Title of Invention	QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS
Abstract	A quinazoline derivative of the formula I: wherein: m is an integer from 1 to 3; R1 represents halogeno or C1-3alkyl; R2 is selected from one of the following three groups: 1) C1-5alkylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C1-4alkyl, C1-4 hydroxyalkyl and C1-4alkoxy; 2) C2-5alkenylR3 (wherein R3 is as defined herein); 3) C2-5alkynylR3 (wherein R3 is as defined herein); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; or a salt of the kind such as herein described.

Title of Invention

QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS

Abstract

A quinazoline derivative of the formula I: wherein: m is an integer from 1 to 3; R1 represents halogeno or C1-3alkyl; R2 is selected from one of the following three groups: 1) C1-5alkylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C1-4alkyl, C1-4 hydroxyalkyl and C1-4alkoxy; 2) C2-5alkenylR3 (wherein R3 is as defined herein); 3) C2-5alkynylR3 (wherein R3 is as defined herein); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; or a salt of the kind such as herein described.

Full Text	FORM 2 THE PATENTS ACT, 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; rule 13] "QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS" ASTRAZENECA AB, a Swedish company of S-151 85 Sodertalje, Sweden, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- 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. 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: 27-3 i). 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 (lakeman 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 VEGEawith antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844). 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 memhcane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor resultsin stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Fit or Fltl, the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fit and KDR, have been shown to bind 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. Quinazoline derivatives which are inhibitors of VEGF receptor tyrosine kinase are described in International Patent Applications Publication Nos. WO 97/30035 and WO 98/1335C In WO 97/30035 and WO 98/13354 compounds are described which possess activity against VEGF receptor tyrosine kinase whilst possessing some activity against EGF receptor tyrosine kinase. Compounds of the present invention fall within the broad general disclosure of WO 97/30035 and WO 98/13354; We have found that compounds of the present invention possess very good inhibitory activity against VEGF receptor tyrosine kinase. Compounds of the present invention, which have been tested, show in vivo activity against a range of tumour xenografts in mice. Compounds of the present invention possess a beneficial toxicological profile when tested over 14 days in rats. Compounds of the present invention possess very good inhibitory activity against VEGF receptor tyrosine kinase show in vivo activity against a range of tumour xenografts in mice and possess a beneficial toxicological profile when tested over 14 days in rats. Compounds of the present invention 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: possess good activity againstrVEGF receptor tyrosine kinase whilst possessing some activity against EGF receptor tyrosine kinase. Furthermore, some compounds of the present invention, possess substantially higher potency against VEGF receptor tyrosine kinase than against EGF receptor tyrosine kinase or FGF Rl receptor tyrosine kinase. While we do not wish to be bound by theoretical considerations such compounds may for example be of interest in treating tumours which are associated with 5 VEGF, especially those tumours which are dependent on VEGF for their growth. It is further believed that these compounds may be of interest in treating tumour states associated with both VEGF and EGF, especially where a patient is suffering from a condition in which tumours are present which are dependent on both VEGF and EGF for their growth. According to one aspect of the present invention there is provided a quinazoline 10 derivative of the formula I: (I) wherein: 15 m is an integer from 1 to 3; R1 represents halogeno or C1-3alkyl; X1 represents -0-; R2 is selected from one of the following three groups: 1) C,.jalkylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected 20 from hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy; 2) C2.5alkenylR3 (wherein R3 is as defined hereinbefore); 3) C2.5alkynylR3 (wherein R3 is as defined hereinbefore); and wherein anyalkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; 25 or a salt thereof or a prodrug thereof. Preferably m is 2. Preferably the phenyl group bearing (R')m is selected from 2-fluoro-4-methylphenyl, 4- chloro-2,6-difluorophenyl, 4-bromo-2,6-difluorophenyl, 4-chloro-2-fluorophenyl group and 4-bromo-2-fluorophenyl. More preferably the phenyl group bearing (R})m is selected from 4-chloro-2-fluorophenyl and 5 4-bromo-2-fluorophenyl. Most preferably the phenyl group bearing (R')m is 4-bromo-2-fluorophenyl. Preferably R2 is C1-5alkylR3 (wherein R3 is as defined hereinbefore). More preferably R2 is C1-3alkylR3(wherein R3 is as defined hereinbefore). Particularly R2 is piperidin-4-ylmethyl in which the piperidine ring may bear one or two 10 substituents as defined hereinbefore. More particularly R2 is piperidin-4-ylmethyl in which the piperidine ring may bear one or two substituents selected from C1-4alkyl. Especially R2 is l-methylpiperidin-4-ylmethyl. According to a further aspect of the present invention there is provided a quinazoline 15 derivative of the formula II: wherein: 20 ma is an integer from 1 to 3; Rla represents halogeno or C,.3alkyl; X1" represents -0-; R2* is selected from one of the following three groups: 1) C1-5alkylR3 (wherein R3 is as defined hereinbefore); 25 2) C2-5alkenylR3 (wherein R3 is as defined hereinbefore); 3) C2-5alkynylR3 (wherein R3 is as defined hereinbefore); or a salt thereof or a prodrug thereof. Preferably ma is 2. Preferably the phenyl group bearing (Rli,)ma is selected from 2-fluoro-4~methylphenyl, 4-chloro-2,6-difluorophenyl, 4-brOmo-2,6-difluorophenyl3 4-chloro-2-fluorophenyl group and 4-bromo-2-fluorophenyl. 5 More preferably the phenyl group bearing (R1")ma is selected from 4-chloro-2-fluorophenyl and 4-bromo-2-fluorophenyl. Most preferably the phenyl group bearing (R,a)ma is 4-bromo-2-fluorophenyl. Preferably R2 4 is C1-5alky R.3 (wherein R3 is as defussd hereinbefore). More preferably K2* is C1.3alkylR3(wherein R3 is as defined hereinbefore). 10 Particularly R2" is piperidin-4-ylmethyl in which the piperidine ring may bear one or two substituents as defined hereinbefore. More particularly R2" is piperidin-4-ylrnethyl in which the piperidine ring may bear one or two substituents selected from C1-4alkyl. Especially R2" is l-methylpiperidin-4-yImethyl. 15 Preferred compounds of the present invention include: 4-(4-chloro-2-fluoroanilino)-6-niethoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, 4-(2-fluoro-4-memylaniIino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline3 4^4-bromo-2-fluoroanilino)-6^niemoxy-7^1-memylpiperidin^ylmethoxy)quinazoline, 4-(4-chloro-2,6-difluoroanilino)'6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazolineJ 20 4-(4-bromo-2,6-difluoroanilino)'6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline3 -4-(2-fluro-4-methylanilmo)-6-methoxy- 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, and 25 4-(4-bromo-2,6-difluoroanilino)'6-methoxy-7-(piperidin-4-ylmethoxy)quinazolmeJ and salts thereof especially hydrochloride salts thereof. More preferred compounds of the present invention include: - 4-4-chloro-2-fluoroanilino)-6-memoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, 4-(4-bromo-2-fiuoroanilino>6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline) 30 4-(4^hloro-2,6-difluoroanilmo)^-memoxy-7^1-me1hylpiperidb^ylmemoxy)qumazoline, 4-(4^hloro-2,6--difluoroanilino)'6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinaz0line3 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline3 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline? and 4-(4-bromo-2J6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, and salts thereof especially hydrochloride salts thereof. 5 Particularly preferred compounds of the present invention include: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7^1-methylpiperidin-4-ylmethoxy)quinazolineJ 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-raethylpiperidin-4-ylmethoxy)quinazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, and 10 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, and salts thereof especially hydrochloride salts thereof. More particularly preferred compounds of the present invention include: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline and 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperiddin-4-ylmethoxy)quina2oline, 15 and salts thereof especially hydrochloride salts thereof. An especially preferred compound of the present invention is 4-(4-bromo-2-fiuoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline and salts thereof especially hydrochloride salts thereof. For the avoidance of doubt it is to be understood that where in this specification a 20 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. .And asimilar convention applies to 'hereinafter defined' or 'defined hereinafter'. In this specification unless stated otherwise the term "alkyl" includes both straight and 25 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 1-5 carbon atoms, preferably 1-3 carbon atoms. The term "alkoxy" as used herein, unless stated otherwise includes "alkyl"-0- groups in which "alkyl" is as hereinbefore defined. The term 30 "aryl" as used herein unless stated otherwise includes reference to a C6-10 aryl group which may, if desired, carr^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"-0-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 alkyiC=0 groups in 5 which "alkyl" is as defined hereinbefore, for example C^alkanoyl is ethanoyl and refers to CH3OO, C,alkanoyl is formyl and refers to CHO. In this specification unless stated otherwise the term "alkenyl" includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl are specific for the straight chain version only. Unless otherwise stated the term "alkenyl" advantageously refers to chains with 2-5 carbon 10 atoms, preferably 3-5 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 3-5 carbon atoms. 15 In formula I, as hereinbefore defined, hydrogen will be present at positions 2, 5 and 8 of the quinazoline group. 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 20 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. 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 25 understood that the invention encompasses all such solvated forms which inhibit VEGF receptor tyrosine kinase activity. For the avoidance of any doubt, it is to be understood that in a compound of the formula I when R2 is, for example, a group of formula C^alkenylR3 it is the C25alkenyl moiety which is bound to X1 and an analogous convention applies to other groups. When R2 30 is a group 1 -R3prop-l -en-3-yl it is the first carbon to which the group R3 is attached and it is -the third carbon which is linked to X1, similarly when R2 is_a_group„2-R3pent-3-en-5-yl it is the second carbon to which the group R3 is attached and it is the fifth carbon which is linked to X1, and an analogous convention applies to other groups. Compounds of Formula I may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the Formula I. Examples of 5 prodrugs include in vivo hydrolysable esters of a compound of the Formula I. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, V6l~32, p. 309-396;edited by K. Widder, et al. (Academic Press, 1985); 10 b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191(1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and 15 e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984). An in vivo hydrolysable ester of a compound of Formula I containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of a-acyloxyalkyl 20 ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyLand phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl: Examples of substituents on benzoyl include 25 morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3-or 4- position of the benzoyl ring. 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 30 compounds of formula I and theirpharmaceutically 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 5 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, 10 piperidine, morpholine or tris-(2-hydroxyethyl)amine. A compound of the formula I, or salt thereof, and other compounds of the invention (as hereinafter defined) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes include, for example, those illustrated in European Patent Applications, Publication Nos. 0520722, 0566226, 0602851 and 0635498 and 15 in International Patent Applications Publication Nos. WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354. 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 20 obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. Thus the following processes (a) to (d) and (i) to (iv) constitute further features of the present invention. Synthesis of Compounds of Formula I 25 (a) Compounds of the formula I and salts thereof may be prepared by the reaction of a compound of the formula HI: (wherein R2 and X1 are as defined hereinbefore and L1 is a displaceable moiety), with a compound of the formula IV: 10 (wherein R1 and m are as defined hereinbefore) whereby to obtain compounds of the formula and salts thereof. A convenient displaceable moiety L1 is, for example, a halogeno, alkoxy (preferably C,.4alkoxy), aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group. The reaction is advantageously effected in the presence of either an acid or a base. 15 Such an acid is, for example, an anhydrous inorganic acid such as hydrogen chloride. 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, or for example, an alkali metal or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium 20 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 or sodium bis(trimethylsilyl)amide. The reaction is preferably effected in the presence of an inert solvent or diluent, for example an alkanol or ester such as methanol, ethanol, 2-propanol or ethyl acetate, a halogenated solvent 25 such as methylene chloride, trichloromethane or carbon tetrachloride, 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-2rone or dimethylsulphoxide. The reaction is conveniently effected at a temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 80°C. 30 The compound of the invention may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L1 wherein L1 has the meaning defined hereinbefore. When it is desired to obtain the free base from the salt, the salt may be treated with a base as defined hereinbefore using a conventional procedure. (b) Compounds of the formula I and salts thereof may be prepared by the reaction, conveniently in the presence of a base as defined hereinbefore, of a compound of the formula 5 V: 10 (V) (wherein m, X1 and R' are as hereinbefore defined) with a compound of formula VI: 15 R2-L' (VI) (wherein R2 and L1 are as hereinbefore defined); L1 is a displaceable moiety for example a halogeno or sulphonyloxy group such as a bromo or methanesulphonyloxy group. Conveniently L1 is a group 0-+P(Y)3 (wherein Y is butyl or phenyl) and in such cases the 20 compound of formula VI is conveniently formed in situ. 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 may be prepared by the reaction of a 25 compound of the formula VII: 30 with a compound of the formula VIII: R2-X'-H (VIII) 5 (wherein L1, R1, R2, m and X1 are all 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 range7for example" 10 to 150°C, 10 conveniently at about 100°C. (d) Compounds of the formula I and salts thereof may be prepared by the deprotection of a compound of the formula IX: 15 20 wherein R1, m and X1 are all as hereinbefore defined, and R4 represents a protected R2 group wherein R2 is as defined hereinbefore but additionally bears one or more protecting groups P2. The choice of protecting group P2 is within the standard knowledge of an organic chemist, for example those included in standard texts such as "Protective Groups in Organic Synthesis" 25 T.W. Greene and RG.M.Wuts, 2nd Ed. Wiley 1991. Preferably P2 is a protecting group such as a carbamate (alkoxycarbonyl) (such as, for example, tert-butoxycarbonyl, tert-amyloxycarbonyl, cyclobutoxycarbonyl, propoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl). More preferably P2 is tert-butoxycarbonyl. The reaction is preferably effected in the presence of an 30 acid. Such an acid is, for example, an inorganic acid such as hydrogen chloride, hydrogen bromide or an organic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid. The reaction may be effected in the presence of an inert solvent such as methylene chloride, trichloromethane and in the presence of a trace of water. The reaction is conveniently effected at a temperature in the range, for example, 10-100°C, preferably in the range 20-80°C. Synthesis of Intermediates 5 (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 X: 10 (X) 15 (wherein R2 and X1 are as hereinbefore defined). Convenient halogenating agents include inorganic acid halides, for example thionyl chloride, phosphorus(m)chloride, phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenation reaction is conveniently effected in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or 20 carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene. The reaction is conveniently effected at a temperature in the range, for example 10 to 150°C, preferably in the range 40 to 100°C. The compounds of formula X and salts thereof may for example be prepared by reacting a compound of the formula XI: 25 30 (wherein L1 is 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 5 example 10 to 150°C, conveniently at about 100°C. The compounds of formula X and salts thereof may also be prepared by cyclising a compound of the formula XII: 10 15 (wherein R2 and X1, are as hereinbefore defined, and A1 is an hydroxy, alkoxy (preferably C,_ 4alkoxy) or amino group) whereby to form a compound of formula X or salt thereof. The cyclisation may be effected by reacting a compound of the formula XII, where A1 is an hydroxy or alkoxy group, with formamide or an equivalent thereof effective to cause cyclisation whereby a compound of formula X or salt thereof is obtained, such as [3- 20 (dimethylamino)-2-azaprop-2-enylidene]dimethylanimonium 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 l,4?dioxan. The cyclisation is conveniently effected at an elevated temperature, preferably in the range 80 to 200°C. The compounds of formula X may also be prepared by cyclising a compound of the formula XH, where A1 is an 25 amino group, with formic acid or an equivalent thereof effective to cause cyclisation whereby a compound of formula X or salt thereof is obtained. Equivalents of formic acid effective to cause cyclisation include for example a tri-C1-4alkoxymethane, for example triethoxymethane and trimethoxyrnethane. 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, 30 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. Compounds of formula XII and salts thereof may for example be prepared by the reduction of the nitro group in a compound of the formula XHI: 10 (wherein R2, X1 and A1 are as hereinbefore defined) to yield a compound of formula XII 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 15 example, by the hydrogenation of a solution of the nitro compound in the presence of an inert solvent or diluent as defined hereinbefore in the presence of a metal effective to catalyse hydrogenation reactions such as palladium or platinum. A further reducing agent is, for example, an activated metal such as activated iron (produced for example by washing iron powder with a dilute solution of an acid such as hydrochloric acid). Thus, for example, the 20 reduction may be effected by heating the nitro compound and the activated metal in the presence of a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature in the range, for example 5Q.to ISOJX^conyeniently at about 70°C. Compounds of the formula XTII and salts thereof may for example be prepared by the reaction of a compound of the formula XTV: (wherein L1 and A1 are as hereinbefore defined) with a compound of the formula VIII as hereinbefore defined to give a compound of the formual XIII. The reaction of the compounds of formulae XTV and VTA is conveniently effected under conditions as described for process 5 (c) hereinbefore. Compounds of formula XIII and salts thereof, may for example also be prepared by the reaction of a compound of the formula XV: 10 15 (wherein X1 and A1 are as hereinbefore defined) with a compound of the formula VI as hereinbefore defined to yield a compound of formula XIII as hereinbefore defined. The reaction of the compounds of formulae XV and VI is conveniently effected under conditions as described for process (b) hereinbefore. The compounds of formula HI and salts thereof may also be prepared for example by 20 reacting a compound of the formula XVI: 25 (wherein X' is as hereinbefore defined and L2 represents a displaceable protecting moiety) with a compound of the formula: VI as hereinbefore defined, whereby to obtain a compound of 30 formula III in which L1 isTepresented by L2. A compound nf formula YVT 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. The compounds of formula XVI and salts thereof as hereinbefore defined may for' example be prepared by deprotecting a compound of the formula XVII: (XVH) 10 (wherein X1 and L2 are as hereinbefore defined and P1 represents a phenolic hydroxy protecting group). The choice of phenolic hydroxy 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 ethers 15 (for example, methyl, methoxymethyl, allyl and benzyl and benzyl substituted with up to two substituents selected from C1-4alkoxy and nitro), silyl ethers (for example, t-butyldiphenylsilyl and t-butyldimethylsilyl), esters (for example, acetate and benzoate) and carbonates (for example, methyl and benzyl and benzyl substituted with up to two substituents selected from C1-4alkoxy and nitro). Deprotection may be effected by techniques well known in the 20 literature, for example where P1 represents a benzyl group deprotection may be effected by hydrogenolysis or by treatment with trifluoroacetic acid. The removal of such a phenolic hydroxy 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. The reaction 25 conditions preferably being such that the hydroxy derivative is produced without unwanted reactions at other sites within the starting or product compounds. For example, where the protecting group P1 is acetate, the transformation may conveniently be effected by treatment of the quinazoline derivative with a base as defined hereinbefore and including ammonia, and its mono and di-alkylated derivatives, preferably in the presence of a protic solvent or co-solvent 30 such as water or an alcohol, for example methanol or ethanol. Such a reaction can be effected in the presence of an addttional, intex solcent or dilluent as defined hereinbefore and at a temperature in the range 0 to 50°C, conveniently at about 20°C. One compound of formula in may if desired be converted into another compound of fonnula HI in which the moiety L1 is different. Thus for example a compound of formula HI in which L1 is other than halogeno, for example optionally substituted phenoxy, may be converted to a compound of formula HI in which L1 is halogeno by hydrolysis of a compound 5 of formula III (in which L1 is other than halogeno) to yield a compound of formula X as hereinbefore defined, followed by introduction of halide to the compound of fonnula X, thus obtained as hereinbefore defined, to yield a compound of formula III in which L' represents halogeno. (ii) Compounds of the formula V as hereinbefore defined and salts thereof rffay be made by " 10 deprotecting the compound of formula XVIII: 15 (xvm) (wherein R1, P1, X1 and m are as hereinbefore defined) by a process for example as described in 20 (i) above. Compounds of the formula XVHI and salts thereof may be made by reacting compounds of the formulae XVD; and IV as hereinbefore defined, under the conditions "described in (a) hereinbefore, to give a compound of the formula XVm or salt thereof. >±: (iii) Compounds of the formula VQ and salts thereof as hereinbefore defined may be 25 ?i made by reacting a compound of the formula XIX: 30 (wherein L1 is as hereinbefore defined, and L1 in the 4- and 7- positions may be the same or different) with a compound of formual IV as hereinbefore defined, the reaction for example being effected by a process as described in (a) above. (iv) A compound of the formula IX may be prepared by the reaction of a compound of 5 the formula V as defined hereinbefore with a compound of the formula XX: R4-L' (XX) wherein R4 and L1 are as defined hereinbefore under the conditions described in (b0) 10 hereinbefore to give a compound of the formula IX or salt thereof. 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 in the range 20-50°C. 15 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, or it may be obtained by reaction of said compound with a base by a conventional procedure. The identification of compounds which potently inhibit the tyrosine kinase activity 20 associated with the VEGF receptorsfsuch as Fit and/or KDR and which inhibit angiogenesis and/or increased vascular permeability is desirable and is the subject of the present invention. These properties may be assessed for example, using one or more of the procedures set out below: 25 (a) In Vitro Receptor Tyrosine Kinase Inhibition Test This assay determines the. ability of a test compound to inhibit tyrosine kinase activity. DNA encoding VEGF or epidermal growth factor (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 30 polypeptide with tyrosine kinase-activity. For example VEGF 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 Fit (Genbank accession number X51602), a 1.7kb 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 exainple pAcYMl (see The Baculovirus Expression System: A 5 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 frugiperda21(Sf21)) with viral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus. (Details of the methods for the - assembly of-recombinant DNA moiecuiesand the'preparation and use of recombinant 10 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) and methionine 668 15 (EGF receptor, Genbank accession number X00588) may be cloned and expressed in a similar manner. For expression of cFlt tyrosine kinase activity, Sf21 cells were infected with plaque-pure cFlt recombinant virus at a multiplicity of infection of 3 and harvested 48 hours later. Harvested cells were washed with ice cold phosphate buffered saline solution (PBS) (10mM 20 sodium phosphate pH7.4, 138mM sodium chloride, 2.7mM potassium chloride) then resuspended in ice cold HNTG/PMSF (20mM Hepes pH7.5, 150mM sodium chloride, 10% v/v glycerol, 1% v/v Triton X100, L5mM magnesium chloride, ImM ethylene glycol-bis(Paminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), ImM PMSF (phenylmethylsulphonyl fluoride); the PMSF is added just before use from a freshly-prepared 25 lOOmM solution in methanol) using 1ml 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 (100mM Hepes pH 7.4, 0.2mM sodium orthovanadate, 0.1% v/v Triton X100, 0.2mM dithiothreitol). For a typical batch, stock enzyme is diluted 1 in 30 2000 with enzyme diluent and 50µl of dilute enzyme is used for each assay well. A stock of substrate solution was prepared from a random copolymer containing tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (Sigma P3899), stored as 1 mg/ml stock in PBS at -20°C and diluted 1 in 500 with PBS for plate coating. On the day before the assay 100µl of diluted substrate solution was dispensed into all 5 wells of assay plates (Nunc maxisorp 96-well immunoplates) which were sealed and left overnight at 4°C. On the day of the assay the substrate solution was discarded and the assay plate wells were washed once with PBST (PBS containing 0.05% v/v Tween 20) and once with 50mM HepespH7.4. 10 Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25µl of diluted compound was transferred to wells in the washed assay plates. "Total" control wells contained 10% DMSO instead of compound. Twenty five microlitres of 40mM manganese(IJ.)chloride containing 8uM adenosine-5'-triphosphate (ATP) was added to all test wells except "blank" control wells which contained manganese(II)chloride without ATP. To 15 start the reactions 50ui 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 1 in 6000 with PBST containing 0.5% w/v bovine serum albumin (BSA), was added to each well and the plates were incubated 20 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)-Iinked 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'-25 azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution, freshly prepared using one 50mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50mM phosphate-citrate buffer pH5.0 + 0.03% sodium perborate (made with 1 phosphate citrate buffer with sodium perborate (PCSB) capsule (Sigma P4922) per 100ml distilled water), was added to each well. Plates were then incubated for 20-60 minutes at room temperature until the optical density .30 value of the "total" control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1.0. "Blank" (no ATP) and "total" (no compound) control values were used to determine the dilution range of test compound which gave 50% inhibtion of enzyme activity. (b) In Vitro HUVEC Proliferation Assay This assay determines the ability of a test compound to inhibit the growth factor-stimulated proliferation of human umbilical vein endothelial cells (HUVEC). HUVEC cells were isolated in MCDB 131 (Gibco BRL) + 7.5% v/v foetal calf serum (FCS) and were plated out (at passage 2 to 8), in MCDB 131+ 2% v/v FCS + 3µg/ml heparin + lµg/ml hydrocortisone, at a concentration of 1000 cells/well in 96 well plates. After a minimum of 4 hours they were dosed with the appropriate growth factor (i.e. VEGF 3ng/ml, EGF 3ng/ml or b-FGF 0.3ng/ml) and compound. The cultures were then incubated for 4 days at 37°C withr7.5% carbon dioxide on day the ltures were pulsed with lµ.Ci/well of tritiated-thymidine (Amersham product TRA 61) and incubated for 4 hours. The cells were harvested using a 96-well plate harvester (Tomtek) and then assayed for 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 This test measures the capacity of compounds to inhibit solid tumour growth. CaLu-6 tumour xenografts were established in the flank of female athymic Swiss nu/nu mice, by subcutaneous injection of 1x10s CaLu-6 cells/mouse in 100p.l 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: (1 x w) x V(l x w) x (TI/6) , where 1 is the longest diameter and w the diameter perpendicular to the longest diameter. 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, and statistical significance determined using a Students' t-test and/or a Mann-Whitney Rank Sum Test. The inhibitory effect of compound treatment was considered significant when p The toxicological profile of compounds of the present invention may be assessed, for example using a rat 14 day study as described hereinafter. (dl 14 Pay Toxicity Test in Rat This test measures the activity of compounds in increasing the zone of hypertrophy in the femoral epiphyseal growth plates of the distal femur and proximal tibia, and allows assessment of histopathological changes in other tissues. 5 Angiogenesis is an essential event in endochondral ossification during long bone elongation, and vascular invasion of the growth plate has been suggested to depend upon VEGF production by hypertrophic chondrocytes. Expansion of the hypertrophic chondrocyte zone and inhibition of angiogenesis has been demonstrated following treatment with agents which specifically sequester VEGF, such as, for example, (i) a soluble VEGF receptor 10 chimeric protein (Flt-(l-3)-IgG) in mice (Gerber, H-P., Vu, T.H., Ryan, A.M., Kowalski, J., Werb, Z. and Ferrara, N. VEGF couples hypertrophic cartilage remodelling, ossification and angiogenesis during endochondral bone formation, Nature Med., 5: 623-628, 1999) and (ii) a recombinant humanised anti-VEGF monoclonal IgGl antibody in cynomologus monkey (Ryan, A.M., Eppler, D.B., Hagler, K.E., Bruner, R.H., Thomford, P.J., Hall, R.L., Shopp, 15 G.M. and CNiell, C.A. Preclinical Safety Evaluation of rhuMAbVEGF, an antiangiogenic humanised monoclonal antibody, Tox. Path., 27: 78-86, 1999). An inhibitor of VEGF receptor tyrosine kinase activity should therefore also inhibit vascular invasion of cartilage, and increase the zone of hypertrophy in the femoral epiphyseal growth plates of the distal femur and proximal tibia in growing animals. 20 Compounds were initially formulated by suspension in a 1% (v/v) solution of polyoxyethylene (20) sorbitan mono-oleate in deionised water, by ball-milling at 4°C overnight (at least 15 hours). Compounds were re-suspended by agitation immediately prior fo dosing. Young Alderley Park rats (Wistar derived, 135-150g in weight, 4 to 8 weeks of age, 5-6 per group) were dosed once-daily by oral gavage for 14 consecutive days with 25 compound (at 0.25 ml/lOOg body weight) or vehicle. On day 15 animals were humanely terminated using a rising concentration of carbon dioxide, and a post-mortem performed. A range of tissues, which included femoro-tibial joints, were collected and processed by standard histological techniques to produce paraffin wax sections. Histological sections were . stained with haematoxylin and eosin and examined by light microscopy for histopathology. 30 The femoral epiphyseal growth plate areas of the distal femur and proximal tibia were measured in sections of femur and tibia using morphometric image analysis. The increase in the zone of hypertrophy was determined by comparison of the mean epiphyseal growth plate area of the control group versus the treatment group, and statistical significance determined using a one-tailed Students' t-test. The inhibitory effect of compound treatment was considered significant when p Although the pharmacological properties of the compounds of Formula I vary with 5 structural change, in general, activity possessed by compounds of the Formula I, may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d): Test (a):- IC50 in the range, for example, Test (b)> — IG50- in the range, for example, 0.001 - 5µM; 10 Test (c): - activity in the range, for example, 0.1-100mg/kg; Test (d):- activity in the range, for example, 0. l-100mg/kg. According to one aspect of the present invention compounds of Formula I, assessed in the 14 day toxicity test in rat, have a beneficial toxicological profile over other compounds within the scope of International Patent Application Publication No. WO 98/13354. 15 According to another aspect of the present invention compounds of Formula I, assessed in the 14 day toxicity test in rat, have a beneficial toxicological profile over other compounds within the scope of International Patent Application Publication No. WO 97/30035. Although the pharmacological properties of the compounds* of Formula I vary with 20 structural change and between species, at doses in the rat, preferably at doses less than or equal to 150mg/kg, more preferably at doses less than or equal to lOOmg/kg, especially at doses less than or equal to 50mg/kg, compounds of Formula I which produce a statistically significant increase in the femoral epiphyseal growth plate area of the distal femur and/or proximal tibia, produce no unacceptable histopathological changes in other tissues in tests (d) 25 that we have conducted. Thus by way of example, the compound 4-{4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, (Example 2), tested according to (a), (b), (c) and (d) above gave the following results: (a) Flt-IC50 of l.6µM 30 KDR-IC50 of 0.04µM EGFR-IQ50 of 0.5µM (b) VEGF - IC30 of 0.06µM EGF-IC50 of 0.017µM Basal-IC50 of >3µM (c) 78% inhibition of tumour growth at 50mg/kg; p 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 10 excipient or carrier. The composition may be in a form suitable for oral administration, (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a 15 finely divided powder), for parenteral injection (for example as a sterile solution, suspension or emulsion for intravenous, subcutaneous, intramuscular, intravascular or infusion dosing), for topical administration (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), or for rectal administration (for example as a suppository). In general the above compositions may be prepared in a conventional manner using conventional excipients. 20 The compositions of the present invention are advantageously presented in unit dosage form. The compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000mg per square metre body area of the animal, i.e. approximately 0.1-100mg/kg. A unit dose in the range, for example, 1-100mg/kg, preferably l-50mg/kg is envisaged and this normally provides a therapeutically-effective dose. A unit dose form such 25 as a tablet or capsule will usually contain, for example l-250mg of active ingredient. According to a further aspect of the present invention there is provided a compound of the formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy. We have found that compounds of the present invention inhibit VEGF receptor tyrosine 30 kinase activity and are therefore of interest for their antiangiogenic effects and/or their ability to cause a reduction in vascular permeability. A further feature of the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament, conveniently a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded 5 animal such as a human being. Thus according to a further aspect of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being. 10 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. 15 As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of l-50mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the 20 illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient. The antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may 25 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 treatmenfrto treat each patient with cancer. In medical oncology the other components) of such conjoint treatment in addition to the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be: 30 surgery, radiotherapy or chemotherapy. Such chemotherapy may cover five main categories of therapeutic agent: (i) other antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example linomide, inhibitors of integrin αvβ3 function, angiostatin, endostatin, razoxin, thalidomide) and including vascular targeting agents (for example combretastatin phosphate and the vascular damaging agents described in International Patent 5 Application Publication No. WO 99/02166 the entire disclosure of which document is incorporated herein by reference, (for example N-acerylcolchinol-O-phosphate)); (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), 10 antiprogestogens, antiandrogenS (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide, abarelix), inhibitors of testosterone 5a-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 15 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); (iii) biological response modifiers (for example interferon); i (iv) antibodies (for example edrecolomab); and 20 (v) 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, dflctmomycin, mithramycin); platinum derivatives (for example 25 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); enzymes (for example asparaginase); thytnidylate synthase inhibitors (for example raltitrexed); topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, 30 amsacrine, topotecan, irinotecan). 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 such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4- ylmethoxy)quinazoline or a salt thereof especially a hydrochloride salt thereof, and a vascular targeting agent described in WO 99/02166 such as N-acetylcolchinol-O-phosphate (Exampe 1 of WO 99/02166). 5 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,-arteriar restenosis, autoimmune diseases, acute inflammation, 10 excessive scar fonnation 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 15 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. In another aspect of the present invention compounds of Formula I are expected to inhibit the growm of those primary and recurrent solid tumours which are associated with 20 EGF especially those tumours which are significantly dependent on EGF for their growth and spread. . In another aspect of the present invention compounds of Formula I are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with both VEGF and EGF especially those tumours which are significantly dependent on VEGF 25 and EGF for their growth and spread. 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, 30 rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. It is to be understood that where the term "ether" is used anywhere in this specification it refers to diethyl ether. The invention will now be illustrated, but not limited, by the following Examples in which, unless otherwise stated:- (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration; 5 (ii) operations were carried out at ambient temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon; (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck,T)armstadt, 10 Germany; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus, an oil-bath apparatus or a Koffler hot plate apparatus. 15 (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; NMR spectra were run on a 400MHz machine at 24°C. 20 (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; (viii) the following abbreviations have been used:- 25 DMF N,N-dimethylformamide DMSO dimethylsulphoxide THF tetrahydrofuran TFA trifluoroacetic acid NMP l-methyl-2-pyrrolidinone.] Example 1 TFA (3ml) was added to a suspension of 4-(4-bromo-2-fluoroanilino)-7-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (673 mg, 1.2mmol) in methylene chloride (10ml). After stirring for 1 hour at ambient temperature, the volatiles 5 were removed under vacuum. The residue was triturated with a mixture of water/ether. The organic layer was separated. The aqueous layer was washed again with ether. The aqueous layer was adjusted to pHIO with 2N aqueous sodium hydroxide. The aqueous layer was extracted with methylene chloride. The organic layer was dried (MgS04) and the solvent was removed under vacuum. The solid was triturated with a mixture ether/petroleum ether (1/1), 10 filtered, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroaniIino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoIine (390mg, 70.5%). MS-ESI: 461-463 [MH]+ 'HNMR Spectrum: (DMSOcQ 1.13-1.3 (m, 2H), 1.75 (d, 2H), 1.87-2.0 (m, 1H), 2.5 (d, 2H), 3.0 (d, 2H), 3.96 (s, 3H), 3.98 (d, 2H), 7.2 (s, 1H), 7.5 (dd, 1H), 7.55 (t, 1H), 7.68 (dd, 1H), 15 7.80 (s, 1H), 8.36 (s, 1H), 9.55 (br s, 1H) Elemental analysis: Found C 54.5 H 4.9 N 12.1 C21H22N4O2BiF Requires C 54.7 H 4.8 N 12.1% The starting material was prepared as follows: 20 A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (8.35g, 27.8mmol), (prepared, for example, as described in WO 97/22596, Example 1), and 4-bromo- 2-fluoroaniline (5.65g, 29.7mmol)in2-propanol(200mtywas heated at reflux for 4 hours. The resulting precipitate was collected by filtration, washed with 2-propanol and then ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2-fluoroaniIino)-6-25 methoxyquinazoline hydrochloride (9.46g, 78%). 'HNMR Spectrum:(DMSOd6; CD3COOD) 4.0(s, 3H); 5.37(s, 2H); 7.35-7.5(m, 4H); 7.52- 7.62(m, 4H); 7.8(d, 1H); 8.14(9s, 1H); 8.79(s, 1H) MS - ESI: 456 [MH]+ Elemental analysis: Found . C 54.0 H 3.7 N 8.7 30 C22H17N3O2BrF 0.9HCI Requires C 54.2 H 3.7 N 8.6% A solution of 7-benzyloxy-4-(4-bromo-2- fluroanilino)-6-methoxyqum hydrochloride (9.4g, 19. lmmol) in TFA (90ml) was heated at reflux for 50 minutes. The mixture was allowed to cool and was poured on to ice. The resulting precipitate was collected by filtration and dissolved in methanol (70ml). The solution was adjusted to pH9-10 with concentrated aqueous ammonia solution. The mixture was concentrated to half initial volume by evaporation. The resulting precipitate was collected by filtration, washed with 5 water and then ether, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (5.66g, 82%). 'HNMR Spectrum: (DMSOd; CD3COOD) 3.95(s, 3H); 7.09(s, 1H); 7.48(s, 1H); 7.54(t, 1H); 7.64(d, 1H); 7.79(s, 1H); 8.3l(s, 1H) •MS-ESI:366[MH]+ 10 Elemental analysis: Found C 49.5 H 3.1 N 11.3 C15HnN302BrF Requires C 49.5 H 3.0 N 11.5% While maintaining the temperature in the range 0-5°C, a solution of di-tert-butyl dicarbonate (41.7g, 0.19moI) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0A9mol) in ethyl acetate (150ml) cooled at 5°C. After 15 stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ml). The organic layer was separated, washed successively with water (200ml), 0.1N aqueous hydrochloric acid (200ml), saturated sodium hydrogen carbonate (200ml) and brine (200ml), dried (MgS04) and evaporated to give ethyl 4-(l-(tert-butoxycarbonyl)piperidine)carboxylate (48g, 98%). 'HNMR Spectrum: (CDC13) 1.25(t, 3H); 1.45(s, 9H); 1.55-1.70(m, 2H); 1.8-2.0(d, 2H); 2.35-2.5(m, 1H); 2.7-2.95(t, 2H); 3.9-4.l(br s, 2H); 4.15 (q, 2H) A solution of 1M lithium aluminium hydride in THF (133ml, 0.133mol) was added in portions to a solution of ethyl 4-(l-(tert-butoxycarbonyl)piperidine)carboxylate (48g, 0.19mol) in dry THF (180ml) cooled at 0°C. After stirring at 0°C for 2 hours, water (30ml) 25 was added followed by 2N sodium hydroxide (10ml). The precipitate was removed by filtration through diatomaceous earth and washed with ethyl acetate. The filtrate was washed with water, brine, dried (MgS04) and evaporated to give l-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (36.3g, 89%). MS (EI): 215 [M.]+ 30 'HNMR Spectrum: (CDC13) 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^.2(br s, 2H) l,4-Diazabicyclo[2.2.2]octane (42.4g, 0.378mol) was added to a solution of \-(tert~ butoxycarbonyl)-4-hydroxymethylpiperidine (52.5g, 0.244mol) in tert-butyl methyl ether (525ml). After stirring for 15 minutes at ambient temperature, the mixture was cooled to 5°C and a solution of toluene sulphonyl chloride (62.8g, 0.33mmol) in tert-butyl methyl ether 5 (525ml) was added in portions over 2 hours while maintaining the temperature at 0°C. After stirring for 1 hour at ambient temperature, petroleum ether (II) 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 0.5N aqueous hydrochloric acid (2x500ml), water, saturated-sodium hydrogen carbonate and brine, dried-(MgS04) and evaporated to give 10 l-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (76.7g, 85%). MS (ESI): 392 [MNa]+ 'HNMR Spectrum: (CDC13) 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, IH); 4.0-4.2(br s, 2H); 7.35(d, 2H); 7.8(d, 2H) Potassium carbonate (414mg, 3mmol) was added to a suspension of 4-(4-bromo-2- 15 fluoroanilino)-7-hydroxy-6-methoxyquinazoline(546mg, 1.5mmol) inDMF (5ml). After stirring for 10 minutes at ambient temperature, l-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (636mg,T.72mmol) was added and the mixture was heated at 95°C for 2 hours. After cooling, the mixture was poured onto cooled water (20ml). The precipitate was collected by filtration, washed with water, and dried under 20 vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (665mg, 79%). MS-ESI: 561-563 [MH]+ 'HNMR Spectrum: (DMSOdJ 1.15-1.3 (m, 2H)7146 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, IH), 2.65-2.9 (m, 2H), 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, IH), 7.48 (d, IH), 7.55 (t, 25 IH), 7.65 (d, IH), 7.8 (s, IH), 8.35 (s, IH), 9.55 (br s, IH) Example 2a A solution of 37% aqueous formaldehyde (50ul, 0.6mmol) followed by sodium cyanoborohydride (23mg, 0.36mmol) were added to a solution of 4-(4-bromo-2-30 fluoroaniImo)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (139mg, 0.3mmol), (prepared as described in Example 1), in a mixture of THF/methanol (1.4ml/1.4ml). After stirring for 1 hour at ambien"! temperature, water was added and the volatiles were removed under vacuum The residue was triturated with water, filtered, washed with water, and dried under vacuum. The solid was purified by chromatography on neutral alumina eluting with methylene chloride followed by methylene chloride/ethyl acetate (1/1) followed by methylene chloride/ethyl acetate/methanol (50/45/5). The fractions containing the expected product 5 were evaporated under vacuum. The resulting white solid was dissolved in methylene chloride/methanol (3ml/3ml) and 3N hydrogen chloride in ether (0.5ml) was added. The volatiles were removed under vacuum. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoiy-7-(l-methyIpiperidin-4-ylmethtncy)quiTrazoline hy$fochl6ride^l2©mlgf69%). 10 MS - ESI: 475-477 [MH]+ The NMR spectrum of the protonated form of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride shows the presence of 2 forms A and B in a ratio A:B of approximately 9:1. 'H NMR Spectrum: (DMSOd6; CF^COOD) 1.55-1.7 (m, form A 2H) ; 1.85-2.0 (m, form B 15 4H) ; 2.03 (d, form A 2H) ; 2.08-2.14 (br s, form A IH) ; 2.31-2.38 (br s, form B IH) ; 2.79 (s, form A 3H) ; 2.82 (s, form B 3H) ; 3.03 (t, form A 2H) ; 3.21 (br s, form B 2H) ; 3.30 (br s, form B 2H) ; 3.52 (d, form A 2H) ; 4.02 (s, 3H) ; 4.12 (d, form A 2H) ; 4.30 (d, form B 2H) ; 7.41 (s, IH) ; 7.5-7.65 (m, 2H) ; 7.81 (d, IH) ; 8.20 (s, IH) ; 8.88 (s, IH) Elemental analysis: Found C 46.0 H 5.2 N 9.6 20 C22H24N4O2BrF 0.3H2O 2.65HC1 Requires C 45.8 H 4.8 N' 9.7% Example 2b 37% Aqueous formaldehyde (3.5ml, 42mmol) was added to a solution of 4-(4-bromo-2-fluoroanilino)-7-(l-(tert-butoxycaihonyl)piperidm-4-ylmemoxy)-6-inethoxyquinazoline 25 (3.49g, 6.22mmol), (prepared as described for the starting material in Example 1), in formic acid (35ml). After heating at 95°C for 4 hours the volatiles were removed under vacuum. The residue was suspended in water and the mixture was adjusted to pH10.5 by slow addition of a solution of 2N sodium hydroxide. The suspension was extracted with etiiyl acetate. The organic layer was washed with brine, dried MgS04 and evaporated to give 4-(4-bromo-2- 30 fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmetIioxy)quiaazoline (2.61g, 88%). MS - ESI: 475-477 [MH]+ 'H NMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, 1H), 1.95 (t, 2H), 2.2 (s, 3H), 2.85 (d, 2H), 3.96 (s, 3H), 4.05 (d, 2H), 7.19 (s, 1H), 7.5 (d, 1H), 7.55 (t, 1H), 7.67 (d, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 9.54 (s, 1H) Elemental analysis: Found C 55.4 H 5.1 N 11.6 5 C22H24N402BrF Requires C 55.6 H 5.1 N 11.8% Example 2c A suspension of 4-chloro-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline 0.62mmol)-and 4-bromo-2-fluoroaniline (142mg, 0.74mmol) in isopropanol^ ml) ~ 10 containing 6N hydrogen chloride in isopropanol (110ul, 0.68ml) was heated at reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol followed by ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy- 7-(l-methyipiperidin-4-ylmetboxy)quinazoline hydrochloride (304mg, 90%). Elemental analysis: Found C 47.9 H 4.9 N 10.0 15 C22H24N4O2BrFO.5H2Ol.8HCl Requires C 48.2 H 5.0 N 10.1% 0.08 isopropanol The NMR spectrum of the protonated form of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidih-4-ylmethoxy)quinazoline hydrochloride shows the presence of two forms A and B in a ratio A:B of approximately 9:1. 20 'H NMR Spectrum: (DMSOd6) 1.6-1.78 (m, form A 2H); 1.81-1.93 (br s, form B 4H); 1.94-2.07 (d, form.A 2H); 2.08-2.23 (br s, form A 1H); 2.29-2.37 (br s, form B 1H); 2.73 (d, form A 3H); 2.77 (d, form B 3H); 2.93-3.10 (q, form A 2H); 3.21 (br s, form B 2H); 3.27 (br s, form B 2H);3-42-3.48 (d, form A 2H); 4.04 (s, 3H); 4.10 (d, form A 2H); 4.29 (d, form B 2H); 7.49(s, 1H) ; 7.53-7.61 (m, 2H); 7.78 (d, 1H); 8.47 (s, 1H); 8.81 (s, 1H); 10.48 (br s, 25 form A 1H); 10.79 (br s, form B 1H); 11.90 (br s, 1H) 'tFor another NMR reading, some solid potassium carbonate was added into the DMSO solution^of the 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1 -methy lpiperidin-4-ylmethoxy)quinazoline hydrochloride described above, in order to release the free base in the NMR tube. The NMR spectrum was then recorded again and showed only one form as 30 described below: 'HNMR Spectrum: (DMSOd6; solid potassium carbonate) 1.3-1.45 (m, 2H); 1.75 (d, 2H); 1.7-1.9(m, IH) ; 1.89 (t, 2H) ; 2.18 (s, 3H) ; 2.8 (d, 2H) ; 3.98 (s, 3H); 4.0 (d, 2H) ; 7.2 (s, IH); 7.48 (d, IH); 7.55 (t, IH) ; 7.68 (d, IH); 7.8 (s, IH); 8.35 (s, IH) ; 9.75 (s, IH) A sample of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-5 ylmethoxy)quinazoline (free base) was generated from the 4-(4-bromo-2-fluoroanilino)-6- methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride, (prepared as described above), as follows: 4-(4-Bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4- ylmemoxyquinazoline-hydrocloride (50g) was suspended in methylene chloride (2ml) and 10 was washed with saturated sodium hydrogen carbonate. The methylene chloride solution was dried (MgS04) and the volatiles were removed by evaporation to give 4-(4-bromo-2- fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (free base). The NMR of the free base so generated shows only one form as described below: 'HNMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H) ; 1.76 (d, 2H) ; 1.7-1.9(m, IH) ; 1.9 (t, 2H); 15 2.19 (s, 3H); 2.8 (d, 2H) ; 3.95 (s, 3H) ; 4.02 (d, 2H); 7.2 (s, IH); 7.48 (d, IH) ; 7.55 (t, IH) ; 7.68 (dd, IH) ; 7.8 (s, IH) ; 8.38 (s, IH) ; 9.55(br s, IH) For another NMR reading, some CF3COOD was added into the NMR DMSO solution of the 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4- ylmethoxy)quinazoline (free base) described above and the NMR spectrum was recorded 20 again. The spectrum of the protonated form of the 4-(4-bromo-2-fiuoroanilino)-6-methoxy- 7-(l-methylpiperidin-4-ylmethoxy)quinazoline trifluoroacetate salt so obtained shows the presence of two forms A and B in a ratio A:B of approximately 9:1. 'H NMR Spectrum: (DMSOd; CF3COOD) 1.5-1.7 (m, form A 2H); 1.93 (br s, form B 4H); 2.0-2.1 (d, form A 2H); 2.17 (br s, form A IH); 2.35 (br s, fomrBlH); 2.71 (s, form A 3H); 25 2.73 (s, form B 3H); 2.97-3.09 (t, form A 2H); 3.23 (br s, form B 2H); 3.34 (br s, form B 2H); 3.47-3.57 (d, form A 2H); 4.02 (s, 3H); 4.15 (d, form A 2H); 4.30 (d, form B 2H); 7.2 (s, IH); 7.3-7.5 (m, 2H); 7.6 (d, IH); 7.9 (s, IH); 8.7 (s, IH) The starting material was prepared as follows: 30 /--(tert-Butoxycarbonyl)-4-(4-methylphnylsulphonyloxymethyl)piperidine (40g, 0.1 lmol), (prepared as described for the starting material in Example 1), was added to a suspension of ethyl 4-hydroxy-3-methoxybenzoate (19.6g, 0.1mol) and potassium carbonate (28g, 0.2mol) in dry DMF (200ml). 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 (MgS04) and evaporated. The resulting oil was crystallised from petroleum ether and the suspension was stored overnight at 5°C. The 5 solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 4-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-3-methoxyben2oate (35g, 89%). m.p. 81-83°C MS (ESI): 416 [MNaf - 'H NMR-Spectrum: {CDG13> 1.2-1.35(m, 2H); 1.4(t, 3H)rl48(s; ?H); 1.8-1.9(d, 2H); TXF1^ 10 2.15(m, 2H); 2.75(t, 2H); 3.9(d, 2H); 3.95(s, 3H); 4.05-4J25(br s, 2H); 4.35(q, 2H); 6.85(d, 1H); 7.55(s, 1H); 7.65(d, 1H) Elemental analysis: Found C 63.4 H 8.0 N 3.5 C21H31N06 0.3H2O Requires C 63.2 H 8.0 N 3.5% Formaldehyde (12M, 37% in water, 35ml, 420mmol) was added to a solution of ethyl 15 4-(l-(tert-butoxycarbonyl)piperidin-4-ylmemoxy)-3-methoxybenzoate (35g, 89mmol) in formic acid (35ml). 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 (40ml, 120mmol) 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 20 vacuum overnight at 50°C to give ethyl 3-methoxy-4-(l-methylpiperidin-4-ylmethoxy)benzoate (30.6g, quant). MS (ESI): 308 [MFfT 'HNMR Spectrum: (DMSOd6) 1.29(1, 3H); 1.5-1.7(m, 2H); 1.95(d, 2H); 2.0-2.15(brs, 1H); 2.72(s, 3H); 2.9-3.l(m, 2H); 3.35-3.5(br s, 2H); 3.85(s, 3H); 3.9-4.05(br s, 2H); 4.3(q, 2H); 25 7.1(d, 1H); 7.48(s, 1H); 7.6(d, 1H) A solution of ethyl 3 -methoxy-4-( 1 -methy lpiperidin-4-ylmethoxy)benzoate (3 0. 6g, 89mmol) in methylene chloride (75ml) was cooled to 0-5°C. TFA (37.5ml) was added followed by the drop wise addition over 15 minutes of a solution of fuming 24N nitric acid (7.42ml, 178mmol) in methylene chloride (15ml). After completion of the addition, the 30 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 (50ml). 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 (500ml) and 3M hydrogen chloride in ether (30ml) was added followed by ether (500ml). The solid was collected by filtration and dried under vacuum at 50°C to give ethyl 3-methoxy-4-(l-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4g, 82%). 5 MS (ESI): 353 [MH]+ 'H NMR Spectrum: (DMSOdJ 1.3(t, 3H); 1.45-1.65(m, 2H); 1.75-2.l(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, IH); 7.66(s, 1H) A suspension of ethyl 3-methoxy-4-( 1 -methylpiperidin-4-ylmethoxy)-6-nitrobenzoate 10 (3.89g, lOmmoI) in methanol (80ml) containing 10% platinum on activated carbon (50% wet) (389mg) 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 (30ml) and adjusted to pHIO 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 15 aqueous layer was further extracted with ethyl acetate/ether and the organic layers were combined. The organic layers were washed with water, brine, dried (MgS04), 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-(l-methylpiperidin-4-ylmethoxy)benzoate (2.58g, 80%). 20 m.p. 111-112°C MS (ESI): 323 [MHf 'H NMR Spectrum: (CDC13) 1.35(t3H); 1.4-1.5(m, 2H); l,85(m, 3H); 1.95(t, 2H); 2.29(s, 3H); 2.9(d, 2H); 3.8(s, 3H); 3.85(d, 2H)r4.3(q, 2H); 5.55(brs, 2H); 6.13(s, IH); 7.33(s, IH) Elemental analysis: Found C 62.8 H 8.5 N 8.3 25 C12H26N2O4 0.2H2O Requires C 62.6 H 8.2 N 8.6% A solution of ethyl 6-ammo-3-memoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1g, 50mmol) in 2-methoxyethanol (160ml) containing formamidine acetate (5.2g, 50mmol) was heated at 115°C for.2 hours. Formamidine acetate (10.4g, lOOmmol) was added in portions every 30 minutes over 4 hours. Heating was prolonged for 30 minutes after 30 the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100ml) and methylene chloride (50ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100ml. 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-(l-methylpiperidin-4- ylmethoxy)-3,4-dihydroquinazolin-4-one (12.7g, 70%). MS (ESI): 304 [MH]+ 5 'HNMR Spectrum: (DMSOd6) 1.25-1.4(m, 2H); 1.75(d, 2H); 1.9(t, IH); 1.9(s, 3H); 2.16(s, 2H); 2.8(d, 2H); 3.9(s, 3H); 4.0(d, 2H); 7.11(s, IH); 7.44(s, IH); 7.97(s, IH) A solution of 6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)-3,4-dihydroquinazolin- 4-one (2.8g, 9.24mmol) in thionyl chloride (28ml) containing DMF (280fi.l) was heated at reflux at 85DC for 1-hour. After-cooling, thevolatrles wereremovedisy evaporation The 10 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 (MgS04) and evaporated to give 4-chloro-6-methoxy-7-(l-methylpiperidin^-ylmethoxy)quinazoline (2.9g, 98%). 15 MS (ESI): 322 [MH]+ 'HNMR Spectrum: (DMSOd6 1.3-1.5(m, 2H); 1.75-1.9(m, 3H); 2.0(1, IH); 2.25(s, 3H); 2.85(d, 2H); 4.02(s, 3H); 4.12(d, 2H); 7.41(s, IH); 7.46(s, IH); 8.9(s, IH) Alternatively, the 6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)-3,4-20 dihydroquinazolin-4-one can be prepared as follows: Sodium hydride (1.44g of a 60% suspension in mineral oil, 36mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46g, 30mmol), (prepared, for example, as described in WO 97/22596, Example 1), in DMF (70ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65g, 25 37.5mmol) was added in portions and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100ml) and poured onto ice/water (400ml) and 2N hydrochloric acid (4ml). Ths organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgS04) and the solvent removed by evaporation. The residue was triturated with a mixture of ether and 30 petroleum elbej; the solid was collected by filtration and dtied under vacuum to give 7-benzyloxy-6-memoxy-3-((pivaloyloxy)memyl)-3,4-ihydroquinazolin-4-one(10g, 84%) - 'HNMR Spectrum: (DMSOd6) 1.1 l(s, 9H); 3.89(s, 3H); 5.3(s, 2H); 5.9(s, 2H), 7.27(s, IH); 7.35(m, IH); 7.47(t, 2H); 7.49(d, 2H); 7.5l(s, IH); 8.34(s, IH) A mixture of 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7g, 17.7mmol) and 10% palladium-on-charcoal catalyst (700mg) in 5 ethyl acetate (250ml), DMF (50ml), methanol (50ml) and acetic acid (0.7ml) 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 (4.36g, 80%). 10 'HNMR Spectrum: (DMSOd6) l.l(s, 9H); 3.89(s, 3H); 5.89(s, 2H); 7.0(s, IH); 7.48(s, IH); 8.5(s, IH) Triphenylphosphine (1.7g, 6.5mmol) was added under nitrogen to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.53g, 5mmol) in methylene chloride (20ml), followed by the addition of l-(tert-butoxycarbonyl)-4-15 (hydroxymethyl)piperidine (1.29g, 6mmol), (prepared as described for the starting material in Example 1), and by a solution of diethyl azodicarboxylate (1.13g, 6.5mmol) in methylene chloride (5ml). After stirring for 30 minutes at ambient temperature, the reaction mixture was poured onto a column of silica and was eluted with ethyl acetate/petroleum ether (1/1 followed by 6/5, 6/4 and 7/3). Evaporation of the fractions containing the expected product 20 led to an oil that crystallised following trituration with pentane. The solid was collected by filtration and dried under vacuum to give 7-(l-(fer/-butoxycarbonyl)piperi$n-4-ylmethoxy)- 6-meftoxy-3-pivaloyloxy)memyl)-3,4-dihydroquina2x)lin-4-one (232g, 92%). MS - ESI: 526 [MNaf 'HNMR Spectrum: (CDC13) 1.20 (s, 9H), 1.2-1.35 (m, 2H), 1.43 (s, 9H), 1.87 (d, 2H), 2.05-25 2.2 (m, IH), 2.75 (t, 2H), 3.96 (d, 2H), 3.97 (s, 3H), 4.1-4.25 (br s, 2H), 5.95 (s, 2H), 7.07 (s, lH),7.63(s, IH), 8.17 (s, IH) Elemental analysis: Found C 61.8 H 7.5 N 8.3 C26H37N3O7 - Requires C 62.0 H 7.4 N 8.3% A solution of 7-(l*(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-3-30 ((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.32g, 4.6mmol) in methylene chloride (23ml) cdhtaining-TFA (5ml) was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum, the residue was partitioned between ethyl acetate and sodium hydrogen carbonate. The organic solvent was removed under vacuum and the residue was filtered. The precipitate was washed with water, and dried under vacuum. The solid was azeotroped with toluene and dried under vacuum to give 6-methoxy-7-(piperidin-4-5 ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.7g, 92%). MS - ESI: 404 [MH]+ 'HNMR Spectrum: (DMSOd6; CF3COOD) 1.15 (s, 9H), 1.45-1.6 (m, 2H), 1.95 (d, 2H), 2.1- 2.25 (m, 1H), 2.95 (t, 2H), 3.35 (d, 2H), 3.95 (s, 3H), 4.1 (d, 2H), 5.95 (s, 2H), 7.23 (s, 1H), 7.54 (s, 1H), 8.45 (s, 1H) 10 A 37% aqueous solution 0f formaldehyde (501 ul, 6mmoI) followed by sodium cyanoborohydride (228mg, 3.6%mol) were added in portions to a solution of 6-methoxy-7-(piperidin-4-ylmethoxy)-3((pivaloyioxy)methy) -3,4-dihydroquinazolin-4-one (l.251g, 3mmol) in a mixture of THF/methanol (lOml/lOml). After stirring for 30 minutes at ambient temperature, the organic solvent were removed under vacuum and the residue was 15 partitioned between methylene chloride and water. The organic layer was separated, washed with water and brine, dried (Mgso4) and the volatiles were removed by evaporation. The residue was triturated with ether and the resulting solid was collected by filtration, washed with ether and dried under vacuum to give 6-memoxy-7-(l-methylpiperidin--4-ylmethoxy)-3- ((pivaloyloxy)methyl)-3,4-dihy%0quinazolin-4-one (1.02g, 82%). 20 MS-ESI:418[MH]+ 'H NMR Spectrum: (CDC13) U9 (S, 9H), 1.4-1.55 (ra, 2H), 1.9 (d, 2H), 2.0 (t, 2H), 1.85-2.1 (m, 1H), 2.3 (s, 3H), 2.92 (d, 2H) 3.96 (S, 3H), 3.99 (d, 2H), 5.94 (s, 2H), 7.08 (s, 1H), 7.63 (S,1H),8.17(S,1H) A saturated solution of ammonia in methanol (14ml) was added to a solution of 6-25 methoxy-7-(l-methylpiperidin-4-yimethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.38g, 3.3mmol) in methanol (5ml). After stirring for 20 hours at ambient temperature, the suspension was diluted with methylene chloride (10ml). The solution was filtered. The filtrate was evaporated under vacuum and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(l - 30 methylpiperidin-4-ylmethoxy)-3,4.dihydroquinazolin-4-one (910mg, 83%). MS-ESI:304[MH]+ 'HNMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.75 (d, 2H), 1.7-1.85 (m, 1H), 1.9 (t, 2H), 2.2 (s, 3H), 2.8 (d, 2H), 3.9 (s, 3H), 4.0 (d, 2H), 7.13 (s, 1H), 7.45 (s, 1H), 7.99 (s, 1H) Example 3a 5 3.5M Hydrogen chloride in ethanol (75µl, 0.26mmol) was added to a suspension of 4- chloro-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (80mg, 0.25mmol), (prepared as described for the starting material in Example 2c), in isopropanol (3 ml), the mixture was heated to 50°C and 4-chloro-2-fluoroaniline (44mg, 0.3mmol) was added. The - mixture was heated at reflux for 30 minutes. After cooling, the mixture was diluted with 10 ether (3ml). The precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoiy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (105mg, 82%). MS-ESI: 431-433 [MH]+ The NMR spectrum of the protonated form of 4-(4-chloro-2-fluoroaniIino)-6- 15 methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride shows the presence of two forms A and B in a ratio A:B of approximately 9:1. 'HNMR Spectrum: (DMSOd6; CF3COOD) 1.55-1.7 (m, form A2H), 1.85-2.0 (m, form B 4H), 2.05 (d, form A 2H), 2.1-2.2 (m, form A 1H), 2.35 (s, 3H); 2.79 (s, form A 3H), 2.82 (s, form B 3H), 3.03 (t, form A 2H), 3.2-3.3 (m, form B 2H); 3.3-3.4 (m, form B 2H), 3.52 (d, 20 form A 2H), 4.02 (s, 3H) 4.13 (d, form A 2H), 4.3 (d, form B 2H), 7.41 (s, 1H), 7.47 (dd, 1H), 7.63 (t, 1H), 7.69 (dd, 1H), 8.19 (s, 1H), 8.88 (s, 1H) Elemental analysis: Found C 51.8 H 5.6 N 10.9 C22H24N4O2CIF 0.04H2O 2HCIRequires C 51.7 H 5.3 N 11.0% 25 Example 3b An alternative method of preparation is as follows: Triphenylphosphine (6l5mg, 2.3mmol) followed by diethyl azodicarboxylate (369ul, 2.3mmol) were added to a solution of 4-hydroxymethyl-l-methylpiperidine (151mg, l.lmmol), (JMed. Chem 1973, 16, 156), and 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-30 methoxyqitiaazoline (250aig, 0.78mmol), (prepared as described for the startiag material in Example 7), in methylene chloride (5ml). After stirring for 30 minutes at ambient temperature, 4-hydroxymethyl-l-methylpiperidine (51mg, 0.39mmol), triphenylphosphine (102mg, 0.39mmol) and diethyl azodicarboxylate (61 ul, 0.39mmol) were added. After stirring for 15 minutes, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (70/10/20 followed by 75/5/20 and 80/0/20). The fractions containing the expected product 5 were combined and the volatiles were removed by evaporation. The residue was dissolved in a mixture of methylene chloride and methanol and 5M hydrogen chloride in isopropanol was added. The suspension was concentrated and the solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chIoro-2-fluoroaniIino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoltne hydrochloride (16mg7 4%). 10 Example 4 Under argon, sodium hydride (60%, 372mg, 9.3mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (1.67g, 8.08mmol) in DMF. After stirring for 30 minutes at ambient temperature, 4-chloro-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline 15 (1.3g, 4.04mmol) was added and stirring was continued for a further 20 hours. The mixture was poured onto water (130ml) and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (MgS04) and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica, eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol containing ammonia (1%) 20 (90/10). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 50°C to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoIine (1.4g, 70%). MS-ESI: 493-495 [MH]+ 25 'H NMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, 1H), 1.9 (t, 2H), 2.17 (s, 3H), 2.8 (d, 2H), 3.95 (s, 3H), 4.02 (d, 2H), 7.2 (s, 1H), 7.63 (S; 1H), 7.6 (s, 1H), 7.82 (s, 1H), 8.35 (s, 1H) Elemental analysis: Found C 53.8 H 4.8 N 11.3 C22H23N402BrF2 Requires C 53.6 H 4.7 N 11.4% Example 5 Using an analogous procedure to that described in Example 4, 4-chloro-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (246mg, 0.764mmol), (prepared as described for the starting material in Example 2c), was reacted with 4-chloro-2,6-difluoroaniline 5 (250mg, 1.53mmol), (see WO 97/30035 Example 15), in DMF (9ml) and in the presence of sodium hydride (60%, 76.5mg, 1.9mmol) to give 4-(4-chloro-2,6-difluoroaiulino)-6-methoxy-7-(l-methyIpiperidin-4-yImethoxy)quinazoIine(210mg, 61%). MS-ESI: 449-451{MH]+ "~'H NMR Spectrum (DMS0d6) 1.3-1.45 (m~ 2H), 1.8 (d, 2H), 1.7-1.9 (m, IH), 1.9 (t 2H), 10 2.2 (s, 3H), 2.8 (d, 2H), 3.96 (s, 3H), 4.02 (d, 2H), 7.21 (s, IH), 7.52 (s, IH), 7.54 (s, IH), 7.82 (s, IH), 8.35 (s, IH) Elemental analysis: Found C 59.0 H 5.3 N 12.5 C22H23N4O2ClF2 Requires C 58.9 H 5.2 N 12.5% 15 The starting material was prepared as follows: 4-Chloro-2,6-difluoroaniline hydrochloride (see WO 97/30035 Example 15) was partitioned between methylene chloride and water and aqueous sodium hydrogen carbonate was added until the pH of the aqueous layer was approximately 9. The organic layer was separated, washed with brine, dried (MgS04) and evaporated to give 4-chloro-2,6- 20 difluoroaniline free base. Example 6 A suspension of 4-chloro-6-methoxy-7-(l-methyIpiperidin-4-ylmethoxy)quinazoline (200mg, 0.622mmol)j (prepared as described for the starting material in Example 2c) and 2- 25 fluoro-4-methylaniline (94mg, 0.764mmol) in isopropanol (5ml) containing 6.2M hydrogen chloride in isopropanol (1 lOul) was stirred at 80°C for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum. The solid was purified by column chromatography, eluting with methylene chloride/methanol (90/10) followed by 5 % ammonia in methanol/methylene chloride 30 (10/90). Evaporation of the fractions containing the expected product gave 4-(2-ftuoro-4-methy!anilino)-6-methoxy-7-{l-methylpiperidin-4-ylniethoxy)quinazoIine (170mg, 61%). MS-ESI:411[MH]+ 'HNMR Spectrum: (DMS0d6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, IH), 1.9 (t, 2H), 2.2 (s, 3H), 2.35 (s, 3H), 2.8 (d, 2H), 3.95 (s, 3H), 4.01 (d, 2H), 7.1 (d, IH), 7.13 (d, IH), 7.16 (s, IH), 7.4 (t, IH), 7.81 (s, IH), 8.32 (s, IH), 9.4 (s, IH) Elemental analysis: Found C 66.5 H 6.7 N 13.7 5 C23H27N4O2F 0.3H2O Requires C 66.4 H 6.7 N 13.5% Example 7 l-tert-Butoxycarbonyl-4-hydroxymethylpiperidine (590mg, 2.75mmoI), (prepared as described for the starting-material in Example'l), followed by triphenylphosphine (1.2g, 10 4.58mmol) and diethyl azodicarboxylate (0.72ml, 4.58mmol) were added to a solution of 4- (4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (585mg, 1.83mmol) in methylene chloride (20ml). After stirring for 1 hour at ambient temperature, further triphenylphosphine (239mg, 0.91mmol) and diethyl azodicarboxylate (0.14ml, 0.91mmol) were added. After stirring for 1.5 hours, the volatiles were removed under vacuum and the 15 residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1). The crude product was used directly in the next step. A solution of the crude product in methylene chloride (15ml) containing TFA (4.5ml) was stirred at ambient temperature for 1.5 hours. The volatiles were removed under vacuum. The residue was partitioned between water and ethyl acetate. The aqueous layer was adjusted 20 to pH9.5 with 2N sodium hydroxide. The organic layer was separated, washed with water, followed by brine, dried (MgS04) and evaporated to give 4-(4-chloro-2-fluoroanilino)-6- methoxy-7-(piperidin-4~yImethoxy)quinazoiiiie. MS -ESI: 417-419 [MHf 'H NMR Spectrum: (DMSOd6) 1.1-1.3 (m, 2H), 1.75 (d, 2H), 1.85-2.0 (br s, IH), 2.55 (d, 25 2H), 2.95 (d, 2H), 3.95 (s, 3H), 4.0 (d, 2H), 7.2 (s, IH), 7.35 (dd, IH), 7.55 (dd, IH), 7.6 (t, IH), 7.8 (s, IH), 8.35 (s, IH), 9.55 (s, IH) The hydrochloride salt was made as follows: 4-(4-Chloro-2-fluoroanilino)-6-memoxy-7-(piperidin-4-ylmethoxy)quinazoline was 30 dissolved in a mixture of methanol/methylene chloride and 6M hydrogen chloride in ether was added. The volatiles were removed under vacuum, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2- fluoro)-6-methoxy-7-(piperidin-4-yImethoxy)quinazoIine hydrochloride (390mg, 47% over 2 steps). Elemental analysis: Found C 50.4 H 5.2 N 11.0 C21H22O2N4CIF 2.25HC1 Requires C 50.6 H 4.9 N 11.2% 5 The starting material was prepared as follows: A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.2g, 4mmol), (prepared as described in WO 97/22596, Example 1), and 4-chloro-2-fluoroaniline (444µl 4mmol) in 2-propanol (40ml) was heated at reflux for 1.5 hours. After cooling, the 10 precipitate was collected by filtration, washed with 2-propanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13g, 64%). m.p. 239-242°C 'HNMR Spectrum: (DMSOd6) 4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 15 1H) MS-ESI:410[MH]+ Elemental analysis: Found C 59.2 H 4.3 N 9.4 C22H17N3O2 1HC1 Requires C 59.2 H 4.1 N 9.4% A solution of 7-benzyloxy-4-(4-chloro-2-fIuoroanilino)-6-methoxyquinazoline 20 hydrochloride (892mg, 2mmol) in TFA (10ml) was heated at reflux for 50 minutes. After cooling, the mixture was poured onto ice. The precipitate was collected by filtration, dissolvedin methanol (10ml) and basified to pHl 1 with aqueous ammonia. After concentration by evaporation, the solid product was collected by filtration, washed with water then ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-25 methoxyquinazoline as a yellow solid (460mg, 72%), m.p. 141-143°C MS - ESI: 320-322 [MH]+ 'HNMR Spectrum: (DMSOd6) 3.95(s, 3H); 7.05(s, 1H); 7.35(d, 1H); 7.54-7.59(m, 2H); 7.78(s, IB); 8.29(s, 1H) Example 8 A suspension of 7-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (318mg, 0.64mmol) in methylene chloride (5ml) containing TFA (2.5ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH10-l 1. The organic layer was separated, washed with water, brine, dried (MgS04) and the volatiles were removed by evaporation to give 4-(2-fluoro-4-methylaniIino)-6-methoxy-7-(piperidin-4-ylinethoxy)quinazoIine(220mg, 87%). MS.-. ESI: 397 [MH]+ 'HNMR Spectrum: (DMSOd6) 1.15-1.3 (m, 2H); 1.75 (d, 2H); 1.85-2.0 (m, IH); 2.4 (s, 3H); 3.0 (d, 2H); 3.3-3.4 (d, 2H); 3.95 (s, 3H); 4.0 (d, 2H); 7.04 (d, IH); 7.15 (d, IH); 7.17 (s, IH); 7.4 (t, IH); 7.8 (s, IH); 8.3 (s, IH); 9.4 (s, IH) The starting material was prepared as follows: Using an analogous procedure to that described in Example 6, 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.55g, 5.15mmol), (prepared, for example, as described in WO 97/22596, Example 1), was reacted with 2-fluoro-4-methylaniline (700mg, 5.67mmol) in isopropanol (90ml) containing 6.2M hydrogen chloride in isopropanol (80µl, 0.51mmol) to give 7-benzyloxy-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline 20 hydrochloride (2g, 91%). MS - ESI: 390 [MH]+ 'H NMR Spectrum: (DMSOd.0 2.4 (s, 3H), 4.01~(s, 3H), 7.15 (d, IH), 7.25 (d, IH), 7.35-7.6 (m, 7H), 8.3 (s, IH), 8.78 (s, IH) A solution of 7-benzyloxy-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline 25 hydrochloride (2g, 4.7mmol) in TFA (20ml) was heated at 80°C for 5 hours and stirred at ambient temperature overnight. The volatiles were removed under vacuum and the residue was suspended in water (50ml). Solid sodium hydrogen carbonate was added until the pH • was approximately 7. The precipitate was then collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with 30 methanol/methylene chloride (5/95). After removal of the solvent by evaporation, the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(2-fluoro-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (1.04g, 74%). MS-ESI:300[MH]+ 'HNMR Spectrum: (DMSOd6) 2.4 (s, 3H), 4.0 (s, 3H), 7.15 (d, IH), 7.22 (s, IH), 7.25 (d, IH), 7.41 (t, IH), 8.05 (s, IH), 8.7 (s, IH), 11.0 (s, IH), 11.5-11.8 (br s, IH) Triphenylphosphine (2.19g, 8.36mmol) was added to a suspension of 4-(2-fluoro-4-5 methylanilino)-7-hydroxy-6-methoxyquinazoline (lg, 3.34mmol) in methylene chloride (10ml) cooled at 0°C, followed by l-(tert-butoxycarbonyI)-4-hydroxymethylpiperidine (1.08g, 5.01mmol), (prepared as described for the starting material in Example 1), and diethyl azodicarboxylate (1.31ml, 8.36mmol). After stirring for 2 hours at ambient temperature, the voiatrlesnvere removed under vacuum. The residue was purified by column chromatography 10 eluting with methylene chloride/methanol (2/98). After removal of the solvent by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (327mg, 20%). MS - ESI: 497 [MH]+ 15 'HNMR Spectrum: (DMSOd6) 1.15-1.3 (m, 2H); 1.45 (s, 9H); 1.8 (d, 2H); 2.0-2.1 (m, IH); 2.4 (s, 3H); 2.75-2.9 (br s, 2H); 3.95 (s, 3H); 4.0 (br s, 2H); 4.05 (d, 2H); 7.1 (d, IH); 7.15 (d, IH); 7.2 (s, IH); 7.4 (t, IH); 7.85 (t, IH); 8.32 (s, IH); 9.45 (s, IH) Example 9 20 A solution of 4-(4-bromo-2,6-difluoroanilino)-7-(l-(tert-butoxycarbonyl)piperidin-4- ylmethoxy)-6-methoxyquinazoline (578mg, lmmol) in methylene chloride (10ml) containing TFA (4ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was suspended in water. The aqueous layer was adjusted to approximately pHIO and was extracted with methylene chloride. The organic layer was 25 washed with water, brine, dried (MgS04) and the volatiles were removed by evaporation. The residue was triturated with ether and dried under vacuum to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)qiiinazoline (1 lOmg, 23%). MS - ESI: 479-481 [MH]+ 'HNMR Spectrum: (DMSOd,) 1.15-1.3 (m, 2H); 1.75 (d, 2H) ; 1.85-2.0 (brs, IH) ; 2.5 (d, 30 2H) ; 3:0 (d, 2H) ; 3.97 (s, 3H) ; 4.0 (d, 2H) ; 7.2 (s, IH) ; 7.62 (d, 2H) ; 7.82 (s, IH) ; 8.35 (s, IH) 'HNMR Spectrum: (DMSOd6; CF3COOD) 1.5-1.65 (m, 2H) ; 2.0 (d, 2H) ; 2.15-2.3 (br s, 1H); 3.0 (t, 2H); 3.4 (d, 2H) ; 4.02 (s, 3H) ; 4.15 (d, 2H) ; 7.4 (s, 1H) ; 7.75 (d, 2H); 8.1 (s, 1H); 8.92 (s, 1H) 5 The starting material was prepared as follows: Sodium hydride (60%, 6l2mg, 15.3mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (2.77g, 6.65mmol) in DMF (80ml). After stirring for 30 minutes at ambient temperature, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2g, 6.65mmol), (prepared, for example, as described in W0 97/22596;-Example 1, but the free base was generated prior to 10 use), was added and stirring was maintained for 4 hours. The mixture was partitioned between ethyl acetate and water (200ml). The organic layer was separated, washed with water, brine, dried (MgS04) and the volatiles were removed by evaporation. The residue was triturated with isopropanol, collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline (1.95g, 62%). 15 MS -ESI: 472-474 [MH]+ 'HNMR Spectrum: (DMSOd6) 3.94 (s, 3H), 5.3 (s, 2H), 7.3 (s, 1H), 7.4 (d, 1H), 7.45 (t, 2H), 7.5 (s, 1H), 7.55 (d, 1H), 7.65 (d, 2H), 7.85 (s, 1H), 8.35 (s, 1H), 9.4-9.6 (br s, 1H) Using an analogous procedure to that described for the synthesis of the starting material in Example 8, 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline 20 (1.9g, 4.02mmol) was reacted with TFA (20ml) to give 4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.5g, 98%). 'HNMR Spectrum: (DMSOdg) 3.95 (s, 3H), 7.1 (s, 1H), 7.6,(s, 1H), 7.65 (s, 1H), 7.8 (s, 1H), 8.3 (s, 1H), 9.45 (br s, 1H), 10.5 (br s, 1H) Using an analogous procedure to that described in the preparation of the starting 25 material in Example 8,4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoIine (lg, 2.62mmol) was reacted with l-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (845mg, 3.93mmol), (prepared as described for the starting material in Example 1), to give 4-(4-bromo-2,6-difluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (620mg, 41%), 30 MS-ESI: 579-581 [MH]+ 'HNMR Spectrum: (DMSOd6) 1.15-1.3 (m, 2H); 1.45 (s, 9H); 1.8 (d, 2H); 2.0-2.1 (m, 1H); 2.7-2.9 (m, 2H); 3.95 (s, 3H) ; 4.0 (br s, 2H) ; 4.05 (d, 2H) ; 7.22 (s, 1H) ; 7.65 (d, 2H); 7.85 (s, 1H) ; 8.35 (s, 1H); 9.4-9.6 (br s, 1H) 5 Example 10 Using an analogous procedure to that described in Example 9, 7-(l-(/ert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-chloro-2J6-difluoroanilino)-6-methoxyquinazoline (95mg, 0.2mmol) in methylene chloride (2ml) was treated with TFA (800ul) to give 4-(4-chIoro-2,6-dinuoroaniIino)-^nietitoxys7-(pipeHdin-4-10 ylmethoxy)quinazoline (20mg, 26%). MS-ESI: 435-437 [MH]+ 'HNMR Spectrum: (DMSOd6) 1.2-1.3 (m, 2H); 1.75 (d, 2H); 1.85-2.0 (br s, 1H) ; 2.5 (d, 2H); 3.0 (d, 2H); 3.97 (s, 3H); 4.0 (d, 2H) ; 7.2 (s, 1H); 752 (d, 2H); 7.85 (s, 1H); 8.35 (s, 1H) 15 The starting material was prepared as follows. Using an analogous procedure to that described for the preparation of the starting material in Example 9, 7-benzyloxy-4-chloro-6-methoxyquinazoline (184mg, 0.61mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was 20 generated prior to use), was reacted with 4-chloro-2,6-difluoroaniline (200mg, 1.22mmol) in the presence of sodium hydride (60%, 87mg, 1.4mmol) in DMF (8ml) to give 7-benzyloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (212mg, 74%). MS - ESI: 428 [MH]+ 'HNMR Spectrum: (DMSOd6) 3.96 (s, 3H); 5.31 (s, 2H); 7.32 (s, 1H); 7.4 (d, 1H); 7.45 (t, 25 2H); 7.5-7.6 (m, 4H); 7.85 (s, 1H); 8.35 (br s, 1H); 9.55 (br s, 1H) A solution of 7-ben2yloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquina2X>line (200mg, 0.47mmol) in TFA (3ml) was stirred at 80°C for 3 hours. After cooling, the volatiles were removed under vacuum and the residue was dissolved in water containing 5% methanol. The pH was adjusted to 8 with sodium hydrogen carbonate and the solid was 30 collected by filtration and washed with water. The solid was solubilised in a mixture of ethyl acetate/methanol/methylene chloride (47/6/47). The volatiles were removed under vacuum to give 4-(4-chloro-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (126mg, 80%). MS - ESI: 338 [MH]+ 'HNMR Spectrum: (DMSOcLJ 3.95 (s, 3H); 7.1 (s, 1H); 7.55 (d, 2H); 7.8 (s, 1H); 8.3 (s5 1H); 9.42 (br s, 1H) Using an analogous procedure to that described for the preparation of the starting 5 material in Example 9, 4-(4-chloro-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (150mg, 0.44mmol) was reacted with l-(fer£-butoxycarbonyl)-4-hydroxymethylpiperidine (150mg, 0.88mmol), (prepared as described for the starting material in Example 1), to give 7- (1 -(tert-butoxy carbony l)piperidin-4-ylmethoxy)-4-(4-chloro-2,6-difluoroanilino)-6- meth©xyquinazoline(113mg, 59%). 10 MS - ESI: 535 [MH]+ 'HNMR Spectrum: (DMSOd6) 1.15-1.3 (m, 2H); 1.45 (s, 9H); 1.8 (d, 2H); 2.0-2.1 (m, 1H); 2.7-2.9 (m, 2H); 3.95 (s, 3H); 4.0 (br s, 2H); 4.05 (d, 2H); 7.2 (s, 1H); 7.6 (m, 2H); 7.8 (s, 1H); 8.35 (s, 1H); 9.4-9.6 (br s, 1H) 15 Example 11 The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a pharmaceutically acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans: 20 (a) 25 (b) 30 Tablet I ma/tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 Tablet II me/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c) 10 (d) 15 (e) Tablet m mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0 Capsule me/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium stearate 1.5 Injection I (50 me/ml) Compound X 5.0% w/v IM Sodium hydroxide solution 15.0% v/v 20 0. IM Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 Water for injection to 100% 4.5% w/v (f) Injection II Compound X 25 Sodium phosphate BP 0.1M Sodium hydroxide solution Water for injection to 100% 10mg/ml) 1.0% w/v 3.6% w/v 15.0% v/v (g) Injection III 30 Compound X Sodium phosphate BP Citric acid (lmg/ml.buffered to pH6) 0.1% w/v 2.26% w/v 0.38% w/v Polyethylene glycol 400 Water for injection to 100% 3.5% w/v Note The above formulations may be obtained by conventional procedures well known in the 5 pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. Claim: 1. A quinazoline derivative of the formula I: wherein: m is an integer from 1 to 3; R1 represents halogeno or C1-3alkyl; R2 is selected from one of the following three groups: 1) C1-5alkylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C1-4alkyl, C1-4 hydroxyalkyl and C1-4alkoxy; 2) C2-5alkenylR3 (wherein R3 is as defined herein); 3) C2-5alkynylR3 (wherein R3 is as defined herein); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; or a salt of the kind such as herein described. 2 A quinazoline derivative as claimed in claim 1 wherein the phenyl group bearing (R1)m is selected from 2-fluoro-4-methylphenyl, 4-chloro-2,6-difluorophenyl, 4-bromo-2,6- difluorophenyl, 4-chloro-2-fluorophenyl group and 4-bromo-2-fluorophenyl. 3. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R2 is C1-5alkylR3. 4. A quinazoline derivative as claimed in any one of the preceding claims wherein R2 is piperidin-4-ylmethyl in which the piperidine ring may bear one or two substituents selected from C1-4alkyl. 5. A quinazoline derivative as claimed in claim 1 of the formula II: wherein: ma is an integer from 1 to 3; Rla epresents halogeno or Ci-3alkyl; R2a is selected from one of the following three groups: 1) C1-5alkylR3 (wherein R3 is as defined in claim 1); 2) C2-5alkenylR3 (wherein R3 is as defined in claim 1); 3) C2-5alkynylR3 (wherein R3 is as defined in claim 1); or a salt of the kind such as herein described. 6. A quinazoline derivative as claimed in claim 1 selected from: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline, 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline, 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1-methylpiperidin-4-ylmethoxy) quinazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(l -methylpiperidin-4-ylmethoxyjquinazoline, 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline, 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy) quinazoline, 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(piperidin-4-ylmethoxy) quinazoline, 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy) quinazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, and 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy) quinazoline, and salts of the kind such as herein described. 7 A quinazoline derivative as claimed in claim 1 selected from: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline, 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, and 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, and salts of the kind such as herein described. 8. A quinazoline as claimed in claim 1 derivative selected from: 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1-methylpiperidin-4-ylmethoxy)quinazoline and salts of the kind such as herein described. 9. A quinazoline derivative as claimed in any one of the preceding claims in the form of a pharmaceutically acceptable salt of the kind such as herein described. 10. A process for the preparation of a quinazoline derivative of formula I, as claimed in claim 1, or a salt of the kind such as herein described which comprises: (a) the reaction of a compound of the formula III: cm) wherein R2 is as claimed in claim 1 and L1 is a displaceable moiety, with a. compound of the formula IV: wherein R1 and m are as claimed in claim 1; (b) the reaction of a compound of the formula V: wherein m and R1 are as defined in claim 1 with a compound of formula VI; wherein R2 is as claimed in claim 1 and L1 is as denned herein; (c) the reaction of a compound of the formula VII: (vn) with a compound of the formula VIII: R2-Q-H (VIII) wherein R1, R2 and m are as claimed in claim 1 and L1 is as defined herein; or (d) the deprotection of a compound of the formula IX: wherein R1 and m are as claimed in claim 1, and R4 represents a protected R2 group wherein R2 is as claimed in claim 1 but additionally bears one or more protecting groups P2; and when a pharmaceutically acceptable salt of a quinazoline derivative of formula I is required, reaction of the compound obtained with an acid or base whereby to obtain the desired pharmaceutically acceptable salt of the kind such as herein described. Dated this 21st day of March, 2002. [RANJNA MEHTA-DUTT] OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Full Text

FORM 2
THE PATENTS ACT, 1970
[39 OF 1970]
COMPLETE SPECIFICATION [See Section 10; rule 13]
"QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS"
ASTRAZENECA AB, a Swedish company of S-151 85 Sodertalje, Sweden,
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-

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.
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: 27-3 i). 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 (lakeman 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 VEGEawith antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844).
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 memhcane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor resultsin stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular

molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Fit or Fltl, the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fit and KDR, have been shown to bind 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.
Quinazoline derivatives which are inhibitors of VEGF receptor tyrosine kinase are described in International Patent Applications Publication Nos. WO 97/30035 and WO 98/1335C In WO 97/30035 and WO 98/13354 compounds are described which possess activity against VEGF receptor tyrosine kinase whilst possessing some activity against EGF receptor tyrosine kinase.
Compounds of the present invention fall within the broad general disclosure of WO 97/30035 and WO 98/13354; We have found that compounds of the present invention possess very good inhibitory activity against VEGF receptor tyrosine kinase. Compounds of the present invention, which have been tested, show in vivo activity against a range of tumour xenografts in mice. Compounds of the present invention possess a beneficial toxicological profile when tested over 14 days in rats. Compounds of the present invention possess very good inhibitory activity against VEGF receptor tyrosine kinase show in vivo activity against a range of tumour xenografts in mice and possess a beneficial toxicological profile when tested over 14 days in rats.
Compounds of the present invention 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: possess good activity againstrVEGF receptor tyrosine kinase whilst possessing some activity against EGF receptor tyrosine kinase.

Furthermore, some compounds of the present invention, possess substantially higher potency against VEGF receptor tyrosine kinase than against EGF receptor tyrosine kinase or FGF Rl receptor tyrosine kinase. While we do not wish to be bound by theoretical considerations such compounds may for example be of interest in treating tumours which are associated with 5 VEGF, especially those tumours which are dependent on VEGF for their growth. It is further believed that these compounds may be of interest in treating tumour states associated with both VEGF and EGF, especially where a patient is suffering from a condition in which tumours are present which are dependent on both VEGF and EGF for their growth.
According to one aspect of the present invention there is provided a quinazoline 10 derivative of the formula I:

(I) wherein: 15 m is an integer from 1 to 3;
R1 represents halogeno or C1-3alkyl;
X1 represents -0-;
R2 is selected from one of the following three groups:
1) C,.jalkylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected 20 from hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy;
2) C2.5alkenylR3 (wherein R3 is as defined hereinbefore);
3) C2.5alkynylR3 (wherein R3 is as defined hereinbefore);
and wherein anyalkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; 25 or a salt thereof or a prodrug thereof. Preferably m is 2.

Preferably the phenyl group bearing (R')m is selected from 2-fluoro-4-methylphenyl, 4-
chloro-2,6-difluorophenyl, 4-bromo-2,6-difluorophenyl, 4-chloro-2-fluorophenyl group and
4-bromo-2-fluorophenyl.
More preferably the phenyl group bearing (R})m is selected from 4-chloro-2-fluorophenyl and 5 4-bromo-2-fluorophenyl.
Most preferably the phenyl group bearing (R')m is 4-bromo-2-fluorophenyl.
Preferably R2 is C1-5alkylR3 (wherein R3 is as defined hereinbefore).
More preferably R2 is C1-3alkylR3(wherein R3 is as defined hereinbefore).
Particularly R2 is piperidin-4-ylmethyl in which the piperidine ring may bear one or two 10 substituents as defined hereinbefore.
More particularly R2 is piperidin-4-ylmethyl in which the piperidine ring may bear one or two
substituents selected from C1-4alkyl.
Especially R2 is l-methylpiperidin-4-ylmethyl.
According to a further aspect of the present invention there is provided a quinazoline 15 derivative of the formula II:

wherein: 20 ma is an integer from 1 to 3;
Rla represents halogeno or C,.3alkyl;
X1" represents -0-;
R2* is selected from one of the following three groups:
1) C1-5alkylR3 (wherein R3 is as defined hereinbefore); 25 2) C2-5alkenylR3 (wherein R3 is as defined hereinbefore);
3) C2-5alkynylR3 (wherein R3 is as defined hereinbefore);
or a salt thereof or a prodrug thereof.

Preferably ma is 2.
Preferably the phenyl group bearing (Rli,)ma is selected from 2-fluoro-4~methylphenyl, 4-chloro-2,6-difluorophenyl, 4-brOmo-2,6-difluorophenyl3 4-chloro-2-fluorophenyl group and 4-bromo-2-fluorophenyl. 5 More preferably the phenyl group bearing (R1")ma is selected from 4-chloro-2-fluorophenyl and 4-bromo-2-fluorophenyl.
Most preferably the phenyl group bearing (R,a)ma is 4-bromo-2-fluorophenyl. Preferably R2 4 is C1-5alky R.3 (wherein R3 is as defussd hereinbefore). More preferably K2* is C1.3alkylR3(wherein R3 is as defined hereinbefore). 10 Particularly R2" is piperidin-4-ylmethyl in which the piperidine ring may bear one or two substituents as defined hereinbefore.
More particularly R2" is piperidin-4-ylrnethyl in which the piperidine ring may bear one or two substituents selected from C1-4alkyl. Especially R2" is l-methylpiperidin-4-yImethyl. 15 Preferred compounds of the present invention include:
4-(4-chloro-2-fluoroanilino)-6-niethoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, 4-(2-fluoro-4-memylaniIino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline3 4^4-bromo-2-fluoroanilino)-6^niemoxy-7^1-memylpiperidin^ylmethoxy)quinazoline, 4-(4-chloro-2,6-difluoroanilino)'6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazolineJ 20 4-(4-bromo-2,6-difluoroanilino)'6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline3
-4-(2-fluro-4-methylanilmo)-6-methoxy-
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, and 25 4-(4-bromo-2,6-difluoroanilino)'6-methoxy-7-(piperidin-4-ylmethoxy)quinazolmeJ and salts thereof especially hydrochloride salts thereof. More preferred compounds of the present invention include: - 4-4-chloro-2-fluoroanilino)-6-memoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, 4-(4-bromo-2-fiuoroanilino>6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline) 30 4-(4^hloro-2,6-difluoroanilmo)^-memoxy-7^1-me1hylpiperidb^ylmemoxy)qumazoline, 4-(4^hloro-2,6--difluoroanilino)'6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinaz0line3 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline,

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline3 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline? and 4-(4-bromo-2J6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, and salts thereof especially hydrochloride salts thereof. 5 Particularly preferred compounds of the present invention include:
4-(4-chloro-2-fluoroanilino)-6-methoxy-7^1-methylpiperidin-4-ylmethoxy)quinazolineJ 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-raethylpiperidin-4-ylmethoxy)quinazoline, 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, and 10 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, and salts thereof especially hydrochloride salts thereof. More particularly preferred compounds of the present invention include: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline and 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperiddin-4-ylmethoxy)quina2oline,
15 and salts thereof especially hydrochloride salts thereof.
An especially preferred compound of the present invention is
4-(4-bromo-2-fiuoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline and salts thereof especially hydrochloride salts thereof.
For the avoidance of doubt it is to be understood that where in this specification a
20 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. .And asimilar convention applies to 'hereinafter defined' or 'defined hereinafter'.
In this specification unless stated otherwise the term "alkyl" includes both straight and
25 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 1-5 carbon atoms, preferably 1-3 carbon atoms. The term "alkoxy" as used herein, unless stated otherwise includes "alkyl"-0- groups in which "alkyl" is as hereinbefore defined. The term
30 "aryl" as used herein unless stated otherwise includes reference to a C6-10 aryl group which may, if desired, carr^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"-0-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 alkyiC=0 groups in 5 which "alkyl" is as defined hereinbefore, for example C^alkanoyl is ethanoyl and refers to CH3OO, C,alkanoyl is formyl and refers to CHO. In this specification unless stated otherwise the term "alkenyl" includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl are specific for the straight chain version only. Unless otherwise stated the term "alkenyl" advantageously refers to chains with 2-5 carbon
10 atoms, preferably 3-5 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 3-5 carbon atoms.
15 In formula I, as hereinbefore defined, hydrogen will be present at positions 2, 5 and 8
of the quinazoline group.
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
20 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.
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
25 understood that the invention encompasses all such solvated forms which inhibit VEGF receptor tyrosine kinase activity.
For the avoidance of any doubt, it is to be understood that in a compound of the formula I when R2 is, for example, a group of formula C^alkenylR3 it is the C25alkenyl moiety which is bound to X1 and an analogous convention applies to other groups. When R2
30 is a group 1 -R3prop-l -en-3-yl it is the first carbon to which the group R3 is attached and it is -the third carbon which is linked to X1, similarly when R2 is_a_group„2-R3pent-3-en-5-yl it is

the second carbon to which the group R3 is attached and it is the fifth carbon which is linked to X1, and an analogous convention applies to other groups.
Compounds of Formula I may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the Formula I. Examples of 5 prodrugs include in vivo hydrolysable esters of a compound of the Formula I.
Various forms of prodrugs are known in the art. For examples of such prodrug derivatives see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, V6l~32, p. 309-396;edited by K. Widder, et al. (Academic Press, 1985); 10 b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191(1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and 15 e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
An in vivo hydrolysable ester of a compound of Formula I containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of a-acyloxyalkyl
20 ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyLand phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl: Examples of substituents on benzoyl include
25 morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3-or 4- position of the benzoyl ring.
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
30 compounds of formula I and theirpharmaceutically 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 5 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,
10 piperidine, morpholine or tris-(2-hydroxyethyl)amine.
A compound of the formula I, or salt thereof, and other compounds of the invention (as hereinafter defined) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes include, for example, those illustrated in European Patent Applications, Publication Nos. 0520722, 0566226, 0602851 and 0635498 and
15 in International Patent Applications Publication Nos. WO 97/22596, WO 97/30035, WO
97/32856 and WO 98/13354. 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
20 obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
Thus the following processes (a) to (d) and (i) to (iv) constitute further features of the present invention. Synthesis of Compounds of Formula I
25 (a) Compounds of the formula I and salts thereof may be prepared by the reaction of a
compound of the formula HI:

(wherein R2 and X1 are as defined hereinbefore and L1 is a displaceable moiety), with a compound of the formula IV:

10 (wherein R1 and m are as defined hereinbefore) whereby to obtain compounds of the formula and salts thereof. A convenient displaceable moiety L1 is, for example, a halogeno, alkoxy (preferably C,.4alkoxy), aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
The reaction is advantageously effected in the presence of either an acid or a base.
15 Such an acid is, for example, an anhydrous inorganic acid such as hydrogen chloride. 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, or for example, an alkali metal or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium
20 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 or sodium bis(trimethylsilyl)amide. The reaction is preferably effected in the presence of an inert solvent or diluent, for example an alkanol or ester such as methanol, ethanol, 2-propanol or ethyl acetate, a halogenated solvent
25 such as methylene chloride, trichloromethane or carbon tetrachloride, 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-2rone or dimethylsulphoxide. The reaction is conveniently effected at a temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 80°C.
30 The compound of the invention may be obtained from this process in the form of the
free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L1 wherein L1 has the meaning defined hereinbefore. When it is desired to obtain the free

base from the salt, the salt may be treated with a base as defined hereinbefore using a conventional procedure.
(b) Compounds of the formula I and salts thereof may be prepared by the reaction, conveniently in the presence of a base as defined hereinbefore, of a compound of the formula 5 V:

10

(V)
(wherein m, X1 and R' are as hereinbefore defined) with a compound of formula VI:
15
R2-L' (VI)
(wherein R2 and L1 are as hereinbefore defined); L1 is a displaceable moiety for example a halogeno or sulphonyloxy group such as a bromo or methanesulphonyloxy group. Conveniently L1 is a group 0-+P(Y)3 (wherein Y is butyl or phenyl) and in such cases the
20 compound of formula VI is conveniently formed in situ. 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 may be prepared by the reaction of a
25 compound of the formula VII:

30

with a compound of the formula VIII:
R2-X'-H (VIII)
5
(wherein L1, R1, R2, m and X1 are all 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 range7for example" 10 to 150°C, 10 conveniently at about 100°C.
(d) Compounds of the formula I and salts thereof may be prepared by the deprotection of a compound of the formula IX:

15
20
wherein R1, m and X1 are all as hereinbefore defined, and R4 represents a protected R2 group wherein R2 is as defined hereinbefore but additionally bears one or more protecting groups P2. The choice of protecting group P2 is within the standard knowledge of an organic chemist, for example those included in standard texts such as "Protective Groups in Organic Synthesis"
25 T.W. Greene and RG.M.Wuts, 2nd Ed. Wiley 1991. Preferably P2 is a protecting group such as a carbamate (alkoxycarbonyl) (such as, for example, tert-butoxycarbonyl, tert-amyloxycarbonyl, cyclobutoxycarbonyl, propoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl). More preferably P2 is tert-butoxycarbonyl. The reaction is preferably effected in the presence of an
30 acid. Such an acid is, for example, an inorganic acid such as hydrogen chloride, hydrogen bromide or an organic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid. The reaction may be effected in the presence of an inert solvent such as methylene chloride,

trichloromethane and in the presence of a trace of water. The reaction is conveniently effected at a temperature in the range, for example, 10-100°C, preferably in the range 20-80°C.
Synthesis of Intermediates
5 (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 X:

10

(X)
15 (wherein R2 and X1 are as hereinbefore defined).
Convenient halogenating agents include inorganic acid halides, for example thionyl chloride, phosphorus(m)chloride, phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenation reaction is conveniently effected in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or
20 carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene. The reaction is conveniently effected at a temperature in the range, for example 10 to 150°C, preferably in the range 40 to 100°C.
The compounds of formula X and salts thereof may for example be prepared by reacting a compound of the formula XI:
25

30

(wherein L1 is 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 5 example 10 to 150°C, conveniently at about 100°C.
The compounds of formula X and salts thereof may also be prepared by cyclising a compound of the formula XII:

10

15 (wherein R2 and X1, are as hereinbefore defined, and A1 is an hydroxy, alkoxy (preferably C,_ 4alkoxy) or amino group) whereby to form a compound of formula X or salt thereof. The cyclisation may be effected by reacting a compound of the formula XII, where A1 is an hydroxy or alkoxy group, with formamide or an equivalent thereof effective to cause cyclisation whereby a compound of formula X or salt thereof is obtained, such as [3-
20 (dimethylamino)-2-azaprop-2-enylidene]dimethylanimonium 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 l,4?dioxan. The cyclisation is conveniently effected at an elevated temperature, preferably in the range 80 to 200°C. The compounds of formula X may also be prepared by cyclising a compound of the formula XH, where A1 is an
25 amino group, with formic acid or an equivalent thereof effective to cause cyclisation whereby a compound of formula X or salt thereof is obtained. Equivalents of formic acid effective to cause cyclisation include for example a tri-C1-4alkoxymethane, for example triethoxymethane and trimethoxyrnethane. 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,
30 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.
Compounds of formula XII and salts thereof may for example be prepared by the reduction of the nitro group in a compound of the formula XHI:

10

(wherein R2, X1 and A1 are as hereinbefore defined) to yield a compound of formula XII 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
15 example, by the hydrogenation of a solution of the nitro compound in the presence of an inert solvent or diluent as defined hereinbefore in the presence of a metal effective to catalyse hydrogenation reactions such as palladium or platinum. A further reducing agent is, for example, an activated metal such as activated iron (produced for example by washing iron powder with a dilute solution of an acid such as hydrochloric acid). Thus, for example, the
20 reduction may be effected by heating the nitro compound and the activated metal in the
presence of a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature in the range, for example 5Q.to ISOJX^conyeniently at about 70°C.
Compounds of the formula XTII and salts thereof may for example be prepared by the reaction of a compound of the formula XTV:

(wherein L1 and A1 are as hereinbefore defined) with a compound of the formula VIII as hereinbefore defined to give a compound of the formual XIII. The reaction of the compounds of formulae XTV and VTA is conveniently effected under conditions as described for process 5 (c) hereinbefore.
Compounds of formula XIII and salts thereof, may for example also be prepared by the reaction of a compound of the formula XV:

10

15 (wherein X1 and A1 are as hereinbefore defined) with a compound of the formula VI as hereinbefore defined to yield a compound of formula XIII as hereinbefore defined. The reaction of the compounds of formulae XV and VI is conveniently effected under conditions as described for process (b) hereinbefore.
The compounds of formula HI and salts thereof may also be prepared for example by
20 reacting a compound of the formula XVI:

25

(wherein X' is as hereinbefore defined and L2 represents a displaceable protecting moiety) with a compound of the formula: VI as hereinbefore defined, whereby to obtain a compound of 30 formula III in which L1 isTepresented by L2.
A compound nf formula YVT 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.
The compounds of formula XVI and salts thereof as hereinbefore defined may for' example be prepared by deprotecting a compound of the formula XVII:

(XVH)
10
(wherein X1 and L2 are as hereinbefore defined and P1 represents a phenolic hydroxy protecting group). The choice of phenolic hydroxy 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 ethers
15 (for example, methyl, methoxymethyl, allyl and benzyl and benzyl substituted with up to two substituents selected from C1-4alkoxy and nitro), silyl ethers (for example, t-butyldiphenylsilyl and t-butyldimethylsilyl), esters (for example, acetate and benzoate) and carbonates (for example, methyl and benzyl and benzyl substituted with up to two substituents selected from C1-4alkoxy and nitro). Deprotection may be effected by techniques well known in the
20 literature, for example where P1 represents a benzyl group deprotection may be effected by hydrogenolysis or by treatment with trifluoroacetic acid.
The removal of such a phenolic hydroxy 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. The reaction
25 conditions preferably being such that the hydroxy derivative is produced without unwanted reactions at other sites within the starting or product compounds. For example, where the protecting group P1 is acetate, the transformation may conveniently be effected by treatment of the quinazoline derivative with a base as defined hereinbefore and including ammonia, and its mono and di-alkylated derivatives, preferably in the presence of a protic solvent or co-solvent
30 such as water or an alcohol, for example methanol or ethanol. Such a reaction can be effected in the presence of an addttional, intex solcent or dilluent as defined hereinbefore and at a temperature in the range 0 to 50°C, conveniently at about 20°C.

One compound of formula in may if desired be converted into another compound of fonnula HI in which the moiety L1 is different. Thus for example a compound of formula HI in which L1 is other than halogeno, for example optionally substituted phenoxy, may be converted to a compound of formula HI in which L1 is halogeno by hydrolysis of a compound 5 of formula III (in which L1 is other than halogeno) to yield a compound of formula X as hereinbefore defined, followed by introduction of halide to the compound of fonnula X, thus obtained as hereinbefore defined, to yield a compound of formula III in which L' represents halogeno.
(ii) Compounds of the formula V as hereinbefore defined and salts thereof rffay be made by " 10 deprotecting the compound of formula XVIII:

15

(xvm)
(wherein R1, P1, X1 and m are as hereinbefore defined) by a process for example as described in 20 (i) above.
Compounds of the formula XVHI and salts thereof may be made by reacting compounds of the formulae XVD; and IV as hereinbefore defined, under the conditions "described in (a) hereinbefore, to give a compound of the formula XVm or salt thereof. >±: (iii) Compounds of the formula VQ and salts thereof as hereinbefore defined may be 25 ?i made by reacting a compound of the formula XIX:

30

(wherein L1 is as hereinbefore defined, and L1 in the 4- and 7- positions may be the same or different) with a compound of formual IV as hereinbefore defined, the reaction for example being effected by a process as described in (a) above.
(iv) A compound of the formula IX may be prepared by the reaction of a compound of 5 the formula V as defined hereinbefore with a compound of the formula XX:
R4-L' (XX)
wherein R4 and L1 are as defined hereinbefore under the conditions described in (b0)
10 hereinbefore to give a compound of the formula IX or salt thereof. 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 in the
range 20-50°C.
15 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, or it may be obtained by reaction of said compound with a base by a conventional procedure.
The identification of compounds which potently inhibit the tyrosine kinase activity 20 associated with the VEGF receptorsfsuch as Fit and/or KDR and which inhibit angiogenesis and/or increased vascular permeability is desirable and is the subject of the present invention. These properties may be assessed for example, using one or more of the procedures set out below:
25 (a) In Vitro Receptor Tyrosine Kinase Inhibition Test
This assay determines the. ability of a test compound to inhibit tyrosine kinase activity. DNA encoding VEGF or epidermal growth factor (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
30 polypeptide with tyrosine kinase-activity. For example VEGF 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 Fit (Genbank

accession number X51602), a 1.7kb 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 exainple pAcYMl (see The Baculovirus Expression System: A 5 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 frugiperda21(Sf21)) with viral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus. (Details of the methods for the - assembly of-recombinant DNA moiecuiesand the'preparation and use of recombinant 10 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) and methionine 668
15 (EGF receptor, Genbank accession number X00588) may be cloned and expressed in a similar manner.
For expression of cFlt tyrosine kinase activity, Sf21 cells were infected with plaque-pure cFlt recombinant virus at a multiplicity of infection of 3 and harvested 48 hours later. Harvested cells were washed with ice cold phosphate buffered saline solution (PBS) (10mM
20 sodium phosphate pH7.4, 138mM sodium chloride, 2.7mM potassium chloride) then
resuspended in ice cold HNTG/PMSF (20mM Hepes pH7.5, 150mM sodium chloride, 10% v/v glycerol, 1% v/v Triton X100, L5mM magnesium chloride, ImM ethylene glycol-bis(Paminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), ImM PMSF (phenylmethylsulphonyl fluoride); the PMSF is added just before use from a freshly-prepared
25 lOOmM solution in methanol) using 1ml 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 (100mM Hepes pH 7.4, 0.2mM sodium orthovanadate, 0.1% v/v Triton X100, 0.2mM dithiothreitol). For a typical batch, stock enzyme is diluted 1 in
30 2000 with enzyme diluent and 50µl of dilute enzyme is used for each assay well.

A stock of substrate solution was prepared from a random copolymer containing tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (Sigma P3899), stored as 1 mg/ml stock in PBS at -20°C and diluted 1 in 500 with PBS for plate coating.
On the day before the assay 100µl of diluted substrate solution was dispensed into all 5 wells of assay plates (Nunc maxisorp 96-well immunoplates) which were sealed and left overnight at 4°C.
On the day of the assay the substrate solution was discarded and the assay plate wells
were washed once with PBST (PBS containing 0.05% v/v Tween 20) and once with 50mM
HepespH7.4.
10 Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25µl of
diluted compound was transferred to wells in the washed assay plates. "Total" control wells contained 10% DMSO instead of compound. Twenty five microlitres of 40mM manganese(IJ.)chloride containing 8uM adenosine-5'-triphosphate (ATP) was added to all test wells except "blank" control wells which contained manganese(II)chloride without ATP. To 15 start the reactions 50ui 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 1 in 6000 with PBST containing 0.5% w/v bovine serum albumin (BSA), was added to each well and the plates were incubated 20 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)-Iinked 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'-25 azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution, freshly prepared using one 50mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50mM phosphate-citrate buffer pH5.0 + 0.03% sodium perborate (made with 1 phosphate citrate buffer with sodium perborate (PCSB) capsule (Sigma P4922) per 100ml distilled water), was added to each well. Plates were then incubated for 20-60 minutes at room temperature until the optical density .30 value of the "total" control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1.0. "Blank" (no ATP) and "total" (no compound) control values were used to determine the dilution range of test compound which gave 50% inhibtion of enzyme activity.

(b) In Vitro HUVEC Proliferation Assay
This assay determines the ability of a test compound to inhibit the growth factor-stimulated proliferation of human umbilical vein endothelial cells (HUVEC).
HUVEC cells were isolated in MCDB 131 (Gibco BRL) + 7.5% v/v foetal calf serum (FCS) and were plated out (at passage 2 to 8), in MCDB 131+ 2% v/v FCS + 3µg/ml heparin + lµg/ml hydrocortisone, at a concentration of 1000 cells/well in 96 well plates. After a minimum of 4 hours they were dosed with the appropriate growth factor (i.e. VEGF 3ng/ml, EGF 3ng/ml or b-FGF 0.3ng/ml) and compound. The cultures were then incubated for 4 days at 37°C withr7.5% carbon dioxide on day the ltures were pulsed with lµ.Ci/well of tritiated-thymidine (Amersham product TRA 61) and incubated for 4 hours. The cells were harvested using a 96-well plate harvester (Tomtek) and then assayed for 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
This test measures the capacity of compounds to inhibit solid tumour growth.
CaLu-6 tumour xenografts were established in the flank of female athymic Swiss nu/nu mice, by subcutaneous injection of 1x10s CaLu-6 cells/mouse in 100p.l 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: (1 x w) x V(l x w) x (TI/6) , where 1 is the longest diameter and w the diameter perpendicular to the longest diameter. 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, and statistical significance determined using a Students' t-test and/or a Mann-Whitney Rank Sum Test. The inhibitory effect of compound treatment was considered significant when p The toxicological profile of compounds of the present invention may be assessed, for example using a rat 14 day study as described hereinafter.

(dl 14 Pay Toxicity Test in Rat
This test measures the activity of compounds in increasing the zone of hypertrophy in
the femoral epiphyseal growth plates of the distal femur and proximal tibia, and allows
assessment of histopathological changes in other tissues.
5 Angiogenesis is an essential event in endochondral ossification during long bone
elongation, and vascular invasion of the growth plate has been suggested to depend upon VEGF production by hypertrophic chondrocytes. Expansion of the hypertrophic chondrocyte zone and inhibition of angiogenesis has been demonstrated following treatment with agents which specifically sequester VEGF, such as, for example, (i) a soluble VEGF receptor
10 chimeric protein (Flt-(l-3)-IgG) in mice (Gerber, H-P., Vu, T.H., Ryan, A.M., Kowalski, J., Werb, Z. and Ferrara, N. VEGF couples hypertrophic cartilage remodelling, ossification and angiogenesis during endochondral bone formation, Nature Med., 5: 623-628, 1999) and (ii) a recombinant humanised anti-VEGF monoclonal IgGl antibody in cynomologus monkey (Ryan, A.M., Eppler, D.B., Hagler, K.E., Bruner, R.H., Thomford, P.J., Hall, R.L., Shopp,
15 G.M. and CNiell, C.A. Preclinical Safety Evaluation of rhuMAbVEGF, an antiangiogenic humanised monoclonal antibody, Tox. Path., 27: 78-86, 1999).
An inhibitor of VEGF receptor tyrosine kinase activity should therefore also inhibit vascular invasion of cartilage, and increase the zone of hypertrophy in the femoral epiphyseal growth plates of the distal femur and proximal tibia in growing animals.
20 Compounds were initially formulated by suspension in a 1% (v/v) solution of
polyoxyethylene (20) sorbitan mono-oleate in deionised water, by ball-milling at 4°C overnight (at least 15 hours). Compounds were re-suspended by agitation immediately prior fo dosing. Young Alderley Park rats (Wistar derived, 135-150g in weight, 4 to 8 weeks of age, 5-6 per group) were dosed once-daily by oral gavage for 14 consecutive days with
25 compound (at 0.25 ml/lOOg body weight) or vehicle. On day 15 animals were humanely
terminated using a rising concentration of carbon dioxide, and a post-mortem performed. A
range of tissues, which included femoro-tibial joints, were collected and processed by
standard histological techniques to produce paraffin wax sections. Histological sections were
. stained with haematoxylin and eosin and examined by light microscopy for histopathology.
30 The femoral epiphyseal growth plate areas of the distal femur and proximal tibia were measured in sections of femur and tibia using morphometric image analysis. The increase in the zone of hypertrophy was determined by comparison of the mean epiphyseal growth plate

area of the control group versus the treatment group, and statistical significance determined using a one-tailed Students' t-test. The inhibitory effect of compound treatment was considered significant when p Although the pharmacological properties of the compounds of Formula I vary with 5 structural change, in general, activity possessed by compounds of the Formula I, may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d):
Test (a):- IC50 in the range, for example, Test (b)> — IG50- in the range, for example, 0.001 - 5µM;
10 Test (c): - activity in the range, for example, 0.1-100mg/kg;
Test (d):- activity in the range, for example, 0. l-100mg/kg.
According to one aspect of the present invention compounds of Formula I, assessed in
the 14 day toxicity test in rat, have a beneficial toxicological profile over other compounds
within the scope of International Patent Application Publication No. WO 98/13354.
15 According to another aspect of the present invention compounds of Formula I,
assessed in the 14 day toxicity test in rat, have a beneficial toxicological profile over other compounds within the scope of International Patent Application Publication No. WO 97/30035.
Although the pharmacological properties of the compounds* of Formula I vary with 20 structural change and between species, at doses in the rat, preferably at doses less than or equal to 150mg/kg, more preferably at doses less than or equal to lOOmg/kg, especially at doses less than or equal to 50mg/kg, compounds of Formula I which produce a statistically significant increase in the femoral epiphyseal growth plate area of the distal femur and/or proximal tibia, produce no unacceptable histopathological changes in other tissues in tests (d) 25 that we have conducted.
Thus by way of example, the compound 4-{4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, (Example 2), tested according to (a), (b), (c) and (d) above gave the following results:
(a) Flt-IC50 of l.6µM
30 KDR-IC50 of 0.04µM
EGFR-IQ50 of 0.5µM
(b) VEGF - IC30 of 0.06µM

EGF-IC50 of 0.017µM Basal-IC50 of >3µM (c) 78% inhibition of tumour growth at 50mg/kg; p 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 10 excipient or carrier.
The composition may be in a form suitable for oral administration, (for example as
tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), for administration by inhalation (for example as a
finely divided powder or a liquid aerosol), for administration by insufflation (for example as a
15 finely divided powder), for parenteral injection (for example as a sterile solution, suspension or
emulsion for intravenous, subcutaneous, intramuscular, intravascular or infusion dosing), for
topical administration (for example as creams, ointments, gels, or aqueous or oily solutions or
suspensions), or for rectal administration (for example as a suppository). In general the above
compositions may be prepared in a conventional manner using conventional excipients.
20 The compositions of the present invention are advantageously presented in unit dosage
form. The compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000mg per square metre body area of the animal, i.e. approximately 0.1-100mg/kg. A unit dose in the range, for example, 1-100mg/kg, preferably l-50mg/kg is envisaged and this normally provides a therapeutically-effective dose. A unit dose form such 25 as a tablet or capsule will usually contain, for example l-250mg of active ingredient.
According to a further aspect of the present invention there is provided a compound of the formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
We have found that compounds of the present invention inhibit VEGF receptor tyrosine 30 kinase activity and are therefore of interest for their antiangiogenic effects and/or their ability to cause a reduction in vascular permeability.

A further feature of the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament, conveniently a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded 5 animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being.
10 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.
15 As stated above the size of the dose required for the therapeutic or prophylactic
treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of l-50mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the
20 illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
The antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may
25 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 treatmenfrto treat each patient with cancer. In medical oncology the other components) of such conjoint treatment in addition to the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be:
30 surgery, radiotherapy or chemotherapy. Such chemotherapy may cover five main categories of therapeutic agent:

(i) other antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example linomide, inhibitors of integrin αvβ3 function, angiostatin, endostatin, razoxin, thalidomide) and including vascular targeting agents (for example combretastatin phosphate and the vascular damaging agents described in International Patent 5 Application Publication No. WO 99/02166 the entire disclosure of which document is incorporated herein by reference, (for example N-acerylcolchinol-O-phosphate));
(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),
10 antiprogestogens, antiandrogenS (for example flutamide, nilutamide, bicalutamide,
cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate,
luprolide, abarelix), inhibitors of testosterone 5a-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
15 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);
(iii) biological response modifiers (for example interferon);
i (iv) antibodies (for example edrecolomab); and
20 (v) 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, dflctmomycin, mithramycin); platinum derivatives (for example 25 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); enzymes (for example asparaginase); thytnidylate synthase inhibitors (for example raltitrexed); topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, 30 amsacrine, topotecan, irinotecan).
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

such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-
ylmethoxy)quinazoline or a salt thereof especially a hydrochloride salt thereof, and a vascular
targeting agent described in WO 99/02166 such as N-acetylcolchinol-O-phosphate (Exampe 1
of WO 99/02166).
5 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,-arteriar restenosis, autoimmune diseases, acute inflammation, 10 excessive scar fonnation 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 15 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.
In another aspect of the present invention compounds of Formula I are expected to inhibit the growm of those primary and recurrent solid tumours which are associated with 20 EGF especially those tumours which are significantly dependent on EGF for their growth and spread.
. In another aspect of the present invention compounds of Formula I are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with both VEGF and EGF especially those tumours which are significantly dependent on VEGF 25 and EGF for their growth and spread.
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, 30 rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
It is to be understood that where the term "ether" is used anywhere in this specification it refers to diethyl ether.

The invention will now be illustrated, but not limited, by the following Examples in which, unless otherwise stated:-
(i) evaporations were carried out by rotary evaporation in vacuo and work-up
procedures were carried out after removal of residual solids such as drying agents by filtration;
5 (ii) operations were carried out at ambient temperature, that is in the range 18-25°C
and under an atmosphere of an inert gas such as argon;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck,T)armstadt, 10 Germany;
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) melting points are uncorrected and were determined using a Mettler SP62
automatic melting point apparatus, an oil-bath apparatus or a Koffler hot plate apparatus.
15 (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; NMR
spectra were run on a 400MHz machine at 24°C.
20 (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;
(viii) the following abbreviations have been used:-
25 DMF N,N-dimethylformamide
DMSO dimethylsulphoxide THF tetrahydrofuran TFA trifluoroacetic acid NMP l-methyl-2-pyrrolidinone.]

Example 1
TFA (3ml) was added to a suspension of 4-(4-bromo-2-fluoroanilino)-7-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (673 mg, 1.2mmol) in methylene chloride (10ml). After stirring for 1 hour at ambient temperature, the volatiles 5 were removed under vacuum. The residue was triturated with a mixture of water/ether. The organic layer was separated. The aqueous layer was washed again with ether. The aqueous layer was adjusted to pHIO with 2N aqueous sodium hydroxide. The aqueous layer was extracted with methylene chloride. The organic layer was dried (MgS04) and the solvent was removed under vacuum. The solid was triturated with a mixture ether/petroleum ether (1/1),
10 filtered, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroaniIino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoIine (390mg, 70.5%). MS-ESI: 461-463 [MH]+
'HNMR Spectrum: (DMSOcQ 1.13-1.3 (m, 2H), 1.75 (d, 2H), 1.87-2.0 (m, 1H), 2.5 (d, 2H), 3.0 (d, 2H), 3.96 (s, 3H), 3.98 (d, 2H), 7.2 (s, 1H), 7.5 (dd, 1H), 7.55 (t, 1H), 7.68 (dd, 1H),
15 7.80 (s, 1H), 8.36 (s, 1H), 9.55 (br s, 1H)
Elemental analysis: Found C 54.5 H 4.9 N 12.1
C21H22N4O2BiF Requires C 54.7 H 4.8 N 12.1%
The starting material was prepared as follows:
20 A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (8.35g,
27.8mmol), (prepared, for example, as described in WO 97/22596, Example 1), and 4-bromo-
2-fluoroaniline (5.65g, 29.7mmol)in2-propanol(200mtywas heated at reflux for 4 hours.
The resulting precipitate was collected by filtration, washed with 2-propanol and then ether
and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2-fluoroaniIino)-6-25 methoxyquinazoline hydrochloride (9.46g, 78%).
'HNMR Spectrum:(DMSOd6; CD3COOD) 4.0(s, 3H); 5.37(s, 2H); 7.35-7.5(m, 4H); 7.52-
7.62(m, 4H); 7.8(d, 1H); 8.14(9s, 1H); 8.79(s, 1H)
MS - ESI: 456 [MH]+
Elemental analysis: Found . C 54.0 H 3.7 N 8.7
30 C22H17N3O2BrF 0.9HCI Requires C 54.2 H 3.7 N 8.6%
A solution of 7-benzyloxy-4-(4-bromo-2- fluroanilino)-6-methoxyqum
hydrochloride (9.4g, 19. lmmol) in TFA (90ml) was heated at reflux for 50 minutes. The

mixture was allowed to cool and was poured on to ice. The resulting precipitate was collected by filtration and dissolved in methanol (70ml). The solution was adjusted to pH9-10 with concentrated aqueous ammonia solution. The mixture was concentrated to half initial volume by evaporation. The resulting precipitate was collected by filtration, washed with 5 water and then ether, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (5.66g, 82%).
'HNMR Spectrum: (DMSOd*; CD3COOD) 3.95(s, 3H); 7.09(s, 1H); 7.48(s, 1H); 7.54(t,
1H); 7.64(d, 1H); 7.79(s, 1H); 8.3l(s, 1H)
•MS-ESI:366[MH]+
10 Elemental analysis: Found C 49.5 H 3.1 N 11.3
C15HnN302BrF Requires C 49.5 H 3.0 N 11.5%
While maintaining the temperature in the range 0-5°C, a solution of di-tert-butyl dicarbonate (41.7g, 0.19moI) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0A9mol) in ethyl acetate (150ml) cooled at 5°C. After 15 stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ml). The organic layer was separated, washed successively with water (200ml), 0.1N aqueous hydrochloric acid (200ml), saturated sodium hydrogen carbonate (200ml) and brine (200ml), dried (MgS04) and evaporated to give ethyl 4-(l-(tert-butoxycarbonyl)piperidine)carboxylate (48g, 98%). 'HNMR Spectrum: (CDC13) 1.25(t, 3H); 1.45(s, 9H); 1.55-1.70(m, 2H); 1.8-2.0(d, 2H);
2.35-2.5(m, 1H); 2.7-2.95(t, 2H); 3.9-4.l(br s, 2H); 4.15 (q, 2H)
A solution of 1M lithium aluminium hydride in THF (133ml, 0.133mol) was added in
portions to a solution of ethyl 4-(l-(tert-butoxycarbonyl)piperidine)carboxylate (48g, 0.19mol) in dry THF (180ml) cooled at 0°C. After stirring at 0°C for 2 hours, water (30ml) 25 was added followed by 2N sodium hydroxide (10ml). The precipitate was removed by
filtration through diatomaceous earth and washed with ethyl acetate. The filtrate was washed with water, brine, dried (MgS04) and evaporated to give l-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (36.3g, 89%). MS (EI): 215 [M.]+ * 30 'HNMR Spectrum: (CDC13) 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^.2(br s, 2H)

l,4-Diazabicyclo[2.2.2]octane (42.4g, 0.378mol) was added to a solution of \-(tert~ butoxycarbonyl)-4-hydroxymethylpiperidine (52.5g, 0.244mol) in tert-butyl methyl ether (525ml). After stirring for 15 minutes at ambient temperature, the mixture was cooled to 5°C and a solution of toluene sulphonyl chloride (62.8g, 0.33mmol) in tert-butyl methyl ether 5 (525ml) was added in portions over 2 hours while maintaining the temperature at 0°C. After stirring for 1 hour at ambient temperature, petroleum ether (II) 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 0.5N aqueous hydrochloric acid (2x500ml), water, saturated-sodium hydrogen carbonate and brine, dried-(MgS04) and evaporated to give
10 l-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (76.7g, 85%). MS (ESI): 392 [MNa]+
'HNMR Spectrum: (CDC13) 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, IH); 4.0-4.2(br s, 2H); 7.35(d, 2H); 7.8(d, 2H)
Potassium carbonate (414mg, 3mmol) was added to a suspension of 4-(4-bromo-2-
15 fluoroanilino)-7-hydroxy-6-methoxyquinazoline(546mg, 1.5mmol) inDMF (5ml). After stirring for 10 minutes at ambient temperature, l-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (636mg,T.72mmol) was added and the mixture was heated at 95°C for 2 hours. After cooling, the mixture was poured onto cooled water (20ml). The precipitate was collected by filtration, washed with water, and dried under
20 vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (665mg, 79%). MS-ESI: 561-563 [MH]+
'HNMR Spectrum: (DMSOdJ 1.15-1.3 (m, 2H)7146 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, IH), 2.65-2.9 (m, 2H), 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, IH), 7.48 (d, IH), 7.55 (t,
25 IH), 7.65 (d, IH), 7.8 (s, IH), 8.35 (s, IH), 9.55 (br s, IH)
Example 2a
A solution of 37% aqueous formaldehyde (50ul, 0.6mmol) followed by sodium cyanoborohydride (23mg, 0.36mmol) were added to a solution of 4-(4-bromo-2-30 fluoroaniImo)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (139mg, 0.3mmol),
(prepared as described in Example 1), in a mixture of THF/methanol (1.4ml/1.4ml). After stirring for 1 hour at ambien"! temperature, water was added and the volatiles were removed

under vacuum The residue was triturated with water, filtered, washed with water, and dried under vacuum. The solid was purified by chromatography on neutral alumina eluting with methylene chloride followed by methylene chloride/ethyl acetate (1/1) followed by methylene chloride/ethyl acetate/methanol (50/45/5). The fractions containing the expected product 5 were evaporated under vacuum. The resulting white solid was dissolved in methylene chloride/methanol (3ml/3ml) and 3N hydrogen chloride in ether (0.5ml) was added. The volatiles were removed under vacuum. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoiy-7-(l-methyIpiperidin-4-ylmethtncy)quiTrazoline hy$fochl6ride^l2©mlgf69%).
10 MS - ESI: 475-477 [MH]+
The NMR spectrum of the protonated form of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride shows the presence of 2 forms A and B in a ratio A:B of approximately 9:1. 'H NMR Spectrum: (DMSOd6; CF^COOD) 1.55-1.7 (m, form A 2H) ; 1.85-2.0 (m, form B
15 4H) ; 2.03 (d, form A 2H) ; 2.08-2.14 (br s, form A IH) ; 2.31-2.38 (br s, form B IH) ; 2.79
(s, form A 3H) ; 2.82 (s, form B 3H) ; 3.03 (t, form A 2H) ; 3.21 (br s, form B 2H) ; 3.30 (br
s, form B 2H) ; 3.52 (d, form A 2H) ; 4.02 (s, 3H) ; 4.12 (d, form A 2H) ; 4.30 (d, form B
2H) ; 7.41 (s, IH) ; 7.5-7.65 (m, 2H) ; 7.81 (d, IH) ; 8.20 (s, IH) ; 8.88 (s, IH)
Elemental analysis: Found C 46.0 H 5.2 N 9.6
20 C22H24N4O2BrF 0.3H2O 2.65HC1 Requires C 45.8 H 4.8 N' 9.7%
Example 2b
37% Aqueous formaldehyde (3.5ml, 42mmol) was added to a solution of 4-(4-bromo-2-fluoroanilino)-7-(l-(tert-butoxycaihonyl)piperidm-4-ylmemoxy)-6-inethoxyquinazoline
25 (3.49g, 6.22mmol), (prepared as described for the starting material in Example 1), in formic acid (35ml). After heating at 95°C for 4 hours the volatiles were removed under vacuum. The residue was suspended in water and the mixture was adjusted to pH10.5 by slow addition of a solution of 2N sodium hydroxide. The suspension was extracted with etiiyl acetate. The organic layer was washed with brine, dried MgS04 and evaporated to give 4-(4-bromo-2-
30 fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmetIioxy)quiaazoline (2.61g, 88%). MS - ESI: 475-477 [MH]+

'H NMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, 1H), 1.95 (t, 2H),
2.2 (s, 3H), 2.85 (d, 2H), 3.96 (s, 3H), 4.05 (d, 2H), 7.19 (s, 1H), 7.5 (d, 1H), 7.55 (t, 1H),
7.67 (d, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 9.54 (s, 1H)
Elemental analysis: Found C 55.4 H 5.1 N 11.6
5 C22H24N402BrF Requires C 55.6 H 5.1 N 11.8%
Example 2c
A suspension of 4-chloro-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline
0.62mmol)-and 4-bromo-2-fluoroaniline (142mg, 0.74mmol) in isopropanol^ ml) ~
10 containing 6N hydrogen chloride in isopropanol (110ul, 0.68ml) was heated at reflux for 1.5
hours. After cooling, the precipitate was collected by filtration, washed with isopropanol
followed by ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-
7-(l-methyipiperidin-4-ylmetboxy)quinazoline hydrochloride (304mg, 90%).
Elemental analysis: Found C 47.9 H 4.9 N 10.0
15 C22H24N4O2BrFO.5H2Ol.8HCl Requires C 48.2 H 5.0 N 10.1%
0.08 isopropanol
The NMR spectrum of the protonated form of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidih-4-ylmethoxy)quinazoline hydrochloride shows the presence of two forms A and B in a ratio A:B of approximately 9:1.
20 'H NMR Spectrum: (DMSOd6) 1.6-1.78 (m, form A 2H); 1.81-1.93 (br s, form B 4H); 1.94-2.07 (d, form.A 2H); 2.08-2.23 (br s, form A 1H); 2.29-2.37 (br s, form B 1H); 2.73 (d, form A 3H); 2.77 (d, form B 3H); 2.93-3.10 (q, form A 2H); 3.21 (br s, form B 2H); 3.27 (br s, form B 2H);3-42-3.48 (d, form A 2H); 4.04 (s, 3H); 4.10 (d, form A 2H); 4.29 (d, form B 2H); 7.49(s, 1H) ; 7.53-7.61 (m, 2H); 7.78 (d, 1H); 8.47 (s, 1H); 8.81 (s, 1H); 10.48 (br s,
25 form A 1H); 10.79 (br s, form B 1H); 11.90 (br s, 1H)
'tFor another NMR reading, some solid potassium carbonate was added into the DMSO solution^of the 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1 -methy lpiperidin-4-ylmethoxy)quinazoline hydrochloride described above, in order to release the free base in the NMR tube. The NMR spectrum was then recorded again and showed only one form as
30 described below:

'HNMR Spectrum: (DMSOd6; solid potassium carbonate) 1.3-1.45 (m, 2H); 1.75 (d, 2H);
1.7-1.9(m, IH) ; 1.89 (t, 2H) ; 2.18 (s, 3H) ; 2.8 (d, 2H) ; 3.98 (s, 3H); 4.0 (d, 2H) ; 7.2 (s,
IH); 7.48 (d, IH); 7.55 (t, IH) ; 7.68 (d, IH); 7.8 (s, IH); 8.35 (s, IH) ; 9.75 (s, IH) A sample of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-5 ylmethoxy)quinazoline (free base) was generated from the 4-(4-bromo-2-fluoroanilino)-6-
methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride, (prepared as
described above), as follows:
4-(4-Bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-
ylmemoxyquinazoline-hydrocloride (50g) was suspended in methylene chloride (2ml) and
10 was washed with saturated sodium hydrogen carbonate. The methylene chloride solution was
dried (MgS04) and the volatiles were removed by evaporation to give 4-(4-bromo-2-
fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (free base). The
NMR of the free base so generated shows only one form as described below:
'HNMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H) ; 1.76 (d, 2H) ; 1.7-1.9(m, IH) ; 1.9 (t, 2H); 15 2.19 (s, 3H); 2.8 (d, 2H) ; 3.95 (s, 3H) ; 4.02 (d, 2H); 7.2 (s, IH); 7.48 (d, IH) ; 7.55 (t, IH)
; 7.68 (dd, IH) ; 7.8 (s, IH) ; 8.38 (s, IH) ; 9.55(br s, IH)
For another NMR reading, some CF3COOD was added into the NMR DMSO solution
of the 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4-
ylmethoxy)quinazoline (free base) described above and the NMR spectrum was recorded 20 again. The spectrum of the protonated form of the 4-(4-bromo-2-fiuoroanilino)-6-methoxy-
7-(l-methylpiperidin-4-ylmethoxy)quinazoline trifluoroacetate salt so obtained shows the
presence of two forms A and B in a ratio A:B of approximately 9:1.
'H NMR Spectrum: (DMSOd*; CF3COOD) 1.5-1.7 (m, form A 2H); 1.93 (br s, form B 4H);
2.0-2.1 (d, form A 2H); 2.17 (br s, form A IH); 2.35 (br s, fomrBlH); 2.71 (s, form A 3H); 25 2.73 (s, form B 3H); 2.97-3.09 (t, form A 2H); 3.23 (br s, form B 2H); 3.34 (br s, form B
2H); 3.47-3.57 (d, form A 2H); 4.02 (s, 3H); 4.15 (d, form A 2H); 4.30 (d, form B 2H); 7.2
(s, IH); 7.3-7.5 (m, 2H); 7.6 (d, IH); 7.9 (s, IH); 8.7 (s, IH)
The starting material was prepared as follows:
30 /--(tert-Butoxycarbonyl)-4-(4-methylphnylsulphonyloxymethyl)piperidine (40g,
0.1 lmol), (prepared as described for the starting material in Example 1), was added to a suspension of ethyl 4-hydroxy-3-methoxybenzoate (19.6g, 0.1mol) and potassium carbonate

(28g, 0.2mol) in dry DMF (200ml). 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 (MgS04) and evaporated. The resulting oil was crystallised from petroleum ether and the suspension was stored overnight at 5°C. The 5 solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 4-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-3-methoxyben2oate (35g, 89%). m.p. 81-83°C MS (ESI): 416 [MNaf - 'H NMR-Spectrum: {CDG13> 1.2-1.35(m, 2H); 1.4(t, 3H)rl48(s; ?H); 1.8-1.9(d, 2H); TXF1^
10 2.15(m, 2H); 2.75(t, 2H); 3.9(d, 2H); 3.95(s, 3H); 4.05-4J25(br s, 2H); 4.35(q, 2H); 6.85(d, 1H); 7.55(s, 1H); 7.65(d, 1H)
Elemental analysis: Found C 63.4 H 8.0 N 3.5
C21H31N06 0.3H2O Requires C 63.2 H 8.0 N 3.5%
Formaldehyde (12M, 37% in water, 35ml, 420mmol) was added to a solution of ethyl
15 4-(l-(tert-butoxycarbonyl)piperidin-4-ylmemoxy)-3-methoxybenzoate (35g, 89mmol) in formic acid (35ml). 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 (40ml, 120mmol) 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
20 vacuum overnight at 50°C to give ethyl 3-methoxy-4-(l-methylpiperidin-4-ylmethoxy)benzoate (30.6g, quant). MS (ESI): 308 [MFfT
'HNMR Spectrum: (DMSOd6) 1.29(1, 3H); 1.5-1.7(m, 2H); 1.95(d, 2H); 2.0-2.15(brs, 1H); 2.72(s, 3H); 2.9-3.l(m, 2H); 3.35-3.5(br s, 2H); 3.85(s, 3H); 3.9-4.05(br s, 2H); 4.3(q, 2H);
25 7.1(d, 1H); 7.48(s, 1H); 7.6(d, 1H)
A solution of ethyl 3 -methoxy-4-( 1 -methy lpiperidin-4-ylmethoxy)benzoate (3 0. 6g, 89mmol) in methylene chloride (75ml) was cooled to 0-5°C. TFA (37.5ml) was added followed by the drop wise addition over 15 minutes of a solution of fuming 24N nitric acid (7.42ml, 178mmol) in methylene chloride (15ml). After completion of the addition, the
30 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 (50ml). 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 (500ml) and 3M hydrogen chloride in ether (30ml) was added followed by ether (500ml). The solid was collected by filtration and dried under vacuum at 50°C to give ethyl 3-methoxy-4-(l-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4g, 82%). 5 MS (ESI): 353 [MH]+
'H NMR Spectrum: (DMSOdJ 1.3(t, 3H); 1.45-1.65(m, 2H); 1.75-2.l(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, IH); 7.66(s, 1H)
A suspension of ethyl 3-methoxy-4-( 1 -methylpiperidin-4-ylmethoxy)-6-nitrobenzoate 10 (3.89g, lOmmoI) in methanol (80ml) containing 10% platinum on activated carbon (50% wet) (389mg) 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 (30ml) and adjusted to pHIO 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
15 aqueous layer was further extracted with ethyl acetate/ether and the organic layers were combined. The organic layers were washed with water, brine, dried (MgS04), 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-(l-methylpiperidin-4-ylmethoxy)benzoate (2.58g, 80%).
20 m.p. 111-112°C
MS (ESI): 323 [MHf
'H NMR Spectrum: (CDC13) 1.35(t*3H); 1.4-1.5(m, 2H); l,85(m, 3H); 1.95(t, 2H); 2.29(s,
3H); 2.9(d, 2H); 3.8(s, 3H); 3.85(d, 2H)r4.3(q, 2H); 5.55(brs, 2H); 6.13(s, IH); 7.33(s, IH)
Elemental analysis: Found C 62.8 H 8.5 N 8.3
25 C12H26N2O4 0.2H2O Requires C 62.6 H 8.2 N 8.6%
A solution of ethyl 6-ammo-3-memoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1g, 50mmol) in 2-methoxyethanol (160ml) containing formamidine acetate (5.2g, 50mmol) was heated at 115°C for.2 hours. Formamidine acetate (10.4g, lOOmmol) was added in portions every 30 minutes over 4 hours. Heating was prolonged for 30 minutes after
30 the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100ml) and methylene chloride (50ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100ml. 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-(l-methylpiperidin-4-
ylmethoxy)-3,4-dihydroquinazolin-4-one (12.7g, 70%).
MS (ESI): 304 [MH]+ 5 'HNMR Spectrum: (DMSOd6) 1.25-1.4(m, 2H); 1.75(d, 2H); 1.9(t, IH); 1.9(s, 3H); 2.16(s,
2H); 2.8(d, 2H); 3.9(s, 3H); 4.0(d, 2H); 7.11(s, IH); 7.44(s, IH); 7.97(s, IH)
A solution of 6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)-3,4-dihydroquinazolin-
4-one (2.8g, 9.24mmol) in thionyl chloride (28ml) containing DMF (280fi.l) was heated at
reflux at 85DC for 1-hour. After-cooling, thevolatrles wereremovedisy evaporation The 10 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 (MgS04) and
evaporated to give 4-chloro-6-methoxy-7-(l-methylpiperidin^-ylmethoxy)quinazoline (2.9g,
98%). 15 MS (ESI): 322 [MH]+
'HNMR Spectrum: (DMSOd6 1.3-1.5(m, 2H); 1.75-1.9(m, 3H); 2.0(1, IH); 2.25(s, 3H);
2.85(d, 2H); 4.02(s, 3H); 4.12(d, 2H); 7.41(s, IH); 7.46(s, IH); 8.9(s, IH)
Alternatively, the 6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)-3,4-20 dihydroquinazolin-4-one can be prepared as follows:
Sodium hydride (1.44g of a 60% suspension in mineral oil, 36mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46g, 30mmol), (prepared, for example, as described in WO 97/22596, Example 1), in DMF (70ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65g,
25 37.5mmol) was added in portions and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100ml) and poured onto ice/water (400ml) and 2N hydrochloric acid (4ml). Ths organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgS04) and the solvent removed by evaporation. The residue was triturated with a mixture of ether and
30 petroleum elbej; the solid was collected by filtration and dtied under vacuum to give 7-benzyloxy-6-memoxy-3-((pivaloyloxy)memyl)-3,4-ihydroquinazolin-4-one(10g, 84%) -

'HNMR Spectrum: (DMSOd6) 1.1 l(s, 9H); 3.89(s, 3H); 5.3(s, 2H); 5.9(s, 2H), 7.27(s, IH); 7.35(m, IH); 7.47(t, 2H); 7.49(d, 2H); 7.5l(s, IH); 8.34(s, IH)
A mixture of 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7g, 17.7mmol) and 10% palladium-on-charcoal catalyst (700mg) in 5 ethyl acetate (250ml), DMF (50ml), methanol (50ml) and acetic acid (0.7ml) 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 (4.36g, 80%).
10 'HNMR Spectrum: (DMSOd6) l.l(s, 9H); 3.89(s, 3H); 5.89(s, 2H); 7.0(s, IH); 7.48(s, IH); 8.5(s, IH)
Triphenylphosphine (1.7g, 6.5mmol) was added under nitrogen to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.53g, 5mmol) in methylene chloride (20ml), followed by the addition of l-(tert-butoxycarbonyl)-4-15 (hydroxymethyl)piperidine (1.29g, 6mmol), (prepared as described for the starting material in Example 1), and by a solution of diethyl azodicarboxylate (1.13g, 6.5mmol) in methylene chloride (5ml). After stirring for 30 minutes at ambient temperature, the reaction mixture was poured onto a column of silica and was eluted with ethyl acetate/petroleum ether (1/1 followed by 6/5, 6/4 and 7/3). Evaporation of the fractions containing the expected product 20 led to an oil that crystallised following trituration with pentane. The solid was collected by filtration and dried under vacuum to give 7-(l-(fer/-butoxycarbonyl)piperi$n-4-ylmethoxy)-
6-meftoxy-3-pivaloyloxy)memyl)-3,4-dihydroquina2x)lin-4-one (232g, 92%).
MS - ESI: 526 [MNaf
'HNMR Spectrum: (CDC13) 1.20 (s, 9H), 1.2-1.35 (m, 2H), 1.43 (s, 9H), 1.87 (d, 2H), 2.05-25 2.2 (m, IH), 2.75 (t, 2H), 3.96 (d, 2H), 3.97 (s, 3H), 4.1-4.25 (br s, 2H), 5.95 (s, 2H), 7.07 (s, lH),7.63(s, IH), 8.17 (s, IH)
Elemental analysis: Found C 61.8 H 7.5 N 8.3
C26H37N3O7 - Requires C 62.0 H 7.4 N 8.3%
A solution of 7-(l*(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-3-30 ((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.32g, 4.6mmol) in methylene chloride (23ml) cdhtaining-TFA (5ml) was stirred at ambient temperature for 1 hour. The volatiles

were removed under vacuum, the residue was partitioned between ethyl acetate and sodium hydrogen carbonate. The organic solvent was removed under vacuum and the residue was filtered. The precipitate was washed with water, and dried under vacuum. The solid was azeotroped with toluene and dried under vacuum to give 6-methoxy-7-(piperidin-4-5 ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.7g, 92%). MS - ESI: 404 [MH]+
'HNMR Spectrum: (DMSOd6; CF3COOD) 1.15 (s, 9H), 1.45-1.6 (m, 2H), 1.95 (d, 2H), 2.1-
2.25 (m, 1H), 2.95 (t, 2H), 3.35 (d, 2H), 3.95 (s, 3H), 4.1 (d, 2H), 5.95 (s, 2H), 7.23 (s, 1H),
7.54 (s, 1H), 8.45 (s, 1H)
10 A 37% aqueous solution 0f formaldehyde (501 ul, 6mmoI) followed by sodium
cyanoborohydride (228mg, 3.6%mol) were added in portions to a solution of 6-methoxy-7-(piperidin-4-ylmethoxy)-3((pivaloyioxy)methy) -3,4-dihydroquinazolin-4-one (l.251g, 3mmol) in a mixture of THF/methanol (lOml/lOml). After stirring for 30 minutes at ambient temperature, the organic solvent were removed under vacuum and the residue was 15 partitioned between methylene chloride and water. The organic layer was separated, washed with water and brine, dried (Mgso4) and the volatiles were removed by evaporation. The residue was triturated with ether and the resulting solid was collected by filtration, washed with ether and dried under vacuum to give 6-memoxy-7-(l-methylpiperidin--4-ylmethoxy)-3-
((pivaloyloxy)methyl)-3,4-dihy%0quinazolin-4-one (1.02g, 82%). 20 MS-ESI:418[MH]+
'H NMR Spectrum: (CDC13) U9 (S, 9H), 1.4-1.55 (ra, 2H), 1.9 (d, 2H), 2.0 (t, 2H), 1.85-2.1 (m, 1H), 2.3 (s, 3H), 2.92 (d, 2H) 3.96 (S, 3H), 3.99 (d, 2H), 5.94 (s, 2H), 7.08 (s, 1H), 7.63 (S,1H),8.17(S,1H)
A saturated solution of ammonia in methanol (14ml) was added to a solution of 6-25 methoxy-7-(l-methylpiperidin-4-yimethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.38g, 3.3mmol) in methanol (5ml). After stirring for 20 hours at ambient temperature, the suspension was diluted with methylene chloride (10ml). The solution was filtered. The filtrate was evaporated under vacuum and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(l -
30 methylpiperidin-4-ylmethoxy)-3,4.dihydroquinazolin-4-one (910mg, 83%). MS-ESI:304[MH]+

'HNMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.75 (d, 2H), 1.7-1.85 (m, 1H), 1.9 (t, 2H), 2.2 (s, 3H), 2.8 (d, 2H), 3.9 (s, 3H), 4.0 (d, 2H), 7.13 (s, 1H), 7.45 (s, 1H), 7.99 (s, 1H)
Example 3a
5 3.5M Hydrogen chloride in ethanol (75µl, 0.26mmol) was added to a suspension of 4-
chloro-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (80mg, 0.25mmol), (prepared as described for the starting material in Example 2c), in isopropanol (3 ml), the mixture was heated to 50°C and 4-chloro-2-fluoroaniline (44mg, 0.3mmol) was added. The
- mixture was heated at reflux for 30 minutes. After cooling, the mixture was diluted with
10 ether (3ml). The precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoiy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (105mg, 82%). MS-ESI: 431-433 [MH]+
The NMR spectrum of the protonated form of 4-(4-chloro-2-fluoroaniIino)-6-
15 methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride shows the presence of two forms A and B in a ratio A:B of approximately 9:1.
'HNMR Spectrum: (DMSOd6; CF3COOD) 1.55-1.7 (m, form A2H), 1.85-2.0 (m, form B 4H), 2.05 (d, form A 2H), 2.1-2.2 (m, form A 1H), 2.35 (s, 3H); 2.79 (s, form A 3H), 2.82 (s, form B 3H), 3.03 (t, form A 2H), 3.2-3.3 (m, form B 2H); 3.3-3.4 (m, form B 2H), 3.52 (d,
20 form A 2H), 4.02 (s, 3H) 4.13 (d, form A 2H), 4.3 (d, form B 2H), 7.41 (s, 1H), 7.47 (dd,
1H), 7.63 (t, 1H), 7.69 (dd, 1H), 8.19 (s, 1H), 8.88 (s, 1H)
Elemental analysis: Found C 51.8 H 5.6 N 10.9
C22H24N4O2CIF 0.04H2O 2HCIRequires C 51.7 H 5.3 N 11.0%
25 Example 3b
An alternative method of preparation is as follows:
Triphenylphosphine (6l5mg, 2.3mmol) followed by diethyl azodicarboxylate (369ul, 2.3mmol) were added to a solution of 4-hydroxymethyl-l-methylpiperidine (151mg, l.lmmol), (JMed. Chem 1973, 16, 156), and 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-30 methoxyqitiaazoline (250aig, 0.78mmol), (prepared as described for the startiag material in Example 7), in methylene chloride (5ml). After stirring for 30 minutes at ambient temperature, 4-hydroxymethyl-l-methylpiperidine (51mg, 0.39mmol), triphenylphosphine

(102mg, 0.39mmol) and diethyl azodicarboxylate (61 ul, 0.39mmol) were added. After stirring for 15 minutes, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (70/10/20 followed by 75/5/20 and 80/0/20). The fractions containing the expected product 5 were combined and the volatiles were removed by evaporation. The residue was dissolved in a mixture of methylene chloride and methanol and 5M hydrogen chloride in isopropanol was added. The suspension was concentrated and the solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chIoro-2-fluoroaniIino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoltne hydrochloride (16mg7 4%).
10
Example 4
Under argon, sodium hydride (60%, 372mg, 9.3mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (1.67g, 8.08mmol) in DMF. After stirring for 30 minutes at ambient temperature, 4-chloro-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline
15 (1.3g, 4.04mmol) was added and stirring was continued for a further 20 hours. The mixture was poured onto water (130ml) and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (MgS04) and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica, eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol containing ammonia (1%)
20 (90/10). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 50°C to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoIine (1.4g, 70%). MS-ESI: 493-495 [MH]+
25 'H NMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, 1H), 1.9 (t, 2H), 2.17 (s, 3H), 2.8 (d, 2H), 3.95 (s, 3H), 4.02 (d, 2H), 7.2 (s, 1H), 7.63 (S; 1H), 7.6 (s, 1H), 7.82 (s, 1H), 8.35 (s, 1H)
Elemental analysis: Found C 53.8 H 4.8 N 11.3
C22H23N402BrF2 Requires C 53.6 H 4.7 N 11.4%

Example 5
Using an analogous procedure to that described in Example 4, 4-chloro-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (246mg, 0.764mmol), (prepared as described for the starting material in Example 2c), was reacted with 4-chloro-2,6-difluoroaniline 5 (250mg, 1.53mmol), (see WO 97/30035 Example 15), in DMF (9ml) and in the presence of sodium hydride (60%, 76.5mg, 1.9mmol) to give 4-(4-chloro-2,6-difluoroaiulino)-6-methoxy-7-(l-methyIpiperidin-4-yImethoxy)quinazoIine(210mg, 61%). MS-ESI: 449-451{MH]+
"~'H NMR Spectrum (DMS0d6) 1.3-1.45 (m~ 2H), 1.8 (d, 2H), 1.7-1.9 (m, IH), 1.9 (t 2H), 10 2.2 (s, 3H), 2.8 (d, 2H), 3.96 (s, 3H), 4.02 (d, 2H), 7.21 (s, IH), 7.52 (s, IH), 7.54 (s, IH), 7.82 (s, IH), 8.35 (s, IH)
Elemental analysis: Found C 59.0 H 5.3 N 12.5
C22H23N4O2ClF2 Requires C 58.9 H 5.2 N 12.5%
15 The starting material was prepared as follows:
4-Chloro-2,6-difluoroaniline hydrochloride (see WO 97/30035 Example 15) was partitioned between methylene chloride and water and aqueous sodium hydrogen carbonate was added until the pH of the aqueous layer was approximately 9. The organic layer was separated, washed with brine, dried (MgS04) and evaporated to give 4-chloro-2,6-
20 difluoroaniline free base.
Example 6
A suspension of 4-chloro-6-methoxy-7-(l-methyIpiperidin-4-ylmethoxy)quinazoline (200mg, 0.622mmol)j (prepared as described for the starting material in Example 2c) and 2-
25 fluoro-4-methylaniline (94mg, 0.764mmol) in isopropanol (5ml) containing 6.2M hydrogen chloride in isopropanol (1 lOul) was stirred at 80°C for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum. The solid was purified by column chromatography, eluting with methylene chloride/methanol (90/10) followed by 5 % ammonia in methanol/methylene chloride
30 (10/90). Evaporation of the fractions containing the expected product gave 4-(2-ftuoro-4-methy!anilino)-6-methoxy-7-{l-methylpiperidin-4-ylniethoxy)quinazoIine (170mg, 61%). MS-ESI:411[MH]+

'HNMR Spectrum: (DMS0d6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, IH), 1.9 (t, 2H),
2.2 (s, 3H), 2.35 (s, 3H), 2.8 (d, 2H), 3.95 (s, 3H), 4.01 (d, 2H), 7.1 (d, IH), 7.13 (d, IH),
7.16 (s, IH), 7.4 (t, IH), 7.81 (s, IH), 8.32 (s, IH), 9.4 (s, IH)
Elemental analysis: Found C 66.5 H 6.7 N 13.7
5 C23H27N4O2F 0.3H2O Requires C 66.4 H 6.7 N 13.5%
Example 7
l-tert-Butoxycarbonyl-4-hydroxymethylpiperidine (590mg, 2.75mmoI), (prepared as
described for the starting-material in Example'l), followed by triphenylphosphine (1.2g, 10 4.58mmol) and diethyl azodicarboxylate (0.72ml, 4.58mmol) were added to a solution of 4-
(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (585mg, 1.83mmol) in
methylene chloride (20ml). After stirring for 1 hour at ambient temperature, further
triphenylphosphine (239mg, 0.91mmol) and diethyl azodicarboxylate (0.14ml, 0.91mmol)
were added. After stirring for 1.5 hours, the volatiles were removed under vacuum and the 15 residue was purified by column chromatography eluting with ethyl acetate/methylene chloride
(1/1). The crude product was used directly in the next step.
A solution of the crude product in methylene chloride (15ml) containing TFA (4.5ml)
was stirred at ambient temperature for 1.5 hours. The volatiles were removed under vacuum.
The residue was partitioned between water and ethyl acetate. The aqueous layer was adjusted 20 to pH9.5 with 2N sodium hydroxide. The organic layer was separated, washed with water,
followed by brine, dried (MgS04) and evaporated to give 4-(4-chloro-2-fluoroanilino)-6-
methoxy-7-(piperidin-4~yImethoxy)quinazoiiiie.
MS -ESI: 417-419 [MHf
'H NMR Spectrum: (DMSOd6) 1.1-1.3 (m, 2H), 1.75 (d, 2H), 1.85-2.0 (br s, IH), 2.55 (d, 25 2H), 2.95 (d, 2H), 3.95 (s, 3H), 4.0 (d, 2H), 7.2 (s, IH), 7.35 (dd, IH), 7.55 (dd, IH), 7.6 (t,
IH), 7.8 (s, IH), 8.35 (s, IH), 9.55 (s, IH)
The hydrochloride salt was made as follows:
4-(4-Chloro-2-fluoroanilino)-6-memoxy-7-(piperidin-4-ylmethoxy)quinazoline was 30 dissolved in a mixture of methanol/methylene chloride and 6M hydrogen chloride in ether was added. The volatiles were removed under vacuum, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-

fluoro)-6-methoxy-7-(piperidin-4-yImethoxy)quinazoIine hydrochloride (390mg, 47%
over 2 steps).
Elemental analysis: Found C 50.4 H 5.2 N 11.0
C21H22O2N4CIF 2.25HC1 Requires C 50.6 H 4.9 N 11.2%
5
The starting material was prepared as follows:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.2g,
4mmol), (prepared as described in WO 97/22596, Example 1), and 4-chloro-2-fluoroaniline
(444µl 4mmol) in 2-propanol (40ml) was heated at reflux for 1.5 hours. After cooling, the 10 precipitate was collected by filtration, washed with 2-propanol then ether and dried under
vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline
hydrochloride (1.13g, 64%).
m.p. 239-242°C
'HNMR Spectrum: (DMSOd6) 4.0(s, 3H); 5.36(s, 2H); 7.39-7.52(m, 9H); 8.1(s, 1H); 8.75(s, 15 1H)
MS-ESI:410[MH]+
Elemental analysis: Found C 59.2 H 4.3 N 9.4
C22H17N3O2 1HC1 Requires C 59.2 H 4.1 N 9.4%
A solution of 7-benzyloxy-4-(4-chloro-2-fIuoroanilino)-6-methoxyquinazoline 20 hydrochloride (892mg, 2mmol) in TFA (10ml) was heated at reflux for 50 minutes. After
cooling, the mixture was poured onto ice. The precipitate was collected by filtration,
dissolvedin methanol (10ml) and basified to pHl 1 with aqueous ammonia. After
concentration by evaporation, the solid product was collected by filtration, washed with water
then ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-25 methoxyquinazoline as a yellow solid (460mg, 72%),
m.p. 141-143°C
MS - ESI: 320-322 [MH]+
'HNMR Spectrum: (DMSOd6) 3.95(s, 3H); 7.05(s, 1H); 7.35(d, 1H); 7.54-7.59(m, 2H);
7.78(s, IB); 8.29(s, 1H)

Example 8
A suspension of 7-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (318mg, 0.64mmol) in methylene chloride (5ml) containing TFA (2.5ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH10-l 1. The organic layer was separated, washed with water, brine, dried (MgS04) and the volatiles were removed by evaporation to give 4-(2-fluoro-4-methylaniIino)-6-methoxy-7-(piperidin-4-ylinethoxy)quinazoIine(220mg, 87%). MS.-. ESI: 397 [MH]+
'HNMR Spectrum: (DMSOd6) 1.15-1.3 (m, 2H); 1.75 (d, 2H); 1.85-2.0 (m, IH); 2.4 (s, 3H); 3.0 (d, 2H); 3.3-3.4 (d, 2H); 3.95 (s, 3H); 4.0 (d, 2H); 7.04 (d, IH); 7.15 (d, IH); 7.17 (s, IH); 7.4 (t, IH); 7.8 (s, IH); 8.3 (s, IH); 9.4 (s, IH)
The starting material was prepared as follows:
Using an analogous procedure to that described in Example 6, 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.55g, 5.15mmol), (prepared, for example, as described in WO 97/22596, Example 1), was reacted with 2-fluoro-4-methylaniline (700mg, 5.67mmol) in isopropanol (90ml) containing 6.2M hydrogen chloride in isopropanol (80µl, 0.51mmol) to give 7-benzyloxy-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline
20 hydrochloride (2g, 91%). MS - ESI: 390 [MH]+
'H NMR Spectrum: (DMSOd.0 2.4 (s, 3H), 4.01~(s, 3H), 7.15 (d, IH), 7.25 (d, IH), 7.35-7.6 (m, 7H), 8.3 (s, IH), 8.78 (s, IH)
A solution of 7-benzyloxy-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline
25 hydrochloride (2g, 4.7mmol) in TFA (20ml) was heated at 80°C for 5 hours and stirred at ambient temperature overnight. The volatiles were removed under vacuum and the residue was suspended in water (50ml). Solid sodium hydrogen carbonate was added until the pH • was approximately 7. The precipitate was then collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with
30 methanol/methylene chloride (5/95). After removal of the solvent by evaporation, the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(2-fluoro-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (1.04g, 74%).

MS-ESI:300[MH]+
'HNMR Spectrum: (DMSOd6) 2.4 (s, 3H), 4.0 (s, 3H), 7.15 (d, IH), 7.22 (s, IH), 7.25 (d,
IH), 7.41 (t, IH), 8.05 (s, IH), 8.7 (s, IH), 11.0 (s, IH), 11.5-11.8 (br s, IH)
Triphenylphosphine (2.19g, 8.36mmol) was added to a suspension of 4-(2-fluoro-4-5 methylanilino)-7-hydroxy-6-methoxyquinazoline (lg, 3.34mmol) in methylene chloride (10ml) cooled at 0°C, followed by l-(tert-butoxycarbonyI)-4-hydroxymethylpiperidine (1.08g, 5.01mmol), (prepared as described for the starting material in Example 1), and diethyl azodicarboxylate (1.31ml, 8.36mmol). After stirring for 2 hours at ambient temperature, the voiatrlesnvere removed under vacuum. The residue was purified by column chromatography
10 eluting with methylene chloride/methanol (2/98). After removal of the solvent by
evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(l-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (327mg, 20%). MS - ESI: 497 [MH]+
15 'HNMR Spectrum: (DMSOd6) 1.15-1.3 (m, 2H); 1.45 (s, 9H); 1.8 (d, 2H); 2.0-2.1 (m, IH); 2.4 (s, 3H); 2.75-2.9 (br s, 2H); 3.95 (s, 3H); 4.0 (br s, 2H); 4.05 (d, 2H); 7.1 (d, IH); 7.15 (d, IH); 7.2 (s, IH); 7.4 (t, IH); 7.85 (t, IH); 8.32 (s, IH); 9.45 (s, IH)
Example 9
20 A solution of 4-(4-bromo-2,6-difluoroanilino)-7-(l-(tert-butoxycarbonyl)piperidin-4-
ylmethoxy)-6-methoxyquinazoline (578mg, lmmol) in methylene chloride (10ml) containing TFA (4ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was suspended in water. The aqueous layer was adjusted to approximately pHIO and was extracted with methylene chloride. The organic layer was
25 washed with water, brine, dried (MgS04) and the volatiles were removed by evaporation. The residue was triturated with ether and dried under vacuum to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)qiiinazoline (1 lOmg, 23%). MS - ESI: 479-481 [MH]+ 'HNMR Spectrum: (DMSOd,) 1.15-1.3 (m, 2H); 1.75 (d, 2H) ; 1.85-2.0 (brs, IH) ; 2.5 (d,
30 2H) ; 3:0 (d, 2H) ; 3.97 (s, 3H) ; 4.0 (d, 2H) ; 7.2 (s, IH) ; 7.62 (d, 2H) ; 7.82 (s, IH) ; 8.35 (s, IH)

'HNMR Spectrum: (DMSOd6; CF3COOD) 1.5-1.65 (m, 2H) ; 2.0 (d, 2H) ; 2.15-2.3 (br s, 1H); 3.0 (t, 2H); 3.4 (d, 2H) ; 4.02 (s, 3H) ; 4.15 (d, 2H) ; 7.4 (s, 1H) ; 7.75 (d, 2H); 8.1 (s, 1H); 8.92 (s, 1H)
5 The starting material was prepared as follows:
Sodium hydride (60%, 6l2mg, 15.3mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (2.77g, 6.65mmol) in DMF (80ml). After stirring for 30 minutes at ambient temperature, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2g, 6.65mmol), (prepared, for example, as described in W0 97/22596;-Example 1, but the free base was generated prior to
10 use), was added and stirring was maintained for 4 hours. The mixture was partitioned between ethyl acetate and water (200ml). The organic layer was separated, washed with water, brine, dried (MgS04) and the volatiles were removed by evaporation. The residue was triturated with isopropanol, collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline (1.95g, 62%).
15 MS -ESI: 472-474 [MH]+
'HNMR Spectrum: (DMSOd6) 3.94 (s, 3H), 5.3 (s, 2H), 7.3 (s, 1H), 7.4 (d, 1H), 7.45 (t, 2H), 7.5 (s, 1H), 7.55 (d, 1H), 7.65 (d, 2H), 7.85 (s, 1H), 8.35 (s, 1H), 9.4-9.6 (br s, 1H)
Using an analogous procedure to that described for the synthesis of the starting material in Example 8, 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline
20 (1.9g, 4.02mmol) was reacted with TFA (20ml) to give 4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.5g, 98%).
'HNMR Spectrum: (DMSOdg) 3.95 (s, 3H), 7.1 (s, 1H), 7.6,(s, 1H), 7.65 (s, 1H), 7.8 (s, 1H), 8.3 (s, 1H), 9.45 (br s, 1H), 10.5 (br s, 1H)
Using an analogous procedure to that described in the preparation of the starting
25 material in Example 8,4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoIine (lg, 2.62mmol) was reacted with l-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (845mg, 3.93mmol), (prepared as described for the starting material in Example 1), to give 4-(4-bromo-2,6-difluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (620mg, 41%),
30 MS-ESI: 579-581 [MH]+

'HNMR Spectrum: (DMSOd6) 1.15-1.3 (m, 2H); 1.45 (s, 9H); 1.8 (d, 2H); 2.0-2.1 (m, 1H); 2.7-2.9 (m, 2H); 3.95 (s, 3H) ; 4.0 (br s, 2H) ; 4.05 (d, 2H) ; 7.22 (s, 1H) ; 7.65 (d, 2H); 7.85 (s, 1H) ; 8.35 (s, 1H); 9.4-9.6 (br s, 1H)
5 Example 10
Using an analogous procedure to that described in Example 9, 7-(l-(/ert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-chloro-2J6-difluoroanilino)-6-methoxyquinazoline (95mg, 0.2mmol) in methylene chloride (2ml) was treated with TFA (800ul) to give 4-(4-chIoro-2,6-dinuoroaniIino)-^nietitoxys7-(pipeHdin-4-10 ylmethoxy)quinazoline (20mg, 26%). MS-ESI: 435-437 [MH]+
'HNMR Spectrum: (DMSOd6) 1.2-1.3 (m, 2H); 1.75 (d, 2H); 1.85-2.0 (br s, 1H) ; 2.5 (d, 2H); 3.0 (d, 2H); 3.97 (s, 3H); 4.0 (d, 2H) ; 7.2 (s, 1H); 752 (d, 2H); 7.85 (s, 1H); 8.35 (s, 1H) 15
The starting material was prepared as follows.
Using an analogous procedure to that described for the preparation of the starting material in Example 9, 7-benzyloxy-4-chloro-6-methoxyquinazoline (184mg, 0.61mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was 20 generated prior to use), was reacted with 4-chloro-2,6-difluoroaniline (200mg, 1.22mmol) in the presence of sodium hydride (60%, 87mg, 1.4mmol) in DMF (8ml) to give 7-benzyloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (212mg, 74%). MS - ESI: 428 [MH]+
'HNMR Spectrum: (DMSOd6) 3.96 (s, 3H); 5.31 (s, 2H); 7.32 (s, 1H); 7.4 (d, 1H); 7.45 (t, 25 2H); 7.5-7.6 (m, 4H); 7.85 (s, 1H); 8.35 (br s, 1H); 9.55 (br s, 1H)
A solution of 7-ben2yloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquina2X>line (200mg, 0.47mmol) in TFA (3ml) was stirred at 80°C for 3 hours. After cooling, the volatiles were removed under vacuum and the residue was dissolved in water containing 5% methanol. The pH was adjusted to 8 with sodium hydrogen carbonate and the solid was 30 collected by filtration and washed with water. The solid was solubilised in a mixture of ethyl acetate/methanol/methylene chloride (47/6/47). The volatiles were removed under vacuum to give 4-(4-chloro-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (126mg, 80%).

MS - ESI: 338 [MH]+
'HNMR Spectrum: (DMSOcLJ 3.95 (s, 3H); 7.1 (s, 1H); 7.55 (d, 2H); 7.8 (s, 1H); 8.3 (s5
1H); 9.42 (br s, 1H)
Using an analogous procedure to that described for the preparation of the starting 5 material in Example 9, 4-(4-chloro-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline
(150mg, 0.44mmol) was reacted with l-(fer£-butoxycarbonyl)-4-hydroxymethylpiperidine
(150mg, 0.88mmol), (prepared as described for the starting material in Example 1), to give 7-
(1 -(tert-butoxy carbony l)piperidin-4-ylmethoxy)-4-(4-chloro-2,6-difluoroanilino)-6-
meth©xyquinazoline(113mg, 59%).
10 MS - ESI: 535 [MH]+
'HNMR Spectrum: (DMSOd6) 1.15-1.3 (m, 2H); 1.45 (s, 9H); 1.8 (d, 2H); 2.0-2.1 (m, 1H);
2.7-2.9 (m, 2H); 3.95 (s, 3H); 4.0 (br s, 2H); 4.05 (d, 2H); 7.2 (s, 1H); 7.6 (m, 2H); 7.8 (s,
1H); 8.35 (s, 1H); 9.4-9.6 (br s, 1H)
15 Example 11
The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a pharmaceutically acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:

20 (a)
25
(b)
30

Tablet I ma/tablet
Compound X 100
Lactose Ph.Eur 182.75
Croscarmellose sodium 12.0
Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0
Tablet II me/tablet
Compound X 50
Lactose Ph.Eur 223.75
Croscarmellose sodium 6.0
Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25

Magnesium stearate

3.0

(c)
10 (d)
15 (e)

Tablet m mg/tablet
Compound X 1.0
Lactose Ph.Eur 93.25
Croscarmellose sodium 4.0
Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0
Capsule me/capsule
Compound X 10
Lactose Ph.Eur 488.5
Magnesium stearate 1.5
Injection I (50 me/ml)
Compound X 5.0% w/v
IM Sodium hydroxide solution 15.0% v/v

20

0. IM Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 Water for injection to 100%

4.5% w/v

(f) Injection II
Compound X
25 Sodium phosphate BP
0.1M Sodium hydroxide solution Water for injection to 100%

10mg/ml) 1.0% w/v 3.6% w/v 15.0% v/v

(g) Injection III
30 Compound X
Sodium phosphate BP Citric acid

(lmg/ml.buffered to pH6) 0.1% w/v 2.26% w/v 0.38% w/v

Polyethylene glycol 400 Water for injection to 100%

3.5% w/v

Note
The above formulations may be obtained by conventional procedures well known in the 5 pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

Claim:
1. A quinazoline derivative of the formula I:

wherein:
m is an integer from 1 to 3;
R1 represents halogeno or C1-3alkyl;
R2 is selected from one of the following three groups:
1) C1-5alkylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C1-4alkyl, C1-4 hydroxyalkyl and C1-4alkoxy;
2) C2-5alkenylR3 (wherein R3 is as defined herein);
3) C2-5alkynylR3 (wherein R3 is as defined herein);
and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; or a salt of the kind such as herein described.

2 A quinazoline derivative as claimed in claim 1 wherein the phenyl group bearing (R1)m is selected from 2-fluoro-4-methylphenyl, 4-chloro-2,6-difluorophenyl, 4-bromo-2,6- difluorophenyl, 4-chloro-2-fluorophenyl group and 4-bromo-2-fluorophenyl.
3. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R2 is C1-5alkylR3.
4. A quinazoline derivative as claimed in any one of the preceding claims wherein R2 is piperidin-4-ylmethyl in which the piperidine ring may bear one or two substituents selected from C1-4alkyl.
5. A quinazoline derivative as claimed in claim 1 of the formula II:

wherein:
ma is an integer from 1 to 3;
Rla epresents halogeno or Ci-3alkyl;
R2a is selected from one of the following three groups:
1) C1-5alkylR3 (wherein R3 is as defined in claim 1);
2) C2-5alkenylR3 (wherein R3 is as defined in claim 1);

3) C2-5alkynylR3 (wherein R3 is as defined in claim 1);
or a salt of the kind such as herein described.
6. A quinazoline derivative as claimed in claim 1 selected from:
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline,
4-(2-fluoro-4-methylanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline,
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1-methylpiperidin-4-ylmethoxy) quinazoline,
4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(l -methylpiperidin-4-ylmethoxyjquinazoline,
4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline,
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy) quinazoline,
4-(2-fluoro-4-methylanilino)-6-methoxy-7-(piperidin-4-ylmethoxy) quinazoline,
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy) quinazoline,
4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline, and

4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy) quinazoline,
and salts of the kind such as herein described.
7 A quinazoline derivative as claimed in claim 1 selected from:
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline,
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline,
4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, and
4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline, and salts of the kind such as herein described.
8. A quinazoline as claimed in claim 1 derivative selected from:
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1-methylpiperidin-4-ylmethoxy)quinazoline and salts of the kind such as herein described.
9. A quinazoline derivative as claimed in any one of the preceding
claims in the form of a pharmaceutically acceptable salt of the kind
such as herein described.

10. A process for the preparation of a quinazoline derivative of formula
I, as claimed in claim 1, or a salt of the kind such as herein
described which comprises:
(a) the reaction of a compound of the formula III:

cm)
wherein R2 is as claimed in claim 1 and L1 is a displaceable moiety, with a. compound of the formula IV:

wherein R1 and m are as claimed in claim 1; (b) the reaction of a compound of the formula V:

wherein m and R1 are as defined in claim 1 with a compound of formula VI;

wherein R2 is as claimed in claim 1 and L1 is as denned herein;
(c) the reaction of a compound of the formula VII:

(vn)
with a compound of the formula VIII:

R2-Q-H

(VIII)

wherein R1, R2 and m are as claimed in claim 1 and L1 is as defined herein; or

(d) the deprotection of a compound of the formula IX:

wherein R1 and m are as claimed in claim 1, and R4 represents a protected R2 group wherein R2 is as claimed in claim 1 but additionally bears one or more protecting groups P2; and when a pharmaceutically acceptable salt of a quinazoline derivative of formula I is required, reaction of the compound obtained with an acid or base whereby to obtain the desired pharmaceutically acceptable salt of the kind such as herein described.
Dated this 21st day of March, 2002.
[RANJNA MEHTA-DUTT]
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS

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Patent Number

209328

Indian Patent Application Number

IN/PCT/2002/00344/MUM

PG Journal Number

38/2007

Publication Date

21-Sep-2007

Grant Date

24-Aug-2007

Date of Filing

21-Mar-2002

Name of Patentee

ASTRAZENECA AB

Applicant Address

S-151 85 SODERTALJE, SWEDEN.

Inventors:

#	Inventor's Name	Inventor's Address
1	LAURENT FRANCOIS ANDRE HENNEQUIN	Z.I LA POMPELLE, BOITE POSTALE 1050, F- 51689 REIMS CEDEX 2, FRANCE.
2	ELAINE SOPHIE ELIZABETH STOKES	MERESIDE, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK 10 4TG, ENGLAND.
3	ANDREW PETER THOMAS	MERESIDE, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK10 4TG, ENGLAND.

PCT International Classification Number

C07D 401/12

PCT International Application Number

PCT/GB00/04181

PCT International Filing date

2000-11-01

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	99402759.7	1999-11-05	EPO
2	99402877.7	1999-11-19	EPO