WO2010146351A1 - Derives d'indolylmethyl-morpholine en tant qu'inhibiteurs des kinases - Google Patents

Derives d'indolylmethyl-morpholine en tant qu'inhibiteurs des kinases Download PDF

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WO2010146351A1
WO2010146351A1 PCT/GB2010/001171 GB2010001171W WO2010146351A1 WO 2010146351 A1 WO2010146351 A1 WO 2010146351A1 GB 2010001171 W GB2010001171 W GB 2010001171W WO 2010146351 A1 WO2010146351 A1 WO 2010146351A1
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mmol
alkyl
methyl
compound
reaction mixture
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PCT/GB2010/001171
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Mezher Hussein Ali
Julien Alistair Brown
Benjamin Charles De Candole
Brian Woodside Hutchinson
Barry John Langham
Judi Charlotte Neuss
Joanna Rachel Quincey
Graham Peter Trevitt
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Ucb Pharma S.A.
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Publication of WO2010146351A1 publication Critical patent/WO2010146351A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a class of substituted morpholine derivatives, and to their use in therapy. More particularly, the invention provides a family of morpholine derivatives, substituted in the 4-position by a substituted carbonyl or sulfonyl moiety, and in the 3 -position by an optionally substituted indol-3-ylmethyl group. 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
  • the PI3K pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases.
  • PDKs 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 03/002561 describes a class of cyclic amine derivatives, and includes within its scope substituted morpholine derivatives.
  • the compounds described therein are alleged to be antagonists of human orexin receptors which are of potential use in the treatment of a wide variety of medical conditions, in particular obesity.
  • 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 50 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 of
  • 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 PI3K ⁇ and/or PI3K ⁇ isoform relative to other human kinases.
  • the compounds of the invention possess notable advantages in terms of their high potency and selectivity, and valuable pharmacokinetic properties (including low clearance and high bioavailability).
  • the present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • X represents oxygen, N-R 5 or a covalent bond
  • R 1 represents 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;
  • R 2 represents hydrogen; or optionally substituted Ci -6 alkyl;
  • R 3 and R 4 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR a , -SR a , -SOR a , -SO 2 R 3 , -NR b R c , -CH 2 NR b R c , -NR c COR d , -CH 2 NR c COR d , -NR c CO 2 R d , -NHC0NR b R c , -NR c SO 2 R e , -N(SO 2 R e ) 2 , -NHS0 2 NR b R c , -COR d , -CO 2 R d , -CONR b R c , -CON(OR a )R b or -SO 2 NR b R c ; or
  • R a represents Ci -6 alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R b and R c independently represent hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C ⁇ -6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or R b and R c , when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, ox
  • R e represents C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • the present invention also provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • R 3 and R 4 independently represent hydrogen, halogen, trifluoromethyl, -OR a , -SR a , -SOR ⁇ -SO 2 R 3 , -NR b R c , -NR c C0R d , -NR c C0 2 R d , -NR c SO 2 R e , -COR d , -CO 2 R d , -CONR b R c or -SO 2 NR b R e ; or C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl- (Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R > b represents hydrogen or trifluoromethyl; 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; and
  • R c represents hydrogen, Ci -6 alkyl or C 3-7 cycloalkyl; or R b and R c , when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, isoxazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin- 1 -yl, homopiperidin- 1 -yl, homomorpholin- 4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R d represents hydrogen; or C] -6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and X, R 1 , R 2 , R a and R e are as defined above.
  • any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substitutents. Suitably, such groups will be unsubstituted or monosubstituted.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g.
  • solvates of the compounds of formula (I) above include common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
  • the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
  • Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched Ci -6 alkyl groups, for example Ci -4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, H-propyl, isopropyl, «-butyl, sec-butyl, isobutyl, fert-butyl, 2,2-dimethylpropyl and 3-methylbutyl.
  • Ci -6 alkoxy such as "Ci -6 alkoxy”, “Ci -6 alkylthio”, “Ci -6 alkylsulphonyl” and “Ci -6 alkylamino” are to be construed accordingly.
  • Specific C 3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(C 1-6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • Suitable heterocycloalkyl groups which may comprise benzo-fused analogues thereof, include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3- ⁇ ]pyridinyl, pyrrolyl, indolyl, isoindolyl, pyrrolo[2,3-6]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- ⁇ ]pyridinyl, imidazo[l,2- ⁇ ]pyrimidinyl, imidazo[l,2- ⁇ ]pyrazinyl, oxadiazolyl,
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. It is to be understood that each individual atom present in formula (I), or in the formulae depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
  • each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 1 H, 2 H (deuterium) or 3 H (tritium) atom, preferably 1 H.
  • each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
  • the present invention provides a compound of formula (I) as depicted above or an /V-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • X represents oxygen or N-R 5 ; and R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the present invention provides a compound of formula (I) as depicted above or an TV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • X represents a covalent bond
  • R 1 represents Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl(Ci. 6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci -6 )alkyl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents; and R 2 , R 3 and R 4 are as defined above.
  • the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • Y represents S(O) 2 ;
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • X represents oxygen or a covalent bond.
  • X represents oxygen. In another embodiment, X represents N-R 5 , in which R 5 is as defined above. In a further embodiment, X represents a covalent bond.
  • Specific sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IP) and (IQ):
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • R la represents Cj -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl(Ci- 6 )alkyl,
  • R 1 represents Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci -6 )- alkyl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylmethyl, arylmethyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkylmethyl, C 3-7 heterocycloalkylethyl or heteroarylmethyl, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents optionally substituted Ci -6 alkyl.
  • R 1 represents optionally substituted C 3-7 cycloalkyl.
  • R 1 represents optionally substituted C 3-7 cycloalkyl(Ci -6 )alkyl.
  • R 1 represents optionally substituted C 3-7 cycloalkylmethyl. In a fourth embodiment, R 1 represents optionally substituted aryl. In a fifth embodiment, R 1 represents optionally substituted aryl(Ci -6 )alkyl. In one aspect of that embodiment, R 1 represents optionally substituted arylmethyl. In a sixth embodiment, R 1 represents optionally substituted C 3-7 heterocycloalkyl. In a seventh embodiment, R 1 represents optionally substituted C 3-7 heterocycloalkyl(C 1-6 )alkyl. In one aspect of that embodiment, R 1 represents optionally substituted C 3-7 heterocycloalkylmethyl.
  • R 1 represents optionally substituted C 3-7 heterocycloalkylethyl. In an eighth embodiment, R 1 represents optionally substituted heteroaryl. In a ninth embodiment, R 1 represents optionally substituted heteroaryl(C 1-6 )alkyl. In one aspect of that embodiment, R 1 represents optionally substituted heteroarylmethyl.
  • R 1 selected values include methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclohexylmethyl, phenyl, naphthyl, benzyl, tetrahydrofuryl, oxetanylmethyl, pyrrolidinylethyl, furyl, thienyl, thieno[2,3- ⁇ ]pyridinyl, indolyl, pyrrolo[2,3-Z>]pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2- ⁇ ]pyridinyl, oxadiazolyl, triazolyl, pyridinyl, quinolinyl, 3,4-dihydro-2H-pyrido[3,2- Z)][1, 4]oxazinyl, pyrimidinyl
  • R 1 Typical values of R 1 include methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclohexylmethyl, phenyl, naphthyl, benzyl, tetrahydrofuryl, oxetanylmethyl, pyrrolidinylethyl, furyl, thienyl, pyrrolo[2,3-Z>]pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2- ⁇ ]pyridinyl, oxadiazolyl, triazolyl, pyridinyl, quinolinyl, furylmethyl, indolylmethyl, thiazolylmethyl, imidazolylmethyl, imidazo[l,2- ⁇ ]pyridinylmethyl, triazolylmethyl, benzotriazolylmethyl,
  • R 1 represents phenyl or pyridinyl, either of which groups may be optionally substituted by one or more substituents.
  • substituents on R 1 include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, aryl(Ci -6 )alkyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, aryloxy, hydroxybenzoyloxy, (hydroxy)(methyl)benzoyloxy, Ci -4 alkylenedioxy, Ci -6 alkoxy(Ci -6 )alkyl, Ci -6 alkylthio, Ci -6 alkylsulphonyl, oxo, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, aryl(Ci -6 )al
  • R 1 examples include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, aryl(Ci -6 )alkyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci -4 alkylenedioxy, Ci -6 alkoxy(Ci -6 )alkyl, Ci -6 alkylthio, Ci -6 alkylsulphonyl, oxo, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, aryl(Ci -6 )alkoxycarbonylamino, Ci -6 alkylaminocarbonylamino, arylaminocarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C
  • R 1 Definitive examples of selected substituents on R 1 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, aryl(Ci -6 )alkyl, hydroxy, Ci -6 alkoxy, trifluoromethoxy, trifluoroethoxy, hydroxybenzoyloxy, (hydroxy)(methyl)benzoyloxy, Ci -4 alkylenedioxy, Ci -6 alkoxy(Ci -6 )alkyl, Ci -6 alkylthio, Ci -6 alkylsulphonyl, oxo, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, aryl(Ci -6 )- alkoxycarbonylamino, Ci -6 alkylaminocarbonylamino, arylaminocarbonylamino, Ci -6 alkylsulphon
  • Examples of apposite substituents on R 1 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, aryl(Ci -6 )alkyl, Ci -6 alkoxy, Ci -4 alkylenedioxy, Ci -6 alkoxy(Ci -6 )alkyl, oxo, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, aryl(Ci -6 )alkoxycarbonylamino, Ci -6 alkylaminocarbonylamino, arylaminocarbonylamino and C 2-6 alkoxycarbonyl.
  • R 1 examples include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, hydroxybenzoyloxy, (hydroxy)(methyl)benzoyloxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylamino- carbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonyl- amino, formy
  • R 1 examples include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonylamino,
  • R 1 Definitive examples of specific substituents on R 1 include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, hydroxybenzoyloxy, (hydroxy )(methyl)- benzoyloxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonyl- amino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonylamino, methoxycarbonyl
  • R 1 examples include fluoro, chloro, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, methoxy, ethylenedioxy, methoxy- methyl, oxo, amino, methylamino, dimethylamino, acetylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino and methoxycarbonyl.
  • R 1 selected values include methyl, ethyl, cyanoethyl, oxopropyl, tert-butyl, cyclopropyl, oxocyclohexylmethyl, phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, cyanophenyl, (fluoro)(nitro)phenyl, methylphenyl, (fiuoro)(methyl)- phenyl, (chloro)(methyl)phenyl, trifluoromethylphenyl, (fluoro)(trifiuoromethyl)phenyl, (chloro)(trifluoromethyl)phenyl, (methyl)(trifluoromethyl)phenyl, hydroxyphenyl, (fluoro)(hydroxy)phenyl, (difluoro)(hydroxy)phenyl, (chloro)(hydroxy)phenyl, (bromo)- (hydroxy)-
  • Suitable values of R 1 include methyl, ethyl, cyanoethyl, oxopropyl, tert-butyl, cyclopropyl, oxocyclohexylmethyl, phenyl, chlorophenyl, methylphenyl, (fluoro)- (trifluoromethyl)phenyl, (methyl)(trifluoromethyl)phenyl, methoxyphenyl, (methoxy)- (trifluoromethyl)phenyl, ethylenedioxyphenyl, aminophenyl, naphthyl, trifiuoromethyl- benzyl, (dimethyl)(oxo)tetrahydrofuryl, methyloxetanylmethyl, oxopyrrolidinylethyl, dioxopyrrolidinylethyl, furyl, nitrofuryl, methoxymethylthienyl, pyrrolo[2,3-6]pyridinyl, pyr
  • R 1 is chloropyridinyl, especially 6-chloropyridin-3-yl.
  • R 1 is methylpyridinyl, especially 6-methylpyridin-3-yl.
  • R 1 is methoxypyridinyl, especially 6-methoxypyridin-3-yl.
  • R 1 is (chloro)(methoxy)pyridinyl, especially 5-chloro-6- methoxypyridin-3-yl.
  • R 1 is (chloro)(fluoro)(methoxy)pyridinyl, especially 2- chloro-5-fluoro-6-methoxypyridin-3-yl.
  • R 2 include hydrogen, optionally substituted methyl and optionally substituted ethyl.
  • suitable substituents on R 2 include hydroxy, C 1-6 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, aminocarbonyl, Ci -6 alkylaminocarbonyl and di(Ci -6 )alky laminocarbonyl .
  • R 2 examples include hydroxy, Ci -6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl and di(C 1-6 )alky laminocarbonyl.
  • R 2 examples include hydroxy, di(C 1-6 )alkylamino, aminocarbonyl and C 1-6 alkylaminocarbonyl.
  • Suitable examples of specific substituents on R 2 include hydroxy, methoxy, amino, methylamino, dimethylamino, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.
  • Typical examples of specific substituents on R 2 include hydroxy, methoxy, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.
  • R 2 Selected examples of specific substituents on R 2 include hydroxy, dimethylamino, aminocarbonyl and methylaminocarbonyl.
  • R 2 represents hydrogen.
  • R 2 represents optionally substituted C 1-6 alkyl.
  • R 2 represents unsubstituted C 1-6 alkyl, especially methyl.
  • R 2 represents substituted Cj -6 alkyl, especially substituted methyl or substituted ethyl.
  • Specific values of R 2 include hydrogen, methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, hydroxyethyl and dimethylaminoethyl.
  • R 2 include hydrogen and methyl.
  • R 3 and R 4 independently represent hydrogen, halogen, trifluoromethyl, -OR a , -SR a , -SOR a , -SO 2 R 3 , -NR b R c , -NR c COR d , -NR c CO 2 R d , -NR c SO 2 R e , -COR d , -CO 2 R d , -CONR b R c or -SO 2 NR b R c ; or C -6 alkyl, aryl, aryl-
  • R 3 include hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR a , -SO 2 R 3 , -NR b R c , -CH 2 NR b R c , -NR c COR d , -CH 2 NR c COR d , -NR c CO 2 R d , -NHCONR b R c , -NR c SO 2 R e , -N(SO 2 R e ) 2 , -NHSO 2 NR b R c , -COR d , -CO 2 R d , -CONR b R c , -CON(OR 3 )R b or -SO 2 NR b R c ; or Ci -6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents. Typical values of R
  • R 3 represents hydrogen.
  • R 3 represents -OR a , wherein R a is as defined above.
  • R 3 represents -CO 2 R d , wherein R d is as defined above.
  • R 3 represents -CONR b R c , wherein R b and R c are as defined above.
  • R 3 represents optionally substituted aryl.
  • R 3 represents optionally substituted heteroaryl.
  • R 3 represents halogen. In one aspect of that embodiment, R 3 represents fluoro. In another aspect of that embodiment, R 3 represents chloro. In an eighth embodiment, R 3 represents cyano.
  • R 3 represents nitro. In a tenth embodiment, R 3 represents hydroxy. In an eleventh embodiment, R 3 represents trifluoromethyl. In a twelfth embodiment, R 3 represents trifluoromethoxy. In a thirteenth embodiment, R 3 represents -SO 2 R a , wherein R a is as defined above. In a fourteenth embodiment, R 3 represents -NR b R c , wherein R b and R c are as defined above. In a fifteenth embodiment, R 3 represents -CH 2 NR b R c , wherein R b and R c are as defined above.
  • R 3 represents -NR c COR d , wherein R c and R d are as defined above.
  • R 3 represents -CH 2 NR c COR d , wherein R c and R d are as defined above.
  • R 3 represents -NR c CO 2 R d , wherein R c and R d are as defined above.
  • R 3 represents -NHCONR b R c , wherein R b and R c are as defined above.
  • R 3 represents -NR c SO 2 R e , wherein R c and R e are as defined above.
  • R 3 represents -N(SO 2 R e ) 2 , wherein R e is as defined above.
  • R 3 represents -NHSO 2 NR b R c , wherein R b and R c are as defined above.
  • R 3 represents -COR , wherein R d is as defined above.
  • R 3 represents -CON(OR a )R b , wherein R a and R b are as defined above.
  • R 3 represents -SO 2 NR b R c ; wherein R b and R c are as defined above.
  • R 3 represents optionally substituted Ci -6 alkyl.
  • substituents on R 3 and/or R 4 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, aryl(Ci -6 )alkyl, hydroxy, Ci -6 alkoxy, difiuoromethoxy, trifluoromethoxy, aryloxy, C )-4 alkylenedioxy, Ci -6 alkoxy(Ci -6 )alkyl, Ci -6 alkylthio, Ci -6 alkylsulphonyl, oxo, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, aryl(C 1-6 )alkoxycarbonylamino, Ci -6 alkylaminocarbonyl- amino, arylaminocarbonylamino,
  • R 3 and/or R 4 Selected examples of typical substituents on R 3 and/or R 4 include halogen, C ]-6 alkyl, Ci -6 alkoxy and Ci -4 alkylenedioxy.
  • Examples of apposite substituents on R 3 and/or R 4 include halogen and Ci -6 alkyl.
  • R 3 and/or R 4 examples include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxy- carbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonyl- amino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbony
  • R 3 and/or R 4 include fluoro, methyl, methoxy and methylenedioxy.
  • suitable substituents on R 3 and/or R 4 include fluoro and methyl.
  • R 3 Definitive values of R 3 include hydrogen, fluoro, chloro, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR a , -SO 2 R 3 , -NR b R c , -CH 2 NR b R c , -NR c COR d , -CH 2 NR c COR d , -NR c CO 2 R d , -NHCONR b R c , -NR c SO 2 R e , -N(SO 2 R e ) 2 , -NHSO 2 NR b R c , -COR d , -CO 2 R d , -CONR b R c , -CON(OR a )R b , -SO 2 NR b R c , methyl, phenyl, fluorophenyl, methylphenyl, methoxyphenyl, methyl
  • Suitable values of R 3 include hydrogen, -OR a , -CO 2 R d , -CONR b R c , phenyl, fluorophenyl, methylphenyl and methylimidazolyl.
  • Typical values of R 4 include hydrogen, halogen, -COR d , -CO 2 R d , -CONR b R c and Ci -6 alkyl, wherein R b , R c and R d are as defined above.
  • R 4 include hydrogen, halogen, -COR d , -CO 2 R d and -CONR b R c , wherein R b , R c and R d are as defined above.
  • R examples include hydrogen and Ci -6 alkyl.
  • R represents hydrogen.
  • R 4 represents halogen, especially chloro.
  • R 4 represents -COR d , wherein R is as defined above.
  • R 4 represents -CO 2 R d , wherein R d is as defined above.
  • R 4 represents -CONR b R c , wherein R b and R c are as defined above.
  • R 4 represents C 1-6 alkyl, especially methyl.
  • R 5 represents hydrogen or methyl.
  • R 5 represents hydrogen. In another embodiment, R 5 represents Ci -6 alkyl, especially methyl.
  • suitable substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include halogen, Ci -6 alkyl, C 1-6 alkoxy, difluoromethoxy, trifiuoromethoxy, C 1-6 alkoxy(C 1-6 )alkyl, C 1-6 alkylthio, C 1-6 alkylsulphonyl, hydroxy, hydroxy(Ci -6 )alkyl, amino(Ci -6 )alkyl, cyano, trifluoromethyl, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, phenylamino, pyridinylamin
  • Ci -6 alkylsulphinyl C 2-6 alkylcarbonyloxy, C 2-6 alkylcarbonylamino(Ci -6 )alkyl and Ci -6 alkyl- sulphonylamino.
  • R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include halogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl, Ci -6 alkylsulphonyl, hydroxy, hydroxy(Ci- 6 )alkyl, amino(Ci -6 )alkyl, cyano, oxo, C 2-6 alkylcarbonyl, C 2-6 alkylcarbonyloxy, carboxy, C 2-6 alkoxycarbonyl, amino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkylcarbonylamino(Ci -6 )alkyl, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino and aminocarbonyl.
  • Typical examples of specific substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include fiuoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifiuoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, tert-butoxycarbonylamino, amino
  • Additional examples include methylsulphinyl, acetoxy, acetylaminomethyl and methylsulphonylamino.
  • Selected examples of specific substituents on R ⁇ R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include fluoro, chloro, methyl, methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, acetoxy, carboxy, ethoxycarbonyl, tert-butoxycarbonyl, amino, dimethylamino, acetylamino, acetylaminomethyl, fert-butoxycarbonylamino, methylsulphonylamino and aminocarbonyl.
  • R a represents Ci -6 alkyl, aryl(C 1-6 )alkyl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Selected values of R a include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Selected examples of suitable substituents on R a include Ci -6 alkoxy and oxo.
  • R a Selected examples of specific substituents on R a include methoxy and oxo.
  • R a represents optionally substituted Ci -6 alkyl. In one aspect of that embodiment, R a ideally represents unsubstituted Ci -6 alkyl, especially methyl. In another aspect of that embodiment, R a ideally represents substituted Ci -6 alkyl, e.g. methoxyethyl. In another embodiment, R a represents optionally substituted aryl. In one aspect of that embodiment, R a represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R a represents monosubstituted aryl, especially methylphenyl.
  • R a represents optionally substituted aryl(Ci -6 )alkyl, ideally unsubstituted aryl(Ci -6 )alkyl, especially benzyl.
  • R a represents optionally substituted heteroaryl.
  • R a represents optionally substituted heteroaryl(Ci -6 )alkyl, e.g. dioxoisoindolylpropyl.
  • R a examples include methyl, methoxyethyl, benzyl and dioxoisoindolylpropyl.
  • R b represents hydrogen or trifluoromethyl; 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.
  • R b include hydrogen; or Ci -6 alkyl, aryl(Ci. 6 )alkyl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkyl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b examples include hydrogen and Ci -6 alkyl.
  • R b represents hydrogen or trifluoromethyl; or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl,
  • R b include hydrogen; or methyl, ethyl, w-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R b Selected examples of suitable substituents on R b include Ci -6 alkoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl, Ci -6 alkylsulphonyl, hydroxy, cyano, C 2-6 alkoxycarbonyl, di- (Ci -6 )alkylamino and C 2-6 alkoxycarbonylamino.
  • R b Selected examples of specific substituents on R b include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.
  • R examples include hydrogen, methyl, methoxyethyl, methylthioethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino- ethyl, fert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert- butoxycarbonylpyrrolidinyl and morpholinylpropyl.
  • R represents hydrogen. In another embodiment, R b represents Ci -6 alkyl, especially methyl.
  • R c include hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R c represents hydrogen, Ci -6 alkyl or C 3-7 cycloalkyl.
  • Representative values of R c include hydrogen; or methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
  • R c Selected examples of suitable substituents on R c include C 2-6 alkylcarbonyl and C 2-6 alkoxycarbonyl.
  • R c Selected examples of specific substituents on R c include acetyl and tert- butoxy carbony 1.
  • R c examples include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl, Suitably, R c represents hydrogen or C 1-6 alkyl. In one embodiment, R c is hydrogen.
  • R c represents Ci -6 alkyl, especially methyl or ethyl, particularly methyl.
  • R c represents C 3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the moiety -NR b R c may suitably represent azetidin-1-yl, pyrrolidin- 1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1- yl, morpholin-4-yl, thiomo ⁇ holin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
  • the moiety -NR b R c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, isoxazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
  • Selected values for the moiety -NR b R c suitably include azetidin-1-yl, pyrrolidin-1- yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl and homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of suitable substituents on the heterocyclic moiety -NR b R c include Ci -6 alkyl, Ci -6 alkylsulphonyl, hydroxy, hydroxy(Ci- 6 )alkyl, amino(Ci -6 )alkyl, cyano, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, C 2-6 alkylcarbonyl- amino, C 2-6 alkylcarbonylamino(Ci -6 )alkyl, C 2-6 alkoxycarbonylamino, Ci -6 alkyl- sulphonylamino and aminocarbonyl.
  • Selected examples of specific substituents on the heterocyclic moiety -NR b R c include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulphonylamino and aminocarbonyl.
  • Specific values of the moiety -NR b R c include azetidin-1-yl, hydroxyazetidin-1-yl, hydroxymethylazetidin- 1 -yl, (hydroxy)(hydroxymethyl)azetidin- 1 -yl, aminomethyl- azetidin- 1 -yl, cyanoazetidin- 1 -yl, carboxyazetidin- 1 -yl, aminoazetidin- 1 -y 1, aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl, oxopyrrolidin-1- yl, acetylaminomethylpyrrolidin-1-yl, tert-butoxycarbonylaminopyrrolidin-l-yl, oxo- oxazolidin-3-yl, hydroxyisoxazolidin-2-yl, thiazolidin-3-yl,
  • R d represents hydrogen; or Ci -6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R d examples include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of suitable substituents on R d include halogen, C 1-6 alkyl, Ci -6 alkoxy, oxo, C 2-6 alkylcarbonyloxy and di(Ci -6 )alkylamino.
  • R d Selected examples of particular substituents on R d include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
  • R d represents hydrogen. In another embodiment, R d represents optionally substituted Ci -6 alkyl. In one aspect of that embodiment, R d ideally represents unsubstituted Ci -6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert- butyl, especially methyl. In another aspect of that embodiment, R d ideally represents substituted Ci -6 alkyl, e.g. substituted methyl or substituted ethyl, including acetoxymethyl, dimethylaminomethyl and trifluoroethyl. In another embodiment, R d represents optionally substituted aryl.
  • R d represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R d represents monosubstituted aryl, especially methylphenyl. In a further aspect of that embodiment, R d represents disubstituted aryl, e.g. dimethoxyphenyl. In a further embodiment, R d represents optionally substituted heteroaryl,,e.g. thienyl, chlorothienyl, methylthienyl, methylimidazolyl or thiazolyl. In another embodiment, R d represents optionally substituted C 3-7 cycloalkyl, e.g. cyclopropyl or cyclobutyl. In a further embodiment, R d represents optionally substituted C 3-7 heterocycloalkyl, e.g. thiazolidinyl or oxo- thiazolidinyl.
  • R d Selected examples of specific values for R d include hydrogen, methyl, acetoxy- methyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.
  • R e represents C] -6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
  • R e Selected examples of suitable substituents on R e include Cj -6 alkyl, especially methyl.
  • R e represents optionally substituted Ci -6 alkyl, ideally unsubstituted Ci -6 alkyl, e.g. methyl or propyl, especially methyl.
  • R e represents optionally substituted aryl.
  • R e represents unsubstituted aryl, especially phenyl.
  • R e represents monosubstituted aryl, especially methylphenyl.
  • R e represents optionally substituted heteroaryl. Selected values of R e include methyl, propyl and methylphenyl.
  • the substituent at the 3 -position of the morpholine ring in the compounds of formula (I) as depicted above is in the (S) configuration.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (HA) and iV-oxides thereof, and pharmaceutically acceptable salts and solvates thereof:
  • R z and R J are as defined above;
  • R 11 represents hydrogen, halogen, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, trifluoromethoxy or Ci -6 alkylaminosulphonyl;
  • R 12 represents hydrogen, halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, trifluoromethoxy, Ci -6 alkylthio, Ci -6 alkylsulphonyl, amino or di(Ci -6 )alkylamino;
  • R 13 represents hydrogen, halogen, trifluoromethyl or Ci -6 alkoxy.
  • Suitable values of R 11 include hydrogen, fluoro, chloro, methyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy and methylaminosulphonyl.
  • a particular value of R 1 ' is hydroxy.
  • Suitable values of R 12 include hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, methylthio, methyl- sulphonyl, amino and dimethylamino.
  • R 12 is methoxy.
  • Suitable values of R 13 include hydrogen, fluoro, chloro, bromo, trifluoromethyl and methoxy.
  • R 13 represents hydrogen. In another embodiment, R 13 represents halogen. In one aspect of that embodiment, R 13 represents fluoro. In another aspect of that embodiment, R 13 represents chloro. In a further aspect of that embodiment, R 13 represents bromo. In another embodiment, R 13 represents trifluoromethyl. In a further embodiment, R 13 represents C 1-6 alkoxy, especially methoxy.
  • R 2 and R 3 are as defined above;
  • R 21 represents hydrogen, halogen, cyano, Ci -6 alkyl, Ci -6 alkoxy, trifluoroethoxy,
  • Ci -6 alkylthio amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, aryl(Ci -6 )alkoxycarbonylamino, Ci -6 alkylaminocarbonylamino, arylaminocarbonylamino or Ci -6 alkylsulphonylamino;
  • R 22 represents hydrogen, halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, amino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino or Cj -6 alkylsulphonylamino; and R 23 represents hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or amino.
  • Suitable values of R 21 include hydrogen, chloro, cyano, methyl, tert-butyl, methoxy, ethoxy, isopropoxy, trifluoroethoxy, methylthio, amino, methylamino, dimethylamino, acetylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino and methylsulphonylamino .
  • R 21 include halogen, C 1-6 alkyl, Cj -6 alkoxy and amino.
  • R 21 represents hydrogen. In another embodiment, R 21 represents halogen, especially chloro. In another embodiment, R 21 represents Ci -6 alkyl, especially methyl. In a particular embodiment, R 21 represents Ci -6 alkoxy, especially methoxy. In a further embodiment, R 21 represents amino.
  • Suitable values of R 22 include hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, methoxycarbonylamino and methylsulphonylamino.
  • Particular values of R 22 include hydrogen, halogen, cyano and Ci -6 alkyl.
  • R 22 represents hydrogen. In another embodiment, R 22 represents halogen, especially fluoro or chloro. In one aspect of that embodiment, R 22 represents fluoro. In one aspect of that embodiment, R 22 represents chloro. In a further embodiment, R represents cyano. In another embodiment, R represents Ci -6 alkyl, especially methyl.
  • Suitable values of R 23 include hydrogen, chloro, cyano, methyl, methoxy and amino.
  • R 23 include hydrogen and halogen.
  • R 23 represents hydrogen. In another embodiment, R 23 represents halogen, especially chloro.
  • R 21 is chloro
  • R 22 and R 23 are both hydrogen.
  • R 21 is methyl, and R 22 and R 23 are both hydrogen.
  • R 21 is methoxy
  • R 22 and R 23 are both hydrogen.
  • R 21 is methoxy
  • R 22 is chloro and R 23 is hydrogen.
  • R 21 is methoxy
  • R 22 is fluoro and R 23 is chloro.
  • 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. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
  • 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.
  • Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
  • the quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
  • the compounds of formula (I) above wherein X represents a covalent bond may be prepared by a process which comprises reacting a compound of formula R 1 -Y-Cl with a compound of formula (III):
  • the reaction is conveniently effected in a suitable solvent, typically under basic conditions, e.g. in the presence of an organic base such as triethylamine or N,N- diisopropylethylamine.
  • suitable solvents include chlorinated solvents such as dichloromethane, cyclic ether solvents such as tetrahydrofuran, and dipolar aprotic solvents such as N, ./V-dimethylformamide.
  • the coupling agent of use in the above reaction is suitably l-(3-dimethylamino- propyl)-3-ethylcarbodiimide (EDC), in which case the reaction is conveniently effected in the presence of an additive such as 1-hydroxybenzotriazole hydrate (HOBT), typically under basic conditions, e.g. in the presence of an organic base such as ⁇ N-diisopropyl- ethylamine.
  • HOBT 1-hydroxybenzotriazole hydrate
  • the coupling agent employed may be polymer-supported Mukaiyama resin, in which case the reaction is conveniently effected under basic conditions, e.g. in the presence of an organic base such as N,N-diisopropylethylamine.
  • the coupling agent employed may be polymer-supported carbodiimide (PS-CDI), in which case the reactants may be brought together in the presence of the coupling agent and the material thereby obtained may then be treated with polymer-supported isocyanate (PS-NCO) in the presence of a base, typically an organic base such as triethylamine.
  • PS-CDI polymer-supported carbodiimide
  • PS-NCO polymer-supported isocyanate
  • a condensing agent such as 4-nitrophenyl chloroformate
  • Both stages of the above process may conveniently be performed in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, typically under basic conditions, e.g. in the presence of an organic base such as ⁇ f,N-diisopropylethylamine.
  • a suitable solvent e.g. a chlorinated solvent such as dichloromethane
  • organic base e.g. in the presence of an organic base such as ⁇ f,N-diisopropylethylamine.
  • reaction may conveniently be performed in a suitable solvent, e.g. a cyclic ether solvent such as tetrahydrofuran, typically in the presence of iV,iV-dimethylacetamide.
  • a suitable solvent e.g. a cyclic ether solvent such as tetrahydrofuran, typically in the presence of iV,iV-dimethylacetamide.
  • the compounds of formula (I) wherein R 2 is hydrogen may be prepared by a process which comprises reacting a compound of formula (IV) with a compound of formula (V):
  • X, Y, R 1 , R 3 and R 4 are as defined above; in the presence of a transition metal catalyst; followed by removal of the trimethylsilyl moiety from the 2-position of the resulting cycloaddition product.
  • the transition metal catalyst of use in the reaction between compounds (IV) and (V) is suitably palladium(II) acetate, in which case the reaction may conveniently be effected at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as jV,N-dimethylformamide, in the presence of lithium chloride and a base, typically an inorganic base, e.g. an alkaline earth metal carbonate such as sodium carbonate.
  • a suitable solvent e.g. a dipolar aprotic solvent such as jV,N-dimethylformamide
  • a base typically an inorganic base, e.g. an alkaline earth metal carbonate such as sodium carbonate.
  • Removal of the trimethylsilyl moiety from the resulting cycloaddition product may be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid.
  • an acid e.g. a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 1 contains an amino (-NH 2 ) group may be converted into the corresponding compound wherein R 1 contains a C 2-6 alkoxycarbonylamino or aryl(C 1-6 )alkoxycarbonylamino moiety by treatment with the appropriate alkyl or aryl- (Ci -6 )alkyl chloroformate respectively.
  • a compound of formula (I) wherein R 1 contains an amino (-NH 2 ) group may be converted into the corresponding compound wherein R 1 contains a Ci -6 alkylaminocarbonylamino or arylaminocarbonylamino moiety by treatment with the appropriate alkyl or aryl isocyanate respectively.
  • a compound of formula (I) wherein R 1 contains an amino (-NH 2 ) group may be converted into the corresponding compound wherein R 1 contains a Ci -6 alkylsulphonylamino moiety by treatment with the appropriate alkyl sulphonyl chloride, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a base e.g. an organic base such as triethylamine.
  • a compound of formula (I) wherein R 1 contains a halogen atom, e.g. chloro may be converted into the corresponding compound wherein R 1 contains a Ci -6 alkoxy moiety, e.g. methoxy or ethoxy, by treatment with an alkali metal alkoxide, e.g. sodium methoxide; or by treatment with a Ci -6 alkanol, e.g. methanol or ethanol, in the presence of a base, e.g. an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide.
  • a compound of formula (I) wherein R 1 contains a halogen atom e.g.
  • R 1 may be converted into the corresponding compound wherein R 1 contains a Ci -6 alkylamino or di(Ci -6 )alkylamino moiety, e.g. methylamino or dimethylamino, by treatment with the appropriate alkylamine or dialkylamine, e.g. methylamine or dimethyl- amine respectively, optionally in the presence of a base, typically an inorganic base, e.g. an alkali metal carbonate such as potassium carbonate.
  • a compound of formula (I) wherein R 1 contains a halogen atom, e.g. chloro may be converted into the corresponding compound wherein R 1 contains a C 1-6 alkylthio moiety, e.g.
  • a compound of formula (I) wherein R 1 contains a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein R 1 contains a C 1-6 alkylsulphonyl- amino moiety, e.g. methylsulphonylamino, by treatment with the appropriate alkyl sulphonamide, e.g. methanesulphonamide, generally in the presence of a transition metal catalyst.
  • a suitable transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0), in which case the reaction is conveniently effected in the presence of 4,5-bis(diphenyl- phosphino)-9,9-dimethylxanthene (Xantphos) and a base, typically an inorganic base, e.g. an alkali metal carbonate such as caesium carbonate.
  • a compound of formula (I) wherein R 1 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 1 contains a hydroxy (-OH) group by treatment with a hydroxide salt, e.g. an alkali metal hydroxide such as potassium hydroxide, generally in the presence of a transition metal catalyst.
  • a suitable transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0), in which case the reaction is conveniently effected in the presence of a reagent such as 2-di-tert-butylphosphino- 3,4,5,6-tetramethyl-2',4',6'-triisopropyl-l,l'-biphenyl.
  • a compound of formula (I) wherein R 1 contains a nitro (-NO 2 ) group may be converted into the corresponding compound wherein R 1 contains an amino (-NH 2 ) group by treatment with a reducing agent, which may typically be elemental zinc in the presence of an acid, e.g. an organic acid such as acetic acid, or a mineral acid such as hydrochloric acid.
  • a reducing agent which may typically be elemental zinc in the presence of an acid, e.g. an organic acid such as acetic acid, or a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 1 contains a N-H moiety may be converted into the corresponding compound wherein R 1 contains a N-methyl moiety by treatment with a methylating agent, e.g. iodomethane, typically under basic conditions, e.g. in the presence of sodium hydride.
  • a compound of formula (I) wherein R 2 represents hydrogen may be converted into the corresponding compound wherein R 2 represents optionally substituted C 1-6 alkyl, e.g. methyl or 2-(dimethylamino)ethyl, by treatment with an appropriate alkylating agent, e.g. iodomethane, methyl carbonate or 7V-(2-chloroethyl)dimethylamine, typically under basic conditions, e.g. in the presence of sodium hydride, l,4-diazabicyclo[2.2.2]octane (DABCO) or lithium bis(trimethylsilyl)amide.
  • an appropriate alkylating agent e.g. iodomethane, methyl carbonate or 7V-(2-chloroethyl)dimethylamine
  • a compound of formula (I) wherein R 3 represents nitro (-NO 2 ) may be converted into the corresponding compound wherein R 3 represents amino (-NH 2 ) by treatment with a reducing agent, which may typically be elemental zinc in the presence of an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as acetic acid.
  • a reducing agent which may typically be elemental zinc in the presence of an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as acetic acid.
  • a compound of formula (I) wherein R 3 represents amino (-NH 2 ) may be converted into the corresponding compound wherein R 3 represents -NHC0R d by treatment with the appropriate compound of formula Cl-COR d , typically in the presence of a base, e.g. an organic base such as triethylamine, or an alkali metal carbonate such as potassium carbonate.
  • a base e.g. an organic base such as triethylamine, or an alkali metal carbonate such as potassium carbonate.
  • a compound of formula (I) wherein R 3 represents -NHCO(CH 2 ) 3 C1 may be cyclised to the corresponding compound wherein R 3 represents 2-oxopyrrolidin-l-yl by treatment with a base such as lithium bis(trimethylsilyl)amide or potassium carbonate.
  • a compound of formula (I) wherein R 3 represents amino (-NH 2 ) may be converted into the corresponding compound wherein R 3 represents -NHCO 2 R d by treatment with the appropriate compound of formula Cl-CO 2 R d , typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a compound of formula (I) wherein R 3 represents -NHCO 2 (CH 2 ) 2 C1 may be cyclised to the corresponding compound wherein R 3 represents 2-oxooxazolidin-3-yl by treatment with a base, e.g. an alkali metal carbonate such as potassium carbonate.
  • a compound of formula (I) wherein R 3 contains an amino (-NH 2 ) group may be converted into the corresponding compound wherein R 3 contains a -NHSO 2 R 6 or -N(SO 2 R e ) 2 moiety by treatment with the appropriate compound of formula Cl-SO 2 R 6 , typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a base e.g. an organic base such as triethylamine.
  • a compound of formula (I) wherein R 3 represents -NHSO 2 (CH 2 ) 3 C1 may be cyclised to the corresponding compound wherein R 3 represents l,l-dioxoisothiazolidin-2-yl by treatment with a base, e.g. an alkali metal carbonate such as potassium carbonate.
  • a compound of formula (I) wherein R 3 represents -NHC0 2 R d or -NHSO 2 R 6 may be converted into the corresponding compound wherein R 3 represents -NR c CO 2 R d or -NR 0 SO 2 R 6 in which R c is Ci -6 alkyl, e.g. methyl, by treatment with an appropriate alkylating agent, e.g. iodomethane, typically under basic conditions, e.g. in the presence of sodium hydride.
  • an appropriate alkylating agent e.g. iodomethane
  • a compound of formula (I) wherein R 3 contains a N-H moiety may be converted into the corresponding compound wherein R 3 contains a N-COCH 3 moiety by treatment with an acetylating agent, which may suitably be acetic anhydride and optionally acetic acid, typically under basic conditions, e.g. in the presence of an organic base such as triethylamine or 4-(dimethylamino)pyridine.
  • an acetylating agent which may suitably be acetic anhydride and optionally acetic acid, typically under basic conditions, e.g. in the presence of an organic base such as triethylamine or 4-(dimethylamino)pyridine.
  • a compound of formula (I) wherein R 3 represents an ester moiety -CO 2 R d (wherein R d is other than hydrogen) may be converted into the corresponding compound wherein R 3 represents a carboxy moiety -CO 2 H by standard saponification methodology, generally by treatment with a base, typically an inorganic base, e.g. an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide.
  • a base typically an inorganic base, e.g. an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide.
  • a compound of formula (I) wherein R 3 represents a carboxy moiety -CO 2 H may be converted into the corresponding compound wherein R 3 represents an ester moiety -CO 2 R d (wherein R d is other than hydrogen) by treatment with the appropriate compound of formula R d -OH in the presence of a coupling reagent, which will suitably be l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and an additive such as 1-hydroxy- benzotriazole hydrate (HOBT), typically under basic conditions, e.g. in the presence of an organic base such as N,iV-diisopropylethylamine.
  • a coupling reagent which will suitably be l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and an additive such as 1-hydroxy- benzotriazole hydrate (HOBT), typically under basic conditions, e.g. in the presence of an organic
  • a compound of formula (I) wherein R 3 represents -CO 2 H may be converted into the corresponding compound wherein R 3 represents tert-butoxycarbonyl by treatment with ⁇ f ⁇ f-dimethylformamide di-tert-buty ⁇ acetal.
  • a compound of formula (I) wherein R 3 represents -CO 2 H may be converted into the corresponding compound wherein R 3 represents -CONR b R c by treatment with the appropriate compound of formula H-NR b R c in the presence of a coupling reagent, which will suitably be l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and an additive such as 1-hydroxybenzotriazole hydrate (HOBT), typically under basic conditions, e.g. in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine.
  • a coupling reagent which will suitably be l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and an additive such as 1-hydroxybenzotriazole hydrate (HOBT), typically under basic conditions, e.g. in the presence of an organic base such as N,N-diisoprop
  • the coupling agent may be 2-(lH-7-azabenzotriazol-l-yl)-l, 1,3,3- tetramethyl uronium hexafluorophosphate ( ⁇ ATU), in which case the reaction will conveniently be performed in the presence of an organic base such as N,./V-diisopropyl- ethylamine.
  • ⁇ ATU 1,3,3- tetramethyl uronium hexafluorophosphate
  • a compound of formula (I) wherein R 3 represents pentafluorophenoxycarbonyl may be converted into the corresponding compound wherein R 3 represents -CONR R c by treatment with the appropriate compound of formula H-NR b R c , typically under basic conditions, e.g. in the presence of an organic base such as ⁇ N-diisopropylethylamine.
  • a compound of formula (I) wherein R 3 represents -CO 2 H may be converted into the corresponding compound wherein R 3 represents -C0N(0R a )R b by treatment with the appropriate compound of formula H-N(0R a )R b , typically in the presence of 2-chloro-4,6- dimethoxy [l,3,5]triazine and an organic base such as A ⁇ jV-diisopropylethylamine.
  • a compound of formula (I) wherein R 3 represents -CON(OR a )R b may be converted into the corresponding compound wherein R 3 represents -COR d , in which R d is optionally substituted aryl or optionally substituted heteroaryl, by treatment with the appropriate arylmagnesium bromide or heteroarylmagnesium bromide.
  • a compound of formula (I) wherein R 3 represents -CON(OR a )R b may be converted into the corresponding compound wherein R 3 represents -COR d , in which R d is optionally substituted heteroaryl, by treatment with the appropriate heteroaromatic compound, e.g.
  • a compound of formula (I) wherein R 3 represents halogen, e.g. chloro, may be converted into the corresponding compound wherein R 3 represents hydrogen by treatment with a hydrogenation catalyst, e.g. 10% palladium on charcoal, ideally under transfer hydrogenation conditions, e.g. in the presence of ammonium formate.
  • a hydrogenation catalyst e.g. 10% palladium on charcoal, ideally under transfer hydrogenation conditions, e.g. in the presence of ammonium formate.
  • a compound of formula (I) wherein R 3 represents halogen, e.g. chloro, may be converted into the corresponding compound wherein R 3 represents optionally substituted aryl or optionally substituted heteroaryl by treatment with the appropriate arylboronic acid or heteroarylboronic acid, in the presence of a transition metal catalyst.
  • a suitable transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0), in which case the reaction is conveniently effected in the presence of 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (XPhos) and a base, typically an inorganic base, e.g. an alkali metal phosphate such as potassium phosphate.
  • a compound of formula (I) wherein R 3 represents halogen, e.g. bromo may be converted into the corresponding compound wherein R 3 represents optionally substituted heteroaryl by treatment with the appropriate tri-r ⁇ -butyltin(IV)-substituted heteroaromatic compound, e.g. 2-(tributylstannanyl)thiazole, in the presence of a transition metal catalyst.
  • a transition metal catalyst is tetrakis(triphenylphosphine)- palladium(O), in which case the reaction is conveniently effected in the presence of lithium chloride.
  • a compound of formula (I) wherein R 3 represents benzyloxy may be converted into the corresponding compound wherein R 3 represents hydroxy by treatment with a hydrogenation catalyst, e.g. 10% palladium on charcoal, ideally under transfer hydrogenation conditions, e.g. in the presence of ammonium formate.
  • a compound of formula (I) wherein R 3 represents hydroxy may be converted into the corresponding compound wherein R 3 represents an optionally substituted Ci -6 alkoxy, aryl(Ci -6 )alkoxy or heteroaryl(Ci -6 )alkoxy moiety, e.g.
  • alkylating agent e.g. an alkyl halide, typically an alkyl bromide, such as l-bromo-2-methoxyethane or 2-(3-bromo- propyl)isoindole- 1 ,3 -dione, typically in the presence of a base, e.g. an alkali metal carbonate such as caesium carbonate.
  • a base e.g. an alkali metal carbonate such as caesium carbonate.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents formyl (-CHO) by treatment with an oxidising agent, which may suitably be manganese dioxide.
  • a compound of formula (I) wherein R 3 represents -CHO may be converted into the corresponding compound wherein R 3 represents -CH 2 NR b R c by treatment with the appropriate compound of formula H-NR b R c in the presence of a reducing agent, which may suitably be polymer-supported cyanoborohydride (PS-BH 3 CN).
  • a compound of formula (I) wherein R 3 represents -CHO may be converted into the corresponding compound wherein R 3 represents lH-imidazol-2-yl by treatment with glyoxal and ammonia.
  • a compound of formula (I) wherein R 3 represents -COCH 3 may be converted into the corresponding compound wherein R 3 represents isopropylcarbonyl or tert-butyl- carbonyl by treatment with iodomethane in the presence of lithium bis(trimethylsilyl)- amide.
  • a compound of formula (I) wherein R 3 contains a -S- moiety may be converted into the corresponding compound wherein R 3 contains a -S(O)- (sulfinyl) moiety by treatment with 3-chloroperoxybenzoic acid (MCPBA).
  • MCPBA 3-chloroperoxybenzoic acid
  • prolonged treatment with MCPBA may give rise to the corresponding compound wherein R 3 contains a -S(O) 2 - (sulfonyl) moiety.
  • a compound of formula (I) wherein R 3 contains a cyano moiety may be converted into the corresponding compound wherein R 3 contains an aminocarbonyl or carboxy moiety by treatment with hydrogen peroxide and a base, e.g. an inorganic base which may suitably be an alkali metal hydroxide, e.g. sodium hydroxide.
  • a base e.g. an inorganic base which may suitably be an alkali metal hydroxide, e.g. sodium hydroxide.
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents C 1-6 alkyl, e.g. methyl, by standard alkylation procedures, e.g. by treatment with an alkylating agent such as iodomethane in the presence of a base such as sodium hydride; or by treatment with a carbonyl compound such as formaldehyde in the presence of a reducing agent such as sodium cyano- borohydride.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
  • the following Examples illustrate the preparation of compounds according to the invention.
  • the compounds in accordance with this invention potently inhibit the activity of human PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ and/or POK ⁇ .
  • 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.
  • HOBT 1-hydroxybenzotriazole hydrate
  • LiHMDS lithium bis(trimethylsilyl)amide
  • TBME ter t-buty ⁇ methyl ether
  • TBAF tetrabutylammonium fluoride
  • PS-CDI polymer-supported carbodiimide
  • PS-NCO polymer-supported isocyanate
  • SiO 2 silica r.t: room temperature br: broad h: hour
  • PS-BH 3 CN polymer-supported cyanoborohydride
  • HPLC High Performance Liquid Chromatography
  • Method 1 Waters XBridge, C 18, 2.1 x 20 mm, 2.5 ⁇ m column.
  • Mobile phase A 10 mM ammonium formate in water + 0.1% formic acid
  • Mobile phase B acetonitrile + 5%
  • Gradient program (flow rate 1.0 niL/min, column temperature 4O 0 C):
  • Method 2 Waters XBridge, C 18, 2.1 x 20 mm, 2.5 ⁇ m column.
  • Method 3 Luna C18, 21.2 mm, 5 mm column, pH 2.5.
  • Mobile phase A 99.92% water and 0.08% formic acid.
  • Mobile phase B 99.92% MeCN and 0.08% formic acid.
  • Gradient program flow rate 25 mL/min, column temperature ambient: variable gradient.
  • Method 4 Waters XBridge Prep MS Cl 8 ODB, 30 x 50 mm, 5 ⁇ m column.
  • Mobile phase A water.
  • Mobile phase B MeCN.
  • Mobile Phase C NH 4 HCO 3 in water (40g/5L).
  • Gradient program (flow rate 35 mL/min - ⁇ 60 mL/min):
  • 6-Aminonicotinic acid (1 g, 7.24 mmol) was dissolved in pyridine (30 mL) and treated with acetic anhydride (0.81 mL, 7.96 mmol). The reaction mixture was heated at 13O 0 C for 16 h. After cooling, the mixture was stirred at room temperature for 2 h. A precipitate was formed, which was filtered and dried on a freeze drier, yielding the title compound (641 mg, 49%) as a white solid.
  • Example 306 (3.1 g, 7.56 mmol) in MeOH (200 mL) was added zinc (3.0 g, 4.59 mol) and cone. HCl (3 mL). The reaction mixture was heated at 5O 0 C for 30 minutes until a clear solution was obtained. The excess zinc was removed by filtration and the solution was concentrated in vacuo. The residue was partitioned between saturated sodium carbonate solution (200 mL) and DCM (200 mL).
  • Example 280 1 -Methyl-3 -[(S)-4-(6-methylpyridine-3 -carbonyl)morpholin-3 -ylmethyl] - 1 H-indole-5- carboxylic acid
  • MeOH 50 niL
  • 10% NaOH solution 2.5M, 10 mL
  • the reaction mixture was heated to reflux and stirred for 5 h.
  • the reaction mixture was cooled to r.t., acidified with IM HCl and then concentrated in vacuo.
  • the residue was washed with DCM to give a precipitate, which was washed with water and filtered.
  • Example 99 To a stirred solution of Example 99 (550 mg, 1.2 mmol) in DMF (10 mL) at O 0 C was added sodium hydride (60% dispersion in oil, 58 mg, 1.44 mmol). The reaction mixture was stirred at r.t. for 1 h and then cooled to O 0 C prior to the addition of bromo- acetic acid methyl ester (138 ⁇ L, 1.44 mmol). The reaction mixture was stirred at r.t. for 2 h, then partitioned between DCM (20 mL) and water (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo.
  • Example 3 (150 mg, 0.35 mmol) was dissolved in ethyl isocyanate (2 mL). The reaction mixture was heated at 6O 0 C for 1 h. After cooling, the solution was concentrated in vacuo and purified using preparative ⁇ PLC to yield the title compound (111 mg, 64%) as a white solid.
  • Example 5 r6-Aminopyridin-3-yl)-[(.S ⁇ -3-( ' l-methyl-lH-indol-3-ylmethyl)morpholin-4-yl1- methanone
  • methyl carbonate 60 ⁇ L, 0.67 mmol
  • DABCO 5 mg, 45 ⁇ mol
  • the reaction mixture was heated in a microwave at 160 0 C for 20 minutes. Additional methyl carbonate (40 ⁇ L) was added, and the mixture was heated for a further 20 minutes.
  • Example 12 To a stirred solution of Example 12 (200 mg, 475 ⁇ mol) in ethyl isocyanate (3 mL) was added DMAP (3 mg). The reaction mixture was heated at reflux for 30 minutes and concentrated in vacuo to give an oil, which was purified by preparative HPLC to afford the title compound (28 mg, 12%) as a yellow solid.
  • Example 12 To a stirred solution of Example 12 (93 mg, 221 ⁇ mol) in «-butyl isocyanate (2 mL) was added DMAP (2 mg). The mixture was heated at 8O 0 C for 1 h and concentrated in vacuo to give an oil, which was purified by preparative HPLC to afford the title compound (28 mg, 24%) as a white solid.
  • Example 72 l-Methyl-3- ⁇ (5 r )-4-r6-(3-phenylureido)pyridine-3-carbonyl1morpholin-3-ylmethyl ⁇ -lH- indole-5-carboxylic acid dimethylamide
  • phenyl isocyanate 500 ⁇ L
  • the mixture was heated at 60 0 C for 30 minutes, cooled and concentrated in vacuo.
  • the residue was purified by preparative ⁇ PLC to afford the title compound (50 mg, 37%) as a white solid.
  • Example 12 (5 - ( (ff) ⁇ - [5 -(Dimethylcarbamoyl)- 1 -methyl- 1 H-indol-3 - ylmethvHmorpholine-4- carbonvUpyridin-2-yl ' )carbamic acid benzyl ester
  • TEA 70 ⁇ L, 484 ⁇ mol
  • benzyl chloroformate 51 ⁇ L, 363 ⁇ mol
  • Example 12 To a stirred solution of Example 12 (170 mg, 403 ⁇ mol) in DCM at 0 0 C was added TEA (115 ⁇ L, 810 ⁇ mol) and ethyl chloroformate (42 ⁇ L, 440 ⁇ mol). The reaction mixture was stirred at r.t. for 30 minutes, and shaken with water (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo to afford a yellow oil which was purified by preparative ⁇ PLC to afford the title compound (49 mg, 25%) as a white solid.
  • TEA 115 ⁇ L, 810 ⁇ mol
  • ethyl chloroformate 42 ⁇ L, 440 ⁇ mol
  • Example 6 Dimethylamine (3 mL) at O 0 C was added to Example 6 (20 mg, 0.045 mmol) in a microwave vial. The reaction mixture was then heated to 100 0 C for 3 h. The experiment was repeated four more times. The products were combined, dissolved in EtOAc, concentrated in vacuo and the residue was purified by preparative HPLC to yield the title compound (75 mg, 93%) as a white solid.
  • Example 6 To a stirred solution of Example 6 (100 mg, 0.227 mmol) in MeOH (2 mL) was added sodium methoxide (120 mg, 2.27 mmol). The resulting solution was heated in a microwave at 100 0 C for 1 h. The reaction mixture was quenched with water (0.5 mL) and concentrated in vacuo after stirring for 2 minutes. The residue was dissolved in DCM (5 mL), washed with water (5 mL), dried (MgSO 4 ) and concentrated in vacuo. The crude product was purified by preparative ⁇ PLC to yield the title compound (43 mg, 43%) as a white solid.
  • Example 29 (200 mg, 0.475 mmol) was dissolved in a solution OfH 2 SO 4 (1 mL; 600 ⁇ L cone. H 2 SO 4 and 400 ⁇ L water) and stirred at r.t. for 5 minutes. A solution of sodium nitrite (36 mg, 0.523 mmol) in water (0.5 mL) was added dropwise to the reaction mixture whilst the temperature was maintained between 0 and 5 0 C. On complete addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was neutralized with cone, sodium hydroxide solution and extracted with DCM (3 x 10 mL). The combined organic layers were dried (MgSO 4 ) and concentrated in vacuo.
  • Example 365 To a stirred solution of Example 365 (193 mg, 0.48 mmol) in «-BuO ⁇ (4 mL) were added 4-methoxybenzeneboronic acid (109 mg, 0.72 mmol), potassium phosphate (212 mg, 1.0 mmol), XPhos (9 mg, 0.019 mmol) and Pd 2 (dba) 3 (4.4 mg, 0.005 mmol). The reaction mixture was heated to reflux for 4 h, then partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting brown oil was purified by preparative HPLC, yielding the title compound (40 mg, 18%) as an off-white solid.
  • Example 376 To a stirred solution of Example 376 (190 mg, 0.44 mmol) in T ⁇ F (1 mL) at -7O 0 C under nitrogen was added 2-thienylmagnesium bromide (IM solution in T ⁇ F; 874 ⁇ L, 0.087 mmol) dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 16 h, then partitioned between DCM (10 mL) and brine (10 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo.
  • IM solution in T ⁇ F 874 ⁇ L, 0.087 mmol
  • Example 133 200 mg, 0.4 mmol
  • DCM DCM
  • sodium hydroxide 500 mg
  • MeOH MeOH
  • the resulting mixture was stirred for 0.5 h at r.t. prior to the addition of water (10 mL) and DCM (10 mL).
  • the organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and chromatographed (SiO 2 , 75% EtOAc/hexanes + 1% MeOH), yielding the title compound (95 mg, 50%) as a white solid after freeze-drying with 1:1 MeCN-water.
  • Example 349 To Example 349 (95 mg, 0.23 mmol) was added DMF.DBA (0.5mL). The reaction mixture was heated at 100-130 0 C for 20 minutes. The excess reagent was removed in vacuo and the residue was chromatographed (SiO 2 , 75% EtOAc/hexanes), yielding the title compound (74 mg, 69%) as an off-white solid.
  • Example 277 To a stirred solution of Example 277 (3.71 g, 8.0 mmol) in T ⁇ F (50 mL) at -78 0 C was added methyl iodide (1.5 mL, 24 mmol) followed by a solution of Li ⁇ MDS (1.06M solution in T ⁇ F; 15 mL, 16 mmol). The reaction mixture was stirred for 2 h at -78°C, then allowed to warm to r.t. and stirred for 2 h. The reaction mixture was partitioned between brine (100 mL) and EtOAc (100 mL). The organic layer was separated, dried (sodium sulphate) and concentrated in vacuo.
  • Example 277 To a stirred solution of Example 277 (1 g, 2.15 mmol) in T ⁇ F (12 mL) was added HCl (4M in 1,4-dioxane, 12 mL). The reaction mixture was stirred at r.t. for 5 h, then partitioned between 2M sodium carbonate solution (50 mL) and EtOAc (50 mL). The aqueous layer was washed with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried (sodium sulphate) and concentrated in vacuo.
  • Example 3 [(iSy4-(6-Methylpyridine-3-carbonyl)morpholin-3 - ylmethyll - 1 H-indole-5 -carboxylic acid
  • MeOH MeOH
  • 10% NaOH solution 2.5M, 4 mL
  • the reaction mixture was heated to reflux and stirred for 5 h.
  • the reaction mixture was cooled to r.t., acidified with IM HCl and then concentrated in vacuo.
  • the residue was washed with DCM to give a precipitate, which was washed with water, then filtered.
  • Example 362 To a stirred solution of Example 362 (100 mg, 0.27 mmol) and l-bromo-2- methoxyethane (52 ⁇ L, 0.55 mmol) in T ⁇ F (10 mL) was added caesium carbonate (62 mg, 0.19 mmol). The reaction mixture was heated to 9O 0 C for 2 h, then cooled and partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The brown oil was purified using preparative ⁇ PLC, yielding the title compound (25 mg, 22%) as a white solid.
  • Example 362 To a stirred solution of Example 362 (100 mg, 0.27 mmol) and 2-(3-bromo- propyl)isoindole-l,3-dione (147 mL, 0.55 mmol) in T ⁇ F (10 mL) was added caesium carbonate (62 mg, 0.19 mmol). The reaction mixture was heated to 90 0 C for 2 h, then cooled and partitioned between DCM (10 mL) and water (1OmL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The brown oil was purified using preparative ⁇ PLC, yielding the title compound (50 mg, 33%) as a white solid.
  • Example 278 ⁇ ( ⁇ -3-r5-Chloro-l-methyl-2- ⁇ rimethylsilanylVlH-indol-3-ylmethyllmorpholin-4-vU-(6- methylpyridin-3 - yl)-methanone
  • Example 311 To a stirred solution of Example 311 (114 mg, 0.26 mmol) in THF (5 mL) at O 0 C was added sodium hydride (16 mg, 0.39 mmol). The reaction mixture was stirred at 0 0 C for 20 minutes prior to the addition of methyl iodide (41 mg, 0.29 mmol). The reaction mixture was allowed to warm to r.t and stirred for 2 h, then partitioned between DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo.
  • Example 328 To a stirred solution of Example 328 (119 mg, 0.26 mmol) in T ⁇ F (5 mL) at O 0 C was added sodium hydride (16 mg, 0.39 mmol). The reaction mixture was stirred at O 0 C for 20 minutes prior to the addition of methyl iodide (41 mg, 0.29 mmol). The reaction mixture was allowed to warm to r.t and stirred for 2 h, then partitioned between DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo.
  • Example 339 To a stirred solution of Example 339 (200 mg, 0.33 mmol) in MeOH (2 mL) was added 4M HCl in 1,4-dioxane (4 mL). The reaction mixture was stirred at r.t. for 16 h prior to being concentrated in vacuo. The reaction mixture was partitioned between DCM (25 mL) and sodium carbonate solution (25 mL). The organic layer was dried (phase separator) and concentrated in vacuo. To a stirred solution of the residue in acetic acid (2 mL) and acetic anhydride (400 ⁇ L) was added DMAP (5 mg). The reaction mixture was heated at 90 0 C for 1 h, then allowed to cool and concentrated in vacuo.
  • Example 157 To a stirred solution of Example 157 (90 mg, 0.2 mmol) in MeOH (1 mL) was added sodium methoxide (12 mg, 0.22 mmol). The reaction mixture was stirred at r.t. for 30 minutes. Sodium methoxide (5 mg, 0.10 mmol) was added and the reaction mixture was heated at 50 0 C for 1.5 h. The reaction mixture was concentrated in vacuo and then partitioned between DCM (5 mL) and saturated ammonium chloride solution (2 mL). The aqueous layer was extracted with DCM (1 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo.
  • Example 376 200 mg, 0.46 mmol
  • thiazole 40 ⁇ L, 0.56 mmol
  • T ⁇ F 0.2 mL
  • w-butyllithium 2.5M; 62 ⁇ L, 0.16 mmol
  • the reaction mixture was allowed to warm to r.t. and stirred for 16 h, then partitioned between DCM (10 mL) and water (10 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo.
  • reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (12 mg) as an off-white solid.
  • reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo.
  • the residue was purified by column chromatography (SiO 2 , 0-1% MeOH/DCM), yielding the title compound (3 mg) as a white solid.
  • Example 99 To a stirred solution of Example 99 (150 mg, 0.30 mmol) in DMF (5 mL) at O 0 C was added sodium hydride (60% dispersion in oil; 32 mg, 0.78 mmol). The reaction mixture was stirred at r.t. for 1 h and then cooled to O 0 C prior to the addition ofN-(2- chloroethyl)dimethylamine hydrochloride (50 mg, 0.46 mmol). The reaction mixture was heated at 5O 0 C for 18 h, then partitioned between DCM (20 mL) and water (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo.
  • Example 99 To a stirred solution of Example 99 (150 mg, 0.30 mmol) in DMF (5 mL) at 0 0 C was added sodium hydride (60% dispersion in oil; 32 mg, 0.78 mmol). The reaction mixture was stirred at r.t. for 1 h and then cooled to O 0 C prior to the addition of (2-bromo- ethoxy)-fert-butyldimethylsilane (94 ⁇ L, 0.46 mmol). The reaction mixture was heated at 50 0 C for 18 h, then partitioned between EtOAc (20 mL) and 10% aqueous NH 4 Cl solution (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo.
  • Example 3 [(5 r )-4-(5-Chloro-6-methoxypyridine-3 -carbonyl)morpholin-3-ylmethyl1 - 1 -methyl- 1 H- indole-5-carboxylic acid 2-(methanesulfinyl)ethylamide
  • DCM dimethylethyl
  • 3-chloroperoxybenzoic acid 58 mg, 0.24 mmol.
  • the reaction mixture was stirred at r.t. for 2 h, then partitioned between DCM (10 mL) and saturated sodium bicarbonate solution (10 mL). The organics were separated, dried (sodium sulphate) and concentrated in vacuo.
  • Example 394 (3 - [(S)-4-(5-Chloro-6-methoxypyridine-3 -carbonyl)morpholin-3 -ylmethyl] - 1 -methyl- 1 H- indol-5-vU -(I -oxo- 1 ⁇ 4-thiazolidin-3-yl)-methanone
  • DCM dimethyl sulfoxide
  • 3-chloroperoxybenzoic acid 57 mg, 0.25 mmol
  • Example 210 (60 mg, 0.12 mmol) in DMSO (1 mL) in a microwave vial. Potassium carbonate (35 mg, 0.26 mmol) was added and the reaction mixture was then heated to 100 0 C for 0.5 h. Water (5 mL) was added and the mixture was extracted with DCM (2 x 10 mL). The combined organics were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by preparative ⁇ PLC to yield the title compound as a white solid.

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Abstract

La présente invention concerne une série de dérivés de morpholine substitués en position 4 par un groupe fonctionnel carbonyle ou sulfonyle substitué, et en position 3 par un groupe indol-3-méthyle éventuellement substitué, qui sont des inhibiteurs sélectifs d'enzymes de kinases PI3, et donc utiles en médecine, par exemple, dans le traitement de conditions inflammatoires, auto-immunes, cardiovasculaires, neurodégénératives, métaboliques, oncologiques, nociceptives ou ophtalmiques.
PCT/GB2010/001171 2009-06-17 2010-06-15 Derives d'indolylmethyl-morpholine en tant qu'inhibiteurs des kinases WO2010146351A1 (fr)

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WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008047109A1 (fr) * 2006-10-19 2008-04-24 Ucb Pharma S.A. Dérivés de thiazole utilisés en tant qu'inhibiteurs de kinase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008047109A1 (fr) * 2006-10-19 2008-04-24 Ucb Pharma S.A. Dérivés de thiazole utilisés en tant qu'inhibiteurs de kinase

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Title
GRAY ET AL., ANAL. BIOCHEM., vol. 313, 2003, pages 234 - 245
M.P. WYMANN ET AL., TRENDS IN PHARMACOL. SCI., vol. 24, 2003, pages 366 - 376
S. BRADER; S.A. ECCLES, TUMORI, vol. 90, 2004, pages 2 - 8
S. WARD ET AL., CHEMISTRY & BIOLOGY, vol. 10, 2003, pages 207 - 213
S.G. WARD; P. FINAN, CURRENT OPINION IN PHARMACOLOGY, vol. 3, 2003, pages 426 - 434

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant

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