WO2009093013A1 - Dérivés de thiophène condensés servant d'inhibiteurs de mek - Google Patents

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

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Publication number
WO2009093013A1
WO2009093013A1 PCT/GB2009/000151 GB2009000151W WO2009093013A1 WO 2009093013 A1 WO2009093013 A1 WO 2009093013A1 GB 2009000151 W GB2009000151 W GB 2009000151W WO 2009093013 A1 WO2009093013 A1 WO 2009093013A1
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alkyl
compound
formula
optionally substituted
cycloalkyl
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PCT/GB2009/000151
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Daniel Christopher Brookings
Victoria Elizabeth Laing
Barry John Langham
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Ucb Pharma S.A.
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Publication of WO2009093013A1 publication Critical patent/WO2009093013A1/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
    • C07D495/04—Ortho-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

Definitions

  • the present invention relates to a class of fused thiophene derivatives and to their use in therapy. More particularly, the invention is concerned with 7-oxo-4,5,6,7- tetrahydrothieno[2,3-c]pyridine derivatives, and analogues thereof, 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.
  • 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 maybe useful as radioligands in assays for detecting compounds capable of binding to human MEK enzymes.
  • WO 2005/023818 describes abroad-ranging class of compounds based on a fused heterobicyclic ring system, which generically encompasses 5,6-dihydro-l-benzothiophen- 7(4H)-one and 5,6-dihydrothieno[2,3-c] ⁇ yridin-7(4H)-one derivatives attached to a substituted anilino moiety but nowhere specifically discloses any actual compound of this type. Whilst no discrete pharmacological activity is ascribed to the compounds described therein, they are nevertheless stated to be useful inter alia in the treatment of cell proliferative diseases such as cancer.
  • 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 iiM 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 iiM 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 compounds of the present invention possess interesting pharmacokinetic properties owing to their improved solubility and clearance.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • Y represents oxygen, sulphur or N-R 7 ;
  • R 1 and R 2 independently represent hydrogen; or 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- (Ci -6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R 1 and R 2 when both are attached to the same carbon atom, 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 optionally substituted by one or more substituents; or
  • R 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 hydrogen, C 1-6 alkyl, C 3-7 heterocycloalkenyl (optionally substituted by one or two methyl groups), cyano, -CO 2 R a , -COR D , -CONR b 0 rR>c 0 , -SO 2 NR . b 0 ⁇ R-> o 0 ,
  • 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, trifluoromethoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl or Ci -6 alkylsulphonyl;
  • R s represents halogen, nitro, cyano, Ci -6 alkyl, C 2-6 alkynyl, hydroxy(Ci.6)alkyl or formyl;
  • R 6 represents hydrogen, Ci -6 alkyl, formyl, C 2-6 alkylcarbonyl, trifluoromethylcarbonyl or Ci -6 alkylsulphonyl
  • R 7 represents hydrogen or Ci -6 alkyl
  • R 8 represents halogen, -OR X , -S(O) n R" or -NR y R z ; n is zero, 1 or 2;
  • R a represents hydrogen, Cj -6 alkyl or C 3-7 heterocycloalkyl(Ci- 6 )alkyl
  • R b represents hydrogen or trifluoromethyl
  • R c represents hydrogen or C 1-6 alkyl (optionally substituted by hydroxy); or 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;
  • R d and R e independently represent hydrogen or Cj -6 alkyl
  • R x , R y and R z independently represent hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl orheteroaryl(Ci. 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • this 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 monosubstituted.
  • 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) may be 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 Ci -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, n-butyl, sec-butyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as "Ci -6 alkoxy", “Ci -6 alkylthio", "Ci -6 alkylsulphonyl” and "C 1-6 alkylamino" are to be construed accordingly.
  • 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, 1,2,3,4-tetrahydroquinoxalinyl, morpholinyl, thiomorpholinyl, homopiperidinyl and homopiperazinyl.
  • a typical C 3-7 heterocycloalkenyl group is dihydroimidazolyl (e.g. 4,5-dihydro- lH-imidazol-2-yl).
  • a typical C 4-9 heterobicycloalkyl group is azabicyclo[2.2.2]octyl (e.g. quinuclidin- 3-yl).
  • 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.
  • compounds of formula (I) may accordingly exist as enantiomers.
  • 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 depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • the compounds according to the present invention are represented by formula (IA) as depicted above.
  • the compounds according to the present invention are represented by formula (IB) as depicted above.
  • the compounds according to the present invention are represented by formula (IC) as depicted above.
  • -X- represents a group of formula (a) as depicted above.
  • -X- represents a group of formula (b) as depicted above.
  • -X- represents a group of formula (c) as depicted above.
  • Y is oxygen. In another embodiment, Y is sulphur. In a further embodiment, Y is N-R 7 in which R 7 is as defined above.
  • 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 2 represents hydrogen or optionally substituted C 1-6 alkyl.
  • R and/or R" examples include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C) -6 alkylthio, C 1-6 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.
  • R 1 and/or R 2 alkylaminosul ⁇ honyl; especially halogen, Ci -6 alkoxy or Ci -6 alkylthio.
  • substituents on R 1 and/or R 2 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, r ⁇ -propyl, isopropyl, phenyl, chlorophenyl, methoxyphenyl, methylthiophenyl and furyl.
  • R 1 is hydrogen.
  • R 1 is Ci -6 alkyl, especially methyl.
  • R 2 Typical values of R 2 include hydrogen and methyl. In one embodiment, R 2 is hydrogen. In another embodiment, R 2 is Ci -6 alkyl, especially methyl.
  • R 1 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 X.
  • 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 X. Also in this
  • 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 X.
  • 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 C 1-6 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 heterobicycloalkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • Suitable values of R b include 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 include C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino(Ci -6 )alkoxy, Ci -6 alkoxy(C 1-6 )alkyl, C 1 ⁇ alkylthio, C 1-6 alkylsulphonyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(Ci -6 )alkyl, nitro(Ci.
  • Suitable examples of specific substituents on R b , or on the heterocyclic moiety -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, trifiuoromethyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, bis(hydroxyethyl)amino, ethylaminoethylamino, phenylamino, pyridinylamino, acetylamino, tert- butoxy
  • 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-hydiOxy-3,3,3-trifluoro ⁇ ropyl), carboxyethyl (especially 2-carboxyethyl), ethoxycarbonylethyl (especially 2-(ethoxycarbonyl)ethyl), aminoethyl (especially 2- aminoethyl),
  • R c represents hydrogen or Ci -6 alkyl.
  • R c is hydrogen.
  • R° represents Ci -6 alkyl, especially methyl or ethyl, particularly methyl.
  • R c represents hydroxy-substituted Ci -6 alkyl, e.g. hydroxyethyl (especially 2-hydroxyethyl).
  • the moiety -NR b R c may suitably represent azetidin-1-yl, pyrrolidin- 1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin- 1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
  • the moiety -NR R c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or homopi ⁇ erazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
  • the moiety -NR b R c may suitably represent azetidin-1-yl, pyrrolidin-1-yl or piperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
  • Typical substituents on the heterocyclic moiety -NR b R c include Ci -6 alkyl, Cj -6 alkoxy(C[_ 6 )alkyl, hydroxy, hydroxy(C ]-6 )alkyl, amino(C 1-6 )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[(C 2-6 )alkoxycarbonyl(Ci -6 )alkyl]amino, C 2-6 alkoxycarbonyl- amino(Ci -6 )alkyl and aminocarbonyl.
  • substituents include methyl, ethyl, methoxymethyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, nitromethyl, oxo, acetyl, carboxy, methoxycarbonyl, tert-butoxycarbonyl, amino, acetylamino, tert- butoxycarbonylamino, bis(ethoxycarbonylmethyl)amino, ter/-butoxycarbonylamino ⁇ methyl and aminocarbonyl.
  • Definitive values of -NR b R° include hydroxyazetidin-1-yl, (hydroxy)(nitro- methyl)azetidin-l-yl, aminoazetidin-1-yl, (aminomethyl)azetidin-l-yl, (aminomethyl)- (hydroxy)azetidin- 1 -yl, (ter ⁇ butoxycarbonylammomethyl)azetidin- 1 -yl, pyrrolidin- 1 -yl, (methoxymethyl)pyrrolidin- 1 -yl, hydroxypyrrolidin- 1 -yl, (hydroxymethyl)pyrrolidin- 1 -yl, (aminomethyl)pyrrolidin- 1 -yl, carboxypyrrolidin- 1 -yl, (methoxycarbonyl)pyrrolidin- 1 -yl, aminopyrrolidin-1 -yl, (acetylamino)pyrrolidin-l-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.
  • R e is hydrogen. In another embodiment, R e represents C 1-6 alkyl, especially methyl.
  • R 3 represents a five-membered heteroaromatic ring, this ring may be optionally substituted by one or, where possible, two substituents. As will be appreciated, where 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 . Where 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 Ci -6 alkyl, C 3-7 cycloalkyl, aryl, aryl(Ci. 6 )alkyl, C 3-7 heterocycloalkyl, heteroaryl, heteroaryltCu ⁇ )- alkyl, Ci -6 alkoxy, C 1-6 alkylthio, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, halogen, cyano and trifluoromethyl.
  • R 3 represents hydrogen. In another embodiment, R 3 represents Ci -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-li/-imidazol-2-yl. In another embodiment, R 3 represents cyano. In another embodiment, R 3 represents -CO 2 R* 1 , 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 -CONHNR 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 Ci -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(Cj -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 5 represents cyano. In another embodiment, R 5 represents Ci -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 -6 )alkyl, especially hydroxymethyl. In an additional embodiment, R 5 represents formyl. Suitably, R 6 represents hydrogen or Ci -6 alkyl. In one embodiment, R 6 represents hydrogen. In another embodiment, R 6 represents Ci -6 alkyl, especially methyl.
  • R 7 represents hydrogen. In another embodiment, R 7 represents Ci -6 alkyl, especially methyl. In one embodiment, n is zero. In another embodiment, n is 1. In a further embodiment, n is 2.
  • R x represents hydrogen or Ci -6 alkyl. In one embodiment, R x represents hydrogen. In another embodiment, R x represents C 1-6 alkyl, especially methyl.
  • R y represents hydrogen or C 1-6 alkyl. In one embodiment, R y represents hydrogen. In another embodiment, R y represents C] -6 alkyl, especially methyl.
  • R z represents hydrogen or Ci -6 alkyl. In one embodiment, R z represents hydrogen. In another embodiment, R z represents Cj -6 alkyl, especially methyl.
  • R 8 represents halogen, especially chloro. In another embodiment, R 8 represents -OR X , especially methoxy. In a further embodiment, R 8 represents -S(O) n R". In another embodiment, R 8 represents -NR y R z , especially amino.
  • R 8 represents halogen, -OR X or -NR y R z , wherein R x , R y and R z are as defined above.
  • Suitable values of R 8 include chloro, methoxy and amino.
  • R 3 , R 4a , R 4b , R 5 and R 8 are as defined above;
  • R 11 represents hydrogen or optionally substituted Ci -6 alkyl
  • R 12 represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci_ 6 )alkyl, heteroaryl or heteroaryl(Ci_ 6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R 11 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 (HA) 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 1 J and/or R 12 will be unsubstituted or monosubstituted. Suitably, R 11 represents hydrogen or unsubstituted Ci -6 alkyl.
  • R represents hydrogen; or Ci -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 Ci -6 alkyl.
  • R 11 and/or R 12 examples include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Cj -6 alkylthio, C 1-6 alkylsulphonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C2- 6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylamino- carbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, Cj -6 alkylaminosulphonyl and di(C] -6 )alkylaminosulphonyl; especially
  • R 11 and/or R 12 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, methylamino sulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
  • Typical values of R 11 include hydrogen and methyl. In one embodiment, R 11 is hydrogen. In another embodiment, R 1 ! is Ci -6 alkyl, especially methyl. Typical values of R 12 include hydrogen, methyl, r ⁇ -propyl, isopropyl, phenyl, chlorophenyl, methoxyphenyl, methylthiophenyl and furyl, especially hydrogen or methyl. In one embodiment, R 12 is hydrogen. In another embodiment, R 12 is Ci -6 alkyl, especially methyl. Alternatively, R 11 and R 12 may together form an optionally substituted spiro linkage.
  • R 1 ] 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 11 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 , R , R ⁇ , R , ⁇ " and R , 1 i 2 l are as defined above;
  • R 1 represents halogen
  • R 15 represents halogen, nitro, cyano, C 2-6 alkynyl, hydroxy(C], 6 )alkyl or formyl.
  • R M is fluoro. In another specific embodiment, R 14 is chloro.
  • R 15 represents halogen, nitro, hydroxy(Ci -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[ -6 )aIkyl, especially hydroxymethyl. In an additional embodiment, R 15 represents formyl.
  • R 3 , R 8 , R 11 , R 12 , R 14 and R 15 are as defined above.
  • a further sub-group of the compounds of formula (HA) is represented by the compounds of formula (HD), and pharmaceutically acceptable salts and solvates thereof:
  • R 3 , R 6 , R 8 , R 11 , R 12 , R 14 and R 15 are as defined above.
  • 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.
  • Pharmaceutical 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.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pha ⁇ naceutically 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. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • 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. potato starch or sodium
  • 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, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, 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.
  • 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.
  • 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.
  • 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 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
  • halogenating agent of use in the reaction with compound (III) is suitably an JV " -halosuccinimide, e.g. AT-chlorosuccinimide, in which case the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran.
  • the halogenating agent may be iodine monochloride, in which case the reaction is conveniently effected in an inert organic solvent such as dichloromethane.
  • R 5a corresponds to the group R 5 or represents a precursor group thereto
  • L 1 represents a suitable leaving group
  • a suitable precursor group R 5a is trimethylsilyl (TMS).
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • the reaction is conveniently effected at an elevated temperature in the presence of a transition metal catalyst.
  • a suitable catalyst is bis(dibenzylideneacetone)palladium, in which case the reaction will typically be performed in the presence of 2,2'-bis(diphenyl- phosphino)-l,r-binaphthyl (BINAP), generally under basic conditions, e.g. in the presence of an inorganic base such as caesium carbonate.
  • R 5a represents TMS
  • this group may be converted into the desired group R 5 wherein R 5 represents iodo by treatment with iodine monochloride.
  • the intermediates of formula (III) above may be prepared by reacting a compound of formula (VI) with a compound of formula (VII):
  • the leaving group L 2 is typically a halogen atom, e.g. bromo.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. ⁇ jV-dimethylformamide, typically under basic conditions, e.g. in the presence of a base such as cesium carbonate.
  • the intermediates of formula (VII) 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
  • R 4a , R 4b and R 5 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.
  • intermediates of formula (VII) above wherein R 3 is cyano may be prepared by a process which comprises reacting compound (VIII) with acetonitrile, typically in the presence of a strong base such as sodium hexamethyldisilazide.
  • the intermediates of formula (VIII) above may be prepared by reacting a compound of formula (V) as defined above with thiophosgene.
  • reaction is conveniently effected in a suitable solvent, typically a mixture of chloroform and water.
  • the compounds of formula (III) above may be prepared by reacting a compound of formula (IX) with a compound of formula (X):
  • reaction is conveniently effected, at an elevated temperature if required, in a suitable solvent, e.g. N,N-dimethylformamide, typically under basic conditions, e.g. in the presence of a base such as cesium carbonate.
  • a suitable solvent e.g. N,N-dimethylformamide
  • the compounds of formula (III) above may be prepared by reacting a compound of formula (V) as defined above with a compound of formula (XI):
  • reaction is conveniently effected in the presence of a strong base such as sodium hexamethyldisilazide.
  • the intermediates of formula (XI) above may be prepared from the precursors of formula (IV) above wherein L 1 represents bromo by treatment with dimethyl disulphide, typically in the presence of a strong base such as tert-butyllithium; followed by oxidation of the methylthio derivative thereby obtained, typically with an oxidising agent such as 3- chloroperoxybenzoic acid, to afford the desired compound of formula (XI).
  • 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 8 represents halogen, e.g. chloro can be converted into the corresponding compound wherein R 8 represents -OR X , e.g. methoxy, by treatment with the appropriate substance of formula H-OR X , e.g. methanol.
  • a compound of formula (I) wherein R represents halogen, e.g. chloro can be converted into the corresponding compound wherein R 8 represents -NR y R z , e.g.
  • a compound of formula (IA), (IB) or (IC) wherein Y is oxygen may be converted into the corresponding compound wherein Y is sulphur by treatment with Lawesson's Reagent (i.e. 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-di ⁇ hosphetane-2,4-disulphide).
  • Lawesson's Reagent i.e. 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-di ⁇ hosphetane-2,4-disulphide.
  • a compound of formula (IB) wherein Y is oxygen and R 1 is hydrogen may be converted into the corresponding compound wherein R 1 is methyl by treatment with a methyl halide, e.g.
  • a compound of formula (IC) wherein Y is sulphur may be converted into the corresponding compound wherein Y is NH by treatment with dimethyl sulphate or iodomethane, followed by treatment of the methylthio-substituted cyclic imine thereby obtained with ammonia, typically at elevated temperature and pressure, or with ammonium acetate, typically at elevated temperature.
  • a compound of formula (IC) wherein R 6 represents hydrogen may be converted into the corresponding compound wherein R 6 represents C 1-6 alkyl by treatment with a trialkylsilyl halide, e.g. trimethylsilyl chloride or fert-butyldimethylsilyl chloride, in the presence of a base, e.g. sodium hydride, followed by treatment with a Ci -6 alkyl halide, e.g. iodomethane, in the presence of a base, e.g. sodium hydride.
  • a trialkylsilyl halide e.g. trimethylsilyl chloride or fert-butyldimethylsilyl chloride
  • a base e.g. sodium hydride
  • Ci -6 alkyl halide e.g. iodomethane
  • a compound of formula (I) wherein R 3 represents -CO 2 R a in which R a is other than hydrogen may be saponified to give the corresponding compound in which R 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 8 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.
  • a compound of formula (I) wherein R 3 represents -CO 2 H may be converted into the corresponding compound wherein R 3 represents -C0NR b R c , -CON(OR b )R c or
  • a compound of formula (I) wherein R 3 represents -CO 2 H may be converted into the corresponding compound wherein R 3 represents -CONR b R c , -CON(OR b )R c or -CON(R d )NR b R c 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°, H-N(OR b )R c 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
  • 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 3 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 pentafluoro- phenyl 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 pentafluoro- phenyl 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 3 represents -CONR b 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
  • a compound of formula (I) wherein R 3 represents -CO 2 R 11 may be converted into the corresponding compound wherein R 3 represents methyl by treatment with a reducing agent such as diisobutylaginanium 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 represents 4,4-dimethyl-4,5-dihydro-lH- imidazol-2-yl in a single step by treatment with 1 ,2-diamino-2-methylpropane in the presence of trimethylaluminium.
  • a compound of formula (I) wherein R 3 represents cyano may be 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 cyanoborohydri.de.
  • a suitable reducing agent e.g. sodium cyanoborohydri.de.
  • a compound of formula (I) wherein R 3 contains an amino moiety protected by a tert-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 compound of formula (I) wherein R 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.
  • 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 + 5mM MgCl 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 5 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 wat
  • Solvent B 90% CH 1 C ⁇ N / 0.1% formic a ⁇ Gradient Program
  • the aqueous solvent was approximately pH 3.2.
  • Lithium hydroxide monohydrate (49 mg, 1.16 mmol) was added to a solution of Intermediate 4 (300 mg, 0.58 mmol) in T ⁇ F (20 mL) and water (5 mL) and heated to reflux for 18 h. 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 cream solid (225 mg, 79%).
  • Example 1 (50 mg, 0.1 mmol) was suspended in 7N ammonia in methanol (2 mL). The reaction mixture was heated in a microwave at 6O 0 C for 5 minutes. The reaction mixture was concentrated in vacuo and the crude products were purified by chromatography (silica, 0-100% EtOAc in DCM) to give the title compound as a white solid (5 mg, 10%).

Abstract

Cette invention concerne une série de dérivés 7-oxo-4,5,6,7-tétrahydro- thiéno[2,3-c]-pyridine, et leurs analogues, substitués à la position 2 par une fraction anilino substituée. Les dérivés et analogues selon l'invention sont des inhibiteurs sélectifs des enzymes MEK humaines (MAPKK) et sont, par conséquent, utiles en médecine, par exemple, dans le traitement des affections inflammatoires, auto-immunes, cardiovasculaires, prolifératives (y compris, oncologiques) et nociceptives.
PCT/GB2009/000151 2008-01-21 2009-01-20 Dérivés de thiophène condensés servant d'inhibiteurs de mek WO2009093013A1 (fr)

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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
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US9540396B2 (en) 2010-11-02 2017-01-10 Centaurus Biopharma Co., Ltd. 6-arylamino pyridone carboxamide as MEK inhibitors
WO2012059041A1 (fr) 2010-11-02 2012-05-10 Centaurus Biopharma Co., Ltd. Nouveaux 6-arylaminopyridonecarboxamides comme inhibiteurs de mek
CN102020651B (zh) * 2010-11-02 2012-07-18 北京赛林泰医药技术有限公司 6-芳基氨基吡啶酮甲酰胺mek抑制剂
CN102020651A (zh) * 2010-11-02 2011-04-20 北京赛林泰医药技术有限公司 6-芳基氨基吡啶酮甲酰胺mek抑制剂
WO2013107283A1 (fr) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Composés benzohétérocycliques et leur utilisation
US9937158B2 (en) 2012-01-17 2018-04-10 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US9290468B2 (en) 2012-01-17 2016-03-22 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US9718879B2 (en) 2012-01-26 2017-08-01 Imperial Innovations Ltd. Methods of treating pain by inhibition of VGF activity
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
JP2020520994A (ja) * 2017-05-19 2020-07-16 エヌフレクション セラピューティクス インコーポレイテッド 皮膚障害の処置用の融合複素環式芳香族アニリン化合物
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
US11542271B2 (en) 2017-05-19 2023-01-03 Nflection Therapeutics, Inc. Fused heteroaromatic-aniline compounds for treatment of dermal disorders
JP7237941B2 (ja) 2017-05-19 2023-03-13 エヌフレクション セラピューティクス インコーポレイテッド 皮膚障害の処置用の融合複素環式芳香族アニリン化合物
US11572344B2 (en) 2018-11-20 2023-02-07 Nflection Therapeutics, Inc. Cyanoaryl-aniline compounds for treatment of dermal disorders
EP4233834A3 (fr) * 2018-11-20 2023-10-25 NFlection Therapeutics, Inc. Composés d'aryl-aniline et d'hétéroaryl-aniline pour le traitement de marques de naissance

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