WO2009071888A1 - Pyrrolothiazoles as pi3-kinase inhibitors - Google Patents

Pyrrolothiazoles as pi3-kinase inhibitors Download PDF

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Publication number
WO2009071888A1
WO2009071888A1 PCT/GB2008/004000 GB2008004000W WO2009071888A1 WO 2009071888 A1 WO2009071888 A1 WO 2009071888A1 GB 2008004000 W GB2008004000 W GB 2008004000W WO 2009071888 A1 WO2009071888 A1 WO 2009071888A1
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alkyl
amino
alkylamino
methyl
pyrazolyl
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PCT/GB2008/004000
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French (fr)
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Julien Alistair Brown
Benjamin Charles De Candole
Trevor Morgan
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Ucb Pharma S.A.
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Publication of WO2009071888A1 publication Critical patent/WO2009071888A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of fused thiazole derivatives, and to their use in therapy. More particularly, the invention provides a family of 4,5-dihydro-6//- pyrrolo[3,4-i/][l,3]thiazol-6-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety. These compounds are selective inhibitors of phosphoinositide 3 -kinase (PI3K) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • PI3K phosphoinositide 3 -kinase
  • PI3K pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases.
  • PI3Ks provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite oufgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sd., 2003, 24, 366-376).
  • Aberrant upregulation of the PI3K pathway is implicated in a wide variety of human cancers (cf. S. Brader & S. A. Eccles, Tumori, 2004, 90, 2-8).
  • the compounds in accordance with the present invention are therefore beneficial in the treatment and/or prevention of various human ailments.
  • autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g.
  • neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; pain and nociceptive disorders; and ophthalmic disorders including age- related macular degeneration (ARMD).
  • age- related macular degeneration AMD
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting compounds capable of binding to human PI3K enzymes.
  • WO 2006/114606 describes a class of fused bicyclic thiazole derivatives which are selective inhibitors of PB kinase enzymes and are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • a related series of compounds is described in copending international patent application no. PCT/GB2007/002390, published on 3 January 2008 as WO 2008/001076.
  • the compounds in accordance with the present invention are potent and selective PI3K inhibitors having a binding affinity (IC 50 ) for the human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ isoform of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
  • IC 50 binding affinity for the human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ isoform of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of
  • the compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50- fold selective affinity, and ideally at least a 100-fold selective affinity, for the human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ isoform relative to other human kinases.
  • the compounds of the present invention possess interesting pharmacokinetic properties, including good oral exposure and low in vitro clearance.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • X represents oxygen or sulphur;
  • R and R independently represent hydrogen, hydroxy or amino; or Ci -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(Ci -6 )alkylamino, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C ⁇ -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 1 and R 2 may together form an isopropylidene moiety; or
  • R 1 and R 2 when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents;
  • R 3 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(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci -6 )alkyl, heteroaryl-aryl(C 1-6 )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
  • R and R when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
  • R 5 represents hydrogen or Ci -6 alkyl.
  • 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 Cj -4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci -6 alkoxy", “Ci -6 alkylthio", "Ci -6 alkylsulphonyl” and "Ci -6 alkylamino" are to be construed accordingly.
  • a specific C 2-6 alkynyl group is prop-2-yn-l-yl.
  • C 3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci -6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • aryl(C 2-6 )alkenyl groups include 2-phenylethenyl and 3-phenylprop-2-en- 1-yl.
  • a specific aryl(C 2-6 )alkynyl group is 3-phenylprop-2-yn-l-yl.
  • biaryl groups include biphenyl and naphthylphenyl.
  • Suitable heterocycloalkyl groups which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-&]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolyl, pyrazolo[l,5- ⁇ ]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2- ⁇ ]pyridinyl, imidazo[4,5-6]pyridinyl, imidazo[ 1 ,2- ⁇ ]pyrimidinyl, imidazo[ 1 ,2- ⁇ ]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetra
  • 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.
  • X represents oxygen.
  • X represents sulphur.
  • 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 C 1-6 alkyl. In one aspect of that embodiment, R 1 is methyl. In another aspect of that embodiment, R 1 is ethyl.
  • R 2 represents hydrogen; or Ci -6 alkyl, Ci -6 alkoxy, C 3-7 cycloalkyl or aryl, . any of which groups may be optionally substituted by one or more substituents.
  • R 1 and/or R 2 examples include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifiuoromethoxy, aryloxy, C 1-6 alkylthio, Ci -6 alkylsulphonyl, amino, C 1-6 alkylamino, di(Ci -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(Ci -6 )alkylaminocarbonyl, aminosulphonyl, Ci -6 alkylaminosulphonyl and di(C i -6 )alkylaminosulphonyl; especially
  • R 1 and/or R 2 examples include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifiuoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
  • R 2 examples include hydrogen, methyl, ethoxy, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl. A particular value of R 2 is methyl. In another embodiment, R 1 and R 2 may together form an isopropylidene moiety
  • R 1 and R 2 may together form an optionally substituted spiro linkage.
  • R 1 and R 2 when taken together with the carbon atom to which they are both attached, may represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 1 and R 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 3 represents hydrogen; or Ci -6 alkyl, aryl, aryl(Ci.6)alkyl, aryl- (C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heter ⁇ cycloalkyl- carbonyl, heteroaryl(Ci -6 )alkyl, heteroaryl-aryl(Ci -6 )alkyl or aryl-heteroaryl(Ci. 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents hydrogen; or C 2-6 alkynyl, aryl(C 1-6 )alkyl or heteroaryl-
  • R 3 represents aryl(C i ⁇ alkyl or heteroaryl(Ci- 6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 3 represents hydrogen. 0
  • R 3 represents C 1-6 alkyl, aryl(Ci -6 )alkyl, biaryl-
  • 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 5 represents arylmethyl or heteroarylmethyl, either of which groups may be optionally substituted by one or more substituents.
  • R 3 represents substituted or unsubstituted indolyl- (Ci -6 )alkyl.
  • R 3 represents substituted or unsubstituted indolylmethyl.
  • R 3 represents substituted or unsubstituted phenyl-0 (Ci -6 )alkyl.
  • R 3 represents substituted or unsubstituted benzyl.
  • R 3 represents substituted or unsubstituted benzofuryl- (Ci -6 )alkyl.
  • R 3 represents substituted or unsubstituted benzofurylmethyl.
  • R 3 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, 5 indolinylmethyl, 1,2,3,4-tetrahydroquinolinylmethyl, 1,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3 ,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-6]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazolylmethyl
  • R 4 represents hydrogen or optionally substituted Ci -6 alkyl.
  • substituents on R 3 and/or R 4 include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (C 1-6 )alkylaryl, di(C 1 .
  • R 3 and/or R 4 include Ci -6 alkyl, (Ci -6 )alkylimidazolyl, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylaminocarbonyl, di(C 1 -6 )alkylaminocarbonyl, [(C 1 -6 )alkoxy] [(C 1 -6 )alkyl] aminocarbonyl, [(C 1 -6 )alkoxy(C 1 -6 )- alkyl][(Ci -6 )alkyl]aminocarbonyl, C 3-7 cycloalkylaminocarbonyl, C 3-7 cycloalkyl- (C 1-6 )alkylaminocarbonyl, iV-[(Ci- 6 )alkyl]-iV " -(aryl)aminocarbonyl, aryl(C 1-6 )alkylamino- carbonyl, hydroxyazetidin
  • R 3 and/or R 4 include C 1-6 alkyl, C 2-6 alkoxycarbonyl 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, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, mo ⁇ holinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoind
  • (methoxy)propyl]pyrazolyl aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (phenyl)(trifluoromethyl)pyrazolyl, benzylpyrazolyl, aminobenzylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranylmethylpyrazolyl, (dimethyl)(tetrahydropyranyl- methyl)pyrazolyl, pyrrolidinylethyl
  • Additional examples include (methoxy)(methyl)aminocarbonyl, cyclopropylaminocarbonyl, iV-(methyl)-N-(phenyl)aminocarbonyl, hydroxypyrrolidinylcarbonyl and methylsulphonylpiperazinylcarbonyl.
  • R 3 and/or R 4 include methyl, methylimidazolyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethyl- aminocarbonyl, diethylaminocarbonyl, (methoxy)(methyl)aminocarbonyl, 7V-(methoxy- ethyl)-iV-methylaminocarbonyl, cyclopropylaminocarbonyl, cyclopropylmethylamino- carbonyl, N-(methyl)-iV-(phenyl)aminocarbonyl, benzylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl, methylsulphonylpiperazinylcarbonyl and morpholinylcarbonyl.
  • R 3 and/or R 4 include methyl, methoxycarbonyl and dimethylaminocarbonyl.
  • Typical values of R 3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-iV-phenylaminomethyl, pyridinylamino- methyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyl- methylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolyl- phenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltri
  • Additional values include methylimidazolylindolylmethyl, (methyl)(methylimidazolyl)indolylmethyl, (aminocarbonyl)(methyl)indolylmethyl, (methyl)(methylaminocarbonyl)indolylmethyl, (diethylaminocarbonyl)(methyl)indolylmethyl, [(methoxy)(methyl)aminocarbonyl]- (methyl)indolylmethyl, (cyclopropylaminocarbonyl)(methyl)indolylmethyl,
  • R 3 Definitive values of R 3 include indolylmethyl, methylimidazolylindolylmethyl, (methyl)(methylimidazolyl)indolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, (aminocarbonyl)(methyl)indolylmethyl, (methyl)(methylaminocarbonyl)indolylmethyl, (dimethylaminocarbonyl)(methyl)indolylmethyl, (diethylaminocarbonyl)(methyl)indolyl- methyl, [(methoxy)(methyl)aminocarbonyl](methyl)indolylmethyl, [N-(methoxyethyl)-N- methylaminocarbonyl](methyl)indolylmethyl, (cyclopropylaminocarbonyl)(methyl)- indolylmethyl, (cyclopropylaminocarbony ⁇ ethyOindolylmethyl, (methyl)
  • R 3 Selected values of R 3 include indolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl and (dimethylaminocarbonyl)(methyl)indolylmethyl.
  • a particular value of R 3 is indolylmethyl.
  • R 4 Typical values of R 4 include hydrogen and methyl. In a preferred embodiment, R 4 is hydrogen. In another embodiment, R 4 is Cj -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, substiruents.
  • 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, substiruents.
  • 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, substiruents.
  • R 3 and R 4 when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e.
  • indanyl moiety fused to the morpholine ring which indanyl moiety may be unsubstituted, or substituted by one or more, typically by one or two, substiruents.
  • typical substiruents on the fused rings referred to in the preceding paragraph include halogen, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (C 1-6 )alkylaryl, di(C i -6 )alkylaryl, piperidinyl(C i ⁇ alkylaryl, piperazinyl(C ⁇ -6 )alkylaryl, (Ci -6 )aIkyIpiperazinyl(Ci -6 )alkylaryl, morpholinyl(C 1-6 )alkylaryl, (Ci -6 )alkoxyaryl, cyano(C i - 6 )alkoxyaryl, di(C i -6 )alkyl
  • substituents on the fused rings referred to in the three preceding paragraphs include bromo, nitro, methyl, n-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazin
  • R 11 represents hydrogen or Ci -6 alkyl
  • R 12 represents hydrogen; or C 1-6 alkyl, C 1-6 alkoxy, 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(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R and R may together form an isopropylidene moiety; 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; and
  • R 13 represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, 8TyI(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.
  • 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.
  • R 11 Typical values include hydrogen, methyl and ethyl, hi one embodiment, R ⁇ 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.
  • R 12 examples include halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci -6 alkyl thio, Ci -6 alkylsulphonyl, amino, Ci -6 alkylamino, di(Ci- 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, Ci -6 alkylaminocarbonyl, di(Ci -6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl and di(Ci -6 )alkylaminosulphonyl; especially halogen, Ci -6
  • R 12 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 i2 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl.
  • a particular value of R 12 is methyl.
  • R 1 ' and R 12 may together form an optionally substituted spiro linkage.
  • R 1 ' and R 12 when taken together with the carbon atom to which they are both attached, may represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents.
  • R 1 ' and R 12 when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
  • R 13 represents hydrogen; or C 1-6 alkyl, aryl(Ci. 6 )alkyl, aryl(C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl(C i -6 )alkyl, heteroaryl-aryl(C i -6 )alkyl or aryl-heteroaryl(C i -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 13 represents hydrogen; or C 2-6 alkynyl, aryl(Ci -6 )alkyl or heteroaryl- (Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R 13 represents aryl(C[. 6 )alkyl or heteroaryl(Ci -6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 13 represents hydrogen
  • R 13 represents Ci -6 alkyl, aryl(Ci -6 )alkyl, biaryl- (Ci -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 1 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 may be 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 1 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, indoli ⁇ ylmethyl, 1 ,2,3,4-tetrahydroquinolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4-
  • R 13 examples include halogen, cyano, nitro, Ci -6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, diCd- ⁇ alkylaryl, piperidinyl- (Ci- 6 )alkylaryl, piperazinyl(C 1-6 )alkylaryl, (Ci -6 )alkylpiperazinyl(C 1-6 )alkylaryl, morpholinyl(C 1-6 )alkylaryl, (C 1-6 )alkoxyaryl, cyano(C 1-6 )alkoxyaryl, di(Ci.
  • Additional examples include [(Ci -6 )alkoxy][(Ci -6 )- alkyl] aminocarbonyl, C 3-7 cycloalkylaminocarbonyl, iV-[(Ci -6 )alkyl]-iV-(aryl)amino- carbonyl, hydroxypyrrolidinylcarbonyl and (Ci- ⁇ alkylsulphonylpiperazinylcarbonyl.
  • R 13 Definitive examples of typical substituents on R 13 include Ci -6 alkyl, (Ci -6 )alkylimidazolyl, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylaminocarbonyl, di(C i -6 )alkylaminocarbonyl, [(C i -6 )alkoxy] [(C i -6 )alkyl] aminocarbonyl, [(C i -6 )alkoxy(C i -6 )- alkyl][(Ci -6 )alkyl]aminocarbonyl, C 3-7 cycloalkylaminocarbonyl, C 3-7 cycloalkyl- (C i -6 )alkylaminocarbonyl, N-[(C ⁇ -6 )alkyl]-N-(aryl)aminocarbonyl, aryl(Ci . ⁇ alkylaminocarbonyl, hydroxyazetidin
  • R 13 Particular examples of typical substituents on R 13 include C ⁇ 6 alkyl, C 2-6 alkoxycarbonyl and di(Ci -6 )alkylaminocarbonyl.
  • R 13 Selected examples of specific substituents on R 13 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidin
  • Additional examples include (methoxy)(methyl)aminocarbonyl, cyclopropylaminocarbonyl, ⁇ /-(methyl)-iV-(phenyl)aminocarbonyl, hydroxypyrrolidinylcarbonyl and methylsulphonylpiperazinylcarbonyl.
  • R 13 Definitive examples of specific substituents on R 13 include methyl, methylimidazolyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethyl- aminocarbonyl, diethylaminocarbonyl, (methoxy)(methyl)aminocarbonyl, N-(methoxy- ethyl)-iV-methylaminocarbonyl, cyclopropylaminocarbonyl, cyclopropylmethylaminocarbonyl, N-(methyl)-N-(phenyl)aminocarbonyl, benzylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl, methylsulphonylpiperazinylcarbonyl and morphollnylcarbonyl .
  • R 13 Particular examples of specific substituents on R 13 include methyl, methoxycarbonyl and dimethylaminocarbonyl.
  • Typical values of R 3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-jV-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienylmethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isox
  • Additional values include methylimidazolylindolylmethyl, (methyl)(methylimidazolyl)indolylmethyl, (aminocarbonyl)(methyl)indolylniethyl, (methyl)(methylaminocarbonyl)indolylmethyl, (diethylaminocarbonyl)(methyl)indolylmethyl, [(methoxy)(methyl)aminocarbonyl]- (methyl)indolylmethyl, (cyclopropylaminocarbonyl)(methyl)indolylmethyl,
  • R 13 Definitive values of R 13 include indolylmethyl, methylimidazolylindolylmethyl, (methyl)(methylimidazolyl)indolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, (aminocarbonyl)(methyl)indolylmethyl, (methyl)(methylaminocarbonyl)indolylmethyl, (dimethylaminocarbonyl)(methyl)indolylmethyl, (diethylaminocarbonyl)(methyl)indolyl- methyl, [(methoxy)(methyl)aminocarbonyl](methyl)indolylmethyl, [iV-(methoxyethyl)-iV- methylaminocarbonyl](methyl)indolylmethyl, (cyclopropylaminocarbonyl)(methyl)- indolylmethyl, (cycIopropylmemylaminocarbonylXmethyty
  • R 13 Selected values of R 13 include indolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl and (dimethylaminocarbonyl)(methyl)indolylmethyl.
  • a particular value of R 13 is indolylmethyl.
  • R 11 and R 12 are as defined above; T represents oxygen or N-R 25 ;
  • R represents hydrogen, halogen, cyano, nitro, C 1-6 alkyl, hydroxy(C 1-6 )alkyl, trifluoromethyl, aryl(C 1-6 )alkyl, oxazolinyl, imidazolyl, (C 1-6 )alkylimidazolyl, triazolyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkyl(C 1-6 )alkoxy, morphoIinyl(C 1-6 )alkoxy, aryloxy, aryl(Ci- 6 )alkoxy, C 1-6 alkylthio, Cj- 6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, C 1-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C 2-6 alkylcarbon
  • R 24 represents hydrogen, halogen, Cj -6 alkoxy or di(C 1-6 )alkylaminocarbonyl; or
  • R 2 and R 24 when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy;
  • R 25 represents hydrogen or Cj -6 alkyl.
  • the present invention also provides a compound of formula (HB) as depicted above, or a pharmaceutically acceptable salt or solvate thereof, wherein
  • R represents hydrogen, halogen, cyano, nitro, C 1-6 alkyl, hydroxy(C 1-6 )aUcyl, trifluoromethyl, aryl(Ci -6 )alkyl, oxazolinyl, triazolyl, hydroxy, Ci -6 alkoxy, difluoromethoxy, trifluoromethoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkyl(Ci -6 )alkoxy, morpholinyl(Ci -6 )alkoxy, aryloxy, -UyI(C 1 ⁇ alkoxy, C 1-6 alkylthio, Ci -6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, Ci -6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C 2-6 alkylcarbonylamino, C 2-6 alkylcarbonylaminomethyl, C
  • T, R 11 , R 12 and R 24 are as defined above.
  • T is N-R 25 .
  • T is oxygen.
  • R 23 include hydrogen, (Ci -6 )alkylimidazolyl, C 2-6 alkoxycarbonyl, aminocarbonyl, Ci -6 alkylaminocarbonyl, di(Ci, 6 )alkylaminocarbonyl, [(C i -6 )alkoxy] [(C i -6 )alkyl] aminocarbonyl, [(C i -6 )alkoxy(C i -6 )alkyl] [(C i -6 )alkyl] amino- carbonyl, C 3-7 cycloalkylaminocarbonyl, C 3-7 cycloalkyl(Ci -6 )alkylaminocarbonyl, N-[(C 1-6 )alkyl]-N-(aryl)aminocarbonyl, aryl(Ci -6 )alkylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxy
  • Typical values of R 23 include hydrogen, C 2-6 alkoxycarbonyl and di(C 1-6 )alkyl- aminocarbonyl.
  • Illustrative values of R 23 include hydrogen, fluoro, chloro, cyano, nitro, oxazolinyl, triazolyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, morpholinylethoxy, azetidinyl, morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino, iV-methoxycarbonyl-N-methylamino, methylsulphonylamino, acetyl, acetyl oxime, acetyl 0-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethylaminoethyl)aminocarbonyl, (1 -hydroxyprop-2-
  • Additional values include methylimidazolyl, iV-(methoxy)-N-(methyl)- aminocarbonyl, cyclopropylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, hydroxypyrrolidinylcarbonyl and methylsulphonylpiperazinylcarbonyl.
  • R 23 Definitive values of R 23 include hydrogen, methylimidazolyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, N-(methoxy)-iV-(methyl)- aminocarbonyl, JV-(methoxyethyl)-N-methylaminocarbonyl, diethylaminocarbonyl, cyclopropylaminocarbonyl, cyclopropylmethylaminocarbonyl, N-methyl-N-phenylamino- carbonyl, benzylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl, methylsulphonylpiperazinylcarbonyl and mo ⁇ holinylcarbonyl.
  • R 23 includes hydrogen, methoxycarbonyl and dimethylaminocarbonyl.
  • Definitive values of R 24 include hydrogen, chloro, methoxy and dimethylaminocarbonyl.
  • a particular value of R 24 is hydrogen.
  • R 25 is hydrogen, hi another embodiment, R 25 is Ci -6 alkyl, especially methyl.
  • R 1 ' and R 12 are as defined above;
  • R 33 represents halogen or -NHR 34 ; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more 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, (Q ⁇ alkylpyrimidinylphenyl, pyrazolyl(C 1-6 )alkyl- phenyl, triazolyl(Ci -6 )alkylphenyl, Ci -6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci -6 alkylsulphonylphenyl, mo ⁇ holinylsulphonylphenyl, dihydrobenzofuranyl, Ci -6 alkylsulphonylindolinyl,
  • R 33 represents halogen or -NHR 34 , in which R 34 is as defined above.
  • R 33 represents halogen, especially bromo.
  • R 33 represents -NHR 34 , in which R 34 is as defined above.
  • R 33 represents unsubstituted or substituted aryl. In another embodiment, R 33 represents unsubstituted or substituted heteroaryl.
  • Typical values of R 34 include pyridinyl, halopyridinyl, (Q ⁇ alkylpyridinyl, di(Ci- 6 )alkylpyridinyl and (C 1-6 )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 may be optionally substituted by one or more substituents.
  • R 33 Selected examples of suitable substituents on R 33 include halogen, cyano, Ci -6 alkyl, hydroxy(Ci. 6 )alkyl, trifluoromethyl, Ci -6 alkoxy, trifluoromethoxy, aryloxy, methylenedioxy, C 1-6 alkylthio, arylsulphonyl, amino, C 2-6 alkylcarbonylamino, Ci -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, methyl enedioxyphenylamino, 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.
  • 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:
  • R 11 and R 12 are as defined above;
  • R 43 represents hydrogen, halogen, nitro, Ci -6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, (Ci -6 )alkylaryl, di(Ci -6 )alkylaryl, piperidinyl(C 1-6 )alkylaryl, piperazinyl(Ci -6 )alkylaryl, (C i -6 )alkylpiperazinyl(C i -6 )alkylaryl, morpholinyl(C i .
  • R 44 represents hydrogen, halogen, Ci -6 alkyl or Ci -6 alkoxy.
  • a suitable value of R 43 is (Ci -6 )alkylpyrazolyl.
  • R 43 Specific values of R 43 include bromo, nitro, methyl, n-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethyl- phenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazinyl, methylpiperazinyl, chloroph
  • R 43 is methylpyrazolyl.
  • R 44 represents hydrogen.
  • R 44 represents halogen, especially bromo.
  • R 44 represents C 1-6 alkyl, especially methyl.
  • R 44 represents Ci -6 alkoxy, especially methoxy.
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
  • 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.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.
  • the compounds according to the present invention may be conveniently formulated as microionized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • compounds may be formulated in an ointment such as petrolatum.
  • the compounds according to the present invention may be conveniently formulated as suppositories.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • the quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
  • L 1 represents a suitable leaving group.
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as ivyV-dimethylformamide, typically under basic conditions, e.g. in the presence of an organic base such as ⁇ N-diisopropylethylamine or 2,6-lutidine.
  • a suitable solvent e.g. a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as ivyV-dimethylformamide
  • a suitable solvent e.g. a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as ivyV-d
  • the reaction may be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium tert-butoxide, in the presence of a transition metal catalyst.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene
  • an inorganic base such as sodium tert-butoxide
  • the transition metal catalyst is suitably palladium(II) acetate, in which case the reaction will ideally be performed in the presence of tert-butylphosphonium tetrafluoroborate or dicyclohexyl diphenylphosphine.
  • reaction is conveniently effected by stirring compound (V) with tert-butyl nitrite and copper(II) bromide in a suitable solvent, e.g. acetonitrile.
  • a suitable solvent e.g. acetonitrile.
  • the intermediates of formula (V) above may be prepared by reacting thiourea with a compound of formula (VI):
  • L 2 represents a suitable leaving group.
  • the leaving group L 2 is typically a halogen atom, e.g. bromo or iodo.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, typically under basic conditions, e.g. in the presence of an organic base such as N,iV-diisopropylethylamine.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran
  • an organic base such as N,iV-diisopropylethylamine.
  • the reaction may be accomplished by heating the reactants in a lower alkanol solvent, e.g. a Ci -6 alkyl alcohol such as ethanol.
  • the compounds of formula (I) may be prepared by a process which comprises reacting a compound of formula (VI) as defined above with a compound of formula (VII):
  • R 3 and R 4 are as defined above; under conditions analogous t ⁇ those described above for the reaction between thiourea and compound (VI).
  • the reaction may additionally be accomplished by heating the reactants in acetic acid, optionally in the presence of sodium acetate.
  • the intermediates of formula (VII) above may be prepared by reacting a compound of formula (IV) as defined above with l,l'-thiocarbonyldiimidazole; followed by treatment with ammonia or ammonium hydroxide.
  • the compounds of formula (I) wherein R 1 and R 2 together form an isopropylidene moiety may be prepared by a process which comprises reacting a compound of formula (VIII):
  • N-chlorosuccimmide N-chlorosuccimmide
  • reaction between compound (VIII) and NCS is conveniently carried out at an elevated temperature in an organic solvent such as acetonitrile.
  • organic solvent such as acetonitrile.
  • subsequent treatment with base is conveniently effected at ambient temperature in an organic solvent, e.g. acetonitrile.
  • R 3 represents an optionally substituted indolylmethyl moiety
  • R 3 represents an optionally substituted indolylmethyl moiety
  • a compound of formula (HB) as defined above wherein T represents NH may be prepared by a process which comprises reacting a compound of formula (X) with a compound of formula (XI):
  • R , 1"1, R r, 1 1 2 Z , R n 2 Z 3 J and R 24 are as defined above; in the presence of a transition metal catalyst; followed by hydrolytic cleavage of the trimethylsilyl group.
  • the transition metal catalyst of use in the reaction between compounds (X) and (XI) is suitably palladium(II) acetate, in which case the reaction is conveniently effected in the presence of lithium chloride and a base such as sodium carbonate.
  • the reaction will ideally be carried out at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as ⁇ -dimethylformamide.
  • Cleavage of the trimethylsilyl group from the product thereby obtained may suitably be accomplished by treatment with a mineral acid such as aqueous hydrochloric acid.
  • the starting materials of formula (IV), (VI), (IX), (XI) and (XIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
  • a compound of formula (I) wherein X represents oxygen may be converted into the corresponding compound wherein X represents sulphur by treatment with Lawesson's Reagent (i.e.
  • a compound of formula (I) wherein R 3 and/or R 4 contains an aryl or heteroaryl moiety may be halogenated (e.g. brominated) on the aryl or heteroaryl moiety by treatment with the appropriate JV-halosuccinimide (e.g. N-bromosuccinimide).
  • a compound of formula (I) wherein R 3 and/or R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by amino (-NH 2 ) by treatment with benzophenone imine and tris(dibenzylidene- acetone)dipalladium(0) in the presence of 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP) and a strong base such as sodium tert-bntoxide.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound of formula (I) wherein the halogen atom is replaced by an optionally substituted C 3-7 cycloalkyl, aryl, aryl(C 1-6 )alkyl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted C 3-7 cycloalkyl, aryl, aryl(C ⁇ -6 )alkyl or heteroaryl boronic acid or a cyclic ester thereof, e.g. a pinacol ester thereof, in the presence of a catalyst.
  • a halogen atom e.g. bromo
  • -6 )alkyl, substituted on the aryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 3 represents biaryl(C 1-6 )alkyl or heteroarylaryl(Ci- 6 )alkyl by treatment with, respectively, an aryl or heteroaryl boronic acid, in the presence of a catalyst.
  • a compound of formula (I) wherein R 3 represents heteroaryl(C 1-6 )alkyl, substituted on the heteroaryl moiety by a halogen atom such as bromo may be converted into the corresponding compound wherein R 3 represents aryl-heteroaryl(Ci -6 )alkyl by treatment with an aryl boronic acid, in the presence of a catalyst.
  • a compound of formula (I) wherein R 3 contains a cyclic borane moiety e.g.
  • 4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl may be converted into the corresponding compound wherein the cyclic borane moiety is replaced by an optionally substituted aryl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted aryl or heteroaryl halide, e.g. chloride, bromide or iodide, in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, in an inert solvent such as 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonium bromide.
  • the catalyst may be palladium(II) acetate, in which case the transformation may conveniently be effected at an elevated temperature in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and potassium phosphate.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents a substituted aminomethyl moiety, e.g. phenylaminomethyl, iV-methyl-N-phenylaminomethyl, pyridin- 3-ylaminomethyl, indolin-1-ylmethyl, 1,2,3,4-tetrahydroquinolin-l-ylmethyl or 1,2,3,4- tetrahydroisoquinolin-2-ylmethyl, by a two-stage procedure which comprises (i) Swern oxidation of the hydroxymethyl derivative by treatment with oxalyl chloride and dimethyl sulphoxide in the presence of triethylamine; and (ii) reductive animation of the formyl derivative thereby obtained by treatment with the appropriate amine, e.g.
  • aniline N- methylaniline, 3-aminopyridine, indoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4- tetrahydroisoquinoline, in the presence of a reducing agent such as sodium cyanoborohydride.
  • a reducing agent such as sodium cyanoborohydride.
  • any compound of formula (I) which contains a carbonyl-containing functionality may be converted into a substituted amino analogue thereof by application of the reductive animation procedure described in step (ii) in the preceding paragraph, which comprises treatment with the appropriately-substituted amine in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • Any compound of formula (I) wherein R 3 contains an amino moiety can be alkylated on the amino moiety by a reductive amination procedure which comprises treatment with the appropriate aldehyde in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
  • a compound of formula (I) wherein R 3 represents hydroxymethyl may be converted into the corresponding compound wherein R 3 represents an optionally substituted C 3-7 heterocycloalkylcarbonyl moiety, e.g. piperidin-1-ylcarbonyl, 1,2,3,4- tetrahydroquinolin- 1 -ylcarbonyl, 6-methyl- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 6- methoxy- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 1 ,2,3 ,4-tetrahydroisoquinolin-2- ylcarbonyl or 1,2,3,4-tetrahydroquinoxalin-l -ylcarbonyl, by a two-stage procedure which comprises (i) oxidation of the hydroxymethyl moiety by treatment with potassium permanganate; and (ii) reaction of the carboxy derivative thereby obtained with the appropriate amine,
  • piperidine 1,2,3,4-tetrahydroquinoline, 6-methyl-l, 2,3,4- tetrahydroquinoline, 6-methoxy- 1 ,2,3 ,4-tetrahydroquinoline, 1 ,2,3 ,4-tetrahydro- isoquinoline or 1,2,3,4-tetrahydroquinoxaline, in the presence of a condensing agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or 0-(berizotriazol-l-yl)-N,N,iV > N'- tetramethyluronium hexafluorophosphate (HBTU).
  • a condensing agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or 0-(berizotriazol-l-yl)-N,N,iV > N'- tetramethyluronium he
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by chloro may be converted into the corresponding compound wherein the phenyl ring is substituted by morpholin-4-yl by treatment with morpholine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(di-tert-butylphosphino)biphenyl and sodium tert-butoxide.
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by pyrrolidin- 1 -yl by treatment with pyrrolidine in the presence oftris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-1,1 '-biphenyl and a base such as potassium carbonate.
  • a compound of formula (I) wherein R 3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by an amino'moiety (e.g. a group of formula - ⁇ HR 34 as defined above) by treatment with the appropriate amine (e.g. a compound of formula H 2 N-R 34 ) in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-2',4',6'-tri- isopropyl-l,l'-biphenyl (X-Phos) and a base such as sodium tert-butoxide.
  • the appropriate amine e.g. a compound of formula H 2 N-R 34
  • a base such as sodium tert-butoxide
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by cafboxy (-CO 2 H) by treatment with «-butyllithium followed by carbon dioxide.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 contains an indole moiety may be methylated on the indole ring by treatment with a methyl halide, e.g. iodomethane, in the presence of a strong base such as sodium hydride.
  • a compound of formula (I) wherein R 3 contains an indole moiety may be acetylated on the indole ring by treatment with acetic anhydride and 4-dimethylamino-pyridine, typically in the presence of an organic base such as triethylamine.
  • a compound of formula (I) wherein R 3 contains an indoline moiety may be converted into the corresponding compound wherein R 3 contains an indole moiety by treatment with an oxidising agent such as manganese dioxide.
  • a compound of formula (I) wherein R 3 contains a hydroxy substituent may be converted into the corresponding compound wherein R 3 contains a Ci -6 alkylsulphonyloxy substituent, e.g. methyl- sulphonyloxy, by treatment with a C 1-6 alkylsulphonyl halide, e.g. methanesulphonyl chloride.
  • a compound of formula (I) wherein R 3 contains an amino (-NH 2 ) or carboxy (-CO 2 H) moiety may be converted into the corresponding compound wherein R 3 contains an amido moiety by treatment with, respectively, a compound containing a carboxy or amino group, in the presence of O- ⁇ enzotriazol-l-y ⁇ -Ny ⁇ Vy/V-tetramethyluronium hexafluorophosphate (HBTU), typically in a dipolar aprotic solvent such as NJf- dimethylformamide; or in the presence of 1 - [3 -(dimethylamino)propyl] -3 -ethyl- carbodiimide and 1-hydroxybenzotriazole.
  • HBTU O- ⁇ enzotriazol-l-y ⁇ -Ny ⁇ Vy/V-tetramethyluronium hexafluorophosphate
  • a compound of formula (I) wherein R 3 contains an amino substituent may be converted into the corresponding compound wherein R 3 contains an alkyl- or arylsulphonylamino substituent, e.g. methylsulphonylamino or phenylsulphonylamino, by treatment with an alkyl- or arylsulphonyl halide, e.g. methanesulphonyl chloride or benzenesulphonyl chloride.
  • a compound of formula (I) wherein R 3 contains an amino moiety may be acylated by treatment with a C 2-6 alkylcarbonyl halide, e.g. acetyl chloride; or a C 2-6 alkylcarbonyl anhydride, e.g. acetic anhydride.
  • a compound of formula (I) wherein R 3 contains an amino moiety may be converted into the corresponding carbamate ester by treatment with a C 1-6 alkyl haloformate, e.g. methyl chloroformate.
  • a compound of formula (I) wherein R 3 contains a C 2-6 alkoxycarbonyl substituent, e.g. methoxycarbonyl, may be converted into the corresponding compound wherein R 3 contains a carboxy (-CO 2 H) substituent under standard saponification conditions, e.g. by treatment with a base such as lithium hydroxide or sodium hydroxide.
  • a compound of formula (I) wherein R 3 contains a carboxy (-CO 2 H) substituent may be converted into the corresponding compound wherein R 3 contains an amido substituent, e.g.
  • methylaminocarbonyl 2-hydroxyethylaminocarbonyl, dimethylaminocarbonyl, N-(2- hydroxyethyl)-N-methylaminocarbonyl, benzylaminocarbonyl, azetidin- 1 -ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1 -ylcarbonyl, 4-methylpiperazin-l -ylcarbonyl or morpholin-4-ylcarbonyl, by a two-stage procedure which comprises (i) treatment of the carboxy derivative with pentafluorophenol in the presence of a condensing agent such as l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide; and (ii) reaction of the pentaf ⁇ uorophenyl ester thereby obtained with the appropriate amine, e.g.
  • a condensing agent such as l-[3-(dimethyla
  • methylamine 2- hydroxyethylamine, dimethylamine, ⁇ / -(2-hydroxyethyl)- ⁇ r -methylamine, benzylamine, azetidine, pyrrolidine, piperidine, 1-methylpiperazine or morpholine.
  • a compound of formula (I) wherein R 3 /R 4 contains a nitro moiety may be converted into the corresponding compound wherein R 3 /R 4 contains an amino (-NH 2 ) moiety by catalytic hydrogenation, typically by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal.
  • a compound of formula (I) wherein R 3 /R 4 contains an amino (-NH 2 ) moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a heteroaryl-amino moiety, e.g. 6-methylpyridin-3- ylamino, by treatment with the appropriate heteroaryl halide, e.g. 5-bromo-2- methylpyridine, in the presence of palladium(II) acetate, 2-bis(dicyclohexylphosphino)- biphenyl and a base such as sodium tert-butoxide.
  • any compound of formula (I) wherein R 3 /R 4 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein the halogen atom is replaced by a substituted amino functionality by treatment with the appropriately- substituted amine derivative and palladium(II) acetate in the presence of a base, e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate.
  • a base e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate.
  • reaction may be effected by treatment with the appropriately-substituted amine derivative and [l,r-bis(di-/ert-butylphosphino)ferrocene]palladium(II) dichloride in the presence of a base, e.g. sodium tert-butoxide.
  • a base e.g. sodium tert-butoxide.
  • any compound of formula (I) wherein R 3 /R 4 contains an amino functionality may be converted into the corresponding compound wherein the amino functionality is substituted by an optionally substituted aryl or heteroaryl moiety by treatment with an appropriately-substituted aryl or heteroaryl halide (e.g.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a heteroaryl group, e.g.
  • pyrazol-3-yl 1- methylpyrazol-4-yl, l-propylpyrazol-4-yl, l-isobutylpyrazol-4-yl, 1 -benzylpyrazol-4-yl, 1- [2-(morpholin-4-yl)ethyl]pyrazol-4-yl, 6-methylpyridin-3-yl or pyrimidin-5-yl, by treatment with the appropriate heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst.
  • an organic diol e.g. pinacol
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a boronic acid [-B(OH) 2 ] moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a heteroaryl group, e.g. methylimidazolyl, by treatment with the appropriate heteroaryl halide, e.g. bromide, derivative in the presence of a catalyst.
  • the catalyst may typically be a transition metal catalyst.
  • a suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, optionally in the presence of tetrabutylammonium bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group by treatment with a strong base, e.g. /j-butyllithium, and ⁇ jV-dimethylformamide.
  • a compound of formula (I) wherein R /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by hydroxymethyl by treatment with a reducing agent such as sodium borohydride.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by an aminomethyl moiety (e.g. dimethylaminomethyl, pyridin-3-ylaminomethyl, 4-methylpiperazin-l-ylmethyl or morpholin-4-ylmethyl) by treatment with the appropriate amine (e.g. dimethylamine, pyridin-3-ylamine, 1 -methylpiperazine or morpholine) and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride.
  • an aminomethyl moiety e.g. dimethylaminomethyl, pyridin-3-ylaminomethyl, 4-methylpiperazin-l-ylmethyl or morpholin-4-ylmethyl
  • the appropriate amine e.g. dimethylamine, pyridin-3
  • a compound of formula (I) wherein R 3 /R 4 contains an amino moiety may be converted into the corresponding compound wherein R 3 /R 4 is methylated on the amino moiety by treatment with formaldehyde and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by a pyridinyloxymethyl moiety by treatment with the appropriate hydroxypyridine in the presence of a mixture of triphenylphosphine and diethyl azodicarboxylate.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety substituted by a C 2-6 alkoxycarbonyloxy group, e.g. tert-butoxycarbonyloxy may be converted into the corresponding compound wherein R 3 /R 4 contains a benzo moiety substituted by hydroxy under standard hydrolytic conditions, e.g. by treatment with trifluoroacetic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R 3 ZR 4 contains hydroxy by treatment with sodium hydroxide in the presence of tris(dibenzylideneacetone)- dipalladium(O) and 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-l ,1 '-biphenyl.
  • a compound of formula (I) wherein R 3 /R 4 contains hydroxy may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted C 1-6 alkoxy, C 3-7 heterocycloalkoxy or C 3-7 heterocycloalkyKC ⁇ alkoxy by treatment with the appropriately substituted C 1-6 alkyl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkyl(Ci- 6 )- alkyl halide, e.g. bromide, ideally at an elevated temperature in the presence of cetyl- ammonium bromide.
  • a compound of formula (I) wherein R 3 /R 4 contains hydroxy may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted pyridinyloxy, pyrimidinyloxy or pyrazinyloxy by treatment with the appropriately substituted pyridinyl, pyrimidinyl or pyrazinyl halide, e.g. fluoride or chloride, typically in the presence of a strong base such as sodium tert-butoxide.
  • a strong base such as sodium tert-butoxide.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein R 3 /R 4 contains optionally substituted aryloxy or heteroaryloxy by treatment with an appropriately-substituted hydroxyaryl or hydroxyheteroaryl derivative and a base such as caesium carbonate, ideally in the presence of a copper(I) halide, e.g. copper(I) chloride or copper(I) bromide.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R 3 /R 4 contains an amino (-NH 2 ) group may be converted into the corresponding compound wherein R 3 /R 4 contains 2,5-dioxopyrrolidin- 1-yl by treatment with succinic anhydride.
  • a compound of formula (I) wherein R 3 /R 4 contains an aryl or heteroaryl moiety substituted by a halogen atom, e.g. chloro, may have the halogen atom removed by catalytic hydrogenation.
  • a compound of formula (I) wherein R 3 /R 4 contains a benzo moiety may be alkylated on the aromatic ring by treatment with w-butyllithium and an alkyl halide (e.g. iodopropane); or by treatment with an organozinc reagent (e.g. isopropylzinc bromide) in the presence of [ 1 , 1 '-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride and copper(I) iodide.
  • w-butyllithium and an alkyl halide e.g. iodopropane
  • an organozinc reagent e.g. isopropylzinc bromide
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by an optionally substituted alkynyl moiety (e.g. 3-hydroxyprop-l-yn-l-yl) by treatment with an appropriately-substituted alkyne derivative (e.g. 3-hydroxyprop-l-yne) and a catalyst such as tetrakis(triphenylphosphine)palladiurn(0), typically in the presence of co ⁇ per(I) iodide and a base such as triethylamine.
  • a halogen atom e.g. chloro
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by acetyl by a two-stage procedure which comprises (i) treatment with butyl vinyl ether and palladium acetate, suitably in the presence of l,3-bis(diphenylphosphino)propane and an organic base such as triethylamine; and (ii) hydrolysis with a mineral acid such as hydrochloric acid.
  • a halogen atom e.g. bromo
  • a compound of formula (I) wherein R /R contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by 1 -hydroxy- 1-methylethyl by treatment with n-butyllithium and acetone.
  • a compound of formula (I) wherein R 3 /R 4 contains a halogen atom may be converted into the corresponding compound wherein the halogen atom is replaced by C 1-6 alkylthio (e.g. isopropylthio) by treatment with n-butyllithium and the appropriate disulphide derivative (e.g isopropyl disulphide).
  • Ci -6 alkylthio moiety into Ci -6 alkylsulphinyl or C 1-6 alkylsulphonyl may be accomplished by treatment with an oxidising agent, e.g. m-chloroperbenzoic acid.
  • an oxidising agent e.g. m-chloroperbenzoic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a pyridinyl moiety may be converted into the corresponding pyridine-iV-oxide analogue by treatment with peracetic acid.
  • a compound of formula (I) wherein R 3 /R 4 contains a carbonyl-containing moiety may be converted into the corresponding oxime analogue by treatment with an appropriately-substituted hydroxylamine derivative.
  • a compound of formula (I) wherein R 3 /R 4 contains a formyl moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a vinyl moiety by treatment with methyltriphenylphosphonium bromide and a strong base such as sodium hexamethyldisilazide.
  • a compound of formula (I) wherein R 3 /R 4 contains a formyl moiety may be converted into the corresponding compound wherein R 3 /R 4 contains a 1-hydroxyethyl moiety by treatment with methyllithium.
  • a compound of formula (I) wherein R 3 /R 4 contains a (2-hydroxyethyl)amino- carbonyl group may be converted into the corresponding compound wherein R 3 /R contains an oxazolin-1-yl moiety by treatment with thionyl chloride.
  • a compound of formula (I) wherein R 3 /R 4 contains an ester functionality may be converted into the corresponding compound wherein R 3 /R 4 contains an amide functionality (e.g. methylaminocarbonyl or dimethylaminocarbonyl) by treatment with an appropriately-substituted amine (e.g. methylamine or dimethylamine) in the presence of trimethylaluminium.
  • R 3 /R 4 contains an ester functionality e.g. methoxycarbonyl
  • R 3 /R 4 contains an amide functionality e.g. methylaminocarbonyl or dimethylaminocarbonyl
  • an appropriately-substituted amine e.g. methylamine or dimethylamine
  • Alkenyl-containing compounds may be converted into the corresponding vic- dihydroxy analogues by treatment with osmium tetroxide.
  • Alkenyl- and alkynyl-containing compounds may be converted into the corresponding alkyl analogues by catalytic hydrogenation.
  • a compound of formula (I) wherein R 5 represents hydrogen may be converted into the corresponding compound wherein R 5 represents Ci -6 alkyl by treatment with the appropriate alkyl halide, e.g. a methyl halide such as iodomethane, in the presence of a strong base such as sodium hydride.
  • the appropriate alkyl halide e.g. a methyl halide such as iodomethane
  • 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.
  • the compounds in accordance with this invention potently inhibit the activity of human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K6.
  • the concentration of inhibitor required to inhibit the enzyme activity by 50% is quoted as the IC 50 .
  • the compounds of the accompanying Examples were all found to possess ICs 0 values for inhibition of activity of human PI3K ⁇ and/or PI3K ⁇ and/or PI3K ⁇ and/or PI3K5 of 50 ⁇ M or better.
  • SiO 2 silica br: broad v: volume
  • NIS N-iodoosuccinimide
  • NBS N-bromosuccinimide Et: ethyl
  • NCS iV-chlorosuccinimide prep.: preparative
  • DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • EDC 1 -[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride brine: saturated aqueous sodium chloride solution
  • NEt 3 (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in T ⁇ F (80 mL).
  • the reaction mixture was cooled to 0 0 C, chloroacetyl chloride (1.12 mL, 14 mmol) was added portionwise and then stirred at 0 0 C for 10 minutes before being allowed to warm to r.t. and stirred for a further 2 h.
  • the reaction mixture was cooled to 0 0 C and NaH (1.05 g, 60% dispersion in oil, 26 mmol) was added portionwise.
  • the reaction mixture was stirred at O 0 C for 20 minutes then at r.t.
  • the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL) and washed with brine (50 mL). The organic fraction was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was then purified by preparative ⁇ PLC, the resulting material being partitioned between EtOAc (100 mL) and aqueous sat. NaHCO 3 solution (100 mL). The organic fractions were combined and washed with a mixture of brine and water (100 mL), dried (MgSO 4 ), filtered and concentrated in vacuo.
  • the precipitate was filtered, rinsed with IPA (70 mL) and dried under vacuum at 55 0 C for 48 hours to yield the title compound (53.06 g; containing 5% w/w of IPA by NMR; corrected weight 50.41 g, 69.4% yield).
  • a second crop was recovered by crystallization of the mother liquors (8.35 g, 11.5% yield). Total yield 80%.
  • the reaction mixture was heated to HO 0 C for 50 minutes.
  • the reaction mixture was then cooled to room temperature, filtered through celite and concentrated in vacuo.
  • the resulting brown oil was separated between isopropyl acetate and water.
  • the aqueous layer was back-extracted with isopropyl acetate (2 x 150 mL).
  • the combined organic layers were dried (MgSO 4 ), treated with decolourising charcoal (5% by weight of crude material) for 30 minutes at room temperature, and purified by column chromatography (SiO 2 , DCM) to give the title compound (9.0 g, 19%) as a pale cream solid.

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Abstract

A series of 4,5-dihydro-6H-pyrrolo[3,4-d][1,3]thiazol-6-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.

Description

PYRROLOTHIAZOLES AS PI3-KINASE INHIBITORS
The present invention relates to a class of fused thiazole derivatives, and to their use in therapy. More particularly, the invention provides a family of 4,5-dihydro-6//- pyrrolo[3,4-i/][l,3]thiazol-6-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety. These compounds are selective inhibitors of phosphoinositide 3 -kinase (PI3K) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
The PI3K pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases. Thus, PI3Ks provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite oufgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sd., 2003, 24, 366-376). Aberrant upregulation of the PI3K pathway is implicated in a wide variety of human cancers (cf. S. Brader & S. A. Eccles, Tumori, 2004, 90, 2-8).
The compounds in accordance with the present invention, being potent and selective PI3K inhibitors, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g. during heart failure); neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; pain and nociceptive disorders; and ophthalmic disorders including age- related macular degeneration (ARMD). In addition, the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of this invention may be useful as radioligands in assays for detecting compounds capable of binding to human PI3K enzymes.
Various fused thiazole derivatives are disclosed in Liebigs Annalen der Chemie, 1986, 780-784; and in Russian Journal of General Chemistry (translation of Zhurnal Obshchei Khimii), 2000, 70[5], 784-787. However, none of the compounds disclosed in either of those publications corresponds to a compound of the present invention; and no therapeutic utility is ascribed to any of the compounds disclosed therein.
WO 2006/114606 describes a class of fused bicyclic thiazole derivatives which are selective inhibitors of PB kinase enzymes and are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions. A related series of compounds is described in copending international patent application no. PCT/GB2007/002390, published on 3 January 2008 as WO 2008/001076.
The compounds in accordance with the present invention are potent and selective PI3K inhibitors having a binding affinity (IC50) for the human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ isoform of 50 μM or less, generally of 20 μM or less, usually of 5 μM or less, typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower 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 PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ isoform relative to other human kinases.
The compounds of the present invention possess interesting pharmacokinetic properties, including good oral exposure and low in vitro 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 oxygen or sulphur; R and R independently represent hydrogen, hydroxy or amino; or Ci-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(Ci-6)alkylamino, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(Cι-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 R2 may together form an isopropylidene moiety; or
R1 and R2, when taken together with the carbon atom to which they are both attached, represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents;
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(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
R and R , when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; and
R5 represents hydrogen or Ci-6 alkyl. 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 Cj-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci-6 alkoxy", "Ci-6 alkylthio", "Ci-6 alkylsulphonyl" and "Ci-6 alkylamino" are to be construed accordingly.
A specific C2-6 alkynyl group is prop-2-yn-l-yl.
Specific C3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
Suitable aryl(Ci-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Specific aryl(C2-6)alkenyl groups include 2-phenylethenyl and 3-phenylprop-2-en- 1-yl.
A specific aryl(C2-6)alkynyl group is 3-phenylprop-2-yn-l-yl.
Particular biaryl groups include biphenyl and naphthylphenyl.
Suitable heterocycloalkyl groups, which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.
Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-&]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolyl, pyrazolo[l,5-α]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2-α]pyridinyl, imidazo[4,5-6]pyridinyl, imidazo[ 1 ,2-α]pyrimidinyl, imidazo[ 1 ,2-α]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl, quinoxalinyl and chromenyl groups.
The term "halogen" as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.
Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (I) may exist as tautomers, for example keto (CH2C=O)<→enol (CH=CHOH) tautomers or amide (NHC=O)<→hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. In a preferred embodiment, X represents oxygen. In another embodiment, X represents sulphur.
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 C1-6 alkyl. In one aspect of that embodiment, R1 is methyl. In another aspect of that embodiment, R1 is ethyl.
Suitably, R2 represents hydrogen; or Ci-6 alkyl, Ci-6 alkoxy, C3-7 cycloalkyl or aryl, . any of which groups may be optionally substituted by one or more substituents.
Examples of typical substituents on R1 and/or R2 include halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, hydroxy, Ci-6 alkoxy, difluoromethoxy, trifiuoromethoxy, aryloxy, C1-6 alkylthio, Ci-6 alkylsulphonyl, amino, C1-6 alkylamino, di(Ci-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulphonyl, Ci-6 alkylaminosulphonyl and di(C i -6)alkylaminosulphonyl; especially halogen, C i -6 alkoxy or C i -6 alkylthio.
Examples of particular substituents on R1 and/or R2 include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifiuoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.
Typical values of R2 include hydrogen, methyl, ethoxy, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl. A particular value of R2 is methyl. In another embodiment, R1 and R2 may together form an isopropylidene moiety
[i.e. C(R1XR2) represents C=C(CH3)2].
Alternatively, R1 and R2 may together form an optionally substituted spiro linkage. Thus, R1 and R2, when taken together with the carbon atom to which they are both attached, may represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, R1 and 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. Typically, R3 represents hydrogen; or Ci-6 alkyl, aryl, aryl(Ci.6)alkyl, aryl- (C2-6)alkynyl, biaryl(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterόcycloalkyl- carbonyl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroaryl(Ci.6)alkyl, any of which groups may be optionally substituted by one or more substituents. 5 Generally, R3 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(C i^alkyl or heteroaryl(Ci-6)alkyl, either of which groups may be optionally substituted by one or more substituents. In one specific embodiment, R3 represents hydrogen. 0 In a representative embodiment, R3 represents C1-6 alkyl, aryl(Ci-6)alkyl, biaryl-
(C1-6)alkyl, heteroaryl(Cι-6)alkyl or heteroaryl-arylCQ^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 5 represents arylmethyl or heteroarylmethyl, either of which groups may be optionally substituted by one or more substituents.
In a particular embodiment, R3 represents substituted or unsubstituted indolyl- (Ci-6)alkyl. Advantageously, R3 represents substituted or unsubstituted indolylmethyl.
--: In a typical embodiment, R3 represents substituted or unsubstituted phenyl-0 (Ci-6)alkyl. Advantageously, R3 represents substituted or unsubstituted benzyl.
In another embodiment, R3 represents substituted or unsubstituted benzofuryl- (Ci-6)alkyl. Advantageously, R3 represents substituted or unsubstituted benzofurylmethyl.
Illustratively, R3 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, 5 indolinylmethyl, 1,2,3,4-tetrahydroquinolinylmethyl, 1,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4- tetrahydroisoquinolinylcarbonyl, 1 ,2,3 ,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-6]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazolylmethyl, 0 pyridinylmethyl, quinolinylmethyl, isoquinolinylmethyl, benzofurylbenzyl, thienylbenzyl, benzothienylbenzyl, indolylbenzyl, isoxazolylbenzyl, pyrazolylbenzyl, pyridinylbenzyl, pyrimidinylbenzyl or phenylpyridinylmethyl, any of which groups may be optionally substituted by one or more substituents. Suitably, R4 represents hydrogen or optionally substituted Ci-6 alkyl. Examples of typical substituents on R3 and/or R4 include halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, C2-6 alkenyl, C3-7 cycloalkyl, (C1-6)alkylaryl, di(C1.6)alkylaryl, piperidinyl(C i -6)alkylaryl, piperazinyl(C i -6)alkylaryl, (C i -6)alkylpiperazinyl(C \ -6)- alkylaryl, morpholinyl(C1-6)alkylaryl, (C1-6)alkoxyaryl, cyano(C1-6)alkoxyaryl, di(C1-6)- alkylamino(Ci-6)alkylaryl, (C1-6)alkylaminocarbonylaryl, 8TyI(C1 -6)alkyl, oxazolinyl, azetidinyl, pyrrolidinyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di- (Ci^alkylaminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonyl- piperidinyl, di(C1.6)alkylaminocarbonylpiperidinyl, piperazinyl, (C1-6)alkylpiperazinyl, haloarylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (C1 -6)alkylhomopiperazinyl , morpholinyl, (C i -6)alkylpiperazinyl(C i _6)alkyl, moφholinyl(Cι-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (C1-6)alkylpyrazolyl, di(C1-6)- alkylpyrazolyl, tri(C1-6)alkylpyrazolyl, [di(C1-6)alkyl](trifluoromethyl)pyrazolyl, cyano- (C \ -6)alkylpyrazolyl, [cyano(C i -6)alkyl] [di(C1-6)alkyl]pyrazolyl, hydroxy(C i -6)alkyl- pyrazolyl, [hydroxy(Ci -6)alkyl] [di(Ci-6)alkyl]pyrazolyl, methoxy(Ci -6)alkylpyrazolyl,
[(hydroxy)(methoxy)(C1-6)alkyl]pyrazolyl, amino(Ci.6)alkylpyrazolyl, [(Ci.6)alkyl][amino- (Ci-6)alkyl]pyrazolyl, [amino(C1-6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(C1.6)alkylamino(Ci-6)- alkylpyrazolyl, di(Ci.6)alkoxyphosphono(Ci-6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl(C i -6)alkylpyrazolyl, [(C3-7)cycloalkyl(C i -6)alkyl] [di(C i -6)alkyl]ρyrazolyl, [(C1-6)alkyl](aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(C1-6)alkylpyrazolyl, aminoaryl(Ci-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(C1-6)alkyI- pyrazolyl, [di(Ci-6)alkyl][tetrahydropyranyl(Ci-6)alkyl]pyrazolyl, pyrrolidinyl(C1-6)alkyl- pyrazolyl, piperidinyl(C i ^alkylpyrazolyl, (C i -6)alkylpiperidinyl(C i -6)alkylpyrazolyl, morpholiny^d^alkylpyrazolyl, pyridinyl(Ci-6)alkylpyrazolyl, oxypyridinyl(C1-6)alkyl- pyrazolyl, [arylcarbonyl(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(Ci-6)alkyl](piperazinyl- carbonyl)pyrazolyl, [(C1-6)alkylaminocarbonyl][(C1-6)alkylaryl]pyrazolyl, [(C1-6)alkyl]- [amino(C1^)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl, [aminocarbonyl(C i -6)alkyl] [di(C \ -6)alkyl]pyrazolyl, di(C i .6)alkylaminocarbonyl(C i -6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(Ci-6)alkylisoxazolyl, (amino)[(C1-6)alkyl]- isoxazolyl, thiazolyl, di(Ci-6)alkylthiazolyl, imidazolyl, (Ci-6)alkylimidazolyl, di(Ci-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (Ci^alkylimidazofl^-αjpyridinyl, (C]-6)- alkylimidazo[4,5-b]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (C1-6)- alkylthiadiazolyl, triazolyl, pyridinyl, halopyridinyl, (Ci-6)alkylpyridinyl, [(C1-6)alkyl]- (halo)pyridinyl, di(Ci-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C1-6)alkylpiperazinyl- pyridinyl, [(C i -6)alkylj(piperazinyl)pyridinyl, [(C i -6)alkoxycarbonylpiperazinyl J [(C i -6)- alkyl]pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(C1-6)alkylpyridinyl, (C]-6)alkoxypyridinyl, [(C1-6)alkoxy]- [(C1-6)alkyl]pyridinyl, [(C1-6)alkoxy][di(Ci-6)alkyl]pyridinyl, (C1-6)alkoxy(C,-6)alkyl- pyridinyl, aminopyridinyl, carboxy(C1-6)alkylpyridinyl, (Ci-6)alkoxycarbonyl(C1-6)alkyl- pyridinyl, pyridazinyl, (Ci-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (Ci-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(Ci-6)alkylaminopyridazinyl, di- (Ci-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(C1-6)alkyl](halo)- pyrimidinyl, di(Ci-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinyl- pyrimidinyl, [(C i -6)alkyl](piperazinyl)pyrimidinyl, [(C i ^alkoxycarbonyl] [(C i -6)alkyl]- piperazinylpyrimidinyl, hydroxypyrimidinyl, [(C1-6)alkyl](hydroxy)pyrimidinyl, [(C1-6)- alkyl][hydroxy(Ci.6)alkyl]pyrimidinyl, [(C1-6)alkyl][hydroxy(C2-6)alkynyl]pyrimidinyl, (Ci-6)alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminopyrimidinyl, [di(Ci-6)alkyl- amino] (halo)pyrimidinyl, carboxypyrimidinyl, [(C|-6)alkoxycarbonyl(Ci-6)alkyl][(Ci-6)- alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (C1-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (Ci-6)alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(C1.6)alkoxy, aryl(C1-6)alkoxycarbonylpiperidinyloxy, morpholinyl (C1-6)- alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C1-6)alkylpiperazinylpyridinyloxy, (C1-6)alkylpyrazolyl- pyridinyloxy, (Ci-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (C]-6)alkylpyridazinyloxy, pyrimidinyloxy, (Ci.6)alkylpyrimidinyloxy, [(C i -6)alkyl] (halo)pyrimidinyloxy, hydroxy(C ] -6)alkyl, dihydroxy(C i .6)alkyl, pyridinyloxy(Ci-6)alkyl, methylenedioxy, trifluoromethylenedioxy, amino, (C1-6)alkyl- amino, dihydroxy(C1-6)alkylamino, (Ci-6)alkoxy(C1-6)alkylamino, di(C1-6)alkylamino, N- [(C i -6)alkoxy(C \ -6)alkyl] -N- [(C i -6)alkyl] amino, di(C i -6)alkylamino(C \ -6)alkylamino, N- [(Ci-6)alkyl]-N-[di(C1-6)alkylamino(C1.6)alkyl]amino, N-[(C1-6)alkyl]-N-[(C3-7)cycloalkyl]- amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, methylenedioxyphenylamino, morpholinyl(C i ^alkylphenylamino, oxazolinylphenylamino, [(C i -6)alkyl](oxo)pyrazolyl- phenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino,
(C J -6)alkyltriazolylphenylamino, (C \ ^alkylpyrimidinylphenylamino, pyrazolyl(C i -6)alkyl- phenylamino, triazolyl(Ci-6)alkylphenylamino, Ci-6 alkylsulphonylaminophenylamino, morpholinylcarbonylphenylamino, Ci-6 alkylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-[(Ci-6)alkyl]-N-[aryl(Ci.6)alkyl]amino, 7V-[di(Ci-6)alkylamino(C1-6)alkyl]-N-[aryl(Ci-6)alkyl]amino, cyanoaryl(Ci-6)alkylamino, (cyano)(halo)aryl(C1-6)alkylamino, methylenedioxyaryl(Ci-6)alkylamino, dihydrobenzofuranylamino, N- [(C \. _6)alkyl] -N- [(C \ -6)alkylpyrrolidinyl] amino, C i .(, alkylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-[(C1-6)alkyl]-N- (piperidinyl)amino, N-[(C3-7)cycloalkyl(C1.6)alkyl]-N-(piperidinyl)amino, (C1-6)alkyl- piperidinylamino^-^d-^alkylJ-N-t^i^alkylpiperidinyllamino, N-[(C1-6)alkyl]- N-[(C3-7)cycloalkylpiperidinyl]amino, N-[(C i -6)alkyl]-N-[(C2-6)alkylcarbonylpiperidinyl] - amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinyl(Ci-6)alkylamino, N-[(C1-6)alkyl]-J/V-[pyrroHdinyl(C1-6)alkyl]amino, N-[(C1-6)alkyl]-N-[piρeridinyl(Ci-6)- alkyl]amino, benzothienylamino, indolylamino, dioxoindolylamino, (C1-6)alkylpyrazolyl- amino, [(C1-6)alkyl](halo)pyrazolylamino, di(Ci.6)alkylpyrazolylamino, tri(Ci-6)alkyl- pyrazolylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkylpyrazolyl]amino, (Ci-6)alkylindazolylamino, benzoxazolylamino, benzoxazolonylamino, di(C1-6)alkylisoxazolylamino, thiazolylamino, benzothiazolylamino,
Figure imgf000011_0001
imidazolylamino, [(C1-6)alkoxy- carbonyl] [(C i ^alkyl] imidazolylamino, (C i .6)alkylbenzimidazolylamino, benzimidazolonylamino, di(C1-6)alkylbenzimidazolonylamino, (C^alkyloxadiazolyl- amino, furyloxadiazolylamino, (C1-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (C1-6)alkylpyridinylamino, di(C1-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C1-6)alkylpyridinylamino, dihydroxy(C i -6)alkylpyridinylamino, (C \ -6)alkoxypyridinylamino, dihydroxy(C i _6)alkoxy- pyridinylamino, di(C i -6)alkyldioxolanyl(C i -6)alkoxypyridinylamino, (C i -6)alkoxy(C \^)- alkylpyridinylamino, (Ci-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(Ci-6)alkyl- aminopyridinylamino, di(Ci-6)alkylaminopyridinylamino, (Ci-6)alkylamino(C1-6)alkyl- pyridinylamino, di(Ci-6)alkylamino(Ci-6)alkylpyridinylamino, oxopyridinylamino, carboxypyridinylamino, N-[(Ci-6)alkyl]-N-[(C1-6)alkylpyridinyl]amino, bis[(C1-6)alkyl- pyridinyl] amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, (Ci.6)alkyl- pyridazinylamino, ^[(Cj-^alkylJ-N-f^j^alkylpyridaziny^amino, N-[aryl(C1-6)alkyl]-N- [(C 1 -6)alkylpyridazinyl]amino, di(Ci -6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (Ci-6)alkoxypyridazinylamino, [(Ci-6)alkoxyJ(halo)- pyridazinylamino, di(Ci-6)alkylaminopyridazinylamino, bis[(C]-6)alkylpyridazinyl]amino, (C] -6)alkylcinnolinylamino, oxopyrimidinylaniino, thioxopyrimidinylamino, quinoxalinylamino, (Ci-6)alkylchromenylamino, benzofuryl(Ci-6)alkylamino, thienyl(C1-6)- alkylamino, indolyl(Ci-6)alkylamino, (C1-6)alkylpyrazolyl(C1-6)alkylamino, [di(Ci-6)alkyl]- (halυ)pyrazolyl(C i .6)alkylamino, di(C i -6)alkylisoxazolyl(C i -6)alkylamino, thiazolyl(C i -6)- alkylamino, imidazolyl(C i -6)alkylamino, (C i -6)alkylimidazolyl(C i -6)alkylamino, pyridinyl(C i -6)alkylamino, (C i -6)alkylpyridinyl(C i -6)alkylamino, N- [(C i -6)alkyl] -N- [pyridinyl(Ci-6)alkyl]amino, N-[dihydroxy(Ci-6)alkyl]-N-[pyridinyl(Ci-6)alkyI]aniino, N- [(C i -6)alkylpyridinyl(C i -6)alkyl]-N-[dihydroxy(C i -6)alkyl] amino, amino(Ci .^alkyl, (C \ -6)- alkylamino(Ci.6)alkyl, di(Ci-6)alkylamino(Ci-6)alkyl, pyridinylamino(Ci.6)alkyl, C2-6 alkylcarbonylamino, N-[(C2-6)alkylcarbonyl]-N-[(C1-6)alkylpyridinyl(Ci-6)alkyl]amino, di(C1-6)alkylamino(Ci-6)alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, (C3-7)- cycloalkylcarbonylamino, (C 1 -6)alkylpiperidinylcarbonylamino, (C 1 -6)alkylimidazolyl- carbonylamino, C2-6 alkoxycarbonylamino, [(C2.6)alkoxycarbonyl] [(C i-6)alkyl] amino, Ci-6 alkylsulphonylamino, formyl, C2,6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl £?-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Cj-6 alkylaminocarbonyl, [hydroxy(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)- alkylamino(C 1 -6)alkyl] aminocarbonyl, di(C j -6)alkylaminocarbonyl, [(C 1 ^alkyl] [cyano- (C 1 -6)alkyl] aminocarbonyl, [(C 1 -6)alkyl] [hydroxy(C \ -6)alkyl] aminocarbonyl, [(C 1.όjalkoxy- (C 1 -6)alkyl] [(C \ -6)alkyl] aminocarbonyl, [di(C \ -6)alkylamino(C j -6)alkyl] [(C \ -6)alkyl] aminocarbonyl, C3-7 cycloalkyl(Ci-6)alkylaminocarbonyl, aryl(Ci-6)alkylaminocarbonyl, (C1-6)- alkylpiperidinylaminocarbonyl, N- [(C 1 -6)alkyl] -N- [(C \ -6)alkylpiperidinyl] aminocarbonyl, piperidinyl(C1-6)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, (Ci-6)alkylpiperazinylcarbonyl, morpholinylcarbonyl, Ci-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonylmethyl, aminosulphonyl, Ci-6 alkylaminosulphonyl, di(Ci-6)alkylaminosuIphonyl, C2-6 alkoxycarbonyloxy, trimethylsilyl and tetra(Ci.6)alkyldioxaborolanyl. Additional examples include [(Ci-6)alkoxy][(Ci-6)- alkyl] aminocarbonyl, C3-7 cycloalkylaminocarbonyl, N-[(Ci-6)alkyl]-N-(aryl)amino- carbonyl, hydroxypyrrolidinylcarbonyl and (C i-6)alkylsulphonylpiperazinyl carbonyl. Definitive examples of typical substituents on R3 and/or R4 include Ci-6 alkyl, (Ci-6)alkylimidazolyl, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(C 1 -6)alkylaminocarbonyl, [(C 1 -6)alkoxy] [(C 1 -6)alkyl] aminocarbonyl, [(C 1 -6)alkoxy(C 1 -6)- alkyl][(Ci-6)alkyl]aminocarbonyl, C3-7 cycloalkylaminocarbonyl, C3-7 cycloalkyl- (C1-6)alkylaminocarbonyl, iV-[(Ci-6)alkyl]-iV"-(aryl)aminocarbonyl, aryl(C1-6)alkylamino- carbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, (Ci-6)alkylpiperazinylcarbonyl, (C1-6)alkylsulphonylpiperazinyl- carbonyl and morpholinylcarbonyl.
Particular examples of typical substituents on R3 and/or R4 include C1-6 alkyl, C2-6 alkoxycarbonyl and di(C1-6)alkylaminocarbonyl.
Selected examples of specific substituents on R3 and/or R4 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, moφholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, morpholinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylpropylpyrazolyl, 3- methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)pyrazolyl, (dimethyl)(3 - methylbutyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2- hydroxy-2-methylpropylpyrazolyl, (hydroxyethyl)(dimethyl)pyτazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, [(hydroxy)-
(methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (phenyl)(trifluoromethyl)pyrazolyl, benzylpyrazolyl, aminobenzylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranylmethylpyrazolyl, (dimethyl)(tetrahydropyranyl- methyl)pyrazolyl, pyrrolidinylethylpyrazolyl, piperidinylethylpyrazolyl, methyl- piperidinylethylpyrazolyl, morpholinylethylpyrazolyl, pyridinylmethylpyrazolyl, oxypyridinylmethylpyrazolyl, (dimethyl)(phenylcarbonylmethyl)pyrazolyl, (ethyl)(piperazinylcarbonyl)pyrazolyl, (methylaminocarbonyl)(methylphenyl)pyrazolyl, (aminoethylaminocarbonyl)(methyl)pyrazolyl, aminocarbonylmethylpyrazolyl, (aminocarbonylmethyl)(dimethyl]pyrazolyl, dimethylaminocarbonylmethylpyrazolyl, pyrazolo[l,5-α]pyridinyl, dimethylisoxazolyl, (amino)(methyl)isoxazolyl, thiazolyl, dimethylthiazolyl, imidazolyl, methylimidazolyl, dimethylimidazolyl, imidazo[l,2- α]pyridinyl, methylimidazo[l,2-α]pyridinyl, methylimidazo[4,5-6]pyridinyl, imidazo[l,2- α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, methylthiadiazolyl, triazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methylpiperazinyl)pyridinyl, (methyl)(piperazinyl)pyridinyl, (tert- butoxycarbonylpiperazinyl)(methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)- pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, methoxypyridinyl, (methoxy)(methyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonyl- methylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylamino- pyridazinyl, pyrimidinyl, methylpyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethyl- pyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)- (piperazinyl)pyrimidinyl, (tert-butoxycarbonylpiperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxypropynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, (dimethylamino)- (fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonylmethyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinyl- pyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxy- pyridinyloxy, aminocarbonylpyridinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1- methylethyl, dihydroxypropyl, pyridinyloxymethyl, methylenedioxy, difluoromethylenedioxy, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, dimethylamino, N-(methoxyethyl)-N- (methyl)amino, N-(methoxypropyl)-N-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N-(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-(methyI)amino, fluorophenylamino, N-fluorophenyl-N-methylamino, methylenedioxyphenylamino, morpholinylmethylphenylainino, 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)ainino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)- benzylamino, methylenedioxybenzylamino, dihydrobenzofuranylamino, N-(methyl)-N- (methylpyrrolidinyl)amino, methylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N-(piperidinyl)amino, N- (cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinylamino, N-(methyl)-N- (methylpiperidinyl)amino, N-(methyl)-N-(2-methylpropylpiperidinyl)atnino, N- (cyclopentylpiperidinyl)-N-(methyl)amino, N-(acetylpiperidinyl)-N-(methyl)amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N-(pyrrolidinylethyl)amino, N-(methyl)-N-
(pyrrolidinylpropyl)amino, N-(methyl)-N-(piperidinylmethyl)amino, benzothienylamino, indolylamino, dioxoindolylamino, methylpyrazolylamino, (bromo)(methyl)pyrazolyl- amino, dimethylpyrazolylamino, trimethylpyrazolylamino, N-(ethyl)-N-(methylpyrazolyl)- amino, methylindazolylamino, benzoxazolylamino, benzoxazolonylamino, dimethyl- isoxazolylamino, thiazolylamino, benzothiazolylamino, methylisothiazolylamino, imidazolylamino, (ethoxycarbonyl)(methyl)imidazolylamino, methylbenzimidazolyl- amino, benzimidazolonylamino, dimethylbenzimidazolonylamino, methyloxadiazolyl- amino, furyloxadiazolylamino, methylthiadiazolylamino, pyridinylamino, chloropyridinyl- amino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, oxopyridinylamino, carboxypyridinylamino, N-(methyl)-7V-(methylpyridinyl)- amino, iV-(ethyl)-N-(methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, JV-(methyl)-N- (methylpyridazinyl)amino, N-(benzyl)-N-(methylpyridazinyl)amino, dimethyl- pyridazinylamino, phenylpyridazinylamino, piperidinylpyridazinylamino, methoxypyridazinylamino, (chloro)(methoxy)pyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, methylcinnolinylamino, oxopyrimidinyl- amino, thioxopyrimidinylamino, quinoxalinylamino, methylchromenylamino, benzofurylmethylamino, thienylmethylamino, indolylmethylamino, methylpyrazolyl- methylamino, (chloro)(dimethyl)pyrazolylmethylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethylamino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethylamino, iV-(methyl)-iV-(pyridinylethyl)- amino, iV-(dihydroxypropyl)-JV-(pyridinylmethyl)amino, ^-(dihydroxypropyl)-^- (methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, acetylamino, 7V-(acetyl)-N-(methylpyridinyl)amino, dimethylaminoethylcarbonylamino, acetylaminomethyl, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, methoxycarbonyl- amino, N-methoxycarbonyl-JV-methylamino, methylsulphonylamino, formyl, acetyl, acetyl oxime, acetyl 6>-(methyl)oxime, trifluoromethylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, (hydroxyethyl)aminocarbonyl, (dimethyl- aminoethyl)aminocarbonyl, ( 1 -hydroxyprop-2-yl)aminocarbonyl, dimethylamino- carbonyl, N-(cyanomethyl)-iV-methylaminocarbonyl, N-(cyanoethyl)-N-methylamino- carbonyl, N-(hydroxyethyl)-N-methylaminocarbonyl, 7V-(methoxyethyl)-iV-methyl- aminocarbonyl, N-(dimethylaminoethyl)-N-methylaminocarbonyl, iV-isopropyl-iV-methyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(methylpiperidinyl)amino- carbonyl, piperidinylethylaminocarbonyl, pyrazolylaminocarbonyl, pyridinylmethylamino- carbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, tert- butoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, methylpyrrolidinyl- carbonyl, methoxymethylpyrrolidinylcarbonyl, dimethylaminopyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinyl- carbonyl, morpholinylcarbonyl, isopropylthio, isopropylsulphinyl, methylsulphonyl, isopropylsulphonyl, methylsulphonylmethyl, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, tert-butoxycarbonyloxy, trimethylsilyl and tetramethyl- dioxaborolanyl. Additional examples include (methoxy)(methyl)aminocarbonyl, cyclopropylaminocarbonyl, iV-(methyl)-N-(phenyl)aminocarbonyl, hydroxypyrrolidinylcarbonyl and methylsulphonylpiperazinylcarbonyl.
Definitive examples of specific substituents on R3 and/or R4 include methyl, methylimidazolyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethyl- aminocarbonyl, diethylaminocarbonyl, (methoxy)(methyl)aminocarbonyl, 7V-(methoxy- ethyl)-iV-methylaminocarbonyl, cyclopropylaminocarbonyl, cyclopropylmethylamino- carbonyl, N-(methyl)-iV-(phenyl)aminocarbonyl, benzylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl, methylsulphonylpiperazinylcarbonyl and morpholinylcarbonyl.
Particular examples of specific substituents on R3 and/or R4 include methyl, methoxycarbonyl and dimethylaminocarbonyl.
Typical values of R3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-iV-phenylaminomethyl, pyridinylamino- methyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienyl- methylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, 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, furyloxadiazolyl- amlnobenzyl, pyridlnylaminobenzyl, chloropyridinylaminobenzyl, methylpyridinylamino- benzyl, dimethylpyridinylaminobenzyl, methoxypyridinylaminobenzyl, oxopyridinyl- aminobenzyl, oxopyrimidinylaminobenzyl, thioxopyrimidinylaminobenzyl, (chloro)- (methoxy)pyridazinylaminobenzyl, methylcinnolinylaminobenzyl, quinoxalinylamino- benzyl, methylchromenylaminobenzyl, benzofurylmethyl, cyanobenzoftirylmethyl, methoxycarbonylbenzofurylmethyl, dimethylaminocarbonylbenzofurylmethyl, azetidinylcarbonylbenzofurylmethyl, indolylmethyl, fluoroindolylmethyl, cyanoindolylmethyl, (cyano)(methyl)indolylmethyl, nitroindolylmethyl, methylindolylmethyl, oxazolinylindolylmethyl, triazolylindolylmethyl, methoxyindolylmethyl, (chloro)(methoxy)indolylmethyl, di(methoxy)indolylmethyl, difluoromethoxyindolylmethyl, trifluoromethoxyindolylmethyl, (chloro)(trifluoro- methoxy)indolylmethyl, cyclobutyloxyindolylmethyl, cyclopropylmethoxyindolylmethyl, morpholinylethoxyindolylmethyl, methylenedioxyindolylmethyl, difluoromethylenedioxy- indolylmethyl, azetidinylindolylmethyl, morpholinylindolylmethyl, acetylamino- indolylmethyl, acetylaminomethylindolylmethyl, methoxycarbonylaminoindolylmethyl, N-methoxycarbonyl-N-methylaminoindolylmethyl, methylsulphonylaminoindolylmethyl, acetylindolylmethyl, [acetyl oxime]indolylmethyl, [acetyl O-(methyl)oxime]- indolylmethyl, trifluoromethylcarbonylindolylmethyl, carboxyindolylmethyl, (carboxy)- (methyl)indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl, (chloro)(methoxycarbonyl)indolylmethyl, aminocarbonylindolylmethyl, (aminocarbonyl)(chloro)indolylmethyl, methylaminocarbonylindolylmethyl, (chloro)- (methylaminocarbonyl)indolylmethyl, (hydroxyethyOaminocarbonylindolylmethyl, (dimethylaminoethyl)aminocarbonylindolylmethyl, ( 1 -hydroxyprop-2-yl)aminocarbonyl- indolylmethyl, dimethylaminocarbonylindolylmethyl, (dimethylaminocarbonyl)(methyl)- indolylmethyl, (chloro)(dimethylaminocarbonyl)indolylmethyl, bis(dimethylamino- carbonyl)indolylmethyl, iV-(cyanomethyl)-N-methylaminocarbonylindolylmethyl, [N- (cyanomethyl)-N-methylaminocarbonyl](methyl)indolylmethyl, N-(cyanoethyl)-N- methylaminocarbonylindolylmethyl, N-(hydroxyethyl)-N-methylaminocarbonyl- indolylmethyl, N-(methoxyethyl)-N-methylaminocarbonylindolylmethyl, [N-(methoxy- ethyl)-N-methylaminocarbonyl](methyl)indolylmethyl, N-(dimethylaminoethyl)-N- methylaminocarbonylindolylmethyl, N-isopropyl-N-methylaminocarbonylindolylmethyl, diethylaminocarbonylindolylmethyl, cyclopropylmethylaminocarbonylindolylmethyl, benzylaminocarbonylindolylmethyl, pyrazolylaminocarbonylindolylmethyl, pyridinylmethylaminocarbonylindolylmethyl, azetidinylcarbonylindolylmethyl, (azetidinylcarbonyl)(methyl)indolylmethyl, hydroxyazetidinylcarbonylindolylmethyl, aminoazetidinylcarbonylindolylmethyl, tert-butoxycarbonylaminoazetidinylcarbonyl- indolylmethyl, pyrrolidinylcarbonylindolylmethyl, methylpyrrolidinylcarbonyl- indolylmethyl, methoxymethylpyrrolidinylcarbonylindolylmethyl, dimethylamino- pyrrolidinylcarbonylindolylmethyl, thiazolidinylcarbonylindolylmethyl, oxothiazolidinyl- carbonylindolylmethyl, piperidinylcarbonylindolylmethyl, methylpiperazinylcarbonyl- indolylmethyl, moφholinylcarbonylindolylmethyl, methylsulphonylindolylmethyl, methylsulphonylmethylindolylmethyl, dimethylaminosulphonylindolylmethyl, trimethylsilylindolylmethyl and pyrrolo[3,2-c]pyridinylmethyl. Additional values include methylimidazolylindolylmethyl, (methyl)(methylimidazolyl)indolylmethyl, (aminocarbonyl)(methyl)indolylmethyl, (methyl)(methylaminocarbonyl)indolylmethyl, (diethylaminocarbonyl)(methyl)indolylmethyl, [(methoxy)(methyl)aminocarbonyl]- (methyl)indolylmethyl, (cyclopropylaminocarbonyl)(methyl)indolylmethyl,
(cyclopropylmethylaminocarbony^^ethy^indolylmethyl, (methyl)[iV-(methyl)-N- (phenyl)aminocarbonyl]indolylmethyl, (benzylaminocarbonyl)(methyl)indolylmethyl, (hydroxyazetidinylcarbonyl)(methyl)indolylmethyl, (methyl)(pyrrolidinylcarbonyl)- indolylmethyl, (hydroxypyrrolidinylcarbonyl)(methyl)indolylmethyl, (methyl)(piperidinyl- carbonyl)indolylmethyl, (methyl)(methylpiperazinylcarbonyl)indolylmethyl, (methyl)- (methylsulphonylpiperazinylcarbonyl)indolylmethyl and (methyl)(morpholinylcarbonyl)- indolylmethyl.
Definitive values of R3 include indolylmethyl, methylimidazolylindolylmethyl, (methyl)(methylimidazolyl)indolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, (aminocarbonyl)(methyl)indolylmethyl, (methyl)(methylaminocarbonyl)indolylmethyl, (dimethylaminocarbonyl)(methyl)indolylmethyl, (diethylaminocarbonyl)(methyl)indolyl- methyl, [(methoxy)(methyl)aminocarbonyl](methyl)indolylmethyl, [N-(methoxyethyl)-N- methylaminocarbonyl](methyl)indolylmethyl, (cyclopropylaminocarbonyl)(methyl)- indolylmethyl, (cyclopropylmethylaminocarbony^^ethyOindolylmethyl, (methyl)[iV- (methyl)-N-(phenyl)aminocarbonyl]indolylmethyl, (benzylaminocarbonyl)(methyl)- indolylmethyl, (hydroxyazetidinylcarbonyl)(methyl)indolylmethyl, (methyl)(pyrrolidinyl- carbonyl)indolylmethyl, (hydroxypyrrolidinylcarbonyl)(methyl)indolylmethyl, (methyl)(piperidinylcarbonyl)indolylmethyl, (methyl)(methylpiperazinylcarbonyl)indolyl- methyl, (methyl)(methylsulphonylpiperazinylcarbonyl)indolylmethyl and (methyl)(morphollnylcarbonyl)lndolylmethyl.
Selected values of R3 include indolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl and (dimethylaminocarbonyl)(methyl)indolylmethyl. A particular value of R3 is indolylmethyl.
Typical values of R4 include hydrogen and methyl. In a preferred embodiment, R4 is hydrogen. In another embodiment, R4 is Cj-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, substiruents. 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, substiruents. 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, substiruents. Also in this context, in another embodiment, R3 and R4, when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e. an indanyl moiety fused to the morpholine ring, which indanyl moiety may be unsubstituted, or substituted by one or more, typically by one or two, substiruents. Examples of typical substiruents on the fused rings referred to in the preceding paragraph include halogen, nitro, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, (C1-6)alkylaryl, di(C i -6)alkylaryl, piperidinyl(C i ^alkylaryl, piperazinyl(C \ -6)alkylaryl, (Ci-6)aIkyIpiperazinyl(Ci-6)alkylaryl, morpholinyl(C1-6)alkylaryl, (Ci-6)alkoxyaryl, cyano(C i -6)alkoxyaryl, di(C i -6)alkylamino(Ci -6)alkylaryl, (Ci ^alkylaminocarbonylaryl, aryl(Ci.6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(C1-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (C1-6)alkylaminocarbonylpiperidinyl, piperazinyl, (C^alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (C1-6)alkyl- homopiperazinyl, (Ci-6)alkylpiperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl, benzofiαryl, benzothienyl, pyrazolyl, (Ci.6)alkylpyrazolyl, di(Ci-6)alkylpyrazolyl, tri(C1-6)alkyl- pyrazolyl, [di(Ci-6)alkyl](trifluoromethyl)pyrazolyl,
Figure imgf000021_0001
[cyano- (C i -6)alkyl] [di(C i _6)-alkyl]pyrazolyl, hydroxy(C i -6)alkylpyrazolyl, [hydroxy(C i -6)- alkyl][di(Ci-6)alkyl]pyrazolyl, HIeIhOXy(C1 ^alkylpyrazolyl, [(hydroxy)(methoxy)(Ci-6)- alkyl]pyrazolyl, amino(C1-6)alkylpyrazolyl, [(C1-6)alkyl] [amino(C1-6)alkyl]pyrazolyl, [amino(Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, di(Ci-6)alkylamino(Ci-6)alkylpyrazolyl, di(C1-6)alkoxyphosphono(C1-6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl- (C,.6)alkylpyτazolyl, [(C3-7)cycloalkyl(C1-6)alkyl][di(Cι-6)alkyl]pyrazolyl, [(Ci-6)alkyl]- (aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(Ci.6)alkylpyrazolyl, aminoaryl- (C1-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyKCi.^alkylpyrazolyl, [di- (C1 -6)alkyl] [tetrahydropyranyl(C i -6)alkyl]pyrazolyl, pyrrolidinyl(C i -6)alkylpyrazolyl, piperidinyl(C i -6)alkylpyrazolyl, (C i -6)alkylpiperidinyl(C i .6)alkylpyrazolyl, morpholinyl(C i .6)alkylpyrazolyl, pyridinyl(C i -6)alkylpyrazolyl, oxypyridinyl(C i -6)alkyl- pyrazolyl, [arylcarbonyl(C1-6)alkyl][di(Cι-6)alkyl]pyrazolyl,
Figure imgf000021_0002
carbonyl)pyrazolyl, [(Ci-6)alkylaminocarbonyl][(Ci-6)alkylaryl]pyrazolyl, [(C1-6)alkylj- [amino(Ci-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(Ci-6)alkylpyrazolyl, [aminocarbonyl(C ] -6)alkyl] [di(C \ ^alkyljpyrazolyl, di(C i -6)alkylaminocarbonyl(C i .6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1-6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]- isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (Ci-6)alkylimidazolyl, di(C1-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (C1-6)alkylimidazo[l,2-α]pyridinyl, (C1-6)- alkylimidazo[4,5-6]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (C1-6)- alkylthiadiazolyl, pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, [(Ci-6)alkyl](halo)- pyridinyl, di(Ci-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C1-6)alkylpiperazinylpyridinyl, [(C i -6)alkyl](piperazinyl)pyridinyl, [(Ci -6)alkoxycarbonylpiperazinyl] [(C i -6)alkyl] - pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(C i -6)alkylpyridinyl, (Ci -6)alkoxypyridinyl, [(Ci -6)alkoxy] [(C i -6)alkyl]pyridinyl, [(C i .6)alkoxy] [di(Ci -6)alkyl]pyridinyl, (C i -6)alkoxy(C i -6)alkylpyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (Ci-6)alkoxycarbonyl(C1-6)alkylpyridinyl, pyridazinyl, (C1-6)- alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (C1-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(C1-6)alkylaminopyridazinyl, di(C].6)alkylaminopyridazinyl, pyrimidinyl, (C1-6)alkylpyrimidinyl, [(C1-6)alkyl](halo)pyrimidinyl, di(C1-6)alkyl- pyrimidinyl, pyrrolidinylpyrimidinyl, (C1-6)alkylpiperazinylpyrimidinyl,
[(C i -6)alkyl] (piperazinyl)pyrimidinyl, [(C i -o)alkoxycarbonyl] [(C i _6)alkyl]piperazinyl- pyrimidinyl, hydroxypyrimidinyl, [(C1-6)alkyl](hydroxy)pyrimidinyl,
Figure imgf000022_0001
[hydroxy(Ci-6)alkyl]pyrimidinyl, [(C1-6)alkyl][hydroxy(C2-6)alkynyl]pyrimidinyl, (C1-6)- alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminopyrimidinyl, [di(C1-6)alkyl- amino](halo)pyrimidinyl, carboxypyrimidinyl, [(C 1-6)alkoxycarbonyl(C1-6)alkyl] [(C1-6)- alkyljpyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (Ci-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (C]-6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy, morpholinyl- (Ci-6)alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C i -6)alkylpyrazolyl- pyridinyloxy, (C1-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C i .$)alkyl] (halo)pyrimidinyloxy, hydroxy(C \ -6)alkyl, dihydroxy(C i -6)alkyl, PJaIdIHyIoXy(C1 -6)alkyl, amino, (C1-6)alkylamino, dihydroxy(C1-6)alkylamino, (C1-6)- alkoxy(Ci-6)alkylamino, N-[(C1-6)alkoxy(Ci-6)alkyl]-iV-[(C1-6)alkyl]amino, di(Ci-6)- alkylamino(Ci-6)alkylamino, N-[(C1-6)alkyl]-7V-[di(C1-6)alkylamino(Ci-6)alkyl]amino, N- [(Ci-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino, N-[(Ci-6)alkyl]-N-(haloaryl)amino, N-[(Ci-6)alkyl]-N-[aryl(Ci-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, methylene- dioxyaryl(C \ .6)alkylamino, N- [(C j .0)3^1] -N- [(C \ -6)alkylpyrrolidinyl] amino, piperidinyl- amino, N-[(Ci-6)alkyl]-N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(C1-6)alkyl]-N- (piperidinyl)amino, (C1-6)alkylpiperidinylamino, N-[(C1-6)alkyl]-N-[(Ci-6)alkyl- piperidinyljamino, N-[(C1-6)alkyl]-N-[(C3-7)cycloalkylpiperidinyl]amino, N-[(C1-6)alkyl]- N-[(C2-6)alkylcarbonylpiperidinyl]amino, pyrrolidinyl(Ci-6)alkylamino, N-[(C].6)alkyl]-N-
Figure imgf000022_0002
N-[(Ci-6)alkyl]-N-[piperidinyl(Ci-6)alkyl]amino, (Ci-6)- alkylpyrazolylamino, di(Ci-6)alkylpyrazolylamino, tri(C1-6)alkylpyrazolylamino, N-[(Ci-6)- alkyl]-N-[(Cι-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(Ci-6)alkoxy- carbonyl][(C1-6)alkyl]imidazolylamino, (Ci-6)alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (Ci-6)alkylpyridinylamino, di(Ci.6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(C i -6)alkylpyridinylamino, dihydroxy(C j -6)alkylpyridinylamino, (C i -6)alkoxypyridinylamino, dihydroxy(C i -6)alkoxy- pyridinylamino, di(C \ -6)alkyldioxolanyl(C \ -6)alkoxypyridinylamino, (C i -6)alkoxy(C i -6)- alkylpyridinylamino, (C1-6)alkoxy(C2-6)alkenylpyridinylaniino, dihydroxy(Ci-6)alkyl- aminopyridinylamino, di(C1-6)alkylaminopyridinylamino, (C1-6)alkylamino(C1-6)alkyl- pyridinylamino, di(C1-6)alkylamino(Ci-6)alkylpyridinylamino, carboxypyridinylamino, N- [(Ci^alkylJ-N-t^i-^alkylpyridinyljamino, bis[(Ci.6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (Ci-6)alkylpyridazinylamino, N-[(Ci-6)alkyl]- N-[(Ci-6)alkylpyridazinyl]amino, N-[aryl(Ci-6)alkyl]-N-[(C1-6)alkylpyridazinyl]amino, di(Ci-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (Ci-6)- alkoxypyridazinylamino, di(C \ -6)alkylaminopyridazinylamino, bis[(C \ -6)alkylpyridazinyl]- amino, benzofuryl(C1-6)alkylamino, thienyl(C1-6)alkylamino, indolyl(C]-6)alkylamino, (C i -6)alkylpyrazolyl(C i -6)alkylamino, [di(C i .6)alkyl] (halo)pyrazolyl(C \ -6)alkyl amino, di(C1,6)alkylisoxazolyl(C1-6)alkylamino, thiazolyl(C1-6)alkylamino, imidazolyl(C1-6)alkyl- amino, (C i -6)alkylimidazolyl(C i -6)alkylamino, pyridinyl(C i -6)alkylamino, (C \ -6)alkyl-
Figure imgf000023_0001
(Ci-6)alkyl]-N-[pyridinyl(C1-6)alkyl]amino, N-[(C1-6)alkylpyridinyl(Ci-6)alkyl]-N- [dihydroxy(C1-6)alkyl]amino, amino(C1-6)alkyl, (C1-6)alkylamino(C1-6)alkyl, di(Ci-6)alkyl- amino(C i -6)alkyl, pyridinylamino(C i -6)alkyl, N-[(C2-6)alkylcarbonyl] -N-[(C \ ,6)alkyl- pyridinyl(C1-6)alkyl]amino, di(C1-6)alkylamino(C1-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (C1-6)alkylpiperidinylcarbonylamino, (C1-6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (C1-6)alkylpiperidinylaminocarbonyl, N-[(C1-6)alkyl]-N-[(C1-6)- alkylpiperidinyljaminocarbonyl, piperidinyl(Ci-6)alkylaminocarbonyl,
Figure imgf000023_0002
piperazinylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy and tetra(C1-6)alkyldioxaborolanyl.
A particular example of a typical substituent on the fused rings referred to in the two preceding paragraphs is (C1-6)alkylpyrazolyl.
Selected examples of specific substituents on the fused rings referred to in the three preceding paragraphs include bromo, nitro, methyl, n-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methyl- propylpyrazolyl, 3-methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)- pyrazolyl, (dimethyl)(3-methylbutyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2-hydroxy-2-methylpropylpyrazolyl, (hydroxyethyl)(dimethyl)- pyrazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, [(hydroxy)- (methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyτazolyl, (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- αjpyridinyl, methylimidazo[l,2-α]pyridinyl, methylimidazo[4,5-b]pyridinyl, imidazo[l,2- αjpyrimidinyl, imidazo[l,2-α]pyrazinyl, methylthiadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methyl- piperazinyl)pyridinyl, (methyl)(piperazinyl)pyridinyl, (ter/-butoxycarbonylpiperazinyl)- (methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, methoxypyridinyl, (methoxy)(methyl)- pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonylmethylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylaminopyridazinyl, pyrimidinyl, methyl- pyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)(piperazinyl)pyrimidinyl, (tert-butoxycarbonyl- piperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxy- propynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylamino- pyrimidinyl, (dimethylamino)(fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonyl- methyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinylpyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)- pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1 -methylethyl, dihydroxypropyl, pyridinyloxymethyl, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, N-(methoxyethyl)-N-(methyl)amino, ^-(methoxypropyl)-^- (methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N- (dimethylammoethyl)-N-(methyl)amino, N-(diethylaminoethyl)-N-(methyl)amino, N- (dimethylaminopropyl)-N-(methyl)amino, N-(dimethylaminoethyl)-N-(ethyl)amino, N- (dimethylaminopropyl)-N-(ethyl)amino, N-(cyclohexyl)-N-(methyl)amino, fluorophenyl- amino, N-fluorophenyl-N-methylamino, N-benzyl-N-methylamino, iV-(benzyl)-N- (dimethylaminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)benzylamino, methylenedioxybenzylamino, N-(methyl)-N-(methyl- pyrrolidinyl)amino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N- (piperidinyl)amino, N-(cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinyl- amino, N-(methyl)-N-(methylpiperidinyl)amino, N-(methyl)-N-(2-methylpropyl- piperidinyl)amino, N-(cyclopentylpiperidinyl)-N-(methyl)amino, N-(acetylpiperidinyl)-N- (methyl)amino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N- (pyrrolidinylethyl)amino, N-(methyl)-N-(pyrrolidinylpropyl)amino, 7V-(methyl)-N- (piperidinylmethyl)amino, methylpyrazolylamino, dimethylpyrazolyl amino, trimethylpyrazolylamino, N-(ethyl)-N-(methylpyrazolyl)arnino, 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-(memyl)-N-(methylpyridinyl)arnino, N-(ethyl)-N- (methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-iV-(methylpyridazinyl)amino, N- (benzyl)-N-(methylpyridazinyl)amino, dimethylpyridazinylamino, phenylpyridazinyl- amino, piperidinylpyridazinylamino, methoxypyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, benzofurylmethylamino, thienylmethyl- amino, indolylmethylaniino, methylpyrazolylmethylamino, (chloro)(dimethyl)pyrazolyl- methylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethyl- amino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethyl- amino, N-(methyl)-iV-(pyridinylethyl)amino, N-(dihydroxypropyl)-N-(pyridinylmethyl)- amino, N-(dihydroxypropyl)-N-(methylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, N-(acetyl)-N-(methyl- pyridinyl)amino, dimethylaminoethylcarbonylamino, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, formyl, acetyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(methylpiperidinyl)aminocarbonyl, piperidinylethylaminocarbonyl, methylpiperazinylcarbonyl, isopropylthio, isopropyl- sulphinyl, isopropylsulphonyl, tert-butoxycarbonyloxy and tetramethyldioxaborolanyl. A particular example of such a substituent is methylpyrazolyl. In one embodiment, R5 represents hydrogen. In another embodiment, R5 represents Ci-6 alkyl, especially methyl.
One sub-class of compounds according to the invention is represented by the compounds of formula (HA), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000027_0001
(HA)
wherein
R11 represents hydrogen or Ci-6 alkyl; and R12 represents hydrogen; or C1-6 alkyl, C1-6 alkoxy, 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(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R and R may together form an isopropylidene moiety; 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 Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, 8TyI(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.
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, hi one embodiment, Rπ 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, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci-6 alkyl thio, Ci-6 alkylsulphonyl, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulphonyl, C1-6 alkylaminosulphonyl and di(Ci-6)alkylaminosulphonyl; especially halogen, Ci-6 alkoxy or Ci-6 alkylthio. Examples of particular substituents on R12 include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, 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 Ri2 include hydrogen, methyl, n-propyl, isopropyl, isobutyl, cyclohexyl and phenyl. A particular value of R12 is methyl.
In another embodiment, R1 { and R12 may together form an isopropylidene moiety [i.e. C(R11XR12) represents C=C(CH3)2] .
Alternatively, R1 ' and R12 may together form an optionally substituted spiro linkage. Thus, R1 ' and R12, when taken together with the carbon atom to which they are both attached, may represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, R1 ' and R12, when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.
Typically, R13 represents hydrogen; or C1-6 alkyl, aryl(Ci.6)alkyl, aryl(C2-6)alkynyl, biaryl(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl(C i -6)alkyl, heteroaryl-aryl(C i -6)alkyl or aryl-heteroaryl(C i -6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Generally, R13 represents hydrogen; or C2-6 alkynyl, aryl(Ci-6)alkyl or heteroaryl- (Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R13 represents aryl(C[.6)alkyl or heteroaryl(Ci-6)alkyl, either of which groups may be optionally substituted by one or more substituents.
In one specific embodiment, R13 represents hydrogen.
In a representative embodiment, R13 represents Ci-6 alkyl, aryl(Ci-6)alkyl, biaryl- (Ci-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, R1 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 may be 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, R1 represents substituted or unsubstituted phenyl- (C1-6)alkyl. Advantageously, R13 represents substituted or unsubstituted benzyl. In another embodiment, R13 represents substituted or unsubstituted benzofuryl-
(C1-6)alkyl. Advantageously, R13 represents substituted or unsubstituted benzofurylmethyl.
Illustratively, R13 represents hydrogen; or methyl, propynyl, benzyl, phenylethyl, naphthylmethyl, phenylpropynyl, biphenylmethyl, naphthylphenylmethyl, indoliήylmethyl, 1 ,2,3,4-tetrahydroquinolinylmethyl, 1 ,2,3,4-tetrahydroisoquinolinyl- methyl, piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolinylcarbonyl, 1,2,3,4-
( tetrahydroisoquinolinylcarbonyl, 1,2,3,4-tetrahydroquinoxalinylcarbonyl, benzofurylmethyl, benzothienylmethyl, indolylmethyl, pyrrolo[2,3-Z>]pyridinylmethyl, pyrrolo[3,2-c]pyridinylmethyl, benzimidazolylmethyl, benzotriazolylmethyl, pyridinylmethyl, quinolinylmethyl, isoquinolinylmethyl, benzofurylbenzyl, thienylbenzyl, benzothienylbenzyl, indolylbenzyl, isoxazolylbenzyl, pyrazolylbenzyl, pyridinylbenzyl, pyrimidinylbenzyl or phenylpyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.
Examples of typical substituents on R13 include halogen, cyano, nitro, Ci-6 alkyl, trifluoromethyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci-6)alkylaryl, diCd-^alkylaryl, piperidinyl- (Ci-6)alkylaryl, piperazinyl(C1-6)alkylaryl, (Ci-6)alkylpiperazinyl(C1-6)alkylaryl, morpholinyl(C1-6)alkylaryl, (C1-6)alkoxyaryl, cyano(C1-6)alkoxyaryl, di(Ci.6)alkyl- amino(Ci-6)alkylaryl, (C^alkylaminocarbonylaryl, aryl(C1-6)alkyl, oxazolinyl, azetidinyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(C1-6)alkylaminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di(Ci-6)alkylamino- carbonylpiperidinyl, piperazinyl, (Ci-6)alkylpiperazinyl, haloarylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (Ci-6)alkylhomopiperazinyl, morpholinyl, (Ci-6)alkylpiperazinyl(C1-6)alkyl, morpholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(Ci-6)alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, [di(Ci-6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano- (C i -6)alkyl] [(Ii(C1 ^alkyljpyrazolyl, hydroxy(C i -6)alkylpyrazolyl, [hydroxy(C i -6)- alkyl] [di(C1-6)alkyl]pyrazolyl, methoxy(Ci-6)alkylpyrazolyl, [(hydroxy)(methoxy)(C1-6)- alkyljpyrazolyl, 3HImO(C1 -6)alkylpyrazolyl, [(Ci-6)alkyl][amino(C1-6)alkyl]pyrazolyl, [amino(C i -6)alkyl] [di(C i ^alkyljpyrazolyl, di(C i -6)alkylamino(C i .6)alkylpyrazolyl, di(Ci-6)alkoxyphosphono(Ci-6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl- (Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl(Ci-6)alkyl][di(CI-6)alkyl]pyrazolyl, [(C1.6)alkyl]- (aryl)pyrazolyl, (aryl)(trifluoroniethyl)pyrazolyl, aryl(C1-6)alkylpyrazolyl, aminoaryl- (C1-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(Ci-6)alkylpyrazolyl, [di- (C ] -6)alkyl] [tetrahydropyranyl(C i -6)alkyl]pyrazolyl, pyrrolidinyl(C i -6)alkylpyrazolyl, piperidinyl(C i -6)alkylpyrazolyl, (C i -6)alkylpiperidinyl(C i -6)alkylpyrazolyl, moφholinyl(C1-6)alkylpyrazolyl, pyridinyl(C1-6)alkylpyrazolyl, oxypyridinyl(C1-6)alkyl- pyrazolyl, [arylcarbonyl(Ci-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(Ci-6)alkyl](piperazinyl- carbonyl)pyrazolyl, [(Ci-6)alkylaminocarbonyl][(Ci-6)alkylaryl]pyrazolyl, [(Ci.6)alkyl]- [amino(C \ .6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C i^alkylpyrazolyl,
[aminocarbonyl(C i -6)alkyl] [di(C \ -6)alkyl]pyrazolyl, di(C i ^alkylaminocarbony^C \ .6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1-6)alkylisoxazolyl, (amino)[(C1-6)alkyl]- isoxazolyl, thiazolyl, di(C1-6)alkylthiazolyl, imidazolyl, (C1-6)alkylimidazolyl, di(Ci-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (Ci-6)alkylimidazo[l,2-α]pyridinyl, (Ci-6)- alkylimidazo[4,5-όjpyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (Ci-6)- alkylthiadiazolyl, triazolyl, pyridinyl, halopyridinyl, (Ci-6)alkylpyridinyl, [(Ci-6)alkyl]- (halo)pyridinyl, di(Ci-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (Ci-6)alkylpiperazinyl- pyridinyl, [(C i -6)alkyl] (piperazinyl)pyridinyl, [(C i -6)alkoxycarbonylpiperazinyl] [(C i -6)- alkyljpyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(C i -6)alkylpyridinyl, (C i -6)alkoxypyridinyl, [(C i -6)alkoxy] - [(Ci-6)alkyl]pyridinyl, [(C1-6)alkoxy][di(Ci-6)alkyl]pyridinyl, (Ci-6)alkoxy(Ci-6)alkyl- pyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (C1-6)alkoxycarbonyl(C1-6)alkyl- pyridinyl, pyridazinyl, (Ci-6)alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (C].6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(Ci-6)alkylaminopyridazinyl, di- (Ci-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(Ci-6)alkyl](halo)- pyrimidinyl, di(Ci-6)alkylpyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinyl- pyrimidinyl, [(C i-6)alkyl] (piperazinyl)pyrimidinyl, [(C i -6)alkoxycarbonyl] [(C i -6)alkyl] - piperazinylpyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(Ci-6)- alkyl] [hydroxy(Cj -6)alkyl]pyrimidinyl, [(C i .6)alkyl] [hydroxy(C2-6)alkynyl]pyriπiidinyl, (Cj-6)alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminoρyrimidinyl, [di(Ci-6)alkyl- amino] (halo)pyrimidinyl, carboxypyrimidinyl, [(C i -6)alkoxycarbonyl(C i -6)alkyl] [(C i -β)- alkyl]pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (C1-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (Q^alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(C1-6)alkoxy, aryl(Ci-6)alkoxycarbonylpiperidinyloxy, morpholinyl(C1-6)- alkoxy, aryloxy, haloaryloxy, di(Ci-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C1-6)alkylpiperazinylpyridinyloxy, (Ci^alkylpyrazolyl- pyridinyloxy, (C1-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci^alkylpyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(Cj-6)alkyl](halo)pyrimidinyloxy, hydroxy(Ci-6)alkyl, dihydroxy(C1-6)alkyl, pyridinyloxy(C1-6)alkyl, methylenedioxy, difluoromethylenedioxy, amino, (C1-6)alkyl- amino, dihydroxy(Ci-6)aIkylamino, (C1-6)alkoxy(C1-6)alkylamino, di(C1-6)alkylamino, N- [(C i -6)alkoxy(C i -6)alkyl]-N- [(C \ _6)alkyl] amino, di(C i .6)alkylamino(C i -6)alkylamino, N- [(C1-6)alkyl]-N-[di(C|-6)alkylamino(Ci-6)alkyl]amino, N-[(Ci-6)alkyl]-N-[(C3-7)cycloalkyl]- amino, haloarylamino, N-[(C1-6)alkyl]-N-(haloaryl)amino, methylenedioxyphenylamino, morpholinyl(C i -6)alkylphenylamino, oxazolinylphenylamino, [(C \ ^alkyl] (oxo)pyrazolyl- phenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, (C 1-6)alkyltriazolylphenylamino, (C \ -6)alkylpyrimidinylphenylamino, pyrazolyl(C \ _6)alkyl- phenylamino, triazolyl(Ci-6)alkylphenylamino, Ci-6 alkylsulphonylaminophenylamino, morpholinylcarbonylphenylamino, C1-6 alkylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-[(Ci-6)alkyl]-N-[aryl(Ci-6)alkyl]amino, N- [di(C i -6)alkylamino(C i -6)alkyl] -N-[aryl(C j ^alkyl] amino, cyanoaryl(C i -ό)alkyl amino, (cyano)(halo)aryl(C i -6)alkylamino, methylenedioxyaryl(C i -6)alkylamino, dihydrobenzofuranylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkylpyrrolidinyl]amino, C1-6 alkylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-[(Ci_6)alkyl]-N- (piperidinyl)amino, N-[(C3-7)cycloalkyl(C1-6)alkyl]-N-(piperidinyl)amino, (C1-6)alkyl- piperidinylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpiperidiriyl]amino, N-[(Ci-6)alkyl]- N-[(C3-7)cycloalkylpiperidinyl]amino, N-[(Ci-6)alkyl]-N-[(C2-6)alkylcarbonylpiperidinyl]- amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinyl(C(-6)alkylamino, N-[(Ci-6)alkyl]-N-[pyrrolidinyl(C,-6)alkyl]amino, N-[(Ci-6)alkyl]-N-[piperidinyl(Ci-6)- alkyl] amino, benzothienylamino, indolylamino, dioxoindolylamino, (C!.6)alkylpyrazolyl- amino, [(Ci-6)alkyl](halo)pyrazolylamino, di(Ci-6)alkylpyrazolylamino, tri(Ci-6)alkyl- pyrazolylamino, N-[(Ci-6)alkyl]-N-[(Ci-6)alkylpyrazolyl]amino, (C1-6)alkylindazolylamino, benzoxazolylamino, benzoxazolonylamino, di(Ci-6)alkylisoxazolylamino, thiazolylamino, benzothiazolylamino, (C1-6)alkylisothiazolylamino, imidazolylamino, [(Ci-6)alkoxy- carbonyl] [(C \ ^alkyl] imidazolylamino, (C i -6)alkylbenzimidazolylamino, benzimidazolonylamino, di(Ci-6)alkylbenzimidazolonylamino, (C1-6)alkyloxadiazolyl- amino, fiiryloxadiazolylamino,
Figure imgf000032_0001
pyridinylamino, halopyridinylamino, (C1-6)alkylpyridinylamino, di(Cj.6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(Ci-6)alkylpyridinylamino, dihydroxy(C \ -6)alkylpyridinylamino, (C \ -6)alkoxypyridinylamino, dihydroxy(C i -6)alkoxy- pyridinylamino, di(C1-6)alkyldioxolanyl(C1.6)alkoxypyridinylamino, (Ci-δ)alkoxy(C1-6)- alkylpyridinylamino, (Ci-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C1-6)alkyl- aminopyridinylamino, di(Ci-6)alkylaminopyridinylammo, (C1-6)alkylamino(C1-6)alkyl- pyridinylamino, di(C i .6)alkylamino(C i -6)alkylpyridinylamino, oxopyridinylamino, carboxypyridinylamino, N-[(Ci-6)alkyl]-iV-[(Ci-6)alkylpyridinyl]amino, bis[(Cj.6)alkyl- pyridinyl] amino, bis(trifluoromethylpyridinyl)amino, isoquinolinylamino, (C i ,6)alkyl- pyridazinylamino, N- [(C \ -6)alkyl] -N- [(C \ -6)alkylpyridazinyl] amino, N- [aryl(C i -6)alkyl] -N- [(C i -6)alkylpyridazinyl] amino, di(C \ -6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C1-6)alkoxypyridazinylamino, [(Ci-6)alkoxy](halo)- pyridazinylamino, di(C1-6)alkylaminopyridazinylamino, bis[(Ci-6)alkylpyridazinyl]amino, (Ci-6)alkylcinnolinylamino, oxopyrimidinylamino, thioxopyrimidinylamino, quinoxalinylamino,
Figure imgf000032_0002
benzofuryl(Ci.6)alkylamino, thienyl(Ci-6)- alkylamino,
Figure imgf000032_0003
(C1-6)alkylpyrazolyl(C1-6)alkylamino, [di(Ci-6)alkyl]- (halo)pyrazolyl(C1.6)alkylamino, di(C1-6)alkylisoxazolyl(C1-6)alkylamino, IWaZoIyI(C1-6)- alkylamino, imidazolyl(C \ -6)alkylamino, (C \ -6)alkylimidazolyl(C1 -6)alkylamino, pyridinyl(Ci.6)alkylamino, (Ci-6)alkylpyridinyl(C1-6)alkylamino, N-[(Ci-6)alkyl]-N-
[pyridinyl(C \ -6)alkyl]amino, 7V-[dihydroxy(C \ -6)alkyl] -N-[pyridinyl(Ci -6)alkyl]amino, N- [(C] -6)alkylpyridinyl(C1 -6)alkyl]-iV-[dihydroxy(C \ -6)alkyl]amino, amino(C i -6)alkyl, (C \ -6)- alkylamino(Ci-6)alkyl, di(C[-6)alkylamino(Ci-6)alkyl, pyridinylamino(Ci-6)alkyl, C2-6 alkylcarbonylamino, N-[(C2-6)alkylcarbonyl]-N-[(Ci-6)alkylpyridinyl(Ci-6)alkyl]amino, di(Ci-6)alkylamino(C1-6)alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, (C3-7)- cycloalkylcarbonylamino, (C i _6)alkylpiperidinylcarbonylamino, (C \ -6)alkylimidazolyl- carbonylamino, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl] [(C i-6)alkyl] amino, Ci-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl 0-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Cj-6 alkylaminocarbonyl, [hydroxy(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)~ alkylamino(Ci-6)alkyl]aminocarbonyl, di(C1-6)alkylaminocarbonyl, [(C1-6)alkyl][cyano- (C1-6)alkyl]aminocarbonyl, [(C1-6)alkyl][hydroxy(C1-6)alkyl]aminocarbonyl, [(Ci^alkoxy- (C1-6)alkyl][(C1-6)alkyl]aminocarbonyl, [di(C1-6)alkylamino(C1-6)alkyl][(C1-6)alkyl]amino- carbonyl, C3-7 cycloalkyl(C1-6)alkylaminocarbonyl, aryl(C1-6)alkylaminocarbonyl, (C1-6)- alkylpiperidinylaminocarbonyl, N-[(Ci-6)alkyl]-N-[(Ci-6)-alkylpiperidinyl]aminocarbonyl, piperidinyl(Ci -6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C] ^alkylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, (Ci-6)alkyl- pyrrolidinylcarbonyl, C1-6 alkoxy(C1-6)alkylpyrrolidinylcarbonyl, di(C1-6)alkylamino- pyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinyl- carbonyl, (C1-6)alkylpiperazinylcarbonyl, morpholinylcarbonyl, C1-6 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. Additional examples include [(Ci-6)alkoxy][(Ci-6)- alkyl] aminocarbonyl, C3-7 cycloalkylaminocarbonyl, iV-[(Ci-6)alkyl]-iV-(aryl)amino- carbonyl, hydroxypyrrolidinylcarbonyl and (Ci-^alkylsulphonylpiperazinylcarbonyl. Definitive examples of typical substituents on R13 include Ci-6 alkyl, (Ci-6)alkylimidazolyl, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(C i -6)alkylaminocarbonyl, [(C i -6)alkoxy] [(C i -6)alkyl] aminocarbonyl, [(C i -6)alkoxy(C i -6)- alkyl][(Ci-6)alkyl]aminocarbonyl, C3-7 cycloalkylaminocarbonyl, C3-7 cycloalkyl- (C i -6)alkylaminocarbonyl, N-[(C \ -6)alkyl]-N-(aryl)aminocarbonyl, aryl(Ci .^alkylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, (Ci-6)alkylpiperazinylcarbonyl, (Ci-6)alkylsulphonylpiperazinyl- carbonyl and morpholinylcarbonyl.
Particular examples of typical substituents on R13 include C^6 alkyl, C2-6 alkoxycarbonyl and di(Ci-6)alkylaminocarbonyl.
Selected examples of specific substituents on R13 include fluoro, chloro, bromo, cyano, nitro, methyl, n-propyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethylphenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, oxazolinyl, azetidinyl, pyrrolidinyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylaminopyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylaminocarbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, fiiroylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, morpholinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofiiryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methylpropylpyrazolyl, 3- methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)pyrazolyl, (dimethyl)(3 - methylbutyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2- hydroxy-2-methylpropylpyrazolyl, (hydroxyethyl)(dimethyl)pyrazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, [(hydroxy)- (methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethyl)(dimethyl)pyrazolyl, (methyl)(phenyl)- pyrazolyl, (phenyl)(trifluoromethyl)pyrazolyl, benzylpyrazolyl, aminobenzylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranylmethylpyrazolyl, (dimethyl)(tetrahydropyranyl- methyl)pyrazolyl, pyrrolidinylethylpyrazolyl, piperidinylethylpyrazolyl, methyl- piperidinylethylpyrazolyl, morpholinylethylpyrazolyl, pyridinylmethylpyrazolyl, oxypyridinylmethylpyrazolyl, (dimethyl)(phenylcarbonylmethyl)pyrazolyl, (ethyl)(piperazinylcarbonyl)pyrazolyl, (methylaminocarbonyl)(methylphenyl)pyrazolyl, (aminoethylaminocarbonyl)(methyl)pyrazolyl, aminocarbonylmethylpyrazolyl, (aminocarbonylmethyl)(dimethyl]pyrazolyl, dimethylaminocarbonylmethylpyrazolyl, pyrazolo[l,5-α]pyridinyl, dimethylisoxazolyl, (amino)(methyl)isoxazolyl, thiazolyl, dimethylthiazolyl, imidazolyl, methylimidazolyl, dimethylimidazolyl, imidazo[l,2- α]pyridinyl, methylimidazo[l,2-α]pyridinyl, methylimidazo[4,5-6]pyridinyl, imidazo[l,2- αjpyrimidinyl, imidazo[l,2-a]pyrazinyl, methylthiadiazolyl, triazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methylpiperazinyl)pyridinyl, (methyl)(piperazinyl)pyridinyl, (tert- butoxycarbonylpiperazinyl)(methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)- pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, methoxypyridinyl, (methoxy)(methyl)pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonyl- methylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylamino- pyridazinyl, pyrimidinyl, methylpyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethyl- pyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyrimidinyl, (methyl)- (piperazinyl)pyrimidinyl, (terJ-butoxycarbonylpiperazinylXmethyOpyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxypropynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, (dimethylamino)- (fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonylmethyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinyl- pyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxy- pyridinyloxy, aminocarbonylpyridinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1- methylethyl, dihydroxypropyl, pyridinyloxymethyl, methylenedioxy, difluoromethylenedioxy, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, dimethylamino, N-(methoxyethyl)-N- (methyl)amino, N-(methoxypropyl)-N-(methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, iV-(dimethylaminoethyl)-iV-(methyl)amino, iV- (diethylaminoethyl)-N-(methyl)amino, iV-(dimethylaminopropyl)-N-(methyl)amino, N- (dimethylaminoethyl)-N-(ethyl)amino, N-(dimethylaminopropyl)-N-(ethyl)amino, N- (cyclohexyl)-N-(methyl)amino, fluorophenylamino, N-fluorophenyl-N-methylamino, methylenedioxyphenylamino, morpholinylmethylphenylamino, oxazolinylphenylamino, (methyl)(oxo)pyrazolylphenylamino, oxazolylphenylamino, isoxazolylphenylamino, triazolylphenylamino, methyltriazolylphenylamino, methylpyrimidinylphenylamino, pyrazolylmethylphenylamino, triazolylmethylphenylamino, methylsulphonylamino- phenylamino, morpholinylcarbonylphenylamino, methylsulphonylphenylamino, morpholinylsulphonylphenylamino, N-benzyl-N-methylamino, N-(benzyl)-N-(dimethyl- aminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)- benzylamino, methylenedioxybenzylamino, dihydrobenzofuranylamino, N-(methyl)-N- (methylpyrrolldinyl)amino, methylsulphonylindolinylamino, chromanonylamino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N-(piperidinyl)amino, N- (cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinylamino, N-(methyl)-N- (methylpiperidinyl)amino, N-(methyl)-N-(2-methylpropylpiperidinyl)amino, N- (cyclopentylpiperidinyl)-N-(methyl)amino, N-(acetylpiperidinyl)-N-(methyl)amino, dihydroquinolinonylamino, benzoxazinonylamino, pyrrolidinylethylamino, pyrrolidinylpropylamino, N-(methyl)-N-(pyrrolidinylethyl)amino, N-(methyl)-N- (pyrrolidinylpropyl)amino, N-(methyl)-N-(piperidinylmethyl)amino, benzothienylamino, indolylamino, dioxoindolylamino, methylpyrazolylamino, (bromo)(methyl)pyrazolyl- amino, dimethylpyrazolylamino, trimethylpyrazolylamino, N-(ethyl)-N-(methylpyrazolyl)- amino, methylindazolylamino, benzoxazolylamino, benzoxazolonylamino, dimethyl- isoxazolylamino, thiazolylamino, benzothiazolylamino, methylisothiazolylamino, imidazolylamino, (ethoxycarbonyl)(methyl)imidazolylamino, methylbenzimidazolyl- amino, benzimidazolonylamino, dimethylbenzimidazolonylamino, methyloxadiazolyl- amino, furyloxadiazolylamino, methylthiadiazolylamino, pyridinylamino, chloropyridinyl- amino, bromopyridinylamino, methylpyridinylamino, dimethylpyridinylamino, trifluoromethylpyridinylamino, hydroxypyridinylamino, hydroxyethylpyridinylamino, dihydroxyethylpyridinylamino, methoxypyridinylamino, dihydroxypropoxypyridinyl- amino, dimethyldioxolanylmethoxypyridinylamino, methoxyethylpyridinylamino, methoxyvinylpyridinylamino, dihydroxypropylaminopyridinylamino, dimethylamino- pyridinylamino, methylaminomethylpyridinylamino, dimethylaminomethylpyridinyl- amino, oxopyridinylamino, carboxypyridinylamino, N-(methyl)-N-(methylpyridinyl)- amino, N-(ethyl)-N-(methylpyridinyl)amino, bis(methylpyridinyl)amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, methylpyridazinylamino, N-(methyl)-N- (methylpyridazinyl)amino, N-(benzyl)-N-(methylpyridazinyl)amino, dimethyl- pyridazinylamino, phenylpyridazinylamino, piperidinylpyridazinylamino, methoxypyridazinylamino, (chloro)(methoxy)pyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, methylcinnolinylamino, oxopyrimidinyl- amino, thioxopyrimidinylamino, quinoxalinylamino, methylchromenylamino, benzofurylmethylamino, thienylmethylamino, indolylmethylamino, methylpyrazolyl- methylamino, (chloro)(dimethyl)pyrazolylmethylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethylamino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethylamino, N-(methyl)-N-(pyridinylethyl)- amino, N-(dihydroxypropyl)-N-(pyridinylmethyl)amino, N-(dihydroxypropyl)-N- (methylpyridinylmethyl)aniino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, acetylamino, Λf-(acetyl)-N-(methylpyridinyl)amino, dimethylaminoethylcarbonylamino, acetylaminomethyl, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, methoxycarbonyl- amino, N-methoxycarbonyl-7V-methylamino, methylsulphonylamino, foπnyl, acetyl, acetyl oxime, acetyl 0-(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)-N-methylamino- carbonyl, N-(hydroxyethyl)-N-methylaminocarbonyl, iV-(methoxyethyl)-N-methyl- aminocarbonyl, N-(dimethylaminoethyl)-N-methylaminocarbonyl, N-isopropyl-N-methyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(methylpiperidinyl)amino- carbonyl, piperidinylethylaminocarbonyl, pyrazolylaminocarbonyl, pyridinylmethylamino- carbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, tert- butoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, methylpyrrolidinyl- carbonyl, methoxymethylpyrrolidinylcarbonyl, dimethylaminopyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinyl- carbonyl, morpholinylcarbonyl, isopropylthio, isopropylsulphinyl, methylsulphonyl, isopropylsulphonyl, methylsulphonylmethyl, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, tert-butoxycarbonyloxy, trimethylsilyl and tetramethyl- dioxaborolanyl. Additional examples include (methoxy)(methyl)aminocarbonyl, cyclopropylaminocarbonyl, Λ/-(methyl)-iV-(phenyl)aminocarbonyl, hydroxypyrrolidinylcarbonyl and methylsulphonylpiperazinylcarbonyl.
Definitive examples of specific substituents on R13 include methyl, methylimidazolyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethyl- aminocarbonyl, diethylaminocarbonyl, (methoxy)(methyl)aminocarbonyl, N-(methoxy- ethyl)-iV-methylaminocarbonyl, cyclopropylaminocarbonyl, cyclopropylmethylaminocarbonyl, N-(methyl)-N-(phenyl)aminocarbonyl, benzylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl, methylsulphonylpiperazinylcarbonyl and morphollnylcarbonyl .
Particular examples of specific substituents on R13 include methyl, methoxycarbonyl and dimethylaminocarbonyl. Typical values of R 3 include hydrogen, methyl, phenoxymethyl, phenylthiomethyl, aminomethyl, phenylaminomethyl, N-methyl-jV-phenylaminomethyl, pyridinylaminomethyl, benzofurylcarbonylaminomethyl, phenylsulphonylaminomethyl, benzothienylmethylaminocarbonylmethyl, propynyl, trimethylsilylpropynyl, benzyl, chlorobenzyl, bromobenzyl, methylenedioxyphenylaminobenzyl, morpholinylmethylphenylaminobenzyl, oxazolinylphenylaminobenzyl, (methyl)(oxo)pyrazolylphenylaminobenzyl, oxazolylphenylaminobenzyl, isoxazolylphenylaminobenzyl, triazolylphenylaminobenzyl, methyltriazolylphenylaminobenzyl, methylpyrimidinylphenylaminobenzyl, pyrazolylmethylphenylaminobenzyl, triazolylmethylphenylaminobenzyl, methylsulphonylaminophenylaminobenzyl, moφholinylcarbonylphenylaminobenzyl, methylsulphonylphenylaminobenzyl, morpholinylsulphonylphenylaminobenzyl, 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, methylsulphonylaminoindσlylmethyl, acetylindolylmethyl, [acetyl oxime]indolylmethyl, [acetyl O-(methyl)oxime]- indolylmethyl, trifluoromethylcarbonylindolylmethyl, carboxyindolylmethyl, (carboxy)- (methyl)indolylmethyl, methoxycarbonylindolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl, (chloro)(methoxycarbonyl)indolylmethyl, aminocarbonylindolylmethyl, (aminocarbonyl)(chloro)indolylmethyl, methylaminocarbonylindolylmethyl, (chloro)- (methylaminocarbonyl)indolylmethyl, (hydroxyethytyaminocarbonylindolylmethyl, (dimethylaminoethyl)aminocarbonylindolylmethyl, ( 1 -hydroxyprop-2-yl)aminocarbonyl- indolylmethyl, dimethylaminocarbonylindolylmethyl, (dimethylaminocarbonyl)(methyl)- indolylmethyl, (chloro)(dimethylaminocarbonyl)indolylmethyl, bis(dimethylamino- carbonyl)indolylmethyl, iV-(cyanomethyl)-N-methylaminocarbonylindolylmethyl, [N- (cyanomethyl)-N-methylaminocarbonyl](methyl)indolylπiethyl, N-(cyanoethyl)-N- methylaminocarbonylindolylmethyl, N-(hydroxyethyl)-N-methylaminocarbonyl- indolylmethyl, N-(methoxyethyl)-N-methylaminocarbonylindolylmethyl, [N-(methoxy- ethyl)-jV-methylaminocarbonyl](methyl)indolylmethyl, N-(dimethylaminoethyl)-N- methylaminocarbonylindolylmethyl, N-isopropyl-N-methylaminocarbonylindolylmethyl, diethylaminocarbonylindolylmethyl, cyclopropylmethylaminocarbonylindolylmethyl, benzylaminocarbonylindolylmethyl, pyrazolylaminocarbonylindolylmethyl, pyridinylmethylaminocarbonylindolylmethyl, azetidinylcarbonylindolylmethyl,
(azetidinylcarbonyl)(methyl)indolylmethyl, hydroxyazetidinylcarbonylindolylmethyl, aminoazetidinylcarbonylindolylmethyl, tert-butoxycarbonylaminoazetidinylcarbonyl- indolylmethyl, pyrrolidinylcarbonylindolylmethyl, methylpyrrolidinylcarbonyl- indolylmethyl, methoxymethylpyrrolidinylcarbonylindolylmethyl, dimethylamino- pyrrolidinylcarbonylindolylmethyl, thiazolidinylcarbonylindolylmethyl, oxothiazolidinyl- carbonylindolylmethyl, piperidinylcarbonylindolylmethyl, methylpiperazinylcarbonyl- indolylmethyl, morpholinylcarbonylindolylmethyl, methylsulphonylindolylmethyl, methylsulphonylmethylindolylmethyl, dimethylaminosulphonylindolylmethyl, trimethylsilylindolylmethyl and pyrrolo[3,2-c]pyridinylmethyl. Additional values include methylimidazolylindolylmethyl, (methyl)(methylimidazolyl)indolylmethyl, (aminocarbonyl)(methyl)indolylniethyl, (methyl)(methylaminocarbonyl)indolylmethyl, (diethylaminocarbonyl)(methyl)indolylmethyl, [(methoxy)(methyl)aminocarbonyl]- (methyl)indolylmethyl, (cyclopropylaminocarbonyl)(methyl)indolylmethyl,
(cyclopropylmethylammocarbonylXmethytymdolylmethyl, (methyl)[iV-(methyl)-iV- (phenyl)aminocarbonyl]indolylmethyl, (benzylaminocarbonyl)(methyl)indolylmethyl, (hydroxyazetidinylcarbonyl)(methyl)indolylmethyl, (methyl)(pyrrolidinylcarbonyl)- indolylmethyl, (hydroxypyrrolidinylcarbonyl)(methyl)indolylmethyl, (methyl)(piperidinyl- carbonyl)indolylmethyl, (methyl)(methylpiperazinylcarbonyl)indolylmethyl, (methyl)- (methylsulphonylpiperazinylcarbonyl)indolylmethyl and (methyl)(morpholinylcarbonyl)- indolylmethyl.
Definitive values of R13 include indolylmethyl, methylimidazolylindolylmethyl, (methyl)(methylimidazolyl)indolylmethyl, (methoxycarbonyl)(methyl)indolylmethyl, (aminocarbonyl)(methyl)indolylmethyl, (methyl)(methylaminocarbonyl)indolylmethyl, (dimethylaminocarbonyl)(methyl)indolylmethyl, (diethylaminocarbonyl)(methyl)indolyl- methyl, [(methoxy)(methyl)aminocarbonyl](methyl)indolylmethyl, [iV-(methoxyethyl)-iV- methylaminocarbonyl](methyl)indolylmethyl, (cyclopropylaminocarbonyl)(methyl)- indolylmethyl, (cycIopropylmemylaminocarbonylXmethytyindolylmethyl, (methyl)[N- (methyl)-N-(phenyl)aminocarbonyl]indolylmethyl, (benzylaminocarbonyl)(methyl)- indolylmethyl, (hydroxyazetidinylcarbonyl)(methyl)indolylmethyl, (methyl)(pyrrolidinyl- carbonyl)indolylmethyl, (hydroxypyrrolidinylcarbonyl)(methyl)indolylmethyl, (methyl)(piperidinylcarbonyl)indolylmethyl, (methyl)(methylpiperazinylcarbonyl)indolyl- methyl, (methyl)(methylsulphonylpiperazinylcarbonyl)indolylmethyl and (methyl)(morpholinylcarbonyl)indolylmethyl.
Selected values of R13 include indolylmethyl, (methoxycarbonyl)(methyl)- indolylmethyl and (dimethylaminocarbonyl)(methyl)indolylmethyl. A particular value of R13 is indolylmethyl.
One particular sub-group of the compounds of formula (HA) is represented by the compounds of formula (IIB), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000041_0001
(IIB)
wherein
R11 and R12 are as defined above; T represents oxygen or N-R25;
R represents hydrogen, halogen, cyano, nitro, C1-6 alkyl, hydroxy(C1-6)alkyl, trifluoromethyl, aryl(C1-6)alkyl, oxazolinyl, imidazolyl, (C1-6)alkylimidazolyl, triazolyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(C1-6)alkoxy, morphoIinyl(C1-6)alkoxy, aryloxy, aryl(Ci-6)alkoxy, C1-6 alkylthio, Cj-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, C1-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(Ci-6)alkyl]amino, Ci-6 alkylsulphonyl- amino, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylamino- carbonyl, [hydroxy(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)alkylamino(Ci-6)alkyl] aminocarbonyl, di(Ci-6)alkylaminocarbonyl, [(C i-6)alkyl][cyano(C1-6)alkyl] aminocarbonyl, [(C i .^alkyl] [hydroxy(C 1 -6)alkyl] aminocarbonyl, [(C1 -6)alkoxy] [(C 1 -6)alkyl]aminocarbonyl, [(C 1 -6)alkoxy(C 1 -6)alkyl] [(C 1 -6)alkyl]aminocarbonyl, [di(C 1 -6)alkylamino(C 1 -6)alkyl]- [(C i-6)alkyl] aminocarbonyl, C3-7 cycloalkylaminocarbonyl, C3-7 cycloalkyl(Ci-6)alkyl- aminocarbonyl, iV-[(C1-6)alkyl]-N-(aryl)aminocarbonyl, aryl(C1-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(Ci-6)alkylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylamino- azetidinylcarbonyl, pyrrolidinylcarbonyl, (Ci-6)alkylpyrrolidinylcarbonyl, hydroxy- pyrrolidinylcarbonyl, C1-6 alkoxy(Ci-6)alkylpyrrolidinyl carbonyl, di(Ci-6)alkylamino- pyrrolidinylcarbonyl, thiazolidinykarbonyl, oxothiazølidinylcarbonyl, piperidinyl- carbonyl, (C 1 -6)alkylpiperazinyl carbonyl, (C 1 -6)alkylsulphonylpiperazinyl carbonyl, morpholinylcarbonyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonylmethyl or di(Ci-6)alkyl- aminosulphonyl; and
R24 represents hydrogen, halogen, Cj-6 alkoxy or di(C1-6)alkylaminocarbonyl; or
R2 and R24, when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and
R25 represents hydrogen or Cj-6 alkyl.
The present invention also provides a compound of formula (HB) as depicted above, or a pharmaceutically acceptable salt or solvate thereof, wherein
R represents hydrogen, halogen, cyano, nitro, C1-6 alkyl, hydroxy(C1-6)aUcyl, trifluoromethyl, aryl(Ci-6)alkyl, oxazolinyl, triazolyl, hydroxy, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(Ci-6)alkoxy, morpholinyl(Ci-6)alkoxy, aryloxy, -UyI(C1 ^alkoxy, C1-6 alkylthio, Ci-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, Ci-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(Ci-6)alkyl]amino, C1-6 alkylsulphonylamino, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, [hydroxy(Ci-6)- alkyl] aminocarbonyl, [di(C i -6)alkylamino(C i -6)alkyl] aminocarbonyl, di(C i -6)alkyl- aminocarbonyl, [(C i -6)alkyl] [cyano(C i -6)alkyl] aminocarbonyl, [(C1 -6)alkyl] [hydroxy(C \ -6)- alkyljaminocarbonyl, [(Ci-6)alkoxy(C1-6)alkyl][(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)alkyl- amino(C]-6)alkyl][(Ci-6)alkyl]aminocarbonyl, C3-7 cycloalkyl(Ci-6)alkylaminocarbonyl, aryl(Ci-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C]-6)alkylamino- carbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl, (C i -6)alkylpyrrolidinyl- carbonyl, Ci-6 alkoxy(Ci-6)alkylpyrrolidinylcarbonyl, di(Ci-6)alkylaminopyrrolidinyl- carbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinyl carbonyl, (Ci-6)- alkylpiperazinylcarbonyl, morpholinylcarbonyl, Ci-6 alkylsulphonyl, Ci-6 alkylsulphonylmethyl or di(Ci-6)alkylaminosulphonyl; and
T, R11, R12 and R24 are as defined above. In a preferred embodiment, T is N-R25. In another embodiment, T is oxygen.
Selected values of R23 include hydrogen, (Ci-6)alkylimidazolyl, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(Ci,6)alkylaminocarbonyl, [(C i -6)alkoxy] [(C i -6)alkyl] aminocarbonyl, [(C i -6)alkoxy(C i -6)alkyl] [(C i -6)alkyl] amino- carbonyl, C3-7 cycloalkylaminocarbonyl, C3-7 cycloalkyl(Ci-6)alkylaminocarbonyl, N-[(C1-6)alkyl]-N-(aryl)aminocarbonyl, aryl(Ci-6)alkylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, (C1-6)alkylpiperazinylcarbonyl, (C^alkylsulphonylpiperazinyl- carbonyl and morpholinylcarbonyl.
Typical values of R23 include hydrogen, C2-6 alkoxycarbonyl and di(C1-6)alkyl- aminocarbonyl.
Illustrative values of R23 include hydrogen, fluoro, chloro, cyano, nitro, oxazolinyl, triazolyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopropyl- methoxy, morpholinylethoxy, azetidinyl, morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino, iV-methoxycarbonyl-N-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, -/V-(cyanomethyl)-N-methylaminocarbonyl, JV-(cyanoethyl)-N-methyl- aminocarbonyl, iV-(hydroxyethyl)-N-methylaminocarbonyl, iV-(methoxyethyl)-N-methyl- aminocarbonyl, iV-(dimethylaminoethyl)-N-methylaminocarbonyl, N-isopropyl-N-methyl- aminocarbonyl, diethylaminocarbonyl, cyclopropylmethylaminocarbonyl, benzylamino- carbonyl, pyrazolylaminocarbonyl, pyridinylmethylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, tert-butoxycarbonylamino- azetidinylcarbonyl, pyrrolidinylcarbonyl, methylpyrrolidinylcarbonyl, methoxymethyl- pyrrolidinylcarbonyl, dimethylaminopyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl, morpholinylcarbonyl, methylsulphonyl, methylsulphonylmethyl and dimethylamino- sulphonyl. Additional values include methylimidazolyl, iV-(methoxy)-N-(methyl)- aminocarbonyl, cyclopropylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, hydroxypyrrolidinylcarbonyl and methylsulphonylpiperazinylcarbonyl.
Definitive values of R23 include hydrogen, methylimidazolyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, N-(methoxy)-iV-(methyl)- aminocarbonyl, JV-(methoxyethyl)-N-methylaminocarbonyl, diethylaminocarbonyl, cyclopropylaminocarbonyl, cyclopropylmethylaminocarbonyl, N-methyl-N-phenylamino- carbonyl, benzylaminocarbonyl, hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl, methylsulphonylpiperazinylcarbonyl and moφholinylcarbonyl.
Particular values of R23 include hydrogen, methoxycarbonyl and dimethylaminocarbonyl. Definitive values of R24 include hydrogen, chloro, methoxy and dimethylaminocarbonyl. A particular value of R24 is hydrogen.
In one embodiment, R25 is hydrogen, hi another embodiment, R25 is Ci-6 alkyl, especially methyl.
Another particular sub-group of the compounds of formula (HA) is represented by the compounds of formula (HC), and pharmaceutically acceptable salts and solvates thereof:
Figure imgf000044_0001
(IIC)
wherein
R1 ' and R12 are as defined above;
R33 represents halogen or -NHR34; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; and
R34 represents methylenedioxyphenyl, morpholinyl(Ci-6)alkylphenyl, oxazolinyl- phenyl, [(C1-6)alkyl](oxo)pyrazolylphenyl, oxazolylphenyl, isoxazolylphenyl, triazolyl- phenyl, (C1-6)alkyltriazolylphenyl, (Q^alkylpyrimidinylphenyl, pyrazolyl(C1-6)alkyl- phenyl, triazolyl(Ci-6)alkylphenyl, Ci-6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, Ci-6 alkylsulphonylphenyl, moφholinylsulphonylphenyl, dihydrobenzofuranyl, Ci-6 alkylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, [(Ci.6)alkyl](halo)pyrazolyl,
Figure imgf000044_0002
(C]-6)alkylindazolyl, benzoxazolyl, benzoxazolonyl, di(C].6)alkylisoxazolyl, benzothiazolyl, (Ci-6)alkylisothiazolyl, (Ci-6)alkylbenzimidazolyl, benzimidazolonyl, di(Ci-6)alkylbenzimidazolonyl, (C1-6)alkyloxadiazolyl, furyloxadiazolyl, pyridinyl, halopyridinyl, (C1-6)alkylpyridinyl, di(C1-6)alkylpyridinyl,
Figure imgf000045_0001
oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl, [(Ci-6)alkoxy](halo)pyridazinyl, (C1-6)alkylcinnolinyl, quinoxalinyl or (C1-6)alkylchromenyl.
Suitably, R33 represents halogen or -NHR34, in which R34 is as defined above. In one embodiment, R33 represents halogen, especially bromo. In another embodiment, R33 represents -NHR34, in which R34 is as defined above.
In one embodiment, R33 represents unsubstituted or substituted aryl. In another embodiment, R33 represents unsubstituted or substituted heteroaryl.
Typical values of R34 include pyridinyl, halopyridinyl, (Q^alkylpyridinyl, di(Ci-6)alkylpyridinyl and (C1-6)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 may be optionally substituted by one or more substituents.
Selected examples of suitable substituents on R33 include halogen, cyano, Ci-6 alkyl, hydroxy(Ci.6)alkyl, trifluoromethyl, Ci-6 alkoxy, trifluoromethoxy, aryloxy, methylenedioxy, C1-6 alkylthio, arylsulphonyl, amino, C2-6 alkylcarbonylamino, Ci-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, methyl enedioxyphenylamino, 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)(rnethoxy)pyridazinylamino, methylcinnolinyl- amino, quinoxalinylamino, methylchromenylamino, phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, cyanophenyl, methylphenyl, (fluoro)(methyl)phenyl, dimethylphenyl, hydroxymethylphenyl, trifluoromethylphenyl, bis(trifluoromethyl)phenyl, methoxyphenyl, dimethoxyphenyl, ethoxyphenyl, methylenedioxyphenyl, trifluoromethoxyphenyl, phenoxyphenyl, methylthiophenyl, aminophenyl, acetylamino-phenyl, methylsulphonylaminophenyl, acetylphenyl, aminocarbonylphenyl, naphthyl, benzofuryl, thienyl, methylthienyl, acetylthienyl, benzothienyl, phenylsulphonylindolyl, dimethylisoxazolyl, methylpyrazolyl, benzylpyrazolyl, pyridinyl, fluoropyridinyl, chloropyridinyl, methoxypyridinyl and pyrimidinylbenzyl.
A particular value of R33 is bromo. 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 imgf000047_0001
wherein
R11 and R12 are as defined above;
R43 represents hydrogen, halogen, nitro, Ci-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, (Ci-6)alkylaryl, di(Ci-6)alkylaryl, piperidinyl(C1-6)alkylaryl, piperazinyl(Ci-6)alkylaryl, (C i -6)alkylpiperazinyl(C i -6)alkylaryl, morpholinyl(C i .6)alkylaryl, (C i -6)alkoxyaryl, cyano(C i ^alkoxyaryl, di(C \ -6)alkylamino(C i -6)alkylaryl, (C i -6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (C \ -6)alkylaminocarbonylpiperidinyl, piperazinyl, (C i -6)alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl,
Figure imgf000047_0003
homopiperazinyl, (Ci-6)alkylpiperazinyl(Ci-6)alkyl, morpholinyl(Ci-6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, di(C1-6)alkylpyrazolyl, tri(C].6)alkyl- pyrazolyl, [di(Ci.6)alkyl](trifluoromethyl)pyrazolyl, cyano(Ci-6)alkylpyrazolyl, [cyano- (C i -6)alkyl] [di(C , -6)alkyl]pyrazolyl, hydroxy(C i -6)alkylpyrazolyl, [hydroxy(C i -6)- alkyl] [di(C i -6)alkyl]pyrazolyl, methoxy(C i -6)alkylpyrazolyl, [(hydroxy)(methoxy)(Ci -6)-
Figure imgf000048_0001
[amlno(C i -6)alkyl] [di(C i ^)alkyl]pyrazolyl, di(C i -6)alkylamino(C i -6)alkylpyrazolyl, di(C! -6)alkoxyphosphono(C i .6)alkylpyrazolyl, (C2-6)alkenylpyrazolyl, (C3-7)cycloalkyl- (Ci-6)alkylpyrazolyl, [(C3-7)cycloalkyl(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(C1-6)alkyl]- (aryl)pyrazolyl, (aryl)(trifluoromethyl)pyrazolyl, aryl(C1-6)alkylpyrazolyl, aminoaryl- (Cj-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(Ci-6)alkylpyrazolyl, [di- (C1-6)alkyl][tetrahydropyranyl(C)-6)alkyl]pyrazolyl, pyrrolidinyl(Ci-6)alkylpyrazolyl, piperidinyl(C i -6)alkylpyrazolyl, (C i -6)alkylpiperidinyl(Ci -6)alkylpyrazolyl, morpholinyl(C i -6)alkylpyrazolyl, pyridinyl(C i -6)alkylpyrazolyl, oxypyridinyl(C i -6)alkyl- pyrazolyl, [arylcarbonyl(Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, [(C1-6)alkyl](piperazinyl- carbonyl)pyrazolyl, [(C i ^alkylaminocarbonyl] [(C i -6)alkylaryl]pyrazolyl, [(C1 -6)alkyl] - [amino(Ci-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl, [aminocarbonyl(C i -6)alkyl] [di(C \ -6)alkyl]pyrazolyl, di(C \ -6)alkylaminocarbonyl(C i ,6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(Ci-6)alkylisoxazolyl, (amino)[(Ci-6)alkyl]- isoxazolyl, thiazolyl, di(Ci-6)alkylthiazolyl, imidazolyl, (Ci-6)alkylimidazolyl, di(Ci-6)- alkylimidazolyl, imidazo[l,2-α]pyridinyl, (Ci-6)alkylimidazo[l,2-α]pyridinyl, (C1-6)- alkylimidazo[4,5-6]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (C1-6)- alkylthiadiazolyl, pyridinyl, halopyridinyl, (Ci-6)alkyl-pyridinyl, [(Ci-6)alkyl](halo)- pyridinyl, di(C1-6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (Ci-6)alkylpiperazinylpyridinyl, [(C J -6)alkyl](piperazinyl)pyridinyl, [(C] .6)alkoxycarbonylpiperazinyl] [(C \ -6)alkyl]- pyridinyl, piperidinyl(Ci.6)alkylpyridinyl, [(Ci-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (Ci.6)alkoxyρyridinyl, [(Ci-6)alkoxy][(Ci-6)alkyl]pyridinyl, [(C ! -6)alkoxy] [di(C i -6)alkyl]pyridinyl, (C i -ό)alkoxy(C i -6)alkylpyridinyl, aminopyridinyl, carboxy(C1-6)alkylpyridinyl, (C1-6)alkoxycarbonyl(C1-6)alkylpyridinyl, pyridazinyl, (C1-6)- alkylpyridazinyl, 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)alkyl- pyrimidinyl, pyrrolidinylpyrimidinyl, (C1-6)alkylpiperazinylpyrimidinyl, [(C i -6)alkyl] (piperazinyl)pyrimidinyl, [(C i ^alkoxycarbonyl] [(Ci ^alkyllpiperazinyl- pyrimidinyl, hydroxypyrimidinyl, [(Ci-6)alkyl](hydroxy)pyrimidinyl, [(C)-6)alkyl]-
[hydroxy(C i -6)alkyl]pyrimidinyl, [(C \ -6)alkyl] [hydroxy(C2-6)alkynyl]pyrimidinyl, (C I-6)- alkoxypyrimidinyl, aminopyrimidinyl, di(C1-6)alkylaminopyrimidinyl, [di(C1-6)alkyl- amino](halo)pyrimidinyl, carboxypyrimidinyl, [(C i -6)alkoxycarbonyl(C i -6)alkyl] [(C i ^)- alkyljpyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (C1-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (Ci-6)alkoxy, aryl(C1-6)alkoxycarbonylpiperidinyloxy, morpholinyl- (C!.6)alkoxy, aryloxy, haloaryloxy, di(C1-6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C i -6)alkylpiperazinylpyridinyloxy, (C \ ^alkylpyrazolyl- pyridinyloxy, (Ci-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (Ci-6)alkylpyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C i -6)alkyl] (halo)pyrimidinyloxy, hydroxy(C i -6)alkyl, dihydroxy(C i -6)alkyl, pyridinyloxy(C1-6)alkyl, amino, (d-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(Ci-6)- alkylamino(C j -6)alkylamino, N- [(C i -6)alkyl] -N- [di(C i -6)alkylamino(C i -6)alkyl] amino, N-
Figure imgf000049_0001
^[(d^alkyη-N-CaryKCK^alkyηamino^-fdi^L^alkylamino^i^alkyll-N-taryKd-ό)- alkyl]amino, cyanoaryl(C1-6)alkylamino, (cyano)(halo)aryI(C1-6)alkylamino, methylene- dioxyaryl(Ci-6)alkylamino, N-[(Ci-6)alkyl]-N-[(C|-6)alkylpyrrolidinyl]amino, piperidinyl- amino, N-[(d-6)alkyl]-N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(Ci-6)alkyl]-N- (piperidinyl)amino, (C j ^alkylpiperidinylamino, N- [(C \ ^)alkyl]-N- [(C i -6)alkyl- piperidinyl] amino, N- [(C1 -6)alkyl] -N- [(C3-7)cycloalkylpiperidinyl] amino, N- [(C \ ^alkyl] - N-[(C2-6)alkylcarbonylpiperidinyl]amino, pyrrolidinyl(Ci-6)alkylamino, N-[(C1-ό)alkyl]-N- [pyrrolidinyl(C \ -6)alkyl] amino, N-[(C i -6)alkyl] -N- [piperidinyl(C i ,6)alkyl] amino, (C \ -6)- alkylpyrazolylamino, di(C1-6)alkylpyrazolylamino, tri(Ci-6)alkylpyrazolylamino, N-[(C1-6)- alkyl]-N-[(Ci-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(C1^aIkOXy- carbonyl][(C1-6)alkyl]imidazolylamino,
Figure imgf000049_0002
pyridinylamino, halopyridinylamino, (C^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(Ci-6)alkoxypyridinylamino, (C1^aIkOXy(C1-6)- alkylpyridinylamino, (C1-6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C1-6)alkyl- aminopyridinylamino, di(Ci-6)alkylaminopyridinylamino, (C1-6)alkylamino(C1-6)alkyl- pyridinylamino, di(Ci.6)alkylamino(Ci-6)alkylpyridinylamino, carboxypyridinylamino, N- [(C i-6)alkyl]-N-[(Ci-6)alkylpyridinyl] amino, bis[(Ci-6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (Ci-6)alkylpyridazinylamino, N-Kd^alkyl]- N-[(C i .6)alkylpyridazinyl] amino, N-[aryl(C i -6)alkyl]-N-[(C i -6)alkylpyridazinyl]amino, di(d-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (Ci-6)- alkoxypyridazinylamino, di(C1-6)alkylaminopyridazinylamino, bis[(C1-6)alkylpyridazinyl]- aϊninό, Beήl:ofuryr(Cr-6)Mk^raϊnino7tHienyr(C uδJallcylaΗiiSorindόlyrCCj.e^lkylamino^ (C J -6)alkylpyrazolyl(C i -6)alkylamino, [di(C i -6)alkyl] (halo)pyrazolyl(C i -6)alkylamino, di(Ci-6)alkylisoxazolyl(Ci-6)alkylamino, thiazolyl(C1-6)alkylamino, imidazolyl(C1-6)alkyl- amino, (Ci-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- (C1-6)alkyl]-N-[pyridinyl(Ci-6)alkyl]amino, N-[(Ci.6)alkylpyridinyl(Ci-6)alkyl]-N- [dihydroxy(C1-6)alkyl] amino, amino(C1-6)alkyl, (Ci-6)alkylamino(C1-6)alkyl, di(C1-6)alkyl- amino(C i -6)alkyl, pyridinylamino(C i -6)alkyl, N- [(C2-6)alkylcarbonyl] -N- [(C i -6)alkyl- pyridinyl(Ci-6)alkyl] amino, di(C1-6)alkylamino(Ci-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (C1-6)alkylpiperidinylcarbonylamino, (Ci-6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (Ci-^alkylpiperidinylaminocarbonyl, N-[(Ci-6)alkyl]-N-[(Ci-6)- alkylpiperidinyljaminocarbonyl, piperidinyl(C1-6)alkylaminocarbonyl, (Ci-6)alkyl- piperazinylcarbonyl, Cj-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy or tetra(C i -6)alkyldioxaborolanyl; and
R44 represents hydrogen, halogen, Ci-6 alkyl or Ci-6 alkoxy. A suitable value of R43 is (Ci-6)alkylpyrazolyl.
Specific values of R43 include bromo, nitro, methyl, n-propyl, isopropyl, allyl, cyclopropyl, methylphenyl, dimethylphenyl, piperidinylmethylphenyl, piperazinylmethyl- phenyl, methylpiperazinylmethylphenyl, morpholinylmethylphenyl, methoxyphenyl, cyanomethoxyphenyl, dimethylaminomethylphenyl, methylaminocarbonylphenyl, benzyl, chlorophenylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, dimethylamino- pyrrolidinyl, indolinyl, oxoindolinyl, phenylpiperidinyl, benzoylpiperidinyl, diethylamino- carbonylpiperidinyl, piperazinyl, methylpiperazinyl, chlorophenylpiperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, methylhomopiperazinyl, methylpiperazinylmethyl, methylpiperazinylethyl, morpholinylmethyl, benzofuryl, benzothienyl, pyrazolyl, methylpyrazolyl, ethylpyrazolyl, propylpyrazolyl, 2-methyl- propylpyrazolyl, 3-methylbutylpyrazolyl, dimethylpyrazolyl, trimethylpyrazolyl, (dimethyl)(ethyl)pyrazolyl, (dimethyl)(isopropyl)pyrazolyl, (dimethyl)(2-methylpropyl)- pyrazolyl, (dimethyl)(3-methylbutyl)pyrazolyl, (dimethyl)(trifluoromethyl)pyrazolyl, cyanomethylpyrazolyl, (cyanomethyl)(dimethyl)pyrazolyl, hydroxyethylpyrazolyl, hydroxypropylpyrazolyl, 2-hydroxy-2-methylpropylpyrazolyl, (hydroxyethyl)(dimethyl)- pyrazolyl, (hydroxypropyl)(dimethyl)pyrazolyl, methoxypropylpyrazolyl, [(hydroxy)- (methoxy)propyl]pyrazolyl, aminoethylpyrazolyl, aminopropylpyrazolyl, (aminopropyl)- (methyl)pyrazolyl, (aminopropyl)(dimethyl)pyrazolyl, dimethylaminoethylpyrazolyl, dimethylaminopropylpyrazolyl, diethoxyphosphonopropylpyrazolyl, allylpyrazolyl, cyclopropylmethylpyrazolyl, (cyclopropylmethylXdimethytypyrazolyl, (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- αjpyridinyl, methylimidazof 1 ,2-a]pyridinyl, methylimidazo[4,5-Z>]pyridinyl, imidazo[ 1 ,2- α]pyrimidinyl, imidazo[l,2-α]pyτazinyl, methylthiadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, (fluoro)(methyl)pyridinyl, dimethylpyridinyl, vinylpyridinyl, (methyl- piperazinyl)pyridinyl, (methyl)(piperazinyl)pyridinyl, (tert-butoxycarbonylpiperazinyl)- (methyl)pyridinyl, piperidinylmethylpyridinyl, (methyl)(oxy)pyridinyl, hydroxypyridinyl, hydroxymethylpyridinyl, hydroxyethylpyridinyl, methoxypyridinyl, (methoxy)(methyl)- pyridinyl, (dimethyl)(methoxy)pyridinyl, methoxymethylpyridinyl, aminopyridinyl, carboxymethylpyridinyl, ethoxycarbonylmethylpyridinyl, pyridazinyl, methylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, methoxypyridazinyl, aminopyridazinyl, hydroxyethylaminopyridazinyl, dimethylaminopyridazinyl, pyrimidinyl, methyl- pyrimidinyl, (chloro)(methyl)pyrimidinyl, dimethylpyrimidinyl, pyrrolidinylpyrimidinyl, methylpiperazinylpyriniidinyl, (methyl)(piperazinyl)pyrimidinyl, (tert-butoxycarbonyl- piperazinyl)(methyl)pyrimidinyl, hydroxypyrimidinyl, (hydroxy)(methyl)pyrimidinyl, (hydroxyethyl)(methyl)pyrimidinyl, (hydroxypropyl)(methyl)pyrimidinyl, (hydroxy- propynyl)(methyl)pyrimidinyl, methoxypyrimidinyl, aminopyrimidinyl, dimethylamino- pyrimidinyl, (dimethylamino)(fluoro)pyrimidinyl, carboxypyrimidinyl, (methoxycarbonyl- methyl)(methyl)pyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, methoxypyrazinyl, aminopyrazinyl, hydroxy, methoxy, isopropoxy, benzyloxycarbonylpiperidinyloxy, morpholinylethoxy, phenoxy, fluorophenoxy, dimethylpyrazolyloxy, bromopyridinyloxy, pyrrolidinylpyridinyloxy, methylpiperazinylpyridinyloxy, methylpyrazolylpyridinyloxy, isopropylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonylpyridinyloxy, methylpyridazinyloxy, pyrimidinyloxy, methylpyrimidinyloxy, (chloro)(methyl)- pyrimidinyloxy, hydroxymethyl, 1 -hydroxy- 1-methylethyl, dihydroxypropyl, pyridinyloxymethyl, amino, isopropylamino, dihydroxypropylamino, methoxyethylamino, methoxypropylamino, N-(methoxyethyl)-N-(methyl)amino, N-(methoxypropyl)-N- (methyl)amino, dimethylaminoethylamino, dimethylaminopropylamino, N- (dimethylaminoethyl)-N-(methyl)aniino, N-(diethylaminoethyl)-N-(methyl)amino, N- (dimethylaminopropyl)-Nτ(methyl)amino, N-(dimethylaminoethyl)-N-(ethyl)amino, N- (dimethylaminopropyl)-N-(ethyl)amino, N-(cyclohexyl)-N-(methyl)amino, fluorophenyl- amino, N-fluorophenyl-N-methylamino, N-benzyl-N-methylamino,,N-(benzyl)-N- (dimethylaminoethyl)amino, cyanobenzylamino, (cyano)(phenyl)ethylamino, (cyano)(fluoro)benzylamino, methylenedioxybenzylamino, N-(methyl)-N-(methyl- pyrrolidinyl)amino, piperidinylamino, N-(methyl)-N-(piperidinyl)amino, N-(ethyl)-N- (piperidinyl)amino, N-(cyclopropylmethyl)-N-(piperidinyl)amino, methylpiperidinyl- amino, N-(methyl)-N-(methylpiperidinyl)amino, N-(methyl)-N-(2-methylpropyl- piperidinyl)amino, N-(cyclopentylpiperidinyl)-N-(methyl)amino, N-(acetylpiperidinyl)-N- (methyl)amiηo, pyrrolidinylethylamiηp, pyrrolidinylpropylamino, N-(methyl)-N- (pyrrolidinylethyl)amino, N-(methyl)-N-(pyrrolidinylpropyl)amino, N-(methyl)-N- (piperidinylmethyl)amino, methylpyrazolylamino, dimethylpyrazolylamino, trimethylpyrazolylamino, Nτ(ethyl)-N-(methylpyrazolyl)amino, thiazolylamino, imidazolylamino, (ethoxycarbonyl)(methyl)imidazolyl amino, 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)amino, dimethylpyridazinylamino, phenylpyridazinyl- amino, piperidinylpyridazinylamino, methoxypyridazinylamino, dimethylamino- pyridazinylamino, bis(methylpyridazinyl)amino, benzofurylmethylamino, thienylmethyl- amino, indolylmethylamino, methylpyrazolylmethylamino, (chloro)(dimethyl)pyrazolyl- methylamino, dimethylisoxazolylmethylamino, thiazolylmethylamino, imidazolylmethyl- amino, methylimidazolylmethylamino, pyridinylmethylamino, methylpyridinylmethyl- amino, N-(methyl)-N-(pyridinylethyl)amino, N-(dihydroxypropyl)-iV-(pyridinylmethyl)- amino, N-(dihydroxypropyl)-N-(meΛylpyridinylmethyl)amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, pyridinylaminomethyl, iV-(acetyl)-N-(methyl- pyridinyl)amino, dimethylaminoethylcarbonylamino, cyclohexylcarbonylamino, methylpiperidinylcarbonylamino, methylimidazolylcarbonylamino, formyl, acetyl, methylpiperidinylaminocarbonyl, N-(methyl)-N-(methylpiperidinyl)aminocarbonyl, piperidinylethylaminocarbonyl, methylpiperazinylcarbonyl, isopropylthio, isopropyl- sulphinyl, isopropylsulphonyl, tert-butoxycarbonyloxy and tetramethyldioxaborolanyl. A particular value of R43 is methylpyrazolyl. In one embodiment, R44 represents hydrogen. In another embodiment, R44 represents halogen, especially bromo. In a further embodiment, R44 represents C1-6 alkyl, especially methyl. In an additional embodiment, R44 represents Ci-6 alkoxy, especially methoxy.
Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
The present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
For topical administration the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.
For ophthalmic administration the compounds according to the present invention may be conveniently formulated as microionized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum. For rectal administration the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols. The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
The compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
Figure imgf000056_0001
(ffl) (IV)
wherein X, R1, R2, R3, R4 and R5 are as defined above, and L1 represents a suitable leaving group. The leaving group L1 is typically a halogen atom, e.g. bromo.
The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as isopropanol, a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as ivyV-dimethylformamide, typically under basic conditions, e.g. in the presence of an organic base such as ΛζN-diisopropylethylamine or 2,6-lutidine. Alternatively, the reaction may be effected at an elevated temperature in a solvent such as 2-ethoxyethanol in the presence of a catalytic quantity of a mineral acid, e.g. concentrated hydrochloric acid.
In another alternative, the reaction may be effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or an aromatic solvent such as toluene, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium tert-butoxide, in the presence of a transition metal catalyst. The transition metal catalyst is suitably palladium(II) acetate, in which case the reaction will ideally be performed in the presence of tert-butylphosphonium tetrafluoroborate or dicyclohexyl diphenylphosphine. The intermediates of formula (III) above wherein L1 is bromo may be prepared from a compound of formula (V):
Figure imgf000056_0002
(V) wherein X, R1, R2 and R5 are as defined above; by diazotization/bromination.
The reaction is conveniently effected by stirring compound (V) with tert-butyl nitrite and copper(II) bromide in a suitable solvent, e.g. acetonitrile. The intermediates of formula (V) above may be prepared by reacting thiourea with a compound of formula (VI):
Figure imgf000057_0001
(VI)
wherein X, R1, R2 and R5 are as defined above, and L2 represents a suitable leaving group. The leaving group L2 is typically a halogen atom, e.g. bromo or iodo. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, typically under basic conditions, e.g. in the presence of an organic base such as N,iV-diisopropylethylamine. Alternatively, the reaction may be accomplished by heating the reactants in a lower alkanol solvent, e.g. a Ci-6 alkyl alcohol such as ethanol.
In another procedure, the compounds of formula (I) may be prepared by a process which comprises reacting a compound of formula (VI) as defined above with a compound of formula (VII):
Figure imgf000057_0002
R3
(vπ)
wherein R3 and R4 are as defined above; under conditions analogous tα those described above for the reaction between thiourea and compound (VI). The reaction may additionally be accomplished by heating the reactants in acetic acid, optionally in the presence of sodium acetate.
The intermediates of formula (VII) above may be prepared by reacting a compound of formula (IV) as defined above with l,l'-thiocarbonyldiimidazole; followed by treatment with ammonia or ammonium hydroxide.
The compounds of formula (I) wherein R1 and R2 together form an isopropylidene moiety may be prepared by a process which comprises reacting a compound of formula (VIII):
Figure imgf000058_0001
(VHI)
wherein X, R3, R4 and R5 are as defined above; with N-chlorosuccimmide (NCS); followed by treatment with a base such as aqueous sodium hydroxide.
The reaction between compound (VIII) and NCS is conveniently carried out at an elevated temperature in an organic solvent such as acetonitrile. The subsequent treatment with base is conveniently effected at ambient temperature in an organic solvent, e.g. acetonitrile.
The intermediates of formula (VIII) above may be prepared by reacting a compound of formula (VII) as defined above with a compound of formula (IX):
Figure imgf000058_0002
(IX) wherein X, R5 and L2 are as defined above, under conditions analogous to those described above for the reaction between thiourea and compound (VI).
The compounds according to the invention wherein R3 represents an optionally substituted indolylmethyl moiety may be prepared by standard methods. Thus, by way of example, a compound of formula (HB) as defined above wherein T represents NH may be prepared by a process which comprises reacting a compound of formula (X) with a compound of formula (XI):
Figure imgf000059_0001
(X)
wherein R , 1"1, R r, 112Z, R n2Z3J and R24 are as defined above; in the presence of a transition metal catalyst; followed by hydrolytic cleavage of the trimethylsilyl group.
The transition metal catalyst of use in the reaction between compounds (X) and (XI) is suitably palladium(II) acetate, in which case the reaction is conveniently effected in the presence of lithium chloride and a base such as sodium carbonate. The reaction will ideally be carried out at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as Λζ^-dimethylformamide.
Cleavage of the trimethylsilyl group from the product thereby obtained may suitably be accomplished by treatment with a mineral acid such as aqueous hydrochloric acid.
The intermediates of formula (X) above may be prepared by reacting a compound of formula (VI) as defined above with a compound of formula (XII):
Figure imgf000060_0001
under conditions analogous to those described above for the reaction between compounds (VI) and (VII). The intermediates of formula (XII) above may be prepared by reacting a compound of formula (Xm):
Figure imgf000060_0002
(xm)
with 1 , 1 '-thiocarbonyldiimidazole; followed by treatment with ammonia or ammonium hydroxide.
Where they are not commercially available, the starting materials of formula (IV), (VI), (IX), (XI) and (XIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of example, a compound of formula (I) wherein X represents oxygen may be converted into the corresponding compound wherein X represents sulphur by treatment with Lawesson's Reagent (i.e. 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulphide). A compound of formula (I) wherein R3 and/or R4 contains an aryl or heteroaryl moiety may be halogenated (e.g. brominated) on the aryl or heteroaryl moiety by treatment with the appropriate JV-halosuccinimide (e.g. N-bromosuccinimide).
A compound of formula (I) wherein R3 and/or R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by amino (-NH2) by treatment with benzophenone imine and tris(dibenzylidene- acetone)dipalladium(0) in the presence of 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP) and a strong base such as sodium tert-bntoxide.
A compound of formula (I) wherein R3 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound of formula (I) wherein the halogen atom is replaced by an optionally substituted C3-7 cycloalkyl, aryl, aryl(C1-6)alkyl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted C3-7 cycloalkyl, aryl, aryl(Cι-6)alkyl or heteroaryl boronic acid or a cyclic ester thereof, e.g. a pinacol ester thereof, in the presence of a catalyst. More particularly, a compound of formula (I) wherein R3 represents aryl(C|-6)alkyl, substituted on the aryl moiety by a halogen atom such as bromo, may be converted into the corresponding compound wherein R3 represents biaryl(C1-6)alkyl or heteroarylaryl(Ci-6)alkyl by treatment with, respectively, an aryl or heteroaryl boronic acid, in the presence of a catalyst. Similarly, a compound of formula (I) wherein R3 represents heteroaryl(C1-6)alkyl, substituted on the heteroaryl moiety by a halogen atom such as bromo, may be converted into the corresponding compound wherein R3 represents aryl-heteroaryl(Ci-6)alkyl by treatment with an aryl boronic acid, in the presence of a catalyst. Furthermore, a compound of formula (I) wherein R3 contains a cyclic borane moiety, e.g. 4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl, may be converted into the corresponding compound wherein the cyclic borane moiety is replaced by an optionally substituted aryl or heteroaryl moiety by treatment with, respectively, an appropriately-substituted aryl or heteroaryl halide, e.g. chloride, bromide or iodide, in the presence of a catalyst. The catalyst may typically be a transition metal catalyst. A suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, in an inert solvent such as 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, optionally in the presence of tetra-n- butylammonium bromide. Alternatively, the catalyst may be palladium(II) acetate, in which case the transformation may conveniently be effected at an elevated temperature in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and potassium phosphate.
A compound of formula (I) wherein R3 represents hydroxymethyl may be converted into the corresponding compound wherein R3 represents a substituted aminomethyl moiety, e.g. phenylaminomethyl, iV-methyl-N-phenylaminomethyl, pyridin- 3-ylaminomethyl, indolin-1-ylmethyl, 1,2,3,4-tetrahydroquinolin-l-ylmethyl or 1,2,3,4- tetrahydroisoquinolin-2-ylmethyl, by a two-stage procedure which comprises (i) Swern oxidation of the hydroxymethyl derivative by treatment with oxalyl chloride and dimethyl sulphoxide in the presence of triethylamine; and (ii) reductive animation of the formyl derivative thereby obtained by treatment with the appropriate amine, e.g. aniline, N- methylaniline, 3-aminopyridine, indoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4- tetrahydroisoquinoline, in the presence of a reducing agent such as sodium cyanoborohydride.
In general, any compound of formula (I) which contains a carbonyl-containing functionality, e.g. formyl or a ketone moiety, may be converted into a substituted amino analogue thereof by application of the reductive animation procedure described in step (ii) in the preceding paragraph, which comprises treatment with the appropriately-substituted amine in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride. Any compound of formula (I) wherein R3 contains an amino moiety can be alkylated on the amino moiety by a reductive amination procedure which comprises treatment with the appropriate aldehyde in the presence of a reducing agent, e.g. sodium cyanoborohydride or sodium triacetoxyborohydride.
A compound of formula (I) wherein R3 represents hydroxymethyl may be converted into the corresponding compound wherein R3 represents an optionally substituted C3-7 heterocycloalkylcarbonyl moiety, e.g. piperidin-1-ylcarbonyl, 1,2,3,4- tetrahydroquinolin- 1 -ylcarbonyl, 6-methyl- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 6- methoxy- 1 ,2,3 ,4-tetrahydroquinolin- 1 -ylcarbonyl, 1 ,2,3 ,4-tetrahydroisoquinolin-2- ylcarbonyl or 1,2,3,4-tetrahydroquinoxalin-l -ylcarbonyl, by a two-stage procedure which comprises (i) oxidation of the hydroxymethyl moiety by treatment with potassium permanganate; and (ii) reaction of the carboxy derivative thereby obtained with the appropriate amine, e.g. piperidine, 1,2,3,4-tetrahydroquinoline, 6-methyl-l, 2,3,4- tetrahydroquinoline, 6-methoxy- 1 ,2,3 ,4-tetrahydroquinoline, 1 ,2,3 ,4-tetrahydro- isoquinoline or 1,2,3,4-tetrahydroquinoxaline, in the presence of a condensing agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or 0-(berizotriazol-l-yl)-N,N,iV>N'- tetramethyluronium hexafluorophosphate (HBTU).
A compound of formula (I) wherein R3 contains a phenyl moiety substituted by chloro may be converted into the corresponding compound wherein the phenyl ring is substituted by morpholin-4-yl by treatment with morpholine in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(di-tert-butylphosphino)biphenyl and sodium tert-butoxide. A compound of formula (I) wherein R3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by pyrrolidin- 1 -yl by treatment with pyrrolidine in the presence oftris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-1,1 '-biphenyl and a base such as potassium carbonate. Similarly, a compound of formula (I) wherein R3 contains a phenyl moiety substituted by bromo may be converted into the corresponding compound wherein the phenyl ring is substituted by an amino'moiety (e.g. a group of formula -ΝHR34 as defined above) by treatment with the appropriate amine (e.g. a compound of formula H2N-R34) in the presence of tris(dibenzylideneacetone)dipalladium(0), 2-(dicyclohexylphosphino)-2',4',6'-tri- isopropyl-l,l'-biphenyl (X-Phos) and a base such as sodium tert-butoxide.
A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by cafboxy (-CO2H) by treatment with «-butyllithium followed by carbon dioxide.
A compound of formula (I) wherein R3 contains an indole moiety may be methylated on the indole ring by treatment with a methyl halide, e.g. iodomethane, in the presence of a strong base such as sodium hydride. A compound of formula (I) wherein R3 contains an indole moiety may be acetylated on the indole ring by treatment with acetic anhydride and 4-dimethylamino-pyridine, typically in the presence of an organic base such as triethylamine. A compound of formula (I) wherein R3 contains an indoline moiety may be converted into the corresponding compound wherein R3 contains an indole moiety by treatment with an oxidising agent such as manganese dioxide. A compound of formula (I) wherein R3 contains a hydroxy substituent may be converted into the corresponding compound wherein R3 contains a Ci-6 alkylsulphonyloxy substituent, e.g. methyl- sulphonyloxy, by treatment with a C1-6 alkylsulphonyl halide, e.g. methanesulphonyl chloride. A compound of formula (I) wherein R3 contains an amino (-NH2) or carboxy (-CO2H) moiety may be converted into the corresponding compound wherein R3 contains an amido moiety by treatment with, respectively, a compound containing a carboxy or amino group, in the presence of O-φenzotriazol-l-y^-NyΛ^Vy/V-tetramethyluronium hexafluorophosphate (HBTU), typically in a dipolar aprotic solvent such as NJf- dimethylformamide; or in the presence of 1 - [3 -(dimethylamino)propyl] -3 -ethyl- carbodiimide and 1-hydroxybenzotriazole. A compound of formula (I) wherein R3 contains an amino substituent may be converted into the corresponding compound wherein R3 contains an alkyl- or arylsulphonylamino substituent, e.g. methylsulphonylamino or phenylsulphonylamino, by treatment with an alkyl- or arylsulphonyl halide, e.g. methanesulphonyl chloride or benzenesulphonyl chloride.
A compound of formula (I) wherein R3 contains an amino moiety may be acylated by treatment with a C2-6 alkylcarbonyl halide, e.g. acetyl chloride; or a C2-6 alkylcarbonyl anhydride, e.g. acetic anhydride. A compound of formula (I) wherein R3 contains an amino moiety may be converted into the corresponding carbamate ester by treatment with a C1-6 alkyl haloformate, e.g. methyl chloroformate.
A compound of formula (I) wherein R3 contains a C2-6 alkoxycarbonyl substituent, e.g. methoxycarbonyl, may be converted into the corresponding compound wherein R3 contains a carboxy (-CO2H) substituent under standard saponification conditions, e.g. by treatment with a base such as lithium hydroxide or sodium hydroxide. A compound of formula (I) wherein R3 contains a carboxy (-CO2H) substituent may be converted into the corresponding compound wherein R3 contains an amido substituent, e.g. methylaminocarbonyl, 2-hydroxyethylaminocarbonyl, dimethylaminocarbonyl, N-(2- hydroxyethyl)-N-methylaminocarbonyl, benzylaminocarbonyl, azetidin- 1 -ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1 -ylcarbonyl, 4-methylpiperazin-l -ylcarbonyl or morpholin-4-ylcarbonyl, by a two-stage procedure which comprises (i) treatment of the carboxy derivative with pentafluorophenol in the presence of a condensing agent such as l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide; and (ii) reaction of the pentafϊuorophenyl ester thereby obtained with the appropriate amine, e.g. methylamine, 2- hydroxyethylamine, dimethylamine, Λ/-(2-hydroxyethyl)-Λr-methylamine, benzylamine, azetidine, pyrrolidine, piperidine, 1-methylpiperazine or morpholine.
A compound of formula (I) wherein R3/R4 contains a nitro moiety may be converted into the corresponding compound wherein R3/R4 contains an amino (-NH2) moiety by catalytic hydrogenation, typically by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal. A compound of formula (I) wherein R3/R4 contains an amino (-NH2) moiety may be converted into the corresponding compound wherein R3/R4 contains a heteroaryl-amino moiety, e.g. 6-methylpyridin-3- ylamino, by treatment with the appropriate heteroaryl halide, e.g. 5-bromo-2- methylpyridine, in the presence of palladium(II) acetate, 2-bis(dicyclohexylphosphino)- biphenyl and a base such as sodium tert-butoxide.
In general, any compound of formula (I) wherein R3/R4 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein the halogen atom is replaced by a substituted amino functionality by treatment with the appropriately- substituted amine derivative and palladium(II) acetate in the presence of a base, e.g. sodium tert-butoxide, and tri-tert-butylphosphonium tetrafluoroborate. Alternatively, the reaction may be effected by treatment with the appropriately-substituted amine derivative and [l,r-bis(di-/ert-butylphosphino)ferrocene]palladium(II) dichloride in the presence of a base, e.g. sodium tert-butoxide. Conversely, any compound of formula (I) wherein R3/R4 contains an amino functionality may be converted into the corresponding compound wherein the amino functionality is substituted by an optionally substituted aryl or heteroaryl moiety by treatment with an appropriately-substituted aryl or heteroaryl halide (e.g. bromide) and [l,r-bis(di-tert-butylphosphino)ferrocene]palladium(II) dihloride in the presence of a base, e.g. sodium tert-butoxide. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by a heteroaryl group, e.g. pyrazol-3-yl, 1- methylpyrazol-4-yl, l-propylpyrazol-4-yl, l-isobutylpyrazol-4-yl, 1 -benzylpyrazol-4-yl, 1- [2-(morpholin-4-yl)ethyl]pyrazol-4-yl, 6-methylpyridin-3-yl or pyrimidin-5-yl, by treatment with the appropriate heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, in the presence of a catalyst. Similarly, a compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a boronic acid [-B(OH)2] moiety may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by a heteroaryl group, e.g. methylimidazolyl, by treatment with the appropriate heteroaryl halide, e.g. bromide, derivative in the presence of a catalyst. The catalyst may typically be a transition metal catalyst. A suitable catalyst is tetrakis(triphenylphosphine)palladium(0), in which case the transformation may conveniently be effected at an elevated temperature in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, optionally in the presence of tetrabutylammonium bromide.
A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by a formyl (-CHO) group by treatment with a strong base, e.g. /j-butyllithium, and ΛζjV-dimethylformamide. A compound of formula (I) wherein R /R4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by hydroxymethyl by treatment with a reducing agent such as sodium borohydride. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by an aminomethyl moiety (e.g. dimethylaminomethyl, pyridin-3-ylaminomethyl, 4-methylpiperazin-l-ylmethyl or morpholin-4-ylmethyl) by treatment with the appropriate amine (e.g. dimethylamine, pyridin-3-ylamine, 1 -methylpiperazine or morpholine) and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride. Conversely, a compound of formula (I) wherein R3/R4 contains an amino moiety may be converted into the corresponding compound wherein R3/R4 is methylated on the amino moiety by treatment with formaldehyde and a reducing agent which typically consists of a mixture of phenylsilane and dibutyltin dichloride. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a formyl (-CHO) group may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by a pyridinyloxymethyl moiety by treatment with the appropriate hydroxypyridine in the presence of a mixture of triphenylphosphine and diethyl azodicarboxylate. A compound of formula (I) wherein R3/R4 contains a benzo moiety substituted by a C2-6 alkoxycarbonyloxy group, e.g. tert-butoxycarbonyloxy, may be converted into the corresponding compound wherein R3/R4 contains a benzo moiety substituted by hydroxy under standard hydrolytic conditions, e.g. by treatment with trifluoroacetic acid.
A compound of formula (I) wherein R3/R4 contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R3ZR4 contains hydroxy by treatment with sodium hydroxide in the presence of tris(dibenzylideneacetone)- dipalladium(O) and 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-l ,1 '-biphenyl. A compound of formula (I) wherein R3/R4 contains hydroxy may be converted into the corresponding compound wherein R3/R4 contains optionally substituted C1-6 alkoxy, C3-7 heterocycloalkoxy or C3-7 heterocycloalkyKC^alkoxy by treatment with the appropriately substituted C1-6 alkyl, C3-7 heterocycloalkyl or C3-7 heterocycloalkyl(Ci-6)- alkyl halide, e.g. bromide, ideally at an elevated temperature in the presence of cetyl- ammonium bromide. Alternatively, a compound of formula (I) wherein R3/R4 contains hydroxy may be converted into the corresponding compound wherein R3/R4 contains optionally substituted pyridinyloxy, pyrimidinyloxy or pyrazinyloxy by treatment with the appropriately substituted pyridinyl, pyrimidinyl or pyrazinyl halide, e.g. fluoride or chloride, typically in the presence of a strong base such as sodium tert-butoxide.
A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein R3/R4 contains optionally substituted aryloxy or heteroaryloxy by treatment with an appropriately-substituted hydroxyaryl or hydroxyheteroaryl derivative and a base such as caesium carbonate, ideally in the presence of a copper(I) halide, e.g. copper(I) chloride or copper(I) bromide.
A compound of formula (I) wherein R3/R4 contains an amino (-NH2) group may be converted into the corresponding compound wherein R3/R4 contains 2,5-dioxopyrrolidin- 1-yl by treatment with succinic anhydride.
A compound of formula (I) wherein R3/R4 contains an aryl or heteroaryl moiety substituted by a halogen atom, e.g. chloro, may have the halogen atom removed by catalytic hydrogenation.
A compound of formula (I) wherein R3/R4 contains a benzo moiety may be alkylated on the aromatic ring by treatment with w-butyllithium and an alkyl halide (e.g. iodopropane); or by treatment with an organozinc reagent (e.g. isopropylzinc bromide) in the presence of [ 1 , 1 '-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride and copper(I) iodide.
A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. chloro) may be converted into the corresponding compound wherein the halogen atom is replaced by an optionally substituted alkynyl moiety (e.g. 3-hydroxyprop-l-yn-l-yl) by treatment with an appropriately-substituted alkyne derivative (e.g. 3-hydroxyprop-l-yne) and a catalyst such as tetrakis(triphenylphosphine)palladiurn(0), typically in the presence of coρper(I) iodide and a base such as triethylamine. A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by acetyl by a two-stage procedure which comprises (i) treatment with butyl vinyl ether and palladium acetate, suitably in the presence of l,3-bis(diphenylphosphino)propane and an organic base such as triethylamine; and (ii) hydrolysis with a mineral acid such as hydrochloric acid.
A compound of formula (I) wherein R /R contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by 1 -hydroxy- 1-methylethyl by treatment with n-butyllithium and acetone. A compound of formula (I) wherein R3/R4 contains a halogen atom (e.g. bromo) may be converted into the corresponding compound wherein the halogen atom is replaced by C1-6 alkylthio (e.g. isopropylthio) by treatment with n-butyllithium and the appropriate disulphide derivative (e.g isopropyl disulphide). Conversion of the Ci-6 alkylthio moiety into Ci-6 alkylsulphinyl or C1-6 alkylsulphonyl may be accomplished by treatment with an oxidising agent, e.g. m-chloroperbenzoic acid.
A compound of formula (I) wherein R3/R4 contains a pyridinyl moiety may be converted into the corresponding pyridine-iV-oxide analogue by treatment with peracetic acid.
A compound of formula (I) wherein R3/R4 contains a carbonyl-containing moiety (e.g. acetyl) may be converted into the corresponding oxime analogue by treatment with an appropriately-substituted hydroxylamine derivative.
A compound of formula (I) wherein R3/R4 contains a formyl moiety may be converted into the corresponding compound wherein R3/R4 contains a vinyl moiety by treatment with methyltriphenylphosphonium bromide and a strong base such as sodium hexamethyldisilazide.
A compound of formula (I) wherein R3/R4 contains a formyl moiety may be converted into the corresponding compound wherein R3/R4 contains a 1-hydroxyethyl moiety by treatment with methyllithium.
A compound of formula (I) wherein R3/R4 contains a (2-hydroxyethyl)amino- carbonyl group may be converted into the corresponding compound wherein R3/R contains an oxazolin-1-yl moiety by treatment with thionyl chloride.
A compound of formula (I) wherein R3/R4 contains an ester functionality (e.g. methoxycarbonyl) may be converted into the corresponding compound wherein R3/R4 contains an amide functionality (e.g. methylaminocarbonyl or dimethylaminocarbonyl) by treatment with an appropriately-substituted amine (e.g. methylamine or dimethylamine) in the presence of trimethylaluminium.
Alkenyl-containing compounds may be converted into the corresponding vic- dihydroxy analogues by treatment with osmium tetroxide.
Alkenyl- and alkynyl-containing compounds may be converted into the corresponding alkyl analogues by catalytic hydrogenation.
A compound of formula (I) wherein R5 represents hydrogen may be converted into the corresponding compound wherein R5 represents Ci-6 alkyl by treatment with the appropriate alkyl halide, e.g. a methyl halide such as iodomethane, in the presence of a strong base such as sodium hydride.
Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in
Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art. The following Examples illustrate the preparation of compounds according to the invention.
The compounds in accordance with this invention potently inhibit the activity of human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3K6.
Enzyme Inhibition Assays
Measurement of the ability of compounds to inhibit the lipid kinase activity of the four class 1 PI3 kinase isoforms (α, β, γ and δ) was performed using a commercially available homogeneous time-resolved fluorescence assay as described by Gray et al., Anal. Biochem., 2003, 313, 234-245, according to the manufacturer's instructions (Upstate). All assays were performed at 2 μM ATP and a concentration of purified class 1 PI3 kinase known to generate product within the linear range of the assay. Dilutions of inhibitor in DMSO were added to the assay and compared with assays run in the presence of 2% (v/v) DMSO alone (100% activity). The concentration of inhibitor required to inhibit the enzyme activity by 50% is quoted as the IC50. When tested in the above assay, the compounds of the accompanying Examples were all found to possess ICs0 values for inhibition of activity of human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3K5 of 50 μM or better. EXAMPLES
Abbreviations
DCM: dichloromethane EtOAc: ethyl acetate
DMSO: dimethylsulphoxide wt: weight
Et2O: diethyl ether THF: tetrahydrofuran r.t.: room temperature sat.: saturated
MeOH: methanol AcOH: acetic acid
EtOH: ethanol IPA: isopropyl alcohol
Me: methyl DIPEA: N,N-diisopropylethylamine h: hour cone: concentrated
MeCN: acetonitrile M: mass
SiO2: silica br: broad v: volume NIS: N-iodoosuccinimide
NBS: N-bromosuccinimide Et: ethyl
NCS: iV-chlorosuccinimide prep.: preparative
DMF: Λζ^V-dimethylformamide HOBT : 1 -hydroxybenzotriazole
DMPU: 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
EDC: 1 -[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride brine: saturated aqueous sodium chloride solution
ΗPLC: 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, 10.0 or 11.01) supplied by Advanced Chemical Development, Toronto, Canada.
All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware. INTERMEDIATE 1
Ethyl 3-amino-3-methylbutanoate hydrochloride
To a stirred solution of ethyl 3,3-dimethylacrylate (5.0 g, 39.1 mmol) in EtOH (20 mL) in a PARR® reactor was added liquid NH3 (ca 20 mL) at 00C. The reactor was sealed and heated to 900C for 24 h. The reaction mixture was then cooled to r.t., bubbled with N2 to remove the residual NH3 and treated with 4M HCl in 1,4-dioxane (10 mL). The reaction mixture was stirred for 30 minutes at r.t. and then evaporated in vacuo to dryness. The resulting grey paste was triturated with DCM, filtered and dried to give the title compound as a grey solid (5.0 g, 70%) that was used without further purification. 5H (CDCl3) 8.27 (3H, br. s), 4.10 (2H, q), 2.65 (2H, s), 1.26 (6H, s), 1.20 (3H, t).
INTERMEDIATE 2
Ethyl 3-f(3-ethoxy-3-oxopropanoyl)arnino1-3-methylbutanoate
To a stirred suspension of Intermediate 1 (5.0 g, 27.4 mmol) in DCM (40 mL) was added NEt3 (11.1 g, 15.3 mL, 109.6 mmol). The reaction mixture was then cooled to 00C and ethyl malonyl chloride (4.4 g, 3.7 mL, 28.8 mmol) was added dropwise. The suspension was stirred at r.t. for 2 h before it was diluted with DCM (50 mL) and washed with aqueous IM HCl (50 mL) and water (2 x 50 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange oil (5.0 g, 71%) that was used without further purification. δH (DMSO-d6) 7.75 (IH, br. s), 4.15-3.95 (4H, m), 3.14 (2H, s), 2.71 (2H, s), 1.29 (6H, s), 1.21-1.11 (6H, m).
INTERMEDIATE 3
6,6-Dimethylpiperidine-2,4-dione
To a stirred solution of NaOEt, prepared in situ from Na (0.53 g, 23.16 mmol) in EtOH (30 mL), was added dropwise a solution of Intermediate 2 (5.00 g, 19.30 mmol) in toluene (30 mL) and the reaction mixture was heated to 800C for 2 h. The solution was then concentrated to ca 10 mL and the residue was dissolved in toluene (30 mL) and extracted with water (3 x 30 mL). The combined aqueous layers were acidified to pH 2-3 with aqueous IM HCl and extracted with EtOAc (4 x 50 mL). The combined organic fractions were dried (MgSO4), filtered and evaporated in vacuo to give a pale yellow solid that was dissolved in MeCN (90 mL) containing 1 % water. The solution was heated to reflux for 2 h and then evaporated in vacuo to dryness. The resulting solid was triturated with diisopropyl ether, filtered and dried to give the title compound (1.55 g, 57%) as a cream solid that was used without further purification. Both the keto and enol forms were observed (ratio 3.6:1 keto/enol). δH (DMSO-d6) 10.29 (IH, br. s, enόl), 8.14 (IH, br. s, keto), 6.66 (IH, s, enol), 4.81 (IH, s, enol), 3.15 (2H, s), 2.51 (2H, s), 1.20 (6H, s, keto), 1.18 (6H, s, enol).
mTERMEDIATE 4
3-Bromo-6,6-dimethyrpiperidine-2,4-dione
To a stirred suspension of Intermediate 3 (10.00 g, 70.9 mmol) in THF (200 mL) was added NaHSO4 (2.12 g, 17.7 mmol). The suspension was cooled to 00C and NBS (12.62 g, 70.9 mmol) was added portionwise. The reaction mixture was stirred at r.t. for 5 h then DCM (200 mL) and water (100 mL) were added. The aqueous fraction was extracted with DCM (2 x 100 mL). The combined organic fractions were washed with water (3 x 200 mL), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The white solid was triturated with IPA (3 x 50 mL), then filtered to give the title compound (10.3 g, 66%) as a white solid. δH (DMSO-d6) 10.80 (IH, br. s), 7.26 (IH, br. s), 2.50 (2H, s) for the main tautomer. LCMS (ES+) 220.0 and 222.0 (1 :1 ratio) (M+H)+.
INTERMEDIATE 5
6-Bromo-4H-benzo[ 1 ,4]oxazin-3-one
NEt3 (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in TΗF (80 mL). The reaction mixture was cooled to 00C, chloroacetyl chloride (1.12 mL, 14 mmol) was added portionwise and then stirred at 00C for 10 minutes before being allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled to 00C and NaH (1.05 g, 60% dispersion in oil, 26 mmol) was added portionwise. The reaction mixture was stirred at O0C for 20 minutes then at r.t. for 2 h before being quenched with water (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered, washed with water (3 x 50 mL) and dried in vacuo to give the title compound (2.14 g, 70%) as a beige solid. 5H (DMSO-(I6) 10.81 (IH, br. s), 7.08 (IH, dd, J 8.5 and 2.3 Hz), 7.02 (IH5 d, J2.3 Hz), 6.92 (IH, d, J 8.5 Hz), 4.60 (2H, s).
INTERMEDIATE 6
6-Bromo-3,4-dihydro-2//-benzori,4]oxazine
Borane-THF (13.2 mL, IM solution in THF, 13.2 mmol) was added portionwise to Intermediate 5 (2.0 g, 8.0 mmol) in THF (50 mL) at r.t. The resulting solution was stirred at r.t. for 10 minutes, heated to reflux for 1 h and then allowed to cool to r.t. The reaction mixture was cooled to 00C and quenched with water (20 mL) and aqueous 2N NaOH (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The aqueous fraction was extracted with EtOAc (100 mL), washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (2 g, quantitative) as a brown oil. δH (DMSO-d6) 6.68 (3H, m), 4.25-4.18 (2H, m), 3.81 (IH, br. s), 3.44-3.36 (2H, m).
INTERMEDIATE 7
6-Bromo-3,4-dihvdro-2H-benzo[l,41oxazine-4-carbothioic acid amide
Intermediate 6 (1.7 g, 8 mmol) and lj'-thiocarbonyldiimidazole (2.84 g, 16 mmol) were combined in THF (15 mL) and heated to 12O0C under microwave irradiation for 15 minutes. After cooling to r.t., NH3 (40 mL, 7N solution in MeOH, 280 mmol) was added, and the mixture stirred at r.t. for 3 h. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with Et2O and heptane to give the title compound (0.5 g, 23%) as a white solid. δH (DMSO-d6) 8.20 (2H, br. s), 7.60 (IH, d, J2.3 Hz), 7.21 (IH, dd, J 8.7 and 2.3 Hz), 6.88 (IH, d, J8.9 Hz), 4.30-4.16 (4H, m).
INTERMEDIATE 8 2-(6-Bromo-2J-dihydrobenzo|'l,4]oxazin-4-yl)-6,6-dimethyl-6,7-dihvdro- r 1 ,31thiazolo[5,4-c]pyridin-4(5Hr)-one
Two batches each of Intermediate 4 (0.25 g, 1.14 mmol), Intermediate 7 (0.25 g, 0.87 mmol) and DIPEA (0.23 mL, 1.3 mmol) in TΗF (4 mL) were heated to 12O0C under microwave irradiation for 20 minutes. After cooling to r.t., the reaction mixtures were combined and partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was separated, washed with brine (100 mL) and concentrated in vacuo. The crude material was purified by preparative ΗPLC to give the title compound (0.101 g, 15%) as an off-white solid. δΗ (CDCl3) 8.18 (IH, d, J2.3 Hz), 7.08 (IH, dd, J8.9 and 2.3 Hz), 6.76 (IH, d, J 8.7 Hz), 5.28 (IH, br. s), 4.29-4.22 (2H, m), 4.04-3.98 (2H, m), 2.83 (2H, s), 1.33 (6H, s). LCMS (ES+) 394.0 (M+H)+.
INTERMEDIATE 9
6,6-Dimethyl-2-r6-(l-methyl-lH-pyrazol-4-yl)-2J-dihvdrobenzorL41oxazin-4-vn-6.7- dihydro[ 1 ,31thiazolo[5,4-c1pyridin-4(57/)-one
A stirred suspension of Intermediate 8 (0.090 g, 0.23 mmol), l-methyl-4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (0.142 g, 0.69 mmol), Na2CO3 (0.073 g, 0.69 mmol), tetra-n-butylammonium bromide (0.212 g, 0.69 mmol) and tetrakis- (triphenylphosρhine)ρalladium(O) (0.026 g, 0.02 mmol) in TΗF (4 mL) was heated to 1500C under microwave irradiation for 40 minutes. After cooling to r.t., the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL) and washed with brine (50 mL). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. The residue was then purified by preparative ΗPLC, the resulting material being partitioned between EtOAc (100 mL) and aqueous sat. NaHCO3 solution (100 mL). The organic fractions were combined and washed with a mixture of brine and water (100 mL), dried (MgSO4), filtered and concentrated in vacuo. This residue was then triturated with EtOAc (100 mL) and the mother liquors decanted to give the title compound (0.024 g, 27%) as a white solid. δH (CDCl3) 7.92 (IH, d, J2.1 Hz), 7.62 (IH, s), 7.49 (IH, s), 7.10 (IH, dd, J8.5 and 2.1 Hz), 6.88 (IH, d, J8.5 Hz), 5.26 (IH, s), 4.30-4.23 (2H, m), 4.16- 4.09 (2H, m), 3.88 (3H, s), 2.81 (2H, s), 1.33 (6H, s). LCMS (ES+) 396.0 (M+H)+. INTERMEDIATE 10
3-Iodo-5,5-dimethylpyrrolidine-2.4-dione
To a stirred solution of 5,5-dimethylpyrrolidine-2,4-dione (prepared according to the method of Matsuo, K. and Tanaka, K., Chem. Pharm. Bull, 1984, 32(9), 3724-3729) (0.422 g, 3.32 mmol) in AcOH (10 mL) was added NIS (0.747 g, 3.32 mmol). The reaction mixture was stirred for 1 hour and partitioned between EtOAc and water. The organic layer was washed with water, aqueous sodium bicarbonate, and brine, passed through a phase separator and concentrated to an oil which was purified by column chromatography (SiO2, 1 : 1 EtO Ac/hexanes) to afford the title compound as an oil (0.129 g, 15%). δH (DMSO-d6) 8.81 (IH, br. s), 1.40 (6H, s). LCMS (ES+) 253.9 (M+H)+.
INTERMEDIATE 11
(3S)-2> -( lH-Indol-3 -ylmethyl)moφholine-4-carbothioarnide
To a stirred suspension of l,l'-thiocarbonyldiimidazole (56.85 g, 319 mmol) in MeCN (350 mL) at r.t. was added dropwise, over a period of 30 minutes, a solution of (3<S)-3-(lH-indol-3-ylmethyl)morpholine (prepared according to the method described in WO 2006/114606) (57 g, 207 mmol) in MeCN (800 mL). The reaction mixture was then stirred for 1 hour at room temperature, after which 28% NH4OH (300 ml) was added and the solution was heated at 400C for 16 h. Three further portions OfNH4OH were added (120 mL; 60 mL after 8 hours; and 40 mL after 24 hours). The reaction mixture was stirred at 400C for 16 h after the last addition OfNH4OH and the MeCN was evaporated. Water (300 mL) was added and the mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with IN HCl (3 x 500 mL), and brine (4 x 250 mL), dried over MgSO4 and evaporated in vacuo to dryness to afford an off-white solid (78 g). This solid was dissolved in IPA (700 mL) at reflux for 1 hour, and the resulting solution was cooled to room temperature and stirred for 16 hours. The precipitate was filtered, rinsed with IPA (70 mL) and dried under vacuum at 550C for 48 hours to yield the title compound (53.06 g; containing 5% w/w of IPA by NMR; corrected weight 50.41 g, 69.4% yield). A second crop was recovered by crystallization of the mother liquors (8.35 g, 11.5% yield). Total yield 80%. δH (DMSO-d6) 10.85 (IH, s), 7.86 (IH, d, J7 Hz), 7.49 (2H, s), 7.34 (IH, d, J8 Hz), 7.17 (IH, d, J2 Hz), 7.07 (IH, X, Jl Hz), 6.97 (IH, t, Jl Hz), 3.90 (IH, br. d, J8 Hz), 3.60 (IH, d, J 12 Hz), 3.40-3.15 (5H, m), 2.79 (IH, dd, J4 and lO Hz).
INTERMEDIATE 12
(3,SV3-(Prop-2-vn- 1 -ylimorpholine
To a solution of trimethylsilylacetylene (27.59 mL, 195.2 mmol) dissolved in anhydrous THF (250 mL) at 00C was added «-butyllithium (78.1 mL, 2.5M in hexanes, 201 mmol) dropwise over 15 minutes. After stirring at this temperature for 40 minutes, a solution of (3a,i?)-tetrahydro-3H-[l,2,3]oxathiazolo[4,3-c][l,4]oxazine 1,1-dioxide (prepared according to the method described in WO 2006/114606) (11.65g, 65.083 mmol) dissolved in DMPU (11 mL) was added slowly over 15 minutes and the reaction mixture was allowed to warm to r.t. After stirring at r.t. for 18 h, the reaction mixture was quenched by the addition of water (ca 4 mL) and the solvent (not DMPU) was removed in vacuo. To the resultant dark oil were added aqueous HCl (10% v/v, 200 mL) and MeOH (100 mL) and the reaction mixture was stirred at r.t. for 18 h. The solution was then concentrated in vacuo to give the title compound (17.06 g, ca 74% yield) as a crude dark oil (containing ca ll mL DMPU) that was used without further purification. 5Η (CD3OD) 3.89 (1Η, dd, J 11.2 and 3.1 Hz), 3.76 (IH, dt, J 11.2 and 2.7 Hz), 3.45-3.56 (IH, m), 3.25 (IH, m), 2.89 (3H, m), 2.39 (IH, t, J2.7 Hz), 2.25 (2H, dd, J6.8 and 2.7 Hz). Exchangeable proton was not observed.
INTERMEDIATE 13
fert-Butyl (3-?)-3-(prop-2-vn-l -yl)morpholine-4-carboxylate
To a solution of crude Intermediate 12 (17.06 g, containing 11 mL DMPU) dissolved in anhydrous DCM (300 mL) at 00C was added DIPEA (13.04 mL, 74.85 mmol) and di-tert-butyl dicarbonate (15.62 g, 71.6 mmol) and the reaction mixture warmed to r.t. After stirring for 18 h, the reaction mixture was washed with brine and the organic fraction was dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 10:1 EtOAc/hexanes) gave the title compound (8.79 g, 59% from Intermediate 12) as a yellow oil. δH (CD3OD) 3.95 (IH, m), 3.75 (IH, d, J 14.2 Hz), 3.70 (IH, m), 3.58 (IH, m), 3.42 (IH, m), 3.30 (IH, m), 2.95 (IH, m), 2.51 (IH, m), 2.37 (IH, m), 2.19 (IH, t, J2.7 Hz), 1.35 (9H, s).
INTERMEDIATE 14
fert-Butyl (35V3 -[3 -(trimethylsilyl)prop-2-yn- 1 -yl]morpholine-4-carboxylate
To a solution of Intermediate 13 (8.05 g, 35.7 mmol) dissolved in anhydrous THF (250 mL) at 00C was added «-butyllithium (15.7 mL, 2.5 M in hexanes, 39.3 mmol) dropwise over 15 minutes. After stirring for 30 minutes, chlorotrimethylsilane was added slowly over 5 minutes and the reaction mixture stirred for 45 minutes and then allowed to warm to r.t. After stirring at r.t. for 18 h, the reaction mixture was quenched by the addition of water {ca 1 mL) and the solvent was removed in vacuo. The crude mixture was dissolved in DCM and washed with water, the aqueous phase was extracted with further DCM (500 mL) and the. combined organic fractions were dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 5-20% EtOAc/hexaηes) gave the title compound (8.1 g, 76%) as a colourless oil and recovered starting material (1.25 g, 15%). 6H (CD3OD) 3.91 (IH, m), 3.82 (IH, d, J 11.7 Hz), 3.70 (IH, dd, J3.6 and 11.4 Hz), 3.58 (IH, dd, J 2.9 and 13.7 Hz), 3.40-3.20 (2H, m), 2.95 (IH, m), 2.60 (IH, dd, J9.1 and 16.7 Hz), 2.38 (IH, dd, J6.4 and 16.7 Hz), 1.35 (9H, s), 0.00 (9H, s).
INTERMEDIATE 15
4-Amino-3-iodo-iV,./V-dimethylbenzamide < To a stirred solution of dimethylamine (9.0 mL, 135 mmol) in THF at O0C was added trimethylaluminium (50 mL, 2.0M solution in toluene, 100 mmol). The resulting solution was stirred at 00C for 10 minutes before addition of a solution of methyl 4- amino-3-iodobenzoate (19 g, 70 mmol) in THF (50 mL). The solution was heated to reflux for 1.5 h then allowed to cool to r.t before being poured onto ice (100 g). The resulting suspension was treated with aqueous 2M NaOH solution (100 mL) and partitioned with diisopropyl ether (2 x 100 mL). The combined organics were passed through a phase separator and concentrated to give the title compound (20 g, 96%) as a pale yellow oil which was used without further purification. 5H (CDCl3) 7.79 (IH, d, J 1.5 Hz), 7.29-7.26 (IH, m), 6.72 (IH, d, J8.2 Hz), 4.31 (2H, br. s), 3.07 (6H, s). LCMS (ES+) 261 (M+H)+.
INTERMEDIATE 16
fert-Butyl Q^-S-irS-fdimethylcarbamoylVΣ-ftrimethylsilylVlH-indol-S- yl]methyl}moφholine-4-carboxylate
The title compound was prepared from Intermediate 15 and Intermediate 14 according to Method A and was isolated as white solid. δH (CDCl3) 8.04 (IH, s), 7.90 (IH, br. s), 7.39-7.28 (2H, m), 4.30 (IH, m), 3.95-3.80 (2H, m), 3.66 (IH, d, J 11.7 Hz), 3.50-3.29 (4H, m), 3.11 (6H, br. s), 2.97 (IH, m), 1.47 (9H, s), 0.45 (9H, s). LCMS (ES+) 460 (M+H)+.
INTERMEDIATE 17
fe/t-Butyl (3ff)-3- (r5-(dimethylcarbamo ylV 1 -methyl-2-(trimethylsilvD- lH-indol-3- yl1methyl}morpholine-4-carboxylate
A mixture of Intermediate 16 (1.35 g. 2.9 mmol) and methyl iodide (0.31 mL, 5 mmol) in THF (40 mL) was cooled to -78°C and treated with lithium bis(trimethylsilyl)- amide solution (4.5 mL, IM in THF, 4.5 mmol). The reaction mixture was stirred at this temperature for 10 minutes and then allowed to reach room temperature. The reaction was quenched by addition of sat. aqueous NH4Cl solution (15 mL) and partitioned into EtOAc (3OmL). The aqueous was separated and extracted into DCM (2 x 50 mL). The combined organics were washed with brine (20 mL), passed through a phase separator and concentrated in vacuo to give a crude foam. This was purified by column chromatography (SiO2, 0:1 → 2:3 EtOAc/hexanes) to afford the title compound (0.90 g, 66%) as an off-white foam. δH (DMSO-d6) 7.73 (IH, br s), 7.23 (IH, br s), 7.15 (IH, d, J 2.4 Hz), 4.07 (IH, br), 3.81 (IH, d, J 8.6 Hz), 3.73 (3H, s), 3.15-3.44 (7H, m), 2.89 (6H, s), 1.35 (9H, s), 0.39 (9H, s). LCMS (ES+) 474.1 (M+H)+.
INTERMEDIATE 18
N,N,l-Trimethyl-3-rf35^-morpholin-3-ylmethyn-lH-indole-5-carboxamide Intermediate 17 (0.90 g, 1.9 mmol) was treated with HCl (40 mL, 4M in 1,4- dioxane, 160 mmol) and the mixture stirred at room temperature for 4 h. The solution was concentrated in vacuo to give a beige solid, which was partitioned between DCM (50 mL) and sat. aqueous Na2CO3 solution (50 mL). The organic layer was separated and the aqueous extracted into DCM (3 x 20 mL). The combined organics were washed with brine (20 mL), passed through a phase separator and concentrated in vacuo to give the title compound (0.52 g, 91%) as a a beige foam. δH (DMSO-d6) 7.58 (IH, d, J 1.0 Hz), 7.35 (IH, d, J8.6 Hz), 7.13 (2H, m), 3.69 (3H, s), 3.58 (2H, m), 3.27 (IH, td, J 10.6 and 2.8 Hz), 2.92 (6H, s), 2.88-2.48 (6H, m). LCMS (ES+) 302.0 (M+H)+.
INTERMEDIATE 19
3-{r(3-Sr)-4-Carbamothioylmoφholin-3-yllmethyll-N.7V.l-trimethyl-lH-indole-5- carboxamide To a solution of Intermediate 18 (0.68 g, 2.2 mmol) in TΗF (8 mL) at room temperature was added 1,1 '-thiocarbonyldiimidazole (0.40 g, 2.2 mmol). The mixture was stirred overnight and then concentrated in vacuo. The residue was treated with NH3 solution (25 mL, 25% in water) and heated to 600C for 4 h. The mixture was cooled and extracted into DCM (4 x 30 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to give a beige foam which was purified by column chromatography (SiO2, 0:1 → 23:2 EtOAc/hexanes) to give the title compound (0.54 g, 62%) as a yellow foam. δH (DMSO-d6) 7.86 (IH, br s), 7.43 (2H, br s), 7.32 (IH, d, J 8.3 Hz), 7.16 (IH, s), 7.11 (IH, dd, J8.3 and 1.3 Hz), 3.82 (IH, m), 3.67 (3H, s), 3.50 (IH, d, J 11.6 Hz), 3.06-3.29 (6H, m), 2.89 (6H, s), 2.69 (IH, dd, J 13.4 and 3.8 Hz). LCMS (ES+) 361.2 (M+H)+.
INTERMEDIATE 20
3-Bromo-5,5-dimethylpyrrolidine-2,4-dione To a stirred solution of 5,5-dimethylpyrrolidine-2,4-dione (prepared according to the method of Matsuo, K. and Tanaka, K., Chem. Pharm. Bull, 1984, 32(9), 3724-3729) (0.85 g, 6.7 mmol) in THF (10 mL) at O0C was added NBS (1.19 g, 6.7 mmol) in one portion. The reaction mixture was stirred for 2 h and partitioned between EtOAc and water. The organic layer was washed with water, sat. aqueous NaHCO3 solution, brine, passed through a phase separator and concentrated to a yellow solid which was washed with Et2O to give the title compound (0.79 g, 57%) as a white solid. δH (DMSO-d6) 11.69 (IH, s), 7.87 (IH, s), 1.27 (6H, s). LCMS (ES+) 208.1 (M+H)+.
INTERMEDIATE 21 (METHOD A)
Methyl 3- {r(35f)-4-(fert-butoxycarbonyl)morpholin-3-yl]methyl } -2-(trimethylsilvD- IH- indole-5-carboxylate To a stirred solution of Intermediate 14 (31.9 g, 107 mmol) in DMF (160 ml) was added methyl 4-amino-3-iodobenzoate (29.8 g 107 mmol), LiCl (4.5 g 107 mmol) and Na2CO3 (22.8 g 215 mmol). The resulting suspension was degassed, Pd(OAc)2 (0.96 g, 4.3 mmol) added, and degassing repeated. The reaction mixture was heated to HO0C for 50 minutes. The reaction mixture was then cooled to room temperature, filtered through celite and concentrated in vacuo. The resulting brown oil was separated between isopropyl acetate and water. The aqueous layer was back-extracted with isopropyl acetate (2 x 150 mL). The combined organic layers were dried (MgSO4), treated with decolourising charcoal (5% by weight of crude material) for 30 minutes at room temperature, and purified by column chromatography (SiO2, DCM) to give the title compound (9.0 g, 19%) as a pale cream solid. δΗ (CDCl3) 8.50 (IH, br s), 8.05 (IH, s), 7.88 (IH, d), 7.32 (IH, d), 4.32 (IH, m), 3.99 (IH, t), 3.91 (3H, s), 3.65 (IH, d), 3.50-3.28 (3H, m), 3.05 (IH, dd), 1.48 (9H, s), 0.40 (9H, s). LCMS (ES+) 469.1 (M+Na).
INTERMEDIATE 22
Methyl 3- {|"(35f)-4-(tgr?-butoxycarbonyl')moφholin-3-yl]methvU -1 -methyl-2- (trimethylsilyl*)-lH-indole-5-carboxylate
To a stirred solution of Intermediate 21 (2.0 g, 4.48 mmol) in TΗF (30 mL) at 00C was added NaH (0.19 g, 60% dispersion in oil, 4.93 mmol). The reaction mixture was stirred at this temperature for 30 minutes. Methyl iodide (0.33 mL, 5.37 mmol) was then added, and the reaction mixture allowed to warm to r.t., then stirred for 18 h. Water (1 mL) was added, and the reaction mixture concentrated in vacuo. DCM (25 mL) and water (10 mL) were added. The organic fraction was separated, washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 10-25% EtOAc/hexanes) gave the title compound (1.95 g, 95%) as a pale yellow oil. LCMS (ES+) 405.1 ((M-'Bu)+H)+.
INTERMEDIATE 23
Methyl 1 -methyl-3-[(3ty)-morpholin-3- ylmethyl]- l//-indole-5-carboxylate
To a stirred solution of Intermediate 22 (1.95 g, 4.23 mmol) in MeOH (15 mL) was added 4M HCl in 1,4-dioxane (20 mL, 80 mmol). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. Water (10 mL) and DCM (10 mL) were added. The aqueous fraction was separated, basified by the addition of sat. aqueous NaHCO3 solution, then extracted with DCM (5 x 30 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (1.02 g, 84%) as a yellow solid that was used without further purification. 6H (DMSO-d6) 8.10 (IH, s), 7.65 (IH, d, J 8.6 Hz), 7.35 (IH, d, J 8.6 Hz), 7.15 (IH, s), 3.75 (3H, s), 3.65 (3 H, s), 3.50 (2H, m), 3.20 (IH, m), 2.95 (IH, t, J 8.6 Hz), 2.75 (IH, m) 2.45-2.65 (4H, m) 2.10 (IH, br s). LCMS (ES+) 289.2 (M+H)+.
INTERMEDIATE 24
Methyl 3- {f(35r)-4-carbamothioylmorpholin-3-yl1methyU-lH-indole-5-carboxylate
To a stirred slurry of Intermediate 23, (31.64 g, 109 mmol) in TΗF (221 ml) was added 1,1 '-thiocarbonyldiimidazole (21.51 g, 120.7 mmol, 1.1 eq) portionwise over about 10 minutes at ambient temperature. The reaction mixture was stirred for 5 h, transferred to a pressure vessel and NH3 solution (111 mL, 28% in water, 1646 mmol) added. This mixture was stirred at 6O0C for 17 h, then cooled to ambient temperature. The mixture was diluted with water (158 mL) and the THF removed in vacuo to give an aqueous slurry. The solid was filtered, washed with water (158 mL) and dried under vacuum at 45°C, to give the title compound (37.79 g, 99%) as a crystalline solid. δH (DMSO-d6) 8.60 (IH, br s), 7.80 (IH, m), 7.40-7.60 (3H, m), 7.30 (IH, s), 3.90 (IH, br d), 3.85 (3H, s), 3.80 (3H, s), 3.60 (IH, br d), 3.20-3.40 (6H, m), 2.80 (IH, dd). LCMS (ES+) 348.0 (M+H)+. INTERMEPIATE 25
3-(r(35f)-4-(4.4-Dimethyl-6-oxo-5.6-dihvdro-4H-pyrrolor3,4-cπ[l,31thiazol-2- yl)morpholin-3 - yl]methyl 1-1 -methyl- 1 H-indole-5 -carboxylic acid To Example 3 (2.98 g, 6.56 mmol) in ethanol (60 ml) and water (20 ml) was added sodium hydroxide (2 molar equivalents). The mixture was heated and stirred at reflux for 1 hour. The ethanol was evaporated in vacuo and the aqueous residue diluted with water (100 ml) and acidified with cone. HCl. The precipitated solid was filtered, washed with water and dried under high vacuum to give the title compound (2.43 g, 84%) as a white solid. δΗ (DMSOd6) 12.44 (IH, br s), 8.55 (IH, s), 7.95 (IH, s), 7.78 (IH, dd, J 8.6 and 1.5 Hz), 7.46 (IH, d, J 8.8 Hz), 7.31 (IH, s), 4.27-4.36 (IH, m), 4.01 (IH, d, J 7.6 Hz), 3.77 (3H, s), 3.71 (IH, d, J 11.7 Hz), 3.62 (2H, m), 3.53 (2H, d, J 2.5 Hz), 3.30 (IH, m), 3.02 (IH, dd, J4.5 and 13.7 Hz), 1.45 (3H5 s), 1.40 (3H, s). LCMS (ES+) 441.0 (M+H)+.
INTERMEDIATE 26
4,4-Dimethyl-2-((3^-3-[3-ftrimethylsilyl)prop-2-vn-l-yllmorpholin-4-yl|-4,5-dihvdro- 6H-pyrrolor3.4-fiπri,31thiazol-6-one
To a solution of Intermediate 20 (0.10 g, 0.49 mmol) and (35)-3-[3- (trimethylsilyl)prop-2-yn- 1 -yl]morpholine-4-carbothioamide (WO 2008/001076) (0.125 g, 0.49 mmol) in TΗF (5 mL) was added DIPEA (0.086 mL, 0.49 mmol) and the mixture was stirred at room temperature overnight. The mixture was partitioned between water (20 mL) and EtOAc (20 mL), then the organics were separated, washed with water (2 x 20 mL) and brine (10 mL), dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a yellow oil. This was re-dissolved in AcOH (1 mL) and heated to 600C for 4 h. The mixture was cooled and partitioned between EtOAc (10 mL) and sat. aqueous Na2CO3 solution (10 mL), then the organics were separated and washed with sat. aqueous Na2CO3 solution (10 mL) and brine (10 mL), dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a yellow oil. This was purified by column chromatography using a Biotage SP4 (SiO2, 0-100% EtOAc/hexane) to give the title compound (100 mg, 54%) as a white solid. δΗ (DMSO-d6) 7.95 (IH, s), 4.11 (IH, m), 3.83 (2HT m\ 3.63 (2Hy m), 3.51 (IH, m)τ 3.36 (6H, m), 2.73 (2H, m), 2.4a (13H, s), 1.35 (6H, d, J 3.0 Hz), 0.00 (9H, s). LCMS (ES+) 364.0 (M+H)+. INTERMEDIATE 27
2-Methyl- 1 -(4-nitrophenyl)- lH-imidazole
5 To 1 -fluoro-4-nitrobenzene (11.0 g, 0.078 mol) in DMF (40 mL) were added 2- methyl-lH-imidazole (6.41 g, 0.078 mol) and potassium carbonate (16.16 g, 0.117 mol) and the reaction stirred at 500C for 18 h. Residual solids were filtered off and the solvent removed from the filtrate. The residues were dissolved in ethyl acetate/water and extracted into ethyl acetate. The solvent was removed and, the residues triturated with 10 diethyl ether to give the title compound (13.93 g, 88%) as an off-white solid. δΗ (DMSO- d6) 8.38 (2H, d, J8.8 Hz), 7.78 (2H, d, J9.1 Hz), 7.46 (IH, s), 6.99 (IH, s), 2.38 (3H, s). LCMS (ES+) 204.0 (M+H+).
INTERMEDIATE 28
!5
4τ(2-Meth yl- lH-imidazol- 1 -vDaniline
Intermediate 27 (13.9 g, 68 mmol) was dissolved in ethanol to a final concentration of 0.05M. The solution was passed through a palladium on carbon catalyst cartridge (using an Η-cube reactor from ThalesNano) at 2 mL/min, 25°C and full 20 hydrogen to give the title compound (11.69 g, 99%) as an off-white solid. 5Η (DMSOd6) 7.08 (1Η, s), 7.01 (2Η, d, J8.5 Hz), 6.82 (IH, s), 6.63 (2H, d, J8.5 Hz), 5.35 (2H, s), 2.51 (3H, s). LCMS (ES+) 174.0 (M+H+).
INTERMEDIATE 29
25
2-Iodo-4-(2-methyl-lH-imidazol-l-yl')aniline
Intermediate 28 (11.69 g, 0.068 mol) was dissolved in glacial acetic acid (150 mL) and to the stirred solution was added solid NIS (14.47 g, 0.064 mol). After 1 h the solvent was removed in vacuo, then the residue was dissolved in 0.5M HCl and washed
30 three times with DCM. The aqueous layer was basified with sodium carbonate, extracted into dichloromethane, dried over magnesium sulphate and the solvent removed to yield a dark brown gum/foam. This material was dissolved in a minimum quantity of dichloromethane, loaded onto a short silica column and eluted with ethyl acetate to give the title compound (14.61 g, 73%) as an off-white solid. δH (DMSOd6) 7.56 (IH, d, J2.2 Hz), 7.13 (2H, m), 6.83 (2H, m), 5.49 (2H, s), 2.51 (3H, s). LCMS (ES+) 299.9 (M+H+).
INTERMEDIATE 30
fert-ButvU35^-3-{[5-(2-methyl-lH-imida2ol-l-ylV2-(trimethylsilylVlH-indol-3- vHmethvUmorpholine-4-carboxylate
A mixture of Intermediate 14 (2.5 g, 8.4 mmol) Intermediate 29 (2.5 g, 8.4mmol), LiCl (0.353 g, 8.4 mmol), Pd(OAc)2 (150 mg, 8 mol %) and Na2CO3 (1.8 g, 17 mmol) in DMF (20 mL) was degassed and heated at 10O0C overnight. The mixture was cooled and diluted with EtOAc (30 mL) and water (30 mL), and the mixture was filtered through a celite plug. The filtrate was washed with water (4 x 40 mL) and brine (40 mL), dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a brown foam. This was purified by column chromatography using a Biotage SP4 (SiO2, 0-100% EtOAc/hexane) to give the title compound (2.25 g, 57%) as a pale yellow foam. 5Η (DMSO-d6) 10.86 (1Η, s), 7.47 (1Η, d, J 8.6 Hz), 7.18 (IH, s), 7.07 (IH, dd, J 8.6, 1.3 Hz), 6.88 (IH, s), 4.04 (IH, m), 3.87 (IH, m), 3.72 (IH, m), 3.59 (IH, m), 2.25 (3H, s), 1.23 (1OH, m), 0.41 (9H, s). LCMS (ES+) 469.2 (M+H)+.
INTERMEDIATE 31
fert-Butyl (3S)-3 - { r 1 -methyl-5-(2-methyl- l//-imidazol- 1 -ylV2-(trimethylsilyl)- 1 H-indol- 3-yl1methvπmorpholine-4-carboxylate
To a cold (-780C) solution of Intermediate 30 (2.25 g, 4.8 mmol) in TΗF (40 mL) was added methyl iodide (0.6 mL, 9.6 mmol) followed by lithium bis(trimethylsilyl)- amide (9.6 mL of a IM solution in TΗF). The mixture was stirred at this temperature and then allowed to warm to room temperature overnight. Methyl iodide (2 mL, 32 mmol) and lithium bis(trimethylsilyl)amide (3 mL of a IM solution in TΗF) were added and the mixture stirred for an additional 3 h at room temperature. The reaction was partitioned between EtOAc (100 mL) and water (100 mL), the aqueous was separated, then the organics were washed with water (2 x 50 mL) and brine (50 mL), dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a foam. This was purified by column chromatography on a Biotage SP4 (SiO2, 0-100% EtOAc/hexane) to give the title compound (1.8 g, 77%) as a white foam. LCMS (ES+) 483.2 (M+H)+.
INTERMEDIATE 32
l-Methyl-S-α-methyl-lH-imidazol-l-ylVB-rO^-morpholin-S-ylmethvn-lH-indole
To a solution of Intermediate 31 (1.8 g, 3.7 mmol) in methanol (8 mL) was added HCl (20 mL, 4M in 1 ,4-dioxane, 80 mmol). The mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc (100 mL) and sat. aqueous Na2CO3 solution (100 mL). The organics were separated and the aqueous extracted into EtOAc (2 x 50 mL) and DCM (50 mL). The combined organics were dried (Na2CO3) and filtered through an Isolute® phase separator cartridge, then the solvent was removed in vacuo to give the title compound (1.1 g, quantitative) as an amber oil. LCMS (ES+) 311.2 (M+Η)+.
INTERMEDIATE 33
(3^-3-{ri-Methyl-5-(2-methyl-lH-imidazol-l-ylVlH-indol-3-yl1methvUmorρholine-4- carbothioamide To a solution of Intermediate 32 (1.1 g, 3.5 mmol) in TΗF was added 1,1'- thiocarbonyldiimidazole (0.75 g, 4.2 mmol) and the mixture stirred at room temperature for 1 h. The mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organics were separated and the aqueous extracted into EtOAc (50 mL). NaOH (2M aq.) was added until the solution became pΗ12 before extraction into DCM (50 mL). The combined organics were dried (Na2CO3), filtered through an Isolute® phase separator cartridge and concentrated in vacuo to give a foam. This was treated with aqueous NH4OH (100 mL, d = 0.770) and heated at 600C overnight. The mixture was cooled and diluted with EtOAc (100 mL), then the aqueous was separated and extracted into EtOAc (2 x 50 mL). The combined organics were dried using an Isolute® phase separator cartridge and concentrated in vacuo to give the title compound (1.05 g, 80%) as a pale foam which was used without further purification. LCMS (ES+) 370.2 (M+H)+.
EXAMPLE 1 4-Isopropylidene-2-[6-(l-tnethyl-lH-pyra2ol-4-yl)-2,3-dihydro-4H-l,4-benzoxazin-4-yl]- 4,5-dihvdro-6//-pyπOlor3,4-^]ri.31thiazol-6-one
A mixture of Intermediate 9 (0.50 g, 1.22 mmol) and NCS (0.19 g, 1.39 mmol) in MeCN (20 mL) was heated to 8O0C for 2 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. Half of the resulting residue was dissolved in MeCN (15 mL) and aqueous NaOH (20 mL of a IM solution, 20 mmol) was added. The mixture was stirred at r.t. for 4h. The acetonitrile was removed in vacuo, and the resulting precipitate filtered off. The solid was suspended in DMSO, filtered off and dried in vacuo to give the title compound (0.1 g, 42%) as a white solid. δH (DMSO-d6) 11.41 (IH, s), 8.52 (IH, s), 8.04 (IH, s), 7.76 (IH, s), 7.29 (IH, d, J8.3 Hz), 6.97 (IH, d, J8.3 Hz), 4.27-4.46 (2H, m), 4.06-4.24 (2H, m), 3.86 (3H, s), 2.24 (6H, s). LCMS (ES+) 394 (M+H)+.
EXAMPLE 2
2-r(35^-3-(lH-Indol-3-ylmethyl)morpholin-4-yl]-4.4-dimethyl-4.5-dihvdro-6H- pyrrolor3.4-cf][l ,3]thiazol-6-one
To Intermediate 10 (129 mg, 0.51 mmol) in THF (10 ml) was added Intermediate 11 (143 mg, 0.52 mmol, 1.05 eq) and DIPEA (0.177 mL, 1.04 mmol, 2 eq). The mixture was heated for 1 h at reflux and concentrated to dryness in vacuo. The residue was dissolved in AcOH (10 mL) and heated at reflux for 1 h. The mixture was concentrated to dryness in vacuo and the residue partitioned between EtOAc and water. The organic layer was washed with water, aqueous Na2CO3, and brine, passed through a phase separator and concentrated to an oil which was purified by column chromatography (SiO2, 1 : 1 -→2: 1 EtOAc/hexanes) to afford a green oil. This oil was further purified by prep. HPLC to afford the title compound as a white solid after freeze-drying from MeCN- water (0.023 g, 12%). δH (CDCl3) 8.07 (2H, s), 7.41 (IH, d, J 7.8 Hz), 7.25-7.14 (3H, m), 5.57 (IH, s), 4.31 (IH, d, J 11.4 Hz), 4.09 (IH, d, J 9.3 Hz), 3.93 (IH, d, J 11.9 Hz), 3.71 (3H, m), 3.56-3.43 (2H, m), 3.11 (IH, m), 1.59 (6H, s). LCMS (ES+) 383.7 (M+H)+.
EXAMPLE 3 Methyl 3-(rf3iy)-4-r4.4-dimethyl-6-oxo-5,6-dihvdro-4H-pyτrolor3.4-^]rL31thia2θl-2- yl)morpholin-3 - yl"|methyl } - 1 -methyl- 1 H-indole-5-carboxylate
To a mixture of Intermediate 20 (0.047 g, 0.23 mmol) and Intermediate 24 (0.08 g, 0.23 mmol) in TΗF (2 mL) was added DIPEA (0.044 mL, 0.25 mmol). This was stirred at room temperature for 1 h and concentrated to dryness in vacuo. The residue was dissolved in AcOH (2 mL), stirred at room temperature overnight and then at 600C for 2 h. The mixture was partitioned between DCM and sat. aqueous Na2CO3 solution, the aqueous was separated and extracted into DCM. The combined organics were washed with brine, passed through a phase separator and concentrated in vacuo to give a pale yellow solid which was purified by column chromatography (SiO2, 0:1— >1 :0 EtOAc/ hexanes) to give the title compound (0.030 g, 30%) as a white solid. δΗ (DMSO-d6) 8.50 (IH, d, J 1.3 Hz), 7.99 (IH, s), 7.79 (IH, dd, J8.8 and 1.8 Hz), 7.50 (IH, d, J8.8 Hz), 7.34 (IH, s), 4.22 (IH, br), 4.01 (IH, d, J6.8 Hz), 3.87 (3H, s), 3.77 (3H, s), 3.72 (IH, d, J 11.7 Hz), 3.60 (4H, m), 3.53 (IH, dd, J 11.6 and 2.53 Hz), 3.02 (IH, d, J 13.9 and 4.8 Hz), 1.43 (3H, s), 1.37 (3H, s). LCMS (ES+) 455.2 (M+H)+.
EXAMPLE 4
3-{r(3^-4-(4.4-Dimethyl-6-oxo-5.6-dihvdro-4H-pyrrolor3.4-tfl[1.31thiazol-2- yl)morpholin-3- yl]methyl I -N.N, 1 -trimethyl- lH-indole-5-carboxamide
To a mixture of Intermediate 20 (0.271 g, 1.32 mmol) and Intermediate 19 (0.474 g, 1.32 mmol) in TΗF (10 mL) at room temperature was added DIPEA (0.26 mL, 1.46 mmol). The mixture was stirred at room temperature for 2 h, filtered and then concentrated in vacuo. The residue was redissolved in AcOH (10 mL) and heated at 65°C for 3.5 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with sat. aqueous Na2CO3 solution, brine, passed through a phase separator and concentrated in vacuo to give a crude solid. This was purified by prep. ΗPLC to give the title compound (0.136 g, 22%) as a white solid after freeze drying from MeCN-water. 5Η (DMSO-d6) 7.99 (2Η, d, J6.8 Hz), 7.43 (IH, d, J 8.4 Hz), 7.28 (IH, s), 7.18 (IH, dd, J 1.4 and 8.4 Hz), 4.26 (IH, br), 4.00 (IH, d, J7.4 Hz), 3.76 (3H, s), 3.74 (IH, d, J5.3 Hz), 3.59 (2H, d, J8.1 Hz), 3.50 (2H, d, J8.1 Hz), 3.29 (IH, dd, J 10.8 and 2.9 Hz), 2.98-2.91 (7H, m). 1.41 (3H, s), 1.36 (3H, s). LCMS (ES+) 468.5 (M+H)+. EXAMPLE 5 (METHOD B)
4,4-Dimethyl-2-r(3lS)-3-{ri-methyl-5-(morpholin-4-ylcarbonvn-l//-indol-3- yl]methyUmoφholin-4-yll-4,5-dihydro-6-H-pyiτolo|'3,4-firH'1.3]thiazol-6-one To Intermediate 25 (100 mg, 0.227 mmol) in DCM (3 mL) was added morpholine
(3 eq), HOBT.H2O (1 eq, 35 mg) and EDC (1.5 eq, 65 mg). The mixture was stirred for 18 h, diluted with DCM (10 mL) and stirred with water (15 mL) for 1 h. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by prep. HPLC to afford the title compound (60 mg, 52%) as a white solid. δH (DMSO-d6) 8.01 (2H, m), 7.44 (IH, d, J8.6 Hz), 7.30 (IH, s), 7.19 (IH, dd, J 8.3 and 1.3 Hz), 4.24 (IH, m), 4.00 (IH, d, J 7.1 Hz), 3.76 (3H, s), 3.73 (IH, d, J 11.6 Hz), 3.60 (6H, d, J8.3 Hz), 3.53 (6H, m), 3.28 (IH, dd, J 13.6 and 10.6 Hz), 2.96 (IH, s), 1.39 (6H, d, J 18.4 Hz). LCMS (ES+) 510.2 (M+H)+.
EXAMPLE 6
4,4-Dimethyl-2-r(3^-3-(ri-methyl-5-fpiperidin-l-ylcarbonyl)-l/ir-indol-3- yl1methyl)morpholin-4-yl]-4,5-dihvdro-6H-pyrrolo[3,4-<f|[L31thiazol-6-one
Prepared using Method B above (piperidine was the amine used) to afford the title compound (35 mg, 30%) as a white solid. δΗ (DMSO-d6) 7.96 (2H, d, J 1.3 Hz), 7.42
(IH, d, J 8.3 Hz), 7.28 (IH, s), 7.14 (IH, dd, J 8.3 and 1.5 Hz), 4.25 (IH, m), 4.00 (IH, d, J7.3 Hz), 3.76 (3H, s), 3.73 (IH, s), 3.60 (8H, m), 3.51 (6H, m), 3.27 (IH, dd, J 13.6 and 10.6 Hz), 2.95 (IH, dd, J 13.4 and 4.0 Hz), 1.39 (6H, d, J 18.9 Hz). LCMS (ES+) 508.2 (M+H)+.
EXAMPLE 7
3-{[(35')-4-(4,4-Dimethyl-6-oxo-5,6-dihvdro-4//-pyrrolor3.4-^]ri,31thiazol-2- vπmorpholin-3-yl]methvU-iV,l-dimethyl-l//-indole-5-carboxamide To Intermediate 25 (100 mg, 0.227 mmol) in DCM (3 mL) was added methylamine (2M in THF; 10 mL), HOBT-H2O (1 eq, 35 mg) and EDC (1.5 eq, 65 mg). The mixture was stirred for 18 h, diluted with DCM (40 mL) and washed with water (50 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by prep. HPLC to afford the title compound (68 mg, 66%) as a white solid. δH (DMSO-d6) 8.30 (IH, m), 8.24 (IH, d, J4.5 Hz), 7.96 (IH, s), 7.62 (IH, dd, J8.6 and 1.5 Hz), 7.41 (IH, d, J8.6 Hz), 7.27 (IH, s), 4.24 (IH, d, J 1.5 Hz), 4.01 (IH, d, J7.3 Hz), 3.77 (IH, s), 3.74 (3H, s), 3.56 (4H, m), 3.28 (2H, m), 3.03 (IH, dd, J 13.9 and 5.1 Hz), 2.80 (2H, d, J4.5 Hz), 1.40 (3H, s), 1.33 (3H, s). LCMS (ES+) 454.2 (M+H)+.
EXAMPLE 8
NJV-Diethyl-3-(r(3^-4-(4.4-dimethyl-6-oxo-5,6-dihvdro-4H-pyrrolor3,4-^iπ.31thiazol-
2-yl)moφholin-3-yl]methvU-l-methyl-lH-indole-5-carboxamide
Prepared using Method B above (diethylamine was the amine used) to afford the title compound (40 mg, 36%) as a white solid. δΗ (DMSOd6) 8.00 (IH, s), 7.93 (IH, s),
7.43 (IH, d, J8.3 Hz), 7.28 (IH, s), 7.11 (IH, dd, J8.3 and 1.3 Hz), 4.28 (IH, m), 4.00 (IH, m), 3.76 (3H, s), 3.73 (IH, d, J 11.9 Hz), 3.59 (2H, d, J 8.3 Hz), 3.50 (2H, m), 3.34
(1OH, m), 3.27 (IH, dd, J 13.6 and 10.9 Hz), 2.93 (IH, dd, J 13.6 and 3.8 Hz), 1.41 (3H, s), 1.37 (3H, s). LCMS (ES+) 496.2 (M+H)+.
EXAMPLE 9
N-Benzyl-S-irfS^^-f^-dimethyl-ό-oxo-S.ό-dihvdro^H-pyrrolorS^-t/iriJlthiazol^- yl)morpholin-3 - yl]methyl 1-1 -methyl- lH-indole-5-carboxamide
Prepared using Method B above (benzylamine was the amine used) to afford the title compound (53 mg, 44%) as a white solid. δΗ (DMSO-d6) 8.87 (IH, m), 8.39 (IH, d, J 1.0 Hz), 7.95 (IH, s), 7.71 (IH5 dd, J8.6 and 1.5 Hz), 7.43 (IH, d, J8.6 Hz), 7.30 (6H, m), 4.51 (2H, dd, J 5.8 and 2.0 Hz), 4.27 (IH, m), 4.00 (IH, d, J 7.8 Hz), 3.76 (4H, m),
3.59 (4H, m), 3.29 (IH, dd, J 14.1 and 9.9 Hz), 3.05 (IH, dd, J 13.9 and 5.3 Hz), 1.39
(3H, s), 1.31 (3H, s). LCMS (ES+) 530.2 (M+H)+.
EXAMPLE 10
4.4-Dimethyl-2-r(35V3-( ( 1 -methyl-5-[(4-rnethylpiperazin-l -yl)carbonyll-l//-indol-3- vUmethyl)morpholin-4-yll-4,5-dihvdro-6H-pyrrolor3.4-cπri,31thiazol-6-one Prepared using Method B above (1-methylpiperazine was the amine used) to afford the title compound (70 mg, 59%) as a white solid. δH (DMSOd6) 8.00 (2H, m), 7.43 (IH, d, J8.6 Hz), 7.29 (IH, s), 7.16 (IH, dd, J8.3 and 1.3 Hz), 4.25 (IH, m), 4.00 (IH, d, J7.3 Hz), 3.76 (3H, s), 3.73 (2H, d, J 11.9 Hz), 3.59 (4H, d, J8.3 Hz), 3.51 (4H, m), 3.27 (IH, dd, J 13.6 and 10.6 Hz), 2.94 (IH, dd, J 13.6 and 3.8 Hz), 2.31 (3H, s), 2.19 (3H, s), 1.42 (3H, s), 1.37 (3H, s). LCMS (ES+) 523.2 (M+H)+.
EXAMPLE 11
4,4-Dimethyl-2-r(35V3- ( f 1 -methyl-5-(pyrrolidin- 1 -ylcarbonvn-lH-indol-3- yl]methvUmorpholin-4-yll-4,5-dihvdro-6H-pyrrolo[3,4-</1|'l,3]thiazol-6-one
Prepared using Method B above (pyrrolidine was the amine used) to afford the title compound (48 mg, 43%) as a white solid. δΗ (DMSOd6) 8.07 (IH, s), 8.00 (IH, s), 7.42 (IH, m), 7.30 (2H, m), 4.26 (IH, m), 4.00 (IH, d, J7.3 Hz), 3.76 (3H, s), 3.72 (IH, m), 3.59 (2H, d, J8.6 Hz), 3.51 (6H, m), 3.28 (IH, dd, J 13.6 and 10.6 Hz), 2.94 (IH, dd, J 13.6 and 3.8 Hz), 1.83 (4H, m), 1.41 (3H, s), 1.35 (3H, s). LCMS (ES+) 494.2 (M+H)+.
EXAMPLE 12
2-{r35)-3-[(5-{r(3/?V3-Hvdroxypyrrolidin-l-yl1carbonyll-l-methyl-lH-indol-3- yl)methyllmoφholin-4-vU-4.4-dimethyl-4.5-dihydro-6H-pyrrolor3,4-</]π,31thiazol-6-one Prepared using Method B above (/?-(+)-3-hydroxypyrrolidine was the amine used) to afford the title compound (46 mg, 40%) as a white solid. δΗ (DMSOd6) 8.09 (IH, m), 8.00 (IH, m), 7.42 (IH, m), 7.30 (2H, m), 4.25 (2H, m), 4.00 (IH, m), 3.76 (3H, s), 3.72 (IH, m), 3.57 (4H, m), 3.32 (5H, m), 2.94 (IH, m), 1.86 (2H, m), 1.42 (3H, s), 1.34 (3H, s). LCMS (ES+) 510.2 (M+H)+.
EXAMPLE 13
3-{[(3^-4-(4.4-Dimethyl-6-oxo-5,6-dihvdro-4//-pyiτolor3.4-cπri,31thiazol-2- yQmorpholin-3-yl]methvU-l-memyl-lH-indole-5-carboxamide
To Intermediate 25 (100 mg, 0.227mmol) in DMF (3 mL) was added ammonium chloride (2 eq), DIPEA (4 eq, 150 μL), HOBT-H2O (1 eq, 35 mg) and EDC (1.5 eq, 65 mg). The mixture was stirred for 18 h, diluted with DCM (40 mL) and washed with water (50 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by prep. HPLC to afford the title compound (5 mg, 5%) as a white solid. δH (DMSOd6) 8.39 (IH, s), 7.95 (IH, s), 7.80 (IH, s), 7.69 (IH, dd, J8.8 and 1.5 Hz), 7.40 (IH, d, J 8.6 Hz), 7.27 (IH, s), 7.15 (IH, s), 4.28 (IH, d, J 1.3 Hz), 4.00 (IH, d, J7.3 Hz), 3.74 (4H, m), 3.61 (2H, s), 3.56 (2H, m), 3.28 (IH, dd, J 14.1 and 10.1 Hz), 3.04 (IH, dd, J 13.9 and 5.3 Hz), 1.41 (3H, s), 1.34 (3H, s). LGMS (ES+) 440.0 (M+H)+.
EXAMPLE 14
3-{[(35f)-4-(4.4-Dimethyl-6-oxo-5.6-dihvdro-4i/-pyrrolor3.4-cηri.31thiazol-2- yl)morpholin-3 -yl]methyl } -7V-methoxy-iV, 1 -dimethyl- 1 H-indole-5-carboxamide
To Intermediate 25 (100 mg, 0.227 mmol) in DCM (3 mL) was added N,O- dimethylhydroxylamine hydrochloride (2 eq, 44 mg), DIPEA (4 eq, 150 μL), ΗOBT.Η2O (1 eq, 35 mg) and EDC (1.5 eq, 65 mg). The mixture was stirred for 18 h, diluted with DCM (40 mL) and washed with water (50 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to, dryness in vacuo. The residue was purified by prep. HPLC to afford the title compound (65 mg, 59%) as a white solid. δH (DMSO-dβ) 8.18 (IH, s), 7.97 (IH, s), 7.42 (2H, m), 7.29t(lH, s), 4.25 (IH, m), 4.01 (IH, d, J7.1 Hz), 3.77 (3H, s), 3.73 (IH, m), 3.59 (3H, m), 3.54 (3H, s), 3.51 (IH, d, J2.5 Hz), 3.29 (IH, m), 3.27 (3H, s), 2.97 (IH, dd, J 13.6 and 4.0 Hz), 1.42 (3H, s), 1.37 (3H, s). LCMS (ES+) 484.2 (M+H)+.
EXAMPLE 15
N-Cvclopropyl-3-(r(3S)-4-(4.4-dimethyl-6-oxo-5.6-dihvdro-4H-pyrrolor3.4- d] \ 1 ,31thiazol-2-yl)moφholin-3-yl1methyl) - 1 -methyl- lH-indole-5-carboxamide
Prepared using Method B above (cyclopropylamine was the amine used) to afford the title compound (60 mg, 55%) as a white solid. δΗ (DMSOd6) 8.27 (IH, d, J 1.0 Hz), 8.22 (IH, d, J3.8 Hz), 7.93 (IH, s), 7.61 (IH, dd, J8.6 and 1.3 Hz), 7.39 (IH, d, J8.6 Hz), 7.26 (IH, s), 4.23 (IH, br s), 4.01 (IH, m), 3.78 (IH, m), 3.74 (3H, s), 3.60 (4H, m), 3.29 (IH, dd, J 14.1 and 9.9 Hz), 3.04 (IH, dd, J 13.9 and 5.3 Hz), 2.86 (IH, m), 1.40 (3H, s), 1.33 (3H, s), 0.69 (2H, m), 0.59 (2H, m). LCMS (ES+) 480.2 (M+H)+.
EXAMPLE 16
3- {r(35r)-4-(4.4-Dimethyl-6-oxo-5.6-dihvdro-4H-pyrrolor3 A-d] \ 1.31thiazol-2- yl)moφholin-3-yl]methvU-iVL(2-methoxyethyl)-JV,l-dimethyl-lH-indole-5-carboxamide
Prepared using Method B above (N-(2-methoxyethyl)-N-methylamine was the amine used) to afford the title compound (83 mg, 71%) as a white solid. 5Η (DMSO-d6) 7.97 (2Η, d, J6.8 Hz), 7.43 (IH, d, J8.6 Hz), 7.28 (IH, s), 7.16 (IH, m), 4.26 (IH, m), 4.00 (IH, m), 3.76 (3H, s), 3.73 (IH, m), 3.58 (5H, m), 3.51 (6H, m), 3.28 (IH, dd, J 13.6 and 10.9 Hz), 2.99 (3H, s), 2.94 (IH, dd, J 13.6 and 3.8 Hz), 1.41 (3H, s), 1.37 (3H, s). LCMS (ES+) 512.2 (M+H)+.
EXAMPLE 17
N-fCvclopropylmethyl)-3-{rf35)-4-r4,4-dimethyl-6-oxo-5.6-dihvdro-4H-pyrrolor3,4- t/1[l,31thiazol-2-yl)morpholin-3-yl]methvU-l-methyl-lH-indole-5-carboxamide
Prepared using Method B above (cyclopropylmethylamine was the amine used) to afford the title compound (65 mg, 58%) as a white solid. δΗ (DMSO-d6) 8.34 (2H, m), 7.92 (IH, s), 7.66 (IH, dd, J8.6 and 1.5 Hz), 7.41 (IH, d, J8.6 Hz), 7.27 (IH, s), 4.25 (IH, br s), 4.01 (IH, m), 3.78 (IH, m), 3.75 (3H, s), 3.60 (4H, m), 3.30 (IH, dd, J 13.9 and 9.9 Hz), 3.17 (2H, dd, J 6.6 and 3.8 Hz), 3.04 (IH, dd, J 14.1 and 5.3 Hz), 1.40 (3H, s), 1.33 (3H, s), 1.07 (IH, m), 0.44 (2H, m), 0.26 (2H, m). LCMS (ES+) 494.2 (M+H)+.
EXAMPLE 18
3- {r(3^-4-(4.4-Dimethyl-6-oxo-5.6-dihvdro-4H-pyrrolor3 A-d] f 1 ,31thiazol-2- yl)morpholin-3-yl1methyl}-N,l-dimethyl-iV-phenyl-li/-indole-5-carboxamide To Intermediate 25 (100 mg, 0.227 mmol) in DMF (3 mL) was added N- methylaniline (2 eq, 36 μL), DIPEA (2 eq, 75 μL), HOBTH2O (1 eq, 35 mg) and EDC (1.5 eq, 65 mg). The mixture was stirred at 600C for 18 h, diluted with DCM (40 mL) and washed with water (50 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by prep. HPLC to afford the title compound (10 mg, 8%) as a white solid. δH (DMSO-d6) 8.01 (IH, s), 7.90 (IH, s), 7.16 (7H, m), 3.99 (IH, m), 3.77 (IH, m), 3.66 (3H, s), 3.57 (5H, m), 3.39 (3H, s), 3.16 (IH, dd, J 13.6 and 10.6 Hz), 2.83 (IH, m), 1.47 (3H, s), 1.40 (3H, s). LCMS (ES+) 530.2 (M+H)+.
EXAMPLE 19
4.4-Dimethyl-2-{(3^-3-rπ-methyl-5-{r4-(methylsulfonvnpiρerazin-l-vncarbonvU-lH- indol-3-yl)methyl]morpholin-4-yl}-4,5-dihydro-6H-pyrrolo[3,4.-cπ[l,31thiazol-6-one Prepared using Method B above (1-methanesulfonylpiperazine was the amine used) to afford the title compound (65 mg, 49%) as a white solid. δH (DMSOd6) 7.99 (2H, s), 7.45 (IH, d, J 8.6 Hz), 7.30 (IH, s), 7.22 (IH, dd, J8.3 and 1.5 Hz), 4.22 (IH, m), 4.00 (IH, d, J6.6 Hz), 3.76 (3H, s), 3.73 (IH, m), 3.60 (1 IH, m), 3.53 (IH, dd, J 11.6 and 2.3 Hz), 3.29 (IH, dd, J 13.6 and 10.4 Hz), 2.96 (IH, dd, J 13.6 and 4.0 Hz), 2.91 (3H, s), 1.40 (3H, s), 1.36 (3H, s). LCMS (ES+) 587.2 (M+H)+.
EXAMPLE 20
2-r(3^-3-({5-r(3-Hvdroxyazetidin-l-vncarbonvn-l-methyl-l//-indol-3- yl|methyl)morpholin-4-yll-4.4-dimethyl-4,5-dihvdro-6H-pyrrolo[3,4-cπrL31thiazol-6-one
To Intermediate 25 (100 mg,' 0.227 mmol) in DCM (3 mL) was added 3- hydroxyazetidine hydrochloride (2 eq, 50 mg), DIPEA (4 eq, 150 μL), ΗOBT.Η2O (1 eq, 35 mg) and EDC (1.5 eq, 65 mg). The mixture was stirred for 18 h, diluted with DCM (40 mL) and washed with water (50 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by prep. HPLC to afford the title compound (64 mg, 57%) as a white solid. 5H (DMSO-d6) 8.10 (IH, s), 7.97 (IH, s), 7.42 (2H, m), 7.29 (IH, s), 5.70 (IH, br s), 4.50 (IH, m), 4.45-4.16 (3H, m), 4.01 (IH, m), 3.75 (3H, s), 3.71 (IH, m), 3.60-3.51 (3H, m), 2.29 (4H, m), 2.95 (IH, dd, J 13.7 and 4.6 Hz), 1.44 (3H, s), 1.36 (3H, s). LCMS (ES+) 496.2 (M+H)+.
EXAMPLE 21 4.4-Dimethyl-2-r(35)-3- { [5-(2-methyl- lH-imidazol- 1 -vn-lH-indol-3- yl1methvUmoφholin-4-yl]-4,5-dihvdro-6//-pyrrolor3,4-cπi'l,3]thia2ol-6-one
A mixture of Intermediate 26 (0.363 g, 1 mmol), Intermediate 29 (299 mg, 1 mmol), LiCl (42 mg, 1 mmol), Pd(OAc)2 (11 mg, 5 mol %) and Na2CO3 (212 mg, 2 mmol) in DMF (3 mL) was degassed. The mixture was heated at 10O0C for 4 h, Pd(OAc)2 (10 mg) was added and the mixture degassed before heating at 1 100C overnight. The reaction was cooled, and treated with EtOAc (20 mL) and water (20 mL). The mixture was filtered through a celite plug and the filtrate diluted with EtOAc (30 mL). The organic layer was separated, then washed with water (4 x 20 mL) and brine (20 mL), dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a brown solid. This was dissolved in HCl (2 mL, 4M in 1 ,4-dioxane, 8 mmol), stirred for 2 h and then concentrated in vacuo. The residue was partitioned between EtOAc (5 mL) and sat. aqueous Na2CO3 solution (5 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to give a crude solid which was washed with Et2O to give the title compound (20 mg, 4%) as a white solid. δΗ (DMSO-d6) 11.17 (IH, s), 7.91 (2H, d, J2.8 Hz), 7.46 (IH, d, J8.3 Hz), 7.35 (IH, d, J 1.8 Hz), 7.20 (IH, s), 7.05 (IH, dd, J8.3, 1.5 Hz), 7.05 (IH, dd, J8.3, 1.5 Hz), 6.89 (IH, s), 4.34 (IH, m), 4.01 (IH, m), 3.75 (IH, d, J 11.9 Hz), 3.53 (5H, m), 2.96 (IH, dd, J 13.6, 4.0 Hz), 2.21 (3H, s), 1.22 (3H, s), 1.11 (3H, s). LCMS (ES+) 463.2 (M+H)+.
EXAMPLE 22
4.4-Dimethyl-2-r(3S)-3- { \ 1 -methyl-5-(2-methyl- 1 H-imidazol- 1 -yl)- lH-indol-3 - yllmethvUmorpholin-4-yl1-4,5-dihvdro-6i/-pyrrolor3,4-t/1[l,31thiazol-6-one
To a solution of Intermediate 20 (206 mg, 1 mmol) and Intermediate 33 (369 mg, 1 mmol) in THF (5 mL) at room temperature was added DIPEA (0.21 mL, 1.2 mmol) and the mixture stirred at room temperature overnight. The reaction was partitioned between EtOAc (50 mL) and water (20 mL), then the organics were separated, washed with brine (20 mL), dried using an Isolute® phase separator cartridge and concentrated in vacuo to give a pale yellow solid. This was dissolved in AcOH (3 mL) and heated to 600C for 12 h. The mixture was partitioned between EtOAc (100 mL) and sat. aqueous Na2CO3 solution (50 mL). The aqueous was separated and extracted into DCM (2 x 50 mL), then the organics were combined, dried (MgSO4), filtered through an Isolute® phase separator cartridge and concentrated in vacuo to give a yellow solid. This was dissolved in hot DCM and Et2O added to cause the title compound (0.088 g, 18%) to precipitate as a white solid. δH (DMSO-d6) 7.52 (IH, d, J8.7 Hz), 7.35 (IH, s), 7.20 (IH, d, J 1.3 Hz), 7.12 (IH, dd, J 8.5, 1.9 Hz), 6.90 (IH, d, J 1.3 Hz), 4.30 (IH, m), 4.01 (IH, m), 3.79 (4H, s), 3.54 (4H, m), 3.30 (4H, s), 2.93 (IH, ddd, J 13.6, 3.8, 0.6 Hz), 2.21 (3H, s), 1.25 (3H, s), 1.10 (3H, m). LCMS (ES+) 477.2 (M+H)+.

Claims

Claims:
1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000097_0001
(D
wherein
X represents oxygen or sulphur;
R and R independently represent hydrogen, hydroxy or amino; or C1-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, di(C1-6)alkylamino, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C)-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R and R may together form an isopropylidene moiety; or
R1 and R2, when taken together with the carbon atom to which they are both attached, represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents;
R3 and R4 independently represent hydrogen; or Ct-6 alkyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)- alkynyl, biaryl(Ci-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci.6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(Ci.6)alkyl or aryl-heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R3 and R4, when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or R3 and R4, when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; and R5 represents hydrogen or C1-6 alkyl.
2. A compound as claimed in claim 1 represented by formula (HA), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000098_0001
(KA)
wherein
R11 represents hydrogen or C1-6 alkyl; and
R12 represents hydrogen; or Cj-6 alkyl, Ci-6 alkoxy, 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 maybe optionally substituted by one or more substituents; or
R11 and R12 may together form an isopropylidene moiety; 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(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(Ci-6)alkyl, heteroaryl-aryl(Ci-6)alkyl or aryl-heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
3. A compound as claimed in claim 2 represented by formula (HB), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000099_0001
(IIB)
wherein
R11 and R12 are as defined in claim 2;
T represents oxygen or N-R25;
R23 represents hydrogen, halogen, cyano, nitro, Ci-6 alkyl, hydroxy(Ci-6)alkyl, trifluoromethyl, aryl(Ci-6)alkyl, oxazolinyl, imidazolyl, (C1-6)alkylimidazolyl, triazolyl, hydroxy, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl(Ci-6)alkoxy, morpholinyl(Ci-6)alkoxy, aryloxy, aryl(Ci-6)alkoxy, Ci-6 alkylthio, Ci-6 alkylsulphinyl, arylsulphinyl, arylsulphonyl, Ci-6 alkylsulphonyloxy, amino, azetidinyl, morpholinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylaminomethyl, C2-6 alkoxycarbonylamino, [(C2-6)alkoxycarbonyl][(Ci-6)alkyl]amino, CL6 alkylsulphonyl- amino, C2-6 alkylcarbonyl, C2-6 alkylcarbonyl oxime, C2-6 alkylcarbonyl 0-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylamino- carbonyl, [hydroxy(Ci-6)alkyl]aminocarbonyl, [di(Ci-6)alkylamino(Ci-6)alkyl]amino- carbonyl, di(C i -6)alkylaminocarbonyl, [(C i -6)alkyl] [cyano(Cj -6)alkyl]aminocarbonyl, [(C i ^alkyl] [hydroxy(C i ^alkyl] aminocarbonyl, [(C) ^alkoxy] [(C i-6)alkyl] aminocarbonyl, [(C i -6)alkoxy(C i -6)alkyl] [(C i -6)alkyl] aminocarbonyl, [di(C i -6)alkylamino(C i -6)alkyl] - [(C i-6)alkyl] aminocarbonyl, C3-7 cycloalkylaminocarbonyl, C3-7 cycloalkyl(Ci,6)alkyl- aminocarbonyl, N-[(Ci-6)alkyl]-N-(aryl)aminocarbonyl, aryl(Ci-6)alkylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl(C i -6)alkylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl, C2-6 alkoxycarbonylamino- azetidinylcarbonyl, pyrrolidinylcarbonyl, (Ci-6)alkylpyrrolidinylcarbonyl, hydroxy- pyrrolidinylcarbonyl, C1-6 alkoxy(C1-6)alkylpyrrolidinylcarbonyl, di(Cj.6)alkylamino- pyrrolidinylcarbonyl, thiazolidinylcarbonyl, oxothiazolidinylcarbonyl, piperidinyl- carbonyl, (C1-6)alkylpiperazinylcarbonyl, (d^alkylsulphonylpiperazinylcarbonyl, morpholinylcarbonyl, C1-6 alkylsulphonyl, C1-6 alkylsulphonylmethyl or di(Ci-6)alkyl- aminosulphonyl; and
R2 represents hydrogen, halogen, C1-6 alkoxy or di(C1-6)alkylaminocarbonyl; or
R23 and R24, when situated on adjacent carbon atoms, together represent methylenedioxy or difluoromethylenedioxy; and
R25 represents hydrogen or Ci-6 alkyl.
4. A compound as claimed in claim 2 represented by formula (HC), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000100_0001
(IIC)
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, (d^alkyltriazolylphenyl, (Ci-6)alkylpyrimidinylphenyl, pyrazolyl(Ci-6)alkyl- phenyl, triazolyl(Ci-6)alkylphenyl, C1-6 alkylsulphonylaminophenyl, morpholinylcarbonyl- phenyl, C1-6 alkylsulphonylphenyl, morpholinylsulphonylphenyl, dihydrobenzofuranyl, Ci-6 alkylsulphonylindolinyl, chromanonyl, dihydroquinolinonyl, benzoxazinonyl, benzothienyl, indolyl, dioxoindolyl, [(Ci-6)alkyl](halo)pyrazolyl, tri(C1-6)alkylpyrazolyl, (C)-6)alkylindazolyl, benzoxazolyl, benzoxazolonyl, di(Ci.6)alkylisoxazolyl, benzothiazolyl, (C1-6)alkylisothiazolyl, (Ci-6)alkylbenzimidazolyl, benzimidazolonyl, di(Ci-6)alkylbenzimidazolonyl, (C1-6)alkyloxadiazolyl, furyloxadiazolyl, pyridinyl, halopyridinyl, (Ci-6)alkylpyridinyl, di(C1.6)alkylpyridinyl, (C1-6)alkoxypyridinyl, oxopyridinyl, oxopyrimidinyl, thioxopyrimidinyl, [(Ci-6)alkoxy](halo)pyridazinyl, (C1-6)alkylcinnolinyl, quinoxalinyl or (C1-6)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 imgf000101_0001
Figure imgf000101_0002
wherein
R11 and R12 are as defined in claim 2; R43 represents hydrogen, halogen, nitro, Ci-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl,
(C1-6)alkylaryl, di(C1-6)alkylaryl, piperidinyl(Ci-6)alkylaryl, piperazinyl(Ci-6)alkylaryl, (C i -6)alkylpiperazinyl(C 1-6)alkylaryl, morpholinyl(C i -6)alkylaryl, (C i -6)alkoxyaryl, cyano(C1-6)alkoxyaryl, di(Ci-6)alkylamino(Ci-6)alkylaryl, (Ci-6)alkylaminocarbonylaryl, aryl(Ci-6)alkyl, haloarylpyrrolidinyl, dioxopyrrolidinyl, aminopyrrolidinyl, di(Ci-6)alkyl- aminopyrrolidinyl, indolinyl, oxoindolinyl, arylpiperidinyl, arylcarbonylpiperidinyl, di- (Ci-6)alkylaminocarbonylpiperidinyl, piperazinyl, (Ci-6)alkylpiperazinyl, haloaryl- piperazinyl, pyridinylpiperazinyl, furoylpiperazinyl, homopiperazinyl, (C1-6)alkyl- homopiperazinyl, (C1-6)alkylpiperazinyl(Ci-6)alkyl, morpholinyl(C1.6)alkyl, benzofuryl, benzothienyl, pyrazolyl, (Ci-6)alkylpyrazolyl, ^(d^alkylpyrazolyl, tri(Ci-6)alkyl- pyrazolyl, [di(C1-6)alkyl](trifluoromethyl)pyrazolyl, cyano(C1-6)alkylpyrazolyl, [cyano- (Ci-6)alkyl][di(Ci-6)alkyl]pyrazolyl, hydroxy(C1-6)alkylpyrazolyl, [hydroxy(C1-6)- alkyl] [di(C! -6)alkyl]pyrazolyl, methoxy(C i -6)alkylpyrazolyl, [(hydroxy)(methoxy)(C i -6)- alkyl]pyrazolyl, amino(C i -6)alkylpyrazolyl, [(C j -6)alkyl] [amino(C i ^alkyljpyrazolyl, [amino(Ci-6)alkyl][di(C]-6)alkyl]pyrazolyl, di(C1-6)alkylamino(Ci-6)alkylpyrazolyl, di(C i -6)alkoxyphosphono(C i -6)alkylpyrazolyl, (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, 8TyI(C1 -6)alkylpyrazolyl, aminoaryl- (Ci-6)alkylpyrazolyl, piperidinylpyrazolyl, tetrahydropyranyl(C1-6)alkylpyrazolyl, [di- (C1-6)alkyl][tetrahydropyranyl(C1-6)alkyl]pyrazolyl, pyrrolidinyl(C1-6)alkylpyrazolyl,
Figure imgf000102_0001
(C1-6)alkylpiperidinyl(C1-6)alkylpyrazolyl, morpholinyltQ^alkylpyrazolyl, pyridinyl(Ci-6)alkylpyrazolyl, oxypyridinyl(Ci-6)alkyl- pyrazolyl, [arylcarbonyl(C1-6)alkyl][di(C1-6)alkyl]pyrazolyl, [(C1-6)alkyl](piperazinyl- carbonyl)pyrazolyl, [(C i ^alkylaminocarbonyl] [(C i -6)alkylaryl]pyrazolyl, [(C i -6)alkyl] - [amino(C1-6)alkylaminocarbonyl]pyrazolyl, aminocarbonyl(C1-6)alkylpyrazolyl, [aminocarbonyl(C i -6)alkyl] [di(C i -6)alkyl]pyrazolyl, di(C i .6)alkylaminocarbonyl(C i -6)alkyl- pyrazolyl, pyrazolo[l,5-α]pyridinyl, di(C1-6)alkylisoxazolyl, (amino)[(C1-6)alkyl]- isoxazolyl, thiazolyl,
Figure imgf000102_0002
imidazolyl, (Ci-6)alkylimidazolyl, di(Ci.6)- alkylimidazolyl, imidazo[l,2-«]pyridinyl, (Ci-6)alkylimidazo[l,2-α]pyridinyl, (C1-6)- alkylimidazo[4,5-Z>]pyridinyl, imidazo[l,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, (C]-6)- alkylthiadiazolyl, pyridinyl, halopyridinyl, (C1-6)alkyl-pyridinyl, [(C1-6)alkyl](halo)- pyridinyl, di(Ci.6)alkylpyridinyl, (C2-6)alkenylpyridinyl, (C1-6)alkylpiperazinylpyridinyl, [(C i -6)alkyl] (piρerazinyl)pyridinyl, [(C \ -6)alkoxycarbonylpiperazinyl] [(C \ -6)alkyl] - pyridinyl, piperidinyl(Ci-6)alkylpyridinyl, [(C1-6)alkyl](oxy)pyridinyl, hydroxypyridinyl, hydroxy(Ci-6)alkylpyridinyl, (C1-6)alkoxypyridinyl, [(C1-6)alkoxy][(C1-6)alkyl]pyridinyl, [(Ci-6)alkoxy][di(Ci.6)alkyl]pyridinyl, (C1-6)alkoxy(C1-6)alkylpyridinyl, aminopyridinyl, carboxy(Ci-6)alkylpyridinyl, (Ci-6)alkoxycarbonyl(Ci-6)alkylpyridinyl, pyridazinyl, (Cj-6)- alkylpyridazinyl, piperidinylpyridazinyl, oxypyridazinyl, (C1-6)alkoxypyridazinyl, aminopyridazinyl, hydroxy(Ci-6)alkylaminopyridazinyl, di(Ci-6)alkylaminopyridazinyl, pyrimidinyl, (Ci-6)alkylpyrimidinyl, [(Ci-6)alkyl](halo)pyrimidinyl, di(Ci-6)alkyl- pyrimidinyl, pyrrolidinylpyrimidinyl, (Ci-6)alkylpiperazinylpyrimidinyl, [(C1-6)alkyl](piperazinyl)pyrimidinyl, [(Ci-6)alkoxycarbonyl][(Ci-6)alkyl]piperazinyl- pyrimidinyl, hydroxypyrimidinyl, [(C1-6)alkyl](hydroxy)pyrimidinyl, [(C1-6)alkyl]- [hydroxy(C1-6)alkyl]pyrimidinyl, [(C1-6)alkyl][hydroxy(C2-6)alkynyl]pyrimidinyl, (C1-6)- alkoxypyrimidinyl, aminopyrimidinyl, di(Ci-6)alkylaminopyrimidinyl, [di(C1-6)alkyl- amino] (halo)pyrimidinyl, carboxypyrimidinyl, [(C i -6)alkoxycarbonyl(C i -6)alkyl] [(C i -6)- alkyljpyrimidinyl, aminocarbonylpyrimidinyl, pyrazinyl, (C1-6)alkoxypyrazinyl, amino- pyrazinyl, hydroxy, (C1-6)alkoxy, 8TyI(C1 -6)alkoxycarbonylpiperidinyloxy, morpholinyl- (Ci-6)alkoxy, aryloxy, haloaryloxy, di(Ci.6)alkylpyrazolyloxy, halopyridinyloxy, pyrrolidinylpyridinyloxy, (C1-6)alkylpiperazinylpyridinyloxy, (Ci^alkylpyrazolyl- pyridinyloxy, (Ci-6)alkylaminopyridinyloxy, carboxypyridinyloxy, aminocarbonyl- pyridinyloxy, (C1-6)alkylpyridazinyloxy, pyrimidinyloxy, (C1-6)alkylpyrimidinyloxy, [(C i -6)alkyl] (halo)pyrimidinyloxy, hydroxy(C i .6)alkyl, dihydroxy(C i -6)alkyl, PyHdIHyIoXy(C1 -6)alkyl, amino, (C1-6)alkylamino, dihydroxy^i^alkylamino, (C1-6)- alkoxy(C1-6)alkylamino, 7V-[(C1-6)alkoxy(C1-6)alkyl]-N-[(Ci-6)alkyl]amino, di(C1-6)- alkylamino(C i -6)alkylamino, N-[(C i-6)alkyl]-iV-[di(C i-6)alkylamino(C i -6)alkyl]amino, N- [(Ci-6)alkyl]-N-[(C3-7)cycloalkyl]amino, haloarylamino, N-[(Ci-6)alkyl]-iV-(haloaryl)amino, N-[(C1-6)alkyl]-N-[aryl(Ci-6)alkyl]amino, N-[di(C1-6)alkylamino(C1-6)alkyl]-iV-[aryl(C1-6)- alkyl]amino, cyanoaryl(C1-6)alkylamino, (cyano)(halo)aryl(Ci-6)alkylamino, methylene- dioxyaryl(C1-6)alkylamino, iV-[(C1-6)alkyl]-iV-[(C1-6)alkylpyrrolidinyl]amino, piperidinyl- amino, N-[(C1-6)alkyl]-N-(piperidinyl)amino, N-[(C3-7)cycloalkyl(C1-6)alkyl]-N- (piperidinyl)amino, (Ci-6)alkylpiperidinylamino, N-[(C1-6)alkyl]-N-[(C1-6)alkyl- piperidinyl] amino, Λr-[(C1-6)alkyl]-Λr-[(C3-7)cycloalkylpiperidinyl]amino, 7V-[(C1-6)alkyl]- N-[(C2-6)alkylcarbonylpiperidinyl]amino, pyrrolidinyl(Ci-6)alkylamino, iV-[(C]-6)alkyl]-N- [pyrrolidinyl(C1-6)alkyl]amino, N-[(C1-6)alkyl]-iV-[piperidinyl(C1-6)alkyl]amino, (C1-6)- alkylpyrazolylamino, di(C1-6)alkylpyrazolylamino, ^(d^alkylpyrazolylamino, N-[(Ci-6)- alkyl]-Λ/-[(Ci-6)alkylpyrazolyl]amino, thiazolylamino, imidazolylamino, [(C1-6)alkoxy- carbonyl] [(C \ -6)alkyl]imidazolylamino, (C \ ^alkylthiadiazolylamino, pyridinylamino, halopyridinylamino, (Ci-6)alkylpyridinylamino, di(C1-6)alkylpyridinylamino, trifluoro- methylpyridinylamino, hydroxypyridinylamino, hydroxy(Ci-6)alkylpyridinylamino, dihydroxy(C i -6)alkylpyridinylamino,
Figure imgf000103_0001
dihydroxy(C1 -6)alkoxy- pyridinylamino, di(C i -6)alkyldioxolanyl(C i -6)alkoxypyridinylamino, (C i _6)alkoxy(C i -6)- alkylpyridinylamino, (C \ -6)alkoxy(C2-6)alkenylpyridinylamino, dihydroxy(C i -ό)alkyl- aminopyridinylamino, diCCj^alkylaminopyridinylamino, (Ci-6)alkylamino(Ci-6)alkyl- pyridinylamino, di(C1-6)alkylamino(C1-6)alkylpyridinylamino, carboxypyridinylamino, iV- [(Ci-6)alkyl]-N-[(Ci-6)alkylpyridinyl]amino, bis[(Ci-6)alkylpyridinyl]amino, bis(trifluoro- methylpyridinyl)amino, isoquinolinylamino, (C1-6)alkylpyridazinylamino, N-[(C1-6)alkyl]- N- [(C j -^alkylpyridazinyl] amino, N- [aryl(C i -6)alkyl] -N-[CC1 -6)alkylpyridazinyl] amino, di(C1-6)alkylpyridazinylamino, arylpyridazinylamino, piperidinylpyridazinylamino, (C1-6)- alkoxypyridazinylamino, di^i^alkylaminopyridazinylamino, bis[(C1-6)alkylpyridazinyl]- amino, benzofuryl(Ci-6)alkylamino, thienyl(Ci-6)alkylamino, indolyl(Ci.6)alkylamino, (C i -6)alkylpyrazolyl(C i ^alkylamino, [di(C i -6)alkyl](halo)pyrazolyl(C i ^alkylamino, di(C1-6)alkylisoxazolyl(C1-6)alkylamino, thiazolyl(C1-6)alkylamino, imidazolyl(Ci-6)alkyl- amino, (Ci-6)alkylimidazolyl(C1-6)alkylamino, pyridinyl(C1-6)alkylamino, (C1-6)alkyl- pyridinyl(C i -6)alkylamino, N- [(C i -6)alkyl] -N- [pyridinyl(C i -6)alkyl] amino, N-[dihydroxy- (C1-6)alkyl]-N-[pyridinyl(Ci-6)alkyl]amino, N-[(Ci-6)alkylpyridinyl(Ci-6)alkyl]-N- [dihydroxy(C1-6)alkyl]amino, amino(C1-6)alkyl, (C1-6)alkylamino(C1-6)alkyI, di(C1-6)alkyl- amino(Ci-6)alkyl, pyridinylamino(C1-6)alkyl, N-[(C2-6)alkylcarbonyl]-N-[(C1-6)alkyl- pyridinyl(Ci-6)alkyl] amino, di(Ci-6)alkylamino(Ci-6)alkylcarbonylamino, (C3-7)cycloalkyl- carbonylamino, (Ci-^alkylpiperidinylcarbonylamino, (C1-6)alkylimidazolylcarbonylamino, formyl, C2-6 alkylcarbonyl, (Ci.6)alkylpiperidinylaminocarbonyl, N-[(Ci-6)alkyl]-N-[(C1-6)- alkylpiperidinyl] aminocarbonyl, piperidinyl(C i ^alkylaminocarbonyl, (C t -6)alkyl- piperazinylcarbonyl, C1-6 alkylthio, Ci-6 alkylsulphinyl, C1-6 alkylsulphonyl, C2-6 alkoxycarbonyloxy or tetra(Ci-6)alkyldioxaborolanyl; and
R44 represents hydrogen, halogen, C1-6 alkyl or Ci-6 alkoxy.
6. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.
7. 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.
8. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
9. 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 PI3K inhibitor is indicated.
10. 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.
11. A method for the treatment and/or prevention of a disorder for which the administration of a selective PI3K inhibitor is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof.
PCT/GB2008/004000 2007-12-04 2008-12-03 Pyrrolothiazoles as pi3-kinase inhibitors WO2009071888A1 (en)

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WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
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