ZA200207382B - Quinazoline compounds. - Google Patents

Description

QUINAZOLINE COMPOUNDS t

The present invention relates to quinazoline derivatives, processes for their ) 5 preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans.

Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995,

Nature Medicine 1: 27-31). Alteration 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 (aF GF & bFGF) and vascular endothelial growth factor (VEGF). By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, in contrast to that of the FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859;

Kolch et al, 1995, Breast Cancer Research and Treatment, 36:139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024). Antagonism of VEGF action by sequestration of VEGF with antibody can result in inhibition of tumour growth (Kim . et al, 1993, Nature 362: 841-844).

Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical ¢ signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular : molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by ) 5 amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Flt or Flt1, the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fms-like tyrosine kinase receptor, Fit4. 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.

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 higher potency against VEGF receptor tyrosine kinase whilst possessing some activity against EGF receptor tyrosine kinase.

Furthermore, compounds of the present invention, possess substantially higher potency against VEGF receptor tyrosine kinase than against EGF receptor tyrosine kinase or FGF R1 receptor tyrosine kinase.

According to the present invention there is provided a quinazoline derivative of the formula I: 3

R! or)

RX “W @

[wherein: ring A is phenyl or a 5-or 6-membered heterocyclic ring which may be saturated, partially saturated or unsaturated and may be aromatic or non-aromatic and which contains 1, 2 or 3 ring heteroatoms selected from O, N and S;

Zis -0-, -NH- or -S-; m is an integer from 0 to 5 inclusive;

R! is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C, ;alkyl,

C,salkoxy, C, alkylthio, or -NR’R® (wherein R® and R®, which may be the same or different, are hydrogen or C, alkyl),

Ris hydrogen, hydroxy, halogeno, C, alkyl, C,salkoxy, trifluoromethyl, amino or nitro;

R® is hydroxy, halogeno, C, ,alkyl, C, jalkoxy, C, salkanoyloxy, trifluoromethyl, cyano, amino or nitro; provided that when ring A is a 5- or 6-membered heterocyclic ring, at least one R’ is either hydroxy or halogeno;

X! is -0-, -CH,-, -S-, -SO-, -SO,-, -NR’-, -NR’CO-, -CONR’-, -SO,NR’- or -NR’SO,-, (wherein R is hydrogen, C, alkyl or C,.salkoxyC, alkyl);

R* is selected from one of the following groups: 1) -Y'X?COR’ [wherein -Y' - is a C, ;alkylene chain wherein each methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C, jalkanoyloxy, provided that there is at least 1 and no more than 3 substituents on the C, ;alkylene chain; X? is -O- or -NR’- (in which R is hydrogen, C, alkyl or C, jalkoxyC, ;alkyl) and R® is C, salkyl, -NRR! or -OR'? (wherein

R”, R" and R”, which may be the same or different, are hydrogen, C, jalkyl or C,salkoxyC,. salkyD)}; 2) -Y?- X°R" [wherein -Y*- is C, salkylene, C, ;alkenylene or C, ;alkynylene wherein each methylene group (other than that of the oi-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C, ,alkanoyloxy, provided that there is at least 1 substituent and no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; X’ is -O-, -S-, -SO-, -SO,-, -OCO-, -NR’CO-, -CONR’-, -SO,NR’-, -

NR'SO,- or -NR'- (wherein R’ is as hereinabove defined) and R" is hydrogen or C, jalkyl, wherein the C, alkyl group may bear one or two substituents selected from 0x0, hydroxy, halogeno and C,_,alkoxy;

® | | PCT/GB01/015614 3) -Y'-X°C, salkyIR' [wherein Y' is as hereinabove defined and X° is -O-, -S-, -§0O-, -SO,-, - ~ NR'CO-, -CONR’-, -SO,NR’-, -NRSO,- or -NR'- (wherein R'is as hereinabove defined ) and R" is Cy cycloalkyl ora 3 to 7 membered saturated or partially saturated heterocyclic group containing up to 3 ring heteroatoms selected independently from O, S and N, wherein the carbocyclic or heterocyclic group is optionally substituted by one or two substituents selected from oxo, hydroxy, halogeno, C, alkyl, (wherein the C, alkyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, cyano, halogeno, amino, nitro, morpholino, C, ;cycloalkyl, piperidin-1-y! and piperazin-1-yl), C, jalkenyl, C, alkynyl, C,. shydroxyalkyl; C,_ alkoxy, carbamoyl, C, jalkylcarbamoyl, N,N-di(C, salkyl)carbamoyl, C.. -

Co 10 alkanoyl, C, alkoxycarbonyl, C, alkylthio, C, jalkylsulphinyl, C, ,alkylsulphonyl, C,. salkanoylamino, N-C, ,alkyl-C, ,alkanoylamino, Bp

N-C, ;alkylsulphamoyl, N.N-di-[C, salkyl}sulphamoyl, C, salkanesulphanylamino and

N-C, salkyl- C, ,alkanesulphonylamino, or R' is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituerits selected from halogeno, amino, C,.alkyl, C, jalkoxy, C, hydroxyalkyl, C, ,aminoalkyl, C,_ salkylamino, C,_hydroxyalkoxy, carboxy, cyano, C, alkylthio, C, ,alkylsulphinyl, C,. : «alkylsulphonyl, N-C, ,alkylsulphamoyl, N,N-di-[C, ;alkyl]sulphamoyl, C,. salkanesulphonylamino, N-C, ;alkyl-C, salkanesulphonylamino, -CONR'R'' and -NR'°COR" (wherein R' and R" are as hereinabove defined)]; Co 4) -Y'-X*C, salkylX°R" [wherein Y' is as hereinabove defined and X* and X® which may be the same or different are each -O-, -S-, -SO-, -SO,-, -NR’CO-, -CONR'-, -SO,NR-, -

NR'SO.- or -NR’- (wherein R’, is as hereinabove defined and R*” is hydrogen or C, salkyl)]; 5)-Y'-O-C, alkyl (wherein Y' is as hereinabove defined) provided that X' is -O-, -S-, -SO- or -SO,; : © 6) -Y>-R'® {wherein -Y>- is as hereinabove defined and R'® is a saturated or partially saturated 3 to 7 membered heterocyclic ring containing up to 3 heteroatoms selected from O, Sand N ) [wherein the heterocyclic ring is optionally substituted by up to 3 substitutents selected from oxo, hydroxy, halogeno, C, alkyl, C, ;alkenyl, C, alkynyl and C; ;cycloalkyl (wherein C,. alkyl, C alkenyl, C, alkynyl and C, cycloalkyl are themsclves optionally substituted by up to 3 substituents selected from hydroxy, halogeno, cyano, Cy jalkyl, C,.salkoxy, Cy.

AMENDED SHEET salkanoyloxy, trifluoromethyl, amino, nitro and R™ as hereinabove defined), C, ,alkoxy, carbamoyl, C, ,alkylcarbamoy!l, N-N- di(C, _jalkyl)carbamoyl, C, ,alkanoyl, C,.

- salkoxycarbonyl, C, ;cycloalkyl, C, alkylthio, C,_salkylsulphinyl, C, ,alkylsulphonyl, C,. salkanoylamino, N-C, ;alkyl-C, ,alkanoylamino, N-C, ;alkylsulphamoyl, N,N-di-[C,.

) 5 jalkyl}sulphamoyl, C, jalkanesulphonylamino and N-C, ;alkyl- C,_jalkanesulphonylamino or R'° is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents selected from halogeno, amino, C,_alkyl, C,.alkoxy, C hydroxyalkyl, C,_,aminoalkyl, C,.

,alkylamino, C, ;hydroxyalkoxy, carboxy, cyano, C, alkylthio, C,alkylsulphinyl, C,. salkylsulphonyl, N-C, ;alkylsulphamoyl, N,N-di-[C, ;alkyl]sulphamoyl, C,. salkanesulphonylamino, N-C, ;alkyl-C, ;alkanesulphonylamino, ~CONR’R!" and -NR!°COR!! (wherein R'® and R"" are as hereinabove defined)];

7 -Y*-X°-R'" (wherein Y?, X° and R' are as hereinabove defined); and

8) -Y2-NR'R" [wherein Y? is as hereinabove defined and R'” and R'® are independently selected from hydrogen, C, alkyl, C, calkenyl, C, alkynyl or C,salkoxyC, salkyl (wherein any alkyl group in R" or R'® is optionally substituted by up to 2 substituents selected from hydroxy, halogeno, C, ;alkyl, C, jalkoxy, C, jalkanoyloxy, trifluoromethyl, cyano, amino or nitro)];

9) -Y’-R® (wherein Y? is C, ;alkylene, C, ;alkenylene or C, salkynylene wherein each methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C, ,alkanoyloxy, provided that there are no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; and R® is C5 ;cycloalkyl which is substituted by 1 substituent selected from hydroxy, amino and halogeno on the ring carbon linked to Y’ and additionally optionally substituted byupto3 substitutents selected from oxo, hydroxy, halogeno, C, alkyl, C,..alkenyl, C, jalkynyl, C,_

. (alkoxy, carbamoyl, C, jalkylcarbamoyl, N-N- di(C,_,alkyl)carbamoyl, C,alkanoyl, C,_ salkoxycarbonyl and C, ;cycloalkyl (wherein C, jalkyl, C, ,alkenyl, C, salkynyl and ‘ Cy cycloalkyl are themselves optionally substituted by up to 3 substitutents selected from hydroxy, halogeno, cyano, C, alkyl, C, alkoxy, C, ;alkanoyloxy, trifluoromethyl, cyano,

amino, nitro and R'* as hereinabove defined));

provided that when: m is an integer from 1 to 3; . R' is methoxy; R? is hydrogen; Z is -NH-;

R’ is halogeno or C, ,alkyl; and ) 5 X'is-0O-; then

R* is not selected from one of the following three groups: a) -C, salkylR'® (wherein R" is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C, alkyl, C, hydroxyalkyl and C, ,alkoxy); b) -C,salkenylR' (wherein R' is as defined hereinbefore), ¢)-C,salkynylR' (wherein R" is as defined hereinbefore); wherein any alkylene, alkenylene or alkynylene chain in groups a) to c) above are optionally substituted by one or more substituents selected from hydroxy, halogeno and amino; or a pharmaceutically-acceptable salt or prodrug thereof.

According to another aspect of the present invention there is provided a quinazoline derivative of the formula I: 3

R! : ~ "N @ [wherein: ring A is phenyl or a 5-or 6-membered heterocyclic ring which may be saturated, partially saturated or unsaturated and may be aromatic or non-aromatic and which contains 1, 2 or 3 ring heteroatoms selected from O, N and S;

Z is -O-, -NH- or -S-; - m is an integer from 0 to 5 inclusive;

R' is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C, alkyl, ) 25 C, alkoxy, C, alkylthio, or -NR°R® (wherein R’ and R®, which may be the same or different, are hydrogen or C,_;alkyl);

R? is hydrogen, hydroxy, halogeno, C, ;alkyl, C, ;alkoxy, trifluoromethyl, amino or nitro;

R? is hydroxy, halogeno, C, alkyl, C, salkoxy, C, salkanoyloxy, trifluoromethyl, cyano, amino or nitro; provided that when ring A is a 5- or 6-membered heterocyclic ring, at least , one R’ is either hydroxy or halogeno;

X' is -O-, -CH,-, -S-, -S0O-, -S0,-, -NR’-, -NR'CO-, -CONR’-, -SO,NR’- or -NR’SO,-, (wherein R’ is hydrogen, C, alkyl or C, salkoxyC, salkyl);

R* is selected from one of the following groups: 1) -Y'X’COR® [wherein -Y' - is a C, salkylene chain wherein each methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno and amino, provided that there is at least 1 and no more than 3 substituents on the C, ;alkylene chain; X* is -O- or -NR®’- (in which R® is hydrogen, C, ;alky! or C, ;alkoxyC, ;alkyl) and R® is C, salkyl, -NR'’R" or -OR" (wherein R'°, R' and R?, which may be the same or different, are hydrogen, C, ;alkyl or C, ;alkoxyC, ;alkyl)]; 2) -Y?- X°R" [wherein -Y?- is C, salkylene, C, ;alkenylene or C, salkynylene wherein each methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno and amino, provided that there is at least 1 substituent and no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; xX? is -O-, -S-, -SO-, -S0,-, -OCO-, -NR’CO-, -CONR’-, -SO,NR’-, -NR’SO,- or -NR’- (wherein R’ is as hereinabove defined) and R'® is hydrogen or C, jalkyl, wherein the C, alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C,_jalkoxy; 3) -Y'-X°C,_salkylR" [wherein Y' is as hereinabove defined and X°® is -O-, -S-, -SO-, -SO,-, -

NR'CO-, -CONR’-, -SO,NR’-, -NR’SO,- or -NR'- (wherein R’ is as hereinabove defined ) and R" is C, ;cycloalkyl or a 3 to 7 membered saturated or partially saturated heterocyclic group containing up to 3 ring heteroatoms selected independently from O, S and N, wherein the carbocyclic or heterocyclic group is optionally substituted by one or two substituents selected from oxo, hydroxy, halogeno, C, alkyl, (wherein the C, alkyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, cyano, halogeno, amino, nitro, . morpholino, C, scycloalkyl, piperidin-1-yl and piperazin-1-yl), C, ,alkenyl, C, alkynyl, C,_ shydroxyalkyl, C, jalkoxy, carbamoyl, C, jalkylcarbamoyl, N,N-di(C, alkyl)carbamoyl, C, : .alkanoyl, C, ,atkoxycarbonyl, C, jalkylthio, C, ,alkylisulphinyl, C,.,alkyisulphonyl, C, ,alkanoylamino, N-C,_jalkyl-C, ,alkanoylamino,

N-C, ;alkylsulphamoyl, N,N-di-[C, ;alkyl]sulphamoyl, C, ;alkanesulphonylamino and

N-C, ;alkyl- C, ;alkanesulphonylamino, ) or R" is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group " containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents ) 5 selected from halogeno, amino, C, alkyl, C, ,alkoxy, C, hydroxyalkyl, C, ,aminoalkyl, C,. salkylamino, C, jhydroxyalkoxy, carboxy, cyano, C, ,alkylthio, C,_jalkylsulphinyi, C, salkylsulphonyl, N-C, ;alkylsulphamoyl, N,N-di-[C, ;alkyl]sulphamoyl, C,. ,alkanesulphonylamino, N-C, ;alkyl-C, jalkanesulphonylamino, -CONR'’R" and -NR'°COR™ (wherein R' and RY! are as hereinabove defined)]; 4) -Y'-X'C, salkylX°R"’ [wherein Y' is as hereinabove defined and X* and X* which may be the same or different are each -O-, -S-, -SO-, -8O,-, -NR’CO-, -CONR’-, -SO,NR'-, -

NR’SO,- or -NR’- (wherein R’, is as hereinabove defined and R'’ is hydrogen or C, alkyl)]; 5) -Y'-O-C, ;alkyl (wherein Y' is as hereinabove defined) provided that X' is -O-, -S-, -SO- or -SO,; 6) -Y2R'® {wherein -Y- is as hereinabove defined and R'° is a saturated or partially saturated 3 to 7 membered heterocyclic ring containing up to 3 heteroatoms selected from O, S and N [wherein the heterocyclic ring is optionally substituted by up to 3 substitutents selected from oxo, hydroxy, halogeno, C, ,alkyl, C, jalkenyl, C, ,alkynyl and C, ;cycloalkyl (wherein C,_ alkyl, C, alkenyl, C, alkynyl and C, ;cycloalkyl are themselves optionally substituted by up to 3 substitutents selected from hydroxy, halogeno, cyano, C, alkyl, C, alkoxy, C,_ ,alkanoyloxy, trifluoromethyl, amino, nitro and R'* as hereinabove defined), C, ,alkoxy, carbamoyl, C, ,alkylcarbamoyl, N-N- di(C,_jalkyl)carbamoyl, C, ,alkanoyl, C,. ,alkoxycarbonyl, C; ;cycloalkyl, C, alkylthio, C, ,alkylsulphinyl, C, ,alkylsulphonyl, C, ,2alkanoylamino, N-C, ;alkyl-C, ,alkanoylamino, N-C, ;alkylsulphamoyl, N.N-di-[C,. alkyl]sulphamoyl, C, jalkanesulphonylamino and N-C, ;alkyl- C, ;alkanesulphonylamino or R'¢ is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group . containing 1 to 3 ring heteroatoms independently selected from O, N and §, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents : selected from halogeno, amino, C, alkyl, C, alkoxy, C, hydroxyalkyl, C, ;aminoalkyl, C,_ ,alkylamino, C, shydroxyalkoxy, carboxy, cyano, C, alkylthio, C, salkylsulphinyl, C,_

Lalkylsulphonyl, N-C,_salkylsulphamoyl, N,N-di-[C, ;alkyl]sulphamoyl, C,.

® | PCT/GBO1/01514 alkanesulphonylamino, N-C, ;alkyl-C, ;alkanesulphonylamino, -CONR''R"" and -NR'°COR" (wherein R'® and R"! are as hereinabove defined)];

UN “Y:XS-RY (wherein Y? X°® and R' are as hereinabove defined); and 8) -Y*NR"R"™ [wherein Y? is as hercinabove defincd and R'” and R'® are independently selected from hydrogen, C, salkyl, C,qalkenyl, C, alkynyl or C,_jalkoxyC, alkyl (wherein any alkyl group in R'” or R" is optionally substituted by up to 2 substituents selected from hydroxy, halogeno, C, ;alkyl, C, salkoxy, C, salkanoyloxy, trifluoromethyl, cyano, amino or nitro); 9 YAR" (wherein Y? js C, alkylene, C, salkenylene or C, ;alkynylenc wherein cach methylene group (other thn that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno and amino, provided that there arc no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; and R® is C, cycloalkyl which is substituted by 1 substituent selected from hydroxy, amino and halogeno on the ring carbon linked 10 Y? and additionally optionally substituted by up to 3 substitutents selected from oxo, hydroxy, halogeno, C, alkyl, C. ,alkenyl, C, alkynyl, C, jalkoxy, carbamoyl, C,. salkylcarbamoyl, N-N- di(C,_alkyl)carbamoyl, C, alkanoyl, C, alkoxycarbonyl and C,. scycloalkyl (wherein C, alkyl, C, alkenyl, C, alkynyl and Cs.scycloalkyl arc themselves optionally substituted by up lo 3 substitutents selected from hydroxy, halogeno, cyano, C,. : salkyl, C,;alkoxy, C, ;alkanoyloxy, trifluoromethyl, cyano, amino, nitro and R" as hereinabove defined)]; provided that when: m is an integer from 1 © 3;

R! is methoxy; R* is hydrogen; Z is -NH-;

R® is halogeno or C, alkyl; and

X'is-O-; then

R‘ is not selected from one of the following three groups: a) -C, salkyIR™ (wherein R* is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C, jalkyl, C, hydroxyalkyl and C, ,alkoxy); b) -C, salkenyIR'® (wherein R" is as defined hereinbefore); c)-C,salkynylR" (wherein R"” is as defined hereinbefore); wherein any alkylene, alkenylene or alkynylene chain in group-a) to c) above are optionally substituted by one or more substituents selected from hydroxy, halogeno and amino,

AMENDED SHEET or a pharmaceutically-acceptable salt or prodrug thereof.

According to another aspect of the present invention there is provided a quinazoline : derivative of the formula I:

JER

2 _ 0

Ré—X1 7 '¢)) [wherein:

Z is -O-, -NH- or -S-; m is an integer from O to 5 inclusive;

R' is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C, alkyl,

C, alkoxy, C, ;alkylthio, or -NR’R® (wherein R®> and R®, which may be the same or different, are hydrogen or C, ;alkyl);

R? is hydrogen, hydroxy, halogeno, C, ,alkyl, C, ;alkoxy, trifluoromethyl, amino or nitro;

R’ is hydroxy, halogeno, C, alkyl, C, ;alkoxy, C, ;alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

X'is -O-, -CH,-, -S-, -SO-, -SO,~, -NR’-, -NR’CO-, -CONR’-, -SO,NR’- or -NR"SO,-, (wherein R’ is hydrogen, C, alkyl or C, salkoxyC, ;alkyl);

R’ is selected from one of the following groups: 1) -Y'X?COR’® [wherein -Y' - is a C, s alkylene chain wherein each methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno and amino, provided that there is at least 1 and no more than 3 substituents on the C, ;alkylene chain; X is -O- or -NR’- (in which R® is hydrogen, C, ;alkyl or C, ;alkoxyC, ;alkyl) and R® is C, alkyl, -NR'’R" or -OR'? (wherein R'®, R"! and : R', which may be the same or different, are hydrogen, C, ;alkyl or C, ;alkoxyC, ;alkyl)]; 2) -Y?- X’R"® [wherein -Y>- is C, ;alkylene, C, ;alkenylene or C, salkynylene wherein each ) 25 methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno and amino, provided that there is at least 1 substituent and no more than 3 substituents on the alkylene, alkenylene or alkynylene chain;

® PCT/GB01/01514 ~11-

X is -O-, -S-, -80-, -50,-, -OCO-, -NR'CO-, -CONR-, -SO,NR’-, -NR"SO,- or -NR- (wherein R’ is as hereinabove defined) and Ris hydrogen or C, jalkyl, wherein the C, salkyl : group may bear one or two substituents selected from oxo, hydroxy, halogeno and C,_,alkoxy; 3) YXC, ,alkylR [wherein Y' is as hereinabove defined and X° is -O-, -$-, -SO-, -SO, -

NR’CO-, -CONR’-, -SO.NR’-, -NR’SQ.- or -NR’- (wherein R’is as hereinabove defined ) and R" is C, , cycloalkyl or a 3 to 7 membered saturated or partially saturated heterocyclic group containing up to 3 ring heteroatoms selected independently from O, S and N, wherein the carbocyclic or heterocyclic group is optionally substituted by one or two substituents selected from oxo, hydroxy, halogeno, C, alkyl, (wherein the C,_jalkyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, cyano, halogeno, amino, nitro, oo morpholino, C, scycloalkyl, piperidin-1-yl and piperazin-1-yl), C, alkenyl, C, alkynyl, C,. «alkoxy, carbamoyl, C, ;alkylcarbamoyl, N,N-di(C, salkyl)carbamoyl, C, ,alkanoyl, C,. : - qalkoxycarbonyl, C, alkylthio, C, _alkylsulphinyl, C, _alkylsulphonyl, C,_;alkanoylamino, N-

C,.salkyl-C, ,alkanoylamino, N-C, ;alkylsulphamoyl, N,N-di-[C, salkylJsulphamoyl, C,. salkanesulphonylamino and N-C, alkyl- C,_;alkancsulphonylamino, or R* is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents selected from halogeno, amino, C, alkyl, C, alkoxy, C, jhydroxyalkyl, C, ;aminoalkyl, C,. ,alkylamino, C, jhydroxyalkoxy, carboxy, cyano, C,_ alkylthio, C, alkylsulphinyl, C. salkylsulphonyl, N-C, ;alkylsulphamoyl, N.N-di-[C,_;alkyl}sulphamoyl, C,. salkanesulphonylamino, N-C, ,alkyl-C, salkanesulphonylamino, -CONR'R and -NR'°COR™ (wherein R" and R" are as hereinabove defined)]; 4) -Y'-X'C,_salky[X’R" [wherein Y' is as hereinabove defined and X* and X* which may be the same or different are each -O-, -S-, -SO-, -SO,-, -NR’CO-, -CONR’-, -SO.NR-, -

NR'SO,- or -NR’- (wherein R’, is as hereinabove defined and R" is hydrogen or C, salkyl)]; 5) -Y'-O- C, alkyl (wherein Y' is as hereinabove defined) provided that X' is -O-, -S-, -SO- or -50,; 6) -Y*-R'® {wherein -Y?- is as hereinabove defined and R'® is a saturated or partially saturated 3 to 7 membered heterocyclic ring containing up to 3 heteroatoms selected from O, S and N [wherein the heterocyclic ring is optionally substituted by up to 3 substitutents selected from oxo, hydroxy, halogeno, C, alkyl, C, alkenyl, C, jalkynyl and C, cycloalkyl (wherein

C,.

AMENDED SHEET alkyl, C, alkenyl, C, alkynyl and C, ,cycloalkyl are themselves optionally substituted by up to 3 substitutents selected from hydroxy, halogeno, cyano, C, ;alkyl, C, alkoxy, C,. . salkanoyloxy, trifluoromethyl, amino, nitro and R' as hereinabove defined), C, ,alkoxy, carbamoyl, C, jalkylcarbamoyl, N-N- di(C, ,alkyl)carbamoyl, C, ,alkanoyl, C,. ) 5 alkoxycarbonyl, C, cycloalkyl, C, ,alkylthio, C, ,alkylsulphinyl, C,_,alkylsulphonyl, C,. «alkanoylamino, N-C, _;alkyl-C, ,alkanoylamino, N-C, ;alkylsulphamoyl, N,N-di-{C,. salkyl]sulphamoyl, C, ;alkanesulphonylamino and N-C, ;alkyi- C, jalkanesulphonylamino or R'® is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents selected from halogeno, amino, C, alkyl, C, alkoxy, C, hydroxyalkyl, C, ;aminoalkyl, C,. salkylamino, C, hydroxyalkoxy, carboxy, cyano, C, alkylthio, C, ,alkylsulphinyl, C,

Jalkylsulphonyl, N-C, ;alkylsulphamoyl, N,N-di-[C,_;alkyl}sulphamoyl, C,. salkanesulphonylamino, N-C, ;alkyl-C, ;alkanesulphonylamino, -CONR'’R"' and -NR'°COR" (wherein R' and R" are as hereinabove defined)]; 7 -Y2-X°-R'* (wherein Y?, X® and R'* are as hereinabove defined); and 8) -Y2NR'R'® [wherein Y? is as hereinabove defined and R' and R'® are independently selected from hydrogen, C, salkyl, C, alkenyl, C, salkynyl or C, ;alkoxyC, alkyl (wherein any alkyl group in R'7 or R" is optionally substituted by up to 2 substituents selected from hydroxy, halogeno, C, ;alkyl, C, ;alkoxy, C, ;alkanoyloxy, trifluoromethyl, cyano, amino or nitro)]; 9) -Y3-R® (wherein Y? is C, alkylene, C, salkenylene or C, salkynylene wherein each methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno and amino, provided that there are no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; and R* is C, ;cycloalkyl which is substituted by 1 substituent selected from hydroxy, amino and halogeno on the ring carbon linked to Y° and additionally optionally substituted by up to 3 substitutents selected from oxo, hydroxy, halogeno, C, alkyl, C, ,alkenyl, C, ,alkynyl, C, ,alkoxy, carbamoyl, C,_ ) .alkylcarbamoyl, N-N- di(C,_,alkyl)carbamoyl, C, ,alkanoyl, C, jalkoxycarbonyl and C,_ cycloalkyl (wherein C, alkyl, C, ,alkenyl, C, alkynyl and C; cycloalkyl are themselves optionally substituted by up to 3 substitutents selected from hydroxy, halogeno, cyano, C,_

® PCT/GB01/01514 salkyl, C, ;alkoxy, C, ;alkanoyloxy, trifluoromethyl, cyano, amino, nitro and R' as hereinabove defined)]; provided that when: m is.an integer from 1 to 3;

R'is methoxy; R® is hydrogen; Z is -NH-;

R? is halogeno or C, alkyl; and

X' is -O-; then

R‘ is not selected from one of the following three groups: a) -C. salkyIR" (wherein R' is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C, alkyl, C, hydroxyalkyl and C,_alkoxy); - b) -C, salkenylR" (wherein R'" is as defined hercinbefore); c) -C, salkynyIR' (wherein R'® is as defined hercinbefore); wherein any alkylene, alkenylene or alkynylene chain in groups a) to ¢) above are optionally substituted by one or more substituents selected from hydroxy, halogeno and amino; or a pharmaceutically-acceptable salt or prodrug thereof. : In this specification the generic term “alkyl” includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only. An analogous convention applies to other generic terms. ~~ Itis to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter. -

In foririuila I, as hereinbefore defined, hydrogen will be present at positions 2 and 8 of the quinazoline group. . :

Within the present invention it is to be understood that a quinazoline of the formula I or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae

AMENDED SHEET

: ® PCT/GB01/01514 drawings within this specification can represent only one of the possible tautomeric forms. It is 10 be understood that the invention encompasses any tautomeric form which inhibits VEGF : receptor tyrosine Kinase activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.

It 1s also to be understood that certain quinazolines of the formula 1 and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which inhibit VEGF receptor tyrosine kinase activity.

For the avoidance of any doubt, it is to be understood that when X' is, for example, a group of formula -NRCO-, it is the nitrogen atom bearing the R” group which is attached to the quinazoline ring and the carbonyl (CO) group is attached to R*, whereas when X! is, for example, a group of formula -CONR’-, it is the carbonyl group which is attached to the * Quinazoline ring and the nitrogen atom bearing the R” group is attached to R*. A similar convention applies to the other two atom X' linking groups. When X' is -NR’- it is the oo nitrogen atom bearing the R’ group which is linked to the quinazoline ring and to R*. An analogous convention applies to other groups. It is further to be understood that when X' is -

NR’- and R’ is C, jalkoxyC, jalkyl it is the C, ;alkyl moiety which is finked to the nitrogen atom of X' and an analogous convention applies to other groups. : :

The a-carbon in the alkylene, alkenylene or alkynylenc chains in Y* and Y* is the carbon atom in the chain which is linked to X'. The B-carbon is the carbon atom in the carbon chain linked to the a-carbon.

Preferred values for Y' include 2-acetoxypropylene, 2-hydroxyethylene, 2- hydroxypropylene, 3-hydroxypropylene, 2-hydroxybutylene, 3-hydroxybutylene and 4- hydroxybutylene.

Suitable values for Y' include 2-hydroxyethylene, 2-hydroxypropylen, 3- hydroxypropylene, 2-hydroxybutylene, 3-hydroxybutylene and 4-hydroxybutylene.

Suitable values for Y* include those mentioned above for Y' and 2-hydroxybut-3- enylene, 2-hydroxypent-3-enylene, 4-hydroxybut-2-enylene and 3-hydroxypent-4-enylene.

More preferred values of Y' are 2-hydroxypropylene and 2-acetoxypropylene.

More preferred values of Y? are 2-hydroxypropylene and 2-acetoxypropylene.

Examples of suitable 5 or 6 membered saturated or partially saturated heterocyclic groups for ring A include pyrrolidine, piperidine, piperazine, homopiperidine, pyrroline,

AMENDED SHEET morpholine, thiomorpholine, (tetrahydro-1,4-thiazine), thiazolidine, 1,2,6-tetrahydropyridine, tetrahydrofuran, tetrahydropyran, 1,1-dioxotetrahydro-1,4-thiazine, homopiperazine : dihydropyridine, tetrahyrdropyridine, dihydropyrimidine and tetrahydropyrimidine.

Examples of 5 or 6 membered aromatic heterocyclic groups for ring A include furan, pyrrole, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, indole,

Examples of suitable 3 to 7 membered saturated or partially saturated heterocyclic groups for R'* and R'® include pyrrolidine, piperidine, aziridine, azetidine, piperazine, homopiperidine, pyrroline, morpholine, thiomorpholine, (tetrahydro-1,4-thiazine), thiazolidine, 1,2,6-tetrahydropyridine, tetrahydrofuran, tetrahydropyran, 1,1-dioxotetrahydro- 1,4-thiazine, homopiperazine dihydropyridine, tetrahyrdropyridine, dihydropyrimidine and tetrahydropyrimidine.

Examples of suitable C, ;cycloalkyl groups in R', R'® and R® include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Particularly cyclopropyl, cyclopentyl and cyclohexyl.

Examples of 5 or 6 membered aromatic heterocyclic groups for R'* and R'® include furan, pyrrole, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5- triazine, indole.

Preferred 5 or 6-membered aromatic heterocyclic groups for R'* and R'® include pyridine, imidazole, thiophene, triazole, and pyridazine. Most preferably pyridine, imidazole or triazole.

Suitable values for any of the ‘R’ groups (R' to R'®), or for various substituent groups on an alkyl chain or ring system in R* include:- . for halogeno fluoro, chloro, bromo and iodo; for C,_calkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; : for C, ;alkenyl: vinyl, allyl and but-2-enyl; for C, alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for C,_qalkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;

® PCT/GB01/01514

C ~16- for C, calkenyloxy: vinyloxy and allyloxy; for C, ;alkynyloxy: ethynyloxy and 2-propynyloxy; for GC alkylthio: methylthio, ethylthio and propytthio; for C,_jalkylsulphinyl: methylsulphinyl and ethylsulphinyl; for C _,alkylsulphonyl: methylsulphonyl and ethylsulphonyl, for C, jalkylamino: methylamino, cthylamino, propylamino, or isopropylamino and butylamino; :

Yor di-[C, jalkylJamino: dimethylamino, diethylamino, N-ethyl-

N-methylamino and diisopropylamino: for C, alkoxycarbonyl: : methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl, for N-C, salkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and

N-propylcarbamoyl; for N,.N-di-[C, ,alkyl]carbamoy!: N,N-dimethylcarbamoyl, N-ethyl-

N-methylcarbamoy! and N,N-diethylcarbamoyl; for C, ;alkanoyl: acetyl and propionyl; for C, jalkanoyloxy: acetoxy and propionyloxy; . for C_ ,alkanoylamino: acetamido and propionamido; : for N-C, ;alkyl-C, ,alkanoylamino: N-methylacctamido and N-methylpropionamido; for N-C,alkylsulphamoyl: =. N-methylsulphamoyl and N-ethylsulphamoyl; for N,N-di-[C, ;alkyl]sulphamoy!: N,N-dimethylsulphamoyl,; for C, ;alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino; for N- C, ;alkyl- C, ;alkanesulphonylamino: N-methylmethanesulphonylamino and

N-methylethanesulphonylamino.

Preferrred substituents for saturated or partially saturated heterocyclic groups in R™ and R' include oxo, hydroxy, halogeno, C,_salkyl, (wherein the C, alkyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, cyano, halogeno, amino, nitro, morpholino, C, cycloalkyl, piperidin-1-y! and piperazin-1-y1), C, ,alkenyl, C, alkynyl, Cc. salkoxy, carbamoyl, C, ;alkylcarbamoyl, N,N-di(C, ;alkyl)carbamoyl, C, ,alkanoyl and C,. ,alkoxycarbonyl. =

In another aspect of the present invention preferred substituents for saturated or partially saturated heterocyclic groups in R!4 and R1® include oxo, hydroxy, halogeno,

Ci.

AMENDED SHEET

® PCT/GB01/01514 alkyl, (wherein the C, alkyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, cyano, halogeno, amino, morpholino, C; scycloalkyl, piperidin-1-yl and piperazin-1-yl), C, jalkenyl, C, salkynyl, C, ,alkoxy, carbamoyl, C, ;alkylcarbamoyl, N.N- di(C,_;alkyl)carbamoyl, C, alkanoy! and C, jalkoxycarbonyl.

More preferrred substituents for saturated or partially saturated heterocyclic groups in

R" and R'® include oxo, hydroxy, halogeno, C, alky] (optionally substituted by hydroxy, cyano, morpholino, cyclopentyl, piperidin-1-yl or piperazin-1-yl), allyl, C,_jalkoxy, C,. salkanoyl or C, alkoxycarbonyl. | :

More preferred substituents for saturated or partially saturated heterocyclic groups in in R™ and R* include oxo; hydroxy, fluoro, chloro, bromo, methyl, ethyl, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, 2-morpholinoethyl, cyclopropyl, allyl, methoxy, acetyl and methoxycarbonyl.

Preferred substituents for ring carbon atoms in saturated or partially saturated heterocyclic groups in R' and R'® include hydroxy, bromo and methyl. Most preferably ring carbon atoms in saturated or partially saturated heterocyclic groups in R'* and R'® are unsubstituted.

Preferred substituents for ring NH groups in saturated or partially saturated heterocyclic groups in R' and R'® include C, , alkyl (optionally substituted as hereinabove defined), C, ; alkyl, C, ,alkanoyl or C, alkoxycarbonyl. More preferably, C, alkyl (optionally substituted by hydroxy, fluoro, chloro, bromo, cyclopentyl, morpholino, piperazin-l-yl or piperidin-[-yl), acetyl, allyl or methoxycarbonyl.

Preferably the aromatic group in R' and R'® is substituted by up io 3 substituents.

More preferably up to 2 substituents.

Preferred substituents for aromatic groups in R" and R'® include halogeno, C,_, alkyl, amino, C,, alkoxy, hydroxyC, jalkyl or C,_jhyrdoxyalkoxy. More preferred substituents include fluoro, chloro, bromo, methyl, ethyl, methoxy, hydroxymethyl and 2-hydroxyethyl.

Preferably ring A is phenyl or a 5-6-membered heteroaromatic moicty which contains 1-3 heteroatoms selected independently from O, N and S. oo

More preferably ring A is phenyl or a 6-membered heteroaromatic moiety which contains 1-3 heteroatoms selected independently from O, N and S.

Yet more preferably ring A is phenyl or a 6-membered heteroaromatic moiety which contains 1 or 2 ring N heteroatoms.

AMENDED SHEET

Yet more preferably ring A is phenyl or pyridyl.

Most preferably ring A is phenyl. . In another aspect ring A is pyridyl.

Preferably m is an integer from 1 to 5 inclusive. More preferably m is 2 or 3. Most } 5 preferably m is 2.

Preferably R' is hydrogen, hydroxy, cyano, nitro, trifluoromethyl, C,_alkyl, C,. ;alkoxy or amino.

More preferably, R' is hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy. Even more preferably R' is hydrogen, methyl or methoxy. Most preferably R' is hydrogen or methoxy, but especially methoxy.

Preferably, R? is hydrogen, fluoro, amino or nitro. Most preferably R? is hydrogen.

Preferably R® is hydroxy, halogeno, C, ,alkyl, C, ,alkoxy, trifluoromethyl, cyano, amino or nitro.

More preferably, R® is fluoro, chloro, bromo, methyl or methoxy. . 15 Particular values for ring A bearing (R>),, are 2-fluoro-4-chloro-5-hydroxyphenyl, 2- fluoro-4-bromo-5-hydroxyphenyl, 2-fluoro-4-chlorophenyl or 2-fluoro-4-bromophenyl.

Preferably, when ring A is phenyl, m is 2 and the phenyl ring is substituted in the 2- and 4-positions.

Preferably, when ring A is phenyl, m is 2 and the phenyl! ring is substituted in the 2- and 4-positions by substituents independently selected from fluoro, chloro and bromo.

More preferably, ring A bearing (R%),, is 2-fluoro-4-chloropheny! or 2-fluoro-4- bromophenyl. In another aspect ring A bearing (R%),, is 2-chloro-3-methoxyphenyl, 2-bromo- 3-chlorophenyl, 2,3-dibromophenyl, 2,3-dichlorophenyl! 2,4-dichlorophenyl, 2-bromo-4- chlorophenyl, 2-chloro-3-methylphenyl, 2-bromo-4-methylphenyl, 2-chloro-3- methoxyphenyl or 3-chloro-4-fluorophenyl.

Preferably X' is -O-, -S-, -NR’CO-, -NR'SO,- or -NR’- (wherein R” is hydrogen, . C,.;alkyl or C, ,alkoxyethyl).

Preferably X' is -O-, -S-, -NR'CO- or -NR'SO,- (wherein R’ is hydrogen, methyl or ethyl). ; More preferably X' is -O-, -S-, -NR’CO- (wherein R’ is hydrogen or methyl).

Yet more preferably X' is ~O-, or -NHCO-, or -S-. Yet more preferably X' is -O-, or -S-.

Most preferably X' is -O-.

Claims (1)

1. A compound of the formula (I): 3 Rl Z °N x RX? N ® [wherein: ring A is phenyl or a 5-or 6-membered heterocyclic ring which may be saturated, partially saturated or unsaturated and may be aromatic or non-aromatic and which contains 1, 2 or 3 ring heteroatoms selected from O, Nand S; Z is -O-, -NH- or -S-; m is an integer from O to 5 inclusive; R' is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C, alkyl, C, ;alkoxy, C, alkylthio, or -NR’R® (wherein R® and R®, which may be the same or different, are hydrogen or C, alkyl); R? is hydrogen, hydroxy, halogeno, C, ;alkyl, C, ;alkoxy, trifluoromethyl, amino or nitro; R? is hydroxy, halogeno, C, alkyl, C, jalkoxy, C, salkanoyloxy, trifluoromethyl, cyano, amino or nitro; provided that when ring A. is a 5- or 6-membered heterocyclic ring, at least one R? is either hydroxy or halogeno; X!'is-O-, -CH,-, -S-, -80-, -SO,-, -NR’-, -NR’CO-, -CONR’-, -SO,NR’- or -NR’SO,-, (wherein R’ is hydrogen, C, alkyl or C, alkoxyC, .alkyl); R* is selected from one of the following groups: ’ 1) -Y'X?COR’ [wherein -Y' - is a C, salkylene chain wherein each methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C, ,alkanoyloxy, provided that there is at least 1 and no more than 3 substituents on the C, ;alkylene chain; X* is -O- or -NR’- (in which R® is hydrogen, C, ;alkyl or C, salkoxyC, alkyl) and R® is C, salkyl, -NR'R"" or -OR'? (wherein

RR" and R"%, which may be the same or different, are hydrogen, C, alkyl or C, salkoxyC, salkyD]; } 2) -Y?- X°R" [wherein -Y?- is C, salkylene, C, salkenylene or C, alkynylene wherein each ] methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent S independently selected from hydroxy, halogeno, amino and C,_jalkanoyloxy, provided that there is at least 1 substituent and no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; X is -O-, -S-, -SO-, -SO,-, -OCO-, -NR’CO-, -CONR’-, -SO,NR’-, - NR’SO,- or -NR’- (wherein R’ is as herein defined) and R is hydrogen or C, alkyl, wherein the C, ;alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C,_alkoxy; 3) -Y'-X°C, salkyIR" [wherein Y' is as herein defined and X° is -O-, -S~, -SO-, -SO,-, - NR’CO-, -CONR’-, -SO,NR’-, -NR"SO,- or -NR’- (wherein R'is as herein defined ) and R* is C, cycloalkyl or a 3 to 7 membered saturated or partially saturated heterocyclic group containing up to 3 ring heteroatoms selected independently from O, S and N, wherein the carbocyclic or heterocyclic group is optionally substituted by one or two substituents selected from oxo, hydroxy, halogeno, C, alkyl, (wherein the C, jalkyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, cyano, halogeno, amino, nitro, morpholino, C,_ scycloalkyl, piperidin-1-yl and piperazin-1-yl), C, alkenyl, C, ,alkynyl, C, ;shydroxyalkyl, C,. salkoxy, carbamoyl, C, ;alkylcarbamoyl, N.N-di(C, ;alkyl)carbamoyl, C, ,alkanoyl, C,. ,alkoxycarbonyl, C, salkylthio, C, ,alkylsulphinyl, C, ,alkylsulphonyl, C, ,alkanoylamino, N- C,salkyl-C, ,alkanoylamino, N-C, salkylsulphamoyl, N,N-di-{C, ;alkyljsulphamoyl, C, ;alkanesulphonylamino and N-C, ;alkyl- C, ;alkanesulphonylamino, or R" is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents : selected from halogeno, amino, C, ,alkyl, C, alkoxy, C, hydroxyalkyl, C, ,aminoalkyl, C,. salkylamino, C, jhydroxyalkoxy, carboxy, cyano, C, alkylthio, C, ,alkylsulphinyl, C,. salkylsulphonyl, N-C, jalkylsulphamoyl, N.N-di-[C, ,alkyl]sulphamoyl, C,. salkanesulphonylamino, N-C, ;alkyl-C, jalkanesulphonylamino, -CONR'R" and -NR'°COR!! (wherein R'° and R" are as herein defined)];

4) -Y'-X*C, salkyIX°R* [wherein Y' is as herein defined and X* and X® which may be the same or different are each -O-, -S-, -SO-, -80,-, -NR’CO-, -CONR’-, -SO,NR’-, -NR’SO,- or -NR’- (wherein R’, is as herein defined and R" is hydrogen or C, alkyl); 5) -Y'-O-C, ;alkyl (wherein Y' is as herein defined) provided that X' is -O-, -S-, -SO- or - SO,; 6) -Y?-R'® {wherein -Y?- is as herein defined and R® is a saturated or partially saturated 3 to 7 membered heterocyclic ring containing up to 3 heteroatoms selected from O, § and N [wherein the heterocyclic ring is optionally substituted by up to 3 substitutents selected from oxo, hydroxy, halogeno, C,_jalkyl, C, ,alkenyl, C, ,alkyny! and C, cycloalkyl (wherein C,. alkyl, C, alkenyl, C, ,alkyny! and C, cycloalkyl are themselves optionally substituted by up to 3 substitutents selected from hydroxy, halogeno, cyano, C, alkyl, C, alkoxy, C,. salkanoyloxy, trifluoromethyl, amino, nitro and R" as herein defined), C, alkoxy, carbamoyl, C,_salkylcarbamoyl, N-N- di(C,_,alkyl)carbamoyl, C, ,alkanoyl, C, alkoxycarbonyl, C;. cycloalkyl, C, alkylthio, C, jalkylsulphinyl, C, ,alkylsulphonyl, C, ,alkanoylamino, N-C,. ,alkyl-C, jalkanoylamino, N-C, ;alkylsulphamoyl, N,N-di-[C, ;alkyl]sulphamoyl, C,. salkanesulphonylamino and N-C, jalkyl- C, ;alkanesulphonylamino or R' is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents selected from halogeno, amino, C, alkyl, C, alkoxy, C hydroxyalkyl, C,..aminoalkyl, C, salkylamino, C,_hydroxyalkoxy, carboxy, cyano, C, alkylthio, C, ,alkylsulphinyl, C,. salkylsulphonyl, N-C, jalkylsulphamoyl, N,N-di-[C, ;alkyljsulphamoyl, C,_ : salkanesulphonylamino, N-C, ;alkyl-C, ;alkanesulphonylamino, -CONR!’R" and -NR!°COR" (wherein R'® and R"! are as herein defined)]; 7) -Y2-X6-R" (wherein Y?, X°® and R" are as herein defined); and 8) -Y>-NR'R' [wherein Y? is as herein defined and R'” and R'® are independently

. selected from hydrogen, C, alkyl, C, calkenyl, C, alkynyl or C, ;alkoxyC, calkyl (wherein any alkyl group in R"” or R'® is optionally substituted by up to 2 substituents selected from hydroxy, halogeno, C, alkyl, C, jalkoxy, C, ;alkanoyloxy, trifluoromethyl, cyano, amino or nitro)];

9) -Y>-R* (wherein Y? is C, salkylene, C, ;alkenylene or C, ;alkynylene wherein each methylene group (other than that of the a-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C, ,alkanoyloxy, provided that there are no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; and R® is C, cycloalkyl which is substituted by 1 substituent selected from hydroxy, amino and halogeno on the ring carbon linked to Y* and additionally optionally substituted by up to 3 substitutents selected from oxo, hydroxy, halogeno, C, alkyl, C, ,alkenyl, C, alkynyl, C,. «alkoxy, carbamoyl, C, ,alkylcarbamoyl, N-N- di(C, ,alkyl)carbamoyl, C, ,alkanoyl, C,. slkoxycarbonyl and C, ;cycloalkyl (wherein C, alkyl, C, alkenyl, C, alkynyl and C, cycloalkyl are themselves optionally substituted by up to 3 substitutents selected from hydroxy, halogeno, cyano, C, ;alkyl, C, ;alkoxy, C, ;alkanoyloxy, trifluoromethyl, cyano, amino, nitro and R'*as herein defined); provided that when: m is an integer from 1 to 3; R!is methoxy; R? is hydrogen; Z is -NH-; R® is halogeno or C, alkyl; and X' is -O-; then R* is not selected from one of the following three groups: a) -C, salkyIR" (wherein R" is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C, alkyl, C, ,hydroxyalkyl and C, alkoxy); b) -C,salkenyIR"® (wherein RY is_as defined herein); c) -C, salkynyIR'® (wherein R* is as defined herein); wherein any alkylene, alkenylene or alkynylene chain in groups a) to c) above are optionally substituted by one or more substituents selected from hydroxy, halogeno and amino; or a salt thereof.

: 2. A compound according to claim 1 wherein R? is hydrogen.

3. A compound according to claim 1 or claim 2 wherein R' is hydrogen or methoxy.

4. A compound according to any one of the preceding claims wherein ring A is phenyl or pyridyl.

5. A compound according to any one of the preceding claims wherein R? is hydroxy, halogeno, C, ,alkyl, C, alkoxy, trifluoromethyl, cyano, amino or nitro.

6. A compound according to any one of the preceding claims wherein m is 2 or 3.

7. A compound according to any one of the preceding claims wherein ring A bearing bearing (R?),, is 2-fluoro-4-chloro-5-hydroxyphenyl, 2-fluoro-4-bromo-5-hydroxyphenyl, 2- fluoro-4-chlorophenyl or 2-fluoro-4-bromophenyl.

8. A compound according to any one of the preceding claims wherein X' is -O-, -S-, - NR’CO- or -NR’SO,- (wherein R” is hydrogen, methyl or ethyl).

9. A compound according to any one of the preceding claims wherein R* is of the formula -Y>-R'¢, -Y>-NR'R® or -Y>-R®, wherein Y?, Y>, R?, R!®, Rand R® are as defined in claim 1.

10. A compound according to any one of the preceding claims wherein the alkylene, alkenylene or alkynylene chain in Y' or Y?in R* is substitued by hydroxy or acetoxy, wherein Y?, Y? and R* are as defined in claim 1.

11. A compound selected from 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy}-6- methoxy)quinazoline : 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy]-6- methoxy)quinazoline 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy}-6- methoxy)quinazoline

4-(4-chloro-2-fluorophenylamino)-7~(2-hydroxy-3-(morpholino)propoxy)-6-

methoxy)quinazoline 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(thiazolidin-3-yl)propoxy]-6- methoxy)quinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(3-pyrrolin-1-yl)propoxy]-6-

methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-(2-morpholinoethyl)piperazin-1-

yl)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-(3-hydroxypropyl)piperazin-1-

yl)propoxyl-6-methoxyquinazoline 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-(2-hydroxyethyl)piperazin-1- yl)propoxy]-6-methoxyquinazoline 4-(4-bromo-2-fluorophenylamino)-7-{2-hydroxy-3-(1,2,3,6-tetrahydropyridin-1-yl)propoxy]- 6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(N-tertbutyl-N-methylamino)propoxy]-6-

methoxyquinazoline 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(N-isopropyl-N-methylamino)propoxy1-6-

methoxyquinazoline hydrochloride 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(N-isobutyl-N-methylamino)propoxy]-6-

methoxyquinazoline 4-(4-bromo-2-fluorophenylamino)-7-[ 2-hydroxy-3-(N-(2-hydroxyethyl)~N- methylamino)propoxy}-6-methoxyquinazoline 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(morpholino)propoxy]-6- methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-(2-hydroxy-3-(N,N-dimethylamino)propoxy]-6- methoxyquinazoline

: 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(piperidin-1-yl)propoxy}-6- methoxyquinazoline 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy}-6-

methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N,N-dimethylamino)propoxy ]-6- methoxyquinazoline 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(piperidin-1-yl)propoxy]-6-

] methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(homopiperidin-1-yl)propoxy]-6-

methoxyquinazoline 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N-(2-hydroxyethyl)-N- methylamino)propoxy]-6-methoxyquinazoline 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(3-pyrrolin-1-yl)propoxy}-6-

methoxyquinazoline 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(thiomorpholin-4-yl)propoxy]-6- methoxyquinazoline 4-(4~chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(3-hydroxypyrrolidin-1-yl)propoxy]-6-

methoxyquinazoline . 4-(4-chloro-2-fluorophenylamino)-7-{2-hydroxy-3-[4-(2-morpholinoethyl)piperazin-1- yllpropoxy }-6-methoxyquinazoline 4-(4-chloro-2-fluorophenylamino)-7-{ 2-hydroxy-3-[4-(2-hydroxyethyl)]piperazin-1- yl)propoxy }-6-methoxyquinazoline 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(2,5-dimethyl-3-pyrrolin-1-yl)propoxy]-6-

methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(4-methylpiperidin-1-yl)propoxy]-6- methoxyquinazoline 4-(4-chloro-2-fluorophenylamino)-7-{2-hydroxy-3-(2-methylpyrrolidin-1-yl)propoxy}-6- methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N-(2-cyanoethyl)-N-

methylamino)propoxy}-6-methoxyquinazoline : 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N-isopropyl-N-methylamino)propoxy]-6- methoxyquinazoline 4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N-isobutyl-N-methylamino)propoxy]-6- methoxyquinazoline

4-chloro-2-fluoro-5-hydroxyphenylamino-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy]-6- methoxyquinazoline 4-chloro-2-fluoro-5-hydroxyphenylamino-7-(2-acetoxy-3-piperidinopropoxy)-6- methoxyquinazoline 4-bromo-2-fluoro-5-hydroxyphenylamino-7-[2-acetoxy-3-(pyrrolidin-1-yl)propoxy]-6- methoxyquinazoline 4-bromo-2-fluoro-5-hydroxyphenylamino-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy]-6- methoxyquinazoline; or a salt thereof.

12. A compound according to any one of the preceding claims in the form of a pharmaceutically acceptable salt.

13. A process for the preparation of a compound of the formula (I) as defined in claim 1 or a salt thereof which comprises: (a) the reaction of a compound of the formula III: 2 R 1 ~~ N Rx! SN uy (wherein R', R?, X' and R* are as defined in claim 1 and L' is a displaceable moiety), with a compound of the formula IV: (®3), ZH av)

(wherein ring A, Z, R® and m are as defined in claim 1); ) (b) where the group of formula Ila: os

(a)

(wherein ring A, R® and m are as defined in claim 1) is a ring carrying one or more hydroxy groups, the deprotection of a compound of formula V:

(a R2 Z Rl (OP),1 ZZ 'N RX SN J Vv)

(wherein ring A, X', m, R', R?, R’, R* and Z are as defined in claim 1, P is a hydroxy protecting group and p' is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that m-p' is equal to the number of R? substituents which are not protected hydroxy);

(c) compounds of formula (I) and salts thereof wherein the substituent X' is -O-, -S- or

-NR’- (wherein R’ is as defined in claim 1) can be prepared by the reaction of a compound of the formula VI:

(Dr rR? . Z R! }o 9, . ' x J HX N (VD) (wherein ring A, m, X', R', R>, R?, and Z are as defined in claim 1) with a compound of formula VII: RL! (viD) (wherein R® is as defined in claim 1 and L' is as defined herein); (d) the reaction of a compound of the formula VIII: Tas R2 Z rR! Lr ) Lt N J (VID with a compound of the formula IX: R-X!\-H Ix) ’ (wherein ring A, R", R?, R>, R*, Z, m and X' are all as defined in claim 1 and L' is as defined herein); e) compounds of the formula (I) and salts thereof wherein R* is a 2-hydroxypropyl! chain substituted by -NR''R'® (wherein R' and R'® are as defined in claim 1) or a saturated or partially saturated heterocyclic ring containing and linked through a ring nitrogen atom and containing up to 2 additional ring heteroatoms selected from O, S and N, can be prepared by reacting a compound of the formula X: , Lay 2 R Z R! rt ) J — x1 N 0 ® (wherein ring A, R', R% R® Z, m and X' are all as defined in claim 1) with the appropriate amine and analagous reactions may be used to produce compounds of the formula (1) wherein R* comprises longer hydroxy-substituted alkylene, alkenylene or alkynylene chains; f) compounds of the formula (I) and salts thereof wherein the group in R* linked to -Y'- or -Y* is linked via a N, O or S atom may be prepared by reacting a compound of the formula (XI): 2 R Zz Rr ZN J L -Q —X1 N (XD) (wherein ring A, X', R', R%, R?, Z and m are as defined in claim 1, L' is as defined herein and Qis-Y'- or -Y*- (wherein -Y’- or -Y>- are as defined in claim 1) with the appropriate compound containing a HN, HO or HS group; and when a pharmaceutically acceptable salt of a compound of the formula I is required,

. reaction of the compound obtained with an acid or base whereby to obtain the desired pharmaceutically acceptable salt.

PCT/GB01/01514

14. A pharmaceutical composition which comprises a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.

15. Use of a compound of the formula (I) as defined in claim 1, 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.

16. A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal which comprises administering to said animal an effective amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt.

17. A substance or composition for use in a method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal, said substance or composition comprising a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt, and said method comprising administering said substance or composition to said animal.

18. A compound according to claim 1, or claim 11, substantially as herein described and illustrated.

19. A process according to claim 13, substantially as herein described and illustrated.

20. A composition according to claim 14, substantially as herein described and illustrated.

21. Use according to claim 15, substantially as herein described and illustrated.

22. A method according to claim 16, substantially as herein described and illustrated. AMENDED SHEET

PCT/GB01/01514

23. A substance or composition for use in a method of treatment according to claim 17, substantially as herein described and illustrated.

24. A new compound, a new process for the preparation of a compound, a new composition, a new use of a compound of formula (I) as defined in claim 1, a new non- therapeutic method of treatment, or a substance of composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET