WO2009071890A1 - Inhibiteurs tricycliques de kinase - Google Patents

Inhibiteurs tricycliques de kinase Download PDF

Info

Publication number
WO2009071890A1
WO2009071890A1 PCT/GB2008/004002 GB2008004002W WO2009071890A1 WO 2009071890 A1 WO2009071890 A1 WO 2009071890A1 GB 2008004002 W GB2008004002 W GB 2008004002W WO 2009071890 A1 WO2009071890 A1 WO 2009071890A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
amino
heteroaryl
alkylamino
Prior art date
Application number
PCT/GB2008/004002
Other languages
English (en)
Inventor
Rikki Peter Alexander
Pavandeep Singh Aujla
Julien Alistair Brown
Benjamin Charles De Candole
Graham Peter Trevitt
Original Assignee
Ucb Pharma S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0723750A external-priority patent/GB0723750D0/en
Priority claimed from GB0723751A external-priority patent/GB0723751D0/en
Priority claimed from GB0812558A external-priority patent/GB0812558D0/en
Application filed by Ucb Pharma S.A. filed Critical Ucb Pharma S.A.
Publication of WO2009071890A1 publication Critical patent/WO2009071890A1/fr

Links

Classifications

    • 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
    • C07D513/04—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]

Definitions

  • the present invention relates to a class of fused tricylic thiazole and thiophene derivatives, and to their use in therapy. More particularly, the invention provides a family of fused tricylic thiazole and thiophene derivatives which are substituted in the 2-position of the thiazole or thiophene ring by an optionally substituted morpholin-4-yl moiety. These compounds are selective inhibitors of phosphoinositide 3-kinase (PI3K) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • PI3K phosphoinositide 3-kinase
  • PI3K pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases.
  • PBKs provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sci., 2003, 24, 366-376).
  • Aberrant upregulation of the PI3K pathway is implicated in a wide variety of human cancers (cf. S. Brader & S.A. Eccles, Tumori, 2004, 90, 2-8).
  • the compounds in accordance with the present invention are therefore beneficial in the treatment and/or prevention of various human ailments.
  • autoimmune and inflammatory disorders such as rheumatoid arthritis, 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.
  • neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; 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; pain and nociceptive disorders; and ophthalmic disorders including age- related macular degeneration (ARMD).
  • age- related macular degeneration AMD
  • the compounds in accordance with 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 this invention may be useful as radioligands in assays for detecting compounds capable of binding to human PI3K enzymes.
  • WO 2006/040281 describes a class of 4,5-dihydrothiazolo[4,5- ⁇ ]indazoles which are stated to be suitable for use in the treatment of diseases that are characterized by excessive or abnormal cell proliferation.
  • the compounds described in that publication do not, however, possess an optionally substituted morpholin-4-yl moiety at the 2-position of the thiazole ring.
  • WO 2006/114606 describes a class of fused bicyclic thiazole derivatives which are selective inhibitors of PI3 kinase enzymes and are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • a related series of compounds is described in copending international patent application no. PCT/GB2007/002390, published on 3 January 2008 as WO 2008/001076.
  • the compounds in accordance with the present invention are potent and selective PI3K inhibitors having a binding affinity (IC 50 ) for the human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ isoform 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 PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ isoform 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
  • 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 PI3K ⁇ and/or PI3K ⁇ and/or PDK ⁇ and/or PBK ⁇ isoform relative to other human kinases.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • V represents a covalent bond or a methylene linkage
  • W represents a covalent bond or a methylene linkage
  • the moiety X-Y-Q represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 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, hydroxy or amino; or Ci -6 alkyl, Ci -6 alkoxy, Ci -6 alkylamino, di(Ci -6 )alkylamino, 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 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 - A -
  • 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 and R 4 independently represent hydrogen; or Ci -6 alkyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )- alkynyl, biaryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C 1-6 )alkyl
  • R 3 and R 4 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 3 and R 4 , 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 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b or -CONR c R d ; or R 5 represents Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkenylcarbonyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci.
  • R a represents Ci -6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
  • R b represents hydrogen; or optionally substituted Ci -6 alkyl
  • R c represents hydrogen; or Ci -6 alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl, heteroaryl(Ci -6 )alkyl or (aryl)(heteroaryl)(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents
  • R d represents hydrogen or Ci -6 alkyl
  • R e represents Ci -6 alkyl
  • R 6 is absent when V represents a covalent bond
  • R 6 represents hydrogen, hydroxy, oxo or -NR 6a R 6b
  • R 6a and R 6b independently represent hydrogen, Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alky
  • the present invention also provides a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • R 1 and R 2 independently represent 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 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 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;
  • any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted, where possible, by one or more substituents. Typically, such groups will be unsubstituted, or substituted, where possible, by one or two substituents. Suitably, such groups will be unsubstituted or, where possible, 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 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, w-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci -6 alkoxy", “Ci -6 alkylthio", "Ci -6 alkylsulphonyl” and "Ci -6 alkylamino" are to be construed accordingly.
  • Typical C 2-6 alkenyl groups include vinyl and allyl.
  • Typical C 2-6 alkynyl groups include ethynyl, prop-1-yn-l-yl, prop-2-yn-l-yl, but-1- yn-l-yl and 3-methylbut-l-yn-l-yl.
  • a specific C 2-6 alkynyl group is prop-2-yn-l-yl.
  • Specific C 3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci -6 )alkyl groups include benzyl, phenyl ethyl, phenylpropyl and naphthylmethyl.
  • Specific aryl(C 2-6 )alkenyl groups include 2-phenylethenyl and 3-phenylprop-2-en-
  • Typical aryl(C 2-6 )alkynyl groups include phenylethynyl, 3-phenylprop-l-yn-l-yl and 3-phenylprop-2-yn-l-yl.
  • a specific aryl(C 2-6 )alkynyl group is 3-phenylprop-2-yn-l- yi.
  • Particular biaryl groups include biphenyl and naphthylphenyl.
  • Suitable heterocycloalkyl groups which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomo ⁇ holinyl.
  • Typical heterobicycloalkyl groups include quinuclidinyl, 8-azabicyclo[3.2.1]octyl and 3,8-diazabicyclo[3.2.1]octyl.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3- ⁇ ]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrazolyl, pyrazolo[l,5- ⁇ ]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2- ⁇ ]pyridinyl, imidazo[4,5-&]pyri
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.
  • 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 moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 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 a pyrazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl or pyrimidinyl ring, any of which may be optionally substituted, where possible, by one or more substituents.
  • the five-membered or six-membered 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 more, typically by one or two, substituents. In one embodiment, this ring is unsubstituted. In another embodiment, this ring is monosubstituted. hi a further embodiment, this ring is disubstituted. Examples of typical substituents on the five-membered or six-membered heteroaromatic ring as specified for the moiety X-Y-Q include Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci.
  • U represents N.
  • the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt or solvate thereof:
  • V, W, the moiety X-Y-Q, R 1 , R 2 , R 3 , R 4 and R 6 are as defined above.
  • U represents C-R 5 .
  • the present invention provides a compound of formula (B), or a pharmaceutically acceptable salt or solvate thereof:
  • V, W, the moiety X-Y-Q, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
  • Specific sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA), (IB), (IC), (ID), (IE) and (IF):
  • R x represents hydrogen, 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, heteroaryl(Ci -6 )alkyl, Ci -6 alkylsulphonyl or C 2-6 alkylcarbonyl; and
  • R y and R z independently represent hydrogen, 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, heteroaryl(Ci -6 )alkyl, hydroxy, Ci -6 alkoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl, Ci -6 alkylsulphonyl, C 2-6 alkylcarbonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, halogen, cyano or trifluoromethyl.
  • R x represents hydrogen or Ci -6 alkylsulphonyl.
  • R" represents hydrogen.
  • R" represents Ci -6 alkylsulphonyl, especially methylsulphonyl.
  • R y and R z independently represent hydrogen, 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 hetero- cycloalkyl(Ci -6 )alkyl, heteroaryl, heteroaryl(Ci_ 6 )alkyl, Ci -6 alkoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl, Ci -6 alkylsulphonyl, C 2-6 alkylcarbonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, halogen, cyano or trifluoromethyl.
  • Typical values of R y and/or R z include hydrogen, hydroxy and Ci -6 alkyl.
  • Suitable values of R y and/or R z include hydrogen and Ci -6 alkyl.
  • R y represents hydrogen. In another embodiment, R y represents Ci -6 alkyl, especially methyl. In a further embodiment, R y represents hydroxy.
  • R z represents hydrogen. In another embodiment, R z represents Ci -6 alkyl, especially methyl.
  • V represents a covalent bond. In another embodiment, V represents a methylene linkage. In one embodiment, W represents a covalent bond. In another embodiment, W represents a methylene linkage.
  • R 1 represents hydrogen or Ci -6 alkyl. Typical values of R 1 include hydrogen, methyl and ethyl. In one embodiment, R 1 is hydrogen. In another embodiment, R 1 is Ci -6 alkyl. In one aspect of that embodiment, R 1 is methyl. In another aspect of that embodiment, R 1 is ethyl.
  • R 2 represents hydrogen; or Ci -6 alkyl, Ci -6 alkoxy, C 3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents.
  • substituents on R 1 and/or R 2 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, 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 alkylaminocarbonyl, di(C
  • 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.
  • Typical values of R 2 include hydrogen, methyl, ethoxy, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl.
  • 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 V and/or 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 V and/or W.
  • R 1 and R 2 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 V and/or W.
  • R 3 represents hydrogen; or Ci -6 alkyl, aryl, aryl(Ci -6 )alkyl, aryl- (C 2-6 )alkynyl, biaryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, C 3-7 heterocycloalkyl- carbonyl, heteroaryl(Ci -6 )alkyl, heteroaryl-aryl(Ci -6 )alkyl or aryl-heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents hydrogen; or C 2-6 alkynyl, aryl(Ci -6 )alkyl or heteroaryl- (Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 3 represents aryl(Ci -6 )alkyl or heteroaryl(Ci -6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 3 represents hydrogen
  • R 3 represents Ci -6 alkyl, aryl(Ci -6 )alkyl, biaryl- (Ci -6 )alkyl, heteroaryl(Ci -6 )alkyl or heteroaryl-aryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents methyl, arylmethyl, biarylmethyl, heteroarylmethyl or heteroaryl-arylmethyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 3 represents arylmethyl or heteroarylmethyl, either of which groups may be optionally substituted by one or more substituents.
  • R 3 represents substituted or unsubstituted indolyl-
  • R 3 represents substituted or unsubstituted indolylmethyl.
  • R 3 represents substituted or unsubstituted phenyl- (Ci -6 )alkyl.
  • R 3 represents substituted or unsubstituted benzyl.
  • R 3 represents substituted or unsubstituted benzofuryl- (Ci -6 )alkyl.
  • R 3 represents substituted or unsubstituted benzofurylmethyl.
  • R 3 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1 ,2,3,4-tetrahydroquinolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-6]pyridinylmethyl, pyrrolo[3 ,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazo
  • R 4 represents hydrogen or optionally substituted Ci -6 alkyl.
  • substituents on R and/or R 4 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl(C i -6 )alkylaryl, piperazinyl(C i -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i .(,)- alkylaryl, morpholinyl(Ci -6 )alkylaryl, (Ci -6 )alkoxyaryl, cyano(Ci -6 )alkoxyaryl, di(Ci -6 )- alkylamino(Ci -6 )alkylaryl, (Ci -6 )alkylaminocarbonyla
  • R 3 and/or R 4 include halogen, cyano, Ci -6 alkyl, (Ci -6 )alkylpyrazolyl, C 2-6 alkoxycarbonyl and di(Ci -6 )alkylaminocarbonyl.
  • a further example is carboxy.
  • R 3 and/or R 4 Selected examples of specific substituents on R 3 and/or R 4 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifiuoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, mo ⁇ holinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxo
  • Typical values of R 3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, TV-methyl-TV-phenylaminomethyl, pyridinylamino- methyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyl- methylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolyl- phenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazo
  • R 3 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, (carboxy)(methyl)- indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, dimethylaminocarbonylindolylmethyl and (dimethylaminocarbonyl)(methyl)indolyl- methyl.
  • R 3 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, methoxycarbonylindolylmethyl and dimethylaminocarbonylindolylmethyl.
  • R 4 Typical values of R 4 include hydrogen and methyl. In a preferred embodiment, R 4 is hydrogen. In another embodiment, R 4 is Ci -6 alkyl, especially methyl.
  • R 3 and R 4 when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage.
  • R 3 and R 4 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 3 and R 4 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.
  • R 3 and R 4 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 morpholine ring.
  • R 3 and R 4 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 3 and R 4 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the morpholine ring, which phenyl ring may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 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 morpholine ring which indanyl moiety may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • substituents on the fused rings referred to in the preceding paragraph include halogen, nitro, Ci -6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(C i - 6 )alkylaryl, piperidinyl(C i -6 )alkylaryl, piperazinyl(C i -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i -6 )alkylaryl, morpholinyl(C i _ 6 )alkylaryl, (C i -6 )alkoxyaryl, cyano(C i -6 )alkoxyaryl, di(C i -6 )
  • Selected examples of specific substituents on the fused rings referred to in the three preceding paragraphs include bromo, nitro, methyl, «-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazin
  • R a represents substituted or unsubstituted aryl.
  • R c represents hydrogen; or aryl, aryl(Ci -6 )alkyl, heteroaryl(Ci -6 )alkyl or
  • R a and/or R b and/or R c include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, 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 )alkyl
  • R a and/or R b and/or R c 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 .
  • a particular value of R a is phenyl.
  • R b represents hydrogen. In another embodiment, R b represents Ci -6 alkyl, especially methyl or ethyl.
  • R c include hydrogen, phenyl, benzyl, pyridinylmethyl and (phenyl)(pyridinyl)methyl .
  • R d represents hydrogen.
  • R d represents Ci -6 alkyl, especially methyl or ethyl, particularly ethyl.
  • R e represents methyl
  • R 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b or -CONR c R d ; or R 5 represents Ci -6 alkyl, C 2-6 alkenylcarbonyl, C 2-6 alkynyl, C 3-7 cycloalkyl(C 2-6 )alkynyl, aryl, aryl(Ci -6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, C 3-7 heterocycloalkyl(C 2-6 )alkynyl, C 3-7 heterocycloalkylcarbonyl(C 2-6 )alkynyl, C 5-9 heterobicycloalkyl(C 2-6 )alkynyl, C 3-7 heterocycloalkyl-aryl, C 3
  • R 5 represents hydrogen; or optionally substituted aryl(C 2-6 )alkynyl.
  • R 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b or
  • R 5 represents methyl, propyl, ethenylcarbonyl, ethynyl, propynyl, butynyl, 3-methylbutynyl, cyclopropylethynyl, cyclohexylethynyl, phenyl, naphthyl, benzyl, phenylethyl, phenylethenyl, phenylethynyl, phenylpropynyl, biphenyl, piperidinylethyl, pyrrolidinyl ethynyl, piperidinylethynyl, 1 ,2,3 ,4-tetrahydroisoquinolinylpropynyl, piperazinylpropynyl, pyrrolidinyl carbonylethynyl, quinuclidinyl ethynyl, piperazinyl- pheny
  • R 5 represents hydrogen; or optionally substituted phenylethynyl.
  • substituents on R 5 include halogen, cyano, nitro, oxo, Ci -6 alkyl, trifluoromethyl, hydroxy, hydroxy(Ci.
  • R 5 examples include fluoro, chloro, bromo, cyano, nitro, oxo, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, ethoxy, dihydroxypropoxy, isobutoxy, benzyloxy, methoxybenzyloxy, amino, methylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, N-isopropyl-N-methylaminomethyl, dimethylaminoethylamino, methoxybenzylamino, acetylamino, ethoxycarbonylacetylamino, ethylcarbonylamino, methoxycarbonyl- ethylcarbonylamino, acetylaminomethyl, tert-butoxycarbonylamino, N-(tert-butoxy- carbonyl)-N
  • R 5 include hydrogen, fluoro, chloro, bromo, iodo, cyano, phenylthio, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, pyridinylmethylaminocarbonyl, (phenyl)(pyridinyl)methylaminocarbonyl, N-ethyl-N-pyridinylmethylaminocarbonyl, dimethylaminomethyl, dimethylaminosulphonylaminopropyl, dimethylamino- ethenylcarbonyl, ethynyl, triethylsilylethynyl, diethylaminopropynyl, methylsulphonylaminopropynyl, dimethylaminosulphonylaminopropynyl, hydroxybutynyl, 3-hydroxy-3-
  • R 5 in the compounds of formula (B) above is hydrogen
  • R and/or R >4 is other than hydrogen.
  • R when present, represents hydrogen, hydroxy or -NR 6ar R> 6b .
  • R 6 represents hydrogen.
  • R represents hydroxy.
  • R 6 represents -NR 6a R 6 .
  • R 6 represents oxo.
  • R 6a represents Ci -6 alkyl, C 3-7 cycloalkyl, aryl or aryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6a and R 6b examples include halogen, cyano, trifiuoromethyl, hydroxy, Ci -6 alkoxy and trifluoromethoxy, especially hydroxy.
  • R 6a examples include methyl, hydroxyethyl, cyclopropyl, phenyl and benzyl.
  • R 6b represents hydrogen or Ci -6 alkyl.
  • R 6b represents hydrogen.
  • R 6 represents Ci -6 alkyl, especially methyl.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (BA), and pharmaceutically acceptable salts and solvates thereof:
  • R 1 ' represents hydrogen or Ci -6 alkyl
  • R 12 represents hydrogen; or Ci -6 alkyl, Ci -6 alkoxy, 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 5 in the compounds of formula (BA) is other than hydrogen.
  • any of the groups in the compounds of formula (BA) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted.
  • R 1 ' Typical values of R 1 ' include hydrogen, methyl and ethyl. In one embodiment, R 1 ' is hydrogen. In another embodiment, R 1 ' is Ci -6 alkyl, especially methyl.
  • R 12 represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents.
  • substituents on R 12 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difiuoromethoxy, trifluoromethoxy, 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 alkylaminocarbonyl, di(Ci -6 )alkylamino,
  • R 12 examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difiuoromethoxy, 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.
  • Typical values of R 12 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl.
  • a particular value of R 12 is methyl.
  • R 1 ' 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 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.
  • W, the moiety X-Y-Q, R 1 ' and R 12 are as defined above;
  • R 13 represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(C, -6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2 .
  • any of the groups in the compounds of formula (IIA-A) or (IIA-B) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted.
  • R 13 represents hydrogen; or Ci -6 alkyl, aryl(Ci -6 )alkyl, aryl(C 2-6 )alkynyl, biaryl(C
  • R 13 represents hydrogen; or C 2-6 alkynyl, aryl(C 1-6 )alkyl or heteroaryl- (Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 13 represents aryl(Ci -6 )alkyl or heteroaryl(Ci -6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 13 represents hydrogen
  • R 13 is other than hydrogen.
  • R 13 represents C 1-6 alkyl, aryl(Ci -6 )alkyl, biaryl- (C i -6 )alkyl, heteroaryl(C i -6 )alkyl or heteroaryl-aryl(C i -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 13 represents methyl, arylmethyl, biarylmethyl, heteroarylmethyl or heteroaryl-arylmethyl, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents arylmethyl or heteroarylmethyl, either of which groups may be optionally substituted by one or more substituents.
  • R 13 represents substituted or unsubstituted indolyl- (Ci -6 )alkyl.
  • R 13 represents substituted or unsubstituted indolylmethyl.
  • R 13 represents substituted or unsubstituted phenyl- (Ci -6 )alkyl.
  • R 13 represents substituted or unsubstituted benzyl.
  • R 13 represents substituted or unsubstituted benzofuryl-
  • R 13 represents substituted or unsubstituted benzofurylmethyl.
  • R 13 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1 ,2,3,4-tetrahydroquinolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3 ,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-6]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazo
  • R 13 examples include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl- (C i -6 )alkylaryl, piperazinyl(C i -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i -6 )alkylaryl, morpholinyl(Ci -6 )alkylaryl, (Ci -6 )alkoxyaryl, cyano(Ci -6 )alkoxyaryl, di(Ci -6 )alkyl- amino(Ci -6 )alkylaryl, aryl(Ci -6 )alkyl, oxazolinyl, azetidinyl, haloarylpyrrolidin
  • substituents on R 13 include halogen, cyano, Ci -6 alkyl, C 2-6 alkoxycarbonyl and di(Ci -6 )alkylaminocarbonyl. A further example is carboxy.
  • Selected examples of specific substituents on R 13 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidin
  • R 13 Particular examples of specific substituents on R 13 include bromo, cyano, methyl, methoxycarbonyl and dimethylaminocarbonyl. A further example is carboxy.
  • Typical values of R 13 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienylmethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazolylphenylamin
  • R 13 Representative values of R 13 include hydrogen, bromobenzyl, benzof ⁇ irylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, (carboxy)(methyl)- indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, dimethylaminocarbonylindolylmethyl and (dimethylaminocarbonyl)(methyl)indolyl- methyl.
  • R 13 Particular values of R 13 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, methoxycarbonylindolylmethyl and dimethylaminocarbonylindolylmethyl.
  • One particular sub-group of the compounds of formula (II A- A) is represented by the compounds of formula (HB), and pharmaceutically acceptable salts and solvates thereof:
  • W the moiety X-Y-Q, R 1 ' and R 12 are as defined above; T represents oxygen or N-R 5 ; R 23 represents hydrogen, halogen, cyano, nitro, Ci -6 alkyl, hydroxy(Ci. 6 )alkyl, trifluoromethyl, aryl(Ci.
  • R 24 represents hydrogen, halogen, Ci -6 alkoxy or di(Ci -6 )alkylaminocarbonyl; or R 23 and R 24 , when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and
  • R 25 represents hydrogen or Ci -6 alkyl.
  • T is N-R 25 . In another embodiment, T is oxygen.
  • Typical values of R 23 include hydrogen, cyano, carboxy, C 2-6 alkoxycarbonyl and di(C
  • Suitable values of R 23 include hydrogen, cyano, C 2-6 alkoxycarbonyl and di(C i -6 )alkylaminocarbonyl .
  • Illustrative values of R 23 include hydrogen, fluoro, chloro, cyano, nitro, oxazolinyl, triazolyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, morpholinylethoxy, azetidinyl, morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino, N-methoxycarbonyl-TV-methylamino, methylsulphonylamino, acetyl, acetyl oxime, acetyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethylaminoethyl)aminocarbonyl, (1 -hydroxyprop-2-yl
  • R 23 include hydrogen, cyano, carboxy, methoxycarbonyl and dimethylaminocarbonyl. Selected values of R 23 include hydrogen, cyano, methoxycarbonyl and dimethylaminocarbonyl.
  • R 23 is hydrogen.
  • R 24 Definitive values of R 24 include hydrogen, chloro, methoxy and dimethylaminocarbonyl. A particular value of R 24 is hydrogen.
  • R is hydrogen. In another embodiment, R is Ci -6 alkyl, especially methyl.
  • R 33 represents halogen or -NHR 34 ; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents;
  • R 34 represents methyl enedioxyphenyl, morpholinyl(Ci -6 )alkylphenyl, oxazolinyl- phenyl, [(Ci -6 )alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (Ci -6 )alkyltriazolylphenyl, (Ci -6 )alkylpyrimidinylphenyl, pyrazolyl(Ci -6 )alkyl- phenyl, triazolyl(Ci -6 )alkylphenyl, Ci -6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci -6 alkylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, Cj -6 alkyls
  • R 33 represents halogen or -NHR 34 , in which R 34 is as defined above.
  • R 33 represents halogen, especially bromo.
  • R 33 represents -NHR 34 , in which R 34 is as defined above.
  • R 33 represents unsubstituted or substituted aryl. In another embodiment, R 33 represents unsubstituted or substituted heteroaryl.
  • Typical values of R 34 include pyridinyl, halopyridinyl, (Ci -6 )alkylpyridinyl, di(C 1-6 )alkylpyridinyl and (Ci -6 )alkoxypyridinyl.
  • R 34 include methylenedioxyphenyl, morpholinylmethylphenyl, oxazolinylphenyl, (methyl)(oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolylphenyl, methyltriazolylphenyl, methylpyrimidinylphenyl, pyrazolylmethylphenyl, triazolylmethylphenyl, methylsulphonylaminophenyl, morpholinylcarbonylphenyl, methylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, methylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, (bromo)(methyl)pyrazolyl, trimethyl
  • R 33 represents halogen or -NHR 4 , in which R 34 is as defined above. Additionally, R 33 represents phenyl, naphthyl, benzofuryl, thienyl, benzothienyl, indolyl, isoxazolyl, pyrazolyl, pyridinyl or pyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
  • R 33 Selected examples of suitable substituents on R 33 include halogen, cyano, Ci -6 alkyl, hydroxy(Ci -6 )alkyl, trifiuoromethyl, Ci -6 alkoxy, trifluoromethoxy, aryloxy, methylenedioxy, Ci -6 alkylthio, arylsulphonyl, amino, C 2-6 alkylcarbonylamino, Ci -6 alkylsulphonylamino, C 2-6 alkylcarbonyl and aminocarbonyl.
  • R selected examples include fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, phenoxy, methylenedioxy, methylthio, phenylsulphonyl, amino, acetylamino, methylsulphonylamino, acetyl and aminocarbonyl.
  • R 33 Specific values of R 33 include bromo, methyl enedioxyphenylamino, morpholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenyl- amino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenyl- amino, triazolylmethylphenylamino, methylsulphonylaminophenylamino, morpholinyl- carbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, dihydrobenzofuranylamino, methylsulphonylindolinylamino, chromanonylamino, dihydroquinolinonylamino,
  • R 43 represents hydrogen, halogen, nitro, Ci -6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl(Ci -6 )alkylaryl, piperazinyl(Ci -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i -6 )alkylaryl, morpholinyl(C i -6 )alkylaryl, (C i -6 )alkoxyaryl, cyano(C i .
  • R 44 represents hydrogen, halogen, Ci -6 alkyl or Ci -6 alkoxy.
  • a suitable value of R 43 is (Ci -6 )alkylpyrazolyl.
  • R 43 Specific values of R 43 include bromo, nitro, methyl, w-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethyl- phenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazinyl, methylpiperazinyl, chloroph
  • R 43 is methylpyrazolyl.
  • R 44 represents hydrogen. In another embodiment, R 44 represents halogen, especially bromo. In a further embodiment, R 44 represents Ci -6 alkyl, especially methyl. In an additional embodiment, R 44 represents Ci -6 alkoxy, especially methoxy.
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described 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.
  • 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. 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 glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds 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. 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.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, dimethylsulphoxide, a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as N,7V-dimethylformamide, optionally under basic conditions, e.g. in the presence of an organic base such as NJV- diisopropylethylamine or 2,6-lutidine.
  • a suitable solvent e.g. acetonitrile, dimethylsulphoxide, a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as N,7V-dimethylformamide
  • an organic base such as NJV- diisopropylethylamine or 2,6-lutidine.
  • reaction may be effected at an elevated temperature in a solvent such as 2-ethoxyethanol in the presence of a catalytic quantity of a mineral acid, e.g. concentrated hydrochloric acid.
  • a solvent such as 2-ethoxyethanol
  • a catalytic quantity of a mineral acid e.g. concentrated hydrochloric acid.
  • the reaction may be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium tert-butoxide, in the presence of a transition metal catalyst.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene
  • an inorganic base such as sodium tert-butoxide
  • the transition metal catalyst is suitably palladium(II) acetate, in which case the reaction will ideally be performed in the presence of tert-butylphosphonium tetrafluoroborate or dicyclohexyl diphenylphosphine.
  • reaction is conveniently effected by stirring compound (V) with tert-butyl nitrite and copper(II) bromide in a suitable solvent, e.g. acetonitrile.
  • a suitable solvent e.g. acetonitrile.
  • V, W, the moiety X-Y-Q, R 1 , R 2 and R 6 are as defined above, and L 2 represents a suitable leaving group.
  • the leaving group L 2 is typically a halogen atom, e.g. bromo or iodo.
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, typically under basic conditions, e.g. in the presence of an organic base such as TVyV-diisopropylethylamine.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran
  • organic base such as TVyV-diisopropylethylamine.
  • the reaction may be accomplished by heating the reactants in a lower alkanol solvent, e.g. a Ci -6 alkyl alcohol such as ethanol.
  • a lower alkanol solvent e.g. a Ci -6 alkyl alcohol such as ethanol.
  • the compounds of formula (I) wherein U represents N may be prepared by a process which comprises reacting a compound of formula (VI) as defined above with a compound of formula (VII):
  • the reaction may additionally be accomplished by heating the reactants in acetic acid in the presence of sodium acetate.
  • the intermediates of formula (VII) above may be prepared by reacting a compound of formula (IV) as defined above with l,l'-thiocarbonyldiimidazole; followed by treatment with ammonia or ammonium hydroxide.
  • the reaction between compound (VIII) and Bredereck's reagent may conveniently be effected by heating the reactants together, typically at the reflux temperature.
  • the subsequent treatment with hydrazine hydrochloride or hydrazine hydrate may conveniently be effected in a suitable solvent, e.g. a lower alkanol solvent such as methanol or ethanol, optionally at an elevated temperature.
  • U, V, W, R 1 , R 2 , R 3 , R 4 and R 6 are as defined above, and L 3 represents a suitable leaving group; with aminoacetaldehyde dimethyl acetal; followed by treatment with an acid, typically an organic acid such as p-toluenesulphonic acid.
  • the leaving group L 3 is typically a halogen atom, e.g. chloro, or a methylthio (-SCH 3 ) group.
  • reaction between compound (IX) and aminoacetaldehyde dimethyl acetal may conveniently be effected by heating the reactants together.
  • the subsequent acid treatment may conveniently be effected by heating in a suitable solvent, e.g. a hydrocarbon solvent such as toluene, or a lower alkanol solvent such as isopropanol.
  • the compounds of formula (IC) above wherein R y is methyl and R z is hydrogen may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with propargylamine.
  • the reaction may conveniently be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether solvent such as tetrahydrofuran.
  • a suitable solvent e.g. a cyclic ether solvent such as tetrahydrofuran.
  • reaction is conveniently effected in a suitable organic solvent, e.g. acetonitrile.
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a hydrocarbon solvent such as toluene.
  • a suitable solvent e.g. a hydrocarbon solvent such as toluene.
  • the intermediates of formula (IX) above wherein L 3 is chloro may be prepared by reacting a compound of formula (XI) as defined above with phosphorus oxychloride, typically at an elevated temperature.
  • the compounds of formula (ID) above may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with a compound of formula R y -CONHNH 2 .
  • the reaction may be conveniently accomplished in the presence of an organic acid such as acetic acid.
  • the compounds of formula (IE) above may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with a metal azide such as sodium azide.
  • a suitable solvent e.g. a lower alkanol solvent such as methanol.
  • V, W, R 1 , R 2 , R 5 , R 6 and L 1 are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (IV).
  • V, W, R 1 , R 2 and R 6 are as defined above; followed by treatment of the resulting compound with sulphur.
  • the reaction between malononitrile and compound (XIV) is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of piperidine.
  • a suitable solvent e.g. a lower alkanol such as ethanol
  • sulphur is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of morpholine.
  • the starting materials of formula (IV), (VI) and (XIV) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be understood that 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 (IA) wherein R x represents hydrogen may be converted into the corresponding compound wherein R" is an alkylsulphonyl substituent, e.g. methylsulphonyl, by treatment with the appropriate alkylsulphonyl halide, e.g. methanesulphonyl chloride.
  • a compound of formula (I) wherein R 6 represents hydroxy may be converted into the corresponding compound wherein R 6 represents oxo by treatment with an oxidising agent such as Dess-Martin periodinane.
  • a compound of formula (I) wherein R 3 and/or R 4 contains an aryl or heteroaryl moiety may be halogenated (e.g. brominated) on the aryl or heteroaryl moiety by treatment with the appropriate TV-halosuccinimide (e.g. N-bromosuccinimide).
  • halogenated e.g. brominated
  • TV-halosuccinimide e.g. N-bromosuccinimide
  • a compound of formula (I) wherein R 3 and/or R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by amino (-NH 2 ) by treatment with benzophenone imine and tris(dibenzylidene- acetone)dipalladium(O) in the presence of 2,2 '-bis(diphenylphosphino)- 1 , 1 '-binaphthyl (BINAP) and a strong base such as sodium tert-butoxide.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound of formula (I) wherein the halogen atom is replaced by an optionally substituted C 3-7 cycloalkyl, aryl, aryl(Ci -6 )alkyl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted C 3-7 cycloalkyl, aryl, aryl(Ci- 6 )alkyl or heteroaryl boronic acid or a cyclic ester thereof, e.g. a pinacol ester thereof, in the presence of a catalyst.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 represents aryl(Ci -6 )alkyl, substituted on the aryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 3 represents biaryl(Ci -6 )alkyl or heteroarylaryl(Ci -6 )alkyl by treatment with, respectively, an aryl or heteroaryl boronic acid, in the presence of a catalyst.
  • a compound of formula (I) wherein R 3 represents heteroaryl(Ci -6 )alkyl, substituted on the heteroaryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 3 represents aryl-heteroaryl(Ci. 6 )alkyl by treatment with an aryl boronic acid, in the presence of a catalyst.
  • a compound of formula (I) wherein R 3 contains a cyclic borane moiety e.g.
  • 4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl may be converted into the corresponding compound wherein the cyclic borane moiety is replaced by an optionally substituted aryl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted aryl or heteroaryl halide, e.g. chloride, bromide or iodide, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, in an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonium bromide.
  • a base such as sodium carbonate, potassium carbonate or potassium phosphate
  • an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonium bromide.
  • the catalyst may be palladium(II) acetate, in which case the transformation may conveniently be effected at an elevated temperature in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and potassium phosphate.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents a substituted aminomethyl moiety, e.g. phenylaminomethyl, iV-methyl-N-phenylaminomethyl, pyridin- 3-ylaminomethyl, indolin-1-ylmethyl, 1,2,3,4-tetrahydroquinolin-l-ylmethyl or 1,2,3,4- tetrahydroisoquinolin-2-ylmethyl, by a two-stage procedure which comprises (i) Swern oxidation of the hydroxymethyl derivative by treatment with oxalyl chloride and dimethyl sulphoxide in the presence of triethylamine; and (ii) reductive animation of the formyl derivative thereby obtained by treatment with the appropriate amine, e.g.
  • aniline JV- methylaniline, 3-aminopyridine, indoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4- tetrahydroisoquinoline, in the presence of a reducing agent such as sodium cyanoborohydride.
  • any compound of formula (I) which contains a carbonyl-containing functionality e.g. formyl or a ketone moiety
  • a carbonyl-containing functionality e.g. formyl or a ketone moiety
  • a reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • Any compound of formula (I) wherein R 3 contains an amino moiety can be alkylated on the amino moiety by a reductive amination procedure which comprises treatment with the appropriate aldehyde in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents an optionally substituted C 3-7 heterocycloalkylcarbonyl moiety, e.g. piperidin-1-ylcarbonyl, 1,2,3,4- tetrahydroquinolin- 1 -ylcarbonyl, 6-methyl- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 6- methoxy- 1 ,2,3,4-tetrahydroquinolin- 1 -ylcarbonyl, 1 ,2,3 ,4-tetrahydroisoquinolin-2- ylcarbonyl or 1, 2,3, 4-tetrahydroquinoxalin-l -ylcarbonyl, by a two-stage procedure which comprises (i) oxidation of the hydroxymethyl moiety by treatment with potassium permanganate; and (ii) reaction of the carboxy derivative thereby obtained with the appropriate amine, e.g
  • piperidine 1,2,3,4-tetrahydroquinoline, 6-methyl- 1,2,3,4- tetrahydroquinoline, 6-methoxy-l ,2,3,4-tetrahydroquinoline, 1 ,2,3,4-tetrahydro- isoquinoline or 1,2,3,4-tetrahydroquinoxaline, in the presence of a condensing agent such as l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, or 0-(benzotriazol-l-yl)-N,JV,iV,7V- tetramethyluronium hexafluorophosphate (HBTU).
  • a condensing agent such as l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, or 0-(benzotriazol-l-yl)-N,JV,iV,7V- tetramethyluronium
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by chloro may be converted into the corresponding compound wherein the phenyl ring is substituted by morpholin-4-yl by treatment with morpholine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(di-te/-t-butylphosphino)biphenyl and sodium tert-butoxide.
  • a compound of formula (I) wherein R contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by pyrrolidin-1-yl by treatment with pyrrolidine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1 , 1 '-biphenyl and a base such as potassium carbonate.
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by an amino moiety (e.g. a group of formula -NHR 34 as defined above) by treatment with the appropriate amine (e.g. a compound of formula H 2 N-R 34 ) in the presence of tris(dibenzylideneacetone)dipalladium(0), isopropyl- 1 ,l'-biphenyl (X-Phos) and a base such as sodium tert-butoxide.
  • an amino moiety e.g. a group of formula -NHR 34 as defined above
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by carboxy (-CO 2 H) by treatment with M-butyllithium followed by carbon dioxide.
  • a compound of formula (I) wherein R 3 contains an indole moiety may be methylated on the indole ring by treatment with a methyl halide, e.g. iodomethane, in the presence of a strong base such as sodium hydride.
  • a compound of formula (I) wherein R 3 contains an indole moiety may be acetylated on the indole ring by treatment with acetic anhydride and 4-dimethylamino-pyridine, typically in the presence of an organic base such as triethylamine.
  • a compound of formula (I) wherein R 3 contains an indoline moiety may be converted into the corresponding compound wherein R 3 contains an indole moiety by treatment with an oxidising agent such as manganese dioxide.
  • a compound of formula (I) wherein R 3 contains a hydroxy substituent may be converted into the corresponding compound wherein R 3 contains a Ci -6 alkylsulphonyloxy substituent, e.g.
  • a compound of formula (I) wherein R 3 contains an amino (-NH 2 ) or carboxy (-CO 2 H) moiety may be converted into the corresponding compound wherein R 3 contains an amido moiety (-NHCO- or -CONH- respectively) by treatment with, respectively, a compound containing a carboxy or amino group, in the presence of O-(benzotriazol-l-yl)- ⁇ /V ⁇ -tetramethyluronium hexafluorophosphate (HBTU), typically in a dipolar aprotic solvent such as ⁇ /V-dimethylformamide; or in the presence of l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide and 1-hydroxybenzotriazole.
  • HBTU O-(benzotriazol-l-yl)- ⁇ /V ⁇ -tetramethyluronium hexafluorophosphate
  • a compound of formula (I) wherein R contains an amino substituent may be converted into the corresponding compound wherein R 3 contains an alkyl- or arylsulphonylamino substituent, e.g. methylsulphonylamino or phenylsulphonylamino, by treatment with an alkyl- or arylsulphonyl halide, e.g. methanesulphonyl chloride or benzenesulphonyl chloride.
  • a compound of formula (I) wherein R 3 contains an amino moiety may be acylated by treatment with a C 2-6 alkylcarbonyl halide, e.g. acetyl chloride; or a C 2-6 alkylcarbonyl anhydride, e.g. acetic anhydride.
  • a compound of formula (I) wherein R 3 contains an amino moiety may be converted into the corresponding carbamate ester by treatment with a C 1 . 6 alkyl haloformate, e.g. methyl chloro formate.
  • a compound of formula (I) wherein R contains a C 2-6 alkoxycarbonyl substituent, e.g. methoxycarbonyl, may be converted into the corresponding compound wherein R 3 contains a carboxy (-CO 2 H) substituent under standard saponification conditions, generally by treatment with a base, e.g. an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.
  • a base e.g. an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.
  • R 3 contains an amido substituent e.g.
  • a condensing agent such as l-[3-(dimethylamino
  • methylamine 2-hydroxyethylamine, dimethylamine, N-(2- hydroxyethyl)-N-methylamine, benzylamine, azetidine, pyrrolidine, piperidine, 1- methylpiperazine or morpholine.
  • a compound of formula (I) wherein R 3 /R 4 contains a nitro moiety may be converted into the corresponding compound wherein R 3 /R 4 contains an amino (-NH 2 ) moiety by catalytic hydrogenation, typically by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino (-NH 2 ) moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a heteroaryl-amino moiety, e.g. 6-methylpyridin-3- ylamino, by treatment with the appropriate heteroaryl halide, e.g. 5-bromo-2- methylpyridine, in the presence of palladium(II) acetate, 2-bis(dicyclohexylphosphino)- biphenyl and a base such as sodium tert-butoxide.
  • any compound of formula (I) wherein R 3 /R 4 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein the halogen atom is replaced by a substituted amino functionality by treatment with the appropriately- substituted amine derivative and palladium(II) acetate in the presence of a base, e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate.
  • a base e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate.
  • reaction may be effected by treatment with the appropriately-substituted amine derivative and [l,r-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride in the presence of a base, e.g. sodium tert-butoxide.
  • a base e.g. sodium tert-butoxide.
  • any compound of formula (I) wherein R 3 /R 4 contains an amino functionality may be converted into the corresponding compound wherein the amino functionality is substituted by an optionally substituted aryl or heteroaryl moiety by treatment with an appropriately-substituted aryl or heteroaryl halide (e.g.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a heteroaryl group, e.g.
  • pyrazol-3-yl 1- methylpyrazol-4-yl, l-propylpyrazol-4-yl, l-isobutylpyrazol-4-yl, l-benzylpyrazol-4-yl, 1- [2-(morpholin-4-yl)ethyl]pyrazol-4-yl, 6-methylpyridin-3-yl or pyrimidin-5-yl, by treatment with the appropriate heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst.
  • an organic diol e.g. pinacol
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a boronic acid [-B(OH) 2 ] moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a heteroaryl group, e.g. methylimidazolyl, by treatment with the appropriate heteroaryl halide, e.g. bromide, derivative in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, optionally in the presence of tetrabutylammonium bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group by treatment with a strong base, e.g. n-butyllithium, and 7V,7V-dimethylformamide.
  • a strong base e.g. n-butyllithium
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by hydroxymethyl by treatment with a reducing agent such as sodium borohydride.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by an aminomethyl moiety (e.g.
  • the appropriate amine e.g. dimethylamine, pyridin-3-ylamine, 1-methylpiperazine or morpholine
  • a reducing agent typically consists of a mixture of phenylsilane and dibutyltin dichloride.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino moiety may be converted into the corresponding compound wherein R /R 4 is methylated on the amino moiety by treatment with formaldehyde and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a pyridinyloxymethyl moiety by treatment with the appropriate hydroxypyridine in the presence of a mixture of triphenylphosphine and diethyl azodicarboxylate.
  • R 3 /R 4 contains a benzo moiety substituted by a C 2-6 alkoxycarbonyloxy group, e.g.
  • tert-butoxycarbonyloxy may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by hydroxy under standard hydrolytic conditions, e.g. by treatment with trifluoroacetic acid.
  • R 3 /R 4 contains a halogen atom, e.g. bromo,
  • R 3 /R 4 contains hydroxy by treatment with sodium hydroxide in the presence of tris(dibenzylideneacetone)- dipalladium(O) and 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-l,r-biphenyl.
  • a compound of formula (I) wherein R /R contains hydroxy may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted Ci -6 alkoxy, C 3-7 heterocycloalkoxy or C 3-7 heterocycloalkyl(Ci -6 )alkoxy by treatment with the appropriately substituted Ci -6 alkyl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkyl(C[ -6 )- alkyl halide, e.g. bromide, ideally at an elevated temperature in the presence of cetyl- ammonium bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains hydroxy may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted pyridinyloxy, pyrimidinyloxy or pyrazinyloxy by treatment with the appropriately substituted pyridinyl, pyrimidinyl or pyrazinyl halide, e.g. fluoride or chloride, typically in the presence of a strong base such as sodium t ⁇ rt-butoxide.
  • R 3 /R 4 contains a halogen atom e.g.
  • bromo may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted aryloxy or heteroaryloxy by treatment with an appropriately-substituted hydroxyaryl or hydroxyheteroaryl derivative and a base such as caesium carbonate, ideally in the presence of a copper(I) halide, e.g. copper(I) chloride or copper(I) bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino (-NH 2 ) group may be converted into the corresponding compound wherein R 3 /R 4 contains 2,5-dioxopyrrolidin- 1-yl by treatment with succinic anhydride.
  • a compound of formula (I) wherein R 3 /R 4 contains an aryl or heteroaryl moiety substituted by a halogen atom, e.g. chloro, may have the halogen atom removed by catalytic hydrogenation.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety may be alkylated on the aromatic ring by treatment with n-butyllithium and an alkyl halide (e.g. iodopropane); or by treatment with an organozinc reagent (e.g. isopropylzinc bromide) in the presence of [l,r-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride and copper(I) iodide.
  • n-butyllithium and an alkyl halide e.g. iodopropane
  • an organozinc reagent e.g. isopropylzinc bromide
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by an optionally substituted alkynyl moiety (e.g. 3-hydroxyprop-l-yn-l-yl) by treatment with an appropriately- substituted alkyne derivative (e.g. 3-hydroxyprop-l-yne) and a catalyst such as tetrakis(triphenylphosphine)palladium(0), typically in the presence of copper(I) iodide and a base such as triethylamine.
  • an optionally substituted alkynyl moiety e.g. 3-hydroxyprop-l-yn-yl
  • an appropriately- substituted alkyne derivative e.g. 3-hydroxyprop-l-yne
  • a catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by acetyl by a two-stage procedure which comprises (i) treatment with butyl vinyl ether and palladium acetate, suitably in the presence of l,3-bis(diphenylphosphino)propane and an organic base such as triethylamine; and (ii) hydrolysis with a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by 1 -hydroxy- 1-methylethyl by treatment with n-butyllithium and acetone.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by Ci -6 alkylthio (e.g. isopropylthio) by treatment with n-butyllithium and the appropriate disulphide derivative (e.g isopropyl disulphide).
  • Conversion of the Ci -6 alkylthio moiety into Ci -6 alkylsulphinyl or Ci -6 alkylsulphonyl may be accomplished by treatment with an oxidising agent, e.g. m-chloroperbenzoic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a pyridinyl moiety may be converted into the corresponding pyridine-TV-oxide analogue by treatment with peracetic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a formyl moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a vinyl moiety by treatment with methyltriphenylphosphonium bromide and a strong base such as sodium hexamethyldisilazide.
  • a compound of formula (I) wherein R 3 /R 4 contains a formyl moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a 1-hydroxyethyl moiety by treatment with methyllithium.
  • a compound of formula (I) wherein R 3 /R 4 contains a (2-hydroxyethyl)amino- carbonyl group may be converted into the corresponding compound wherein R /R 4 contains an oxazolin-1-yl moiety by treatment with thionyl chloride.
  • a compound of formula (I) wherein R 3 /R 4 contains an ester functionality may be converted into the corresponding compound wherein R 3 /R 4 contains an amide functionality (e.g. methylaminocarbonyl or dimethylaminocarbonyl) by treatment with an appropriately-substituted amine (e.g. methylamine or dimethylamine) in the presence of trimethylaluminium.
  • R 3 /R 4 contains an ester functionality e.g. methoxycarbonyl
  • R 3 /R 4 contains an amide functionality e.g. methylaminocarbonyl or dimethylaminocarbonyl
  • an appropriately-substituted amine e.g. methylamine or dimethylamine
  • Alkenyl-containing compounds may be converted into the corresponding vic- dihydroxy analogues by treatment with osmium tetroxide.
  • Alkenyl- and alkynyl-containing compounds may be converted into the corresponding alkyl analogues by catalytic hydrogenation.
  • a compound of formula (I) wherein R 5 represents -CO 2 R b in which R b is other than hydrogen may be saponified and then decarboxylated to give the corresponding compounds in which R 5 represents -CO 2 H and hydrogen respectively by treatment with a base such as lithium hydroxide.
  • a base such as lithium hydroxide.
  • any compound of formula (I) wherein R 5 contains a lower alkyl ester moiety may be converted into the corresponding compound wherein R 5 contains a carboxy (-CO 2 H) group by treatment with a base such as lithium hydroxide or sodium hydroxide.
  • a compound of formula (I) wherein R 5 represents -CO 2 H may be converted into the corresponding compound wherein R 5 represents -CONR c R d by treatment with an amine of formula H-NR c R d and a condensing agent such as EDC, typically in the presence of an organic base such as triethylamine.
  • any compound of formula (I) wherein R 5 contains a carboxy moiety may be converted into the corresponding compound wherein R 5 contains an amide moiety by treatment with the appropriate amine and a condensing agent such as EDC, typically in the presence of 1- hydroxybenzotriazole (HOBT); alternative condensing agents include isobutyl chloroformate/triethylamine and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate.
  • EDC 1- hydroxybenzotriazole
  • alternative condensing agents include isobutyl chloroformate/triethylamine and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate.
  • any compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound wherein R 5 contains an amide moiety by treatment with the appropriate carboxylic acid under analogous conditions
  • a compound of formula (I) wherein R 5 represents cyano may be converted into the corresponding compound wherein R 5 represents -CONH 2 by heating under acidic conditions, e.g. in a mixture of acetic acid and sulphuric acid; prolonged treatment leads to conversion to the corresponding carboxylic acid followed by decarboxylation, i.e. conversion into the corresponding compound wherein R 5 represents hydrogen.
  • a compound of formula (I) wherein R 5 contains a carboxy moiety may be converted into the corresponding compound containing an arylcarbonyl moiety (e.g. benzoyl) by a two-stage procedure which comprises (i) treatment with N,Odimethyl- hydroxylamine hydrochloride and a condensing agent such as EDC, typically in the presence of HBTU; and (ii) reaction of the compound thereby obtained with the appropriate aryl lithium derivative, e.g. phenyllithium.
  • arylcarbonyl moiety e.g. benzoyl
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents fluoro by treatment with SelectfluorTM [i.e. l-(chloromethyl)-4- fluoro- l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)].
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents chloro, bromo or iodo by treatment with TV-chlorosuccinimide, ⁇ /-bromosuccinimide or N-iodosuccinimide respectively.
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents dimethylaminomethyl by treatment with Eschenmoser's salt (i.e. N,7V-dimethylmethyleneammonium iodide).
  • Eschenmoser's salt i.e. N,7V-dimethylmethyleneammonium iodide
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo or chloro, may be converted into the corresponding compound wherein R 5 represents -CO 2 R by treatment with carbon monoxide and an alcohol of formula R -OH, in the presence of a catalyst. Indeed, this procedure is generally applicable for converting any compound of formula (I) wherein R 5 contains a halogen atom into the corresponding compound containing a lower alkyl ester functionality.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is [l,l'-bis(diphenylphosphino)ferrocene]dichloro- palladium(II)-dichloromethane complex, in which case the transformation may conveniently be effected at an elevated temperature and pressure in the presence of an organic base such as triethylamine.
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. bromo or iodo, may be converted into the corresponding compound wherein R 5 represents aryl, biaryl, C 3-7 heterocycloalkyl-aryl, C 3-7 heterocycloalkyl(Ci -6 )alkyl-aryl, heteroaryl or heteroaryl-aryl by treatment with, respectively, an aryl, biaryl, C 3-7 heterocycloalkyl-aryl, C 3-7 heterocycloalkyl(Ci -6 )alkyl-aryl, heteroaryl or heteroaryl-aryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g.
  • a compound of formula (I) wherein R 5 represents aryl, substituted on the aryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 5 represents biaryl or heteroaryl-aryl by treatment with, respectively, an aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst.
  • a compound of formula (I) wherein R 5 represents heteroaryl, substituted on the heteroaryl moiety by a halogen atom such as chloro or bromo may be converted into the corresponding compound wherein R 5 represents aryl-heteroaryl or bi(heteroaryl) by treatment with, respectively, an aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol or 7V-phenyldiethanolamine, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate, potassium hydroxide or potassium phosphate, in an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1 ,4-dioxane.
  • the catalyst may be palladium(II) acetate, in which case the transformation may conveniently be effected at an elevated temperature in the presence of 1 ,3-bis(diphenylphosphino)propane and potassium phosphate, or in the presence of PdCl 2 .dppf and potassium phosphate.
  • any compound of formula (I) wherein R 5 represents or contains a halogen atom, e.g. bromo or iodo, may be converted by means of the foregoing procedure into the corresponding compound wherein the halogen atom is replaced by a substituted or unsubstituted aryl, heteroaryl or alkenyl group.
  • a halogen atom e.g. bromo or iodo
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo, may be converted into the corresponding compound wherein R 5 represents aryl(Ci -6 )alkyl, e.g. benzyl, by treatment with a suitable organozinc reagent, in the presence of a catalyst.
  • the organozinc reagent may conveniently be prepared by reacting the appropriate aryl(Ci -6 )- alkyl halide, e.g. benzyl bromide, with zinc dust.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is dichlorobis(triphenylphosphine)- palladium(II), in which case the transformation may conveniently be effected at an elevated temperature in the presence of an inert solvent such as tetrahydrofuran.
  • a compound of formula (I) wherein R 5 contains a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein the halogen atom is replaced by an arylamino or heteroarylamino moiety, e.g. phenylamino, by treatment with the appropriate amine, e.g. aniline, and a transition metal catalyst, e.g. palladium acetate, typically in the presence of tributylphosphine tetrafluoroborate and a base such as sodium tert-butoxide.
  • R 5 represents a halogen atom, e.g.
  • R 5 represents C 2-6 alkynyl, C 3-7 cycloalkyl(C 2-6 )alkynyl, aryl(C 2-6 )alkynyl, C 3-7 heterocycloalkyl(C 2-6 )alkynyl, C 5-9 heterobicycloalkyl(C 2-6 )alkynyl or heteroaryl(C 2-6 )alkynyl by treatment with, respectively, a suitable C 2-6 alkyne, C 3-7 cycloalkyl(C 2-6 )alkyne, aryl(C 2-6 )alkyne, C 3-7 heterocycloalkyl- (C 2-6 )alkyne, C 5-9 heterobicycloalkyl(C 2-6 )alkyne or heteroaryl(C 2-6 )alkyne, in the presence of a catalyst.
  • a compound of formula (I) wherein R 5 represents C 2-6 alkynyl, e.g. ethynyl may be converted into the corresponding compound wherein R 5 represents aryl(C 2-6 )alkynyl, heteroaryl(C 2-6 )alkynyl or C 3-7 cycloalkyl-heteroaryl(C 2-6 )alkynyl by treatment with, respectively, a suitable aryl, heteroaryl or C 3-7 cycloalkyl-heteroaryl iodide, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is dichlorobis(triphenylphosphine)palladium(II), in which case the transformation may conveniently be effected at an elevated temperature in the presence of copper(I) iodide and an organic base such as diisopropylamine.
  • a compound of formula (I) wherein R 5 represents arylethynyl, e.g. phenylethynyl, may be converted into the corresponding compound wherein R 5 represents arylethyl, e.g. 2-phenylethyl, by catalytic hydrogenation.
  • this procedure is generally applicable for converting any compound of formula (I) wherein R 5 contains a -C ⁇ C- moiety into the corresponding compound containing a -CH 2 CH 2 - moiety.
  • a compound of formula (I) wherein R 5 contains a -C ⁇ C- moiety may be converted into the corresponding compound containing a -COCH 2 - moiety by treatment with a pH 2 buffer solution.
  • a compound of formula (I) wherein R 5 contains a -C ⁇ C- moiety may be converted into the corresponding compound containing a -COCO- moiety by treatment with a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 5 represents nitro may be converted into the corresponding compound wherein R 5 represents amino by catalytic hydrogenation, which typically comprises reacting the nitro compound with hydrogen in the presence of a catalyst such as palladium on charcoal.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a -OCH 2 - moiety by treatment with the appropriate alkyl halide, typically in the presence of a base such as potassium carbonate.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a -OSO 2 - moiety by treatment with the appropriate sulphonyl halide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a trifluoromethylsulphonyloxy moiety by treatment with N-phenyltrifluoromethanesulphonimide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a methylsulphonyloxymethyl moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a halomethyl (e.g. chloromethyl) moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative (including cyclic amines), typically in the presence of a base such as potassium carbonate.
  • a compound of formula (I) wherein R 5 contains a hydroxymethyl moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative (including cyclic amines), generally in the presence of triphenylphosphine and diethyl azodicarboxylate.
  • a compound of formula (I) wherein R 5 contains a trifluoromethylsulphonyloxy moiety may be converted into the corresponding compound wherein the trifluoromethylsulphonyloxy moiety is replaced by an amino functionality by treatment with the appropriate amine derivative (including cyclic amines) and a transition metal catalyst, e.g.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be alkylated by treatment with the appropriate alkyl halide (e.g. methyl iodide, ethyl bromide, benzyl bromide or tert-butyl bromoacetate), typically in the presence of a base such as sodium hydride or triethylamine.
  • alkyl halide e.g. methyl iodide, ethyl bromide, benzyl bromide or tert-butyl bromoacetate
  • a base such as sodium hydride or triethylamine.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a -NCH 2 - motif by a reductive amination procedure which comprises treatment with the appropriate aldehyde derivative in the presence of a base such as sodium triacetoxyborohydride.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a carbonylamino moiety by treatment with the appropriate carbonyl halide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a urea functionality by treatment with the appropriate isocyanate derivative.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a urea functionality by a two-stage procedure which comprises (i) treatment with triphosgene, typically in the presence of a base such as triethylamine; and (ii) reaction of the compound thereby obtained with the appropriate amine derivative (including cyclic amines).
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a sulphonylamino moiety by treatment with the appropriate sulphonyl halide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo, may be converted into the corresponding compound wherein R 5 represents acetyl by a two- stage procedure which comprises (i) reaction with butyl vinyl ether and a transition metal catalyst such as tris(dibenzylideneacetone)dipalladium(0), typically in the presence of 1 ,3- bis(diphenylphosphino)propane and a base such as potassium carbonate; and (ii) hydrolysis of the resulting compound by treatment with a mineral acid, e.g. hydrochloric acid.
  • a transition metal catalyst such as tris(dibenzylideneacetone)dipalladium(0), typically in the presence of 1 ,3- bis(diphenylphosphino)propane and a base such as potassium carbonate
  • a compound of formula (I) wherein R 5 represents acetyl may be converted into the corresponding compound wherein R 5 represents 3-(dimethylamino)-l-oxoprop-2-en-l-yl by treatment with N ⁇ V-dimethylformamide dimethyl acetal, typically at an elevated temperature.
  • a compound of formula (I) wherein R 5 represents 3-(dimethylamino)-l- oxoprop-2-en-l-yl may be converted into the corresponding compound wherein R 5 represents a substituted or unsubstiruted pyrimidinyl moiety by treatment with the appropriate amidine derivative, typically at an elevated temperature in the presence of a base such as sodium ethoxide.
  • 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. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 rd edition, 1999.
  • the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
  • the compounds in accordance with this invention potently inhibit the activity of human PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ .
  • the compounds of the accompanying Examples were all found to possess IC 50 values for inhibition of activity of human PI3K ⁇ and/or PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ of 50 ⁇ M or better.
  • NBS TV-bromosuccinimide
  • NIS TV-iodoosuccinimide r.t.: room temperature sat.: saturated h: hour min: minute cone: concentrated v: volume wt: weight M: mass
  • SiO 2 silica br.: broad
  • DIPEA NiV-diisopropylethylamine RT: retention time
  • EDC l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride brine: saturated aqueous sodium chloride solution
  • Electrospray Positive Ionisation Bredereck' s reagent t ⁇ rt-butoxybis(dimethylamino)methane
  • Lawesson's reagent 2,4-bis(4-methoxyphenyl)-l ,3-dithia-2,4-diphosphetane-2,4- disulfide
  • Aqueous HCl solution (2M; 80 mL) was added and the reaction mixture stirred vigorously at r.t. MeOH (80 mL) was added and the reaction mixture was stirred at r.t. for 3 h, then concentrated in vacuo. The residue was dissolved in DCM (150 mL), and DIPEA (9.7 mL, 55.86 mmol) was added. The reaction mixture was cooled to 0 0 C and a solution of di-tert-butyl dicarbonate (9.2 g, 41.89 mmol) in DCM (50 mL) was added. The reaction mixture was stirred at r.t. for 16 h before addition of water (100 mL).
  • the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic fraction was washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was pre-purified by preparative ⁇ PLC, then partitioned between EtOAc (100 mL) and aqueous sat. NaHCO 3 solution (100 mL). The combined organic fractions were washed with a mixture of brine and water (100 mL), dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Methyl 4-amino-3-iodobenzoate (5 g, 18 mmol) was dissolved in formic acid (35 mL) and the reaction mixture heated at reflux for 90 minutes. Volatiles and formic acid were removed by evaporation in vacuo. The residue was taken up in DCM (200 mL) and washed with sat. NaHCO 3 solution (40 mL). The organic layer was isolated and washed with water (2 x 40 mL), dried (MgSO 4 ) and the solvent removed by evaporation in vacuo. The residue was dissolved in THF (200 mL), BH 3 -Me 2 S (5 mL, 53 mmol) added and the reaction mixture heated at reflux for 90 minutes.
  • Example 3 To a stirred solution of Example 3 (0.103 g, 0.34 mmol) in DCM (15 mL) was added NEt 3 (0.05 mL, 0.36 mmol), followed by a solution of methanesulfonyl chloride (0.03 mL, 0.36 mmol) in DCM (1 mL) dropwise. The reaction mixture was stirred at r.t. for 24 h under a nitrogen atmosphere. Additional methanesulfonyl chloride (0.01 mL, 0.14 mmol) was added and the reaction mixture stirred for a further 24 h before being concentrated in vacuo.
  • Example 10 To a stirred solution of Example 10 (0.20 g, 0.45 mmol) in DMF (5 mL) at 0 0 C was added methyl iodide (0.5 mL, excess), followed by NaH (50 mg, 60% dispersion in oil, excess). The reaction mixture was stirred at this temperature for 5 minutes, and then partitioned between EtOAc (5 mL) and water (5mL). The organic fraction was dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by column chromatography (SiO 2 , 0-5% MeOH/EtOAc) gave the title compound (0.03 g, 16%) as a yellow solid.
  • the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL), then the aqueous layer was separated and extracted into EtOAc (2 x 10 mL). The organic fractions were combined, washed with water (10 mL), brine (10 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo and washed with Et 2 O to give a pale yellow solid. A portion of this solid (0.30 g) was dissolved in AcOH (2 mL) and heated by microwave radiation to 140 0 C for 10 min. The reaction mixture was partitioned between EtOAc (20 mL) and sat. NaHCO 3 solution (20 mL).
  • Example 22 To a stirred solution of Example 22 (0.20 g, 0.4 mmol) dissolved in ethanol (5 mL) and water (5 mL) was added sodium hydroxide (0.10 g, 2.5 mmol) and the reaction mixture heated at reflux for 2 h. Upon cooling, the solvents were removed by evaporation in vacuo and the residue dissolved in water. The resulting solution was neutralized with citric acid, resulting in the precipitation of the title compound which was isolated by filtration, washed with water and dried in vacuo (0.19 g, 98%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une série de dérivés thiazole et thiophène tricycliques fusionnés qui sont substitués en position 2 du cycle thiazole ou thiophène par un groupement morpholin-4-yle éventuellement substitué, qui sont des inhibiteurs sélectifs des enzymes PI3 kinase, qui sont obtenus de sorte à être bénéfiques en médecine, par exemple dans le traitement d'états inflammatoires, auto-immuns, cardiovasculaires, neurodégénératifs, métaboliques, oncologiques, nociceptifs ou ophtalmiques.
PCT/GB2008/004002 2007-12-04 2008-12-03 Inhibiteurs tricycliques de kinase WO2009071890A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0723750A GB0723750D0 (en) 2007-12-04 2007-12-04 Therapeutuic agents
GB0723751.4 2007-12-04
GB0723750.6 2007-12-04
GB0723751A GB0723751D0 (en) 2007-12-04 2007-12-04 Therapeutic agents
GB0812558A GB0812558D0 (en) 2008-07-09 2008-07-09 Therapeutic agents
GB0812558.5 2008-07-09

Publications (1)

Publication Number Publication Date
WO2009071890A1 true WO2009071890A1 (fr) 2009-06-11

Family

ID=40351930

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/004002 WO2009071890A1 (fr) 2007-12-04 2008-12-03 Inhibiteurs tricycliques de kinase

Country Status (1)

Country Link
WO (1) WO2009071890A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
US8097622B2 (en) 2008-10-14 2012-01-17 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013080156A1 (fr) 2011-11-30 2013-06-06 Actelion Pharmaceuticals Ltd Antibiotiques d'octahydro-2h-pyrido[4,3-e][1,3]oxazin-2-one 3,7-disubstituée
WO2014068070A1 (fr) 2012-10-31 2014-05-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour prévenir le syndrome des antiphospholipides (sapl)
WO2014191632A1 (fr) 2013-05-31 2014-12-04 Medeia Therapeutics Ltd Utilisation de dérivés de benzo[b]thiazine en tant qu'agents cytoprotecteurs
WO2016059220A1 (fr) 2014-10-16 2016-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Agents d'activation du tcr à utiliser dans le traitement de la lla-t
EP4067347A1 (fr) * 2016-05-24 2022-10-05 Genentech, Inc. Inhibiteurs hétérocycliques de cbp/ep300 pour le traitement du cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037843A1 (fr) * 2003-10-14 2005-04-28 Vertex Pharmaceuticals Incorporated Compositions utiles comme inhibiteurs de proteines kinases
WO2006114606A1 (fr) * 2005-04-26 2006-11-02 Ucb Pharma S.A. Derives de thiazole fusionne en tant qu'inhibiteurs de la kinase
WO2007141504A1 (fr) * 2006-06-06 2007-12-13 Ucb Pharma S.A. Dérivés de thiophène fusionnés utilisés en tant qu'inhibiteurs de kinase
WO2008001076A1 (fr) * 2006-06-26 2008-01-03 Ucb Pharma S.A. Dérivés de thiazole à cycle fusionnés en tant qu'inhibiteurs de kinase

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037843A1 (fr) * 2003-10-14 2005-04-28 Vertex Pharmaceuticals Incorporated Compositions utiles comme inhibiteurs de proteines kinases
WO2006114606A1 (fr) * 2005-04-26 2006-11-02 Ucb Pharma S.A. Derives de thiazole fusionne en tant qu'inhibiteurs de la kinase
WO2007141504A1 (fr) * 2006-06-06 2007-12-13 Ucb Pharma S.A. Dérivés de thiophène fusionnés utilisés en tant qu'inhibiteurs de kinase
WO2008001076A1 (fr) * 2006-06-26 2008-01-03 Ucb Pharma S.A. Dérivés de thiazole à cycle fusionnés en tant qu'inhibiteurs de kinase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KADOYA, S., NAGASAKI, S.: "Synthetic chemotherapeutic agents. V. Antibacterial activities of thiazolo[5,4-f]quinolinecarboxylic acid derivatives", YAKUGAKU ZASSHI, vol. 99, no. 5, 1979, pages 483 - 492, XP009112737 *
KADOYA, S., TAKAMURA, I., SUZUKI, N., DOHMORI, R.: "Synthetic chemotherapeutic agents. II. Synthesis of 2-substituted thiazolo[5,4-f]quinoline derivatives. (2)", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 24, no. 1, 1976, pages 136 - 146, XP009112744 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8097622B2 (en) 2008-10-14 2012-01-17 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
US8309546B2 (en) 2008-10-14 2012-11-13 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013080156A1 (fr) 2011-11-30 2013-06-06 Actelion Pharmaceuticals Ltd Antibiotiques d'octahydro-2h-pyrido[4,3-e][1,3]oxazin-2-one 3,7-disubstituée
US9029368B2 (en) 2011-11-30 2015-05-12 Actelion Pharmaceuticals Ltd. 3,7-disubstituted octahydro-2H-pyrido[4,3-E][1,3]oxazin-2-one antibiotics
WO2014068070A1 (fr) 2012-10-31 2014-05-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour prévenir le syndrome des antiphospholipides (sapl)
WO2014191632A1 (fr) 2013-05-31 2014-12-04 Medeia Therapeutics Ltd Utilisation de dérivés de benzo[b]thiazine en tant qu'agents cytoprotecteurs
WO2016059220A1 (fr) 2014-10-16 2016-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Agents d'activation du tcr à utiliser dans le traitement de la lla-t
EP4067347A1 (fr) * 2016-05-24 2022-10-05 Genentech, Inc. Inhibiteurs hétérocycliques de cbp/ep300 pour le traitement du cancer

Similar Documents

Publication Publication Date Title
WO2009071890A1 (fr) Inhibiteurs tricycliques de kinase
US8338592B2 (en) Fused thiazole derivatives as kinase inhibitors
AU2006239018B2 (en) Fused thiazole derivatives as kinase inhibitors
WO2009071888A1 (fr) Pyrrolothiazoles comme inhibiteurs de la pi3 kinase
WO2009071895A1 (fr) Dérivés thiazole et thiophène fusionnés comme inhibiteurs de kinase
EP2499144B1 (fr) Dérivés quinoline et quinoxaline en tant qu' inhibiteurs de kinase
EP2872511A1 (fr) Dérivés d'imidazopyrazine en tant que modulateurs de l'activité tnf
WO2010133836A1 (fr) Dérivés bicycliques fusionnés de pyrazole convenant comme inhibiteurs de kinases
WO2009122148A1 (fr) Dérivés de thiophène et de thiazole fusionnés en tant qu'inhibiteurs de kinases pi3k
WO2013068458A1 (fr) Dérivés thiazolo-pyrimidine thérapeutiquement actifs
US8168634B2 (en) Thiazole derivatives as kinase inhibitors
WO2009093009A1 (fr) Dérivés de thiophène tricyclique condensés servant d'inhibiteurs de mek
EP2076512A1 (fr) Dérivés fusionnés de thiazole en tant qu'inhibiteurs de kinase
WO2009001089A1 (fr) Dérivés de thiazole fusionné comme inhibiteurs de kinase

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08857023

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08857023

Country of ref document: EP

Kind code of ref document: A1