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WO2002016348A1 - Antiangiogenic bicyclic derivatives - Google Patents

Antiangiogenic bicyclic derivatives Download PDF

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Publication number
WO2002016348A1
WO2002016348A1 PCT/GB2001/003585 GB0103585W WO0216348A1 WO 2002016348 A1 WO2002016348 A1 WO 2002016348A1 GB 0103585 W GB0103585 W GB 0103585W WO 0216348 A1 WO0216348 A1 WO 0216348A1
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Prior art keywords
alkyl
ethyl
group
propyl
piperidin
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PCT/GB2001/003585
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French (fr)
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Laurent François André HENNEQUIN
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU2001277621A priority Critical patent/AU2001277621A1/en
Publication of WO2002016348A1 publication Critical patent/WO2002016348A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to indole, azaindole and indazole derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans.
  • Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function.
  • Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31).
  • Alteration ofvascular permeability is thought to play a role in both normal and pathological physiological processes (Cullinan-Bove et al, 1993,
  • aFGF & bFGF acidic and basic fibroblast growth factors
  • NEGF vascular endothelial growth factor
  • VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36:139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024).
  • Antagonism of NEGF action by sequestration of NEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844).
  • Basic FGF (bFGF) is a potent stimulator of angiogenesis (e.g. Hayek et al, 1987, Biochem. Biophys. Res.
  • Receptor tyrosine kinases are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified.
  • fms-like tyrosine kinase receptor Fit or Fltl
  • the kinase insert domain-containing receptor KDR (also referred to as Flk-1)
  • Flt4 kinase insert domain-containing receptor
  • Flt4 Flt4
  • Two of these related RTKs, Fit and KDR have been shown to bind NEGF with high affinity (De Nries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586).
  • the present invention is based on the discovery of compounds that surprisingly inhibit the effects of NEGF, a property of value in the treatment of disease states associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, lymphoedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • disease states associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, lymphoedema
  • Compounds of the present invention generally possess higher potency against NEGF receptor tyrosine kinase than against epidermal growth factor (EGF) receptor tyrosine kinase.
  • Compounds of the invention which have been tested possess activity against NEGF receptor tyrosine kinase such that they may be used in an amount sufficient to inhibit NEGF receptor tyrosine kinase whilst demonstrating no significant activity against EGF receptor tyrosine kinase.
  • Compounds of the present invention generally possess higher potency against NEGF receptor tyrosine kinase than against FGF Rl receptor tyrosine kinase.
  • Compounds of the invention which have been tested possess activity against NEGF receptor tyrosine kinase such that they maybe used in an amount sufficient to inhibit NEGF receptor tyrosine kinase whilst demonstrating no significant activity against FGF Rl receptor tyrosine kinase.
  • ring C is a 5 or 6-membered heteroaromatic ring containing at least one nitrogen atom and optionally containing a further 1-2 heteroatoms, selected independently from O, S and N; either any one of Gi, G 2 , G 3 , G and G 5 is nitrogen and the other four are -CH-, or Gi, G 2 , G 3 , G 4 and G 5 are all -CH-;
  • Z is -O-, -NH-, -S-, -CH ⁇ or a direct bond; Z is linked to any one of Gi, G 2 , G 3 and G 4 which is a free carbon atom; n is an integer from 0 to 5; any of the substituents R maybe attached at any free carbon atom of the indole, azaindole or indazole group, such free carbon atoms maybe Gi, G 2 , G 3 , G or G 5 or may be at the 3-position of the indole, azaindole or indazole group; m is an integer from 0 to 4;
  • R represents hydrogen, C ⁇ - 4 alkyl, C ⁇ . 4 alkoxyC ⁇ . 4 alkyl, aminoC ⁇ - 4 alkyl, C ⁇ _ alkylaminoC ⁇ - alkyl, di(C ⁇ - 3 alkyl)aminoC ⁇ - 4 alkyl, C 2 . 5 alkenylaminoC ⁇ . alkyl, C 2 - 5 alkynylaminoC ⁇ - 4 alkyl, -
  • ring A is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, mo holino and thiomorpholino and wherein ring A may bear one or more substituents selected from C ⁇ - 4 alkyl, C 2 - 5 alkenyl, C 2 - 5 alkynyl, hydroxy, oxo, halogeno, cyano, cyanoC ⁇ _ 4 alkyl, C ⁇ _ 4 alkylsulphonyl and C ⁇ . alkanoyl;
  • R 1 represents hydrogen, oxo, hydroxy, halogeno, C ⁇ . 4 alkyl, C ⁇ . 4 alkoxy, C ⁇ _ 4 alkoxyC ⁇ _ alkyl, aminoC ⁇ - alkyl, C ⁇ _ 3 alkylaminoC ⁇ . alkyl, di(C ⁇ . 3 alkyl)aminoC ⁇ . alkyl, -C ⁇ .
  • R represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C _ 3 alkyl, C ⁇ . 3 alkoxy, C ⁇ _ alkylsulphanyl, -NR 3 R 4 (wherein R 3 and R 4 , which may be the same or different, each represents hydrogen or or R 5 X 1 - (wherein X 1 represents a direct bond, -O-, -
  • R 6 , R 7 , R 8 , R 9 and R 10 each independently represents hydrogen, C ⁇ . alkyl or C ⁇ _ 3 alkoxyC 2 - 3 alkyl), and R 5 is selected from one of the following twenty-two groups:
  • R 16 represents hydrogen, C ⁇ - 3 alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which Cj. 3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C ⁇ profession 4 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Ci- 4 cyanoalkyl, C ⁇ - alkyl, C ⁇ .
  • R represents hydrogen, C ⁇ _ 3 alkyl or C ⁇ _ 3 alkoxyC 2 . 3 alkyl
  • R 22 represents hydrogen, C ⁇ _ 3 alkyl or C ⁇ - 3 alkoxyC 2 . 3 alkyl);
  • R 28 wherein R is a 4-, 5- or 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ . cyanoalkyl, C ⁇ _ 4 alkyl, C ⁇ _ hydroxyalkyl, C ⁇ _ alkoxy, C ⁇ - alkanoyl, C ⁇ _ 4 alkoxyC ⁇ _ alkyl, Ci.
  • R 29 represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, C ⁇ thread alkyl, C ⁇ . 4 alkoxy, C ⁇ .
  • C 2 - 5 alkenyl which may be unsubstituted or which may be substituted with one or more 15 groups selected from hydroxy, fluoro, amino, C ⁇ . 4 alkylamino, N,N-di(C ⁇ . 4 alkyl)amino, aminosulphonyl, N-C ⁇ . 4 alkylaminosulphonyl and N,N-di(C ⁇ . 4 alkyl)aminosulphonyl;
  • C 2 . 5 alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C ⁇ _ alkylamino, N,N-di(C ⁇ . 4 alkyl)amino, aminosulphonyl, N-C ⁇ . 4 alkylaminosulphonyl and N,N-di(C ⁇ . 4 alkyl)aminosulphonyl;
  • C ⁇ - 3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C ⁇ . 4 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ _ 4 cyanoalkyl, C ⁇ _ 4 alkyl, Ci- 4 hydroxyalkyl, C ⁇ . alkoxy, C ⁇ - 4 alkoxyC ⁇ . 4 alkyl, C ⁇ - 4 alkylsulphonylC ⁇ . alkyl, C ⁇ _ 4 alkoxycarbonyl, C ⁇ _ 4 aminoalkyl, C ⁇ . alkylamino, di(C ⁇ - alkyl)amino, C ⁇ _ 4 alkylaminoC ⁇ -
  • 5 alkynyl group in R 5 X ! - may bear one or more substituents selected from hydroxy, halogeno and amino); or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
  • ring C is a 5 or 6-membered heteroaromatic ring containing at least one nitrogen atom and optionally containing a further 1-2 heteroatoms, selected independently from O, S and N;
  • Z is -O-, -NH-, -S-, -CH 2 - or a direct bond; Z is linked to the benz ring of the indole group at any of the positions 4-, 5-, 6- or 7- of the indole group; n is an integer from 0 to 5; any of the substitutents R 1 maybe attached at any free carbon atom of the indole group, such free carbon atoms may be at positions 2-, 3-, 4-, 5-, 6-, or 7- of the indole group; m is an integer from 0 to 4; R represents hydrogen, C ⁇ _ 4 alkyl, C ⁇ - 3 alkoxyC ⁇ . 4 alkyl, aminoC ⁇ .
  • alkyl C ⁇ - alkylaminoC ⁇ _ 4 alkyl, di(C ⁇ - 3 alkyl)aminoC ⁇ - 4 alkyl, -C ⁇ - 5 alkyl(ring A) wherein ring A is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, morpholino and thiomorpholino;
  • R 1 represents hydrogen, oxo, hydroxy, halogeno, C ⁇ . alkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, aminoC ⁇ - 4 alkyl, C ⁇ - 3 alkylaminoC ⁇ . 4 alkyl, di(C ⁇ .
  • ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N- methylpiperazinyl, N-ethylpiperazinyl, morpholino and thiomorpholino;
  • R represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C ⁇ - 3 alkyl, Ci-
  • R 3 and R 4 which may be the same or different, each represents hydrogen or C ⁇ - 3 alkyl
  • R 5 X l - (wherein X 1 represents a direct bond, -O-, - CH 2 -, -OC(O)-, -C(O)-, -S-, -SO-, -SO 2 -, -NR 6 C(O)-, -C(O)NR 7 -, -SO 2 NR 8 -, -NR 9 SO 2 - or - NR 10 - (wherein R 6 , R 7 , R 8 , R 9 and R 10 each independently represents hydrogen, C ⁇ _ 3 alkyl or C ⁇ - 3 alkoxyC 2 - 3 alkyl), and R 5 is selected from one of the following twenty-two groups:
  • R 23 , R 24 , R 25 , R 26 and R 27 each independently represents hydrogen, C ⁇ _ 3 alkyl or C ⁇ - alkoxyC 2 . 3 alkyl) and R 22 represents hydrogen, C ⁇ . 3 alkyl or C . 3 alkoxyC 2 - 3 alkyl);
  • R 28 (wherein R 28 is a 4-, 5- or 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ _ cyanoalkyl, C ⁇ - 4 alkyl, C ⁇ _ 4 hydroxyalkyl, C ⁇ - 4 alkoxy, C ⁇ _ 4 alkoxyC ⁇ _ 4 alkyl, C ⁇ _ 4 alkylsulphonylC ⁇ _ 4 alkyl, C ⁇ .
  • alkoxycarbonyl C ⁇ _ 4 aminoalkyl, C ⁇ _ 4 alkylamino, di(C ⁇ _ 4 alkyl)amino, C ⁇ _ 4 alkylaminoC ⁇ . alkyl, di(C ⁇ - 4 alkyl)aminoC ⁇ - 4 alkyl, C ⁇ . 4 alkylaminoC ⁇ .
  • R 29 represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, C ⁇ _ alkyl, C ⁇ _ 4 alkoxy, C ⁇ .
  • C 2 - 5 alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C ⁇ - alkylamino, N,N-di(C ⁇ - 4 alkyl)amino, aminosulphonyl, N-C ⁇ _ 4 alkylaminosulphonyl and N,N-di(C ⁇ - 4 alkyl)aminosulphonyl;
  • C 2 - 5 alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C ⁇ . 4 alkylamino, N,N-di(C ⁇ - alkyl)amino, aminosulphonyl, N-C ⁇ . 4 alkylaminosulphonyl and N,N-di(C ⁇ - alkyl)aminosulphonyl; 98 Q 8
  • Ci. 4 alkylR 54 (Ci. 4 alkyl) q (X 9 ) r R 55 (wherein X 9 is as defined hereinbefore, q is 0 or 1, r is 0 or 1, and R 54 and R 55 are each independently selected from hydrogen, C ⁇ - 3 alkyl, cyclopentyl, cyclohexyl and a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which C ⁇ . 3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C ⁇ .
  • R 5 alkynyl group in R 5 X l - may bear one or more substituents selected from hydroxy, halogeno and amino); or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
  • ring C is selected from one of the following seven moieties:
  • ring C is a pyrimidine ring or a pyridyl ring.
  • Z is -O-, -NH-, -S- or a direct bond. More preferably Z is -O-, -NH- or -S-. Particularly Z is -O- or -NH-, especially -O-.
  • Z is linked to the indole, azaindole or indazole group at the 5- or 6-positions of the indole, azaindole or indazole group.
  • Z is linked to the indole, azaindole or indazole group at the 5-position of the indole, azaindole or indazole group.
  • Z is linked to an indole group at the 5- or 6-positions of the indole group. More preferably Z is linked to an indole group at the 5-position of the indole group.
  • R b represents hydrogen, C ⁇ .2alkyl, C2-3alkenylaminoC 2 - 3 alkyl, C 2 . 3alkynylaminoC 2 - 3 alkyl or -C 2 - 4 alkyl(ring A) wherein ring A is selected from piperidinyl and piperazinyl and wherein ring A may bear one or more substituents selected from ⁇ alkyl, C 2 .
  • R b represents hydrogen, methyl, C 2 - 3 alkenylaminoC 2 - 3 alkyl, C 2 - 3 alkynylaminoC 2 - 3 alkyl or -C 2 - 3 alkyl(ring A) wherein ring A is selected from 4- acetylpiperazin-1-yl, 4-methylsulphonylpiperazin-l-yl, 4-cyanopiperazin-l-yl, 4- cyanomethylpiperazin- 1 -yl, 4-(prop-2-en- 1 -yl)piperazin- 1 -yl, 4-(prop-2-yn- 1 -yl)piperazin- 1 -yl and 4-hydroxypiperidino.
  • R b is hydrogen or methyl, especially hydrogen.
  • R 1 represents hydrogen, oxo, hydroxy, halogeno, C ⁇ _ alkyl, C ⁇ _ 4 alkoxy, C ⁇ . 4 alkoxyC ⁇ . 4 alkyl, aminoC ⁇ . 4 alkyl, C ⁇ . 3 alkylaminoC ⁇ - 4 alkyl, di(C ⁇ .
  • ring B is selected from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, N-methylpiperazin-1-yl, N-ethylpiperazin-1-yl, morpholino and thiomorpholino.
  • R 1 represents methyl, ethyl, trifluoromethyl or halogeno.
  • R 1 represents methyl, fluoro, chloro or bromo, more especially methyl or fluoro.
  • n is an integer from 0 to 3.
  • n 0, 1 or 2.
  • Gi is nitrogen and G 2 , G 3 , G 4 and G 5 are -CH- forming an azaindole moiety which may bear one or more substituents R 1 as defined hereinbefore.
  • G 5 is nitrogen and G 1 ⁇ G 2 , G 3 and G 4 are -CH- forming an indazole moiety which may bear one or more substituents R 1 as defined hereinbefore.
  • Gi, G 2 , G 3 , G 4 and G 5 are all -CH- forming an indole moiety which may bear one or more substituents R 1 as defined hereinbefore.
  • indole moieties are preferred over the azaindole and indazole moieties. fn one embodiment of the invention the optionally substituted indole moiety of formula ⁇ 1 :
  • R 1 , R b and n are as defined hereinbefore; is selected from 4-fluoro-2-methylindol-5-yl, 2-methylindol-5-yl, 2-methylindol-6-yl, 2,3- dimethylindol-5-yl, l-methylindol-5-yl, l,2-dimethylindol-5-yl, 4-fluoroindol-5-yl, 6- fluoroindol-5-yl and indol-5-yl.
  • the optionally substituted indole moiety of formula II is selected from 4-fluoro-2- methylindol-5-yl, 4-fluoroindol-5-yl and 6-fluoroindol-5-yl, more especially from 4-fluoro-2- methylindol-5-yl.
  • m is 1 or 2.
  • X 1 represents a direct bond, -O-, -S-, -NR 6 C(O)-, -NR 9 SO 2 - or -
  • NR 10 - (wherein R 6 , R 9 and R 10 each independently represents hydrogen, C ⁇ - 2 alkyl or . 2 alkoxyethyl).
  • X 1 represents a direct bond, -O-, -S-, -NR 6 C(O)-, -NR 9 SO 2 - (wherein R 6 and R 9 each independently represents hydrogen or Ci ⁇ alkyl) or NH. More preferably X 1 represents -O-, -S-, -NR°C(O)- (wherein R 6 represents hydrogen or C ⁇ . 2 alkyl) orNH.
  • X 1 represents -O- or -NR 6 C(O)- (wherein R 6 represents hydrogen or C ⁇ _ 2 alkyl), more particularly -O- or -NHC(O)-, especially -O-.
  • X 1 represents -O- or a direct bond.
  • X 2 represents -O- or NR 12 (wherein R 12 represents hydrogen, C ⁇ _ 3 alkyl or C ⁇ alkoxyethyl).
  • X 3 represents -O-, -S-, -SO-, -SO 2 -, -NR 17 C(O)-, -NR 20 SO 2 - or -NR 21 - (wherein R 17 , R 20 and R 21 each independently represents hydrogen, C ⁇ . 2 alkyl or C ⁇ _ 2 alkoxyethyl).
  • X 3 represents -O-, -S-, -SO-, -SO 2 - or -NR 21 - (wherein R 21 represents hydrogen, C ⁇ - 2 alkyl or C ⁇ _ 2 alkoxyethyl). More preferably X 3 represents -O- or -NR 21 - (wherein R 21 represents hydrogen or C ⁇ . 2 alkyl).
  • X 3 represents -O-, -SO 2 -, - NR 20 SO 2 - or -NR 21 - (wherein R 20 and R 21 each independently represents hydrogen, or C ⁇ _2alkoxyethyl).
  • X 4 and X 5 which may be the same or different each represents -O-, - S-, -SO-, -SO 2 - or -NR 27 - (wherein R 27 represents hydrogen, C ⁇ - 3 alkyl or C ⁇ . 2 alkoxyethyl).
  • X 4 and X 5 which may be the same or different each represents -O-, -S- or -NR 27 - (wherein R 27 represents hydrogen, C ⁇ - 2 alkyl or C ⁇ -2alkoxyethyl).
  • X 4 and X 5 which may be the same or different each represents -O- or -NH-.
  • Especially X 4 and X 5 each represents -O-.
  • X 6 represents -O-, -S- or -NR 38 - (wherein R 38 represents hydrogen, C ⁇ - 2 alkyl or C ⁇ . 2 alkoxyethyl).
  • X represents -O- or -NR - (wherein R represents hydrogen or C ⁇ _ alkyl).
  • Especially X represents -O-.
  • X 7 represents -O-, -S- or -NR 3 - (wherein R 43 represents hydrogen, C ⁇ . 2 alkyl or C ⁇ alkoxyethyl).
  • X 7 represents -O- or -NR 43 - (wherein R 43 represents hydrogen or C ⁇ _ 2 alkyl).
  • X represents -O-, -S- or -NR - (wherein R represents hydrogen, C ⁇ -2alkyl or C ⁇ . 2 alkoxyethyl).
  • X 8 represents -O- or -NR 48 - (wherein R 48 represents hydrogen or d ⁇ alkyl).
  • X 9 represents -O-, -S- or -NR 53 - (wherein R 53 represents hydrogen, C ⁇ -2alkyl or C ⁇ _ 2 alkoxyethy ⁇ ).
  • X 9 represents -O- or -NR 53 - (wherein R 53 represents hydrogen or C ⁇ _ 2 alkyl).
  • X 9 represents -O-, -CONR 50 - or - NR - (wherein R 50 and R 53 each independently represents hydrogen or C ⁇ -2alkyl).
  • R 28 is pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ . 3 cyanoalkyl, C ⁇ _ 3 alkyl, C ⁇ - 3 hydroxyalkyl, C ⁇ - 3 alkoxy, Q. 2alkoxyC ⁇ - 3 alkyl, C ⁇ - 2 alkylsulphonylC ⁇ -3alkyl, C ⁇ - 3 alkoxycarbonyl, C ⁇ - 3 alkylamino, di(C 1 .
  • R 28 is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ - 3 cyanoalkyl, C ⁇ _ 3 alkyl, C ⁇ _ 3 alkoxy, C ⁇ _ 2 alkoxyC ⁇ - 3 alkyl, C ⁇ . 2 alkylsulphonylC ⁇ - 3 alkyl, C ⁇ - 3 alkoxycarbonyl, di(C ⁇ - 3 alkyl)amino, C ⁇ _ 3alkylaminoC ⁇ . 3 alkyl, di(C ⁇ .
  • R is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomo ⁇ holino which group may bear 1 or 2 substituents selected from a group ⁇ (-O-) (C ⁇ - 3 alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino and thiomo ⁇ holino).
  • R is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, mo ⁇ holino or thiomo ⁇ holino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ _3cyanoalkyl, C ⁇ _ 3 alkyl, C ⁇ . 3 hydroxyalkyl, C ⁇ .2alkoxyC ⁇ - 3 alkyl and C ⁇ .2alkylsulphonylC ⁇ - 3 alkyl.
  • R 28 is pyrrolidinyl, piperazinyl, piperidinyl, mo ⁇ holino or thiomo ⁇ holino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ - 3 cyanoalkyl, C ⁇ _ 3 alkyl, C ⁇ _ 3 hydroxyalkyl, C ⁇ _ 3 alkoxy, C ⁇ -2alkoxyC ⁇ - 3 alkyl and Ci- 2 alkylsulphonylCi- 3 alkyl.
  • R 29 is a 5 -6-membered aromatic heterocyclic g oup s it preferably has 1 or 2 heteroatoms, selected from O, N and S, of which more preferably one is N, and may be substituted as hereinbefore defined.
  • R 29 is particularly a pyridone, phenyl, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl or pyridazinyl group which group may be substituted as hereinbefore defined, more particularly a pyridone, pyridyl, imidazolyl, thiazolyl or triazolyl group, especially a pyridone, pyridyl, imidazolyl or triazolyl group which group may be substituted as hereinbefore defined.
  • R represents a pyridone, phenyl or 5- 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which group may preferably carry up to 2 substituents, more preferably up to one substituent, selected from the group of substituents as hereinbefore defined.
  • substituents are selected from halogeno, Ci. 4 alkyl, C ⁇ _ alkoxy, cyano and a group -(-O-) f (C ⁇ - 3 alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino, which cyclic group may bear one or more substituents selected from C ⁇ _ 3 alkyl).
  • substituents are selected from chloro, fluoro, methyl, ethyl and a group -(-O-) f (C ⁇ - 3 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino).
  • R 54 and R 55 are each independently a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S andN, which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, d- 3 cyanoalkyl, C ⁇ . 3 alkyl, C ⁇ - 3 alkoxy, Ci. 2 alkoxyCi.
  • R 54 and R 55 are each selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ - 3 cyanoalkyl, C ⁇ .
  • Ci- 3 alkyl Ci- 3 hydroxyalkyl, C ⁇ - 3 alkoxy, d- ⁇ alkoxyd ⁇ alkyl, d- 2 alkylsulphonylC ⁇ -3alkyl, Ci- 3 alkoxycarbonyl and a group -(-O-)f(d-3alky ⁇ ) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino, which cyclic group may bear one or more substituents selected from C ⁇ - 3 alkyl).
  • R 54 and R 55 are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ - 3 cyanoalkyl, Ci- 3hydroxyalkyl, C ⁇ -2alkoxyC ⁇ - 3 alkyl, C ⁇ -2alkylsulphonylC ⁇ -3alkyl, Ci- 3 alkoxycarbonyl and a group -( ⁇ O-) f (C ⁇ _ 3 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino).
  • R 54 and R 55 are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino which group may bear 1 or 2 substituents selected from a group -(-O-) f (C ⁇ . 3 alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino) .
  • R 54 and R 55 are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, mo ⁇ holino and thiomo ⁇ holino which group is unsubstituted.
  • R 2 represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, Ci ⁇ alkyl, amino or R X - [wherein X is as hereinbefore defined and R is selected from one of the following twenty-two groups:
  • Ci-salkylR 56 (wherein R 56 is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to
  • R 57 is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, of which one is N and the other may be selected independently from O, S and N, which heterocyclic group is linked to d-salkyl through a nitrogen atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ - cyanoalkyl, C ⁇ _ 4 alkyl, C ⁇ . 4 hydroxyalkyl, d. 4 alkoxy, C ⁇ - 4 alkanoyl, C ⁇ . 4 alkoxyC ⁇ .
  • alkyl gringD
  • f is 0 or 1
  • g is 0 or 1
  • ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C ⁇ _ 4 alkyl
  • C 3 . 4 alkenylR 58 (wherein R 58 represents R 56 or R 57 as defined hereinbefore);
  • C 2 - 5 alkenyl which may be unsubstituted or which may be substituted with one or more 10 groups selected from hydroxy, fluoro, amino, C ⁇ - 4 alkylamino, N,N-di(C ⁇ _ 4 alkyl)amino, aminosulphonyl, N-C ⁇ . 4 alkylaminosulphonyl and N,N-di(C ⁇ . 4 alkyl)aminosulphonyl;
  • C 2 - 5 alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C ⁇ - 4 alkylamino, N,N-di(C ⁇ . alkyl)amino, aminosulphonyl, N-C ⁇ _ alkylaminosulphonyl and N,N-di(C ⁇ - alkyl)aminosulphonyl;
  • Ci-salkyl, d-salkenyl or d-salkynyl group in R 5 X ! - may bear 20 one or more substituents selected from hydroxy, halogeno and amino].
  • R 2 represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, Ci- 3 alkyl, amino or R 5 X ] - [wherein X 1 is as hereinbefore defined and R 5 is selected from one of the following twenty-two groups:
  • C ⁇ _ 4 alkyl which may be unsubstituted or which may be substituted with one or more groups 25 selected from fluoro, chloro and bromo, or d-salkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
  • alkylX 3 R 16 (wherein X 3 is as hereinbefore defined and R 16 is a group selected from C ⁇ _ 3 alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl and tetrahydropyranyl, which C ⁇ - 3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C ⁇ .
  • alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl or tetrahydropyranyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ - 3 cyanoalkyl, Ci. 3hydroxyalkyl, C ⁇ . 2 alkoxyC ⁇ . 3 alkyl, Ci- 3 alkoxycarbonyl,'C ⁇ - 3 alkylamino, ⁇ (d- 3 alkyl)amino, C ⁇ . 3 alkylaminoC ⁇ - 3 alkyl, di(C ⁇ _
  • R 59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to C ⁇ - 4 alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ - 3 cyanoalkyl, Ci- 3 alkyl, C ⁇ - 3 hydroxyalkyl, C ⁇ - 3 alkoxy, C ⁇ - 2 alkylsulphonylC ⁇ - 3 alkyl, C ⁇ - 3 alkoxycarbonyl, C ⁇ -3alkylamino, di(C ⁇ - 3 alkyl)a group selected from pyrrolidinyl, piperazin
  • C - 5 alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- 4 alkylamino, N,N-di(C ⁇ . alkyl)amino, aminosulphonyl, N-C ⁇ _ 4 alkylaminosulphonyl and N,N- di(C ⁇ _ alkyl)aminosulphonyl;
  • Ci- 3 alkylR 54 (Ci. 3 alkyl) q (X 9 ) r R 55 (wherein X 9 , q, r, R 54 and R 55 are as defined hereinbefore); and additionally wherein any Ci-salkyl, d- 5 alkenyl or C 2 - 5 alkynyl group in R 5 X 1 - may bear 30 one or more substituents selected from hydroxy, halogeno and amino].
  • R 2 represents hydroxy, halogeno, nitro, trifluoromethyl, C ⁇ -3alkyl, cyano, amino or R 5 X ! -
  • X 1 is as hereinbefore defined and R 5 is selected from one of the following twenty groups: 1) C ⁇ - 3 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C 2 - 3 alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino; 2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3- methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3- (N,N,N-
  • alkylsul ⁇ honylC ⁇ . alkyl C ⁇ - 3 alkylamino, di(C ⁇ - 3 alkyl)amino, C ⁇ . 3 alkylaminoC ⁇ - 3 alkyl, di(C ⁇ - 3 alkyl)aminoC ⁇ - 3 alkyl, C ⁇ . 3 alkylaminoC ⁇ . 3 alkoxy, di(C ⁇ . 3 alkyl)aminoC ⁇ .
  • R 28 (wherein R 28 is as defined hereinbefore); 6) C ⁇ _3alkylR 59 (wherein R 59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, imidazolidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to C ⁇ - 3 alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ .
  • alkoxyC ⁇ - 3 alkyl Ci- 2 alkylsulphonyl, C ⁇ - 2 alkylsulphonylC ⁇ - 3 alkyl, C ⁇ .2alkoxycarbonyl, C ⁇ - 3 alkylamino, di(C ⁇ - 3alkyl)amino, C ⁇ . 3 alkylaminoC ⁇ - 3 alkyl, di(C ⁇ - 3 alkyl)aminoC ⁇ - 3 alkyl, C ⁇ - 3 alkylaminoC ⁇ . 3 alkoxy, di(C ⁇ - 3 alkyl)aminoC ⁇ - 3 alkoxy and a group -(-O-) f (C ⁇ .
  • C 2 - 5 alkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- 4 alkylamino, N,N-di(C ⁇ . 4 alkyl)amino, aminosulphonyl, N-C ⁇ - 4 alkylaminosulphonyl and N,N- di(C ⁇ - alkyl)aminosulphonyl;
  • R 2 represents hydroxy, trifluoromethyl, amino or R 5 X 1 - [wherein X 1 is as hereinbefore defined and R 5 represents methyl, ethyl, benzyl, trifluoromethyl, 2,2,2- trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-
  • R 2 represents trifluoromethyl, amino or R 5 X 1 - [wherein X 1 is as hereinbefore defined and R 5 represents ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2- (ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2- sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)ethyl, 3- (ethylamino)
  • R 2 represents trifluoromethyl, Ci ⁇ alkyl, amino or R 5 X 1 - [wherein X 1 is as hereinbefore defined and R 5 represents ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2- hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,N- dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)ethyl, 3-(ethylamino)
  • R 2 represents trifluoromethyl, ethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-(methylsulphinyl)ethoxy, 2-(methylsulphonyl)ethoxy, 2-(ethylsulphinyl)ethoxy, 2- (ethylsulphonyl)ethoxy, 2-(N,N-dimethylsulphamoyl)ethoxy, 2-(N-methylsulphamoyl)ethoxy, 2-sulphamoylethoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, 2- (ethylamino)ethoxy, 3-(ethylamino)propoxy, 2-(N,N-dimethylamino)ethoxy, 3-(N,N- dimethylamino)propoxy, 2-(N,N-diethylamino
  • R 2 represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, Ci ⁇ alkyl, amino or R 5 X ! - [wherein X 1 is as hereinbefore defined and R 5 is selected from one of the following twenty-two groups: 1) oxiranylC ⁇ .
  • R 56 is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C ⁇ - 5 alkyl through a carbon atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ _ cyanoalkyl, C ⁇ . 4 alkyl, C ⁇ - 4 hydroxyalkyl, C ⁇ _ alkoxy, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, C ⁇ . alkylsulphonylC ⁇ .
  • C 2 - 5 alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C ⁇ - 4 all ylamino, N,N-di(C ⁇ _ 4 alkyl)amino, aminosulphonyl, N-C ⁇ _ alkylaminosulphonyl and N,N-di(C ⁇ . 4 alkyl)aminosulphonyl;
  • C2- 5 alkynyl which may be unsubstituted or which may be substituted with one or more 30 groups selected from hydroxy, fluoro, amino, C ⁇ - 4 alkylamino, N,N-di(C ⁇ _ 4 alkyl)amino, aminosulphonyl, N-C ⁇ _ alkylaminosulphonyl and N,N-di(C ⁇ _ 4 alkyl)aminosulphonyl;
  • R 2 represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, amino or R 5 X l - [wherein X 1 is as hereinbefore defined and R 5 is selected from one of the following twenty-two groups:
  • C ⁇ - 4 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or d-salkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
  • C ⁇ _ 4 alkylR 59 (wherein R 59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to C ⁇ - 4 alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C ⁇ _ 3 cyanoalkyl, Ci- 3alkyl, C ⁇ - 3 hydroxyalkyl, Cualkoxy, C ⁇ -2alkoxyC ⁇ .
  • C 2 - 5 alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, C ⁇ _ alkylamino, N,N-di(C ⁇ . 4 alkyl)amino, aminosulphonyl, N-C ⁇ . 4 alkylaminosulphonyl and N,N- di(C ⁇ - alkyl)aminosulphonyl;
  • R 2 represents hydroxy, halogeno, nitro, trifluoromethyl, C ⁇ alkyl, cyano, amino or R 5 X 1 - [wherein X 1 is as hereinbefore defined and R 5 is selected from one of the following twenty groups:
  • C h alky! which may be unsubstituted or which may be substituted with one or more groups 0 selected from fluoro, chloro and bromo, or d ⁇ alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
  • C ⁇ . 3 alkyl group may bear 1 or 2 substituents selected from hydroxy, halogeno and Ci- 2 alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl or tetrahydropyranyl group may bear one substituent selected from oxo, hydroxy, halogeno, cyano, C ⁇ _ 2 cyanoalkyl, C ⁇ - 2 alkyl, C ⁇ -2hydroxyalkyl, d.
  • R 28 (wherein R 28 is as defined hereinbefore); 6) C ⁇ _ 3 alkylR 59 (wherein R 59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, imidazolidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to C ⁇ .
  • C 2 - 5 al enyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- 4 alkylamino, N,N-di(C ⁇ . 4 alkyl)amino, aminosulphonyl, N-C ⁇ - 4 alkylaminosulphonyl and N,N- di(C i . 4 alkyl)aminosulphonyl;
  • C 2 - 5 alkynyl which may be unsubstituted or which may be substituted with one or more 10 fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- alkylamino, N,N-di(C ⁇ . 4 alkyl)amino, aminosulphonyl, N-C ⁇ - 4 alkylaminosulphonyl and N,N- di(C ⁇ . 4 alkyl)aminosulphonyl;
  • R 2 represents
  • R 5 represents methyl, ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2- (methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,N- dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-
  • R 2 represents trifluoromethyl, C ⁇ - 3 alkyl, amino or R 5 X J - [wherein X 1 is as hereinbefore defined and R 5 represents ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3- hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2- (methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,N- dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)eth
  • R 2 represents trifluoromethyl, C ⁇ - 3 alkyl, amino or R 5 X l - [wherein X 1 is as hereinbefore defined and R 5 represents ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3 -hydroxypropyl, 2- methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2- (ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N- methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)eth
  • R 2 represents trifluoromethyl, ethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, 2-hydroxyethoxy, 3 -hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-(methylsulphinyl)ethoxy, 2-(methylsulphonyl)ethoxy, 2-(ethylsulphinyl)ethoxy, 2- (ethylsulphonyl)ethoxy, 2-(N,N-dimethylsulphamoyl)ethoxy, 2-(N-methylsulphamoyl)ethoxy, 2-sulphamoylethoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, 2-(methylsulphinyl)ethoxy, 2-(methylsulphonyl)ethoxy, 2-(ethylsulphinyl)ethoxy, 2-(ethylsulphonyl)ethoxy, 2-(N,N-dimethylsulph
  • ring C, R b , R 1 , R 2 , m and n are as defined hereinbefore and Zb represents -O-, -NH- or -S-; or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
  • Zb represents -O-, -NH- or -S-; or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
  • ring C, R , R 1 , R 2 , m and n are as defined hereinbefore and Zc represents -O-; or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
  • R is not selected from hydrogen, methyl, trifluoromethyl, nitro, amino, carbamoyl, methylsulphonyl, benzyl, phenylcarbonylamino, benzylcarbamoyl and benzylsulphanyl and if R 2 is a group R 5 -X ! then X 1 is not selected from -NR 10 - and a direct bond; and salts thereof, and prodrugs thereof for example esters and amides.
  • a compound of the formula Ic as defined hereinbefore with the proviso that at least one R 2 is not selected from hydrogen, methoxy, nitro, cyano, chloro and amino and if R 2 is a group R 5 -X* then X 1 is not selected from -NR 10 -, -C(O)NR 7 - and -C(O)-; and salts thereof, and prodrugs thereof for example esters and amides.
  • R 2 is not selected from hydrogen, methoxy, nitro, cyano, chloro and amino and if R 2 is a group R 5 -X* then X 1 is not selected from -NR 10 -, -C(O)NR 7 - and -C(O)-; and salts thereof, and prodrugs thereof for example esters and amides.
  • a preferred compound of the present invention is
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only. An analogous convention applies to other generic terms. Unless otherwise stated the term “alkyl” advantageously refers to chains with 1-6 carbon atoms, preferably 1-4 carbon atoms.
  • alkoxy as used herein, unless stated otherwise includes “alkyl”-O- groups in which "alkyl” is as hereinbefore defined.
  • aryl as used herein unless stated otherwise includes reference to a C 6 - ⁇ o aryl group which may, if desired, carry one or more substituents selected from halogeno, alkyl, alkoxy, nitro, trifluoromethyl and cyano, (wherein alkyl and alkoxy are as hereinbefore defined).
  • aryloxy as used herein unless otherwise stated includes “aryl”-O-groups in which "aryl” is as hereinbefore defined.
  • sulphonyloxy as used herein refers to alkylsulphonyloxy and arylsulphonyloxy groups in which "alkyl" and "aryl” are as hereinbefore defined.
  • alkenyl includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl are specific for the straight chain version only. Unless otherwise stated the term “alkenyl” advantageously refers to chains with 2-5 carbon atoms, preferably 3-4 carbon atoms.
  • alkynyl includes both straight and branched chain alkynyl groups but references to individual alkynyl groups such as 2-butynyl are specific for the straight chain version only. Unless otherwise stated the term “alkynyl” advantageously refers to chains with 2-5 carbon atoms, preferably 3-4 carbon atoms. Unless stated otherwise the term “haloalkyl” refers to an alkyl group as defined hereinbefore which bears one or more halogeno groups, such as for example trifluoromethyl.
  • R 2 has a value of substituted or unsubstituted C ⁇ - 5 alkyl
  • R 2 has been selected from C ⁇ _ alkyl or from a group R 5 X ! wherein X 1 is a direct bond or -CH 2 - and R 5 is C ⁇ _ 5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino.
  • a compound of the formula I or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric fo ⁇ n which inhibits NEGF receptor tyrosine kinase activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
  • the formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein.
  • compounds of the formula I or a salt thereof may possess an asymmetric carbon atom.
  • Such an asymmetric carbon atom is also involved in the tautomerism described above, and it is to be understood that the present invention encompasses any chiral form (including both pure enantiomers, scalemic and racemic mixtures) as well as any tautomeric form which inhibits NEGF receptor tyrosine kinase activity, and is not to be limited merely to any one tautomeric form or chiral form utilised within the formulae drawings. It is to be understood that the invention encompasses all optical and diastereomers which inhibit NEGF receptor tyrosine kinase activity.
  • NR 10 - and R 10 is C 1 . 3 alkoxyC 2 - 3 alkyl it is the d ⁇ alkyl moiety which is linked to the nitrogen atom of X 1 and an analogous convention applies to other groups.
  • R 5 is, for example, a group of formula C ⁇ - 3 alkyLX 9 C ⁇ - 3 alkylR 29 , it is the terminal moiety which is linked to X 1
  • R 5 is, for example, a group of formula d-salkenylR 28 it is the d-salkenyl moiety which is linked to X 1 and an analogous convention applies to other groups.
  • R 5 is a group l-R 29 prop-l-en-3-yl it is the first carbon to which the group R 29 is attached and it is the third carbon which is linked to X 1 and an analogous convention applies to other groups.
  • R 28 and R 28 is a pyrrolidinyl ring which bears a group -(-O)
  • R 28 carries a d. 4 alkoxyC ⁇ - alkyl substituent it is the C ⁇ _ 4 alkyl moiety which is attached to R 28 and an analogous convention applies to other groups.
  • the present invention relates to the compounds of formula I as hereinbefore defined as well as to the salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I and their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula I as hereinbefore defined which are sufficiently basic to form such salts.
  • Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid.
  • pharmaceutically acceptable salts maybe formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
  • Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, mo ⁇ holine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, mo ⁇ holine or tris-(2-hydroxyethyl)amine.
  • a compound of the formula I, or salt thereof, and other compounds of the invention may be prepared by any process known to be applicable to the preparation of chemically-related compounds.
  • Such processes include, for example, those illustrated in International Patent Application Publicaiton No. WO 00/47212 (Application No. PCT/GB00/00373).
  • Such processes also include, for example, solid phase synthesis.
  • Such processes are provided as a further feature of the invention and are as described hereinafter.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting
  • a convenient displaceable moiety L 1 is, for example, a halogeno, alkoxy (preferably d.
  • alkoxy aryloxy, alkylsulphanyl, arylsulphanyl, alkoxyalkylsulphanyl or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methylsulphanyl, 2-methoxyethylsulphanyl, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, ⁇ -methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or for example, an alkali metal or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • such a base is, for example, an alkali metal hydride, for example sodium hydride, or an alkali metal or alkaline earth metal amide, for example sodium amide, sodium bis(trimethylsilyl)amide, potassium amide or potassium bis(trimethylsilyl)amide.
  • the reaction is preferably effected in the presence of an inert solvent or diluent, for example an ether such as tetraliydrofuran or 1,4-dioxan, an aromatic hydrocarbon solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethyl sulphoxide.
  • the reaction is conveniently effected at a temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 110°C.
  • an acid is for example, an anhydrous inorganic acid such as hydrochloric acid, in the presence of a protic solvent or diluent, for example an alcohol or ester such as methanol, ethanol, 2-propanol, 2-pentanol.
  • a protic solvent or diluent for example an alcohol or ester such as methanol, ethanol, 2-propanol, 2-pentanol.
  • the free base may be treated with an acid such as a hydrogen halide, for example hydrogen chloride, sulphuric acid, a sulphonic acid, for example methane sulphonic acid, or a carboxylic acid, for example acetic or citric acid, using a conventional procedure.
  • an acid such as a hydrogen halide, for example hydrogen chloride, sulphuric acid, a sulphonic acid, for example methane sulphonic acid, or a carboxylic acid, for example acetic or citric acid, using a conventional procedure.
  • R 2 is R 5 X l wherein R 5 is as defined hereinbefore and X 1 is -O-, -S-, -OC(O)- or -NR 10 -
  • L 1 is a displaceable moiety for example a halogeno or sulphonyloxy group such as a bromo, methanesulphonyloxy or toluene-4- sulphonyloxy group, or L 1 may be generated in situ from an alcohol under standard Mitsunobu conditions ("Organic Reactions", John Wiley & Sons hie, 1992, vol 42, chapter 2, David L Hughes).
  • the reaction is preferably effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about 50°C.
  • reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about
  • R 63 and R 64 which may be the same or different are each hydrogen, C ⁇ _ 3 alkyl or
  • X 12 R 29 (wherein X 12 represents -O-, -S-, -SO 2 -, -NR 70 C(O)-, -NR 71 SO 2 -, or-NR 72 -
  • R , R , and R which may be the same or different are each hydrogen, Ci ⁇ alkyl or
  • T 1A 7 (wherein R , R and R each independently represents hydrogen, C h alky! or
  • R 54 (Ci. 4 alkyl) q (X 9 ) r R 55 (wherein q, r, X 9 , R 54 and R 55 are as defined hereinbefore); may be prepared by reacting a compound of the formula IX:
  • reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), and at a temperature in the range, for example 0 to 150°C, conveniently at about 50°C.
  • a base as defined hereinbefore in process (a)
  • an inert solvent or diluent as defined hereinbefore in process (a)
  • Processes (a) and (b) are preferred over processes (c) and (d).
  • Process (a) is preferred over processes (b), (c) and (d).
  • Process (e) The production of those compounds of the formula I and salts thereof wherein one or more of the substituents (R 2 ) m is represented by -NR 76 R 77 , where one (and the other is hydrogen) or both of R 76 and R 77 are C ⁇ - 3 alkyl, may be effected by the reaction of compounds of formula I wherein the substituent (R ) m is an amino group and an alkylating agent, preferably in the presence of a base as defined hereinbefore.
  • Such alkylating agents are C ⁇ _ 3 alkyl moieties bearing a displaceable moiety as defined hereinbefore such as C ⁇ - 3 alkyl halides for example C ⁇ _ 3 alkyl chloride, bromide or iodide.
  • the reaction is preferably effected hi the presence of an inert solvent or diluent (as defined hereinbefore in process (a)) and at a temperature in the range, for example, 10 to 100°C, conveniently at about ambient temperature.
  • the production of compounds of formula I and salts thereof wherein one or more of the substituents R 2 is an amino group may be effected by the reduction of a corresponding compound of formula I wherein the substituent(s) at the corresponding position(s) of ring C is/are a nitro group(s).
  • the reduction of the nitro group may conveniently be effected by any of the procedures known for such a transformation.
  • the reduction may be carried out, for example, by the hydrogenation of a solution of the nitro compound in the presence of an inert solvent or diluent as defined hereinbefore in the presence of a metal effective to catalyse hydrogenation reactions such as palladium or platinum.
  • a further reducing agent is, for example, an activated metal such as activated iron (produced for example by washing iron powder with a dilute solution of an acid such as hydrochloric acid).
  • an activated metal such as activated iron (produced for example by washing iron powder with a dilute solution of an acid such as hydrochloric acid).
  • the reduction may be effected by heating the nitro compound and the activated metal in the presence of a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature in the range, for example 50 to 150°C, conveniently at about 70°C.
  • Convenient halogenating agents include inorganic acid halides, for example thionyl chloride, phosphoras(IlT)chloride, phosphorus(N)oxychloride and phosphorus(V)chloride.
  • the halogenation reaction may be effected in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachlori.de, or an aromatic hydrocarbon solvent such as benzene or toluene, or the reaction may be effected without the presence of a solvent.
  • the reaction is conveniently effected at a temperature in the range, for example 10 to 150°C, preferably in the range 40 to 100°C.
  • the compounds of formula XI and salts thereof may, for example, be prepared by reacting a compound of the formula XH:
  • reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about 110°C.
  • the compounds of formula XI and XII and salts thereof may be prepared by any of the methods known in the art of heterocyclic organic chemistry.
  • R 10 each independently represents hydrogen, or C ⁇ _3alkoxyC 2 - 3 alkyl), may also be prepared for example by reacting a compound of the formula XITJ:
  • a compound of formula Xrfl is conveniently used in which L represents a chloro group or a phenoxy group which may if desired carry up to 5 substituents, preferably up to 2 substituents, selected from halogeno, nitro and cyano.
  • the reaction may be conveniently effected under conditions as described for process (b) hereinbefore.
  • the compounds of formula Xrfl and salts thereof may for example be prepared by deprotecting a compound of the formula X1N:
  • protecting group P 1 is within the standard knowledge of an organic chemist, for example those included in standard texts such as "Protective Groups in Organic Synthesis” T.W. Greene and RG.M.Wuts, 2nd Ed.
  • ⁇ -sulphonyl derivatives for example, p- toluenesulphonyl
  • carbamates for example, t-butyl carbonyl
  • ⁇ -alkyl derivatives for example, 2-chloroethyl, benzyl
  • amino acetal derivatives for example benzyloxymethyl.
  • the removal of such a protecting group may be effected by any of the procedures known for such a transformation, including those reaction conditions indicated in standard texts such as that indicated hereinbefore, or by a related procedure.
  • Deprotection may be effected by techniques well known in the literature, for example where P 1 represents a benzyl group deprotection may be effected by hydrogenolysis or by treatment with trifluoroacetic acid.
  • One compound of formula m may if desired be converted into another compound of formula m in which the moiety L 1 is different.
  • a compound of formula HI in which L 1 is other than halogeno for example optionally substituted phenoxy
  • a compound of formula HI in which L 1 is halogeno by hydrolysis of a compound of formula m (in which L 1 is other than halogeno) to yield a compound of formula XI as hereinbefore defined, followed by introduction of halide to the compound of formula XI, thus obtained as hereinbefore defined, to yield a compound of formula m in which L 1 represents halogen.
  • Compounds of formula TV may be prepared by any of the methods known in the art, such as for example those described in “Indoles Part I", “Indoles Part II”, 1972 John Wiley & Sons Ltd and “Indoles Part UI” 1979, John Wiley & Sons Ltd, edited by W. J. Houlihan.
  • Compounds of formula IN may be prepared by any of the methods described in the Examples hereinafter.
  • Compounds of formula IN may be prepared by any of the processes described in International Patent Application Publication No. WO 00/47212, the entire content of which is included herein by reference, with particular reference to the processes described in WO 00/47212 in Examples 48, 182 237, 242, 250 and 291 therein.
  • the azaindole 2-methyl-lH-pyrrolo[2,3-b]pyridin-5-ol may be prepared according to the method described in Reference Example 1 hereinafter.
  • a pharmaceutically acceptable salt of a compound of the formula I When a pharmaceutically acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with, for example, an acid using a conventional procedure, the acid having a pharmaceutically acceptable anion.
  • D ⁇ A encoding NEGF, FGF or EGF receptor cytoplasmic domains may be obtained by total gene synthesis (Edwards M, International Biotechnology Lab 5(3), 19-25, 1987) or by cloning. These may then be expressed in a suitable expression system to obtain polypeptide with tyrosine kinase activity.
  • NEGF, FGF and EGF receptor cytoplasmic domains which were obtained by expression of recombinant protein in insect cells, were found to display intrinsic tyrosine kinase activity.
  • NEGF receptor Fit (Genbank accession number X51602), a 1.7kb D ⁇ A fragment encoding most of the cytoplasmic domain, commencing with methionine 783 and including the termination codon, described by Shibuya et al (Oncogene, 1990, 5: 519-524), was isolated from cD ⁇ A and cloned into a baculovirus transplacement vector (for example pAcYMl (see The Baculovirus Expression System: A Laboratory Guide, L.A. King and R. D. Possee, Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available from frwitrogen Co ⁇ oration)).
  • pAcYMl see The Baculovirus Expression System: A Laboratory Guide, L.A. King and R. D. Possee, Chapman and Hall, 1992
  • pAc360 or pBlueBacHis available from frwitrogen Co ⁇ oration
  • This recombinant construct was co-transfected into insect cells (for example Spodoptera frugiperda 21(Sf21)) with viral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus.
  • insect cells for example Spodoptera frugiperda 21(Sf21)
  • viral DNA eg Pharmingen BaculoGold
  • cytoplasmic fragments starting from methionine 806 (KDR, Genbank accession number L04947), methionine 668 (EGF receptor, Genbank accession number X00588) and methionine 399 (FGF Rl receptor, Genbank accession number X51803) maybe cloned and expressed in a similar manner.
  • cFlt tyrosine kinase activity Sf21 cells were infected with plaque-pure cFlt recombinant virus at a multiplicity of infection of 3 and harvested 48 hours later.
  • Harvested cells were washed with ice cold phosphate buffered saline solution (PBS) (lOmM sodium phosphate pH7.4, 138mM sodium chloride, 2.7mM potassium chloride) then resuspended in ice cold HNTG/PMSF (20mM Hepes pH7.5, 150mM sodium chloride, 10% v/v glycerol, 1% v/v Triton X100, 1.5mM magnesium chloride, lmM ethylene glycol- bis( ⁇ aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), lmM PMSF (phenylmethylsulphonyl fluoride); the PMSF is added just before use from a freshly-prepared
  • a stock of substrate solution was prepared from a random copolymer containing tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (Sigma P3899), stored as 1 mg/ml stock in PBS at -20°C and diluted 1 in 500 with PBS for plate coating.
  • a random copolymer containing tyrosine for example Poly (Glu, Ala, Tyr) 6:3:1 (Sigma P3899)
  • Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25 ⁇ l of diluted compound was transferred to wells in the washed assay plates. "Total" control wells contained 10% DMSO instead of compound. Twenty five microlitres of 40mM manganese(II)chloride containing 8 ⁇ M adenosine-5'-triphosphate (ATP) was added to all test wells except "blank” control wells which contained manganese(II)chloride without ATP. To start the reactions 50 ⁇ l of freshly diluted enzyme was added to each well and the plates were incubated at room temperature for 20 minutes. The liquid was then discarded and the wells were washed twice with PBST.
  • DMSO dimethylsulphoxide
  • mice IgG anti-phosphotyrosine antibody Upstate Biotechnology hie. product 05-321
  • PBST containing 0.5% w/v bovine serum albumin
  • HRP horse radish peroxidase
  • SSA bovine serum albumin
  • ABTS 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)
  • HUVEC cells were isolated in MCDB 131 (Gibco BRL) + 7.5% v/v foetal calf serum (FCS) and were plated out (at passage 2 to 8), in MCDB 131 + 2% v/v FCS + 3 ⁇ g/ml heparin + l ⁇ g/ml hydrocortisone, at a concentration of 1000 cells/well in 96 well plates. After a minimum of 4 hours they were dosed with the appropriate growth factor (i.e.
  • VEGF 3ng/ml, EGF 3ng/ml or b-FGF 0.3ng/ml The cultures were then incubated for 4 days at 37°C with 7.5% CO 2 . On day 4 the cultures were pulsed with l ⁇ Ci/well of tritiated-thymidine (Amersham product TRA 61) and incubated for 4 hours. The cells were harvested using a 96-well plate harvester (Tomtek) and then assayed for inco ⁇ oration of tritium with a Beta plate counter. Inco ⁇ oration of radioactivity into cells, expressed as cpm, was used to measure inhibition of growth factor-stimulated cell proliferation by compounds.
  • Test compounds were administered orally once daily for a minimum of 21 days, and control animals received compound diluent. Tumours were measured twice weekly. The level of growth inhibition was calculated by comparison of the mean tumour volume of the control group versus the treatment group using a Student T test and/or a Mann- Whitney Rank Sum Test. The inhibitory effect of compound treatment was considered significant when p ⁇ 0.05.
  • a pharmaceutical composition which comprises a compound of the formula I as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.
  • the composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream or for rectal administration for example as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution, suspension or emulsion for topical administration for example as an ointment or cream or for rectal administration for example as a suppository.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • the compositions of the present invention are advantageously presented in unit dosage form.
  • the compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000mg per square metre body area of the animal, i.e. approximately 0.1-lOOmg/kg
  • a unit dose form such as a tablet or capsule will usually contain, for example l-250mg of active ingredient.
  • a compound of the formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
  • compounds of the present invention inhibit NEGF receptor tyrosine kinase activity and are therefore of interest for their antiangiogenic effects and/or their ability to cause a reduction in vascular permeability.
  • a further feature of the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament, conveniently a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being.
  • a method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a daily dose in the range of l-50mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • the other component(s) of such conjoint treatment in addition to the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy.
  • Such chemotherapy may cover three main categories of therapeutic agent:
  • cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5 ⁇ - dihydroreductase (for example finasteride), anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase
  • antioestrogens for example tamoxifen,toremifene, raloxif
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of a compound of formula I as defined hereinbefore, and a vascular targeting agent described in WO 99/02166 such as N-acetylcolchinol-O-phosphate (Exampe 1 of WO 99/02166).
  • a vascular targeting agent described in WO 99/02166 such as N-acetylcolchinol-O-phosphate (Exampe 1 of WO 99/02166).
  • the compounds defined in the present invention are of interest for their antiangiogenic and/or vascular permeability reducing effects.
  • Such compounds of the invention are expected to be useful in a wide range of disease states including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, lymphoedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin. More particularly such compounds of the invention are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with NEGF, especially those tumours which are significantly dependent on NEGF for their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, vulva and skin.
  • the compounds of formula I and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of NEGF receptor tyrosine kinase activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • Citric acid 0.38% w/v
  • the above formulations maybe obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

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Abstract

The invention relates to compounds of the formula I: wherein: ring C is a 5 or 6-membered heteroaromatic ring containing at least one nitrogen atom and optionally containing a further 1-2 heteroatoms, selected independently from O, S and N; either any one of G1, G2, G3, G4 and G5 is nitrogen and the other four are -CH-, or G1, G2, G3, G4, and G5 are all - CH-; Z is -O-, -NH-, -S-, CH2-, or a direct bond; Z is linked to any one of G1, G2, G3, and G4; n is an integer from 0 to 5; any of the substituents R1 may be attached at any free carbon atom of the indole, azaindole or indazole group; m is an integer from 0 to 4, Rb represents hydrogen or another value as defined herein; R1 represents hydrogen, oxo, hydroxy, halogeno, C¿1-4?alkyl, C1-4alkoxy, C1-4alkyxyC1-4alkyl, aminoC1-4alkyl, aminoC1-4alkyl, C1-3alkylaminoC1-4alkyl, di(C1-3alkyl)aminoC1-4alkyl, -C1-5alkyl(ring B) wherein ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperzinyl, N-ethylpiperazinyl, morpholino and thiomorpholino; R?2¿ represents hydrogen, hydroxy, halogeno, cyano, nitro, trifuloromethyl, C ¿1-3?alkyl, C1-3alkoxy, C1-3alkylsulphanyl,-NR?3R4¿ /wherein R?3 and R4¿, which may be the same or different, each represents hydrogen or C¿1-3?alkyl), or R?5X1¿-(wherein R?5 and X1¿ are as defined herein) and salts thereof, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and the use of compound of formula I in the manufacture of a medicament for the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals. The compounds of formula I and the pharmaceutically acceptable slats thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

Description

ANTIANGIOGENIC BICYCLIC DERIVATIVES
The present invention relates to indole, azaindole and indazole derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans.
Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). Alteration ofvascular permeability is thought to play a role in both normal and pathological physiological processes (Cullinan-Bove et al, 1993,
Endocrinology 133: 829-837; Senger et al, 1993, Cancer and Metastasis Reviews, 12: 303- 324). Several polypeptides with in vitro endothelial cell growth promoting activity have been identified including, acidic and basic fibroblast growth factors (aFGF & bFGF) and vascular endothelial growth factor (NEGF). By virtue of the restricted expression of its receptors, the growth factor activity of NEGF, in contrast to that of the FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36:139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024). Antagonism of NEGF action by sequestration of NEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844). Basic FGF (bFGF) is a potent stimulator of angiogenesis (e.g. Hayek et al, 1987, Biochem. Biophys. Res. Commun. 147: 876-880) and raised levels of FGFs have been found in the serum (Fujimoto et al, 1991, Biochem. Biophys. Res. Commun. 180: 386-392) and urine (Nguyen et al, 1993, J. Natl. Cancer, hist. 85: 241-242) of patients with cancer.
Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Fit or Fltl, the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fit and KDR, have been shown to bind NEGF with high affinity (De Nries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of NEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes. The present invention is based on the discovery of compounds that surprisingly inhibit the effects of NEGF, a property of value in the treatment of disease states associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, lymphoedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. Compounds of the present invention generally possess higher potency against NEGF receptor tyrosine kinase than against epidermal growth factor (EGF) receptor tyrosine kinase. Compounds of the invention which have been tested possess activity against NEGF receptor tyrosine kinase such that they may be used in an amount sufficient to inhibit NEGF receptor tyrosine kinase whilst demonstrating no significant activity against EGF receptor tyrosine kinase. Compounds of the present invention generally possess higher potency against NEGF receptor tyrosine kinase than against FGF Rl receptor tyrosine kinase. Compounds of the invention which have been tested possess activity against NEGF receptor tyrosine kinase such that they maybe used in an amount sufficient to inhibit NEGF receptor tyrosine kinase whilst demonstrating no significant activity against FGF Rl receptor tyrosine kinase.
According to one aspect of the present invention there is provided the use of a compound of the formula I:
Figure imgf000005_0001
wherein: ring C is a 5 or 6-membered heteroaromatic ring containing at least one nitrogen atom and optionally containing a further 1-2 heteroatoms, selected independently from O, S and N; either any one of Gi, G2, G3, G and G5 is nitrogen and the other four are -CH-, or Gi, G2, G3, G4 and G5 are all -CH-;
Z is -O-, -NH-, -S-, -CH ~ or a direct bond; Z is linked to any one of Gi, G2, G3 and G4 which is a free carbon atom; n is an integer from 0 to 5; any of the substituents R maybe attached at any free carbon atom of the indole, azaindole or indazole group, such free carbon atoms maybe Gi, G2, G3, G or G5 or may be at the 3-position of the indole, azaindole or indazole group; m is an integer from 0 to 4;
R represents hydrogen, Cι-4alkyl, Cι.4alkoxyCι.4alkyl, aminoCι-4alkyl, Cι_ alkylaminoCι- alkyl, di(Cι-3alkyl)aminoCι-4alkyl, C2.5alkenylaminoCι. alkyl, C2-5alkynylaminoCι-4alkyl, -
Cι-5alkyl(ring A) wherein ring A is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, mo holino and thiomorpholino and wherein ring A may bear one or more substituents selected from Cι-4alkyl, C2-5alkenyl, C2-5alkynyl, hydroxy, oxo, halogeno, cyano, cyanoCι_4alkyl, Cι_4alkylsulphonyl and Cι. alkanoyl;
R1 represents hydrogen, oxo, hydroxy, halogeno, Cι.4alkyl, Cι.4alkoxy, Cι_4alkoxyCι_ alkyl, aminoCι- alkyl, Cι_3alkylaminoCι. alkyl, di(Cι.3alkyl)aminoCι. alkyl, -Cι.5alkyl(ring B) wherein ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N- methylpiperazinyl, N-ethylpiperazinyl, morpholino and thiomorpholino; R represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C _3alkyl, C\. 3alkoxy, Cι_ alkylsulphanyl, -NR3R4 (wherein R3 and R4, which may be the same or different, each represents hydrogen or
Figure imgf000006_0001
or R5X1- (wherein X1 represents a direct bond, -O-, -
CH2-, -OC(O)-, -C(O)-, -S-, -SO-, -SO2-, -NR6C(O , -C(O)NR7-, -SO2NR8-, -NR9SO2- or - NR10- (wherein R6, R7, R8, R9 and R10 each independently represents hydrogen, Cι. alkyl or Cι_3alkoxyC2-3alkyl), and R5 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylCι. alkyl or Cι-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
2) Cι.5alkylX2C(O)Rπ (wherein X2 represents -O- or -NR12- (in which R12 represents hydrogen, Cι„3alkyl or Cι-3alkoxyC2.3alkyl) and R11 represents Cι-3alkyl, -NR13R14 or -OR15 (wherein R13, R14 and R15 which may be the same or different each represents hydrogen, Cι_ 5alkyl or Cι_3alkoxyC2-3alkyl)); 3) Cι-5alkylX3R16 (wherein X3 represents -O-, -S-, -SO-, -SO2-, -OC(O)-, -NR17C(O)-, - C(O)NR18-, -SO2NR19-, -NR20SO2- or -NR21- (wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, Cι.3alkyl or Cι_ alkoxyC2-3alkyl) and R16 represents hydrogen, Cι-3alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which Cj.3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Cι„4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Ci- 4cyanoalkyl, Cι- alkyl, Cι. hydroxyalkyl, Cι_4alkoxy, C alkoxyCι-4alkyl, Cι_ alkylsulphonylCι_ alkyl, Cι.4alkoxycarbonyl, Cι_ aminoalkyl, Cι.4alkylamino, di(Cι. 4alkyl)amino, Cι_4alkylaminoCι. alkyl, di(Cι.4alkyl)aminoCι. alkyl, Cι.4alkylaminoCι. alkoxy, di(Cι-4alkyl)aminoCι- alkoxy and a group -(-O-)f(Cι.4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι_4alkyl)); 4) Cι-5alkyK4Cι-5alkyιX5R22 (wherein X4 and X5 which maybe the same or different are each -O-, -S-, -SO-, -SO2-, -NR23C(O)-, -C(O)NR24-, -SO2NR25-, -NR26SO2- or -NR27- (wherein R23, R24, R25, R26 and R27 each independently represents hydrogen, Cι.3alkyl or Cι_3alkoxyC2. 3alkyl) and R22 represents hydrogen, Cι_3alkyl or Cι-3alkoxyC2.3alkyl); 5) R28 (wherein R is a 4-, 5- or 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι. cyanoalkyl, Cι_4alkyl, Cι_ hydroxyalkyl, Cι_ alkoxy, Cι- alkanoyl, Cι_4alkoxyCι_ alkyl, Ci. 4alkylsulphonyl, Cι.4alkylsulphonylCι_4alkyl, Cι_4alkoxycarbonyl, Cι_ aminoalkyl, Ci. alkylamino, di(Cι.4alkyl)amino, Cι_4alkylaminoCι. alkyl, di(Cι.4alkyl)aminoCι. alkyl, Ci.
4alkylaminoCι. alkoxy, di(Cι_4alkyl)aminoCι.4alkoxy and a group -(-O-) (Cι. alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι.4alkyl));
6) Cι-5alkylR28 (wherein R28 is as defined hereinbefore);
7) C2-5alkenylR (wherein R is as defined hereinbefore); 8) C2-5alkynylR28 (wherein R28 is as defined hereinbefore);
9) R29 (wherein R29 represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, Cι„ alkyl, Cι.4alkoxy, Cι. hydroxyalkyl, Cι_ 4aminoalkyl, Cι_4alkylamino,
Figure imgf000007_0001
carboxy, trifluoromethyl, cyano, - C(O)NR30R31, -NR32C(O)R33 (wherein R30, R31, R32 and R33, which may be the same or different, each represents hydrogen, Cι_4alkyl or Cι_3alkoxyC2.3alkyl) and a group -(-O-)f(Cι. 4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι.4alkyl));
10) Cι.5alkylR29 (wherein R29 is as defined hereinbefore);
11) C2-5alkenylR29 (wherein R29 is as defined hereinbefore);
12) C2-5alkynylR29 (wherein R29 is as defined hereinbefore);
13) Cι.5alkylX6R29 (wherein X6 represents -O-, -S-, -SO-, -SO2-, -NR34C(O)-, -C(O)NR35-, - SO2NR36-, -NR37SO2- or -NR38- (wherein R34, R35, R36, R37 and R38 each independently represents hydrogen, Cι_3alkyl or Cι.3alkoxyC2.3alkyl) and R is as defined hereinbefore); 14) C2.5alkenylX7R29 (wherein X7 represents -O-, -S-, -SO-, -SO2-, -NR39C(O)-, -C(O)NR40-, -SO2NR41-, -NR42SO2- or -NR43- (wherein R39, R40, R41, R42 and R43 each independently represents hydrogen, Cι-3alkyl or Cι.3alkoxyC2-3alkyl) and R29 is as defined hereinbefore); 5 15) C2.5alkynylX8R29 (wherein X8 represents -O-, -S-, -SO-, -SO2-, -NR4 C(O)-, -C(O)NR45-, -SO2NR46-, -NR47SO2- or -NR48- (wherein R44, R45, R46, R47 and R48 each independently
90 represents hydrogen, Cι-3alkyl or Cι-3alkoxyC2.3alkyl) and R is as defined hereinbefore);
16) C^alkylX^^alkylR29 (wherein X9 represents -O-, -S-, -SO-, -SO2-, -NR49C(O)-, - C(O)NR50-, -SO2NR51-, -NR52SO2- or -NR53- (wherein R49, R50, R51, R52 and R53 each
10 independently represents hydrogen, Cι_3alkyl or Cι-3alkoxyC2-3alkyl) and R29 is as defined hereinbefore);
17) Cι.4alkylX9Cι_4alkylR28 (wherein X9 and R28 are as defined hereinbefore);
18) C2-5alkenyl which may be unsubstituted or which may be substituted with one or more 15 groups selected from hydroxy, fluoro, amino, Cι.4alkylamino, N,N-di(Cι.4alkyl)amino, aminosulphonyl, N-Cι.4alkylaminosulphonyl and N,N-di(Cι.4alkyl)aminosulphonyl;
19) C2.5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, Cι_ alkylamino, N,N-di(Cι.4alkyl)amino, aminosulphonyl, N-Cι.4alkylaminosulphonyl and N,N-di(Cι.4alkyl)aminosulphonyl;
20 20) C2-5alkenylX9Cι.4alkylR28 (wherein X9 and R28 are as defined hereinbefore);
21) C2-5alkynylX9Ci.4alkylR28 (wherein X9 and R28 are as defined hereinbefore); and
22) CMalkylR54(Cι_4alkyl)q(X9)rR55 (wherein X9 is as defined hereinbefore, q is 0 or 1, r is 0 or 1, and R54 and R55 are each independently selected from hydrogen, Cι.3alkyl, cyclopentyl, cyclohexyl and a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms,
25 selected independently from O, S and N, which Cι-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Cι.4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_4cyanoalkyl, Cι_4alkyl, Ci- 4hydroxyalkyl, Cι. alkoxy, Cι-4alkoxyCι.4alkyl, Cι-4alkylsulphonylCι. alkyl, Cι_ 4alkoxycarbonyl, Cι_4aminoalkyl, Cι. alkylamino, di(Cι- alkyl)amino, Cι_4alkylaminoCι-
30 4alkyl, di(Cι.4alkyl)aminoCι.4alkyl, Cι- alkylaminoCι-4alkoxy, di(Cι. alkyl)aminoCι.4alkoxy and a group -(-O-)f(Cι-4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6- membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι_4alkyl), with the proviso that R54 cannot be hydrogen); and additionally wherein any Ci-salkyl, C2.5alkenyl or C2.5alkynyl group in R5X!- may bear one or more substituents selected from hydroxy, halogeno and amino); or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
According to another aspect of the present invention there is provided the use of a compound of the formula I1 :
Figure imgf000009_0001
(I1) wherein: ring C is a 5 or 6-membered heteroaromatic ring containing at least one nitrogen atom and optionally containing a further 1-2 heteroatoms, selected independently from O, S and N;
Z is -O-, -NH-, -S-, -CH2- or a direct bond; Z is linked to the benz ring of the indole group at any of the positions 4-, 5-, 6- or 7- of the indole group; n is an integer from 0 to 5; any of the substitutents R1 maybe attached at any free carbon atom of the indole group, such free carbon atoms may be at positions 2-, 3-, 4-, 5-, 6-, or 7- of the indole group; m is an integer from 0 to 4; R represents hydrogen, Cι_4alkyl, Cι-3alkoxyCι.4alkyl, aminoCι. alkyl, Cι- alkylaminoCι_ 4alkyl, di(Cι-3alkyl)aminoCι-4alkyl, -Cι-5alkyl(ring A) wherein ring A is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, morpholino and thiomorpholino;
R1 represents hydrogen, oxo, hydroxy, halogeno,
Figure imgf000010_0001
Cι. alkoxy, Cι-4alkoxyCι-4alkyl, aminoCι-4alkyl, Cι-3alkylaminoCι.4alkyl, di(Cι.3alkyl)aminoCι-4alkyl, -Cι_5alkyl(ring B) wherein ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N- methylpiperazinyl, N-ethylpiperazinyl, morpholino and thiomorpholino; R represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, Cι-3alkyl, Ci-
3alkoxy, Cι.3alkylsulphanyl, -NR3R4 (wherein R3 and R4, which may be the same or different, each represents hydrogen or Cι-3alkyl), or R5Xl- (wherein X1 represents a direct bond, -O-, - CH2-, -OC(O)-, -C(O)-, -S-, -SO-, -SO2-, -NR6C(O)-, -C(O)NR7-, -SO2NR8-, -NR9SO2- or - NR10- (wherein R6, R7, R8, R9 and R10 each independently represents hydrogen, Cι_3alkyl or Cι-3alkoxyC2-3alkyl), and R5 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylCι_4alkyl or Ci^alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
2) Cι-5alkylX2C(O)Ru (wherein X2 represents -O- or -NR12- (in which R12 represents hydrogen, Cι-3alkyl or Cι-3alkoxyC2-3alkyl) and R11 represents d.3alkyl, -NR13R14 or -OR15 (wherein R13, R14 and R15 which may be the same or different each represents hydrogen, C\. 5alkyl or Cι.3alkoxyC2.3alkyl));
3) Cι_5alkylX3R16 (wherein X3 represents -O-, -S-, -SO-, -SO2-, -OC(O)-, -NR17C(O)-, - C(O)NR18-, -SO2NR19-, -NR20SO2- or -NR21- (wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, Cι.3alkyl or Cι-3alkoxyC2-3alkyl) and R16 represents hydrogen, Cι.3alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which Cι.3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Cι-4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Ci- 4cyanoalkyl, Cι-4alkyl, Cι-4hydroxyalkyl, Cι_4alkoxy, Cι- alkoxyCι_4alkyl, Ci- alkylsulρhonylCι.4alkyl, Cι-4alkoxycarbonyl, Ci.4aminoalkyl, Cι.4alkylamino, di(Cι.
4alkyl)amino, Cι-4alkylaminoCι-4alkyl, di(Ci-4alkyl)aminoCi.4alkyl, Cι_4alkylaminoCι-4alkoxy, di(Ci- alkyl)aminoCi.4alkoxy and a group -(-O-)f(Cι-4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι-4alkyl));
4) Cι.5alkylX4Cι-5alkylX5R22 (wherein X4 and X5 which may be the same or different are each -O-, -S-, -SO-, -SO2-, -NR23C(O)-, -C(O)NR24-, -SO2NR25-, -NR26SO2- or -NR27- (wherein
R23, R24, R25, R26 and R27 each independently represents hydrogen, Cι_3alkyl or Cι- alkoxyC2. 3alkyl) and R22 represents hydrogen, Cι.3alkyl or C .3alkoxyC2-3alkyl);
5) R28 (wherein R28 is a 4-, 5- or 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_ cyanoalkyl, Cι-4alkyl, Cι_4hydroxyalkyl, Cι-4alkoxy, Cι_4alkoxyCι_4alkyl, Cι_ 4alkylsulphonylCι_4alkyl, Cι. alkoxycarbonyl, Cι_4aminoalkyl, Cι_4alkylamino, di(Cι_ 4alkyl)amino, Cι_4alkylaminoCι. alkyl, di(Cι-4alkyl)aminoCι-4alkyl, Cι.4alkylaminoCι. alkoxy, di(Cι-4alkyl)aminoCι- alkoxy and a group -(-O-)f(Cι-4alkyl)grmgD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι_ alkyl));
6) Ci-5alkylR28 (wherein R28 is as defined hereinbefore);
7) C2-5alkenylR28 (wherein R28 is as defined hereinbefore); 8) C2-5alkynylR28 (wherein R28 is as defined hereinbefore);
9) R29 (wherein R29 represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, Cι_ alkyl, Cι_4alkoxy, Cι.4hydroxyalkyl, Cι_ 4aminoalkyl, Cι_ alkylamino, Cι-4hydroxyalkoxy, carboxy, trifluoromethyl, cyano, - C(O)NR30R31, -NR32C(O)R33 (wherein R30, R31, R32 and R33, which may be the same or different, each represents hydrogen, Cι_4alkyl or Cι-3alkoxyC2-3alkyl) and a group -(-O-)f(Cι- 4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S andN, which cyclic group may bear one or more substituents selected from Cι_4alkyl));
10) Cι.5alkylR29 (wherein R29 is as defined hereinbefore);
11) C2.5alkenylR29 (wherein R29 is as defined hereinbefore);
12) C2.5alkynylR29 (wherein R29 is as defined hereinbefore); 13) Cι.5alkylX6R29 (wherein X6 represents -O-, -S-, -SO-, -SO2-, -NR34C(O)-, -C(O)NR35-, - SO2NR36-, -NR37SO2- or -NR38- (wherein R34, R35, R36, R37 and R38 each independently represents hydrogen, Cι-3alkyl or Cι-3alkoxyC2-3alkyl) and R29 is as defined hereinbefore); 14) C2.5alkenylX7R29 (wherein X7 represents -O-, -S-, -SO-, -SO -, -NR3 C(O)-, -C(O)NR40-, -SO2NR41-, -NR42SO2- or -NR43- (wherein R39, R40, R41, R42 and R43 each independently represents hydrogen, Cι.3alkyl or Cι-3alko yC2-3alkyl) and R is as defined hereinbefore);
15) C2-5alkynylX8R29 (wherein X8 represents -O-, -S-, -SO-, -SO2-, -NR44C(O)-, -C(O)NR45-, -SO2NR46-, -NR47SO2- or -NR48- (wherein R44, R45, R46, R47 and R48 each independently
90 represents hydrogen, Cι-3alkyl or Cι.3alkoxyC2-3alkyl) and R is as defined hereinbefore);
16) Cι.4alkylX9Cι.4alkylR29 (wherein X9 represents -O-, -S-, -SO-, -SO2-, -NR49C(O)-, - C(O)NR50-, -SO2NR51-, -NR52SO2- or -NR53- (wherein R49, R50, R51, R52 and R53 each independently represents hydrogen, Cι-3alkyl or Cι-3alkoxyC2-3alkyl) and R29 is as defined hereinbefore); 17) Cι-4alkylX9Cι.4alkylR28 (wherein X9 and R28 are as defined hereinbefore);
18) C2-5alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, Cι- alkylamino, N,N-di(Cι-4alkyl)amino, aminosulphonyl, N-Cι_4alkylaminosulphonyl and N,N-di(Cι-4alkyl)aminosulphonyl;
19) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, Cι.4alkylamino, N,N-di(Cι- alkyl)amino, aminosulphonyl, N-Cι.4alkylaminosulphonyl and N,N-di(Cι- alkyl)aminosulphonyl; 98 Q 8
20) C2-5alkenylX Cι- alkylR (wherein X and R are as defined hereinbefore);
21) C2-5alkynylX9Cι-4alkylR28 (wherein X9 and R28 are as defined hereinbefore); and
22) Ci.4alkylR54(Ci.4alkyl)q(X9)rR55 (wherein X9 is as defined hereinbefore, q is 0 or 1, r is 0 or 1, and R54 and R55 are each independently selected from hydrogen, Cι-3alkyl, cyclopentyl, cyclohexyl and a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which Cι.3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Cι.4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-4cyanoalkyl, Cι-4alkyl, Ci. 4hydroxyalkyl, Cι_ alkoxy, Cι_ alkoxyCι. alkyl, Cι_ alkylsulρhonylCι.4alkyl, .
4alkoxycarbonyl, Ci- aminoalkyl, Cι_4alkylamino, di(Cι-4alkyl)amino, Cι.4alkylaminoCι. 4alkyl, di(Cι.4alkyl)aminoCι.4alkyl, Cι.4alkylaminoCι.4alkoxy, di(Cι. alkyl)aminoCι-4alkoxy and a group -(-O-) (Cι.4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6- membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι. alkyl), with the proviso that R54 cannot be hydrogen); and additionally wherein any Ci-salkyl, C2.5alkenyl or C2.5alkynyl group in R5Xl- may bear one or more substituents selected from hydroxy, halogeno and amino); or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans. Preferably ring C is selected from one of the following seven moieties:
Figure imgf000013_0001
0) (ϋ) (iϋ) (iv)
Figure imgf000013_0002
(v) (vi) (vii)
wherein Z is as defined hereinbefore but is not part of ring C, it is shown for the purpose of clarity, and wherein alternatives for the values at certain positions of ring C are indicated by the possible values separated by commas.
More preferably ring C is a pyrimidine ring or a pyridyl ring. Preferably Z is -O-, -NH-, -S- or a direct bond. More preferably Z is -O-, -NH- or -S-. Particularly Z is -O- or -NH-, especially -O-. Preferably Z is linked to the indole, azaindole or indazole group at the 5- or 6-positions of the indole, azaindole or indazole group.
More preferably Z is linked to the indole, azaindole or indazole group at the 5-position of the indole, azaindole or indazole group.
Preferably Z is linked to an indole group at the 5- or 6-positions of the indole group. More preferably Z is linked to an indole group at the 5-position of the indole group. Preferably Rb represents hydrogen, Cι.2alkyl, C2-3alkenylaminoC2-3alkyl, C2. 3alkynylaminoC2-3alkyl or -C2-4alkyl(ring A) wherein ring A is selected from piperidinyl and piperazinyl and wherein ring A may bear one or more substituents selected from ^alkyl, C2. 3alkenyl, C2-3alkynyl, hydroxy, cyano,
Figure imgf000014_0001
and Cι.2alkanoyl. More preferably Rb represents hydrogen, methyl, C2-3alkenylaminoC2-3alkyl, C2- 3alkynylaminoC2-3alkyl or -C2-3alkyl(ring A) wherein ring A is selected from 4- acetylpiperazin-1-yl, 4-methylsulphonylpiperazin-l-yl, 4-cyanopiperazin-l-yl, 4- cyanomethylpiperazin- 1 -yl, 4-(prop-2-en- 1 -yl)piperazin- 1 -yl, 4-(prop-2-yn- 1 -yl)piperazin- 1 -yl and 4-hydroxypiperidino.
Particularly Rb is hydrogen or methyl, especially hydrogen. Advantageously R1 represents hydrogen, oxo, hydroxy, halogeno, Cι_ alkyl, Cι_ 4alkoxy, Cι.4alkoxyCι.4alkyl, aminoCι.4alkyl, Cι.3alkylaminoCι-4alkyl, di(Cι.3alkyl)aminoCι_ 4alkyl, -Cι_5alkyl(ring B) wherein ring B is selected from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, N-methylpiperazin-1-yl, N-ethylpiperazin-1-yl, morpholino and thiomorpholino.
Particularly R1 represents methyl, ethyl, trifluoromethyl or halogeno. Especially R1 represents methyl, fluoro, chloro or bromo, more especially methyl or fluoro. Preferably n is an integer from 0 to 3.
More preferably n is 0, 1 or 2.
According to one aspect of the present invention Gi is nitrogen and G2, G3, G4 and G5 are -CH- forming an azaindole moiety which may bear one or more substituents R1 as defined hereinbefore. According to another aspect of the present invention G5 is nitrogen and G1} G2, G3 and G4 are -CH- forming an indazole moiety which may bear one or more substituents R1 as defined hereinbefore.
According to another aspect of the present invention Gi, G2, G3, G4 and G5 are all -CH- forming an indole moiety which may bear one or more substituents R1 as defined hereinbefore.
In one embodiment of the invention the optionally substituted indole, azaindole or indazole moiety of formula II:
Figure imgf000015_0001
(D) wherein R1, R , Gi, G , G3, G4 and G5 and 11 are as defined hereinbefore; is selected from the indole moieties:
4-fluoro-2-methylindol-5-yl, 2-methylindol-5-yl, 2-methylindol-6-yl, 2,3-dimethylindol-5-yl, l-methylindol-5-yl, l,2-dimethylindol-5-yl, 4-fluoroindol-5-yl, 6-fluoroindol-5-yl, indol-5-yl and 3-methylindol-5-yl, the azaindole moieties:
Figure imgf000015_0002
lH-pyπ-olo[2,3-b]pyridin-5-yl and 2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl, and the indazole moiety:
Figure imgf000015_0003
lH-indazol-5-yl.
The indole moieties are preferred over the azaindole and indazole moieties. fn one embodiment of the invention the optionally substituted indole moiety of formula π1:
Figure imgf000016_0001
(π1) wherein R1, Rb and n are as defined hereinbefore; is selected from 4-fluoro-2-methylindol-5-yl, 2-methylindol-5-yl, 2-methylindol-6-yl, 2,3- dimethylindol-5-yl, l-methylindol-5-yl, l,2-dimethylindol-5-yl, 4-fluoroindol-5-yl, 6- fluoroindol-5-yl and indol-5-yl.
Particularly the optionally substituted indole moiety of formula II is selected from 4-fluoro-2- methylindol-5-yl, 4-fluoroindol-5-yl and 6-fluoroindol-5-yl, more especially from 4-fluoro-2- methylindol-5-yl.
Preferably m is 1 or 2. Advantageously X1 represents a direct bond, -O-, -S-, -NR6C(O)-, -NR9SO2- or -
NR10- (wherein R6, R9 and R10 each independently represents hydrogen, Cι-2alkyl or . 2alkoxyethyl).
Preferably X1 represents a direct bond, -O-, -S-, -NR6C(O)-, -NR9SO2- (wherein R6 and R9 each independently represents hydrogen or Ci^alkyl) or NH. More preferably X1 represents -O-, -S-, -NR°C(O)- (wherein R6 represents hydrogen or Cι.2alkyl) orNH.
Particularly X1 represents -O- or -NR6C(O)- (wherein R6 represents hydrogen or Cι_ 2alkyl), more particularly -O- or -NHC(O)-, especially -O-.
According to another aspect of the present invention X1 represents -O- or a direct bond.
Advantageously X2 represents -O- or NR12 (wherein R12 represents hydrogen, Cι_ 3alkyl or C^alkoxyethyl).
Advantageously X3 represents -O-, -S-, -SO-, -SO2-, -NR17C(O)-, -NR20SO2- or -NR21- (wherein R17, R20 and R21 each independently represents hydrogen, Cι.2alkyl or Cι_ 2alkoxyethyl).
Preferably X3 represents -O-, -S-, -SO-, -SO2- or -NR21- (wherein R21 represents hydrogen, Cι-2alkyl or Cι_2alkoxyethyl). More preferably X3 represents -O- or -NR21- (wherein R21 represents hydrogen or Cι.2alkyl).
According to another aspect of the present invention X3 represents -O-, -SO2-, - NR20SO2- or -NR21- (wherein R20 and R21 each independently represents hydrogen,
Figure imgf000017_0001
or Cι_2alkoxyethyl).
Advantageously X4 and X5 which may be the same or different each represents -O-, - S-, -SO-, -SO2- or -NR27- (wherein R27 represents hydrogen, Cι-3alkyl or Cι.2alkoxyethyl).
Preferably X4 and X5 which may be the same or different each represents -O-, -S- or -NR27- (wherein R27 represents hydrogen, Cι-2alkyl or Cι-2alkoxyethyl).
More preferably X4 and X5 which may be the same or different each represents -O- or -NH-.
Especially X4 and X5 each represents -O-.
Advantageously X6 represents -O-, -S- or -NR38- (wherein R38 represents hydrogen, Cι-2alkyl or Cι.2alkoxyethyl).
Preferably X represents -O- or -NR - (wherein R represents hydrogen or Cι_ alkyl).
Especially X represents -O-.
Advantageously X7 represents -O-, -S- or -NR 3- (wherein R43 represents hydrogen, Cι.2alkyl or C^alkoxyethyl).
Preferably X7 represents -O- or -NR43- (wherein R43 represents hydrogen or Cι_ 2alkyl).
Advantageously X represents -O-, -S- or -NR - (wherein R represents hydrogen, Cι-2alkyl or Cι.2alkoxyethyl). Preferably X8 represents -O- or -NR48- (wherein R48 represents hydrogen or d^alkyl).
Advantageously X9 represents -O-, -S- or -NR53- (wherein R53 represents hydrogen, Cι-2alkyl or Cι_2alkoxyethyι).
Preferably X9 represents -O- or -NR53- (wherein R53 represents hydrogen or Cι_2alkyl). According to another aspect of the present invention X9 represents -O-, -CONR50- or - NR - (wherein R50 and R53 each independently represents hydrogen or Cι-2alkyl).
Conveniently R28 is pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι.3cyanoalkyl, Cι_3alkyl, Cι-3hydroxyalkyl, Cι-3alkoxy, Q. 2alkoxyCι-3alkyl, Cι-2alkylsulphonylCι-3alkyl, Cι-3alkoxycarbonyl, Cι-3alkylamino, di(C1. 3alkyl)amino, Cι-3alkylaminoCι_3alkyl, di(Cι.3alkyl)aminoCι.3alkyl, Cι-3alkylaminoCι_3alkoxy, di(Cι.3alkyl)aminoCι.3alkoxy and a group -(-O-)f(Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino, which cyclic group may bear one or more substituents selected from
Figure imgf000018_0001
Advantageously R28 is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-3cyanoalkyl, Cι_3alkyl,
Figure imgf000018_0002
Cι_3alkoxy, Cι_2alkoxyCι-3alkyl, Cι.2alkylsulphonylCι-3alkyl, Cι-3alkoxycarbonyl,
Figure imgf000018_0003
di(Cι-3alkyl)amino, Cι_ 3alkylaminoCι.3alkyl, di(Cι.3alkyl)aminoCι-3alkyl, Cι-3alkylaminoCι.3alkoxy, di(Cι- 3alkyl)aminoCι.3alkoxy and a group -(-O-)f(Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino). no
In one embodiment of the present invention R is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomoφholino which group may bear 1 or 2 substituents selected from a group ~(-O-) (Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino and thiomoφholino).
9R
Particularly R is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, moφholino or thiomoφholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_3cyanoalkyl, Cι_3alkyl, Cι.3hydroxyalkyl,
Figure imgf000018_0004
Cι.2alkoxyCι-3alkyl and Cι.2alkylsulphonylCι-3alkyl. According to another aspect of the present invention, preferably R28 is pyrrolidinyl, piperazinyl, piperidinyl, moφholino or thiomoφholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-3cyanoalkyl, Cι_3alkyl, Cι_ 3hydroxyalkyl, Cι_3alkoxy, Cι-2alkoxyCι-3alkyl and Ci-2alkylsulphonylCi-3alkyl.
Where R29 is a 5 -6-membered aromatic heterocyclic g oups it preferably has 1 or 2 heteroatoms, selected from O, N and S, of which more preferably one is N, and may be substituted as hereinbefore defined.
R29 is particularly a pyridone, phenyl, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl or pyridazinyl group which group may be substituted as hereinbefore defined, more particularly a pyridone, pyridyl, imidazolyl, thiazolyl or triazolyl group, especially a pyridone, pyridyl, imidazolyl or triazolyl group which group may be substituted as hereinbefore defined.
90 hi one embodiment of the invention R represents a pyridone, phenyl or 5- 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which group may preferably carry up to 2 substituents, more preferably up to one substituent, selected from the group of substituents as hereinbefore defined.
9Q hi the definition of R , conveniently substituents are selected from halogeno, Ci. 4alkyl, Cι_ alkoxy, cyano and a group -(-O-)f(Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino, which cyclic group may bear one or more substituents selected from Cι_3alkyl).
90
In the definition of R , more conveniently substituents are selected from chloro, fluoro, methyl, ethyl and a group -(-O-)f(Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino).
90
According to another emodiment of the present invention in the definition of R , conveniently substituents are selected from halogeno, Cι_4alkyl, Cι.4alkoxy and cyano, more conveniently substituents are selected from chloro, fluoro, methyl and ethyl. Advantageously R54 and R55 are each independently a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S andN, which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, d- 3cyanoalkyl, Cι.3alkyl, Cι-3alkoxy, Ci.2alkoxyCi.3alkyl, Ci- 2alkylsulphonylCι.3alkyl, Cι-3alkoxycarbonyl and a group -(-O-)f(Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι-3alkyl).
Preferably R54 and R55 are each selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-3cyanoalkyl, Cι.3alkyl, Ci- 3hydroxyalkyl, Cι-3alkoxy, d-^alkoxyd^alkyl, d-2alkylsulphonylCι-3alkyl, Ci- 3alkoxycarbonyl and a group -(-O-)f(d-3alkyι)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino, which cyclic group may bear one or more substituents selected from Cι-3alkyl).
More preferably R54 and R55 are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-3cyanoalkyl,
Figure imgf000020_0001
Ci- 3hydroxyalkyl,
Figure imgf000020_0002
Cι-2alkoxyCι-3alkyl, Cι-2alkylsulphonylCι-3alkyl, Ci- 3alkoxycarbonyl and a group -(~O-)f(Cι_3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino).
Particularly R54 and R55 are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino which group may bear 1 or 2 substituents selected from a group -(-O-)f(Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino) .
More particularly R54 and R55 are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino which group is unsubstituted.
Conveniently R2 represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, Ci^alkyl, amino or R X - [wherein X is as hereinbefore defined and R is selected from one of the following twenty-two groups:
1) oxiranylCι- alkyl or Cι.5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C2-5alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
2) C2-3alkylX2C(O)Rπ (wherein X2 is as hereinbefore defined and R11 represents Cι-3alkyl, - NR13R14 or -OR15 (wherein R13, R14 and R15 which may be the same or different are each Ci. alkyl or
Figure imgf000020_0003
3) C2.4alkylX3R16 (wherein X3 is as hereinbefore defined and R16 represents hydrogen, Ci- 3alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclic group with 1- 2 heteroatoms, selected independently from O, S and N, which Cι-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Cι-3alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι„4cyanoalkyl, Ci- 4alkyl, Cι.4hydroxyalkyl, Cι-4alkoxy, Cι„ alkoxyCι-4alkyl, Cι.4alkylsulphonylCι.4alkyl, Cι_ 4alkoxycarbonyl, Cι- alkylamino, di(Cι.4alkyl)amino, Ci-4alkylaminoCi.4alkyl, di(Cι. 4alkyl)aminoCi.4alkyl, Cι-4alkylaminoCι. alkoxy, di(Cι.4alkyl)aminoCι. alkoxy and a group - (-O-)f(Cι-4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι_4alkyl));
4) C2-3alkylX4C2-3alkylX5R22 (wherein X4 and X5 are as hereinbefore defined and R22 represents hydrogen or Cι.3alkyl);
5) R28 (wherein R28 is as defined hereinbefore);
6) Ci-salkylR56 (wherein R56 is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to
Cι.5alkyl through a carbon atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_4cyanoalkyl, Cι-4alkyl, C].4hydroxyalkyl, . 4alkoxy, Cι. alkanoyl, Cι_ alkoxyCι-4alkyl, Cι_ alkylsulphonyl, Cι-4alkylsulphonylCι. alkyl, Cι_4alkoxycarbonyl, Cι-4alkylamino, di(Cι. alkyl)amino, Cι_4alkylaminoCι. alkyl, di(Cι. 4alkyl)aminoCι-4alkyl, Cι.4alkylaminoCι.4alkoxy, di(Cι-4alkyl)aminoCι. alkoxy and a group - (-O-)f(Cι-4alkyl)griιιgD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι_4alkyl)) or C2. 5alkylR57 (wherein R57 is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, of which one is N and the other may be selected independently from O, S and N, which heterocyclic group is linked to d-salkyl through a nitrogen atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι- cyanoalkyl, Cι_4alkyl, Cι.4hydroxyalkyl, d.4alkoxy, Cι-4alkanoyl, Cι.4alkoxyCι.4alkyl, Cι_ 4alkylsulphonyl, Cι-4alkylsulphonylCι.4alkyl, Cι-4alkoxycarbonyl, Cι-4alkylamino, di(Cι- alkyl)amino, Cι.4alkylaminoCι. alkyl, di(Cι-4alkyl)aminoCι. alkyl, Cι. alkylaminoCι.4alkoxy, di(Cι.4alkyl)aminoCι.4alkoxy and a group -(-O-)f{Cι. alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι_4alkyl)); 7) C3.4alkenylR58 (wherein R58 represents R56 or R57 as defined hereinbefore);
8) C3-4alkynylR58 (wherein R58 represents R56 or R57 as defined hereinbefore);
9) R29 (wherein R29 is as defined hereinbefore);
10) Cι_5alkylR29 (wherein R29 is as defined hereinbefore); -lO-
ll) C3_5alkenylR29 (wherein R29 is as defined hereinbefore);
12) C3.5alkynylR29 (wherein R29 is as defined hereinbefore);
13) Cι.5alkylX6R29 (wherein X6 and R29 are as defined hereinbefore);
5 14) C4.5alkenylX7R29 (wherein X7 and R29 are as defined hereinbefore);
15) C4.5alkynylX8R29 (wherein X8 and R29 are as defined hereinbefore);
16) C2-3alkylX9Cι.3alkylR29 (wherein X9 and R29 are as defined hereinbefore);
17) C2-3alkylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
18) C2-5alkenyl which may be unsubstituted or which may be substituted with one or more 10 groups selected from hydroxy, fluoro, amino, Cι-4alkylamino, N,N-di(Cι_4alkyl)amino, aminosulphonyl, N-Cι.4alkylaminosulphonyl and N,N-di(Cι.4alkyl)aminosulphonyl;
19) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, Cι-4alkylamino, N,N-di(Cι. alkyl)amino, aminosulphonyl, N-Cι_ alkylaminosulphonyl and N,N-di(Cι- alkyl)aminosulphonyl;
15 20) C2-5alkenylX9Cι-3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
21) C2-5alkynylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore); and
22) d.3alkylR54(Cι.3alkyl)q(X9)rR55 (wherein X9, q, r, R54 and R55 are as defined hereinbefore); and additionally wherein any Ci-salkyl, d-salkenyl or d-salkynyl group in R5X!- may bear 20 one or more substituents selected from hydroxy, halogeno and amino].
Advantageously R2 represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, Ci- 3alkyl, amino or R5X]- [wherein X1 is as hereinbefore defined and R5 is selected from one of the following twenty-two groups:
1) Cι_4alkyl which may be unsubstituted or which may be substituted with one or more groups 25 selected from fluoro, chloro and bromo, or d-salkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
2) C2-3all ylX2C(O)Rn (wherein X2 is as hereinbefore defined and R11 represents -NR13R14 or -OR15 (wherein R13, R14 and R15 which may be the same or different are each Cι.4alkyl or Ci- 2alkoxyethyl));
30 3) C2. alkylX3R16 (wherein X3 is as hereinbefore defined and R16 is a group selected from Cι_ 3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl and tetrahydropyranyl, which Cι-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Cι. alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl or tetrahydropyranyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-3cyanoalkyl,
Figure imgf000023_0001
Ci. 3hydroxyalkyl,
Figure imgf000023_0003
Cι.2alkoxyCι.3alkyl,
Figure imgf000023_0002
Ci- 3alkoxycarbonyl,'Cι-3alkylamino, ό (d-3alkyl)amino, Cι.3alkylaminoCι-3alkyl, di(Cι_
3alkyl)aminoCι-3alkyl, d-3alkylaminoCι-3alkoxy, di(Cι-3alkyl)aminoCι-3alkoxy and a group - (-O-)f(Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino, which cyclic group may bear one or more substituents selected from Ci- 3alkyl));
4) C2-3alkylX4C2-3alkylX5R22 (wherein X4 and X5 are as hereinbefore defined and R22 represents hydrogen or Ci^alkyl);
5) R28 (wherein R28 is as defined hereinbefore);
6) Cι-4alkylR59 (wherein R59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to Cι-4alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-3cyanoalkyl, Ci- 3alkyl, Cι-3hydroxyalkyl, Cι-3alkoxy,
Figure imgf000023_0004
Cι-2alkylsulphonylCι-3alkyl, Cι-3alkoxycarbonyl, Cι-3alkylamino, di(Cι-3alkyl)amino, Ci- 3alkylaminoCι-3alkyl, di(Cι-3alkyl)aminoCι-3alkyl, Cι.3alkylaminoCι.3alkoxy, di(Cι-
3alkyl)aminoCι_3alkoxy and a group -(-O-)f(Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino, which cyclic group may bear one or more substituents selected from
Figure imgf000023_0005
or C2-4alkylR60 (wherein R60 is a group selected from moφholino, thiomoφholino, azetidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, d_ 3cyanoalkyl, Cι_3alkyl,
Figure imgf000023_0006
Cι-3alkoxy, Cι_2alkanoyl, Cι.2alkoxyCι-3alkyl, Ci. 2alkylsulphonyl, Cι-2alkylsulphonylCι.3alkyl, Cι-3alkoxycarbonyl, Cι.3alkylamino, di(Cι. 3alkyl)amino, Cι.3alkylammoCι.3alkyl, di(Cι-3alkyl)aminoCι-3alkyl, Cι.3alkylaminoCι.3alkoxy, di(Cι-3alkyl)aminoCι-3alkoxy and a group -(-O-)f(d-3 lkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino, which cyclic group may bear one or more substituents selected from Chalky!)); 7) C3-4alkenylRδl (wherein Rδl represents R59 or R60 as defined hereinbefore);
8) C3-4alkynylR61 (wherein R61 represents R59 or R60 as defined hereinbefore);
9) R29 (wherein R29 is as defined hereinbefore);
5 10) Cι-4alkylR29 (wherein R29 is as defined hereinbefore);
11) 1-R prop-l-en-3-yl or 1-R but-2-en-4-yl (wherein R is as defined hereinbefore with the proviso that when R5 is l-R29prop-l-en-3-yl, R29 is linked to the alkenyl group via a carbon atom);
12) l-R29prop-l-yn-3-yl or l-R29but-2-yn-4-yl (wherein R29 is as defined hereinbefore with 10 the proviso that when R5 is l-R29prop-l-yn-3-yl, R29 is linked to the alkynyl group via a carbon atom);
13) Ci.5alkylX6R29 (wherein X6 and R29 are as defined hereinbefore);
14) l-(R29X7)but-2-en-4-yl (wherein X7 and R29 are as defined hereinbefore);
15) l-(R29X8)but-2-yn-4-yl (wherein X8 and R29 are as defined hereinbefore); 15 16) C2-3alkylX9Cι-3alkylR29 (wherein X9 and R29 are as defined hereinbefore);
17) C2-3alkylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
18) C2-5alkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci. 4alkylamino, N,N-di(Cι. alkyl)amino, aminosulphonyl, N-Cι.4alkylaminosulphonyl and N,N-
20 di(Cι.4alkyl)aminosulphonyl;
19) C -5alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- 4alkylamino, N,N-di(Cι. alkyl)amino, aminosulphonyl, N-Cι_4alkylaminosulphonyl and N,N- di(Cι_ alkyl)aminosulphonyl;
25 20) C2.4alkenylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
21) C2- alkynylX9Cι-3alkylR28 (wherein X9 and R28 are as defined hereinbefore); and
22) Ci-3alkylR54(Ci.3alkyl)q(X9)rR55 (wherein X9, q, r, R54 and R55 are as defined hereinbefore); and additionally wherein any Ci-salkyl, d-5alkenyl or C2-5alkynyl group in R5X1- may bear 30 one or more substituents selected from hydroxy, halogeno and amino].
Preferably R2 represents hydroxy, halogeno, nitro, trifluoromethyl, Cι-3alkyl, cyano, amino or R5X!- [wherein X1 is as hereinbefore defined and R5 is selected from one of the following twenty groups: 1) Cι-3alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C2-3alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino; 2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3- methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3- (N,N-dimethylcarbamoyloxy)ρropyl, 2-(N-methylcarbamoyloxy)ethyl, 3 -(N- methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl, or 2-(N- methyl-N-(butoxycarbonyl)amino)ethyl; 3) C2-3alkylX3R16 (wherein X3 is as hereinbefore defined and R16 is a group selected from Cι_ 3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl and tetrahydropyranyl which group is linked to X3 through a carbon atom and which Cι-3alkyl group may bear 1 or 2 substituents selected from hydroxy, halogeno and Ci- 2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl or tetrahydropyranyl group may bear one substituent selected from oxo, hydroxy, halogeno, cyano, Cι_2cyanoalkyl,
Figure imgf000025_0001
Cι-2alkoxy, Ci- 2alkoxyCι- alkyl, Cι.2alkylsulρhonylCι. alkyl,
Figure imgf000025_0002
Cι-3alkylamino, di(Cι- 3alkyl)amino, Cι.3alkylaminoCι-3alkyl, di(Cι-3alkyl)aminoCι-3alkyl, Cι.3alkylaminoCι.3alkoxy, di(Cι.3alkyl)aminoCι.3alkoxy and a group -(-O-)f(Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino));
4) C2-3alkylX4C2-3alkylX5R22 (wherein X4 and X5 are as hereinbefore defined and R22 represents hydrogen or d_2alkyl);
5) R28 (wherein R28 is as defined hereinbefore); 6) Cι_3alkylR59 (wherein R59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, imidazolidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to Cι-3alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι.2cyanoalkyl, d- 2alkyl, Cι.2hydroxyalkyl, Cι-2alkoxy, C^alkanoyl, Cι.2al oxyCι.3al yl, Cι-2alkylsulphonyl, Cι-2ailcylsulphonylCι-3alkyl, Cι.2alkoxycarbonyl, Cι-3alkylamino, di(Cι.3alkyl)amino, Cι_ 3alkylaminoCι-3alkyl, di(Cι- alkyl)aminoCι.3alkyl, d-3alkylaminoCι-3alkoxy, di(Cι- 3alkyl)arninoCι-3alkoxy and a group -(-O-)f(Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino)) or d^alkylR60 (wherein R60 is a group selected from moφholino, thiomoφholino, azetidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, d- 5 2cyanoalkyl,
Figure imgf000026_0001
Cι-2hydroxyalkyl,
Figure imgf000026_0002
Cι.2alkanoyl, Cι. alkoxyCι-3alkyl, Ci- 2alkylsulphonyl, Cι-2alkylsulphonylCι-3alkyl, Cι.2alkoxycarbonyl, Cι-3alkylamino, di(Cι- 3alkyl)amino, Cι.3alkylaminoCι-3alkyl, di(Cι-3alkyl)aminoCι-3alkyl, Cι-3alkylaminoCι.3alkoxy, di(Cι-3alkyl)aminoCι-3alkoxy and a group -(-O-)f(Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, 10 piperidinyl, azetidinyl, moφholino and thiomoφholino));
7) R29 (wherein R29 is as defined hereinbefore);
8) Cι_ alkylR29 (wherein R29 is as defined hereinbefore);
9) l-R29but-2-en-4-yl (wherein R29 is as defined hereinbefore);
10) l-R29but-2-yn-4-yl (wherein R29 is as defined hereinbefore);
15 11) d-3alkylX R (wherein X and R are as defined hereinbefore);
12) l-(R29X7)but-2-en-4-yl (wherein X7 and R29 are as defined hereinbefore);
13) l-(R29X8)but-2-yn-4-yl (wherein X8 and R29 are as defined hereinbefore);
14) C2-3arkylX9Ci.3alkylR29 (wherein X9 and R29 are as defined hereinbefore);
15) C2-3alkylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
20 16) C2-5alkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- 4alkylamino, N,N-di(Cι.4alkyl)amino, aminosulphonyl, N-Cι-4alkylaminosulphonyl and N,N- di(Cι- alkyl)aminosulphonyl;
17) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more 25 fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Cι_
4alkylamino, N,N-di(d-4alkyl)amino, aminosulphonyl, N-Cι. alkylaminosulphonyl and N,N- di(Cι.4alkyl)aminosulphonyl;
18) C2.3alkenylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
19) C2_3alkynylX9Ci.3alkylR28 (wherein X9 and R28 are as defined hereinbefore); and 30 20) Cι_3alkylR54(Cι-3alkyl)q(X9)rR55 (wherein X9, q, r, R54 and R55 are as defined hereinbefore); and additionally wherein any Cι-5alkyl, C2.5alkenyl or C2-5alkynyl group in R5Xl- may bear one or more substituents selected from hydroxy, halogeno and amino]. More preferably R2 represents hydroxy, trifluoromethyl,
Figure imgf000027_0001
amino or R5X1- [wherein X1 is as hereinbefore defined and R5 represents methyl, ethyl, benzyl, trifluoromethyl, 2,2,2- trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-
(ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2- sulphamoylethyl, 2-(methylamino)ethyl, 3~(methylamino)propyl, 2-(ethylamino)ethyl, 3- (ethylamino)propyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-(N,N- diethylamino)ethyl, 3-(N,N-diethylamino)propyl, 2-(N-methyl-N- methylsulphonylamino)ethyl, 3-(N-methyl-N-methylsulphonylamino)propyl, 2- moφholinoethyl, 3-moφholinoρropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (methylpiperidino)ethyl, 3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl, 3- (ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl, 3 -((2- methoxyethyl)piperidino)propyl, 2-((2-methylsulphonyl)ethylpiρeridino)ethyl, 3-((2- methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, 2- (piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl, 3-(piperidin-4- yl)propyl, 2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl, (l-methylpiperidin-3-yl)methyl, (l-methylpiperidin-4-yl)methyl, 2-(4-hydroxypiperidino)ethyl, 3-(4-hydroxypiperidino)propyl, (1 -cyanomethylpiperidin-3-yl)methyl, (1 -cyanomethylpiperidin-4-yl)methyl, 2- (methylpiperidin-3-yl)ethyl, 2-(methylpiperidin-4-yl)ethyl, 2-(l-cyanomethylpiperidin-3- yl)ethyl, 2-(l-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl, 3- (methylpiperidin-4-yl)propyl, 3 -( 1 -cyanomethylpiperidin-3 -yl)propyl, 3 -( 1 - cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperidin-4-yl)ethyl, 3- (ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3- yl)methyl, ((2-methoxyethyl)piperidin-4-yl)methyl, 2-((2-methoxyethyl)piperidin-3-yl)ethyl, 2-((2-methoxyethyl)piperidin-4-yl)ethyl, 3-((2-methoxyethyl)piρeridin-3-yl)propyl, 3-((2- methoxyethyl)piperidin-4-yl)propyl, (l-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (l-(2- methylsulphonylethyl)piperidin-4-yl)methyl, 2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl, 2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3- yl)propyl, 3-((2-methylsulphonylethyl)piperidin-4-yl)propyl, l-isopropylpiperidin-2-ylmethyl, 1 -isopropylpiperidin-3-ylmethyl, 1 -isopropylpiperidin-4-ylmethyl, 2-(l -isopropylpiperidin-2- yl)ethyl, 2-(l-isopropylpiρeridin-3-yl)ethyl, 2-(l-isopropylpiperidin-4-yl)ethyl, 3-(l- isopropylpiperidin-2-yl)propyl, 3-(l-isopropylρiperidin-3-yl)propyl, 3-(l-isopropylpiρeridin- 4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(l- (cyanomethyl)piperidin-4-yloxy)ethyl, 3-( 1 -(cyanomethyl)piperidin-4-yloxy)propyl, 2-( 1 -(2- cyanoethyl)piperidin-4-yloxy)ethyl, 3-(l -(2-cyanoethyl)piperidin-4-yloxy)propyl, 2- (piperazin-l-yl)ethyl, 3-(piperazin-l-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-l- yl)ethyl, 3-(pyrrolidin-l-yl)propyl, (2-oxo-tefrahydro-2H-pyrrolidin-5-yl)methyl, 5(R)-(2-oxo- tetrahydro-2H-pyrrolidin-5-yl)methyl, (5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3- dioxolan-2-yl)methyl, 2-(l,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(N-(2- methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2- methoxyethylamino)propyl, 3-(N-(2-methoxyethyl)-N-methylamino)propyl, 3-(2- hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1- methylimidazol-2-ylmethyl, 2-(imidazol-l-yl)ethyl, 2-(2-methylimidazol-l-yl)ethyl, 2-(2- ethylimidazol-l-yl)ethyl, 3-(2-methylimidazol-l-yl)propyl, 3-(2-ethylimidazol-l-yl)propyl, 2- (l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4-triazol-l-yl)ethyl, 2-(l,2,4- triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, 3-pyridylmethyl, 2- (3-pyridyl)ethyl, 3-(3-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4- oxo- 1 ,4-dihydro- 1 -pyridyl)ethyl, 2-(2-oxo-imidazolidin- 1 -yl)ethyl, 3 -(2-oxo-imidazolidin- 1 - yl)propyl, 2-thiomoφholinoethyl, 3-thiomoφholinopropyl, 2-(l,l-dioxothiomoφholino)ethyl, 3-(l , 1 -dioxothiomoφholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin- 1 - yl)ethyl, 3-(4-methylpiperazin-l-yl)propyl, 2-(4-cyanomethylpiperazin-l-yl)ethyl, 3-(4- cyanomethylpiperazin- 1 -yl)propyl, 2-(4-acetylpiperazin- 1 -yl)ethyl, 3-(4-acetylpiperazin- 1 - yl)propyl, 2-(4-methylsulphonylpiperazin-l-yl)ethyl, 3-(4-methylsulphonylpiperazin-l- yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3- (ethylsulphonyl)propyl, 2-(5-methyl-l,2,4-triazol-l-yl)ethyl, moφholino, 2-((N-(l- methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-moφholinopropylsulphonyl)- N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomoφholino)propyl, 2-(2-(4-methylpiperazin-l-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-l-yl)ethoxy)propyl, 2-(2- moφholinoethoxy)ethyl, 3-(2-moφholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3- (tetrahydropyran-4-yloxy)propyl, 2-((2-(pyrrolidin- 1 -yl)ethyl)carbamoyl)vinyl, 3-((2- (pyrrolidin- 1 -yl)ethyl)carbamoyl)prop-2-en- 1 -yl, 1 -(2-pyrrolidinylethyl)piperidin-4-ylmethyl, l-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl, l-(2-piperidinylethyl)piperidin-4-ylmethyl, l-(3- piperidinylpropyl)piperidin-4-ylmethyl, 1 -(2-moφholinoethyl)piperidin-4-ylmethyl, 1 -(3- moφholinopropyl)piperidin-4-ylmethyl, l-(2-thiomoφholinoethyl)piperidin-4-ylmethyl, l-(3- thiomoφholinopropyl)piperidin-4-ylmethyl, l-(2-azetidinylethyl)piperidin-4-ylmethyl, 1 -(3- azetidinylpropyl)piperidin-4-ylmethyl, 2-(l -(2-ρyrrolidinylethyl)piperidin-4-yl)ethyl, 2-(l -(3- pyrrolidinylpropyl)piperidin-4-yl)ethyl, 2-(l-(2-piperidinylethyl)piperidin-4-yl)ethyl, 2-(l-(3- piperidinylpropyl)piperidin-4-yl)ethyl, 2-(l-(2-moφholinoethyl)piperidin-4-yl)ethyl, 2-(l-(3- moφholinopropyl)piperidin-4-yl)ethyl, 2-( 1 -(2-thiomoφholinoethyl)piperidin-4-yl)ethyl, 2- (l-(3-thiomoφholinopropyl)piperidin-4-yl)ethyl, 2-(l-(2-azetidinylethyl)piperidin-4-yl)ethyl, 2-(l -(3-azetidinylpropyl)piperidin-4-yl)ethyl, 3-moφholino-2-hydroxypropyl, (2R)-3- moφholino-2 -hydroxypropyl, (2S)-3-moφholino-2-hydroxypropyl, 3-piperidino-2- hydroxypropyl, (2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl, 3- pyrrolidin- 1 -yl-2-hydroxypropyl, (2R)-3-pyrrolidin- 1 -yl-2-hydroxypropyl, (2S)-3 -pyrrolidin- 1 - yl-2-hydroxypropyl, 3 -(1 -methylpiperazin-4-yl)-2 -hydroxypropyl, (2R)-3 -( 1 -methylpiperazin- 4-yl)-2-hydroxypropyl, (2S)-3-(l-methylpiperazin-4-yl)-2-hydroxypropyl, 3-(N,N- diethylamino)-2-hydroxypropyl, (2R)-3-(N,N-diethylamino)-2-hydroxypropyl, (2S)-3-(N,N- diethylamino)-2-hydroxypropyl, 3-(isopropylamino)-2-hydroxypropyl, (2R)-3-
(isopropylamino)-2-hydroxypropyl, (2S)-3-(isopropylamino)-2-hydroxypropyl, 3-(N,N- diisopropylamino)-2-hydroxypropyl, (2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or (2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].
Particularly R2 represents trifluoromethyl,
Figure imgf000029_0001
amino or R5X1- [wherein X1 is as hereinbefore defined and R5 represents ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2- (ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2- sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)ethyl, 3- (ethylamino)propyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-(N,N- diethylamino)ethyl, 3-(N,N-diethylamino)propyl, 2-(N-methyl-N- methylsulphonylamino)ethyl, 3-(N-methyl-N-methylsulphonylamino)propyl, 2- moφholinoethyl, 3-moφholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (methylpiperidino)ethyl, 3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl, 3- (ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl, 3-((2- methoxyethyl)piρeridino)propyl, 2-((2-methylsulphonyl)ethylρiρeridino)ethyl, 3-((2- methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, 2- (piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl, 3-(ρiρeridin-3-yl)propyl, 3-(piperidin-4- yl)propyl, 2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl, (l-methylpiperidin-3-yl)methyl, (l-methylpiperidin-4-yl)methyl, 2-(4-hydroxypiperidino)ethyl, 3-(4-hydroxypiperidino)propyl, (l-cyanomethylpiperidin-3-yl)methyl, (l-cyanomethylpiperidin-4-yl)methyl, 2- (methylpiperidin-3-yl)ethyl, 2-(methylpiperidin-4-yl)ethyl, 2-(l-cyanomethylpiperidin-3- yl)ethyl, 2-(l-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl, 3- (methylpiperidin-4-yl)propyl, 3-(l -cyanomethylpiperidin-3-yl)propyl, 3-(l - cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperidin-4-yl)ethyl, 3- (ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3- yl)methyl, ((2-methoxyethyl)piperidin-4-yl)methyl, 2-((2-methoxyethyl)piperidin-3-yl)ethyl, 2-((2-methoxyethyl)piperidin-4-yl)ethyl, 3-((2-methoxyethyl)piρeridin-3-yl)ρropyl, 3-((2- methoxyethyl)piperidin-4-yl)propyl, (l-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (l-(2- methylsulphonylethyl)piperidin-4-yl)methyl, 2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl, 2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3- yl)propyl, 3-((2-methylsulphonylethyl)piperidin-4-yl)propyl, l-isopropylpiperidin-2-ylmethyl, l-isopropylpiperidin-3-ylmethyl, l-isopropylpiperidin-4-ylmethyl, 2-(l-isopropylpiperidin-2- yl)ethyl, 2-(l-isopropylpiperidin-3-yl)ethyl, 2-(l-isopropylpiperidin-4-yl)ethyl, 3-(l- isopropylpiperidin-2-yl)propyl, 3-(l-isopropylpiperidin-3-yl)propyl, 3-(l-isopropylpiperidin- 4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(l- (cyanomethyl)piperidin-4-yloxy)ethyl, 3-(l-(cyanomethyl)piperidin-4-yloxy)propyl, 2-(l-(2- cyanoethyl)piperidin-4-yloxy)ethyl, 3-(l -(2-cyanoethyl)piperidin-4-yloxy)propyl, 2- (piperazin-l-yl)ethyl, 3-(piperazin-l-yl)propyl, (pyrrohdin-2-yl)methyl, 2-(pyrrolidin-l- yl)ethyl, 3-(pyrrolidin-l-yl)propyl, (2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, 5(R)-(2-oxo- tetrahydro-2H-pyrrolidin-5-yl)methyl, (5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1 ,3- dioxolan-2-yl)methyl, 2-(l,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(N-(2- methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2- methoxyethylamino)propyl, 3-( -(2-methoxyethyl)-N-methylamino)propyl, 3-(2- hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1- methylimidazol-2-ylmethyl, 2-(imidazol-l-yl)ethyl, 2-(2-methylimidazol-l-yl)ethyl, 2-(2- ethylimidazol-l-yl)ethyl, 3-(2-methylimidazol-l-yl)propyl, 3-(2-ethylimidazol-l-yl)propyl, 2- (l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4-triazol-l-yl)ethyl, 2-(l,2,4- triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, 3-pyridylmethyl, 2- (3-pyridyl)ethyl, 3-(3-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4- oxo- 1 ,4-dihydro- 1 -pyridyl)ethyl, 2-(2-oxo-imidazolidin- 1 -yl)ethyl, 3-(2-oxo-imidazolidin- 1 - yl)propyl, 2-thiomoφholinoethyl, 3-thiomoφholinopropyl, 2-(l,l-dioxothiomoφholino)ethyl, 3-(l,l-dioxothiomoφholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-l- yl)ethyl, 3-(4-methylpiperazin-l-yl)propyl, 2-(4-cyanomethylpiperazin-l-yl)ethyl, 3-(4- cyanomethylpiperazin- 1 -yl)propyl, 2-(4-acetylpiperazin- 1 -yl)ethyl, 3-(4-acetylpiperazin- 1 - yl)propyl, 2-(4-methylsulphonylρiperazin- 1 -yl)ethyl, 3 -(4-methylsulphonylpiperazin- 1 - yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3- (ethylsulphonyl)propyl, 2-(5-methyl-l,2,4-triazol-l-yl)ethyl, moφholino, 2-((N-(l- methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-moφholinopropylsulphonyl)- N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomoφholino)propyl, 2-(2-(4-methylpiperazin- 1 -yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin- 1 -yl)ethoxy)propyl, 2-(2- moφholinoethoxy)ethyl, 3-(2-moφholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3- (tetrahydropyran-4-yloxy)propyl, 2-((2-(pyrrolidin-l-yl)ethyl)carbamoyl)vinyl, 3-((2- (pyrrolidin- 1 -yl)ethyl)carbamoyl)prop-2-en- 1 -yl, 1 -(2-pyrrolidinylethyl)piperidin-4-ylmethyl, 1 -(3-pyrrolidinylpropyl)piperidin-4-ylmethyl, 1 -(2-piperidinylethyl)piperidin-4-ylmethyl, 1 -(3- piperidinylpropyl)piperidin-4-ylmethyl, 1 -(2-moφholinoethyl)piperidin-4-ylmethyl, 1 -(3- moφholinopropyl)piperidin-4-yhnethyl, l-(2-thiomoφholinoethyl)piperidin-4-ylmethyl, l-(3- thiomoφholinopropyl)piperidin-4-ylmethyl, 1 -(2-azetidinylethyl)piperidin-4-ylmethyl, 1 -(3- azetidinylpropyl)piperidin-4-ylmethyl, 2-(l-(2-pyrrolidinylethyl)piperidin-4-yl)ethyl, 2-(l-(3- pyrrolidinylpropyl)piperidin-4-yl)ethyl, 2-(l-(2-piperidinylethyl)piperidin-4-yl)ethyl, 2-(l-(3- piperidinylpropyl)piperidin-4-yl)ethyl, 2-(l -(2-moφholinoethyl)piperidin-4-yl)ethyl, 2-(l -(3- moφholinopropyl)piperidin-4-yl)ethyl, 2-( 1 -(2-thiomoφholinoethyl)piperidin-4-yl)ethyl, 2- (l-(3-thiomoφholinopropyl)piperidin-4-yl)ethyl, 2-(l-(2-azetidinylethyl)piperidin-4-yl)ethyl, 2-(l-(3-azetidinylpropyl)piperidin-4-yl)ethyl, 3-moφholino-2-hydroxypropyl, (2R)-3- moφholino-2-hydroxypropyl, (2S)-3-moφholino-2-hydroxypropyl, 3-piperidino-2- hydroxypropyl, (2R)-3-piperidino-2-hydroxypiOpyl, (2S)-3-piperidino-2-hydroxypropyl, 3- pyrrolidin- 1 -yl-2-hydroxypropyl, (2R)-3 -pyrrolidin- 1 -yl-2-hydroxypropyl, (2S)-3 -pyrrolidin- 1 - yl-2 -hydroxypropyl, 3-(l -methylpiperazin-4-yl)-2 -hydroxypropyl, (2R)-3-(l -methylpiperazin- 4-yl)-2-hydroxypropyl, (2S)-3-(l-methylpiperazin-4-yl)-2-hydroxypropyl, 3-(N,N- diethylamino)-2-hydroxypropyl, (2R)-3-(N,N-diethylamino)-2-hydroxypropyl, (2S)-3-Q^,N- diethylamino)-2-hydroxypropyl, 3-(isopropylamino)-2-hydroxypropyl, (2R)-3- (isopropylamino)-2-hydroxypropyl, (2S)-3-(isopropylamino)-2-hydroxypropyl, 3-(N,N- diisopropylamino)-2-hydroxypropyl, (2R)-3 -(N,N-diisopropylamino)-2-hydiOxypropyl or (2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].
More particularly R2 represents trifluoromethyl, Ci^alkyl, amino or R5X1- [wherein X1 is as hereinbefore defined and R5 represents ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2- hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,N- dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2- (N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl, 3- (N,N-diethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl, 3-(N-methyl-N- methylsulphonylamino)propyl, 2-moφholinoethyl, 3-moφholinopropyl, 2-piperidinoethyl, 3- piperidinopropyl, 2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl, 2- (ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl, 3-((2- methoxyethyl)piperidino)propyl, 2-((2-methylsulphonyl)ethylρiperidino)ethyl, 3-((2- methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, 2- (piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl, 3-(piperidin-4- yl)ρropyl, 2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl, (l-methylpiperidin-3-yl)methyl, (1 -methylpiperidin-4-yl)methyl, 2-(4-hydroxypiperidino)ethyl, 3-(4-hydroxypiperidino)propyl, (l-cyanomethylpiperidin-3-yl)methyl, (l-cyanomethylpiperidin-4-yl)methyl, 2-
(methylpiperidin-3-yl)ethyl, 2-(methylpiperidin-4-yl)ethyl, 2-(l-cyanomethylpiperidin-3- yl)ethyl, 2-(l-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl, 3- (methylpiperidin-4-yl)propyl, 3-(l-cyanomethylpiperidin-3-yl)propyl, 3-(l- cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperidin-4-yl)ethyl, 3- (ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3- yl)methyl, ((2-methoxyethyl)piperidin-4-yl)methyl, 2-((2-methoxyethyl)piperidin-3-yl)ethyl, 2-((2-methoxyethyl)piperidin-4-yl)ethyl, 3-((2-methoxyethyl)piperidin-3-yl)propyl, 3-((2- methoxyethyl)piperidin-4-yl)propyl, (l-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (l-(2- methylsulphonylethyl)piperidin-4-yl)methyl, 2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl, 2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3- yl)propyl, 3 -((2-methylsulphonylethyl)piperidin-4-yl)propyl, 1 -isopropylpiperidin-2-ylmethyl, l-isopropylρiρeridin-3-ylmethyl, l-isopropylpiperidin-4-ylmethyl, 2-(l-isopropylpiperidin-2- yl)ethyl, 2-(l-isopropylpiρeridin-3-yl)ethyl, 2-(l-isopropylpiperidin-4-yl)ethyl, 3-(l- isopropylpiperidin-2-yl)propyl, 3-(l-isopropylpiperidin-3-yl)propyl, 3-(l-isopropylpiperidin- 4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(l- (cyanomethyl)piperidin-4-yloxy)ethyl, 3-(l-(cyanomethyl)piperidin-4-yloxy)propyl, 2-(l-(2- cyanoethyl)piperidin-4-yloxy)ethyl, 3-(l-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2- (piperazin-l-yl)ethyl, 3-(piperazin-l-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-l- yl)ethyl, 3 -(pyrrolidin- l-yl)propyl, (2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, 5(R)-(2-oxo- tetrahydro-2H-pyrrolidin-5-yl)methyl, (5S)-(2-oxo-tetrahydro-2H-pyrrolidm-5-yl)methyl, (1 ,3- dioxolan-2-yl)methyl, 2-(l,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(N-(2- methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2- methoxyethylamino)propyl, 3-(N-(2-methoxyethyl)-N-methylamino)propyl, 3-(2- hydroxyethylamino)propyl, 2-(l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4- triazol-l-yl)ethyl, 2-(l,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4- pyridyl)propyl, 3-pyridylmethyl, 2-(3-pyridyl)ethyl, 3-(3-pyridyl)propyl, 2-(4- pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4-oxo- 1 ,4-dihydro- 1 -pyridyl)ethyl, 2-(2-oxo~ imidazolidin-l-yl)ethyl, 3-(2-oxo-imidazolidin-l-yl)propyl, 2-thiomoφholinoethyl, 3- thiomoφholinopropyl, 2-(l,l-dioxothiomoφholino)ethyl, 3-(l,l-dioxothiomoφholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-l-yl)ethyl, 3-(4-methylpiperazin-l-yl)propyl, 2-(4-cyanomethylpiperazin-l-yl)ethyl, 3-(4-cyanomethylpiperazin-l-yl)ρropyl, 2-(4- acetylpiperazin- 1 -yl)ethyl, 3 -(4-acetylpiperazin- 1 -yl)propyl, 2-(4-methylsulphonylpiperazin- 1 - yl)ethyl, 3-(4-methylsulphonylpiperazin-l-yl)propyl, 3-(methylsulphinyl)propyl, 3- (methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl, 2-(5-methyl- l,2,4-triazol-l-yl)ethyl, moφholino, 2-((N-(3-moφholinopropylsulphonyl)-N- methyl)amino)ethyl, 2-((K-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomoφholino)propyl, 2- (2-(4-methylpiperazin-l-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-l-yl)ethoxy)propyl, 2-(2- moφholinoethoxy) ethyl, 3-(2-moφholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3- (tetrahydropyran-4-yloxy)propyl, 2-((2-(pyrrolidin-l-yl)ethyl)carbamoyl)vinyl, 3-((2- (pyrrolidin- 1 -yl)ethyl)carbamoyl)prop-2-en- 1 -yl, 1 -(2-pyrrolidinylethyl)piperidin-4-ylmethyl, l-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl, l-(2-piperidinylethyl)piρeridin-4-ylmethyl, l-(3- piρeridinylpropyl)piperidin-4-ylmethyl, l-(2-moφholinoethyl)piperidin-4-ylmethyl, l-(3- moφholinopropyl)piperidin-4-ylmethyl, l -(2-thiomoφholinoethyl)piperidin-4-ylmethyl, 1 -(3 - tl iomoφholinopropyl)piperidin-4-ylmethyl, 1 -(2-azetidinylethyl)piperidin-4-ylmethyl, 1 -(3- azetidinylpropyl)piρeridin-4-ylmethyl, 2-(l-(2-pyrrolidinylethyl)piperidin-4-yl)ethyl, 2-(l-(3- pyrrolidinylpropyl)piperidin-4-yl)ethyl, 2-(l-(2-piperidinylethyl)piperidin-4-yl)ethyl, 2-(l-(3- piperidinylpropyl)piperidin-4-yl)ethyl, 2-(l-(2-moφholinoethyl)piperidin-4-yl)ethyl, 2-(l-(3- moφholinopropyl)piperidin-4-yl)ethyl, 2-( 1 -(2-thiomoφholinoethyl)piperidin-4-yl)ethyl, 2- ( 1 -(3 -thiomoφholinopropyl)piperidin-4-yl)ethyl, 2-( 1 -(2-azetidinylethyl)piperidin-4-yl)ethyl, 2-(l-(3-azetidinylpiOpyl)piperidin-4-yl)ethyl, 3-moφholino-2-hydroxypropyl, (2R)-3- moφholino-2-hydroxypropyl, (2S)-3-moφholino-2-hydroxypropyl, 3-piperidino-2- hydroxypropyl, (2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl, 3- pyrrolidin-l-yl-2-hydroxypropyl, (2R)-3-ρyrrolidin-l-yl-2-hydroxypropyl, (2S)-3-pyrrolidin-l- yl-2-hydroxypropyl, 3-(l-methylpiperazin-4-yl)-2-hydroxypropyl, (2R)-3-(l-methylpiperazin- 4-yl)-2-hydroxypropyl, (2S)-3-(l-methylpiperazin-4-yl)-2-hydroxypropyl, 3-(N,N- diethylamino)-2-hydroxypropyl, (2R)-3-(N,N-diethylamino)-2-hydroxypropyl, (2S)-3-(N,N- diethylamino)-2-hydroxypropyl, 3-(isopropylamino)-2-hydroxypropyl, (2R)-3- (isopropylamino)-2-hydroxypropyl, (2S)-3-(isopropylamino)-2-hydroxypropyl, 3-(N,N- diisopropylamino)-2-hydroxypropyl, (2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or (2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl]. hi another aspect R2 represents trifluoromethyl, ethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-(methylsulphinyl)ethoxy, 2-(methylsulphonyl)ethoxy, 2-(ethylsulphinyl)ethoxy, 2- (ethylsulphonyl)ethoxy, 2-(N,N-dimethylsulphamoyl)ethoxy, 2-(N-methylsulphamoyl)ethoxy, 2-sulphamoylethoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, 2- (ethylamino)ethoxy, 3-(ethylamino)propoxy, 2-(N,N-dimethylamino)ethoxy, 3-(N,N- dimethylamino)propoxy, 2-(N,N-diethylamino)ethoxy, 3-(N,N-diethylamino)propoxy, 2-(N- methyl-N-methylsulphonylamino)ethoxy, 3-(N-methyl-N-methylsulphonylamino)propoxy, 2- moφholinoethoxy, 3-moφholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2- (methylpiperidino)ethoxy, 3-(methylpiperidino)propoxy, 2-(ethylpiperidino)ethoxy, 3- (ethylpiperidino)propoxy, 2-((2-methoxyethyl)piperidino)ethoxy, 3 -((2- methoxyethyl)piperidino)propoxy, 2-((2-methylsulphonyl)ethylpiperidino)ethoxy, 3-((2- methylsulphonyl)ethylpiperidino)propoxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2- (piperidin-3-yl)ethoxy, 2-(piperidin-4-yl)ethoxy, 3-(piperidin-3-yl)propoxy, 3-(piperidin-4- yl)propoxy, 2-(piperidin-2-yl)ethoxy, 3-(piperidin-2-yl)propoxy, (l-methylpiperidin-3- yl)methoxy, (l-methylρiρeridin-4-yl)methoxy, 2-(4-hydroxypiperidino)ethoxy, 3-(4- hydroxypiperidino)propoxy, (l-cyanomethylpiperidin-3-yl)methoxy, (1- cyanomethylpiperidin-4-yl)methoxy, 2-(methylpiperidin-3-yl)ethoxy, 2-(methylpiperidin-4- yl)ethoxy, 2-(l-cyanomethylpiperidin-3-yl)ethoxy, 2-(l-cyanomethylpiperidin-4-yl)ethoxy, 3- (methylpiperidin-3-yl)propoxy, 3-(methylpiperidin-4-yl)propoxy, 3-(l -cyanomethylpiperidin- 3-yl)ρropoxy, 3-(l-cyanomethylpiperidin-4-yl)propoxy, 2-(ethylpiperidin-3-yl)ethoxy, 2- (ethylpiperidin-4-yl)ethoxy, 3-(ethylpiperidin-3-yl)propoxy, 3-(ethylpiperidin-4-yl)propoxy, ((2-methoxyethyl)piperidin-3 -yl)methoxy, ((2-methoxyethyl)piperidin-4-yl)methoxy, 2-((2- methoxyethyl)piperidin-3-yl)ethoxy, 2-((2-methoxyethyl)piperidin-4-yl)ethoxy, 3-((2- methoxyethyl)piperidin-3-yl)ρropoxy, 3-((2-methoxyethyl)piperidin-4-yl)piOpoxy, (l-(2- methylsulphonylethyl)ρiperidin-3 -yl)methoxy, ( 1 -(2-methylsulphonylethyl)ρiperidin-4- yl)methoxy, 2-((2-methylsulphonylethyl)piperidin-3-yl)ethoxy, 2-((2- methylsulphonylethyl)piperidin-4-yl)ethoxy, 3-((2-methylsulphonylethyl)piperidin-3- yl)propoxy, 3 -((2-methylsulphonylethyl)piperidin-4-yl)propoxy, 1 -isoρroρylρiperidin-2- ylmethoxy, l-isopropylpiperidin-3-ylmethoxy, l-isopropylpiperidin-4-ylmethoxy, 2-(l- isopropylpiperidin-2-yl)ethoxy, 2-(l-isopropylpiperidin-3-yl)ethoxy, 2-(l-isopropylpiperidin- 4-yl)ethoxy, 3-(l-isopropylpiperidin-2-yl)propoxy, 3-(l-isopropylpiperidin-3-yl)propoxy, 3- (1 -isopropylpiperidin-4-yl)propoxy, 2-(piperidin-4-yloxy)ethoxy, 3-(piperidin-4- yloxy)propoxy, 2-(l-(cyanomethyl)piperidin-4-yloxy)ethoxy, 3-(l-(cyanomethyl)piperidin-4- yloxy)propoxy, 2-(l-(2-cyanoethyl)piperidin-4-yloxy)ethoxy, 3-(l-(2-cyanoethyl)piperidin-4- yloxy)propoxy, 2-(piperazin-l-yl)ethoxy, 3-(piperazin-l-yl)propoxy, (pyrrolidin-2- yl)methoxy, 2-(pyrrolidin-l-yl)ethoxy, 3 -(pyrrolidin- l-yl)propoxy, (2-oxo-tetrahydro-2H- pyrrolidin-5-yl)methoxy, 5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy, (5S)-(2-oxo- tetrahydro-2H-pyrrolidin-5-yl)methoxy, (l,3-dioxolan-2-yl)methoxy, 2-(l,3-dioxolan-2- yl)ethoxy, 2-(2-methoxyethylamino)ethoxy, 2-(N-(2-methoxyethyl)-N-methylamino)ethoxy, 2-(2-hydroxyethylamino)ethoxy, 3-(2-methoxyethylamino)propoxy, 3-(N-(2-methoxyethyl)- N-methylamino)propoxy, 3-(2-hydroxyethylamino)propoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 2- (l,2,3-triazol-2-yl)ethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 2-(l,2,4-triazol-4-yl)ethoxy, 4- pyridylmethyl, 2-(4-pyridyl)ethyl, 4-pyridylmethoxy, 2-(4-pyridyl)ethoxy, 3-(4- pyridyl)propoxy, 3-pyridylmethoxy, 2-(3-pyridyl)ethoxy, 3-(3-pyridyl)propoxy, 2-(4- pyridyloxy)ethoxy, 2-(4-pyridylamino)ethoxy, 2-(4-oxo-l,4-dihydro-l-pyridyl)ethoxy, 2-(2- oxo-imidazolidin- 1 -yl)ethoxy, 3-(2-oxo-imidazolidin- 1 -yl)propoxy, 2-thiomoφholinoethoxy, 3-thiomoφholinopropoxy, 2-(l,l-dioxothiomoφholino)ethoxy, 3-(l,l- dioxothiomoφholino)propoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-methylpiperazin- 1 - yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4- cyanomethylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l- yl)propoxy, 2-(4-methylsulphonylpiperazin- 1 -yl)ethoxy, 3-(4-methylsulphonylpiperazin- 1 - yl)propoxy, 3-(methylsulphinyl)propoxy, 3-(methylsulphonyl)propoxy, 3-
(ethylsulphinyl)propoxy, 3-(ethylsulphonyl)propoxy, 2-(5-methyl-l,2,4-triazol-l-yl)ethoxy, 2- ((K-(3-moφholinopropylsulphonyl)-N-methyl)amino)ethoxy, 2-((N-methyl-N-4- pyridyl)amino)ethoxy, 3 -(4-oxidomoφholino)propoxy, 2-(2-(4-methylpiperazin- 1 - yl)ethoxy)ethoxy, 3-(2-(4-methylpiperazin- 1 -yl)ethoxy)propoxy, 2-(2- moφholinoethoxy)ethoxy, 3-(2-moφholinoethoxy)propoxy, 2-(tetrahydropyran-4- yloxy)ethoxy, 3 -(tetrahydropyran-4-yloxy)propoxy, 2-((2-(pyrrolidin- 1 - yl)ethyl)carbamoyl)vinyl, 3 -((2-(pyrrolidin- 1 -yl)ethyl)carbamoyl)prop-2-en- 1 -yloxy, 1 -(2- pyrrolidinylethyl)piperidin-4-ylmethoxy, l-(3-pyrrolidinylpropyl)piperidin-4-ylmethoxy, l-(2- piperidinylethyl)piperidin-4-ylmethoxy, 1 -(3-piperidinylpropyl)piperidin-4-ylmethoxy, 1 -(2- moφholinoethyl)piperidin-4-ylmethoxy, l-(3-moφholinopropyl)piperidin-4-ylmethoxy, l-(2- thiomoφholinoethyl)piperidin-4~ylmethoxy, l-(3-thiomoφholinopropyl)piperidin-4- ylmethoxy, 1 -(2-azetidinylethyl)piperidin-4-ylmethoxy, 1 -(3-azetidinylpropyl)piperidin-4- ylmethoxy, 2-(l-(2-pyrrolidinylethyl)piperidin-4-yl)ethoxy, 2-(l-(3- pyrrolidinylpropyl)piperidin-4-yl)ethoxy, 2-(l -(2-piperidinylethyl)piperidin-4-yl)ethoxy, 2-(l - (3-piperidinylpropyl)piperidin-4-yl)ethoxy, 2-(l-(2-moφholinoethyl)piperidin-4-yl)ethoxy, 2- (l-(3-moφholinopropyl)piperidin-4-yl)ethoxy, 2-(l-(2-thiomoφholinoethyl)piperidin-4- yl)ethoxy, 2-(l-(3-thiomoφholinopropyl)piperidin-4-yl)ethoxy, 2-(l-(2- azetidinylethyl)piperidin-4-yl)ethoxy, 2-(l-(3-azetidinylpropyl)piperidin-4-yl)ethoxy, 3- moφholino-2-hydroxypropoxy, (2R)-3-moφholino-2-hydroxypropoxy, (2S)-3-moφholino-2- hydroxypropoxy, 3-piperidino-2-hydroxypropoxy, (2R)-3-piperidino-2-hydroxypropoxy, (2S)- 3-piperidino-2-hydroxypropoxy, 3-pyrrolidin-l-yl-2-hydroxypropoxy, (2R)-3-pyrrolidin-l-yl- 2-hydroxypropoxy, (2S)-3-pyrrolidin- 1 -yl-2-hydroxypropoxy, 3 -( 1 -methylpiperazin-4-yl)-2- hydroxypropoxy, (2R)-3-(l-methylpiperazin-4-yl)-2-hydroxypropoxy, (2S)-3-(l- methylpiperazin-4-yl)-2-hydroxypropoxy, 3 -Q^,N-diethylamino)-2-hydroxypropoxy, (2R)-3 - (N,N-diethylamino)-2-hydroxypropoxy, (2S)-3-(N,N-diethylamino)-2-hydroxypropoxy, 3- (isopropylamino)-2-hydroxypropoxy, (2R)-3-(isopropylamino)-2-hydroxypropoxy, (2S)-3- (isopropylamino)-2-hydroxypropoxy, 3-(N,N-diisopropylamino)-2 -hydroxypropoxy, (2R)-3- (N,N-diisopropylamino)-2-hydroxypropoxy or (2S)-3-(N,N-diisopropylamino)-2- hydroxypropoxy.
According to another aspect of the present invention conveniently R2 represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, Ci^alkyl, amino or R5X!- [wherein X1 is as hereinbefore defined and R5 is selected from one of the following twenty-two groups: 1) oxiranylCι.4alkyl or Cι-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or d-salkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino; 2) C2-3alkylX2C(O)R11 (wherein X2 is as hereinbefore defined and R11 represents
Figure imgf000037_0001
- NR13R14 or -OR15 (wherein R13, R14 and R15 which may be the same or different are each Cι_ 4alkyl or Cι-2alkoxyethyl));
3) C2-4alkylX3R16 (wherein X3 is as hereinbefore defined and R16 represents hydrogen, Cι_ 3alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclic group with 1- 2 heteroatoms, selected independently from O, S and N, which Cι-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Cι-3alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι- cyanoalkyl, d- alkyl, Cι.4hydroxyalkyl, Cι_4alkoxy, Cι.4alkoxyCι-4alkyl, Cι-4alkylsulphonylCι-4alkyl, d- 4alkoxycarbonyl, Cι. alkylamino, di(Cι-4alkyl)amino, Cι.4alkylaminoCι_4alkyl, di(Cι. 4alkyl)aminoCι-4alkyl, Cι-4alkylaminoCι.4alkoxy, di(Cι.4alkyl)aminoCι. alkoxy and a group - (-O-)f(Cι- alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι.4alkyl));
4) C2-3alkylX4C2-3alkylX5R22 (wherein X4 and X5 are as hereinbefore defined and R22 represents hydrogen or Cι.3alkyl);
5) R28 (wherein R28 is as defined hereinbefore);
6) Cι.5alkylR56 (wherein R56 is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to Cι-5alkyl through a carbon atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_ cyanoalkyl, Cι.4alkyl, Cι-4hydroxyalkyl, Cι_ alkoxy, Cι-4alkoxyCι-4alkyl, Cι. alkylsulphonylCι.4alkyl, Cι_4alkoxycarbonyl, Ci- 4alkylamino, di(Cι_ alkyl)amino, Cι. alkylaminoCι. alkyl, di(Cι-4alkyl)aminoCι-4alkyl, Ci- 4alkylaminoCι-4alkoxy, di(Cι.4aιkyl)aminoCι.4alkoxy and a group -(-O-)f(Ci.4allcyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι. alkyl)) or d-salkylR57 (wherein R57 is a 4-, 5- 5 or 6-membered saturated heterocyclic group with 1-2 heteroatoms, of which one is N and the other may be selected independently from O, S and N, which heterocyclic group is linked to C2.5alkyl through a nitrogen atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-4cyanoalkyl, Cι_ alkyl, d.4hydroxyalkyl, Cι_ 4alkoxy, Cι-4alkoxyCι.4alkyl, Cι-4alkylsulphonylCι- alkyl, Cι„4alkoxycarbonyl, Cι_
10 4alkylamino, di(Cι.4alkyl)amino, Cι-4alkylaminoCι-4alkyl, di(Cι-4alkyl)aminoCι-4alkyl, d_ 4alkylaminoCι_ alkoxy, di(Cι. alkyl)aminoCι.4alkoxy and a group -(-O-)f(Cι- alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι_4alkyl));
15 7) C3-4alkenylR58 (wherein R58 represents R56 or R57 as defined hereinbefore);
8) C3- alkynylR58 (wherein R58 represents R56 or R57 as defined hereinbefore);
9) R29 (wherein R29 is as defined hereinbefore);
10) Cι_5alkylR29 (wherein R29 is as defined hereinbefore);
11) C3-5alkenylR29 (wherein R29 is as defined hereinbefore); 20 12) C3.5alkynylR29 (wherein R29 is as defined hereinbefore);
13) Cι.5alkylX6R29 (wherein X6 and R29 are as defined hereinbefore);
14) C4.5alkenylX7R29 (wherein X7 and R29 are as defined hereinbefore);
15) C4.5alkynylX8R29 (wherein X8 and R29 are as defined hereinbefore);
16) C2.3alkylX9Cι_3aιkyιR29 (wherein X9 and R29 are as defined hereinbefore); 25 17) C2-3alkylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
18) C2-5alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, Cι-4all ylamino, N,N-di(Cι_4alkyl)amino, aminosulphonyl, N-Cι_ alkylaminosulphonyl and N,N-di(Cι.4alkyl)aminosulphonyl;
19) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more 30 groups selected from hydroxy, fluoro, amino, Cι-4alkylamino, N,N-di(Cι_4alkyl)amino, aminosulphonyl, N-Cι_ alkylaminosulphonyl and N,N-di(Cι_4alkyl)aminosulphonyl;
20) C2-5alkenylX9Ci-3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
21) C2-5alkynylX9d-3alkylR28 (wherein X9 andR28 are as defined hereinbefore); and 22) Cι.3allcylR54(Cι.3alkyl)q(X9)rR55 (wherein X9, q, r, R54 and R55 are as defined hereinbefore); and additionally wherein any Cι_5alkyl, C2-5alkenyl or C2-5alkynyl group in R5X!- may bear one or more substituents selected from hydroxy, halogeno and amino].
According to another aspect of the present invention advantageously R2 represents hydroxy, halogeno, cyano, nitro, trifluoromethyl,
Figure imgf000039_0001
amino or R5Xl- [wherein X1 is as hereinbefore defined and R5 is selected from one of the following twenty-two groups:
1) Cι-4alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or d-salkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
2) C2-3alkylX2C(O)Rπ (wherein X2 is as hereinbefore defined and R11 represents -NR13R14 or -OR15 (wherein R13, R14 and R15 which may be the same or different are each Cι-4alkyl or Cι_ 2alkoxyethyl)); 3) C2-4alkylX R (wherein X is as hereinbefore defined and R is a group selected from Ci- 3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl and tetrahydropyranyl, which Cι-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Cι-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl or tetrahydropyranyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-3cyanoalkyl, Cι-3alkyl, Ci- 3hydroxyalkyl, Cι-3alkoxy, Cι-2alkoxyCι-3alkyl, d-2alkylsulphonylCι-3alkyl, d_ 3alkoxycarbonyl,
Figure imgf000039_0002
di(Cι.3alkyl)amino, Cι-3alkylaminoCι-3alkyl, di(Cι. 3alkyl)aminoCι-3alkyl, d-3alkylaminoCι-3alkoxy, di(Cι-3alkyl)aminoCι-3alkoxy and a group - (-O-)f(Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino, which cyclic group may bear one or more substituents selected from d. 3alkyl));
4) C2-3alkylX4C2-3alkylX5R22 (wherein X4 and X5 are as hereinbefore defined and R22 represents hydrogen or Ci^alkyl); 5) R28 (wherein R28 is as defined hereinbefore);
6) Cι_4alkylR59 (wherein R59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to Cι-4alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_3cyanoalkyl, Ci- 3alkyl, Cι-3hydroxyalkyl, Cualkoxy, Cι-2alkoxyCι.3alkyl, Cι.2alkylsulphonylCι-3alkyl, Ci- 3alkoxycarbonyl, Cι-3alkylamino, di(d-3alkyl)amino, Cι.3alkylaminoCι.3alkyl, di(Cι. 3alkyl)aminoCι-3alkyl, Cι-3alkylaminoCι-3alkoxy, di(d-3alkyl)aminoCι-3alkoxy and a group - (-O-)f(Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino, which cyclic group may bear one or more substituents selected from Ci- 3alkyl)) or C2- alkylR60 (wherein R60 is a group selected from moφholino, thiomoφholino, azetidin-1-yl, pyrrolidin- 1-yl, piperazin-1-yl and piperidino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-3cyanoalkyl, Ci^alkyl, Ci- 3hydroxyalkyl, Cι-3alkoxy, Cι.2al oxyCι.3alkyl, Cι-2alkylsulphonylCι_3alkyl, Ci- 3alkoxycarbonyl, Cι-3alkylamino, di(Cι-3alkyl)amino, Cι_3alkylaminoCι_3alkyl, di(Cι_ 3alkyl)aminoCι-3alkyl, Cι.3alkylaminoCι.3alkoxy, di(Cι-3alkyl)aminoCι-3alkoxy and a group - (-O-)f(Cι-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, moφholino and thiomoφholino, which cyclic group may bear one or more substituents selected from Cι_ salkyl));
7) C3-4alkenylR61 (wherein R61 represents R59 or R60 as defined hereinbefore); 8) C3.4alkynylR61 (wherein R61 represents R59 or R60 as defined hereinbefore);
9) R29 (wherein R29 is as defined hereinbefore);
10) Cι_4alkylR29 (wherein R29 is as defined hereinbefore);
11) l-R29prop-l-en-3-yl or l-R29but-2-en-4-yl (wherein R29 is as defined hereinbefore with the proviso that when R5 is l-R29prop-l-en-3-yl, R29 is linked to the alkenyl group via a carbon atom);
12) l-R29prop-l-yn-3-yl or l-R29but-2-yn-4-yl (wherein R29 is as defined hereinbefore with the proviso that when R5 is l-R29prop-l-yn-3-yl, R29 is linked to the alkynyl group via a carbon atom);
13) Cι-5alkyιX6R29 (wherein X6 and R29 are as defined hereinbefore); 14) l-(R29X7)but-2-en-4-yl (wherein X7 and R29 are as defined hereinbefore);
15) l-(R29X8)but-2-yn-4-yl (wherein X8 and R29 are as defined hereinbefore);
16) C2-3alkylX9Cι.3alkylR29 (wherein X9 andR29 are as defined hereinbefore);
17) C2-3alkylX9d.3alkylR28 (wherein X9 and R28 are as defined hereinbefore); 18) d-salkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- 4alkylamino, N,N-di(Cι-4alkyl)amino, aminosulphonyl, N-Ci-4alkylaminosulphonyl and N,N-
5 di(Cι. alkyl)aminosulphonyl;
19) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Cι_ alkylamino, N,N-di(Cι.4alkyl)amino, aminosulphonyl, N-Cι.4alkylaminosulphonyl and N,N- di(Cι- alkyl)aminosulphonyl;
10 20) C2- alkenylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
21) C2-4alkynylX9Cι.3alkylR28 (wherein X9 and R28 are as defined hereinbefore); and
22) d.3allcylR54(Cι.3alkyl)q(X9)rR55 (wherein X9, q, r, R54 and R55 are as defined hereinbefore); and additionally wherein any Cι_5alkyl, d-salkenyl or C2-5alkynyl group in R5X1- may bear 15 one or more substituents selected from hydroxy, halogeno and amino].
According to another aspect of the present invention preferably R2 represents hydroxy, halogeno, nitro, trifluoromethyl, C^alkyl, cyano, amino or R5X1- [wherein X1 is as hereinbefore defined and R5 is selected from one of the following twenty groups:
1) Chalky! which may be unsubstituted or which may be substituted with one or more groups 0 selected from fluoro, chloro and bromo, or d^alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3- methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3- (N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl, 3 -(N-
25 methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl, or 2-(N- methyl-N-(butoxycarbonyl)amino)ethyl;
3) C2-3alkylX3R16 (wherein X3 is as hereinbefore defined and R16 is a group selected from d- 3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl and tetrahydropyranyl which group is linked to X3 through a carbon atom and
30 which Cι.3alkyl group may bear 1 or 2 substituents selected from hydroxy, halogeno and Ci- 2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl or tetrahydropyranyl group may bear one substituent selected from oxo, hydroxy, halogeno, cyano, Cι_2cyanoalkyl, Cι-2alkyl, Cι-2hydroxyalkyl, d.2alkoxy, d_ 2alkoxyCι-3allcyl, d-2alkylsulphonylCι_3alkyl, Cι.2alkoxycarbonyl, Cι-3alkylamino, di(Cι- 3alkyl)amino, Cι_3alkylaminoCι-3alkyl, di(Cι-3alkyl)aminoCι_3alkyl, Cι-3alkylaminoCι-3alkoxy, di(Cι-3alkyl)aminoCι-3alkoxy and a group -(-O-)f{Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino));
4) C2-3alkylX4C2-3alkylX5R22 (wherein X4 and X5 are as hereinbefore defined and R22 represents hydrogen or Ci^alkyl);
5) R28 (wherein R28 is as defined hereinbefore); 6) Cι_3alkylR59 (wherein R59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, imidazolidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to Cι.3alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_2cyanoalkyl, Cι_ alkyl,
Figure imgf000042_0002
Cι-2alkoxy,
Figure imgf000042_0001
Cι.2alkylsulphonylCι-3alkyl, Ci. 2alkoxycarbonyl, Cι-3alkylamino, di(Cι-3alkyl)amino, Cι-3alkylaminoCι-3alkyl, di(Cι.
3alkyl)aminoCι-3alkyl, Cι-3alkylaminoCι-3alkoxy, di(Cι.3alkyl)aminoCι-3alkoxy and a group - (-O-)f(Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino)) or C2-3alkylR60 (wherein R60 is a group selected from moφholino, thiomoφholino, azetidin- 1 -yl, pyrrolidin- 1 -yl, piperazin- 1 -yl and piperidino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι„2cyanoalkyl, Cι_ 2alkyl,
Figure imgf000042_0003
Cι_2alkoxyCι-3alkyl, d-2alkylsulphonylCι-3alkyl, Ci- 2alkoxycarbonyl, Cι-3alkylamino, di(Cι.3alkyl)amino, Cι-3alkylaminoCι-3alkyl, di(Cι. 3alkyl)aminoCι-3alkyl, Cι-3alkylaminoCι_3alkoxy, di(Cι-3alkyl)aminoCι-3alkoxy and a group - (-O-) (Cι.3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino));
7) R29 (wherein R29 is as defined hereinbefore);
8) Cι.4alkylR29 (wherein R29 is as defined hereinbefore); 9) l-R29but-2-en-4-yl (wherein R29 is as defined hereinbefore);
10) l-R29but-2-yn-4-yl (wherein R29 is as defined hereinbefore);
11) Cι.3alkylX6R29 (wherein X6 and R29 are as defined hereinbefore);
12) l-(R29X7)but-2-en-4-yl (wherein X7 and R29 are as defined hereinbefore); 13) l-(R29X8)but-2-yn-4-yl (wherein X8 and R29 are as defined hereinbefore);
14) C2-3alkylX9Cι_3alkylR29 (wherein X9 and R29 are as defined hereinbefore);
15) C2.3all ylX9C1.3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
5 16) C2-5al enyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- 4alkylamino, N,N-di(Cι.4alkyl)amino, aminosulphonyl, N-Cι-4alkylaminosulphonyl and N,N- di(C i .4alkyl)aminosulphonyl;
17) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more 10 fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Ci- alkylamino, N,N-di(Cι.4alkyl)amino, aminosulphonyl, N-Cι-4alkylaminosulphonyl and N,N- di(C ι.4alkyl)aminosulphonyl;
18) C2-3alkenylX9Cι-3alkylR28 (wherein X9 and R28 are as defined hereinbefore);
19) C2-3alkynylX9Cι-3alkylR28 (wherein X9 and R28 are as defined hereinbefore); and 15 20) d_3alkylR54(Cι.3alkyl)q(X9)rR55 (wherein X9, q, r, R54 and R55 are as defined hereinbefore); and additionally wherein any d_5alkyl, d-salkenyl or d-salkynyl group in R5X!- may bear one or more substituents selected from hydroxy, halogeno and amino].
According to another aspect of the present invention more preferably R2 represents
20 hydroxy, trifluoromethyl,
Figure imgf000043_0001
amino or R5X]- [wherein X1 is as hereinbefore defined and R5 represents methyl, ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2- (methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,N- dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-
25 (methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2- (N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl, 3- (N,N-diethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl, 3 -(N-methyl-N- methylsulphonylamino)propyl, 2-moφholinoethyl, 3-moφholinopropyl, 2-piperidinoethyl, 3- piperidinopropyl, 2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl, 2-
30 (ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl, 3-((2- methoxyethyl)piperidino)propyl, 2-((2-methylsulphonyl)ethylpiperidino)ethyl, 3-((2- methylsulphonyl)ethylpiperidino)propyl, piρeridin-3-ylmethyl, piperidin-4-ylmethyl, 2- (piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl, 3-(ρiperidin-3-yl)propyl, 3-(piperidin-4- yl)propyl, 2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl, (l-methylpiperidin-3-yl)methyl, (1 -methylpiperidin-4-yl)methyl, (1 -cyanomethylpiperidin-3-yl)methyl, (1 - cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl, 2-(methylpiperidin-4- yl)ethyl, 2-(l-cyanomethylpiperidin-3-yl)ethyl, 2-(l-cyanomethylpiperidin-4-yl)ethyl, 3- (methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl, 3-(l-cyanomethylpiperidin-3- yl)propyl, 3-(l-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl, 2- (ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl, ((2- methoxyethyl)piperidin-3-yl)methyl, ((2-methoxyethyl)piperidin-4-yl)methyl, 2-((2- methoxyethyl)piperidin-3-yl)ethyl, 2-((2-methoxyethyl)piperidin-4-yl)ethyl, 3-((2- methoxyethyl)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (1 -(2- methylsulphonylethyl)piperidin-3-yl)methyl, (l-(2-methylsulphonylethyl)piperidin-4- yl)methyl, 2-((2-methylsulphonylethyl)piperidin-3 -yl)ethyl, 2-((2- methylsulphonylethyl)piperidin-4-yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3-yl)propyl, 3-((2-methylsulphonylethyl)piperidin-4-yl)propyl, l-isopropylpiperidin-2-ylmethyl, 1- isopropylpiperidin-3-ylmethyl, l-isopropylpiperidin-4-ylmethyl, 2-(l-isopropylpiperidin-2- yl)ethyl, 2-(l-isopropylpiperidin-3-yl)ethyl, 2-(l-isopropylpiperidin-4-yl)ethyl, 3-(l- isopropylpiperidin-2-yl)propyl, 3-(l-isopropylpiperidin-3-yl)propyl, 3-(l-isopropylpiperidin- 4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(l- (cyanomethyl)piperidin-4-yloxy)ethyl, 3-(l-(cyanomethyl)piperidin-4-yloxy)propyl, 2-(l-(2- cyanoethyl)piρeridin-4-yloxy)ethyl, 3-(l -(2-cyanoethyl)piperidin-4-yloxy)propyl, 2- (ρiperazm-l-yl)ethyl, 3-(piperazin-l-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-l- yl)ethyl, 3 -(pyrrolidin- l-yl)propyl, (2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, 5(R)-(2-oxo- tetrahydro-2H-pyrrolidin-5-yl)methyl, (5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1 ,3- dioxolan-2-yl)methyl, 2-(l,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(N-(2- methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3 -(2- methoxyethylamino)propyl, 3-(N-(2-methoxyethyl)-N-methylamino)propyl, 3-(2- hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1- methylimidazol-2-ylmethyl, 2-(imidazol-l-yl)ethyl, 2-(2-methylimidazol-l-yl)ethyl, 2-(2- ethylimidazol-l-yl)ethyl, 3-(2-methylimidazol-l-yl)propyl, 3-(2-ethylimidazol-l-yl)propyl, 2- (l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4-triazol-l-yl)ethyl, 2-(l,2,4- triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, 2-(4- pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4-oxo-l,4-dihydro-l-pyridyl)ethyl, 2-(2-oxo- imidazolidin-l-yl)ethyl, 3-(2-oxo-imidazolidin-l-yl)propyl, 2-thiomoφholinoethyl, 3- thiomoφholinopropyl, 2-( 1 , 1 -dioxothiomoφholino)ethyl, 3 -( 1 , 1 -dioxothiomoφholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-l-yl)ethyl, 3-(4-methylpiperazin-l-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3- (ethylsulphonyl)propyl, 2-(5-methyl-l,2,4-triazol-l-yl)ethyl, moφholino, 2-((N-(l- methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-moipholinopropylsulphonyl)- N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3 -(4-oxidomoφholino)propyl, 2-(2-(4-methylpiperazin-l-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-l-yl)ethoxy)propyl, 2-(2- moφholinoethoxy)ethyl, 3-(2-moφholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3- (tetrahydropyran-4-yloxy)ρroρyl, 2-((2-(pyrrolidin-l-yl)ethyl)carbamoyl)vinyl, 3-((2- (pyrrolidin- 1 -yl)ethyι)carbamoyl)prop-2~en~ 1 -yl, 1 -(2-pyrrolidinylethyl)piperidin-4-ylmethyl, l-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl, l-(2-piρeridinylethyl)piperidin-4-ylmethyl, l-(3- piperidinylpropyl)piperidin-4-ylmethyl, 1 -(2-moφholinoethyl)piperidin-4-ylmethyl, 1 -(3- moφholinopropyl)piperidin-4-ylmethyl, l-(2-thiomoφholinoethyl)piperidin-4-ylmethyl, l-(3- tlήomoφholinopropyl)piperidin-4-ylmethyl, l-(2-azetidinylethyl)piperidin-4-ylmethyl or l-(3- azetidinylpropyl)piperidin-4-ylmethyl, 3-moφholino-2-hydroxypropyl, (2R)-3-moφholino-2- hydroxypropyl, (2S)-3-moφholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl, (2R)-3- piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl, 3-pyrrolidin-l-yl-2- hydroxypropyl, (2R)-3-pyrrolidin-l-yl-2-hydroxypropyl, (2S)-3-pyrrolidin-l-yl-2- hydroxypropyl, 3-(l-methylpiperazin-4-yl)-2-hydroxypropyl, (2R)-3-(l-methylpiperazin-4-yl)- 2-hydroxyproρyl, (2S)-3-(l-methylpiperazin-4-yl)-2-hydroxypropyl, 3-(N,N-diethylamino)-2- hydroxypropyl, (2R)-3-(N,N-diethylamino)-2-hydroxypropyl, (2S)-3-(N,N-diethylamino)-2- hydroxypropyl, 3-(isopropylamino)-2-hydroxypropyl, (2R)-3-(isopropylamino)-2- hydroxypropyl, (2S)-3-(isopropylamino)-2-hydroxypropyl, 3-(N,N-diisopropylamino)-2- hydroxypropyl, (2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or (2S)-3-(N,N- diisopropylamino)-2-hydroxypropyl].
According to another aspect of the present invention particularly R2 represents trifluoromethyl, Cι-3alkyl, amino or R5XJ- [wherein X1 is as hereinbefore defined and R5 represents ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3- hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2- (methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,N- dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2- (methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2- (N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl, 3- (K,N-diethylamino)proρyl, 2-(N-methyl-N-methylsulphonylamino)ethyl, 3-(N-methyl-N- methylsulphonylamino)propyl, 2-moφholinoethyl, 3-moφholinoρropyl, 2-piperidinoethyl, 3- piperidinopropyl, 2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl, 2- (ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl, 3-((2- methoxyethyl)piperidino)propyl, 2-((2-methylsulphonyl)ethylpiperidino)ethyl, 3-((2- methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, 2- (piperidin-3-yl) ethyl, 2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl, 3-(piperidin-4- yl)propyl, 2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl, (l-methylpiperidin-3-yl)methyl, (l-methylpiperidin-4-yl)methyl, (l-cyanomethylpiperidin-3-yl)methyl, (1- cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl, 2-(methylpiperidin-4- yl)ethyl, 2-(l-cyanomethylpiρeridin-3-yl)ethyl, 2-(l-cyanomethylpiperidin-4-yl)ethyl, 3- (methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl, 3-(l-cyanomethylpiperidin-3- yl)propyl, 3-(l-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl, 2- (ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl, ((2- methoxyethyl)piperidin-3-yl)methyl, ((2-methoxyethyl)piperidin-4-yl)methyl, 2-((2- methoxyethyl)piperidin-3-yl)ethyl, 2-((2-methoxyethyl)piperidin-4-yl)ethyl, 3-((2- methoxyethyl)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (l-(2- methylsulphonylethyl)piperidin-3-yl)methyl, (l-(2-methylsulphonylethyl)piperidin-4- yl)methyl, 2-((2-methylsulphonylethyl)piperidin-3 -yl)ethyl, 2-((2- methylsulphonylethyl)piperidin-4-yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3-yl)propyl, 3 -((2-methylsulphonylethyl)piperidin-4-yl)propyl, 1 -isopropylpiperidin-2-ylmethyl, 1 - isopropylpiperidin-3-ylmethyl, l-isopropylpiperidin-4-ylmethyl, 2-(l-isopropylpiperidin-2- yl)ethyl, 2-(l-isopropylpiperidin-3-yl)ethyl, 2-(l-isopropylpiperidin-4-yl)ethyl, 3-(l- isopropylpiperidin-2-yl)propyl, 3-(l-isopropylpiperidin-3-yl)propyl, 3-(l-isopropylpiperidin- 4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(l- (cyanomethyl)piperidin-4-yloxy)ethyl, 3 -(1 -(cyanomethyl)piperidin-4-yloxy)propyl, 2-(l -(2- cyanoethyl)ρiρeridin-4-yloxy)ethyl, 3-(l-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2- (piperazin-l-yl)ethyl, 3-(ρiperazin-l-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-l- yl)ethyl, 3 -(pyrrolidin- l-yl)propyl, (2-oxo-tetrahydrp-2H-pyrrolidin-5-yl)methyl, 5(R)-(2-oxo- tetrahydro-2H-pyrrolidin-5-yl)methyl, (5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3- dioxolan-2-yl)methyl, 2-(l,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(N-(2- methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3 -(2- methoxyethylamino)propyl, 3 -(N-(2-methoxyethyl)-N-methylamino)propyl, 3 -(2- hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1- methylimidazol-2-ylmethyl, 2-(imidazol-l-yl)ethyl, 2-(2-methylimidazol-l-yl)ethyl, 2-(2- ethylimidazol-l-yl)ethyl, 3-(2-methylimidazol-l-yl)propyl, 3-(2-ethylimidazol-l-yl)propyl, 2- (l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4-triazol-l-yl)ethyl, 2-(l,2,4- triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, 2-(4- pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4-oxo- 1 ,4-dihydro- 1 -pyridyl)ethyl, 2-(2-oxo- imidazolidin-l-yl)ethyl, 3-(2-oxo-imidazolidin-l-yl)propyl, 2-thiomoφholinoethyl, 3- thiomoφholinopropyl, 2-(l , 1 -dioxothiomoφholino)ethyl, 3-(l , 1 -dioxothiomoφholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-l-yl)ethyl, 3-(4-methylpiperazin-l-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3- (ethylsulphonyl)propyl, 2-(5-methyl-l,2,4-triazol-l-yl)ethyl, moφholino, 2-((N-(l- methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-moφholinopropylsulphonyl)- N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomoφholino)propyl, 2-(2-(4-methylpiperazin- 1 -yl)ethoxy)ethyl, 3 -(2-(4-methylpiperazin- 1 -yl)ethoxy)propyl, 2-(2- moφholinoethoxy)ethyl, 3-(2-moφholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3- (tetrahydropyran-4-yloxy)propyl, 2-((2-(pyrrolidin-l-yl)ethyl)carbamoyl)vinyl, 3-((2-
(pyrrolidin- 1 -yl)ethyl)carbamoyl)prop-2-en- 1 -yl, 1 -(2-pyrrolidinylethyl)piperidin-4-ylmethyl, l-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl, l-(2-piperidinylethyl)piperidin-4-ylmethyl, l-(3- piperidinylpropyl)piperidin-4-ylmethyl, 1 -(2-moφholinoethyl)piperidin-4-ylmethyl, 1 -(3- moφholinopropyl)piperidin-4-ylmethyl, 1 -(2-thiomoφholinoethyl)piperidin-4-ylmethyl, 1 -(3- thiomoφholinopropyl)piperidin-4-ylmethyl, l-(2-azetidinylethyl)piperidin-4-ylmethyl or l-(3- azetidinylpropyl)piperidin-4-ylmethyl, 3 -moφholino-2-hydroxypropyl, (2R)-3 -moφholino-2- hydroxypropyl, (2S)-3-moφholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl, (2R)-3- piperidino-2-hydroxypropyl, (2S)-3-piρeridino-2 -hydroxypropyl, 3 -pyrrolidin- l-yl-2- hydroxypropyl, (2R)-3-pyrrolidin-l-yl-2-hydroxypropyl, (2S)-3-ρyrrolidin-l-yl-2- hydroxypropyl, 3-(l-methylρiperazin-4-yl)-2-hydroxypropyl, (2R)-3-(l-methylpiperazin-4-yl)- 2-hydroxypropyl, (2S)-3-(l -methylpiperazin-4-yl)-2-hydroxypropyl, 3-(N,N-diethylamino)-2- hydroxypropyl, (2R)-3-(N,N-diethylamino)-2-hydroxypropyl, (2S)-3-(N,N-diethylamino)-2- hydroxypropyl, 3-(isopropylamino)-2-hydroxypropyl, (2R)-3-(isopropylamino)-2- hydroxypropyl, (2S)-3-(isopropylamino)-2-hydroxypropyl, 3-(N,N-diisopropylamino)-2- hydroxypropyl, (2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or (2S)-3-(N,N- diisopropylamino)-2-hydroxypropyl]. According to another aspect of the present invention more particularly R2 represents trifluoromethyl, Cι-3alkyl, amino or R5Xl- [wherein X1 is as hereinbefore defined and R5 represents ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3 -hydroxypropyl, 2- methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2- (ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N- methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N- dimethylamino)propyl, 2-(N,N-diethylamino)ethyl, 3-(N,N-diethylamino)propyl, 2-(N-methyl- N-methylsulphonylamino)ethyl, 3 -(N-methyl-N-methylsulphonylamino)propyl, 2- moφholinoethyl, 3-moφholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (methylpiperidino)ethyl, 3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl, 3- (ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl, 3-((2- methoxyethyl)piperidino)propyl, 2-((2-methylsulphonyl)ethylpiperidino)ethyl, 3-((2- methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, 2- (piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl, 3-(piperidin-4- yl)propyl, 2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl, (l-methylpiperidin-3-yl)methyl, ( 1 -methylpiperidin-4-yl)methyl, ( 1 -cyanomethylpiperidin-3 -yl)methyl, ( 1 - cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl, 2-(methylpiperidin-4- yl)ethyl, 2-(l-cyanomethylpiperidin-3-yl)ethyl, 2-(l-cyanomethylpiperidin-4-yl)ethyl, 3- (methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl, 3-(l -cyanomethylpiperidin-3 - yl)propyl, 3-(l-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl, 2-
(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl, ((2- n ethoxyethyl)piperidin-3 -yl)methyl, ((2-methoxyethyl)piperidin-4-yl)methyl, 2-((2- methoxyethyl)piperidin-3-yl)ethyl, 2-((2-methoxyethyl)piperidin-4-yl)ethyl, 3-((2- methoxyethyl)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (l-(2- methylsulphonylethyl)piperidin-3-yl)methyl, (l-(2-methylsulphonylethyl)piperidin-4- yl)methyl, 2-((2-methylsulphonylethyl)piperidin-3 -yl)ethyl, 2-((2- methylsulphonylethyl)piperidin-4-yl)ethyl, 3-((2-methylsulphonylethyl)piperidin-3-yl)propyl, 3-((2-methylsulphonylethyl)piperidin-4-yl)propyl, l-isopropylpiperidin-2-ylmethyl, 1- isopropylpiperidin-3 -ylmethyl, 1 -isopropylpiperidin-4-ylmethyl, 2-(l -isopropylpiperidin-2- yl)ethyl, 2-(l-isopropylpiperidin-3-yl)ethyl, 2-(l-isopropylpiperidin-4-yl)ethyl, 3-(l- isopropylpiperidin-2-yl)ρropyl, 3-(l-isopropylpiperidin-3-yl)propyl, 3-(l-isopropylpiperidin- 4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(l-
(cyanomethyl)piperidin-4-yloxy)ethyl, 3-(l-(cyanomethyl)piperidin-4-yloxy)propyl, 2-(l-(2- cyanoethyl)piperidin-4-yloxy)ethyl, 3-(l -(2-cyanoethyl)piperidin-4-yloxy)propyl, 2- (piperazin-l-yl)ethyl, 3-(piperazin-l-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-l- yl)ethyl, 3-(pyrrolidin-l-yl)propyl, (2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, 5(R)-(2-oxo- tetrahydro-2H-pyrrolidin-5-yl)methyl, (5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3- dioxolan-2-yl)methyl, 2-(l,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(N-(2- methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2- methoxyethylamino)propyl, 3-(N-(2-methoxyethyl)-N-methylamino)propyl, 3-(2- hydroxyethylamino)propyl, 2-(l,2,3-triazol-l-yl)ethyl, 2-(l,2,3-triazol-2-yl)ethyl, 2-(l,2,4- triazol-l-yl)ethyl, 2-(l,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4- ρyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4-oxo-l,4-dihydro-l- pyridyl)ethyl, 2-(2-oxo-imidazolidin-l-yl)ethyl, 3-(2-oxo-imidazolidin-l-yl)propyl, 2- thiomoφholinoethyl, 3-thiomoφholinopropyl, 2-(l,l-dioxothiomoφholino)ethyl, 3-(l,l- dioxothiomoφholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-l-yl)ethyl, 3- (4-methylpiperazin-l-yl)ρropyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 3- (ethylsulphinyl)propyl, 3 -(ethylsulphonyl)propyl, 2-(5 -methyl- 1 ,2,4-triazol- 1 -yl)ethyl, moφholino, 2-(Q^-(3 -moφholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4- pyridyl)amino)ethyl, 3-(4-oxidomoφholino)propyl, 2-(2-(4-methylpiperazin-l- yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-l-yl)ethoxy)propyl, 2-(2-moφholinoethoxy)ethyl, 3- (2-moφholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3-(tetrahydropyran-4- yloxy)propyl, 2-((2-(pyrrolidin-l-yl)ethyl)carbamoyl)vinyl, 3-((2-(pyrrolidin-l- yl)ethyl)carbamoyl)prop-2-en-l-yl, l-(2-pyrrolidinylethyl)piperidin-4-ylmethyl, l-(3- pyrrolidinylpropyl)piperidin-4-ylmethyl, 1 -(2-piperidinylethyl)piperidin-4-ylmethyl, 1 -(3 - piperidinylpropyl)piperidin-4-ylmethyl, l-(2-moφholinoethyl)piperidin-4-ylmethyl, l-(3- moφholinopropyl)piρeridin-4-ylmethyl, l-(2-thiomoφholinoethyl)piperidin-4-ylmethyl, l-(3- thiomoφholinopropyl)piρeridin-4-ylmethyl, l-(2-azetidinylethyl)piperidin-4-ylmethyl or l-(3- azetidinylpropyl)piperidin-4-ylmethyl, 3-moφholino-2-hydroxypropyl, (2R)-3-moφholino-2- hydroxypropyl, (2S)-3-moφholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl, (2R)-3- piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl, 3 -pyrrolidin- 1 -yl-2- hydroxypropyl, (2R)-3 -pyrrolidin- 1 -yl-2-hydroxypropyl, (2S)-3 -pyrrolidin- 1 -yl-2- hydroxypropyl, 3-(l-methylpiperazin-4-yl)-2-hydroxypropyl, (2R)-3-(l-methylpiperazin-4-yl)- 2-hydroxypropyl, (2S)-3-(l-methylpiperazin-4-yl)-2-hydroxypropyl, 3-(N,N-diethylamino)-2- hydroxypropyl, (2R)-3 -(N,N-diethylamino)-2-hydroxypropyl, (2S)-3 -(N,N-diethylamino)-2- hydroxypropyl, 3 -(isopropylamino)-2-hydroxypropyl, (2R)-3 -(isopropylamino)-2- hydroxypropyl, (2S)-3-(isopropylamino)-2-hydroxypropyl, 3-(N,N-diisopropylamino)-2- hydroxypropyl, (2R)-3-(N,N-diisopropylamino)-2 -hydroxypropyl or (2S)-3-(N,N- diisopropylamino)-2-hydroxypropyl] .
In another aspect R2 represents trifluoromethyl, ethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, 2-hydroxyethoxy, 3 -hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-(methylsulphinyl)ethoxy, 2-(methylsulphonyl)ethoxy, 2-(ethylsulphinyl)ethoxy, 2- (ethylsulphonyl)ethoxy, 2-(N,N-dimethylsulphamoyl)ethoxy, 2-(N-methylsulphamoyl)ethoxy, 2-sulphamoylethoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy, 2-
(ethylamino)ethoxy, 3-(ethylamino)proρoxy, 2-(N,N-dimethylamino)ethoxy, 3-(N,N- dimethylamino)propoxy, 2-(N,N-diethylamino)ethoxy, 3-(N,N-diethylamino)propoxy, 2-(N- methyl-N-methylsulphonylamino)ethoxy, 3 -(N-methyl-N-methylsulphonylamino)propoxy, 2- moφholinoethoxy, 3-moφholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2- (methylpiperidino)ethoxy, 3-(methylpiperidino)propoxy, 2-(ethylpiperidino)ethoxy, 3- (ethylpiperidino)propoxy, 2-((2-methoxyethyl)piperidino)ethoxy, 3-((2- methoxyethyl)piperidino)propoxy, 2-((2-methylsulρhonyl)ethylpiperidino)ethoxy, 3-((2- methylsulphonyl)ethylpiperidino)propoxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2- (piperidin-3-yl)ethoxy, 2-(piperidin-4-yl)ethoxy, 3-(piperidin-3-yl)propoxy, 3-(piperidin-4- yl)propoxy, 2-(piperidin-2-yl)ethoxy, 3-(piperidin-2-yl)propoxy, (l-methylpiperidin-3- yl)methoxy, (l-methylpiperidin-4-yl)methoxy, (l-cyanomethylpiperidin-3-yl)methoxy, (1- cyanomethylpiperidin-4-yl)methoxy, 2-(methylpiperidin-3-yl)ethoxy, 2-(methylpiperidin-4- yl)ethoxy, 2-(l-cyanomethylpiperidin-3-yl)ethoxy, 2-(l-cyanomethylpiperidin-4-yl)ethoxy, 3- (methylpiperidin-3-yl)propoxy, 3-(methylpiperidin-4-yl)ρropoxy, 3-(l -cyanomethylpiperidin- 3-yl)propoxy, 3-(l-cyanomethylpiperidin-4-yl)propoxy, 2-(ethylpiperidin-3-yl)ethoxy, 2- (ethylpiperidin-4-yl)ethoxy, 3-(ethylpiperidin-3-yl)propoxy, 3-(ethylpiperidin-4-yl)propoxy, ((2-methoxyethyl)piperidin-3-yl)methoxy, ((2-methoxyethyl)piperidin-4-yl)methoxy, 2-((2- methoxyethyl)piperidin-3-yl)ethoxy, 2-((2-methoxyethyl)piperidin-4-yl)ethoxy, 3-((2- methoxyethyl)piperidin-3-yl)propoxy, 3-((2-methoxyethyl)piperidin-4-yl)proρoxy, (l-(2- methylsulphonylethyl)piperidin-3 -yl)methoxy, ( 1 -(2-methylsulphonylethyl)piperidin-4- yl)methoxy, 2-((2-methylsulphonylethyl)piperidin-3 -yl)ethoxy, 2-((2- methylsulphonylethyl)piperidin-4-yl)ethoxy, 3 -((2-methylsulphonylethyl)piperidin-3 - yl)propoxy, 3 -((2-methylsulphonylethyl)piρeridin-4-yl)propoxy, 1 -isopropylpiperidin-2- ylmethoxy, l-isopropylpiperidin-3-ylmethoxy, l-isopropylpiperidin-4-ylmethoxy, 2-(l- isopropylpiperidin-2-yl)ethoxy, 2-(l -isopropylpiperidin-3-yl)ethoxy, 2-(l -isopropylpiperidin- 4-yl)ethoxy, 3-(l-isopropylpiperidin-2-yl)propoxy, 3-(l-isopropylpiperidin-3-yl)propoxy, 3- (l-isopropylpiperidin-4-yl)propoxy, 2-(piperidin-4-yloxy)ethoxy, 3-(piperidin-4- yloxy)propoxy, 2-(l -(cyanomethyl)piperidin-4-yloxy)ethoxy, 3-(l -(cyanomethyl)piperidin-4- yloxy)propoxy, 2-(l-(2-cyanoethyl)piperidin-4-yloxy)ethoxy, 3-(l-(2-cyanoethyl)piperidin-4- yloxy)propoxy, 2-(piperazin-l-yl)ethoxy, 3-(piperazin-l-yl)propoxy, (pyrrolidin-2- yl)methoxy, 2-(pyrrolidin-l-yl)ethoxy, 3 -(pyrrolidin- l-yl)propoxy, (2-oxo-tetrahydro-2H- pyrrolidin-5-yι)rnethoxy, 5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy, (5S)-(2-oxo- tetrahydro-2H-pyrrolidin-5-yl)methoxy, (l,3-dioxolan-2-yl)methoxy, 2-(l,3-dioxolan-2- yl)ethoxy, 2-(2-methoxyethylamino)ethoxy, 2-(N-(2-methoxyethyl)-N-methylamino)ethoxy, 2-(2-hydroxyethylamino)ethoxy, 3-(2-methoxyethylamino)propoxy, 3-(N-(2-methoxyethyl)- N-methylamino)propoxy, 3-(2-hydroxyethylamino)propoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 2- (l,2,3-triazol-2-yl)ethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 2-(l,2,4-triazol-4-yl)ethoxy, 4- pyridylmethyl, 2-(4-pyridyl)ethyl, 4-pyridylmethoxy, 2-(4-pyridyl)ethoxy, 3-(4- pyridyl)propoxy, 2-(4-pyridyloxy)ethoxy, 2-(4-pyridylamino)ethoxy, 2-(4-oxo-l,4-dihydro-l- pyridyl)ethoxy, 2-(2-oxo-imidazolidin-l-yl)ethoxy, 3-(2-oxo-imidazolidin-l-yl)propoxy, 2- thiomoφholinoethoxy, 3-thiomoφholinopropoxy, 2-(l,l-dioxothiomoφholino)ethoxy, 3- (1,1 -dioxothiomoφholino)propoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-methylpiperazin- 1 - yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 3-(methylsulphinyl)propoxy, 3- (methylsulphonyl)propoxy, 3-(ethylsulphinyl)propoxy, 3-(ethylsulphonyl)propoxy, 2-(5- methyl- 1 ,2,4-triazol- 1 -yl)ethoxy, 2-((N-(3 -moφholinopropylsulphonyl)-N- methyl)amino)ethoxy, 2-((N-methyl-N-4-pyridyl)amino)ethoxy, 3-(4- oxidomoφholino)propoxy, 2-(2-(4-methylpiperazin-l-yl)ethoxy)ethoxy, 3-(2-(4- methylpiperazin- 1 -yl)ethoxy)propoxy, 2-(2-moφholinoethoxy)ethoxy, 3-(2- moφholinoethoxy)propoxy, 2-(tetrahydropyran-4-yloxy)ethoxy, 3-(tetrahydropyran-4- yloxy)propoxy, 2-((2-(pyrrolidin- 1 -yl)ethyl)carbamoyl)vinyl, 3 -((2-(pyrrolidin- 1 - yl)ethyl)carbamoyl)prop-2-en- 1 -yloxy, 1 -(2-pyrrolidinylethyl)piperidin-4-ylmethoxy, 1 -(3- pyrrolidinylpropyl)piperidin-4-ylmethoxy, 1 -(2-piperidinylethyl)piperidin-4-ylmethoxy, 1 -(3 - piperidinylpropyl)piperidin-4-ylmethoxy, 1 -(2-moφholinoethyl)piρeridin-4-ylmethoxy, 1 -(3- moφholinopropyl)piperidin-4-ylmethoxy, 1 -(2-thiomoφholinoethyl)piperidin-4-ylmethoxy, 1 -(3-thiomoφholinopropyl)piperidin-4-ylmethoxy, 1 -(2-azetidinylethyl)piperidin-4- ylmethoxy or l-(3-azetidinylpropyl)piperidin-4-ylmethoxy, 3-moφholino-2-hydroxypropoxy, (2R)-3 -moφholino-2-hydroxypropoxy, (2S)-3 -moφholino-2-hydroxypropoxy, 3 -piperidino-2- hydroxypropoxy, (2R)-3-piperidino-2-hydroxypropoxy, (2S)-3-piperidino-2-hydroxypropoxy, 3 -pyrrolidin- l-yl-2-hydiOxypropoxy, (2R)-3-pyrrolidin-l-yl-2-hydroxypropoxy, (2S)-3- pyrrolidin-l-yl-2 -hydroxypropoxy, 3-(l-methylpiperazin-4-yl)-2-hydroxypropoxy, (2R)-3-(l- methylpiperazin-4-yl)-2-hydroxypropoxy, (2S)-3 -( 1 -methylpiperazin-4-yl)-2-hydroxypropoxy, 3-(N,N-diethylamino)-2-hydroxypropoxy, (2R)-3-(N,N-diethylamino)-2-hydroxypropoxy, (2S)-3-(N,N-diethylamino)-2-hydroxypropoxy, 3-(isopropylamino)-2-hydroxypropoxy, (2R)- 3-(isopropylamino)-2-hydroxypropoxy, (2S)-3-(isopropylamino)-2-hydroxypropoxy, 3-(N,N- diisopropylamino)-2-hydroxypropoxy, (2R)-3-(N,N-diisopropylamino)-2-hydroxypropoxy or (2S)-3-(N,N-diisopropylamino)-2-hydroxypropoxy.
In another aspect of the present invention there is provided the use of compounds of the formula la:
Figure imgf000052_0001
(la) wherein ring C, Rb, R1, R2, m and n are as defined hereinbefore and Za represents -O-, -CH2-, -NH- or -S-; or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
In another aspect of the present invention there is provided the use of compounds of the formula lb:
Figure imgf000053_0001
(I )
wherein ring C, Rb, R1, R2, m and n are as defined hereinbefore and Zb represents -O-, -NH- or -S-; or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans. In another aspect of the present invention there is provided the use of compounds of the formula Ic:
Figure imgf000053_0002
(Ic)
wherein ring C, R , R1, R2, m and n are as defined hereinbefore and Zc represents -O-; or a salt thereof, or a prodrug thereof for example an ester or an amide, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
According to another aspect of the present invention there is provided a compound of the formula I as defined hereinbefore and salts thereof, and prodrugs thereof for example esters and amides. According to another aspect of the present invention there is provided a compound of the formula I1 as defined hereinbefore and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides. According to another aspect of the present invention there is provided a compound of the formula la as defined hereinbefore and salts thereof, and prodrugs thereof for example esters and amides.
According to another aspect of the present invention there is provided a compound of the formula lb as defined hereinbefore and salts thereof, and prodrugs thereof for example esters and amides.
According to another aspect of the present invention there is provided a compound of the formula Ic as defined hereinbefore and salts thereof, and prodrugs thereof for example esters and amides.
According to another aspect of the present invention there is provided a compound of the formula lb as defined hereinbefore with the proviso that: if Z is -S- then at least one R2 is not hydrogen; if Z is -O- then at least one R2 is not selected from hydrogen, methoxy, nitro, cyano, chloro ι i 1 1 n -^_ π and amino and if R is a group R -X then X is not selected from -NR -, -C(O)NR - and
-C(O)-; if Z is -NH- then at least one R is not selected from hydrogen, methyl, trifluoromethyl, nitro, amino, carbamoyl, methylsulphonyl, benzyl, phenylcarbonylamino, benzylcarbamoyl and benzylsulphanyl and if R2 is a group R5-X! then X1 is not selected from -NR10- and a direct bond; and salts thereof, and prodrugs thereof for example esters and amides. According to another aspect of the present invention there is provided a compound of the formula Ic as defined hereinbefore with the proviso that at least one R2 is not selected from hydrogen, methoxy, nitro, cyano, chloro and amino and if R2 is a group R5-X* then X1 is not selected from -NR10-, -C(O)NR7- and -C(O)-; and salts thereof, and prodrugs thereof for example esters and amides. A preferred compound of the present invention is
2-(2-methylindol-5-yloxy)-5-trifluoromethylpyridine and salts thereof. For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined' or 'defined hereinbefore' the said group encompasses the first occurring and broadest definition as well as each and all of the preferred definitions for that group.
In this specification unless stated otherwise the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. An analogous convention applies to other generic terms. Unless otherwise stated the term "alkyl" advantageously refers to chains with 1-6 carbon atoms, preferably 1-4 carbon atoms. The term "alkoxy" as used herein, unless stated otherwise includes "alkyl"-O- groups in which "alkyl" is as hereinbefore defined. The term "aryl" as used herein unless stated otherwise includes reference to a C6-ιo aryl group which may, if desired, carry one or more substituents selected from halogeno, alkyl, alkoxy, nitro, trifluoromethyl and cyano, (wherein alkyl and alkoxy are as hereinbefore defined). The term "aryloxy" as used herein unless otherwise stated includes "aryl"-O-groups in which "aryl" is as hereinbefore defined. The term "sulphonyloxy" as used herein refers to alkylsulphonyloxy and arylsulphonyloxy groups in which "alkyl" and "aryl" are as hereinbefore defined. The term "alkanoyl" as used herein unless otherwise stated includes formyl and alkylC=O groups in which "alkyl" is as defined hereinbefore, for example C2alkanoyl is ethanoyl and refers to CH3C=O, Ci alkanoyl is formyl and refers to CHO. In this specification unless stated otherwise the term "alkenyl" includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl are specific for the straight chain version only. Unless otherwise stated the term "alkenyl" advantageously refers to chains with 2-5 carbon atoms, preferably 3-4 carbon atoms. In this specification unless stated otherwise the term "alkynyl" includes both straight and branched chain alkynyl groups but references to individual alkynyl groups such as 2-butynyl are specific for the straight chain version only. Unless otherwise stated the term "alkynyl" advantageously refers to chains with 2-5 carbon atoms, preferably 3-4 carbon atoms. Unless stated otherwise the term "haloalkyl" refers to an alkyl group as defined hereinbefore which bears one or more halogeno groups, such as for example trifluoromethyl.
For the avoidance of any doubt, where R2 has a value of substituted or unsubstituted Cι-5alkyl, R2 has been selected from Cι_ alkyl or from a group R5X! wherein X1 is a direct bond or -CH2- and R5 is Cι_5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino.
Within the present invention it is to be understood that a compound of the formula I or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric foπn which inhibits NEGF receptor tyrosine kinase activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein.
It will be appreciated that compounds of the formula I or a salt thereof may possess an asymmetric carbon atom. Such an asymmetric carbon atom is also involved in the tautomerism described above, and it is to be understood that the present invention encompasses any chiral form (including both pure enantiomers, scalemic and racemic mixtures) as well as any tautomeric form which inhibits NEGF receptor tyrosine kinase activity, and is not to be limited merely to any one tautomeric form or chiral form utilised within the formulae drawings. It is to be understood that the invention encompasses all optical and diastereomers which inhibit NEGF receptor tyrosine kinase activity. It is further to be understood that in the names of chiral compounds (R,S) denotes any scalemic or racemic mixture while (R) and (S) denote the enantiomers. In the absence of (R,S), (R) or (S) in the name it is to be understood that the name refers to any scalemic or racemic mixture, wherein a scalemic mixture contains R and S enantiomers in any relative proportions and a racemic mixture contains R and S enantiomers in the ration 50:50.
It is also to be understood that certain compounds of the formula I and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which inhibit NEGF receptor tyrosine kinase activity. For the avoidance of any doubt, it is to be understood that when X1 is, for example, a group of formula -ΝR6C(O)-, it is the nitrogen atom bearing the R6 group which is attached to ring C and the carbonyl (C(O)) group is attached to R5, whereas when X1 is, for example, a group of formula -C(O)NR7-, it is the carbonyl group which is attached to ring C and the nitrogen atom bearing the R group is attached to R . A similar convention applies to the other two atom X1 linking groups such as -NR9SO2- and -SO2NR8-. When X1 is -NR10- it is the nitrogen atom bearing the R10 group which is linked to ring C and to R5. An analogous convention applies to other groups. It is further to be understood that when X1 represents -
NR10- and R10 is C 1.3 alkoxyC2-3 alkyl it is the d^alkyl moiety which is linked to the nitrogen atom of X1 and an analogous convention applies to other groups.
For the avoidance of any doubt, it is to be understood that in a compound of the formula I when R5 is, for example, a group of formula Cι-3alkyLX9Cι-3alkylR29, it is the terminal moiety which is linked to X1, similarly when R5 is, for example, a group of formula d-salkenylR28 it is the d-salkenyl moiety which is linked to X1 and an analogous convention applies to other groups. When R5 is a group l-R29prop-l-en-3-yl it is the first carbon to which the group R29 is attached and it is the third carbon which is linked to X1 and an analogous convention applies to other groups. For the avoidance of any doubt, it is to be understood that in a compound of the formula I when R5 is, for example, R28 and R28 is a pyrrolidinyl ring which bears a group -(-O
)f(Cι-4alkyl)gringD, it is the -O- or Cι_4alkyl which is linked to the pyrrolidinyl ring, unless f and g are both 0 when it is ring D which is linked to the pyrrolidinyl ring and an analogous convention applies to other groups. For the avoidance of any doubt, it is to be understood that when R29 carries a d.
4aminoalkyl substituent it is the d^alkyl moiety which is attached to R29 whereas when R29 carries a Cι. alkylamino substituent it is the amino moiety which is attached to R29 and an analogous convention applies to other groups.
For the avoidance of any doubt, it is to be understood that when R28 carries a d. 4alkoxyCι- alkyl substituent it is the Cι_4alkyl moiety which is attached to R28 and an analogous convention applies to other groups.
For the avoidance of any doubt, it is to be understood that when R1 is -Cι.5alkyl(ring
B) it is the alkyl chain which is linked to the indole group and ring B is attached to the alkyl chain and an analogous convention applies to other groups. For the avoidance of any doubt, it is to be understood that when Rb is C2.
5alkenylaminoCι-4alkyl, it is the Cι-4alkyl group which is linked to the nitrogen atom of the 5- membered ring and an analogous convention applies to other groups. The present invention relates to the compounds of formula I as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula I as hereinbefore defined which are sufficiently basic to form such salts. Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid. In addition where the compounds of formula I are sufficiently acidic, pharmaceutically acceptable salts maybe formed with an inorganic or organic base which affords a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, moφholine or tris-(2-hydroxyethyl)amine.
A compound of the formula I, or salt thereof, and other compounds of the invention (as hereinafter defined) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes include, for example, those illustrated in International Patent Application Publicaiton No. WO 00/47212 (Application No. PCT/GB00/00373). Such processes also include, for example, solid phase synthesis. Such processes, are provided as a further feature of the invention and are as described hereinafter. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting
Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
Thus, the following processes (a) to (f) and (i) to (vi) constitute further features of the present invention.
Synthesis of Compounds of Formula I
(a) Compounds of the formula I and salts thereof may be prepared by the reaction of a compound of the formula III:
Figure imgf000059_0001
9 ι
(wherein ring C, R and m are as defined hereinbefore and L is a displaceable moiety), with a compound of the formula IN:
Figure imgf000059_0002
(IN) (wherein Rb, R1, Gi, G2, G3, G4, G5, Z and n are as defined hereinbefore) to obtain compounds of the formula I and salts thereof. A convenient displaceable moiety L1 is, for example, a halogeno, alkoxy (preferably d.4alkoxy), aryloxy, alkylsulphanyl, arylsulphanyl, alkoxyalkylsulphanyl or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methylsulphanyl, 2-methoxyethylsulphanyl, methanesulphonyloxy or toluene-4-sulphonyloxy group.
The reaction is advantageously effected in the presence of a base. When Z is -O- such a base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, moφholine, Ν-methylmoφholine or diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or for example, an alkali metal or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. Alternatively such a base is, for example, an alkali metal hydride, for example sodium hydride, or an alkali metal or alkaline earth metal amide, for example sodium amide, sodium bis(trimethylsilyl)amide, potassium amide or potassium bis(trimethylsilyl)amide. The reaction is preferably effected in the presence of an inert solvent or diluent, for example an ether such as tetraliydrofuran or 1,4-dioxan, an aromatic hydrocarbon solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethyl sulphoxide. The reaction is conveniently effected at a temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 110°C.
When Z is -NH- the reaction is advantageously effected in the presence of either an acid or a base. Such an acid is for example, an anhydrous inorganic acid such as hydrochloric acid, in the presence of a protic solvent or diluent, for example an alcohol or ester such as methanol, ethanol, 2-propanol, 2-pentanol.
When it is desired to obtain the acid salt, the free base may be treated with an acid such as a hydrogen halide, for example hydrogen chloride, sulphuric acid, a sulphonic acid, for example methane sulphonic acid, or a carboxylic acid, for example acetic or citric acid, using a conventional procedure.
(b) Production of those compounds of formula I and salts thereof wherein at least one
R2 is R5Xl wherein R5 is as defined hereinbefore and X1 is -O-, -S-, -OC(O)- or -NR10-
(wherein R independently represents hydrogen, Cι.3alkyl or d-3alkoxyC2-3alkyl) can be achieved by the reaction, conveniently in the presence of a base (as defined hereinbefore in process (a)) of a compound of the formula V:
Figure imgf000060_0001
(N)
(wherein ring C, Rb, Z, Gi, G2, G3, G4, G5, R1, R2 and n are as hereinbefore defined and X1 is as hereinbefore defined in this section and s is an integer from 0 to 3) with a compound of formula VI: R5-LJ (NI)
(wherein R5 and L1 are as hereinbefore defined), L1 is a displaceable moiety for example a halogeno or sulphonyloxy group such as a bromo, methanesulphonyloxy or toluene-4- sulphonyloxy group, or L1 may be generated in situ from an alcohol under standard Mitsunobu conditions ("Organic Reactions", John Wiley & Sons hie, 1992, vol 42, chapter 2, David L Hughes). The reaction is preferably effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about 50°C.
9 I
(c) Compounds of the formula I and salts thereof wherein at least one R is R X wherein R5 is as defined hereinbefore and X1 is -O-, -S-, -OC(O)- or -ΝR10- (wherein R10 represents hydrogen, Cι-3alkyl or Cι_3alko yC2-3alkyl) maybe prepared by the reaction of a compound of the formula Nil:
Figure imgf000061_0001
(NH)
with a compound of the formula NAT:
Figure imgf000061_0002
(wherein ring C, L1, Rb, R1, R2, R5, Gi, G , G3, G4, G5, Z, n and s are all as hereinbefore defined and X1 is as hereinbefore defined in this section). The reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about
100°C.
(d) Compounds of the formula I and salts thereof wherein at least one R2 is R5X1 wherein X1 is as defined hereinbefore and R5 is Cι-5alkylR62, wherein R62 is selected from one of the following nine groups:
1) X10Cι_3alkyl (wherein X10 represents -O-, -S-, -SO2-, -NR63C(O)- or-NR64SO2- (wherein
R63 and R64 which may be the same or different are each hydrogen, Cι_3alkyl or
Figure imgf000062_0001
3alkyl); 2) NR65R66 (wherein R65 and R66 which may be the same or different are each hydrogen, Ci-
3alkyl or Cι-3alkoxyC2.3alkyl);
3) X11Cι.5alkylX5R22 (wherein X11 represents -O-, -S-, -SO2-, -NR67C(O)-, -NR68SO2- or -
NR69- (wherein R67, R68, and R69 which maybe the same or different are each hydrogen, d_
3alkyl or Cι-3alkoxyC2-3alkyl) and X5 and R22 are as defined hereinbefore); 4) R28 (wherein R28 is as defined hereinbefore);
5) X12R29 (wherein X12 represents -O-, -S-, -SO2-, -NR70C(O)-, -NR71SO2-, or-NR72-
7fϊ 71 79
(wherein R , R , and R which may be the same or different are each hydrogen, Ci^alkyl or
9Q
Cι-3alkoxyC2-3alkyl) and R is as defined hereinbefore); and
6) X13Cι_3alkylR29 (wherein X13 represents -O-, -S-, -SO2-, -NR73C(O , -NR74SO2- or-NR75-
T 1A 7 (wherein R , R and R each independently represents hydrogen, Chalky! or
90
Cι-3alkoxyC2-3alkyl) and R is as defined hereinbefore);
7) R29 (wherein R29 is as defined hereinbefore);
8) X13Cι- alkylR28 (wherein X13 and R28 are as defined hereinbefore); and
9) R54(Ci.4alkyl)q(X9)rR55 (wherein q, r, X9, R54 and R55 are as defined hereinbefore); may be prepared by reacting a compound of the formula IX:
Figure imgf000063_0001
(K)
(wherein ring C, L1, X1, R , R1, R2, Gi, G2, G3, G4, G5, Z, n and s are as hereinbefore defined) with a compound of the formula X:
R62-H (X)
(wherein R ,62 is as defined hereinbefore) to give a compound of the formula I or salt thereof. The reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), and at a temperature in the range, for example 0 to 150°C, conveniently at about 50°C. Processes (a) and (b) are preferred over processes (c) and (d).
Process (a) is preferred over processes (b), (c) and (d). (e) The production of those compounds of the formula I and salts thereof wherein one or more of the substituents (R2)m is represented by -NR76R77, where one (and the other is hydrogen) or both of R76 and R77 are Cι-3alkyl, may be effected by the reaction of compounds of formula I wherein the substituent (R )m is an amino group and an alkylating agent, preferably in the presence of a base as defined hereinbefore. Such alkylating agents are Cι_3alkyl moieties bearing a displaceable moiety as defined hereinbefore such as Cι-3alkyl halides for example Cι_ 3alkyl chloride, bromide or iodide. The reaction is preferably effected hi the presence of an inert solvent or diluent (as defined hereinbefore in process (a)) and at a temperature in the range, for example, 10 to 100°C, conveniently at about ambient temperature. The production of compounds of formula I and salts thereof wherein one or more of the substituents R2 is an amino group may be effected by the reduction of a corresponding compound of formula I wherein the substituent(s) at the corresponding position(s) of ring C is/are a nitro group(s). The reduction of the nitro group may conveniently be effected by any of the procedures known for such a transformation. The reduction may be carried out, for example, by the hydrogenation of a solution of the nitro compound in the presence of an inert solvent or diluent as defined hereinbefore in the presence of a metal effective to catalyse hydrogenation reactions such as palladium or platinum. A further reducing agent is, for example, an activated metal such as activated iron (produced for example by washing iron powder with a dilute solution of an acid such as hydrochloric acid). Thus, for example, the reduction may be effected by heating the nitro compound and the activated metal in the presence of a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature in the range, for example 50 to 150°C, conveniently at about 70°C.
Where the reduction is effected in the presence of activated iron, this is advantageously produced in situ, conveniently by the use of iron, generally iron powder, in the presence of acetic acid/water and preferably at about 100°C. The production of a compound of formula I and salts thereof wherein the substituent(s) at the corresponding position(s) of ring C is/are a nitro group(s) may be effected by the processes described hereinbefore and hereinafter in processes (a-d) and (i-v) using a compound selected from the compounds of the formulae (I-XVIi) in which the substituent(s) at the corresponding position(s) of ring C is/are a nitro group(s).
(f) Compounds of the formula I and salts thereof wherein X1 is -SO- or -SO2- may be prepared by oxidation from the corresponding compound in which X1 is -S- or -SO- (when X1 is -SO2- is required in the final product). Conventional oxidation conditions and reagents for such reactions are well known to the skilled chemist. Synthesis of Intermediates
(i) The compounds of formula III and salts thereof in which L1 is halogeno may for example be prepared by halogenating a compound of the formula XI:
Figure imgf000064_0001
(XI) wherein ring C, R2 and m are as hereinbefore defined.
Convenient halogenating agents include inorganic acid halides, for example thionyl chloride, phosphoras(IlT)chloride, phosphorus(N)oxychloride and phosphorus(V)chloride. The halogenation reaction may be effected in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachlori.de, or an aromatic hydrocarbon solvent such as benzene or toluene, or the reaction may be effected without the presence of a solvent. The reaction is conveniently effected at a temperature in the range, for example 10 to 150°C, preferably in the range 40 to 100°C. The compounds of formula XI and salts thereof may, for example, be prepared by reacting a compound of the formula XH:
Figure imgf000065_0001
(xπ)
(wherein ring C, R2, s and L1 are as hereinbefore defined) with a compound of the formula
Nπi as hereinbefore defined. The reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about 110°C.
The compounds of formula XI and XII and salts thereof may be prepared by any of the methods known in the art of heterocyclic organic chemistry. The compounds of formula m and salts thereof wherein at least one R2 is R5Xl and wherein X1 is -O-, -S-, -SO2-, -OC(O)-, -C(O)ΝR7-, -SO2NR8- or -NR10- (wherein R7, R8 and
R10 each independently represents hydrogen,
Figure imgf000065_0002
or Cι_3alkoxyC2-3alkyl), may also be prepared for example by reacting a compound of the formula XITJ:
Figure imgf000066_0001
(xm)
(wherein ring C, R2 and s are as hereinbefore defined, X1 is as hereinbefore defined in this section and L2 represents a displaceable protecting moiety) with a compound of the formula
NI as hereinbefore defined, whereby to obtain a compound of formula m in which L1 is represented by L2.
A compound of formula Xrfl is conveniently used in which L represents a chloro group or a phenoxy group which may if desired carry up to 5 substituents, preferably up to 2 substituents, selected from halogeno, nitro and cyano. The reaction may be conveniently effected under conditions as described for process (b) hereinbefore.
The compounds of formula Xrfl and salts thereof may for example be prepared by deprotecting a compound of the formula X1N:
L2
Figure imgf000066_0002
(XIV)
9 9 1 1
(wherein ring C, R , s and L are as hereinbefore defined, P is a protecting group and X is as hereinbefore defined in the section describing compounds of the formula XTTT). The choice of protecting group P1 is within the standard knowledge of an organic chemist, for example those included in standard texts such as "Protective Groups in Organic Synthesis" T.W. Greene and RG.M.Wuts, 2nd Ed. Wiley 1991, including Ν-sulphonyl derivatives (for example, p- toluenesulphonyl), carbamates (for example, t-butyl carbonyl), Ν-alkyl derivatives (for example, 2-chloroethyl, benzyl) and amino acetal derivatives (for example benzyloxymethyl). The removal of such a protecting group may be effected by any of the procedures known for such a transformation, including those reaction conditions indicated in standard texts such as that indicated hereinbefore, or by a related procedure. Deprotection may be effected by techniques well known in the literature, for example where P1 represents a benzyl group deprotection may be effected by hydrogenolysis or by treatment with trifluoroacetic acid.
One compound of formula m may if desired be converted into another compound of formula m in which the moiety L1 is different. Thus for example a compound of formula HI in which L1 is other than halogeno, for example optionally substituted phenoxy, may be converted to a compound of formula HI in which L1 is halogeno by hydrolysis of a compound of formula m (in which L1 is other than halogeno) to yield a compound of formula XI as hereinbefore defined, followed by introduction of halide to the compound of formula XI, thus obtained as hereinbefore defined, to yield a compound of formula m in which L1 represents halogen. (ii) Compounds of formula TV may be prepared by any of the methods known in the art, such as for example those described in "Indoles Part I", "Indoles Part II", 1972 John Wiley & Sons Ltd and "Indoles Part UI" 1979, John Wiley & Sons Ltd, edited by W. J. Houlihan. Compounds of formula IN may be prepared by any of the methods described in the Examples hereinafter. Compounds of formula IN may be prepared by any of the processes described in International Patent Application Publication No. WO 00/47212, the entire content of which is included herein by reference, with particular reference to the processes described in WO 00/47212 in Examples 48, 182 237, 242, 250 and 291 therein. For example the azaindole 2-methyl-lH-pyrrolo[2,3-b]pyridin-5-ol, may be prepared according to the method described in Reference Example 1 hereinafter.
(iii) Compounds of formula V as hereinbefore defined and salts thereof may be made by deprotecting the compound of formula XV:
Figure imgf000068_0001
(XV)
(wherein ring C, Rb, Z, R1, R2, d, G2, G3, G , G5, P1, n and s are as hereinbefore defined and X1 is as hereinbefore defined in the section describing compounds of the formula N) by a process for example as described in (i) above.
Compounds of the formula XN and salts thereof may be made by reacting compounds of the formulae XJN and IN as hereinbefore defined, under the conditions described in (a) hereinbefore, to give a compound of the formula XN or salt thereof, (iv) Compounds of the formula NJJ and salts thereof may be made by reacting a compound of the formula XVI:
Figure imgf000068_0002
(XVI) (wherein ring C, R2, s and each L1 are as hereinbefore defined and the L1 in the 4-position and the other L1 in a further position on ring C may be the same or different) with a compound of the formula IN as hereinbefore defined, the reaction for example being effected by a process as described in (a) above.
(v) Compounds of formula LX as defined hereinbefore and salts thereof may for example be made by the reaction of compounds of formula N as defined hereinbefore with compounds of the formula XNU:
Figure imgf000068_0003
(wherein L1 is as hereinbefore defined) to give compounds of formula IX or salts thereof. The reaction may be effected for example by a process as described in (b) above, (vi) Intermediate compounds wherein X1 is -SO- or -SO2- may be prepared by oxidation from the corresponding compound in which X1 is -S- or -SO- (when X1 is -SO2- is required in the final product). Conventional oxidation conditions and reagents for such reactions are well known to the skilled chemist.
When a pharmaceutically acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with, for example, an acid using a conventional procedure, the acid having a pharmaceutically acceptable anion.
Many of the intermediates defined herein, for example, those of the formulae TV, V, Vπ, LX and XV are novel and these are provided as a further feature of the invention. The preparation of these compounds is as described herein and/or is by methods well known to persons skilled in the art of organic chemistry. The identification of compounds which potently inhibit the tyrosine kinase activity associated with NEGF receptors such as Fit and/or KDR and which inhibit angiogenesis and/or increased vascular permeability is desirable and is the subject of the present invention. These properties may be assessed, for example, using one or more of the procedures set out below: (a) In Nitro Receptor Tyrosine Kinase Inhibition Test
This assay determines the ability of a test compound to inhibit tyrosine kinase activity. DΝA encoding NEGF, FGF or EGF receptor cytoplasmic domains may be obtained by total gene synthesis (Edwards M, International Biotechnology Lab 5(3), 19-25, 1987) or by cloning. These may then be expressed in a suitable expression system to obtain polypeptide with tyrosine kinase activity. For example NEGF, FGF and EGF receptor cytoplasmic domains, which were obtained by expression of recombinant protein in insect cells, were found to display intrinsic tyrosine kinase activity. In the case of the NEGF receptor Fit (Genbank accession number X51602), a 1.7kb DΝA fragment encoding most of the cytoplasmic domain, commencing with methionine 783 and including the termination codon, described by Shibuya et al (Oncogene, 1990, 5: 519-524), was isolated from cDΝA and cloned into a baculovirus transplacement vector (for example pAcYMl (see The Baculovirus Expression System: A Laboratory Guide, L.A. King and R. D. Possee, Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available from frwitrogen Coφoration)). This recombinant construct was co-transfected into insect cells (for example Spodoptera frugiperda 21(Sf21)) with viral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus. (Details of the methods for the assembly of recombinant DNA molecules and the preparation and use of recombinant baculovirus can be found in standard texts for example Sambrook et al, 1989, Molecular cloning - A Laboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press and O'Reilly et al, 1992, Baculovirus Expression Vectors - A Laboratory Manual, W. H. Freeman and Co, New York). For other tyrosine kinases for use in assays, cytoplasmic fragments starting from methionine 806 (KDR, Genbank accession number L04947), methionine 668 (EGF receptor, Genbank accession number X00588) and methionine 399 (FGF Rl receptor, Genbank accession number X51803) maybe cloned and expressed in a similar manner.
For expression of cFlt tyrosine kinase activity, Sf21 cells were infected with plaque-pure cFlt recombinant virus at a multiplicity of infection of 3 and harvested 48 hours later. Harvested cells were washed with ice cold phosphate buffered saline solution (PBS) (lOmM sodium phosphate pH7.4, 138mM sodium chloride, 2.7mM potassium chloride) then resuspended in ice cold HNTG/PMSF (20mM Hepes pH7.5, 150mM sodium chloride, 10% v/v glycerol, 1% v/v Triton X100, 1.5mM magnesium chloride, lmM ethylene glycol- bis(βaminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), lmM PMSF (phenylmethylsulphonyl fluoride); the PMSF is added just before use from a freshly-prepared lOOmM solution in methanol) using 1ml HNTG/PMSF per 10 million cells. The suspension was centrifuged for 10 minutes at 13,000 φm at 4°C, the supernatant (enzyme stock) was removed and stored in aliquots at -70°C. Each new batch of stock enzyme was titrated in the assay by dilution with enzyme diluent (lOOmM Hepes pH 7.4, 0.2mM sodium orthovanadate, 0.1% v/v Triton X100, 0.2mM dithiothreitol). For a typical batch, stock enzyme is diluted 1 in 2000 with enzyme diluent and 50μl of dilute enzyme is used for each assay well.
A stock of substrate solution was prepared from a random copolymer containing tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (Sigma P3899), stored as 1 mg/ml stock in PBS at -20°C and diluted 1 in 500 with PBS for plate coating. On the day before the assay lOOμl of diluted substrate solution was dispensed into all wells of assay plates (Nunc maxisoφ 96-well immunoplates) which were sealed and left overnight at 4°C. On the day of the assay the substrate solution was discarded and the assay plate wells were washed once with PBST (PBS containing 0.05% v/v Tween 20) and once with 50mM Hepes pH7.4. Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25μl of diluted compound was transferred to wells in the washed assay plates. "Total" control wells contained 10% DMSO instead of compound. Twenty five microlitres of 40mM manganese(II)chloride containing 8μM adenosine-5'-triphosphate (ATP) was added to all test wells except "blank" control wells which contained manganese(II)chloride without ATP. To start the reactions 50μl of freshly diluted enzyme was added to each well and the plates were incubated at room temperature for 20 minutes. The liquid was then discarded and the wells were washed twice with PBST. One hundred microlitres of mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology hie. product 05-321), diluted 1 in 6000 with PBST containing 0.5% w/v bovine serum albumin (BSA), was added to each well and the plates were incubated for 1 hour at room temperature before discarding the liquid and washing the wells twice with PBST. One hundred microlitres of horse radish peroxidase (HRP)-linked sheep anti-mouse Ig antibody (Amersham product NXA 931), diluted 1 in 500 with PBST containing 0.5% w/v BSA, was added and the plates were incubated for 1 hour at room temperature before discarding the liquid and washing the wells twice with PBST. One hundred microlitres of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution, freshly prepared using one 50mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50mM phosphate-citrate buffer pH5.0 + 0.03% sodium perborate (made with 1 phosphate citrate buffer with sodium perborate (PCSB) capsule (Sigma P4922) per 100ml distilled water), was added to each well. Plates were then incubated for 20-60 minutes at room temperature until the optical density value of the "total" control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1.0. "Blank" (no ATP) and "total" (no compound) control values were used to determine the dilution range of test compound which gave 50% inhibtion of enzyme activity.
Co) In Vitro HUVEC Proliferation Assay
This assay determines the ability of a test compound to inhibit the growth factor- stimulated proliferation of human umbilical vein endothelial cells (HUNEC). HUVEC cells were isolated in MCDB 131 (Gibco BRL) + 7.5% v/v foetal calf serum (FCS) and were plated out (at passage 2 to 8), in MCDB 131 + 2% v/v FCS + 3μg/ml heparin + lμg/ml hydrocortisone, at a concentration of 1000 cells/well in 96 well plates. After a minimum of 4 hours they were dosed with the appropriate growth factor (i.e. VEGF 3ng/ml, EGF 3ng/ml or b-FGF 0.3ng/ml) and compound. The cultures were then incubated for 4 days at 37°C with 7.5% CO2. On day 4 the cultures were pulsed with lμCi/well of tritiated-thymidine (Amersham product TRA 61) and incubated for 4 hours. The cells were harvested using a 96-well plate harvester (Tomtek) and then assayed for incoφoration of tritium with a Beta plate counter. Incoφoration of radioactivity into cells, expressed as cpm, was used to measure inhibition of growth factor-stimulated cell proliferation by compounds.
(c) hi Vivo Solid Tumour Disease Model
This test measures the capacity of compounds to inhibit solid tumour growth. CaLu-6 tumour xenografts were established in the flank of female athymic Swiss nu/nu mice, by subcutaneous injection of lxl 06 CaLu-6 cells/mouse in lOOμl of a 50% (v/v) solution of Matrigel in serum free culture medium. Ten days after cellular implant, mice were allocated to groups of 8-10, so as to achieve comparable group mean volumes. Tumours were measured using vernier calipers and volumes were calculated as: (/ x w) x ( x w) x (π/6) , where / is the longest diameter and w the diameter peφendicular to the longest. Test compounds were administered orally once daily for a minimum of 21 days, and control animals received compound diluent. Tumours were measured twice weekly. The level of growth inhibition was calculated by comparison of the mean tumour volume of the control group versus the treatment group using a Student T test and/or a Mann- Whitney Rank Sum Test. The inhibitory effect of compound treatment was considered significant when p<0.05. According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier. The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream or for rectal administration for example as a suppository. In general the above compositions may be prepared in a conventional manner using conventional excipients. The compositions of the present invention are advantageously presented in unit dosage form. The compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000mg per square metre body area of the animal, i.e. approximately 0.1-lOOmg/kg. A unit dose in the range, for example, 1-lOOmg/kg, preferably l-50mg/kg is envisaged and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example l-250mg of active ingredient.
According to a further aspect of the present invention there is provided a compound of the formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy. We have found that compounds of the present invention inhibit NEGF receptor tyrosine kinase activity and are therefore of interest for their antiangiogenic effects and/or their ability to cause a reduction in vascular permeability.
A further feature of the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament, conveniently a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being.
According to a further feature of the invention there is provided a method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of l-50mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
The antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer, hi medical oncology the other component(s) of such conjoint treatment in addition to the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may cover three main categories of therapeutic agent:
(i) other antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example linomide, inhibitors of integrin αvβ3 function, angiostatin, razoxin, thalidomide), and including vascular targeting agents (for example combretastatin phosphate and the vascular damaging agents described in International Patent Application Publication No. WO 99/02166 the entire disclosure of which document is incoφorated herein by reference, (for example N-acetylcolchinol-O-phosphate), and in International Patent Application Publication No. WO 00/40529 the entire disclosure of which document is incoφorated herein by reference); (ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5α- dihydroreductase (for example finasteride), anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function) and inhibitors of growth factor function, (such growth factors include for example platelet derived growth factor and hepatocyte growth factor such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors); and (iii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as antimetabolites (for example antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); antitumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example vinca alkaloids like vincristine and taxoids like taxol, taxotere); topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, and also irinotecan); also enzymes (for example asparaginase); and thymidylate synthase inhibitors (for example raltitrexed); and additional types of chemotherapeutic agent include: (iv) biological response modifiers (for example interferon); and (v) antibodies (for example edrecolomab).
For example such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of a compound of formula I as defined hereinbefore, and a vascular targeting agent described in WO 99/02166 such as N-acetylcolchinol-O-phosphate (Exampe 1 of WO 99/02166).
As stated above the compounds defined in the present invention are of interest for their antiangiogenic and/or vascular permeability reducing effects. Such compounds of the invention are expected to be useful in a wide range of disease states including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, lymphoedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. In particular such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin. More particularly such compounds of the invention are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with NEGF, especially those tumours which are significantly dependent on NEGF for their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, vulva and skin. h addition to their use in therapeutic medicine, the compounds of formula I and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of NEGF receptor tyrosine kinase activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
It is to be understood that where the term "ether" is used anywhere in this specification it refers to diethyl ether.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated: -
(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration; (ii) operations were carried out at ambient temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany;
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus, an oil-bath apparatus or a Koffler hot plate apparatus. (vi) the structures of the end-products of the formula I were confirmed by nuclear
(generally proton) magnetic resonance (ΝMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin, quintet; (vii) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), infra-red (IR) or ΝMR analysis; (viii) HPLC were run under 2 different conditions:
1) on a TSK Gel super ODS 2μM 4.6mm x 5cm column, eluting with a gradient of methanol in water (containing 1% acetic acid) 20 to 100% in 5 minutes. Flow rate 1.4 ml/minute. Detection: U.N. at 254 nm and light scattering detections;
2) on a TSK Gel super ODS 2μM 4.6mm x 5cm column, eluting with a gradient of methanol in water (containing 1% acetic acid) 0 to 100% in 7 minutes. Flow rate 1.4 ml/minute. Detection: U.N. at 254 nm and light scattering detections.
(ix) petroleum ether refers to that fraction boiling between 40-60°C (x) the following abbreviations have been used:-
DMF Ν,Ν-dimethylformamide
DMSO dimethylsulphoxide
TFA trifluoroacetic acid
NMP l-methyl-2-pyrrolidinone
THF tetrahydrofuran
HMDS 1,1,1 ,3 ,3 ,3-hexamethyldisilazane.
HPLC RT HPLC retention time
DEAD diethyl azodicarboxylate
DMA dimethylacetamide
DMAP 4-dimethylaminopyridine
Example 1
Figure imgf000077_0001
Under nitrogen to a suspension of sodium hydride (60%) (24mg, 0.6 mmol) in DMF was added 5-hydroxy-2-methylindole (88 mg, 0.6 mmol) followed by 2-chloro-5- trifluoromethylpyridine (91 mg, 0.5 mmol). After stirring for 24 hours at 80°C, the mixture was poured onto a column of silica and eluted with methylene chloride to give 2-(2- methylmdol-5-yloxy)-5-trifluoromethylpyridine (72 mg, 49%). 1H NMR Spectrum: (CDC13) 2.46 (s, 3H) ; 6.25 (s, IH) ; 6.82-6.97 (m, 2H) ; 7.25 (s, IH) ; 7.32 (s, IH) ; 7.85 (dd, IH) ; 7.95 (br s, IH) ; 8.45 (s, IH) MS - ESI : 293 [MH]+
Example 2
The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a pharmaceutically acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:
(a) Tablet I mg/tablet
Compound X 100
Lactose Ph.Eur 182.75
Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0
(b) Tablet TL mg/tablet Compound X 50 Lactose Ph.Eur 223.75
Croscarmellose sodium 6.0
Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25
Magnesium stearate 3.0
(c) Tablet πj mg/tablet
Compound X 1.0
Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0
Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0 (d) Capsule mg/capsule
Compound X 10
Lactose Ph.Eur 488.5
Magnesium stearate 1.5
(e) Injection I (50 mg/ml)
Compound X 5.0% w/v
IN Sodium hydroxide solution 15.0% v/v
0. IN Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v
Water for injection to 100%
(f) Injection II 10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v
0.1N Sodium hydroxide solution 15.0% v/v
Water for injection to 100%
(g) Injection III (lmg/mlbuffered to pH6 Compound X 0.1% w/v
Sodium phosphate BP 2.26% w/v
Citric acid 0.38% w/v
Polyethylene glycol 400 3.5% w/v
Water for injection to 100%
Note The above formulations maybe obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
Reference Example 1 2-methyl-lHr-pyrrolo[2,3-b]pyridin-5-ol
Figure imgf000080_0001
To a solution of 5-methoxy-lH-pyrrolo[2,3-b]pyridine (920 mg, 6.2 mmol)
(Ηeterocycles 50, (2) 1065-1080, 1999) in methylene chloride (20ml) was added benzylrriethylammoiiium chloride (37 mg, 0.16 mmol) followed by sodium hydroxide powder (771 mg, 19.2 mmol). The mixture was cooled to 0°C and benzylsulfonyl chloride (991 μl, 7.77 mmol) was added dropwise. The mixture was stirred at 0°C for 15 minutes followed by 2 hours at ambient temperature. The mixture was filtered over diatomaceous earth and the filtrate was evaporated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (20/80 followed by 30/70). The fractions containing the expected product were combined and evaporated to give 5-methoxy-l- (phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (1.69 g ; 94%) 1H NMR Spectrum: (DMSO d6) 3.86 (s, 3Η) ; 6.78 (d, IH) ; 7.6-7.7 (m, 3H) ; 7.72 (dd, IH) ; 7.88 (d, IH) ; 8.02-8.12 (m, 3H) MS: 289.47 [M+H]+
A solution of 5-methoxy-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (900 mg, 3.12 mmol) in TΗF (22.5 ml) was added dropwise to a solution of lithium diisopropylamide (prepared from nBu-Li (2.5M in hexane) ; 2.5 ml) and diisopropylamine (874 μl) in TΗF (13.5 ml)) cooled at -25°C and the mixture was stirred for 30 minutes. Methyl iodide (215 μl, 3.44 mmol) in THF (9 ml) was then added dropwise and the mixture was stirred for 10
minutes at -25°C, left to warm up to ambient temperature and stirred for 15 minutes. The mixture was then poured onto ice/water. The mixture was then extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether (20/80 followed by 30/70). The fractions containing the expected product were combined and evaporated to give 5-methoxy-2-methyl-l-(phenylsulfonyl)-lH- pyrrolo[2,3-b]pyridine (805 mg, 85%).
1H NMR Spectrum: (DMSOd6) 2.7 (s, 3Η) ; 3.82 (s, 3H) ; 6.51 (d, IH) ; 7.49 (d, IH) ; 7.59 (dd, 2H) ;7.7 (m, IH) ; 8.0-8.1 (m, 3H) MS: 303.5 [M+H]+ A solution of 5-methoxy-2-methyl-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (950 mg, 3.14 mmol) and 40% aqueous sodium hydroxyde (106 ml) in methanol (160 ml) was heated at reflux for 30 minutes. After cooling, the mixture was poured onto cooled water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1/1). The fractions containing the expected product were combined and evaporated to give 5-methoxy-2-methyl-lH-pyrrolo[2,3- bjpyridine (462 mg, 91%).
1H NMR Spectrum: (DMSO d6) 2.38 (s, 3Η) ; 3.8 (s, 3H) ; 6.06 (d, IH) ; 7.39 (d, IH) ; 7.82 (d, IH) MS: 163.3 [M+H]+
A solution of boron tribromide (64 μl, 0.68 mmol) in methylene chloride (200 μl) was added to a solution of 5-methoxy-2-methyl-lH-pyrrolo[2,3-b]pyridine (50 mg, 0.308 mmol) in methylene chloride (4 ml) cooled at -30°C. The mixture was left to warm up to ambient temperature and further stirred for 3 hours. The mixture was poured onto ice. The pΗ was adjusted to 6.2 with 6N aqueous sodium hydroxide followed by 2 N aqueous hydrogen chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with water, followed by brine and dried (MgSO4), filtered and the filtrate was evaporated. The residue was purified by column chromatography, eluting with with methylene chloride followed by methylene chloride/methanol (98/2 followed by 95/5). The fractions containing the expected product were combined and evaporated to give 2-methyl-lH-pyrrolo[2,3- 6]pyridin-5-ol (45 mg, quantitative).
1H NMR Spectrum: (DMSO d6) 2.4 (s, 3H) ; 5.96 (s, IH) ; 7.12 (d, IH) ; 7.69 (d, IH) ; 8.9 (s, IH) ; 11.07 (br s, IH) MS: 149.2 [M+H]+

Claims

1. The use of a compound of the formula I:
Figure imgf000083_0001
(I)
wherein: ring C is a 5 or 6-membered heteroaromatic ring containing at least one nitrogen atom and optionally containing a further 1-2 heteroatoms, selected independently from O, S andN; either any one of Gi, G2, G3, G4 and G5 is nitrogen and the other four are -CH-, or Gi, G2, G3, G4 and G5 are all -CH-; Z is -O-, -NH-, -S-, -CH2- or a direct bond; Z is linked to any one of Gi, G2, G3 and G4 which is a free carbon atom; n is an integer from 0 to 5; any of the substituents R1 may be attached at any free carbon atom of the indole, azaindole or indazole group, such free carbon atoms maybe Gi, G2, G3, G4 or G5 or may be at the 3-position of the indole, azaindole or indazole group; m is an integer from 0 to 4; R represents hydrogen, Cι-4alkyl, Cι.4alkoxyCι.4alkyl, aminod-4alkyl, Cι-3alkylaminoCι- 4alkyl, di(Cι_3alkyl)aminoCι-4alkyl, C2.5alkenylaminoCι^alkyl, C2-5alkynylaminoCι.4alkyl, - Cι-5alkyl(ring A) wherein ring A is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, moφholino and thiomoφholino and wherein ring A may bear one or more substituents selected from
Figure imgf000083_0002
d-salkenyl, d-salkynyl, hydroxy, oxo, halogeno, cyano, cyanoCι_4alkyl, Cι_ alkylsulρhonyl and Cι_4alkanoyl;
R represents hydrogen, oxo, hydroxy, halogeno, Cι-4alkyl, d.4alkoxy, Cι.4alkoxyCι.4alkyl, aminoCι_4alkyl, Ci-3alkylaminoCi-4alkyl, di(Cι.3alkyl)aminoCι. alkyl, -Cι-5alkyl(ring B) wherein ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N- methylpiperazinyl, N-ethylpiperazinyl, moφholino and thiomoφholino; R2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl,
Figure imgf000084_0001
Ci- 3alkoxy,
Figure imgf000084_0002
-NR3R4 (wherein R3 and R4, winch may be the same or different, each represents hydrogen or
Figure imgf000084_0003
or R5X!- (wherein X1 represents a direct bond, -O-, - CH2-, -OC(O)-, -C(O)-, -S-, -SO-, -SO2-, -NR6C(O)-, -C(O)NR7-, -SO2NR8-, -NR9SO2- or - NR10- (wherein R6, R7, R8, R9 and R10 each independently represents hydrogen, Cι_3alkyl or Cι-3alkoxyC2-3alkyl), and R5 is selected from one of the following twenty-two groups: 1) hydrogen, oxiranylCι. alkyl or Ci-salkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
2) Cι_5alkylX2C(O)Rn (wherein X2 represents -O- or -NR12- (in which R12 represents hydrogen, Cι_3alkyl or Cι-3alkoxyC2-3alkyl) and R11 represents d.3alkyl, -NR13R14 or -OR15 (wherein R13, R14 and R15 which may be the same or different each represents hydrogen, Cμ 5alkyl or Cι-3alkoxyC2-3alkyl));
3) Cι.5alkylX3R16 (wherein X3 represents -O-, -S-, -SO-, -SO2-, -OC(O)-, -NR17C(O)-, - C(O)NR18-, -SO2NR19-, -NR20SO2- or -NR21- (wherein R17, R18, R19, R20 and R21 each independently represents hydrogen, Ci^alkyl or Cι_3alkoxyC2-3alkyl) and R represents hydrogen, Ci^alkyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which Ci^alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and d. alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_ 4cyanoalkyl, Cι.4alkyl, Cι-4hydroxyalkyl, Cι_ alkoxy, Cι_4alkoxyCι-4alkyl, d. 4alkylsulphonylCι-4alkyl, Cι„4alkoxycarbonyl, Cι.4aminoalkyl, Cι.4alkylamino, di(Cι_ 4alkyl)amino, Cι_ alkylaminoCι_4alkyl, di(Cι. alkyl)aminoCι.4alkyl,
Figure imgf000084_0004
4alkoxy, di(Ci.4alkyl)aminoCi.4alkoxy and a group -(-O-)f(Cι-4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι_4alkyl)); 4) Cι.5alkylX4Cι-5alkylX5R22 (wherein X4 and X5 which may be the same or different are each -O-, -S-, -SO-, -SO2-, -NR23C(O)-, -C(O)NR24-, -SO2NR25-, -NR26SO2- or -NR27- (wherein R23, R24, R25, R26 and R27 each independently represents hydrogen, Chalky! or d-3alkoxyC2-
3 alkyl) and R represents hydrogen, Cι_3alkyl or Cι_3alkoxyC2-3alkyl); 5) R28 (wherein R2 is a 4-, 5- or 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι. cyanoalkyl, Cι-4alkyl, Cι_ hydroxyalkyl, Cι_4alkoxy, Cι_4alkanoyl, Cι-4alkoxyCι.4alkyl, Ci- 4alkylsulphonyl, Cι-4alkylsulphonylCι. alkyl, Cι_4alkoxycarbonyl, Cι. aminoalkyl, Cι_ 4alkylamino, di(Cι-4alkyl)amino, Cι.4alkylaminoCι-4alkyl, di(Cι. alkyl)aminoCι-4alkyl, Ci- 4alkylaminoCι-4alkoxy, di(Cι-4alkyl)aminoCι.4alkoxy and a group -(-O-)f(Cι.4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Cι.4alkyl));
6) Cι_5alkylR28 (wherein R28 is as defined herein);
7) C2-5alkenylR28 (wherein R28 is as defined herein);
8) C2-5alkynylR28 (wherein R28 is as defined herein); 9) R29 (wherein R29 represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, Cι_4alkyl, Cι-4alkoxy, Cι_4hydroxy alkyl, Cι_ 4aminoalkyl, Cι_4alkylamino,
Figure imgf000085_0001
carboxy, trifluoromethyl, cyano, - C(O)NR30R31, -NR32C(O)R33 (wherein R30, R31, R32 and R33, which may be the same or different, each represents hydrogen, Cι_4alkyl or C 1.3 alkoxyd-:? alkyl) and a group -(-O-)f(Cι- 4alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from d-4alkyl)); 10) Ci.salkylR29 (wherein R29 is as defined herein);
11) C2-5alkenylR29 (wherein R29 is as defined herein);
12) C2-5alkynylR29 (wherein R29 is as defined herein);
13) Cι.5alkylX6R29 (wherein X6 represents -O-, -S-, -SO-, -SO2-, -NR34C(O)-, -C(O)NR35-, - SO2NR36-, -NR37SO2- or -NR38- (wherein R34, R35, R36, R37 and R38 each independently
90 represents hydrogen, Cι.3alkyl or C1.3alkoxyC2-3alkyl) and R is as defined herein);
14) C2-5alkenylX7R29 (wherein X7 represents -O-, -S-, -SO-, -SO2-, -NR39C(O , -C(O)NR40-, -SO2NR41-, -NR42SO2- or -NR43- (wherein R39, R40, R41, R42 and R43 each independently represents hydrogen, Chalky! or C1.3alkoxyC2-3alkyl) and R29 is as defined herein); 15) C2.5alkynylX8R29 (wherein X8 represents -O-, -S-, -SO-, -SO2-, -NR44C(O)-, -C(O)NR45-, -SO2NR46-, -NR47SO2- or -NR48- (wherein R44, R45, R46, R47 and R48 each independently represents hydrogen, Cι-3alkyl or Cι_3alkoxyC2-3alkyl) and R29 is as defined herein); 5 16) Cι_4alkylX9Cι-4alkylR29 (wherein X9 represents -O-, -S-, -SO-, -SO2-, -NR49C(O)-, - C(O)NR50-, -SO2NR51-, -NR52SO2- or -NR53- (wherein R49, R50, R51, R52 andR53 each independently represents hydrogen,
Figure imgf000086_0001
or C 1.3 alkoxyC2-3 alkyl) and R29 is as defined herein);
17) Ci.4alkylX9Ci- alkylR28 (wherein X9 and R28 are as defined herein); 10 18) d-salkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, Cι-4alkylamino, N,N-di(Cι.4alkyl)amino, aminosulphonyl, N-Cι. alkylaminosulphonyl and N,N-di(Cι_4alkyl)aminosulphonyl;
19) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, Cι-4alkylamino, N,N-di(Cι_4alkyl)amino,
15 aminosulphonyl, N-Cι.4alkylaminosulphonyl and N,N-di(Cι. alkyl)aminosulphonyl;
20) C2.5alkenylX9Cι.4alkylR28 (wherein X9 and R28 are as defined herein);
21) C2-5alkynylX9Cι-4alkylR28 (wherein X9 and R28 are as defined herein); and
22) Ci.4alkylR54(Ci.4alkyl)q(X9)rR55 (wherein X9 is as defined herein, q is 0 or 1, r is 0 or 1, and R54 and R55 are each independently selected from hydrogen, Ci^alkyl, cyclopentyl,
20 cyclohexyl and a 4-, 5- or 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which d^alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and Ci_4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, d-4cyanoalkyl, Cι_4alkyl, Ci- 4hydroxyalkyl, Cι-4alkoxy, Cι-4alkoxyCι.4alkyl, Ci- alkylsulphonylCi.4alkyl, Cι_
25 4alkoxycarbonyl, Cι.4aminoalkyl, Cι_4alkylamino, di(Cι_4alkyl)amino, Cι.4alkylaminoCι- 4alkyl, di(Cι-4alkyl)aminoCι. alkyl, Cι.4alkylaminoCι.4alkoxy, di(Cι.4alkyl)aminoCι-4alkoxy and a group -(-O-)f(d_ alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-, 5- or 6- membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from Chalky!), with
30 the proviso that R54 cannot be hydrogen); and additionally wherein any Cι_5alkyl, C2-5alkenyl or C2-5alkynyl group in R5X!- may bear one or more substituents selected from hydroxy, halogeno and amino); or a salt thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
2. The use of a compound of the formula I according to claim 1 wherein the optionally substituted indole moiety of formula II:
Figure imgf000087_0001
(II) wherein R ,ι , R , Gls G2, G3, G4 and G5 and n are as defined in claim 1; is selected from the indole moieties:
4-fluoro-2-methylindol-5-yl, 2-methylindol-5-yl, 2-methylindol-6-yl, 2,
3-dimethylindol-5-yl, l-methylindol-5-yl, l,2-dimethylindol-5-yl, 4-fluoroindol-5-yl, 6-fluoroindol-5-yl, indol-5-yl, and 3-methylindol-5-yl.
A compound of the formula lb:
Figure imgf000087_0002
(lb) wherein ring C, Rb, R1, R2, m and n are as defined in claim 1 and Zb represents -O- -NH- or -S-; with the proviso that: if Z is -S- then at least one R2 is not hydrogen; if Z is -O- then at least one R2 is not selected from hydrogen, methoxy, nitro, cyano, chloro and amino and if R2 is a group R5-X then X1 is not selected from -NR10-, -C(O)NR7- and - C(O)- wherein R5, R7 and R10 are as defined in claim 1; if Z is -NH- then at least one R2 is not selected from hydrogen, methyl, trifluoromethyl, nitro, amino, carbamoyl, methylsulphonyl, benzyl, phenylcarbonylamino, benzylcarbamoyl and benzylsulphanyl and if R2 is a group R^X1 then X1 is not selected from -NR10- and a direct bond wherein R5 and R10 are as defined in claim 1; or a salt thereof.
4. A compound according to claim 3 wherein ring C is selected from one of the following seven moieties:
Figure imgf000088_0001
(') (ϋ) (iϋ) "v)
Figure imgf000088_0002
(v) (vi) (vii)
wherein Z is Zb as defined in claim 3 but is not part of ring C.
5. A compound according to claim 3 or claim 4 wherein ring C is a pyrimidine ring or a pyridyl ring.
6. A compound according to any one of claims 3 to 5 wherein Z is -O- or -NH-.
7. A compound according to any one of claims 3 to 6 wherein Rb is hydrogen.
8. A compound according to any one of claims 3 to 7 wherein R represents methyl, ethyl, trifluoromethyl or halogeno.
9. A compound according to any one of claims 3 to 8 wherein R2 represents hydroxy, halogeno, nitro, trifluoromethyl, Ci^alkyl, cyano, amino or R5X!- [wherein X1 is as defined in claim 1 and R5 is selected from one of the following twenty groups:
1) Cι.3alkyl which may be imsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C2-3 alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3- methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3- (N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl, 3 -(N- methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)ρropyl, or 2-(N- methyl-N-(butoxycarbonyl)amino)ethyl;
3) C2-3alkylX3R16 (wherein X3 is as defined in claim 1 and R16 is a group selected from d. 3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl and tetrahydropyranyl which group is linked to X3 through a carbon atom and which Ci-θalkyl group may bear 1 or 2 substituents selected from hydroxy, halogeno and Ci- 2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl or tetrahydropyranyl group may bear one substituent selected from oxo, hydroxy, halogeno, cyano,
Figure imgf000089_0001
Cι_2alkoxy, Ci- 2alkoxyCι-3alkyl, d-2alkylsulphonylCι-3alkyl, Cι_2alkoxycarbonyl, Cι_3alkylamino, di(Cι_ 3alkyl)amino, d-3alkylaminoCι-3alkyl, di(Ci-3alkyl)aminoCi-3alkyl,
Figure imgf000089_0002
3alkoxy, di(Cι-3alkyl)aminoCι.3alkoxy and a group -(-O- d-3alkyl)grmgD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino));
4) C2-3alkylX4C2-3alkylX5R22 (wherein X4 and X5 are as defined in claim 1 and R22 represents hydrogen or
Figure imgf000089_0003
5) R28 (wherein R28 is as defined in claim 1);
6) d-3alkylR59 (wherein R59 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, imidazolidinyl, l,3-dioxolan-2-yl, l,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1,3- dithian-2-yl, which group is linked to Chalky! through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι_2cyanoalkyl, Cι_ 2alkyl, Cι.2hydroxy alkyl, Cι.2alkoxy,
Figure imgf000090_0001
Cι-2alkylsulphonyl, Cι.2alkylsulphonylCι.3alkyl,
Figure imgf000090_0002
C1.3alkylam.ino, di(C1.3alkyl)amino, Cι_ 5 3alkylaminoCι-3alkyl, di(Cι.3alkyl)aminoCι.3alkyl, Cι.3alkylaminoCι.3alkoxy, di(Cι.
3alkyl)aminoCι-3alkoxy and a group -(-O-)f(d-3alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino)) or C2-3alkylR60 (wherein R60 is a group selected from moφholino, thiomoφholino, azetidin- 1-yl, pyrrolidin- 1-yl, piperazin-1-yl and
10 piperidino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, Cι-2cyanoalkyl, Cι-2alkyl, Cι-2hydroxyalkyl,
Figure imgf000090_0003
Cι.2alkoxyCι- 3alkyl, Cι-2alkylsulphonyl, Cι.2alkylsulphonylCι-3alkyl, Cι-2alkoxycarbonyl,
Figure imgf000090_0004
di(Cι_3alkyl)amino, Cι.3alkylaminoCι.3alkyl, di(Cι-3alkyl)aminoCι_3alkyl, d-3alkylaminoCι- 3alkoxy, di(Cι-3alkyl)aminoCι-3alkoxy and a group -(-O-)f(Cι-3alkyl)gringD (wherein f is 0 or
15 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, moφholino and thiomoφholino));
7) R29 (wherein R29 is as defined in claim 1);
8) Ci_4alkylR29 (wherein R29 is as defined in claim 1);
9) l-R29but-2-en-4-yl (wherein R29 is as defined in claim 1); 20 10) l-R29but-2-yn-4-yl (wherein R29 is as defined in claim 1);
11) Cι.3alkylX6R29 (wherein X6 and R29 are as defined in claim 1);
12) l-(R29X7)but-2-en-4-yl (wherein X7 and R29 are as defined in claim 1);
13) l-(R29X8)but-2-yn-4-yl (wherein X8 and R29 are as defined in claim 1);
14) C2-3alkylX9Cι.3alkylR29 (wherein X9 and R29 are as defined in claim 1); 25 15) C -3alkylX9Ci.3alkylR28 (wherein X9 and R28 are as defined in claim 1);
16) C2-5alkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, d_ 4alkylamino, N,N-di(Cι_4alkyl) amino, aminosulphonyl, N-Cι_4alkylaminosulphonyl and N,N- di(Cι_4alkyl)aminosulphonyl; 30 17) C2-5alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, Cι_ 4alkylamino, N,N-di(Cι_ alkyl)amino, aminosulphonyl, N-Ci.4alkylaminosulphonyl and N,N- di(Ci_4alkyl)aminosulphonyl; 18) C2-3alkenylX9Cι-3alkylR28 (wherein X9 and R28 are as defined in claim 1);
19) C2-3alkynylX9Cι-3alkylR28 (wherein X9 and R28 are as defined in claim 1); and
20) Cι.3alkylR54(Cι-3alkyl)q(X9)rR55 (wherein X9, q, r, R54 and R55 are as defined in claim 1); and additionally wherein any Cι-5alkyl, d-salkenyl or d-salkynyl group in R5X1- may bear one or more substituents selected from hydroxy, halogeno and amino].
10. A compound selected from: 2-(2-methylindol-5-yloxy)-5-trifluoromethylpyridine or a salt thereof.
11. A compound according to any one of claims 3 to 10 in the form of a pharmaceutically acceptable salt.
12. A process for the preparation of a compound of formula lb or a salt thereof which comprises: (a) the reaction of a compound of the formula III:
Figure imgf000091_0001
(III)
9 1 (wherein πng C, R and m are as defined in claim 1 and L is a displaceable moiety), with a compound of the formula IN:
'
Figure imgf000092_0001
(IV)
(wherein Rb, R1 and n are as as defined in claim 1, Gi, G2, G3, G4 and G5 are all -CH-, and Zb is as defined in claim 3);
(b) a compound of formula I or a salt thereof wherein at least one R2 is R5XJ wherein
R5 is as defined in claim 1 and X1 is -O-, -S-, -OC(O)- or -NR10- (wherein R10 independently represents hydrogen, Ci^alkyl or Cι-3alkoxyC2-3alkyl) may be prepared by the reaction of a compound of the formula N:
Figure imgf000092_0002
(V)
(wherein ring C, R , R1, R2 and n are as defined in claim 1, Gi, G2, G3, G4 and G5 are all -CH-, Zb is as defined in claim 3 and X1 is as herein defined in this section and s is an integer from 0 to 3) with a compound of formula NI:
R5-V (NI)
(wherein R5 is as defined in claim 1 and L1 is as defined herein);
(c) a compound of the formula I or a salt thereof wherein at least one R2 is R5Xl wherein R5 is as defined in claim 1 and X1 is -O-, -S-, -OC(O)- or -ΝR10- (wherein R10 represents hydrogen, Cι.3alkyl or Cι.3alkoxyC2-3alkyl) may be prepared by the reaction of a compound of the formula Nil:
Figure imgf000093_0001
(Nil)
with a compound of the formula NIII:
R^-H (NIII)
(wherein ring C, Rb, R1, R2, R5 and n are all as defined in claim 1, Gi, G2, G3, G4 and G5 are all -CH-, Zb is as defined in claim 3, L1 and s are as defined herein and X1 is as herein defined in this section); (d) a compound of the formula I or a salt thereof wherein at least one R2 is R5XX wherein
1 Λ Λ9
X is as defined in claim 1 and R is Cι.5alkylR , wherein R is selected from one of the following nine groups:
1) X10Cι.3alkyl (wherein X10 represents -O-, -S-, -SO2-, -ΝR63C(O)- or -NR64SO2- (wherein R63 and R64 which maybe the same or different are each hydrogen,
Figure imgf000093_0002
or Cι_3alkoxyC2- 3alkyl);
2) NR65R66 (wherein R65 and R66 which maybe the same or different are each hydrogen, Cι_ 3 alkyl or C 1.3 alkoxy C2-3 alkyl);
3) XnCι.5alkylX5R22 (wherein X11 represents -O-, -S-, -SO2-, -NR67C(O)-, -NR68SO2- or - NR69- (wherein R67, R68, and R69 which maybe the same or different are each hydrogen, Ci 3alkyl or Cι_3alkoxyC2-3alkyl) and X5 and R22 are as defined in claim 1);
4) R28 (wherein R28 is as defined in claim 1); 5) X12R29 (wherein X12 represents -O-, -S-, -SO2-, -NR70C(O)-, -NR71SO2-, or-NR72- (wherein R , R , and R which may be the same or different are each hydrogen, Cι_3alkyl or Cι_3alkoxyC2-3alkyl) and R29 is as defined in claim 1); and
6) X13Cι.3alkylR29 (wherein X13 represents -O-, -S-, -SO2-, -NR73C(O)-, -NR74SO2- or -NR 75
TX 1A 7*ϊ
(wherein R , R and R each independently represents hydrogen, d-3alkyl or
90
Cι.3alkoxyC2-3 alkyl) and R is as defined in claim 1);
7) R29 (wherein R29 is as defined in claim 1);
8) X13Cι-4alkylR28 (wherein X13 and R28 are as defined in claim 1); and 9) R54(Cι-4alkyl)q(X9)rR55 (wherein q, r, X9, R54 and R55 are as defined in claim 1); may be prepared by reacting a compound of the formula IX:
Figure imgf000094_0001
(IX)
(wherein ring C, X1, R , R1, R2 and n are as defined in claim 1, Gls G2, G3, G4 and G5 are all CH-, Zb is as defined in claim 3 and L1 and s are as defined herein) with a compound of the formula X: R62-H (X)
(wherein R62 is as defined herein);
(e) a compound of the formula lb or a salt thereof wherein one or more of the substituents (R2)m is represented by -NR76R77, where one (and the other is hydrogen) or both of R76 and R77 are Cι-3alkyl, may be effected by the reaction of compounds of formula I
9 • • wherein the substituent (R )m is an amino group and an alkylating agent; (f) a compound of the formula lb or a salt thereof wherein X1 is -SO- or -SO2- may be prepared by oxidation from the coπesponding compound in which X1 is -S- or -SO- (when X1 is -SO2- is required in the final product); and when a salt of a compound of formula lb is required, reaction of the compound obtained with an acid or base whereby to obtain the desired salt.
13. A pharmaceutical composition which comprises a compound of the foπnula lb as defined in claim 3 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.
14. A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof.
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