Quinazoline derivatives as angiogenesis inhibitors

[0001] This application is the National Phase of International Application PCT/GB00/00373 filed Feb. 8, 2000 which designated the U.S. and that International Application.

[0002] The present invention relates to quinazoline 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.

[0003] 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 of vascular 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 (VEGF). By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, 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 VEGF action by sequestration of VEGF 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. Inst. 85: 241–242) of patients with cancer.

[0004] 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, Flt or Flt1, 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, Flt and KDR, have been shown to bind VEGF with high affinity (De Vries et al, 1992, Science 255: 989–991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579–1586). Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.

[0005] The present invention is based on the discovery of compounds that surprisingly inhibit the effects of VEGF, 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, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. Compounds of the present invention generally possess higher potency against VEGF receptor tyrosine kinase than against epidermal growth factor (EGF) receptor tyrosine kinase. Compounds of the invention which have been tested possess activity against VEGF receptor tyrosine kinase such that they may be used in an amount sufficient to inhibit VEGF receptor tyrosine kinase whilst demonstrating no significant activity against EGF receptor tyrosine kinase. Compounds of the present invention generally possess higher potency against VEGF receptor tyrosine kinase than against FGF R1 receptor tyrosine kinase. Compounds of the invention which have been tested possess activity against VEGF receptor tyrosine kinase such that they may be used in an amount sufficient to inhibit VEGF receptor tyrosine kinase whilst demonstrating no significant activity against FGF R1 receptor tyrosine kinase.

[0006] According to one aspect of the present invention there is provided the use of a compound of the formula I:

[0007]
wherein:

• [0008] ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which moiety may be saturated or unsaturated, which may be aromatic or non-aromatic, and which optionally may contain 1–3 heteroatoms selected independently from O, N and S;
• [0009] Z is —O—, —NH—, —S—, —CH₂— or a direct bond;
• [0010] n is an integer from 0 to 5;
• [0011] m is an integer from 0 to 3;
• [0012] R² represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylsulphanyl, —NR³R⁴ (wherein R and R⁴, which may be the same or different, each represents hydrogen or C_1-3alkyl), 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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R⁵ is selected from one of the following twenty-two groups:
• [0013] 1) hydrogen, oxiranylC_1-4alkyl or C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
• [0014] 2) C_1-5alkylX²C(O)R¹¹ (wherein X² represents —O— or —NR¹²— (in which R¹² represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R¹ represents C_1-3alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be the same or different each represents hydrogen, C_1-5alkyl or C_1-3alkoxyC_2-3alkyl));
• [0015] 3) C_1-5alkylX³R¹⁶ (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R¹⁶ represents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4aminoalkyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl));
• [0016] 4) C_1-5alkylX⁴C_1-5alkylX⁵R²² (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²² represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);
• [0017] 5) R²⁸ (wherein R²⁸ is a 4–6-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_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4aminoalkyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_qringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl));
• [0018] 6) C_1-5alkylR²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0019] 7) C_2-5alkenylR²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0020] 8) C_2-5alkynylR²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0021] 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, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4aminoalkyl, C_1-4alkylamino, C_1-4hydroxyalkoxy, 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, C_1-4alkyl or C_1-3alkoxyC_2-3alkyl) and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl));
• [0022] 10) C_1-5alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0023] 11) C_2-5alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0024] 12) C_2-5alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0025] 13) C_1-5alkylX⁶R²⁹ (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
• [0026] 14) C_2-5alkenylX⁷R²⁹ (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
• [0027] 15) C_2-5alkynylX⁸R²⁹ (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
• [0028] 16) C_1-4alkylX⁹C_1-4alkylR²⁹ (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
• [0029] 17) C_1-4alkylX⁹C_1-4alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0030] 18) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0031] 19) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0032] 20) C_2-5alkenylX⁹C_1-4alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0033] 21) C_2-5alkynylX⁹C_1-4alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and
• [0034] 22) C_1-4alkylR⁵⁴(C_1-4alkyl)_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, C_1-3alkyl, cyclopentyl, cyclohexyl and a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4aminoalkyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl), with the proviso that R⁵⁴ cannot be hydrogen); and additionally wherein any C_1-5alkyl, C_2-5alkenyl or C_2-5alkynyl group in R⁵X¹— may bear one or more substituents selected from hydroxy, halogeno and amino);
  • [0035] R¹ represents hydrogen, oxo, halogeno, hydroxy, C_1-4alkoxy, C_1-4alkyl, C_1-4alkoxymethyl, C_1-4alkanoyl, C_1-4haloalkyl, cyano, amino, C_2-5alkenyl, C_2-5alkynyl, C_1-3alkanoyloxy, nitro, C_1-4alkanoylamino, C_1-4alkoxycarbonyl, C_1-4alkylsulphanyl, C_1-4alkylsulphinyl, C_1-4alkylsulphonyl, carbamoyl, N—C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, aminosulphonyl, N—C_1-4alkylaminosulphonyl, N,N-di(C_1-4alkyl)aminosulphonyl, N—(C_1-4alkylsulphonyl)amino, N—(C_1-4alkylsulphonyl)-N—(C_1-4alkyl)amino, N,N-di(C_1-4alkylsulphonyl)amino, a C_3-7alkylene chain joined to two ring C carbon atoms, C_1-4alkanoylaminoC_1-4alkyl, carboxy or a group R⁵⁶X¹⁰ (wherein X¹⁰ represents a direct bond, —O—, —CH₂—, —OC(O)—, —C(O)—, —S—, —SO—, —SO₂—, —NR⁵⁷C(O)—, —C(O)NR⁵⁸—, —SO₂NR⁵⁹—, —NR⁶⁰SO₂— or —NR⁶¹— (wherein R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰ and R⁶¹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R⁵⁶ is selected from one of the following twenty-two groups:
• [0036] 1) hydrogen, oxiranylC_1-4alkyl or C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;
• [0037] 2) C_1-5alkylX¹¹C(O)R⁶² (wherein X¹¹ represents —O— or —NR⁶³—(in which R⁶³ represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R⁶² represents C_1-3alkyl, —NR⁶⁴R⁶⁵ or —OR⁶⁶ (wherein R⁶⁴, R⁶⁵ and R⁶⁶ which may be the same or different each represents hydrogen, C_1-5alkyl or C_1-3alkoxyC_2-3alkyl));
• [0038] 3) C_1-5alkylX¹²R⁶⁷ (wherein X¹² represents —O—, —S—, —SO—, —SO₂—, —OC(O)—, —NR⁶⁸C(O)—, —C(O)NR⁶⁹—, —SO₂NR⁷⁰—, —NR⁷¹SO₂— or —NR⁷²— (wherein R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹ and R⁷² each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R⁶⁷ represents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4aminoalkyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl));
• [0039] 4) C_1-5alkylX¹³C_1-5alkylX¹⁴R⁷³ (wherein X¹³ and X¹⁴ which may be the same or different are each —O—, —S—, —SO—, —SO₂—, —NR⁷⁴C(O)—, —C(O)NR⁷⁵—, —SO₂NR⁷⁶—, —NR⁷⁷SO₂— or —NR⁷⁸— (wherein R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁷ and R⁷⁸ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R⁷³ represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);
• [0040] 5) R⁷⁹ (wherein R⁷⁹ is a 4–6-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_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4aminoalkyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl));
• [0041] 6) C_1-5alkylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);
• [0042] 7) C_2-5alkenylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);
• [0043] 8) C_2-5alkynylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);
• [0044] 9) R⁸⁰ (wherein R⁸⁰ 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_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4aminoalkyl, C_1-4alkylamino, C_1-4hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR⁸¹R⁸², —NR⁸³C(O)R⁸⁴ (wherein R⁸¹, R⁸², R⁸³ and R⁸⁴, which may be the same or different, each represents hydrogen, C_1-4alkyl or C_1-3alkoxyC_2-3alkyl) and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl));
• [0045] 10) C_1-5alkylR⁸⁰ (wherein R⁸⁰ is as defined hereinbefore);
• [0046] 11) C_2-5alkenylR⁸⁰ (wherein R⁸⁰ is as defined hereinbefore);
• [0047] 12) C_2-5alkynylR⁸⁰ (wherein R⁸⁰ is as defined hereinbefore);
• [0048] 13) C_1-5alkylX¹⁵R⁸⁰ (wherein X¹⁵ represents —O—, —S—, —SO—, —SO₂—, —NR⁸⁵C(O)—, —C(O)NR⁸⁶—, —SO₂NR⁸⁷—, —NR⁸⁸SO₂— or —NR⁸⁹— (wherein R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R⁸⁰ is as defined hereinbefore);
• [0049] 14) C_2-5alkenylX¹⁶R⁸⁰ (wherein X¹⁶ represents —O—, —S—, —SO—, —SO₂—, —NR⁹⁰C(O)—, —C(O)NR⁹¹—, —SO₂NR⁹²—, —NR⁹³SO₂— or —NR⁹⁴— (wherein R⁹⁰, R⁹¹, R⁹², R⁹³ and R⁹⁴ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R⁸⁰ is as defined hereinbefore);
• [0050] 15) C_2-5alkynylX¹⁷R⁸⁰ (wherein X¹⁷ represents —O—, —S—, —SO—, —SO₂—, —NR⁹⁵C(O)—, —C(O)NR⁹⁶—, —SO₂NR⁹⁷, —NR⁹⁸SO₂— or —NR⁹⁹— (wherein R⁹⁵, R⁹⁶, R⁹⁷, R⁹⁸ and R⁹⁹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R⁸⁰ is as defined hereinbefore);
• [0051] 16) C_1-4alkylX¹⁸C_1-4alkylR⁸⁰ (wherein X¹⁸ represents —O—, —S—, —SO—, —SO₂—, —NR¹⁰⁰C(O)—, —C(O)NR¹⁰¹—, —SO₂NR¹⁰²—, —NR¹⁰³SO₂— or —NR¹⁰⁴— (wherein R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ and R¹⁰⁴ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R⁸⁰ is as defined hereinbefore);
• [0052] 17) C_1-4alkylX¹⁸C_1-4alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined hereinbefore);
• [0053] 18) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0054] 19) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(Cl₄alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0055] 20) C_2-5alkenylX¹⁸C_1-4alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined hereinbefore);
• [0056] 21) C_2-5alkynylX¹⁸C_1-4alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined hereinbefore); and
• [0057] 22) C_1-4alkylR¹⁰⁵(C_1-4alkyl)_x(X¹⁸)_yR¹⁰⁶ (wherein X¹⁸ is as defined hereinbefore, x is 0 or 1, y is 0 or 1, and R¹⁰⁵ and R¹⁰⁶ are each independently selected from hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl and a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4aminoalkyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6membered 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_1-4alkyl) with the proviso that R¹⁰⁵ cannot be hydrogen);
  and additionally wherein any C_1-5alkyl, C_2-5alkenyl or C_2-5alkynyl group in R⁵⁶X¹⁰— 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.

[0058] According to another aspect of the present invention there is provided the use of compounds of the formula I:

[0059]
wherein:

• [0060] ring C is a 9–10-membered bicyclic moiety which may be saturated or unsaturated, which may be aromatic or non-aromatic, and which optionally may contain 1–3 heteroatoms selected independently from O, N and S;
• [0061] Z is —O—, —NH—, —S—, —CH₂— or a direct bond;
• [0062] R¹ represents hydrogen, oxo, halogeno, hydroxy, C_1-4alkoxy, C_1-4alkyl, C_1-4alkoxymethyl, C_1-4alkanoyl, C_1-4haloalkyl, cyano, amino, C_2-5alkenyl, C_2-5alkynyl, C_1-3alkanoyloxy, nitro, C_1-4alkanoylamino, C_1-4alkoxycarbonyl, C_1-4alkylsulphanyl, C_1-4alkylsulphinyl, C_1-4alkylsulphonyl, carbamoyl, N—C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, aminosulphonyl, N—C_1-4alkylaminosulphonyl, N,N-di(C_1-4alkyl)aminosulphonyl, N—(C_1-4alkylsulphonyl)amino, N—(C_1-4alkylsulphonyl)-N—(C_1-4alkyl)amino, N,N-di(C_1-4alkylsulphonyl)amino or a C_3-7alkylene chain joined to two ring C carbon atoms;
• [0063] n is an integer from 0 to 5;
• [0064] m is an integer from 0 to 3;
• [0065] R² represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylsulphanyl, —NR³R⁴ (wherein R³ and R⁴, which may be the same or different, each represents hydrogen or C_1-3alkyl), 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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R⁵ is selected from one of the following twenty-one groups:
• [0066] 1) hydrogen or C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino;
• [0067] 2) C_1-5alkylX²C(O)R¹¹ (wherein X² represents —O— or —NR¹²— (in which R¹² represents hydrogen, C_1-3 alkyl or C_1-3alkoxyC_2-3alkyl) and R¹¹ represents C_1-3alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));
• [0068] 3) C_1-3alkylX³R¹⁶ (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R¹⁶ represents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
• [0069] 4) C_1-5alkylX⁴C_1-5alkylX⁵R²² (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²² represents hydrogen or C_1-3alkyl);
• [0070] 5) R²⁸ (wherein R²⁸ is a 5–6-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_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl and C_1-4alkylsulphonylC_1-4alkyl);
• [0071] 6) C_1-5alkylR²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0072] 7) C_2-5alkenylR²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0073] 8) C_2-5alkynylR²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0074] 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 on an available carbon atom selected from hydroxy, halogeno, amino, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4aminoalkyl, C_1-4alkylamino, C_1-4hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR³⁰R³¹ and —NR³²C(O)R³³ (wherein R³⁰, R³¹, R³² and R³³, which may be the same or different, each represents hydrogen, C_1-4alkyl or C_1-3alkoxyC_2-3alkyl));
• [0075] 10) C_1-5alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0076] 11) C₂ alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0077] 12) C_2-5alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0078] 13) C_1-5alkylX⁶R²⁹ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—, —NR³⁴C(O)—, —C(O)NR³⁵—, —SO₂NR³⁶—, —NR³⁷S₂— or —NR³⁸— (wherein R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
• [0079] 14) C_2-5alkenylX⁷R²⁹ (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
• [0080] 15) C_2-5alkynylX⁸R²⁹ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—, —NR⁴⁴C(O)—, —C(O)NR⁴⁵—, —SO₂NR⁴⁶—, —NR⁴⁷ SO₂— or —NR⁴⁸— (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
• [0081] 16) C_1-3alkylX⁹C_1-3alkylR²⁹ (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, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
• [0082] 17) C_1-3alkylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0083] 18) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0084] 19) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0085] 20) C_2-5alkenylX⁹C_1-4alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and
• [0086] 21) C_2-5alkynylX⁹C_1-4alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and salts thereof, and prodrugs thereof for example esters, amides and sulphides, 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.

[0087] Preferably ring C is a 9–10-membered aromatic bicyclic moiety which may optionally contain 1–3 heteroatoms selected independently from O, N and S.

[0088] More preferably ring C is a 9–10-membered heteroaromatic bicyclic moiety which contains 1–3 heteroatoms selected independently from O, N and S.

[0089] Particularly ring C is a 9–10-membered heteroaromatic bicyclic moiety which contains 1 or 2 nitrogen atoms.

[0090] According to one aspect of the present invention ring C is a 9-membered heteroaromatic bicyclic moiety which contains 1 or 2 nitrogen atoms, for example indolyl.

[0091] According to another aspect of the present invention ring C is a 10-membered heteroaromatic bicyclic moiety which contains 1 or 2 nitrogen atoms, for example quinolinyl.

[0092] Especially ring C is indolyl or quinolinyl.

[0093] Preferably Z is —O—, —NH—, —S— or a direct bond.

[0094] More preferably Z is —O—, —NH- or —S—.

[0095] Particularly Z is —O— or —S—, especially —O—.

[0096] Advantageously X¹⁰ represents a direct bond, —O—, —S—, —NR⁵⁷C(O)—, —NR⁶⁰SO₂— or —NR⁶¹— (wherein R⁵⁷, R⁶⁰ and R⁶¹ each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0097] Preferably X¹⁰ represents a direct bond, —O—, —S—, —NR⁵⁷C(O)—, —NR⁶⁰SO₂— (wherein R⁵⁷ and R⁶⁰ each independently represents hydrogen or C_1-2alkyl) or NH.

[0098] More preferably X¹⁰ represents —O—, —S—, —NR⁵⁷C(O)— (wherein R⁵⁷ represents hydrogen or C_1-2alkyl) or NH.

[0099] Particularly X¹⁰ represents —O— or —NR⁵⁷C(O)— (wherein R⁵⁷ represents hydrogen or C_1-2alkyl), more particularly —O— or —NHC(O)—, especially —O—.

[0100] According to another aspect of the present invention X¹⁰ represents —O— or a direct bond.

[0101] Advantageously X¹² represents —O—, —S—, —SO—, —SO₂—, —NR⁶⁸C(O)—, —NR⁷¹SO₂— or —NR⁷²— (wherein R⁶⁸, R⁷¹ and R⁷² each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0102] Preferably X¹² represents —O—, —S—, —SO—, —SO₂— or —NR⁷²— (wherein R⁷² represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0103] More preferably X¹² represents —O— or —NR⁷²— (wherein R⁷² represents hydrogen or C_1-2alkyl).

[0104] According to another aspect of the present invention X¹² represents —O—, —SO₂—, —NR⁷¹SO₂— or —NR⁷²— (wherein R⁷¹ and R⁷² each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0105] Advantageously X¹⁸ represents —O—, —S— or —NR¹⁰⁴— (wherein R¹⁰⁴ represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0106] Preferably X¹⁸ represents —O— or —NR¹⁰⁴— (wherein R¹⁰⁴ represents hydrogen or C_1-2alkyl).

[0107] According to another aspect of the present invention X¹⁸ represents —O—, —CONR¹⁰¹— or —NR¹⁰⁴— (wherein R¹⁰¹ and R¹⁰⁴ each independently represents hydrogen or C_1-2alkyl).

[0108] Advantageously R⁶⁷ represents a 5–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5–6-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_1-3alkyl).

[0109] Preferably R⁶⁷ is pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl).

[0110] More preferably R⁶⁷ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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).

[0111] Particularly R⁶⁷ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from a group —(—O—)_f(C_1-3alkyl)_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).

[0112] Preferably R⁷⁹ is pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl).

[0113] More preferably R⁷⁹ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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).

[0114] Particularly R⁷⁹ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from a group —(—O—)_f(C_1-3alkyl)_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).

[0115] Advantageously R¹⁰⁵ and R¹⁰⁶ are each independently a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-3alkyl).

[0116] Preferably R¹⁰⁵ and R¹⁰⁶ are each independently selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl).

[0117] More preferably R¹⁰⁵ and R¹⁰⁶ are each independently selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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).

[0118] Particularly R¹⁰⁵ and R¹⁰⁶ are each independently selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino which group may bear 1 or 2 substituents selected from a group —(—O—)_f(C_1-3alkyl)_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).

[0119] Advantageously R¹ represents oxo, halogeno, hydroxy, C_1-4alkoxy, C_1-4alkyl, C_1-4alkoxymethyl, C_1-4alkanoyl, C_1-4haloalkyl, cyano, amino, C_2-5alkenyl, C_2-5alkynyl, C_1-3alkanoyloxy, nitro, C_1-4alkanoylamino, C_1-4alkoxycarbonyl, C_1-4alkylsulphanyl, C_1-4alkylsulphinyl, C_1-4alkylsulphonyl, carbamoyl, N—C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, aminosulphonyl, N—C_1-4alkylaminosulphonyl, N,N-di(C_1-4alkyl)aminosulphonyl, N—(C_1-4alkylsulphonyl)amino, N—(C_1-4alkylsulphonyl)-N—(C_1-4alkyl)amino, N,N-di(C_1-4alkylsulphonyl)amino, a C_3-7alkylene chain joined to two ring C carbon atoms, C_1-4alkanoylaminoC_1-4alkyl, carboxy or a group R⁵⁶X¹⁰ (wherein X¹⁰ is as defined hereinbefore and R⁵⁶ is selected from one of the following nine groups:

• [0120] 1) C_1-5alkylX¹²R⁶⁷ (wherein X¹² and R⁶⁷ are as defined hereinbefore);
• [0121] 2) R⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);
• [0122] 3) C_1-5alkylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);
• [0123] 4) C_2-5alkenylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);
• [0124] 5) C_2-5alkynylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);
• [0125] 6) C_1-3alkylX¹⁸C_1-3alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined hereinbefore);
• [0126] 7) C_2-5alkenylX¹⁸C_1-4alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined hereinbefore);
• [0127] 8) C_2-5alkynylX¹⁸C_1-4alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined hereinbefore); and
• [0128] 9) C_1-3alkylR¹⁰⁵(C_1-3alkyl)_x(X¹⁸)_yR¹⁰⁶ (wherein X¹⁸, x, y, R¹⁰⁵ and R¹⁰⁶ are as defined hereinbefore;
  and additionally wherein any C_1-5alkyl, C_2-5alkenyl or C_2-5alkynyl group in R⁵⁶X¹⁰— may bear one or more substituents selected from hydroxy, halogeno and amino,
  with the proviso that when X¹⁰ is a direct bond R⁵⁶ is not R⁷⁹).

[0129] Preferably R¹ represents oxo, halogeno, hydroxy, C_1-2alkoxy, C_1-2alkyl, C_1-2alkoxymethyl, C_2-3alkanoyl, C_1-2haloalkyl, cyano, amino, C_2-4alkenyl, C_2-4alkynyl, C_2-3alkanoyloxy, nitro, C_2-3alkanoylamino, C_1-2alkoxycarbonyl, C_1-2alkylsulphanyl, C_1-2alkylsulphinyl, C_1-2alkylsulphonyl, carbamoyl, N—C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, aminosulphonyl, N—C_1-2alkylaminosulphonyl, N,N-di(C_1-2alkyl)aminosulphonyl, N—(C_1-2alkylsulphonyl)amino, N—(C_1-2alkylsulphonyl)-N—(C_1-2alkyl)amino or a C_3-7alkylene chain joined to two ring C carbon atoms.

[0130] More preferably R¹ represents oxo, hydroxy, C_1-2alkoxymethyl, amino, halogeno, C_1-2alkyl, C_1-2alkoxy, trifluoromethyl, cyano, nitro, C_2-3alkanoyl.

[0131] Particularly R¹ represents methyl, ethyl, trifluoromethyl or halogeno.

[0132] Especially R¹ represents methyl, fluoro, chloro or bromo, more especially methyl or fluoro.

[0133] Preferably n is an integer from 0 to 3.

[0134] More preferably n is 0, 1 or 2.

[0135] Preferably m is an integer from 0 to 2, more preferably 1 or 2, most preferably 2.

[0136] Advantageously X¹ represents a direct bond, —O—, —S—, —NR⁶C(O)—, —NR⁹SO₂—or —NR¹⁰— (wherein R⁶, R⁹ and R¹⁰ each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0137] Preferably X¹ represents a direct bond, —O—, —S—, —NR⁶C(O)—, —NR⁹SO₂— (wherein R⁶ and R⁹ each independently represents hydrogen or C_1-2alkyl) or NH.

[0138] More preferably X¹ represents —O—, —S—, —NR⁶C(O)— (wherein R⁶ represents hydrogen or C_1-2alkyl) or NH.

[0139] Particularly X¹ represents —O— or —NR⁶C(O)— (wherein R⁶ represents hydrogen or C, ₂alkyl), more particularly —O— or —NHC(O)—, especially —O—.

[0140] According to another aspect of the present invention X¹ represents —O— or a direct bond.

[0141] Advantageously X² represents —O— or NR¹² (wherein R¹² represents hydrogen, C_1-3alkyl or C_1-2alkoxyethyl).

[0142] Advantageously X³ represents —O—, —S—, —SO—, —SO₂—, —NR¹⁷C(O)—, —NR²SO₂— or —NR²¹— (wherein R¹⁷, R²⁰ and R²¹ each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0143] Preferably X³ represents —O—, —S—, —SO—, —SO₂— or —NR²¹— (wherein R²¹ represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0144] More preferably X³ represents —O— or —NR²¹— (wherein R²¹ represents hydrogen or C_1-2alkyl).

[0145] According to another aspect of the present invention X³ represents —O—, —SO₂—, —NR²⁰SO₂— or —NR²¹— (wherein R²⁰ and R²¹ each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0146] Advantageously X⁴ and X⁵ which may be the same or different each represents —O—, —S—, —SO—, —SO₂— or —NR²⁷— (wherein R²⁷ represents hydrogen, C_1-3alkyl or C_1-2alkoxyethyl).

[0147] Preferably X⁴ and X⁵ which may be the same or different each represents —O—, —S— or —NR²⁷— (wherein R²⁷ represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0148] More preferably X⁴ and X⁵ which may be the same or different each represents —O— or NH—.

[0149] Advantageously X⁶ represents —O—, —S— or —NR³⁸— (wherein R³⁸ represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0150] Preferably X⁷ represents —O— or —NR³⁸— (wherein R³⁸ represents hydrogen or C_1-2alkyl).

[0151] Advantageously X⁷ represents —O—, —S— or —NR⁴³— (wherein R⁴³ represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0152] Preferably X⁷ represents —O— or —NR⁴³— (wherein R⁴³ represents hydrogen or C_1-2alkyl).

[0153] Advantageously X⁸ represents —O—, —S— or —NR⁴⁸— (wherein R⁴⁸ represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0154] Preferably X⁸ represents —O— or —NR⁴⁸— (wherein R⁴⁸ represents hydrogen or C_1-2alkyl).

[0155] Advantageously X⁹ represents —O—, —S— or —NR⁵³— (wherein R⁵³ represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0156] Preferably X⁹ represents —O— or —NR⁵³— (wherein R⁵³ represents hydrogen or C_1-2alkyl).

[0157] According to another aspect of the present invention X⁹ represents —O—, —CONR⁵⁰— or —NR⁵³— (wherein R⁵⁰ and R⁵³ each independently represents hydrogen or C_1-2alkyl).

[0158] 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, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl).

[0159] Advantageously R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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).

[0160] In one embodiment of the present invention R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from a group —(—O—)_f(C_1-3alkyl)_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).

[0161] Particularly R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl and C_1-2alkylsulphonylC_1-3alkyl.

[0162] According to another aspect of the present invention, preferably R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl and C_1-2alkylsulphonylC_1-3alkyl.

[0163] Where R²⁹ is a 5–6-membered aromatic heterocyclic group, 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.

[0164] 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.

[0165] In one embodiment of the invention R²⁹ 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.

[0166] In the definition of R²⁹, conveniently substituents are selected from halogeno, C_1-4alkyl, C_1-4alkoxy, cyano and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl).

[0167] In the definition of R²⁹, more conveniently substituents are selected from chloro, fluoro, methyl, ethyl and a group —(—O—)_f(C_1-3alkyl)_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).

[0168] According to another emodiment of the present invention in the definition of R²⁹, conveniently substituents are selected from halogeno, C_1-4alkyl, C_1-4alkoxy and cyano, more conveniently substituents are selected from chloro, fluoro, methyl and ethyl.

[0169] Advantageously R⁵⁴ and R⁵⁵ are each independently a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl and a group —(—O—)_f(C_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-3alkyl).

[0170] Preferably R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl).

[0171] More preferably R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl and a group —(—O—)_f(C_1-3alkyl)_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).

[0172] Particularly R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino which group may bear 1 or 2 substituents selected from a group —(—O—)_f(C_1-3alkyl)_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).

[0173] More particularly R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino which group is unsubstituted.

[0174] Conveniently R² represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selected from one of the following twenty-two groups:

• [0175] 1) oxiranylC_1-4alkyl or C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C_2-5alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
• [0176] 2) C_2-3alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹ represents C_1-3alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be the same or different are each C_1-4alkyl or C_1-2alkoxyethyl));
• [0177] 3) C_2-4alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ represents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-3alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl));
• [0178] 4) C_2-3alkylX⁴C_2-3alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore defined and R²² represents hydrogen or C_1-3alkyl);
• [0179] 5) R²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0180] 6) C_1-5alkylR¹⁰⁷ (wherein R¹⁰⁷ is a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C_1-5alkyl through a carbon atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl)) or C_2-5alkylR¹⁰⁸ (wherein R¹⁰⁸ is a 4–6membered 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 C_2-5alkyl through a nitrogen atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(Cl₄alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl));
• [0181] 7) C_3-4alkenylR¹⁰⁹ (wherein R¹⁰⁹ represents R¹⁰⁷ or R¹⁰⁸ as defined hereinbefore);
• [0182] 8) C_3-4alkynylR¹⁰⁹ (wherein R¹⁰⁹ represents R¹⁰⁷ or R¹⁰⁸ as defined hereinbefore);
• [0183] 9) R²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0184] 10) C_1-5alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0185] 11) C_3-5alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0186] 12) C_3-5alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0187] 13) C_1-5alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);
• [0188] 14) C_4-5alkenylX⁷R²⁹ (wherein X⁷ and R²⁹ are as defined hereinbefore);
• [0189] 15) C_4-5alkynylX⁸R²⁹ (wherein X⁸ and R²⁹ are as defined hereinbefore);
• [0190] 16) C_2-3alkylX⁹C_1-3alkylR²⁹ (wherein X⁹ and R²⁹ are as defined hereinbefore);
• [0191] 17) C_2-3alkylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0192] 18) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0193] 19) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0194] 20) C_2-5alkenylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0195] 21) C_2-5alkynylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and
• [0196] 22) C_1-3alkylR⁵⁴(C_1-3alkyl)_q(X⁹)_rR⁵⁵ (wherein X⁹, q, r, R⁵⁴ and R⁵⁵ are as defined hereinbefore); and additionally wherein any C_1-5alkyl, C_2-5alkenyl or C_2-5alkynyl group in R⁵X¹— may bear one or more substituents selected from hydroxy, halogeno and amino].

[0197] Advantageously R² represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selected from one of the following twenty-two groups:

• [0198] 1) C_1-4alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C_2-5alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
• [0199] 2) C_2-3alkylX²C(O)R¹¹ (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 C_1-4alkyl or C_1-2alkoxyethyl));
• [0200] 3) C_2-4alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is a group selected from C_1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl and tetrahydropyranyl, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl or tetrahydropyranyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl));
• [0201] 4) C_2-3alkylX⁴C_2-3alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore defined and R²² represents hydrogen or C_1-3alkyl);
• [0202] 5) R²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0203] 6) C_1-4alkylR¹¹⁰ (wherein R¹¹⁰ is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C_1-4alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl)) or C_2-4alkylR¹¹¹ (wherein R¹¹¹ is a group selected from morpholino, thiomorpholino, 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, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl));
• [0204] 7) C_3-4alkenylR¹¹² (wherein R¹¹² represents R¹¹⁰ or R¹¹¹ as defined hereinbefore);
• [0205] 8) C_3-4alkynylR¹¹² (wherein R¹¹² represents R¹¹⁰ or R¹¹¹ as defined hereinbefore);
• [0206] 9) R²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0207] 10) C_1-4alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0208] 11) 1-R²⁹prop-1-en-3-yl or 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined hereinbefore with the proviso that when R⁵ is 1-R²⁹prop-1-en-3-yl, R²⁹ is linked to the alkenyl group via a carbon atom);
• [0209] 12) 1-R²⁹prop-1-yn-3-yl or 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined hereinbefore with the proviso that when R⁵ is 1-R²⁹prop-1-yn-3-yl, R²⁹ is linked to the alkynyl group via a carbon atom);
• [0210] 13) C_1-5alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);
• [0211] 14)1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined hereinbefore);
• [0212] 15)1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined hereinbefore);
• [0213] 16) C_2-3alkylX⁹C_1-3alkylR²⁹ (wherein X⁹ and R²⁹ are as defined hereinbefore);
• [0214] 17) C_2-3alkylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0215] 18) C_2-5alkenyl 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, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C _1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0216] 19) C_2-5alkynyl 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, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0217] 20) C_2-4alkenylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0218] 21) C_2-4alkynylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and
• [0219] 22) C_1-3alkylR⁵⁴(C_1-3alkyl)_q(X⁹)_rR⁵⁵ (wherein X, q, r, R⁵⁴ and R⁵⁵ are as defined hereinbefore);
  and additionally wherein any C_1-5alkyl, C_2-5alkenyl or C_2-5alkynyl group in R⁵X¹— may bear one or more substituents selected from hydroxy, halogeno and amino].

[0220] Preferably R² represents hydroxy, halogeno, nitro, trifluoromethyl, C_1-3alkyl, cyano, amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selected from one of the following twenty groups:

• [0221] 1) C_1-3alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C_2-3alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
• [0222] 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)propyl, or 2-(N-methyl-N-(butoxycarbonyl)amino)ethyl;
• [0223] 3) C_2-3alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is a group selected from C_1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl and tetrahydropyranyl which group is linked to X³ through a carbon atom and which C_1-3alkyl group may bear 1 or 2 substituents selected from hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl or tetrahydropyranyl group may bear one substituent selected from oxo, hydroxy, halogeno, cyano, C_1-2cyanoalkyl, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-2alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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));
• [0224] 4) C_2-3alkylX⁴C_2-3alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore defined and R²² represents hydrogen or C_1-2alkyl);
• [0225] 5) R²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0226] 6) C_1-3alkylR¹¹⁰ (wherein R¹¹⁰ is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, imidazolidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C_1-3alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-2cyanoalkyl, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-2alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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)) or C_2-3alkylR¹¹¹ (wherein R¹¹¹ is a group selected from morpholino, thiomorpholino, 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, C_1-2cyanoalkyl, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-2alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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));
• [0227] 7) R²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0228] 8) C_1-4alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0229] 9) 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined hereinbefore);
• [0230] 10) 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined hereinbefore);
• [0231] 11) C_1-3alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);
• [0232] 12) 1(R²⁹X⁷)but-2-en-4-yl (wherein X^{7 and R29} are as defined hereinbefore);
• [0233] 13)1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined hereinbefore);
• [0234] 14) C_2-3alkylX⁹C_1-3alkylR²⁹ (wherein X⁹ and R²⁹ are as defined hereinbefore);
• [0235] 15) C_2-3alkylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0236] 16) C_2-5alkenyl 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, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0237] 17) C_2-5alkynyl 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, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4 alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0238] 18) C_2-3alkenylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0239] 19) C_2-3alkynylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and
• [0240] 20) C_1-3alkylR⁵⁴(C_1-3alkyl)_q(X⁹)_rR⁵⁵ (wherein X⁹, q, r, R⁵⁴ and R⁵⁵ are as defined hereinbefore); and additionally wherein any C_1-5alkyl, C_2-5 alkenyl or C_2-5alkynyl group in R⁵X¹— may bear one or more substituents selected from hydroxy, halogeno and amino].

[0241] More preferably R² represents hydroxy, C_1-3alkyl, 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-morpholinoethyl, 3-morpholinopropyl, 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, (1-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-(1-cyanomethylpiperidin-3-yl)ethyl, 2-(1-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)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (1-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (1-(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, 1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl, 2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl, 3-(1-isopropylpiperidin-2-yl)propyl, 3-(1-isopropylpiperidin-3-yl)propyl, 3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl, 3-(1-(cyanomethyl)piperidin-4-yloxy)propyl, 2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl, 3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-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-(1,3-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-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl, 2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-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-1-yl)ethyl, 3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)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, 1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl, 1-(2-piperidinylethyl)piperidin-4-ylmethyl, 1-(3-piperidinylpropyl)piperidin-4-ylmethyl, 1-(2-morpholinoethyl)piperidin-4-ylmethyl, 1-(3-morpholinopropyl)piperidin-4-ylmethyl, 1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl, 1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl, 1-(2-azetidinylethyl)piperidin-4-ylmethyl, 1-(3-azetidinylpropyl)piperidin-4-ylmethyl, 3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl, (2S)-3-morpholino-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-(1-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].

[0242] Particularly R² represents C_1-3alkyl, 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-morpholinoethyl, 3-morpholinopropyl, 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, (1-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-(1-cyanomethylpiperidin-3-yl)ethyl, 2-(1-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)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (1-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (1-(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, 1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl, 2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl, 3-(1-isopropylpiperidin-2-yl)propyl, 3-(1-isopropylpiperidin-3-yl)propyl, 3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl, 3-(1-(cyanomethyl)piperidin-4-yloxy)propyl, 2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl, 3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-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-(1,3-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-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl, 2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-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-1-yl)ethyl, 3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-(²-morpholinoethoxy)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, 1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl, 1-(2-piperidinylethyl)piperidin-4-ylmethyl, 1-(3-piperidinylpropyl)piperidin-4-ylmethyl, 1-(2-morpholinoethyl)piperidin-4-ylmethyl, 1-(3-morpholinopropyl)piperidin-4-ylmethyl, 1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl, 1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl, 1-(2-azetidinylethyl)piperidin-4-ylmethyl, 1-(3-azetidinylpropyl)piperidin-4-ylmethyl, 3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl, (2S)-3-morpholino-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-(1-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].

[0243] More particularly R² represents C_1-3alkyl, 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-dimethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl, 3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 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, (1-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-(1-cyanomethylpiperidin-3-yl)ethyl, 2-(1-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)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (1-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (1-(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, 1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl, 2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl, 3-(1-isopropylpiperidin-2-yl)propyl, 3-(1-isopropylpiperidin-3-yl)propyl, 3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl, 3-(1-(cyanomethyl)piperidin-4-yloxy)propyl, 2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl, 3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-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-(1,3-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-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-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-1-yl)ethyl, 3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)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, 1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl, 1-(2-piperidinylethyl)piperidin-4-ylmethyl, 1-(3-piperidinylpropyl)piperidin-4-ylmethyl, 1-(2-morpholinoethyl)piperidin-4-ylmethyl, 1-(3-morpholinopropyl)piperidin-4-ylmethyl, 1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl, 1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl, 1-(2-azetidinylethyl)piperidin-4-ylmethyl, 1-(3-azetidinylpropyl)piperidin-4-ylmethyl, 3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl, (2S)-3-morpholino-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-(1-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].

[0244] In another aspect R² represents 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-morpholinoethoxy, 3-morpholinopropoxy, 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, (1-methylpiperidin-3-yl)methoxy, (1-methylpiperidin-4-yl)methoxy, (1-cyanomethylpiperidin-3-yl)methoxy, (1-cyanomethylpiperidin-4-yl)methoxy, 2-(methylpiperidin-3-yl)ethoxy, 2-(methylpiperidin-4-yl)ethoxy, 2-(1-cyanomethylpiperidin-3-yl)ethoxy, 2-(1-cyanomethylpiperidin-4-yl)ethoxy, 3-(methylpiperidin-3-yl)propoxy, 3-(methylpiperidin-4-yl)propoxy, 3-(1-cyanomethylpiperidin-3-yl)propoxy, 3-(1-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)propoxy, (1-(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)piperidin-4-yl)propoxy, 1-isopropylpiperidin-2-ylmethoxy, 1-isopropylpiperidin-3-ylmethoxy, 1-isopropylpiperidin-4-ylmethoxy, 2-(1-isopropylpiperidin-2-yl)ethoxy, 2-(1-isopropylpiperidin-3-yl)ethoxy, 2-(1-isopropylpiperidin-4-yl)ethoxy, 3-(1-isopropylpiperidin-2-yl)propoxy, 3-(1-isopropylpiperidin-3-yl)propoxy, 3-(1-isopropylpiperidin-4-yl)propoxy, 2-(piperidin-4-yloxy)ethoxy, 3-(piperidin-4-yloxy)propoxy, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethoxy, 3-(1-(cyanomethyl)piperidin-4-yloxy)propoxy, 2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy, 3-(1-(2-cyanoethyl)piperidin-4-yloxy)propoxy, 2-(piperazin-1-yl)ethoxy, 3-(piperazin-1-yl)propoxy, (pyrrolidin-2-yl)methoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-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, (1,3-dioxolan-2-yl)methoxy, 2-(1,3-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-(1,2,3-triazol-1-yl)ethoxy, 2-(1,2,3-triazol-2-yl)ethoxy, 2-(1,2,4-triazol-1-yl)ethoxy, 2-(1,2,4-triazol-4-yl)ethoxy, 4-pyridylmethoxy, 2-(4-pyridyl)ethoxy, 3-(4-pyridyl)propoxy, 2-(4-pyridyloxy)ethoxy, 2-(4-pyridylamino)ethoxy, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy, 2-(2-oxo-imidazolidin-1-yl)ethoxy, 3-(2-oxo-imidazolidin-1-yl)propoxy, 2-thiomorpholinoethoxy, 3-thiomorpholinopropoxy, 2-(1,1-dioxothiomorpholino)ethoxy, 3-(1,1-dioxothiomorpholino)propoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-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-morpholinopropylsulphonyl)-N-methyl)amino)ethoxy, 2-((N-methyl-N-4-pyridyl)amino)ethoxy, 3-(4-oxidomorpholino)propoxy, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy, 3-(2-(4-methylpiperazin-1-yl)ethoxy)propoxy, 2-(2-morpholinoethoxy)ethoxy, 3-(2-morpholinoethoxy)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-morpholinoethyl)piperidin-4-ylmethoxy, 1-(3-morpholinopropyl)piperidin-4-ylmethoxy, 1-(2-thiomorpholinoethyl)piperidin-4-ylmethoxy, 1-(3-thiomorpholinopropyl)piperidin-4-ylmethoxy, 1-(2-azetidinylethyl)piperidin-4-ylmethoxy, 1-(3-azetidinylpropyl)piperidin-4-ylmethoxy, 3-morpholino-2-hydroxypropoxy, (2R)-3-morpholino-2-hydroxypropoxy, (2S)-3-morpholino-2-hydroxypropoxy, 3-piperidino-2-hydroxypropoxy, (2R)-3-piperidino-2-hydroxypropoxy, (2S)-3-piperidino-2-hydroxypropoxy, 3-pyrrolidin-1-yl-2-hydroxypropoxy, (2R)-3-pyrrolidin-1-yl-2-hydroxypropoxy, (2S)-3-pyrrolidin-1-yl-2-hydroxypropoxy, 3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy, (2R)-3-(1-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.

[0245] According to another aspect of the present invention conveniently R² represents hydroxy, halogeno, nitro, trifluoromethyl, C_1-3alkyl, cyano, amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selected from one of the following twenty-one groups:

• [0246] 1) C_1-5alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C_2-5alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
• [0247] 2) C_2-3alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹ represents C_1-3alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be the same or different are each C_1-2alkyl or C_1-2alkoxyethyl));
• [0248] 3) C_2-4alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ represents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-3alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
• [0249] 4) C_2-3alkylX⁴C_2-3alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore defined and R²² represents hydrogen or C_1-3alkyl);
• [0250] 5) C_1-5alkylR¹²⁹ (wherein R¹²⁹ is a 5–6-membered saturated heterocyclic group with 1–2 heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C_1-5alkyl through a carbon atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl and C_1-4alkylsulphonylC_1-4alkyl) or C_2-5alkylR¹³⁰ (wherein R¹³⁰ is a 5–6-membered saturated heterocyclic group with 1–2 heteroatoms of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to C_2-5alkyl though a nitrogen atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl and C_1-4alkylsulphonylC_1-4alkyl);
• [0251] 6) C_3-4alkenylR¹³¹ (wherein R¹³¹ represents R¹²⁹ or R¹³⁰ as defined hereinbefore);
• [0252] 7) C_3-4alkynylR¹³¹ (wherein R¹³¹ represents R¹²⁹ or R¹³⁰ as defined hereinbefore);
• [0253] 8) R²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0254] 9) C_1-5alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0255] 10) C_3-5alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0256] 11) C_3-5alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0257] 12) C_1-5alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);
• [0258] 13) C_4-5alkenylX⁷R²⁹ (wherein X⁷ and R²⁹ are as defined hereinbefore);
• [0259] 14) C_4-5alkynylX⁸R²⁹ (wherein X⁸ and R²⁹ are as defined hereinbefore);
• [0260] 15) C_2-3alkylX⁹C_1-2alkylR²⁹ (wherein X⁹ and R²⁹ are as defined hereinbefore);
• [0261] 16) R²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0262] 17) C_2-3alkylX⁹C_1-2alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0263] 18) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0264] 19) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0265] 20) C_2-5alkenylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and
• [0266] 21) C_2-5alkynylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore)].

[0267] According to another aspect of the present invention advantageously R² represents hydroxy, halogeno, nitro, trifluoromethyl, C_1-3alkyl, cyano, amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selected from one of the following twenty-one groups:

• [0268] 1) C_1-4alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C_2-4alkyl which may be unsubstituted or substituted with 1 or 2 groups selected from hydroxy and amino;
• [0269] 2) C_2-3alkylX²C(O)R¹¹ (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 C_1-2alkyl or C_1-2alkoxyethyl));
• [0270] 3) C_2-4alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is a group selected from C_1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydropyranyl which group is linked to X³ through a carbon atom and which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy);
• [0271] 4) C_2-3alkylX⁴C_2-3alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore defined and R²² represents hydrogen or C_1-3alkyl);
• [0272] 5) C_1-4alkylR¹³² (wherein R¹³² is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C_1-4alkyl through a carbon atom and which group may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl and C_1-2alkylsulphonylC_1-3alkyl) or C_2-4alkylR¹³³ (wherein R¹³³ is a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl and C_1-2alkylsulphonylC_1-3alkyl);
• [0273] 6) C_3-4alkenylR¹³⁴ (wherein R¹³⁴ represents R¹³² or R¹³³ as defined hereinbefore);
• [0274] 7) C_3-4alkynylR¹³⁴ (wherein R¹³⁴ represents R¹³² or R¹³³ as defined hereinbefore);
• [0275] 8) R²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0276] 9) C₁4alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0277] 10) 1-R²⁹prop-1-en-3-yl or 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined hereinbefore with the proviso that when R⁵ is 1-R²⁹prop-1-en-3-yl, R²⁹ is linked to the alkenyl group via a carbon atom);
• [0278] 11) 1-R²⁹prop-1-yn-3-yl or 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined hereinbefore with the proviso that when R⁵ is 1-R²⁹prop-1-yn-3-yl, R²⁹ is linked to the alkynyl group via a carbon atom);
• [0279] 12) C_1-5alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);
• [0280] 13) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined hereinbefore);
• [0281] 14)1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined hereinbefore);
• [0282] 15) C_2-3alkylX⁹C_1-2alkylR²⁹ (wherein X⁹ and R²⁹ are as defined hereinbefore);
• [0283] 16) R²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0284] 17) C_2-3alkylX⁹C_1-2alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0285] 18) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0286] 19) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0287] 20) C_2-4alkenylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and
• [0288] 21) C_2-4alkynylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore)].

[0289] According to another aspect of the present invention preferably R² represents hydroxy, halogeno, nitro, trifluoromethyl, C_1-3alkyl, cyano, amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selected from one of the following nineteen groups:

• [0290] 1) C_1-3alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C_2-3alkyl which may be unsubstituted or substituted with 1 or 2 groups selected from hydroxy and amino;
• [0291] 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)propyl;
• [0292] 3) C_2-3alkylX³R¹⁶ (wherein X³ is as defined hereinbefore and R¹⁶ is a group selected from C_1-2alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydropyranyl which group is linked to X³ through a carbon atom and which C_1-2alkyl group may bear 1 or 2 substituents selected from hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy);
• [0293] 4) C_2-3alkylX⁴C_2-3alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore defined and R²² represents hydrogen or C_1-2alkyl);
• [0294] 5) C_1-2alkylR¹³² (wherein R¹³² is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C_1-2alkyl through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl and C_1-2alkylsulphonylC_1-3alkyl) or C_2-3alkylR¹³³ (wherein R¹³³ is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl which group may carry one or two substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl and C_1-2alkylsulphonylC_1-3alkyl);
• [0295] 6) R²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0296] 7) C_1-4alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0297] 8) 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined hereinbefore);
• [0298] 9)1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined hereinbefore);
• [0299] 10) C_1-5alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);
• [0300] 11)1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined hereinbefore);
• [0301] 12)1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined hereinbefore);
• [0302] 13) ethylX⁹methylR²⁹ (wherein X⁹ and R²⁹ are as defined hereinbefore);
• [0303] 14) R²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0304] 15) ethylX⁹C_1-2alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore);
• [0305] 16) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0306] 17) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;
• [0307] 18) C_2-3alkenylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore); and
• [0308] 19) C_2-3alkynylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined hereinbefore)].

[0309] According to another aspect of the present invention more preferably R² represents hydroxy, C_1-3alkyl, 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-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 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, (1-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-(1-cyanomethylpiperidin-3-yl)ethyl, 2-(1-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)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (1-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (1-(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, 1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl, 2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl, 3(1-isopropylpiperidin-2-yl)propyl, 3-(1-isopropylpiperidin-3-yl)propyl, 3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-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-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl, 2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-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-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3-(tetrahydropyran-4-yloxy)propyl, 2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or 3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].

[0310] According to another aspect of the present invention particularly R² represents C_1-3alkyl, 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-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 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, (1-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-(1-cyanomethylpiperidin-3-yl)ethyl, 2-(1-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)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (1-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (1-(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, 1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl, 2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl, 3-(1-isopropylpiperidin-2-yl)propyl, 3-(1-isopropylpiperidin-3-yl)propyl, 3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-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-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl, 2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-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-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino, 2-((N-(]-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3-(tetrahydropyran-4-yloxy)propyl, 2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or 3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].

[0311] According to another aspect of the present invention more particularly R² represents C_1-3alkyl, 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-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 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, (1-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-(1-cyanomethylpiperidin-3-yl)ethyl, 2-(1-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)piperidin-3-yl)propyl, 3-((2-methoxyethyl)piperidin-4-yl)propyl, (1-(2-methylsulphonylethyl)piperidin-3-yl)methyl, (1-(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, 1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl, 2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl, 3-(1-isopropylpiperidin-2-yl)propyl, 3-(1-isopropylpiperidin-3-yl)propyl, 3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-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-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, morpholino, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-(N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl, 3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl, 3-(tetrahydropyran-4-yloxy)propyl, 2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or 3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].

[0312] According to another embodiment of the present invention in another aspect R² represents methoxy, 2-methoxyethoxy, 2-(2-methoxyethoxy)ethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, benzyloxy, 2-(tetrahydropyran-4-yloxy)ethoxy, 3-(tetrahydropyran-4-yloxy)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy 2-(1,1-dioxothiomorpholino)ethoxy, 3-(1,1-dioxothiomorpholino)propoxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy, 2-(1,2,4-triazol-1-yl)ethoxy, 2-((N-methyl-N-4-pyridyl)amino)ethoxy, 2-(N,N-dimethylamino)ethoxy, 3-(N,N-dimethylamino)propoxy, 2-(N-methoxyacetyl-N-methylamino)ethoxy, 3-(N-methoxyacetyl-N-methylamino)propoxy, 1-methylpiperidin-3-ylmethoxy, 1-methylpiperidin-4-ylmethoxy, (1-cyanomethylpiperidin-3-yl)methoxy, (1-cyanomethylpiperidin-4-yl)methoxy, 2-(1-cyanomethylpiperidin-3-yl)ethoxy, 2-(1-cyanomethylpiperidin-4-yl)ethoxy, 3-(1-cyanomethylpiperidin-3-yl)propoxy, 3-(1-cyanomethylpiperidin-4-yl)propoxy, ((2-methoxyethyl)piperidin-3-yl)methoxy, ((2-methoxyethyl)piperidin-4-yl)methoxy, 2-N-(2-methoxyethyl)-N-methylamino)ethoxy, 4-(pyrrolidin-1-yl)but-2-en-yloxy, 2-(2-oxopyrrolidin-1-yl)ethoxy, 3-(2-oxopyrrolidin-1-yl)propoxy, (pyrrolidin-2-yl)methoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-(2-(pyrrolidin-1-yl)ethoxy)ethoxy, (2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy, 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, 1-(2-methylsulphonylethyl)piperidin-3-ylmethoxy, 1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy, 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-(methylpiperidin-3-yl)ethoxy, 2-(methylpiperidin-4-yl)ethoxy, 3-(methylpiperidin-3-yl)propoxy, 3-(methylpiperidin-4-yl)propoxy, 2-(ethylpiperidin-3-yl)ethoxy, 2-(ethylpiperidin-4-yl)ethoxy, 3-(ethylpiperidin-3-yl)propoxy, 3-(ethylpiperidin-4-yl)propoxy, 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)propoxy, 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-isopropylpiperidin-2-ylmethoxy, 1-isopropylpiperidin-3-ylmethoxy, 1-isopropylpiperidin-4-ylmethoxy, 2-(1-isopropylpiperidin-2-yl)ethoxy, 2-(1-isopropylpiperidin-3-yl)ethoxy, 2-(1-isopropylpiperidin-4-yl)ethoxy, 3-(1-isopropylpiperidin-2-yl)propoxy, 3-(1-isopropylpiperidin-3-yl)propoxy, 3-(1-isopropylpiperidin-4-yl)propoxy, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy, 3-(2-(4-methylpiperazin-1-yl)ethoxy)propoxy, 2-(2-morpholinoethoxy)ethoxy, 3-(2-morpholinoethoxy)propoxy, 2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or 3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl.

[0313] Where one of the R² substituents is R⁵X¹— the substituent R⁵X¹— is preferably at the 6- or 7-position of the quinazoline ring, more preferably at the 7-position of the quinazoline ring.

[0314] When one of the R² substituents is at the 6-position of the quinazoline ring it is preferably hydrogen, halogeno, C_1-3alkyl, trifluoromethyl, C_1-3alkoxy, C_1-3alkylsulphanyl or —NR³R⁴ (wherein R³ and R⁴ are as defined hereinbefore).

[0315] When one of the R² substituents is at the 6-position of the quinazoline ring it is more preferably C_1-3alkoxy, especially methoxy.

[0316] In another aspect of the present invention there is provided the use of compounds of the formula Ia:

[0317]
[wherein:

• [0318] ring C, R¹, R², n and Z are as defined hereinbefore with the provisos that R² is not hydrogen and that Z is not CH₂ or a direct bond; and
• [0319] R^2a represents hydrogen, halogeno, C_1-3alkyl, trifluoromethyl, C_1-3alkoxy, C_1-3alkylsulphanyl, —NR^3aR^4a (wherein R^3a and R^4a, which may be the same or different, each represents hydrogen or C_1-3alkyl), or R^5a(CH₂)_zaX^1a (wherein R^5a is a 4-, 5- or 6-membered saturated heterocyclic group 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_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, C_1-4alkylsulphonylC_1-4alkyl, C_1-4alkoxycarbonyl, C_1-4aminoalkyl, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl, C_1-4alkylaminoC_1-4alkoxy, di(C_1-4alkyl)aminoC_1-4alkoxy and a group —(—O—)_f(C_1-4alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-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_1-4alkyl), za is an integer from 0 to 4 and X^1a represents a direct bond, —O—, —CH₂—, —S—, —SO—, —SO₂—, —NR^6aC(O)—, —C(O)NR^7a—, —SO₂NR^8a—, —NR^9aSO₂— or —NR^10a— (wherein R^6a, R^7a, R^8a, R^9a and R^10a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));
  and salts thereof, and prodrugs thereof for example esters and amides, 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.

[0320] In another aspect of the present invention there is provided the use of compounds of the formula Ia:

[0321]
[wherein:

• [0322] ring C, R¹, R², n and Z are as defined hereinbefore with the provisos that R² is not hydrogen and that Z is not CH₂ or a direct bond; and
• [0323] R^2a represents hydrogen, halogeno, C_1-3alkyl, trifluoromethyl, C_1-3alkoxy, C_1-3alkylsulphanyl, —NR^3aR^4a (wherein R^3a and R^4a, which may be the same or different, each represents hydrogen or C_1-3alkyl), or R^5a(CH₂)_zaX^1a (wherein R^5a is a 5- or 6-membered saturated heterocyclic group 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, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy, za is an integer from 0 to 4 and X^1a represents a direct bond, —O—, —CH₂—, —S—, —SO—, —SO₂—, —NR^6aC(O)—, —C(O)NR^7a—, —SO₂NR^8a—, —NR^9aSO₂— or —NR^10a— (wherein R^6a, R^7a, R^8a, R^9a and R^10a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));
  and salts thereof, and prodrugs thereof for example esters, amides and sulphides, 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.

[0324] Advantageously X^1a represents —O—, —S—, —NR^6aC(O)—, —NR^9aSO₂— or —NR^10a— (wherein R^6a, R^9a and R^10a each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

[0325] Preferably X^1a represents —O—, —S—, —NR^6aCO—, —NR^9aSO₂— (wherein R^6a and R^9a each independently represents hydrogen or C_1-2alkyl) or NH.

[0326] More preferably X^1a represents —O—, —S—, —NR^6aCO— (wherein R^6a represents hydrogen or C_1-2alkyl) or NH.

[0327] Particularly X^1a represents —O— or —NR^6aCO— (wherein R^6a represents hydrogen or C_1-2alkyl), more particularly —O— or —NHCO—, especially —O—.

[0328] Preferably za is an integer from 1 to 3.

[0329] Preferably R^5a is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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 C_1-3alkyl).

[0330] More preferably R^5a is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —(—O—)_f(C_1-3alkyl)_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).

[0331] Particularly R^5a is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2 substituents selected from a group —(—O—)_f(C_1-3alkyl)_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).

[0332] According to another aspect of the present invention preferably R^5a is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholino and thiomorpholino which group may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy.

[0333] Advantageously R^2a represents C_1-3alkyl, C_1-3alkoxy, amino or R^5a(CH₂)_zaX^1a (wherein R^5a, X^1a and za are as defined hereinbefore). Another advantageous value of R^2a is hydrogen.

[0334] Preferably R^2a is methyl, ethyl, methoxy, ethoxy or R^5a(CH₂)_zaX^1a (wherein R^5a, X^1a and za are as defined hereinbefore). Another preferred value of R^2a is hydrogen.

[0335] More preferably R^2a is methyl, ethyl, methoxy, ethoxy or R^5a(CH₂)_zaX^1a (wherein R^5a is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholino and thiomorpholino which group may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy, X^1a is —O—, —S—, —NR^6aC(O)—, —NR^9aSO₂— (wherein R^6a and R^9a each independently represents hydrogen or C_1-2alkyl) or NH, and za is an integer from 1 to 3).

[0336] Particularly R^2a represents methyl, methoxy or R^5a(CH₂)_zaX^1a (wherein R^5a, X^1a and za are as defined hereinbefore).

[0337] More particularly R^2a represents methoxy.

[0338] In a further aspect of the present invention there is provided the use of compounds of the formula Ib:

[0339]
[wherein:

• [0340] ring C, R¹, R², R^2a and n are as defined hereinbefore with the proviso that R² is not hydrogen; and
• [0341] Zb is —O— or —S—;
  and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides, 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.

[0342] Preferably Zb is —O—.

[0343] According to another aspect of the present invention there are provided compounds of the formula II:

[0344]
[wherein:

• [0345] ring C, R¹, R², R^2a, Zb and n are as defined hereinbefore with the proviso that R² is not hydrogen and excluding the compounds:
• [0346] 6,7-dimethoxy-4-(1-naphthylsulphanyl)quinazoline, 6,7-dimethoxy-4-(2-naphthylsulphanyl)quinazoline, 6,7-dimethoxy-4-(1-naphthyloxy)quinazoline and 6,7-dimethoxy-4-(2-naphthyloxy)quinazoline;
  and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.

[0347] According to another aspect of the present invention there are provided compounds of the formula IIa:

[0348]
[wherein:

• [0349] ring C, R¹, R², R^2a, Zb and n are as defined hereinbefore with the proviso that R² does not have any of the following values:
• [0350] hydrogen, substituted or unsubstituted C_1-5alkyl, halogeno or phenoxy and excluding the compounds:
• [0351] 6,7-dimethoxy-4-(1-naphthylsulphanyl)quinazoline, 6,7-dimethoxy-4-(2-naphthylsulphanyl)quinazoline, 6,7-dimethoxy-4-(1-naphthyloxy)quinazoline and 6,7-dimethoxy-4-(2-naphthyloxy)quinazoline;
  and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.

[0352] According to another aspect of the present invention there are provided compounds of the formula IIb:

[0353]
[wherein:

• [0354] ring C, R¹, R², R^2a, Zb and n are as defined hereinbefore with the proviso that R² does not have any of the following values:
• [0355] hydrogen, substituted or unsubstituted C_1-5alkyl, halogeno, C_1-5alkoxy, C_2-5alkenyl, phenoxy or phenylC_1-5alkoxy;
  and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.

[0356] Preferred compounds of the present invention include

• [0357] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline,
• [0358] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0359] 7-(3-(1, 1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline,
• [0360] 6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0361] 6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0362] 4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
• [0363] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline,
• [0364] 6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,
• [0365] 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0366] 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0367] 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,
• [0368] 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0369] 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,
• [0370] 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,
• [0371] (R,S)-4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline,
• [0372] 4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,
• [0373] 7-(3-N,N-dimethylaminopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0374] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline,
• [0375] 7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0376] 6-methoxy-7-(3-piperidinopropoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0377] 4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,
• [0378] 4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline,
• [0379] 4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline,
• [0380] 6-methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quinazoline,
• [0381] 7-(3-(methylsulphonyl)propoxy)-4-(2-methylindol-5-yloxy)quinazoline,
• [0382] 7-(3-(N,N-dimethylamino)propoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline,
• [0383] 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline,
• [0384] 7-(2-(N,N-diethylamino)ethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0385] 4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quinazoline,
• [0386] 4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazoline,
• [0387] 4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
• [0388] 7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0389] 6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline,
• [0390] 7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0391] 7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0392] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazoline, and
• [0393] 7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
  and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters and amides.

[0394] Especially preferred compounds of the present invention include

• [0395] 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0396] 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0397] 4-(indol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-ylmethoxy)quinazoline,
• [0398] 4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0399] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,
• [0400] 7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0401] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline,
• [0402] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-pyrrolidin-1-ylethoxy)quinazoline,
• [0403] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methylpiperidin-3-ylmethoxy)quinazoline,
• [0404] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline,
• [0405] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline,
• [0406] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,
• [0407] 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)4-(2-methylindol-5-yloxy)quinazoline,
• [0408] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline,
• [0409] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy)quinazoline,
• [0410] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline,
• [0411] 4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
• [0412] 6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline,
• [0413] 6-methoxy-4-(2-methylindol-5-yloxy)-7-((2-(2-pyrrolidin-1-ylethyl)carbamoyl)vinyl)quinazoline,
• [0414] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline,
• [0415] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,
• [0416] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinazoline,
• [0417] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulphonylamino)ethoxy)quinazoline,
• [0418] 7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0419] 4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline,
• [0420] 4-(2-methylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinazoline,
• [0421] 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,
• [0422] 4-(indol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,
• [0423] 7-(3-(N,N-dimethylamino)propoxy)4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0424] 7-(3-(N,N-diethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0425] 7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0426] 4-(indol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline,
• [0427] 4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,
• [0428] 7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline,
• [0429] 7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0430] 7-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0431] 7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0432] 7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0433] 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0434] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline,
• [0435] 4-(indol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
• [0436] (2R)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3piperidinopropoxy)quinazoline,
• [0437] (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline,
• [0438] 4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,
• [0439] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-(pyrrolidin-1-yl)ethyl)-piperidin-4-ylmethoxy)quinazoline,
• [0440] (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0441] (2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0442] (2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0443] (2S)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0444] (2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
• [0445] (2R)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline,
• [0446] (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline,
• [0447] (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0448] (2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0449] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-morpholinoethyl)piperidin-4-ylmethoxy)quinazoline,
• [0450] 4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,
• [0451] 4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,
• [0452] 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)quinazoline,
• [0453] (2S)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropoxy)quinazoline, and
• [0454] 4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,
  and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters and amides.

[0455] More especially preferred compounds of the present invention include

• [0456] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,
• [0457] 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,
• [0458] 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,
• [0459] 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,
• [0460] 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,
• [0461] 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,
• [0462] 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,
• [0463] 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,
• [0464] 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0465] 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,
• [0466] 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,
• [0467] (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline, and
• [0468] 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,
  and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters and amides.

[0469] Thus preferred compounds of the present invention include those, the preparation of which is described in Examples 23, 10, 5, 176, 7, 22, 13, 15, 177, 12, 35, 47, 44, 45, 157, 52, 62, 66, 75, 159, 87, 88, 89, 167, 83, 97, 101, 108, 113, 114, 121, 124, 178, 162, 165, 150 and 166,

and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters and amides.

[0470] Thus especially preferred compounds of the present invention include those, the preparation of which is described in Examples 2, 11, 34, 36, 186, 151, 57, 54, 55, 58, 56, 60, 61, 64, 65, 67, 68, 71, 72, 74, 70, 77, 79, 80, 82, 86, 122, 107, 110, 112, 117, 118, 119, 123, 161, 147, 163, 164, 63, 78, 115, 320, 318, 290, 252, 292, 293, 294, 301, 299, 279, 280, 305, 269, 246, 266, 267, 182, 321 and 250,

and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters and amides.

[0471] Thus more especially preferred compounds of the present invention include those, the preparation of which is described in Examples 9, 243, 251, 245, 247, 249, 240, 238, 237, 239, 241, 258 and 322,

and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters and amides.

[0472] In another embodiment, preferred compounds of the present invention include

• [0473] 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-6-yloxy)quinazoline,
• [0474] (S)-6-methoxy-7-((]-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0475] 6-methoxy-7-(3-morpholinopropoxy)-4-(1-naphthyloxy)quinazoline,
• [0476] 4-(1H-indazol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
• [0477] 6,7-dimethoxy-4-(quinolin-7-yloxy)quinazoline,
• [0478] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline,
• [0479] 6-methoxy-7-((2-piperidin-1-yl)ethoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0480] 6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0481] 6-methoxy-4-(2-methylquinolin-7-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline,
• [0482] 6-methoxy-4-(2-methylquinolin-7-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0483] 4-(2-chloro-1H-benzimidazol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0484] 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0485] 4-(1H-indazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
• [0486] 4-(1,3-benzothiazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
• [0487] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline,
• [0488] 7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline,
• [0489] 6-methoxy-4-(2-methyl-1,3-benzothiazol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,
• [0490] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(tetrahydropyran-4-yloxy)ethoxy)quinazoline,
• [0491] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(1,2-cycloheptanebenzimidazol-5-yloxy)quinazoline,
• [0492] 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-2-yloxy)quinazoline,
• [0493] 6-methoxy-7-(3-morpholinopropoxy)-4-(3-oxo-1,2-dihydro-3H-indazol-1-yl)quinazoline,
• [0494] 4-(2,3-dihydro-1H-indan-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
• [0495] 6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0496] 6-methoxy-4-(4-methyl-4H-1,4-benzoxazin-6-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0497] 6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-((3-pyrrolidin-1-yl)propoxy)quinazoline,
• [0498] 6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0499] 7-benzyloxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline,
• [0500] 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0501] 6-methoxy-7-(3-methylsulphonylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,
• [0502] 6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,
• [0503] 6-methoxy-7-(3-morpholinopropoxy)4-(quinazolin-7-yloxy)quinazoline,
• [0504] 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline,
• [0505] 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0506] 6,7-dimethoxy-4-(2-methyl-1H-benzimidazol-5-yloxy)quinazoline,
  and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.

[0507] In another embodiment more preferred compounds of the present invention include

• [0508] 6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-morpholinopropoxy)quinazoline,
• [0509] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-6-yloxy)quinazoline,
• [0510] 6-methoxy-4-(2-methyl-1,3-benzothiazol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,
• [0511] (R)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0512] 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline,
• [0513] 6-methoxy-7-(2-morpholinoethoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0514] 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline,
• [0515] 6-methoxy-4-(2-methylindol-5-ylamino)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0516] 6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0517] 4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,
• [0518] 4-(7-hydroxy-2-naphthyloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,
• [0519] 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,
• [0520] 7-(2-(N,N-dimethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0521] 6-methoxy-7-(2—(2-methoxyethyl)-N-methylamino)ethoxy)-4-(2-methylindol-5-yloxy)quinazoline,
• [0522] 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0523] 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0524] (S)-6-methoxy-7-((2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,
  and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.

[0525] In another embodiment especially preferred compounds of the present invention include

• [0526] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0527] 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0528] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,
• [0529] 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-3-yl)methoxy)quinazoline,
• [0530] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline,
• [0531] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0532] 6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0533] 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0534] 4-(indol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0535] 4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0536] 6-methoxy-7-(3-methylsulphonylpropoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0537] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline,
• [0538] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline,
• [0539] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,
• [0540] 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0541] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline,
• [0542] 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline,
• [0543] 6-methoxy-7-(3-(1-methylpiperazin-4-yl)propoxy)-4-(quinolin-7-yloxy)quinazoline,
• [0544] 4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
• [0545] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline,
• [0546] 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)-quinazoline,
• [0547] 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)-quinazoline,
• [0548] 7-((1-cyanomethylpiperidin-4-yl)methoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0549] 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,
• [0550] 4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline,
• [0551] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline,
• [0552] 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)4-(2-methylindol-5-yloxy)quinazoline,
• [0553] 7-(3-N,N-dimethylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0554] 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,
• [0555] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(1-methylpiperazin-4-yl)ethoxy)ethoxy)quinazoline,
• [0556] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline,
• [0557] 6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
• [0558] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline,
• [0559] 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0560] 4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,
  and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.

[0561] In another aspect of the present invention preferred compounds include

• [0562] 6-methoxy-7-((1-(2-methoxyethyl)piperidin-4-yl)methoxy)-4-(2-methylindol-5-yloxy)quinazoline,
• [0563] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(pyrrolidin-1-yl)ethylcarbamoyl)vinyl)quinazoline,
• [0564] 4-(3-cyanoquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0565] 6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(4-trifluoromethylquinolin-7-yloxy)quinazoline,
• [0566] 6-methoxy-4-(2-methyl-1H-benzimidazol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0567] 4-(3-carbamoylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,
• [0568] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(1-methylpiperazin-4-yl)propoxy)quinazoline,
• [0569] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,
  and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.

[0570] An especially preferred compound of the present invention is

• [0571] 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline
  and salts thereof especially hydrochloride salts thereof and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.

[0572] 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.

[0573] 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 C_6-10 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, C₁alkanoyl 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.

[0574] For the avoidance of any doubt, where R² has a value of substituted or unsubstituted C_1-5alkyl, R² has been selected from C_1-3alkyl or from a group R⁵X¹ wherein X¹ is a direct bond or —CH₂— and R⁵ is C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino.

[0575] 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 form which inhibits VEGF 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.

[0576] 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 VEGF 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 VEGF 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.

[0577] 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 VEGF receptor tyrosine kinase activity.

[0578] For the avoidance of any doubt, it is to be understood that when X¹ is, for example, a group of formula —NR⁶C(O)—, it is the nitrogen atom bearing the R⁶ group which is attached to the quinazoline ring 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 the quinazoline ring and the nitrogen atom bearing the R⁷ group is attached to R⁵. 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 the quinazoline ring 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_1-3alkoxyC_2-3alkyl it is the C_2-3alkyl moiety which is linked to the nitrogen atom of X¹ and an analogous convention applies to other groups.

[0579] 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 C_1-3alkylX⁹C_1-3alkylR²⁹, it is the terminal C_1-3alkyl moiety which is linked to X¹, similarly when R⁵ is, for example, a group of formula C_2-5alkenylR²⁸ it is the C_2-5alkenyl moiety which is linked to X¹ and an analogous convention applies to other groups. When R⁵ is a group 1-R²⁹prop-1-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.

[0580] 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(C_1-4alkyl)_gringD, it is the —O— or C_1-4alkyl 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.

[0581] For the avoidance of any doubt, it is to be understood that when R²⁹ carries a C_1-4aminoalkyl substituent it is the C_1-4alkyl moiety which is attached to R²⁹ whereas when R²⁹ carries a C_1-4alkylamino substituent it is the amino moiety which is attached to R²⁹ and an analogous convention applies to other groups.

[0582] For the avoidance of any doubt, it is to be understood that when R²⁸ carries a C_1-4alkoxyC_1-4alkyl substituent it is the C_1-4alkyl moiety which is attached to R²⁸ and an analogous convention applies to other groups.

[0583] 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 may be 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, morpholine or tris-(2-hydroxyethyl)amine.

[0584] 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 European Patent Applications Publication Nos. 0520722, 0566226, 0602851 and 0635498. 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.

[0585] 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:

[0586]
(wherein R² and m are as defined hereinbefore and L¹ is a displaceable moiety), with a compound of the formula IV:

[0587]
(wherein ring C, R¹, 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 C_1-4alkoxy), aryloxy, alkylsulphanyl, arylsulphanyl, alkoxyalkylsulphanyl or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methylsulphanyl, 2-methoxyethylsulphanyl, methanesulphonyloxy or toluene-4-sulphonyloxy group.

[0588] The reaction is advantageously effected in the presence of a base. Such a base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine 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, 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 tetrahydrofuran 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 90° C.

[0589] 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.

[0590] (b) Production of those compounds of formula I and salts thereof wherein at least one R² is R⁵X¹ wherein R⁵ is as defined hereinbefore and X¹ is —O—, —S—, —OC(O)— or —NR¹⁰— (wherein R¹⁰ independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) 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:

[0591]
(wherein ring C, Z, 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 2) with a compound of formula VI:
R⁵—L¹  (VI)
(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 Inc, 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.
(c) Compounds of the formula I and salts thereof wherein at least one R² is R⁵X¹ wherein R⁵ is as defined hereinbefore and X¹ is —O—, —S—, —OC(O)— or —NR¹⁰— (wherein R¹⁰ represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) may be prepared by the reaction of a compound of the formula VII:

[0592]
with a compound of the formula VIII:
R⁵—X¹—H  (VIII)
(wherein L¹, R¹, R², R⁵, ring C, 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 C_1-5alkylR¹¹³, wherein R¹¹³ is selected from one of the following six groups:

• [0593] 1) X¹⁹C_1-3alkyl (wherein X¹⁹ represents —O—, —S—, —SO₂—, —NR¹¹⁴C(O)— or —NR¹¹⁵SO₂— (wherein R¹¹⁴ and R¹¹⁵ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);
• [0594] 2) NR¹¹⁶R¹¹⁷ (wherein R¹¹⁶ and R¹¹⁷ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);
• [0595] 3) X²⁰C_1-5alkylX⁵R²² (wherein X²⁰ represents —O—, —S—, —SO₂—, —NR¹¹⁸C(O)—, —NR¹¹⁹SO₂—or —NR¹²⁰— (wherein R¹¹⁸, R¹¹⁹, and R¹²⁰ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and X⁵ and R²² are as defined hereinbefore);
• [0596] 4) R²⁸ (wherein R²⁸ is as defined hereinbefore);
• [0597] 5) X²¹R²⁹ (wherein X²¹ represents —O—, —S—, —SO₂—, —NR¹²¹C(O)—, —NR¹²²SO₂—, or —NR¹²³— (wherein R¹²¹, R¹²², and R¹²³ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore); and
• [0598] 6) X²²C_1-3alkylR²⁹ (wherein X²² represents —O—, —S—, —SO₂—, —NR¹²⁴C(O)—, —NR¹²⁵SO₂— or —NR¹²⁶— (wherein R¹²⁴, R¹²⁵ and R¹²⁶ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined hereinbefore);
  and additionally R¹¹³ may be selected from the following three groups:
• [0599] 7) R²⁹ (wherein R²⁹ is as defined hereinbefore);
• [0600] 8) X²²C_1-4alkylR²⁸ (wherein X²² and R²⁸ are as defined hereinbefore); and
• [0601] 9) R⁵⁴(C_1-4alkyl)_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:

[0602]
(wherein L¹, X¹, R¹, R², ring C, Z, n and s are as hereinbefore defined) with a compound of the formula X:
R¹¹³—H  (X)
(wherein R¹¹³ 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.

[0603] Processes (a) and (b) are preferred over processes (c) and (d).

[0604] Process (a) is preferred over processes (b), (c) and (d).

[0605] (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 —NR¹²⁷R¹²⁸, where one (and the other is hydrogen) or both of R¹²⁷ and R¹²⁸ are C_1-3alkyl, may be effected by the reaction of compounds of formula I wherein the substituent (R²)_m is an amino group and an alkylating agent, preferably in the presence of a base as defined hereinbefore. Such alkylating agents are C_1-3alkyl moieties bearing a displaceable moiety as defined hereinbefore such as C_1-3alkyl halides for example C_1-3alkyl chloride, bromide or iodide. The reaction is preferably effected in 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 the quinazoline group is/are a nitro group(s). The reduction may conveniently be effected as described in process (i) hereinafter. The production of a compound of formula I and salts thereof wherein the substituent(s) at the corresponding position(s) of the quinazoline group 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-XXII) in which the substituent(s) at the corresponding position(s) of the quinazoline group 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:

[0606]
wherein R² and m are as hereinbefore defined).

[0607] Convenient halogenating agents include inorganic acid halides, for example thionyl chloride, phosphorus(III)chloride, phosphorus(V)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 tetrachloride, 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.

[0608] The compounds of formula XI and salts thereof may, for example, be prepared by reacting a compound of the formula XII:

[0609]
(wherein R², s and L¹ are as hereinbefore defined) with a compound of the formula VIII 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 100° C.

[0610] Compounds of formula XI and salts thereof wherein at least one R² is R⁵X¹ and wherein X¹ is —O—, —S—, —SO—, —SO₂—, —C(O)—, —C(O)NR⁷—, —SO₂NR⁸— or —NR¹⁰— (wherein R⁷, R⁸ and R¹⁰ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), may for example also be prepared by the reaction of a compound of the formula XIII:

[0611]
(wherein R² and s are as hereinbefore defined and X¹ is as hereinbefore defined in this section) with a compound of the formula VI as hereinbefore defined. The reaction may for example be effected as described for process (b) hereinbefore. The pivaloyloxymethyl group can then be cleaved by reacting the product with a base such as, for example, aqueous ammonia, triethylamine in water, an alkali metal or alkaline earth metal hydroxide or alkoxide, preferably aqueous ammonia, aqueous sodium hydroxide or aqueous potassium hydroxide, in a polar protic solvent such as an alcohol, for example methanol or ethanol. The reaction is conveniently effected at a temperature in the range 20 to 100° C., preferably in the range 20 to 50° C.

[0612] The compounds of formula XI and salts thereof may also be prepared by cyclising a compound of the formula XIV:

[0613]
(wherein R² and m, are as hereinbefore defined, and A¹ is an hydroxy, alkoxy (preferably C_1-4alkoxy) or amino group) whereby to form a compound of formula XI or salt thereof. The cyclisation may be effected by reacting a compound of the formula XIV, where A¹ is an hydroxy or alkoxy group, with formamide or an equivalent thereof effective to cause cyclisation whereby a compound of formula XI or salt thereof is obtained, such as [3-(dimethylamino)-2-azaprop-2-enylidene]dimethylammonium chloride. The cyclisation is conveniently effected in the presence of formamide as solvent or in the presence of an inert solvent or diluent such as an ether for example 1,4-dioxan. The cyclisation is conveniently effected at an elevated temperature, preferably in the range 80 to 200° C. The compounds of formula XI may also be prepared by cyclising a compound of the formula XIV, where A¹ is an amino group, with formic acid or an equivalent thereof effective to cause cyclisation whereby a compound of formula XI or salt thereof is obtained. Equivalents of formic acid effective to cause cyclisation include for example a tri-C_1-4alkoxymethane, for example triethoxymethane and trimethoxymethane. The cyclisation is conveniently effected in the presence of a catalytic amount of an anhydrous acid, such as a sulphonic acid for example p-toluenesulphonic acid, and in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, an ether such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent such as toluene. The cyclisation is conveniently effected at a temperature in the range, for example 10 to 100° C., preferably in the range 20 to 50° C.

[0614] Compounds of formula XIV and salts thereof may for example be prepared by the reduction of the nitro group in a compound of the formula XV:

[0615]
(wherein R², m and A¹ are as hereinbefore defined) to yield a compound of formula XIV as hereinbefore defined. 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 stirring a solution of the nitro compound under hydrogen at 1 to 4 atmospheres pressure 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 under hydrogen at 2 atmospheres pressure in the presence of the activated metal and a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, at a temperature in the range, for example 50 to 150° C., conveniently at about 70° C.

[0616] Compounds of the formula XV and salts thereof may for example be prepared by the reaction of a compound of the formula XVI:

[0617]
(wherein R², s, L¹ and A¹ are as hereinbefore defined) with a compound of the formula VIII as hereinbefore defined to give a compound of the formula XV. The reaction of the compounds of formulae XVI and VIII is conveniently effected under conditions as described for process (c) hereinbefore.

[0618] Compounds of formula XV and salts thereof wherein at least one R² is R⁵X¹ and wherein X¹ is —O—, —S—, —SO₂—, —C(O)—, —C(O)NR⁷—, —SO₂NR⁸— or —NR¹⁰— (wherein R⁷, R⁸ and R¹⁰ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), may for example also be prepared by the reaction of a compound of the formula XVII:

[0619]
(wherein R², s and A¹ are as hereinbefore defined and X¹ is as hereinbefore defined in this section) with a compound of the formula VI as hereinbefore defined to yield a compound of formula XV as hereinbefore defined. The reaction of the compounds of formulae XVII and VI is conveniently effected under conditions as described for process (b) hereinbefore.

[0620] The compounds of formula III and salts thereof wherein at least one R² is R⁵X¹ and wherein X¹ is —CH₂— may be prepared for example as described above from a compound of the formula XV (in which R² is —CH₃) or XIII (in which HX¹— is —CH₃), by radical bromination or chlorination to give a —CH₂Br or —CH₂Cl group which may then be reacted with a compound of the formula R⁵—H under standard conditions for such substitution reactions.

[0621] The compounds of formula III and salts thereof wherein at least one R² is R⁵X¹ and wherein X¹ is a direct bond may be prepared for example as described above from a compound of the formula XI, wherein the R⁵ group is already present in the intermediate compounds (for example in a compound of the formula XV) used to prepare the compound of formula XI.

[0622] The compounds of formula III and salts thereof wherein at least one R² is R⁵X¹ and wherein X¹ is —NR⁶C(O)— or —NR⁹SO₂— may be prepared for example from a compound of the formula XIII in which HX¹— is an —NHR⁶—or —NHR⁹— group (prepared for example from an amino group (later functionalised if necessary) by reduction of a nitro group) which is reacted with an acid chloride or sulfonyl chloride compound of the formula R⁵COCl or R⁵SO₂Cl.

[0623] The compounds of formula III and salts thereof wherein at least one R² is R⁵X¹ and wherein X¹ is —O—, —S—, —SO₂—, —OC(O)—, —C(O)NR⁷—, —SO₂NR⁸— or —NR¹⁰— (wherein R⁷, R⁸ and R¹⁰ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), may also be prepared for example by reacting a compound of the formula XVIII:

[0624]
(wherein 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 VI as hereinbefore defined, whereby to obtain a compound of formula III in which L¹ is represented by L².

[0625] A compound of formula XVIII is conveniently used in which L² represents 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.

[0626] The compounds of formula XVIII and salts thereof may for example be prepared by deprotecting a compound of the formula XIX:

[0627]
(wherein R², s and L² are as hereinbefore defined, P¹ is a protecting group and X¹ is as hereinbefore defined in the section describing compounds of the formula XVIII). 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 R. G. M. Wuts, 2nd Ed. Wiley 1991, including N-sulphonyl derivatives (for example, p-toluenesulphonyl), carbamates (for example, t-butyl carbonyl), N-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.

[0628] One compound of formula III may if desired be converted into another compound of formula III in which the moiety L¹ is different. Thus for example a compound of formula III in which L¹ is other than halogeno, for example optionally substituted phenoxy, may be converted to a compound of formula III in which L¹ is halogeno by hydrolysis of a compound of formula III (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 III in which L¹ represents halogen.

[0629] (ii) Compounds of formula IV and salts thereof in which ring C is an indolyl 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 III” 1979, John Wiley & Sons Ltd, edited by W. J. Houlihan.

[0630] Examples of the preparation of indoles are given in the Examples hereinafter, such as Examples 48, 237, 242, 250 and 291.

[0631] Compounds of formula IV and salts thereof in which ring C is a quinolinyl may be prepared by any of the methods known in the art, such as for example those described in “The Chemistry of Heterocyclic Compounds: Quinolines Parts I, II and III”, 1982 (Interscience publications) John Wiley & Sons Ltd, edited by G. Jones, and in “Comprehensive Heterocyclic Chemistry Vol II by A. R. Katritzky”, 1984 Pergamon Press, edited by A. J. Boulton and A McKillop.

(iii) Compounds of formula V as hereinbefore defined and salts thereof may be made by deprotecting the compound of formula XX:

[0632]
(wherein ring C, Z, R¹, R², P¹, n and s are as hereinbefore defined and X¹ is as hereinbefore defined in the section describing compounds of the formula V) by a process for example as described in (i) above.

[0633] Compounds of the formula XX and salts thereof may be made by reacting compounds of the formulae XIX and IV as hereinbefore defined, under the conditions described in (a) hereinbefore, to give a compound of the formula XX or salt thereof.

[0634] (iv) Compounds of the formula VII and salts thereof may be made by reacting a compound of the formula XXI:

[0635]
(wherein 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 the quinazoline ring may be the same or different) with a compound of the formula IV as hereinbefore defined, the reaction for example being effected by a process as described in (a) above.
(v) Compounds of formula IX as defined hereinbefore and salts thereof may for example be made by the reaction of compounds of formula V as defined hereinbefore with compounds of the formula XXII:
L¹—C_1-5alkyl-L¹  (XXII)
(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.

[0636] (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.

[0637] 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.

[0638] Many of the intermediates defined herein, for example, those of the formulae V, VII, IX and XX 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.

[0639] The identification of compounds which potently inhibit the tyrosine kinase activity associated with VEGF receptors such as Flt 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 Vitro Receptor Tyrosine Kinase Inhibition Test

[0640] This assay determines the ability of a test compound to inhibit tyrosine kinase activity. DNA encoding VEGF, 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 VEGF, 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 VEGF receptor Flt (Genbank accession number X51602), a 1.7 kb DNA 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 cDNA and cloned into a baculovirus transplacement vector (for example pAcYM1 (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 Invitrogen Corporation)). 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 R1 receptor, Genbank accession number X51803) may be cloned and expressed in a similar manner.

[0641] 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) (10 mM sodium phosphate pH7.4, 138 mM sodium chloride, 2.7 mM potassium chloride) then resuspended in ice cold HNTG/PMSF (20 mM Hepes pH7.5, 150 mM sodium chloride, 10% v/v glycerol, 1% v/v Triton X100, 1.5 mM magnesium chloride, 1 mM ethylene glycol-bis(βaminoethyl ether) N,N,N′,N′-tetraacetic acid (EGTA), 1 mM PMSF (phenylmethylsulphonyl fluoride); the PMSF is added just before use from a freshly-prepared 100 mM solution in methanol) using 1 ml HNTG/PMSF per 10 million cells. The suspension was centrifuged for 10 minutes at 13,000 rpm 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 (100 mM Hepes pH 7.4, 0.2 mM sodium orthovanadate, 0.1% v/v Triton X¹⁰⁰, 0.2 mM dithiothreitol). For a typical batch, stock enzyme is diluted I in 2000 with enzyme diluent and 50 μl of dilute enzyme is used for each assay well.

[0642] 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.

[0643] On the day before the assay 100 μl of diluted substrate solution was dispensed into all wells of assay plates (Nunc maxisorp 96-well immunoplates) which were sealed and left overnight at 4° C.

[0644] 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 50 mM Hepes pH7.4.

[0645] Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25 μl 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 40 mM manganese(II)chloride containing 8 μM 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 μl 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 Inc. product 05-321), diluted I 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 50 mg ABTS tablet (Boehringer 1204 521) in 50 ml freshly prepared 50 mM phosphate-citrate buffer pH5.0+0.03% sodium perborate (made with 1 phosphate citrate buffer with sodium perborate (PCSB) capsule (Sigma P4922) per 100 ml 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 405 nm 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.

(b) In Vitro HUVEC Proliferation Assay

[0646] This assay determines the ability of a test compound to inhibit the growth factor-stimulated proliferation of human umbilical vein endothelial cells (HUVEC).

[0647] 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 μg/ml heparin+1 μg/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 3 ng/ml, EGF 3 ng/ml or b-FGF 0.3 ng/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 1 μCi/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 incorporation of tritium with a Beta plate counter. Incorporation of radioactivity into cells, expressed as cpm, was used to measure inhibition of growth factor-stimulated cell proliferation by compounds.

(c) In Vivo Solid Tumour Disease Model

[0648] This test measures the capacity of compounds to inhibit solid tumour growth.

[0649] CaLu-6 tumour xenografts were established in the flank of female athymic Swiss nu/nu mice, by subcutaneous injection of 1×10⁶ CaLu-6 cells/mouse in 100 μl 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: (l×w)×√(l×w)×(π/6), where l is the longest diameter and w the diameter perpendicular 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.

[0650] 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.

[0651] 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.

[0652] 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 5–5000 mg per square meter body area of the animal, i.e. approximately 0.1–100 mg/kg. A unit dose in the range, for example, 1–100 mg/kg, preferably 1–50 mg/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 1–250 mg of active ingredient.

[0653] 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.

[0654] We have found that compounds of the present invention inhibit VEGF receptor tyrosine kinase activity and are therefore of interest for their antiangiogenic effects and/or their ability to cause a reduction in vascular permeability.

[0655] 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.

[0656] 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.

[0657] 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.

[0658] 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 1–50 mg/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.

[0659] 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. In 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:

• [0660] (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 incorporated herein by reference, (for example N-acetylcolchinol-O-phosphate));
• [0661] (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
• [0662] (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:
• [0663] (iv) biological response modifiers (for example interferon); and
• [0664] (v) antibodies (for example edrecolomab).

[0665] 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).

[0666] 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, 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 VEGF, especially those tumours which are significantly dependent on VEGF for their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, vulva and skin.

[0667] In 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 VEGF 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.

[0668] It is to be understood that where the term “ether” is used anywhere in this specification it refers to diethyl ether.

[0669] The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:—

[0670] (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;

[0671] (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;

[0672] (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;

[0673] (iv) yields are given for illustration only and are not necessarily the maximum attainable;

[0674] (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.

[0675] (vi) the structures of the end-products of the formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) 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;

[0676] (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 NMR analysis;

[0677] (viii) HPLC were run under 2 different conditions:

• [0678] 1) on a TSK Gel super ODS 2 μM 4.6 mm×5 cm 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.V. at 254 nm and light scattering detections;
• [0679] 2) on a TSK Gel super ODS 2 μM 4.6 mm×5 cm 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.V. at 254 nm and light scattering detections.
  • [0680] (ix) petroleum ether refers to that fraction boiling between 40–60° C.
  • [0681] (x) the following abbreviations have been used:—
    • [0682] DMF N,N-dimethylformamide
    • [0683] DMSO dimethylsulphoxide
    • [0684] TFA trifluoroacetic acid
    • [0685] NMP 1-methyl-2-pyrrolidinone
    • [0686] THF tetrahydrofuran
    • [0687] HMDS 1,1,1,3,3,3-hexamethyldisilazane.
    • [0688] HPLC RT HPLC retention time
    • [0689] DEAD diethyl azodicarboxylate
    • [0690] DMA dimethylacetamide
    • [0691] DMAP 4-dimethylaminopyridine

[0692] A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), potassium carbonate (106 mg, 0.77 mmol) and 6-hydroxyquinoline (112 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The crude solid was collected by filtration and washed with water. The resultant solid was dissolved in dichloromethane (2 ml) and filtered through phase separating paper. The filtrate was evaporated under vacuum and the residue was triturated with ether, collected by filtration and dried to give 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-6-yloxy)quinazoline (163 mg, 55%).

[0693] ¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.40(m, 4H); 2.48(t, 2H); 3.59(m, 4H); 4.00(s, 3H); 4.25(t, 2H); 7.40(s, 1H); 7.58(m, 1H); 7.62(s, 1H); 7.74(dd, 1H); 7.92(d, 1H); 8.10(d, 1H); 8.38(d, 1H); 8.55(s, 1H); 8.92(m, 1H)

[0694] MS (ESI): 447 (MH)⁺

[0695]

Elemental analysis:	Found	C 65.9	H 5.7	N 12.4
C25H26N4O4 0.5H2O	Requires	C 65.9	H 6.0	N 12.3%

[0696] The starting material was prepared as follows:

[0697] A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol), (J. Med. Chem. 1977, vol 20, 146–149), and Gold's reagent (7.4 g, 0.05 mol) in dioxane (100ml) was stirred and heated at reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and it was heated for a further 3 hours. The volatiles were removed by evaporation, water was added to the residue, the solid was collected by filtration, washed with water and dried. Recrystallisation from acetic acid gave 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).

[0698] 7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (35 g, 124 mmol) was suspended in thionyl chloride (440 ml) and DMF (1.75 ml) and heated at reflux for 4 hours. The thionyl chloride was evaporated under vacuum and the residue azeotroped with toluene three times. The residue was dissolved in NMP (250 ml) to give a solution of 7-benzyloxy-4-chloro-6methoxyquinazoline.

[0699] Phenol (29.05 g, 309 mmol) was dissolved in NMP (210 ml), sodium hydride (11.025 g, 60% dispersion in mineral oil) was added in portions with cooling and the mixture was stirred for 3 hours. The viscous suspension was diluted with NMP (180 ml) and stirred overnight. The solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline was added and the suspension stirred at 100° C. for 2.5 hours. The suspension was allowed to cool to ambient temperature and poured into water (1.51) with vigorous stirring. The precipitate was collected by filtration, washed with water and dried under vacuum. The residue was dissolved in dichloromethane, washed with brine and filtered through phase separating paper. The filtrate was evaporated under vacuum then triturated with ether to give 7-benzyloxy-6-methoxy-4-phenoxyquinazoline (87.8 g, 83%) as a pale cream solid.

[0700] ¹H NMR Spectrum: (CDCl₃) 4.09(s, 3H); 5.34(s, 2H); 7.42(m, 12H); 7.68(s, 1H)

[0701] MS (ESI): 359 (MH)⁺

[0702] 7-Benzyloxy-6-methoxy-4-phenoxyquinazoline (36.95 g, 105.5 mmol) was suspended in TFA (420 ml) and heated at reflux for 3 hours. The reaction mixture was allowed to cool and evaporated under vacuum. The residue was stirred mechanically in water then basified with saturated aqueous sodium hydrogen carbonate solution and stirred overnight. The water was decanted and the solid suspended in acetone. After stirring the white solid was collected by filtration, washed with acetone and dried to give 7-hydroxy-6-methoxy-4-phenoxyquinazoline (26.61 g, 96%).

[0703] ¹H NMR Spectrum: (DMSOd₆) 3.97(s, 3H); 7.22(s, 1H); 7.30(m, 3H); 7.47(t, 2H); 7.56(s, 1H); 8.47(s, 1H); 10.70(s, 1H)

[0704] MS (ESI): 269 (MH)⁺

[0705] Morpholine (52.2 ml, 600 mmol) and 1-bromo-3-chloropropane (30 ml, 300 mmol) were dissolved in dry toluene (180 ml) and heated to 70° C. for 3 hours. The solid was removed by filtration and the filtrate evaporated under vacuum. The resulting oil was decanted from the additional solid residue and the oil was vacuum distilled to yield 1-chloro-3-morpholinopropane (37.91 g, 77%) as an oil.

[0706] ¹H NMR Spectrum: (DMSOd₆) 1.85(m, 2H); 2.30(t, 4H); 2.38(t, 2H); 3.53(t, 4H); 3.65(t, 2H)

[0707] MS (ESI): 164 (MH)⁺

[0708] 7-Hydroxy-6-methoxy-4-phenoxyquinazoline (25.27 g, 0.1 mol) and 1-chloro-3-morpholinopropane (18.48 g, 0.11 mol) were taken up in DMF (750 ml) and potassium carbonate (39.1 g, 0.33 mol) was added. The suspension was heated at 90° C. for 3 hours then allowed to cool. The suspension was filtered and the volatiles were removed by evaporation. The residue was triturated with ethyl acetate and 6-methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (31.4 g, 84%) was collected by filtration as a yellow crystalline solid.

[0709] ¹H NMR Spectrum: (DMSOd₆) 1.97(m, 2H); 2.39(t, 4H); 2.47(t, 2H); 3.58(t, 4H); 3.95(s, 3H); 4.23(t, 2H); 7.31(m, 3H); 7.36(s, 1H); 7.49(t, 2H); 7.55(s, 1H); 8.52(s, 1H)

[0710] MS (ESI): 396 (MH)⁺

[0711] 6-Methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (33.08 g, 84 mmol) was dissolved in 6M aqueous hydrochloric acid (800 ml) and heated at reflux for 1.5 hours. The reaction mixture was decanted and concentrated to 250 ml then basified (pH9) with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane (4×400 ml), the organic layer was separated and filtered through phase separating paper. The solid was triturated with ethyl acetate to give 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (23.9 g, 89%) as a white solid.

[0712] ¹H NMR Spectrum: (DMSOd₆) 1.91(m, 2H); 2.34(t, 4H); 2.42(t, 2H); 3.56(t, 4H); 3.85(s, 3H); 4.12(t, 2H); 7.11(s, 1H); 7.42(s, 1H); 7.96(s, 1H); 12.01(s, 1H)

[0713] MS (ESI): 320 (MH)⁺

[0714] 6-Methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (23.9 g, 75 mmol) was suspended in thionyl chloride (210 ml) and DMF (1.8 ml) then heated at reflux for 1.5 hours. The thionyl chloride was removed by evaporation under vacuum and the residue azeotroped with toluene three times. The residue was taken up in water and basified (pH8) with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane (4×400 ml), the organic layer was washed with water and brine then dried (MgSO₄). After filtration the organic layer was concentrated under vacuum to give a yellow solid which was triturated with ethyl acetate to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (17.39 g, 52%) as a pale cream solid.

[0715] ¹H NMR Spectrum: (CDCl₃) 2.10–2.16(m, 2H); 2.48(br s, 4H); 2.57(t, 2H); 3.73(t, 4H); 4.05(s, 3H); 4.29(t, 2H); 7.36(s, 1H); 7.39(s, 1H); 8.86(s, 1H)

[0716] MS-ESI: 337 [MH]+

[0717] A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (106 g, 0.77 mmol) and 7-hydroxyquinoline (112 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane (2 ml) and filtered through phase separating paper. The filtrate was evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline (116 mg, 39%).

[0718] ¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.39(m, 4H); 2.48(t, 2H); 3.59(m, 4H); 4.00(s, 3H); 4.25(t, 2H); 7.40(s, 1H); 7.58(m, 2H); 7.62(s, 1H); 7.92(d, 1H); 8.10(d, 1H); 8.44(d, 1H); 8.55(s, 1H); 8.92(m, 1H)

[0719] MS (ESI): 447 (MH)⁺

[0720]

Elemental analysis:	Found	C 66.6	H 5.7	N 12.4
C25H26N4O4 0.25H2O	Requires	C 66.6	H 5.9	N 12.4%

[0721] A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (106 mg, 0.77 mmol) and 1-naphthol (111 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The reaction mixture was extracted with ethyl acetate and the organic extracts were washed with water. The organic extracts were dried (MgSO₄) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give a solid which was triturated with ether, filtered and dried to give 6-methoxy-7-(3-morpholinopropoxy)-4-(1-naphthyloxy)quinazoline (194 mg, 65%).

[0722] ¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.39(m, 4H); 2.48(t, 2H); 3.59(m, 4H); 4.00(s, 3H); 4.26(t, 2H); 7.40(s, 1H); 7.48(m, 2H); 7.58(m, 2H); 7.74(s, 1H); 7.75(d, 1H); 7.92(d, 1H); 8.03(d, 1H); 8.42(s, 1H)

[0723] MS (ESI): 446 (MH)⁺

[0724]

Elemental analysis:	Found	C 69.9	H 6.2	N 9.4
C26H27N3O4	Requires	C 70.1	H 6.1	N 9.4%

[0725] A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (106 mg, 0.77 mmol) and 7-hydroxy-4-methylquinoline (122 mg, 0.77 mmol), (Chem. Berich. 1967, 100, 2077), in DMF (7.5 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane (2 ml) and was filtered through phase separating paper. The filtrate was evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-morpholinopropoxy)quinazoline (175 mg, 57%).

[0726] ¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.39(m, 4H); 2.48(t, 2H); 2.71(s, 3H); 3.59(m, 4H); 4.00(s, 3H); 4.26(t, 2H); 7.40(s, 1H); 7.41(m, 1H); 7.61(dd, 1H); 7.62(s, 1H); 7.90(d, 1H); 8.20(d, 1H); 8.52(s, 1H); 8.78(d, 1H)

[0727] MS (ESI): 461 (MH)⁺

[0728]

Elemental analysis:	Found	C 67.1	H 5.9	N 12.1
C26H28N4O4 0.2H2O	Requires	C 67.3	H 6.2	N 12.1%

[0729] A mixture of 4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (220 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and 7-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane (2 ml) and was filtered through phase separating paper. The filtrate was evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline (205 mg, 73%).

[0730] ¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.65(t, 2H); 2.92(m, 4H); 3.10(m, 4H); 4.00(s, 3H); 4.28(t, 2H); 7.42(s, 1H); 7.58(m, 2H); 7.64(s, 1H); 7.92(d, 1H); 8.10(d, 1H); 8.44(d, 1H); 8.55(s, 1H); 8.92(m, 1H)

[0731] MS (ESI): 495 (MH)⁺

[0732]

Elemental analysis:	Found	C 60.0	H 5.0	N 11.1
C23H26N4O5S 0.25H2O	Requires	C 60.2	H 5.4	N 11.2%

[0733] The starting material was prepared as follows:

[0734] 7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.3 g, 124 mmol), (prepared as described for the starting material in Example 1), was taken up in thionyl chloride (440 ml) and DMF (1.75 ml) then heated at reflux for 4 hours. The thionyl chloride was evaporated under vacuum and the residue azeotroped with toluene three times to give 7-benzyloxy-4-chloro-6-methoxyquinazoline.

[0735] A mixture of the crude 7-benzyloxy-4-chloro-6-methoxyquinazoline, potassium carbonate (50 g, 362 mmol) and 4-chloro-2-fluorophenol (8.8 ml, 83 mmol) in DMF (500 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature overnight. The reaction mixture was poured into water (21) and was stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane and filtered through diatomaceous earth. The filtrate was treated with decolourising charcoal, boiled for a few minutes then filtered through diatomaceous earth. The filtrate was filtered through phase separating paper and then evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (23.2 g, 76%).

[0736] ¹H NMR Spectrum: (DMSOd₆) 3.98(s, 3H); 5.34(s, 2H); 7.42(m, 9H); 7.69(dd, 1H); 8.55(s, 1H)

[0737] MS (ESI): 411 (MH)⁺

[0738] 7-Benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (1.4 g, 3.4 mmol) was suspended in TFA (15 ml) and heated at reflux for 3 hours. The reaction mixture was allowed to cool, toluene was added and the volatiles were removed by evaporation under vacuum. The residue was triturated with ether and then acetone. The precipitate was collected by filtration and dried to give 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (21.8 g). This was used without further purification in the next step.

[0739] ¹H NMR Spectrum: (DMSOd₆) 3.97(s, 3H); 7.22(s, 1H); 7.39(d, 1H); 7.53(m, 2H); 7.67(dd, 1H); 8.46(s, 1H)

[0740] MS (ESI): 321 (MH)⁺

[0741] A mixture of 3-amino-1-propanol (650 μl, 8.4 mmol) and vinyl sulphone (1 g, 8.4 mmol) was heated at 110° C. for 45 minutes. The mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 3-(1,1-dioxothiomorpholino)-1-propanol (800 mg, 90%).

[0742] ¹H NMR Spectrum: (CDCl₃) 1.7–1.8(m, 2H); 2.73(t, 2H); 3.06(br s, 8H); 3.25(s, 1H); 3.78(t, 2H)

[0743] MS-ESI: 194 [MH]⁺

[0744] 4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (5.0 g, 15.6 mmol) was suspended in dichloromethane (150 ml) and tributylphosphine (11.1 ml, 44.6 mmol) was added followed by stirring at ambient temperature for 30 minutes. To this mixture was added 3-(1,1-dioxothiomorpholino)-1-propanol (4.2 g, 21.8 mmol) followed by the addition of 1,1′-(azodicarbonyl)dipiperidine (11.7 g, 46.4 mmol) in portions. The mixture was stirred at ambient temperature overnight then diluted with ether (300 ml) and the precipitate was removed by filtration. The residue was chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give a solid which was triturated with ethyl acetate filtered and dried to give 4-(4-chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (5.4 g, 70%). This was used without further purification in the next step.

[0745] ¹H NMR Spectrum: (DMSOd₆) 1.86(m, 2H); 2.65(t, 2H); 2.92(m, 4H); 3.08(m, 4H); 3.97(s, 3H); 4.26(t, 2H); 7.40(m, 1H); 7.42(s, 1H); 7.56(m, 2H); 7.68(dd, 1H); 8.54(s, 1H)

[0746] MS (ESI): 496 (MH)⁺

[0747]

Elemental analysis:	Found	C 52.7	H 4.4	N 8.3
C22H23N3ClFO5S 0.25H2O	Requires	C 52.8	H 4.7	N 8.4%

[0748] 4-(4-Chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (3.5 g, 7 mmol) was dissolved in 2M aqueous hydrochloric acid (56 ml) and heated at 95° C. for 2 hours. The cooled reaction mixture was treated with solid sodium hydrogen carbonate solution to give a thick paste which was diluted with water and filtered. The solid was transferred to a flask and azeotroped with toluene twice to give a dry solid. The solid was flash chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (2.26 g, 87%) as a white solid.

[0749] MS (ESI): 368 (MH)⁺

[0750] 7-(3-(1, 1-Dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (4.2 g, 11.4 mmol) was suspended in thionyl chloride (45 ml) and DMF (0.1 ml) then heated at reflux for 2.5 hours. The residue was diluted with toluene, the thionyl chloride was evaporated under vacuum, the residue was then azeotroped with toluene three times. The residue was taken up in water and basified (pH8) with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane (×4), the organic layer was washed with water and brine then filtered through phase separating paper. The organic layer was concentrated under vacuum to give an orange solid. The solid was flash chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give a solid which was triturated with ether then filtered and dried to give 4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (2.27 g, 52%).

[0751] MS (ESI): 386 (MH)⁺

[0752] 6,7-Dimethoxy-3,4-dihydroquinazolin-4-one (290 mg, 1.4 mmol) was suspended in thionyl chloride (5 ml) and DMF (2 drops) and heated at reflux for 2 hours. The thionyl chloride was evaporated under vacuum and the residue azeotroped with toluene three times to give 4-chloro-6,7-dimethoxyquinazoline. A mixture of the crude 4-chloro-6,7-dimethoxyquinazoline, potassium carbonate (970 mg, 7 mmol) and 7-hydroxyquinoline (235 mg, 1.62 mmol) in DMF (10 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature overnight. The reaction mixture was treated with 1M aqueous sodium hydroxide solution and stirred at ambient temperature for a few minutes. The reaction mixture was extracted with ethyl acetate (×4) and the organic extracts washed with water and brine. The organic extracts were dried (MgSO₄), filtered and the solvent removed under vacuum. The residue was triturated with ethyl acetate and then recrystallised from hot ethyl acetate to give 6,7-dimethoxy-4-(quinolin-7-yloxy)quinazoline (110 mg, 24%) as a white solid.

[0753] ¹H NMR Spectrum: (DMSOd₆) 4.00(s, 3H); 4.00(s, 3H); 7.40(s, 1H); 7.59(m, 3H); 7.92(d, 1H); 8.08(d, 1H); 8.42(d, 1H); 8.55(s, 1H); 8.92(dd, 1H)

[0754] MS (ESI): 334 (MH)⁺

[0755]

Elemental analysis:	Found	C 68.2	H 4.3	N 12.5
C19H15N3O3	Requires	C 68.5	H 4.5	N 12.6%

[0756] The starting material was prepared as follows:

[0757] A mixture of 4,5-dimethoxyanthranilic acid (19.7 g) and formamide (10 ml) was stirred and heated at 190° C. for 5 hours. The mixture was allowed to cool to approximately 80° C. and water (50 ml) was added. The mixture was then allowed to stand at ambient temperature for 3 hours. The precipitate was collected by filtration, washed with water and dried to give 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g).

[0758] A mixture of (R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline (183 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and 7-hydroxyquinoline (111 mg, 0.77 mmol) in DMF (7 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (30 ml) and stirred for 10 minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane (2 ml) and filtered through phase separating paper. The filtrate was evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give a scalemic mixture of 6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4(quinolin-7-yloxy)quinazoline (149 mg, 61%).

[0759] ¹H NMR Spectrum: (DMSOd₆) 1.10(m, 1H); 1.51(m, 1H); 1.64(m, 1H); 1.85(m, 3H); 2.09(m, 1H); 2.15(s, 3H); 2.62(m, 1H); 2.82(m, 1H); 3.99(s, 3H); 4.09(d, 2H); 7.38(s, 1H); 7.55(m, 2H); 7.63(s, 1H); 7.91(d, 1H); 8.10(d, 1H); 8.44(d, 1H); 8.54(s, 1H); 8.93(d, 1H)

[0760] MS (ESI): 431 (MH)⁺

[0761]

Elemental analysis:	Found	C 68.7	H 5.7	N 12.8
C25H26N4O3 0.3H2O	Requires	C 68.9	H 6.2	N 12.8%

[0762] The starting material was prepared as follows:

[0763] (R)-Ethyl nipecotate (5.7 g 365 mmol), (prepared by resolution of ethyl nipecotate by treatment with L(+)-tartaric acid as described in J. Org. Chem. 1991, (56), 1168), was dissolved in 38.5% aqueous formaldehyde solution (45 ml) and formic acid (90 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and added dropwise to cooled saturated aqueous sodium hydrogen carbonate solution. The mixture was adjusted to pH12 by addition of sodium hydroxide and the mixture was extracted with methylene chloride. The organic extract was washed with brine, dried (MgSO₄) and the solvent removed by evaporation to give (R)-ethyl 1-methylpiperidine-3-carboxylate (4.51 g, 73%) as a colourless oil.

[0764] MS-ESI: 172 [MH]⁺

[0765] A solution of (R)-ethyl 1-methylpiperidine-3-carboxylate (5.69 g, 33 mmol) in ether (20 ml) was added dropwise to a stirred solution of lithium aluminium hydride (36.6 ml of a 1M solution in THF, 36.6 mmol) in ether (85 ml) cooled to maintain a reaction temperature of 20° C. The mixture was stirred for 1.5 hours at ambient temperature and then water (1.4 ml), 15% aqueous sodium hydroxide solution (1.4 ml) and then water (4.3 ml) were added. The insolubles were removed by filtration and the volatiles removed from the filtrate by evaporation to give (R)-(1-methylpiperidin-3-yl)methanol (4.02 g, 94%) as a colourless oil.

[0766] ¹H NMR Spectrum: (DMSOd₆) 1.06(q, 1H); 1.51–1.94(m, 5H); 2.04(s, 3H); 2.34(br s, 1H); 2.62(m, 1H); 2.78(d, 1H); 3.49(m, 1H); 3.59(m, 1H)

[0767] MS-ESI: 130 [MH]⁺

[0768] 4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (12.1 g, 38 mmol), (prepared as described for the starting material in Example 5), was suspended in dichloromethane (375 ml) and treated with triphenylphosphine (29.6 g, 113 mmol) then stirred at ambient temperature for 30 minutes. (1-Methylpiperidin-3-yl)methanol (8.25 g, 63.8 mmol) and (R)-(1-methylpiperidin-3-yl)methanol (1.46 g, 11.3 mmol), (CAS 205194-11-2), giving R:S (57.5:42.5 by chiral HPLC) (9.7 g, 75 mmol) were dissolved in dichloromethane (75 ml) and added to the suspension. Diethyl azodicarboxylate (17.7 ml, 75 mmol) was added in portions using a syringe pump and the mixture was then allowed to warm to ambient temperature and stirred overnight. The residue was concentrated under vacuum then chromatographed on silica eluting with dichloromethane followed by dichloromethane/methanol/ammonia (93/6/1). The relevant fractions were combined and evaporated to give an oil. The residue was triturated with ether, filtered and dried to give (R,S)-4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline (8.7 g, 53%).

[0769] ¹H NMR Spectrum: (DMSOd₆) 1.11 (m, 1H); 1.50(m, 1H); 1.58–1.98(m, 4H); 2.09(m, 1H); 2.15(s, 3H); 2.62(d, 1H); 2.81(d, 1H); 3.95(s, 3H); 4.09(d, 2H); 7.39(m, 2H); 7.55(m, 2H); 7.67(d, 1H); 8.53(s, 1H)

[0770] MS (ESI): 432 (MH)⁺

[0771] (R,S)-4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline (8.7 g, 20 mmol) was dissolved in 2M aqueous hydrochloric acid (150 ml) and heated at reflux for 1.5 hours. The reaction mixture was concentrated then basified (pH9) with saturated aqueous ammonia solution (0.88). The aqueous layer was extracted with dichloromethane (4×400 ml) and the organic extracts filtered through phase separating paper then evaporated under vacuum. The solid was triturated with ether to give (R,S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-3,4-dihydroquinazolin-4-one (4.05 g, 66%) as a white solid.

[0772] ¹H NMR Spectrum: (DMSOd₆) 1.05(m, 1H); 1.401.95(m, 5H); 2.02(m, 1H); 2.14(s, 3H); 2.59(d, 1H); 2.78(d, 1H); 3.85(s, 3H); 3.95(d, 2H); 7.09(s, 1H); 7.42(s, 1H); 7.95(s, 1H); 12.00(s, 1H)

[0773] MS (ESI): 304 (MH)⁺

[0774] (R,S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-3,4-dihydroquinazolin-4-one (2.72 g, 8.9 mmol) was suspended in thionyl chloride (90 ml) and DMF (0.5 ml) and heated at reflux for 45 minutes. The thionyl chloride was evaporated under vacuum and the residue azeotroped with toluene three times. The residue was taken up in water and basified (pH8) with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate (4×400 ml). The organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, water and brine then dried (MgSO₄). After filtration the organic extracts were concentrated under vacuum then dried overnight at 40° C. under vacuum to give (R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline (2.62 g, 91%) as a solid.

[0775] ¹H NMR Spectrum: (DMSOd₆) 1.10(m, 1H); 1.42–1.96(m, 5H); 2.09(m, 1H); 2.15(s, 3H); 2.60(d, 1H); 2.80(d, 1H); 3.98(s, 3H); 4.10(d, 2H); 7.35(s, 1H); 7.42(s, 1H); 8.84(s, 1H)

[0776] MS (ESI): 322 (MH)⁺

[0777] (R,S)-6-Methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline, (prepared as described in Example 7), was chromatographed on Chiral CEL OD (250 mm×4.6 mm), (trade mark of Daicel Chemical Industries Ltd), in isohexane/ethanol/triethylamine/TFA (80/20/0.5/0.25). The relevant fractions for S (RT 12.55) and R (RT 15.88) enantiomers were each combined separately and worked up as follows.

[0778] The solution was evaporated under vacuum to give a liquid. This was treated with 5M aqueous sodium hydroxide solution (15 ml) and extracted with ethyl acetate. The organic extracts were washed with water then brine and filtered through phase separating paper. The filtrate was evaporated to give (S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline (50 mg). The same method was used to give (R)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline (71 mg).

[0779] A suspension of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), 5-hydroxy-2-methylindole (74 mg, 0.5 mmol) and potassium carbonate (83 mg, 0.6 mmol) in DMF (1.5 ml) was stirred at 100° C. for 2 hours. After cooling to ambient temperature, water (20 ml) was added. The precipitate was collected by filtration, washed with water and dried under vacuum at 60° C. to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (80 mg, 46%).

[0780] ¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.9–2.0(m, 2H); 2.05–2.2(m, 2H); 2.25–2.4(m, 2H); 2.43(s, 3H); 3.05–3.2(m, 2H); 3.35–3.5(m, 2H); 3.65–3.75(m, 2H); 4.12(s, 3H); 4.35–4.5(t, 2H); 7.0(dd, 1H); 7.35(d, 1H); 7.42(d, 1H); 7.6(s, 1H); 7.85(s, 1H); 9.15(s, 1H)

[0781] MS (ESI): 433 (MH)⁺

[0782] The starting material was prepared as follows:

[0783] A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g, 50 mmol), 3-(pyrrolidin-1-yl)propyl chloride (14.75 g, 0.1 mol), (J. Am. Chem. Soc. 1955, 77, 2272), potassium carbonate (13.8 g, 0.1 mol) and potassium iodide (1.66 g, 10 mmol) in DMF (150 ml) was stirred and heated at 100° C. for 3 hours. The mixture was allowed to cool and the insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was dissolved in ethanol (75 ml), 2M aqueous sodium hydroxide (75 ml) was added and the mixture was heated at 90° C. for 2 hours. The mixture was concentrated by evaporation, acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with a gradient of methanol (0 to 25%) in dilute hydrochloric acid (pH2.2). The methanol was removed by evaporation and the aqueous residue was freeze dried to give 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.2 g, 77%).

[0784] ¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 2.2(m, 2H); 3.15(t, 2H); 3.3(t, 2H); 3.5(d, 2H); 3.7(t, 2H); 3.82(s, 3H); 4.05(d, 2H); 4.15(t, 2H); 7.07(d, 1H); 7.48(s, 1H); 7.59(d, 1H)

[0785] MS-EI: 279 [M^•]⁺

[0786] Fuming nitric acid (2.4 ml, 57.9 mmol) was added slowly at 0° C. to a solution of 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.15 g, 38.17 mmol) in TFA (40 ml). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 1 hour. The TFA was removed by evaporation and ice/water was added to the residue and the solvent removed by evaporation. The solid residue was dissolved in dilute hydrochloric acid (pH2.2), poured onto a Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted with methanol (gradient 0 to 50%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.1 g, 90%).

[0787] ¹H NMR Spectrum: (DMSOd₆, TFA) 1.8–1.9 (m, 2H); 2.0–2.1(m, 2H); 2.1–2.2(m, 2H); 3.0–3.1(m, 2H); 3.3(t, 2H); 3.6–3.7(m, 2H); 3.95(s, 3H); 4.25(t, 2H); 7.35(s, 1H); 7.62(s, 1H)

[0788] A solution of 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (9.63 g, 24 mmol) in thionyl chloride (20 ml) and DMF (50 μl) was heated at 45° C. for 1.5 hours. The excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The resulting solid was suspended in THF (250 ml) and methylene chloride (100 ml) and ammonia was bubbled though the mixture for 30 minutes and the mixture stirred for a further 1.5 hours at ambient temperature. The volatiles were removed by evaporation, the residue was dissolved in water and applied to a Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted with water/methanol (100/0 to 95/5). The solvent was removed by evaporation from the fractions containing product and the residue was dissolved in a minimum of methanol and the solution was diluted with ether. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzamide (7.23 g, 73%).

[0789] ¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.85–1.95(m, 2H); 2–2.1(m, 2H); 2.15–2.25(m, 2H); 3.0–3.1(m, 2H); 3.31(t, 2H); 3.62(t, 2H); 3.93(s, 3H); 4.2(t, 2H); 7.16(s, 1H); 7.60(s, 1H)

[0790] MS-EI: 323 μM^•]⁺

[0791] Concentrated hydrochloric acid (5 ml) was added to a suspension of 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzamide (1.5 g, 4.64 mmol) in methanol (20 ml) and the mixture was heated at 50° C. to give a solution. Iron powder (1.3 g, 23.2 mmol) was added in portions and the reaction mixture was then heated at reflux for 1 hour. The mixture was allowed to cool, the insolubles were removed by filtration through diatomaceous earth and the volatiles were removed from the filtrate by evaporation. The residue was purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with dilute hydrochloric acid (pH2). The fractions containing product were concentrated by evaporation and the resulting precipitate was collected by filtration and dried under vacuum over phosphorus pentoxide to give 2-amino-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzamide hydrochloride (1.44 g, 85%).

[0792] ¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.9(br s, 2H); 2.05(br s, 2H); 2.2(br s, 2H); 3.05(br s, 2H); 3.3(t, 2H); 3.61(br s, 2H); 3.8(s, 3H); 4.11(t, 2H); 7.05(s, 1H); 7.53(s, 1H)

[0793] MS-EI: 293 [M^•]⁺

[0794] A mixture of 2-amino-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzamide hydrochloride (5.92 g, 16.2 mmol) and Gold's reagent (3.5 g, 21.4 mmol) in dioxane (50 ml) was heated at reflux for 5 hours. Acetic acid (0.7 ml) and sodium acetate (1.33 g) were added to the reaction mixture which was heated at reflux for a further 5 hours. The mixture was allowed to cool and the volatiles were removed by evaporation. The residue was dissolved in water, adjusted to pH8 with 2M aqueous sodium hydroxide solution and purified on a Diaion (trademark of Mitsubishi) HP20SS resin column eluting with methanol (gradient 0–50%) in water. The fractions containing product were concentrated by evaporation and then freeze dried to give 4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (4.55 g, 83%).

[0795] ¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.9(m, 2H); 2.0–2.1(m, 2H); 2.2–2.3(m, 2H); 3.05(m, 2H); 3.34(t, 2H); 3.6–3.7(br s, 2H); 3.94(s, 3H); 4.27(t, 2H); 7.31(s, 1H); 7.55(s, 1H); 9.02(s, 1H)

[0796] A mixture of 4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.7 g, 5 mmol) and thionyl chloride (25 ml) containing DMF (0.2 ml) was heated at reflux for 3 hours. Excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The residue was suspended in ether and 10% aqueous solution of sodium hydrogen carbonate was added to the mixture. The organic layer was separated, dried (MgSO₄) and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.94 g, quantitative).

[0797] ¹H NMR Spectrum: (CDCl₃) 1.8(br s, 4H); 2.17(m, 2H); 2.6(br s, 4H); 2.7(t, 2H); 4.05(s, 3H); 4.3(t, 2H); 7.35(s, 1H); 7.38(s, 1H); 8.86(s, 1H)

[0798] MS-ESI: 322 [MH]⁺

[0799] A suspension of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74 mg, 0.23 mmol), potassium carbonate (48 mg, 0.35 mmol) and 7-hydroxyquinoline (40.6 mg, 0.28 mmol) in DMF (1.5 ml) was heated at 100° C. for 3 hours. After cooling, the mixture was stirred for 10 hours at ambient temperature and then overnight at 5° C. After dilution with methylene chloride (5 ml), the mixture was poured onto a column of silica and was eluted with an increasing gradient of methanol/methylene chloride (10/90, 20/80) followed by ammonia/methanol (5%) in methylene chloride (25/75) to give, after removal of the volatiles by evaporation and drying under vacuum, 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline (82 mg, 88%).

[0800] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.751.9(m, 3H); 1.9–2.05(m, 2H); 2.12(s, 3H); 2.8–2.9(d, 2H); 4.5(s, 3H); 4.1(d, 2H); 7.4(s, 1H); 7.6(dd, 1H); 7.62(dd, 1H)

[0801] MS (ESI): 431 [MH]⁺

[0802] The starting material was prepared as follows:

[0803] To a solution of ethyl 4-piperidinecarboxylate (30 g, 0.19 mol) in ethyl acetate (150 ml) cooled at 5° C. was added dropwise a solution of di-tert-butyl dicarbonate (41.7 g, 0.19 mol) in ethyl acetate (75 ml) while maintaining the temperature in the range 0–5° C. After stirring for 48 hours at ambient temperature, the mixture was poured onto water (300 ml). The organic layer was separated, washed successively with water (200 ml), 0.1M aqueous hydrochloric acid (200 ml), saturated sodium hydrogen carbonate (200 ml) and brine (200 ml); dried (MgSO₄) and evaporated to give ethyl 4-(1-tert-butyloxycarbonylpiperidine)carboxylate (48 g, 98%).

[0804] ¹H NMR Spectrum: (CDCl₃) 1.25(t, 3H); 1.45(s, 9H); 1.55–1.70(m, 2H); 1.8–2.0(d, 2H); 2.352.5(m, 1H); 2.7–2.95(t, 2H); 3.9–4.1(br s, 2H); 4.15 (q, 2H)

[0805] To a solution of ethyl 4-(1-tert-butyloxycarbonylpiperidine)carboxylate (48 g, 0.19 mol) in dry THF (180 ml) cooled at 0° C. was added dropwise a solution of 1M lithium aluminium hydride in THF (133 ml, 0.133 mol). After stirring at 0° C. for 2 hours, water (30 ml) was added followed by 2M sodium hydroxide (10 ml). The precipitate was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was washed with water, brine, dried (MgSO₄) and evaporated to give 4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (36.3 g, 89%).

[0806] ¹H NMR Spectrum: (CDCl₃) 1.05–1.2(m, 2H); 1.35–1.55(m, 10H); 1.6–1.8(m, 2H); 2.6–2.8(t, 2H); 3.4–3.6(t, 2H); 4.0–4.2(br s, 2H)

[0807] MS (EI): 215 μM.]⁺

[0808] To a solution of 4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (52.5 g, 0.244 mol) in tert-butyl methyl ether (525 ml) was added 1,4-diazabicyclo[2.2.2]octane (42.4 g, 0.378 mol). After stirring for 15 minutes at ambient temperature, the mixture was cooled to 5° C. and a solution of toluene sulphonyl chloride (62.8 g, 0.33 mmol) in tert-butyl methyl ether (525 ml) was added dropwise over 2 hours while maintaining the temperature at 0° C. After stirring for 1 hour at ambient temperature, petroleum ether (11) was added. The precipitate was removed by filtration. The filtrate was evaporated to give a solid. The solid was dissolved in ether and washed successively with 0.5M aqueous hydrochloric acid (2×500 ml), water, saturated sodium hydrogen carbonate and brine, dried (MgSO₄) and evaporated to give 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (76.7 g, 85%).

[0809] ¹H NMR Spectrum: (CDCl₃) 1.0–1.2(m, 2H); 1.45(s, 9H); 1.65(d, 2H); 1.75–1.9(m, 2H); 2.45(s, 3H); 2.55–2.75(m, 2H); 3.85(d, 1H); ⁴0.04.2(br s, 2H); 7.35(d, 2H); 7.8(d, 2H)

[0810] MS (ESI): 392 [MNa]⁺

[0811] To a suspension of ethyl 3-methoxy-4-hydroxybenzoate (19.6 g, 0.1 mol) and potassium carbonate (28 g, 0.2 mol) in dry DMF (200 ml) was added 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (40 g, 0.11 mol). After stirring at 95° C. for 2.5 hours, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate/ether. The organic layer was washed with water, brine, dried (MgSO₄) and evaporated. The resulting oil was crystallised from petroleum ether and the suspension was stored overnight (at 5° C.). The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35 g, 89%).

[0812] m.p. 81–83° C.

[0813] ¹H NMR Spectrum: (CDCl₃) 1.2–1.35(m, 2H); 1.4(t, 3H); 1.48(s, 9H); 1.8–1.9(d, 2H); 2.02.15(m, 2H); 2.75(t, 2H); 3.9(d, 2H); 3.95(s, 3H); 4.05–4.25(br s, 2H); 4.35(q, 2H); 6.85(d, 1H); 7.55(s, 1H); 7.65(d, 1H)

[0814] MS (ESI): 416 [MNa]⁺

[0815]

Elemental analysis:	Found	C 63.4	H 8.0	N 3.5
C21H31NO6 0.3H2O	Requires	C 63.2	H 8.0	N 3.5%

[0816] To a solution of ethyl 3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35 g, 89 mmol) in formic acid (35 ml) was added formaldehyde (12M, 37% in water, 35 ml, 420 mmol). After stirring at 95° C. for 3 hours, the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and 3M hydrogen chloride in ether (40 ml, 120 mmol) was added. After dilution with ether, the mixture was triturated until a solid was formed. The solid was collected by filtration, washed with ether and dried under vacuum overnight at 50° C. to give ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, quant.).

[0817] ¹H NMR Spectrum: (DMSOd₆) 1.29(t, 3H); 1.5–1.7(m, 2H); 1.95(d, 2H); 2.0–2.15(br s, 1H); 2.72(s, 3H); 2.9–3.1(m, 2H); 3.35–3.5(br s, 2H); 3.85(s, 3H); 3.9–4.05(br s, 2H); 4.3(q, 2H); 7.1(d, 1H); 7.48(s, 1H); 7.6(d, 1H)

[0818] MS (ESI): 308 [MH]⁺

[0819] A solution of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, 89 mmol) in methylene chloride (75 ml) was cooled to 0–5° C. TFA (37.5 ml) was added followed by the dropwise addition over 15 minutes of a solution of fuming 24M nitric acid (7.42 ml, 178 mmol) in methylene chloride (15 ml). After completion of the addition, the solution was allowed to warm up and stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was dissolved in methylene chloride (50 ml). The solution was cooled to 0–5° C. and ether was added. The precipitate was collected by filtration, and dried under vacuum at 50° C. The solid was dissolved in methylene chloride (500 ml) and 3M hydrogen chloride in ether (30 ml) was added followed by ether (500 ml). The solid was collected by filtration and dried under vacuum at 50° C. to give ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4 g, 82%).

[0820] ¹H NMR Spectrum: (DMSOd₆) 1.3(t, 3H); 1.45–1.65(m, 2H); 1.75–2.1 (m, 3H); 2.75(s, 3H); 2.9–3.05(m, 2H); 3.4–3.5(d, 2H); 3.95(s, 3H); 4.05(d, 2H); 4.3(q, 2H); 7.32(s, 1H); 7.66(s, 1H)

[0821] MS (ESI): 353 [MH]⁺

[0822] A suspension of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (3.89 g, 10 mmol) in methanol (80 ml) containing 10% platinum on activated carbon (50% wet) (389 mg) was hydrogenated at 1.8 atmospheres pressure until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in water (30 ml) and adjusted to pH10 with a saturated solution of sodium hydrogen carbonate. The mixture was diluted with ethyl acetate/ether (1/1) and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate/ether and the organic layers were combined. The organic layers were washed with water, brine, dried (MgSO₄), filtered and evaporated. The resulting solid was triturated in a mixture of ether/petroleum ether, filtered, washed with petroleum ether and dried under vacuum at 60° C. to give ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (2.58 g, 80%).

[0823] m.p. 111–112° C.

[0824] ¹H NMR Spectrum: (CDCl₃) 1.35(t, 3H); 1.4–1.5(m, 2H); 1.85(m, 3H); 1.95(t, 2H); 2.29(s, 3H); 2.9(d, 2H); 3.8(s, 3H); 3.85(d, 2H); 4.3(q, 2H); 5.55(br s, 2H); 6.13(s, 1H); 7.33(s, 1H)

[0825] MS (ESI): 323 [MH]⁺

[0826]

Elemental analysis:	Found	C 62.8	H 8.5	N 8.3
C17H26N2O4 0.2H2O	Requires	C 62.6	H 8.2	N 8.6%

[0827] A solution of ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2 g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4 g, 100 mmol) was added in portions every 30 minutes during 4 hours. Heating was prolonged for 30 minutes after the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100 ml) and methylene chloride (50 ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100 ml. The suspension was cooled to 5° C. and the solid was collected by filtration, washed with cold ethanol followed by ether and dried under vacuum overnight at 60° C. to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (12.7 g, 70%).

[0828] ¹H NMR Spectrum: (DMSOd₆) 1.25–1.4(m, 2H); 1.75(d, 2H); 1.9(t, 1H); 1.9(s, 3H); 2.16(s, 2H); 2.8(d, 2H); 3.9(s, 3H); 4.0(d, 2H); 7.11(s, 1H); 7.44(s, 1H); 7.97(s, 1H)

[0829] MS (ESI): 304 [MH]⁺

[0830] A solution of 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (2.8 g, 9.24 mmol) in thionyl chloride (28 ml) containing DMF (2801 μl) was refluxed at 85° C. for 1 hour. After cooling, the volatiles were removed by evaporation. The precipitate was triturated with ether, filtered, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and saturated aqueous sodium hydrogen carbonate was added. The organic layer was separated, washed with water, brine, dried (MgSO₄) and evaporated to give 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (2.9 g, 98%).

[0831] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.75–1.9(m, 3H); 2.0(t, 1H); 2.25(s, 3H); 2.85(d, 2H); 4.02(s, 3H); 4.12(d, 2H); 7.41(s, 1H); 7.46(s, 1H); 8.9(s, 1H)

[0832] MS (ESI): 322 [MH]⁺

[0833] Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 5-hydroxy-2-methylindole (74 mg, 0.5 mol) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (137 mg, 79%).

[0834] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.45(m, 2H); 1.7–1.95(m, 5H); 2.15(s, 3H); 2.4(s, 3H); 2.8(d, 2H); 3.98(s, 3H); 4.05(d, 2H); 6.14(s, 1H); 6.88(d, 1H); 7.29(s, 1H); 7.32(d, 1H); 7.35(s, 1H); 7.6(s, 1H); 8.45(s, 1H)

[0835] MS (ESI): 433 [MH]+

[0836] To a solution of 4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (115 mg, 0.28 mmol) and 7-hydroxyquinoline (50 mg, 0.33 mmol) in DMF (1.5 ml) was added potassium carbonate (60 mg, 0.42 mmol). The mixture was stirred for 2 hours at 100° C. After cooling, and removal of the volatiles by evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO₄) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/methylene chloride/methanol (1/1/0 followed by 40/50/10 and 0/9/1). After removal of the volatiles by evaporation, the residue was triturated with pentane, filtered and dried under vacuum to give 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline (110 mg, 76%).

[0837] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.45(m, 2H); 1.75–1.9(m, 3H); 2.05(t, 2H); 2.72(t, 2H); 2.95(d, 2H); 3.05(s, 3H); 3.35–3.45(m, 2H); 4.00(s, 3H); 4.1(d, 2H); 7.41(s, 1H); 7.57(dd, 1H); 7.62(dd, 1H); 7.65(s, 1H); 7.93(s, 1H); 8.12(d, 1H); 8.45(d, 1H); 8.55(s, 1H); 8.95(d, 1H)

[0838] MS (ESI): 523 [MH]⁺

[0839]

Elemental analysis:	Found	C 61.3	H 6.0	N 10.6
C27H30N4O5S 0.4H2O	Requires	C 61.2	H 5.9	N 10.6%

[0840] The starting material was prepared as follows:

[0841] Sodium hydride (1.44 g of a 60% suspension in mineral oil, 36 mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol), (prepared as described for the starting material in Example 1), in DMF (70 ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100 ml) and poured onto ice/water (400 ml) and 2M hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgSO₄) and the solvent removed by evaporation. The residue was triturated with a mixture of ether and petroleum ether, the solid was collected by filtration and dried under vacuum to give 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10 g, 84%).

[0842] ¹H NMR Spectrum: (DMSOd₆) 1.11(s, 9H); 3.89(s, 3H); 5.3(s, 2H); 5.9(s, 2H); 7.27(s, 1H); 7.35(m, 1H); 7.47(t, 2H); 7.49(d, 2H); 7.51(s, 1H); 8.34(s, 1H)

[0843] A mixture of 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7 g, 17.7 mmol) and 10% palladium-on-charcoal catalyst (700 mg) in ethyl acetate (250 ml), DMF (50 ml), methanol (50 ml) and acetic acid (0.7 ml) was stirred under hydrogen at atmospheric pressure for 40 minutes. The catalyst was removed by filtration and the solvent removed from the filtrate by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (4.36 g, 80%).

[0844] ¹H NMR Spectrum: (DMSOd₆) 1.1(s, 9H); 3.89(s, 3H); 5.89(s, 2H); 7.0(s, 1H); 7.48(s, 1H); 8.5(s, 1H)

[0845] A suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6.12 g, 20 mmol) potassium carbonate (5.52 g, 40 mmol) in DMF (60 ml) was stirred at ambient temperature for 30 minutes. 4-(4-Methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (8.86 g, 24 mmol), (prepared as described for the starting material in Example 10), was added and the mixture was stirred at 100° C. for 2 hours. After cooling, the mixture was poured onto water/ice (400 ml, 1/1) containing 2M hydrochloric acid (10 ml). The precipitate was collected by filtration, washed with water and dried under vacuum over phophorus pentoxide. The solid was triturated in a mixture of ether/pentane (1/1), collected by filtration and dried to give 6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (7.9 g, 78.5%).

[0846] ¹H NMR Spectrum: (DMSOd₆) 1.1 (s, 9H); 1.1–1.3(m, 2H); 1.42(s, 9H); 1.73(d, 2H); 1.932.1(br s, 1H); 2.65–2.9(br s, 2H); 3.9(s, 3H); 3.9–4.1(m, 4H); 5.9(s, 2H); 7.2(s, 1H); 7.5(s, 1H); 8.35(s, 1H)

[0847] MS (ESI): 526 [MNa]+

[0848] A solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (7.9 g, 16 mmol) in methylene chloride (80 ml) containing 5.5M hydrogen chloride in isopropanol (80 ml) was stirred for 1 hour at ambient temperature. Ether was added and the solid was collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one hydrochloride (6.9 g, 100%).

[0849] ¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.15(s, 9H); 1.5–1.7(m, 2H); 2.0(d, 2H); 2.2–2.3(br s, 1H); 3.0(t, 2H); 3.4(d, 2H); 3.94(s, 3H); 4.15(d, 2H); 5.97(s, 2H); 7.3(s, 1H); 7.6(s, 1H); 8.65(s, 1H)

[0850] MS (ESI): 404 [MH]⁺

[0851] To a solution of 6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one hydrochloride (0.88 g, 2 mmol) and triethylamine (0.3 ml, 2.1 mmol) in methanol (10 ml) and methylene chloride (10 ml) was added potassium carbonate (280 mg, 2 mmol) and methyl vinyl sulfone (0.4 ml, 2.1 mmol). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO₄) and evaporated to give 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (0.55 g, 54%).

[0852] ¹H NMR Spectrum: (DMSOd₆) 1.09(s, 9H); 1.25–1.4(m, 2H); 1.7–1.9(m, 3H); 2.0(t, 2H); 2.7(t, 2H); 2.95(d, 2H); 3.02(s, 3H); 3.25–3.45(m, 2H); 3.9(s, 3H); 4.0(d, 2H); 5.9(s, 2H); 7.15(s, 1H); 7.49(s, 1H); 8.35(s, 1H)

[0853] MS (ESI): 510 [MH]^+.

[0854] To a suspension of 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (90 mg, 0.18 mmol) in methanol (3 ml) was added 2M aqueous sodium hydroxide (180 μl, 0.35 mmol). After stirring for 2 hours at ambient temperature, the mixture was adjusted to pH10 with 2M hydrochloric acid. The volatiles were removed under vacuum and the residue was suspended in water, filtered, washed with water followed by ether and dried under vacuum at 60° C. to give 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (55 mg, 79%).

[0855] ¹H NMR Spectrum: (DMSOd₆) 1.2–1.4(m, 2H); 1.7–1.85(m, 3H); 2.0(t, 2H); 2.7(t, 2H); 2.9(d, 2H); 3.02(s, 3H); 3.3–3.5(m, 2H); 3.9(s, 3H); 4.0(d, 2H); 7.11(s, 1H); 7.45(s, 1H); 7.97(s, 1H)

[0856] MS (ESI): 396 [MH]⁺

[0857] A solution of 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (335 mg, 0.85 mmol) in thionyl chloride (5 ml) containing DMF (50 μl) was refluxed for 1 hour. After cooling, the volatiles were removed under vacuum and the residue was triturated with ether and filtered. The solid was suspended in methylene chloride and sodium hydrogen carbonate was added. The organic layer was washed with water, brine, dried (MgSO₄) and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give 4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (335 mg, 95%).

[0858] ¹H NMR Spectrum: (DMSOd₆) 1.25–1.45(m, 2H); 1.751.90(m, 3H); 2.0(t, 2H); 2.7(t, 2H); 2.92(d, 2H); 3.03(s, 3H); 3.2–3.35(m, 2H); 4.0(s, 3H); 4.1(d, 2H); 7.40(s, 1H); 7.45(s, 1H); 8.9(s, 1H)

[0859] MS (ESI): 414 [MH]⁺

[0860] Using a procedure analogous to that described for Example 10, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (130 mg, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 4-methyl-7-hydroxyquinoline (80 mg, 0.5 mol), (Chem. Ber. 1967, 100, 2077), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline (160 mg, 90%).

[0861] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.7–1.95(m, 3H); 1.9(t, 2H); 2.17(s, 3H); 2.74(s, 3H); 2.8(d, 2H); 4.07(s, 3H); 4.1(d, 2H); 7.4(m, 2H); 7.65(dd, 1H); 7.65(s, 1H); 7.9(s, 1H); 8.21(d, 1H); 8.54(s, 1H); 8.78(d, 1H)

[0862] MS (ESI): 445 [MH]⁺

[0863] A solution of 4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (115 mg, 0.28 mmol), (prepared as described for the starting material in Example 12), 5-hydroxy-2-methylindole (50 mg, 0.33 mmol) and potassium carbonate (60 mg, 0.42 mmol) in DMF (1.5 ml) was stirred at 100° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO₄) and evaporated. The residue was purified by chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5 and 1/0/9) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (60 mg, 41%).

[0864] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.45(m, 2H); 1.75–1.92(m, 3H); 2.02(t, 2H); 2.4(s, 3H); 2.7(t, 2H); 2.95(d, 2H); 3.05(s, 3H); 4.0(s, 3H); 4.05(d, 2H); 6.15(s, 1H); 6.85(dd, 1H); 7.25(s, 1H); 7.3(d, 1H); 7.38(s, 1H); 7.6(s, 1H); 8.45(s, 1H)

[0865] MS (ESI): 525 [MH]⁺

[0866]

Elemental analysis:	Found	C 60.7	H 6.2	N 10.5
C27H32O5S 0.5H2O	Requires	C 60.8	H 6.2	N 10.5%

[0867] Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 9), was reacted with 7-hydroxy-4-methylquinoline (80 mg, 0.5 mol), (Chem. Berich. 1967, 100, 2077), to give 6-methoxy-4-(4-methylquinolin-7yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (155 mg, 87%).

[0868] ¹H NMR Spectrum: (DMSOd₆) 1.7(br s, 4H); 2.05(m, 2H); 2.5(br s, 4H); 2.6(t, 2H); 2.75(s, 3H); 4.02(s, 3H); 4.3(t, 2H); 7.41(s, 1H); 7.45(d, 1H); 7.65(s, 1H); 7.65(d, 1H); 7.95(s, 1H); 8.25(d, 1H); 8.55(s, 1H); 8.8(d, 1H)

[0869] MS (ESI): 445 [MH]⁺

[0870] Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 9), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (90 mg, 47%).

[0871] ¹H NMR Spectrum: (DMSOd₆) 1.23(s, 6H); 1.7(br s, 4H); 1.85(s, 3H); 2.0(m, 2H); 2.45(br s, 4H); 2.57(t, 2H); 3.95(s, 3H); 4.25(t, 2H); 5.35(s, 1H); 5.9(s, 1H); 6.5(d, 1H); 6.8(dd, 1H); 6.85(s, 1H); 7.32(s, 1H); 7.52(s, 1H); 8.5(s, 1H)

[0872] MS (ESI): 475 [MH]⁺

[0873] Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (140 mg, 74%).

[0874] ¹H NMR Spectrum: (DMSOd₆) 1.15(s, 6H); 1.3–1.45(m, 2H); 1.7–2.0(m, 8H); 2.16(s, 3H); 2.65–2.85(d, 2H); 4.0(s, 3H); 4.05(d, 2H); 5.35(s, 1H); 5.9(s, 1H); 6.5(d, 1H); 6.80(d, 1H); 6.82(s, 1H); 7.33(s, 1H); 7.5(s, 1H); 8.52(s, 1H)

[0875] MS (ESI): 475 [MH]⁺

[0876] Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,4-dimethyl-7-hydroxyquinoline (87 mg, 0.5 mmol), (Chem. Berichte, 1903, 36, 4016), to give 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (61 mg, 33%).

[0877] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.7–1.95(m, 5H); 2.2(s, 3H); 2.65(s, 3H); 2.7(s, 3H); 2.75–2.9(br d, 2H); 4.05(s, 3H); 4.1(d, 2H); 7.3(s, 1H); 7.4(s, 1H); 7.52(d, 1H); 7.65(s, 1H); 7.8(s, 1H); 8.15(d, 1H); 8.55(s, 1H)

[0878] MS (ESI): 459 [MH]⁺

[0879] Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5 mmol), (J. Chem. Soc. C, 1971, 2696), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline (158 mg, 88%).

[0880] ¹H NMR Spectrum: (DMSOd₆) 1.25–1.45(m, 2H); 1.8(d, 2H); 1.7–1.9(m, 1H); 1.9(t, 2H); 2.2(s, 3H); 2.8(d, 2H); 3.97(s, 3H); 4.05(d, 2H); 4.65(s, 2H); 6.8(s, 1H); 6.85(d, 1H); 7.05(d, 1H); 7.35(s, 1H); 7.52(s, 1H); 8.55(s, 1H)

[0881] MS (ESI): 451 [MH]⁺

[0882] Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the (starting material in Example 9), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5 mmol), (J. Chem. Soc. C, 1971, 2696), to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline (170 mg, 94%).

[0883] ¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.8–2.0(m, 2H); 2.0–2.15(m, 2H); 2.2–2.35(m. 2H); 3.0–3.2(m, 2H); 3.4(t, 2H); 3.6–3.75(m, 2H); 4.05(s, 3H); 4.35(t, 2H); 4.65(s, 2H); 6.85(s, 1H); 6.9(d, 1H); 7.1(d, 1H); 7.5(s, 1H); 7.7(s, 1H); 8.9(s, 1H)

[0884] MS (ESI): 451 [MH]⁺

[0885] Using a procedure analogous to that described for Example 10, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 10), was reacted with 6-hydroxyquinoline (41 mg, 0.28 mol) to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-6-yloxy)quinazoline (89 mg, 94%).

[0886] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.8(d, 2H); 1.9(t, 2H); 1.81.9(m, 1H); 2.2(s, 3H); 2.82(d, 2H); 4.02(s, 3H); 4.1(d, 2H); 7.4(s, 1H); 7.6(dd, 1H); 7.65(s, 1H); 7.75(d, 1H); 7.95(s, 1H); 8.15(d, 1H); 8.4(d, 1H); 8.55(s, 1H); 8.95(d, 1H)

[0887] MS (ESI): 431 [MH]⁺

[0888] To 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (250 mg, 0.74 mmol), (prepared as described for the starting material in Example 1), in suspension in DMF (4 ml) were successively added 4-chloro-7-hydroxyquinoline (133 mg, 0.74 mmol) and potassium carbonate (153 mg, 1 mmol) and the reaction mixture heated to 100° C. More 4-chloro-7hydroxyquinoline (27 mg, 0.15 mmol) was added after one hour and heating was continued for a further 30 minutes. The product precipitated upon cooling to ambient temperature. The reaction mixture was diluted with water, the product was collected by filtration and washed with more water. The dried solid was triturated with ether and filtered to give 4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (166 mg, 47%).

[0889] ¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 2.3(m, 2H); 3.2(m, 2H); 3.4(m, 2H); 3.5(m, 2H); 3.7(m, 2H); 4.0(m, 2H); 4.1(s, 3H); 4.4(m, 2H); 7.55(s, 1H); 7.75(s, 1H); 7.90(dd, 1H); 7.95(d, 1H); 8.15(d, 1H); 8.45 (d, 1H); 8.80(s, 1H); 9.05(d, 1H)

[0890] MS-ESI: 481 [MH]⁺

[0891]

Elemental analysis:	Found	C 61.8	H 5.1	N 11.5
C25H25ClN4O4	Requires	C 62.4	H 5.2	N 11.7%

[0892] The starting material was prepared as follows:

[0893] A solution of 7-benzyloxy-4-chloroquinoline (17 g, 56 mmol), (Konishi et al. WO 96/11187), in TFA (170 ml) was heated at reflux for 2 hours. The solvent was removed under vacuum and the residue was triturated with ether, filtered and washed with ether. The solid was suspended in an aqueous solution of sodium hydrogen carbonate (5.5 g, 65 mmol in 200 ml of water) and stirred at ambient temperature for 30 minutes. The solid was collected by filtration, washed with water and dried overnight under vacuum and over phosphorus pentoxide to give 4-chloro-7-hydroxyquinoline (9.85 g, 98%).

[0894] ¹H NMR Spectrum: (DMSOd₆) 7.37(s, 1H); 7.39(d, 1H); 7.62(d, 1H); 8.15(d, 1H); 8.8(d, 1H)

[0895] MS-EI: m/z 179 [M.]+

[0896] A solution of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 10), and 2-hydroxynaphthalene (40 mg, 0.28 mmol) in DMF (1.5 ml) containing potassium carbonate (48 mg, 0.35 mmol) was stirred at 100° C. for 3.5 hours. After cooling, methylene chloride (4.5 ml) was added and the mixture was poured onto a column of silica (SiO2 Isolute®) and eluted with, successively, methylene chloride, methylene chloride/methanol (9/1), methylene chloride/methanol/3M ammonia in methanol (75/20/5). The fractions containing the product were evaporated under vacuum. The residues was triturated with ether, filtered and dried under vacuum to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline (80 mg, 83%).

[0897] MS-ESI: 430 [MH]+

[0898] ¹H NMR Spectrum: (DMSOd₆) 1.35–1.45 (m, 2H), 1.8 (d, 2H), 2.0 (t, 1H), 2.2 (s, 3H). 2.85 (d, 2H), 3.3–3.4 (m, 2H), 4.02 (s, 3H), 4.1 (d, 2H), 7.4 (s, 1H), 7.5 (dd, 1H), 7.55 (m, 2H), 7.65 (s, 1H), 7.88 (s, 1H), 7.98 (d, 1H), 8.0 (d, 1H), 8.1 (d, 1H), 8.55 (s, 1H)

[0899] A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 1), and 3,4-(methylenedioxy)aniline (53 mg, 0.24 mmol) in a solution of isopropanol (3.5 ml) containing 5.5M hydrogen chloride in isopropanol (42 μl) was heated for 3 hours. After cooling to ambient temperature, the reaction mixture was cooled to 0° C. and maintained at this temperature overnight. The precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum to give 4-(1,3-benzodioxol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (82 mg, 76%).

[0900] MS-ESI: 439 [MH]⁺

[0901] ¹H NMR Spectrum: (DMSOd₆) 2.3–2.4 (m, 2H), 3.05–3.2 (m,2H), 3.25–3.35 (m, 2H), 3.5 (d, 2H), 3.82 (t, 2H), 4.0 (d, 2H), 4.05 (s, 3H), 4.32 (t, 2H), 6.1 (s, 2H), 7.02 (d, 1H), 7.1 (dd, 1H), 7.3 (s, 1H), 7.4 (s, 1H), 8.32 (s, 1H), 8.8 (s, 1H)

[0902] Using an analogous procedure to that described in Example 24, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline, (prepared as described for the starting material in Example 1), was used in the synthesis of the compounds described in Table I hereinafter as detailed in the notes a)–e) to Table I.

[0903]

TABLE I
Example	Weight	yield	MS-ESI
No.	(mg)	%	[MH]+	note	R
25	104	90	435.1	a	1-H-indazol-6-yl
26	102	89	435.1	b	1-H-indazol-5-yl
27	99	84	452	c	1,3-benzothiazol-6-yl
28	108	91	466	d	2-methyl-1,3-
					benzothiazol-5-yl
29	102	95	435.1	e	2,3-dihydro-1H-inden-5-yl
Notes
a 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was reacted with 6-aminoindazole (32 mg) to give 4-(1-H-indazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.3–2.4(m, 2H), 3.05–3.2(m, 2H), 3.2–3.3(m, 2H), 3.52(d, 2H), 3.85(t, 2H), 4.0(d, 2H), 4.05(s, 3H), 4.32(t, 2H), 7.42(s, 1H), 7.45(d, 1H), 7.85(d, 1H), 7.98(s, 1H), 8.1(s, 1H), 8.42(s, 1H), 8.85(s, 1H)
b 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was reacted with 5-aminoindazole (32 mg) to give 4-(1-H-indazol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.3–2.4(m, 2H), 3.05–3.2(m, 2H), 3.25–3.3(m, 2H), 3.45–3.55(m, 2H), 3.8–3.9(m, 2H), 3.9–4.02(m, 2H), 4.05(s, 3H), 4.32(t, 2H), 7.42(s, 1H), 7.65(m, 2H), 8.05(s, 1H), 8.15(s, 1H), 8.4(s, 1H), 8.75(s, 1H)
c 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was reacted with 6-aminothiazole (36 mg) to give 4-(1,3-benzothiazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.3–2.4(m, 2H), 3.05–3.2(m, 2H), 3.2–3.3(m, 2H), 3.55(d, 2H), 3.8(t, 2H), 4.0(d, 2H), 4.08(s, 3H), 4.32(t, 2H), 7.4(s, 1H), 7.88(dd, 1H), 8.2(d, 1H), 8.4(s, 1H), 8.55(s, 1H), 8.85(s, 1H), 9.42(s, 1H)
d 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was reacted with 6-amino-2-methylthiazole (57 mg) to give 6-methoxy-4-(2-methyl-1,3-benzothiazol-5-ylamino)-7-(3-morpholinopropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.3–2.4(m, 2H), 2.85(s, 3H), 3.05–3.2(m, 2H), 3.3(t, 2H), 3.4–3.5(m, 2H), 3.85(t, 2H), 4.0(d, 2H), 4.05(s, 3H), 4.35(t, 2H), 7.42(s, 1H), 7.75(dd, 1H), 8.15(d, 1H), 8.3(s, 1H), 8.42(s, 1H), 8.85(s, 1H)
e 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was reacted with 5-aminoindan (32 mg) to give 4-(2,3-dihydro-1H-inden-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.08(m, 2H), 2.3–2.4(m, 2H), 2.9(m, 4H), 3.05–3.2(m, 2H), 3.2–3.3(m, 2H), 3.5(d, 2H), 3.82(t, 2H), 4.0(d, 2H), 4.05(s, 3H), 4.3(t, 2H), 7.32(d, 1H), 7.4(m, 2H), 7.55(s, 1H), 8.32(s, 1H), 8.8(s, 1H)

[0904] A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (130 mg, 0.4 mmol), (prepared as described for the starting material in Example 10), 7-hydroxy-2-methylchromone (88 mg, 0.5 mmol), (Bull Soc. Chim. Fr. 1995, 132, 233), and potassium carbonate (83 mg, 0.6 mmol) was heated at 100° C. for 1.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried (MgSO₄), and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (170 mg, 92%).

[0905] MS-ESI: 462 [MH]+

[0906] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.5 (m, 2H); 1.75–1.95 (m, 5H); 2.2 (s, 3H), 2.42 (s, 3H); 4.0 (s, 3H); 4.1 (d, 2H); 6.3 (s, 2H); 7.4 (s, 1H); 7.45 (dd, 1H); 7.6 (s, 1H); 7.7 (s, 1H); 8.15 (d, 1H); 8.61 (s, 1H)

[0907] Using an analogous procedure to that described in Example 30, the compounds described in Table II hereinafter and detailed in the notes a)–c) to Table II, were made.

[0908]

TABLE II
Example	Weight	yield	MS-ESI
No.	(mg)	%	[MH]+	note	Q	R
31	180	85	451	a	1-methylpiperidin-	4-methyl-3,4-dihydro-2H-
					4-ylmethoxy	1,4-benzoxazin-6-yloxy
32	160	87	462	b	3-pyrrolidin-1-	2-methyl-4-oxo-4H-
					ylpropoxy	chromen-7-yloxy
33	100	56	451	c	3-pyrrolidin-1-	4-methyl-3,4-dihydro-2H-
					ylpropoxy	1,4-benzoxazin-6-yloxy
a 4-Chloro-6-methoxy-7-(1-methylpiperidin-4-yloxy)quinazoline (130 mg), (prepared as described for the starting material in Example 10), was reacted with 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-ol (83 mg), (J. Org. Chem. 1971, 36 (1)), to give 6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yloxy)-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
1H NMR Spectrum: (DMSOd6) 1.6–1.75(m, 2H); 1.9–2.3(m, 5H); 2.8(s, 3H); 2.9(s, 3H); 3.0–3.15(m, 2H); 3.3(br s, 2H); 3.5–3.6(d, 2H); 4.1(s, 3H); 4.2(d, 2H); 4.3(t, 2H); 6.55(m, 1H); 6.75(s, 1H); 6.8(d, 1H); 7.6(s, 1H); 7.75(s, 1H); 9.15(s, 1H)
b 4-Chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (130 mg), (prepared as described for the starting material in Example 9), was reacted with 7-hydroxy-2-methylchromone (88 mg), (Bull Soc. Chim Fr. 1995, 132, 233). After cooling, water was added (20 ml) and the precipitate was collected by filtration and dried under vacuum over phosphorus pentoxide at 60° C. to give 6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6, CF3COOD) 1.8–2.0(m, 2H); 2.0–2.15(m, 2H); 2.2–2.3(m, 2H); 2.4(s, 3H); 3.05–3.15(m, 2H); 3.3–3.4(m, 2H); 3.6–3.7(m, 2H); 4.05(s, 3H); 4.35 (t, 2H); 6.3(s, 1H); 7.45(d, 1H); 7.5(s, 1H); 7.65(s, 1H); 7.72(s, 1H); 8.15(d, 1H); 8.75(s, 1H)
c 4-Chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (130 mg), (prepared as described for the starting material in Example 9), was reacted with 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-ol (83 mg), (J. Org. Chem. 1971, 36 (1)), to give 6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.85–2.0(m, 2H); 2.0–2.15(m, 2H); 2.25–2.35(m, 2H); 2.83(s, 3H); 3.05–3.15(m, 2H); 3.3(t, 2H); 3.4(t, 2H); 3.7(br m, 2H); 4.1(s, 3H); 4.3(t, 2H); 4.4(t, 2H); 6.52(d, 1H); 6.7(s, 1H); 6.8(d, 1H); 7.55(s, 1H); 7.75(s, 1H); 9.1(s, 1H)

[0909] A solution of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 10), and 5-hydroxyindole (55 mg, 0.41 mmol) in DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51 mmol) was heated at 100° C. for 2 hours. After cooling, water was added and the precipitate was collected by filtration, washed with water followed by ether, and dried under vacuum over phosphorus pentoxide to give 4-(indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (90 mg, 64%).

[0910] MS-ESI: 419 [MH]+

[0911] ¹H NMR Spectrum: (DMSOd₆) 1.35–1.5 (m, 2H); 1.8 (d, 2H); 1.95 (t, 2H); 1.7–2.0 (m, 1H); 2.2 (s, 3H); 2.85 (d, 2H); 4.02 (s, 3H); 4.1 (d, 2H); 6.45 (s, 1H); 7.0 (d, 1H); 7.35 (s, 1H); 7.4–7.5 (m, 3H); 7.6 (s, 1H); 8.5 (s, 1H)

[0912]

Elemental analysis:	Found	C 67.4	H 6.5	N 13.1
C24H26N4O3 0.5H2O	Requires	C 67.4	H 6.4	N 13.1%

[0913] Using an analogous procedure to that described in Example 34, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol), (Arch. Pharm. 1972, 305, 159). The crude product was purified by column chromatography eluting with methanol/methylene chloride (1/9) followed by 3M ammonia in methanol/methanol/methylene chloride (5/15/80) to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (60 mg, 40%).

[0914] MS-ESI: 447 [MH]+

[0915] ¹H NMR Spectrum: (DMSOd₆) 1.2–1.4 (m, 2H); 1.7 (d, 2H); 1.8 (t, 2H); 1.7–1.9 (m, 1H); 2.05 (s, 3H); 2.12 (s, 3H); 2.25 (s, 3H); 2.75 (d, 2H); 3.9 (s, 3H); 4.0 (d, 2H); 6.8 (d, 1H); 7.15 (s, 1H); 7.2 (d, 1H); 7.3 (s, 1H); 7.52 (s, 1H); 8.45 (s, 1H)

[0916]

Elemental analysis:	Found	C 68.6	H 6.9	N 12.5
C26H30N4O3 0.4H2O	Requires	C 68.8	H 6.8	N 12.4%

[0917] Using an analogous procedure to that described in Example 34, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (10 mg, 0.34 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-hydroxyindole (55 mg, 0.41 mmol). The crude product was purified by chromatography on alumina, eluting with methanol/ethyl acetate/methylene chloride (5/45/50) to give 4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (70 mg, 50%).

[0918] MS-ESI 419 [MH]+

[0919] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.9–2.0 (m, 2H); 2.1 (m, 2H); 2.3 (t, 2H); 3.0–3.15 (m, 2H); 3.4 (t, 2H); 3.6–3.75 (m, 2H); 4.1 (s, 3H); 4.4 (t, 2H); 6.5 (s, 1H); 7.05 (d, 1H); 7.5 (s, 1H); 7.5–7.6 (m, 2H); 7.85 (s, 1H); 9.11 (s, 1H)

[0920]

Elemental analysis:	Found	C 63.7	H 6.4	N 12.1
C24H26N4O3 1.9H2O	Requires	C 63.7	H 6.6	N 12.4%

[0921] A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 10), and 5-amino-2,3-dimethylindole (55 mg, 0.34 mmol) in isopropanol (6 ml) containing 5.5M hydrogen choride in isopropanol (60 μL) was heated for 30 minutes at 70° C. After cooling, the solid was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (118 mg, 74%).

[0922] MS-ESI: 446 [MH]+

[0923] ¹H NMR Spectrum: (DMSOd₆): 1.8–1.9 (m, 2H); 2.0 (d, 2H); 2.1–2.2 (m, 1H); 2.16 (s, 3H); 2.33 (s, 3H); 2.75 (br s, 3H); 2.95–3.05 (m, 2H); 3.5 (d, 2H); 4.0 (s, 3H); 4.07 (d, 2H); 7.25 (d, 1H); 7.4 (d, 1H); 7.42 (s, 1H); 7.52 (s, 1H); 8.25 (s, 1H); 8.75 (s, 1H); 10.0 (br s, 1H); 10.9 (s, 1H); 11.25 (br s, 1H)

[0924]

Elemental analysis:	Found	C 58.5	H 6.8	N 12.9
C26H31N5O2 1H2O 1.9HCl	Requires	C 58.6	H 6.6	N 13.1%

[0925] Using an analogous procedure to that described in Example 37, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-amino-2,3-dimethylindole (55 mg, 0.34 mmol) to give 4(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline hydrochloride (114 mg, 72%).

[0926] MS-ESI: 446 [MH]+

[0927] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.85–2.0 (m, 2H); 2.05–2.15 (m, 2H); 2.1 (s, 3H);

• • [0928] 2.2 (s, 3H); 2.25–2.35 (m, 2H); 2.35 (s, 3H); 3.0–3.15 (m, 2H); 3.32–3.42 (m, 2H); 3.6–3.7 (m, 2H); 4.05 (s, 3H); 4.3 (t, 2H); 7.2 (d, 1H); 7.3 (s, 1H); 7.35 (d, 1H); 7.57 (s, 1H); 8.2 (s, 1H); 8.8 (s, 1H)

[0929]

Elemental analysis:	Found	C 58.8	H 7.0	N 12.5
C26H31N5O 1.9H2O 1.9HCl	Requires	C 58.6	H 7.1	N 12.9%
0.1isopropanol

[0930] Using an analogous procedure to that described in Example 38, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-amino-2-methylindole (50 mg, 0.34 mmol) to give 6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline hydrochloride (138 mg, 89%).

[0931] MS-ESI: 432 [MH]+

[0932] ¹H NMR Spectrum: (DMSOd₆) 1.8–1.9 (m, 2H); 2.0–2.1 (m, 2H); 2.15–2.35 (m, 2H); 2.4 (s, 3H); 3.0–3.1 (m, 2H); 3.2–3.3 (m, 2H); 3.5–3.6 (m, 2H); 4.0 (s, 3H); 4.32 (t, 2H); 6.2 (s, 1H); 7.2 (d, 1H); 7.3 (m, 2H); 7.65 (s, 1H); 8.25 (s, 1H); 8.75 (s, 1H); 10.75 (br s, 1H); 11.15 (s, 1H); 11.25 (br s, 1H)

[0933]

Elemental analysis:	Found	C 58.9	H 6.6	N 13.5
C25H29N5O2 2.2HCl	Requires	C 58.7	H 6.2	N 13.5%
0.1isopropanol

[0934] A mixture of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), and 7-hydroxy-2,4-dimethylquinoline (64 mg, 0.36 mmol), (Chem. Berichte, 1903, 36, 4016), in DMF (3 ml) containing potassium carbonate (86 mg, 0.62 mmol) was heated at 90° C. for 3 hours. After cooling, the mixture was poured onto a column of silica and eluted with 2.5M ammonia in methanol/methylene chloride (5/95) to give 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (50 mg, 35%).

[0935] MS-ESI: 459 [MH]+

[0936] ¹H NMR Spectrum: (CDCl₃) 1.8 (br s, 4H); 2.2 (m, 4H); 2.55 (br s, 4H); 2.7 (2s, 6H); 2.68 (m, 2H); 4.05 (s, 3H); 4.3 (t, 2H); 7.15 (s, 1H); 7.35 (s, 1H); 7.45 (d, 1H); 7.6 (s, 1H); 7.9 (s, 1H); 8.05 (d, 1H); 8.6 (s, 1H)

[0937]

Elemental analysis:	Found	C 70.4	H 7.1	N 12.1
C27H30N4O3 0.2ether	Requires	C 70.5	H 6.8	N 11.8%

[0938] Using an analogous procedure to that described in Example 37, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (50 mg, 0.155 mmol), (prepared as described for the starting material in Example 10), was reacted with 5-amino-2-methylindole (0.171 mmol) to give 6-methoxy-4-(2-methylindol-5-ylamino)-7-(1-methylpiperidin 4-ylmethoxy)quinazoline hydrochloride (72 mg, quant.).

[0939] MS-ESI: 432 [MH]+

[0940] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.5–1.7 (m, 2H); 2.05 (d, 2H); 2.1–2.2 (m, 1H); 2.45 (s, 3H); 2.8 (s, 3H); 3.05 (t, 2H); 3.5 (d, 2H); 4.0 (s, 3H); 4.1 (d, 2H); 6.2 (s, 1H); 7.2 (d, 1H); 7.32 (d, 1H); 7.4 (d, 1H); 7.6 (s, 1H); 8.2 (s, 1H); 8.85 (s, 1H)

[0941]

Elemental analysis:	Found	C 53.9	H 6.8	N 12.4
C25H29N5O2 2.6H2O 2.07HCl	Requires	C 54.2	H 6.6	N 12.6%

[0942] A suspension of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), and 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J. Med. Chem. 1998, 41, 4062), in DMF (3 ml) containing potassium carbonate (86 mg, 0.62 mmol) was heated at 90° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried and the volatiles were removed by evaporation. The residue was triturated with minimal ether, collected by filtration and dried under vacuum to give 6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (95 mg, 69%).

[0943] MS-ESI: 445 [MH]+

[0944] ¹H NMR Spectrum: (CDCl₃) 1.8 (br s, 4H); 2.2 (m, 2H); 2.5 (br s, 4H); 2.7 (t, 2H); 2.8 (s, 3H); 4.1 (s, 3H); 4.3 (t, 2H); 7.3 (d, 1H); 7.35 (s, 1H); 7.45 (dd, 1H); 7.6 (s, 1H); 7.85 (d, 1H); 7.9 (s, 1H); 8.1 (d, 1H); 8.6 (s, 1H)

[0945] Using an analogous procedure to that described in Example 42, 4-chloro-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (156 mg, 0.38 mmol), (prepared as described for the starting material in Example 12), was reacted with 7-hydroxy-2-methylquinoline (66 mg, 0.4 mmol), (J. Med. Chem. 1998, 41, 4062), to give 6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)quinazoline (166 mg, 82%).

[0946] MS-ESI: 537 [MH]+

[0947] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.5 (m, 2H); 1.75–1.95 (m, 3H); 1.95–2.15 (m, 2H); 2.7 (s, 3H); 2.7–2.8 (m, 2H); 2.9–3.0 (m, 2H); 3.05 (s, 3H); 3.2–3.35 (m, 2H), 4.02 (s, 3H); 4.1 (d, 2H); 7.4 (s, 1H); 7.45 (d, 1H); 7.55 (d, 1H); 7.65 (s, 1H); 7.8 (s, 1H); 8.05 (d, 1H); 8.35 (d, 1H); 8.55 (s, 1H)

[0948]

Elemental analysis:	Found	C 62.2	H 6.3	N 10.4
C28H32N4O5S 0.35ether	Requires	C 62.4	H 6.4	N 10.2%
0.2DMF

[0949] A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (50 mg, 0.155 mmol), (prepared as described for the starting material in Example 10), and 5-hydroxy-2-trifluoromethylindole (34 mg, 0.17 mmol) in DMF (1.5 ml) containing potassium carbonate (43 mg, 0.31 mmol) was heated at 90° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO₄) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methanol/ethyl acetate/methylene chloride (10/50/40) followed by 2.5M ammonia in methanol/ethyl acetate/methylene chloride (10/50/40) to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5yloxy)quinazoline (35 mg, 48%).

[0950] MS-ESI: 487 [MH]+

[0951] ¹H NMR Spectrum: (DMSOd₆) 1.25–1.4 (m, 2H); 1.75 (d, 2H); 1.8 (t, 2H); 1.7–2.0 (m, 1H); 2.2 (s, 3H); 2.75 (d, 2H); 4.0 (s, 3H); 4.1 (d, 2H); 7.0 (s, 1H); 7.25 (d, 1H); 7.4 (s, 1H); 7.6 (d, 1H); 7.8 (s, 1H); 8.5 (s, 1H); 12.5 (s, 1H)

[0952]

Elemental analysis:	Found	C 60.2	H 5.8	N 10.9
C25H25F3N4O3 0.7H2O 0.2ether	Requires	C 60.3	H 5.6	N 10.9%

[0953] The starting material was prepared as follows:

[0954] A solution of (4-methoxy-2-methylphenyl)-carbamic acid-1,1-dimethylethyl ester (2 g, 8.43 mmol), (J. Med. Chem. 1996, 39,5119), in dry THF (25 ml) was cooled to −40° C. and sec-butyllithium (15 ml, 19.5 mmol) was added. After stirring for 15 minutes at this temperature, N-methyl-N-methoxytrifluoroacetamide (1.32 g, 8.43 mmol) in THF (20 ml) was added in portions. Stirring was continued for 1 hour at −40° C. and then the mixture was allowed to warm to ambient temperature. The mixture was poured onto ether/1M hydrochloric acid. The organic layer was separated, washed with water, brine, dried (MgSO₄) and the volatiles were removed by evaporation.

[0955] The crude residue (1.4 g) was dissolved in methylene chloride (8 ml) and TFA was added (1.5 ml). After stirring for 3 hours at ambient temperature, the volatiles were removed under vacuum. The crude product was partitoned between methylene chloride and water. The organic layer was separated, washed with water, brine, dried (MgSO₄) and the volatiles were removed by evaporation. The residue was purified by column chromatography, eluting with ether/petroleum ether (1/9) to give 5-methoxy-2-trifluoromethylindole (845 mg, 47% over 2 steps).

[0956] ¹H NMR Spectrum: (CDCl₃) 3.83 (s, 3H), 6.82 (s, 1H), 7.0 (dd, 1H), 7.1 (s, 1H), 7.3 (d, 1H), 8.15 (br s, 1H)

[0957] A solution of 5-methoxy-2-trifluoromethylindole (800 mg, 3.7 mmol) in methylene chloride (6 ml) was cooled to −15° C. and a solution of 1M boron tribromide in methylene chloride (7.44 ml, 7.4 mmol) was added in portions. The mixture was allowed to warm to ambient temperature and was stirred for 45 minutes. After cooling to 0° C., saturated aqueous sodium hydrogen carbonate (25 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was dried (MgSO₄) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether. After removal of the volatiles by evaporation, the solid was triturated with pentane, collected by filtration and dried under vacuum to give 5-hydroxy-2-trifluoromethylindole (290 mg, 39%).

[0958] MS-EI: 201 μM.]+

[0959] ¹H NMR Spectrum: (CDCl₃) 4.64 (s, 1H), 6.8 (s, 1H), 6.92 (dd, 1H), 7.1 (s, 1H), 7.3 (d, 1H), 8.3 (br s, 1H)

[0960]

Elemental analysis:	Found	C 53.3	H 2.9	N 6.8
C9H6F3NO 0.1 H2O	Requires	C 53.3	H 3.1	N 6.9%

[0961] Using an analogous procedure to that described in Example 44, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.3 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-hydroxy-2-trifluoromethylindole (75 mg, 0.37 mmol), (prepared as described for the starting material in Example 44), to give 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)4-(2-trifluoromethylindol-5-yloxy)quinazoline (105 mg, 70%).

[0962] MS-ESI: 487 [MH]+

[0963] ¹H NMR Spectrum: (CDCl₃) 1.8 (m, 4H); 2.1–2.3 (m, 2H); 2.55 (br s, 4H); 2.7 (t, 2H); 4.1 (s, 3H); 4.3 (t, 2H); 6.95 (s, 1H); 7.2 (dd, 1H); 7.35 (s, 1H); 7.5 (d, 1H); 7.55 (s, 1H); 7.6 (s, 1H); 8.6 (s, 1H); 8.8 (s, 1H)

[0964]

Elemental analysis:	Found	C 61.7	H 5.5	N 11.5
C25H25F3N4O3	Requires	C 61.7	H 5.2	N 11.5%

[0965] Using an analogous procedure to that described in Example 42, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 10), was reacted with 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J. Med. Chem. 1998, 41, 4062), to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)quinazoline (86 mg, 63%).

[0966] MS-ESI: 445 [MH]+

[0967] ¹H NMR Spectrum: (CDCl₃) 1.4–1.6 (m, 2H); 1.95 (d, 2H); 2.05 (t, 2H); 1.9–2.1 (m, 1H); 2.35 (s, 3H); 2.8 (s, 3H); 2.95 (d, 2H); 4.1 (s, 3H); 4.15 (d, 2H); 7.3 (m, 2H); 7.45 (dd, 1H); 7.6 (s, 1H); 7.9 (d, 1H); 7.95 (s, 1H); 8.1 (d, 1H); 8.6 (s, 1H)

[0968]

Elemental analysis:	Found	C 69.7	H 6.5	N 12.8
C26H28N4O3 0.2H2O	Requires	C 69.7	H 6.4	N 12.5%

[0969] A suspension of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (10 mg, 0.34 mmol), (prepared as described for the starting material in Example 9), and 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol), (Arch. Pharm. 1972, 305, 159), in DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51 mmol) was heated at 100° C. for 2 hours. After cooling, the residue was purified by chromatography, eluting with methanol/methylene chloride (1/9) followed by 2.5M ammonia in methanol/methanol/methylene chloride (5/10/85) to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (50 mg, 33%).

[0970] MS-ESI: 447 [MH]+

[0971] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.9–2.0 (m, 2H); 2.05–2.15 (m, 2H); 2.15 (s, 3H); 2.3–2.4 (m, 2H); 2.4 (s, 3H), 3.05–3.15 (m, 2H); 3.35–3.45 (t, 2H); 3.7 (br s, 2H); 4.1 (s, 3H); 4.4 (t, 2H); 6.95 (d, 1H); 7.3 (s, 1H); 7.35 (d, 1H); 7.55 (s, 1H); 7.85 (s, 1H); 9.15 (s, 1H)

[0972]

Elemental analysis:	Found	C 67.7	H 6.8	N 12.2
C26H30N4O3 0.8H2O	Requires	C 67.8	H 6.9	N 12.2%

[0973] Using an analogous procedure to that described in Example 32, 7-benzyloxy-4-chloro-6-methoxyquinazoline (1 g, 3.33 mmol), (prepared as described for the starting material in Example 1), was reacted with 5-hydroxy-2-methylindole (0.59 g, 4 mmol) to give 7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.25 g, 91%).

[0974] MS-ESI: 412 [MH]+

[0975] ¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H); 4.0 (s, 3H); 5.35 (s, 2H); 6.15 (s, 1H); 6.85 (s, 1H); 7.2–7.6 (m, 9H); 8.5 (s, 1H)

[0976]

Elemental analysis:	Found	C 72.2	H 5.1	N 10.2
C25H21N3O3 0.2H2O	Requires	C 72.3	H 5.2	N 10.1%

[0977] The starting material may be prepared as follows:

[0978] A solution of boron tribromide (32.5 ml, 341 mmol) in methylene choride (60 ml) was added in portions to a solution of 5-methoxy-2-methylindole (25 g, 155 mmol) in methylene chloride (250 ml) cooled at −45° C. After stirring for 15 minutes at −30° C., the mixture was warmed up to ambient temperature and stirred for 1 hour. Methylene chloride (300 ml) was added in portions and the mixture was cooled to 0° C. Water was added in portions and the mixture was adjusted to pH6 with 4N sodium hydroxide. The organic layer was separated. The aqueous layer was extracted with methylene chloride and the organic layers were combined, washed with water, brine, dried (MgSO₄) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/9 followed by 15/85) to give 5-hydroxy-2-methylindole (21.2 g, 93%).

[0979] ¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 5.95 (s, 1H); 6.5 (dd, 1H); 6.7 (s, 1H); 7.05 (d, 1H); 8.5 (s, 1H)

[0980] A solution of 7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (0.2 g, 0.5 mmol), (prepared as described in Example 48), in a mixture of methylene chloride (5 ml) and DMF (2 ml) containing 10% palladium-on-charcoal (50 mg) was treated with hydrogen at 1.8 atmospheres pressure for 2 hours. The suspension was filtered and the catalyst was washed with methanol followed by methylene chloride. The volatiles were removed from the filtrate by evaporation. The residue was triturated with water. The resulting solid was washed with water and dried under vacuum over phosphorus pentoxide at 60° C. to give 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (140 mg, 89%).

[0981] MS-ESI: 322 [MH]+

[0982] ¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H); 4.0 (s, 3H); 6.15 (s, 1H); 6.9 (d, 1H); 7.2 (s, 1H); 7.25 (s, 1H); 7.3 (d, 1H); 7.6 (s, 1H); 8.4 (s, 1H)

[0983] A suspension of 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45 mmol) and 5-hydroxy-2-trifluoromethylindole (109 mg, 0.54 mmol), (prepared as described for the starting material in Example 44), in DMF (1.5 ml) containing potassium carbonate (94 mg, 0.67 mmol) was heated at 100° C. for 1 hour. After cooling, the precipitate was collected by filtration, washed with ether, and dried under vacuum to give 6-methoxy-7-(3-methylsulphonylpropoxy)4-(2-trifluoromethylindol-5-yloxy)quinazoline (195 mg, 87%).

[0984] MS-ESI: 496 [MH]⁺

[0985] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.25–2.4 (m, 2H), 3.1 (s, 3H), 3.35 (t, 2H), 4.1 (s, 3H), 4.4 (t, 2H), 7.1 (s, 1H), 7.3 (d, 1H), 7.5 (s, 1H), 7.6 (d, 1H), 7.7 (s, 1H), 7.78 (s, 1H), 8.9 (s, 1H)

[0986] The starting material was prepared as follows:

[0987] A solution of 3-(methylthio)-1-propanol (5.3 g, 50 mmol) in methanol (500 ml) was added to a solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co., Inc), (30 g) in water (150 ml) and the mixture stirred at ambient temperature for 24 hours. The precipitated solid was removed by filtration and the methanol removed from the filtrate by evaporation. The aqueous residue was saturated with sodium chloride and extracted with methylene chloride (4×25 ml). The aqueous residue was then saturated with ammonium chloride and extracted with ethyl acetate (4×25 ml). The extracts were combined, dried (MgSO₄) and the solvent removed by evaporation to give 3-(methylsulphonyl)-1-propanol (610 mg, 9%) as an oil.

[0988] ¹H NMR Spectrum: (CDCl₃) 2.10(m, 2H); 2.96(s, 3H); 3.20(t, 2H); 3.80(t, 2H)

[0989] MS-ESI: 139 [MH]⁺

[0990] Alternatively the 3-(methylsulphonyl)-1-propanol may be prepared as follows:

• • [0991] m-Chloroperoxybenzoic acid (67%, 25 g, 97.2 mmol) was added in portions to 3-(methylthio)-1-propanol (5 ml, 48.6 mmol) in solution in dichloromethane. Some m-chlorobenzoic acid precipitated out and was removed by filtration. The filtrate was evaporated and the residue was purified over alumina using first dichloromethane (100%) then dichloromethane/methanol (95/5) to give 3-(methylsulphonyl)-1-propanol (4.18 g, 62%) as an oil.

[0992] Triphenylphosphine (8.9 g, 35.2 mmol) was added to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 19.6 mmol), (prepared as described for the starting material in Example 12), in methylene chloride (150 ml). This was followed by the addition of 3-(methylsulphonyl)-1-propanol (3.5 g, 25.4 mmol) and diethyl azodicarboxylate (5.55 ml, 35.2 mmol) in portions. The reaction was complete once the reaction became homogeneous. Silica was added and the volatiles were removed by evaporation. The free flowing powder was placed on the top of a flash chromatography column pre-equilibrated with ethyl acetate (100%). Elution was done using ethyl acetate (100%) followed by methylene chloride/ethyl acetate/methanol (60/35/5). The volatiles were removed by evaporation to give 6-methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7.58 g, 91%) as a white solid.

[0993] ¹H NMR Spectrum: (CDCl₃) 1.2(s, 9H); 2.4–2.5(m, 2H); 3.0(s, 3H); 3.25–3.35(t, 2H); 5.95(s, 1H); 7.1(s, 1H); 7.65(s, 1H); 8.2(s, 1H)

[0994] 6-Methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7 g, 17 mmol) was suspended in methanol and 2M sodium hydroxide (3.3 ml, 6.6 mmol) was added with continuous stirring. The reaction mixture became homogeneous after 15 minutes. After a further 45 minutes water was added (7 ml) and the reaction mixture was adjusted to pH10 with 2M hydrochloric acid. The precipitate (a white solid) was collected by filtration, washed with water and dried over phosphorus pentoxide under vacuum to give 6-methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (5 g, 90%).

[0995] ¹H NMR Spectrum: (DMSOd₆) 2.2–2.3(m, 2H); 3.05(s, 3H); 3.35(t, 2H); 3.9(s, 3H); 4.25(t, 2H); 7.15(s, 1H); 7.5(s, 1H); 8.0(s, 1H)

[0996] 6-Methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (3.6 g, 11.5 mmol) was suspended in thionyl chloride (40 ml). DMF (1.8 ml) was added under argon and the mixture was heated at reflux for 1.5 hours. The thionyl chloride was eliminated by several azeotropic distillations using toluene. The solid residue was suspended in ice/water and a saturated solution of sodium hydrogen carbonate was added to adjust the mixture to pH7. The solid was collected by filtration, washed with water and dried in a vacuum dessicator over phosphorus pentoxide to give 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (3.35 g, 88%).

[0997] Using an analogous procedure to that described in Example 50, 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline, (prepared as described for the starting material in Example 50), was reacted with the appropriate phenol to give the compounds described in Table III:

[0998]

TABLE III
Example	Weight	Yield	MS-ESI
No.	(mg)	%	[MH]+	Ar	Note
51	189	92	454	2-methylquinolin-7-yl	a
52	175	90	428	indol-5-yl	b
a 4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45 mmol) was reacted with 7-hydroxy-2-methylquinoline (86.6 mg, 0.54 mmol), (J. Med. Chem. 1998, 41, 4062). After cooling, water was added and the precipitate was collected by filtration, washed with water, followed by ether and dried under vacuum to give 6-methoxy-7-(3-methylsulphonylpropoxy)-4-(2-methylquinolin-7-yloxy)quinazoline.
1H NMR Spectrum: (DMSOd6, CF3COOD) 2.2–2.35(m, 2H), 2.95(s, 3H), 3.1(s, 3H), 3.35(m, 2H), 4.05(s, 3H), 4.4(t, 2H), 7.5(s, 1H), 7.7(s, 1H), 7.95(dd, 1H), 8.02(d,; 1H), 8.2(s, 1H), 8.48(d, 1H), 8.7(s, 1H), 9.12(d, 1H)
b Using an analogous procedure to that described in note a, 4-chloro-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline (150 mg, 0.45 mmol) was reacted with 5-hydroxyindole (72.4 mg, 0.54 mmol) to give 4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.2–2.35(m, 2H), 3.1(s, 3H), 3.3–3.4(t, 2H), 4.0(s, 3H), 4.4(t, 2H), 6.5(s, 1H), 7.0(dd, 1H), 7.4(s, 1H), 7.4–7.5(m, 3H), 7.6(s, 1H), 8.5(s, 1H), 11.25(s, 1H)

[0999] 0.5M Triphenylphosphine in methylene chloride and diisopropyl azodicarboxylate (150 μl, 0.75 mmol) were added in portions to a suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (112 mg, 0.35 mmol), (prepared as described in Example 49), and N,N-dimethylethanolamine (62 mg, 0.7 mmol) in methylene chloride (2 ml). After stirring for 2 hours at ambient temperature, the reaction mixture was poured onto an isolute® column (10 g of silica) and eluted with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (10/40/50), methanol/methylene chloride (10/90), and 3M ammonia in methanol/methanol/methylene chloride (5/15/80). After removal of the volatiles by evaporation, the residue was dissolved in the minimum amount of methylene chloride (about 3 ml) and ether and petroleum ether (about 10 ml) was added. The resulting precipitate was collected by filtration and dried under vacuum to give 7-(2-(N,N-dimethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (52 mg, 38%).

[1000] MS-ESI: 393 [MH]⁺

[1001] ¹H NMR Spectrum: (DMSOd₆) 2.25 (s, 6H), 2.4 (s, 3H), 2.75 (t, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 6.15 (s, 1H), 6.87 (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 7.5 (s, 1H)

[1002] Using an analogous procedure to that described in Example 53, the appropriate alcohols were reacted with 7-hydroxy-6-methoxy-4(2-methylindol-5-yloxy)quinazoline, (prepared as described in Example 49), in analogous proportions to give the compounds described in Table IV:

[1003]

TABLE IV
Example	Weight	Yield	MS-ESI
No.	(mg)	%	[MH]+	R	Note
54	25	17	419	2-pyrrolidin-1-ylethoxy	a
55	112	74	433	1-methylpiperidin-3-	b
				ylmethoxy
56	115	72	456	2-(N-methyl-N-(4-	c
				pyridyl)amino)ethoxy
a 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 1-(2-hydroxyethyl)pyrrolidine (81 mg) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-pyrrolidin-1-ylethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.65–1.8(m, 4H), 2.4(s, 3H), 2.6(br s, 4H), 2.9(t, 2H), 4.0(s, 3H), 4.3(t, 2H), 6.15(s, 1H), 6.9(d, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H)
b 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 1-methyl-3-piperidinemethanol (90 mg) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methylpiperidin-3-ylmethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.45–2.2(m, 7H), 2.18(s, 3H), 2.4(s, 3H), 2.6(br d, 1H), 2.85(br d, 1H), 4.0(s, 3H), 4.1(d, 2H), 6.15(s, 1H), 6.9(d, 1H), 7.25(d, 1H), 7.3(d, 1H), 7.35(s, 1H), 7.6(s, 1H), 8.5(s, 1H)
c 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 2-(N-methyl-N-(4-pyridyl)amino)ethanol (106 mg), (EP 0359389), to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.4(s, 3H), 3.1(s, 3H), 3.9(t, 2H), 3.97(s, 3H), 4.4(t, 2H), 6.15(s, 1H), 6.75(d, 2H), 6.87(dd, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.35(s, 1H), 7.6(s, 1H), 8.15(d, 2H), 8.5(s, 1H)

[1004] Using an analogous procedure to that described in Example 53, except that ammonia in methanol was not necessary during the column chromatography, the appropriate alcohols were reacted with 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline, (prepared as described in Example 49), in analogous proportions to give the compounds described in Table V:

[1005]

TABLE V
Example	Weight	Yield	MS-ESI
No.	(mg)	%	[MH]+	R	Note
57	115	76	435	2-morpholinoethoxy	a
58	64	42	433	2-piperidinoethoxy	b
59	66	43	437	2-(N-(2-methoxyethyl)-N-	c
				methylamino)ethoxy
`60	118	75	449	3-morpholinopropoxy	d
61	101	68	424	2-(2-methoxyethoxy)ethoxy	e
62	81	57	407	3-(N,N-dimethylamino)-	f
				propoxy
63	160	92	497	3-(1,1-dioxothiomor-	g
				pholino)propoxy
64	121	83	417	2-(1H-1,2,4-triazol-1-	h
				yl)ethoxy
65	38	22	492	2-(2-(4-methylpiperazin-1-	i
				yl)ethoxy)ethoxy
66	80	48	479	2-(2-morpholinoethoxy)-	j
				ethoxy
a 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 4-(2-hydroxyethyl)morpholine (92 mg) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.4(s, 3H), 2.5–2.7(m, 4H), 2.8(t, 2H), 3.6(t, 4H), 4.0(s, 3H), 4.35(t, 2H), 6.15(s, 1H), 6.87(dd, 1H), 7.25(s, 1H), 7.32(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H)
b 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 1-(2-hydroxyethyl)piperidine (90 mg) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.3–1.45(m, 2H), 1.4–1.6(m, 4H), 2.4(s, 3H), 2.4–2.5(m, 4H), 2.75(t, 2H), 3.97(s, 3H), 4.3(t, 2H), 6.15(s, 1H), 6.9(d, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H)
c 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (93 mg) to give 6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy)-4-(2-methylindol-5-yloxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.35(s, 3H), 2.4(s, 3H), 2.65(t, 2H), 2.85(t, 2H), 3.25(s, 3H), 3.45(t, 2H), 3.97(s, 3H), 4.25(t, 2H), 6.15(s, 1H), 6.9(dd, 1H), 7.25(s, 1H), 7.32(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H)
The starting material was prepared as follows:
A mixture of 2-(methylamino)ethanol (5.4 g, 72 mmol), 2-bromoethyl methyl ether (10 g, 72 mmol) and triethylamine (10 ml, 72 mmol) in acetonitrile (70 ml) was refluxed overnight. After cooling, the solid was filtered and the filtrate was evaporated. The residue was triturated with ether. The ether layer was separated and evaporated to give 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (3 g, 31%).
MS-EI: 134 [MH]+
1H NMR Spectrum: (CDCl3) 2.35(s, 3H); 2.6(t, 2H); 2.65(t, 2H); 3.35(s, 3H); 3.5(t, 2H); 3.6(t, 2H)
d 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 4-(3-hydroxypropyl)morpholine (102 mg) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.9–2.1(m, 2H), 2.4(s, 3H), 2.45(t, 2H), 2.45–2.6(s, 4H), 3.6(t, 4H), 4.0(s, 3H), 4.25(t, 2H), 6.15(s, 1H), 6.9(d, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.38(s, 1H), 7.6(s, 1H), 8.5(s, 1H)
The starting material was prepared as follows:
Morpholine (94 g, 1.08 mol) was added dropwise to a solution of 3-bromo-1-propanol (75 g, 0.54 mol) in toluene (750 ml) and the reaction then heated at 80° C. for 4 hours. The mixture was allowed to cool to ambient temperature and the precipitated solid was removed by filtration. The volatiles were removed from the filtrate and the resulting yellow oil was purified by distillation at 0.4–0.7 mmHg to give 4-(3-hydroxypropyl)morpholine (40 g, 50%) as a colourless oil.
b.p. 68–70° C. (~0.5 mmHg)
1H NMR Spectrum: (DMSOd6) 1.65–1.78(m, 2H); 2.50(t, 4H); 2.60(t, 2H); 3.68(t, 4H); 3.78(t, 2H); 4.90(br d, 1H)
e 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 2-(2-methoxyethoxy)ethanol (84 mg) to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-yloxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.42(s, 3H), 3.27(s, 3H), 3.5(t, 2H), 3.65(t, 2H), 3.85(t, 2H), 4.0(s, 3H), 4.32(t, 2H), 6.15(s, 1H), 6.9(d, 1H), 7.3(s, 1H), 7.35(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H)
f 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 3-(N,N-dimethylamino)propanol (72 mg) to give 7-(3-N,N-dimethylaminopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.9–2.0(m, 2H), 2.17(s, 6H), 2.4(s, 3H), 3.98(s, 3H), 4.22(t, 2H), 6.14(s, 1H), 6.88(dd, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.35(s, 1H), 7.6(s, 1H), 8.47(s, 1H)
g 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (135 mg), (prepared as described for the starting material in Example 5), to give 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.9–2.0(m, 2H), 2.38(s, 3H), 2.65(t, 2H), 2.9(br s, 4H), 3.1(br s, 4H), 3.96(s, 3H), 4.25(t, 2H), 6.12(s, 1H), 6.85(dd, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.37(s, 1H), 7.56(s, 1H), 8.46(s, 1H)
h 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 2-(1H-1,2,4-triazol-1-yl)ethanol (79 mg), (Ann. Phar. Fr. 1977, 35, 503–508), to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.42(s, 3H), 3.96(s, 3H), 4.62(m, 2H), 4.75(m, 2H), 6.15(s, 1H), 6.9(dd, 1H), 7.27(s, 1H), 7.32(d, 1H), 7.47(s, 1H), 7.63(s, 1H), 8.03(s, 1H), 8.51(s, 1H), 8.60(s, 1H)
i 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethanol (132 mg), (Arzneim. Forsch. 1966, 16, 1557–1560), to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.15(s, 3H), 2.2–2.6(m, 10H), 2.4(s, 3H), 3.65(t, 2H), 3.85(t, 2H), 4.03(s, 3H), 4.35(m, 2H), 6.16(s, 1H), 6.9(dd, 1H), 7.3(s, 1H), 7.35(d, 1H), 7.4(s, 1H), 7.61(s, 1H), 8.5(s, 1H)
j 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reacted with 2-(2-morpholinoethoxy)ethanol (123 mg) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7(2-(2-morpholinoethoxy)ethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.40(s, 3H), 2.4–2.5(m, 4H), 2.4–2.6(m, 2H), 3.55(t, 4H), 3.6(t, 2H), 3.85(t, 2H), 3.97(br s, 3H), 4.15(br s, 2H), 6.15(s, 1H), 6.9(d, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.48(s, 1H)
The starting material was prepared as follows:
2-(2-Chloroethoxy)ethanol (1.25 g, 10 mmol) was added to a mixture of morpholine (2.58 g, 30 mmol) and potassium carbonate (5.5 g, 40 mmol) in acetonitrile (50 ml). The mixture was heated at reflux for 6 hours and then stirred for 18 hours at ambient temperature. The insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10 and then 80/20) to give 2-(2-morpholinoethoxy)ethanol (600 mg, 34%).
MS-(EI): 175 [M.]+
1H NMR Spectrum: (CDCl3) 2.5(br s, 4H); 2.59(t, 2H); 3.6–3.85(m, 10H)

[1006] A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100 mg, 0.29 mmol), 5-hydroxy-2-methylindole (53 mg, 0.36 mmol), (prepared as described for the starting material in Example 48), and potassium carbonate (62 mg, 0.44 mmol) in DMF (2 ml) was heated at 85° C. for 3 hours, followed by heating at 95° C. for 2 hours. After cooling, ice/water (15 ml) was added and the precipitate was collected by filtration and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol/3M ammonia in methanol (95/3/2) to give 6-methoxy-4-(2-methylindol-5yloxy)-7-(3-piperidinopropoxy)quinazoline (71 mg, 54%).

[1007] MS-ESI: 447 [MH]⁺

[1008] ¹H NMR Spectrum: (DMSOd₆) 1.35–1.4 (m, 2H), 1.45–1.55 (m, 4H), 1.92–2.0 (m, 2H), 2.3–2.4 (m, 4H), 2.40 (s, 3H), 2.4–2.5 (m, 2H), 3.97 (s, 3H), 4.22 (t, 2H), 6.15 (s, 1H), 6.9 (d, 1H), 7.27 (s, 1H), 7.8 (d, 1H), 7.35 (s, 1H), 7.58 (s, 1H), 8.48 (s, 1H)

[1009] The starting material was prepared as follows:

[1010] Diethyl azodicarboxylate (3.9 ml, 24.5 mmol) was added in portions to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (5 g, 16.3 mmol), (prepared as described for the starting material in Example 12), 3-bromo-1-propanol (2.21 ml, 24.5 mmol) and triphenylphosphine (6.42 g, 24.5 mmol) in methylene chloride (50 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/methanol (95/5) to give 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 86%).

[1011] MS-ESI: 427–429 [MH]⁺

[1012] ¹H NMR Spectrum: (DMSOd₆) 1.12 (s, 9H), 2.32 (t, 2H), 3.7 (t, 2H), 3.9 (s, 3H), 4.25 (t, 2H), 5.9 (s, 2H), 7.20 (s, 1H), 7.51 (s, 1H), 8.36 (s, 1H)

[1013]

Elemental analysis:	Found	C 50.1	H 5.4	N 6.4
C18H23BrN2O5 0.2H2O	Requires	C 50.2	H 5.5	N 6.5%

[1014] A solution of 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.89 g, 6.78 mmol) in piperidine (100 ml) was heated at 100° C. for 1 hour. After cooling, the volatiles were removed under vacuum. The residue was dissolved in methylene chloride, and washed with saturated ammonium chloride and brine. The organic layer was dried (MgSO₄) and the volatiles were removed by evaporation. The residue was dried under vacuum to give 6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.4 g, 83%).

[1015] MS-ESI: 432 [MH]⁺

[1016] ¹H NMR Spectrum: (DMSOd₆) 1.15 (s, 9H), 1.35–1.5 (m, 1H), 1.6–1.8 (m, 3H), 1.8–1.9 (d, 2H), 2.2–2.3 (m, 2H), 2.95 (t, 2H), 3.25 (t, 2H), 3.55 (d, 2H), 3.95 (s, 3H), 4.25 (t, 2H), 5.94 (s, 2H), 7.24 (s, 1H), 7.56 (s, 1H), 8.46 (s, 1H)

[1017] A solution of 6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.35 g, 5.45 mmol) in 7M ammonia in methanol (50 ml) was stirred overnight at ambient temperature. The volatiles were removed under vacuum and the residue was triturated with ether, filtered and washed with ether followed by ether/methylene chloride (1/1) and dried under vacuum to give 6-methoxy-7-(3-piperidinopropoxy)-3,4dihydroquinazolin-4-one (1.65 g, 95%).

[1018] MS-ESI: 318 [MH]⁺

[1019] ¹H NMR Spectrum: (DMSOd₆) 1.3–1.4 (m, 2H), 1.4–1.55 (m, 4H), 1.85–1.95 (m, 2H), 2.35 (br s, 4H), 2.4 (t, 2H), 3.9 (s, 3H), 4.15 (t, 2H), 7.11 (s, 1H), 7.44 (s, 1H), 7.9 (s, 1H)

[1020]

Elemental analysis:	Found	C 63.5	H 7.4	N 13.1
C17H23N3O3 0.2H2O	Requires	C 63.6	H 7.4	N 13.0%

[1021] A solution of 6-methoxy-7-(3-piperidinopropoxy)-3,4-dihydroquinazolin-4-one (1.5 g, 4.7 mmol) in thionyl chloride (15 ml) containing DMF (1.5 ml) was heated at reflux for 3 hours. After cooling, the volatiles were removed under vacuum. The residue was azeotroped with toluene. The solid was partitioned between methylene chloride and sodium hydrogen carbonate. The aqueous layer was adjusted to pH10 with 6M aqueous sodium hydroxide. The organic layer was separated, washed with brine, dried (MgSO₄) and the volatiles were removed by evaporation. The residue was purified by column chromatography to give 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.21 g, 76%).

[1022] MS-ESI: 336 [MH]⁺

[1023] ¹H NMR Spectrum: (DMSOd₆) 1.35–1.45 (m, 2H), 1.5–1.6 (m, 4H), 1.9–2.05 (m, 2H), 2.4 (br s, 4H), 2.45 (t, 2H), 4.0 (s, 3H), 4.29 (t, 2H), 7.41 (s, 1H), 7.46 (s, 1H), 8.9 (s, 1H)

[1024] Using an analogous procedure to that described in Example 67, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (10 mg), (prepared as described for the starting material in Example 67), was reacted with 5-hydroxyindole (48 mg, 0.36 mmol) to give 4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (57 mg, 45%).

[1025] MS-ESI: 433 [MH]⁺

[1026] ¹H NMR Spectrum: (DMSOd₆) 1.4 (br s, 2H), 1.45–1.6 (br s, 4H), 1.9–2.1 (m, 2H), 2.4 (br s, 4H), 2.45 (t, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.47 (s, 1H), 7.0 (d, 1H), 7.35 (s, 1H), 7.45 (s, 2H), 7.47 (d, 1H), 7.61 (s, 1H), 8.49 (s, 1H)

[1027] A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (161 mg, 0.5 mmol), (prepared as described in Example 49), 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine (222 mg, 0.6 mmol), (prepared as described for the starting material in Example 10), and potassium carbonate (188 mg, 1 mol) in DMF (1.6 ml) was heated at 100° C. for 2 hours. After cooling, water was added. The precipitate was collected by filtration, washed with water, and dried under vacuum over phosphorus pentoxide at 60° C. The solid was triturated with petroleum ether, collected by filtration, washed with a mixture of ether/petroleum ether (1/1) and dried under vacuum to give 6-methoxy-4(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (200 mg, 77%).

[1028] MS-ESI: 541 [MNa]⁺

[1029] ¹H NMR Spectrum: (DMSOd₆) 1.1–1.3 (m, 2H), 1.4 (s, 9H), 1.8 (d, 2H), 1.95–2.1 (m, 1H), 2.4 (s, 1H), 2.7–2.85 (br s, 2H), 3.95 (s, 3H), 4.05 (d, 2H), 6.12 (s, 1H), 6.8% (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.35 (s, 1H), 7.55 (s, 1H), 8.45 (s, 1H)

[1030] A solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (155 mg, 0.3 mmol), (prepared as described in Example 69), in methylene chloride (5 ml) containing TFA (1 ml) was stirred at ambient temperature for 30 minutes. The volatiles were removed under vacuum and the residue was treated with water and adjusted to pH12 with 2M sodium hydroxide. The mixture was extracted with methylene chloride. The organic layer was dried (MgSO₄), and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate/methanol (5/4/1) followed by methylene chloride/methanol (9/1) and by 3M ammonia in methanol/methanol/methylene chloride (5/15/80). After removal of the solvent by evaporation, the residue was dissolved in the minimum of methylene chloride, ether was added followed by petroleum ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (120 mg, 96%).

[1031] MS-ESI: 419 [MH]⁺

[1032] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.5–1.7 (m, 2H), 2.05 (br d, 2H), 2.3–2.4 (m, 1H), 2.4 (s, 3H), 3.05 (t, 2H), 3.4 (d, 2H), 4.09 (s, 3H), 4.25 (d, 2H), 6.95 (dd, 1H), 7.35 (s, 1H), 7.4 (d, 1H), 7.6 (s, 1H), 7.85 (s, 1H), 9.15 (s, 1H)

[1033] Methoxyacetaldehyde (368 mg, 3.47 mmol) (freshly distilled) followed by sodium triacetoxyborohydride (552 mg, 2.6 mol) were added to a solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (726 mg, 1.74 mmol), (prepared as described in Example 70), in a mixture of methylene chloride (15 ml) and methanol (15 ml). After stirring for 1.5 hours at ambient temperature, saturated sodium hydrogen carbonate was added. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The organic layer, was separated, washed with water, brine, dried (MgSO₄) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (80/20). After removal of the solvent, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (392 mg, 47%).

[1034] MS-ESI 477 [MH]⁺

[1035] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.6–1.8 (m, 2H), 2.05 (br d, 2H), 2.15–2.3 (m, 1H), 2.4 (s, 3H), 3.05 (t, 2H), 3.3 (br s, 2H), 3.32 (s, 3H), 3.58 (d, 2H), 3.65 (br s, 2H), 4.05 (s, 3H), 4.18 (d, 2H), 6.2 (s, 0.5H (partly exchanged)), 6.92 (dd, 1H), 7.32 (s, 1H), 7.35 (d, 1H), 7.55 (s, 1H), 7.8 (s, 1H), 9.15 (s, 1H)

[1036]

Elemental analysis:	Found	C 68.0	H 6.8	N 11.8
C27H32N4O4	Requires	C 68.1	H 6.8	N 11.8%

[1037] The starting material was prepared as follows:

[1038] A solution of 1,1,2-trimethoxyethane (90 g, 750 mmol) in water (570 ml) containing 12 N hydrochloric acid (3.75 ml) was stirred at 40° C. for 1.5 hours. After cooling, solid sodium chloride was added and the mixture was extracted with ether. The organic layer was dried (MgSO₄). The organic layer was distilled and the fraction from 70–90° C. was collected to give methoxyacetaldehyde (20.3 g) which was used directly in the next step.

[1039] Diphenylphosphoryl azide (83 mg, 0.3 mmol) was added in portions to a solution of 7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (75 mg, 0.2 mmol), triethylamine (40 mg, 0.4 mmol) and 1-(2-aminoethyl)pyrrolidine (46 mg, 0.4 mmol) in DMF (1.5 ml). After stirring for 5 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO₄) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) followed by methylene chloride/3M ammonia in methanol (9/1). After removal of the solvent, the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((2-(2-pyrrolidin-1-ylethyl)carbamoyl)vinyl)quinazoline (25 mg, 26%).

[1040] MS-ESI: 472 [MH]⁺

[1041] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.8–1.95 (m, 2H), 1.95–2.1 (m, 2H), 2.48 (s, 3H), 3.0–3.2 (m, 2H), 3.35 (t, 2H), 3.6 (t, 2H), 3.65 (br s, 2H), 4.11 (s, 3H), 6.18 (s, 0.5H, partially exchanged), 6.95 (dd, 1H), 7.05 (d, 1H), 7.35 (s, 1H), 7.37 (d, 1H), 7.8 (s, 1H), 7.86 (d, 1H), 8.2 (s, 1H), 8.76 (s, 1H)

[1042] The starting material was prepared as follows:

[1043] Trifluoromethanesulphonic anhydride (338 mg, 1.2 mmol) was added to a suspension of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg, I mmol), (prepared as described for the starting material in Example 5), in methylene chloride (2 ml) containing pyridine (2 ml) cooled at 5° C. When the addition was complete, the mixture was left to warm to ambient temperature and stirred for 1 hour. After removal of the volatiles by evaporation, the residue was partitioned between ethyl acetate/ether and water. The organic layer was separated, washed with 0.5M hydrochloric acid, followed by water, brine, dried (MgSO₄) and evaporated to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (400 mg, 88%).

[1044] MS-ESI: 453–455 [MH]⁺

[1045] ¹H NMR Spectrum: (DMSOd₆) 4.15 (s, 3H), 7.5 (d, 1H), 7.62 (t, 1H), 7.78 (d, 1H), 8.02 (s, 1H), 8.27 (s, 1H), 8.77 (s, 1H)

[1046] Triethylamine (33 mg, 0.33 mmol) and tert-butyl acrylate (77 mg, 0.6 mmol) followed by diphenylpropylphosphine (3.4 mg, 0.008 mmol) and palladium(II) acetate (1.7 mg, 0.0075 mmol) were added to a solution of 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (136 mg, 0.3 mmol) in DMF (1.5 ml) under argon. When the addition was complete the reaction flask was purged with argon. The mixture was stirred at 80–85° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH6 with 2M hydrochloric acid. The organic layer was separated, washed with water, brine, dried (MgSO₄) and evaporated. The residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/ether (95/5). After removal of the solvent under vacuum, the solid was triturated with pentane/ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline (63 mg, 49%).

[1047] MS-ESI: 431 [MH]⁺

[1048] ¹H NMR Spectrum: (DMSOd₆) 1.51 (s, 9H), 4.07 (s, 3H), 6.87 (d, 1H), 7.45 (d, 1H), 7.6 (t, 1H), 7.7 (s, 1H), 7.75 (d, 1H), 7.91 (d, 1H), 8.39 (s, 1H), 8.65 (s, 1H)

[1049]

Elemental analysis:	Found	C 61.1	H 4.8	N 6.6
C22H20ClFN2O3	Requires	C 61.3	H 4.7	N 6.5%

[1050] A solution of 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline (581 mg, 1.31 mmol) in a mixture of methylene chloride/TFA (2.5 ml/2.5 ml) was stirred at ambient temperature for 1.5 hours. After removal of the volatiles under vacuum, the residue was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH3 with 0.5M sodium hydroxide. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO₄) and evaporated to give 7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (430 mg, 85%).

[1051] ¹H NMR Spectrum: (DMSOd₆) 4.08 (s, 3H), 6.9 (d, 1H), 7.45 (s, 1H), 7.6 (t, 1H), 7.70 (s, 1H), 7.73 (d, 1H), 7.95 (d, 1H), 8.39 (s, 1H), 8.66 (s, 1H)

[1052] 1M Sodium HMDS in THF (0.84 ml, 8.4 mmol) was added to a suspension of 7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (105 mg, 0.28 mmol) and 5-hydroxy-2methylindole (82 mg, 0.56 mmol), (prepared as described for the starting material in Example 48), in DMSO (1.5 ml). After stirring for 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH3 with 2M hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO₄) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10 and 70/30) to give 7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (75 mg, 71%).

[1053] ¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H), 4.06 (s, 3H), 6.15 (s, 1H), 6.82 (d, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.68 (s, 1H), 7.84 (d, 1H), 8.25 (s, 1H), 8.55 (s, 1H)

[1054] A suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321 mg, 1 mmol), (prepared as described in Example 49), 1-bromo-3-chloropropane (120 μl, 1.2 mmol) and potassium carbonate (359 mg, 2.6 mmol) in DMF (5 ml) was stirred at ambient temperature overnight. After addition of water, the precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide at 60° C. to give 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg, 70%).

[1055] MS-ESI: 398 [MH]⁺

[1056] ¹H NMR Spectrum: (DMSOd₆) 2.2–2.35 (m, 2H), 2.4 (s, 3H), 3.85 (t, 2H), 4.0 (s, 3H), 4.32 (t, 2H), 6.15 (s, 1H), 6.88 (d, 1H), 7.27 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H)

[1057] A solution of 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (150 mg, 0.38 mmol), (prepared as described in Example 73), in 1-methylpiperazine (2 ml) was heated at 100° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and aqueous 5% sodium hydrogen carbonate. The organic layer was separated, washed with water, brine, dried (MgSO₄) and evaporated. The residue was purified by column chromatography on an isolute column eluting with methanol/ethyl acetate/methylene chloride (1/4/5 followed by 1/9/0) and 3M ammonia in methanol/methanol/methylene chloride (5/10/80). After removal of the solvent under vacuum, the solid was dissolved in the minimum of methylene chloride and ether/petroleum ether was added. The precipitate was collected by filtration, and dried under vacuum to give 6-methoxy-4(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline (55 mg, 32%).

[1058] MS-ESI: 462 [MH]⁺

[1059] ¹H NMR Spectrum: (DMSOd₆, CF₃COOD, 60° C.) 2.2–2.3 (m, 2H), 2.4 (s, 3H), 2.9 (s, 3H), 3.4–3.5 (m, 4H), 3.5–3.8 (m, 6H), 4.07 (s, 3H), 4.4 (t, 2H), 6.95 (d, 1H), 7.35 (s, 1H), 7.4 (d, 1H), 7.55 (s, 1H), 7.8 (s, 1H), 8.95 (s, 1H)

[1060] Triphenylphosphine (262 mg, 1 mmol) and N,N-diethylethanolamine (88 mg, 0.75 mmol) were added to a suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (160 mg, 0.5 mmol), (prepared as described in Example 49), in methylene chloride (5 ml), followed by the addition, in portions, of diethyl azodicarboxylate (165 μl, 1 mmol). After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) followed by methylene chloride/3M ammonia in methanol (90/10) to give 7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (147 mg, 70%).

[1061] MS-ESI 421 [MH]⁺

[1062] ¹H NMR Spectrum: (DMSOd₆) 1.0 (t, 6H), 2.41 (s, 3H), 2.6 (q, 4H), 2.88 (t, 2H), 3.97 (s, 3H), 4.24 (t, 2H), 6.14 (s, 1H), 6.89 (dd, 1H), 7.25 (s, 1H), 7.32 (d, 1H), 7.38 (s, 1H), 7.58 (s, 1H), 8.48 (s, 1H)

[1063]

Elemental analysis:	Found	C 66.2	H 6.9	N 13.1
C24H28N4O3 0.8H2O	Requires	C 66.3	H 6.9	N 12.9%

[1064] Using an analogous procedure to that described in Example 75, 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321 mg, 1 mmol), (prepared as described in Example 49), was reacted with 2-((1-tertbutoxycarbonyl)piperidin-4-yloxy)ethanol (294 mg, 1.2 mmol) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-((]-tertbutoxycarbonyl)piperidin-4-yloxy)ethoxy)quinazoline (420 mg, 76%).

[1065] MS-ESI: 549 [MH]⁺

[1066] ¹H NMR Spectrum: (DMSOd₆) 1.4 (s, 9H), 1.3–1.5 (m, 2H), 1.7–1.9 (m, 2H), 2.38 (s, 3H), 3.0 (br t, 2H), 3.5–3.7 (m, 3H), 3.85 (m, 2H), 3.98 (s, 3H), 4.3 (t, 2H), 6.12 (s, 1H), 6.85 (d, 1H), 7.22 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.55 (s, 1H), 8.48 (s, 1H)

[1067] The starting material was prepared as follows:

[1068] tert-Butoxycarbonyl anhydride (1.52 g, 7 mmol) in acetone (3.5 ml) was added to a solution of 4,4-(ethylenedioxy)piperidine (1 g, 7 mmol) in acetone/trichloromethane (3.5 ml/3.5 ml) cooled at 0° C. After stirring for 4 hours at ambient temperature, the volatiles were removed under vacuum. The residue was dissolved in ether and the ether solution was washed with water, brine, dried (MgSO₄) and evaporated to give 4,4-(ethylenedioxy)-1-tertbutoxycarbonylpiperidine (1.7 g, quant.).

[1069] ¹H NMR Spectrum: (CDCl₃): 1.46 (s, 9H), 1.65 (t, 4H), 3.5 (t, 4H), 3.97 (s, 4H)

[1070] Freshly distilled boron trifluoride etherate (52 μl, 0.41 mmol), followed by sodium cyanoborohydride (38 mg, 0.6 mmol) were added to a solution of 4,4-(ethylenedioxy)-1-tertbutoxycarbonylpiperidine (100 mg, 0.41 mmol) in THF (1.4 ml) cooled at 0° C. After stirring for 6 hours at ambient temperature, boron trifluoride etherate (52 μl) and sodium cyanoborohydride (26 mg, 0.41 mmol) were added. After stirring overnight at ambient temperature, the mixture was partitioned between ethyl acetate and 2M sodium hydroxide. The organic layer was washed with water, brine, dried (MgSO₄) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol/3M ammonia in methanol (80/15/5) to give 2-((1-tertbutoxycarbonyl)piperidin-4-yloxy)ethanol (42 mg, 42%).

[1071] MS-ESI: 268 [MNa]⁺

[1072] ¹H NMR Spectrum: (CDCl₃) 1.48 (s, 9H), 1.5–1.6 (m, 2H), 1.8–1.9 (m, 2H), 2.0 (t, 1H), 3.053.15 (m, 2H), 3.5 (m, 1H), 3.57 (t, 2H), 3.7–3.9 (m, 4H)

[1073] A solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-((1-tertbutoxycarbonyl)piperidin-4-yloxy)ethoxy)quinazoline (379 mg, 0.69 mmol), (prepared as described in Example 76), in methylene chloride (7 ml) containing TFA (2.5 ml) was stirred for 1.5 hours at ambient temperature. After removal of the volatiles under vacuum, the residue was partitioned between ethyl acetate and water. Solid sodium hydrogen carbonate and 2N sodium hydroxide were added to adjust the aqueous layer to about pH10. The organic layer was washed with water, followed by brine, dried (MgSO₄) and evaporated. The residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinazoline (164 mg, 53%).

[1074] ¹HNMR Spectrum: (DMSOd₆) 1.2–1.4 (m, 2H), 1.8–1.9 (m, 2H), 2.47 (s, 3H), 2.4–2.5 (m, 2H), 2.9–3.0 (d, 2H), 3.3–3.5 (m, 1H), 3.95 (s, 2H), 4.0 (s, 3H), 4.35 (s, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.28 (s, 1H), 7.32 (d, 1H), 7.41 (s, 1H), 7.60 (s, 1H), 8.49 (s, 1H)

[1075] MS-ESI: 448 μM.]⁺

[1076] A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (193 mg, 0.6 mmol), (prepared as described in Example 49), 4-(2-hydroxyethoxy)pyridine (166 mg, 1.2 mmol), (J. Chem. Soc. Perkin II, 1987, 1867), in methylene chloride (5 ml) containing triphenylphosphine (330 mg, 1.26 mmol) and diisopropyl azodicarboxylate (255 mg, 1.26 mmol) was stirred at ambient temperature for 2 hours. The precipitate was filtered, triturated with ether followed by ethyl acetate, and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline (142 mg, 54%).

[1077] ¹HNMR Spectrum: (DMSOd₆) 2.40 (s, 3H), 3.97 (s, 3H), 4.52 (t, 2H), 4.58 (t, 2H), 6.14 (s, 1H), 6.89 (dd, 1H), 7.07 (d, 2H), 7.26 (s, 1H), 7.31 (d, 1I), 7.46 (s, 1H), 7.61 (s, 1H), 8.41 (d, 2H), 8.5 (s, 1H)

[1078] MS-ESI: 443 [MH]⁺

[1079]

Elemental analysis	Found	C 66.6	H 5.0	N 12.5
C25H22N4O4 0.12 CH2Cl2	Requires	C 66.9	H 5.0	N 12.4%

[1080] A suspension of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)quinazoline (148 mg, 0.31 mmol), (prepared as described in Example 149), in methylene chloride (4 ml) containing TFA (1 ml) was stirred for 1 hour. After removing the volatiles under vacuum, the residue was azeotroped with toluene. The residue was dissolved in methylene chloride (3 ml) and triethylamine (215 μl, 1.5 mmol) was added followed by methanesulphonyl chloride (48 μl, 0.62 mmol). After stirring for 1 hour at ambient temperature, the mixture was partitioned between methylene chloride and water. The organic layer was separated, washed with water, brine, dried (MgSO₄) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/methanol (99/1 followed by 97/3). After evaporation of the solvent, the solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulphonylamino)ethoxy)quinazoline (54 mg, 38%).

[1081] ¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H), 2.93 (s, 3H), 3.0 (s, 3H), 3.62 (t, 2H), 4.0 (s, 3H), 4.38 (t, 2H), 6.14 (s, 1H), 6.88 (dd, 1H), 7.26 (s, 1H), 7.3 (d, 1H), 7.43 (s, 1H), 7.61 (s, 1H), 8.49 (s, 1H)

[1082] MS-ESI: 457 [MH]⁺

[1083] A solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinazoline (76 mg, 0.17 mmol), (prepared as described in Example 77), in acrylonitrile (0.5 ml), methylene chloride (1 ml) and methanol (1 ml) was stirred overnight at ambient temperature. After removal of the volatiles under vacuum the residue was purified by column chromatography eluting with methylene chloride/methanol (98/2 followed by 95/5 and 90/10). The residue was triturated with ethyl acetate and ether. The resulting solid was filtered and dried under vacuum to give 7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (73 mg, 86%).

[1084] ¹H NMR Spectrum: (DMSOd₆) 1.4–1.55 (m, 2H), 1.8–1.9 (m, 2H), 2.15 (t, 2H), 2.4 (s, 3H), 2.55 (t, 2H), 2.65 (t, 2H), 2.7–2.8 (m, 2H), 3.4–3.5 (m, 1H), 3.85 (m, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H)

[1085] MS-ESI: 502 [MH]⁺

[1086]

Elemental analysis	Found	C 67.0	H 6.2	N 14.0
C28H31N5O4	Requires	C 67.1	H 6.2	N 14.0%

[1087] A solution of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 m g, 0.31 mmol), (prepared as described for the starting material in Example 9), 6-hydroxyindole (50 mg, 0.37 mmol) and potassium carbonate (64 mg, 0.466 mmol) in DMF (1 ml) was heated at 95° C. for 4 hours. After cooling, the mixture was diluted with methylene chloride and poured onto a silica column. The product was eluted with methylene chloride, followed by methylene chloride/methanol (80/20 followed by 70/30 and 50/50). After removal of the solvent by evaporation, the precipitate was triturated with ether, filtered and dried under vacuum to give 6-methoxy-4-(indol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (90 mg, 69%).

[1088] ¹H NMR Spectrum: (DMSOd₆) 1.85 (br s, 4H), 2.15–2.25 (m, 2H), 2.85–3.15 (m, 6H), 4.01 (s, 3H), 4.32 (t, 2H), 6.5 (s, 1H), 6.95 (dd, 1H), 7.32 (s, 1H), 7.4 (s, 2H), 7.6 (d, 1H), 7.65 (s, 1H), 8.52 (s, 1H)

[1089] MS-ESI: 419 [MH]⁺

[1090] Diisopropyl azodicarboxylate (146 mg, 0.72 mmol) was added to a solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.34 mmol), triphenyl phosphine (189 mg, 0.72 mol), and 3-pyrrolidinopropan-1-ol (89 mg, 0.686 mmol), (J. Org. Chem. 1988, 53, 3164), in methylene chloride (2.5 ml). After stirring overnight at ambient temperature, the solid was filtered. The filtrate was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by ethyl acetate/methylene chloride/methanol (4/5/1), methylene chloride/methanol (9/1) and 3N ammonia in methanol/methylene chloride (1/9). After removal of the solvent, the residue was triturated with ether, filtered, and dried under vacuum to give 4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline (49 mg, 35%)

[1091] ¹H NMR Spectrum: (DMSOd₆) 1.8–2.0 (m, 2H), 2.0–2.15 (m, 2H), 2.2–2.32 (m, 2H), 2.41 (s, 3H), 3.0–3.2 (m, 2H), 3.4 (t, 2H), 3.6–3.7 (m, 2H), 4.35 (t, 2H), 6.2 (s, 1H), 6.95 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.5 (s, 1H), 7.57 (dd, 1H), 8.5 (d, 1H), 9.15 (s, 1H)

[1092] MS-ESI: 403 [MH]⁺

[1093] The starting material was prepared as follows:

[1094] Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml, 96 mmol) and the mixture was heated at 148° C. for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J. Chem. Soc. section B 1967, 449), was added and the mixture maintained at 148° C. for 24 hours. The reaction mixture was allowed to cool, the solution was poured on to water (170 ml) and the aqueous mixture adjusted to pH3 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, ether and dried under vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white solid.

[1095] m.p. 267–269° C.

[1096] ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 5.32(s, 2H); 7.25(d, 1H); 7.32–7.52(m, 6H); 8.12(d, 1H); 8.99(s, 1H)

[1097] MS-ESI: 252 [MH]⁺

[1098]

Elemental analysis:	Found	C 71.4	H 4.9	N 10.7
C15H12N2O2 0.04H2O	Requires	C 71.2	H 4.8	N 11.1%

[1099] A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (1 g, 43.6 mmol) and DMF (1 ml) in thionyl chloride (100 ml) was heated at reflux for 1.5 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The residue was partitioned between methylene chloride and water and saturated aqueous sodium hydrogen carbonate was added until the aqueous layer was at about pH9. The organic layer was separated, washed with water, brine, dried (MgSO₄) and evaporated to give 7-benzyloxy-4-chloroquinazoline (10.5 g, 89%).

[1100] ¹H NMR Spectrum: (DMSOd₆) 5.4 (s, 2H); 7.35–7.65 (m, 6H); 8.2 (d, 1H); 9.0 (s, 1H)

[1101] MS-ESI: 270 [MH]⁺

[1102] A solution of 7-benzyloxy-4-chloroquinazoline (2 g, 7.4 mmol), 5-hydroxy-2-methylindole (1.3 g, 8.9 mmol), (prepared as described for the starting material in Example 48), in DMF (20 ml) containing potassium carbonate (1.53 g, 11.1 mmol) was stirred at 80° C. for 3 hours. After cooling, the mixture was poured in portions into ice/water. The precipitate was filtered and washed with water and dried under vacuum. The solid was dissolved in methylene chloride and was purified by column chromatography eluting with ethyl acetate and methylene chloride (1/1) to give 7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (2.28 g, 81%).

[1103] MS-ESI: 382 [MH]⁺

[1104] ¹H NMR Spectrum: (DMSOd₆) 2.41 (s, 3H), 5.4 (s, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.4 (d, 1H), 7.4–7.5 (m, 4H), 7.55 (d, 2H), 8.32 (d, 1H), 8.6 (s, 1H).

[1105] 10% Palladium on charcoal (200 mg) followed by ammonium formate (4.34 g, 69 mmol) were added to a solution of 7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (1.75 g, 4.58 mmol) in DMF (60 ml). After stirring for 1 hour at ambient temperature, the mixture was filtered. The filtrate was evaporated. The residue was triturated with water, filtered, washed with ethyl acetate, and dried under vacuum to give 7-hydroxy-4-(2-methylindol-5yloxy)quinazoline (1.24 g, 93%).

[1106] ¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H), 6.14 (s, 1H), 6.88 (dd, 1H), 7.17 (s, 1H), 7.25–7.3 (m, 2H), 7.30 (d, 1H), 8.24 (d, 1H), 8.5 (s, 1H)

[1107] Using an analogous procedure to that described in Example 82, the appropriate alcohols were reacted with 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline, (prepared as described for the starting material in Example 82), to give the compounds described in Table VI below.

[1108]

TABLE VI
Example	Weight	Yield	MS-ESI
number	(mg)	%	[MH]+	R	Note
83	34	24	412		a
84	45	32	405		b
85	5	3	417		c
86	56	35	467		d
87	63	44	419		e
88	24	17	403		f
89	84	63	387		g
a 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with 3-(methylsulphonyl)-1-propanol (95 mg), (prepared as described for the starting material in Example 50), to give 7-(3-(methylsulphonyl)propoxy)-4-(2-methylindol-5-yloxy)quinazoline.
1H NMR Spectrum: (DMSOd6, CF3COOD) 2.2–2.3(m, 2H), 2.4(s, 3H), 3.05(s, 3H), 3.3–3.45(m, 2H), 4.4(t, 2H), 6.2(s, 1H), 6.95(dd, 1H), 7.38(s, 1H), 7.4(d, 1H), 7.5(s, 1H), 7.6(dd, 1H), 8.5(d, 1H), 9.2(s, 1H)
Elemental analysis	Found	C 60.2 H 5.3 N 10.6
C21H21N3O4S 0.4 DMF	Requires	C 60.5 H 5.4 N 10.8%
b 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with 4-(2-hydroxyethyl)morpholine (90 mg) to give 4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6, CF3COOD) 2.4(s, 3H), 3.1–3.3(m, 2H), 3.62(d, 2H), 3.7–3.9(m, 4H), 4.05(d, 2H), 4.7(t, 2H), 6.2(s, 0.5H, partially exchanged), 6.95(dd, 1H), 7.35(s, 1H), 7.39(d, 1H), 7.6(s, 1H), 7.65(dd, 1H), 8.55(d, 1H), 9.15(s, 1H)
Elemental analysis	Found	C 67.2 H 6.0 N 13.5
C23H24N4O3 0.3 H2O	Requires	C 67.4 H 6.1 N 13.7%
c 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with 1-(3-hydroxypropyl)piperidine (98 mg) to give 4-(2-methylindol-5-yloxy)-7-(3-(piperidin-1-yl)propoxy)quinazoline.
1H NMR Spectrum: (DMSOd6, CF3COOD) 1.2–1.5(m, 2H), 1.6–1.8(m, 2H), 1.8–1.9(m, 2H), 2.25–2.35(m, 2H), 2.45(s, 3H), 2.95(t, 2H), 3.25–3.3(m, 2H), 3.55(d, 2H), 4.4(t, 2H), 6.95(dd, 1H), 7.4(s, 1H), 7.45(d, 1H), 7.5(s, 1H), 7.6(d, 1H), 8.55(d, 1H), 9.15(s, 1H)
d 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (133 mg), (prepared as described for the starting material in Example 5), to give 4-(2-methylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.9–2.0(m, 2H), 2.4(s, 3H), 1.6–1.7(m, 2H), 2.9(br s, 4H), 3.1(br s, 4H), 4.25(t, 2H), 6.12(s, 1H), 6.85(d, 1H), 7.22(s, 1H), 7.3(d, 1H), 7.3–7.4(m, 2H), 8.25(d, 1H), 8.55(s, 1H)
e 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with 4-(3-hydroxypropyl)morpholine (100 mg), (prepared as described for the starting material in Example 60), to give 4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.95–2.05(m, 2H), 2.42(s, 3H), 2.5(t, 2H), 2.55(t, 4H), 3.6(t, 4H), 4.3(t, 2H), 6.18(s, 1H), 6.9(dd, 1H), 7.3(s, 1H), 7.35(d, 1H), 7.3–7.4(m, 2H), 8.3(d, 1H), 8.6(s, 1H)
Elemental analysis	Found	C 66.5 H 6.2 N 12.7
C24H26N4O3 0.14 CH2Cl2 0.7 H2O	Requires	C 66.7 H 6.4 N 13.0%
f 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with 1-(2-hydroxyethyl)piperidine (89 mg) to give 4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 1.4–1.5(br s, 2H), 1.5–1.7(br s, 4H), 2.42(s, 3H), 2.5–2.7(br s, 4H), 2.8–3.0(br s, 2H), 4.35(br s, 2H), 6.18(s, 1H), 6.9(dd, 1H), 7.3(s, 1H), 7.35(d, 1H), 7.4(d, 1H), 7.42(s, 1H), 8.3(d, 1H), 8.6(s, 1H)
Elemental analysis	Found	C 69.0 H 6.6 N 13.4
C24H26N4O2 0.8 H2O	Requires	C 69.1 H 6.7 N 13.4%
g 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with 2-(1H-1,2,4-triazol-1-yl)ethanol (78 mg), (Ann. Phar. Fr. 1977, 35, 503–508), to give 4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline.
1H NMR Spectrum: (DMSOd6) 2.4(s, 3H), 4.6(m, 2H), 4.7(m, 2H), 6.15(s, 1H), 6.9(dd, 1H), 7.28(s, 1H), 7.3(d, 2H), 7.4(s, 1H), 8.02(s, 1H), 8.3(d, 1H), 8.6(s, 1H), 8.65(s, 1H)
Elemental analysis	Found	C 63.7 H 4.8 N 21.5
C21H18N6O2 0.5 H2O	Requires	C 63.8 H 4.8 N 21.3%