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WO2009093009A1 - Dérivés de thiophène tricyclique condensés servant d'inhibiteurs de mek - Google Patents

Dérivés de thiophène tricyclique condensés servant d'inhibiteurs de mek Download PDF

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Publication number
WO2009093009A1
WO2009093009A1 PCT/GB2009/000145 GB2009000145W WO2009093009A1 WO 2009093009 A1 WO2009093009 A1 WO 2009093009A1 GB 2009000145 W GB2009000145 W GB 2009000145W WO 2009093009 A1 WO2009093009 A1 WO 2009093009A1
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Prior art keywords
alkyl
compound
formula
optionally substituted
heterocycloalkyl
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PCT/GB2009/000145
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English (en)
Inventor
Daniel Christopher Brookings
Martin Clive Hutchings
Victoria Elizabeth Laing
Barry John Langham
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Ucb Pharma S.A.
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Publication of WO2009093009A1 publication Critical patent/WO2009093009A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/06—Peri-condensed systems

Definitions

  • the present invention relates to a class of fused tricyclic thiophene derivatives and to their use in therapy. More particularly, the invention provides a family of fused tricyclic thiophene derivatives which are substituted in the 2-position by a substituted anilino moiety. These compounds are selective inhibitors of MEK (MAPKK) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive conditions.
  • MAPKK MEK
  • MEK enzymes are implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases. These functions are summarised in paragraphs [0004] and [0005] of US 2005/0049276 Al.
  • the compounds of use in the present invention are therefore beneficial in the treatment and/or prevention of various human ailments.
  • autoimmune and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g.
  • proliferative disorders such as restenosis, and oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; and pain and nociceptive disorders, including chronic pain and neuropathic pain.
  • the compounds of use in the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of use in this invention may be useful as radioligands in assays for detecting compounds capable of binding to human MEK enzymes.
  • MEK inhibitors based on a fused bicyclic aromatic ring system attached to a substituted aniline moiety are known from the art, such as from WO 2007/088345. Also relevant is copending international patent application no. PCT/GB2007/003114, published on 21 February 2008 as WO 2008/020206. Nowhere in the prior art, however, is there any disclosure of a class of fused tricylic thiophene derivatives attached at the 2-position of the thiophene ring to a substituted anilino moiety. It has now been found that such compounds are particularly valuable as selective inhibitors of MEK enzymes.
  • the compounds of the present invention are potent and selective MEK inhibitors having a binding affinity (IC 50 ) for the human MEKl and/or MEK2 enzyme of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 5O figure denotes a more active compound).
  • IC 50 binding affinity for the human MEKl and/or MEK2 enzyme of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 5O figure denotes a more active compound).
  • the compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for the human MEKl and/or MEK2 enzyme relative to other human kinases.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • W represents a covalent bond or a methylene linkage
  • the moiety X-Y-Q represents an optionally substituted five-membered heteroaliphatic or heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolinyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; R 1 and R 2 independently represent hydrogen; or Cj -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(Ci -6
  • R 1 and R 2 when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
  • R 3 represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or R 3 represents an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl;
  • R 4a and R 4b independently represent hydrogen, halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, Ci -6 alkoxy, trifiuoromethoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl or C 1-6 alkylsulphonyl;
  • R 5 represents halogen, nitro, cyano, Cj -6 alkyl, C 2-6 alkynyl, hydroxy(Ci. 6 )alkyl or formyl;
  • R a represents hydrogen, C 1-6 alkyl or C 3-7 heterocycloalkyl(C 1-6 )alkyl
  • R b represents hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(C 1- 6)alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl- (Ci -6 )alkyl, C 4-9 heterobicycloalkyl, heteroaryl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents; and
  • R c represents hydrogen or Ci -6 alkyl (optionally substituted by hydroxy); or - A -
  • R b and R c when taken together with the nitrogen atom to which they are both attached, represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, homomorpholinyl or homopiperazinyl, any of which groups may be optionally substituted by one or more substituents; or the moiety -N(OR b )R c represents an optionally substituted heterocyclic ring wherein R b and R c are taken together and represent a C 2-5 alkylene linkage; and R d and R e independently represent hydrogen or C 1-6 alkyl.
  • a group in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such a group will be unsubstituted, or substituted by one or two substituents. Suitably, such a group will be unsubstituted or monosubstiruted.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • the compounds of the invention carry an acidic moiety, e.g.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • alkali metal salts e.g. sodium or potassium salts
  • alkaline earth metal salts e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • solvates of the compounds of formula (I) above include within its scope solvates of the compounds of formula (I) above.
  • Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
  • the solvates of the compounds of formula (I) maybe formed with water, in which case they will be hydrates.
  • Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched C 1-6 alkyl groups, for example Ci -4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, rc-butyl, sec-butyl, isobutyl, tert-butyl and 2,2-dimethylpropyl.
  • C 1-6 alkoxy such as "C 1-6 alkoxy”, “C 1-6 alkylthio”, “C 1-6 alkylsulphonyl” and “C 1-6 alkylamino” are to be construed accordingly.
  • Specific C 3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(C 1-6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • Suitable heterocycloalkyl groups which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, l,2,3,4-tetrahydroquinoxalinyl, morpholinyl, thiomorpholinyl, homopiperidinyl and homopiperazinyl.
  • a typical C 3-7 heterocycloalkenyl group is dihydroimid
  • a typical C 4-9 heterobicycloalkyl group is azabicyclo[2.2.2]octyl (e.g. quinuclidin-
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrrolo[2,3- ⁇ >]pyridinyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazo[l,2- ⁇ ]pyridinyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups.
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms.
  • the compounds of formula (I) may accordingly exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers.
  • the invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates.
  • Formula (I) and the formulae depicte depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • the moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted f ⁇ ve-membered heteroaliphatic or heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolinyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
  • the moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • the moiety X-Y-Q represents an imidazolinyl, imidazolyl or triazolyl ring, any of which may be optionally substituted by one or more substituents.
  • the five-membered or six-membered heteroaliphatic or heteroaromatic ring represented by the moiety X-Y-Q in the compounds of formula (I) above may be unsubstituted, or may suitably be substituted, where possible, by one or more, typically by one or two, substituents. In one embodiment, this ring is unsubstituted. In another embodiment, this ring is monosubstiruted. In a further embodiment, this ring is disubstituted.
  • Examples of typical substituents on the five-membered or six-membered heteroaliphatic or heteroaromatic ring as specified for the moiety X-Y-Q include C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl, heteroaryl(Ci -6 )alkyl, hydroxy, C 1-6 alkoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl, Cu 6 alkylsulphonyl, C 2-6 alkylcarbonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, halogen, cyano and trifluoromethyl.
  • suitable substituents include Ci -6 alkyl, C 3-7 cycl
  • R y and R z independently represent hydrogen, Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl- (C 1-6 )alkyl, heteroaryl, heteroaryl(C 1-6 )alkyl, C 1-6 alkoxy, Cj -6 alkylthio, Ci -6 alkylsulphinyl, Ci -6 alkylsulphonyl, C 2-6 alkylcarbonyl, amino, Ci -6 alkylamino, di(C] -6 )alkylamino, halogen, cyano or trifluoromethyl.
  • Suitable values of R y and/or R z include hydrogen, Ci -6 alkyl, C 3-7 cycloalkyl, aryl and trifluoromethyl.
  • R y represents hydrogen. In another embodiment, R y represents Ci -6 alkyl, especially methyl. In another embodiment, R y represents C 3-7 cycloalkyl, especially cyclopropyl or cyclobutyl. In another embodiment, R y represents aryl, especially phenyl. In a further embodiment, R y represents trifluoromethyl.
  • R z represents hydrogen
  • W represents a covalent bond. In another embodiment, W represents a methylene linkage.
  • R 1 represents hydrogen; or C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R represents hydrogen or optionally substituted C 1-6 alkyl.
  • R and/or R examples include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C 1-6 alkylthio, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylamino- carbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, Ci -6 alkylaminosulphonyl and di(Ci -6 )alkylaminosulphonyl; especially halogen, C cyano, nitro
  • R 1 and/or R 2 examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
  • R 1 Typical values of R 1 include hydrogen, methyl, n-propyl, isopropyl, phenyl, chlorophenyl, methoxyphenyl, methylthiophenyl and furyl. In one embodiment, R 1 is hydrogen. In another embodiment, R 1 is C 1-6 alkyl, especially methyl.
  • R Typical values of R include hydrogen and methyl.
  • R is hydrogen.
  • R 2 is C 1-6 alkyl, especially methyl.
  • R and R 2 when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage.
  • R 1 and R 2 when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 1 and R 2 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl.
  • R 1 and R 2 when attached to adjacent carbon atoms, may together form an optionally benzo-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the ring containing the variable W.
  • R 1 and R 2 when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 1 and R 2 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the ring containing the variable W.
  • R and R when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e. an indanyl moiety fused to the ring containing the variable W.
  • R a represents hydrogen or Ci -6 alkyl.
  • R a represents hydrogen, methyl or ethyl, especially hydrogen or ethyl.
  • R a represents hydrogen.
  • R a represents Ci -6 alkyl.
  • R a represents methyl.
  • R a represents ethyl.
  • R a represents C 3-7 heterocycloalkyl(Ci -6 )alkyl, especially piperidinylmethyl.
  • R b represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl(Ci_ 6 )alkyl, aryl- (Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, C 4-9 heterobicyclo- alkyl, heteroaryl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b examples include Ci -6 alkyl, C 3-7 heterocycloalkyl and C 3-7 heterocycloalkyl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b represents hydrogen; or methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexylmethyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, quinuclidinyl, azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylethyl, morpholinylpropyl, pyridinyl, in
  • Suitable substituents on R b , or on the heterocyclic moiety -NR b R c or -N(OR b )R° include C 1-6 alkyl, C 1-6 alkoxy, Ci -6 alkylamino(Ci -6 )alkoxy, Ci -6 alkoxy(C 1-6 )alkyl, C 1-6 alkylthio, C 1-6 alkylsulphonyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, nitro(Ci -6 )alkyl, cyano, trifluoromethyl, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, Ci -6 alkylamino, di(C 1-6 )alkylamino, bis[hydroxy(Ci -6 )alkyl]amino, Ci -6 alkylamino(Ci -6 )alkylamino,
  • Examples of typical substituents on R , or on the heterocyclic moiety -NR R c or -N(OR b )R c include C 1-6 alkyl, hydroxy, amino(C 1-6 )alkyl, C 2-6 alkylcarbonyl, amino and C 2-6 alkoxycarbonylamino(C 1-6 )alkyl.
  • -NR b R c or -N(OR b )R c include methyl, ethyl, isopropyl, methoxy, isopropoxy, methylaminoethoxy, methoxymethyl, methylthio, ethylthio, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, nitromethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, t ⁇ rt-butoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, bis(hydroxyethyl)amino, ethylaminoethylamino, phenylamino, pyridinylamino, acetylamino, tert- butoxycarbonylamino, (/ert-butoxycarbonyl)(methyl)amin
  • R b examples include methyl, hydroxy, aminomethyl, fe?t-butoxycarbonyl, amino and tert-butoxycarbonylaminomethyl.
  • R b represents Ci -6 alkyl, optionally substituted by one or more, preferably one or two, hydroxy groups.
  • R b include hydrogen, methyl, carboxymethyl, aminocarbonyl- methyl, methoxyethyl (especially 2-methoxyethyl), methylaminoethoxyethyl (especially 2-[2-(methylamino)ethoxy]ethyl), ethylthioethyl (especially 2-(ethylthio)ethyl), methylsulphonylethyl (especially 2-(methylsulphonyl)ethyl), hydroxyethyl (especially 2- hydroxyethyl), cyanoethyl (especially 2-cyanoethyl), (hydroxy)(trifluoromethyl)ethyl (especially 2-hydroxy-3,3,3-trifluoropropyl), carboxyethyl (especially 2-carboxyethyl), ethoxycarbonylethyl (especially 2-(2-(methyl
  • R b Typical values of R b include dihydroxypropyl (especially 2,3-dihydroxypropyl), aminobutyl (especially 2-amino-2-methylpropyl), pyrrolidinyl, tert-butoxycarbonyl- pyrrolidinyl, piperidinyl, fer ⁇ -butoxycarbonylpiperidinyl, pyrrolidinylmethyl and tert- butoxycarbonylpyrrolidinylmethyl.
  • R c represents hydrogen or Ci -6 alkyl.
  • R° is hydrogen.
  • R c represents Cj -6 alkyl, especially methyl or ethyl, particularly methyl.
  • R c represents hydroxy-substituted C 1-6 alkyl, e.g. hydroxyethyl (especially 2-hydroxyethyl).
  • the moiety -NR b R° may suitably represent azetidin-1-yl, pyrrolidin-
  • the moiety -NR b R° may suitably represent azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, mor ⁇ holin-4-yl, pi ⁇ erazin-1-yl or homopiperazin- 1 -yl, any of which groups may be optionally substituted by one or more substiruents.
  • the moiety -NR b R c may suitably represent azetidin-1-yl or piperazin-1-yl, any of which groups may be optionally substituted by one or more substiruents.
  • Typical substituents on the heterocyclic moiety -NR b R c include Ci -6 alkyl, C 1-6 alkoxy(C 1-6 )alkyl, hydroxy, hydroxy(Ci -6 )alkyl, amino(Ci -6 )alkyl, nitro(Ci -6 )alkyl, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, bis[(C2- 6 )alkoxycarbonyl(Ci.
  • substituents include methyl, ethyl, methoxymethyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, nitromethyl, oxo, acetyl, carboxy, methoxycarbonyl, tert-butoxycarbonyl, amino, acetylamino, tert-butoxycarbonylamino, bis(ethoxycarbonylmethyl)amino, tert-butoxycarbonylaminomethyl and aminocarbonyl; especially aminomethyl or tert-butoxycarbonylaminomethyl.
  • heterocyclic moiety -NR b R c include (aminomethyl)- azetidin-1-yl, (tert-butoxycarbonylaminomethyl)azetidin-l-yl and piperazin-1-yl.
  • moiety -N(OR b )R c represents an optionally substituted heterocyclic ring wherein R b and R c are taken together and represent a C 2-5 alkylene linkage
  • this is suitably a C 3 alkylene linkage
  • moiety -N(OR b )R c represents an optionally substituted isoxazolidin-2-yl ring.
  • suitable substituents on this heterocylic ring are as described above.
  • a particular substituent is hydroxy.
  • R d is hydrogen. In another embodiment, R d represents C 1-6 alkyl, especially methyl. In one embodiment, R e is hydrogen. In another embodiment, R e represents Ci -6 alkyl, especially methyl.
  • R 3 represents a five-membered heteroaromatic ring
  • this ring may be optionally substituted by one or, where possible, two substituents.
  • R 3 represents an oxadiazolyl, thiadiazolyl or tetrazolyl ring
  • only one substituent will be possible; otherwise, one or two optional substituents may be accommodated around the five-membered heteroaromatic ring R 3 .
  • R 3 represents a six-membered heteroaromatic ring
  • this ring may be optionally substituted by one or more substituents, typically by one or two substituents.
  • Examples of suitable substituents on the five- membered or six-membered heteroaromatic ring as specified for R 3 include C 1-6 alkyl, C 3-7 cycloalkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, heteroaryl, heteroaryl(C 1-6 )- alkyl, Ci -6 alkoxy, Ci -6 alkylthio, amino, C 1-6 alkylamino, di(Ci -6 )alkylamino, halogen, cyano and trifluoromethyl.
  • R 3 represents hydrogen, -CO 2 R 3 , -CONR b R c , -CON(OR b )R c or -CONHNR b R c , in which R a , R b and R c are as defined above.
  • R 3 represents hydrogen, -CO 2 R 3 or -CONR b R c , in which R a , R b and R c are as defined above.
  • R 3 represents hydrogen. In another embodiment, R 3 represents Cj -6 alkyl, especially methyl. In another embodiment, R 3 represents C 3-7 heterocycloalkenyl (optionally substituted by one or two methyl groups), e.g. 4,4- dimethyl-4,5-dihydro-lH-imidazol-2-yl. In another embodiment, R 3 represents cyano. In another embodiment, R 3 represents -CO 2 R a , in which R a is as defined above. In a further embodiment, R 3 represents -CONR b R c , in which R b and R c are as defined above.
  • R 3 represents -CON(OR b )R c , in which R b and R c are as defined above.
  • R 3 represents -CON ⁇ NR b R c , in which R b and R c are as defined above.
  • Suitable values of R 4a and/or R 4b include hydrogen, halogen (especially fluoro or chloro) and C 1-6 alkyl (especially methyl).
  • R 4a is attached at the 2-position relative to the anilino nitrogen atom.
  • R 4a represents halogen. In one embodiment, R 4a is fluoro. In another embodiment, R 4a is chloro.
  • R 4b may be attached at the 6-position relative to the anilino nitrogen atom.
  • R 4b is hydrogen
  • R 5 represents halogen, nitro, cyano, C 2-6 alkynyl, hydroxy(Ci -6 )alkyl or formyl.
  • R 5 represents halogen, nitro, hydroxy(Ci -6 )alkyl or formyl.
  • R 5 represents halogen, especially bromo or iodo, particularly iodo. In another embodiment, R 5 represents nitro. In another embodiment, R represents cyano. In another embodiment, R 5 represents C 1-6 alkyl, especially methyl. In another embodiment, R 5 represents C 2-6 alkynyl, especially ethynyl. In a further embodiment, R 5 represents hydroxy(Ci,g)alkyl, especially hydroxymethyl. In an additional embodiment, R 5 represents formyl.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (IIA), and pharmaceutically acceptable salts and solvates thereof:
  • W the moiety X-Y-Q, R 3 , R 4a , R 4b and R 5 are as defined above;
  • R 11 represents hydrogen or optionally substituted C 1-6 alkyl;
  • R 12 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or R u and R 12 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 11 and/or R 12 in the compounds of formula (IIA) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, R 11 and/or R 12 will be unsubstituted, or substituted by one or two substituents. Suitably, R 11 and/or R 12 will be unsubstituted or monosubstituted.
  • R l represents hydrogen or unsubstituted Ci -6 alkyl.
  • R 12 represents hydrogen; or Cj -6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • Particular values of R 12 include hydrogen and unsubstituted C 1-6 alkyl.
  • R 11 and/or R 12 examples include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifiuoromethoxy, aryloxy, Ci -6 alkylthio, Ci -6 alkylsulphonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylamino- carbonyl, di(Ci -6 )alkylaminocarbonyl, aminosulphonyl, Ci -6 alkylaminosulphonyl and di(Ci -6 )alkylaminosulphonyl; especially
  • Exatnples of particular substituents on R 11 and/or R 12 include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, amino sulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
  • R 11 Typical values of R 11 include hydrogen and methyl. In one embodiment, R 11 is hydrogen. In another embodiment, R 11 is Ci -6 alkyl, especially methyl.
  • R 1 Typical values of R 1 include hydrogen, methyl, n-propyl, isopropyl, phenyl, chlorophenyl, methoxyphenyl, methylthiophenyl and furyl, especially hydrogen or methyl.
  • R 12 is hydrogen.
  • R 12 is C 1-6 alkyl, especially methyl.
  • R 11 and R 12 may together form an optionally substituted spiro linkage.
  • R 11 and R 12 when taken together with the carbon atom to which they are both attached, may represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 1 ' and R 12 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl.
  • R 3 , R y , R z , R 1 ' and R 12 are as defined above;
  • R 14 represents halogen
  • R 15 represents halogen, nitro, cyano, C 2-6 alkynyl, hydroxy(C 1-6 )alkyl or formyl. In one specific embodiment, R 14 is fluoro. In another specific embodiment, R 14 is chloro.
  • R 15 represents halogen, nitro, hydroxy(C]. 6 )alkyl or formyl.
  • R 15 represents halogen, especially iodo. In another embodiment, R 15 represents nitro. In another embodiment, R 15 represents cyano. In another embodiment, R 15 represents C 2-6 alkynyl, especially ethynyl. In a further embodiment, R 15 represents hydroxy(C 1-6 )alkyl, especially hydroxymethyl. In an additional embodiment, R 15 represents formyl.
  • R 3 , R y , R z , R 12 , R 14 and R 15 are as defined above.
  • a further sub-group of the compounds of formula (IIA) is represented by the compounds of formula (HD), and pharmaceutically acceptable salts and solvates thereof:
  • R 3 , R y , R", R 12 , R 14 and R 15 are as defined above.
  • Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
  • the present invention also provides a pharmaceutical composition which comprises a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • 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 methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g.
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium
  • 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 or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • compositions for oral administration may be suitably formulated to give controlled release of the active compound.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) 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 ampoules or multi-dose containers, e.g. glass vials.
  • the compositions 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 (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoro ethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoro ethane, 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.
  • the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.
  • the compounds according to the present invention may be conveniently formulated as microionized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • compounds may be formulated in an ointment such as petrolatum.
  • the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
  • L 1 represents a suitable leaving group.
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. ⁇ V-dimethylformamide, typically under basic conditions, e.g. in the presence of a base such as cesium carbonate.
  • a suitable solvent e.g. ⁇ V-dimethylformamide
  • basic conditions e.g. in the presence of a base such as cesium carbonate.
  • the intermediates of formula (IV) above wherein R 3 is ethoxycarbonyl may be prepared by a process which comprises reacting the product formed by reacting ethyl acetoacetate and sodium ethoxide with a compound of formula (V):
  • R a , R and R are as defined above.
  • the reaction is conveniently effected by stirring the reactants in a suitable solvent, e.g. a lower alkanol such as ethanol.
  • a suitable solvent e.g. a lower alkanol such as ethanol.
  • the intermediates of formula (IV) above wherein R 3 is cyano may be prepared by a process which comprises reacting compound (V) with acetonitrile, typically in the presence of a strong base such as sodium hexamethyldisilazide.
  • R 1 4a , ⁇ R)4b and R are as defined above; with thiophosgene.
  • the reaction is conveniently effected in a suitable solvent, typically a mixture of chloroform and water.
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (VII) with a compound of formula (VIII):
  • the intermediates of formula (VII) above wherein R 3 represents -CO 2 R 3 may be prepared by reacting a compound of formula N ⁇ C-CH 2 -CO 2 R a with the appropriate compound of formula (IX):
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (VI) as defined above with a compound of formula (X):
  • reaction is conveniently effected in the presence of a strong base such as sodium hexamethyldisilazide.
  • the intermediates of formula (X) above may be prepared from the precursors of formula (VII) as defined above by a multi-stage procedure which comprises the following steps: (i) diazotisation/bromination by treatment with tert-butyl nitrite and copper(II) bromide; (ii) treatment of the bromo derivative thereby obtained with dimethyl disulphide, typically in the presence of a strong base such as fert-butyllithium; and subsequently (iii) oxidation of the methylthio derivative thereby obtained, typically with an oxidising agent such as 3-chloroperoxybenzoic acid, to afford the desired compound of formula (X).
  • a multi-stage procedure which comprises the following steps: (i) diazotisation/bromination by treatment with tert-butyl nitrite and copper(II) bromide; (ii) treatment of the bromo derivative thereby obtained with dimethyl disulphide, typically in the presence of a strong base such as fert-butyllith
  • the compounds of formula (IA) above may be prepared by a process which comprises reacting a compound of formula (XI) with an ethanolamine derivative of formula (XII):
  • W, R 1 , R 2 , R 3 , R 4a , R 4b and R 5 are as defined above; with Lawesson's Reagent (i.e. 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulphide); followed by treatment of the thiolactam derivative thereby obtained with a methyl halide, e.g. iodomethane.
  • Lawesson's Reagent i.e. 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulphide
  • Reaction of compound (XIII) with Lawesson's Reagent is conveniently carried out at an elevated temperature in a hydrocarbon solvent such as toluene.
  • Treatment of the resulting thiolactam with iodomethane is conveniently effected in a suitable solvent, e.g. acetonitrile.
  • the compounds of formula (IB) above maybe prepared by a process which comprises reacting a compound of formula (XIII) as defined above with phosphorus oxychloride; followed by reaction of the product thereby obtained with a compound of formula (XIV):
  • R y and R z are as defined above; or a suitable carbonyl-protected form thereof, e.g. the dimethyl acetal or ketal derivative; followed in turn by cyclisation of the product thereby obtained.
  • Reaction of compound (XIII) with phosphorus oxychloride is conveniently carried out at an elevated temperature. Reaction of the resulting product with compound (XIV) is also conveniently effected at an elevated temperature.
  • the subsequent cyclisation reaction is conveniently accomplished by treatment with a reagent such as p-tohxene- sulphonic acid, in which case the reaction is conveniently accomplished at an elevated temperature in a hydrocarbon solvent such as toluene.
  • the compounds of formula (IC) above may be prepared by a process which comprises reacting a compound of formula (XI) as defined above with a hydrazide derivative of formula (XV):
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, typically in the presence of an organic acid such as acetic acid.
  • a suitable solvent e.g. acetonitrile
  • the compounds of formula (IC) above wherein R y is hydrogen may be prepared by a process which comprises reacting a compound of formula (XVI):
  • W, R 1 , R 2 , R 3 , R 4a , R 4b and R 5 are as defined above; with a tri(Ci -6 )alkyl orthoformate, e.g. triethyl orthoformate.
  • the compounds of formula (IC) above may be prepared by a process which comprises reacting a compound of formula (XVI) as defined above with a compound of formula R y C(O)L 2 , wherein L 2 represents a suitable leaving group; followed by cyclisation of the product thereby obtained.
  • the leaving group L is typically a halogen atom, e.g. chloro.
  • the reaction between compound (XVI) and the compound of formula R y C(O)L 2 is conveniently effected in a suitable solvent, e.g. a halogenated solvent such as dichloromethane, typically in the presence of an organic base such as triethylamine.
  • a suitable solvent e.g. a halogenated solvent such as dichloromethane
  • organic base such as triethylamine
  • the subsequent cyclisation reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, typically in the presence of an organic acid such as acetic acid.
  • the intermediates of formula (XVI) may be prepared by reacting a compound of formula (XI) as defined above with hydrazine or a salt thereof, e.g. hydrazine acetate. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile.
  • the intermediates of formula (XIII) above may be prepared by reacting a compound of formula (IV) as defined above with a compound of formula (XVII):
  • any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
  • a compound of formula (I) wherein R 3 represents -CO 2 R 8 in which R a is other than hydrogen may be saponified to give the corresponding compound in which R 3 represents -CO 2 H by treatment with a base such as lithium hydroxide; more prolonged treatment with lithium hydroxide gives rise to the decarboxylated product in which R 3 represents hydrogen.
  • a compound of formula (I) wherein R 3 represents -CO 2 R a may be converted into the corresponding compound wherein R 3 represents -CONH 2 by treatment with ammonia, typically at elevated temperature and optionally also at elevated pressure.
  • CDI carbonyldiimidazole
  • EDC 4-methylmorpholine
  • HOBT 1-hydroxybenzotriazole
  • a compound of formula (I) wherein R 3 represents -CO 2 H maybe converted into the corresponding compound wherein R 3 represents -CONR b R°, -CON(OR b )R c or -CON(R d )NR b R° by a two-stage procedure which comprises (i) treatment with pentafluorophenol and a condensing agent such as EDC, typically in the presence of NMM and HOBT; and (ii) reaction of the pentafluorophenyl ester thereby obtained with the appropriate amine of formula H-NR b R c , H-N(OR b )R° or H-N(R d )NR b R c respectively, typically in the presence of an organic base such as triethylamine.
  • a two-stage procedure which comprises (i) treatment with pentafluorophenol and a condensing agent such as EDC, typically in the presence of NMM and HOBT; and (ii) reaction of the pent
  • a compound of formula (I) wherein R 3 represents -CO 2 H may be converted into the corresponding compound wherein R 3 represents -CO 2 R 8 by a two-stage procedure which comprises (i) treatment with pentafluorophenol and a condensing agent such as EDC, typically in the presence of NMM and HOBT; and (ii) reaction of the pentafluorophenyl ester thereby obtained with the appropriate alcohol of formula R a OH, typically in the presence of an organic base such as triethylamine.
  • a two-stage procedure which comprises (i) treatment with pentafluorophenol and a condensing agent such as EDC, typically in the presence of NMM and HOBT; and (ii) reaction of the pentafluorophenyl ester thereby obtained with the appropriate alcohol of formula R a OH, typically in the presence of an organic base such as triethylamine.
  • a compound of formula (I) wherein R 3 represents -CO 2 H may be converted into the corresponding compound wherein R J represents -CONR R c by a two-stage procedure which comprises (i) treatment with tetrafluorophenol resin and a condensing agent such as 1,3-diisopropylcarbodiimide, typically in the presence of 4-(dimethylamino)pyridine; and (ii) reaction of the tetrafluorophenyl ester functionalised resin thereby obtained with the appropriate amine of formula H-NR b R c .
  • a two-stage procedure which comprises (i) treatment with tetrafluorophenol resin and a condensing agent such as 1,3-diisopropylcarbodiimide, typically in the presence of 4-(dimethylamino)pyridine; and (ii) reaction of the tetrafluorophenyl ester functionalised resin thereby obtained with the appropriate amine of formula H-NR b R c
  • a compound of formula (I) wherein R 3 represents -CO 2 R a (e.g. ethoxycarbonyl) may be converted into the corresponding compound wherein R 3 represents methyl by treatment with a reducing agent such as diisobutylaluminium hydride.
  • a compound of formula (I) wherein R 3 represents -CO 2 R a (e.g. ethoxycarbonyl) may be converted into the corresponding compound wherein R 3 represents -CONR b R c by treatment with the appropriate amine of formula H-NR b R° in the presence of trimethyl- aluminium.
  • a compound of formula (I) wherein R 3 represents cyano may be converted into the corresponding compound wherein R 3 represents 4,4-dimethyl-4,5-dihydro-l ⁇ f- imidazol-2-yl in a single step by treatment with l,2-diamino-2-methylpropane in the presence of trimethylaluminium.
  • a compound of formula (I) wherein R 3 represents cyano maybe converted into the corresponding compound wherein R 3 represents -CONH 2 by treatment with hydroxylamine.
  • a compound of formula (I) wherein R 3 contains a NH functionality may be converted into the corresponding compound wherein R 3 contains a N-methyl functionality by treatment with formaldehyde in the presence of a suitable reducing agent, e.g. sodium cyanoborohydride.
  • a suitable reducing agent e.g. sodium cyanoborohydride.
  • a compound of formula (I) wherein R 3 contains an amino moiety protected by a fert-butoxycarbonyl (BOC) group may be deprotected by treatment with an acid, e.g. an organic acid such as trifluoroacetic acid, or a mineral acid such as hydrochloric acid.
  • an acid e.g. an organic acid such as trifluoroacetic acid, or a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 5 represents formyl may be converted into the corresponding compound wherein R 5 represents hydroxymethyl by treatment with a suitable reducing agent, e.g. sodium borohydride.
  • a suitable reducing agent e.g. sodium borohydride.
  • a compound of formula (I) wherein R 5 represents iodo may be converted into the corresponding compound wherein R 5 represents ethynyl by treatment at an elevated temperature with (trimethylsilyl)acetylene and a transition metal catalyst, e.g. bis(triphenylphosphine)palladium(II) dichloride, typically in the presence of copper(I) iodide and a base such as diisopropylamine.
  • a transition metal catalyst e.g. bis(triphenylphosphine)palladium(II) dichloride
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
  • the compounds in accordance with this invention potently inhibit the activity of human MEK enzyme.
  • MEKl activity was measured in a cascade assay initiated by active Raf, via activation of MEK, Erk2 and subsequent phosphorylation of fluorescein-labelled Erk-tide substrate in an assay based on fluorescence polarisation (IMAP).
  • the assay was carried out in 20mMTris + 5mMMgCl 2 + 2mMDL-dithiothreitol + 0.01% Tween 20 pH 7.2, containing 1.5nMunactive MEK, lOOnMunactive Erk and 20OnM Erk-tide (all concentrations are final concentrations).
  • the LC-MS system used comprises a Waters Alliance 2795 HT quaternary HPLC, Waters 996 Photo Diode Array (PDA) detector and Waters ZQ 4000 single quadrupole mass spectrometer.
  • the ZQ can acquire data simultaneously in positive and negative electrospray ionisation modes.
  • the reverse phase separation was carried out on a Gemini Cl 8 from Phenomenex 50 x 4.6 mm with 5 ⁇ m silica.
  • Solvent A 90% 1 OmM NH 4 HCO 2 in water / 0.1% formic acid / 10% CH 3 CN
  • Solvent B 90% CH 3 CN / 0.1 % formic acid / 10% 1 OmMNH 4 HCO 2 in water
  • the aqueous solvent was approximately pH 3.2.
  • Example 1 (385 mg, 0.7 mmol) in THF (10 mL) and water (5 mL) and heated to reflux for 18 hours. The reaction mixture was concentrated in vacuo and 5% citric acid (10 mL) added. The resulting precipitate was filtered and dried in vacuo to give the title compound as a yellow solid (307 mg, 84%).
  • ⁇ H (DMSO-d6) 11.74 (IH, s), 8.29 (IH, s), 7.67 (IH, dd, J 10.4, 1.8 Hz), 7.56 (IH, d, J8.4 Hz), 7.38 (IH, t, J 8.6 Hz), 3.95 (2H, s), 3.06 (2H, s), 0.89 (6H, s).
  • LCMS (ES + ) RT 2.66 minutes, 499 (M+H) + .
  • Example 11 A mixture of Example 11 (240 mg, 0.3 mmol) in DCM (5 mL) and 4M HCl in 1 ,4-dioxane (0.2 mL) was stirred at r.t. for 18 h. The resulting precipitate was filtered and dried in vacuo to give the title compound as a yellow solid (128 mg, 57%).
  • 1,2-diol 80 mg, 0.7 mmol by the method of Example 6.
  • Title compound obtained as a cream solid (154 mg, 70%).
  • Example 23 Prepared from Example 23 (190 mg, 0.3 mmol) and HCl in 1,4-dioxane by the method of Example 14.
  • Title compound obtained as a yellow solid (152 mg, 80%).
  • 5H (DMSO-d6) 9.48 (IH, br s), 9.27 (IH 5 br s), 9.09 (IH, s), 8.53 (IH, d, J 7.7 Hz), 7.64 (IH, dd, J 10.5, 1.7 Hz), 7.48 (IH, d, J 8.5 Hz), 7.08 (IH, t, J8.7 Hz), 4.10-4.02 (IH, m), 4.00 (2H, s), 3.19-3.00 (4H, m), 2.79-2.70 (2H, m), 2.62 (3H, s), 1.80-1.67 (3H, m), 1.52- 1.45 (IH, m), 1.07 (6H, d, J 3.1 Hz).
  • LCMS (ES + ) RT
  • Example 25 Prepared from Example 25 (240 mg, 0.4 mmol) and HCl in 1,4-dioxane by the method of Example 14.
  • Title compound obtained as a yellow solid (160 mg, 73%).
  • 5 H (DMSO-d6) 9.83 (IH, br s), 9.54 (IH, s), 9.23 (IH, br s), 8.54 (IH, t, J 5.1 Hz), 7.69 (IH, dd, J 10.5, 1.5 Hz), 7.54 (IH, d, J 8.3 Hz), 7.22 (IH, t, J 8.5 Hz), 4.01 (2H, s), 3.64-3.59 (IH, m), 3.54-3.47 (2H, m), 3.14-3.06 (4H, m), 2.62 (3H, s), 2.01-1.80 (3H, m), 1.69-1.60 (IH, m), 1.06 (6H, s).
  • LCMS (ES + ) RT 1.74 minutes, 595

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Abstract

Cette invention concerne une série de dérivés de thiophène tricyclique condensés substitués à la position 2 par une fraction anilino substituée. Les dérivés selon l'invention sont des inhibiteurs sélectifs des enzymes MEK humaines (MAPKK) et sont, par conséquent, bénéfiques en médecine, par exemple, dans le traitement des affections inflammatoires, auto-immunes, cardiovasculaires, prolifératives (y compris, oncologiques) et nociceptives.
PCT/GB2009/000145 2008-01-21 2009-01-20 Dérivés de thiophène tricyclique condensés servant d'inhibiteurs de mek WO2009093009A1 (fr)

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GBGB0801080.3A GB0801080D0 (en) 2008-01-21 2008-01-21 Therapeutic agents
GB0801080.3 2008-01-21

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012059041A1 (fr) 2010-11-02 2012-05-10 Centaurus Biopharma Co., Ltd. Nouveaux 6-arylaminopyridonecarboxamides comme inhibiteurs de mek
WO2013107283A1 (fr) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Composés benzohétérocycliques et leur utilisation
WO2013110945A1 (fr) 2012-01-26 2013-08-01 Imperial Innovations Ltd Méthodes de traitement de la douleur par le biais de l'inhibition de l'activité du vgf
WO2014071183A1 (fr) 2012-11-02 2014-05-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Méthode de réduction des effets secondaires chez un patient souffrant de cancer traité par un inhibiteur de la mek
CN105503884A (zh) * 2016-02-17 2016-04-20 上海皓元生物医药科技有限公司 一种用于合成bet蛋白抑制剂的关键中间体的合成方法
US10988483B2 (en) 2017-05-19 2021-04-27 Nflection Therapeutics, Inc. Fused heteroaromatic-aniline compounds for treatment of dermal disorders
US11161845B2 (en) 2017-05-19 2021-11-02 Nflection Therapeutics, Inc. Pyrrolopyridine-aniline compounds for treatment of dermal disorders
US11572344B2 (en) 2018-11-20 2023-02-07 Nflection Therapeutics, Inc. Cyanoaryl-aniline compounds for treatment of dermal disorders
US12123019B2 (en) 2014-06-19 2024-10-22 Whitehead Institute For Biomedical Research Uses of kinase inhibitors for inducing and maintaining pluripotency
US12371667B2 (en) 2021-05-13 2025-07-29 Washington University Enhanced methods for inducing and maintaining naive human pluripotent stem cells
US12378240B2 (en) 2018-11-20 2025-08-05 Nflection Therapeutics, Inc. Naphthyridinone-aniline compounds for treatment of dermal disorders

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012059041A1 (fr) 2010-11-02 2012-05-10 Centaurus Biopharma Co., Ltd. Nouveaux 6-arylaminopyridonecarboxamides comme inhibiteurs de mek
WO2013107283A1 (fr) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Composés benzohétérocycliques et leur utilisation
US9290468B2 (en) 2012-01-17 2016-03-22 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US9937158B2 (en) 2012-01-17 2018-04-10 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
WO2013110945A1 (fr) 2012-01-26 2013-08-01 Imperial Innovations Ltd Méthodes de traitement de la douleur par le biais de l'inhibition de l'activité du vgf
US9718879B2 (en) 2012-01-26 2017-08-01 Imperial Innovations Ltd. Methods of treating pain by inhibition of VGF activity
WO2014071183A1 (fr) 2012-11-02 2014-05-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Méthode de réduction des effets secondaires chez un patient souffrant de cancer traité par un inhibiteur de la mek
US12123019B2 (en) 2014-06-19 2024-10-22 Whitehead Institute For Biomedical Research Uses of kinase inhibitors for inducing and maintaining pluripotency
CN105503884A (zh) * 2016-02-17 2016-04-20 上海皓元生物医药科技有限公司 一种用于合成bet蛋白抑制剂的关键中间体的合成方法
US10988483B2 (en) 2017-05-19 2021-04-27 Nflection Therapeutics, Inc. Fused heteroaromatic-aniline compounds for treatment of dermal disorders
US11542271B2 (en) 2017-05-19 2023-01-03 Nflection Therapeutics, Inc. Fused heteroaromatic-aniline compounds for treatment of dermal disorders
US12065439B2 (en) 2017-05-19 2024-08-20 Nflection Therapeutics, Inc. Pyrrolopyridine-aniline compounds for treatment of dermal disorders
US11161845B2 (en) 2017-05-19 2021-11-02 Nflection Therapeutics, Inc. Pyrrolopyridine-aniline compounds for treatment of dermal disorders
US12428418B2 (en) 2017-05-19 2025-09-30 Nflection Therapeutics, Inc. Pyrrolopyridine-aniline compounds for treatment of dermal disorders
US11572344B2 (en) 2018-11-20 2023-02-07 Nflection Therapeutics, Inc. Cyanoaryl-aniline compounds for treatment of dermal disorders
US12378240B2 (en) 2018-11-20 2025-08-05 Nflection Therapeutics, Inc. Naphthyridinone-aniline compounds for treatment of dermal disorders
US12371667B2 (en) 2021-05-13 2025-07-29 Washington University Enhanced methods for inducing and maintaining naive human pluripotent stem cells

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