WO2002087587A2 - 4-aminosulfonylquinazolines and -quinolines as tyrosine kinase inhibitors - Google Patents

4-aminosulfonylquinazolines and -quinolines as tyrosine kinase inhibitors Download PDF

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WO2002087587A2
WO2002087587A2 PCT/GB2002/002011 GB0202011W WO02087587A2 WO 2002087587 A2 WO2002087587 A2 WO 2002087587A2 GB 0202011 W GB0202011 W GB 0202011W WO 02087587 A2 WO02087587 A2 WO 02087587A2
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group
optionally substituted
groups
atom
compound according
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WO2002087587A3 (en
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David Festus Charles Moffat
Mark James Batchellor
Daniel Christopher Brookings
Peter David Davis
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Celltech R & D Limited
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Publication of WO2002087587A3 publication Critical patent/WO2002087587A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • 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
    • 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
    • C07D239/93—Sulfur atoms
    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to a series of fused bicyclic amines, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
  • tyrosine kinases may belong to one of two general classes, namely, the transmembrane growth factor receptor tyrosine kinases (EGFr, c-ErbB-2, PDGF, KDR, etc.) [Iwashita S. and Kobayashi M., Cellular Signalling, 4, 123-132 (1992)] and cytoplasmic nonreceptor tyrosine kinases (src, lck, ZAP70 etc.) [Chan C.
  • EGFr transmembrane growth factor receptor tyrosine kinases
  • src, lck, ZAP70 etc. cytoplasmic nonreceptor tyrosine kinases
  • EGFr and c-Erb-2 occur in a significant percentage of breast and non-small cell lung carcinomas in which overexpression correlates with shortened survival times and increased relapse rates.
  • the ability of these receptors to undergo homo- and heterodimerisation leads to an intensification of the transforming signal and contributes to the complexity of the EGFr family signalling network.
  • the disruption of the normal functions of these tyrosine kinases has been implicated in a number of other hyperproliferative disorders such as psoriasis, restenosis, atherosclerosis and fibrosis of the liver and kidney.
  • the present invention relates to a series of fused bicyclic amines that are able to inhibit the activity of Class I receptor tyrosine kinases, thus permitting a new therapeutic approach for disease states such as cancer, psoriasis, restenosis, atherosclerosis and fibrosis.
  • Ar is an optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl or alkyl group
  • R is a hydrogen atom or an optionally substituted alkyl group
  • R 1 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy,-N(alkyl), -N(alkyl)2 or cyano (-CN) group
  • X is a nitrogen atom or a C(R 1 a ) group where R 1 a is as defined for R 1 and may be the same or different;
  • R 4 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, nitro (-NO2), cyano (-CN), -CO2R 5 [where R 5 is a hydrogen atom or an alkyl group], -SO3H, -SOR 5 , S0 2 R 5 , -SO3R 5 , -OCO2R 5 , - CONR 5 R 6 [where R 6 is as just defined for R 5 and may be the same or different], -SR5, -NR5R6, -OC(0)NR5R6, -CSNR5R6, COR5, -OCOR5, -N(R5)COR6, -N(R5)CSR6, -S0 2 N(R5)(R6), -N(R5)S0 2 R 6 , -N(R5)S0 2 R 6 , -N(R5)S0 2 R 6 , -N(R5)S0 2 R 6 , -
  • R 7 is a hydrogen atom or an alkyl group
  • R 7 is a hydrogen atom or an alkyl group
  • n is zero or the integer 1 or 2;
  • R 2 and R 3 which may be the same or different is each an atom or group - L 1 (Alk 1 )tL 2 (R 8 ) u in which L 1 and L 2 which may be the same or different is each a covalent bond or a linker atom or group, t is zero or the integer 1 , u is the integer 1 , 2 or 3, Alk 1 is an aliphatic or heteroaliphatic chain and R 8 is an atom or group as defined for R 4 or an optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, polyheterocyclo- aliphatic, aromatic or heteroaromatic group, provided that:
  • R 2 and R 3 are not both hydrogen atoms or methoxy groups
  • R is a hydrogen atom
  • R 1 is a chlorine atom or methyl or methoxy group
  • one of R 2 and R 3 is a chlorine atom or methyl, methoxy or ethoxy group then the other of R 2 and R 3 is other than a hydrogen atom
  • the salts, solvates, hydrates and N-oxides thereof when Ar is an optionally substituted phenyl group, R is a hydrogen atom, R 1 is a chlorine atom or methyl or methoxy group and one of R 2 and R 3 is a chlorine atom or methyl, methoxy or ethoxy group then the other of R 2 and R 3 is other than a hydrogen atom; and the salts, solvates, hydrates and N-oxides thereof.
  • certain compounds of formula (1) may exist as geometric isomers (E or Z isomers).
  • the compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers.
  • the invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates.
  • Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
  • Formula (1 ) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.
  • the compounds of formula (1) are potent and selective inhibitors of transmembrane growth factor receptor tyrosine kinases (Class 1 receptor tyrosine kinases) such as EGFr.
  • Class 1 receptor tyrosine kinases transmembrane growth factor receptor tyrosine kinases
  • EGFr transmembrane growth factor receptor tyrosine kinases
  • Members of the group are able to inhibit the action of EGFr at concentrations at which they generally have no or minimal action on tyrosine kinases of other subgroups.
  • the compounds are thus of use in medicine, for example in the prophylaxis and treatment of hyperproliferative disorders such as cancer, psoriasis, restenosis, athersclerosis and fibrosis ' as described hereinafter.
  • alkyl whether present as a group or part of a group includes straight or branched C-
  • alkenyl or “alkynyl” are intended to mean straight or branched C 2 .-
  • Optional substituents that may be present include those optional substituents mentioned hereinafter in relation to optionally substituted aliphatic groups.
  • halogen atom is intended to include fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF3, -CCI3, -CHF 2 , -CHCI 2 , - CH 2 F, and -CH 2 CI groups.
  • alkoxy as used herein is intended to include straight or branched C ⁇ - ⁇ oalkoxy for example C-i- ⁇ alkoxy such as methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy.
  • "Haloalkoxy” as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include -OCF3, -OCCI3, - OCHF 2) -OCHCI 2 , -OCH 2 F and -OCH 2 CI groups.
  • alkylthio is intended to include straight or branched C-
  • Aryl groups represented by the group Ar in compounds of formula (1 ) include for example mono- or bicyclic-C6- ⁇ 2 optionally substituted aromatic groups, for example optionally substituted phenyl, 1- or 2-naphthyl, or indenyl groups.
  • Heteroaryl groups represented by Ar include for example C1-9 optionally substituted heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • the heteroaromatic groups may be for example monocyclic or bicyclic heteroaromatic groups.
  • Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Bicyclic heteroaromatic groups include for example nine- to thirteen-membered heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • aryl or heteroaryl groups represented by Ar may be attached to the remainder of the compound of formula (1) through any available ring carbon or heteroatom as appropriate.
  • Aralkyl or heteroaralkyl groups represented by the group Ar in compounds of formula (1) include optionally substituted arylC-i- ⁇ alkyl and heteroarylC ⁇ -6alkyl groups in which the aryl, heteroaryl and C ⁇ -6alkyl groups and the optional substitution are as defined above.
  • heteroaromatic groups represented by Ar include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethyl-imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1 ,3,5-triazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, benzofuryl, isobenzofuryl,
  • Optional substituents which may be present on the aromatic or heteroaromatic groups represented by the group Ar include one, two, three or more substituents, each selected from an atom or group R 10 in which R 10 is -R 1 1 or -Alk 2 (R 1 1 ) m , where R 1 1 is a halogen atom, or an amino (-NH ), substituted amino, nitro, cyano, amidino, hydroxyl (-OH), substituted hydroxyl, formyl, carboxyl (-C0 2 H), esterified carboxyl, thiol (-SH), substituted thiol, -COR 12 [where R 12 is an -Alk 2 (R 1 1 ) m> aryl or heteroaryl group], -CSR 12 , -S0 3 H, -SOR 12 , -S0 2 R 12 , -SO3R 12 , -S0 2 NH 2 , -S0 2 NHR 12 S0 2 N(R
  • R 9 or R 12 groups may be the same or different.
  • m is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R 1 1 may be present on any suitable carbon atom in -Alk 2 . Where more than one R 11 substituent is present these may be the same or different and may be present on the same or different atom in -Alk 2 . Clearly, when m is zero and no substituent R 1 1 is present the alkylene, alkenylene or alkynylene chain represented by Alk 2 becomes an alkyl, alkenyl or alkynyl group.
  • R 11 is a substituted amino group it may be for example a group - NHR 12 [where R 12 is as defined above] or a group -N(R 12 ) 2 wherein each
  • R 12 group is the same or different.
  • Esterified carboxyl groups represented by the group R 11 include groups of formula -C0 2 Alk 3 wherein Alk 3 is a straight or branched, optionally substituted C-i-salkyl group such as a methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl or t-butyl group; a C6- ⁇ 2 arylC-
  • Alk 2 When Alk 2 is present in or as a substituent R 10 it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s- butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3- butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or - S(0>, -S(0) 2 - or -N(R 13 )- groups.
  • Cycloaliphatic or heterocycloaliphatic groups represented by the groups R 11 include those optionally substituted C3- ⁇ ocycloaliphatic or C3- ⁇ rjhetero- cycloaliphatic groups described hereinafter for R 8 .
  • Aryl or heteroaryl groups represented by the groups R 1 1 or R 12 include mono- or bicyclic optionally substituted C ⁇ -1 2 aromatic or C1-9 heteroaromatic groups as described above for the group Ar.
  • the aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1 ) by any carbon or hetero e.g. nitrogen atom as appropriate.
  • each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group.
  • Het 2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group.
  • Optional substituents which may be present on -NHet 1 or -Het 2 include those substituents described below in relation to R 8 heterocycloaliphatic groups.
  • Particularly useful atoms or groups represented by R 10 include fluorine, chlorine, bromine or iodine atoms, or Ci- ⁇ alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, dioxolanyl, dioxanyl, piperidinyl, oxazolidinyl, thiazolidinyl or imidazolidinyl, C-
  • -6alkyl e.g. carboxyethyl, C ⁇ -6alkylthio e.g. methylthio or ethylthio, carboxyC-i- ⁇ alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C-
  • 2-hydroxyethoxy optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C4-7cycloalkyl, e.g. cyclobutyl, cyclopentyl, Cs ⁇ cycloalkoxy, e.g. cyclopentyloxy, haloCi- ⁇ alkyl, e.g. trifluoromethyl, haloC ⁇ -6alkoxy, e.g. trifluoromethoxy, C ⁇ -6alkylamino, e.g.
  • methylamino, ethylamino or propylamino amino (-NH 2 ), aminoC-i- ⁇ alkyl, e.g. aminomethyl or aminoethyl, C-
  • ethylaminoethyl C ⁇ -6dialkyl-aminoC-
  • methylamino- carbonyl ethylaminocarbonyl or propylaminocarbonyl
  • Ci- ⁇ dialkylamino- carbonyl e.g. dimethylaminocarbonyl or diethylaminocarbonyl
  • aminoCi- ⁇ alkylaminocarbonyl e.g. aminoethylaminocarbonyl, C ⁇ -6alkyl-aminoC-
  • ⁇ alkylaminocarbonyl e.g. methylaminoethylaminocarbonyl, C-
  • diethylaminoethylaminocarbonyl aminocarbonylamino, C-
  • . ⁇ dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, Ci -6alkylaminothiocarbonylC ⁇ -6alkylamino, e.g. ethylaminothiocarbonylmethylamino, -CONHC( NH)NH 2 , C-
  • C ⁇ -6alkylaminosulphonylamino e.g. methylaminosulphonyl- amino or ethylaminosulphonylamino
  • C ⁇ -6dialkylaminosulphonylamino e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino
  • optionally substituted morpholinesulphonylamino or morpholinesulphonylC ⁇ -6alkyl- amino optionally substituted phenylaminosulphonylamino, C-
  • aminoacetylamino C ⁇ -6dialkylaminoC ⁇ -6alkanoylamino, e.g. dimethylaminoacetylamino, C-
  • two R 10 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C-i- ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy.
  • a cyclic group such as a cyclic ether, e.g. a C-i- ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy.
  • R 10 substituents are present, these need not necessarily be the same atoms and/or groups.
  • the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group represented by Ar.
  • R 3 in compounds of formula (1) it may be any divalent linking atom or group.
  • Particular examples include -O- or -S- atoms or -C(O)-, -C(0)0-, - OC(O)-, -C(S)-, -S(O)-, -S(0) 2 -, -N(R 14 )- [where R 14 is a hydrogen atom or an alkyl group], -N(R 4 )N(R 14 )-, -N(R 4 )0-, -CON(R 14 )-, - OC(0)N(R 14 )-, -CSN(R 14 )-, -N(R 1 )CO-, -N(R 1 )C(0)0-, -N(R 1 )CS-, - S(0) 2 N(R 14 )-, -N(R 14 )S(0) 2 -, -N(R 1 )C0N(R 14 )-, -N(R
  • chain Alk 1 is present in the group R 2 and/or R 3 in compounds of formula (1) as an optionally substituted aliphatic chain it may be an optionally substituted C ⁇ - ⁇ oaliphatic chain.
  • Particular examples include optionally substituted straight or branched chain Ci- ⁇ alkylene, C 2 . 6alkenylene, or C 2 -6 alkynylene chains.
  • Particular examples of aliphatic chains represented by Alk 1 include optionally substituted -CH 2 -, -(CH 2 ) 2 -, -CH(CH 3 )CH 2 -, -(CH 2 ) 2 CH 2 -, - (CH 2 ) 3 CH 2 -, -CH(CH 3 )(CH 2 ) 2 -, -CH 2 CH(CH 3 )CH 2 -, -C(CH 3 ) 2 CH 2 -, - CH 2 C(CH 3 ) 2 CH 2 -, -(CH 2 ) 2 C(CH 3 ) 2 CH 2 -, -(CH 2 ) 4 CH 2 -, -(CH 2 ) 5 CH 2 -, - CHCH-, -C(CH 3 )CH-, -CHCHCH 2 -, -CH 2 CHCH-, -CHCHCHCH 2 CH 2 -, -CHCHCHCH 2 CH 2 -, -CHCHCHCH 2 -, -CH
  • Heteroaliphatic chains represented by the group Alk 1 in compounds of formula (1 ) include the aliphatic chains just described for Alk 1 but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.
  • Particular heteroatoms or groups include atoms or groups L 3 where L 3 is as defined above for L 1 when L 1 is a linker atom or group.
  • Each L 3 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group.
  • Particular examples include optionally substituted -L 3 CH 2 -, -CH 2 L 3 CH 2 -, -L 3 CH 2 CH 2 -, -L 3 CH 2 CH 2 L 3 -, - CH 2 L 3 CH 2 CH 2 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 -, -L 3 (CH 2 ) 2 -, and - (CH 2 ) 2 L 3 CH 2 CH 2 - chains.
  • the optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk 1 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or -OH, -C0 2 H, -C0 2 R 15 [where R 15 is an optionally substituted straight or branched C ⁇ -6alkyl group as defined above] -CONHR 15 , - CON(R 1 5) 2 , -COR 15 , eg -COCH3, C-
  • Substituted amino groups include -NHR 15 and -N(R 15 ) 2 groups . Where two R 15 groups are present in any of the above substituents these may be the same or different.
  • Optionally substituted cycloaliphatic groups represented by the group R 8 when present in the group R 2 and/or R 3 in compounds of the invention include optionally substituted C3- ⁇ ocycloaliphatic groups.
  • Particular examples include optionally substituted C 3 -iocycloalkyl, e.g. C 3 . 7 cycloalkyl or C 3 - ⁇ ocycloalkenyl, e.g C 3 -7cycloalkenyl groups.
  • Optionally substituted heterocycloaliphatic groups represented by the group R 8 include optionally substituted C 3 - ⁇ oheterocycloaliphatic groups. Particular examples include optionally substituted C3- ⁇ oheterocycloalkyl, e.g. C3- 7 heterocycloalkyl, or C3- ⁇ oheterocycloalkenyl, e.g. C 3 - 7 hetero- cycloalkenyl groups, each of said groups containing one, two, three or four heteroatoms or heteroatom-containing groups L 3 as defined above.
  • Optionally substituted polycycloaliphafic groups represented by the group R 8 include optionally substitued C 7 . 10 bi- or tricycloalkyl or C 7 - ⁇ obi- or tricycloalkenyl groups.
  • Optionally substituted polyheterocycloaliphatic groups represented by the group R 8 include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L 3 atoms or groups.
  • cycloaliphatic, polycycloaliphafic, heterocycloaliphatic and polyheterocycloaliphatic groups represented by the group R 8 include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3- cyclopenten-1-yl, adamantyl, norbornyl, norbornenyl, tetrahydrofuranyl, pyrroline, e.g.
  • the optional substituents which may be present on the cycloaliphatic, polycycloaliphafic, heterocycloaliphatic or polyheterocycloaliphatic groups represented by the group R 8 include one, two, three or more substituents each selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C-
  • halogen atoms e.g. fluorine, chlorine, bromine or iodine atoms
  • -6alkyl e.g. methyl or ethyl, haloC-i- ⁇ alkyl, e.g. halomethyl or haloethyl
  • Ci- ⁇ alkoxy e.g. methoxy or ethoxy, haloC-i- ⁇ alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, Ci- ⁇ alkylthio e.g. methylthio or ethylthio, or -(Alk 4 ) v R 16 groups in which Alk 4 is a straight or branched C-
  • R 16 is a -OH, -SH, - N(R 17 ) 2 , (in which R 17 is a hydrogen atom or an alkyl group) -CN, C0 2 R 17 , -N0 2 , -CON(R 17 ) 2 , -CSN(R 7 ) 2 , -COR 17 , -CSN(R 17 ) 2 , -SOR 17 , -S0 2 R 17 , -N(R 1 )COR 17 , -N(R 1 )CSR 17 , -S0 2 N(R 1 ) 2 , -N(R 17 )S0 2 R 17 , -N(R 17 )CON(R 17 ) 2 , -N(R 17 )CSN(R 17 ), N(R 17 )S0 2 N(R 1 ) 2 or optionally substituted phenyl group.
  • R 17 is a hydrogen atom or an alkyl group
  • each nitrogen atom may be optionally substituted by a group -(L 4 ) q (Alk 5 ) r R 18 in which L 4 is -C(O)-, -C(0)0-, -C(S)-, -S(0) 2 -, -CON(R 17 )-, -CSN(R 17 )- or S0 2 N(R 17 )-; q is zero or the integer 1 ; Alk 5 is an optionally substituted aliphatic or heteroaliphatic chain; r is zero or an integer 1 ; and R 18 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphafic, polyheterocycloaliphatic, aromatic or heteroaromatic group as herein defined.
  • -3alkylene chains represented by Alk 4 include - CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 - and -CH 2 CH(CH 3 ) 2 - chains.
  • Optionally substituted aliphatic or heteroaliphatic chains represented by Alk 5 include those optionally substituted chains described above for Alk 1 .
  • Cycloaliphatic, heterocycloaliphatic, polycycloaliphafic or polyheterocycloaliphatic groups represented by R 18 include those groups just described for the group R 8 .
  • Optional substituents which may be present on these groups include those described above in relation to Alk 1 aliphatic and heteroaliphatic chains.
  • Aromatic and heteroaromatic groups represented by R 18 include those groups as described hereinbefore for the group Ar.
  • Optional substituents which may be present on these groups include those described above in relation to Ar.
  • R 2 and/or R 3 substituents represented by -L 1 (Alk 1 )tL(R 8 ) u when present in compounds of the invention include atoms or groups - L 1 Alk 1 L 2 R 8 , -L 1 Alk 1 R 8 , -L R 8 , -R 8 and -Alk R 8 wherein L , Alk 1 , L 2 and R 8 are as defined above.
  • substituents include -L 1 CH 2 L 2 R 8 , -L 1 CH 2 CH 2 L 2 R 8 , -L 1 (CH 2 ) 3 L 2 R 8 , -L 1 CH(CH 3 )L R 8 , -L 1 CH 2 R 8 , -L (CH 2 ) 2 R 8 , -L 1 (CH 2 ) 3 R 8 , -L 1 CH(CH 3 )R 8 , -L 1 CHCHR 8 , - L 1 CHCHCH 2 R 8 , -L 1 CCR 8 , -L 1 CCCH 2 R 8 , -CH 2 R 8 , -(CH 2 ) 2 R 8 , -(CH 2 ) 3 R 8 , - CH(CH3)R 8 and -R 8 atoms or groups.
  • R 2 and/or R 3 in compounds of the invention may be for example a halogen atom, e.g. fluorine, chlorine, bromine or iodine atoms, and/or C-
  • ⁇ alkyl e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, C3- ⁇ cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C-
  • ⁇ hydroxyalkyl e.g.
  • hydroxy methyl, hydroxyethyl or -C(OH)(CF3) 2 pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolidinyl, carboxyC ⁇ -6alkyl, e.g. carboxyethyl, C-
  • -6alkyl e.g. ethylaminoethyl, C ⁇ -6 dialkylaminoC ⁇ -6alkyl, e.g. diethylaminoethyl, aminoC ⁇ -6alkylamino e.g. aminoethylamino, aminoC-i- ealkoxy, e.g. aminoethoxy, hydroxyC-i-ealkylamino e.g. hydroxyethylamino or hydroxyropylamino, C ⁇ -6alkylaminoC ⁇ -ealkoxy, e.g. methylaminoethoxy, C ⁇ -6dialkylaminoC-
  • sulphonyl (-SO3H), - SOsAlk 3 , C ⁇ -6alkylsulphinyl e.g. methylsulphinyl, ethylsulphinyl or propylsulphinyl, C ⁇ -6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (-S0 2 NH 2 ), C1-6 alkylamino-sulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C ⁇ -6dialkylaminosulphonyl, e.g.
  • C ⁇ -6alkylaminocarbonyl e.g. methylaminocarbonyl or ethyl- aminocarbonyl
  • C ⁇ -6dialkylaminocarbonyl e.g. dimethylaminocarbonyl or diethylaminocarbonyl
  • aminoC ⁇ -6alkylaminocarbonyl e.g. aminoethyl- aminocarbonyl
  • C ⁇ -6dialkylaminoC ⁇ -6alkylaminocarbonyl e.g.
  • diethyl- aminoethylaminocarbonyl aminocarbonylamino, C-
  • Ci-6dialkylaminothiocarbonylamino e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C-
  • acryloxylamino methacryloylamino, crotonylamino, C3-6alkynylcarbonylamino e.g. proparylcarbonylamino, aminoCi- ⁇ alkanoyl-amino e.g. aminoacetylamino, Ci- ⁇ dialkylaminoCi. ealkanoylamino, e.g. dimethylaminoacetylamino, C ⁇ -6alkanoylaminoC ⁇ . ealkyl, e.g. acetylamino-methyl, C ⁇ -6alkanoylaminoC ⁇ -6alkylamino, e.g.
  • Ci- ⁇ alkoxycarbonylamino e.g. methoxycarbonylamino, ethoxycarbonylamino, t-butoxycarbonylamino, optionally substituted C3-7heterocycloalkylC ⁇ -6alkoxy e.g.
  • pyrolylpropoxy optionally substituted pyrolylpropoxy, furylpropoxy, thienylpropoxy, imidazolylpropoxy, pyridylpropoxy, pyrimidinylpropoxy, pyridazinylpropoxy or pyrazinylpropoxy, optionally substituted C3-7heterocycloalkylC-
  • morpholinoethylamino optionally substituted morpholinoethylamino, morpholinopropylamino, morpholinobutylamino, pyrrolidinylpropylamino, imidazolinylpropylamino, imidazolidinylpropylamino, piperidinylpropyl- amino, thiomorpholinylpropylamino or piperazinylpropylamino, optionally substitutedC6- ⁇ 2 arylC ⁇ -6alkylamino e.g. optionally substituted phenylpropylamino, optionally substituted C-
  • pyrrolylpropylamino optionally substituted pyrrolylpropylamino, furylpropylamino, thienylpropylamino, imidazolylpropylamino, pyridylpropylamino, pyrimidinylpropylamino, pyridazinylpropylamino or pyrazinylpropylamino optionally substituted C3-7heterocycloalkylC-
  • morpholinoethylcarbonyl optionally substituted morpholinoethylcarbonyl, morpholinopropylcarbonyol, morpholinobutylcarbonyl, pyrrolidinylpropylcarbonyl, imidazolinylpropyl- carbonyl, imidazolidinylpropylcarbonyl, piperazinpropylcarbonyl, thio- morpholinylpropylcarbonyl, or piperazinylpropylcarbonyl, optionally substituted C6- ⁇ 2 arylC ⁇ -6alkylcarbonyl, e.g.
  • optionally substituted phenyl- propoylcarbonyl optionally substituted C-i-gheteroaryl Ci- ⁇ alkylcarbonyl e.g. optionally substituted pyrrolylpropylcarbonyl, furylpropylcarbonyl, thienylpropylcarbonyl, imidazolinylpropylcabonyl, pyridylpropylcarbonyl, pyrimidinylpropylcarbonyl, pyridazinylpropylcarbonyl or pyrazinylpropyl- carbonyl, optionally substituted C3-7heterocycloalkylC-
  • morpholinoethylthio optionally substituted morpholinoethylthio, morpholinopropylthio, morpholinobutylthio, pyrrolidinylpropylthio, imidazolinylpropylthio, imidazolidinylpropylthio, piperidinylpropylthio, thiomorpholinylpropylthio or piperazinylpropylthio, optionally substituted C6- ⁇ 2 arylC-
  • pyrrolylproylthio optionally substituted pyrrolylproylthio, furylpropylthio, thienylpropylthio, imidazolylpropylthio, pyridylpropylthio, pyrimidinylpropylthio, pyridazinylpropylthio or pyrazinylpropylthio group.
  • two -L 2 (Alk 2 )tL 3 (R 4 ) u substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C-
  • a cyclic group such as a cyclic ether, e.g. a C-
  • Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
  • Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
  • One group of compounds of the invention has the formula (1) above in which Ar is an optionally substituted aryl or heteroaryl group and R, R 1 , X, R 4 , n, R 2 and R 3 are as generally and specifically defined for formula (1) and the salts, solvates, hydrates and N-oxides thereof.
  • Ar is an optionally substituted aromatic group.
  • Particularly useful compounds of this type are those wherein Ar is an optionally substituted phenyl group.
  • Ar may be in particular a phenyl group or a phenyl group substituted by one or two R 10 groups as defined herein.
  • Particularly useful substituents include one or two methyl groups and, especially, one or two halogen atoms.
  • Ar is an optionally substituted heteroaromatic group, particularly an optionally substituted quinolinyl, isoquinolinyl or, especially, thienyl group.
  • substituents are present in these groups these may be one or two R 10 atoms or groups as defined herein. Particularly useful substituents include one or two halogen atoms.
  • R is a hydrogen atom.
  • Particularly useful compounds of this type include compounds of formula (1 a):
  • Ar, R 1 , R 2 , R 3 , R 4 , n and x are as generally and specifically defined previously, and the salts, solvates, hydrates and N-oxides thereof.
  • Ar may in particular be an optionally substituted aryl or heteroaryl group.
  • R 1 is in particular a hydrogen atom.
  • n is zero.
  • n is the integer 1.
  • R 4 is preferably a halogen atom, especially a fluorine or chlorine atom or a methyl, halomethyl, especially -CF3, methoxy, halomethoxy, especially -OCF 3 , -CN, -C0 2 R 5 e.g. -C0 2 CH3, - N0 2 , amino, substituted amino, especially -NHCH3 or -N(CH3) 2 or - N(R 5 )COR6, especially -N(R 5 )COCH 3 eg -NHCOCH3 group.
  • X is a nitrogen atom.
  • X is a C(R 1 a ) group in which R 1 a is preferably a cyano (-CN) group.
  • one of R 2 and R 3 is a hydrogen atom and the other is a group -L 1 Alk 1 R 8 in which L 1 and Alk 1 are as previously defined and R 8 is a hydrogen atom or an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group.
  • Especially preferred optionally substituted heterocycloaliphatic groups include optionally substituted Cs ⁇ heterocycloalkyl or C3-7hetero- cycloalkenyl groups, most especially optionally substituted, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, e.g.
  • Especially preferred optionally substituted aromatic groups include optionally substituted phenyl groups.
  • Especially preferred optionally substituted heteroaromatic groups include monocyclic heteroaromatic groups, especially five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • optionally substituted five- or six-membered heteroaromatic groups include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyridizinyl triazinyl, triazolyl e.g. 1 ,2,4-triazolyl or 1 ,3,4-triazolyl or pyrazinyl groups.
  • R 2 and R 3 is each a group -L 1 Alk 1 R 8 in which L 1 and Alk 1 are as previously defined and R 8 is a hydrogen atom or an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group.
  • Especially preferred optionally substituted heterocycloaliphatic groups include optionally substituted C3-7heterocycloalkyl or C3-7hetero-cycloalkenyl groups, most especially optionally substituted, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, e.g. N-methylpiperidinyl, morpholinyl, thiomorpholinyl and piperazinyl e.g. N-methylpiperazinyl groups.
  • Especially preferred optionally substituted aromatic groups include optionally substituted phenyl groups.
  • Especially preferred optionally substituted heteroaromatic groups include monocyclic heteroaromatic groups, especially five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Especially preferred optionally substituted five- or six-membered heteroaromatic groups include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyridizinyl triazinyl, triazolyl e.g. 1 ,2,4-triazolyl or 1 ,3,4-triazolyl or pyrazinyl groups.
  • R 2 and R 3 is a group -L 1 Alk 1 R 8 in which R 8 is a hydrogen atom, L 1 is a - 0-, -S-, -C(O)-, -N(R 14 -)-, e.g. -NH- or -N(CH 3 )-, or -N(R 14 )CO-, e.g. - NHCO- or -N(CH3)CO- linker atom or group and Alk 1 is an aliphatic chain, e.g.
  • -6alkyl chain especially a -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH(CH 3 )CH 2 - chain or a C 2 -6alkenyl chain, especially a -CHCH-, -C(CH 3 )CH- or -CHCHCH 2 - chain or a C 2 -6alkynyl chain, especially a -CC- or -CCCH 2 - chain.
  • R 2 and R 3 is preferably a group -L 1 Alk 1 R 8 in which L 1 is a - 0-, -S-, -C(O)- or -N(R 14 )-, especially -NH- or -N(CH 3 )- linker atom or group, Alk 1 is an aliphatic chain, especially a Chalky! chain, most especially a -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or CH 2 CH(CH3)CH 2 - chain and R 8 is an optionally substituted, heterocycloaliphatic, aromatic or heteroaromatic group.
  • L 1 is a - 0-, -S-, -C(O)- or -N(R 14 )-, especially -NH- or -N(CH 3 )- linker atom or group
  • Alk 1 is an aliphatic chain, especially a Chalky! chain, most especially
  • Especially preferred optionally substituted heterocycloaliphatic groups include optionally substituted C3-7hetero-cycloalkyl or C3-7heterocycloalkenyl groups, most especially optionally substituted, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, e.g. N-methylpiperidinyl, morpholinyl, thiomorpholinyl and piperazinyl e.g. N-methylpiperazinyl groups.
  • Especially preferred optionally substituted aromatic groups include optionally substituted phenyl groups.
  • Especially preferred optionally substituted heteroaromatic groups include monocyclic heteroaromatic groups, especially five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Especially preferred optionally substituted five- or six-membered heteroaromatic groups include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyridizinyl triazinyl, triazolyl e.g. 1 ,2,4-triazolyl or 1 ,3,4-triazolyl or pyrazinyl groups.
  • R 2 is a group -L 1 Alk 1 R 8 in which L 1 is an -O- atom, Alk 1 is a C-
  • R 3 is preferably a group - L 1 Alk 1 R 8 in which L 1 is an -O- atom, Alk 1 is a C ⁇ -6alkyl chain, especially a -CH 2 -, -CH 2 CH 2 , -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 - chain and R 8 is an optionally substituted heterocycloaliphatic group, especially an optionally substituted C3-7heterocycloalkyl or C3-7heterocycloalkenyl groups, most especially an optionally substituted pyrrolidinyl, imidazolinyl, piperidinyl, e.g.
  • R 3 is a group -L 1 Alk 1 R 8 as just defined and R 2 is preferably a group - L 1 Alk 1 R 8 in which L is a -N(R 14 )CO, especially -NHCO- linker group, Alk 1 is a C 2 -6alkenyl chain, especially -CHCH-, -C(CH 3 )CH- or - CHCHCH 2 - or a C 2 -6alkynyl chain, especially -CC- or -CCCH 2 - and R 8 is a hydrogen atom.
  • R 2 is a group -L 1 Alk 1 R 8 in which L 1 is an -O- atom, Alk 1 is a Ci- ⁇ alkyl chain, especially a -CH -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 - chain and R 8 is an optionally substituted heterocycloalphatic group, especially an optionally substituted C3-7heterocycloalkyl or C3- 7heterocycloalkenyl groups, most especially an optionally substituted pyrrolidinyl, imidazolyl, piperidinyl, e.g.
  • R 3 is preferably a group - L 1 Alk 1 R 8 in which L 1 is an -O- atom, Alk 1 is a Chalky! chain, especially a -CH 2 -, -CH 2 CH 2 - or -CH(CH3)CH- chain and R 8 is a hydrogen atom.
  • R 2 is a group -L 1 Alk 1 R 8 as just defined and R 3 is preferably a group -L 1 Alk 1 R 8 in which L 1 is a -N(R 14 )CO, especially -NHCO- linker group, Alk 1 is a C 2 -6alkenyl chain, especially -CHCH-, -C(CH )CH- or - CHCHCH 2 - or a C 2 -6alkynyl chain, especially -CC- or -CCCH 2 - and R 8 is a hydrogen atom.
  • One especially useful group of compounds of the invention has the formula (1 ) or (1a) in which one of R 2 and R 3 , particularly R 2 , is a methoxy group and the other is a group -OAIk 1 R 8 .
  • R 8 is in particular a -NR 5 R 6 or heterocycloaliphatic group.
  • Alk 1 may in particular be a -(CH 2 ) 2 - or -(CH 2 )3- chain.
  • Particular R 8 groups include -NHCH3, -N(CH3) 2 , optionally substituted morpholinyl or optionally substituted piperazinyl groups, especially - N(CH3) 2 , morpholino, piperazinyl and N-methylpiperazinyl groups.
  • Particularly useful compounds according to the invention include those in the Examples herein, particularly the compounds of Examples 1 , 4, 5, 8, 9, 12, 13, 14, 18, 25, 28, 31 , 36, 39, 41 , 42, 68, 74, 75, 76, 82, 83, 86, 87, 144, 145, 146, 152 or 153 and the salts, solvates, hydrates or N-oxides thereof.
  • Compounds according to the invention are potent and selective inhibitors of Class I receptor tyrosine kinases, especially EGFr kinase as demonstrated by differential inhibition of this enzyme when compared to inhibition of other protein kinases such as p56 lck kinase, protein kinase C, KDR kinase and FGFr2 kinase.
  • the ability of the compounds to act in this way may be simply determined by the tests described in the Examples hereinafter.
  • the compounds according to the invention are thus of particular use in the prophylaxis and treatment of diseases in which inappropriate Class I receptor tyrosine kinase action plays a role, for example in hyperproliferative disorders such as tumours, psoriasis, restenosis following angioplasty, atherosclerosis, and fibrosis e.g. of the liver and kidney.
  • the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non- aqueous vehicles and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials.
  • the composifions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (1 ) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro-fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • suitable propellant e.g. dichlorodifluoromethane, trichloro-fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter.
  • the symbols R 1 , R 2 , R 3 , R 4 n, and x when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated.
  • reactive functional groups for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in "Protective Groups in Organic Synthesis", John Wiley and Sons, 1999].
  • a compound of formula (1) may be prepared by reaction of a sulphonamide ArS0 2 NH 2 with a compound of formula (2):
  • Hal is a halogen atom such as a chlorine atom.
  • the reaction may be performed at an elevated temperature, for example the reflux temperature, where necessary in the presence of a solvent, for example a substituted amide such as dimethylformamide, optionally in the presence of a base, for example an inorganic base such as sodium hydride or most preferably a carbonate such as potassium or caesium carbonate.
  • a solvent for example a substituted amide such as dimethylformamide
  • a base for example an inorganic base such as sodium hydride or most preferably a carbonate such as potassium or caesium carbonate.
  • Intermediate sulphonamides represented by ArS0 2 NH 2 and intermediates of formula (2) are either known compounds or may be obtained by conventional procedures, for example from the known compounds by using one or more of the standard substitution and/or oxidation, reduction or cleavage reactions described below in relation to interconversion of compounds of formula (1) or by methods known to those skilled in the art following procedures set forth in references such as Rodd's Chemistry of Carbon Compounds, Volumes 1 -15 and Supplemental (Elsevier Science Publishers, 1989), Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed.
  • compounds of formula (1) may also be prepared by interconversion of other compounds of formula (1) and it is to be understood that the invention extends to such interconversion processes.
  • standard substitution approaches employing for example alkylation, arylation, acylation, thioacylation, sulphonylation, formylation or coupling reactions may be used to add new substitutents to and/or extend existing substituents in compounds of formula (1 ).
  • existing substituents in compounds of formula (1) may be modified by for example oxidation, reduction or cleavage reactions to yield other compounds of formula (1).
  • alkylation or arylation of a compound of formula (1 ) for example to introduce a group -Alk 2 (R 1 1 ) m or R 11 where R 1 1 is an aryl group may be achieved by reaction of a compound of formula (1 ) containing an appropriate nucleophilic group (eg an amine or hydroxyl group) with a reagent (R 11 ) m Alk 2 L or R 11 L, where L is a leaving group such as a halogen atom, e.g. a bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g.
  • an appropriate nucleophilic group eg an amine or hydroxyl group
  • R 11 m Alk 2 L or R 11 L where L is a leaving group such as a halogen atom, e.g. a bromine, iodine or chlorine atom or a sulphonyloxy group such
  • the alkylation or arylation reaction may be carried out in the presence of a base, e.g. an inorganic base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substitued amide such as diemethylformamide or an ether, e.g.
  • a base e.g. an inorganic base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride
  • a dipolar aprotic solvent such as an amide, e.g. a substitued amide such as diemethylformamide or an ether, e.g.
  • a compound of formula (1) may be acylated or thioacylated, for example to introduce a group -C(0)R 12 or -C(S)R 12 .
  • the reaction may be performed for example with an acyl or thioacyl halide or anhydride in the presence of a base, such as an organic amine e.g. triethylamine or pyridine in a solvent such as an aromatic or halogenated hydrocarbon, e.g. toluene, optionally in the presence of a catalyst, e.g. dimethylaminopyridine dichloromethane at for example ambient up to the reflux temperature, or by reaction with a thioester in an inert solvent such as tetrahydrofuran at a low temperature such as around 0°C.
  • a base such as an organic amine e.g. triethylamine or pyridine
  • solvent such as an aromatic or halogenated hydrocarbon, e.g. toluen
  • Compounds of formula (1) may be prepared in another general interconversion reaction by sulphonylation, for example by reaction of the compound with a reagent R 1 S(0)L or R 12 S0 2 L where L is a leaving group as described above in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
  • a base for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
  • the reaction may in particular be performed with compounds of formula (1) in which Ar possesses a primary or secondary amino group.
  • compounds of formula (1) may be prepared from other compounds of formula (1) by modification of existing functional groups in the latter.
  • ester groups -C0 2 Alk 3 in compounds of formula (1 ) may be converted to the corresponding acid [-C0 2 H] by acid- or base- catalysed hydrolysis depending on the nature of the group Alk 3 .
  • Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
  • -OR 12 [where R 12 represents an alkyl group such as methyl group] groups in compounds of formula (1) may be cleaved to the corresponding alcohol -OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
  • alcohol -OH groups in compounds of formula (1) may be converted to a corresponding -OR 12 group by coupling with a reagent R 12 OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • Aminosulphonylamino [-NHS0 2 NH 2 ] groups in compounds of formula (1) may be obtained, in another example, by reaction of a corresponding amine [-NH 2 ] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
  • amine (-NH 2 ) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • a halogenated hydrocarbon e.g. dichloromethane
  • ketone such as acetone
  • alcohol e.g. ethanol
  • amine [-NH 2 ] groups in compounds of formula (1 ) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
  • a nitro [-N0 2 ] group may be reduced to an amine [- NH 2 ], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • amide [-CONHR 12 ] groups in compounds of formula (1) may be obtained by coupling a corresponding acid [-C0 2 H] or an active derivative thereof, e.g.
  • the coupling reaction may be performed using standard conditions for reactions of this type.
  • the reaction may be carried out in a solvent, for example an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, at a low temperature, e.g. -30°C to ambient temperature, optionally in the presence of a base, e.g. an organic base such as a cyclic amine, e.g.
  • N-methylmorpholine and where necessary in the presence of a condensing agent, for example a diimide such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxytriazole, e.g. 1 - hyd roxy benzotriazole .
  • a condensing agent for example a diimide such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide
  • a catalyst such as a N-hydroxytriazole, e.g. 1 - hyd roxy benzotriazole .
  • Aromatic halogen substituents in compounds of the invention may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a base for example, a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using dimethylformamide as the electrophile;
  • a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
  • sulphur atoms in compounds of the invention may be oxidised to the corresponding sulphoxide using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
  • an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid
  • an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane
  • a compound of the invention containing a substituent R 10 in which R 10 is an aryl or heteroaryl group may be prepared by coupling a corresponding compound in which the R 10 substituent is a halogen atom such as a bromine atom, with a boronic acid Ar 1 B(OH) 2 [in which Ar 1 is an aryl or heteroaryl group as defined above for Ar] in the presence of a complex metal catalyst.
  • Suitable catalysts include heavy metal catalysts, for example palladium catalysts such as tetrakis(triphenylphosphine) palladium.
  • the reaction may be performed in an inert organic solvent, for example an ether such as dimethoxyethane, in the presence of a base, e.g. an alkali carbonate such as sodium carbonate, at an elevated temperature, e.g. the reflux temperature.
  • a base e.g. an alkali carbonate such as sodium carbonate
  • N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
  • an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid
  • an elevated temperature for example around 70°C to 80°C
  • a peracid such as peracetic acid in a solvent, e.g. dichloromethane
  • the aqueous phase was extracted with chloroform (3 x 20mL).
  • the organic phases were dried (MgS04), filtered and the solvents removed in vacuo.
  • the crude residue was purified by column chromatography (Si0 2 ; 5% MeOH / DCM) to give the title product as an off white crystalline solid (128mg, 42 %).
  • the title product was prepared in a similar fashion to Example 1 , from 2- methylbenzenesulphonamide (308mg, 1.8mmol). The crude residue was purified by column chromatography (Si0 2 ; 5% MeOH in DCM) to give the title product as an off white crystalline solid (138mg, 49%).
  • the title product was prepared in a similar manner to Example 1 , from 3- chlorobenzene sulphonamide (69mg, 0.36mmol). The crude residue was purified by column chromatography (Si0 2 ; EtOAc 20-60%:hexane to give the title compound as a white solid (61 mg).
  • the title product was prepared in a similar manner to Example 1 , from 4- chlorobenzene sulphonamide (69mg, 0.36mmol). The crude residue was purified by column chromatography (Si0 2 , EtOAc 20-60% / hexane) to give the title compound as a white solid (20.6mg).
  • the title product was prepared in a similar manner to Example 1 from 4- methylbenzene sulphonamide (62mg, 0.36mmol). The crude residue was purified by column chromatography (Si0 2 ; EtOAc 20-60% / hexane) to give the title compound as a yellow solid (12.5mg).
  • MS was acquired by API electrospray in positive ion mode, at 70V, scanning from 120 to 750amu.
  • the activities of recombinant KDR kinase and FGFr2 kinase were determined by measuring their ability to transfer the ⁇ -phosphate from [33pjATP to polyglutamic acid - tyrosine (pEY).
  • the assay methodology employed for both kinases is identical except that in the assay of KDR kinase the diluent used throughout was 20mM HEPES pH 7.25 containing 2mM MnCI 2 , 2mM MnCI 2 , 5mM DTT and 0.05% Brij 35, whereas in the FGFr2 assay 10mM MnCI 2 is used instead of 2mM MnCI 2 and 2mM MnCI 2 .
  • the assay was conducted in a total volume of 202 ⁇ l containing 1-1 Ong kinase, 5 ⁇ g/ml pEY (4:1 ) (Sigma, UK), 1 ⁇ M ATP (containing ⁇ 50,000cpm [33p]ATP (Amersham International, UK) (Sigma, UK) and test inhibitors at the appropriate concentration.
  • the test inhibitors were dissolved in DMSO and added such that the final concentration of DMSO in the assay did not exceed 2% (v/v).
  • the assay was initiated by addition of kinase and terminated after 10 minutes incubation at room temperature by addition of 50 ⁇ l of 20mM HEPES pH 7.25 containing 0.125M EDTA and 10mM ATP.
  • the tyrosine kinase activity of p56 lck was determined using a RR-src peptide (RRLIEDNEYTARG) and [ ⁇ -33p]ATP as substrates. Quantitation of the 33p.phosphorylated peptide formed by the action of p56 lck was achieved using an adaption of the method of Geissler et al (J. Biol. Chem. (1990) 265, 22255-22261 ).
  • DMSO dimethylsulphoxide
  • the dpm obtained being directly proportional to the amount of 33p.RR- S rc produced by p56 lck , were used to determine the IC50 for each compound.
  • the IC50 was defined as the concentration of compound required to reduce the production of 33p-RR. src y 50%.
  • EGFr EGF receptor
  • PKC protein kinase C
  • compounds of the invention have IC50 values in the EGFr kinase assay of around 1 ⁇ M and below.
  • the same compounds had IC50 values in each assay of greater than 10 ⁇ M.
  • the compound clearly had potent and selective EGFR kinase inhibitory action.

Abstract

Compounds of formula (1) are described wherein Ar is an optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl or alkyl group, X is a nitrogen atom or a C(R1a) group, n is zero or the integer 1 or 2 and R, R?1, R2, R3 and R4¿ are substituents defined in the specification. The compounds are able to inhibit the activity of Class 1 receptor tyrosine kinases and are of use in the treatment of hyperproliferative disorders such as psoriasis.

Description

FUSED BICYCLIC AMINES
This invention relates to a series of fused bicyclic amines, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Regulation of protein tyrosine phosphorylation by tyrosine kinases is essential for the regulation of cell growth and differentiation [Hanks, S. K. Hunter T., FASEB J. 9, 576-596 (1995)]. The tyrosine kinases may belong to one of two general classes, namely, the transmembrane growth factor receptor tyrosine kinases (EGFr, c-ErbB-2, PDGF, KDR, etc.) [Iwashita S. and Kobayashi M., Cellular Signalling, 4, 123-132 (1992)] and cytoplasmic nonreceptor tyrosine kinases (src, lck, ZAP70 etc.) [Chan C. et al, Ann. Rev. Immunol. 12, 555-592 (1994)]. In the case of receptor tyrosine kinases, growth factors, such as epidermal growth factor (EGF), bind to the extracellular binding domain of the receptor, leading to receptor dimerisation and activation of the receptor kinase domain leading to autophosphorylation. This initiates a signal transduction cascade leading ultimately to proliferation. Considerable evidence has emerged to implicate Class 1 receptor tyrosine kinases, such as EGFr and c-ErbB-2 in the progression of several human cancers [Carraway K. & Cantley L, Cell, 78, 5-8 (1994)]. In particular, increased levels of EGFr and c-Erb-2 occur in a significant percentage of breast and non-small cell lung carcinomas in which overexpression correlates with shortened survival times and increased relapse rates. The ability of these receptors to undergo homo- and heterodimerisation leads to an intensification of the transforming signal and contributes to the complexity of the EGFr family signalling network. The disruption of the normal functions of these tyrosine kinases has been implicated in a number of other hyperproliferative disorders such as psoriasis, restenosis, atherosclerosis and fibrosis of the liver and kidney.
The present invention relates to a series of fused bicyclic amines that are able to inhibit the activity of Class I receptor tyrosine kinases, thus permitting a new therapeutic approach for disease states such as cancer, psoriasis, restenosis, atherosclerosis and fibrosis.
Thus according to one aspect of the invention we provide a compound of formula (1):
Figure imgf000003_0001
(1 ) wherein Ar is an optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl or alkyl group;
R is a hydrogen atom or an optionally substituted alkyl group; R1 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy,-N(alkyl), -N(alkyl)2 or cyano (-CN) group; X is a nitrogen atom or a C(R1 a) group where R1 a is as defined for R1 and may be the same or different;
R4 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, nitro (-NO2), cyano (-CN), -CO2R5 [where R5 is a hydrogen atom or an alkyl group], -SO3H, -SOR5, S02R5, -SO3R5, -OCO2R5, - CONR5R6 [where R6 is as just defined for R5 and may be the same or different], -SR5, -NR5R6, -OC(0)NR5R6, -CSNR5R6, COR5, -OCOR5, -N(R5)COR6, -N(R5)CSR6, -S02N(R5)(R6), -N(R5)S02R6, -
N(R5)CON(R6)(R7) [where R7 is a hydrogen atom or an alkyl group], - N(R5)CSN(R6)(R7) or -N(R5)S02N(R6)(R7) group; n is zero or the integer 1 or 2;
R2 and R3 which may be the same or different is each an atom or group - L1(Alk1)tL2(R8)u in which L1 and L2 which may be the same or different is each a covalent bond or a linker atom or group, t is zero or the integer 1 , u is the integer 1 , 2 or 3, Alk1 is an aliphatic or heteroaliphatic chain and R8 is an atom or group as defined for R4 or an optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, polyheterocyclo- aliphatic, aromatic or heteroaromatic group, provided that:
1) R2 and R3 are not both hydrogen atoms or methoxy groups;
2) when Ar is an optionally substituted phenyl group, R is a hydrogen atom, R1 is a chlorine atom or methyl or methoxy group and one of R2 and R3 is a chlorine atom or methyl, methoxy or ethoxy group then the other of R2 and R3 is other than a hydrogen atom; and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that certain compounds of formula (1) may exist as geometric isomers (E or Z isomers). The compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (1) may exist as tautomers, for example keto (CH2C=0)-enol (CH=CHOH) tautomers. Formula (1 ) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.
The compounds of formula (1) are potent and selective inhibitors of transmembrane growth factor receptor tyrosine kinases (Class 1 receptor tyrosine kinases) such as EGFr. Members of the group are able to inhibit the action of EGFr at concentrations at which they generally have no or minimal action on tyrosine kinases of other subgroups. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of hyperproliferative disorders such as cancer, psoriasis, restenosis, athersclerosis and fibrosis' as described hereinafter.
In the compounds of the invention as represented by formula (1) and the more detailed description hereinafter certain of the general terms used in relation to substituents are to be understood to include the following atoms or groups unless specified otherwise. Thus as used herein the term "alkyl", whether present as a group or part of a group includes straight or branched C-|-ιoalkyl groups, for example C-|-6alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl groups and C3-ιocycloalkyl groups, for example C3- 7cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Similarly, the terms "alkenyl" or "alkynyl" are intended to mean straight or branched C2.-|nalkenyl, C3-ιocycloalkenyl or C2. loalkynyl groups such as C2-6alkenyl, C3-7cycloalkenyl or C2-6alkynyl groups, for example -CHCH2, -CHCHCH3, -CH2CHCHCH3, -CCH, - CH2CCH , -CH2CCCH3, cyclopentenyl or cyclohexenyl groups. Each of these groups may be optionally substituted on any carbon atom. Optional substituents that may be present include those optional substituents mentioned hereinafter in relation to optionally substituted aliphatic groups.
The term "halogen atom" is intended to include fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF3, -CCI3, -CHF2, -CHCI2, - CH2F, and -CH2CI groups.
The term "alkoxy" as used herein is intended to include straight or branched Cι-ιoalkoxy for example C-i-βalkoxy such as methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy. "Haloalkoxy" as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include -OCF3, -OCCI3, - OCHF2) -OCHCI2, -OCH2F and -OCH2CI groups.
As used herein the term "alkylthio" is intended to include straight or branched C-|-ιoalkylthio, e.g. Ci-βalkylthio such as methylthio or ethylthio groups.
Aryl groups represented by the group Ar in compounds of formula (1 ) include for example mono- or bicyclic-C6-ι2 optionally substituted aromatic groups, for example optionally substituted phenyl, 1- or 2-naphthyl, or indenyl groups.
Heteroaryl groups represented by Ar include for example C1-9 optionally substituted heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
The aryl or heteroaryl groups represented by Ar may be attached to the remainder of the compound of formula (1) through any available ring carbon or heteroatom as appropriate.
Aralkyl or heteroaralkyl groups represented by the group Ar in compounds of formula (1) include optionally substituted arylC-i-βalkyl and heteroarylCι-6alkyl groups in which the aryl, heteroaryl and Cι-6alkyl groups and the optional substitution are as defined above.
Particular examples of heteroaromatic groups represented by Ar include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethyl-imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1 ,3,5-triazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1 ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2- b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8- tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl. Optional substituents which may be present on the aromatic or heteroaromatic groups represented by the group Ar include one, two, three or more substituents, each selected from an atom or group R10 in which R10 is -R1 1 or -Alk2(R1 1)m, where R1 1 is a halogen atom, or an amino (-NH ), substituted amino, nitro, cyano, amidino, hydroxyl (-OH), substituted hydroxyl, formyl, carboxyl (-C02H), esterified carboxyl, thiol (-SH), substituted thiol, -COR12 [where R12 is an -Alk2(R1 1)m> aryl or heteroaryl group], -CSR12, -S03H, -SOR12, -S02R12, -SO3R12, -S02NH2, -S02NHR12 S02N(R12)2, -CONH2, -CSNH2, -CONHR12, -CSNHR12, - CON(R12)2, -CSN(R12)2, -N(R9)S02R12, [where R9 is a hydrogen atom or an alklyl group] -N(S02R12)2, -NH(R9)S02NH2, -N(R9)S02NHR12, - N(R9)S02N(R1 )2, -N(R9)COR12, -N(R9)CONH2, -N(R9)CONHR12, - N(R9)C0N(R1 )2, -N(R9)CSNH2, -N(R9)CSNHR12, -N(R9)CSN(R12)2I - N(R9)CSR12, -N(R9)C(0)OR12, -S02NHet1 [where -NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other -O- or -S- atoms or -N(R9)-, -C(O)-, -C(S)-, S(O) or -S(0)2 groups], - CONHet1, -CSNHetl, -N(R9)S02NHef>, -N(R9)C0NHetl, N(R9)CSNHetι , -S02N(R9)Het2 [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more -O- or -S- atoms or -N(R9)-, -C(O)- or -C(S)- groups], -Het2, -CON(R9)Het2, - CSN(R9)Het2, -N(R9)CON(R9)Het2, -N(R9)CSN(R9)Het2, cycloaliphatic, heterocyclo-aliphatic, aryl or heteroaryl group; Alk2 is a straight or branched C-|-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S(0)n [where n is an integer 1 or 2] or -N(R13)- groups [where R13 is a hydrogen atom or C-|. βalkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1 , 2 or 3. It will be appreciated that when two R9 or R12 groups are present in one of the above substituents, the R9 or R12 groups may be the same or different.
When in the group -Alk2(R1 1)m m is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R1 1 may be present on any suitable carbon atom in -Alk2. Where more than one R11 substituent is present these may be the same or different and may be present on the same or different atom in -Alk2. Clearly, when m is zero and no substituent R1 1 is present the alkylene, alkenylene or alkynylene chain represented by Alk2 becomes an alkyl, alkenyl or alkynyl group.
When R11 is a substituted amino group it may be for example a group - NHR12 [where R12 is as defined above] or a group -N(R12)2 wherein each
R12 group is the same or different.
When R1 1 is a substituted hydroxyl or substituted thiol group it may be for example a group -OR12 or a -SR12 or -SC(=NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R11 include groups of formula -C02Alk3 wherein Alk3 is a straight or branched, optionally substituted C-i-salkyl group such as a methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl or t-butyl group; a C6-ι2arylC-|-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1 -naphthylmethyl or 2-naphthylmethyl group; a C6-ι2aryl group such as an optionally substituted phenyl, 1 -naphthyl or 2-naphthyl group; a C6-i2aryloxyC-|-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1 -naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C-i-salkanoyloxyC-i-βalkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-ι2aroyloxyC-|-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyl- oxypropyl group. Optional substituents present on the Alk3 group include R4 substituents described above.
When Alk2 is present in or as a substituent R10 it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s- butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3- butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or - S(0>, -S(0)2- or -N(R13)- groups.
Cycloaliphatic or heterocycloaliphatic groups represented by the groups R11 include those optionally substituted C3-ιocycloaliphatic or C3-ιrjhetero- cycloaliphatic groups described hereinafter for R8. Aryl or heteroaryl groups represented by the groups R1 1 or R12 include mono- or bicyclic optionally substituted Cδ-12 aromatic or C1-9 heteroaromatic groups as described above for the group Ar. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1 ) by any carbon or hetero e.g. nitrogen atom as appropriate.
When -NHet1 or -Het2 forms part of a substituent R10 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or -Het2 include those substituents described below in relation to R8 heterocycloaliphatic groups.
Particularly useful atoms or groups represented by R10 include fluorine, chlorine, bromine or iodine atoms, or Ci-βalkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, dioxolanyl, dioxanyl, piperidinyl, oxazolidinyl, thiazolidinyl or imidazolidinyl, C-|-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC-|-6alkyl, e.g. carboxyethyl, Cι-6alkylthio e.g. methylthio or ethylthio, carboxyC-i-βalkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C-|-6alkoxy, e.g. methoxy or ethoxy, hydroxyCi- βalkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C4-7cycloalkyl, e.g. cyclobutyl, cyclopentyl, Cs^cycloalkoxy, e.g. cyclopentyloxy, haloCi-βalkyl, e.g. trifluoromethyl, haloCι-6alkoxy, e.g. trifluoromethoxy, Cι-6alkylamino, e.g. methylamino, ethylamino or propylamino, amino (-NH2), aminoC-i-βalkyl, e.g. aminomethyl or aminoethyl, C-|-6dialkylamino, e.g. dimethylamino or diethylamino, aminoCi-βalkylamino e.g. aminoethylamino or aminopropyl- amino, optionally substituted Het1 NC-|-6alkylamino e.g. morpholinopropyl- amino, Cι-6alkylaminoC-|-6alkyl, e.g. ethylaminoethyl, Cι-6dialkyl-aminoC-|- βalkyl, e.g. diethylaminoethyl, aminoC-|-6alkoxy, e.g. aminoethoxy, C-|. 6alkylaminoC-|-6alkoxy, e.g. methylaminoethoxy, Ci-6dialkylaminoC-|- βalkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylamino- ethoxy, or dimethylaminopropoxy, hydroxyC-i-βalkylamino, e.g. hydroxy- ethylamino, hydroxypropylamino, or hydroxybutylamino, imido, such as phthalimido or naphthalimido, e.g. 1 ,8-naphthalimido, nitro, cyano, amidino, hydroxyl (-OH), formyl [HC(O)-], carboxyl (-C02H), -C02Alk3 [where Alk3 is as defined above], C-ι-6 alkanoyl e.g. acetyl, propyryl or butyryl, optionally substituted benzoyl, thiol (-SH), thioCi-βalkyl, e.g. thiomethyl or thioethyl, -SC(=NH)NH2, sulphonyl (-SO3H), -S03Alk3, Cι- 6alkylsulphinyl, e.g. methylsulphinyl, ethylsulphinyl or propylsulphinyl, C-|. 6alkylsulphonyl, e.g. methylsulphonyl, ethylsulphonyl, or propylsulphonyl, optionally substituted C6-ιoarylaminosulphonyl, e.g. phenylsulphonyl or dichlorophenylsulphonyl, aminosulphonyl (-S02NH2), Ci-βalkylamino- sulphonyl, e.g. methylaminosulphonyl, ethylaminosulphonyl or propyl- aminosulphonyl, Ci-βdialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, optionally substituted phenylaminosulphonyl, carboxamido (-CONH2), Cι-6alkylaminocarbonyl, e.g. methylamino- carbonyl, ethylaminocarbonyl or propylaminocarbonyl, Ci-βdialkylamino- carbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoCi- βalkylaminocarbonyl, e.g. aminoethylaminocarbonyl, Cι-6alkyl-aminoC-|. βalkylaminocarbonyl, e.g. methylaminoethylaminocarbonyl, C-|-6dialkyl- aminoC-|-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C-|-6alkylaminocarbonylamino, e.g. methylamino- carbonylamino or ethylaminocarbonylamino, C-|-6dialkylaminocarbonyl- amino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, Cι-6alkylaminocabonylCι-6alkylamino, e.g. methylaminocarbonylmethyl- amino, aminothiocarbonylamino, Cι-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C-|. βdialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, Ci -6alkylaminothiocarbonylCι -6alkylamino, e.g. ethylaminothiocarbonylmethylamino, -CONHC(=NH)NH2, C-|-6alkyl- sulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, haloCi-βalkylsulphonylamino, e.g. trifluoromethylsulphonylamino, C-|. edialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonyl- amino, optionally substituted phenylsulphonylamino, aminosulphonylamino
(-NHS02NH2), Cι-6alkylaminosulphonylamino, e.g. methylaminosulphonyl- amino or ethylaminosulphonylamino, Cι-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylCι-6alkyl- amino, optionally substituted phenylaminosulphonylamino, C-|-6alkanoyl- amino, e.g. acetylamino, aminoC-|-6alkanoylamino e.g. aminoacetylamino, Cι-6dialkylaminoCι-6alkanoylamino, e.g. dimethylaminoacetylamino, C-|. 6alkanoylaminoCι-6alkyl, e.g. acetylaminomethyl, Cι-6alkanoylaminoCι- βalkylamino, e.g. acetamidoethylamino, C-|-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, benzylamino, pyridylmethoxy, thiazolyl- methoxy, benzyloxycarbonylamino, benzyloxycarbonylaminoC-|-6alkyl e.g. benzyloxycarbonylaminoethyl, thiobenzyl, pyridylmethylthio or thiazolyl- methylthio groups.
Where desired, two R10 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C-i-βalkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R10 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group represented by Ar.
When L1 and/or L2 is present as a linker or group in the group R2 and/or
R3 in compounds of formula (1) it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(O)-, -C(0)0-, - OC(O)-, -C(S)-, -S(O)-, -S(0)2-, -N(R14)- [where R14 is a hydrogen atom or an alkyl group], -N(R 4)N(R14)-, -N(R 4)0-, -CON(R14)-, - OC(0)N(R14)-, -CSN(R14)-, -N(R1 )CO-, -N(R1 )C(0)0-, -N(R1 )CS-, - S(0)2N(R14)-, -N(R14)S(0)2-, -N(R1 )C0N(R14)-, -N(R1 )CSN(1 R)- or - N(R14)S02N(R14)- groups. Where the linker group contains two R14 substituents these may be the same or different.
When the chain Alk1 is present in the group R2 and/or R3 in compounds of formula (1) as an optionally substituted aliphatic chain it may be an optionally substituted Cι-ιoaliphatic chain. Particular examples include optionally substituted straight or branched chain Ci-βalkylene, C2. 6alkenylene, or C2-6 alkynylene chains. Particular examples of aliphatic chains represented by Alk1 include optionally substituted -CH2-, -(CH2)2-, -CH(CH3)CH2-, -(CH2)2CH2-, - (CH2)3CH2-, -CH(CH3)(CH2)2-, -CH2CH(CH3)CH2-, -C(CH3)2CH2-, - CH2C(CH3)2CH2-, -(CH2)2C(CH3)2CH2-, -(CH2)4CH2-, -(CH2)5CH2-, - CHCH-, -C(CH3)CH-, -CHCHCH2-, -CH2CHCH-, -CHCHCH2CH2-, - CH2CHCHCH2-, -(CH2)2CHCH-, -CC-, -CCCH2-, -CH2CC-, -CCCH2CH2-ι -CH2CCCH2- or -(CH2)2CCH- chains
Heteroaliphatic chains represented by the group Alk1 in compounds of formula (1 ) include the aliphatic chains just described for Alk1 but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L3 where L3 is as defined above for L1 when L1 is a linker atom or group. Each L3 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group. Particular examples include optionally substituted -L3CH2-, -CH2L3CH2-, -L3CH2CH2-, -L3CH2CH2L3-, - CH2L3CH2CH2-, -(CH2)2L3CH2-, -(CH2)3L3CH2-, -L3(CH2)2-, and - (CH2)2L3CH2CH2- chains.
The optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk1 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or -OH, -C02H, -C02R15 [where R15 is an optionally substituted straight or branched Cι-6alkyl group as defined above] -CONHR15, - CON(R15)2, -COR15, eg -COCH3, C-|-6alkoxy, e.g. methoxy or ethoxy, thiol, -S(0)R15, -S(0)2R15, Cι-6alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include -NHR15 and -N(R15)2 groups . Where two R15 groups are present in any of the above substituents these may be the same or different.
Optionally substituted cycloaliphatic groups represented by the group R8 when present in the group R2 and/or R3 in compounds of the invention include optionally substituted C3-ιocycloaliphatic groups. Particular examples include optionally substituted C3-iocycloalkyl, e.g. C3. 7cycloalkyl or C3-ιocycloalkenyl, e.g C3-7cycloalkenyl groups.
Optionally substituted heterocycloaliphatic groups represented by the group R8 include optionally substituted C3-ιoheterocycloaliphatic groups. Particular examples include optionally substituted C3-ιoheterocycloalkyl, e.g. C3-7heterocycloalkyl, or C3-ιoheterocycloalkenyl, e.g. C3-7hetero- cycloalkenyl groups, each of said groups containing one, two, three or four heteroatoms or heteroatom-containing groups L3 as defined above.
Optionally substituted polycycloaliphafic groups represented by the group R8 include optionally substitued C7.10 bi- or tricycloalkyl or C7-ιobi- or tricycloalkenyl groups. Optionally substituted polyheterocycloaliphatic groups represented by the group R8 include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L3 atoms or groups.
Particular examples of cycloaliphatic, polycycloaliphafic, heterocycloaliphatic and polyheterocycloaliphatic groups represented by the group R8 include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3- cyclopenten-1-yl, adamantyl, norbornyl, norbornenyl, tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1 ,3-dioxolanyl, imidazolinyl, e.g. 2- imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, homopiperidinyl, heptamethyleneiminyl, piperidinone, 1 ,4-dioxanyl, morpholinyl, morpholinone, 1 ,4-dithianyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1 ,3,5-trithianyl, oxazinyl, e.g. 2H-1 ,3-, 6H-1.3-, 6H-1.2-, 2H-1 ,2- or 4H-1.4- oxazinyl, 1 ,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p- isoxazinyl, oxathiazinyl, e.g. 1 ,2,5 or 1 ,2,6-oxathiazinyl, or 1 ,3,5,- oxadiazinyl groups.
The optional substituents which may be present on the cycloaliphatic, polycycloaliphafic, heterocycloaliphatic or polyheterocycloaliphatic groups represented by the group R8 include one, two, three or more substituents each selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C-|-6alkyl, e.g. methyl or ethyl, haloC-i-βalkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g. -C(OH)(CF3)2, Ci-βalkoxy, e.g. methoxy or ethoxy, haloC-i-βalkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, Ci-βalkylthio e.g. methylthio or ethylthio, or -(Alk4)vR16 groups in which Alk4 is a straight or branched C-|. 3alkylene chain, v is zero or an integer 1 and R16 is a -OH, -SH, - N(R17)2, (in which R17 is a hydrogen atom or an alkyl group) -CN, C02R17, -N02, -CON(R17)2, -CSN(R 7)2, -COR17, -CSN(R17)2, -SOR17, -S02R17, -N(R1 )COR17, -N(R1 )CSR17, -S02N(R1 )2, -N(R17)S02R17, -N(R17)CON(R17)2, -N(R17)CSN(R17), N(R17)S02N(R1 )2 or optionally substituted phenyl group. Where two R17 atoms or groups are present in these substituents these may be the same or different. Optionally substituted phenyl groups include phenyl substituted by one, two or three of the R10 groups as hereinbefore described.
Additionally, when the group R8 is a heterocycloaliphatic or heteropoly- cyclolaliphatic group containing one or more nitrogen atoms each nitrogen atom may be optionally substituted by a group -(L4)q(Alk5)rR18 in which L4 is -C(O)-, -C(0)0-, -C(S)-, -S(0)2-, -CON(R17)-, -CSN(R17)- or S02N(R17)-; q is zero or the integer 1 ; Alk5 is an optionally substituted aliphatic or heteroaliphatic chain; r is zero or an integer 1 ; and R18 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphafic, polyheterocycloaliphatic, aromatic or heteroaromatic group as herein defined.
Straight or branched C-|-3alkylene chains represented by Alk4 include - CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2- and -CH2CH(CH3)2- chains.
Optionally substituted aliphatic or heteroaliphatic chains represented by Alk5 include those optionally substituted chains described above for Alk1.
Cycloaliphatic, heterocycloaliphatic, polycycloaliphafic or polyheterocycloaliphatic groups represented by R18 include those groups just described for the group R8. Optional substituents which may be present on these groups include those described above in relation to Alk1 aliphatic and heteroaliphatic chains.
Aromatic and heteroaromatic groups represented by R18 include those groups as described hereinbefore for the group Ar. Optional substituents which may be present on these groups include those described above in relation to Ar.
Examples of R2 and/or R3 substituents represented by -L1(Alk1)tL(R8)u when present in compounds of the invention include atoms or groups - L1Alk1 L2R8, -L1Alk1 R8, -L R8, -R8 and -Alk R8 wherein L , Alk1, L2 and R8 are as defined above. Particular examples of such substituents include -L1CH2L2R8, -L1CH2CH2L2R8, -L1 (CH2)3L2R8, -L1CH(CH3)L R8, -L1CH2R8, -L (CH2)2R8, -L1(CH2)3R8, -L1CH(CH3)R8, -L1CHCHR8, - L1CHCHCH2R8, -L1CCR8, -L1CCCH2R8, -CH2R8, -(CH2)2R8, -(CH2)3R8, - CH(CH3)R8 and -R8 atoms or groups.
Thus R2 and/or R3 in compounds of the invention may be for example a halogen atom, e.g. fluorine, chlorine, bromine or iodine atoms, and/or C-|. βalkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, C3- βcycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C-|. δhydroxyalkyl, e.g. hydroxy methyl, hydroxyethyl or -C(OH)(CF3)2, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolidinyl, carboxyCι-6alkyl, e.g. carboxyethyl, C-|-6alkylthio e.g. methylthio or ethylthio, carboxyC-i- βalkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropyl- thio, Ci -ealkoxy, e.g. methoxy or ethoxy, hydroxyCi-βalkoxy, e.g. 2- hydroxyethoxy, haloCi-βalkyl, e.g. -CF3, -CHF2, -CH2F, haloCi -ealkoxy, e.g. -OCF3, -OCHF2, -OCH2F, Cι-6alkylamino, e.g. methylamino or ethylamino, amino (-NH2), aminoCi-βalkyl, e.g. aminomethyl or aminoethyl, Ci-βdialkylamino, e.g. dimethylamino or diethylamino, C-|.
6alkylaminoC-|-6alkyl, e.g. ethylaminoethyl, Cι-6 dialkylaminoCι-6alkyl, e.g. diethylaminoethyl, aminoCι-6alkylamino e.g. aminoethylamino, aminoC-i- ealkoxy, e.g. aminoethoxy, hydroxyC-i-ealkylamino e.g. hydroxyethylamino or hydroxyropylamino, Cι-6alkylaminoCι -ealkoxy, e.g. methylaminoethoxy, Cι-6dialkylaminoC-|-6alkoxy, e.g. dimethylaminoethoxy, diethylamino- ethoxy, diisopropylamino-ethoxy, or dimethylaminopropoxy, nitro, cyano, amidino, hydroxyl (-OH), formyl [HC(O)-], carboxyl (-C02H), -C02Alk3 [where Alk3 is as defined below for Alk7], C-|-6 alkanoyl e.g. acetyl, thiol (-SH), thioCι-6alkyl, e.g. thiomethyl or thioethyl, sulphonyl (-SO3H), - SOsAlk3, Cι-6alkylsulphinyl e.g. methylsulphinyl, ethylsulphinyl or propylsulphinyl, Cι-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (-S02NH2), C1-6 alkylamino-sulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, Cι-6dialkylaminosulphonyl, e.g. dimethylamino- sulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (-CONH2), Cι-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethyl- aminocarbonyl, Cι-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoCι-6alkylaminocarbonyl, e.g. aminoethyl- aminocarbonyl, Cι-6dialkylaminoCι-6alkylaminocarbonyl, e.g. diethyl- aminoethylaminocarbonyl, aminocarbonylamino, C-|-6alkylaminocarbonyl- amino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C-|. 6dialkylaminocarbonylamino, e.g. dimethyl-aminocarbonylamino or diethylaminocarbonylamino, Cι-6alkylamino-carbonylCι-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, Ci .βalkyl- aminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethyl- aminothiocarbonylamino, Ci-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C-|. 6alkylaminothiocarbonylCι -6alkylamino, e.g. ethylaminothiocarbonyl- methylamino, Cι-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, Ci-6dialkylsulphonylamino, e.g. dimethylsulphonyl- amino or diethylsulphonylamino, aminosulphonylamino (-NHS02NH2), Cι-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, Cι-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, C-|. ealkanoylamino, e.g. acetylamino, ethanoylamino or propanoylamino, C3- 6alkenoylamino e.g. acryloxylamino, methacryloylamino, crotonylamino, C3-6alkynylcarbonylamino e.g. proparylcarbonylamino, aminoCi- βalkanoyl-amino e.g. aminoacetylamino, Ci-βdialkylaminoCi. ealkanoylamino, e.g. dimethylaminoacetylamino, Cι-6alkanoylaminoCι. ealkyl, e.g. acetylamino-methyl, Cι-6alkanoylaminoCι-6alkylamino, e.g. acetamidoethylamino, Ci-βalkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino, t-butoxycarbonylamino, optionally substituted C3-7heterocycloalkylCι-6alkoxy e.g. optionally substituted morpholinoethoxy, morpholinopropoxy, morphilinobutoxy, pyrrolidinylpropoxy, imidazolylpropoxy, imidazolidinyl-propoxy, piperidinylpropoxy, thiomorpholinylpropoxy, or piperazinyl-propoxy, optionally substituted C6-ι2arylC-|-6alkoxy e.g. optionally substituted phenylpropoxy, optionaly substituted Cι-gheteroarylC-|-6alkoxy, e.g. optionally substituted pyrolylpropoxy, furylpropoxy, thienylpropoxy, imidazolylpropoxy, pyridylpropoxy, pyrimidinylpropoxy, pyridazinylpropoxy or pyrazinylpropoxy, optionally substituted C3-7heterocycloalkylC-|- 6alkylamino e.g. optionally substituted morpholinoethylamino, morpholinopropylamino, morpholinobutylamino, pyrrolidinylpropylamino, imidazolinylpropylamino, imidazolidinylpropylamino, piperidinylpropyl- amino, thiomorpholinylpropylamino or piperazinylpropylamino, optionally substitutedC6-ι2arylCι-6alkylamino e.g. optionally substituted phenylpropylamino, optionally substituted C-|-gheteroarylCι-6alkylamino e.g. optionally substituted pyrrolylpropylamino, furylpropylamino, thienylpropylamino, imidazolylpropylamino, pyridylpropylamino, pyrimidinylpropylamino, pyridazinylpropylamino or pyrazinylpropylamino optionally substituted C3-7heterocycloalkylC-|-6alkylcarbonyl e.g. optionally substituted morpholinoethylcarbonyl, morpholinopropylcarbonyol, morpholinobutylcarbonyl, pyrrolidinylpropylcarbonyl, imidazolinylpropyl- carbonyl, imidazolidinylpropylcarbonyl, piperazinpropylcarbonyl, thio- morpholinylpropylcarbonyl, or piperazinylpropylcarbonyl, optionally substituted C6-ι2arylCι-6alkylcarbonyl, e.g. optionally substituted phenyl- propoylcarbonyl, optionally substituted C-i-gheteroaryl Ci-βalkylcarbonyl e.g. optionally substituted pyrrolylpropylcarbonyl, furylpropylcarbonyl, thienylpropylcarbonyl, imidazolinylpropylcabonyl, pyridylpropylcarbonyl, pyrimidinylpropylcarbonyl, pyridazinylpropylcarbonyl or pyrazinylpropyl- carbonyl, optionally substituted C3-7heterocycloalkylC-|-6alkylthio e.g. optionally substituted morpholinoethylthio, morpholinopropylthio, morpholinobutylthio, pyrrolidinylpropylthio, imidazolinylpropylthio, imidazolidinylpropylthio, piperidinylpropylthio, thiomorpholinylpropylthio or piperazinylpropylthio, optionally substituted C6-ι2arylC-|-6alkylthio e.g. optionally substituted phenylpropylthio, optionally substituted C-|. gheteroarylCi-δalkylthio e.g. optionally substituted pyrrolylproylthio, furylpropylthio, thienylpropylthio, imidazolylpropylthio, pyridylpropylthio, pyrimidinylpropylthio, pyridazinylpropylthio or pyrazinylpropylthio group.
Where desired, two -L2(Alk2)tL3(R4)u substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C-|-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
It will be appreciated that where compounds of formula (1) exist as geometrical isomers and/or enantiomers or diasteromers then the invention extends to all such isomers of the compounds of formula (1), and to mixtures thereof, including racemates.
One group of compounds of the invention has the formula (1) above in which Ar is an optionally substituted aryl or heteroaryl group and R, R1 , X, R4, n, R2 and R3 are as generally and specifically defined for formula (1) and the salts, solvates, hydrates and N-oxides thereof.
One particularly useful group of compounds according to the invention is that wherein Ar is an optionally substituted aromatic group. Particularly useful compounds of this type are those wherein Ar is an optionally substituted phenyl group. In compounds of this type Ar may be in particular a phenyl group or a phenyl group substituted by one or two R10 groups as defined herein. Particularly useful substituents include one or two methyl groups and, especially, one or two halogen atoms.
In another useful group of compounds of formula (1) Ar is an optionally substituted heteroaromatic group, particularly an optionally substituted quinolinyl, isoquinolinyl or, especially, thienyl group. Where substituents are present in these groups these may be one or two R10 atoms or groups as defined herein. Particularly useful substituents include one or two halogen atoms.
In a further preference R is a hydrogen atom. Particularly useful compounds of this type include compounds of formula (1 a):
Figure imgf000019_0001
wherein Ar, R1 , R2, R3, R4, n and x are as generally and specifically defined previously, and the salts, solvates, hydrates and N-oxides thereof. In compounds of this type Ar may in particular be an optionally substituted aryl or heteroaryl group.
In compounds of formulae (1 ) and (1 a) R1 is in particular a hydrogen atom. In one preferred class of compounds of formulae (1) and (1a) n is zero.
In another preferred class of compounds of formula (1a) n is the integer 1. In this class of compounds R4 is preferably a halogen atom, especially a fluorine or chlorine atom or a methyl, halomethyl, especially -CF3, methoxy, halomethoxy, especially -OCF3, -CN, -C02R5 e.g. -C02CH3, - N02, amino, substituted amino, especially -NHCH3 or -N(CH3)2 or - N(R5)COR6, especially -N(R5)COCH3 eg -NHCOCH3 group.
In another preferred class of compounds of formulae (1) and (1 a) X is a nitrogen atom.
In a further preferred class of compounds of formulae (1) and (1a) X is a C(R1 a) group in which R1 a is preferably a cyano (-CN) group.
In one preferred class of compounds of formulae (1) and (1a) one of R2 and R3 is a hydrogen atom and the other is a group -L1Alk1 R8 in which L1 and Alk1 are as previously defined and R8 is a hydrogen atom or an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group. Especially preferred optionally substituted heterocycloaliphatic groups include optionally substituted Cs^heterocycloalkyl or C3-7hetero- cycloalkenyl groups, most especially optionally substituted, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, e.g. N-methylpiperidinyl, morpholinyl, thiomorpholinyl and piperazinyl e.g. N-methylpiperazinyl groups. Especially preferred optionally substituted aromatic groups include optionally substituted phenyl groups. Especially preferred optionally substituted heteroaromatic groups include monocyclic heteroaromatic groups, especially five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Especially preferred optionally substituted five- or six-membered heteroaromatic groups include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyridizinyl triazinyl, triazolyl e.g. 1 ,2,4-triazolyl or 1 ,3,4-triazolyl or pyrazinyl groups. In another preferred class of compounds of formulae (1) and (1 b) R2 and R3 is each a group -L1Alk1 R8 in which L1 and Alk1 are as previously defined and R8 is a hydrogen atom or an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group. Especially preferred optionally substituted heterocycloaliphatic groups include optionally substituted C3-7heterocycloalkyl or C3-7hetero-cycloalkenyl groups, most especially optionally substituted, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, e.g. N-methylpiperidinyl, morpholinyl, thiomorpholinyl and piperazinyl e.g. N-methylpiperazinyl groups. Especially preferred optionally substituted aromatic groups include optionally substituted phenyl groups. Especially preferred optionally substituted heteroaromatic groups include monocyclic heteroaromatic groups, especially five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Especially preferred optionally substituted five- or six-membered heteroaromatic groups include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyridizinyl triazinyl, triazolyl e.g. 1 ,2,4-triazolyl or 1 ,3,4-triazolyl or pyrazinyl groups.
In another preferred class of compounds of formulae (1) and (1a) one of R2 and R3 is a group -L1Alk1 R8 in which R8 is a hydrogen atom, L1 is a - 0-, -S-, -C(O)-, -N(R14-)-, e.g. -NH- or -N(CH3)-, or -N(R14)CO-, e.g. - NHCO- or -N(CH3)CO- linker atom or group and Alk1 is an aliphatic chain, e.g. a C-|-6alkyl chain, especially a -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH2CH2CH2CH2- or -CH2CH(CH3)CH2- chain or a C2-6alkenyl chain, especially a -CHCH-, -C(CH3)CH- or -CHCHCH2- chain or a C2-6alkynyl chain, especially a -CC- or -CCCH2- chain. In this class of compounds the other of R2 and R3 is preferably a group -L1Alk1 R8 in which L1 is a - 0-, -S-, -C(O)- or -N(R14)-, especially -NH- or -N(CH3)- linker atom or group, Alk1 is an aliphatic chain, especially a Chalky! chain, most especially a -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2- or CH2CH(CH3)CH2- chain and R8 is an optionally substituted, heterocycloaliphatic, aromatic or heteroaromatic group. Especially preferred optionally substituted heterocycloaliphatic groups include optionally substituted C3-7hetero-cycloalkyl or C3-7heterocycloalkenyl groups, most especially optionally substituted, pyrrolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, e.g. N-methylpiperidinyl, morpholinyl, thiomorpholinyl and piperazinyl e.g. N-methylpiperazinyl groups. Especially preferred optionally substituted aromatic groups include optionally substituted phenyl groups. Especially preferred optionally substituted heteroaromatic groups include monocyclic heteroaromatic groups, especially five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Especially preferred optionally substituted five- or six-membered heteroaromatic groups include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyridizinyl triazinyl, triazolyl e.g. 1 ,2,4-triazolyl or 1 ,3,4-triazolyl or pyrazinyl groups.
In one particularly preferred class of compounds of formulae (1) and (1a)
R2 is a group -L1Alk1 R8 in which L1 is an -O- atom, Alk1 is a C-|-6alkyl chain, especially a -CH2-, -CH2CH2- or -CH(CH3)CH2- chain and R8 is a hydrogen atom. In this class of compounds R3 is preferably a group - L1Alk1R8 in which L1 is an -O- atom, Alk1 is a Cι-6alkyl chain, especially a -CH2-, -CH2CH2, -CH2CH2CH2- or -CH2CH2CH2CH2- chain and R8 is an optionally substituted heterocycloaliphatic group, especially an optionally substituted C3-7heterocycloalkyl or C3-7heterocycloalkenyl groups, most especially an optionally substituted pyrrolidinyl, imidazolinyl, piperidinyl, e.g. N-methylpiperidinyl, morpholinyl, thiomorpholinyl or piperazinyl e.g. N-methylpiperazinyl group or an optionally substituted heteroaromatic group, especially a five or six-membered monocyclic heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms, such as optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, triazinyl, pyridizinoyl, pyrazinyl or most especially triazolyl e.g. 1 ,2,4-triazolyl or 1 ,3,4-triazolyl groups.
In another particularly preferred class of compounds of formulae (1) and (1a) R3 is a group -L1Alk1 R8 as just defined and R2 is preferably a group - L1Alk1 R8 in which L is a -N(R14)CO, especially -NHCO- linker group, Alk1 is a C2-6alkenyl chain, especially -CHCH-, -C(CH3)CH- or - CHCHCH2- or a C2-6alkynyl chain, especially -CC- or -CCCH2- and R8 is a hydrogen atom. In another particularly preferred class of compounds of formulae (1) and (1a) R2 is a group -L1Alk1 R8 in which L1 is an -O- atom, Alk1 is a Ci-βalkyl chain, especially a -CH -, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- chain and R8 is an optionally substituted heterocycloalphatic group, especially an optionally substituted C3-7heterocycloalkyl or C3- 7heterocycloalkenyl groups, most especially an optionally substituted pyrrolidinyl, imidazolyl, piperidinyl, e.g. N-methylpiperidinyl, morpholinyl, thiomorpholinyl or piperazinyl group or an optionally substituted heteroaromatic group, especially a five- or six-membered monocyclic heteroaromatic grop containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms, such as optionally substituted pyrridyl, furyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, triazinyl, pyridizolyl, pyrazinyl or most especially triazolyl e.g. 1 ,2,4-triazolyl or 1 ,3,4-triazolyl group. In this class of compounds R3 is preferably a group - L1Alk1 R8 in which L1 is an -O- atom, Alk1 is a Chalky! chain, especially a -CH2-, -CH2CH2- or -CH(CH3)CH- chain and R8 is a hydrogen atom.
In another particularly preferred class of compounds of formulae (1) and (1a) R2 is a group -L1Alk1 R8 as just defined and R3 is preferably a group -L1Alk1 R8 in which L1 is a -N(R14)CO, especially -NHCO- linker group, Alk1 is a C2-6alkenyl chain, especially -CHCH-, -C(CH )CH- or - CHCHCH2- or a C2-6alkynyl chain, especially -CC- or -CCCH2- and R8 is a hydrogen atom.
One especially useful group of compounds of the invention has the formula (1 ) or (1a) in which one of R2 and R3, particularly R2, is a methoxy group and the other is a group -OAIk1 R8. In these compounds R8 is in particular a -NR5R6 or heterocycloaliphatic group. In this group of compounds Alk1 may in particular be a -(CH2)2- or -(CH2)3- chain. Particular R8 groups include -NHCH3, -N(CH3)2, optionally substituted morpholinyl or optionally substituted piperazinyl groups, especially - N(CH3)2, morpholino, piperazinyl and N-methylpiperazinyl groups.
Particularly useful compounds according to the invention include those in the Examples herein, particularly the compounds of Examples 1 , 4, 5, 8, 9, 12, 13, 14, 18, 25, 28, 31 , 36, 39, 41 , 42, 68, 74, 75, 76, 82, 83, 86, 87, 144, 145, 146, 152 or 153 and the salts, solvates, hydrates or N-oxides thereof.
Compounds according to the invention are potent and selective inhibitors of Class I receptor tyrosine kinases, especially EGFr kinase as demonstrated by differential inhibition of this enzyme when compared to inhibition of other protein kinases such as p56lck kinase, protein kinase C, KDR kinase and FGFr2 kinase. The ability of the compounds to act in this way may be simply determined by the tests described in the Examples hereinafter.
The compounds according to the invention are thus of particular use in the prophylaxis and treatment of diseases in which inappropriate Class I receptor tyrosine kinase action plays a role, for example in hyperproliferative disorders such as tumours, psoriasis, restenosis following angioplasty, atherosclerosis, and fibrosis e.g. of the liver and kidney.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non- aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The composifions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1 ) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro-fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols R1 , R2, R3, R4 n, and x when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in "Protective Groups in Organic Synthesis", John Wiley and Sons, 1999]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. Thus according to a further aspect of the invention, a compound of formula (1) may be prepared by reaction of a sulphonamide ArS02NH2 with a compound of formula (2):
Figure imgf000027_0001
where Hal is a halogen atom such as a chlorine atom.
The reaction may be performed at an elevated temperature, for example the reflux temperature, where necessary in the presence of a solvent, for example a substituted amide such as dimethylformamide, optionally in the presence of a base, for example an inorganic base such as sodium hydride or most preferably a carbonate such as potassium or caesium carbonate.
Intermediate sulphonamides represented by ArS02NH2 and intermediates of formula (2) are either known compounds or may be obtained by conventional procedures, for example from the known compounds by using one or more of the standard substitution and/or oxidation, reduction or cleavage reactions described below in relation to interconversion of compounds of formula (1) or by methods known to those skilled in the art following procedures set forth in references such as Rodd's Chemistry of Carbon Compounds, Volumes 1 -15 and Supplemental (Elsevier Science Publishers, 1989), Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed. Katritzky et al, Volumes 1 -8, 1984 and Volumes 1-11 , 1994 (Pergamon), Comprehensive Organic Functional Group Transformations, Ed. Katritzky et al, Volumes 1-7, 1995 (Pergamon), Comprehensive Organic Synthesis, Ed. Trost and Flemming, Volumes 1- 9, (Pergamon, 1991), Encyclopedia of Reagents for Organic Synthesis Ed. Paquette, Volumes 1-8 (John Wiley and Sons, 1995), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) and March's Advanced Organic Chemistry (John Wiley and Sons, 1992).
Thus compounds of formula (1) may also be prepared by interconversion of other compounds of formula (1) and it is to be understood that the invention extends to such interconversion processes. Thus, for example, standard substitution approaches employing for example alkylation, arylation, acylation, thioacylation, sulphonylation, formylation or coupling reactions may be used to add new substitutents to and/or extend existing substituents in compounds of formula (1 ). Alternatively existing substituents in compounds of formula (1) may be modified by for example oxidation, reduction or cleavage reactions to yield other compounds of formula (1).
The following describes in general terms a number of approaches which can be employed to modify existing Ar and R2 and R3 in compounds of formula (1 ). It will be appreciated that each of these reactions will only be possible where one or more appropriate functional groups exist in the compound of formula (1).
Thus, for example alkylation or arylation of a compound of formula (1 ), for example to introduce a group -Alk2(R1 1)m or R11 where R1 1 is an aryl group may be achieved by reaction of a compound of formula (1 ) containing an appropriate nucleophilic group (eg an amine or hydroxyl group) with a reagent (R11)mAlk2L or R11L, where L is a leaving group such as a halogen atom, e.g. a bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoro- methylsulphonyloxy or arylsulphonyloxy, e.g. phenylsulphonyloxy group. The alkylation or arylation reaction may be carried out in the presence of a base, e.g. an inorganic base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substitued amide such as diemethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran, at around 0°C to 100°C. In another general example of an interconversion process, a compound of formula (1) may be acylated or thioacylated, for example to introduce a group -C(0)R12 or -C(S)R12. The reaction may be performed for example with an acyl or thioacyl halide or anhydride in the presence of a base, such as an organic amine e.g. triethylamine or pyridine in a solvent such as an aromatic or halogenated hydrocarbon, e.g. toluene, optionally in the presence of a catalyst, e.g. dimethylaminopyridine dichloromethane at for example ambient up to the reflux temperature, or by reaction with a thioester in an inert solvent such as tetrahydrofuran at a low temperature such as around 0°C.
Compounds of formula (1) may be prepared in another general interconversion reaction by sulphonylation, for example by reaction of the compound with a reagent R1 S(0)L or R12S02L where L is a leaving group as described above in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature. The reaction may in particular be performed with compounds of formula (1) in which Ar possesses a primary or secondary amino group.
In further examples of interconversion reactions according to the invention compounds of formula (1) may be prepared from other compounds of formula (1) by modification of existing functional groups in the latter.
Thus in one example, ester groups -C02Alk3 in compounds of formula (1 ) may be converted to the corresponding acid [-C02H] by acid- or base- catalysed hydrolysis depending on the nature of the group Alk3. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a second example, -OR12 [where R12 represents an alkyl group such as methyl group] groups in compounds of formula (1) may be cleaved to the corresponding alcohol -OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
In another example, alcohol -OH groups in compounds of formula (1) may be converted to a corresponding -OR12 group by coupling with a reagent R12OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [-NHS02NH2] groups in compounds of formula (1) may be obtained, in another example, by reaction of a corresponding amine [-NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In another example of an interconversion reaction, amine (-NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [-NH2] groups in compounds of formula (1 ) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [-N02] group may be reduced to an amine [- NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid. In a further example, amide [-CONHR12] groups in compounds of formula (1) may be obtained by coupling a corresponding acid [-C02H] or an active derivative thereof, e.g. an acid anhydride, ester, imide or halide, with an amine R12NH2. The coupling reaction may be performed using standard conditions for reactions of this type. Thus for example the reaction may be carried out in a solvent, for example an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, at a low temperature, e.g. -30°C to ambient temperature, optionally in the presence of a base, e.g. an organic base such as a cyclic amine, e.g. N-methylmorpholine, and where necessary in the presence of a condensing agent, for example a diimide such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxytriazole, e.g. 1 - hyd roxy benzotriazole .
Aromatic halogen substituents in compounds of the invention may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
In another example, sulphur atoms in compounds of the invention may be oxidised to the corresponding sulphoxide using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
In a further example of an interconversion reaction, a compound of the invention containing a substituent R10 in which R10 is an aryl or heteroaryl group may be prepared by coupling a corresponding compound in which the R10 substituent is a halogen atom such as a bromine atom, with a boronic acid Ar1B(OH)2 [in which Ar1 is an aryl or heteroaryl group as defined above for Ar] in the presence of a complex metal catalyst. Suitable catalysts include heavy metal catalysts, for example palladium catalysts such as tetrakis(triphenylphosphine) palladium. The reaction may be performed in an inert organic solvent, for example an ether such as dimethoxyethane, in the presence of a base, e.g. an alkali carbonate such as sodium carbonate, at an elevated temperature, e.g. the reflux temperature.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
The following Examples illustrate the invention.
All temperatures are in °C.
The following abbreviations are used:
DEAD - Diethyl azodicarboxylate; THF - tetrahydrofuran;
EtOAc - ethyl acetate; RT - retention time;
DCM - dichloromethane; DMF - dimethylformamide;
MeOH - methanol; LCMS - liquid chromatography mass spectroxcopy.
All NMR's were obtained at 300MHz, unless otherwise indicated.
INTERMDIATE 1 Ethyl 4-(3-bromo-propoxy)-3-methoxy-benzoic acid
To a solution of triphenylphosphine (25.18g, 96mmol), and ethyl vanillate (15.70g, 80mmol), in dry THF (125mL) at 0°, was added under nitrogen, a solution of DEAD (16.7g, 96mmol), and 3-bromo-1-propanol (11.12g, δOmmol), in dry THF (30mL). The reaction was allowed to warm to room temperature and stirred for 5h. A further 0.2 equivalents of DEAD, triphenylphosphine and 3-bromo-1-propanol was added and the reaction allowed to stir for 60h. The reaction was diluted with EtOAc (150mL) and filtered, the filtrate washed with further EtOAc (2 x 100mL). The combined organic phases were washed with saturated aqueous NaHCθ3 (2 x 150mL) and brine (150mL), dried with MgSO_ι, filtered and the solvents removed in vacuo. The crude was purified by column chromatography (Si02; 10-15 % EtOAc in hexanes) to give the title product as a white waxy solid (17.0g, 67 %). δH (CDCI3) 7.66 (1 H, dd, J 8.4, 2.0Hz), 7.55 (1 H, d, J 2.0Hz), 6.91 (1 H, d, J 8.4Hz), 4.35 (2H, q, J 7.1 Hz), 4.21 (2H, t, J 6.0Hz), 3.90 (3H, s), 3.62 (2H, t, J 6.4Hz), 2.39 (2H, quintet, J 6.2Hz), 1.38 (3H, t, J 7.1 Hz). LCMS (EI+, 70eV): m/z 318 (M+H)+, RT = 3.60 min.
INTERMEDIATE 2
Ethyl 4-(3-bromo-propoxy)-5-methoxy-2-nitro-benzoic acid
Intermediate 1 (16g) was added portion-wise to stirred ice cold 69% nitric acid (100mL). The reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was poured onto ice/water (500mL) and the aqueous phase extracted with DCM (3 x 200mL). The combined organics were washed with brine (500 mL), dried MgS04, filtered and the solvents removed in vacuo to give the title product as an orange crystaline solid (16.63g, 91 %). δH (CDCI3) 7.49 (1 H, s), 7.07 (1 H, s), 4.37 (2H, q, J 7.2Hz), 4.23 (2H, t, J 5.9Hz), 3.96 (3H, s), 3.62 (2H, t, J 6.3Hz), 2.40 (2H, quintet, J 6.3Hz), 1.35 (3H, t, J 7.2Hz).
INTERMEDIATE 3 Ethyl 5-methoxy-4-(3-morpholin-4-yl-propoxy)-2-nitro-benzoic acid
To a solution of morpholine (4.76mL, 54.7mmol) in DMF (50mL) was added K C03 (7.54g, 54.7mmol), followed by a solution of Intermediate 2
(16.5g, 45.6mmol) in DMF (50mL). The solution was heated to 60° with stirring for 18h, after which time the volatile components were removed in vacuo. The residue was partitioned between EtOAc (200mL) and brine (300mL). The aqueous phase was extracted with EtOAc (3 x 100mL), the combined organics washed with brine (3 x 200mL), dried (MgS04), filtered and the solvents removed in vacuo to give the title product as a viscous yellow oil (16.69g, 99 %). δH (CDCI3) 7.47 (1 H, s), 7.06 (1 H, s), 4.36 (2H, q, J 7.1 Hz), 4.17 (2H, t, J 6.5Hz), 3.94 (3H, s), 3.71 (4H, m), 2.52 (2H, t, J 7.0Hz), 2.46 (4H, m), 2.06 (2H, quintet, J 6.7Hz), 1.34 (3H, t, J 7.1 Hz). LCMS (EI+ 70eV): m/z 369 (M+H)+.
INTERMEDIATE 4 Ethyl 2-amino-5-methoxy-4-(3-morpholin-4-yl-propoxy)-ben2oic acid
To a degassed (nitrogen) solution of Intermediate 3 (16.6g, 45.1 mmol) in ethanol (180mL), was added a slurry of 10% palladium on carbon (2.8g) in iso-propanol (ca. ~15mL). Under a nitrogen atmosphere ammonium formate (14.25g, 226mmol) was added. The reaction was allowed to stir for one hour at room temperature. The reaction mixture was filtered through a pad of celite® and the solvents removed in vacuo. The residue was dissolved in DCM (300mL) and washed with water (200mL). The aqueous phase was extracted with further DCM (2 x 100mL) and the combined organics washed with brine (3 x 150mL), dried (MgSO_ι), filtered and the solvents removed in vacuo to give the title product as a pale brown solid (14.29g, 94 %). δH (CDCI3) 7.34 (1 H, s), 6.18 (1 H, s), 5.57
(2H, bs), 4.33 (2H, q, J 7.1 Hz), 4.09 (2H, t, J 6.6 Hz), 3.82 (3H, s), 3.80 - 3.77 (4H, m), 2.65 - 2.48 (6H, m), 2.15 - 2.08 (2H, m), 1.39 (3H, t, J 7.1 Hz). LCMS (EI+, 70eV): m/z 339 (M+H)+, RT = 2.20 min.
INTERMEDIATE 5
6-Methoxy-7-(3-morpholin-4-yl-propoxy)-3H-quinazolin-4-one
A mixture of Intermediate 4 (14.3g, 42.3mmol) and formamide (70mL) were heated to 170° for 5h. The reaction mixture was poured into brine (300mL) and the aqueous slurry extracted with chloroform (3 x 200mL). The organic phases were dried (MgS04), filtered and the solvents removed in vacuo to give the title product as an off white solid (7.18g, 53%). Further extraction of the aqueous phase with chloroform gave further product of lower purity (4g). δH (CDCI3) 11.72 (1 H, bs), 8.02 (1 H, s), 7.59 (1 H, s), 7.17 (1 H, s), 4.24 (2H, t, J 6.6Hz), 3.99 (3H, s), 3.74 (4H, m), 2.59 - 2.50 (6H, m), 2.12 (2H, m). LCMS (EI+, 70eV): m/z 320 (M+H)+, RT = 1.52min.
INTERMEDIATE 6 4-Chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinazoline Intermediate 5 (6.67g, 20.9 mmol) was suspended in POCI3 (120mL) and DMF (1 mL) added. The mixture was heated at reflux for two hours. The volatile material was removed in vacuo and the residue cooled to 0°, and saturated aqueous NaHC03 (200mL) added. The aqueous phase was extracted with DCM (3 x 150mL). The combined organic phases were washed with saturated aqueous NaHC03 (1 x 200mL) and brine (1 x 200mL), dried (MgS04), filtered and the solvents removed in vacuo to give a crude tan solid. The crude product was purified by column chromatography (Si02; 5 % MeOH / DCM) to give the title product as a pale yellow solid ( 5.06g, 71 %). δH (CDCI3) 8.85 (1 H, s), 7.39 (1 H, s), 7.36 (1 H, s), 4.31 (2H, t, J 6.7Hz), 4.08 (3H, s), 3.71 (4H, m), 2.68 - 2.41 (6H, m), 2.13 (2H, m). LCMS (EI+, 70eV): m/z 338 (M+H)+, RT = 1.73 min.
INTERMEDIATE 7
6-Methoxy-7-(2-morpholin-4-ylethoxy)-4- pentafluorophenoxyquinazoline
A stirred mixture of 7-hydroxy-6-methoxy-4- pentafluorophenoxyquinazoline (2.0g, 5.6mmol), Cs2C03 (7.2g, 22.4mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.2g, 6.5mmol) in anhydrous DMF (40mL) was heated at 100° for 4h. The reaction mixture was poured into water and extracted with several portions of EtOAc. The combined organic phases were washed sequentially with water and brine, then dried (MgS04) and concentrated. The residue was purified by column chromatography (Si02, 2-5% MeOH / DCM) to produce the title compound as a beige solid (2.47g). δH (CDCI3) 8.58 (1 H, s), 7.51 (1 H, s), 7.36 (1 H, s), 4.40 (2H, br s), 4.05 (3H, s), 3.78 (4H, br s), 3.00 (2H, br s), 2.69 (4H, br s). LCMS (ES+) 472 (MH+).
INTERMEDIATE 8
7-(2-Diethylaminoethoxy)-6-methoxy-4- pentafluorophenoxyquinazoline
The title compound was prepared in a similar manner to Intermediate 7, from 7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline (1.4g, 3.9mmol) and 2-(diethylamino)ethyl chloride hydrochloride (0.81 g) to give a white solid (1.2g). δH (CDCI3) 8.51 (1 H, s), 7.43 (1 H, s), 7.30 (1 H, s), 4.25 (2H, m), 3.98 (3H, s), 3.00 (2H, m), 2.65 (4H, m) and 1.06 (6H, m). LCMS (ES+) 458 (MH+).
INTERMEDIATE 9 7- 3-Dimethylaminopropoxy)-6-methoxy-4- pentafluorophenoxyquinazoline
The title compound was prepared in a similar manner to Intermediate 7, from 7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline (1.4g, 3.9mmol) and 3-(dimethylamino)propyl chloride hydrochloride (0.74g) to give a white solid
(0.7g). δH (CDCI3) 8.35 (1 H, s), 7.28 (1 H, s), 7.14 (1 H, s), 4.07 (2H, t, J =
6.4Hz), 3.83 (3H, s), 2.49 (2H, m), 2.21 (6H, m) and 2.01 (2H, m). LCMS (ES+) 444 (MH+).
INTERMEDIATE 10
6-Methoxy-7-(2-(4-methyl-1-piperazinyl)ethyl)-4- pentafluorophenoxyquinazoline
A stirred mixture of 7-hydroxy-6-methoxy-4- pentafluorophenoxyquinazoline (1.0g, 2.7mmol), triphenylphosphine (1.1g, 4.2mmol) and 1 -(2-hydroxyethyl)-4-methylpiperazine (0.48g, 3.3mmol) in anhydrous THF (15mL) was treated with a solution of diethylazodicarboxylate (0.73g, 4.2mmol) in anhydrous THF (1.5mL) and the resulting mixture stirred at room temperature for 3h. The mixture was evaporated and the residue purified by column chromatography (Si02, 2- 8% MeOH / DCM) to afford the title compound as a white solid (0.96g). δH (CDCI3) 8.36 (1 H, s), 7.28 (1 H, s), 7.13 (1 H, s), 4.12 (2H, t, J = 5.8Hz),
3.83 (3H, s), 2.78 (2H, t, J = 5.8Hz), 2.50 (8H, complex) and 2.22 (3H, s). LCMS (ES+) 485 (MH+).
INTERMEDIATE 11
6-Methoxy-4-pentafluorophenoxy-7- 2-piperidinoethyl)-quinazoline
The title compound was prepared in a similar manner to Intermediate 10, from 7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline (1.0g,
2.7mmol) and 1-piperidineethanol (0.43g) to give a white solid (0.74g). δH (CDCI3) 8.58 (1 H, s), 7.50 (1 H, s), 7.37 (1 H, s), 4.38 (2H, m), 4.06 (3H, s), 2.97 (2H, m), 2.61 (4H, m), 1.66 (4H, M) and 1.48 (2H, m). LCMS (ES+) 470 (MH+).
INTERMEDIATE D 6-Methoxy-7-(1-methyl-4-piperidinoxy)-4- pentafluorophenoxyquinazoline
The title compound was prepared in a similar manner to Intermediate 10, from 7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline (1.0g,
2.7mmol) and 4-hydroxy-1-methylpiperidine (0.38g) to give a white solid (0.70g). δH (CDCI3) 8.49 (1 H), 7.44 (1 H, s), 7.29 (1 H, s), 4.53 (1 H, m),
3.98 (3H, s), 2.79 (2H, m), 2.32 (5H, complex), 2.15 (2H, m) and 1.95 (2H, m). LCMS (ES+) 456 (MH+).
EXAMPLE 1 2-Chloro-N-r6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yll- benzenesulphonamide
To a mixture of Intermediate 6 (100mg, 0.3mmol), and 2-chloro- benzenesulphonamide (69mg, 0.36mmol) in dry DMF (2mL) was added Cs2Cθ3 (326mg, 1.Ommol). The mixture was heated to 80° for 6h. The reaction was partitioned between brine (50mL) and chloroform (50mL). The pH of the aqueous phase was adjusted to pH = 5 (2M HCl) and the aqueous phase extracted with further chloroform (2 x 50mL). The organic phases were washed with brine (100mL), dried (MgSθ4), filtered and the solvents removed in vacuo. The crude product was purified by column chromatography (Si02; 5% MeOH / DCM) to give the title product as a white crystalline solid (115mg, 78%). δH (CDCI3) 8.20 (1 H, d, J 7.2Hz), 8.03 (1 H, s), 7.51 (1 H, s), 7.40 - 7.30 (3H, m), 7.10 (1 H, s), 4.17 (2H, t, J 6.6Hz), 3.84 (3H, s), 3.65 - 3.61 (4H, m), 2.48 - 2.43 (2H, m), 2.40 - 2.37 (4H, m), 2.05 - 1.98 (2H, m). LCMS (EI+, 70eV): m/z 493 (M+H)+, RT = 2.50 min.
EXAMPLE 2
[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4yπ-quinolin-8- ylsulphonamide To a mixture of Intermediate 6 (200mg, 0.6mmol), and 8-quinoline- sulphonamide (374mg, 1.8mmol) in dry DMF (6 mL) was added Cs2C03 (978mg, 3.0mmol). The mixture was heated to 80° for 20h. The reaction was filtered through a pad of celite® and the solvents removed in vacuo. The reaction was dissolved in distilled water (20mL) and the pH of the aqueous phase was adjusted to pH = 5 (2M HCl). The aqueous phase was extracted with chloroform (3 x 20mL). The organic phases were dried (MgS04), filtered and the solvents removed in vacuo. The crude residue was purified by column chromatography (Si02; 5% MeOH / DCM) to give the title product as an off white crystalline solid (128mg, 42 %). δH (CDCI3) 8.71 - 8.69 (2H, m), 8.26 (1 H, s), 8.22 (1 H, dd, J 8.3, 1.8Hz), 8.02 (1 H, dd, j 8.2, 1.3Hz), 7.70 (1 H, t, J 7.5Hz), 7.59 (1 H, s), 7.42 (1 H, dd, j 8.3, 4.2Hz), 7.18 (1 H, s), 4.24 (2H, t, J 6.6Hz), 3.88 (3H, s), 3.74 - 3.70 (4H, m), 2.56 - 2.45 (6H, m), 2.13 - 2.06 (2H, m). LCMS (EI+, 70eV): m/z 510 (M+H)+, RT = 3.08 min.
EXAMPLE 3
/V-r6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-vn-2-methyl- benzenesulphonamide
The title product was prepared in a similar fashion to Example 1 , from 2- methylbenzenesulphonamide (308mg, 1.8mmol). The crude residue was purified by column chromatography (Si02; 5% MeOH in DCM) to give the title product as an off white crystalline solid (138mg, 49%). δH (CDCI3) 7.56 (1 H, s), 7.54 (1 H, s), 7.31 - 7.27 (2H, m), 7.23 - 7.18 (2H, m), 7.10 (1 H, s), 4.36 (3H, s), 4.16 (2H, t, J 6.6Hz), 3.94 (3H, s), 3.65 - 3.62 (4H, m), 2.50 - 2.45 (2H, m), 2.41 - 2.38 (4H, m), 2.04 - 1.99 (2H, m). LCMS (EI+, 70eV): m/z 473 (M+H)+, RT = 2.50 min.
EXAMPLE 4
2.4-Dichloro-M-r6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4- yll-benzenesulphonamide The title product was prepared in a similar fashion to Example 1 , from 2,4- dichlorobenzenesulphonamide (382 mg, 1.8 mmol). The crude residue was purified by column chromatography (Si02; 5% MeOH / DCM) to give the title product as an off white crystalline solid (123mg, 39%). δH (CDCI3) 8.23 (1 H, d, J 8.5Hz), 8.10 (1 H, s), 7.58 (1 H, s), 7.50 (1 H, s), 7.43 (1 H, dd, J 8.5, 2.0Hz), 7.21 (1 H, s), 4.27 (2H, t, J 6.7Hz), 3.94 (3H, s), 3.74 - 3.71 (4H, m), 2.55 (2H, t, J 7.0Hz), 2.49 - 2.46 (4H, m), 2.12 - 2.05 (2H, m). LCMS (EI+, 70eV): m/z 528 (M+H)+, RT = 2.41 min.
EXAMPLE 5 2-Bromo-N-f6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yll- benzenesulphonamide
The title product was prepared in an identical fashion to Example 1 , from 2-bromobenzenesulphonamide (423mg, 1.8mmol). The crude residue was purified by column chromatography (Si02, 5% MeOH / DCM) to give the title product as an off white crystalline solid (163mg, 50%). δH (CDCI3) 8.34 (1 H, d, J 7.8Hz), 8.10 (1 H, s), 7.72 (1 H, d, J 7.8Hz), 7.63
(1 H, s), 7.50 (1 H, m), 7.40 (1 H, m), 7.20 (1 H, s), 4.26 (2H, t, J 6.6Hz), 3.94 (3H, s), 3.75 - 3.71 (4H, m), 2.55 (2H, t, J 7.0Hz), 2.49 - 2.46 (4H, m), 2.12 - 2.08 (2H, m). LCMS (EI+, 70eV): m/z 538 (M+H)+ RT = 2.32 min.
EXAMPLE 6
2-Cvano-M-r6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl1- benzenesulphonamide The title product was prepared in a similar fashion to Example 1 , from 2- cyanobenzenesulphonamide (327mg, 1.8mmol). The crude residue was purified by column chromatography (Si02, 5% MeOH / DCM) to give the title product as an off white crystalline solid (74mg, 26%). δH (400 MHz, DMSO, 360K) 8.72 (1 H, s), 8.30 (1 H, m), 8.05 (1 H, s), 7.97 (1 H, m), 7.86 - 7.82 (2H, m), 7.40 (1 H, s), 4.35 (2H, t, J 6.4Hz), 4.04 (3H, s), 3.65 - 3.62 (4H, m), 2.59 - 2.47 (6H, m), 2.07 - 2.00 (2H, m). LCMS (EI+, 70eV): m/z 484 (M+H)+ RT = 3.64 min.
EXAMPLE 7 3.5-Dichloro-Λ/-r6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolazolin- 4-yllbenzene sulphonamide
The title product was prepared in a similar manner to Example 1 , from 3,5- dichlorobenzene sulphanamide (81 mg, 0.36mmol). The crude residue was purified by column chromatography (Si02; EtOAc:hexane 20:60%) to give the title compound as a white solid (67mg). δH (d6- DMSO) 8.30 (1 H, s), 7.85 (2H, s), 7.76 (2H, s), 4.15-4.11 (2H, t, J 6.1 Hz), 3.86 (3H, s), 3.58 (4H, m), 2.47-2.44 (4H, m), 2.24-2.22 (2H, m). LCMS (ES+, 70eV) 527, (M+H)+, RT 2.47min.
EXAMPLE 8 3-Chloro-Λ/-r6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolazolin-4- yllbenzene sulphonamide
The title product was prepared in a similar manner to Example 1 , from 3- chlorobenzene sulphonamide (69mg, 0.36mmol). The crude residue was purified by column chromatography (Si02; EtOAc 20-60%:hexane to give the title compound as a white solid (61 mg). δH (d8-DMSO) 8.32 (1 H, s), 7.96-7.95 (1 H, d, J 6.8Hz), 7.90-7.88 (1 H, d J 6.8Hz), 7.55-7.50 (4H, m), 4.19-4.15 (2H, t, J 6.4Hz), 3.89 (3H, s), 3.61-3.58 (4H, m), 3.25 (2H, m), 2.49 (4H, m), 2.00-1.95 (2H, m). LCMS (ES+ 70eV) m/z 493 (M+H)+, RT 2.42 min.
EXAMPLE 9
4-Chloro-ΛH6-methoxy-7-(3-morpholiin-4-yl-propoxy)-quinolazolin-4- yll benzene sulphonamide
The title product was prepared in a similar manner to Example 1 , from 4- chlorobenzene sulphonamide (69mg, 0.36mmol). The crude residue was purified by column chromatography (Si02, EtOAc 20-60% / hexane) to give the title compound as a white solid (20.6mg). δH (d6-DMSO) 8.31 (1 H, s), 7.97-7.87 (2H, d, J 7.4Hz), 7.58-7.50 (3H, m), 7.11 (1 H, s), 4.19- 4.15 (2H, t, J 6.3Hz), 3.89 (3H, s), 3.61 -3.58 (4H, m), 3.30 (2H, m), 2.49 (4H,m ), 2.00-1.99 (2H, m). LCMS (ES+ 70eV) m/z 493, (M+H)+ RT 2.41 min.
EXAMPLE 10
4-Methyl-Λ/-r6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolazolin-4- yl] benzene sulfonamide
The title product was prepared in a similar manner to Example 1 from 4- methylbenzene sulphonamide (62mg, 0.36mmol). The crude residue was purified by column chromatography (Si02; EtOAc 20-60% / hexane) to give the title compound as a yellow solid (12.5mg). δH (d6-DMSO) 8.34 (1 H, s), 7.94-7.91 (2H, d, J 8.1 Hz), 7.44-7.41 (2H, d, J 8.1Hz), 7.22 (1 H, s), 4.27-4.22 (2H, t, J 6.5Hz), 3.94 (3H, s), 3.66-3.63 (4H, m), 3.37-3.35 (2H, m), 2.58-2.56 (4H, m), 2.42 (3H, s), 2.07-2.04 (2H, m). LCMS (m/z ES+, 70eV) m/z 473 (M+H)+ RT 2.32min.
EXAMPLE 11
N-r6-Methoxy-7-(2-morpholin-4-ylethoxy)quinazolinv-4-vn- benzenesulphonamide
A mixture of Intermediate 7 (20mg, 0.042mmol), benzenesulphonamide (8mg, 0.051 mmol) and Cs2Cθ3 (60mg, 0.18mmol) in anhydrous DMF
(0.3mL) was heated at 100°C for 24h. The reaction mixture was decanted from any solids and then concentrated. The crude residue was purified by preparative HPLC to afford the title compound (2mg). LCMS Retention time: 2.06min, MH+ 445.
EXAMPLES 12 - 155 Using the method described in EXAMPLE 11 , the appropriate sulphonamides were reacted with the appropriate Intermediates to give the compounds described in TABLE 1. In the table the symbols Xi and X2 represent the point of attachment of the substituent shown to the rest of the molecule.
Analytical LCMS conditions
Phenomenex Luna C18(2) 50 x 4.6mm (3um) column, running a gradient of 95% [0.1 % aqueous formic acid], 5% [0.1 % formic acid in acetonitrile] to 5% [0.1% aqueous formic acid], 95% [0.1% formic acid in acetonitrile] over 2min, then maintaining the mobile phase at that ratio for a further 2min. Flow rate 0.9ml/min.
MS was acquired by API electrospray in positive ion mode, at 70V, scanning from 120 to 750amu.
TABLE 1
Figure imgf000041_0001
TABLE 1 (contd)
Figure imgf000042_0001
TABLE 1 fcontd)
Figure imgf000043_0001
TABLE 1 (contd)
Figure imgf000044_0001
TABLE 1 (contd)
Figure imgf000045_0001
TABLE 1 (contd)
Figure imgf000046_0001
TABLE 1 (contd)
Figure imgf000047_0001
TABLE 1 (contd)
Figure imgf000048_0001
TABLE 1 (contd)
Figure imgf000049_0001
TABLE 1 (contd)
Figure imgf000050_0001
TABLE 1 (contd)
Figure imgf000051_0001
TABLE 1 (contd)
Figure imgf000052_0001
TABLE 1 (contd)
Figure imgf000053_0001
TABLE 1 (contd)
Figure imgf000054_0001
TABLE 1 (contd)
Figure imgf000055_0001
TABLE 1 (contd)
Figure imgf000056_0001
TABLE 1 (contd)
TABLE 1 (contd)
Figure imgf000058_0001
TABLE 1 (contd)
Figure imgf000059_0001
TABLE 1 (contd)
Figure imgf000060_0001
TABLE 1 (contd)
Figure imgf000061_0001
TABLE 1 (contd)
Figure imgf000062_0001
TABLE 1 (contd)
Figure imgf000063_0001
BIOLOGICAL ACTIVITY
The following assays were used to demonstrate the activity and selectivity of compounds according to the invention: KDR Kinase and FGFr2 Kinase
The activities of recombinant KDR kinase and FGFr2 kinase were determined by measuring their ability to transfer the γ-phosphate from [33pjATP to polyglutamic acid - tyrosine (pEY).
The assay methodology employed for both kinases is identical except that in the assay of KDR kinase the diluent used throughout was 20mM HEPES pH 7.25 containing 2mM MnCI2, 2mM MnCI2, 5mM DTT and 0.05% Brij 35, whereas in the FGFr2 assay 10mM MnCI2 is used instead of 2mM MnCI2 and 2mM MnCI2.
The assay was conducted in a total volume of 202μl containing 1-1 Ong kinase, 5μg/ml pEY (4:1 ) (Sigma, UK), 1 μM ATP (containing ~50,000cpm [33p]ATP (Amersham International, UK) (Sigma, UK) and test inhibitors at the appropriate concentration. The test inhibitors were dissolved in DMSO and added such that the final concentration of DMSO in the assay did not exceed 2% (v/v). The assay was initiated by addition of kinase and terminated after 10 minutes incubation at room temperature by addition of 50μl of 20mM HEPES pH 7.25 containing 0.125M EDTA and 10mM ATP. A 200μl aliquot was applied to the well of a Millipore (UK) MAFC filter plate containing 100μl of 30% (w/v) trichloroacetic acid (TCA). The plate was then placed on a suitable manifold and connected to a vacuum. After complete elimination of the liquid each well was washed under vacuum using five volumes (100μl per wash) of 10% (w/v) TCA and finally two volumes (100μl per wash) of ethanol. The bottom of the filter plate was then sealed and 100μl per well of Ultima Gold (Beckham, UK) scintillant was added to each well. The readioactivity was measured using an appropiate scintillation counter such as a Wallac Trilux or Packard TopCount. The IC50 value for each inhibitor was obtained from log dose inhibition curves fitted to the four-parameters logistic equation.
p56lck kinase
The tyrosine kinase activity of p56lck was determined using a RR-src peptide (RRLIEDNEYTARG) and [γ-33p]ATP as substrates. Quantitation of the 33p.phosphorylated peptide formed by the action of p56lck was achieved using an adaption of the method of Geissler et al (J. Biol. Chem. (1990) 265, 22255-22261 ).
All assays were performed in 20mM HEPES pH 7.5 containing 10mM MgCI2, 10mM MnCI2, 0.05% Brij, 1μM ATP (0.5μCi[γ-33p]ATP) and
0.8mg/ml RR-src. Inhibitors in dimethylsulphoxide (DMSO) were added such that the final concentration of DMSO did not exceed 1%, and enzyme such that the consumption of ATP was less than 10%. After incubation at 30°C for 15min, the reaction was terminated by the addition of one-third volume of stop reagent (0.25mM EDTA and 33mM ATP in dH20). A 15μl aliquot was removed, spotted onto a P-30 filtermat
(Wallac, Milton Keynes, UK), and washed sequentially with 1 % acetic acid and de-ionised water to remove ATP. The bound 33p-RR.src was quantitated by scintillation counting of the filtermat in a Betaplate scintillation counter (Wallac, Milton Keynes, UK) after addition of Meltilex scintillant (Wallac, Milton Keynes, UK).
The dpm obtained, being directly proportional to the amount of 33p.RR-Src produced by p56lck, were used to determine the IC50 for each compound. The IC50 was defined as the concentration of compound required to reduce the production of 33p-RR.src y 50%.
EGFr kinase
The tyrosine kinase activity of the EGF receptor (EGFr) was determined using a similar methodology to the p56lck kinase assay, except that the RR-src peptide was replaced by a peptide substrate for EGFr obtained from Amersham International pic (Little Chalfont, UK) and used at the manufacturer's recommended concentration. IC50 values were determined as described previously in the p56lck assay.
Protein kinase C assay
Inhibitor activity against protein kinase C (PKC) was determined using PKC obtained from Sigma Chemical Company (Poole, UK) and a commercially available assay system (Amersham International pic, Amersham, UK). Briefly, PKC catalyses the transfer of the γ-phosphate (32p) of ATP to the threonine group on a peptide specific for PKC. Phosphorylated peptide is bound to phosphocellulose paper and subsequently quantified by scintillation counting. The inhibitor potency is expressed as either (i) the concentration required to inhibit 50% of the enzyme activity (IC50) or (ii) the percentage inhibition achieved by 10μM inhibitor.
In these tests, compounds of the invention have IC50 values in the EGFr kinase assay of around 1μM and below. In contrast, in the other assays described, the same compounds had IC50 values in each assay of greater than 10μM. In each instance the compound clearly had potent and selective EGFR kinase inhibitory action.

Claims

1. A compound of formula (1):
Figure imgf000067_0001
(1)
wherein
Ar is an optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl or alkyl group;
R is a hydrogen atom or an optionally substituted alkyl group;
R1 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy,-N(alkyl), -N(alkyl)2 or cyano (-CN) group;
X is a nitrogen atom or a C(R1 a) group where R1 a is as defined for R1 and may be the same or different;
R4 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, nitro (-N02), cyano (-CN), -C02R5 [where R5 is a hydrogen atom or an alkyl group], -S03H, -SOR5, S02R5, -SO3R5, -OC02R5, - CONR5R6 [where R6 is as just defined for R5 and may be the same or different], -SR5, -NR5R6, -OC(0)NR5R6, -CSNR5R6, COR5, -OCOR5, -N(R5)COR6, -N(R5)CSR6, -S02N(R5)(R6), -N(R5)S02R6, -
N(R5)CON(R6)(R7) [where R7 is a hydrogen atom or an alkyl group], - N(R5)CSN(R6)(R7) or -N(R5)S02N(R6)(R7) group; n is zero or the integer 1 or 2; R2 and R3 which may be the same or different is each an atom or group - L1(Alk1)tL2(R8)u in which L1 and L2 which may be the same or different is each a covalent bond or a linker atom or group, t is zero or the integer 1 , u is the integer 1 , 2 or 3, Alk1 is an aliphatic or heteroaliphatic chain and R8 is an atom or group as defined for R4 or an optionally substituted cycloaliphatic, polycycloaliphafic, heterocycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group, provided that:
1) R2 and R3 are not both hydrogen atoms or methoxy groups;
2) when Ar is an optionally substituted phenyl group, R is a hydrogen atom, R1 is a chlorine atom or methyl or methoxy group and one of R2 and R3 is a chlorine atom or methyl, methoxy or ethoxy group then the other of R2 and R3 is other than a hydrogen atom; and the salts, solvates, hydrates and N-oxides thereof.
2. A compound according to Claim 1 wherein Ar is an optionally substituted aryl or heteroaryl group.
3. A compound according to Claim 2 wherein Ar is an optionally substituted phenyl, thienyl, quinolinyl or isoquinolinyl group.
4. A compound according to Claims 1 to 3 wherein R is a hydrogen atom.
5. A compound according to Claims 1 to 4 wherein X is a nitrogen atom.
6. A compound according to Claims 1 to 5 wherein R1 is a hydrogen atom.
7. A compound according to Claims 1 to 6 wherein n is zero.
8. A compound according to Claims 1 to 7 wherein one of R2 and R3 is a methoxy group and the other is a group -OAIk1R8.
9. A compound according to Claim 8 wherein R8 is a -NR5R6 or heteroaliphatic group.
10. A compound according to Claim 9 wherein R8 is a -NHCH3, -N(CH3)2, optionally substituted morpholino or optionally substituted piperazinyl group.
11. A compound according to Claim 8 wherein Alk1 is a -(CH2)2- or - (CH2)3- chain.
12. A compound as described in any one of the Examples herein and the salt, solvates, hydrates and N-oxides thereof.
13. A pharmaceutical composition comprising a compound according to any of Claims 1 to 12 together with one or more pharmaceutically acceptable carriers, excipients or diluents.
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