WO2009071890A1 - Tricyclic kinase inhibitors - Google Patents

Tricyclic kinase inhibitors Download PDF

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Publication number
WO2009071890A1
WO2009071890A1 PCT/GB2008/004002 GB2008004002W WO2009071890A1 WO 2009071890 A1 WO2009071890 A1 WO 2009071890A1 GB 2008004002 W GB2008004002 W GB 2008004002W WO 2009071890 A1 WO2009071890 A1 WO 2009071890A1
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Prior art keywords
alkyl
aryl
amino
heteroaryl
alkylamino
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PCT/GB2008/004002
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French (fr)
Inventor
Rikki Peter Alexander
Pavandeep Singh Aujla
Julien Alistair Brown
Benjamin Charles De Candole
Graham Peter Trevitt
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Ucb Pharma S.A.
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Priority claimed from GB0723750A external-priority patent/GB0723750D0/en
Priority claimed from GB0723751A external-priority patent/GB0723751D0/en
Priority claimed from GB0812558A external-priority patent/GB0812558D0/en
Application filed by Ucb Pharma S.A. filed Critical Ucb Pharma S.A.
Publication of WO2009071890A1 publication Critical patent/WO2009071890A1/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]

Definitions

  • the present invention relates to a class of fused tricylic thiazole and thiophene derivatives, and to their use in therapy. More particularly, the invention provides a family of fused tricylic thiazole and thiophene derivatives which are substituted in the 2-position of the thiazole or thiophene ring by an optionally substituted morpholin-4-yl moiety. These compounds are selective inhibitors of phosphoinositide 3-kinase (PI3K) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • PI3K phosphoinositide 3-kinase
  • PI3K pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases.
  • PBKs provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sci., 2003, 24, 366-376).
  • Aberrant upregulation of the PI3K pathway is implicated in a wide variety of human cancers (cf. S. Brader & S.A. Eccles, Tumori, 2004, 90, 2-8).
  • the compounds in accordance with the present invention are therefore beneficial in the treatment and/or prevention of various human ailments.
  • autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g.
  • neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; pain and nociceptive disorders; and ophthalmic disorders including age- related macular degeneration (ARMD).
  • age- related macular degeneration AMD
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting compounds capable of binding to human PI3K enzymes.
  • WO 2006/040281 describes a class of 4,5-dihydrothiazolo[4,5- ⁇ ]indazoles which are stated to be suitable for use in the treatment of diseases that are characterized by excessive or abnormal cell proliferation.
  • the compounds described in that publication do not, however, possess an optionally substituted morpholin-4-yl moiety at the 2-position of the thiazole ring.
  • WO 2006/114606 describes a class of fused bicyclic thiazole derivatives which are selective inhibitors of PI3 kinase enzymes and are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • a related series of compounds is described in copending international patent application no. PCT/GB2007/002390, published on 3 January 2008 as WO 2008/001076.
  • the compounds in accordance with the present invention are potent and selective PI3K inhibitors having a binding affinity (IC 50 ) for the human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ isoform of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 5O figure denotes a more active compound).
  • IC 50 binding affinity for the human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ isoform of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably
  • the compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for the human PI3K ⁇ and/or PI3K ⁇ and/or PDK ⁇ and/or PBK ⁇ isoform relative to other human kinases.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • V represents a covalent bond or a methylene linkage
  • W represents a covalent bond or a methylene linkage
  • the moiety X-Y-Q represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;
  • R 1 and R 2 independently represent hydrogen, hydroxy or amino; or Ci -6 alkyl, Ci -6 alkoxy, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, heteroaryl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R 1 and R 2 when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or - A -
  • R 1 and R 2 when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
  • R 3 and R 4 independently represent hydrogen; or Ci -6 alkyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )- alkynyl, biaryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C 1-6 )alkyl
  • R 3 and R 4 when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or R 3 and R 4 , when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
  • R 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b or -CONR c R d ; or R 5 represents Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkenylcarbonyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci.
  • R a represents Ci -6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
  • R b represents hydrogen; or optionally substituted Ci -6 alkyl
  • R c represents hydrogen; or Ci -6 alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl, heteroaryl(Ci -6 )alkyl or (aryl)(heteroaryl)(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents
  • R d represents hydrogen or Ci -6 alkyl
  • R e represents Ci -6 alkyl
  • R 6 is absent when V represents a covalent bond
  • R 6 represents hydrogen, hydroxy, oxo or -NR 6a R 6b
  • R 6a and R 6b independently represent hydrogen, Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alky
  • the present invention also provides a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • R 1 and R 2 independently represent hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci. 6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl - (Ci -6 )alkyl, heteroaryl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or R 1 and R 2 , when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or
  • R 1 and R 2 when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
  • any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted, where possible, by one or more substituents. Typically, such groups will be unsubstituted, or substituted, where possible, by one or two substituents. Suitably, such groups will be unsubstituted or, where possible, monosubstituted.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • the compounds of the invention carry an acidic moiety, e.g.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • alkali metal salts e.g. sodium or potassium salts
  • alkaline earth metal salts e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • solvates of the compounds of formula (I) above include within its scope solvates of the compounds of formula (I) above.
  • Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
  • the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
  • Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched C 1-6 alkyl groups, for example Ci -4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, w-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci -6 alkoxy", “Ci -6 alkylthio", "Ci -6 alkylsulphonyl” and "Ci -6 alkylamino" are to be construed accordingly.
  • Typical C 2-6 alkenyl groups include vinyl and allyl.
  • Typical C 2-6 alkynyl groups include ethynyl, prop-1-yn-l-yl, prop-2-yn-l-yl, but-1- yn-l-yl and 3-methylbut-l-yn-l-yl.
  • a specific C 2-6 alkynyl group is prop-2-yn-l-yl.
  • Specific C 3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci -6 )alkyl groups include benzyl, phenyl ethyl, phenylpropyl and naphthylmethyl.
  • Specific aryl(C 2-6 )alkenyl groups include 2-phenylethenyl and 3-phenylprop-2-en-
  • Typical aryl(C 2-6 )alkynyl groups include phenylethynyl, 3-phenylprop-l-yn-l-yl and 3-phenylprop-2-yn-l-yl.
  • a specific aryl(C 2-6 )alkynyl group is 3-phenylprop-2-yn-l- yi.
  • Particular biaryl groups include biphenyl and naphthylphenyl.
  • Suitable heterocycloalkyl groups which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomo ⁇ holinyl.
  • Typical heterobicycloalkyl groups include quinuclidinyl, 8-azabicyclo[3.2.1]octyl and 3,8-diazabicyclo[3.2.1]octyl.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3- ⁇ ]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrazolyl, pyrazolo[l,5- ⁇ ]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2- ⁇ ]pyridinyl, imidazo[4,5-&]pyri
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.
  • compounds of formula (I) may accordingly exist as enantiomers.
  • compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers.
  • the invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • the moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
  • the moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted six- membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • the moiety X-Y-Q represents a pyrazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl or pyrimidinyl ring, any of which may be optionally substituted, where possible, by one or more substituents.
  • the five-membered or six-membered heteroaromatic ring represented by the moiety X-Y-Q in the compounds of formula (I) above may be unsubstituted, or may suitably be substituted, where possible, by one more, typically by one or two, substituents. In one embodiment, this ring is unsubstituted. In another embodiment, this ring is monosubstituted. hi a further embodiment, this ring is disubstituted. Examples of typical substituents on the five-membered or six-membered heteroaromatic ring as specified for the moiety X-Y-Q include Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci.
  • U represents N.
  • the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt or solvate thereof:
  • V, W, the moiety X-Y-Q, R 1 , R 2 , R 3 , R 4 and R 6 are as defined above.
  • U represents C-R 5 .
  • the present invention provides a compound of formula (B), or a pharmaceutically acceptable salt or solvate thereof:
  • V, W, the moiety X-Y-Q, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
  • Specific sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA), (IB), (IC), (ID), (IE) and (IF):
  • R x represents hydrogen, Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci- 6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, heteroaryl, heteroaryl(Ci -6 )alkyl, Ci -6 alkylsulphonyl or C 2-6 alkylcarbonyl; and
  • R y and R z independently represent hydrogen, Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl- (Ci -6 )alkyl, heteroaryl, heteroaryl(Ci -6 )alkyl, hydroxy, Ci -6 alkoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl, Ci -6 alkylsulphonyl, C 2-6 alkylcarbonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, halogen, cyano or trifluoromethyl.
  • R x represents hydrogen or Ci -6 alkylsulphonyl.
  • R" represents hydrogen.
  • R" represents Ci -6 alkylsulphonyl, especially methylsulphonyl.
  • R y and R z independently represent hydrogen, Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci. 6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 hetero- cycloalkyl(Ci -6 )alkyl, heteroaryl, heteroaryl(Ci_ 6 )alkyl, Ci -6 alkoxy, Ci -6 alkylthio, Ci -6 alkylsulphinyl, Ci -6 alkylsulphonyl, C 2-6 alkylcarbonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, halogen, cyano or trifluoromethyl.
  • Typical values of R y and/or R z include hydrogen, hydroxy and Ci -6 alkyl.
  • Suitable values of R y and/or R z include hydrogen and Ci -6 alkyl.
  • R y represents hydrogen. In another embodiment, R y represents Ci -6 alkyl, especially methyl. In a further embodiment, R y represents hydroxy.
  • R z represents hydrogen. In another embodiment, R z represents Ci -6 alkyl, especially methyl.
  • V represents a covalent bond. In another embodiment, V represents a methylene linkage. In one embodiment, W represents a covalent bond. In another embodiment, W represents a methylene linkage.
  • R 1 represents hydrogen or Ci -6 alkyl. Typical values of R 1 include hydrogen, methyl and ethyl. In one embodiment, R 1 is hydrogen. In another embodiment, R 1 is Ci -6 alkyl. In one aspect of that embodiment, R 1 is methyl. In another aspect of that embodiment, R 1 is ethyl.
  • R 2 represents hydrogen; or Ci -6 alkyl, Ci -6 alkoxy, C 3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents.
  • substituents on R 1 and/or R 2 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci -6 alkylthio, Ci -6 alkylsulphonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylaminocarbonyl, di(C
  • R 1 and/or R 2 examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
  • Typical values of R 2 include hydrogen, methyl, ethoxy, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl.
  • R 1 and R 2 when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage.
  • R 1 and R 2 when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 1 and R 2 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl.
  • R 1 and R 2 when attached to adjacent carbon atoms, may together form an optionally benzo-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the ring containing the variable V and/or W.
  • R 1 and R 2 when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 1 and R 2 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the ring containing the variable V and/or W.
  • R 1 and R 2 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e. an indanyl moiety fused to the ring containing the variable V and/or W.
  • R 3 represents hydrogen; or Ci -6 alkyl, aryl, aryl(Ci -6 )alkyl, aryl- (C 2-6 )alkynyl, biaryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, C 3-7 heterocycloalkyl- carbonyl, heteroaryl(Ci -6 )alkyl, heteroaryl-aryl(Ci -6 )alkyl or aryl-heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents hydrogen; or C 2-6 alkynyl, aryl(Ci -6 )alkyl or heteroaryl- (Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 3 represents aryl(Ci -6 )alkyl or heteroaryl(Ci -6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 3 represents hydrogen
  • R 3 represents Ci -6 alkyl, aryl(Ci -6 )alkyl, biaryl- (Ci -6 )alkyl, heteroaryl(Ci -6 )alkyl or heteroaryl-aryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents methyl, arylmethyl, biarylmethyl, heteroarylmethyl or heteroaryl-arylmethyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 3 represents arylmethyl or heteroarylmethyl, either of which groups may be optionally substituted by one or more substituents.
  • R 3 represents substituted or unsubstituted indolyl-
  • R 3 represents substituted or unsubstituted indolylmethyl.
  • R 3 represents substituted or unsubstituted phenyl- (Ci -6 )alkyl.
  • R 3 represents substituted or unsubstituted benzyl.
  • R 3 represents substituted or unsubstituted benzofuryl- (Ci -6 )alkyl.
  • R 3 represents substituted or unsubstituted benzofurylmethyl.
  • R 3 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1 ,2,3,4-tetrahydroquinolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-6]pyridinylmethyl, pyrrolo[3 ,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazo
  • R 4 represents hydrogen or optionally substituted Ci -6 alkyl.
  • substituents on R and/or R 4 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl(C i -6 )alkylaryl, piperazinyl(C i -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i .(,)- alkylaryl, morpholinyl(Ci -6 )alkylaryl, (Ci -6 )alkoxyaryl, cyano(Ci -6 )alkoxyaryl, di(Ci -6 )- alkylamino(Ci -6 )alkylaryl, (Ci -6 )alkylaminocarbonyla
  • R 3 and/or R 4 include halogen, cyano, Ci -6 alkyl, (Ci -6 )alkylpyrazolyl, C 2-6 alkoxycarbonyl and di(Ci -6 )alkylaminocarbonyl.
  • a further example is carboxy.
  • R 3 and/or R 4 Selected examples of specific substituents on R 3 and/or R 4 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifiuoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, mo ⁇ holinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxo
  • Typical values of R 3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, TV-methyl-TV-phenylaminomethyl, pyridinylamino- methyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyl- methylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolyl- phenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazo
  • R 3 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, (carboxy)(methyl)- indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, dimethylaminocarbonylindolylmethyl and (dimethylaminocarbonyl)(methyl)indolyl- methyl.
  • R 3 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, methoxycarbonylindolylmethyl and dimethylaminocarbonylindolylmethyl.
  • R 4 Typical values of R 4 include hydrogen and methyl. In a preferred embodiment, R 4 is hydrogen. In another embodiment, R 4 is Ci -6 alkyl, especially methyl.
  • R 3 and R 4 when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage.
  • R 3 and R 4 when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
  • R 3 and R 4 when attached to adjacent carbon atoms, may together form an optionally benzo-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the morpholine ring.
  • R 3 and R 4 when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the morpholine ring, which phenyl ring may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e.
  • an indanyl moiety fused to the morpholine ring which indanyl moiety may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • substituents on the fused rings referred to in the preceding paragraph include halogen, nitro, Ci -6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(C i - 6 )alkylaryl, piperidinyl(C i -6 )alkylaryl, piperazinyl(C i -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i -6 )alkylaryl, morpholinyl(C i _ 6 )alkylaryl, (C i -6 )alkoxyaryl, cyano(C i -6 )alkoxyaryl, di(C i -6 )
  • Selected examples of specific substituents on the fused rings referred to in the three preceding paragraphs include bromo, nitro, methyl, «-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazin
  • R a represents substituted or unsubstituted aryl.
  • R c represents hydrogen; or aryl, aryl(Ci -6 )alkyl, heteroaryl(Ci -6 )alkyl or
  • R a and/or R b and/or R c include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci -6 alkylthio, Ci -6 alkylsulphonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylamino- carbonyl, di(Ci -6 )alkyl
  • R a and/or R b and/or R c examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl .
  • a particular value of R a is phenyl.
  • R b represents hydrogen. In another embodiment, R b represents Ci -6 alkyl, especially methyl or ethyl.
  • R c include hydrogen, phenyl, benzyl, pyridinylmethyl and (phenyl)(pyridinyl)methyl .
  • R d represents hydrogen.
  • R d represents Ci -6 alkyl, especially methyl or ethyl, particularly ethyl.
  • R e represents methyl
  • R 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b or -CONR c R d ; or R 5 represents Ci -6 alkyl, C 2-6 alkenylcarbonyl, C 2-6 alkynyl, C 3-7 cycloalkyl(C 2-6 )alkynyl, aryl, aryl(Ci -6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, C 3-7 heterocycloalkyl(C 2-6 )alkynyl, C 3-7 heterocycloalkylcarbonyl(C 2-6 )alkynyl, C 5-9 heterobicycloalkyl(C 2-6 )alkynyl, C 3-7 heterocycloalkyl-aryl, C 3
  • R 5 represents hydrogen; or optionally substituted aryl(C 2-6 )alkynyl.
  • R 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b or
  • R 5 represents methyl, propyl, ethenylcarbonyl, ethynyl, propynyl, butynyl, 3-methylbutynyl, cyclopropylethynyl, cyclohexylethynyl, phenyl, naphthyl, benzyl, phenylethyl, phenylethenyl, phenylethynyl, phenylpropynyl, biphenyl, piperidinylethyl, pyrrolidinyl ethynyl, piperidinylethynyl, 1 ,2,3 ,4-tetrahydroisoquinolinylpropynyl, piperazinylpropynyl, pyrrolidinyl carbonylethynyl, quinuclidinyl ethynyl, piperazinyl- pheny
  • R 5 represents hydrogen; or optionally substituted phenylethynyl.
  • substituents on R 5 include halogen, cyano, nitro, oxo, Ci -6 alkyl, trifluoromethyl, hydroxy, hydroxy(Ci.
  • R 5 examples include fluoro, chloro, bromo, cyano, nitro, oxo, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, ethoxy, dihydroxypropoxy, isobutoxy, benzyloxy, methoxybenzyloxy, amino, methylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, N-isopropyl-N-methylaminomethyl, dimethylaminoethylamino, methoxybenzylamino, acetylamino, ethoxycarbonylacetylamino, ethylcarbonylamino, methoxycarbonyl- ethylcarbonylamino, acetylaminomethyl, tert-butoxycarbonylamino, N-(tert-butoxy- carbonyl)-N
  • R 5 include hydrogen, fluoro, chloro, bromo, iodo, cyano, phenylthio, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, pyridinylmethylaminocarbonyl, (phenyl)(pyridinyl)methylaminocarbonyl, N-ethyl-N-pyridinylmethylaminocarbonyl, dimethylaminomethyl, dimethylaminosulphonylaminopropyl, dimethylamino- ethenylcarbonyl, ethynyl, triethylsilylethynyl, diethylaminopropynyl, methylsulphonylaminopropynyl, dimethylaminosulphonylaminopropynyl, hydroxybutynyl, 3-hydroxy-3-
  • R 5 in the compounds of formula (B) above is hydrogen
  • R and/or R >4 is other than hydrogen.
  • R when present, represents hydrogen, hydroxy or -NR 6ar R> 6b .
  • R 6 represents hydrogen.
  • R represents hydroxy.
  • R 6 represents -NR 6a R 6 .
  • R 6 represents oxo.
  • R 6a represents Ci -6 alkyl, C 3-7 cycloalkyl, aryl or aryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6a and R 6b examples include halogen, cyano, trifiuoromethyl, hydroxy, Ci -6 alkoxy and trifluoromethoxy, especially hydroxy.
  • R 6a examples include methyl, hydroxyethyl, cyclopropyl, phenyl and benzyl.
  • R 6b represents hydrogen or Ci -6 alkyl.
  • R 6b represents hydrogen.
  • R 6 represents Ci -6 alkyl, especially methyl.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (BA), and pharmaceutically acceptable salts and solvates thereof:
  • R 1 ' represents hydrogen or Ci -6 alkyl
  • R 12 represents hydrogen; or Ci -6 alkyl, Ci -6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl- (Ci- 6 )alkyl, heteroaryl or heteroaryl(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R 11 and R 12 when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 5 in the compounds of formula (BA) is other than hydrogen.
  • any of the groups in the compounds of formula (BA) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted.
  • R 1 ' Typical values of R 1 ' include hydrogen, methyl and ethyl. In one embodiment, R 1 ' is hydrogen. In another embodiment, R 1 ' is Ci -6 alkyl, especially methyl.
  • R 12 represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents.
  • substituents on R 12 include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difiuoromethoxy, trifluoromethoxy, aryloxy, Ci -6 alkylthio, Ci -6 alkylsulphonyl, amino, Ci -6 alkylamino, di(Ci -6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylaminocarbonyl, di(Ci -6 )alkylamino,
  • R 12 examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difiuoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
  • Typical values of R 12 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl.
  • a particular value of R 12 is methyl.
  • R 1 ' and R 12 may together form an optionally substituted spiro linkage.
  • R 1 ' and R 12 when taken together with the carbon atom to which they are both attached, may represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 1 ' and R 12 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
  • W, the moiety X-Y-Q, R 1 ' and R 12 are as defined above;
  • R 13 represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(C, -6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2 .
  • any of the groups in the compounds of formula (IIA-A) or (IIA-B) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted.
  • R 13 represents hydrogen; or Ci -6 alkyl, aryl(Ci -6 )alkyl, aryl(C 2-6 )alkynyl, biaryl(C
  • R 13 represents hydrogen; or C 2-6 alkynyl, aryl(C 1-6 )alkyl or heteroaryl- (Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 13 represents aryl(Ci -6 )alkyl or heteroaryl(Ci -6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 13 represents hydrogen
  • R 13 is other than hydrogen.
  • R 13 represents C 1-6 alkyl, aryl(Ci -6 )alkyl, biaryl- (C i -6 )alkyl, heteroaryl(C i -6 )alkyl or heteroaryl-aryl(C i -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 13 represents methyl, arylmethyl, biarylmethyl, heteroarylmethyl or heteroaryl-arylmethyl, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents arylmethyl or heteroarylmethyl, either of which groups may be optionally substituted by one or more substituents.
  • R 13 represents substituted or unsubstituted indolyl- (Ci -6 )alkyl.
  • R 13 represents substituted or unsubstituted indolylmethyl.
  • R 13 represents substituted or unsubstituted phenyl- (Ci -6 )alkyl.
  • R 13 represents substituted or unsubstituted benzyl.
  • R 13 represents substituted or unsubstituted benzofuryl-
  • R 13 represents substituted or unsubstituted benzofurylmethyl.
  • R 13 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1 ,2,3,4-tetrahydroquinolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3 ,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-6]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazo
  • R 13 examples include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl- (C i -6 )alkylaryl, piperazinyl(C i -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i -6 )alkylaryl, morpholinyl(Ci -6 )alkylaryl, (Ci -6 )alkoxyaryl, cyano(Ci -6 )alkoxyaryl, di(Ci -6 )alkyl- amino(Ci -6 )alkylaryl, aryl(Ci -6 )alkyl, oxazolinyl, azetidinyl, haloarylpyrrolidin
  • substituents on R 13 include halogen, cyano, Ci -6 alkyl, C 2-6 alkoxycarbonyl and di(Ci -6 )alkylaminocarbonyl. A further example is carboxy.
  • Selected examples of specific substituents on R 13 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidin
  • R 13 Particular examples of specific substituents on R 13 include bromo, cyano, methyl, methoxycarbonyl and dimethylaminocarbonyl. A further example is carboxy.
  • Typical values of R 13 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienylmethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazolylphenylamin
  • R 13 Representative values of R 13 include hydrogen, bromobenzyl, benzof ⁇ irylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, (carboxy)(methyl)- indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, dimethylaminocarbonylindolylmethyl and (dimethylaminocarbonyl)(methyl)indolyl- methyl.
  • R 13 Particular values of R 13 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, methoxycarbonylindolylmethyl and dimethylaminocarbonylindolylmethyl.
  • One particular sub-group of the compounds of formula (II A- A) is represented by the compounds of formula (HB), and pharmaceutically acceptable salts and solvates thereof:
  • W the moiety X-Y-Q, R 1 ' and R 12 are as defined above; T represents oxygen or N-R 5 ; R 23 represents hydrogen, halogen, cyano, nitro, Ci -6 alkyl, hydroxy(Ci. 6 )alkyl, trifluoromethyl, aryl(Ci.
  • R 24 represents hydrogen, halogen, Ci -6 alkoxy or di(Ci -6 )alkylaminocarbonyl; or R 23 and R 24 , when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and
  • R 25 represents hydrogen or Ci -6 alkyl.
  • T is N-R 25 . In another embodiment, T is oxygen.
  • Typical values of R 23 include hydrogen, cyano, carboxy, C 2-6 alkoxycarbonyl and di(C
  • Suitable values of R 23 include hydrogen, cyano, C 2-6 alkoxycarbonyl and di(C i -6 )alkylaminocarbonyl .
  • Illustrative values of R 23 include hydrogen, fluoro, chloro, cyano, nitro, oxazolinyl, triazolyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, morpholinylethoxy, azetidinyl, morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino, N-methoxycarbonyl-TV-methylamino, methylsulphonylamino, acetyl, acetyl oxime, acetyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethylaminoethyl)aminocarbonyl, (1 -hydroxyprop-2-yl
  • R 23 include hydrogen, cyano, carboxy, methoxycarbonyl and dimethylaminocarbonyl. Selected values of R 23 include hydrogen, cyano, methoxycarbonyl and dimethylaminocarbonyl.
  • R 23 is hydrogen.
  • R 24 Definitive values of R 24 include hydrogen, chloro, methoxy and dimethylaminocarbonyl. A particular value of R 24 is hydrogen.
  • R is hydrogen. In another embodiment, R is Ci -6 alkyl, especially methyl.
  • R 33 represents halogen or -NHR 34 ; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents;
  • R 34 represents methyl enedioxyphenyl, morpholinyl(Ci -6 )alkylphenyl, oxazolinyl- phenyl, [(Ci -6 )alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (Ci -6 )alkyltriazolylphenyl, (Ci -6 )alkylpyrimidinylphenyl, pyrazolyl(Ci -6 )alkyl- phenyl, triazolyl(Ci -6 )alkylphenyl, Ci -6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci -6 alkylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, Cj -6 alkyls
  • R 33 represents halogen or -NHR 34 , in which R 34 is as defined above.
  • R 33 represents halogen, especially bromo.
  • R 33 represents -NHR 34 , in which R 34 is as defined above.
  • R 33 represents unsubstituted or substituted aryl. In another embodiment, R 33 represents unsubstituted or substituted heteroaryl.
  • Typical values of R 34 include pyridinyl, halopyridinyl, (Ci -6 )alkylpyridinyl, di(C 1-6 )alkylpyridinyl and (Ci -6 )alkoxypyridinyl.
  • R 34 include methylenedioxyphenyl, morpholinylmethylphenyl, oxazolinylphenyl, (methyl)(oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolylphenyl, methyltriazolylphenyl, methylpyrimidinylphenyl, pyrazolylmethylphenyl, triazolylmethylphenyl, methylsulphonylaminophenyl, morpholinylcarbonylphenyl, methylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, methylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, (bromo)(methyl)pyrazolyl, trimethyl
  • R 33 represents halogen or -NHR 4 , in which R 34 is as defined above. Additionally, R 33 represents phenyl, naphthyl, benzofuryl, thienyl, benzothienyl, indolyl, isoxazolyl, pyrazolyl, pyridinyl or pyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
  • R 33 Selected examples of suitable substituents on R 33 include halogen, cyano, Ci -6 alkyl, hydroxy(Ci -6 )alkyl, trifiuoromethyl, Ci -6 alkoxy, trifluoromethoxy, aryloxy, methylenedioxy, Ci -6 alkylthio, arylsulphonyl, amino, C 2-6 alkylcarbonylamino, Ci -6 alkylsulphonylamino, C 2-6 alkylcarbonyl and aminocarbonyl.
  • R selected examples include fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, phenoxy, methylenedioxy, methylthio, phenylsulphonyl, amino, acetylamino, methylsulphonylamino, acetyl and aminocarbonyl.
  • R 33 Specific values of R 33 include bromo, methyl enedioxyphenylamino, morpholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenyl- amino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenyl- amino, triazolylmethylphenylamino, methylsulphonylaminophenylamino, morpholinyl- carbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, dihydrobenzofuranylamino, methylsulphonylindolinylamino, chromanonylamino, dihydroquinolinonylamino,
  • R 43 represents hydrogen, halogen, nitro, Ci -6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl(Ci -6 )alkylaryl, piperazinyl(Ci -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i -6 )alkylaryl, morpholinyl(C i -6 )alkylaryl, (C i -6 )alkoxyaryl, cyano(C i .
  • R 44 represents hydrogen, halogen, Ci -6 alkyl or Ci -6 alkoxy.
  • a suitable value of R 43 is (Ci -6 )alkylpyrazolyl.
  • R 43 Specific values of R 43 include bromo, nitro, methyl, w-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethyl- phenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazinyl, methylpiperazinyl, chloroph
  • R 43 is methylpyrazolyl.
  • R 44 represents hydrogen. In another embodiment, R 44 represents halogen, especially bromo. In a further embodiment, R 44 represents Ci -6 alkyl, especially methyl. In an additional embodiment, R 44 represents Ci -6 alkoxy, especially methoxy.
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.
  • the compounds according to the present invention may be conveniently formulated as microionized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • compounds may be formulated in an ointment such as petrolatum.
  • the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
  • L 1 represents a suitable leaving group.
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, dimethylsulphoxide, a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as N,7V-dimethylformamide, optionally under basic conditions, e.g. in the presence of an organic base such as NJV- diisopropylethylamine or 2,6-lutidine.
  • a suitable solvent e.g. acetonitrile, dimethylsulphoxide, a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as N,7V-dimethylformamide
  • an organic base such as NJV- diisopropylethylamine or 2,6-lutidine.
  • reaction may be effected at an elevated temperature in a solvent such as 2-ethoxyethanol in the presence of a catalytic quantity of a mineral acid, e.g. concentrated hydrochloric acid.
  • a solvent such as 2-ethoxyethanol
  • a catalytic quantity of a mineral acid e.g. concentrated hydrochloric acid.
  • the reaction may be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium tert-butoxide, in the presence of a transition metal catalyst.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene
  • an inorganic base such as sodium tert-butoxide
  • the transition metal catalyst is suitably palladium(II) acetate, in which case the reaction will ideally be performed in the presence of tert-butylphosphonium tetrafluoroborate or dicyclohexyl diphenylphosphine.
  • reaction is conveniently effected by stirring compound (V) with tert-butyl nitrite and copper(II) bromide in a suitable solvent, e.g. acetonitrile.
  • a suitable solvent e.g. acetonitrile.
  • V, W, the moiety X-Y-Q, R 1 , R 2 and R 6 are as defined above, and L 2 represents a suitable leaving group.
  • the leaving group L 2 is typically a halogen atom, e.g. bromo or iodo.
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, typically under basic conditions, e.g. in the presence of an organic base such as TVyV-diisopropylethylamine.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran
  • organic base such as TVyV-diisopropylethylamine.
  • the reaction may be accomplished by heating the reactants in a lower alkanol solvent, e.g. a Ci -6 alkyl alcohol such as ethanol.
  • a lower alkanol solvent e.g. a Ci -6 alkyl alcohol such as ethanol.
  • the compounds of formula (I) wherein U represents N may be prepared by a process which comprises reacting a compound of formula (VI) as defined above with a compound of formula (VII):
  • the reaction may additionally be accomplished by heating the reactants in acetic acid in the presence of sodium acetate.
  • the intermediates of formula (VII) above may be prepared by reacting a compound of formula (IV) as defined above with l,l'-thiocarbonyldiimidazole; followed by treatment with ammonia or ammonium hydroxide.
  • the reaction between compound (VIII) and Bredereck's reagent may conveniently be effected by heating the reactants together, typically at the reflux temperature.
  • the subsequent treatment with hydrazine hydrochloride or hydrazine hydrate may conveniently be effected in a suitable solvent, e.g. a lower alkanol solvent such as methanol or ethanol, optionally at an elevated temperature.
  • U, V, W, R 1 , R 2 , R 3 , R 4 and R 6 are as defined above, and L 3 represents a suitable leaving group; with aminoacetaldehyde dimethyl acetal; followed by treatment with an acid, typically an organic acid such as p-toluenesulphonic acid.
  • the leaving group L 3 is typically a halogen atom, e.g. chloro, or a methylthio (-SCH 3 ) group.
  • reaction between compound (IX) and aminoacetaldehyde dimethyl acetal may conveniently be effected by heating the reactants together.
  • the subsequent acid treatment may conveniently be effected by heating in a suitable solvent, e.g. a hydrocarbon solvent such as toluene, or a lower alkanol solvent such as isopropanol.
  • the compounds of formula (IC) above wherein R y is methyl and R z is hydrogen may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with propargylamine.
  • the reaction may conveniently be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether solvent such as tetrahydrofuran.
  • a suitable solvent e.g. a cyclic ether solvent such as tetrahydrofuran.
  • reaction is conveniently effected in a suitable organic solvent, e.g. acetonitrile.
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a hydrocarbon solvent such as toluene.
  • a suitable solvent e.g. a hydrocarbon solvent such as toluene.
  • the intermediates of formula (IX) above wherein L 3 is chloro may be prepared by reacting a compound of formula (XI) as defined above with phosphorus oxychloride, typically at an elevated temperature.
  • the compounds of formula (ID) above may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with a compound of formula R y -CONHNH 2 .
  • the reaction may be conveniently accomplished in the presence of an organic acid such as acetic acid.
  • the compounds of formula (IE) above may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with a metal azide such as sodium azide.
  • a suitable solvent e.g. a lower alkanol solvent such as methanol.
  • V, W, R 1 , R 2 , R 5 , R 6 and L 1 are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (IV).
  • V, W, R 1 , R 2 and R 6 are as defined above; followed by treatment of the resulting compound with sulphur.
  • the reaction between malononitrile and compound (XIV) is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of piperidine.
  • a suitable solvent e.g. a lower alkanol such as ethanol
  • sulphur is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of morpholine.
  • the starting materials of formula (IV), (VI) and (XIV) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
  • a compound of formula (IA) wherein R x represents hydrogen may be converted into the corresponding compound wherein R" is an alkylsulphonyl substituent, e.g. methylsulphonyl, by treatment with the appropriate alkylsulphonyl halide, e.g. methanesulphonyl chloride.
  • a compound of formula (I) wherein R 6 represents hydroxy may be converted into the corresponding compound wherein R 6 represents oxo by treatment with an oxidising agent such as Dess-Martin periodinane.
  • a compound of formula (I) wherein R 3 and/or R 4 contains an aryl or heteroaryl moiety may be halogenated (e.g. brominated) on the aryl or heteroaryl moiety by treatment with the appropriate TV-halosuccinimide (e.g. N-bromosuccinimide).
  • halogenated e.g. brominated
  • TV-halosuccinimide e.g. N-bromosuccinimide
  • a compound of formula (I) wherein R 3 and/or R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by amino (-NH 2 ) by treatment with benzophenone imine and tris(dibenzylidene- acetone)dipalladium(O) in the presence of 2,2 '-bis(diphenylphosphino)- 1 , 1 '-binaphthyl (BINAP) and a strong base such as sodium tert-butoxide.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound of formula (I) wherein the halogen atom is replaced by an optionally substituted C 3-7 cycloalkyl, aryl, aryl(Ci -6 )alkyl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted C 3-7 cycloalkyl, aryl, aryl(Ci- 6 )alkyl or heteroaryl boronic acid or a cyclic ester thereof, e.g. a pinacol ester thereof, in the presence of a catalyst.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 represents aryl(Ci -6 )alkyl, substituted on the aryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 3 represents biaryl(Ci -6 )alkyl or heteroarylaryl(Ci -6 )alkyl by treatment with, respectively, an aryl or heteroaryl boronic acid, in the presence of a catalyst.
  • a compound of formula (I) wherein R 3 represents heteroaryl(Ci -6 )alkyl, substituted on the heteroaryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 3 represents aryl-heteroaryl(Ci. 6 )alkyl by treatment with an aryl boronic acid, in the presence of a catalyst.
  • a compound of formula (I) wherein R 3 contains a cyclic borane moiety e.g.
  • 4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl may be converted into the corresponding compound wherein the cyclic borane moiety is replaced by an optionally substituted aryl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted aryl or heteroaryl halide, e.g. chloride, bromide or iodide, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, in an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonium bromide.
  • a base such as sodium carbonate, potassium carbonate or potassium phosphate
  • an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonium bromide.
  • the catalyst may be palladium(II) acetate, in which case the transformation may conveniently be effected at an elevated temperature in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and potassium phosphate.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents a substituted aminomethyl moiety, e.g. phenylaminomethyl, iV-methyl-N-phenylaminomethyl, pyridin- 3-ylaminomethyl, indolin-1-ylmethyl, 1,2,3,4-tetrahydroquinolin-l-ylmethyl or 1,2,3,4- tetrahydroisoquinolin-2-ylmethyl, by a two-stage procedure which comprises (i) Swern oxidation of the hydroxymethyl derivative by treatment with oxalyl chloride and dimethyl sulphoxide in the presence of triethylamine; and (ii) reductive animation of the formyl derivative thereby obtained by treatment with the appropriate amine, e.g.
  • aniline JV- methylaniline, 3-aminopyridine, indoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4- tetrahydroisoquinoline, in the presence of a reducing agent such as sodium cyanoborohydride.
  • any compound of formula (I) which contains a carbonyl-containing functionality e.g. formyl or a ketone moiety
  • a carbonyl-containing functionality e.g. formyl or a ketone moiety
  • a reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • Any compound of formula (I) wherein R 3 contains an amino moiety can be alkylated on the amino moiety by a reductive amination procedure which comprises treatment with the appropriate aldehyde in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents an optionally substituted C 3-7 heterocycloalkylcarbonyl moiety, e.g. piperidin-1-ylcarbonyl, 1,2,3,4- tetrahydroquinolin- 1 -ylcarbonyl, 6-methyl- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 6- methoxy- 1 ,2,3,4-tetrahydroquinolin- 1 -ylcarbonyl, 1 ,2,3 ,4-tetrahydroisoquinolin-2- ylcarbonyl or 1, 2,3, 4-tetrahydroquinoxalin-l -ylcarbonyl, by a two-stage procedure which comprises (i) oxidation of the hydroxymethyl moiety by treatment with potassium permanganate; and (ii) reaction of the carboxy derivative thereby obtained with the appropriate amine, e.g
  • piperidine 1,2,3,4-tetrahydroquinoline, 6-methyl- 1,2,3,4- tetrahydroquinoline, 6-methoxy-l ,2,3,4-tetrahydroquinoline, 1 ,2,3,4-tetrahydro- isoquinoline or 1,2,3,4-tetrahydroquinoxaline, in the presence of a condensing agent such as l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, or 0-(benzotriazol-l-yl)-N,JV,iV,7V- tetramethyluronium hexafluorophosphate (HBTU).
  • a condensing agent such as l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, or 0-(benzotriazol-l-yl)-N,JV,iV,7V- tetramethyluronium
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by chloro may be converted into the corresponding compound wherein the phenyl ring is substituted by morpholin-4-yl by treatment with morpholine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(di-te/-t-butylphosphino)biphenyl and sodium tert-butoxide.
  • a compound of formula (I) wherein R contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by pyrrolidin-1-yl by treatment with pyrrolidine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1 , 1 '-biphenyl and a base such as potassium carbonate.
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by an amino moiety (e.g. a group of formula -NHR 34 as defined above) by treatment with the appropriate amine (e.g. a compound of formula H 2 N-R 34 ) in the presence of tris(dibenzylideneacetone)dipalladium(0), isopropyl- 1 ,l'-biphenyl (X-Phos) and a base such as sodium tert-butoxide.
  • an amino moiety e.g. a group of formula -NHR 34 as defined above
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by carboxy (-CO 2 H) by treatment with M-butyllithium followed by carbon dioxide.
  • a compound of formula (I) wherein R 3 contains an indole moiety may be methylated on the indole ring by treatment with a methyl halide, e.g. iodomethane, in the presence of a strong base such as sodium hydride.
  • a compound of formula (I) wherein R 3 contains an indole moiety may be acetylated on the indole ring by treatment with acetic anhydride and 4-dimethylamino-pyridine, typically in the presence of an organic base such as triethylamine.
  • a compound of formula (I) wherein R 3 contains an indoline moiety may be converted into the corresponding compound wherein R 3 contains an indole moiety by treatment with an oxidising agent such as manganese dioxide.
  • a compound of formula (I) wherein R 3 contains a hydroxy substituent may be converted into the corresponding compound wherein R 3 contains a Ci -6 alkylsulphonyloxy substituent, e.g.
  • a compound of formula (I) wherein R 3 contains an amino (-NH 2 ) or carboxy (-CO 2 H) moiety may be converted into the corresponding compound wherein R 3 contains an amido moiety (-NHCO- or -CONH- respectively) by treatment with, respectively, a compound containing a carboxy or amino group, in the presence of O-(benzotriazol-l-yl)- ⁇ /V ⁇ -tetramethyluronium hexafluorophosphate (HBTU), typically in a dipolar aprotic solvent such as ⁇ /V-dimethylformamide; or in the presence of l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide and 1-hydroxybenzotriazole.
  • HBTU O-(benzotriazol-l-yl)- ⁇ /V ⁇ -tetramethyluronium hexafluorophosphate
  • a compound of formula (I) wherein R contains an amino substituent may be converted into the corresponding compound wherein R 3 contains an alkyl- or arylsulphonylamino substituent, e.g. methylsulphonylamino or phenylsulphonylamino, by treatment with an alkyl- or arylsulphonyl halide, e.g. methanesulphonyl chloride or benzenesulphonyl chloride.
  • a compound of formula (I) wherein R 3 contains an amino moiety may be acylated by treatment with a C 2-6 alkylcarbonyl halide, e.g. acetyl chloride; or a C 2-6 alkylcarbonyl anhydride, e.g. acetic anhydride.
  • a compound of formula (I) wherein R 3 contains an amino moiety may be converted into the corresponding carbamate ester by treatment with a C 1 . 6 alkyl haloformate, e.g. methyl chloro formate.
  • a compound of formula (I) wherein R contains a C 2-6 alkoxycarbonyl substituent, e.g. methoxycarbonyl, may be converted into the corresponding compound wherein R 3 contains a carboxy (-CO 2 H) substituent under standard saponification conditions, generally by treatment with a base, e.g. an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.
  • a base e.g. an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.
  • R 3 contains an amido substituent e.g.
  • a condensing agent such as l-[3-(dimethylamino
  • methylamine 2-hydroxyethylamine, dimethylamine, N-(2- hydroxyethyl)-N-methylamine, benzylamine, azetidine, pyrrolidine, piperidine, 1- methylpiperazine or morpholine.
  • a compound of formula (I) wherein R 3 /R 4 contains a nitro moiety may be converted into the corresponding compound wherein R 3 /R 4 contains an amino (-NH 2 ) moiety by catalytic hydrogenation, typically by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino (-NH 2 ) moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a heteroaryl-amino moiety, e.g. 6-methylpyridin-3- ylamino, by treatment with the appropriate heteroaryl halide, e.g. 5-bromo-2- methylpyridine, in the presence of palladium(II) acetate, 2-bis(dicyclohexylphosphino)- biphenyl and a base such as sodium tert-butoxide.
  • any compound of formula (I) wherein R 3 /R 4 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein the halogen atom is replaced by a substituted amino functionality by treatment with the appropriately- substituted amine derivative and palladium(II) acetate in the presence of a base, e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate.
  • a base e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate.
  • reaction may be effected by treatment with the appropriately-substituted amine derivative and [l,r-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride in the presence of a base, e.g. sodium tert-butoxide.
  • a base e.g. sodium tert-butoxide.
  • any compound of formula (I) wherein R 3 /R 4 contains an amino functionality may be converted into the corresponding compound wherein the amino functionality is substituted by an optionally substituted aryl or heteroaryl moiety by treatment with an appropriately-substituted aryl or heteroaryl halide (e.g.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a heteroaryl group, e.g.
  • pyrazol-3-yl 1- methylpyrazol-4-yl, l-propylpyrazol-4-yl, l-isobutylpyrazol-4-yl, l-benzylpyrazol-4-yl, 1- [2-(morpholin-4-yl)ethyl]pyrazol-4-yl, 6-methylpyridin-3-yl or pyrimidin-5-yl, by treatment with the appropriate heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst.
  • an organic diol e.g. pinacol
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a boronic acid [-B(OH) 2 ] moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a heteroaryl group, e.g. methylimidazolyl, by treatment with the appropriate heteroaryl halide, e.g. bromide, derivative in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, optionally in the presence of tetrabutylammonium bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group by treatment with a strong base, e.g. n-butyllithium, and 7V,7V-dimethylformamide.
  • a strong base e.g. n-butyllithium
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by hydroxymethyl by treatment with a reducing agent such as sodium borohydride.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by an aminomethyl moiety (e.g.
  • the appropriate amine e.g. dimethylamine, pyridin-3-ylamine, 1-methylpiperazine or morpholine
  • a reducing agent typically consists of a mixture of phenylsilane and dibutyltin dichloride.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino moiety may be converted into the corresponding compound wherein R /R 4 is methylated on the amino moiety by treatment with formaldehyde and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a pyridinyloxymethyl moiety by treatment with the appropriate hydroxypyridine in the presence of a mixture of triphenylphosphine and diethyl azodicarboxylate.
  • R 3 /R 4 contains a benzo moiety substituted by a C 2-6 alkoxycarbonyloxy group, e.g.
  • tert-butoxycarbonyloxy may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by hydroxy under standard hydrolytic conditions, e.g. by treatment with trifluoroacetic acid.
  • R 3 /R 4 contains a halogen atom, e.g. bromo,
  • R 3 /R 4 contains hydroxy by treatment with sodium hydroxide in the presence of tris(dibenzylideneacetone)- dipalladium(O) and 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-l,r-biphenyl.
  • a compound of formula (I) wherein R /R contains hydroxy may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted Ci -6 alkoxy, C 3-7 heterocycloalkoxy or C 3-7 heterocycloalkyl(Ci -6 )alkoxy by treatment with the appropriately substituted Ci -6 alkyl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkyl(C[ -6 )- alkyl halide, e.g. bromide, ideally at an elevated temperature in the presence of cetyl- ammonium bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains hydroxy may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted pyridinyloxy, pyrimidinyloxy or pyrazinyloxy by treatment with the appropriately substituted pyridinyl, pyrimidinyl or pyrazinyl halide, e.g. fluoride or chloride, typically in the presence of a strong base such as sodium t ⁇ rt-butoxide.
  • R 3 /R 4 contains a halogen atom e.g.
  • bromo may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted aryloxy or heteroaryloxy by treatment with an appropriately-substituted hydroxyaryl or hydroxyheteroaryl derivative and a base such as caesium carbonate, ideally in the presence of a copper(I) halide, e.g. copper(I) chloride or copper(I) bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino (-NH 2 ) group may be converted into the corresponding compound wherein R 3 /R 4 contains 2,5-dioxopyrrolidin- 1-yl by treatment with succinic anhydride.
  • a compound of formula (I) wherein R 3 /R 4 contains an aryl or heteroaryl moiety substituted by a halogen atom, e.g. chloro, may have the halogen atom removed by catalytic hydrogenation.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety may be alkylated on the aromatic ring by treatment with n-butyllithium and an alkyl halide (e.g. iodopropane); or by treatment with an organozinc reagent (e.g. isopropylzinc bromide) in the presence of [l,r-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride and copper(I) iodide.
  • n-butyllithium and an alkyl halide e.g. iodopropane
  • an organozinc reagent e.g. isopropylzinc bromide
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by an optionally substituted alkynyl moiety (e.g. 3-hydroxyprop-l-yn-l-yl) by treatment with an appropriately- substituted alkyne derivative (e.g. 3-hydroxyprop-l-yne) and a catalyst such as tetrakis(triphenylphosphine)palladium(0), typically in the presence of copper(I) iodide and a base such as triethylamine.
  • an optionally substituted alkynyl moiety e.g. 3-hydroxyprop-l-yn-yl
  • an appropriately- substituted alkyne derivative e.g. 3-hydroxyprop-l-yne
  • a catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by acetyl by a two-stage procedure which comprises (i) treatment with butyl vinyl ether and palladium acetate, suitably in the presence of l,3-bis(diphenylphosphino)propane and an organic base such as triethylamine; and (ii) hydrolysis with a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by 1 -hydroxy- 1-methylethyl by treatment with n-butyllithium and acetone.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by Ci -6 alkylthio (e.g. isopropylthio) by treatment with n-butyllithium and the appropriate disulphide derivative (e.g isopropyl disulphide).
  • Conversion of the Ci -6 alkylthio moiety into Ci -6 alkylsulphinyl or Ci -6 alkylsulphonyl may be accomplished by treatment with an oxidising agent, e.g. m-chloroperbenzoic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a pyridinyl moiety may be converted into the corresponding pyridine-TV-oxide analogue by treatment with peracetic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a formyl moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a vinyl moiety by treatment with methyltriphenylphosphonium bromide and a strong base such as sodium hexamethyldisilazide.
  • a compound of formula (I) wherein R 3 /R 4 contains a formyl moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a 1-hydroxyethyl moiety by treatment with methyllithium.
  • a compound of formula (I) wherein R 3 /R 4 contains a (2-hydroxyethyl)amino- carbonyl group may be converted into the corresponding compound wherein R /R 4 contains an oxazolin-1-yl moiety by treatment with thionyl chloride.
  • a compound of formula (I) wherein R 3 /R 4 contains an ester functionality may be converted into the corresponding compound wherein R 3 /R 4 contains an amide functionality (e.g. methylaminocarbonyl or dimethylaminocarbonyl) by treatment with an appropriately-substituted amine (e.g. methylamine or dimethylamine) in the presence of trimethylaluminium.
  • R 3 /R 4 contains an ester functionality e.g. methoxycarbonyl
  • R 3 /R 4 contains an amide functionality e.g. methylaminocarbonyl or dimethylaminocarbonyl
  • an appropriately-substituted amine e.g. methylamine or dimethylamine
  • Alkenyl-containing compounds may be converted into the corresponding vic- dihydroxy analogues by treatment with osmium tetroxide.
  • Alkenyl- and alkynyl-containing compounds may be converted into the corresponding alkyl analogues by catalytic hydrogenation.
  • a compound of formula (I) wherein R 5 represents -CO 2 R b in which R b is other than hydrogen may be saponified and then decarboxylated to give the corresponding compounds in which R 5 represents -CO 2 H and hydrogen respectively by treatment with a base such as lithium hydroxide.
  • a base such as lithium hydroxide.
  • any compound of formula (I) wherein R 5 contains a lower alkyl ester moiety may be converted into the corresponding compound wherein R 5 contains a carboxy (-CO 2 H) group by treatment with a base such as lithium hydroxide or sodium hydroxide.
  • a compound of formula (I) wherein R 5 represents -CO 2 H may be converted into the corresponding compound wherein R 5 represents -CONR c R d by treatment with an amine of formula H-NR c R d and a condensing agent such as EDC, typically in the presence of an organic base such as triethylamine.
  • any compound of formula (I) wherein R 5 contains a carboxy moiety may be converted into the corresponding compound wherein R 5 contains an amide moiety by treatment with the appropriate amine and a condensing agent such as EDC, typically in the presence of 1- hydroxybenzotriazole (HOBT); alternative condensing agents include isobutyl chloroformate/triethylamine and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate.
  • EDC 1- hydroxybenzotriazole
  • alternative condensing agents include isobutyl chloroformate/triethylamine and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate.
  • any compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound wherein R 5 contains an amide moiety by treatment with the appropriate carboxylic acid under analogous conditions
  • a compound of formula (I) wherein R 5 represents cyano may be converted into the corresponding compound wherein R 5 represents -CONH 2 by heating under acidic conditions, e.g. in a mixture of acetic acid and sulphuric acid; prolonged treatment leads to conversion to the corresponding carboxylic acid followed by decarboxylation, i.e. conversion into the corresponding compound wherein R 5 represents hydrogen.
  • a compound of formula (I) wherein R 5 contains a carboxy moiety may be converted into the corresponding compound containing an arylcarbonyl moiety (e.g. benzoyl) by a two-stage procedure which comprises (i) treatment with N,Odimethyl- hydroxylamine hydrochloride and a condensing agent such as EDC, typically in the presence of HBTU; and (ii) reaction of the compound thereby obtained with the appropriate aryl lithium derivative, e.g. phenyllithium.
  • arylcarbonyl moiety e.g. benzoyl
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents fluoro by treatment with SelectfluorTM [i.e. l-(chloromethyl)-4- fluoro- l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)].
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents chloro, bromo or iodo by treatment with TV-chlorosuccinimide, ⁇ /-bromosuccinimide or N-iodosuccinimide respectively.
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents dimethylaminomethyl by treatment with Eschenmoser's salt (i.e. N,7V-dimethylmethyleneammonium iodide).
  • Eschenmoser's salt i.e. N,7V-dimethylmethyleneammonium iodide
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo or chloro, may be converted into the corresponding compound wherein R 5 represents -CO 2 R by treatment with carbon monoxide and an alcohol of formula R -OH, in the presence of a catalyst. Indeed, this procedure is generally applicable for converting any compound of formula (I) wherein R 5 contains a halogen atom into the corresponding compound containing a lower alkyl ester functionality.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is [l,l'-bis(diphenylphosphino)ferrocene]dichloro- palladium(II)-dichloromethane complex, in which case the transformation may conveniently be effected at an elevated temperature and pressure in the presence of an organic base such as triethylamine.
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. bromo or iodo, may be converted into the corresponding compound wherein R 5 represents aryl, biaryl, C 3-7 heterocycloalkyl-aryl, C 3-7 heterocycloalkyl(Ci -6 )alkyl-aryl, heteroaryl or heteroaryl-aryl by treatment with, respectively, an aryl, biaryl, C 3-7 heterocycloalkyl-aryl, C 3-7 heterocycloalkyl(Ci -6 )alkyl-aryl, heteroaryl or heteroaryl-aryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g.
  • a compound of formula (I) wherein R 5 represents aryl, substituted on the aryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 5 represents biaryl or heteroaryl-aryl by treatment with, respectively, an aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst.
  • a compound of formula (I) wherein R 5 represents heteroaryl, substituted on the heteroaryl moiety by a halogen atom such as chloro or bromo may be converted into the corresponding compound wherein R 5 represents aryl-heteroaryl or bi(heteroaryl) by treatment with, respectively, an aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol or 7V-phenyldiethanolamine, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate, potassium hydroxide or potassium phosphate, in an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1 ,4-dioxane.
  • the catalyst may be palladium(II) acetate, in which case the transformation may conveniently be effected at an elevated temperature in the presence of 1 ,3-bis(diphenylphosphino)propane and potassium phosphate, or in the presence of PdCl 2 .dppf and potassium phosphate.
  • any compound of formula (I) wherein R 5 represents or contains a halogen atom, e.g. bromo or iodo, may be converted by means of the foregoing procedure into the corresponding compound wherein the halogen atom is replaced by a substituted or unsubstituted aryl, heteroaryl or alkenyl group.
  • a halogen atom e.g. bromo or iodo
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo, may be converted into the corresponding compound wherein R 5 represents aryl(Ci -6 )alkyl, e.g. benzyl, by treatment with a suitable organozinc reagent, in the presence of a catalyst.
  • the organozinc reagent may conveniently be prepared by reacting the appropriate aryl(Ci -6 )- alkyl halide, e.g. benzyl bromide, with zinc dust.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is dichlorobis(triphenylphosphine)- palladium(II), in which case the transformation may conveniently be effected at an elevated temperature in the presence of an inert solvent such as tetrahydrofuran.
  • a compound of formula (I) wherein R 5 contains a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein the halogen atom is replaced by an arylamino or heteroarylamino moiety, e.g. phenylamino, by treatment with the appropriate amine, e.g. aniline, and a transition metal catalyst, e.g. palladium acetate, typically in the presence of tributylphosphine tetrafluoroborate and a base such as sodium tert-butoxide.
  • R 5 represents a halogen atom, e.g.
  • R 5 represents C 2-6 alkynyl, C 3-7 cycloalkyl(C 2-6 )alkynyl, aryl(C 2-6 )alkynyl, C 3-7 heterocycloalkyl(C 2-6 )alkynyl, C 5-9 heterobicycloalkyl(C 2-6 )alkynyl or heteroaryl(C 2-6 )alkynyl by treatment with, respectively, a suitable C 2-6 alkyne, C 3-7 cycloalkyl(C 2-6 )alkyne, aryl(C 2-6 )alkyne, C 3-7 heterocycloalkyl- (C 2-6 )alkyne, C 5-9 heterobicycloalkyl(C 2-6 )alkyne or heteroaryl(C 2-6 )alkyne, in the presence of a catalyst.
  • a compound of formula (I) wherein R 5 represents C 2-6 alkynyl, e.g. ethynyl may be converted into the corresponding compound wherein R 5 represents aryl(C 2-6 )alkynyl, heteroaryl(C 2-6 )alkynyl or C 3-7 cycloalkyl-heteroaryl(C 2-6 )alkynyl by treatment with, respectively, a suitable aryl, heteroaryl or C 3-7 cycloalkyl-heteroaryl iodide, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is dichlorobis(triphenylphosphine)palladium(II), in which case the transformation may conveniently be effected at an elevated temperature in the presence of copper(I) iodide and an organic base such as diisopropylamine.
  • a compound of formula (I) wherein R 5 represents arylethynyl, e.g. phenylethynyl, may be converted into the corresponding compound wherein R 5 represents arylethyl, e.g. 2-phenylethyl, by catalytic hydrogenation.
  • this procedure is generally applicable for converting any compound of formula (I) wherein R 5 contains a -C ⁇ C- moiety into the corresponding compound containing a -CH 2 CH 2 - moiety.
  • a compound of formula (I) wherein R 5 contains a -C ⁇ C- moiety may be converted into the corresponding compound containing a -COCH 2 - moiety by treatment with a pH 2 buffer solution.
  • a compound of formula (I) wherein R 5 contains a -C ⁇ C- moiety may be converted into the corresponding compound containing a -COCO- moiety by treatment with a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 5 represents nitro may be converted into the corresponding compound wherein R 5 represents amino by catalytic hydrogenation, which typically comprises reacting the nitro compound with hydrogen in the presence of a catalyst such as palladium on charcoal.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a -OCH 2 - moiety by treatment with the appropriate alkyl halide, typically in the presence of a base such as potassium carbonate.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a -OSO 2 - moiety by treatment with the appropriate sulphonyl halide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a hydroxy moiety may be converted into the corresponding compound containing a trifluoromethylsulphonyloxy moiety by treatment with N-phenyltrifluoromethanesulphonimide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a methylsulphonyloxymethyl moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains a halomethyl (e.g. chloromethyl) moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative (including cyclic amines), typically in the presence of a base such as potassium carbonate.
  • a compound of formula (I) wherein R 5 contains a hydroxymethyl moiety may be converted into the corresponding compound containing an aminomethyl moiety by treatment with the appropriate amine derivative (including cyclic amines), generally in the presence of triphenylphosphine and diethyl azodicarboxylate.
  • a compound of formula (I) wherein R 5 contains a trifluoromethylsulphonyloxy moiety may be converted into the corresponding compound wherein the trifluoromethylsulphonyloxy moiety is replaced by an amino functionality by treatment with the appropriate amine derivative (including cyclic amines) and a transition metal catalyst, e.g.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be alkylated by treatment with the appropriate alkyl halide (e.g. methyl iodide, ethyl bromide, benzyl bromide or tert-butyl bromoacetate), typically in the presence of a base such as sodium hydride or triethylamine.
  • alkyl halide e.g. methyl iodide, ethyl bromide, benzyl bromide or tert-butyl bromoacetate
  • a base such as sodium hydride or triethylamine.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a -NCH 2 - motif by a reductive amination procedure which comprises treatment with the appropriate aldehyde derivative in the presence of a base such as sodium triacetoxyborohydride.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a carbonylamino moiety by treatment with the appropriate carbonyl halide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a urea functionality by treatment with the appropriate isocyanate derivative.
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a urea functionality by a two-stage procedure which comprises (i) treatment with triphosgene, typically in the presence of a base such as triethylamine; and (ii) reaction of the compound thereby obtained with the appropriate amine derivative (including cyclic amines).
  • a compound of formula (I) wherein R 5 contains an amino moiety may be converted into the corresponding compound containing a sulphonylamino moiety by treatment with the appropriate sulphonyl halide, typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein R 5 represents a halogen atom, e.g. iodo, may be converted into the corresponding compound wherein R 5 represents acetyl by a two- stage procedure which comprises (i) reaction with butyl vinyl ether and a transition metal catalyst such as tris(dibenzylideneacetone)dipalladium(0), typically in the presence of 1 ,3- bis(diphenylphosphino)propane and a base such as potassium carbonate; and (ii) hydrolysis of the resulting compound by treatment with a mineral acid, e.g. hydrochloric acid.
  • a transition metal catalyst such as tris(dibenzylideneacetone)dipalladium(0), typically in the presence of 1 ,3- bis(diphenylphosphino)propane and a base such as potassium carbonate
  • a compound of formula (I) wherein R 5 represents acetyl may be converted into the corresponding compound wherein R 5 represents 3-(dimethylamino)-l-oxoprop-2-en-l-yl by treatment with N ⁇ V-dimethylformamide dimethyl acetal, typically at an elevated temperature.
  • a compound of formula (I) wherein R 5 represents 3-(dimethylamino)-l- oxoprop-2-en-l-yl may be converted into the corresponding compound wherein R 5 represents a substituted or unsubstiruted pyrimidinyl moiety by treatment with the appropriate amidine derivative, typically at an elevated temperature in the presence of a base such as sodium ethoxide.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 rd edition, 1999.
  • the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
  • the compounds in accordance with this invention potently inhibit the activity of human PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ .
  • the compounds of the accompanying Examples were all found to possess IC 50 values for inhibition of activity of human PI3K ⁇ and/or PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ of 50 ⁇ M or better.
  • NBS TV-bromosuccinimide
  • NIS TV-iodoosuccinimide r.t.: room temperature sat.: saturated h: hour min: minute cone: concentrated v: volume wt: weight M: mass
  • SiO 2 silica br.: broad
  • DIPEA NiV-diisopropylethylamine RT: retention time
  • EDC l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride brine: saturated aqueous sodium chloride solution
  • Electrospray Positive Ionisation Bredereck' s reagent t ⁇ rt-butoxybis(dimethylamino)methane
  • Lawesson's reagent 2,4-bis(4-methoxyphenyl)-l ,3-dithia-2,4-diphosphetane-2,4- disulfide
  • Aqueous HCl solution (2M; 80 mL) was added and the reaction mixture stirred vigorously at r.t. MeOH (80 mL) was added and the reaction mixture was stirred at r.t. for 3 h, then concentrated in vacuo. The residue was dissolved in DCM (150 mL), and DIPEA (9.7 mL, 55.86 mmol) was added. The reaction mixture was cooled to 0 0 C and a solution of di-tert-butyl dicarbonate (9.2 g, 41.89 mmol) in DCM (50 mL) was added. The reaction mixture was stirred at r.t. for 16 h before addition of water (100 mL).
  • the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic fraction was washed with brine (50 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was pre-purified by preparative ⁇ PLC, then partitioned between EtOAc (100 mL) and aqueous sat. NaHCO 3 solution (100 mL). The combined organic fractions were washed with a mixture of brine and water (100 mL), dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Methyl 4-amino-3-iodobenzoate (5 g, 18 mmol) was dissolved in formic acid (35 mL) and the reaction mixture heated at reflux for 90 minutes. Volatiles and formic acid were removed by evaporation in vacuo. The residue was taken up in DCM (200 mL) and washed with sat. NaHCO 3 solution (40 mL). The organic layer was isolated and washed with water (2 x 40 mL), dried (MgSO 4 ) and the solvent removed by evaporation in vacuo. The residue was dissolved in THF (200 mL), BH 3 -Me 2 S (5 mL, 53 mmol) added and the reaction mixture heated at reflux for 90 minutes.
  • Example 3 To a stirred solution of Example 3 (0.103 g, 0.34 mmol) in DCM (15 mL) was added NEt 3 (0.05 mL, 0.36 mmol), followed by a solution of methanesulfonyl chloride (0.03 mL, 0.36 mmol) in DCM (1 mL) dropwise. The reaction mixture was stirred at r.t. for 24 h under a nitrogen atmosphere. Additional methanesulfonyl chloride (0.01 mL, 0.14 mmol) was added and the reaction mixture stirred for a further 24 h before being concentrated in vacuo.
  • Example 10 To a stirred solution of Example 10 (0.20 g, 0.45 mmol) in DMF (5 mL) at 0 0 C was added methyl iodide (0.5 mL, excess), followed by NaH (50 mg, 60% dispersion in oil, excess). The reaction mixture was stirred at this temperature for 5 minutes, and then partitioned between EtOAc (5 mL) and water (5mL). The organic fraction was dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by column chromatography (SiO 2 , 0-5% MeOH/EtOAc) gave the title compound (0.03 g, 16%) as a yellow solid.
  • the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL), then the aqueous layer was separated and extracted into EtOAc (2 x 10 mL). The organic fractions were combined, washed with water (10 mL), brine (10 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo and washed with Et 2 O to give a pale yellow solid. A portion of this solid (0.30 g) was dissolved in AcOH (2 mL) and heated by microwave radiation to 140 0 C for 10 min. The reaction mixture was partitioned between EtOAc (20 mL) and sat. NaHCO 3 solution (20 mL).
  • Example 22 To a stirred solution of Example 22 (0.20 g, 0.4 mmol) dissolved in ethanol (5 mL) and water (5 mL) was added sodium hydroxide (0.10 g, 2.5 mmol) and the reaction mixture heated at reflux for 2 h. Upon cooling, the solvents were removed by evaporation in vacuo and the residue dissolved in water. The resulting solution was neutralized with citric acid, resulting in the precipitation of the title compound which was isolated by filtration, washed with water and dried in vacuo (0.19 g, 98%).

Abstract

A series of fused tricyclic thiazole and thiophene derivatives which are substituted in the 2-position of the thiazole or thiophene ring by an optionally substituted morpholin-4-yl moiety, 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.

Description

TRICYCLIC KINASE INHIBITORS
The present invention relates to a class of fused tricylic thiazole and thiophene derivatives, and to their use in therapy. More particularly, the invention provides a family of fused tricylic thiazole and thiophene derivatives which are substituted in the 2-position of the thiazole or thiophene ring by an optionally substituted morpholin-4-yl moiety. These compounds are selective inhibitors of phosphoinositide 3-kinase (PI3K) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
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. Sci., 2003, 24, 366-376). Aberrant upregulation of the PI3K pathway is implicated in a wide variety of human cancers (cf. S. Brader & S.A. Eccles, Tumori, 2004, 90, 2-8).
The compounds in accordance with the present invention, 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 PI3K enzymes.
Various fused thiazole derivatives are disclosed in Liebigs Annalen der Chemie, 1986, 780-784; and in Russian Journal of General Chemistry (translation oϊZhurnal 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 2006/040281 describes a class of 4,5-dihydrothiazolo[4,5-^]indazoles which are stated to be suitable for use in the treatment of diseases that are characterized by excessive or abnormal cell proliferation. The compounds described in that publication do not, however, possess an optionally substituted morpholin-4-yl moiety at the 2-position of the thiazole ring.
WO 2006/114606 describes a class of fused bicyclic thiazole derivatives which are selective inhibitors of PI3 kinase enzymes and are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions. A related series of compounds is described in copending international patent application no. PCT/GB2007/002390, published on 3 January 2008 as WO 2008/001076.
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 or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC5O 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 PI3Kα and/or PI3Kβ and/or PDKγ and/or PBKδ isoform relative to other human kinases. 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 ;
V represents a covalent bond or a methylene linkage; W represents a covalent bond or a methylene linkage; the moiety X-Y-Q represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;
R1 and R2 independently represent hydrogen, hydroxy or amino; or Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, di(Ci-6)alkylamino, 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
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 - A -
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 Ci-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)- alkynyl, biaryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroaryl(C1-6)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, -SRa, -CORe, -CO2Rb or -CONRcRd; or R5 represents Ci-6 alkyl, C2-6 alkenyl, C2-6 alkenylcarbonyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci.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(Ci-6)alkyl, C3-7 heterocycloalkyl(C2-6)alkenyl, C3-7 heterocycloalkyl- (C2-6)alkynyl, C3-7 heterocycloalkylcarbonyl(C2-6)alkynyl, C5-Q heterobicycloalkyl- (C2-6)alkynyl, C3-7 heterocycloalkyl-aryl, C3-7 heterocycloalkyl(Ci-6)alkyl-aryl, C3-7 heterocycloalkyl -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, heteroaryl-aryl(Ci-6)alkyl, aryl-heteroaryl, aryl-heteroaryl(Ci-6)alkyl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 heterocycloalkyl(Ci-6)alkyl-aryl -heteroaryl, C5-9 heterobicycloalkyl(C i -6)alkyl-aryl -heteroaryl, heteroaryl-aryl-heteroaryl, bi (heteroaryl), C3-7 heterocycloalkylcarbonyl-bi(heteroaryl), aryloxyaryl, aryl(Ci-6)alkoxyaryl, heteroaryl(Ci_6)alkoxyaryl, aryl(Ci-6)alkylaminoaryl, heteroaryl(Ci-6)alkylaminoaryl, C3-7 cycloalkylcarbonylaminoaryl, arylcarbonylaminoaryl, aryl(C i -6)alkylcarbonylaminoaryl, C3-7 heterocycloalkylcarbonylaminoaryl, heteroarylcarbonylaminoaryl, aryl- (C3-7)heterocycloalkylcarbonylaminoaryl, arylsulphonylaminoaryl, aryl(C i -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 -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 i -6)alkylaryl, C3-7 heterocycloalkyl(C i -6)alkylaminocarbonyl(C i -6)alkylaryl, heteroarylaminocarbonyl(C i -6)alkylaryl, heteroaryl(C i -6)alkylaminocarbonyl(C i -6)alkyl- aryl, arylaminoheteroaryl, C3-7 heterocycloalkylamino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonylamino-aryl-heteroaryl, C3-7 heterocycloalkylaminocarbonyl- amino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(Ci.6)alkylcarbonyl-aryl-heteroaryl, Cs.g heterobicycloalkylcarbonyl-aryl- heteroaryl, C3-7 heterocycloalkylcarbonyl(Ci.6)alkyl-aryl-heteroaryl, C3-7 heterocycloalkyl- aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(C i -6)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 Ci-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 (aryl)(heteroaryl)(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; Rd represents hydrogen or Ci-6 alkyl; Re represents Ci-6 alkyl; R6 is absent when V represents a covalent bond; or R6 represents hydrogen, hydroxy, oxo or -NR6aR6b; and R6a and R6b independently represent hydrogen, Ci-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
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 - (Ci-6)alkyl, heteroaryl or heteroaryl(Ci-6)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, C5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; and
U, V, W, the moiety X-Y-Q, R3, R4 and R6 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, where possible, by one or more substituents. Typically, such groups will be unsubstituted, or substituted, where possible, by one or two substituents. Suitably, such groups will be unsubstituted or, where possible, monosubstituted.
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 Ci-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, w-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci-6 alkoxy", "Ci-6 alkylthio", "Ci-6 alkylsulphonyl" and "Ci-6 alkylamino" are to be construed accordingly.
Typical 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, phenyl ethyl, 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-phenylprop-l-yn-l-yl and 3-phenylprop-2-yn-l-yl. A specific aryl(C2-6)alkynyl group is 3-phenylprop-2-yn-l- yi. Particular biaryl groups include biphenyl and naphthylphenyl.
Suitable heterocycloalkyl groups, which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and 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-ό]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrazolyl, pyrazolo[l,5-α]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2-α]pyridinyl, imidazo[4,5-&]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl, quinoxalinyl and chromenyl groups.
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, the moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl. In another embodiment, the moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted six- membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Suitably, the moiety X-Y-Q represents a pyrazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl or pyrimidinyl ring, any of which may be optionally substituted, where possible, by one or more substituents.
The five-membered or six-membered heteroaromatic ring represented by the moiety X-Y-Q in the compounds of formula (I) above may be unsubstituted, or may suitably be substituted, where possible, by one more, typically by one or two, substituents. In one embodiment, this ring is unsubstituted. In another embodiment, this ring is monosubstituted. hi a further embodiment, this ring is disubstituted. Examples of typical substituents on the five-membered or six-membered heteroaromatic ring as specified for the moiety X-Y-Q include Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci.6)alkyl, aryl, aryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, heteroaryl, heteroaryl(Ci-6)alkyl, hydroxy, Ci-6 alkoxy, Ci-6 alkyl thio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkyl carbonyl, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, halogen, cyano and trifluoromethyl. Examples of particular substituents include Ci-6 alkyl, hydroxy and Ci-6 alkylsulphonyl. Examples of suitable substituents include Ci-6 alkyl and Ci-6 alkylsulphonyl.
In one embodiment of the present invention, U represents N. In accordance with that embodiment, the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000010_0001
(A)
wherein
V, W, the moiety X-Y-Q, R1, R2, R3, R4 and R6 are as defined above. In another embodiment of the present invention, U represents C-R5. In accordance with that embodiment, the present invention provides a compound of formula (B), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0001
(B)
wherein
V, W, the moiety X-Y-Q, R1, R2, R3, R4, R5 and R6 are as defined above. Specific sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA), (IB), (IC), (ID), (IE) and (IF):
Figure imgf000011_0002
Figure imgf000012_0001
wherein U, V, W, R1, R2, R3, R4 and R6 are as defined above;
Rx represents hydrogen, 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, heteroaryl(Ci-6)alkyl, Ci-6 alkylsulphonyl or C2-6 alkylcarbonyl; and
Ry and Rz independently represent hydrogen, 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, heteroaryl(Ci-6)alkyl, hydroxy, Ci-6 alkoxy, Ci-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkylcarbonyl, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, halogen, cyano or trifluoromethyl.
Where U represents C-R5, a particular sub-class of compounds in accordance with the present invention is represented by the compounds of formula (IA) as depicted above. Where U represents N, particular sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA), (IB), (IC), (ID), (IE) and (IF) as depicted above.
Suitably, Rx represents hydrogen or Ci-6 alkylsulphonyl. In one embodiment, R" represents hydrogen. In another embodiment, R" represents Ci-6 alkylsulphonyl, especially methylsulphonyl.
Suitably, Ry and Rz independently represent hydrogen, Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci.6)alkyl, aryl, aryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 hetero- cycloalkyl(Ci-6)alkyl, heteroaryl, heteroaryl(Ci_6)alkyl, Ci-6 alkoxy, Ci-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkylcarbonyl, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, halogen, cyano or trifluoromethyl.
Typical values of Ry and/or Rz include hydrogen, hydroxy and Ci-6 alkyl.
Suitable values of Ry and/or Rz include hydrogen and Ci-6 alkyl.
In one embodiment, Ry represents hydrogen. In another embodiment, Ry represents Ci-6 alkyl, especially methyl. In a further embodiment, Ry represents hydroxy.
In one embodiment, Rz represents hydrogen. In another embodiment, Rz represents Ci-6 alkyl, especially methyl.
In one embodiment, V represents a covalent bond. In another embodiment, V represents a methylene linkage. In one embodiment, W represents a covalent bond. In another embodiment, W represents a methylene linkage.
Suitably, R1 represents hydrogen or Ci-6 alkyl. Typical values of R1 include hydrogen, methyl and ethyl. In 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 Ci-6 alkyl, Ci-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, Ci-6 alkyl, trifluoromethyl, hydroxy, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci-6 alkylthio, Ci-6 alkylsulphonyl, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, 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, Ci-6 alkylaminosulphonyl and di(Ci-6)alkylaminosulphonyl; especially halogen, Ci-6 alkoxy or Ci-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, R1 and R2, when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage. Thus, R1 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, substituents. In 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-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the ring containing the variable V and/or W. Thus, R1 and R2, 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, 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 V and/or W. 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 V and/or W.
Typically, R3 represents hydrogen; or Ci-6 alkyl, aryl, aryl(Ci-6)alkyl, aryl- (C2-6)alkynyl, biaryl(Ci-6)alkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C3-7 heterocycloalkyl- carbonyl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Generally, R3 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, R3 represents aryl(Ci-6)alkyl or heteroaryl(Ci-6)alkyl, either of which groups may be optionally substituted by one or more substituents.
In one specific embodiment, R3 represents hydrogen.
In a representative embodiment, R3 represents Ci-6 alkyl, aryl(Ci-6)alkyl, biaryl- (Ci-6)alkyl, heteroaryl(Ci-6)alkyl or heteroaryl-aryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents. Preferably, R3 represents methyl, arylmethyl, biarylmethyl, heteroarylmethyl or heteroaryl-arylmethyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R3 represents arylmethyl or heteroarylmethyl, either 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- (Ci-6)alkyl. Advantageously, R3 represents substituted or unsubstituted benzyl.
In another embodiment, R3 represents substituted or unsubstituted benzofuryl- (Ci-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[2,3-6]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.
Suitably, R4 represents hydrogen or optionally substituted Ci-6 alkyl. Examples of typical substituents on R and/or R4 include halogen, cyano, nitro, Ci-6 alkyl, trifluoromethyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci-6)alkylaryl, di(Ci-6)alkylaryl, piperidinyl(C i -6)alkylaryl, piperazinyl(C i -6)alkylaryl, (C i -6)alkylpiperazinyl(C i .(,)- alkylaryl, morpholinyl(Ci-6)alkylaryl, (Ci-6)alkoxyaryl, cyano(Ci-6)alkoxyaryl, di(Ci-6)- alkylamino(Ci-6)alkylaryl, (Ci-6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, oxazolinyl, azetidinyl, pyrrolidinyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di- (Ci-6)alkylaminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonyl- piperidinyl, di(C1-6)alkylaminocarbonylpiperidinyl, piperazinyl, (Ci-6)alkylpiperazinyl, haloarylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (C i .6)alkylhomopiperazinyl, moφholinyl, (C i -6)alkylpiperazinyl(C i -6)alkyl, moφholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(Ci-6)- alkylpyrazolyl, tri(Ci-6)alkylpyrazolyl, [di(Ci-6)alkyl](trifluoromethyl)pyrazolyl, cyano- (C i -6)alkylpyrazolyl, [cyano(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, hydroxy(C i -6)alkyl- pyrazolyl, [hydroxy(C i .6)alkyl] [di(C i -6)alkyl]pyrazolyl, methoxy(C i -6)alkylpyrazolyl, [(hydroxy)(methoxy)(Ci-6)alkyl]pyrazolyl, amino(Ci-6)alkylpyrazolyl, [(Ci-6)alkyl][amino- (Ci-6)alkyl]pyrazolyl, [amino(Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(Ci-6)alkylamino(C1-6)- alkylpyrazolyl, di(Ci-6)alkoxyphosphono(Ci.6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl(C1-6)alkylρyrazolyl, [(C3-7)cycloalkyl(Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, [(C i -6)alkyl] (aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(C i -6)alkylpyrazolyl, aminoaryl(Ci-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(Ci-6)alkyl- pyrazolyl, [di(Ci-6)alkyl][tetrahydropyranyl(Ci.6)alkyl]pyrazolyl, pyrrolidinyl(Ci-6)alkyl- pyrazolyl, piperidinyl(Ci.6)alkylpyrazolyl, (Ci.6)alkylpiperidinyl(Ci-6)alkylpyrazolyl, morpholinyl(C i .6)alkylpyrazolyl, pyridinyl(C i -6)alkylpyrazolyl, oxypyridinyl(C i -6)alkyl- pyrazolyl, [arylcarbonyl(Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, [(Ci-6)alkyl](piperazinyl- carbonyl)pyrazolyl, [(C i .6)alkylaminocarbonyl] [(C i -6)alkylaryl]pyrazolyl, [(C i -6)alkyl] - [amino(Ci-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(Ci.6)alkylpyrazolyl,
[aminocarbonyl(Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(Ci-6)alkylaminocarbonyl(Ci.6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(Ci-6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]- isoxazolyl, thiazolyl, di(Ci-6)alkylthiazolyl, imidazolyl, (C|-6)alkylimidazolyl, di(Ci-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkylimidazo[l,2-α]pyridinyl, (Ci-6)- alkylimidazo[4,5-b]pyridinyl, imidazo[l,2-α] pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)- alkylthiadiazolyl, triazolyl, pyridinyl, halopyridinyl, (Ci-6)alkylpyridinyl,
Figure imgf000017_0001
(halo)pyridinyl, di(Ci.6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (Ci-6)alkylpiperazinyl- pyridinyl, [(Ci-6)alkyl](piperazinyl)pyridinyl, [(Cι-6)alkoxycarbonylpiperazinyl][(Ci-6)- alkyl]pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (Ci.6)alkoxypyridinyl, [(Ci-6)alkoxy]- [(C,-6)alkyl]pyridinyl, [(Ci-6)alkoxy][di(Ci-6)alkyl]pyridinyl, (Ci-6)alkoxy(Ci-6)alkyl- pyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (Ci-6)alkoxycarbonyl(Ci-6)alkyl- pyridinyl, pyridazinyl, (Ci_6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Ci-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(Ci-6)alkylaminopyridazinyl, di- (Ci-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(Ci-6)alkyl](halo)- pyrimidinyl, di(Ci-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinyl- pyrimidinyl, [(Ci-6)alkyl](piperazinyl)pyrimidinyl, [(Ci-6)alkoxycarbonyl][(Ci-6)alkyl]- piperazinylpyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(Ci-6)- alkyl] [hydroxy(C i -6)alkyl]pyrimidinyl, [(C i ^alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (Ci-6)alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminopyrimidinyl, [di(Ci-6)alkyl- amino](halo)pyrimidinyl, carboxypyrimidinyl, [(C i -6)alkoxycarbonyl(C i -6)alkyl] [(C i ^)- alkyl] pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (Ci-6)alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(Ci.6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy, morpholinyl(Ci-6)- alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i -6)alkylpyrazolyl- pyridinyloxy, (Ci-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy, (Ci-6)alkylpyrimidinyloxy, [(C i -6)alkyl] (halo)pyrimidinyloxy, hydroxy(C i -6)alkyl, dihydroxy(C i -6)alkyl, pyridinyloxy(Ci-6)alkyl, methylenedioxy, trifluoromethylenedioxy, amino, (Ci-6)alkyl- amino, dihydroxy(Ci-6)alkylamino, (Ci-6)alkoxy(Ci-6)alkylamino, di(Ci-6)alkylamino, N- [(C i -6)alkoxy(C i -6)alkyl]-N-[(C i -6)alkyl] amino, di(C i _6)alkylamino(C i -6)alkylamino, N- [(Ci-6)alkyl]-N-[di(C,-6)alkylamino(C,-6)alkyl]amino, N-[(Ci-6)alkyl]-N-[(C3-7)cycloalkyl]- amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, methylenedioxyphenylamino, morpholinyl(C i -6)alkylphenylamino, oxazolinylphenylamino, [(C i -6)alkyl] (oxo)pyrazolyl- phenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, (C i -6)alkyltriazolylphenylamino, (C i -6)alkylpyrimidinylphenylamino, pyrazolyl(C i -6)alkyl- phenylamino, triazolyl(Ci-6)alkylphenylamino, Ci-6 alkylsulphonylaminophenylamino, moφholinylcarbonylphenylamino, Ci-6 alkylsulphonylphenylamino, moφholinylsulphonylphenylamino, 7V-[(Ci-6)alkyl]-N-[aryl(Ci-6)alkyl]amino, N-[di(Ci-6)alkylamino(Ci-6)alkyl]-iV-[aryl(Ci-6)alkyl]amino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(C i -6)alkylamino, methylenedioxyaryl(C i -6)alkylamino, dihydrobenzofuranylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpyrrolidinyl]amino, Cj-6 alkylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-[(Ci-6)alkyl]-N- (piperidinyl)amino, iV-[(C3-7)cycloalkyl(Ci-6)alkyl]-N-(piperidinyl)amino, (Ci-6)alkyl- piperidinylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpiperidinyl]amino, N-[(Ci-6)alkyl]-
N-[(C3-7)cycloalkylpiperidinyl]amino, Λ/-[(Ci.6)alkyl]-iV-[(C2-6)alkylcarbonylpiperidinyl]- amino, dihydroquinolinonylamino, benzoxazinonylamino, pyiτolidinyl(Ci-6)alkylaniino, N-[(C,-6)alkyl]-N-[pyrrolidinyl(C,-6)alkyl]amino, 7V-[(Ci-6)alkyl]-N-[piperidinyl(C,-6)- alkyl]amino, benzothienylamino, indolylamino, dioxoindolylamino, (Ci-6)alkylpyrazolyl- amino, [(C i -6)alkyl] (halo)pyrazolylamino, di(C i -6)alkylpyrazolylamino, tri(C i .6)alkyl- pyrazolylamino, N- [(C i -6)alkyl] -7V-[(C i .6)alkylpyrazolyl] amino, (C i -6)alkylindazolylamino, benzoxazolylamino, benzoxazolonylamino, di(Ci-6)alkylisoxazolylamino, thiazolylamino, benzothiazolylamino, (Ci-6)alkylisothiazolylamino, imidazolylamino, [(Ci-6)alkoxy- carbonyl] [(C i -6)alkyl] imidazolylamino, (C i -6)alkylbenzimidazolylamino, benzimidazolonylamino, di(Ci-6)alkylbenzimidazolonylamino, (Ci-6)alkyloxadiazolyl- amino, furyloxadiazolylamino, (Ci.6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (Ci-6)alkylpyridinylamino, di(Ci-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C i -6)alkylpyridinylamino, dihydroxy(C i -6)alkylpyridinylamino, (C i -6)alkoxypyridinylamino, dihydroxy(C i -6)alkoxy- pyridinylamino, di(Ci-6)alkyldioxolanyl(Ci-6)alkoxypyridinylamino, (Ci-^aIkOXy(Ci-6)- alkylpyridinylamino, (C i -6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C i -6)alkyl- aminopyridinylamino, di(C i-6)alkylaminopyridinylamino, (C i -6)alkylamino(C i -6)alkyl- pyridinylamino, di(C i -6)alkylamino(C i -6)alkylpyridinylamino, oxopyridinylamino, carboxypyridinylamino, ^[(Ci-^alkylJ-N-f^i^alkylpyridiny^amino, bis[(Ci-6)alkyl- pyridinyl] amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, (Ci-6)alkyl- pyridazinylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpyridazinyl]amino, N-[aryl(Ci-6)alkyl]-iV- [(C i .6)alkylpyridazinyl] amino, di(C i -6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (Ci-6)alkoxypyridazinylamino, [(Ci-6)alkoxy](halo)- pyridazinyl amino, di (C i -6)alkylaminopyridazinylamino, bis[(C i -6)alkylpyridazinyl]amino, (C i -6)alkylcinnolinylamino, oxopyrimidinylamino, thioxopyrimidinylamino, quinoxalinylamino, (Ci_6)alkylchromenylamino, benzofuryl(Ci-6)alkylamino, thienyl(Ci-6)- alkylamino, indolyl(Ci-6)alkylamino, (Ci-6)alkylpyrazolyl(Ci.6)alkylamino, [di(Ci-6)alkyl]- (halo)pyrazolyl(Ci-6)alkylamino, di(Ci-6)alkylisoxazolyl(Ci-6)alkylamino, thiazolyl(Ci-6)- alkylamino, imidazolyl(C i -6)alkylamino, (C i -6)alkylimidazolyl(C i ^alkylamino, pyridinyl(C i -6)alkylamino, (C i _6)alkylpyridinyl(C i -6)alkylamino, N-[(C i -6)alkyl]-N- [pyridinyl(C i -6)alkyl] amino, N-[dihydroxy(Ci -6)alkyl] -./V-[pyridinyl(C i -6)alkyl] amino, N- [(C i -6)alkylpyridinyl(C i -6)alkyl]-N-[dihydroxy(C i -6)alkyl] amino, amino(C i -6)alkyl, (Ci-6)- alkylamino(Ci-6)alkyl, di(Ci-6)alkylamino(Ci-6)alkyl, pyridinylamino(Ci-6)alkyl, C2-6 alkylcarbonylamino, 7V-[(C2-6)alkylcarbonyl] -N- [(C i -6)alkylpyridinyl(C i -6)alkyl]amino, di(C1-6)alkylamino(Ci-6)alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, (C3-7)- cycloalkylcarbonylamino, (C i -6)alkylpiperidinylcarbonylamino, (C i -6)alkylimidazolyl- carbonylamino, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl] [(C i-6)alkyl] amino, C1-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, [hydroxy(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)- alkylamino(C i -6)alkyl]aminocarbonyl, di(C i -6)alkylaminocarbonyl, [(C i -6)alkyl] [cyano- (C i -6)alkyl] aminocarbonyl, [(C i -6)alkyl] [hydroxy(C i -6)alkyl]aminocarbonyl, [(C i -6)alkoxy- (C i -6)alkyl] [(C i -6)alkyl]aminocarbonyl, [di(C i -6)alkylamino(C i -6)alkyl] [(C i -6)alkyl] aminocarbonyl, C3-7 cycloalkyl(Ci-6)alkylaminocarbonyl, aryl(Ci-6)alkylaminocarbonyl, (C I-6)- alkylpiperidinylaminocarbonyl, N-[(Ci-6)alkyl]-7V-[(Ci-6)alkylpiperidinyl]aminocarbonyl, piperidinyl(C i -6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C i -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-6)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(C i -6)alkyldioxaborolanyl. Particular examples of typical substituents on R3 and/or R4 include halogen, cyano, Ci-6 alkyl, (Ci-6)alkylpyrazolyl, C2-6 alkoxycarbonyl and di(Ci-6)alkylaminocarbonyl. A further example is carboxy.
Selected examples of specific substituents on R3 and/or R4 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifiuoromethyl, 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, 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, moφholinylethylpyrazolyl, 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- αjpyridinyl, methylimidazo[l,2-α]pyridinyl, methylimidazo[4,5-b]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, 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, 7V-(methoxyethyl)-N- (methyl)amino, N-(methoxypropyl)-N-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, Λr-(dimethylaminoethyl)-iV-(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, moφholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenylaminό, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenylamino, triazolylmethylphenylamino, methylsulphonylamino- phenylamino, morpholinylcarbonylphenylamino, methylsulphonylphenylamino, moφholinylsulphonylphenylamino, 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, benzothienylamino, indolylamino, dioxoindolylamino, methylpyrazolylamino, (bromo)(methyl)pyrazolyl- amino, dimethylpyrazolylamino, trimethylpyrazolylamino, N-(ethyl)-N-(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, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, oxopyridinylamino, carboxypyridinylamino, N-(methyl)-N-(methylpyridinyl)- amino, N-(ethyl)-N-(methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-N- (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, benzofurylmethylamino, thienylmethylamino, indolylmethylamino, methylpyrazolyl- methylamino, (chloro)(dimethyl)pyrazolylmethylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethylamino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethylamino, N-(methyl)-N-(pyridinylethyl)- amino, iV-(dihydroxypropyl)-N-(pyridinylmethyl)amino, 7V-(dihydroxypropyl)-./V-
(methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, acetylamino, N-(acetyl)-7V-(methylpyridinyl)amino, dimethylaminoethylcarbonylamino, acetylaminomethyl, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, methoxycarbonyl- amino, N-methoxycarbonyl-TV-methylamino, methylsulphonylamino, formyl, acetyl, acetyl oxime, acetyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethyl- aminoethyl)aminocarbonyl, ( 1 -hydroxyprop-2-yl)aminocarbonyl, dimethyl aminocarbonyl, N-(cyanomethyl)-N-methylaminocarbonyl, N-(cyanoethyl)-N-methylamino- carbonyl, N-(hydroxyethyl)-7V-methylaminocarbonyl, N-(methoxyethyl)-N-methyl- aminocarbonyl, N-(dimethylaminoethyl)-N-methylaminocarbonyl, N-isopropyl-N-methyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(methylpiperidinyl)amino- carbonyl, piperidinylethylaminocarbonyl, pyrazolylaminocarbonyl, 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, tert-butoxycarbonyloxy, trimethylsilyl and tetramethyl- dioxaborolanyl. Particular examples of specific substituents on R3 and/or R4 include bromo, cyano, methyl, methylpyrazolyl, methoxycarbonyl and dimethylaminocarbonyl. A further example is carboxy.
Typical values of R3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, TV-methyl-TV-phenylaminomethyl, pyridinylamino- methyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyl- methylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolyl- phenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazolylphenylaminobenzyl, methylpyrimidinylphenylaminobenzyl, pyrazolylmethylphenylaminobenzyl, triazolylmethylphenylaminobenzyl, methylsulphonylaminophenylaminobenzyl, moφholinylcarbonylphenylaminobenzyl, 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, 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 oximejindolylmethyl, [acetyl 0-(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, (dimethylaminoethytyaminocarbonylindolylmethyl, ( 1 -hydroxyprop-2-yl)aminocarbonyl- indolylmethyl, dimethylaminocarbonylindolylmethyl, (dimethylaminocarbonyl)(methyl)- indolylmethyl, (chloro)(dimethylaminocarbonyl)indolylmethyl, bis(dimethylamino- carbonyl)indolylmethyl, N-(cyanomethyl)-7V-methylaminocarbonylindolylmethyl, [N- (cyanomethy^-N-methylaminocarbonylJCmethyOindolylmethyl, 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-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, morpholinylcarbonylindolylmethyl, methylsulphonylindolylmethyl, methylsulphonylmethylindolylmethyl, dimethylaminosulphonylindolylmethyl, trimethylsilylindolylmethyl and pyrrolo[3,2-c]pyridinylmethyl. Representative values of R3 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, (carboxy)(methyl)- indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, dimethylaminocarbonylindolylmethyl and (dimethylaminocarbonyl)(methyl)indolyl- methyl.
Particular values of R3 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, methoxycarbonylindolylmethyl and dimethylaminocarbonylindolylmethyl.
Typical values of R4 include hydrogen and methyl. In a preferred embodiment, R4 is hydrogen. In another embodiment, R4 is Ci-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 cyclopentyl ring, i.e. an indanyl moiety fused to the morpholine ring, which indanyl moiety may be unsubstituted, or substituted by one or more, typically by one or two, substituents. Examples of typical substituents on the fused rings referred to in the preceding paragraph include halogen, nitro, Ci-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci-6)alkylaryl, di(C i -6)alkylaryl, piperidinyl(C i -6)alkylaryl, piperazinyl(C i -6)alkylaryl, (C i -6)alkylpiperazinyl(C i -6)alkylaryl, morpholinyl(C i _6)alkylaryl, (C i -6)alkoxyaryl, cyano(C i -6)alkoxyaryl, di(C i -6)alkylamino(C i -6)alkylaryl, (C i .6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (Ci-6)alkylaminocarbonylpiperidinyl, piperazinyl, (Ci-6)alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (Ci-6)alkyl- homopiperazinyl, (Ci.6)alkylpiperazinyl(Ci-6)alkyl, moφholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(Ci-6)alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, [di(Ci-6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano- (C i -6)alkyl] [di(C i -6)-alkyl]pyrazolyl, hydroxy^ -6)alkylpyrazolyl, [hydroxy(C i -6)- alkyl][di(Ci-6)alkyl]pyrazolyl, methoxy(Ci-6)alkylpyrazolyl, [(hydroxy)(methoxy)(C1-6)- alkyl]pyrazolyl, amino(Ci-6)alkylpyrazolyl, [(Ci-6)alkyl][amino(Ci-6)alkyl]pyrazolyl, [amino(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, di^i^alkylamino^i-^alkylpyrazolyl, di(C1-6)alkoxyphosphono(Ci-6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl- (Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(Ci-6)alkyl]- (aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(Ci-6)alkylpyrazolyl, aminoaryl- (Ci_6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(C1-6)alkylpyrazolyl, [di- (C i -6)alkyl] [tetrahydropyranyl(C i -6)alkyl]pyrazolyl, pyrrolidinyl(C i -6)alkylpyrazolyl, piperidinyl(C i.6)alkylpyrazolyl, (C i -6)alkylpiperidinyl(C i -6)alkylpyrazolyl, morpholinyl(C i -6)alkylpyrazolyl, pyridinyl(C i -6)alkylpyrazolyl, oxypyridinyl(C i -6)alkyl- pyrazolyl, [arylcarbonyl(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, [(C i -6)alkyl] (piperazinyl- carbonyl)pyrazolyl, [(Ci.6)alkylaminocarbonyl][(Ci.6)alkylaryl]pyrazolyl, [(Ci-6)alkyl]- [amino(Ci.6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(Ci-6)alkylpyrazolyl, [aminocarbonyl(Ci.6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(Ci-6)alkylaminocarbonyl(Ci-6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(Ci-6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]- isoxazolyl, thiazolyl, di(Ci-6)alkylthiazolyl, imidazolyl, (Ci-6)alkylimidazolyl, di(Ci_6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (Ci-6)alkylimidazo[l,2-α]pyridinyl, (C I-6)- alkylimidazo[4,5-ό]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)- alkylthiadiazolyl, pyridinyl, halopyridinyl, (Ci-6)alkylpyridinyl, [(Ci-6)alkyl](halo)- pyridinyl, di(Ci-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (Ci-6)alkylpiperazinylpyridinyl, [(C i -6)alkyl](piperazinyl)pyridinyl, [(C i -6)alkoxycarbonylpiperazinyl] [(C i -6)alkyl] - pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(C i -6)alkylpyridinyl, (C i -6)alkoxypyridinyl, [(C i _6)alkoxy] [(C i .6)alkyl]pyridinyl, [(C i -6)alkoxy] [di(C i -6)alkyl]pyridinyl, (C i ,6)alkoxy(C i -6)alkylpyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (Ci^alkoxycarbony^Ci^alkylpyridinyl, pyridazinyl, (C1-6)- alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Ci-6)alkoxypyridazinyl, aminopyridazinyl, hydro xy(C i -6)alkylaminopyridazinyl, di(C i -6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(C1-6)alkyl](halo)pyrimidinyl, di(Ci-6)alkyl- pyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinylpyrimidinyl, [(C i -6)alkyl](piperazinyl)pyrimidinyl, [(C i -6)alkoxycarbonyl] [(C i -6)alkyl]piperazinyl- pyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(Cι-6)alkyl]- [hydroxy(C i -6)alkyl]pyrimidinyl, [(C i -6)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (C i -6)- alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminopyrimidinyl, [di(Ci-6)alkyl- amino](halo)pyrimidinyl, carboxypyrimidinyl, [(Ci-6)alkoxycarbonyl(Ci-6)alkyl][(Ci-6)- alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (C1-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (Ci-6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy, morpholinyl- (Ci-6)alkoxy, aryloxy, haloaryloxy, di(C1-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i -6)alkylpyrazolyl- pyridinyloxy, (Ci-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy, (Ci-6)alkylpyrimidinyloxy, [(C i .6)alkyl](halo)pyrimidinyloxy, hydroxy(C i -6)alkyl, dihydroxy(C i -6)alkyl, pyridinyloxy(Ci-6)alkyl, amino, (Ci-6)alkylamino, dihydroxy(Ci-6)alkylamino, (Ci-6)- alkoxy(C i -6)alkylamino, N- [(C i -6)alkoxy(C i -6)alkyl] -N- [(C i -6)alkyl] amino, di(C i -6)- alkylamino(C i -6)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, N-[(Ci-6)alkyl]-N-(haloaryl)amino, N-[(C1-6)alkyl]-N-[aryl(Ci-6)alkyl]amino, N-[di(Ci-6)alkylamino(C1-6)alkyl]-N-[aryl(Ci-6)- alkyl] amino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(Ci-6)alkylamino, methyl ene- dioxyaryl(Ci-6)alkylamino, N-[(Ci-6)alkyl]-N-[(C1-6)alkylpyrrolidinyl]amino, piperidinyl- amino, N-[(Ci-6)alkyl]-N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(C1-6)alkyl]-N- (piperidinyl)amino, (Ci-6)alkylpiperidinylamino, N-[(Ci-6)alkyl]-N-[(Ci.6)alkyl- piperidinyl] amino, N-[(Ci-6)alkyl]-N-[(C3.7)cycloalkylpiperidinyl]amino, N-[(Ci-6)alkyl]- N-[(C2-6)alkylcarbonylpiperidinyl]amino, pyrrolidinyl(Ci-6)alkylamino, N-[(Ci.6)alkyl]-N-
Figure imgf000028_0001
N-[(Ci-6)alkyl]-N-[piperidinyl(C|-6)alkyl]amino, (Ci-6)- alkylpyrazolylamino, di(Ci.6)alkylpyrazolylamino, tri(Ci-6)alkylpyrazolylamino, N-[(C1-6)- alkyl]-N-[(Ci-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(Ci-6)alkoxy- carbonyl][(Ci-6)alkyl]imidazolylamino, (Ci-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (Ci-6)alkylpyridinylamino, di(C1-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(Ci-6)alkylpyridinylamino, dihydroxy(C i -6)alkylpyridinylamino, (C i -6)alkoxypyridinylamino, dihydroxy(C i -6)alkoxy- pyridinylamino, di(C i -6)alkyldioxolanyl(C i -6)alkoxypyridinylamino, (C i -6)alkoxy(C i -6)- alkylpyridinylamino, (C i -6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C i -6)alkyl- aminopyridinylamino, di(C i -6)alkylaminopyridinylamino, (C 1-6)alkylamino(C i -6)alkyl- pyridinylamino, di(Ci-6)alkylamino(Ci-6)alkylpyridinylamino, carboxypyridinylamino, TV- [(C i -6)alkyl] -N-[(C i -6)alkylpyridinyl] amino, bis[(C i -6)alkylpyridinyl] amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (Ci-6)alkylpyridazinylamino, N-[(Ci.6)alkyl]- N-[(C ! -6)alkylpyridazinyl] amino, N-[aryl(C i -6)alkyl]-N-[(C i ^alkylpyridazinyl] amino, di(Ci-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C1-6)- alkoxypyridazinylamino, di(Ci-6)alkylaminopyridazinylamino,
Figure imgf000029_0001
amino, benzofuryl(Ci-6)alkylamino, thienyl(Ci-6)alkylamino, indolyl(Ci-6)alkylamino, (C i .6)alkylpyrazolyl(C i -6)alkylamino, [di(C i -6)alkyl](halo)pyrazolyl(C i -6)alkylamino, di(C i .6)alkylisoxazolyl(C i -6)alkylamino, thiazolyl(Cj -6)alkylamino, imidazolyl(C \ -6)alkyl- amino, (Ci-6)alkylimidazolyl(Ci-6)alkylamino, pyridinyl(Ci-6)alkylamino, (Ci-6)alkyl- pyridinyl(Ci-6)alkylamino, Λ/-[(Ci-6)alkyl]-N-[pyridinyl(Ci-6)alkyl]amino, N-[dihydroxy- (C i -6)alkyl] -N- [pyridinyl(C i -6)alkyl] amino, N- [(C i -6)alkylpyridinyl(C i -6)alkyl] -N- [dihydroxy(Ci.6)alkyl]amino, amino(Ci-6)alkyl, (Ci-6)alkylamino(Ci-6)alkyl, di(Ci-6)alkyl- amino(Ci-6)alkyl, pyridinylamino(Ci-6)alkyl, 7V-[(C2-6)alkylcarbonyl]-N-[(Ci.6)alkyl- pyridinyl(C \ -6)alkyl]amino, di(C i -6)alkylamino(C i -6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (Ci.6)alkylpiperidinylcarbonylamino, (Ci-6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (Ci-^alkylpiperidinylaminocarbonyl, N-[(Ci-6)alkyl]-7V-[(C1-6)- alkylpiperidinyl] aminocarbonyl, piperidinyl(C i -6)alkylaminocarbonyl, (C i -6)alkyl- piperazinylcarbonyl, Ci-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy and tetra(Ci-6)alkyldioxaborolanyl. A particular example of a typical substituent on the fused rings referred to in the two preceding paragraphs is (Ci-6)alkylpyrazolyl.
Selected examples of specific substituents on the fused rings referred to in the three preceding paragraphs include bromo, nitro, methyl, «-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methyl- propylpyrazolyl, 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, 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[ 1 ,2-α]pyridinyl, methylimidazo[4,5-6]pyridinyl, imidazo[ 1 ,2- αjpyrimidinyl, imidazo[l,2-α]pyrazinyl, methylthiadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methyl- piperazinyl)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, ethoxycarbonylmethylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylaminopyridazinyl, pyrimidinyl, methyl- pyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)(piperazinyl)pyrimidinyl, (tert-butoxycarbonyl- piperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxy- propynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylamino- pyrimidinyl, (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, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)- pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1-methylethyl, dihydroxypropyl, pyridinyloxymethyl, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, 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, fluorophenyl- amino, N-fluorophenyl-N-methylamino, N-benzyl-N-methylamino, N-(benzyl)-N- (dimethylaminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)benzylamino, methylenedioxybenzylamino, N-(methyl)-N-(methyl- pyrrolidinyl)amino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N- (piperidinyl)amino, N-(cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinyl- amino, N-(methyl)-N-(methylpiperidinyl)amino, N-(methyl)-N-(2-methylpropyl- piperidinyl)amino, N-(cyclopentylpiperidinyl)-N-(methyl)amino, N-(acetylpiperidinyl)-N- (methyl)amino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N- (pyrrolidinylethyl)amino, 7V-(methyl)-N-(pyrrolidinylpropyl)amino, JV-(methyl)-N- (piperidinylmethyl)amino, methylpyrazolylamino, dimethylpyrazolylamino, trimethylpyrazolylamino, 7V-(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, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, carboxypyridinylamino, N-(methyl)-N-(methylpyridinyl)amino, JV-(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, 7V-(dihydroxypropyl)-Λ/-(methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, 7V-(acetyl)-N-(methyl- pyridinyl)amino, dimethylaminoethylcarbonylamino, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, formyl, acetyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(methylpiperidinyl)aminocarbonyl, piperidinylethylaminocarbonyl, methylpiperazinylcarbonyl, isopropylthio, isopropyl- sulphinyl, isopropylsulphonyl, tert-butoxycarbonyloxy and tetramethyldioxaborolanyl. A particular example of such a substituent is methylpyrazolyl. Suitably, Ra represents substituted or unsubstituted aryl. Suitably, Rc represents hydrogen; or aryl, aryl(Ci-6)alkyl, heteroaryl(Ci-6)alkyl or
(aryl)(heteroaryl)(C|-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 include halogen, cyano, nitro, Ci-6 alkyl, trifluoromethyl, hydroxy, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci-6 alkylthio, Ci-6 alkylsulphonyl, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylamino- carbonyl, di(Ci-6)alkylaminocarbonyl, aminosulphonyl, Ci-6 alkylaminosulphonyl and di(C i -6)alkylaminosulphonyl.
Examples of particular substituents on Ra and/or Rb and/or Rc include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl . A particular value of Ra is phenyl.
In one embodiment, Rb represents hydrogen. In another embodiment, Rb represents Ci-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 Ci-6 alkyl, especially methyl or ethyl, particularly ethyl.
Suitably, Re represents methyl.
Generally, R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb or -CONRcRd; or R5 represents Ci-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 heterocycloalkyl(Ci-6)alkyl, 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(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, aryl-heteroaryl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 heterocycloalkyl (C i-6)alkyl-aryl -heteroaryl, C5-9 heterobicycloalkyl(C i -6)alkyl-aryl-heteroaryl, heteroaryl-aryl -heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl-bi(heteroaryl), aryloxyaryl, aryl(Ci.6)alkoxyaryl, heteroaryl(Ci-6)alkoxyaryl, aryl(Ci-6)alkylaminoaryl, heteroaryl(Ci.6)alkylaminoaryl, C3-7 cycloalkylcarbonylaminoaryl, arylcarbonylaminoaryl, aryl(C i -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(C1-6)alkyl- aminocarbonylaminoaryl, C3-7 heterocycloalkylcarbonylcarbonylaminoaryl, C3-7 heterocycloalkyl(Ci-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 \ -6)alkylaryl, C3-7 heterocycloalkyl(C i -6)alkylaminocarbonyl(C i -6)alkylaryl, heteroarylaminocarbonyl(C i -6)alkylaryl, heteroaryl(C i -6)alkylaminocarbonyl(C i -6)alkyl- aryl, arylaminoheteroaryl, C3-7 heterocycloalkylamino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonylamino-aryl-heteroaryl, C3-7 heterocycloalkylaminocarbonyl- amino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(C1-6)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(C i -6)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.
Typically, R5 represents hydrogen; or optionally substituted aryl(C2-6)alkynyl. Suitably, R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb or
-CONRcRd; or R5 represents methyl, propyl, ethenylcarbonyl, ethynyl, propynyl, butynyl, 3-methylbutynyl, cyclopropylethynyl, cyclohexylethynyl, phenyl, naphthyl, benzyl, phenylethyl, phenylethenyl, phenylethynyl, phenylpropynyl, biphenyl, piperidinylethyl, pyrrolidinyl ethynyl, piperidinylethynyl, 1 ,2,3 ,4-tetrahydroisoquinolinylpropynyl, piperazinylpropynyl, pyrrolidinyl carbonylethynyl, quinuclidinyl ethynyl, piperazinyl- phenyl, morpholinylphenyl, piperidinylmethylphenyl, piperazinyl-biphenyl, benzofuryl, dibenzofuryl, 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, piperazinylphenylpyridinyl, moφholinylphenylpyridinyl, piperazinylphenylpyrimidinyl, pyrrolidinylmethylphenylpyridinyl, piperidinylmethyl- phenylpyridinyl, piperazinylmethylphenylpyridinyl, homopiperazinylmethylphenyl- pyridinyl, morpholinylmethylphenylpyridinyl, azabicyclo[3.2.1]octylmethylphenyl- pyridinyl, diazabicyclo[3.2.1 ]octylmethylphenylpyridinyl, tetrazolylphenylpyridinyl, benzofiirylpyridinyl, benzothienylpyridinyl, indolylpyridinyl, isoxazolylpyridinyl, bi(pyridinyl), isoquinolinylpyridinyl, moφholinylcarbonylbi(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, azetidinylaminocarbonyl- aminophenyl, morpholinylethylaminocarbonylaminophenyl, imidazolylmethyl- aminocarbonylaminophenyl, moφholinylcarbonylcarbonylaminophenyl, pyrrolidinyl- ethylaminocarbonylcarbonylaminophenyl, phenylcarbonylphenyl, moφholinylcarbonyl- phenyl, pyrrolidinylcarbonylmethylphenyl, piperidinylcarbonylmethylphenyl, benzylaminocarbonylphenyl, moφholinylethylaminocarbonylphenyl, imidazolyl- aminocarbonylphenyl, imidazolylmethylaminocarbonylphenyl, pyridinylmethyl- aminocarbonylphenyl, azetidinylaminocarbonylmethylphenyl, pyrrolidinylmethyl- aminocarbonylmethylphenyl, pyridinylaminocarbonylmethylphenyl, pyridinylmethyl- aminocarbonylmethylphenyl, phenylaminopyridinyl, azetidinylaminophenylpyridinyl, pyrrolidinylaminophenylpyridinyl, piperazinylcarbonylaminophenylpyridinyl, piperidinylaminocarbonylaminophenylpyridinyl, azetidinylcarbonylphenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl, piperidinylcarbonylphenylpyridinyl, piperazinylcarbonylphenylpyridinyl, moφholinylcarbonylphenylpyridinyl, piperidinylcarbonylphenylpyrimidinyl, moφholinylmethylcarbonylphenylpyridinyl, azabicyclo[3.2.1 Joctylcarbonylphenylpyridinyl, azetidinylcarbonylmethylphenyl- pyridinyl, pyrrolidinylcarbonylmethylphenylpyridinyl, piperidinylcarbonylmethylphenyl- pyridinyl, piperazinylcarbonylmethylphenylpyridinyl, azetidinylaminocarbonylphenyl- pyridinyl, pyrrolidinylaminocarbonylphenylpyridinyl, piperidinylaminocarbonylphenyl- pyridinyl, piperidinylmethylaminocarbonylphenylpyridinyl or azetidinylaminocarbonyl- methylphenylpyridinyl, any of which groups may be optionally substituted by one or more substituents.
Illustratively, R5 represents hydrogen; or optionally substituted phenylethynyl. Examples of representative substituents on R5 include halogen, cyano, nitro, oxo, Ci-6 alkyl, trifluoromethyl, hydroxy, hydroxy(Ci.6)alkyl, Ci-6 alkoxy, dihydroxy(Ci-6)- alkoxy, aryl(Ci-6)alkoxy, methoxyaryl(Ci-6)alkoxy, amino, Ci-6 alkylamino, di(Ci-6)- alkylamino, amino(Ci-6)alkyl, Ci-6 alkylamino(Ci-6)alkyl, di(Ci-6)alkylamino(Ci-6)alkyl, di(Ci-6)alkylamino(Ci-6)alkylamino, methoxyaryl(Ci-6)alkylamino, Ci-6 alkylcarbonyl- amino, Ci-6 alkoxycarbonyl(Ci-6)alkylcarbonylamino, Ci-6 alkyl carbonylamino(C i-6)alkyl, Ci-6 alkoxycarbonylamino, N-(C i -6 alkoxycarbonyl)-N-(C i -6 alkyl)amino, C i -6 alkoxy- carbonylamino(Ci-6)alkyl, N-(Ci-6 alkoxycarbonyl)-N-(Ci-6 alkyl)amino(Ci-6)alkyl, Ci-6 alkylsulphonylamino, Ci-6 alkylsulphonylamino(Ci-6)alkyl, Ci-6 alkylaminocarbonylamino, di(C i -6)alkylamino(C i -6)alkylaminocarbonylamino, N-(C i -6 alkyl)-N-[di(C i -6)alkylamino- (Ci-6)alkyl]aminocarbonylamino, carboxycarbonylamino, Ci-6 alkoxycarbonyl- carbonylamino, C i -6 alkylaminocarbonylcarbonylamino, di(C i -6)alkylamino(C i -6)alkyl- aminocarbonylcarbonylamino, di(Ci-6)alkylaminosulphonylamino, formyl, Ci-6 alkylcarbonyl, di(Ci-6)alkylamino(Ci-6)alkylcarbonyl, carboxy, carboxy(Ci-6)alkyl, Ci-6 alkoxycarbonyl, Ci-6 alkoxycarbonyl(Ci-6)alkyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(C i -6)alkylaminocarbonyl, cyano(C i -6)alkylaminocarbonyl, di(C i -6)alkylamino(C i -6)- alkylaminocarbonyl, dihydroxy(Ci-6)alkylaminocarbonyl, N-(Ci-6 alkyl)-N-[amino(Ci-6)- alkyl] aminocarbonyl, N-(Ci-6 alkyl)-N-[di(Ci.6)alkylamino(Ci-6)alkyl]aminocarbonyl, di(C i -6)alkylaminocarbonyl(C i -6)alkyl, N-(C i -6 alkyl)-N-[di(C i -6)alkylamino(C { -6)alkyl] - aminocarbonyl(Ci-6)alkyl, aminocarbonyl(Ci-6)alkoxy, Ci-6 alkoxyaminocarbonyl, N-(Ci-6 alkoxy)-N-(Ci-6 alkylaminocarbonyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonyloxy(Ci-6)- alkyl, trifluoromethylsulphonyloxy and tri(Ci-6)alkylsilyl.
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, N-(tert-butoxy- carbonyl)-N-(methyl)amino, tert-butoxycarbonylaminomethyl, N-(tert-butoxycarbonyl)-N- (methyl)aminomethyl, methylsulphonylamino, ethylsulphonylamino, methylsulphonyl- aminomethyl, ethylaminocarbonylamino, dimethylaminoethylaminocarbonylamino, N- (dimethylaminoethyl)-N-(methyl)aminocarbonylamino, carboxycarbonylamino, ethoxycarbonylcarbonylamino, ethylaminocarbonylcarbonylamino, dimethylaminoethyl- aminocarbonylcarbonylamino, dimethylaminosulphonylamino, formyl, acetyl, dimethyl- aminoacetyl, ethylcarbonyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, tert-butoxycarbonylmethyl, aminocarbonyl, methylaminocarbonyl, cyanomethylaminocarbonyl, ethylaminocarbonyl, dimethylamino- ethylaminocarbonyl, dihydroxypropylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-(aminoethyl)-N-(methyl)- aminocarbonyl, N-(dimethylaminoethyl)-N-(methyl)aminocarbonyl, diethylamino- carbonyl, dimethylaminocarbonylmethyl, N-(diethylaminoethyl)-N-(methyl)amino- carbonylmethyl, aminocarbonylmethoxy, methoxyaminocarbonyl, N-(methoxy)-N- (methyl)aminocarbonyl, methylsulphonyl, methylsulphonyloxymethyl, trifluoromethyl- sulphonyloxy and tri(Ci-6)alkylsilyl.
Specific values of R5 include hydrogen, fluoro, chloro, bromo, iodo, cyano, phenylthio, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, pyridinylmethylaminocarbonyl, (phenyl)(pyridinyl)methylaminocarbonyl, N-ethyl-N-pyridinylmethylaminocarbonyl, dimethylaminomethyl, dimethylaminosulphonylaminopropyl, dimethylamino- ethenylcarbonyl, ethynyl, triethylsilylethynyl, diethylaminopropynyl, methylsulphonylaminopropynyl, dimethylaminosulphonylaminopropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, cyclopropyl ethynyl, hydroxycyclohexyl- ethynyl, aminocyclohexylethynyl, 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)-ΛL(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)-N-(methyl)aminocarbonylmethylphenyl, naphthyl, benzyl, phenylethyl, phenylethenyl, phenylethynyl, fluorophenylethynyl, nitrophenylethynyl, hydroxyphenylethynyl, methoxyphenylethynyl, dimethylaminophenylethynyl, phenylpropynyl, biphenyl, (bromo)(dinitro)biphenyl, methoxybiphenyl, aminobiphenyl, dimethylaminobiphenyl, dimethylaminomethylbiphenyl, (dimethylaminocarbonyl)- (methyl)biphenyl, acetylpiperidinylethyl, tert-butoxycarbonylpyrrolidinylethynyl, piperidinylethynyl, acetylpiperidinylethynyl, tert-butoxycarbonylpiperidinylethynyl, methylsulphonylpiperidinylethynyl, 1,2,3,4-tetrahydroisoquinolinylpropynyl, methylpiperazinylpropynyl, pyrrolidinylcarbonylethynyl, hydroxyquinuclidinylethynyl, piperazinylphenyl, tert-butoxycarbonylpiperazinylphenyl, morpholinylphenyl, piperidinylmethylphenyl, piperazinylbiphenyl, tert-butoxycarbonylpiperazinylbiphenyl, benzofiiryl, 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- benzomorpholinylpyridinyl, hydroxymethylpyrrolidinylpyridinylethynyl, pyrazolylphenyl, methylpyrazolylphenyl, pyridinylphenyl, (amino)(chloropyridinyl)phenyl, phenyl- isoxazolyl, phenyl thiazolyl, (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, iV-isopropyl-N-methylaminomethylphenylpyridinyl, methoxybenzylamino- phenylpyridinyl, acetylaminophenylpyridinyl, acetylaminomethylphenylpyridinyl, tert- butoxycarbonylaminomethylphenylpyridinyl, N-(tert-butoxycarbonyl)-N-(methyl)- aminomethylphenylpyridinyl, methylsulphonylaminomethylphenylpyridinyl, formylphenylpyridinyl, acetylphenylpyridinyl, dimethylaminomethylcarbonyl- phenylpyridinyl, carboxyphenylpyridinyl, (amino)(carboxy)phenylpyridinyl, ethoxycarbonylphenylpyridinyl, tert-butoxycarbonylphenylpyridinyl, methoxycarbonyl- methylphenylpyridinyl, aminocarbonylphenylpyridinyl, methylaminocarbonylphenyl- pyridinyl, dimethylaminoethylaminocarbonylphenylpyridinyl, dihydroxypropylamino- carbonylphenylpyridinyl, dimethylaminocarbonylphenylpyridinyl, (dimethyl amino- carbonyl)(fluoro)phenylpyridinyl, (dimethylaminocarbonyl)(nitro)phenylpyridinyl, (amino)(dimethylaminocarbonyl)phenylpyridinyl, N-ethyl-N-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, tert-butoxycarbonylpiperazinylphenylpyridinyl, tert-butoxycarbonyl- methylpiperazinylphenylpyridinyl, morpholinylphenylpyridinyl, piperazinylphenyl- pyrimidinyl, pyrrolidinylmethylphenylpyridinyl, hydroxypyrrolidinylmethylphenyl- pyridinyl, dioxopyrrolidinylmethylphenylpyridinyl, aminopyrrolidinylmethylphenyl- pyridinyl, carboxypyrrolidinylmethylphenylpyridinyl, tert-butoxycarbonylpyrrolidinyl- methylphenylpyridinyl, aminopiperidinylmethylphenylpyridinyl, methylaminopiperidinyl- methylphenylpyridinyl, piperazinylmethylphenylpyridinyl, methylpiperazinylmethyl- phenylpyridinyl, oxopiperazinylmethylphenylpyridinyl, homopiperazinylmethylphenyl- pyridinyl, moφholinylmethylphenylpyridinyl, dimethylmoφholinylmethylphenyl- pyridinyl, aminoazabicyclo[3.2.1 ]octylmethylphenylpyridinyl, diazabicyclo[3.2.1 Joctyl- methylphenylpyridinyl, tetrazolylphenylpyridinyl, benzofurylpyridinyl, benzothienylpyridinyl, indolylpyridinyl, dimethylisoxazolylpyridinyl, bi(pyridinyl), chlorobi(pyridinyl), carboxybi(pyridinyl), methoxycarbonylbi(pyridinyl), isoquinolinylpyridinyl, moφholinylcarbonylbi(pyridinyl), phenoxyphenyl, benzyloxyphenyl, methoxybenzyloxyphenyl, pyridinylmethoxyphenyl, N-(benzyl)-N- (ethylcarbonyl)aminophenyl, methylfurylmethylaminophenyl, pyridinylmethylamino- phenyl, cyclopentylcarbonylaminophenyl, phenylcarbonylaminophenyl, benzyl carbonyl- aminophenyl, hydroxypyrrolidinylcarbonylaminophenyl, aminopyrrolidinylcarbonyl- aminophenyl, tert-butoxycarbonylaminopyrrolidinylcarbonylaminophenyl, (isopropyl)- (oxo)pyrrolidinylcarbonylaminophenyl, tert-butoxycarbonylpiperidinylcarbonylamino- phenyl, piperazinylcarbonylaminophenyl, methylpiperazinylcarbonylaminophenyl, tert- butoxycarbonylpiperazinylcarbonylaminophenyl, moφholinylcarbonylaminophenyl, indolylcarbonylaminophenyl, methylisoxazolylcarbonylaminophenyl, pyridinylcarbonyl- aminophenyl, hydroxypyridinylcarbonylaminophenyl, (oxo)(phenyl)pyrrolidinylcarbonyl- aminophenyl, phenylsulphonylaminophenyl, benzylsulphonylaminophenyl, dimethyl- isoxazolylsulphonylaminophenyl, cyclopentylaminocarbonylaminophenyl, phenylamino- carbonylaminophenyl, methylazetidinylaminocarbonylaminophenyl, moφholinylethyl- aminocarbonylaminophenyl, methylimidazolylmethylaminocarbonylaminophenyl, moφholinylcarbonylcarbonylaminophenyl, pyrrolidinylethylaminocarbonylcarbonyl- aminophenyl, phenylcarbonylphenyl, moφholinylcarbonylphenyl, aminopyrrolidinyl- carbonylmethylphenyl, tert-butoxycarbonylaminopyrrolidinylcarbonylmethylphenyl, aminopiperidinylcarbonylmethylphenyl, methylaminopiperidinylcarbonylmethylphenyl, tert-butoxycarbonylaminopiperidinylcarbonylmethylphenyl, N-(tert-butoxycarbonyl)-N- (methyl)aminopiperidinylcarbonylmethylphenyl, benzylaminocarbonylphenyl, moφholinylethylaminocarbonylphenyl, imidazolylaminocarbonylphenyl, methyl- imidazolylmethylaminocarbonylphenyl, pyridinylmethylaminocarbonylphenyl, azetidinylaminocarbonylmethylphenyl, tert-butoxycarbonylazetidinylaminocarbonyl- methylphenyl, pyrrolidinylmethylaminocarbonylmethylphenyl, tert-butoxycarbonyl- pyrrolidinylmethylaminocarbonylmethylphenyl, pyridinylaminocarbonylmethylphenyl, pyridinylmethylaminocarbonylmethylphenyl, phenylaminopyridinyl, N-methyl-N- phenylaminopyridinyl, azetidinylaminophenylpyridinyl, pyrrolidinylaminophenyl- pyridinyl, tert-butoxycarbonylpyrrolidinylaminophenylpyridinyl, piperazinylcarbonyl- aminophenylpyridinyl, piperidinylaminocarbonylaminophenylpyridinyl, aminoazetidinyl- carbonylphenylpyridinyl, methylaminoazetidinylcarbonylphenylpyridinyl, tert-butoxy- carbonylaminoazetidinylcarbonylphenylpyridinyl, iV-(tert-butoxycarbonyl)-iV-(methyl)- aminoazetidinylcarbonylphenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl, hydroxypyrrolidinylcarbonylphenylpyridinyl, aminopyrrolidinylcarbonylphenylpyridinyl, aminopyrrolidinylcarbonylphenyl(amino)pyridinyl, methylaminopyrrolidinylcarbonyl- phenylpyridinyl, tert-butoxycarbonylaminopyrrolidinylcarbonylphenylpyridinyl, tert- butoxycarbonylaminopyπOlidinylcarbonylphenyl(methoxybenzylamino)pyridinyl, piperidinylcarbonylphenylpyridinyl, aminopiperidinylcarbonylphenylpyridinyl, methyl- aminopiperidinylcarbonylphenylpyridinyl, tert-butoxycarbonylaminopiperidinylcarbonyl- phenylpyridinyl, dimethylaminopiperidinylcarbonylphenylpyridinyl, 7V-(tert-butoxy- carbonyl)-N-(methyl)aminopiperidinylcarbonylphenylpyridinyl, piperazinylcarbonyl- phenylpyridinyl, methylpiperazinylcarbonylphenylpyridinyl, tert-butoxycarbonyl- piperazinylcarbonylphenylpyridinyl, morpholinylcarbonylphenylpyridinyl, methylamino- piperidinylcarbonylphenylpyrimidinyl, dimethylaminopiperidinylcarbonylphenyl- pyrimidinyl, morpholinylmethylcarbonylphenylpyridinyl, aminoazabicyclo[3.2.1 ]octyl- carbonylphenylpyridinyl, aminoazetidinylcarbonylmethylphenylpyridinyl, tert-butoxy- carbonylaminoazetidinylcarbonylmethylphenylpyridinyl, pyrrolidinylcarbonylmethyl- phenylpyridinyl, aminopyrrolidinylcarbonylmethylphenylpyridinyl, tert-butoxycarbonyl- aminopyrrolidinylcarbonylmethylphenylpyridinyl, methylaminopiperidinylcarbonyl- methylphenylpyridinyl, ^-(tert-butoxycarbony^-jV-Cmethy^aminopiperidinylcarbonyl- methylphenylpyridinyl, methylpiperazinylcarbonylmethylphenylpyridinyl, azetidinyl- aminocarbonylphenylpyridinyl, tert-butoxycarbonylazetidinylaminocarbonylphenyl- pyridinyl, ^-(tert-butoxycarbonylazetidinyO-N-Cethy^aminocarbonylphenylpyridinyl, tert- butoxycarbonylpyrrolidinylaminocarbonylphenylpyridinyl, 7V-(methylpyrrolidinyl)-7V- (methyl)aminocarbonylphenylpyridinyl, N-(methylpiperidinyl)-N-(methyl)aminocarbonyl- phenylpyridinyl, piperidinylmethylaminocarbonylphenylpyridinyl, tert-butoxycarbonyl- piperidinylmethylaminocarbonylphenylpyridinyl, azetidinylaminocarbonylmethylphenyl- pyridinyl and tert-butoxycarbonylazetidinylaminocarbonylmethylphenylpyridinyl. Particular values of R5 include hydrogen and phenylethynyl. 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 R and/or R >4 is other than hydrogen. Suitably, R , when present, represents hydrogen, hydroxy or -NR 6ar R> 6b . In a preferred embodiment, R6 represents hydrogen. In an alternative embodiment, R represents hydroxy. In another embodiment, R6 represents -NR6aR6 . In a further embodiment, R6 represents oxo.
Suitably, R6a represents Ci-6 alkyl, C3-7 cycloalkyl, aryl or aryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Examples of suitable substituents on R6a and R6b include halogen, cyano, trifiuoromethyl, hydroxy, Ci-6 alkoxy and trifluoromethoxy, especially hydroxy.
Typical values of R6a include methyl, hydroxyethyl, cyclopropyl, phenyl and benzyl. Suitably, R6b represents hydrogen or Ci-6 alkyl. In one embodiment, R6b represents hydrogen. In another embodiment, R6 represents Ci-6 alkyl, especially methyl.
One sub-class of compounds according to the invention is represented by the compounds of formula (BA), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000042_0001
(BA)
wherein
W, the moiety X-Y-Q and R5 are as defined above;
R1 ' represents hydrogen or Ci-6 alkyl; and
R12 represents hydrogen; or Ci-6 alkyl, Ci-6 alkoxy, 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.
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 monosubstituted.
Typical values of R1 ' include hydrogen, methyl and ethyl. In one embodiment, R1 ' is hydrogen. In another embodiment, R1 ' is Ci-6 alkyl, especially methyl.
Suitably, R12 represents hydrogen; or Ci-6 alkyl, C3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents. Examples of typical substituents on R12 include halogen, cyano, nitro, Ci-6 alkyl, trifluoromethyl, hydroxy, Ci-6 alkoxy, difiuoromethoxy, trifluoromethoxy, aryloxy, Ci-6 alkylthio, Ci-6 alkylsulphonyl, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, 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, Ci-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, difiuoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
Typical values of R12 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl. A particular value of R12 is methyl.
Alternatively, R1 ' and R12 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. In this context, R1 ' and R12, 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.
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 imgf000044_0001
wherein
W, the moiety X-Y-Q, 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(C,-6)alkyl, aryl(C2-6)alkenyl, aryl(C2.6)alkynyl, biaryl(C,-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Where any of the groups in the compounds of formula (IIA-A) or (IIA-B) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted.
Typically, R13 represents hydrogen; or Ci-6 alkyl, aryl(Ci-6)alkyl, aryl(C2-6)alkynyl, biaryl(C|-6)alkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Generally, R13 represents hydrogen; or C2-6 alkynyl, aryl(C1-6)alkyl or heteroaryl- (Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R13 represents aryl(Ci-6)alkyl or heteroaryl(Ci-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- (C i -6)alkyl, heteroaryl(C i -6)alkyl or heteroaryl-aryl(C i -6)alkyl, any of which groups may be optionally substituted by one or more substituents. 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, R1 represents arylmethyl or heteroarylmethyl, either of which groups may be optionally substituted by one or more substituents.
In a particular embodiment, R13 represents substituted or unsubstituted indolyl- (Ci-6)alkyl. Advantageously, R13 represents substituted or unsubstituted indolylmethyl.
In a typical embodiment, R13 represents substituted or unsubstituted phenyl- (Ci-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, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-6]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, Ci-6 alkyl, trifluoromethyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci-6)alkylaryl, di(Ci-6)alkylaryl, piperidinyl- (C i -6)alkylaryl, piperazinyl(C i -6)alkylaryl, (C i -6)alkylpiperazinyl(C i -6)alkylaryl, morpholinyl(Ci-6)alkylaryl, (Ci-6)alkoxyaryl, cyano(Ci-6)alkoxyaryl, di(Ci-6)alkyl- amino(Ci-6)alkylaryl,
Figure imgf000046_0001
aryl(Ci-6)alkyl, oxazolinyl, azetidinyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci.6)alkylaminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di(Ci-6)alkylamino- carbonylpiperidinyl, piperazinyl, (Ci-6)alkylpiperazinyl, haloarylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (Ci-6)alkylhomopiperazinyl, moφholinyl, (Ci-6)alkylpiperazinyl(C1-6)alkyl, moφholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(Ci-6)alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, [di(Ci-6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano- (C i -6)alkyl] [di(C i -6)alkyl] pyrazolyl, hydroxy(C i -6)alkylpyrazolyl, [hydroxy(C I-6)- alkyl] [di(C i -6)alkyl]pyrazolyl, methoxy(C i -6)alkylpyrazolyl, [(hydroxy)(methoxy)(C i -6)- alkyl]pyrazolyl, amino(Ci-6)alkylpyrazolyl, [(Ci-6)alkyl][amino(Ci-6)alkyl]pyrazolyl, [amino(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, di(C i -6)alkylamino(C i -6)alkylpyrazolyl, di(C i -6)alkoxyphosphono(C i -6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl- (C,-6)alkylpyrazolyl, [(C3-7)cycloalkyl(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(Ci-6)alkyl]- (aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(Ci-6)alkylpyrazolyl, aminoaryl- (Ci-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(Ci-6)alkylpyrazolyl, [di- (C i -6)alkyl] [tetrahydropyranyl(C i -6)alkyl]pyrazolyl, pyrrolidinyl(C i -6)alkylpyrazolyl, piperidinyl(C i -6)alkylpyrazolyl, (C i -6)alkylpiperidinyl(C i -6)alkylpyrazolyl, morpholinyl(C i -6)alkylpyrazolyl, pyridinyl(C i .6)alkylpyrazolyl, oxypyridinyl(C i -6)alkyl- pyrazolyl, [arylcarbonyl(C i -6)alkyl] [di(C i ^)alkyl] pyrazolyl, [(C i -6)alkyl](piperazinyl- carbonyl)pyrazolyl, [(Ci-6)alkylaminocarbonyl][(Ci-6)alkylaryl]pyrazolyl,
Figure imgf000046_0002
[amino(C i -6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C i -6)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(Ci-6)alkylthiazolyl, imidazolyl, (Ci-6)alkylimidazolyl, di(Ci-6)- alkylimidazolyl, imidazo[ 1 ,2-α]pyridinyl, (Ci-6)alkylimidazo[l ,2-α]pyridinyl, (Ci-6)- alkylimidazo[4,5-έ>]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)- alkylthiadiazolyl, triazolyl, pyridinyl, halopyridinyl, (Ci-6)alkylpyridinyl, [(Ci-6)alkyl]- (halo)pyridinyl, di(Ci-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (Ci-6)alkylpiperazinyl- pyridinyl, [(Ci-6)alkyl](piperazinyl)pyridinyl, [(Ci^alkoxycarbonylpiperazinylJKCi-ό)- alkyl]pyridinyl, piped dinyl (Ci -6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (Ci_6)alkoxypyridinyl, [(Ci-6)alkoxy]- [(C,-6)alkyl]pyridinyl, [(Ci.6)alkoxy][di(C,-6)alkyl]pyridinyl, (C1-6)alkoxy(Ci-6)alkyl- pyridinyl, aminopyridinyl, carboxy(C i -6)alkylpyri dinyl, (C i -6)alkoxycarbonyl(C i -6)alkyl- pyridinyl, pyridazinyl, (Ci-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Ci-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(Ci-6)alkylaminopyridazinyl, di- (Ci-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(Ci-6)alkyl](halo)- pyrimidinyl, di(Ci-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (C1-6)alkylpiperazinyl- pyrimidinyl, [(C i -6)alkyl] (piperazinyl)pyrimidinyl, [(C i .6)alkoxycarbonyl] [(C i -6)alkyl] - piperazinylpyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(Ci-6)- alkyl] [hydroxy(C i -6)alkyl]pyrimidinyl, [(C i -6)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (Ci.6)alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminopyrimidinyl, [di(Ci-6)alkyl- amino] (halo)pyrimidinyl, carboxypyrimidinyl, [(C i -6)alkoxycarbonyl(C i -6)alkyl] [(C i -6)- alkyljpyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (Ci-6)alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(Ci-6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy, moφholinyl(Ci-6)- alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i -6)alkylpyrazolyl- pyridinyloxy, (Ci-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy, (Ci-6)alkylpyrimidinyloxy, [(C i ^)alkyl] (halo)pyrimidinyloxy, hydroxy(C i -6)alkyl, dihydroxy(C i -6)alkyl, pyridinyloxy(Ci-6)alkyl, methylenedioxy, difluoromethylenedioxy, amino, (Ci-6)alkyl- amino, dihydroxy(Ci-6)alkylamino, (Ci-6)alkoxy(Ci-6)alkylamino, di(Ci-6)alkylamino, N- [(Ci-6)alkoxy(Ci-6)alkyl]-N-[(Ci-6)alkyl]amino, di(d.6)alkylamino(Ci-6)alkylamino, N-
[(Ci-6)alkyl]-N-[di(Ci-6)alkylamino(C,-6)alkyl]amino, N-[(Ci-6)alkyl]-N-[(C3.7)cycloalkyl]- amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, methylenedioxyphenylamino, morpholinyl(Ci-6)alkylphenylamino, oxazolinylphenylamino, [(Ci-6)alkyl](oxo)pyrazolyl- phenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, (C i -6)alkyl triazolylphenylamino, (C i -6)alkylpyrimidinylphenylamino, pyrazolyl(C i -6)alkyl- phenylamino, triazolyl(Ci-6)alkylphenylamino, Ci-6 alkylsulphonylaminophenylamino, moφholinylcarbonylphenylamino, Ci-6 alkylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-[(Ci-6)alkyl]-N-[aryl(Ci.6)alkyl]amino, N-[di(C i -6)alkylamino(C \ -6)alkyl]-N-[aryl(C i -6)alkyl] amino, cyanoaryl(C i -6)alkyl amino, (cyano)(halo)aryl(C i -6)alkylamino, methylenedioxyaryl(C i -6)alkylamino, dihydrobenzofuranylamino, N-[(C i -6)alkyl] -7V-[(C i -6)alkylpyrrolidinyl] amino, C \ -6 alkylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-[(Ci-6)alkyl]-jV- (piperidinyl)amino, N-[(C3-7)cycloalkyl(Ci-6)alkyl]-N-(piperidinyl)amino, (Ci-6)alkyl- piperidinylamino, N-[(C\ -6)alkyl] -N-[(C i -6)alkylpiperidinyl] amino, N-[(C i -6)alkyl] - N-[(C3-7)cycloalkylpiperidinyl]amino, iV-fCCi^alkylj-N-t^-^alkylcarbonylpiperidinyl]- amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinyl(Ci-6)alkylamino, J/V-[(Ci-6)alkyl]-7V-[pyrrolidinyl(C1-6)alkyl]amino, J/V-[(Ci-6)alkyl]-N-[piperidinyl(C1-6)- alkyl]amino, benzothienylamino, indolylamino, dioxoindolylamino, (C1-6)alkylpyrazolyl- amino, [(C1-6)alkyl](halo)pyrazolylamino, di(Ci-6)alkylpyrazolylamino, tri(Ci-6)alkyl- pyrazolylamino, N-[(C\ -6)alkyl] -N-[(C \ ^alkylpyrazolyl] amino, (C i -6)alkylindazolylamino, benzoxazolylamino, benzoxazolonylamino, di(Ci.6)alkylisoxazolylamino, thiazolylamino, benzothiazolylamino, (Ci-6)alkylisothiazolylamino, imidazolylamino, [(Ci-6)alkoxy- carbonyl][(Ci-6)alkyl]imidazolylamino, (Ci-6)alkylbenzimidazolylamino, benzimidazolonylamino, di(Ci-6)alkylbenzimidazolonylamino, (Ci-6)alkyloxadiazolyl- amino, fiiryloxadiazolylamino, (C1-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (C1-6)alkylpyridinylamino, di(Ci-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C i -6)alkylpyridinylamino, dihydroxy(Ci-6)alkylpyridinylamino, (Ci-6)alkoxypyridinylamino, dihydroxy(Ci-6)alkoxy- pyridinylamino, di(C i .6)alkyldioxolanyl(C i -6)alkoxypyridinylamino, (C i -6)alkoxy(C i -6)- alkylpyridinylamino, (C i -6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C i -6)alkyl- aminopyridinylamino, di(C i .6)alkylaminopyridinylamino, (C i _6)alkylamino(C \ .6)alkyl- pyridinylamino, di(C i -6)alkylamino(C i -6)alkylpyridinylamino, oxopyridinylamino, carboxypyridinylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpyridinyl]amino, bis[(Ci-6)alkyl- pyridinyl] amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, (Ci_6)alkyl- pyridazinylamino, ^-[(Ci^alkyll-N-f^i^alkylpyridazinylJamino, N-[aryl(Ci-6)alkyl]-N- [(Ci-6)alkylpyridazinyl]amino, di(C1-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C i -6)alkoxypyridazinylamino, [(C i -6)alkoxy] (halo)- pyridazinylamino, di(Ci.6)alkylaminopyridazinylamino, bis[(Ci-6)alkylpyridazinyl] amino, (Ci-6)alkylcinnolinylamino, oxopyrimidinylamino, thioxopyrimidinylamino, quinoxalinylamino, (Ci-6)alkylchromenylamino, benzofuryl(Ci-6)alkylamino, thienyl(Ci-6)- alkylamino, indolyl(Ci-6)alkylamino, (Ci-6)alkylpyrazolyl(Ci-6)alkylamino, [di(Ci-6)alkyl]- (halo)pyrazolyl(Ci-6)alkylamino, (Ii(C1 -6)alkylisoxazolyl (Ci .6)alkylamino, thiazolyl(Ci-6)- alkylamino, imidazolyl(Ci.6)alkylamino, (Ci-6)alkylimidazolyl(Ci-6)alkylamino, pyridinyl(C i -6)alkylamino, (C i .6)alkylpyridinyl(C i -6)alkylamino, N-[(C i _6)alkyl] -N- [pyridinyl(Ci-6)alkyl] amino, N-[dihydroxy(C1-6)alkyl]-N-[pyridinyl(Ci-6)alkyl]amino, N- [(Ci-6)alkylpyridinyl(C1-6)alkyl]-N-[dihydroxy(C1-6)alkyl]amino, amino(Ci-6)alkyl, (Ci-6)- alkylamino(Ci-6)alkyl, di(Ci-6)alkylamino(Ci-6)alkyl, pyridinylamino(Ci-6)alkyl, C2-6 alkylcarbonylamino, N-[(C2-6)alkylcarbonyl]-N-[(Ci-6)alkylpyridinyl(Ci-6)alkyl]amino, di(Ci-6)alkylamino(Ci-6)alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, (C3-7)- cycloalkylcarbonylamino, (C i -6)alkylpiperidinylcarbonylamino, (C i -6)alkylimidazolyl- carbonylamino, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl] [(C i-6)alkyl] amino, Ci-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl 0-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, [hydroxy(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)- alkylamino(C i -6)alkyl] aminocarbonyl, di(C i -6)alkylaminocarbonyl, [(C i -6)alkyl] [cyano- (C i -6)alkyl] aminocarbonyl, [(C i -6)alkyl] [hydroxy(C i -6)alkyl] aminocarbonyl, [(C i -6)alkoxy- (C i -6)alkyl] [(C i -6)alkyl] aminocarbonyl, [di(C i -6)alkylamino(Ci -6)alkyl] [(C i -6)alkyl] aminocarbonyl, C3-7 cycloalkyl(Ci-6)alkylaminocarbonyl, aryl(Ci-6)alkylaminocarbonyl, (Ci-6)- alkylpiperidinylaminocarbonyl, N-[(Ci-6)alkyl]-N-[(Ci-6)-alkylpiperidinyl]aminocarbonyl, piperidinyl(C i -6)alkylaminocarbonyl, heteroaryl aminocarbonyl, heteroaryl(C i -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-6)alkylpiperazinylcarbonyl, morpholinylcarbonyl, Cj-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 R13 include halogen, cyano, Ci-6 alkyl, C2-6 alkoxycarbonyl and di(Ci-6)alkylaminocarbonyl. A further example is carboxy. 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, fiiroylpiperazinyl, 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, 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, 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, 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)ammo, N-(methoxypropyl)-N-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N-(dimethylaminoethyl)-N-(methyl)amino, N- (diethylaminoethyl)-7V-(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, morpholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenylamino, triazolylmethylphenylamino, methylsulphonylamino- phenylamino, morpholinylcarbonylphenylamino, 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, benzothienylamino, indolylamino, dioxoindolylamino, methylpyrazolylamino, (bromo)(methyl)pyrazolyl- amino, dimethylpyrazolylamino, trimethylpyrazolylamino, N-(ethyl)-N-(methylpyrazolyl)- amino, methylindazolylamino, benzoxazolylamino, benzoxazolonylamino, dimethyl- isoxazolylamino, thiazolylamino, benzothiazolylamino, methylisothiazolylamino, imidazolylamino, (ethoxycarbonyl)(methyl)imidazolylamino, methylbenzimidazolyl- amino, benzimidazolonylamino, dimethylbenzimidazolonylamino, methyloxadiazolyl- amino, fiiryloxadiazolylamino, 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, N-(methyl)-N-(methylpyridinyl)- amino, N-(ethyl)-N-(methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-N- (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, benzofurylmethylamino, thienylmethylamino, indolylmethylamino, methylpyrazolyl- methylamino, (chloro)(dimethyl)pyrazolylmethylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethylamino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethylamino, 7V-(methyl)-N-(pyridinylethyl)- amino, N-(dihydroxypropyl)-N-(pyridinylmethyl)amino, N-(dihydroxypropyl)-N- (methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, acetylamino, 7V-(acetyl)-N-(methylpyridinyl)amino, dimethylaminoethylcarbonylamino, acetylaminomethyl, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, methoxycarbonyl- amino, TV-methoxycarbonyl-N-methylamino, methylsulphonylamino, formyl, acetyl, acetyl oxime, acetyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethyl - aminoethyl)aminocarbonyl, ( 1 -hydroxyprop-2-yl)aminocarbonyl, dimethylamino- carbonyl, 7V-(cyanomethyl)-Λ/-methylaminocarbonyl, Λ/-(cyanoethyl)-iV-methylamino- carbonyl, N-(hydroxyethyl)-N-methylaminocarbonyl, N-(methoxyethyl)-N-methyl- aminocarbonyl, N-(dimethylaminoethyl)-N-methylaminocarbonyl, N-isopropyl-7V-methyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, methylpiperidinylaminocarbonyl, 7V-(methyl)-7V-(methylpiperidinyl)amino- carbonyl, piperidinylethylaminocarbonyl, pyrazolylaminocarbonyl, 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, tert-butoxycarbonyloxy, trimethylsilyl and tetramethyl- dioxaborolanyl.
Particular examples of specific substituents on R13 include bromo, cyano, methyl, methoxycarbonyl and dimethylaminocarbonyl. A further example is carboxy.
Typical values of R13 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienylmethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazolylphenylaminobenzyl, methylpyrimidinylphenylaminobenzyl, pyrazolylmethylphenylaminobenzyl, triazolylmethylphenylaminobenzyl, methylsulphonylaminophenylaminobenzyl, moφholinylcarbonylphenylaminobenzyl, methylsulphonylphenylaminobenzyl, morpholinylsulphonylphenylaminobenzyl, dihydrobenzofiαranylaminobenzyl, methylsulphonylindolinylaminobenzyl, chromanonylaminobenzyl, dihydroquinolinonylaminobenzyl, benzoxazinonyl- aminobenzyl, benzothienylaminobenzyl, indolylaminobenzyl, dioxoindolylaminobenzyl, (bromo)(methyl)pyrazolylaminobenzyl, trimethylpyrazolylaminobenzyl, methylindazolyl- aminobenzyl, benzoxazolylaminobenzyl, benzoxazolonylaminobenzyl, dimethyl- isoxazolylaminobenzyl, benzothiazolylaminobenzyl, methylisothiazolylaminobenzyl, 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, cyanobenzofiirylmethyl, methoxycarbonylbenzofurylmethyl, dimethylaminocarbonylbenzofurylmethyl, azetidinylcarbonylbenzofiirylmethyl, 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-N-methylaminoindolylmethyl, methylsulphonylaminoindolylmethyl, acetylindolylmethyl, [acetyl oximejindolylmethyl, [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, (hydroxyethyl)aminocarbonylindolylmethyl, (dimethylaminoethytyaminocarbonylindolylmethyl, ( 1 -hydroxyprop-2-yl)aminocarbonyl- indolylmethyl, dimethylaminocarbonylindolylmethyl, (dimethylaminocarbonyl)(methyl)- indolylmethyl, (chloro)(dimethylaminocarbonyl)indolylmethyl, bis(dimethylamino- carbonyl)indolylmethyl, N-CcyanomethyO-N-methylaminocarbonylindolylmethyl, [N- (cyanomethy^-N-methylaminocarbonylJCmethy^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-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, morpholinylcarbonylindolylmethyl, methylsulphonylindolylmethyl, methylsulphonylmethylindolylmethyl, dimethylaminosulphonylindolylmethyl, trimethylsilylindolylmethyl and pyrrolo[3,2-c]pyridinylmethyl. Representative values of R13 include hydrogen, bromobenzyl, benzofϊirylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, (carboxy)(methyl)- indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, dimethylaminocarbonylindolylmethyl and (dimethylaminocarbonyl)(methyl)indolyl- methyl. Particular values of R13 include hydrogen, bromobenzyl, benzofurylmethyl, indolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, methoxycarbonylindolylmethyl and dimethylaminocarbonylindolylmethyl. One particular sub-group of the compounds of formula (II A- A) is represented by the compounds of formula (HB), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000056_0001
(HB)
wherein
W, the moiety X-Y-Q, R1 ' and R12 are as defined above; T represents oxygen or N-R 5; R23 represents hydrogen, halogen, cyano, nitro, Ci-6 alkyl, hydroxy(Ci.6)alkyl, trifluoromethyl, aryl(Ci.6)alkyl, oxazolinyl, triazolyl, hydroxy, Ci-6 alkoxy, difiuoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(Ci-6)alkoxy, morpholinyl(Ci-6)alkoxy, aryloxy, aryl(Ci-6)alkoxy, Ci-6 alkylthio, Ci-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, Ci-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, C2-6 alkoxycarbonylamino,
[(C2-6)alkoxycarbonyl] [(C i-6)alkyl] amino, Ci-6 alkylsulphonylamino, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl 0-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, [hydroxy(Ci-6)- alkyl] aminocarbonyl, [di(C i -6)alkylamino(C i -6)alkyl] aminocarbonyl, di(C i -6)alkyl- aminocarbonyl, [(C i-6)alkyl][cyano(Ci-6)alkyl] aminocarbonyl, [(Ci-6)alkyl][hydroxy(Ci-6)- alkyl] aminocarbonyl, [(Ci-6)alkoxy(Ci-6)alkyl][(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)alkyl- amino(Ci-6)alkyl][(Ci.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, (Ci-6)alkylpyrrolidinyl- carbonyl, Ci-6 alkoxy(Ci-6)alkylpyrrolidinylcarbonyl, di(Ci-6)alkylaminopyrrolidinyl- carbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, (C I-6)- alkylpiperazinylcarbonyl, morpholinylcarbonyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonyl- methyl or di(Ci-6)alkylaminosulphonyl; and
R24 represents hydrogen, halogen, Ci-6 alkoxy or di(Ci-6)alkylaminocarbonyl; or R23 and R24, when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and
R25 represents hydrogen or Ci-6 alkyl.
In a preferred embodiment, T is N-R25. In another embodiment, T is oxygen.
Typical values of R23 include hydrogen, cyano, carboxy, C2-6 alkoxycarbonyl and di(C|-6)alkylaminocarbonyl.
Suitable values of R23 include hydrogen, cyano, C2-6 alkoxycarbonyl and di(C i -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-TV-methylamino, methylsulphonylamino, acetyl, acetyl oxime, acetyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethylaminoethyl)aminocarbonyl, (1 -hydroxyprop-2-yl)aminocarbonyl, dimethyl- aminocarbonyl, N-(cyanomethyl)-N-methylaminocarbonyl, N-(cyanoethyl)-N-methyl- aminocarbonyl, N-(hydroxyethyl)-iV-methylaminocarbonyl, iV-(methoxyethyl)-iV-methyl- aminocarbonyl, Λ/-(dimethylaminoethyl)-N-methylaminocarbonyl, N-isopropyl-N-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.
Representative values of R23 include hydrogen, cyano, carboxy, methoxycarbonyl and dimethylaminocarbonyl. Selected values of R23 include hydrogen, cyano, methoxycarbonyl and dimethylaminocarbonyl.
A particular value of R23 is hydrogen.
Definitive values of R24 include hydrogen, chloro, methoxy and dimethylaminocarbonyl. A particular value of R24 is hydrogen.
In one embodiment, R is hydrogen. In another embodiment, R is Ci-6 alkyl, especially methyl.
Another particular sub-group of the compounds of formula (II A- A) is represented by the compounds of formula (IIC), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000058_0001
(IIC)
wherein W, the moiety X-Y-Q, R1 ' 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 substituents; and
R34 represents methyl enedioxyphenyl, morpholinyl(Ci-6)alkylphenyl, oxazolinyl- phenyl, [(Ci-6)alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (Ci-6)alkyltriazolylphenyl, (Ci-6)alkylpyrimidinylphenyl, pyrazolyl(Ci-6)alkyl- phenyl, triazolyl(Ci-6)alkylphenyl, Ci-6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci-6 alkylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, Cj-6 alkylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, [(Ci-6)alkyl](halo)pyrazolyl, tri(Ci-6)alkylpyrazolyl, (Ci-6)alkylindazolyl, benzoxazolyl, benzoxazolonyl, di(Ci-6)alkylisoxazolyl, benzothiazolyl, (Ci-6)alkylisothiazolyl, (Ci-6)alkylbenzimidazolyl, benzimidazolonyl, di(Ci-6)alkylbenzimidazolonyl, (Ci-6)alkyloxadiazolyl, fliryloxadiazolyl, pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, di(Ci-6)alkylpyridinyl, (C1-6)alkoxypyridinyl, oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl, [(C1-6)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, (Ci-6)alkylpyridinyl, di(C1-6)alkylpyridinyl 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, morpholinylsulphonylphenyl, 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)(methoxy)pyridazinyl, methylcinnolinyl, quinoxalinyl and methylchromenyl. Suitable values of R34 include pyridinyl, chloropyridinyl, methylpyridinyl, dimethylpyridinyl and methoxypyridinyl.
Illustratively, R33 represents halogen or -NHR 4, 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 substituents. Selected examples of suitable substituents on R33 include halogen, cyano, Ci-6 alkyl, hydroxy(Ci-6)alkyl, trifiuoromethyl, 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 substituents on R 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, methyl enedioxyphenylamino, morpholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenyl- amino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenyl- amino, triazolylmethylphenylamino, methylsulphonylaminophenylamino, morpholinyl- carbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, dihydrobenzofuranylamino, methylsulphonylindolinylamino, chromanonylamino, dihydroquinolinonylamino, 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, chlorophenyl, dichlorophenyl, bromophenyl, cyanophenyl, methylphenyl, (fluoro)(methyl)phenyl, dimethylphenyl, hydroxymethylphenyl, trifluoromethylphenyl, bis(trifluoromethyl)phenyl, methoxyphenyl, dimethoxyphenyl, ethoxyphenyl, 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.
Further sub-classes of compounds according to the invention are represented by the compounds of formula (HD- 1) and (IID-2), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000061_0001
wherein W, the moiety X-Y-Q, R1 ' and R12 are as defined above;
R43 represents hydrogen, halogen, nitro, Ci-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci-6)alkylaryl, di(Ci-6)alkylaryl, piperidinyl(Ci-6)alkylaryl, piperazinyl(Ci-6)alkylaryl, (C i -6)alkylpiperazinyl(C i -6)alkylaryl, morpholinyl(C i -6)alkylaryl, (C i -6)alkoxyaryl, cyano(C i .6)alkoxyaryl, di(C i -6)alkylamino(C i -6)alkylaryl, (C i -6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (Ci-6)alkylaminocarbonylpiperidinyl, piperazinyl, (Ci_6)alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, fiiroylpiperazinyl, homopiperazinyl, (Ci-6)alkyl- homopiperazinyl, (Ci-6)alkylpiperazinyl(Ci-6)alkyl, moφholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(Ci-6)alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, [di(Ci-6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano- (C i -6)alkyl] [di(C i -6)alkyl] pyrazolyl, hydroxy(C i -6)alkylpyrazolyl, [hydroxy(C i -6)-
Figure imgf000061_0002
methoxy(Ci-6)alkyl pyrazolyl, [(hydroxy)(methoxy)(Ci-6)- alkyl]pyrazolyl, amino(Ci-6)alkylpyrazolyl, [(Ci-6)alkyl][amino(Ci-6)alkyl]pyrazolyl, [amino(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, di(C i -6)alkylamino(C i -6)alkylpyrazolyl, di(C i -6)alkoxyphosphono(C i .6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl- (C,-6)alkylpyrazolyl, [(C3-7)cycloalkyl(C1-6)alkyl][di(C,-6)alkyl]pyrazolyl, [(C1-6)alkyl]- (aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(Ci-6)alkylpyrazolyl, aminoaryl- (Ci-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(Ci-6)alkylpyrazolyl, [di- (C i -6)alkyl] [tetrahydropyranyl(C i -6)alkyl]pyrazolyl, pyrrolidinyl(C i -6)alkylpyrazolyl, piperidinyl(C \ .6)alkylpyrazolyl, (C i -6)alkylpiperidinyl(C i -6)alkylpyrazolyl, morpholinyl(C i -6)alkylpyrazolyl, pyridinyl(C i -6)alkylpyrazolyl, oxypyridinyl(C i -6)alkyl- pyrazolyl, [arylcarbonyl(C i ^alkyl] [di(C i -6)alkyl]pyrazolyl, [(C i -6)alkyl] (piperazinyl- carbonyl)pyrazolyl, [(C i .6)alkylaminocarbonyl] [(C i -6)alkylaryl]pyrazolyl, [(C i -6)alkyl] - [amino(Ci.6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl,
[aminocarbonyl(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, di(C i .6)alkylaminocarbonyl(C i ^alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(Ci-6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]- isoxazolyl, thiazolyl, di(Ci.6)alkylthiazolyl, imidazolyl,
Figure imgf000062_0001
di(Ci_6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (Ci-6)alkylimidazo[l,2-α]pyridinyl, (Ci-6)- alkylimidazo[4,5-6]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)- alkylthiadiazolyl, pyridinyl, halopyridinyl,
Figure imgf000062_0002
[(Ci-6)alkyl](halo)- pyridinyl, di(Ci-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (Ci-6)alkylpiperazinylpyridinyl, [(C i -6)alkyl] (piperazinyl)pyridinyl, [(C i .6)alkoxycarbonylpiperazinyl] [(C i -6)alkyl] - pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (Ci-6)alkoxypyridinyl, [(Ci-6)alkoxy][(Ci-6)alkyl]pyridinyl, [(C i -6)alkoxy] [di(C i .6)alkyl]pyridinyl, (C i .6)alkoxy(C i -6)alkylpyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (Ci-^alkoxycarbonyKCi-^alkylpyridinyl, pyridazinyl, (Ci-6)- alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Ci.6)alkoxypyridazinyl, aminopyridazinyl, hydro xy(C i -6)alkylaminopyridazinyl, di(C i -6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(Ci-6)alkyl](halo)pyrimidinyl, di(Ci-6)alkyl- pyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinylpyrimidinyl, [(Ci-6)alkyl](piperazinyl)pyrimidinyl, [(Ci-6)alkoxycarbonyl][(Ci-6)alkyl]piperazinyl- pyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(Ci-6)alkyl]- [hydroxy(C i -6)alkyl]pyrimidinyl, [(C i _6)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (C i -6)- alkoxypyrimidinyl, aminopyrimidinyl, di(Ci.6)alkylaminopyrimidinyl, [di(Ci-6)alkyl- amino](halo)pyrimidinyl, carboxypyrimidinyl, [(Ci_6)alkoxycarbonyl(Ci.6)alkyl][(Ci-6)- alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (C|-6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy, moφholinyl- (Ci-6)alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i -6)alkylpyrazolyl- pyridinyloxy, (Ci.6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci.6)alkylpyridazinyloxy, pyrimidinyloxy, (Ci-6)alkylpyrimidinyloxy, [(C1-6)alkyl](halo)pyrimidinyloxy, hydroxy(Ci-6)alkyl, dihydroxy(C]-6)alkyl, pyridinyloxy(Ci-6)alkyl, amino, (Ci-6)alkylamino, dihydroxy(Ci-6)alkylamino, (Ci-6)- alkoxy(C i -6)alkylamino, N-[(Ci -6)alkoxy(C i -6)alkyl]-N-[(C i -6)alkyl] amino, di(C i -6)- alkylamino(C i -6)alkylamino, N-[(C i -6)alkyl]-N-[di(C i -6)alkylamino(C i -6)alkyl] amino, N- [(Ci-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, N-[(Ci-6)alkyl]-N-[aryl(C,-6)alkyl]amino, N-[di(Ci-6)alkylamino(C1-6)alkyl]-N-[aryl(C1-6)- alkyl]amino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(C1-6)alkylamino, methylene- dioxyaryl(C1-6)alkylamino, N-[(C1-6)alkyl]-N-[(C1.6)alkylpyrrolidinyl]amino, piperidinyl- amino, N-[(C i -6)alkyl] -N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(C i -6)alkyl] -N- (piperidinyl)amino, (C i -6)alkylpiperidinylamino, N-[(C i -6)alkyl] -N-[(C i -6)alkyl- piperidinyl]amino, N-[(Ci-6)alkyl]-N-[(C3.7)cycloalkylpiperidinyl]amino, N-[(Ci.6)alkyl]- N-[(C2-6)alkylcarbonylpiperidinyl]amino, pyrrolidinyl(C1-6)alkylamino, N-[(Ci_6)alkyl]-N- [pyrrolidinyl(C i .6)alkyl]amino, N-[(C i -6)alkyl] -N-[piperidinyl(C i -6)alkyl]amino, (C i -6)- alkylpyrazolylamino, di(Ci-6)alkylpyrazolylamino, In(C1 -6)alkylpyrazolylamino, N-[(C1-6)- alkyl]-N-[(Ci-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(Ci^alkoxy- carbonyl][(Ci-6)alkyl]imidazolylamino, (Ci-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (Ci-6)alkylpyridinylamino, di(C1-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C i -6)alkylpyridinylamino, dihydroxy(C i -6)alkylpyridinylamino, (C i -6)alkoxypyridinylamino, dihydroxy(C i -6)alkoxy- pyridinylamino, di(C i .6)alkyldioxolanyl(C i -6)alkoxypyridinylamino, (C \ -6)alkoxy(C i -6)- alkylpyridinylamino, (Ci.6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(Ci-6)alkyl- aminopyridinylamino, di(C i -6)alkylaminopyridinylamino, (C i -6)alkylamino(C i .6)alkyl- pyridinylamino, di(Ci-6)alkylamino(Ci-6)alkylpyridinylamino, carboxypyridinylamino, N- [(Ci-6)alkyl]-N-[(Ci-6)alkylpyridinyl]amino, bis[(Ci.6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (Ci-6)alkylpyridazinylamino, N-[(Ci-6)alkyl]- N-[(Ci-6)alkylpyridazinyl]amino, N-[aryl(Ci-6)alkyl]-N-[(Ci-6)alkylpyridazinyl]amino, di(Ci-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C I-6)- alkoxypyridazinylamino, di(Ci.6)alkylaminopyridazinylamino, bis[(Ci.6)alkylpyridazinyl]- amino, benzofuryl(Ci-6)alkylamino, thienyl(C1-6)alkylamino, indolyl(Ci-6)alkylamino, (C i -6)alkylpyrazolyl(C i -6)alkylamino, [di(C i -6)alkyl] (halo)pyrazolyl(C i -6)alkylamino, di(C [ -6)alkylisoxazolyl(C i -6)alkylamino, thiazolyl(C i -6)alkylamino, imidazolyl(C i -6)alkyl- amino, (Ci-6)alkylimidazolyl(Ci-6)alkylamino, pyridinyl(Ci-6)alkylamino, (Ci-6)alkyl- pyridinyl(Ci-6)alkylamino, ^[(Ci-^alkylJ-AZ-fpyridiny^Ci^alkylJamino, N-[dihydroxy- (C i -6)alkyl]-iV-[ρyridinyl(C i -6)alkyl] amino, N-[(C i -6)alkylpyridinyl(C i -6)alkyl] -N-
[dihydroxy(Ci-6)alkyl] amino, amino(C1-6)alkyl, (Ci-6)alkylamino(Ci-6)alkyl, di(Ci-6)alkyl- amino(Ci-6)alkyl, pyridinylamino(Ci-6)alkyl, 7V-[(C2-6)alkylcarbonyl]-N-[(Ci-6)alkyl- pyridinyl(C]-6)alkyl] amino, di(Ci.6)alkylamino(Ci-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (C i -6)alkylpiperidinylcarbonylamino, (C i .6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (Ci^alkylpiperidinylaminocarbonyl, 7V-[(Ci-6)alkyl]-Λ/-[(Ci-6)- alkylpiperidinyl] aminocarbonyl, piperidinyl(C i -6)alkylaminocarbonyl, (C i -6)alkyl- piperazinylcarbonyl, Ci-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy or tetra(Ci-6)alkyldioxaborolanyl; and
R44 represents hydrogen, halogen, Ci-6 alkyl or Ci-6 alkoxy. A suitable value of R43 is (Ci-6)alkylpyrazolyl.
Specific values of R43 include bromo, nitro, methyl, w-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethyl- phenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, methylpiperazinylmethyl, methylpiperazinylethyl, moφholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methyl- propylpyrazolyl, 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, 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, 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, (tert-butoxycarbonylpiperazinyl)- (methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, methoxypyridinyl, (methoxy)(methyl)- pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonylmethylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylaminopyridazinyl, pyrimidinyl, methyl- pyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)(piperazinyl)pyrimidinyl, (tert-butoxycarbonyl- piperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxy- propynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylamino- pyrimidinyl, (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, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)- pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1 -methylethyl, dihydroxypropyl, pyridinyloxymethyl, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, 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, fluorophenyl- amino, N-fluorophenyl-N-methylamino, N-benzyl-N-methylamino, N-(benzyl)-N- (dimethylaminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino,
(cyano)(fluoro)benzylamino, methylenedioxybenzylamino, N-(methyl)-N-(methyl- pyrrolidinyl)amino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N- (piperidinyl)amino, N-(cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinyl- amino, N-(methyl)-N-(methylpiperidinyl)amino, N-(methyl)-N-(2-methylpropyl- piperidinyl)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, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, carboxypyridinyl amino, 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, benzofiirylmethylamino, 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, Λ/-(dihydroxypropyl)-N-(methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, N-(acetyl)-N-(methyl- pyridinyl)amino, dimethylaminoethylcarbonylamino, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, formyl, acetyl, methylpiperidinylaminocarbonyl, N-(methyl)-7V-(methylpiperidinyl)aminocarbonyl, piperidinylethylaminocarbonyl, methylpiperazinylcarbonyl, isopropylthio, isopropyl- sulphinyl, isopropylsulphonyl, tert-butoxycarbonyloxy and tetramethyldioxaborolanyl.
A particular value of R43 is methylpyrazolyl.
In one embodiment, R44 represents hydrogen. In another embodiment, R44 represents halogen, especially bromo. In a further embodiment, R44 represents Ci-6 alkyl, especially methyl. In an additional embodiment, R44 represents Ci-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) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. 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, fluorotrichloromethane, 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 phenylmercuric nitrate, benzylalkonium 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 may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
Figure imgf000070_0001
m (IV)
wherein U, V, W, the moiety X-Y-Q, R1, R2, R3, R4 and R6 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 N,7V-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 reaction will ideally be performed in the presence of tert-butylphosphonium tetrafluoroborate or dicyclohexyl diphenylphosphine.
The intermediates of formula (HI) above wherein L1 is bromo may be prepared from a compound of formula (V):
Figure imgf000071_0001
(V)
wherein U, V, W, the moiety X-Y-Q, R1, R2 and R6 are as defined above; by diazotization/ bromination.
The reaction is conveniently effected by stirring compound (V) with tert-butyl nitrite and copper(II) bromide in a suitable solvent, e.g. acetonitrile.
The intermediates of formula (V) above wherein U represents N may be prepared by reacting thiourea with a compound of formula (VI):
Figure imgf000071_0002
(VI)
wherein V, W, the moiety X-Y-Q, R1, R2 and R6 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 TVyV-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. In another procedure, the compounds of formula (I) wherein U represents N may be prepared by a process which comprises reacting a compound of formula (VI) as defined above with a compound of formula (VII):
Figure imgf000072_0001
R3
(VII)
wherein R3 and R4 are as defined above; under conditions analogous to those described above for the reaction between thiourea and compound (VI).
The reaction may additionally be accomplished by heating the reactants in acetic acid in the presence of sodium acetate.
The intermediates of formula (VII) above may be prepared by reacting a compound of formula (IV) as defined above with l,l'-thiocarbonyldiimidazole; followed by treatment with ammonia or ammonium hydroxide.
The compounds of formula (IA) above wherein Rx and Ry are both hydrogen may be prepared by a process which comprises reacting a compound of formula (VIII):
Figure imgf000072_0002
(VIII)
wherein U, V, W, R1, R2, R3, R4 and R6 are as defined above; with tert-butoxy- bis(dimethylamino)methane (Bredereck's reagent); followed by treatment with hydrazine, typically in the form of its hydrochloride salt, or in the form of its monohydrate.
The reaction between compound (VIII) and Bredereck's reagent may conveniently be effected by heating the reactants together, typically at the reflux temperature. The subsequent treatment with hydrazine hydrochloride or hydrazine hydrate may conveniently be effected in a suitable solvent, e.g. a lower alkanol solvent such as methanol or ethanol, optionally at an elevated temperature.
The compounds of formula (IC) above wherein Ry and Rz are both hydrogen may be prepared by a process which comprises reacting a compound of formula (IX):
Figure imgf000073_0001
(IX)
wherein U, V, W, R1, R2, R3, R4 and R6 are as defined above, and L3 represents a suitable leaving group; with aminoacetaldehyde dimethyl acetal; followed by treatment with an acid, typically an organic acid such as p-toluenesulphonic acid.
The leaving group L3 is typically a halogen atom, e.g. chloro, or a methylthio (-SCH3) group.
The reaction between compound (IX) and aminoacetaldehyde dimethyl acetal may conveniently be effected by heating the reactants together. The subsequent acid treatment may conveniently be effected by heating in a suitable solvent, e.g. a hydrocarbon solvent such as toluene, or a lower alkanol solvent such as isopropanol.
The compounds of formula (IC) above wherein Ry is methyl and Rz is hydrogen may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with propargylamine.
The reaction may conveniently be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether solvent such as tetrahydrofuran.
The intermediates of formula (IX) above wherein L3 is methylthio may be prepared by reacting a compound of formula (X):
Figure imgf000074_0001
(X)
wherein U, V, W, R1, R2, R3, R4 and R6 are as defined above; with a methyl halide, e.g. iodomethane.
The reaction is conveniently effected in a suitable organic solvent, e.g. acetonitrile.
The intermediates of formula (X) above may be prepared by reacting a compound of formula (XI):
Figure imgf000074_0002
(XI)
wherein U, V, W, R , R , R , R and R are as defined above; with 2,4-bis(4-methoxy- phenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent).
The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a hydrocarbon solvent such as toluene.
The intermediates of formula (IX) above wherein L3 is chloro may be prepared by reacting a compound of formula (XI) as defined above with phosphorus oxychloride, typically at an elevated temperature.
The compounds of formula (ID) above may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with a compound of formula Ry-CONHNH2. The reaction may be conveniently accomplished in the presence of an organic acid such as acetic acid. The compounds of formula (IE) above may be prepared by a process which comprises reacting a compound of formula (IX) as defined above with a metal azide such as sodium azide. The reaction is conveniently accomplished in a suitable solvent, e.g. a lower alkanol solvent such as methanol.
The compounds of formula (VIII) and (XI) above may be prepared by the methods described in WO 2006/114606; in copending international patent application no. PCT/GB2007/002390, published on 3 January 2008 as WO 2008/001076; and in copending international patent application no. PCT/GB2007/002051 , published on 13 December 2007 as WO 2007/141504.
By way of example, the intermediates of formula (VIII) above wherein U represents C-R5 may be prepared by reacting a compound of formula (IV) as defined above with a compound of formula (XII):
Figure imgf000075_0001
(XII)
wherein V, W, R1, R2, R5, R6 and L1 are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (IV).
The intermediates of formula (XII) above wherein L1 is bromo may be prepared from a compound of formula (XIII):
Figure imgf000075_0002
(XIII) wherein V, W, R1, R2, R5 and R6 are as defined above; by diazotization/bromination; under conditions analogous to those described above for the diazotization/bromination of compound (V).
The intermediates of formula (XIII) above wherein R5 represents cyano may be prepared by reacting malononitrile with a compound of formula (XIV):
Figure imgf000076_0001
(XIV)
wherein V, W, R1, R2 and R6 are as defined above; followed by treatment of the resulting compound with sulphur.
The reaction between malononitrile and compound (XIV) is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of piperidine. Treatment of the resulting compound with sulphur is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of morpholine.
Where they are not commercially available, the starting materials of formula (IV), (VI) and (XIV) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of example, a compound of formula (IA) wherein Rx represents hydrogen may be converted into the corresponding compound wherein R" is an alkylsulphonyl substituent, e.g. methylsulphonyl, by treatment with the appropriate alkylsulphonyl halide, e.g. methanesulphonyl chloride. A compound of formula (I) wherein R6 represents hydroxy may be converted into the corresponding compound wherein R6 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 TV-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(O) 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 heteroarylaryl(Ci-6)alkyl 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 heteroaryl(Ci-6)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(Ci.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 carbonate or potassium phosphate, in an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonium bromide. 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 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and potassium phosphate.
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, iV-methyl-N-phenylaminomethyl, pyridin- 3-ylaminomethyl, indolin-1-ylmethyl, 1,2,3,4-tetrahydroquinolin-l-ylmethyl or 1,2,3,4- tetrahydroisoquinolin-2-ylmethyl, by a two-stage procedure which comprises (i) Swern oxidation of the hydroxymethyl derivative by treatment with oxalyl chloride and dimethyl sulphoxide in the presence of triethylamine; and (ii) reductive animation of the formyl derivative thereby obtained by treatment with the appropriate amine, e.g. aniline, JV- methylaniline, 3-aminopyridine, indoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4- tetrahydroisoquinoline, in the presence of a reducing agent such as sodium cyanoborohydride.
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- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 6- methoxy- 1 ,2,3,4-tetrahydroquinolin- 1 -ylcarbonyl, 1 ,2,3 ,4-tetrahydroisoquinolin-2- ylcarbonyl or 1, 2,3, 4-tetrahydroquinoxalin-l -ylcarbonyl, by a two-stage procedure which comprises (i) oxidation of the hydroxymethyl moiety by treatment with potassium permanganate; and (ii) reaction of the carboxy derivative thereby obtained with the appropriate amine, e.g. piperidine, 1,2,3,4-tetrahydroquinoline, 6-methyl- 1,2,3,4- tetrahydroquinoline, 6-methoxy-l ,2,3,4-tetrahydroquinoline, 1 ,2,3,4-tetrahydro- isoquinoline or 1,2,3,4-tetrahydroquinoxaline, in the presence of a condensing agent such as l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, or 0-(benzotriazol-l-yl)-N,JV,iV,7V- tetramethyluronium hexafluorophosphate (HBTU).
A 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-te/-t-butylphosphino)biphenyl and sodium tert-butoxide. A compound of formula (I) wherein R contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by pyrrolidin-1-yl by treatment with pyrrolidine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1 , 1 '-biphenyl and a base such as potassium carbonate. 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),
Figure imgf000079_0001
isopropyl- 1 ,l'-biphenyl (X-Phos) and a base 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 M-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 an indole moiety by treatment with an oxidising agent such as manganese dioxide. A compound of formula (I) wherein R3 contains a hydroxy substituent may be converted into the corresponding compound wherein R3 contains a Ci-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)- ΛζΛ^/V^-tetramethyluronium hexafluorophosphate (HBTU), typically in a dipolar aprotic solvent such as Λ^/V-dimethylformamide; or in the presence of l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide and 1-hydroxybenzotriazole. A compound of formula (I) wherein R 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 C 1.6 alkyl haloformate, e.g. methyl chloro formate.
A compound of formula (I) wherein R 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, generally by treatment with a base, e.g. an alkali metal hydroxide such as lithium hydroxide or sodium 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-hydroxyethylamino- carbonyl, dimethylaminocarbonyl, 7V-(2-hydroxyethyl)-iV-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-(dimethylamino)propyl]-3-ethyl- carbodiimide; and (ii) reaction of the pentafluorophenyl ester thereby obtained with the appropriate amine, e.g. methylamine, 2-hydroxyethylamine, dimethylamine, N-(2- hydroxyethyl)-N-methylamine, benzylamine, azetidine, pyrrolidine, piperidine, 1- methylpiperazine or morpholine.
A compound of formula (I) wherein R3/R4 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]palladium(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 R3/R4 contains a benzo moiety substituted by a heteroaryl group, e.g. pyrazol-3-yl, 1- methylpyrazol-4-yl, l-propylpyrazol-4-yl, l-isobutylpyrazol-4-yl, l-benzylpyrazol-4-yl, 1- [2-(morpholin-4-yl)ethyl]pyrazol-4-yl, 6-methylpyridin-3-yl or pyrimidin-5-yl, by treatment with the appropriate heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst. 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 compound wherein R3/R4 contains a benzo moiety substituted by a heteroaryl group, e.g. methylimidazolyl, by treatment with the appropriate heteroaryl halide, e.g. bromide, derivative in the presence of a catalyst. The catalyst may typically be a transition metal catalyst. A suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, optionally in the presence of tetrabutylammonium bromide.
A compound of formula (I) wherein R3/R4 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 7V,7V-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 R /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 be converted into the corresponding compound wherein R3/R4 contains hydroxy by treatment with sodium hydroxide in the presence of tris(dibenzylideneacetone)- dipalladium(O) and 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-l,r-biphenyl. A compound of formula (I) wherein R /R contains hydroxy may be converted into the corresponding compound wherein R3/R4 contains optionally substituted Ci-6 alkoxy, C3-7 heterocycloalkoxy or C3-7 heterocycloalkyl(Ci-6)alkoxy by treatment with the appropriately substituted Ci-6 alkyl, C3-7 heterocycloalkyl or C3-7 heterocycloalkyl(C[-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 tørt-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 R3/R4 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 [l,r-bis(di-tert-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. 3-hydroxyprop-l-yn-l-yl) by treatment with an appropriately- substituted alkyne derivative (e.g. 3-hydroxyprop-l-yne) and a catalyst such as tetrakis(triphenylphosphine)palladium(0), typically in the presence of copper(I) iodide and a base such as triethylamine.
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 Ci-6 alkylthio (e.g. isopropylthio) by treatment with n-butyllithium and the appropriate disulphide derivative (e.g isopropyl disulphide). Conversion of the Ci-6 alkylthio moiety into Ci-6 alkylsulphinyl or Ci-6 alkylsulphonyl may be accomplished by treatment with an oxidising agent, e.g. m-chloroperbenzoic acid.
A compound of formula (I) wherein R3/R4 contains a pyridinyl moiety may be converted into the corresponding pyridine-TV-oxide analogue by treatment with peracetic acid.
A compound of formula (I) wherein 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/R4 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 R /R4 contains an oxazolin-1-yl moiety by treatment with thionyl chloride.
A compound of formula (I) wherein R3/R4 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 vic- dihydroxy analogues by treatment with osmium tetroxide.
Alkenyl- and alkynyl-containing compounds may be converted into the corresponding alkyl analogues by catalytic hydrogenation.
A compound of formula (I) wherein 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-NRcRd 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 R5 represents -CONH2 by heating under acidic conditions, e.g. in a mixture of acetic acid and sulphuric acid; prolonged treatment leads to conversion to the corresponding carboxylic acid followed by decarboxylation, i.e. conversion into the corresponding compound wherein R5 represents hydrogen.
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,Odimethyl- hydroxylamine hydrochloride and a condensing agent such as EDC, typically in the presence of HBTU; and (ii) reaction of the compound thereby obtained with the appropriate aryl lithium derivative, e.g. phenyllithium.
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(tetrafluoroborate)]. 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 TV-chlorosuccinimide, Λ/-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,7V-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 -CO2R by treatment with carbon monoxide and an alcohol of formula R -OH, in the presence of a catalyst. Indeed, this procedure is generally applicable for converting any compound of formula (I) wherein R5 contains a halogen atom into the corresponding compound containing a lower alkyl ester functionality. The catalyst may typically be a transition metal catalyst. A suitable catalyst is [l,l'-bis(diphenylphosphino)ferrocene]dichloro- palladium(II)-dichloromethane complex, in which case the transformation may conveniently be effected at an elevated temperature and pressure in the presence of an organic base such as triethylamine.
A compound of formula (I) wherein 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 heterocycloalkyl(Ci-6)alkyl-aryl, heteroaryl or heteroaryl-aryl by treatment with, respectively, an aryl, biaryl, C3-7 heterocycloalkyl-aryl, C3-7 heterocycloalkyl(Ci-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 7V-phenyldiethanolamine, in the presence of a catalyst. The catalyst may typically be a transition metal catalyst. A suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate, potassium hydroxide or potassium phosphate, in an inert solvent such as 1 ,2-dimethoxyethane, tetrahydrofuran or 1 ,4-dioxane. 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 1 ,3-bis(diphenylphosphino)propane and potassium phosphate, or in the presence of PdCl2.dppf and potassium phosphate. In 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 the 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)alkyne, 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 N-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 aminomethyl moiety by treatment with the appropriate amine derivative (including cyclic amines), generally in the presence of triphenylphosphine and diethyl azodicarboxylate. A compound of formula (I) wherein R5 contains a trifluoromethylsulphonyloxy moiety may be converted into the corresponding compound wherein the trifluoromethylsulphonyloxy moiety is replaced by an amino functionality by treatment with the appropriate amine derivative (including cyclic amines) and a transition metal catalyst, e.g. acetato(2'-di-tert-butylphosphino- 1 , 1 '-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 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(dibenzylideneacetone)dipalladium(0), typically in the presence of 1 ,3- bis(diphenylphosphino)propane and a base such as potassium carbonate; and (ii) hydrolysis of the resulting compound by treatment with a mineral acid, e.g. hydrochloric acid. A 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 N^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 unsubstiruted pyrimidinyl moiety by treatment with the appropriate amidine derivative, typically at an elevated temperature in the presence of a base such as sodium ethoxide.
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 conventional 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 racemate, and an appropriate chiral 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, 3rd 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 PDKα and/or PDKβ and/or PDKγ and/or PDKδ.
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 of 2% (v/v) DMSO alone (100% activity). The concentration of inhibitor required to inhibit the enzyme activity by 50% is quoted as the IC5o-
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 PI3Kα and/or PDKβ and/or PDKγ and/or PDKδ of 50 μM or better.
EXAMPLES
Abbreviations
DCM: dichloromethane DMF: jVyV-dimethylformamide DMSO: dimethylsulphoxide MeCN: acetonitrile Et2O: diethyl ether THF: tetrahydrofuran MeOH: methanol AcOH: acetic acid EtOH: ethanol IPA: isopropyl alcohol Ac: acetyl EtOAc: ethyl acetate
Me: methyl Et: ethyl
NBS: TV-bromosuccinimide NIS: TV-iodoosuccinimide r.t.: room temperature sat.: saturated h: hour min: minute cone: concentrated v: volume wt: weight M: mass
SiO2: silica br.: broad
DIPEA: NiV-diisopropylethylamine RT: retention time EDC: l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride brine: saturated aqueous sodium chloride solution
HPLC: High Performance Liquid Chromatography
LCMS: Liquid Chromatography Mass Spectrometry
ES+: Electrospray Positive Ionisation Bredereck' s reagent: tørt-butoxybis(dimethylamino)methane
Lawesson's reagent: 2,4-bis(4-methoxyphenyl)-l ,3-dithia-2,4-diphosphetane-2,4- disulfide
Analytical Conditions All NMRs were obtained either at 300 MHz or 400 MHz.
Compounds were named with the aid of ACD Labs Name (v. 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.
INTERMEDIATE 1
3-Bromo-6,6-dimethylpiperidine-2,4-dione
To a stirred suspension of 6,6-dimethylpiperidine-2,4-dione (WO 2005/013986) (10.0 g, 70.92 mmol) in THF (200 mL) at 00C was added NaHSO4 (2.1 g, 17.73 mmol), followed by NBS (12.6 g, 70.92 mmol) portionwise over 2 h. The reaction mixture was warmed to r.t., stirred for 5 h, and then partitioned between DCM (200 mL) and water (100 mL). The aqueous fraction was separated and 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. Trituration with IPA (3 x 50 mL) gave 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) for the main tautomer. LCMS (ES+) 220.0 and 222.0 (1 :1 ratio) (M+H)+.
INTERMEDIATE 2 (METHOD A)
6,6-Dimethyl-2-(morpholin-4-yl)-6,7-dihvdro[l,31thiazolo[5,4-c]pyridin-4(5H)-one
To a stirred solution of Intermediate 1 (0.16 g, 0.71 mmol) in TΗF (3 mL) was added morpholine-4-carbothioamide (WO 2006/114606) (0.11 g, 0.71 mmol) and DIPEA (0.25 mL, 1.42 mmol). The reaction mixture was heated to 600C for 1.5 h, then cooled to r.t. and partitioned between EtOAc (10 mL) and water (10 mL). The aqueous fraction was separated and extracted with EtOAc (3 x 5 mL). The combined organic fractions were washed with water (3 x 10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 1 : 1 EtOAc/hexanes) gave the title compound (0.07 g, 35%) as a yellow solid. δΗ (DMSO-d6) 7.30 (IH, br. s), 3.72-3.65 (4H, m), 3.51-3.45 (4H, m), 2.70 (2H, s), 1.24 (6H, s). LCMS (ES+) 268.0 (M+H)+.
INTERMEDIATE 3 (METHOD B)
6,6-Dimethyl-2-(moφholin-4-yl)-6,7-dihvdrori,31thiazolo[5,4-c1pyridine-4(5H)-thione
To a stirred solution of Intermediate 2 (0.80 g, 2.99 mmol) in toluene (20 mL) was added Lawesson's reagent (0.61 g, 1.50 mmol). The reaction mixture was heated to reflux for 30 minutes, then cooled to r.t. and concentrated in vacuo. Purification by column chromatography (SiO2, 1 :1 EtOAc/hexanes) gave the title compound (0.65 g,
77%) as a yellow solid. δΗ (CDCl3) 6.92 (IH, br. s), 3.84-3.81 (4H, m), 3.61-3.58 (4H, m), 2.80 (2H, s), 1.42 (6H, s). LCMS (ES+) 284.0 (M+H)+.
INTERMEDIATE 4 (METHOD C)
6.6-Dimethyl-4-(methylsulfanyl)-2-(morpholin-4-yl)-6,7-dihvdro[L31thiazolo[5,4- clpyridine hvdroiodide To a stirred solution of Intermediate 3 (0.65 g, 2.30 mmol) in MeCN (15 mL) was added methyl iodide (0.17 mL, 2.76 mmol). The reaction mixture was stirred for 16 h, then concentrated in vacuo. Trituration with acetone (3 x 3 mL) gave the title compound (0.92 g, 94%) as a yellow solid. δH (CDCl3) 9.82 (IH, br. s, HI), 3.89-3.83 (4H, m), 3.79- 3.74 (4H, m), 3.31 (3H, s), 2.97 (2H, s), 1.85 (6H, s). LCMS (ES+) 298.0 (M+H)+.
INTERMEDIATE 5
fert-Butyl (35)-3-[3-(trimethylsilyl)prop-2-yn-l-yllmoφholine-4-carboxylate To a stirred solution of (trimethylsilyl)acetylene (9.9 mL, 69.83 mmol) in THF
(120 mL) at 00C was added n-butyllithium (28 mL, 2.5M in hexanes, 69.83 mmol) dropwise over 15 minutes. After stirring at this temperature for 30 minutes, a suspension of (3ai?)-tetrahydro-3H-[l,2,3]oxathiazolo[4,3-c][l,4]oxazine 1,1-dioxide (WO 2006/ 114606) (5.0 g, 27.93 mmol) in TΗF (50 mL) was added dropwise and the reaction mixture stirred at 00C for 30 minutes, then a further 30 minutes at r.t. Aqueous HCl solution (2M; 80 mL) was added and the reaction mixture stirred vigorously at r.t. MeOH (80 mL) was added and the reaction mixture was stirred at r.t. for 3 h, then concentrated in vacuo. The residue was dissolved in DCM (150 mL), and DIPEA (9.7 mL, 55.86 mmol) was added. The reaction mixture was cooled to 00C and a solution of di-tert-butyl dicarbonate (9.2 g, 41.89 mmol) in DCM (50 mL) was added. The reaction mixture was stirred at r.t. for 16 h before addition of water (100 mL). The aqueous layer was separated and extracted with EtOAc (2 x 50 mL). The combined organic fractions were washed with water (3 x 150 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-2% EtOAc/DCM) gave the title compound (7.3 g, 88%) as a light orange oil. δΗ (CD3OD) 3.95-3.88 (IH, m), 3.82 (IH, d, J 11.7 Hz), 3.70 (IH, dd, J3.6 and 11.4 Hz), 3.58 (IH, dd, J2.9 and 13.7 Hz), 3.40- 3.20 (2H, m), 2.99-2.85 (IH, m), 2.60 (IH, dd, J9.1 and 16.7 Hz), 2.38 (IH, dd, J6.4 and 16.7 Hz), 1.35 (9H, s), 0.00 (9H, s).
INTERMEDIATE 6 (METHOD D)
fert-Butyl (3S)-3-\(2-tert-but\\- 1 -benzofuran-3-vπmethyllmorpholine-4-carboxylate To a stirred solution of Intermediate 5 (0.83 g, 2.79 mmol) in DMF (25 mL) were added 2-iodophenol (0.61 g, 2.79 mmol), LiCl (0.12 g, 2.79 mmol), Na2CO3 (0.53 g, 5.58 mmol) and Pd(OAc)2 (0.025 g, 0.04 mmol). The reaction mixture was stirred at 900C for 16 h, then cooled to r.t. and concentrated in vacuo. Purification by column chromatography (SiO2, 5-20% EtOAc/hexanes) gave the title compound (0.70 g, 64%) as a clear oil. LCMS (ES+) 334.0 ((M-'Bu)+H)+.
INTERMEDIATE 7 (METHOD E)
(35V3-(l-Benzofuran-3-ylmethyl)morpholine
To a solution of Intermediate 6 (0.70 g, 1.79 mmol) in MeOH (15 mL) at 00C was added 4M HCl in 1,4-dioxane (10 mL) portionwise. The reaction mixture was warmed to r.t., stirred for 2 h, and then concentrated in vacuo. EtOAc (25 mL) and sat. aqueous NaHCO3 solution (5 mL) were added and the layers separated. The organic fraction was washed with water (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.29 g, 75%) as a white solid that was used without further purification. LCMS (ES+) 218.1 (M+H)+.
INTERMEDIATE 8 (METHOD F)
(35^-3-(l-Benzofuran-3-ylmethyl)moφholine-4-carbothioamide
To a stirred solution of l,l'-thiocarbonyldiimidazole (0.26 g, 1.47 mmol) in THF (10 mL) was added Intermediate 7 (0.29 g, 1.33 mmol). The reaction mixture was stirred at r.t. for 4 h, and then concentrated in vacuo. The residue was dissolved in MeCN (15 mL) and aqueous NH3 (20% v/v, 15 mL) was added. The reaction mixture was stirred at 600C for 16 h, cooled at r.t., and then concentrated in vacuo. Purification by column chromatography (SiO2, 40% EtOAc/hexanes) gave the title compound (0.25 g, 68%) as a yellow solid. LCMS (ES+) 277.1 (M+H)+.
INTERMEDIATE 9
2-r(35)-3-(l-Benzofuran-3-ylmethyl)morpholin-4-yll-5.5-dimethyl-5.6-dihvdro-1.3- benzothiazol-7(4H)-one The title compound was prepared from 2-bromo-5,5-dimethylcyclohexane-l,3- dione (WO 2006/114606) and Intermediate 8 according to Method A (after stirring at 600C for 2 h, additional Intermediate 8 (1 equivalent) and DIPEA (2 equivalents) were added and the reaction mixture stirred at 600C for 16 h) and was isolated as a glassy solid (47%) after purification by column chromatography (SiO2, 50-70% EtOAc/hexanes, followed by SiO2, 0-1% MeOH/DCM). LCMS (ES+) 485.1 (M+H)+.
INTERMEDIATE 10
Methyl 3- {r(35V4-(fe^butoxycarbonyl)morpholin-3-yllmethvU -2-(trimethylsilyl)- IH- indole-5-carboxylate
The title compound was prepared from methyl 4-amino-3-iodobenzoate and Intermediate 5 according to Method D and was isolated as a yellow solid (59%) after purification by column chromatography (SiO2, 10-25% EtOAc/hexanes). LCMS (ES+) 392.0 ((M-'Bu)+Η)+.
INTERMEDIATE 11
Methyl 3-[Y35)-morpholin-3-ylmethyl1- lH-indole-5-carboxylate The title compound was prepared from Intermediate IO according to Method E and was isolated as a brown gum (quantitative) that was used without further purification. LCMS (ES+) 275.0 (M+Η)+.
INTERMEDIATE 12
Methyl 3-{[(35)-4-(aminocarbonothioyl)morpholin-3-yl]methyl|-lH-indole-5- carboxylate
The title compound was prepared from Intermediate II according to Method F and was isolated as a yellow solid (99%) after purification by column chromatography (SiO2, 0-4% MeOΗ/DCM). LCMS (ES+) 334.0 (M+Η)+.
INTERMEDIATE 13 Methyl 3-(r(35r)-4-(6,6-dimethyl-4-oxo-4.5.6.7-tetrahvdrori,31thiazolor5,4-clpyridin-2- yl)moφholin-3-yl1methylMH-indole-5-carboxylate
The title compound was prepared from Intermediate 12 and Intermediate 1 according to Method A and was isolated as a yellow solid (69%) after purification by column chromatography (SiO2, 0-5% MeOΗ/DCM). δΗ (CD3OD) 8.62 (1 H, d, J 1.0 Hz), 7.81 (IH, dd, J8.6 and 1.6 Hz), 7.39 (IH, d, J8.6 Hz), 7.24 (IH, s), 4.41-4.35 (IH, m), 4.11-4.05 (IH, m), 3.95 (3H, s), 3.90 (IH, d, J 11.7 Hz), 3.73-3.52 (4H, m), 3.45-3.38 (IH, m), 3.18 (IH, dd, J 13.9 and 5.4 Hz), 2.87 (IH, d, J 16.9 Hz), 2.81 (IH, d, J 16.9 Hz), 1.37 (3H, s), 1.36 (3H, s). Exchangeable protons were not observed. LCMS (ES+) 455.0 (M+H)+.
INTERMEDIATE 14
Methyl 3- (r(35)-4-(6.6-dimethyl-4-thioxo-4.5.6.7-tetrahydror 1 ,31thiazolor5.4-c1pyridin- 2-yl)morpholin-3-yl]methyU-lH-indole-5-carboxylate
The title compound was prepared from Intermediate 13 according to Method B and was isolated as a yellow oil (66%) after purification by column chromatography (SiO2, 1 :2 EtOAc/hexanes). δΗ (CDCl3) 8.70 (IH, s), 8.30 (IH, br. s), 7.95 (IH, dd, J 8.6 and 1.3 Hz), 7.38 (IH, d, J 8.6 Hz), 7.18 (IH, d, J 1.6 Hz), 6.87 (IH, br. s), 4.45-4.30 (IH, m), 4.17-4.08 (IH, m), 3.98 (3H, s), 3.88 (IH, d, J 11.8 Hz), 3.75-3.61 (3H, m), 3.56 (IH, dd, J 11.7 and 2.1 Hz), 3.43 (IH, dd, J 13.9 and 10.9 Hz), 3.16 (IH, dd, J 13.9 and 4.5 Hz), 2.90 (2H, d, J 3.0 Hz), 2.07 (6H, s). LCMS (ES+) 471.1 (M+H)+.
INTERMEDIATE 15
Methyl 3-( {(35l)-4-r6.6-dimethyl-4-(methylsulfanyl)-6.7-dihydror 1.31thiazolor5.4- clpyridin-2-yl1morpholin-3-vUmethyl)-lH-indole-5-carboxylate
The title compound was prepared from Intermediate 14 according to Method C and was isolated as a yellow solid (quantitative) that was used without further purification. LCMS (ES+) 485.1 (M+Η)+.
INTERMEDIATE 16 fert-Butyl (35V3- {[5-cvano-2-(trimethylsilylHH-indol-3-yl]methyl}morpholine-4- carboxylate
The title compound was prepared from Intermediate 5 and 4-amino-3-iodo- benzonitrile according to Method D and was isolated as a yellow solid (50%) after work- up (EtOAc and water) and purification by column chromatography (SiO2, 5-100% EtOAc/hexanes). LCMS (ES+) 414.0 (M+Η)+.
INTERMEDIATE 17
3-r(35^-Morpholin-3-ylmethyll-lH-indole-5-carbonitrile
The title compound was prepared from Intermediate 16 according to Method E and was isolated as a brown solid (87%) that was used without further purification. LCMS (ES+) 242.0 (M+Η)+.
INTERMEDIATE 18
(35)-3-[(5-Cyano-lH-indol-3-yl)methyl1moφholine-4-carbothioamide
The title compound was prepared from Intermediate 17 according to Method F and was isolated as an off-white solid (39%) after purification by column chromatography (SiO2, 0-5% MeOΗ/DCM). LCMS (ES+) 301.0 (M+Η)+.
INTERMEDIATE 19
3-(r(3.S^-4-(6,6-Dimethyl-4-oxo-4,5,6.7-tetrahvdrori.31thiazolor5.4-clpyridin-2- yl)moφholin-3-yl1methvU-lH-indole-5-carbonitrile
The title compound was prepared from Intermediate 1 and Intermediate 18 according to Method A and was isolated as a yellow solid (35%) after recrystallisation from MeOH. δΗ (DMSO-d6) 11.45 (IH, s), 8.44 (IH, s), 7.49 (IH, d, J 8.5 Hz), 7.43-7.40 (2H, m), 7.29 (IH, s), 4.33-4.22 (IH, m), 3.99 (IH, d, J7.0 Hz), 3.73 (IH, d, J 11.6 Hz), 3.59-3.16 (5H, m), 2.97 (IH, dd, J 13.9 and 4.7 Hz), 2.75 (2H, s), 1.25 (6H, s). LCMS (ES+) 422.0 (M+H)+. INTERMEDIATE 20 (METHOD H)
3-{r(3^-4-f4-Chloro-6,6-dimethyl-6.7-dihvdroπ.31thiazolor5,4-clpyridin-2- yl)moipholin-3-yl1methyl}-lH-indole-5-carbonitrile A stirred solution of Intermediate 19 (0.34 g, 0.81 mmol) in phosphorus oxychloride (5 mL) was heated to reflux under nitrogen for 10 minutes, then cooled to r.t. and concentrated in vacuo. Water (15 mL) and EtOAc (15 mL) were added, and the layers separated. The organic fraction was washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (0.25 g, 69%) as a brown solid that was used without further purification. LCMS (ES+) 442.0 and 440.1 (M+H)+.
INTERMEDIATE 21
(35V3-[3-(Trimethylsilyl)prop-2-vn-l-yl]morpholine hydrochloride A solution of Intermediate 5 (25.0 g, 8.40 mmol) in 4N HCl in 1 ,4-dioxane (200 mL) was stirred at r.t. for 15 minutes, and then concentrated in vacuo, azeotroping with toluene. The residue was triturated with hexanes, and then filtered to give the title compound (17.5 g, quantitative) as a white solid that was used without further purification. δH (CD3OD) 3.98-3.88 (IH, m), 3.87-3.81 (IH, m), 3.77-3.51 (IH, m), 3.53- 3.43 (IH, m), 3.37-3.25 (2H, m), 3.22-3.04 (IH, m), 2.56-2.49 (2H, m), 0.00 (9H, s). Exchangeable proton was not observed.
INTERMEDIATE 22
7J-Dimethyl-2-{(35)-3-r3-(trimethylsilvnprop-2-vn-l-yllmorpholin-4-vU -5.6.7.8- tetrahvdro-4H-r 1 ,3")thiazolo[5,4-clazepin-4-one
To a stirred solution of 2-bromo-7,7-dimethyl-5,6,7,8-tetrahydro-4H- [l,3]thiazolo[5,4-c]azepine-4-one (WO 2006/114606) (5.0 g, 18.18 mmol) in DMF (5 mL) was added Intermediate 21 (3.5 g, 15.09 mmol), followed by DIPEA (7.8 mL, 45.27 mmol). The reaction mixture was heated to 1800C under microwave irradiation, in a sealed tube, then cooled to r.t. EtOAc (10 mL) and brine (10 mL) were added, and the layers separated. The organic fraction was washed with brine (4 x 10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% EtOAc/DCM), followed by trituration with EtOAc, gave the title compound (3.8 g, 65%) as a white solid. δH (DMSO-d6) 5.82-5.73 (IH, m), 4.02 (IH, d, J 11.9 Hz), 3.93-3.86 (IH, m), 3.83 (IH, dd, J 10.6 and 3.3 Hz), 3.56-3.49 (2H, m), 3.49- 3.43 (IH, m), 3.25-3.15 (IH, m), 3.00-2.95 (2H, m), 2.73-2.67 (IH, m), 2.66 (2H, s), 2.50 (IH, dd, J 16.4 and 5.3 Hz), 0.96 (6H, s), 0.00 (9H, s). LCMS (ES+) 392.1 (M+H)+.
INTERMEDIATE 23
3-(r(35l)-4-(7.7-Dimethyl-4-oxo-5,6,7;8-tetrahvdro-4H-[1.31thiazolor5,4-clazepin-2- yl)morpholin-3-yl1methyll-2-(trimethylsilyl)-lH-indole-5-carbonitrile
The title compound was prepared from Intermediate 22 and 4-amino-3-iodo- benzonitrile according to Method D and was isolated as a white solid (79%) after work-up (EtOAc and water) and purification by column chromatography (SiO2, 33-50% EtOAc/ hexanes). LCMS (ES+) 508.1 (M+Η)+.
INTERMEDIATE 24
3-Ethoxy-5,5-dimethylcyclohex-2-en-l-one
To a stirred solution of NaOEt (50 mL, 50.0 mmol), freshly prepared from Na (2.17 g, 50.0 mmol) and EtOH (50 mL), was added 3-chloro-5,5-dimethyl-2-cyclohexene- 1-one (3.17 g, 20.0 mmol). The reaction mixture was refluxed for 20 minutes, then cooled to r.t. and partitioned between water (30 mL) and EtOAc (50 mL). The organic fraction was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (2.74 g, 82%) as a yellow oil that was used without further purification. 5H (CDCl3) 5.36 (IH, s), 3.92 (2H, q, J6.8 Hz), 2.29 (2H, s), 2.23 (2H, s), 1.39 (3H, t, J7.1 Hz), 1.09 (6H, s). LCMS (ES+) 169.1 (M+H)+.
INTERMEDIATE 25
4-Ethoxy-6.6-dimethyl-2-oxocyclohex-3-ene- 1 -carbaldehvde
To a stirred suspension of NaH (1.12 g, 60% dispersion in oil, 28.0 mmol) in Et2O (50 mL) was added a solution of Intermediate 24 (4.71 g, 28.0 mmol) and ethyl formate (4.5 mL, 56.0 mmol) in Et2O dropwise over 20 minutes. The reaction mixture was stirred at r.t. for 18 h. An additional portion of NaH (0.90 g, 60% dispersion in oil, 22.5 mmol) was added and the reaction mixture stirred at r.t. for a further 2 h. Water (100 mL) was added, and the layers were separated. The aqueous fraction was acidified to pH 3 with cone. HCl. The precipitate formed was filtered, washed with water (2 x 30 mL) and dried to give the title compound (2.91 g, 53%) as a yellow solid that was used without further purification. δH (CDCl3) 14.70 (IH, d, J9.9 Hz), 7.36 (IH, d, J9.9 Hz), 5.35 (IH, s), 3.98 (2H, q, J7.1 Hz), 2.31 (2H, s), 1.40 (3 H, t, J 7.1 Hz), 1.23 (6H, s). LCMS (ES+) 197.1 (M+H)+.
INTERMEDIATE 26
6-Ethoxy-4,4-dimethyl-4,5-dihvdro- 1 ,2-benzisoxazole
To a stirred solution of Intermediate 25 (3.0 g, 15.30 mmol) in EtOH (50 mL) was added hydroxylamine (1.2 mL, 50% wt. in water, 91.8 mmol). The reaction mixture was stirred at r.t. for 2 h, then concentrated in vacuo. AcOH (50 mL) was added. The reaction mixture was refluxed for 20 minutes, then cooled to r.t. and partitioned between EtOAc (50 mL) and aqueous sat. Na2CO3 solution (50 mL). The organic fraction was dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 5-10% EtOAc/hexanes, loading in toluene) gave the title compound (1.33 g, 45%) as a white solid. δH (CDCl3) 8.00 (IH, s), 5.63 (IH, s), 3.94 (2H, q, J 6.8 Hz), 2.41 (2H, s), 1.40 (3H, t, J 6.8 Hz), 1.25 (6H, s). LCMS (ES+) 194.1 (M+H)+.
INTERMEDIATE 27
4,4-Dimethyl-4J-dihydro- 1 ,2-benzisoxazol-6(5H)-one
To a stirred solution of Intermediate 26 (0.46 g, 2.38 mmol) in EtOH (10 mL) was added 4M aqueous HCl (10 mL). The reaction mixture was stirred at r.t. for 2 h, then concentrated to a low volume and partitioned between EtOAc (10 mL) and water (10 mL). The organic fraction was concentrated in vacuo to give the title compound (0.24 g, 62%) as a yellow oil that was used without further purification. 6Η (CDCl3) 8.24 (1Η, s), 3.61 (2Η, s), 2.56 (2H, s), 1.33 (6H, s). LCMS (ES+) 166.1 (M+H)+. INTERMEDIATE 28
7-Iodo-4,4-dimethyl-4,7-dihydro- 1 ,2-benzisoxazol-6(5H)-one
To a stirred solution of Intermediate 27 (0.50 g, 3.00 mmol) in AcOH (10 mL) was added NIS (0.71 g, 3.15 mmol). The reaction mixture was stirred at r.t. for 16 h. Water (10 mL) and EtOAc (15 mL) were added and the layers separated. The aqueous fraction was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (2 x 20 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a mixture of the title compound and starting material (1 :1 ratio, 0.46 g, 33% of title compound) that was used without further purification. LCMS (ES+) 291.9 (M+Η)+.
INTERMEDIATE 29
(35)-3 -( 1 H-Indol-3 - ylmethyl)morpholine-4-carbothioamide The title compound was prepared from 3-[(35)-morpholin-3-ylmethyl]- lH-indole
(WO 2006/114606) according to Method F and was isolated as an orange foam (44%) after purification by column chromatography (SiO2, EtOAc). 5Η (DMSO-d6) 10.85 (1Η, br. s), 7.86 (1Η, d, J7.2 Hz), 7.49 (2H, br. s), 7.33 (IH, d, J8.0 Hz), 7.18 (IH, d, J2.2 Hz), 7.09-7.01 (IH, m), 7.00-6.94 (IH, m), 3.87 (IH, m), 3.60 (IH, d, J 11.6 Hz), 3.36- 3.18 (6H, m), 2.81 (IH, dd, J 13.6 and 4.8 Hz). LCMS (ES+) 276.0 (M+H)+.
INTERMEDIATE 30
7-Ethoxy-5,5-dimethyl-5,6-dihydroquinazoline To boiling formamidine acetate (100 mL) was added Intermediate 25 (2.0 g, 10.20 mmol). The reaction mixture was refluxed for 15 minutes, then cooled to r.t. and partitioned between DCM (50 mL) and water (50 mL). The aqueous fraction was extracted with DCM (2 x 50 mL). The combined organic fractions were washed with water (2 x 100 mL), dried (Na2SO4), filtered, then concentrated in vacuo. Purification by column chromatography (SiO2, 33-50% EtOAc/hexanes) gave the title compound (0.45 g, 22%) as a yellow oil. δH (CDCl3) 8.83 (IH, s), 8.38 (IH, s), 5.70 (IH, s), 4.04 (2H, q, J 6.8 Hz), 2.41 (2H, s), 1.42 (3H, t, J7.3 Hz), 1.37 (6H, s). LCMS (ES+) 194.1 (M+H)+. INTERMEDIATE 31
5,5-Dimethyl-5,8-dihydroquinazolin-7(6//)-one
To a stirred solution of Intermediate 30 (0.45 g, 2.21 mmol) in EtOH (10 mL) was added 6M aqueous HCl (30 mL). The reaction mixture was stirred at r.t. for 16 h, and then concentrated in vacuo (co-distilling with water) to give the title compound (0.319 g, 82%) as a yellow oil that was used without further purification. δH (CDCl3) 8.99 (IH, s), 8.70 (IH, s), 3.73 (2H, s), 2.53 (2H, s), 1.34 (6H, s). LCMS (ES+) 177.0 (M+H)+.
INTERMEDIATE 32
6-Bromo-4H-benzor 1 ,4]oxazin-3-one
To a stirred solution of 2-amino-4-bromophenol (2.5 g, 13.3 mmol) in TΗF (80 mL) at 00C was added NEt3 (2.4 mL, 17.3 mmol), followed by chloroacetyl chloride (1.12 mL, 14.6 mmol) portionwise. The reaction mixture was stirred at this temperature for 10 minutes, then allowed to warm to r.t. and stirred for a further 2 h. It was then cooled to 00C and NaH (1.05 g, 60% dispersion in oil, 26 mmol) was added portionwise. The reaction mixture was stirred at 00C for 20 minutes, then at r.t. for 2 h before being quenched with water (20 mL) and concentrated in vacuo. The residue was diluted with water (100 mL). The precipitate formed was filtered, washed with water (3 x 50 mL) and dried in vacuo to give the title compound (2.14 g, 70%) as a beige solid that was used without further purification. δH (DMSO-d6) 10.81 (IH, br. s), 7.08 (IH, dd, J8.5 and 2.3 Hz), 7.02 (IH, d, J 2.3 Hz), 6.92 (IH, d, J 8.5 Hz), 4.60 (2H, s).
INTERMEDIATE 33
6-Bromo-3 ,4-dihydro-2H-benzo[ 1 ,4]oxazine
To a stirred solution of Intermediate 32 (2.0 g, 8.0 mmol) in TΗF (50 mL) was added borane-TΗF (13.2 mL, IM solution in TΗF, 13.2 mmol) portionwise. The reaction mixture was stirred at r.t. for 10 minutes, then heated to reflux for 1 h and allowed to cool to r.t. The reaction mixture was cooled to 00C and quenched with water (20 mL), then 2M aqueous NaOH (20 mL), and concentrated in vacuo. Water (100 mL) and EtOAc (100 mL) were added and the layers separated. The organic fraction was washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2 g, quantitative) as a brown oil. δH (DMSOd6) 6.68 (3 H, m), 4.25-4.18 (2H, m), 3.81 (IH, br. s), 3.44-3.36 (2H, m).
INTERMEDIATE 34
6-Bromo-3.4-dihydro-2H-benzo[L41oxazine-4-carbothioic acid amide
A solution of Intermediate 33 (1.7 g, 8 mmol) and l,r-thiocarbonyldiimidazole (2.84 g, 16 mmol) in TΗF (15 mL) was heated to 1200C under microwave irradiation, in a sealed tube, for 15 minutes. After cooling to r.t., NH3 (40 mL, 7N solution in MeOH, 280 mmol) was added. The reaction mixture was stirred at r.t. for 3 h, concentrated in vacuo, and then partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with water (100 mL), then brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. Trituration with Et2O and heptane gave the title compound (0.5 g, 23%) as a white solid. δH (DMSO-d6) 8.20 (2H, br. s), 7.60 (IH, d, J 2.3 Hz), 7.21 (IH, dd, J 8.7 and 2.3 Hz), 6.88 (IH, d, J 8.9 Hz), 4.30-4.16 (4H, m).
INTERMEDIATE 35
2-(6-Bromo-2,3-dihvdrobenzo[l,41oxazin-4-yl)-6,6-dimethyl-6J-dihvdro- fl,31thiazolo[5,4-c]pyridin-4(5H)-one
Two batches each of Intermediate 1 (0.25 g, 1.14 mmol), Intermediate 34 (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, in a sealed tube, for 20 minutes. After cooling to r.t., the reaction mixtures were combined and partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with brine (100 mL) and concentrated in vacuo. Purification by preparative ΗPLC gave the title compound (0.10 g, 11%) as an off-white solid. δΗ (CDCl3) 8.18 (IH, d, J 2.3 Hz), 7.08 (IH, dd, J 8.9 and 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)+.
INTERMEDIATE 36 6.6-Dimethyl-2-r6-(l -methyl- lH-pyrazol-4-vπ-2.3-dihvdrobenzor 1 ,41oxazin-4-yll-6.7- dihydrof 1 ,3]thiazolo[5,4-c1pyridin-4(5H)-one
A stirred suspension of Intermediate 35 (0.090 g, 0.23 mmol), l-methyl-4- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (0.142 g, 0.69 mmol), Na2CO3 (0.073 g, 0.69 mmol), tetra-n-butylammonium bromide (0.212 g, 0.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.026 g, 0.02 mmol) in TΗF (4 mL) was heated to 1500C under microwave irradiation, in a sealed tube, 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 pre-purified by preparative ΗPLC, then partitioned between EtOAc (100 mL) and aqueous sat. NaHCO3 solution (100 mL). The combined organic fractions were washed with a mixture of brine and water (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was then triturated with EtOAc (100 mL) to give the title compound (0.024 g, 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 and 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)+.
INTERMEDIATE 37
6-Ethoxy-4,4-dimethyl-4,5-dihvdro-2H-indazole
To a solution of Intermediate 25 (1.0 g, 5.1 mmol) in ethanol (15 mL) was added hydrazine hydrate (5.61 mmol, 0.272 mL). The reaction mixture was stirred for 5 minutes and allowed to stand for 2 weeks. The reaction mixture was concentrated to an oil in vacuo and purified by column chromatography (SiO2, 66-50% hexanes/EtOAc) to afford the title compound as a yellow oil (0.84 g, 86%). δΗ (CDCl3) 7.23 (IH, s), 5.64 (IH, s), 3.92 (2H, q, J7.0 Hz), 2.32 (2H, s), 1.39 (3H, t, J7.0 Hz), 1.27 (6H, s). LCMS (ES+) 193.0 (M+H)+.
INTERMEDIATE 38
4,4-Dimethyl-2.4,5,7-tetrahydro-6H-indazol-6-one To a solution of Intermediate 37 (0.84 g, 4.38 mmol) in ethanol (10 mL) was added 6N HCl (20 mL) and the reaction mixture stirred for 16 h. The reaction mixture was concentrated to dryness in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, passed through a phase separator and concentrated in vacuo to afford the title compound as an oil which crystallised on standing (0.708 g, 99%). δH (CDCl3) 7.46 (IH, s), 3.61 (2H, s), 2.54 (2H, s), 1.32 (7H, s). LCMS (ES+) 165.0 (M+H)+.
INTERMEDIATE 39
7-Bromo-4,4-dimethyl-2,4,5,7-tetrahvdro-6H-indazol-6-one
To a stirred solution of Intermediate 38 (0.53 g, 3.23 mmol) in glacial acetic acid (10 mL) was added N-bromosuccinimide (0.575 g, 3.23 mmol). The reaction mixture was stirred for 10 minutes and then water (50 mL) was added. The reaction mixture was extracted with ethyl acetate, the organic fraction washed with water, brine, passed through a phase separator and concentrated in vacuo to afford the title compound as a brown oil (0.76 g, 97%) which was used without purification. δH (CDCl3) 7.53 (IH, s), 5.43 (IH, s), 3.22 (2H, d, J 13.7 Hz), 2.46 ( 1 H, d, J 13.4 Hz), 1.23 (6H, d).
INTERMEDIATE 40
Pentafluorophenyl 3- (r(35V4-(5.5-dimethyl-5,6-dihydror 1.31thiazolor5.4-cl-
[L2,41triazolo[4,3-fl1pyridin-8-yl)moφholin-3-yllmethyl|-l-methyl-lH-indole-5- carboxylate Example 23 (0.18 g, 0.4 mmol), pentafluorophenol (0.075 g, 0.44 mmol) and
DIPEA (0.08 mL, 0.48 mmol) were dissolved in DMF (2 mL) and cooled to O0C. EDC (0.08 g, 0.44 mmol) was added and the reaction mixture allowed to warm to r.t. and stirred for 16 h. Water (15 mL) was added, resulting in the precipitation of the crude product which was isolated by filtration and dried in vacuo. Purification by column chromatography (SiO2, EtOAc/MeOΗ, 0-10%) gave 0.15 g (58%) of the title compound. LCMS (ES+) 645.1 (M+Η)+.
INTERMEDIATE 41 Methyl 3 -iodo-4-(methylamino)benzoate
Methyl 4-amino-3-iodobenzoate (5 g, 18 mmol) was dissolved in formic acid (35 mL) and the reaction mixture heated at reflux for 90 minutes. Volatiles and formic acid were removed by evaporation in vacuo. The residue was taken up in DCM (200 mL) and washed with sat. NaHCO3 solution (40 mL). The organic layer was isolated and washed with water (2 x 40 mL), dried (MgSO4) and the solvent removed by evaporation in vacuo. The residue was dissolved in THF (200 mL), BH3-Me2S (5 mL, 53 mmol) added and the reaction mixture heated at reflux for 90 minutes. Upon cooling the reaction mixture was quenched by the dropwise addition of methanol (20 mL). The solvents were removed by evaporation in vacuo and the residue purified by column chromatography (SiO2, EtOAc/ isohexane, 1 :1) to give the title compound (5 g, 95%) as a white solid. 6H (CDCl3) 8.36 (IH, s), 7.93 (IH, d, J 8.6 Hz), 6.15 (IH, d, J 8.6 Hz), 4.73 (IH, br s), 3.87 (3H, s), 2.96 (3H, d, J 5 Hz).
INTERMEDIATE 42
3-Iodo-NJV-dimethyl-4-(methylamino)benzamide
Me2NH (1.3 g, 29 mmol) was dissolved in THF (40 mL), the solution cooled to 00C and Me3Al (10.2 mL of a 2M solution in toluene, 20.4 mmol) added dropwise. The reaction mixture was stirred at 00C for 5 minutes. Intermediate 41 (4 g, 13.7 mmol) was added and the reaction mixture heated at reflux for 2 h. Upon cooling, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (2 x 25 mL), dried (MgSO4) and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography (SiO2, EtOAc/isohexane, 1 :1) to give the title compound (4.1 g, 98%) as a clear oil. LCMS (ES+) 304.9 (M+H)+.
INTERMEDIATE 43
tert-Butyl (35r)-3-ir5-(dimethylcarbamoyl)-l-methyl-2-(trimethylsilvn-lH-indol-3- yllmethyl|morpholine-4-carboxylate
Intermediate 5 (2.2 g, 7.7 mmol), Intermediate 42 (2.1 g, 7 mmol), LiCl (0.3 g, 7 mmol) and KOAc (1.4 g, 14 mmol) were dissolved in DMF (25 mL) and the solution was degassed and flushed with nitrogen three times. To this solution was added catalytic Pd(OAc)2 (0.01 g) and the reaction mixture was heated to 1050C for 210 minutes. Upon cooling, the volatiles were removed by evaporation in vacuo. The residue was dissolved in EtOAc (50 mL), washed with water (50 mL), dried (MgSO4) and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography (SiO2, EtOAc/isohexane) to give the title compound (2.2 g, 66%) as a yellow solid. LCMS (ES+) 474.1 (M+H)+.
INTERMEDIATE 44
NJV,l-Trimethyl-3-[(35^-moφholin-3-ylmethyll-lH-indole-5-carboxamide
Intermediate 43 (2.6 g, 5.5 mmol) was stirred in a solution of 4M HCl in 1 ,4-dioxane (20 mL) for 60 minutes at r.t. Volatiles and solvent were removed by evaporation in vacuo. The residue was dissolved in EtOAc (20 mL) and washed with sat. Na2CO3 solution (10 mL). The aqueous layer was saturated with sodium chloride and the organic layer isolated. The aqueous layer was further extracted with EtOAc (3 x 20 mL), the combined organic extracts dried (K2CO3) and the solvent removed by evaporation in vacuo to afford the title compound in quantative yield as a yellow oil. LCMS (ES+) 302.2 (M+Η)+.
INTERMEDIATE 45
3-( r(35)-4-Carbamothioylmorpholin-3 - yl]methyl } -NJV, 1 -trimethyl- 1 H-indole-5- carboxamide Intermediate 44 (0.9 g, 3 mmol) and l,l'-thiocarbonyldiimidazole (0.62 g, 3.6 mmol) were dissolved in TΗF (20 mL) and stirred for 90 minutes at r.t. Ammonium hydroxide solution (20 mL, 28-30% as NH3) was added and the reaction mixture stirred for 18 h at r.t. in a stoppered flask. The solvent was removed by evaporation in vacuo, and the residue purified by column chromatography (SiO2, DCM/MeOH, 0-5%) to give the title compound (0.7 g, 65%) as a yellow solid. LCMS (ES+) 361.0 (M+H)+.
INTERMEDIATE 46 (3,3-Dimethyl-5-oxocyclohexylidene)malononitrile
To a stirred solution of 5,5-dimethylcyclohexane-l,3-dione (98.0 g, 699.1 mmol) and malononitrile (46.2 g, 699.1 mmol) in EtOH (400 mL) at r.t. was added piperidine (10 mL, 99.9 mmol) dropwise over 15 minutes. The reaction mixture was heated to reflux for 3 days, cooled to r.t. and then concentrated in vacuo. The residue was dissolved in EtOAc (500 mL), and the solution was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 15% MeOH/ DCM) gave the title compound (108.2 g, 82%) as a yellow solid. δH (DMSO-d6) 8.31 (2H, br. s), 2.51 (2H, t, J 1.8 Hz), 2.30 (2H, s), 1.04 (6H, s).
INTERMEDIATE 47
2-Amino-5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-l-benzothiophene-3-carbonitrile
To a stirred solution of Intermediate 46 (50.8 g, 269.9 mmol) and sulphur (10.3 g, 323.9 mmol) in EtOH (600 mL) at r.t. was added morpholine (47.0 mL, 539.8 mmol) dropwise. The reaction mixture was heated to 800C for 24 h, and then cooled. The precipitate formed was filtered and washed with cold Et2O to give the title compound (41.2 g, 53%) as a brown solid that was used without further purification. 5H (DMSO-d6) 8.31 (2H, br. s), 2.51 (2H, t, J 1.8 Hz), 2.30 (2H, s), 1.04 (6H, s). LCMS (ES+) 221.0 (M+H)+.
INTERMEDIATE 48
2-Bromo-5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-l-benzothiophene-3-carbonitrile To a stirred solution of CuBr2 (4.2 g, 19.1 mmol) in MeCN (100 mL) at 00C was added nitrite (2 mL, 15.0 mmol) dropwise. The reaction mixture was stirred at this temperature for 10 minutes, and then Intermediate 47 (3.0 g, 13.6 mmol) was added portionwise. The reaction mixture was allowed to warm to r.t., stirred for 4 h, and then partitioned between 2M aqueous HCl (200 mL) and EtOAc. The aqueous fraction was extracted with EtOAc (2 x 200 mL). The combined organic fractions were dried
(MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 25% DCM/hexanes) gave the title compound (1.5 g, 40%) as an off-white solid. δH (DMSO-d6) 2.84 (2H, s), 2.51 (2H, s), 1.07 (6H, s). INTERMEDIATE 49
5,5-Dimethyl-2-(moφholin-4-yl)-7-oxo-4,5,6,7-tetrahydro-l-benzothiophene-3- carbonitrile
To a stirred solution of Intermediate 48 (18.3 g, 64.4 mmol) in DMSO (150 mL) at r.t. was added morpholine (14.7 mL, 168.0 mmol). The reaction mixture was heated to 1000C for 30 minutes, then cooled to r.t., diluted with water (450 mL) and stirred rigorously. The precipitate formed was filtered, washed with water and dried to give the title compound (14.4 g, 77%) as a pale green solid. δH (DMSOd6) 3.83-3.72 (4H, m), 3.69-3,58 (4H, m), 2.64 (2H, s), 2.35 (2H, s), 1.05 (6H, s). LCMS (ES+) 291.0 (M+H)+.
INTERMEDIATE 50
5,5-Dimethyl-2-(moφholin-4-yl)-5,6-dihydro-l-benzothiophen-7(4H)-one
To a stirred solution of Intermediate 49 (10.0 g, 34.5 mmol) in glacial AcOH (100 mL) at 1200C was added cone. H2SO4 (40 mL). The reaction mixture was stirred at this temperature for 24 h, then cooled to r.t. and poured into a well-stirred mixture of EtOAc (950 mL) and water (950 mL) at 00C. The resulting emulsion was filtered through Celite®. The organic fraction 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. 5H (DMSO-d6) 6.15 (IH, s), 3.84-3.70 (4H, m), 3.30-3.20 (4H, m), 2.58 (2H, s), 2.26 (2H, s), 1.01 (6H, s). LCMS (ES+) 266.0 (M+H)+.
INTERMEDIATE 51
3-Iodo-5,5-dimethyl-2-(moφholin-4-yl)-5,6-dihvdro-l-benzothiophen-7(4H)-one
To a stirred solution of Intermediate 50 (0.20 g, 0.75 mmol) in TΗF (10 mL) at r.t. was added NIS (0.18 g, 0.82 mmol) portionwise. The reaction mixture was stirred for 30 minutes. EtOAc (100 mL) and sat. aqueous Na2CO3 solution (25 ml) were added and the layers separated. The organic fraction was washed with sat. aqueous Na2CO3 solution (2 x 25 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 1 : 1 EtOAc/hexanes) gave the title compound (0.26 g, 90%) as a white powder. δH (DMSO-d6) 3.84-3.70 (4H, m), 3.22- 3.18 (4H, m), 2.60 (2H, s), 2.41 (2H, s), 1.05 (6H, s).
INTERMEDIATE 52
5,5-Dimethyl-2-(moφholin-4-yl)-3-(phenylethvnyl)-5,6-dihvdro-l-benzothiophen-7(4HV one
To a stirred solution of Intermediate 51 (1.63 g, 4.17 mmol) and phenylacetylene (0.64 g, 6.26 mmol) in diisopropylamine (150 mL) at 600C was added Pd(PPh3)2Cl2 (0.20 g, 0.28 mmol) and CuI (0.05 g, 0.26 mmol). The reaction mixture was stirred at this temperature for 45 minutes, and then cooled to r.t. The precipitate formed was filtered and triturated with water to give the title compound (1.18 g, 78%) as a fluffy white solid that was used without further purification. δΗ (DMSO-d6) 7.53-7.48 (2H, m), 7.46-7.38 (3 H, m), 3.83-3.75 (4H, m), 3.68-3.60 (4H, m), 2.70 (2H, s), 2.36 (2H, s), 1.07 (6H, s).
EXAMPLE 1 (METHOD G)
7-r(35l)-3-(3-Bromobenzvπmorpholin-4-vn-4,4-dimethyl-4.5-dihvdro-2H- rL31thiazolor4,5-glindazole
A stirred solution of 2-[(35)-3-(3-bromobenzyl)moφholin-4-yl]-5,5-dimethyl-5,6- dihydro-l,3-benzothiazol-7(4H)-one (WO 2006/114606) (0.50 g, 1.15 mmol) in Bredereck's reagent (5 mL, excess) was heated to reflux for 16 h, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in MeOH (5 mL), and hydrazine hydrochloride (0.12 g, 1.72 mmol) was added. The reaction mixture was heated to reflux for 16 h, then cooled to r.t. and concentrated in vacuo. Purification by column chromatography (SiO2, EtOAc) gave the title compound (0.20 g, 40%) as a white solid. δΗ (DMSO-d6) 12.26 (IH, br. s), 7.51-7.46 (2H, m), 7.41-7.36 (IH, m), 7.32-7.21 (2H, m), 4.08-4.00 (IH, m), 4.00-3.91 (IH, m), 3.68-3.44 (5H, m), 3.12-3.02 (IH, m), 3.02- 2.92 (IH, m), 2.60 (2H, s), 1.21 (6H, s). LCMS (ES+) 461.1 (M+H)+.
EXAMPLE 2 7-r(35>)-3-(l-benzofiiran-3-ylmethyl)moφholin-4-yl1-4,4-dimethyl-4,5-dihvdro-2H- |"l,3"|thiazolo|"4,5-g"|indazole
The title compound was prepared from Intermediate 9 according to Method G (using hydrazine monohydrate (5 equivalents) and EtOH) and was isolated as a white solid (21%) after purification by column chromatography (SiO2, 0-5% MeOΗ/DCM, followed by SiO2, 2% MeOΗ/DCM), then by preparative ΗPLC. δΗ (CDCl3) 8.03-7.98 (IH, m), 7.58 (IH, s), 7.53-7.47 (IH, m), 7.37-7.30 (3H, s), 4.29-4.19 (IH, m), 4.08 (IH, dd, J 11.1 and 3.0 Hz), 3.88 (IH, d, J 11.6 Hz), 3.81-3.67 (2H, m), 3.65-3.55 (2H, m), 3.41 (IH, J 13.9 and 11.4 Hz), 3.07-2.97 (IH, m), 2.84 (2H, s), 1.36 (6H, s). Exchangeable proton was not observed. LCMS (ES+) 421.2 (M+H)+.
EXAMPLE 3
4,4-Dimethyl-7-(moφholin-4-yl)-4,5-dihydro-2H-ri,31thiazolo[4,5-glindazole A stirred solution of 5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro- 1 ,3- benzothiazol-7(4H)-one (WO 2006/114606) (0.63 g, 2.35 mmol) in Bredereck's reagent (5 ml, excess) was heated to reflux for 5 h, then cooled to r.t. and concentrated in vacuo. The residue was triturated with toluene, dissolved in MeOH (10 mL), and then hydrazine hydrochloride (0.16 g, 2.35 mmol) was added. The reaction mixture was stirred at r.t. for 24 h, and then concentrated in vacuo. Purification by column chromatography (SiO2, 50% EtOAc/hexanes) gave the title compound (0.20 g, 30%) as a pale yellow solid. 6Η (DMSO-d6) 12.38 (1Η, br. s), 7.49 (1Η, s), 3.83-3.77 (4Η, m), 3.18-3.14 (4H, m), 2.61 (2H, s), 1.20 (6H, s). LCMS (ES+) 291.9 (M+H)+.
EXAMPLE 4
4.4-Dimethyl-2-(methylsulfonyl')-7-(morpholin-4-yl)-4.5-dihvdro-2H-rL31thiazolor4.5- g]indazole
To a stirred solution of Example 3 (0.103 g, 0.34 mmol) in DCM (15 mL) was added NEt3 (0.05 mL, 0.36 mmol), followed by a solution of methanesulfonyl chloride (0.03 mL, 0.36 mmol) in DCM (1 mL) dropwise. The reaction mixture was stirred at r.t. for 24 h under a nitrogen atmosphere. Additional methanesulfonyl chloride (0.01 mL, 0.14 mmol) was added and the reaction mixture stirred for a further 24 h before being concentrated in vacuo. Purification by column chromatography (SiO2, 50% EtOAc/ hexanes), followed by trituration with a mixture of EtOAc and hexanes (1 :1 ratio) then cold hexanes, gave the title compound (0.01 g, 7%) as an off-white solid. 5H (DMSO-d6) 8.03 (IH, s), 3.75-3.68 (4H, m), 3.55-3.42 (4H, m), 3.45 (3H, s), 2.70 (2H, s), 1.27 (6H, s). LCMS (ES+) 370.0 (M+H)+.
EXAMPLE 5
5,5-Dimethyl-2-(morpholin-4-yl)-4,5-dihvdroimidazori.2-α][l,31thiazolor5,4-clpyridine A stirred solution of Intermediate 4 (0.24 g, 0.56 mmol) in aminoacetaldehyde dimethyl acetal (2 mL) was heated to reflux for 15 minutes, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in toluene (20 mL), and/?-toluene- sulfonic acid (ca. 1 g) was added. The reaction mixture was heated to reflux for 2 h, then cooled to r.t. and concentrated in vacuo. Purification by column chromatography (SiO2, 5-10% MeOH/EtOAc), followed by trituration with EtOAc, gave the title compound (0.06 g, 37%) as an off-white solid. δH (DMSO-d6) 7.28 (IH, d, J0.7 Hz), 6.86 (IH, d, J0.6 Hz), 3.73-3.71 (4H, m), 3.46-2.43 (4H, m), 2.93 (2H, s), 1.43 (6H, s). LCMS (ES+) 291.1 (M+H)+.
EXAMPLE 6
5.5-Dimethyl-8-fmorpholin-4-yl')-5.6-dihvdron.31thiazolor5.4-cirL2.41triazolor4.3- a] pyridine
To a stirred solution of Intermediate 4 (0.08 g, 0.19 mmol) in MeCN (30 mL) were added formic hydrazide (0.11 g, 1.86 mmol) and AcOH (0.1 mL, 1.86 mmol). The reaction mixture was heated to reflux for 4 h. Additional formic hydrazide (0.11 mg, 1.86 mmol) and AcOH (0.1 mL, 1.86 mmol) were added, and the reaction mixture stirred under reflux for 16 h before being concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.014 g, 26%) as an off-white solid. δH (DMSO-d6) 8.64 (IH, s), 3.75-3.3.72 (4H, m), 3.51-3.49 (4H, m), 2.99 (2H, s), 1.24 (6H, s). LCMS (ES+) 292.1 (M+H)+.
EXAMPLE 7 3,5,5-Trimethyl-8-(morpholin-4-vn-5.6-dihvdrori.31thiazolor5.4-ciπ.2,41triazolor4.3- αlpyridine
To a stirred solution of Intermediate 4 (0.24 g, 0.57 mmol) in AcOH (10 mL) was added acethydrazide (0.42 g, 5.74 mmol). The reaction mixture was heated to reflux for 16 h, then cooled to r.t. and concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.08 g, 46%) as an off-white solid. δH (DMSO-d6) 3.74-3.71 (4H, m), 3.49-3.47 (4H, m), 3.00 (2H, s), 2.50 (3 H, s), 1.54 (6H, s). LCMS (ES+) 306.1 (M+H)+.
EXAMPLE 8
Methyl 3-{r(3^-4-(5.5-dimethyl-4.5-dihvdroimidazori,2-airi,31thiazolor5,4-clpyridin-2- yl)morpholin-3-yllmethvU-lH-indole-5-carboxylate A solution of Intermediate 15 (0.37 g, 0.76 mmol) in aminoacetaldehyde dimethyl acetal (3 mL) was stirred at 600C for 2 h, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in MeOH (10 mL), and/?-toluenesulfonic acid (ca. 1 g) and toluene (20 mL) were added. The reaction mixture was heated to reflux for 4 h, then cooled to r.t. and concentrated in vacuo. EtOAc (20 mL) and sat. aqueous Na2CO3 solution (20 mL) were added, and the layers separated. The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-5% MeOΗ/EtOAc) gave the title compound (0.23 g, 64%) as a yellow oil. δΗ (CDCl3) 8.76 (IH, s), 8.53 (IH, br. s), 7.94 (IH, dd, J8.6 and 1.3 Hz), 7.38 (IH, d, J8.6 Hz), 7.18 (IH, d, J 1.8 Hz), 7.05 (IH, d, J 1.0 Hz), 7.01 (IH, d, J 1.0 Hz), 4.24 (IH, J7.6 and 2.8 Hz), 4.13-4.07 (IH, m), 3.99 (3H, s), 3.89 (IH, d, J 11.6 Hz), 3.78-3.55 (4H, m), 3.45 (IH, dd, J 13.9 and 10.9 Hz), 3.16 (IH, dd, J 10.4 and 3.8 Hz), 3.10 (2H, d, J7.6 Hz), 1.56 (6H, s). LCMS (ES+) 478.2 (M+H)+.
EXAMPLE 9
3- (r(35V4-(5.5-Dimethyl-4,5-dihvdroimidazor 1 ,2-αif 1 ,31thiazolor5,4-c1pyridin-2- yl)morpholin-3-yllmethyl } -TVJV-dimethyl- 1 H-indole-5-carboxamide To a stirred solution of dimethylamine (1 mL, 15.60 mmol) in THF (2 mL) at 00C was added trimethylaluminium (3.9 mL, 2M in toluene, 7.80 mmol) dropwise, followed by Example 8 (0.18 g, 0.39 mmol). The reaction mixture was stirred at this temperature for 15 minutes, and then quenched with the addition of water (10 mL), filtered through Celite® and washed with EtOAc (2 x 10 mL). The organic fraction of the filtrate was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.07 g, 38%) as a white solid. δH (DMSO-d6) 11.10 (IH, s), 8.05 (IH, s), 7.37 (IH, d, J 8.3 Hz), 7.29 (2H, s), 7.16 (IH, d, J8.6 Hz), 6.87 (IH, s), 4.21-4.13 (IH, s), 4.04-3.96 (IH, m), 3.75 (IH, d, J 11.6 Hz), 3.65-3.45 (4H, m), 3.04 (6H, s), 2.97 (2H, d, J 4.5 Hz), 2.89-2.69 (2H, m), 1.47 (3H, s), 1.44 (3H, s). LCMS (ES+) 491.3 (M+H)+.
EXAMPLE 10 (METHOD I)
3-{r(35)-4-(5,5-Dimethyl-4.5-dihvdroimidazori.2-αiπ,31thiazolor5.4-clpyridin-2- yl)morpholin-3-yl1methyl}-lH-indole-5-carbonitrile
A solution of Intermediate 20 (0.25 g, 0.56 mmol) in aminoacetaldehyde dimethyl acetal (3 mL) was stirred at 1000C for 30 minutes, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in warm IPA (25 mL), and a sufficient amount oϊp- toluenesulfonic acid to render the mixture acidic was added. The reaction mixture was heated to reflux for 1 h, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL), and sat. aqueous Na2CO3 solution (20 mL) was added. The organic fraction was separated, dried (K2CO3), filtered and concentrated in vacuo. Trituration with a small volume of MeOH gave the title compound (0.12 g, 49%) as an off-white solid. δΗ (DMSO-d6) 11.48 (IH, s), 8.53 (IH, s), 7.54-7.47 (IH, m), 7.47-7.40 (2H, m), 7.28 (IH, s), 6.86 (IH, s), 4.27-4.19 (IH, m), 4.05-3.96 (IH, m), 3.74 (IH, d, J 11.6 Hz), 3.65-3.46 (4H, m), 3.36-3.27 (IH, m), 3.02 (2H, s), 2.97 (IH, dd, J 13.6 and 3.5 Hz), 1.47 (3H, s), 1.45 (3H, s). LCMS (ES+) 445.1 (M+H)+.
EXAMPLE U
S-irO^^-rS.S-Dimethyl-S.ό-dihvdro^H-imidazoπ^-fliriJlthiazolorS^-clazepin^- vOmorpholin-3-yllmethyl|-lH-indole-5-carbonitrile The title compound was prepared from Intermediate 23 according to Method E, then Method H, followed by Method I, and was isolated as a yellow solid (41%) after trituration with MeOH. δH (DMSOd6) 11.47 (IH, s), 8.59 (IH, s), 7.53-7.49 (IH, m), 7.46-7.41 (2H, m), 7.06 (IH, s), 6.80 (IH, s), 4.28-4.19 (IH, m), 4.03-3.94 (3H, m), 3.69 (IH, d, J 11.6 Hz), 3.63-3.43 (3H, m), 3.40-3.34 (IH, m), 3.30-3.22 (IH, m), 2.99 (2H, s), 2.92 (IH, dd, J 13.4 and 2.3 Hz), 1.02 (6H, s). LCMS (ES+) 459.2 (M+H)+.
EXAMPLE 12 (METHOD J)
3-{r(35f)-4-(5.5-Dimethyl-4.5-dihvdroimidazori,2-αirL31thiazolor5,4-c1pyridin-2- yl)morpholin-3 - yl]methyl 1-1 -methyl- 1 H-indole-5-carbonitrile
To a stirred solution of Example 10 (0.20 g, 0.45 mmol) in DMF (5 mL) at 00C was added methyl iodide (0.5 mL, excess), followed by NaH (50 mg, 60% dispersion in oil, excess). The reaction mixture was stirred at this temperature for 5 minutes, and then partitioned between EtOAc (5 mL) and water (5mL). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-5% MeOH/EtOAc) gave the title compound (0.03 g, 16%) as a yellow solid. δH (DMSO-d6) 8.54 (IH, s), 7.60 (IH, d, J8.6 Hz), 7.51 (IH, d, J8.6 Hz), 7.45 (IH, s), 7.29 (IH, s), 6.87 (IH, s), 4.24-4.16 (IH, m), 4.05-3.97 (IH, m), 3.80 (3H, s), 3.77-3.70 (IH, m), 3.66-3.45 (5H, m), 3.04 (2H, s), 2.94 (IH, dd, J 13.6 and 2.5 Hz), 1.46 (6H, s). LCMS (ES+) 459.2 (M+H)+.
EXAMPLE 13
3-(r(3^)-4-(5,5-Dimethyl-5.6-dihvdro-4H-imidazori,2-αiri,31thiazolor5,4-clazepin-2- yl)morpholin-3-vHmethyl|-l -methyl- lH-indole-5-carbonitrile
The title compound was prepared from Example 11 according to Method J and was isolated as an off-white solid (84%) after filtration of the solid formed from concentration of the organic fraction to a reduced volume, followed by trituration with EtOAc. δΗ (DMSO-d6) 8.59 (IH, s), 7.60 (IH, d, J8.6 Hz), 7.51 (IH, d, J 8.6 Hz), 7.43 (IH, s), 7.07 (IH, s), 6.81 (IH, s), 4.26-4.16 (IH, m), 4.03-3.94 (3H, m), 3.80 (3H, s), 3.69 (IH, d, J 11.6 Hz), 3.64-3.41 (3H, m), 3.39-3.33 (IH, m), 3.31-3.23 (IH, m), 3.00 (2H, s), 2.94-2.85 (IH, m), 1.03 (3H, s), 1.02 (3H, s). LCMS (ES+) 473.3 (M+H)+. EXAMPLE 14
7-r(35^-3-(lH-Indol-3-ylniethyl')morpholin-4-vn-4,4-dimethyl-4,5-dihvdro- [ 1 ,3]thiazolo[4,5-g| [ 1 ,2]benzisoxazole
The title compound was prepared from Intermediate 28 and Intermediate 29 according to Method A and was isolated as a yellow oil (65%) after purification by column chromatography (SiO2, 25-50% EtOAc/hexanes). δΗ (CDCl3) 8.12 (IH, s), 8.10 (IH, br. s), 7.97 (IH, d, J 7.6 Hz), 7.40 (IH, d, J7.8 Hz), 7.28-7.19 (2H, m), 7.17-7.14 (IH, m), 4.20-4.11 (2H, m), 3.92 (IH, d, J 11.9 Hz), 3.81-3.60 (3H, m), 3.60-3.53 (IH, m), 3.52-3.42 (IH, m), 3.10 (IH, dd, J 13.9 and 3.3 Hz), 2.89 (2H, s), 1.35 (6H, d, J2.5 Hz). LCMS (ES+) 421.7 (M+H)+.
EXAMPLE 15
2-r(3^-3-(lH-Indol-3-ylmethvnmoφholin-4-vn-5.5-dimethyl-4.5-dihvdro- [ 1 ,31thiazolo[4,5-/z]quinazoline
To a stirred solution of Intermediate 31 (0.112 g, 0.64 mmol) in AcOH (5 mL) was added NIS (0.150 g, 0.67 mmol). The reaction mixture was stirred at r.t. for 16 h. Intermediate 29 (0.176 g, 0.64 mmol) was added, followed by NaOAc (0.16 g, 2.00 mmol). The reaction mixture was heated to 1000C for 30 minutes, then cooled to r.t. and partitioned between EtOAc (20 mL) and water (20 mL). The organic fraction was washed with water (20 mL), then brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 33-50% EtOAc/ hexanes) gave the title compound (0.048 g, 17%) as a yellow solid. δΗ (CDCl3) 8.88 (IH, s), 8.46 (IH, s), 8.11 (IH, s), 7.97 (IH, d, J7.3 Hz), 7.43-7.39 (IH, m), 7.28-7.19 (2H, m), 7.17 (IH, d, J2.0 Hz), 4.26-4.18 (IH, m), 4.16-4.05 (IH, m), 3.92 (IH, d, J 11.9 Hz), 3.89-3.80 (IH, m), 3.78-3.62 (2H, m), 3.61-3.44 (2H, m), 3.12 (IH, dd, J 13.9 and 3.8 Hz), 2.91 (2H, s), 1.56 (3H, s), 1.32 (3H, s). LCMS (ES+) 432.6 (M+H)+.
EXAMPLE 16 9-rf3^0-(lH-Indol-3-ylmeihyl)moroholin^-yl1-6,6^imethyl-6J-dihvdro-5i/- tetrazolof 1 ,5-a] f 1 ,3"|thiazolo|~5,4-c]azepine
A stirred solution of 2-[(3S)-3-(lH-indol-3-ylmethyl)morpholin-4-yl]-7,7- dimethyl-5,6,7,8-tetrahydro-4//-[l,3]thiazolo[5,4-c]azeρin-4-one (WO 2006/114606) (0.41 g, 0.94 mmol) in phosphorus oxychloride (5 mL) was heated to 95°C for 1.5 h, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in MeOH (8 mL), and NaN3 (0.40 g, 6.15 mmol) was added. The reaction mixture was stirred at r.t. for 16 h, then filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc, and the solution washed with water (2 x 20 mL), then brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-50% EtOAc/hexanes), followed by stirring in water at 800C for 1 h, gave the title compound (0.09 g, 22%) as a white solid. δH (CDCl3) 8.08 (IH, s), 7.96 (IH, d, J 7.6 Hz), 7.40 (IH, d, J8.1 Hz), 7.28-7.18 (2H, m), 7.16 (IH, d, J 1.8 Hz), 4.43 (2H, s), 4.24-4.16 (IH, m), 4.13-4.06 (IH, m), 3.92 (IH, d, J 11.9 Hz), 3.78-3.63 (3H, m), 3.56 (IH, dd, J 11.6 and 1.8 Hz), 3.51-3.42 (IH, m), 3.15-3.10 (IH, m), 3.11-3.03 (2H, m), 1.17 (6H, s). LCMS (ES+) 436.7 (M+H)+.
EXAMPLE 17
5,5-Dimethyl-2-r6-(l-methyl-lH-pyrazol-4-vn-2.3-dihvdro-4H-1.4-benzoxazin-4-yll-4.5- dihydroimidazo[ 12-ά\ [ 1 ,31thiazolor5,4-c]pyridine
The title compound was prepared from Intermediate 36 according to Method H, followed by work-up (EtO Ac/water), then according to Method I, and was isolated as a pale orange solid (16%) after purification by preparative ΗPLC. δΗ (CDCl3) 8.01 (IH, d, J 1.7 Hz), 7.70 (IH, s), 7.57 (IH, s), 7.14 (IH, dd, J 8.5 and 1.9 Hz), 7.02 (2H, d, J7.2
Hz), 6.95 (IH, d, J 8.3 Hz), 4.44-4.26 (2H, m), 4.29-4.09 (2H, m), 3.94 (3H, s), 3.02 (2H, s), 1.54 (6H, s). LCMS (ES+) 419.20 (M+H)+.
EXAMPLE 18
5.5-Dimethyl-2-(moiτ>holin-4-yl)-5.6-dihvdro-4H-imidazori,2-αiri,31thiazolor5.4- clazepine The title compound was prepared from 7,7-dimethyl-2-(morpholin-4-yl)-5,6,7,8- tetrahydro-4H-[l,3]thiazolo[5,4-c]azepin-4-one (WO 2006/114606) according to Method H, followed by Method I, and was isolated as a white solid (29%) after purification by column chromatography (SiO2, 0-10% MeOH/EtOAc), followed by preparative HPLC. δH (CDCl3) 6.97 (IH, d, J 1.1 Hz), 6.76 (IH, d, J 1.1 Hz), 3.88 (2H, s), 3.86-3.80 (4H, m), 3.53-3.46 (4H, m), 2.92 (2H, s), 1.09 (6H, s). LCMS (ES+) 305.6 (M+H)+.
EXAMPLE 19
7-r(35)-3-(lH-Indol-3-ylmethvnmorpholin-4-vn-4.4-dimethyl-4.5-dihvdro-2H- ri,31thiazolo[4,5-glindazole
To a solution of Intermediate 39 (0.729 g, 3.0 mmol) in tetrahydrofuran (20 mL) was added Intermediate 29 (0.825 g, 3.0 mmol) and DIPEA (2.65 mL, 15 mmol). The reaction mixture was heated at reflux for 2 h, cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, passed through a phase separator and concentrated in vacuo to afford an oil which was purified by column chromatography (SiO2, 66-50% EtOAc/hexanes) to afford the title compound as an off-white solid (0.277 g, 22%). δΗ (CDCl3) 8.14 (IH, s), 8.00 (IH, d, J7.3 Hz), 7.37 (IH, d, J7.3 Hz), 7.33 (IH, s), 7.22 (2H, m), 7.15 (IH, d, J2.0 Hz), 4.08 (2H, m), 3.90 (IH, d, J 11.6 Hz), 3.82- 3.44 (5H, m), 3.10 (IH, dd, J 13.6, 3.3 Hz), 2.84 (2H, s), 1.36 (6H, s). LCMS (ES+) 420.6 (M+H)+.
EXAMPLE 20
9-[(35)-3-(lH-Indol-3-ylmethyl)morρholin-4-yll-6.6-dimethyl-2.5.6.7-tetrahvdro-3H- [ 1 ,31thiazolo|"5,4-c"|[ 1 ,2,41triazolo[4,3-α1azepin-3-one
A solution of 2-[(3S)-3-(lH-indol-3-ylmethyl)morρholin-4-yl]-7,7-dimethyl- 5,6,7,8-tetrahydro-4H-[l,3]thiazolo[5,4-c]azepin-4-one (WO 2006/114606) (0.50 g, 1.1 mmol) in POCl3 (5 mL) was heated at 95°C for 1.5 h. The reaction mixture was concentrated in vacuo, and the residue was redissolved in MeCN (10 mL), treated with methyl hydrazinocarboxylate (0.55 g, 6.1 mmol), and stirred at room temperature for 1 h and then at 9O0C for a further 1 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL), then the aqueous layer was separated and extracted into EtOAc (2 x 10 mL). The organic fractions were combined, washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo and washed with Et2O to give a pale yellow solid. A portion of this solid (0.30 g) was dissolved in AcOH (2 mL) and heated by microwave radiation to 1400C for 10 min. The reaction mixture was partitioned between EtOAc (20 mL) and sat. NaHCO3 solution (20 mL). The organics were separated, washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a white foam, which was washed with Et2O to give the title compound as a white solid (0.08 g, 18%). δH (CDCl3) 9.42 (IH, br s), 8.13 (IH, br s), 7.95 (IH, d, J7.6 Hz), 7.39 (IH, m), 7.22 (2H, m), 7.14 (IH, d, J2.3 Hz), 4.13 (IH, m), 4.07 (IH, d, J 3.3 Hz), 3.90 (IH, d, J 11.9 Hz), 3.61-3.71 (5H, m), 3.54 (IH, m), 3.45 (IH, dd, J 13.9, 11.1 Hz), 3.09 (IH, dd, J 13.9, 3.8 Hz), 2.98 (2H, d, J2.5 Hz), 1.15 (6H, s). LCMS (ES+) 451.7 (M+H)+, RT 2.25 minutes.
EXAMPLE 21
2-r(35f)-3-πH-Indol-3-ylmethvnmorpholin-4-yl1-5,5,8-trimethyl-5,6-dihvdro-4//- imidazo[l,2-a"||"l,3"|thiazolo|"5,4-c1azepine
A solution of 2-[(35)-3-(lH-indol-3-ylmethyl)moφholin-4-yl]-7,7-dimethyl- 5,6,7,8-tetrahydro-4H-[l,3]thiazolo[5,4-c]azepin-4-one (WO 2006/114606) (0.40 g, 1.1 mmol) in POCl3 (4 mL) was heated at 95°C for 1.5 h. The mixture was then concentrated in vacuo and redissolved in TΗF (5mL). To this was added propargylamine (1 mL, 16 mmol). The reaction mixture was stirred overnight at room temperature, then at 400C for 6 h and overnight at 600C. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL), then the organics were separated and washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a crude foam. Purification by column chromatography (SiO2, EtOAc/hexanes) gave a beige foam. This was further purified by preparative ΗPLC to give the title compound as a white solid (0.21 g, 44%). δΗ (CDCl3) 8.10 (IH, s), 7.99 (IH, m), 7.38 (IH, m), 7.20 (3H, m), 6.78 (IH, d, J 1.0 Hz), 4.08 (2H, m), 3.87 (IH, d, J 11.6 Hz), 3.75 (2H, s), 3.70 (2H, m), 3.57 (2H, m), 3.45 (IH, dd, J 13.6, 11.4 Hz), 3.10 (IH, m), 2.98 (2H, d, J 1.5 Hz), 2.22 (3H, d, J 0.8 Hz), 1.13 (6H, s). LCMS (ES+) 448.8 (M+H)+, RT 2.75 minutes.
EXAMPLE 22 Methyl 3-{r(35r)-4-(5,5-dimethyl-5,6-dihvdroπ,31thiazolor5.4-c1[l,2,41triazolor4.3- αlpyridin-8-yl)moφholin-3-yl1methvU-l-methyl-lH-indole-5-carboxylate
Methyl 3-{[(35)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]- pyridin-2-yl)morρholin-3-yl]methyl} -1 -methyl- lH-indole-5-carboxylate (WO 2008/ 001076) (0.24 mg, 0.5 mmol) was heated at 900C in phosphorus oxychloride (4 mL) for 90 minutes. The reaction mixture was cooled to r.t. and the volatiles and excess phosphorus oxychloride were removed by evaporation in vacuo, yielding methyl 3- {[(35)-4-(4-chloro-6,6-dimethyl-6,7-dihydro[l,3]thiazolo[5,4-c]pyridin-2-yl)moφholin- 3-yl]methyl}-l-methyl-lH-indole-5-carboxylate as a yellow solid. This was slurried in MeCN (5 mL) and formyl hydrazide (0.07 g, 1.1 mmol) was added. The resulting mixture was heated at reflux for 16 h. Upon cooling, the solvent was removed by evaporation in vacuo. The residue was taken up in EtOAc (20 mL), washed with water (5 mL) twice, dried (MgSO4), filtered and the solvent removed by evaporation in vacuo. Purification by column chromatography (SiO2, EtOAc/MeOΗ, 0-10%) gave the title compound as a white solid (0.10 g, 42%). δΗ (CDCl3) 8.75 (IH, s), 8.19 (IH, s), 7.97- 7.95 (IH, d, J 8.7 Hz), 7.40-7.20 (IH, m), 7.05 (IH, s), 4.35-4.20 (IH, br s), 4.20-4.09 (IH, m), 3.99 (3H, s), 3.98-3.55 (8H, m),3.50-3.40 (IH, m), 3.30-3.10 (3H, m), 1.64-1.63 (6H, d, J 5.7 Hz). LCMS (ES+) 493.1 (M+H)+.
EXAMPLE 23
3-{r(35l)-4-(5.5-Dimethyl-5.6-dihvdrori.31thiazolor5.4-ciπ,2,41triazolor4,3-qlpyridin-8- yl)morpholin-3-yl]methyl} - 1 -methyl- lH-indole-S-carboxylic acid
To a stirred solution of Example 22 (0.20 g, 0.4 mmol) dissolved in ethanol (5 mL) and water (5 mL) was added sodium hydroxide (0.10 g, 2.5 mmol) and the reaction mixture heated at reflux for 2 h. Upon cooling, the solvents were removed by evaporation in vacuo and the residue dissolved in water. The resulting solution was neutralized with citric acid, resulting in the precipitation of the title compound which was isolated by filtration, washed with water and dried in vacuo (0.19 g, 98%). δΗ (DMSO-d6) 8.64-8.63 (2H, m), 7.79-7.77 (IH, d, J8.6 Hz), 7.46-7.43 (IH, d, J8.6 Hz), 7.32 (IH, s), 4.27-4.25 (IH, br s), 4.03-4.01 (IH, d, J 7.5 Hz), 3.80-3.70 (4H, m), 3.65-3.45 (2H, m), 3.40-3.00 (6H, m), 2.97-2.94 (IH, m), 1.53 (6H, s). LCMS (ES+) 479.0 (M+H)+.
EXAMPLE 24
3-(r(35)-4-r5.5-Dimethyl-5,6-dihvdroπ.31thiazolor5,4-cirK2,41triazolor4.3-αlpyridin-8- yl)morpholin-3 - yl"|methyl } -NjV, 1 -trimethyl- lH-indole-5-carboxamide
To Intermediate 40 (0.15 g, 0.23 mmol) in MeCN (4 mL) at 00C was added excess dimethylamine. The flask was stoppered, allowed to warm to r.t. and stirred for 16 h. The solvent was removed by evaporation in vacuo and the residue purified by column chromatography (SiO2, EtOAc/MeOΗ, 0-10%) to give the title compound (0.06 g, 52%) as a white solid. δΗ (DMSOd6) 8.65 (IH, s), 8.03 (IH, s), 7.42 (IH, m), 7.30 (IH, s), 7.21 (IH, m), 4.30-4.10 (IH, br s), 4.00 (IH, br s), 3.76 (IH, s), 3.70-3.50 (4H, m), 3.31 (3H, s), 3.20-2.80 (1OH, m), 1.52 (6H, d, J 10.3 Hz). LCMS (ES+) 506.1 (M+H)+.
EXAMPLE 25
3-{r(35)-4-(4,4-Dimethyl-4.5-dihvdro-3aH-rK31thiazolor4,5-glindazol-7-yl)moφholin-3- yl1methvU-Njy,l-trimethyl-lH-indole-5-carboxamide Intermediate 45 (0.12 g, 0.3 mmol), Intermediate 39 (0.146 g, 0.6 mmol) and
DIPEA (0.06 mL, 0.34 mmol) in TΗF (10 mL) were heated to reflux for 18 h. Upon cooling the title compound (0.055 g, 36%) was isolated by filtration, washed with TΗF followed by EtOAc and dried in vacuo. δΗ (DMSO-d6) 12.30 (IH, s), 8.09 (IH, s), 7.52 (IH, s), 7.43 (IH, d, J 8.5 Hz), 7.29 (IH, s), 7.21 (IH, d, J 8.4 Hz), 4.20-3.90 (2H, m), 3.77-3.70 (4H, m), 3.70-3.40 (3H, m), 3.40-3.20 (2H, m), 3.03 (6H, s), 2.89-2.86 (IH, m), 2.51 (2H, s), 1.24 (6H, s). LCMS (ES+) 505.3 (M+H)+.
EXAMPLE 26
4,4-Dimethyl-7-(moφholin-4-yl)-4,5-dihvdro-2H-thieno[3,2-g]indazole
A stirred solution of Intermediate 50 (0.20 g, 0.75 mmol) in Bredereck's reagent (5 mL, excess) was heated to reflux for 16 h, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and hydrazine monohydrate (0.056 g, 1.12 mmol) was added. The reaction mixture was stirred at 400C for 2.5 h, then cooled to r.t. and concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.06 g, 27%) as a white solid. δH (DMSOd6) 12.25 (IH, br. s), 7.53 (IH, s), 6.16 (IH, s), 3.83-3.78 (4H, m), 3.17-3.14 (4H, m), 2.60 (2H, s), 1.27 (6H, s). LCMS (ES+) 290.1 (M+H)+.
EXAMPLE 27
4,4-Dimethyl-7-(moφholin-4-yl)-6-(phenylethvnyl)-4,5-dihydro-2H-thieno[3,2- g]indazole
A stirred solution of Intermediate 52 (0.13 g, 0.35 mmol) in Bredereck's reagent (5 mL, excess) was heated at 900C for 3 days, then at 1000C for 2 days. The reaction mixture was then cooled to r.t. and partitioned between EtOAc (10 mL) and water (10 mL). The organic fraction was washed with water (10 mL), then brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in EtOH (10 mL) and hydrazine monohydrate (0.1 mL, 1.75 mmol) was added. The reaction mixture was heated at 600C for 16 h, then cooled to r.t. and concentrated in vacuo. Purification by column chromatography (SiO2, 30-50% EtOAc/hexanes) gave the title compound (0.05 g, 4%) as a white solid. δΗ (DMSO-d6) 12.38 (IH, br. s), 7.54 (IH, d, J 1.1 Hz), 7.51-7.48 (2H, m), 7.45-7.39 (3H, m), 3.81-3.79 (4H, m), 3.35-3.32 (4H, m), 2.66 (2H, s), 1.23 (6H, s). LCMS (ES+) 390.1 (M+H)+.

Claims

Claims:
1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000125_0001
(i)
wherein
U represents N or C-R5; V represents a covalent bond or a methylene linkage;
W represents a covalent bond or a methylene linkage; the moiety X-Y-Q represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;
R1 and R2 independently represent hydrogen, hydroxy or amino; or Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, di(Ci-6)alkylamino, 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
R and R , 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 Ci-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, aryl(C2-6)alkenyl, aryl (C2-6)- alkynyl, biaryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; 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 or -CONRcRd; or R5 represents Ci-6 alkyl, C2-6 alkenyl, C2-6 alkenylcarbonyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-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(Ci-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(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, heteroaryl-aryl(Ci-6)alkyl, aryl-heteroaryl, aryl-heteroaryl(Ci-6)alkyl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 heterocycloalkyl(Ci-6)alkyl-aryl -heteroaryl, C5-9 heterobicycloalkyl(C i -6)alkyl-aryl-heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl-bi(heteroaryl), aryloxyaryl, aryl(Ci_6)alkoxyaryl, heteroaryl(Ci-6)alkoxyaryl, aryl(Ci-6)alkylaminoaryl, heteroaryl(Ci-6)alkylaminoaryl, C3-7 cycloalkylcarbonylaminoaryl, arylcarbonylaminoaryl, aryl(C i .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(C i -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 i -6)alkylaryl, C3-7 heterocycloalkyl(C i -6)alkylaminocarbonyl(C i -6)alkylaryl, heteroarylaminocarbonyl(C i -6)alkylaryl, heteroaryl(C i -6)alkylaminocarbonyl(C i -6)alkyl- aryl, arylaminoheteroaryl, C3-7 heterocycloalkylamino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonylamino-aryl-heteroaryl, C3-7 heterocycloalkylaminocarbonyl- amino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(Ci-6)alkylcarbonyl-aryl-heteroaryl, Cs-9 heterobicycloalkylcarbonyl-aryl- heteroaryl, C3-7 heterocycloalkylcarbonyl(Ci.6)alkyl-aryl-heteroaryl, C3-7 heterocycloalkyl- aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(C i -6)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 Ci-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 (aryl)(heteroaryl)(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; Rd represents hydrogen or Ci-6 alkyl; Re represents Ci-6 alkyl;
R6 is absent when V represents a covalent bond; or R6 represents hydrogen, hydroxy, oxo or -NR6aR6b; and R6a and R6b independently represent hydrogen, Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(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.
2. A compound as claimed in claim 1 represented by formula (BA), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000128_0001
(BA)
wherein
W, the moiety X-Y-Q and R5 are as defined in claim 1 ;
R11 represents hydrogen or Ci-6 alkyl; and R12 represents hydrogen; or Ci-6 alkyl, Ci-6 alkoxy, 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
R1 ' 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.
3. A compound as claimed in claim 1 represented by formula (ILA-A) or (II A-B), or a pharmaceutically acceptable salt or solvate thereof:
(ILA-A)
Figure imgf000128_0002
Figure imgf000129_0001
wherein
W and the moiety X-Y-Q are as defined in claim 1 ;
R11 and R12 are as defined in claim 2; and
R13 represents hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, biaryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)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.
4. A compound as claimed in claim 3 represented by formula (HB), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000129_0002
(IIB)
wherein
W and the moiety X-Y-Q are as defined in claim 1; R11 and R12 are as defined in claim 2;
T represents oxygen or N-R 25. R2 represents hydrogen, halogen, cyano, nitro, Ci-6 alkyl, hydroxy(Ci-6)alkyl, trifluoromethyl, aryl(Ci-6)alkyl, oxazolinyl, triazolyl, hydroxy, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(Ci-6)alkoxy, morpholinyl(Ci-6)alkoxy, aryloxy, aryl(Ci-6)alkoxy, Ci-6 alkylthio, Cj-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, Ci-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl] [(C i-6)alkyl] amino, Ci-6 alkylsulphonylamino, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl <9-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, [hydroxy(Ci-6)- alkyl] aminocarbonyl, [di(C i -6)alkylamino(C i -6)alkyl] aminocarbonyl, di(C i -6)alkyl- aminocarbonyl, [(C i -6)alkyl] [cyano(C i -6)alkyl] aminocarbonyl, [(C i -6)alkyl] [hydroxy(C i -6)- alkyl] aminocarbonyl, [(C i -6)alkoxy(C i -6)alkyl] [(C i -6)alkyl]aminocarbonyl, [di(C \ -6)alkyl- amino(Ci-6)alkyl] [(C i-6)alkyl] aminocarbonyl, C3-7 cycloalkyl(Ci-6)alkylaminocarbonyl, aryl(C i -6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C i -6)alkylamino- carbonyl, azetidinyl carbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, (C i -6)alkylpyrrolidinyl- carbonyl, Ci-6 alkoxy(Ci.6)alkylpyrrolidinylcarbonyl, di(Ci-6)alkylaminopyrrolidinyl- carbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, (Ci-6)- alkylpiperazinylcarbonyl, moφholinylcarbonyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonyl- methyl or di(Ci-6)alkylaminosulphonyl; and
R24 represents hydrogen, halogen, Ci-6 alkoxy or di(Ci-6)alkylaminocarbonyl; or
R23 and R24, when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and
R25 represents hydrogen or Ci-6 alkyl.
5. A compound as claimed in claim 3 represented by formula (IIC), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000131_0001
(iic)
wherein
W and the moiety X-Y-Q are as defined in claim 1 ; R1 ' and R12 are as defined in claim 2;
R33 represents halogen or -NHR34; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more substiruents; and
R34 represents methyl enedioxyphenyl, morpholinyl(Ci-6)alkylphenyl, oxazolinyl- phenyl, [(Ci-6)alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (C i -6)alkyltriazolylphenyl, (C i -6)alkylpyrimidinylphenyl, pyrazolyl(C i -6)alkyl- phenyl, triazolyl(Ci-6)alkylphenyl, Ci-6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci-6 alkylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, Ci-6 alkylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, [(Ci-6)alkyl](halo)pyrazolyl, tri(Ci-6)alkylpyrazolyl, (Ci.6)alkylindazolyl, benzoxazolyl, benzoxazolonyl, di(Ci-6)alkylisoxazolyl, benzothiazolyl, (Ci-6)alkylisothiazolyl, (Ci-6)alkylbenzimidazolyl, benzimidazolonyl, di(Ci-6)alkylbenzimidazolonyl, (Ci-6)alkyloxadiazolyl, furyloxadiazolyl, pyridinyl, halopyridinyl, (Ci-6)alkylpyridinyl, di(Ci-6)alkylpyridinyl, (Ci-6)alkoxypyridinyl, oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl, [(Ci.6)alkoxy](halo)pyridazinyl, (Ci_6)alkylcinnolinyl, quinoxalinyl or (Ci.6)alkylchromenyl.
6. A compound as claimed in claim 1 represented by formula (IID-1) or (IID-2), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000132_0001
wherein
W and the moiety X-Y-Q are as defined in claim 1 ; R11 and R12 are as defined in claim 2;
R43 represents hydrogen, halogen, nitro, Ci-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci-6)alkylaryl, di(Ci-6)alkylaryl, piperidinyl(Ci-6)alkylaryl, piperazinyl(Ci-6)alkylaryl, (C i .6)alkylpiperazinyl(C i -6)alkylaryl, morpholinyl(C i -6)alkylaryl, (C i -6)alkoxyaryl, cyano(C i -6)alkoxyaryl, di(C i -6)alkylamino(C i -6)alkylaryl, (C i -6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (Ci-6)alkylaminocarbonylpiperidinyl, piperazinyl, (Ci-6)alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (Ci-6)alkyl- homopiperazinyl, (Ci.6)alkylpiperazinyl(Ci-6)alkyl, morpholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(Ci_6)alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, [di(Ci-6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano- (C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, hydro xy(C i _6)alkylpyrazolyl, [hydroxy(C i -6)- alkyl][di(Ci-6)alkyl]pyrazolyl, methoxy(Ci-6)alkylpyrazolyl, [(hydroxy)(methoxy)(Ci-6)- alkyl] pyrazolyl, amino(C i ^alkylpyrazolyl, [(C i -6)alkyl] [amino(C i -6)alkyl]pyrazolyl, [amino(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, di(C i .6)alkylamino(C i -6)alkylpyrazolyl, di(C i -6)alkoxyphosphono(C i -6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl- (C,-6)alkylpyrazolyl, [(C3-7)cycloalkyl(C,-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(C1-6)alkyl]- (aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(Ci.6)alkylpyrazolyl, aminoaryl- (Ci-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(Ci-6)alkylpyrazolyl, [di- (C i -6)alkyl] [tetrahydropyranyl(C i .6)alkyl]pyrazolyl, pyrrolidinyl(C i -6)alkylpyrazolyl, piperidinyl(C i -6)alkylpyrazolyl, (C i -6)alkylpiperidinyl(C i -6)alkylpyrazolyl, morpholinyl(C i -6)alkylpyrazolyl, pyridinyl(C i -6)alkylpyrazolyl, oxypyridinyl(C i -6)alkyl- pyrazolyl, [arylcarbonyl(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, [(C1 -6)alkyl] (piperazinyl- carbonyl)pyrazolyl, [(C \ -6)alkylaminocarbonyl] [(C i -6)alkylaryl]pyrazolyl, [(C i -6)alkyl] - [amino(Ci-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(Ci-6)alkylpyrazolyl,
[aminocarbonyl(C i .6)alkyl] [di(C \ -6)alkyl]pyτazolyl, 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(Ci.6)alkylthiazolyl, imidazolyl, (Ci-6)alkylimidazolyl, di(Ci-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (Ci-6)alkylimidazo[l,2-a]pyridinyl, (C 1.6)- alkylimidazo[4,5-£]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)- alkylthiadiazolyl, pyridinyl, halopyridinyl, (Ci-6)alkylpyridinyl, [(Ci-6)alkyl](halo)- pyridinyl, di(Ci-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (Ci-6)alkylpiperazinylpyridinyl, [(Ci-6)alkyl](piperazinyl)pyridinyl, [(Ci-6)alkoxycarbonylpiperazinyl][(C1-6)alkyl]- pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl,
Figure imgf000133_0001
[(Ci-6)alkoxy][(Ci.6)alkyl]pyridinyl, [(C i -6)alkoxy] [di(Ci -6)alkyl]pyridinyl, (C i -6)alkoxy(C i -6)alkylpyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (Ci-6)alkoxycarbonyl(Ci-6)alkylpyridinyl, pyridazinyl, (C I-6)- alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Ci.6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(C i -6)alkylaminopyridazinyl, di(C i -6)alkylaminopyridazinyl, pyrimidinyl, (Ci.6)alkylpyrimidinyl, [(Ci-6)alkyl](halo)pyrimidinyl, di(Ci-6)alkyl- pyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinylpyrimidinyl, [(Ci-6)alkyl](piperazinyl)pyrimidinyl, [(Ci.6)alkoxycarbonyl][(Ci-6)alkyl]piperazinyl- pyrimidinyl, hydroxypyrimidinyl, [(C|.6)alkyl](hydroxy)pyrimidinyl, [(Ci.6)alkyl]- [hydroxy(C i -6)alkyl]pyrimidinyl, [(C i -6)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (C i -6)- alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminopyrimidinyl, [di(Ci-6)alkyl- amino](halo)pyrimidinyl, carboxypyrimidinyl, [(C i -6)alkoxycarbonyl(C i -6)alkyl] [(C i -6)- alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (Ci.6)alkoxy, aryl(Ci.6)alkoxycarbonylpiperidinyloxy, moφholinyl- (Ci-6)alkoxy, aryloxy, haloaryloxy, di(C].6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i ^alkylpyrazolyl- pyridinyloxy, (Ci.6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy, (Ci-6)alkylpyrimidinyloxy, [(Ci-6)alkyl](halo)pyrimidinyloxy, hydroxy(Ci-6)alkyl, dihydroxy(Ci-6)alkyl, pyridinyloxy(Ci-6)alkyl, amino, (Ci-6)alkylamino, dihydroxy(C1-6)alkylamino, (C I-6)- alkoxy(Ci-6)alkylamino, 7V-[(Ci-6)alkoxy(Ci-6)alkyl]-iV-[(Ci-6)alkyl]amino, di(Ci-6)- alkylamino(C i -6)alkylamino, N-[(C \ -6)alkyl] -N-[di(C i -6)alkylamino(C i -6)alkyl] amino, N- [(C i -6)alkyl] -N-[(C3-7)cycloalkyl] amino, haloarylamino, N-[(C i -6)alkyl]-N-(haloaryl)amino, ^-[(Ci.^alkyη-N-taryKCi^alkyηamino^-Cdi^i.^alkylamino^i.^alkyη-N-taryKd.δ)- alkyl] amino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(Ci-6)alkylamino, methylene- dioxyaryl(Ci-6)alkylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpyrrolidinyl]amino, piperidinyl- amino, N-[(Ci-6)alkyl]-N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(Ci-6)alkyl]-N- (piperidinyl)amino, (Ci-6)alkylpiperidinylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkyl- piperidinyl] amino, N-[(Ci-6)alkyl]-N-[(C3-7)cycloalkylpiperidinyl]amino, N-[(Ci-6)alkyl]- N-[(C2-6)alkylcarbonylpiperidinyl]amino, pyrrolidinyl(C1-6)alkylamino, jV-[(Ci-6)alkyl]-N- [pyrrolidinyl(Ci-6)alkyl]amino, N-[(Ci-6)alkyl]-N-[piperidinyl(Ci-6)alkyl]amino, (Ci-6)- alkylpyrazolylamino, di(Ci-6)alkylpyrazolylamino, tri(Ci-6)alkylpyrazolylamino, N-[(Ci-6)- alkyl]-7V-[(Ci,6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(Ci-6)alkoxy- carbonyl][(Ci.6)alkyl]imidazolylamino,
Figure imgf000134_0001
pyridinylamino, halopyridinylamino, (Ci-6)alkylpyridinylamino, di(Ci.6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C i -6)alkylpyridinylamino, dihydroxy(Ci-6)alkylpyridinylamino, (Ci-6)alkoxypyridinylamino, dihydroxy(Ci-6)alkoxy- pyridinylamino, di(C i -6)alkyldioxolanyl(C i -6)alkoxypyridinylamino, (C i -6)alkoxy(C i -6)- alkylpyridinylamino, (C1-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(Ci_6)alkyl- aminopyridinylamino, di(C i -6)alkylaminopyridinylamino, (C i -6)alkylamino(C i -6)alkyl- pyridinylamino, di(Ci-6)alkylamino(Ci-6)alkylpyridinylamino, carboxypyridinylamino, N- [(Ci.6)alkyl]-N-[(Ci-6)alkylpyridinyl]amino, bis[(Ci-6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (Ci-6)alkylpyridazinylamino, N-[(Ci-6)alkyl]- N-[(Ci-6)alkylpyridazinyl]amino, N-[aryl(Ci-6)alkyl]-N-[(Ci-6)alkylpyridazinyl]amino, di(Ci-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C I-6)- alkoxypyridazinylamino, di(Ci-6)alkylaminopyridazinylamino, bis[(Ci.6)alkylpyridazinyl]- amino, benzofuryl(Ci-6)alkylamino, thienyl(Ci-6)alkylamino, indolyl(Ci-6)alkylamino, (Ci-6)alkylpyrazolyl(Ci-6)alkylamino, [di(Ci.6)alkyl](halo)pyrazolyl(Ci-6)alkylamino, di(Ci-6)alkylisoxazolyl(Ci-6)alkylamino, thiazolyl(Ci_6)alkylamino, imidazolyl(Ci-6)alkyl- amino, (Ci^alkylimidazoly^Ci-^alkylamino, pyridinyl(Ci-6)alkylamino, (Ci-6)alkyl- pyridinyl(C i -6)alkylamino, N- [(C i _6)alkyl] -N-[pyridinyl(C i -6)alkyl]amino, N-[dihydroxy- (C^alkyη-N-CpyridinylCC^alkyllamino^-tCd^alkylpyridinyKC^alkyη-N-
[dihydroxy(Ci-6)alkyl] amino, amino(Ci.6)alkyl, (Ci-6)alkylamino(Ci-6)alkyl, di(Ci-6)alkyl- amino(Ci-6)alkyl, pyridinylamino(Ci-6)alkyl, N-[(C2-6)alkylcarbonyl]-7V-[(Ci.6)alkyl- pyridinyl(C i -6)alkyl] amino, di(C i -6)alkylamino(C i -6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (Ci-6)alkylpiperidinylcarbonylamino, (Ci-6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (Ci^alkylpiperidinylaminocarbonyl, iV-[(Ci-6)alkyl]-7V-[(Ci-6)- alkylpiperidinyl]aminocarbonyl, piperidinyl(Ci-6)alkylaminocarbonyl,
Figure imgf000135_0001
piperazinylcarbonyl, C1-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy or tetra(Ci-6)alkyldioxaborolanyl; and
R44 represents hydrogen, halogen, Ci-6 alkyl or Ci-6 alkoxy.
7. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.
8. 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.
9. A compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
10. 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 PDK inhibitor is indicated.
11. 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 PI3K inhibitor is indicated.
12. 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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