Title of Invention

"WATER SOLUBLE GRANULES"

Abstract

The invention relates to meloxicam granulates which are rapidly soluble in water and which contain meloxicam, a salt forming agent forming the meglumine, sodium, potassium or ammonium salt of the meloxicam, a binding agent, a sugar or sweetener, a carrier, optionally an aromatic compound and optionally additional auxiliary substances. The invention also relates to a method for the production thereof and to the use thereof in the treatment of respiratory or inflammatory diseases in mammals.

Full Text

The present invention relates to meloxicam granules which dissolve rapidly in water, containing meloxicam, a salt forming agent which forms the meglumine, sodium, potassium or ammonium salt of meloxicam, binders, a sugar or sweetener, a carrier, optionally a flavouring and optionally other excipients, processes for preparing them and their use for treating respiratory or inflammatory complaints in mammals. Background to the Invention Meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) is an active substance which belongs to the group of NSAID's (non-steroidal-antiinflammatory drugs). Meloxicam and the sodium and meglumine salt thereof (N-memyl-D-glucamine salt) are described in EP-A-0 002 482. EP-A-0 945 134 discloses the pH-dependent solubility characteristics of meloxicam and its salts, i.e. the sodium salt, the ammonium salt and the meglumine salt, in aqueous solution. According to this, meloxicam is an active substance which does not dissolve readily in water. The meloxicam salts, particularly the meglumine salt, exhibit improved solubility as the pH increases between 4 and 10, as shown in Table 1 of EP-0 945 134. It is known that administering medicaments to sick animals, particularly those suffering from fever, can be done particularly easily and successively through their drinking water. Administering to their food can also make it easier to give the medicament to the animal. It is known from EP 0945134 that meloxicam and meglumin cannot easily be compressed. The aim of the present invention is therefore to develop a granulated form of meloxicam which can be administered to the animals by mixing it into their drinking water or as a food supplement. Description of the Invention Surprisingly, meloxicam granules have been discovered which can easily be produced by a fluidised bed method and which, when dissolved in water, form a drinking water solution which is stable over at least 48 hours. It was also found that these granules can be added to the animals food. The invention therefore relates to water soluble granules containing meloxicam, a salt forming agent which forms the meglumin, sodium, potassium or ammonium salt of meloxicam, binders, a sugar or sweetener, a carrier, optionally a flavouring and optionally other excipients. The meloxicam granules according to the invention have a number of advantages over existing preparations. In sick animals an increased uptake of drinking water can be observed when a drink containing meloxicam is given. Suitable dilution of the dissolved granules allows a variable, precise dosing of the active substance meloxicam. Because of the good solubility of the meloxicam granules according to the invention in water the effects of meloxicam in the body of the sick animal set in very rapidly. The good flavour of the meloxicam granules also makes it possible to administer them as a food supplement. In addition the granules according to the invention have very good How properties, a uniform meloxicam content, they are virtually free from dust and have a narrow particle size distribution of 125 µm to 500 µm. The total solubility of the granules in water ensures optical control of a totally dissolved active substance which is only available for therapeutic use in this form when administered in drinking water. In a preferred embodiment of the invention the salt forming agent is meglumin. In another preferred embodiment of the invention the binder may be selected from among hydroxypropyl-methylcellulose, polyvinylpyrrolidone, gelatine, starch and polyethyleneglycolether, preferably hydroxypropyl-methylcellulose, polyvinylpyrrolidone and polyethyleneglycolether, most preferably hydroxypropyl-methylcellulose and polyvinylpyrrolidone. In another preferred embodiment of the invention the sugar or sweetener may be selected from among sodium saccharine, aspartame and Sunett®, preferably sodium saccharine or aspartame. Particularly preferred according to the invention are meloxicam granules in which the flavouring is selected from among vanilla, honey flavouring, apple flavouring and contramarum, preferably honey flavouring and apple flavouring. Also particularly preferred are meloxicam granules in which the carrier is selected from among lactose, glucose, mannitol, xylitol, sucrose and sorbitol, preferably glucose, lactose or sorbitol, more preferably glucose or lactose, most preferably glucose. Particularly preferred are meloxicam granules in which the content of meloxicam is between 0.05 % and 4 %, preferably between 0.1 and 2 %, preferably between 0.3 % and 1.5 %, more preferably between 0.4 % and 1 %, most preferably 0.6 %. Also particularly preferred are meloxicam granules which contain meglumin and meloxicam in a molar ratio of about 9:8 to 12:8, preferably 10:8. The invention further relates to process for preparing the meloxicam granules according to the invention in which the steps a) to c) are carried out successively: a) Preparing an aqueous granulating liquid containing binder, optionally a sugar or sweetener, meloxicam, meglumin and/or a flavouring. b) Spraying the granulating liquid on to a carrier in a topspray fluidised bed method with an air current supplied at a constsnt temperature from 50 to 80 °C, preferably 65 °C. c) A subsequent coating process with an aqueous granulating liquid by the topspray fluidised bed method containing a binder, a sugar or sweetener and/or a flavouring. In a preferred process according to the invention the granulating liquid is prepared by stirring and heating the components to 70 to 100 °C, preferably about 90 °C. A particular feature of the meloxicam granules according to he invention is that they have a long term stability of 24 months or more when stored in their original package at room temperature. A particularly preferred granulated meloxicam preparation contains meloxicam, meglumin, hydroxypropylmethylcellulose, povidone and glucose monohydrate. The present invention further relates to the use of meloxicam granules for preparing a pharmaceutical composition for treating pain, inflammation, fever, acute mastitis, diarrhoea, lameness, problems of mobility and respiratory complaints in animals, preferably acute mastitis, diarrhoea, lameness, mobility problems and respiratory complaints, preferably acute mastitis, diarrhoea, lameness, mobility problems and respiratory complaints, most preferably mobility problems or respiratory complaints. The treatment may be given in conjunction with antibiotic treatment. The formulation according to the invention is suitable for treating animals, preferably mammals, particularly domestic pets or farm animals, such as pigs, horses, cattle, dogs or cats, preferably pigs or horses. The meloxicam granules according to the invention are preferably used in amounts corresponing to a dosage range from 0.2 to 1.0 mg of active substance per kg of bodyweight, preferably 0.4 to 0.8 mg/kg of body weight, preferably 0.5 to 0.7 mg/kg of bodyweight, more preferably 0.6 mg/kg of bodyweight. It is also preferable to use the meloxicam granules according to the invention to prepare a pharmaceutical composition which can be administered both in drink and also as a feed supplement. The formulation according to the invention may contain, as the meloxicam salt, the meglumin, sodium, potassium or ammonium salt, preferably the meloxicam meglumin salt. The proportion of meglumin is between 0.035 and 2.8 %, preferably 0.07 to 1.4%, preferably 0.21-1.05 %, more preferably 0.28-0.7 % mg/g, particularly about 0.42 % in the meloxicam granules. The possible concentrations of sodium, potassium and ammonium may be calculated accordingly. The concentration of the binder may be in the range from 20-80 mg/g, preferably 30-70 mg/g, preferably 40-60 mg/g, most preferably 50 mg/g of granules. The concentration of the sugar may be in the range from 50-150 mg/g, preferably 75-125 mg/g, more preferably about 100 mg/g of granules. The concentration of the sweetener may be in the range from 1-10 mg/g, preferably 2-5 mg/g, more preferably about 3 mg/g of granules. The ceoncentration of the carrier may be in the range from 800-985 mg/g, preferably 900-960 mg/g, more preferably about 930 mg/g of granules. The concentration of the flavouring may be in the range from 0.1-10 mg/g, preferably 0.2-1.0 mg/g, more preferably about 0.5 mg/g of granules. The packaging material used for the formulation according to the invention may be any of a number of standard commercial materials for granules. These include for example plastic containers, e.g. made of HPPE (High pressure polyethylene), aluminium bags or paper bags with an aluminium lining. The meloxicam granules are produced by the top spray fluidised bed method. In this, first of all an aqueous granulating liquid solution consisting of about 50 to 70 g/kg of binder, such as PVP 25000, hydroxypropylmethyl-cellulose or Macrogol 6000, preferably hydroxypropylmethyl-cellulose and/or about 1 to 5 g/kg of sweeteners such as Sunett® or Na saccharine, preferably Sunett®, and/or about 0.5 to 2.5 g of flavouring, such as vanilla, honey, flavouring 203180 or contramarum, preferably honey, about 10 to 15 g of meloxicam (peg milled) and about 7 to 11 g of meglumin is produced with stirring by heating to about 70 to 100°C. The granulating liquid is then sprayed on to a carrier such as lactose, glucose or sorbitol, preferably glucose, by a counter flow process (Top Spray). This is done, for example, using a two-component nozzle, spraying at a constant air pressure at about 50 to 80 °C , preferably at about 65 °C. The coating process may then be carried out using a second aqueous granulating liquid. In order to prepare a solution ready for use a stock solution should be dissolved completely in water. Then the stock solution may be adjusted to the desired concentration for use by mixing with water. To increase safety in use, the granules may have water soluble colour markings. The meloxicam granules according to the invention will be illustrated by the examples that follows. The skilled man will be aware that this example is intended solely as an illustration and should not be regarded as limiting. Example 1 0.6% meloxicam granules Recipe: g/100g Meloxicam 0.6 Meglumin 0.42 Hydroxypropylmethylcellulose 3.00 Povidone 2.00 Glucose monohydrate 93.98 Example 2 1.2% meloxicam granules Meloxicam 1.2 Meglumin 0.84 Hydroxypropylmethylcellulose 3.00 Collidone 25 2.0 Glucose Monohydrate 92.96 Example 3 0.6% meloxicam granules Meloxicam 0.6 Meglumin 0.42 Pharmacoat 606 4.0 Macrogol6000 1.0 Acesulfame K 0.3 Lactose 93.68 Example 4 0.6% meloxicam granules Meloxicam 0.6 Meglumin 0.42 Pharmacoat 606 4.75 Macrogol 6000 0.25 Acesulfame K 0.3 Liquid vanilla flavouring 0.05 Lactose 93.63 Bright yellow free flowing meloxicam granules corresponding to Examples 1 to 4 may be prepared as follows: The granules are stored for 3 months at 25 °C at a relative humidity of 60 %. No significant changes were observed in terms of the active substance content, the water content (according to Karl-Fischer), the visual solubility characteristics, the pH in demineralised water and the visual wettability. In order to determine the visual solubility characteristics, 5 g of the granules were dissolved in 100 ml of demineralised water at ambient temperature. After about 1 min a clear yellowish solution was obtained. " WE CLAIM: 1. A quinazoline derivative of formula (I): (Formula Removed) or a salt, ester or amide thereof such as herein described, where: X is O or S, S(O) or S(O)2, or NR6 where R6 is hydrogen or C1-6alkyl; R5 is a group of formula (a) or (b): (Formula Removed) where * indicates the point of attachment to the group X in formula (I); R1, R2, R3, R4 are independently selected from hydrogen, halo, cyano, nitro, trifluoromethyl, C1-3alkyl, -NR7R8 or -X1R9 R7 and R8 are independently hydrogen or C1-3alkyl; X1 is a direct bond, -O-, -CH2-, -OCO-, carbonyl, -S-, -SO-, -SO2-, -NR10CO- -CONR11-, -SO2NR12-, -NR13SO2- or -NR14-; R10, R11, R12, R13 and R14 are independently hydrogen, C1-3alkyl or Ci-3alkoxyC2-3alkyl Rg is selected from one of the following groups: 1) hydrogen or C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro or amino; 2) C1-5alkylX2COR15 (wherein X2 represents -O- or -NR16- (in which R15 represents hydrogen, C1-6alkyl or C1-3alkoxyC2-3alkyl) and R16 represents Ci- salkyl, -NR17R18 or -OR19 (wherein R17, R18 and R19 which may be the same or different each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl)); 3) C1-5alkylX3R20 (wherein X3..represents -O-, -S-, -SO-, -SO2-, -OCO-, - NR21CO-, -CONR22-, -SO2NR23-, -NR24SO2- or -NR25- (wherein R21, R22, R23, R24 and R25 each independently represents hydrogen, C1-3alkyl or Ci- 3alkoxyC2-3alkyl) and R20 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5- or 6-membered saturated heterocyclic group with 1 or 2 heteroatoms, selected independently from O, S and N, which Ci-salkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halo and C1-4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halo, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy); 4) C1-5alkylX4C1-5alkylX5R26 (wherein X4 and X5 which may be the same or different are each -O-, -S-, -SO-, -SO2-, -NR27CO-, -CONR28-, -SO2NR29-, - NR30SO2- or -NR31- (wherein R27, R28, R29, R30 and R31 each independently represents hydrogen,C1-3alkyl or C1-3alkoxyC2-3alkyl) and R26 represents hydrogen or C1-3alkyl); 5) R32 (wherein R32 is a 5- or 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1 or 2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halo, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl and C1-4alkylsulphonylC1-4alkyl); 6) C1-5alkylR32 (wherein R32 is as defined hereinbefore); 7) C2-5alkenylR32 (wherein R32 is as defined hereinbefore); 8) C2-5alkynylR32 (wherein R32 is as defined hereinbefore); 9) R33 (wherein R33 represents a pyridone group, a phenyl group or a 5- or 6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1, 2 or 3 heteroatoms selected from O, N and 5, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents on available carbon atoms selected from hydroxy, halo, amino, C1-4alkyl, Ci- _4alkoxy, C1-4hydroxyalkyl, .C1-4aminoalkyl, C1-4alkylamino, Ci-4hydroxyalkoxy, carboxy, trifluoromethyl, cyano, -CONR34R35 and -NR36COR37 (wherein R34, R35, R36 and R37, which may be the same or different, each represents hydrogen, C1-4alkyl or C1-4alkoxyC2-3alkyl)); 10) C1-5alkylR33 (wherein R33 is as defined hereinbefore); 11) C2-5alkenylR33 (wherein R33 is as defined hereinbefore); 12) C2-5alkynylR33 (wherein R33 is as defined hereinbefore); 13) C1-5alkylX6R33 (wherein X6 represents -O-, -S-, -SO-, -SO2-, -NR38CO-, -CONR39-, -SO2NR40-, -NR41SO2- or -NR42- (wherein R38, R39, R40, R41 and R42 each independently represents hydrogen, C1-3alkyl or Ci-salkoxyC2- salkyl) and R33 is as defined hereinbefore); 14) C2-5alkenylX7R33 (wherein X7 represents -O-, -S-, -SO-, -SO2-, - NR43CO-, - CONR44-, -S02NR45-, -NR46SO2- or -NR47- (wherein R43, R44, R45, R46 and R47 each independently represents hydrogen, C1-3alkyl or Ci- 3alkoxyC2-3alkyl) and R33 is as defined hereinbefore); 15) C2-5alkynylX8R33 (wherein X8 represents -O-, -S-, -SO-, -SO2-, - NR48CO-, -CONR49-, -SO2NR50-, -NR51SO2- or -NR52- (wherein R48, R49, R50, R51 and R52 each independently represents hydrogen, C1-3alkyl or Ci- 3alkoxyC2-3alkyl) and R33 is as defined hereinbefore); 16) C1-3alkylX9C1-3alkylR33 (wherein X9 represents -O-, -S-, -SO-, -SO2-, -NR53CO-, -CONR54-, -SO2NR55-, -NR56SO2- or -NR57- (wherein R53, R54, R55, R56 and R57 each independently represents hydrogen, C1-3alkyl or Ci-3alkoxyC2-3alkyl) and R33 is as defined hereinbefore); 17) C1-3alkylX9C1-3alkylR32 (wherein X9 and R32 are as defined hereinbefore); 18) C1-5alkyl optionally substituted by 1, 2 or 3 halo; 19) C1-5alkylXioC1-5alky1X'R90 (wherein X10 and X11, which maybe the same or different, are each -O-, -S-, -SO-, -SO2-, -NR91CO-, -CONR92-, - S02NR93-, -NR94S02- or —NR95- (wherein R91, R92, R93, R94 and R95 each independently represents C1-5alkyl, C1-3alkyl (substituted by 1, 2 or 3 halo, C1-4alkyl or C1-4alkoxy groups (and where there are 2 C1-4alkoxy groups the C1-4alkyl groups of alkoxy may together form a 5- or 6-membered saturated heterocyclic group having 2 oxygen atoms)), C2-salkenyl, C2-salkynyl, Cs- ecycloalkyl (optionally substituted by halo, hydroxy, C1-3alkyl or Ci- 4hydroxyalkyl), C3-6cycloalkylC1-3alkyl (optionally substituted by halo, hydroxy; C1-3alkyl or C1-4hydroxyalkyl) or C1-3alkoxyC2-3alkyl) and R90 represents hydrogen or C1-3alkyl); 20) C3-6cycloalkyl; 21) R96 (wherein R96 is a 5- or 6-membered heterocyclic group which may be saturated or unsaturated (linked via carbon or nitrogen) with 1 or 2 heteroatoms, selected independently from O, S and N which heterocyclic group may bear 1 or 2 substitutents selected from C1-4hydroxyalkyl, Ci- 4alkyl, hydroxy and C1-4alkoxyC1-4alkyl; 22) C1-5alkylR96 (wherein R96 is defined hereinbefore); and where: R60 is hydrogen, nitro, halo, cyano, oxo or C1-3alkyl; R61 is a group of sub-formula (Formula Removed) where: p is 0 or 1; Ri' and Ri" are independently hydrogen or C1-3alkyl; R63 is (CH2)q' J or heteroaryl where the latter two groups are optionally substituted by 1 or 2 substituents independently selected from halo, Ci-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, difluoromethyl, difluoromethoxy and cyano; R64 is hydrogen or C1-3alkyl; q'is 0 or 1; J is aryl or heteroaryl which are both optionally substituted by 1, 2 or 3 substituents selected from halo, C1-3alkyl, C3-4cycloalkyl, C3-4cycloalkylC1-3alkyl, cyano and C1-3alkoxy; and R62 is hydrogen, halo or C1-3alkyl. 2. A quinazoline derivative as claimed in claim 1 or a salt, ester or amide thereof wherein R60 and R62 are both hydrogen. 3. A quinazoline derivative as claimed in claim 1 or 2 or a salt, ester or amide thereof wherein R63 is aryl optionally substituted by 1 or 2 substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, difluoromethyl, difluoromethoxy and cyano. 4. A quinazoline derivative as claimed in claim 1 or 2 or a salt, ester or amide thereof wherein J is phenyl optionally substituted by 1 or 2 halo. 5. A quinazoline derivative as claimed in claim 1 or 2 or a salt, ester or amide thereof wherein R61 is —CEb—COR64—J and wherein J is phenyl optionally substituted by 1 or 2 halo. 6. _ A quinazoline derivative as claimed in any of the preceding claims or a salt, ester or amide thereof wherein X is NR6 or O. 7. A quinazoline derivative as claimed in claim 6 or a salt, ester or amide thereof wherein X is NH. 8. A quinazoline derivative as claimed in claim 1 of formula (IB) (Formula Removed) or a salt, ester or amide thereof wherein Ar is indazole or pyridine (optionally substituted by methyl) or aryl (optionally substituted by 1 or 2 substitutents independently selected from halo, methoxy, trifluoromethyl, hydroxy, nitro, cyano and difluoromethoxy); and R1, R2, R3 and R4 are as claimed in claim 1. 9. A quinazoline derivative as claimed in any of the preceding claims or a salt, ester or amide thereof wherein R9 is a group selected from group 1), 3), 4), 5), 6), 9), 18), 19), 20) and 22) as claimed in claim 1. 10. A quinazoline derivative as claimed in any of the preceding claims or a salt, ester or amide thereof wherein R9 is hydrogen, C3-6cycloalkyl, —Ci- salkyl—O—C1-3alkyl or a 5- to 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1 or 2 heteroatoms selected independently from O, S or N which heterocyclic group is optionally substituted by C1-4alkyl or R9 is a 5- or 6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1, 2 or 3 heteroatoms or R9 is -C1-5alkylR32, -C1-5alkylR96, C1-5alkyl (optionally substituted by halo), -C1- salkyl- NHR20, -C1-5alkyl—NHR20, —C1-5alkyl—N(C1-3alkyl)—R20, -C1-5alkyl, C1-5alkyl—NH—C1-5alkyl—OH,—C1-5alkyl—N(C1-3alkyl)—C1-5alkyl—OH and —C1-5alkyl—NR95—C1-5alkyl—OH and wherein R32, R96, R20 and R95 are as claimed in claim 1. 11. A quinazoline derivative as claimed in any of the preceding claims or a salt, ester or amide thereof wherein R4 is hydrogen. 12. A quinazoline derivative as claimed in any of the preceding claims or a salt, ester or amide thereof wherein R2 is hydrogen, halo or —X1R9 where X1 is a direct bond or —0— and R9 is a group 1) as claimed in claim 1. 13. A quinazoline derivative as claimed in any of claims 1 to 11 or a salt, ester or amide thereof wherein R2 is hydrogen, halo, hydroxy, methoxy or — OC1-3alkyl (optionally substituted by 1 or 2 hydroxy or halo). 14. A quinazoline derivative as claimed in claim 13 or a salt, ester or amide thereof wherein R2 is hydrogen or methoxy. 15. A quinazoline derivative as claimed in any of the preceding claims or a salt, ester or amide thereof wherein R1 is hydrogen or —X1R9. 16. A quinazoline derivative as claimed in claim 15 or a salt, ester or amide thereof wherein X1 is a direct bond, —O—, —NH— or —NMe— and R9 is selected from a group 1), 3), 5), 9) or 20) as claimed in claim 1. 17. A quinazoline derivative as claimed in claim 16 or a salt, ester or amide thereof wherein R1 is hydrogen or —X1R9 where X1 is a direct bond, —O— or —NH— and R9 is hydrogen, C1-5alkyl, C3-6cycloalkyl, — C1-5alkyl— O—C1-3alkyl or a 5- to 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1 or 2 heteroatoms selected independently from 0, S or N which heterocyclic groups is optionally substituted by C1-4alkyl or a 5- or 6-membered aromatic heterocyclic group (linked via carbon or nitrogen with 1, 2 or 3 heteroatoms. 18. A quinazoline derivative as claimed in claim 17 or a salt, ester or amide thereof wherein R1 is hydrogen, methoxy, N-(C1-5alkyl)piperidin-4- yloxy, prop-2-yloxy or methoxyethoxy. 19. A quinazoline derivative as claimed in claim 18 or a salt, ester or amide thereof wherein R1 is hydrogen. 20. A quinazoline derivative as claimed in any of the preceding claims or a salt, ester or amide thereof wherein R3 is X1R9 21. A quinazoline derivative as claimed in claim 20 or a salt, ester or amide thereof wherein R3 is — X1R9 where -X1 is — O — and R9 is selected from a group 3), 4), 6), 18), 19) or 22) as claimed in claim 1. 22. A quinazoline derivative as claimed in claim 21 or a salt, ester or amide thereof wherein R3 is — X1R9 where X1 is — O — and R9 is — C1-5- alkylR32, — C1-5alkylR96, C1-5alkyl (optionally substituted by halo), —C1- 5alkyl— OR20, — C1-5alkyl— NHR2o, — C1-5alkyl— N(C1-5alkyl)— Rao, — C1- 5alkyl— NH—C1-5alkyl— OH, — C1-5alkyl— N(C1-3alkyl)— C1-5alkyl— OH and — C1-5alkyl— NR95— C1-5alkyl-OH . 23. A quinazoline derivative as claimed in claim 22 or a salt, ester or amide thereof wherein R3 is — X1R9 where X1 is — O — and R9 is — Ci- salkylR32 (where R32 is pyrrolidinyl, piperidinyl or piperazinyl each being optionally substituted by hydroxy, hydroxymethyl, 2-hydroxyethyl, methyl or 2-(tert-butoxy)ethyl), — C1-5alkyl— NHR20,— C1-5alkyl— NH— C1-5alkyl— OH, — C1-5alkyl— N(C1-3alkyl)— C1-5alkyl— OH and — C1-5alkyl— NR95— C1-5alkyl— OH. 24. A quinazoline derivative as claimed in claim 20 or a salt, ester or amide thereof wherein R3 is 3-morpholinopropoxy, 3-chloropropoxy, 3-[N- ethyl-N-(2-hydroxyethyl)amino]propoxy, 3-(2-hydroxymethylpyrrolidin-l- yljpropoxy, 3-piperidin-l-yl)propoxy, 3-(pyrrolidin-l-yl)propoxy, 3-(N-(2- hydroxyethyl)amino]propoxy,3-[N-(2-hydroxy-l,l- dimethylethyl)amino}propoxy, 3-[N-methyl-N-(2- hydroxyethyl)amino]propoxy, 3-[N-(l-hydroxymethyl-2- methylpropyl)amino]propoxy, 3-(4-methylpiperazin- l-yl)propoxy, 3-[N-(2- hydroxy-1 -methylethyl)amino]propoxy, 3-[N-(4- hydroxybutyl)amino]propoxy, 3-(4-hydroxypiperidin-1 -yl)propoxy, 3-[2-(2- hydroxyethyl)piperidin-1 -yl]propoxy, 3-[4-(2-hydroxyethyl)piperazin-1 - yljpropoxy, 3-[4-(2-hydroxyethyl)piperidin-l-yl]propoxy, 3-(3- hydroxypiperidin- 1-yljpropoxy, 3-[N-2- (hydroxybutyl)amino]propoxy, 3-(4-hydroxymethylpiperidin-1 -yljpropoxy, 3 -[N-(3-hydroxy-2,2-dimethylpropyl)amino]propoxy, 3-[N-(l- hydroxymethylcyclopent-1 -yl)amino]propoxy, 3-[N-(2- hydroxypropyl)amino]propoxy, 3-(3-hydroxypyrrolidin-1 -yljpropoxy, 3-[N-(2- fluoroethyl)-N-(2-hydroxyethyl)amino]propoxy, 2-[ l-(2- hydroxyethyl)piperidin-4-yl]ethoxy, 3-[N-(2-hydroxyethyl)-N- propylamino]propoxy, 3-[N-(2-hydroxyethyl)-N-(prop-2-yl)amino]propoxy, 3 -[N-(2-hydroxyethyl)-N-isobutylamino]propoxy, 3-[N-(2-hydroxyethyl)-N- neopentylaminojpropoxy, 3-[N-allyl-N-(2-hydroxyethyl)amino]propoxy, 3-[N- (2-hydroxyethyl)-N-(prop-2-yn-l-yl)amino]propoxy, 3-[N-cyclopropyl-N-(2- hydroxyethyl)amino]propoxy, 3-[N-cyclopropylmethyl-N-(2- hydroxyethyljaminojpropoxy, 3-[N-cyclobutyl-N-(2- hydroxyethyljaminojpropoxy, 3-[N-cyclopentyl-N-(2- hydroxyethyl)amino]propoxy, 3-[N-(2,2-dimethoxyet±iyl) -N-(2- hydroxyethyl)amino]propoxy, 3-[N-(2,2-difluoroethyl)-N-(2- hydroxyethyl)amino]propoxy, 3-[N-(2-hydroxyethyl)-N-(3,3,3- trifluoropropyl)amino]propoxy, 3-[N-cyclobutylmethyl-N-(2- hydroxyethyl)amino]propoxy, 3-[N-(2-hydroxyethyl)-N-(2- methoxyethyl)amino]propoxy, 3-{N-(l,3-dioxolan-2-ylmethyl)-N-(2- hydroxyethyl) amino] propoxy, 4-chlorobutoxy, 4- [(2 - hydroxymethyl)pyrrolidin- l-yl]butoxy, 4-[N-(2-hydroxyethyl)-N- isobutylaminojbutoxy, l-(2-tert- butoxyethyl)pyrrolidin-2-ylmethoxy, 1 -(2-hydroxyethyl)pyrrolidin-2- ylmethoxy, 3-[N-2-(hydroxyethyl)-N-(iso-butyl)amino]propoxy, 3-[N-2-(hydroxyethyl)-N- (neopentyl)amino]propoxy, 3-[N-2-(hydroxyethyl)-N-(tert-butyl)amino]propoxy, methoxy and methoxyethoxy. 25. A quinazoline derivative selected from: 2-(3-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino)-lH- pyrazol5-yl)-N-phenylacetamide; N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-lH-pyrazol-5-yl)acetamide; 2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino)-lH-pyrazol-5-yl)-N- (3-fluorophenyl)acetamide; 2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-lH-pyrazol-5- yl)-N-(3,5-difluorophenyl)acetamide; 2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino)-lH-pyrazol-5- yl)-N-(2,3-difluorophenyl)acetamide; N-(3-chlorophenyl)-2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4- yljamino}-1 H-pyrazol-5-yl)acetamide; 2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy)-6-methoxyquinazolin-4- yl)amino]-lH-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide; N-(3-nuorophenyl)-2-{3-[(7-{3-[(25)-2-(hydroxymethyl)pyrrolidin-l- yl]propoxy)-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-piperidin-l-ylpropoxy)quinazolin- 4-yl]amino)-lH-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-(3-{[6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazolin- 4-yl]amino)-1 H-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)amino]propoxy)-6- methoxyquinazolin-4-yl)amino] - lH-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-imethylethyl)amino]propoxy)- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(methyl)amino]propoxy)-6- methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl)acetamide; N-(3-nuorophenyl)-2-(3-{[7-(3-{[l-(hydroxymethyl)-2- methylpropyl]amino)propoxy)-6-methoxyquinazolin-4-yl]amino)-lH-pyrazol- 5- yl)acetamide; N-(3-fluorophenyl)-2-[3-({6-methoxy-7-[3-(4-methylpiperazin-l- yl)propoxy]quinazolin-4-yl)amino)-lH-pyrazol-5-yl]acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-l-methylethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3-{(7-{3-[(4-hydroxybutyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino-1 H-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-[3-({7-[3-(4-hydroxypiperidin-l-yl)propoxy]-6- methoxyquinazolin-4-yl}amino)-lH-pyrazol-5-yl]acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[2-(2-hydroxyethyl)piperidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-{4-(2-hydroxyethyl)piperazin-l-yl]propoxy}-6- methoxyquinazolin- 4 -yl) amino] -1 H-pyrazol- 5 -yl}acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-l-yl)propoxy]-6- methoxyquinazolin-4-yl}amino)-lH-pyrazol-5-yl]acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxybutyl)amino]propoxy}-6- methoxyquinazolin-4-yl)aniino]-lH-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-2,2- dimethylpropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH- pyrazol-5-yl}acetamide; N-(3-nuorophenyl)-2-(3-{[7-(3-{[l- (hydroxymethyl) cyclopentyl]amino}propoxy)-6-methoxyquinazolin-4- yljamino}-1 H-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-(3-{[7-(3-{[(25)-2-hydroxypropyl]amino}propoxy)-6- methoxyquinazolin-4-yl]amino}-lH-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-(3-{[7-(3-{[(2R)-2-hydroxypropyl]amino}propoxy)-6- methoxyquinazolin-4-yl]amino}-1 H-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(3S)-3-hydroxypyrrolidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(3R)-3-hydroxypyrrolidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; 2-{3-[(7-{3-[(2-fluoroethyl)(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-1 H-pyrazol-5-yl}-N-(3- fluorophenyl)acetamide; N-(3-fluorophenyl)-2-{3-[(7-{2-[l-(2-hydroxyethyl)piperidin-4-yljethoxy}-6- methoxyquinazolin-4-yl)amino-1 H-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)Q>ropyl)ammojpropoxy}-6- methoxyquinazolin-4-yl)amino]-1 H-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3 -[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-1 H-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; 2-{3-[(7-{3-{(2,2-dimethylpropyl)(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(3- flu orophenyl) acetamide; 2 -{3- [ (7 -{3- [alkyl(2 -hydroxyethyl) amino] propoxy}-6 -met±ioxyquinazolin-4 - yl)amino]-lH-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; N-(3-nuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-l- yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5- yl}acetamide; 2-{3-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(3- fluorophenyl) acetamide; 2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(3- fluorophenyl)acetamide; 2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin- 4-yl)amino]-lH-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; 2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}-N-(3- fluorophenyljacetamide; 2-{3-{(7-{3-[(2,2-dimethoxyethyl)(2-hydroxy-ethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(3- fluorophenyl)acetamide; 2-{3-[(7-{3-{(2,2-difluoroethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(3,3,3-trifluoropropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol- 5 -yl}acetamide; 2-{3-{(7-{3-{(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}-N-(3-fluorophenyljacetamide; N-(3-nuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2- methoxyethyl)aminojpropoxy}-6-methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; 2-{3-[(7-{3-[(l,3-dioxolan-2-ylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methojcyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; 2-(3-{[7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino}-lH-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide; N-(3-fluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl)pyrrolidin-l- yl]butoxy}-6-methoxyquinazolin-4-yl)amino-lH-pyrazol-5-yl}acetamide; N-(3-fluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(isobutyl)amino]butoxy}-6- methoxyquinazolin-4-yl) amino] -1 H-pyrazol-5-yl}acetamide; 2-{3-[(7-{[(2R)-l-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(3- fluorophenyl) acetarnide; N-(3-fluorophenyl)-2-{3-[(7-{[(2R)-l-(2-hydroxyethyl)pyrrolidin-2- yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3,5-difluorophenyl)-2-(3-{[6-methoxy-7-(3-pyrrolidin-l- ylpropoxy)quinazolin-4-yl] amino}-1 H-pyrazol-5-yl)acetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]- lH-pyrazol-5-yl}acetamide; N-(3,5-dinuorophenyl)-2-{3-[(7-{3-[(2-hydroxy-l,l- dimethylethyl)amino]propoxy}[6-methoxyquinazolin-4-yl)amino]-lH-pyrazol- 5-yl}acetamide; N-(3,5-difluorophenyl)-2-[3-({6-methoxy-7-[3-(4-methylpiperazin-l- yl)propoxy]quinazolin-4-yl}amino)-lH-pyrazol-5-yl]acetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; N-(3,5-dinuorophenyl)-2-{3-[(7-{3-[2-(2-hydro3^ethyl)piperidin-l-yl]propoxy}- 6-methoxyquinazolin-4-yl)amino]-1 H-pyrazol-5-yl}acetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-l- yljpropoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-l-yl]propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3,5-difluorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-l-yl)propoxy]-6- methox7quinazolin-4-yl}amino)-1 H-pyrazol-5-yl]acetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxybutyl)amino]propoxy}-6- methoxyquinazolin-4-yl) amino]-1 H-pyrazol-5-yl}acetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3,5-dinuorophenyl)-2-{3-[(7-{3-[(3-hydroxy-2,2- dimethylpropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH- pyrazol- 5-yl}acetamide; N-(3,5-difluorophenyl)-2-{3-{(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N- (3,5-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydro3C7methyl)pyrrolidin-l- yljpropoxy}-6-methoxyquinazolin-4-yl)amino]-1 H-pyrazol-5-yl}acetamide; N- (3,5-difluorophenyl)-2-(3-{[7-(3-{[(2S)-2-hydroxypropyl]amino}propoxy)-6- methoxyquinazolin-4-yl]amino}-1 H-pyrazol-5-yl)acetamide; N-(3,5-difluorophenyl)-2-(3-{[7-(3-{[(2R)-2-hydroxypropyl]amino}propoxy)-6- methoxyquinazolin-4-yl]amino}-1 H-pyrazol-5-yl)acetamide; N-(3,5-difluorophenyl)-2-{3-[(7- {3-[(3S)-3-hydroxypyrrolidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3,5-dinuorophenyl)-2-{3-[(7-{3-[(3R)-3-hydroxypyrrolidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; 2-{3-[(7-{3-[alkyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazoliri-4- yl)amino]-lH-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide; N-(3,5-dinuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-l- yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5- yljacetamide; N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2- hydroxyethyl)(isopropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]- 1 H-pyrazol-5-yl}acetamide; N-(3,5-dmuorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2- hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol- 5-yl}acetamide; 2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide; 2-{3-[(7-{3-{(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}-N-(3,5-difluorophenyl)acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(2,3-dmuorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2- hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol- yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propo3ty}- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; 2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin- 4-yl)amino]-lH-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide; 2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(2,3- difluorophenyljacetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-l- yljpropoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-l- yl)aminojpropoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5- yl}acetamide; 2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(2,3- difluorophenyl)acetamide; 2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(2,3- difluorophenyl) acetamide; N-(2,3-difluorophenyl)-2-{ 3-{(7-{3-[(2,2-dimethoxyethyl)(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)aminoj- lH-pyrazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-l-yl]propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyTazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-[3-({7-[3-(4-hydroxypiperidin-l-yl)propoxy]-6- methoxyquinazolin-4-yl}amino)-1 H-pyrazol-5-yl]acetamide; N-(2,3-difluorophenyl)-2-{3-{(7-{3-[4-(2-hydroxyethyl)piperazin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyTazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2- methoxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol- 5-yl}acetamide; 2-{3-[(7-{3-[alkyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-N- (2,3-difluorophenyl)-2-{3-[(7-{3-{(l,3-dioxolan-2-ylmethyl)(2- hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]- IH-pyrazol- 5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2- hydroxyethyl)(isopropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]- 1 H-pyrazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-l,l- dimethylethyl)amino]propoxy}6-methoxyquinazolin-4-y l)amino]-1 H-pyrazol- 5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{[(2R)-l-(2-hydroxyethyl)pyrrolidin-2- yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-chlorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-chlorophenyl)-2-{3-{(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-chlorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-l-yl)propo3cyl-6- methoxyquinazolin-4-yl}amino)-lH-pyrazol-5-yl]acetamide; N-(3-chlorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl) amino] -1 H-pyrazol-5-yl}acetamide; 2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6-methoxyquinazolin- 4-yl)amino]-1 H-pyrazol-5-yl}-N-(3-methoxyphenyl)acetamide; 2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6-methoxyquinazolin- 4-yl)amino] -1 H-pyrazol-5-yl}-N-phenylacetamide; N-(4-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; N-(3,5-dichlorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l- yl] propoxy}-6-methoxyquinazolin-4-yl) amino] -1 H-pyrazol- 5 -yl}acetamide; N-(5-chloro-2-methoxyphenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; 2- {3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6-methoxyquinazolin-4- yl)amino]-lH-pyrazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamide; 2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6-methoxyquinazolin- 4-yl)amino]-lH-pyrazol-5-yl}-N-(3-hydroxyphenyl)acetamide; 2-i{3-[(7-{3-[4-(hydroxymethyl)piperidin-1 -yl]propoxy}-6-methoxyquinazolin- 4-yl)amino]-lH-pyrazol-5-yl}-N-(3-nitrophenyl)acetamide; 2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6-methoxyquinazolin- 4-yl)amino]-lH-pyrazol-5-yl}-N-lH-indazol-5-yl]acetamide; N-(4-bromo-2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-chlorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6- metJioxyquinazolin-4-yl) amino] -1 H-pyrazol-5-yl}acetamide; N-(2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6- methoxyqumazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3,5-dimethoxyphenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)aminoj-lH-pyrazol-5-yl}acetamide; 2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l -yl]propoxy}-6-methoxyquinazolin- 4-yl)amino]-lH-pyrazol-5-yl}-N-(5-methylpyridin-2-yl)acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyra2;ol-5-yl}acetamide; N-(3-chloro-2-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N- (2,5-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-[2-fluoro-5-(trifluoromethyl)phenyl]-2-{3-{(7-{3-{4- (hydroxymethyl)piperidin-l-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]- lH-pyrazol-5-yl}acetamide;N-(3,4-dinuorophenyl)-2-{3-[(7-{3-{4- (hydroxymethyl)piperidin-l-yl]propoxy}-6-met±ioxyquinazolin-4-yl)amino]- 1 H-pyrazol-5-yl}acetamide; N-(2,4-difluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl)propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(3-chloro-4-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l- yl]propoxy}-6-methoxyquiilazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N- [2-(difluoromethoxy)phenyl]-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N- (3-cyanophenyl)-2-{3-{(7-{3-[4-(hydroxymethyl)piperidin-1 -yl]propoxy}-6^ methoxyquinazolin-4-yl) amino] -1 H-pyrazol-5-yl}acetamide; N-(3-bromophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-l-yl]propoxy}-6- methoxyquinazolin-4-yl) amino] -1 H-pyrazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2- hydroxyethyl)aminqjpropoxy}quinazolin-4-yl)amino]-1 H-pyrazol-5- yljacetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-{(2- hydroxyethyl)(isopropyl)amino]propoxy}quinazolin-4-yl)amino]-lH-pyrazol- 5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-l- yl]propoxy}quinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2- hydroxyethyl)(propyl)amino]propoxy}quinazolin-4-yl)amino]-lH-pyrazol-5-yl} acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yl-l- yl)amino]jpropoxy}qumazolin-4-yl)amino-lH-pyrazol-5-yl}acetamide; N-(2,3- difluorophenyl)-2-{3-[(7-{3-[(2- hydroxyethyl) (isobutyl)amino]propoxy}quinazolin-4-yl)amino] -1 H-pyrazol-5- yl}acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2- hydroxyethyl)amino]propoxy}quinazolin-4-yl)amino]-lH-pyrazol-5- yl}acetamide; N-(3-fluorophenyl)-2-[3-({5-{[l-(2-hydroxyethyl)piperidin-4- yljoxy}-7-[3-(4-methylpiperazin-l-yl)propoxy]quinazolin-4-yl}amino)-lH- pyrazol-5-yl]acetamide;N-(3-fluorophenyl)-2-[5-({7-methoxy-5-[(l- methylpiperidin-4-yl)oxy]quinazolin-4-yl}amino)-1 H-pyrazol-3 -yl]acetamide; N-(2,3-difluorophenyl)-2-{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-lH- pyrazol-5-yl}acetamide; 2-(3-{[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-lH-pyrazol-5-yl)-N- (2,3-difluorophenyl)acetamide; N-(2,3-difluorophenyl)-2-(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin- 4-yl]amino}-1 H-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-(3-{[5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4- yljamino}-1 H-pyrazol-5-yl)acetamide; N-(3-fluorophenyl)-2-{3-[(5-{[l-(2-hydroxyethyl)piperidin-4-yl]oxy}-7- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; 2-{3-[(5,7-dimethoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(3- fluorophenyljacetamide; 2-(3-{{5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino}-lH-pyrazol-5-yl)-N- (3 -fluorophenyl) acetamide; N-(3-fluorophenyl)-3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazole-5-carboxamide; and N-(2,3-difluorophenyl)-3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazole-5-carboxamide. 26. A quinazoline derivative selected from: N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(25)-2-(hydroxymethyl)pyrrolidin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2,2-dimethylpropyl)(2- hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1 H-pyrazol- 5-yl}acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}- 6-methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}- 6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; 2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin- 4-yl)amino] -1 H-pyrazol-5-yl}-N- (2,3-difluorophenyl)acetamide; 2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(2,3- difluorophenyljacetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-l- yljpropoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N- (2,3-dinuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-l- yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5- yl}acetamide; 2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}-N-(2,3- difluorophenyl)acetamide; 2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl) amino] -1 H-pyrazol-5-yl}-N- (2,3 -difluorophenyl) acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2,2-dimethoxyethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol- 5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperidin-l-yl]propoxy}- 6-methoxyquinazolin-4-yl)amino] -1 H-pyrazol-5-yl}acetamide; N- (2,3-difluorophenyl) -2 - [3- ({7-{3- (4 -hydroxypiperidin-1 -yljpropoxy] -6- methoxyquinazolin-4-yl}amino)-lH-pyrazol-5-yl]acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[4-(2-hydroxyethyl)piperazin-l- yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(2,3-dinuorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2- methoxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino] -1 H-pyrazol- 5-yl}acetamide; 2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4- yl)amino]-lH-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(l,3-dioxolan-2-ylmethyl)(2- hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol- 5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6- methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2- hydroxyethyl)(isopropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]- 1 H-pyrazol-5-yl}acetamide; N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1- dimethylethyl)amino]propoxy}6-methoxyquinazolin-4-yl)amino]-lH-pyrazol- 5-yl}acetamide; and N-(2,3-dinuorophenyl)-2-{3-[(7-{[(2R)-l-(2-hydroxyethyl)pyrrolidin-2-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-lH-pyrazol-5-yl}acetamide; or a pharmaceutically acceptable salt thereof. 27. A process for the preparation of a compound as claimed in claim 1 comprising the step of: reacting a compound of formula (X) (Formula Removed) where R1, R2, R3 and R4 are as defined in claim 1, and R85 is a leaving group selected from halo, mesylate and tosylate, with a compound of formula (XI) (Formula Removed) where X is defined in claim 1 and R5 is as defined in claim 1 in an organic solvent at elevated temperatures.

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