93 (dt, J = 5.2 and 9.3 Hz, 1 H), 4.00 (2 x s, 6H).
Example 61 - 3-((6,7-dimethoxyquinazolin-4-yl)oxy)-2,4-difluorophenol.
[0018] LCMS: Low_pH_2min RT 0.96 min, purity >95% [M+H]+ 335.5. High_pH_2min RT 0.72 min, purity >95% [M+H]+ 335.5.
[0019] 1 HNMR: (DMSO-d6): δ 8.56 (s, 1 H), 8.39 (s, 1 H), 7.55 (s, 1 H), 7.41 (s, 1 H), 7.01 (m, 1 H), 6.69 (m, 1 H), 4.00 (s, 3H), 3.98 (s, 3H).
EXAMPLES 63-77 Intermediate Synthesis
Phenols
3-Amino-5-fluoro-2-methyl-phenol
[00401 ] Using a similar method described in Method phenol-3 1 -bromo-5-fluoro-2- methyl-3-nitrobenzene was converted to 3-amino-5-fluoro-2-methylphenol.
Step 1
Figure imgf000098_0001
[00402] Ammonium chloride (571 mg, 10.7 mmol) was added to 1 -bromo-5-fluoro-2- methyl-3-nitrobenzene (500 mg, 2.14 mmol) and iron (powder) (0.6 g, 10.68 mmol) in water (24 mL) and ethanol (24 mL). The reaction was refluxed for 5 hours then filtered through celite and the filter cake washed with ethanol (100 mL) and EtOAc (100 mL). The organics were removed in vacuo to leave an aqueous solution which was extracted with DCM (3 x 30 mL). The organics were isolated and concentrated to give crude 3-bromo-5-fluoro-2-methyl-aniline (390 mg, 1 .87 mmol, 87.7%) which was clean by NMR and used without further purification.
[00403] 1 H NMR (DMSO-d6): δ 6.60 (dd, J = 2.8 and 8.4 Hz, 1 H), 6.42 (dd, J = 2.8 and
1 1 .6 Hz, 1 H), 5.54 (bs, 2H), 2.09 (s, 3H).
Step 2
Figure imgf000099_0001
[00404] 3-Bromo-5-fluoro-2-methyl-aniline (725 mg, 3.55 mmol), bis(pinacolato)diboron (1 .08 g, 4.26 mmol) and potassium acetate (1 .05 mg, 10.7 mmol) were mixed in 1 ,4-dioxane (35 mL) and nitrogen gas was blown through for 5 minutes. 1 ,1 -Bis(diphenyl-phosphino)ferrocene- palladium(1 ,1 )dichloride DCM adduct (174 mg, 0.21 mmol) was added and the mixture was heated under reflux conditions for 4 hours. The reaction was allowed to cool - excess dioxane was removed and the residue was diluted with EtOAc and filtered through celite. The organic solution was concentrated. The crude material was purified by column chromatography (24g silica) with a gradient 0 - 50% EtOAc in hexanes to give 5-fluoro-2-methyl-3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (0.761 g, 2.79 mmol, 78.5%).
[00405] 1 H NMR (DMSO-d6): δ 6.91 (dd, J = 2.7 and 9.0 Hz, 1 H), 6.50 (dd, J = 2.6 and 10.0 Hz, 1 H), 3.88 (bs, 2H), 2.34 (s, 3H), 1 .36 (s, 12H).
Step 3
Figure imgf000099_0002
[00406] 5-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (18.6 g, 44.4 mmol) was completely dissolved in THF (500 mL) , water (250 mL) was added followed by sodium perborate (23.47 g, 152.5 mmol) . The mixture was stirred at ambient temperature overnight. THF was removed under in vacuo and the aqueous extracted with DCM (50 mL). The organics were isolated and a solid precipitated out of solution. The solid was collected by filtration and dried under vacuum to give 3-amino-5-fluoro-2-methyl-phenol (5.72 g, 37.3 mmol, 83.9%) as a light brown solid. [00407] 1 H NMR (DMSO-d6): δ 9.2 (bs, 1 H), 5.85 (m, 2H), 4.99 (bs, 2H), 1 .81 (s, 3H).
3-Amino-2-bromo-phenol
Figure imgf000100_0001
[00408] 2-Bromo-3-nitro-phenol (3.35 g, 15.4 mmol), acetic acid (35 mL) and iron powder
(4.5 g, 77.2 mmol) were stirred in ethanol (50 mL) under reflux overnight. The mixture was diluted with 100ml of water and neutralised with potassium carbonate before extraction with DCM. The organics were dried with sodium sulfate and concentrated in vacuo to leave the crude product as a brown oil. This was dry-packed on to silica and purified by column chromatography using a 0-50% gradient of ethyl acetate in isohexane. The resulting fragments were concentrated in vacuo to give 3-amino-2-bromo-phenol (1 .27 g, 6.75 mmol, 43.9%) as a pale yellow solid.
[00409] 1 H NMR (DMSO-d6): δ 7.02 (t, J = 8.0 Hz, 1 H), 6.45 (dd, J = 1 .6 and 8.0 Hz,
1 H), 6.38 (dd, J = 1 .6 and 8.0 Hz, 1 H) 5.44 (bs, 1 H), 4.89 (bs, 2H).
3-Benzyloxy-2-(trifluoromethyl)aniline
Step 1
Figure imgf000100_0002
[00410] Benzyl alcohol (2.24 mL, 21 .6 mmol) was dissolved in DMF (10 mL) and cooled in an ice bath. Sodium hydride 60% dispersion in oil (0.99 g, 24.7 mmol) was added portionwise. The mixture was stirred for 1 hour then 3-fluoro-2-(trifluoromethyl)bromobenzene (5.0 g, 20.6 mmol) was added portionwise. The mixture became very thick so additional DMF (10 mL) was added. The mixture was allowed to warm to ambient temperature and then stirred overnight under a nitrogen atmosphere. Water was added carefully and stirring was continued for 30 minutes. Excess water and DMF were removed in vacuo. The residue was mixed with DCM and water then passed through a hydrophobic frit. The DCM phase was concentrated down and loaded directly on to a (preconditioned with isohexane) 10Og SNAP biotage cartridge. The crude products were eluted with 0-50% ethyl acetate/isohexane over 40 minutes to give 1 - benzyloxy-3-bromo-2-(trifluoromethyl)benzene (3.7g, 52%).
[0041 1] 1 H NMR (DMSO-d6): δ 7.43 (m, 8H), 5.28 (s, 2H). Step 2
Figure imgf000101_0001
[00412] Benzophenone imine (1 .39 mL, 8.31 mmol), cesium carbonate (2.2 g, 1 1 .3 mmol), palladium acetate (84.8 mg, 0.38 mmol), BINAP (470.5 mg, 0.76 mmol) and 1 - benzyloxy-3-bromo-2-(trifluoromethyl)benzene (2.5 g, 7.56 mmol) were added to a 100ml_ flask and stirred in toluene (40 mL) and the reaction mixture was flushed with nitrogen. The reaction mixture was stirred at reflux under nitrogen overnight. The reaction mixture was allowed to cool to room temperature, the cesium carbonate filtered off, and the solution washed with ethyl acetate 2 x 25mL, 0.5M HCI 2 x 25 mL, then with sodium bicarbonate 2 x 25 mL. The organic solution was separated and concentrated in vacuo to give an orange solid. The solid was dissolved in DCM and preabsorbed onto silica and purified by column chromatography 50 g, 0- 30% EtOAc in isohexane. The relevant fragments were collected and concentrated in vacuo to give A/-[3-benzyloxy-2-(trifluoromethyl)phenyl]-1 ,1 -diphenyl-methanimine (2.00 g, 4.64 mmol, 61 .4%) as a yellow solid.
[00413] 1 H NMR (DMSO-d6): δ 7.81 (m, 2H), 7.32 (m, ~20H), 6.61 (d, J = 8.4 Hz, 1 H),
6.17 (d, J = 8.4 Hz, 1 H) - still contains some benzophenone imine or by-products.
Step 3
Figure imgf000101_0002
[00414] At room temperature A/-[3-benzyloxy-2-(trifluoromethyl)phenyl]-1 ,1 -diphenyl- methanimine (100 mg, 0.23 mmol) was stirred and dissolved in THF (5 mL) and 2M hydrochloric acid (0.5 mL, 1 mmol) was added. The reaction mixture was left to stir overnight at room temperature. The reaction mixture was believed to contain a 1 :1 ratio of the benzophenone product and the desired product. The reaction mixture was worked up by adding 50mL EtOAc and washing with twice with 25 mL portions of sodium bicarbonate. The organics were separated and concentrated in vacuo. The organics were pre-absorbed on to silica and purified by column chromatography 0-25% EtOAc in isohexane on a 25 g column The relevant fragments were collected and concentrated in vacuo to give 3-benzyloxy-2- (trifluoromethyl)aniline (286 mg, 1 .07 mmol, 76.9%) as a yellow oil.
[00415] 1 H NMR (DMSO-d6): δ 7.42 (m, 4H), 7.33 (m, 1 H), 6.40 (d, J = 8.4 Hz, 1 H), 6.35
(d, J = 8.4 Hz, 1 H), 5.59 (bs, 1 H), 5.10 (bs, 1 H).
Synthesis using method Mitsunobu coupling 1
[00416] 4-Chloro-6-methoxy-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazoline
Figure imgf000102_0001
[00417] Diisopropyl azodicarboxylate (0.07 mL, 0.37 mmol) was added to 4-chloro-6- methoxy-quinazolin-7-ol (60 mg, 0.28 mmol), triphenylphosphine (97.1 mg, 0.37 mmol) and tetrahydropyran-4-methanol (0.03 mL, 0.28 mmol) in THF (5 mL). The reaction was heated to 50 °C for 16 hours. The reaction was concentrated to dryness and the crude material purified by column chromatography ( 4g silica) with a gradient 0 - 100% EtOAc in hexanes to give 4-chloro- 6-methoxy-7-(tetrahydropyran-4-ylmethoxy)quinazoline (35 mg, 0.1 13 mmol, 39.8%) as an off white solid (contaminated with a little triphenylphosphine).
[00418] 1 H NMR (DMSO-d6): δ 8.71 (s, 1 H), 7.29 (s, 1 H), 7.23 (s, 1 H), 3.93 (d, J = 6.4 Hz, 2H), 3.83 (s, 2H), 3.71 (m, 2H), 1 .94 (m, 1 H), 1 .53 (m, 2H), 1 .21 (m, 2H).
4-Chloro-6-methoxy-7-(tetrahydrofuran-2-ylmethoxy)quinazoline
Figure imgf000102_0002
[00419] Diisopropyl azodicarboxylate (0.07 mL, 0.37 mmol) was added to a slurry of 4- chloro-6-methoxy-quinazolin-7-ol (60 mg, 0.28 mmol), triphenylphosphine (97.1 mg, 0.37 mmol) and tetrahydro-2-furanylmethanol (0.03 mL, 0.28 mmol) in THF (10 mL). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated to dryness then triturated with ether (3 mL) to remove reduced DIAD. The solid was purified by column chromatography (4g silica) with a gradient of 0 - 50% EtOAc in hexanes (wet loaded in DCM) to give 4-chloro-6-methoxy-7-(tetrahydrofuran-2-ylmethoxy)quinazoline (77 mg, 0.26 mmol, 91 .7%) as a white solid (contaminated with a little triphenylphosphine).
[00420] Ή NMR (DMSO-d6): δ 8.88 (s, 1 H), 7.49 (s, 1 H), 7.41 (s, 1 H), 4.23 (m, 3H), 4.00
(s, 3H), 3.76 (m, 2H), 1 .7-2.1 (m, 4H). Method for preparation of formimidamide intermediates
[00421] Outline of synthetic route:
Figure imgf000103_0001
(i≡)-A -(2-Cyano-5-hydroxy-4-methoxyphenyl)-A/,A^dimethylformimidamide trifluoroacetic acid salt
Figure imgf000103_0002
[00422] A suspension of /V-(5-benzyloxy-2-cyano-4-methoxy-phenyl)-A/,A/-dimethyl- formamidine (1 .99 g, 6.43 mmol) in trifluoroacetic acid (20. ml_, 261 mmol) was heated at 75 °C for 45 min in the microwave reactor. The mixture was concentrated in vacuo to remove TFA then added toluene (20 ml) and concentrated again. The viscous brown oil was triturated with ether and the resulting solid was isolated by filtration. The solid was washed with ether then dried in vacuo at 50 C overnight to return ( E)-/V-(2-cyano-5-hydroxy-4-methoxyphenyl)-A/,A/- dimethylformimidamide trifluoroacetic acid salt (2.04 g, 6.1 mmol, 95.1 %) as a light grey solid.
[00423] Ή NMR (DMSO-d6): δ 10.8 (bs, 1 H), 8.39 (s, 1 H), 7.40 (s, 1 H), 6.92 (s, 1 H),
3.27 (s, 3H), 3.16 (s, 3H).
[00424] LCMS High_pH_2min RT 0.58 min, purity 93% [M+H]+ 220.5. (£)-Ethyl 2-(4-cyano-5-(((dimethylamino)methylene)amino)-2-methoxyphenoxy)acetate
Figure imgf000103_0003
[00425] Ethyl bromoacetate (0.33 mL, 3 mmol) was added to a slurry of (£)-/V-(2-cyano- 5-hydroxy-4-methoxyphenyl)-A/,A/-dimethylformimidamide trifluoroacetic acid salt (1 g, 3 mmol) and cesium carbonate (1 .75 g, 9 mmol) in acetonitrile (10 mL) at 50 °C. The reaction was then refluxed for 5 hours. The slurry was filtered and the solid washed with EtOAc (100 mL). The organics were concentrated to dryness and the resulting solid purified by column chromatography (12 g silica) with a gradient 10 - 30% EtOAc in hexanes to give ( r)-ethyl 2-(4- cyano-5-(((dimethylamino)methylene)amino)-2-methoxyphenoxy)acetate (866 mg, 2.69 mmol, 89.8) as a yellow solid.
[00426] 1 H NMR (DMSO-d6): δ 7.86 (s, 1 H), 7.14 (s, 1 H), 6.71 (s, 1 H), 4.87 (s, 1 H), 4.18
(q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.04 (s, 3H), 2.96 (s, 3H), 1 .20 (t, J = 7.0 Hz, 3H).
(£)-Af-(2-Cyano-5-(2,2-dimethoxyethoxy)-4-methoxyphen
Figure imgf000104_0001
[00427] Cesium carbonate (3.49 g, 18 mmol) and (≡)-/V-(2-cyano-5-hydroxy-4- methoxyphenyl)-A/,A/-dimethylformimidamide trifluoroacetic acid salt (2 g, 6 mmol) were slurried in acetonitrile (20 mL) at 50 °C for 10 minutes. 2-Bromo-1 ,1 -dimethoxy-ethane (7.09 mL, 60 mmol) was added and the reaction mixture heated to reflux over the weekend. The reaction was incomplete, so additional 2-bromo-1 ,1 -dimethoxy-ethane (7.09 mL, 60 mmol) was added and the reaction refluxed for an additional 16 hours. Reaction still incomplete but was worked up. The reaction mixture was filtered and the solid washed with EtOAc (100 mL). The organics were concentrated. The crude material was purified by column chromatography (12 g silica) with a gradient of 0 - 100% EtOAc in hexanes (25 minutes) to give (E)-/V-(2-cyano-5-(2,2- dimethoxyethoxy)-4-methoxyphenyl)-A/,A/-dimethylformimidamide (1 .2 g, 3.83 mmol, 63.8%) as a yellow solid.
[00428] 1 H NMR (DMSO-d6): δ 7.94 (s, 1 H), 7.10 (s, 1 H), 6.79 (s, 1 H), 4.72 (t, J = 5.2 Hz,
1 H), 4.04 (d, J = 5.3 Hz, 2H), 3.74 (s, 3H), 3.35 (s, 6H), 3.06 (s, 3H), 2.96 (s, 3H).
[00429] LCMS High_pH_2min RT 0.96 min, [M+H]+ 308. (£)-ferf-Butyl 4-((4-cyano-5-(((dimethylamino)methylene)amino) methoxyphenoxy)methyl)piperidine-1-carboxylate
Figure imgf000105_0001
[00430] A mixture of /V-(2-cyano-5-hydroxy-4-methoxy-phenyl)-A/,A/-dimethyl- formamidine; trifluoroacetic acid salt (280 mg, 0.84 mmol) , f-butyl 4-(p- tolylsulfonyloxymethyl)piperidine-1 -carboxylate (372 mg, 1 .01 mmol) and caesium carbonate (821 mg, 2.52 mmol) in MeCN (5 mL) was heated at reflux overnight.
[00431] LCMS showed a major new peak at (86%, [M+H]+ 361 .4). The mixture was concentrated in vacuo to remove MeCN, and then the residue was suspended in sat. NaHC03 (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (10 mL), dried over MgS04, filtered and concentrated in vacuo to give ( r)-ferf-butyl 4-((4-cyano- 5-(((dimethylamino)methylene)amino)-2-methoxyphenoxy)methyl)piperidine-1 -carboxylate (350 mg, 0.84 mmol, 100%).
[00432] LCMS High_pH_2min RT 1 .24 mins (88%); [M+H]+ 361 .4/317.4 (fragments for loss of isobutene and Boc, respectively).
Final compounds
Using Condensation Method C2
Example 63 - 2-Bromo-3-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol hydrochloride was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-2-bromo-phenol using microwave heating at 100 °C for 30min.
[00433] LCMS: Low_pH_2min RT 0.68min, purity >95% [M+H]+ 378.2 (Br isotope pattern). High_pH_2min RT 0.77min, purity >95% [M+H]+ 378.2 (Br isotope pattern).
[00434] 1 H NMR (DMSO-d6): δ 1 1 .30 (s, 1 H), 10.60 (s, 1 H), 8.75 (s, 1 H), 8.14 (s, 1 H),
7.31 (m, 2H), 7.04 (dd, J = 1 .4 and 8.2 Hz, 1 H), 6.97 (dd, J = 1 .5 and 7.8 Hz, 1 H), 4.01 (s, 3H), 3.99 (s, 3H).
Example 64 - 2-Bromo-3-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol hydrochloride was prepared from 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline and 3- amino-2-bromo-phenol using microwave heating at 100 °C for 30min.
[00435] LCMS: Low_pH_2min RT 0.71 min, purity >95% [M+H]+ 420.3 (Br isotope pattern). High_pH_2min RT 0.79min, purity >95% [M+H]+ 378.2 (Br isotope pattern).
[00436] Ή NMR: (DMSO-d6): δ 1 1 .38 (bs, 1 H), 10.63 (s, 1 H), 8.75 (s, 1 H), 8.18 (s, 1 H),
7.35 (s, 1 H), 7.32 (t, J = 8.1 Hz, 1 H), 7.05 (dd, J = 1 .6 and 8.2 Hz, 1 H), 6.97 (dd, J = 1 .3 and 7.9 Hz, 1 H), 4.33 (m, 2H), 4.00 (s, 3H), 3.78 (m, 2H), 3.35 (s, 3H).
Example 65 - 5-Fluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared from 4-chloro-6-methoxy-7-(3-pyridylmethoxy)quinazoline and 3- amino-2-bromo-phenol.
[00437] LCMS: Low_pH_2min RT 0.74min, purity >95% [M+H]+ 407. High_pH_2min RT
0.88min, purity >95% [M+H]+ 407.
[00438] 1 H NMR: (DMSO-d6): δ 1 1 .53 (s, 1 H), 10.23 (bs, 1 H), 8.96 (d, J = 1 .7 Hz, 1 H),
8.81 (d, J = 1 .7 and 5.4 Hz, 1 H) 8.76 (s, 1 H), 8.38 (m, 2H), 7.85 (m, 1 H), 7.55 (s, 1 H), 6.71 (m, 2H), 5.50 (s, 2H), 4.02 (s, 3H), 1 .96 (s, 3H).
Example 66 - 3-((6,7-Dimethoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol was prepared from 4-chloro-6,7-dimethoxy-quinazoline and 3-amino-5-fluoro-2-methyl-phenol using microwave heating at 100 °C for 30min.
[00439] LCMS: Low_pH_2min RT 0.72min, purity >95% [M+H]+ 330. High_pH_2min RT
0.85min, purity >95% [M+H]+ 330.
[00440] 1 H NMR: (DMSO-d6): δ 1 1 .33 (bs, 1 H), 10.26 (s, 1 H), 8.74 (s, 1 H), 8.24 (s, 1 H)
7.34 (s, 1 H), 6.70 (m, 2H), 4.0 (s, 3H), 1 .96 (s, 3H).
Example 67 - 5-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared from 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline and 3- amino-5-fluoro-2-methyl-phenol using microwave heating at 100 °C for 30min.
[00441] LCMS: Low_pH_2min RT 0.76min, purity >95% [M+H]+ 374. High_pH_2min RT
0.87min, purity >95% [M+H]+ 374.
[00442] Ή NMR: (DMSO-d6): δ 9.96 (bs, 1 H), 9.34 (s, 1 H), 8.30 (s, 1 H), 7.80 (s, 1 H)
7.18 (s, 1 H), 6.61 (m, 2H), 4.26 (m, 2H), 3.94 (s, 3H), 3.75 (m, 2H), 1 .96 (s, 3H).
Example 68 - 4-Fluoro-3-((6-methoxy-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared from 4-chloro-6-methoxy-7-(tetrahydropyran-4- ylmethoxy)quinazoline and 3-amino-5-fluoro-2-methyl-phenol using microwave heating at 100 °C for 30min.
[00443] LCMS: Low_pH_2min RT 0.80min, purity >95% [M+H]+ 414. High_pH_2min RT
0.91 min, purity >95% [M+H]+ 414.
Example 69 - 4-Fluoro-3-((6-methoxy-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared from 4-chloro-6-methoxy-7-(tetrahydrofuran-2- ylmethoxy)quinazoline and 3-amino-5-fluoro-2-methyl-phenol using microwave heating at 100 °C for 30min.
[00444] LCMS: Low_pH_2min RT 0.78min, purity >95% [M+H]+ 400. High_pH_2min RT 0.90min, purity >95% [M+H]+ 400.
[00445] 1 H NMR: (DMSO-d6): δ 9.39 (s, 1 H), 9.24 (s, 1 H), 8.26 (s, 1 H), 7.84 (s, 1 H), 7.19
(s, 1 H), 6.95 (t, J = 9.3 Hz, 1 H), 6.77 (m, 1 H), 4.25 (m, 1 H), 4.10 (m, 2H), 3.94 (s, 3H),3.82 (m, 1 H), 3.70 (m, 1 H), 1 .96 (s, 3H), 1 .7 - 2.2 (m, 4H).
Example 70 - 3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2- methylphenol was prepared from 4-chloro-7-(2-chloroethoxy)-6-methoxy-quinazoline and 3- amino-5-fluoro-2-methyl-phenol.
[00446] LCMS: Low_pH_2min RT 0.81 min, purity >95% [M+H]+ 378. High_pH_2min RT
0.95min, purity >95% [M+H]+ 378.
[00447] 1 H NMR: (DMSO-d6): δ 1 1 .3 (bs, 1 H), 10.3 (s, 1 H), 8.74 (s, 1 H), 8.24 (s, 1 H), 7.35 (s, 1 H), 6.70 (s, 2H), 4.49 (m, 2H), 4.09 (m, 2H), 4.01 (s, 3H), 1 .95 (s, 3H)
Final compounds using condensation/cvclisation method
Example 71 - Ethyl 2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyq u i nazol i n-7-yl )oxy)acetate
[00448] Ethyl 2-[4-cyano-5-[(£)-dimethylaminomethyleneamino]-2-methoxy- phenoxy]acetate (215 mg, 0.70 mmol) and 3-amino-5-fluoro-2-methyl-phenol (149.1 mg, 1 .06 mmol) were dissolved in acetic acid (2 mL). The reaction was heated at 120°C for 3 hours. The reaction was allowed to stand overnight and a solid precipitated out. The solid was collected by filtration and washed with DCM (10 mL) and water (10 mL). The solid was dried under filtration to give ethyl 2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetate (252 mg, 0.61 mmol, 86.5%) as an off-white solid.
[00449] LCMS High_pH_2min RT 0.93 min, purity >95% [M+H]+ 402, LOWJDH RT 0.80 min, purity >95% [M+H]+ 402.
[00450] 1 H NMR: (DMSO-d6): δ 9.38 (bs, 1 H), 8.29 (s, 1 H), 7.84 (s, 1 H), 7.08 (s, 1 H),
5.00 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 1 .92 (s, 3H), 1 .23 (t, J = 7.2 Hz, 3H).
Example 72 - 3-((7-(2,2-Dimethoxyethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2- methylphenol
[00451] /V-[2-Cyano-5-(2,2-dimethoxyethoxy)-4-methoxy-phenyl]-A/,A/-dimethyl- formamidine (1 .3 g, 4.23 mmol) and 3-amino-5-fluoro-2-methyl-phenol (776 mg, 5.5 mmol) were dissolved in acetic acid (2 mL). The reaction was heated at 120 *Ό for 3 hours. The reaction was allowed to stand overnight. The solid formed was collected by filtration and washed with water and EtOAc to give 3-((7-(2,2-dimethoxyethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2- methylphenol (900 mg, 2.1 mmol, 50.1 %) (acetic acid salt) as an off-white solid.
[00452] LCMS High_pH_2min RT 0.91 min, purity >95% [M+H+ 404, Low_pH RT 0.77 min, [M+H+ 404.
[00453] Ή NMR: (DMSO-d6): 0 1 1 .96 (bs, 2H), 9.93 (bs, 1 H), 9.35 (s, 1 H), 7.81 (s, 1 H),
7.21 (s, 1 H), 6.60 (m, 2H), 4.78 (m, 1 H), 4.14 (d, J = 5.1 Hz, 2H), 3.94 (s, 3H), 3.38 (s, 6H), 1 .92 (m, 6H).
Example 73 - 5-Fluoro-3-((6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl)amino)-2- methylphenol
[00454] ferf-Butyl 4-[[4-cyano-5-[( r)-dimethylaminomethyleneamino]-2-methoxy- phenoxy]methyl]piperidine-1 -carboxylate (0.26 g, 0.63 mmol) and 3-amino-5-fluoro-2-methyl- phenol (1 16 mg, 0.82 mmol) were dissolved in acetic acid (2 mL). The reaction was heated at 120 *Ό for 2 hours. The reaction was cooled to room temperature and allowed to stand overnight. The resulting solid was dissolved in EtOAc (20 mL) and sat. Na2C03, and the organics were isolated and concentrated to dryness. The resulting solid was triturated with DCM (2 mL) and filtered to give 5-fluoro-3-((6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4- yl)amino)-2-methylphenol (80 mg, 0.194 mmol, 30.6%) as a light brown solid.
[00455] LCMS High_pH_2min RT 0.87 min, purity 85-90% [M+H]+ 314, Low_pH RT 0.59 min, purity 85-90%, [M+H]+ 314.
[00456] Ή NMR: (DMSO-d6): δ 9.34 (bs, 1 H), 8.29 (s, 1 H), 7.14 (s, 1 H), 3.95 (m, 5H), signals obscured by large water peak, 1 .91 (s, 3H), 1 .73 (m, 2H), 1 .19 (m, 2H). Final compounds by group manipulation
Example 74 - 2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetic acid.
[00457] Lithium hydroxide (202.4 mg, 8.45 mmol) was added to ethyl 2-[4-(5-fluoro-3- hydroxy-2-methyl-anilino)-6-methoxy-quinazolin-7-yl]oxyacetate (848 mg, 2.1 1 mmol) in THF (9 mL) and water (9 mL). The reaction was stirred at ambient temperature for 16 hours. The reaction was quenched with 5 mL of sat NH4CI and 2 drops of 2M HCI. Product precipitated out of the reaction mixture. The product was collected by filtration and dried under vacuum to give 2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetic acid (527 mg, 1 .38 mmol, 65.5%) (hydrochloride salt) as a pale yellow solid.
[00458] LCMS High_pH_2min RT 0.62 min, purity 90-95% [M+H]+ 374.
[00459] 1 H NMR: (DMSO-d6): δ 9.94 (s, 1 H), 9.38 (s, 1 H), 8.29 (s, 1 H), 7.84 (s, 1 H), 7.04
(s, 1 H), 6.60 (s, 2H), 4.88 (s, 2H), 3.95 (s, 3H), 1 .92 (s, 3H). Example 75 - 2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-1-morpholinoethanone
[00460] Morpholine (0.02 mL, 0.27 mmol) was added to a stirring solution of 2-[4-(5- fluoro-3-hydroxy-2-methyl-anilino)-6-methoxy-quinazolin-7-yl]oxyacetic acid (50 mg, 0.13 mmol), 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56.5 mg, 0.29 mmol) and 4- dimethylaminopyridine (0.82 mg, 0.010 mmol) in DCM (0.5 mL). The reaction was stirred for 24 hours at 20°C. The reaction was diluted with extra DCM (7 mL) and washed with water (5 mL). The organics were isolated and concentrated. The resulting solid was purified by HPLC High pH run to give 2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-1 - morpholinoethanone (5 mg, 0.0102 mmol, 7.6%) as a white solid.
[00461 ] LCMS High_pH_2min RT 0.78 min, purity 90-95% [M+H]+ 443, Low_pH_2min RT
0.78 min, purity 85-90% [M+H]+ 433.
[00462] 1 H NMR: (DMSO-d6): δ 9.92 (s, 1 H), 9.35 (s, 1 H), 8.29 (s, 1 H), 7.82 (s, 1 H), 6.60
(s, 2H), 5.06 (s, 2H), 3.95 (s, 3H), 3.56 (m, 8H), 1 .92 (s, 3H).
Example 76 - 2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetaldehyde
[00463] 3-((7-(2,2-Dimethoxyethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2- methylphenol (120 mg, 0.30 mmol) and 2M hydrochloric acid (2.98 mL, 5.95 mmol) were refluxed for 20 minutes. The reaction was removed from heat and solid Na2C03 was added carefully until solution was neutralized. Solution was extracted with EtOAc (30 mL). The organics were isolated and concentrated. The crude material was purified by preparative HPLC High pH to give 2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetaldehyde (10 mg, 0.0238 mmol) contaminated with approximately 15% 2-[4-(5-fluoro- 3-hydroxy-2-methyl-anilino)-6-methoxy-quinazolin-7-yl]oxyethane-1 ,1 -diol.
[00464] LCMS High_pH_2min RT 0.70 min, purity 85-90% [M+H]+ 358, Low_pH_2min RT
0.68 min, purity 85-90% [M+H]+ 358.
Example 77 - 1-(2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)piperidin-4-ol
[00465] 3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol (70 mg, 0.19 mmol) and 4-hydroxypiperidine (187.4 mg, 1 .85 mmol) were refluxed in DMF (1 mL) for 8 hours. The reaction was concentrated to dryness and purified by preparative HPLC High pH to give 1 -(2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)piperidin-4-ol (6.2 mg, 0.0128 mmol, 6.9%) as a white solid.
[00466] LCMS High_pH_2min RT 0.79 min, purity 90-95% [M+H]+ 443, Low_pH_2min RT
0.55 min, purity 90-95% [M+H]+ 443. [00467] Ή NMR: (DMSO-d6): δ 9.33 (s, 1 H), 8.24 (s, 1 H), 7.80 (s, 1 H), 7.19 (s, 1 H),
6.64 (dd, J = 2.5, 10.5 Hz, 1 H), 6.57 (dd, J = 2.5, 10.5 Hz, 1 H), 4.23 (t, J = 5.7 Hz, 2H), 3.44 (m, 1 H), 2.84 (m, 2H), 2.76 (dd, J= 5.7 Hz, 2H), 1 .72 (m, 2H), 1 .40 (m, 2H). EXAMPLES 78-215
General experimental 2
Flash chromatography was performed using pre-packed silica gel cartridges (YMC 4g, 40 to 60μηι silica particle) max operating pressure 200psi/14bar. Thin layer chromatography was conducted with 5 χ 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., and used without further drying. HPLC grade solvents were obtained from Merck Chemicals Ltd.
All compounds were > 90% purity as determined by examination of both the LC-MS and 1 H
NMR spectra unless otherwise indicated. Where CI or Br were present, expected isotopic distribution patterns were observed.
Ή NMR
Proton (1 H) and carbon (13C) NMR spectra were recorded on a 400 MHz Varian spectrometer. Solutions were typically prepared in either deuteromethanol (CD3OD) or deuterated dimethylsulfoxide (c^-DMSO) with chemical shifts referenced to tetramethylsilane (TMS) or deuterated solvent as an internal standard. 1 H NMR data are reported indicating the chemical shift (< ), the integration (e.g. 1 H), the multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublets etc.) and the coupling constant {J) in Hz (app implies apparent coupling on broadened signals). Deuterated solvents were obtained from the Sigma-Aldrich Chemical Company.
Analytical LC-MS.
LC-MS analyses were performed on a Shimadzu LCMS system fitted with YMC triat C18 or YMC ODS C18, 3.0 μΜ columns (4.6 χ 50 mm) and with UV diode array detection (210-400 nm). Positive and negative mass ion detection was performed using a Shimadzu SQD detector. Analyses were performed with either buffered acidic or basic solvents or gradients as detailed below:
Low pH:
Solvent A - Water + 5 mM ammonium formate + 0.1 % formic acid
Solvent B - 5% Solvent A in Acetonitrile + 0.1 % formic acid High pH:
Solvent A - Water + 5 mM ammonium formate + 0.1 % ammonia solution
Solvent B - Acetonitrile + 5% Solvent A + 0.1 % ammonia solution Gradient:
Figure imgf000111_0001
Preparative HPLC
Some compounds were purified by preparative HPLC with a YMC-ODS 10 μηι C18, 500 mm χ 30 mm i.e. column, running at a flow rate of 40 mL/min with UV diode array detection (210-400 nm) and mass-directed collection using both positive and negative mass ion detection.
Purifications were performed using buffered acidic or basic solvent systems as appropriate. Compound retention times on the system were routinely assessed using a 30-50 μΐ test injection and a standard gradient, then purified using an appropriately chosen focussed gradient as detailed below, based upon observed retention time.
Low pH:
Solvent A - Water + 10mM ammonium bicarbonate + 0.1 % formic acid
Solvent B - Acetonitrile + 5% water +0.1 % formic acid
Standard Gradient:
Figure imgf000111_0002
The following compounds were prepared and analysed using the techniques described in general experimental 2: Methods for guinazoline intermediates
Step 1
Synthesis of Scaffold 1
Figure imgf000112_0001
Scaffold 1 i≡)-Ethyl-2-(4-cyano-5-(((dimethylamino)methylene)amino)-2-methoxyphenoxy) acetate
[00468] To solution of ( E)-/V-(2-cyano-5-hydroxy-4-methoxyphenyl)-A/,A/- dimethylformimidamide Int-A (5 g, 15 mmol) in acetonitrile (50 mL) was added ethyl bromo acetate (16.6 ml, 150 mmol) and cesium carbonate (7.4 g, 22.5 mmol) at 50 °C and further refluxed at 80 °C for 5 h. Reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was cooled to room temperature, filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo resulting in crude product which crystallized from THF:hexane to afford (£)-ethyl 2-(4-cyano-5-(((dimethylamino)methylene)amino)-2-methoxyphenoxy) acetate 6 (2.5 g, 54%). Product was confirmed by LCMS and 1 HNMR analysis.
[00469] 1 H NMR (400 MHz, DMSO-cfe) δ 8.21 (s, 1 H), 7.39 (s, 1 H), 7.02 (s, 1 H), 4.91 (s, 2 H), 4.14 - 4.22 (m, 2 H), 3.81 (s, 3 H), 3.21 (s, 3 H), 3.12 (s, 3 H), 1 .18 - 1 .24 (m, 3 H); LCMS: m/e 306.15 [M+H]+.
Ethyl 2-((6-f I uoro-3-hydroxy-2-methyl phenyl)ami no)-6-methoxyqui nzol i n-7-yl)oxy)acetate
[00470] To solution of 2-(4-cyano-5-(((dimethylamino)methylene)amino)-2- methoxyphenoxy) acetate 6 (2.5 g, 8.2 mmol) in acetic acid (1 1 .3 mL) was added 3-amino-4- fluoro-2-methylphenol (1 .4 g, 9.8 mmol) at room temperature and the mixture was refluxed at 120 °C for 3 h. Reaction monitored by TLC (10% methanol in DCM). The reaction was concentrated in vacuo resulting in crude residue which was stripped with toluene twice. Reaction mixture was diluted with water and DCM, stirred for 30 min. The solid obtained was filtered, washed with DCM and dried to obtain ethyl 2-((6-fluoro-3-hydroxy-2- methylphenyl)amino)-6-methoxyquinzolin-7-yl)oxy)acetate 7 (1 .1 g, 34%). Product was confirmed by LCMS and 1 HNMR analysis.
[00471] Ή NMR (400 MHz, DMSO-cfe) δ 9.40 (s, 1 H), 9.28 (s, 1 H), 8.25 (s, 1 H), 7.88
(s, 1 H), 7.08 (s, 1 H), 6.95 (t, J=9.0 Hz, 1 H), 6.77 (dd, J=9.0, 4.4 Hz, 1 H), 5.00 (s, 2 H), 4.20 (q, J=6.9 Hz, 2 H), 3.95 (s, 3 H), 1 .99 (s, 3 H), 1 .23 (t, J=7.1 Hz, 3 H); LCMS: m/e 402 [M+H]+.
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl) oxy)acetic acid
[00472] To a stirred solution of ethyl 2-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinzolin-7-yl)oxy)acetate 7 (1 .1 g, 2.7 mmol) in THF/water [1 :1 ] (23.2 mL) was added LiOH (0.5 g, 1 1 mmol) at room temperature and the mixture was stirred for 16 h. Reaction was monitored by TLC (10% methanol in DCM). After completion, reaction mixture was quenched with saturated aqueous NH4CI and adjusted pH to 4 with cone HCI, diluted with ethyl acetate (20 mL) and stirred for 2 h. The solid precipitated out was filtered and washed with water and dried well to obtain pure 2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl) oxy)acetic acid Scaffold 1 (0.8 g, 78%). Product was confirmed by LCMS and 1 HNMR analysis.
[00473] Ή NMR (400 MHz, DMSO-cfe) δ 1 1 .48 (br. s, 1 H), 9.86 (br. s, 1 H), 9.36 (s, 1 H), 9.04 (s, 1 H), 8.85 - 8.70 (m, 1 H), 8.16 (s, 1 H), 7.32 (t, J=9.0 Hz, 1 H), 7.23 (dd, J = 9.0, 4.4 Hz, 1 H), 4.86 (s, 3 H), 4.05 (s, 2H), 3.89 (s, 3 H); LCMS: m/e 374 [M+H]+.
Step 2
Amide coupling reaction
Figure imgf000113_0001
Scaffold 1
General procedure for the library synthesis using Scaffold 1
[00474] To solution of 2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl) oxy)acetic acid Scaffold 1 (1 eq.) in DCM: DMF (10:1 ) was added TEA (3 eq.) and the corresponding amine (1 eq.), followed by drop-wise addition of propyl phosphoryl anhydride T3P (3 eq.). The reaction mixture was stirred at room temperature for 2 h. Reaction was monitored by LCMS analysis. On completion, the reaction mixture was concentrated in vacuo resulting in a crude compound which was purified by preparative HPLC, SFC or combiflash. All the reactions were performed on 80 mg scale. The following compounds were prepared according to the general procedure for amide coupling using Scaffold 1 described above.
Example 78 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetamide was prepared (22 mg, off-white solid, 25% yield).
[00475] LCMS: Low_pH_3min RT 0.19min, purity 90-95%, [M+H]+ 373. High_pH_5min
RT 0.99min, purity 90-95%, [M+H]+ 373.3.
[00476] 1 H NMR (400 MHz, DMSO): δ 9.26 (br. s, 1 H), 8.25 (s, 1 H), 7.87 (s, 1 H), 7.45
(d, J=12.12 Hz, 2 H), 7.06 (s, 1 H), 6.95 (t, J=9.20 Hz, 1 H), 6.75 - 6.78 (m, 1 H), 5.75 (s, 1 H), 4.65 (s, 2 H), 3.95 (s, 3 H), 1 .99 (s, 3 H).
Example 79 - 2((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V-methyl acetamide was prepared (15 mg, white solid, 16% yield).
[00477] LCMS: Low_pH_3min RT 0.95min, purity 90-95%, [M+H]+ 387. High_pH_4.5min
RT 0.82min, purity 90-95%, [M+H]+ 387.2.
[00478] Ή NMR (400 MHz, DMSO-cfe) δ 9.39 (br. s, 1 H), 9.28 (s, 1 H), 8.25 (s, 1 H), 7.99 (d, J=4.5 Hz, 1 H), 7.87 (s, 1 H), 7.07 (s, 1 H), 6.95 (t, J=9.0 Hz, 1 H), 6.77 (dd, J=9.0, 4.5 Hz, 1 H), 4.67 (s, 2 H), 3.96 (s, 3 H), 2.67 (d, J=4.5 Hz, 3 H), 1 .98 (s, 3 H).
Example 80 - V-Ethyl-2((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy) acetamide was prepared (13 mg, off-white solid, 12% yield).
[00479] LCMS: Low_pH_3min RT 1 .02min, purity >95%, [M+H]+ 401 . High_pH_4.5min RT 1 .42min, purity 90-95%, [M+H]+ 401 .3.
[00480] Ή NMR (400 MHz, CD3OD): δ 8.10 (s, 1 H), 7.89 (s, 1 H), 7.21 (s, 1 H), 6.91 (t,
J=9.0 Hz, 1 H), 6.83 - 6.77 (m, 1 H), 4.76 (s, 2H), 4.08 (s, 3H), 2.1 1 (s, 3H), 1 .18 (t, J=7.0 Hz, 2H), 1 .05 - 0.96 (m, 3H).
Example 81 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V-isopropylacetamide was prepared (12 mg, pale yellow solid, 12% yield).
[00481] LCMS: Low_pH_3min RT 1 .08min, purity >95%, [M+H]+ 415. High_pH_4.5min
RT 1 .72min, purity >95%, [M+H]+ 415.3.
[00482] 1 H NMR (400 MHz, CD3OD): δ 8.28 ( s, 1 H), 7.85 (s, 1 H), 7.18 (s, 1 H), 6.90 (t,
J=9.2 Hz, 1 H), 6.76 - 6.80 (m, 1 H), 4.72 (s, 2 H), 4.1 1 (m, 1 H), 4.07 (s, 3 H), 2.1 1 (s, 3 H), 1 .21 (d, J=6.4 Hz, 6 H). Example 82 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V-propylacetamide was prepared (18 mg, off-white solid, 17% yield)
[00483] LCMS: Low_pH_3min RT 1 .15min, purity >95%, [M+H]+ 415. High_pH_4.5min
RT 1 .77min, purity 90-95%, [M+H]+ 415.3.
[00484] Ή NMR (400 MHz, DMSO): δ 9.47 (br. s, 1 H), 8.31 (br. s, 1 H), 8.1 1 (s, 1 H),
7.90 (s, 1 H), 7.10 (s, 1 H), 6.96 (t, J=9.20 Hz, 1 H), 6.75 - 6.80 (m, 1 H), 4.69 (s, 2 H), 3.96 (s, 3 H), 3.17 (s, 1 H), 3.06 - 3.1 1 (m, 2 H), 1 .99 (s, 3 H), 1 .42 - 1 .46 (m, 2 H), 0.82 - 0.86 (m, 3 H).
Example 83 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-A/,/V-dimethylacetamide was prepared (12 mg, off-white solid, 12% yield).
[00485] LCMS: Low_pH_4.5min RT 1 .15min, purity >95%, [M+H]+ 401 . High_pH_4.5min
RT 1 .33min, purity 90-95%, [M+H]+ 401 .3.
[00486] 1 H NMR (400 MHz, DMSO): δ 9.51 (br. s, 1 H), 8.32 (s, 1 H), 7.89 (s, 1 H), 7.08
(s, 1 H), 6.96 (t, J=9.0 Hz, 1 H), 6.79 (s, 1 H), 5.06 - 5.10 (s, 2 H), 3.96 (br. s, 3 H), 3.55 (br. s, 1 H) 3.04 (s, 3 H), 2.87 (s, 3 H), 1 .99 (s, 3 H).
Example 84 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-A sopropyl-N-methylacetamide was prepared (21 mg, off-white solid, 21 % yield).
[00487] LCMS: Low_pH_3min RT 1 .07min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 1 .83min, purity 90-95%, [M+H]+ 429.3.
[00488] Ή NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H) 7.81 (s, 1 H) 7.08 (d, J=17.61 Hz, 1 H) 6.86 - 6.93 (m, 1 H) 6.78 (dd, J=9.03, 4.51 Hz, 1 H) 5.08 (s, 2 H) 4.87 (m, 1 H), 4.03 (s, 3 H) 2.99 (s, 3 H), 2.1 1 (s, 3 H) 1 .31 (d, J=6.32 Hz, 3 H) 1 .18 (d, J=6.77 Hz, 3 H).
Example 85 - A/-(ieri-Butyl)-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)-W-methylacetamide was prepared (12 mg, white solid, 1 1 % yield).
[00489] LCMS: Low_pH_3min RT 1 .13min, purity >95%, [M+H]+ 443. High_pH_5min RT
2.18min, purity >95%, [M+H]+ 443.3.
[00490] Ή NMR (400 MHz, CD3OD): δ 8.21 (s, 1 H), 7.81 (s, 1 H), 7.08 (d, J=17.61 Hz, 1
H), 6.86 - 6.93 (m, 1 H), 6.78 (dd, J=9.03, 4.51 Hz, 1 H), 4.97 (s, 2 H), 4.03 (s, 3 H), 3.05 (s, 3 H), 2.14 (s, 3 H) 1 .45 (s, 6 H) 1 .41 (s, 3 H).
Example 86 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V-methyl-/V-propylacetamide was prepared (20 mg, white solid, 20% yield).
[00491] LCMS: Low_pH_3min RT 1 .14min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 1 .83min, purity <85%, [M+H]+ 429.4.
[00492] 1 H NMR (400 MHz, DMSO-cfe): δ 9.39 (br. s, 1 H), 8.28 ( s, 1 H), 7.87 (s, 1 H), 7.06 (s, 1 H), 6.95 (t, J=9.0 Hz, 1 H), 6.78 (s, 1 H), 5.04 (d, J=7.2 Hz, 2 H), 3.95 (br. s, 3 H), 3.23 - 3.31 (m, 3 H), 3.03 (s, 2 H), 2.84 (s, 1 H), 1 .99 (s, 3 H), 1 .57 - 1 .66 (m, 1 H), 1 .48 (dd, J=14.4, 7.2 Hz, 1 H), 0.78 - 0.93 (m, 3 H).
Example 87 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V,/V-dipropylacetamide was prepared (14 mg, white solid, 12% yield).
[00493] LCMS: Low_pH_3min RT 1 .33min, purity >95%, [M+H]+ 457. High_pH_4.5min
RT 2.23min, purity >95%, [M+H]+ 457.4.
[00494] Ή NMR (400 MHz, CD3OD): δ 8.54 (s, 1 H), 7.97 (s, 1 H), 7.12 (s, 1 H), 6.91 -
6.96 (m, 1 H), 6.80 - 6.86 (m, 1 H), 5.16 (s, 2 H), 4.08 (s, 3 H), 3.35 - 3.41 (m, 4 H), 2.12 (s, 3 H), 1 .71 - 1 .77 (m, 2 H), 1 .60 - 1 .65 (m, 2 H), 0.99 - 1 .04 (m, 3 H), 0.89 - 0.93 (m, 3 H).
Example 88 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V-isobutylacetamide was prepared (12 mg, off-white solid, 1 1 % yield).
[00495] LCMS: Low_pH_3min RT 1 .22min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 1 .97min, purity >95%, [M+H]+ 429.3.
[00496] 1 H NMR (400 MHz, CD3OD): δ 8.49 (s, 1 H), 7.94 (s, 1 H), 7.27 (s, 1 H), 6.90 -
6.95 (m, 1 H), 6.80 - 6.84 (m, 1 H), 4.82 (s, 2 H), 4.09 (s, 3 H), 3.13 (d, J=6.43 Hz, 2 H), 2.12 (s, 3 H), 1 .84 (m, 1 H), 0.93 (d, J=6.43 Hz, 6 H).
Example 89 - V-Butyl2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)- acetamide was prepared (12 mg, pale yellow solid, 1 1 % yield).
[00497] LCMS: Low_pH_4.5min RT 2.27min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 1 .98min, purity >95%, [M+H]+ 429.3.
[00498] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.83 (s, 1 H), 7.18 (s, 1 H), 6.87 -
6.92 (m, 1 H), 6.78 (dd, J=8.6, 4.5 Hz, 1 H), 4.73 (s, 2 H), 4.06 (s, 3 H), 2.1 1 (s, 3 H), 1 .51 - 1 .57 (m, 4 H), 1 .28 - 1 .39 (m, 2 H), 0.93 (t, J=7.5 Hz, 3 H).
Example 90 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V-(2-hydroxyethyl)acetamide was prepared (12 mg, brown solid, 12% yield).
[00499] LCMS: Low_pH_3min RT 0.94min, purity >95%, [M+H]+ 417.3. High_pH_4.5min
RT 0.55min, purity <85%, [M+H]+ 417.3.
[00500] 1 H NMR (400 MHz, CD3OD): δ 8.31 (s, 1 H) 7.83 (s, 1 H), 7.20 (s, 1 H), 6.87 - 6.91 (m, 1 H), 6.80 (s, 1 H), 6.78 (d, J=4.06 Hz, 1 H), 4.76 (s, 2 H), 4.06 (s, 3 H), 3.65 - 3.68 (m, 2 H) 3.43 - 3.46 (m, 2 H), 2.1 1 (s, 3 H).
Example 91 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V-(2-methoxyethyl)acetamide was prepared (32 mg, white solid, 33% yield).
[00501] LCMS: Low_pH_3min RT 0.19min, purity >95%, [M+H]+ 431 . High_pH_4.5min RT 1 .50min, purity >95%, [M+H]+ 431 .3.
[00502] Ή NMR (400 MHz,DMSO): δ 9.39 (br. s, 1 H), 9.28 (s, 1 H), 8.25 (s, 1 H), 8.1 1 (t,
J=5.39 Hz, 1 H), 7.87 (s, 1 H), 7.09 (s, 1 H), 6.95 (t, J=9.20 Hz, 1 H), 6.76 - 6.79 (m, 1 H), 4.70 (s, 2 H), 3.96 (s, 3 H), 3.35 - 3.40 (m, 4 H), 3.26 (s, 3 H), 1 .99 (s, 3 H).
Example 92 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-W-(2-hydroxyethyl)-W-methylacetamide was prepared (29 mg, off-white solid, 29% yield).
[00503] LCMS: Low_pH_3min RT 0.92min, purity >95%, [M+H]+ 431 . High_pH_4.5min
RT 0.64min, purity >95%, [M+H]+ 431 .3.
[00504] 1 H NMR (400 MHz, DMSO-cfe): δ 9.40 (br. s, 1 H), 9.24 (br. s, 1 H), 8.23 (d, J=3.1
Hz, 1 H), 7.85 (s, 1 H), 7.08 (s, 1 H), 6.94 (t, J=9.2 Hz, 1 H), 6.77 (dd, J=8.5, 4.5 Hz, 1 H), 4.96 - 5.13 (m, 3 H), 3.95 (s, 3 H), 3.61 (d, J=4.5 Hz, 2 H), 3.40 - 3.51 (m, 3 H), 2.87 (s, 2 H), 1 .99 (s, 3 H
Example 93 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-W-(2-methoxyethyl)-W-methylacetamide was prepared (35 mg, off-white solid, 34% yield).
[00505] LCMS: Low_pH_3min RT 1 .02min, purity >95%, [M+H]+ 445. High_pH_4.5min
RT 1 .35min, purity >95%, [M+H]+ 445.3.
[00506] Ή NMR (400 MHz, CD3OD): δ 8.21 (d, J=3.16 Hz, 1 H), 7.78 (d, J=4.06 Hz, 1 H), 7.09 (s, 1 H), 6.85 - 6.92 (m, 1 H), 6.78 (dd, J=9.03, 4.51 Hz, 1 H), 5.15 (s, 1 H), 5.06 (s, 1 H), 4.03 (s, 3 H), 3.65 (s, 3 H), 3.56 (d, J=4.51 Hz, 2 H), 3.45 (s, 2 H), 3.20 (s, 1 H), 3.01 (s, 2 H), 2.1 1 (s, 3 H).
Example 94 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-/V-(3-methoxypropyl)acetamide was prepared (13 mg, pale yellow solid, 1 1 % yield).
[00507] LCMS: Low_pH_3min RT 1 .05min, purity >95%, [M+H]+ 445. High_pH_4.5min
RT 1 .27min, purity >95%, [M+H]+ 445.1 .
[00508] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.83 (s, 1 H), 7.18 (s, 1 H), 6.90 (t,
J=9.2 Hz, 1 H), 6.78 (dd, J=8.7, 4.6 Hz, 1 H), 4.73 (s, 2 H), 4.06 (s, 3 H), 3.42 (dt, J=15.3, 6.4 Hz, 4 H), 2.1 1 (s, 3 H), 1 .78 - 1 .86 (m, 3 H), 1 .27 - 1 .38 (m, 2 H).
Example 95 - V-Cyclobutyl-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)acetamide was prepared (30 mg, off-white solid, 31 % yield).
[00509] LCMS: Low_pH_3min RT 1 .16min, purity >95%, [M+H]+ 427. High_pH_4.5min
RT 1 .87min, purity >95%, [M+H]+ 427.3.
[00510] 1 H NMR (400 MHz, DMSO-cfe): δ 9.28 (br. s, 1 H), 8.38 (d, J=7.6 Hz, 1 H), 8.24 (s, 1 H), 7.87 (s, 1 H), 7.06 (s, 1 H), 6.94 (t, J=9.2 Hz, 1 H), 6.78 (s, 1 H), 4.64 (s, 2 H), 4.22 - 4.27 (m, 1 H), 3.96 (s, 3 H), 3.44 (d, J=9.9 Hz, 4 H), 3.17 (s, 1 H), 2.14 - 2.18 (m, 2 H), 1 .98 (s, 3 H).
Example 96 - V-Cyclopenyl-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)acetamide was prepared (26 mg, off-white solid, 25% yield).
[00511] LCMS: Low_pH_3min RT 1 .23min, purity >95%, [M+H]+ 441 . High_pH_4.5min
RT 2.01 min, purity >95%, [M+H]+ 441 .3.
[00512] Ή NMR (400 MHz, DMSO-cfe): δ 9.28 (br. s, 1 H), 8.24 (s, 1 H), 8.09 (d, J=6.9
Hz, 1 H), 7.87 (s, 1 H), 7.06 (s, 1 H), 6.94 (t, J=9.0 Hz, 1 H), 6.78 (s, 1 H), 4.65 (s, 2 H), 4.03 - 4.10 (m, 1 H), 3.95 (s, 3 H), 3.17 (s, 1 H), 1 .98 (s, 3 H), 1 .37 - 1 .67 (m, 8 H).
Example 97 - V-Cyclohexyl-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)acetamide was prepared (30 mg, off-white solid, 30% yield).
[00513] LCMS: Low_pH_4.5min RT 2.53min, purity >95%, [M+H]+ 455. High_pH_4.5min
RT 1 .78min, purity 90-95%, [M+H]+ 455.4.
[00514] 1 H NMR (400 MHz, CD3OD): δ 8.50 (s, 1 H), 7.94 (s, 1 H), 7.25 (s, 1 H), 6.89 -
6.96 (m, 1 H), 6.82 (dd, J=8.7, 4.6 Hz, 1 H), 4.79 (s, 2 H), 4.09 (s, 3 H), 3.76 (d, J=10.1 Hz, 1 H), 2.12 (s, 3 H), 1 .90 (d, J=1 1 .5 Hz, 2 H), 1 .76 (m, 2 H), 1 .66 (d, J=13.8 Hz, 2 H), 1 .28 - 1 .37 (m, 4 H).
Example 98 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-W-(tetrahydro-2H-pyran-4-yl)acetamide was prepared (28 mg, white solid, 26% yield).
[00515] LCMS: Low_pH_3min RT 1 .08min, purity >95%, [M+H]+ 457. High_pH_4.5min
RT 1 .49min, purity >95%, [M+H]+ 457.4.
[00516] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.83 (s, 1 H), 7.17 (s, 1 H), 6.86 -
6.92 (m, 1 H), 6.78 (dd, J=8.58, 4.51 Hz, 1 H), 4.74 (s, 2 H), 4.06 (s, 3 H), 3.98 - 4.02 (m, 1 H), 3.95 (d, J=1 1 .74 Hz, 2 H), 3.48 - 3.54 (m, 2 H), 2.1 1 (s, 3 H), 1 .87 (d, J=12.19 Hz, 2 H), 1 .57 - 1 .66 (m, 2 H).
Example 99 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-1-(pyrrolidin-1 -yl)ethanone was prepared (26 mg, off-white solid, 26% yield).
[00517] LCMS: Low_pH_4.5min RT 1 .46min, purity >95%, [M+H]+ 427. High_pH_4.5min RT 1 .32min, purity >95%, [M+H]+ 427.1 .
[00518] 1 H NMR (400 MHz, CD3OD): δ 8.47 - 8.51 (m, 1 H), 7.93 (s, 1 H), 7.14 (s, 1 H),
6.90 - 6.96 (m, 1 H), 6.82 (dd, J=8.7, 4.1 Hz, 1 H), 5.06 (s, 2 H), 4.07 (s, 3 H), 3.63 (t, J=6.7 Hz, 2 H), 3.51 (t, J=6.9 Hz, 2 H), 2.12 (s, 3 H), 2.02 - 2.09 (m, 2 H), 1 .93 (quin, J=6.5 Hz, 2 H). Example 100 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-1-(piperidin-1-yl)ethanone was prepared (15 mg, off-white solid, 14% yield).
[00519] LCMS: Low_pH_4.5min RT 2.01 min, purity >95%, [M+H]+ 441 . High_pH_4.5min
RT 1 .88min, purity >95%, [M+H]+ 441 .4.
[00520] Ή NMR (400 MHz, DMSO-cfe): δ 9.81 (br. s, 1 H), 8.40 (s, 1 H), 7.94 (s, 1 H),
7.09 (s, 1 H), 6.98 (t, J=9.0 Hz, 1 H), 6.81 (s, 1 H), 5.08 (s, 2 H), 3.97 (br. s, 3 H), 3.44 (m, 5 H), 2.00 (s, 3 H), 1 .60 (m, 6 H).
Example 101 - 1 -(Azepan-1 -yl)-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethanone was prepared (43 mg, white solid, 42% yield).
[00521] LCMS: Low_pH_3min RT 1 .19min, purity >95%, [M+H]+ 455. High_pH_4.5min
RT 2.00min, purity >95%, [M+H]+ 455.4.
[00522] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.79 (s, 1 H), 7.10 (s, 1 H), 6.88 (d,
J=9.03 Hz, 1 H), 6.78 (dd, J=8.58, 4.51 Hz, 1 H), 5.05 (s, 2 H), 4.03 (s, 3 H), 3.57 - 3.64 (m, 4 H), 2.1 1 (s, 3 H), 1 .87 (d, J=5.87 Hz, 2 H), 1 .74 (d, J=5.42 Hz, 2 H), 1 .66 (m, 4 H).
Example 102 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-1-morpholinoethanone was prepared (12 mg, white solid, 1 1 % yield).
[00523] LCMS: Low_pH_3min RT 0.99min, purity >95%, [M+H]+ 443. High_pH_4.5min
RT 0.97min, purity >95%, [M+H]+ 443.3.
[00524] Ή NMR (400 MHz, DMSO): δ 9.40 (br. s, 1 H), 9.26 (br. s, 1 H), 8.25 (s, 1 H), 7.86 (s, 1 H), 7.13 (s, 1 H), 6.95 (t, J=9.20 Hz, 1 H), 6.78 (d, J=4.49 Hz, 1 H), 5.07 (s, 2 H), 3.95 (s, 3 H), 3.58 - 3.65 (m, 4 H), 3.50 (d, J=16.16 Hz, 4 H), 1 .99 (s, 3 H).
Example 103 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-1-(4-methylpiperazin-1 -yl)ethanone was prepared (16 mg, white solid, 14% yield).
[00525] LCMS: Low_pH_3min RT 0.77min, purity >95%, [M+H]+ 456. High_pH_4.5min RT 1 .18min, purity <85%, [M+H]+ 456.1 .
[00526] 1 H NMR (400 MHz, CD3OD): 5 8.26 (s, 1 H), 7.81 (s, 1 H), 7.12 (s, 1 H), 6.85 - 6.92
(m, 1 H), 6.78 (dd, J=4.4, 9.0 Hz, 1 H), 5.05 (s, 2H), 4.03 (s, 3H), 3.72 (m, 4H), 2.73 (m, 2H), 2.65 (m, 2H), 2.47 (s, 3H), 2.12 (s, 3H).
Example 104 - 1-(4-Acetylpiperazin-1-yl)-2-((4-((6-fluoro-3-hydroxy-2- methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethanone was prepared (32 mg, white solid, 29% yield).
[00527] LCMS: Low_pH_3min RT 0.91 min, purity >95%, [M+H]+ 484. High_pH_4.5min
RT 0.49min, purity >95%, [M+H]+ 484.4.
[00528] 1 H NMR (400 MHz, DMSO-cfe): δ 9.26 (s, 1 H), 8.24 (s, 1 H), 7.86 (s, 1 H), 7.14 (s, 1 H), 6.95 (t, J=9.2 Hz, 1 H), 6.77 (dd, J=9.0, 4.5 Hz, 1 H), 5.09 (s, 2 H), 3.95 (s, 3 H), 3.54 (m, 4 H), 3.45 (m, 4 H), 3.17 (s, 1 H), 2.04 (d, J=5.4 Hz, 3 H), 1 .99 (s, 3 H).
Example 105 - 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-1-(4-methoxylpiperidiin-1-yl)-ethanone was prepared (25 mg, off-white solid, 23% yield).
[00529] LCMS: Low_pH_3min RT 1 .03min, purity >95%, [M+H]+ 471 . High_pH_4.5min
RT 1 .58min, purity >95%, [M+H]+ 471 .4.
[00530] Ή NMR (400 MHz, DMSO): δ 8.22 (s, 1 H), 7.79 (s, 1 H), 7.1 1 (s, 1 H), 6.86 -
6.92 (m, 1 H), 6.78 (dd, J=8.80, 4.29 Hz, 1 H), 5.04 (s, 2 H), 4.02 (s, 3 H), 3.81 - 3.92 (m, 2 H), 3.53 (dt, J=7.22, 3.61 Hz, 2 H), 3.40 - 3.45 (m, 1 H), 3.38 (s, 3 H), 2.1 1 (s, 3 H), 1 .87 - 2.01 (m, 2 H), 1 .57 - 1 .71 (m, 2 H).
Synthesis of Scaffold 2
Figure imgf000120_0001
E-AT-(5-(2-Chloroethoxy)-2-cyano-4-methoxyphenyl)-A/,A^dimethylformimidamide
[00531] To a solution of (≡)-/V-(2-cyano-5-hydroxy-4-methoxyphenyl)-A/,A/- dimethylformimidamide Int-A (5 g, 15 mmol) in acetonitrile (100 mL) was added potassium carbonate (6.5 g, 47 mmol) and the mixture heated at 50 °C for 3 h. 1 -Bromo-2-chloroethane (7.3 g, 47 mmol) was added at 50 °C and the mixture further heated to 80 °C for 3h. Reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was cooled to room temperature and filtered through a pad of Celite and washed with ethyl acetate. The filtrate obtained was concentrated in vacuo resulting in crude product which was purified by using flash column chromatography in 10-50% ethyl acetate: hexane to afford E-/V-(5-(2-chloroethoxy)-2- cyano-4-methoxyphenyl)-A/,A/-dimethyl formimidamide (2.7 g, 61 %). Product was confirmed by LCMS and 1 HNMR analysis.
1 H NMR (400 MHz, CDCI3): 5 7.56 (s, 1 H), 6.96 (s, 1 H), 6.48 (s, 1 H), 4.29 (t, J=6.09 Hz, 2 H), 3.84 - 3.87 (m, 2 H), 3.84 (s, 3 H), 3.07 (s, 6 H); LCMS: m/e 282 (M+H)+. 3-((7-(2-chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol
[00532] To E-/V-(5-(2-chloroethoxy)-2-cyano-4-methoxyphenyl)-A/,A/-dimethyl formimidamide (2.6 g, 9.6 mmol) in acetic acid (27 mL) was added 3-amino-4-fluoro-2- methylphenol (1 .6 g, 15 mmol) at room temperature and the mixture was refluxed at 120 °C for 2 h. Reaction was monitored by TLC (10% methanol in CHCI3). The reaction mixture was concentrated in vacuo to dryness, diluted with DCM and stirred for 30 min. The solid obtained was filtered and dried to afford pure 3-((7-(2-chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methylphenol Scaffold 2 (1 .7g, 48%). Product was confirmed by 1 HNMR analysis.
1 H NMR (400 MHz, DMSO-cfe): δ 9.39 (s, 1 H), 9.26 (s, 1 H), 8.26 (s, 1 H), 7.87 (s, 1 H), 7.21 (s, 1 H), 6.95 (t, J=9.2 Hz, 1 H), 6.77 (dd, J=8.8, 4.3 Hz, 1 H), 4.43 (t, J=4.9 Hz, 2 H), 4.01 - 4.06 (m, 2 H), 3.95 (s, 3 H), 1 .99 (s, 3 H).
Amine substitution reaction
Figure imgf000121_0001
Scaffold 2
General procedure for the library synthesis using Scaffold 2
[00533] To a 5 mL sealed tube was added Scaffold 2 (1 eq.) and corresponding amine (10 eq.). Sealed properly and heat at 100 °C. Reaction completion monitored by LCMS (2-16h). On completion of reaction, solvent evaporated in Genevac and product was purified using SFC or preparative HPLC. All the reactions were performed on 80 mg scale. The following compounds were prepared according to the general procedure for chloro substitution with amines using Scaffold 2 described above.
Example 106 - 3-((7-(2-Aminoethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared (17 mg, brown solid, 20% yield).
[00534] LCMS: Low_pH_4.5min RT 1 .54min, purity >95%, [M+H]+ 359.3. High_pH_5min
RT 0.90min, purity <85%, [M+H]+ 359.3.
[00535] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.85 (s, 1 H), 7.24 (s, 1 H), 6.89 (d,
J=9.21 Hz, 1 H), 6.77 - 6.81 (m, 1 H), 4.43 (t, J=4.82 Hz, 2 H), 4.04 (s, 3 H), 3.46 - 3.51 (m, 2 H), 2.1 1 (s, 3 H). Example 107 - 4-Fluoro-3-((6-methoxy-7-(2-(methylamino)ethoxy)quinazolin-4-yl)amino)-2- methyl phenol was prepared (12 mg, brown solid, 13% yield).
[00536] LCMS: Low_pH_3min RT 0.69min, purity >95%, [M+H]+ 373. High_pH_4.5min
RT 1 .68min, purity 90-95%, [M+H]+ 373.3.
[00537] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.90 (d,
J=9.21 Hz, 1 H), 6.76 - 6.79 (m, 1 H), 4.29 (d, J=4.94 Hz, 2 H), 4.03 (s, 3 H), 3.10 (t, J=5.16 Hz, 2 H), 2.52 (s, 3 H), 2.1 1 (s, 3 H).
Example 108 - 3-((7-(2-(Ethylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared (33 mg, brown solid, 36% yield).
[00538] LCMS: Low_pH_3.5min RT 1 .58min, purity >95%, [M+H]+ 387. High_pH_5min
RT 1 .94min, purity >95%, [M+H]+ 387.3.
[00539] 1 H NMR (400 MHz, CD3OD) δ 8.26 (s, 1 H), 7.85 (s, 1 H), 7.24 (s, 1 H), 6.88 -
6.93 (m, 1 H), 6.78 - 6.81 (m, 1 H), 4.46 - 4.48 (m, 2 H), 4.07 (s, 3 H), 3.57 (d, J=4.82 Hz, 2 H), 3.25 (m, 2 H), 2.1 1 (s, 3 H), 1 .36 - 1 .39 (m, 3 H).
Example 109 - 4-Fluoro-3-((7-(2-(isopropylamino)ethoxy)-6-methoxyquinazolin-4- yl)amino)-2-methyl phenol was prepared (69 mg, off-white solid, 79% yield).
[00540] LCMS: Low_pH_3min RT 0.86min, purity >95%, [M+H]+ 401 . High_pH_4.5min
RT 2.05min, purity 90-95%, [M]+ 401 .3.
[00541] Ή NMR (400 MHz, CD3OD): δ 8.27 (s, 1 H), 7.86 (s, 1 H), 7.24 (s, 1 H), 6.87 - 6.93 (m, 1 H), 6.77 - 6.80 (m, 1 H), 4.46 - 4.49 (m, 2 H), 4.08 (s, 3 H), 3.55 - 3.59 (m, 3 H), 2.1 1 (s, 3 H), 1 .42 (d, J=6.90 Hz, 6 H).
Example 110 - 3-((7-(2-(ieri-Butylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methylphenol was prepared (58 mg, white solid, 51 % yield).
[00542] LCMS: Low_pH_3.5min RT 1 .36min, purity >95%, [M+H]+ 415. High_pH_5min RT 2.38min, purity >95%, [M+H]+ 415.4.
[00543] Ή NMR (400 MHz, CD3OD) δ 8.26 (s, 1 H), 7.85 (s, 1 H), 7.24 (s, 1 H), 6.88 -
6.92 (m, 1 H), 6.79 (dd, J=8.88, 4.49 Hz, 1 H), 4.45 (t, J=4.82 Hz, 2 H), 4.08 (s, 3 H), 3.52 - 3.56 (m, 2 H), 2.1 1 (s, 3 H), 1 .45 (s, 9 H).
Example 111 - 4-Fluoro-3-((6-methoxy-7-(2-(propylamino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared (83 mg, off-white solid, 95% yield).
[00544] LCMS: Low_pH_3min RT 0.88min, purity 90-95%, [M+H]+ 401 . High_pH_4.5min
RT 2.13min, purity 90-95%, [M+H]+ 401 .3.
[00545] 1 H NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.85 (s, 1 H), 7.24 (s, 1 H), 6.89 (d, J=9.05 Hz, 1 H), 6.79 (d, J=4.31 Hz, 1 H), 4.46 (d, J=4.74 Hz, 2 H), 4.07 (s, 3 H), 3.55 (d, J=4.74 Hz, 2 H), 3.13 (m, 2 H), 2.1 1 (s, 3 H), 1 .75 - 1 .80 (m, 2 H), 1 .07 (m, 3 H).
Example 112 - 4-Fluoro-3-((7-(2-(isobutylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)- 2-methylphenol was prepared (51 mg, white solid, 55% yield).
[00546] LCMS: Low_pH_3min RT 0.80min, purity >95%, [M+H]+ 415. High_pH_4.5min
RT 2.26min, purity >95%, [M+H]+ 415.3.
[00547] Ή NMR (400 MHz, CD3OD): δ 8.24 - 8.26 (m, 1 H), 7.84 - 7.86 (m, 1 H), 7.23 (s,
1 H), 6.85 - 6.93 (m, 1 H), 6.79 (dd, J=9.05, 4.31 Hz, 1 H), 4.47 (d, J=4.74 Hz, 2 H), 4.07 (s, 3 H), 3.53 (t, J=4.96 Hz, 2 H), 2.98 - 3.01 (m, 2 H), 2.10 - 2.12 (m, 3 H), 2.03 - 2.08 (m, 1 H), 1 .06 - 1 .09 (m, 6 H).
Example 113 - 3-((7-(2-(Butylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methyl phenol was prepared (16 mg, white solid, 16% yield).
[00548] LCMS: Low_pH_3min RT 0.89min, purity >95%, [M+H]+ 415. High_pH_4.5min
RT 2.41 min, purity >95%, [M+H]+ 415.3.
[00549] 1 H NMR (400 MHz, DMSO): δ 9.25 (br. s, 1 H), 8.25 (s, 1 H), 8.22 (s, 1 H), 7.85
(s, 1 H), 7.19 (s, 1 H), 6.93 (d, J=8.98 Hz, 1 H), 6.75 - 6.78 (m, 1 H), 4.20 - 4.24 (m, 2 H), 3.93 (s, 3 H), 3.17 (s, 1 H), 3.01 - 3.04 (m, 2 H), 2.66 - 2.69 (m, 2 H), 1 .99 (s, 3 H), 1 .42 - 1 .47 (m, 2 H), 1 .31 - 1 .36 (m, 2 H), 0.89 (t, J=7.18 Hz, 3 H).
Example 114 - 4-Fluoro-3-((7-(2-((2-hydroxyethyl)amino)ethoxy)-6-methoxyquinazolin-4- yl)amino)-2-methylphenol was prepared (16 mg, yellow solid, 17% yield).
[00550] LCMS: Low_pH_3min RT 0.82min, purity >95%, [M+H]+ 403.1 . High_pH_4.5min
RT 1 .08min, purity >95%, [M]+ 403.1 .
[00551] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.83 (s, 1 H), 7.23 (s, 1 H), 6.88 -
6.92 (m, 1 H), 6.78 (d, J=4.31 Hz, 1 H), 4.44 - 4.47 (m, 2 H), 4.06 (s, 3 H), 3.84 (d, J=5.17 Hz, 2 H), 3.50 (d, J=4.74 Hz, 2 H), 3.20 (d, J=5.17 Hz, 2 H), 2.1 1 (s, 3 H).
Example 115 - 4-Fluoro-3-((6-methoxy-7-(2-((2-methoxyethyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (15 mg, off-white solid, 15% yield).
[00552] LCMS: Low_pH_3min RT 0.77min, purity >95%, [M+H]+ 417. High_pH_4.5min
RT 1 .62min, purity 90-95%, [M+H]+ 417.3.
[00553] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.87 -
6.92 (m, 1 H), 6.76 - 6.80 (m, 1 H), 4.31 (t, J=4.51 Hz, 2 H), 4.03 (s, 3 H), 3.56 (t, J=5.19 Hz, 2 H), 3.38 (s, 3 H), 3.16 (t, J=4.74 Hz, 2 H), 2.99 (m, 1 H), 2.93 (m, 1 H), 2.1 1 (s, 3 H).
Example 116 - 4-Fluoro-3-((7-(2-((3-hydroxypropyl)amino)ethoxy)-6-methoxyquinazolin-4- yl)amino)-2-methylphenol was prepared (39 mg, white solid, 42% yield).
[00554] LCMS: Low_pH_3min RT 0.82min, purity >95%, [M+H]+ 417. High_pH_4.5min
RT 1 .12min, purity >95%, [M]+ 417.1 .
[00555] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.84 (s, 1 H), 7.23 (s, 1 H), 6.88 - 6.93 (m, 1 H), 6.79 (dd, J=9.05, 4.31 Hz, 1 H), 4.46 (m, 2 H), 4.06 (s, 3 H), 3.74 - 3.76 (m, 2 H), 3.55 (d, J=4.74 Hz, 2 H), 3.26 (m, 2 H), 2.1 1 (s, 3 H), 1 .95 (m, 2 H).
Example 117 - 4-Fluoro-3-((6-methoxy-7-(2-((3-methoxypropyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (31 mg, yellow solid, 32% yield).
[00556] LCMS: Low_pH_3min RT 0.18min, purity 90-95%, [M+H]+ 431 . High_pH_4.5min RT 1 .88min, purity 90-95%, [M+H]+ 431 .3.
[00557] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.87 -
6.92 (m, 1 H), 6.76 - 6.79 (m, 1 H), 4.27 - 4.30 (m, 2 H), 4.03 (s, 3 H), 3.49 (m, 2 H), 3.34 (s, 3 H), 3.10 (m, 2 H), 2.80 (m, 2 H), 2.1 1 (s, 3 H), 1 .83 (s, 2 H).
Example 118 - 3-((2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethyl)amino)propanenitrile was prepared (25 mg, yellow solid, 26% yield).
[00558] LCMS: Low_pH_3min RT 0.97min, purity >95%, [M+H]+ 412. High_pH_4.5min
RT 1 .33min, purity >95%, [M+H]+ 412.1 .
[00559] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.87 - 6.92 (m, 1 H), 6.78 (d, J=4.74 Hz, 1 H), 4.28 - 4.31 (m, 2 H), 4.03 (s, 3 H), 3.16 - 3.18 (m, 2 H), 3.05 - 3.08 (m, 2 H), 2.70 (m, 2 H), 2.1 1 (s, 3 H).
Example 119 - 3-((7-(2-(Cyclobutylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methylphenol was prepared (15 mg, pale yellow solid, 15% yield).
[00560] LCMS: Low_pH_3min RT 0.81 min, purity >95%, [M+H]+ 413. High_pH_6.5min RT 1 .75min, purity 90-95%, [M+H]+ 413.1 .
[00561] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.83 (s, 1 H), 7.22 (s, 1 H), 6.90 (d,
J=8.98 Hz, 1 H), 6.77 - 6.80 (m, 1 H), 4.38 (d, J=4.97 Hz, 2 H), 4.07 (s, 3 H), 3.48 (m, 1 H), 2.38 (d, J=9.48 Hz, 2 H), 2.32 - 2.41 (m, 4 H), 2.1 1 (s, 3 H), 1 .91 (d, J=6.77 Hz, 2 H).
Example 120 - 3-((7-(2-(Cyclopentylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methyl phenol was prepared (15 mg, off-white solid, 15% yield).
[00562] LCMS: Low_pH_3min RT 0.87min, purity >95%, [M+H]+ 427. High_pH_4.5min
RT 2.37min, purity 90-95%, [M+H]+ 427.3.
[00563] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.90 (d, J=8.98 Hz, 1 H), 6.76 - 6.79 (m, 1 H), 4.27 - 4.30 (m, 2 H), 4.03 (s, 3 H), 3.21 (t, J=7.00 Hz, 1 H), 3.1 1 (m, 2 H), 2.1 1 (s, 3 H), 1 .97 (d, J=5.42 Hz, 2 H), 1 .75 (m, 2 H), 1 .60 (d, J=4.06 Hz, 2 H), 1 .42 (dd, J=1 1 .96, 6.55 Hz, 2 H).
Example 121 - 3-((7-(2-(Cyclohexylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methyl phenol was prepared (27 mg, off-white solid, 27% yield).
[00564] LCMS: Low_pH_3min RT 0.94min, purity >95%, [M+H]+ 441 . High_pH_4.5min
RT 2.54min, purity >95%, [M+H]+ 441 .4.
[00565] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.90 (s,
1 H), 6.78 (d, J=4.52 Hz, 1 H), 4.29 (t, J=4.74 Hz, 2 H), 4.03 (s, 3 H), 3.14 (m, 2 H), 2.60 (br. s, 1 H), 2.1 1 (s, 3 H), 2.00 (d, J=10.38 Hz, 2 H), 1 .80 (d, J=13.09 Hz, 2 H), 1 .29 - 1 .38 (m, 3 H), 1 .14 - 1 .23 (m, 3 H).
Example 122 - 4-Fluoro-3-((6-methoxy-7-(2-((3-methyloxetan-3- yl)amino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (16 mg, off-white solid, 15% yield).
[00566] LCMS: Low_pH_3min RT 0.74min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 1 .13min, purity 90-95%, [M+H]+ 429.
[00567] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.79 (s, 1 H), 7.19 (s, 1 H), 6.86 -
6.92 (m, 1 H), 6.76 - 6.80 (m, 1 H), 4.64 (s, 2 H), 4.41 (s, 2 H), 4.26 (t, J=4.74 Hz, 2 H), 4.04 (s, 3 H), 3.12 (t, J=4.53 Hz, 2 H), 2.1 1 (s, 3 H), 1 .56 (s, 3 H).
Example 123 - 4-Fluoro-3-((6-methoxy-7-(2-((2-morpholinoethyl)amino)ethoxy)quinazolin- 4-yl)amino)-2-methylphenol was prepared (35 mg, brown solid, 32% yield).
[00568] LCMS: Low_pH_3min RT 0.72min, purity >95%, [M+H]+ 472. High_pH_4.5min
RT 2.07min, purity 90-95%, [M]+ 471 .4.
[00569] Ή NMR (400 MHz, CD3OD): δ 8.27 (s, 1 H), 7.85 (s, 1 H), 7.24 (s, 1 H), 6.88 - 6.92 (m, 1 H), 6.79 (dd, J=8.84, 4.53 Hz, 1 H), 4.51 (d, J=4.74 Hz, 2 H), 4.07 (s, 3 H), 3.72 (d, J=4.31 Hz, 4 H), 3.59 - 3.62 (m, 2 H), 3.33 - 3.37 (m, 2 H), 2.71 - 2.74 (m, 2 H), 2.56 (m, 4 H), 2.1 1 (s, 3 H).
Example 124 - 4-Fluoro-3-((6-methoxy-7-(2-(((tetrahydrofuran-2- yl)methyl)amino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (14 mg, white solid, 13% yield).
[00570] LCMS: Low_pH_3min RT 0.80min, purity >95%, [M+H]+ 443. High_pH_4.5min
RT 1 .42min, purity >95%, [M+H]+ 443.1 .
[00571] 1 H NMR (400 MHz, DMSO): δ 9.24 (s, 1 H), 8.25 (s, 2 H), 7.85 (s, 1 H), 7.18 (s, 1 H), 6.94 (t, J=9.20 Hz, 1 H), 6.77 (dd, J=8.75, 4.71 Hz, 1 H), 4.21 (t, J=5.39 Hz, 2 H), 3.94 (s, 3 H), 3.86 - 3.91 (m, 1 H), 3.69 - 3.77 (m, 2 H), 3.58 - 3.65 (m, 2 H), 3.01 (d, J=3.14 Hz, 2 H), 2.66 - 2.71 (m, 2 H), 1 .95 (s, 4 H), 1 .76 - 1 .84 (m, 2 H).
[00572]
Example 125 - 4-Fluoro-3-((6-methoxy-7-(2-((tetrahydro-2H-pyran-4- yl)amino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (43 mg, off-white solid, 44% yield).
[00573] LCMS: Low_pH_3min RT 0.77min, purity >95%, [M+H]+ 443. High_pH_4.5min
RT 1 .27min, purity >95%, [M+H]+ 443.4.
[00574] 1 H NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.85 (s, 1 H), 7.24 (s, 1 H), 6.88 -
6.93 (m, 1 H), 6.76 - 6.80 (m, 1 H), 4.46 (d, J=4.74 Hz, 2 H), 4.09 (m, 1 H), 4.07 (s, 3 H), 3.57 - 3.59 (m, 2 H), 3.50 - 3.50 (m, 1 H), 3.51 (m, 1 H), 3.48 (s, 2 H), 2.1 1 (s, 3 H), 1 .69 (dd, J=12.29, 4.53 Hz, 2 H), 1 .29 (s, 2 H).
Example 126 - 4-Fluoro-3-((6-methoxy-7-(2-(((1 -methyl-1 H-imidazol-5- yl)methyl)amino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (20 mg, off- white solid, 19% yield).
[00575] LCMS: Low_pH_3min RT 0.57min, purity 90-95%, [M+H]+ 453. High_pH_4.5min
RT 0.89min, purity 90-95%, [M+H]+ 453.4.
[00576] Ή NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.77 (s, 1 H), 7.58 (s, 1 H), 7.18 (s, 1 H), 6.95 (d, J=8.98 Hz, 1 H), 6.74 - 6.78 (m, 2 H), 4.29 (t, J=5.17 Hz, 2 H), 4.03 (s, 3 H), 3.93 (m, 2 H), 3.73 (s, 3 H), 3.1 1 - 3.14 (m, 2 H), 2.1 1 (s, 3 H).
Example 127 - 4-Fluoro-3-((6-methoxy-7-(2-(((1 -methyl-1 H-imidazol-4- yl)methyl)amino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (87 mg, off- white solid, 89% yield).
[00577] LCMS: Low_pH_3.5min RT 1 .38min, purity >95%, [M+H]+ 453. High_pH_5min
RT 1 .37min, purity >95%, [M+H]+ 453.2.
[00578] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.84 (s, 1 H), 7.81 (s, 1 H), 7.65 (s,
1 H), 7.22 (s, 1 H), 6.87 - 6.92 (m, 1 H), 6.77 - 6.80 (m, 1 H), 4.46 (d, J=4.60 Hz, 2 H), 4.27 (s, 2 H), 4.06 (s, 3 H), 3.92 (s, 3 H), 3.51 - 3.54 (m, 2 H), 2.1 1 (s, 3 H).
Example 128 - 4-Fluoro-3-((6-methoxy-7-(2-(((1 -methyl-1 H-pyrazol-4- yl)methyl)amino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (52 mg, off- white solid, 51 % yield).
[00579] LCMS: Low_pH_3min RT 0.77min, purity >95%, [M+H]+ 453. High_pH_4.5min RT 1 .60min, purity 90-95%, [M+H]+ 453.4.
[00580] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.85 (s, 1 H), 7.81 (s, 1 H), 7.65 (s,
1 H), 7.22 (s, 1 H), 6.86 - 6.92 (m, 1 H), 6.78 (dd, J=8.62, 4.31 Hz, 1 H), 4.48 (d, J=4.74 Hz, 2 H), 4.28 (s, 2 H), 4.06 (s, 3 H), 3.92 (s, 3 H), 3.53 (d, J=4.74 Hz, 2 H), 2.1 1 (s, 3 H).
Second general procedure for the library synthesis using Scaffold 2
[00581] To a 5 ml sealed tube was added Scaffold 2 (1 eq.), the corresponding amine (10 eq.) and DMF (12.5 times of Scaffold 2). Sealed properly and heated to 100 °C for 2-4 h. Reaction was completion monitored by LCMS. On completion of reaction, the reaction mixture was concentrated in vacuo resulting in the crude product which was purified using SFC or preparative HPLC. All the reactions were performed on 80 mg scale. The following compounds were prepared according to the general procedure for chloro substitution with amines using Scaffold 2 (Scheme 5) described above.
Example 129 - 3-((7-(2-(Azetidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared (12 mg, off-white solid, 12% yield).
[00582] LCMS: Low_pH_3min RT 0.75min, purity >95%, [M+H]+ 399. High_pH_4.5min
RT 2.07min, purity 85-90%, [M+H]+ 399.3.
[00583] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.83 (s, 1 H), 7.21 (s, 1 H), 6.89 (d,
J=9.05 Hz, 1 H), 6.77 - 6.80 (m, 1 H), 4.42 (d, J=4.74 Hz, 2 H), 4.32 - 4.36 (m, 3 H), 4.05 (s, 3 H), 3.72 - 3.76 (m, 1 H), 2.79 - 2.92 (m, 2 H), 2.52 - 2.61 (m, 2 H), 2.1 1 (s, 3 H).
Example 130 - 4-Fluoro-3-((6-methoxy-7-(2-(pyrrolidin-1 -yl)ethoxy)-quinazolin-4-yl)amino)- 2-methylphenol was prepared (20 mg, white solid, 21 % yield).
[00584] LCMS: Low_pH_4.5min RT 0.80min, purity >95%, [M+H]+ 413.2.
High_pH_4.5min RT 2.1 1 min, purity 90-95%, [M+H]+ 413.3.
[00585] 1 H NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.81 (s, 1 H), 7.23 (s, 1 H), 6.89 (d,
J=9.48 Hz, 1 H), 6.76 - 6.80 (m, 1 H), 4.47 (t, J=4.74 Hz, 2 H), 4.05 (s, 3 H), 3.54 (m, 2 H), 3.48 (m, 2 H), 3.13 (m, 2 H), 2.1 1 (s, 3 H), 2.05 (s, 4 H).
Example 131 - 4-Fluoro-3-((6-methoxy-7-(2-(piperdin-1-yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared (23 mg, off-white solid, 23% yield).
[00586] LCMS: Low_pH_4.5min RT 0.81 min, purity >95%, [M+H]+ 427. High_pH_4.5min
RT 2.21 min, purity >95%, [M+H]+ 427.4.
[00587] Ή NMR (400 MHz, CD3OD): δ 8.26 - 8.27 (m, 1 H), 7.84 - 7.85 (m, 1 H), 7.24 -
7.25 (m, 1 H), 6.90 (s, 1 H), 6.80 (d, J=4.51 Hz, 1 H), 4.56 (d, J=4.51 Hz, 2 H), 4.06 (s, 3 H), 3.64 (m, 2 H), 3.40 (m, 4 H), 2.1 1 (s, 3 H), 1 .91 (m, 4 H), 1 .71 (m, 2 H). Example 132 - 3-((7-(2-(Azepan-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared (39 mg, white solid, 40% yield).
[00588] LCMS: Low_pH_4.5min RT 0.84min, purity >95%, [M+H]+ 441 .2.
High_pH_4.5min RT 2.51 min, purity >95%, [M+H]+ 441 .4.
[00589] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.75 (s, 1 H), 7.18 (s, 1 H), 6.89 (s,
1 H), 6.76 - 6.79 (m, 1 H), 4.31 - 4.33 (m, 2 H), 4.01 (s, 3 H), 3.09 - 3.1 1 (m, 2 H), 2.91 (d, J=4.51 Hz, 4 H), 2.1 1 (s, 3 H), 1 .74 (m, 4 H), 1 .66 (m, 4 H).
Example 133 - 4-Fluoro-3-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared (23 mg, white solid, 23% yield).
[00590] LCMS: Low_pH_4.5min RT 0.73min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 1 .56min, purity 90-95%, [M+H]+ 429.2.
[00591] 1 H NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.88 -
6.92 (m, 1 H), 6.78 (dd, J=8.58, 4.51 Hz, 1 H), 4.39 (t, J=4.97 Hz, 2 H), 4.02 (s, 3 H), 3.78 (d, J=4.51 Hz, 4 H), 3.09 (m, 2 H), 2.84 (m, 4 H), 2.1 1 (s, 3 H).
Example 134 - 1-(4-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1 -yl)ethan-1-one was prepared (15 mg, off- white solid, 13% yield).
[00592] LCMS: Low_pH_3min RT 0.80min, purity >95%, [M+H]+ 470. High_pH_4.5min
RT 1 .27min, purity >95%, [M+H]+ 470.4.
[00593] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.76 (s, 1 H), 7.19 (s, 1 H), 6.89 (d,
J=9.03 Hz, 1 H), 6.76 - 6.79 (m, 1 H), 4.35 (s, 2 H), 4.01 (s, 3 H), 3.58 - 3.65 (m, 4 H), 2.98 (d, J=4.06 Hz, 2 H), 2.65 - 2.73 (m, 4 H), 2.1 1 (s, 6 H).
Example 135 - 4-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)thiomorpholine 1 ,1-dioxide was prepared (22 mg, off-white solid, 20% yield).
[00594] LCMS: Low_pH_3min RT 1 .01 min, purity 90-95%, [M+H]+ 477. High_pH_4.5min
RT 1 .56min, purity >95%, [M+H]+ 477.4.
1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.76 (s, 1 H), 7.19 (s, 1 H), 6.86 - 6.92 (m, 1 H), 6.78 (dd, J=8.80, 4.29 Hz, 1 H), 4.29 - 4.34 (m, 2 H), 4.02 (s, 3 H), 3.23 (d, J=4.51 Hz, 4 H), 3.09 - 3.17 (m, 6 H), 2.1 1 (s, 3 H).
Example 136 1-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)piperidin-4-ol was prepared (61 mg, off-white solid, 63% yield).
[00595] LCMS: Low_pH_4.5min RT 0.81 min, purity >95%, [M+H]+ 443.3.
High_pH_4.5min RT 1 .09min, purity >95%, [M+H]+ 443.1 . [00596] Ή NMR (400 MHz, CD3OD): δ 8.61 (s, 1 H), 8.02 (s, 1 H), 7.36 (s, 1 H), 6.91 -
6.97 (m, 1 H), 6.80 - 6.85 (m, 1 H), 4.66 (m, 2 H), 4.10 (s, 3 H), 3.75 (m, 2 H), 3.48 - 3.54 (m, 1 H), 3.57 (d, J=12.19 Hz, 2H), 2.18 (m, 2 H), 2.13 (s, 3 H), 1 .94 - 2.07 (m, 2 H), 1 .81 (m, 2 H).
Example 137 - 4-Fluoro-3-((6-methoxy-7-(2-(4-methoxypiperidin-1-yl)ethoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (15 mg, white solid, 14% yield).
[00597] LCMS: Low_pH_4.5min RT 0.82min, purity >95%, [M+H]+ 457.3.
High_pH_4.5min RT 1 .84min, purity >95%, [M+H]+ 457.4.
[00598] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.82 (s, 1 H), 7.23 (s, 1 H), 6.87 -
6.92 (m, 1 H), 6.74 - 6.80 (m, 1 H), 4.49 (s, 2 H), 4.05 (s, 3 H), 3.51 (m, 1 H), 3.48 - 3.55 (m, 2 H), 3.38 (s, 3 H), 3.14 (m, 2 H), 2.1 1 (s, 3 H), 2.06 (m, 2 H), 1 .92 (m., 2 H), 1 .29 (m, 2 H).
Example 138 - 3-((7-(2-(Dimethylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro- 2-methylphenol was prepared (13 mg, white solid, 13% yield).
[00599] LCMS: Low_pH_3min RT 0.18min, purity >95%, [M+H]+ 387. High_pH_4.5min
RT 1 .84min, purity >95%, [M+H]+ 387.2.
[00600] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.76 (s, 1 H), 7.19 (s, 1 H), 6.87 -
6.93 (m, 1 H), 6.73 - 6.81 (m, 1 H), 4.32 (t, J=5.19 Hz, 2 H), 4.01 (s, 3 H), 2.94 (d, J=4.97 Hz, 2 H), 2.43 (s, 6 H), 2.1 1 (s, 3 H).
Example 139 - 3-((7-(2-(Diethylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared (15 mg, white solid, 15% yield).
[00601] LCMS: Low_pH_4.5min RT 0.78min, purity 90-95%, [M+H]+ 415.2.
High_pH_4.5min RT 2.23min, purity 85-90%, [M+H]+ 415.4.
[00602] Ή NMR (400 MHz, CD3OD): δ 8.27 (br. s, 1 H), 7.82 (s, 1 H), 7.23 (s, 1 H), 6.92
(t, J=8.80 Hz, 1 H), 6.78 - 6.84 (m, 1 H), 4.46 (m, 2 H), 4.05 (s, 3 H), 3.46 (m, 2 H), 3.16 (m, 4 H), 2.13 (s, 3 H), 1 .28 - 1 .37 (m, 6 H).
Example 140 - 4-Fluoro-3-((7-(2-(isopropyl(methyl)amino)ethoxy)-6-methoxyquinazolin-4- yl)amino)-2-methylphenol was prepared (13 mg, white solid, 12% yield).
[00603] LCMS: Low_pH_4.5min RT 0.82min, purity >95%, [M+H]+ 416. High_pH_6.5min
RT 1 .78min, purity <85%, [M+H]+ 416.2.
[00604] 1 H NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.81 (s, 1 H), 7.21 (s, 1 H), 6.90 (t, J=9.25 Hz, 1 H), 6.79 (dd, J=9.03, 4.51 Hz, 1 H), 4.49 - 4.53 (m, 2 H), 4.05 (s, 3 H), 2.71 (br. s, 3 H), 2.53 - 2.39 (m, 3 H), 2.1 1 (s, 3 H), 1 .45 (s, 6H). Example 141 - 3-((7-(2-(ίer Butyl(methyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)- 4-fluoro-2-methyl phenol was prepared (16 mg, white solid, 15% yield).
[00605] LCMS: Low_pH_4.5min RT 0.80min, purity 90-95%, [M+H]+ 429.2.
High_pH_4.5min RT 2.32min, purity 85-90%, [M+H]+ 429.3.
[00606] 1 H NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.84 (s, 1 H), 7.24 (s, 1 H), 6.90 (t,
J=9.25 Hz, 1 H), 6.79 (dd, J=9.03, 4.51 Hz, 1 H), 4.49 - 4.53 (m, 2 H), 4.05 (s, 3 H), 3.71 (m, 2 H), 3.01 (s, 3 H), 2.1 1 (s, 3 H), 1 .65 (s, 9H).
Example 142 - 4-Fluoro-3-((6-methoxy-7-(2-(methyl(propyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (25 mg, white solid, 26% yield).
[00607] LCMS: Low_pH_4.5min RT 0.84min, purity 90-95%, [M+H]+ 415.2.
High_pH_4.5min RT 2.23min, purity 90-95%, [M+H]+ 415.3.
[00608] 1 H NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.82 (s, 1 H), 7.23 (s, 1 H), 6.88 -
6.93 (m, 1 H), 6.77 - 6.82 (m, 1 H), 4.51 (t, J=4.74 Hz, 2 H), 4.04 (s, 3 H), 3.56 (m, 2 H), 3.1 1 (d, J=8.13 Hz, 2 H), 2.91 (s, 3 H), 2.1 1 (s, 3 H), 1 .80 (dd, J=16.03, 7.45 Hz, 2 H), 1 .05 (t, J=7.45 Hz, 3 H).
Example 143 - 3-((-7-(2-(Dipropylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro- 2-methylphenol was prepared (23 mg, off-white solid, 22% yield).
[00609] LCMS: Low_pH_3min RT 0.67min, purity >95%, [M+H]+ 443.3. High_pH_4.5min
RT 2.69min, purity >95%, [M+H]+ 443.4.
[00610] Ή NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.80 (s, 1 H), 7.21 (s, 1 H), 6.86 -
6.93 (m, 1 H), 6.78 (d, J=4.51 Hz, 1 H), 4.46 (m, 2 H), 4.03 (s, 3 H), 3.51 (m, 2 H), 3.06 (m, 4 H), 2.1 1 (s, 3 H), 1 .72 - 1 .81 (m, 4 H), 1 .03 (t, J=7.22 Hz, 6 H).
Example 144 - 4-Fluoro-3-((7-(2-((2-hydroxyethyl)(methyl)amino)ethoxy)-6- methoxyquinazolin-4-yl)amino)-2-methylphenol was prepared (13 mg, tan solid, 12% yield).
[00611] LCMS: Low_pH_3min RT 0.72min, purity 90-95%, [M+H]+ 417. High_pH_6.5min
RT 1 .39min, purity 85-90%, [M+H]+ 417.1 .
[00612] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.86 -
6.92 (m, 1 H), 6.78 (dd, J=9.03, 4.51 Hz, 1 H), 4.39 (t, J=4.97 Hz, 2 H), 4.02 (s, 3 H), 3.78 (t, J=5.42 Hz, 2 H), 3.25 (t, J=4.74 Hz, 2 H), 2.95 (t, J=5.64 Hz, 2 H), 2.65 (s, 3 H), 2.1 1 (s, 3 H). Example 145 - 4-Fluoro-3-((6-methoxy-7-(2-((2- methoxyethyl)(methyl)amino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (36 mg, pale yellow solid, 38% yield).
[00613] LCMS: Low_pH_4.5min RT 0.70min, purity 90-95%, [M+H]+ 431 .2. High_pH_4.5min RT 1 .77min, purity >95%, [M+H]+ 431 .4.
[00614] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.86 -
6.91 (m, 1 H), 6.76 - 6.80 (m, 1 H), 4.39 (t, J=4.74 Hz, 2 H), 4.02 (s, 3 H), 3.64 (t, J=5.42 Hz, 2 H), 3.38 (s, 3 H), 3.26 (m, 2 H), 3.03 (m, 2 H), 2.65 (s, 3 H), 2.1 1 (s, 3 H).
Example 146 - 3-((7-(2-(3,4-Dihydroisoquinolin-2(1 H)-yl)ethoxy)-6-methoxyquinazolin-4- yl)amino)-4-fluoro-2-methylphenol was prepared (19 mg, off-white solid, 17% yield).
[00615] LCMS: Low_pH_4.5min RT 0.87min, purity >95%, [M+H]+ 475.3.
High_pH_4.5min RT 2.43min, purity 85-90%, [M+H]+ 475.4.
[00616] Ή NMR (400 MHz, CD3OD): δ 8.32 (br. s., 1 H), 8.26 (s, 1 H), 7.82 (s, 1 H), 7.15 - 7.28 (m, 4 H), 6.90 (t, J=9.03 Hz, 1 H), 6.78 (dd, J=9.03, 4.51 Hz, 1 H), 4.55 (t, J=4.74 Hz, 2 H), 4.31 (s, 2 H), 4.06 (s, 3 H), 3.51 (m, 2 H), 3.42 (t, J=6.09 Hz, 2 H), 3.07 - 3.16 (m, 2 H), 2.1 1 (s, 3 H).
Example 147 - 4-Fluoro-3-((7-(2-(2-(hydroxymethyl)piperdin-1-yl)ethoxy)-6-methoxy- quinazolin-4-yl)amino)-2-methylphenol was prepared (18 mg, white solid, 17% yield).
[00617] LCMS: Low_pH_3min RT 0.79min, purity >95%, [M+H]+ 457. High_pH_4.5min
RT 1 .94min, purity 90-95%, [M+H]+ 457.4.
[00618] 1 H NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.82 (s, 1 H), 7.23 (s, 1 H), 6.89 (d,
J=9.05 Hz, 1 H), 6.79 (dd, J=8.84, 4.53 Hz, 1 H), 4.58 (m, 2 H), 4.04 (s, 3 H), 3.80 - 3.86 (m, 2 H), 3.73 - 3.78 (m, 2 H), 3.42 - 3.31 (m, 2 H), 2.12 (s, 3 H), 1 .90 (m, 5 H), 1 .63 (m, 2 H).
Example 148 - 4-Fluoro-3-((7-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4- yl)amino)-2-methylphenol was prepared (14 mg, brown solid, 13% yield).
[00619] LCMS: Low_pH_3min RT 0.76min, purity >95%, [M+H]+ 431 . High_pH_4.5min
RT 1 .90min, purity 85-90%, [M+H]+ 431 .3.
[00620] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.79 (s, 1 H), 7.20 (s, 1 H), 6.86 - 6.92 (m, 1 H), 6.78 (dd, J=8.80, 4.29 Hz, 1 H), 4.39 (t, J=4.97 Hz, 2 H), 4.02 (s, 3 H), 3.59 (m, 1 H), 3.37 - 3.50 (m, 2 H), 2.91 - 2.98 (m, 2 H), 2.70 (t, J=4.97 Hz, 2 H), 2.1 1 (s, 3 H), 1 .30 (d, J=7.67 Hz, 1 H), 1 .18 (t, J=7.22 Hz, 1 H).
Example 149 - 4-Fluoro-3-((6-methoxy-7-(2-(3-trifluoromethylpyrrolidin-1 - yl)ethoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (12 mg, brown solid, 10% yield).
[00621] LCMS: Low_pH_3min RT 1 .37min, purity >95%, [M+H]+ 481 . High_pH_4.5min
RT 2.47min, purity >95%, [M+H]+ 481 .3.
[00622] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.76 (s, 1 H), 7.17 (s, 1 H), 6.87 - 6.92 (m, 1 H), 6.77 - 6.80 (m, 1 H), 4.28 - 4.35 (m, 2 H), 4.01 (s, 3 H), 3.57 (d, J=8.13 Hz, 1 H), 3.16 - 3.26 (m, 2 H), 2.70 - 2.77 (m, 2 H), 2.1 1 (s, 3 H), 2.06 (d, J=9.03 Hz, 2 H), 1 .88 (d, J= 12.64 Hz, 2 H).
Example 150 - 4-Fluoro-3-((6-methoxy-7-(2-(4-methyl-1 ,4-diazepan-1 -yl)ethoxy)quinazolin- 4-yl)amino)-2-methylphenol was prepared (23 mg, brown solid, 21 % yield).
[00623] LCMS: Low_pH_3min RT 0.69min, purity >95%, [M+H]+ 456. High_pH_4.5min
RT 2.37min, purity >95%, [M+H]+ 456.4.
[00624] Ή NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.78 (s, 1 H), 7.20 (s, 1 H), 6.85 -
6.92 (m, 1 H), 6.75 - 6.80 (m, 1 H), 4.28 - 4.35 (m, 2 H), 4.02 (s, 3 H), 3.37 - 3.42 (m, 2 H), 3.34 (d, J=4.74 Hz, 2 H), 3.16 (m, 4 H), 2.97- 3.03 (m, 2 H), 2.89 (s, 3 H), 2.1 1 (s, 3 H), 2.05 (d, J=5.60 Hz, 2 H).
Example 151 - 3-((7-(2-(1 ,4-Oxazepan-4-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methylphenol was prepared (14 mg, pale yellow solid, 12% yield).
[00625] LCMS: Low_pH_4.5min RT 0.84min, purity 90-95%, [M+H]+ 443.2. High _pH_4.5min RT 1 .65min, purity <85%, [M+H]+ 443.3.
[00626] 1 H NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.81 (s, 1 H), 7.23 (s, 1 H), 6.90 (t,
J=9.25 Hz, 1 H), 6.78 (dd, J=8.80, 4.74 Hz, 1 H), 4.48 (m, 2 H), 4.04 (s, 3 H), 3.80 - 3.93 (m, 4 H), 3.52 (m, 2 H), 3.36 (d, J=5.42 Hz, 4 H), 2.1 1 (s, 3 H), 1 .29 (m, 2 H).
Example 152 - 4-Fluoro-3-((6-methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)amino)- 2-methylphenol was prepared (81 mg, off-white solid, 87% yield).
[00627] LCMS: Low_pH_3min RT 0.74min, purity >95%, [M+H]+ 428. High_pH_4.5min
RT 1 .27min, purity 85-90%, [M+H]+ 428.3.
[00628] Ή NMR (400 MHz, CD3OD): δ 8.63 (s, 1 H), 8.05 (s, 1 H), 7.34 (s, 1 H), 6.93 (d,
J=9.05 Hz, 1 H), 6.82 - 6.87 (m, 1 H), 4.74 (m, 2 H), 4.1 1 (s, 3 H), 3.79 (m, 2 H), 3.75 (d, J=5.17 Hz, 2 H), 3.67 (d, J=5.17 Hz, 4 H), 3.55 - 3.61 (m, 2 H), 2.13 (s, 3 H).
Synthesis of Scaffold 3
Figure imgf000132_0001
Int-A £-AT-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-A/,A/-dimethylformimidam
[00629] To solution of Int-A (7.8 g, 24.6 mmol) in acetonitrile (75 mL) was added potassium carbonate (16.9 g, 123 mmol) and the mixture heated at 50 °C for 3 h. 1 -Bromo-3- chloropropane (7.7 g, 49 mmol) was added at 50 °C and the mixture further heated to 1 10 °C for 3 h. Reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate. The filtrate obtained was concentrated in vacuo resulting in crude product which was purified by crystallization using THF:hexane to afford E-/V-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)- A/,A/-dimethylformimidamide (6.7 g, 63%). Product was confirmed by LCMS and 1 HNMR analysis.
[00630] 1 H NMR (400 MHz, DMSO-cfe) δ 7.91 (s, 1 H), 7.10 (s, 1 H), 6.77 (s, 1 H), 4.15 (t,
J=6.1 Hz, 2 H), 3.78 (t, J=6.5 Hz, 2 H), 3.73 (s, 3 H), 3.05 (s, 3 H), 2.96 (s, 3 H), 2.19 (quin, J=6.1 Hz, 2 H); LCMS: m/e 296 (M+H)+.
3-((7-(3-Chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol
[00631 ] To E-/V-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-A/,/V- dimethylformimidamide (4 g, 13.5 mmol) in acetic acid (12 mL) was added 3-amino-4-fluoro-2- methylphenol (2.3 g, 16 mmol) at room temperature and the mixture was refluxed at 120 °C for 3 h. Reaction monitored by TLC (10% methanol in CHCI3). The reaction mixture was concentrated in vacuo resulting in crude product which was stripped with toluene twice and purified using flash column chromatography eluting with 1 -3% MeOH in DCM to obtain 3-((7-(3- Chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol Scaffold 3 (1 .3 g, 24%). Product was confirmed by LCMS and 1 HNMR analysis.
[00632] Ή NMR (400 MHz, DMSO-cfe): δ 9.38 (s, 1 H), 9.25 (s, 1 H), 8.25 (s, 1 H), 7.85
(s, 1 H), 7.17 - 7.22 (m, 1 H), 6.94 (t, J=9.2 Hz, 1 H), 6.76 (dd, J=9.0, 4.5 Hz, 1 H), 4.26 (t, J=5.8 Hz, 2 H), 3.94 (s, 3 H), 3.82 (t, J=6.5 Hz, 2 H), 2.22 - 2.29 (m, 2 H), 1 .98 (s, 3 H); LCMS: m/e 392 (M+H) +
General procedure for the library synthesis using Scaffold 3
Figure imgf000133_0001
Scaffold 3
[00633] To a 5 mL sealed tube was added Scaffold 3 (1 eq.) and corresponding amine (10 eq.). Sealed properly and heated at 100 °C. Reaction completion monitored by LCMS (2- 16h). On completion, the reaction was concentrated in vacuo resulting in crude compound which was purified using SFC or preparative HPLC. All the reactions were performed on 100 mg scale. The following compounds were prepared according to the general procedure for chloro substitution with an amine using Scaffold 3 described above.
Example 153 - 3-((7-(3-Aminopropoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared (14 mg, brown solid, 13% yield).
[00634] LCMS: Low_pH_3.5min RT 0.67min, purity 90-95%, [M+H]+ 373.2.
High_pH_5min RT 1 .73min, purity <85%, [M+H]+ 373.3.
[00635] 1 H NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.80 (s, 1 H), 7.19 (s, 1 H), 6.87 -
6.93 (m, 1 H), 6.76 - 6.80 (m, 1 H), 4.35 (t, J=5.62 Hz, 2 H), 4.04 (s, 3 H), 3.24 - 3.28 (m, 2 H), 2.26 - 2.31 (m, 2 H), 2.1 1 (s, 3 H).
Example 154 - 4-Fluoro-3-((6-methoxy-7-(3-(methylamino)propoxy)quinazolin-4-yl)amino)- 2-methylphenol was prepared (40 mg, off-white solid, 35% yield).
[00636] LCMS: Low_pH_3min RT 0.70min, purity >95%, [M+H]+ 387. High_pH_4.5min
RT 2.18min, purity >95%, [M+H]+ 387.
[00637] 1 H NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.80 (d, J=2.16 Hz, 1 H), 7.19 (s, 1
H), 6.88 - 6.92 (m, 1 H), 6.77 - 6.80 (m, 1 H), 4.31 - 4.36 (m, 2 H), 4.05 (d, J=1 .29 Hz, 3 H), 2.95 (s, 3 H), 2.80 (s, 2 H), 2.29 - 2.37 (m, 2 H), 2.1 1 (s, 3 H).
Example 155 - 3-((7-(3-(Dimethylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methylphenol was prepared (24 mg, off-white solid, 22% yield).
[00638] LCMS: Low_pH_3min RT 0.75min, purity >95%, [M+H]+ 401 . High_pH_4.5min
RT 2.10min, purity >95%, [M+H]+ 401 .3.
[00639] Ή NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.75 (s, 1 H), 7.17 (s, 1 H), 6.87 - 6.92 (m, 1 H), 6.76 - 6.79 (m, 1 H), 4.23 (t, J=6.09 Hz, 2 H), 4.01 (s, 3 H), 2.63 (t, J=7.67 Hz, 2 H), 2.34 (s, 6 H), 2.09 - 2.15 (m, 5 H).
Example 156 - 3-((7-(3-(Ethylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared (21 mg, off-white solid, 19% yield).
[00640] LCMS: Low_pH_3min RT 0.75min, purity >95%, [M+H]+ 401 . High_pH_4.5min RT 2.50min, purity >95%, [M+H]+ 401 .3.
[00641] 1 H NMR (400 MHz, CD3OD): δ 8.25 (br. s, 1 H), 7.79 (d, J=7.80 Hz, 1 H), 7.19 (s,
1 H), 6.90 (t, J=9.21 Hz, 1 H), 6.75 - 6.81 (m, 1 H), 4.33 (d, J=18.64 Hz, 2 H), 4.04 (s, 3 H), 3.12 - 3.20 (m, 2 H), 2.79 (s, 3 H), 2.30 (s, 2 H), 2.1 1 (s, 3 H), 1 .37 (t, J=7.15 Hz, 2 H). Example 157 - 4-Fluoro-3-((7-(3-(isopropylamino)propoxy)-6-methoxyquinazolin-4- yl)amino)-2-methylphenol was prepared (13 mg, off-white solid, 10% yield).
[00642] LCMS: Low_pH_3min RT 0.82min, purity >95%, [M+H]+ 415. High_pH_4.5min
RT 2.58min, purity 90-95%, [M+H]+ 415.3.
[00643] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.77 (s, 1 H), 7.17 (s, 1 H), 6.89 (d,
J=9.48 Hz, 1 H), 6.79 (d, J=4.06 Hz, 1 H), 4.29 (t, J=5.64 Hz, 2 H), 4.02 (s, 3 H), 2.93 (m, 3 H), 2.15 (d, J=5.87 Hz, 2 H), 2.1 1 (s, 3 H), 1 .16 (d, J=6.32 Hz, 6 H).
Example 158 - - 4-Fluoro-3-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared (33 mg, off-white solid, 27% yield).
[00644] LCMS: Low_pH_3min RT 0.79min, purity 90-95%, [M+H]+ 443. High_pH_4.5min
RT 1 .74min, purity 85-90%, [M+H]+ 443.4.
[00645] 1 H NMR (400 MHz, DMSO): δ 9.39 (s, 1 H), 9.25 (s, 1 H), 8.25 (s, 1 H), 7.84 (s, 1
H), 7.17 (s, 1 H), 6.94 (t, J=8.98 Hz, 1 H), 6.77 (dd, J=8.75, 4.26 Hz, 1 H), 4.19 (t, J=6.28 Hz, 2 H), 3.93 (s, 3 H), 3.62 (m, 6 H), 2.33 (m, 3 H), 1 .84 - 2.07 (m, 6 H).
Example 159 - 1-(4-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethan-1-one was prepared (23 mg, off- white solid, 17% yield).
[00646] LCMS: Low_pH_4.5min RT 0.86min, purity >95%, [M+H]+ 484.3.
High_pH_4.5min RT 1 .67min, purity 90-95%, [M+H]+ 484.4.
[00647] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.76 (s, 1 H), 7.18 (s, 1 H), 6.90 (m,
1 H), 6.77 - 6.80 (m, 1 H), 4.25 - 4.28 (m, 2 H), 4.02 (s, 3 H), 3.60 - 3.66 (m, 4 H), 2.75 (d, J=7.67 Hz, 2 H), 2.66 (d, J=4.97 Hz, 2 H), 2.60 - 2.63 (m, 2 H), 2.14 - 2.18 (m, 2 H), 2.1 1 (s, 6 H).
Example 160 - 4-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)thiomorpholine 1 ,1-dioxide was prepared (13 mg, pale yellow solid, 17% yield).
[00648] LCMS: Low_pH_3min RT 0.98min, purity >95%, [M+H]+ 491 . High_pH_4.5min
RT 1 .65min, purity <85%, [M+H]+ 491 .4.
[00649] 1 H NMR (400 MHz, DMSO): δ 9.45 (br. s, 1 H), 9.24 (s, 1 H), 8.25 (s, 1 H), 7.84 (s, 1 H), 7.19 (s, 1 H), 6.90 - 6.97 (m, 1 H), 6.74 - 6.79 (m, 1 H), 4.16 - 4.22 (m, 2 H), 3.93 (s, 3 H), 3.1 1 (m, 4 H), 2.92 (m, 4 H), 2.66 (d, J=8.53 Hz, 2 H), 2.29 - 2.34 (m, 2 H), 1 .89 - 2.02 (m, 3H). Example 161 - 1-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)piperidin-4-ol was prepared (49 mg, off-white solid, 41 % yield).
[00650] LCMS: Low_pH_4.5min RT 0.80min, purity >95%, [M+H]+ 457.3.
High_pH_4.5min RT 1 .60min, purity >95%, [M+H]+ 457.4.
[00651] 1 H NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.80 (s, 1 H), 7.19 (s, 1 H), 6.89 (d,
J=9.48 Hz, 1 H), 6.75 - 6.80 (m, 1 H), 4.32 (t, J=5.42 Hz, 2 H), 4.04 (s, 3 H), 3.96 (m, 1 H), 3.43 - 3.52 (m, 2 H), 3.03 - 3.17 (m, 2 H), 2.34 (d, J=5.42 Hz, 2 H), 2.1 1 (s, 3 H), 2.01 - 2.09 (m, 2 H), 1 .86 (m, 2 H), 1 .29 (m, 2 H).
Example 162 - 4-Fluoro-3-((6-methoxy-7-(3-(4-methoxypiperidin-1-yl)propoxy)quinazolin- 4-yl)amino)-2-methylphenol was prepared (18 mg, off-white solid, 14% yield).
[00652] LCMS: Low_pH_4.5min RT 0.84min, purity >95%, [M+H]+ 471 .3.
High_pH_4.5min RT 1 .99min, purity >95%, [M+H]+ 471 .4.
[00653] 1 H NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.79 (s, 1 H), 7.19 (s, 1 H), 6.86 -
6.92 (m, 1 H), 6.78 (dd, J=9.03, 4.51 Hz, 1 H), 4.31 (t, J=5.64 Hz, 2 H), 4.03 (s, 3 H), 3.54 (m, 1 H), 3.48 (s, 3 H), 3.21 (m, 2 H), 2.31 (m, 2 H), 2.1 1 (s, 3 H), 2.06 (m, 2 H), 1 .90 (m, 4 H), 1 .29 (m, 2 H).
Example 163 - 3-((7-(3-(Azetidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro 2-methylphenol was prepared (18 mg, off-white solid, 16% yield).
[00654] LCMS: Low_pH_4.5min RT 0.98min, purity 90-95%, [M+H]+ 413.3. High _pH_4.5min RT 2.54min, purity 90-95%, [M+H]+ 413.3.
[00655] Ή NMR (400 MHz, CD3OD): δ 8.26 (br. s, 1 H), 7.83 (d, J=4.97 Hz, 1 H), 7.20 (d,
J=7.68 Hz, 1 H), 6.86 - 6.93 (m, 1 H), 6.79 (dd, J=8.58, 4.51 Hz, 1 H), 4.27 - 4.38 (m, 2H), 4.10 (s, 3 H), 3.47 - 3.51 (m, 2 H), 3.19 (d, J=7.67 Hz, 2 H), 2.75 - 2.81 (m, 2H), 2.26 - 2.38 (m, 2 H), 2.22 (dt, J=1 1 .96, 6.21 Hz, 2 H), 2.1 1 (s, 3 H).
Example 164 - 4-Fluoro-3-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (55 mg, off-white solid, 51 % yield).
[00656] LCMS: Low_pH_4.5min RT 0.82min, purity 90-95%, [M+H]+ 427.2.
High_pH_4.5min RT 2.54min, purity >95%, [M+H]+ 427.3.
[00657] 1 H NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.80 (s, 1 H), 7.19 (s, 1 H), 6.88 - 6.93 (m, 1 H), 6.78 (dd, J=8.35, 4.29 Hz, 1 H), 4.33 (t, J=5.42 Hz, 2 H), 4.04 (s, 3 H), 3.48 (m, 4 H), 2.40 (m, 2 H), 2.28 - 2.36 (m, 2 H), 2.1 1 (m, 5 H), 1 .29 (m, 2 H). Example 165 - 4-Fluoro-3-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-yl)amino)- 2-methylphenol was prepared (62 mg, off-white solid, 54% yield).
[00658] LCMS: Low_pH_4.5min RT 0.84min, purity >95%, [M+H]+ 441 .2.
High_pH_4.5min RT 2.54min, purity >95%, [M+H]+ 441 .4.
[00659] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.79 (s, 1 H), 7.19 (s, 1 H), 6.86 -
6.92 (m, 1 H), 6.75 - 6.80 (m, 1 H), 4.30 (t, J=5.64 Hz, 2 H), 4.03 (s, 3 H), 3.15 (d, J=17.15 Hz, 4 H), 2.31 (m, 2 H), 2.1 1 (s, 3 H), 1 .84 (m, 4 H), 1 .67 (m, 2 H), 1 .19 - 1 .35 (m, 2 H).
Example 166 - 3-((7-(3-(Azepan-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol was prepared (12 mg, pale yellow solid, 9% yield).
[00660] LCMS: High_pH_4.5min RT 3.06min, purity <85%, [M+H]+ 455.4.
[00661] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.75 (s, 1 H), 7.17 (s, 1 H), 6.87 -
6.93 (m, 1 H), 6.78 (dd, J=8.80, 4.29 Hz, 1 H), 4.23 (t, J=5.87 Hz, 2 H), 4.01 (s, 3 H), 2.82 (m, 6 H), 2.1 1 (s, 3 H), 1 .74 (m, 4 H), 1 .67 (m, 4 H), 1 .18 (t, J=7.00 Hz, 2 H).
Example 167 - 3-((7-(3-(Diethylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro- 2-methylphenol was prepared (34 mg, off-white solid, 27% yield).
[00662] LCMS: Low_pH_4.5min RT 0.84min, purity >95%, [M+H]+ 429.2.
High_pH_4.5min RT 2.52min, purity >95%, [M+H]+ 429.3.
[00663] 1 H NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.79 (s, 1 H), 7.19 (s, 1 H), 6.90 (t,
J=9.25 Hz, 1 H), 6.76 - 6.80 (m, 1 H), 4.31 (t, J=5.64 Hz, 2 H), 4.03 (s, 3 H), 3.22 - 3.28 (m, 2 H), 3.17 (m, 4 H), 2.27 (m, 2 H), 2.1 1 (s, 3 H), 1 .31 (t, J=7.22 Hz, 6 H).
Example 168 - 3-((7-(3-(Dipropylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methylphenol was prepared (37 mg, off-white solid, 30% yield).
[00664] LCMS: Low_pH_4.5min RT 0.84min, purity >95%, [M+H]+ 457.3.
High_pH_4.5min RT 2.94min, purity >95%, [M+H]+ 457.4.
[00665] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.78 (s, 1 H), 7.19 (s, 1 H), 6.90 (t,
J=8.80 Hz, 1 H), 6.78 (dd, J=8.80, 4.29 Hz, 1 H), 4.30 (t, J=5.64 Hz, 2 H), 4.03 (s, 3 H), 3.21 (m, 2 H), 2.95 (m, 4 H), 2.24 (m, 2 H), 2.1 1 (s, 3 H), 1 .67 - 1 .76 (m, 4 H), 1 .01 (t, J=7.22 Hz, 6 H).
Example 169 - 4-Fluoro-3-((7-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-6- methoxyquinazolin-4-yl)amino)-2-methylphenol was prepared (31 mg, colourless gum, 27% yield).
[00666] LCMS: Low_pH_3min RT 0.18min, purity >95%, [M+H]+ 431 . High_pH_4.5min
RT 1 .60min, purity <85%, [M+H]+ 431 .3.
[00667] 1 H NMR (400 MHz, CD3OD): δ 8.28 (s, 1 H), 7.82 (s, 1 H), 7.18 - 7.22 (m, 1 H), 6.90 (t, J=9.03 Hz, 1 H), 6.79 (dd, J=8.58, 4.51 Hz, 1 H), 4.36 (t, J=5.19 Hz, 2 H), 4.05 (s, 3 H), 3.92 (t, J=4.97 Hz, 2 H), 3.48 (m, 2 H), 3.36 - 3.43 (m, 2 H), 3.04 (s, 3 H), 2.40 (m, 2 H), 2.1 1 (s, 3 H).
Example 170 - 4-Fluoro-3-((6-methoxy-7-(3-((2- methoxyethyl)(methyl)amino)propoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (12 mg, off-white solid, 10.5% yield).
[00668] LCMS: Low_pH_3min RT 0.82min, purity >95%, [M+H]+ 445. High_pH_4.5min
RT 1 .97min, purity 90-95%, [M+H]+ 445.4.
[00669] Ή NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.75 (s, 1 H), 7.17 (s, 1 H), 6.89 (t, J=9.43 Hz, 1 H), 6.77 (dd, J=9.10, 4.12 Hz, 1 H), 4.23 (t, J=5.96 Hz, 2 H), 4.01 (s, 3 H), 3.54 (t, J=5.42 Hz, 2 H), 2.66 - 2.75 (m, 4 H), 2.36 (s, 3 H), 2.05 - 2.16 (m, 6 H), 2.19 (s, 3 H), 2.1 1 (m, 3 H), 1 .29 (m, 2 H).
Example 171 - 3-((7-(3-(ieri-Butyl(methyl)amino)propoxy)-6-methoxyquinazolin-4- yl)amino)-4-fluoro-2-methylphenol was prepared (10 mg, off-white solid, 9% yield).
[00670] LCMS: Low_pH_4.5min RT 1 .22min, purity 90-95%, [M+H]+ 443.4.
High_pH_4.5min RT 2.94min, purity 85-90%, [M+H]+ 443.4.
[00671 ] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.73 - 7.77 (m, 1 H), 7.17 (s, 1 H),
6.87 - 6.92 (m, 1 H), 6.78 (dd, J=9.03, 4.51 Hz, 1 H), 4.23 - 4.25 (m, 2 H), 4.01 (s, 3 H), 2.75 (m, 2 H), 2.34 (s, 3 H), 2.08 - 2.12 (m, 5 H), 1 .14 (s, 9 H).
Example 172 - 4-Fluoro-3-((6-methoxy-7-(3-(methyl(propyl)amino)propoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (15 mg, off-white solid, 14% yield).
[00672] LCMS: Low_pH_3min RT 0.85min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 2.58min, purity >95%, [M+H]+ 429.4.
[00673] Ή NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.75 (s, 1 H), 7.16 (s, 1 H), 6.89 (t, J=9.00 Hz, 1 H), 6.78 (dd, J=8.89, 4.34 Hz, 1 H), 4.23 (t, J=5.74 Hz, 2 H), 4.01 (s, 3 H), 2.67 - 2.75 (m, 2 H), 2.42 - 2.46 (m, 2 H), 2.34 (s, 3 H), 2.1 1 (s, 3 H), 1 .57 (dd, J=15.39, 7.59 Hz, 2 H), 1 .18 (t, J=6.94 Hz, 2 H), 0.93 (t, J=7.26 Hz, 3 H).
Example 173 - 3-((7-(3-(3,4-Dihydroisoquinolin-2(1 H)-yl)propoxy)-6-methoxyquinazolin-4- yl)amino)-4-fluoro-2-methylphenol was prepared (18 mg, off-white solid, 14.5% yield).
[00674] LCMS: Low_pH_3min RT 1 .33min, purity >95%, [M+H]+ 489.3. High_pH_4.5min
RT 2.59min, purity 85-90%, [M+H]+ 489.4.
[00675] 1 H NMR (400 MHz, DMSO): δ 9.37 (s, 1 H), 9.22 (s, 1 H), 8.24 (s, 1 H), 7.84 (s, 1
H), 7.16 (s, 1 H), 7.03 - 7.12 (m, 4 H), 6.94 (t, J=9.07 Hz, 1 H), 6.76 (dd, J=8.84, 4.65 Hz, 1 H), 4.22 (t, J=6.05 Hz, 2 H), 3.94 (s, 3 H), 3.60 (s, 2 H), 3.17 (d, J=5.12 Hz, 2 H), 2.80 - 2.85 (m, 2 H), 2.70 (d, J=5.58 Hz, 2 H), 2.03 - 2.09 (m, 2 H), 1 .98 (s, 3 H).
Example 174 - 4-Fluoro-3-((7-(3(2-(hydroxymethyl)piperidin-1 -yl)propoxy)-6- methoxyquinazolin-4-yl)amino)-2-methylphenol was prepared (26 mg, off-white solid, 22% yield).
[00676] LCMS: Low_pH_4.5min RT 0.88min, purity 90-95%, [M+H]+ 471 .4.
High_pH_4.5min RT 2.13min, purity >95%, [M+H]+ 471 .4.
[00677] Ή NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.75 (s, 1 H), 7.17 (s, 1 H), 6.87 -
6.92 (m, 1 H), 6.78 (dd, J=8.84, 4.53 Hz, 1 H), 4.22 (t, J=6.25 Hz, 2 H), 4.02 (s, 3 H), 3.73 - 3.78 (m, 1 H), 3.59 - 3.64 (m, 1 H), 3.10 - 3.15 (m, 1 H), , 2.71 (d, J=12.07 Hz, 2 H), 2.41 (d, J=12.93 Hz, 2H), 2.1 1 (s, 3 H), 1 .78 - 1 .86 (m, 2 H), 1 .29 - 1 .59 (m, 4 H), 1 .18 (t, J=7.1 1 Hz, 2 H).
Example 175 - 4-Fluoro-3-((7-(3-(3-fluoropyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4- yl)amino)-2-methylphenol was prepared (16 mg, white solid, 14% yield).
[00678] LCMS: Low_pH_3.5min RT 1 .87min, purity <85%, [M+H]+ 445. High_pH_5min RT 2.10min, purity >95%, [M+H]+ 445.4.
[00679] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.77 (s, 1 H), 7.18 (s, 1 H), 6.86 -
6.92 (m, 1 H), 6.78 (dd, J=8.88, 4.28 Hz, 1 H), 4.28 (t, J=5.81 Hz, 2 H), 4.02 (s, 3 H), 3.03 - 3.1 1 (m, 3H), 2.89 (d, J=13.59 Hz, 2 H), 2.27 - 2.39 (m, 2 H), 2.23 (d, J=6.80 Hz, 2 H), 2.1 1 (s, 3 H), 1 .29 (m, 2 H).
Example 176 - 4-Fluoro-3-((6-methoxy-7-(3-(2-(trifluoromethyl)pyrrolidin-1 - yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (14 mg, tan solid, 1 1 % yield).
[00680] LCMS: Low_pH_3min RT 1 .48min, purity 90-95%, [M+H]+ 495. High_pH_4.5min
RT 2.57min, purity <85%, [M+H]+ 495.4.
[00681] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.72 - 7.77 (m, 1 H), 7.16 (s, 1 H),
6.87 - 6.92 (m, 1 H), 6.79 (d, J = 8.08, 1 H), 4.25 (t, J=6.32 Hz, 2 H), 4.03 (s, 3 H), 3.35 (m, 1 H), 3.21 - 3.25 (m, 2 H), 3.09 - 3.18 (m, 2 H), 2.77 - 2.83 (m, 2 H), 2.38 - 2.53 (m, 2 H), 2.09 - 2.14 (s, 3 H), 1 .86 - 1 .95 (m, 2 H).
Example 177 - 4-Fluoro-3-((7-(3-(isopropyl(methyl)amino)propoxy)-6-methoxyquinazolin- 4-yl)amino)-2-methylphenol was prepared (20 mg, off-white solid, 18% yield).
[00682] LCMS: Low_pH_3min RT 0.81 min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 2.65min, purity >95%, [M+H]+ 429.3.
[00683] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.75 (s, 1 H), 7.17 (s, 1 H), 6.87 - 6.92 (m, 1 H), 6.76 (d, J = 8.12, 1 H), 4.23 (t, J=6.09 Hz, 2 H), 3.99 - 4.02 (m, 3 H), 3.46 - 3.52 (m, 1 H), 2.71 - 2.75 (m, 2 H), 2.32 (s, 3 H), 2.10 - 2.12 (m, 3H), 1 .15 - 1 .20 (m, 2 H), 1 .09 (d, J=6.32 Hz, 6 H).
Example 178 - 4-Fluoro-3-((6-methoxy-7-(3-(4-methyl-1 ,4-diazepan-1- yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol was prepared (20 mg, off-white solid, 18% yield).
[00684] LCMS: Low_pH_3min RT 0.68min, purity >95%, [M+H]+ 470. High_pH_4.5min
RT 2.74min, purity >95%, [M+H]+ 470.4.
[00685] Ή NMR (400 MHz, CD3OD): δ 8.33 (s, 1 H), 7.82 (s, 1 H), 7.22 (s, 1 H), 6.87 - 6.94 (m, 1 H), 6.79(d, J = 8.88, 1 H), 4.30 (t, J = 6.03 Hz, 2 H), 4.03 (s, 3 H), 3.04 - 3.10 (m, 4H), 2.91 - 3.00 (m, 4 H), 2.84 (s, 3 H), 2.13 - 2.19 (m, 4H), 2.10 (s, 3 H), 2.03 - 2.09 (m, 2 H).
Example 179 - 3-((7-(3-(1 ,4-Oxezepan-4-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4- fluoro-2-methylphenol was prepared (14 mg, off-white solid, 12% yield).
[00686] LCMS: Low_pH_3min RT 0.82min, purity >95%, [M+H]+ 457. High_pH_4.5min RT 1 .89min, purity 90-95%, [M+H]+ 457.4.
[00687] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.76 (s, 1 H), 7.17 (s, 1 H), 6.86 -
6.91 (m, 1 H), 6.80 (d, J = 8.08, 1 H), 4.25 (t, J=5.87 Hz, 2 H), 4.02 (s, 3 H), 3.84 - 3.84 (m, 1 H), 3.76 - 3.85 (m, 4 H), 3.58 (d, J=5.87 Hz, 1 H), 3.46 - 3.52 (m, 1 H), 2.89 (m, 5 H), 2.15 (s, 3 H), 1 .98 (d, J=5.42 Hz, 2 H).
Example 180 - 4-Fluoro-3-((6-methoxy-7-(3-(piperazin-1-yl)propoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (13 mg, off-white solid, 1 1 .5% yield).
[00688] LCMS: Low_pH_3min RT 0.71 min, purity >95%, [M+H]+ 442. High_pH_4.5min
RT 1 .97min, purity 90-95%, [M+H]+ 442.4.
[00689] Ή NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.77 (s, 1 H), 7.19 (s, 1 H), 6.88 - 6.93 (m, 1 H), 6.78 (dd, J=9.05, 4.74 Hz, 1 H), 4.28 (t, J=6.04 Hz, 2 H), 4.02 (s, 3 H), 3.48 (m, 1 H), 3.21 - 3.26 (m, 3 H), 2.69 - 2.80 (m, 6 H), 2.09 - 2.16 (m, 5 H).
Example 181 - 4-Fluoro-3-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (18 mg, off-white solid, 15.5% yield).
[00690] LCMS: Low_pH_3min RT 0.74min, purity >95%, [M+H]+ 456. High_pH_4.5min RT 1 .87min, purity >95%, [M+H]+ 456.4.
[00691] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.75 (s, 1 H), 7.17 (s, 1 H), 6.87 -
6.92 (m, 1 H), 6.76 - 6.80 (d, J=8.05, 1 H), 4.24 (t, J=5.87 Hz, 2 H), 4.01 (s, 3 H), 3.46 - 3.52 (m, 2 H), 2.61 - 2.73 (m, 8 H), 2.39 (s, 3 H), 2.10 - 2.14 (m, 5 H). Synthesis of Scaffold 4
Figure imgf000141_0001
3-((7-(2-aminoethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol
To Scaffold 2 (1 .2 g, 1 .59 mmol) was added aqueous ammonia solution (10 mL) and the mixture was heated in a sealed tube at 1 10 °C for 3 h. Reaction was monitored by TLC (10% methanol in CHCI3). The reaction mixture was concentrated in vacuo resulting in a crude residue which was triturated with DCM & diethyl ether to afford pure 3-((7-(2-aminoethoxy)-6- methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol Scaffold 4 (800 mg, 84%). Product was confirmed by LCMS and 1 HNMR analysis.
[00692] Ή NMR (400 MHz, CD3OD): δ 8.26 (s, 1 H), 7.85 (s, 1 H), 7.24 (s, 1 H), 6.89 (d,
J=9.21 Hz, 1 H), 6.77 - 6.81 (m, 1 H), 4.43 (t, J=4.82 Hz, 2 H), 4.04 (s, 3 H), 3.46 - 3.51 (m, 2 H), 2.1 1 (s, 3 H); LCMS: m/e 358(M+H)+.
General procedure for library synthesis using Scaffold 4
Figure imgf000141_0002
Scaffold 4 [00693] To Scaffold 4 (1 eq.) in dry DCM:DMF (10:1 ) [20 equivalents of Scaffold 4] was added triethylamine (3 eq.) and the corresponding acid (1 .5 eq.) or acid/sulfonyl chloride (1 eq.). The reaction mixture was stirred at room temperature for 15 min. For reactions using the corresponding acid, propyl phosphoryl anhydride T3P (3 eq.) was added dropwise to the reaction mixture and stirred at room temperature for 2 h. Reaction completion was monitored by LCMS. On completion, the reaction was concentrated in vacuo resulting in the crude compound which was purified using SFC or preparative HPLC. All the reactions were performed on 80 mg scale. The following compounds were prepared according to the general procedure library synthesis using Scaffold 4 described above. Example 182 - A^(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)acetamide was prepared (14 mg, white solid, 13% yield.
[00694] LCMS: Low_pH_3.5min RT 1 .05min, purity >95%, [M+H]+ 401 . High_pH_4.5min
RT 1 .03min, purity 90-95%, [M+H]+ 401 .
[00695] Ή NMR (400 MHz, CD3OD): δ 8.33 (s, 1 H), 7.83 (s, 1 H), 7.22 (br. s., 1 H), 6.89
- 6.94 (m, 1 H), 6.80 (dd, J=8.77, 4.39 Hz, 1 H), 4.26 (t, J=5.04 Hz, 2 H), 4.04 (s, 3 H), 3.67 - 3.70 (m, 2 H), 2.1 1 (s, 3 H), 1 .99 (s, 3 H).
Example 183 - A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)propionamide was prepared (12 mg, pale yellow solid, 1 1 % yield).
[00696] LCMS: Low_pH_4.5min RT 1 .33min, purity >95%, [M+H]+ 415. High_pH_5min
RT 1 .13min, purity 90-95%, [M+H]+ 415.3.
[00697] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.83 (s, 1 H), 7.22 (s, 1 H), 6.89 -
6.94 (m, 1 H), 6.80 (dd, J=8.77, 4.39 Hz, 1 H), 4.24 (t, J=5.04 Hz, 2 H), 4.04 (s, 3 H), 3.67 - 3.70 (m, 2 H), 2.24 (m, 2 H), 2.04 (s, 3 H), 1 .87 (m, 3H).
Example 184 - A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)isobutyramide was prepared (16 mg, pale yellow solid, 15% yield).
[00698] LCMS: Low_pH_4.5min RT 1 .15min, purity >95%, [M+H]+ 429. High_pH_5min
RT 1 .77min, purity 90-95%, [M+H]+ 429.4.
[00699] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.77 (s, 1 H), 7.17 (s, 1 H), 6.86 - 6.92 (m, 1 H), 6.78 (dd, J=8.82, 4.41 Hz, 1 H), 4.24 (t, J=5.29 Hz, 2 H), 4.02 (s, 3 H), 3.68 (t, J=5.29 Hz, 2 H), 2.45 - 2.51 (m, 1 H), 2.1 1 (s, 3 H), 1 .13 (d, J=6.62 Hz, 6 H).
Example 185 - 2-(Dimethylamino)- V-(2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethyl)acetamide was prepared (13 mg, white solid, 1 1 % yield).
[00700] LCMS: Low_pH_6.5min RT 0.97min, purity >95%, [M+H]+ 444.1 . High_pH_6.5min RT 1 .49min, purity <85%, [M+H]+ 444.1 .
[00701] Ή NMR (400 MHz, CD3OD): δ 8.27 (s, 1 H), 7.80 (s, 1 H), 7.22 (br. s., 1 H), 6.89
(d, J=9.29 Hz, 1 H), 6.79 (dd, J=8.91 , 4.26 Hz, 1 H), 4.30 (s, 2 H), 4.02 (s, 3 H), 3.71 - 3.79 (m, 4 H), 2.72 - 2.84 (m, 6 H), 2.1 1 (s, 3 H).
Example 186 - 3-(Dimethylamino)- V-(2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethyl)propanamide was prepared (41 mg, white solid, 38% yield).
[00702] LCMS: Low_pH_4.5min RT LOOmin, purity 90-95%, [M+H]+ 458. High_pH_5min
RT 1 .39min, purity 85-90%, [M+H]+ 458.4. [00703] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.77 (s, 1 H), 7.18 (s, 1 H), 6.89 (t,
J=9.00 Hz, 1 H), 6.78 (dd, J=8.79, 4.50 Hz, 1 H), 4.26 (t, J=5.14 Hz, 2 H), 4.02 (s, 3 H), 3.71 (t, J=5.36 Hz, 2 H), 2.99 (t, J=6.64 Hz, 2 H), 2.52 - 2.64 (m, 8 H), 2.1 1 (s, 3 H).
Example 187 - A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)methanesulfonamide was prepared (9 mg, off-white solid, 7% yield).
[00704] LCMS: Low_pH_4.5min RT 1 .40min, purity 90-95%, [M+H]+ 437. High_pH_5min
RT 1 .42min, purity 90-95%, [M+H]+ 437.3.
[00705] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.79 (s, 1 H), 7.19 (s, 1 H), 6.87 -
6.92 (m, 1 H), 6.78 (dd, J=8.82, 4.41 Hz, 1 H), 4.27 (t, J=5.29 Hz, 2 H), 4.03 (s, 3 H), 3.62 (t, J=4.85 Hz, 2 H), 3.09 (s, 3 H), 2.1 1 (s, 3 H).
Example 188 - V-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)-1 -methyl-1 H-pyrazole-3-carboxamide was prepared (21 mg, pale yellow solid, 18% yield).
[00706] LCMS: Low_pH_4.5min RT 1 .38min, purity >95%, [M+H]+ 467. High_pH_5min RT 1 .49min, purity 85-90%, [M+H]+ 467.4.
[00707] 1 H NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.79 (s, 1 H), 7.61 (d, 1 H), 7.21 (s,
1 H), 6.87 - 6.92 (m, 1 H), 6.78 (dd, J=8.82, 4.41 Hz, 1 H), 6.65 (d, 1 H), 4.27 (t, J=5.3 Hz, 2 H), 4.03 (s, 3 H), 3.95 (s, 3 H), 3.69 (t, J=4.8 Hz, 2 H), 3.09 (s, 3 H), 2.1 1 (s, 3 H).
Synthesis of Scaffold 5
Figure imgf000143_0001
Scaffold 5
4-Fluoro-3-((6-methoxy-7-(2-(methylamino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol
[00708] To Scaffold 2 (1 .5 g, 3.97 mmol) was added 40% aqueous solution of methyl amine (10 mL) in a sealed tube and heated at 1 10 °C for 16 h. Reaction was monitored by TLC (10% Methanol in CHCI3). The reaction mixture was cooled to room temperature and concentrated in vacuo to afford crude 4-fluoro-3-((6-methoxy-7-(2- (methylamino)ethoxy)quinazolin-4-yl)amino)-2-methylphenol Scaffold 5 (1 g, 67%) which was used as such in next step. Product was confirmed by 1 H NMR analysis.
[00709] Ή NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.83 (s, 1 H), 7.23 (s, 1 H), 6.86 - 6.93 (m, 1 H), 6.78 (dd, J=8.71 , 4.45 Hz, 1 H), 4.42 (t, J=4.65 Hz, 2 H), 4.05 (s, 3 H), 3.39 - 3.46 (m, 2H), 2.76 (s, 3 H), 2.1 1 (s, 3 H).
General procedure for library synthesis using Scaffold 5
Figure imgf000144_0001
[00710] To Scaffold 5 (1 eq.) in dry DCM:DMF (10:1 ) [20 equivalents of Scaffold 5] was added triethylamine (3 eq.) and the corresponding acid (1 .5 eq.) or acid chloride/sulfonyl chloride (1 eq.). The reaction mixture was stirred at room temperature for 15 min. For reactions using the corresponding acid, propyl phosphoryl anhydride T3P (3 eq.) was added dropwise to the reaction mixture and stirred at room temperature for 2 h. Reaction completion was monitored by LCMS. On completion, the reaction was concentrated in vacuo resulting in crude compound which purified using SFC or preparative HPLC. All the reactions were performed on 80 mg scale. The following compounds were prepared according to the general procedure for library synthesis using Scaffold 5 described above.
Example 189 - A/-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)-/V-methylacetamide was prepared (13 mg, off-white solid, 12% yield).
[0071 1] LCMS: Low_pH_4.5min RT 1 .23min, purity >95%, [M+H]+ 415. High_pH_5min
RT 1 .36min, purity 85-90%, [M+H]+ 415.3.
[00712] 1 H NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.77 (d, J=1 .71 Hz, 1 H), 7.17 (d, J=9.00 Hz, 1 H), 6.86 - 6.93 (m, 1 H), 6.78 (dd, J=8.79, 4.50 Hz, 1 H), 4.31 - 4.37 (m, 2 H), 4.01 (d, J=6.00 Hz, 3 H), 3.86 - 3.93 (m, 2 H), 3.26 (s, 2 H), 3.03 (s, 1 H), 2.1 1 (s, 3 H), 1 .25 - 1 .33 (m, 3 H).
Example 190 - V-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)-W-methylcyclopropanecarboxamide was prepared (12 mg, off-white solid, 1 1 % yield).
[00713] LCMS: Low_pH_4.5min RT 1 .52min, purity >95%, [M+H]+ 441 . High_pH_5min
RT 1 .88min, purity >95%, [M+H]+ 441 .4.
[00714] Ή NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1 H), 9.25 (br. s, 1 H), 8.25 (d, J=3.53
Hz, 1 H), 7.85 (s, 1 H), 7.21 (d, J=6.62 Hz, 1 H), 6.95 (t, J=9.26 Hz, 1 H), 6.77 (dd, J=8.82, 4.41 Hz, 1 H), 4.35 (m, 1 H), 4.19 - 4.25 (m, 1 H), 3.98 (m, 1 H), 3.93 (d, J=6.17 Hz, 3 H), 3.74 (t, J=5.51 Hz, 1 H), 2.94 (s, 3 H), 2.1 1 (s, 1 H), 1 .93 - 2.02 (m, 3 H), 0.73 (d, J=2.65 Hz, 4 H).
Example 191 - 2-(Dimethylamino)-A^(2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethyl)- V-methylacetamide was prepared (13 mg, white solid, 1 1 % yield).
[00715] LCMS: Low_pH_4.5min RT 0.85min, purity >95%, [M+H]+ 458. High_pH_5min
RT 1 .58min, purity <85%, [M+H]+ 458.4.
[00716] Ή NMR (400 MHz, DMSO-d6): δ 9.26 (br. s, 1 H), 8.25 (d, J=3.53 Hz, 1 H), 7.85
(d, J=3.97 Hz, 1 H), 7.20 (d, J=4.41 Hz, 1 H), 6.88 - 6.96 (m, 1 H), 6.77 (dd, J=8.82, 4.41 Hz, 1 H), 5.76 (s, 1 H), 4.31 (d, J=4.85 Hz, 1 H), 4.24 (t, J=5.73 Hz, 1 H), 3.87 - 3.94 (s, 3 H), 3.29 - 3.38 (m, 7 H), 2.19 (d, J=8.38 Hz, 6 H), 1 .96 - 2.05 (m, 3 H).
Example 192 - 3-(Dimethylamino)- V-(2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethyl)- V-methylpropanamide was prepared (36 mg, off-white solid, 34% yield).
[00717] LCMS: Low_pH_4.5min RT 0.91 min, purity >95%, [M+H]+ 472. High_pH_5min
RT 1 .87min, purity 85-90%, [M+H]+ 472.5.
[00718] 1 H NMR (400 MHz, CD3OD): δ 8.23 (d, J=5.14 Hz, 1 H), 7.77 (d, J=5.57 Hz, 1 H),
7.18 (d, J=12.00 Hz, 1 H), 6.87 - 6.92 (m, 1 H), 6.73 - 6.79 (m, 1 H), 4.33 - 4.38 (m, 2 H), 4.01 (d, J=1 .71 Hz, 3 H), 3.93 - 3.96 (m, 1 H), 3.88 - 3.91 (m, 1 H), 3.26 (s, 2 H), 3.13 (m, 2 H), 3.03 - 3.07 (m, 3 H), 2.65 (s, 3 H), 2.60 (s, 3 H), 2.10 (s, 3 H).
Example 193 - V-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)ethyl)-W-methylmethanesulfonamide was prepared (34 mg, white solid, 33% yield).
[00719] LCMS: Low_pH_4.5min RT 1 .80min, purity >95%, [M+H]+ 451 . High_pH_5min
RT 1 .84min, purity <85%, [M+H]+ 451 .3.
[00720] Ή NMR (400 MHz, CD3OD): δ 8.24 (d, J=6.00 Hz, 1 H), 7.79 (d, J=8.00 Hz, 1 H),
7.21 (d, J=8.14 Hz, 1 H), 6.90 (s, 1 H), 6.78 (dd, J=8.36, 4.07 Hz, 1 H), 4.39 (t, J=4.93 Hz, 1 H), 4.31 - 4.36 (m, 1 H), 3.99 - 4.06 (m, 3 H), 3.34 - 3.37 (m, 2 H), 3.04 (d, J=12.43 Hz, 3 H), 2.65 - 2.72 (m, 3 H), 2.1 1 (s, 3 H).
Figure imgf000146_0001
3-((7-(2-aminoethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol
[00721] A solution of Scaffold 4 (800 mg, 1 .02 mmol) in aqueous ammonia solution (10 mL) was heated in a sealed tube at 100 °C for 6 h. Reaction was monitored by TLC (10% methanol in CHCI3). The reaction mixture was concentrated in vacuo resulting in a residue which was triturated with diethyl ether to afford pure 3-((7-(2-aminoethoxy)-6- methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol Scaffold 6 (700 mg, 92%) as brown solid. Product was confirmed by 1 HNMR analysis.
[00722] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.80 (s, 1 H), 7.19 (s, 1 H), 6.87 -
6.93 (m, 1 H), 6.78 (dd, J=8.91 , 4.26 Hz, 1 H), 4.35 (t, J=5.62 Hz, 2 H), 4.04 (s, 3 H), 3.25 (t, J=6.78 Hz, 2 H), 2.28 (m, 2 H), 2.1 1 (s, 3 H).
General procedure for library synthesis using Scaffold 6
Figure imgf000146_0002
Scaffold 6
[00723] To Scaffold 6 (1 eq.) in dry DCM:DMF (10:1 ) [20 equivalents of Scaffold 6] was added triethylamine (3 eq.) and the corresponding acid (1 .5 eq.) or acid/sulfonyl chloride (1 eq.). The reaction mixture was stirred at room temperature for 15 min. For reactions using the corresponding acid, propyl phosphoryl anhydride T3P (3 eq.) was added dropwise to the reaction mixture and stirred at room temperature for 2 h. Reaction completion was monitored by LCMS. On completion, the reaction was concentrated in vacuo resulting in crude compound which was purified using SFC or preparative HPLC. All the reactions were performed on 80 mg scale. The following compounds were prepared according to the general procedure for library synthesis using Scaffold 6 (Scheme 13) described above. Example 194 - A^(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)acetamide was prepared (15 mg, white solid, 15% yield).
[00724] LCMS: Low_pH_4.5min RT 1 .44min, purity >95%, [M+H]+ 415. High_pH_4.5min
RT 1 .13min, purity 90-95%, [M+H]+ 415.1 .
[00725] Ή NMR (400 MHz, CD3OD): δ 8.32 ( s, 1 H), 7.79 (s, 1 H), 7.20 (s, 1 H), 6.86 -
6.92 (m, 1 H), 6.79 (dd, J=9.03, 4.51 Hz, 1 H), 4.24 (t, J=5.87 Hz, 2 H), 4.02 (s, 3 H), 3.42 (t, J=6.55 Hz, 2 H), 2.1 1 (s, 3H), 2.04 - 2.10 (m, 2 H), 1 .96 (s, 3 H)
Example 195 - A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)propionamide was prepared (12 mg, white solid, 1 1 % yield).
[00726] LCMS: Low_pH_4.5min RT 1 .55min, purity >95%, [M+H]+ 429. High_pH_4.5min
RT 1 .21 min, purity 90-95%, [M+H]+ 429.
[00727] 1 H NMR (400 MHz, CD3OD): δ 8.30 (s, 1 H), 7.79 (s, 1 H), 7.20 (s, 1 H), 6.87 -
6.93 (m, 1 H), 6.79 (dd, J=9.03, 4.51 Hz, 1 H), 4.25 (t, J=5.87 Hz, 2 H), 4.03 (s, 3 H), 3.44 (t, J=6.55 Hz, 2 H), 2.22 (q, J=7.68 Hz, 2 H), 2.1 1 (s, 3 H), 1 .13 (t, J=7.67 Hz, 3 H), 0.97 - 1 .06 (m, 1 H), 0.89 (d, J=7.22 Hz, 1 H).
Example 196 - V-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)isobutyramide was prepared (36 mg, brown solid, 35% yield).
[00728] LCMS: Low_pH_4.5min RT 1 .64min, purity 90-95%, [M+H]+ 443. High_pH_5min
RT 1 .83min, purity 90-95%, [M+H]+ 443.4.
[00729] Ή NMR (400 MHz, CD3OD): δ 7.41 (s, 1 H), 6.94 (s, 1 H), 6.36 (s, 1 H), 6.04 -
6.1 1 (m, 1 H), 5.96 (dd, J=9.04, 4.63 Hz, 1 H), 3.42 (t, J=5.95 Hz, 2 H), 3.21 (s, 3 H), 2.62 (t, J=6.62 Hz, 2 H), 1 .60 - 1 .67 (m, 1 H), 1 .32 (s, 3 H), 1 .19 - 1 .29 (m, 2 H), 0.31 (d, J=7.06 Hz, 6 H).
Example 197 - 2-(Dimethylamino)- V-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)propyl)acetamide was prepared (26 mg, off-white solid, 25% yield).
[00730] LCMS: Low_pH_4.5min RT 1 .06min, purity 90-95%, [M+H]+ 458. High_pH_5min
RT 1 .75min, purity <85%, [M+H]+ 458.4.
[00731] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.76 (s, 1 H), 7.17 (s, 1 H), 6.87 - 6.92 (m, 1 H), 6.74 - 6.80 (m, 1 H), 4.24 (t, J=6.00 Hz, 2 H), 4.02 (s, 3 H), 3.50 (t, J=6.64 Hz, 2 H), 3.07 (s, 2 H), 2.35 (s, 6 H), 2.10 - 2.14 (m, 5 H).
Example 198 - 3-(Dimethylamino)- V-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)propyl)propanamide was prepared (17 mg, white solid, 15% yield).
[00732] LCMS: Low_pH_4.5min RT 1 .1 1 min, purity >95%, [M+H]+ 472. High_pH_5min
RT 1 .67min, purity 90-95%, [M+H]+ 472.5.
[00733] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.76 (s, 1 H), 7.17 (s, 1 H), 6.90 (t, J=9.22 Hz, 1 H), 6.75 - 6.80 (m, 1 H), 4.24 (t, J=6.00 Hz, 2 H), 4.02 (s, 3 H), 3.47 (t, J=6.43 Hz, 2 H), 3.03 (t, J=6.86 Hz, 2 H), 2.54 - 2.61 (m, 8 H), 2.08 - 2.14 (m, 5 H).
Example 199 - A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)methanesulfonamide was prepared (19 mg, off-white solid, 17% yield).
[00734] LCMS: Low_pH_4.5min RT 1 .56min, purity >95%, [M+H]+ 451 . High_pH_5min RT 1 .63min, purity 90-95%, [M+H]+ 451 .4.
[00735] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.76 (s, 1 H), 7.18 (s, 1 H), 6.90 (t,
J=9.00 Hz, 1 H), 6.75 - 6.80 (m, 1 H), 4.30 (t, J=5.79 Hz, 2 H), 4.01 - 4.05 (m, 3 H), 3.35 - 3.38 (m, 2 H), 2.94 - 2.99 (m, 3 H), 2.13 - 2.21 (m, 2 H), 2.1 1 (s, 3 H).
Example 200 - A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)ethanesulfonamide was prepared (15 mg, white solid, 13% yield).
[00736] LCMS: Low_pH_4.5min RT 1 .80min, purity >95%, [M+H]+ 465. High_pH_5min
RT 1 .83min, purity >95%, [M+H]+ 465.4.
[00737] 1 H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.76 (s, 1 H), 7.19 (s, 1 H), 6.87 -
6.92 (m, 1 H), 6.76 - 6.79 (m, 1 H), 4.30 (t, J=5.79 Hz, 2 H), 4.03 (s, 3 H), 3.05 - 3.1 1 (m, 2 H), 2.13 - 2.18 (m, 2 H), 2.1 1 (s, 3 H), 1 .31 (t, J=7.29 Hz, 5 H).
Example 201 - V-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)-1 -methyl-1 H-pyrazole-3-carboxamide was prepared (17 mg, off-white solid, 15% yield).
[00738] LCMS: Low_pH_4.5min RT 1 .57min, purity 90-95%, [M+H]+ 481 . High_pH_5min RT 1 .65min, purity 90-95%, [M+H]+ 481 .4.
[00739] Ή NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.74 (s, 1 H), 7.61 (d, J=2.14 Hz, 1
H), 7.18 (s, 1 H), 6.90 (t, J=9.00 Hz, 1 H), 6.75 - 6.80 (m, 1 H), 6.68 - 6.71 (m, 1 H), 4.28 (t, J=6.00 Hz, 2 H), 3.99 (s, 3 H), 3.93 - 3.96 (m, 3 H), 3.63 (t, J=6.43 Hz, 2 H), 2.20 (t, J=6.21 Hz, 2 H), 2.1 1 (s, 3 H). Synthesis of Scaffold 7
Figure imgf000149_0001
Scaffold 7
4-Fluoro-3-((6-methoxy-7-(2-(methylamino)ethoxy)quinazolin-4-yl)amino)-2-methylphen
[00740] To Scaffold 4 (2 g, 5.10 mmol) was added 40% aqueous solution of methylamine (20 mL) in a sealed tube and the mixture was heated at 1 10 °C for 4 h. Reaction was monitored by LCMS analysis. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford crude Scaffold 7 (900 mg, 46%) which was used as such in next step. Product was confirmed by LCMS and 1 H NMR analysis.
[00741] Ή NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.80 (d, J=2.16 Hz, 1 H), 7.19 (s, 1 H), 6.88 - 6.92 (m, 1 H), 6.77 - 6.80 (m, 1 H), 4.31 - 4.36 (m, 2 H), 4.05 (d, J=1 .29 Hz, 3 H), 2.95 (s, 3 H), 2.80 (s, 2 H), 2.29 - 2.37 (m, 2 H), 2.1 1 (s, 3 H); LCMS: m/e 387(M+H)+.
General procedure for library synthesis using Scaffold 7
Figure imgf000149_0002
[00742] To Scaffold 7 (1 eq.) in dry DCM:DMF (10:1 ) [20 equivalents of Scaffold 7] was added triethylamine (3 eq.) and the corresponding acid (1 .5 eq.) or acid chloride/sulfonyl chloride (1 eq.). The reaction mixture was stirred at room temperature for 15 min. For reactions using the corresponding acid, propyl phosphoryl anhydride T3P (3 eq.) was added dropwise to the reaction mixture and stirred at room temperature for 2 h. Reaction completion was monitored by LCMS. On completion, the reaction was concentrated in vacuo resulting in crude compound which was purified using SFC or preparative HPLC. All the reactions were performed on 80 mg scale. The following compounds were prepared according to the general procedure for library synthesis using Scaffold 7 described above.
Example 202 - A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)-/V-methylacetamide was prepared (13 mg, off-white solid, 12% yield). [00743] LCMS: Low_pH_4.5min RT 1 .45min, purity >95%, [M+H]+ 429.3. High_pH_5min
RT 1 .44min, purity 90-95%, [M+H]+ 429.4.
[00744] Ή NMR (400 MHz, CD3OD): δ 8.25 (s, 1 H), 7.78 (d, J=3.53 Hz, 1 H), 7.17 (dd,
J=13.23, 2.21 Hz, 1 H), 6.89 (d, J=9.26 Hz, 1 H), 6.75 - 6.80 (m, 1 H), 4.20 - 4.24 (m, 2 H), 4.02 (s, 3 H), 3.61 - 3.68 (m, 2 H), 3.12 (d, J=2.65 Hz, 2 H), 2.96 (d, J=2.21 Hz, 1 H), 2.16 - 2.24 (m, 2 H), 2.13 (d, J=2.21 Hz, 2 H), 2.1 1 (d, J=2.21 Hz, 3 H), 2.08 (d, J=2.21 Hz, 1 H).
Example 203 - A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)-W-methylcyclopropanecarboxamide was prepared (41 mg, white solid, 42% yield).
[00745] LCMS: Low_pH_4.5min RT 1 .84min, purity 90-95%, [M+H]+ 455. High_pH_5min
RT 2.00min, purity 90-95%, [M+H]+ 455.4.
[00746] 1 H NMR (400 MHz, CD3OD): δ 8.23 (d, J=4.71 Hz, 1 H), 7.75 (d, J=2.57 Hz, 1 H),
7.16 (d, J=16.29 Hz, 1 H), 6.87 - 6.92 (m, 1 H), 6.78 (dd, J=9.00, 4.29 Hz, 1 H), 4.23 - 4.26 (m,
1 H), 4.20 (t, J=5.79 Hz, 1 H), 4.01 (d, J=9.86 Hz, 3 H), 3.86 (s, 1 H), 3.64 - 3.67 (m, 1 H), 3.28 (s, 1 H), 2.99 (s, 2 H), 2.27 (d, J=5.57 Hz, 1 H), 2.16 (d, J=6.43 Hz, 1 H), 2.1 1 (s, 3 H), 1 .28 -
1 .33 (m, 1 H), 0.77 - 0.83 (m, 4 H).
Example 204 - A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)-W-methylisobutyramide was prepared (27 mg, white solid, 26% yield).
[00747] LCMS: Low_pH_4.5min RT 1 .90min, purity >95%, [M+H]+ 457. High_pH_5min RT 2.03min, purity 90-95%, [M+H]+ 457.4.
[00748] Ή NMR (400 MHz, CD3OD): δ 8.22 (d, J=4.29 Hz, 1 H), 7.76 (d, J=8.57 Hz, 1 H),
7.16 (d, J=12.43 Hz, 1 H), 6.87 - 6.92 (m, 1 H), 6.78 (dd, J=9.00, 4.29 Hz, 1 H), 4.19 - 4.23 (m,
2 H), 4.02 (s, 3 H), 3.71 (t, J=6.86 Hz, 1 H), 3.64 (t, J=6.86 Hz, 1 H), 3.17 (m, 1 H), 3.10 (dd, J=12.64, 5.79 Hz, 1 H), 2.94 - 2.98 (m, 2 H), 2.14 - 2.22 (m, 2 H), 2.1 1 (s, 3 H), 1 .07 (d, J=6.43 Hz, 3 H), 1 .03 (d, J=6.43 Hz, 3 H).
Example 205 - 2-(Dimethylamino)- V-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)propyl)- V-methylacetamide was prepared (30 mg, white solid, 27% yield).
[00749] LCMS: Low_pH_4.5min RT 1 .29min, purity >95%, [M+H]+ 472. High_pH_5min RT 1 .73min, purity >95%, [M+H]+ 472.5.
[00750] 1 H NMR (400 MHz, CD3OD): δ 8.22 (d, J=4.88 Hz, 1 H), 7.76 (d, J=8.87 Hz, 1 H),
7.16 (d, J=15.97 Hz, 1 H), 6.85 - 6.91 (m, 1 H), 6.78 (dd, J=8.65, 4.21 Hz, 1 H), 4.20 (d, J=4.88 Hz, 2 H), 4.02 (s, 3 H), 3.61 - 3.71 (m, 2 H), 3.21 (d, J=10.65 Hz, 2 H), 3.1 1 (s, 2 H), 2.96 (s, 1 H), 2.20 - 2.30 (m, 6 H), 2.13 - 2.19 (m, 2 H), 2.1 1 (s, 3 H). Example 206 - 3-(Dimethylamino)-A^(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)propyl)- V-methylpropanamide was prepared (13 mg, off-white solid, 1 1 % yield).
[00751] LCMS: Low_pH_4.5min RT 1 .07min, purity >95%, [M+H]+ 486.3. High_pH_5min RT 1 .94min, purity 90-95%, [M+H]+ 486.4.
[00752] 1 H NMR (400 MHz, CD3OD): δ 8.24 (d, J=3.43 Hz, 1 H), 7.74 - 7.80 (m, 1 H),
7.14 - 7.23 (m, 1 H), 6.86 - 6.93 (m, 1 H), 6.78 (dd, J=9.00, 4.71 Hz, 1 H), 4.23 (dt, J=8.57, 5.79 Hz, 2 H), 4.03 (d, J=3.86 Hz, 3 H), 3.63 - 3.70 (m, 2 H), 3.12 (s, 3 H), 2.96 - 3.03 (m, 2 H), 2.83 - 2.93 (m, 2 H), 2.73 - 2.82 (m, 6 H), 2.15 - 2.26 (m, 2 H), 2.1 1 (s, 3 H).
Example 207 - A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)-W-methylmethanesulfonamide was prepared (13 mg, off-white solid, 1 1 % yield).
[00753] LCMS: Low_pH_4.5min RT 1 .61 min, purity >95%, [M+H]+ 465. High_pH_5min
RT 1 .95min, purity >95%, [M+H]+ 465.4.
[00754] 1 H NMR (400 MHz, DMSO-cfe): δ 9.38 (br. s, 1 H), 9.24 (s, 1 H), 8.25 (s, 1 H),
7.85 (s, 1 H), 7.16 (s, 1 H), 6.90 - 6.97 (m, 1 H), 6.77 (dd, J=8.82, 4.41 Hz, 1 H), 4.18 (t, J=6.17 Hz, 2 H), 3.93 (s, 3 H), 3.26 (t, J=7.06 Hz, 2 H), 2.89 (s, 3 H), 2.80 (s, 3 H), 2.05 - 2.1 1 (m, 2 H), 1 .99 (s, 3 H).
Example 208 - V-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)-W-methylethanesulfonamide was prepared (7 mg, off-white solid, 5% yield).
[00755] LCMS: Low_pH_4.5min RT 1 .42min, purity >95%, [M+H]+ 479. High_pH_5min
RT 2.10min, purity 90-95%, [M+H]+ 479.4.
[00756] Ή NMR (400 MHz, CD3OD): δ 8.24 (s, 1 H), 7.76 (s, 1 H), 7.17 - 7.21 (m, 1 H),
6.87 - 6.92 (m, 1 H), 6.78 (dd, J=9.00, 4.29 Hz, 1 H), 4.26 (t, J=6.00 Hz, 2 H), 4.02 (s, 3 H), 3.46 (t, J=6.64 Hz, 2 H), 3.08 (q, J=7.29 Hz, 2 H), 2.93 (s, 3 H), 2.17 - 2.22 (m, 2 H), 2.1 1 (s, 3 H), 1 .31 (s, 3 H).
Example 209 - A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)-A/,1 -dimethyl-1 H-pyrazole-3-carboxamide was prepared (27 mg, off-white solid, 25% yield).
[00757] LCMS: Low_pH_4.5min RT 1 .74min, purity >95%, [M+H]+ 495. High_pH_5min
RT 1 .69min, purity >95%, [M+H]+ 495.4.
[00758] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.73 (s, 1 H), 7.51 - 7.62 (m, 1 H),
7.10 - 7.19 (m, 1 H), 6.87 - 6.93 (m, 1 H), 6.78 (dd, J=8.79, 4.50 Hz, 1 H), 6.51 - 6.58 (m, 1 H), 4.28 (t, J=5.79 Hz, 1 H), 4.19 (t, J=5.79 Hz, 1 H), 3.97 - 4.06 (m, 5 H), 3.93 (s, 1 H), 3.85 (s, 2 H), 3.80 (t, J=6.86 Hz, 1 H), 3.14 (s, 2 H), 2.24 - 2.31 (m, 2 H), 2.1 1 (s, 3 H).
Example 210 - A^(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin- 7-yl)oxy)propyl)- V,3-dimethylisoxazole-5-carboxamide was prepared (41 mg, white solid, 28% yield).
[00759] LCMS: Low_pH_4.5min RT 1 .51 min, purity >95%, [M+H]+ 496. High_pH_5min
RT 1 .96min, purity 90-95%, [M+H]+ 496.4.
[00760] Ή NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.73 (d, J=2.57 Hz, 1 H), 7.10 - 7.17
(m, 1 H), 6.87 - 6.93 (m, 1 H), 6.78 (dd, J=9.00, 4.29 Hz, 1 H), 6.55 - 6.68 (m, 1 H), 4.29 (t, J=5.57 Hz, 1 H), 4.16 - 4.19 (m, 1 H), 3.97 (d, J=17.14 Hz, 3 H), 3.83 (q, J=6.86 Hz, 2 H), 3.26 (d, J=1.71 Hz, 1 H), 3.12 - 3.18 (m, 2 H), 2.34 (s, 2 H), 2.21 (s, 1 H), 2.1 1 (s, 3 H), 1 .29 - 1 .36 (m, 2 H).
Example 211 - V-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)propyl)-A/,1-dimethyl-1 H-imidazole-2-carboxamide was prepared (12 mg, white solid, 10% yield).
[00761] LCMS: Low_pH_4.5min RT 1 .43min, purity >95%, [M+H]+ 495. High_pH_6.5min
RT 0.81 min, purity >95%, [M+H]+ 495.4.
[00762] 1 H NMR (400 MHz, CD3OD): δ 8.22 (s, 1 H), 7.72 (d, J=16.29 Hz, 1 H), 7.17 -
7.21 (m, 1 H), 7.09 (s, 1 H), 6.97 (d, J=6.43 Hz, 1 H), 6.89 (d, J=9.00 Hz, 1 H), 6.78 (dd, J=9.00, 4.29 Hz, 1 H), 4.31 (t, J=5.79 Hz, 1 H), 4.09 (t, J=5.36 Hz, 1 H), 3.95 (s, 3 H), 3.26 (dt, J=3.1 1 , 1 .66 Hz, 3 H), 2.1 1 (s, 3 H), 1 .27 - 1 .39 (m, 7 H).
Example 212 - 3-((6-Methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol was prepared (5 mg, pink solid, 2.5% yield).
[00763] 4-Chloro-6-methoxy-7-[(1 -methyl-4-piperidinyl)methoxy]quinazoline (64 mg, 0.20 mmol), 3-amino-2-methylphenol (366 mg, 0.50 mmol) and 3 drops of cone HCI were mixed with MeCN (21 mL) and heated in the microwave at 130 °C for 1 h. The reaction mixture was concentrated, diluted with water, basified with aqueous sodium carbonate and extracted with CH2CI2 (x3). The combined extracts were concentrated and the residue purified by prep hplc to give the title compound.
[00764] LCMS: Low_pH_2min RT 0.54min, purity 90-95%, [M-H]" 407.2. High_pH_2min RT 1 .02min, purity >95%, [M-H]" 407.2.
[00765] 1 H NMR (300 MHz, DMSO-cfe): δ 1 .29 - 1 .47 (m, 2 H), 1 .72 - 1 .90 (m, 3 H), 1 .95
(s, 3 H), 1 .97 - 2.12 (m, 2 H), 2.25 (s, 3 H), 2.83 - 2.94 (m, 2 H), 3.92 (s, 3 H), 4.00 (d, J=6.0 Hz, 2 H), 6.80 (t, J=7.6 Hz, 2 H), 7.00 (t, J=7.6 Hz, 1 H), 7.14 (s, 1 H), 7.81 (s, 1 H), 8.20 (s, 1 H), 8.24 (s, 1 H), 9.33 (br s, 1 H). Example 213 - -Chloro-3-((6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4- yl)amino)phenol was prepared (3 mg, off-white solid, 1 .4% yield).
[00766] 4-Chloro-6-methoxy-7-[(1 -methyl-4-piperidinyl)methoxy]quinazoline (64 mg, 0.20 mmol) and 3-amino-2-chlorophenol (72 mg, 0.50 mmol) were mixed with MeCN (6 mL) and 2 drops of cone. HCI and heated in the microwave at 130 °C for 1 h. The reaction mixture was concentrated, diluted with water, basified with aqueous sodium carbonate and extracted with EtOAc (x3). The combined extracts were concentrated and the residue purified by prep hplc to give the title compound.
[00767] LCMS: Low_pH_2min RT 0.56min, purity >95%, [M-H]" 427.2. High_pH_2min RT 0.84min, purity >95%, [M-H]" 427.2.
[00768] 1 H NMR (300 MHz, DMSO-cfe): δ 1 .29 - 1 .47 (m, 2 H), 1 .73 - 1 .89 (m, 3 H), 1 .94
- 2.06 (m, 2 H), 2.23 (s, 3 H), 2.82 - 2.92 (m, 2 H), 3.94 (s, 3 H), 4.00 (d, J=6.0 Hz, 2 H), 6.89- 7.00 (m, 2 H), 7.14-7.22 (m, 2 H), 7.82 (s, 1 H), 8.21 (s, 1 H), 8.28 (s, 1 H), 9.43 (br s, 1 H).
Example 214 - 2-Chloro-3-((6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4- yl)amino)-6-methylphenol was prepared (9 mg, off-white solid, 4.1 % yield)
[00769] LCMS: Low_pH_2min RT 0.61 min, purity >95%, [M-H]" 441 .3. High_pH_2min RT
0.94min, purity >95%, [M-H]" 441 .3.
[00770] 1 H NMR (300 MHz, DMSO-cfe): δ 1 .27 - 1 .46 (m, 2 H), 1 .70 - 1 .86 (m, 3 H), 1 .86
- 1 .99 (m, 2 H), 2.20 (s, 3 H), 2.25 (s, 3 H), 2.78 - 2.87 (m, 2 H), 3.93 (s, 3 H), 4.00 (d, J=6.0 Hz, 2 H), 6.90 (d, J=8.0 Hz, 1 H), 7.1 1 (d, J=8.0 Hz, 1 H), 7.15 (s, 1 H), 7.81 (s, 1 H), 8.25 (s, 1
H), 9.14 (br s, 1 H), 9.44 (br s, 1 H).
Example 215 - 4-Fluoro-3-((6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4- yl)amino)-2-methylphenol was prepared (4 mg, beige solid, 1 .9% yield).
[00771] LCMS: Low_pH_2min RT 0.55min, purity 90-95%, [M-H]" 425.3. High_pH_2min RT 0.90min, purity >95%, [M-H]" 425.3.
[00772] Ή NMR (300 MHz, DMSO-cfe): δ 1 .29 - 1 .47 (m, 2 H), 1 .73 - 1 .88 (m, 3 H), 1 .92
- 2.09 (m, 2 H), 1 .99 (s, 3 H), 2.24 (s, 3 H), 2.83 - 2.93 (m, 2 H), 3.93 (s, 3 H), 4.01 (d, J=6.0 Hz, 2 H), 6.73-6.81 (m, 1 H), 6.89-6.99 (m, 1 H), 7.16 (s, 1 H), 7.84 (s, 1 H), 8.21 (s, 1 H), 8.25 (s, 1 H), 9.24 (br s, 1 H).
Example 216 - Enzyme Assays and Cell Line Assays (Biological Activity)
The biological activity of the compounds of the invention can be assessed using a RET assay as described further below. The selectivity of the compounds of the invention can be assessed using the RET assay in combination with a KDR assay, as described below, and comparing the relative inhibition of each kinase. RET Assay
[00773] RET Protein Kinase In vitro assays were conducted in a reaction volume of 10ul in a standard 384 well format. Human RET catalytic domain (supplied by Carna Biosciences: 08-159) was used at a final reaction concentration of 6.5pM with 1 μΜ TK biotinylated substrate (supplied by CisBio: 61 TK0BLC) and 9μΜ ATP in assay buffer (50mM Hepes pH7.0, 0.2% NaN3, 0.01 % BSA, 0.1 mM Orthovanadate, 10nM Supplementary Enzyme Buffer (CisBio: 61 SEBALB), 1 mM DTT, 5mM MgCI2 and 0.01 % Triton X100). The reaction was incubated at room temperature for 20minutes and then stopped with 10ul of Europium Cryptate Antibody at a 1 X concentration from a 200X stock (CisBio : supplied with the KinEASE-TK kit, part number 62TK0PEB) and 128nM SA-XL665 (CisBio: 610SAXLG) made up in 1X HTRF Detection Buffer (CisBio: 62SDBRDF). Following incubation for a further 60minutes at room temperature in the dark, TR-FRET signal was measured at Ex 540 and Em 665 and Em 620. A ratio is calculated as Em665/EM620x104 for each well.
KDR Assay
[00774] KDR Protein Kinase In vitro assays were conducted in a reaction volume of 10ul in a standard 384 well format. Human KDR catalytic domain (supplied by Carna Biosciences: 08-191 ) was used at a final reaction concentration of 50pM with 0.5uM TK biotinylated substrate (supplied by CisBio: 61 TK0BLC) and 8uM ATP in assay buffer (50mM Hepes pH7.0, 0.2% NaN3, 0.01 % BSA, 0.1 mM Orthovanadate, 10nM Supplementary Enzyme Buffer (CisBio: 61 SEBALB), 1 mM DTT, 5mM MgCI2, 2mM MnCI2 and 0.01 % Triton X100). The reaction was incubated at room temperature for 20minutes and then stopped with 10ul of Europium Cryptate Antibody at a 1 X concentration from a 200X stock (CisBio : supplied with the KinEASE-TK kit, part number 62TK0PEB) and 128nM SA-XL665 (CisBio: 610SAXLG) made up in 1 X HTRF Detection Buffer (CisBio: 62SDBRDF). Following incubation for a further 60minutes at room temperature in the dark, TR-FRET signal was measured at Ex 540 and Em 665 and Em 620. A ratio is calculated as Em665/EM620x104 for each well.
RET and KDR Cell Line assays
[00775] This method is based on the detection of endogenous levels of tyrosine- phosphorylated RET protein and total VEGFR-2/phospho VEGFR-2 (Tyr1 175) protein in the MZ-CRC-1 cell line, using a solid phase sandwich enzyme-linked immunosorbent assay (ELISA).
[00776] Briefly, following compound treatment and VEGF stimulation, cell lysates were incubated with pre-coated microwells specific for the protein of interest, capturing both nonphosphorylated and phosphorylated forms of the protein. Following extensive washing, detection antibody (anti-phosphotyrosine; pRET or anti-phosphoKDR: pKDR) was added, followed by a HRP-linked secondary antibody which recognises the bound detection antibody. The HRP substrate, TMB, was added to develop the colour. The magnitude of optical density for this developed colour is proportional to the quantity of endogenous phospho protein present.
• MZ-CRC-1 cells, seeded in 96-well plates, at 100k/well in 100μΙ_ advanced DMEM/F12 media, supplemented with 5% FBS and 2mM Glutamax, were incubated overnight at 37°C, 5% C02.
• The following day, media was replaced with 10Oul/well of serum-free advanced
DMEM/F12, supplemented with 2mM Glutamax and cells were incubated overnight at 37°C, 5% C02.
• Cells were dosed in quadruplicate with compound and incubated for 2h at 37 °C, 5%
C02.
• At the end of the 2h dosing period, VEGF was added to a final concentration of
50ng/ml_, for 5mins. Following a PBS wash, 30μΙ_ cell lysis (CST lysis buffer was added to each well and the plates incubated at 4°C for 1 h.
• Cell lysates were pooled according to dose and levels of phospho-RET and phospho- KDR measured, according to the manufacturer's instructions, using CST PathScan ELISA kits (#7034 and #7335 respectively).
Results
RET IC50 KDR IC50
RET IC50 CELL KDR IC50 CELL
Example GEOM MEAN GEOM MEAN Selectivity
(μΜ) (μΜ) (μΜ) (μΜ)
1 0.0136 0.6563 48 1 .605 2.892
2 0.0212 2.015 95 3.097 3.238
3 0.2242 44.95 200 10 10
4 0.1998 4.865 24
5 0.012 0.3856 32 0.6371 2.384
6 0.0436 5.684 130 1 .99 10
7 0.002 0.2286 1 14 1 .753 10
8 0.1806 1 1 .97 66 5.773 10
9 1 .393 30 22
10 0.0098 2.064 21 1 1 .594 5.773
1 1 0.2863 10.67 37 10 10
12 0.0145 3.314 229 1 .799 10
13 0.0834 6.733 81 3.333 10
14 0.1856 6.816 37 10 10
15 2.002 30 15
16 0.0036 0.2065 57 0.31 14 0.6814 0.1697 6.34 37 10 10
0.0011 0.4086 371 0.2134 1.91
0.0464 13.43 289 3.333 10
0.009 1.205 134 1.208 3.333
0.1166 30 257 3.333 10
0.0017 0.0689 41 0.1207 0.5805
0.0048 0.2303 48 0.5243 2.493
0.0142 1.8 127 0.7345 10
0.0381 5.674 149 1.596 10
0.0301 3.204 106 1.896 10
0.0774 5.172 67 3.333 10
1.147 11.57 10
0.4476 13.35 30
0.0092 1.795 195 0.8877 10
0.0002 0.0204 102 0.0822 0.1861
0.0351 4.326 123 1.011 10
0.0359 3.319 92 3.196 10
0.0013 0.1224 94 0.4322 1.141
0.0039 1.061 272 0.5009 10
0.024 6.437 268 3.333 10
0.0117 7.474 639 1.52 10
0.0054 1.172 217 0.6395 10
0.0568 10.38 183 5.773 10
0.0006 0.0809 135 0.1785 0.4956
0.0458 8.618 188 3.333 10
0.0285 4.106 144 7.598 7.598
0.0382 11.59 303 2.424 10
0.2907 30 103
0.013 4.857 374
0.0238 4.473 188 2.12 10
0.0007 0.0747 107 0.2413 0.4514
0.4045 18.72 46
0.1148 14.41 126 10 10
0.0075 2.688 358 3.333 7.598
0.0436 11.93 274 7.598 10
0.0825 2.01 24 0.8574 1.508
0.2139 4.38 20
0.0647 1.173 18 3.333 3.333
0.4932 4.47 9
0.0646 0.4869 8
0.086 0.535 6
0.1744 1.332 8
0.409 17.27 42
0.007 0.0314 4 0.3807 0.3968
0.1097 0.6766 6
0.0235 4.091 Most preferred 1.022 2.734
0.0049 1.161 Most preferred 2.406 >10
0.0146 6.892 Most preferred 1.054 5.575
0.0211 5.891 Most preferred >10 >10 0.01 14 3.31 Most preferred 0.5741 >10
0.0631 1 1 .84 Most preferred 3.823 5.809
0.0185 7.674 Most preferred 1 .013 >10
0.0084 3.691 Most preferred
0.0397 16.97 Most preferred
0.0127 7.516 Most preferred
0.0133 3.348 Most preferred >10 >10
0.4226 30 Acceptable
0.3665 40.6 Most preferred 5.773 >10
0.0323 9.598 Most preferred
0.058 15.07 Most preferred 0.2756 0.1927
0.0899 30.07 Most preferred
0.0855
0.084 15.64 Most preferred
0.0888 17.08 Most preferred
0.0876 24.26 Most preferred
0.809 38.14 Preferred
0.079 55.74 Most preferred >10 >10
0.16 41 .68 Most preferred
0.5052
0.9576 69.57 Preferred
0.0893 44.27 Most preferred
0.0549 >150 Most preferred
0.0522 32.26 Most preferred >10 >10
0.0574 24.75 Most preferred >10 >10
0.239 64.57 Most preferred >10 >10
0.3464 69.94 Most preferred >10 >10
0.0772 29.21 Most preferred
0.0678 20.69 Most preferred
0.0998 32.36 Most preferred
0.1419 96.26 Most preferred
0.0419 23.87 Most preferred
0.3705 57.49 Most preferred
0.2997 82.85 Most preferred
0.0925 >150 Most preferred >10 >10
0.5127 >150 Most preferred
0.6954 >150 Most preferred
0.1763 43.9 Most preferred
0.1507 73.87 Most preferred
0.1273 1 1 .39 Preferred
0.0995 28.42 Most preferred
0.1352
0.0985 25.04 Most preferred
0.2797 37.56 Most preferred
0.0839 21 .57 Most preferred
0.0744 23.67 Most preferred
0.121 30.48 Most preferred
0.0866 24.44 Most preferred
0.1222 18.22 Most preferred 0.1369 22.04 Most preferred
0.1249 25.38 Most preferred
0.0237 6.41 1 Most preferred >5.773 >10
0.0451 17.19 Most preferred
0.1285 14.63 Most preferred
0.1243 12.44 Most preferred
0.0285 9.888 Most preferred 1 .873
0.0591 15.75 Most preferred
0.1 149 20.09 Most preferred
0.1001 18.36 Most preferred
0.0235 10.94 Most preferred >10 >10
0.0982 14.22 Most preferred
0.0515 1 1 .98 Most preferred
0.0259 19.07 Most preferred >10 >10
0.0995 24.86 Most preferred
0.1223 26.44 Most preferred
0.065 17.61 Most preferred >5.773 >10
0.0082 9.155 Most preferred >5.773 >10
0.0194 6.597 Most preferred >10 >10
0.0139 9.038 Most preferred >10 >10
0.0499 29.19 Most preferred
0.0424 16.83 Most preferred
0.3457 27.52 Most preferred
0.0893 27.61 Most preferred
0.1423 44.39 Most preferred
0.0502 17.24 Most preferred
0.0953 28.88 Most preferred
0.1 166 35.57 Most preferred
0.171 50.51 Most preferred
0.0757 29.59 Most preferred
0.0786 22.24 Most preferred
0.0388 18.79 Most preferred >10 >10
0.0362 1 1 .61 Most preferred
0.1468 >30 Most preferred
0.0349 1 1 .09 Most preferred >3.333 2.796
0.0401 18.38 Most preferred >10 >10
0.0167 15.32 Most preferred >10 >10
0.0477 6.887 Most preferred
0.023 7.365 Most preferred 2.163 >10
0.007 6.29 Most preferred 2.134 >10
0.0071 6.085 Most preferred 3.288 >10
0.0055 2.441 Most preferred >10 >10
0.0122 >3 Most preferred >3.33 >10
0.0081 5.768 Most preferred >10 >10
0.0063 >3 Most preferred >10 >10
0.013 5.94 Most preferred >7.598 >10
0.0088 5.404 Most preferred 2.69 >10
0.0036 7.161 Most preferred >10 >10
0.0165 5.8 Most preferred 3.005 >10 165 0.0139 5.7 Most preferred 3.293 >10
166 0.0077 >3 Most preferred 8.185 >10
167 0.021 1 7.303 Most preferred 2.315 >10
168 0.0225 5.821 Most preferred 1.341 >5.773
169 0.0217 9.043 Most preferred >5.773 >10
170 0.0131 5.744 Most preferred 1.569 >10
171 0.018 4.432 Most preferred 3.074 >10
172 0.0105 17.21 Most preferred 2.279 >10
173 0.009 6.1 16 Most preferred 1.857 >10
174 0.0161 5.376 Most preferred >3.333 >10
175 0.0298 3.195 Most preferred
176 0.108 18.35 Most preferred 0.6209 >10
177 0.0092 3.207 Most preferred >3.333 >10
178 0.0051 3.926 Most preferred >5.773 >10
179 0.0504 9.328 Most preferred
180 0.005 3.173 Most preferred >5.773 >10
181 0.5583 15.05 Preferred
182 0.2256 47.58 Most preferred
183 0.0427 1 1 .22 Most preferred >10 >10
184 0.0444 23.31 Most preferred >10 >10
185 0.0858 24.36 Most preferred
186 0.0761 13.2 Most preferred
187 0.0215 4.668 Most preferred >10 >10
188 0.0246 2.542 Most preferred >5.773 >10
189 0.0423 5.033 Most preferred >10 >10
190 0.0493 9.361 Most preferred
191 0.0782 18.61 Most preferred
192 0.075 1 1 .45 Most preferred
193 0.0422 9.028 Most preferred >3.333 >10
194 0.0223 8.408 Most preferred >10 >10
195 0.0273 8.827 Most preferred >10 >10
196
197 0.0405 14.54 Most preferred >10 >10
198 0.037 14.26 Most preferred >10 >10
199
200 0.0459 8.909 Most preferred
201
202 0.0457 10.22 Most preferred >10 >10
203 0.0646 1 1 .57 Most preferred
204 0.0514 7.627 Most preferred
205 0.0634 16.21 Most preferred
206 0.0587 16.87 Most preferred
207 0.0694 18.03 Most preferred
208 0.0988 20.6 Most preferred
209 0.1003 19.74 Most preferred
210 0.0691 22.08 Most preferred
21 1 0.092 13.63 Most preferred
212 0.356 13.61 Most preferred
213 2.308
Figure imgf000160_0001
Acceptable is > 5; Preferred is > 10; Most preferred is > 100.
References
[1] Carlomagno, F., Guida, T., Anagantil, S., Vecchio, G., Fusco, A., Ryan, A., Billaud, M., Santoro, M. (2004). Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23, 6056-6063
[2] Chao, B., Briesewitz, R., Villalona-Calero, M. (2012) RET fusion genes in Non-Small- Cell Lung Cancer. JCO 30, 4439-4441 .
[3] Diner, P., Alao, J., Soderland, J., Sunnerhagen, P. Grotli, M. (2012) J Med Chem 2012 55 (10) 4872-6
[4] Elisei, R., Cosci, B., Romei, C, Bottici, V., Renzini, G., Molinaro, E., Agate, L, Vivaldi, A., Faviana, P., Basolo, F., Miccoli, P., Berti, P., Pacini, F., Pinchera, A. (2008) RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. Journal of Clinical Endocrinology and Metabolism 93, 682-687.
[5] Ju, Y., Lee, W., Shin, J., Lee, S., Bleazard, T., Won, J., Kim, Y., Kim, J., Kang, J., Seo, J. (201 1 ). A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 3, 436-445.
[6] Kohno, T., Ichikawa, H., Totoki, Y., Yasuda, K., Hiramoto, M., Nammo, T., Sakamoto, H., Tsuta, K., Furuta, K., Shimada, Y., Iwakawa, R., Ogiwara, H., Oike, T., Enari, M., Schetter, A., Okayama, H., Haugen, A., Skaug, V. Chiku, S., Yamanaka, I., Arai, Y., Watanabe, S., Sekine, I., Ogawa, S., Harris, C, Tsuda, H., Yoshida, T., Yokota, J., Shibata, T. (2012) KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 12, 375-377.
[7] Lipson, D., Capelletti, M., Yelensky, R., Otto, G., Parker, A., Jaroszi, M., Curran, J., Balasubramanian, S., Bloom, T., Brennan, K., Donahue, A., Downing, S., Frampton, G., Garcia,
L., Juhn, F., Mitchell, K., White, E., White, J., Zwirko, Z., Peretz, T., Nechushtan, H., Soussan-
Gutman, L., Kim, J., Sasaki, H., Kim, H., Park, S., Ercan, D., Sheehan, C, Ross, J. Cronin, M.,
Janne, P., Stephens, P. (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 12, 382-384.
[8] Matsubara, D., Kanai, Y., Ishikawa, S., Ohara, S., Yoshimoto, T., Sakatani, T., Oguni,
S., Tamura, T., Kataoka, H., Endo, S., Murakami, Y., Aburatani, H., Fukayama, M., Niki, T.
(2012). Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-
2/ad. J Thorac Oncol. 12, 1872-6.
[9] Nagilla, M., Brown, R., Cohen, E. (2012). Cabozantinib for the treatment of Advanced Medullary Thyroid Cancer. Adv Ther 1 1 , 925-934.
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Claims

Figure imgf000162_0001
Formula I
wherein:
X is NH, NRx, O or S, wherein Rx 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 cycloalkyi group is optionally substituted with one or more fluoro;
R2 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;
R3 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;
R4 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;
R5 is selected from hydrogen or a group defined by the formula:
Figure imgf000162_0002
wherein
L5 is absent or a linear or branched (1 -4C)alkylene;
X5 is absent or -C(0)0-, -0-, -C(O)-, -OC(O)-, -CH(OR5L)-, -N(Rj)-, -N(R5L)-C(0)-, -N(R5L)-C(0)0-, -C(0)-N(R5L)-, -S-, -SO-, -SO2-, -S(0)2N(R5L)-, or -N(R5L)S02- wherein R5i_ is selected from hydrogen or methyl; and Q5 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;
R6 is selected from hydrogen, or a group defined by the formula:
-O-Le-Xe-Qe
wherein
L6 is absent or a linear or branched (1 -4C)alkylene;
X6 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6L)-, -N(R6L), -N(R6L)-C(0)-, -N(R6L)-C(0)0-, -C(0)-N(R6L)-, -S-, -SO-, -S02-, -S(0)2N(R6L)-, or -N(R6L)S02- wherein R6L is selected from hydrogen or (1 -3C)alkyl;
Q6 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,
or Q6 and RL6 are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein R6 is optionally substituted (e.g. substituted on L6 and/or Q6) with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR6x, SR6x, S(0)R6X, S(0)2R6x, C(0)OR6x or C(0)NR6xR'6x, wherein R6x and R'6x are independently hydrogen, (1 -8C)alkyl, or R6x and R'6x are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
R7 is selected from hydrogen, (1 -6C)alkoxy, or a group defined by the formula:
Figure imgf000163_0001
wherein
L7 is absent or a linear or branched (1 -4C)alkylene;
X7 is absent or selected from -0-, -C(0)-, -C(0)0-, -0C(0)-, -CH(OR6L)-, -N(R7L)-, -N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -S02-, -S(0)2N(R7L)-, or -N(R7L)S02- wherein R7i_ is selected from hydrogen or (1 -3C)alkyl;
Q7 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,
or Q7 and R7i_ are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein R7 is optionally substituted (e.g. substituted on L7 and/or Q7) with one or more halo, hydroxyl, nitro, cyano, (1 -8C)alkyl, (1 -8C)alkanoyl, OR7x, SR7x, S(0)R7X, S(0)2R7X, C(0)OR7x or C(0)NR7XR'7x, wherein R7X and RVx are independently hydrogen, (1 -8C)alkyl, or R7x and RVx are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; or
R7 is optionally substituted with one or more groups selected from oxo, (1 - 4C)haloalkyl, (1 -4C)hydroxyalkyl, C(0)R7y or NR7yR'7y, wherein R7y and R'7y are independently hydrogen or (1 -8C)alkyl;
or a pharmaceutically acceptable salt and/or solvate thereof.
2. A compound according to claim 1 , wherein the compounds have the structural formula la shown below:
Figure imgf000164_0001
Formula la
wherein Ri , R2, R3, R4, Re and R7 are each as defined in claim 1 ;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
3. A compound according to claim 1 or claim 2, wherein the compounds have the structural formula Id shown below:
Figure imgf000164_0002
Formula Id
wherein Ri , R2, R3, R4, and R7 are each as defiend in claim 1 ;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
4. A compound according to any one of the preceding claims, wherein said compound not 6-chloro-2-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol, or pharmaceutically acceptable salt and/or solvate thereof.
5. A compound according to claim 1 , wherein X is NH, NRX or O, wherein Rx is methyl.
6. A compound according to claim 1 , wherein X is NH.
7. A compound according to any one of the preceding claims, wherein Ri is selected from halo, trifluoromethyl, (1 -2C)alkyl, (1 -2C)alkoxy or (3-6C)cycloalkyl, wherein an alkyl or cycloalkyi group is optionally substituted with one or more fluoro.
8. A compound according to claim 7, wherein Ri is selected from fluoro, chloro, bromo, methyl, ethyl or methoxy.
9. A compound according to any one of the preceding claims, wherein R2 is selected from hydrogen, fluoro, chloro, bromo, 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.
10. A compound according to claim 9, wherein R2 is selected from hydrogen, fluoro, chloro, bromo, or (1 -2C)alkyl.
1 1 . A compound according to any one of the preceding claims, wherein R3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, cyano, trifluoromethyl, (1 -2C)alkyl or (1 -2C)alkoxy, wherein an alkyl or alkoxy group is optionally substituted with one or more fluoro.
12. A compound according to claim 1 1 , wherein R3 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, or (1 -2C)alkyl.
13. A compound according to any one of the preceding claims, wherein R4 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.
14. A compound according to claim 13, wherein R4 is selected from hydrogen, fluoro, chloro, (1 -2C)alkyl or (1 -2C)alkoxy.
15. A compound according to any one of clams 1 and 4 to 14, wherein R5 is selected from hydrogen or a group defined by the formula:
-O-L5-X5-Q5; wherein
L5 is absent;
X5 is absent; and
Q5 is (1 -6C)alkyl or (3-6C)cycloalkyl.
16. A compound according to claim 15, wherein R5 is hydrogen.
17. A compound according to any one of claims 1 , 2, or 4 to 16, wherein R6 is selected from hydrogen, or a group defined by the formula:
-O-Le-Xe-Qe
wherein
L6 is absent or a linear or branched (1 -4C)alkylene;
X6 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6L)-, -N(R6l_), - N(R6L)-C(0)-, -N(R6L)-C(0)0-, -C(0)-N(R6L)-, -S-, -SO-, -S02-, -S(0)2N(R6L)-, or - N(R6L)S02- wherein R6L is selected from hydrogen or (1 -3C)alkyl;
Q6 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 - 6C)alkyl, 4, 5 or 6-membered heterocyclyl, or 4, 5 or 6-membered heterocyclyl-(1 - 6C)alkyl,
or Q6 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 R6 is optionally substituted (e.g. substituted on L6 and/or Q6) with one or more (1 -6C)alkyl, (1 -6C)alkanoyl, OR6x, SR6X, S(0)R6x, S(0)2R6x, C(0)OR6X or C(0)NR6xR'6x, wherein R6x and R'6x are independently hydrogen, (1 -8C)alkyl, or R6x and R'6x are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring.
18. A compound according to claim 17, wherein R6 is selected from hydrogen or methoxy.
19. A compound according to any one of the preceding claims, wherein R7 is selected from hydrogen, (1 -6C)alkoxy, or a group defined by the formula:
Figure imgf000166_0001
wherein
L7 is absent or a linear or branched (1 -4C)alkylene;
X7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6i_)-, -N(R7L)-, -
N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -S02-, -S(0)2N(R7L)-, or - N(R7L)S02- wherein R7L is selected from hydrogen or (1 -2C)alkyl; Q7 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 Q7 and R7i_ are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring;
wherein R7 is optionally substituted (e.g. substituted on L7 and/or Q7) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR7x, SR7x, S(0)R7x, S(0)2R7x, C(0)OR7x or C(0)NR7XR'7x, wherein R7X and R'7x are independently hydrogen, (1 -4C)alkyl, or R7X and R'7x are linked such that, together with the nitrogen atom to which they are attached, they form a heterocyclic ring; or
R7 is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, (1 -4C)hydroxyalkyl, C(0)R7y or NR7yR'7y, wherein R7y and R'7y are independently hydrogen or (1 -8C)alkyl;
20. A compound according to any one of the preceding claims, wherein R7 is selected from hydrogen, ( 1 -4C)alkoxy, or a group defined by the formula:
-0-L7-X7-Q7
wherein
L7 is absent or a linear or branched (1 -4C)alkylene;
X7 is absent or selected from -0-, -C(O)-, -C(0)0-, -OC(O)-, -CH(OR6i_)-, -N(R7L)-, - N(R7L)-C(0)-, -N(R7L)-C(0)0-, -C(0)-N(R7L)-, -S-, -SO-, -S02-, -S(0)2N(R7L)-, or - N(R7L)S02- wherein R7L is selected from hydrogen or ( 1 -2C)alkyl;
Q7 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 Q7 and R7L 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 R7 is optionally substituted (e.g. substituted on L7 and/or Q7) with one or more halo, hydroxyl, nitro, cyano, (1 -4C)alkyl, (1 -4C)alkanoyl , OR7x, SR7x, S(0)R7x, S(0)2R7x, C(0)OR7x or C(0)NR7XR'7x, wherein R7X and R'7x are independently hydrogen, (1 -4C)alkyl; or
R7 is optionally substituted with one or more groups selected from oxo, (1 -4C)haloalkyl, ( 1 -4C)hydroxyalkyl, C(0) R7Y or NR7YR'7Y, wherein R7Y and R'7Y are independently hydrogen or ( 1 -8C)alkyl;
21 . A compound which is selected from any one of the following:
3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2-methylphenol; 3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,4,6-trimethylphenol;
2-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenol ;
2- Bromo-3-((6,7-dimetrioxyquinazolin-4-yl)oxy)prienol;
3- ((6,7-Dimethoxyquinazolin-4-yl)oxy)-2-ethylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,5-dimethylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)oxy)-2,6-difluorophenol;
3-((6,7-dimethoxyquinazolin-4-yl)oxy)-2,4-difluorophenol;
2-Chloro-3-[(5-isopropoxyquinazolin-4-yl)amino]phenol;
2-Chloro-3-((5-cyclobutoxyquinazolin-4-yl)amino)phenol;
2-Criloro-3-[(6,7-dimetrioxyquinazolin-4-yl)amino]-6-metriyl-phenol hydrochloride;
2- Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)phenol;
3- [(6,7-Dimethoxyquinazolin-4-yl)amino]-2-methyl-phenol hydrochloride;
3-((6,7-dimethoxyquinazolin-4-yl)amino)-2,6-dimethylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2-fluorophenol;
3-[(6,7-Dimethoxyquinazolin-4-yl)amino]-4-fluoro-2-methyl-phenol hydrochloride;
3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2,6-difluorophenol hydrochloride;
3- [[7-(2-Hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]-2-methyl-phenol;
Methyl 2-((4-((3-hydroxy-2-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propanoate;
2- Chloro-3-[[7-(2-hydroxyethoxy)-6-methoxy-quinazolin-4-yl]amino]phenol;
Methyl 2-((4-((2-chloro-3-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propanoate;
4- Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
Methyl 2-((4-((2-chloro-3-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)acetate hydrochloride;
3- ((6,7-Bis(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
3-((7-methoxy-6-((1 -morpholinopropan-2-yl)oxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
4- fluoro-3-((7-Methoxy-6-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-4-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2- ((4-((2-Chloro-3-hydroxyphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetamide;
N-(2-((4-((2-Chloro-3-hydroxyphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide hydrochloride;
4-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-2-methylphenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2,4-difluorophenol;
4- Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-2-fluorophenol;
2-Chloro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)phenol hydrochloride; 4-Fluoro-3-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-3-((6-methoxy-7-(2-(methylthio)ethoxy)quinazolin-4-yl)amino)phenol; 2- Chloro-3-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)amino)phenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2-metrioxyprienol;
2-Methoxy-3-((6-metrioxy-7-(2-metrioxyetrioxy)quinazolin-4-yl)amino)prienol hydrochloride; 2-Chloro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2,4-Difluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
4- Chloro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-Chloro-3-((6-methoxy-7-((3-methyloxetan-3-yl)methoxy)quinazolin-4-yl)amino)phenol;
4-Chloro-2-fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenol;
2-Chloro-3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-fluorophenol;
N-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide;
4-Fluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2- Chloro-3-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)phenol;
N-(2-((4-((6-Chloro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)-N- methylmethanesulfonamide;
2,4-Difluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)phenol;
3- ((6,7-Dimethoxyquinazolin-4-yl)amino)-2,6-difluorophenol;
4- Fluoro-3-((6-methoxy-7-((3-methyloxetan-3-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
1 -(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)pyrrolidin-2-one;
3-((7-(Cyclopropylmethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
3-((6,7-Dimethoxyquinazolin-4-yl)amino)-2,4-dimethylphenol;
3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol hydrochloride; 4-Fluoro-3-((6-methoxy-7-((5-methyl-1 ,2,4-oxadiazol-3-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
2,4-Difluoro-3-((6-methoxy-7-((5-methyl-1 ,2,4-oxadiazol-3-yl)methoxy)quinazolin-4- yl)amino)phenol;
2- chloro-4-fluoro-3-((6-methoxy-7-((5-methylfuran-2-yl)methoxy)quinazolin-4-yl)amino)phenol; 4-Fluoro-3-((6-methoxy-7-((1 -methyl-1 H-imidazol-5-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-(1 H-lmidazol-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(4-methylpiperazin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
2-Bromo-3-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol hydrochloride;
2-Bromo-3-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol hydrochloride;
5- Fluoro-3-((6-methoxy-7-(pyridin-3-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol; 3-((6,7- Dimethoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
5-Fluoro-3-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((7-(2-Chloroethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
Ethyl 2-((4-((5 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetate; 3-((7-(2,2-Dimethoxyethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol;
5-Fluoro-3-((6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol;
2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetic acid;
2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-1 - morpholinoethanone;
2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetaldehyde; 1 -(2-((4-((5-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)piperidin-4-ol;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetamide;
2((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-N-methyl acetamide;
A/ithyl-2((4-((6 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy) acetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/- isopropylacetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/- propylacetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/,A/- dimethylacetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-isopropyl-N- methylacetamide;
Λ/-(fer Butyl)-2-((4-((6 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)- A/-methylacetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-methyl-A/- propylacetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/,A/- dipropylacetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/- isobutylacetamide; A/-Butyl2-((4-((6 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)- acetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-(2- hydroxyethyl)acetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-(2- methoxyethyl)acetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-(2- hydroxyethyl)-A/-methylacetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-(2- methoxyethyl)-A/-methylacetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-(3- methoxypropyl)acetamide;
A/-Cyclobutyl-2-((4-((6 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetamide;
A/-Cyclopenyl-2-((4-((6 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetamide;
A/-Cyclohexyl-2-((4-((6 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)acetamide;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-A/-(tetrahydro- 2 - -pyran-4-yl)acetamide;
[00777] 2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)-1 -(pyrrolidin-1 -yl)ethanone;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-1 -(piperidin-1 ^ yl)ethanone;
1 -(Azepan-1 -yl)-2-((4-((6 luoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethanone;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-1 - morpholinoethanone;
2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-1 -(4- methylpiperazin-1 -yl)ethanone;
1 - (4-Acetylpiperazin-1 -yl)-2-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6- methoxyquinazolin-7-yl)oxy)ethanone;
2- ((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)-1 -(4- methoxylpiperidiin-1 -yl)-ethanone;
4-Fluoro-3-((6-methoxy-7-(2-(methylamino)ethoxy)quinazolin-4-yl)amino)-2-methyl phenol;
3- ((7-(2-(Ethylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((7-(2-(isopropylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2-methyl phenol; 3- ((7-(2-(fert-Butylamino)et oxy)-6-met oxyqm^
4- Fluoro-3-((6-met oxy-7-(2-(propylamino)et oxy)quinazolin-4-yl)amino)-2-met ylphenol; 4-Fluoro-3-((7-(2-(isobutylamino)et oxy)-6-met oxyquinazolin-4-yl)amino)-2-met ylphenol
3- ((7-(2-(Butylamino)et oxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro-2-met yl phenol;
4-Fluoro-3-((7-(2-((2-hydroxyethyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-((2-methoxyethyl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((7-(2-((3-hydroxypropyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-((3-methoxypropyl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)amino)propanenitrile;
3-((7-(2-(Cyclobutylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4 luoro-2-methylphenol; 3-((7-(2-(Cyclopentylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4 luoro-2-methylphenol;
3- ((7-(2-(Cyclohexylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4 luoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-((3-methyloxetan-3-yl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-((2-morpholinoethyl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(((tetrahydrofuran-2-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-((tetrahydro-2H-pyran-4-yl)amino)ethoxy)quinazolin-4-yl)amino)-^ methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(((1 -methyl-1 H-imidazol-5-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(((1 -methyl-1 H-imidazol-4-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(((1 -methyl-1 H-pyrazol-4-yl)methyl)amino)ethoxy)quinazolin-4- yl)amino)-2-methylphenol;
3- ((7-(2-(Azetidin-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(pyrrolidin-1 -yl)ethoxy)-quinazolin-4-yl)amino)-2-methylphenol; 4-Fluoro-3-((6-methoxy-7-(2-(piperdin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2-methylphenol; 3-((7-(2-(Azepan-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol; 4-Fluoro-3-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)amino)-2-methylphenol;
1 -(4-(2-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7- yl)oxy)ethyl)piperazin-1 -yl)ethan-1 -one;
4-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)ethyl)thiomorpholine 1 ,1 -dioxide
1 -(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)ethyl)piperidin-4-ol;
4-Fluoro-3-((6-met oxy-7-(2-(4-met oxypiperidin-1 -yl)et oxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((7-(2-(Dimet ylamino)et oxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro-2-met ylphenol; 3-((7-(2-(Diet ylamino)et oxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro-2-met ylphenol; 4-Fluoro-3-((7-(2-(isopropyl(methyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-(ferf-Butyl(methyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(methyl(propyl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((-7-(2-(Dipropylamino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((7-(2-((2-hydroxyethyl)(methyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-((2-methoxyethyl)(methyl)amino)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-(3,4-Dihydroisoquinolin-2(1 H)-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol;
4- Fluoro-3-((7-(2-(2-(hydroxymethyl)piperdin-1 -yl)ethoxy)-6-methoxy-quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((7-(2-(3-fluoropyrrolidin-1 -yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(3-trifluoromethylpyrrolidin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(2-(4-methyl-1 ,4-diazepan-1 -yl)ethoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(2-(1 ,4-Oxazepan-4-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(2-(piperazin-1 -yl)ethoxy)quinazolin-4-yl)amino)-2-methylphenol
3- ((7-(3-Aminopropoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(3-(methylamino)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 3-((7-(3-(Dimethylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
3- ((7-(3-(Ethylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((7-(3-(isopropylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2-methylphenol; 4-Fluoro-3-((6-met oxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)-2-met ylphenol;
1 -(4-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)piperazin-1 -yl)ethan-1 -one;
4-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)thiomorpholine 1 ,1 -dioxide;
1 -(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)piperidin-4-ol;
4-Fluoro-3-((6-methoxy-7-(3-(4-methoxypiperidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((7-(3-(Azetidin-1 -yl)propoxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro 2-methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-(pyrrolidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 4-Fluoro-3-((6-methoxy-7-(3-(piperidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 3-((7-(3-(Azepan-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
3- ((7-(3-(Diet ylamino)propoxy)-6-met oxyquinazolin-4-yl)amino)-4-fluoro-2-met ylphenol; 3-((7-(3-(Dipropylamino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((7-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-((2-methoxyethyl)(methyl)amino)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3-((7-(3-(ferf-Butyl(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-(methyl(propyl)amino)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(3-(3,4-Dihydroisoquinolin-2(1 H)-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2- methylphenol;
4- Fluoro-3-((7-(3(2-(hydroxymethyl)piperidin-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((7-(3-(3-fluoropyrrolidin-1 -yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-(2-(trifluoromethyl)pyrrolidin-1 -yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((7-(3-(isopropyl(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-2- methylphenol;
4-Fluoro-3-((6-methoxy-7-(3-(4-methyl-1 ,4-diazepan-1 -yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
3- ((7-(3-(1 ,4-Oxezepan-4-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol;
4- Fluoro-3-((6-methoxy-7-(3-(piperazin-1 -yl)propoxy)quinazolin-4-yl)amino)-2-methylphenol; 4-Fluoro-3-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yl)amino)-2- methylphenol;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)ethyl)acetamide;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)ethyl)propionamide;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)ethyl)isobutyramide;
2- (Dimet ylamino)-A/-(2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin yl)oxy)ethyl)acetamide;
3- (Dimet ylamino)-A/-(2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin yl)oxy)ethyl)propanamide;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)ethyl)methanesulfonamide;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)et yl)-1- methyl-1 --pyrazole-3-carboxamide;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)et yl)-A/- methylacetamide;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)et yl)-/V- methylcyclopropanecarboxamide;
2- (Dimet ylamino)-A/-(2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin yl)oxy)ethyl)-A/-methylacetamide;
3- (Dimet ylamino)-A/-(2-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin yl)oxy)ethyl)-A/-methylpropanamide;
A/-(2-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7-yl)oxy)et yl)-A/- met ylmet anesulfonamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)acetamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)propionamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)isobutyramide;
2-(Dimet ylamino)-A/-(3-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin yl)oxy)propyl)acetamide;
3-(Dimet ylamino)-A/-(3-((4-((6 luoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin yl)oxy)propyl)propanamide; A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)methanesulfonamide;
A/-(3-((4-((6-Fluoro-3- ydroxy-2-met ylphenyl)amino)-6-met oxyquinazolin-7- yl)oxy)propyl)ethanesulfonamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-1 - methyl- 1 H-pyrazole-3-carboxamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-A/- methylacetamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-/V- methylcyclopropanecarboxamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-/V- methylisobutyramide;
2- (Dimethylamino)-A/-(3-((4-((6-fluoro-3-hydroxy-2-methylph
yl)oxy)propyl)-A/-methylacetamide;
3-(Dimethylamino)-A/-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazoli yl)oxy)propyl)-A/-methylpropanamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-/V- methylmethanesulfonamide;
A/-(3-((4-((6-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-A/- methylethanesulfonamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-A/,1 - dimethyl-1 - -pyrazole-3-carboxamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-A/,3- dimethylisoxazole-5-carboxamide;
A/-(3-((4-((6-Fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)-A/,1 - dimethyl-1 - -imidazole-2-carboxamide;
3- ((6-Methoxy-7-((1 -methylpiperidin-4-yl)methoxy)quinazolin-4-yl)amino)-2-methylphenol^ 2-Chloro-3-((6-methoxy-7-((1 -methylpiperidin-4-yl)methoxy)quinazolin-4-yl)amino)phenol;
2-Chloro-3-((6-methoxy-7-((1 -methylpiperidin-4-yl)methoxy)quinazolin-4-yl)amino)-6- methylphenol;
4- Fluoro-3-((6-methoxy-7-((1 -methylpiperidin-4-yl)methoxy)quinazolin-4-yl)amino)-2- methylphenol;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
22. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in therapy.
23. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 21 , or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier or excipient.
24. A compound according to any one of claims 1 to 21 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 23, for use in the treatment of cancer.
25. A compound or a pharmaceutical composition according to claim 24, wherein said cancer is medullary thyroid cancer or non-small cell lung cancer.
26. A method for the treatment of cancer in a subject in need of such treatment, said method comprising administering a therapeutically effective amount of a compound according to any of claims 1 to 21 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 23.
27. A method according to claim 26, wherein said cancer is medullary thyroid cancer small cell lung cancer.
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