WO2009122148A1 - Fused thiophene and thiazole derivatives as pi3k kinase inhibitors - Google Patents

Fused thiophene and thiazole derivatives as pi3k kinase inhibitors Download PDF

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WO2009122148A1
WO2009122148A1 PCT/GB2009/000818 GB2009000818W WO2009122148A1 WO 2009122148 A1 WO2009122148 A1 WO 2009122148A1 GB 2009000818 W GB2009000818 W GB 2009000818W WO 2009122148 A1 WO2009122148 A1 WO 2009122148A1
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alkyl
aryl
amino
heteroaryl
pyrazolyl
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PCT/GB2009/000818
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French (fr)
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Benjamin Garfield Perry
Verity Margaret Sabin
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Ucb Pharma S.A.
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Publication of WO2009122148A1 publication Critical patent/WO2009122148A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a class of fused thiophene and thiazole derivatives, and to their use in therapy. More particularly, the invention provides a family of fused bicylic thiophene and thiazole derivatives which are substituted in the 2-position of the thiophene or thiazole ring by an optionally substituted morpholin-4-yl moiety. These compounds are selective inhibitors of phosphoinositide 3-kinase (PDK) 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.
  • PDK phosphoinositide 3-kinase
  • the PBK pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases.
  • PDKs provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et ai, Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sd., 2003, 24, 366-376).
  • Aberrant upregulation of the PDK pathway is implicated in a wide variety of human cancers (cf. S. Brader & S.A. Eccles, Tumori, 2004, 90, 2-8).
  • the compounds in accordance with the present invention are therefore beneficial in the treatment and/or prevention of various human ailments.
  • autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g.
  • neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; pain and nociceptive disorders; and ophthalmic disorders including age- related macular degeneration (ARMD).
  • age- related macular degeneration AMD
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting compounds capable of binding to human PDK enzymes.
  • WO 2006/114606 and WO 2008/001076 describe related classes of fused bicyclic thiazole derivatives; as also does copending international patent application no. PCT/GB2007/003853, which was published on 17 April 2008 as WO 2008/044022.
  • WO 2007/141504 describes a class of fused bicyclic thiophene derivatives.
  • the compounds disclosed in all of those patent filings are selective inhibitors of PD 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 PDK inhibitors having a binding affinity (IC 50 ) for the human PD Ka and/or PDK ⁇ and/or PDK ⁇ and/or PI3K ⁇ isoform of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
  • IC 50 binding affinity for the human PD Ka and/or PDK ⁇ and/or PDK ⁇ 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
  • 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 PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ and/or PDK ⁇ isoform relative to other human kinases.
  • the compounds of the present invention possess markedly improved affinity for
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • X represents N or C-R 5 ;
  • R 1 and R 2 independently represent hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocyclo alkyl, C 3-7 heterocycloalkyl- (C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R 1 and R 2 when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or
  • R 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 C 1-6 alkyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )- alkynyl, biaryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci- 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 a represents Cj -6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
  • R b represents hydrogen; or optionally substituted Ci -6 alkyl
  • R c represents hydrogen; or Cj -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 C 1-6 alkyl
  • R f represents C 1-6 alkyl, aryl, aryl(Ci -6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • a pharmaceutically acceptable 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.
  • solvates of the compounds of formula (I) above include within its scope solvates of the compounds of formula (I) above.
  • Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
  • the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
  • Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched C 1-6 alkyl groups, for example C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, w-propyl, isopropyl, 77-butyl, sec-butyl, isobutyl, tert-bvAyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "C 1-6 alkoxy", “C 1-6 alkylthio", "C 1-6 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, but-1-yn-l-yl and 3- methylbut- 1 -yn- 1 -yl.
  • C 3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci- 6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • aryl(C 2 . 6 )alkenyl groups include 2-phenylethenyl and 3-phenylprop-2-en- 1-yl.
  • aryl(C 2-6 )alkynyl groups include phenylethynyl, 3-phenylprop-l-yn-l-yl and 3-phenylprop-2-yn-l-yl.
  • Particular biaryl groups include biphenyl and naphthylphenyl.
  • Suitable heterocyclo alkyl 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 thiomorpholinyl.
  • Typical heterobicycloalkyl groups include quinuclidinyl, 8-azabicyclo[3.2.1]octyl and 3,8-diazabicyclo[3.2.1]octyl.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrazolyl, pyrazolo[l,5- ⁇ ]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, irnidazolyl, benzimidazolyl, imidazo[ 1 ,2- ⁇ ]pyridinyl, imidazo[4,5- ⁇
  • Typical bi(heteroaryl) groups include benzofuryl-pyridinyl, benzothienyl-pyridinyl, indolyl-pyridinyl, isoxazolyl-pyridinyl, bipyridinyl and isoquinolinyl-pyridinyl.
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • X represents N. In another embodiment, X represents C-R 5 .
  • R 1 represents hydrogen or C 1-6 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 C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents.
  • R and/or R examples include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C 1-6 alkylthio, Ci -6 alkylsulphonyl, amino, Ci -6 alkylamino, 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 include hydrogen, methyl, ethoxy, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl.
  • R and R 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 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 ⁇ -hydroxyketone moiety.
  • 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 ⁇ -hydroxyketone moiety.
  • 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 ⁇ -hydroxyketone moiety.
  • R 3 represents hydrogen; or Cj -6 alkyl, aryl, aryl(Ci. ⁇ )alkyl, aryl- (C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkyl- carbonyl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R represents hydrogen; or C 2-6 alkynyl, aryl(C 1-6 )alkyl or heteroaryl- (C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 3 represents aryl(C 1-6 )alkyl or heteroaryl(Ci -6 )alkyl, either of which groups may be optionally substituted by one or more substituents. In one specific embodiment, R represents hydrogen.
  • R 3 represents C 1-6 alkyl, aryl(C 1-6 )alkyl, biaryl- (C 1-6 )alkyl, heteroaryl(C 1-6 )alkyl or heteroaryl-aryl(C 1-6 )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- (C 1-6 )alkyl.
  • R 3 represents substituted or unsubstituted indolylmethyl.
  • R 3 represents substituted or unsubstituted phenyl-
  • R 3 represents substituted or unsubstituted benzyl.
  • R 3 represents substituted or unsubstituted benzofuryl- (C 1-6 )alkyl.
  • R 3 represents substituted or unsubstituted benzofurylmethyl.
  • R represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1 ,2,3,4-tetrahydroqumolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3 ,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienyl
  • R 3 and/or R 4 examples include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (C 1-6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl(C i -6 )alkylaryl, piperazinyl(C ⁇ -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C ⁇ . ⁇ )- alkylaryl, morpholinyl(Ci -6 )alkylaryl, (Ci_ 6 )alkoxyaryl, cyano(C 1-6 )alkoxyaryl, di(C 1-6 )- alkylamino(Cj -6 )alkylaryl, (Ci -6 )alkylaminocarbonylaryl, aryl(Ci -6 )alkyl, oxazolinyl
  • R 3 and/or R 4 include Cj -6 alkyl and di(C 1 -6 )alkylaminocarbonyl .
  • 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, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoin
  • R 3 and/or R 4 include methyl and dimethylaminocarbonyl.
  • Typical values of R 3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, iV-methyl-iV-phenylaminomethyl, pyridinylamino- methyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyl- methylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolyl- phenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl,
  • R 3 is (dimethylaminocarbonyl)(methyl)indolylmethyl.
  • Typical values of R 4 include hydrogen and methyl.
  • R 4 is hydrogen.
  • R is C 1-6 alkyl, especially methyl.
  • R 3 and R 4 when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage.
  • R 3 and R 4 when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
  • R 3 and R 4 when attached to adjacent carbon atoms, may together form an optionally benzo-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the morpholine ring.
  • R 3 and R 4 when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 4 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the morpholine ring, which phenyl ring may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 3 and R 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, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(C] -6 )alkylaryl, piperidinyl(Ci. 6 )alkylaryl, piperazinyl(Ci -6 )alkylaryl, (Ci -6 )alkylpiperazinyl(C 1-6 )alkylaryl, morpholinyl(C 1-6 )alkylaryl, (Ci -6 )alkoxyaryl, cyano(C 1-6 )alkoxyaryl, di(Ci.
  • substituents on the fused rings referred to in the three preceding paragraphs include fluoro, chloro, bromo, nitro, methyl, n-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl
  • substituents include bromo, hydroxyethylpyrazolyl and (dihydroxypropyl)pyrazolyl.
  • R a represents substituted or unsubstituted aryl.
  • R c represents hydrogen; or aryl, aryl(C 1-6 )alkyl, heteroaryl(C 1-6 )alkyl or (aryl)(heteroaryl)(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R a and/or R b and/or R c and/or R f include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C 1-6 alkylthio, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, Ci -6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl and di(Ci -6 )alky
  • R a and/or R b and/or R c 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.
  • R a is phenyl.
  • R b represents hydrogen, hi 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 represents optionally substituted aryl, especially phenyl.
  • R 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b ,
  • R 5 represents C 1-6 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 .
  • R 5 represents hydrogen, halogen, cyano, -SR a , -COR e , -CO 2 R b or -CONR c R d ; or R 5 represents methyl, propyl, ethenylcarbonyl, ethynyl, propynyl, butynyl, 3-methylbutynyl, cyclopropylethynyl, cyclohexylethynyl, phenyl, naphthyl, benzyl, phenylethyl, phenylethenyl, phenylethynyl, phenylpropynyl, biphenyl, piperidinyl ethyl, pyrrolidinylethynyl, piperidinylethynyl, 1 ,2,3 ,4-tetrahydroisoquinolinylpropynyl, piperazinylpropynyl,
  • R 5 examples include halogen, cyano, nitro, oxo, Ci -6 alkyl, trifluoromethyl, hydroxy, hydroxy(Ci -6 )alkyl, C 1-6 alkoxy, dihydroxy(C ]-6 )- alkoxy, aryl(C 1-6 )alkoxy, methoxyaryl(C 1-6 )alkoxy, amino, Ci -6 alkylamino, di(Ci_ 6 )- alkylamino, amino(C 1-6 )alkyl, Ci -6 alkylamino(Ci -6 )alkyl, di(C 1-6 )alkylamino(C 1-6 )alkyl, di(Ci -6 )alkylamino(Ci -6 )alkylamino, methoxyaryl(C 1-6 )alkylamino, C 1-6 alkylcarbonyl- amino, C 1-6 alkoxycarbonyl(Ci -6 )alkyl
  • Ci -6 alkoxycarbonylamino N-(C 1-6 alkoxycarbonyl)-N-(Ci -6 alkyl)amino, C 1-6 alkoxy- carbonylamino(Ci -6 )alkyl, N-(Ci -6 alkoxycarbonyl)-N-(C 1-6 alkyl)amino(Ci -6 )alkyl, C 1-6 alkylsulphonylamino, Cj -6 alkylsulphonylamino(Ci_ 6 )alkyl, Ci -6 alkylaminocarbonylamino, di(Ci -6 )alkylamiiio(C 1-6 )alkylaminocarbonylamino, N-(C 1-6 alkyl)-N-[di(Ci -6 )alkylamino- (C 1-6 )alkyl]aminocarbonylamino, carboxycarbonylamino, Ci -6 alkoxycarbonylamino
  • 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, fert-butoxycarbonylamino, N-(tert-butoxy- carbonyl)-N
  • R 5 include hydrogen, fluoro, chloro, bromo, iodo, cyano, phenylthio, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, pyridinylmethylaminocarbonyl,
  • R 5 is hydrogen
  • R 5 is other than hydrogen
  • R 5 is hydrogen
  • R 3 and/or R 4 is other than hydrogen
  • X 1 represents N or CH
  • R 11 represents hydrogen or C 1-6 alkyl
  • R 12 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )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 13 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1 . 6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • X 1 represents N. In another embodiment, X 1 represents CH.
  • 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 11 Typical values of R 11 include hydrogen, methyl and ethyl. In one embodiment, R 11 is hydrogen. In another embodiment, R 11 is Cj -6 alkyl, especially methyl.
  • R 12 represents hydrogen; or C 1-6 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, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difiuoromethoxy, trifluoromethoxy, aryloxy, Ci -6 alkylthio, Ci -6 alkylsulphonyl, amino, Ci -6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbon
  • 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 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl.
  • a particular value of R 12 is methyl.
  • R l and R 12 may together form an optionally substituted spiro linkage.
  • R 11 and R 12 when taken together with the carbon atom to which they are both attached, may represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 11 and R 12 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
  • R 13 represents hydrogen; or C 1-6 alkyl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 13 represents hydrogen; or C 2-6 alkynyl, aryl(Ci-o)alkyl or heteroaryl- (C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 13 represents aryl(C 1-6 )alkyl or heteroaryl(C 1-6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 13 represents hydrogen
  • R 13 represents C 1-6 alkyl, aryl(C 1-6 )alkyl, biaryl- (C 1-6 )alkyl, heteroaryl(Ci -6 )alkyl or heteroaryl-aryl(C[, 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. More particularly, R 13 represents arylmethyl or heteroarylmethyl, either of which groups maybe optionally substituted by one or more substituents.
  • R 13 represents substituted or unsubstituted indolyl- (C 1-6 )alkyl.
  • R 13 represents substituted or unsubstituted indolylmethyl.
  • R 13 represents substituted or unsubstituted phenyl- (C 1-6 )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-tetrahydroquinolinylniethyl, 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-b]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazoly
  • R 13 examples include halogen, cyano, nitro, Ci -6 alkyl, trifiuoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci. 6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl- (C 1-6 )alkylaryl, piperazinyl(Ci -6 )alkylaryl, (C 1-6 )alkylpiperazinyl(C 1-6 )alkylaryl, morpholinyl(Ci -6 )alkylaryl, (C 1-6 )alkoxyaryl, cyano(C 1-6 )alkoxyaryl, di(C 1 .
  • R 13 Selected examples of specific substituents on R 13 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimemylammomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperid
  • R 13 Particular examples of specific substituents on R 13 include methyl and dimethylaminocarbonyl.
  • Typical values of R 13 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienylmethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylamino
  • R 13 is (dimethylaminocarbonyl)(methyl)indolylmethyl.
  • R 11 and R 12 are as defined above;
  • T represents oxygen or N-R ;
  • R 23 represents hydrogen, halogen, cyano, nitro, Ci -6 alkyl, hydroxy(C 1-6 )alkyl, trifluoromethyl, aryl(C 1-6 )alkyl, oxazolinyl, triazolyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkyl(C 1-6 )alkoxy, morpholinyl(C 1-6 )alkoxy, aryloxy, aryl(C 1-6 )alkoxy, C 1-6 alkylthio, Ci -6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, C 1-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C 2-6 alkylcarbonylamino, C 2-6 alkylcarbonylaminomethyl, C 2-6 alkoxy
  • R 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 .
  • T is oxygen.
  • a suitable value of R 23 is di(C 1-6 )alkylaminocarbonyl.
  • R 23 Illustrative values of R 23 include hydrogen, fluoro, chloro, cyano, nitro, oxazolinyl, triazolyl, methoxy, difiuoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, morpholinylethoxy, azetidinyl, morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino, iV-methoxycarbonyl-iV-methylamino, methylsulphonylamino, acetyl, acetyl oxime, acetyl 0-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethylaminoethyl)aminocarbonyl, (1
  • R 23 is dimethylaminocarbonyl.
  • R 24 includes hydrogen, chloro, methoxy and dimethylaminocarbonyl.
  • a particular value of R 24 is hydrogen.
  • R 25 is hydrogen.
  • R 25 is C 1-6 alkyl, especially methyl.
  • R and R are as defined above;
  • R 33 represents halogen or -NHR 34 ; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents;
  • R 34 represents methylenedioxyphenyl, morpholinyl(Ci -6 )alkylphenyl, oxazolinyl- phenyl, [(C 1-6 )alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (C 1-6 )alkyltriazolylphenyl, (C 1-6 )alkylpyrimidinylphenyl, pyrazolyl(C 1-6 )alkyl- phenyl, triazolyl(Ci -6 )alkylphenyl, Cj -6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, C 1-6 alkylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, C 1-6 alkylsulphonylindolin
  • R 33 represents halogen or -NHR 3 , in which R 34 is as defined above.
  • R 3 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 represents unsubstituted or substituted heteroaryl.
  • Typical values of R 34 include pyridinyl, halopyridinyl, (C 1-6 )alkylpyridinyl, di(C] -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 34 , 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 maybe optionally substituted by one or more substituents.
  • R 33 Selected examples of suitable substituents on R 33 include halogen, cyano, C 1-6 alkyl, hydroxy(C 1-6 )alkyl, trifluoromethyl, Ci -6 alkoxy, trifluoromethoxy, aryloxy, methylenedioxy, C 1-6 alkylthio, arylsulphonyl, amino, C 2-6 alkylcarbonylamino, C 1-6 alkylsulphonylamino, C 2-6 alkylcarbonyl and aminocarbonyl.
  • Selected examples of representative substituents on R 33 include fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, phenoxy, methylenedioxy, methylthio, phenylsulphonyl, amino, acetylamino, methylsulphonylamino, acetyl and aminocarbonyl.
  • R 33 Specific values of R 33 include bromo, methylenedioxyphenylamino, mo ⁇ holinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenyl- amino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenyl- amino, triazolylmethylphenylamino, methylsulphonylaminophenylamino, morpholinyl- carbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, dihydrobenzofuranylamino, methylsulphonylindolinylamino, chromanonylamino, dihydroquinolinonylamino,
  • R 33 is bromo.
  • R 11 and R 1Z are as defined above;
  • R ⁇ 3 represents hydrogen, halogen, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl,
  • R 4 represents hydrogen, halogen, Ci -6 alkyl or C 1-6 alkoxy.
  • Suitable values of R 43 include halogen, hydroxy(C 1-6 )alkylpyrazolyl and [dihydroxy(C 1-6 )alkyl]pyrazolyl.
  • R 3 include fluoro, chloro, bromo, nitro, methyl, r ⁇ -propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chloroph
  • R 44 represents hydrogen. In another embodiment, R 44 represents halogen, especially fluoro, chloro or bromo. In a further embodiment, R 44 represents C 1-6 alkyl, especially methyl. In an additional embodiment, R represents C 1-6 alkoxy, especially methoxy.
  • a further sub-class of compounds according to the invention is represented by the compounds of formula (HE), and pharmaceutically acceptable salts and solvates thereof:
  • R , R . 11 and R , 12 are as defined above.
  • 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.
  • 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 micronized 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 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):
  • R z represents Ci -6 alkyl; with an oxidising agent.
  • R 2 represents methyl
  • the oxidising agent of use in the reaction with compound (III) is suitably a peroxyacid, e.g. m-chloroperbenzoic acid, in which case the reaction is conveniently effected in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • a peroxyacid e.g. m-chloroperbenzoic acid
  • a suitable solvent e.g. a chlorinated solvent such as dichloromethane.
  • the halogen atom L is suitably chloro.
  • the strong base of use in the reaction with compound (IV) is suitably a hexa(C 1-6 )- alkyldisilazide reagent, e.g. sodium bis(trimethylsilyl)amide, in which case the reaction is conveniently effected in an inert solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • a hexa(C 1-6 )- alkyldisilazide reagent e.g. sodium bis(trimethylsilyl)amide
  • an inert solvent e.g. a cyclic ether such as tetrahydrofuran.
  • the intermediates of formula (IV) above may be prepared by the methods described in WO 2006/114606, WO 2007/141504, WO 2008/001076, and copending international patent application no. PCT/GB2007/003853, which was published on 17 April 2008 as WO 2008/044022; or by procedures analogous thereto.
  • 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, e.g. by methods analogous to those described in WO 2006/114606, WO 2007/141504, WO 2008/001076, and copending international patent application no. PCT/GB2007/003853, which was published on 17 April 2008 as WO 2008/044022.
  • 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 r 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 PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ .
  • the concentration of inhibitor required to inhibit the enzyme activity by 50% is quoted as the IC 5 0.
  • the compounds of the accompanying Examples were all found to possess IC 5O values for inhibition of activity of human PI3K ⁇ and/or PDK ⁇ and/or PBK ⁇ and/or PDK ⁇ of 50 ⁇ M or better.
  • SiO 2 silica brine: sat. aqueous sodium chloride solution sat: saturated r.t: room temperature RT: retention time h: hour br: broad M: mass
  • Method 1 Phenomenex Luna Cl 8(2) 250 x 21.2 mm, 5 ⁇ m column.
  • Mobile phase A 99.92% water, 0.08% formic acid.
  • Mobile phase B 99.92% MeCN, 0.08% formic acid.
  • Gradient program flow rate 25.0 mL/min
  • column temperature ambient, variable gradient.
  • Method 2 Phenomenex Luna Cl 8(2) 250 x 21.2 mm, 5 ⁇ m column.
  • Mobile phase A 10 mM ammonium acetate in water.
  • Mobile phase B 10 mM ammonium acetate in MeCN.
  • Gradient program flow rate 25.0 mL/min
  • column temperature ambient, variable gradient.
  • Method 3 Phenomenex Luna Cl 8(2) 100 x 4.6 mm, 5 ⁇ m column.
  • Mobile phase A 99.92% water, 0.08% formic acid.
  • Mobile phase B 99.92% MeCN, 0.08% formic acid.
  • Gradient program (flow rate 3.0 mL/min, column temperature 35°C): Time A % B % 0.00 95.0 5.0 4.40 5.0 95.0 5.30 5.0 95.0 5.32 95.0 5.0

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Abstract

A series of fused bicyclic thiophene and thiazole derivatives (I) which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, and wherein the thiophene or thiazole ring is fused to a six-membered carbocyclic ring containing an alpha-hydroxyketone functionality, 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

FUSED THIOPHENE AND THIAZOLE DERIVATIVES AS PI3K KINASE
INHIBITORS
The present invention relates to a class of fused thiophene and thiazole derivatives, and to their use in therapy. More particularly, the invention provides a family of fused bicylic thiophene and thiazole derivatives which are substituted in the 2-position of the thiophene or thiazole ring by an optionally substituted morpholin-4-yl moiety. These compounds are selective inhibitors of phosphoinositide 3-kinase (PDK) 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 PBK pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases. Thus, PDKs provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et ai, Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sd., 2003, 24, 366-376). Aberrant upregulation of the PDK 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 PDK inhibitors, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g. during heart failure); neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; pain and nociceptive disorders; and ophthalmic disorders including age- related macular degeneration (ARMD).
In addition, the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of this invention may be useful as radioligands in assays for detecting compounds capable of binding to human PDK enzymes.
Various fused thiazole derivatives are disclosed in Liebigs Annalen der Chemie, 1986, 780-784; and in Russian Journal of General Chemistry (translation 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 2006/114606 and WO 2008/001076 describe related classes of fused bicyclic thiazole derivatives; as also does copending international patent application no. PCT/GB2007/003853, which was published on 17 April 2008 as WO 2008/044022. WO 2007/141504 describes a class of fused bicyclic thiophene derivatives. The compounds disclosed in all of those patent filings are selective inhibitors of PD 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 PDK inhibitors having a binding affinity (IC50) for the human PD Ka and/or PDKβ and/or PDKγ 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 IC50 figure denotes a more active compound). The compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for the human PDKα and/or PDKβ and/or PDKγ and/or PDKδ isoform relative to other human kinases. The compounds of the present invention possess markedly improved affinity for
PDK isoforms relative to their structurally closest prior art analogues; and also display interesting pharmacokinetic properties owing to their improved solubility and clearance. The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000004_0001
(I)
wherein
X represents N or C-R5;
R1 and R2 independently represent hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocyclo alkyl, C3-7 heterocycloalkyl- (C1-6)alkyl, heteroaryl or heteroaryl(C1-6)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; R3 and R4 independently represent hydrogen; or C1-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)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(C1-6)alkyl, heteroaryl-aryl(C1-6)alkyl or aryl-heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R3 and R4, when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or
R3 and R4, when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb, -CONRcRd or -C(=N-ORf)Re; or R5 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkenylcarbonyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, C3-7 cycloalkyl(C2-6)alkenyl, C3-7 cycloalkyl- (C2-6)alkynyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, biaryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkyl(C2-6)alkenyl, C3-7 heterocycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkylcarbonyl(C2-6)alkynyl, C5-9 heterobicycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkyl-aryl, C3-7 heterocycloalkyl(C1-6)- alkyl-aryl, C3-7 heterocycloalkyl-biaryl, heteroaryl, heteroaryl(C1-6)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(C1-6)alkyl-aryl-heteroaryl, C5-9 heterobicycloalkyl(C1-6)alkyl-aryl-heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl-biφeteroaryl), aryloxyaryl, aryl(C1-6)alkoxyaryl, heteroaryl(C1-6)alkoxyaryl, aryl(C]-6)alkylaminoaryl, heteroaryl(C1-6)alkylaminoaryl, C3-7 cycloalkylcarbonylaminoaryl, arylcarbonylaminoaryl, aryl(Ci-6)alkylcarbonylaminoaryl, C3-7 heterocycloalkylcarbonylaminoaryl, heteroarylcarbonylaminoaryl, aryl- (C3-7)heterocycloalkylcarbonylaminoaryl, arylsulphonylaminoaryl, aryl(C1-6)alkyl- sulphonylaminoaryl, heteroaryl(C1-6)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)alkylaminocarbonylcarbonylaininoaryl,, arylcarbonylaryl, C3-7 heterocycloalkylcarbonylaryl, C3-7 heterocycloalkylcarbonyl(C1-6)alkylaryl, aryl(C1-6)- alkylaminocarbonylaryl, C3-7 heterocycloalkyl(Ci.6)alkylaminocarbonylaryl, heteroaryl- aminocarbonylaryl, heteroaryl(Ci-6)alkylaminocarbonylaryl, C3-7 heterocycloalkylamino- carbonyl(C 1-6)alkylaryl, C3-7 heterocycloalkyl(C i-6)alkylaminocarbonyl(C i -6)alkylaryl, heteroarylaminocarbonyl(C 1-6)alkylaryl, heteroaryl(C j -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 cycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- carbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(C1-6)alkylcarbonyl-aryl-heteroaryl, C5-9 heterobicycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl(C1-6)alkyl-aryl- heteroaryl, C3-7 heterocycloalkyl-aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- (C1-6)alkylaminocarbonyl-aryl-heteroaryl or C3-7 heterocycloalkylarninocarbonyl(Ci-6)- alkyl-aryl-heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Ra represents Cj-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Rb represents hydrogen; or optionally substituted Ci-6 alkyl;
Rc represents hydrogen; or Cj-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 C1-6 alkyl; and
Rf represents C1-6 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.
Where any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted. For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched C1-6 alkyl groups, for example C1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, w-propyl, isopropyl, 77-butyl, sec-butyl, isobutyl, tert-bvAyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "C1-6 alkoxy", "C1-6 alkylthio", "C1-6 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, but-1-yn-l-yl and 3- methylbut- 1 -yn- 1 -yl.
Specific C3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
Suitable aryl(Ci-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Specific aryl(C2.6)alkenyl groups include 2-phenylethenyl and 3-phenylprop-2-en- 1-yl.
Specific aryl(C2-6)alkynyl groups include phenylethynyl, 3-phenylprop-l-yn-l-yl and 3-phenylprop-2-yn-l-yl. Particular biaryl groups include biphenyl and naphthylphenyl.
Suitable heterocyclo alkyl 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 thiomorpholinyl.
Typical heterobicycloalkyl groups include quinuclidinyl, 8-azabicyclo[3.2.1]octyl and 3,8-diazabicyclo[3.2.1]octyl. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrazolyl, pyrazolo[l,5-β]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, irnidazolyl, benzimidazolyl, imidazo[ 1 ,2-α]pyridinyl, imidazo[4,5-ό]pyridinyl, imidazo[ 1 ,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl, quinoxalinyl and chromenyl groups.
Typical bi(heteroaryl) groups include benzofuryl-pyridinyl, benzothienyl-pyridinyl, indolyl-pyridinyl, isoxazolyl-pyridinyl, bipyridinyl and isoquinolinyl-pyridinyl. The term "halogen" as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.
Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (I) may exist as tautomers, for example keto (CH2C=O)<→enol (CH=CHOH) tautomers or amide (NHC=O)<→hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
Specific sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA) and (IB):
Figure imgf000009_0001
wherein R1, R2, R3, R4 and R5 are as defined above.
In one embodiment, X represents N. In another embodiment, X represents C-R5.
Suitably, R1 represents hydrogen or C1-6 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 C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl or aryl, any of which groups may be optionally substituted by one or more substituents.
Examples of typical substituents on R and/or R include halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C1-6 alkylthio, Ci-6 alkylsulphonyl, amino, Ci-6 alkylamino, di(C].6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylarnino, Ci-6 alkylsulphonylamino, formyl, C%-β alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulphonyl, Ci-6 alkylaminosulphonyl and di(C1-6)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 R include hydrogen, methyl, ethoxy, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl. A particular value of R2 is methyl.
Alternatively, R and R , when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage. Thus, 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, R 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 α-hydroxyketone moiety. 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 α-hydroxyketone moiety. 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 α-hydroxyketone moiety.
Typically, R3 represents hydrogen; or Cj-6 alkyl, aryl, aryl(Ci.ό)alkyl, aryl- (C2-6)alkynyl, biaryl(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkyl- carbonyl, heteroaryl(C1-6)alkyl, heteroaryl-aryl(C1-6)alkyl or aryl-heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Generally, R represents hydrogen; or C2-6 alkynyl, aryl(C1-6)alkyl or heteroaryl- (C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R3 represents aryl(C1-6)alkyl or heteroaryl(Ci-6)alkyl, either of which groups may be optionally substituted by one or more substituents. In one specific embodiment, R represents hydrogen. In a representative embodiment, R3 represents C1-6 alkyl, aryl(C1-6)alkyl, biaryl- (C1-6)alkyl, heteroaryl(C1-6)alkyl or heteroaryl-aryl(C1-6)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- (C1-6)alkyl. Advantageously, R3 represents substituted or unsubstituted indolylmethyl. In a typical embodiment, R3 represents substituted or unsubstituted phenyl-
(C1-6)alkyl. Advantageously, R3 represents substituted or unsubstituted benzyl.
In another embodiment, R3 represents substituted or unsubstituted benzofuryl- (C1-6)alkyl. Advantageously, R3 represents substituted or unsubstituted benzofurylmethyl. Illustratively, R represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indolinylmethyl, 1 ,2,3,4-tetrahydroqumolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3 ,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-ό]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, 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 C1-6 alkyl.
Examples of typical substituents on R3 and/or R4 include halogen, cyano, nitro, Ci-6 alkyl, trifluoromethyl, C2-6 alkenyl, C3-7 cycloalkyl, (C1-6)alkylaryl, di(Ci-6)alkylaryl, piperidinyl(C i -6)alkylaryl, piperazinyl(C \ -6)alkylaryl, (C i -6)alkylpiperazinyl(C \.β)- alkylaryl, morpholinyl(Ci-6)alkylaryl, (Ci_6)alkoxyaryl, cyano(C1-6)alkoxyaryl, di(C1-6)- alkylamino(Cj-6)alkylaryl, (Ci-6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, oxazolinyl, azetidinyl, pyrrolidinyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di- (C1-6)alkylaminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonyl- piperidinyl, di(Ci-6)alkylaminocarbonylpiperidinyl, piperazinyl, (C1-6)alkylpiperazinyl, haloarylpiperazinyl, pyridinylpiperazinyl, foroylpiperazinyl, homopiperazinyl, (C1-6)alkylhomopiperazinyl, morpholinyl, (C1-6)alkylpiperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (C1-6)alkylpyrazolyl, di(C1-6)- alkylpyrazolyl, tri(Ci_6)alkylpyrazolyl, [d^Ci^alkylXtrifluoromethytypyrazolyl, cyano- (C1-6)alkylpyrazolyl, [cyano(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, hydroxy(C1-6)alkyl- pyrazolyl, [hydroxy(C1-6)alkyl] [di(C1-6)alkyl]pyrazolyl, methoxy(C1-6)alkylpyrazolyl, [dihydroxy(C1-6)alkyl]pyrazolyl, [(hydroxy)(methoxy)(C1-6)alkyl]pyrazolyl, amino- (C1-6)alkylpyrazolyl, [(C1-6)alkyl] [amino(C1-6)alkyl]pyrazolyl, [amino(C1-6)alkyl] [di- (C1-6)alkyl]pyrazolyl, di(C1-6)alkylamino(C1-6)alkylpyrazolyl, di(C1-6)alkoxyphosphono- (C1-6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl(Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl(C1-6)alkyl][di(Ci-6)alkyl]pyrazolyl, [(C1-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(C1-6)alkylpyrazolyl, aminoaryl(C1-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(C1-6)alkylpyrazolyl, [di(C1-6)alkyl]- [tetrahydropyranyl(Ci.6)alkyl]pyrazolyl, pyrrolidinyl(C1-6)alkylpyrazolyl, piperidinyl- (C1-6)alkylpyrazolyl, (C1-6)alkylpiperidinyl(Ci-6)alkylpyrazolyl, morpholinyl(C1-6)alkyl- pyrazolyl, pyridinyl(C1-6)alkylpyrazolyl, oxypyridinyl(C1-6)alkylpyrazolyl, • [arylcarbonyl(Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, [(Ci-6)alkyl](piperazinyl- carbonyl)pyrazolyl, [(C1-6)alkylaminocarbonyl] [(C1-6)alkylaryl]pyrazolyl, [(C^alkyl]- [amino(C1-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl, [aminocarbonyl(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, di(Ci-6)alkylaminocarbonyl(C1-6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(Cj.6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]- isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (C1-6)alkylimidazolyl, di(C1-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkylimidazo[l,2-α]pyridinyl, (C1-6)- alkylimidazo[4,5-Zj]pyridinyl, imidazo[l,2-fl]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)- alkylthiadiazolyl, triazolyl, pyridinyl, halopyridinyl, (C^alkylpyridinyl, [(C1-6)alkyl]- (halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C1-6)alkylpiperazinyl- pyridinyl, [(Ci-6)alkyl](piperazinyl)pyridinyl, [(Ci-6)alkoxycarbonylpiperazinyl][(C1-6)- alkyl]pyridinyl, ρiperidinyl(C1-6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (C1-6)alkoxypyridinyl, [(C1-6)alkoxy]- [(Ci-6)alkyl]pyridinyl, [(C1-6)alkoxy][di(C1-6)alkyl]pyridinyl, (C1-6)alkoxy(C1-6)alkyl- pyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (Ci-6)alkoxycarbonyl(Ci-6)alkyl- pyridinyl, pyridazinyl, (Ci-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (C1-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(Ci-6)alkylaminopyridazinyl, di- (Ci-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrirnidinyl, [(C1-6)alkyl](halo)- pyrimidinyl, di(C1-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (C1-6)alkylpiperazinyl- pyrimidinyl, [(Ci-6)alkyl](piρerazinyl)pyrimidinyl, [(Cj-6)alkoxycarbonyl] [(Ci-6)alkyl]- piperazinylpyrimidinyl, hydroxypyrimidinyl, [(C1-6)alkyl](hydroxy)pyrimidinyl, [(Ci-6)- alkyl][hydroxy(C1-6)alkyl]pyrimidinyl, [(C1-6)alkyl][hydroxy(C2-6)alkynyl]pyrimidinyl, (C1-6)alkoxypyrimidinyl, aminopyrimidinyl, di(C1-6)alkylaminopyrimidinyl, [di(C1-6)alkyl- amino](halo)ρyrimidinyl, carboxypyrimidinyl, [(Ci-6)alkoxycarbonyl(C1-6)alkyl][(Ci-6)- alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (C1-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (C1-6)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, (C1-6)alkylpiperazinylpyridinyloxy, (C1-6)alkylpyrazolyl- pyridinyloxy, (C1-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C1-6)alkyl](halo)pyrimidinyloxy, hydroxy(C1-6)alkyl, dihydroxy(Ci-6)alkyl, pyridinyloxy(Ci.6)alkyl, methylenedioxy, trifluoromethylenedioxy, amino, (Ci-6)alkyl- amino, dihydroxy(C1_6)alkylamino, (Ci-6)alkoxy(C1.6)alkylamino, di(Ci-6)alkylamino, N- [(Ci-6)alkoxy(C1-6)alkyl]-N-[(C1-6)alkyl]amino5 di(C1-6)alkylamino(Ci-6)alkylamino, N- [(CI-6)alkyl]-N-[di(C1-6)alkylamino(Ci-6)alkyl]amino, N-[(C1-6)alkyl]-N-[(C3-7)cycloalkyl]- amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, methylenedioxyphenylamino, morpholinyl(Ci-6)alkylphenylamino, oxazolinylphenylamino, [(Ci-6)alkyl](oxo)pyrazolyl- phenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, (Ci-6)alkyltriazolylphenylamino, (Ci-6)alkylpyrimidinylphenylamino, pyrazolyl(C1-6)alkyl- phenylamino, triazolyl(Ci-6)alkylphenylamino, C1-6 alkylsulphonylaminophenylamino, morpholinylcarbonylphenylamino, C1-6 alkylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-[(C1-6)alkyl]-N-[aryl(C1-6)alkyl]amino, N-[di(Ci,6)alkylamino(Ci-6)alkyl]-N-[aryl(Ci-6)alkyl]amino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(C1-6)alkylamino, methylenedioxyary^Cμ^alkylamino, dihydrobenzofuranylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkylpyrrolidinyl]amino, Ci-6 alkylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-[(Ci-6)alkyl]-N- (piperidinyl)amino, N-[(C3-7)cycloalkyl(C1-6)alkyl]-N-(piperidinyl)amino, (Ci.6)alkyl- piperidinylamino, N-t(Ci-6)alkyl]-N-[(Ci-6)alkylρiρeridinyl]amino, N-[(Ci.6)alkyl]- N-[(C3-7)cycloalkylρiperidinyl]amino, N-[(C1-6)alkyl]-N-[(C2-6)alkylcarbonylpiperidmyl]- amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinyl(Ci-6)alkylamino, N-[(C1-6)alkyl]-N-[pyrrolidinyl(C1-6)alkyl]amino, N-[(C1-6)alkyl]-N-[ρiρeridinyl(C1-6)- alkyl]amino, benzothienylamino, indolylamino, dioxoindolylamino, (C1-6)alkylpyrazolyl- amino, [(Ci-6)alkyl](halo)pyrazolylamino, di(C1-6)alkylpyrazolylamino, tri(Ci.6)alkyl- pyrazolylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkylpyrazolyl]amino, (C1-6)alkylindazolylamino, benzoxazolylamino, benzoxazolonylamino, di(C1-6)alkylisoxazolylamino, thiazolylamino, benzothiazolylamino, (C1-6)alkylisothiazolylamino, imidazolylamino, [(Ci-6)alkoxy- carbonyl][(C1-6)alkyl]imidazolylamino, (Ci-6)alkylbenzimidazolylamino, benzimidazolonylamino, di(C1-6)alkylbenzimidazolonylamino, (C1.6)alkyloxadiazolyl- amino, furyloxadiazolylamino, (C1-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (C1-6)alkylpyridinylamino, di(Ci-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C1-6)alkylρyridinylamino, dihydroxy(C1-6)alkylpyridinylamino, (C1-6)alkoxypyridinylamino, dihydroxy(C1-6)alkoxy- pyridinylamino, di(Ci-6)alkyldioxolanyl(Ci-6)alkoxypyridinylamino, (Ci-6)alkoxy(Ci.6)- alkylpyridinylaniino, (C1-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C1-6)alkyl- aminopyridinylamino, di(C1-6)alkylaminopyridinylamino, (C1-6)alkylamino(C1-6)alkyl- pyridinylamino, di(C i -6)alkylamino(C i -6)alkylpyridinylamino, oxopyridinylamino, carboxypyridinylamino, N-[(C1-6)alkyl]-Λ/-[(C1-6)alkylpyridinyl]amino, bis[(C1-6)alkyl- pyridinyl] amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, (C1-6)alkyl- pyridazinylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkylpyridazinyl]amino, iV-[aryl(C1-6)alkyl]-iV- [(C1-6)alkylpyridazinyl]amino, di(Ci.6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C1-6)alkoxypyridazinylamino, [(C1-6)alkoxy](halo)- pyridazinylamino, di(C1-6)alkylaminopyridazinylamino, bis[(C1-6)alkylpyridazinyl]amino, (Ci-6)alkylcinnolinylamino, oxopyrimidinylamino, thioxopyrimidinylamino, quinoxalinylamino, (C1-6)alkylchromenylamino, benzofuryl(C1-6)alkylamino, thienyl(C1-6)- alkylamino, indolyl(C1-6)alkylamino, (C1-6)alkylpyrazolyl(C1-6)alkylamino, [di(C1-6)alkyl]- (halo)pyrazolyl(C1-6)alkylamino, di(C1-6)alkylisoxazolyl(Ci-6)alkylamino, thiazolyl(C1-6)- alkylamino, imidazolyl(C i -6)alkylamino, (C1 -6)alkylimidazolyl(C j -6)alkylamino, pyridinyl(C1-6)alkylammo, (C1-6)alkylpyridinyl(C1-6)alkylamino, N-[(Ci-6)alkyl]-N- [pyridinyl(Ci-6)alkyl]amino, iV-[dihydroxy(C1-6)alkyl]-iV-[pyridinyl(C1-6)alkyl]amino, iV- [(Ci-6)alkylpyridinyl(Ci-6)alkyl]-N-[dihydroxy(Ci-6)alkyl]amino, amino(Ci-6)alkyl, (Ci-6)- alkylamino(C1-6)alkyl, di(C1-6)alkylamino(Ci-6)alkyl, pyridinylamino(C1-6)alkyl, C2-6 alkylcarbonylamino, -/V-[(C2-6)alkylcarbonyl]-N-[(Ci-6)alkylpyridinyl(C1-6)alkyl]amino, di(Ci.6)alkylamino(C1-6)alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, (C3-7)- cycloalkylcarbonylamino, (C1-6)alkylpiperidinylcarbonylamino, (C1-6)alkylimidazolyl- carbonylamino, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(C1-6)alkyl]amino, Ci-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(C1-6)- alkylamino(Ci-6)alkyl]aminocarbonyl, di(Ci-6)alkylaminocarbonyl, [(C]-6)alkyl][cyano- (C1-6)alkyl]aminocarbonyl, [(C1-6)alkyl][hydroxy(Ci-6)alkyl]aminocarbonyl, [(C1-6)alkoxy- (C1-6)alkyl][(C1-6)alkyl]aminocarbonyl, [di(C1-6)alkylamino(C1-6)alkyl][(Ci-6)alkyl]amino- carbonyl, C3-7 cycloalkyl(Ci.6)alkylaminocarbonyl, aryl(Ci-6)alkylaminocarbonyl, (Ci-6)- alkylpiperidinylaminocarbonyl, N-[(Ci-6)alkyl]-N-[(Ci-6)-alkylpiperidinyl]ammocarbonyl, piperidinyl(Ci-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C1-6)alkyl- aminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, (Q^alkyl- pyrrolidinylcarbonyl, C1-6 alkoxy(C1-6)alkylpyrrolidinylcarbonyl, di(C1-6)alkylamino- pyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinyl- carbonyl,
Figure imgf000015_0001
morpholinylcarbonyl, Ci-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonylmethyl, aminosulphonyl, C1-6 alkylaminosulphonyl, di(Ci-6)alkylaminosulphonyl, C2-6 alkoxycarbonyloxy, trimethylsilyl and tetra(Ci.6)alkyldioxaborolanyl.
Particular examples of typical substituents on R3 and/or R4 include Cj-6 alkyl and di(C 1 -6)alkylaminocarbonyl .
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, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, morpholinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofiiryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylproρylpyrazolyl, 3-methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylρropyl)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, (dihydroxyρropyl)pyrazolyl, [(hydroxy)- (methoxy)propyl]ρyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (ammopropyl)(diniethyl)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- αjpyrimidinyl, imidazo[l,2-α]pyrazinyl, methylthiadiazolyl, triazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methylpiperazinyl)pyridinyl, (niethyl)(piperazinyl)pyridinyl, (tert- butoxycarbonylpiperazinyl)(methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)- pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, methoxypyridinyl, (methoxy)(methyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxyniethylpyridinyl, 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, methoxypyriniidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, (dimethylamino)- (fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonylmethyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aniinopyrazinyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinyl- pyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxy- pyridinyloxy, aminocarbonylpyridinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1- methylethyl, dihydroxypropyl, pyridinyloxymethyl, methylenedioxy, difluoromethylenedioxy, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, dimethylamino, N-(methoxyethyl)-N- (methyl)amino, N-(methoxypropyl)-iV-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N-(dimethylaminoethyl)-N-(methyl)amino, N- (diethylaminoethyl)-N-(methyl)amino, N-(dimethylaminopropyl)-N-(methyl)amino, N- (dimethylaminoethyl)-N-(ethyl)amino, N-(dimethylaminopropyl)-N-(ethyl)amino, N- (cyclohexyl)-N-(methyl)amino, fluorophenylamino, N-fluorophenyl-N-methylamino, methylenedioxyphenylamino, morpholinylmethylphenylamino, oxazolinylphenylaniino, (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- (methylρyrrolidinyl)amino, methylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N-(piperidinyl)amino, N- (cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinylamino, N-(methyl)-N- (methylρiperidinyl)amino, N-(methyl)-N-(2-methylρroρylpiρeridinyl)amino, N- (cyclopentylpiperidinyl)-N-(methyl)amino, N-(acetylpiperidinyl)-N-(methyl)amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N-(pyrrolidinylethyl)amino, iV-(methyl)-JV- (pyrrolidinylpropyl)amino, iV-(methyl)-iV-(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)imidazolylaniino, methylbenzimidazolyl- amino, benzimidazolonylamino, dimethylbenzimidazolonylamino, methyloxadiazolyl- amino, furyloxadiazolylamino, methylthiadiazolylamino, pyridinylamino, chloropyridinyl- amino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylaniino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino5 dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylammomethylpyridinyl- amino, oxopyridinylamino, carboxypyridinylamino, N-(methyl)-N-(methylpyridinyl)- amino, iV-(ethyl)-N-(methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, Λ/"-(methyl)-N- (methylpyridazinyl)amino, iV-(benzyl)-7V-(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, iV-(methyl)-N-(pyridinylethyl)- amino, N-(dihydroxypropyl)-N-(pyridinylmethyl)amino, N-(dihydroxypropyl)-N- (methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, acetylaminOj iV-Cacety^-TV-^ethylpyridinyOamino, dimethylaminoethylcarbonylamino, acetylaminomethyl, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, methoxycarbonyl- amino, N-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, N-(cyanomethyl)-N-methylaminocarbonyl, Λf-(cyanoethyl)-N-methylamino- carbonyl, N-(hydroxyethyl)-iV-methylaminocarbonyl, N-(methoxyethyl)-N-methyl- aminocarbonyl, Λ^(dimethylaminoethyl)-iV-methylaminocarbonyl, N-isopropyl-iV-methyl- aminocarbonyl, dietliylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(metriylpiperidinyl)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, fe?t-butoxycarbonyloxy, trimethylsilyl and tetramethyl- dioxaborolanyl.
Particular examples of specific substituents on R3 and/or R4 include methyl and dimethylaminocarbonyl.
Typical values of R3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, iV-methyl-iV-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, morpholinylcarbonylphenylaminobenzyl, methylsulphonylphenylaminobenzyl, morpholinylsulphonylphenylaminobenzyl, dihydrobenzofuranylaminobenzyl, methylsulphonylindolinylaminobenzyl, chromanonylaminobenzyl, dihydroquinolinonylaminobenzyl, benzoxazinonyl- aminobenzyl, benzothienylaminobenzyl, indolylaminobenzyl, dioxoindolylaminobenzyl, (bromo)(methyl)pyrazolylaminobenzyl, trimethylpyrazolylaminobenzyl, methylindazolyl- aminobenzyl, benzoxazolylaminobenzyl, benzoxazolonylaminobenzyl, dimethyl- isoxazolylaminobenzyl, benzothiazolylaminobenzyl, methylisothiazolylaminobenzyl, methylbenzimidazolylaminobenzyl, benzimidazolonylaminobenzyl, dimethyl- benzimidazolonylaminobenzyl, methyloxadiazolylaminobenzyl, foryloxadiazolyl- aminobenzyl, pyridinylaminobenzyl, chloropyridinylaminobenzyl, methylpyridinylamino- benzyl, dimethylpyridinylaminobenzyl, methoxypyridinylaminobenzyl, oxopyridinyl- aminobenzyl, oxopyrimidinylaminobenzyl, thioxopyrimidinylaminobenzyl, (chloro)- (methoxy)pyridazinylaminobenzyl, methylcinnolinylaminobenzyl, quinoxalinylamino- benzyl, methylchromenylaminobenzyl, benzofurylmethyl, cyanobeήzofurylmethyl, 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-methylaminoindolylmetliyl, methylsulphonylaminoindolylmethyl, acetylindolylmethyl, [acetyl oxime] indolylmethyl, [acetyl <9-(methyl)oxime]- indolylmethyl, trifluoromethylcarbonylindolylmethyl, carboxyindolylmethyl, (carboxy)- (methyl)indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl, (chloro)(methoxycarbonyl)indolylmethyl, aminocarbonylindolylmethyl, (aminocarbonyl)(chloro)indolylmethyl, methylaminocarbonylindolylmethyl, (chloro)- (methylaminocarbonyl)indolylmethyl, (hydroxyethy^aminocarbonylindolylmethyl, (dimethylaminoethy^aminocarbonylindolylmethyl, (l-hydiOxyprop-2-yl)aminocarbonyl- indolylmethyl, dimethylaminocarbonylindolylmethyl, (dimethylaminocarbonyl)(methyl)- indolylmethyl, (chloro)(dimethylaminocarbonyl)indolylmethyl, bis(dimethylamino- carbonyl)indolylmethyl, N-(cyanomethyl)-iV-methylaminocarbonylindolylmethyl, [iV- (cyanomethyl)-N-methylaminocarbonyl](methyl)indolylniethyl, JV-(cyanoethyl)-iV- methylaminocarbonylindolylmethyl, iV"-(hydroxyethyl)-N-methylaminocarbonyl- indolylmethyl, iV-(methoxyethyl)-N-metliylaminocarbonylindolylmethyl, [N-(methoxy- ethyl)-iV-methylaminocarbonyl](methyl)indolylmetliyl, iV-(dimethylaminoethyl)-iV- methylaminocarbonylindolylmethylj iV-isopropyl-iV-methylaminocarbonylindolylmethyl, diethylaminocarbonylindolylmethyl, cyclopropylmethylaminocarbonylindolylmethyl, benzylaminocarbonylindolylmethyl, pyrazolylaminocarbonylindolylmethyl, pyridinylmethylaminocarbonylindolylmethyl, azetidinylcarbonylindolylmethyl, (azetidinylcarbonyl)(memyl)indolylmethyl, hydroxyazetidinylcarbonylindolylmethyl, aminoazetidinylcarbonylindolylmethyl, fe/'t-butoxycarbonylammoazetidinylcarbonyl- indolylmethyl, pyrrolidinylcarbonylindolylmethyl, methylpyrrolidinylcarbonyl- indolylmetbyl, methoxymethylpyrrolidinylcarbonylindolylmethyl, dimethylamino- pyrrolidinylcarbonylindolylmethyl, thiazolidinylcarbonylindolylmethyl, oxothiazolidinyl- carbonylindolylmethyl, piperidinylcarbonylindolylmethyl, methylpiperazinylcarbonyl- indolylmethyl, morpholinylcarbonylindolylmethyl, methylsulphonylindolylmethyl, methylsulphonylmethylindolylmethyl, dimethylaminosulphonylindolylmethyl, trimethylsilylindolylmethyl and pyrrolo[3,2-e]pyridinylmethyl.
A particular value of R3 is (dimethylaminocarbonyl)(methyl)indolylmethyl. Typical values of R4 include hydrogen and methyl. In a preferred embodiment, R4 is hydrogen. In another embodiment, R is C1-6 alkyl, especially methyl. Alternatively, R3 and R4, when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage. Thus, R3 and R4, when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, R3 and R4, when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
Alternatively, R3 and R4, when attached to adjacent carbon atoms, may together form an optionally benzo-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the morpholine ring. Thus, R3 and R4, when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, in one embodiment, R3 and R4, when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the morpholine ring, which phenyl ring may be unsubstituted, or substituted by one or more, typically by one or two, substituents. Also in this context, in another embodiment, R3 and R , when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e. an indanyl moiety fused to the 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]-6)alkylaryl, piperidinyl(Ci.6)alkylaryl, piperazinyl(Ci-6)alkylaryl, (Ci-6)alkylpiperazinyl(C1-6)alkylaryl, morpholinyl(C1-6)alkylaryl, (Ci-6)alkoxyaryl, cyano(C1-6)alkoxyaryl, di(Ci.6)alkylamino(Ci.6)alkylaryl, (Ci-6)alkylaminocarbonylaryl, aryl(C1-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (Ci-6)alkylaminocarbonylpiperidinyl, piperazinyl, (C1-6)alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (C1-6)alkyl- homopiperazinyl, (Ci-6)alkylpiperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (C1-6)alkylpyrazolyl, di(C1-6)alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, (difluoromethyl)pyrazolyl, [di(Ci.6)alkyl](trifluoromethyl)pyrazolyl, cyano(C1-6)alkylpyrazolyl, [cyano(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, hydroxy(Ci-6)alkyl- pyrazolyl, [hydroxy(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, methoxy(Ci-6)alkylpyrazolyl, [dihydroxy(C1-6)alkyl]pyrazolyl, [(hydroxy)(methoxy)(C1-6)alkyl]pyrazolyl, amino(C1-6)- alkylpyrazolyl, [(C1-6)alkyl][amino(Ci-6)alkyl]pyrazolyl, [amino(Ci-6)alkyl][di(Ci.6)alkyl]- pyrazolyl, di(C1-6)alkylamino(C1-6)alkylpyrazolyl, di(C1-6)alkoxyphosphono(C1-6)alkyl- pyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl(Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl- (C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(Ci-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)- pyrazolyl, aryl(C1-6)alkylρyrazolyl, aminoaryl(Ci.6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(C1-6)alkylpyrazolyl, [di(C1-6)alkyl][tetrahydropyranyl(Ci-6)alkyl]- pyrazolyl, pyrrolidinyl(C1-6)alkylρyrazolyl, piρeridinyl(Ci-6)alkylpyrazolyl, (C1-6)alkyl- piperidinyl(Ci-6)alkylpyrazolyl, morpholinyl(Cj_6)alkylpyrazolyl, pyridinyl(Ci_6)alkyl- pyrazolyl, oxypyridinyl(C1-6)alkylpyrazolyl, [arylcarbonyl(Ci-6)alkyl][di(Ci-6)alkyl]- pyrazolyl, [(C1-6)alkyl](piperazinylcarbonyl)pyrazolyl, [(Ci-6)alkylaminocarbonyl] [(C1-6)- alkylaryljpyrazolyl, [(C1-6)alkyl][amino(C1-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl, [aminocarbonyl(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, di(Ci-6)alkylaminocarbonyl(C1-6)alkylpyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1-6)alkyl- isoxazolyl, (amino)[(Ci.6)alkyl]isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (C1-6)alkylimidazolyl, di(C1-6)alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkyl- imidazo[l,2-α]pyridinyl, (C1-6)alkyliraidazo[4,5-ό]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (C1-6)alkylthiadiazolyl, pyridinyl, halopyridinyl, (Ci-6)alkyl- pyridinyl, [(C1-6)alkyl](halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C \ -6)alkylpiperazinylpyridinyl, [(C i .6)alkyl] (piperazinyl)pyridinyl, [(C \ _6)alkoxycarbonyl- piperazinyl][(C1-6)alkyl]pyridinyl, piperidinyl(C1-6)alkylpyridinyl, [(C1-6)alkyl]-
(oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (C1-6)alkoxypyridinyl, [(Ci-6)alkoxy][(Ci-6)alkyl]pyridmyl, [(C1-6)alkoxy][di(C1-6)alkyl]pyridinyl, (C1-6)alkoxy(C1-6)alkylpyridinyl, aminopyridinyl, carboxy(C1-6)alkylpyridinyl, (C]-6)alkoxycarbonyl(C1-6)alkylpyridinyl, pyridazinyl,
Figure imgf000023_0001
piperidinylpyridazinyl, oxypyridazinyl, (C1-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(C1-6)alkylaminopyridazinyl, di(C1-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(C1-6)alkyl](halo)pyrimidinyl, di(C1-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (C1-6)alkylpiperazinylpyrimidinyl, [(C1-6)alkyl](piperazinyl)- pyrimidinyl, [(C1-6)alkoxycarbonyl][(C1-6)alkyl]piperazinylpyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(C1-6)alkyl][hydroxy(C1-6)alkyl]- pyrimidinyl, [(C1-6)alkyl][hydroxy(C2-6)alkynyl]pyrimidinyl, (C1-6)alkoxypyrimidinyl, aminopyrimidinyl, di(C1-6)alkylaminopyrimidinyl, [di(C1-6)alkylamino](halo)pyrimidinyl, carboxypyrimidinyl, [(C1-6)alkoxycarbonyl(Ci-6)alkyl][(C1-6)alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, aminopyrazinyl, hydroxy, (C1-6)alkoxy, aryl(C1-6)alkoxycarbonylpiperidinyloxy, morpholinyl(C1-6)alkoxy, aryloxy, haloaryloxy, di(C1-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (Ci-6)alkylpiperazinylpyridinyloxy, (Ci-6)alkylpyrazolylpyridinyloxy, (Ci-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy, (C1-6)alkylpyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C1-6)alkyl](halo)pyrimidinyloxy, hydroxy(C1-6)alkyl, dihydroxy(C1-6)alkyl, pyridinyloxy(Ci.6)alkyl, amino, (C1-6)alkylamino, dihydroxy(C1-6)alkylamino, (Ci-6)- alkoxy(Ci-6)alkylamino, iV-[(C1-6)alkoxy(Ci-6)alkyl]-N-[(C1-6)alkyl]animo, di(C1-6)- alkylamino(C1-6)alkylammo, iVr-[(Ci-6)alkyl]--Λ/:-[di(C1-6)alkylamino(C1-6)alkyl]amino, N- [(Ci_6)alkyl]-7V-[(C3-7)cycloalkyl]amino, haloarylamino, iV-[(C1-6)alkyl]-iV-(haloaryl)amino, N-[(C1-6)alkyl]-N-[aryl(C1-6)alkyl]amino, N-[di(C1-6)alkylamino(C1-6)alkyl]-iV-[aryl(C1-6)- alkyl]amino, cyanoaryl(C1-6)alkylamino, (cyano)(halo)aryl(C1-6)alkylamino, methylene- dioxyary^Ci^alkylamino, ^[(Cj-^alkylJ-TV-tCCj^alkylpyrrolidinyljamino, piperidinyl- amino, iV-[(Ci-6)alkyl]-N-(piperidinyl)ammo, N-[(C3-7)cycloalkyl(C1-6)alkyl]-iV- (piperidinyl)amino, (C1-6)alkylpiperidinylamino, JV-[(C1-6)alkyl]-iV-[(C1-6)alkyl- piperidinyl] amino, iV-[(C i -6)alkyl] -N- [(C3-7)cycloalkylpiperidinyl] amino, N-[(C\ -6)alkyl] - N-[(C2-6)alkylcarbonylpipeiidinyl]amino, pyrrolidinyl(C1-6)alkylamino, iV-[(Ci-6)alkyl]-N- [pyrrolidinyl(C1-6)alkyl]amino, N-[(C1-6)alkyl]-iV-[piperidmyl(C1-6)alkyl]amino, (C1-6)- alkylpyrazolylamino, di(C1-6)alkylpyrazolylamino, tri(C1-6)alkylpyrazolylamino, iV-[(C1-6)- alkyl]-N-[(C1-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(Ci.6)alkoxy- carbonyl] [(C^alkyljimidazolylamino, (C1-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (C1-6)alkylpyridinylammo, di(C1-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(Ci-6)alkylpyridinylamino, dihydroxy(C1-6)alkylpyridinylamino, (C1-6)alkoxypyridinylamino, dihydroxy(C1-6)alkoxy- pyridinylamino, di(C1-6)alkyldioxolanyl(C1-6)alkoxypyridinylamino, (C1-6)alkoxy(C1-6)- alkylpyridinylamino, (C i-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C i-6)alkyl- aminopyridinylamino, di(C1-6)alkylaminopyridinylamino, (C1-6)alkylamino(C1-6)alkyl- pyridinylamino, di(C1-6)alkylamino(C1-6)alkylpyridmylamino, carboxypyridinylamino, N- [(Ci-6)alkyl]-iV-[(Ci-6)alkylpyridinyl]amino, bis[(C1.6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (Ci-6)alkylpyridazinylamino, iV-[(Ci-6)alkyl]- iV-[(C1-6)alkylpyridazinyl]amino, N-[aryl(C1-6)alkyl]-iV-[(Ci-6)alkylpyridazinyl]amino, di(C1-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C1-6)- alkoxypyridazinylamino, di(Ci-6)alkylaminopyridazinylamino, bis[(Ci-6)alkylpyridazinyl]- amino, benzofuryl(Ci-6)alkylamino, thienyl(Ci-6)alkylamino, indolyl(Ci-6)alkylamino, (C1-6)alkylpyrazolyl(C1-6)alkylamino, [di(C1-6)alkyl](halo)pyrazolyl(C1-6)alkylamino, di(C1-6)alkylisoxazolyl(C1-6)alkylamino, thiazolyl(C1-6)alkylamino, imidazolyl(C1-6)alkyl- amino, (C1-6)alkylimidazolyl(C1-6)alkylamino, pyridinyl(C1-6)alkylamino, (Ci-6)alkyl- ρyridinyl(C1-6)alkylamino, N-[(Ci-6)alkyl]-N-[pyridinyl(C1-6)alkyl]amino, N-[dihydroxy- (C1-6)alkyl]-N-[pyridinyl(C1-6)alkyl]amino, iV-[(C1-6)alkylpyiidinyl(C1.6)alkyl]-iV-
[dihydroxy(Ci-6)alkyl]amino, amino(Ci-6)alkyl,
Figure imgf000024_0001
di(C1-6)alkyl- amino(Ci-6)alkyl, pyridinylamino(C1-6)alkyl, N-[(C2-6)alkylcarbonyl]-N-[(C1-6)alkyl- pyridinyl(C 1-6)alkyl] amino, di(C i-6)alkylamino(C j -6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (C^alkylpiperidinylcarbonylamino, (C1-6)alkylimidazolylcarbonylamino, fόrmyl, C2-6 alkylcarbonyl, (C1-6)alkylpiperidinylaminocarbonyl, iV-[(Ci-6)alkyl]-N-[(C1-6)- alkylpiperidinyljaminocarbonyl, piperidinyl(C1-6)alkylaminocarbonyl, (C1-6)alkyl- piperazinylcarbonyl, Ci-6 alkylthio, C1-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy and tetra(C1-6)alkyldioxaborolanyl.
Particular examples of typical substituents on the fused rings referred to in the two preceding paragraphs include halogen, hydroxy(Ci-6)alkylpyrazolyl and [dihydroxy(Ci-6)- alkyl]pyrazolyl.
Selected examples of specific substituents on the fused rings referred to in the three preceding paragraphs include fluoro, chloro, bromo, nitro, methyl, n-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylpropylpyrazolyl, 3-methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)pyrazolyl, (dimethyl)(3-methylbutyl)pyrazolyl, (difluoromethyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2- hydroxy-2-methylpropylpyrazolyl, (hydroxymethyl)(isopropyl)(methyl)pyrazolyl, (hydroxyethyl)(dimethyl)ρyrazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, (dihydroxypropyl)pyrazolyl, [(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, tetrahydropyranymiethylpyrazolyl, (dimethyl)(tetrahydroρyranyl- methyl)pyrazolyl, pyrrolidinylethylpyrazolyl, piperidinylethylpyrazolyl, methyl- piperidinylethylpyrazolyl, morpholinylethylpyrazolyl, pyridinylmethylpyrazolyl, oxypyridinylmethylpyrazolyl, (dimethyl)(phenylcarbonylmethyl)pyrazolyl, (ethyl)(piperazinylcarbonyl)pyrazolyl, (methylaminocarbonyl)(methylphenyl)pyrazolyl, (aminoethylaminocarbonyl)(methyl)pyrazolyl, aniinocarbonylmethylpyrazolyl,
(aminocarbonylmethyl)(dimethyl)pyrazolyl, dimethylaminocarbonylmethylpyrazolyl, pyrazolo[l,5-α]ρyridinyl, dimethylisoxazolyl, (amino)(methyl)isoxazolyl, thiazolyl, dimethylthiazolyl, imidazolyl, methylimidazolyl, dimethylimidazolyl, imidazo[l,2- αjpyridinyl, methylirnidazo[l,2-α]pyridinyl, methylimidazo[4,5-6]pyridinyl, imidazo[l,2- β]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, (1 -hydroxy- 1 -methyl ethyl)pyridinyl, methoxypyridinyl, (methoxy)(niethyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonylmethylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylaminopyridazinyl, pyrimidinyl, methylpyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl,
(methyl)(piperazinyl)pyrimidinyl, (tert-butoxycarbonylpiperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydiOxypiOpynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, (dimethylamino)(fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonyl- methyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinylpyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)ρyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1 -methylethyl, dihydroxypropyl, pyridinyloxymethyl, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, N-(methoxyethyl)-N-(methyl)amino, N- (methoxyρropyl)-N-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N-(dimethylaminoethyl)-N-(methyl)amino, N- (diethylaminoethyl)-N-(methyl)amino, N-(dimethylaminopropyl)-N-(methyl)amino, N- (dimethylaminoethyl)-N-(ethyl)amino, N-(dimethylaminopropyl)-N-(ethyl)amino, N- (cyclohexyl)-N-(methyl)amino, fluorophenylamino, N-fluorophenyl-N-methylamino, N- benzyl-N-methylamino, N-(benzyl)-N-(dimethylaminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)benzylamino, methylenedioxybenzylamino, N- (methyl)-N-(methylpyrrolidinyl)amino, piperidinylamino, N-(methyl)-N- (piperidinyl)amino, N-(ethyl)-N-(piperidinyl)amino, N-(cyclopropylmethyl)-N-
(piperidinyl)amino, methylpiperidinylamino, N-(methyl)-N-(methylpiperidinyl)amino, N- (methyl)-N-(2-methylpropylpiperidinyl)amino, N-(cyclopentylpiperidinyl)-N- (methyl)amino, N-(acetylpiperidinyl)-N-(methyl)amino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N-(pyrrolidinylethyl)amino, N-(methyl)-N- (pyrrolidinylpropyl)amino, N-(methyl)-N-(piperidinylmethyl)amino, methylpyrazolylamino, dimethylpyrazolylamino, trimethylpyrazolylamino, N-(ethyl)-N- (methylpyrazolyl)amino, thiazolylamino, imidazolylamino,
(ethoxycarbonyl)(methyl)imidazolylamino, methylthiadiazolylamino, pyridinylamino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, carboxypyridinylamino, N-(methyl)-N-(methylpyridinyl)amino, N-(ethyl)-N-
(methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-N-(methylpyridazinyl)amino, N- (benzyl)-N-(methylpyridazinyl)aniino, dimethylpyridazinylamino, phenylpyridazinyl- amino, piperidinylpyridazinylamino, methoxypyridazinylaniino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, benzoflxrylmethylamino, thienylmethyl- amino, indolylmethylamino, methylpyrazolylmethyl amino, (chloro)(dimethyl)pyrazolyl- methylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethyl- amino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethyl- amino, iV-(methyl)-N-(pyridinylethyl)amino, N-(dihydroxypropyl)-N-(pyridinylmethyl)- amino, iV-(dihydroxypropyl)-N-(methylpyridmylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, N-(acetyl)-iV-(methyl- pyridinyl)amino, dimethylaminoethylcarbonylamino, cyclohexylcarbonyl amino, methylpiperidinylcarbonylamino, niethylimidazolylcarbonylamino, formyl, acetyl, methylpiperidinylaminocarbonyl, ^-(methy^-N-^ethylpiperidmy^aminocarbonyl, piperidinylethylaminocarbonyl, methylpiperazinylcarbonyl, isopropylthio, isopropyl- sulphinyl, isopropylsulphonyl, tert-butoxycarbonyloxy and tetramethyldioxaborolanyl.
Particular examples of such substituents include bromo, hydroxyethylpyrazolyl and (dihydroxypropyl)pyrazolyl.
Suitably, Ra represents substituted or unsubstituted aryl.
Suitably, Rc represents hydrogen; or aryl, aryl(C1-6)alkyl, heteroaryl(C1-6)alkyl or (aryl)(heteroaryl)(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents. Examples of typical substituents on Ra and/or Rb and/or Rc and/or Rf include halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C1-6 alkylthio, C1-6 alkylsulphonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulphonyl, C1-6 alkylaminosulphonyl and di(Ci-6)alkylaminosulphonyl.
Examples of particular substituents on Ra and/or Rb and/or Rc and/or 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, hi 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.
Suitably, R represents optionally substituted aryl, especially phenyl. Generally, R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb,
-CONRcRd or -C(=N-ORf)Re; or R5 represents C1-6 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(C1-6)alkyl, 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(C1-6)alkyl-aryl, C3-7 heterocycloalkyl-biaryl, heteroaryl, heteroaryl(C1-6)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(Ci.6)alkyl-aryl -heteroaryl, C5-9 heterobicycloalkyl(Ci-6)alkyl-aryl-heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl-biφeteroaryl), aryloxyaryl, aryl(Ci-6)alkoxyaryl, heteroaryl(C1-6)alkoxyaryl, aryl(Ci-6)alkylaminoaryl, heteroaryl(C1-6)alkylaminoaryl, C3-7 cycloalkylcarbonylaminoaryl, arylcarbonylaminoaryl, aryl(C1-6)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(Ci-6)alkylaminocarbonylcarbonylaminoaryl, arylcarbonylaryl, C3-7 heterocycloalkylcarbonylaryl, C3-7 heterocycloalkylcarbonyl(C1-6)alkylaryl, aryl(Ci-6)- alkylaminocarbonylaryl, C3-7 heterocycloalkyl(Ci-6)alkylaminocarbonylaryl, heteroaryl- aminocarbonylaryl, heteroaryl(Ci-6)alkylaminocarbonylaryl, C3-7 heterocycloalkylamino- carbonyl(C1.6)alkylaryl, C3-7 heterocycloalkyl(C1,6)alkylaminocarbonyl(Ci-6)alkylaryl, heteroarylaminocarbonyl(C1-6)alkylaryl, heteroaryl(Ci.6)alkylaminocarbonyl(Ci-6)alkyl- aryl, arylaminoheteroaryl, C3-7 heterocycloalkylamino-aryl-heteroaryl, C3-7 heterocycloalkylcarbonylamino-aryl-heteroaryl, C3-7 heterocycloalkylaminocarbonyl- amino-aryl-heteroaryl, C3-7 cycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- carbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(Ci-6)alkylcarbonyl-aryl-heteroaryl, C5-9 heterobicycloalkylcarbonyl-aryl-heteroaryl, C3.7 heterocycloalkylcarbonyl(Ci-6)alkyl-aryl- heteroaryl, C3-7 heterocycloalkyl-aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- (C1-6)alkylaminocarbonyl-aryl-b.eteroaryl or C3-7 heterocycloalkylaminocarbonyl(Ci..g)- alkyl-aryl-heteroaryl, any of which groups may be optionally substituted by one or more substituents.
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, piperidinyl ethyl, pyrrolidinylethynyl, piperidinylethynyl, 1 ,2,3 ,4-tetrahydroisoquinolinylpropynyl, piperazinylpropynyl, pyrrolidinylcarbonylethynyl, quinuclidinylethynyl, piperazinyl- phenyl, morpholinylphenyl, piperidinylmethylphenyl, piperazinylbiphenyl, benzofuryl, dibenzofuryl, benzothienyl, dibenzothienyl, pyridinyl, isoquinolinyl, imidazolylethyl, imidazolylmethylcarbonyl, imidazolylethenyl, indolylethynyl, pyrazolylethynyl, imidazolylethynyl, pyridinylethynyl, pyrimidinylethynyl, imidazo[l,2-α]pyridinylethynyl, imidazolylcarbonylcarbonyl, benzomorpholinylpyridinyl, pyrrolidinylpyridinylethynyl, . pyrazolylphenyl, pyridinylphenyl, phenylisoxazolyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, azetidinylphenylpyridinyl, pyrrolidinylphenylpyridinyl, piperidinylphenylpyridinyl, piperazinylphenylpyridinyl, moφholinylphenylpyridinyl, piper azinylphenylpyrimidinyl, pyrrolidinylmethylphenylpyridinyl, piperidinylmethyl- phenylpyridinyl, piperazinylmethylphenylpyridinyl, homopiperazinylmethylphenyl- pyridinyl, morpholinylmethylphenylpyridinyl, azabicyclo[3.2.1 Joctylmethylphenyl- pyridinyl, diazabicyclotS^.lJoctylmethylphenylpyridinyl, tetrazolylphenylpyridinyl, benzofurylpyridinyl, benzothienylpyridinyl, indolylpyridinyl, isoxazolylpyridinyl, bi(pyridinyl), isoquinolinylpyridinyl, morpholinylcarbonylbi(pyridinyl), phenoxyphenyl, benzyloxyphenyl, pyridinylmethoxyphenyl, benzylaminophenyl, furylmethylaminophenyl, pyridinylmethylaminophenyl, cyclopentylcarbonylaminophenyl, phenylcarbonylamino- phenyl, benzylcarbonylaminophenyl, pyrrolidinylcarbonylaminophenyl, piperidinyl- carbonylaminophenyl, piperazinylcarbonylaminophenyl, morpholinylcarbonylamino- phenyl, indolylcarbonylaminophenyl, isoxazolylcarbonylaminophenyl, pyridinylcarbonyl- aminophenyl, phenylpyrrolidinylcarbonylaminophenyl, phenylsulphonylaminophenyl, benzylsulphonylaminophenyl, isoxazolylsulphonylaminophenyl, cyclopentylamino- carbonylaminophenyl, phenylaniinocarbonylaminophenyl, azetidinylaminocarbonyl- aminophenyl, morpholinylethylaminocarbonylaminophenyl, iniidazolylmethyl- aminocarbonylaminophenyl, morpholinylcarbonylcarbonylaminophenyl, pyrrolidinyl- ethylaminocarbonylcarbonylaminophenyl, phenylcarbonylphenyl, morpholinylcarbonyl- phenyl, pyrrolidinylcarbonylmethylphenyl, piperidinylcarbonylmethylphenyl, benzylaminocarbonylphenyl, morpholinylethylaminocarbonylphenyl, imidazolyl- aminocarbonylphenyl, imidazolylmethylaminocarbonylphenyl, pyridmylmethyl- aminocarbonylphenyl, azetidinylaminocarbonyltnethylphenyl, pyrrolidinylmethyl- aminocarbonylmethylphenyl, pyridinylaminocarbonylmethylphenyl, pyridinylmethyl- aminocarbonylmethylphenyl, phenylaminopyridinyl, azetidinylaminophenylpyridinyl, pyrrolidinylaniinophenylpyridinyl, piperazinylcarbonylaminophenylpyridinyl, piperidinylaminocarbonylaminophenylpyridinyl, azetidinylcarbonylphenylpyridinyl, cyclopropylcarbonylphenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl, piperidinylcarbonylphenylpyridinyl, piperazinylcarbonylphenylpyridinyl, morpholinylcarbonylphenylpyridinyl, piperidinylcarbonylphenylpyrimidinyl, morpholinylmethylcarbonylphenylpyridinyl, azabicyclo[3.2.1 ]octylcarbonylphenyl- pyridinyl, azetidinylcarbonylmethylphenylpyridinyl, pyrrolidinylcarbonylmethylphenyl- pyridinyl, piperidinylcarbonylmethylphenylpyridinyl, piperazinylcarbonylmethylphenyl- pyridinyl, azetidinylaminocarbonylphenylpyridinyl, pyrrolidinylaminocarbonylphenyl- pyridinyl, piperidinylaminocarbonylphenylpyridinyl, piperidinylmethylaminocarbonyl- phenylpyridinyl or azetidinylaminocarbonylmemylphenylpyridinyl, any of which groups may be optionally substituted by one or more substituents.
Examples of representative substituents on R5 include halogen, cyano, nitro, oxo, Ci-6 alkyl, trifluoromethyl, hydroxy, hydroxy(Ci-6)alkyl, C1-6 alkoxy, dihydroxy(C]-6)- alkoxy, aryl(C1-6)alkoxy, methoxyaryl(C1-6)alkoxy, amino, Ci-6 alkylamino, di(Ci_6)- alkylamino, amino(C1-6)alkyl, Ci-6 alkylamino(Ci-6)alkyl, di(C1-6)alkylamino(C1-6)alkyl, di(Ci-6)alkylamino(Ci-6)alkylamino, methoxyaryl(C1-6)alkylamino, C1-6 alkylcarbonyl- amino, C1-6 alkoxycarbonyl(Ci-6)alkylcarbonylamino, C1-6 alkylcarbonylamino(Ci.6)alkyl, Ci-6 alkoxycarbonylamino, N-(C1-6 alkoxycarbonyl)-N-(Ci-6 alkyl)amino, C1-6 alkoxy- carbonylamino(Ci-6)alkyl, N-(Ci-6 alkoxycarbonyl)-N-(C1-6 alkyl)amino(Ci-6)alkyl, C1-6 alkylsulphonylamino, Cj-6 alkylsulphonylamino(Ci_6)alkyl, Ci-6 alkylaminocarbonylamino, di(Ci-6)alkylamiiio(C1-6)alkylaminocarbonylamino, N-(C1-6 alkyl)-N-[di(Ci-6)alkylamino- (C1-6)alkyl]aminocarbonylamino, carboxycarbonylamino, Ci-6 alkoxycarbonyl- carbonylamino, C1-6 alkylaminocarbonylcarbonylamino, di(C1-6)alkylamino(C1-6)alkyl- aminocarbonylcarbonylamino, di(Ci.6)alkylaminosulphonylamino, formyl, C1-6 alkylcarbonyl, di(C1-6)alkylamino(Ci-6)alkylcarbonyl, carboxy, carboxy(C1-6)alkyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl(C].6)alkyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, cyano(C1-6)alkylaminocarbonyl, di(C1_6)alkylamino(C1-6)- alkylaminocarbonyl, dihydroxy(C1-6)alkylaminocarbonyl, N-(C1-6 alkyl)-N-[amino(C1-6)- alkyl] aminocarbonyl, N-(C1-6 alkyl)-N-[di(C1-6)alkylamino(C1-6)alkyl]aminocarbonyl, di(C1-6)alkylaminocarbonyl(C1-6)alkyl, N-(C1-6 alkyl)-N-[di(C1-6)alkylamino(C1-6)alkyl]- aminocarbonyl(C1-6)alkyl, aminocarbonyl(C1-6)alkoxy, C1-6 alkoxyaminocarbonyl, N-(C1-6 alkoxy)-N-(C1-6 alkyl)aminocarbonyl, C1-6 alkylsulphonyl, C1-6 alkylsulphonyloxy(C1-6)- alkyl, trifluoromethylsulphonyloxy and tri(C1-6)alkylsilyl; especially halogen or di(C1-6)- alkylaminocarbonyl.
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, fert-butoxycarbonylamino, N-(tert-butoxy- carbonyl)-N-(methyl)amino, tert-butoxycarbonylaminomethyl, N-(fert-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, ter^-butoxycarbonyl, methoxycarbonylmethyl, /ert-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(C1-6)alkylsilyl; especially fluoro or dimethylaminocarbonyl.
Specific values of R5 include hydrogen, fluoro, chloro, bromo, iodo, cyano, phenylthio, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, pyridinylmethylaminocarbonyl,
(phenyl)(pyridinyl)methylaminocarbonyl, N-ethyl-N-pyridinylmethylaminocarbonyl, dimethylaminomethyl, dimethylaminosulphonylaminopropyl, dimethylamino- ethenylcarbonyl, ethynyl, triethylsilylethynyl, diethylaminopropynyl, methylsulphonylaminopropynyl, dimethylaminosulphonylaminopropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, cyclopropylethynyl, hydroxycyclohexyl- ethynyl, aminocyclohexylethynyl, phenyl, bromophenyl, (bromo)(nitro)phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, isobutoxyphenyl, (benzyloxy)(chloro)- phenyl, aminophenyl, (amino)(bromo)phenyl, aminomethylphenyl, acetylaminophenyl, ethoxycarbonylacetylarαinophenyl, ethylcarbonylaminophenyl, methoxycarbonyl- ethylcarbonylaminophenyl, methylsulphonylaminophenyl, ethylsulphonylaminophenyl, ethylaminocarbonylaminophenyl, dimethylaminoethylaminocarbonylaminophenyl, N- (dimethylaminoethyl)-N-(methyl)aminocarbonylaminophenyl, carboxycarbonylamino- phenyl, ethoxycarbonylcarbonylaminophenyl, ethylaminocarbonylcarbonylaminophenyl, dimethylaminoethylaminocarbonylcarbonylaminophenyl, acetylphenyl, carboxyphenyl, carboxymethylphenyl, methoxycarbonylphenyl, (chloro)(methoxycarbonyl)phenyl, ethoxycarbonylphenyl, methoxycarbonylmethylphenyl, aminocarbonylphenyl, methylaminocarbonylphenyl, cyanomethylaminocarbonylphenyl, ethylaminocarbonyl- phenyl, dihydroxypropylaminocarbonylphenyl, isopropylaminocarbonylphenyl, dimethylaminocarbonylphenyl, dimethylaminocarbonylmethylphenyl, N-(diethylamino- ethyl)-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, benzofuryl, dibenzofuryl, benzothienyl, dibenzothienyl, pyridinyl, chloropyridinyl, dichloropyridinyl, bromopyridinyl, carboxypyridinyl, ethoxycarbonylpyridinyl, isoquinolinyl, methyliniidazolylethyl, niethyliniidazolylmethylcarbonyl, methyl- imidazolylethenyl, indolylethynyl, methylindolylethynyl, pyrazolylethynyl, methyl- pyrazolylethynyl, methylimidazolylethynyl, dimethylimidazolylethynyl, pyridinylethynyl, chloropyridinylethynyl, aminopyridinylethynyl, dimethylaminoethylaminopyridinyl- ethynyl, aminopyriniidinylethynyl, imidazo[l,2-α]pyridinylethynyl, dimethylamino- methylimidazo[ 1 ,2-<3]pyridinylethynyl, methylimidazolylcarbonylcarbonyl, methyl- benzomorpholinylpyridinyl, hydroxymethylpyrrolidinylpyridinylethynyl, pyrazolylphenyl, methylpyrazolylphenyl, pyridinylphenyl, (amino)(chloropyridinyl)phenyl, phenyl- isoxazolyl, phenylthiazolyl, (methyl)(trifluoromethylphenyl)thiazolyl, phenylpyridinyl, fluorophenylpyridinyl, chlorophenylpyridinyl, cyanophenylpyridinyl, methylphenyl- pyridinyl, (bromo)(niethyl)phenylpyridinyl, ethylphenylpyridinyl, hydroxyphenyl- pyridinyl, hydroxymethylphenylpyridinyl, methoxyphenylpyridinyl, aminocarbonyl- methoxyphenylpyridinyl, dihydroxypropoxyphenylpyridinyl, methoxybenzyloxy- phenylpyridinyl, trifluoromethylsulphonyloxyphenylpyridinyl, methylsulphonyl- oxymethylphenylpyridinyl, aminophenylpyridinyl, (amino)(cyano)phenylpyridinyl, dimethylaminophenylpyridinyl, aminomethylphenylpyridinyl, (aminomethyl)(fluoro)- phenylpyridinyl, methylaminomethylphenylpyridinyl, dimethylaminomethylphenyl- pyridinyl, N-isopropyl-N-methylaminomethylphenylpyridinyl, methoxybenzylamino- phenylpyridinyl, acetylaminophenylpyridinyl, acetylaminomethylphenylpyridinyl, fer/- butoxycarbonylaminomethylphenylpyridinyl, iV-(tert-butoxycarbonyl)-iV-(methyl)- aminomethylphenylpyridinyl, methylsulphonylaminomethylphenylpyridinyl, formylphenylpyridinyl, acetylphenylpyridinyl, dimethylaminomethylcarbonyl- phenylpyridinyl, carboxyphenylpyridinyl, (amino)(carboxy)phenylpyridinyl, ethoxycarbonylphenylpyridinyl, tert-butoxycarbonylphenylpyridinyl, methoxycarbonyl- methylphenylpyridinyl, aminocarbonylphenylpyridinyl, methylaminocarbonylphenyl- pyridinyl, dimethylaminoethylammocarbonylphenylpyridinyl, dihydroxypropylamino- carbonylphenylpyridinyl, dimethylaminocarbonylphenylpyridinyl, (dimethylamino- carbonyl)(fluoro)phenylpyridinyl, (dimethylaminocarbonyl)(nitiO)phenylpyridinyl, (amino)(dimethylaminocarbonyl)phenylpyridinyl, vV-ethyl-N-methylaminocarbonyl- phenylpyridinyl, iV-(aminoethyl)-N-(methyl)aminocarbonylphenylpyridinyl, JV- (dimethylaminoethyl)-JV-(methyl)aminocarbonylphenylpyridinyl, diethylaminocarbonyl- phenylpyridinyl, methoxyaminocarbonylphenylpyridinyl, iV-methoxy-N-methylamino- carbonylphenylpyridinyl, dimethylaminocarbonylmethylphenylpyridinyl, JV-(diethyl- aminoethyl)-JV-(methyl)aminocarbonylmethylphenylpyridinyl, methylsulphonylphenyl- pyridinyl, phenylpyrimidinyl, bromophenylpyrimidinyl, aminoazetidinylphenylpyridinyl, methylaminoazetidinylphenylpyridinyl, aminopyrrolidinylphenylpyridinyl, amino- piperidinylphenylpyridinyl, methylaminopiperidinylphenylpyridinyl, piperazinyl- phenylpyridinyl, føt-butoxycarbonylpiperazinylphenylpyridinyl, teft-butoxycarbonyl- methylpiperazinylphenylpyridinyl, morpholinylphenylpyridinyl, piperazinylphenyl- pyrimidinyl, pyrrolidinylmethylphenylpyridinyl, hydroxypyrrolidmylmethylphenyl- pyridinyl, dioxopyrrolidinylmethylphenylpyridinyl, aminopyrrolidinylmethylplienyl- pyridinyl, carboxypyrrolidinylmethylphenylpyridinyl, tert-butoxycarbonylpyrrolidinyl- methylphenylpyridinyl, aminopiperidinylmethylphenylpyridinyl, methylaminopiperidinyl- methylphenylpyridinyl, piperazinylmethylphenylpyridinyl, methylpiperazinylmethyl- phenylpyridinyl, oxopiperazinylmethylphenylpyridinyl, homopiperazinylmethylphenyl- pyridinyl, morpholinylmethylphenylpyridinyl, dimethylmorpholinylmethylphenyl- pyridinyl, aminoazabicyclo[3.2. ljoctylmethylphenylpyridinyl, diazabicyclo[3.2. ljoctyl- methylphenylpyridinyl, tetrazolylphenylpyridinyl, benzoforylpyridinyl, benzothienylpyridinyl, indolylpyridinyl, dimethylisoxazolylpyridinyl, bi(pyridinyl), chlorobi(pyridinyl), carboxybi(pyridinyl), methoxycarbonylbi(pyridinyl), isoquinolinylpyridinyl, morpholinylcarbonylbiCpyridinyl), phenoxyphenyl, benzyloxyphenyl, methoxybenzyloxyphenyl, pyridinylmethoxyphenyl, JV-(benzyl)-JV- (ethylcarbonyl)aminophenyl, methylfurylmethylaminophenyl, pyridinylmethylamino- phenyl, cyclopentylcarbonylaminophenyl, phenylcarbonylaminophenyl, benzylcarbonyl- aminophenyl, hydroxypyrrolidinylcarbonylaminophenyl, aminopyrrolidinylcarbonyl- aminophenyl, tert-butoxycarbonylaminopyrrolidinylcarbonylaminophenyl, (isopropyl)- (oxo)pyrrolidinylcarbonylaminophenyl, te/t-butoxycarbonylpiperidinylcarbonylamino- phenyl, piperazinylcarbonylaminophenyl, methylpiperazinylcarbonylaminophenyl, tert- butoxycarbonylpiperazinylcarbonylaminophenyl, morpholinylcarbonylaminophenyl, indolylcarbonylaminophenyl, methylisoxazolylcarbonylaminophenyl, pyridinylcarbonyl- aminophenyl, hydroxypyridinylcarbonylaminophenyl, (oxo)(phenyl)pyrrolidinylcarbonyl- aminophenyl, phenylsulphonylaminophenyl, benzylsulphonylaminophenyl, dimethyl- isoxazolylsulphonylaminophenyl, cyclopentylaminocarbonylaminophenyl, phenylamino- carbonylaminophenyl, methylazetidinylaminocarbonylaminophenyl, morpholinylethyl- aminocarbonylaminophenyl, methylimidazolylmethylaminocarbonylaminophenyl, moφholinylcarbonylcarbonylaminophenyl, pyrrolidinylethylaminocarbonylcarbonyl- aminophenyl, phenylcarbonylphenyl, morpholinylcarbonylphenyl, aminopyrrolidinyl- carbonylmethylphenyl, tert-butoxycarbonylaminopyrrolidinylcarbonylmethylphenyl, aminopiperidinylcarbonylmethylphenyl, methylaminopiperidinylcarbonylmethylphenyl, tert-butoxycarbonylaminopiperidinylcarbonylmethylphenyl, 7V-(ter?-butoxycarbonyl)-N- (methyl)aminopiperidinylcarbonylmethylphenyl, benzylaminocarbonylphenyl, morpholinylethylaminocarbonylphenyl, imidazolylaminocarbonylphenyl, methyl- imidazolylmethylaminocarbonylphenyl, pyridinylmethylaminocarbonylphenyl, azetidinylaminocarbonylmethylphenyl, fer^-butoxycarbonylazetidinylaminocarbonyl- methylphenyl, pyrrolidinylmethylaminocarbonylmethylphenyl, fe/t-butoxycarbonyl- pyrrolidinylmethylaminocarbonylmethylphenyl, pyridinylaminocarbonylmethylphenyl, pyridinylmethylaminocarbonylmethylphenyl, phenylaminopyridinyl, N-methyl-N- phenylaminopyridinyl, azetidinylaminophenylpyridinyl, pyrrolidinylaminophenyl- pyridinyl, ter^-butoxycarbonylpyrrolidinylaminophenylpyridinyl, piperazinylcarbonyl- aminophenylpyridinyl, piperidinylaminocarbonylaminophenylpyridinyl, (cyclopropylcarbonyl)(fluoro)phenylpyridinyl, aminoazetidinylcarbonylphenylpyridinyl, methylaminoazetidinylcarbonylphenylpyridinyl, tert-butoxycarbonylaminoazetidinyl- carbonylphenylpyridinyl, N-(tert-butoxycarbonyl)-iV-(methyl)ammoazetidinylcarbonyl- phenylpyridinyl, pyrrolidinylcarbonylphenylpyridinyl, hydroxypyrrolidinylcarbonyl- phenylpyridinyl, aminopyrrolidinylcarbonylphenylpyridinyl, aminopyrrolidinylcarbonyl- phenyl(amino)pyridinyl, methylaminopyrrolidinylcarbonylphenylpyridinyl, tert- butoxycarbonylaminopyrrolidinylcarbonylphenylpyridinyl, tert-butoxycarbonyl- aminopyrrolidinylcarbonylphenyl(methoxybenzylamino)pyridinyl, piperidinylcarbonylphenylpyridinyl, aminopiperidinylcarbonylphenylpyridinyl, methyl- aminopiperidinylcarbonylphenylpyridinyl, tert-butoxycarbonylaminopiperidinylcarbonyl- phenylpyridinyl, dimethylaminopiperidinylcarbonylphenylpyridinyl, iV-(tert-butoxy- carbonyl)-iV-(methyl)aminopiperidinylcarbonylphenylpyridinyl, piperazinylcarbonyl- phenylpyridinyl, methylpiperazinylcarbonylphenylpyridinyl, tert-butoxycarbonyl- piperazinylcarbonylphenylpyridinyl, morpholinylcarbonylphenylpyridinyl, (fluoro)- (morpholinylcarbonyl)phenylpyridinyl, methylaminopiperidinylcarbonylphenyl- pyrimidinyl, dimethylaminopiperidinylcarbonylphenylpyrimidinyl, morpholinylmethylcarbonylphenylpyridinyl, aminoazabicyclo[3.2.1]octyl- carbonylphenylpyridinyl, aminoazetidinylcarbonylmethylphenylpyridinyl, tert-butoxy- carbonylaminoazetidinylcarbonylmethylphenylpyridinyl, pyrrolidinylcarbonylmethyl- phenylpyridinyl, aminopyrrolidinylcarbonylmethylphenylpyridinyl, tert-butoxycarbonyl- aminopyrrolidinylcarbonylmethylphenylpyridinyl, methylaminopiperidinylcarbonyl- methylphenylpyridinyl, iV-(/ert-butoxycarbonyl)-iV-(methyl)aminopiperidinylcarbonyl- methylphenylpyridinyl, methylpiperazinylcarbonylmethylphenylpyridinyl, azetidinyl- aminocarbonylphenylpyridinyl, tert-butoxycarbonylazetidinylaminocarbonylphenyl- pyridinyl, Λ7-(tert-butoxycarbonylazetidinyl)-Λr-(ethyl)aminocarbonylphenylpyridinyl, tert- butoxycarbonylpyrrolidinylaminocarbonylphenylpyridinyl, 7V-(methylpyrrolidinyl)-iV- (methyl)aminocarbonylphenylpyridinyl, N-(methylpiperidinyl)-N-(methyl)aminocarbonyl- phenylpyridinyl, piperidinylmethylaminocarbonylphenylpyridinyl, fer£-butoxycarbonyl- piperidinylmethylaminocarbonylphenylpyridinyl, azetidinylaminocarbonylmethylphenyl- pyridinyl and te/'t-butoxycarbonylazetidinylaininocarbonylmetliylphenylpyridinyl.
In one embodiment, R5 is hydrogen.
Suitably, when R3 and R4 are both hydrogen, then R5 is other than hydrogen.
Suitably, when R5 is hydrogen, then R3 and/or R4 is other than hydrogen.
One sub-class of compounds according to the invention is represented by the compounds of formula (IIA), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000037_0001
(HA)
wherein X1 represents N or CH;
R11 represents hydrogen or C1-6 alkyl; and
R12 represents hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)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; and
R13 represents hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1.6)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(C1-6)alkyl or aryl-heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
In one embodiment, X1 represents N. In another embodiment, X1 represents CH. Where any of the groups in the compounds of formula (HA) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. Suitably, such groups will be unsubstituted or monosubstituted.
Typical values of R11 include hydrogen, methyl and ethyl. In one embodiment, R11 is hydrogen. In another embodiment, R11 is Cj-6 alkyl, especially methyl.
Suitably, R12 represents hydrogen; or C1-6 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, C1-6 alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difiuoromethoxy, trifluoromethoxy, aryloxy, Ci-6 alkylthio, Ci-6 alkylsulphonyl, amino, Ci-6 alkylamino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulphonyl, C1-6 alkylaminosulphonyl and di(Ci-6)alkylaminosulphonyl; especially halogen, Ci-6 alkoxy or Ci-6 alkylthio.
Examples of particular substituents on R12 include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, 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 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl. A particular value of R12 is methyl.
Alternatively, R l and R12 may together form an optionally substituted spiro linkage. Thus, R11 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, R11 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. Typically, R13 represents hydrogen; or C1-6 alkyl, aryl(C1-6)alkyl, aryl(C2-6)alkynyl, biaryl(C1-6)alkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl(C1-6)alkyl, heteroaryl-aryl(C1-6)alkyl or aryl-heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Generally, R13 represents hydrogen; or C2-6 alkynyl, aryl(Ci-o)alkyl or heteroaryl- (C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R13 represents aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, either of which groups may be optionally substituted by one or more substituents.
In one specific embodiment, R13 represents hydrogen.
In a representative embodiment, R13 represents C1-6 alkyl, aryl(C1-6)alkyl, biaryl- (C1-6)alkyl, heteroaryl(Ci-6)alkyl or heteroaryl-aryl(C[,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, R13 represents arylmethyl or heteroarylmethyl, either of which groups maybe optionally substituted by one or more substituents.
In a particular embodiment, R13 represents substituted or unsubstituted indolyl- (C1-6)alkyl. Advantageously, R13 represents substituted or unsubstituted indolylmethyl.
In a typical embodiment, R13 represents substituted or unsubstituted phenyl- (C1-6)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-tetrahydroquinolinylniethyl, 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-b]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, trifiuoromethyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci.6)alkylaryl, di(Ci-6)alkylaryl, piperidinyl- (C1-6)alkylaryl, piperazinyl(Ci-6)alkylaryl, (C1-6)alkylpiperazinyl(C1-6)alkylaryl, morpholinyl(Ci-6)alkylaryl, (C1-6)alkoxyaryl, cyano(C1-6)alkoxyaryl, di(C1.6)alkyl- amino(Ci-6)alkylaryl, (Cj-6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, oxazolinyl, azetidinyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkylaminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di(C1-6)alkylamino- carbonylpiperidinyl, piperazinyl, (Ci.6)alkylpiperazinyl, haloarylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (C1-6)alkylhomopiperazinyl, morpholinyl, (C1-6)alkylpiperazinyl(Ci-6)alkyl, morpholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(Ci-6)alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, [di(C]-6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci.6)alkylpyrazolyl, [cyano- (Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, hydroxy(C1-6)alkylpyrazolyl, [hydroxy(C1-6)- alkyl] [di(Ci-6)alkyl]pyrazolyl, methoxy(C1-6)alkylpyrazolyl, [dihydroxy(Ci-6)alkyl]- pyrazolyl, [(hydroxy)(methoxy)(Ci.6)alkyl]pyrazolyl, aminoCd^alkylpyrazolyl, [(C1-6)alkyl][amino(Ci-6)alkyl]pyrazolyl, [amino(Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(C1-6)alkylamino(C1-6)alkylpyrazolyl, di(Ci-6)alkoxyphosphono(Ci-6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl(C1-6)alkylpyrazolyl, [(C3-7)cycloalkyl(Ci-6)alkyl]- [di(Ci-6)alkyl]pyrazolyl, [(Ci-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(Ci-6)alkylpyrazolyl, aminoaryl(Ci-6)alkylρyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(C i -6)alkylpyrazolyl, [Oi(C1 -6)alkyl] [tetrahydropyranyl(C i .6)alkyl] - pyrazolyl, pyrrolidinyl(Ci-6)alkylpyrazolyl, piperidinyl(C1-6)alkylpyrazolyl, (C1-6)alkyl- piperidinyl(C i -6)alkylpyrazolyl, morpholinyl(C i -6)alkylpyrazolyl, pyridinyl(C 1 -6)alkyl- pyrazolyl, oxypyridinyl(Ci-6)alkylpyrazolyl, [arylcarbonyl(Ci-6)alkyl][di(Ci-6)alkyl]- pyrazolyl, [(C1-6)alkyl](piperazinylcarbonyl)pyrazolyl, [(C1-6)alkylaminocarbonyl]- [(Ci-6)alkylaryl]pyrazolyl, [(C1-6)alkyl][aniino(C1-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl, [aminocarbonyl(C1-6)alkyl][di(Cj-6)alkyl]pyrazolyl, di(C1-6)alkylaminocarbonyl(Ci-6)alkylρyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1-6)alkyl- isoxazolyl, (amino)[(C1.6)alkyl]isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (C1-6)alkylimidazolyl, di(C1-6)alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkyl- imidazo[l,2-α]pyridinyl, (C1.6)alkyliniidazo[4,5-£]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (C1-6)alkylthiadiazolyl, triazolyl, pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, [(C1-6)alkyl](halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenyl- pyridinyl,
Figure imgf000041_0001
[(C1-6)alkyl](piperazinyl)pyridinyl,
[(C1-6)alkoxycarbonylpiperazinyl][(C1-6)alkyl]pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(C1-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(C1-6)alkylpyridinyl, (C1-6)alkoxy- pyridinyl, [(C1-6)alkoxy][(Cμ6)alkyl]ρyridmyl, [(C1-6)alkoxy][di(C1-6)alkyl]ρyridinyl, (Ci-6)alkoxy(Ci.6)alkylpyridinyl, aminopyridinyl, carboxy(Ci_6)alkylpyridinyl, (C1-6)alkoxycarbonyl(C1-6)alkylpyridinyl, pyridazinyl, (C1-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (C1-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(C1-6)alkylaminopyridazinyl, di(Ci-6)alkylaminopyridazinyl, pyrimidinyl, (C1-6)alkylpyrimidinyl, [(C1-6)alkyl](halo)pyrimidinyl, di(C1-6)alkylpyriniidinyl, pyrrolidinylpyrimidinyl, (C1-6)alkylpiperazinylpyrimidinyl, [(C1-6)alkyl](piperazinyl)- pyrimidinyl, [(C 1-6)alkoxycarbonyl] [(C i -6)alkyl]piperazinylpyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(C1-6)alkyl] [hydroxy(Ci_6)alkyl]- pyriniidinyl, [(C1-6)alkyl][hydroxy(C2-6)alkynyl]pyrimidinyl, (C1-6)alkoxypyrimidinyl, aminopyrimidinyl, di(C i -6)alkylaminopyrimidinyl, [di(C \ .6)alkylamino] (halo)pyrimidinyl, carboxypyrimidinyl, [(Ci-6)alkoxycarbonyl(C1-6)alkyl][(Ci-6)alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, aminopyrazinyl, hydroxy, (C1-6)alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl- (Ci-6)alkoxy, aryl(C1-6)alkoxycarbonylpiperidinyloxy, morpholinyl(C1-6)alkoxy, aryloxy, haloaryloxy, di(C1-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (Ci-6)alkylpiperazinylpyridinyloxy, (Ci-6)alkylpyrazolylpyridinyloxy, (Ci-6)alkylamino- pyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, (Ci-6)alkyl- pyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C]-6)alkyl](halo)- pyrimidinyloxy, hydroxy(C1.6)alkyl, dihydroxy(Ci-6)alkyl, pyridinyloxy(C1-6)alkyl, methylenedioxy, difluoromethylenedioxy, amino, (Ci-6)alkylamino, dihydroxy(C1-6)alkyl- amino, (C1-6)alkoxy(C1-6)alkylamino, di(C1-6)alkylamino, N-[(C1-6)alkoxy(C1.6)alkyl]-N- [(Ci-6)alkyl]amino, di(Ci-6)alkylamino(C1-6)alkylamino, iV'-[(Ci-6)alkyl]-N-[di(C1-6)alkyl- amino(Ci-6)alkyl] amino, N-[(C1-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino, N-
Figure imgf000042_0001
methylenedioxyphenylamino, morpholinyl(C1-6)alkyl- phenylamino, oxazolinylphenylamino, [(C1-6)alkyl](oxo)pyrazolylphenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, (Ci-6)alkyltriazolylphenylamino, (C1-6)alkylpyrimidinylphenylamino, pyrazolyl(Ci_6)alkyl- phenylamino, triazolyl(C1-6)alkylphenylamino, Ci-6 alkylsulphonylaminophenylamino, niorpholinylcarbonylphenylamino, C1-6 alkylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-[(Ci-6)alkyl]-N-[aryl(C 1-6)alkyl]amino5
N-[di(C1-6)alkylamino(C].6)alkyl]-N-[aryl(C1-6)alkyl]atnino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(C1-6)alkylamino, methylenedioxyaryl(C1-6)alkylamino, dihydrobenzofuranylamino, N- [(C \ -6)alkyl] -N- [(C \ -6)alkylpyrrolidinyl] amino, C i -6 alkylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-[(Ci.6)alkyl]-N- (piperidinyl)amino, N-[(C3-7)cycloalkyl(Ci-6)alkyl]-N-(piperidinyl)amino, (Ci-6)alkyl- piperidinylamino, N-[(C1-6)alkyl]-N-[(Ci-6)alkylpiperidinyl]amino, N-[(C1-6)alkyl]- N-[(C3-7)cycloalkylpiperidinyl]amino, N-[(Cj-6)alkyl]-N-[(C2-6)alkylcarbonylpiperidinyl]- amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidiny^d-^alkylamino, N-[(C1-6)alkyl]-N-[pyrrolidinyl(C1-6)alkyl]amino, N-[(C1-6)alkyl]-N-[piperidinyl(C1-6)- alkyl] amino, benzothienylamino, indolylamino, dioxoindolylamino, (C1-6)alkylpyrazolyl- amino, [(Ci-6)alkyl](halo)pyrazolylamino, di(Ci-6)alkylpyrazolylamino, tri(Ci-6)alkyl- pyrazolylamino, N- [(C i-6)alkyl] -N- [(C1-6)alkylpyrazolyl] amino, (C i -6)alkylindazolylamino, benzoxazolylamino, benzoxazolonylamino, di(C1-6)alkylisoxazolylamino, thiazolylamino, benzothiazolylamino, (C1-6)alkylisothiazolylamino, imidazolylamino, [(Ci^alkoxy- carbonyl][(Ci..6)alkyl]imidazolylamino, (Ci^alkylbenzimidazolylamino, benzimidazolonylamino, di(Ci-6)alkylbenzimidazolonylamino, (C1-6)alkyloxadiazolyl- amino, fiiryloxadiazolylamino, (Ci-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (C1-6)alkylpyridinylamino, di(C1-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C1-6)alkylpyridinylamino, dihydroxy(C1-6)alkylpyridinylamino, (C1-6)alkoxypyridinylamino, dihydroxy(C[-6)alkoxy- pyridinylamino, di(Ci-6)alkyldioxolanyl(Ci-6)alkoxypyridinylamino, (Ci.6)alkoxy(C1-6)- 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(C1.6)alkylρyridinylamino, oxopyridinylamino, carboxypyridinylamino, N-[(C1,6)alkyl]-N-[(C1-6)alkylpyridinyl]amino, bis[(C1-6)alkyl- pyridinyl] amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, (C1-6)alkyl- pyridazinylamino, Λ/"-[(C1-6)alkyl]-N-[(C1-6)alkylpyridazinyl]amino3 iV-[aryl(C1-6)alkyl]-Λr- [(C1-6)alkylpyridazinyl]amino,
Figure imgf000043_0001
arylpyridazinylamino, piperidinylpyridazinylamino, (C1-6)alkoxypyridazinylamino, [(C1-6)alkoxy](halo)- pyridazinylamino, di(Ci-6)alkylaminopyridazinylamino, bis[(C1-6)alkylpyridazinyl]amino, (C1-6)alkylcinnolinylamino, oxopyrimidinylamino, thioxopyrimidinylamino, quinoxalinylamino, (C1-6)alkylchromenylamino, benzofuryl(C1-6)alkylamino, thienyl(C1-6)- alkylamino, indolyl(Ci-6)alkylamino, (Ci-6)alkylpyrazolyl(Ci-6)alkylamino, [di(C1-6)alkyl]- (halo)pyrazolyl(Ci.6)alkylamino, di(C1-6)alkylisoxazolyl(C1-6)alkylamino, thiazolyl(C1-6)- alkylamino, imidazolyl(C1-6)alkylamino, (C1-6)alkylimidazolyl(C1-6)alkylamino, pyridinyl(C1-6)alkylamino, (C1-6)alkylpyridinyl(Ci-6)alkylamino, N-[(Cι^)a\kyϊ\-N- [pyridinyl(C i _6)alkyl] amino, JV- [dihydroxy(C i -6)alkyl] -JV- [pyridinyl(C j _6)alkyl] amino, JV- [(C1-6)alkylpyridinyl(C1-6)alkyl]-JV-[dihydroxy(C1-6)alkyl]amino, amino(C1-6)alkyl, (C1-6)- alkylamino(Ci-6)alkyl, di(Ci-6)alkylamino(C1-6)alkyl, pyridinylamino(Ci-6)alkyl, C2-6 alkylcarbonylamino, JV-[ (C2-6)alkylcarbonyl] -JV- [(C i -6)alkylpyridinyl(C i -6)alkyl] amino, di(C1-6)alkylamino(C1-6)alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, (C3-7)- cycloalkylcarbonylamino, (C1-6)alkylpiperidinylcarbonylamino, (Q^alkylimidazolyl- carbonylamino, C2.6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(Ci-6)alkyl]amino, Ci-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,
Figure imgf000043_0002
[di(C1-6)- alkylamino(Ci-6)alkyl]aminocarbonyl, di(Ci-6)alkylaminocarbonyl, [(Ci-6)alkyl][cyano- (C 1-6)alkyl] aminocarbonyl, [(Ci,6)alkyl][hydroxy(Ci-6)alkyl]aminocarbonyl, [(Ci-6)alkoxy- (C1-6)alkyl] [(Ci-6)alkyl]aminocarbonyl, [di(C1-6)alkylamino(C1-6)alkyl] [(C 1-6)alkyl] aminocarbonyl, C3-7 cycloalkyl(C1-6)alkylaminocarbonyl, aryl(Ci.6)alkylaminocarbonyl, (Ci-6)- alkylpiperidinylaminocarbonyl, JV-[(C1-6)alkyl]-JV-[(C1-6)alkylpiperidinyl]aminocarbonyl, piperidinyl(Ci-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C1-6)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, (Q^alkylpiperazinylcarbonyl, morpholinylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, C1-6 alkylsulphonylmethyl, aminosulphonyl, C1-6 alkylaminosulphonyl, di(C1-6)alkylaminosulphonyl, C2-6 alkoxycarbonyloxy, trimethylsilyl and tetra(C } -6)alkyldioxaborolanyl . Particular examples of typical substituents on R13 include C1-6 alkyl and di(C i .(,) alkylamino carbonyl .
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, dimemylammomethylphenyl, 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)(emyl)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, (dihydroxypropyl)pyrazolyl, [(hydroxy)- (methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cycloρropylmethyl)(dimethyl)pyrazolyl, (memyl)(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- tfjpyridinyl, methylimidazo[l,2-α]pyridinyl, methylirnidazo[4,5-Z>]pyridinyl, imidazo[l,2- αjpyrimidinyl, 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, hydroxyniethylpyridinyl, 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, pynOlidinylpyridinyloxy, methylpiperazinyl- pyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxy- pyridinyloxy, aminocarbonylpyridinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1- methylethyl, dihydroxypropyl, pyridinyloxymethyl, methylenedioxy, difluoromethylenedioxy, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, dimethylamino, N-(methoxyethyl)-N- (methyl)amino, N-(methoxypropyl)-jV-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N-(dimethylaminoethyl)-N-(methyl)amino, iV- (diethylaminoethyl)-N-(methyl)amino, N-(dimethylaminopropyl)-N-(methyl)amino, N- (dimethylaminoethyl)-N-(ethyl)amino, N-(dimethylaminoproρyl)-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, dihydrobenzbfuranylamino, 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-(niethyl)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, methylisothiazolyl amino, imidazolylamino, (ethoxycarbonyl)(methyl)imidazolylamino, methylbenzimidazolyl- amino, benzimidazolonylamino, dimethylbenzmαidazolonylamino, methyloxadiazolyl- amino, furyloxadiazolylamino, methylthiadiazolylamino, pyridinylamino, chloropyridinyl- amino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylaniino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, oxopyridinylamino, carboxypyridinylamino, iV-(niethyl)-iV-(methylpyridinyl)- amino, N-(ethyl)-N-(methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, iV-(methyl)-iV- (methylpyridazinyl)amino, N-(benzyl)-N-(methylpyridazinyl)amino, dimethyl- pyridazinylaniino, phenylpyridazinylamino, piperidinylpyridazinylamino, methoxypyridazinylamino, (chloro)(methoxy)pyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)aniino, methylcinnolinylamino, oxopyrimidinyl- amino, thioxopyrimidinylamino, quinoxalinylamino, methylchronienylamino, benzofurylmethylamino, thienylmethylamino, indolylmethylamino, methylpyrazolyl- methylamino, (chloro)(dimethyl)pyrazolylmethylamino, dimethylisoxazolylmethylamino, thiazolylmethylaniino, imidazolylmethylamino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethylamino, N-(methyl)--/V-(pyridinylethyl)- amino, 7V-(dihydroxypropyl)-iV-(pyridinylmethyl)aniino, iV-(dihydroxypropyl)-iV- (methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, acetylamino, N-(acetyl)-N-(methylpyridinyl)amino, dimethylaminoethylcarbonylamino, acetylaminomethyl, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, methoxycarbonyl- amino, N-methoxycarbonyl-N-methylamino, methylsulphonylamino, formyl, acetyl, acetyl oxime, acetyl (9-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethyl- aminoethyl)aminocarbonyl, (1 -hydroxyprop-2-yl)aminocarbonyl, dimethylamino- carbonyl, N"-(cyanomethyl)-N-methylaminocarbonyl, N-(cyanoethyl)-iV-methylamino- carbonyl, N-(hydroxyethyl)-N-methylaminocarbonyl, /^-(methoxyethy^-N-methyl- aminocarbonyl, iV-(dimethylaminoethyl)-N-niethylaminocarbonyl, JV-isopropyl-JV-methyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, methylpiperidinylaminocarbonyl, iV-(methyl)-iV-(niethylpiperidinyl)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, ferf-butoxycarbonyloxy, trimethylsilyl and tetramethyl- dioxaborolanyl.
Particular examples of specific substituents on R13 include methyl and dimethylaminocarbonyl. Typical values of R13 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-N-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienylmethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazolylphenylaminobenzyl, methylpyrimidinylphenylaminobenzyl, pyrazolylmethylphenylaminobenzyl, triazolylmethylphenylaminobenzyl, methylsulphonylaminophenylaminobenzyl, morpholinylcarbonylphenylaminobenzyl, methylsulphonylplienylaminobenzyl, 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 oxime] indolylmethyl, [acetyl O-(methyl)oxime]- indolylmethyl, trifluoromethylcarbonylindolylmethyl, carboxyindolylmethyl, (carboxy)- (methyl)indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl, (chloro)(methoxycarbonyl)indolylmethyl, aminocarbonylindolylmethyl, (aminocarbonyl)(chloro)indolylmethyl, methylaniinocarbonylindolylmethyl, (chloro)- (methylaminocarbonyl)indolylmethyl, (hydroxyethytyaminocarbonylindolylmethyl, (dimethylaminoethy^aminocarbonylindolylmethyl, ( 1 -hydroxyprop-2-yl)aminocarbonyl- indolylmethyl, dimethylaminocarbonylindolyhnethyl, (dimethylaminocarbonyl)(methyl)- indolylmethyl, (chloro)(dimethylaminocarbonyl)indolylmethyl, bis(dimethylamino- carbonyl)indolylmethyl, N-(cyanomethyl)-iV-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, dimethylaminosulphonylindolylniethyl, trimethylsilylindolylmethyl and pyrrolo[3,2-c]pyridinylniethyl.
A particular value of R13 is (dimethylaminocarbonyl)(methyl)indolylmethyl.
One particular sub-group of the compounds of formula (HA) is represented by the compounds of formula (HB), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000050_0001
(IIB)
wherein R11 and R12 are as defined above;
T represents oxygen or N-R ;
R23 represents hydrogen, halogen, cyano, nitro, Ci-6 alkyl, hydroxy(C1-6)alkyl, trifluoromethyl, aryl(C1-6)alkyl, oxazolinyl, triazolyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(C1-6)alkoxy, morpholinyl(C1-6)alkoxy, aryloxy, aryl(C1-6)alkoxy, C1-6 alkylthio, Ci-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, C1-6 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, C1-6 alkylaminocarbonyl, [hydroxy(Ci-6)- alkyljaminocarbonyl, [di(Ci-6)alkylamino(Ci-6)alkyl]aminocarbonyl, di(Ci.6)alkyl- aminocarbonyl, [(Ci.6)alkyl][cyano(C1-6)alkyl]aminocarbonyl, [(Ci-6)alkyl][hydroxy(C1-6)- alkyl] aminocarbonyl, [(Ci-6)alkoxy(C1-6)alkyl][(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)alkyl- amino(C1.6)alkyl][(Ci-6)alkyl]aminocarbonyl, C3-7 cycloalkyl(C1-6)alkylaminocarbonyl, aryl(Ci-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C1-6)alkylamino- carbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaniinoazetidinylcarbonyl, pyrrolidinylcarbonyl, (C1-6)alkylpyrrolidinyl- carbonyl, C1-6 alkoxy(Ci-6)alkylpyrrolidinylcarbonyl, di(C1-6)alkylaminopyrrolidinyl- carbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, (Ci-6)- alkylpiperazinylcarbonyl, morpholinylcarbonyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonyl- methyl or di(C1-6)alkylaminosulphonyl; and
R 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. A suitable value of R23 is di(C1-6)alkylaminocarbonyl.
Illustrative values of R23 include hydrogen, fluoro, chloro, cyano, nitro, oxazolinyl, triazolyl, methoxy, difiuoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, morpholinylethoxy, azetidinyl, morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino, iV-methoxycarbonyl-iV-methylamino, methylsulphonylamino, acetyl, acetyl oxime, acetyl 0-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethylaminoethyl)aminocarbonyl, (1 -hydroxyprop-2-yl)aminocarbonyl, dimethyl- aminocarbonyl, iV-(cyanomethyl)-iV-methylaminocarbonyl, iV-(cyanoethyl)-iV-methyl- aminocarbonyl, N-(hydroxyethyl)-N-methylaminocarbonyl, N-(methoxyethyl)-iV-methyl- aminocarbonyl, 7V-(dimethylaminoethyl)-Λ/-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.
A particular value of R23 is dimethylaminocarbonyl.
Definitive values of R24 include hydrogen, chloro, methoxy and dimethylaminocarbonyl. A particular value of R24 is hydrogen. In one embodiment, R25 is hydrogen. In another embodiment, R25 is C1-6 alkyl, especially methyl.
Another particular sub-group of the compounds of formula (HA) is represented by the compounds of formula (IIC), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000052_0001
(HC)
wherein R and R 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 methylenedioxyphenyl, morpholinyl(Ci-6)alkylphenyl, oxazolinyl- phenyl, [(C1-6)alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (C1-6)alkyltriazolylphenyl, (C1-6)alkylpyrimidinylphenyl, pyrazolyl(C1-6)alkyl- phenyl, triazolyl(Ci-6)alkylphenyl, Cj-6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, C1-6 alkylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, C1-6 alkylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, [(C1-6)alkyl](halo)pyrazolyl, tri(C1-6)alkylpyrazolyl, (C1-6)alkylindazolyl, benzoxazolyl, benzoxazolonyl, di(Ci.6)alkylisoxazolyl, benzothiazolyl, (Ci-6)alkylisothiazolyl, (C1-6)alkylbenzimidazolyl, benzimidazolonyl, di(C1-6)alkylbenzimidazolonyl, (Ci-6)alkyloxadiazolyl, furyloxadiazolyl, pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, di(Ci-6)alkylpyridinyl, (Ci-6)alkoxypyridinyl, oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl, [(Ci-6)alkoxy](halo)pyridazinyl, (C1-6)alkylcinnolinyl, quinoxalinyl or (C1-6)alkylchromenyl. Suitably, R33 represents halogen or -NHR3 , in which R34 is as defined above. In one embodiment, R3 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, R represents unsubstituted or substituted heteroaryl.
Typical values of R34 include pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, di(C]-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 -NHR34, in which R34 is as defined above. Additionally, R33 represents phenyl, naphthyl, benzofuryl, thienyl, benzothienyl, indolyl, isoxazolyl, pyrazolyl, pyridinyl or pyrimidinyl, any of which groups maybe optionally substituted by one or more substituents.
Selected examples of suitable substituents on R33 include halogen, cyano, C1-6 alkyl, hydroxy(C1-6)alkyl, trifluoromethyl, Ci-6 alkoxy, trifluoromethoxy, aryloxy, methylenedioxy, C1-6 alkylthio, arylsulphonyl, amino, C2-6 alkylcarbonylamino, C1-6 alkylsulphonylamino, C2-6 alkylcarbonyl and aminocarbonyl. Selected examples of representative substituents on R33 include fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, phenoxy, methylenedioxy, methylthio, phenylsulphonyl, amino, acetylamino, methylsulphonylamino, acetyl and aminocarbonyl. Specific values of R33 include bromo, methylenedioxyphenylamino, moφholinylmethylphenylamino, 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, trifluoroniethylphenyl, bis(trifluoromethyl)phenyl, methoxyphenyl, dimethoxyphenyl, ethoxyphenyl, methylenedioxyphenyl, trifluoromethoxyphenyl, phenoxyphenyl, methylthiophenyl, aminophenyl, acetylaminophenyl, methylsulphonylaminophenyl, acetylphenyl, aminocarbonylphenyl, naphthyl, benzofuryl, thienyl, methylthienyl, acetylthienyl, benzothienyl, phenylsulphonylindolyl, dimethylisoxazolyl, methylpyrazolyl, benzylpyrazolyl, pyridinyl, fluoropyridinyl, chloropyridinyl, methoxypyridinyl and pyrimidinylbenzyl.
A particular value of R33 is bromo.
Other sub-classes of compounds according to the invention are represented by the compounds of formula (IID-1) and (IID-2), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000055_0001
wherein
R11 and R1Z are as defined above; R^3 represents hydrogen, halogen, nitro, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl,
(C1-ό)alkylaryl, di(C1-6)alkylaryl, ρiperidinyl(C1-6)alkylaryl, piperazinyl(C1-6)alkylaryl, (C1-6)alkylpiperazinyl(C1-6)alkylaryl, morpholinyl(C1-6)alkylaryl, (C1-6)alkoxyaryl, cyano(C1-6)alkoxyaryl, di(Ci-6)alkylamino(Ci-6)alkylaryl, (Ci-6)alkylaminocarbonylaryl, aryl(C1-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aniinopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (Ci-6)alkylaminocarbonylpiperidinyl, piperazinyl, (Q^alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (Ci^alkyl- homopiperazinyl, (C1-6)alkylpiperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (C1-6)alkylpyrazolyl, di(C1-6)alkylpyrazolyl, tri(C1-6)alkyl- pyrazolyl, (difluoromethyl)pyrazolyl, [di(Ci-6)alkyl](trifluoromethyl)pyrazolyl, cyano(C1-6)alkylpyrazolyl, [cyano(Ci-6)alkyl][di(C1-6)alkyl]ρyrazolyl, hydroxy(Ci_6)alkyl- pyrazolyl, [hydroxy(C1-6)alkyl] [di(C1-6)alkyl]ρyrazolyl, methoxy(C1-6)alkylρyrazolyl, [dihydroxy(Ci-6)alkyl]pyrazolyl, [(hydroxy)(methoxy)(C1-6)alkyl]pyrazolyl, amino(C1-6)- alkylpyrazolyl, [(C1 -6)alkyl] [amino(C1-6)alkyl]pyrazolyl, [amino(Ci-6)alkyl] [di(C1-6)alkyl]- pyrazolyl, di(C1-6)alkylamino(Ci-6)alkylpyrazolyl, di(Ci-6)alkoxyphosphono(C1-6)alkyl- pyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl(C1-6)alkylpyrazolyl, [(C3-7)cycloalkyl- (C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(C1-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)- pyrazolyl, aryl(Ci-6)alkylpyrazolyl, aminoaryl(C1-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydroρyranyl(C1.6)alkylpyrazolyl, [di(C1-6)alkyl][tetrahydropyranyl(C1-6)alkyl]- pyrazolyl, pyrrolidiny^C^alkylpyrazolyl, piperidinyl(Ci-6)alkylpyrazolyl, (Ci.6)alkyl- piρeridinyl(C1-6)alkylpyrazolyl, morpholinyl(C1-6)alkylpyrazolyl, pyridinyl(C1-6)alkyl- pyrazolyl, oxypyridinyl(C1-6)alkylρyrazolyl, [arylcarbonyl(C1-6)alkyl][di(C1-6)alkyl]- pyrazolyl, [(C1-6)alkyl](piperazinylcarbonyl)pyrazolyl, [(Ci-6)alkylaminocarbonyl][(C1-6)- alkylaryljpyrazolyl, [(C1-6)alkyl][amino(C1-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl, [aminocarbonyl(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, di(C1-6)alkylaminocarbonyl(Ci-6)alkylpyrazolyl, pyrazolo[l,5-<z]pyridinyl, di(C1-6)alkyl- isoxazolyl, (ammo)[(C1-6)alkyl]isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (C1-6)alkylimidazolyl, di(C1-6)alkylimidazolyl, imidazo[l,2-α]pyridinyl, (Ci-6)alkyl- imidazo[ 1 ,2-α]pyridinyl, (C1-6)alkylimidazo[4,5-ό]pyridinyl, imidazo[ 1 ,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)alkylthiadiazolyl, pyridinyl, halopyridinyl, (Ci-6)alkyl- pyridinyl, [(Ci-6)alkyl](halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenylpyridinyl,
(C1-6)alkylpiperazinylpyridinyl, [(Ci-6)alkyl](piperazinyl)pyridinyl, [(C1-6)alkoxycarbonyl- piperazinyl][(Ci-6)alkyl]pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(C1-6)alkyl]- (oxy)pyridinyl, hydroxypyridinyl, hydroxy(C1-6)alkylpyridinyl, (Ci-6)alkoxypyridinyl, [(Ci-6)alkoxy][(C1-6)alkyl]pyridinyl, [(C1-6)alkoxy][di(C1-6)alkyl]pyridinyl, (Ci-6)alkoxy(C1-6)alkylpyridinyl, aminopyridinyl, carboxy(C1-6)alkylρyridinyl, (C1-6)alkoxycarbonyl(Ci-6)alkylpyridinyl, pyridazinyl, (C1-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (C1-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(C1-6)alkylaminopyridazinyl, di(C1-6)alkylaminopyridazinyl, pyrimidinyl, (C1-6)alkylpyrimidinyl, [(C1-6)alkyl](halo)pyrimidinyl, di(Ci-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (C1-6)alkylpiperazinylpyrimidinyl, [(C1-6)alkyl](piperazinyl)- pyrimidinyl, [(C1-6)alkoxycarbonyl][(C1-6)alkyl]piperazinylpyrimidinyl, hydroxypyrimidinyl, [(C1-6)alkyl](hydroxy)pyrimidinyl, [(Ci-6)alkyl][hydroxy(Ci-6)alkyl]- pyrimidinyl, [(Ci-6)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (Ci.6)alkoxypyrimidinyl, aminopyrimidinyl, di(C1-6)alkylaminopyrimidinyl, [di(C1-6)alkylamino](halo)pyrimidinyl, carboxypyrimidinyl, [(Ci-6)alkoxycarbonyl(C1-6)alkyl][(Ci-6)alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci^alkoxypyrazinyl, aminopyrazinyl, hydroxy, (Ci-6)alkoxy, aryl(C1-6)alkoxycarbonylρiρeridinyloxy, morpholinyl(C1-6)alkoxy, aryloxy, haloaryloxy, di(C1-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C1-6)alkylpiperazinylpyridinyloxy, (Ci-6)alkylpyrazolylpyridinyloxy, (C i -6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy, (C1-6)alkylpyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C1-6)alkyl](halo)pyrimidinyloxy, hydroxy(Ci-6)alkyl, dihydroxy(C1-6)alkyl, pyridinyloxy(Ci-6)alkyl, amino, (C1-6)alkylamino, dihydroxy(C1-6)alkylamino, (Ci-6)- alkoxy(C1.6)alkylamino, iV-[(C1-6)alkoxy(C1-6)alkyl]-7V-[(C1-6)alkyl]ainmo, di(C1-6)- alkylamino(Ci.6)alkylamino, N-[(Ci-6)alkyl]-iV-[di(C1-6)alkylaniino(Ci-6)alkyl]amino, N- [(C1-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, ^[(Ci^alkyll-N-CaryKCi-^alkyηamino^-tditCi^alkylamino^i^alkyy-iV-taryKCi-ό)- alkyljamino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(C1-6)alkylamino, methylene- dioxyaryl(C1-6)alkylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpyriOlidinyl]amino, piperidinyl- amino, N-[(C1-6)alkyl]-N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(C1-6)alkyl]-N- (piperidinyl)amino, (C1-6)alkylpiperidinylamino, N-[(C1-6)alkyl]-N-[(C1-6)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(Ci-6)alkyl]amino, iV-[(Ci-6)alkyl]-N-[ρiperidinyl(Ci-6)alkyl]amino, (C1-6)- alkylpyrazolylamino, di(Ci.6)alkylpyrazolylamino, tri(C1-6)alkylpyrazolylamino, N-[(C1-6)- alkyl]-N-[(C1-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(Ci^alkoxy- carbonyl][(C1-6)alkyl]imidazolylamino, (Ci-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (Ci-6)alkylpyridinylamino, di(Ci-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C1-6)alkylpyridinylamino, dihydroxy(Ci-6)alkylpyridinylamino, (C1-6)alkoxypyridinylamino, dihydroxy(Ci-6)alkoxy- pyridinylamino, di(C1-6)alkyldioxolanyl(C1,6)alkoxypyridinylamino, (C1-6)alkoxy(C1-6)- alkylpyridinylamino, (Ci-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(Ci-6)alkyl- aminopyridinylamino, di(C1-6)alkylaminopyridinylamino, (Ci-6)alkylamino(C1-6)alkyl- pyridinylamino, di(C1-6)alkylamino(Ci-6)alkylpyridinylamino, carboxypyridinylamino, N- [(Ci -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-[(Ci-6)alkylpyridazinyl]amino, N-[aryl(Ci-6)alkyl]-N-[(Ci-6)alkylpyridazinyl]amino, di(Ci-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (Ci,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(C1-6)alkylamino, [di(C1-6)alkyl](halo)pyrazolyl(Ci-6)alkylamino, di(C1-6)alkylisoxazolyl(C1-6)alkylamino, thiazolyl(C1-6)alkylamino, imidazolyl(C1-6)alkyl- amino, (C1-6)alkylimidazolyl(C1-6)alkylamino, ρyridinyl(C1-6)alkylamino, (Ci-6)alkyl- ρyridinyl(C j -6)alkylamino, N-[(Cι -6)alkyl] -N- [pyridinyl(C i -6)alkyl] amino, N- [dihydroxy- (Ci.6)alkyl]-N-[pyridinyl(Ci.6)alkyl]ammo, N-[(C1-6)alkylpyiidinyl(Ci-6)alkyl]-iV- [dihydroxy(Ci-6)alkyl]amino, amino(C1-6)alkyl, (C1-6)alkylamino(C1-6)alkyl, di(Ci-6)alkyl- amino(C1.6)alkyl, pyridinylamino(C1-6)alkyl, Λr-[(C2-6)alkylcarbonyl]-iV-[(C1-6)alkyl-
Figure imgf000058_0001
di(Ci-6)alkylamino(C1-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (C1-6)alkylpiperidinylcarbonylamino, (C1-6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (C1-6)alkylpiperidinylaminocarbonyl, iV-[(C1-6)alkyl]-iV-[(C1-6)- alkylpiperidinyljammocarbonyl, piperidinyl(Ci-6)alkylaminocarbonyl, (Ci.6)alkyl- piperazinylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy and tetra(C1-6)alkyldioxaborolanyl; and
R4 represents hydrogen, halogen, Ci-6 alkyl or C1-6 alkoxy.
Suitable values of R43 include halogen, hydroxy(C1-6)alkylpyrazolyl and [dihydroxy(C1-6)alkyl]pyrazolyl.
Specific values of R 3 include fluoro, chloro, bromo, nitro, methyl, rø-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, methylpiperazinyhnethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylpropylpyrazolyl, 3-methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isoproρyl)pyrazolyl, (dimethyl)(2-methylpropyl)pyrazolyl, (dimethyl)(3-methylbutyl)pyrazolyl, (difluoromethyl)pyrazolyl, (dimethyl)(trifiuoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)ρyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2- hydroxy-2-methylpropylpyrazolyl, (hydroxymethyl)(isopropyl)(methyl)ρyrazolyl, (hydroxyethyl)(dimethyl)pyrazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, (dihydroxypropyl)pyrazolyl, [(hydroxy)- (methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (ρhenyl)(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-&]pyridinyl, imidazo[l,2~ α]pyrimidmyl, 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, (1 -hydroxy- l-methylethyl)pyridinyl, methoxypyridinyl, (methoxy)(methyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonylmethylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylaminopyridazinyl, pyrimidinyl, methylpyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)(piperazinyl)pyrimidinyl, (te/t-butoxycarbonylpiperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxypropynyl)(methyl)ρyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl,
(dimethylamino)(fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonyl- methyl)(methyl)pyriniidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinylpyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1-methylethyl, dihydroxypropyl, pyridinyloxymethyl, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropyl amino, N-(methoxyethyl)-iV-(methyl)amino, JV- (methoxypropyl)-iV-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, iV-(dimethylaminoethyl)-N-(methyl)amino, JV- (diethylaminoethyl)-JV-(methyl)amino, 7V-(dimethylaminopropyl)-JV-(methyl)amino, JV- (dimethylaminoethyl)-JV-(ethyl)amino, JV-(dimethylammopropyl)-JV-(ethyl)amino, JV- (cyclohexyl)-JV-(methyl)amino, fluorophenylamino, JV-fluorophenyl-JV-methylamino, JV- benzyl-JV-methylamino, JV-(benzyl)-JV-(dimethylaminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)benzylamino, methylenedioxybenzylamino, JV- (methyl)-JV-(methylpyrrolidinyl)ammo, piperidinylamino, JV-(methyl)-JV-
(piperidinyl)amino, JV-(ethyl)-JV-(ρiperidinyl)amino, JV-(cyclopropylmethyl)-JV- (piperidinyl)amino, methylpiperidinylamino, JV-(methyl)-JV-(methylpiperidinyl)amino, JV- (methyl)-JV-(2-methylpropylpiperidinyl)amino, JV-(cyclopentylpiperidinyl)-JV- (methyl)amino, JV-(acetylpiperidinyl)-JV-(methyl)amino, pyrrolidinylethylamino, pyrrolidinylpropylamino, JV-(methyl)-JV-(pyrrolidinylethyl)amino, JV-(methyl)-JV- (pyrrolidinylpropyl)amino, JV-(methyl)-JV-(piperidinylmethyl)amino, methylpyrazolylamino, diniethylpyrazolylamino, trimethylpyrazolylamino, JV-(ethyl)-JV- (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, JV-(methyl)-JV-(methylpyridinyl)amino, JV-(ethyl)-JV- (methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, JV-(methyl)-JV-(methylpyridazinyl)amino, JV- (benzyl)-N-(methylρyridazinyl)amino, dimethylpyridazinylamino, phenylpyridazinyl- amino, piperidinylpyridazinylamino, methoxypyridazinylamino, dimethylamino- pyridazinylamino, bis(methylρyridazinyl)amino, benzofurylmethylamino, thienylmethyl- amino, indolylmethylamino, methylpyrazolylmethylamino, (chloro)(dimethyl)pyrazolyl- methylamino, dimethylisoxazolylmethylamino, thiazolylniethylamino, imidazorylmethyl- amino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethyl- amino, 7V-(methyl)-iV-(pyridinylethyl)amino, iV-(dihydroxypropyl)-Λ/'-(pyridinylmethyl)- amino, N-(dihydroxypropyl)-N-(methylpyridinylmethyl)amino, aminoniethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, JV-(acetyl)-./V-(methyl- pyridinyl)amino, dimethylaminoethylcarbonylamino, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, formyl, acetyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(methylpiperidinyl)aminocarbonyl, piperidinylethylaminocarbonyl, methylpiperazinylcarbonyl, isopropylthio, isopropyl- sulpbinyl, isopropylsulphonyl, ter/-butoxycarbonyloxy and tetramethyldioxaborolanyl. Particular values of R43 include bromo, hydroxyethylpyrazolyl and
(dihydroxypropyl)pyrazolyl.
In one embodiment, R44 represents hydrogen. In another embodiment, R44 represents halogen, especially fluoro, chloro or bromo. In a further embodiment, R44 represents C1-6 alkyl, especially methyl. In an additional embodiment, R represents C1-6 alkoxy, especially methoxy.
A further sub-class of compounds according to the invention is represented by the compounds of formula (HE), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000061_0001
(HE)
wherein
R , R . 11 and R , 12 are as defined above. 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 micronized 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):
Figure imgf000064_0001
(III)
wherein X, R1, R2, R3 and R4 are as defined above, and Rz represents Ci-6 alkyl; with an oxidising agent.
Suitably, R2 represents methyl.
The oxidising agent of use in the reaction with compound (III) is suitably a peroxyacid, e.g. m-chloroperbenzoic acid, in which case the reaction is conveniently effected in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
The compounds of formula (III) above may be prepared by treating a compound of formula (IV):
Figure imgf000065_0001
(IV)
wherein X, R1, R2, R3 and R4 are as defined above; with a strong base; followed by reaction with a compound of formula L1-Si(Rz)3, wherein Rz is as defined above, and L1 represents a halogen atom.
The halogen atom L is suitably chloro.
The strong base of use in the reaction with compound (IV) is suitably a hexa(C1-6)- alkyldisilazide reagent, e.g. sodium bis(trimethylsilyl)amide, in which case the reaction is conveniently effected in an inert solvent, e.g. a cyclic ether such as tetrahydrofuran. The intermediates of formula (IV) above may be prepared by the methods described in WO 2006/114606, WO 2007/141504, WO 2008/001076, and copending international patent application no. PCT/GB2007/003853, which was published on 17 April 2008 as WO 2008/044022; or by procedures analogous thereto.
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, e.g. by methods analogous to those described in WO 2006/114606, WO 2007/141504, WO 2008/001076, and copending international patent application no. PCT/GB2007/003853, which was published on 17 April 2008 as WO 2008/044022. 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, 3r edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
The following Examples illustrate the preparation of compounds according to the invention. The compounds in accordance with this invention potently inhibit the activity of human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ.
Enzyme Inhibition Assays
Measurement of the ability of compounds to inhibit the lipid kinase activity of the four class 1 PI3 kinase isoforms (α, β, γ and δ) was performed using a commercially available homogeneous time-resolved fluorescence assay as described by Gray et al., Anal. Biochem., 2003, 313, 234-245, according to the manufacturer's instructions (Upstate). All assays were performed at 2 μM ATP and a concentration of purified class 1 PD 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 IC50. When tested in the above assay, the compounds of the accompanying Examples were all found to possess IC5O values for inhibition of activity of human PI3Kα and/or PDKβ and/or PBKγ and/or PDKδ of 50 μM or better.
EXAMPLES Abbreviations
EtOAc: ethyl acetate DCM: dichloromethane
MeOH: methanol THF: tetrahydrofuran
MeCN: acetonitrile Et2O: diethyl ether DMF: iV,N-dimethylformamide DIPEA : ΛξJV-diisopropylethylamine
SiO2: silica brine: sat. aqueous sodium chloride solution sat: saturated r.t: room temperature RT: retention time h: hour br: broad M: mass
HPLC: High Performance Liquid Chromatography
LCMS: Liquid Chromatography Mass Spectrometry
ES+: Electrospray Positive Ionisation
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. Preparative HPLC methods
Method 1: Phenomenex Luna Cl 8(2) 250 x 21.2 mm, 5 μm column. Mobile phase A: 99.92% water, 0.08% formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid. Gradient program (flow rate 25.0 mL/min), column temperature: ambient, variable gradient.
Method 2: Phenomenex Luna Cl 8(2) 250 x 21.2 mm, 5 μm column. Mobile phase A: 10 mM ammonium acetate in water. Mobile phase B: 10 mM ammonium acetate in MeCN. Gradient program (flow rate 25.0 mL/min), column temperature: ambient, variable gradient.
Analytical LCMS method
Method 3: Phenomenex Luna Cl 8(2) 100 x 4.6 mm, 5 μm column. Mobile phase A: 99.92% water, 0.08% formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid. Gradient program (flow rate 3.0 mL/min, column temperature 35°C): Time A % B % 0.00 95.0 5.0 4.40 5.0 95.0 5.30 5.0 95.0 5.32 95.0 5.0
6.50 95.0 5.0
INTERMEDIATE 1
2-f6-Bromo-2.3-dihvdrobenzori,41oxazin-4-yl)-5.5-dimethyl-5,6-dihvdro-4H- benzothiazol-7-one
6-Bromo-3,3-dihydro-2/f-benzo[l,4]oxazine (WO 2008/001076, Intermediate 62) (2.0 g, 9.4 mmol) and l,l'-thiocarbonyldiimidazole (3.3 g, 18.8 mmol) were combined in THF (16 niL) and heated to 1250C under microwave irradiation for 15 minutes. The mixture was cooled to r.t., reduced in vacuo, and ammonia (50 mL of a 7N solution in methanol, 0.35 mol) was added. It was stirred for 2 h, then concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and 2N HCl (100 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with Et2O and heptane to give a yellow solid. Of this material, 0.5 g (1.8 mmol) was combined with 2-bromo-5,5-dimethyl- cyclohexane-l,3-dione (0.69 g, 3.1 mmol) and DIPEA (0.6 mL, 3.4 mmol) in THF (18 mL) and heated to 14O0C under microwave irradiation for 30 minutes. After cooling to r.t. the mixture was partitioned between EtOAc (130 mL) and water (130 mL). The combined organic phases were washed with water (150 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC {Method 1) to yield the title compound (166 mg, 23%) as an off- white solid. δH (CDCl3) 8.22 (d, J2.3 Hz, IH), 7.17 (dd, J 8.7, 2.3 Hz, IH), 6.84 (d, J 8.7 Hz, IH), 4.27-4.38 (m, 2H), 4.07-4.17 (m, 2H), 2.79 (s, 2H), 2.44 (s, 2H), 1.16 (s, 6H). LCMS (ES+) 393 (M+H)+, RT 4.4 minutes (Method 1).
INTERMEDIATE 2
2-[4-(4,4,5,5-Tetramethyl-ri,3,21dioxaborolan-2-vnpyrazol-l-yllethanol
4-Pyrazoleboronic acid pinacol ester (250 mg, 1.29 mmol), ethylene carbonate (125 mg, 1.42 mmol) and sodium hydroxide (5 mg, 0.13 mmol) were dissolved in DMF (1 mL) and the reaction mixture was heated to reflux for 2.5 h. It was cooled to r.t. before addition of activated charcoal (25 mg). The resulting suspension was stirred at r.t. for 1 h and then filtered through celite, washed with DMF (6 mL) and concentrated in vacuo to give the title compound (0.26g, 85%) as a yellow oil. LCMS (ES+) 239.18 (M+H)+.
INTERMEDIATE 3
2-{6-ri-(2-HvdroxyethvD-lH-Pyrazol-4-yl1-23-dihvdro-4H-1.4-benzoxazin-4-yli-5.5- dimethyl-5,6-dihydro- 1 ,3 -benzothiazol-7(4i/)-one
A mixture of Intermediate 1 (275 mg, 0.70 mmol), Intermediate 2 (0.25 g, 1.05 mmol), potassium acetate (82 mg, 0.84 mmol) and bis(tri-tert-butylphosphino)- palladium(O) (32 mg, 0.063 mmol) in DMF (2 mL) was heated to 14O0C under microwave irradiation for 1 h. After cooling to r.t. activated charcoal (25 mg) was added and the resulting suspension stirred for 2 h. It was filtered through celite, washed with DMF (3 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (Method 3) then dissolved in DCM (15 mL), washed with aqueous potassium carbonate solution (0.7M, 15 πiL) and the organic fraction was concentrated in vacuo to give the title compound (113 mg, 38%) as a pale yellow solid. δH (CDCl3) 7.99 (d, J 1.9 Hz5 IH), 7.74 (d, JO.ό Hz, IH), 7.64 (s, IH), 7.19 (dd, J8.5, 2.1 Hz, IH), 6.96 (d, J8.3 Hz, IH), 4.22- 4.36 (m, 6H), 4.02-4.08 (m, 2H), 3.06 (t, J 6.0 Hz, IH), 2.77 (s, 2H), 2.43 (s, 2H), 1.16 (s, 6H). LCMS (ES+) 425.17 (M+H)+, RT 3.1 minutes (Method 1).
INTERMEDIATE 4
2-[6-(l-Allyl-lH"-Pyrazol-4-ylV2.3-dihvdrobenzo[L41oxazin-4-yll-5,5-dimethyl-5.6- dihydro-4//-benzothiazol-7-one
A mixture of Intermediate 1 (1.1 g, 2.76 mmol), l-allyl-4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-lH-pyrazole (WO 2008/001076, Intermediate 130) (1.29 g, 5.53 mmol), tetrakis(triphenylphosphine)palladium(0) (661 mg, 0.55 mmol), potassium phosphate (1.76 g, 8.3 mmol) and tetra-72-butylammonium bromide (894 mg, 2.76 mmol) in TΗF (10 mL) and water (5 mL) was heated to 14O0C under microwave irradiation for 20 minutes. After cooling to r.t. the reaction mixture was concentrated in vacuo. Purification by column chromatography (SiO2, gradient elution 10-100% EtOAc in heptane) gave the title compound (400 mg, 34%) as a yellow oil. δΗ (CDCl3) 7.99 (d, J 1.9 Hz, IH), 7.73 (s, IH), 7.60 (s, IH), 7.20 (dd, J 8.5, 2.1 Hz, IH), 6.96 (d, J 8.5 Hz, IH), 5.98-6.16 (m, IH), 5.23-5.36 (m, 2H), 4.74-4.82 (m, 2H), 4.31-4.38 (m, 2H), 4.21- 4.27 (m, 2H), 2.77 (s, 2H), 2.43 (s, 2H), 1.16 (s, 6H).
INTERMEDIATE 5
2- (6-r 1 -(2,3 -Dihvdroxypropyiy IH-P yrazol-4- yl] -2,3 -dihydro-4H- 1 ,4-benzoxazin-4-vU - 5,5-dimethyl-5,6-dihydro-l,3-benzothiazol-7(4HVone
A mixture of Intermediate 4 (0.40 g, 0.95 mmol), osmium tetroxide (12 mg, 0.05 mmol), 4-methylmorpholine iV-oxide (134 mg, 1.14 mmol), acetone (10 mg, 0.2 mmol), tert-butanol (0.035 mL, 0.4 mmol) and water (1 mL) was stirred at r.t. overnight. Purification by preparative ΗPLC {Method 2) gave the title compound (116 mg, 22%) as a beige foam. δΗ (CDCl3) 8.00 (d, J2.1 Hz, IH), 7.75 (s, IH), 7.65 (s, IH), 7.19 (dd, J8.5, 2.1 Hz, IH), 6.97 (d, J 8.5 Hz, IH), 4.09-4.39 (m, 7H), 3.64-3.70 (m, 2H), 2.77 (s, 2H), 2.44 (s, 2H), 1.16 (s, 6H). LCMS (ES+) 455.3 (M+H)+, RT 2.96 minutes (Method 3). EXAMPLE 1
6-Hydroxy-5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l,3-benzothiazol-7(4i:f)-one A solution of 5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-l ,3-benzothiazol-
7(4H)-one (WO 2006/114606, Example 48) (578 mg, 2.17 mmol) in TΗF (25 mL) was cooled to -700C. A solution of sodium bis(trimethylsilyl)amide in TΗF (IN, 2.40 mL, 2.40 mmol) was added gradually and the reaction mixture was allowed to warm to O0C. The mixture was recooled to -7O0C before the addition of chlorotrimethylsilane (0.28 mL, 2.21 mmol), then allowed to warm to r.t. The solvent was removed in vacuo, then redissolved in DCM (15 mL). zn-Chloroperbenzoic acid (535 mg, 2.39 mmol) was added and the reaction mixture was stirred at r.t. for 2 h. The mixture was partitioned between sat. aqueous NaHCO3 solution (50 mL) and DCM (50 mL), and the aqueous phase reextracted with DCM (75 mL). The organic phase was washed with sat. aqueous NaHCO3 solution (150 mL), dried (MgSO4) and the solvent removed in vacuo. A sample of the crude product was purified by preparative HPLC (Method 1) to give the title compound (30 mg, 11%) as a white solid. δH (DMSO-d6) 5.24 (d, J4.3 Hz, IH), 3.91 (d, J4.3 Hz, IH), 3.67-3.74 (m, 4H), 3.52-3.58 (m, 4H), 2.64-2.79 (m, 2H), 1.09 (s, 3H), 0.85 (s, 3H). LCMS (ES+) 283.2 (M+H)+, RT 2.29 minutes (Method 3).
EXAMPLE 2
2-(6-Bromo-2,3-dihydro-4H'-l,4-benzoxazm-4-yl)-6-hydroxy-5,5-dimethyl-5,6-dihvdro- 1 ,3-benzothiazol-7(4ijr)-one The title compound was prepared in a similar manner to Example 1, using
Intermediate 1, and was obtained as a solid (15%) after purification by preparative HPLC (Method 1). δH (DMSO-d6) 8.47 (d, J2.3 Hz, IH), 7.16 (dd, J8.7, 2.3 Hz, IH), 6.86 (d, J 8.9 Hz, IH), 5.35 (d, J4.5 Hz, IH), 4.23-4.30 (m, 2H), 3.93-4.00 (m, 2H), 3.88-3.92 (m, IH), 2.69-2.85 (m, 2H), 1.04 (s, 3H)5 0.81 (s, 3H). LCMS (ES+) 411.0, 409.0 (M+H)+, RT 4.10 minutes (Method 3). EXAMPLE 3
6-Hydroxy-2-(6-[l-(2-hydroxyethyl')-lH-pyrazol-4-yll-2,3-dihydro-4i7-l,4-benzoxazin- 4-vU -5 ,5-dimethyl-5 ,6-dihvdro- 1 ,3 -benzothiazol-7(4H)- one The title compound was prepared in a similar manner to Example 1, using
Intermediate 3, and was obtained as a solid (31%) after stirring the crude product in a mixture of TΗF/aqueous HCl at 7O0C for 1 h, evaporation to dryness in vacuo and purification by preparative ΗPLC (Method 1). δΗ (CDCl3) 7.96 (d, J 2.1 Hz, IH), 7.74 (d, J0.8 Hz, IH), 7.65 (d, J0.6 Hz, IH), 7.27 (s, IH), 7.21 (dd, J8.5, 2.1 Hz, IH), 6.97 (d, J 8.5 Hz, IH), 4.26-4.42 (m, 5H), 4.18-4.24 (m, IH), 4.16 (s, IH), 4.01-4.08 (m, 2H), 2.87 (s, 2H), 1.32 (s, 3H), 0.94 (s, 3H). LCMS (ES+) 441.2 (M+H)+, RT 2.82 minutes (Method 3).
EXAMPLE 4
2- {6-[ 1 -(2,3 -Dihydroxyprop vD- lH-pyrazol-4- yl] -2,3 -dihydro-4Hr- 1 ,4-benzoxazin-4-yl} - 6-hydroxy-5,5-dimethyl-5,6-dmydro-l,3-benzomiazol-7(4//)-one
A mixture of Intermediate 5 (75 mg, 0.17 mmol) and 4-toluenesulfonic acid monohydrate (5 mg, 0.03 mmol) in acetone (3.0 mL) was heated at 1200C under microwave irradiation for 50 minutes. The reaction mixture was partitioned between
DCM and aqueous NaHCO3 solution and the organic phase was evaporated to dryness in vacuo to give 2-{6-[l-(2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-lif-pyrazol-4-yl]-2,3- dihydro-477-l,4-benzoxazin-4-yl}-5,5-dimethyl-5,6-dihydro-l,3-benzothiazol-7(4H)-one. The title compound was then prepared in a similar manner to Example 1, using 2-{6-[l- (2,2-dimethyl-[l ,3]dioxolan-4-ylmethyl)-lH-pyrazol-4-yl]-2,3-dihydro-4H-l ,4- benzoxazin-4-yl}-5,5-dimethyl-5,6-dihydro-l,3-benzothiazol-7(4/-/)-one, and was obtained as a solid (34%) after stirring the crude product in a mixture of TΗF/aqueous HCl at 6O0C for 17 h, evaporation to dryness in vacuo and purification by preparative ΗPLC (Method 1). δΗ (CDCl3) 7.97 (d, J 1.9 Hz, IH), 7.74 (s, IH), 7.65 (s, IH), 7.26 (s, 2H), 7.21 (dd, J8.5, 2.1 Hz, IH), 6.97 (d, J8.5 Hz, IH), 4.26-4.42 (m, 5H), 4.11-4.24 (m, 3H), 3.64-3.70 (m, 2H), 2.87 (s, 2H), 1.32 (s, 3H), 0.94 (s, 3H). LCMS (ES+) 471.1 (M+H)+, RT 2.63 minutes (Method 3). EXAMPLE 5
6-Hydroxy-5,5-dimethyl-2-(moφholm-4-yl)-5,6-dihydro-l-benzothiophen-7(4/-r)-one A solution of 5,5-dimethyl-2-(moφholin-4-yl)-5,6-dihydro-l-benzothiophen- 7(4H)-one (WO 2007/141504, Example 13) (1.0 g, 3.77 mmol) in THF (20 mL) was cooled to -6O0C. A solution of sodium bis(trimethylsilyl)amide in THF (IN, 4.1 mL, 4.1 mmol) was added gradually and the reaction mixture was allowed to warm to 00C. The mixture was recooled to -6O0C before the addition of chlorotrimethylsilane (0.48 mL, 3.78 mmol), then allowed to warm to r.t. and stirred for 1.5 h. The solvent was removed in vacuo, then redissolved in DCM (20 mL). m-Chloroperbenzoic acid (840 mg, 3.75 mmol) was added and the reaction mixture was stirred at r.t. for 1.5 h. The mixture was partitioned between sat. aqueous NaHCO3 solution (75 mL) and DCM (75 mL). The organic phase was washed with sat. aqueous NaHCO3 solution (2 x 75 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 2% MeOH in DCM) and a sample of this product was then further purified by preparative HPLC (Method 1) to give the title compound (27 mg, 13%) as a white solid. δH (DMSO-d6) 6.14 (s, IH), 5.03 (d, J4.0 Hz, IH), 3.89 (d, J4.0 Hz, IH), 3.68-3.75 (m, 4H), 3.23-3.29 (m, 4H), 2.58-2.72 (m, 2H), 1.08 (s, 3H), 0.81 (s, 3H). LCMS (ES+) 282.1 (M+H)+, RT 2.71 minutes (Method 3).

Claims

Claims:
1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000074_0001
(I)
wherein
X represents N or C-R5; R1 and R2 independently represent hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl-
(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;
R3 and R4 independently represent hydrogen; or Ci-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(C1-6)alkyl, aryl(C2-δ)alkenyl, aryl(C2-6)- alkynyl, biaryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(C1-6)alkyl or aryl-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 R3 and R4, when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
R5 represents hydrogen, halogen, cyano, -SRa, -CORe, -CO2Rb, -CONRcRd or -C(=N-ORf)Re; or R5 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkenylcarbonyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, C3-7 cycloalkyl(C2-6)alkenyl, C3-7 cycloalkyl- (C2-6)alkynyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, biaryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkyl(C2-6)alkenyl, C3-7 heterocycloalkyl(C2-6)alkynyl, C3-7 heterocycloalkylcarbonyl(C2-6)alkynyl, Cs-g heterobicycloalkyl(C2.6)alkynyl, C3-7 heterocycloalkyl-aryl, C3-7 heterocycloalkyl(C1-6)- alkyl-aryl, C3-7 heterocycloalkyl-biaryl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C1-6)- alkylcarbonyl, heteroaryl(C2-6)alkenyl, heteroaryl(C2-6)alkynyl, heteroaroylcarbonyl, C3-7 heterocycloalkyl-heteroaryl, C3-7 heterocycloalkyl-heteroaryl(C2-6)alkynyl, heteroaryl-aryl, heteroaryl-aryl(Ci-6)alkyl, aryl-heteroaryl, aryl-heteroaryl(C1-6)alkyl, C3-7 heterocycloalkyl-aryl-heteroaryl, C3-7 heterocycloalkyl(Ci-6)alkyl-aryl-heteroaryl, C5-9 heterobicycloalkyl(Ci-6)alkyl-aryl-heteroaryl, heteroaryl-aryl-heteroaryl, bi(heteroaryl), C3-7 heterocycloalkylcarbonyl-bi(heteroaryl), aryloxyaryl, aryl(C1-6)alkoxyaryl, heteroaryl(Ci-6)alkoxyaryl, aryl(C1-6)alkylaminoaryl, heteroaryl(C1-6)alkylaminoaryl, C3-7 cycloalkylcarbonylaminoaryl, arylcarbonylaminoaryl, aryl(Ci-6)alkylcarbonylaminoaryl, C3-7 heterocycloalkylcarbonylaminoaryl, heteroarylcarbonylaminoaryl, aryl-
(C3-7)heterocycloalkylcarbonylaminoaryl, arylsulphonylaminoaryl, aryl(C1.6)alkyl- sulphonylaminoaryl, heteroaryl(C1-6)alkylsulphonylaminoaryl, C3-7 cycloalkylamino- carbonylaminoaryl, arylaminocarbonylaminoaryl, C3-7 heterocycloalkylaminocarbonyl- aminoaryl, C3-7 heterocycloalkylaminocarbonylaminoaryl, heteroaryl(C1-6)alkyl- aminocarbonylaminoaryl, C3-7 heterocycloalkylcarbonylcarbonylaminoaryl, C3-7 heterocycloalkyl(Ci-6)alkylaminocarbonylcarbonylaminoaryl, arylcarbonylaryl, C3-7 heterocycloalkylcarbonylaryl, C3-7 heterocycloalkylcarbonyl(C1-6)alkylaryl, aryl(C1-6)- alkylaminocarbonylaryl, C3-7 heterocycloalkyl(Ci.6)alkylaminocarbonylaryl, heteroaryl- aminocarbonylaryl, heteroaryl(Ci-6)alkylaminocarbonylaryl, C3-7 heterocycloalkylamino- carbonyl(Ci-6)alkylaryl, C3-7 heterocycloalkyl(C1-6)alkylaminocarbonyl(C1-6)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 cycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- carbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl(C1-6)alkylcarbonyl-aryl-heteroaryl, C5-Q heterobicycloalkylcarbonyl-aryl-heteroaryl, C3-7 heterocycloalkylcarbonyl(C1-6)alkyl-aryl- heteroaryl, C3-7 heterocycloalkyl-aminocarbonyl-aryl-heteroaryl, C3-7 heterocycloalkyl- (Ci-6)alkylaminocarbonyl-aryl-heteroaryl or C3-7 heterocycloalkylaminocarbonyl(C I-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; R 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 C1-6 alkyl; Re represents Ci-6 alkyl; and
Rf represents C1-6 alkyl, aryl, aryl(C1-6)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 (HA), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000076_0001
(DA) wherein
X1 represents N or CH;
R11 represents hydrogen or C1-6 alkyl; and
R12 represents hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci.6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R1 and R 2, when taken together with the carbon atom to which they are both attached, represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups maybe optionally substituted by one or more substituents; and
R13 represents hydrogen; or Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, biaryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl-aryl(C1-6)alkyl or aryl-heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
3. A compound as claimed in claim 2 represented by formula (HB), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000077_0001
(IIB)
wherein
R1 ' and R12 are as defined in claim 2;
T represents oxygen or N-R 25. R23 represents hydrogen, halogen, cyano, nitro, C1-6 alkyl, hydroxy(C1-6)alkyl, trifluoromethyl, aryl(Ci-6)alkyl, oxazolinyl, triazolyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(C[-6)alkoxy, morpholinyl(Ci-6)alkoxy, aryloxy, aryl(C1-6)alkoxy, C1-6 alkylthio, C1-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, C1-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(C1-6)alkyl]amino, C1-6 alkylsulphonylamino, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl O(methyl)oxime, trifiuoromethylcarbonyl, carboxy, C2.6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, [hydroxy(C1-6)- alkyl]aminocarbonyl, [di(C1-6)alkylamino(Ci.6)alkyl] aminocarbonyl, di(Ci-6)alkyl- aminocarbonyl, [(Ci-6)alkyl][cyano(C1-6)alkyl]aminocarbonyl, [(C1-6)alkyl][hydroxy(C1-6)- alkyl] aminocarbonyl, [(Ci-6)alkoxy(C1-6)alkyl][(Ci-6)alkyl]aminocarbonyl, [di(C1-6)alkyl- amino(Ci-6)alkyl][(Ci-6)alkyl]aminocarbonyl, C3-7 cycloalkyl(C1-6)alkylaminocarbonyl, aryl(C1-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(Ci-6)alkylamino- carbonyl, azetidinyl carbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, (C1.6)alkylpyrrolidinyl- carbonyl, C1-6 alkoxy(Ci-6)alkylpyrrolidinylcarbonyl, di(Ci-6)alkylaminopyrrolidinyl- carbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinyl carbonyl, (C1-6)- alkylpiperazinylcarbonyl, morpholinylcarbonyl, C1-6 alkylsulphonyl, C1-6 alkylsulphonyl- methyl or di(Ci-6)alkylaminosulphonyl; and
R24 represents hydrogen, halogen, Ci-6 alkoxy or di(Ci-6)alkylaminocarbonyl; or R23 and R24, when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and
R25 represents hydrogen or Ci-6 alkyl.
4. A compound as claimed in claim 2 represented by formula (IIC), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000079_0001
(HC)
wherein
R11 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 substituents; and
R34 represents methylenedioxyphenyl, morpholinyl(C1-6)alkylphenyl, oxazolinyl- phenyl, [(C1-6)alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl,
Figure imgf000079_0002
(Ci-6)alkylpyrimidinylphenyl, pyrazolyl(Ci-6)alkyl- phenyl, MaZoIyI(C1 -6)alkylphenyl, C1-6 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, (Cμ6)alkylindazolyl, benzoxazolyl, benzoxazolonyl, di(Ci-6)alkylisoxazolyl, benzothiazolyl, (Ci-6)alkylisothiazolyl, (C1-6)alkylbenzimidazolyl, benzimidazolonyl, di(Ci-6)alkylbenzimidazolonyl,
Figure imgf000079_0003
furyloxadiazolyl, pyridinyl, halopyridinyl, (Ci_6)alkylpyridinyl, di(Ci-6)alkylpyridinyl, (C1-6)alkoxypyridinyl, oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl, [(C1-6)alkoxy](halo)pyridazinyl, (Ci-6)alkylcinnolinyl, quinoxalinyl or (Ci-6)alkylchromenyl.
5. A compound as claimed in claim 1 represented by formula (IID-1) or (IID-2), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000080_0001
wherein
R11 and R12 are as defined in claim 2; R43 represents hydrogen, halogen, nitro, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl,
(Ci-6)alkylaryl, di(C1.6)alkylaryl, piperidinyl(C1-6)alkylaryl, piperazinyl(C1-6)alkylaryl, (C(-6)alkylpiperazinyl(C i-6)alkylaryl, moφholinyl(Ci-6)alkylaryl, (Q^alkoxyaryl, cyano(C]-6)alkoxyaryl, di(C1-6)alkylamino(Ci-6)alkylaryl, (Cj.6)alkylaminocarbonylaryl, aryl(C1-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (C].6)alkylaminocarbonylpiperidinyl, piperazinyl, (C1-6)alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (C1-6)alkyl- homopiperazinyl, (C1-6)alkylpiperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (C1-6)alkylpyrazolyl, di(Ci-6)alkylpyrazolyl, tri(C[-6)alkyl- pyrazolyl, (difluoromethyl)pyrazolyl, [di(C1-6)alkyl](trifluoromethyl)pyrazolyl, cyano(C1-6)alkylpyrazolyl, [cyano(Ci.6)alkyl][di(C1-6)alkyl]pyrazolyl, hydroxy(C1-6)alkyl- pyrazolyl, [hydroxy(C1-6)alkyl][di(Ci-6)alkyl]pyrazolyl, methoxy(C1-6)alkylpyrazolyl, [dihydroxy(C1-6)alkyl]pyrazolyl, [(hydroxy)(methoxy)(Ci-6)alkyl]pyrazolyl, amino(Ci-6)- alkylpyrazolyl, [(C1-6)alkyl][amino(Ci-6)alkyl]pyrazolyl, [amino(C1-6)alkyl][di(C1-6)alkyl]- pyrazolyl, di(Ci-6)alkylamino(C1-6)alkylρyrazolyl, di(C1-6)alkoxyphosρhono(Ci-6)alkyl- pyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl(Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl- (Ci.6)alkyl][di(C1-6)alkyl]pyrazolyl, [(C1.6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)- pyrazolyl, aryl(Ci-6)alkylpyrazolyl, aminoaryl(C1-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydroρyranyl(C1-6)alkylpyrazolyl, [di(C1-6)alkyl][tetrahydropyranyl(Ci-6)alkyl]- pyrazolyl, pyrrolidiny^Cμ^alkylpyrazolyl, piperidinyl(Ci-6)alkylpyrazolyl, (Ci-6)alkyl- piperidinyl(C1-6)alkylpyrazolyl, morpholinyl(Ci-6)alkylpyrazolyl, ρyridinyl(Ci.6)alkyl- pyrazolyl, oxypyridinyl(C1-6)alkylpyrazolyl, [arylcarbonyl(C1-6)alkyl][di(C1-6)alkyl]- pyrazolyl, [(C 1-6)alkyl] (piρerazinylcarbonyl)pyrazolyl, [(C I-6)alkylaminocarbonyl] [(C i -6)- alkylaryljpyrazolyl, [(C1-6)alkyl][amino(C1-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl, [aminocarbonyl(C1-6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(C1-6)alkylaminocarbonyl(C1-6)alkylpyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1-6)alkyl- isoxazolyl, (amino)[(C1-6)alkyl]isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (C[-6)alkylimidazolyl, di(C1-6)alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkyl- imidazo[ 1 ,2-α]pyridinyl, (Ci-6)alkylimidazo[4,5-b]pyridinyl, imidazo[l ,2-fl]pyrimidinyl, imidazo[l,2-α]pyrazinyl,
Figure imgf000081_0001
pyridinyl, halopyridinyl, (Ci-6)alkyl- pyridinyl, [(C1-6)alkyl](halo)pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenylρyridinyl,
(Ci.6)alkylpiperazinylpyridinyl, [(C1-6)alkyl](piperazinyl)pyridinyl, [(C1-6)alkoxycarbonyl- piperazinyl][(C1-6)alkyl]pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(Ci^)alkyl]- (oxy)pyridinyl, hydroxypyridinyl, hydroxy(C1-6)alkylpyridinyl, (C1-6)alkoxypyridinyl, [(C1-6)alkoxy][(Ci-6)alkyl]pyridinyl, [(Ci-6)alkoxy][di(C1-6)alkyl]pyridinyl, (C1-6)alkoxy(C1-6)alkylpyridinyl, aminopyridinyl, carboxy(C1-6)alkylpyridinyl, (Ci-^alkoxycarbony^Cμ^alkylpyridinyl, pyridazinyl, (C1-6)alkylρyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Ci-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(C1-6)alkylaminopyridazinyl, di(Ci-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(C1-6)alkyl](halo)ρyrimidinyl, di(Ci-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (Ci.6)alkylpiperazinylpyrimidinyl, [(C1-6)alkyl](piperazinyl)- pyrimidinyl, [(Ci-6)alkoxycarbonyl][(C1-6)alkyl]piperazinylpyrimidinyl, hydroxypyriniidinyl, [(C1-6)alkyl](hydroxy)pyrimidinyl, [(C1-6)alkyl][hydroxy(C1-6)alkyl]- pyrimidinyl, [(C1-6)alkyl][hydroxy(C2-6)alkynyl]pyrimidinyl, (C^alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminopyrimidinyl, [di(Ci-6)alkylamino](halo)pyrimidinyl, carboxypyrimidinyl, [(Ci.6)alkoxycarbonyl(Ci.6)alkyl][(Ci-6)alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci.6)alkoxypyrazinyl, aminopyrazinyl, hydroxy, (Ci-6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy, morρholinyl(C1-6)alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (Ci-6)alkylpiperazinylpyridinyloxy, (Ci-6)alkylpyrazolylpyridinyloxy, (C i -6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, pyridazinyloxy, (C1-6)alkylpyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C]-6)alkyl](halo)pyrimidinyloxy, hydroxy(Ci-6)alkyl, dihydroxy(C1-6)alkyl, pyiidinyloxy(C1-6)alkyl, amino, (C1-6)alkylamino, dihydroxy(C1-6)alkylamino, (C1-6)- alkoxy(C1-6)alkylamino, iV-[(C1-6)alkoxy(C1-6)alkyl]-N-[(Ci-6)alkyl]amino, di(C1-6)- alkylamino(C1-6)alkylamino, N-[(C1-6)alkyl]-N-[di(C1-6)alkylamino(Ci-6)alkyl]aniino, N- [(C1-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, N-[(C1-6)alkyl]-N-[aryl(C1-6)alkyl]amino, N-[di(C1.6)aIkylamino(Ci-6)alkyl]-N-[aryl(Ci-6)- alkyl]amino, cyanoaryl(C1-6)alkylamino, (cyano)(halo)aryl(Ci-6)alkylamino, methylene- dioxyaryl(C1-6)alkylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkylpyrrolidinyl]amino, piperidinyl- amino, N-[(C1-6)alkyl]-N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(Ci-6)alkyl]-iV- (piperidinyl)amino, (C1-6)alkylpiperidinylamino, N-[(C1-6)alkyl]-N-[(Ci-6)alkyl- piperidinyl] amino, N-[(C1-6)alkyl]-iV-[(C3-7)cycloalkylpiperidmyl]amino, N-[(Ci-6)alkyl]- N-[(C2-6)alkylcarbonylpiperidinyl]amino, pynOlidinyl(Ci-6)alkylamino, N-[(Ct.6)alkyl]-N- [pyrrolidinyl(C1-6)alkyl]amino, N-[(Ci-6)alkyl]-N-[piperidinyl(Ci-6)alkyl]amino, (C1-6)- alkylpyrazolylamino, di(C1-6)alkylpyrazolylamino, tri(C1-6)alkylpyrazolylamino, N-[(C1-6)- alkyl]-N-[(C1-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(C1-6)alkoxy- carbonyl][(C1.6)alkyl]imidazolylamino, (C1-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (C1-6)alkylpyridinylamino, di(C1-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C [ -6)alkylpyridinyl amino, dihydroxy(C1-6)alkylpyridinylamino, (C1-6)alkoxypyridinylamino, dihydroxy(C1-6)alkoxy- pyridinylamino, di(C1-6)alkyldioxolanyl(C1.6)alkoxypyridinylamino, (C1-6)alkoxy(Cμ6)- alkylpyridinylamino, (C1-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(Ci-6)alkyl- aminopyridinylamino, di(C1-6)alkylaminopyridinylamino, (Ci-6)alkylamino(C1-6)alkyl- pyridinylamino, di(Ci-6)alkylamino(C1-6)alkylpyridinylamino, carboxypyridinylamino, N- [(C1-6)alkyl]-N-[(C1-6)alkylpyridinyl]amino, bis[(Ci-6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (C1-6)alkylpyridazinylamino, N-[(C1-6)alkyl]- N-[(C i -6)alkylpyridazinyl] amino, N- [aryl(C i -6)alkyl] -N- [(C 1-6)alkylpyridazinyl] amino, di(Ci-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C I-6)- alkoxypyridazinylamino, di(C1-6)alkylaminopyridazinylamino, bis[(Ci-6)alkylpyridazinyl]- amino, benzofuryl(Ci-6)alkylamino, thienyl(Ci-6)alkylamino, indolyl(Ci-6)alkylamino, (C 1-6)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(C i-6)alkylamino, imidazolyl(C i -6)alkyl- amino, (C1-6)alkylimidazolyl(C1-6)alkylamino, pyridinyl(C1-6)alkylamino, (Ci-6)alkyl- pyridinyl(C i -6)alkylamino, N- [(C i -6)alkyl] -N- [pyridinyl(C i -6)alkyl] amino, N- [dihydroxy- (Ci-6)alkyl]-N-[pyridinyl(C1-6)alkyl]amino, iV-[(C1-6)alkylpyridinyl(Ci-6)alkyl]-N- [dihydroxy(C1-6)alkyl]amino, amino(C1-6)alkyl, (C1-6)alkylamino(C1-6)alkyl, di(C1-6)alkyl- amino(C1-6)alkyl, pyridinylamino(C1-6)alkyl, N-[(C2-6)alkylcarbonyl]-iV-[(C1-6)alkyl- pyridinyl(C1-6)alkyl]amino, di(C1-6)alkylamino(C1-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (C1-6)alkylpiperidinylcarbonylamino, (Ci-6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (C1-6)alkylpiperidinylaminocarbonyl, N- [(C1 -6)alkyl]-iV- [(C1-6)- alkylpiperidinyljaminocarbonyl, piperidinyl(C1-6)alkylaminocarbonyl, (C1-6)alkyl- piperazinylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy and tetra(Ci-6)alkyldioxaborolanyl; and
R44 represents hydrogen, halogen, Ci-6 alkyl or C1-6 alkoxy.
6. A compound as claimed in claim 1 represented by formula (HE), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000083_0001
(HE)
wherein
R is as defined in claim 1 ; and
R11 and R12 are as defined in claim 2.
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 PBK 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 PBK inhibitor is indicated.
12. A method for the treatment and/or prevention of a disorder for which the administration of a selective PBK 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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