WO2009071895A1 - Fused thiazole and thiophene derivatives as kinase inhibitors - Google Patents

Fused thiazole and thiophene derivatives as kinase inhibitors Download PDF

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Publication number
WO2009071895A1
WO2009071895A1 PCT/GB2008/004011 GB2008004011W WO2009071895A1 WO 2009071895 A1 WO2009071895 A1 WO 2009071895A1 GB 2008004011 W GB2008004011 W GB 2008004011W WO 2009071895 A1 WO2009071895 A1 WO 2009071895A1
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Prior art keywords
alkyl
aryl
amino
heteroaryl
pyrazolyl
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PCT/GB2008/004011
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French (fr)
Inventor
Natasha Kinsella
Christopher Lowe
Trevor Morgan
Benjamin Garfield Perry
Verity Margaret Sabin
Andrew Sharpe
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Ucb Pharma S.A.
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Priority claimed from GBGB0723748.0A external-priority patent/GB0723748D0/en
Priority claimed from GB0723749A external-priority patent/GB0723749D0/en
Application filed by Ucb Pharma S.A. filed Critical Ucb Pharma S.A.
Publication of WO2009071895A1 publication Critical patent/WO2009071895A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of fused thiazole and thiophene derivatives, and to their use in therapy. More particularly, the invention provides a family of fused bicylic thiazole and thiophene derivatives which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, and in the 4-position by hydroxy, oxo or an amine moiety. These compounds are selective inhibitors of phosphoinositide 3 -kinase (PI3K) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • PI3K phosphoinositide 3 -kinase
  • PI3K pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases.
  • PBKs provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sd., 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 PDK enzymes.
  • WO 2006/114606 describes a class of fused bicyclic thiazole derivatives which are selective inhibitors of PI3 kinase enzymes and are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • a related series of compounds is described in copending international patent application no. PCT/GB2007/002390, published on 3 January 2008 as WO 2008/001076.
  • 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 orless, 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 orless, 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
  • 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 PBK ⁇ and/or PBK ⁇ and/or PI3K ⁇ and/or PBK ⁇ isoform relative to other human kinases.
  • the compounds of the present invention possess interesting pharmacokinetic properties owing to their improved solubility and clearance.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • U represents N or C-R 5 ;
  • -X- represents a group of formula (a), (b), (c), (d), (e), (f) or (g):
  • Y represents oxygen or sulphur
  • R 1 and R 2 independently represent hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci. 6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl- (C 1-6 )alkyl, heteroaryl or heteroary ⁇ C t ⁇ alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R 1 and R 2 when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or R 1 and R 2 , when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, Cs-i cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; R 3 and R 4 independently represent hydrogen; or Ci -6 alkyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, ary ⁇ C ⁇ alkyl, aryl(C 2-6 )alkenyl, 3TyI(C 2-6 )- alkynyl,
  • R 3 and R 4 when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or R 3 and R 4 , when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
  • R a represents Cj -6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
  • R b represents hydrogen; or optionally substituted Ci -6 alkyl
  • R c represents hydrogen; or Ci -6 alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl, heteroaryl(Ci- 6 )alkyl or any of which groups may be optionally substituted by one or more substituents;
  • R d represents hydrogen or C 1-6 alkyl;
  • R e represents Cj -6 alkyl
  • R represents C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C
  • R 6 and R 7 independently represent hydrogen or Cj -6 alkyl;
  • R 8 represents hydroxy, oxo or -NR ⁇ R h ;
  • R ⁇ and R h independently represent hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci- 6 )alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • the present invention also provides a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • -X- represents a group of formula (a) or (b) as depicted above; R 1 and R 2 are both attached to the carbon atom between the moiety X and the moiety C(H)R 8 ; and
  • R 1 and R 2 independently represent hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 aryl, aryl(Ci. 6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl- (C 1-6 )alkyl, heteroaryl or any of which groups may be optionally substituted by one or more substituents; or
  • R 1 and R 2 when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents;
  • R 3 , R 4 and R 8 are as defined above.
  • the present invention also provides a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 8 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 substituents. 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.
  • the compounds of the invention carry an acidic moiety, e.g.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • alkali metal salts e.g. sodium or potassium salts
  • alkaline earth metal salts e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • solvates of the compounds of formula (I) above include within its scope solvates of the compounds of formula (I) above.
  • Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
  • the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
  • Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched C 1-6 alkyl groups, for example C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, .sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci -6 alkoxy", “Ci -6 alkylthio", "Ci -6 alkylsulphonyl" and "Ci- 6 alkylamino" are to be construed accordingly.
  • Typical C 2-6 alkenyl groups include vinyl and allyl.
  • Typical C 2-6 alkynyl groups include ethynyl, prop-1-yn-l-yl, prop-2-yn-l-yl, but-1- yn-l-yl and 3-methylbut-l-yn-l-yl.
  • a specific C 2-6 alkynyl group is prop-2-yn-l-yl.
  • C 3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci -6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • aryl(C 2-6 )alkenyl groups include 2-phenylethenyl and 3-phenylprop-2-en- 1-yl.
  • Typical aryl(C 2-6 )alkynyl groups include phenylethynyl, 3-phenylpro ⁇ -l-yn-l-yl and 3-phenylprop-2-yn-l-yl.
  • a specific aryl(C 2-6 )alkynyl group is 3-phenylprop-2-yn-l- Particular biaryl groups include biphenyl and naphthylphenyl.
  • Suitable heterocycloalkyl groups which may comprise benzo-f ⁇ sed analogies thereof, include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomo ⁇ holinyl.
  • Typical heterobicycloalkyl groups include quinuclidinyl, 8-azabicyclo[3.2.1]octyl and 3,8-diazabicyclo[3.2.1]octyl.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazof 1 ,2- ⁇ ]pyridinyl, imidazo[4,5-6]pyridinyl, imidazo[ 1 ,2- ⁇ ]pyrimidinyl, imidazo[l,2- ⁇ ]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotri
  • Typical bi(heteroaryl) groups include benzofuryl-pyridinyl, benzothienyl-pyridinyl, indolyl-pyridinyl, isoxazolyl-pyridinyl, bipyridinyl and isoquinolinyl-pyridinyl.
  • 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.
  • U represents N.
  • the present invention provides a compound offprrnula (A) 5 or a pharmaceutically acceptable salt or solvate thereof:
  • V represents a group of formula CH 2 or N-R 6 ; and Y, R 1 , R 2 , R 3 , R 4 , R 6 and R 8 are as defined above.
  • Specific sub-classes of compounds of formula (A) above are represented by the compounds of formula (IA-A), (IB-A), (IC-A) and (ID-A):
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 8 are as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are as defined above.
  • -X- suitably represents a group of formula (a), (b) or (c) as depicted above, especially (a) or (b).
  • -X- represents a group of formula (a).
  • -X- represents a group of formula (b).
  • -X- represents a group of formula (c).
  • Y represents oxygen
  • hi another embodiment Y represents sulphur.
  • V represents CH 2 .
  • V represents N-R 6 .
  • R 1 represents hydrogen or C] -6 alkyl. Typical values of R 1 include hydrogen, methyl and ethyl, hi one embodiment, R 1 is hydrogen. In another embodiment, R 1 is Ci- 6 alkyl. In one aspect of that embodiment, R 1 is methyl. In another aspect of that embodiment, R 1 is ethyl.
  • R 2 represents hydrogen; or C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents.
  • R 1 and/or R 2 examples include halogen, cyano, nitro, C 1 ⁇ alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C 1-6 alkylthio, Ci -6 alkylsulphonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2- 6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylaminocarbonyl, di(Ci -6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl and di(Ci_ 6 )alkylaminosulphonyl; especially hal
  • R 1 and/or R 2 examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
  • R 2 examples include hydrogen, methyl, ethoxy, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl.
  • a particular value of R 2 is methyl.
  • R and R when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage.
  • R l and R 2 when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substiruents.
  • R 1 and R 2 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl.
  • R 1 and R 2 when attached to adjacent carbon atoms, may together form an optionally benzo-fiised and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the ring containing the variable X.
  • R and R when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substiruents.
  • R 1 and R 2 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the ring containing the variable X. Also in this context, in another embodiment, R 1 and R 2 , when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e. an indanyl moiety fused to the ring containing the variable X.
  • R 3 represents hydrogen; or Ci -6 alkyl, aryl, aryl(Ci.6)alkyl, aryl- (C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalky ⁇ C ⁇ alkyl, C 3-7 heterocycloalkyl- carbonyl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1 - 6 )alkyl, any of which groups may be optionally substituted by one or more substiruents.
  • R 3 represents hydrogen; or C 2-6 alkynyl, 8TyI(C 1 . 6 )alkyl or heteroaryl-
  • R 3 represents aryl(C 1-6 )alkyl or heteroaryl(C 1-6 )alkyl, either of which groups may be optionally substituted by one or more substiruents.
  • R 3 represents hydrogen.
  • R 3 represents Cj -6 alkyl, aryl(Ci -6 )alkyl, biaryl-
  • R 3 represents methyl, aryhnethyl, biarylmethyl, heteroaryhnethyl or heteroaryl-arylmethyi, any of which groups may be optionally substituted by one or more substituents. More particularly, R 3 represents ⁇ rylmcthyl or hctcro ⁇ rylmothyl, oithor of which groups may be optionally substituted by one or more substituents.
  • R 3 represents substituted or unsubstituted indolyl- (Ci- 6 )alkyl.
  • R 3 represents substituted or unsubstituted indolylmethyl.
  • R 3 represents substituted or unsubstituted phenyl- (C 1-6 )alkyl.
  • R 3 represents substituted or unsubstituted benzyl.
  • R 3 represents substituted or unsubstituted benzofuryl- (C 1-6 )alkyl.
  • R 3 represents substituted or unsubstituted benzofurylmethyl.
  • R 3 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1 ,2,3,4-tetrahydroquinolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1,2,3,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, in
  • R 4 represents hydrogen or optionally substituted Ci -6 alkyl.
  • substituents on R 3 and/or R 4 include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (C 1-6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl(C i ⁇ alkylaryl, piperazinyl(C ⁇ ⁇ alkylaryl, (C j -6 )alkylpiperazinyl(C i -6 )- (C 1-6 )alkoxyaryl, cyano(C 1-6 )alkoxyaryl, di(Ci -6 )- alkylamino(C 1-6 )alkylaryl, (C 1-6 )alkylaminocarbonylaryl, aryl(Ci -6 )alkyl, oxazolinyl, azetidin
  • R 3 and/or R 4 include C 1-6 alkyl and di(C i ⁇ alkylaminocarbonyl .
  • R 3 and/or R 4 Selected examples of specific substituents on R 3 and/or R 4 include fiuoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, mo ⁇ holinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoin
  • R 3 and/or R 4 include methyl and dimethylaminocarbonyl .
  • Typical values of R 3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-iV-phenylaminomethyl, pyridinylamino- methyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyl- methylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, phenyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl,
  • R 3 is (dimethylaminocarbonyl)(methyl)indolylmethyl.
  • Typical values of R 4 include hydrogen and methyl.
  • R 4 is hydrogen.
  • R 4 is C 1-6 alkyl, especially methyl.
  • R 3 and R 4 when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage.
  • R 3 and R 4 when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
  • R 3 and R 4 when attached to adjacent carbon atoms, may together form an optionally benzo-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the morpholine ring.
  • R 3 and R 4 when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the morpholine ring, which phenyl ring may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyelnpentyl ring, i c an indanyl moiety fused to the morpholine ring, which indanyl moiety may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • Examples of typical substituents on the fused rings referred to in the preceding paragraph include halogen, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (d ⁇ alkylaryl, di(Ci -6 )alkylaryl, piperazinyl(C 1-6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i .6)alkylaryl, morpholinyl(C ⁇ -6 )alkylaryl, (C i -6 )alkoxyaryl, cyano(C i ⁇ alkoxyaryl, di(C i ⁇ alkylaminotQ -6 )alkylaryl, (C ⁇ ⁇ alkylaminocarbonylaryl, 8TyI(C 1 .
  • (Ci- 6 )alkylpyrazolyl [aminocarbonyl(C I-6 )alkyl][di(C 1-6 )alkyl]pyrazolyl, di(Ci- 6 )alkyl- aminocarbonyl(C 1-6 )alkylpyrazolyl, pyrazolo[l,5- ⁇ ]pyridinyl, di(C 1-6 )alkylisoxazolyl, (amino)[(Ci -6 )alkyl]isoxazolyl, thiazolyl, di(Ci.
  • substituents on the fused rings referred to in the two preceding paragraphs include halogen, (C ⁇ alkylpyrazolyl, tri(Ci -6 )alkylpyrazolyl, (difluoromethyl)pyrazolyl, hydroxy(C i ⁇ alkylpyrazolyl, [hydroxy(C i ⁇ alkyl] [di(C i -6 )- alkyljpyrazolyl, [(hydroxy)(methoxy)(C ] -6 )alkyl]pyrazolyl, (C ⁇ -6 )alkylpyridinyl, hydroxy(C 1-6 )alkylpyridinyl, pyridazinyloxy, amino and (Q ⁇ alkylpyridazinylamino.
  • substituents include fluoro, chloro, bromo, methylpyrazolyl, trimethylpyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (difiuoromethyl)- pyrazolyl, hydroxyethylpyrazolyl, (hydroxymethyl)(isopropyl)(methyl)pyrazolyl, [(hydroxy)(methoxy)propyl]pyrazolyl, methylpyridinyl, (1 -hydroxy- 1 -methylethyl)- pyridinyl, pyridazinyloxy, amino and methylpyridazinylamino.
  • R a represents substituted or unsubstituted aryl.
  • R c represents hydrogen; or aryl, 8TyI(C 1 ⁇ alkyl, heteroaryl(Ci. 6 )alkyl or (aryl)(heteroaryl)(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R a and/or R b and/or R c and/or R f examples include halogen, cyano, nitro, Ci -6 alkyl, trifiuoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci -6 alkylthio, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl and di(Ci- 6 )
  • R a and/or R b and/or R c and/or R f examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifiuoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl.
  • R a is phenyl.
  • R b represents hydrogen.
  • R b represents C 1-6 alkyl, especially methyl or ethyl.
  • Particular values of R c include hydrogen, phenyl, benzyl, pyridinylmethyl and (phenyl)(pyridinyl)methyl.
  • R d represents hydrogen. In another embodiment, R d represents C 1-6 alkyl, especially methyl or ethyl, particularly ethyl. Suitably, R e represents methyl.
  • R f represents optionally substituted aryl, especially phenyl.
  • 6 alkyl-aryl-heteroaryl, Cs -9 heterobicycloalkyl(C ]. 6 )ailkyl-aryl -heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C 3-7 heterocycloalkylcarbonyl-bi(heteroaryl), aryloxyaryl, aryl(C 1-6 )alkoxyaryl, heteroaryl(C 1-6 )alkoxyaryl, 8TyI(C 1 ⁇ alkylaminoaryl, heteroaryl(Ci -6 )alkylaminoaryl, C 3-7 cycloalkylcarbonylarnirioaryl, arylcarbonylaminoaryl, arylCC t ⁇ alkylcarbonylaminoaryl, C 3-7 heterocycloalkylc ⁇ ubonylaminoaryl, heteroarylcarbonylaminoaryl, aryl- (C 3-7 )he
  • R 5 represents aryl-heteroaryl, C 3-7 heterocycloalkyl-aryl-heteroaryl, C 3-7 cycloalkylcarbonyl-aryl-heteroaryl or C 3-7 heterocycloalkylcarbonyl-aryl-heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 5 may typically represent C 3-7 heterocycloalkylcarbonyl-biaryl, which group may be optionally substituted by one or more substituents.
  • R 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b or -CONR 0 R ; or R 5 represents methyl, propyl, ethenylcarbonyl, ethynyl, propynyl, butynyl, 3-methylbutynyl, cyclopropylethynyl, cyclohexylethynyl, phenyl, naphthyl, benzyl, phenylethyl, phenyl ethenyl, phenylethynyl, phenylpropynyl, biphenyl, piperidinylethyl, pyrrolidinylethynyl, piperidinylethynyl, 1 ,2,3,4-tetrahydroisoquinolinylpropynyl, piperazinylpropynyl, pyrrol
  • R 5 include morpholinylcarbonylbiphenyl, phenylpyridinyl, morpholinylphenylpyridinyl, cyclopropylcarbonylphenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl and morpholinylcarbonylphenylpyridinyl, any of which groups may be optionally substituted by one or more substituents.
  • R 5 represents phenylpyridinyl, morpholinylphenylpyridinyl, cyclopropylcarbonylphenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl or morpholinylcarbonylphenylpyridinyl, any of which groups may be optionally substituted by one or more substituents.
  • R 5 examples include halogen, cyano, nitro, oxo, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, Cj -6 alkoxy, dihydroxy(Ci -6 )- alkoxy, aryl(Ci ⁇ alkoxy, methoxyaryl(Ci. 6 )alkoxy, amino, Ci -6 aikylamino, di(Ci -6 )- aikylamino, amino ⁇ ⁇ alkyl, Ci -6 alkylamino(Ci.
  • R 5 examples include fluoro, chloro, bromo, cyano, nitro, oxo, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, ethoxy, dihydroxypropoxy, isobutoxy, benzyloxy, methoxybenzyloxy, amino, methylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, N-isopropyl-N-methylaminomethyl, dimethylaminoethylamino, methoxybenzylamino, acetylamino, ethoxycarbonylacetylamino, ethylcarbonylamino, methoxycarbonyl- ethylcarbonylamino, acetylaminomethyl, tert-butoxycarbonylamino, JV-(tert-butoxy- carbonyl)-
  • R 5 include hydrogen, fluoro, chloro, bromo, iodo, cyano, phenylthio, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, pyridinylmethylaminocarbonyl, (phenyl)(pvridinyl)methylaminocarbonyl, N-ethyl-N-pyridinylmethylaminocarbonyl, dimethylaminomethyl, dimethylaminosulphonylaminopropyl, dimethylamino- ethenylcarbonyl, ethynyl, triethylsilylethynyl, diethylaminopropynyl, methylsulphonylaminopropynyl, dimethylaminosulphonylaminopropynyl, hydroxybutynyl, 3-hydroxy-3
  • R 5 Additional specific values of R 5 include (fluoro)(morpholinylcarbonyl)biphenyl, (cWoro)(mo ⁇ holinyl)phenylpyridinyl and (fluoro)(pyi ⁇ olidinylcarbonyl)phenylpyridinyl.
  • R 5 include (fluoro)(morpholinylcarbonyl)biphenyl, dimethylaminocarbonylphenylpyridinyl, morpholinylphenylpyridinyl,
  • R 5 include dimethylaminocarbonylphenylpyridinyl, morpholinylphenylpyridinyl, (cyclopropylcarbonyl)(fluoro)phenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl and (fluoro)(morpholinylcarbonyl)phenylpyridinyl.
  • R 3 and R 4 in the compounds of formula (B) above are both hydrogen, then R 5 is other than hydrogen.
  • R 5 in the compounds of formula (B) above is hydrogen
  • R 3 and/or R 4 is other than hydrogen
  • R 6 represents hydrogen. In another embodiment, R 6 represents Ci -6 alkyl, especially methyl. hi one embodiment, R 7 represents hydrogen. In another embodiment, R 7 represents Ci -6 alkyl, especially methyl.
  • R represents hydroxy or -NR g R .
  • R represents hydroxy
  • R 8 represents -NR g R h .
  • R 8 represents oxo.
  • R g represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl or aryl(C 1-6 )- alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 8 represents Ci -6 alkyl, C 3-7 cycloalkyl, aryl or aryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R g and R h examples include halogen, cyano, trifluoromethyr, hydroxy, C 1-6 alkoxy andtrffluoromethoxy, especially hydroxy.
  • Selected values of R 8 include hydrogen, methyl, hydroxyethyl, cyclopropyl, phenyl and .benzyl. .
  • R g examples include methyl, hydroxyethyl, cyclopropyl, phenyl and benzyl.
  • R h represents hydrogen or C 1-6 alkyl.
  • R h represents hydrogen, hi another embodiment, R h represents C 1-6 alkyl, especially methyl.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (BA), and pharmaceutically acceptable salts and solvates thereof:
  • R 5 and R 8 are as defined above;
  • R u represents hydrogen or C 1-6 alkyl;
  • R 12 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, 8TyI(C 1 -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or R 1 x and R 12 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups maybe optionally substituted by one or more substituents.
  • -X - represents a group of formula (a) or (b).
  • -X 1 - represents a group of formula (a)
  • -X 1 - represents a group of formula (a)
  • -X 1 - represents a group of formula (b)
  • -X 1 - represents a group of formula (c).
  • R 5 in the compounds of formula (BA) is other than hydrogen.
  • any of the groups in the compounds of formula (BA) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosub ⁇ titutcd.
  • R 11 examples include hydrogen, methyl and ethyl.
  • R 11 is hydrogen.
  • R 11 is C 1-6 alkyl, especially methyl.
  • R 12 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • Particular values of R 12 include hydrogen and unsubstituted C 1-6 alkyl.
  • R 12 examples include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difiuoromethoxy, trifiuoromethoxy, aryloxy, C 1-6 alkylthio, C 1-6 alkylsulphonyl, amino, Ci -6 alkylamino, di(C 1-6 )alkylarnino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylaminocarbonyl, di(Ci- 6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl and di(Ci -6 )- alkylaminosulphonyl; especially hal
  • R 12 examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifiuoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
  • R 12 Typical values of R 12 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl, phenyl, chlorophenyl, methoxyphenyl, methylthiophenyl and furyl, especially hydrogen or methyl.
  • R 12 is hydrogen.
  • R 12 is methyl.
  • R 11 and R i2 may together form an optionally substituted spiro linkage.
  • R 1 ' and R 12 when taken together with the carbon atom to which they are both attached, may represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R and R when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl.
  • Other sub-classes of compounds according to the invention are represented by the compounds of formula (IIA-A) and (IIA-B), and pharmaceutically acceptable salts and solvates thereof:
  • R 13 represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci. 6 )alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalky ⁇ C ⁇ alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci. 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • any of the groups in the compounds of formula (IIA-A) or (ILA-B) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted.
  • R 13 represents hydrogen; or C 1-6 alkyl, aryl(Ci -6 )alkyl, aryl(C 2-6 )alkynyl, biaryt( €i -6 )alkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl(Ci. 6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 13 represents hydrogen; or C 2-6 alkynyl, aryl(Ci. 6 )alkyl or heteroaryl- (Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 13 represents aryl(C 1-6 )alkyl or heteroaryl(C ⁇ -6 )alkyl, either of which groups may be optionally substituted by one or more substituents. In one specific embodiment, R 13 represents hydrogen. Typically, R 13 is other than hydrogen.
  • R 13 represents C 1-6 alkyl, aryl(Ci-6)alkyl, biaryl- (Ci- 6 )alkyl, heteroaryl(Ci. 6 )alkyl or heteroaryl-aryl(C 1-6 )alkyl, any of which groups maybe optionally substituted by one or more substituents.
  • R 13 represents methyl, arylmethyl, biarylmethyl, heteroarylmethyl or heteroaryl-arylmethyl, any of which groups may be optionally substituted by one or more substituents.
  • R 13 represents arylmethyl or heteroarylmethyl, either of which groups maybe optionally substituted by one or more substituents.
  • R 13 represents substituted or unsubstituted indolyl-
  • R 13 represents substituted or unsubstituted indolylmethyl.
  • R 13 represents substituted or unsubstituted phenyl- (C]- 6 )alkyl.
  • R 13 represents substituted or unsubstituted benzyl.
  • R 13 represents substituted or unsubstituted benzofuryl- (Ci- 6 )alkyl.
  • R 13 represents substituted or unsubstituted benzofurylmethyl.
  • R 13 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1,2,3 ,4-tetrahydroquinolinylmethyl, 1,2,3 ,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3,4-tetrahydroquinoxalinylcarbonyl, benzorurylmethyl, benzothienyhnethyl, indolylmethyl, pyrrolo[2,3-&]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, benzo
  • R 13 examples include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci ⁇ alkylaryl, di(C 1-6 )alkylaryl, piperidinyl- (C i .
  • R 13 Particular examples of typical substituents on R 13 include Cj -6 alkyl and di(C 1-6 )alkylaminocarbonyl.
  • R 13 Selected examples of specific substituents on R 13 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidin
  • R 13 Particular examples of specific substituents on R 13 include methyl and dimethylaminocarbonyl.
  • Typical values of R 13 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyhnethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, phenyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazo
  • R 13 is (dimethylaminocarbonyl)(methyl)indolylmethyl.
  • One particular sub-group of the compounds of formula (IIA-A) is represented by the compounds of formula (HB), and pharmaceutically acceptable salts and solvates thereof:
  • V, R 8 , R 1 ' and R 12 are as defined above;
  • T represents oxygen or M-R 25 ;
  • R 23 represents hydrogen, halogen, cyano, nitro, Ci -6 alkyl, hydroxy(Ci-6)alkyl, trifluoromethyl, aryl(Ci- 6 )alkyl, oxazolinyl, triazolyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 3-7 cycloalkoxy, C 3-7 CyClOaIlCyI(C 1-6 )BIkOXy, mo ⁇ holinyl(C ⁇ .
  • R 24 represents hydrogen, halogen, Ci -6 alkoxy or di(Ci -6 )alkylaminocarbonyl; or
  • R 23 and R when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy
  • R 25 represents hydrogen or C 1-6 alkyl.
  • T is N-R 25 . In another embodiment, T is oxygen.
  • R 23 is di(Ci -6 )alkylaminocarbonyl.
  • R 23 Illustrative values of R 23 include hydrogen, fluoro, chloro, cyano, nitro, oxazolinyl, triazolyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, morpholinylethoxy, azetidinyl, morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino, N-methoxycarbonyl-iV-methylamino, methylsulphonylamino, acetyl, acetyl oxime, acetyr tx ifluoroiiiothyt carboiiyr, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dime(.hylaniiii ⁇ elhyl)ain
  • R 23 is dimethylaminocarbonyl.
  • Definitive values of R 24 include hydrogen, chloro, methoxy and dimethylaminocarbonyl.
  • a particular value of R 24 is hydrogen.
  • R 25 is hydrogen. In another embodiment, R 25 is C 1 ⁇ alkyl, especially methyl.
  • V, R 8 , R 11 and R 12 are as defined above;
  • R 33 represents halogen or -NHR 34 ; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more s ⁇ bsrit ⁇ ents; and
  • R 34 represents methylenedioxyphenyl, oxazolinyl- phenyl, [(C 1-6 )alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (C 1-6 )alkyltriazolylphenyl, (C 1-6 )alkylpyrimidinylphenyl, pyrazolyl(Ci -6 )alkyl- phenyl, MaZoIyI(C 1 -6 )alkylphenyl, C 1-6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci -6 alkylsulphonylphenyl, mo ⁇ holinylsulphonylphenyl, dihydrobenzofuranyl, C 1-6 alkylsulphonylindolinyl, chromanonyl, dihydroquinolin
  • R 33 represents halogen or -NHR 34 , in which R 34 is as defined above.
  • R 33 represents halogen, especially bromo.
  • R 33 represents -NHR 34 , in which R 34 is as defined above.
  • R 33 represents unsubstituted or substituted aryl. In another embodiment, R 33 represents unsubstituted or substituted heteroaryl.
  • Typical values of R 34 include pyridinyl, halopyridinyl, (C 1-6 )alkylpyridinyl, and (Ci -6 )alkoxypyridinyl.
  • R 34 include methylenedioxyphenyl, morpholinylmethylphenyl, oxazolinylphenyl, (methyl)(oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolylphenyl, methyltriazolylphenyl, methylpyrimidinylphenyl, pyrazolylmethylphenyl, triazolylmethylphenyl, methylsulphonylaminophenyl, morpholinylcarbonylphenyl, methylsulphonylphenyl, mo ⁇ holinylsulphonylphenyl, dihydrobenzofuranyl, methylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, (bromo)(methyl)pyrazolyl, tri
  • R 34 examples include pyridinyl, chloropyridinyl, methylpyridinyl, dimethylpyridinyl and methoxypyridinyl.
  • R 33 represents halogen or -NHR 34 , in which R 34 is as defined above.
  • R 33 represents phenyl, naphthyl, benzofuryl, thienyl, benzothienyl, indolyl, isoxazolyl, pyrazolyl, pyridinyl or pyrimidinyl, any of which groups may be optionally substituted by one or more substiruents.
  • Selected examples of suitable substiruents on R 33 include halogen, cyano, C 1-6 alkyl, hydroxy(Ci- 6 )alkyl, trifluoromethyl, Ci -6 alkoxy, trifluoromethoxy, aryloxy, methylenedioxy, Ci -6 alkylthio, arylsulphonyl, amino, C 2-6 alkylcarbonylamino, Ci -6 alkylsulphonylamino, C 2-6 alkylcarbonyl and aminocarbonyl.
  • Selected examples of representative substiruents on R 33 include fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, phenoxy, methylenedioxy, methylthio, phenylsulphonyl, amino, acetylamino, methylsulphonylamino, acetyl and aminocarbonyl.
  • R 33 Specific values of R 33 include bromo, methylenedioxyphenylamino, morpholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenyl- amino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenyl- amino, triazolylmethylphenylamino, methylsulphonylaminophenylamino, morpholinyl- carbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, dihydrobenzofuranylamino, methylsulphonylindolinylamino, chromanonylamino, dihydroquinolinonylamino, be
  • R 33 is bromo.
  • V, R 8 , R 11 and R 12 are as defined above;
  • R 43 represents hydrogen, halogen, nitro, Ci -6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl,
  • R 44 represents hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy. Suitable values of R 43 include halogen, (Ci -6 )alkylpyrazolyl, tri(C 1-6 )alkyl- pyrazolyl, (difluoromethyl)pyrazolyl, hydroxy(C 1-6 )alkylpyrazolyl, [hydroxy(C 1-6 )alkyl]- [di(Ci -6 )alkyl]pyrazolyl, [(hydroxy)(methoxy)(Ci -6 )alkyl]pyrazolyl, (Ci. 6 )alkylpyridinyl, hydroxy(Ci. 6 )alkylpyridmyl, pyridazinyloxy, amino and (Ci ⁇ alkylpyridazinylamino.
  • R 43 include fluoro, chloro, bromo, nitro, methyl, n-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazfnymiethylphenyr, morphoEnylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylpbenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazin
  • (methoxy)propyl]pyrazolyl aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (phenyl)(trifluoromethyl)pyrazolyl, benzylpyrazolyl, aminobenzylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranylmethylpyrazolyl, (dimethyl)(tetrahydropyranyl- methyl)pyrazolyl, pyrrolidinylethyl
  • R 43 include fluoro, chloro, bromo, methylpyrazolyl, trimethylpyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (difluoromethyl)pyrazolyl, hydroxyethylpyrazolyl, (hydroxymethyl)(isopropyl)(methyl)pyrazolyl, [(hydroxy)(methoxy)propyl]pyrazolyl, methylpyridinyl, ( 1 -hydroxy- 1 -methylethyl)- pyridinyl, pyridazinyloxy, amino and melhylpyridazinylamino.
  • R 44 represents hydrogen. In another embodiment, R 44 represents halogen, especially fluoro, chloro or bromo. In a further embodiment, R 44 represents C 1 ⁇ alkyl, especially methyl. In an additional embodiment, R 44 represents Cj -6 alkoxy, especially methoxy.
  • novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • compositions for oral administration may be suitably formulated to give controlled release of the active compound.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) maybe 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, fluorotrichlorornethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichlorornethane, 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 phenylmereurie nilrale, benzylalkoiiium chloride or chlorhexidine acetate.
  • a bactericidal or fungicidal agent for example phenylmereurie nilrale, benzylalkoiiium chloride or chlorhexidine acetate.
  • compounds may be formulated in an ointment such as petrolatum.
  • the compounds according to the present invention may be conveniently formulated as suppositories.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • the quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
  • halogenating agent of use in the reaction with compound (III) is suitably a chlorinating agent, e.g. N-chlorosuccinimide, in which case the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, or a cyclic ether such as tetrahydrofuran.
  • a suitable solvent e.g. acetonitrile, or a cyclic ether such as tetrahydrofuran.
  • the subsequent treatment with water is conveniently accomplished at an elevated temperature.
  • the compounds of formula (I) above wherein R 8 represents -NR g R h may be prepared by a process which comprises reacting a compound of formula (III) with a halogenating agent, as described above; followed by treatment with a compound of formula H-NR ⁇ R h .
  • the subsequent treatment with a compound of formula H-NR g R h is conveniently accomplished at an elevated temperature, typically in a suitable solvent such as methanol or acetonitrile, optionally in the presence of a base such as N ⁇ /V-diisopropylethylamine or potassium carbonate.
  • a suitable solvent such as methanol or acetonitrile
  • a base such as N ⁇ /V-diisopropylethylamine or potassium carbonate.
  • the compounds of formula (III) above may be prepared by reacting a compound of formula (IV) with a compound of formula (V):
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, dimethylsulphoxide, a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as NJV-dimethylformamide, optionally under basic conditions, e.g. in the presence of an organic base such as NJV- diisopropylethylamine or 2,6-lutidine.
  • a suitable solvent e.g. acetonitrile, dimethylsulphoxide, a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as NJV-dimethylformamide
  • reaction may be effected at an elevated temperature in a solvent such as 2-ethoxyethanol in the presence of a catalytic quantity of a mineral acid, e.g. concentrated hydrochloric acid.
  • a solvent such as 2-ethoxyethanol
  • a catalytic quantity of a mineral acid e.g. concentrated hydrochloric acid.
  • the reaction may be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium tert-butoxide, in the presence of a transition metal catalyst.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene
  • an inorganic base such as sodium tert-butoxide
  • the transition metal catalyst is suitably palladium(II) acetate, in which case the icacti ⁇ n will ideally be performed in the presence of tert-butylphosphonium tetrafluoroborate or dicyclohexyl diphenylphosphine.
  • reaction is conveniently effected by stirring compound (VI) with tert-butyl nitrite and copper(II) bromide in a suitable solvent, e.g. acetonitrile.
  • a suitable solvent e.g. acetonitrile.
  • the leaving group L 2 is typically a halogen atom, e.g. bromo or iodo.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, typically under basic conditions, e.g. in the presence of an organic base such as ⁇ N-diisopropylethylamine.
  • reaction may be accomplished by heating the reactants in a lower alkanol solvent, e.g. a Ci -6 alkyl alcohol such as ethanol.
  • a lower alkanol solvent e.g. a Ci -6 alkyl alcohol such as ethanol.
  • the intermediates of formula (VI) above wherein U represents C-R 5 , -X- r ⁇ pr ⁇ G ⁇ nt ⁇ ⁇ group of formula (a), (b) or (c) in whioh Y is oxygen, and R 5 repretionts oyano or -CO 2 R b may be prepared by reacting a compound of formula R 5a -CH 2 -CN with the appropriate compound of formula (VIIIA), (VIIIB) or (VIIIC):
  • R 1 and R 2 are as defined above, and R 5a represents cyano or -CO 2 R b in which R is as defined above; in the presence of sulphur.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of morpholine.
  • the compounds of formula (I) may be prepared by a process which comprises reacting a compound of formula (VII) as defined above with a compound of formula (IX):
  • the reaction may additionally be accomplished by heating the reactants in acetic acid in the presence of sodium acetate.
  • the intermediates of formula (IX) above may be prepared by reacting a compound ⁇ f formula (V) as defined above with l,r-lluocaibonyldiimidazole; followed by treatment with ammonia or ammonium hydroxide.
  • the starting materials of formula (V), (VII) and (VIIIAy(VIIIBy(VIIIC) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
  • any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. Similar considerations apply to the compounds of formula (III).
  • a compound of formula (IA-B), (IB-B), (IC-B) or (ID-B) wherein Y is oxygen may be converted into the corresponding compound wherein Y is sulphur by treatment with Lawesson's Reagent (i.e. 2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulphide).
  • a compound of formula (IA-A) or (IC-A) may be converted into the corresponding compound of formula (IB-A) or (ID-A) respectively by treatment with Lawesson's Reagent.
  • a compound of formula (IB-B) wherein Y is oxygen may be converted into the corresponding compound of formula (ID-B) by treatment with hydroxylamine-O-sulfonic acid, typically in the presence of formic acid at an elevated temperature.
  • a compound of formula (IB-B) wherein Y is oxygen may be converted into the corresponding compound of formula (IE-B) by treatment with a reducing agent such as lithium aluminium hydride.
  • a compound of formula (IB-B) wherein Y is oxygen may be converted into the corresponding compound of formula (IF-B) by treatment with a hydroxylamine derivative of formula H 2 N-OR 7 .
  • a compound of formula (IB-B) wherein Y is oxygen may be converted into the corresponding compound of formula (IG-B) by treatment with hydrazine hydrate.
  • a compound of formula (IF-B) may be converted into the corresponding compound of formula (IC-B) by treatment with/7-toluenesulphonyl chloride, typically in the presence of pyridine at an elevated temperature.
  • a compound of formula (IB-B) wherein Y is oxygen and R 1 is hydrogen may be converted into the corresponding compound wherein R 1 is methyl by treatment with a methyl halide, e.g. iodomethane, in the presence of a strong base, e.g. lithium diisopropylamide.
  • a compound of formula (I) wherein R 8 represents hydroxy may be converted into the corresponding compound wherein R 8 represents oxo by treatment with an oxidising agent such as Dess-Martin periodinane.
  • a compound of formula (I) wherein R 3 and/or R 4 contains an aryl or heteroaryl moiety may be halogenated (e.g. brominated) on the aryl or heteroaryl moiety by treatment with the appropriate N-halosuccinimide (e.g. N-bromosuccinimide).
  • a compound of formula (I) wherein R 3 and/or R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by amino (-NH 2 ) by treatment with benzophenone imine and tris(dibenzylidene- acetone)dipalladium(0) in the presence of 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl (BINAP) and a strong base such as sodium tert-butoxide.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound of formula (I) wherein the halogen atom is replaced by an optionally substituted C 3-7 cycloalkyl, aryl, aryl(Ci -6 )alkyl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted C 3-7 cycloalkyl, aryl, aryl(Ci -6 )alkyl or heteroaryl boronic acid or a cyclic ester thereof, e.g. a pinacol ester thereof, in the presence of a catalyst.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 represents aryl(Ci. 6 )alkyl, substituted on the aryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 3 represents biaryl(Ci-6)alkyl or by treatment with, respectively, an aryl or heteroaryl boronic acid, in the presence of a catalyst.
  • a compound of formula (I) wherein R 3 represents heteroary ⁇ C ⁇ alkyl, substituted on the heteroaryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 3 represents aryl-heteroaryl(C 1-6 )alkyl by treatment with an aryl boronic acid, in the presence of a catalyst.
  • a compound of formula (I) wherein R 3 contains a cyclic borane moiety e.g.
  • 4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl may be converted into the corresponding compound wherein the cyclic borane moiety is replaced by an optionally substituted aryl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted aryl or heteroaryl halide, e.g. chloride, bromide or iodide, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonateor potassium phosphate, in art inert solvent such as 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonlum bromide.
  • a base such as sodium carbonate, potassium carbonateor potassium phosphate
  • solvent such as 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonlum bromide.
  • the catalyst may be palladiuin(II)vestle, in which case the transformation may conveniently be effected at an elevated temperature in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and potassium phosphate.
  • the catalyst may be bis(dibenzylideneacetone)- palladium(O), in which case the transformation may conveniently be effected at an elevated temperature in the presence of tricyclohexylphosphine and cesium carbonate.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents a substituted aminomethyl moiety, e.g. phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridin- 3-ylaminomethyl, indolin-1-ylmethyl, 1,2,3,4-tetrahydroquinolin-l-ylmethyl or 1,2,3,4- tetrahydroisoquinolin-2-ylmethyl, by a two-stage procedure which comprises (i) Swern oxidation of the hydroxymethyl derivative by treatment with oxalyl chloride and dimethyl sulphoxide in the presence of triethylamine; and (ii) reductive amination of the formyl derivative thereby obtained by treatment with the appropriate amine, e.g.
  • aniline N- methylaniline, 3-aminopyridine, indoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4- tetrahydroisoquinoline, in the presence of a reducing agent such as sodium cyanoborohydride.
  • a reducing agent such as sodium cyanoborohydride.
  • any compound of formula (I) which contains a carbonyl-containing functionality may be converted into a substituted amino analogue thereof by application of the reductive amination procedure described in step (ii) in the preceding paragraph, which comprises treatment with the appropriately-substituted amine in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • Any compound of formula (I) wherein R 3 contains an amino moiety can be alkylated on the amino moiety by a reductive amination procedure which comprises treatment with the appropriate aldehyde in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents an optionally substituted C 3-7 heterocycloalkylcarbonyl moiety, e.g. piperidin-1-ylcarbonyl, 1,2,3,4- tetrahydroquinolin-1-ylcarbonyl, 6-methyl-l ,2,3,4-tetrahydroquinolin-l-ylcarbonyl, 6- methoxy- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 1 ,2,3 ,4-tetrahydroisoquinolin-2- ylcarbonyl or 1,2,3,4-tetrahydroquinoxalin-l-ylcarbonyl, by a two-stage procedure which comprises (i) oxidation of the hydroxymcthyl moioty by troatmont with potassium permanganate; and (ii) reaction of the carboxy derivative thereby obtained with the appropriate amine
  • piperidine 1,2,3,4-tetrahydroquinoline, 6-methyl-l,2,3,4- tetrahydroquinoline, 6-methoxy- 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydro- isoquinoline or 1,2,3,4-tetrahydroquinoxaline, in the presence of a condensing agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or ⁇ >(benzotriazol-l-yl)-N,N,ivyV'- tetramethyluronium hexafluorophosphate (HBTU).
  • a condensing agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or ⁇ >(benzotriazol-l-yl)-N,N,ivyV'- tetramethyluronium hexafluorophosphat
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by chloro may be converted into the corresponding compound wherein the phenyl ring is substituted by morpholin-4-yl by treatment with morpholine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(di-tert-butylphosphino)biphenyl and sodium tert-butoxide.
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by pyrrolidin- 1 -yl by treatment with pyrrolidine in the presence oftris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl and a base such as potassium carbonate.
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by an amino moiety (e.g. a group of formula -NHR 34 as defined above) by treatment with the appropriate amine (e.g. a compound of formula H 2 N-R 34 ) in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-2',4',6'-tri- isopropyl-l,l'-biphenyl (X-Phos) and abase such as sodium tert-butoxide.
  • the appropriate amine e.g. a compound of formula H 2 N-R 34
  • abase such as sodium tert-butoxide
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by carboxy (-CO 2 H) by treatment with n-butyllithium followed by carbon dioxide.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 contains an indole moiety may be methylated on the indole ring by treatment with a methyl halide, e.g. iodomethane, in the presence of a strong base such as sodium hydride.
  • a compound of formula (I) wherein R 3 contains an indole moiety may be acetylated on the indole ring by treatment with acetic anhydride and 4-dimethylamino-pyridine, typically in the presence of an organic base such as triethylamine.
  • a compound of formula (I) wherein R 3 contains an indoline moiety may be converted into the corresponding compound wherein R 3 contains air indole moiety by treatment with an oxidising agent such as manganese dioxide.
  • a compound of formula (I) wherein R ⁇ contains a hydroxy substituent may be converted into the corresponding compound wherein R 3 contains a Cj -6 alkylsulphonyloxy substituent, e.g. methyl- sulphonyloxy, by treatment with a Ci -6 alkylsulphonyl halide, e.g. methanesulphonyl chloride.
  • a compound of formula (I) wherein R 3 contains an amino (-NH 2 ) or carboxy (-CO 2 H) moiety may be converted into the corresponding compound wherein R 3 contains an amido moiety (-NHCO- or -CONH- respectively) by treatment with, respectively, a compound containing a carboxy or amino group, in the presence of O-(benzotriazol-l-yl)- N ⁇ vyV ⁇ V-tetramethyluronium hexafluorophosphate (HBTU), typically in a dipolar aprotic solvent such as iVyV-dimethylformamide; or in the presence of 1 -(3-dimethylaminopropyl)- 3-ethylcarbodiimide and 1-hydroxybenzotriazole.
  • HBTU O-(benzotriazol-l-yl)- N ⁇ vyV ⁇ V-tetramethyluronium hexafluorophosphate
  • a compound of formula (I) wherein R 3 contains an amino substituent may be converted into the corresponding compound wherein R 3 contains an alkyl- or arylsulphonylamino substituent, e.g. methylsulphonylamino or phenylsulphonylamino, by treatment with an alkyl- or arylsulphonyl halide, e.g. methanesulphonyl chloride or benzenesulphonyl chloride.
  • a compound of formula (I) wherein R 3 contains an amino moiety may be acylated by treatment with a C 2- 6 alkylcarbonyl halide, e.g. acetyl chloride; or a C 2-6 alkylcarbonyl anhydride, e.g. acetic anhydride.
  • a compound of formula (I) wherein R 3 contains an amino moiety may be converted into the corresponding carbamate ester by treatment with a Ci- 6 alkyl haloformate, e.g. methyl chloroformate.
  • a compound of formula (I) wherein R 3 contains a C 2-6 alkoxycarbonyl substituent, e.g. methoxycarbonyl, may be converted into the corresponding compound wherein R 3 contains a carboxy (-CO 2 H) substituent under standard saponification conditions, e.g. by treatment with a base such as lithium hydroxide.
  • a compound of formula (I) wherein R 3 contains a carboxy (-CO 2 H) substituent may be converted into the corresponding compound wherein R 3 contains an amido substituent, e.g.
  • methylaminocarbonyl 2- hydroxyethylaminocarbonyl, dimethylaminocarbonyl, iV-(2-hydroxyethyl)-N- methylaminocarbonyl, benzylaminocarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1- ylcarbonyl, piperidin-1-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl or morpholin-4- ylcarbonyl, by a two-stage procedure which comprises (i) treatment of the carboxy derivative with pentafluorophenol in the presence of a condensing agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide; and (ii) reaction of the pentafluorophenyl ester thereby obtained with the appropriate amine, e.g.
  • a condensing agent such as l-(3- dimethylaminopropyl)
  • methylamine 2-hydroxy- ethylamine, dimethylamine, iV-(2-hydroxyethyl)-N-methylamine, benzylamine, azetidine, pyrrolidine, piperidine, l ⁇ methylpiperazine or morpholine.
  • a compound of formula (I) wherein R 3 ZR 4 contains a nitro moiety may be converted into the corresponding compound wherein R 3 /R 4 contains an amino (-NH 2 ) moiety by catalytic hydrogenation, typically by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino (-NH 2 ) moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a heteroaryl-amino moiety, e.g. 6-methylpyridin-3- ylamino, by treatment with the appropriate heteroaryl halide, e.g. 5-bromo-2- methylpyridine, in the presence of palladium(II) acetate, 2-bis(dicyclohexylphosphino)- biphenyl and a base such as sodium tert-butoxide.
  • any compound of formula (I) wherein R 3 /R 4 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein the halogen atom is replaced by a substituted amino functionality by treatment with the appropriately- substituted amine derivative and palladium(II) acetate in the presence of a base, e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate.
  • a base e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate.
  • reaction may be effected by treatment with the appropriately-substituted amine derivative and [l,r-bis(di-tert-butylphosphino)ferrocene]palladiurn(II) dichloride in the presence of a base, e.g. sodium tert-butoxide.
  • a base e.g. sodium tert-butoxide.
  • any compound of formula (I) wherein R 3 /R 4 contains an amino functionality may be converted into the corresponding compound wherein the amino functionality is substituted by an optionally substituted aryl or heteroaryl moiety by treatment with an appropriately-substituted aryl or heteroaryl halide (e.g.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 ZR 4 contains a benzo moiety substituted by a heteroaryl group, e.g.
  • pyrazol-3-yl 1- methylpyrazol-4-yl, l-propylpyrazol-4-yl, 1 -isobutylpyrazol-4-yl, l-benzylpyrazol-4-yl, 1- [2-(morpholin-4-yl)ethyl]pyrazol-4-yl, 6-methylpyridin-3-yl or pyrimidin-5-yl, by treatment with the appropriate heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst.
  • an organic diol e.g. pinacol
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a boronic acid [-B(OH) 2 ] moiety may be converted" into the corresponding " coiiipu und wherein R /R contains a benzo moiety substituted by a heteroaryl group, e.g. methylimidazolyl, by treatment with the appropriate heteroaryl halide, e.g. bromide, derivative in Lhe presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, optionally in the presence of tetrabutylammonium bromide.
  • a compound of formula (I) wherein R 3 /R contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group by treatment with a strong base, e.g. n-butyllithium, and N,JV-dimethylformamide.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by hydroxymethyl by treatment with a reducing agent such as sodium borohydride.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by an aminomethyl moiety (e.g. dimethylaminomethyl, pyridin-3-ylaminomethyl, 4-methylpiperazin-l-ylmethyl or morpholin-4-ylmethyl) by treatment with the appropriate amine (e.g. dimethylamine, pyridin-3-ylamine, 1-methylpiperazine or morpholine) and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride.
  • an aminomethyl moiety e.g. dimethylaminomethyl, pyridin-3-ylaminomethyl, 4-methylpiperazin-l-ylmethyl or morpholin-4-ylmethyl
  • the appropriate amine e.g. dimethylamine, pyridin-3-y
  • a compound of formula (I) wherein R 3 /R 4 contains an amino moiety may be converted into the corresponding compound wherein R 3 /R 4 is methylated on the amino moiety by treatment with formaldehyde and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a pyridinyloxymethyl moiety by treatment with the appropriate hydroxypyridine in the presence of a mixture of triphenylphosphine and diethyl azodicarboxylate.
  • R 3 /R 4 contains a benzo moiety substituted by a C 2-6 alkoxycarbonyloxy group, e.g.
  • tert-butoxycarbonyloxy may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by hydroxy under standard hydrolytic conditions, e.g. by treatment with trifluoroacetic acid.
  • R 3 /R 4 contains a halogen atom, e.g.
  • bromo may bo oonvortod into tho corresponding compound wherein R 3 ZR 4 contains hydroxy by treatment with sodium hydroxide in the presence of tris(dibenzylideneacetone)- dipalladium(O) and 2-(di-/er/-butylphosphino)-2',4',6'-triisopropyl-l,l '-biphenyl.
  • a compound of formula (I) wherein R 3 /R 4 contains hydroxy may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted Ci -6 alkoxy, C 3-7 heterocycloalkoxy or C 3-7 heterocycloalkyl(C 1-6 )alkoxy by treatment with the appropriately substituted C 1-6 alkyl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkyl(C 1-6 )- alkyl halide, e.g. bromide, ideally at an elevated temperature in the presence of cetyl- ammonium bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains hydroxy may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted pyridinyloxy, pyrimidinyloxy or pyrazinyloxy by treatment with the appropriately substituted pyridinyl, pyrimidinyl or pyrazinyl halide, e.g. fluoride or chloride, typically in the presence of a strong base such as sodium ter/-butoxide.
  • R 3 /R 4 contains a halogen atom e.g.
  • bromo may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted aryloxy or heteroaryloxy by treatment with an appropriately-substituted hydroxyaryl or hydroxyheteroaryl derivative and a base such as caesium carbonate, ideally in the presence of a copper(I) halide, e.g. copper(I) chloride or copper(I) bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino (-NH 2 ) group may be converted into the corresponding compound wherein R 3 ZR 4 contains 2,5-dioxopyrrolidin- 1-yl by treatment with succinic anhydride.
  • a compound of formula (I) wherein R 3 /R 4 contains an aryl or heteroaryl moiety substituted by a halogen atom, e.g. chloro, may have the halogen atom removed by catalytic hydrogenation.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety may be alkylated on the aromatic ring by treatment with n-butyllithium and an alkyl halide (e.g. iodopropane); or by treatment with an organozinc reagent (e.g. isopropylzinc bromide) in the presence of [1,1 '-bis(di-ter/-butylphosphino)ferrocene]palladium(II) dichloride and copper(I) iodide.
  • n-butyllithium and an alkyl halide e.g. iodopropane
  • an organozinc reagent e.g. isopropylzinc bromide
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by an optionally substituted alkynyl moiety (e.g. ?-hydroxyprop-t-yn-I-yi) by treatment with an appropriately-substituted alkyne derivative (e.g. 3-hydroxyprop-l-yne) and a catalyst such as tetfakis(triphenylph ⁇ sphifte)palladium(O), typically in the presence of copper(I) iodide and a base such as triethylamine.
  • a halogen atom e.g. chloro
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by acetyl by a two-stage procedure which comprises (i) treatment with butyl vinyl ether and palladium acetate, suitably in the presence of l,3-bis(diphenylphosphino)propane and an organic base such as triethylamine; and (ii) hydrolysis with a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by 1 -hydroxy- 1-methylethyl by treatment with n-butyllithium and acetone.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by C 1-6 alkylthio (e.g. isopropylthio) by treatment with n-butyllithium and the appropriate disulphide derivative (e.g isopropyl disulphide).
  • Conversion of the Ci -6 alkylthio moiety into C 1- ⁇ alkylsulphinyl or C 1-6 alkylsulphonyl may be accomplished by treatment with an oxidising agent, e.g. m-chloroperbenzoic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a pyridinyl moiety may be converted into the corresponding pyridine- ⁇ r -oxide analogue by treatment with peracetic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a formyl moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a vinyl moiety by treatment with methyltriphenylphosphonium bromide and a strong base such as sodium hexamethyldisilazide.
  • a compound of formula (I) wherein R 3 /R 4 contains a formyl moiety may be converted into the corresponding compound wherein R 3 /R contains a 1-hydroxyethyl moiety by treatment with methyllithium.
  • a compound of formula (I) wherein R 3 /R 4 contains a (2-hydroxyethyl)amino- carbonyl group may be converted into the corresponding compound wherein R 3 /R 4 contains an oxazolin-1-yl moiety by treatment with thionyl chloride.
  • a compound of formula (I) wherein R 3 /R contains an ester functionality may be converted into the corresponding compound wherein R 3 /R 4 contains an amide functionality (e.g. methylaminocarbonyl or dimethylaminocarbonyl) by treatment with an appropriately-substituted amine (e.g. methylamine or dimethylamine) in the presence of trimethylaluminium.
  • R 3 /R contains an ester functionality e.g. methoxycarbonyl
  • R 3 /R 4 contains an amide functionality (e.g. methylaminocarbonyl or dimethylaminocarbonyl) by treatment with an appropriately-substituted amine (e.g. methylamine or dimethylamine) in the presence of trimethylaluminium.
  • Alkenyl-containing compounds may be converted into the corresponding vie- dihydroxy analogues by treatment with osmium tetroxide.
  • Alkenyl- and alkynyl-containing compounds may be converted into the corresponding alkyl analogues by catalytic hydrogenation.
  • a compound of formula (I) wherein R 5 represents -CO 2 R b in which R b is other than hydrogen may be saponified and then decarboxylated to give the corresponding compounds in which R 5 represents -CO 2 H and hydrogen respectively by treatment with a base such as lithium hydroxide.
  • a base such as lithium hydroxide.
  • any compound of formula (I) wherein R 5 contains a lower alkyl ester moiety may be converted into the corresponding compound wherein R 5 contains a carboxy (-CO 2 H) group by treatment with a base such as lithium hydroxide or sodium hydroxide.
  • a compound of formula (I) wherein R 5 represents -CO 2 H may be converted into the corresponding compound wherein R 5 represents -CONR c R d by treatment with an amine of formula H-NR C R and a condensing agent such as EDC, typically in the presence of an organic base such as triethylamine.
  • any compound of formula (I) wherein R 5 contains a carboxy moiety may be converted into the corresponding compound wherein R 5 contains an amide moiety by treatment with the appropriate amine and a condensing agent such as EDC, typically in the presence of 1 - hydroxybenzotriazole (HOBT); alternative condensing agents include isobutyl chloroformate/triethylamine and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate.
  • EDC 1 - hydroxybenzotriazole
  • alternative condensing agents include isobutyl chloroformate/triethylamine and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate.
  • any compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound wherein R 5 contains an amide moiety by treatment with the appropriate carboxylic acid
  • a compound of formula (I) wherein R 5 represents cyano may be converted into the corresponding compound wherein R represents -CONH 2 by heating under acidic conditions, e.g; hr a mixture of acetic acid and sulphuric acid; prolonged treatment leads to conversion to the corresponding carboxylic acid followed by decarboxylation, i.e. umveisi ⁇ n into the c ⁇ ncsp ⁇ iiding compound whciciii R 5 iepiescnls liydi ⁇ gcn.
  • Any compound wherein R 5 contains a lower alkyl ester moiety e.g. tert- butoxycarbonyl, may be converted into the corresponding compound wherein R 5 contains a carboxy (-CO 2 H) group by treatment with trifluoroacetic acid.
  • a compound of formula (I) wherein R 5 contains a carboxy moiety may be converted into the corresponding compound containing an arylcarbonyl moiety (e.g. benzoyl) by a two-stage procedure which comprises (i) treatment with N,0-dimethyl- hydroxylamine hydrochloride and a condensing agent such as EDC, typically in the presence of HBTU; and (ii) reaction of the compound thereby obtained with the appropriate aryl lithium derivative, e.g. phenyllithium.
  • arylcarbonyl moiety e.g. benzoyl
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents fluoro by treatment with SelectfluorTM [i.e. l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafiuoroborate)].
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents chloro, bromo or iodo by treatment with iV-chlorosuccinimide, JV-bromosuccinimide or N-iodosuccinimide respectively.
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents dimethylaminomethyl by treatment with Eschenmoser's salt (i.e. N,N-dimethylmethyleneammonium iodide).
  • Eschenmoser's salt i.e. N,N-dimethylmethyleneammonium iodide
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo or chloro, may be converted into the corresponding compound wherein R 5 represents -CO 2 R 15 by treatment with carbon monoxide and an alcohol of formula R b -OH, in the presence of a catalyst.
  • a catalyst may typically be a transition mot ⁇ l catalyst.
  • ⁇ 3uitablo oataly3t is [l,l'-bia(diphonylphoaphino)fcrrocenc]dichloro- palladium(II)-dichloromethane complex, in which case the transformation may conveniently be effected at an elevated temperature and pressure in the presence of an organic base such as triethylamine.
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. bromo or iodo, may be converted into the corresponding compound wherein R 5 represents aryl, biaryl, C 3-7 heterocycloalkyl-aryl, C 3-7 heterocycloalky ⁇ C ⁇ alkyl-aryl, heteroaryl or heteroaryl-aryl by treatment with, respectively, an aryl, biaryl, C 3 , 7 heterocycloalkyl-aryl, C 3-7 heterocycloalkyI(C 1-6 )alkyl-aryl, heteroaryl or heteroaryl-aryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g.
  • a compound of formula (I) wherein R 5 represents aryl, substituted on the aryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 5 represents biaryl or heteroaryl-aryl by treatment with, respectively, an aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst.
  • a compound of formula (I) wherein R 5 represents heteroaryl, substituted on the heteroaryl moiety by a halogen atom such as chloro or bromo may be converted into the corresponding compound wherein R 5 represents aryl-heteroaryl or bi(heteroaryl) by treatment with, respectively, an aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol or N-phenyldiethanolamine, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate, potassium hydroxide or potassium phosphate, in an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane.
  • a base such as sodium carbonate, potassium carbonate, potassium hydroxide or potassium phosphate
  • an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane.
  • the catalyst may be palladium(II) acetate, in which case the transformation may conveniently be effected at an elevated temperature in the presence of l,3-bis(diphenylphosphino)propane and potassium phosphate, or in the presence of PdCl 2 .dppf and potassium phosphate, hi general, any compound of formula (I) wherein R 5 represents or contains a halogen atom, e.g. bromo or iodo, may be converted by means of the foregoing procedure into the corresponding compound wherein the halogen atom is replaced by a substituted or unsubstituted aryl, heteroaryl or alkenyl group.
  • a halogen atom e.g. bromo or iodo
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo, may be converted Into IKe corresponding compound wherein R 5 represents aryl(Ci. 6 )alkyl, e.g. benzyl, by treatment with a suitable organozinc reagent, in the presence of a catalyst.
  • the organozinc reagent may conveniently be prepared by reacting the appropriate aryl(C I-6 )- alkyl halide, e.g. benzyl bromide, with zinc dust.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is dichlorobis(triphenylphosphine)- palladium(II), in which case the transformation may conveniently be effected at an elevated temperature in the presence of an inert solvent such as tetrahydrofuran.
  • a compound of formula (I) wherein R 5 contains a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein the halogen atom is replaced by an arylamino or heteroarylamino moiety, e.g. phenylamino, by treatment with the appropriate amine, e.g. aniline, and a transition metal catalyst, e.g. palladium acetate, typically in the presence of tributylphosphine tetrafluoroborate and a base such as sodium tert-butoxide.
  • R 5 represents a halogen atom, e.g.
  • R 5 represents C 2-6 alkynyl, C 3-7 cycloalkyl(C 2-6 )alkynyl, aryl(C 2 - 6 )alkynyl, C 3-7 heterocycloalkyl(C 2 - 6 )alkynyl, C 5-9 heterobicycloalkyl(C 2-6 )alkynyl or heteroaryl(C 2-6 )alkynyl by treatment with, respectively, a suitable C 2- 6 alkyne, C 3-7 cycloalkyl(C 2-6 )alkyne, aryl(C 2-6 )alkyne, C 3-7 heterocycloalkyl- (C 2-6 )aIkyne, C 5-9 heterobicycloalkyl(C 2 - 6 )alkyne or heteroaryl(C 2 - 6 )alkyne, in the presence of a catalyst.
  • a compound of formula (I) wherein R 5 represents C 2-6 alkynyl, e.g. ethynyl may be converted into the corresponding compound wherein R 5 represents aryl(C 2 -6)alkynyl, heteroaryl(C 2 - 6 )alkynyl or C 3-7 cycloalkyl-heteroaryl(C 2 - 6 )alkynyl by treatment with, respectively, a suitable aryl, heteroaryl or C 3-7 cycloalkyl-heteroaryl iodide, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is dichlorobis(triphenylphosphine)palladium(II), in which case the transformation may conveniently be effected at an elevated temperature in the presence of copper(I) iodide and an organic base such as diisopropylamine.
  • a compound of formula (I) wherein R 5 represents arylethynyl, e.g. phenylethynyl, may be converted into the corresponding compound wherein R 5 represents arylethyl, e.g. 2-phenylethyl, by catalytic hydrogenation. Indeed, this procedure is generally applicable for converting any compound of formula (I) wherein R 5 contains a -C ⁇ C- moiety into the corresponding compound containing a -CH 2 CH 2 - moiety.
  • a suitable hydrogenation catalyst is palladium on carbon, in which case the conversion can conveniently be accomplished at an elevated temperature in a suitable solvent, e.g.
  • a compound of formula (I) wherein R 5 contains a -C ⁇ C- moiety may be converted into the corresponding compound containing a -COCO- moiety by treatment with a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 5 represents nitro may be converted into the corresponding compound wherein R 5 represents amino by catalytic hydrogenation, which typically comprises reacting the nitro compound with hydrogen in the presence of a catalyst such as palladium on charcoal.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a -OCH 2 - moiety by treatment with the appropriate alkyl halide, typically in the presence of a base such as potassium carbonate.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a -OSO 2 - moiety by treatment with the appropriate sulphonyl halide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a trifluoromethylsulphonyloxy moiety by treatment with iV-phenyltrifluoromethanesulphonimide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a methylsulphonyloxymethyl moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a halomethyl (e.g. chloromethyl) moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative (including cyclic amines), typically in the presence of a base such as potassium carbonate.
  • a compound of formula (I) wherein R 5 contains a hydroxymethyl moiety may be converted " into the corresponding compound containing an aminomethyi moiety by treatment with the appropriate amine derivative (including cyclic amines), generally in the presence of triphenylphosphine and diethyl azodicarboxylate.
  • a compound of formula (I) wherein R 5 contains a trifluoromethylsulphonyloxy moiety may be converted into the corresponding compound wherein the trifluoromethyl- sulphonyloxy moiety is replaced by an amino functionality by treatment with the appropriate amine derivative (including cyclic amines) and a transition metal catalyst, e.g. acetato(2'-di-tert-butylphosphino-l,r-biphenyl-2-yl)palladium(II), typically at an elevated temperature in the presence of a base such as potassium tert-butoxide.
  • a transition metal catalyst e.g. acetato(2'-di-tert-butylphosphino-l,r-biphenyl-2-yl)palladium(II
  • a compound of formula (I) wherein R 5 contains an amino moiety may be alkylated by treatment with the appropriate alkyl halide (e.g. methyl iodide, ethyl bromide, benzyl bromide or tert-butyl bromoacetate), typically in the presence of a base such as sodium hydride or triethylamine.
  • alkyl halide e.g. methyl iodide, ethyl bromide, benzyl bromide or tert-butyl bromoacetate
  • a base such as sodium hydride or triethylamine.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a -NCH 2 - motif by a reductive amination procedure which comprises treatment with the appropriate aldehyde derivative in the presence of a base such as sodium triacetoxyborohydride.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a carbonylamino moiety by treatment with the appropriate carbonyl halide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a urea functionality by treatment with the appropriate isocyanate derivative.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a urea functionality by a two-stage procedure which comprises (i) treatment with triphosgene, typically in the presence of a base such as triethylamine; and (ii) reaction of the compound thereby obtained with the appropriate amine derivative (including cyclic amines).
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a sulphonylamino moiety by treatment with the appropriate sulphonyl halide, typically in the presence of a base such as triethylamine.
  • a compound wherein R contains an amino moiety may be converted into the corresponding compound containing a bromo moiety by diazotization/bromination, which entails treatment with sodium nitrite and copper(I) bromide in the presence of HBr.
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo, may be converted into the corresponding compound wherein R 5 represents acetyl by a two- stage procedure which comprises (i) reaction with butyl vinyl ether and a transition metal catalyst such as tris(dibcnzylidcncaccto ⁇ c)dipalIadium(0), typically in the presence of 1,3- bis(diphenylphosphino)propane and a base such as potassium carbonate; and (ii) hydrolysis of the resulting compound by treatment with a mineral acid, e.g. hydrochloric acid.
  • a transition metal catalyst such as tris(dibcnzylidcncaccto ⁇ c)dipalIadium(0), typically in the presence of 1,3- bis(diphenylphosphino)propane and a base such as potassium carbonate
  • a compound of formula (I) wherein R 5 represents acetyl may be converted into the corresponding compound wherein R 5 represents 3-(dimethylamino)-l-oxoprop-2-en-l-yl by treatment with i ⁇ V-dimethylformamide dimethyl acetal, typically at an elevated temperature.
  • a compound of formula (I) wherein R 5 represents 3-(dimethylamino)-l- oxoprop-2-en-l-yl may be converted into the corresponding compound wherein R 5 represents a substituted or unsubstituted pyrimidinyl moiety by treatment with the appropriate amidine derivative, typically at an elevated temperature in the presence of a base such as sodium ethoxide.
  • a compound wherein R 5 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by morpholin-4-yl by treatment with morpholine and tris(dibenzylideneacetone)dipalladium(0) in the presence of 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP) and a strong base such as sodium tert-butoxide.
  • a halogen atom e.g. bromo
  • BINAP 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl
  • a compound wherein R 5 contains a formyl moiety may be converted into the corresponding compound wherein R 5 contains a (cyclopropyl)(hydroxy)methyl moiety by treatment with cyclopropylmagnesium bromide.
  • the resulting (cyclopropyl)(hydroxy)- methyl derivative may be converted into the corresponding compound wherein R 5 contains a cyclopropylcarbonyl moiety by treatment with an oxidising agent such as Dess-Martin periodinane.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
  • the compounds in accordance with this invention potently inhibit the activity of human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ .
  • the compounds of the accompanying Examples were all found to possess IC 50 values for inhibition of activity of human PBK ⁇ and/or PDK ⁇ and/or PDK ⁇ and/or PBK ⁇ of 50 ⁇ M or better.
  • Method 1 Luna Cl 8(2) 100 x 4.6 mm, 5 ⁇ m column.
  • Mobile phase A 99.92% water, 0.08% formic acid.
  • Mobile phase B 99.92% MeCN, 0.08% formic acid.
  • Gradient program (flow rate 3.0 mL/min, column temperature 35°C): Time A% B% 0.00 95.0 5.0 4.40 5.0 95.0 5.30 5.0 95.0
  • Method 2 Luna Cl 8(2) 100 x 4.6 mm, 5 ⁇ m column.
  • Mobile phase A 5mM NH 4 OAc, pH 5.8.
  • Mobile phase B 95:5 MeCNrIOOmM NH 4 OAc, pH 5.8.
  • Method 3 Gemini Cl 8 50 x 4.6 mm, 5 ⁇ m column.
  • Mobile phase A 99.9% 1OmM ammonium formate, 0.1% formic acid.
  • Mobile phase B 94.9% MeCN, 0.1% formic acid, 5% mobile phase A.
  • Method 4 Gemini Cl 8 50 x 4.6 mm, 5 ⁇ m column.
  • Mobile phase A 99.9% 1 OmM ammonium formate, 0.1% ammonia.
  • Mobile phase B 94.9% MeCN, 0.1% ammonia, 5% mobile phase A.
  • Method 6 Phenomenex Luna Cl 8(2) 250 x 21.2 mm, 5 ⁇ m column.
  • Mobile phase A 99.92% water, 0.08% formic acid.
  • Mobile phase B 99.92% MeCN, 0.08% formic acid.
  • Gradient program (flow rate 25.0 mL/min), column temperature: ambient, variable gradient.
  • Melh ⁇ d 7 Plieiiomeiiex Lima C18(2) 250 x 21.2 mm, 5 ⁇ in c ⁇ luimi.
  • Mobile phase A 10 mM ammonium acetate in water.
  • Mobile Phase B 10 mM ammonium acetate in MeCN.
  • Gradient program flow rate 25.0 mL/min
  • column temperature ambient, variable gradient.
  • IPA isopropyl alcohol
  • TFA trifluoroacetic acid
  • m multiplet
  • THF tetrahydrofuran
  • BINAP 2,2 '-bis(diphenylphosphino)- 1 , 1 '-binaphthyl brine: saturated aqueous sodium chloride solution
  • DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- ⁇ yrimidone
  • EDC l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
  • HBTU O-( lH-benzotriazol- 1 -yO-N.N.iV'.N-tetramethyluronium hexafluorophosphate .
  • LCMS Liquid Chromatography Mass Spectrometry TBAB: tetfabutylammonium bromide
  • Triethylamine (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL).
  • the reaction was cooled in ice and chloroacetyl chloride (1.12 mL, 14 mmol) added portionwise. It was stirred with cooling for 10 minutes then allowed to warm to r.t. and stirred for a further 2 h.
  • the reaction mixture was cooled in ice and sodium hydride (1.05 g of a 60% suspension in oil, 26 mmol) was added portionwise. The mixture was stirred with ice-bath cooling for 20 minutes then at r.t.
  • Triethylamine (0.72 mL, 5.1 mmol) was added to 3,4-dihydro-2H- benzo[l,4]oxazin-6-ol hydrobromide (0.4 g, 1.7 mmol) in THF (25 mL).
  • the reaction mixture was stirred for 5 minutes before addition of di-tert-butyl dicarbonate (0.75 g, 3.4 mmol) and DMAP (20 mg, 0.16 mmol), and then stirred for 3 h before being concentrated in vacuo.
  • the residue was partitioned between DCM (10O mL) and water (10O mL).
  • the resulting residue was dissolved in a mixture of DCM (45 mL) and methanol (5 mL), and filtered through celite. The organic fraction was washed with water (50 mL) and and concentrated in vacuo. The resulting material was dissolved in THF (50 mL). 4N HCl (20 mL) was added, and the mixture heated to reflux for 16 h. After cooling to r.t. the precipitate was removed by filtration, washed with THF and dried in vacuo. The resulting solid was dissolved in a hot mixture of methanol (250 mL) and DCM (250 mL). Activated charcoal (1 g) was added, and the mixture stirred for 10 minutes. It was filtered hot through celite.
  • Example 4 7-Hvdroxy-6.6-dimethyl-2-r6-(4,4,5,5-tetramethyl-
  • a mixture of Example 4 500 mg, 1.22 mmol), potassium acetate (180 mg, 1.83 niiiiol), bis(pinacolato)diboron (464 mg, 1.83 mmol) and l,2'-[bis(diphenylphosphino)- ferrocene]dichloropalladium(II) dichloromethane complex (200 mg, 0.24 mmol) in THF (10 mL) was heated to reflux overnight.
  • the organic fraction was extracted with aqueous 2M HCl (2 x 150 mL). The combined acidic aqueous fractions were then basified to pH 14 (by addition of solid NaOH) and were re-extracted with EtOAc (2 x 150 mL). The combined organic fractions were washed with brine (150 mL), dried (MgSO 4 ), filtered and concentrated in vacuo to give the title compound (13.5 g, 87%) as a clear oil.
  • Pentafluorophenyl 3- (
  • Example 1 was separated into its enantiomefs by chiral HPLC using a Chiralpak column eluted with isopropanol:heptane:diethylamine 50:50:0.5. Enantiomer A: RT 8.02 minutes. Enantiomer B: RT 9.92 minutes.
  • Example 4 Using Example 4 (150 mg, 0.37 mmol), Intermediate 51 (129 mg, 0.54 mmol), potassium phosphate tribasic (155 mg, 0.73 mmol) and tetrakis(triphenylphosphine)- palladium(O) (21 mg, 0.018 mmol) in T ⁇ F (3 mL) and water (1 mL) heated to 12O 0 C under microwave irradiation for 1 h. Purification by preparative ⁇ PLC ⁇ Method 6) followed by trituration with heptane and ether gave the title compound (62 mg, 38%) as a pale yellow solid.
  • Example 4 A mixture of Example 4 (135 mg, 0.33 mmol), 2-methyl-5-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)pyridine (87 mg, 0.40 mmol), bis(dibenzylideneacetone)- palladium(O) (19 mg, 0.03 mmol), tricyclohexylphosphine (9 mg, 0.03 mmol) and cesium carbonate (322 mg, 0.99 mmol) in THF (3 mL) and water (1 mL) was heated to 12O 0 C under microwave irradiation for 20 minutes. After cooling to r.t. it was partitioned between water and DCM.
  • Example I A mixture of Example I (140 mg, 0.34 mmol) and Dess-Martin periodinane reagent (173 mg, 4.09 mmol) in DCM (15 mL) was stirred overnight at r.t. An aqueous solution of 10% sodium thiosulfate (15 mL) was added, and stirring continued for a further 15 minutes. The reaction mixture was partitioned between DCM and 10% aqueous sodium thiosulfate (50 mL each). The organic fraction was washed with saturated aqueous NaHCO 3 followed by brine (50 mL each), dried (MgSO 4 ) and concentrated in vacuo.
  • N-Chlorosuccinirnide (12 mg, 0.09 mmol) was added to a suspension of Intermediate 60 (40 mg, 0.08 mmol) in MeCN (5 mL). The reaction was stirred at 80 0 C for 100 minutes, then cooled to r.t. Water (5 mL) was then added and the reaction mixture heated at 100 0 C for 1 h, then left to stand at r.t overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC (Method 6) to give the title compound (15 mg, 36%) as a beige solid.
  • Example 30 and was obtained as a yellow solid (44%) after purification by preparative ⁇ PLC (Method 6).
  • ⁇ ⁇ (CD 3 OD) 8.78 (dd, J 5.1, 0.6 Hz, IH), 8.18 (s, IH), 8.01 (dd, J7.3,
  • N-Chlorosuccinimide (6.5 mg, 0.05 mmol) was added to a solution of Intermediate 64 (23 mg, 0.04 mmol) in MeCN (5 mL). The reaction mixture was stirred at 80 0 C for 5 h, then cooled to r.t.. Water (5 mL) was then added, and the reaction mixture was heated at 100 0 C for 2.5 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Method 6) to give the title compound (7 mg, 30%) as a white solid.
  • Tris(dibenzylidene- acetone)dipalladium(0) (28 mg, 0.03 mmol) was added; the mixture was degassed for a further 5 minutes and then heated at 120 0 C under microwave irradiation for 2 h. The solvent was removed in vacuo and the residue purified by column chromatography (SiO 2 , 0-10% MeOH in DCM) to give an orange solid.
  • iV-chlorosuccinimide 15 mg, 0.11 rnmol
  • Water (10 mL) was then added and the reaction mixture heated at 100 0 C overnight.
  • Example 37 3- ⁇ 4-[4-Amino-5,5-dimethyl-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydro- 1 -benzothien-3-yl]pyridin-2-yl ⁇ -N ⁇ AZ-dimethylbenzamide
  • Example 38 3-[2'-Fluoro-5'-(moipholin-4-ylcarbonyl)biphenyl-3-yl]-4-hydroxy-5,5- dimethyl-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one
  • Example 39 3- ⁇ 2-[2-Fluoro-5-(pyrrolidin-l-ylcarbonyl)phenyl]pyridin-4-yl ⁇ -4- hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one
  • Example 40 3- ⁇ 4-[(45)-4- ⁇ ydroxy-5,5-dimethyl-2-(morpholin-4-yl)-7-oxo-4,5,6,7- tetrahydro- 1 -benzothien-3-yl]pyridin-2-yl ⁇ -iV ⁇ V
  • Example 52 (4/?)-3- ⁇ 2-[2-Fluoro-5-(pyrrolidin-l-ylcarbonyl)phenyl]pyridin-4-yl ⁇ -4- hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one
  • Example 53 (45)-3- ⁇ 2-[2-Fluoro-5-(py- ⁇ olidin-l-ylcarbonyl)phenyl]pyridin-4-yl ⁇ -4- hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one
  • Example 54 (4.S)-4-Amino-5,5-dimethyl-2-(morpholin-4-yl)-3- ⁇ 2-[3-(morpholin-4- yl)phenyl]pyridin-4-yl ⁇ -5 ,6-dihydro- 1 -benz
  • Example 58 (4 ⁇ )-4- ⁇ ydroxy-5,5-dimethyl-2-(morpholin-4-yl)-3- ⁇ 2-[3-(morpholin-4- yl)phenyl]pyridin-4-yl ⁇ -5,6-dihydro- 1 -benzothiophen-7(4H)-one
  • Example 59 (45)-4- ⁇ ydroxy-5,5-dimethyl-2-(morpholin-4-yl)-3- ⁇ 2-[3-(mo ⁇ holin-4- yl)phenyl]pyridin-4-yl ⁇ -5,6-dihydro-l-benzothiophen-7(4H)-one

Abstract

A series of fused bicyclic thiazole and thiophene derivatives which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, and in the 4-position by hydroxy, oxo or an amine moiety, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions. (I)

Description

FUSED THIAZOLE AND THIOPHENE DERIVATIVES AS KINASE
INHIBITORS
The present invention relates to a class of fused thiazole and thiophene derivatives, and to their use in therapy. More particularly, the invention provides a family of fused bicylic thiazole and thiophene derivatives which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, and in the 4-position by hydroxy, oxo or an amine moiety. These compounds are selective inhibitors of phosphoinositide 3 -kinase (PI3K) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
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. Thus, PBKs provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sd., 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, being potent and selective PI3K inhibitors, are therefore beneficial in the treatment and/or prevention of various human ailments. These include 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. during heart failure); 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).
In addition, 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. Thus, the compounds of this invention may be useful as radioligands in assays for detecting compounds capable of binding to human PDK enzymes.
Various fused thiazole derivatives are disclosed in Liebigs Annalen der Chemie, 1986, 780-784; and in Russian Journal of General Chemistry (translation of Zhurnal Obshchei Khimii), 2000, 70[5], 784-787. However, none of the compounds disclosed in either of those publications corresponds to a compound of the present invention; and no therapeutic utility is ascribed to any of the compounds disclosed therein.
WO 2006/114606 describes a class of fused bicyclic thiazole derivatives which are selective inhibitors of PI3 kinase enzymes and are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions. A related series of compounds is described in copending international patent application no. PCT/GB2007/002390, published on 3 January 2008 as WO 2008/001076.
Copending international patent application no. PCT/GB2007/002051, published on 13 December 2007 as WO 2007/ 141504, describes a class of fused bicyclic thiophene derivatives which are selective inhibitors of PI3 kinase enzymes and are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions. The compounds in accordance with the present invention are potent and selective
PI3K inhibitors having a binding affinity (IC50) for the human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ isoform of 50 μM or less, generally of 20 μM or less, usually of 5 μM or less, typically of 1 μM orless, 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 IC50 figure denotes a more active compound). The compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50- fold selective affinity, and ideally at least a 100-fold selective affinity, for the human PBKα and/or PBKβ and/or PI3Kγ and/or PBKδ isoform relative to other human kinases. The compounds of the present invention possess interesting pharmacokinetic properties owing to their improved solubility and clearance.
The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000004_0001
(I)
wherein
U represents N or C-R5; -X- represents a group of formula (a), (b), (c), (d), (e), (f) or (g):
Figure imgf000004_0002
(a) (b) (C) (d)
Figure imgf000004_0003
(e) (f) (g)
Y represents oxygen or sulphur; R1 and R2 independently represent hydrogen; or Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci.6)alkyl, aryl, aryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl- (C1-6)alkyl, heteroaryl or heteroary^Ct^alkyl, any of which groups may be optionally substituted by one or more substituents; or
R1 and R2, when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or R1 and R2, when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, Cs-i cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; R3 and R4 independently represent hydrogen; or Ci-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, ary^C^alkyl, aryl(C2-6)alkenyl, 3TyI(C2-6)- alkynyl, biaryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalky^Ct^alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R3 and R4, when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or R3 and R4, when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
R5 represents hydrogen, halogen, cyano, -SR\ -CORe, -CO2Rb, -CONRcRd or -C(=N-ORf)Re; or R5 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkenylcarbonyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, C3-7 cycloalkyl(C2-6)alkenyl, C3-7 cycloalkyl- (C2-6)alkynyl, aryl, 8TyI(C1 -6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, biaryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkyl(C2-6)alkenyl, C3-7 heterocycloalkyl(C2,6)alkynyl, C3-7 heterocycloalkylcarbonyl(C2-6)alkynyl, C5-9 heterobicycloalkyl(C2-6)alkynyl, C3^7 heterocycloalkyl-aryl, C3-7 heterocycloalkyl(Ci-6)- alkyl-aryl, C3-7 heterocycloalkyl-biaryl, C3-7 heterocycloalkylcarbonyl-biaryl, heteroaryl, heteroaryl(Ci-6)alkyl, heteroaryl(Ci-6)alkylcarbonyl, heteroaryl(C2-6)alkenyl, heteroaryl(C2-6)alkynyl, heteroaroylcarbonyl, C3-7 heterocycloalkyl-heteroaryl, C3-7 heterocycloalkyl-heteroaryl(C2-6)alkynyl, heteroaryl-aryl,
Figure imgf000005_0001
aryl-heteroaryl, aryl-heteroaryl(C1-6)alkyl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 heterocycloalky^Ci^alkyl-aryl-heteroaryl, C5-9 heterobicycloalkyl(Ci-6)alkyl-aryl- heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl- bi(heteroaryl), aryløxyaryl, aryl(Cι-(s)alkoxyaryl, heteroaryl(Cf.6)alkoxyaryl, aryl(Ci.6)alkylaminoaryl, heteroaryl(Ci.6)alkylaminoaryl, C3-7 cycloalkyl- carbonylaminoaryl, arylcarbonylaminoaryl, aryl(Ci.6)alkylcarbonylaminoaryl, C3.7 heterocycloalkylcarbonylaminoaryl, heteroarylcarbonylaminoaryl, aryl- (C3-7)heterocycloalkylcarbonylaminoaryl, arylsulphonylaminoaryl, aryl(Ci-6)alkyl- sulphonylaminoaryl, heteroaryl(Ci-6)alkylsulphonylaminoaryl, C3-7 cycloalkylamino- carbonylaminoaryl, arylaminocarbonylaminoaryl, C3-7 heterocycloalkylaminocarbonyl- aminoaryl, C3-7 heterocycloalkylaminocarbonylaminoaryl, heteroaryl(Ci-6)alkyl- aminocarbonylaminoaryl, C3-7 heterocycloalkylcarbonylcarbonylaminoaryl, C3-7 heterocycloalkyl(C1-6)alkylaminocarbonylcarbonylaminoaryl, arylcarbonylaryl, C3-7 heterocycloalkylcarbonylaryl, C3-7 heterocycloalkylcarbonyl(Ci-6)alkylaryl, aryl(C1-6)- alkylaminocarbonylaryl, C3-7 heterocycloalkyl(Ci-6)alkylaminocarbonylaryl, heteroaryl- aminocarbonylaryl, heteroaryl(Ci-6)alkylaminocarbonylaryl, C3-7 heterocycloalkylamino- carbonyl(C 1 -6)alkylaryl, C3-7 heterocycloalkyl(C 1.6)alkylaminocarbonyl(C 1 -6)alkylaryl, heteroarylaminocarbonyl(Ci-6)alkylaryl, heteroaryl(C1-6)alkylaminocarbonyl(C1-6)alkyl- aryl, arylaminoheteroaryl, C3-7 heterocycloalkylamino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonylamino-aryl-heteroaryl, C3-7 heterocycloalkylaminocarbonyl- amino-aryl-heteroaryl, C3-7 cycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- carbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(C1-6)alkylcarbonyl-aryl-heteroaryl, C5-9 heterobicycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl(C1-6)alkyl-aryl- heteroaryl, C3-7 heterocycloalkyl-aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- (Ci^alkylaminocarbonyl-aryl-heteroaryl or C3-7 heterocycloalkylaminocarbonyl(Ci-6)- alkyl-aryl-heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Ra represents Cj-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Rb represents hydrogen; or optionally substituted Ci-6 alkyl;
Rc represents hydrogen; or Ci-6 alkyl, aryl, aryl(Ci-6)alkyl, heteroaryl, heteroaryl(Ci-6)alkyl or
Figure imgf000006_0001
any of which groups may be optionally substituted by one or more substituents; Rd represents hydrogen or C1-6 alkyl;
Re represents Cj-6 alkyl;
R represents C1-6 alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C|-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R6 and R7 independently represent hydrogen or Cj-6 alkyl;
R8 represents hydroxy, oxo or -NRεRh; and
Rε and Rh independently represent hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
The present invention also provides a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt or solvate thereof, wherein
U represents N;
-X- represents a group of formula (a) or (b) as depicted above; R1 and R2 are both attached to the carbon atom between the moiety X and the moiety C(H)R8; and
R1 and R2 independently represent hydrogen; or Ci-6 alkyl, C3-7 cycloalkyl, C3-7
Figure imgf000007_0001
aryl, aryl(Ci.6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl- (C1-6)alkyl, heteroaryl or
Figure imgf000007_0002
any of which groups may be optionally substituted by one or more substituents; or
R1 and R2, when taken together with the carbon atom to which they are both attached, represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; and
R3, R4 and R8 are as defined above. The present invention also provides a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt or solvate thereof, wherein
U represents C-R5; and
-X-, R1, R2, R3, R4, R5 and R8 are as defined above.
Where 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 substituents. Suitably, such groups will be unsubstituted or monosubstituted.
For use in medicine, 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. Furthermore, where the compounds of the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, 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 C1-6 alkyl groups, for example C1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, .sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci-6 alkoxy", "Ci-6 alkylthio", "Ci-6 alkylsulphonyl" and "Ci-6 alkylamino" are to be construed accordingly.
Typical C2-6 alkenyl groups include vinyl and allyl.
Typical C2-6 alkynyl groups include ethynyl, prop-1-yn-l-yl, prop-2-yn-l-yl, but-1- yn-l-yl and 3-methylbut-l-yn-l-yl. A specific C2-6 alkynyl group is prop-2-yn-l-yl.
Specific C3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
Suitable aryl(Ci-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Specific aryl(C2-6)alkenyl groups include 2-phenylethenyl and 3-phenylprop-2-en- 1-yl.
Typical aryl(C2-6)alkynyl groups include phenylethynyl, 3-phenylproρ-l-yn-l-yl and 3-phenylprop-2-yn-l-yl. A specific aryl(C2-6)alkynyl group is 3-phenylprop-2-yn-l- Particular biaryl groups include biphenyl and naphthylphenyl.
Suitable heterocycloalkyl groups, which may comprise benzo-fυsed analogies thereof, include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomoφholinyl.
Typical heterobicycloalkyl groups include quinuclidinyl, 8-azabicyclo[3.2.1]octyl and 3,8-diazabicyclo[3.2.1]octyl.
Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazof 1 ,2-α]pyridinyl, imidazo[4,5-6]pyridinyl, imidazo[ 1 ,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl, quinoxalinyl and chromenyl groups.
Typical bi(heteroaryl) groups include benzofuryl-pyridinyl, benzothienyl-pyridinyl, indolyl-pyridinyl, isoxazolyl-pyridinyl, bipyridinyl and isoquinolinyl-pyridinyl.
The term "halogen" as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.
Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (I) may exist as tautomers, for example keto (CH2C=O)<→enol (CH=CHOH) tautomers or amide (NHC=O)<→hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. In one embodiment of the present invention, U represents N. In accordance with one aspect of that embodiment, the present invention provides a compound offprrnula (A)5 or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000010_0001
(A)
wherein
V represents a group of formula CH2 or N-R6; and Y, R1, R2, R3, R4, R6 and R8 are as defined above. Specific sub-classes of compounds of formula (A) above are represented by the compounds of formula (IA-A), (IB-A), (IC-A) and (ID-A):
Figure imgf000010_0002
Figure imgf000011_0001
wherein R1, R2, R3, R4, R6 and R8 are as defined above.
Particular sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA-A) and (IC-A) as depicted above. hi another embodiment of the present invention, U represents C-R5. hi accordance with that embodiment, the present invention provides a compound of formula (B), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0002
(B)
wherein
-X-, R1, R2, R3, R4, R5 and R8 are as defined above.
Specific sub-classes of compounds of formula (B) above are represented by the compounds of formula (IA-B), (IB-B), (IC-B), (ID-B), (IE-B), (LF-B) and (IG-B):
(IA-B)
Figure imgf000011_0003
Figure imgf000012_0001
wherein Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above. Particular sub-classes of compounds in accordance with the present invention are represented by Qie compounds υf formula (IA-B), (IB-B) and (IC-B) as depicted above, especially (IA-B) and (IB-B).
In the compounds of formula (I), -X- suitably represents a group of formula (a), (b) or (c) as depicted above, especially (a) or (b). In one embodiment, -X- represents a group of formula (a). In another embodiment, -X- represents a group of formula (b). In a further embodiment, -X- represents a group of formula (c). hi a preferred embodiment, Y represents oxygen, hi another embodiment, Y represents sulphur. In one embodiment, V represents CH2. hi another embodiment, V represents N-R6.
Suitably, R1 represents hydrogen or C]-6 alkyl. Typical values of R1 include hydrogen, methyl and ethyl, hi one embodiment, R1 is hydrogen. In another embodiment, R1 is Ci-6 alkyl. In one aspect of that embodiment, R1 is methyl. In another aspect of that embodiment, R1 is ethyl. Suitably, R2 represents hydrogen; or C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents.
Examples of typical substituents on R1 and/or R2 include halogen, cyano, nitro, C1^ alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C1-6 alkylthio, Ci-6 alkylsulphonyl, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulphonyl, C1-6 alkylaminosulphonyl and di(Ci_6)alkylaminosulphonyl; especially halogen, C1-6 alkoxy or C1-6 alkylthio.
Examples of particular substituents on R1 and/or R2 include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
Typical values of R2 include hydrogen, methyl, ethoxy, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl. A particular value of R2 is methyl. Alternatively, R and R , when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage. Thus, R l and R2, when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substiruents. hi this context, R1 and R2, when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl.
Alternatively, R1 and R2, when attached to adjacent carbon atoms, may together form an optionally benzo-fiised and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the ring containing the variable X. Thus, R and R , when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substiruents. hi this context, in one embodiment, R1 and R2, when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the ring containing the variable X. Also in this context, in another embodiment, R1 and R2, when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e. an indanyl moiety fused to the ring containing the variable X.
Typically, R3 represents hydrogen; or Ci-6 alkyl, aryl, aryl(Ci.6)alkyl, aryl- (C2-6)alkynyl, biaryl(C1-6)alkyl, C3-7 heterocycloalky^C^alkyl, C3-7 heterocycloalkyl- carbonyl, heteroaryl(C1-6)alkyl, heteroaryl-aryl(C1-6)alkyl or aryl-heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substiruents. Generally, R3 represents hydrogen; or C2-6 alkynyl, 8TyI(C1.6)alkyl or heteroaryl-
(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substiruents. More particularly, R3 represents aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, either of which groups may be optionally substituted by one or more substiruents. In one specific embodiment, R3 represents hydrogen. In a representative embodiment, R3 represents Cj-6 alkyl, aryl(Ci -6)alkyl, biaryl-
(Ci-6)alkyl, heteroaryl(C1-6)alkyl or heteroaryl-aryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substiruents. Preferably, R3 represents methyl, aryhnethyl, biarylmethyl, heteroaryhnethyl or heteroaryl-arylmethyi, any of which groups may be optionally substituted by one or more substituents. More particularly, R3 represents αrylmcthyl or hctcroαrylmothyl, oithor of which groups may be optionally substituted by one or more substituents.
In a particular embodiment, R3 represents substituted or unsubstituted indolyl- (Ci-6)alkyl. Advantageously, R3 represents substituted or unsubstituted indolylmethyl.
In a typical embodiment, R3 represents substituted or unsubstituted phenyl- (C1-6)alkyl. Advantageously, R3 represents substituted or unsubstituted benzyl.
In another embodiment, R3 represents substituted or unsubstituted benzofuryl- (C1-6)alkyl. Advantageously, R3 represents substituted or unsubstituted benzofurylmethyl. Illustratively, R3 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1 ,2,3,4-tetrahydroquinolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1,2,3,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-ό]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazolyhnethyl, pyridinylmethyl, quinolinylmethyl, isoquinolinylmethyl, benzofurylbenzyl, thienylbenzyl, benzothienylbenzyl, indolylbenzyl, isoxazolylbenzyl, pyrazolylbenzyl, pyridinylbenzyl, pyrimidinylbenzyl or phenylpyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.
Suitably, R4 represents hydrogen or optionally substituted Ci-6 alkyl. Examples of typical substituents on R3 and/or R4 include halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, C2-6 alkenyl, C3-7 cycloalkyl, (C1-6)alkylaryl, di(Ci-6)alkylaryl, piperidinyl(C i ^alkylaryl, piperazinyl(C \ ^alkylaryl, (C j -6)alkylpiperazinyl(C i -6)-
Figure imgf000015_0001
(C1-6)alkoxyaryl, cyano(C1-6)alkoxyaryl, di(Ci-6)- alkylamino(C1-6)alkylaryl, (C1-6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, oxazolinyl, azetidinyl, pyrrolidinyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di- (d^alkylaminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonyl- piperidinyl, di(C1-6)alkylaminocarbonylpiperidinyl, piperazinyl, (C|-6)alkylpiρerazinyl, haloarylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (C i-6)alkylhomopiperazinyl, morpholinyl, (C i -6)alkylpiperazinyl(C i -6)alkyl, morpholinyl(C1.6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(Ci-6)- alkylpyrazolyl, tri(Ci-6)alkyIpyrazoIyl, [di(C1-6)alkyl](trifluoromethyI)pyrazoIyI, cyano- (Ci-6)alkylρyrazolyl, [cyano(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, hydroxy(Ci-6)alkyl- pyrazolyl, [hyήmxy(C\ a)^]kyl][ήi(C] fi)alkyl]pyrazolyl,, methoxy(Ci..6)alkylpyrazolyl, [(hydroxy)(methoxy)(Ci-(5)alkyl]pyrazolyl, amino(C|-6)alkylpyrazolyl, [(Ci..6)alkyl][ammo- (Ci-6)alkyl]pyrazolyl, [amino(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, di(Cj-6)alkylamino(C1-6)- alkylpyrazolyl, di(Ci-6)alkoxyphosphono(Ci-6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl(Ci^)alkylpyrazolyl, [(C3-7)cycloalkyl(C1-6)alkyl][di(Ci-6)alkyl]pyra2olyl, [(Ci-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(C1-6)alkylpyrazolyl, aminoaryl(C1-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(C1.6)alkyl- pyrazolyl, [di(C1-6)alkyl] [tetrahydropyranyl(C1-6)alkyl]pyrazolyl, pyrrolidinyl(Ci-6)alkyl- pyrazolyl, piperidinyl(C i -6)alkylpyrazolyl, (C i -6)alkylpiperidinyl(C \ -6)alkylpyrazolyl, morpholinyl(C i .^alkylpyrazolyl, pyridinyl(C i _6)alkylpyrazolyl, oxypyridinyl(C 1-6)alkyl- pyrazolyl, [arylcarbony^Ci^alkylJfdi^i^alkylJpyrazolyl, [(Ci-6)alkyl](piperazinyl- carbonyl)pyrazolyl, [(C i -6)alkylaminocarbonyl] [(C \ -6)alkylaryl]pyrazolyl, [(C i ^alkyl]- [8TnInO(C1 -6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C \ ^alkylpyrazolyl, [aminocarbonyl(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, di(Ci-6)alkylaminocarbonyl(C1-6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1_6)alkylisoxazolyl, (amino)[(C1-6)alkyl]- isoxazolyl, thiazolyl, di(Ci-6)alkylthiazolyl, imidazolyl, (C1-6)alkylimidazolyl, di(Ci-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkylimidazo[l,2-α]pyridinyl, (C1-6)- alkylimidazo[4,5-Z>]pyridinyl, imidazo[l,2-ύr]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (C1-6)- alkylthiadiazolyl, triazolyl, pyridinyl, halopyridinyl,
Figure imgf000016_0001
(halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C1-6)alkylpiperazinyl- pyridinyl, [(C i -6)alkyl] (piperazinyl)pyridinyl, [(C \ .6)alkoxycarbonylpiperazinyl] [(C i -6)- alkyl]pyridinyl, piperidinyl(C i -6)alkylpyridinyl, [(C \ .6)alkyl] (oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (Ci^alkoxypyridinyl, [(C1-6)alkoxy]- [(C1-6)alkyl]pyridinyl, [(C1-6)alkoxy][di(C1-6)alkyl]pyridinyl, (C1-6)alkoxy(C1-6)alkyl- pyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (Ci-6)alkoxycarbonyl(C1-6)alkyl- pyridinyl, pyridazinyl, (C1-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (C1-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(Ci-6)alkylaminopyridazinyl, di- (C1-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(C].6)alkyl](halo)- pyrimidinyl, di(C1-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinyl- pyrimidinyl, [(Ci-6)alkyl](piperazinyl)pyrimidinyl, [(Ci-6)alkoxycarbonyl][(C1-6)alkyl]- piperazinylpyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(C1-6)- aHcyl}[hydroxy(C r-6)aHcyl]pyrimidinyl, [(C N6)alkyl}[hydroxy(C2.6)alkynyl}pyrimidinyl, (Ci.6)alkoxypyrimidinyl, aminopyrimidinyl, di(C1-6)alkylaminopyrimidinyl, [di(Ci-6)alkyl- αinino](hαlo)pyrimidinyl, cαrboxypyrimidinyl, [(Ci-tt)αlkoxycorbonyl(Ci-6)αlkyl][(C|-(>)- alkyljpyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl,
Figure imgf000017_0001
amino- pyrazinyl, hydroxy,
Figure imgf000017_0002
difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(Ci.6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy,
Figure imgf000017_0003
alkoxy, aryloxy, haloaryloxy, d^C^alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (Ci^alkylpiperazinylpyridinyloxy, (C1-6)alkylpyrazolyl- pyridinyloxy, (Ci-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy,
Figure imgf000017_0004
[(C1-6)alkyl](halo)pyrimidinyloxy, hydroxy(C1-6)alkyl, dihydroxy(C1-6)alkyl,
PyHdUIyIoXy(C1.6)alkyl, methylenedioxy, trifluoromethylenedioxy, amino, (C1-6)alkyl- amino, dihydroxy(Ci-6)alkylamino,
Figure imgf000017_0005
di(C1-6)alkylamino, N- [(Ci^alkoxyCCi^alkyll-N-fCCi^alkyllaniino, difCi^alkylaminoCCi^alkylaminOj N- [(Ci-6)alkyl]-N-[di(C1-6)dkylamino(Ci-6)alkyl]amino, N-[(C1-6)alkyl]-N-[(C3-7)cycloalkyl]- amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, methylenedioxyphenylamino, morpholinyKCi^alkylphenylamino, oxazolinylphenylamino, [(C1-6)alkyl](oxo)pyrazolyl- phenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, (C i -6)alkyltriazolylphenylamino, (C i -6)alkylpyrimidinylphenylamino, pyrazolyl(C i -6)alkyl- phenylamino, triazolyl(C1-6)alkylphenylamino, C1-6 alkylsulphonylaminophenylamino, morpholinylcarbonylphenylamino, C1-6 alkylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-[(Ci-6)alkyl]-N-[aryl(Ci-6)alkyl]amino, N-[di(C1-6)alkylamino(C1-6)alkyl]-N-[aryl(C1-6)alkyl]amino, cyanoary^Ct^alkylamino, (cyano)(halo)aryl(C1.6)alkylamino, methylenedioxyary^d^alkylamino, dihydrobenzofuranylamino, N-[(C1-6)alkyl]-N-[(Ci-6)alkylpyrrolidinyl]amino, C1-6 alkylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-[(C1-6)alkyl]-N- (piperidinyl)amino, N-[(C3-7)cycloalkyl(C1-6)alkyl]-N-(piperidinyl)amino, (Ci-6)alkyl- piperidinylamino,
Figure imgf000017_0006
[(C \ -6)alkyl] - N-[(C3-7)cycloalkylpiperidinyl]amino, N-[(Ci-6)alkyl]-N-[(C2-6)alkylcarbonylpiperidinyl]- amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinyl(Ci-6)alkylamino, N-[(Ci-6)alkyl]-N-[pyrrolidinyl(Ci-6)alkyl]amino, N-[(Ci-6)alkyl]-N-[piperidinyl(C,^)- alkyl] amino, benzothienylamino, indolylamino, dioxoindolylamino, (C1-6)alkylpyrazolyl- amino, [(Ci-6)alkyl](halo)pyrazolylamino,
Figure imgf000017_0007
tri(C1-6)alkyl- pyrazolylamino, N-[(C1-6)aIkyrf-N-[(Ci-6)aIkyIpyrazoIyI]amino, (C1-6)alkylindazolylamino, benzoxazolylamino, benzoxazolonylamino, di(Ci-6)aIkylisoxazolylamino, thiazolylamino, benznthia/olyiamino, (Ci 6)alkylisothiazotylaniino, imidazolylamino, [(d^alkoxy* carbonyl] [(C i ^alkyl] imidazolylamino, (C i ^alkylbenzimidazolylamino, benzimidazolonylamino, di(C i ^alkylbenzimidazolonylamino, (C i -6)alkyloxadiazolyl- amino, furyloxadiazolylamino,
Figure imgf000018_0001
pyridinylamino, halopyridinylamino, (C1-6)alkylpyridinylamino, di(C1-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C i .6)alkylpyridinylamino, dihydroxy(C i -6)alkylpyridinylamino, (C i-6)alkoxypyridinylaniino, dihydroxy(C \ -6)alkoxy- pyridinylamino, di(C i -6)alkyldioxolanyl(C i -6)alkoxypyridinylamino, (C i -6)alkoxy(C ^6)- alkylpyridinylamino, (C \ -6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C i -6)alkyl- aminopyridinylamino, di(C1-6)alkylaminopyridinylamino, (Ci-6)alkylamino(C1-6)alkyl- pyridinylamino, di(Cu6)alkylamino(Ci-6)alkylpyridinylamino, oxopyridinylamino, carboxypyridinylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkylpyridinyl]amino, bis[(C1-6)alkyl- pyridinyl]amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, (C1-6)alkyl- pyridazinylamino, iV-[(Ci-6)alkyl]-N-[(Ci-6)alkylpyridazinyl]amino, iV-[aryl(Ci-6)alkyl]-iV-
Figure imgf000018_0002
arylpyridazinylamino, piperidinylpyridazinylamino,
Figure imgf000018_0003
[(C \ -6)alkoxy] (halo)- pyridazinylamino, di(Ci_6)alkylanimopyridazinylamino,
Figure imgf000018_0004
(C1-6)alkylcinnolinylamino, oxopyrimidinylamino, thioxopyrimidinylamino, quinoxalinylamino, (Ci^alkylchromenylamino, benzofury^Ci^alkylamino, IbJeHyI(C1-6)- alkylamino, indolyl(Ci-6)alkylamino, (Ci^alkylpyrazoly^Ci-^alkylamino, [di(C1-6)alkyl]- (halo)pyrazolyl(C1-6)alkylamino, di(C1-6)alkylisoxazolyl(C1-6)alkylamino, IhIaZoIyI(C1-6)- alkylamino, imidazolyl(C1-6)alkylamino, (Ci-6)alkylimidazolyl(C1-6)alkylamino, pyridinyl(C i ^alkylamino, (C i .6)alkylpyridinyl(C \ -6)alkylamino, -^-[(C1 -6)alkyl] -N- [pyridinyl(C1-6)alkyl]amino, N-[dihydroxy(Cι-6)alkyl]-iV-[pyridinyl(Ci-6)alkyl]amino, N- [(Ci-6)alkylpyridinyl(C1-6)alkyl]-N-[dihydroxy(Ci-6)alkyl]amino, amino(C1-6)alkyl, (C1-6)- alkylamino(C1-6)alkyl, di(C1-6)alkylamino(Ci-6)alkyl, pyridinylamino(Ci-6)alkyl, C2-6 alkylcarbonylamino, N-[(C2-6)alkylcarbonyl]-N-[(Ci-6)alkylpyridinyl(Ct-6)alkyl]amino, di(Ci-6)alkylamino(Ci-6)alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, (C3-7)- cycloalkylcarbonylamino, (C1-6)alkylpiperidinylcarbonylamino,
Figure imgf000018_0005
carbonylamino, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(C1-6)alkyl]amino, Ci-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarboπyl O-(methyl)oxime, trifluσromethylcarbonyl, carboxy, C2-6 alkoxycarboπyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, [hydroxyCCi-βJalkylJaminocarbonyl, [(Ii(Ci-6)- alkyleunino(Ci-6)alkyl]aminocarbonyl, di(Ci-6)αlkylαminocαrbonyI, [(C|-6)αlkyl][oyαno- (Ci-6)alkyl]aminocarbonyl, [(Ci-6)alkyl][hydroxy(Ci-6)alkyl]aminocarbonyl,
Figure imgf000019_0001
(Ci-6)alkyl][(C1-6)alkyl]aminocarbonyl, [di(Ci-6)alkylammo(C1-6)alkyl][(Ci-6)alkyl]amino- carbonyl, C3-7 cycloalkyl(Ci-6)alkylaminocarbonyl, aryl(Ci ^alkylaminocarbonyl, (Ci-6)- alkylpiperidinylaminocarbonyl, N-[(C i ^alkyl] -N- [(C i ^alkylpiperidinyl] aminocarbonyl, piperidiny^Ci^alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(Ci-6)alkyl- aminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, (Ci-6)alkyl- pyrrolidinylcarbonyl, Ci-6 alkoxy(Ci-6)alkylpyrrolidinylcarbonyl, di(Ci-6)alkylamino- pyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinyl- carbonyl, (Ci^alkylpiperazinylcarbonyl, morpholinylcarbonyl, Ci-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonylmethyl, aminosulphonyl, Ci-6 alkylaminosulphonyl, di(Ci-6)alkylaminosulphonyl, C2-6 alkoxycarbonyloxy, trimethylsilyl and tetra(Ci-6)alkyldioxaborolanyl.
Particular examples of typical substituents on R3 and/or R4 include C1-6 alkyl and di(C i ^alkylaminocarbonyl .
Selected examples of specific substituents on R3 and/or R4 include fiuoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, moφholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, morpholinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylpropylpyrazolyl, 3- methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)pyrazolyl, (dimethyl)(3- methylbutyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2- hydroxy-2-methylpropylpyrazolyl, (hydroxyethyl)(dimethyl)pyrazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyraznlyl, [(hydroxy)- (methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (phenyl)(trifluoromethyl)pyrazolyl, benzylpyrazolyl, aminobenzylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranylmethylpyrazolyl, (dimethyl)(tetrahydropyranyl- methyl)pyrazolyl, pyrrolidinylethylpyrazolyl, piperidinylethylpyrazolyl, methyl- piperidinylethylpyrazolyl, morpholinylethylpyrazolyl, pyridinylmethylpyrazolyl, oxypyridinylmethylpyrazolyl, (dimethyl)(phenylcarbonylmethyl)pyrazolyl, (ethyl)(piperazinylcarbonyl)pyrazolyl, (methylaminocarbonyl)(methylphenyl)pyrazolyl, (aminoethylaminocarbonyl)(methyl)pyrazolyl, aminocarbonylmethylpyrazolyl, (aminocarbonylmethyl)(dimethyl]pyrazolyl, dimethylaminocarbonylmethylpyrazolyl, pyrazolo[l,5-α]pyridinyl, dimethylisoxazolyl, (amino)(methyl)isoxazolyl, thiazolyl, dimethylthiazolyl, imidazolyl, methylimidazolyl, dimethylimidazolyl, imidazo[l,2- α]pyridinyl, methylimidazo[l,2-α]pyridinyl, methylimidazo[4,5-6]pyridinyl, imidazo[l,2- α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, methylthiadiazolyl, triazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methylpiperazinyl)pyridinyl, (methyl)(piperazinyl)pyridinyl, (tert- butoxycarbonylpiperazinyl)(methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)- pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, methoxypyridinyl, (methoxy)(methyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonyl- methylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylamino- pyridazinyl, pyrimidinyl, methylpyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethyl- pyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)- (piperazinyl)pyrimidinyl, (tert-butoxycarbonylpiperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxypropynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, (dimethylamino)- (fluoro)pyrimidinyl, earboxypyrimidinyt, (methoxyearbonylmethyiχmethyl^>yrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, mcthoxy, isopropoxy, difluoromothoxy, trifluoromcthoxy, cyclobutyloxy, oyolopropyl- methoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinyl- pyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxy- pyridinyloxy, aminocarbonylpyridinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1- methylethyl, dihydroxypropyl, pyridinyloxymethyl, methylenedioxy, difluoromethylenedioxy, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, dimethylamino, N-(methoxyethyl)-N- (methyl)amino, N-(methoxypropyl)-N-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N-(dimethylaminoethyl)-N-(methyl)amino, N- (diethylaminoethyl)-N-(methyl)amino, N-(dimethylaminopropyl)-N-(methyl)amino, N- (dimethylaminoethyl)-N-(ethyl)amino, N-(dimethylaminopropyl)-N-(ethyl)amino, N- (cyclohexyl)-N-(methyl)amino, fluorophenylamino, N-fluorophenyl-N-methylamino, methylenedioxyphenylamino, morpholinyhnethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenylamino, triazolylmethylphenylamino, methylsulphonylamino- phenylamino, moφholinylcarbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-benzyl-N-methylamino, N-(benzyl)-N-(dimethyl- aminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)- benzylamino, methylenedioxybenzylamino, dihydrobenzofuranylamino, N-(methyl)-N- (methylpyrrolidinyl)amino, methylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N-(piperidinyl)amino, N- (cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinylamino, N-(methyl)-N- (methylpiperidinyl)amino, N-(methyl)-N-(2-methylpropylpiperidinyl)amino, N- (cyclopentylpiperidinyl)-N-(methyl)amino, N-(acetylpiperidinyl)-N-(methyl)amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N-(pyrrolidinylethyl)amino, N-(methyl)-N-
(pyrrolidinylpropyl)amino, N-(methyl)-N-(piperidinylmethyl)amino, benzothienylatnino, indolylamino, dioxoindolylamino, methylpyrazolylamino, (bromo)(methyl)pyrazolyl- amino, dϊmethylpyrazolylamlno, trimethylpyrazolylamino, N-(ethyl)-N-(methylpyrazoIyl)- amino, methylindazolylamino, benzoxazolylamino, benzoxazolonylamino, dimethyl- isoxazolylamino, thiazolylamino, benzothiazolylamino, methylisothiazolylamino, imidazolylamino, (ethoxycarbonyl)(methyl)imidazolylamino, methylbenzimidazolyl- amino, benzimidazolonylamino, dimethylbenzimidazolonylamino, methyloxadiazolyl- amino, furyloxadiazolylamino, methylthiadiazolylamino, pyridinylamino, chloropyridinyl- amino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, oxopyridinylamino, carboxypyridinylamino, 7V-(methyl)-7V-(methylpyridinyl)- amino, N-(ethyl)-iV-(methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-iV- (methylpyridazinyl)amino, N-(benzyl)-N-(methylpyridazinyl)amino, dimethyl- pyridazinylamino, phenylpyridazinylamino, piperidinylpyridazinylamino, methoxypyridazinylamino, (chloro)(methoxy)pyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, methylcinnolinylamino, oxopyrimidinyl- amino, thioxopyrimidinylamino, quinoxalinylamino, methylchromenylamino, benzofiirylmethylamino, thienylmethylamino, indolylmethylamino, methylpyrazolyl- methylamino, (chloro)(dimethyl)pyrazolylmethylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethylamino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethylamino, iV-(methyl)-7V-(pyridinylethyl)- amino, iV-(dihydroxypropyl)-Λ/-(pyridinylmethyl)amino, N-(dihydroxypropyl)-N- (methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylatninomethyl, acetylamino, iV-(acetyl)-N-(methylpyridinyl)aniino, dimethylaminoethylcarbonylamino, acetylaminomethyl, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, methoxycarbonyl- amino, N-methoxycarbonyl-iV-methylamino, methylsulphonylamino, formyl, acetyl, acetyl oxime, acetyl (9-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethyl- aminoethyl)aminocarbonyl, (1 -hydroxyprop-2-yl)aminocarbonyl, dimethylamino- carbonyl, N-(cyanoπiethyl)-iV-methy}aminocarbOny}, iV-(cyaπoethyi)-iV-methylamiπo- carbonyl, N-(hydroxyethyl)-7V-methylaminocarbonyl, N-(methoxyethyl)-iV-methyl- aminocarbonyl, N-(dimcthylaminocthyl)-N-mcthylaininocarbonyl, N-isopropyl-N-mcthyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, methylpiperidinylaminocarbonyl, N-(methyl)-jV-(methylpiperidinyl)amino- carbonyl, piperidinylethylaminocarbonyl, pyrazolylatninocarbonyl, pyridinylmethylamino- carbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, tert- butoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, methylpyrrolidinyl- carbonyl, methoxymethylpyrrolidinylcarbonyl, dimethylaminopyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinyl- carbonyl, morpholinylcarbonyl, isopropylthio, isopropylsulphinyl, methylsulphonyl, isopropylsulphonyl, methylsulphonylmethyl, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, fert-butoxycarbonyloxy, trimethylsilyl and tetramethyl- dioxaborolanyl.
Particular examples of specific substituents on R3 and/or R4 include methyl and dimethylaminocarbonyl .
Typical values of R3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-iV-phenylaminomethyl, pyridinylamino- methyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyl- methylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, phenyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazolylphenylaminobenzyl, methylpyrimidinylphenylaminobenzyl, pyrazolylmethylphenylaminobenzyl, triazolyhnethylphenylaminobenzyl, methylsulphonylaminophenylaminobenzyl, morpholinylcarbonylphenylaminobenzyl, methylsulphonylphenylaminobenzyl, morpholinylsulphonylphenylaminobenzyl, dihydrobenzofuranylaminobenzyl, methylsulphonylindolinylaminobenzyl, chromanonylaminobenzyl, dihydroquinolinonylaminobenzyl, benzoxazinonyl- aminobenzyl, benzothienylaminobenzyl, indolylaminobenzyl, dioxoindolylaminobenzyl, (bromo)(methyl)pyrazolylaminobenzyl, trimethylpyrazolylaminobenzyl, methylindazolyl- aminobenzyl, benzoxazolylaminobenzyl, benzoxazolonylaminobenzyl, dimethyl- isoxazolylaminobenzyl, benzothiazolylaminobenzyl, methylisothiazolylaminobenzyl, methylbenzimidazolylaminobenzyl, benzimidazolonylaminobenzyl, dimethyl- benzimidazolonylaminobenzyl, mathyloxadiazolylaminobenzyl, fiiryloxadiazolyl- aminobenzyl, pyridinylaminobenzyl, chloropyridinylaminobenzyl, methylpyridinylamino- benzyl, dimethylpyridinylaminobenzyl, methoxypyridinylaminobenzyl, oxopyridinyl- aminobenzyl, oxopyrimidinylaminobenzyl, thioxopyrimidinylaminobenzyl, (chloro)- (methoxy)pyridazinylaminobenzyl, methylcinnolinylaminobenzyl, quinoxalinylamino- benzyl, methylchromenylaminobenzyl, benzofirrylmethyl, cyanobenzofurylmethyl, methoxycarbonylbenzofurylmethyl, dimethylaminocarbonylbenzofurylmethyl, azetidinylcarbonylbenzofurylmethyl, indolylmethyl, fluoroindolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, nitroindolylmethyl, methylindolylmethyl, oxazolinylindolylmethyl, triazolylindolylmethyl, methoxyindolylmethyl, (chloro)(methoxy)indolylmethyl, di(methoxy)indolylmethyl, difluoromethoxyindolylmethyl, trifluoromethoxyindolylmethyl, (chloro)(trifluoro- methoxy)indolylmethyl, cyclobutyloxyindolylmethyl, cyclopropylmethoxyindolylmethyl, moφholinylethoxyindolylmethyl, methylenedioxyindolylmethyl, difluoromethylenedioxy- indolylmethyl, azetidinylindolylmethyl, morpholinylindolylmethyl, acetylamino- indolylmethyl, acetylaminomethylindolylmethyl, methoxycarbonylaminoindolylmethyl, N-methoxycarbonyl-TV-methylaminoindolylmethyl, methylsulphonylaminoindolylmethyl, acetylindolylmethyl, [acetyl oxime]indolylmethyl, [acetyl <9-(methyl)oxime]- indolylmethyl, trifluoromethylcarbonylindolylmethyl, carboxyindolylmethyl, (carboxy)- (methyl)indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl, (chloro)(methoxycarbonyl)indolylmethyl, aminocarbonylindolylmethyl, (aminocarbonyl)(chloro)indolylmethyl, methylaminocarbonylindolylmethyl, (chloro)- (methylaminocarbonyl)indolylmethyl, (hydroxyethyl)aminocarbonylindolylmethyl, (dimethylaminoethyOaminocarbonylindolylmethyl, (1 -hydroxyprop-2-yl)aminocarbonyl- indolylmethyl, dimethylaminocarbonylindolylmethyl, (dimethylaminocarbonyl)(methyl)- indolylmethyl, (chloro)(dimethylaminocarbonyl)indolylniethyl, bis(dimethylamino- carbonyl)indolylmethyl, N-(cyanomethyl)-N-methylaminocarbonylindolylmethyl, [N- (cyanomethyl)-N-methylaminocarbonyl](methyl)indolylmethyl, N-(cyanoethyl)-N- methylaminocarbonylindolylmethyl, N-(hydroxyethyl)-N-methylaminocarbonyl- indolylmethyl, N-(methoxyethyl)-N-methylaminocarbonylindolylmethyl, [N-(methoxy- ethyl)-N-methylaminocarbonyl](methyl)indolylmethyl, N-(dimethylaminoethyl)-N- methylaminocarbonylindolylmethyl, N-isopropyl-N-methyiamiπocarboπyiiπdσlyimethyi, diethylaminocarbonylindolylmethyl, cyclopropylmethylaminocarbonylindolylmethyl, bonzylαininυcαrbυnyliiidϋlylniϋthyl, pyriu-υlyluiiihiυϋtubυiiyliiidolylmothyl, pyridinylmethylaminocarbonylindolylmethyl, azetidinylcarbonylindolylmethyl, (azetidinylcarbonyl)(methyl)indolylmethyl, hydroxyazetidinylcarbonylindolylmethyl, aminoazetidinylcarbonylindolylmethyl, /er/-butoxycarbonylaminoazetidinylcarbonyl- indolylmethyl, pyrrolidinylcarbonylindolylmethyl, methylpyrrolidinylcarbonyl- indolylmethyl, methoxymethylpyrrolidinylcarbonylindolylmethyl, dimethylamino- pyrrolidinylcarbonylindolybnethyl, thiazolidinylcarbonylindolylmethyl, oxothiazolidinyl- carbonylindolylmethyl, piperidinylcarbonylindolylmethyl, methylpiperazinylcarbonyl- indolylmethyl, morpholinylcarbonylindolylmethyl, methylsulphonylindolylmethyl, methylsulphonylmethylindolylmethyl, dimethylaminosulphonylindolylmethyl, trimethylsilylindolylmethyl and pyrrolo[3,2-c]pyridinylmethyl.
A particular value of R3 is (dimethylaminocarbonyl)(methyl)indolylmethyl. Typical values of R4 include hydrogen and methyl. In a preferred embodiment, R4 is hydrogen. In another embodiment, R4 is C1-6 alkyl, especially methyl.
Alternatively, R3 and R4, when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage. Thus, R3 and R4, when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, R3 and R4, when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
Alternatively, R3 and R4, when attached to adjacent carbon atoms, may together form an optionally benzo-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the morpholine ring. Thus, R3 and R4, when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, in one embodiment, R3 and R4, when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the morpholine ring, which phenyl ring may be unsubstituted, or substituted by one or more, typically by one or two, substituents. Also in this context, in another embodiment, R3 and R4, when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyelnpentyl ring, i c an indanyl moiety fused to the morpholine ring, which indanyl moiety may be unsubstituted, or substituted by one or more, typically by one or two, substituents. Examples of typical substituents on the fused rings referred to in the preceding paragraph include halogen, nitro, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, (d^alkylaryl, di(Ci-6)alkylaryl,
Figure imgf000026_0001
piperazinyl(C1-6)alkylaryl, (C i -6)alkylpiperazinyl(C i .6)alkylaryl, morpholinyl(C \ -6)alkylaryl, (C i -6)alkoxyaryl, cyano(C i ^alkoxyaryl, di(C i ^alkylaminotQ -6)alkylaryl, (C \ ^alkylaminocarbonylaryl, 8TyI(C1.6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (Ci-6)alkylaminocarbonylpiperidinyl, piperazinyl,
Figure imgf000026_0002
haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (Ci^alkyl- homopiperazinyl, (Ci.6)alkylpiperazinyl(C1-6)alkyl, morpholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (C i ^alkylpyrazolyl, di(C i -6)alkylpyrazolyl, tri(C i ^alkyl- pyrazolyl, (difluoromethyl)pyrazolyl, [d^Ci^alkylKtrifluoromethyOpyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, hydroxy(C1-6)alkyl- pyrazolyl, [hydroxy^-eJalkylJfd^C^alkylJpyrazolyl, methoxy(Ci.6)alkylpyrazolyl, [(hydroxy)(methoxy)(C i -6)alkyl]pyrazolyl, amino(C i .6)3^^50-370^1, [(C \ ^alkyl]- [amino(Ci-6)alkyl]pyrazolyl, [amino(Ci-6)alkyl][di(Ci.6)alkyl]pyrazolyl, di(Ci-6)alkyl- amino(C1-6)alkylpyrazolyl, di(Ci-6)alkoxyphosphono(C1-6)alkylpyrazolyl, (C2-6)alkenyl- pyrazolyl, (C3-7)cycloalkyl(Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl(C1-6)alkyl][di(C1-6)alkyl]- pyrazolyl, [(C1-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(Ci-6)alkyl- pyrazolyl,
Figure imgf000026_0003
piperidinylpyrazolyl, tetrahydropyranyl- (C1-6)alkylpyrazolyl, [di^i^alkylJttetrahydropyranyKCi^alkylJpyrazolyl, pyrrolidinyl(C1-6)alkylpyrazolyl, piperidinyl(Ci-6)alkylpyrazolyl, (Ci-6)alkylpiperidinyl- (C1-6)alkylpyrazolyl,
Figure imgf000026_0004
pyridinyl(C1-6)alkylpyrazolyl, oxypyridinyl(C 1.6)alkylpyrazolyl, [arylcarbonyl(C 1 -6)alkyl] [di(C 1 -β)alkyl]pyrazolyl, [(Ci-6)alkyl](piperazinylcarbonyl)pyrazolyl, [(Ci-6)alkylaminocarbonyl][(Cj-6)alkylaryl]- pyrazolyl, [(C1-6)aucyl][amino(Ci-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl-
(Ci-6)alkylpyrazolyl, [aminocarbonyl(CI-6)alkyl][di(C1-6)alkyl]pyrazolyl, di(Ci-6)alkyl- aminocarbonyl(C1-6)alkylpyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1-6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]isoxazolyl, thiazolyl, di(Ci.6)aHcylthiazolyl, imidazolyl, (C1-6)alkyl- imidazolyl, (Ii(C1 ^alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkylimidazo[l,2-αj- pyridihyl, (C|-6)olkyhmidαzό[4,b-bjpyridinyl, imϊdαzo[l,2-α]pyrimidinyl, imidαzo- [l,2-α]pyrazinyl, (Ci.6)alkylthiadiazolyl, pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, [(Ci-6)alkyl](halo)pyridinyl, di(Ci-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C1-6)alkyl- piperazinylpyridinyl, [(C1-6)alkyl](piperazinyl)pyridinyl, [(d^alkoxycarbonyl-
Figure imgf000027_0001
(oxy)pyridinyl, hydroxypyridinyl, hydroxy^ ^alkylpyridinyl, (d^alkoxypyridinyl, [(C1-6)alkoxy][(Ci-6)alkyl]pyridinyl, [(Ci-6)alkoxy][di(C1-6)alkyl]pyridinyl, (Ci-6)alkoxy(Ci^)alkylpyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (C1-6)alkoxycarbonyl(Ci-6)alkylpyridinyl, pyridazinyl, (Q^alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Q^alkoxypyridazinyl, aminopyridazinyl, hydroxy(Ci-6)alkylaminopyridazinyl, di(Ci.6)alkylaminopyridazinyl, pyrimidinyl, (C i .6)alkylpyrimidinyl, [(C i -6)alkyl](halo)pyrimidinyl, di(C \ -6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (C i -6)alkylpiperazinylpyrimidinyl, [(C i -6)alkyl] (piperazinyl)- pyrimidinyl, [(Ci^alkoxycarbonyljf^i^alkyljpiperazinylpyrimidinyl, hydroxypyrimidinyl, [(C ι-6)alkyl](hydroxy)pyrimidinyl, [(C i ^alkyl] [hydroxy(C i -6)alkyl] - pyrimidinyl, [(C i -6)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (C \ .6)alkoxypyrimidinyl, aminopyrimidinyl, di(C \ -6)alkylaminopyrimidinyl, [di(C \ ^alkylamino] (halo)pyrimidinyl, carboxypyrimidinyl, [(C1.6)alkoxycarbonyl(Ci-6)alkyl][(C1-6)alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, aminopyrazinyl, hydroxy, (C1-6)alkoxy, 8TyI(C1.6)alkoxycarbonylpiperidinyloxy, morpholinyl(C1-6)alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i ^alkylpyrazolylpyridinyloxy,
Figure imgf000027_0002
carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy,
Figure imgf000027_0003
pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C i ^alkyl] (halo)pyrimidinyloxy, hydroxy(C \ ^)alkyl, dihydroxy(C i .6)alkyl, pyridinyloxy(C1-6)alkyl, amino, (Ci-6)alkylamino, dihydroxy(C1-6)alkylamino, (Ci-ό)- alkoxy(Cι-6)alkylamino, N-[(Ci.6)alkoxy(Ci-6)alkyl]-N-[(C1-6)alkyl]amino, di(C1-6)- alkylamino(C1-6)alkylamino, N-[(C1.6)alkyl]-N-[di(C1-6)alkylamino(Ci-6)alkyl]amino, N- [(C1-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino, N-[(C1-6)alkyl]-N-(haloaryl)amino, N-[(C,-6)alkyl]-N-[aryl(C1-6)alkyl]amino, N-[di(C1-6)alkylamino(Ci-6)alkyl]-N-[aryl(Ci-6)- alkyljamino, cyanoary^Ci^alkylamino, (cyano)(halo)aryl(Ci-6)alkylamino, methylene- dioxyaryl(Ci-6)alkylamino, N-[(Ci-6)alkyl]-N-[(C1-6)alkylpyrrolidinyl]amino, piperidinyl- aminOj N-tCCi^alky^-N-CpiperidinyOaminOj N-tCCB^JcycloalkylCCj-eJalky^-iV- (piperidinyOamino, (C1 6)alkylpipcridinylnmino,
Figure imgf000028_0001
piperidinyl]amino, N-[(C1-6)alkyl]-iV-[(C3-7)cycloalkylpiperidinyl]amino, N-[(Ci-6)alkyl]- N-[(C2-6)alkylcarbonylpiperidinyl]amino, pyrrolidinyl(Ci.6)alkylamino,
Figure imgf000028_0002
Figure imgf000028_0003
N-[(C1-6)alkyl]-N-[piperidinyl(C1-6)alkyl]amino, (Ci-6)- alkylpyrazolylamino, di(C1-6)alkylpyrazolylaniino,
Figure imgf000028_0004
N-[(C1-6)- alkyl]-iV-[(C1-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(C1^aIkOXy- carbonyl][(Ci^)alkyl]imidazolylamino, (C1-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (d^alkylpyridinylamino, di(Ci-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C1-6)alkylpyridinylamino, dihydroxy(C \ .ojalkylpyridinylamino, (C \ .6)alkoxypyridinylamino, dihydroxy(C 1-6)alkoxy- pyridinylamino, di(C i -6)alkyldioxolanyl(C 1-6)alkoxypyridinylamino, (C i -6)alkoxy(C i .(,)- alkylpyridinylamino, (C i -6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C \ -6)alkyl- aminopyridinylamino, di(C i .όjalkylaminopyridinylamino, (C i ^alkylamino^ \ _6)alkyl- pyridinylamino, di(C1-6)alkylamino(Ci-6)alkylpyridinylamino, carboxypyridinylamino, N- [(C1-6)alkyl]-N-[(Ci-6)alkylpyridinyl]amino, bis[(Ci-6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino,
Figure imgf000028_0005
N-[(C1-6)alkyl]-
Figure imgf000028_0006
di(C1-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C I-6)- alkoxypyridazinylamino,
Figure imgf000028_0007
amino, benzofuryl(Ci.6)alkylamino, thieny^Ci^alkylamino, indolyl(Ci-6)alkylamino, (C1-6)alkylpyrazolyl(Ci-6)alkylamino, [di(C1-6)alkyl](halo)pyrazolyl(C1-6)alkylamino, di(C i -6)alkylisoxazolyl(C \ ^alkylamino, thiazolyl(C i ^alkylamino, imidazolyl(C i -6)alkyl- amino, (Ci-6)alkylimidazolyl(C1-6)alkylamino, pyridinyl(Ci.6)alkylamino, (C1-6)alkyl- pyridinyl(Cj.6)alkylamino, ^[(Ct^alkylJ-N-tpyridiny^Cj^alkylJamino, N-[dihydroxy- (Ci-6)alkyl]-N-[pyridinyl(Ci-6)alkyl]amino, N-[(Ci-6)alkylpyridinyl(Ci-6)alkyl]-N-
Figure imgf000028_0008
amino(Ci-6)alkyl, (Ci-6)alkylamino(Ci-6)alkyl, di(Ci-6)alkyl- amino(C1-6)alkyl, pyridinylamino(C1-6)alkyl, N-[(C2.6)alkylcarbonyl]-N-[(C1-6)alkyl- pyridinyl(Ci-6)alkyl] amino, di(Ci-6)alkylamino(Ci-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (Ci^alkylpiperidinylcarbonylamino, (C1-6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (Ci^alkylpiperidinylaminocarbonyl, N-[(Ci_6)alkyl]-N-[(Ci-6)- alkylpiperidinyl] aminocarbonyl, piperidinyl(C \ -6)alkylaminocarbonyl, (C \ _6)alkyl- piperazinylcarbonyl, C1-6 alkylthio, Ci-6 alkylsulphinyl, C1-6 alkylsulphonyl, C2-6 alkoxyearbonyloxy and tctra(Ci-6)alkyldioxaborolanyl.
Particular examples of typical substituents on the fused rings referred to in the two preceding paragraphs include halogen, (C^alkylpyrazolyl, tri(Ci-6)alkylpyrazolyl, (difluoromethyl)pyrazolyl, hydroxy(C i ^alkylpyrazolyl, [hydroxy(C i ^alkyl] [di(C i -6)- alkyljpyrazolyl, [(hydroxy)(methoxy)(C ] -6)alkyl]pyrazolyl, (C \ -6)alkylpyridinyl, hydroxy(C1-6)alkylpyridinyl, pyridazinyloxy, amino and (Q^alkylpyridazinylamino.
Selected examples of specific substituents on the fused rings referred to in the three preceding paragraphs include fluoro, chloro, bromo, nitro, methyl, ra-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylpropylpyrazolyl, 3- methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)pyrazolyl, (dimethyl)(3 - methylbutyl)pyrazolyl, (difluoromethyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2-hydroxy-2-methylpropylpyrazolyl, (hydroxymethyl)- (isopropyl)(methyl)pyrazolyl, (hydroxyethyl)(dimethyl)pyrazolyl,
(hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, [(hydroxy)- (methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropyhnethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (phenyl)(rrifluoromethyl)pyrazolyl, benzylpyrazolyl, aminobenzylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranylmethylpyrazolyl, (dimethyl)(tetrahydropyranyl- methyl)pyrazolyl, pyrrolidinylethylpyrazolyl, piperidinylethylpyrazolyl, methyl- piperidinylethylpyrazolyl, morpholinylethylpyrazolyl, pyridinylmethylpyrazolyl, nxypyridinylmethylpyrazntyl, (dτmeth)'l)(phenylcarbonylmethyl)pyra7θlylJ . - . (ethyl)(piperazinylcarbonyl)pyrazolyl, (methylaminocarbonyl)(methylphenyl)pyrazolyl, (aminoethylaminocarbonyl)(methyl)pyrazolyl, aminocarbonylmethylpyrazolyl, (aminocarbonylmethyl)(dimethyl]pyrazolyl, dimethylaminocarbonylmethylpyrazolyl, pyrazolo[l,5-α]pyridinyl, dimethylisoxazolyl, (amino)(methyl)isoxazolyl, thiazolyl, dimethylthiazolyl, imidazolyl, methylimidazolyl, dimethylimidazolyl, imidazo[l,2- α]pyridinyl, methylimidazo[l,2-α]pyridinyl, methylimidazo[4,5-6]pyridinyl, imidazo[l,2- α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, methylthiadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methyl- piperazinyl)pyridinyl, (methyl)(piperazinyl)pyridinyl, (fert-butoxycarbonylpiperazinyl)- (methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, ( 1 -hydroxy- 1 -methylethyl)pyridinyl, methoxypyridinyl, (methoxy)(methyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonylmethylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylaminopyridazinyl, pyrimidinyl, methylpyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)(piperazinyl)pyrimidinyl, (ϊer/-butoxycarbonylpiperazinyl)(raethyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxypropynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, (dimethylamino)(fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonyl- tnethyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinylpyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1 -methylethyl, dihydroxypropyl, pyridinyloxymethyl, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methσxypropylaπriπo, 7V-(methoxyethyl)-iV-(methyl)amino, N- (methoxypropyl)-N-(methyl)amino, dimethylaminoethylamino, dimcthylaminopropylamino, N-(dimcthylaminocthyl)-N-(methyl)aminu, N- (diethylaminoethyl)-N-(methyl)amino, N-(dimethylaminopropyl)-N-(methyl)amino, N- (dimethylaminoethyl)-N-(ethyl)amino, N-(dimethylaminopropyl)-N-(ethyl)amino, N- (cyclohexyl)-N-(methyl)amino, fluorophenylatnino, N-fluorophenyl-N-methylamino, N- benzyl-N-methylamino, N-(benzyl)-N-(dimethylaminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)benzylamino, methylenedioxybenzylamino, N- (methyl)-N-(methylpyrrolidinyl)amino, piperidinylamino, N-(methyl)-N- (piperidinyl)amino, N-(ethyl)-N-(piperidinyl)amino, N-(cyclopropylmethyl)-N- (piperidinyl)amino, methylpiperidinylamino, N-(methyl)-N-(methylpiperidinyl)amino, N- (methyl)-N-(2-methylpropylpiperidinyl)amino, N-(cyclopentylpiperidinyl)-N- (methyl)amino, N-(acetylpiperidinyl)-N-(methyl)amino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N-(pyrrolidinylethyl)amino, N-(methyl)-N- (pyrrolidinylpropyl)amino, N-(methyl)-N-(piperidinylmethyl)amino, methylpyrazolylamino, dimethylpyrazolylamino, trimethylpyrazolylamino, N-(ethyl)-N- (methylpyrazolyl)amino, thiazolylamino, imidazolylamino,
(ethoxycarbonyl)(methyl)imidazolylamino, methylthiadiazolylamino, pyridinylamino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridπtylammo7hydrσxypyridi^^ dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, carboxypyridinylamino, N-(methyl)-N-(methylpyridinyl)amino, N-(ethyl)-N- (methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-N-(methylpyridazinyl)amino, N- (benzyl)-N-(methylpyridazinyl)amino, dimethylpyridazinylamino, phenylpyridazinyl- amino, piperidinylpyridazinylamino, methoxypyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, benzofurylmethylamino, thienylmethyl- amino, indolylmethylamino, methylpyrazolylmethylamino, (chloro)(dimethyl)pyrazolyl- methylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethyl- amino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethyl- amino, N-(methyl)-N-(pyridinylethyl)amino, N-(dihydroxypropyl)-N-(pyridinylmethyl)- amino, N-(dihydroxypropyl)-iV-(methylpyridinylmethyl)aniino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, M(acetyl)-N-(methyl- pyridinyl)amino, dimethylaminoethylcarbonylamino, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, foπnyl, acetyl, methylpiperidinylaminocarbonyl, ^(methyO-N-Cmethylpiperidiny^aniinocarbonyl, piperidinylethylaminocarbonyl, methylpiperazinylcarbonyl, isopropylthio, isopropyl- sulphinyl, isopropylsulphonyl, tert-butoxycarbonyloxy and tetramethyldioxaborolanyl.
Particular examples of such substituents include fluoro, chloro, bromo, methylpyrazolyl, trimethylpyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (difiuoromethyl)- pyrazolyl, hydroxyethylpyrazolyl, (hydroxymethyl)(isopropyl)(methyl)pyrazolyl, [(hydroxy)(methoxy)propyl]pyrazolyl, methylpyridinyl, (1 -hydroxy- 1 -methylethyl)- pyridinyl, pyridazinyloxy, amino and methylpyridazinylamino.
Suitably, Ra represents substituted or unsubstituted aryl.
Suitably, Rc represents hydrogen; or aryl, 8TyI(C1 ^alkyl, heteroaryl(Ci.6)alkyl or (aryl)(heteroaryl)(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Examples of typical substituents on Ra and/or Rb and/or Rc and/or Rf include halogen, cyano, nitro, Ci-6 alkyl, trifiuoromethyl, hydroxy, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci-6 alkylthio, C1-6 alkylsulphonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulphonyl, C1-6 alkylaminosulphonyl and di(Ci-6)alkylaminosulphonyl.
Examples of particular substituents on Ra and/or Rb and/or Rc and/or Rf include fluoro, chloro, bromo, cyano, nitro, methyl, trifiuoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl.
A particular value of Ra is phenyl. hi one embodiment, Rb represents hydrogen. In another embodiment, Rb represents C1-6 alkyl, especially methyl or ethyl. Particular values of Rc include hydrogen, phenyl, benzyl, pyridinylmethyl and (phenyl)(pyridinyl)methyl.
In one embodiment, Rd represents hydrogen. In another embodiment, Rd represents C1-6 alkyl, especially methyl or ethyl, particularly ethyl. Suitably, Re represents methyl.
Suitably, Rf represents optionally substituted aryl, especially phenyl. By way of example, R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb, -CONRcRd or -C(=N-ORf)Re; or R5 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkenylcarbonyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, C3-7 cycloalkyl(C2-6)alkenyl, C3-7 cycloalkyl(C2-6)alkynyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)- alkenyl, aryl(C2-6)alkynyl, biaryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkyl(C2-6)alkenyl, C3-7 heterocycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkylcarbonyl(C2-6)alkynyl, C5..9 heterobicycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkyl-aryl, C3-7 heterocycloalkyl(Ci-6)alkyl-aryl, C3-7 heterocycloalkyl-biaryl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C1-6)alkylcarbonyl, heteroaryl(C2-6)alkenyl, heteroaryl(C2-6)alkynyl, heteroaroylcarbonyl, C3-7 heterocycloalkyl-heteroaryl, C3-7 heterocycloalkyl-heteroaryl(C2-6)alkynyl, heteroaryl-aryl, heteroaryl-aryl(C1-6)alkyl, aryl- heteroaryl, aryl-heteroaryl(C1-6)alkyl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 heterocycloalkyl(C|-6)alkyl-aryl-heteroaryl, Cs-g heterobicycloalkylCQ^alkyl-aryl- heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl- bi(heteroaryl), aryloxyaryl, aryl(C1-6)alkoxyaryl, heteroaryl(Ci-6)alkoxyaryl,
Figure imgf000033_0001
C3-7 cycloalkyl- carbonylaminoaryl, arylcarbonylaminoaryl, aryl(C1-6)alkylcarbonylaminoaryl, C3-7 heterocycloalkylcarbonylaminoaryl, heteroarylcarbonylaminoaryl, aryl- (C3-7)heterocycloalkylcarbonylaminoaryl, arylsulphonylaminoaryl, ary^d^alkyl- sulphonylaminoaryl, heteroaryl(C1-6)alkylsulphonylaminoaryl, C3-7 cycloalkylamino- carbonylaminoaryl, arylaminocarbonylaminoaryl, C3-7 heterocycloalkylaminocarbonyl- aminoaryl, C3-7 heterocycloalkylaminocarbonylaminoaryl, heteroaryl(C1-6)alkyl- aminocarbonylaminoaryl, C3-7 heterocycloalkylcarbonylcarbonylaminoaryl, C3-7 heterocycloalkyl(Ci-6)alkylaminocarbonylcarbonylaminoaryl, arylcarbonylaryl, C3-7 heterocycloalkylcarbonylaryl, C3-7 heterocycloalkylcarbonyl(Ci.6)alkylaryl, aryl(Ci.6)- alkylaminocarbonylaryl, C3-7 heterocycloalkyl(Ci-6)alkylaminocarbonylaryl, heteroaryl- aminocarbonylaryl, heteroaryl(Ci-6)alkylaminocarbonylaryl, C3-7 heterocycloalkylamino- carbonyl(C \ -6)alkylaryl, Cj .7 heterocycloalkyl(C 1.6)alkylaininocarbonyl(C 1 -6)alkylaryl, heteroarylaminocarbonyl<Ci.6)alkylaryl, heteroaryl(C1-0)alkylaminocarbonyl(CM)alkyl- aryl, arylaminoheteroaryl, C3-7 heterocycloalkylamino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl amino-aryl-heteroaryl, C3-7 heterocycloalkylaminocarbonyl- amino-aryl-heteroaryl, C3.7 cycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- carbonyl-aryl-heteroaryl, Cj-7 heterocycloalkyl(C1-6)alkylcarbonyl-aryl-heteroaryl, C5-9 heterobicycloalkylcarton yl-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl(C 1 -6)alkyl-aryl- heteroaryl, C3-7 heterocycloalkyl-aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- (Ci^alkylaminocarbonyL-aryl-heteroaryl or C3-7 heterocycloalkylaminocarbony^Q-e)- alkyl-aryl-heteroaryl, any of which groups may be optionally substituted by one or more substituents.
Generally, R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb, -CONRcRd or -CC=N-OR^)R6; or R5 represents Cj-6 alkyl, C2-6 alkenylcarbonyl, C2-6 alkynyl, C3-7 cycloalkyl(C2-6)alkynyl, aryl, aryl(Ci-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)- alkynyl, biaryl, C3-7 heterocycloalkylCC^alkyl, C3-7 heterocycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkylcarbGnyL{C2-6)alkynyl, C5-9 heterobicycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkyl-aryl, C3-7 heterocycloalkyKQ ^alkyl-aryl, C3-7 heterocycloalkyl-biaryl, heteroaryl, heteroaryl(Ci_4)alkyl, heteroaryl(Ci-6)alkylcarbonyl, heteroaryl(C2-6)alkenyl, heteroaryl(C2-6)alkynyl, heteroaroylcarbonyl, C3-7 heterocycloalkyl-heteroaryl, C3-7 heterocycloalkyl-heteroaiyl(C2-6)alkynyl, heteroaryl-aryl, aryl-heteroaryl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 heterocycloalkyl(Ci.6)alkyl-aryl-heteroaryl, Cs-9 heterobicycloalkyl(C ].6)ailkyl-aryl -heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl-bi(heteroaryl), aryloxyaryl, aryl(C1-6)alkoxyaryl, heteroaryl(C1-6)alkoxyaryl, 8TyI(C1 ^alkylaminoaryl, heteroaryl(Ci-6)alkylaminoaryl, C3-7 cycloalkylcarbonylarnirioaryl, arylcarbonylaminoaryl, arylCCt^alkylcarbonylaminoaryl, C3-7 heterocycloalkylcεubonylaminoaryl, heteroarylcarbonylaminoaryl, aryl- (C3-7)heterocycloalkylcarbonylaminoaryl, arylsulphonylaminoaryl, aryl(Ci-6)alkyl- sulphonylaminoaryl, heteroaryl(Ci-6)alkylsulphonylaminoaryl, C3-7 cycloalkylamino- carbonylaminoaryl, arylaminocarbonylaminoaryl, C3-7 heterocycloalkylaminocarbonyl- aminoaryl, C3-7 heterocycloalkylaminocarbonylaminoaryl, heteroaryl(Ci-6)alkyl- aminocarbonylaminoaryl, C3-7 heterocycloalkylcarbonylcarbonylaminoaryl, C3-7 heterocycloalkylCCi-eJalkylaminocarbonylcarbonylaminoaryl, arylcarbonylaryl, C3-7 heterocycloalkylcarbonylaryl, C3-7 heterocycloalkylcarbonyl(Ci-6)alkylaryi, aτyi(Ci.6)- alkylaminocarbonylaryl, C3-7 heterocycloalkyl(C1-6)alkylaminocarbonylaryl, heteroaryl- aminocarbonylaryl, heteroary^Ci^alkylarmnocarbonylaryl, C3-7 heterocycloalkylamino- carbonyl(C1-6)alkylaryl, C3-7 heterocycloalkyl(Ci-6)alkylaminocarbonyI(Ci-6)alkylaryl, heteroarylaminocarbonyl(C 1-6)alkylaryl, heteroaryl(C i -6)alkylaminocarbonyl(C1 -6)alkyl- aryl, arylaminoheteroaryl, C3-7 heterocycloalkylamino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonylamino-aryl-heteroaryl, C3-7 hetCTocycloalkylaminocarbonyl- amino-aryl-heteroaryl, C3.7 cycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- carbonyl-aryl-heteroaryl, C3-7 heterocycloalky^d^alkylcarbonyl-aryl-heteroaryl, C5-9 heterobicycloalkylcarbonyl-aryl-heteroaryl, C^ heterocycloalkylcarbonylζCi^alkyl-aryl- heteroaryl, C3-7 heterocycloalkyl-aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- (Ci-6)alkylaminocarbonyl-aryl-heteroaryl or C3-7 heterocycloalkylarninocarbonyl(Ci-6)- alkyl-aryl-heteroaryl, any of which groups may be optionally substituted by one or more substituents.
Typically, R5 represents aryl-heteroaryl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 cycloalkylcarbonyl-aryl-heteroaryl or C3-7 heterocycloalkylcarbonyl-aryl-heteroaryl, any of which groups may be optionally substituted by one or more substituents. In addition, R5 may typically represent C3-7 heterocycloalkylcarbonyl-biaryl, which group may be optionally substituted by one or more substituents.
Suitably, R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb or -CONR0R ; or R5 represents methyl, propyl, ethenylcarbonyl, ethynyl, propynyl, butynyl, 3-methylbutynyl, cyclopropylethynyl, cyclohexylethynyl, phenyl, naphthyl, benzyl, phenylethyl, phenyl ethenyl, phenylethynyl, phenylpropynyl, biphenyl, piperidinylethyl, pyrrolidinylethynyl, piperidinylethynyl, 1 ,2,3,4-tetrahydroisoquinolinylpropynyl, piperazinylpropynyl, pyrrolidinylcarbonylethynyl, quinuclidinylethynyl, piperazinyl- phenyl, morpholinylphenyl, piperidinylmethylphenyl, piperazinyl-biphenyl, benzofuryl, dibenzofiiryl, benzothienyl, dibenzothienyl, pyridinyl, isoquinolinyl, imidazolylethyl, imidazolylmethylcarbonyl, imidazolylethenyl, indolylethynyl, pyrazolylethynyl, imidazolylethynyl, pyridinylethynyl, pyrimidinylethynyl, imidazo[l,2-α]pyridinylethynyl, imidazolylcarbonylcarbonyl, benzomorpholinyl-pyridinyl, pyrrolidinylpyridinylethynyl, pyrazolylphenyl, pyridinylphenyl, phenylisoxazolyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, azetidinylphenylpyridinyl, pyrrolidinylphenylpyridinyl, piperidinylphenylpyridinyl, piper azinylphenylpyridinyl, moφholinylphenylpyridinyl, piperazinylphenylpyrimidinyl, pyrrolidinylmethylphenylpyridinyl, piperidinylmethyl- phenylpyridinyl, piper azinylmethylphenylpyridinyl, homopiperazinylmethylphenyl- pyridinylj morpholinylmethylphenylpyridinylj αzαbicyclnfλ 2 1 JoπtylmethyJphenyl- pyridinyl, diazabicyclotS^.lJoctylmethylphenylpyridinyl, tetrazolylphenylpyridinyl, benzofurylpyridinyl, benzothienylpyridinyl, indolylpyridinyl, isoxazolylpyridinyl, bi(pyridinyl), isoquinolinylpyridinyl, morpholinylcarbonylbi(pyridinyl), phenoxyphenyl, benzyloxyphenyl, pyridinylmethoxyphenyl, benzylaminophenyl, furylmethylaminophenyl, pyridinylmethylaminophenyl, cyclopentylcarbonylaminophenyl, phenylcarbonylamino- phenyl, benzylcarbonylaminophenyl, pyrrolidinylcarbonylaminophenyl, piperidinyl- carbonylaminophenyl, piperazinylcarbonylaminophenyl, morpholinylcarbonylamino- phenyl, indolylcarbonylaminophenyl, isoxazolylcarbonylaminophenyl, pyridinylcarbonyl- aminophenyl, phenylpyrrolidinylcarbonylaminophenyl, phenylsulphonylaminophenyl, benzylsulphonylaminophenyl, isoxazolylsulphonylaminophenyl, cyclopentylamino- carbonylaminophenyl, phenylaminocarbonylaminophenyl, azetidinylatninocarbonyl- aminophenyl, morpholinylethylaminocarbonylaminophenyl, imidazolylmethyl- aminocarbonylaminophenyl, morpholinylcarbonylcarbonylaminophenyl, pyrrolidinyl- ethylaminocarbonylcarbonylaminophenyl, phenylcarbonylphenyl, morpholinylcarbonyl- phenyl, pyrrolidinylcarbonylmethylphenyl, piperidinylcarbonylmethylphenyl, benzylaminocarbonylphenyl, moφholinylethylaminocarbonylphenyl, imidazolyl- aminocarbonylphenyl, imidazolylmethylaminocarbonylphenyl, pyridinylmethyl- aminocarbonylphenyl, azetidinylaminocarbonylmethylphenyl, pyrrolidinylmethyl- aminocarbonylmethylphenyl, pyridinylaminocarbonylmethylphenyl, pyridinylmethyl- aminocarbonylmethylphenyl, phenylaminopyridinyl, azetidinylaminophenylpyridinyl, pyrrolidinylaminophenylpyridinyl, piperazinylcarbonylaminophenylpyridinyl, piperidinylaminocarbonylaminophenylpyridinyl, cyclopropylcarbonylphenylpyridinyl, azetidinylcarbonylphenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl, piperidinylcarbonylphenylpyridinyl, piperazinylcarbonylphenylpyridinyl, moφholinylcarbonylphenylpyridinyl, piperidinylcarbonylphenylpyrimidinyl, morpholinylmethylcarbonylphenylpyridinyl, azabicyclo[3.2.1 joctylcarbonylphenyl- pyridinyl, azetidinylcarbonylmethylphenyl-pyridinyl, pyrrolidinylcarbonylmethylphenyl- pyridinyl, piperidinylcarbonylmethylphenylpyridinyl, piperazinylcarbonylmethylphenyl- pyridinyl, azetidinylaminocarbonylphenylpyridinyl, pyrrolidinylaminocarbonylphenyl- pyridinyl, piperidinylaminocarbonylphenylpyridinyl, piperidinylmethylaminocarbonyl- phenylpyridinyl or azetidinylaminocarbonylmethylphenylpyridinyl, any of which groups may be optionally substituted by one or more substituents. In addition, R5 may suitably represent morpholinyloarbonylbiphenyl, which group may be optionally substituted by one or more substituents.
Representative values of R5 include morpholinylcarbonylbiphenyl, phenylpyridinyl, morpholinylphenylpyridinyl, cyclopropylcarbonylphenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl and morpholinylcarbonylphenylpyridinyl, any of which groups may be optionally substituted by one or more substituents.
Illustratively, R5 represents phenylpyridinyl, morpholinylphenylpyridinyl, cyclopropylcarbonylphenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl or morpholinylcarbonylphenylpyridinyl, any of which groups may be optionally substituted by one or more substituents.
Examples of representative substituents on R5 include halogen, cyano, nitro, oxo, C1-6 alkyl, trifluoromethyl, hydroxy, hydroxy(C1-6)alkyl, Cj-6 alkoxy, dihydroxy(Ci-6)- alkoxy, aryl(Ci ^alkoxy, methoxyaryl(Ci.6)alkoxy, amino, Ci-6 aikylamino, di(Ci-6)- aikylamino, amino^ ^alkyl, Ci-6 alkylamino(Ci.6)alkyl, di(C1-6)alkylamino(C1-6)alkyl, di(Ci-6)alkylamino(C1-6)alkylamino, methoxyaryl(Ci-6)alkylamino, Cj-6 alkylcarbonyl- amino, C1-6 alkoxycarbonyl(Cι-6)alkylcarbonylamino, C1-6 alkylcarbonylaminotC^alkyl, C1-6 alkoxycarbonylamino, N-(C1-6 alkoxycarbonyl)-N-(C1-6 alkyl)amino, C1-6 alkoxy- carbonylamino(C1-6)alkyl, N-(Ci-6 alkoxycarbonyl)-N-(C1-6 alkyl)amino(C1-6)alkyl, Ci-6 alkylsulphonylamino, C1-6 alkylsulphonylamino(C1-6)alkyl, C1-6 alkylaminocarbonylamino, di(C i -6)alkylamino(C i-6)alkylaminocarbonylamino, N-(C i -6 alkyl)-N- [di(C i -6)alkylamino- (Ci^alkyljaminocarbonylamino, carboxycarbonylamino, Cj-6 alkoxycarbonyl- carbonylamino, Ci-6 alkylaminocarbonylcarbonylamino,
Figure imgf000037_0001
aminocarbonylcarbonylamino, di(C1-6)alkylaminosulphonylamino, formyl, C1-6 alkylcarbonyl, di(C1-6)alkylamino(Ci-6)alkylcarbonyl, carboxy, CaTbOXy(C1 -6)alkyl, Ci-6 alkoxycarbonyl, C1-6 alkoxycarbonyl(Ci-6)alkyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, cyano(C1-6)alkylaminocarbonyl, di(Ci-6)alkylamino(Ci-6)- alkylaminocarbonyl, dihydroxy(C1-6)alkylaminocarbonyl, N-(C1-6 alkyl)-N-[amino(Ci-6)- alkyljaminocarbonyl, N-(C1-6 alkyl)-N-[di(Ci-6)alkylamino(Ci-6)alkyl]aminocarbonyl, di(C1-6)alkylaminocarbonyl(Ci-6)alkyl, N-(C1-6 alkyl)-N-[di(Ci-6)alkylamino(Ci-6)alkyl]- aminocarbonyl(Ci-6)alkyl, aminocarbonyl(Ci-6)alkoxy, Ci-6 alkoxyaminocarbonyl, N-(Ci-6 alkoxy)-N-(Ci-6 alkyl)aminocarbonyl, C1-6 alkylsulphonyl, Ci-6 alkylsulphonyloxy(Ci-6)- alkyl, trifluoromethylsulphonyloxy and tri(Ci-6)alkylsilyl; especially halogen or (Ii(C1-6)- aJkylaminocarbonyl.
Examples of specific substituents on R5 include fluoro, chloro, bromo, cyano, nitro, oxo, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, ethoxy, dihydroxypropoxy, isobutoxy, benzyloxy, methoxybenzyloxy, amino, methylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, N-isopropyl-N-methylaminomethyl, dimethylaminoethylamino, methoxybenzylamino, acetylamino, ethoxycarbonylacetylamino, ethylcarbonylamino, methoxycarbonyl- ethylcarbonylamino, acetylaminomethyl, tert-butoxycarbonylamino, JV-(tert-butoxy- carbonyl)-iV-(methyl)amino, tert-butoxycarbonylaminomethyl, N-(ter£-butoxycarbonyl)-iV- (methyl)aminomethyl, methylsulphonylamino, ethylsulphonylamino, methylsulphonyl- aminomethyl, ethylaminocarbonylamino, dimethylaminoethylaminocarbonylamino, TV- (dimethylatninoethyl)-N-(methyl)aminocarbonylamino, carboxycarbonylamino, ethoxycarbonylcarbonylamino, ethylaminocarbonylcarbonylamino, dimethylaminoethyl- aminocarbonylcarbonylamino, dimethylaminosulphonylamino, formyl, acetyl, dimethyl- aminoacetyl, ethylcarbonyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonyhnethyl, tert-butoxycarbonylmethyl, aminocarbonyl, methylaminocarbonyl, cyanomethylaminocarbonyl, ethylaminocarbonyl, dimethylamino- ethylaminocarbonyl, dihydroxypropylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, jV-ethyl-7V-methylaminocarbonyl, jV-(aminoethyl)-jV-(methyl)- aminocarbonyl, N-(dimethylaminoethyl)-iV-(methyl)aminocarbonyl, diethylamino- carbonyl, dimethylaminocarbonylmethyl, ^-(diethylaminoethy^-iV-^ethyOamino- carbonymiethyl, aminocarbonylmethoxy, methoxyaminocarbonyl, JV-(methoxy)-JV- (methyl)aminocarbonyl, methylsulphonyl, methylsulphonyloxymethyl, trifluoromethyl- sulphonyloxy and
Figure imgf000038_0001
particularly fluoro, chloro or dimethylaminocarbonyl; especially fluoro or dimethylaminocarbonyl.
Specific values of R5 include hydrogen, fluoro, chloro, bromo, iodo, cyano, phenylthio, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, pyridinylmethylaminocarbonyl, (phenyl)(pvridinyl)methylaminocarbonyl, N-ethyl-N-pyridinylmethylaminocarbonyl, dimethylaminomethyl, dimethylaminosulphonylaminopropyl, dimethylamino- ethenylcarbonyl, ethynyl, triethylsilylethynyl, diethylaminopropynyl, methylsulphonylaminopropynyl, dimethylaminosulphonylaminopropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, cyclopropylethynyl, hydroxycyclohexyl- ethynyl, aminocyelohexylethynyl, phenyl, bromophenyl, (bromo)(nitro)phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, isobutoxyphenyl, (benzyloxy)(chloro)- phenyl, aminophenyl, (amino)(bromo)phenyl, aminomethylphenyl, acetylaminophenyl, ethoxycarbonylacetylaminophenyl, ethylcarbonylaminophenyl, methoxycarbonyl- ethylcarbonylaminophenyl, methylsulphonylaminophenyl, ethylsulphonylaminophenyl, ethylaminocarbonylaminophenyl, dimethylaminoethylaminocarbonylaminophenyl, N- (dimethylaminoethyl)-N-(methyl)aminocarbonylaminophenyl, carboxycarbonylamino- phenyl, ethoxycarbonylcarbonylaminophenyl, ethylaminocarbonylcarbonylaminophenyl, dimethylaminoethylaminocarbonylcarbonylaminophenyl, acetylphenyl, carboxyphenyl, carboxymethylphenyl, methoxycarbonylphenyl, (chloro)(methoxycarbonyl)phenyl, ethoxycarbonylphenyl, methoxycarbonylmethylphenyl, aminocarbonylphenyl, methylaminocarbonylphenyl, cyanomethylaminocarbonylphenyl, ethylaminocarbonyl- phenyl, dihydroxypropylaminocarbonylphenyl, isopropylaminocarbonylphenyl, dimethylaminocarbonylphenyl, dimethylaminocarbonylmethylphenyl, N-(diethylamino- ethyl)-iV-(methyl)aminocarbonyhnethylphenyl, naphthyl, benzyl, phenylethyl, phenylethenyl, phenylethynyl, fluorophenylethynyl, nitrophenylethynyl, hydroxyphenylethynyl, methoxyphenylethynyl, dimethylaminophenylethynyl, phenylpropynyl, biphenyl, (bromo)(dinitro)biphenyl, methoxybiphenyl, aminobiphenyl, dimethylaminobiphenyl, dimethylaminomethylbiphenyl, (dimethylaminocarbonyl)- (methyl)biphenyl, acetylpiperidinylethyl, ter^butoxycarbonylpyrrolidinylethynyl, piperidinylethynyl, acetylpiperidinylethynyl, terf-butoxycarbonylpiperidinylethynyl, methylsulphonylpiperidinylethynyl, 1 ,2,3 ,4-tetrahydroisoquinolinylpropynyl, methylpiperazinylpropynyl, pyrrolidinylcarbonylethynyl, hydroxyquinuclidinylethynyl, piperazinylphenyl, tert-butoxycarbonylpiperazinylphenyl, morpholinylphenyl, piperidinylmethylphenyl, piperazinylbiphenyl, tert-butoxycarbonylpiperazinylbiphenyl, benzofuryl, dibenzofuryl, benzothienyl, dibenzothienyl, pyridinyl, chloropyridinyl, dichloropyridinyl, bromopyridinyl, carboxypyridinyl, ethoxycarbonylpyridinyl, isoquinolinyl, methylimidazolylethyl, methylimidazolylmethylcarbonyl, methyl- imidazolylethenyl, indolylethynyl, methylindolylethynyl, pyrazolylethynyl, methyl- pyrazolylethynyl, methylimidazolylethynyl, dimethylimidazolylethynyl, pyridinylethynyl, chloropyridinylethynyl, aminopyridinylethynyl, dimethylaminoethylaminopyridinyl- ethynyl, aminopyrimidinylethynyl, imidazo[l,2-α]pyridinylethynyl, dimethylamino- methylimidazo[ 1 ,2-α]pyridinylethynyl, methylimidazolylcarbonylcarbonyl, methyl- honτ:oττιorρholiny1pyridinyl, hydroxymethylpyrrolidinylpyridinylethynyl, pyrαzolylphenyl, methylpyrazolylphenyl, pyridinylphenyl, (amino)(chloropyridinyl)phenyl, phenyl- isoxazolyl, phenylthiazolyl, (methyl)(trifluoromethylphenyl)thiazolyl, phenylpyridinyl, fluorophenylpyridinyl, chlorophenylpyridinyl, cyanophenylpyridinyl, methylphenyl- pyridinyl, (bromo)(methyl)phenylpyridinyl, ethylphenylpyridinyl, hydroxyphenyl- pyridinyl, hydroxymethylphenylpyridinyl, methoxyphenylpyridinyl, aminocarbonyl- methoxyphenylpyridinyl, dihydroxypropoxyphenylpyridinyl, methoxybenzyloxy- phenylpyridinyl, trifluoromethylsulphonyloxyphenylpyridinyl, methylsulphonyl- oxymethylphenylpyridinyl, aminophenylpyridinyl, (amino)(cyano)phenylpyridinyl, dimethylaminophenylpyridinyl, aminomethylphenylpyridinyl, (aminomethyl)(fluoro)- phenylpyridinyl, methylaminomethylphenylpyridinyl, dimethylaminomethylphenyl- pyridinyl, N-isopropyl-N-methylaminomethylphenylpyridinyl, methoxybenzylamino- phenylpyridinyl, acetylaminophenylpyridinyl, acetylaminomethylphenylpyridinyl, tert- butoxycarbonylaminomethylphenylpyridinyl, N-(tert-butoxycarbonyl)-iV-(methyl)- aminomethylphenylpyridinyl, methylsulphonylaminomethylphenylpyridinyl, formylphenylpyridinyl, acetylphenylpyridinyl, dimethylaminomethylcarbonyl- phenylpyridinyl, carboxyphenylpyridinyl, (amino)(carboxy)phenylpyridinyl, ethoxycarbonylphenylpyridinyl, fert-butoxycarbonylphenylpyridinyl, methoxycarbonyl- methylphenylpyridinyl, aminocarbonylphenylpyridinyl, methylaminocarbonylphenyl- pyridinyl, dimethylaminoethylaminocarbonylphenylpyridinyl, dihydroxypropylamino- carbonylphenylpyridinyl, dimethylaminocarbonylphenylpyridinyl, (dimethylamino- carbonyl)(fluoro)phenylρyridinyl, (dimethylaminocarbonyl)(nitro)phenylpyridinyl, (amino)(dimethylaminocarbonyl)phenylpyridinyl, iV-ethyl-iV-methylaminocarbonyl- phenylpyridinyl, N-(aminoethyl)-N-(methyl)aminocarbonylphenylpyridinyl, N-
(dimethylaminoethyl)-N-(methyl)aminocarbonylphenylpyridinyl, diethylaminocarbonyl- phenylpyridinyl, methoxyaminocarbonylphenylpyridinyl, N-methoxy-N-methylamino- carbonylphenylpyridinyl, dimethylaminocarbonylmethylphenylpyridinyl, N-(diethyl- aminoethyl)-N-(methyl)aminocarbonylmethylphenylpyridinyl, methylsulphonylphenyl- pyridinyl, phenylpyrimidinyl, bromophenylpyrimidinyl, aminoazetidinylphenylpyridinyl, methylaminoazetidinylphenylpyridinyl, aminopyrrolidinylphenylpyridinyl, amino- piperidinylphenylpyridinyl, methylaminopiperidinylphenylpyridinyl, piperazinyl- phenylpyridinyl, terZ-butoxycarbonylpiperazinylphenylpyridinyl, fer/-butoxycarbonyl- methylpiperazinylphenylpyridinyl, morpholinylphenylpyridinyl, piperazinylphenyl- pyrimidinyl, pyfrυlidinyhnelliylphcnylpyridinyl, hydroxypyrrolidinylmethylphcnyl* pyridinyl, dioxopyrrolidinylmethylphenylpyridinyl, atninopyrrolidinylmethylphenyl- pyridinyl, carboxypyrrolidinylmethylphenylpyridinyl, tert-butoxycarbonylpyrrolidinyl- methylphenylpyridinyl, aminopiperidinylmethylphenylpyridinyl, methylaminopiperidinyl- methylphenylpyridinyl, piperazinylmethylphenylpyridinyl, methylpiperazinylmethyl- phenylpyridinyl, oxopiperazinylmethylphenylpyridinyl, homopiperazinyhnethylphenyl- pyridinyl, morpholinylmethylphenylpyridinyl, dimethylmorpholinylmethylphenyl- pyridinyl, aminoazabicyclo[3.2.1 Joctylmethylphenylpyridinyl, diazabicyclo[3.2.1 ]octyl- methylphenylpyridinyl, tetrazolylphenylpyridinyl, benzofurylpyridinyl, benzothienylpyridinyl, indolylpyridinyl, dimethylisoxazolylpyridinyl, bi(pyridinyl), chlorobi(pyridinyl), carboxybi(pyridinyl), methoxycarbonylbi(pyridinyl), isoquinolinylpyridinyl, moφholinylcarbonylbi(pyridinyl), phenoxyphenyl, benzyloxyphenyl, methoxybenzyloxyphenyl, pyridinylmethoxyphenyl, #-(benzyl)-iV- (ethylcarbonyl)aminophenyl, methylforylmethylaminophenyl, pyridinyhnethylamino- phenyl, cyclopentylcarbonylaminophenyl, phenylcarbonylaminophenyl, benzylcarbonyl- aminophenyl, hydroxypyrrolidinylcarbonylaminophenyl, aminopyrrolidinylcarbonyl- aminophenyl, ϊert-butoxycarbonylaminopyrrolidinylcarbonylaminophenyl, (isopropyl)- (oxo)pyrrolidinylcarbonylaminophenyl, tert-butoxycarbonylpiperidinylcarbonylamino- phenyl, piperazinylcarbonylaminophenyl, methylpiperazinylcarbonylaminophenyl, fer^- butoxycarbonylpiperazinylcarbonylaminophenyl, moφholinylcarbonylaminophenyl, indolylcarbonylaminophenyl, methylisoxazolylcarbonylaminophenyl, pyridinylcarbonyl- atninophenyl, hydroxypyridinylcarbonylaminophenyl, (oxo)(phenyl)pyrrolidinylcarbonyl- aminophenyl, phenylsulphonylaminophenyl, benzylsulphonylaminophenyl, dimethyl- isoxazolylsulphonylaminophenyl, cyclopentylaminocarbonylaminophenyl, phenylamino- carbonylaminophenyl, methylazetidinylaminocarbonylaminophenyl, morpholinylethyl- aminocarbonylaminophenyl, methylimidazolyhnethylaminocarbonylaminophenyl, morpholinylcarbonylcarbonylaminophenyl, pyrrolidinylethylaminocarbonylcarbonyl- aminophenyl, phenylcarbonylphenyl, morpholinylcarbonylphenyl, aminopyrrolidinyl- carbonylmethylphenyl, terf-butoxycarbonylaminopyrrolidinylcarbonylmethylphenyl, aminopiperidinylcarbonylmethylphenyl, methylaminopiperidinylcarbonylmethylphenyl, tert-butoxycarbonylaminopiperidinylcarbonylmethylphenyl, N-(tert-butoxycarbonyl)-N- (methyl)aminopiperidinylcarbonylmethylphenyl, benzylaminocarbonylphenyl, moφholinylethylaminocarbonylphenyl, imidazolylaminocarbonylphenyl, methyl- imiria7ojy1methy]aminocarbonylpheny], pyridinylinethylaminocarbonylphenyl, azetidinylaminocarbonylmethylphenyl, tert-butoxycarbonylazetidinylaminocarbonyl- methylphenyl, pyrrolidinylmethylaminocarbonylmethylphenyl, tert-butoxycarbonyl- pyrrolidinylmethylaminocarbonylmethylphenyl, pyridinylaminocarbonylmethylphenyl, pyridinylmethylaminocarbonylmethylphenyl, phenylaminopyridinyl, N-methyl-JV- phenylaminopyridinyl, azetidinylaminophenylpyridinyl, pyrrolidinylaminophenyl- pyridinyl, tert-butoxycarbonylpyrrolidinylaminophenylpyridinyl, piperazinylcarbonyl- aminophenylpyridinyl, piperidinylaminocarbonylaminophenylpyridinyl, (cyclopropylcarbonyl)(fluoro)phenylpyridinyl, aminoazetidinylcarbonylphenylpyridinyl, methylaminoazetidinylcarbonylphenylpyridinyl, tørt-butoxycarbonylarninoazetidinyl- carbonylphenylpyridinyl, N-^ert-butoxycarbony^-iV-CmethyOaniinoazetidinylcarbonyl- phenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl, hydroxypyrrolidinylcarbonyl- phenylpyridinyl, aminopyrrolidinylcarbonylphenylpyridinyl, aminopyrrolidinylcarbonyl- phenyl(amino)pyridinyl, methylaminopyrrolidinylcarbonylphenylpyridinyl, /ert- butoxycarbonylaminopyrrolidinylcarbonylphenylpyridinyl, /ert-butoxycarbonyl- aminopyrrolidinylcarbonylphenyl(methoxybenzylamino)pyridinyl, piperidinylcarbonylphenylpyridinyl, aminopiperidinylcarbonylphenylpyridinyl, methyl- aminopiperidinylcarbonylphenylpyridinyl, te/'Z-butoxycarbonylaminopiperidinylcarbonyl- phenylpyridinyl, dimethylaminopiperidinylcarbonylphenylpyridinyl, N-(tert-butoxy- carbonyl)-iV-(methyl)aminopiperidinylcarbonylphenylpyridinyl, piperazinylcarbonyl- phenylpyridinyl, methylpiperazinylcarbonylphenylpyridinyl, tert-butoxycarbonyl- piperazinylcarbonylphenylpyridinyl, morpholinylcarbonylphenylpyridinyl, (fluoro)- (morpholinylcarbonyl)phenylpyridinyl, methylaminopiperidinylcarbonylphenyl- pyrimidinyl, dimethylaminopiperidinylcarbonylphenylpyrimidinyl, morpholinylmethylcarbonylphenylpyridinyl, aminoazabicyclo[3.2.1 ]octyl- carbonylphenylpyridinyl, aminoazetidinylcarbonylmethylphenylpyridinyl, fer/-butoxy- carbonylaminoazetidinylcarbonylmethylphenylpyridinyl, pyrrolidinylcarbonylmethyl- phenylpyridinyl, aminopyrrolidinylcarbonylmethylphenylpyridinyl, tert-butoxycarbonyl- aminopyrrolidinylcarbonylmethylphenylpyridinyl, methylaminopiperidinylcarbonyl- methylphenylpyridinyl, N-(tert-butoxycarbonyl)-N-(methyl)aniinopiperidinylcarbonyl- methylphenylpyridinyl, methylpiperazinylcarbonylmethylphenylpyridinyl, azetidinyl- aminoearbonylphenylpyridmyH ^er^b^itoxyeffl^wiyl^etidinylaϊππrø€arlκmyiphαϊyl- pyridinyl, N-(tej-t-butoxycarbonylazetidinyl)-N-(ethyl)aminocarbonylphenylpyridinyl, terf- butoxycaibonylpyrrolidinylaininocaibonylphcnylpyridiiiyl, N-(mcthylpyπOlidinyl)-N- (methyl)aminocarbonylphenylpyridinyl, ^-(methylpiperidinylJ-N-^ethyOaminocarbonyl- phenylpyridinyl, piperidinylmethylaminocarbonylphenylpyridinyl, tert-butoxycarbonyl- piperidinylmethylaminocarbonylphenylpyridinyl, azetidinylaminocarbonylmethylphenyl- pyridinyl and tert-butoxycarbonylazetidinylaminocarbonylmethylphenylpyridinyl. Additional specific values of R5 include (fluoro)(morpholinylcarbonyl)biphenyl, (cWoro)(moφholinyl)phenylpyridinyl and (fluoro)(pyiτolidinylcarbonyl)phenylpyridinyl.
Selected values of R5 include (fluoro)(morpholinylcarbonyl)biphenyl, dimethylaminocarbonylphenylpyridinyl, morpholinylphenylpyridinyl,
(chloro)(morpholinyl)phenylpyridinyl, (cyclopropylcarbonyl)(fluoro)phenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl, (fluoro)(pyrrolidinylcarbonyl)phenylpyridinyl and (fluoro)(morpholinylcarbonyl)phenylpyridinyl.
Particular values of R5 include dimethylaminocarbonylphenylpyridinyl, morpholinylphenylpyridinyl, (cyclopropylcarbonyl)(fluoro)phenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl and (fluoro)(morpholinylcarbonyl)phenylpyridinyl.
Suitably, when R3 and R4 in the compounds of formula (B) above are both hydrogen, then R5 is other than hydrogen.
Suitably, when R5 in the compounds of formula (B) above is hydrogen, then R3 and/or R4 is other than hydrogen.
In one embodiment, R6 represents hydrogen. In another embodiment, R6 represents Ci-6 alkyl, especially methyl. hi one embodiment, R7 represents hydrogen. In another embodiment, R7 represents Ci-6 alkyl, especially methyl.
S K B Suitably, R represents hydroxy or -NRgR . hi one embodiment, R represents hydroxy, hi another embodiment, R8 represents -NRgRh. hi a further embodiment, R8 represents oxo.
Typically, Rg represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl or aryl(C1-6)- alkyl, any of which groups may be optionally substituted by one or more substituents. Suitably, R8 represents Ci-6 alkyl, C3-7 cycloalkyl, aryl or aryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Examples of suitable substituents on Rg and Rh include halogen, cyano, trifluoromethyr, hydroxy, C1-6 alkoxy andtrffluoromethoxy, especially hydroxy. Selected values of R8 include hydrogen, methyl, hydroxyethyl, cyclopropyl, phenyl and .benzyl. .
Typical values of Rg include methyl, hydroxyethyl, cyclopropyl, phenyl and benzyl. Suitably, Rh represents hydrogen or C1-6 alkyl. In one embodiment, Rh represents hydrogen, hi another embodiment, Rh represents C1-6 alkyl, especially methyl.
One sub-class of compounds according to the invention is represented by the compounds of formula (BA), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000044_0001
(BA)
wherein
-X1- represents a group of formula (a), (b) or (c) as defined above;
R5 and R8 are as defined above; Ru represents hydrogen or C1-6 alkyl; and
R12 represents hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, 8TyI(C1 -6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or R1 x and R12, when taken together with the carbon atom to which they are both attached, represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups maybe optionally substituted by one or more substituents.
Suitably, -X - represents a group of formula (a) or (b). In one embodiment, -X1- represents a group of formula (a), hi another embodiment, -X1- represents a group of formula (b). In a further embodiment, -X1- represents a group of formula (c).
Suitably, R5 in the compounds of formula (BA) is other than hydrogen.
Where any of the groups in the compounds of formula (BA) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubβtitutcd.
Typical values of R11 include hydrogen, methyl and ethyl. In one embodiment, R11 is hydrogen. In another embodiment, R11 is C1-6 alkyl, especially methyl. Suitably, R12 represents hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents. Particular values of R12 include hydrogen and unsubstituted C1-6 alkyl.
Examples of typical substituents on R12 include halogen, cyano, nitro, Ci-6 alkyl, trifluoromethyl, hydroxy, Ci-6 alkoxy, difiuoromethoxy, trifiuoromethoxy, aryloxy, C1-6 alkylthio, C1-6 alkylsulphonyl, amino, Ci-6 alkylamino, di(C1-6)alkylarnino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulphonyl, C1-6 alkylaminosulphonyl and di(Ci-6)- alkylaminosulphonyl; especially halogen, Ci-6 alkoxy or Ci-6 alkylthio. Examples of particular substituents on R12 include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifiuoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
Typical values of R12 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl, phenyl, chlorophenyl, methoxyphenyl, methylthiophenyl and furyl, especially hydrogen or methyl. In one embodiment, R12 is hydrogen. In another embodiment, R12 is methyl.
Alternatively, R11 and Ri2 may together form an optionally substituted spiro linkage. Thus, R1 ' and R12, when taken together with the carbon atom to which they are both attached, may represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents. hi this context, R and R , when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl. Other sub-classes of compounds according to the invention are represented by the compounds of formula (IIA-A) and (IIA-B), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000046_0001
Figure imgf000046_0002
wherein -X1-, V, R8, R1 ! and R12 are as defined above; and
R13 represents hydrogen; or Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci.6)alkyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, biaryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalky^C^alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci.6)alkyl,
Figure imgf000046_0003
any of which groups may be optionally substituted by one or more substituents.
Where any of the groups in the compounds of formula (IIA-A) or (ILA-B) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted. Typically, R13 represents hydrogen; or C1-6 alkyl, aryl(Ci-6)alkyl, aryl(C2-6)alkynyl, biaryt(€i-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl(Ci.6)alkyl, heteroaryl-aryl(C1-6)alkyl or aryl-heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Generally, R13 represents hydrogen; or C2-6 alkynyl, aryl(Ci.6)alkyl or heteroaryl- (Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R13 represents aryl(C1-6)alkyl or heteroaryl(Cι-6)alkyl, either of which groups may be optionally substituted by one or more substituents. In one specific embodiment, R13 represents hydrogen. Typically, R13 is other than hydrogen.
In a representative embodiment, R13 represents C1-6 alkyl, aryl(Ci-6)alkyl, biaryl- (Ci-6)alkyl, heteroaryl(Ci.6)alkyl or heteroaryl-aryl(C1-6)alkyl, any of which groups maybe optionally substituted by one or more substituents. Preferably, R13 represents methyl, arylmethyl, biarylmethyl, heteroarylmethyl or heteroaryl-arylmethyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R13 represents arylmethyl or heteroarylmethyl, either of which groups maybe optionally substituted by one or more substituents. In a particular embodiment, R13 represents substituted or unsubstituted indolyl-
(C1-6)alkyl. Advantageously, R13 represents substituted or unsubstituted indolylmethyl.
In a typical embodiment, R13 represents substituted or unsubstituted phenyl- (C]-6)alkyl. Advantageously, R13 represents substituted or unsubstituted benzyl.
In another embodiment, R13 represents substituted or unsubstituted benzofuryl- (Ci-6)alkyl. Advantageously, R13 represents substituted or unsubstituted benzofurylmethyl.
Illustratively, R13 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1,2,3 ,4-tetrahydroquinolinylmethyl, 1,2,3 ,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3,4-tetrahydroquinoxalinylcarbonyl, benzorurylmethyl, benzothienyhnethyl, indolylmethyl, pyrrolo[2,3-&]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazolylmethyl, pyridinylmethyl, quinolinylmethyl, isoquinolinylmethyl, benzofurylbenzyl, thienylbenzyl, benzothienylbenzyl, indolylbenzyl, isoxazolylbenzyl, pyrazolylbenzyl, pyridinylbenzyl, pyrimidinylbenzyl or phenylpyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.
Examples of typical substituents on R13 include halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci^alkylaryl, di(C1-6)alkylaryl, piperidinyl- (C i .6)alkylaryl, piperazinyl(C i -6)alkylaryl, (C i -6)alkylpiperazinyl(C i -6)alkylaryl, morpholinyl(Ci-6)alkylaryl, (Ci-6)alkoxyaryl, cyano(C]-6)alkoxyaryl, di(Ci-6)alkyl- amino(Cι-6)alkylaryl,
Figure imgf000047_0001
aryl(Ci.6)alkyl, oxazolinyl, azetidinyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkylaminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di(C1-6)alkyIamino- carbonylpiperidinyl, piperazinyl, (Ci-6)alkylpiρerazinyl, haloarylpiperazinyl, pyridinylpiperazinyl, fπrnylpiperazinyl, hnmopipera/inyl, (Ci 6)alky1homopiperazinyl, morpholinyl, (d-6)alkylpiperazinyl(C].6)alkyl, morpholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (C1-6)alkylpyrazolyl, (Ii(C1 -6)alkylpyrazolyl, tri(C1-6)alkyl- pyrazolyl, [di(C1-6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano- (Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, hydroxy(Ci-6)alkylpyrazolyl, [hydroxy(Ci-6)- alkyl][di(C1-6)alkyl]pyrazolyl, methoxy(C1-6)alkylpyrazolyl, [(hydroxy)(methoxy)(C1-6)- alkyl]pyrazolyl, amino(Ci-6)alkylpyrazolyl, [(Ci-6)alkyl][amino(C1-6)alkyl]ρyrazolyl, [amino(C1-6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(Ci-6)alkylamino(C1-6)alkylpyrazolyl, di(C1-6)alkoxyphosphono(Ci-6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl- (C,-6)alkylpyrazolyl, [(C3-7)cycloalkyl(CI-6)alkyl][di(C,-6)alkyl]pyrazolyl, [(Ci^alkyl]- (aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(C1-6)alkylpyrazolyl, aminoaryl- (C1-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(Ci-6)alkylpyrazolyl, [di- (Ci^alkyllftetrahydropyrany^Ci^alkylJpyrazolyl, pyrrolidinyl(C1-6)alkylpyrazolyl, piperidinyl(C1-6)alkylpyrazolyl, (d^alkylpiperidiny^d-^alkylpyrazolyl, morpholinyl(C i ^alkylpyrazolyl, pyridinyl(C \ ^alkylpyrazolyl, oxypyridinyl(C i ^alkyl- pyrazolyl,
Figure imgf000048_0001
[(C λ -6)alkyl] (piperazinyl- carbonyl)pyrazolyl, [(C1-6)alkylaminocarbonyl][(C1-6)alkylaryl]pyrazolyl,
Figure imgf000048_0002
[amino(C]-6)alkylaminocarbonyl]pyrazolyl, aminocarbony^Ci^alkylpyrazolyl, [aminocarbonyl(C i -6)alkyl] [di(C i .6)alkyl]pyrazolyl, di(C i -6)alkylaminocarbonyl(C i -6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(Ci-6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]- isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (C1-6)alkylimidazolyl, di(Ci-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkylimidazo[l,2-α]pyridinyl, (C1-6)- alkylimidazo[4,5-Z?]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)- alkylthiadiazolyl, triazolyl, pyridinyl, halopyridinyl, (d-ejalkylpyridinyl, [(C1-6)alkyl]- (halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C1-6)alkylpiperazinyl- pyridinyl, [(Ci -6)alkyl] (piperazinyl)pyridinyl, [(C i -6)alkoxycarbonylpiperazinyl] [(C i ^)- alkyl]pyridinyl,
Figure imgf000048_0003
[(Cj -6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (C1-6)alkoxypyridinyl, [(C1-6)BIkOXy]- [(C1-6)alkyl]pyridinyl, [(C1-6)alkoxy][di(C1-6)alkyl]pyridinyl, (C1-6)alkoxy(Ci-6)alkyl- pyridinyl, aminopyridinyl, CaTbOXy(C1 -6)alkylpyridinyl,
Figure imgf000048_0004
pyridinyl, pyridazinyl, (Ci-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Cι-6)sAkσx.ypyήάaziny\, aminopyridazmyV, hydro-xy(Ci-6)alkylaroinopyridazinyl, di- (Ci.6)alkylaminopyridazinyl, pyrimidinyl, (Ci.6)alkylpyrimidinyl, [(Ci-6)alkyl](halo)- pyrimidinyl, di(Ci.o)αlkylpyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-(s)αlkylpiperαzinyl pyrimidinyl, [(Ci-6)alkyl](piρerazinyl)pyrimidinyl, [(Ci-6)alkoxycarbonyl][(Ci-6)alkyl]- piperazinylpyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(Ci-6)- alkyl][hydroxy(C1-6)alkyl]pyrimidinyl, [(C1-6)alkyl][hydroxy(C2-6)alkynyl]pyrimidinyl, (C1-6)alkoxypyrimidinyl, aminopyrimidinyl, di(Ci.6)alkylaminopyriinidinyl, [di(C1-6)alkyl- amino](halo)pyrimidinyl, carboxypyrimidinyl, [(C1-6)alkoxycarbonyl(Ci-6)alkyl] [(C1-6)- alkyljpyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (C1-6)alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(Ci-6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy, morpholinyl(C1-6)- alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i -6)alkylpyrazolyl- pyridinyloxy,
Figure imgf000049_0001
carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy,
Figure imgf000049_0002
[(Ci-6)alkyl](halo)pyrimidinyloxy, hydroxy(Ci-6)alkyl, dihydroxy^^alkyl, pyridinyloxy(Ci-6)alkyl, methylenedioxy, difluoromethylenedioxy, amino, (Ci-6)alkyl- amino, dihydroxy(Ci-6)alkylamino, (Ct^alkox^Ci^alkylamino, di(C1-6)alkylamino, N- [(C1-6)alkoxy(C1-6)alkyl]-iV-[(C1-6)alkyl]amino, di(C1-6)alkylamino(C1-6)alkylamino, N- [(Ci-6)alkyl]-N-[di(C1-6)alkylamino(Ci-6)alkyl]amino, N-[(C1-6)alkyl]-N-[(C3-7)cycloalkyl]- amino, haloarylamino, N-[(Ci^)alkyl]-N-(haloaryl)amino, methylenedioxyphenylamino, morpholiny^Ci^alkylphenylamino, oxazolinylphenylamino, [(Ci-6)alkyl](oxo)pyrazolyl- phenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, (C i -6)alkyltriazolylphenylamino, (C \ -6)alkylpyrimidinylphenylamino, pyrazolyl(C i ^alkyl- phenylamino, triazolyl(Ci-6)alkylphenylamino, Ci-6 alkylsulphonylaminophenylamino, morpholinylcarbonylphenylamino, Ci-6 alkylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-[(Ci-6)alkyl]-N-[aryl(Ci-6)alkyl]amino, N- [di(C i -6)alkylamino(C i _6)alkyl] -N- [aryl(C i -6)alkyl] amino, cyanoaryl(C i -6)alkylamino, (cyano)(halo)aryl(C i -6)alkylamino, methylenedioxyaryl(C 1 -6)alkylamino, dihydrobenzofuranylamino, N-[(C i_6)alkyl]-N-[(C i -6)alkylpyrrolidinyl]amino, C i -6 alkylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-[(Ci-6)alkyl]-N- (piperidinyl) amino, N- [(C3-7)cycloalkyl(C i ,6)alkyl] -N-(piperidinyl)amino,
Figure imgf000049_0003
piperidinylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpiperidinyl]amino, N-[(Ci-6)alkyl]- ^fCQ^JcycroalkyrpfperidinylJamino, N-KCi^alkyrj-N-f^-Jalkyrcarbonylpiperidinyl]- amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinyl(C1-6)alkylamino, N^(Ci-6)alkyl]-N4pyrrolidin3'l(C1-6)alk34]amino, N-[(C1-6)alkyl]-N-[piperidinyl(C1-6)- alkyl]amino, benzothienylamino, indolylamino, dioxoindolylamino,
Figure imgf000050_0001
amino, [(Ci-6)alkyl](halo)pyrazolylamino, di(Ci-6)alkylpyrazolylaniino, tri(Ci-6)alkyl- pyrazolylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkylpyrazolyl]amino, (C1-6)alkylindazolylamino, benzoxazolylamino, benzoxazolonylamino, di(Ci.6)alkylisoxazolylamino, thiazolylamino, benzothiazolylamino,
Figure imgf000050_0002
imidazolylamino, [(Ci.6)alkoxy- carbonyl] [(C^alkyljimidazolylamino, (C1-6)alkylbenzimidazolylamino, benzimidazolonylamino, di(C i -6)alkylbenzimidazolonylamino, (C 1 ^alkyloxadiazolyl- amino, furyloxadiazolylamino, (Ci^alkylthiadiazolylamino, pyridinylamino, halopyridinylamino,
Figure imgf000050_0003
di(Ci-6)alkylpyridinylaniino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(Ci-6)alkylpyridinylaniino, dihydroxy(C \ ^alkylpyridinylamino, (C \ -6)alkoxypyridinylamino , dihydroxy(C i ^alkoxy- pyridinylamino, di(C i ^alkyldioxolany^C 1.6)alkoxypyridinylamino, (C \ -6)alkoxy(C \ ^)- alkylpyridinylamino, (C1^)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(Ci.6)alkyl- aminopyridinylamino,
Figure imgf000050_0004
pyridinylamino, di(Ci-6)alkylamino(C1-6)alkylpyridinylamino, oxopyridinylamino, carboxypyridinylammo, N-[(C1-6)alkyl]-N-[(Ci-6)alkylpyridmyl]amino, bis[(C1-6)aIkyl- pyridinyl]amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, (Ci-όjalkyl- pyridazinylamino, N-[(C1-6)alkyl]-iV-[(Ci-6)alkylpyridazinyl]amino, JV-[aryl(Ci-6)alkyl]-JV- [(C i -6)alkylpyridazinyl] amino,
Figure imgf000050_0005
arylpyridazinylamino, piperidinylpyridazinylamino, (Ci-6)alkoxypyridazinylamino, [(Ci.6)alkoxy](halo)- pyridazinylamino, di(C1-6)alkylaminopyridazinylamino, bis[(C1-6)alkylpyridazinyl]amino, (C1-6)alkylcinnolinylamino, oxopyrimidinylamino, thioxopyrimidinylamino, quinoxalinylamino,
Figure imgf000050_0006
alkylamino, UIdOIyI(C1 -6)alkylamino, (Ci^alkylpyrazoly^C^alkylamino, [di(C1-6)alkyl]- (halo)pyrazolyl(C1-6)alkylamino, di(C1-6)alkylisoxazolyl(C1-6)alkylamino, thiazolyl(C1-6)- alkylamino, imidazolyl(C \ .6)alkylamino, (Ci -6)alkylimidazolyl(C i ^alkylamino, pyridinyl(C j ^alkylamino, (C i .6)alkylpyridinyl(C j ^alkylamino, N-[(C i ^alkyl] -N- [pyridinyl(C1-6)alkyl]amino, N-[dihydroxy(Ci.6)alkyl]-N-[pyridinyl(C1-6)alkyl]amino, N- [(C i -6)alkylpyridinyl(C i .6)alkyl]-N- [dihydroxy(C i -6)alkyl] amino, amino(C i ^)alkyl, (C i .6)- alkylamino(Ci-6)alkyl, di(C1-6)alkylamino(C1-6)alkyl,
Figure imgf000050_0007
C2-6 aikyfcarbonylaπimσ, JV-[(C2-6)alkyicaτbonyh}-Λ^[(C1-6)alkyipyridiπyl(C1-6)alkyt}amine, di(C1-6)alkylamino(C1-6)alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, (C3-7)- eyolυalkyleaibυnylaiiiinυ, (Ci-^alkylpipeπdiiiylcaibuiiylamino, (Ci-6)alkyliniidazolyl- carbonylamino, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(Cι-6)alkyl]amino, C1-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl 0-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, [hydroxy(Ci-6)alkyl] aminocarbonyl, [di(Ci-6)- alkylamino(C 1-6)alkyl] aminocarbonyl, di(C i ^alkylaminocarbonyl, [(C \ -6)alkyl] [cyano- (C i -6)alkyl] aminocarbonyl, [(C i .6)alkyl] [hydroxy(C \ -6)alkyl] aminocarbonyl, [(C1 -6)alkoxy- (C 1-6)alkyl] [(C i -6)alkyl] aminocarbonyl, [di(C \ -6)alkylamino(C i -6)alkyl] [(C 1-6)alkyl] amino- carbonyl, C3-7 cycloalkyl(Cι-6)alkylaminocarbonyl, 8TyI(C1 -6)alkylaminocarbonyl, (C1-6)- alkylpiperidmylaminocarbonyl, ^[(Ci-όJalkylJ-N-f^i^-alkylpiperidinylJaminocarbonyl, piperidinyl(C1-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(Ci-6)alkyl- aminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, (d^alkyl- pyrrolidinylcarbonyl, C1-6 alkoxy(C1-6)alkylpyrrolidinylcarbonyl, di(Ci-6)alkylamino- pyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinyl- carbonyl, (C1-6)alkylpiperazinylcarbonyl, morpholinylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C1-6 alkylsulphonylmethyl, aminosulphonyl, Ci-6 alkylaminosulphonyl, di(C1-6)aIkylaminosulphonyl, C2-6 alkoxycarbonyloxy, trimethylsilyl and tetra(C1-6)alkyldioxaborolanyl.
Particular examples of typical substituents on R13 include Cj-6 alkyl and di(C1-6)alkylaminocarbonyl.
Selected examples of specific substituents on R13 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, morpholinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazofyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylpropylpyrazolyl, 3- methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazotyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)pyrazolyl, (dimethyl)(3 - methylbutyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2- hydroxy-2-methylpropylpyrazolyl, (hydroxyethyl)(dimethyl)pyrazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, [(hydroxy)- (methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (phenyl)(trifluoromethyl)pyrazolyl, benzylpyrazolyl, aminobenzylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranylmethylpyrazolyl, (dimethyl)(tetrahydropyranyl- methyl)pyrazolyl, pyrrolidinylethylpyrazolyl, piperidinylethylpyrazolyl, methyl- piperidinylethylpyrazolyl, morpholinylethylpyrazolyl, pyridinylmethylpyrazolyl, oxypyridinylmethylpyrazolyl, (dimethyl)(phenylcarbonylmethyl)pyrazolyl, (ethyl)(piperazinylcarbonyl)pyrazolyl, (methylaminocarbonyl)(methylphenyl)pyrazolyl, (aminoethylarninocarbonyl)(methyl)pyrazolyl, aminocarbonylmethylpyrazolyl, (aminocarbonylmethyl)(dimethyl]pyrazolyl, dimethylaminocarbonylmethylpyrazolyl, pyrazolo[l,5-β]pyridinyl, dimethylisoxazolyl, (amino)(methyl)isoxazolyl, thiazolyl, dimethylthiazolyl, imidazolyl, methylimidazolyl, dimethylimidazolyl, imidazo[l,2- ύi]pyridinyl, methylimidazo[l,2-α]ρyridinyl, methylimidazo[4,5-ό]pyridinyl, imidazo[l,2- α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, methylthiadiazolyl, triazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methylpiperazinyl)pyridinyl, (methyl)(piperazinyl)pyridinyl, (tert- butoxycarbonylpiperazinyl)(methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)- pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, methoxypyridinyl, (methoxy)(methyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonyl- methylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylamino- pyridazinyl, pyrimidinyl, methylpyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethyl- pyπrπidπryr,
Figure imgf000052_0001
iπετhyrpτpeτazπryrpyrτrπidπryτ, (metπyr^ (piperazinyl)pyrimidinyl, (tert-butoxycarbonylpiperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(inelliyl)pyϊimidinyl, (hydϊoxyethyl)(methyl)pyrimidmyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxypropynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, (dimethylamino)- (fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonylmethyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinyl- pyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxy- pyridinyloxy, aminocarbonylpyridinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1- methylethyl, dihydroxypropyl, pyridinyloxymethyl, methylenedioxy, difluoromethylenedioxy, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, dimethylamino, N-(methoxyethyl)-N- (methyl)amino, N-(methoxypropyl)-N-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N-(dimemylaminoethyl)-N-(memyl)amino, N- (diethylaminoethyl)-N-(methyl)amino, N-(dimethylaminopropyl)-7V-(methyl)amino, N- (dimethylaminoethyl)-N-(ethyl)amino, N-(dimethylaminopropyl)-N-(ethyl)amino, N- (cyclohexyl)-N-(methyl)amino, fluorophenylamino, N-fluorophenyl-N-methylamino, methylenedioxyphenylamino, morpholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenylamino, triazolyhnethylphenylamino, methylsulphonylamino- phenylamino, morpholinylcarbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-benzyl-N-methylamino, N-(benzyl)-N-(dimethyl- aminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)- benzylamino, methylenedioxybenzylamino, dihydrobenzofiiranylamino, N-(methyl)-N- (methylpyrrolidinyl)amino, methylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N-(piperidinyl)amino, N- (cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinylamino, N-(methyl)-N- (methylpiperidinyl)amino, N-(methyl)-N-(2-methylpropylpiperidinyl)amino, N- (cycIopentyIpiperidinyI)-N-(methyI) amino, N-(acetyIpϊperidinyI)-N-(methyI)amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-Λ'-(pyrro1idinylethyl)amino, Λ^(methyl)-N- (pyrrolidinylpropyl)amino, N-(methyl)-N-(piperidinylmethyl)amino, benzothienylamino, indolylamino, dioxoindolylamino, methylpyrazolylamino, (bromo)(methyl)pyrazolyl- amino, dimethylpyrazolylamino, trimethylpyrazolylamino, N-(ethyl)-iV-(methylpyrazolyl)- amino, methylindazolylamino, benzoxazolylamino, benzoxazolonylamino, dimethyl- isoxazolylamino, thiazolylamino, benzothiazolylamino, methylisothiazolylamino, imidazolylamino, (ethoxycarbonyl)(methyl)imidazolylamino, methylbenzimidazolyl- amino, benzimidazolonylamino, dimethylbenzimidazolonylamino, methyloxadiazolyl- amino, furyloxadiazolylamino, methylthiadiazolylamino, pyridinylamino, chloropyridinyl- amino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinylτ amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, oxopyridinylamino, carboxypyridinylamino, N-(methyl)-N-(methylpyridinyl)- amino, ^-(ethy^-jV-^ethylpyridiny^amino, bis(methylpyridinyl)amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-N- (methylpyridazinyl)amino, iV-(benzyl)-N-(methylpyridazinyl)amino, dimethyl- pyridazinylamino, phenylpyridazinylamino, piperidinylpyridazinylamino, methoxypyridazinylamino, (chloro)(methoxy)pyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, methylcinnolinylamino, oxopyrimidinyl- amino, thioxopyrimidinylamino, quinoxalinylamino, methylchromenylamino, benzofurylmethylamino, thienylmethylamino, indolylmethylamino, methylpyrazolyl- methylamino, (chloro)(dimethyl)pyrazolylmethylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethylamino, methylimidazolylmethylamino, pyridinylmethyl amino, methylpyridinylmethylamino, iV-(methyl)-iV-(pyridinylethyl)- amino, N-(dihydroxypropyl)-N-(pyridinylmethyl)amino, N-(dihydroxypropyl)-N- (methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, acetylamino, N-(acetyl)-N-(methylpyridinyl)amino, dimethylaminoethylcarbonylamino, acetylaminomethyl, cyclohexylcarbonylamino, mettiylpipα'idinyiearbofiylamino, methyKmidazolyicarbonylamino, methoxyearbonyl- amino, N-methoxycarbonyl-N-methylamino, methylsulphonylamino, formyl, acetyl, acetyl oxime, acetyl <9-(methyl)oximc, trifluoromcthylcarbonyl, carboxy, mcthoxycarbonyl, aminocarbonyl, methylaminocarboπyl, (hydroxyethyl)aminocarbonyl, (dimethyl- aminoethyl)aminocarbonyl, (l-hydroxyprop-2-yl)aminocarbonyl, dimethylamino- carbonyl, N-(cyanomethyl)-N-methylaminocarbonyl, iV-(cyanoethyl)-N-methylamino- carbonyl, iV-(hydroxyethyl)-N-methylaminocarbonyl, N-(methoxyethyl)-iV-methyl- aminocarbonyl, iV-(dimethylaminoethyl)-iV-methylaminocarbonyl, iV-isopropyl-N-methyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(methylpiperidinyl)amino- carbonyl, piperidinylethylaminocarbonyl, pyrazolylaminocarbonyl, pyridinylmethylamino- carbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, tert- butoxycarbonylaminoazetidmylcarbonyl, pyrrolidinylcarbonyl, methylpyrrolidinyl- carbonyl, methoxymethylpyrrolidinylcarbonyl, dimethylaminopyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinyl- carbonyl, morpholinylcarbonyl, isopropylthio, isopropylsulphinyl, methylsulphonyl, isopropylsulphonyl, methylsulphonylmethyl, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, terf-butoxycarbonyloxy, trimethylsilyl and tetramethyl- dioxaborolanyl.
Particular examples of specific substituents on R13 include methyl and dimethylaminocarbonyl.
Typical values of R13 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyhnethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, phenyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazolylphenylaminobenzyl, methylpyrimidinylphenylaminobenzyl, pyrazolylmethylphenylaminobenzyl, triazolylmethylphenylaminobenzyl, methylsulphonylaminophenylaminobenzyl, morpholinylcarbonylphenylaminobenzyl, methylsulphonylphenylaminobenzyl, morpholinylsulphonylphenylaminobenzyl, dϊhydrobenzofύranyraminobenzyl, methylsurphonylmdolinyraminobenzyt, chromanonylaminobenzyl, dihydroquinolinonylaminobenzyl, benzoxazinonyl- aminobenzyl, benzothienylaminobenzyl, indolylaminobenzyl, dioxoindolylaminobenzyl, (bromo)(methyl)pyrazolylaminobenzyl, trimethylpyrazolylaminobenzyl, methylindazolyl- aminobenzyl, benzoxazolylaminobenzyl, benzoxazolonylaminobenzyl, dimethyl- isoxazolylaminobenzyl, benzothiazolylarninobenzyl, methylisothiazolylarninobenzyl, methylbenzimidazolylaminobenzyl, benzimidazolonylaminobenzyl, dimethyl- benzimidazolonylaminobenzyl, methyloxadiazolylaminobenzyl, furyloxadiazolyl- aminobenzyl, pyridinylaminobenzyl, chloropyridinylaminobenzyl, methylpyridinylamino- benzyl, dimethylpyridinylaminobenzyl, methoxypyridinylaminobenzyl, oxopyridinyl- aminobenzyl, oxopyrimidinylaminobenzyl, thioxopyrimidinylaminobenzyl, (chloro)- (methoxy)pyridazinylaminobenzyl, methylcinnolinylaminobenzyl, quinoxalinylamino- benzyl, methylchromenylaminobenzyl, benzofurylmethyl, cyanobenzofurylmethyl, methoxycarbonylbenzofurylmethyl, dimethylaminocarbonylbenzofurylmethyl, azetidinylcarbonylbenzofurylmethyl, indolylmethyl, fluoroindolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, nitroindolylmethyl, methylindolylmethyl, oxazolinylindolylmethyl, triazolylindolylmethyl, methoxyindolylmethyl, (chloro)(methoxy)indolylmethyl, di(methoxy)indolylmethyl, difluoromethoxyindolylmethyl, trifluoromethoxyindolylmethyl, (chloro)(trifluoro- methoxy)indolylmethyl, cyclobutyloxyindolylmethyl, cyclopropylmethoxyindolylmethyl, morpholinylethoxyindolylmethyl, methylenedioxyindolylmethyl, difluoromethylenedioxy- indolylmethyl, azetidinylindolylmethyl, morpholinylindolylmethyl, acetylamino- indolylmethyl, acetylaminomethylindolylmethyl, methoxycarbonylaminoindolylmethyl, N-methoxycarbonyl-N-methylaminoindolylmethyl, methylsulphonylaminoindolylmethyl, acetylindolylmethyl, [acetyl oxime]indolylmethyl, [acetyl O-(methyl)oxime]- indolylmethyl, trifluoromethylcarbonylindolylmethyl, carboxyindolylmethyl, (carboxy)- (methyl)indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl, (chloro)(methoxycarbonyl)indolylmethyl, aminocarbonylindolylmethyl, (aminocarbonyl)(chloro)indolylmethyl, methylaminocarbonylindolylmethyl, (chloro)- (methylaminocarbonyl)indolylmethyl, (hydroxyethy^aminocarbonylindolylmethyl, (dimethylaminoethyl)aminocarbonylindolylmethyl, (l-hydroxyprop-2-yl)aminocarbonyl- indolylmethyl, dimethylaminocarbonylindolylmethyl, (dimethylaminocarbonyl)(methyl)- indolylmethyl, (chloro)(dimethylaminocarbonyl)indolylmethyl, bis(dimethylamino- cartyσπyt)πτdσtylmethyh M((^πoiτiethy^Λ^-me^laτmirøcarbOnyiiπdOly}mefttyl, [N- (cyanomethyl)-N-methylaminocaτbonyl](methyl)indolylmethyl, N-(cyanoethyl)-N- methylaminocarbonylindolylmethyl, N-(hydroxyethyl)-N-methylaminocarbonyl- indolylmethyl, ^-(methoxyethyO-jV-methylaininocarbonylindolylmethyl, [N-(methoxy- ethyl)-N-methylaminocarbonyl](methyl)indolylmethyl, N-(dimethylaminoethyl)-N- methylaminocarbonylindolylmethyl, N-isopropyl-N-methylaminocarbonylindolylmethyl, diethylaminocarbonylindolylmethyl, cyclopropylmethylaminocarbonylindolylmethyl, benzylaminocarbonylindolylmethyl, pyrazolylaminocarbonylindolylmethyl, pyridinylmethylaminocarbonylindolylmethyl, azetidinylcarbonylindolylmethyl, (azetidinylcarbonyl)(methyl)indolylmethyl, hydroxyazetidinylcarbonylindolylmethyl, aminoazetidinylcarbonylindolylmethyl, tert-butoxycarbonylaminoazetidinylcarbonyl- indolylmethyl, pyrrolidinylcarbonylindolylmethyl, methylpyrrolidinylcarbonyl- indolylmethyl, methoxymethylpyrrolidinylcarbonylindolylmethyl, dimethylamino- pyrrolidinylcarbonylindolylmethyl, thiazolidinylcarbonylindolylmethyl, oxothiazolidinyl- carbonylindolylmethyl, piperidinylcarbonylindolylmethyl, methylpiperazinylcarbonyl- indolylmethyl, moφholinylcarbonylindolylmethyl, methylsulphonylindolylmethyl, methylsulphonylmethylindolylmethyl, dimethylaminosulphonylindolylmethyl, trimethylsilylindolylmethyl and pyrrolo[3,2-c]pyridinylmethyl.
A particular value of R13 is (dimethylaminocarbonyl)(methyl)indolylmethyl. One particular sub-group of the compounds of formula (IIA-A) is represented by the compounds of formula (HB), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000057_0001
(IB)
wherein V, R8, R1 ' and R12 are as defined above;
T represents oxygen or M-R25;
R23 represents hydrogen, halogen, cyano, nitro, Ci-6 alkyl, hydroxy(Ci-6)alkyl, trifluoromethyl, aryl(Ci-6)alkyl, oxazolinyl, triazolyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 CyClOaIlCyI(C1-6)BIkOXy, moφholinyl(Cι.6)alkoxy, aryloxy, 8TyI(C1 -6)alkoxy, C1-6 alkylthio, Ci-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, Cj-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(Ci-6)alkyl]amino, Ci-6 alkylsulphonylamino, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl <2-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, [hydroxy(C1-6)- alkyl] aminocarbonyl, [di(C i .6)alkylamino(C i ^alkyl] aminocarbonyl, di(C i ^alkylaminocarbonyl, [(Ci-6)alkyl][cyano(Ci-6)alkyl]aminocarbonyl, [(Ci-6)alkyl][hydroxy(C1-6)- alkyl] aminocarbonyl,
Figure imgf000058_0001
amino(Ci-6)alkyl][(C1-6)alkyl]aminocarbonyl, C3-7 cycloalkyl(Ci-6)alkylaminocarbonyl, aryl(C i -6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C i .^alkylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, (C i -6)alkylpyrrolidinyl- carbonyl, Ci-6 alkoxy(Ci-6)alkylpyrrolidinylcarbonyl, di(C1-6)alkylarmnopyrrolidinyl- carbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, (Ci-6)- alkylpiperazinylcarbonyl, morpholinylcarbonyl, Ci-6 alkylsulphonyl, C1-6 alkylsulphonyl- methyl or di(Ci-6)alkylaminosulphonyl; and
R24 represents hydrogen, halogen, Ci-6 alkoxy or di(Ci-6)alkylaminocarbonyl; or
R23 and R , when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and
R25 represents hydrogen or C1-6 alkyl.
In a preferred embodiment, T is N-R25. In another embodiment, T is oxygen.
A suitable value of R23 is di(Ci-6)alkylaminocarbonyl.
Illustrative values of R23 include hydrogen, fluoro, chloro, cyano, nitro, oxazolinyl, triazolyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, morpholinylethoxy, azetidinyl, morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino, N-methoxycarbonyl-iV-methylamino, methylsulphonylamino, acetyl, acetyl oxime, acetyr
Figure imgf000058_0002
tx ifluoroiiiothyt carboiiyr, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dime(.hylaniiiiυelhyl)ainiiiυυaibonyl, (1 -liydiυλypιυp-2-yl)amiiiυeaibυnyl, dimetliyl- aminocarbonyl, ^-(cyanomethyO-iV-niethylaminocarbonyl, N-(cyanoethyl)-N-methyl- aminocarbonyl, N-(hydroxyethyl)-7V-methylaininocarbonyl, iV-(methoxyethyl)-JV-methyl- aminocarbonyl, N-(dimethylaminoethyl)-N-methylaminocarbonyl, iV-isopropyl-iV-methyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, pyrazolylaminocarbonyl, pyridinylmethylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, tert-butoxycarbonylamino- azetidinylcarbonyl, pyrrolidinylcarbonyl, methylpyrrolidinylcarbonyl, methoxymethyl- pyrrolidinylcarbonyl, dimethylaminopyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl, morpholinylcarbonyl, methylsulphonyl, methylsulphonylmethyl and dimethylamino- sulphonyl.
A particular value of R23 is dimethylaminocarbonyl. Definitive values of R24 include hydrogen, chloro, methoxy and dimethylaminocarbonyl. A particular value of R24 is hydrogen.
In one embodiment, R25 is hydrogen. In another embodiment, R25 is C1^ alkyl, especially methyl.
Another particular sub-group of the compounds of formula (IIA-A) is represented by the compounds of formula (IIC), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000059_0001
(HC)
wherein
V, R8, R11 and R12 are as defined above; R33 represents halogen or -NHR34; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more sυbsritπents; and
R34 represents methylenedioxyphenyl,
Figure imgf000060_0001
oxazolinyl- phenyl, [(C1-6)alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (C1-6)alkyltriazolylphenyl, (C1-6)alkylpyrimidinylphenyl, pyrazolyl(Ci-6)alkyl- phenyl, MaZoIyI(C1 -6)alkylphenyl, C1-6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci-6 alkylsulphonylphenyl, moφholinylsulphonylphenyl, dihydrobenzofuranyl, C1-6 alkylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, [(Ci-6)alkyl](halo)pyrazolyl, tri(C1-6)alkylpyrazolyl, (Ci-6)alkylindazolyl, benzoxazolyl, benzoxazolonyl, di(C1-6)alkylisoxazolyl, benzothiazolyl,
Figure imgf000060_0002
benzimidazolonyl, di(C1-6)alkylbenzimidazolonyl, (Q^alkyloxadiazolyl, furyloxadiazolyl, pyridinyl, halopyridinyl,
Figure imgf000060_0003
oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl, [(Ci-6)alkoxy](halo)pyridazinyl, (Ci-6)alkylcinnolinyl, quinoxalinyl or (C1-6)alkylchromenyl.
Suitably, R33 represents halogen or -NHR34, in which R34 is as defined above. In one embodiment, R33 represents halogen, especially bromo. In another embodiment, R33 represents -NHR34, in which R34 is as defined above.
In one embodiment, R33 represents unsubstituted or substituted aryl. In another embodiment, R33 represents unsubstituted or substituted heteroaryl.
Typical values of R34 include pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl,
Figure imgf000060_0004
and (Ci-6)alkoxypyridinyl.
Particular values of R34 include methylenedioxyphenyl, morpholinylmethylphenyl, oxazolinylphenyl, (methyl)(oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolylphenyl, methyltriazolylphenyl, methylpyrimidinylphenyl, pyrazolylmethylphenyl, triazolylmethylphenyl, methylsulphonylaminophenyl, morpholinylcarbonylphenyl, methylsulphonylphenyl, moφholinylsulphonylphenyl, dihydrobenzofuranyl, methylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, (bromo)(methyl)pyrazolyl, trimethylpyrazolyl, methylindazolyl, benzoxazolyl, benzoxazolonyl, dimethylisoxazolyl, benzothiazolyl, methylisothiazolyl, methylbenzimidazolyl, benzimidazolonyl, dimethylbenzimidazolonyl, methyloxadiazolyl, furyloxadiazolyl, pyridinyl, chloropyridinyl, methylpyridinyl, dimethylpyridinyl, methoxypyridinyl, oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl, (chloro)(mcthoxy)pyridozinyl, mcthylcinnolinyl, quinoxolinyl and mothylohromonyl.
Suitable values of R34 include pyridinyl, chloropyridinyl, methylpyridinyl, dimethylpyridinyl and methoxypyridinyl. Illustratively, R33 represents halogen or -NHR34, in which R34 is as defined above.
Additionally, R33 represents phenyl, naphthyl, benzofuryl, thienyl, benzothienyl, indolyl, isoxazolyl, pyrazolyl, pyridinyl or pyrimidinyl, any of which groups may be optionally substituted by one or more substiruents.
Selected examples of suitable substiruents on R33 include halogen, cyano, C1-6 alkyl, hydroxy(Ci-6)alkyl, trifluoromethyl, Ci-6 alkoxy, trifluoromethoxy, aryloxy, methylenedioxy, Ci-6 alkylthio, arylsulphonyl, amino, C2-6 alkylcarbonylamino, Ci-6 alkylsulphonylamino, C2-6 alkylcarbonyl and aminocarbonyl.
Selected examples of representative substiruents on R33 include fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, phenoxy, methylenedioxy, methylthio, phenylsulphonyl, amino, acetylamino, methylsulphonylamino, acetyl and aminocarbonyl.
Specific values of R33 include bromo, methylenedioxyphenylamino, morpholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenyl- amino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenyl- amino, triazolylmethylphenylamino, methylsulphonylaminophenylamino, morpholinyl- carbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, dihydrobenzofuranylamino, methylsulphonylindolinylamino, chromanonylamino, dihydroquinolinonylamino, benzoxazinonylamino, benzothienylamino, indolylamino, dioxoindolylamino, (bromo)(methyl)pyrazolylamino, trimethylpyrazolylamino, methyl- indazolylamino, benzoxazolylamino, benzoxazolonylamino, dimethylisoxazolylamino, benzothiazolylamino, methylisothiazolylamino, methylbenzimidazolylamino, benzimidazolonylamino, dimethylbenzimidazolonylamino, methyloxadiazolylamino, furyloxadiazolylamino, pyridinylamino, chloropyridinylamino, methylpyridinylamino, dimethylpyridinylamino, methoxypyridinylamino, oxopyridinylamino, oxopyrimidinyl- amino, thioxopyrimidinylamino, (chloro)(methoxy)pyridazinylamino, methylcinnolinyl- amino, quinoxalinylamino, methylchromenylamino, phenyl, fluorophenyl, difluorophenyl, cMorophenyl, dichlorophenyr, bromophenyt, cyanophenyt, methytphenyl, (fluoro)(methyl)phenyl, dimethylphenyl, hydroxymethylphenyl, trifluoromethylphenyl, bis(trifluoromethyl)phenyl, mefhoxyphenyl, dimethoxyphenyl, ethnxyphenyl, methylenedioxyphenyl, trifluoromethoxyphenyl, phenoxyphenyl, methylthiophenyl, aminophenyl, acetylamino-phenyl, methylsulphonylaminophenyl, acetylphenyl, aminocarbonylphenyl, naphthyl, benzofuryl, thienyl, methylthienyl, acetylthienyl, benzothienyl, phenylsulphonylindolyl, dimethylisoxazolyl, methylpyrazolyl, benzylpyrazolyl, pyridinyl, fluoropyridinyl, chloropyridinyl, methoxypyridinyl and pyrimidinylbenzyl.
A particular value of R33 is bromo.
Other sub-classes of compounds according to the invention are represented by the compounds of formula (IID-1) and (IID-2), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000062_0001
Figure imgf000062_0002
wherein
V, R8, R11 and R12 are as defined above; R43 represents hydrogen, halogen, nitro, Ci-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl,
(Ci-6)alkylaryl, di(C1-6)alkylaryl, piperidinyl(Ci-6)alkylaryl, piperazinyl(Ci.6)alkylaryl, (C1-6)alkylpiperazinyl(Cι-6)alkylaryl, moφholinyl(Ci-6)alkylaryl,
Figure imgf000062_0003
cyano(C i .6)alkoxyaryl, di(C i -6)alkylamino(C i -6)alkylaryl, (C i -6)alkylaminocarbonylaryl, aryl(C1-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aiiiliiυp3/i i υlidiiiy 1, iiidoliiiyl, oxoindolinyl, arylpiperidinyl, αrylcαrbonylpipcridinyl, di- (Ci.6)alkylaminocarbonylpiperidinyl, piperazinyl, (C1-6)alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl,
Figure imgf000063_0001
homopiperazinyl, (Ci-6)alkylpiperazinyl(C1-6)alkyl, morpholiny^C^alkyl, benzofuryl, benzothienyl, pyrazolyl, (C1-6)alkylpyrazolyl, di(Cι.6)alkylpyrazolyl, tri(C1-6)alkyl- pyrazolyl, (difluoromethyl)pyrazolyl, [di(C i -6)alkyl] (trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, hydroxyCCt^alkyl- pyrazolyl, [hydroxy(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, methoxy(Ci.6)alkylpyrazolyl, [(hydroxy)(methoxy)(C1-6)alkyl]pyrazolyl, amino(C1-6)alkylpyrazolyl, [(Q^alkyl]- [amino(C i -6)alkyl]pyrazolyl, [amino(C \ ^alkyl] [di(C i -6)alkyl]pyrazolyl, di(Q -6)alkyl- amino(C i -6)alkylpyrazolyl, di(C t -6)alkoxyphosphono(C i .6)alkylpyrazolyl, (C2-6)alkenyl- pyrazolyl, (C3-7)cycloalkyl(Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl(Ci-6)alkyl][di(Ci-6)alkyl]- pyrazolyl, [(Ci-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(Ci.6)alkyl- pyrazolyl, aminoary^Q-δJalkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl- (C i -6)alkylpyrazolyl, [di(C \ -6)alkyl] [tetrahydropyranyl(C \ -6)alkyl]pyrazolyl, pyrrolidinyl(C i ^alkylpyrazolyl, piperidinyl(C i .6)alkylpyrazolyl, (C ^alkylpiperidinyl- (C i -6)alkylpyrazolyl, moφholinyl(C i ^)alkylpyrazolyl, pyridinyl(C \ -6)alkylpyrazolyl, oxypyridinyl(Ci-6)alkylpyrazolyl, [arylcarbonyl(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(Ci-6)alkyl](piperazinylcarbonyl)pyrazolyl, [(C1-6)alkylaminocarbonyl][(C1-6)alkylaryl]- pyrazolyl, [(Ci-6)alkyl][amino(Ci-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl- (C i .6)alkylpyrazolyl, [aminocarbonyl(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, di(C i _6)alkyl- aminocarbonyl(C1-6)alkylpyrazolyl, pyrazolofl ,5-α]pyridinyl, di(C1-6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (C1-6)alkyl- imidazolyl, di(Ci-6)alkyliinidazolyl, imidazo[l,2-α]pyridinyl, (Ci-6)alkylimidazo[l,2-α]- pyridinyl, (Ci-6)alkylimidazo[4,5-b]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo- [l,2-α]pyrazinyl, (C1-6)alkylthiadiazolyl, pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, [(Ci-6)alkyl](halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C1-6)alkyl- piperazinylpyridinyl, [(Ci-6)alkyl](piperazinyl)pyridinyl, [(Ci.6)alkoxycarbonyl-
Figure imgf000063_0002
(oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (C1-6)alkoxypyridinyl, [(C1-6)alkoxy][(C1-6)alkyl]pyridinyl, [(C1-6)alkoxy][di(Ci-6)alkyl]pyridinyl, (Ci-6)alkoxy(Ci.6)aIkyfpyridrnyr, aminopyridfnyr, carboxy(Ci.6)aIkyIpyridinyr, (Ci-6)alkoxycarbonyl(Ci-6)alkylpyridinyl, pyridazinyl, (Ci-6)alkylpyridazinyl, pjperidinylpyridazinyl, oxypyridazinyl, (Ci 6)alVoxypyrida7inyl, aminopyridazinyl, hydroxy(Ci^)alkylaminopyridazinyl, di(Ci-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-δjalkylpyriniidinyl, [(C1-6)alkyl](halo)pyrimidinyl,
Figure imgf000064_0001
pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinylpyrimidinyl, [(Ci-6)alkyl](piperazinyl)- pyrimidinyl, [(Ci^aUcoxycarbonyl] [(Ci^)alkyl]piperazinylpyrimidinyl, hydroxypyrimidinyl, [(Ci,6)alkyl](hydroxy)pyrimidinyl, [(Ci-6)alkyl][hydroxy(Ci-6)alkyl]- pyrimidinyl, [(Ci-6)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (Ci.6)alkoxypyrimidinyl, aminopyrimidinyl, di(C1-6)alkylaminopyrimidinyl, [di(C1-6)alkylamino](halo)pyrimidinyl, carboxypyrimidinyl, [(C1-6)alkoxycarbonyl(Ci-6)alkyl][(Ci-6)alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (C1-6)OIkOXyPyTaZUIyI, aminopyrazinyl, hydroxy, (Ci-6)alkoxy, ary^Ci^alkoxycarbonylpiperidinyloxy, morpholinyl(Ci-6)alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i ^alkylpyrazolylpyridinyloxy,
Figure imgf000064_0002
carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy,
Figure imgf000064_0003
pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C1-6)alkyl](halo)pyrimidinyloxy, hydroxy(Ci-6)alkyl, dihydroxy(Ci-6)alkyl, pyridinyloxy(Ci-6)alkyl, amino, (C1-6)alkylamino, dihydroxy(C1-6)alkylamino, (C1-6)- alkoxy(Ci-6)alkylamino, N-[(CN6)alkoxy(Ci-6)alkyl]-N-[(Ci-6)alkyl]amino, di(CN6)- alkylamino(C]-6)alkylamino, JV-[(Ci^)alkyl]-iV-[di(C1-6)alkylamino(Ci-6)alkyl]amino, N- [(Ci-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, N-[(C1-6)dkyl]-N-[aryl(Ci-6)alkyl]amino, N-[di(C1-6)alkylamino(C1-6)alkyl]-N-[aryl(C1-6)- alkyl]amino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(Ci-6)alkylamino, methylene- dioxyaryl(C \ -6)alkylamino, N- [(C i ^alkyl] -N- [(C1 -6)alkylpyrrolidinyl] amino, piperidinyl- amino, N-[(C1-6)alkyl]-N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(Ci-6)alkyl]-N- (piperidinyl)amino, (Ci-6)alkylpiperidinylamino,
Figure imgf000064_0004
piperidinyl] amino, N-[(Ci -6)alkyl] -N- [(C3-7)cycloalkylpiperidinyl]amino, N- [(C \ ^alkyl] - N-[(C2-6)alkylcarbonylpiperidinyl]amino, pyrrolidinyl(Ci-6)alkylamino, N-[(Ci-6)alkyl]-N- [pyrrolidinyl(Ci^)alkyl]amino, N-[(Ci-6)alkyl]-N-[piperidinyl(Ci-6)alkyl]amino, (Ci-6)- alkylpyrazolylamino, di(C1-6)alkylpyrazolylamino, In(C1 ^)alkylpyrazolylamino, N-J(C1-6)- alkyl]-N-[(Ci-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(Ci-6)alkoxy- carbonyl] [(C \ ^alkyljimidazolylamino, (C i -6)alkylthiadiazolylamino, pyridinylamino, halopyridmylamino,
Figure imgf000064_0005
di(Ci-6)alkylpyridinylaϊnino, trifhrøro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C1-6)alkylpyridinylamino, dihydroxj^Ci^alkylpyridinylamino, (Ci-6)alfcoxypyridinyl-uiiino, dihydiOxy(C1-6)alkoxy- pyridinylamino, di(C i -6)alkyldioxolanyl(C i -6)alkoxypyridinylamino, (C1 -6)alkoxy(C i -6)- alkylpyridinylamino, (Cj-^alkoxy^^alkenylpyridinylamino, dihydroxy(Ci-6)alkyl- aminopyridinylamino, di(Ci-6)alkylaminopyridinylamino, (Ci-6)alkylamino(Cι-6)alkyl- pyridinylamino, di(C1-6)alkylamino(Ci-6)alkylpyridinylamino, carboxypyridinylamino, N- [(C 1-6)alkyl] -N- [(C i -6)alkylpyridinyl] amino, WSf(C1 ^alkylpyridinyl] amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (C1-6)alkylpyridazinylamino, N-[(Ci-6)alkyl]- N-[(C1-6)alkylpyridazinyl]amino, N-[aryl(C1-6)alkyl]-N-[(C1-6)alkylpyridazinyl]amino, di(Ci.6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C1-6)- alkoxypyridazinylamino, di(C1-6)alkylaminopyridazinylamino, bisKQ^alkylpyridazinyl]- amino, benzofuryl(Ci-6)alkylamino, thienyl(Ci.6)alkylamino, indolyl(Ci.6)alkylamino, (C \ -6)alkylpyrazolyl(C \ .6)alkylamino, [di(C i -6)alkyl](halo)pyrazolyl(C i ^alkylamino, di(Ci-6)alkylisoxazolyl(Ci-6)dkylamino, thiazolyl(Ci-6)alkylamino, imidazoly^Ci^alkyl- amino, (C1-6)alkylimidazolyl(C1.6)alkylamino, pyridinyl(Ci.6)alkylamino, (Ci-6)alkyl- pyridinylζC^alkylamino, ^[(d^alky^-N-fpyridiny^Ci^alky^amino, N-[dihydroxy- (C1-6)alkyl]-N-[pyridinyl(Ci-6)alkyl]amino, N-[(C1-6)alkylpyridinyl(C1-6)alkyl]-N- [dihydroxy(C1-6)alkyl] amino,
Figure imgf000065_0001
amino(Ci-6)alkyl, pyridinylamino(C1-6)alkyl, N-[(C2.6)alkylcarbonyl]-N-[(C1-6)alkyl- pyridinyl(Ci-6)alkyl]amino, di(Ci-6)alkylamino(C1-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (Ci-6)alkylpiperidinylcarbonylamino, (Ci^alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (Ci^alkylpiperidinylaminocarbonyl, N-[(C1-6)alkyl]-N-[(C1-6)- alkylpiperidinyl] aminocarbonyl, piperidinyl(C \ ^alkylaminocarbonyl, (C i -6)alkyl- piperazinylcarbonyl, C1-6 alkylthio, Ci-6 alkylsulphinyl, C1-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy and tetra^^^alkyldioxaborolanyl; and
R44 represents hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy. Suitable values of R43 include halogen, (Ci-6)alkylpyrazolyl, tri(C1-6)alkyl- pyrazolyl, (difluoromethyl)pyrazolyl, hydroxy(C1-6)alkylpyrazolyl, [hydroxy(C1-6)alkyl]- [di(Ci-6)alkyl]pyrazolyl, [(hydroxy)(methoxy)(Ci-6)alkyl]pyrazolyl, (Ci.6)alkylpyridinyl, hydroxy(Ci.6)alkylpyridmyl, pyridazinyloxy, amino and (Ci^alkylpyridazinylamino.
Specific values of R43 include fluoro, chloro, bromo, nitro, methyl, n-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazfnymiethylphenyr, morphoEnylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylpbenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, ftiroylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofiiryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylpropylpyrazolyl, 3- methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)pyrazolyl, (dimethyl)(3- methylbutyl)pyrazolyl, (difluoromethyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2-hydroxy-2-methylpropylpyrazolyl, (hydroxymethyl)- (isopropyl)(methyl)pyrazolyl, (hydroxyethyl)(dimethyl)pyrazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, [(hydroxy)-
(methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (phenyl)(trifluoromethyl)pyrazolyl, benzylpyrazolyl, aminobenzylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranylmethylpyrazolyl, (dimethyl)(tetrahydropyranyl- methyl)pyrazolyl, pyrrolidinylethylpyrazolyl, piperidinylethylpyrazolyl, methyl- piperidinylethylpyrazolyl, morpholinylethylpyrazolyl, pyridinylmethylpyrazolyl, oxypyridinylmethylpyrazolyl, (dimethyl)(phenylcarbonylmethyl)pyrazolyl, (ethyl)(piperazinylcarbonyl)pyrazolyl, (methylaminocarbonyl)(methylphenyl)pyrazolyl, (aminoethylaminocarbonyl)(methyl)pyrazolyl, aminocarbonylmethylpyrazolyl, (aminocarbonylmethyl)(dimethyl]pyrazolyl, dimethylaminocarbonylmethylpyrazolyl, pyrazolo[l,5-α]pyridinyl, dimethylisoxazolyl, (amino)(methyl)isoxazolyl, thiazolyl, dimethylthiazolyl, imidazolyl, methylimidazolyl, dimethylimidazolyl, imidazo[l,2- α]pyridinyl, methylimidazo[l,2-α]pyridinyl, methylimidazo[4,5-b]pyridinyl, itnidazo[l,2- α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, methylthiadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methyl- piperaziπyl)pyridinyt, (methyl)(piperazittyl)pyridmyi, (tertAmtoxycaήκmy\^ipeτazmyϊ)~ (methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)pyridinyl, hydroxypyridinyl, hydroxymetliylpyridinyl, hydiOxyethylpyridinyl, ( 1 -hydroxy- 1 -methylethyl)pyi'idinyl, methoxypyridinyl, (methoxy)(methyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonylmethylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylarninopyridazinyl, dimethylaminopyridazinyl, pyrimidinyl, methylpyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)(piperazinyl)pyrimidinyl, (tert-butoxycarbonylpiperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxypropynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, (dimethylamino)(fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonyl- methyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinylpyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1-methylethyl, dihydroxypropyl, pyridinyloxymethyl, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, N-(methoxyethyl)-N-(methyl)amino, JV- (methoxypropyl)-7V-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N-(dimethylaminoethyl)-N-(methyl)amino, N- (diethylaminoethyl)-N-(methyl)amino, N-(dimethylaminopropyl)-N-(methyl)amino, N- (dimethylarninoethyl)-N-(ethyl)amino, N-(dimethylaminopropyl)-N-(ethyl)arnino, N- (cyclohexyl)-N-(methyl)amino, fluorophenylamino, N-fluorophenyl-N-methylamino, N- benzyl-N-methylamino, N-(benzyl)-N-(dimethyIaminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)benzylamino, methylenedioxybenzylamino, N- (methyl)-N-(methylρyrrolidinyl)amino, piperidinylamino, N-(methyl)-N-
(piperidinyl)amino, N-(ethyl)-N-(piperidinyl)amino, N-(cyclopropylmethyl)-N- (piperidinyl)amino, methylpiperidinylamino, N-(methyl)-N-(methylpiperidinyl)amino, N- (methyl)-N-(2-methylpropylpiperidinyl)amino, N-(cyclopentylpiperidinyl)-N- (methyl)amino, 7V-(acetylpiperidinyl)-N-(methyl)amino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N-(pyrrolidinylethyl)amino, ^-(methyO-Λ'- (pyrrolidinylpropyl)amino, iV-(methyl)-N-(piperidinylmethyl)amino, methylpyrazolylamino, dimethylpyrazolylamino, trimethylpyrazolylamino, N-(ethyl)-N- (methylpyrazolyl)amino, thiazolylamino, imidazolylamino,
(ethoxycarbonyl)(methyl)imidazolylamino, methylthiadiazolylamino, pyridinylamino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomeihylpyridinylamino, dimethylaminomethylpyridinyl- amino, carboxypyridinylamino, N-(methyl)-N-(methylpyridinyl)amino, N-(ethyl)-N- (methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-N-(methylpyridazinyl)amino, N- (benzyl)-N-(methylpyridazinyl)amino, dimethylpyridazinylamino, phenylpyridazinyl- amino, piperidinylpyridazinylamino, methoxypyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, benzofurylmethylamino, thienylmethyl- amino, indolylmethylamino, methylpyrazolylmethylamino, (chloro)(dimethyl)pyrazolyl- methylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethyl- amino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethyl- amino, N-(methyl)-N-(pyridinylethyl)amino, N-(dihydroxypropyl)-N-(pyridinylmethyl)- amino, N-(dihydroxypropyl)-N-(methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, N-(acetyl)-N-(methyl- pyridinyl)amino, dimethylaminoethylcarbonylamino, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, formyl, acetyl, methylpiperidinylaminocarbonyl, ^(methyO-N-^ethylpiperidinyOaminocarbonyl, piperidinylethylaminocarbonyl, methylpiperazinylcarbonyl, isopropylthio, isopropyl- sulphinyl, isopropylsulphonyl, tert-butoxycarbonyloxy and tetramethyldioxaborolanyl. Particular values of R43 include fluoro, chloro, bromo, methylpyrazolyl, trimethylpyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (difluoromethyl)pyrazolyl, hydroxyethylpyrazolyl, (hydroxymethyl)(isopropyl)(methyl)pyrazolyl, [(hydroxy)(methoxy)propyl]pyrazolyl, methylpyridinyl, ( 1 -hydroxy- 1 -methylethyl)- pyridinyl, pyridazinyloxy, amino and melhylpyridazinylamino.
In one embodiment, R44 represents hydrogen. In another embodiment, R44 represents halogen, especially fluoro, chloro or bromo. In a further embodiment, R44 represents C1^ alkyl, especially methyl. In an additional embodiment, R44 represents Cj-6 alkoxy, especially methoxy.
Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof. The present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl 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). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles 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. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (I) maybe 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. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds 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, fluorotrichlorornethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
For topical 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. Alternatively, 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.
For ophthalmic administration 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 phenylmereurie nilrale, benzylalkoiiium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum. For rectal administration 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. 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. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
The compounds of formula (I) above wherein R represents hydroxy may be prepared by a process which comprises reacting a compound of formula (III):
Figure imgf000071_0001
R3
(HI)
wherein U, -X-, R1, R2, R3 and R4 are as defined above; with a halogenating agent; followed by treatment with water. The halogenating agent of use in the reaction with compound (III) is suitably a chlorinating agent, e.g. N-chlorosuccinimide, in which case the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, or a cyclic ether such as tetrahydrofuran. The subsequent treatment with water is conveniently accomplished at an elevated temperature.
Likewise, the compounds of formula (I) above wherein R8 represents -NRgRh may be prepared by a process which comprises reacting a compound of formula (III) with a halogenating agent, as described above; followed by treatment with a compound of formula H-NRεRh.
The subsequent treatment with a compound of formula H-NRgRh is conveniently accomplished at an elevated temperature, typically in a suitable solvent such as methanol or acetonitrile, optionally in the presence of a base such as N^/V-diisopropylethylamine or potassium carbonate.
The compounds of formula (III) above may be prepared by reacting a compound of formula (IV) with a compound of formula (V):
Figure imgf000072_0001
(IV) (V)
wherein U, -X-, R1, R2, R3 and R4 are as defined above, and L1 represents a suitable leaving group.
The leaving group L1 is typically a halogen atom, e.g. bromo.
The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, dimethylsulphoxide, a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as NJV-dimethylformamide, optionally under basic conditions, e.g. in the presence of an organic base such as NJV- diisopropylethylamine or 2,6-lutidine.
Alternatively, the reaction may be effected at an elevated temperature in a solvent such as 2-ethoxyethanol in the presence of a catalytic quantity of a mineral acid, e.g. concentrated hydrochloric acid.
In another alternative, the reaction may be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium tert-butoxide, in the presence of a transition metal catalyst. The transition metal catalyst is suitably palladium(II) acetate, in which case the icactiυn will ideally be performed in the presence of tert-butylphosphonium tetrafluoroborate or dicyclohexyl diphenylphosphine.
The intermediates of formula (IV) above wherein L1 is bromo may be prepared from a compound of formula (VI):
Figure imgf000073_0001
(VI)
wherein U, -X-, R1 and R2 are as defined above; by diazotization/bromination.
The reaction is conveniently effected by stirring compound (VI) with tert-butyl nitrite and copper(II) bromide in a suitable solvent, e.g. acetonitrile.
The intermediates of formula (VI) above wherein U represents N may be prepared by reacting thiourea with a compound of formula (VII):
Figure imgf000073_0002
(vπ)
wherein -X-, R1 and R2 are as defined above, and L2 represents a suitable leaving group.
The leaving group L2 is typically a halogen atom, e.g. bromo or iodo. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, typically under basic conditions, e.g. in the presence of an organic base such as ΛζN-diisopropylethylamine.
Alternatively, the reaction may be accomplished by heating the reactants in a lower alkanol solvent, e.g. a Ci-6 alkyl alcohol such as ethanol. The intermediates of formula (VI) above wherein U represents C-R5, -X- rθprθGθntβ α group of formula (a), (b) or (c) in whioh Y is oxygen, and R5 repretionts oyano or -CO2Rb, may be prepared by reacting a compound of formula R5a-CH2-CN with the appropriate compound of formula (VIIIA), (VIIIB) or (VIIIC):
Figure imgf000074_0001
wherein R1 and R2 are as defined above, and R5a represents cyano or -CO2Rb in which R is as defined above; in the presence of sulphur. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of morpholine.
In another procedure, the compounds of formula (I) may be prepared by a process which comprises reacting a compound of formula (VII) as defined above with a compound of formula (IX):
Figure imgf000074_0002
R3 (DC)
wherein R3 and R4 are as defined above; under conditions analogous to those described above for the reaction between thiourea and compound (VII).
The reaction may additionally be accomplished by heating the reactants in acetic acid in the presence of sodium acetate. The intermediates of formula (IX) above may be prepared by reacting a compound υf formula (V) as defined above with l,r-lluocaibonyldiimidazole; followed by treatment with ammonia or ammonium hydroxide.
Where they are not commercially available, the starting materials of formula (V), (VII) and (VIIIAy(VIIIBy(VIIIC) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. Similar considerations apply to the compounds of formula (III). By way of example, a compound of formula (IA-B), (IB-B), (IC-B) or (ID-B) wherein Y is oxygen may be converted into the corresponding compound wherein Y is sulphur by treatment with Lawesson's Reagent (i.e. 2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulphide). Similarly, a compound of formula (IA-A) or (IC-A) may be converted into the corresponding compound of formula (IB-A) or (ID-A) respectively by treatment with Lawesson's Reagent. A compound of formula (IB-B) wherein Y is oxygen may be converted into the corresponding compound of formula (ID-B) by treatment with hydroxylamine-O-sulfonic acid, typically in the presence of formic acid at an elevated temperature. A compound of formula (IB-B) wherein Y is oxygen may be converted into the corresponding compound of formula (IE-B) by treatment with a reducing agent such as lithium aluminium hydride. A compound of formula (IB-B) wherein Y is oxygen may be converted into the corresponding compound of formula (IF-B) by treatment with a hydroxylamine derivative of formula H2N-OR7. A compound of formula (IB-B) wherein Y is oxygen may be converted into the corresponding compound of formula (IG-B) by treatment with hydrazine hydrate. A compound of formula (IF-B) may be converted into the corresponding compound of formula (IC-B) by treatment with/7-toluenesulphonyl chloride, typically in the presence of pyridine at an elevated temperature. A compound of formula (IB-B) wherein Y is oxygen and R1 is hydrogen may be converted into the corresponding compound wherein R1 is methyl by treatment with a methyl halide, e.g. iodomethane, in the presence of a strong base, e.g. lithium diisopropylamide. A compound of formula (I) wherein R8 represents hydroxy may be converted into the corresponding compound wherein R8 represents oxo by treatment with an oxidising agent such as Dess-Martin periodinane.
A compound of formula (I) wherein R3 and/or R4 contains an aryl or heteroaryl moiety may be halogenated (e.g. brominated) on the aryl or heteroaryl moiety by treatment with the appropriate N-halosuccinimide (e.g. N-bromosuccinimide).
A compound of formula (I) wherein R3 and/or R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by amino (-NH2) by treatment with benzophenone imine and tris(dibenzylidene- acetone)dipalladium(0) in the presence of 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl (BINAP) and a strong base such as sodium tert-butoxide.
A compound of formula (I) wherein R3 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound of formula (I) wherein the halogen atom is replaced by an optionally substituted C3-7 cycloalkyl, aryl, aryl(Ci-6)alkyl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted C3-7 cycloalkyl, aryl, aryl(Ci-6)alkyl or heteroaryl boronic acid or a cyclic ester thereof, e.g. a pinacol ester thereof, in the presence of a catalyst. More particularly, a compound of formula (I) wherein R3 represents aryl(Ci.6)alkyl, substituted on the aryl moiety by a halogen atom such as bromo, may be converted into the corresponding compound wherein R3 represents biaryl(Ci-6)alkyl or
Figure imgf000076_0001
by treatment with, respectively, an aryl or heteroaryl boronic acid, in the presence of a catalyst. Similarly, a compound of formula (I) wherein R3 represents heteroary^C^alkyl, substituted on the heteroaryl moiety by a halogen atom such as bromo, may be converted into the corresponding compound wherein R3 represents aryl-heteroaryl(C1-6)alkyl by treatment with an aryl boronic acid, in the presence of a catalyst. Furthermore, a compound of formula (I) wherein R3 contains a cyclic borane moiety, e.g. 4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl, may be converted into the corresponding compound wherein the cyclic borane moiety is replaced by an optionally substituted aryl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted aryl or heteroaryl halide, e.g. chloride, bromide or iodide, in the presence of a catalyst. The catalyst may typically be a transition metal catalyst. A suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonateor potassium phosphate, in art inert solvent such as 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonlum bromide. Alternatively, the catalyst may be palladiuin(II) acelale, in which case the transformation may conveniently be effected at an elevated temperature in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and potassium phosphate. In another alternative, the catalyst may be bis(dibenzylideneacetone)- palladium(O), in which case the transformation may conveniently be effected at an elevated temperature in the presence of tricyclohexylphosphine and cesium carbonate.
A compound of formula (I) wherein R3 represents hydroxymethyl may be converted into the corresponding compound wherein R3 represents a substituted aminomethyl moiety, e.g. phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridin- 3-ylaminomethyl, indolin-1-ylmethyl, 1,2,3,4-tetrahydroquinolin-l-ylmethyl or 1,2,3,4- tetrahydroisoquinolin-2-ylmethyl, by a two-stage procedure which comprises (i) Swern oxidation of the hydroxymethyl derivative by treatment with oxalyl chloride and dimethyl sulphoxide in the presence of triethylamine; and (ii) reductive amination of the formyl derivative thereby obtained by treatment with the appropriate amine, e.g. aniline, N- methylaniline, 3-aminopyridine, indoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4- tetrahydroisoquinoline, in the presence of a reducing agent such as sodium cyanoborohydride.
In general, any compound of formula (I) which contains a carbonyl-containing functionality, e.g. formyl or a ketone moiety, may be converted into a substituted amino analogue thereof by application of the reductive amination procedure described in step (ii) in the preceding paragraph, which comprises treatment with the appropriately-substituted amine in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride. Any compound of formula (I) wherein R3 contains an amino moiety can be alkylated on the amino moiety by a reductive amination procedure which comprises treatment with the appropriate aldehyde in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
A compound of formula (I) wherein R3 represents hydroxymethyl may be converted into the corresponding compound wherein R3 represents an optionally substituted C3-7 heterocycloalkylcarbonyl moiety, e.g. piperidin-1-ylcarbonyl, 1,2,3,4- tetrahydroquinolin-1-ylcarbonyl, 6-methyl-l ,2,3,4-tetrahydroquinolin-l-ylcarbonyl, 6- methoxy- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 1 ,2,3 ,4-tetrahydroisoquinolin-2- ylcarbonyl or 1,2,3,4-tetrahydroquinoxalin-l-ylcarbonyl, by a two-stage procedure which comprises (i) oxidation of the hydroxymcthyl moioty by troatmont with potassium permanganate; and (ii) reaction of the carboxy derivative thereby obtained with the appropriate amine, e.g. piperidine, 1,2,3,4-tetrahydroquinoline, 6-methyl-l,2,3,4- tetrahydroquinoline, 6-methoxy- 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydro- isoquinoline or 1,2,3,4-tetrahydroquinoxaline, in the presence of a condensing agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or <>(benzotriazol-l-yl)-N,N,ivyV'- tetramethyluronium hexafluorophosphate (HBTU).
A compound of formula (I) wherein R3 contains a phenyl moiety substituted by chloro may be converted into the corresponding compound wherein the phenyl ring is substituted by morpholin-4-yl by treatment with morpholine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(di-tert-butylphosphino)biphenyl and sodium tert-butoxide. A compound of formula (I) wherein R3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by pyrrolidin- 1 -yl by treatment with pyrrolidine in the presence oftris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl and a base such as potassium carbonate. Similarly, a compound of formula (I) wherein R3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by an amino moiety (e.g. a group of formula -NHR34 as defined above) by treatment with the appropriate amine (e.g. a compound of formula H2N-R34) in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-2',4',6'-tri- isopropyl-l,l'-biphenyl (X-Phos) and abase such as sodium tert-butoxide.
A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by carboxy (-CO2H) by treatment with n-butyllithium followed by carbon dioxide.
A compound of formula (I) wherein R3 contains an indole moiety may be methylated on the indole ring by treatment with a methyl halide, e.g. iodomethane, in the presence of a strong base such as sodium hydride. A compound of formula (I) wherein R3 contains an indole moiety may be acetylated on the indole ring by treatment with acetic anhydride and 4-dimethylamino-pyridine, typically in the presence of an organic base such as triethylamine. A compound of formula (I) wherein R3 contains an indoline moiety may be converted into the corresponding compound wherein R3 contains air indole moiety by treatment with an oxidising agent such as manganese dioxide. A compound of formula (I) wherein R^ contains a hydroxy substituent may be converted into the corresponding compound wherein R3 contains a Cj-6 alkylsulphonyloxy substituent, e.g. methyl- sulphonyloxy, by treatment with a Ci-6 alkylsulphonyl halide, e.g. methanesulphonyl chloride. A compound of formula (I) wherein R3 contains an amino (-NH2) or carboxy (-CO2H) moiety may be converted into the corresponding compound wherein R3 contains an amido moiety (-NHCO- or -CONH- respectively) by treatment with, respectively, a compound containing a carboxy or amino group, in the presence of O-(benzotriazol-l-yl)- N^vyV^V-tetramethyluronium hexafluorophosphate (HBTU), typically in a dipolar aprotic solvent such as iVyV-dimethylformamide; or in the presence of 1 -(3-dimethylaminopropyl)- 3-ethylcarbodiimide and 1-hydroxybenzotriazole. A compound of formula (I) wherein R3 contains an amino substituent may be converted into the corresponding compound wherein R3 contains an alkyl- or arylsulphonylamino substituent, e.g. methylsulphonylamino or phenylsulphonylamino, by treatment with an alkyl- or arylsulphonyl halide, e.g. methanesulphonyl chloride or benzenesulphonyl chloride.
A compound of formula (I) wherein R3 contains an amino moiety may be acylated by treatment with a C2-6 alkylcarbonyl halide, e.g. acetyl chloride; or a C2-6 alkylcarbonyl anhydride, e.g. acetic anhydride. A compound of formula (I) wherein R3 contains an amino moiety may be converted into the corresponding carbamate ester by treatment with a Ci-6 alkyl haloformate, e.g. methyl chloroformate.
A compound of formula (I) wherein R3 contains a C2-6 alkoxycarbonyl substituent, e.g. methoxycarbonyl, may be converted into the corresponding compound wherein R3 contains a carboxy (-CO2H) substituent under standard saponification conditions, e.g. by treatment with a base such as lithium hydroxide. A compound of formula (I) wherein R3 contains a carboxy (-CO2H) substituent may be converted into the corresponding compound wherein R3 contains an amido substituent, e.g. methylaminocarbonyl, 2- hydroxyethylaminocarbonyl, dimethylaminocarbonyl, iV-(2-hydroxyethyl)-N- methylaminocarbonyl, benzylaminocarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1- ylcarbonyl, piperidin-1-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl or morpholin-4- ylcarbonyl, by a two-stage procedure which comprises (i) treatment of the carboxy derivative with pentafluorophenol in the presence of a condensing agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide; and (ii) reaction of the pentafluorophenyl ester thereby obtained with the appropriate amine, e.g. methylamine, 2-hydroxy- ethylamine, dimethylamine, iV-(2-hydroxyethyl)-N-methylamine, benzylamine, azetidine, pyrrolidine, piperidine, l~methylpiperazine or morpholine.
A compound of formula (I) wherein R3ZR4 contains a nitro moiety may be converted into the corresponding compound wherein R3/R4 contains an amino (-NH2) moiety by catalytic hydrogenation, typically by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal. A compound of formula (I) wherein R3/R4 contains an amino (-NH2) moiety may be converted into the corresponding compound wherein R3/R4 contains a heteroaryl-amino moiety, e.g. 6-methylpyridin-3- ylamino, by treatment with the appropriate heteroaryl halide, e.g. 5-bromo-2- methylpyridine, in the presence of palladium(II) acetate, 2-bis(dicyclohexylphosphino)- biphenyl and a base such as sodium tert-butoxide.
In general, any compound of formula (I) wherein R3/R4 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein the halogen atom is replaced by a substituted amino functionality by treatment with the appropriately- substituted amine derivative and palladium(II) acetate in the presence of a base, e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate. Alternatively, the reaction may be effected by treatment with the appropriately-substituted amine derivative and [l,r-bis(di-tert-butylphosphino)ferrocene]palladiurn(II) dichloride in the presence of a base, e.g. sodium tert-butoxide. Conversely, any compound of formula (I) wherein R3/R4 contains an amino functionality may be converted into the corresponding compound wherein the amino functionality is substituted by an optionally substituted aryl or heteroaryl moiety by treatment with an appropriately-substituted aryl or heteroaryl halide (e.g. bromide) and [l,r-bis(di-tert-butylphosphino)ferrocene]palladium(II) dihloride in the presence of a base, e.g. sodium tert-butoxide. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R3ZR4 contains a benzo moiety substituted by a heteroaryl group, e.g. pyrazol-3-yl, 1- methylpyrazol-4-yl, l-propylpyrazol-4-yl, 1 -isobutylpyrazol-4-yl, l-benzylpyrazol-4-yl, 1- [2-(morpholin-4-yl)ethyl]pyrazol-4-yl, 6-methylpyridin-3-yl or pyrimidin-5-yl, by treatment with the appropriate heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst. Similarly, a compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a boronic acid [-B(OH)2] moiety may be converted" into the corresponding" coiiipu und wherein R /R contains a benzo moiety substituted by a heteroaryl group, e.g. methylimidazolyl, by treatment with the appropriate heteroaryl halide, e.g. bromide, derivative in Lhe presence of a catalyst. The catalyst may typically be a transition metal catalyst. A suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, optionally in the presence of tetrabutylammonium bromide.
A compound of formula (I) wherein R3/R contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by a formyl (-CHO) group by treatment with a strong base, e.g. n-butyllithium, and N,JV-dimethylformamide. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by hydroxymethyl by treatment with a reducing agent such as sodium borohydride. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by an aminomethyl moiety (e.g. dimethylaminomethyl, pyridin-3-ylaminomethyl, 4-methylpiperazin-l-ylmethyl or morpholin-4-ylmethyl) by treatment with the appropriate amine (e.g. dimethylamine, pyridin-3-ylamine, 1-methylpiperazine or morpholine) and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride. Conversely, a compound of formula (I) wherein R3/R4 contains an amino moiety may be converted into the corresponding compound wherein R3/R4 is methylated on the amino moiety by treatment with formaldehyde and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by a pyridinyloxymethyl moiety by treatment with the appropriate hydroxypyridine in the presence of a mixture of triphenylphosphine and diethyl azodicarboxylate. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a C2-6 alkoxycarbonyloxy group, e.g. tert-butoxycarbonyloxy, may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by hydroxy under standard hydrolytic conditions, e.g. by treatment with trifluoroacetic acid. A compound of formula (I) wherein R3/R4 contains a halogen atom, e.g. bromo, may bo oonvortod into tho corresponding compound wherein R3ZR4 contains hydroxy by treatment with sodium hydroxide in the presence of tris(dibenzylideneacetone)- dipalladium(O) and 2-(di-/er/-butylphosphino)-2',4',6'-triisopropyl-l,l '-biphenyl. A compound of formula (I) wherein R3/R4 contains hydroxy may be converted into the corresponding compound wherein R3/R4 contains optionally substituted Ci-6 alkoxy, C3-7 heterocycloalkoxy or C3-7 heterocycloalkyl(C1-6)alkoxy by treatment with the appropriately substituted C1-6 alkyl, C3-7 heterocycloalkyl or C3-7 heterocycloalkyl(C1-6)- alkyl halide, e.g. bromide, ideally at an elevated temperature in the presence of cetyl- ammonium bromide. Alternatively, a compound of formula (I) wherein R3/R4 contains hydroxy may be converted into the corresponding compound wherein R3/R4 contains optionally substituted pyridinyloxy, pyrimidinyloxy or pyrazinyloxy by treatment with the appropriately substituted pyridinyl, pyrimidinyl or pyrazinyl halide, e.g. fluoride or chloride, typically in the presence of a strong base such as sodium ter/-butoxide. A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein R3/R4 contains optionally substituted aryloxy or heteroaryloxy by treatment with an appropriately-substituted hydroxyaryl or hydroxyheteroaryl derivative and a base such as caesium carbonate, ideally in the presence of a copper(I) halide, e.g. copper(I) chloride or copper(I) bromide. A compound of formula (I) wherein R3/R4 contains an amino (-NH2) group may be converted into the corresponding compound wherein R3ZR4 contains 2,5-dioxopyrrolidin- 1-yl by treatment with succinic anhydride.
A compound of formula (I) wherein R3/R4 contains an aryl or heteroaryl moiety substituted by a halogen atom, e.g. chloro, may have the halogen atom removed by catalytic hydrogenation.
A compound of formula (I) wherein R3/R4 contains a benzo moiety may be alkylated on the aromatic ring by treatment with n-butyllithium and an alkyl halide (e.g. iodopropane); or by treatment with an organozinc reagent (e.g. isopropylzinc bromide) in the presence of [1,1 '-bis(di-ter/-butylphosphino)ferrocene]palladium(II) dichloride and copper(I) iodide.
A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. chloro) may be converted into the corresponding compound wherein the halogen atom is replaced by an optionally substituted alkynyl moiety (e.g. ?-hydroxyprop-t-yn-I-yi) by treatment with an appropriately-substituted alkyne derivative (e.g. 3-hydroxyprop-l-yne) and a catalyst such as tetfakis(triphenylphόsphifte)palladium(O), typically in the presence of copper(I) iodide and a base such as triethylamine.
A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by acetyl by a two-stage procedure which comprises (i) treatment with butyl vinyl ether and palladium acetate, suitably in the presence of l,3-bis(diphenylphosphino)propane and an organic base such as triethylamine; and (ii) hydrolysis with a mineral acid such as hydrochloric acid. A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by 1 -hydroxy- 1-methylethyl by treatment with n-butyllithium and acetone.
A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by C1-6 alkylthio (e.g. isopropylthio) by treatment with n-butyllithium and the appropriate disulphide derivative (e.g isopropyl disulphide). Conversion of the Ci-6 alkylthio moiety into C1-^ alkylsulphinyl or C1-6 alkylsulphonyl may be accomplished by treatment with an oxidising agent, e.g. m-chloroperbenzoic acid.
A compound of formula (I) wherein R3/R4 contains a pyridinyl moiety may be converted into the corresponding pyridine-Λr-oxide analogue by treatment with peracetic acid.
A compound of formula (I) wherein R3/R4 contains a carbonyl-containing moiety
(e.g. acetyl) may be converted into the corresponding oxime analogue by treatment with an appropriately-substituted hydroxylamine derivative. A compound of formula (I) wherein R3/R4 contains a formyl moiety may be converted into the corresponding compound wherein R3/R4 contains a vinyl moiety by treatment with methyltriphenylphosphonium bromide and a strong base such as sodium hexamethyldisilazide.
A compound of formula (I) wherein R3/R4 contains a formyl moiety may be converted into the corresponding compound wherein R3/R contains a 1-hydroxyethyl moiety by treatment with methyllithium. A compound of formula (I) wherein R3/R4 contains a (2-hydroxyethyl)amino- carbonyl group may be converted into the corresponding compound wherein R3/R4 contains an oxazolin-1-yl moiety by treatment with thionyl chloride.
A compound of formula (I) wherein R3/R contains an ester functionality (e.g. methoxycarbonyl) may be converted into the corresponding compound wherein R3/R4 contains an amide functionality (e.g. methylaminocarbonyl or dimethylaminocarbonyl) by treatment with an appropriately-substituted amine (e.g. methylamine or dimethylamine) in the presence of trimethylaluminium.
Alkenyl-containing compounds may be converted into the corresponding vie- dihydroxy analogues by treatment with osmium tetroxide.
Alkenyl- and alkynyl-containing compounds may be converted into the corresponding alkyl analogues by catalytic hydrogenation.
A compound of formula (I) wherein R5 represents -CO2Rb in which Rb is other than hydrogen may be saponified and then decarboxylated to give the corresponding compounds in which R5 represents -CO2H and hydrogen respectively by treatment with a base such as lithium hydroxide. In general, any compound of formula (I) wherein R5 contains a lower alkyl ester moiety may be converted into the corresponding compound wherein R5 contains a carboxy (-CO2H) group by treatment with a base such as lithium hydroxide or sodium hydroxide. A compound of formula (I) wherein R5 represents -CO2H may be converted into the corresponding compound wherein R5 represents -CONRcRd by treatment with an amine of formula H-NRCR and a condensing agent such as EDC, typically in the presence of an organic base such as triethylamine. In general, any compound of formula (I) wherein R5 contains a carboxy moiety may be converted into the corresponding compound wherein R5 contains an amide moiety by treatment with the appropriate amine and a condensing agent such as EDC, typically in the presence of 1 - hydroxybenzotriazole (HOBT); alternative condensing agents include isobutyl chloroformate/triethylamine and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate. Likewise, any compound of formula (I) wherein R5 contains an amino moiety may be converted into the corresponding compound wherein R5 contains an amide moiety by treatment with the appropriate carboxylic acid under analogous conditions. A compound of formula (I) wherein R5 represents cyano may be converted into the corresponding compound wherein R represents -CONH2 by heating under acidic conditions, e.g; hr a mixture of acetic acid and sulphuric acid; prolonged treatment leads to conversion to the corresponding carboxylic acid followed by decarboxylation, i.e. umveisiυn into the cυncspυiiding compound whciciii R5 iepiescnls liydiυgcn.
Any compound wherein R5 contains a lower alkyl ester moiety, e.g. tert- butoxycarbonyl, may be converted into the corresponding compound wherein R5 contains a carboxy (-CO2H) group by treatment with trifluoroacetic acid.
A compound of formula (I) wherein R5 contains a carboxy moiety may be converted into the corresponding compound containing an arylcarbonyl moiety (e.g. benzoyl) by a two-stage procedure which comprises (i) treatment with N,0-dimethyl- hydroxylamine hydrochloride and a condensing agent such as EDC, typically in the presence of HBTU; and (ii) reaction of the compound thereby obtained with the appropriate aryl lithium derivative, e.g. phenyllithium.
A compound of formula (I) wherein R5 represents hydrogen may be converted into the corresponding compound wherein R5 represents fluoro by treatment with Selectfluor™ [i.e. l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafiuoroborate)]. A compound of formula (I) wherein R5 represents hydrogen may be converted into the corresponding compound wherein R5 represents chloro, bromo or iodo by treatment with iV-chlorosuccinimide, JV-bromosuccinimide or N-iodosuccinimide respectively. Indeed, the latter procedure is generally applicable for converting any compound of formula (I) wherein R5 contains an aryl or heteroaryl moiety into the corresponding compound wherein the aryl or heteroaryl moiety is substituted by chloro, bromo or iodo respectively. Alternatively, a compound of formula (I) wherein R5 represents hydrogen may be converted into the corresponding compound wherein R5 represents bromo or iodo by treatment with elemental bromine or iodine respectively. A compound of formula (I) wherein R5 represents hydrogen may be converted into the corresponding compound wherein R5 represents -SRa by reaction with a compound of formula RaS-Cl. A compound of formula (I) wherein R5 represents hydrogen may be converted into the corresponding compound wherein R5 represents dimethylaminomethyl by treatment with Eschenmoser's salt (i.e. N,N-dimethylmethyleneammonium iodide).
A compound of formula (I) wherein R5 represents a halogen atom, e.g. iodo or chloro, may be converted into the corresponding compound wherein R5 represents -CO2R15 by treatment with carbon monoxide and an alcohol of formula Rb-OH, in the presence of a catalyst. Indeed, this procedure is generally applicable for converting any compound of formula (I) wherein R5 contains a halogen atom into the corresponding compound containing a lower alkyl ester functionality. The catalyst may typically be a transition motαl catalyst. Λ 3uitablo oataly3t is [l,l'-bia(diphonylphoaphino)fcrrocenc]dichloro- palladium(II)-dichloromethane complex, in which case the transformation may conveniently be effected at an elevated temperature and pressure in the presence of an organic base such as triethylamine.
A compound of formula (I) wherein R5 represents a halogen atom, e.g. bromo or iodo, may be converted into the corresponding compound wherein R5 represents aryl, biaryl, C3-7 heterocycloalkyl-aryl, C3-7 heterocycloalky^C^alkyl-aryl, heteroaryl or heteroaryl-aryl by treatment with, respectively, an aryl, biaryl, C3,7 heterocycloalkyl-aryl, C3-7 heterocycloalkyI(C1-6)alkyl-aryl, heteroaryl or heteroaryl-aryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst. Similarly, a compound of formula (I) wherein R5 represents aryl, substituted on the aryl moiety by a halogen atom such as bromo, may be converted into the corresponding compound wherein R5 represents biaryl or heteroaryl-aryl by treatment with, respectively, an aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst. Likewise, a compound of formula (I) wherein R5 represents heteroaryl, substituted on the heteroaryl moiety by a halogen atom such as chloro or bromo, may be converted into the corresponding compound wherein R5 represents aryl-heteroaryl or bi(heteroaryl) by treatment with, respectively, an aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol or N-phenyldiethanolamine, in the presence of a catalyst. The catalyst may typically be a transition metal catalyst. A suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate, potassium hydroxide or potassium phosphate, in an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane. Alternatively, the catalyst may be palladium(II) acetate, in which case the transformation may conveniently be effected at an elevated temperature in the presence of l,3-bis(diphenylphosphino)propane and potassium phosphate, or in the presence of PdCl2.dppf and potassium phosphate, hi general, any compound of formula (I) wherein R5 represents or contains a halogen atom, e.g. bromo or iodo, may be converted by means of the foregoing procedure into the corresponding compound wherein the halogen atom is replaced by a substituted or unsubstituted aryl, heteroaryl or alkenyl group. A compound of formula (I) wherein R5 represents a halogen atom, e.g. iodo, may be converted Into IKe corresponding compound wherein R5 represents aryl(Ci.6)alkyl, e.g. benzyl, by treatment with a suitable organozinc reagent, in the presence of a catalyst. The organozinc reagent may conveniently be prepared by reacting the appropriate aryl(CI-6)- alkyl halide, e.g. benzyl bromide, with zinc dust. The catalyst may typically be a transition metal catalyst. A suitable catalyst is dichlorobis(triphenylphosphine)- palladium(II), in which case the transformation may conveniently be effected at an elevated temperature in the presence of an inert solvent such as tetrahydrofuran.
A compound of formula (I) wherein R5 contains a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein the halogen atom is replaced by an arylamino or heteroarylamino moiety, e.g. phenylamino, by treatment with the appropriate amine, e.g. aniline, and a transition metal catalyst, e.g. palladium acetate, typically in the presence of tributylphosphine tetrafluoroborate and a base such as sodium tert-butoxide. A compound of formula (I) wherein R5 represents a halogen atom, e.g. iodo, may be converted into the corresponding compound wherein R5 represents C2-6 alkynyl, C3-7 cycloalkyl(C2-6)alkynyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C2-6)alkynyl, C5-9 heterobicycloalkyl(C2-6)alkynyl or heteroaryl(C2-6)alkynyl by treatment with, respectively, a suitable C2-6 alkyne, C3-7 cycloalkyl(C2-6)alkyne, aryl(C2-6)alkyne, C3-7 heterocycloalkyl- (C2-6)aIkyne, C5-9 heterobicycloalkyl(C2-6)alkyne or heteroaryl(C2-6)alkyne, in the presence of a catalyst. Similarly, a compound of formula (I) wherein R5 represents C2-6 alkynyl, e.g. ethynyl, may be converted into the corresponding compound wherein R5 represents aryl(C2-6)alkynyl, heteroaryl(C2-6)alkynyl or C3-7 cycloalkyl-heteroaryl(C2-6)alkynyl by treatment with, respectively, a suitable aryl, heteroaryl or C3-7 cycloalkyl-heteroaryl iodide, in the presence of a catalyst. The catalyst may typically be a transition metal catalyst. A suitable catalyst is dichlorobis(triphenylphosphine)palladium(II), in which case the transformation may conveniently be effected at an elevated temperature in the presence of copper(I) iodide and an organic base such as diisopropylamine.
A compound of formula (I) wherein R5 represents arylethynyl, e.g. phenylethynyl, may be converted into the corresponding compound wherein R5 represents arylethyl, e.g. 2-phenylethyl, by catalytic hydrogenation. Indeed, this procedure is generally applicable for converting any compound of formula (I) wherein R5 contains a -C≡C- moiety into the corresponding compound containing a -CH2CH2- moiety. A suitable hydrogenation catalyst is palladium on carbon, in which case the conversion can conveniently be accomplished at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, in the presence of a hydrogen donor such as ammonium formate Under appropriate, generally less forcing, hydrogenation conditions, it is also possible to convert a compound of formula (I) wherein R5 contains a -C≡C- moiety into the corresponding compound containing a -CH=CH- moiety.
A compound of formula (I) wherein R5 contains a -C=C- moiety may be converted into the corresponding compound containing a -COCH2- moiety by treatment with a pH 2 buffer solution. Moreover, a compound of formula (I) wherein R5 contains a -C≡C- moiety may be converted into the corresponding compound containing a -COCO- moiety by treatment with a mineral acid such as hydrochloric acid.
A compound of formula (I) wherein R5 represents nitro may be converted into the corresponding compound wherein R5 represents amino by catalytic hydrogenation, which typically comprises reacting the nitro compound with hydrogen in the presence of a catalyst such as palladium on charcoal. A compound of formula (I) wherein R5 contains a hydroxy moiety may be converted into the corresponding compound containing a -OCH2- moiety by treatment with the appropriate alkyl halide, typically in the presence of a base such as potassium carbonate. A compound of formula (I) wherein R5 contains a hydroxy moiety may be converted into the corresponding compound containing a -OSO2- moiety by treatment with the appropriate sulphonyl halide, typically in the presence of a base such as triethylamine. A compound of formula (I) wherein R5 contains a hydroxy moiety may be converted into the corresponding compound containing a trifluoromethylsulphonyloxy moiety by treatment with iV-phenyltrifluoromethanesulphonimide, typically in the presence of a base such as triethylamine. A compound of formula (I) wherein R5 contains a methylsulphonyloxymethyl moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative, typically in the presence of a base such as triethylamine. Similarly, a compound of formula (I) wherein R5 contains a halomethyl (e.g. chloromethyl) moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative (including cyclic amines), typically in the presence of a base such as potassium carbonate. Furthermore, a compound of formula (I) wherein R5 contains a hydroxymethyl moiety may be converted" into the corresponding compound containing an aminomethyi moiety by treatment with the appropriate amine derivative (including cyclic amines), generally in the presence of triphenylphosphine and diethyl azodicarboxylate.
A compound of formula (I) wherein R5 contains a trifluoromethylsulphonyloxy moiety may be converted into the corresponding compound wherein the trifluoromethyl- sulphonyloxy moiety is replaced by an amino functionality by treatment with the appropriate amine derivative (including cyclic amines) and a transition metal catalyst, e.g. acetato(2'-di-tert-butylphosphino-l,r-biphenyl-2-yl)palladium(II), typically at an elevated temperature in the presence of a base such as potassium tert-butoxide.
A compound of formula (I) wherein R5 contains an amino moiety may be alkylated by treatment with the appropriate alkyl halide (e.g. methyl iodide, ethyl bromide, benzyl bromide or tert-butyl bromoacetate), typically in the presence of a base such as sodium hydride or triethylamine. A compound of formula (I) wherein R5 contains an amino moiety may be converted into the corresponding compound containing a -NCH2- motif by a reductive amination procedure which comprises treatment with the appropriate aldehyde derivative in the presence of a base such as sodium triacetoxyborohydride. A compound of formula (I) wherein R5 contains an amino moiety may be converted into the corresponding compound containing a carbonylamino moiety by treatment with the appropriate carbonyl halide, typically in the presence of a base such as triethylamine. A compound of formula (I) wherein R5 contains an amino moiety may be converted into the corresponding compound containing a urea functionality by treatment with the appropriate isocyanate derivative. Alternatively, a compound of formula (I) wherein R5 contains an amino moiety may be converted into the corresponding compound containing a urea functionality by a two-stage procedure which comprises (i) treatment with triphosgene, typically in the presence of a base such as triethylamine; and (ii) reaction of the compound thereby obtained with the appropriate amine derivative (including cyclic amines). A compound of formula (I) wherein R5 contains an amino moiety may be converted into the corresponding compound containing a sulphonylamino moiety by treatment with the appropriate sulphonyl halide, typically in the presence of a base such as triethylamine. A compound wherein R contains an amino moiety may be converted into the corresponding compound containing a bromo moiety by diazotization/bromination, which entails treatment with sodium nitrite and copper(I) bromide in the presence of HBr.
A compound of formula (I) wherein R5 represents a halogen atom, e.g. iodo, may be converted into the corresponding compound wherein R5 represents acetyl by a two- stage procedure which comprises (i) reaction with butyl vinyl ether and a transition metal catalyst such as tris(dibcnzylidcncacctoπc)dipalIadium(0), typically in the presence of 1,3- bis(diphenylphosphino)propane and a base such as potassium carbonate; and (ii) hydrolysis of the resulting compound by treatment with a mineral acid, e.g. hydrochloric acid. A compound of formula (I) wherein R5 represents acetyl may be converted into the corresponding compound wherein R5 represents 3-(dimethylamino)-l-oxoprop-2-en-l-yl by treatment with i\^V-dimethylformamide dimethyl acetal, typically at an elevated temperature. A compound of formula (I) wherein R5 represents 3-(dimethylamino)-l- oxoprop-2-en-l-yl may be converted into the corresponding compound wherein R5 represents a substituted or unsubstituted pyrimidinyl moiety by treatment with the appropriate amidine derivative, typically at an elevated temperature in the presence of a base such as sodium ethoxide.
A compound wherein R5 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by morpholin-4-yl by treatment with morpholine and tris(dibenzylideneacetone)dipalladium(0) in the presence of 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP) and a strong base such as sodium tert-butoxide.
A compound wherein R5 contains a formyl moiety may be converted into the corresponding compound wherein R5 contains a (cyclopropyl)(hydroxy)methyl moiety by treatment with cyclopropylmagnesium bromide. The resulting (cyclopropyl)(hydroxy)- methyl derivative may be converted into the corresponding compound wherein R5 contains a cyclopropylcarbonyl moiety by treatment with an oxidising agent such as Dess-Martin periodinane.
Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, 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.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventionaf procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e;g. a racerhate, and an appropriate chiraJ compound, e.g. a chiral base. 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. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
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 PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ.
Enzyme Inhibition Assays
Measurement of the ability of compounds to inhibit the lipid kinase activity of the four class 1 PI3 kinase isoforms (α, β, γ and δ) was performed using a commercially available homogeneous time-resolved fluorescence assay as described by Gray et al., Anal. Biochem., 2003, 313, 234-245, according to the manufacturer's instructions (Upstate). All assays were performed at 2 μM ATP and a concentration of purified class 1 PI3 kinase known to generate product within the linear range of the assay. Dilutions of inhibitor in DMSO were added to the assay and compared with assays run in the presence υf 2% (v/v) DMSO alυne (100% activity). The concentration of inhibitor required to inhibit the enzyme activity by 50% is quoted as the IC50.
When tested in the above assay, the compounds of the accompanying Examples were all found to possess IC50 values for inhibition of activity of human PBKα and/or PDKβ and/or PDKγ and/or PBKδ of 50 μM or better.
EXAMPLES
Analytical Conditions
All NMRs were obtained either at 300 MHz or 400 MHz.
Compounds were named with the aid of ACD Labs Name (v. 7.0, 9.0 or 10.0) supplied by Advanced Chemical Development, Toronto, Canada.
All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware. Degassing was performed by bubbling nitrogen through the reaction mixture.
Analytical HPLC methods
Method 1: Luna Cl 8(2) 100 x 4.6 mm, 5 μm column. Mobile phase A: 99.92% water, 0.08% formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid. Gradient program (flow rate 3.0 mL/min, column temperature 35°C): Time A% B% 0.00 95.0 5.0 4.40 5.0 95.0 5.30 5.0 95.0
5.32 95.0 5.0 6.50 95.0 5.0
Method 2: Luna Cl 8(2) 100 x 4.6 mm, 5 μm column. Mobile phase A: 5mM NH4OAc, pH 5.8. Mobile phase B: 95:5 MeCNrIOOmM NH4OAc, pH 5.8.
Gradient program (flow rate 3.0 mL/min, column temperature 35°C):
Time A% B%
0.00 95.0 5.0 4.40 5.0 95.0
5.30 5.0 95.0
5.32 95.0 5.0
6.50 95.0 5.0
Method 3: Gemini Cl 8 50 x 4.6 mm, 5 μm column. Mobile phase A: 99.9% 1OmM ammonium formate, 0.1% formic acid. Mobile phase B: 94.9% MeCN, 0.1% formic acid, 5% mobile phase A.
Gradient program (flow rate 0.9 mL/min, column temperature 40°C): Time A% B%
0.00 95.0 5.0
2.00 5.0 95.0
5.50 5.0 95.0
Method 4: Gemini Cl 8 50 x 4.6 mm, 5 μm column. Mobile phase A: 99.9% 1 OmM ammonium formate, 0.1% ammonia. Mobile phase B: 94.9% MeCN, 0.1% ammonia, 5% mobile phase A.
Gradient program (flow rate 3.0 mL/min, column temperature 40°C):
Time A% B% 0.00 95.0 5.0
2.00 5.0 95.0 5.50 5.0 95.0
Preparative HPLC methods Method 5: Phenomenex Luna C18(2) 250 x 21.2 mm, 5 μm column. Mobile phase A: 10 mM NH4OAc, pH 5.8. Mobile phase B: 95% MeCN, 5% 200 mM NH4OAc, pH 5.8. Gradient program (flow rate 25.0 mL/min), column temperature: ambient, variable gradient.
Method 6: Phenomenex Luna Cl 8(2) 250 x 21.2 mm, 5 μm column. Mobile phase A: 99.92% water, 0.08% formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid. Gradient program (flow rate 25.0 mL/min), column temperature: ambient, variable gradient. Melhυd 7: Plieiiomeiiex Lima C18(2) 250 x 21.2 mm, 5 μin cυluimi. Mobile phase A: 10 mM ammonium acetate in water. Mobile Phase B: 10 mM ammonium acetate in MeCN. Gradient program (flow rate 25.0 mL/min), column temperature: ambient, variable gradient.
Abbreviations
AcOH: acetic acid Me: methyl br: broad MeCN : acetonitrile d: doublet MeOH : methanol dd: double doublet NaOEt : sodium ethoxide
DCM: dichloromethane ΝBS: N-bromosuccinimide
DEPEA: iV,N-diisopropylethylamine ΝCS: N-chlorosuccinimide DMAP: 4-dimethylaminopyridine ΝIS: N-iodosuccinimide
DME: ethylene glycol dimethyl ether ΝMP: 1 -methyl-2-pyrrolidinone
DMF: AζiV-dimethylformamide q: quartet
DMSO: dimethylsulphoxide r.t.: room temperature
Et2O: diethyl ether RT: retention time EtOAc: ethyl acetate s: singlet
EtOH: ethanol sat.: saturated h: hour SiO2: silica
HOBT: 1-hydroxybenzotriazole hydrate t: triplet
IPA: isopropyl alcohol TFA: trifluoroacetic acid m: multiplet THF: tetrahydrofuran
M: mass TMA: trimethylamine
BINAP : 2,2 '-bis(diphenylphosphino)- 1 , 1 '-binaphthyl brine: saturated aqueous sodium chloride solution
DMPU: 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-ρyrimidone EDC: l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
ES+: Electrospray Positive Ionisation
HBTU: O-( lH-benzotriazol- 1 -yO-N.N.iV'.N-tetramethyluronium hexafluorophosphate .
ΗPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry TBAB: tetfabutylammonium bromide
INTERMEDIATE 1
Ethyl 3-amino-3-methylbutanoate hydrochloride
To a stirred solution of ethyl 3,3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a Parr® reactor at O0C was added liquid NH3 (ca 20 mL). The reactor was sealed and heated to 9O0C for 24 h. The reaction mixture was then cooled to r.t, bubbled with nitrogen to remove the residual NH3 and treated with 4M HCl in 1 ,4-dioxane (10 mL). The reaction mixture was stirred for 30 minutes at r.t. and then evaporated in vacuo to dryness. The resulting grey paste was triturated with DCM, filtered and dried (MgSO4) to give the title compound (5.0 g, 70%) as a grey solid that was used without further purification. δH (CDCl3) 8.27 (3H, br s), 4.10 (2H, q, J 7.1 Hz), 2.65 (2H, s), 1.26 (6H, s), 1.20 (3H, t, J7.1 Hz).
INTERMEDIATE 2
Ethyl 3 -f (3 -ethox v-3 -oxopropano vDamino] -3 -methylbutanoate To a stirred suspension of Intermediate 1 (5.0 g, 27.4 mmol) in DCM (40 mL) was added triethylamine (15.3 mL, 109.6 mmol). The reaction mixture was then cooled to O0C and ethyl malonyl chloride (3.7 mL, 28.8 mmol) added dropwise. The suspension was stirred at r.t. for 2 h before being diluted with DCM (50 mL) and washed with aqueous IM HCl (50 mL) and water (2 x 50 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound (5.0 g, 71 %) as an orange oil. δH (DMSO-d6) 7.75 (IH, br s), 4.15-3.95 (4H, m), 3.14 (2H, s), 2.71 (2H, s), 1.29 (6H, s), 1.21 -1.11 (6H, m).
INTERMEDIATE 3
6,6-Dimethylpiperidine-2,4-dione
To a stirred solution of NaOEt in EtOH [prepared in situ from sodium (0.53 g, 23.16 mmol) in EtOH (30 mL)] was added dropwise a solution of Intermediate 2 (5.0 g, 19.3 mmol) in toluene (30 mL) and the reaction mixture was heated to 800C for 2 h. The solution was then cooled to r.t. and concentrated in vacuo to ca 10 mL, and the residue dissolved in toluene (30 mL) and extracted with water (3 x 30 mL). The combined aqueous layers were acidified to pH 2-3 with aqueous IM HCl and extracted with EtOAc (4 x 50 mL). The combined organic fractions were dried (MgSO4), filtered and evaporated in vacuo to give a pale yellow solid that was dissolved in MeCN (90 mL) containing 1% water. The solution was heated to reflux for 2 h and then concentrated in vacuo. The resulting solid was triturated with diisopropyl ether, filtered and dried (MgSO4) to give the title compound (1.55 g, 57%) as a cream solid. Both the keto and enol forms were observed (3.6:1 keto/enol). δH (DMSO-d6) 10.29 (IH, br s, enol), 8.14 (IH, br s, keto), 6.66 (IH, s, enol), 4.81 (IH, s, enol), 3.15 (2H, s), 2.51 (2H, s), 1.20 (6H, s, keto), 1.18 (6H, s, enol).
INTERMEDIATE 4
3-Bromo-6,6-dimethylpiperidine-2,4-dione
To a stirred suspension of Intermediate 3 (10.0 g, 70.9 mmol) in THF (200 mL) was added NaHSO4 (2.12 g, 17.7 mmol). The suspension was cooled to 00C and NBS (12.62 g, 70.9 mmol) was added portionwise. The reaction mixture was stirred at r.t. for 5 h then DCM (200 mL) and water (100 mL) were added. The aqueous fraction was extracted with DCM (2 x 100 mL). The combined organic fractions were washed with water (3 x 200 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting solid was triturated with IPA (3 x 50 mL), then filtered and dried to give the title compound (10.3 g, 66%) as a white solid. δH (DMSO-d6) 10.80 (IH, br s), 7.26 (IH, br s), 2.50 (2H, s), 1.18 (6H, s) for the main tautomer.
INTERMEDIATE 5
2-Bromo-5,5-dimethylcyclohexane- 1 ,3-dione Bromine (0.51 mL, 10 mmol) was added dropwise to a solution of 5,5- dimethylcyclohexane-l,3-dione (1.4 g, 10 mmol) in AcOH (20 mL) at r.t. The reaction mixture was stirred for 2 h and then the product was isolated by filtration. The precipitate was washed with ether (2 x 100 mL) and dried in vacuo to give the title compound (2.19 g, quantitative) as a light brown solid, which was used without further purification. LCMS (ES+) 218.9 (M+H)+ (Method 1).
INTERMEDIATE 6
7-Fluoro-4H-benzof 1.41oxazin-3-one
To an ice-bath cooled solution of 2-amino-5-fluorophenol (15.0 g, 118 mmol) and DIPEA (22.6 mL, 130 mmol) in THF (80 mL) was added, dropwise, a solution of chloroacetyl chloride (10.4 mL, 130 mmol) in THF (20 mL). After stirring with cooling for 10 minutes, an additional portion of DIPEA (22.6 mL, 130 mmol) was added, and the reaction mixture allowed to warm to r.t. It was stirred overnight at r.t. Then acetonitrile (100 mL) was added, and the mixture heated to 700C for 6 h. After cooling to r.t. the mixture was filtered through a pad of silica and washed with EtOAc. The filtrate was concentrated in vacuo. The resulting residue was partitioned between water and EtOAc (100 mL each) causing precipitation of a solid which was filtered off, dissolved in THF (300 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (15.9 g, 81%) as a brown solid. LCMS (ES+) 209 (M+MeCN)+, RT 2.41 minutes (Method 1).
INTERMEDIATE 7
6-Bromo-7-fluoro-4H-benzori.4]oxazin-3-one
To a solution of Intermediate 6 (4.1 g, 25.0 mmol) in MeCN (120 mL) was added NBS (5.41 g, 30 mmol). The reaction mixture was stirred for 4 h at r.t. before addition of further NBS (0.45 g, 2.5 mmol) and MeCN (30 mL) and stirring for a further 1 h. It was then concentrated in vacuo. The resulting residue was slurried in water (10O mL). The solid material was filtered off, washed with water and dried in vacuo to give the title compound (2.7 g, 44%) as an off-white solid. δΗ (DMSO-d6) 10.81 (IH, s), 7.12 (IH, d, J 9.4 Hz), 7.09 (IH, d, J 7.0 Hz), 4.63 (2H, s).
INTERMEDIATE 8
6-Bromo-4H-benzor 1 ,41oxazin-3-one Triethylamine (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL). The reaction was cooled in ice and chloroacetyl chloride (1.12 mL, 14 mmol) added portionwise. It was stirred with cooling for 10 minutes then allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled in ice and sodium hydride (1.05 g of a 60% suspension in oil, 26 mmol) was added portionwise. The mixture was stirred with ice-bath cooling for 20 minutes then at r.t. for 2 h before being quenched with water (20 mL). The THF was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered off, washed with water (3 x 50 mL) and dried in vacuo to yield the title compound (2.14 g, 70%) as a beige solid. δH (DMSO-dδ) 10.81 (IH, br s), 7.08 (IH, dd, J 8.5, 2.3 Hz), 7.02 (IH, d, J 2.3 Hz), 6.92 (IH, d, J 8.5 Hz), 4.60 (2H, s).
INTERMEDIATE 9
6-Bromo-7-fluoro-3,4-dihvdro-2H-benzo[ 1 ,4]oxazine
To a solution of Intermediate 7 (2.7 g, 11.0 mmol) in TΗF (30 mL) was added borane-TΗF (16.5 mL of a IM solution in TΗF, 16.5 mmol). The mixture was stirred at r.t. for 5 minutes, then heated to reflux for 2 h. After cooling to r.t. it was quenched with water (30 mL) and then concentrated in vacuo. The resulting residue was partitioned between DCM (10O mL) and water (10O mL). The organic fraction was washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (1.8 g, 70%) as a colourless oil. δΗ (CDCl3) 6.72 (IH, d, J6.8 Hz), 6.60 (IH, J 9.2 Hz), 4.19- 4.28 (2H, m), 3.68 (IH, br s), 3.33-3.42 (2H, m).
INTERMEDIATE 10
6-Bromo-3,4-dihvdro-2H-benzo[ 1 ,4]oxazine
Borane-THF (13.2 mL of a IM solution in THF, 13.2 mmol) was added portionwise to Intermediate 8 (2.0 g, 8.0 mmol) in THF (50 mL) at r.t. The resulting solution was stirred at r.t. for 10 minutes, heated to reflux for 1 h and then allowed to cool to r.t. The reaction was cooled in an ice bath and quenched with water (20 mL) and 2N aqueous sodium hydroxide solution (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). It was extracted with EtOAc (100 mL), washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (2 g, quantitative) as a brown oil. δH (DMSO-d6) 6.68 (3H, m), 4.18- 4.25 (2H, m), 3.81 (IH, br s), 3.36-3.44 (2H, m).
INTERMEDIATE 11
6-Bromo-7-fluoro-2,3-dihvdrobenzo[l,4]oxazine-4-carbothioic acid amide
A mixture of Intermediate 9 (0.9 g, 3.90 mmol) and l,l'-thiocarbonyldiimidazole (1.25 g, 7.02 mmol) in THF (15 mL) was divided into two batches. Each batch was heated to 1200C under microwave irradiation for 16 minutes. After cooling to room temperature, they were recombined, poured into NH3 (50 mL of a 2N solution in methanol, 0.1 mol) and stirred for 3 h. The reaction mixture was then concentrated in vacuo. The resulting residue was washed with 2N HCl (50 mL), water (50 mL) and a mixture of ether and heptane (50 mL), then dried in vacuo to give the title compound (1.4 g, quantitative) as an off-white solid. LCMS (ES+) 292, 294 (M+H)+, RT 3.04 minutes (Method 1).
INTERMEDIATE 12
4-(Aminocarbonothioyl)-3.4-dihvdro-2i/-benzori,4]oxazin-6-yl fert-butyl carbonate
Triethylamine (0.72 mL, 5.1 mmol) was added to 3,4-dihydro-2H- benzo[l,4]oxazin-6-ol hydrobromide (0.4 g, 1.7 mmol) in THF (25 mL). The reaction mixture was stirred for 5 minutes before addition of di-tert-butyl dicarbonate (0.75 g, 3.4 mmol) and DMAP (20 mg, 0.16 mmol), and then stirred for 3 h before being concentrated in vacuo. The residue was partitioned between DCM (10O mL) and water (10O mL). The organic fraction was washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a brown oil which was dissolved in THF (15 mL). 1 , 1 '-Thiocarbonyldiimidazole (0.178 g, 3.4 mmol) was added, and the mixture heated to 1200C under microwave irradiation for 15 minutes. After cooling to r.t., NH3 (15 mL of a TN solution in MeOH, 105 mmol) was added, and the mixture stirred at r.t. for 3 h. The reaction mixture was concentrated in vacuo and then partitioned between DCM (100 mL) and aqueous IN HCl (100 mL). The organic fraction was washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ether/hepane to give the title compound (0.16 g, 30%) as a beige solid. δH (DMSO' dβ) 8.13 (2H, br a), 7.30 (IH, d, J1.9 Hz), 6.94 -6.90 (2H, m), 4.32-4.17 (4H, m), 1.48 (9H, s).
INTERMEDIATE 13
6-Bromo-3,4-dihvdro-2H-benzo[l,41oxazine-4-carbothioic acid amide
Intermediate 10 (1.7 g, 8.0 mmol) and l,r-thiocarbonyldiimidazole (2.84 g, 16 mmol) were combined in TΗF (15 mL) and heated to 1200C under microwave irradiation for 15 minutes. After cooling to r.t., NH3 (40 mL of a 7N solution in MeOH, 280 mmol) was added, and the mixture stirred at r.t. for 3 h. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ether and heptane to give the title compound (0.5 g, 23%) as a white solid. δH (DMSO-de) 8.20 (2H, br s), 7.60 (IH, d, J2.3 Hz), 7.21 (IH, dd, J 8.7, 2.3 Hz), 6.88 (IH, d, J 8.9 Hz), 4.30-4.16 (4H, m).
INTERMEDIATE 14
2-(6-Bromo-2,3-dihvdrobenzo[l,41oxazin-4-yl)-6,6-dimethyl-6.7-dihvdro- π.31thiazolor5,4-clpyridin-4(5H)-one
Two batches each of Intermediate 4 (0.25 g, 1.14 mmol), Intermediate 13 (0.25 g, 0.87 mmol) and DIPEA (0.23 mL, 1.3 mmol) in TΗF (4 mL) were heated to 1200C under microwave irradiation for 20 minutes. After cooling to r.t., the reaction mixtures were combined and partitioned between EtO Ac (10O mL) and water (10O mL). The organic fraction was separated, washed with brine (100 mL) and concentrated in vacuo. The crude material was purified by preparative ΗPLC (Method 6) to give the title compound (0.101 g, 15%) as an off-white solid. δΗ (CDCl3) 8.18 (IH, d, J2.3 Hz), 7.08 (IH, dd, J 8.9, 2.3 Hz), 6.76 (IH, d, J 8.7 Hz), 5.28 (IH, br s), 4.29-4.22 (2H, m), 4.04-3.98 (2H, m), 2.83 (2H, s), 1.33 (6H, s). LCMS (ES+) 394.0 (M+H)+, RT 3.64 minutes (Method 1).
INTERMEDIATE 15 2-f 6-Bromo-7-fluoro-2.3 -dihvdro-4H- 1 ,4-benzoxazin-4-ylV 6.6-dimethyl-6.7- dilivdiorh31Qria/olor5i4-duyridm-4f5ff>oiie - - -
A mixture of Intermediate 4 (1.4 g, 4.81 mmol), Intermediate 11 (1.06 g, 4.81 mmol) and DPEA (1.1 mL, 6.25 mmol) in TΗF (14 mL) was heated to 12O0C under microwave irradiation for 16 minutes. After cooling to r.t. it was concentrated in vacuo. The resulting residue was slurried in a mixture of water and ether, then filtered, followed by DCM, then filtered again. The combined filtrates were concentrated in vacuo to give the title compound (570 mg, 29%) as a brown solid. δΗ (CDCl3) 8.30 (IH, d, J 7.0 Hz), 6.77 (IH, d, J9.0 Hz), 5.28 (IH, s), 4.31-4.38 (2H, m), 4.02-4.10 (2H, m), 1.40 (6H, s).
INTERMEDIATE 16
7ert-Butyl 4-f6.6-dimethyl-4-oxo-4.5.6.7-tetrahvdror 1.31thiazolor5.4-glPyridin-2-yl)-3.4- dihvdro-2//-benzor 1 ,4]oxazin-6-yl carbonate Intermediate 12 (0.160 g, 0.5 mmol), Intermediate 4 (0.147 g, 0.6 mmol) and
DIPEA (0.24 mL, 1.3 mmol) in THF (4 mL) were heated to 1200C under microwave irradiation for 20 minutes. After cooling to r.t., the reaction mixture was concentrated in vacuo and partitioned between DCM (50 mL) and water (50 mL). The organic fraction was washed with aqueous IN HCl (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting material was triturated with ether to give the title compound (46 mg, 21%) as a yellow solid. δH (CDCl3) 8.01 (IH, d, J2.4 Hz), 6.97- 6.84 (2H, m), 5.25 (IH, br. s), 4.39-4.29 (2H, m), 4.13-4.03 (2H, m), 2.89 (2H, s), 1.61 (3H, s), 1.56 (6H, s), 1.40 (6H, s). LCMS (ES+) 432.0 (M+H)+, RT 3.87 minutes (Method 2).
INTERMEDIATE 17
6,6-Dimethyl-2-(6-hvdroxy-2,3-dihvdrobenzo[l,41oxazin-4-ylV6,7-dihvdro- ri.31thiazolor5.4-clpyridin-4f5H)-one Intermediate 16 (40 mg, 0.09 mmol) and TFA (15 mL, 10% v/v solution in DCM) were combined and stirred for 18 h at r.t. The mixture was concentrated in vacuo and azeotroped with heptane and DCM to give the title compound (29 mg, quantitative) as a brown solid. δH (CDC13/CD3OD) 7.39 (IH, d, J 2.6 Hz), 6.70 (IH, d, J 8.9 Hz), 6.46 (IH, dd, J8.9, 2.8 Hz), 4.68 (2H, br. s), 4.21-4.14 (2H, m), 4.02 (2H, m), 2.79 (2H, s), 1.31 (6H, a). LCMS (ES+) 332.0 (M+H)+, RT 2.69 minutes (Method 2).
INTERMEDIATE 18
6,6-Dimethyl-2-[6-(l -methyl- lH-pyrazol-4-ylV2,3-dihydrobenzo[ 1 ,4]oxazin-4-yr|-6,7- dihydrof 1 ,31thiazolor5,4-c]pyridin-4(5H)-one
A stirred suspension of Intermediate 14 (90 mg, 0.23 mmol), l-methyl-4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (142 mg, 0.69 mmol), Na2CO3 (73 mg, 0.69 mmol), TBAB (212 mg, 0.69 mmol) and tetrakis(triphenylphosphine)- ρalladium(O) (26 mg, 0.02 mmol) in TΗF (4 mL) was heated to 15O0C under microwave irradiation for 40 minutes. After cooling to r.t, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic fraction was washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was then purified by preparative HP LC {Method 6), the resulting material being partitioned between EtOAc (100 mL) and a saturated aqueous solution OfNaHCO3 (100 mL). The organic fractions were combined and washed with a mixture of brine and water (100 mL), dried (MgSO4), filtered and concentrated in vacuo. This residue was then triturated with EtOAc (100 mL) and the mother liquors decanted to give the title compound (24 mg, 27%) as a white solid. δH (CDCl3) 7.92 (IH, d, J2.1 Hz), 7.62 (IH, s), 7.49 (IH, s), 7.10 (IH, dd, J8.5, 2.1 Hz), 6.88 (IH, d, J8.5 Hz), 5.26 (IH, s), 4.30-4.23 (2H, m), 4.16-4.09 (2H, m), 3.88 (3H, s), 2.81 (2H, s), 1.33 (6H, s). LCMS (ES+) 396.0 (M+H)+, RT 2.87 minutes {Method 1).
INTERMEDIATE 19
2-r7-Fluoro-6-(l-methyl-lH-pyrazol-4-vπ-2.3-dihvdro-4H-1.4-benzoxazin-4-yll-6.6- dimethyl-6,7-dihydro|'l,31thiazolo[5,4-clpyridin-4(r5//)-one
A mixture of Intermediate 15 (50 mg, 0.12 mmol), cesium carbonate (79 mg, 0.24 mmol), l-methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (25 mg, 0.12 mmol), bis(dibeπzylideneacetone)palladium(0) (7 mg, 0.012 mmol) and tricyclohexylphosphine (3.4 mg, 0.012 mmol) in TΗF (2 mL) and water (0.5 mL) was heated to I20°C under microwave irradiation for 20 min. After cooling to r.t. it was diluted with EtOAc and filtered through Celite®. The filtrate was washed with water and brine, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, gradient elution 100% heptane- 100% EtOAc, followed by 5% methanol in DCM) gave the title compound (43 mg, 86%) as a cream solid. δH (CDCl3) 8.10 (IH, d, J 7.5 Hz), 7.78 (IH, s), 7.69 (IH, d, J2Λ Hz), 6.74 (IH, d, J 11.3 Hz), 5.28 (IH, s), 4.31-4.38 (2H, m), 4.12-4.19 (2H, m), 3.96 (3H, s), 2.88 (2H, s), 1.40 (6H, s).
INTERMEDIATE 20
2- (6-r 1 -(2-i?.S-Hvdroxy-3-methoxypropylV lHr-pyrazol-4-yll-2.3-dihvdro-4H- 1.4- benzoxazin-4-yl)-6,6-dimethyl-6.7-dihvdro[L31thiazolo[5,4-clpyridin-4(5.H)-one A mixture of Intermediate 14 (1.04 g, 2.6 mmol), l-methoxy-3-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)pyrazol-l-yl]propan-2-ol (1.12 g, 4.0 mmol), potassium phosphate tribasic (2.12 g, 10 mmol), TBAB (128 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (270 mg, 0.23 mmol) in DME (40 mL) and water (8 mL) was heated to reflux for 2.5 h. After cooling to r.t. the mixture was concentrated in vacuo. The resulting residue was partitioned between water and DCM (40 mL each). The aqueous phase was extracted with DCM (40 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, gradient elution 0-6% MeOH in DCM) gave the title compound (1.2 g, quantitative) as a pale yellow solid. δH (CDCl3) 8.02 (IH, d, J 1.9 Hz), 7.73 (IH, d, J0.4 Hz), 7.65 (IH, s), 7.18 (IH, dd, J8.5, 2.1 Hz), 6.96 (IH, d, J8.5 Hz), 5.35 (IH, s), 4.35-4.15 (7H, m), 3.42-3.34 (5H, m), 2.89 (2H, s), 1.41 (6H, s). One exchangeable proton was not observed. LCMS (ES+) 470.0 (M+H)+, RT 2.68 minutes {Method 1).
INTERMEDIATE 21
2-(6-ri-(2-HvdroxyethylVlH-pyrazol-4-yl1-2.3-dihvdro-4H-1.4-benzoxazin-4-vU-6,6- dimemyl-6,7-dihydro[l,31thiazolor5.4-c1pyridin-4f5H)-one A mixture of Intermediate 14 (2.7 g, 6.86 mmol), 2-[4-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)pyrazol-l-yl]ethanol (3.67 g, 10.3 mmol), potassium acetate (807 mg, 8.2 mmol) and bis(tri-tert-butylphosphine)palladium(0) (306 mg, 0.60 mmol) in DMF (14 mL) was heated to 1400C for 1.5 h. Purification by preparative ΗPLC {Method 6) gave the title compound (640 mg, 22%) as a pale yellow solid. δH (CDCl3) 7.99 (IH, d,J 1.9 Hz), 7.72 (IH, s), 7.65 (IH, s), 7.16 (IH, dd, J8.3, 1.9 Hz), 6.95 (IH, d, J8.3 Hz), 5.52 (IH, s), 4.37-4.31 (2H, m), 4.31-4.25 (2H, m), 4.21-4.15 (2H, m), 4.07-4.01 (2H, m), 2.87 (2H, s), 1.40 (6H, s). One exchangeable proton was not observed. LCMS (ES+) 426.0 (M+H)+, RT 2.59 minutes {Method 1).
INTERMEDIATE 22
2-(6-Amino-2,3-dihvdrobenzo[l,41oxazin-4-yl)-6,6-dimethyl-6,7-dihydro- r 1.3 ]thiazolor5,4-c1pyridin-4(5H)-one
A mixture of Intermediate 14 (440 mg, 1.11 mmol), benzophenone imine (0.29 mL, 1.7 mmol), tris(dibenzylideneacetone)dipalladium(II) (51 mg, 0.06 mmol), BINAP (37 mg, 0.06 mmol) and sodium tert-butoxide (164 mg, 1.7 mmol) in TΗF (5 mL) was heated to 1200C under microwave irradiation for 30 minutes. After cooling to r.t, 2N HCl (5 mL) was added, and the mixture stirred at r.t overnight, then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate and DCM. The organic fraction was concentrated in vacuo to give, after trituration with ether and drying in vacuo, the title compound (320 mg, 87%) as an off-white solid. δΗ (CDCl3) 7.27 (IH, d, J2.6 Hz), 6.70 (IH, d, J 8.7 Hz), 6.36 (IH, dd, J 8.7, 2.6 Hz), 5.25 (IH, br s), 4.22-4.14 (2H, m), 4.08-4.00 (2H, m), 3.50 (2H, br s), 2.80 (2H, s), 1.32 (6H, s). LCMS (ES+) 331.0 (M+H)+, RT 2.57 minutes (Method 2).
INTERMEDIATE 23
6,6-Dimethyl-2-r6-(lH-pyrazol-4-yl)-2.3-dihvdro-4H-L4-benzoxazin-4-yll-6.7- dihydro[ 1 ,31thiazolo|"5,4-c1pyridin-4(5HVone
A mixture of Intermediate 14 (10.02 g, 25.38 mmol), 4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)pyrazole-l-carboxylic acid tert-butyl ester (9.33 g, 31.73 mmol), cesium carbonate (16.59 g, 50.92 mmol), tricyclohexylphosphine (709 mg, 2.53 mmol) and bis(dibenzylideneacetone)palladium(0) (1.47 g, 2.55 mmol) in TΗF (80 mL) and water (20 mL) was heated to reflux for 29 h. After cooling to r.t. it was concentrated in vacuo. The resulting residue was dissolved in a mixture of DCM (45 mL) and methanol (5 mL), and filtered through celite. The organic fraction was washed with water (50 mL) and and concentrated in vacuo. The resulting material was dissolved in THF (50 mL). 4N HCl (20 mL) was added, and the mixture heated to reflux for 16 h. After cooling to r.t. the precipitate was removed by filtration, washed with THF and dried in vacuo. The resulting solid was dissolved in a hot mixture of methanol (250 mL) and DCM (250 mL). Activated charcoal (1 g) was added, and the mixture stirred for 10 minutes. It was filtered hot through celite. After cooling to r.t. it was concentrated to one quarter volume in vacuo, and heptane (50 mL) was added. The resulting precipitate was removed by filtration and dried in vacuo to give the title compound (6.54 g, 61%) as an off-white solid. δH (CDCl3) 8.04 (IH, d, J2.1 Hz), 7.78 (2H, s), 7.22 (IH, dd, J8.5, 2.1 Hz), 6.97 (IH, d, J8.5 Hz), 4.38-4.32 (2H, m), 4.23- 4.17 (2H, m), 2.89 (2H, s), 1.41 (6H, s). LCMS (ES+) 382 (M+H)+, RT 2.67 minutes {Method 1).
INTERMEDIATE 24
6,6-Dimethyl-2-r6-(4.4,5,5-tetramethyl-1.3.2-dioxaborolan-2-vn-2,3-dihvdro-4H-l,4- benzoxazin-4-yl]-6,7-dihvdκ>[ 1.3]thiazolo|"5,4-e1pyridin-4(5H)-one
To a suspension of Intermediate 14 (1.0 g, 2.54 mmol) in TΗF (15 mL) was added potassium acetate (0.37 g, 3.81 mmol), bis(pinacolato)diboron (0.90 g, 3.81 mmol) and dichloro[l,r-bis(di-tert-butylphosphino)ferrocene]palladium(II) (0.41 g, 0.51 mmol). The mixture was heated at 125°C under microwave iradiation for 70 minutes, then allowed to cool to r.t.. The resulting precipitate was filtered off and washed with Et2O (2 x 100 mL). The combined organic fractions were washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was triturated with heptane (100 mL), filtered, washed with heptane (2 x 100 mL) and dried in vacuo to yield the title compound (0.84 g, 75%) as a beige solid. δΗ (CDCl3) 8.16 (IH, d, J 1.3 Hz), 7.53 (IH, dd, J 8.3, 1.5 Hz), 6.94 (IH, d, J8.1 Hz), 5.29 (IH, s), 4.36-4.31 (2H, m), 4.22-4.16 (2H, m), 2.86 (2H, s), 1.40 (6H, s), 1.33 (12H, s). LCMS (ES+) 442.0 (M+H)+, RT 2.91 minutes (Method 1).
INTERMEDIATE 25 2- (6-f 1 -(Difluoromcthyl)- l//-pyrαzol-4- yl-]-2;θ-dihydro-4//- h4-bcnzoxazin-4- yl } -6,6- dimethyl-6,7-dihydro[l,3]thiazolo[5.4-c]pyridin-4(5H>one
A mixture of Intermediate 23 (300 mg, 0.78 mmol), sodium chlorodifluoroacetate (300 mg, 1.97 mmol) and cesium carbonate (384 mg, 1.18 mmol) in DMF (2 mL) and water (2 mL) was heated to 1000C in a sealed tube for 5.5 h, venting periodically to release CO2. After cooling to r.t. the reaction mixture was diluted with EtOAc and water and filtered through celite. The aqueous phase was extracted with EtOAc. The combined organic fractions were washed with aqueous sodium bicarbonate, water and brine, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, gradient elution 100% heptane to 100% EtOAc) followed by trituration with heptane gave the title compound (145 mg, 46%) as a white solid. δH (CDCl3) 8.13 (IH, d, J2.1 Hz), 7.98 (IH, s), 7.88 (IH, s), 7.22 (IH, t, J 60.5 Hz), 7.20 (IH, dd, J 8.4, 1.9 Hz), 6.99 (IH, d, J 8.5 Hz), 5.22 (IH, s), 4.33-4.39 (2H, m), 4.13-4.21 (2H, m), 2.90 (2H, s), 1.41 (6H, s). LCMS (ES+) 432 (M+H)+, RT 3.36 minutes (Method I).
INTERMEDIATE 26
6,6-Dimethyl-2-{6-r(6-methylpyridazin-3-yl)amino]-2,3-dihvdro-4H-l,4-benzoxazin-4- vn-6.7-dihvdrori,31thiazolor5.4-c]pyridin-4(5//)-one
A mixture of Intermediate 22 (197 mg, 0.60 mmol) and 3-chloro-6-methyl- pyridazine (39 mg, 0.30 mmol) in pyridine (1 mL) was heated to 1500C under microwave irradiation for 2 h. After cooling to r.t. it was concentrated in vacuo and purified by preparative HPLC {Method 5) to give the title compound (75 mg, 30%) as an off-white solid. δH (CDCl3) 8.00 (IH, d, J2.5 Hz), 7.29-7.25 (2H, m), 7.17-6.91 (3H, m), 5.40 (IH, s), 4.37-4.30 (2H, m), 4.16-4.08 (2H, m), 2.90 (2H, s), 2.60 (3H, s), 1.40 (6H, s). LCMS (ES+) 423.0 (M+H)+, RT 2.73 minutes (Method 2). INTERMEDIATE 27
2-\6-(l -Isopropyl-3 ,5-dimethyl- lH-pyrazol-4-yl)-2,3-dihvdro-4ϋr- 1 ,4-benzoxazin-4-yl]-6,6- dimethyl-6,7-dihvdrof 1 ,31thiazolo|'5,4-c1pyridin-4(5/-f)-one To a stirred solution of 4-bromo-3,5-dimethyl-l/i-pyrazole (0.1O g, 0.57 mmol) in
EtOH (2 mL) was added KOH (96 mg, 1.71 mmol) and 2-bromopropane (0.159 mL, 1.71 mmol). The reaction was heated at 800C for 16 h in a sealed tube, then cooled to r.t., diluted with DCM (10 mL), filtered and concentrated in vacuo. To the residue (0.04 g, 0.18 mmol) and Intermediate 24 (0.162 g, 0.36 mmol) in DME (2 mL) and water (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (44 mg, 0.036 mmol), TBAB (58 mg, 0.18 mmol) and potassium phosphate (115 mg, 0.54 mmol). The reaction mixture was heated at 1400C under microwave irradiation for 15 minutes, cooled to r.t. and then concentrated in vacuo. The resulting residue was purified by preparative HPLC {Method 6) to give the title compound (24 mg, 29%) as an ivory foam. δH (CDCl3) 7.79 (IH, d, J 1.7 Hz), 6.99 (IH, d, J 8.3 Hz), 6.95 (IH, dd, J 8.5, 1.7 Hz), 5.65 (IH, s), 4.48- 4.40 (IH, m), 4.39-4.34 (2H, m), 4.22-4.16 (2H, m), 2.86 (2H, s), 2.28 (6H, s), 1.51 (6H, d, J 6.6 Hz), 1.39 (6H, s). LCMS (ES+) 452/453 (M+H)+, RT 3.34 minutes (Method 1).
INTERMEDIATE 28
7-Chloro-6,6-dimethyl-2-r6-π-methyl-lH-pyrazol-4-yl)-2,3-dihydrobenzo[l,41oxazin-4- yl]-6,7-dihydro-5H-thiazolo|~5,4-c]pyridin-4-one
To a suspension of Intermediate 18 (300 mg, 0.76 mmol) in TΗF (6 mL) was added NCS (111 mg, 0.84 mmol). The reaction mixture was heated to 1000C under microwave irradiation for 1 h. After cooling to r.t. it was diluted with water, neutrilised, and extracted three times with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (352 mg, quantitative) as a yellow solid. LCMS (ES+) 429 (M+Η)+, RT 3.77 minutes (Method 1).
INTERMEDIATE 29
7-Hvdroxy-6.6-dimethyl-2-r6-(4,4,5,5-tetramethyl-|"l,3,21dioxaborolan-2-yl)-23-dihvdro- benzori.41oxazin-4-yll-6,7-dihvdro-5H-thiazolor5,4-clpyridin-4-one A mixture of Example 4 (500 mg, 1.22 mmol), potassium acetate (180 mg, 1.83 niiiiol), bis(pinacolato)diboron (464 mg, 1.83 mmol) and l,2'-[bis(diphenylphosphino)- ferrocene]dichloropalladium(II) dichloromethane complex (200 mg, 0.24 mmol) in THF (10 mL) was heated to reflux overnight. Additional portions of potassium acetate (90 mg, 0.92 mmol), l,2'-[bis(diphenylphosphino)ferrocene]dichloroρalladium(II) dichloromethane complex (100 mg, 0.12 mmol) and bis(pinacolato)diboron (100 mg, 0.39 mmol) were added, and heating continued for a further 4 h. After cooling to r.t. the reaction mixture was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to give, after trituration with a mixture of heptane and EtOAc, the title compound (283 mg, 51%) as a brown solid. LCMS (ES+) 458 (M+H)+, RT 3.39 minutes (Method 1).
INTERMEDIATE 30
6,6-Dimethyl-2-[6-(pyrida2in-3-yloxy)-2,3-dihvdro-4H-l,4-benzoxazin-4-yl]-6,7- dihvdro[ 1 ,3]thiazolor5,4-clpyridin-4(5H)-one
A mixture of Intermediate 17 (53 mg, 0.16 mmol), cesium carbonate (105 mg,
0.32 mmol) and 3,6-dichloropyridazine (24 mg, 0.16 mmol) in NMP (2 mL) was heated to 1100C for 12 h. After cooling to r.t. it was concentrated in vacuo. Purification by preparative ΗPLC (Method 5) gave the title compound (15 mg, 23%) as an off-white solid. δΗ (CDCl3) 8.94 (IH, dd, J4.5, 1.3 Hz), 8.02 (IH, d, J2.4 Hz), 7.49 (IH, dd, J8.9,
4.5 Hz), 7.19 (IH, dd, J 8.9, 1.3 Hz), 6.89-7.03 (2H, m), 5.21 (IH, s), 4.31-4.39 (2H, m),
4.09-4.18 (2H, m), 2.86 (2H, s), 1.37 (6H, s).
INTERMEDIATE 31
2-(6-Bromo-2J-dihvdrobenzo("l,41oxazin-4-yl)-5,5-dimethyl-5,6-dihvdro-4H- benzothiazol-7-one Intermediate 10 (2.0 g, 9.4 mmol) and l,r-thiocarbonyldiimidazole (3.3 g, 18.8 mmol) were combined in TΗF (16 mL) and heated to 125°C under microwave irradiation for 15 minutes. The mixture was cooled to r.t., concentrated in vacuo, and NH3 (50 mL of a 7N solution in methanol, 0.35 mol) was added. It was stirred for 2 h, then concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and 2N HCl (IUO mL). The organic fraction was washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ether and heptane to give a yellow solid. Of this material, 0.5 g (1.8 mmol) was combined with Intermediate 5 (0.69 g, 3.1 mmol) and DIPEA (0.6 mL, 3.4 mmol) in THF (18 mL) and heated to 1400C under microwave irradiation for 30 minutes. After cooling to r.t. the mixture was partitioned between EtOAc (130 mL) and water (130 mL). The organic fraction was washed with water (150 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (Method 6) to yield the title compound (166 mg, 23%) as an off-white solid. δH (CDCl3) 8.22 (IH, d, J2.3 Hz), 7.17 (IH, dd, J8.7, 2.3 Hz), 6.84 (IH, d, J8.7 Hz), 4.27-4.38 (2H, m), 4.07-4.17 (2H, m), 2.79 (2H, s), 2.44 (2H, s), 1.16 (6H, s).
INTERMEDIATE 32
5.5-Dimethyl-2-f6-(l-methyl-lH-pyrazol-4-vn-2.3-dihvdrobenzoπ.41oxazin-4-yl1-5.6- dihvdro-4H-benzothiazol-7-one
Intermediate 31 (114 mg, 0.29 mmol), l-methyl-4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-lH-pyrazole (120 mg, 0.58 mmol), potassium phosphate tribasic (190 mg, 0.87 mmol), tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.09 mmol) and water (1 mL) in DME (3 mL) were heated to 1400C under microwave irradiation for 90 minutes. After cooling to r.t. the reaction mixture was concentrated in vacuo. The crude material was purified by preparative ΗPLC (Method 6) to give the title compound (17 mg, 15%) as an off-white solid. δΗ (CDCl3) 7.98 (IH, d, J 1.9 Hz), 7.69 (IH, s), 7.56 (IH, s), 7.19 (IH, dd, J8.5, 2.1 Hz), 6.95 (IH, d, J 8.5 Hz), 4.31-4.39 (2H, m), 4.21-4.28 (2H, m), 3.95 (3H, s), 2.77 (2H, s), 2.43 (2H, s), 1.16 (6H, s).
INTERMEDIATE 33
4-Chloro-5,5-dimethyl-2-r6-α -methyl- l/-f-pyrazol-4-yl)-2,3-dihvdrobenzo[l,41oxazin-4- yl]-5,6-ώ'hydro-4H-benzothiazol-7-one
To a suspension of Intermediate 32 (1.0 g, 2.53 mmol) in TΗF (30 mL) was added NCS (338 mg, 2.53 mmol). The reaction mixture was heated to 600C for 1 h. After cooling to r.t. it was diluted with water, neutralised, and extracted with DCM. The combined organic fractions were dried (MgSO4) and concentrated In vacuo to give, aflei trituration with EtOH, the title compound (970 mg, 89%) as a yellow solid that was used directly in the preparation of Example 24 and Example 25.
INTERMEDIATE 34
JV-Benzyl-D-serine
To a stirred solution of D-serine (14.7 g, 140.0 mmol) in aqueous 2M NaOH (70 mL) was added benzaldehyde (14.0 mL, 138.0 mmol). The reaction mixture was stirred at r.t. for 1 h before cooling to 5°C. NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of between 6 and 100C was maintained. After addition, the reaction mixture was allowed to stir at 5°C for 30 minutes and then at r.t. for 1 h. The reaction mixture was cooled to 5°C and further NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of < 100C was maintained. The ice bath was removed on completion of addition and the reaction mixture stirred at r.t. for 16 h. The reaction mixture was then extracted with ether (3 x 100 mL) and the aqueous phase acidified to pH 5 with cone. HCl. The resulting white precipitate was filtered off, washed with water and dried in vacuo to give the title compound (24.0 g, 88%) as a white solid. δH (DMSO-(I6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (IH, t, J 5.8 Hz).
INTERMEDIATE 35
(3i?V4-Benzyl-5-oxomorpholine-3-carboxylic acid
To a stirred solution of Intermediate 34 (35.0 g, 179.0 mmol) in aqueous NaOH (9.3 g in 200 mL water, 232.5 mmol) at 00C was slowly added chloroacetyl chloride (17.0 mL, 214.0 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 30 minutes. Aqueous 1OM NaOH (45.0 mL, 465.0 mmol) was added and the reaction mixture heated to 45°C for 4 h. The reaction mixture was then cooled to 100C and acidified to pH 1 with cone. HCl. On standing at 4°C a solid crystallised from the mixture. It was collected by filtration, washed with cold water and dried in vacuo to give the title compound (18.0 g, 43%) as a white solid. δH (DMSO-df.) 13.51-12.53 (IH, br s), 7.38-7.25 (5H, m), 5.27 (IH, d, J 15.3 Hz), 4.24-4.10 (3H, m), 3.94-3.88 (2H, m), 3.83 (IH, d,V 15.3 Hz).
INTERMEDIATE 36
[(3-SV(4-Benzylmorpholin-3-yl)]methanol
To a stirred solution of Intermediate 35 (17.7 g, 75.3 mmol) in THF (300 mL) was added triethylamine (10.0 mL, 72.0 mmol). The solution was then cooled to O0C and borane-dimethylsulfide complex (1OM in THF, 45.0 mL, 450.0 mmol) was added slowly. The reaction mixture was heated at reflux for 12 h. After cooling to r.t., excess borane was destroyed by slow addition of MeOH at 00C. The reaction mixture was concentrated in vacuo. The resulting white solid was dissolved in EtOAc (120 mL) and washed with aqueous NaOH solution (20% v/v, 2 x 100 mL). The organic fraction was extracted with aqueous 2M HCl (2 x 150 mL). The combined acidic aqueous fractions were then basified to pH 14 (by addition of solid NaOH) and were re-extracted with EtOAc (2 x 150 mL). The combined organic fractions were washed with brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (13.5 g, 87%) as a clear oil. δH (CDCl3) 7.29-7.16 (5H, m), 4.05 (IH, d, J 12.8 Hz), 3.88 (IH, dd, J 11.5, 4.5 Hz), 3.80-3.76 (IH, m), 3.70-3.53 (2H, m), 3.51-3.40 (2H, m), 3.20 (IH, d, J 13.2 Hz), 2.68 (IH, dt, J 12.1, 2.8 Hz), 2.48-2.45 (IH, m), 2.27-2.24 (IH, m), 2.17 (IH, br s).
INTERMEDIATE 37
(3iS)-Morpholin-3-ylmethanol To a nitrogen-flushed solution of Intermediate 36 (10.0 g, 48.3 mmol) in MeOH
(300 mL) was added 10 wt % palladium on carbon (2.0 g) and the reaction mixture stirred in a Parr® apparatus under 50 psi of H2 for 18 h. The resulting mixture was then filtered through Celite® and concentrated in vacuo to give the title compound (5.2 g, 92%) as a colourless oil. δH (CDCl3) 3.81-3.76 (2H, m), 3.58-3.43 (3H, m), 3.35-3.28 (IH, m), 2.99-2.91 (5H, br m).
INTERMEDIATE 38 - H l -
(3 J?)-Tetrahvdro-3H-[ 1.2,3]oxathiazolor4.3-cir 1.4]oxazine 1.1 -dioxide
Tυ a solution at Intermediate 37 (30 g, 257 iniuol) in anhydrous DCM (250 mL) was added pyridine (43.5 mL, 539 mmol) and the solution was cooled to -7O0C (CO2ZJPA bath). A solution of sulphuryl chloride (21.7 mL, 270 mmol) in anhydrous DCM (200 mL) was added dropwise over 1 h (maintaining the reaction temperature below -600C). The reaction was stirred at -700C for 2 h and at -10 to -200C (MeOΗ/ice bath) for 2 h before being quenched by the addition of water (15 mL) and warming to r.t. The aqueous fraction was separated and extracted with further DCM (2 x 100 mL). The combined organic fractions were washed with water (15 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (24.7 g, 54%) as a yellow oil which solidified on standing. δΗ (CDCl3) 4.51 (IH, dd, J8.1, 6.4 Hz), 4.23 (IH, dd, J 9.1, 8.1 Hz), 3.95 (IH, dd, J 11.6, 3.4 Hz), 3.84-3.64 (3H, m), 3.54 (IH, dd, J 11.6, 7.7 Hz), 3.29 (IH, dt, J 12.0, 3.4 Hz), 3.06 (IH, m).
INTERMEDIATE 39
(3,SV3-(Prop-2-vn-l-vnmorpholine
To a solution of trimethylsilylacetylene (27.6 mL, 195.3 mmol) dissolved in anhydrous THF (250 mL) at 00C was added n-butyllithium (78.1 mL, 201 mmol, 2.5M in hexanes) dropwise over 15 minutes. After stirring at this temperature for 40 minutes, a solution of Intermediate 38 (11.7 g, 65.1 mmol) dissolved in DMPU (11 mL) was added slowly over 15 minutes. The reaction mixture was then allowed to warm to r.t. After stirring at r.t. for 18 h, it was quenched by addition of water (4 mL). The volatile solvents were removed in vacuo. To the resulting dark oil were added aqueous HCl (10% v/v, 200 mL) and MeOH (100 mL) and the reaction mixture was stirred at r.t. for 18 h. It was then concentrated in vacuo to give the title compound (17.059 g, ca 74% yield) as a crude dark oil (containing ca 11 mL DMPU) that was used without further purification. 5H (CD3OD) 3.89 (IH, dd, J 11.2, 3.1 Hz), 3.76 (IH, dt, J 11.2, 2.7 Hz), 3.45-3.56 (IH, m), 3.27-3.23 (IH, m), 2.91-2.87 (3H, m), 2.39 (IH, t, J2.7 Hz), 2.25 (2H, dd, J6.8, 2.7 Hz). Exchangeable proton was not observed.
INTERMEDIATE 40 fert-Butyl (3.->)-3-(proρ-2-vn-l-yl)niorpholine-4-carboxylate
To a solution of "crude Intermediate 39 (17.1 g, containing 11 mL DMPU), dissolved in anhydrous DCM (300 mL) at 00C, was added DIPEA (13.0 mL, 74.8 mmol) and di-tert-butyl dicarbonate (15.6 g, 71.6 mmol). The reaction mixture was warmed to r.t. After stirring for 18 h, it was washed with brine and the organic fraction dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 10:1 EtOAc/hexanes) gave the title compound (8.79 g, 59% from Intermediate 38) as a yellow oil. δH (CD3OD) 3.97-3.94 (IH, m), 3.75 (IH, d, J 14.2 Hz), 3.72-3.68 (IH, m), 3.59-3.56 (IH, m), 3.44-3.41 (IH, m), 3.32-3.28 (IH, m), 2.96-2.93 (IH, m), 2.53-2.49 (IH, m), 2.39-2.36 (IH, m), 2.19 (lH, t, J2.7 Hz), 1.35 (9H, s).
INTERMEDIATE 41
fert-Butyl (35^-3-[3-(trimethylsilyl)prop-2-vn-l-yl1morpholine-4-carboxylate
To a solution of Intermediate 40 (8.05 g, 35.7 mmol) in anhydrous THF (250 mL) at 00C was added n-butyllithium (15.7 mL of a 2.5 M solution in hexanes, 39.3 mmol) dropwise over 15 minutes. After stirring for 30 minutes with cooling, chlorotrimethyl- silane (4.5 mL, 35.7 mmol) was added slowly over 5 minutes. The reaction mixture was stirred for 45 minutes with cooling, and then allowed to warm to r.t. After stirring at r.t. for 18 h, the reaction mixture was quenched by the addition of water (ca 1 mL) and the solvent was removed in vacuo. The crude mixture was dissolved in DCM and washed with water. The aqueous phase was extracted with further DCM (500 mL) and the combined organic fractions dried (using an Isolute® phase separator cartridge) and concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 5-20% EtOAc/hexanes) gave the title compound (8.1 g, 76%) as a colourless oil. δH (CD3OD) 3.93-3.89 (IH, m), 3.82 (IH, d, J 11.7 Hz), 3.70 (IH, dd, J 3.6, 11.4 Hz), 3.58 (IH, dd, J2.9, 13.7 Hz), 3.40-3.20 (2H, m), 2.97-2.93 (IH, m), 2.60 (IH, dd, J9.1, 16.7 Hz), 2.38 (IH, dd, J 6.4, 16.7 Hz), 1.35 (9H, s), 0.00 (9H, s). Starting material (1.25 g, 15%) was also recovered.
INTERMEDIATE 42 Methyl 3-{[(3^-4-(tert-butoxycarbonvnmorpholin-3-yl1methvU-2-ftrimethylsilyl')-l//- intlυle-5-earbυxyldle
To a stirred solution of Intermediate 41 (31.9 g, 107.4 mmol) in DMF (160 mL) was added methyl 4-amino-3-iodobenzoate (29.8 g, 107.4 mmol), lithium chloride (4.5 g, 107.4 mmol) and sodium carbonate (22.8 g, 214.8 mmol). The resulting suspension was degassed before addition of palladium acetate (0.96 g, 4.3 mmol). The reaction mixture was heated to 11O0C for 50 minutes. It was cooled to r.t, filtered through celite®, and concentrated in vacuo. The resulting brown oil was partitioned between isopropyl acetate and water (150 mL each). The aqueous fraction was extracted with isopropyl acetate (2 x 15OmL). The combined organic fractions were dried (MgSO4), treated with decolourising charcoal (5% by weight of crude material) for 30 minutes at room temperature, concentrated in vacuo and then purified by column chromatography (SiO2, DCM) to give the title compound (9g, 19%) as a pale cream solid. LCMS (ES+) 469.1 (M+ Na), RT 4.62 minutes {Method ϊ).
INTERMEDIATE 43
Methyl 3-{[(35^-4-(tert-butoxycarbonyl)moφholin-3-yl1methvU-l-methyl-2- (trimethylsilyl)-lH-indole-5-carboxylate To a stirred solution of Intermediate 42 (2.0 g, 4.48 mmol) in TΗF (30 mL) at O0C was added NaH (0.19 g of a 60% dispersion in oil, 4.93 mmol). The reaction mixture was stirred at this temperature for 30 minutes. Methyl iodide (0.33 mL, 5.37 mmol) was then added, and the reaction mixture allowed to warm to r.t., then stirred for 18 h. Water (1 mL) was added, and the reaction mixture concentrated in vacuo. DCM (25 mL) and water (10 mL) were added. The organic fraction was separated, washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 10-25% EtOAc/hexanes) gave the title compound (1.95 g, 95%) as a pale yellow oil. LCMS (ES+) 405.1 ((M-'Bu)+H)+, RT 3.80 minutes (Method 3).
INTERMEDIATE 44
Methyl l-methyl-3-r(3-S^-morpholin-3-ylmethyll-lHr-indole-5-carboxvlate To a stirred solution of Intermediate 43 (1.95 g, 4.23 mmol) in MeOH (15 mL) was added 4M HCl in 1,4-dioxane (20 mL). The reaction mixture was stirred at r.t. tor 16 h, then concentrated in vacuo. Water (1O mL) and DCM (1O mL) were added. The aqueous fraction was separated, basified by the addition of saturated aqueous NaHCO3 solution, then extracted with DCM (5 x 30 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (1.02 g, 84%) as a yellow solid. LCMS (ES+) 289.2 (M+H)+, RT 2.00 minutes (Method 3).
INTERMEDIATE 45
Methyl 3-(f(35r)-4-(aminocarbonothioyl)moφholin-3-yllmethyl|-l-methyl-lH-indole-5- carboxylate
To a stirred slurry of Intermediate 44 (31.64 g, 109.7 mmol) in TΗF (221 mL) at r.t. was added l,r-thiocarbonyldiimidazole (21.51 g, 120.7 mmol) portionwise over 10 minutes. The reaction mixture was stirred at r.t. for 5 h, then transferred to a pressure vessel and NH3 (111 mL of a 28% aqueous solution, 1.6 mol) was added. This mixture was stirred at 600C for 17 h, then cooled to r.t. It was diluted with water (158 mL) and solid product was filtered off, washed with water and dried in vacuo at 450C, to give the title compound (37.79 g, 99.1%) as a white solid. LCMS (ES+) 348.0 (M+H)+, RT 2.88 minutes (Method I).
INTERMEDIATE 46
Methyl 3-{r(3lSf)-4-(6.6-dimethyl-4-oxo-4,5,6,7-tetrahvdrori.31thiazolor5,4-clpyridin-2- vDmorpholin-3-yllmethvU -1 -methyl- lH-indole-5-carboxylate
To a stirred solution of Intermediate 4 (23.94 g, 108.8 mmol) in TΗF (168 mL) at r.t. was added DIPEA (19.8 mL, 119.6 mmol) over 10 minutes. The mixture was stirred for 10 minutes before portionwise addition of Intermediate 45 (37.79 g, 108.8 mmol) over 15 minutes. The mixture was heated to reflux for 4 h and then allowed to cool to r.t. The resulting solid material was filtered off and washed with TΗF. It was then stirred in water for 1.25 h, filtered off, washed with water and dried in vacuo at 45°C, to give the title compound (41.25 g, 80.9%) as a white solid. δΗ (CD3OD) 8.62-8.59 (IH, m), 7.86 (IH, dd, J8.7, 1.6 Hz), 7.41-7.35 (IH, m), 7.18 (IH, s), 4.41-4.31 (IH, m), 4.13-4.02 (IH, m),
\ 3.95 (3H, s), 3.90 (IH, d, J 11.8 Hz), 3.79 (3H, s), 3.76-3.55 (4H, m), 3.44-3.36 (IH, m), 3.15 (IH, dd, J 13.9, 5.4 Hz), 2.85 (IH, d, J 16.9Hz), 2.80 (IH, d, J 16.9 Hz), 1.36 (3H, s), 1.35 (3 H, s). Exchangeable proton was not observed. LCMS (ES+) 469.1 (M+H)+, RT 3.28 minutes (Method I).
INTERMEDIATE 47
3-{r(3^-4-(6.6-Dimethyl-4-oxo-4,5.6.7-tetrahvdrori.31thiazolor5.4-clpyridin-2- yl)morpholin-3-yl]methyl} - 1 -methyl- lH-indole-5-carboxylic acid To a stirred suspension of Intermediate 46 (1.15 g, 2.46 mmol) in 1,4-dioxane (20 mL) and MeOH (5 mL) was added a solution of lithium hydroxide monohydrate (0.21 g, 4.91 mmol) in water (5 mL). The reaction mixture was stirred at 6O0C for 16 h, then concentrated in vacuo. Water (IQO mL) and DCM (20O mL) were added. The aqueous fraction was separated, acidified to pΗ 1 by the addition of IM HCl, then extracted with EtOAc (4 x 200 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo. The resulting solid was washed with EtOAc to give the title compound (1.0 g, 90%) as a white solid. δΗ (CD3OD) 8.64 (IH, d, J 1.1 Hz), 7.88 (IH, dd, J8.7, 1.5 Hz), 7.36 (IH, d, J8.7 Hz), 7.15 (IH, s), 4.52-4.39 (IH, m), 4.12-4.02 (IH, m), 3.91 (IH, d, J 11.7 Hz), 3.79 (3H, s), 3.76-3.65 (2H, m), 3.64-3.50 (2H, m), 3.44-3.34 (IH, m), 3.16 (IH, dd, J 13.9, 5.3 Hz), 2.87 (IH, d, J 17.0 Hz), 2.81 (IH, d, J 17.0 Hz), 1.36 (3H, s), 1.35 (3H, s). Exchangeable protons were not observed. LCMS (ES+) 455.2 (M+H)+, RT 2.57 minutes (Method 3).
INTERMEDIATE 48
Pentafluorophenyl 3- (|"(3-Sr)-4-(6.6-dimethyl-4-oxo-4.5,6J-tetrahydror 1.31thiazolor5.4- c1pyridin-2-yl)morpholin-3-yllmethyl} - 1 -methyl- lH-indole-5-carboxylate
To a stirred solution of Intermediate 41 (1.0 g, 2.20 mmol) in DMF (20 mL) was added pentafluorophenol (0.49 g, 2.64 mmol), DIPEA (0.77 mL, 4.41 mmol) and EDC (0.55 g, 2.86 mmol). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. DCM (15 mL) and water (15 mL) were added. The organic fraction was separated, dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-4% MeOH/DCM) gave the title compound (1.04 g, 76%) as a yellow gum. LCMS (ES+) 621.3 (M+H)+, RT 3.52 minutes (Method 4).
INTERMEDIATE 49
S-irO^^-fό.ό-Dimethyl^-oxo-^S.ό.y-tetrahvdroriJithiazolorS^-cipyridin^- yl")morpholin-3- yl"|methyl} -JVJV, 1 -trimethyl- lH-indole-5-carboxamide
To a solution of dimethylamine hydrochloride (50.5 g, 616.7 mmol) in THF (150 mL), cooled to -8°C, was added, dropwise, TMA (210.3 g of a 2N solution in THF, 619 mmol), maintaining the reaction temperature between -5°C and +40C. The resulting solution was then cooled to -100C. A slurry of Intermediate 48 (41.21 g, 88.1 mmol) in THF (150 mL) was added gradually over 10 minutes to the cooled reaction mixture. The resulting mixture became clear on heating. It was refluxed at 800C for 2 h, and then left to stir at r.t. overnight. It was then cooled to -100C, and quenched by very slow addition of 2M hydrochloric acid (308 mL, 616 mmol). A precipitate formed upon addition of the acid. This was filtered off, washed with water and dried (MgSO_j) to give an off-white solid, which was purified by dissolving in DCM (750 mL) and filtering through GFF to remove inorganic impurities. The filtrate was concentrated in vacuo and recrystallised from EtOH to give the title compound (31.46 g, 84.6%) as a white solid. δH (CD3OD) 8.07 (IH, d, J 1.0 Hz), 7.41 (IH, d, J8.5 Hz), 7.27 (IH, dd, J8.5, 1.6 Hz), 7.18 (IH, s), 4.39-4.29 (IH, m), 4.13-4.01 (IH, m), 3.88 (IH, d, J 11.7 Hz), 3.79 (3H, s), 3.75-3.55 (4H, m), 3.39 (IH, dd, J 13.9, 10.1 Hz), 3.14 (6H, br s), 3.12-3.02 (IH, m), 2.80 (2H, s), 1.37 (6H, s). Exchangeable proton was not observed. LCMS (ES+) 482.3 (M+H)+, RT 2.57 minutes (Method 3).
INTERMEDIATE 50
2-(5-Bromopyridin-2-vD-propan-2-ol
To a suspension of 2,5-dibromopyridine (1.5 g, 6.35 mmol) in toluene (33 mL) cooled to -78°C was added dropwise n-butyllithium (4.5 mL of a 1.6M solution in hexanes, 7.2 mmol). The mixture was stirred for 20 minutes with cooling before addition of acetone (0.56 mL, 7.6 mmol). It was warmed to r.t., stirred for 40 minutes and then poured into a saturated aqueous solution of ammonium chloride (6 mL). The organic fraction was separated. The aqueous layer was extracted with EtOAc. The combined organic fractions were dried (MgSO4) and concentrated in vacito.' Purification by column chromatography (SiO2, gradient elution 0-50% EtOAc in heptane) gave the title compound (713 mg, 52%) as a clear oil. LCMS (ES+) 216, 218 (M+H)+, RT 2.75 minutes (Method 2).
INTERMEDIATE 51
13.5-Trimethyl-4-(4.4.5.5-tetramethyl-ri.3,21dioxaborolan-2-ylVlH-pyrazole To a suspension of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- lH-pyrazole (500 mg, 2.25 mmol) in acetone (5 mL) were added potassium carbonate (622 mg, 4.5 mmol) and iodomethane (0.21 mL, 3.37 mmol). The reaction mixture was heated to 600C for 4.5 h. After cooling to r.t., water was added. The aqueous phase was separated and extracted three times with EtOAc. The combined organic fractions were washed with water, dried (MgSO4) and concentrated in vacuo to give the title compound (403 mg, 76%) as a pale yellow oil. LCMS (ES+) 237 (M+Η)+, RT 3.35 minutes (Method 1).
INTERMEDIATE 52
Ethyl 2-amino-5.5-dimethyl-7-oxo-4,5,6,7-tetrahvdrothieno[2,3-clpyridine-3-carboxylate
To a stirred solution of sulphur (1.0 g, 31.0 mmol), 6,6-dimethylpiperidine-2,4- dione (4.0 g, 28.0 mmol) and ethyl cyanoacetate (3.7 g, 3.5 mL, 29.0 mmol) in EtOH (20 mL) at 45°C was added morpholine (2.9 g, 2.9 mL, 33.0 mmol) dropwise over 15 minutes. The reaction mixture was stirred at this temperature for 15 minutes and then at 65°C for 48 h before it was cooled and concentrated in vacuo. To the residue was added water, and the resulting solid was filtered and washed with water to give the title compound (4.1 g, 54%) as a pale brown solid. δH (DMSO-de) 7.86 (s, 2H), 7.28 (s, IH), 4.21 (q, J 7.0 Hz, 2H), 2.88 (s, 2H), 1.27 (t, J 7.1 Hz, 3H), 1.23 (s, 6H). LCMS (ES+) 269.1 (M+H)+.
INTERMEDIATE 53 Ethyl 2-bromo-5,5-dimethyl-7-oxo-4,5.6,7-tetrahvdrothieno[2,3-clpyridine-3-carboxylate
To a stirred suspension of Intermediate $2 (0.20 g, 0.75 mmol) in MeCN (5 mL) at 0-50C was added copper(II) bromide (0.20 g, 0.90 mmol) followed by tert-butyl nitrite (0.10 mL, 0.80 mmol) dropwise. The reaction mixture was stirred at this temperature for 10 minutes before it was partitioned between EtOAc (50 mL) and water (50 mL). The organics were separated, washed with water (3 x 20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was washed with Et2O to give the title compound (0.15 g, 61%) as a pale brown solid. 5H (DMSO-d6) 8.53 (s, IH), 4.32 (q, J 7.0 Hz, 2H), 3.10 (s, 2H), 1.33 (t, J 7.1 Hz, 3H), 1.26 (s, 6H). LCMS (ES+) 332.0, 334.0 (M+H)+.
INTERMEDIATE 54
Ethyl 5,5-dimethyl-2-(morpholin-4-yl)-7-oxo-4,5.6.7-tetrahvdrothienor2,3-c1pyridine-3- carboxylate
To a stirred solution of Intermediate 53 (1.40 g, 4.10 mmol) in IPA (25 mL) at r.t. was added morpholine (1.0 mL, 11.50 mmol) and the reaction mixture was heated at 600C for 48 h. After cooling, the mixture was partitioned between EtOAc (100 mL) and water (50 mL). The organics were separated, washed with water (2 x 20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was then purified by column chromatography (SiO2, EtOAc) to give the title compound (1.0 g, 76%) as an off-white solid. δH (DMSO-d6) 7.58 (s, IH), 4.23 (q, J 7.2 Hz, 2H), 3.71-3.78 (m, 4H), 3.14-3.21 (m, 4H), 2.89 (s, 2H), 1.28 (t, J 7.0 Hz, 3H), 1.23 (s, 6H). LCMS (ES+) 339.0 (M+H)+.
INTERMEDIATE 55
5,5-Dimethyl-2-(moφholin-4-vπ-5,6-dihydrothieno[2,3-c1pyridin-7(4H)-one
To a stirred solution of Intermediate 54 (0.86 g, 2.50 mmol) in THF (9 mL) and water (8 mL) at r.t. was added LiOH (0.16 g, 3.80 mmol). The reaction mixture was then heated at 600C for 48 h before it was cooled and concentrated in vacuo. To the residue was added aqueous 2M HCl (8 mL) and the reaction mixture was stirred at r.t. for 6 h before it was cooled and basified to pH 10 by the addition of aqueous sat. Na2CO3. The resulting solid was filtered and dried to give the title compound (0.52 g, 80%) as a white powder. δH (DMSO-O6) 7.18 (s, IH), 6.08 (s, IH), 3.69-3.77 (m, 4H), 3.12-3.19 (m, 4H), 2.63 (s, 2H), 1.21 (s, 6H). LCMS (ES+) 267.0 (M+H)+.
INTERMEDIATE 56
3-Iodo-5.5-dimethyl-2-(moφholin-4-yl)-5,6-dihvdrothienor2,3-c1pyridin-7(4/π-one
To a stirred solution of Intermediate 55 (0.45 g, 1.67 mmol) in THF (20 mL) at r.t. was added NIS (0.39 g, 1.76 mmol). After stirring for 2 h, Na2CO3 (2.00 g, 18.87 mmol) was added and the reaction mixture was stirred for a further minute, prior to the addition of sat. aqueous Na2CO3 (10 mL). The resulting solid was filtered and washed with water and Et2O to give the title compound (0.35 g, 53%) as a white solid. δH (DMSO-d6) 7.65 (s, IH), 3.72-3.79 (m, 4H), 3.04-3.10 (m, 4H), 2.65 (s, 2H), 1.25 (s, 6H). LCMS (ES+) 393.0 (M+H)+.
INTERMEDIATE 57
3-(2-Chloropyridin-4-yl)-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydrothieno|'2,3- c1pyridin-7(4iy)-one
A mixture of Intermediate 56 (1.0 g, 2.55 mmol), 2-chloropyridine-4-boronic acid (0.41 g, 2.61 mmol), potassium phosphate (0.55 g, 2.59 mmol) and tetra-n-butyl- ammonium bromide (0.82 g, 2.55 mmol) in DME (30 mL) and water (9 mL) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.3 g, 2.60 mmol) was added and the reaction mixture was heated to 9O0C for 24 h. Sat. NaHCO3 solution was added and the mixture was extracted with EtOAc. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 30-75% EtOAc in heptane) to give the title compound (220 mg, 23%) as a cream solid, δπ (CD3OD) 8.41- 8.47 (m, IH), 7.44-7.70 (m, 3H), 3.69-3.77 (m, 4H), 2.94-3.02 (m, 4H), 2.75 (s, 3H), 1.32 (s, 6H). LCMS (ES+) 378.2, 380.2 (M+H)+.
INTERMEDIATE 58 3-(4-r5.5-Dimethyl-2-fmoφholin-4-yl)-7-oxo-4.5.6J-tetrahvdrothieno[2,3-clpyridin-3- yl]pyridin-2-yl } -4°f.uo.rQbenzaldehvde_ _
A mixture of Intermediate 57 (783 mg, 2.07 mmol), 2-fiuoro-5-formylphenyl- boronic acid (695 mg, 4.14 mmol) and potassium phosphate (500 mg, 2.36 mmol) in DME (16 mL) and water (4 mL) was degassed for 20 minutes. Tetrakis(triphenyl- phosphine)palladium(O) (120 mg, 0.10 mmol) was added, and the reaction mixture was degassed for a further 10 minutes and then heated to 1200C under microwave irradiation for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (40 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic fractions were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 0-100% EtOAc in heptane) and recrystallized from hot MeOH to give the title compound (461 mg, 48%) as a white solid. 6H (DMSO- (I6) 10.09 (s, IH), 8.84 (d, J5.1 Hz, IH), 8.59 (dd, J7.5, 2.1 Hz, IH), 8.03-8.10 (m, IH), 7.99 (s, IH), 7.53-7.69 (m, 3H), 3.57-3.67 (m, 4H), 2.86-2.95 (m, 4H), 2.71 (s, 2H), 1.20 (s, 6H). LCMS (ES+) 466.3 (M+H)+.
INTERMEDIATE 59
3-r2-{5-[Cvclopropyl(hvdroxy)methyll-2-fluorophenyl}pyridin-4-yl)-5,5-dimethyl-2- (morpholin-4-yl)-5,6-dihvdrothieno[2,3-c1pyridin-7(4H)-one
A solution of Intermediate 58 (400 mg, 0.86 mmol) in TΗF (30 mL) was cooled to O0C under a nitrogen atmosphere, and a solution of cyclopropylmagnesium bromide in TΗF (0.5M, 8.60 mL, 4.30 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 00C for 1 h and was then allowed to warm to r.t. and stirred for a further 72 h. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 0-10% MeOH in DCM; followed by SiO2, 0-100% EtOAc in heptane) to give the title compound (123 mg, 28%) as a white solid. δΗ (CDCl3) 8.78 (d, J 5.1 Hz, IH), 8.10 (dd, J7.7, 2.3 Hz, IH), 7.86 (s, IH), 7.48-7.55 (m, IH), 7.31-7.36 (m, IH), 7.18 (dd, J l l.l, 8.5 Hz, IH), 5.24 (s, IH), 4.10 (dd, J8.3, 2.8 Hz, IH), 3.69-3.77 (m, 4H), 2.94-3.03 (m, 4H), 2.73 (s, 2H), 2.02 (d, J 3.0 Hz, IH), 1.32 (s, 6H), 1.24-1.30 (m, IH), 0.40-0.74 (m, 4H). LCMS (ES+) 508.2 (M+H)+. TN IEKMEPIATE 60
3-{2-[5-(Cvclopropylcarbonyl)-2-ϊluorophenyllpyridin-4-yll-5,5-dimethyl-2-(morpholin- 4-vπ-5.6-dihvdrothienor2,3-c]pyridin-7(4H)-one l,l,l-Tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(lH)-one (122 mg, 0.29 mmol) was slowly added to a cooled (00C) solution of Intermediate 59 (123 mg, 0.24 mmol) in DCM (10 mL). The mixture was allowed to warm to r.t. and stirred for 2 h. The mixture was diluted with DCM (100 mL) and washed with water (2 x 30 mL). The organic phase was dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography (SiO2, 0-100% EtOAc in heptane) followed by trituration with Et2O to give the title compound (87 mg, 72%) as a beige-yellow solid. δΗ (CDCl3) 8.81 (dd, J4.9, 0.6 Hz, IH), 8.78 (dd, J7.5, 2.4 Hz, IH), 8.09 (ddd, J8.7, 4.9, 2.4 Hz, IH), 7.90 (s, IH), 7.37 (dd, J5.1, 1.7 Hz, IH), 7.25-7.33 (m, IH), 5.33 (s, IH), 3.69-3.77 (m, 4H), 2.95-3.03 (m, 4H), 2.75-2.82 (m, IH), 2.73 (s, 2H), 1.35 (s, 6H), 1.23-1.31 (m, 2H), 1.05-1.13 (m, 2H). LCMS (ES+) 506.3 (M+H)+.
INTERMEDIATE 61
3-{2-f2-Fluoro-5-(morpholin-4-ylcarbonyl)phenyl]pyridin-4-yl}-5,5-dimethyl-2- (moφholin-4-yl)-5,6-dihvdrothieno[2,3-clpyridin-7(4H)-one
A mixture of Intermediate 57 (1.0 g, 2.65 mmol), (2-fluoro-5-methoxycarbonyl- phenyl)boronic acid (524 mg, 2.65 mmol), tetrakis(triphenylphosphine)palladium(0) (152 mg, 0.13 mmol) and a solution of potassium phosphate tribasic (1.13 g, 5.32 mmol) in water (1.7 mL) was degassed. DME (8 mL) was added and the mixture was degassed further. The reaction mixture was heated at 1300C under microwave irradiation for 2 h. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 0-100% EtOAc in heptane). The product obtained was combined with lithium hydroxide monohydrate (329 mg, 7.88 mmol) in TΗF (30 mL) and water (5 mL) and stirred at r.t. overnight. The solvent was removed in vacuo and the residue was extracted with DCM (3 x 30 mL). The aqueous phase was acidified to pΗ 4 and extracted with further DCM (3 x 30 mL). The combined organic phases were dried (MgSO4) and evaporated in vacuo. A sample of the residue was purified by preparative ΗPLC {Method 6). A sample of the purified material (38 mg, 0.08 mmol) was dissolved in DCM (4 mL). HBTU (60 mg, 0.16 mmol) and morpholine (0.01 mL, 0.16 mmol) were added and the reaction mixture stirred at r.t. overnight. It was then diluted with water and extracted with DCM (2 x 20 mL). The combined organic fractions were dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by preparative HPLC (Method 6) to give the title compound (44 mg, 18%) as a yellow-orange solid. δH (DMSOd6) 8.80 (d, J 5.1 Hz, IH), 8.05 (dd, J 7.5, 2.3 Hz, IH), 7.95 (s, IH), 7.43-7.62 (m, 4H), 3.52-3.73 (m, 12H), 2.86-2.95 (m, 4H), 2.71 (s, 2H), 1.20 (s, 6H). LCMS (ES+) 551.3 (M+H)+.
INTERMEDIATE 62
fert-Butyl 3-(4-f5.5-dimethyl-2-(moφholin-4-yl)-7-oxo-4,5.6.7-tetrahvdrothieno|"2.3- c"|pyridin-3-yl]pyridin-2-yl)benzoate
A mixture of Intermediate 57 (450 mg, 1.19 mmol), 3-(tert-butoxycarbonyl)- phenylboronic acid (305 mg, 1.37 mmol), potassium phosphate tribasic (375 mg, 1.77 mmol) and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) in water (2.5 mL) and DME (9 mL) was heated at 1200C under microwave irradiation for 1.5 h. The reaction mixture was partitioned between EtOAc (40 mL) and sat. aqueous NaHCO3 solution (40 mL). The aqueous phase was reextracted with EtOAc (2 x 40 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-3% MeOH in DCM) to give the title compound (350 mg, 57%) as an off-white solid. δH (DMSO-dό) 8.77 (d, J5.1 Hz, IH), 8.64 (s, IH), 8.35 (d, J7.9 Hz, IH), 8.10 (s, IH), 7.99 (d, J7.7 Hz, IH), 7.65 (t, J7.7 Hz, IH), 7.57 (s, IH), 7.48 (dd, J5.1, 1.1 Hz, IH), 3.67-3.57 (m, 4H), 2.96-2.87 (m, 4H), 2.72 (s, 2H), 1.59 (s, 9H), 1.20 (s, 6H). LCMS (ES+) 520.2 (M+H)+.
INTERMEDIATE 63
3-(4-r5.5-Dimethyl-2-(morpholin-4-yl)-7-oxo-4.5.6.7-tetrahvdrothieno|"2,3-c1pyridin-3- vllpyridin-2-vUbenzoic acid, trifluoroacetic acid salt Trifluoroacetic acid (3 mL) was added to a solution of Intermediate 62 (180 mg,
0.35 mmol) in DCM (10 mL) and the reaction mixture was stirred at r.t. for 90 minutes. The solvent was removed in vacuo and the residue was triturated with Et2O to give the title compound (170 mg, 85%) as- a bright yellow solid, Sn (DMSO-d6> &-77 (ά, J 5.1 Hz, IH), 8.74-8.71 (m, IH), 8.39-8.33 (m, IH), 8.16 (s, IH), 8.06-8.01 (m, IH), 7.67 (t, J7.7 Hz, IH), 7.67 (s, IH), 7.52-7.48 (m, IH), 3.66-3.38 (m, 4H), 2.97-2.87 (m, 4H), 2.73 (s, 2H), 1.20 (s, 6H). LCMS (ES+) 464.3 (M+H)+.
INTERMEDIATE 64
5,5-Dimethyl-2-(morpholin-4-yl)-3-{2-r3-(ρyrrolidin-l-ylcarbonyl)phenyllρyridin-4-yl|- 5,6-dihydrothienof2,3-c|pyridin-7(4H)-one
A mixture of Intermediate 63 (50 mg, 0.11 mmol), triethylamine (30 μL, 0.215 mmol), ΗOBT (approx. 1 mg), EDC (23 mg, 0.12 mmol) and pyrrolidine ( 10 mg, 0.14 mmol) in DCM (6 mL) was stirred at r.t. overnight and for a further 24 h. The reaction mixture was diluted with DCM (5 mL), washed with water (5 mL) and then sat. NaHCO3 solution (5 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was triturated with Et2O to give the title compound (68 mg, 85%) as a pale yellow solid. δH (DMSO-dβ) 8.74 (d, J5.1 Hz, IH), 8.27 (s, IH), 8.24-8.19 (m, IH), 8.10 (s, IH), 7.63-7.54 (m, 3H), 7.47 (dd, J5.1, 1.3 Hz, IH), 3.62-3.56 (m, 4H), 3.53-3.37 (m, 4H), 2.93-2.84 (m, 4H), 2.71 (s, 2H), 1.95-1.76 (m, 4H), 1.19 (s, 6H). LCMS (ES+) 517.3 (M+H)+.
INTERMEDIATE 65
3-[2-(3-Bromophenyl)pyridm-4-yl1-5,5-dimethyl-2-(morpholin-4-yl)-5,6- dihvdrothieno|"2,3-clpyridin-7(4H)-one
A mixture of Intermediate 57 (857 mg, 2.27 mmol), 3-aminobenzeneboronic acid (352 mg, 2.27 mmol) and potassium phosphate tribasic (483 mg, 2.28 mmol) in water (4 mL) and DME (12 mL) was degassed for 10 minutes. Tetrakis(triphenylphosphine)- palladium(O) (50 mg, 0.04 mmol) was added and the reaction mixture was heated at reflux overnight. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 0-10% MeOH in DCM + 1% NH4OH in DCM) to give the intermediate amine as a pale yellow solid. A solution of this intermediate (870 mg, 2.0 mmol) in 1,4-dioxane (4 mL) was treated with hydrobromic acid (48%, 9 mL) and the resulting suspension cooled to 3°C with stirring. A solution of sodium nitrite (138 mg, 2.0 mmol) in water (2 mL) was added dropwise over several minutes, maintaining the reaction temperature below 50C, and the reaction mixture was then stirred at this temperature for 1 h. A solution of copper(I) bromide (344 mg, 2.40 mmol) in hydrobromic acid (48%, 1 mL) was added dropwise and the reaction mixture was stirred at 5°C for 10 minutes and then at r.t. for 2 h. Water (100 mL) was added and the mixture was extracted with EtOAc (150 mL). The organic phase was washed with water (100 mL). All the aqueous phases were combined and washed with EtOAc (150 mL). The combined organic phases were dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography (SiO2, 0-10% MeOH in DCM) to give a yellow solid, which was suspended in EtOAc (150 mL) and THF (20 mL) and washed with water (2 x 70 mL). The organic fraction was dried (MgSO4) and the solvent removed in vacuo to give the title compound (626 mg, 58%) as a yellow solid. δH (DMSO-d6) 8.74 (d, J 5.1 Hz, IH), 8.32-8.36 (m, IH), 8.09-8.17 (m, 2H), 7.62-7.69 (m, IH), 7.45-7.57 (m, 3H), 3.54-3.64 (m, 4H), 2.85-2.93 (m, 4H), 2.71 (s, 2H), 1.19 (s, 6H). LCMS (ES+) 498.3, 500.2 (M+H)+.
INTERMEDIATE 66
(3,3-Dimethyl-5-oxocvclohexylidene)malononitrile
To a stirred solution of dimedone (98.0 g, 700.0 mmol) and malononitrile (46.2 g, 700.0 mmol) in EtOH (400 mL) at r.t. was added piperidine (8.5 g, 9.9 mL, 100.0 mmol) dropwise over 15 minutes. The reaction mixture was then heated to reflux for 3 days before cooling to r.t. The solvent was removed in vacuo and the residue redissolved in EtOAc (500 mL) and dried (MgSO4). Filtration and concentration in vacuo gave a black oil that was purified by column chromatography (SiO2, 1 :6 MeOH/DCM) to give the title compound (108.0 g, 82%) as a yellow solid. δH (DMSO-de) 8.31 (br s, 2H), 2.51 (t, J 1.8 Hz, 2H), 2.30 (s, 2H), 1.04 (s, 6H). LCMS (ES-) 187.3 (M-H)".
INTERMEDIATE 67 v
2-Amino-5.5-dimethyl-7-oxo-4,5,6,7-tetrahvdro-l-benzothiophene-3-carbonitrile
To a stirred solution of Intermediate 66 (50.8 g, 270.0 mmol) and sulphur (10.3 g, 320.0 mmol) in EtOH (600 mL) was slowly added morpholine (46.0 g, 46.0 mL, 530.0 mmol) at r.t. The reaction mixture was stirred at 800C for 24 h and then cooled. The solids formed were isolated by filtration and washed with cold Et2O to give the title compound (41.2 g, 53%) as a buff solid. δH (DMSO-d6) 8.31 (br s, 2H), 2.51 (t, J 1.8 Hz, 2H), 2.30 (s, 2H), 1.04 (s, 6H). LCMS (ES-) 219.2 (M-H)".
INTERMEDIATE 68
2-Bromo-5,5-dimethyl-7-oxo-4.5,6,7-tetrahvdro-l-benzothiophene-3-carbonitrile
A solution of copper(II) bromide (79.3 g, 355 mmol) in MeCN (500 mL) was stirred at O0C for 15 minutes. Tert-butyl nitrite (37.9 mL, 319 mmol) was added dropwise over 10 minutes, followed by portionwise addition of Intermediate 67 (56.6 g, 257 mmol) over 45 minutes. The reaction mixture was stirred at 00C for a further 10 minutes, then at r.t. for 3 h. The reaction mixture was concentrated in vacuo and the resultant slurry was partitioned between aqueous HCl (IN, 500 mL) and EtOAc (300 mL). The aqueous phase was extracted with EtOAc (2 x 200 mL) and the combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound (72.6 g, 99%) as a brown solid. δH (DMSO-d6) 2.84 (s, 2H), 2.51 (s, 2H), 1.07 (s, 6H). LCMS (ES+) 285.9 (M+H)+.
INTERMEDIATE 69
5.5-Dimethyl-2-(morpholin-4-yl)-7-oxo-4.5.6.7-tetrahydro-l-benzothiophene-3- carbonitrile
To a stirred solution of Intermediate 68 (18.3 g, 64.4 mmol) in DMSO (150 mL) was slowly added morpholine (14.6 mL, 168.0 mmol) and the reaction mixture was heated to 1000C for 30 minutes. After cooling, the reaction mixture was diluted with water (450 mL) with vigorous stirring and the resultant precipitate was filtered off, washed with water and dried to give the title compound (14.4 g, 77%) as a pale green solid. δH (DMSO-d6) 3.74-3.80 (m, 4H), 3.62-3.67 (m, 4H)5 2.64 (s, 2H), 2.36 (s, 2H),
1.05 (s, 6H). LCMS (ES+) 291.0 (M+H)+.
INTERMEDIATE 70
5,5-Dimetrr^2-(mυrμhorrπ^4-vi)-5,fr-dihvdrσ- I -beπzσthtopheπ-7(4/-t>-one To a stirred solution of Intermediate 69 (10.0 g, 34.5 mmol) in glacial AcOH (100 mL) at 1200C was added concentrated H2SO4 (40 mL). After stirring for 24 h the reaction mixture was cooled to r.t. prior to pouring into a well-stirred mixture of EtOAc (950 mL) and water (950 mL) at 00C. The resulting emulsion was filtered through Celite® and the organic phase was separated, washed with brine (3 x 100 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 1 : 1 EtOAc/ hexanes) gave the title compound (5.3 g, 58%) as a white powder. 6H (DMSO-d6) 6.15 (s, IH), 3.69-3.75 (m, 4H), 3.22-3.28 (m, 4H), 2.58 (s, 2H), 2.26 (s, 2H), 1.01 (s, 6H). LCMS (ES+) 266.0 (M+H)+.
INTERMEDIATE 71
3-Iodo-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one
A mixture of Intermediate 70 (790 mg, 2.98 mmol) and NIS (738 mg, 3.28 mmol) in TΗF (20 mL) was stirred at r.t. for 40 minutes. The solvent was remoyed in vacuo and the residue purified by column chromatography (SiO2, 10-100% EtOAc in heptane) to give the title compound (722 mg, 62%) as a peach-coloured powder. 5Η (CDCl3) 3.86-
3.91 (m, 4Η), 3.19-3.24 (m, 4H), 2.61 (s, 2H), 2.44 (s, 2H), 1.13 (s, 6H). LCMS (ES+) 392 (M+H)+.
INTERMEDIATE 72
S-^-Chloropyridin^-vD-S^-dimethyl^-rmorpholin^-vD-S.ό-dihvdro-l-benzothiophen- 7(4HVone A mixture of Intermediate 71 (520 mg, 1.33 mmol), 2-chloropyridine-4-boronic acid (319 mg, 1.33 mmol), potassium phosphate tribasic (847 mg, 3.99 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in water (1 mL) and DME (3 mL) was heated at 12O0C under microwave irradiation for 20 minutes. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 0-60% EtOAc in heptane) to give the title compound (136 mg, 27%) as an off-white solid, δπ (DMSO-d6) 8.50 (s, 1Η), 7.59 (s, 1Η), 7.49 (d, J6.0 Hz, IH), 3.64-3.58 (m, 4H), 2.96-
2.92 (m, 4H), 2.54 (s, 2H), 2.38 (s, 2H), 0.97 (s, 6H). LCMS (ES+) 377.3 (M+H)+. INTERMEDIATE 73
3- {4-|"5,5-Dimethyl-2-rniorpholin-4-yl)-7-oxo-4,5.6.7-tetrahvdro- 1 -benzothien-3- yllpyridin-2- yl } -A^JV-dimethylbenzamide The title compound was prepared in a similar manner to Intermediate 62, using
Intermediate 72 and 3-(N,N-dimethylammocarbonyl)phenylboronic acid, and was isolated as an off-white solid (33%) after purification by preparative HPLC {Method 7). δπ (DMSO-d6) 8.76 (d, J5.1 Hz, IH), 8.26-8.21 (m, IH), 8.18 (s, IH), 8.10 (s, IH), 7.59 (t, J 7.7 Hz, IH), 1.52-1 Al (m, IH), 7.44 (dd, J4.9, 1.1 Hz, IH), 3.64-3.55 (m, 4H), 3.08-2.93 (m, 10H), 2.59 (s, 2H), 2.39 (s, 2H), 0.97 (s, 6H). LCMS (ES+) 490.2 (M+H)+.
INTERMEDIATE 74
5,5-Dimethyl-2-(morpholin-4-yl)-3-{2-[3-(moφholin-4-yl)phenyl]pyridin-4-yl)-5,6- dihvdro- 1 -benzothiophen-7(4//)-one
The title compound was prepared in a similar manner to Intermediate 62, using Intermediate 72 and 3-(morpholino)phenylboronic acid, and was isolated as a pale yellow solid (54%) after purification by preparative HPLC {Method 6). δH (DMSO-d6) 8.72 (d, J 4.9 Hz, IH), 8.04 (s, IH), 7.72-7.66 (m, IH), 7.58 (d, J7.5 Hz, IH), 7.42-7.34 (m, 2H), 7.06 (dd, J8.1, 2.1 Hz, IH), 3.83-3.73 (m, 4H), 3.64-3.55 (m, 4H), 3.26-3.16 (m, 4H), 3.03-2.93 (m, 4H), 2.59 (s, 2H), 2.39 (s, 2H), 0.97 (s, 6H). LCMS (ES+) 504.4 (M+H)+.
EXAMPLES 1 & 2
7-Hvdroxy-6.6-dimethyl-2-r6-(l-methyl-lH-pyrazol-4-ylV2,3-dihvdro-4H-L4- benzoxazin-4-yl]-6,7-dihvdrori31thiazolo[5,4-c"|pyridin-4(5.H)-one and 2-r7-Chloro-6-(l- methyl-l//-pyrazol-4-ylV2,3-dihvdro-4/-/-l,4-benzoxazin-4-yl]-7-hydroxy-6,6-dimethyl- 6 j-dihydro[ 1 ,31thiazolor5,4-c]pyridin-4(5H)-one
A mixture of Intermediate 18 (0.85 g, 2.14 mmol) and NCS (0.28 g, 2.14 mmol) in acetonitrile (11 mL) was heated to 7O0C overnight. Water (3 mL) was added and the mixture heated to 1000C over the weekend. After cooling to r.t., the reaction mixture was partitioned between DCM and saturated aqueous NaHCO3. The organic fraction was dried (MgSO4) and concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the first title compound (227 mg, 26%) as a white solid. δH (CDCl3) 8.01 (IH, d, J 1.9 Hz), 7.86 (2H, s), 7.19 (IH, dd, J8.5, 2.1 Hz), 6.93 (IH, br s), 6.91 (IH, d, J8.7 Hz), 4.34-4.50 (2H, m), 4.14-4.25 (2H, m), 3.99 (3H, s), 3.67 (IH, br s), 1.46 (3H, s), 1.34 (3H, s). LCMS (ES+) 412 (M+H)+, RT 2.49 minutes (Method 1). This was followed by the second title compound (62 mg, 6%) as a white solid. 5H
(DMSO-d6) 8.52 (IH, s), 8.08 (IH, s), 7.73 (IH, s), 7.61 (IH, s), 7.14 (IH, s), 5.72 (IH, d, J7.2 Hz), 4.32-4.40 (2H, mj, 4.24 (IH, d, J7.2 Hz), 4.04-4.12 (2H, m), 3.90 (3H, s), 1.25 (3H, s), 1.18 (3H, s). LCMS (ES+) 446 (M+H)+, RT 2.79 minutes (Method 1).
Example 1 was separated into its enantiomefs by chiral HPLC using a Chiralpak column eluted with isopropanol:heptane:diethylamine 50:50:0.5. Enantiomer A: RT 8.02 minutes. Enantiomer B: RT 9.92 minutes.
EXAMPLE 3
2- (6-r 1 -(DifluoromethylV7/ir-Pyrazol-4-yll-2 J-dihvdro-4H-l ,4-benzoxazin-4-yl) -7- hvdroxy-6,6-dimethyl-6,7-dihvdro[ 1 ,31thiazolof 5,4-c]pyridiή-4(5//)-one
A mixture of Intermediate 25 (50 mg, 0.11 πimol) and NCS (19 mg, 0.14 mmol) in MeCN (2 mL) was heated to 800C for 1 h. After cooling to r.t. water (2 mL) was added and the reaction mixture heated to 1000C for 1.5 h. After cooling to r.t. the MeCN was removed in vacuo. The resulting aqueous fraction was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give, after purification by preparative HPLC (Method 6), the title compound (20 mg, 40%) as a white solid. δH (DMSO-de) 8.63 (IH, s), 8.46 (IH, d, J2.1 Hz), 8.21 (IH, s), 7.83 (IH, t, J 59.2 Hz), 7.59 (IH, s), 7.41 (IH, dd, J 8.7, 2.3 Hz), 7.02 (IH, d, J 8.3 Hz), 5.73 (IH, d, J7.0 Hz), 4.30-4.37 (2H, m), 4.26 (IH, d, J7.0 Hz), 4.08-4.15 (2H, m), 1.25 (3H, s), 1.19 (3H, s). LCMS (ES+) 448 (M+H)+, RT 2.88 minutes (Method 1).
EXAMPLES 4 TO 14
All prepared following the procedure of Example 3.
EXAMPLE 4 2-(6-Bromo-2,3-dihvdro-4/-r-l,4-benzoxazin-4-yl)-7-hvdroxy-6,6-dimethyl-6,7- dihvdrof 13]thiazolo[5.4-c]pyridin-4(5H)-one
Using Intermediate 14 (394 mg, 1.0 mmol) and NCS (146 mg, 1.1 mmol) in MeCN (10 mL) heated to 800C overnight followed by addition of water (4 mL) and heating to 1100C overnight to give, after purification by column chromatography (SiO2, DCMrMeOHrNH4OH 94:5:1) followed by trituration with Et2O, the title compound (150 mg, 36%) as a white solid. δH (DMSO-d6) 8.66 (IH, d, J2.4 Hz), 7.63 (IH, s), 7.19 (IH, dd, J 8.7, 2.4 Hz), 6.93 (IH, d, J 8.7 Hz), 5.73 (IH, d, J7.3 Hz), 4.30-4.41 (2H, m), 4.25 (IH, d, J7.3 Hz), 3.96-4.06 (2H, m), 1.26 (3H, s), 1.17 (3H, s). LCMS (ES+) 410, 412 (M+H)+, RT 3.03 minutes {Method 1).
EXAMPLE 5
2-f6-Bromo-7-fluoro-2,3-dihvdro-4H-l,4-benzoxazin-4-yl)-7-hvdroxy-6,6-dimethyl-6,7- dihydro[ 1 ,3"|thiazolor5.4-c]pyridin-4(5H)-one
Using Intermediate 15 (102 mg, 0.24 mmol) and NCS (36 mg, 0.27 mmol) in MeCN (1 mL) heated to 1000C overnight, followed by water (1 mL) and heating to 800C for 6 h to give, after purification by preparative ΗPLC {Method 6), the title compound (6 mg, 6%) as a white solid. δΗ (CDCl3) 8.22 (IH, d, J6.8 Hz), 6.78 (IH, d, J 8.9 Hz), 5.27 (IH, s), 4.55 (IH, d, J 5.5 Hz), 4.35 (2H, s), 4.01-4.21 (2H, m), 2.44 (IH, d, J 5.5 Hz), 1.39 (6H, s). LCMS (ES+) 428, 430 (M+H)+, RT 3.13 minutes {Method 1).
EXAMPLE 6
2-r7-Fluoro-6-n-methyl-l//-pyrazol-4-ylV2.3-dihvdro-4H-1.4-benzoxazin-4-yll-7- hvdroxy-6,6-dimethyl-6,7-dihvdrori,31thiazolof5,4-c]pyridin-4(5H)-one
Using Intermediate 19 (53 mg, 0.13 mmol) and NCS (19 mg, 0.14 mmol) in MeCN (1 mL) heated to 7O0C for 3 h followed by addition of water (1 mL) and heating to 800C overnight, to give, after purification by preparative ΗPLC {Method 6), the title compound (21 mg, 37%) as a white solid. δΗ (CD3OD) 8.35 (IH, d, J7.7 Hz), 7.96 (IH, d, J 1.9 Hz), 7.83 (IH, s), 6.82 (IH, d, J 11.7 Hz), 4.40 (IH, s), 4.35-4.40 (2H, m), 4.16- 4.21 (2H, m), 3.96 (3H, s), 1.41 (3H, s), 1.32 (3H, s). LCMS (ES+) 430 (M+H)+, RT 2.65 minutes {Method 1). EXAMPUE 7
7-Hvdroxy-6,6-dimethyl-2-[6-('pyridazin-3-yloxy)-2,3-dihvdro-4H-l,4-benzoxa2in-4-yl]- 6.7-dihvdrori.31thiazolor5.4-clDyridin-4r5H)-one
Using Intermediate 30 (230 mg, 0.56 mmol) and NCS (83 mg, 0.62 mmol) in MeCN (5 mL) heated to 700C overnight followed by water (3 mL) and heating to 8O0C overnight, to give, after purification by preparative HPLC (Method 6), the title compound (51 mg, 37%) as a white solid. δH (DMSO-(I6) 9.00 (IH, dd, J 4.5, 1.3 Hz), 8.34 (IH, d, J 2.6 Hz), 7.76 (IH, dd, J 9.0, 4.5 Hz), 7.59 (IH, s), 7.45 (IH, dd, J 9.0, 1.3 Hz), 7.02-7.06 (IH, m), 6.91 (IH, dd, J8.9, 2.6 Hz), 5.65 (IH, d, J7.2 Hz), 4.33-4.41 (2H, m), 4.18 (IH, d, J 7.3 Hz), 4.03-4.10 (2H, m), 1.22 (3H, s), 1.14 (3H, s). LCMS (ES+) 426 (M+H)+, RT 2.34 minutes (Method J).
EXAMPLE 8
7-Hvdroxy-2-(6-ri-(2-hvdroxy-3-methoxypropyl)-lH-pyrazol-4-yl]-2,3-dihvdro-4H-l,4- benzoxazin-4-vU -6,6-dimethyl-6,7-dihydro[ 1 ,3]thiazolor5,4-c~lpyridin-4(5H)-one
Using Intermediate 20 (200 mg, 0.42 mmol) and NCS (60 mg, 0.45 mmol) in TΗF (8 mL) heated to 800C for 6 h, followed by addition of water (8 mL) and heating to 800C overnight to give, after purification by preparative ΗPLC (Method 6), the title compound (127 mg, 61%) as an off-white solid. δΗ (DMSOd6) 8.30 (IH, d, J 1.9 Hz), 8.02 (IH, s), 7.81 (IH, s), 7.58 (IH, s), 7.28 (IH, dd, J8.5, 2.1 Hz), 6.96 (IH, d, J8.5 Hz), 5.71 (IH, d, J7.2 Hz), 5.17 (IH, d, J5.1 Hz), 3.91-4.36 (8H, m), 3.30-3.35 (2H, m), 3.34 (3H, s), 1.25 (3H, s), 1.18 (3H, s). LCMS (ES+) 486 (M+H)+, RT 2.36 minutes (Method 1).
EXAMPLE 9
7-Hvdroxy-2-(6-ri-(2-hvdroxyethyl)-lH-pyrazol-4-yl1-2,3-dihvdro-4H-1.4-benzoxazin- 4-vU -6,6-dimethyl-6,7-dihvdrof 1 Jlthiazolof 5,4-c1pyridm-4(5HVone
Using Intermediate 21 (200 mg, 0.47 mmol) and NCS (66 mg, 0.49 mmol) in TΗF (8 mL) heated to reflux for 6 h, followed by addition of water (8 mL) and heating to 8O0C overnight to give, after purification by preparative ΗPLC (Method 6), the title compound (128 mg, 62%) as an off-white solid. δH (DMSO-d6) 8.30 (IH, d, J 2.1 Hz), 8.06 (IH, s), 7.80 (IH, S), 7.58 (IH, s), 7.28 (IH5 dd, JS.5, 2.1 Hz), 6.96 (IH, d, J8.5 Hz), 5.72 (IH, d, J 7.0 Hz), 4.93 (IH, t, J 5.3 Hz), 4.28-4.35 (2H, m), 4.25 (IH, d, J 7.0 Hz), 4.08-4.18 (4H, m), 3.71-3.83 (2H, m), 1.25 (3H, s), 1.18 (3H, s). LCMS (ES+) 442 (M+H)+, RT 2.26 minutes (Method 1).
EXAMPLE 10
7-Hvdroxy-2-{6-[5-(hvdroxyinethylVl-isopropyl-3-niethyl-lH-pyrazol-4-yll-2,3- dihvdro-4H- 1 ,4-benzoxazin-4-yl} -6.6-dimethyl-6,7-dihydro[ 1 ,31thiazolo[5.4-c1pyridin- 4(5H>one
Using Intermediate 27 (200 mg, 0.47 mmol) and NCS (67 mg, 0.49 mmol) in TΗF (8 mL) heated to reflux for 6 h, followed by addition of water (8 mL) and heating to 800C overnight to give, after purification by preparative ΗPLC {Method 6), the title compound (32 mg, 14%) as an off-white solid. δΗ (DMSOd6) 8.14 (IH, d, J 1.7 Hz), 7.57 (IH, s), 6.95-7.10 (2H, m), 5.65 (IH, d, J7.2 Hz), 5.24 (IH, t, J5.1 Hz), 4.61-4.73 (IH, m), 4.46 (2H, d, J5.1 Hz), 4.30-4.39 (2H, m), 4.20 (IH, d, J7.3 Hz), 4.05-4.14 (2H, m), 2.22 (3H, s), 1.41 (6H, d, J6.6 Hz), 1.24 (3H, s), 1.16 (3H, s). LCMS (ES+) 484 (M+H)+, RT 2.59 minutes (Method 1).
EXAMPLE 11
2-{5,7-Dichloro-6-f(6-methylpyridazin-3-yl)amino]-2,3-dihvdro-4H-l,4-benzoxazin-4- vU-7-hvdroxy-6,6-dimethyl-6,7-dihydro[l,31thiazolor5,4-c1pyridin-4(5H)-one Using Intermediate 26 (200 mg, 0.43 mmol) and NCS (67 mg, 0.49 mmol) in TΗF
(8 mL) heated to reflux for 6 h, followed by addition of water (8 mL) and heating to 800C for 7 h to give, after purification by preparative ΗPLC (Method 6), the title compound (15 mg, 6%) as an off-white solid. δΗ (DMSOd6) 8.73 (IH, s), 7.64 (IH, s), 7.24-7.36 (2H, m), 6.84 (IH, d, J9.0 Hz), 5.69 (IH, d, J7.2 Hz), 3.98-4.40 (5H, m), 2.42 (3H, s), 1.23 (3H, s), 1.15 (3H, s). LCMS (ES+) 507 (M+H)+, RT 2.51 minutes (Method 1).
EXAMPLES 12 & 13 4-Hvdroxy-5<5-dimethyl-2-r6-(l -methyl- lH-pyrazol-4-vn-2.3-dihvdro-4Hr- 1 ,4- benzoxazin-4-yl]-5,6-dihvdro-l,3-benzothiazol-7(4H)-one and 5.5-Dimethyl-2-r6-(l- methyl-lH-pyrazol-4-ylV2,3-dihvdro-4H-l,4-benzoxa2in-4-yl]-5.6-dihvdro-l,3- benzothiazole-4,7-dione Using Intermediate 32 (100 mg, 0.25 mmol) and NCS (37 mg, 0.28 mmol) in TΗF
(2 mL) heated to 1000C under microwave irradiation for 1 h, followed by addition of water (1 mL) and heating to 1300C under microwave irradiation for 3.5 h to give, after purification by preparative ΗPLC {Method 6), the first title compound (18 mg, 17%) as a yellow solid. δΗ (CDCl3) 7.90 (IH, d, J 1.9 Hz), 7.69 (IH, s), 7.56 (IH, s), 7.21 (IH, dd, J 8.5, 2.1 Hz), 6.97 (IH, d, J 8.7 Hz), 4.63 (IH, s), 4.08-4.43 (4H, m), 3.95 (3H, s), 2.83 (IH, br s), 2.43-2.62 (2H, m), 1.23 (3H, s), 1.07 (3H, s). LCMS (ES+) 411 (M+H)+, RT 2.95 minutes (Method 1).
This was followed by the second title compound (7 mg, 7%) as a pale yellow solid. δH(CDCl3) 7.82 (IH, d, J2.1 Hz), 7.70 (IH, s), 7.58 (IH, s), 7.24 (IH, dd, J8.5, 2.1 Hz), 6.98 (IH, d, J 8.5 Hz), 4.36 (4H, s), 3.96 (3H, s), 2.91 (2H, s), 1.37 (6H, s). • , LCMS (ES+) 409 (M+H)+, RT 3.31 minutes (Method 1).
EXAMPLE 14
3-(J(35r)-4-(7-Hvdroxy-6.6-dimethyl-4-oxo-4.5,6.7-tetrahvdrori,31thiazolor5,4-c1pyridin- 2-yl)morpholin-3-yllmethyl}-N,JV,l-trimethyl-lH-indole-5-carboxamide
Using Intermediate 49 (100 mg, 0.21 mmol) and NCS (29 mg, 0.22 mmol) in THF (10 mL) heated to 800C for 2 h, followed by addition of water (10 mL) and heating to 9O0C for 48 h to give, after purification by preparative HPLC (Method 6), the title compound (10 mg, 9%) as an off-white solid. δH (DMSO-d6) 7.97 (IH, d, J22.4 Hz),
7.43 (IH, dd, J8.3, 1.5 Hz), 7.38 (IH, d, J2.4 Hz), 7.30 (IH, d, J2.8 Hz), 7.19-7.25 (IH, m), 5.49 (IH, dd, J 15.8, 7.7 Hz), 4.04-4.15 (2H, m), 4.00 (IH, d, J 7.0 Hz), 3.77 (3H, s), 3.44-3.82 (7H, m), 3.02 (6H, s), 1.25 (1.5H, s), 1.24 (1.5H, s), 1.15 (1.5H, s), 1.13 (1.5H, s). LCMS (ES+) 498 (M+H)+, RT 2.43 minutes (Method 1).
EXAMPLE 15 7-Hvdroxy-6,6-dimethyl-2-f 6-(6-methylpyridin-2-yl)-2.3 -dihvdro-4H- 1 ,4-benzoxazin-4- vn-6.7-dihvdror 1.3ithiazolόr5.4-cbyridin-4(5Hyone
A mixture of Intermediate 29 (93 mg, 0.20 mmol), 2-bromo-6-methylpyridine (53 mg, 0.30 mmol), potassium phosphate tribasic (86 mg, 0.40 mmol) and tetrakis(triphenyl- phosphine)palladium(O) (12 mg, 0.01 mmol) in TΗF (3 mL) and water (1 mL) was heated to 1200C under microwave irradiation for 1 h. After cooling to r.t. the mixture was filtered through celite. The organic fraction was washed with water and brine, dried (MgSO4), concentrated in vacuo and purified by preparative ΗPLC {Method 6) to give the title compound (15 mg, 18%) as a white solid. δΗ (DMSOd6) 8.81 (IH, d, J 1.9 Hz), 7.65-7.84 (3H, m), 7.60 (IH, s), 7.18 (IH, d, J7.5 Hz), 7.07 (IH, d, J8.5 Hz), 5.69 (IH, d, J7.3 Hz), 4.33-4.42 (2H, m), 4.23 (IH, d, J7.3 Hz), 4.13-4.21 (2H, m), 3.35 (3H, s), 1.26 (3H, s), 1.18 (3H, s). LCMS (ES+) 423 (M+H)+, RT 1.90 minutes (Method I).
EXAMPLES 16 TO 18
All prepared following the procedure of Example 15.
EXAMPLE 16
7-Hvdroxy-2-(6-r6-fl-hvdroxy-l-methylethvnpyridin-3-yll-2.3-dihvdro-4H-1.4- benzoxazin-4-yl|-6,6-dimethyl-6,7-dihvdroriJlthiazolof5,4-clpyridin-4(5//)-one Using Intermediate 29 (122 mg, 0.27 mmol), Intermediate 50 (86 mg, 0.40 mmol), potassium phosphate tribasic (113 mg, 0.53 mmol) and tetrakis(triphenyl- phosphine)palladium(O) (15 mg, 0.013 mmol) in TΗF (3 mL) and water (1 mL) heated to 1200C under microwave irradiation for 1 h. Purification by preparative ΗPLC (Method 6) gave the title compound (15 mg, 13%) as a white solid. δΗ (DMSO-de) 8.75 (IH, d, J 2.3 Hz), 8.56 (IH, d, J2.3 Hz), 8.00 (IH, dd, J8.3, 2.4 Hz), 7.73 (IH, d, J8.3 Hz), 7.60 (IH, s), 7.43 (IH, dd, J 8.5, 2.1 Hz), 7.09 (IH, d, J 8.5 Hz), 5.71 (IH, d, J 7.2 Hz), 5.26 (IH, s), 4.34-4.40 (2H, m), 4.24 (IH, d, J7.2 Hz), 4.09-4.17 (2H, m), 1.47 (6H, s), 1.25 (3H, s), 1.18 (3H, s). LCMS (ES+) 467 (M+H)+, RT 1.93 minutes (Method 1).
EXAMPLE 17 7-Hvdroxy-6,6-dimethyl-2-r6-(1.3,5-trimethyl-lH-ρyrazol-4-yl)-2.3-dihvdro-4H-l,4- benzoxazin-4-yl]-6,7-dihydror 1 ,31tniazolor5,4-c|pyridin-4(5H)-one
Using Example 4 (150 mg, 0.37 mmol), Intermediate 51 (129 mg, 0.54 mmol), potassium phosphate tribasic (155 mg, 0.73 mmol) and tetrakis(triphenylphosphine)- palladium(O) (21 mg, 0.018 mmol) in TΗF (3 mL) and water (1 mL) heated to 12O0C under microwave irradiation for 1 h. Purification by preparative ΗPLC {Method 6) followed by trituration with heptane and ether gave the title compound (62 mg, 38%) as a pale yellow solid. δΗ (DMSO-d6) 8.09 (IH, d, J 1.9 Hz), 7.57 (IH, s), 6.92-7.03 (2H, m), 5.63 (IH, d, J7.3 Hz), 4.30-4.40 (2H, m), 4.17 (IH, d, J7.2 Hz), 4.05-4.13 (2H, m), 3.70 (3H, s), 2.26 (3H, s), 2.16 (3H, s), 1.25 (3H, s), 1.15 (3H, s). LCMS (ES+) 440 (M+H)+, RT 2.53 minutes {Method 1).
EXAMPLE 18
7-Hvdroxy-2-r6-n-isopropyl-3.5-dimethyl-lH-pyrazol-4-vn-2.3-dihvdro-4H-l.4- benzoxazin-4-yll-6,6-dimethyl-6,7-dihvdro[1.31thiazolo[5.4-clpyridin-4(5H)-one
Using Intermediate 29 (150 mg, 0.33 mmol), 4-bromo-l-isopropyl-3,5-dimethyl- lH-pyrazole (81 mg, 0.39 mmol), potassium phosphate (139 mg, 0.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) in TΗF (3 mL) and water (1 mL) heated to 1200C under microwave irradiation for 15 minutes. Purification by preparative ΗPLC {Method 6) followed by trituration with heptane and drying in vacuo gave the title compound (32 mg, 21%) as an off-white solid. δΗ (CDCl3) 7.70 (IH, s), 6.99 (2H, s), 5.25 (IH, s), 4.51 (IH, d, J 5.7 Hz), 4.39-4.46 (IH, m), 4.33-4.40 (2H, m), 4.22-4.33 (IH, m), 4.08-4.22 (IH, m), 2.56 (6H, d, J 6.0 Hz), 1.52 (3H, s), 1.50 (3H, s), 1.37 (6H, s). LCMS (ES+) 468 (M+H)+, RT 2.89 minutes {Method 1).
EXAMPLE 19
7-Hvdroxy-6.6-dimethyl-2-[6-(6-methylpyridin-3 -vD-2,3 -dihydro-4H- 1 ,4-benzoxazin-4- yli-6 j-dihvdrof 1.31thiazolor5.4-clpyridin-4(5Hy one
A mixture of Example 4 (135 mg, 0.33 mmol), 2-methyl-5-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)pyridine (87 mg, 0.40 mmol), bis(dibenzylideneacetone)- palladium(O) (19 mg, 0.03 mmol), tricyclohexylphosphine (9 mg, 0.03 mmol) and cesium carbonate (322 mg, 0.99 mmol) in THF (3 mL) and water (1 mL) was heated to 12O0C under microwave irradiation for 20 minutes. After cooling to r.t. it was partitioned between water and DCM. The organic fraction was dried (MgSO4) and concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (52 mg, 37%) as a white solid. δH (CDCl3) 8.75 (IH, d, J2.3 Hz), 8.24 (IH, d, J2.1 Hz), 7.76 (IH, dd, J 7.9, 2.3 Hz), 7.30 (IH, d, J2.3 Hz), 7.23 (IH, d, J8.3 Hz), 7.05 (IH, d, J 8.5 Hz), 5.48 (IH, s), 5.30 (IH, s), 4.55 (IH, s), 4.35-4.43 (2H, m), 4.06-4.29 (2H, m), 2.60 (3H, s), 1.41 (3H, s), 1.38 (3H, s). LCMS (ES+) 423 (M+H)+, RT 1.75 minutes (Method
I)-
EXAMPLE 20
6,6-Dimethyl-7-(methylaminoV2-r6-(l-methyl-lH-pyrazol-4-vπ-2.3-dihvdro-4H-1.4- benzoxazin-4-yl]-6,7-dihvdro|"1.31thiazolo[5,4-clpyridin-4(5H)-one A mixture of Intermediate 18 (230 mg, 0.58 mmol) and NCS (78 mg, 0.58 mmol) in MeCN (7 mL) was heated to 5O0C for 3 h. After cooling to r.t., methylamine (1.5mL of a 2N solution in methanol, 2.9 mmol) was added, and the mixture heated to HO0C under microwave irradiation for 30 minutes. It was cooled to r.t. and partitioned between water and DCM. The organic fraction was dried (MgSO4) and concentrated in vacuo. Purification by preparative ΗPLC (Method 6) gave the title compound (33 mg, 13%) as a white solid. δΗ (CD3OD) 8.26 (IH, d, J 1.9 Hz), 7.90 (IH, s), 7.76 (IH, s), 7.28 (IH, dd, J8.3, 1.9 Hz), 6.98 (IH, d, J8.5 Hz), 4.33-4.39 (2H, m), 4.18-4.23 (2H, m), 3.93 (IH, s), 3.54 (3H, s), 2.52 (3H, s), 1.40 (3H, s), 1.35 (3H, s). LCMS (ES+) 425 (M+H)+, RT 1.78 minutes (Method 1).
EXAMPLE 21
7-rN-(2-HvdroxyethylVN-(methyl>)aminol-6,6-dimethyl-2-r6-(l-methyl-lH-pyrazol-4-ylV 2,3-dihvdro-4H-l ,4-benzoxazin-4-yl]-6,7-dihvdro[ 1 ,31thiazolo|"5,4-c1pyridin-4f 5H)-one A mixture of Intermediate 18 (250 mg, 0.63 mmol) and ΝCS (84 mg, 0.63 mmol) in TΗF (5 mL) was heated to reflux for 30 minutes. After cooling to r.t. the mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic fraction was separated, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in MeCN (4 mL) and 2-(methylamino)ethanol (143 mg, 1.9 mmol) was added. The resulting mixture was heated to 1000C under microwave irradiation for 1 h. Purification by preparative HPLC (Method S) gave the title compound (19 mg, 5%) as a colourless oil. δH (CDCl3) 8.01 (IH, d, J 1.9 Hz), 7.69 (IH, s), 7.57 (IH, s), 7.19 (IH, dd, J8.5, 2.1 Hz), 6.97 (IH, d, J8.5 Hz), 5.30 (IH, s), 4.03-4.40 (5H, m), 3.95 (3H, s), 3.64- 3.78 (2H, m), 3.49-3.61 (IH, m), 2.86-3.13 (2H, m), 2.23 (3H, s), 1.44 (3H, s), 1.35 (3H, s). LCMS (ES+) 469 (M+H)+, RT 1.98 minutes (Method 1).
EXAMPLE 22
7-r(2-Hvdroxyethvπaminol-6.6-dimethyl-2-r6-(l-methyl-lH-pyrazol-4-ylV2.3-dihvdro- 4H-l,4-benzoxazin-4-yll-6,7-dihvdro[l,3]thiazolo[5,4-c1pyridin-4(5H)-one
A mixture of Intermediate 18 (220 mg, 0.56 mmol), NCS (74 mg, 0.55 mmol) and methanesulfonic acid (0.036 mL, 0.56 mmol) in MeCN (5 mL) was heated to 6O0C for 4 h. After cooling to r.t., 2-aminoethanol (0.30 mL, 2.78 mmol) was added, and the mixture heated to 1400C under microwave irradiation for 1 h. After cooling to r.t. the mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic fraction was separated, dried (MgSO4) and concentrated in vacuo. Purification by preparative ΗPLC (Method S) gave the title compound (20 mg, 8%) as a clear glass. 5Η (CDCl3) 7.95 (1Η, d, J 1.9 Hz), 7.70 (IH, s), 7.58 (IH, s), 7.18 (IH, dd, J8.5, 2.1 Hz), 6.96 (IH, d, J8.5 Hz), 6.17 (IH, s), 4.32-4.40 (2H, m), 4.09-4.23 (2H, m), 3.95 (3H, s), 3.62-3.73 (3H, m), 2.99-3.08 (2H, m), 2.64 (IH, s), 1.39 (6H, s). One exchangeable proton was not observed. LCMS (ES+) 455 (M+H)+, RT 1.88 minutes (Method 1).
EXAMPLE 23
7-(Cvcloρropylamino)-6,6-dimethyl-2-r6-(l-methyl-lH-pyrazol-4-yl)-2,3-dihydro-4H- 1 ,4-benzoxazin-4-vn-6,7-dihydro[ 1 ,31thiazolo[5,4-clpyridin-4(5H)-one
A mixture of Intermediate 28 (100 mg, 0.23 mmol) and cyclopropylamine (0.30 mL, 6.15 mmol) in MeCN (2 mL) was heated to 1400C under microwave irradiation for 7 h. After cooling to r.t. it was concentrated in vacuo. Purification by preparative ΗPLC (Method S) gave the title compound (40 mg, 38%) as a clear glass. δΗ (CDCl3) 8.17 (1Η, d, J2.1 Hz), 7.68 (IH, s), 7.55 (IH, s), 7.17 (IH, dd, J8.3, 1.9 Hz), 6.96 (IH, d, J8.5 Hz), 4.33-4.41 (2H, m), 4.14-4.23 (2H, m), 3.94 (3H, s), 3.70 (IH, br s), 2.59-2.72 (IH, m), 1.36 (3H, s), 1.27 (3H, s), 0.24-0.54 (4H, m). LCMS (ES+) 451 (M+H)+, RT 2.07 minutes {Method I).
EXAMPLES 24 & 25
Prepared following the procedure of Example 23.
EXAMPLE 24
5,5-Dimethyl-4-(methylamino')-2-r6-( 1 -methyl- lH-pyrazol-4-v0-2.3 -dihvdro-4H- 1 ,4- benzoxazin-4-yl]-5,6-dihydro- 1 ,3-benzothiazol-7(4HVone
Using Intermediate 33 (100 mg, 0.23 mmol) and methylamine (0.01 mL, 0.28 mmol) in MeCN (3 mL) heated to 1400C under microwave irradiation for 3 h. Purification by preparative ΗPLC (Method 6) gave the title compound (5 mg, 5%) as a yellow solid. δΗ (CDCl3) 8.05 (IH, d, J 1.9 Hz), 7.69 (IH, s), 7.56 (IH, s), 7.19 (IH, dd,
J 8.5, 2.1 Hz), 6.96 (IH, d, J 8.5 Hz), 4.17-4.40 (4H, m), 3.95 (3H, s), 3.42 (IH, s), 2.75
(3H, s), 2.38-2.61 (2H, m), 1.17 (3H, s), 1.05 (3H, s). LCMS (ES+) 424 (M+H)+, RT
1.89 minutes {Method 1).
EXAMPLE 25
4-0)imethylamino)-5.5-dimethyl-2-r6-(l-methyl-lH-pyrazol-4-yl)-2,3-dihydro-4H-l,4- benzoxazin-4-yl]-5,6-dihvdro- 1 ,3-benzothiazol-7(4H)-one Using Intermediate 33 (75 mg, 0.17 mmol), dimethylamine hydrochloride (17 mg,
0.20 mmol) and DEPEA (0.05 mL, 0.26 mmol) in MeCN (3 mL) heated to 1400C under microwave irradiation for 3 h. Purification by preparative ΗPLC (Method 6) gave the title compound (9 mg, 12%) as apale yellow solid. δΗ (CDCl3) 8.15 (IH, d, J2.1 Hz), 7.70 (IH, s), 7.57 (IH, s), 7.19 (IH, dd, J 8.5, 2.1 Hz), 6.97 (IH, d, J8.3 Hz), 4.34-4.42 (2H, m), 4.18-4.27 (2H, m), 3.95 (3H, s), 3.47 (IH, s), 2.66-2.76 (IH, m), 2.43 (6H, s), 2.26-2.36 (IH, m), 1.21 (3H, s), 1.09 (3H, s). LCMS (ES+) 438 (M+H)+, RT 1.96 minutes (Method 1). EXAMPLE 26
7-(Benzylamino)-6,6-dimethyl-2-r6-( 1 -methyl- lH-pyrazol-4- ylV2.3 -dihvdro-4H- 1 ,4- benzoxazin-4-yl]-6,7-dihydro[ 1 ,3]thiazolo|'5,4-c]pyridin-4(5H>one A mixture of Intermediate 28 (100 mg, 0.23 mmol), benzylamine (0.5 mL, 4.58 mmol) and potassium carbonate (100 mg, 0.73 mmol) in MeCN (3 mL) was heated to 14O0C under microwave irradiation for 1.5 h. After cooling to r.t. it was concentrated in vacuo. Purification by preparative ΗPLC {Method 6) gave the title compound (19 mg, 16%) as a clear glass. δΗ (CDCl3) 8.06 (IH, d, J 1.9 Hz), 7.69 (IH, s), 7.53 (IH, s), 7.24- 7.39 (5H, m), 7.18 (IH, dd, J8.5, 2.1 Hz), 6.97 (IH, d, J8.3 Hz), 5.36 (IH, s), 4.33-4.40 (2H, m), 4.17-4.27 (2H, m), 4.10-4.17 (IH, m), 3.92-3.99 (IH, m), 3.87 (3H, s), 1.39 (3H, s), 1.33 (3H, s). LCMS (ES+) 501(M+H)+, RT 2.28 minutes (Method 1).
EXAMPLE 27
7-Anilino-6.6-dimethyl-2-r6-(l-methyl-lH-pyrazol-4-ylV2.3-dihvdro-4H-1.4- benzoxazin-4-vn-6,7-dihydror 1 ,3]thiazolo[5,4-c1pyridin-4(5H)-one
Prepared following the procedure for Example 26. Using Intermediate 28 (100 mg, 0.23 mmol), aniline (0.3 mL, 3.29 mmol) and potassium carbonate (100 mg, 0.73 mmol) in MeCN (3 mL) heated to 1400C under microwave irradiation for 1.5 h.
Purification by preparative ΗPLC (Method 6) gave the title compound (24 mg, 21%) as a clear glass. δΗ (DMSOd6) 8.40 (IH, d, J2.1 Hz), 7.90 (IH, s), 7.71 (IH, s), 7.65 (IH, s), 7.22 (IH, dd, J 8.3, 1.9 Hz), 6.98-7.05 (2H, m), 6.93 (IH, d, J 8.5 Hz), 6.87 (2H, d, J 7.7 Hz), 6.50 (IH, t, J7.2 Hz), 5.96 (IH, d, J9.8 Hz), 4.56 (IH, d, J9.6 Hz), 4.23-4.31 (2H, m), 3.97-4.07 (2H, m), 3.83 (3H, s), 1.34 (3H, s), 1.26 (3H, s). LCMS (ES+) 487(M+H)+, RT 3.43 minutes (Method 1).
EXAMPLE 28
6,6-Dimethyl-2-r6-(l-methyl-/H-pyrazol-4-vn-2.3-dihvdro-4H-L4-benzoxazin-4-yll-5,6- dihydrol" 1 ,3 ]thiazok>r5.4-clpyridine-4,7-dione
A mixture of Example I (140 mg, 0.34 mmol) and Dess-Martin periodinane reagent (173 mg, 4.09 mmol) in DCM (15 mL) was stirred overnight at r.t. An aqueous solution of 10% sodium thiosulfate (15 mL) was added, and stirring continued for a further 15 minutes. The reaction mixture was partitioned between DCM and 10% aqueous sodium thiosulfate (50 mL each). The organic fraction was washed with saturated aqueous NaHCO3 followed by brine (50 mL each), dried (MgSO4) and concentrated in vacuo. Purification by preparative HPLC {Method 6) gave the title compound (103 mg, 74%) as a yellow solid. δH (CDCl3) 7.80 (IH, d, J 1.9 Hz), 7.70 (IH, s), 7.58 (IH, s), 7.23 (IH, dd, J 8.5, 2.1 Hz), 6.98 (IH, d, J 8.3 Hz), 6.43 (IH, s), 4.33 (4H, s), 3.96 (3H, s), 1.58 (6H, s). LCMS (ES+) 410 (M+H)+, RT 2.99 minutes {Method
I)-
EXAMPLE 29
2-(6-Amino-2,3-dihydro-4//- 1 ,4-benzoxazin-4-yl)-6.6-dimethyl-5,6- dihydrof 1 ,3]thiazolo[5,4-c]pyridine-4,7-dione A mixture of Example 4 (200 mg, 0.49 mmol), benzophenone imine (0.12 mL,
0.024 mmol), tris(dibenzylideneacetone)dipalladium(II) (22 mg, 0.024 mmol), BINAP (30 mg, 0.048 mmol) and sodium tert-butoxide (94 mg, 0.94 mmol) in THF (10 mL) was heated to 1200C under microwave irradiation for 2 h, then to 1300C under microwave irradiation for 3 h. Additional portions of tris(dibenzylideneacetone)dipalladium(II) (22 mg, 0.024 mmol), BINAP (30 mg, 0.048 mmol) and sodium tert-butoxide (47 mg, 0.49 mmol) were added, and heating continued at 1200C under microwave irradiation for a further 2 h. The reaction mixture was cooled to r.t., filtered through celite® and concentrated in vacuo. The residue was dissolved in HCl (10 mL of a 4N solution in 1 ,4- dioxane) and heated to 1200C under microwave irradiation for 20 minutes. The mixture was concentrated in vacuo, dissolved in DCM and washed with saturated aqueous
NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and purified by prep HPLC {Method 5) to give the title compound (12 mg, 7%) as an orange solid. δH (CDCl3) 7.11 (IH, d, J2.6 Hz), 6.80 (IH, d, J 8.7 Hz), 6.48 (IH, dd, J 8.7, 2.6 Hz), 6.10 (IH, br s), 4.26 (4H, s), 3.56 (2H, s), 1.59 (6H, s). LCMS (ES+) 345 (M+H)+, RT 1.57 minutes {Method 1).
EXAMPLE 30 3-{2-[5-(Cyclopropylcarbonyl)-2-fluorophenyllpyridin-4-yl)-4-hvdroxy-5.5-dimethyl-2- (morpholin-4-yl')-5,6-dihvdrothieno[2.3-c1pyridin-7(4/y)-one
N-Chlorosuccinirnide (12 mg, 0.09 mmol) was added to a suspension of Intermediate 60 (40 mg, 0.08 mmol) in MeCN (5 mL). The reaction was stirred at 800C for 100 minutes, then cooled to r.t. Water (5 mL) was then added and the reaction mixture heated at 1000C for 1 h, then left to stand at r.t overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC (Method 6) to give the title compound (15 mg, 36%) as a beige solid. δH (CDCl3) 8.83 (dd, J 5.1 , 0.8 Hz, IH), 8.78 (dd, J 7.5, 2.4 Hz, IH), 8.17-8.20 (m, IH), 8.08 (ddd, J 8.7, 4.9, 2.4 Hz, IH), 7.65 (dd, J5.1, 1.5 Hz, IH), 7.26-7.33 (m, IH), 5.31 (s, IH), 4.03-4.10 (m, IH), 3.69-3.81 (m, 4H), 2.94-3.10 (m, 4H), 2.73-2.83 (m, IH), 2.15-2.23 (m, IH), 1.44 (s, 3H), 1.24-1.31 (m, 2H), 1.18 (s, 3H), 1.05-1.13 (m, 2H). LCMS (ES+) 522.3 (M+H)+.
EXAMPLE 31
3-{2-[2-Fluoro-5-(morpholin-4-ylcarbonyl')phenyl]pyridin-4-vU-4-hvdroxy-5,5-dimethyl-
2-(morpholin-4-yl)-5,6-dihvdrothienof2,3-clpyridin-7(4H)-one
The title compound was prepared from Intermediate 61 in a similar manner to
Example 30 and was obtained as a yellow solid (44%) after purification by preparative ΗPLC (Method 6). δΗ (CD3OD) 8.78 (dd, J 5.1, 0.6 Hz, IH), 8.18 (s, IH), 8.01 (dd, J7.3,
2.3 Hz, IH), 7.77 (dd, J 5.3, 1.7 Hz, IH), 7.57-7.65 (m, IH), 7.42 (dd, J 10.9, 8.7 Hz,
IH), 4.09 (s, IH), 3.51-3.88 (m, 12H), 2.95-3.10 (m, 4H), 1.40 (s, 3H), 1.15 (s, 3H).
LCMS (ES+) 567.2 (M+H)+.
EXAMPLE 32
4-Hvdroxy-5,5-dimethyl-2-(morpholin-4-yl*)-3-{2-|'3-(pyrrolidin-l-ylcarbonyl')phenyll- pyridin-4-yl)-5,6-dihvdrothieno[2,3-c1pyridin-7(4ij')-one
N-Chlorosuccinimide (6.5 mg, 0.05 mmol) was added to a solution of Intermediate 64 (23 mg, 0.04 mmol) in MeCN (5 mL). The reaction mixture was stirred at 800C for 5 h, then cooled to r.t.. Water (5 mL) was then added, and the reaction mixture was heated at 1000C for 2.5 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Method 6) to give the title compound (7 mg, 30%) as a white solid. δH (CD3OD) 8.71-8.75 (m, IH), 8.28 (s, IH), 8.21 (d, J0.9 Hz, IH), 8.13- 8.19 (m, IH), 7.74 (dd, J5.3, 1.5 Hz, IH), 7.62-7.68 (m, 2H), 4.07 (s, IH), 3.54-3.76 (m, 8H), 2.95-3.10 (m, 4H), 1.90-2.09 (m, 4H), 1.41 (s, 3H), 1.14 (s, 3H). LCMS (ES+) 533.3 (M+H)+.
EXAMPLE 33
4-Hvdroxy-5,5-dimethyl-2-(morpholin-4-yl)-3-{2-[3-(morpholin-4-yl)phenyllpyridin-4- vU-5.6-dihvdrothienor2.3-clpyridin-7(4H)-one To degassed toluene (4 mL) was added Intermediate 65 (150 mg, 0.3 mmol), morpholine (50 μL, 0.6 mmol), potassium tert-butoxide (37 mg, 0.33 mmol) and BINAP (75 mg, 0.12 mmol). The mixture was degassed for 5 minutes. Tris(dibenzylidene- acetone)dipalladium(0) (28 mg, 0.03 mmol) was added; the mixture was degassed for a further 5 minutes and then heated at 1200C under microwave irradiation for 2 h. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 0-10% MeOH in DCM) to give an orange solid. To a solution of this intermediate in MeCN (10 mL) was added iV-chlorosuccinimide (15 mg, 0.11 rnmol) and the reaction mixture was stirred at 800C for 5 h, then cooled to r.t. Water (10 mL) was then added and the reaction mixture heated at 1000C overnight. The solvent was removed in vacuo and the residue purified by preparative ΗPLC βdethod 6) to give the title compound (5 mg, 10%) as a white solid. δΗ (CD3OD) 8.68 (d, J5.1 Hz, IH), 8.23 (d, J0.6 Hz, IH), 7.71 (dd, J5.3, 1.7 Hz, IH), 7.60-7.64 (m, IH), 7.39-7.51 (m, 2H), 7.08-7.14 (m, IH), 4.07 (s, IH), 3.85-3.92 (m, 4H), 3.67-3.76 (m, 4H), 3.24-3.30 (m, 4H), 2.96-3.10 (m, 4H), 1.41 (s, 3H), 1.14 (s, 3H). LCMS (ES+) 521.4 (M+H)+.
EXAMPLE 34
3-{4-r4-Hvdroxy-5,5-dimethyl-2-(morpholin-4-ylV7-oxo-4,5.6.7-tetrahydrothienor2.3- c1pyridin-3-ynpyridin-2-vU-NJV-dimethylbenzamide iV-Chlorosuccinimide (200 mg, 1.45 mmol) was added to a suspension of
Intermediate 57 (500 mg, 0.09 mmol) in MeCN (40 mL). The reaction was stirred at 8O0C for 2 h, then cooled to r.t. Water (20 mL) was then added, and the reaction mixture heated at 1000C for 1 h. Water (50 mL) was added and the mixture extracted with EtOAc (15O mL). The organic phase was washed with brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (SiO2, 0-10% MeOH in DCM). To a solution of the purified intermediate (100 mg) in DME (3.0 mL) and water (0.5 mL) was added 3-(Λ^N-dimethylaminocarbonyl)phenylboronic acid (54 mg, 0.28 mmol), potassium phosphate tribasic (65 mg, 0.30 mmol) and tetrakis-
(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol). The reaction mixture was heated at 12O0C under microwave irradiation for 1 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Method 6 then Method 7) to give the title compound (25 mg, 4%) as a pale yellow solid. δH (CD3OD) 8.73 (dd, J 5.3, 0.8 Hz, IH), 8.26-8.29 (m, IH), 8.10-8.18 (m, 2H), 7.74 (dd, J 5.1, 1.5 Hz, IH), 7.64 (t, J 7.7 Hz, IH), 7.53-7.58 (m, IH), 4.07 (s, IH), 3.68-3.75 (m, 4H), 3.16 (s, 3H), 3.09 (s, 3H), 2.97-3.06 (m, 4H), 1.41 (s, 3H), 1.14 (s, 3H). LCMS (ES+) 507.2 (M+H)+.
EXAMPLE 35
3-{4-[4-Hvdroxy-5,5-dimethyl-2-(moφholin-4-yl')-7-oxo-4,5,6,7-tetrahvdro-l- benzothien-3-yllpyridin-2-yl}-NJV-dimethylbenzamide iV-Chlorosuccinimide (72 mg, 0.54 mmol) was added to a suspension of Intermediate 73 (240 mg, 0.49 mmol) in THF (4 mL) and the reaction mixture heated at 1000C under microwave irradiation for 30 minutes. After cooling, water (2 mL) was added and the mixture heated at 1200C under microwave irradiation for 30 minutes. The solvent was removed in vacuo and the residue purified by preparative HPLC (Method 6) to give the title compound (61 mg, 25%) as a yellow solid. δH (DMSO-d6) 8.76 (d, J 5.1 Hz, IH), 8.29 (s, IH), 8.14-8.24 (m, 2H)5 7.57-7.66 (m, 2H), 7.47-7.52 (m, IH), 5.58-5.69 (m, IH), 3.82-3.90 (m, IH), 3.52-3.68 (m, 4H), 3.21-3.49 (m, 6H), 3.01-3.08 (m, 4H), 2.80-2.90 (m, IH), 2.01-2.12 (m, IH), 1.04 (s, 3H), 0.78 (s, 3H). LCMS (ES+) 506.1 (M+H)+.
EXAMPLE 36
4-Hvdroxy-5,5-dimethyl-2-(morpholin-4-yl)-3-(2-[3-(morpholin-4-yl')phenyllpyridin-4- yl \ -5 ,6-dih vdro- 1 -benzothiophen-7(4H)-one The title compound was prepared from Intermediate 74 in a similar manner to Example 35 and was obtained as a yellow solid (27%) alter purification by preparative HPLC (Method 6). δH (DMSOd6) 8.73 (d, J5.1 Hz, IH), 8.27 (s, IH), 7.70 (s, IH), 7.61 (dd, J4.9, 1.1 Hz, IH), 7.54-7.59 (m, IH), 7.38 (t, J8.1 Hz, IH), 7.04-7.10 (m, IH), 5.63 (d, J7.3 Hz, IH), 3.86 (d, J7.5 Hz, IH), 3.74-3.82 (m, 4H), 3.57-3.66 (m, 4H), 3.16-3.25 (m, 4H), 2.94-3.03 (m, 4H), 2.81-2.90 (m, IH), 2.03-2.12 (m, IH), 1.05 (s, 3H)5 0.77 (s, 3H). LCMS (ES+) 520.4 (M+H)+.
EXAMPLES 37 TO 59
The following compounds were prepared by methods analogous to those described in the preceding Examples. Where individual enantiomers are indicated, the separation thereof from the respective racemate was effected by chiral preparative HPLC. Example 37: 3- {4-[4-Amino-5,5-dimethyl-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydro- 1 -benzothien-3-yl]pyridin-2-yl} -N^AZ-dimethylbenzamide
Example 38: 3-[2'-Fluoro-5'-(moipholin-4-ylcarbonyl)biphenyl-3-yl]-4-hydroxy-5,5- dimethyl-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one Example 39: 3-{2-[2-Fluoro-5-(pyrrolidin-l-ylcarbonyl)phenyl]pyridin-4-yl}-4- hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one Example 40: 3-{4-[(45)-4-Ηydroxy-5,5-dimethyl-2-(morpholin-4-yl)-7-oxo-4,5,6,7- tetrahydro- 1 -benzothien-3-yl]pyridin-2-yl} -iV^V-dimethylbenzamide Example 41: 3 - {4-[(4Λ)-4-Hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-7-oxo-4,5,6,7- tetrahydro- 1 -benzothien-3 -yl]pyridin-2-yl} -N^AZ-dimethylbenzamide Example 42: 3- {2-[2-Fluoro-5-(morpholin-4-ylcarbonyl)phenyl]pyridin-4-yl}-4- hydroxy-5 ,5-dimethyl-2-(moφholin-4-yl)-5,6-dihydro- 1 -benzothiophen-7(4//)-one Example 43: 3 - {2-[2-Fluoro-5 -(pyrrolidin- 1 -ylcarbonyl)phenyl]pyridin-4-yl } -4- hydroxy-5,5-dimethyl-2-(moφholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4//)-one Example 44: (45)-4-Hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-3- {2-[3-(pyrrolidin-l- ylcarbonyl)phenyl]pyridin-4-yl}-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one Example 45: (4Λ)-4-Hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-3-{2-[3-(pyrrolidin-l- ylcarbonyl)phenyl]pyridin-4-yl}-5,6-dihydrothieno[2,3-c]pyridin-7(4//)-one Example 46: (4i?)-3-[2'-Fluoro-5'-(morpholin-4-ylcarbonyl)biphenyl-3-yl]-4-hydroxy- 5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one Example 47: (45)-3-[2'-Fluoro-5'-(morpholin-4-ylcarbonyl)biphenyl-3-yl]-4-hydroxy- 5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one Example 48: (4/?)-4-Amino-3- {2-[2-fluoro-5-(pyrrolidin- 1 -ylcarbonyl)phenyl]pyridin- 4-yl } -5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro- 1 -benzothiophen-7(4H)-one Example 49: (45)-4-Amino-3-{2-[2-fluoro-5-(pyrrolidin-l-ylcarbonyl)phenyl]pyridin- 4-yl}-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one Example 50: 3- {2-[2-Chloro-3-(morpholin-4-yl)phenyl]pyridin-4-yl}-4-hydroxy-5,5- dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one Example 51: 3-{2-[2-Chloro-5-(moφholin-4-yl)phenyl]pyridin-4-yl}-4-hydroxy-5,5- dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one
Example 52: (4/?)-3-{2-[2-Fluoro-5-(pyrrolidin-l-ylcarbonyl)phenyl]pyridin-4-yl}-4- hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one Example 53: (45)-3-{2-[2-Fluoro-5-(py-τolidin-l-ylcarbonyl)phenyl]pyridin-4-yl}-4- hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one Example 54: (4.S)-4-Amino-5,5-dimethyl-2-(morpholin-4-yl)-3-{2-[3-(morpholin-4- yl)phenyl]pyridin-4-yl } -5 ,6-dihydro- 1 -benzothiophen-7(4H)-one Example 55: (4i?)-4- Amino-5,5-dimethyl-2-(morpholin-4-yl)-3- {2-[3-(morpholin-4- yl)phenyl]pyridin-4-yl } -5 ,6-dihydro- 1 -benzothiophen-7(4H)-one Example 56: (4i?)-3-{2-[2-Chloro-5-(moφholin-4-yl)phenyl]pyridin-4-yl}-4-hydroxy- 5,5-dimethyl-2-(moφholin-4-yl)-5,6-dihydro-l-benzothioρhen-7(4H)-one
Example 57: (45)-3- {2-[2-Chloro-5-(morpholin-4-yl)phenyl]pyridin-4-yI} -4-hydroxy-
5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4//)-one
Example 58: (4Λ)-4-Ηydroxy-5,5-dimethyl-2-(morpholin-4-yl)-3- {2-[3-(morpholin-4- yl)phenyl]pyridin-4-yl } -5,6-dihydro- 1 -benzothiophen-7(4H)-one Example 59: (45)-4-Ηydroxy-5,5-dimethyl-2-(morpholin-4-yl)-3-{2-[3-(moφholin-4- yl)phenyl]pyridin-4-yl}-5,6-dihydro-l-benzothiophen-7(4H)-one

Claims

Claims:
1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000146_0001
(I)
wherein
U represents N or C-R5; -X- represents a group of formula (a), (b), (c), (d), (e), (f) or (g):
Figure imgf000146_0002
(a) (b) (C) (d)
Figure imgf000146_0003
(e) (f) (g)
Y represents oxygen or sulphur; R1 and R2 independently represent hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl-
Figure imgf000146_0004
any of which groups may be optionally substituted by one or more substituents; or
R1 and R2, when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or R1 and R2, when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; R3 and R4 independently represent hydrogen; or C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C]-6)alkyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)- alkynyl, biaryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7
Figure imgf000147_0001
C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroarylCCi-δJalkyl, any of which groups may be optionally substituted by one or more substituents; or
R3 and R4, when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or R3 and R4, when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb, -CONRcRd or -C(=N-ORf)Re; or R5 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkenylcarbonyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 CyClOaUCyI(C1 _6)alkyl, C3-7 cycloalkyl(C2-6)alkenyl, C3-7 cycloalkyl- (C2-6)alkynyl, aryl, aryl(Ci-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, biaryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C].6)alkyl, C3-7 heterocycloalkyl(C2-6)alkenyl, C3-7 heterocycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkylcarbonyl(C2-6)alkynyl, C5-9 heterobicycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkyl-aryl, C3-7 heterocycloalkyl(C1-6)- alkyl-aryl, C3-7 heterocycloalkyl-biaryl, C3-7 heterocycloalkylcarbonyl-biaryl, heteroaryl, heteroaryl(C i -6)alkyl, heteroary^C] -6)alkylcarbonyl, heteroaryl(C2-6)alkenyl, heteroaryl(C2-6)alkynyl, heteroaroylcarbonyl, C3-7 heterocycloalkyl-heteroaryl, C3-7 heterocycloalkyl-heteroaryl(C2-6)alkynyl, heteroaryl-aryl, heteroaryl-aryl(C i -6)alkyl, aryl-heteroaryl, aryl-heteroaryl(C1-6)alkyl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 heterocycloalkyl(C i -6)alkyl-aryl-heteroaryl, C5-9 heterobicycloalkyl(C i ^alkyl-aryl- heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl- bi(heteroaryl), aryloxyaryl, 8TyI(C1.6)alkoxyaryl, heteroaryl(Ci-6)alkoxyaryl, aryl(Ci-6)alkylaminoaryl, heteroaryl(Ci-6)alkylaminoaryl, C3-7 cycloalkyl- carbonylaminoaryl, arylcarbonylaminoaryl, .UyI(C1.6)alkylcarbonylaminoaryl, C3-7 heterocycloalkylcarbonylaminoaryl, heteroarylcarbonylaminoaryl, aryl- (C3-7)heterocycloalkylcarbonylaminoaryl, arylsulphonylaminoaryl, aryl(C1-6)alkyl- sulphonylaminoaryl, heteroaryl(Ci-6)alkylsulphonylaminoaryl, C3-7 cycloalkylamino- carbonylaminoaryl, arylaminocarbonylaminoaryl, C3-7 heterocycloalkylaminocarbonyl- aminoaryl, C3-7 heterocycloalkylaminocarbonylaminoaryl, heteroaryl(Ci-6)alkyl- aminocarbonylaminoaryl, C3-7 heterocycloalkylcarbonylcarbonylaminoaryl, C3-7 heterocycloalkyl(C i ^alkylaminocarbonylcarbonylaminoaryl, arylcarbonylaryl, C3-7 heterocycloalkylcarbonylaryl, C3-7 heterocycloalkylcarbonyl(Ci-6)alkylaryl, aryl(Ci-6)- alkylaminocarbonylaryl, C3-7 heterocycloalkyl(C1-6)alkylaminocarbonylaryl, heteroaryl- aminocarbonylaryl, heteroary^Ci^alkylaminocarbonylaryl, C3-7 heterocycloalkylamino- carbony^Ci^alkylaryl, C3-7 heterocycloalkyl(C1-6)alkylaminocarbonyl(C1-6)alkylaryl, heteroarylaminocarbonyl(Ci..6)alkylaryl, heteroaryl(Ci-6)alkylaminocarbonyl(Ci-6)alkyl- aryl, arylaminoheteroaryl, C3-7 heterocycloalkylamino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonylamino-aryl-heteroaryl, C3-7 heterocycloalkylaminocarbonyl- amino-aryl-heteroaryl, C3-7 cycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- carbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(Ci-6)alkylcarbonyl-aryl-heteroaryl, C5-9 heterobicycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl(Ci-6)alkyl-aryl- heteroaryl, C3-7 heterocycloalkyl-aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- (Ci^alkylaminocarbonyl-aryl-heteroaryl or C3-7 heterocycloalkylaminocarbonyl(Ci-6)- alkyl-aryl -heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Ra represents Cj-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Rb represents hydrogen; or optionally substituted Ci-6 alkyl; Rc represents hydrogen; or Ci-6 alkyl, aryl, aryl(C1-6)alkyl, heteroaryl, heteroaryl(C1-6)alkyl or (arylXheteroarylXC! -6)alkyl, any of which groups maybe optionally substituted by one or more substituents; Rd represents hydrogen or Ci-6 alkyl;
Re represents Ci-6 alkyl;
Rf 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; R6 and R7 independently represent hydrogen or Ci-6 alkyl;
R8 represents hydroxy, oxo or -NRεRh; and
Rg and Rh independently represent hydrogen, Ci^ alkyl, C3-7 cycloalkyl, C3-7 cycloalky^Q^alkyl, aryl, aryl(Ci-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
2. A compound as claimed in claim 1 represented by formula (A), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000149_0001
(A)
wherein
V represents a group of formula CH2 or N-R6; and Y, R1, R2, R3, R4, R6 and R8 are as defined in claim 1.
3. A compound as claimed in claim 1 wherein U represents C-R5, in which R5 is as defined in claim 1.
4. A compound as claimed in claim 3 represented by formula (BA), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000149_0002
(BA)
wherein -X1- represents a group of formula (a), (b) or (c) as defined in claim 1;
R and R are as defined in claim 1 ;
R ' represents hydrogen or Ci-6 alkyl; and
R12 represents hydrogen; or Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, heteroaryl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R11 and R12, when taken together with the carbon atom to which they are both attached, represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.
5. A compound as claimed in claim 1 represented by formula (IIA-A) or (IIA-B), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000150_0001
Figure imgf000150_0002
wherein R is as defined in claim 1 ;
V is as defined in claim 2; -X1-, R11 and R12 are as defined in claim 4; and
R13 represents hydrogen; or Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, biaryl(C1-6)alkyl, C3-7 - heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryF, Reteroaryr(Ci-6)aIkyr, heteroaryr-aryr(Ci-6)aIkyror aryr-heteroaryt(Ci-6Jaπs:yt, any of which groups may be optionally substituted by one or more substituents.
6. A compound as claimed in claim 5 represented by formula (HB), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000151_0001
(DB)
wherein
R is as defined in claim 1 ; V is as defined in claim 2; R11 and R12 are as defined in claim 4;
T represents oxygen or N-R25;
R23 represents hydrogen, halogen, cyano, nitro, Ci-6 alkyl, hydroxy(C1-6)alkyl, trifluoromethyl, aryl(Ci.6)alkyl, oxazolinyl, triazolyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(C1-6)alkoxy,
Figure imgf000151_0002
aryloxy, aryl(Ci-6)alkoxy, Ci-6 alkylthio, C1-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, Ci-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C2-6 alkylcarbonylarnino, C2-6 alkylcarbonylaminomethyl, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(C1-6)alkyl]amino, C1-6 alkylsulphonylamino, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Cj-6 alkylaminocarbonyl, [hydroxy(C1-6)- alkyl] aminocarbonyl, [di(C i -6)alkylamino(C i -6)alkyl] aminocarbonyl, di(C \ .^alkylaminocarbonyl, [(C1-6)alkyl][cyano(C1-6)alkyl]aminocarbonyl, [(Ci-6)alkyl][hydroxy(Ci-6)- alkyl]aminocarbonyl, [(C \ -6)alkoxy(C \ -6)alkyl] [(C j -6)alkyl] aminocarbonyl, [di(C i -6)alkyl- amino(C i .6)alkyl] [(C i -6)alkyl] aminocarbonyl, C3-7 cycloalkyl(C i ^alkylaminocarbonyl, aryl(C]-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(Ci-6)alkylamino- carbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl" (Ci-6)alkylpyrrolidiriyl- carbonyl, C1-6 alkoxy(C1-6)alkylpyrrolidinylcarbonyl, di(C1-6)alkylaminopyrrolidinyl- carbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, (Ci-6)- alkylpiperazinylcarbonyl, morpholinylcarbonyl, C1-^ alkylsulphonyl, C1-6 alkylsulphonyl- methyl or di(Ci.6)alkylaminosulphonyl; and
R24 represents hydrogen, halogen, Ci-6 alkoxy or di(C1-6)alkylaminocarbonyl; or R23 and R24, when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and R25 represents hydrogen or C1-6 alkyl.
7. A compound as claimed in claim 5 represented by formula (IIC), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000152_0001
(no
wherein
R8 is as defined in claim 1 ;
V is as defined in claim 2; R11 and R12 are as defined in claim 4;
R33 represents halogen or -NHR34; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; and
R34 represents methylenedioxyphenyl, morpholinyl(C1-6)alkylphenyl, oxazolinyl- phenyl, [(C1-6)alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (Ct.6)aHcyitriazolytpiienyi, (C r -6>atkyjpyjrimtdiny}pbeπyl, pyrazøiyl(Cf.6)alkyi- phenyl, MaZoIyI(C1 ^alkylphenyl, Ci-6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci-6 alkylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, C i-6 alkylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, [(C1-6)alkyl](halo)pyrazolyl, tri(C1-6)alkylpyrazolyl, (Ci-6)alkylindazolyl, benzoxazolyl, benzoxazolonyl, d^Q^alkylisoxazolyl, benzothiazolyl, (C1-6)alkylisothiazolyl, (C1-6)alkylbenzimidazolyl, benzimidazolonyl, di(Ci-6)alkylbenzimidazolonyl, (C1-6)alkyloxadiazolyl, furyloxadiazolyl, pyridinyl, halopyridinyl,
Figure imgf000153_0001
di(C].6)alkylpyridinyl, (Ci-6)alkoxypyridinyl, oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl,
Figure imgf000153_0002
(C i _6)alkyl cinnolinyl, quinoxalinyl or (C1-6)alkylchromenyl.
8. A compound as claimed in claim 1 represented by formula (IID-1) or (IID-2), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000153_0003
Figure imgf000153_0004
wherein
R is as defined in claim 1 ; V is as defined in claim 2;
R11 and R12 are as defined in claim 4;
R4* represents hydrogen, halogen, nitro, Q-6 aficyl, C2-6 alkenyl, C3-7 cycϊoatkyt, (C
Figure imgf000153_0005
piperazinyl(Ci.6)alkylaryl, (Ci^alkylpiperazinylCCi^alkylaryl, moφholinyl(C1-6)alkylaryl, (C1-6)alkoxyaryl, cyano(C i ^alkoxyaryl, di(C \ .6)alkylamino(C i ^alkylaryl, (C \ -6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (d^alkylaminocarbonylpiperidinyl, piperazinyl, (C^alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (Ci-6)alkyl- homopiperazinyl,
Figure imgf000154_0001
morpholinyl(Ci.6)alkyl, benzoftiryl, benzothienyl, pyrazolyl, (C^alkylpyrazolyl, di(Ci-6)alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, (difluoromethyl)pyrazolyl, [di(C1-6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano(C1-6)alkyl][di(Ci-6)alkyl]pyrazolyl, hydroxy(Ci.6)alkyl- pyrazolyl, [hydroxy^ _6)alkyl] [di(C1_6)alkyl]pyrazolyl, methoxy(Ci-6)alkylpyrazolyl, [(hydroxy)(methoxy)(Ci-6)alkyl]pyrazolyl, amino(Ci.6)alkylpyrazolyl,
Figure imgf000154_0002
Figure imgf000154_0003
[amino(C1-6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(Ci-6)alkyl- amino(C i -6)alkylpyrazolyl, di(C j -6)alkoxyphosphono(C \ -6)alkylpyrazolyl, (C2-6)alkenyl- pyrazolyl, (C3-7)cycloalkyl(Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl(Ci-6)alkyl][di(Ci-6)alkyl]- pyrazolyl, [(C1-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl,
Figure imgf000154_0004
pyrazolyl, aminoary^Ci^alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl- (C ! -6)alkylpyrazolyl, [di(C \ -6)alkyl] [tetrahydropyrany^d -6)alkyl]pyrazolyl, pyrrolidinyl(C i ^alkylpyrazolyl, piperidinyl(C i .6)alkylpyrazolyl, (C \ ^alkylpiperidinyl- (Ci.6)alkylpyrazolyl, morpholinyl(Ci.6)alkylpyrazolyl, pyridiny^C^alkylpyrazolyl, oxypyridinyl(C i -6)alkylpyrazolyl, [arylcarbonyl(C i_6)alkyl] [di(C i .6)alkyl]pyrazolyl, [(C1-6)alkyl](piperazinylcarbonyl)pyrazolyl, [(Ci-6)alkylaminocarbonyl][(C1-6)alkylaryl]- pyrazolyl, [(C1-6)alkyl][amino(Ci-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl- (C i .6)alkylpyrazolyl, [aminocarbonyl(C \ ^alkyl] [di(C i _6)alkyl]pyrazolyl, di(C i -6)alkyl- aminocarbony^Ci^alkylpyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1-6)alkylisoxazolyl, (amino)[(C1-6)alkyl]isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl,
Figure imgf000154_0005
imidazolyl, di(C1-6)alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkylimidazo[l,2-α]- pyridinyl, (C1-6)alkylimidazo[4,5-b]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo- [l,2-α]pyrazinyl, (C1-6)alkylthiadiazolyl, pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, [(C1-6)alkyl](halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2.6)alkenylpyridinyl, (Ci-6)alkyl- piperazinylpyridinyl, [(Ci.6)alkyl](piperazinyl)pyridinyl, [(Ci-6)alkoxycarbonyl- piperazinyl][(Ci.6)alkyl]pyridinyl, piperidinyl(Ci.6)alkylpyridinyl, [(Ci^alkyl]- (oxy)pyridinyl, hydroxypyridinyl, hydroxy(C]-6)alkylpyridinyl, (Ci-6)alkoxypyridinyl, [(Ci-6)alkoxy][(C1-6)alkyl]pyridinyl, [(Ci-6)alkoxy][di(C1-6)alkyl]pyridinyl, (C1-6)alkoxy(Ci-6)alkylpyridinyl, aminopyridinyl, carboxy(C1-6)alkylpyridinyl, (Q^alkoxycarbony^C^alkylpyridinyl, pyridazinyl, (C1-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl,
Figure imgf000155_0001
aminopyridazinyl,
Figure imgf000155_0002
pyrimidinyl,
Figure imgf000155_0003
[(Ci-6)alkyl](halo)ρyrimidinyl, di(Ci-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (C i -6)alkylpiperazinylpyrimidinyl, [(C j -6)alkyl] (piperazinyl)- pyrimidinyl, [(C i ^alkoxycarbonyl] [(C \ -6)alkyl]piperazinylpyriπiidinyl, hydroxypyrimidinyl, [(C i -6)alkyl](hydroxy)pyrimidinyl, [(C i -6)alkyl] [hydroxy(C i -6)alkyl] - pyrimidinyl, [(C \ ^)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (C i -6)alkoxypyrimidinyl, aminopyrimidinyl, di(C1-6)alkylaminopyrimidinyl, [di(C1-6)alkylamino](halo)pyrimidinyl, carboxypyrimidinyl, [(C i -6)alkoxycarbonyl(C i ^alkyl] [(C \ ^alkyljpyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (C1-6)alkoxypyrazinyl, aminopyrazinyl, hydroxy,
Figure imgf000155_0004
aryl(Ci-6)alkoxycarbonylpiperidinyloxy,
Figure imgf000155_0005
aryloxy, haloaryloxy, di(C i ^alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C1-6)alkylpiperazinylpyridinyloxy, (Ci-6)alkylpyrazolylpyridinyloxy, (C i .6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy,
Figure imgf000155_0006
[(C i _6)alkyl] (halo)ρyrimidinyloxy, hydroxy(C \ -6)alkyl, dihydroxy(C \ -6)alkyl,
Figure imgf000155_0007
amino, (C1-6)alkylamino, dihydroxy(C1-6)alkylamino, (Ci-6)- alkoxy(Ci-6)alkylamino, iV-[(C1-6)alkoxy(C1-6)alkyl]-iV-[(C1-6)alkyl]amino, di(C1-6)- alkylamino(C i .^alkylamino, N-[(C i ^alkyl] -N-[di(C i -6)alkylamino(C i -6)alkyl] amino, N- [(Ci-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino^-t^i^alky^-N-^aloary^amino, N-[(Ci-6)alkyl]-N-[aryl(C1-6)alkyl]amino, N-[di(Ci-6)alkylamino(C1,6)alkyl]-N-[aryl(Ci-6)- alkyl]amino, cyanoaryl(Ci.6)alkylamino, (cyano)(halo)aryl(C1-6)alkylamino, methylene- dioxyaryl(Ci-6)alkylamino, N-[(Ci-6)alkyl]-N-[(C1-6)alkylpyrrolidinyl]amino, piperidinyl- amino, ^[(d^alkylJ-N-^iperidiny^amino, N-[(C3-7)cycloalkyl(C1-6)alkyl]-N- (piperidinyl)amino, (Ci-6)alkylpiperidinylamino, N-[(Ci-6)alkyl]-N-[(C1-6)alkyl- piperidinyljamino, N-[(C1-6)alkyl]-N-[(C3-7)cycloalkylpiperidinyl]amino, iV-[(Ci-6)alkyl]- N-[(C2-6)alkylcarbonylpiperidmyl]amino, pyrrolidinyl(Cj-6)alkylamino, N-[(Ci-6)alkyl]-N- [pyrrolidinyl(C i -6)alkyl]amino, N-[(Ci -6)alkyl]-N-[piperidinyl(C i-6)alkyl]amino, (C \ -6)- alkylpyrazolylamino, di(C1-6)alkylpyrazolylamino, tri(Ci-6)alkylpyrazolylamino, N-[(Cι-6)- alkyl]-N-[(Ci-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(Ci_6)alkoxy- carbonyl][(Ci-6)alkyl]imidazolylamino, (Ci-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylaminό, (C1-6)alkylpyridinylamino,"di(Ci-6)alkylpyridinylaininb, trifluoro- methylpyridinylamino, hydroxypyridinylamino,
Figure imgf000156_0001
dihydroxy(Ci-6)alkylpyridinylamino, (Ci-6)alkoxypyridinylamino,
Figure imgf000156_0002
pyridinylamino, di(C1-6)alkyldioxolanyl(C1-6)alkoxypyridinylamino, (Ci-6)BIkOXy(Ci-6)- alkylpyridinylamino, (Ci-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(Ci-6)alkyl- aminopyridinylamino, di(C1-6)alkylaminopyridinylamino, (Ci-6)alkylamino(Ci-6)alkyl- pyridinylamino, di(C1.6)alkylamino(C1-6)alkylpyridinylamino, carboxypyridinylamino, N- [(C1-6)alkyl]-N-[(C1-6)alkylpyridinyl]amino, bis[(Ci.6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (Ci-6)alkylpyridazinylamino, JV-[(Ci-6)alkyl]- N-[(Ci-6)alkylpyridazinyl]amino, N-[aryl(Ci-6)alkyl]-N-[(Ci-6)alkylpyridazinyl]amino, di(C1-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (Ci-6)- alkoxypyridazinylamino, di(C1-6)alkylammopyridazinylamino,
Figure imgf000156_0003
amino,
Figure imgf000156_0004
indolyl(Ci-6)alkylamino, (Ci^alkylpyrazolyKCi^alkylamino, [di(C1-6)alkyl](halo)pyrazolyl(C1-6)alkylamino, di(C i ^alkylisoxazoly^C \ -6)alkylamino, thiazolyl(C i ^alkylamino, imidazolyKC] -6)alkyl- amino, (C1-6)alkylimidazolyl(Ci-6)alkylamino, pyridinyl(C1-6)alkylamino, (Ci-6)alkyl- pyridinyl(C i ^alkylamino, N-[(C l^alkyl] -N-[pyridinyl(C \ -6)alkyl] amino, N-[dihydroxy- (C1-6)alkyl]-N-[pyridinyl(Ci-6)alkyl]amino, N-[(Ci-6)alkylpyridinyl(C1-6)alkyl]-iV- [dihydroxy(C1-6)alkyl]amino, amino(C1-6)alkyI, (Ci-6)alkylamino(Ci-6)alkyl, di(C1-6)alkyl- amino(Ci-6)alkyl, pyridinylamino(Ci-6)alkyl, N-[(C2-6)alkylcarbonyl]-N-[(Ci-6)alkyl- pyridinyl(Ci.6)alkyl]ainino, di(Ci-6)alkylamino(Ci-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (C i ^alkylpiperidinylcarbonylamino, (C j ^alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (d^alkylpiperidinylaminocarbonyl, N-[(Ci-6)alkyl]-N-[(C1-6)- alkylpiperidinyl]aminocarbonyl, piperidinyl(Ci-6)alkylaminocarbonyl, (Ci^alkyl- piperazinylcarbonyl, Ci-6 alkylthio, Ci-6 alkylsulphinyl, C1-6 alkylsulphonyl, C2^ alkoxycarbonyloxy and tetra(C1-6)alkyldioxaborolanyl; and
R44 represents hydrogen, halogen, C1-6 alkyl or Ci-6 alkoxy.
9. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.
10. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier.
11. A compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
12. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and/or prevention of a disorder for which the administration of a selective PBK inhibitor is indicated.
13. The use of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of a disorder for which the administration of a selective PDK inhibitor is indicated.
14. A method for the treatment and/or prevention of a disorder for which the administration of a selective PI3K inhibitor is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof.
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